Williams Obstetrics [25 ed.] 9781259644320

Table of contents :
Title......Page 3
Copyright......Page 4
Contents......Page 9
Preface......Page 13
Acknowledgments......Page 15
Section 1: Overview......Page 17
Chapter 1: Overview of Obstetrics......Page 18
Section 2: Maternal Anatomy and Physiology......Page 29
Chapter 2: Maternal Anatomy......Page 30
Chapter 3: Congenital Genitourinary Abnormalities......Page 49
Chapter 4: Maternal Physiology......Page 65
Section 3: Placentation, Embryogenesis, and Fetal Development......Page 95
Chapter 5: Implantation and Placental Development......Page 96
Chapter 6: Placental Abnormalities......Page 127
Chapter 7: Embryogenesis and Fetal Development......Page 140
Section 4: Preconceptional and Prenatal Care......Page 161
Chapter 8: Preconceptional Care......Page 162
Chapter 9: Prenatal care......Page 173
Section 5: The Fetal Patient......Page 197
Chapter 10: Fetal Imaging......Page 198
Chapter 11: Amnionic Fluid......Page 241
Chapter 12: Teratology, Teratogens, and Fetotoxic Agents......Page 250
Chapter 13: Genetics......Page 269
Chapter 14: Prenatal Diagnosis......Page 293
Chapter 15: Fetal Disorders......Page 316
Chapter 16: Fetal Therapy......Page 331
Chapter 17: Fetal Assessment......Page 347
Section 6: Early Pregnancy Complications......Page 361
Chapter 18: Abortion......Page 362
Chapter 19: Ectopic Pregnancy......Page 387
Chapter 20: Gestational Trophoblastic Disease......Page 404
Section 7: Labor......Page 415
Chapter 21: Physiology of Labor......Page 416
Chapter 22: Normal Labor......Page 437
Chapter 23: Abnormal Labor......Page 457
Chapter 24: Intrapartum Assessment......Page 473
Chapter 25: Obstetrical Analgesia and Anesthesia......Page 501
Chapter 26: Induction and Augmentation of Labor......Page 519
Section 8: Delivery......Page 531
Chapter 27: Vaginal Delivery......Page 532
Chapter 28: Breech Delivery......Page 555
Chapter 29: Operative Vaginal Delivery......Page 569
Chapter 30: Cesarean Delivery and Peripartum Hysterectomy......Page 583
Chapter 31: Prior Cesarean Delivery......Page 607
Section 9: The Newborn......Page 620
Chapter 32: The Newborn......Page 621
Chapter 33: Diseases and Injuries of the Term Newborn......Page 634
Chapter 34: The Preterm Newborn......Page 651
Chapter 35: Stillbirth......Page 659
Section 10: The Puerperium......Page 666
Chapter 36: The Puerperium......Page 667
Chapter 37: Puerperal Complications......Page 681
Chapter 38: Contraception......Page 695
Chapter 39: Sterilization......Page 717
Section 11: Obstetrical Complications......Page 724
Chapter 40: Hypertensive Disorders......Page 725
Chapter 41: Obstetrical Hemorrhage......Page 770
Chapter 42: Preterm Birth......Page 818
Chapter 43: Postterm Pregnancy......Page 850
Chapter 44: Fetal-Growth Disorders......Page 859
Chapter 45: Multifetal Pregnancy......Page 878
Section 12: Medical and Surgical Complications......Page 914
Chapter 46: General Considerations and Maternal Evaluation......Page 915
Chapter 47: Critical Care and Trauma......Page 930
Chapter 48: Obesity......Page 951
Chapter 49: Cardiovascular Disorders......Page 963
Chapter 50: Chronic Hypertension......Page 990
Chapter 51: Pulmonary Disorders......Page 1002
Chapter 52: Thromboembolic Disorders......Page 1019
Chapter 53: Renal and Urinary Tract Disorders......Page 1040
Chapter 54: Gastrointestinal Disorders......Page 1057
Chapter 55: Hepatic, Biliary, and Pancreatic Disorders......Page 1073
Chapter 56: Hematological Disorders......Page 1090
Chapter 57: Diabetes Mellitus......Page 1112
Chapter 58: Endocrine Disorders......Page 1133
Chapter 59: Connective Tissue Disorders......Page 1153
Chapter 60: Neurological Disorders......Page 1171
Chapter 61: Psychiatric Disorders......Page 1188
Chapter 62: Dermatological Disorders......Page 1199
Chapter 63: Neoplastic Disorders......Page 1205
Chapter 64: Infectious Diseases......Page 1224
Chapter 65: Sexually Transmitted Infections......Page 1250
Serum and Blood Constltuents......Page 1270
Maternal Echocardiographic Measurements......Page 1276
Fetal Sonographic Measurements......Page 1277
A......Page 1288
B......Page 1293
C......Page 1295
D......Page 1300
E......Page 1303
F......Page 1305
G......Page 1308
H......Page 1309
I......Page 1314
J......Page 1315
L......Page 1316
M......Page 1318
N......Page 1322
O......Page 1323
P......Page 1324
R......Page 1331
S......Page 1333
T......Page 1336
U......Page 1340
V......Page 1341
W......Page 1342
Z......Page 1343

Citation preview

NOTICE Medicine is an ever-changing science. As new research and clinical experience broaden our knowl­ edge, changes in treatment and drug therapy are required. The aurhors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to conirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recom­ mended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs.

illiams

OBSTETRICS 25TH EDITION F. Gary Cunningham

Kenneth J. Leveno Steven L. Bloom Jodi S. Dashe Barbara L. Hofman Brian M. Casey Catherine Y. Spong

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Williams Obstetrics, Twenty-Fih Edition Copyright © 2018 by McGraw-Hill Education. All rights reserved. Printed in the United States of America. Except as permitted under the United States copyright Act of 1976,no part of this publication may be reproduced or distributed in any form or by any means, or stored in a data base or retrieval system, without the prior written permission of the publisher. Copyright © 2014 by McGraw-Hill Education. Copyright © 2010, 2005,2001 by the McGraw-Hill Companies, Inc. Copyright © 1997, 1993, 1989 by Appleton & Lange Copyright © 1985 by Appleton-Century-Crofts Copyright © 1971 by Meredith Corporation Copyright © 1961,1956, 1950 by Appleton-Century-Crofts, Inc. Copyright © 1946,1941,1936 by D. Appleton-Centuy-Co.,Inc. Copyright © 1930,1923,1917,1912,1909.1907,1904,1903.1902 by D. Appleton and Company Copyright © 1964 by Florence C. Stander Copyright © 1951 by Anne W. Niles Copyright © 1935. 1940 by Caroline W. Williams Copyright © 1930. 1931. 1932 by]. Whitridge Williams 1 2 3 4 5 678 9LWI 23 22 21 20 19 18 ISBN 978-1-259-64432-0 MHID 1-259-64432-4 his book was set in Adobe Garamond by Aptara. Inc. he editors were Andrew Moyer and Regina Y. Brown. The production supervisor was Richard Ruzycka. Production management was provided by Indu Jawwad. Aptara. Inc. The illustration manager was Armen Ovsepyan. The designer was Alan Barnett. he cover designer was Randomatrix. his book was printed on acid-free paper. Libray of Congress Cataloging-in-Publication Data Names: Cunningham,F. Gary,editor. Title: Williams obstetrics I editors, F. Gary Cunningham, Kenneth J.Leveno. Steven L. Bloom, Jodi S. Dashe,Barbara L. Hofman, Brian M. Casey. Catherine Y. Spong. Other titles: Obstetrics Description: 25th edition. I New York : McGraw-Hill, [20181

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bibliographical references and index. Identifiers: LCCN 2018002488

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EDITORS F. Gary C u n n i n g ham, MD

Beatrice & Miguel Elias Distinguished Chair i n Obstetrics and Gynecology

Barbara L. Hoffma n, MD Professor, Department o f Obstetrics and Gynecology University of Texas Southwestern Medical Center

Professor, Department of Obstetrics and Gynecology

Parkland Health and Hospital System

University of Texas Southwestern Medical Center

Dallas, Texas

Parkland Health and Hospital System Dallas, Texas

Brian M. Casey, MD Professor, Department of Obstetrics and Gynecology

Ken neth J. Leveno, MD

Director, Division of Maternal-Fetal Medicine

Professor, Department o f Obstetrics and Gynecology

University of Texas Southwestern Medical Center

University of Texas Southwestern Medical Center

Chief of Obstetrics

Parkland Health and Hospital System

Parkland Health and Hospital System

Dallas, Texas

Dallas, Texas

Steven L. Bloom, MD

Catherine Y. Spong, M D

Jack A . Pritchard M D Chair i n Obstetrics and Gynecology

Bethesda, Maryland

Professor and Chair, Department of Obstetrics and Gynecology University of Texas Southwesten Medical Center Chief of Obstetrics and Gynecology Parkland Health and Hospital System Dallas, Texas

Jodi S. Das he, MD Professor, Department o f Obstetrics and Gynecology University of Texas Southwestern Medical Center Director of Prenatal Diagnosis Parkland Health and Hospital System Dallas, Texas

v

ASSOCIATE E DITORS Mala S. Mahendroo, PhD

J. Seth Hawki ns, MD, MBA

Associate Professor, Department o f Obstetrics and Gynecology and

Assistant Professor, Department of Obstetrics and Gynecology

Green Center for Reproductive Biological Sciences

University of Texas Southwestern Medical Center

University of Texas Southwestern Medical Center

Parkland Health and Hospital System

Dallas, Texas

Dallas, Texas

Diane M. Twickler, M D, FACR Dr. Fred Bonte Professorship in Radiology Professor, Department of Radiology and Obstetrics and Gynecology Vice Chairman for Academic Affairs, Department of Radiology University of Texas Southwestern Medical Center Medical Director of Obstetrics and Gynecology Ultrasonography Parkland Health and Hospital System Dallas, Texas

CONTRIBUTING E DITORS Apri l A. Ba i l ey, M D

Weike Tao, MD

Assistant Professor, Department of Radiology and Obstetrics and

Associate Professor, Department o f Anesthesiology and Pain

Gynecology University of Texas Southwestern Medical Center Parkland Health and Hospital System

Parkland Health and Hospital System

Dallas, Texas

Dallas, Texas

Donald D. Mcinti re, PhD

C. Edward Wel ls, MD

Biostatistician

Professor, Department of Obstetrics and Gynecology

Professor, Department of Obstetrics and Gynecology

University of Texas Southwestern Medical Center

University of Texas Southwestern Medical Center

Parkland Health and Hospital System

Dallas, Texas

Dallas, Texas

David B. Nelson, MD

Myra H. Wyckoff, MD

Dedman Family Scholar i n Clinical Care

Professor, Department of Pediatrics

Assistant Professor, Department of Obstetrics and Gynecology

University of Texas Southwestern Medical Center

University of Texas Southwestern Medical Center

Director, Newborn Resuscitation Services

Medical Director of Prenatal Clinics

Parkland Health and Hospital System

Parkland Health and Hospital System

Dallas, Texas

Dallas, Texas

Jeanne S. Sheffield, MD Professor, Department o f Obstetrics and Gynecology Director, Division of Maternal-Fetal Medicine Johns Hopkins University School of Medicine Baltimore, Maryland

vi

Management University of Texas Southwestern Medical Center

DEDICATION To our mentors, who inspire us to strive for excellence in obstetrics, To our colleagues, who are superb role models for obstetricians and gynecologists, To our students and residents, who challenge us to be better teachers each day, To our fellows, who dare us to think more boldly, To our nurses, who encourage us to place patient needs first, To our support staf, who allow us to respond eiciently in the face of emergencies, and To our families, whose love and support make our endeavors possible.

vii

CONTENTS Preface

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xiii

Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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OVERVIEW 1. Overview of Obstetrics.................... 2

MATERNAL ANATOMY AND PHYSIOLOGY 2. Maternal Anatomy

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4. Maternal Physiology

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3. Congenital Genitourinary Abnormalities

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PLACENTATION, EMBRYOGENESIS, AND FETAL DEVELOPMENT 5. Implantation and Placental Development

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6. Placental Abnormalities

7. Embryogenesis and Fetal

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PRECONCEPTIONAL AND PRENATAL CARE 8. Preconceptional Care

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9. Prenatal Care

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THE FETAL PATIENT 10. Fetal Imaging. . . . . . . . . . . . . . . . . . . . . . . . . . . 182

14. Prenatal Diagnosis

11. Amnionic Fluid ..

15. Fetal Disorders ..... ......... ....

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16. Fetal Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . 315

12. Teratology, Teratogens, and Fetotoxic Agents

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17. FetaI Assessment . . . . . . . . . . . . . . . . . . . . . . 331 .

13. Genetics

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EARLY PREGNANCY COMPLICATIONS 18. Abortion

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19. Ectopic Pregnancy .

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20. Gestational Trophoblastic Disease

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LABOR 21. Physiology of Labor

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22. Normal Labor.

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23. Abnormal Labor

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457

24. Intrapartum Assessment

25. Obstetrical Analgesia and Anesthesia . .. . . . . . . . . . . . . . . . . . . . . . . . . . . 485 26. Induction and Augmentation of Labor

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503

Co ntents

DELIVERY 27. Vaginal Delivery ........................516 28. Breech Delivery .........................539 29. Operative Vaginal Delivery ..............553

30. Cesarean Delivery and Peripartum Hysterectomy ..........................567 31. Prior Cesarean Delivery .................591

THE NEWBORN 32. The Newborn. . . . . . . . . . . . . . . . . . . . . . . . . . . 606

34. The Preterm Newborn

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33. Diseases and Injuries of

35. Stillbirth

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the Term Newborn .....................619

THE PUERPERIUM 36. The Puerperium ........................652

38. Contraception .

37. Puerperal Complications . . . . . . . . . . . . . . . . 666

39. Sterilization............................ .702

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OBSTETRICAL COMPLICATIONS 40. Hypertensive Disorders .................710

43. Postterm Pregnancy . . . . . . . . . . . . . . . . . . . . 835

41. Obstetrical Hemorrhage

44. Fetal-Growth Disorders .

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42. Preterm Birth . . . . . . . . . . . . . . . . . . . . . . . . . . . 803

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45. Multifetal Pregnancy. . . . . . . . . . . . . . . . . . . . 863

xi

xii

Contents

MEDICAL AND SURGICAL COMPLICATIONS 46. General Considerations and

56. Hematological Disorders.............. 1075

Maternal Evaluation ....................900 47. Critical Care and Trauma ................915 48. Obesity.................................936 49. Cardiovascular Disorders................948 50. Chronic Hypertension...................975 51. Pulmonary Disorders....................987 52. Thromboembolic Disorders ........... 1004 53. Renal and Urinary Tract Disorders ..... 1025 54. Gastrointestinal Disorders............. 1042

57. Diabetes Mellitus ..................... 1097 58. Endocrine Disorders .................. 1118 59. Connective Tissue Disorders

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60. Neurological Disorders................ 1156 61. Psychiatric Disorders.................. 1173 62. Dermatological Disorders ............. 1184 63. Neoplastic Disorders.................. 1190 64. Infectious Diseases ................... 1209 65. Sexually Transmitted Infections ... . 1235 .

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55. Hepatic, Biliary, and Pancreatic Disorders ............................. 1058

Serum and BI 00 d C0 nst·ltuents ........... 1255 .

Fetal Sonographic Measurements ......... 1262

Maternal Echocardiographic

Mea surements....................... 1261 .

Index

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1273

PREFACE We celebrate this 25th edition of Wiliams Obstetrics with great appreciation for the insight and expertise that the early editors brought to this textbook. To pay tribute to the irst author, J . Whitridge Williams, we begin each chapter with a passage from his 1 st edition that complements the topic. During this selec­ tion process, we were inspired by the strides that modern obstetrics has made since that edition in 1 903. Similarly, we were humbled by some of the classic challenges that still persist. Preterm labor, preeclampsia, and infections are some examples. That said, many of these advances were derived from rigorous, evidence-based research. And, we acknowledge and support the power of this academic ideal to further our specialty in the decades to come. For this 25th edition, we continue to present the detailed staples of basic obstetrics such as maternal anatomy and physi­ ology, preconceptional and prenatal care, labor, delivery, and the puerperium. These accompany detailed discussions of obstetrical complications exempliied by preterm labor, hemor­ rhage, hypertension, and many more. To emphasize the "M" in Maternal-Fetal Medicine, we continue to iterate the many medical and surgical disorders that can complicate pregnancy. And, our second patient-the fetus-has accrued especial attention with an entire section devoted to diagnosis and treat­ ment of fetal disorders. For all of these, we once again empha­ size the science-based underpinnings of clinical obstetrics with special emphasis on biochemical and physiological principles. As was the hallmark of previous editions, these dovetail with descriptions of evidence-based practices. Expert clinical pearls add depth to these discussions and are written for busy practi­ tioners-those "in the trenches." To accomplish these goals, the text has been updated with more than 3000 new literature citations through 20 1 7. Nfany

of the nearly 900 igures are new, and these graphs, sonograms, magnetic resonance images, photographs, photomicrographs, and data graphs are almost all in vivid color. M uch of the original artwork was rendered by our own medical illustrators. lso, as before, we continue to incorporate contemporane­ ous guidelines from professional and academic organizations such as the American College of Obstetricians and Gynecolo­ gists, the Society for Maternal-Fetal Medicine, the N ational Institutes of Health and the National Institute for Child Health and H uman Development, the Centers for Disease Control and Prevention, and other authoritative sources. Many of these data are distilled into nearly 1 00 tables, in which infor­ mation has been arranged in an easy read-and-use format. In addition, several diagnostic and management algorithms are available to quickly guide practitioners. Although we strive to cite numerous sources and provide multiple evidence-based options for such management schemes, we also include our own clinical experiences drawn from the large obstetrical ser­ vice at Parkland Hospital. We are convinced that these are disciplined examples of evidence-based obstetrics but quickly acknowledge that they do not constitute the sole method of management. F. Gary Cunningham Kenneth J. Leveno Steven L. Bloom Jodi S. Dashe Barbara L. Hoffman Brian M. Casey Catherine Y. Spong

xiii

ACKNOWLEDGMENTS During the creation and production of this textbook, we were fortunate to have the assistance and support of countless tal­ ented professionals both within and outside the Department of Obstetrics and Gynecology. To begin, we acknowledge that an undertaking of this magnitude would not be possible without the unwavering support provided by Dr. Barry Schwarz, Vice­ Chairman, whose financial and academic endorsement has been essential. This 25th edition shows a notable absence of three col­ leagues who provided valuable editorial assistance for prior editions of Williams Obstetrics. Colleagues from the University of Texas Southwestern Medical Center include Dr. George Wendel, Jr.-associate editor for the 22nd and 23rd editions­ who has now assumed the important tole of Executive Director of the American Board of Obstetrics and Gynecology. Dr. Jeanne Shefield, with her especial expertise in obstetrical and perinatal infections, has left Dallas and is now the Division Director of Maternal-Fetal Medicine at Johns Hopkins University School of Medicine. From the University of Alabama at Birmingham, Dr. John Hauth, who served as an editor for the 2 1 st through 23rd editions, provided valuable contributions to chapters on chronic hypertension, preterm labor, and labor induction, which have endured in updated forms in this edition. We are especially grateful for the contributions of our two returning Associate Editors. Dr. Mala Mahendroo is a talented basic scientist who continues to perform a magnificent job of ptoviding a coherent translational version of basic science aspects of human reproduction. Dr. Diane Twickler-the con­ summate radiologist-has been an invaluable mentor for our residents, fellows, and faculty. She adds her fantastic experi­ ences and extensive knowledge regarding clinical and techno­ logical advances related to fetal and maternal imaging to add considerable depth to this textbook. Dr. Seth Hawkins served us well as an Associate Editor in this edition and brought addi­ tional strengths to the areas of clinical and academic Maternal­ Fetal Medicine. His rigorous analysis of evidence-based data on topics of maternal physiology, fetal-growth disorders, obesity, liver disease, and labor induction has added new perspectives to these chapters. To add academic breadths to our endeavor, we have enlisted new Contributing Editors-all from UT Southwestern Medical Center-each of whom has expertise in important areas of maternal and perinatal medicine. From the Division of Maternal-Fetal Medicine, Dr. C. Edward Wells adds his exten­ sive clinical experience and his incredible skills with prior cesar­ ean delivery and obstetrical sonography. Dr. April Bailey, with joint appointments in the Departments of Radiology and Obstetrics and Gynecology, shared her tremendous knowledge regarding fetal and maternal imaging with sonography, radiog­ raphy, computed tomography, and magnetic resonance tech­ niques. Dr. David Nelson brings strong clinical knowledge

regarding preterm labor, stillbirth, management of obstetrical hemorrhage, psychiatric disorders in pregnancy, and mul tifetal gestation. From the Department of Anesthesia, Dr. Weike Tao provided academic insight and clinical mastery in obstetrical anesthesia. Similarly, Dr. Erica Grant graciously and skillfully advanced the discussion of this topic. Dr. Myra Wyckoff, from the Department of Pediatrics, contributed greatly to chapters regarding the term and preterm newborn. Her expertise b oth in normal care and in treatment for the more vulnerable neonates has greatly strengthened the evidence-based content of these chapters. In toto, the strength of each contributor has added to create the sum total of our academic endeavor. In constructing such an expansive academic compilation, the expertise of many colleagues was needed to add vital and contem­ poraneous information. It was indeed fortuitous for us to have access to a pantheon of collaborators from here and from other academic medical centers. From our own Department of Obstetrics and Gynecology, our nationally known pelvic anatomist, Dr. Marlene Corton, prepared graphic masterpieces for the anatomy chapter. Dr. Elysia Moschos contributed a number of sonographic images of early pregnancy and uterine malformations. Drs. Claudia Werner and William Griith lent valuable insight into the management of cervical dysplasia. Dr. Emily Adhikari was an invaluable source in the construction of the chapters on maternal and perinatal infections. Finally, clinical photographs were con­ tributed by many faculty and fellows, who include Drs. Patricia Santiago-Munoz, Julie Lo, Elaine Duryea, Jamie Morgan, J udith Head, David Rogers, Kimberly Spoonts, and Emily Adhikari. From the Department of Radiology, Drs. Michael Landy, Jefrey Pruitt, and Douglas Sims added insights and provided computed tomographic and magnetic resonance images. From the Department of Pathology, Dr. Kelley Carrick generously donated exemplary photomicrographs. Dr. Kathleen Wilson, director of the cyrogenomic microarray analysis laboratory, graciously assisted us in updating our cyrogenomic nomenclature. We are also indebted to contributions made by our national and international colleagues. Experts in placental pathology who shared their expertise and images include Drs. Kurt Benirschke, Ona Marie Faye-Petersen, Mandolin Ziadie, Michael Conner, Brian Levenson, Jaya George, and Erika Fong. Input for hypertensive disorders was provided by Drs. John Hauth, Marshall Lindheimer, and Gerda Zeeman; for operative vaginal delivery by Dr. Edward Yeomans; and semi­ nal images were contributed by Drs. Kevin Doody, Timothy Crombleholme, Michael Zaretsky, Togas T ulandi, Edward Lammer, Charles Read, Frederick Elder, April Bleich, Laura Greer, and Roxane Holt. In addition to these contributors, we relied heavily on our colleagues in the Division of Maternal-Fetal Medicine. These professionals, in addition to providing expert content, gra­ ciously assisted us by covering clinical duties when writing and editing were especially time consuming. These include Drs. xv

xvi

Acknowledg m ents

Scott Roberts, Oscar Andujo, Vanessa Rogers, Charles Brown, Julie Lo, Robyn Horsager, Patricia Santiago-Munoz, Shivani Patel, Elaine Duryea, Jamie Morgan, Morris Bryant, Shena Dillon, Denisse Holcomb, Robert Stewart, Stephan Shivvers, Ashley Zink, and Mark Peters. In addition, warm thanks go to our Residency Director, Dr. Vanessa Rogers, and her Associate Program Director, Dr. Stephanie Chang, who have created a nurturing environment for our residents to flourish. Similarly, our Maternal-Fetal Medicine (MF11) D ivision Associate Fellowship Director, Dr. Charles Brown, has aided our work through his talented mentoring of our MFM fellows. We also emphasize that production of Wiliams Obstetrics would not be feasible without the help of our Maternal-Fetal Medicine fellows and our residents in Obstetrics and Gynecology. Their insatiable curiosity serves to energize us to ind new and effective ways to convey age-old truths, new data, and cutting-edge concepts. Their logical and critical questions lead us to weaknesses in the text, and thereby, always help us to improve our work. In addition, we sincerely thank them for their vigilance in capturing photographs of spectacular exam­ ples of both obstetrical pathology and normal indings. For example, included in this edition are photographs contributed by Drs. Devin Macias, Maureen Flowers, Paul Slocum, Jonathan Willms, Stacey Thomas, Kara Ehlers, Nidhi Shah, Abel Moron, Angela Walker, and Elizabeth Mosier. This edition is heavily populated with seminal examples of sonographic indings. We are grateful for the mentorship and talent of Drs. Diane Twickler and April Bailey; Mary Gibbs, RD\1S; Rafael Levy, RDMS; Michael Davidson, RDMS; and the many talented sonographers at Parkland Hospital. Thanks to generous funding from McGraw-Hill Education, this 25th edition now contains more than 200 color illustra­ tions. Most of these were crafted by several skilled medical illustrators who include Ms. Marie Sena, Ms. Erin Frederickson, Mr. Jordan Pietz, Ms. SangEun Cha, and Ms. Jennifer Hulsey. All of these talented artists trained here at UT Southwestern under the tutelage of \1r. Lewis Calver. Additional artistic sup­ port came from Mr. Jason McAlexander and 1I1s. Suzanne Ghuzzi, of MPS North America LLC, who provided the full­ color graphs and line art used to enhance this edition. Their team tirelessly coordinated efforts between author and artist and graciously accommodated our numerous changes and tweaks. Production of the 5000-page manuscript would not have been possible without a dedicated team to bring these efforts together. Once again, we are deeply indebted to Ms. Dawn Wilson and Ms. Melinda Epstein for their untiring efforts with manuscript production. Ms. Mercedes Salinas also provided excellent, conscientious manuscript assistance. Information technology support was provided by the very knowledgeable and responsive Mr. Charles Richards and Mr. Thomas Ames.

For these and many more that go unnamed, we could not have done our job without their expertise. It again has been a privilege and a pleasure to work with the dedicated professionals from McGraw-Hill Education. Mr. Andrew Moyer has brought his considerable intelligence, unwavering work ethic, and creativity to this edition of Williams Obstetrics. His dedication to creating the best text­ book possible equaled our efforts, and we are in awe of his productive, gracious style. H is assistant, Ms. Jessica Gonzalez, provided professional, timely, and ever-sunny aid. Mr. Richard Ruzycka served as production supervisor for this edition of the textbook. He skillfully kept our project on track through an array of potential hurdles. Last, we have had the pleasure to work with Mr. Armen Ovsepyan in coordinating the artwork for many of our editions. His organization and eiciency are unrivaled. Our text took its inal shape under the watchful care of our compositors at Aptara, Inc. We thank Ms. Indu J awwad for her talents in graciously and masterfully coordinating and oversee­ ing composition. Her dedicated attention to detail and organi­ zation were vital to completion of our project. Also, at Aptara, Mr. Mahender Singh performed a crucial task of quality con­ trol. He also assisted, along with Mr. Surendra Mohan Gupta and Mr. Anil Varghese, in creating beautiful chapter layouts to highlight our content aesthetically and informatively. This edi­ tion's chapters, for the irst time, were posted and available online for use prior to print publication. We thank Mr. Braj Bhushan and Mr. Ashish Kumar Sharma for preparing this content so brilliantly. Special thanks go to Ms. Kristin Landon. As copyeditor for now several editions of both Williams Obstetrics and Williams Gynecoloy, Kristin has added precision and clarity to our efforts. Her endurance and pleasant profes­ sionalism through many challenging chapters has made our text better. Finally-but certainly not last-we acknowledge our sig­ niicant debt to the women who have entrusted themselves and their unborn children to us for obstetrical care. The clinical expertise and many graphic illustrations presented in this text would not have been possible without their collaborative spirit to help us advance obstetrical knowledge. We also offer enthu­ siastic and heartfelt appreciation to our families and friends. Without their patience, generosity, love, and encouragement, this task would have been impossible. F. Gary Cunningham Kenneth J. Leveno Steven L. Bloom Jodi S. Dashe Barbara L. Hoffman Brian M. Casey Catherine Y. Spong

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C H A PT E R 1

Ove rvi ew of O b stet r i cs

VITAL STATISTICS

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In theolowingpages I have attempted to setorth, as brily as seemed to be consistent with thoroughness, the scientic basis or and the practical application of the obstetrical art. At the same time, I have endeavored to present the more practical aspects of obstetrics in such a manner as to be of direct service to the obstetrician at the bedside. -J. Whitridge Williams ( 1 903) So reads the introduction to Williams' irst edition of this textbook, Obstetrics-A Text-Book or the Use of Students and Practitioners. In this 25th edition, we strive to follow the tenets described by Williams. And, each chapter begins with a quote from his original textbook. he science and clinical practice of obstetrics is concerned with human reproduction. hrough quality perinatal care, the specialty promotes the health and well-being of the pregnant woman and her fetus. Such care entails appropriate recognition and treatment of complications, supervision of labor and deliv­ ery, initial care of the newborn, and management of the puer­ perium. Postpartum care promotes health and provides family planning options. he importance of obstetrics is relected by the use of mater­ nal and neonatal outcomes as an index of the quality of health and life among nations. Intuitively, indices that refl e ct poor ob­ stetrical and perinatal outcomes would lead to the assumption

that medical care for the entire population is lacking. With those thoughts, we now provide a synopsis of the current state of maternal and newborn health in the United States as it relates to obstetrics.

VITAL STATISTICS The National Vital Statistics System of the United States is the oldest and most successful example of intergovernmental data sharing in public health. This agency collects statistics through vital registration systems that operate in various jurisdictions. These systems are legally responsible for registration of births, fetal deaths, deaths, marriages, and divorces. Legal authority resides individually with the 50 states; two regions-the Dis­ trict of Columbia and New York City; and ive territories­ American Samoa, Guam, the Northern Mariana Islands, Puerto Rico, and the Virgin Islands. The standard birth certifi c ate was revised in 1 989 to include more information on medical and lifestyle risk factors and obstetrical practices. In 2003, an extensively revised Standard Certificate of Live Birth was implemented in the United States. The enhanced data categories and speciic examples of each are summarized in Table 1 - 1 . By 20 1 3 , 3 5 states had implemented the revised birth certificate representing 76 percent of all births (MacDorman, 20 1 5) . Importantly, the 2003 version of the population death certificate contains a pregnancy checkbox to eventually be implemented by all states a oseph, 20 1 7) . • Definitions

The uniform use of standard deinitions is encouraged by the World Health Organization as well as the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (20 1 7) . Such uniformity allows data compar­ ison not only between states or regions of the country but also between countries. Still, not all deinitions are uniformly

Ove rview of Obstetrics TABLE 1 -1 . Genera l Categories of New I nformation Added to the 2003 Revision of the B i rth Certificate

Risk factors in preg na ncy-Exa m ples: prior preterm b i rth, prior ec l a m psia Obstet rica l p roced u res-Exa m p l es: tocolys i s, cerclage, external cep h a l i c vers i o n La bor-Exa m p les: n o n cep h a l i c prese ntat ion, g l ucocorticoids for feta l l u ng matu ration, a nti b i otics d u ri ng l a bo r De l ivery-Exa m ples: u n s uccessfu l operative vag i na l d e l ive ry, t r i a l o f l a bo r w i t h p r i o r cesa rea n del ivery N ewborn- Exa m ples: assisted venti l ation, s u rfa cta nt thera py, co ngen ita l a n o m a l ies

applied. For example, the American College of Obstetri­ cians and Gynecologists recommends that reporting include all fetuses and neonates born weighing at minimum 500 g, whether alive or dead. But, not all states follow this recom­ mendation. Speciically, 28 states stipulate that fetal deaths beginning at 20 weeks' gestation should be recorded as such; eight states report all products of conception as fetal deaths; and still others use a minimum birthweight of 350 g, 400 g, or 500 g to deine fetal death. To further the confusion, the National Vital S tatistics Reports tabulates fetal deaths from gestations that are 20 weeks or older (Centers for Disease Con­ trol and Prevention, 20 1 6) . his is problematic because the 50th percentile for fetal weight at 20 weeks approximates 325 to 350 g-considerably less than the 500-g deinition. Indeed, a birthweight of 500 g corresponds closely with the 50th per­ centile for 22 weeks' gestation. Deinitions recommended by the National Center for Health Statistics and the Centers for Disease Control and Pre­ vention are as follows: Perinatal period. The interval between the birth of a neonate born after 20 weeks' gestation and the 28 completed days after that birth. When perinatal rates are based on birth­ weight, rather than gestational age, it is recommended that the perinatal period be deined as commencing at the birth of a 500-g neonate. Birth. he complete expulsion or extraction from the mother of a fetus after 20 weeks' gestation. As described above, in the absence of accurate dating criteria, fetuses weighing < 500 g are usually not considered as births but rather are termed abortuses for purposes of vital statistics. Birthweight. The weight of a neonate determined immediately after delivery or as soon thereafter as feasible. It should be expressed to the nearest gram. Birth rate. The number of live births per 1 000 population. Fertility rate. The number of live births per 1 000 females aged 1 5 through 44 years. Live birth. he term used to record a birth whenever the new­ born at or sometime after birth breathes spontaneously or shows any other sign of life such as a heartbeat or deinite spontaneous movement of voluntary muscles. Heartbeats are distinguished from transient cardiac contractions, and respirations are diferentiated from fleeting respiratory ef­ forts or gasps. Stillbirth or fetal death. The absence of signs of life at or after birth. Early neonatal death. Death of a liveborn neonate during the irst 7 days after birth. Late neonatal death. Death after 7 days but before 29 days.

Stillbirth rate or fetal death rate. The number of stillborn neo­ nates per 1 000 neonates born, including live births and still­ births. Neonatal mortality rate. The number of neonatal deaths per 1 000 live births. Perinatal mortality rate. he number of stillbirths plus neonatal deaths per 1 000 total births. Infant death. All deaths of liveborn infants from birth through 12 months of age. Infant mortality rate. The number of infant deaths per 1 000 live births. Low birthweight. A newborn whose weight is

-� 65 -Nonpregnant 1 2-1 6 26-30 32-36 postpartum weeks weeks weeks

FIGURE 4-7 Left ventric u l a r stroke vol u me across preg na ncy compared with 1 2-week postpartum (non preg n a nt) va l ues for norma l-weig ht women in the s u p i n e a nd latera l positions. (Data from Nelson, 201 5.) cardiac silhouette (Enein, 1 987) . These factors make it dii­ cult to precisely identiy moderate degrees of cardiomegaly by simple radiographic studies. Normal pregnancy induces characteristic electrocardio­ graphic changes, and the most common is slight left-axis devia­ tion due to the altered heart position. Q waves in leads II, III and avF and lat or inverted T-waves in leads III, V1 -V3 may also occur (Sunitha, 20 1 4) . During pregnancy, many o f the normal cardiac souns are modiied. hese include: ( 1 ) an exaggerated splitting of the irst heart sound and increased loudness of both components, (2) no deinite changes in the aortic and pulmonary elements of the second sound, and (3) a loud, easily heard third sound (Cut­ forth, 1 966) . In 90 percent of gravidas, they also heard a sys­ tolic murmur that was intensiied during inspiration in some or expiration in others and that disappeared shortly after delivery. A soft diastolic murmur was noted transiently in 20 percent, and continuous murmurs arising from the breast vasculature in 10 percent (Fig. 49- 1 , p. 950) . Structurally, the expanding plasma volume seen during nor­ mal pregnancy is relected by enlarging cardiac end-systolic and end-diastolic dimensions. Concurrently, however, septal thick­ ness or ejection fraction does not change. This is because the dimensional changes are accompanied by substantive ventricu­ lar remodeling, which is characterized by left-ventricular mass expansion of 30 to 35 percent near term. In the nonpregnant state, the heart is capable of remodeling in response to stimuli such as hypertension and exercise. Such cardiac plasticiy likely is a continuum that encompasses physiological growth-such as that in exercise, and pathological hypertrophy-such as with hypertension (Hill, 2008) . Stewart and colleagues (20 1 6) used cardiac MR imaging to prospectively evaluate cardiac remodeling during pregnancy. Compared with the first trimester, left ventricular mass increased signiicantly beginning at 26 to 30 weeks' gestation, and this continued until delivery (Fig. 4-8) . This remodeling is concen­ tric and proportional to maternal size for both normal and over­ weight women and resolved within 3 months of delivery. Certainly for clinical purposes, ventricular unction during pregnancy is normal, as estimated by the Braunwad ventricuar unction graph (Fig. 4-9) . For the given illing pressures, cardiac

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FIGURE 4-8 Let ventricu l a r mass of norma l-weight a nd over­ weight women across p reg na ncy com pared with 1 2-week postpa r­ t u m (nonpreg n a nt) va l ues. (Data from Stewart, 20 1 6.)

output is appropriate and thus cardiac unction during pregnancy is eudynamic. Of the metabolic changes that occur in the heart during pregnancy, the eiciency of cardiac work-which is the product of cardiac output X mean arterial pressure-is estimated to rise by approximately 25 percent. The associated increase in oxygen consumption is primarily accomplished via increased coronary blood low rather than increased extraction (Liu, 20 1 4) . • Card iac Output

When measured in the lateral recumbent position at rest, car­ diac output increases signiicantly beginning in early pregnancy. It continues to rise and remains elevated during the remainder of pregnancy. In a supine woman, a large uterus rather consis­ tently compresses veins and diminishes venous return from the lower body. It also may compress the aorta (Bieniarz, 1 968) . In response, cardiac illing may be reduced and cardiac o utput 1 20 110

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FIGURE 4-9 Relationship between let ventricu l a r stroke work i ndex (LVSWI), cardiac output, and p u l monary cap i l l a ry wedge pres­ s u re (PCWP) in 1 0 normal preg n a nt women in the third trimester. (Data from Cla rk, 1 989.)

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Mater n a l A n atomy and Physi o l ogy TABLE 4-4. Centra l H emodyn a m i c Cha nges i n 1 0 N o r m a l N u l l i pa rous Women Nea r Term a n d

Postpa rt u m

Preg na nta (35-38 wk) Mea n a rterial p ress u re ( m m Hg) P u l m o n a ry capi l l a ry wedge pressu re (m m Hg) Centra l venous pres s u re (mm Hg) Heart rate (beats/m i n) Card iac output (L/m i n) System ic vasc u l a r resi sta n ce (dyn/sec/cm-S ) P u l m o n a ry vascu l a r resi sta nce (dyn/sec/cm- S ) Seru m col l o i d o s m otic p ress u re ( m m Hg) COP-PCWP g rad ient (mm Hg) Let ventri c u l a r stroke work i n d ex (g/m/m 2 )

90 8 4 83 6.2 1 21 0 78 1 8.0 1 0.5 48

± ± ± ± ± ± ± ± ± ±

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Postpartum ( 1 1 - 1 3 wk)

Change b

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NSC N SC NSC + 1 7% +43% -21 % - 34% - 1 4% - 28% N SC

aMea s u red i n latera l rec u m bent position. bChanges sig n ificant u n less N SC = no s i g n ifica nt c h a nge. COP = col lo i d o s m otic p ressu re; PCWP = p u l m o na ry ca p i l la ry wedge pressu re. Data from Cla r k, 1 989.

lessened. Speciically, cardiac MR imaging shows that when a woman rolls from her back onto her left side, cardiac output at 26 to 30 weeks' gestation rises by approximately 20 percent and at 32 to 34 weeks by 1 0 percent (Nelson, 20 1 5) . Con­ sistent with this, Simpson and James (2005) found that fetal oxygen saturation is approximately 1 0 percent higher if a labor­ ing woman lies in a lateral recumbent position compared with supine. Upon standing, cardiac output falls to the same degree as in the nonpregnant woman (Easterling, 1 988). In multifetal pregnancies, compared with singletons, mater­ nal cardiac output is augmented further by almost another 20 percent. Ghi and coworkers (20 1 5) used transthoracic echo­ cardiography to show that irst-trimester cardiac output with twins (mean 5 . 50 Umin) was more than 20 percent greater than postpartum values. Cardiac output values in the second (6. 3 1 L/min) and third (6.29 Umin) trimesters were increased an additional 1 5 percent compared with irst-trimester output. Left atrial and left ventricular end-diastolic diameters are also longer with twins due to augmented preload (Kametas, 2003) . The greater heart rate and inotropic contractility imply that car­ diovascular reserve is reduced in multifetal gestations. D uring first-stage labor, cardiac output rises moderately. During the second stage, with vigorous expulsive eforts, it is appreciably greater. The pregnancy-induced increase is lost ater delivery, at times dependent on blood loss.

appreciably. Thus, although cardiac output rises, left ventricular function as measured by stroke work index remains similar to the nonpregnant normal range (see Fig. 4-9) . Put another way, normal pregnancy is not a continuous "high-output" state.

• Hemodynamic Function in Late Pregnancy

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Clark and associates ( 1 989) conducted invasive studies to mea­ sure hemodynamic function late in pregnancy (Table 4-4) . Right heart catheterization was performed i n 1 0 healthy nul­ liparas at 35 to 38 weeks' gestation, and again at 1 1 to 13 weeks postpartum. Late pregnancy was associated with the expected increases in heart rate, stroke volume, and cardiac output. Sys­ temic vascular and pulmonary vascular resistance both dropped signiicantly, as did colloid osmotic pressure. Pulmonary capil­ lary wedge pressure and central venous pressure did not change

• Circulation and Blood Pressure

Changes in posture afect arterial blood pressure (Fig. 4- 1 0) . Brachial artery pressure when sitting is lower than that when in the lateral recumbent supine position (Bamber, 2003) . Addi­ tionally, systolic blood pressure is lower in the lateral positions compared with either the flexed sitting or supine positions (Armstrong, 20 1 1 ) . Arterial pressure usually declines to a nadir at 24 to 26 weeks' gestation and rises thereafter. Diastolic pres­ sure decreases more than systolic. 1 20

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M aternal Phys i o l ogy

Morris and associates (20 1 5) studied measures of vas­ cular compliance before pregnancy, during pregnancy, and postpartum. Compared with healthy nonpregnant controls, signiicant declines in mean arterial pressure and arterial stifness, measured using pulse wave velocity, were observed between the prepregnant and the postpartum time periods. These indings suggest that pregnancy confers a favorable efect on maternal cardiovascular remodeling and may pos­ sibly help explain why the risk of preeclampsia is reduced in subsequent pregnancies. Antecubital venous pressure remains unchanged during pregnancy. In the supine position, however, femoral venous pressure rises steadily, from approximately 8 mm Hg early in pregnancy to 24 mm Hg at term. Venous blood flow in the legs is retarded during pregnancy except when the lateral recumbent position is assumed (Wright, 1 950) . his tendency toward blood stagnation in the lower extremities during later pregnancy is attriburable to occlusion of the pelvic veins and inferior vena cava by the enlarged uterus. he elevated venous pressure returns to normal when the pregnant woman lies on her side and immediately after delivery (McLennan, 1 943) . These alterations contribute to the dependent edema frequently experienced and to the development of varicose veins in the legs and vulva, as well as hemorrhoids. These changes also predis­ pose to deep-vein thrombosis. S u p i n e Hypotension

In approximately 1 0 percent of women, supine compression of the great vessels by the uterus causes signiicant arterial hypotension, sometimes referred to as the supine hypotensive syndrome (Kinsella, 1 994) . Also when supine, uterine arterial pressure-and thus uterine blood flow-is signiicantly lower than that in the brachial artery. Evidence to support whether this directly afects fetal heart rate patterns in uncomplicated low-risk pregnancies is conlicting (Armstrong, 20 1 1 ; Ibrahim, 20 1 5 ; Tamas, 2007) . Similar changes can also be seen with hemorrhage or with spinal analgesia. • Renin, Angiotensin II, and Plasma Volume

The renin-angiotensin-aldosterone axis is intimately involved in blood pressure control via sodium and water balance. All components of this system show increased levels in normal pregnancy. Renin is produced by both the maternal kidney and the placenta, and greater amounts of renin substrate (angiotensinogen) are produced by both maternal and fetal liver. Elevated angiotensinogen levels result, in part, from augmented estrogen production during normal pregnancy and are important in irst-trimester blood pressure mainte­ nance (Lumbers, 20 1 4) . Gant and associates ( 1 973) reported that nulliparas who remained normotensive became and stayed refractory to the pressor efects of infused angiotensin II. Conversely, those who ultimately became hypertensive developed, but then lost, this refractoriness. The diminished vascular responsiveness to angiotensin II may be progesterone related. Normally, preg­ nant women lose their acquired vascular refractoriness to angio­ tensin II within 1 5 to 30 minutes after the placenta is delivered.

Large amounts of intramuscular progesterone given during late labor delay this diminishing refractoriness. • Cardiac Natriuretic Peptides At least two species of these atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)-are secreted by cardiomy­ ocytes in response to chamber-wall stretching. These peptides regulate blood volume by provoking natriuresis, diuresis, and vascular smooth-muscle relaxation. In nonpregnant and preg­ nant patients, levels of BNP and of amino-terminal pro-brain natriuretic peptide (Nt pro-BNP) , as well as newer analytes such as suppressor of tumorigenicity 2 (ST2) , may be useful in screening for depressed left ventricular systolic function and determining chronic heart failure prognosis (Ghashghaei, 20 1 6) . During normal pregnancy, plasma ANP and B N P levels are maintained in the nonpregnant range despite greater plasma volume (Yurteri-Kaplan, 20 1 2) . In one study, median BNP levels were stable across pregnancy with values < 20 pg/mL (Resnik, 2005) . BNP levels are increased in severe preeclamp­ sia, and this may be caused by cardiac strain from increased afterload (Afshani, 20 1 3) . It would appear that ANP-induced physiological adaptations participate in extracellular fl u id vol­ ume expansion and in the elevated plasma aldosterone concen­ trations characteristic of normal pregnancy. -

• Prostaglandins

Elevated prostaglandin production during pregnancy is thought to have a central role in control of vascular tone, blood pres­ sure, and sodium balance. Renal medullary prostaglandin E2 synthesis is markedly elevated during late pregnancy and is presumed to be natriuretic. Levels of prostacyclin (PGI 2 ) , the principal prostaglandin of endothelium, also rise during late pregnancy. PGI 2 regulates blood pressure and platelet function. It helps maintain vasodilation during pregnancy, and its dei­ ciency is associated with pathological vasoconstriction (Shah, 20 1 5) . Thus, the ratio of PGI 2 to thromboxane in maternal urine and blood is considered important in preeclampsia patho­ genesis (Majed, 20 1 2) . • Endothelin

Several endothelins are generated in pregnancy. Endothelin- 1 is a potent vasoconstrictor produced in endothelial and vas­ cular smooth muscle cells and regulates local vasomotor tone (George, 20 1 1 ; Lankhorst, 20 1 6) . Its production is stimulated by angiotensin II, arginine vasopressin, and thrombin. Endo­ thelins, in turn, stimulate secretion of ANP, aldosterone, and catecholamines. Vascular sensitivity to endothelin- 1 is not altered during normal pregnancy. Pathologically elevated levels may play a role in preeclampsia (Saleh, 20 1 6) . • Nitric Oxide

This potent vasodilator is released by endothelial cells and may modiy vascular resistance during pregnancy. Moreover, nitric oxide is an important mediator of placental vascular tone and

63

64

Mate rna l A n atomy a n d Physiology

develop ment (Krause, 20 1 1 ; Kulandavelu, 20 1 3) . Abnormal nitric oxide synthesis has been linked to preeclampsia develop­ ment (Laskowska, 20 1 5; Vignini, 20 1 6) .

RESPIRATORY TRACT Of anatomic changes, the diaphragm rises approximately 4 cm during pregnancy (Fig. 4- 1 1 ) . he subcostal angle widens appreciably as the transverse diameter of the thoracic cage lengthens approximately 2 cm. The thoracic circumference increases about 6 cm, but not suiciently to prevent reduced residual lung volumes created by the elevated diaphragm. Even so, diaphragmatic excursion is greater in pregnant than in non­ pregnant women. • Pulmonary Function

Decreased plasma osmolality also results in less respiratory depression (Moen, 20 1 4) . his provides an additional mecha­ nism for the increased minute ventilation seen in pregnancy, and one that is not dependent on progesterone. Regarding pulmonary function, peak expiratory low rates rise p rogressively as gestation advances (Grindheim, 20 1 2) . Lung compliance i s unafected b y pregnancy. Airway conduc­ tance is increased and total pulmonary resistance reduced, possi­ bly as a result of progesterone. The maximum breathing capaciy and orced or timed vital capaciy are not altered appreciably. It is unclear whether the critical closing volume-the lung volume at which airways in the dependent parts of the lung begin to close during expiration-is higher in pregnancy (Hegewald, 20 1 1 ) . Pulmonary function with a singleton pregnancy does not signiicantly difer from that with twins (MAulife, 2002; Siddiqui, 20 1 4) . Importantly, the greater oxygen requirements and perhaps the increased critical closing volume imposed by pregnancy make respiratory diseases more serious. Demir and colleagues (20 1 5) studied nasal physiology in 85 pregnant women. Although the minimal cross-sectional area decreased between the irst and third trimesters, subjective reports

Of physiological lung changes, unctional residual capaciy (PRe) decreases by approximately 20 to 30 percent or 400 to 700 mL during pregnancy (Fig. 4- 1 2) . his capacity is composed of expiratory reserve volume-which drops 1 5 to 20 percent or 200 to 300 mL-and residual volume-which decreases 20 to 25 percent or 200 to 400 mL. FRe and residual volume decline progressively across pregnancy due to diaphragm elevation. Sig­ niicant reductions are observed by the sixth month. Inspiratory capaciy, the maximum volume " " that can be inhaled from FRe, , " , " " rises by 5 to 1 0 percent or 200 to / 1 03.5° "" 350 mL during pregnancy. Total ,� , , ,,- - - - .."" ' , lung capaci-the combination \ I \ I ' of FRe and inspiratory capac­ , I , ity-is unchanged or decreases � Uterus I by less than 5 percent at term . (37 weeks) I: \ ' \ (Hegewald, 20 1 1 ) . I \ " ,' , The respiratory rate i s essen­ , tially unchanged, but tidal volume and resting minute ven­ tilation increase signiicantly as pregnancy advances. Kolar­ zyk and coworkers (2005) � is-7 e m - . reported significantly greater .. , . , . mean tidal volumes-0.66 to , , \ \\ I 0 . 8 LI min-and resting min­ I I ute ventilations-1 0.7 to 1 4. 1 : --I Llmin-compared with those I , , of nonpregnant women. The \ \ elevated minute ventilation is " � caused by several factors. These " .. include enhanced respira­ < : : ::-- ---- --- toy drive primarily due to the FIGURE 4-1 1 Chest wa l l measureme nts in n o n p reg n a nt (left) a nd preg n a nt women (right) . The stimulatory action of proges­ s u bcosta l a n g le i ncreases, as does the a nteroposterior a nd tra n sverse d i a m eters of the chest wa l l terone, low expiratory reserve a nd chest wa l l circu mference. These c h a n ges compensate for t h e 4-cm elevation o f t h e d i a p h ra g m volume, and compensated respi­ so t h a t tota l l u n g ca pacity is not s i g n ifica ntly red uced . (Redrawn from Hegewa ld MJ, Cra po RO: ratory alkalosis (Heenan, 2003) . Respi ratory physiology in preg n a n cy. C l i n Chest Med 32(1 ) : 1 , 201 1 .) '

,

,

,

'_.;

,;, . ,---- --- - - -. - - ,� . . -

. -

-

-

-

_ ••

Mate r n a l P hys i o l ogy 6

6

Pregnant (7-9 mos . )

Not pregnant

5

---�+ 5

4

4 FVC

�

: 3 3

FVC

: )

TLC 2

2 FAC RV

RV

o �--�--�-------------------�--�--� o

FIGURE 4-1 2 C h a n ges i n l u ng vol u mes with preg n a ncy. The most sig n ificant cha nges a re red uction i n fu nctional residual ca pacity ( F RC) a nd its s u bcom ponents, expi ratory reserve vol u me (ERV) and res i d u a l vol u m e (RV), as wel l as i ncreases i n i n s p i ratory capacity (IC) a nd tidal vol u me (). (Red rawn from Heg ewa ld MJ, Crapo RO: Respiratory physiology i n preg nancy. Clin Chest Med 3 2 ( 1 ) : 1 , 20 1 1 .) of nasal congestion or total nasal resistance did not signiicantly difer among trimesters or compared with nonpregnant controls. • Oxygen Delivery

he amount of oxygen delivered into the lungs by the increased tidal volume clearly exceeds oxygen requirements imposed by pregnancy. Moreover, the total hemoglobin mass and, in turn, total oxygen-carrying capacity rise appreciably during normal pregnancy, as does cardiac output. Consequently, the mater­ nal arteriovenous oxygen diference is diminished. Oxygen con­ sumption grows approximately 20 percent during pregnancy, and it is approximately 1 0 percent higher in multifetal gesta­ tions (Ajjimaporn, 20 1 4) . D uring labor, oxygen consumption increases 40 to 60 percent (Bobrowski, 20 1 0) . • Acid-Base Equilibrium

A greater awareness of a desire to breathe is common even early in pregnancy (Milne, 1 978) . his may be interpreted as dyspnea, which may suggest pulmonary or cardiac abnormalities when none exist. This physiological dyspnea, which should not interfere with normal physical activity, is thought to result from greater tidal volume that lowers the blood Peo2 slightly and paradoxically causes dyspnea. he increased respiratory efort during pregnancy, and in turn the reduction in the partial pressure of carbon dioxide in blood (Peo2) , is likely induced in large part by progesterone and to a lesser degree by estrogen. Progesterone acts centrally, where it lowers the threshold and raises the sensitivity of the che­ moreflex response to carbon dioxide (C02) 0ensen, 2005) . To compensate for the resulting respiratory alkalosis, plasma bicarbonate levels normally drop from 26 to 22 mmollL. Although blood pH is increased only minimally, it does shift the oxygen dissociation curve to the left. his shift increases the ainity of maternal hemoglobin for oxygen-the Bohr fect­ thereby lowering the oxygen-releasing capacity of maternal blood. This is ofset because the slight pH rise also stimulates an increase in 2,3-diphosphoglycerate in maternal erythrocytes.

This shifts the curve back to the right (Tsai, 1 982) . hus, reduced Peo2 from maternal hyperventilation aids CO 2 (waste) transfer from the fetus to the mother while also aiding oxygen release to the fetus .

URINARY SYSTEM

• Kidney

he urinary system undergoes several remarkable changes in pregnancy (Table 4-5 ) . Kidney size grows approximately 1 .0 cm (Cietak, 1 985) . Both the glomerulariltration rate (CPR) and renal plasma low increase early in pregnancy. he GFR rises as much as 25 percent by the second week after concep­ tion and 50 percent by the beginning of the second trimester. his hyperiltration results from two principal factors. First, hypervolemia-induced hemodilution lowers the protein con­ centration and oncotic pressure of plasma entering the glomer­ ular microcirculation. Second, renal plasma flow increases by approximately 80 percent before the end of the irst trimester (Conrad, 20 1 4b; Odutayo, 20 1 2) . As shown in Figure 4- 1 3 , 50 ) ) c � . )

,

S �

25

c )

) ..

O �_--�--�--�-.�-��

o

1 -20

2 1 -30 3 1 -40

Weeks gestation

2

6-8

Weeks postpartum

FIGURE 4-1 3 Percentage i ncrement in g lomeru l a r fi ltration rate (G FR) and rena l plasma flow (RPF) across gestation a n d in the puer­ peri u m . (Data from Od utayo, 20 1 2.)

65

66

Mate r n a l Anatomy a n d Physio l ogy

TABLE 4-5. Ren a l Cha nges in Normal P reg n a ncy

Parameter

Alteration

Clinical Relevance

Ki d n ey size D i latation

Approxi mately 1 c m l o n g e r o n ra d iogra p h Resembles hyd ro n e p h rosis o n sonog ra m o r I V P (more ma rked o n r i g ht)

Re n a l fu n ct i o n

Glomeru la r fi ltrati o n rate a nd ren a l plasma fl ow i ncrease 5 0%

Size ret u rn s to normal postpa rtu m Ca n be co nfu sed with obstructive u ro pathy; reta i ned u ri n e leads to col lecti o n e rrors; ren a l i nfections a re m o re v i ru l ent; may be respon s i b l e for "d istention synd ro me"; e lective pyelog ra p hy s h o u l d be deferred to at l east 1 2 weeks postpa rt u m Seru m creat i n i n e decreases d u ri ng n o rma l gestation; > 0.8 m g/d L ( > 72 �mo l/L) creati n i n e a l ready borderl i ne; p rote i n , a m i no acid, and g l u cose excretion all i n c rease Seru m bicarbo nate decreased by 4-5 m Eq/L; Pc02 decrea sed 1 0 mm Hg; a Pc02 of 40 mm Hg al ready rep resents CO2 retention Seru m os molal ity decrea ses 1 0 mOs m/L (se r u m Na 5 m Eq/L) d u ri n g normal gestation; i ncreased placental meta bol i s m of AVP may cause tra nsient d i a betes i n s i p i d u s d u ri n g p reg n a n cy

...

Ma i nte n a n ce of aci d-base Plasma os m o la l ity

Decreased bica rbonate t h reshold; progestero ne sti m u lates respi ratory center Os m or eg u lation a lte red ; osmotic th resholds for AVP rel ease and t h i rst d ecrease; hormo n a l d is posa l rates i n c rease

...

AVP = va sopressi n; IVP = i ntravenous pye log ra p hy; Pc02= pa rt i a l p ress u re ca rbon d ioxide. Mod ified fro m L i n d hei mer, 2000.

elevated GFR persists until term, even though renal plasma flow declines during late pregnancy. Primarily as a consequence of this elevated GFR, approximately 60 percent of nulliparas during the third trimester experience urinary frequency, and 80 percent experience nocturia (F rederice, 20 1 3) . During the puerperium, a marked GFR persists during the first postpartum day, principally from the reduced glomerular capillary oncotic pressure. A reversal of the gestational hyper­ volemia and hemodilution, still evident on the first postpar­ tum day, eventuates by the second week postpartum (Odutayo, 20 1 2) . Studies suggest that relaxin, discussed earlier (p. 52) , may mediate both increased GFR and renal blood flow dur­ ing pregnancy (Conrad, 20 1 4a; Helal, 20 1 2) . Relaxin boosts renal nitric oxide production, which leads to renal vasodilation and lowered renal aferent and eferent arteriolar resistance. This augments renal blood flow and GFR (Bramham, 20 1 6) . Relaxin may also increase vascular gelatinase activity during pregnancy, which leads to renal vasodilation, glomerular hyper­ iltration, and reduced myogenic reactivity of small renal arter­ ies (Odutayo, 20 1 2) . A s with blood pressure, maternal posture may considerably inluence several aspects of renal function. Late in pregnancy, the sodium excretion rate in the supine position averages less than half that in the lateral recumbent position. The efects of posture on GFR and renal plasma low vary. One unusual feature of the pregnancy-induced changes in renal excretion is the remarkably increased amounts of some nutrients lost in the urine. Amino acids and water-soluble vita­ mins are excreted in much greater amounts (Shibata, 20 1 3) . Renal Fu n ction Tests

Of renal function tests, serum creatinine levels decline during normal pregnancy from a mean of 0.7 to 0 . 5 mg/dL. Values of

0.9 mg/dL or reater sugest underying renal disease and prompt further evaluation. Creatinine clearance in pregnancy averages 30 percent higher than the 1 00 to 1 1 5 mLi min in nonpregnant women. his is a useful test to estimate renal function, provided that complete urine collection is made during an accurately timed period. If this is not done precisely, results are misleading (Lindheimer, 2000, 20 1 0) . During the day, pregnant women tend to accumulate water as dependent edema, and at night, while recumbent, they mobilize this fluid with diuresis. This reversal of the usual nonpregnant diurnal pattern of urinary flow causes nocturia, and urine is more dilute than in nonpregnant women. Failure of a pregnant woman to excrete concentrated urine after withholding fluids for approximately 1 8 hours does not necessarily signiy renal damage. In fact, the kidneys in these circumstances function perfectly normally by excreting mobi­ lized extracellular fluid of relatively low osmolality. U r i na lysis

Glucosuria during pregnancy may not be abnormal. The appre­ ciably increased GFR, together with impaired tubular reab­ sorptive capacity for filtered glucose, accounts for most cases of glucosuria. Chesley ( 1 963) calculated that about a sixth of pregnant women will spill glucose in the urine. hat said, although common during pregnancy, when glucosuria is iden­ tiied, a search for diabetes mellitus is pursued. Hematuria frequently results from contamination during collection. If not, it most often suggests urinary tract disease or infection. Hematuria is common after diicult labor and delivery because of trauma to the bladder and urethra. Proteinuria is typically deined in nonpregnant subjects as a protein excretion rate of more than 1 50 mg/ d. Because of the aforementioned hyperiltration and possible reduction of tubular reabsorption, proteinuria during pregnancy is usu­ ally considered signiicant once a protein excretion threshold

Matern a l Phys i o l ogy

• 6

300

•

...

=

S ­ J

, 200

1 st Trimester 2nd Trimester 3rd Trimester

6

6

6

6 6

• ••

• •

�_-l�--' -r•

95 %

avoided. Disadvantageously, the amount of protein per unit of creatinine excreted during a 24-hour period is not constant, and the thresholds to deine abnormal vary. Nomograms for urinary microalbumin and creatinine ratios during uncompli­ cated pregnancies have been developed (Waugh, 2003) . • Ureters

·w

5 t 1 00 c

o o

10 20 30 Gestational age (weeks)

40

FIGURE 4-1 4 Scatter p l ot of wo m e n s h owi n g 24- h o u r u ri n a ry tot a l p rote i n excretion by gestatio n a l age. Mean a n d 95-percent confidence l i m its a re o u t l i ned. (Red rawn from H i g by K, Su iter C R, P h e l p s JY, et a l : N o r m a l va l u es of u r i n a ry a l bu m i n a n d tota l p rote i n excret i o n d u ri n g p reg n a n cy. Am J Obstet Gynecol 1 7 1 :984, 1 994.) of at least 300 mg/d is reached (Odutayo, 20 1 2) . Higby and coworkers ( 1 994) measured protein excretion in 270 normal women throughout pregnancy (Fig. 4- 1 4) . Mean 24-hour excretion for all three trimesters was 1 1 5 mg, and the upper 9 5-percent conidence limit was 260 mg/d without significant diferences by trimester. They showed that albumin excretion is minimal and ranges from 5 to 30 mg/d. Proteinuria increases with gestational age, which corresponds with the peak in CFR (see Fig. 4- 1 3) (Odutayo, 20 1 2) .

After the uterus completely rises out of the pelvis, it rests on the ureters. This laterally displaces and compresses them at the pel­ vic brim. Above this level, elevated intraureteral tonus results, and ureteral dilatation is impressive (Rubi, 1 968) . It is right sided in 86 percent of women (Fig. 4- 1 5) (Schulman, 1 975). This unequal dilatation may result from cushioning provided the left ureter by the sigmoid colon and perhaps from greater right ureteral compression exerted by the dextrorotated uterus. The right ovarian vein complex, which is remarkably dilated during pregnancy, lies obliquely over the right ureter and may also contribute to right ureteral dilatation. Progesterone likely has some additional efect. Van Wagenen and Jenkins ( 1 939) described continued ureteral dilatation after removal of the monkey fetus but with the placenta left in situ. The relatively abrupt onset of dilatation in women at midpregnancy, however, seems more consistent with ureteral compression. Ureteral elongation accompanies distention, and the ureter is frequently thrown into curves of varying size, the smaller of which may be sharply angulated. hese so-called kinks are

Measuring U rine Protein. The three most commonly employed

approaches for assessing proteinuria are the qualitative classic dipstick, the quantitative 24-hour collection, and the albumin/ creatinine or protein/creatinine ratio of a single voided urine specimen. he pitfalls of each approach have been reviewed by Conrad (20 1 4b) and Bramham (20 1 6) and their colleagues. he principal problem with dipstick assessment is that it fails to account for renal concentration or dilution of urine. For example, with polyuria and extremely dilute urine, a negative or trace dipstick could actually be associated with excessive pro­ tein excretion. he 24-hour urine collection is afected by urinaty tract dilatation, which is discussed in the next section. he dilated tract may lead to errors related both to retention-hundreds of milliliters of urine remaining in the dilated tract-and to timing-the remaining urine may have formed hours before the collection. To minimize these pitfalls, the patient is irst hydrated and positioned in lateral recumbency-the deinitive nonobstructive posture-for 45 to 60 minutes. After this, she is asked to void, and this specimen is discarded. Immediately following this void, her 24-hour collection begins. During the final hour of collection, the patient is again placed in the lat­ eral recumbent position. But, at the end of this hour, the inal collected urine is incorporated into the total collected volume (Lindheimer, 20 1 0) . Last, the protein/creatinine ratio i s a promising approach because data can be obtained quickly and collection errors are

FIGURE 4-1 5 Hyd ronephrosis. P l a i n fi lm from the 1 5- m i n ute image of a n i ntravenous pyelog ra m (IVP). Moderate hyd rone­ p h rosis on the rig ht (arrows) a n d m i l d hyd ronephrosis on the l eft (arrowheads) a re both norma l for this 35-week gestation.

67

68

Maternal Anato m y a n d P hysiol ogy

poorly named, because the term connotes obstruction. hey are usually single or double curves that, when viewed in a radio­ graph taken in the same plane as the curve, may appear as acute angulations. Another exposure at right angles nearly always identiies them to be gentle curves. Despite these anatomical changes, complication rates associated with ureteroscopy in pregnant and nonpregnant patients do not difer signiicantly (Semins, 20 1 4) . • Bladder

he bladder shows few significant anatomical changes before 1 2 weeks' gestation. Subsequently, however, increased uterine size, the hyperemia that afects all pelvic organs, and hyperplasia of bladder muscle and connective tissues elevate the trigone and thicken its intraureteric margin. Continuation of this process to term produces marked deepening and widening of the trigone. The bladder mucosa is unchanged other than an increase in the size and tortuosity of its blood vessels. Bladder pressure in primigravidas increases from 8 cm H20 early in pregnancy to 20 cm H20 at term (Iosif, 1 980) . To compensate for reduced bladder capacity, absolute and func­ tional urethral lengths increased by 6.7 and 4.8 mm, respec­ tively. Concurrently, maximal intraurethral pressure rises from 70 to 93 cm H20, and thus continence is maintained. Still, at least half of women experience some degree of urinary incon­ tinence by the third trimester (Abdullah, 20 1 6a) . Indeed, this is always considered in the diferential diagnosis of ruptured membranes. Near term-particularly in nulliparas, in whom the presenting part often engages before labor-the entire base of the bladder is pushed ventral and cephalad. his converts the normally convex surface into a concavity. As a result, diicul­ ties in diagnostic and therapeutic procedures are greatly accen­ tuated. Moreover, pressure from the presenting part impairs blood and lymph drainage from the bladder base, often render­ ing the area edematous, easily traumatized, and possibly more susceptible to infection.

GASTROI NTESTINAL TRACT As pregnancy progresses, the stomach and intestines are dis­ placed cephalad by the enlarging uterus. Consequently, the physical findings in certain diseases are altered. he appendix, for instance, is usually displaced upward and somewhat later­ ally. At times, it may reach the right lank. Pyrosis (heartburn) is common during pregnancy and is most likely caused by reflux of acidic secretions into the lower esoph­ agus. Although the altered stomach position probably contrib­ utes to its frequency, lower esophageal sphincter tone also is decreased. In addition, intraesophageal pressures are lower and intragastric pressures higher in pregnant women. Concurrently, esophageal peristalsis has lower wave speed and lower ampli­ tude (Ulmsten, 1 978) . Gastric empying time is unchanged during each trimes­ ter and compared with nonpregnant women (Macfie, 1 99 1 ; Wong, 2002, 2007) . During labor, however, and especially after administration of analgesics, gastric emptying time may be appreciably prolonged. As a result, one danger of general

anesthesia for delivery is regurgitation and aspiration of either food-laden or highly acidic gastric contents. Hemorrhoids are common during pregnancy (Shin, 20 1 5) . hey are caused i n large measure b y constipation and elevated pressure in rectal veins below the level of the enlarged uterus. • Liver

Liver size does not enlarge during human pregnancy. Hepatic arterial and portal venous blood flow, however, increase sub­ stantively (Clapp, 2000) . Some laboratory test results of hepatic function are altered in normal pregnancy (Appendix, p. 1 257) . Total alkaline phos­ phatase activity almost doubles, but much of the rise is attrib­ utable to heat-stable placental alkaline phosphatase isozymes. Serum aspartate transaminase (AST) , alanine transaminase (ALT) , 1-glutamyl transpeptidase (GGT) , and bilirubin levels are slightly lower compared with nonpregnant values (Cat­ tozzo, 20 1 3 ; Ruiz-Extremera, 2005) . The serum albumin concentration declines during preg­ nancy. By late pregnancy, albumin levels may be near 3.0 g/dL compared with approximately 4.3 g/dL in nonpregnant women (Mendenhall, 1 970) . Total body albumin levels rise, however, because of pregnancy-associated increased plasma volume. Serum globulin levels are also slightly higher. Leucine aminopeptidase is a proteolytic liver enzyme whose serum levels may be increased with liver disease. Its activity is markedly elevated in pregnant women. he rise, however, results from a pregnancy-speciic enzyme(s) with distinct substrate speciicities (Song, 1 968). Pregnancy-induced ami­ nopeptidase has oxytocinase and vasopressinase activity that occasionally causes transient diabetes insipidus. • Gallbladder

During normal pregnancy, gallbladder contractility is reduced and leads to greater residual volume (Braverman, 1 980) . Progesterone potentially impairs gallbladder contraction by inhibiting cholecystokinin-mediated smooth muscle stimula­ tion, which is the primary regulator of gallbladder contrac­ tion. Impaired emptying, subsequent stasis, and the increased cholesterol saturation of bile in pregnancy contribute to the increased prevalence of cholesterol gallstones in multiparas. In one study, approximately 8 percent of women had gallbladder sludge or stones when imaged at 1 8 and/or 36 weeks' gestation (Ko, 20 1 4) . h e pregnancy efects o n maternal serum bile acid concen­ trations are still incompletely characterized. his is despite the long-acknowledged propensity for pregnancy to cause intrahe­ patic cholestasis and pruritus gravidarum from retained bile salts. Cholestasis of pregnancy is described in Chapter 55 (p. 1 059) .

EN DOCRI NE SYSTEM

• Pituitary Gland

During normal pregnancy, the pUUltary gland enlarges by approximately 1 35 percent (Gonzalez, 1 988) . This increase may suiciently compress the optic chiasma to reduce visual fields.

Maternal Phys i o logy

Impaired vision from this is rare and usually due to macro ad­ enomas (Lee, 20 1 4) . Pituitary enlargement is primarily caused by estrogen-stimulated hypertrophy and hyperplasia of the lactotrophs (Feldt-Rasmussen, 20 1 1 ) . And, as discussed subse­ quently, maternal serum prolactin levels parallel the increasing size. Gonadotrophs decline in number, and corticotrophs and thyrotrophs remain constant. Somatotrophs are generally sup­ pressed due to negative feedback by the placental production of growth hormone. Peak pituitary size may reach 1 2 mm in MR images in the irst days postpartum. he gland then involutes rapidly and reaches normal size by 6 months postpartum (Feldt-Rasmus­ sen, 20 1 1 ) . he incidence of pituitary prolactinomas is not increased during pregnancy (Scheithauer, 1 990) . When these tumors are large before pregnancy-a macroadenoma measur­ ing : 1 0 mm-then growth during pregnancy is more likely (Chap. 58, p. 1 1 32) . he maternal pituitary gland is not essential for pregnancy maintenance. Many women have undergone hypophysectomy, completed pregnancy successfully, and entered spontaneous labor while receiving compensatory glucocorticoids, thyroid hormone, and vasopressin. G rowth Hormone

During the first trimester, growth hormone is secreted predom­ inantly from the maternal pituitary gland, and concentrations in serum and amnionic luid lie within the nonpregnant range of 0 . 5 to 7 . 5 ng/mL (Kletzky, 1 985). As early as 6 weeks' ges­ tation, growth hormone secreted from the placenta becomes detectable, and by approximately 20 weeks, the placenta is the principal source of growth hormone secretion (Perez-Ibave, 20 1 4) . Maternal serum values rise slowly from approximately 3.5 ng/mL at 1 0 weeks to plateau at about 1 4 ng/mL after 28 weeks. Growth hormone in amnionic fluid peaks at 1 4 to 1 5 weeks and slowly declines thereafter to reach baseline values after 36 weeks. Placental growth hormone-which difers from pituitary growth hormone by 1 3 amino acid residues-is secreted by syncytiotrophoblast in a nonpulsatile fashion (Newbern, 20 1 1 ) . Its regulation and physiological efects are incompletely understood, but it inluences fetal growth via up regulation of insulin-like growth factor 1 (IGF- 1 ) . Higher levels have been linked with development of preeclampsia (MinaI, 2007; Perez­ Ibave, 20 1 4) . Further, placental expression correlates positively with birthweight but negatively with fetal-growth restriction (Koutsaki, 20 1 l ) . Maternal serum levels are associated with uterine artery resistance changes (Schiessl, 2007) . hat said, fetal growth still progresses in the complete absence of this hormone. Although not absolutely essential, the hormone may act in concert with placental lactogen to regulate fetal growth (Newbern, 20 1 1 ) . Prolactin

Maternal plasma prolactin levels increase markedly during nor­ mal pregnancy. Concentrations are usually tenfold greater at term-about 1 50 ng/mL-compared with those of nonpreg­ nant women. Paradoxically, plasma concentrations drop after delivery even in women who are breastfeeding. During early

lactation, pulsatile bursts of prolactin secretion are a response to suckling. The principal function of maternal prolactin is to ensure lac­ tation. Early in pregnancy, prolactin acts to initiate DNA syn­ thesis and mitosis of glandular epithelial cells and presecretory alveolar cells of the breast. Prolactin also augments the number of estrogen and prolactin receptors in these cells. Finally, pro­ lactin promotes mammary alveolar cell RNA synthesis, galac­ topoiesis, and production of casein, lactalbumin, lactose, and lipids (Andersen, 1 982) . A woman with isolated prolactin dei­ ciency failed to lactate after two pregnancies (Kauppila, 1 987) . This establishes prolactin as a requisite for lactation but not for pregnancy. Grattan (20 1 5) has reviewed the numerous physi­ ological roles of prolactin for facilitating maternal adaptations to pregnancy. A possible role is proposed for a prolactin frag­ ment in the genesis of peripartum cardiomyopathy (Chap. 49, p. 963) (Cunningham, 20 1 2) . Prolactin is present i n amnionic fluid i n high concen­ trations. Levels of up to 1 0,000 ng/mL are found at 20 to 26 weeks' gestation. Thereafter, levels decline and reach a nadir after 34 weeks. Uterine decidua is the synthesis site of prolactin found in amnionic luid. Although the exact function of amni­ onic luid prolactin is unknown, impaired water transfer from the fetus into the maternal compartment to thereby prevent fetal dehydration is one suggestion. Oxytoci n a n d Antid i u retic Hormone

These two hormones are secreted from the posterior pituitary gland. The roles of oxytocin in parturition and lactation are discussed in Chapters 2 1 (p. 4 1 6) and 36 (p. 657) , respec­ tively. Brown and colleagues (20 1 3) have reviewed the com­ plex mechanisms that promote quiescence of oxytocin systems during pregnancy. Levels of antidiuretic hormone, also called vasopressin, do not change during pregnancy. • Thyroid Gland

hyrotropin-releasing hormone (TRH) is secreted by the hypo­ thalamus and stimulates thyrotrope cells of the anterior pitu­ itary to release thyroid-stimulating hormone (TSH), also called thyrotropin. TRH levels do not rise during normal pregnancy. However, TRH does cross the placenta and may serve to stimu­ late the fetal pituitary to secrete TSH (horpe-Beeston, 1 99 1 ) . Serum TSH and hCG levels vary with gestational age (Fig. 4- 1 6) . As discussed in Chapter 5 (p. 98), the a-subunits of the two glycoproteins are identical, whereas the 3-subunits, although similar, difer in their amino acid sequence. As a result of this structural similarity, hCG has intrinsic thyrotropic activ­ ity, and thus, high serum hCG levels cause thyroid stimulation. Indeed, TSH levels in the irst trimester decline in more than 80 percent of pregnant women, however, they still remain in the normal range for nonpregnant women The thyroid gland boosts production of thyroid hormones by 40 to 1 00 percent to meet maternal and fetal needs (Moleti, 20 1 4) . To accomplish this, the thyroid gland undergoes moder­ ate enlargement during pregnancy caused by glandular hyper­ plasia and greater vascularity. Mean thyroid volume increases from 12 mL in the first trimester to 1 5 mL at term (Glinoer,

69

70

Mate r n a l A natomy a nd Physiology

and triiodothyronine (T3) concentrations, but do not afect the physiologically important serum ree T4 and ree T3 levels. Spe­ cifically, total serum T4 levels rise sharply beginning between 6 and 9 weeks' gestation and reach a plateau at 1 8 weeks. Serum free T4 levels rise only slightly and peak along with hCG levels, and then they return to normal. Interestingly, T4 and T3 secretion is not similar for all preg­ nant women (G linoer, 1 990) . Approximately a third of women experience relative hypothyroxinemia, preferential T3 secretion, and higher, albeit normal, serum TSH levels. hus, thyroidal adjustments during normal pregnancy may vary considerably. The fetus relies on maternal T4, which crosses the placenta in small quantities to maintain normal fetal thyroid function (Chap. 58, p. 1 1 1 8) . Recall that the fetal thyroid does not begin to concentrate iodine until 1 0 to 1 2 weeks' gestation. he syn­ thesis and secretion of thyroid hormone by fetal pituitary TSH ensues at approximately 20 weeks. At birth, approximately 30 percent of the T4 in umbilical cord blood is of maternal origin (Leung, 20 1 2) .

Mother

TBG Total T4

Thyrotropin

Fetus

Thyroid Fu nction Tests

10

20 Week of pregnancy

30

40

FIGURE 4- 1 6 Relative cha nges i n maternal a nd fetal thyroid fu n c­ tion across preg na ncy. Maternal changes i ncl ude a ma rked a n d early i n c rease i n hepatic prod uction o f thyroxine- b i n d i n g g l o b u l i n (TBG) a nd placenta l prod uction o f h u m a n chorion ic g o nadotropin (hCG). I nc reased TBG i ncreases serum thyroxine (T4) concentrations. hCG h a s thyrotropi n-l i ke activity a nd sti m u lates maternal free T4 secretion. Th i s tra n sient hCG-i n d uced increase i n ser u m T4 levels i n h i bits maternal secretion of thyrotropin. Except for m i n i ma l ly increased free T4 levels when hCG pea ks, these levels a re essentia l ly u ncha nged. Feta l levels of a l l serum thyroid a n a lytes i nc rease incre­ menta l ly across preg n a n cy. Fetal triiodothyro n i n e (T3) does not i nc rease u ntil late preg n a n cy. (Mod ified from Bu rrow, 1 994.)

Normal suppression of TSH during pregnancy may lead to a misdiagnosis of subclinical hyperthyroidism. Of greater concern is the potential failure to identiy women with early hypothy­ roidism because of suppressed TSH concentrations. To miti­ gate the likelihood of such misdiagnoses, Dashe and coworkers (2005) conducted a population-based study at Parkland Hos­ pital to develop gestational-age-specific TSH normal curves for both singleton and twin pregnancies (Fig. 4- 1 7) . Similarly, Ashoor and associates (20 1 0) established normal ranges for maternal TSH , free T4, and free T3 at 1 1 to 1 3 weeks' gestation. hese complex alterations of thyroid regulation do not appear to alter maternal thyroid status as measured by meta­ bolic studies. lthough basal metabolic rate increases progres­ sively by as much as 25 percent during normal pregnancy, most 6 5

; 4

s

4.0

-

�

: n �

3 2

50th 0.4

0 0

1 990) . That said, normal pregnancy does not typically cause sig­ nificant thyromegaly, and thus any goiter warrants evaluation. Early in the first trimester, levels of the principal carrier protein-thyroid-binding globulin (TBG)-rise, reach their zenith at about 20 weeks, and stabilize at approximately double baseline values for the remainder of pregnancy (see Fig. 4- 1 6) . h e greater TBG concentrations result from both higher hepatic synthesis rates-due to estrogen stimulation-and lower metab­ olism rates due to greater TBG sialylation and glycosylation. These elevated TBG levels increase total serum thyroxine (T4)

7

\ 10

20

30

40

Gestational age (weeks) FIGURE 4-1 7 Gestational age-specific thyroid-sti m u lating hor­ mone (TSH) nomogra m derived from 1 3,599 singleton preg nan­ cies. The non preg n a nt reference va l u es of 4.0 a n d 0.4 mUll a re represented as solid black li nes. U pper shaded a rea represents the 28 percent of sing leton preg na ncies with TSH va l ues above the 97.5th percentile t h reshold that wou l d not have been identified as a b norma l based on the assay reference va l u e of 4.0 m Ull. lower shaded a rea represents sing leton preg n a n cies that would have been (fa l sely) identified as having TSH s u p p ression based on the assay reference va l ue of 0.4 m Ull. (Data from Dashe, 2005.)

Materna l Phys i o l ogy

of this greater oxygen consumption can be attributed to fetal metabolic activity. If fetal body surface area is considered along with that of the mother, the predicted and observed basal meta­ bolic rates are similar to those in nonpregnant women. Iod i n e Statu s

Iodine requirements increase during normal pregnancy (Chap. 58, p. 1 1 27) . In women with low or marginal intake, deiciency may manifest as low T4 and higher TSH levels. Importantly, more than a third of the world population lives in areas where iodine intake is marginal. For the fetus, early exposure to thy­ roid hormone is essential for the nervous system, and despite public health programs to supplement iodine, severe iodine deiciency resulting in cretinism afects more than 2 million people globally (Syed, 20 1 5) . • Parathyroid Glands

In one longitudinal investigation of 20 women, all markers of bone turnover rose during normal pregnancy and failed to reach baseline levels by 1 2 months postpartum (More, 2003). Investigators concluded that the calcium needed for fetal growth and lactation may be drawn at least in part from the maternal skeleton. he factors afecting bone turnover yield a net result favoring fetal skeletal formation at the expense of the mother, such that pregnancy is a vulnerable period for osteo­ porosis (Sanz-Salvador, 20 1 5) . hat said, prevention is diicult due to a paucity of identiiable risk factors. Pa rathyroid Hormone

Acute or chronic declines in plasma calcium or acute drops in magnesium levels stimulate parathyroid hormone (PTH) release. Conversely, greater calcium and magnesium levels suppress PTH levels. he action of this hormone on bone resorption, intestinal absorption, and kidney reabsorption is to raise extracellular luid calcium concentrations and lower phosphate levels. Fetal skeleton mineralization requires approximately 30 g of calcium, primarily during the third trimester (Sanz-Salvador, 20 1 5) . Although this amounts to only 3 percent of the total calcium held within the maternal skeleton, the provision of cal­ cium still challenges the mother. In most circumstances, aug­ mented maternal calcium absorption provides the additional calcium. During pregnancy, the amount of calcium absorbed rises gradually and reaches approximately 400 mg/ d in the third trimester. Greater calcium absorption appears to be mediated by elevated maternal 1 ,25-dihydroxyvitamin D concentra­ tions. This occurs despite decreased PTH levels during early pregnancy, which is the normal stimulus for active vitamin D production within the kidney. Indeed, PTH plasma concentra­ tions decline during the irst trimester and then rise progres­ sively throughout the remainder of pregnancy (Pitkin, 1 979) . he increased production of active vitamin D is likely due to placental production of either PTH or a PTH-related protein (PTH-rP) . Outside pregnancy and lactation, PTH-rP is usually detectable only in serum of women with hypercalcemia due to malignancy. During pregnancy, however, PTH-rP concentra­ tions increase signiicantly. his protein is synthesized in both fetal tissues and maternal breasts.

Ca lcito n i n

h e C cells that secrete calcitonin are located predominantly in the perifollicular areas of the thyroid gland. Calcitonin opposes actions of PTH and vitamin D and protects the matenal skel­ eton during times of calcium stress. Pregnancy and lactation cause profound maternal calcium stress, ostensibly for the sake of the fetus. Indeed, fetal calcitonin levels are at least twofold higher than maternal levels (Ohata, 20 1 6) . And although maternal levels fall during pregnancy, they generally rise post­ partum (M011er, 20 1 3) . Calcium and magnesium promote the biosynthesis and secretion of calcitonin. Various gastric hormones-gastrin, pentagastrin, glucagon, and pancreozymin-and food inges­ tion also increase calcitonin plasma levels.

• Adrenal Glands

Cortisol

In normal pregnancy, unlike their fetal counterparts, the mater­ nal adrenal glands undergo little, if any, morphological change. The serum concentration of circulating cortisol rises, but much of it is bound by transcortin, the cortisol-binding globulin. The adrenal secretion rate of this principal glucocorticoid is not ele­ vated, and probably it is lower than in the nonpregnant state. he metabolic clearance rate of cortisol, however, is dimin­ ished during pregnancy because its half-life is nearly doubled compared with that for nonpregnant women (Migeon, 1 957) . Administration of estrogen, including most oral contraceptives, causes changes in serum cortisol levels and transcortin similar to those of pregnancy Qung, 20 1 1 ) . During early pregnancy, the levels o f circulating adrenocor­ ticotropic hormone (A CTH) , also known as corticotropin, are dramatically reduced. As pregnancy progresses, ACTH and free cortisol levels rise equally and strikingly (Fig. 4- 1 8) . This

500 400 300

T

200

40

80 60

, S

50

I 0 «

50

30

70

J E

j

20

40 30

10

20 10 0 10

20

30

40

Weeks' gestation

FIGURE 4- 1 8 Seria l increa ses in ser u m cortisol (blue line) a n d adrenocorticotropic hormone (ACTH) (red line) across normal preg n a n cy. (Data fro m Ca rr, 1 98 1 .)

I

71

72

Materna l Anatomy a n d Physiology

apparent paradox is not understood completely. Some suggest that greater free cortisol levels in pregnancy result from a "reset­ ting" of the maternal feedback mechanism to higher thresh­ olds (Nolten, 1 98 1 ) . his might result from tissue reractoriness to cortisol. Others assert that these incongruities stem from an antagonistic action of progesterone on mineralocorticoids (Keller-Wood, 200 1 ) . Thus, in response to elevated progester­ one levels during pregnancy, an elevated free cortisol is needed to maintain homeostasis. Other theories include possible roles for higher free cortisol in preparation for the stress of preg­ nancy, delivery, and lactation. This pattern might also influence postpartum behavior and parenting roles (Conde, 20 1 4) . Al dosterone

As early as 15 weeks' gestation, the maternal adrenal glands secrete considerably increased amounts of aldosterone, the prin­ cipal mineralocorticoid. By the third trimester, approximately 1 mg/d is released. If sodium intake is restricted, aldosterone secretion is even further elevated (Watanabe, 1 963) . Concur­ rently, levels of renin and angiotensin II substrate normally rise, especially during the latter half of pregnancy. his scenario pro­ motes greater plasma levels of angiotensin II, which acts on the zona glomerulosa of the maternal adrenal glands and accounts for the markedly elevated aldosterone secretion. Some suggest the increased aldosterone secretion during normal pregnancy afords protection against the natriuretic efect of progesterone and atrial natriuretic peptide. Gennari-Moser and colleagues (20 1 1 ) provide evidence that aldosterone, as well as cortisol, may modulate trophoblast growth and placental size. Deoxyco rticostero n e

Maternal plasma levels o f this potent mineralocorticosteroid progressively increase during pregnancy. Indeed, plasma lev­ els of deoxycorticosterone rise to near 1 500 pg/mL by term, a more than 1 5-fold increase (Parker, 1 980) . his marked eleva­ tion does not derive from adrenal secretion but instead rep­ resents augmented kidney production resulting from estrogen stimulation. The levels of deoxycorticosterone and its sulfate in fetal blood are appreciably higher than those in maternal blood, which suggests transfer of fetal deoxycorticosterone into the maternal compartment. Androgens

In balance, androgenic aCtiVlty rises during pregnancy, and both maternal plasma levels of androstenedione and testosterone are increased. This inding is not totally explained by alterations in their metabolic clearance. Both androgens are converted to estradiol in the placenta, which increases their clearance rates. Conversely, greater plasma sex hormone-binding globulin lev­ els in gravidas retard testosterone clearance. Thus, the produc­ tion rates of maternal testosterone and androstenedione during human pregnancy are increased. he source of this higher C19-steroid production is unknown, but it likely originates in the ovary. Interestingly, little or no testosterone in maternal plasma enters the fetal circulation as testosterone. Even when massive testosterone levels are found in the circulation of preg­ nant women, as with androgen-secreting tumors, testosterone

concentrations in umbilical cord blood are likely to be unde­ tectable. his results from the near complete trophoblastic con­ version of testosterone to 1 73-estradiol. Maternal serum and urine levels of dehydroepiandrosterone suate are lower during normal pregnancy. his stems from a greater metabolic clearance through extensive maternal hepatic 1 6.-hydroxylation and placental conversion to estrogen (Chap. 5, p. 1 03).

MUSCULOSKELETAL SYSTEM Progressive lordosis is a characteristic feature of normal preg­ nancy. Compensating for the anterior position of the enlarging uterus, lordosis shifts the center of gravity back over the lower extremities. The sacroiliac, sacrococcygeal, and pubic joints have increased mobility during pregnancy. However, as discussed ear­ lier (p. 52) , increased joint laxity and associated discomfort dur­ ing pregnancy do not correlate with increased maternal serum levels of estradiol, progesterone, or relaxin (Aldabe, 20 1 2; Mar­ nach, 2003; V0llestad, 20 1 2) . Most relaxation takes place in the first half of pregnancy. It may contribute to maternal posture alterations and in turn create lower back discomfort. s dis­ cussed in Chapter 36 (p. 66 1 ) , although some symphyseal sepa­ ration likely accompanies many deliveries, those greater than 1 cm may cause significant pain (Shnaekel, 20 1 5) . Aching, numbness, and weakness also occasionally are experienced in the upper extremities. his may result from the marked lordosis and associated anterior neck flexion and shoulder girdle slumping, which produce traction on the ulnar and median nerves (Crisp, 1 964) . he latter may give rise to symptoms mistaken for the carpal tunnel syndrome (Chap. 60, p. 1 1 67) . Joint strengthening begins immediately following delivery and is usually complete within 3 to 5 months. Pelvic dimensions measured by MR imaging up to 3 months after delivery are not significantly diferent from prep regnancy mea­ surements (Huerta-Enochian, 2006) .

CENTRAL N E RVOUS SYSTEM

• Memory

Central nervous system changes are relatively few and mostly subtle. Women often report problems with attention, concen­ tration, and memory throughout pregnancy and the early puer­ perium. Systematic studies of memory in pregnancy, however, are limited and often anecdotal. Keenan and associates ( 1 998) longitudinally investigated memory in pregnant women and a matched control group. hey found pregnancy-related memory decline that was limited to the third trimester. his decline was not attributable to depression, anxiety, sleep deprivation, or other physical changes associated with pregnancy. It was tran­ sient and quickly resolved following delivery. Others have found poorer verbal recall and processing speed and worse spatial rec­ ognition memory in pregnancy (Farrar, 20 1 4; Henry, 20 1 2) . Zeeman and coworkers (2003) used MR imaging t o measure cerebral blood low across pregnancy. They found that mean blood flow in the middle and posterior cerebral arteries declined progressively from 1 47 and 56 mLimin when nonpregnant to

Matern a l Phys i o logy

1 1 8 and 44 mLlmin late in pregnancy, respectively. Mecha­ nisms and signiicance of the decline are unknown. Pregnancy does not . afect cerebrovascular autoregulation (Bergersen, 2006; Cipolla, 20 1 4) . • Eyes

Intraocular pressure drops during pregnancy and is attrib­ uted partly to greater vitreous outlow. Corneal sensitivity is decreased, and the greatest changes are late in gestation. Most pregnant women demonstrate a measurable but slight increase in corneal thickness, thought to be due to edema. Conse­ quently, they may have diiculty with previously comfortable contact lenses. Brownish-red opacities on the posterior sur­ face of the cornea-Krukenberg spindles-are observed with a higher than expected frequency during pregnancy. Hormonal efects similar to those observed for skin lesions are believed to cause this increased pigmentation. Other than transient loss of accommodation reported with both pregnancy and lactation, visual function is unafected by pregnancy. These changes dur­ ing pregnancy and pathological eye aberrations were reviewed by Grant and Chung (20 1 3) . • Sleep

Beginning as early as 1 2 weeks' gestation and extending through the first 2 months postpartum, women have diiculty with falling asleep, frequent awakenings, fewer hours of night sleep, and reduced sleep eiciency (Pavlova, 20 1 1 ) . Abdullah and col­ leagues (20 1 6b) concluded that sleep apnea is more common in pregnancy, especially in obese patients. he greatest disruption of sleep is encountered postpartum and may contribute to post­ partum blues or to frank depression a uulia Paavonen, 20 1 7) .

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C H A PT E R 5

I m pl a ntation a nd Placenta l Development

. . . . . 80

OVARIAN-ENDOMETRIAL CYCLE .

. . . . . 85

DECIDUA. IMPLANTATION AND EARLY TROPHOBLAST FORMATION . . . . . . . . . . . . . . . PLACENTA AND CHORION .

UMBILICAL CORD. . . . . . . . . . . . . . . . . . .

.

All obstetricians should understand the basic biological steps required for women to successully achieve pregnancy. Several

. . . . . 87

abnormalities can fect each of these and lead to infertili' or

. 90

tion continues during almost 40 years between menarche and

. . . . . 95

AMNION .

strides have followed to uncover the steps of implantation and placental structure and function.

pregnancy loss. In most women, spontaneous, cyclical ovula­ menopause. Without contraception, there are approximately

400 opportunities for pregnancy, namely, the day of ovulation

. . . . . . . . . . 97

and its few preceding days. his narrow window for fertiliza­

. 98

steroids. Moreover, these hormones promote optimal endome­

PLACENTAL HORMONES. FETAL ADRENAL GLAND-PLACENTAL INTERACTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . .

tion is controlled by tightly regulated production of ovarian trial regeneration after menstruation in preparation for the next

. . . . 104

implantation window. If fertilization occurs, events thac begin ater blastocyst implantation persist until parturition. hese derive from a unique interaction between fetal trophoblasts and the maternal endometrium. which has been transformed into the

decidua.

The ability of a mother and her fetus to coexist as two distinct immunological systems results from endocrine. paracrine. and

Almost immediately ater the impamltio1 of the ovum, its trophoblast begins to prolerate and lJ1d, the s.rrounding decidual tissue. As it does so, it breaks through the walls of the moumal capilaries, from which the blood escapes and orms cavities, which are boundedparty by trophobast and party by decidua. ?he maternal blood spaces established in this manner represent the earliest stages of the intervillous blood spaces ofthe inure placenta. -). Whitridge Williams ( 1 903)

immunological modiication of fetal and maternal tissues in a manner not seen elsewhere. In addition. the placenta mediates a unique fetal-maternal communication system. which creates a hormonal environment that initially maintains pregnancy and eventually initiates events leading to parturition.

OVARIAN-ENDOMETRIAL CYCLE Predictable. regular. cyclical. and spontaneous ovulatory men­ strual cycles are regulated by complex interactions of the hypo­

1903, the histopathological and embryological descrip­

thalamic-pituitay-ovarian axis. Concurrently, cyclical changes

tions of ovum implanrarion and placental development had

in endometrial histology are faithfully reproduced ( Fig. ;- 1 ).

In

been extensively studied and described. However, the origins

Essentials players in this process include follicle-stimulating

and functions of pregnancy hormones were largely unknown.

hormone (FSH) and luteinizing hormone (LH), which are

Indeed, it was another 2 5 to 30 years before estrogen and pro­

pituitary-derived gonadotropins, and the ovarian sex steroid

gesterone were discovered. In the past 50 years, remarkable

hormones estrogen and progesterone.

Impla ntation and Placental Development

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follicle

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FIGURE 5- 1 Gonadotropin control of the ovarian and endometrial cycles. The ovarian end ometri a l cycle has been structured as a 28-day cycle. The follicular phase (days 1 to 14) is characterized by rising estrogen levels, endometrial t h i c ken ing and selection of the dominant "ovulatory" follicle. During the luteal phase (days 14 to 21 I, the corpus luteum (ell p roduces estrogen and progesterone, which prepare the endometrium for implantation. If implantation occurs, the developing blastocyst begins to produce human chorionic gonadotropin (hCG) and rescues the corpus luteum, thus maintaining progesterone production. FSH follicle-stimulating hormon e; LH luteinizing hor m on e. -

,

=

The average cycle duration approximates 28 days but ranges from 25 to 32 days, even for a given woman. The follicular or proliferative phase shows considerable phase-length variation. This contrasts with the luteal or secretory POStovulatory phase of the cycle, which is remarkably constant at 12 to 14 days. • Ovarian Cycle Follicular Phase

The human ovary contains 2 million oocytes at birth, and approximately 400,000 follicles are present at puberty onset (Baker, 1 963). These are depleted at a rate of approximately 1000 follicles per month until age 35, when this rate accelerates (Faddy, 1992). Only 400 follicles are normally released during female reproductive life. Therefore, more than 99.9 percent of these undergo atresia through a process of cell death termed apoptosis (Gougeon, 1996; Kaipia, 1 997).

=

Follicular development consists of several stages. Primordial follicles undergo gonadotropin-independent recruitment from the resting pool and then progress from primary and secondary follicles to the antral stage. This appears to be controlled by locally produced growth factors. Two members ofthe transform­ ing growth factor-3 family include growth diferentiation fac­ tor 9 (GDF9) and bone morphogenetic protein 1 5 (BMP- 1 5), which regulate granulosa cell proliferation and diferentiation as primary follicles grow (Trombly, 2009; Yan, 2001). hey also stabilize and expand the cumulus oocyte complex in the ovi­ duct (Hreinsson, 2002). These factors are produced by oocytes, suggesting that the early steps in follicular development are, in part, oocyte controlled. As antral follicles develop, surrounding stromal cells are recruited, by a yet-to-be-deined mechanism, to become thecal cells. Although not required for early follicular maturation, FSH is required for further development of large antral follicles

81

82

Placentation, Embryogenesis, and Fetal Development

(Hillier,

2001).

Theca cell

a cohon, begins a phase of semisynchro­ IlOUS

growth based on their marurarion

stare during rhe FSH rise in rhe late luteal phase of rhe previous cycle. This FSH increase leading to further follicular devel­ opmenr is called the seection winow of me ovarian cycle (Macklon, 200 1 ) . Only follicles progressing to this stage develop the capacity

[Q

L

�

� CAMP

_ _ _ _ _ _ _ _

C

;

Theca lutein cell

Cholesterol •

!

Androstenedione

L

�

CAMP- - - - - - - - .

!

Androstenedione

C

�

' C i rculation

Cholesterol

r ' C',,""'.o

Basement membrane

produce estrogen.

During rhe follicular phase, estro­ gen levels rise in proportion to growth of a dominant follicle

and

{Q

rhe

increase in its number of granulosa cells (see Fig. 5 - 1 ) . These cells are rhe exclu­ sive site of FSH receptor expression. lle elevation of Circulating FSH levels during the late luteal phase of the previ­ ous cycle stimulates an increase in FSH receptors and subsequently, the ability of cytochrome P450 aromatase within granulosa cells to conven androstenedi­ one into estradiol. The requirement fo r thecal cells, which respond ro LH, and granulosa cells, which respond to FSH, represents the two-gonadotropin, two­ ceH hypothesis for estrogen biosynthesis (Short, 1 962). As shown in F igure 5-2 , FSH

LUTEAL PHASE/PREGNANCY

FOLLICULAR PHASE

During each ovarian

cycle. a group of antral follicles, known as

induces aromatase and expan­

sion of the antrum of growing follicles. The follicle within the cohorr that is

Estradiol_ Androstenedione �

,, ,, , ,

-:Androstenedione ,

Progesterone LDL

cAMP

J

Estradiol

l

\,

.- - - - - - -

:\AMP

Cholesterol

G ra nu losa

cell

FSH

Granulosa-lutein cell

V W LH

FIGURE 5-2 The two-cell, two-gonadotropin principle of ovarian steroid hormone produc­ tion. During the follicular phase (left panen, l uteinizing hormone (LH) controls theca cell production of androstenedione, which diffuses into the adjacent granulosa cells and acts as precursor for estradiol biosynthesis. The granulosa cell capacity to convert androstenedione to estradiol is controlled by follicle-stimulating hormone (FSH), After ovulation (right panen, the corpus luteum forms and both theca-lutein and granulosa-lutein cells respond to LH. The theca-lutein cells continue to produce androstenedione, whereas granulosa-lutein cells greatly increase their capacity to produce progesterone and to convert androstenedione to estradiol. LH and hCG bind to the same LH-hCG receptor. If pregnancy occurs (right pane�, human chorionic gonadotropin (hCG) rescues the corpus luteum through their shared LH­ hCG receptor. Low-density lipoproteins (LOL) are an important source of cholesterol for steroidogenesis, cAMP cyclic adenosine monophosphate. =

most responsive to FSH is likely to be the irst to produce estradiol and initiate expression of LH

precise predictor of ovulation. It occurs 34 to 36 hours before

receptors.

ovum release from the follicle (see Fig. 5 - 1 ) . LH secretion peaks

Mrer the appearance of LH receptors, the preovulatory

1 0 to 1 2 hours before ovulation and stimulatcs resumption of

granulosa cells begin to secrete small quantities of progesterone.

meiosis in the ovum and release of the irst polar body. Studies

The preovulatory progesterone secrecion, although somewhat

suggest that in response to LH, greater progesterone and pros­

limited, is believed to exert positive feedback on the estrogen­

taglandin production by the cumulus cells, as well as GDF9

primed pituitary to either calise or augment LH release. In addi­

and BMP- 1 5 by the oocyte, activates expression of genes criti­

tion, during the late follicular phase, LH stimulates thecal cell production of androgens, particularly androstenedione, which

cal to formarion of a hyaluronan-rich extracellular matrix by

the cumulus complex (Richards, 2007). As seen in F igu n: ) - 3 ,

are then transferred to the adjacent follicles where they are aro­

during synthesis of this matrix, cumulus cells lose contact with

matized to esnadiol (see Fig. 5-2). During the early follicular

one another and move outward from the oocyte along the hyal­

phase, granulosa cells also produce in hibin 3, which can feed

uronan polymer-this process is called expansion. This results

back on the pituitary to inhibit FSH release (Groome, 1 996).

in a 20-fold augmentation of the cumulus complex volume and

As the dominant foHicle begins to grow, estradiol and inhibin

coincides with an LH-induced remodeling of the ovarian extra­

production rises and results in a decline of follicular-phase

cellular matrix. hese allow release of the mature oocyte and

FSH. This drop in FSH levels is responsible for the failure of

its surrounding cumulus cells through the surface epirhelium.

other follicles to reach preovulatory status-the Graaian fol­

Activation of proteases likely plays a pivotal role in weakening

licle stage-during any one cycle. Thus, 95 percent of plasma

the follicular basement membrane and ovulation (Curry, 2006;

estradiol produced at this time is secreted by the dominant

Ny, 2002).

follicle-thc one destined to ovulate. Concurrently, the con­ tralateral ovary is relatively inactive.

Ovulation

Luteal Phase Following ovulation, rhe corpus luteum develops from the remains of the Graaian follicle in a process referred to as

The onset of rhe gonadotropin surge resulting from increas­

luteiniation. The basement membrane separating the granu­

ing estrogen secretion by preovulatory follicles is a relatively

losa-lutein and theca-lutein cells breaks down, and by day 2

I m p l a ntation a n d P l ace nta l Deve l op m e nt

• Estrogen and Progesterone Action

FIGURE 5-3 An ovu lated c u m u l u s-oocyte co mpl ex. An oocyte is at the center of the com plex. C u m u l u s cel l s a re widely sepa rated from each other by the hya l u ro n a n-rich extracel l u l a r matrix. (Used with permission from Dr. Kevin J . Doody.)

postovulation, blood vessels and capillaries invade the granulosa cell layer. The rapid neo�ascularization of the once-avascular granulosa may be due to angiogenic factors that include vas­ cular endothelial growth factor (VEG F) and others produced by theca-lutein and granulosa-lutein cells in response to LH (Albrecht, 2003; Fraser, 200 1 ) . D uring luteinization, these cells undergo hypertrophy and increase their capacity to synthesize hormones. LH is the primary luteotropic factor responsible for corpus luteum maintenance (Vande Wiele, 1 970) . Indeed, LH injec­ tions can extend the corpus luteum life span in normal women by 2 weeks (Segalof, 1 9 5 1 ) . The hormone secretion pattern o f the corpus luteum difers from that of the follicle (see Fig. 5- 1 ) . As depicted in Figure 5-2, the greater capacity of granulosa-lutein cells to produce progester­ one results from enhanced access to considerably more steroido­ genic precursors through blood-borne, low-densiry lipoprotein (LDL)-derived cholesterol (Carr, 1 98 1 a) . Ovarian progesterone production peaks at 25 to 50 mg/d during the midluteal phase. With pregnancy, the corpus luteum continues progesterone pro­ duction in response to placental human chorionic gonadotropin (hCG) , which binds to the same receptor as LH. Estrogen levels follow a more complex pattern of secretion. Specifically, just after ovulation, estrogen levels decline, but then exhibit a secondary rise that reaches a peak production of 0.25 mg/d of 1 73-estradiol in the midluteal phase. Toward the end of the luteal phase, estradiol production again drops. The human corpus luteum is a transient endocrine organ that, in the absence of pregnancy, will rapidly regress 9 to 1 1 days after ovulation via apoptosis (Vaskivuo, 2002) . The mechanisms that control luteolysis, that is, the regression of the corpus luteum, remain unclear. However, it results in part from dropping levels of circulating LH in the late luteal phase and rising LH insensitivity by luteal cells (Duncan, 1 996; Fili­ cori, 1 986) . he role of other factors is less established. The dramatic drop in circulating estradiol and progesterone levels initiate molecular events that lead to menstruation.

Estrogen is the essential hormonal signal on which most events in the normal menstrual cycle depend. They function in many cell types to regulate follicular development, uterine receptivity, and blood flow. The most biologically potent naturally occur­ ring estrogen is 1 73-estradiol, which is secreted by granulosa cells of the dominant follicle and luteinized granulosa cells of the corpus luteum. Estradiol action is complex and appears to involve wo classic nuclear hormone receptors designated estrogen receptor a (ERa) and 3 (ER3) (Katzenellenbogen, 200 1 ) . These isoforms are the products of separate genes and can exhibit distinct tissue expression. Both estradiol-receptor complexes act as transcriptional factors that become associ­ ated with the estrogen-response element of speciic genes. They share a robust activation by estradiol. However, diferences in their binding ainities to other estrogens and their cell-speciic expression pattens suggest that ERa and ER3 receptors may have both distinct and overlapping function (Saunders, 2005) . Most progesterone actions on the female reproductive tract are mediated through the nuclear hormone receptors, proges­ terone-receptor type A (PR-A) and B (PR-B) . Progesterone enters cells by difusion, and in responsive tissues it becomes associated with its receptors (Conneely, 2002) . Progesterone­ receptor isoforms arise from a single gene and regulate tran­ scription of target genes. hese receptors have unique actions. When PR-A and PR-B receptors are coexpressed, it appears that PR-A can inhibit PR-B gene regulation. The endometrial glands and stroma appear to have diferent expression patterns for progesterone receptors that vary during the menstrual cycle (Mote, 1 999). Progesterone can also evoke rapid responses, such as changes in intracellular free calcium levels, which cannot be explained by genomic mechanisms. G-protein-coupled membrane recep­ tors for progesterone have been identiied, but their role in the ovarian-endometrial cycle remains to be elucidated (Peluso, 2007) . • Endometrial Cycle

Pro l iferative Phase

In the endometrium, epithelial cells line the endometrial glands and are supported by stromal cells. These cells and supplying blood vessels replicate rapidly and cyclically in reproductive­ aged women and are regenerated each ovarian-endometrial cycle. The superficial endometrium, termed the functionalis layer, is shed and reconstructed from the deeper basalis layer (Fig. 5-4) . There is no other example in humans of such cyclical shedding and regrowth of an entire tissue. Fluctuations in estrogen and progesterone levels produce striking efects on the endometrium. Follicular-phase estradiol production is the most important factor in endometrial recov­ ery following menstruation, and both ERa and ER3 receptors are expressed here. Although up to rwo thirds of the functiona­ lis endometrium is fragmented and shed with menses, reepithe­ lialization begins even before menstrual bleeding has ceased. By the fifth day of the endometrial cycle-ifth day of menses-the

83

84

P lacentati on , E m b ryog enesis, a n d Feta l Deve lopment Early prol iferative phase

EPitheli u m Capi llaries

Late prol iferative phase

Secretory phase

Uterine l umen

�

�-_-.. ..�

-

Venous sinus

Functionalis layer

Endometrial gland --· S p iral artery -------��-�_.�I' Basal artery --------�-\\

Basalis layer

Radial artery ---I Myometriu m

FIGURE 5-4 The endometri u m consists of two layers, the fu nction a l i s l ayer a n d basa lis layer. These a re su p plied by the spira l a n d basa l a rteries, respective ly. N u merous g l a n d s a lso s pa n these layers. As the menstru a l cycle prog resses, g reater coi l i n g of the spira l a rteries and i ncreased gland fo l d i ng ca n be seen. Near the end of the menstru a l cycle (day 27), the coiled a rteries constrict, deprive blood su pply to the fu nctiona l i s layer, a nd lead to necrosis and slou g h i ng of this layer.

epithelial surface of the endometrium has been restored, and revascularization has begun. he preovulatory endometrium is characterized by proliferation of glandular, stromal, and vas­ cular endothelial cells. During the early part of the prolifera­ tive phase, the endometrium is usually less than 2 mm thick. he glands are narrow, tubular structures that pursue almost a straight and parallel course from the basalis layer toward the endometrial cavity. Mitotic igures, especially in the glandular epithelium, are identiied by the fifth cycle day. Mitotic activity in both epithelium and stroma persists until day 1 6 to 1 7, that is, 2 to 3 days after ovulation. Blood vessels are numerous and prominent. Clearly, reepithelialization and angiogenesis are impor­ tant to cessation of endometrial bleeding (Chennazhi, 2009; Rogers, 2009) . hese are dependent on tissue regrowth, which is estrogen regulated. Epithelial cell growth also is regulated in part by epidermal growth factor and transforming growth fac­ tor a (TGPa) . Stromal cells proliferate through paracrine and autocrine actions of estrogen and greater local levels of fibro­ blast growth factor-9 (Tsai, 2002) . Estrogens also raise local production of VEGF, which causes angiogenesis through vessel elongation in the basalis (Gargett, 200 1 ; Sugino, 2002) . By the late proliferative phase, the endometrium thickens from both glandular hyperplasia and augmented stromal ground substance, which is edema and proteinaceous material. he loose stroma is especially prominent, and the glands in the functionalis layer are widely separated. his is compared with those of the basalis layer, in which the glands are more crowded and the stroma is denser. At midcycle, as ovulation nears, glandular epithelium becomes taller and pseudostratiied. he surface epithelial cells acquire numerous microvilli, which increase epithelial surface

area, and develop cilia, which move endometrial secretions during the secretory phase (Perenczy, 1 976) . Secreto ry P hase

After ovulation, the estrogen-primed endometrium responds to rising progesterone levels in a highly predictable manner. By day 1 7, glycogen accumulates in the basal portion of glandular epithelium, creating subnuclear vacuoles and pseudostratifica­ tion. hese changes likely result from direct progesterone action through receptors expressed in glandular cells (Mote, 2000) . On day 1 8, vacuoles move to the apical portion of the secre­ tory non ciliated cells. By day 1 9, these cells begin to secrete glycoprotein and mucopolysaccharide contents into the gland lumen (Hafez, 1 975) . Glandular cell mitosis ceases with secre­ tory activity due to rising progesterone levels, which antagonize the mitotic efects of estrogen. Estradiol action also dimin­ ishes because of glandular expression of the type 2 isoform of 1 73-hydroxysteroid dehydrogenase. his converts estradiol to the less active estrone (Casey, 1 996) . On cycle days 2 1 to 24, the stroma becomes edematous. Next, on days 22 to 25, stro­ mal cells surrounding the spiral arterioles begin to enlarge, and stromal mitosis becomes apparent. Days 23 to 28 are character­ ized by pre decidual cells, which surround spiral arterioles. Between days 22 and 25, the secretory-phase endometrium undergoes striking changes associated with predecidual trans­ formation of the upper two thirds of the functionalis layer. The glands exhibit extensive coiling, and luminal secretions become visible. Changes within the endometrium also can mark the so-called window of implantation seen on days 20 to 24. Epi­ thelial surface cells show fewer microvilli and cilia, but lumi­ nal protrusions appear on the apical cell surface (Nikas, 2003) . hese pinopodes help prepare for blastocyst implantation. hey

I m p l a ntation a n d Place nta l Deve l o p m e n t

also coincide with changes in the surface glycocalyx that allow acceptance of a blastocyst (Aplin, 2003) . Another highlight of the secretory phase is the continuing growth and development of the spiral arteries. hese vessels arise from the radial arteries, which are myometrial branches of the arcuate and, ultimately, uterine vessels (see Fig. 5-4). he morphological and functional properties of the spiral arter­ ies are unique and essential to blood flow changes seen during menstruation or implantation. During endometrial growth, spiral arteries lengthen at a rate appreciably greater than the rate of endometrial tissue thickening. his growth discordance obliges even greater coiling. Spiral artery development relects a marked induction of angiogenesis, with widespread vessel sprouting and extension. Such rapid angiogenesis is regulated, in part, through estrogen- and progesterone-regulated synthesis of VEGF (Ancelin, 2002; Chennazhi, 2009) . Menstru ati on

The midluteal-secretory phase of the endometrial cycle is a critical branch point in endometrial development and diferen­ tiation. With corpus luteum rescue and continued progesterone secretion, the endometrium is transformed into the decidua. With luteolysis and declining luteal progesterone production, events leading to menstruation are initiated (Critchley, 2006; Thiruchelvam, 20 1 3) . In the late premenstrual-phase endometrium, the stroma is invaded by neutrophils to create a pseudo inflammatory appear­ ance. These cells iniltrate primarily on the day or two imme­ diately preceding menses onset. he endometrial stromal and epithelial cells produce interleukin-8 (IL-8), a chemotactic-acti­ vating factor for neutrophils (Arici, 1 993) . Similarly, monocyte chemotactic protein- 1 (MCP- 1 ) is synthesized by endometrium and promotes monocyte recruitment (Arici, 1 995). Leukocyte iniltration is considered key to both endometrial extracellular matrix breakdown and repair of the functionalis layer. The term "inflammatory tightrope" refers to the ability of macrophages to assume phenotypes that vary from proin­ flammatory and phagocytic to immunosuppressive and repara­ tive. These are likely relevant to menstruation, in which tissue breakdown and restoration occur simultaneously (Evans, 20 1 2; Maybin, 20 1 5) . Invading leukocytes secrete enzymes that are members of the matrix metalloprotease (MMP) family. These add to the proteases already produced by endometrial stromal cells and efectively initiate matrix degradation. During menses as tissue shedding is completed, microenvironment-regulated changes in macrophage phenotype then promote repair and resolution (Evans, 20 1 2; Thiruchelvam, 20 1 3) . The classic study b y Markee ( 1 940) described tissue and vascular alterations in endometrium before menstruation. With endometrial regression, spiral artery coiling becomes suiciently severe that resistance to blood fl o w rises to cause endometrial hypoxia. Resultant stasis is the primary cause of endometrial ischemia and tissue degeneration. Intense spiral artery vasoconstriction precedes menstruation and also serves to limit menstrual blood loss. Prostaglandins play a key role in the events leading to men­ struation that include vasoconstriction, myometrial contractions, and upregulation of proinflammatory responses (Abel, 2002) .

Large amounts of prostaglandins are present in menstrual blood. Painful menstruation is common and likely caused by myome­ trial contractions and uterine ischemia. This response is believed to be mediated by prostaglandin F 2a (PGF2a)-induced spiral artery vasoconstriction, which render the uppermost endo­ metrial zones hypoxic. The hypoxic environment is a potent inducer of angiogenesis and vascular permeability factors such as VEGF. Progesterone withdrawal increases expression of cyclooxy­ genase 2 (COX-2) , also called prostaglandin synthase 2, to synthesize prostaglandins. Withdrawal also lowers expression of 1 5-hydroxyprostaglandin dehydrogenase (PGDH) , which degrades prostaglandins (Casey, 1 980, 1 989). The net result is higher prostaglandin production by endometrial stromal cells and greater prostaglandin-receptor density on blood vessels and surrounding cells. Actual menstrual bleeding follows rupture of spiral arteri­ oles and consequent hematoma formation. With a hematoma, the superficial endometrium is distended and ruptures. S ubse­ quently, fissures develop in the adjacent functionalis layer, and blood and tissue fragments are sloughed. Hemorrhage stops with arteriolar constriction. Changes that accompany partial tissue necrosis also serve to seal vessel tips. he endometrial surface is restored by growth of langes, or collars, that form the everted free ends of the endometrial glands (Markee, 1 940) . These flanges rapidly grow in diameter, and epithelial continuity is reestablished by fusion of the edges of these sheets of migrating cells.

DECIDUA his is a specialized, highly modiied endometrium of preg­ nancy. It is essential for hemochorialplacentation, that is, o ne in which maternal blood contacts trophoblasts. This relationship requires trophoblast invasion, and considerable research has focused on the interaction between decidual cells and invading trophoblasts. Decidualization, that is, transformation of pro­ liferating endometrial stromal cells into specialized secretory cells, is dependent on estrogen, progesterone, androgens, and factors secreted by the implanting blastocyst (Gibson, 2 0 1 6) . The decidua produces factors that regulate endometrial recep­ tivity and modulate immune and vascular cell functions within the maternal-fetal microenvironment. The special relationship existing between the decidua and the invading trophoblasts ensures success of the pregnancy semiallograft yet seemingly deies the laws of transplantation immunology. • Decidual Structure

The decidua is classiied into three parts based on anatomical location. Decidua directly beneath blastocyst implantation is modiied by trophoblast invasion and becomes the decidua basalis. The decidua capsularis overlies the enlarging blasto­ cyst and initially separates the conceptus from the rest of the uterine cavity (Fig. 5-5) . This portion is most prominent dur­ ing the second month of pregnancy and consists of stromal decidual cells covered by a single layer of lattened epithelial cells. Internally, it contacts the avascular, extraembryonic fetal

85

86

P l ace ntat i o n , E m b ryogenesis, a n d Feta l Development

parietal is Decidua basalis ---.f

Chorionic villi

cavity Cervical canal

FIGURE 5-5 Th ree portions of the decidua-the basa l is, capsu­ l a ri s, and pa rieta l is-are i l l ustrated . membrane-the chorion laeve. he remainder of the uterus is lined by decidua parietalis. During early pregnancy, there is a space between the decidua capsularis and parietalis because the gestational sac does not fill the entire uterine cavity. The gesta­ tion sac is the extraembryonic coelom and also called the cho­ rionic cavity. By 1 4 to 1 6 weeks' gestation, the expanding sac has enlarged to completely ill the uterine cavity. The resulting apposition of the decidua capsularis and parietalis creates the decidua vera, and the uterine cavity is functionally obliterated. In early pregnancy, the decidua begins to thicken, eventu­ ally attaining a depth of 5 to 1 0 mm. With magnification, fur­ rows and numerous small openings, representing the mouths of uterine glands, can be detected. Later in pregnancy, the decidua becomes thinner, presumably because of pressure exerted by the expanding uterine contents. he decidua parietalis and basalis are composed of three layers. here is a surface or compact zone-zona compacta; a middle portion or spongy zone-zona spongiosa-with rem­ nants of glands and numerous small blood vessels; and a basal zone-zona basalis. The zona compacta and spongiosa together form the zona functionalis. The basal zone remains after delivery and gives rise to new endometrium. In human pregnancy, the decidual reaction is completed only with blastocyst implantation. Predecidual changes, how­ ever, commence irst during the midluteal phase in endome­ trial stromal cells adjacent to the spiral arteries and arterioles. hereafter, they spread in waves throughout the uterine endo­ metrium and then from the implantation site. The endometrial stromal cells enlarge to form polygonal or round decidual cells. he nuclei become vesicular, and the cytoplasm becomes clear, slightly basophilic, and surrounded by a translucent membrane. As a consequence of implantation, the blood supply to the decidua capsularis is lost as the embryo-fetus grows. Blood supply to the decidua parietalis through spiral arteries persists. These arteries retain a smooth-muscle wall and endothelium and thereby remain responsive to vasoactive agents. In contrast, the spiral arterial system that supplies the decidua basalis and ultimately the placental intervillous space is altered remarkably. These spiral arterioles and arteries are

invaded by trophoblasts, and during this process, the vessel walls in the basalis are destroyed. Only a shell without smooth muscle or endothelial cells remains. Importantly, as a result, these vascular conduits of maternal blood-which become the uteroplacental vessels-are unresponsive to vasoactive agents. Conversely, the fetal chorionic vessels, which transport blood between the placenta and the fetus, contain smooth muscle and thus do respond to vasoactive agents. • Decidual Histology

Early in pregnancy, the zona spongiosa of the decidua consists of large distended glands, often exhibiting marked hyperplasia and separated by minimal stroma. At first, the glands are lined by typical cylindrical uterine epithelium with abundant secre­ tory activity that contributes to blastocyst nourishment. With advanced pregnancy, the glandular elements largely disappear. he decidua basalis contributes to formation of the pla­ cental basal plate (Fig. 5-6) . he spongy zone of the decidua basalis consists mainly of arteries and widely dilated veins, and by term, glands have virtually disappeared. Also, the decidua basalis is invaded by many interstitial trophoblasts and tropho­ blastic giant cells. Although most abundant in the decidua, the giant cells commonly penetrate the upper myometrium. Their number and invasiveness can be so extensive as to resemble choriocarcinoma. The Nitabuch layer is a zone of fibrinoid degeneration in which invading trophoblasts meet the decidua basalis. If the

Decidua

FIGU RE 5-6 Section thro u g h a j u n ction of chorion, vi l l i, and decid ua basa lis i n early first-trimester p reg n a ncy. (Used with permission from Dr. Kurt Ben i rsc h ke.)

I m p la ntation a n d P l acenta l Develop ment

decidua is defective, as in placenta accreta, the Nitabuch layer is usually absent (Chap. 4 1 , p. 778) . here is also a more super­ icial, but inconsistent, deposition of ibrin-Rohr stria-at the bottom of the intervillous space and surrounding the anchoring villi. Decidual necrosis is a normal phenomenon in the irst and probably second trimesters (McCombs, 1 964) . hus, necrotic decidua obtained through curettage after spontaneous abortion in the irst trimester should not necessarily be interpreted as either a cause or an efect of the pregnancy loss. Both decidua types contain numerous cell groups whose composition varies with gestational stage (Loke, 1 995) . he primary cellular components are the true decidual cells, which diferentiated from the endometrial stromal cells, and numer­ ous maternal bone marrow-derived cells. Accumulation of lym­ phocytes with unique properties at the maternal-fetal interface is essential to evoke tolerance mechanisms that prevent mater­ nal immune rejection of the fetus. These include regulatolY T cells, decidual macrophages, and decidual natural killer cells. Collectively, these cells not only provide immunotolerance but also play an important role in trophoblast invasion and vascu­ logenesis (PrabhuDas, 20 1 5) . • Decidual Prolactin

In addition to placental development, the decidua potentially provides other functions. The decidua is the source of prolac­ tin, which is present in enormous amounts in amnionic luid (Colander, 1 978; Riddick, 1 979) . Decidual prolactin is a prod­ uct of the same gene that encodes for anterior pituitary pro­ lactin, but the exact physiological role of decidual prolactin is unknown. Notably, decidual prolactin is not to be confused with placental lactogen (hPL) , which is produced only by syn­ cytiotrophoblast. Prolactin preferentially enters amnionic luid, and little enters maternal blood. Consequently, prolactin levels in amni­ onic luid are extraordinarily high and may reach 1 0,000 ng/mL at 20 to 24 weeks' gestation (Tyson, 1 972) . This compares with fetal serum levels of 350 ng/mL and maternal serum levels of 1 50 to 200 ngl mL. As a result, decidual prolactin is a clas­ sic example of paracrine function between maternal and fetal tissues.

mother and for maternal immunological acceptance of the con­ ceptus (Cuzeloglu-Kayisli, 2009) . • Fertilization

With ovulation, the secondary oocyte and adhered cells of the cumulus-oocyte complex are freed from the ovary. Although technically this mass of cells is released into the peritoneal cav­ ity, the oocyte is quickly engulfed by the fallopian tube infun­ dibulum. Further transport through the tube is accomplished by directional movement of cilia and tubal peristalsis. Fertiliza­ tion, which normally occurs in the oviduct, must take place within a few hours, and no more than a day after ovulation. Because of this narrow window, spermatozoa must be p resent in the fallopian tube at the time of oocyte arrival. Almost all pregnancies result when intercourse occurs during the 2 days preceding or on the day of ovulation. Fertilization is highly complex. Molecular mechanisms allow spermatozoa to pass between follicular cells; through the zona pellucida, which is a thick glycoprotein layer surrounding the oocyte cell membrane; and into the oocyte cytoplasm. F usion of the two nuclei and intermingling of maternal and paternal chromosomes creates the zygote. Early human development is described by days or weeks postfertilization, that is, postconceptional. By contrast, in most chapters of this book, clinical pregnancy dating is calculated from the irst day of the last menstrual period (LMP) . hus, 1 week postfertilization corresponds to approximately 3 weeks from the LMP in women with regular 28-day cycles. As an example, 8 weeks' gestation refers to 8 completed weeks fol­ lowing the LMP. After fertilization, the zygote-a diploid cell with 46 chro­ mosomes-undergoes cleavage, and zygote cells produced by this division are called blastomeres (Fig. 5-7) . In the two-cell

IMPLANTATION AND EARLY TROPHOBLAST FORMATION The ferus is dependent on the placenta for pulmonary, hepatic, and renal functions. These are accomplished through the ana­ tomical relationship of the placenta and its uterine interface. In overview, maternal blood spurts from uteroplacental vessels into the placental intervillous space and bathes the outer syn­ cytiotrophoblast. his allows exchange of gases, nutrients, and other substances with fetal capillary blood within the core of each villus. hus, fetal and maternal blood does not normally mix in this hemochorial placenta. A paracrine system also links mother and ferus through the anatomical and biochemical jux­ taposition of the maternal decidua parietalis and the extraem­ bryonic chorion laeve, which is fetal. This is an extraordinarily important arrangement for communication between fetus and

1 6-cel l stage ( Moru la)

Blastocyst

I n n e r cell mass Blastocyst cavity Trophoblast

FIGURE 5-7 Zyg ote cleavage a nd blastocyst formation. The moru la period beg i ns at the 1 2- to 1 6-cell stage and ends when the blastocyst forms, which occu rs when there a re 50 to 60 b las­ tomeres present. The p o l a r bod ies, shown i n the 2-ce l l stage, a re s m a l l nonfu nction a l cel l s that soon degenerate.

87

88

P lacentation, E m b ryogen esis, a n d Feta l Devel opment

zygote, the blastomeres and polar body continue to be sur­ rounded by the zona pellucida. he zygote undergoes slow cleavage for 3 days while still remaining in the fallopian tube. As the blastomeres continue to divide, a solid mulberry-like ball of cells-the morula-is produced. The morula enters the uterine cavity approximately 3 days after fertilization. Gradual accumulation of luid beween the morula cells leads to forma­ tion of the early blastocyst. • Blastocyst

As early as 4 to 5 days after fertilization, the 5 8-cell blastula diferentiates into ive embryo-producing cells-the inner cel mass (see Fig. 5-7) . he remaining 53 outer cells, called the trophectoderm, are destined to form trophoblasts (Hertig, 1 962) . Interestingly, the 1 07 -cell blastocyst is found to be no larger than the earlier cleavage stages, despite the accumulated fluid within the blastocyst cavity. At this stage, the eight formative, embryo-producing cells are surrounded by 99 trophoblastic cells. And, the blastocyst is released from the zona pellucida secondary to secretion of specific proteases from the secretory­ phase endometrial glands (O'Sullivan, 2002) . Release from the zona pellucida allows blastocyst-produced cytokines and hormones to directly influence endometrial receptivity (Lindhard, 2002) . IL- l a and I L- l j are secreted by the blastocyst, and these cytokines likely directly influence the endometrium. Embryos also have been shown to secrete hCG, which may influence endometrial receptivity (Licht, 200 1 ; Lobo, 200 1 ) . The receptive endometrium i s thought to respond by producing leukemia inhibitoY factor (LIF), follistatin, and colony-stimulating factor- l (CSF- l ) . LIF and follistatin acti­ vate signaling pathways that collectively inhibit proliferation and promote diferentiation of the endometrial epithelia and stroma to enable uterine receptivity (Rosario, 20 1 6b) . At the maternal-fetal interface, CSF- 1 has proposed immunomodu­ latory actions and pro angiogenic actions that are required for implantation (Rahmati, 20 1 5) . • Implantation

Six or 7 days after fertilization, the blastocyst implants into the uterine wall. This process can be divided into three phases: ( 1 ) apposition-initial contact o f the blastocyst t o the uterine wall; (2) adhesion-increased physical contact between the blasto­ cyst and decidua; and (3) invasion-penetration and invasion of syncytiotrophoblast and cytotrophoblasts into the decidua, inner third of the myometrium, and uterine vasculature. Successful implantation requires a receptive endometrium appropriately primed with estrogen and progesterone by the corpus luteum. Such uterine receptivity is limited to days 20 to 24 of the cycle. Adherence is mediated by cell-surface receptors at the implantation site that interact with blastocyst receptors (Carson, 2002; Lessey, 2002; Lindhard, 2002) . If the blastocyst approaches the endometrium after cycle day 24, the potential for adhesion is diminished because antiadhesive glycoprotein synthesis prevents receptor interactions (N avot, 1 99 1 ) . At the time o f its interaction with the endometrium, the blastocyst is composed of 1 00 to 250 cells. The blastocyst

loosely adheres to the decidua by apposition. This most com­ monly occurs on the upper posterior uterine wall. Attachment of the blastocyst trophectoderm to the decidual surface by apposition and adherence appears to be closely regulated by paracrine interactions between these two tissues. Successful endometrial blastocyst adhesion involves modi­ ication in expression of cellular adhesion molecules (CMs) . The integrins-one of four families of CAMs-are cell-surface receptors that mediate cell adhesion to extracellular matrix proteins (Lessey, 2002) . Endometrial integrins are hormonally regulated, and a specific set of integrins is expressed at implan­ tation (Lessey, 1 995). Recognition-site blockade of integrins needed for binding will prevent blastocyst attachment (Kaneko, 20 1 3) . • Trophoblast Development

Human placental formation begins with the trophectoderm, which gives rise to a trophoblast cell layer encircling the blas­ tocyst. From then until term, trophoblasts play a critical part at the fetal-maternal interface. Trophoblasts exhibit the most vari­ able structure, function, and developmental pattern of all pla­ cental components. Their invasiveness promotes implantation, their nutritional role for the conceptus is relected in their name, and their endocrine organ function is essential to maternal phys­ iological adaptations and to pregnancy maintenance. By the eighth day postfertilization, after initial implantation, trophoblasts have diferentiated into an outer multinucleated syncytium-primitive syncytiotrophoblast, and an inner layer of primitive mononuclear cells-cytotrophoblasts. The latter are germinal cells for the syncytium. As cytotrophoblasts prolifer­ ate, their cell walls disappear, and the cells fuse to add to the expanding outer layer of syncytiotrophoblast. Each cytotro­ phoblast has a well-demarcated cell border, a single nucleus, and ability to undergo DNA synthesis and mitosis (Arnholdt, 1 99 1 ) . These are lacking in the syncytiotrophoblast, which pro­ vides transport functions of the placenta. It is so named because instead of individual cells, it has an amorphous cytoplasm with­ out cell borders, nuclei that are multiple and diverse in size and shape, and a continuous syncytial lining. This coniguration aids transport. After implantation is complete, trophoblasts further dif­ ferentiate along two main pathways, giving rise to villous and extravillous trophoblasts. As shown in Figure 5-8, both have distinct functions (Loke, 1 995). Villous trophoblasts generate chorionic villi, which primarily transport oxygen, nutri­ ents, and other compounds between the fetus and mother. Extravillous trophoblasts migrate into the decidua and myo­ metrium and also penetrate maternal vasculature, thus com­ ing into contact with various maternal cell types (Pijnenborg, 1 994) . Extravillous trophoblasts are further classiied as inter­ stitial trophoblasts and endovascular trophoblasts. he intersti­ tial trophoblasts invade the decidua and eventually penetrate the myometrium to form placental-bed giant cells. These trophoblasts also surround spiral arteries. The endovascular trophoblasts penetrate the spiral artery lumens (Pijnenborg, 1 983) . hese are both discussed in greater detail in subse­ quent sections.

I m p l a ntation a n d Placenta l Deve l o p ment

Anchoring villus

Syncytiotrophoblast Cytotrophoblast Extravi l lous trophoblasts Endothelium

�

�"

I nterstitial extravillous trophoblast Endovascu lar extravillous trophoblast

� �

o l

-

Decidua

-j .. " .

basalis

-

Spiral artery ---1

Myometri u m

M idgestation

End of 1 st

Early

3rd tri mester

trimester

pregnancy

FIGURE 5-8 Extravi l lous trophoblasts a re found outside the vi l l u s a n d ca n be su bd ivided into endovascular a n d interstitia l categories. Endovasc u l a r trophoblasts i nvade and tra n sform spira l a rteries d u ri n g preg nancy to create low-resi sta nce blood flow that i s c h a racteri stic of the placenta. I nterstitial trophoblasts i nvade the decidua and s u rro u n d spiral a rteries. • Early I nvasion

After gentle erosion between epithelial cells of the surface endo­ metrium, invading trophoblasts burrow deeper. At 9 days of development, the blastocyst wall facing the uterine lumen is a single layer of lattened cells. By the 1 0th day, the blastocyst becomes totally encased within the endometrium (Fig. 5-9) . he blastocyst wall opposite the uterine lumen is thicker and com­ prises two zones-the trophoblasts and the embryo-forming inner cell mass. As early as 7Y2 days postfertilization, the inner cell mass or embryonic disc diferentiates into a thick plate of primitive ectoderm and an underlying layer of endoderm. Some small cells appear between the embryonic disc and the tropho­ blasts and enclose a space that will become the amnionic cavity.

Extraembryonic mesenchyme first appears as groups of isolated cells within the blastocyst cavity, and later this meso­ derm completely lines the cavity. Spaces form and then fuse within the extraembryonic mesoderm to form the cho rionic cavity (extraembryonic coelom) . The chorion is composed of trophoblasts and mesenchyme. Some mesenchymal cells even­ tually will condense to form the body stalk. his stalk joins the embryo to the nutrient chorion and later develops into the umbilical cord. The body stalk can be recognized at an early stage at the caudal end of the embryonic disc (Fig. 7-3, p. 1 26) . As the embryo enlarges, more maternal decidua basalis is invaded by syncytiotrophoblast. Beginning approximately 1 2 days after conception, the syncytiotrophoblast is permeated

Spiral artery Maternal blood

Lacunar network Amnionic cavity

Lacunar network Syncytiotrophoblast Amnion

E m bryonic disc E xtraembryon ic e ndoderm

Extraem bryonic mesoderm

A

Primitive yolk sac

B

FIGURE 5-9 Drawi ng of sections thro u g h i m p l a nted blastocysts. A. At 1 0 days. B. At 1 2 days ater ferti l ization. This stage i s cha racterized by the i ntercom m u n ication of the lacu nae fi l led with maternal blood. Note in (B) that l a rge cavities have appeared in the extraem bryon i c mesoderm, forming t h e beg i n n i n g o f t h e extraembryon ic coelom. A l s o note that extraem bryon ic endoderm a l cells h a v e beg u n t o for m on t h e i nside o f t h e prim itive yol k sac. (Red rawn from Moore KL, Persaud, W, Torchia, MG (ed s): The Developing H u m a n. C l i n ica l l y Oriented Embryology, 9th edition, P h i ladelphia, Sa u nders, 201 3.)

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by a system of intercommunicating channels called trophoblas­ tic lacunae. After invasion of supericial decidual capillary walls, lacunae become filled with maternal blood. At the same time, the decidual reaction intensifies in the surrounding stroma. This is characterized by decidual stromal cell enlargement and glycogen storage. • Chorionic Villi

With deeper blastocyst invasion into the decidua, solid primary villi arise from buds of cytotrophoblasts that protrude into the primitive syncytium before 1 2 days postfertilization. Primary villi are composed of a cytotrophoblast core covered by syncytiotro­ phoblast. s the lacunae join, a complicated labyrinth is formed that is partitioned by these solid cytotrophoblastic columns. The trophoblast-lined channels form the intervillous space, and the solid cellular columns form the primay villous stalks. Beginning on approximately the 1 2th day after fertilization, mesenchymal cords derived from extraembryonic mesoderm invade the solid trophoblast columns. These form seconday villi. Once angiogenesis begins in the mesenchymal cords, ter­ tiay villi are formed. Although maternal venous sinuses are tapped early in implantation, maternal arterial blood does not enter the intervillous space until around day 1 5 . By approxi­ mately the 1 7th day, however, fetal blood vessels are functional, and a placental circulation is established. The fetal-placental circulation is completed when the blood vessels of the embryo are connected with chorionic vessels. In some villi, angiogen­ esis fails from lack of circulation. They can be seen normally, but the most striking exaggeration of this process is seen with hydatidiform mole (Fig. 20- 1 , p. 389) . Villi are covered by an outer layer of syncytiotrophoblast and an inner layer of cytotrophoblasts, which are also known as Langhans cels. Cytotrophoblast proliferation at the villous tips produces the trophoblastic cell columns that form anchoring villi. hey are not invaded by fetal mesenchyme, and they are anchored to the decidua at the basal plate. Thus, the base of the intervillous space faces the maternal side and consists of cyto­ trophoblasts from cell columns, the covering shell of syncytio­ trophoblast, and maternal decidua of the basal plate. The base of the chorionic plate forms the roof of the intervillous space. It consists of two layers of trophoblasts externally and fibrous mesoderm internally. The "deinitive" chorionic plate is formed by 8 to 1 0 weeks as the amnionic and primary chorionic plate mesenchyme fuse together. This formation is accomplished by expansion of the amnionic sac, which also surrounds the con­ nective stalk and the allantois and joins these structures to form the umbilical cord (Kaufmann, 1 992) . Interpretation of the ine structure of the placenta came from electron microscopic studies of Wislocki and Dempsey ( 1 9 5 5 ) . There are prominent microvilli on the syncytial sur­ face that correspond to the so-called brush border described by light microscopy. Associated pinocytotic vacuoles and vesicles are related to absorptive and secretory placental functions. Microvilli act to increase surface area in direct contact with maternal blood. This contact between the trophoblast and maternal blood is the deining characteristic of a hemochorial placenta (Fig. 5- 1 0) .

Intervillous space

FIGURE 5-1 0 Electron m icrog ra ph of term h u m a n placenta v i l l u s. A vi l l us ca p i l l a ry fi l led with fetal red blood cel l s (asterisks) is seen i n close proxim ity t o the microvi l l i border. (Reprod uced with permis­ sion from Boyd J D, H a m i lton WJ: The H u m a n Placenta. Cam bridge, Heffer, 1 970.) PLACENTA AND CHORION

• Chorion Development

In early pregnancy, the villi are distributed over the entire periphery of the chorionic membrane (Fig. 5- 1 1 ) . As the blasto­ cyst with its surrounding trophoblasts grows and expands into the decidua, one pole faces the endometrial cavity. he opposite pole will form the placenta. Here, chorionic villi in contact with the decidua basalis proliferate to form the chorion rondosum­ or leay chorion. As growth of embryonic and extraembryonic tissues continues, the blood supply to the chorion facing the endometrial cavity is restricted. Because of this, villi in contact with the decidua capsularis cease to grow and then degenerate. his portion of the chorion becomes the avascular fetal mem­ brane that abuts the decidua parietalis and is called the chorion laeve-or smooth chorion. This smooth chorion is composed of cytotrophoblasts and fetal mesodermal mesenchyme. Until near the end of the third month, the chorion laeve is separated from the amnion by the exocoelomic cavity. hereater, they are in intimate contact to form an avascular amniochorion. These two structures are important sites of molecular transfer and metabolic activity. Moreover, they constitute an important para­ crine arm of the fetal-maternal communication system. • Regulators of Trophoblast I nvasion

Implantation and endometrial decidualization activate a unique population of maternal immune cells that iniltrate the uterus

I m pla ntati o n a n d Placental Develop m ent

for approximately 20 percent of leukocytes in the first trimes­ ter and elicit an M2-immunomodulatory phenotype (Williams, 2009). Remember, M1 macrophages are pro inflammatory, and M2 macrophages counter proinflammatory responses and promote tissue repair. In addition to a role in angiogenesis and spiral artery remodeling, dNK cells promote phagocytosis of cell debris (Faas, 20 1 7). Concurrent with the critical role of maternal dNK cells and macrophages, T cell subsets aid tolerance toward the allogenic fetus. Regulatory T cells (Tregs) are essential for promoting immune toler­ ance. Other T cell subsets are present, such s Th 1 , Th2 and Th 1 7, although their unctions are tightly regulated (Ruocco, 20 14) . • Endometrial Invasion

B FIGURE 5-1 1 Com plete abortion specimens. A. I n itial ly, the entire chorionic sac is covered with vi l l i, a nd the embryo wit h i n is not visible B. With fu rth e r g rowth, stretch a nd pressu re p rom pt pa rtial reg ression of the villi. Remai n i ng vi l l i form the future placenta, whereas the smooth portion i s the chorion. and play critical functions in trophoblast invasion, angiogenesis, spiral artery remodeling, and maternal tolerance to fetal alloan­ tigens. Decidual natural killer cells (dNK) make up 70 percent of decidual leukocytes in the fi r st trimester and are found in direct contact with trophoblasts. In contrast to natural killer cells in peripheral blood, these cells lack cytotoxic functions. They produce specifi c cytokines and angiogenic factors to regu­ late invasion of fetal trophoblasts and spiral artery remodeling (Hanna, 2006) . hese and other unique properties distinguish dNK cells from circulating natural killer cells and from natural killer cells in the endometrium before pregnancy (Fu, 20 1 3 ; Winger, 20 1 3) . dNK cells express both IL-8 and interferon­ inducible protein- 1 0, which bind to receptors on invasive tro­ phoblastic cells to promote their decidual invasion toward the spiral arteries. dNK cells also produce proangiogenic factors, including VEGF and placental growth factor (PIGF), which both promote vascular growth in the decidua. Trophoblasts also secrete speciic chemokines that attract the dNK cells to the maternl-fetal interface. hus, both cell types simultaneously attract each other. Decidual macro phages account

Extravillous trophoblasts of the first-trimester placenta are highly invasive. his process occurs under low-oxygen conditions, and regulatory factors that are induced under hypoxic conditions are contributory (Soares, 20 1 2) . Invasive trophoblasts secrete numer­ ous proteolytic enzymes that digest extracellular matrix and acti­ vate proteinases already present in the decidua. Trophoblasts produce urokinase-type plasminogen activator, which converts plasminogen into the broadly acting serine protease, plasmin. This in turn both degrades matrix proteins and activates M.1Ps. One member of the MMP family, MMP-9, appears to be criti­ cal. The timing and extent of trophoblast invasion is regulated by a balanced interplay between pro- and antiinvasive factors. he relative ability to invade maternal tissue in early preg­ nancy compared with limited invasiveness in late pregnancy is controlled by autocrine and paracrine trophoblastic and decid­ ual factors. Trophoblasts secrete insulin-like growth factor II that promotes invasion into the decidua. Decidual cells secrete insulin-like growth factor binding-protein type 4, which blocks this autocrine loop. Low estradiol levels in the irst trimester are critical for tropho­ blast invasion and remodeling of the spiral arteries. nimal studies suggest that the rise in second-trimester estradiol levels suppresses and limits vessel remodeling by reducing trophoblast expression of VEGF and speciic integrin receptors (Bonagura, 20 1 2) . Namely, extravillous trophoblasts express integrin receptors that recognize the extracellular matrix proteins collagen IV, laminin, and ibro­ nectin. Binding of these matrix proteins and integrin receptors initiates signls to promote trophoblast cell migration and dif­ ferentiation. However, as pregnancy advances, rising estradiol levels downregulate VEGF and integrin receptor expression. This represses and controls the extent of uterine vessel transformation. • Spiral Artery Invasion

One of the most remarkable features of human placental devel­ opment is the extensive modification of maternal vasculature by trophoblasts, which are by defi n ition of fetal origin. These events occur in the first half of pregnancy and are considered in detail because of their importance to uteroplacental blood flow. They are also integral to some pathological conditions such as preeclampsia, fetal-growth restriction, and preterm birth. Spi­ ral artery modiications are carried out by two populations of extravillous trophoblasts-endovascular trophoblasts, which penetrate the spiral-artery lumen, and interstitial trophoblasts, which surround the arteries (see Fig. 5-8 ) .

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Interstitial trophoblasts constitute a major portion of the placental bed. They penetrate the decidua and adjacent myo­ metrium and aggregate around spiral arteries. Although less defined, their functions may include vessel preparation for endovascular trophoblast invasion. Endovascular trophoblasts irst enter the spiral artery lumens and initially form cellular plugs. They then destroy vascular endo­ thelium via an apoptosis mechanism and invade and modiy the vascular media. hus, fibrinoid material replaces smooth muscle and connective tissue of the vessel media. Spiral arteries later regenerate endothelium. Invading endovascular trophoblasts can extend several centimeters along the vessel lumen, and they must migrate against arterial flow. Of note, invasion by trophoblasts involves only the decidual spiral arteries and not decidual veins. Uteroplacental vessel development proceeds in two waves or stages (Ramsey, 1 980) . The irst occurs before 1 2 weeks' postfertilization, and spiral arteries are invaded and modiied up to the border between the decidua and myometrium. he second wave, between 1 2 and 1 6 weeks, involves some invasion of the intramyometrial segments of spiral arteries. Remodeling

converts narrow-lumen, muscular spiral arteries into dilated, low-resistance uteroplacental vessels. Molecular mechanisms of these crucial events, their regulation by cytokines, signaling pathways, and their significance in the pathogenesis of pre­ eclampsia and fetal-growth restriction has been reviewed by sev­ eral authors (Pereira de Sousa, 20 1 7; ie, 20 1 6; Zhang, 20 1 6) . Approximately 1 month after conception, maternal blood enters the intervillous space in fountain-like bursts from the spiral arteries. Blood is propelled outside of the maternal vessels and sweeps over and directly bathes the syncytiotrophoblast. • Villus Branching

Although certain villi of the chorion frondosum extend from the chorionic plate to the decidua to serve as anchoring villi, most villi arborize and end freely within the intervillous space. s gestation proceeds, the short, thick, early stem villi branch to form progressively iner subdivisions and greater numbers of increasingly smaller villi (Fig. 5- 1 2) . Each of the truncal or main stem villi and their ramiications constitutes a placental

F I G U R E 5-1 2 Electron micrographs (A, C) and photo m icrog ra phs (B, D) of early and late h u m a n placentas. A and B. Limited branching of villi is seen in this ea rly placenta. C and D. With placenta l maturation, i ncreasing vi l lous a rborization is seen, and villous ca pilla ries lie closer to the su rface of each vi l l us. (Photomicrogra phs u sed with permi ssion from Dr. Kurt Ben i rschke. Electron m icrog ra phs reproduced with permission from Ki ng BF, Menton DN: Sca nn i ng electron m icroscopy of h u m a n placenta l vi lli from early and late in gestation. Am J Obstet Gynecol 1 22:824, 1 975.)

I m p la ntati o n a n d Placental Deve l o p m ent

lobule, or cotyledon. Each lobule is supplied with a single cho­ rionic artery. And each lobule has a single vein, so that lobules constitute the functional units of placental architecture. • Placental Growth and Maturation

In the irst trimester, placental growth is more rapid than that of the fetus. But by approximately 1 7 weeks' gestation, placen­ tal and fetal weights are approximately equal. By term, placen­ tal weight is approximately one sixth of fetal weight. he mature placenta and its variant forms are discussed in detail in Chapter 6 (p. 1 1 2) . Briely, viewed from the mater­ nal surface, the number of slightly elevated convex areas, called lobes, varies from 1 0 to 38. Lobes are incompletely separated by grooves of variable depth that overlie placental septa, which arise as upward projections of decidua. he total number of placental lobes remains the same throughout gestation, and individual lobes continue to grow-although less actively in the inal weeks (Crawford, 1 959). Although grossly visible lobes are commonly referred to as cotyledons, this is not accurate. Correctly used, lobules or cotyledons are the functional units supplied by each main stem villus. As villi continue to branch and the terminal ramiications become more numerous and smaller, the volume and promi­ nence of cytotrophoblasts decrease. As the syncytium thins, the fetal vessels become more prominent and lie closer to the sur­ face (see Fig. 5- 1 0) . he villous stroma also exhibits changes as gestation progresses. In early pregnancy, the branching connec­ tive-tissue cells are separated by an abundant loose intercellular matrix. Later, the villous stroma becomes denser, and the cells are more spindly and closely packed. Another change in the stroma involves the iniltration of Hobauer cels, which are fetal macrophages. hese are nearly round with vesicular, often eccentric nuclei and very granular or vacuolated cytoplasm. hey grow in number and matura­ tional state throughout pregnancy and appear to be important mediators of protection at the maternal-fetal interface Qohn­ son, 20 1 2) . These macrophages are phagocytic, have an immu­ nosuppressive phenotype, can produce various cytokines, and are capable of paracrine regulation of trophoblastic functions (Cervar, 1 999; Reyes, 20 1 7) . As discussed further in Chapter 64 (p. 1 2 1 9) , recent studies suggest that Zika virus can infect Hofbauer cells to allow fetal transmission (Simoni, 20 1 7) . Some o f the histological changes that accompany placental growth and maturation improve transport and exchange to meet advancing fetal metabolic requirements. Among these changes are a thinner syncytiotrophoblst, signiicantly reduced cytotropho­ blast number, decreased stroma, and increased number of capil­ laries with close approximation to the syncytial surface. By 1 6 weeks' gestation, the apparent continuity o f the cytotrophoblasts is lost. At term, villi may be focally reduced to a thin layer of syn­ cytium covering minimal villous connective tissue in which thin­ walled fetal capillaries abut the trophoblast and dominate the villi. There are some changes in placental architecture that can cause decreased placental exchange eiciency if they are sub­ stantive. These include thickening of the basal lamina of tropho­ blast or capillaries, obliteration of certain fetal vessels, greater villous stroma, and ibrin deposition on the villous surface.

Myometriu m -..:;-

\

Chorion --:U Amnion -W

Decidua basalis Placenta

\. -

-

FIGURE 5-1 3 Uterus showing a normal place nta a nd its mem­ b ra nes i n situ.

• Placental Circulation

Because the placenta is functionally an intimate approximation of the fetal capillary bed to maternal blood, its gross anatomy primarily concerns vascular relations. he fetal surface is cov­ ered by the transparent amnion, beneath which chorionic ves­ sels course. A section through the placenta includes amnion, chorion, chorionic villi and intervillous space, decidual (basal) plate, and myometrium (Figs. 5- 1 3 and 5- 1 4) .

FIGURE 5-1 4 P h otomicrog ra ph of ea rly i m p l a nted bla stocyst. Trophoblasts a re seen i nvad i ng the decidua basal is. eNS ce ntra l nervous system. (Used with perm ission from D r. Kurt Ben i rsch ke.) =

93

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Place ntation, E m bryogenesis, a n d Feta l Deve l o p m e nt

Feta l Ci rcu lation

Deoxygenated venous-like fetal blood flows to the placenta through the two umbilical arteries. As the cord joins the pla­ centa, these umbilical vessels branch repeatedly beneath the amnion as they run across the chorionic plate. Branching con­ tinues within the villi to ultimately form capillary networks in the terminal villous branches. Blood with signiicantly higher oxygen content returns from the placenta via a single umbilical vein to the fetus. The branches of the umbilical vessels that traverse along the fetal surface of the placenta in the chorionic plate are referred to as the placental surface or chorionic vessels. These vessels are responsive to vasoactive substances, but anatomically, mor­ phologically, histologically, and functionally, they are unique. Chorionic arteries always cross over chorionic veins. Vessels are most readily recognized by this interesting relationship, but they are diicult to distinguish by histological criteria. Truncal arteries are perforating branches of the surface arter­ ies that pass through the chorionic plate. Each truncal artery supplies one main stem villus and thus one cotyledon. As the artery penetrates the chorionic plate, its wall loses smooth mus­ cle, and its caliber increases. The loss of muscle continues as the truncal arteries and veins branch into their smaller rami. Before 10 weeks' gestation, there is no end-diastolic low pattern within the umbilical artery at the end of the fetal car­ diac cycle (Fisk, 1 988; Loquet, 1 988). After 1 0 weeks, how­ ever, end-diastolic low appears and is maintained throughout normal pregnancy. Clinically, these fl o w patterns are studied with Doppler sonography to assess fetal well-being (Chap. 1 0, p. 2 1 3) .

low-resistance vessels that can accommodate massive increase in uterine perfusion during gestation. Generally, spiral arteries are perpendicular to, but veins are parallel to, the uterine wall. his arrangement aids closure of veins during a uterine contraction and prevents the exit of maternal blood from the intervillous space. The number of arterial openings into the intervillous space is gradually reduced by cytotrophoblastic invasion. here are about 1 20 spiral arterial entries into the intervillous space at term (Brosens, 1 963) . hese discharge blood in spurts that bathes the adjacent villi (Borell, 1 958). After the 30th week, a prominent venous plexus lies between the decidua basalis and myometrium and helps develop the cleavage plane needed for placental separation after delivery. Both inlow and outlow are curtailed during uterine con­ tractions. BIeker and associates ( 1 975) used serial sonography during normal labor and found that placental length, thickness, and surface area grew during contractions. They attributed this to distention of the intervillous space by impairment of venous outlow compared with arterial inlow. During contractions, therefore, a somewhat larger volume of blood is available for exchange even though the rate of low is decreased. Similarly, Doppler velocimetry has shown that diastolic low veloci ty in spiral arteries is diminished during uterine contractions. Thus, principal factors regulating intervillous space blood low are arterial blood pressure, intrauterine pressure, uterine contrac­ tion pattern, and factors that act specifically on arterial walls. • Breas in the Placental "Barrier"

he placenta does not maintain absolute integrity of the fetal and maternal circulations. here are numerous examples of

Materna l C i rcu lation

Mechanisms of placental blood low must allow blood to leave maternal circulation; flow into an amorphous space lined by syncytiotrophoblast, rather than endothelium; and return through maternal veins without produc­ ing arteriovenous-like shunts that would prevent maternal blood from remaining in contact with villi long enough for adequate exchange. For this, maternal blood enters through the basal plate and is driven high up toward the chorionic plate by arterial pressure before laterally dis­ persing (Fig. 5- 1 5) . After bathing the external microvillous surface of chorionic villi, maternal blood drains back through venous ori­ ices in the basal plate and enters uterine veins. Thus, maternal blood traverses the placenta randomly without preformed channels. The previously described trophoblast invasion of the spiral arteries creates

U mbilical ­ vein

\

U mbilical artery U mbil ical cord

I.

Chorionic plate

Chorionic -­ villus

Basal plate Spiral artery Decidual septum

FIGURE 5-1 5 Schematic d rawing of a section through a fu l l-term placenta. Materna l blood flows i nto the intervi llous spaces in fu n nel-shaped spurts. Excha nges occur with feta l b lood as maternal blood flows a round the vi l l i . I nfiowi ng a rterial blood pushes venous blood i nto the endometrial vei ns, which a re scattered over the entire su rface of the decidua basal is. Note a lso that the u m b ilical a rteries ca rry deoxygenated feta l blood to the placenta and that the umbilica l vei n ca rries oxygen­ ated blood to the fetus. Placenta l lobes a re separated from each other by placental (decidual) septa.

I m p l a ntatio n a n d Placenta l Deve l o p ment

traicking cells between mother and fetus in both directions. This situation is best exempliied clinically by erythrocyte D-antigen alloimmunization (Chap. 1 5, p. 30 1 ) . Fetal cell admixtures likely are small in most cases, although rarely the fetus exsanguinates into the maternal circulation. Fetal cells can also engraft in the mother during pregnancy and can be identiied decades later. Fetal lymphocytes, CD34+ mesenchymal stem cells, and endothelial colony-forming cells all reside in maternal blood, bone marrow, or uterine vascula­ ture (Nguyen, 2006; Piper, 2007; Sipos, 20 1 3) . Termed micro­ chimerism, such residual stem cells have been implicated in the disparate female:male ratio of autoimmune disorders (Greer, 20 1 1 ; Stevens, 2006) . As discussed in Chapter 59 (p. 1 1 39) , they are associated with the pathogenesis of lymphocytic thy­ roiditis, scleroderma, and systemic lupus erythematosus. • Fetal-Maternal Interface

Survival of the semi allogenic fetal graft requires complex interac­ tions between fetal trophoblasts and maternal decidual immune cells. The fetal-maternal interface is not immunologically inert. Rather, it is an active hub of interactions that allows implanta­ tion and appropriate placental development and ensures immu­ no tolerance of the fetus. Despite this, a functional immune system must be maintained to protect the mother. I m m u nogen ic ity of the Trophobl a sts

Trophoblastic cells are the only fetus-derived cells in direct contact with maternal tissues and blood. Fetal syncytiotropho­ blast synthesizes and secretes numerous factors that regulate the immune responses of maternal cells both at the implantation site and systemically. Human leukocyte antigens (HLAs) are the human analogue of the major histocompatibility complex (MHC) (Hunt, 1 992) . There are 1 7 HLA class I genes, including three classic genes, HLA-A, -B, and -C, that encode the major class I (class Ia) transplantation antigens. Three other class I genes, designated HLA-E, -F, and -G, encode class Ib HLA antigens. MHC class I and II antigens are absent from villous trophoblasts, which appear to be immunologically inert at all gestational stages (Weetman, 1 999) . Invasive extravillous cytotrophoblasts do express MHC class I molecules. Thus, the ability of these cells to bypass transplantation rejection is the focus of considerable study. Mofett-King (2002) reasoned that normal implantation depends on controlled trophoblastic invasion of maternal decidua and spiral arteries. Such invasion must proceed far enough to provide for normal fetal growth and development, but a mechanism must regulate invasion depth. She suggests that dNK cells combined with unique expression of three spe­ ciic HLA class I genes in extravillous cytotrophoblasts act in concert to permit and subsequently limit trophoblast invasion. Class I antigens in extravillous cytotrophoblasts are accounted for by the expression of classic HLA-C and nonclas­ sic class Ib molecules of HLA-E and HLA-G. HLA-G anti­ gen is expressed only in humans, with expression restricted to extravillous cytotrophoblasts contiguous with maternal tissues. Embryos used for in vitro fertilization do not implant if they

do not express a soluble HLA-G isoform (Fuzzi, 2002) . hus, HLA-G may be immunologically permissive of the maternal­ fetal antigen mismatch (LeBouteiller, 1 999) . HLA-G has a pro­ posed role in protecting extravillous trophoblasts from immune rejection via modulation of dNK functions (Apps, 201 1 ; Raja­ gopalan, 20 1 2) . Last, Goldman-Wohl and associates (2000) have provided evidence for abnormal HA-G expression in extravillous trophoblasts from women with preeclampsia. Dec i d u a l I m m u ne Cel ls

Natural killer cells are the predominant population of leuko­ cytes present in midluteal phase endometrium and in decidua throughout the fi r st trimester Oohnson, 1 999). By term, however, relatively few dNK cells are present in decidua. In first-trimester decidua, dNK cells lie close to extravillous tro­ phoblasts, and there they purportedly serve to regulate inva­ sion. These dNKs have a distinct phenotype characterized by a high surface density of CD56 or neural cell adhesion molecules (Manaster, 2008; Mofett-King, 2002) . Their infiltration is increased by progesterone and by stromal cell production of IL- 1 5 and decidual prolactin (Dunn, 2002; Gubbay, 2002) . Although dNK cells have the capacity for cytotoxicity, they are not cytotoxic toward fetal trophoblasts. Their cytotoxic poten­ tial is prevented by molecular cues from decidual macrophages. In addition, the expression of specific HLA molecules protects against dNK killing. Also, dNK cells function to restrict tro­ phoblast invasiveness to protect the mother. Of other cell types, decidual macrophages are distinct from proinflammatory M 1 or antiinlammatory M2 macrophages. Decidual macrophages express the complement receptor CO l I c at high or low levels: CD 1 1 cH I and CD 1 1 cLO. These cells function to regulate adaptive T cell responses; control dNK diferentiation, activation, and cytotoxicity; and produce antiinlammatory cytokines such as I L- 1 0 to ensure fetal toler­ ance and inhibition of harmful immune responses. Dendritic cells are cells that present antigens to T cells. hey play an important role in the development of a receptive endo­ metrium for implantation. Maternal T cels, as part of the adaptive immune response, increase in number and function after encounter with a speciic antigen. These cells subsequently retain the ability to respond rapidly in a subsequent encounter with the same antigen. Spe­ cific populations of Treg cells persist and can protect against aberrant immune responses. During pregnancy, there is a systemic expansion of maternal Treg cell populations. These cells are FOXP3 + cells with defined fetal speciicity. They are immunosuppressive and play a role in fetal tolerance.

AMNION At term, the amnion is a tough and tenacious but pliable mem­ brane. his innermost avascular fetal membrane is contiguous with amnionic fluid and plays a role of incredible importance in human pregnancy. he amnion provides almost all tensile strength of the fetal membranes. Thus, its resilience to rupture is vitally important to successful pregnancy outcome. Indeed, preterm rupture of fetal membranes is a major cause of preterm delivery (Chap. 42, p. 8 1 9) .

95

96

P l acentation, E m bryog enesis, a n d Feta l Development

diamnionic-dichorionic twin placentas, amnions are separated by fused chorion laeve. Amnionic luid ills this amnionic sac. Until about 34 weeks' gestation, the normally clear fluid increases in volume as pregnancy progresses. Mter this, the volume declines. At term, amnionic luid averages 1 000 mL, although this may vay widely in normal and especially abnormal conditions. The ori­ gin, composition, circulation, and function of amnionic luid are discussed further in Chapter 1 1 (p. 225). • Amnion Cell Histogenesis

FIGURE 5-1 6 Photomicrog raph of feta l membra nes. F rom left to rig ht: AE = a m n ion epithe l i u m; AM a m n ion mesenchyme; S zon a spong i osa; eM chorionic mesenchyme; TR = trophoblast; 0 = decid ua. (U sed with permission from Dr. J udith R. Head.) =

=

=

Bourne ( 1 962) described five separate amnion layers. he inner surface, which is bathed by amnionic luid, is an unin­ terrupted, single layer of cuboidal epithelium (Fig. 5- 1 6) . his epithelium is attached irmly to a distinct basement membrane that is connected to an acellular compact layer composed pri­ marily of interstitial collagens. On the outer side of the com­ pact layer, there is a row of ibroblast-like mesenchymal cells, which are widely dispersed at term. here also are a few fetal macrophages in the amnion. he outermost amnion layer is the relatively acellular zona spongiosa, which is contiguous with the second fetal membrane, the chorion laeve. he human amnion lacks smooth muscle cells, nerves, lymphatics, and importantly, blood vessels. • Amnion Development

Early during implantation, a space develops between the embryonic cell mass and adjacent trophoblastic cells (see Fig. 5-9) . Small cells that line this inner surface of tropho­ blasts have been called amniogenic cells-precursors of amni­ onic epithelium. The amnion is irst identiiable on the 7th or 8th day of embryo development. It is initially a minute vesicle, which then develops into a small sac that covers the dorsal embryo surface. As the amnion enlarges, it gradually engulfs the growing embryo, which prolapses into its cavity (Benirschke, 20 1 2) . Distention o f the amnionic sac eventually brings i t into con­ tact with the interior surface of the chorion laeve. Apposition of the chorion laeve and amnion near the end of the irst trimes­ ter then causes an obliteration of the extraembryonic coelom. he amnion and chorion laeve, although slightly adhered, are never intimately connected and can be separated easily. Placen­ tal amnion covers the placental surface and thereby is in con­ tact with the adventitial surface of chorionic vessels. Umbilical amnion covers the umbilical cord. With diamnionic-mono­ chorionic placentas, there is no intervening tissue between the fused amnions. In the conjoined portion of membranes of

Epithelial cells of the amnion derive from fetal ectoderm of the embryonic disc. hey do not arise by delamination from trophoblasts. his is an important consideration from both embryological and functional perspectives. For example, HLA class I gene expression in amnion is more akin to that in emby­ onic cells than to that in trophoblasts. he ibroblast-like mesenchymal cell layer of the amnion is likely derived from embryonic mesoderm. Early in human embryogenesis, the amnionic mesenchymal cells lie immedi­ ately adjacent to the basal surface of the amnion epithelium. At this time, the amnion surface is a two-cell layer with approxi­ mately equal numbers of epithelial and mesenchymal cells. Simultaneously with growth and development, interstitial col­ lagens are deposited between these two cell layers. his marks formation of the amnion compact layer, which separates the two layers of amnion cells. As the amnionic sac expands, the compactness of the mes­ enchymal cells is progressively reduced, and they become sparsely distributed. Early in pregnancy, amnionic epithelium replicates at a rate appreciably faster than mesenchymal cells. At term, these cells form a continuous uninterrupted epithe­ lium on the fetal amnionic surface. Conversely, mesenchymal cells are widely dispersed, being connected by a ine lattice network of extracellular matrix with the appearance of long slender ibrils. Am n ion Epith e l i a l Ce l l s

h e apical surface o f the amnionic epithelium i s replete with highly developed microvilli. This structure relects its function as a major site of transfer between amnionic luid and amnion. This epithelium is metabolically active, and its cells synthesize tissue inhibitor of MMP- l , prostaglandin E2 (PGE2) , and fetal ibronectin (FN) (Rowe, 1 997) . Although epithelia produce FN, recent studies suggest that ibronectin functions in the underlying mesenchymal cells. Here, FN promotes synthesis of MMPs that break down the strength-bearing collagens and enhance prostaglandin synthesis to prompt uterine contractions (Mogami, 20 1 3) . This pathway is upregulated in premature rup­ ture of membranes induced by thrombin or infection-induced release of FN (Chigusa, 20 1 6; Mogami, 20 1 4) . Epithelial cells may respond t o signals derived from the fetus or the mother, and they are responsive to various endocrine or paracrine modulators. Examples include oxytocin and vasopres­ sin, both of which increase PGE2 production in vitro (Moore, 1 988) . They may also produce cytokines such as IL-8 during labor initiation (Elliott, 200 1 ) .

I m pla ntation a nd Place n ta l Deve l o p m ent

Amnionic epithelium also synthesizes vasoactive pep tides, including endothelin and parathyroid hormone-related protein (Economos, 1 992; Germain, 1 992) . he tissue produces brain natriuretic peptide (BNP) and corticotropin-releasing hormone (CRH), which are peptides that invoke smooth-muscle relax­ ation (Riley, 1 99 1 ; Warren, 1 995) . BNP production is posi­ tively regulated by mechanical stretch in fetal membranes and is proposed to function in uterine quiescence. Epidermal growth factor, a negative regulator of BNP, is up regulated in the mem­ branes at term and leads to a decline in BNP-regulated uterine quiescence (Carvaj al, 20 1 3) . It seems reasonable that vasoac­ tive peptides produced in amnion gain access to the adventitial surface of chorionic vessels. hus, the amnion may be involved in modulating chorionic vessel tone and blood low. Amnion­ derived vasoactive peptides function in both maternal and fetal tissues in diverse physiological processes. After their secretion, these bioactive agents enter amnionic luid and thereby are available to the fetus by swallowing and inhalation. Am ni o n M esenchym a l Cel l s

Mesenchymal cells o f the amnionic ibroblast layer are respon­ sible for other major functions. Synthesis of interstitial col­ lagens that compose the compact layer of the amnion-the major source of its tensile strength-takes place in mesenchy­ mal cells (Casey, 1 996) . At term the generation of cortisol by l 1 �-hydroxysteroid dehydrogenase may contribute to mem­ brane rupture via reduction of collagen abundance (Mi, 20 1 7) . Mesenchymal cells also synthesize cytokines that include IL-6, IL-8, and MCP- I . Cytokine synthesis rises in response to bacterial toxins and IL- 1 . his functional capacity of amnion mesenchymal cells is an important consideration in amnionic fluid study of labor-associated accumulation of inlammatory mediators (Garcia-Velasco, 1 999) . Finally, mesenchymal cells may be a greater source of PGE2 than epithelial cells, especially in the case of premature membrane rupture (Mogami, 20 1 3; Whittle, 2000) . • Tensile Strength

During tests of tensile strength, the decidua and then the cho­ rion laeve give way long before the amnion ruptures. Indeed, the membranes are elastic and can expand to twice normal size during pregnancy (Benirschke, 20 1 2) . The amnion tensile strength resides almost exclusively in the compact layer, which is composed of cross-linked interstitial collagens I and III and lesser amounts of collagens V and VI. Collagens are the primary macromolecules of most connec­ tive tissues. Collagen I is the major interstitial collagen in tis­ sues characterized by great tensile strength, such as bone and tendon. In other tissues, collagen III is believed to contribute to tissue integrity and provides both tissue extensibility and tensile strength. For example, the ratio of collagen III to collagen I in the walls of a number of highly extensible tissues-amnionic sac, blood vessels, urinary bladder, bile ducts, intestine, and gravid uterus-is greater than that in nonelastic tissues a efrey, 1 99 1 ) . Amnion tensile strength is regulated in part by fibrillar collagen assembly. his process is influenced by the interac­ tion fibrils with proteoglycans such as decorin and biglycan

(Chap. 2 1 , p. 409). Reduction of these proteoglycans is reported to perturb fetal membrane function (Horgan, 20 1 4; Wu, 20 1 4) . Fetal membranes overlying the cervix have a regional shift in gene expression and lymphocyte activation that set in motion an inflammatory cascade (Marcellin, 20 1 7) . his change may contribute to tissue remodeling and loss of tensile strength in the amnion (Moore, 2009) . • Metabolic Functions

The amnion is metabolically active, is involved in solute and water transport for amnionic fluid homeostasis, and produces an impressive array of bioactive compounds. The amnion is responsive both acutely and chronically to mechanical stretch, which alters amnionic gene expression (Carvajal, 20 1 3; Nemeth, 2000) . This in turn may trigger both autocrine and paracrine responses that include production of MMPs, IL-8, and collagenase (Bryant-Greenwood, 1 998; Mogami, 20 1 3) . Such factors may modulate changes i n membrane properties during labor.

UMBI LICAL CORD he yolk sac and the umbilical vesicle into which it develops are prominent early in pregnancy. At irst, the embryo is a lattened disc interposed between amnion and yolk sac (see Fig. 5-9) . Its dorsal surface grows faster than the ventral surface, in associa­ tion with the elongation of its neural tube. Thus, the embryo bulges into the amnionic sac, and the dorsal part of the yolk sac is incorporated into the embryo body to form the gut. The allantois projects into the base of the body stalk from the cau­ dal wall of the yolk sac and later, from the anterior wall of the hindgut. As pregnancy advances, the yolk sac becomes smaller and its pedicle relatively longer. By the middle of the third month, the expanding amnion obliterates the extraembryonic coelom, fuses with the chorion laeve, and covers the bulging placental disc and the lateral surface of the body stalk. The latter is then called the umbilical cord-or funis. A more detailed descrip­ tion of this cord and potential abnormalities is found in Chap­ ter 6 (p. 1 1 7) . h e cord at term normally has two arteries and one vein (Fig. 5- 1 7) . The right umbilical vein usually disappears early during fetal development, leaving only the original left vein. The umbilical cord extends from the fetal umbilicus to the fetal surface of the placenta, that is, the chorionic plate. B lood flows from the umbilical vein toward the fetus. Blood then takes a path of least resistance via two routes within the fetus. One is the ductus venosus, which empties directly into the infe­ rior vena cava (Fig. 7-9, p. 1 30). The other route consists of numerous smaller openings into the hepatic circulation. Blood from the liver flows into the inferior vena cava via the hepatic vein. Resistance in the ductus venosus is controlled by a sphinc­ ter that is situated at the origin of the ductus at the umbilical recess and is innervated by a vagus nerve branch. Blood exits the fetus via the two umbilical arteries. These are anterior branches of the internal iliac artery and become obliterated after birth to form the medial umbilical ligaments.

97

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P l a ce ntation, E m b ryogenesis, a n d Feta l Deve l op m e nt

physiological adaptations of pregnant women to the unique endocrine milieu, and this is discussed throughout Chapter 4 (p. 49) . • Human Chorionic Gonadotropin

Biosynthesis

FIGURE 5-1 7 Cross-section of u m bi l ica l cord. The large u m bi l ica l vei n ca rries oxygenated blood to the fetus (right). To its left a re the two s m a l ler u m bil ica l a rteries, ca rryi n g deoxygenated b lood fro m the fetus to the placenta. (Used with perm ission from Dr. M a n d o l i n S. Ziadie.)

PLACENTAL HORMON ES The production of steroid and protein hormones by human trophoblasts is greater in amount and diversity than that of any single endocrine tissue in all of mammalian physiology. A compendium of average production rates for various steroid hormones in nonpregnant and in near-term pregnant women is given in Table 5- 1 . It is apparent that alterations in steroid hormone production that accompany normal human preg­ nancy are incredible. he human placenta also synthesizes an enormous amount of protein and peptide hormones, summa­ rized in Table 5-2 . Another remarkable feature is the successful

TABLE 5-1 . Ste roid Prod uction Rates in Non preg n a nt

and Nea r-Term Preg n a nt Women

Steroida Estrad iol- 1 7� Estr i o l P rogesterone Al d oste rone Deoxyc o rti costero ne Cortisol

Production Rates (mg/24 h r) Nonpreg nant Pregnant 0. 1 -0.6 0.02-0. 1 0. 1 -40 0.05-0. 1 0.05-0.5 1 0-30

1 5-20 50- 1 50 250-600 0.2 5 0-0.600 1 -1 2 1 0-20

a Estrogens a n d p rogesterone a re p rod uced by placenta. Aldosterone is prod uced by the maternal a d renal in response to the sti m u l us of ang iotensin I I. Deoxycorticosterone is p ro­ d uced i n extrag landular tissue sites by way of the 2 1 -hyd rox­ ylation of plasma progesterone. Cortisol p rod uction d u r i ng p reg nancy is not increased, even though the blood levels a re elevated beca use of decreased clearance ca u sed by i ncreased cortisol-bi nding g lobu l i n.

Chorionic gonadotropin is a glycoprotein with biological activ­ ity similar to that of LH, and both act via the same LH-hCG receptor. hCG has with a molecular weight of 36,000 to 40,000 Da and has the highest carbohydrate content of any human hormone-30 percent. The carbohydrate component, and espe­ cially the terminal sialic acid, protects the molecule from catabo­ lism. As a result, the 36-hour plasma half-life of intact hCG is much longer than the 2 hours for LH. he hCG molecule is composed of two dissimilar subunits termed . and � subunits. hese are noncovalently linked and are held together by elec­ trostatic and hydrophobic forces. Isolated subunits are unable to bind the LH-hCG receptor and thus lack biological activity. hCG is produced almost exclusively in the placenta, but low levels are synthesized in the fetal kidney. Other fetal tissues pro­ duce either the �-subunit or intact hCG molecule (McGregor, 1 98 1 , 1 983) . The hCG hormone is structurally related to three other glycoprotein hormones-LH, FSH, and TSH. All four glyco­ proteins share a common a-subunit. However, each of their 3-subunits, although sharing certain similarities, is character­ ized by a distinctly diferent amino acid sequence. Synthesis of the .- and 3-chains of hCG is regulated sep­ arately. A single gene located on chromosome 6 encodes the a-subunit. Seven genes on chromosome 1 9 encode for the � -hCG-3-LH family of subunits. Six genes code for 3-hCG and one for 3-LH (Miller-Lindholm, 1 997) . Both subunits are synthesized as larger precursors, which are then cleaved by endopeptidases. Intact hCG is then assembled and rapidly released by secretory granule exocytosis (Morrish, 1 987) . There are multiple forms of hCG in maternal plasma and urine that vary enormously in bioactivity and immunoreactivity. Some result from enzymatic degradation, and others from modifica­ tions during molecular synthesis and processing. Before 5 weeks, hCG is expressed both in the syncytiotro­ phoblast and in cytotrophoblasts (Mamo, 1 992) . Later, in the irst trimester when maternal serum levels peak, hCG is pro­ duced almost solely in the syncytiotrophoblast (Beck, 1 986; Kurman, 1 984) . At this time, mRNA concentrations of both .- and 3-subunits in the syncytiotrophoblast are greater than at term (Hoshina, 1 982) . This may be an important consider­ ation when hCG is used as a screening procedure to identiy abnormal fetuses. Circulating free levels of 3-subunit are low to undetectable throughout pregnancy. In part, this is the result of its rate-lim­ iting synthesis. Free a-subunits that do not combine with the 3-subunit are found in placental tissue and maternal plasma. Lev­ els of the a-subunit rise gradually and steadily until they plateau at approximately 36 weeks' gestation. At this time, they account for 30 to 50 percent of hormone (Cole, 1 997) . Thus, .-hCG secretion roughly corresponds to placental mass, whereas secre­ tion of complete hCG molecules is maximal at 8 to 1 0 weeks.

I m p l a ntat i o n a n d Placental Develo p m ent

TABLE 5-2. Protei n Hormones P rod uced by the Human Pl acenta

Prim a ry Non-placental Site of Expression

Hormone

Shares Structura l or Fu nction Simila rity

Fu nctions

H u m a n chori o n i c g o n a d ot ropin (hCG)

LH, FSH, TS H

Ma i nta i n s corpus l ute u m fu ncti on Reg u lates fetal testis testosterone secretion Sti m u lates maternal thyroid

P l acenta l lactoge n (PL)

G H , p ro l acti n

A i d s mate r n a l a d a ptation t o feta l e n e rgy req u i re m ents

Ad renocorticotro p i n (ACTH)

Hypoth a l a m u s

Corticotro p i n-releasing hormone (CRH)

Hypot h a la m u s

Relaxes smooth-muscle; i n itiates partu rition ? P romotes feta l a n d maternal g l u cocorticoid prod uction

Gonadotropi n-re lea s i n g h o r m o n e (G n RH)

Hypoth a l a m u s

Reg u l ates t ro p h o b l ast hCG prod u ction

Thyrotro p i n (TRH)

Hypotha l a m u s

U n known

G rowth horm on e- relea s i n g hormone (G H RH)

Hypotha l a m u s

U n known

G rowt h hormone va riant ( h G H -V) N e u ro peptide Y

GH va ria nt not fou nd i n pituita ry B ra i n

Potenti a l ly med iates preg na ncy i n s u l i n resi sta nce Potential reg u lates CRH release by t rop h o b l a sts

Parathyro i d -relea s i n g prote i n (PTH-rp)

Reg u lates t ra n sfer of ca l c i u m a n d o t h e r solutes; reg u l ates feta l m i neral h o m eosta s i s

I nh i bi n

Ova ry/testis

Potent i a l l y i n h i b its FSH- med iated ovu lation; reg u l ates hCG synthesis

Activin

Ova ry/testis

Reg u l ates placenta l G n RH synthesis

GH

=

g rowth hormone; FSH

=

fol l icle-sti m u lati n g hormone; LH

Concentrati ons in Seru m a n d U ri ne

The combined hCG molecule is detectable in plasma of preg­ nant women 7 to 9 days after the midcycle surge of LH that precedes ovulation. hus, hCG likely enters maternal blood at the time of blastocyst implantation. Plasma levels rise rapidly, doubling every 2 days in the first trimester (Fig. 5- 1 8) . Appre­ ciable fluctuations in levels for a given patient are observed on the same day. Intact hCG circulates as multiple highly related isoforms with variable cross-reactivity between commercial assays. hus, calculated serum hCG levels can vary considerably among the more than a hundred available assays. his emphasizes the need to use the same assay type when clinically measuring serial hCG levels. Peak maternal plasma levels reach approxi­ mately 50,000 to 1 00,000 mIU/mL between the 60th and 80th days after menses. At 10 to 1 2 weeks' gestation, plasma levels begin to decline, and a nadir is reached by approximately 1 6 weeks. Plasma levels are maintained at this lower level for the remainder of pregnancy. The pattern of hCG appearance in fetal blood is similar to that in the mother. Fetal plasma levels, however, are only about 3 percent of those in maternal plasma. Amnionic fl u id hCG concentration early in pregnancy is similar to that in mater­ nal plasma. As pregnancy progresses, hCG concentration in

=

l utei n iz i n g hormone; TS H

=

thyroid-st i m u lat i ng h or m o n e.

amnionic fluid declines, and near term the levels are approxi­ mately 20 percent of those in maternal plasma. Maternal urine contains the same variety of hCG degrada­ tion products as maternal plasma. The principal urinary form is the terminal product of hCG degradation, namely, the

1 40 1 20

1\ I I I I I I I I I I I I , I I I I I I \ I \ , I

_ 1 00

E 80 3 ) 60 > c

40

,

20 0

I

� � hCG

J

0

I I

,,

10

"

h P L �/

,,

500

,

400

, ,,

, " "7..- , ,

,,

,

,,

E

I

30 20 Weeks' gestation

J

300 � 0

I

,

8 7

.

200 £ 1 00 40

: )

6

53 E 4,

:t

3. 1 2 0

FIGURE 5-1 8 Disti nct profi les for the concentrations of h u m a n chorionic gonadotropin (hCG), h u m a n placental lactogen ( h P L), and corticotropin-releasing hormone (CRH) i n seru m of wome n throug hout normal preg nancy.

c

99

1 00

P l a centation, E m b ryogenesis, a n d Feta l Deve lopment

�-core fragment. Concentrations of this fragment follow the same general pattern as that in maternal plasma, peaking at approximately 1 0 weeks' gestation. Importantly, the so-called �-subunit antibody used in most pregnancy tests reacts with both intact hCG-the major form in the plasma, and with fragments of hCG-the major forms found in urine. hCG Reg u l ation

Placental gonadotropin-releasing hormone (GnRH) is likely involved in the regulation of hCG formation. Both GnRH and its receptor are expressed by cytotrophoblasts and by the syn­ cytiotrophoblast (Wolfahrt, 1 998). GnRH administration ele­ vates circulating hCG levels, and cultured trophoblasts respond to GnRH treatment and raise hCG secretion (Iwashita, 1 993; Siler-Khodr, 1 98 1 ) . Pituitary GnRH production also is regu­ lated by inhibin and activin. In cultured placental cells, activin stimulates and inhibin inhibits GnRH and hCG production (Petraglia, 1 989; Steele, 1 993) . Renal clearance of hCG accounts for 30 percent of its meta­ bolic clearance. he remainder is likely cleared by metabolism in the liver (Wehmann, 1 980) . Clearances of�- and .-subunits are approximately 1 0- and 30-fold, respectively, greater than that of intact hCG. In pregnancies complicated by chronic renal disease, hCG clearance can be markedly decreased. Biologica l Fu nctions

Both hCG subunits are required for binding to the LH-hCG receptor in the corpus luteun and the fetal testis. LH-hCG receptors are present in various other tissues, but their roles there are less defined. he best-known biological function of hCG is the so-called rescue and maintenance of corpus luteum function-that is, continued progesterone production. This is only an incomplete explanation for the physiological function of hCG in preg­ nancy. For example, maximum plasma hCG concentrations are attained well after hCG-stimulated corpus luteum secretion of progesterone has ceased. Speciically, luteal progesterone syn­ thesis begins to decline at about 6 weeks despite continued and increasing hCG production. A second hCG role is stimulation of fetal testicular testos­ terone secretion. This is maximum approximately when hCG levels peak. hus, at a critical time in male sexual diferentia­ tion, hCG enters fetal plasma from the syncytiotrophoblast. In the fetus, it acts as an LH surrogate to stimulate Leydig cell rep­ lication and testosterone synthesis to promote male sexual dif­ ferentiation (Chap. 3, p. 35). Before approximately 1 1 0 days, there is no vascularization of the fetal anterior pituitary from the hypothalamus. Thus, pituitary LH secretion is minimal, and hCG acts as LH before this time. hereafter, as hCG levels fall, pituitary LH maintains modest testicular stimulation. The maternal thyroid gland is also stimulated by large quan­ tities of hCG. In some women with gestational trophoblastic disease, biochemical and clinical evidence of hyperthyroidism sometimes develops (Chap. 20, p. 39 1 ) . This once was attrib­ uted to formation of chorionic thyrotropins by neoplastic trophoblasts. It was subsequently shown, however, that some forms ofhCG bind to TSH receptors on thyrocytes (Hershman, 1 999) . And, treatment of men with exogenous hCG increases

thyroid activity. The thyroid-stimulatory activity in plasma of irst-trimester pregnant women varies appreciably from sample to sample. Modiications of hCG oligosaccharides likely are important in the capacity of hCG to stimulate thyroid func­ tion. For example, acidic isoforms stimulate thyroid activity, and some more basic isoforms stimulate iodine uptake (Kraiem, 1 994; Tsuruta, 1 995; Yoshimura, 1 994) . Finally, the LH-hCG receptor is expressed by thyrocytes, which suggests that hCG stimulates thyroid activity via the LH-hCG receptor as well as by the TSH receptor (Tomer, 1 992) . Other hCG functions include promotion of relaxin secre­ tion by the corpus luteum (Duy, 1 996) . LH-hCG receptors are found in myometrium and in uterine vascular tissue. It has been hypothesized that hCG may promote uterine vascu­ lar vasodilatation and myometrial smooth muscle relaxation (Kurtzman, 200 1 ) . Chorionic gonadotropin also regulates expansion of dNK cell numbers during early stages of placen­ tation, thus ensuring appropriate establishment of pregnancy (Kane, 2009) . A b norma l ly H i g h or Low Level s

here are several clinical circumstances i n which substantively higher maternal plasma hCG levels are found. Some examples are multifetal pregnancy, erythroblastosis fetalis associated with fetal hemolytic anemia, and gestational trophoblastic disease. Relatively higher hCG levels may be found in women carry­ ing a fetus with Down syndrome. This observation is used in biochemical screening tests (Chap. 1 4, p. 28 1 ) . The reason for the elevation is not clear, but reduced placental maturity has been speculated. Various malignant tumors also produce hCG, sometimes in large amounts-especially trophoblastic neoplasms (Chaps. 9, p. 1 59 and 20, p. 39 1 ) . Relatively lower hCG plasma levels are found i n women with early pregnancy wastage, including ectopic pregnancy (Chap. 1 9, p. 373) . hCG is produced in very small amounts in normal tissues of men and nonpregnant women, perhaps primarily in the anterior pituitary gland. Nonetheless, the detection of hCG in blood or urine almost always indicates pregnancy (Chap. 9, p. 1 58). • Human Placental Lactogen

B iosynthesi s

This is a single, nonglycosylated polypeptide chain with a molec­ ular weight of 22,279 Da. The sequences of hPL and of human growth hormone (hGH) are strikingly similar, with 96-percent homology. Also, hPL is structurally similar to human prolac­ tin (hPRL) , with a 67-percent amino acid sequence similarity. Because of these similarities, it was called human placental lac­ togen or chorionic growth hormone. Currently, human placen­ tal lactogen is used by most. here are ive genes in the growth hormone-placental lac­ togen gene cluster that are linked and located on chromosome 1 7. hPL is concentrated in syncytiotrophoblast, but similar to hCG, hPL is demonstrated in cytotrophoblasts before 6 weeks (Grumbach, 1 964; Maruo, 1 992) . Within 5 to 1 0 days after conception, hPL is demonstrable in the placenta and can be detected in maternal serum as early as 3 weeks. Levels of

I m pl a ntation and Placenta l Deve l o pment

mRNA for hPL in syncytiotrophoblast remain relatively con­ stant throughout pregnancy. his inding supports the idea that the hPL secretion rate is proportional to placental mass. Levels rise steadily until 34 to 36 weeks' gestation. The hPL produc­ tion rate near term-approximately 1 g/d-is by far the great­ est of aRY known hormone in humans. The hal-life of hPL in maternal plasma is between 1 0 and 30 minutes (Walker, 1 99 1 ) . I n late pregnancy, maternal serum concentrations reach levels of 5 to 1 5 �g/mL (see Fig. 5- 1 8) . Very little hPL i s detected i n fetal blood o r i n the urine of the mother or newborn. Amnionic fluid levels are somewhat lower than in maternal plasma. hPL is secreted primarily into the maternal circulation, with only very small amounts in cord blood. hus, its role in pregnancy is believed to be mediated through actions in maternal rather than in fetal tissues. None­ theless, interest continues for the possibility that hPL serves select functions in fetal growth. Meta bol ic Actions

hPL has putative actions in several important metabolic pro­ cesses. First, hPL promotes maternal lipolysis with increased circulating free fatty acid levels. This provides an energy source for maternal metabolism and fetal nutrition. In vitro studies suggest that hPL inhibits leptin secretion by term syn­ cytiotrophoblast (Coya, 2005) . Prolonged maternal starvation in the irst half of pregnancy leads to higher hPL plasma con­ centrations. Second, hPL may aid maternal adaptation to fetal energy requirements. For example, increased maternal insulin resis­ tance ensures nutrient flow to the fetus. It also favors protein synthesis and provides a readily available amino acid source to the fetus. To counterbalance the greater insulin resistance and prevent maternal hyperglycemia, maternal insulin levels are increased. Both hPL and prolactin signal through the prolactin receptor to increase maternal beta cell proliferation to augment insulin secretion (Georgia, 20 1 0) . In animals, prolactin and hPL upregulate serotonin synthesis, which increases beta cell proliferation (Kim, 20 1 0) . Short-term changes in plasma glu­ cose or insulin, however, have relatively little efect on plasma hPL levels. In vitro studies of syncytiotrophoblast suggest that hPL synthesis is stimulated by insulin and insulin-like growth factor- 1 and inhibited by PGE2 and PGF2: (Bhaumick, 1 987; Genbacev, 1 977) . Last, hPL is a potent angiogenic hormone. It may serve an important function in fetal vasculature formation (Corbacho, 2002) . • Other Placental Protein Hormones

he placenta has a remarkable capacity to synthesize numer­ ous peptide hormones, including some that are analogous or related to hypothalamic and pituitary hormones. In contrast to their counterparts, some of these placental peptide/protein hormones are not subject to feedback inhibition. H ypotha l a m ic-Like R e l ea s i ng Hormones

he known hypothalamic-releasing or -inhibiting hormones include GnRH, CRH , thyrotropin-releasing hormone (TRH) , growth hormone-releasing hormone, and somatostatin. For

each, there is an analogous hormone produced in the human placenta (Petraglia, 1 992; Siler-Khodr, 1 988) . GnH in the placenta shows its highest expression in the first trimester (Siler-Khodr, 1 978, 1 988). Interestingly, it is found in cytotrophoblasts, but not syncytiotrophoblast. Pla­ centa-derived GnRH functions to regulate trophoblast hCG production and extravillous trophoblast invasion via regulation ofMMP-2 and MMP-9 (Peng, 20 1 6) . Placenta-derived G nRH is also the likely cause of elevated maternal GnRH levels in pregnancy (Siler-Khodr, 1 984). CH is a member of a larger family of CRH-related pep­ tides that includes CRH and urocortins (Dautzenberg, 2 002) . Maternal serum CRH levels increase from 5 to 1 0 pmollL in the nonpregnant woman to approximately 1 00 pmollL in the early third trimester of pregnancy and to almost 500 pmollL abruptly during the last 5 to 6 weeks (see Fig. 5- 1 8) . Urocortin also is produced by the placenta and secreted into the maternal circulation, but at much lower levels than seen for CRH (Flo­ rio, 2002) . After labor begins, maternal plasma CRH levels rise even further (Petraglia, 1 989, 1 990) . he biological function of CRH synthesized in the placenta, membranes, and decidua has been somewhat deined. CRH receptors are present in many tissues including placenta. Tro­ phoblast, amniochorion, and decidua express both CRH-R1 and CRH-R2 receptors and several variant receptors (Florio, 2000) . Both CRH and urocortin enhance trophoblast secre­ tion of adrenocorticotropic hormone (ACTH) , supporting an autocrine-paracrine role (Petraglia, 1 999) . Large amounts of trophoblast CRH enter maternal blood. Other proposed biological roles include induction of smooth-muscle relaxation in vascular and myometrial tissue and immunosuppression. The physiological reverse, however, induction of myometrial contractions, has been proposed for the rising CRH levels seen near term. One hypothesis sug­ gests that CRH may be involved with parturition initiation (Wadhwa, 1 998) . Some evidence suggests that urocortin 2 expression is induced at term and induces expression of pro in­ lammatory markers and prostaglandin F receptor expression in the placenta and myometrium (Voltolini, 20 1 5) . Prosta­ glandin formation in the placenta, amnion, chorion laeve, and decidua is increased with CRH treatment Oones, 1 989b). hese observations further support a potential action in par­ turition timing. Glucocorticoids act in the hypothalamus to inhibit CRH release, but in the trophoblast, glucocorticoids stimulate CRH gene expression Oones, 1 989a; Robinson, 1 988). hus, there may be a novel positive feedback loop in the placenta by which placental CRH stimulates placental ACTH to stimulate fetal and maternal adrenal glucocorticoid production with subse­ quent stimulation of placental CRH expression (Nicholson, 200 1 ; Riley, 1 99 1 ) . Growth hormone-releasing hormone has an unknown role (Berry, 1 992) . Ghrelin is another regulator of hGH secretion that is produced by placental tissue (Horvath, 200 1 ) . Tropho­ blast ghrelin expression peaks at midpregnancy and is a para­ crine regulator of diferentiation or is a potential regulator of human growth hormone variant production, described next (Fuglsang, 2005; Gualillo, 200 1 ) .

1 01

1 02

Pl acentati o n, E m b ryog enesis, a n d Feta l Deve l o p m ent

Pitu ita ry-L i ke Hormones

ACTH, lipotropin, and �-endorphin, which are all proteolytic products of pro-opiomelanocortin, are recovered from placen­ tal extracts (Genazzani, 1 975; Odagiri, 1 979) . he physiologi­ cal action of placental ACTH is unclear. As discussed, placental CRH stimulates synthesis and release of chorionic ACTH. A human growth hormone variant (hGH- J that is not expressed in the pituitary is expressed in the placenta. The gene encoding hGH-V is located in the hGH-hPL gene cluster on chromosome 1 7. Sometimes referred to as placental growth hormone, hGH-V is a 1 9 1 -amino-acid protein that difers in 1 5 amino acid positions from the sequence for hGH. Although hGH-V retains growth-promoting and antilipogenic functions similar to those of hGH, it has reduced diabetogenic and lac­ togenic functions relative to hGH (Vickers, 2009) . Placental hGH-V presumably is synthesized in the syncytiotrophoblast. It is believed that hGH-V is present in maternal plasma by 2 1 to 26 weeks' gestation, rises in concentration until approximately 36 weeks, and remains relatively constant thereafter. There is a correlation between the levels of hGH-V in maternal plasma and those of insulin-like growth factor- I . lso, hGH-V secre­ tion by trophoblast in vitro is inhibited by glucose in a dose­ dependent manner (Patel, 1 995). Overexpression of hGH-V in mice causes severe insulin resistance, making it a likely candi­ date to mediate insulin resistance of pregnancy (Liao, 20 1 6) . Relax i n

Expression o f relaxin has been demonstrated i n human corpus luteum, decidua, and placenta (Bogic, 1 995). This peptide is synthesized as a single, 1 05-amino-acid preprorelaxin molecule that is cleaved to A and B molecules. Relaxin is structurally similar to insulin and insulin-like growth factor. Two of the three relaxin genes-H2 and H3-are transcribed in the cor­ pus luteum (Bathgate, 2002; H udson, 1 983, 1 984) . Decidua, placenta, and membranes express H1 and H2 (Hansell, 1 99 1 ) . The rise i n maternal circulating relaxin levels seen i n early pregnancy is attributed to corpus luteum secretion, and levels parallel those of hCG . Relaxin, along with rising progesterone levels, may act on myometrium to promote relaxation and the quiescence of early pregnancy (Chap. 2 1 , p. 407) . In addition, the production of relaxin and relaxin-like factors within the placenta and fetal membranes may play an autocrine-paracrine role in postpartum regulation of extracellular matrix remodel­ ing (Qin, 1 997a,b) . One important relaxin function is enhance­ ment of the glomerular iltration rate (Chap. 4, p. 66) . Pa rat hyroid Hormone-Related Protei n

I n pregnancy, circulating parathyroid hormone-related pro­ tein (PTH-rP) levels are significantly elevated within maternal but not fetal circulation (Bertelloni, 1 994; Saxe, 1 997) . Many functions of this hormone have been proposed. PTH-rP syn­ thesis is found in several normal adult tissues, especially in reproductive organs that include myometrium, endometrium, corpus luteum, and lactating mammary tissue. PTH-rP is not produced in the parathyroid glands of normal adults. Placenta­ derived PTH-rP may have an important function to regulate genes involved in transfer of calcium and other solutes. It also

contributes to fetal mineral homeostasis in bone, amnionic luid, and the fetal circulation (Simmonds, 20 1 0) . Lepti n

This hormone is normally secreted by adipocytes. It functions as an antiobesity hormone that decreases food intake .through its hypothalamic receptor. It also regulates bone growth and immune unction (Cock, 2003; La Cava, 2004) . In the pla­ centa, leptin is synthesized by both cytotrophoblasts and syncy­ tiotrophoblast (Henson, 2002) . Relative contributions of leptin from maternal adipose tissue versus placenta are currently not well defined, although recent evidence highlights a key regula­ tory role of placental leptin in placental amino acid transport and fetal growth (Rosario, 20 1 6a) . Maternal serum levels are sig­ nificantly higher than those in nonpregnant women. Fetal leptin levels correlate positively with birthweight and likely function in fetal development and growth. Studies suggest that reductions in leptin availability contribute to adverse fetal metabolic program­ ing in intrauterine growth-restricted ofspring (Nusken, 20 1 6) . N e u ropeptide Y

This 36-amino-acid peptide is widely distributed in brain. It also is found in sympathetic neurons innervating the cardiovas­ cular, respiratory, gastrointestinal, and genitourinary systems. Neuropeptide Y has been isolated from the placenta and local­ ized in cytotrophoblasts (Petraglia, 1 989) . Trophoblasts possess neuropeptide Y receptors, and treatment of these with neuro­ peptide Y causes CRH release (Robidoux, 2000) . I n h i bi n a n d Activin

hese glycoprotein hormones are expressed in male and female reproductive tissues and belong to the transforming growth factor-� family Gones, 2006) . Inhibin is a heterodimer made up of one a-subunit and one of two distinct �-subunits, either �A or �B. his yields either inhibin A or inhibin B, respectively. Activin is formed by the combination of the two �-subunits. Activin, inhibin, and their respective recep­ tors are expressed in the placenta. Both activin and inhibin A have proposed functions during cytotrophoblast fusion into the syncytiotrophoblast (Debieve, 2000; Jones, 2006) . Activin also stimulates production of placental hormones such as hCG, hPL, progesterone, and estrogen (Luo, 2002; Morrish, 1 99 1 ; Petraglia, 1 989; Song, 1 996) . Inhibin A opposes activin action in the placenta to inhibit production of hCG and steroido­ genesis (Petraglia, 1 989) . Abnormal levels of inhibin or activin correlate with placental pathologies. For example, elevation in inhibin A levels in the second trimester is indicative of fetal Down syndrome. Further, low inhibin levels early in pregnancy may indicate pregnancy failure (Prakash, 2005; Wallace, 1 996) . Elevations in circulating inhibin and activin levels are reported in women with preeclampsia (Bersinger, 2003) . • Placental Progesterone Production

After 6 to 7 weeks' gestation, little progesterone is produced in the ovary (Diczfalusy, 1 96 1 ) . Surgical removal of the corpus luteum or even bilateral oophorectomy during the 7th to 1 0th week does not decrease excretion rates of urinary pregnanediol,

I m pl a ntation a nd P lacenta l Development Progesterone 1 00.0

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Gestational age (weeks)

FIGURE 5-1 9 Plasma levels of progesterone, estrad iol, estrone, estetrol, a n d estriol in women d u ring the course of gestation. (Mod ified a n d red rawn with perm ission from Mesiano S: The endo­ crinology of h u m a n preg nancy a nd fetoplacental neu roendocri ne development. I n Stra uss J F, Ba rbieri RL (eds) Yen a nd Jaffe's Repro­ ductive Endocrinology: P hysiology, Pathophysiology, a n d C l i n ica l Management, 6th ed. P h iladeph ia, Sa u nders, 2009.)

the principal urinary metabolite of progesterone. Before this time, however, corpus luteum removal will result in spontane­ ous abortion unless an exogenous progestin is given (Chap. 63, p. 1 1 98) . After approximately 8 weeks, the placenta assumes progesterone secretion, resulting in a gradual increase in mater­ nal serum levels throughout pregnancy (Fig. 5- 1 9) . By term, these levels are 1 0 to 5000 times those found in nonpregnant women, depending on the stage of the ovarian cycle. The daily production rate of progesterone in late, normal, singleton pregnancies approximates 250 mg. In mulrifetal preg­ nancies, the daily production rate may exceed 600 mg. Proges­ terone is synthesized from cholesterol in a two-step enzymatic reauiuI1. r.l�., L-l1UI:�L:l Ul ;�

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the mitochondria, in a reaction catalyzed by cytochrome P450 cholesterol side-chain cleavage enzyme. Pregnenolone leaves the mitochondria and is converted to progesterone in the endoplas­ mic reticulum by 33-hydroxysteroid dehydrogenase. Progester­ one is released immediately through a process of difusion. Although the placenta produces a prodigious amount of progesterone, the syncytiotrophoblast has a limited capacity for cholesterol biosynthesis. Radiolabeled acetate is incorpo­ rated into cholesterol by placental tissue at a slow rate. he rate-limiting enzyme in cholesterol biosynthesis is 3-hydroxy3-methylglutaryl coenzyme A (HMG-CoA) reductase. Because of this, the placenta must rely on an exogenous source, that

is, maternal cholesterol, for progesterone formation. he tro­ phoblast preferentially uses LDL cholesterol for progesterone biosynthesis (Simpson, 1 979, 1 980) . This mechanism difers from placental production of estrogens, which relies principally on fetal adrenal precursors. Although there is a relationship between fetal well-being and placental estrogen production, this is not the case for placen­ tal progesterone. Thus, placental endocrine function, including the formation of protein hormones such as hCG and proges­ terone biosynthesis, may persist for weeks after fetal demise. he metabolic clearance rate of progesterone in pregnant women is similar to that found in men and nonpregnant women. During pregnancy, the plasma concentration of 5a-dihydroprogesterone disproportionately rises due to syn­ thesis in syncytiotrophoblast from both placenta-produced progesterone and fetus-derived precursor (Dombroski, 1 997) . hus, the concentration ratio of this progesterone metabolite to progesterone is elevated in pregnancy. The mechanisms for this are not deined completely. Progesterone also is converted to the potent mineralocorticoid deoxycorticosterone in preg­ nant women and in the fetus. The concentration of deoxy­ corticosterone is strikingly higher in both maternal and fetal compartments (see Table 5- 1 ) . The extraadrenal formation of deoxycorticosterone from circulating progesterone accounts for most of its production in pregnancy (Casey, 1 982a,b) . • Placental Estrogen Production

During the first 2 to 4 weeks of pregnancy, rising hCG lev­ els maintain production of estradiol in the maternal corpus luteum. Production of both progesterone and estrogens in the maternal ovaries drops signiicantly by the 7th week of preg­ nancy. At this time, there is a luteal-placental transition. By the 7th week, more than half of estrogen entering maternal circula­ tion is produced in the placenta (MacDonald, 1 965a; Siiteri, 1 963, 1 966) . Subsequently, the placenta produces a continually increasing magnitude of estrogen. Near term, normal human pregnancy is a hyperestrogenic state, and syncytiotrophoblast is producing estrogen in amounts equivalent to that produced in 1 day by the ovaries of no fewer than 1 000 ovulatory women. This hyperestrogenic state terminates abruptly after delivery of the placenta. Biosynth esis

In human trophoblast, neither cholesterol nor, in turn, proges­ :e�8!e :�� �e�.'e !s

F"�C�!!S0!" Fo r �'tr0g�n hi)"yn th �." i s . Th i � i s

because steroid 17a-hydroxylasel1,20-yase (CP1 7Al) is not expressed in the human placenta. This essential enzyme con­ verts 1 7-0H progesterone (a C2 I steroid) to androstenedione, which is a C ' 9 steroid and an estrogen precursor. Consequently, the conversion of C2I steroids to C ' 9 steroids is not possible. However, dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) are also C ' 9 steroids and are produced by maternal and fetal adrenal glands. These two steroids can serve as estrogen precursors (Fig. 5-20) . Ryan ( 1 959a) found that the placenta had an exceptionally high capacity to convert appropriate C'9 steroids to estrone and estradiol. The conversion of DHEA-S to estradiol requires placental expression of four key enzymes

1 03

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P l ace ntati on, E m b ryog enesi s, a n d Feta l Deve l o p m e nt

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FIGURE 5-20 Schematic presentation of estrogen biosynthesis in the h u m a n placenta. Dehyd roepia nd rosterone su lfate (DH EAS), secreted in prod igious a mou nts by the fetal a d renal g l a nds, is converted to 1 6a-hyd roxydehyd roepiand rosterone sulfate ( 1 6aO H D H EAS) in the feta l l iver. These steroids, D H EAS a n d 1 6aOH DH EAS, a re converted i n the placenta to estrogens, that is, 1 7�-estradiol (E) a nd estriol (E3). Near term, h a lf of E 2 is derived from fetal a d re n a l DH EAS a n d h a lf from maternal DH EAS. On the other h a nd, 90 percent of E3 in the placenta a ri ses from feta l 1 6aOH DH EAS and o n ly 1 0 percent from a l l other sou rces.

that are located principally in syncytiotrophoblast (Bonenfant, 2000; Salido, 1 990) . First, the placenta expresses high levels of steroid sulfatase (STS) , which converts the conjugated DHEA­ S to DHEA. DHEA is then acted upon by 33-hydroxysteroid dehydrogenase type 1 (33 HSD) to produce androstenedione. Cytochrome P450 aromatase (CYP 1 9) then converts andro­ stenedione to estrone, which is then converted to estradiol by 1 73-hydroxysteroid dehydrogenase type 1 ( 1 73 HSD l ) . DHEA-S i s the major precursor o f estrogens i n pregnancy (Baulieu, 1 963; Siiteri, 1 963) . However, maternal adrenal glands do not produce suicient amounts of DHA-S to account for more than a fraction of total placental estrogen bio­ synthesis. he fetal adrenal glands are quantitatively the most important source of placental estrogen precursors in human pregnancy. hus, estrogen production during pregnancy relects the unique interactions among fetal adrenal glands, fetal liver, placenta, and maternal adrenal glands. D i rectiona l Secretion

More than 90 percent of estradiol and estriol formed in syncy­ tiotrophoblast ' enters maternal plasma (Gurpide, 1 966) . And, 85 percent or more of placental progesterone enters maternal plasma, and little maternal progesterone crosses the placenta to the fetus (Gurpide, 1 972) .

his directional movement of newly formed steroid into the maternal circulation stems from basic characteristics of hemo­ chorioendothelial placentation. In this system, steroids secreted from syncytiotrophoblast can enter maternal blood directly. Steroids that leave the syncytium do not enter fetal blood directly. hey must irst traverse the cytotrophoblast layer and then enter the stroma of the villous core and then fetal capil­ laries. From either of these spaces, steroids can reenter the syn­ cytium. he net result of this hemochorial arrangement is that entry of steroids into the maternal circulation is substantially greater than that into fetal blood.

FETAL ADRENAL G LAND-PLACENTAL I NTERACTIONS Morphologically, functionally, and physiologically, the fetal adrenal glands are remarkable. At term, the fetal adrenal glands weigh the same as those of the adult. More than 85 percent of the fetal gland is composed of a unique fetal zone, which has a great capacity for steroid biosynthesis. Daily steroid production of fetal adrenal glands near term is 1 00 to 200 mg/d. This compares with resting adult steroid secretion of 30 to 40 mg/d.

I m pl a ntat i o n a n d P lacental Development

The fetal zone is lost in the irst year of life and is not present in the adult. In addition to ACTH, fetal adrenal gland growth is influenced by factors secreted by the placenta. This is exem­ pliied by the continued growth of the fetal glands throughout gestation and by rapid involution immediately after birth and placental delivery. • Placental Estriol Synthesis

Estradiol is the primary placental estrogen product at term. In addition, significant levels of estriol and estetrol are found in the maternal circulation, and levels also rise, particularly late in gestation (see Fig. 5- 1 9) . hese hydroxylated forms of estro­ gen derive from the placenta using substrates formed by the combined eforts of the fetal adrenal gland and fetal liver. For this, high levels of fetal hepatic 1 6a-hydroxylase act on adre­ nal-derived steroids. Ryan ( 1 959b) and MacDonald and Siiteri ( 1 965b) found that 1 6a-hydroxylated C19 steroids, particu­ larly 1 6a-hydroxydehydroepiandrosterone ( 1 6-0HDHEA) , were converted to estriol by placental tissue. Thus, the dispro­ portionate increase in estriol formation during pregnancy is accounted for by placental synthesis of estriol principally from plasma-borne 1 6-0HDHEA-sulfate. Near term, the fetus is the source of 90 percent of placental estriol and estetrol precur­ sors in normal human pregnancy. Maternal estriol and estetrol are produced almost solely by fetal steroid precursors. hus, in the past, levels of these steroids were used as an indicator of fetal well-being. However, the low sensitivity and speciicity of such tests have caused them to be discarded. • Fetal Adrenal Steroid Precursor

The precursor for fetal adrenal steroidogenesis is cholesterol. he steroid biosynthesis rate in the fetal gland is so great that its steroidogenesis alone is equivalent to a fourth of the total daily LDL cholesterol turnover in adults. Fetal adrenal glands syn­ thesize cholesterol from acetate. All enzymes involved in choles­ terol biosynthesis are elevated compared with those of the adult adrenal gland (Rainey, 200 1 ) . Thus, the de novo cholesterol synthesis rate by fetal adrenal tissue is extremely high. Even so, it is insuicient to account for the steroids produced by fetal adrenal glands. Therefore, cholesterol must be assimilated from the fetal circulation and mainly from LDL (Carr, 1 980, 1 98 1 b, 1 982; Simpson, 1 979) . Most fetal plasma cholesterol arises by de novo synthesis in the fetal liver (Carr, 1 984) . The low LDL cholesterol level in fetal plasma is not the consequence of impaired fetal LDL syn­ thesis, but instead results from the rapid use of LDL by the fetal adrenal glands for steroidogenesis (Parker, 1 980, 1 983) . • Fetal Conditions Afecting

Estrogen Production

Several fetal disorders alter the availability of substrate for pla­ cental steroid synthesis and thus highlight the interdependence of fetal development and placental function. Fetal demise is followed by a striking reduction in urinary estrogen levels. Similarly, after ligation of the umbilical cord

with the fetus and placenta left in situ, placental estrogen production declines markedly (Cassmer, 1 959) . However, as previously discussed, placental progesterone production is maintained. In sum, an important source of precursors of pla­ cental estrogen-but not progesterone-biosynthesis is elimi­ nated with fetal death. Anencephalic etuses have markedly atrophic adrenal glands. his stems from absent hypothalamic-pituitary function, which precludes adrenal stimulation by ACTH. With absence of the adrenal cortex fetal zone, the placental formation of estrogen-especially estriol-is severely limited because of diminished availability of C 1 9 steroid precursors. Indeed, uri­ nary estrogen levels in women pregnant with an anencephalic fetus are only about 1 0 percent of those found in normal preg­ nancy (Frandsen, 1 96 1 ) . With an anencephalic fetus, almost all estrogens produced arise from placental use of maternal plasma DHEA-S. Fetal adrenal cortical hypoplasia occurs in perhaps 1 in 1 2, 500 births (McCabe, 200 1 ) . Estrogen production in these pregnan­ cies is limited, which suggests the absence of C19 precursors. Fetal-placental suatase diciency is associated with very low estrogen levels in otherwise normal pregnancies (France, 1 969) . Namely, sulfatase deficiency precludes the hydrolysis of C19 steroid sulfates, the fi r st enzymatic step in the placental use of these circulating prehormones for estrogen biosynthesis. This deficiency is an X-linked disorder, and thus all afected fetuses are male. Its estimated frequency is 1 in 2000 to 5000 births and is associated with delayed labor onset. It also is associated with the development of ichthyosis in afected males later in life (Bradshaw, 1 986) . Fetal-placental aromatase diciency i s a rare autosomal reces­ sive disorder in which individuals cannot synthesize endogenous estrogens (Grumbach, 20 1 1 ; Simpson, 2000) . To recall, fetal adrenal DHA-S is converted in the placenta to androstene­ dione, but in cases of placental aromatase deiciency, andro­ stenedione cannot be converted to estradiol. Rather, androgen metabolites of DHEA produced in the placenta, including androstenedione and some testosterone, are secreted into the maternal or fetal circulation, or both. This can cause virilization of the mother and the female fetus (Belgorosky, 2009; Harada, 1 992; Shozu, 1 99 1 ) . Trisomy 21-Down syndrome screening searches for abnor­ mal levels of hCG, alpha-fetoprotein, and other analytes (Chap. 1 4, p. 28 1 ) . It was discovered that serum unconjugated estriol levels were low in women with Down syndrome fetuses (Benn, 2002) . The likely reason for this is inadequate formation of C19 steroids in the adrenal glands of these trisomic fetuses. Fetal eythroblastosis in some cases of severe fetal D-antigen alloimmunization can lead to elevated maternal plasma estro­ gen levels. A suspected cause is the greater placental mass from hypertrophy, which can be seen with such fetal hemolytic ane­ mia (Chap. 1 5, p. 300) . • Maternal Conditions Afecting

Estrogen Production Glucocorticoid treatment can cause a striking reduction in pla­ cental estrogen formation. Glucocorticoids inhibit ACTH

1 05

1 06

P l acentation, Em bryogenesis, a n d Feta l Deve l opment

secretion from the maternal and fetal pituitary glands. This diminishes maternal and fetal adrenal secretion of the placental estrogen precursor DHEA-S. With Addison disease, pregnant women show lower estrogen levels, principally estrone and estradiol levels (Baulieu, 1 956). The fetal adrenal contribution to estriol synthesis, particularly in later pregnancy, is quantitatively much more important. Maternal androgen-producing tumors can present the pla­ centa with elevated androgen levels. Fortunately, placenta is extraordinary eicient in the aromatization of C19 steroids. For example, Edman and associates ( 1 98 1 ) found that virtually all androstenedione entering the intervillous space is taken up by syncytiotrophoblast and converted to estradiol. None of this C 1 9 steroid enters the fetus. Second, a female fetus i s rarely virilized if there is a maternal androgen-secreting tumor. The placenta eiciently converts aromatizable C19 steroids, including testos­ terone, to estrogens, thus precluding transplacental passage. Indeed, virilized female fetuses of women with an androgen­ producing tumor may be cases in which a nonaromatizable C19 steroid androgen is produced by the tumor-for example, 5a-dihydrotestosterone. Another explanation is that testoster­ one is produced very early in pregnancy in amounts that exceed the placental aromatase capacity at that time. Complete hydatidiorm mole and gestational trophoblastic neo­ plasias lack a fetus and also a fetal adrenal source of C19 steroid precursors for trophoblast estrogen biosynthesis. Consequently, placental estrogen formation is limited to the use of C 19 steroids from the maternal plasma, and therefore estradiol is principally produced (MacDonald, 1 964, 1 966) .

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1 08

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111

C H A PT E R 6

P l a ce nta l A b n o rm a l i t i es

NORMAL PLACENTA . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 1 SHAPE AND SIZE VARIANTS . . . . . . . . . . . . . . . . . . . . . . 1 1 2 EXTRACHORIAL PLACENTATION . . . . . . . . . . . . . . . . . . 1 1 3 CI RCU LATORY DISTU RBANCES . . . . . . . . . . . . . . . . . . . 1 1 3

At minimum, the placenta and cord should be inspected in the delivery room. he decision to request pathological examina­ tion should be based on clinical and placental findings (Red­ line, 2008; Roberts, 2008) . Listed in Table 6- 1 are some of the indications at Parkland Hospital for placental anatomical and histopathological examination.

PLACENTAL CALCI F I CATION. . . . . . . . . . . . . . . . . . . . . . 1 1 5 PLACENTAL TU MORS . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 5 AMNIOCHORION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 6 UMBI LICAL CORD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 7

The placenta, as a rule, presents more or less rounded outlines, but now and again when inserted in the neighbourhood of the internal os it may take on a horseshoe-like appearance, its two branches running partialy around the oriice. -J. Whitridge Williams ( 1 903) he placenta is a fantastic organ in its own right. As discussed in Chapter 5 (p. 88), it provides the indispensable interface between mother and fetus. Indeed, placental anatomy, physiol­ ogy, and molecular structure remain some of the most intrigu­ ing and understudied topics in obstetrics. Although a placental examination by the obstetrician is rec­ ommended, by consensus, routine pathological examination is not mandatory. Indeed, speciic conditions that merit submis­ sion for detailed inspection are still debated. By way of example, the College ofAmerican Pathologists has recommended placen­ tal examination for an extensive list of indications (Langston, 1 997) . Data, however, are insuicient to support all of these.

NORMAL PLACENTA At term, the typical placenta weighs 470 g, is round to oval with a 22-cm diameter, and has a central thickness of 2 . 5 cm (Benirschke, 20 1 2) . It is composed of a placental disc, extra­ placental membranes, and three-vessel umbilical cord. The disc surface that lies against the uterine wall is the basal plate, which is divided by clefts into portions-termed cotyledons. he fetal surface is the chorionic plate, into which the umbili­ cal cord inserts, typically in the center. Large fetal vessels that originate from the cord vessels then spread and branch across the chorionic plate before entering stem villi of the placenta parenchyma. In tracing these, fetal arteries almost invariably cross over veins. he chorionic plate and its vessels are covered by thin amnion, which can be easily peeled away from a post­ delivery specimen. As recommended by the American Institute of Ultrasound in Medicine (20 1 3), placental location and relationship to the internal cervical os are recorded during prenatal sonographic examinations. As visualized ultrasonically, the normal placenta is homogenous and 2 to 4 cm thick, lies against the myome­ trium, and indents into the amnionic sac. The retroplacental space is a hypoechoic area that separates the myometrium from the basal plate and measures less than 1 to 2 cm. The umbilical cord is also imaged, its fetal and placental insertion sites exam­ ined, and its vessels counted. Many placental lesions can be identiied grossly or sono­ graphically, but other abnormalities require histopathological examination for clariication. A detailed description of these

1 12

Place ntatio n , E m b ryogenesis, and Feta l Deve l o p m e nt

TABLE 6-1 . Some I nd ication s for Placenta l Path olog ica l

Exa m i nationa

Maternal Indications Abru pti o n Ante pa rt u m i n fection with feta l ri sks Anti-C D E a l l o i m m u n ization Ces a re a n hysterectomy O l i gohydra m n i os o r hyd ra m n ios Peri part u m fever o r i nfection P reter m d e l i very Postterm d e l ive ry Seve re tra u ma S u s pected p l ace nta l i nj u ry System i c d i so rd e rs with known effects Th i c k or viscid meco n i u m U nexp l a i n ed l ate preg na ncy b leed i n g U nexpla i ned o r rec u rrent preg n a n cy c o m p l i cati o n s Feta l and Neonatal I nd ications Ad m i ssion to an acute ca re n u rsery B i rth we i g h t � 1 0th or � 95th percent i l e Feta ! a n e m i a Feta l o r n eonata l com p rom ise Neon ata l seizures Hyd rops feta l i s I n fectio n o r sepsis Maj o r a n o m a l ies o r a bnormal ka ryotype Mu ltifeta l gestati o n Sti l l b i rt h o r n eo nata l death Va n is h i ng twi n beyond the fi rst tri mester Placenta l Indications G ross lesions Marg i na l o r ve l a m ento u s cord i n se rtion Ma rked ly a bnormal placenta l shape o r size Ma rked ly a d h e red placenta Te rm cord < 32 cm or > 1 00 cm U m b i l ical cord lesions a l n d i cat i o n s a re o rga n ized a l pha betica l ly.

is beyond the scope of this chapter, and interested readers are referred to textbooks by Benirschke (20 1 2) , Fox (2007) , and Faye-Petersen (2006) and their colleagues. Moreover, the placenta accrete syndrome and gestational trophoblas­ tic disease are presented in detail in Chapters 20 and 4 1 , respectively.

SHAPE A N D SIZE VARIANTS Of variants, placentas may infrequently form as separate, nearly equally sized discs. his bilobate placenta may also be called bipartite placenta or placenta duplex. In these, the cord inserts between the two placental lobes-either into a connecting chorionic bridge or into intervening membranes. A placenta containing three or more equivalently sized lobes is rare and termed multilobate. Unlike this equal distribution, one or more

FIGURE 6-1 Succentu riate lobe. A. Vessels extend from the main place ntal disc to s u pply the s m a l l rou nd succentu riate l obe located beneath it. (Used with permission from Dr. Jaya George.) B. Sono­ g ra ph ic i ma g i n g with color Doppler shows the m a i n placental disc i m pla nted posteriorly (asterisk). The succenturiate lobe is located on the anterior uteri ne wa l l across the a m n ionic cavity. Vessels a re identified as the long red a n d blue crossing tu b u l a r structu res that travel with i n the membranes to con nect these two portions of place nta. disparately smaller accessory lobes-succenturiate lobes-may develop in the membranes at a distance from the main placenta (Fig. 6- 1 ) . hese lobes have vessels that course through the membranes. Of clinical importance, if these vessels overlie the cervix to create a vasa previa, dangerous fetal hemorrhage can follow vessel laceration (p. 1 1 8) . n accessory lobe can also be retained in the uterus after delivery to cause postpartum uterine atony and hemorrhage or later endometritis. Rarely, the placental surface area varies from the norm. With placenta membranacea, villi cover all or nearly all the uterine cavity. This may occasionally give rise to serious hemorrhage because of associated placenta previa or accreta (Greenberg, 1 99 1 ; Pereira, 20 1 3) . A ring-shaped placenta may be a variant of placenta membranacea. his placenta is annular, and a par­ tial or complete ring of placental tissue is present. hese abnor­ malities appear to be associated with a greater likelihood of

P lacenta l Abnorm a l ities

antepartum and postpartum bleeding and fetal-growth restric­ tion (Faye-Petersen, 2006; Steemers, 1 995). With placenta fenestrata, the central portion of a placental disc is missing. In some instances, there is an actual hole in the placenta, but more often, the defect involves only villous tissue, and the chorionic plate remains intact. Clinically, it may erroneously prompt a search for a retained placental cotyledon. During pregnancy, the normal placenta increases its thick­ ness at a rate of approximately 1 mm per week. lthough not measured as a component of routine sonographic evaluation, this thickness typically does not exceed 40 mm (Hoddick, 1 985). Placentomegay deines those thicker than 40 mm and commonly results from striking villous enlargement. his may be secondary to maternal diabetes or severe maternal anemia, or to fetal hydrops, anemia, or infection caused by syphilis, toxo­ plasmosis, parvovirus, or cytomegalovirus. In these conditions, the placenta is homogeneously thickened. Less commonly with placentomegaly, fetal parts are present, but villi are edematous and appear as small placental cysts, such as in cases of par­ tial mole (Chap. 20, p. 39 1 ) . Cystic vesicles are also seen with placental mesenchymal dysplasia. Vesicles in this rare condition correspond to enlarged stem villi, but unlike molar pregnancy, trophoblast proliferation is not excessive (Woo, 20 1 1 ) . Rather than villous enlargement, placentomegaly often may result from collections of blood or ibrin, which impart heterogeneity to the placenta. Examples of this are discussed on page 1 1 4 and include massive perivillous fibrin deposition, intervillous or subchorionic thromboses, and large retropla­ cental hematomas.

EXTRACHORIAL PLACENTATION he chorionic plate normally extends to the periphery of the placenta and has a diameter similar to that of the basal plate. With extrachorial placentation, however, the chorionic plate fails to extend to this periphery and leads to a chorionic plate that is smaller than the basal plate (Fig. 6-2) . Circummargin­ ate and circumvallate placentas are the two types. In a circum­ marginate placenta, ibrin and old hemorrhage lie between the

Circummarginate

placenta and the overlying sheer amniochorion. In contrast, with a circumvallate placenta, the chorion periphery is a thick­ ened, opaque, gray-white circular ridge composed of a double fold of chorion and amnion. Sonographically, the double fold can be seen as a thick, linear band of echoes extending from one placental edge to the other. On cross section, however, it appears as two "shelves, " with each lying above an opposing placental margin (see Fig. 6-2) . his anatomy can help difer­ entiate this shelf from amnionic bands and amnionic sheets, which are described on page 1 1 6. In relatively small observational studies of circumvallate pla­ centa diagnosed postpartum, it was associated with increased risk for antepartum bleeding, abruption, fetal demise, and preterm birth (Lademacher, 1 98 1 ; Suzuki, 2008; Taniguchi, 20 1 4) . In a prospective sonographic investigation of 1 7 cases, however, Shen and associates (2007a) found most circumval­ late placentas to be transient. Persistent cases were benign. In general, most otherwise uncomplicated pregnancies with either type of extrachorial placentation have normal outcomes, and no increased surveillance is usually required.

CIRCU LATORY DISTURBANCES Functionally, placental perfusion disorders can be grouped into: ( 1 ) those in which maternal blood low to or within the intervillous space is disrupted, and (2) those with disturbed fetal blood flow through the villi. These lesions are frequently identiied in the normal, mature placenta. Although they can limit maximal placental blood flow, functional reserve within the placental prevents harm in most cases. Indeed, some esti­ mate that up to 30 percent of placental villi can be lost without untoward fetal efects (Fox, 2007) . If extensive, however, these lesions can profoundly limit fetal growth. Lesions that disrupt perfusion are frequently seen grossly or sonographically, whereas smaller lesions are seen only his­ tologically. With sonography, many of these, such as sub­ chorionic fibrin deposition, perivillous ibrin deposition , and intervillous thrombosis, appear as focal sonolucencies within the placenta. Importantly, in the absence of maternal or fetal

Circumvallate Double fold of amnion & chorion

Amnion

Fibrin deposition

A

deposition

FIGURE 6-2 A. In this i l l u stration, circu m m a rg i nate (left) and circumva l l ate (right) varieties of extrachoria l pl acentation a re s h own. A circ u m marginate place nta is covered by a s i n g le layer of a m n iochorion. B. This tra nsa bdomi n a l g ray-scale sonog ra phic image s hows a circumva l late placenta. The double fo l d of a m n ion a n d chorion creates a broad, opa q u e wh ite ri ng a nd ridge on the feta l s u rface.

1 13

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P l ace ntation, E m b ryogen esis, a n d Feta l Deve l o pment

complications, isolated placental sonolucencies are considered incidental indings. • Materna l Blood Flow Disruption

S u bc horion ic F i b r i n Deposition

These collections are caused by slowing of maternal blood low within the intervillous space. In the portion of this space near the chorionic plate, blood stasis is prominent and leads to sub­ sequent ibrin deposition. In viewing the placental fetal surface, subchorionic lesions are commonly seen as white or yellow, firm, round, elevated plaques j ust beneath the chorionic plate. Pe rivi l l o u s F i b r i n D e position

Stasis of maternal blood flow around an individual villus also results in fibrin deposition and can lead to diminished villous oxygenation and necrosis of syncytiotrophoblast (Fig. 6-3) . These small yellow-white placental nodules are grossly visible within the parenchyma of a sectioned placenta. Within limits, these relect normal placental aging. Maternal Floor I nfarction. his extreme variant of perivillous

fibrin deposition is a dense ibrinoid layer within the placental basal plate and is erroneously termed an infarction. Maternal loor inarction has a thick, yellow or white, irm corrugated sur­ face that impedes normal maternal blood low into the intervil­ lous space. In specific cases that extend beyond the basal plate to entrap villi and obliterate the intervillous space, the term massive perivillousibrin deposition is used. The etiopathogenesis is unclear, but maternal auto- or alloimmunity appears con­ tributory (Faye-Peterson, 20 1 7; Romero, 20 1 3) . Antiphospho­ lipid antibody syndrome and angiogenic factors involved with preeclampsia have also been implicated (Sebire, 2002, 2003; Whitten, 20 1 3) .

Subchorial thrombosis

These lesions are not reliably imaged with prenatal sonog­ raphy, but they may create a thicker basal plate. Afected preg­ nancies are associated with miscarriage, fetal-growth restriction, preterm delivery, and stillbirth (Andres, 1 990; Mandsager, 1 994) . Importantly, these adverse outcomes can recur in sub­ sequent pregnancies. I nterv i l l o u s Th rombus

This is a collection of coagulated maternal blood normally found in the intervillous space mixed with fetal blood from a break in a villus. Grossly, these round or oval collections vary in size up to several centimeters. hey appear red if recent or white-yellow if older, and they develop at any placental depth. Intervillous thrombi are common and typically not associated with adverse fetal sequelae. Because there is potential for a communication between maternal and fetal circulations, large lesions can cause elevated maternal serum alpha-fetoprotein levels (Salaia, 1 988). I nfa rction

Chorionic villi themselves receive oxygen solely from maternal circulation supplied to the intervillous space. Any uteroplacen­ tal disease that diminishes or obstructs this supply can result in infarction of an individual villus. These are common lesions in mature placentas and are benign in limited numbers. If numer­ ous, however, placental insuiciency can develop. When they are thick, centrally located, and randomly distributed, they may be associated with preeclampsia or lupus anticoagulant. H e mato m a

As depicted in Figure 6-3, the maternal-placental-fetal unit can develop several hematoma types. These include: ( 1 ) ret­ roplacental hematoma-between the placenta and its adjacent decidua; (2) marginal hematoma-between the chorion and

Subam nionic hematoma Fetal thrombotic vasculopathy

Margi nal hematoma ___

Perivillous -fibrinoid deposition

Retroplacental ---. hematoma

.:. :�.-��-7--- Maternal floor i nfarction

F I G U R E 6-3 Potential s ites of matern a l ly and feta l ly related placenta l circ u latory distu rbances. (Ada pted from Faye-Petersen, 2006.)

Placenta l A b n o r m a l ities

decidua at the placental periphery-known clinically as sub­ chorionic hemorrhage; (3) subamnionic hematoma-these are of fetal vessel origin and found beneath the amnion but above the chorionic plate, and (4) subchorial thrombus along the roof of the intervillous space and beneath the chorionic plate. With this last type, massive subchorionic hematomas are also known as a Breus mole. Sonographically, hematomas evolve with time and appear hyperechoic to isoechoic in the irst week after hemorrhage, hypoechoic at 1 to 2 weeks, and inally, anechoic after 2 weeks. Most subchorionic hematomas visible sonographically are fairly small and of no clinical consequence. However, extensive ret­ roplacental, marginal, and subchorial collections have been associated with higher rates of miscarriage, stillbirth, placen­ tal abruption, and preterm delivery (Ball, 1 996; Fung, 20 1 0; vladu, 2006; Tuuli, 20 1 1 ) . In essence, placental abruption is a large, clinically signiicant retroplacental hematoma. • Fetal Blood Flow Disruption

Feta l Th ro m botic Vascu lo pathy

Placental lesions that arise from fetal circulatory disturbances are also depicted in Figure 6-3 . Deoxygenated fetal blood lows from the two umbilical arteries into arteries within the chorionic plate that divide and send branches out across the placental surface. hese eventually supply individual stem villi, and their thrombosis will obstruct fetal blood low. Distal to the obstruction, afected portions of the villus become non­ functional. Thrombi in limited numbers are normally found in mature placentas. If many villi are afected, which can be seen with preeclampsia, the fetus may sufer growth restriction, stillbirth, or nonreassuring fetal heart rate patterns (Chisholm, 20 1 5; Lepais, 20 1 4; Saleemuddin, 20 1 0) . Vi l lo u s Vas c u l a r Lesions

here is a spectrum of villous capillary lesions. Chorangiosis describes an increased number of capillaries within terminal villi. Its deinition requires ::: 10 capillaries to be present in :::10 villi in ::: 10 ields viewed through a l O x microscope lens (Altshuler, 1 984) . Clinically, long-standing hypoperfusion or hypoxia is thought to be causative (Stanek, 20 1 6) . It is often associated with maternal diabetes mellitus (Ogino, 2000) . Cho­ rangiomatosis describes increased capillary number in stem villi, but terminal villi are spared. his inding has been linked with fetal-growth restriction and anomalies (Bagby, 20 1 1 ) . Despite these associations, the clinical signiicance of both vas­ cular conditions remains unclear. Chorioangiomas are described subsequently. S u ba m n io n ic H em atoma

As indicated earlier, these hematomas lie between the chori­ onic plate and amnion. They most often are acute events during third-stage labor when cord traction ruptures a vessel near the cord insertion. Large chronic antepartum lesions may cause fetomaternal hemorrhage or fetal-growth restriction (Deans, 1 998). They also may be confused with other placental masses such as cho­ rio angioma. In most cases, Doppler interrogation will show

absent internal blood low within a hematoma and permit dif­ ferentiation (Sepulveda, 2000) .

PLACENTAL CALCI FICATION Calcium salts can be deposited throughout the placenta but are most common on the basal plate. Calciication accrues with advancing gestation, and greater degrees are associated with smoking and increasing maternal serum calcium levels (Bedir Findik, 20 1 5 ; Klesges, 1 998; McKenna, 2005). These hyperechoic deposits can easily be seen sonographically, and a grading scale from 0 to 3 relects increasing calciication with increasing numerical grade (Grannum, 1 979) . Following this scheme, a grade 0 placenta is homogeneous, lacks calciication, and displays a smooth, lat chorionic plate. A grade 1 placenta has scattered echogenicities and subtle chorionic plate undu­ lations. Grade 2 shows echogenic stippling at the basal plate. Large, echogenic comma shapes originate from an indented chorionic plate, bur their curve falls short of the basal plate. Last, a grade 3 placenta has echogenic indentations extending from the chorionic plate to the basal plate, which create discrete components that resemble cotyledons. Basal plate densities also increase. As a predictor, this grading scale is not useful for neona­ tal outcome near term (Hill, 1 983; McKenna, 2005; Montan, 1 986) . However, data from two small studies link grade 3 pla­ centa prior to 32 weeks with stillbirth and some other adverse pregnancy outcomes (Chen, 20 1 1 , 20 1 5) .

PLACENTAL TUMORS

• Chorioangioma

These benign tumors have components similar to blood ves­ sels and stroma of the chorionic villus. lso called choran­ giomas, these placental tumors occur with an incidence of approximately 1 percent (Guschmann, 2003) . In some cases, fetal-to-maternal hemorrhage across tumor capillaries leads to elevated levels of maternal serum alpha-fetoprotein (MSAFP) , prompting sonographic evaluation. heir characteristic sono­ graphic appearance shows a well-circumscribed, rounded, pre­ dominantly hypoechoic lesion lying near the chorionic plate and protruding into the amnionic cavity (Fig. 6-4) . Document­ ing increased blood low by color Doppler helps to distinguish these lesions from other placental masses such as hematoma, partial hydatidiform mole, teratoma, metastases, and leiomy­ oma (Prapas, 2000) . Although rare, chorangiocarcinoma tumors clinically mirror chorangiomas (Huang, 20 1 5). Small chorioangiomas are usually asymptomatic. Large tumors, typically those measuring >4 em, can create signiicant arteriovenous shunting within the placenta to cause high-out­ put heart failure, hydrops, and fetal death (l Wattar, 20 1 4) . Compression o f fetal erythrocytes within tumor vessels can lead to hemolysis and microangiopathic anemia (Bauer, 1 978) . Hydramnios, preterm delivery, and fetal-growth restriction are other sequelae. Rare cases include tumor vessel rupture, hemor­ rhage, and fetal death (Batukan, 200 1 ) . At the other extreme, rare rumor infarction can lead to symptom reversal (Zalel, 2002) .

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transfusion can treat serious anemia, amnioreduction can tem­ porize hydramnios, and digoxin therapy can assist fetal heart failure. • Metastatic Tumors

Maternal malignant tumors rarely metastasize to the placenta. Of those that do, melanomas, leukemias and lymphomas, and breast cancer are the most common (Al-Adnani, 2007) . Tumor cells usually are confined within the intervillous space. As a result, metastasis to the fetus is uncommon but is most often seen with melanoma (lexander, 2003) . Similarly, cases in which fetal malignancy metastasizes to the placenta are rare (Reif, 20 1 4) . hese are predominantly fetal neuroectodermal tumors, and only one case in the litera­ ture describes transplantation of tumor to the maternal uterus (Nath, 1 995) .

AMN IOCHORION

• Chorioamnionitis

Normal genital-tract flora can colonize and infect the mem­ branes, umbilical cord, and eventually the fetus. Bacteria most commonly ascend after prolonged membrane rupture and dur­ ing labor to cause infection. Organisms initially infect the cho­ rion and adjacent decidua in the area overlying the internal os. Subsequently, progression leads to full-thickness involvement of the membranes-chorioamnionitis. Organisms often then spread along the chorioamnionic surface to colonize and rep­ licate in amnionic luid. Inlammation of the chorionic plate and of the umbilical cord unisitis-may follow (Kim, 20 1 5 ; Redline, 20 1 2) . Most commonly, there i s microscopic o r occult chorioam­ nionitis, which is caused by a wide variety of microorganisms. his is frequently cited as a possible explanation for many otherwise unexplained cases of ruptured membranes, preterm labor, or both as discussed in Chapter 42 (p. 8 1 0) . In some cases, gross infection is characterized by membrane clouding and is sometimes accompanied by a foul odor that depends on bacterial species. -

F I G U R E 6�4 Placenta l chorioa ngioma. A. Color Doppler i ma g i n g displays blood flow through a large chorioa ng ioma w i t h i t s border outli ned by wh ite a rrows. B. Grossly, the chorioa ngioma is a rou nd, wel l-ci rcu mcised mass protrud i ng from the feta l su rface.

Gray-scale and color Doppler interrogation of the placenta and amnionic fluid volume are used to identiy these tumors. Diagnostic tools that can airm associated fetomaternal hem­ orrhage include MSAFP level and Kleihauer-Betke stain. With fetal concern, echocardiography assesses cardiac function, whereas middle cerebral artery interrogation is used to identiy fetal anemia. Several fetal therapies interfere with the vascular supply to the tumor and reverse fetal heart failure. At specialized peri­ natal centers, endoscopic laser ablation of feeder vessels to the tumor is most frequently used and is associated with favorable fetal outcomes (Hosseinzadeh, 20 1 5) . Of other therapy, fetal

• Other Membrane Abnormalities

Amnion nodosum is a condition characterized by numerous small, light-tan nodules on the amnion overlying the chorionic plate. hese may be scraped of the fetal surface and contain deposits of fetal squames and fibrin that relect prolonged and severe oligohydramnios (Adeniran, 2007) . Two notable bandlike structures can be formed by the fetal membranes. Of these, amnionic band sequence is an anatomical disruption sequence in which amnion bands tether, constrict, or amputate fetal parts. Amnionic bands commonly cause limb-reduction defects, facial clefts, or encephalocele (Barzilay, 20 1 5 ; Guzman-Huerta, 20 1 3) . Umbilical cord compromise is another sequela (Barros, 20 1 4; Heifetz, 1 984b) . Severe defects of the spine or ventral wall that accompany amnionic bands suggest a limb-body wall complex, described in Chapter 1 0 (p. 206) .

Place nta l Abnorm a l ities

Clinically, sonography often irst identiies the sequelae of this sequence rather than the bands themselves. As with any fetal anomaly, targeted sonography is indicated. Identiication of a limb-reduction defect, an encephalocele in an atypical location, or an extremity with edema or positional deformity should prompt careful evaluation for amnionic bands. Management depends on the degree of anatomic deformity. Fetoscopic laser interruption of the band may be suitable in highly selected antepartum cases Qavadian, 20 1 3; Mathis, 20 1 5) . In contrast, a n amnionic sheet i s formed b y normal amnio­ chorion draped over a preexisting uterine synechia. Generally, these sheets pose little fetal risk, although slightly higher rates of preterm membrane rupture and placental abruption have been described (Korbin, 1 998; Nelson, 20 1 0; Tuuli, 20 1 2) .

UMBILICAL CORD

• Length

Most umbilical cords at delivery are 40 to 70 cm long, and very few measure 1 00 cm. Cord length is inluenced positively by both amnionic luid volume and fetal mobility (Miller, 1 982) . In retrospective studies, short cords have been linked with congenital malformations and intrapartum distress (Baergen, 200 1 ; Krakowiak, 2004; Yamamoto, 20 1 6) . Exces­ sively long cords are linked with cord entanglement or prolapse and with fetal anomalies (Olaya-C, 20 1 5; Rayburn, 1 98 1 ) . Because antenatal determination o f cord length i s technically limited, cord diameter has been evaluated as a predictive marker for fetal outcomes. Some have linked lean cords with poor fetal growth and large-diameter cords with macrosomia (Proctor, 20 1 3) . However, the clinical utility of this parameter is still unclear (Barbieri, 2008; Cromi, 2007; Raio, 1 999b, 2003) . • Coiling

Cord coiling characteristics have been reported but are not currently part of standard sonographic evaluation. Usually the umbilical vessels spiral through the cord in a sinistral, that is, let-twisting direction (Fletcher, 1 993; Lacro, 1 987) . he num­ ber of complete coils per centimeter of cord length is termed the umbilical coiling index-Uel (Strong, 1 994) . A normal, antepartum, sonographically derived UCI is 0.4, and this con­ trasts with a normal, postpartum, physically measured value of 0.2 (Sebire, 2007) . UCls < 1 0th percentile are considered hypo­ coile, and those > 90th percentile are hypercoiled. Clinically, the signiicance of coiling extremes is controversial. Some studies evaluating large, unselected cohorts ind no associations between UCI values and poor neonatal outcome Qessop, 20 1 4; Pathak, 20 1 0) . In others, extremes are linked with various adverse out­ comes but most consistently with intrapartum fetal heart rate abnormalities, preterm labor, or fetal-growth restriction (Chitra, 20 1 2; de Laat, 2006; Predanic, 2005; Rana, 1 995). • Vessel Number

Counting cord vessel number is a standard component of ana­ tomical evaluation during fetal sonographic examination and immediately after delivery ( Fig. 6-5) . Embryos initially have two

F I G U R E 6-5 Two u m bil ica l a rteries a re typica l ly documented sonog ra p h ica l ly in the second trimester. They encircle the fetal b l adder (asterisk) as extensions of the s u perior ves ical a rteries. I n t h i s color Doppler sonog ra p h ic i m age, a s i ng le u m bi l ica l a rtery, s hown in red, ru ns a long the bladder wa l l before joi n i ng the u m b i l­ ica l vei n (blue) i n the cord . Below th is, the two vessels of the cord, seen as a l a rger red and s m a l ler b l u e circ le, a re a lso seen floati n g in a cross section of a cord seg ment.

umbilical veins. In the irst trimester, the right vein typically atro­ phies to leave one large vein to accompany the two, thick-walled umbilical arteries. Four-vessel cords are rare and often associated with congenital anomalies (Puvabanditsin, 20 1 1 ) . If it is an iso­ lated inding, however, prognosis can be good (Avnet, 20 1 1 ) . The most common aberration i s that o f a single umbilical artery (SUA), with a cited incidence of 0.63 percent in liveborn neonates, 1 .92 percent with perinatal deaths, and 3 percent in twins (Heifetz, 1 984a) . Fetuses with major malformations frequently have a single artery. Thus, its identiication often prompts consideration for targeted sonography and possibly fetal echocardiography. The most frequent anomalies are car­ diovascular and genitourinary (Hua, 20 1 0; Murphy-Kaulbeck, 20 1 0) . In an anomalous fetus, a single artery greatly increases the aneuploidy risk, and amniocentesis is recommended (Dag­ klis, 20 1 0; Lubusky, 2007) . If target sonography inds otherwise normal anatomy, an iso­ lated single artery in an otherwise low-risk pregnancy does not significantly increase the fetal aneuploidy risk. However, as in isolated inding, it has been associated with fetal-growth restric­ tion and perinatal death in some but not all studies (Chetty­ John, 20 1 0; Gutvirtz, 20 1 6; Hua, 20 1 0; Murphy-Kaulbeck, 20 1 0; Voskamp, 20 1 3 ) . hus, while clinical monitoring of growth is reasonable, the value of sonographic surveillance is unclear. A rare anomaly is that of a fused umbilical artery with a shared lumen. It arises from failure of the two arteries to split during embryological development. The common lumen may extend through the entire cord, but, if partial, it is typically found near the placental insertion site (Yamada, 2005) . In one report, these were associated with a higher incidence of mar­ ginal or velamentous cord insertion, but not congenital fetal anomalies (Fuj ikura, 2003) .

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Pl ace ntation, E m b ryogenesis, a n d Fetal Deve l o pment

Found in most placentas, the Hyrtl anastomosis is a connec­ tion between the two umbilical arteries and lies near the cord insertion into the placenta. This anastomosis acts as a pressure­ equalizing system between the arteries (Gordon, 2007) . As a result, redistribution of pressure gradients and blood flow improves placental perfusion, especially during uterine contrac­ tions or during compression of one umbilical artery. Fetuses with a single umbilical artery lack this safety valve (Raio, 1 999a, 200 1 ) . • Remnants and Cysts

Several structures are housed in the umbilical cord during fetal development, and their remnants may be seen when the mature cord is viewed transversely. Indeed, J auniaux and colleagues ( 1 989) sectioned 1 000 cords, and in one fourth of the speci­ mens, they found remnants of vitelline duct, allantoic duct, and embryonic vessels. These were not associated with congenital malformations or perinatal complications. Cysts occasionally are found along the course of the cord. They are designated according to their origin. True cysts are epithelium-lined remnants of the allantoic or vitelline ducts and tend to be located closer to the fetal insertion site. In con­ trast, the more common pseudocysts form from local degenera­ tion of Wharton jelly and occur anywhere along the cord. Both have a similar sonographic appearance. Single umbilical cord cysts identified in the irst trimester tend to resolve completely, however, multiple cysts may portend miscarriage or aneuploidy (Ghezzi, 2003; Hannaford, 20 1 3) . Cysts persisting beyond this time are associated wi th a risk for structural defects and chro­ mosomal anomalies (Bonilla, 20 1 0; Zangen, 20 1 0) . • Insertion

The cord normally inserts centrally into the placental disc, but eccentric, marginal, or velamentous insertions are variants. Of these, eccentric insertions in general pose no identifiable

fetal risk. Marginal insertion is a common variant-sometimes referred to as a battledore placenta-in which the cord anchors at the placental margin. In one population-based study, the rate was 6 percent in singleton gestations and 1 1 percent in twins (Ebbing, 20 l 3). This common insertion variant rarely causes problems, but it and velamentous insertion occasion­ ally result in the cord being pulled of during delivery of the placenta (Ebbing, 20 1 5; Luo, 20 l 3) . In monochorionic twins, this insertion may be associated with weight discordance (Kent, 20 1 1 ) . With velamentous insertion, the umbilical vessels character­ istically travel within the membranes before reaching the pla­ cental margin (Fig. 6-6) The incidence of velamentous insertion approximates 1 percent but is 6 percent with twins (Ebbing, 20 1 3) . It is more commonly seen with placenta previa (Papin­ niemi, 2007; Raisanen, 20 1 2) . Antenatal diagnosis is possible sonographically, and with velamentous insertion, cord vessels are seen traveling along the uterine wall before entering the placental disc. Clinically, vessels are vulnerable to compression, which may lead to fetal hypoperfusion and acidemia. Higher associated rates of low Apgar scores, stillbirth, preterm delivery, and small for gestational age have been noted (Ebbing, 20 1 7; Esakof, 20 1 5 ; Heinonen, 1 996; Vahanian, 20 1 5) . Accord­ ingly, monitoring of fetal growth is reasonable either clinically or sonographically (Vintzileos, 20 1 5) . Last, with the very uncommon furcate insertion, umbilical vessels lose their protective Wharton jelly shortly before they insert. As a result, they are covered only by an amnion sheath and prone to compression, twisting, and thrombosis. Va sa Previa

With this condition, vessels travel within the membranes and overlie the cervical os. here, they can be torn with cervical dila­ tation or membrane rupture, and laceration can lead to rapid fetal exsanguination. Over the cervix, vessels can also be compressed by a presenting fetal part. Fortunately, vasa previa is uncom­ mon and has an incidence of 2 to 6 per 1 0,000 pregnancies

F I G U R E 6-6 Vela mentous cord i n sertion. A. The u m b i l ica l cord inserts i nto the membra nes. F rom here, the cord vessels bra nch and a re s u pported only by mem bra ne u ntil they reach the placental d isc. B. When viewed sonog ra phica l ly a n d u s i n g color Doppler, the cord ves­ sels a ppea r to l ie agai nst the myometri u m as they travel to i n sert m a rg i n a l ly i nto the placenta l d isc, which l ies at the top of this image.

Place nta l A b norm a l ities

(Ruiter, 20 1 6; Sullivan, 20 1 7) . Vasa previa is classiied as type 1 , in which vessels are part of a velamentous cord insertion, and type 2, in which involved vessels span between portions of a bilobate or a succenturiate placenta (Catanzarite, 200 1 ) . Two other risks are conception with i n vitro fertilization and second-trimester placenta previa, with or without later migra­ tion (Baulies, 2007; Schachter, 2003) . Compared with intrapartum diagnosis, antepartum diagno­ sis greatly improves the perinatal survival rate, which ranges from 97 to 1 00 percent (Oyelese, 2004; Rebarber, 20 14; Swank, 20 1 6) . Thus, vasa previa is ideally identiied early, although this is not always possible. Clinically, an examiner is occasionally able to palpate or directly see a tubular fetal ves­ sel in the membranes overlying the presenting part. Efective screening for vasa previa begins during scheduled midtrimes­ ter sonographic examination. In suspicious cases, transvaginal sonography is added and shows cord vessels inserting into the membranes-rather than directly into the placenta-and ves­ sels running above the cervical internal os ( Fig. 6-7) . Routine color Doppler interrogation of the placental cord insertion site, particularly in cases of placenta previa or low-lying placenta, may aid its detection. With this, the vessel waveform relects the fetal heart rate. In one systematic review, the median pre­ natal detection rate was 93 percent (Ruiter, 20 1 5) . Once vasa previa i s identiied, subsequent imaging i s rea­ sonable because 6 to 1 7 percent of cases ultimately resolve (Rebarber, 20 1 5 ; Swank, 20 1 6) . Bed rest apparently has no added advantage. Antenatal corticosteroids can be provided as indicated or given prophylactically at 28 to 32 weeks' gestation to cover possible urgent preterm delivery. Antenatal hospital­ ization may be considered at 30 to 34 weeks to permit sur­ veillance and expedited delivery for labor, bleeding, or rupture of membranes. Data supporting this is limited, and admission may best serve women with risk factors that portend early deliv­ ery (Society for Maternal-Fetal Medicine, 20 1 5) . A few cases

F I G U R E 6-7 Vasa previa. U s i n g color Doppler, an u m bi l ica l ves­ sel (red circle) is seen overlyi n g the i nternal os. At the bottom, the Doppler waveform seen with this vasa previa has the typica l a ppea ra nce of an u m b i l ical a rtery, with a pu lse rate of 1 4 1 beats per m i n ute.

of antepartum fetoscopic surgery with vessel laser ablation are described (Hosseinzadeh, 20 1 5 ; Johnston, 20 1 4) . However, current practice is early scheduled cesarean delivery. Rob inson and Grobman (20 1 1 ) performed a decision analysis and recom­ mend elective cesarean delivery at 34 to 35 weeks' gestation to balance the risks of perinatal exsanguination versus preterm birth morbidity. he Society for Maternal-Fetal Medicine (20 1 5) considers planned cesarean delivery at 34 to 37 weeks' gestation reasonable. At delivery, the fetus is expeditiously delivered after the hys­ terotomy incision in case a vessel is lacerated during uterine entry. Delayed cord clamping is not encouraged. In all pregnancies, otherwise unexplained vaginal bleeding either antepartum or intrapartum should prompt consideration of vasa previa and a lacerated fetal vessel. In many cases, bleed­ ing is rapidly fatal, and infant salvage is not possible. With less hemorrhage, however, it may be possible to distinguish fetal ver­ sus maternal bleeding. Various tests may be used, and each relies on the increased resistance of fetal hemoglobin to denaturing by alkaline or acid reagents (Odunsi, 1 996; Oyelese, 1 999) . • Knots, Strictures, and Loops

Various mechanical abnormalities in the cord can impede blood low and sometimes cause fetal harm. Of these, true knots are found in approximately 1 percent of births. hese form from fetal movement, and associated risks include hydramnios and diabetes (Hershkovitz, 200 1 ; Raisanen, 20 1 3) . Knots are espe­ cially common and dangerous in monoamnionic twins, which are discussed in Chapter 45 (p. 874) . When true knots are associated with singleton fetuses, the stillbirth risk is increased four- to tenfold (Airas, 2002; S0rnes, 2000) . Knots can be found incidentally during antepartum sonog­ raphy, and a "hanging noose" sign is suggestive (Ramon y Cajal, 2006) . hree-dimensional and color Doppler aid diagnostic accuracy (Hasbun, 2007) . With these knots, optimal fetal sur­ veillance is unclear but may include umbilical artery Doppler velocimetry, nonstress testing, or subjective fetal movement monitoring (Rodriguez, 20 1 2; Scioscia, 20 1 l ) . Allowing vagi­ nal delivery is suitable, but abnormal intrapartum fetal heart rate tracings are more often encountered. hat said, cesarean delivery rates are not increased, and cord blood acid-base values are usually normal (Airas, 2002; Maher, 1 996) . In contrast, alse knots form from focal redundancy and fold­ ing of an umbilical cord vessel. hese lack clinical signiicance. Cord strictures are focal narrowings of the diameter that usually develop near the fetal cord insertion site (Peng, 2006) . Characteristic pathological features include an absence of Wharton jelly and stenosis or obliteration of cord vessels at the narrow segment (Sun, 1 995). In most instances, the fetus is stillborn (French, 2005). Even less common is a cord stricture caused by an amnionic band. Cord loops are frequently encountered and are caused by coiling around various fetal parts during movement. A cord around the neck-a nuchal cord-is common, and vaginal delivery is suitable. One loop is reported in 20 to 34 percent of deliveries; two loops in 2 . 5 to 5 percent; and three loops in 0.2 to 0.5 percent (Kan, 1 9 57; S0rnes, 1 995; Spellacy, 1 966) .

119

1 20

P lacentatio n , E m b ryogen esis, a n d Feta l Deve l o pment

During labor, up to 20 percent of fetuses with a nuchal cord have moderate to severe variable heart rate decelerations, and these are associated with a lower umbilical artery pH (Hankins, 1 987) . Cords wrapped around the body can have similar efects (Kobayashi, 20 1 5) . Despite their frequency, nuchal cords are not associated with greater rates of adverse perinatal outcome (Henry, 20 1 3; Sheiner, 2006) . Last, a u nic presentation describes when the umbilical cord is the presenting part in labor. These are uncommon and most often are associated with fetal malpresentation (Kinugasa, 2007) . A funic presentation in some cases is identiied with placental sonography and color low Doppler (Ezra, 2003) . Overt or occult cord prolapse can complicate labor. hus, once identiied at term, cesarean delivery is typically recommended. • Vascular

Cord hematomas are rare and generally follow rupture of an umbilical vessel, usually the vein, and bleeding into the Whar­ ton jelly. Hematomas have been associated with abnormal cord length, umbilical vessel aneurysm, trauma, entanglement, umbilical vessel venipuncture, and funisitis (Gualandri, 2008). Most are identiied postpartum, but hematomas are recognized so nographically as hypoechoic masses that lack blood low (Chou, 2003) . Sequelae include stillbirth or intrapartum abnor­ mal fetal heart rate pattern (Abraham, 20 1 5; Barbati, 2009; Sepulveda, 2005 ; Towers, 2009) . Umbilical cord vessel thromboses are rare in utero events and seldom diagnosed antepartum. Approximately 70 percent are venous, 20 percent are venous and arterial, and 1 0 percent are arterial thromboses (Heifetz, 1 988). hese all have high associ­ ated rates of stillbirth, fetal-growth restriction, and intrapartum fetal distress (Minakami, 200 1 ; Sato, 2006; Shilling, 20 1 4) . If these are identiied antepartum as hypoechoic masses without blood low, data from case reports support consideration of prompt delivery if of viable age (Kanenishi, 20 1 3) . n umbilical vein varix can complicate either the intraam­ nionic or fetal intraabdominal portion of the umbilical vein. So no graphically and complemented by color Doppler, rare intraamnionic varices show cystic dilatation of the umbilical vein that is contiguous with a normal-caliber portion. Of com­ plications, an intraamnionic varix may compress an adjacent umbilical artery or can rupture or thrombose. In cases without these, White and colleagues ( 1 994) recommend fetal surveil­ lance and delivery once fetal maturity is confirmed. However, data are limited and derived from case reports. he rare umbilical artey aneuysm is caused by congeni­ tal thinning of the vessel wall with diminished support from Wharton jelly. Indeed, most form at or near the cord placental insertion site, where this support is absent. These are associ­ ated with single umbilical artery, trisomy 1 8, amnionic luid volume extremes, fetal-growth restriction, and stillbirth (Hill, 20 1 0; Vyas, 20 1 6) . At least theoretically, these aneurysms could cause fetal compromise and death by compression of the umbilical vein. These aneurysms may appear sonographically as a cyst with a hyperechoic rim. Within the aneurysm, color low and spectral Doppler interrogation demonstrate either low­ velocity or turbulent nonpulsatile flow (Olog, 20 1 1 ; Sepulveda,

2003; Shen, 2007b) . Although not codified, management may include fetal karyotyping, antenatal fetal surveillance, and early delivery to prevent stillbirth (Doehrman, 20 1 4) .

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1 22

P lacentation, E m b ryogenesis, a n d Feta l Deve l o p m ent Lubusky M , Dhaifalah I , Prochazka M , et al: Single umbilical artery and its sid­ ing in the second trimester of pregnancy: relation to chromosomal defects. Prenat Diagn 27:327, 2007 Luo G, Redline RW: Peripheral insertion of umbilical cord. Pediatr Dev Pathol 1 6 (6) :399, 20 1 3 Madu AE: Breus' mole i n pregnancy. ] Obstet Gynaecol 26: 8 1 5 , 2006 Maher ]T, Conti ]A: A comparison of umbilical cord blood gas values between newborns with and without true knots. Obstet Gynecol 88:863, 1 996 Mandsager NT, Bendon R, Mostello D, et al: Maternal floor infarction of the placenta: prenatal diagnosis and clinical signiicance. Obstet Gynecol 83:750, 1 994 Mathis ] , Raio L, Baud D: Fetal laser therapy: applications in the management of fetal pathologies. Prenat Diagn 3 5 (7):623, 20 1 5 McKenna D , Tharmaratnam S , Mahsud S , et al: Ultrasonic evidence of pla­ cental calciication at 36 weeks' gestation: maternal and fetal outcomes. Acta Obstet Gynecol Scand 84:7, 2005 Miller ME, Jones Me, Smith DW: Tension: the basis of umbilical cord growth. ] Pediatr 1 0 1 (5):844, 1 982 Minakami H, Akahori A, Sakurai S, et al: Umbilical vein thrombosis as a pos­ sible cause of perinatal morbidity or mortality: report of two cases. ] Obstet Gynaecol Res 27(2):9 ; 200 1 Montan S, Jorgensen C, Svalenius E, et al: Placental grading with ultrasound in hypertensive and normotensive pregnancies: a prospective, consecutive study. Acta Obstet Gynecol Scand 65:477, 1 986 Murphy-Kaulbeck L, Dodds L, Joseph KS, et al: Single umbilical artery risk factors and pregnancy outcomes. Obstet Gynecol 1 1 6(4) :843, 20 1 0 Nath ME, Kanbour A , Hu ] , e t al: Transplantation o f congenital primitive neu­ roectodermal tumor of fetus to the uterus of mother: application of biotin­ labeled chromosome-speciic probes. lnt ] Gynecol Cancer 5 (6) :459, 1 995 Nelson LD, Grobman WA: Obstetric morbidity associated with amniotic sheets. Ultrasound Obstet Gynecol 36(3) :324, 20 1 0 Odunsi K , Bullough C H , Henzel ] , e t al: Evaluation o f chemical tests for fetal bleeding from vasa previa. Int ] Gynaecol Obstet 5 5 (3):20 , 1 9% Ogino S, Redline RW: Villous capillary lesions of the placenta: distinctions between chorangioma, chorangiomatosis, and chorangiosis. Hum Pathol 3 1 :94 5 , 2000 Olaya-C M, Bernal ]E: Clinical associations to abnormal umbilical cord length in Latin American newbons. ] Neonatal Perinatal Med 8(3):25 1 , 20 1 5 Olog A , homas ]T, Petersen S , et al: Large umbilical artery aneurysm with a live healthy baby delivered at 3 1 weeks. Fetal Diagn Ther 29(4) :33 1 , 20 1 1 Oyelese KO, Turner M , Lees e, et al: Vasa previa: an avoidable obstetric trag­ edy. Obstet Gynecol Surv 54: 1 38 , 1 999 Oyelese Y, Catanzarite V, Prefumo F, et al: Vasa previa: the impact of prenatal diagnosis on outcomes. Obstet Gynecol 1 03:937, 2004 Papinniemi M, Keski-Nisula L, Heinonen S: Placental ratio and risk of vela­ mentous umbilical cord insertion are increased in women with placenta pre­ via. Am ] Perinatol 24:353, 2007 Pathak S, Hook E, Hackett G, et al: Cord coiling, umbilical cord insertion and placental shape in an unselected cohort delivering at term: relationship with common obstetric outcomes. Placenta 3 1 ( 1 1 ) :963, 20 1 0 Peng HQ, Levitin-Smith M , Rochelson B , e t al: Umbilical cord stricture and over coiling are common causes of fetal demise. Pediatr Dev Pathol 9: 14, 2006 Pereira N, Yao R, Guilfoil DS, et al: Placenta membranacea with placenta accreta: radiologic diagnosis and clinical implications. Prenat Diagn 33( 1 3) : 1 293, 20 1 3 Prapas N, Liang RI, Hunter D, e t al: Color Doppler imaging o f placental masses: diferential diagnosis and fetal outcome. Ultrasound Obstet Gynecol 1 6: 5 59, 2000 Predanic M, Perni SC, Chasen ST, et al: Ultrasound evaluation of abnormal umbilical cord coiling in second trimester of gestation in association with adverse pregnancy outcome. Am ] Obstet Gynecol 1 93 :387, 2005 Proctor LK, Fitzgerald B , Whittle L , et al: Umbilical cord diameter percen­ tile curves and their correlation to birth weight and placental pathology. Placenta 34( 1 ) :62, 20 1 3 Puvabanditsin S , Garrow E , Bhatt M , e t al: Four-vessel umbilical cord associ­ ated with multiple congenital anomalies: a case report and literature review. Fetal Pediatr Pathol 30(2):98, 20 1 1 Raio L, Ghezzi F , Di Naro E, et al: In-utero characterization of the blood flow in the Hyrtl anastomosis. Placenta 22: 597, 200 1 Raio L, Ghezzi F, Di Naro E, et al: Prenatal assessment of the Hyrtl anastomo­ sis and evaluation of its function: case report. Hum Reprod 1 4 : 1 890, 1 999a Raio L, Ghezzi F, Di Naro E, et al: Sonographic measurement of the umbilical cord and fetal anthropometric parameters. Eur ] Obstet Gynecol Reprod Bioi 83: 1 3 1 , 1 999b Raio L, Ghezzi F, Di Naro E, et al: Umbilical cord morphologic characteristics and umbilical artery Doppler parameters in intrauterine growth-restricted fetuses. ] Ultrasound Med 22: 1 34 1 , 2003

Raisanen S, Georgiadis L, Harju M, et al: Risk factors and adverse pregnancy outcomes among births afected by velamentous umbilical cord insertion: a retrospective population-based register study. Eur ] Obstet Gynecol Reprod BioI 1 65 (2):23 1 , 20 1 2 Raisanen S, Georgiadis L, Harju M , e t al: True umbilical cord knot and obstet­ ric outcome. Int ] Gynaecol Obstet 1 22( 1 ) : 1 8, 20 1 3 Ramon y Cajal CL, Martinez RO: Four-dimensional ultrasonography o f a true knot of the umbilical cord. Am ] Obstet Gynecol 1 95 : 896, 2006 Rana ] , Ebert GA, Kappy A: Adverse perinatal outcome in patients with an abnormal umbilical coiling index. Obstet Gynecol 8 5 (4):573 , 1 995 Rayburn WF, Beynen A, Brinkman DL: Umbilical cord length and intrapar­ tum complications. Obstet Gynecol 5 7(4) :450, 1 98 1 Rebarber A , Dolin e , Fox NS, et al: Natural history o f vasa previa across gesta­ tion using a screening protocol. ] Ultrasound Med 33( 1 ) : 1 4 1 , 20 1 4 Redline RW: I nlammatory response i n acute chorioamnionitis. Semin Fetal Neonatal Med 1 7( 1 ) :20, 20 1 2 Redline RW: Placental pathology: a systematic approach with clinical correla­ tions. Placenta 29(Suppl A):S86, 2008 Reif P, Hofer N, Kolovetsiou-Kreiner V, et al: Metastasis of an undiferenti­ ated fetal soft tissue sarcoma to the maternal compartment of the placenta: maternal aspects, pathology indings and review of the literature on fetal malignancies with placenta metastases. Histopathology 65(6) :933, 20 1 4 Roberts D]: Placental pathology, a survival guide. Arch Pathol Lab Med 1 32 (4) :64 1 , 2008 Robinson BK, Grobman WA: Efectiveness of timing strategies for delivery of individuals with vasa previa. Obstet Gynecol 1 1 7(3) : 542, 20 1 1 Rodriguez N, Angarita M, Casasbuenas A, et al: Three-dimensional high­ deinition low imaging in prenatal diagnosis of a true umbilical cord knot. Ultrasound Obstet Gynecol 39(2):245, 20 1 2 Romero R , Whitten A , Korzeniewski S], e t al: Maternal Boor infarction/mas­ sive perivillous ibrin deposition: a manifestation of maternal antifetal rejec­ tion? Am ] Reprod I mmunol 70(4):285, 20 1 3 Ruiter L, Kok N , Limpens ] , e t al: Incidence o f and risk indicators for vasa praevia: a systematic review. B]OG 1 23(8) : 1 278, 20 1 6 Ruiter L , Kok N, Limpens J, e t al: Systematic review o f accuracy o f ultrasound in the diagnosis of vasa previa. Ultrasound Obstet Gynecol 45(5) : 5 1 6, 20 1 5 Salaia CM, Silberman L , Herrera NE, et al: Placental pathology at term associ­ ated with elevated midtrimester maternal serum alpha-fetoprotein concen­ t·ation. Am ] Obstet Gynecol 1 58(5): 1 064, 1 988 Saleemuddin A, Tantbirojn P, Sirois K, et al: Obstetric and perinatal complica­ tions in placentas with fetal thrombotic vasculopathy. Pediatr Dev Pathol 1 3(6):459 , 20 1 0 Sato Y , Benirschke K: Umbilical arterial thrombosis with vascular wall necrosis: clinicopathologic indings of 1 1 cases. Placenta 27: 1 5, 2006 Schachter M, Tovbin Y, Arieli S, et al: In vitro fertilization is a risk factor for vasa previa. Fertil Steril 78(3) :642, 2003 Scioscia M, Fornale M , Bruni F, et al: Four-dimensional and Doppler sonogra­ phy in the diagnosis and surveillance of a true cord knot. ] Clin Ultrasound 39(3) : 1 57, 20 1 1 Sebire N]: Pathophysiological signiicance of abnormal umbilical cord coiling index. Ultrasound Obstet Gynecol 30(6) :804, 2007 Sebire N], Backos M , El Gaddal S, et al: Placental pathology, antiphospho­ lipid antibodies, and pregnancy outcome in recurrent miscarriage patients. Obstet Gynecol 10 1 :258, 2003 Sebire N], Backos M, Goldin RD, et al: Placental massive perivillous ibrin deposition associated with antiphospholipid antibody syndrome. B]OG 1 09:570, 2002 Sepulveda W, Aviles G , Carstens E, et al: Prenatal diagnosis of solid placental masses: the value of color Bow imaging. Ultrasound Obstet GynecoI 1 6: 554, 2000 Sepulveda W, Corral E, Kottmann C, et al: Umbilical artery aneUlysm: prena­ tal identiication in three fetuses with trisomy 1 8. Ultrasound Obstet Gyne­ col 2 1 :2 1 3, 2003 Sepulveda W, Wong AE, Gonzalez R, et al: Fetal death due to umbilical cord hematoma: a rare complication of umbilical cord cyst. ] Matern-Fetal Neo­ natal Med 1 8(6):387, 2005 Sheiner E, Abramowicz ]S, Levy A, et al: Nuchal cord is not associated with adverse perinatal outcome. Arch Gynecol Obstet 274: 8 1 , 2006 Shen 0 , Golomb E, Lavie 0, et al: Placental shelf-a common, typically tran­ sient and benign inding on early second-trimester sonography. Ultrasound Obstet Gynecol 29: 1 92, 200 a Shen 0, Reinus e, Baranov A, et al: Prenatal diagnosis of umbilical artery aneurysm: a potentially lethal anomaly. ] Ultrasound Med 26(2):25 1 , 2007b Shilling e, Walsh e, Downey P, et al: Umbilical artery thrombosis is a rare but clinically important inding: a series of cases with clinical outcomes. Pediatr Dev PathoI 1 7(2):89 , 20 1 4

P lacenta l Abnorm a l ities Society for Maternal-Fetal (SMFM) Publications Committee, Sinkey RG, Odibo AO, et al: Diagnosis and management of vasa previa. Am J Obstet GynecoI 2 1 3(5):61 5 , 20 1 5 S0nes T : Umbilical cord encirclements and fetal growth restriction. Obstet Gynecol 86:72 5 , 1 995 S0nes T: Umbilical cord knots. Acta Obstet Gynecol Scand 79: 15 , 2000 Spellacy erN , G ravem H, Fisch RO: The umbilical cord complications of true knots, nuchal coils and cords around the body. Report from the collaborative study of cerebral palsy. Am J Obstet Gynecol 94: 1 1 3 6 , 1 966 Stanek J: Chorangiosis of chorionic villi: what does it really mean? Arch Pathol Lab Med 1 40(6) : 5 8, 20 1 6 5teemers NY, De Rop C , Van Assche A: Zonary placenta. I n t J Gynaecol Obstet 5 1 (3):25 1 , 1 995 Strong TH J r, Jarles DL, Vega JS, et al: The umbilical coiling index. Am J Obstet Gynecol 1 700 Pt 1 ) :29, 1 994 Sullivan EA, Javid N , Duncombe G , et al: Vasa previa diagnosis, clinical prac­ tice, and outcomes in Australia. Obstet Gynecol 1 30(3) : 59 1 , 20 1 7 S u n Y, Arbuckle S, Hocking G , e t al: Umbilical cord stricture and intrauterine fetal death. Pediatr Pathol Lab Med 1 5 :723, 1 995 Suzuki S : Clinical signiicance of pregnancies with circumvallate placenta. J Obstet Gynaecol Res 340 ) : 5 1 , 2008 Swank M L, Garite TJ, Maurel K, et al: Vasa previa: diagnosis and manage­ ment. Obstetrix Collaborative Research Network. Am J Obstet Gynecol 2 1 5(2):223.e 1 , 20 1 6 Taniguchi H, Aoki S , Sakamaki K , e t al: Circumvallate placenta: associated clinical manifestations and complications-a retrospective study. Obstet Gynecol Int 20 1 4:986230, 20 1 4 Towers CV, Juratsch CE, Garite TJ: The fetal heart monitor tracing i n preg­ nancies complicated by a spontaneous umbilical cord haematoma. J Perina­ tol 29: 5 1 7, 2009 Tuuli MG, Norman SM, Odibo AO, et al: Perinatal outcomes in women with subchorionic hematoma: a systematic review and meta-analysis. Obstet GynecoI I 1 7( 5) : 1 205, 20 1 1

Tuuli MG, Shanks A, Bernhard L, et al: Uterine synechiae and pregnancy complications. Obstet GynecoI 1 1 9 (4) : 8 1 0, 20 1 2 Vahanian SA, Lavery JA, Ananth CV, e t al: Placental implantation abnormali­ ties and risk of preterm delivery: a systematic review and metaanalysis. Am J Obstet Gynecol 2 1 3(4 Suppl) :S78, 20 1 5 Vintzileos AM, Ananth CV, Smulian JC: Using ultrasound in the clinical management of placental implantation abnormalities. Am J Obstet Gynecol 2 1 3(4 Suppl):S70, 20 1 5 Voskamp BJ, Fleurke-Rozema H , Oude-Rengerink K , e t al: Relationship of isolated single umbilical artery to fetal growth, aneuploidy and perinatal mortality: systematic review and meta-analysis. Ultrasound Obstet Gynecol 42(6):622, 20 1 3 Vyas NM, Manjeera L , Rai S , e t al: Prenatal diagnosis o f umbilical artery aneu­ rysm with good fetal outcome and review of literature. J Clin Diagn Res 1 0 ( l ) :QDO l , 20 1 6 White SP, Koinas A : Prenatal diagnosis and management o f umbilical vein varix of the intra-amniotic portion of the umbilical vein. J Ultrasound Med 1 3 ( 2) :992, 1 994 Whitten E, Romero R, Korzeniewski SJ, et al: Evidence of an imbalance of angiogeniclantiangiogenic factors in massive perivillous ibrin deposition (maternal Aoor infarction) : a placental lesion associated with recurrent mis­ carriage and fetal death. Am J Obstet GynecoI 208(4) :3 1 0 . e l , 20 1 3 Woo GW, Rocha FG, Gaspar-Oishi M , e t al: Placental mesenchymal dysplasia. Am J Obstet Gynecol 205(6):e3, 201 1 Yamada S, Hamanishi J, Tanada S, et al: Embryogenesis of fused umbilical arteries in human embryos. Am J Obstet Gynecol 1 93 : 1 709, 2005 Yamamoto Y, Aoki S, Oba MS, et al: Relationship between short umbilical cord length and adverse pregnancy outcomes. Fetal Pediatr Pathol 3 5 (2) :8 1 , 2016 Zalel Y , Weisz B, Gamzu R, e t a l : Chorioangiomas o f the placenta: sonographic and Doppler low characteristics. Ultrasound Med 21 :909, 2002 Zangen R, Boldes R, Yafe H, et al: Umbilical cord cysts in the second and third trimesters: signiicance and prenatal approach. Ultrasound Obstet Gynecol 36(3):296, 20 1 0

1 23

1 24

C H A PT E R 7

E m b ryog e n es i s a n d Feta l D eve l o p m e n t

GESTATIONAL AGE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 24 EMBRYONIC DEVELOPMENT . . . . . . . . . . . . . . . . . . . . . 1 25 FETAL DEVELOPMENT AND PHYSIOLOGY. . . . . . . . . . . 1 28 ENERGY AND NUTRITION . . . . . . . . . . . . . . . . . . . . . . . . 1 37 PLACENTAL ROLE IN EMBRYOFETAL DEVELOPMENT . . . 1 39

Our knowledge concening thephysioloy oftheoetus has been markedy enriched during recentyears; nevertheless, when com­ pared with the adult, it oers many points concening which we are but slighty inormed or prooundy ignorant. - J . Whitridge Williams ( 1 903) Since these words were written by Williams in 1 903, great strides in the understanding of fetal organogenesis and physiology have been gained. Contemporary obstetrics incorporates physiol­ ogy and pathophysiology of the fetus, its development, and its environment. An important result is that fetal status has been elevated to that of a patient who, in large measure, can be given the same meticulous care that obstetricians provide for gravidas. In our 2yh edition, the entirety of Section 5 is dedicated to the fetal patient, as are individual chapters in other sections. Indeed, virtually every aspect of obstetrics can afect the developing fetus.

GESTATIONAL AGE Several terms define pregnancy duration and thus fetal age (Fig. 7-1 ) . Gestational age or menstrual age is the time elapsed since the first day of the last menstrual period (LMP), a time that actully precedes conception. This starting time, which is usually approximately 2 weeks before ovulation and fertilization and nearly

3 weeks before blastocyst implantation, has traditionally been used because most women know their approximate last period. Embry­ ologists describe embryofetal development in ovuation age, or the time in days or weeks from ovulation. Another term is postconcep­ tional age, which is nearly identical to ovulation age. Until recently, clinicians customarily calculated menstrual age with term pregnancy averaging approximately 280 days, or 40 weeks between the first day of the LMP and birth. This corresponds to 9 and 1 13 calendar months. However, men­ strual cycle length variability among women renders many of these calculations inaccurate. This realization, combined with the frequent use of first-trimester sonography, has led to more accurate gestational age determination (Duryea, 20 1 5) . Much of this change hinges on the accuracy of early sonographic measurement. As a result, the American College of Obstetri­ cians and Gynecologists, the American Institute of Ultrasound in Medicine, and the Society for Maternal-Fetal Medicine (Reddy, 20 1 4) together recommend the following: 1 . First-trimester sonography is the most accurate method to establish or reairm gestational age. 2. In conceptions achieved with assisted-reproductive technol­ ogy, this gestational age is used.

•

2

I MensesI •

weeks

3

weeks

IOvulationl Fertilization Ilmplantationl •

•

}

Gestational age 40 weeks • Menstrual age (280 days) Ovulation age

Postconceptional age

F I G U R E 7-1 Termi nology u sed to descri be preg na ncy d u ration.

E m bryogenesis a n d Feta l Devel o p m e n t

3. If available, the gestational ages calculated from the LMP and from first-trimester sonography are compared, and the estimated date of coninement (EDC) recorded and dis­ cussed with the patient. 4. The best obstetrical estimate of gestational age at delivery is recorded on the birth certiicate.

and gestational age. For example, the American College ofObstetri­ cians and Gynecologists (20 1 6) has developed a calculator applica­ tion that incorporates sonographic criteria and the LMP or embryo transfer date. This is discussed further in Chapter 1 0 (p. 1 83).

he embryofetal crown-rump length in the first trimester is accurate ±5 to 7 days. hus, if sonographic assessment of gestational age difers by more than 5 days prior to 9 weeks' gestation, or by more than 7 days later in the irst trimester, the estimated delivery date is changed.

The complexity of embryofetal development is almost b eyond comprehension. Figure 7-2 shows a developmental sequence of various organ systems. New information regarding organ devel­ opment continues to accrue. For example, imaging techn iques help unravel the contributions of gene regulation and tissue interaction to eventual three-dimensional organ morphology (Anderson, 20 1 6; Mohun, 20 1 1 ) . Others have described the sequence of gene activation that underlies cardiac development.

EMBRYONIC DEVELOPMENT

• Naegele Rule

An EDC based on LMP can be quickly estimated as follows: add 7 days to the irst day of the LMP and subtract 3 months. For example, if the irst day of the LMP was October 5, the due date is 1 0-05 minus 3 (months) plus 7 (days) = 7-1 2, or July 12 of the following year. This calculation has been termed the Naegele rule. The period of gestation can also be divided into three units of approximately 14 weeks each. These three trimesters are important obstetrical milestones. In addition to estimating the EDC with either Naegele rule or pregnancy "wheels," calculator tools in the electronic medical record and smartphone applications can provide a calculated EDC

Period: Weeks Crown-rump length (cm)

1 1 2

3

Implantation

I

I

4

I

6

Embryonic Period (Organogenesis)

5

7

I

Weight (g)

• Zygote and Blastocyst Development

During the irst 2 weeks after ovulation and then fertilization, the zygote-or preembryo-develops to the blastocyst stage. The blastocyst implants 6 or 7 days following fertilization . The 5 8-cell blastocyst diferentiates into ive embryo-prod ucing cells-the inner cel mass-and the remaining 53 cells form pla­ cental trophoblast. Details of implantation and early develop­ ment of the blastocyst and placenta are described in Chapter 5 (p. 87) .

9 1 I 11 21 I I 11 61 I 1 1201 I I 1241 I 1 1281 I I 1321 I 1 1361 138 28 6-7 25 12 16 21 32 2500 110 6 30 1 1 00 320 1 700

8

I

Fetal Period (Growth)

Hemispheres. cerebellum, Brain

II

Neural tube

Face

Ears

I

Lungs

I

I

Transverse septum, diaphragm

Tracheoesophageal septum, bronchi, lobes

I

Heart

:

Canals, ccchlea. inner ears. ossicles

I

Primitive tube, great vessels, valves. chambers

I

I

I

I

Pinnae

Diaphragm

I

OptiC cups, lens, optic nerves, eyelids

I

!

Temporal lobe, sulci, gyri, cellular migration, myelinization

I

Lips , tongue, palate, cavitatio

I

Eyes

r, fusion

ventricles, choroid plexus

I

I

I

� I

l I

Canal

Brows

I

I

I

Pinnae

kuli

I

Eyes op�n

I

Terminal sacs

1 I

I !

Abdominc I wall, Intestines

Foregut, liver, pancreas, midgut

I

Urinary tract

Genitalia

Mesonephric duct

I

I

I

gut rota ion

I

Metanephric duct collecting sytem

I I

Axial skeleton

Limbs

Skin

I

Genital folds, phallus, labioscrotal swelling

I

I

I

! Peni

I

I

I

, urethra, scrotum

� Clit( ris, labia

Vertebral cartilage, ossification centers

Buds, rays, webs, separate digits

I

I

I

I

I I

Fingernails

I I I I

Glomeruli

:

!I I

I

! :

Vernix

I

I i

Lanugo h a i r

I

I

F I G U R E 7-2 Embryofeta l developm ent according to gestational age determ ined by the first day of the last menses. Times are approxi mate.

1 25

1 26

Placentation, E m b ryoge nesis, a n d Feta l Development

-- Yolk

A

�

'I

sac

.

Yolk ­ sac

Embryo

Developing neural groove

- Amnion

Developi ng villi c

B

F I G U R E 7-3 Early h u ma n e m b ryos. Ovu l ation ages: A. 1 9 days (presom ite). B. 2 1 days (7 somites). C. 22 days ( 1 7 somites). (After d rawi ngs a n d models i n the Carneg ie I n stitute.)

• Embryonic Period

gonadotropin (hCG) become positive by this time. As shown in Figure 7-3, the body stalk is now diferentiated. There are villous cores in which angioblastic chorionic mesoderm can be distinguished and a true intervillous space that contains mater­ nal blood. During the third week, fetal blood vessels in the chorionic villi appear. In the fourth week, a cardiovascular system has formed (Fig. 7-4) . hereby, a true circulation is established

he conceptus is termed an embryo at the beginning of the third week after ovulation and fertilization. Primitive chorionic villi form, and this coincides with the expected day of menses. he embryonic period, during which time organogenesis takes place, lasts 6 weeks. It begins the third week from the LMP through the eighth week. The embryonic disc is well deined, and most pregnancy tests that measure human chorionic

- Neural

...-Rostral

Neural fold

.--Neural

rr---Rostral

groove neuropore

--Somites .-- - Neural

Somites ---Caudal neuropore

f.. -- _ Caudal

,.--

___ Th i rd � branchial arch -- "

�

arch

---

Heart prom i nence

---:

c

D

neuropore

pit

-:- Lens

arch

Mandibular arch

� Arm bud

Som ites

tube

---Otic

Otic pit

__ Hyoid

Y --- Mandibular

fold neuropore

placode

Arm bud

Leg bud

E

--� Leg

bud

FIGURE 7-4 Th ree- to four-week-old embryos. A, B. Dorsal views of embryos d u ri ng 22 to 23 days of development showi ng 8 a nd 1 2 som ites, respectively. (-E. Latera l views of embryos d u ring 24 to 28 days, showin g 1 6, 27, and 33 somites, respectively. (Redrawn from Moore KL: The Developing H u man: Clin ically Oriented E m b ryology, 4th ed. Philadel p h ia, Sa u nders, 1 988.)

E m bryogenesis a n d Feta l Develop m e nt

FIGURE 7-5 E m byro photo g ra phs. A. Dorsa l view of a n embryo at 24 to 26 days a nd correspon d i ng to F ig u re 7-4C. B. Lateral view of a n em bryo at 2 8 days a n d correspond i n g to Fig u re 7-40. C . Latera l view o f e m b ryofetus at 5 6 days, which m a rks the end o f the e m bryo n i c period a n d t h e beg i n n ing of t h e feta l period. The l iver is with i n the wh ite, halo circle. (From Werth B , Tsiara s A : F rom Conceptio n t o Bi rth: A Life U nfolds. New York, Dou bleday, 2002.) both within the embryo and between the embryo and the cho­ rionic villi. Partitioning of the primitive heart begins. Also in the fourth week, the neural plate forms, and it subsequently folds to form the neural tube. By the end of the ifth men­ strual week, the chorionic sac measures approximately 1 cm in diameter. he embryo is 3 mm long and can be measured sonographically. Arm and leg buds have developed, and the amnion is beginning to ensheathe the body stalk, which there­ after becomes the umbilical cord. At the end of the sixth week,

FIGURE 7-6 A. Th is image of a 6-week, 4-day embryo depicts

measurement of the crown-ru m p l e n gth, which is 7.4 mm at this gestational age. B. Despite the ea rly gestational age, M-mode imaging rea d i ly demonstrates e m b ryonic cardiac activity. The hea rt rate in this i mage is 1 24 beats per m i n ute.

the embryo measures approximately 9 mm long, and the neural tube has closed (Fig. 7-5) . Cardiac motion is almost always dis­ cern able sonographically (Fig. 7-6) . The cranial end of the neu­ ral tube closes by 38 days from the LMP, and the caudal end closes by 40 days. Thus, the neural tube has closed by the end of the sixth week. And by the end of the eighth week, the crown­ rump length approximates 22 mm. Fingers and toes are present, and the arms bend at the elbows. The upper lip is complete, and the external ears form definitive elevations on either side of the

1 27

1 28

P l acentation, E m b ryogenes i s, and Feta l Deve lop ment

head. hree-dimensional images and videos of human embryos from the MultiDimensional H uman Embryo project are found at: http://embryo.soad. umich.edu/index.html.

F ETAL DEVELOPMENT A N D PHYSIOLOGY

• Fetal Period Epochs

Transition from the embryonic period to the fetal period occurs at 7 weeks after fertilization, corresponding to 9 weeks after onset of the last menses. At this time, the fetus approximates 24 mm in length, most organ systems have developed, and the fetus enters a period of growth and maturation. These phases are outlined in Figure 7-2. 1 2 G estational Wee ks

The uterus usually is just palpable above the symphysis pubis. Fetal growth is rapid, and the fetal crown-rump length is 5 to 6 cm (Fig. 7-7) . Centers of ossiication have appeared in most fetal bones, and the fingers and toes have become diferentiated. Skin and nails develop, and scattered rudiments of hair appear. he external genitalia are beginning to show deinitive signs of male or female gender. he fetus begins to make spontaneous movements. 1 6 Gestationa l Weeks

Fetal growth slows at this time. The crown-rump length is 1 2 cm, and the fetal weight approximates 1 50 g (Hadlock, 1 99 1 ) . Practically speaing, the sonographic crown-rump length is not measured beyond 1 3 weeks, which corresponds to approxi­ mately 8 .4 cm. Instead, biparietal diameter, head circumference, abdominal circumference, and femur length are measured. Fetal weight in the second and third trimesters is estimated from a combination of these measurements (Chap. 1 0, p. 1 84) . Eye movements begin at 1 6 to 1 8 weeks, coinciding with midbrain maturation. By 1 8 weeks in the female fetus, the uterus is formed and vaginal canalization begins. By 20 weeks in the male, testicles start to descend.

20 Gestationa l Weeks

This is the midpoint of pregnancy as estimated from the LMP. The fetus now weighs somewhat more than 300 g, and weight increases substantially in a linear manner. From this point onward, the fetus moves approximately every minute and is active 1 0 to 30 percent of the day (DiPietro, 2005) . Brown fat forms, and the fetal skin becomes less transparent. Downy lanugo covers its entire body, and some scalp hair can be seen. Cochlear function develops between 22 and 25 weeks, and its maturation continues for 6 months after delivery. 24 Gestational Weeks

The fetus now weighs almost 700 g (Duryea, 20 1 4) . he skin is characteristically wrinkled, and fat deposition begins. The head is still comparatively large, and eyebrows and eyelashes are usu­ ally recognizable. By 24 weeks, the secretory type II pneumo­ cytes have initiated surfactant secretion (Chap. 32, p. 607) . The canalicular period of lung development, during which the bron­ chi and bronchioles enlarge and alveolar ducts develop, is nearly completed. Despite this, a fetus born at this time will attempt to breathe, but many will die because the terminal sacs, required for gas exchange, have not yet formed. The overall survival rate at 24 weeks is barely above 50 percent, and only approximately 30 percent survive without severe morbidity (Rysavy, 20 1 5) . By 26 weeks, the eyes open. Nociceptors are present over all the body, and the neural pain system is developed (Kadic, 20 1 2) . The fetal liver and spleen are important sites for hemopoiesis. 28 Gestationa l Weeks

The crown-rump length approximates 25 cm, and the fetus weighs about 1 1 00 g. The thin skin is red and covered with vernix caseosa. The pupillary membrane has j ust disappeared from the eyes. Isolated eye blinking peaks at 28 weeks. The bone marrow becomes the major site of hemopoiesis. he oth­ erwise normal neonate born at this age has a 90-percent chance of survival . without physical or neurological impairment. 32 a n d 36 Gestational Wee ks

At 32 weeks, the fetus has attained a crown-rump length approximating 28 cm and a weight of about 1 800 g. he skin surface is still red and wrinkled. In contrast, by 36 weeks, the fetal crown-rump length averages about 32 cm, and the weight approximates 2800 g (Duryea, 20 1 4) . Because of subcutaneous fat deposition, the body has become more rotund, and the pre­ vious wrinkled facies is now fuller. Normal fetuses have nearly 1 00-percent survival rate. 40 Gestational Weeks

This is considered term, and the fetus is now fully developed. The average crown-rump length measures about 36 cm, and the average weight approximates 3 500 g. • Central Nervous System Development

F I G U R E 7-7 This image of a 1 2-week, 3-day e m b ryo depicts mea­ s u rement of the crown-ru m p length. The feta l profi le, cra n i u m , a n d a h a n d a n d foot a re a l so visible i n this i mage.

Bra i n Development

The cranial end of the neural tube closes by 3 8 days from the LMP , and the caudal end closes by 40 days. Hence, folic

E m b ryogenesis a nd Feta l Develop m ent

acid supplementation to prevent neural-tube defects must be in place before this point to be eicacious (Chap. 9, p . 1 69 ) . The walls of the neural tube form the brain and spinal cord. The lumen becomes the ventricular system of the brain and the central canal of the spinal cord. D uring the sixth week, the cranial end of the neural tube forms three primary vesicles. In the seventh week, five secondary vesicles develop : the telencephalon-future cerebral hemispheres; diencephalon-thalami ; mesencephalon-midbrain; met­ encephalon-pons and cerebellum; and myelencephalon­ medulla. Meanwhile, lexures develop and fold the brain into its typical configuration. The end of the embryonic period signiies completion of primary and secondary neuralization. At 3 to 4 months' gestation, neuronal proleration peaks. As expected, disorders in this cerebral development phase pro­ foundly worsen function (Volpe, 2008) . Neuronal migration occurs almost simultaneously and peaks at 3 to 5 months. This process is characterized by movement of millions of neuronal cells from their ventricular and subventricular zones to areas of the brain in which they reside for life (Fig. 7-8) . U pregulation of gene expression for neuronal migration has been described (Iruretagoyena, 20 1 4) . Noninvasive methods to study fetal neurodevelopment have also been reported (Goetzl, 20 1 6) . As gestation progresses, the fetal brain appearance steadily changes. Thus, it is possible to identiY fetal age from its exter­ nal appearance (Volpe, 2008) . Neuronal proliferation and migration proceed along with gyral growth and maturation (see Fig. 7-8). Sequential maturation studies by Manganaro (2007) and Dubois (20 1 4) and their colleagues have characterized the developing fetal brain image using magnetic resonance (MR) imaging. Other recent investigations that also used MR imag­ ing have quantiied development of subcortical brain structures from 1 2 to 22 weeks (Meng, 20 1 2) . Myelination o f the ventral roots o f the cerebrospinal nerves and brainstem begins at approximately 6 months, but most

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FIGURE 7-8 Neuro n a l prol iferation a n d migration a re com p l ete at 20 to 24 weeks. During the second h a lf of gestation, organ ization a l events proceed with gyral formation a nd proliferation, d ife rentia­ tion, and m i g ration of cel l u l a r elements. Approximate gestation a l ages a re shown. A . 20 weeks. B . 35 weeks. C. 4 0 weeks.

myelination progresses after birth. This lack of myeli n and incomplete skull ossiication permit fetal brain structure to be seen sonographically throughout gestation. S p i n a l Cord

Whereas the superior two thirds of the neural tube give rise to the brain, the inferior third forms the spinal cord. In the embryo, the spinal cord extends along the entire vertebral column length, but after that it lags behind vertebral growth. Ossiication of the entire sacrum is visible sonographically by approximately 2 1 weeks (Chap. 1 0, p. 1 9 1 ) . By 24 weeks, the spinal cord extends to S I at birth to L3, and in the adult to LI . ' Spinal cord myelination begins at midgestation and con tinues through the irst year of life. Synaptic function is suiciently developed by the eighth week to demonstrate flexion of the neck and trunk (Temiras, 1 968) . During the third trimester, integration of nervous and muscular function proceeds rapidly. • Cardiovascular System

The embryology of the heart is complex. At its earliest stages of formation, the fetal heart undergoes molecular programming, and more than a hundred genes and molecular factors are inte­ gral to its morphogenesis. To summarize, the straight cardiac tube is formed by the 23rd day during an intricate morphoge­ netic sequence, during which each segment arises at a unique time. The tube then undergoes looping, and the chambers then fuse and form septa (Manner, 2009) . The valves develop, and the aortic arch forms by vasculogenesis. For a complete descrip­ tion, refer to Chapter 9 in Hurst s he Heart (Keller, 20 1 3) . Feta l C i rcu lation

his unique circulation is substantially diferent from that of the adult and functions until birth, when it changes dramati­ cally. For example, because fetal blood does not need to enter the pulmonary vasculature to be oxygenated, most of the right ventricular output bypasses the lungs. In addition, the fetal heart chambers work in parallel, not in series, which efectively supplies the brain and heart with more highly oxygenated blood than the rest of the body. Oxygen and nutrient materials required for fetal growth and maturation are delivered from the placenta by the single umbilical vein (Fig. 7-9) . The vein then divides into the ductus venosus and the portal sinus. The ductus venosus is the major branch of the umbilical vein and traverses the liver to enter the inferior vena cava directly. Because it does not supply oxygen to the intervening tissues, it carries well-oxygenated blood directly to the heart. In contrast, the portal sinus carries blood to the hepatic veins primarily on the left side of the liver, and oxygen is extracted. The relatively deoxygenated blood from the liver then lows back into the inferior vena cava, which also receives more deoxygenated blood returning from the lower body. Blood flowing to the fetal heart from the inferior vena cava, therefore, consists of an admixture of arterial-like blood that passes directly through the ductus venosus and less well-oxygenated blood that returns from most of the veins below the level of the diaphragm. The oxygen content of blood delivered to the heart from the inferior vena cava is thus lower than that leaving the placenta.

1 29

1 30

P lacentati on, E m bryog enesis, a n d Feta l Deve l o p ment

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As discussed, the ventricles of the fetal heart work in paral­ lel, not in series. Well-oxygenated blood enters the left ven­ tricle, which supplies the heart and brain, and less oxygenated blood enters the right ventricle, which supplies the rest of the body. These two separate circulations are maintained by the right atrial structure, which efectively directs entering blood to either the left atrium or the right ventricle, depending on its oxygen content. his separation of blood according to its

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oxygen content is aided by the pattern of blood flow in the inferior vena cava. The well-oxygenated blood tends to course along the medial aspect of the inferior vena cava and the less oxygenated blood flows along the lateral vessel wall. This aids their shunting into opposite sides of the heart. Once this blood enters the right atrium, the configuration of the upper inter­ atrial septum-the crista dividens-preferentially shunts the well-oxygenated blood from the medial side of the inferior

E m b ryogenesis and Feta l Deve l o pment

vena cava and the ductus venosus through the foramen ovale into the left heart and then to the heart and brain (Dawes, 1 962) . After these tissues have extracted needed oxygen, the resulting less oxygenated blood returns to the right atrium through the superior vena cava. The less oxygenated blood coursing along the lateral wall of the inferior vena cava enters the right atrium and is deflected through the tricuspid valve to the right ventricle. The superior vena cava courses inferiorly and anteriorly as it enters the right atrium, ensuring that less well-oxygenated blood returning from the brain and upper body also will be shunted directly to the right ventricle. Similarly, the ostium of the coronary sinus lies j ust superior to the tricuspid valve so that less oxygenated blood from the heart also returns to the right ventricle. As a result of this blood flow pattern, blood in the right ventricle is 1 5 to 20 percent less saturated than blood in the left ventricle. lmost 90 percent of blood exiting the right ventricle is shunted through the ductus arteriosus to the descending aorta. High pulmonary vascular resistance and comparatively lower resistance in the ductus arteriosus and the umbilical-placental vasculature ensure that only about 8 percent of right ventricular output goes to the lungs (Fineman, 20 1 4) . Thus, one third of the blood passing through the ductus arteriosus is delivered to the body. The remaining right ventricular output returns to the placenta through the two hypogastric arteries. These two arter­ ies course from the level of the bladder along the abdominal wall to the umbilical ring and into the cord as the umbilical arteries. In the placenta, this blood picks up oxygen and other nutrients and is recirculated through the umbilical vein. Ci rc u l atory C h a n g es at B i rth

After birth, the umbilical vessels, ductus arteriosus, foramen ovale, and ductus venosus normally constrict or collapse. With the functional closure of the ductus arteriosus and the expan­ sion of the lungs, blood leaving the right ventricle preferentially enters the pulmonary vasculature to become oxygenated before it returns to the left heart (Hillman, 20 1 2) . Virtually instanta­ neously, the ventricles, which had worked in parallel in fetal life, now efectively work in series. The more distal portions of the hypogastric arteries undergo atrophy and obliteration within 3 to 4 days after birth. hese become the umbilical liga­ ments, whereas the intraabdominal remnants of the umbilical vein form the ligamentum teres. The ductus venosus constricts by 1 0 to 96 hours after birth and is anatomically closed by 2 to 3 weeks. This ultimately forms the ligamentum venosum (Fineman, 20 1 4) . Feto pl a centa l Blood Vo l u me

Although precise measurements of human fetoplacental blood volume are lacking, Usher and associates ( 1 963) reported values in term normal newborns to average 78 mLlkg when immedi­ ate cord clamping was conducted. Gruenwald ( 1 967) found the fetal blood volume contained in the placenta after prompt cord clamping to average 45 mLlkg of fetal weight. Thus, feto­ placental blood volume at term is approximately 1 2 5 mLlkg of fetal weight. This is important when assessing the magnitude of fetomaternal hemorrhage as discussed in Chapter 1 5 (p. 307) .

• Hemopoiesis

In the early embryo, h emopoiesis is demonstrable first in the yolk sac, followed by the liver, and inally spleen and bone marrow. Both myeloid and erythroid cells are continually pro­ duced by progenitors that are from h ematopoietic stem cells (Golub, 20 1 3; Heinig, 20 1 5) . The first erythrocytes released into the fetal circulation are nucleated and macrocytic. The mean cell volume is at least 1 80 L in the embryo and decreases to 1 05 to 1 1 5 L at term. The erythrocytes of aneuploid fetuses generally do not undergo this maturation and maintain high mean cell volumes- 1 30 L on average (Sipes, 1 99 1 ) . As fetal development progresses, more and more of the circulating erythrocytes are smaller and nonnucleated. With fetal growth, both the blood volume in the common fetoplacental circu­ lation and hemoglobin concentration increase. As shown in Figure 7- 1 0, fetal hemoglobin concentrations rise across preg­ nancy. The Society for Maternal-Fetal Medicine (20 1 5) rec­ ommends a cutof hematocrit value of 30 percent to define anemia. Because of their large size, fetal erythrocytes have a short life span, which progressively lengthens to approximately 90 days at term (Pearson, 1 966). As a consequence, red blood cell production rises. Reticulocytes are initially present at high lev­ els, but decrease to 4 to 5 percent of the total at term. Fetal erythrocytes difer structurally and metabolically from those in the adult (Baron, 20 1 2) . They are more deformable, which serves to ofset their higher viscosity. They also contain several enzymes with appreciably diferent activities. Erythropoiesis is controlled primarily by fetal erythro­ poietin because maternal erythropoietin does not cross the placenta. Fetal hormone production is influenced by testos­ terone, estrogen, prostaglandins, thyroid hormone, and lipo­ proteins (Stockman, 1 992). Serum erythropoietin levels rise with fetal maturity. Although the exact production site is dis­ puted, the fetal liver appears to be an important source until renal production begins. There is a close correlation between the erythropoietin concentration in amnionic fl u id and that in umbilical venous blood obtained by cordocentesis. After birth, erythropoietin normally may not be detectable for up to 3 months. In contrast, platelet production reaches stable levels by mid­ pregnancy, although there is some variation across gestation (Fig. 7- 1 1 ) . The fetal and neonatal platelet count is subject to various agents as discussed in Chapter 1 5 (p. 307) . Feta l H e m o g l o b i n

This tetrameric protein is composed of two copies of two diferent peptide chains, which determine the type of hemo­ globin produced. Normal adult hemoglobin A is made of a and 3 chains. During embryonic and fetal life, various a and 3 chain precursors are produced. This results in the serial production of several diferent embryonic hemoglobins. Genes for 3-type chains are on chromosome 1 1 , and those for a-type chains on chromosome 1 6. Each of these genes is turned on and then of during fetal life, until a and 3 genes, which direct the production of adult hemoglobin A, are per­ manently activated.

131

1 32

P l acentation, E m b ryogenesis, a nd Feta l Deve l o pm e nt 18

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Gestational age (weeks) F I G U R E 7- 1 0 Relations h i p between feta l hemog lobin across gestational age. B l ue d ots ind icate fetuses with hyd rops. (Reprod uced with perm ission from Mari G, Deter R L, Ca rpenter R L, et a l : Noni nvasive d iag nosis by Doppler u ltrasonog ra phy of feta l a n e m ia due to maternal red-ce l l a l lo i m m u n ization. Col l a borative Gro u p for Doppler Assessment of the Blood Velocity in Anemic Fetuses (Level I I-I), N Eng l J Med 2000 J a n 6;342( 1 ):9- 1 4.)

The timing of production of each of these early hemoglobins corresponds to the site of hemoglobin production. Fetal blood is fi r st produced in the yolk sac, where hemoglobins Gower 1 , Gower 2, and Portland are made. Erythropoiesis then moves to the liver, where fetal hemoglobin F is produced. When hemopoi­ esis finally moves to the bone marrow, adult-type hemoglobin A appears in fetal red blood cells and is present in progressively greater amounts as the fetus matures (Pataryas, 1 972) . he final adult version of the . chain is produced exclu­ sively by 6 weeks. Mter this, there are no functional alternative 400,000

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24 26 28 30 3 2 3 4 36 38 40 4 2 G estational a g e (weeks) FIGURE 7-1 1 Platelet cou nts by gestational age obta i ned the first day of l ife. Mea n va l ues a n d 5th a nd 95th percenti les a re shown. (Data from C h ristensen RD, Hen ry E, Antonio DV: Throm bocytosis and throm bocytopenia in the N ICU: incidence, mechanisms and treatments, J Matern Feta l Neonata l Med 201 2 Oct;25 SuppI 4: 1 5- 1 7)

versions. If an a-gene mutation or deletion occurs, no alternate a-type chain can be substituted to form functional hemoglo­ bin. In contrast, at least two versions of the � chain-6 and ,-remain in production throughout fetal life and beyond. In the case of a �-gene mutation or deletion, these two other ver­ sions of the � chain often continue to be produced, resulting in hemoglobin A2 or hemoglobin F, which substitute for the abnormal or missing hemoglobin. Genes are turned of by methylation of their control region, which is discussed in Chapter 1 3 (p. 267). In some situations, methylation does not occur. For example, in newborns of diabetic women, hemoglobin F may persist due to hypomethylation of the , gene (Perrine, 1 988). With sickle cell anemia, the , gene remains unmethylated, and large quantities of fetal hemoglobin continue to be produced. s discussed in Chapter 56 (p. 1 08 1 ), elevated hemoglobin F levels are associated with fewer sickle-cell disease symptoms, and pharmacological modiication of these lev­ els by hemoglobin F-inducing drugs is one approach to treatment. As discussed on page 1 40, there is a functional diference between hemoglobins A and F. At any given oxygen tension and at identical pH, fetal erythrocytes that contain mostly hemoglo­ bin F bind more oxygen than do those that contain nearly all hemoglobin A (Fig. 47-2, p. 920) . his is because hemoglobin A binds 2,3-diphosphoglycerate (2,3-DPG) more avidly than does hemoglobin F, thus lowering the ainity of hemoglobin A for oxygen. During pregnancy, maternal 2,3-DPG levels are greater, and because fetal erythrocytes have lower concentra­ tions of 2,3-DPG, the latter has increased oxygen ainity. he amount of hemoglobin F in fetal erythrocytes begins to decrease in the last weeks of pregnancy. At term, approxi­ mately three fourths of total hemoglobin levels are hemoglobin

E m b ryogenesis a n d Feta l Development

F. During the irst 6 to 1 2 months of life, the hemoglobin F proportion continues to decline and eventually reaches the low levels found in adult erythrocytes. Coa g u lation Factors

With the exception of fi b rinogen, there are no embryonic forms of the various hemostatic proteins. he fetus starts pro­ ducing normal, adult-type procoagulant, ibrinolytic, and anti­ coagulant proteins by 1 2 weeks. Because they do not cross the placenta, their concentrations at birth are markedly below the levels that develop within a few weeks of life (Corrigan, 1 992) . In normal neonates, the levels of factors II, VII, IX, X, XI, and of protein S, protein C, antithrombin, and plasminogen all approximate 50 percent of adult levels. In contrast, levels of factors V, VIII, XIII, and ibrinogen are closer to adult values (Saracco, 2009) . Without prophylactic treatment, the levels of vitamin K-dependent coagulation factors usually decrease even further during the irst few days after birth. his decline is ampliied in breastfed infants and may lead to newborn hemor­ rhage (Chap. 33, p. 626). Fetal ibrinogen, which appears as early as 5 weeks, has the same amino acid composition as adult ibrinogen, however, it has diferent properties (Klagsbrun, 1 988). It forms a less compressible clot, and the ibrin monomer has a lower degree of aggregation (Heimark, 1 988) . Although plasma ibrinogen levels at birth are less than those in nonpregnant adults, the protein is functionally more active than adult ibrinogen (Ign­ jatovic, 20 1 1 ) . Levels o f functional fetal factor XIII-ibrin stabilizing fac­ tor-are signiicantly reduced compared with those in adults (Henriksson, 1 974) . Nielsen ( 1 969) described low levels of plasminogen and elevated ibrinolytic activity in cord plasma compared with that of maternal plasma. Platelet counts in cord blood are in the normal range for nonpregnant adults (see Fig. 7- 1 1 ) . Despite this relative reduction i n procoagulants, the fetus appears to be protected from hemorrhage, and fetal bleeding is rare. Even after invasive fetal procedures such as cordocentesis, excessive bleeding is uncommon. Ney and coworkers ( 1 989) have shown that amnionic luid thromboplastins and a factor(s) in Wharton jelly combine to aid coagulation at the umbilical cord puncture site. Various thrombophilias may cause thromboses and preg­ nancy complications in adults (Chap. 52, p. 1 008). If the fetus inherits one of these mutations, thrombosis and infarction can develop in the placenta or fetal organs. his is usually seen with homozygous inheritance. One example is homozygous protein C mutation, which causes purpura fulminans. Plasma Prote i n s

Liver enzymes and other plasma proteins are produced b y the fetus, and these levels do not correlate with maternal levels (Weiner, 1 992) . Concentrations of plasma proteins, which include albumin, lactic dehydrogenase, aspartate aminotrans­ ferase, 1-glutamyl transpeptidase, and alanine transferase, all rise. Conversely, prealbumin levels decline with gestational age (Fryer, 1 993) . At birth, mean total plasma protein and albumin concentrations in fetal blood are similar to maternal levels. This

is important because albumin binds unconjugated bilirubin to prevent kernicterus in the newborn (Chap. 33, p. 626) . • Respiratory System

Lung maturation and biochemical indices of functional fetal lung maturity are important predictors of early neonatal out­ come. Morphological or functional immaturity at birth leads to the development of the respiratoy distress syndrome (Chap. 34, p. 636) . A suicient amount of surface-active materials­ collectively referred to as suactant-in the amnionic fl u id is evidence of fetal lung maturity. As Liggins ( 1 994) emphasized, however, the structural and morphological maturation of fetal lung also is extraordinarily important to proper lung function. A n ato m ic a l Maturation

The limits of viability appear to be determined by the usual process of pulmonary growth. Like the branching of a tree, lung development proceeds along an established timetable that apparently cannot be hastened by antenatal or neonatal ther­ apy. Within this framework, four essential lung development stages are described by Moore (2000) . First, the pseudoglan­ dular stage entails growth of the intrasegmental bronchial tree between the 5 th and 1 7th weeks. During this period, the lung looks microscopically like a gland. Second, during the canalicu­ lar stage, from 1 6 to 25 weeks, the bronchial cartilage plates extend peripherally. Each terminal bronchiole gives rise to sev­ eral respiratory bronchioles, and each of these in turn divides into multiple saccular ducts. Third, the terminal sac stage begins after 25 weeks. During this stage, alveoli give rise to primitive pulmonary alveoli, that is, the terminal sacs. Simultaneously, an extracellular matrix develops from proximal to distal lung segments until term. Finally, the alveolar stage begins during the late fetal period and continues well into childhood. An extensive capillary network is built, the lymph system forms, and type II pneumocytes begin to produce surfactant. At birth, only approximately 1 5 percent of the adult number of alveoli is present. hus, the lung continues to grow, adding more alveoli for up to 8 years. Various insults can upset this process, and their timing determines the sequelae. One example is fetal renal agenesis, in which amnionic luid is absent at the beginning of lung growth, and major defects occur in all four developmental stages. In another instance, the fetus with membrane rupture and sub­ sequent oligohydramnios before 20 weeks usually exhibits nearly normal bronchial branching and cartilage development but has immature alveoli. In contrast, membrane rupture after 24 weeks may have minimal long-term efect on pulmonary structure. In another example, various growth factors are expressed abnormally in the fetus with a diaphragmatic her­ nia (Candilira, 20 1 5) . Finally, vitamin D is thought to be important for several aspects of lung development (Hart, 20 1 5 ; Lykkedegn, 20 1 5). Pul m o n a ry S u rfactant

After the irst breath, the terminal sacs must remain expanded despite the pressure imparted by the tissue-to-air interface, and surfactant keeps them from collapsing. Surfactant is formed

1 33

1 34

P l acentation, E m b ryog enesis, a n d Feta l Deve l opment

in type II pneumonocytes that line the alveoli. These cells are characterized by multivesicular bodies that produce the lamel­ lar bodies in which surfactant is assembled. During late fetal life, at a time when the alveolus is characterized by a water­ to-tissue interface, the intact lamellar bodies are secreted from the lung and swept into the amnionic fluid during respiratory­ like movements that are termed fetal breathing. At birth, with the first breath, an air-to-tissue interface is established in the lung alveolus. Surfactant uncoils from the lamellar bodies and spreads to line the alveolus to prevent alveolar collapse during expiration. hus, the fetal lungs' capacity to produce surfactant establishes lung maturity. Su rfactant Com position. Gluck ( 1 972) and Hallman ( 1 976) and their coworkers approximated that 90 percent of surfac­ tant's dry weight is lipid, speciically glycerophospholipids. Proteins account for the other 1 0 percent. Nearly 80 percent of the glycerophospholipids are phosphatidylcholines (lecithins) . The principal active component that constitutes half of surfac­ tant is a speciic lecithin, which is dipalmitoylphosphatidylcho­ line (DPPC or PC) . Phosphatidylglycerol (PG) accounts for another 8 to 1 5 percent. Its precise role is unclear because new­ borns without PG usually do well. he other major constituent is phosphatidylinositol (PI) . The relative contributions of each component are shown in Figure 7- 1 2. Su rfactant Synthesis. Biosynthesis takes place in the type II pneumocytes. he apoproteins are produced in the endoplas­ mic reticulum, and the glycerophospholipids are synthesized by cooperative interactions of several cellular organelles. Phos­ pholipid is the primary surface tension-lowering component of surfactant, whereas the apoproteins aid the forming and reform­ ing of a surface ilm. The major apoprotein is surfactant A (SP-A) , which is a gly­ coprotein with a molecular weight of 28,000 to 3 5 ,000 Da (Whitsett, 1 992) . It is synthesized in the type II cells, and its content in amnionic fluid increases with gestational age and fetal lung maturity. SP-A gene expression is demonstrable by 29 weeks (Mendelson, 2005) . Specifically, SP-Ai and SP-A2

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are two separate genes on chromosome 1 0, but their regulation is distinctive and diferent (McCormick, 1 994) . Several smaller apoproteins such as SP-B and SP-C are likely important in optimizing the action of surfactant. For example, deletions. in SP-B gene are incompatible with survival despite production of large amounts of surfactant (Hallman, 20 1 3) . Corticosteroids and Feta l Lung Matu ration. Since Liggins

( 1 969) observed accelerated lung maturation in lamb fetuses given glucocorticosteroids prior to preterm delivery, many suggested that fetal cortisol stimulates lung maturation and surfactant synthesis. It is unlikely that corticosteroids are the only stimulus for augmented surfactant formation. However, when these are administered at certain critical times, they may improve preterm fetal lung maturation. As fetal lung therapy, antenatal betamethasone and dexamethasone use and neonatal replacement surfactant therapy are discussed in Chapter 34 (p. 637) . Breath i ng

Fetal respiratory muscles develop early, and chest wall move­ ments are detected sonographically as early as 1 1 weeks (Koos, 20 1 4) . From the beginning of the fourth month, the fetus engages in respiratory movement suiciently intense to move amnionic luid in and out of the respiratory tract. Some extra­ uterine events have efects on fetal breathing, for example, maternal exercise stimulates it (Sussman, 20 1 6) . • Digestive System

After its embryogenic formation from the yolk sac as the pri­ mordial gut, the digestive system forms the intestines and vari­ ous appendages. The foregut gives rise to the pharynx, lower respiratory system, esophagus, stomach, proximal duodenum, liver, pancreas, and biliary tree. The midgut gives rise to the distal duodenum, jejunum, ileum, cecum, appendix, and the right colon. The hindgut develops into the left colon, rectum, and the superior portion of the anal canal. Numerous malfor­ mations develop in these structures from improper rotation, ixation, and partitioning. Swallowing begins at 1 0 to 1 2 weeks, coincident with the ability of the small intestine to undergo peristalsis and actively transport glucose (Koldovsky, 1 965). As a correlate, neo­ nates born preterm may have swallowing diiculties because of immature gut motility (Singendonk, 20 1 4) . Much of the water in swallowed luid is absorbed, and unabsorbed matter is propelled to the lower colon. Gitlin ( 1 974) demonstrated that late in pregnancy, approximately 800 mg of soluble pro­ tein is ingested daily by the fetus. he stimulus for swallow­ ing is unclear, but the fetal neural analogue of thirst, gastric emptying, and change in the amnionic fluid composition are potential factors (Boyle, 1 992) . The fetal taste buds may play a role because saccharin injected into amnionic fluid increases swallowing, whereas injection of a noxious chemical inhibits it (Liley, 1 972) . Fetal swallowing appears to have little efect on amnionic fluid volume early in pregnancy because the volume swallowed is small compared with the total. However, term fetuses swallow

E m b ryogenesis a nd Feta l Developm ent

between 200 and 760 mL per day-an amount comparable to that of the term neonate (Pritchard, 1 966) . hus at term, amnionic fl u id volume regulation can be substantially altered by fetal swallowing. For example, as discussed in Chapter 1 1 (p. 227) , if swallowing is inhibited, hydramnios is common. Hydrochloric acid and some digestive enzymes are pres­ ent in the stomach and small intestine in minimal amounts in the early fetus. Intrinsic factor is detectable by 1 1 weeks, and pepsinogen by 1 6 weeks. The preterm neonate, depending on its gestational age, may have transient defi c iencies of these enzymes (Lebenthal, 1 983) . Stomach emptying appears to be stimulated primarily by volume. Movement of amnionic luid through the gastroin­ testinal system may enhance growth and development of the alimentary canal. That said, other regulatory factors likely are involved. For example, anencephalic fetuses, in which swallow­ ing is limited, often have normal amnionic fluid volume and normal-appearing gastrointestinal tract. Mecon i u m

Fetal bowel contents consist o f various products o f secretion, such as glycerophospholipids from the lung, desquamated fetal cells, lanugo, scalp hair, and vernix. It also contains undigested debris from swallowed amnionic fluid. The dark greenish-black color forms from bile pigments, especially biliverdin. Meconium can pass from normal bowel peristalsis in the mature fetus or from vagal stimulation. It can also pass when hypoxia stimulates arginine vasopressin (AVP) release from the fetal pituitary gland. AVP stimulates colonic smooth muscle to contract, resulting in intraamnionic defecation (deVane, 1 982; Rosenfeld, 1 985). Meconium is toxic to the respiratory system, and its inhalation can result in meconium aspiration syndrome (Chap. 33, p. 620) . Liver

The hepatic diverticulum is an outgrowth of the endodermal lining of the foregut. Epithelial liver cords and primordial cells diferentiate into hepatic parenchyma. Serum liver enzyme levels increase with gestational age. Still, the fetal liver has a gestational-age-related diminished capacity for converting free unconjugated bilirubin to conjugated bilirubin (Morioka, 2 0 1 5). Because of hepatic immaturity, the preterm new­ born is at particular risk for hyperbilirubinemia (Chap. 33, p. 626) . And because the life span of normal fetal macrocytic erythrocytes is shorter than that of the adult, relatively more unconjugated bilirubin is produced. As j ust noted, the fetal liver conjugates only a small fraction, and this is excreted into the intestine and ultimately oxidized to biliverdin. Most of the unconj ugated bilirubin is excreted into the amnionic luid after 12 weeks and transferred across the placenta (Bashore, 1 969) . Importantly, placental bilirubin transfer is bidirectional. Thus, a woman with severe hemolysis from any cause has excess unconjugated bilirubin that readily passes to the fetus and then into the amnionic fluid. Conversely, conjugated bilirubin is not exchanged to any signifi c ant degree between mother and fetus. Most fetal cholesterol derives from hepatic synthesis, which satisies the large demand for low-density lipoprotein (LDL)

cholesterol by the fetal adrenal glands. Hepatic glycogen is pres­ ent in low concentration during the second trimester, but near term, levels rise rapidly and markedly to reach concentrations that are two- to threefold higher than those in the adult liver. After birth, glycogen content falls precipitously. Pa n crea s

This organ arises from dorsal and ventral pancreatic buds from the endoderm of the foregut. Gene regulation of its development was recently reviewed Qennings, 20 1 5) . Insu­ lin-containing granules can be identiied by 9 to 10 weeks, and insulin is detectable in fetal plasma at 12 weeks (Adam, 1 969) . The pancreas responds to hyperglycemia by secreting insulin (Obenshain, 1 970) . Glucagon has been identified in the fetal pancreas at 8 weeks. Although hypoglycemia does not cause an increase in fetal glucagon levels, similar stimuli do so by 12 hours after birth (Chez, 1 975) . At the same time, however, fetal pancreatic a cells do respond to L-dopa infu­ sions (Epstein, 1 977) . Therefore, unresponsiveness to hypo­ glycemia is likely the consequence of failed glucagon release rather than inadequate production. This is consistent with developmental expression of pancreatic genes in the fetus (Mally, 1 994) . Most pancreatic enzymes are present by 1 6 weeks. T ryp­ sin, chymotrypsin, phospholipase A, and lipase are found in the 1 4-week fetus, and their concentrations increase with ges­ tational age (Wedin, 1 992) . Amylase has been identiied in amnionic luid at 1 4 weeks (Davis, 1 986) . The exocrine func­ tion of the fetal pancreas is limited. Physiologically important secretion occurs only after stimulation by a secretagogue such as acetylcholine, which is released locally after vagal stimula­ tion (Werlin, 1 992). Cholecystokinin normally is released only after protein ingestion and thus ordinarily would not be found in the fetus. • Urinary System

Renal development involves interaction between pluripotential stem cells, undiferentiated mesenchymal cells, and epithelial components (Fanos, 20 1 5) . Two primitive urinary systems­ the pronephros and the mesonephros-precede development of the metanephros, which forms the inal kidney (Chap. 3, p. 33) . The pronephros involutes by 2 weeks, and the meso­ nephros produces urine at 5 weeks and degenerates by 1 1 to 1 2 weeks. Failure of these two structures either to form or to regress may result in anomalous urinary system development. Between 9 and 12 weeks, the ureteric bud and the nephrogenic blastema interact to produce the metanephros. he kidney and ureter develop from intermediate mesoderm. The bladder and urethra develop from the urogenital sinus. The bladder also develops in part from the allantois. By week 1 4, the loop of Henle is functional and reabsorp­ tion occurs (Smith, 1 992) . New nephrons continue to be formed until 36 weeks. In preterm neonates, their formation continues after birth. Although the fetal kidneys produce urine, their ability to concentrate and modiy the pH is limited even in the mature fetus. Fetal urine is hypotonic with respect to fetal plasma and has low electrolyte concentrations.

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Place ntati on, Em b ryogenesis, and Feta l Development

Renal vascular resistance is high, and the filtration fraction is low compared with adult values (Smith, 1 992) . Fetal renal blood low and thus urine pro d uction are controlled or inlu­ enced by the renin-angiotensin system, the sympathetic ner­ vous system, prostaglandins, kallikrein, and atrial natriuretic peptide. The glomerular fi l tration rate increases with gesta­ tional age from less than 0. 1 mLimin at 1 2 weeks to 0.3 mLi min at 20 weeks. In later gestation, the rate remains constant when corrected for fetal weight (Smith, 1 992) . Hemorrhage or hypoxia generally results in a decrease in renal blood flow, glomerular filtration rate, and urine output. Urine usually is found in the bladder even in small fetuses. The fetal kidneys start producing urine at 1 2 weeks. By 1 8 weeks, they are producing 7 to 14 mLi day, and at term, this increases to 650 mLiday (Wladimirof, 1 974) . Maternally administered furosemide increases fetal urine formation, whereas uteropla­ cental insuiciency, fetal growth restriction, and other fetal disorders can lower it. Obstruction of the urethra, bladder, ureters, or renal pelves can damage renal parenchyma and dis­ tort fetal anatomy (Muller Brochut, 2 0 1 4) . Kidneys are not essential for survival in utero but inluence control of amnionic luid composition and volume. hus, abnormalities that cause chronic fetal anuria are usually accompanied by oligohydram­ nios and pulmonary hypoplasia. Pathological correlates and prenatal therapy of urinary tract obstruction are discussed in Chapter 1 6 (p. 325). • Endocrine Gland Development

Pitu ita ry G l a nd

The fetal endocrine system is functional for some time before the central nervous system reaches maturity (Mulchahey, 1 987) . he anterior pituitary gland develops from oral ectoderm­ Rathke pouch, whereas the posterior pituitary gland derives from neuroectoderm. As with other organ systems, embryonic development involves a complex and highly spatiotemporally regulated network of signaling molecules and transcription fac­ tors (Bancalari, 20 1 2; de Moraes, 20 1 2) . Anterior a n d Intermediate Lobes. The adenohypophysis, or

anterior pituitary, diferentiates into five cell types that secrete six protein hormones. Of these types, lactotropes produce pro­ lactin (PRL) , somatotropes produce growth hormone (GH), corticotropes produce adrenocorticotropic hormone (ACTH) , thyrotropes produce thyroid-stimulating hormone (TSH), and gonadotropes produce luteinizing hormone (LH) and follicle­ stimulating hormone (FSH). ACTH is irst detected in the fetal pituitary gland at 7 weeks, and GH and LH have been identifi e d by 1 3 weeks. By the end of the 1 7th week, the fetal pituitary gland synthe­ sizes and stores all pituitary hormones. Moreover, the fetal pituitary is responsive to tropic hormones and is capable of secreting these early in gestation (Grumbach, 1 974) . he fetal pituitary secretes �-endorphin, and cord blood levels of �-endorphin and �-lipotrophin rise with fetal PC0 2 (Brown­ ing, 1 983) . The intermediate lobe in the fetal pituitary gland is well developed. The cells of this structure begin to disappear before

term and are absent from the adult pituitary. he principal secre­ tory products of the intermediate lobe cells are .-melanocyte­ stimulating hormone (.-MSH) and �-endorphin. Neurohypop hysis. The posterior pituitary gland or neurohy­ pophysis is well developed by 1 0 to 1 2 weeks, and oxytocin and arginine vasopressin are demonstrable. Both hormones probably unction in the fetus to conserve water by actions directed largely at the lung and placenta rather than kidney. Vasopressin levels in umbilical cord plasma are increased strikingly compared with maternal levels (Chard, 1 97 1 ) .

Thyroid G l a n d

This gland arises from the endoderm o f the second pharyn­ geal pouch. he thyroid migrates to its inal position and the obliterated thyroglossal duct connects to the foramen cecum of the tongue. he pituitary-thyroid system is functional by the end of the first trimester. The thyroid gland is able to synthe­ size hormones by 1 0 to 1 2 weeks, and thyrotropin, thyroxine, and thyroid-binding globulin (TBG) have been detected in fetal serum as early as 1 1 weeks (Bernal, 2007) . he placenta actively concentrates iodide on the fetal side, and by 1 2 weeks and throughout pregnancy, the fetal thyroid concentrates iodide more avidly than does the maternal thyroid. hus, maternal administration of either radioiodide or appreciable amounts of ordinary iodide is hazardous after this time (Chap. 58, p. 1 1 2 1 ) . Normal fetal levels of free thyroxine (T4) , free triiodothyronine (T3)' and thyroxin-binding globulin increase steadily throughout gestation (Ballabio, 1 989). Compared with adult levels, by 36 weeks, fetal serum concentrations of TSH are higher, total and free T3 concentrations are lower, and T4 is similar. This suggests that the fetal pituitary may not become sensitive to feedback until late pregnancy (horpe­ Beeston, 1 99 1 ) . Fetal thyroid hormone plays a role in the normal develop­ ment of virtually all fetal tissues, especially the brain (Forhead, 20 1 4 ; Rovet, 20 1 4) . Its inluence is illustrated by congenital hyperthyroidism, which develops when maternal thyroid­ stimulating antibody crosses the placenta to stimulate the fetal gland to secrete thyroxine (Donnelley, 20 1 5) . These fetuses develop large goiters as shown in Figure 58-3 (p. 1 1 2 1 ) . They also display tachycardia, hepatosplenomegaly, hematological abnormalities, craniosynostosis, and growth restriction. As chil­ dren, they have perceptual motor diiculties, hyperactivity, and reduced growth (Wenstrom, 1 990) . Fetal thyroid disease and its treatment are discussed in Chapter 1 6 (p. 3 1 8) . Neonatal efects of fetal thyroid deficiency are discussed in Chapter 58 (p. 1 1 26) . The placenta prevents substantial passage of maternal thy­ roid hormones to the fetus by rapidly deiodinating maternal T4 and T3 to form reverse T 3' a relatively inactive thyroid hormone (Vulsma, 1 989) . Several antithyroid antibodies cross the pla­ centa when present in high concentrations (Pelag, 2002) . Those include the long-acting thyroid stimulators (LATS) , LATS­ protector (LATS-P) , and thyroid-stimulating immunoglobulin (TSI) . It was previously believed that normal fetal growth and development, which occurred despite fetal hypothyroidism, provided evidence that T4 was not essential for fetal growth. It

E m b ryog enesis a n d Feta l Deve l opment

is now known, however, that growth proceeds normally because small quantities of maternal T4 prevent antenatal cretinism in fetuses with thyroid agenesis (Forhead, 20 1 4; Vulsma, 1 989). The fetus with congenital hypothyroidism typically does not develop stigmata of cretinism until after birth (Abduljabbar, 20 1 2) . Because administration of thyroid hormone will prevent this, by state law, all newborns are tested for high serum levels of TSH (Chap. 32, p. 6 1 4) . Immediately after birth, thyroid function and metabolism undergo major change. Cooling to room temperature evokes sudden and marked increase in TSH secretion. his in turn causes a progressive increase in serum T4 levels that are maximal 24 to 36 hours after birth. here are nearly simultaneous eleva­ tions of serum T3 levels. Ad re n a l G l a n d s

These glands develop from two separate tissues. The medulla derives from neural crest ectoderm, whereas the fetal and adult cortex arise from intermediate mesoderm. The gland grows rap­ idly through cell proliferation and angiogenesis, cellular migra­ tion, hypertrophy, and apoptosis (Ishimoto, 20 1 1 ) . Fetal glands are much larger in relation to total body size than in adults. he bulk is made up of the inner or fetal zone of the adrenal cortex and involutes rapidly after birth. his zone is scant to absent in rare instances in which the fetal pituitary gland is congenitally absent. he function of the fetal adrenal glands is discussed in detail in Chapter 5 (p. 1 04) . • Immunological System

Infections in utero have provided an opportunity to examine mechanisms of the fetal immune response. Evidence of immu­ nological competence has been reported as early as 1 3 weeks (Kohler, 1 973; Stabile, 1 988) . In cord blood at or near term, the average level for most components is approximately half that of the adult values (Adinolfi, 1 977) . B cells diferentiate from pluripotent hemopoietic stem cells that migrate to the liver (Melchers, 20 1 5 ; Muzzio, 20 1 3) . Despite this, i n the absence o f a direct antigenic stimulus such as infection, fetal plasma immunoglobulins consist almost totally of transferred maternal immunoglobulin G (IgG) . hus, antibodies in the newborn are most often relective of maternal immunological experiences (American College of Obstetricians and Gynecologists, 20 1 7) . he interaction between maternal and fetal T cells is described in detail in Chapter 5 (p. 95). I m m u n og lo b u l i n G

Maternal IgG transport to the fetus begins at approximately 1 6 weeks and increases thereafter. he bulk of IgG is acquired during the last 4 weeks of pregnancy (Gitlin, 1 97 1 ) . Accord­ ingly, preterm neonates are poorly endowed with protective maternal antibodies. Newborns begin to slowly produce IgG, and adult values are not attained until age 3 years. In certain situations, the transfer of IgG antibodies from mother to fetus can be harmful rather than protective to the fetus. The classic example is hemolytic disease of the fetus and newborn resulting from Rh-antigen alloimmunization (Chap. 1 5 , p. 30 1 ) .

I m m u n og lo b u l i n s M a nd A

In the adult, production of immunoglobulin M (IgM) in response to an antigenic stimulus is superseded in a week or so predominantly by IgG production. In contrast, very little IgM is produced by normal fetuses. With infection, the IgM response is dominant in the fetus and remains so for weeks to months in the newborn. And, because IgM is not trans­ ported from the mother, any IgM in the fetus or newborn is that which it produced. hus, specific IgM levels in umbilical cord blood may be useful in fetal infection diagnosis. Accord­ ing to the American College of Obstetricians and Gynecologists (20 1 7) , elevated levels of IgM are usually found in newborns with congenital infection such as rubella, cytomegalovirus infection, or toxoplasmosis. In infants, adult levels of IgM are normally attained by age 9 months. Immunoglobulin A (IgA) ingested in colostrum provides mucosal protection against enteric infections. This may explain the small amount of fetal secretory IgA found in amnionic luid (Quan, 1 999) . Lym p h ocytes a n d Monocytes

he immune system develops early, and B lymphocytes appear in fetal liver by 9 weeks and in blood and spleen by 1 2 weeks. T lymphocytes begin to leave the thymus at approximately 1 4 weeks. Despite this, the newborn responds poorly t o immuniza­ tion, and especially poorly to bacterial capsular polysaccharides. his immature response may stem from a deicient response of newborn B cells to polyclonal activators or from a lack of T cells that proliferate in response to specific stimuli (Hayward, 1 983). In the newborn, monocytes are able to process and pres­ ent antigen when tested with maternal antigen-speciic T cells. DNA methylation patterns are developmentally regulated dur­ ing monocyte-macrophage diferentiation and contribute to the antiinlammatory phenotype in macro phages (Kim, 2 0 1 2) . • Musculoskeletal System

The origin of most muscles and bones is mesodermal. he skel­ eton arises from condensed mesenchyme-embryonic connec­ tive tissue-which eventually forms hyaline cartilage models of the bones. By the end of the embryonic period, ossifi c ation cen­ ters have developed, and bones harden by endochondral ossifi­ cation. The limb buds appear by the fourth week. Most skeletal muscle derives from myogenic precursor cells in the somites.

EN ERGY AND NUTRITION Because of the small amount of yolk in the human ovum, growth of the embryofetus is dependent on maternal nutrients during the irst 2 months. During the fi r st few days after implantation, blastocyst nutrition comes from the interstitial fl u id of the endo­ metrium and the surrounding maternal tissue. Maternal adaptations to store and transfer nutrients to the fetus are discussed in Chapter 4 and summarized here. Three major maternal storage depots are the liver, muscle, and adipose tissue. These maternal depots and the storage hormone insu­ lin are intimately involved in the metabolism of the nutrients absorbed from the gut. Maternal insulin secretion is sustained

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Pl ace ntation, E m b ryogenes is, a n d Feta l Deve l o p m ent

by increased serum levels of glucose and amino acids. he net efect is maternal storage of glucose as glycogen primarily in liver and muscle, retention of some amino acids as protein, and storage of the excess as fat. Storage of maternal fat peaks in the second trimester and then declines as fetal energy demands rise in the third trimester (Pipe, 1 979) . Interestingly, the placenta appears to act as a nutrient sensor, altering transport based on the maternal supply and environmental stimuli (Fowden, 2006; Jansson, 2006b) . During times of fasting, glucose is released from glyco­ gen, but maternal glycogen stores cannot provide an adequate amount of glucose to meet requirements for maternal energy and fetal growth. Augmentation is provided by cleavage of tria­ cylglycerols, stored in adipose tissue, which result in free fatty acids and activation of lipolysis. • Glucose and Fetal Growth

Although dependent on the mother for nutrition, the fetus also actively participates in providing its own nutrition. At mid­ pregnancy, fetal glucose concentration is independent of mater­ nal levels and may exceed them (Bozzetti, 1 988). Glucose is the major nutrient for fetal growth and energy. Logically, mecha­ nisms exist during pregnancy to minimize maternal glucose use so that the limited maternal supply is available to the fetus. Human placental lactogen (hPL), a hormone normally abun­ dant in the mother bur not the fetus, has an insulin antagonist efect. It blocks the peripheral uptake and use of glucose, while promoting mobilization and use of free fatty acids by maternal tissues (Chap. 5, p. 1 00) . his hormone is also diabetogenic as discussed in Chapter 57 (p. 1 1 07) . G l u cose Tra nsport

he transfer of D-glucose across cell membranes is accomplished by a carrier-mediated, stereospecific, nonconcentrating process of facilitated difusion. There are 14 glucose transport proteins (GLUTs) encoded by the SLC2A gene family and characterized by tissue-speciic distribution (Leonce, 2006) . GLUT- 1 and GLUT-3 primarily facilitate glucose uptake by the placenta and are located in the plasma membrane of the syncytiotrophoblast microvilli (Acosta, 20 1 5) . DNA methylation regulates expres­ sion of placental GL UT genes, with epigenetic modiication across gestation (Novakovic, 20 1 3) . It increases as pregnancy advances and is induced by almost all growth factors (Frolova, 20 1 1 ) . GLUT-3 expression is upregulated with fetal growth restriction a anzen, 20 1 3) . Lactate i s a product o f glucose metabolism and transported across the placenta also by facilitated difusion. By way of cotransport with hydrogen ions, lactate is probably transported as lactic acid. Feta l Macrosom i a

The precise biomolecular events in the pathophysiology of fetal macrosomia are not deined. Nonetheless, fetal hyperin­ sulinemia is clearly one driving force (Luo, 20 1 2) . As discussed in Chapter 44 (p. 845), insulin-like growth factor, fibroblast growth factor, and corticotropin-releasing hormone (CRH) and are important regulators of placental development and

function (Gao, 20 1 2 ; Giudice, 1 995). Maternal obesity begets fetal macrosomia (Chap. 44, p. 857). In addition, it is hypoth­ esized that maternal obesity afects fetal cardiomyocyte growth that may result in fetal cardiomyopathy or even congenital heart disease (Roberts, 20 1 5) . • Leptin

This polypeptide hormone was originally identified as a prod­ uct of adipocytes and a regulator of energy homeostasis by curbing appetite. It also contributes to angiogenesis, hemopoi­ esis, osteogenesis, pulmonary maturation, and neuroendocrine, immune, and reproductive functions (Brifa, 20 1 5 ; Maymo, 2009). Leptin is produced by the mother, fetus, and placenta. It is expressed in syncytiotrophoblast and fetal vascular endo­ thelial cells. Of placental production, 5 percent enters the fetal circulation, whereas 95 percent is transferred to the mother (Hauguel-de vlouzon, 2006) . Leptin concentrations peak in amnionic fluid at midpregnancy (Scott-Finley, 20 1 5) . Fetal leptin levels begin rising a t approximately 3 4 weeks and are correlated with fetal weight. This hormone is involved in the development and maturation of the heart, brain, kidneys, and pancreas, and its levels are decreased with fetal growth restric­ tion (Brifa, 20 1 5) . Abnormal levels have been associated with fetal growth disorders, gestational diabetes, and preeclampsia (Fasshauer, 20 1 4) . Postpartum, leptin levels decline in both the newborn and mother. Perinatal leptin is associated with the development of metabolic syndromes later in life (Brifa, 20 1 5 ; Granado, 20 1 2) . • Free Fatty Acids a n d Triglycerides

The newborn has a large proportion of fat, which averages 1 5 percent of body weight (Kimura, 1 99 1 ) . Thus, late in pregnancy, a substantial part of the substrate transferred to the human fetus is stored as fat. Although maternal obesity raises placental fatty acid uptake and fetal fat deposition, it does not appear to afect fetal organ growth (Dube, 20 1 2) . Neutral fat in the form of tri­ glycerides does not cross the placenta, but glycerol does. Despite this, evidence supports that abnormal maternal concentrations of triglycerides-both low and high levels-are associated with major congenital anomalies (Nederlof, 20 1 5) . There i s preferential placental-fetal transfer o f long-chain polyunsaturated fatty acids (Gil-Sanchez, 20 1 2) . Lipoprotein lipase is present on the maternal but not on the fetal side of the placenta. his arrangement favors hydrolysis of triacylglycerols in the maternal intervillous space yet preserves these neutral lipids in fetal blood. Fatty acids transferred to the fetus can be converted to triglycerides in the fetal liver. The placental uptake and use of LDL is an alternative mech­ anism for fetal assimilation of essential fatty acids and amino acids (Chap. 5, p. 1 03). LDL binds to specific receptors in the coated-pit regions of the syncytiotrophoblast microvilli. The large LDL particle, measuring about 250,000 Da, is taken up by a process of receptor-mediated endocytosis. The apopro­ tein and cholesterol esters of LD L are hydrolyzed by lysosomal enzymes in the syncytium to yield: ( 1 ) cholesterol for proges­ terone synthesis; (2) free amino acids, including essential amino acids; and (3) essential fatty acids, primarily linoleic acid.

E m b ryogenesis a n d Feta l Develop ment

• Amino Acids

he placenta concentrates many amino acids in the syncytiotro­ phoblast, which are then transferred to the fetal side by difusion. Based on data from cordocentesis blood samples, the amino acid concentration in umbilical cord plasma is greater than in mater­ nal venous or arterial plasma (Morriss, 1 994) . Transport system activity is influenced by gestational age and environmental fac­ tors. hese include heat stress, hypoxia, under- and overnutri­ tion, and hormones such as glucocorticoids, growth hormone, and leptin (Brifa, 20 1 5; Fowden, 2006) . Trophoblastic mam­ malian target of rapamycin complex 1 (mTORC 1 ) regulates placental amino acid transporters and modulates transfer across the placenta Qansson, 20 1 2) . In vivo studies suggest an upregu­ lation of transport for certain amino acids and a greater delivery rate of these to the fetuses of women with gestational diabetes associated with fetal overgrowth Oansson, 2006a) . • Proteins

Placental transfer of larger proteins is limited, but there are exceptions. IgG crosses the placenta in large amounts via endo­ cytosis and trophoblast Fc receptors. IgG transfer depends on maternal levels of total IgG, gestational age, placental integrity, IgG subclass, and antigenic potential (Palmeira, 20 1 2) . Con­ versely, the larger immunoglobulins-IgA and IgM-of mater­ nal origin are efectively excluded from the fetus. • Ions and Trace Metals

Calcium and phosphorus are actively transported from mother to fetus. Calcium is transferred for fetal skeletal mineralization (Olausson, 20 1 2) . A calcium-binding protein is produced in placenta. Parathyroid hormone-related protein (PTH-rP) , as the name implies, acts as a surrogate PTH in many systems (Chap. 5, p. 1 02) . PTH is not found in fetal plasma, but PTH­ rP is present, suggesting that PTH-rP is the fetal parathormone. The expression of PTH-rP in cytotrophoblasts is modulated by the extracellular concentration of Ca2 + (Hellman, 1 992) . It seems possible, therefore, that PTH-rP synthesized in decidua, placenta, and other fetal tissues is important in fetal Ca2 + trans­ fer and homeostasis. Iodide transport is clearly attributable to a carrier-mediated, energy-requiring active process. And indeed, the placenta con­ centrates iodide. he concentrations of zinc in the fetal plasma also are greater than those in maternal plasma. Conversely, cop­ per levels in fetal plasma are less than those in maternal plasma. his fact is of particular interest because important copper­ requiring enzymes are necessary for fetal development. Placenta l Seq uestration of H eavy Meta l s

h e heavy metal-binding protein metallothionein- 1 i s expressed in human syncytiotrophoblast. his protein binds and seques­ ters a host of heavy metals, including zinc, copper, lead, and cadmium. Despite this, fetal exposure is variable (Caserta, 20 1 3) . For example, lead enters the fetal environment at a level 90 percent of maternal concentrations. In contrast, placental transfer of cadmium is limited (Kopp, 20 1 2) . he most com­ mon source of environmental cadmium is cigarette smoke.

Metallothionein also binds and sequesters copper (Cu2 +) in placental tissue. This accounts for the low levels of Cu2+ in cord blood (Iyengar, 200 1 ) . It is possible that cadmium provokes metallothionein synthesis in the amnion. his may cause Cu2 + sequestration, a pseudo-copper deficiency, and in turn, dimin­ ished tensile strength of the amnion. • Vitamins

he concentration of vitamin A (retinol) is greater in fetal than in maternal plasma and is bound to retinol-binding protein and to prealbumin. Retinol-binding protein is transferred from the maternal compartment across the syncytiotrophoblast. The transport of vitamin C-ascorbic acid-from mother to fetus is accomplished by an energy-dependent, carrier-mediated process. Levels of principal vitamin D metabolites, including 1 ,25-dihydroxycholecalciferol, are greater in maternal plasma than in fetal plasma. The 1 3-hydroxylation of 25-hydroxyvi­ tamin D3 is known to take place in placenta and in decidua.

PLACENTAL ROLE IN EM BRYOFETAL DEVELOPMENT The placenta is the organ of transfer between mother and fetus. Within this maternal-fetal interface, oxygen and nutrients transfer from the mother to the fetus, whereas CO 2 and meta­ bolic wastes are directed from fetus to mother. Fetal blood, which is contained in the fetal capillaries of the chorionic villi, has no direct contact with maternal blood, which remains in the intervillous space. Instead, bidirectional transfer depends on processes that allow or aid the transport through the syncy­ tiotrophoblast that lines chorionic villi. Over the past few years, it has become apparent that breaks in the chorionic villi permit escape of fetal cells and other blood­ borne material into the maternal circulation. This leakage is the mechanism by which some D-negative women become sensi­ tized by the erythrocytes of their D-positive fetus (Chap. 1 5, p. 30 1 ) . In fact, after 1 0 weeks, 1 0 to 1 5 percent of cell-free DNA (cDNA) in maternal plasma is placental in origin, that is, trophoblastic DNA (Norton, 20 1 2) . he escape of fetal cells can also lead to fetal microchimerism from entrance of alloge­ neic fetal cells, including trophoblast, into maternal blood and other organs (Rijnik, 20 1 5) . Volumes are estimated to range from 1 to 6 cells/ mL at midpregnancy. Some fetal cells become "immortal" in that they persist in the maternal circulation and organs following pregnancy. As discussed in Chapter 59 (p. 1 1 39) , the clinical corollary is that some maternal autoim­ mune diseases may be provoked by such microchimerism. • The I ntervillous Space

v Iaternal blood within the intervillous space is the primary source of maternal-fetal transfer. Blood from the maternal spiral arteries directly bathes the trophoblast layer that surrounds the villi. Substances transferred from mother to fetus irst enter the intervillous space and are then transported to the syncytiotro­ phoblast. As such, the chorionic villi and intervillous space func­ tion together as the fetal lung, gastrointestinal tract, and kidney.

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1 40

P l acentation, E m b ryoge n es i s, a n d Feta l Deve l opment

Circulation within the intervillous space is described in Chapter 5 (p. 94) . Intervillous and uteroplacental blood flow increases throughout the irst trimester of normal pregnancies (Merce, 2009) . At term, the residual volume of the intervillous space approximates 1 40 mL. Moreover, utero placental blood flow near term is estimated to be 700 to 900 mLl min, and most of this blood apparently goes to the intervillous space (Pates, 20 1 0) . Active labor contractions reduce blood low into the inter­ villous space to a degree that depends on contraction intensity. Blood pressure within the intervillous space is signifi c antly less than uterine arterial pressure, but somewhat greater than venous pressure. he latter, in turn, varies depending on several factors, including maternal position (Nelson, 20 1 5) . When supine, for example, pressure in the lower part of the inferior vena cava is elevated, and consequently, pressure in the uterine and ovarian veins, and in turn in the intervillous space, is increased. • Placental Transfer

Substances that pass from maternal to fetal blood must irst traverse the syncytiotrophoblast, the attenuated cytotropho­ blast layer, the villous stroma, and inally, the fetal capillary wall. Although this histological barrier separates maternal and fetal circulations, it is not a simple physical barrier. First, throughout pregnancy, syncytiotrophoblast actively or pas­ sively permits, facilitates, and adjusts the amount and rate of substance transfer to the fetus. The maternal-facing syncytio­ trophoblast surface is characterized by a complex microvillous structure. he fetal-facing basal cell membrane is the site of transfer to the intravillous space. Finally, the villous capillaries are an additional site for transport from the intravillous space into fetal blood, or vice versa. In determining the efectiveness of the human placenta as an organ of transfer, several variables are important and shown in Table 7- 1 . Zhao and coworkers (20 1 4) have provided a review of the pharmacology of these interactions. Mech a n i s m s of Tra n sfer

Most substances with a molecular mass < 500 Da pass read­ ily through placental tissue by simple difusion. These include

oxygen, CO 2 , water, most electrolytes, and anesthetic gases (Carter, 2009) . Some low-molecular-weight compounds undergo transfer facilitated by syncytiotrophoblast. These are usually those that have low concentrations in maternal plasma but are essential for normal fetal development. Insulin, steroid hormones, and thyroid hormones cross the placenta, but very slowly. he hormones synthesized in situ in the syncytiotrophoblast enter both the maternal and fetal circulations, but not equally (Chap. 5, p. 9 8 ) . Examples are hCG and hPL concentrations, which are m uch lower in fetal plasma than in maternal plasma. H igh-molecular­ weight substances usually do not traverse the placenta, but there are important exceptions. One is immunoglobulin G-molecular weight 1 60,000 Da-which is transferred by way of a speciic trophoblast receptor-mediated mechanism (Stach, 20 1 4) . Tra n sfer o f Oxyge n a n d Carbon Diox i d e

Placental oxygen transfer is blood flow limited. Using esti­ mated uteroplacental blood low, Longo ( 1 99 1 ) calculated oxygen delivery to be approximately 8 mL 02/min/kg of fetal weight. Normal values for oxygen and CO 2 are presented in Figure 7- 1 3. Because of the continuous passage of oxygen from maternal blood in the intervillous space to the fetus, its oxygen saturation resembles that in maternal capillaries. The average oxygen saturation of intervillous blood is estimated to be 65 to 75 percent, with a partial pressure (P02) of 30 to 35 mm Hg. 70

60

; 50 E

10

58

1 mm Hg approx.

0. 1 33 kPa

1 8 20 22 24 26 28 30 32 34 36 38 40 =

=

Gestation (weeks)

; : E E

Tra n sfer

n

--

O -��-

A

TABLE 7-1 . Va r i a b l es of Materna l-Feta l S u bsta nce

Matern a l plasma concentration a n d carrier-protei n b i n d i n g of the s u bsta n ce Maternal b lood flow rate t h ro u g h the i nterv i l l o u s space Trophoblast s u rface a rea size ava i la ble for exc h a n g e P hysical t rophoblast p roperties to perm it s i m p l e d ifu sion Trophoblast bioch e m ical m a c h i n e ry for active tra n s po rt Su bsta nce meta b o l i s m by the pl ace nta d u ri ng tra nsfer Feta l i n te rvi l lo u s cap i l l a ry su rface a rea size for exc h a n g e Feta l b lood concentrat i o n o f the su bsta nce Specific b i n d i n g o r carrier p rote i ns in the feta l o r mate r n a l ci r c u lation Vi l lo u s ca p i l l a ry b l ood fl ow rate

40

.N 30 . 20 :

---

50

40 30

-; 20 o J ..

B

10

1 8 20 22 24 26 28 30 32 34 36 38 40

Gestation (weeks)

F I G U R E 7-1 3 U m b i l ical venous cordocentesis sam ples obta i ned in fetu ses bei n g eva l uated for possi ble i ntra uteri ne i nfections or hemolysis, but who were fou n d to be hea lthy. A. Oxygen press u re (PoJ B. Carbon d ioxide pressure (Pco 2). Shaded a reas represent 5th to 95th percentiles. (Mod ified from Ramsey, MM: Norm a l Va l ues in Preg n a ncy. Ramsay MM, J a mes OK, Steer PJ, et al (eds). London, El sevier, 1 996, p 1 06.)

E m b ryoge n esis a n d F eta l Develo pment

The oxygen saturation of umbilical vein blood is similar but has a somewhat lower oxygen partial pressure. Fetal hemoglo­ bin has a higher oxygen ainity than adult hemoglobin. This is illustrated by the oxyhemoglobin disassociation curve, which is described in Chapter 47 (p. 920) . he placenta is highly permeable to CO2, which traverses the chorionic villus by diusion more rapidly than oxygen. Near term, the partial pressure of carbon dioxide (PC02) in the umbili­ cal arteries averages 50 mm Hg, which is approximately 5 mm Hg higher than in the maternal intervillous blood. Fetal blood has less ainity for CO2 than does maternal blood, thereby favoring CO2 transfer from fetus to mother. Also, mild maternal hyperventila­ tion results in a fall in Pc02 levels, favoring a transfer of CO2 from the fetal compartment to maternal blood. Sel ective Tra nsfer a n d Faci l itated Diffusion

Although simple difusion is an important method of placental transfer, the trophoblast and chorionic villus unit demonstrate enormous selectivity in transfer. his results in diferent metab­ olite concentrations on the two sides of the villus. Importantly, the levels of many substances that are not synthesized by the fetus are several times higher in fetal than in maternal blood. Ascorbic acid is one example. his relatively low-molecular­ weight substance might be expected to traverse the placenta by simple difusion. he concentration of ascorbic acid, however, is two to four times higher in fetal plasma than in maternal plasma (Morriss, 1 994) . Another example is the unidirectional transfer of iron. Typically, maternal plasma iron concentration is much lower than that in her fetus. Even with severe maternal iron-deficiency anemia, the fetal hemoglobin mass is normal.

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E m b ryog enesis a n d Feta l Development Morriss FH ]r, Boyd RD, Manhendren 0: Placental transport. In Knobil E, Neill ] (eds): The Physiology of Reproduction, Vol II. New York, Raven, 1 994, p 8 1 3 Mulchahey JJ, DiBlasio AM, Martin MC, e t al: Hormone production and pep­ tide regulation of the human fetal pituitary gland. Endocr Rev 8:406, 1 987 M .iller Brochut AC, homann 0, Kluwe W, et al: Fetal megacystis: experience of a single tertiary center in Switzerland over 20 years. Fetal Diagn Ther 36(3) :2 1 5 , 20 1 4 Muzzio 0, Zenclussen AC, Jensen F: The role of B cells i n pregnancy: the good and the bad. Am ] Reprod Immunol 69(4):408, 20 1 3 Nederlof M , d e Walle HE, van Poppel M N , e t a1: Deviant early pregnancy matenal triglyceride levels and increased risk of congenital anomalies: a pro­ spective community-based cohon study. B]OG 1 22: 1 1 76, 20 1 5 Nelson DB, Stewart RD, Matulevicius SA, et al: The efects of matenal posi­ tion and habitus on maternal cardiovascular parameters as measured by car­ diac magnetic resonance. Am ] PerinatoI 32( 1 4) : 1 3 1 8, 20 1 5 Ney ]A, Fee Sc, Dooley S L, et al: Factors inluencing hemostasis after umbili­ cal vein puncture in vitro. Am ] Obstet Gynecol 1 60:424, 1 989 Nielsen NC: Coagulation and ibrinolysin in normal women immediately post­ partum and in newborn infants. Acta Obstet Gynecol Scand 48:37 1 , 1 969 Norton ME, ]acobsson B, Swamy GK, et al: Cell-free DNA analysis for nonin­ vasive examination of trisomy. N Engl ] Med 3 2( 1 7) : 1 589, 20 1 5 Novakovic B , Gordon L, Robinson WP, et a1: Glucose as a fetal nutrient: dynamic regulation of several glucose transporter genes by DNA methylation in the human placenta across gestation. ] Nutr Biochem 24( 1 ):282, 20 1 3 Obenshain SS, Adam PAl, King KC, e t al: Human fetal insulin response to sustained maternal hyperglycemia. N Engl ] Med 283: 566, 1 970 Olausson H, Goldberg GR, Laskey A, et al: Calcium economy in human preg­ nancy and lactation. Nutr Res Rev 25( 1 ) :40, 20 1 2 Palmeira P , Quinello C , Silveira-Lessa AL, e t al: IgG placental transfer i n health and pathological pregnancies. C1in Dev Immunol 20 1 2:985646, 20 1 2 Pataryas HA, Stamatoyannopoulos G: Hemoglobins i n human fetuses: evi­ del1Ce for adult hemoglobin production after the 1 1 th gestational week. Blood 39:688, 1 972 Pates ]A, Hatab MR, McIntire DO, et al: Determining uterine blood low in pregnancy with magnetic resonance imaging. Magn Reson Imaging 28(4) : 507, 20 1 0 Pearson HA: Recent advances i n hematology. ] Pediatr 69:466, 1 966 Pelag 0, Cada S, Peleg A, et al: he relationship berween matenal serum thyroid-stimulating immunoglobulin and fetal and neonatal thyrotoxicosis. Obstet Gynecol 99: 1 040, 2002 Perrine SP, G reene MF, Cohen A, et al: A physiological delay in human fetal hemoglobin switching is associated with speciic globin DNA hypo methyl­ ation. FEBS Lett 228: 1 39, 1 988 Pipe NG] , Smith T, Halliday 0, et al: Changes in fat, fat-free mass and body water in human normal pregnancy. B]OG 86:929, 1 979 Pritchard ]A: Fetal swallowing and amniotic fluid volume. Obstet Gynecol 28:606, 1 966 Quan CP, Forestier F, Bouvet ]P: Immunoglobul ins of the human amniotic luid. Am ] Reprod Immunol 42:2 1 9, 1 999 Ramsay MM, James OK, Steer P], et al (eds): Normal Values in Pregnancy. London, Elsevier, 1 996, p 1 06 Reddy UM, Abuhamad AZ, Levine 0, et al: Fetal imaging: executive sum­ mary of a joint Eunice Kennedy Shriver National Institute of Child Health and H uman Development, Society for Maternal-Fetal Medicine, American Institute of Ultrasound in Medicine, American College of Obstetricians and Gynecologists, American College of Radiology, Society for Pediatric Radi­ ology, and Society of Radiologists in Ultrasound Fetal Imaging workshop. Obstet GynecoI 1 23(5) : 1 070, 20 1 4 Rijnink EC, Penning ME, Wolterbeek R , e t al: Tissue microchimerism is increased during pregnancy: a human autopsy study. Mol Hum Reprod Aug 24, 20 1 5 Roberts VH], Frias AE, Grove KL: Impact o f maternal obesity on fetal pro­ gramming of cardiovascular disease. Physiology 30:224, 20 1 5

Rosenfeld CR, Poner JC: Arginine vasopressin in the developing fetus. In Albrecht ED, Pepe GJ (eds): Research i n Perinatal Medicine, Vol 4. Perina­ tal Endocrinology. Ithaca, Perinatology Press, 1 985, p 9 1 Rovet JF: The role of thyroid hormones for brain development and cognitive function. Endocr Dev 26:26, 20 1 4 Rysavy M A, L i L , Bell EF, e t a l : Berween-hospital variation i n treatment and outcomes in extremely preterm infants. N Engl J Med 372( 1 9) : 1 80 1 , 20 1 5 Saracco P, Parodi E, Fabris C, et al: Management and investigation of neona­ tal thromboembolic events: genetic and acquired risk factors. Thromb Res 1 23(6):805, 2009 Scott-Finley M, Woo JG, Habli M, et a1: Standardization of amniotic luid leptin levels and utility in matenal overweight and fetal undergrowth. J Perinatol 3 5 (8):54 , 20 1 5 Singendonk MM, Rommel N , Omari TI, e t al: Upper gastrointestinal motil­ ity: prenatal development and problems in infancy. Nat Rev Gastroenterol Hepatol 1 1 (9) : 545, 20 14 Sipes SL, Weiner CP, Wenstrom KD, et al: The association between fetal karyotype and mean corpuscular volume. Am ] Obstet Gynecol 1 65 : 1 37 1 , 1 99 1 Smith FG, Nakamura KT, Segar JL, et al: I n Polin A , Fox W (eds) : Fetal and Neonatal Physiology, Vol 2, Chap 1 1 4. Philadelphia, Saunders, 1 992, p 1 1 87 Society for Matenal-Fetal Medicine, Mari G, Norton ME, et al: Society for Matenal-Fetal Medicine (SMFM) Clin ical Guidelines #8: the fetus at risk for anemia-diagnosis and management. Am ] Obstet Gynecol 21 2(6) :697, 20 1 5 Stabile I , Nicolaides KH, Bach A, et al: Complement factors in fetal and mater­ nal blood and amniotic luid during the second trimester of normal preg­ nancy. BJOG 95:28 1 , 1 988 Stach Sc, Brizot Mde L, Liao AW, et al: Transplacental total IgG transfer in rwin pregnancies. Am J Reprod Immunol 72(6) : 5 5 5 , 20 1 4 Stockman JA III, deAlarcon PA: Hematopoiesis and granulopoiesis. I n Polin A, Fox WW (eds): Fetal and Neonatal Physiology. Philadelphia, Saunders, 1 992, p 1 327 Sussman 0, Lye S], Wells GO: Impact of matenal physical activity on fetal breathing and body movement-a review. Early Hum Dev 94:53, 2 0 1 6 Temiras PS, Vernadakis A, Sherwood N M : Development and plasticiry o f the nervous system. In AssaJi NS (ed) : Biology of Gestation, Vol VII. h e Fetus and Neonate.. New York, Academic Press, 1 968 Thorpe-Beeston JG, Nicolaides KH, Felton CV, et al: Maturation of the secre­ tion of thyroid hormone and thyroid-sti mulating hormone in the fetus. N Engl J Med 324:532, 1 9 9 1 Usher R , Shephard M, Lind ] : h e blood volume of the newbon infant and placental transfusion. Acta Paediatr 52:497, 1 963 Volpe JJ: Neurology of the Newborn, 5th ed. Saunders, Philadelphia, 2008, p 85 Vulsma T, Gons MH, De Vijlder JJ: Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organi6cation defect or thyroid agenesis. N Engl ] Med 32 1 : 1 3, 1 989 Weiner CP, Sipes SL, Wenstrom K: The efect of fetal age upon normal fetal laboratory values and venous pressure. Obstet Gynecol 79:7 1 3, 199 2 Wenstrom K O , Weiner C P , Williamson A , et al: Prenatal diagnosis of fetal hyperthyroidism using funipuncture. Obstet Gynecol 76:5 1 3, 1 990 Werlin SL: Exocrine pancreas. In Polin A, Fox WW (eds): Fetal and Neonatal Physiology. Philadelphia, Saunders, 1 992, p 1 047 Werth B, Tsiaras A: From Conception to Birth: A Life Unfolds. New York, Doubleday, 2002 Whitsett JA: Composition of pulmonary surfactant lipids and proteins. I n Polin A , Fox W (eds): Fetal and Neonatal Physiology. Philadelphia, Saunders, 1 992, p 941 Wladimirof ]W, Campbell S: Fetal urine-production rates in normal and com­ plicated pregnancy. Lancet 1 : 1 5 1 , 1 974 Zhao Y, Hebert MF, Venkataramanan R: Basic obstetric pharmacology. Semin PerinatoI 38(8):4 5, 20 1 4

1 43

I

1 46

C H A PT E R 8

P reco n ce pt i o n a l Ca re

COUNSELING SESSION . . . . . . . . . . . . . . . . . . . . . . . . . . 1 47 MEDICAL H I STORY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 47 GENETIC DISEASES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 49 REPRODUCTIVE HISTORY . . . . . . . . . . . . . . . . . . . . . . . . 1 5 1 PARENTAL AGE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 5 1 SOCIAL HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 52 SCREEN I N G TESTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 53

Pregnancy may be associated with certain diseases that existed bore the inception ofpregnancy. As a rule, all dis­ eases which subject the organism to a considerable strain are much more serious when occurring in a pregnant woman. -J. Whitridge Williams ( 1 903) he Centers for Disease Control and Prevention (CDC) (20 1 5) defines preconceptional care as "a set of interventions that aim to identiy and modiy biomedical, behavioral, and social risks to a woman's health or pregnancy outcome through preven­ tion and management." To achieve this goal, the CDC has developed an action plan for preconceptional health care in the United States Qohnson, 2006). The American College of Obstetricians and Gynecologists (20 1 7 e) and the Society for Maternal-Fetal 1vI edicine (20 1 4) also reairm the importance of preconceptional care, and the following objectives have been established for advancing it: 1 . Improve knowledge, attitudes, and behaviors of men and women related to preconceptional health

2. Assure that all childbearing-aged women receive preconcep­ tional care services-including evidence-based risk screen­ ing, health promotion, and interventions-that will enable them to enter pregnancy in optimal health 3. Reduce risks indicated by a previous adverse pregnancy out­ come through interconceptional interventions to prevent or minimize recurrent adverse outcomes 4. Reduce the disparities in adverse pregnancy outcomes To illustrate potentilly modifiable conditions, data that describe the health status of women who delivered liveborn neonates in the United States in 2004 are reviewed. Table 8- 1 demonstrates the high prevalence of many conditions that may be amenable to intervention during the preconceptional and interpregnancy periods. To be successul, however, strategies that mitigate these potential pregnancy risks must be provided before conception. By the time most women realize they are pregnant­ usually 1 to 2 weeks ater the first missed period-the embryo has already begun to form. hus, many preventive steps-for exam­ ple, folic acid to avoid neural-tube defects-will be inefective if initiated at this time. Importantly, up to half of all pregnancies in the United States in 2008 were unplanned according to the Guttmacher Institute (20 1 5) , and oten these are at greatest risk. Few randomized trials evaluate preconceptional counseling eicacy, in part because withholding such counseling would be unethical. Also, pregnancy outcomes are dependent on the interaction ofvarious maternal, fetal, and environmental factors. hus, ascribing a salutary outcome to a specific intervention is diicult (Moos, 2004; Temel, 20 1 4) . However, prospective observational and case-control studies have demonstrated the successes of preconceptional counseling (American College of Obstetrics and Gynecologists, 20 1 6b) . \100s and coworkers ( 1 996) assessed the efectiveness of a preconceptional counseling program administered during routine health care provision to reduce unintended pregnancies. he 456 counseled women had a 50-percent greater likelihood of subsequent pregnancies that they considered "intended" compared with 309 uncounseled

P reconceptiona l C a re

TABLE 8- 1 . Preva lence of Prepregna ncy Materna l

Behaviors, Experiences, Hea lth Cond itions, a n d Previous Poor B i rth Outcomesa

Factor Tobacco use Alcohol use M u ltivita m i n u se Contrace ptive non use b Dental visit Hea lth co u n se l i ng P hysica l a buse Stress U n derwei g ht Overweight Obesity Dia betes Asthma Hypertension Hea rt problem Anemia Prior low-bi rthwe i g ht neonate Prior preterm neonate

Prevalence (%) 23 50 35 53 78 30 4 19 13 l3 22 2 7 2 1

10 12 12

a l n the U n ited States i n 2004. bAmong women who were n ot trying to become p reg n a nt. Data from D'Angelo D, Wi l l ia m s L, Morrow 8, et al: P recon­ ception and i nterconception health status of women who recently gave b i rth to a l ive-born i n fant-Preg nancy Risk Assessment Monitori ng System (PRAMS), U n ited States, 2 6 reporting areas, 2004. M MWR 56(1 0): 1 , 2007.

women. Moreover, compared with another group of women who had no health care before pregnancy, the counseled group had a 65-percent higher rate of intended pregnancy. Interesting ethical aspects of paternal lifestyle modification were reviewed by van der Zee and associates (20 1 3) .

COUNSELING SESSION Gynecologists, internists, family practitioners, and pediatricians have the best opportunity to provide preventive counseling dur­ ing periodic health maintenance examinations. The occasion of a negative pregnancy test is also an excellent time for education. Jack and colleagues ( 1 995) administered a comprehensive precon­ ceptional risk survey to 1 36 such women, and almost 95 percent reported at least one problem that could afect a uture preg­ nancy. These included medical or reproductive problems-52 percent; family history of genetic disease-50 percent; increased risk of human immunodeiciency virus infection-30 percent; increased risk of hepatitis B and illegal substance abuse-25 per­ cent; alcohol use- 1 7 percent; and nutritional risks-54 percent. Counselors should be knowledgeable regarding relevant medical diseases, prior surgery, reproductive disorders, or genetic condi­ tions and must be able to interpret data and recommendations provided by other specialists (Simpson, 20 1 4) . If the practitio­ ner is uncomfortable providing guidance, the woman or couple should be referred to an appropriate counselor.

Women presenting specifically for preconceptional evalua­ tion should be advised that information collection may be time consuming, depending on the number and complexity of factors that require assessment. he intake evaluation includes a thorough review of the medical, obstetrical, social, and family histories. Use­ ul information is more likely to be obtained by asking specific questions regarding each of these histories and each family mem­ ber than by asking general, open-ended questions. Some important information can be obtained by questionnaires that address these topics. Answers are reviewed with the couple to ensure appropriate follow-up, including obtaining relevant medical records.

MEDICAL HISTORY With specific medical conditions, general points include how preg­ nancy will afect maternl health and how a high-risk condition might afect the fetus. terward, advice for improving outcome is provided. Some chronic conditions that may ffect pregnancy out­ comes include treated or active cancer, prior peripartum cardiomy­ opathy, and systemic lupus erythematosus (mant, 20 1 5; Buyon, 20 1 5; McNamara, 20 1 5) . Importantly, psychological health should be considered (Lassi, 20 1 4). Detailed preconceptional information regarding a few exemplary conditions is found in the next sections and in the other topic-speciic chapters of this text. • Diabetes Mellitus

Because maternal and fetal pathology associated with hypergly­ cemia is well known, diabetes is the protoype of a condition for which preconceptional counseling is benefi c ial. Diabetes­ associated risks to both mother and fetus are discussed in detail in Chapter 57 (p. 1 099) . Many of these complications can be avoided if glucose control is optimized before conception. Another important aspect of counseling pertains to the frequent use of teratogenic angiotensin-converting enzyme inhibitors in this population (Podymow, 20 1 5) . The American College o f Obstetricians and Gynecologists (20 1 6a) has concluded that preconceptional counseling for women with pregestational diabetes is both beneicial and cost­ efective and should be encouraged. The American Diabetes Association has promulgated consensus recommendations for preconceptional care for diabetic women (Kitzmiller, 2008) . hese guidelines advise obtaining a thorough inventory of dis­ ease duration and related complications and completing a clinical and laboratory examination for end-organ damage. Perhaps most essential, they encourage a preconceptional goal of the lowest hemoglobin Ale level possible without undue hypoglycemic risk to the mother. In addition to assessing diabetic control during the preceding 6 weeks, hemoglobin Ale measurement can also be used to estimate risks for major anomalies as shown in Figure 8- 1 . lthough these data are from women with severe overt dia­ betes, the incidence of fetal anomalies in women who have ges­ tational diabetes with fasting hyperglycemia is increased fourfold compared with that in normal women (Sheield, 2002) . Such counseling in diabetic women has been shown to be efective. Leguizam6n and associates (2007) identiied 1 2 studies that included more than 3200 pregnancies in women with insulin-dependent diabetes. Of the 1 6 1 8 women without precon-

1 47

1 48

P recon ce ptiona l a n d P renata l C a re

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l

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a _

o )

6 i E�

-

0

'u E ..

u

21 10 5

4.6-7.6

7.7-8.6

8 . 7-9.9

1 0 -1 0.5

Glycosylated hemoglobin (percent)

>

1 0.6

FIGURE 8-1 Relatio n s h i p between fi rst-tri m ester g lycosylated hemog l o b i n val ues and risk for major con g e n ita l malformations i n 320 women with insulin-dependent d ia betes. (Data from Kitzm iller JL, Gavin LA, G i n G O, et a l : Preconception care of d ia betics. JAMA 265:73 1 , 1 99 1 .)

ceptional counseling, 8.3 percent had a fetus with a major congeni­ tal anomaly, and this compared with a rate of 2.7 percent in the 1 599 women who did have counseling. Tripathi and coworkers (20 1 0) compared outcomes in 588 women with pregestational diabetes in whom approximately half had preconceptional coun­ seling. hose women who received counseling had improved gly­ cemic control before pregnancy and in the first trimester. his group also had higher folate intake rates preconceptionally, and they experienced lower rates of adverse outcomes-deined as a perinatal death or major congenital anomaly. hese cited ben­ eits are accompanied by reduced helth-care costs in diabetic women. From their review, Reece and Homko (2007) found that each $ 1 expended for a preconceptional care program saved between $ 1 .86 and $5. 1 9 in averted medical costs. Despite such beneits, the proportion of diabetic women receiving preconcep­ tional care is suboptimal. In their study of approximately 300 diabetic women in a managed-care plan, Kim and colleagues (2005) found that only approximately one half had preconcep­ tional counseling. Counseling rates are undoubtedly much lower among uninsured and indigent women.

• Epilepsy

Compared with unafected women, those with a seizure disor­ der carry an undisputed augmented risk of having neonates with structural anomalies (Chap. 1 2, p. 240) . Some early reports indicated that epilepsy conferred an elevated a priori risk for congenital malformations that was independent of anticon­ vulsant treatment efects. Although more recent publications have largely failed to conirm this increased risk in untreated women, it is diicult to refute entirely because women who are controlled without medication generally have less severe disease (Cassina, 20 1 3 ; Vajda, 20 1 5) . Fried and associates (2004) con­ ducted a metaanalysis of studies comparing epileptic women, both treated and untreated, with controls. In this study, greater malformation rates could only be demonstrated in the ofspring of women who had been exposed to anticonvulsant therapy. Veiby and coworkers (2009) used the Medical Birth Registry of Norway and identiied an increased malformation risk only in women who were exposed to valproic acid (5.6 percent) or polytherapy (6. 1 percent) . Untreated women had anomaly

rates that were similar to those of nonepileptic controls. Risks for miscarriage and stillbirths in exposed epileptic women do not appear elevated (Aghajanian, 20 1 5 ; Bech, 20 1 4) . Ideally, seizure control i s optimized preconceptionlly. For example, Vajda and colleagues (2008) nalyzed data from the Aus­ tralian Register of Antiepileptic Drugs in Pregnancy. hey found the seizure risk during pregnancy was 50- to 70-percent lower in women without a seizure in the year preceding pregnancy com­ pared with a group experiencing seizures in this preceding year. No urther advantages accrued if the seizure-free period exceeded a year. Treatment goals attempt to achieve seizure control with monotherapy and with medications considered less terato­ genic (Aguglia, 2009; Tomson, 2009) . As discussed in detail in Chapter 60 (p. 1 1 59) and shown in Table 8-2, some one-drug regimens are more teratogenic than others. Valproic acid, in par­ ticular, is avoided if possible, as this medication has consistently been associated with a greater risk for major congenital malfor­ mations than other antiepileptic drugs Qentink, 20 1 0; Vajda, 20 1 5). Trimethadione is contraindicated (Aghajanian, 20 1 5) . h e American Academy o f Neurology recommends consider­ ation of antiseizure medication discontinuation before pregnancy in suitable candidates Qeha, 2005). hese include women who satisy the following criteria: ( 1 ) have been seizure-free for 2 to 5 years, (2) display a single seizure type, (3) have a normal neuro­ logical examination and normal intelligence, and (4) show elec­ troencephalogram results that have normalized with treatment. Epileptic women should be advised to daily take a 4-mg folic acid supplement. Even so, it is not entirely clear that folate supplementation reduces the fetal malformation risk in pregnant women taking anticonvulsant therapy. In one case-control study, Kjer and associates (2008) reported that the congenital abnor­ mality risk was reduced by maternal folate supplementation in fetuses exposed to carbamazepine, phenobarbitl, phenytoin, and primidone. Conversely, from the United Kingdom Epilepsy and

TABLE 8-2. Fi rst-Trimester . ntiepileptic Monothera py

a n d the Associated Major Malformation Risk

Antiepileptic (n)

Malformations (%)

U nexposed controls (442) La motrig i n e ( 1 562) Ca rba m aze p i n e ( 1 033) P h enyto i n (4 1 6) Leveti ra ceta m (450) Top i ra m ate (359) Va l p roate (323) P h e n obarb ita l ( 1 99) Oxca rbaze p i ne ( 1 82) G a ba penti n ( 1 45) Clo nazepa m (64)

1 .1 2.0 3.0 2.9 2.4 4.2 9.3 5.5 2.2 OJ

3.1

Relative Risk (95% CW Reference

1 .8 2.7 2.6 2.2 3.8 9.0

5.1

2.0 0.6 2.8

(0.7-4 .6) ( 1 .0-7.0) (0.9-7.4) (0.8-6.4) ( 1 .4- 1 0.6) (3.4-23.3) (1 .8- 1 4.9) (0.5-7.4) (0.07-5.2) (0.5- 1 4.8)

a R i s k com pared with t h at of the u nexposed refere n ce pop u l ation of nonepi l e pt i c women.

Data from Hernandez-Oraz 5, Smith CR, Shen A., et al: Compara­ n

=

n u m be r of exposed i nfa nts.

tive safety of a ntiepileptic drugs d u r i ng preg nancy. Neurology

78:1 692, 20 1 2.

P reconceptiona I C a re Pregnancy Register, Morrow and coworkers (2009) compared fetal outcomes of women who received preconceptional folic acid with those who did not receive it until later in pregnancy or not at all. In this study, a paradoxical increse in the number of major congenital malformations was observed in the group who received preconceptional folate. hese investigators concluded that folate metabolism may be only a part of the mechanism by which mal­ formations are induced in women taking these medications.

• Immunizations

Preconceptional counseling includes assessment of immunity against common pathogens. Also, depending on health status, travel plans, and time of year, other immunizations may be indicated as discussed in Chapter 9 (Table 9-7, p. 1 72). Vac­ cines that contain toxoids such as tetanus are suitable before or during gestation. Also, those containing killed bacteria or viruses-such as inluenza, pneumococcus, hepatitis B, menin­ gococcus, and rabies vaccines-are not associated with adverse fetal outcomes and are not contraindicated preconceptionally or during pregnancy. Conversely, live-virus vaccines are not recommended during pregnancy. Examples are vaccines against varicella-zoster, measles, mumps, rubella, polio, chickenpox, and yellow fever. Moreover, 1 month or longer should ideally pass between vaccination and conception attempts. That said, inadvertent administration of measles, mumps, rubella (MMR) or varicella vaccines during pregnancy should not generally be considered indications for pregnancy termination. Most reports indicate that the fetal risk is only theoretical. Immunization to smallpox, anthrax, and other bioterrorism diseases should be discussed if clinically appropriate (Chap. 64 , p. 1 228). With some infections, vaccines are unavailable. One recent example is the Zika virus (Brasil, 20 1 6) . For this virus, the CDC has issued travel advisories for pregnant women (Petersen, 20 1 6; Schuler-Faccini, 20 1 6) .

GENETIC DISEASES he CDC (20 1 6) estimates that 3 percent of neonates born each year in the United States will have at least one birth defect. Importantly, such defects are the leading cause of infant mor­ tality and account for 20 percent of deaths. The benefi t s of preconceptional counseling usually are measured by compar­ ing the incidence of new cases before and after initiation of a counseling program. Congenital conditions that clearly beneit from patient education include neural-tube defects, phenylke­ tonuria, thalassemias, and other genetic diseases more common in individuals of Eastern European Jewish descent.

• Family History

Pedigree construction using the symbols shown in Figure 8-2 is the most thorough method for obtaining a family history as a part of genetic screening. he health and reproductive status of each "blood relative" should be individually reviewed for medi­ cal illnesses, mental retardation, birth defects, infertility, and pregnancy loss. Certain racial, ethnic, or religious backgrounds may indicate elevated risk for specific recessive disorders.

Although most women can provide some information regarding their history, their understanding may be limited. For example, several studies have shown that pregnant women often fail to report a birth defect in the family or they rep ort it incorrectly. hus, any disclosed defect or genetic disease should be conirmed by reviewing pertinent medical records or by con­ tacting afected relatives for additional information.

• Neural-Tube Defects

he incidence of neural-tube defects (NTDs) is 0.9 per 1 000 live births, and they are second only to cardiac anomalies as the most frequent structural fetal malformation (Chap. 1 3, p. 270) . Some NTDs, as well as congenital heart defects, are associated with speciic mutations. One example is the 677C -+ T substitu­ tion in the gene that encodes methylene tetrahydrofolate reduc­ tase. For this and similar gene defects, the trial conducted by the Medical Research Council Vitamin Study Research Group ( 1 99 1 ) showed that preconceptional folic acid therapy signifi­ cantly reduced the risk for a recurrent NTD by 72 percent. More importantly, because more than 90 percent of neonates with NTDs are born to women at low risk, Czeizel and Dudas ( 1 992) showed that supplementation reduced the a priori risk of a irst NTD occurrence. It is currently recommended, therefore, that all women who may become pregnant take daily 400 to 800 j1g of folic acid orally before conception and through the irst trimester (U.S Preventive Services Task Force, 2009) . Folate fortiication of cereal grains has been mandatory in the United States since 1 998, and this practice has also resulted in decreased neural-tube defect rates (Williams, 20 1 5) . Despite the demonstrated benefits of folate supplementation, only half of women have taken folic acid supplementation periconceptionally (de Jong-van den Berg, 2005; Goldberg, 2006) . The strongest predictor of use appears to be consultation with a health-care provider before conception.

• Phenylketonuria

More than 600 mutations have been identified in the phenyl­ alanine hydroxylase gene. The inherited defect in phenylalanine metabolism exempliies diseases in which the fetus may not be at risk to inherit the disorder but may be damaged by maternal disease. Specifically, mothers with phenylketonuria (PKU) who eat an unrestricted diet have abnormally high blood phenylala­ nine levels. his amino acid readily crosses the placenta and can damage developing fetal organs, especially neural and cardiac tissues (Table 8-3) . TABLE 8-3. F requency o f Co m p l i cations i n t h e Offs p r i n g

o f Women w i t h U ntreated P henyl keto n u ria

Complication Sponta neous a bortion Developmental del ays Microcep haly Congenital heart d i sease Feta l-g rowth restriction

Frequency (%) 24 92 73

12 40

Data from American Academy of Ped iatrics: Mate n a l phenyl keto n u ria, Ped iatrics 2 008 \ug; 1 2 2 (2):44 5-449.

1 49

1 50

P reconcept i o n a l a n d P renata l C a re

o o

o

O

Male

Marriage

0---0

Female

Sex u nspecified

Extramarital mati ng

Divorce

Num ber of children of sex indicated

Consanguineous mating

Affected Monozygotic twi ns Heterozygotes for autosomal trait Dizygotic twi ns

Carrie r of X - l i n ked recessive trait Proband

Twins of un known zygosity

Deceased i nd ividual Numberi ng i ndividuals i n pedigrees

Prenatal death Miscarriage

II

3

P roband is II

-

2

Adopted i nto a family No offspring Adopted out of a fam ily F I G U R E 8-2 Sym bols u sed for ped ig ree construction . (Mod ified with permission from Thom pson MW, Mcin nes RR, H u nti ngton FW (eds): Genetics i n Medicine, 5th ed. Ph iladelph ia, Saunders, 1 99 1 .)

With appropriate preconceptional counseling and adherence to a phenylalanine-restricted diet before pregnancy, the inci­ dence of fetal malformations is dramatically reduced (Camp, 20 1 4; Vockley, 20 1 4) . Therefore, the phenylalanine concen­ tration is ideally normalized 3 months before conception and then maintained throughout pregnancy (American College of Obstetricians and Gynecologists, 20 1 7b) . The target phenylala­ nine blood concentration is 1 20 to 360 �mol/L (Camp, 20 1 4) . • Thalassemias

hese disorders of globin-chain synthesis are the most common single-gene disorders worldwide (Forget, 20 1 3; Vichinsky,

20 1 3) . As many as 200 million people carry a gene for one of these hemoglobinopathies, and hundreds of mutations are known to cause thalassemia syndromes (Chap. 56, p. 1 084) . In endemic areas such as Mediterranean and Southeast Asian coun­ tries, counseling and other prevention strategies have reduced the incidence of new cases by up to 80 percent (Cao, 20 1 3) . The American College o f Obstetricians and Gynecologists (20 1 5a) recommends that individuals of high-risk ancestry be ofered carrier screening to allow them informed decision making regarding reproduction and prenatal diagnosis. One method of early prenatal diagnosis is preimplantation genetic diagnosis (PGD), which is coupled with assisted reproduc­ tive technologies. Described in Chapter 14 (p. 295) , PGD is

P recon ce ptio n a l Ca re

available for patients at risk for certain thalassemia syndromes (Kuliev, 20 1 1 ) . • Individuals of Eastern European

Jewish Descent

Most individuals of Jewish ancestry in North America are descended from Ashkenazi Jewish communities and are at increased risk for having ofspring with one of several auto­ somal recessive disorders. These include Tay-Sachs disease, Gaucher disease, cystic ibrosis, Canavan disease, familial dys­ autonomia, mucolipidosis IV, Niemann-Pick disease type A, Fanconi anemia group C, and Bloom syndrome. The American College of Obstetricians and Gynecologists (20 1 6c, 20 1 7a) rec­ ommends preconceptional counseling and screening for these in this population. Carrier frequency and features of these con­ ditions are discussed in Chapter 14 (p. 290) .

REPRODUCTIVE H ISTORY During preconceptional screening, information is sought regarding infertility; abnormal pregnancy outcomes that may include miscarriage, ectopic pregnancy, and recurrent preg­ nancy loss; and obstetrical complications such as cesarean delivery, preeclampsia, placental abruption, and preterm deliv­ ery (Stubblefield, 2008) . As discussed in Chapter 35 (p. 646) , details involving a prior stillbirth are especially important. For example, Korteweg and associates (2008) identiied chromo­ somal abnormalities in 1 3 percent of stillborns who underwent karyotyping. Reddy and colleagues (20 1 2) confirmed that chromosomal micro array analysis (CMA) yielded better detec­ tion of genetic abnormalities than did standard karyotyping, primarily because nonviable tissue can be used for the analy­ sis. CMA is described and illustrated in Chapter 1 3 (p. 27 1 ) . Identiication o f a genetic abnormality i n a stillborn can help determine the recurrence risk and aid in the preconceptional or prenatal management in subsequent pregnancies.

PARENTAL AGE

• Maternal Age

Women at both ends of the reproductive-age spectrum have unique outcomes to be considered. First, according to the CDC, in 20 1 0, 3.4 percent ofbirths in the United States were in women between the ages of 1 5 and 1 9 years (Martin, 20 1 2) . These ado­ lescents are at increased risk for anemia, preterm delivery, and preeclampsia compared with women aged 20 to 35 years (Usta, 2008) . he incidence of sexually transmitted diseases-com­ mon in adolescents-is even higher during pregnancy (Nicco­ lai, 2003) . Unfortunately, because most of their pregnancies are unplanned, adolescents rarely seek preconceptional counseling. Conceptions after age 35 currently comprise approximately 1 5 percent of pregnancies in the United Stares (Martin, 20 1 2) . B y contrast, these older women are more likely t o request preconceptional counseling, either because of postponed pregnancy with a desire to optimize outcomes or because of plans to undergo infertility treatment. Some studies-includ­ ing data from Parland Hospital presented in Figure 8-3-

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F I G U R E 8-3 I n c idence of selected preg n a ncy c o m p l icatio n s i n relatio n t o m aterna l a g e a mo n g 295,667 wo m e n del ivered a t Parkland Hospita l.

indicate that ater age 35, the risks for obstetrical complications and for perinatal morbidity and mortality rise (Cunningham, 1 995; Waldenstrom, 201 5). he older woman who has a chronic illness or who is in poor physical condition usually has readily apparent risks. For rhe physically fit woman without medical prob­ lems, however, the risks are much lower than previously reported. Overall, the maternal mortality rate is higher in women aged 35 and older. Compared wirh women in rheir 20s, women aged 35 to 39 are 2.5 times more likely and women aged 40 or older are 5.3 times more likely to sufer pregnancy-related mortality (Geller, 2006) . Creanga and coworkers (20 1 5) analyzed preg­ nancy-related deaths in the United States for 2006 through 20 1 0. Although women older than 35 years contributed less than 1 5 percent of all live births, they constituted 27 percent of maternal deaths. For the fetus, maternal age-related risks pri­ marily stem from: ( 1 ) indicated preterm delivery for maternal complications such as hypertension and diabetes, (2) spontane­ ous preterm birth, (3) fetal growth disorders related to chronic maternal disease or multifetal gestation, (4) fetal aneuploidy, and (5) pregnancies resulting from assisted reproductive technology. Assisted Reprod u ctive Tech n o log ies

Recall that older women have subfertility problems. And although the incidence of dizygotic twinning increases with maternal age, the more important cause of multifetal gestation in older women follows the use of assisted reproductive technol­ ogy (ART) and ovulation induction. Indeed, according to the CDC, 30 to 40 percent of all multifetal gestations in the United States in 20 1 2 were conceived with the use of ART (Sunderan, 20 1 5) . Morbidity and mortality with multifetal pregnancies stem from preterm delivery. Other obstetrical morbidities, such as placenta previa, abruption, and preeclampsia, are also risks associated with these conceptions (Lukes, 20 1 7; Qin, 20 1 6) . Finally, experience has accrued that links ART t o higher major congenital malformation rates. Davies and colleagues (20 1 2) reported that of 308,974 births in South Australia, 8.3 percent of neonates conceived by ART had major birth defects.

1 51

1 52

P reconceptio n a l a n d P renata l Ca re

In this analysis, after adjustment for maternal age and other risk factors, intracytoplasmic injection continued to be associated with a signiicantly elevated risk for malformations, but in vitro fertilization did not.

• Paternal Age

Parental history and experiences-paternal and maternal-can exert efects through epigenomic information not contained in the DNA sequence. Examples include variations in sperm and oocyte cytosine methylation and other mechanisms (Cedars, 20 1 5 ; Lane, 20 1 4) . Perhaps one example is the possible link between increasing paternal age and complex neuropsychiatric conditions (Malaspina, 20 1 5) . Finally, the incidence of genetic diseases in ofspring caused by new autosomal-dominant mutations in older men is increased. Still, the incidence is low (Chap. 1 3, p. 265). Accordingly, targeted sonographic examination performed solely for advanced maternal or paternal age is controversial.

SOCIAL H ISTORY

• Recreational Drugs and Smoking

Fetal risks associated with alcohol, marijuana, cocaine, amphet­ amines, and heroin are discussed in Chapter 1 2 (p . 239) . he first step in preventing drug-related fetal risk is an honest assess­ ment of use by the patient (American College of Obstetricians and Gynecologists, 20 1 7 c) . Toward this end, questioning should be nonjudgmental. Screening for at-risk drinking can be accomplished using several validated tools. One is the well­ studied TACE questions (American College of Obstetricians and Gynecologists, 20 1 3) . This is a series of four questions con­ cerning .olerance to alcohol, being 4nnoyed by comments about their drinking, attempts to fut down, and a history of drinking early in the morning-the fye opener. In a Canadian study of more than 1 000 postpartum patients, Tough and coworkers (2006) found that a high per­ centage of women reported alcohol use concurrent with con­ ception attempts. Specifically, nearly half of those planning for pregnancy reported a mean of 2.2 drinks daily during early gestation and before they recognized their pregnancy. Of note, Bailey and associates (2008) found that rates of binge drinking and marijuana use by men were unafected by their partner's pregnancy. The frequency and pattern of such behaviors clearly underscore the opportunity for preconceptional counseling. Currently 20 million women in the United States smoke cigarettes (Centers for Disease Control and Prevention, 20 1 4 ) . Smoking i n pregnancy has been consistently associated with numerous adverse perinatal outcomes, listed in Chapter 1 2 (p. 249) . These risks are largely mitigated by cessation before preg­ nancy, highlighting the importance of screening for tobacco use in the preconceptional period and during prenatal care as outlined in Chapter 9 (p. 1 6 1 ) .

• Environmental Exposures

Contact with environmental substances is inescapable. Thus, it is fortunate that only a few agents have been shown to cause adverse pregnancy outcomes (Windham, 2008) . Exposures to

infectious diseases have myriad deleterious efects, and these are detailed in Chapters 64 and 65 . Likewise, contact with some chemicals may impart signiicant maternal and fetal risks. As discussed in Chapters 9 and 1 2 (pp. 1 70 and 244), excess expo­ sure to methyl mercury or lead is associated with neurodevel­ opmental disorders. In the past, some concerns were raised over common every­ day exposure to electromagnetic iels such as those emanated by high-voltage power lines, electric blankets, microwave ovens, and cellular phones. Fortunately, no human or animal evidence links these and adverse fetal outcomes (Robert, 1 999) . he efects of electrical shock are discussed in Chapter 47 (p. 930) .

• Diet

Pica is the craving for and consuming of ice, laundry starch, clay, dirt, or other nonfood items. It should be discouraged due to its inherent replacement of healthul food with nutritionally empty products (Chap. 9, p. 1 74) . In some cases, it may represent an unusual physiological response to iron deficiency. Many vegetar­ ian diets are protein deficient but can be corrected by increas­ ing egg and cheese consumption. Anorexia and bulimia increase maternal risks of nutritional deiciencies, electrolte disturbances, cardiac arrhythmias, and gastrointestinal pathology (Becker, 1 999) . s discussed in Chapter 6 1 (p. 1 1 80), pregnancy-related complications with these disorders include greater risks of low birthweight, smaller head circumference, microcephaly, and small-for-gestational-age newborns (Kouba, 2005) . In contrast to these perinatal morbidities, obesiy is linked with several maternal complications. As discussed in Chapter 48 (p. 939) , these include preeclampsia, gestational diabetes, labor abnormalities, cesarean delivery, and operative complications (American College of Obstetricians and Gynecologists, 20 1 5b) . Obesity also appears to be associated with a range of structural fetal anomalies (Stothard, 2009) .

• Exercise

Conditioned pregnant women usually can continue to exercise throughout gestation (American College of Obstetricians and Gynecologists, 20 1 7d) . As discussed in Chapter 9 (p. 1 70) , no data suggest that exercise is harmful during pregnancy. One caveat is that as pregnancy progresses, balance problems and joint relaxation may predispose to orthopedic injury. A woman is advised not to exercise to exhaustion, and she should aug­ ment heat dissipation and fluid replacement. Further avoid­ ances include prolonged supine position, activities requiring good balance, and extreme weather conditions.

• Intimate Partner Violence

Pregnancy can exacerbate interpersonal problems and is a time of elevated risk from an abusive partner. According to the American College of Obstetricians and Gynecologists (20 1 2) , approximately 324,000 pregnant women are abused each year. As discussed in Chapter 47 (p. 925), intimate partner violence has been asso­ ciated with greater risk for several pregnancy-related complica­ tions, including hypertension, vaginal bleeding, hyperemesis, preterm delivery, and low-birthweight neonates (Silverman,

P reco n ce ptio na l Ca re 2006) . Because domestic violence can escalate during pregnancy, even to the point of homicide, the preconceptional period pro­ vides an ideal time for screening and if indicated, intervention (Cheng, 20 1 0) . s detailed in Chapter 9 (p. 1 62) , the American College of Obstetricians and Gynecologists (20 1 2) provides rec­ ommendations and resources for screening both pregnant and nonpregnant women for domestic violence.

SCREENING TESTS Certain laboratory tests may help assess the risk for and pre­ vent some pregnancy complications. hese include basic tests

that are usually performed during prenatal care and are enu­ merated in Chapter 9. More speciic tests may assist evalua­ tion of women with certain chronic medical diseases. Examples of some chronic diseases that ideally would be assessed before conception are highlighted in Table 8-4. With several of these, optimizing maternal condition before conception will improve pregnancy outcomes. Cox and coworkers ( 1 992) reviewed pregnancy outcomes in 1 075 high-risk women who received such evaluation. hey reported that the 240 women with hypertension, asthma, or renal, thyroid, or cardiac disease had better outcomes compared with the outcomes from their prior pregnancies.

TABLE 8-4. Selected P reconceptiona l Cou ns e l i n g Top ics

Condition

Reference Cha pter

Enviro n menta l expos u re

C h a p. 9, p. 1 70 C h a p. 1 2, p. 244

Abnormal weight

C ha p. 48, p. 93 6 C h a p. 6 1 , p. 1 1 80

Ca rd i ovascu l a r d isease

Cha p. 49, p. 95 1 Cha p. 1 2, pp. 24 1 , 247

C h ronic hyperte nsion

C h a p. 5 0, p. 976

AsthMa

C h a p. 5 1 , p. 988

Th rom boph i l ia

C h a p. 5 2, p. l 006

Ren a l d : sease

Cha p. 53, p. 1 02 5 C h a p. 1 2, p. 24 1

Ga stroi ntest i n a l d isease

Cha p. 54, p. 1 05 0 C h a p. 1 2, pp. 242, 244

Hepato b i l i a ry d i sea se

Chap. 55, p. 1 064

Hematological d i sease

Cha p. 5 6, p. l 075

Recommendations for Preconceptional Counseli ng

Methyl mercury: Avoid s h a rk, swordfi sh, ki ng macke rel, and tile fi s h. I ngest no m o re than 1 2 o u nces or 2 servi n g s of ca n n ed tuna a n d no m o re tha n 6 o u n ces of a l bacore per week. Lead: B lood lea d testing if a risk factor is i dentified; t reat if i n d icated a ccord i ng to reco m m endations. Calcu l ate BMI yea rly from Fig u re 48- 1 , p. 937 BMI .25 kglm2: Cou nsel o n d i et. Test for dia betes a n d m eta bo l i c synd rome if i nd i cated. Consider we i g h t 1 05s prior to co ncepti on. BMI � 7 8. 5 kglm2: Assess for eati n g d isorder. Co u nsel on ca rd iac risks d u ri ng p reg n a ncy; d iscuss situations i n which preg n a n cy is contra i nd i cated . Opti m ize c a rd i a c fu n ction. Di scuss med ication tera toge n i c i ty (wa rfa r i n , ACE i n h ' bitor, A RB) a nd, if poss i ble, switch to less d a ng e rous agent when conception p l a n ned . Ofer g enetic co u n s e l i n g to t h ose with co ngen ita l ca rd iac a noma l ies (Ta b l e 49-4, p. 953). Cou n sel on s pecifi c risks d u ri ng preg n a ncy. Assess those with l o n g-sta n d i ng HTN for ventricu l a r hypertrophy, retinopathy, and ren a ! d isease. O pti m ize b lood p ress u re co tro l . If med ications i nd icated, select or switch to an agent a p p ropriate for preg n a n cy. Cou n se l on asthma risks d u ri n g p reg n a n cy. Optim ize p u l m o n a ry fu n ction preconceptiona l ly. Treat wo m e n with pha rmacologica l step th era py for c h ro n i c asthma. Questi o n for perso n a l o r fa m i ly h i story of thro m botic events o r recu rrent poor p reg na n cy o utcomes. If a t h ro m boph i l ia is fou n d or known, cou nsel and offe r a p p ropriate a nticoag u l ation reg i men. Cou n sel on specific risks d u ri n g p reg n a ncy. Opti m ize b l ood press u re control before conception . Cou n s e l wom e n ta king ACE i n h i bi tors and A R Bs a bolJ t teratog e n i c ity a n d the need to switch agents before preg na n cy. Inlammatory bowel disease: Co u n sel afected women on su bferti l ity r i s ks and risks of adverse preg na ncy o utcom es. Discuss teratoge n icity of methotrexate and the other i m n u nomod u lators. Offer effective contraception d u ri n g their u se and switch agents, if poss i ble, before conception. Hepatitis B: Vaccinate a l l h ig h-ri s k wo men befo re conceptio n (Ta ble 9-7, p. 1 72) . Co u nsel c h ro n i c carriers on tra n s m ission prevention to pa rtners a nd fet us. Treat if i n d i cated. Hepatitis C: Screen h i g h-risk wom en. Cou nsel affected ,fom e n o n r i s ks of d i sease and tra n s m i ssion . If treat m e nt i nd icated, d iscuss ram i fi cations a n d a p p ropriate ness of preg n a n cy. Iron-deficiency anemia: I ro n su pp l e m e ntation . Sickle-cell dis ease: Screen a l l b la c k women. Cou n sel those with trait o r d isease. Test partner if desi red . Thalassemias: Scree n women of Southeast Asian or Med iter ra nean a ncestry. (continued)

1 53

1 54

P reconce pti o n a l a n d P renata l Care

TABLE 8-4. Conti n ued

Condition

Reference Chapter

Recommendations for Preconceptional Counseling

Dia betes

Cha p. 5 7, p. 1 1 04

Thyro id d i sease

Cha p. 5 8, p. 1 1 1 8

Con n ective tissue d i sease

Cha p. 5 9, p. 1 1 3 8 Chap. 1 2, p. 24 1

Psych iatric d i so rders

Cha p. 6 1 , p. 1 1 7 5

Neu rological d i so rd ers Dermatolog ica l d i sease Cancer

C h a p. 60, p. 1 1 5 9

O pt i m ize g lycem i c control t o m i n i m ize teratoge n i city o f hyperg lyce m i a . Eva l uate for end-org a n d a m age such as ret i n opathy, neph ropathy, hypertension, a n d others. D i sconti n u e A C E i n h i b ito rs. Screen t h ose with thyro i d d i sease sym pto ms. E n s u re i od i ne-suficient d iet. Treat overt hyper- or hypothyro i d i s m . Co u n sel on risks to preg na ncy o utcome. RA: Co u n se l o n fla re risk after preg n a n cy. Disc u s s methotrexate and l efl u n o m i d e teratog e n i c i ty, a s we l l as poss i b l e effects o f oth e r i m m u n omod u lators. Switch these agents before co nception . Sto p N SA I Ds by 2 7 weeks' gestation . SLE: Cou n sel on risks d ur i ng preg na ncy. O pt i m ize d i sease before conception. D i sc u ss mycophenolate m ofeti l a nd cyclophos p h a m i d e teratoge n icity a s wel l a s poss i b l e effects o f n ewer i m m u n om od u l ators. Switch these agents before concept i o n. Depression: Screen for sym ptoms of d e p ression. Cou n sel on r i s ks of t reatment a nd of u nt reated i l l ness a n d the h i g h risk of exacerbat i o n d u ri n g preg nancy a n d the puerperi u m . Seizure disorder: Opt i m ize seizu re control u s i ng m o n othera py if pos s i b l e.

I nfectious d i seases

C h a p. 64, p. 1 209

STDs

C h a p. 65, p. 1 23 5

Cha p. 1 2, p. 245 C h a p. 63, p. 1 1 92

D i sc u ss i sotreti n o i n a nd etreti nate teratog e n icity a n d effective contraception d u ri n g the i r u se; switch agents before concept i o n . Cou nsel on ferti l i ty preservation opt i o n s before ca ncer th erapy a n d on decreased fert i l ity fol lowi ng certa i n age nts. D i scuss ap propriateness of preg na n cy ba la nced with n eed fo r ongoing cancer therapy a nd prog nosis of the d i sease state. Influenza: Vacci nate a l l women who wi l l be preg n a nt d u ri ng fl u sea so n . Vacci nate h ig h-ri s k wo m e n prior to fl u seaso n . Malaria: Cou n sel to avo i d travel t o e n d e m i c a reas d u ri n g concepti o n . If u n a b le, offer effective contraception d u ri ng t rave l or provide chemoprophylaxis for t h ose pla n n i ng preg nancy. Zika virus: See t ravel restrictions by CDC. Rubella: Screen fo r r u be l l a i m m u n ity. If n o n i m m u ne, vacci nate a n d cou n sel o n the n eed for effective contraception d u ri n g the su bseq uent m o nt h. Tdap: tetanus, diphtheria, pertussis: U pdate vacc i n ation i n a l l reprod uctive-ag ed wom e n . Varicella: Q uestion reg a rd i n g i m m u n ity. If non i m m u ne, vacc i nate. Gonorrhea, syphilis, chlamydial infection: Screen h i g h-risk women a n d t reat a s i n d i cated. HIV: Screen at-risk women . Cou nsel afected women on risks d u ri n g preg na ncy a n d on pe ri natal t ra n s m i ssion . D i sc u ss i n itiation of treatment before preg nancy to decrease t ra ns m ission risk. Offe r effective contraception to those n ot desi r i ng concept i o n . HPV' P rovid e Pap smear scree n i ng per g u idel i n es (Ch a p. 63, p. 1 1 93) . Vacci nate c a n d i date patie nts. HSV: P rovide sero l og ical scree n i ng to a sym ptomatic women with affected pa rtners. Cou n sel affected women on risks of peri nata l t ra n s m i ssion a n d on preventative meas u res d u ri n g the th i rd tri mester a n d la bor.

ACE a n g i ote n s i n -convert i n g e nzym e; ACOG American Col lege of Obstet r i c i a n s a n d Gynecologists; ARB a n g iote n s i n ­ receptor blocker; B M I body mass i nd ex; C DC Cente rs for D i sease Control a n d P revention; H IV h u m a n i m m u no­ d eficiency vi rus; H PV h u ma n pa p i l l o mavi rus; H SV h erpes s i m plex vi rus; HTN hyperte nsion; NSAID no nstero i d a l a nt i i nfl a m m atory d rug; RA rheu m atoid a rth ritis; SLE syste m i c l u pus erythematosu s; STD sexua l ly t ra n s m itted d i sease. Data from Jack BW, Atras h H, Coon rod DV, et a l : The c l i n i ca l content of preconcept i o n ca re: a n overview a n d pre pa ration of t h i s su pplement, Am J Obstet Gyneco l . 2008 Dec; 1 99(6 S u ppl 2) :5266-S279. =

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P reconce ptiona l Care

REFERENCES Aghajanian P, Gupta M: Helping your epileptic patient. Contemp OB/GYN 60: 1 0, 20 1 5 Aguglia U, Barboni G , Battino 0, et al: Italian consensus conference on epi­ lepsy and pregnancy, labor and puerperium. Epilepsia 50:7, 2009 Amant F, Vandenbroucke T, Verheecke M, et a1: Pediatric outcome after mater­ nal cancer diagnosed during pregnancy. N Engl J Med 3 3 ( 1 9) : 1 824, 20 1 5 American Academy o f Pediatrics: Maternal phenylketonuria. Pediatrics 1 22: 445 , 2008 American College of Obstetricians and Gynecologists: Intimate partner vio­ lence. Committee Opinion No. 5 1 8, 2 0 1 2 American College of Obstetricians and Gynecologists: At-risk drinking and alcohol dependence: obstetric and gynecologic implications. Committee Opinion No. 496, August 20 1 1 , Reairmed 20 1 3 American College o f Obstetricians and Gynecologists: Hemoglobinopathies in pregnancy. Practice Bulletin No. 78, January 2007, Reairmed 20 1 5a American College of Obstetricians and Gynecologists: Obesiry in pregnancy. Committee Opinion No. 549, January 20 1 3, Reairmed 20 1 5b American College of Obstetricians and Gynecologists: Pregestational diabetes mellitus. Practice Bulletin No. 60, March 200 5 , Reairmed 20 1 6a Ame rican College of Obstetricians and Gynecologists: Reproductive life plan­ . . nll1g to reduce unIntended pregnancy. Committee Opinion No. 654, Feb­ ruary 20 1 6b American College of Obstetricians and Gynecologists: Screening for fetal aneu­ ploidy. Practice Bulletin No. 1 63, March 20 1 6c America� Coll �g� of Obstetricians and Gynecologists: Carrier screening for genetIc condltlons. Committee Opinion No. 69 1 , March 20 1 7a Ame :ican College of Obstetricians and Gynecologists: Management of women WIth phenylketonuria. Committee Opinion No. 636, June 20 1 5, Reaf­ firmed 20 1 7b American College of Obstetricians and Gynecologists: Marijuana use during pregnancy and lactation. Committee Opinion No. 722, July 20 1 5, Reaf­ firmed 20 1 7c America n Col �ege of Obstetricians and Gynecologists: Physical activiry and . exerCIse dunng pregnancy and postpartum period. Committee Opinion No. 650, December 20 1 5, Reairmed 20 1 7d American College of Obstetricians and Gynecologists: The importance of preconception care in the continuum of women's health care. Committee Opinion No. 3 1 3, September 2005, Reairmed 20 1 7e Bailey ]A, Hill KG, Hawkins ]0, et al: Men's and women's patterns of sub­ stance use around pregnancy. Birth 3 5: 1 , 2008 Be:h BH, Kjaersgaard MI, Pedersen HS, et al: Use of antiepileptic drugs dur­ Il1g pregnancy and risk of spontaneous abortion and stillbirth: population based cohort study. BM] 349:g5 1 59, 20 1 4 Becker AE, Grinspoon S K , Klibanski A , e t al: Eating disorders. N Engl ] Med 340: 1 4, 1 999 Brasil P, Pereira JP, Gabaglia CR, et al: Zika virus infection in pregnant women in Rio de Janeiro-preliminary report. N Engl J Vied 375(24) : 232 1 , 20 1 6 Buyon ] P , Kim MY, Guerra Mvl, et al: Predictors o f pregnancy outcomes in patients with lupus: a cohort study. Ann Intern Med 1 63(3): 1 53, 20 1 5 Camp M , Paris A, Acosta PB, et al: Phenylketonuria scientific review con­ ference: state of the science and future research needs. Mol Genet Metab 1 1 2(2) :87, 20 1 4 Cao A , Kan W : h e prevention o f thalassemia. Cold Spring Harb Perspect Med 3 (2):aO l l 775, 20 1 3 Cassina M , Dilaghi A, Di Gianantonio E , e t al: Pregnancy outcome in women exposed to antiepileptic drugs: teratogenic role of maternal epilepsy and its pharmacologic treatment. Reprod ToxicoI 39:50, 20 1 3 Cedars MI: Introduction: childhood implications o f parental aging. Fertil Steril 1 03 (6) : 1 379, 20 1 5 Center� for Disease Control and Prevention: Women and smoking. 20 1 4 . AvaIlable at: http://www.cdc.gov/ tobaccol data_statisticslsgrl50th-anniver­ sary/pdfs/fs_women_smokin�508.pdf. Accessed April 5, 20 1 6 Centers for Disease Control and Prevention: Preconception health and health care. 20 1 5 . Available at: http://www.cdc.gov/preconception/index.html. Accessed April 5 , 20 1 6 Centers for Disease Control and Prevention: Birth defects. 20 1 6. Available at: http://www.cdc.gov/ncbddd/birthdefects/data.html. Accessed April 5, 20 1 6 Cheng 0, Horon I L : Intimate-partner homicide among pregnant and postpar­ tum women. Obstet GynecoI I 1 5 (6): 1 l 8 1 , 20 1 0 Cox M , Whittle M], Byrne A , e t al: Prep regnancy counseling: experience from 10 5 cases. B]OG 99:873, 1 992 Creanga A, Berg CJ, Syverson C, et al: Pregnancy-related mortaliry in the United States, 2006-20 1 0. Obstet Gynecol 1 25:5, 201 5

Cunningham FG, Leveno KJ: Childbearing among older women-the message is cautiously optimistic. N Engl J Med 333:953, 1 99 5 Czeize1 AE, Dudas I: � rev� ntion of the irst occurrence of neural-tube defects by . penconceptIonal vltamll1 supplementation. N Engl J Med 327: 1 832, 1 992 D'Angelo 0, Williams L, Morrow B, et al: Preconception and interconception health st� tus of women who recently gave birth to a live-born infant-Preg­ nancy Risk Assessment Monitoring System (PRAMS), United States, 26 reporting areas, 2004. I MWR 56( 1 0) : 1 , 2007 Davies M], Moore VM, Willson KJ, et al: Reproductive technologies and the risk of birth defects. N Engl ] Med 366( 1 9) : 1 803, 20 1 2 d e Jong-van den Berg LT, Hernandez-Diaz S , Weder M M , e t al: Trends and predictors of folic acid awareness and periconceptional use in pregnant women. Am ] Obstet Gynecol l 92: 1 2 1 , 2005 Forget BG, Bunn HF: Classiication of the disorders of hemoglobin. Cold Spring Harb Perspect Med 3 (2):aO I 1 684, 20 1 3 Fried S , Kozer E , Nulman I , e t al: Malformation rates i n children o f women with untreated epilepsy: a meta-analysis. Drug Saf 27(3): 1 97, 2004 Geller SE, C ?X SM, Callaghan WM, et al: Morbidiry and mortaliry in preg­ nancy: layll1g the groundwork for safe motherhood. Womens Health Issues 1 6 : 1 76, 2006 Gold?erg BB, Alvarado 5, Chavez C, et al: Prevalence of periconceptional folic aCId use a�d perceived barriers to the postgestation continuance of supple­ . mental folIc aCId: survey results from a Teratogen Information Service. Birth Defects Res Part A Clin Mol Teratol 76: 1 93, 2006 Guttmacher Institute: State facts about unintended pregnancies. 2015. Available at: https:llwww.guttmacher.org/fact-sheet/ state-facts-abou t-unin tended­ pregnancy. Accessed April 5 , 20 1 6 Hernandez-Dlaz 5 , Smith CR, Shen A , e t al: Comparative safery o f antiepilep­ tic drugs during pregnancy. Neurology 78: 1 692, 20 1 2 Jack BW, Arrash H , Coonrod DV, e t al: h e clinical content o f preconception care: an overview and preparation of this supplement. Am ] Obstet Gynecol 1 99(6 S uppl 2) :5266, 2008 Jack BW, Campanile C, McQuade W, et al: he negative pregnancy test. An opportuniry for preconception care. Arch Fam Med 4:340, 1 995 ]eha LE, Morris HH: Optimizing outcomes in pregnant women with epilepsy. Cleve Clin J Med 72:928 , 2005 Jentink ], Loane MA, Dolk H, et al: Valproic acid mono therapy in pregnancy and major congenital malformations. N Engl ] Med 362(23) :2 1 85 , 20 1 0 Johnson K: Posner S F , Biermann J, e t al: Recommendations t o improve pre­ conception health and health care-United States. A report of the CDCI ATSDR Preconception Care Work Group and the Select Panel on Precon­ ception Care. MMWR 5 5(6): 1 , 2006 Kim C, Ferrara A, McEwen LN, et al: Preconception care in managed care: the translating research into action for diabetes study. Am J Obstet Gynecol 1 92:227, 2005 Kitzmiller JL, Block JM, Brown FH, et al: Managing preexisting diabetes for pregnancy: summary of evidence and consensus recommendations for care. Diabetes Care 3 1 (5) : 1 060, 2008 Kitzmiller JL, Gavin A, Gin GO, et al: Preconception care of diabetics. JAMA 265 :73 1 , 1 9 9 1 Kjer 0, Horvath-Puh6 E , Christensen ] , e t a1: Antiepileptic drug use, folic acid supplementation, and congenital abnormalities: a population-based case-control study. 1 1 5 ( 1 ) :98, 2008 Korteweg FJ, Bouman K, Erwich n , et al: Cytogenetic analysis after evalua­ tion of 750 fetal deaths: proposal for diagnostic workup. Obstet Gynecol I I I (4) : 865, 2008 Kouba 5, Hallstrom T, Lindholm C, et al: Pregnancy and neonatal outcomes in women with eating disorders. Obstet Gynecol 1 05:25 5 , 2005 Kuliev A, Pakhalchuk T, Verlinsky 0, et al: Preimplantation genetic diaanosis 0 for hemoglobinopathies. Hemoglobin 35(5-6) : 547, 20 1 1 Lane M, Robker RL, Robertson SA: Parenting from before conception. Science 345(6 1 98):756, 20 14 Lassi ZS, Imam AM, Dean SV, et al: Preconception care: screening and man­ agement of chronic disease and promoting psychological health. Reprod Health 26: 1 1 , 20 1 4 Leguizam6n G , Igarzabal ML, Reece EA: Periconceptional care o f women with diabetes mellitus. Obstet Gynecol C1in North Am 34:225 , 200 Luke B: Pregnancy and birth outcomes in couples with infertility and with and without assisted reproductive technology: with an emphasis on US population-based studies. Am J Obstet Gynecol 2 1 7:270, 20 1 7 Maillot F, �ook P , Lilburn M, e t al: A practical approach t o maternal phenyl­ ketonufla management. J Inherit Metab Dis 30: 1 98, 2007 Malaspina 0, G ilman C, Kranz TM: Paternal age and mental health of ofspring. Ferti! Steril 1 03(6) : 1 392, 20 1 5 Martin ]A, Hamilton BE, Ventura 5], e t al: Births: inal data for 20 1 0. Nat! Vital Stat Rep 6 1 ( 1 ) : 1 , 20 1 2

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fetal medicine subspecialists' role within a health care system. Am J Obstet Gynecol 2 1 1 (6) :607, 20 1 4 Stothard KJ, Tennant PW, Bell R , e t al: Maternal oveweight and obesity and the risk of congenital anomalies: a systematic review and meta-analysis. JAMA 3 0 1 :636, 2009 Stubbleield PG, Coonrod DV, Reddy UM, et al: he clinical content of pre­ conception care: reproductive history. Am J Obstet Gynecol 1 99 (6 Suppl 2):S373, 2008

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C H A PT E R 9

P re n ata l Ca re

DIAGNOSIS OF PREGNANCY. . . . . . . . . . . . . . . . . . . . . . 1 58 I N ITIAL PRENATAL EVALUATION . . . . . . . . . . . . . . . . . . 1 59 SUBSEQUENT PRENATAL VISITS . . . . .

.

. . . . . . . . . . . . . 1 64

N UTRITIONAL COUNSELING . . . . . . . . . . . . . . . . . . . . . . 1 65 COMMON CONCERNS . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 70

The borderline between health and disease is less distincty marked during gestation, and therore, it accordingy becomes necessary to keep pregnant patients under strict supervision, and to be constanty on the alertor the appear­ ance of untoward symptoms. -J. Whitridge Williams ( 1 903)

s emphasized above by Williams, prenatal care is important. According to the merican Academy of Pediatrics and the Amer­ ican College of Obstetricians and Gynecologists (20 1 7) a com­ prehensive antepartum program is deined as: "a coordinated approach to medical care, continuous risk assessment, and psychological support that optimally begins before conception and extends throughout the postpartum period and intercon­ ceptional period. "

Figure 9- 1 , 6 to 7 percent of women in this country have late or no prenatal care. In 20 1 4, the percentages of non-Hispanic white, Hispanic, and African-American women who received inadequate or no prenatal care were 4.3, 7 . 5 , and 9.7, respec­ tively (Child Trends, 20 1 5) . he Centers for Disease Control and Prevention (CDC) (2000) analyzed birth certificate data and found that half of women with delayed or no prenatal care wanted to begin care earlier. Barriers to care varied by social and ethnic group, age, and payment method. he most common reason cited was late recognition of pregnancy by the patient. The second most com­ monly cited obstacle was lack of money or insurance. he third was inability to obtain an appointment.

• Prenatal Care Efectiveness

Care designed during the early 1 900s focused on lowering the extremely high maternal mortality rate. Prenatal care undoubt­ edly contributed to the dramatic decline in this mortality rate from 690 deaths per 1 00,000 births in 1 920 to 50 per 1 00 ,000 8

2

PRENATAL CARE IN THE U N ITED STATES Almost a century after its introduction, prenatal care has become one of the most frequently used health services in the United States. In 200 1 , there were approximately 50 mil­ lion prenatal visits. The median was 1 2. 3 visits per pregnancy, and many women had 1 7 or more visits. Still, as seen from

• •

Births in all states Births in states using the 1 989 birth certificate/revision Births in states using the 2003 birth certificate/revision

o ---� •

1 990

1 993 1 996 1 999 2002

2005

2008 20 1 1

20 1 4

Year

FIGURE 9-1 Percentage of birt h s to mothers who received late or no prenata l ca re-U n ited States, 1 990-20 1 4. (Data from Ch i ld Trends, 20 1 5.)

1 58

P reconceptional a n d P renatal Ca re

by 1 9 5 5 (Loudon, 1 992) . And, the low current maternal mor­ tality rate of 10 to 1 5 per 1 00,000 is likely associated with the high utilization of this care (Xu, 20 1 0) . Indeed, data from 1 998 to 2005 from the Pregnancy \10rtality Surveillance Sys­ tem identified a ivefold increased risk for maternal death in women who received no prenatal care (Berg, 20 1 0) . Other reports also attest t o prenatal care eicacy. I n a study of almost 29 million births, the risk for preterm birth, still­ birth, early and late neonatal death, and infant death rose lin­ early with decreasing prenatal care (Partridge, 20 1 2) . Similarly, Leveno and associates (2009) found that a significant decline in preterm births at Parkland Hospital correlated closely with increased use of prenatal care by medically indigent women. Moreover, National Center for Health Statistics data showed that women with prenatal care had an overall stillbirth rate of 2 . 7 per 1 000 compared with 1 4. 1 per 1 000 for women without this care (Vintzileos, 2002) . Evaluating the format of care, Ickovics and coworkers (20 1 6) compared individual prenatal care and group prenatal care. he latter provided traditional pregnancy surveillance in a group set­ ting with special focus on support, education, and active health­ care participation. Women enrolled in group prenatal care had significantly better pregnancy outcomes. Carter and colleagues (20 1 6) cited similar results. Childbirth education classes are also reported to result in better pregnancy outcomes (Afshar, 20 1 7) . Adolescent pregnancies carry special risk, and guidelines have been developed that focus on this subgroup (Fleming, 20 1 5) . Few data are available t o recommend the practice o f ofering tangible incentives to improve prenatal care attendance (Till, 20 1 5) .

DIAGNOSIS OF PREGNANCY Pregnancy is usually identifi e d when a woman presents with symptoms and possibly a positive home urine pregnancy test result. Typically, these women receive conirmatory testing of urine or blood for human chorionic gonadotropin (hCG ) . Further, presumptive signs or diagnostic indings of pregnancy may be found during examination. Sonography is often used, particularly if miscarriage or ectopic pregnancy is a concern.

• Symptoms and Signs

Amenorrhea in a healthy reproductive-aged woman who previ­ ously has experienced spontaneous, cyclical, predictable men­ ses is highly suggestive of pregnancy. Menstrual cycles vary appreciably in length among women and even in the same woman (Chap. 5, p. 8 1 ) . hus, amenorrhea is not a reliable pregnancy indicator until 1 0 days or more after expected menses have passed. Occasionally, uterine bleeding that mim­ ics menstruation is noted after conception. During the irst month of pregnancy, these episodes are likely the consequence of blastocyst implantation. Still, irst-trimester bleeding should generally prompt evaluation for an abnormal pregnancy. Of other symptoms, maternal perception of fetal move­ ment depends on factors such as parity and habitus. In gen­ eral, after a irst successful pregnancy, a woman may irst perceive fetal movements between 1 6 and 1 8 weeks' gestation. A primigravida may not appreciate fetal movements until approximately 2 weeks later. At about 20 weeks, depending on maternal habitus, an examiner can begin to detect fetal movements. Of pregnancy signs, changes in the lower reproductive tract, uterus, and breasts develop early. These are described in detail in Chapter 4 (p. 49) . • Pregnancy Tests

Detection of hCG in maternal blood and urine is the basis for endocrine assays of pregnancy. Syncytiotrophoblast produces hCG in amounts that increase exponentially during the irst trimester following implantation. A main function of hCG is to prevent involution of the corpus luteum, which is the prin­ cipal site of progesterone formation during the irst 6 weeks of pregnancy. With a sensitive test, the hormone can be detected in mater­ nal serum or urine by 8 to 9 days after ovulation. he doubling time of serum hCG concentration is 1 .4 to 2.0 days. As shown in Figure 9-2, serum levels range widely and increase from the day of implantation. They reach peak levels at 60 to 70 days. Thereafter, the concentration declines slowly until a plateau is reached at approximately 16 weeks' gestation. Measurement of hCG

1 00,000 50,000

' E 1 0 ,000 5

.

" )

5000

c

o

5

6 7 8

9 1 0 1 1 1 2 1 3 1 4 1 5 1 6 1 7 1 8 1 9 20 21 22 23 24 25 26 27

Weeks' gestation

FIGURE 9-2 Mean concentration (95% CI) of h u m a n chorionic g o nadotro p i n (hCG) in serum of women throug hout norm a l preg n a n cy.

his hormone is a glycoprotein with high carbohydrate content. he general structure of hCG is a heterodimer composed of two dis­ similar subunits, designated a and �, which are non covalently linked. The a-subunit is identical to those of luteinizing hormone (LH), fol­ licle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH), but the �-subunit is struc­ turally distinct among these. hus, antibodies were developed with high speciicity for the hCG �-subunit. This speciicity allows its detec­ tion, and numerous commercial

Prenata l C a re

immunoassays are available for measuring serum and urine hCG levels. Although each immunoassay detects a slightly diferent mixture of hCG variants, its free subunits, or its metabolites, all are appropriate for pregnancy testing (Braunstein, 20 1 4) . Depending o n the assay used, the sensitivity for the laboratory detection limit of hCG in serum is 1 .0 mIU/mL or even lower (Wilcox, 200 1 ) . False-positive hCG test results are rare (Braunstein, 2002) . A few women have circulating serum factors that may bind erroneously with the test antibody directed to hCG in a given assay. The most common factors are heterophilic antibodies. hese are produced by an individual and bind to the animal­ derived test antibodies used in a given immunoassay. Thus, women who have worked closely with animals are more likely to develop these antibodies, and alternative laboratory tech­ niques are available (American College of Obstetricians and Gynecologists, 20 1 7a) . Elevated hCG levels may also reflect molar pregnancy and its associated cancers (Chap. 20, p. 39 1 ) . Other rare causes of positive assays without pregnancy are: ( 1 ) exogenous hCG injection used for weight loss, (2) renal fail­ ure with impaired hCG clearance, (3) physiological pituitary hCG, and (4) hCG-producing tumors that most commonly originate from gastrointestinal sites, ovary, bladder, or lung (Montagnana, 20 1 1 ) . H o m e Preg na ncy Tests

Over-the-counter pregnancy test kits have been available since the early 1 970s, and millions are sold annually in the United States. More than 60 such tests are available in this country (Grenache, 20 1 5) . Unfortunately, many of these are not as accurate as advertised Gohnson, 20 1 5) . For example, Cole and associates (20 1 1 ) found that a detection limit of 1 2. 5 mIU/mL would be required to diagnose 9 5 percent of pregnancies at the time of missed menses, but they reported that only one brand had this degree of sensitivity. Two other brands gave false-positive or invalid results. In fact, with an hCG concentra­ tion of 1 00 mIU/mL, clearly positive results were displayed by only 44 percent of brands. Accordingly, only about 1 5 percent of pregnancies could be diagnosed at the time of the missed menses. Some manufacturers of even newer home urine assays claim > 99-percent accuracy of tests done on the day of-and some up to 4 days before-the expected day of menses. Again, careful analysis suggests that these assays are often not as sensi­ tive as advertised Gohnson, 20 1 5) . • Sonographic Recognition of Pregnancy

Transvaginal sonography has revolutionized early pregnancy imaging and is commonly used to accurately establish gesta­ tional age and conirm pregnancy location. A gestational sac-a small anechoic luid collection within the endometrial cavity­ is the irst sonographic evidence of pregnancy. It may be seen with transvaginal sonography by 4 to 5 weeks' gestation. A luid collection, however, can also be seen within the endometrial cavity with an ectopic pregnancy and is termed a pseudogesta­ tional sac or pseudosac (Fig. 1 9-4, p. 375) . Thus, further evalu­ ation may be warranted if this is the only sonographic inding, particularly in a woman with pain or bleeding. A normal

FIGURE 9-3 Tra n svag i n a l sonog ra m of a fi rst-tri mester i ntra u ter­ ine p reg n a ncy. The dou ble deci d u a l sign is noted su rrou n d i n g the gestationa l sac a nd is defined by the decid u a parieta l i s (white aster­ isk) a nd the decidua ca p s u l a ris (yellow asterisk). The a rrow notes the yol k sac, a n d the crown-r u m p length of the embryo is ma rked with mea s u r i n g ca l i pers. (Used with permission from Dr. Elysia Moschos.) gestational sac implants eccentrically in the endometrium, whereas a pseudosac is seen in the midline of the endometrial cavity. Other potential indicators of early intrauterine preg­ nancy are an anechoic center surrounded by a single echogenic rim-the intradecidual sign-or two concentric echogenic rings surrounding the gestational sac-the double decidual sin shown in Figure 9-3 . If sonography yields equivocal indings, the term pregnancy of unknown location (PUL) is applied. In these cases, serial serum hCG levels and transvaginal sonograms can help diferentiate a normal intrauterine pregnancy from an extra­ uterine pregnancy or an early miscarriage (Chap. 1 9, p. 373) . If the yolk sac-a brightly echogenic ring with an anechoic center-is seen within the gestational sac, an intrauterine loca­ tion for the pregnancy is confi r med. The yolk sac can normally be seen by the middle of the ifth week. As shown in Figure 9-3, after 6 weeks, an embryo is seen as a linear structure imme­ diately adjacent to the yolk sac. Cardiac motion is typically noted at this point. Up to 1 2 weeks' gestation, the crown-rump length is predictive of gestational age within 4 days (Chap. 1 0, p. 1 83).

IN ITIAL PRENATAL EVALUATION Prenatal care is ideally initiated early. Major goals are to: ( 1 ) deine the health status of the mother and fetus, (2) estimate the gestational age, and (3) initiate a plan for continued o bstet­ rical care. Typical components of the initial visit are summa­ rized in Table 9- 1 . Subsequent care may range from relatively infrequent routine visits to prompt hospitalization because of serious maternal or fetal disease. • Prenatal Record

Use of a standardized record within a perinatal health-care system greatly aids antepartum and intrapartum management.

1 59

1 60

P reconceptiona l a n d Prenata l Ca re

TABLE 9-1 . Typical Components of Routi n e P re nata l Care Weeks Text Referral

History Complete U pdated

Fi rst Visit

Chap. 9, p. 1 6 1

Physica l exa m i nation Com plete B l ood pressu re Maternal weig ht Pelvic/cervica l exa m i nation F u n d a l h e i g ht Feta l heart rate/feta l position

C h a p. Chap. Cha p. C h a p. Chap. Chap.

Laboratory tests Hematocrit or h e m og l o b i n B lood type a nd Rh factor A nti body screen Pap s m e a r scree n i ng G l ucose to l e ra nce test Feta l a n e u pl oidy scree n i n g N e u ra l -t u be d efect scree n i ng Cystic fi b rosis scree n i ng U ri n e p rote i n assess ment U ri n e cultu re R u bel l a serology Syph i l i s sero l ogy Gonococca l scree n i ng C h l a myd i a l scree n i n g H epatiti s B serology H IV sero l ogy G ro u p B streptococcus c u l t u re Tuberc u l o s i s scree n i n g

Chap. 56, p. 1 075 Chap. 1 5, p. 30 1 C h a p. 1 5 , p. 30 1 Chap. 63, p. 1 1 93 Cha p. 5 7, p. 1 1 08 Chap. 1 4, p. 2 7 8 C h a p. 1 4, p. 283 Chap. 1 4, p. 289 C h a p. 4, p. 66 Chap. 53, p. 1 026 Chap. 64, p. 1 2 1 5 Chap. 65, p. 1 237 Chap. 65, p. 1 23 9 Chap. 6 5 , p . 1 240 Chap. 55, p. 1 064 Chap. 65, p. 1 247 Chap. 64, p. 1 220 C h a p. 5 1 , p. 996

9, p. 1 63 40, p. 7 1 1 9, p. 1 65 9, p. 1 63 9, p. 1 64 9, p. 1 65

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a F i rst-t ri m ester a n e u p l o i dy scree n i ng may be ofe red betwee n 1 1 a n d 1 4 wee ks. A Performed at 28 weeks, if i n d i cated. 8 Test shou l d be ofered. C H i g h-risk wom e n s h o u l d be retested at the beg i n n i ng of t h e th i rd tri mester. o H i g h- r i s k w o m e n s h o u l d be screened at t h e fi rst p re n ata l visit a n d aga i n i n t h e th i rd tri mester. E Rectova g i n a l c u lt u re s h o u l d b e o bta i n ed between 35 a n d 3 7 weeks. HIV h u ma n i m m u n od eficiency virus. =

Standardizing documentation allows communication and care continuity between providers and enables objective measures of care quality to be evaluated over time and across diferent clinical settings (Gregory, 2006) . A prototype is provided by the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (20 1 7) in their Guidelines or Perinatal Care, 8th edition.

Defi n itions Several deinitions are pertinent to establishment of an accurate prenatal record. 1 . Nulligravida-a woman who currently is not pregnant and has never been pregnant.

2. Gravida-a woman who currently is pregnant or has been in the past, irrespective of the pregnancy outcome. With the establishment of the first pregnancy, she becomes a primi­ gravida, and with successive pregnancies, a multigravida. 3. Nullpara-a woman who has never completed a pregnancy beyond 20 weeks' gestation. She may not have been preg­ nant or may have had a spontaneous or elective abortion(s) or an ectopic pregnancy. 4. Primipara-a woman who has been delivered only once of a fetus or fetuses born alive or dead with an estimated length of gestation of 20 or more weeks. In the past, a 500-g birth­ weight threshold was used to define parity. his threshold is now controversial because many states still use this weight to

Prenata l Ca re diferentiate a stillborn fetus from an abortus (Chap. 1 , p. 3) . However, the survival of neonates with birthweights < 500 g is no longer uncommon. 5. Multpara-a woman who has completed two or more preg­ nancies to 20 weeks' gestation or more. Parity is determined by the number of pregnancies reaching 20 weeks. It is not increased to a higher number if multiples are delivered in a given pregnancy. Moreover, stillbirth does not lower this number. In some locales, the obstetrical history is summa­ rized by a series of digits connected by dashes. hese refer to the number of term infants, preterm infants, abortuses younger than 20 weeks, and children currently alive. For example, a woman who is para 2-1 -0-3 has had two term deliveries, one preterm delivery, no abortuses, and has three living children. Because these are nonconventional, it is helpful to speciy the outcome of any pregnancy that did not end normally.

N ormal Preg na ncy D u ration The normal duration of pregnancy calculated from the irst day of the last normal menstrual period is very close to 280 days or 40 weeks. In a study of 427, 5 8 1 singleton pregnancies from the Swedish Birth Registry, Bergsj0 and coworkers ( 1 990) found that the mean pregnancy duration was 2 8 1 days with a standard deviation of 1 3 days. However, menstrual cycle length varies among women and renders many of these calculations inac­ curate. This, combined with the frequent use of irst-trimester sonography, has changed the method of determining an accu­ rate gestational age (Duryea, 20 1 5) . h e American College o f Obstetricians and Gynecologists (20 1 7e) , the American Institute of Ultrasound in Medicine, and the Society for Maternal-Fetal Medicine have concluded that irst-trimester ultrasound is the most accurate method to establish or reairm gestational age. For pregnancies conceived by assisted reproductive technology, embryo age or transfer date is used to assign gestational age. If available, the gesta­ tional ages calculated from the last menstrual period and from irst-trimester ultrasound are compared, and this estimated date of delivery is recorded. his is discussed in further detail in Chapter 7 (p. 1 24) and in Table 1 0- 1 (p. 1 83) . A quick estimate of a pregnancy due date based on men­ strual data can be made as follows: add 7 days to the irst day of the last period and subtract 3 months. For example, if the irst day of the last menses was October 5, the due date is 1 0-0 5 minus 3 (months) plus 7 (days) = 7- 1 2, or July 1 2 of the following year. his calculation is the Naegele rule (American College of Obstetricians and Gynecologists, 20 1 7 e) .

Tri mesters It has become customary to divide pregnancy into three equal epochs or trimesters of approximately 3 calendar months. His­ torically, the irst trimester extends through completion of 1 4 weeks, the second through 2 8 weeks, and the third includes the 29th through 42nd weeks of pregnancy. Thus, there are three periods of 1 4 weeks each. Certain major obstetrical problems tend to cluster in each of these time periods. For example, most spontaneous abortions take place during the irst trimester,

whereas most women with hypertensive disorders due to preg­ nancy are diagnosed during the third trimester. In modern obstetrics, the clinical use of trimesters to describe a speciic pregnancy is imprecise. For example , it is inappropriate in cases of uterine hemorrhage to categorize the problem temporally as "third-trimester bleeding. " Appropriate management for the mother and her fetus will vary remark­ ably depending on whether bleeding begins early or late in the th ird trimester (Chap. 4 1 , p. 757) . Because precise knowledge of fetal age is imperative for ideal obstetrical management, the clinically appropriate unit is weeks ofgestation complete. And more recently, clinicians designate gestational age using com­ pleted weeks and days, for example, 3 3 4/7 weeks or 33 + 4, for 33 completed weeks and 4 days.

Previous a n d Cu rrent Hea lth Status As elsewhere in medicine, history taking begins with queries concerning medical or surgical disorders. Also, detailed infor­ mation regarding previous pregnancies is essential as many obstetrical complications tend to recur in subsequent pregnan­ cies. The menstrual and contraceptive histories are also impor­ tant. Gestational or menstrual age is the number of weeks since the onset of the last menstrual period in women with menstrual cycles lasting 28 to 30 days. For those with irregular m enses, sonography in early pregnancy will clariy gestational age. Last, some methods of birth control favor ectopic implantation fol­ lowing method failure (Chap. 38, pp. 683 and 689) . Psychosocial Screening. The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (20 1 7) defi n e psychosocial issues as nonbiomedical factors that afect mental and physical well-being. Women should be screened regardless of social status, education level, race, or eth­ nicity. Such screening should seek barriers to care, communica­ tion obstacles, nutritional status, unstable housing, desire for pregnancy, safety concerns that include intimate-partner vio­ lence, depression, stress, and use of substances such as tob acco, alcohol, and illicit drugs. his screening is performed on a regu­ lar basis, at least once per trimester, to identiy important issues and reduce adverse pregnancy outcomes. Coker and colleagues (20 1 2) compared pregnancy outcomes in women before and after implementation of a universal psychosocial screening program and found that screened women were less likely to have preterm or low-birthweight newborns, as well as other adverse outcomes. Speciic screens for depression are presented in Chapter 61 (p. 1 1 74) . Cigarette Smoking. Data on this practice have been included on the birth certiicate since 1 9 89. The number of pregnant women who smoke continues to decline. From 2000 to 2 0 1 0, the prevalences were 1 2 to 1 3 percent (Tong, 20 1 3) . Based on the Pregnancy Risk Assessment Monitoring System, these women were more likely younger, had less education, and were either Alaska Natives or American Indians (Centers for Disease Control and Prevention, 20 1 3a) . Numerous adverse outcomes have been linked to smoking during pregnancy (U. S . D epartment of Health and H uman S ervices, 2000) . Potential teratogenic efects are reviewed in

1 61

1 62

P reconcept i o n a l a n d P renatal Care

TABLE 9-2. Five A's of Smoking Cessation A S K a bo ut s moking at the fi rst and s u bseq uent p renata l visi ts. ADVI S E with clear, stro ng state me nts that expl a i n the risks of conti n ued smoking to the wom a n , fet u s, a n d newborn . ASSESS the patient's wi l l i n g n ess to atte m pt cessation . ASSIST with preg nancy-spec ific, self- h e l p smoking cessatio n mate r i a l s. Ofer a d i rect referra l to the sm oker's q u it l i ne ( 1 -800-Q U IT NOW) to p rovi d e o n g o i n g co u n se l i ng a n d s u pport. ARRANGE to track smoking a b sti nence p rog ress at s u bseq uent vis its.

Ada pted from F io re, 2008.

Chapter 1 2 (p. 249) . Notable among these are greater rates of miscarriage, stillbirth, low birthweight, and preterm delivery (Man, 2006; Tong, 20 1 3) . here is also a twofold risk of placenta previa, placental abruption, and premature mem­ brane rupture compared with nonsmokers. hus, the U.S. Preventive Services Task Force recommends that clinicians ofer counseling and efective intervention options to preg­ nant smokers at the irst and subsequent prenatal visits (Siu, 2 0 1 5 ) . Although beneits are greatest if smoking ceases early in pregnancy or preferably preconceptionally, quitting at any stage of pregnancy can improve perinatal outcomes (Fiore, 2008 ) . Person-to-person psychosocial interventions are signiicantly more successful in achieving smoking abstinence in pregnancy than is simply advising the woman to quit (Fiore, 2008) . One example is a brief counseling session covering the "5As" of smoking cessation (Table 9-2) . This approach can be accom­ plished in 1 5 minutes or less and is efective when initiated by health-care providers (American College of Obstetricians and Gynecologists, 20 1 7i) . Behavioral interventions and nicotine replacement products are successful in reducing smoking rates (Patnode, 20 1 5) . hat said, nicotine replacement has not been suiciently evaluated to determine its efectiveness and safety in pregnancy. Trials evalu­ ating such therapy have yielded confl i cting evidence (Coleman, 20 1 5 ; Pollak, 2007; Spindel, 20 1 6) . Two recent randomized trials also produced nonconclusive results. In the Smoking and Nicotine in Pregnancy (SNAP) trial, Cooper and associates (20 1 4) reported a temporary cessation of smoking that may have been associated with improved infant development. In the Study of Nicotine Patch in Pregnancy (SNIPP) trial, Berlin and coworkers (20 1 4) found no diferences in smoking cessation rates or birthweights. Because of limited available evidence to support pharma­ cotherapy for smoking cessation in pregnancy, the American College of Obstetricians and Gynecologists (20 1 7i) has recom­ mended that if nicotine replacement therapy is used, it should be done with close supervision and after careful consideration of the risks of smoking versus nicotine replacement. Alcohol. Ethyl acohol or ethanol is a potent teratogen that causes a etal syndrome characterized by growth restriction, acial abnor­ malities, and central nervous system dyunction. s discussed in Chapter 1 2 (p. 239), women who are pregnant or consider­ ing pregnancy should abstain from using any alcoholic bever­ ages. The CDC analyzed data from the Behavioral isk Factor

Surveillance System from 20 1 1 to 20 1 3 and estimated that 1 0 percent of pregnant women used alcohol. It is estimated that 3.3 million women are at risk for such exposure (Green, 20 1 6) . h e American College o f Obstetricians and Gynecologists (20 1 6b) in collaboration with the CDC has developed the Fetal Acohol Spectrum Disorders (FASD) Prevention Program, which provides resources for providers and is available at: http://www. acog.org/ alcohol. Il licit Drugs. It is estimated that 1 0 percent of fetuses are exposed to one or more illicit drugs. Agents may include heroin and other opiates, cocaine, amphetamines, barbiturates, and marijuana (American Academy of Pediatrics, 20 1 7; merican College of Obstetricians and Gynecologists, 20 1 5a, 20 1 7d) . As discussed in Chapter 12 (p. 247), chronic use of most of these in large quan­ tities is harmful to the fetus (Metz, 20 1 5) . Well-documented sequelae include fetal-growth restriction, low birthweight, and drug withdrawal soon ater birth. Adverse efects of marijuana are less convincing. Women who use such drugs frequently do not seek prenatal care, which in itself is associated with risks for preterm and low-birthweight newborns (EI-Mohandes, 2003; Eriksen, 20 1 6) . For women who abuse heroin, methadone maintenance can be initiated within a registered methadone treatment program to reduce complications of illicit opioid use and narcotic with­ drawal, to encourage prenatal care, and to avoid drug culture risks (American College of Obstetricians and Gynecologists, 20 1 7£) . Available programs can be found through the treatment locator of the Substance Abuse and Mental Health Services Administration at ww.samhsa.gov. Methadone dosages usually are initiated at 1 0 to 30 mg daily and titrated as needed. In some women, careful methadone taper may be an appropriate option (Stewart, 20 1 3) . Although less commonly used, buprenorphine alone or in combination with naloxone may also be ofered and managed by physicians with specific credentialing. I ntimate-Partner Violence. his term refers to a pattern of assault and coercive behavior that may include physical injury, psychological abuse, sexual assault, progressive isolation, stalk­ ing, deprivation, intimidation, and reproductive coercion (American College of Obstetricians and Gynecologists, 20 1 2) . Such violence has been recognized as a major public health problem. Unfortunately, most abused women continue to be victimized during pregnancy. With the possible exception of preeclampsia, domestic violence is more prevalent than any major medical condition detectable through routine prenatal

P renata l Ca re

screening (American Academy of Pediatrics and the Ameri­ can College of Obstetricians and Gynecologists, 20 1 7) . The prevalence during pregnancy is estimated to range between 4 and 8 percent. Intimate-partner violence is associated with an increased risk of several adverse perinatal outcomes including preterm delivery, fetal-growth restriction, and perinatal death (Chap. 47, p. 925). The American College of Obstetricians and Gynecologists (20 1 2) has provided methods for domestic violence screen­ ing and recommends their use at the irst prenatal visit, then again at least once per trimester, and again at the postpartum visit. Such screening should be done privately and away from family members and friends. Patient self-administered or com­ puterized screenings appear to be as efective for disclosure as clinician-directed interviews (Ahmad, 2009; Chen, 2007) . Physicians should be familiar with state laws that may require reporting of intimate-partner violence. Coordination with social services can be invaluable in these cases. The National Domestic Violence Hotline ( l -800-799-SAFE [7233] ) is a nonprofit telephone referral service that provides individualized information regarding city-speciic shelter locations, counseling resources, and legal advocacy. • Clinical Evaluation

A thorough, general physical examination should be com­ pleted at the initial prenatal encounter. Pelvic examination is performed as part of this evaluation. he cervix is visualized employing a speculum lubricated with warm water or water­ based lubricant gel. Bluish-red passive hyperemia of the cer­ vix is characteristic, but not of itself diagnostic, of pregnancy. Dilated, occluded cervical glands bulging beneath the ectocer­ vical mucosa-nabothian cysts-may be prominent. he cervix is not normally dilated except at the external os. To identiy cytological abnormalities, a Pap test is performed according to current guidelines noted in Chapter 63 (p. 1 1 93). Specimens for identiication of Chlamydia trachomatis and Neisseria gonor­ rhoeae are also obtained when indicated. Bimanual examination is completed by palpation, with spe­ cial attention given to the consistency, length, and dilatation of the cervix; to uterine and adnexal size; to the bony pelvic architecture; and to any vaginal or perineal anomalies. Later in pregnancy, fetal presentation often can also be determined. Lesions of the cevix, vagina, or vulva are further evaluated as needed by colposcopy, biopsy, culture, or dark-field examina­ tion. The perianal region is visualized, and digital rectal exami­ nation performed as required for complaints of rectal pain, bleeding, or mass. Gestationa l Age Assessment

Precise knowledge of gestational age is one of the most impor­ tant aspects of prenatal care because several pregnancy compli­ cations may develop for which optimal treatment will depend on fetal age. As discussed earlier and in Chapter 7 (p. 1 24) , irst-trimester sonographic assessment is best correlated with menstrual history. That said, gestational age can also be esti­ mated with considerable precision by carefully performed clini­ cal uterine size examination that is coupled with knowledge of

the last menses. Uterine size similar to a small orange roughly correlates with a 6-week gestation; a large orange, with an 8-week pregnancy; and a grapefruit, with one at 12 weeks (Margulies, 200 1 ) . • Laboratory Tests

Recommended routine tests at the first prenatal encounter are listed in Table 9- 1 . Initial blood tests include a complete blood count, a determination of blood type with h status, and an antibody screen. The Institute of Medicine recommends universal human immunodeiciency virus (HIV) testing, with patient notiication and right of refusal, as a routine part of pre­ natal care. The CDC (Branson, 2006) as well as the American Academy of Pediatrics and the American College of Obstetri­ cians and Gynecologists (20 1 6f, 20 1 7) continue to suppo rt this practice. If a woman declines testing, this is recorded in the prenatal record. All pregnant women are also screened for hepa­ titis B virus infection, syphilis, and immunity to rubella at the initial visit. Based on their prospective investigation of 1 000 women, Murray and coworkers (2002) concluded that in the absence of hypertension, routine urinalysis beyond the irst pre­ natal visit was not necessary. A urine culture is recommended by most because treating bacteruria signiicantly reduces the likelihood of developing symptomatic urinary tract infections in pregnancy (Chap. 53, p. 1 026) . Cervica l I nfectio n s

Chlamydia trachomatis is isolated from the cervix in 2 to 13 per­ cent of pregnant women. he American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (20 1 7) recommend that all women be screened for chlamydia during the irst prenatal visit, with additional third-trimester testing for those at increased risk. Risk factors include unmarried status, recent change in sexual partner or multiple concurrent partners, age younger than 25 years, inner-city residence, history or presence of other sexually transmitted diseases, and little or no prenatal care. For those testing positive, treatment described in Chapter 65 (p. 1 240) is followed by a second testing-a test ofcure-3 to 4 weeks after treatment completion. Neisseria gonorrhoeae typically causes lower genital tract infection in pregnancy. It also may cause septic arthritis ( Bleich, 20 1 2) . Risk factors for gonorrhea are similar to those for chla­ mydial infection. The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (20 1 7) recommend that pregnant women with risk factors or those liv­ ing in an area of high N gonorrhoeae prevalence be screened at the initial prenatal visit and again in the third trimester. Treat­ ment is given for gonorrhea and simultaneously for possible coexisting chlamydial infection (Chap. 65, p. 1 240) . Test of cure is also recommended following treatment. • Pregnancy Risk Assessment

Many factors can adversely afect maternal and fetal well-being. Some are evident at conception, but many become apparent during the course of pregnancy. The designation of "high-risk pregnancy" is overly vague for an individual woman and prob­ ably is best avoided if a more specific diagnosis can be assigned.

1 63

1 64

P reco n ceptiona l a n d P re natal Care

TABLE 9-3. Conditions for Which Materna l-Feta l Med icine Consu ltation May Be Beneficia l Medical History and Cond itions

Card iac d isease-moderate to severe d i so rd ers D i a betes m e l l itus with evid en ce of e n d-org a n da mage or u n contro i led hyperg lycemia Fa m i l y o r perso n a l h i story of g e n etic a b n o rm a l ities H em og lo b i nopathy C h ro n i c hyperten s i o n if u ncontro l l ed or associated with ren a l r cardiac d i sease Renal i ns ufici ency if a ssoci ated with sig n ificant prote i n u ria ( ::500 m g/24 h o u r), seru m c reat i n i ne ::1 .5 m g/d L, or hyperten s i o n P u l m o n a ry d i sease if seve re restrictive o r obstructive, i n c l u d i n g severe asthma H u ma n i m m u n od eficiency virus i nfection P rior p u l m o n a ry e m bo l u s or d ee p-ve i n t h rom bos is Severe system ic d i sea se, i nc l u d i n g a utoi m m u n e con d itions Ba riatric s u rg e ry E p i lepsy if poorly contro l led or req u i res more t h a n one a nticonvu l s a nt Cancer, espec i a l l y if t reatm e n t is i n d icated i n preg n a n cy Obstetrical History and Conditions

CDE (Rh) o r other b lood g r o u p a l l oi m m u n ization (exc l u d i ng ABO, Lewis) P rior or cu rrent feta l struct u ra l o r c h ro m osoma l a bn o rm a l ity Des i re or need for prenata l d i a g n o s i s or feta l thera py Perico nceptional expo s u re to known teratoge n s I nfection w i t h or expo s u re to o rga n is m s that c a u s e congen ita l i nfection H ig h e r-ord e r m u l tifeta l g estation Severe d i sord e rs of a m n io n ic fl u i d vo l u me

Some common risk factors for which consultation is recom­ mended by the American Academy of Pediatrics and the Amer­ ican College of Obstetricians and Gynecologists (20 1 7) are shown in Table 9-3 . Some conditions may require the involve­ ment of a maternal-fetal medicine subspecialist, geneticist, pediatrician, anesthesiologist, or other medical specialist in the evaluation, counseling, and care of the woman and her fetus.

SU BSEQUENT PRENATAL VISITS hese are traditionally scheduled at 4-week intervals until 28 weeks, then every 2 weeks until 36 weeks, and weekly thereaf­ ter. Women with complicated pregnancies-for example, with twins or diabetes-often require return visits at 1 - to 2-week intervals (Luke, 2003; Power, 20 1 3) . In 1 986, the Department of Health and Human Services convened an expert panel to review the content of prenatal care. his report was subsequently reevaluated and revised in 2005 (Gregory, 2006) . he panel recommended, among other things, early and continuing risk assessment that is patient speciic. It also endorsed lexibility in clinical visit spacing; health promotion and education, includ­ ing preconceptional care; medical and psychosocial interven­ tions; standardized documentation; and expanded prenatal care objectives-to include family health up to 1 year after birth. he World Health Organization conducted a multicenter randomized trial with almost 25 ,000 women comparing rou­ tine prenatal care with an experimental model designed to minimize visits (Villar, 200 1 ) . In the new model, women were seen once in the irst trimester and screened for certain risks. hose without anticipated complications-80 percent of those

screened-were seen again at 26, 32, and 38 weeks. Compared with routine prenatal care, which required a median of eight visits, the new model required a median of only ive. No dis­ advantages were attributed to the regimen with fewer visits, and these indings were consistent with other randomized trials (Clement, 1 999; McDuie, 1 996) .

• Prenatal Surveillance

At each return visit, the well-being of mother and fetus are assessed (see Table 9- 1 ) . Fetal heart rate, growth, and activity and amnionic fluid volume are evaluated. Maternal blood pres­ sure and weight and their extent of change are examined. Symp­ toms such as headache, altered vision, abdominal pain, nausea and vomiting, bleeding, vaginal luid leakage, and dysuria are sought. Mter 20 weeks' gestation, uterine examination mea­ sures size from the symphysis to the fundus. In late pregnancy, vaginal examination often provides valuable information that includes conirmation of the presenting part and its station, clinical estimation of pelvic capacity and configuration, amni­ onic luid volume adequacy, and cervical consistency, eface­ ment, and dilatation (Chap. 22, p. 435) .

F u n d a l H e i g ht Between 20 and 34 weeks' gestation, the height of the uter­ ine fundus measured in centimeters correlates closely with gestational age in weeks Gimenez, 1 983) . his measurement is used to monitor fetal growth and amnionic fluid volume. It is measured along the abdominal wall from the top of the sym­ physis pubis to the top of the fundus. Importantly, the bladder

P renata l Ca re must be emptied before fundal measurement (Worthen, 1 980) . Obesity or the presence of uterine masses such as leiomyomas may also limit fundal height accuracy. Moreover, using fundal height alone, fetal-growth restriction may be undiagnosed in up to a third of cases (American College of Obstetricians and Gynecologists, 20 1 5 b; Haragan, 20 1 5) .

(American College of Obstetricians and Gynecologists, 20 1 6) . Similarly, women who engage i n behaviors that place them at high risk for hepatitis B virus infection are retested at the time of hospitalization for delivery. Women who are D (h) nega­ tive and are unsensitized should have an antibody screening test repeated at 28 to 29 weeks, and anti-D immunoglobulin is given if they remain unsensitized (Chap. 1 5 , p. 305).

Feta l Heart Sou n d s Instruments incorporating Doppler ultrasound are often used to easily detect fetal heart action, and in the absence of maternal obesity, heart sounds are almost always detectable by 1 0 weeks with such instruments (Chap. 1 0, p. 2 1 3) . he fetal heart rate ranges from 1 1 0 to 1 60 beats per minute and is typically heard as a double sound. Using a standard nonampliied stethoscope, the fetal heart is audible by 20 weeks in 80 percent of women, and by 22 weeks, heart sounds are expected to be heard in all (Herbert, 1 987) . Because the fetus moves freely in amni­ onic fl u id, the site on the maternal abdomen where fetal heart sounds can be heard best will vary. Additionally, with ultrasonic auscultation, one may hear the unic soule, which is a sharp, whistling sound that is syn­ chronous with the fetal pulse. It is caused by the rush of blood through the umbilical arteries and may not be heard consistently. In contrast, the uterine soule is a soft, blowing sound that is synchronous with the maternal pulse. It is produced by the pas­ sage of blood through the dilated uterine vessels and is heard most distinctly near the lower portion of the uterus.

Sonog ra phy Sonography provides invaluable information regarding fetal anatomy, growth, and well-being, and most women in the United States have at least one prenatal sonographic exami­ nation during pregnancy (American College of Obstetricians and Gynecologists, 20 1 6h) . Continuing trends suggest that the number of these examinations performed per pregnancy is increasing. Siddique and associates (2009) reported that the average number rose from 1 . 5 in 1 995 through 1 997 to 2.7 almost 10 years later. his trend was noted in both high- and low-risk pregnancies. he actual clinical utility of this increased use in pregnancy has not been demonstrated, and it is unclear that the cost-benefi t ratio is justified (Washington State Health Care Authority, 20 1 0) . The American College of Obstetricians and Gynecologists (20 1 6h) has concluded that sonography should be performed only when there is a valid medical indica­ tion and under the lowest possible ultrasound exposure setting. The College further states that a physician is not obligated to perform sonography without a specific indication in a low-risk patient, but that if she requests sonographic screening, it is rea­ sonable to honor her request.

• Subsequent Laboratory Tests

If initial results were normal, most tests need not be repeated. Hematocrit or hemoglobin determination, along with serology for syphilis if it is prevalent in the population, is repeated at 28 to 32 weeks (Hollier, 2003; Kiss, 2004) . For women at increased risk for HIV acquisition during pregnancy, repeat testing is rec­ ommended in the third trimester, preferably before 36 weeks

Gro u p B Streptococca l I nfection he CDC (20 1 0b) recommends that vaginal and rectal group B streptococcal (GBS) cultures be obtained in all women between 35 and 37 weeks' gestation, and the American College of Obste­ tricians and Gynecologists (20 1 6g) has endorsed this recom­ mendation. Intrapartum antimicrobial prophylaxis is provided to those whose culture results are positive. Women with GBS bacteriuria or a previous infant with invasive disease are given empirical intrapartum prophylaxis. Trials are in progress to test an investigational vaccine (Donders, 20 1 6; Schrag, 20 1 6) . hese infections are described further in Chapter 64 (p. 1 220) .

Gestation a l Dia betes All pregnant women are screened for gestational diabetes mel­ litus, whether by history, clinical factors, or routine laboratory testing. Although laboratory testing between 24 and 28 weeks' gestation is the most sensitive approach, there may be pregnant women at low risk who are less likely to beneit from testing (American College of Obstetricians and Gynecologists, 2 0 1 7c) . Gestational diabetes is discussed in Chapter 57 (p. 1 1 07) .

N e u ra l -Tu be Defect a n d G e n etic Scree n i n g Serum screening for neural-tube defects i s ofered at 1 5 to 20 weeks. Fetal aneuploidy screening may be performed at 1 1 to 1 4 weeks' gestation and/or at 1 5 to 20 weeks, depending on the protocol selected (Rink, 20 1 6) . Additionally, screening for certain genetic abnormalities is ofered to women at increased risk based on family history, ethnic or racial background, or age (American College of Obstetricians and Gynecologists, 20 1 7h) . These are discussed in greater detail in Chapter 1 4 (p. 277) . Some examples include testing for Tay-Sachs disease for persons of Eastern European Jewish or French Canadian ancestry; � -thalassemia for those of Mediterranean, Southeast Asian, Indian, Pakistani, or Mrican ancestry; a-thalassemia for individuals of Southeast Asian or Mrican ancestry; sickle-cell anemia for people of African, Mediterranean, Middle Eastern, Caribbean, Latin American, or Indian descent; and trisomy 2 1 for those with advanced maternal age.

N UTRITIONAL COU NSELING

• Weight Gain Recommendations

In 2009, the Institute of Medicine and National Research Council revised guidelines for weight gain in pregnancy and continued to stratiy suggested weight gain ranges based on prepregnancy body mass index (BMI) (Table 9-4) . The new guidelines included a specific, relatively narrow range of recom­ mended weight gains for obese women. Also, the same recom­ mendations apply to adolescents, short women, and women of

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TABLE 9-4. Reco m m endations for Total a n d Rate of

We i g ht G a i n During Preg na ncy

Category (BMI)

U nd e rwe i g h t « 1 8.5) Normal wei g h t ( 1 8.5-24.9) Ove rweig ht (25 .0-29.9) Obese (::30.0)

Total Weight Gai n Range ( l b)a

Weight Gain i n 2nd and 3rd Tri mesters Mean in I b/wk (range)

28-40

1 ( 1 - 1 .3)

25-35

1 (0.8- 1 )

1 5-25

0.6 (0.5-0.7)

1 1 -20

0.5 (0.4-0.6)

a E m p i rica l reco m me n d at i o n s for wei g h t g a i n i n twi n preg n a ncies i n cl ude: norma l BMI, 3 7-54 I b; ove rwe i g ht wo men, 3 1 -5 0 I b; a n d o bese wom en, 25-42 l b. B M I body mass i n d ex. Mod ifi ed from t h e I n st i tute of Med i c i n e a n d National Research Cou n c i l , 2009. =

all racial and ethnic groups. The American College of Obstetri­ cians and Gynecologists (20 1 6i) has endorsed these measures. When the Institute of Medicine guidelines were formulated, concern focused on low-birthweight newborns, however, cur­ rent emphasis is directed to the obesity epidemic (Catalano, 2007) . This explains renewed interest in lower weight gains dur­ ing pregnancy. Obesity is associated with significantly greater risks for gestational hypertension, preeclampsia, gestational dia­ betes, macrosomia, cesarean delivery, and other complications (Chap. 48, p. 939) . he risk appears "dose related" to prenatal weight gain. In a population-based cohort of more than 1 20,000 obese pregnant women, those who gained 1 0,000 IU / d) during pregnancy. These malformations are similar to those produced by the vitamin A derivative isotretinoin (Accutane), which is a potent teratogen (Chap. 1 2, p. 245 ) . Beta-carotene, the precursor of vitamin A found in fruits and vegetables, has not been shown to produce vitamin A toxicity. Most prena­ tal vitamins contain vitamin A in doses considerably below the teratogenic threshold. Dietary intake of vitamin A in the United States appears to be adequate, and additional supple­ mentation is not routinely recommended. In contrast, vitamin A deiciency is an endemic nutritional problem in the develop­ ing world (McCauley, 20 1 5) . Vitamin A deficiency, whether overt or subclinical, is associated with night blindness and with an increased risk of maternal anemia and spontaneous preterm birth (West, 2003) . Vitamin BJ2 plasma levels drop in normal pregnancy, mostly as a result of reduced plasma levels of their carrier proteins­ transcobalamins. Vitamin B J 2 occurs naturally only in foods of animal origin, and strict vegetarians may give birth to neonates whose BI2 stores are low. Likewise, because breast milk of a vegetarian mother contains little vitamin B 1 2, the deiciency may become profound in the breastfed infant (Higginbottom,

1 978). Excessive ingestion of vitamin C also can lead to a functional deiciency of vitamin B12. Although its role is still controversial, vitamin B I 2 deiciency preconceptionally, similar to folate, may elevate the risk of neural-tube defects (Molloy, 2009) . Vitamin B6, which is pyridoxine, does not require supple­ mentation in most gravidas (Salam, 20 1 5) . For women at high risk for inadequate nutrition, a daily 2-mg supplement is rec­ ommended. As discussed on page 1 74, vitamin B6, when com­ bined with the antihistamine doxylamine, is helpful in many cases of nausea and vomiting of pregnancy. Vitamin C allowances during pregnancy are 80 to 85 mg/ d­ approximately 20 percent more than when nonpregnant (see Table 9-5) . A reasonable diet should readily provide this amount, and supplementation is not necessary (Rumbold, 20 1 5) . Maternal plasma levels decline during pregnancy, whereas cord-blood levels are higher, a phenomenon observed with most water-soluble vitamins. Vitamin D is a fat-soluble vitamin. After being metabolized to its active form, it boosts the eiciency of intestinal calcium absorption and promotes bone mineralization and growth. Unlike most vitamins that are obtained exclusively from dietary intake, vitamin D is also synthesized endogenously with expo­ sure to sunlight. Vitamin D deiciency is common during preg­ nancy. his is especially true in high-risk groups such as women with limited sun exposure, vegetarians, and ethnic minorities­ particularly those with darker skin (Bodnar, 2007) . Maternal deiciency can cause disordered skeletal homeostasis, congeni­ tal rickets, and fractures in the newborn (American College of Obstetricians and Gynecologists, 20 1 7k) . Vitamin D supple­ mentation to women with asthma may decrease the likelihood of childhood asthma in their fetuses (Litonjua, 20 1 6) . The Food and Nutrition Board of the Institute of Medicine (20 1 1 ) estab­ lished that an adequate intake of vitamin D during pregnancy and lactation was 1 5 �g/d (600 IU/d) . In women suspected of having vitamin D deficiency, serum levels of 25-hydroxyvita­ min D can be obtained. Even then, the optimal levels in preg­ nancy have not been established (De-Regil, 20 1 6) .

• Pragmatic Nutritional Surveillance

Although researchers continue to study the ideal nutritional regimen for the pregnant woman and her fetus, basic tenets for the clinician include: 1 . Advise the pregnant woman to eat food types she wants in reasonable amounts and salted to taste. 2. Ensure that food is amply available for socioeconomically deprived women. 3. Monitor weight gain, with a goal of approximately 2 5 to 3 5 lb in women with a normal BMI. 4. Explore food intake by dietary recall periodically to discover the occasional nutritionally errant diet. 5. Give tablets of simple iron salts that provide at least 27 mg of elemental iron daily. Give folate supplementation before and in the early weeks of pregnancy. Provide iodine supple­ mentation in areas of known dietary insuiciency. 6. Recheck the hematocrit or hemoglobin concentration at 28 to 32 weeks' gestation to detect signiicant anemia.

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TABLE 9-6. Some Contra i n d i catio ns to Exercise During P reg n a n cy

Sig n ifi ca nt card i ovasc u l a r or p u l m o na ry d i sease S i g n ifi ca nt ri s k for p reterm labor: cerclage, m u ltifeta l gestation, s i g n ifi ca nt bleed i n g , t h reate ned preterm la bor, prematu rely r u pt u red m e m b ra nes Obstetrical com pl i cations: preecla m psia, p lacenta previa, a n e m i a, poorly contro l led d i abetes or epi lepsy, m o rb i d obesity, feta l -g rowth restriction S u m m a rized fro m America n Co l l ege of Obstet r i c i a n s a nd Gyn ecol og i sts, 201 7g.

COMMON CONCERNS

• Employment

More than half of the children in the United States are born to working mothers. Federal law prohibits employers from excluding women from job categories on the basis that they are or might become pregnant. he Family and Medical Leave Act of 1 993 requires that covered employers must grant up to 1 2 work weeks of unpaid leave to an employee for the birth and care of a newborn child Qackson, 2 0 1 5). In the absence of complications, most women can continue to work until the onset of labor (American Academy of Pediatrics and the Ameri­ can College of Obstetricians and Gynecologists, 20 1 7) . Some types o f work, however, may increase pregnancy com­ plication risks. Mozurkewich and colleagues (2000) reviewed 29 studies that involved more than 1 60,000 pregnancies. With physically demanding work, women had 20- to 60-percent higher rates of preterm birth, fetal-growth restriction, or ges­ tational hypertension. In a prospective study of more than 900 healthy nulliparas, women who worked had a ivefold risk of preeclampsia (Higgins, 2002) . Newman and coworkers (200 1 ) reported outcomes i n more than 2900 women with singleton pregnancies. Occupational fatigue-estimated by the number of hours standing, intensity of physical and mental demands, and environmental stressors-was associated with an increased risk of preterm premature membrane rupture. For women reporting the highest degrees of fatigue, the risk was 7.4 percent. Thus, any occupation that subjects the gravida to severe physical strain should be avoided. Ideally, no work or play is continued to the extent that undue fatigue develops. Adequate periods of rest should be provided. It seems prudent to advise women with prior pregnancy complications that commonly recur to minimize physical work. • Exercise

In general, pregnant women do not need to limit exercise, pro­ vided they do not become excessively fatigued or risk injury (Davenport, 20 1 6) . Clapp and associates (2000) reported that both placental size and birthweight were signiicantly greater in women who exercised. Duncombe and coworkers (2006) reported similar findings in 1 48 women. In contrast, vfagann and colleagues (2002) prospectively analyzed exercise behavior in 750 healthy women and found that working women who exercised had smaller infants and more dysfunctional labors. The American College of Obstetricians and Gynecolo­ gists (20 1 7 g) advises a thorough clinical evaluation before

recommending an exercise program. In the absence of contra­ indications listed in Table 9-6, pregnant women are encour­ aged to engage in regular, moderate-intensity physical activity for at least 1 50 minutes each week. Each activity should be reviewed individually for its potential risk. Examples of safe activities are walking, running, swimming, stationary cycling, and low-impact aerobics. However, they should refrain from activities with a high risk of falling or abdominal trauma. Simi­ larly, scuba diving is avoided because the fetus is at increased risk for decompression sickness. In the setting of certain pregnancy complications, it is wise to abstain from exercise and even limit physical activity. For example, some women with pregnancy-associated hypertensive disorders, preterm labor, placenta previa, or severe cardiac or pulmonary disease may gain from being sedentary. Also, those with multiple or suspected growth-restricted fetuses may be served by greater rest. • Seafood Consumption

Fish are an excellent source of protein, are low in saturated fats, and contain omega-3 fatty acids. The Avon Longitudinal Study of Parents and Children reported beneicial efects on pregnancy outcomes in women who consumed 340 g or more of seafood weekly (Hibbeln, 2007) . Because nearly all fish and shellish contain trace amounts of mercury, pregnant and lac­ tating women are advised to avoid specific types of ish with potentially high methylmercury levels. These include shark, swordfish, king mackerel, and tile fish. It is further recom­ mended that pregnant women ingest 8 to 1 2 ounces of fish weely, but no more than 6 ounces of albacore or "white" tuna (U.S. Environmental Protection Agency, 20 1 4) . If the mercury content of locally caught fish is unknown, then overall fish con­ sumption should be limited to 6 ounces per week (American Academy of Pediatrics and the American College of Obstetri­ cians and Gynecologists, 20 1 7) . • Lead Screening

Maternal lead exposure has been associated with several adverse maternal and fetal outcomes across a range of maternal blood lead levels (Taylor, 20 1 5) . These include gestational hyper­ tension, miscarriage, low birthweight, and neurodevelopmen­ tal impairments in exposed pregnancies (American College of Obstetricians and Gynecologists, 20 1 6c) . The levels at which these risks rise remains unclear. However, recognizing that such exposure remains a significant health issue for reproductive-aged women, the CDC (20 1 Oa) has issued guidance for screening

P renata l Care

and managing exposed pregnant and lactating women. These guidelines, which have been endorsed by the American College of Obstetricians and Gynecologists (20 1 6c) , recommend blood lead testing only if a risk factor is identified. If the levels are > 5 /Lg1dL, then counseling is completed, and the lead source is sought and removed. Subsequent blood levels are obtained. Blood lead levels >45 Lg/dL are consistent with lead poisoning, and women in this group may be candidates for chelation ther­ apy. Afected pregnancies are best managed in consultation with lead poisoning treatment experts. National and state resources are available at the CDC website: ww.cdc.gov/ncehllead/. • Automobile and Air Travel

Pregnant women are encouraged to wear properly positioned three-point restraints as protection against automobile crash injury (Chap. 47, p. 927) . The lap portion of the restraining belt is placed under the abdomen and across her upper thighs. The belt should be comfortably snug. The shoulder belt also is irmly positioned between the breasts. Airbags should not be disabled for the pregnant woman. In general, air travel in a properly pressurized aircraft has no harmful efect on pregnancy (Aerospace Medical Association, 2003). Thus, in the absence of obstetrical or medical complica­ tions, the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (20 1 6a, 20 1 7) have concluded that pregnant women can safely ly up to 36 weeks' gestation. It is recommended that pregnant women observe the same precautions for air travel as the general population. Seatbelts are used while seated. Periodic lower extremity move­ ment and at least hourly ambulation help lower the venous thromboembolism threat. Signiicant risks with travel, espe­ cially international travel, are infectious disease acquisition and development of complications remote from adequate health­ care resources (Ryan, 2002) . • Coitus

In healthy pregnant women, sexual intercourse usually is not harmul. Whenever miscarriage, placenta previa, or preterm labor threatens, however, coitus is avoided. Nearly 1 0,000 women enrolled in a prospective investigation by the Vaginal Infection and Prematurity Study Group were interviewed regarding sex­ ual activity (Read, 1 993) . hey reported a decreased frequency of coitus with advancing gestation. By 36 weeks, 72 percent had intercourse less than once weekly. The decline is attributed to lower desire and fear of harming the pregnancy (Bartellas, 2000; Staruch, 20 1 6) . Intercourse speciically late in pregnancy i s n o t harm­ ful. Grudzinskas and coworkers ( 1 979) noted no association between gestational age at delivery and coital frequency dur­ ing the last 4 weeks of pregnancy. Sayle and colleagues (200 1 ) reported no increased-and actually a decreased-risk o f deliv­ ery within 2 weeks of intercourse. Tan and associates (2007) studied women scheduled for non urgent labor induction and found that spontaneous labor ensued at equal rates in groups either participating in or abstaining from intercourse. Oral-vaginal intercourse is occasionally hazardous. Aronson and Nelson ( 1 967) described a fatal air embolism late in pregnancy

as a result of air blown into the vagina during cunnilingus. Other near-fatal cases have been described (Bernhardt, 1 988) . • Dental Care

Examination of the teeth is included in the prenatal examina­ tion, and good dental hygiene is encouraged. Indeed, periodon­ tal disease has been linked to preterm labor. Unfortunately, although its treatment improves dental health, it does not pre­ vent preterm birth (Michalowicz, 2006). Dental caries are not aggravated by pregnancy. Importantly, pregnancy is not a con­ traindication to dental treatment including dental radiographs (Giglio, 2009) . • Immunization

Current recommendations for immunization during pregnancy are summarized in Table 9-7. Well-publicized concerns regard­ ing a causal link between childhood exposure to the thimerosal preservative in some vaccines and neuropsychological disorders have led to some parents to vaccine prohibition. Although con­ troversy continues, these associations have proven groundless (Sugarman, 2007; Thompson, 2007; Tozzi, 2009) . Thus, many vaccines may be used in pregnancy. The American College of Obstetricians and Gynecologists (20 1 6b) stresses the impor­ tance of integrating an efective vaccine strategy into the care of both obstetrical and gynecological patients. The College fur­ ther emphasizes that information on the safety of vaccines given during pregnancy is subject to change, and recommendations can be found on the CDC website at ww. cdc.gov/vaccines. he frequency of pertussis infection has substantially risen in the United States. Young infants are at increased risk for death from pertussis and are entirely dependent on passive immuniza­ tion from maternal antibodies until the infant vaccine series is initiated at age 2 months. For this reason, a three-agent tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine is recommended and is safe for pregnant women (Cen­ ters for Disease Control and Prevention, 20 1 3b, 20 1 6; Mor­ gan, 20 1 5) . However, as demonstrated by Healy and coworkers (20 1 3) , maternal antipertussis antibodies are relatively short­ lived, and Tdap administration before pregnancy-or even in the first half of the current pregnancy-is not likely to provide a high level of newborn antibody protection. Thus, to maximize passive antibody transfer to the fetus, a dose of Tdap is ideally given to gravidas between 27 and 36 weeks' gestation (American College of Obstetricians and Gynecologists, 20 1 7j; Centers for Disease Control and Prevention, 20 1 3b, 20 1 6) . All women who will b e pregnant during inluenza season should be ofered vaccination, regardless of gestational age. hose with underlying medical conditions that increase the risk for infl u enza complications are provided the vaccine before lu season starts. In addition to maternal protection against infection, prenatal maternal vaccination in one study reduced the infant infl u enza incidence in the irst 6 months of life by 63 percent (Zaman, 2008) . Moreover, it reduced all febrile respiratory illnesses in these infants by a third. Women who are susceptible to rubella during pregnancy should receive measles, mumps, rubella (MMR) vaccination postpartum. Although this vaccine is not recommended during

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TABLE 9-7. Reco m m endations for I m m u n ization D u ri n g Preg nancy I m munobiological Agent

Ind ications for Immunization During Pregnancy

Dose Schedule

Comments

Live Atten uated Virus Vacci nes Measles Contra i n d icated-see i m m u ne g lobu l i ns

Si ng le dose SCI prefera bly as MMRa

Vacci nate suscepti ble women postpartum . B reastfeedi ng is not a co ntra i nd i cation

M u m ps

Contra i n dicated

Si n g le dose SCI prefera b ly as MMR

R u be l l a

Contra i n d i cated, b u t congen ita l rubella synd rome has never been descri bed after vacci ne Not routi nely recom m ended for women i n the U n i ted States, except women at increased risk of expos u re b

Single dose SC, p refera bly as MMR

Vacci nate susceptible women postpartum Teratogenicity of vacci ne is theoretical and not confi rmed to date; vacci nate susceptible women postpart u m Vacci ne i n d i cated for susceptible women t rave l i n g in endemic a reas or i n other h i gh-risk situations

Po! iomyel itis o ra l = l ive atte nuated; i njection = enha ncedpotency i nactivated vi rus

P ri m a ry: Two doses of enha ncedpote ncy i nactivated v i ru s SC at 4- to 8-week i nte rva l s a n d a 3 rd dose 6-1 2 months after 2nd dose I m mediate protection: One dose o ra l po l i o vacci ne (in outbrea k sett i ng) Single dose SC

Yel l ow fever

Travel to h i g h-risk a reas

Va ricella

Contra i nd i cated, but no adverse outco mes reported in preg nancy

Two doses needed: 2nd dose g iven 4-8 weeks after 1 st dose

Sma l l pox (vacci n ia)

Contra i n d icated in p reg nant women a n d i n the i r household co ntacts

One dose SCI m u ltiple pricks with lancet

L i m ited theoretical risk outweig hed by risk of yel low fever Teratogenicity of vacci ne is theoretica l . Vacci nation of susceptible women should be considered postpa rtu m Only vacci n e known to ca use feta l harm

All preg nant women, rega rd l ess of tri mester d u ri ng fl u season (October -May) I n d ications for prophylaxis not altered by preg nancy; each case considered i n d iv i d u a l ly

One dose 1M every yea r

I nactivated virus vacc i ne

P u b l i c health a uthorities to be consulted for i n d ications, dosage, a n d route of a d m i n i stration Th ree-dose series 1M at 0, 1 , a n d 6 months

Ki l l ed-virus vaccine

Other I n fl uenza

Rabies

H u ma n pa p i l lomavirus

Not recom mended

Hepatitis B

P reexposure a n d postexpos u re for women at risk of i nfection, e.g., chronic l iver or kid ney d isease

Th ree-dose series 1M at 0 , 1 , a nd 6 months

He patiti s A

P reexpos u re a n d postexposu re if at risk (i nternational travel); chronic Ii fer d i sease

Two-dose sched u l e 1M, 6 months a part

Polyva lent vacci nes avai lable conta i n i n g i nactivated v i rus. No teratogenicity has been observed Used with hepatitis B i m m u ne g lobu l i n for some exposures. Exposed newborn needs b i rthdose vacci nation a nd i m mune g lobu l i n as soon as poss i ble. All infa nts shou ld rece ive b i rth dose of vacc i ne I nactivated virus

P re nata l Ca re

TABLE 9-7. Conti n ued Immunobiological Agent

Indications for Immunization During Preg nancy

I nactivated Bacterial Vacci nes Pneu mococcu s I n d ications not altered by preg nancy. Recommended for wo men with asplen i a; metabol ic, renal, ca rd iac, or p u l mona ry d i seases; i m m u n osu ppression; or smokers Meni ngococcus I nd ications not a ltered by preg nancy; vacci nation recom mended in u n us u a l outbreaks Typhoid Not recom mended rou t i nely except for close, co nti n ued expos u re or travel to endemic areas

Anth rax

Toxoids Teta n u s-d i p htheria­ ace l l u l a r pert u ss i s (Tdap)

Chapter 64 (p. 1 228)

Recommended in every preg nancy, prefera b ly between 27 and 36 weeks to max i m ize passive a nti body transfer

Specific I m m une Globu l ins Hepatitis B Postexposu re prophylaxis

Rabies

Postexpos u re prophylaxis

Teta n u s

Postexposu re prophylaxis

Va ricella

Should be considered for exposed preg nant women to protect agai nst maternal, not congen ital, i nfecti o n Standard I m m u n e Globu l i n s Hepatitis A: Postexpos u re prophylaxis a n d Hepatitis A those a t h igh risk virus vacci ne shou l d be u sed with hepatitis A i m m u ne g lo b u l i n

Dose Schedule

Comments

I n a d u lts, one dose o n ly; consider repeat dose i n 6 yea rs for high­ risk women

Polyva lent polysaccharide vacci ne; safety in the fi rst tri mester has not been eva l uated

One dose; tetrava lent vacci ne: two doses for asplenia

A nt i m i crobial prophylaxis if sign ificant exposu re

Ki l led Primary: 2 i njections 1M 4 weeks a pa rt Booster: One dose; sched u l e not yet determ i ned S ix-dose primary vacci nation, then a n n u a l booste r vacci nation

Ki l led, i njectable vacci ne or l ive atten u ated ora l vacci ne. O ral vacci ne preferred

P repa ration from ce l l-free fi ltrate of B an thracis. No dead or l ive bacteria. Teratoge n icity of vacci ne theoretica l

P ri m a ry: Two doses 1 M at 1 -2 month i n terva l with 3 rd dose 6- 1 2 months ater the 2nd Booster: Single dose 1 M every 1 0 yea rs, as a pa rt of wou n d ca re if : 5 yea rs si nce last dose, or once per preg nancy

Com b i ned teta n u s-d i phtheria toxoids with ace l l u la r pert u ssis (Tdap) p referred. U pdating i m m u n e status should be part of a ntepa rtu m ca re

Depends on exposu re (Chap. 5 5 , p. 1 064)

U s u a l ly g ive n with hepatitis B virus vacci ne; exposed newborn needs i m med i ate p ro phylaxis Used i n conj u nction with ra b i es kil led-vi rus vacc i n e Used i n conj u nction w i t h teta n u s toxoid I n d i cated a l so for newborns or women who deve loped va ricel la with i n 4 days before del ivery or 2 days fol lowi n g d e l ive ry

Half dose at i nj u ry site, half dose i n deltoid One dose 1M One dose 1 M with i n 96 hours of expos u re

0.02

m Ukg 1 M i n one dose

I m m u ne g lobu l i n s h o u l d be g iven as soon as poss i b l e a n d with i n 2 weeks o f expos u re; i nfants born to women who a re i n c u bati n g the virus or a re acutely i l l at del ivery s h o u l d receive o n e dose of 0 . 5 m L as soo n as poss i ble after b i rth

'Two doses n ecessa ry for students entering i nstitutions of h ig h er ed u cation, n ewly h i red medica l person nel, and t ravel a b road. b l nactlvated pol io vacci n e recom mended for n on i m m u n ized a d u l ts at i n c reased risk. 10 i nt radermal ly; 1 M i nt ra m u s c u l a rly; M M R meas l es, m u m ps, ru bel l a; PO o ra l ly; SC s u bcuta neou sly. F rom the Centers for Disease Control and P reve nt i o n, 20 1 1 ; Ki m, 2 0 1 6. =

=

=

=

=

1 73

1 74

P reconceptio n a l a n d P re nata l Ca re pregnancy, congenital rubella syndrome has never resulted from its inadvertent use. Breastfeeding is compatible with MMR vac­ cination (Centers for Disease Control and Prevention, 20 1 l ) .

• Cafeine

Whether adverse pregnancy outcomes are related to cafeine consumption is somewhat controversial. As summarized from Chapter 1 8 (p. 348) , heavy intake of cofee each day-about five cups or 5 00 mg of cafeine-slightly raises the miscarriage risk. Studies of "moderate" intake-less than 200 mg daily­ did not fi n d a higher risk. It is unclear if cafeine consumption is associated with pre­ term birth or impaired fetal growth. Clausson and coworkers (2002) found no association between moderate cafeine con­ sumption of less than 500 mg/d and low birthweight, fetal­ growth restriction, or preterm delivery. Bech and associates (2007) randomly assigned more than 1 200 pregnant women who drank at least three cups of cofee per day to cafein­ ated versus decafeinated cofee. They found no diference in birthweight or gestational age at delivery between groups. The CARE Study Group (2008), however, evaluated 2635 low­ risk pregnancies and reported a l .4-fold risk for fetal-growth restriction among those whose daily cafeine consumption was > 200 mg/d compared with those who consumed < 1 00 mg/d. he American College of Obstetricians and Gynecolo­ gists (20 1 6d) concludes that moderate consumption of caf­ feine-less than 200 mg/ d-does not appear to be associated with miscarriage or preterm birth, but that the relationship between cafeine consumption and fetal-growth restriction remains unsettled. The American Dietetic Association (2008) recommends that cafeine intake during pregnancy be limited to less than 300 mg/d, which approximates three 5 -oz cups of percolated cofee.

• Nausea and Heartburn

Nausea and vomiting are common complaints during the first half of pregnancy. These vary in severity and usually commence between the first and second missed menstrual period and con­ tinue until 1 4 to 1 6 weeks' gestation. Although nausea and vomiting tend to be worse in the morning-thus erroneously termed morning sickness-both symptoms frequently continue throughout the day. Lacroix and coworkers (2000) found that nausea and vomiting were reported by three fourths of preg­ nant women and lasted an average of 35 days. Half had reliefby 14 weeks, and 90 percent by 22 weeks. In 80 percent of these women, nausea lasted all day. Treatment of pregnancy-associated nausea and vomiting seldom provides complete relief, but symptoms can be mini­ mized. Eating small meals at frequent intervals is valuable. One systematic literature search reported that the herbal remedy ginger was likely efective (Borrelli, 2005). Mild symptoms usu­ ally respond to vitamin BG given along with doxylamine, but some women require phenothiazine or H I -receptor blocking antiemetics (American College of Obstetricians and Gynecolo­ gists, 2 0 1 5c) . In some with hyperemesis gravidarum, vomiting is so severe that dehydration, electrolyte and acid-base distur­ bances, and starvation ketosis become serious problems.

Heartburn is another common complaint of gravidas and is caused by gastric content reflux into the lower esophagus. The greater frequency of regurgitation during pregnancy most likely results from upward displacement and compression of the stomach by the uterus, combined with relaxation of the lower esophageal sphincter. Avoiding bending over or lying flat is preventive. In most pregnant women, symptoms are mild and relieved by a regimen of more frequent but smaller meals. Antacids may provide considerable relief (Phupong, 20 1 5) . Specifically, aluminum hydroxide, magnesium trisilicate, or magnesium hydroxide is given alone or in combination. Man­ agement of heartburn or nausea that does not respond to sim­ ple measures is discussed in Chapter 54 (p. 1 045) .

• Pica and Ptyalism

The craving of pregnant women for strange foods is termed pica. Worldwide, its prevalence is estimated to be 30 percent (Fawcett, 20 1 6) . At times, nonfoods such as ice-pagophagia, starch-amylophagia, or clay-geophagia may predominate. This desire is considered by some to be triggered by severe iron deficiency. Although such cravings usually abate after deficiency correction, not all pregnant women with pica are iron deficient. Indeed, if strange "foods" dominate the diet, iron deficiency will be aggravated or will develop eventually. Patel and coworkers (2004) prospectively completed a dietary inventory on more than 3000 women during the sec­ ond trimester. The prevalence of pica was 4 percent. The most common nonfood items ingested were starch in 64 percent, dirt in 14 percent, sourdough in 9 percent, and ice in 5 percent. he prevalence of anemia was 1 5 percent in women with pica compared with 6 percent in those without it. Interestingly, the rate of spontaneous preterm birth before 35 weeks was twice as high in women with pica. Women during pregnancy are occasionally distressed by profuse salivation p yalism . Although usually unexplained, ptyalism sometimes appears to follow salivary gland stimula­ tion by the ingestion of starch. -

• Headache or Backache

At least 5 percent of pregnancies are estimated to be compli­ cated by new-onset or new-type headache (Spierings, 20 1 6) . Common headaches are virtually universal. Acetaminophen is suitable for most of these, and an in-depth discussion is found in Chapter 60 (p. 1 057) . Low back pain to some extent is reported by nearly 70 per­ cent of gravidas (Liddle, 20 1 5 ; Wang, 2004) . Minor degrees follow excessive strain or significant bending, lifting, or walk­ ing. It can be reduced by squatting rather than bending when reaching down, by using a back-support pillow when sitting, and by avoiding high-heeled shoes. Back pain complaints increase with progressing gestation and are more prevalent in obese women and those with a history of low back pain. In some cases, troublesome pain may persist for years after the pregnancy (Noren, 2002). Severe back pain should not be attributed simply to preg­ nancy until a thorough orthopedic examination has been con­ ducted. Severe pain has other uncommon causes that include

P renata l Care

pregnancy-associated osteoporosis, disc disease, vertebral osteo­ arthritis, or septic arthritis (Smith, 2008) . More commonly, muscular spasm and tenderness are classiied clinically as acute strain or ibrositis. Although evidence-based clinical research directing care in pregnancy is limited, low back pain usually responds well to analgesics, heat, and rest. Acetaminophen may be used chronically as needed. Nonsteroidal antiinlammatory drugs may also be beneicial but are used only in short courses to avoid fetal efects (Chap. 1 2, p. 24 1 ) . Muscle relaxants that include cyclobenzaprine or baclofen may be added when needed. Once acute pain is improved, stabilizing and strength­ ening exercises provided by physical therapy help improve spine and hip stability, which is essential for the increased load of pregnancy. For some, a support belt that stabilizes the sacro­ iliac joint may be helpful (Gutke, 20 1 5) . • Varicosities a n d Hemorrhoids

Venous leg varicosities have a congenital predisposition and accrue with advancing age. They can be aggravated by factors that raise lower extremity venous pressures, such as an enlarg­ ing uterus. Femoral venous pressures in the supine gravida rise from 8 mm Hg in early pregnancy to 24 mm Hg at term. Thus, leg varicosities typically worsen as pregnancy advances, especially with prolonged standing. Symptoms vary from cos­ metic blemishes and mild discomfort at the end of the day to severe discomfort that requires prolonged rest with feet eleva­ tion. Treatment is generally limited to periodic rest with leg elevation, elastic stockings, or both. Surgical correction during pregnancy generally is not advised, although rarely the symp­ toms may be so severe that injection, ligation, or even stripping of the veins is necessary. Vulvar varicosities frequently coexist with leg varicosities, but they may appear without other venous pathology. Uncom­ monly, they become massive and almost incapacitating. If these large varicosities rupture, blood loss can be severe. Treatment is with specially itted pantyhose that will also minimize lower extremity varicosities. With particularly bothersome vulvar var­ icosities, a foam rubber pad suspended across the vulva by a belt can be used to exert pressure on the dilated veins. Hemorrhoids are rectal vein varicosities and may irst appear during pregnancy as pelvic venous pressures rise. Commonly, they are recurrences of previously encountered hemorrhoids. Up to 40 percent of pregnant women develop these (Poskus, 20 1 4) . Pain and swelling usually are relieved by topically applied anesthetics, warm soaks, and stool-softening agents. With thrombosis of an external hemorrhoid, pain can be con­ siderable. This may be relieved by incision and removal of the clot following injection of a local anesthetic. • Sleeping and Fatigue

Beginning early in pregnancy, many women experience fatigue and need greater amounts of sleep. his likely is due to the soporiic efect of progesterone but may be compounded in the irst trimester by nausea and vomiting. In the latter stages, general discomforts, urinary frequency, and dyspnea can be additive. Sleep duration may be related to obesity and gesta­ tional weight gain (Facco, 20 1 6; Lockhart, 20 1 5) . Moreover,

sleep eiciency appears to progressively diminish as pregnancy advances. Wilson and associates (20 1 1 ) performed overnight polysomnography and observed that women in the third tri­ mester had poorer sleep eiciency, more awakenings, and less of both stage 4 (deep) and rapid-eye movement sleep. Women in the irst trimester were also afected, but to a lesser extent. Daytime naps and mild sedatives at bedtime such as diphen­ hydramine (Benadryl) can be helpful. • Cord Blood Banking

Since the irst successful cord blood transplantation in 1 988, more than 2 5,000 umbilical cord blood transplantations have been performed to treat hemopoietic cancers and various genetic conditions (Butler, 20 1 1 ) . There are two types of cord blood banks. Public banks promote allogeneic donation, for use by a related or unrelated recipient, similar to blood product dona­ tion (Armson, 20 1 5) . Private banks were initially developed to store stem cells for future autologous use and charged fees for initial processing and annual storage. The American College of Obstetricians and Gynecologists (20 1 5d) has concluded that if a woman requests information on umbilical cord banking, infor­ mation regarding advantages and disadvantages of public versus private banking should be explained. Some states have passed laws that require physicians to inform patients about cord blood banking options. Importantly, few transplants have been per­ formed by using cord blood stored in the absence of a known indication in the recipient (Screnci, 20 1 6) . The likelihood that cord blood would be used for the child or family member of the donor couple is considered remote, and it is recommended that directed donation be considered when an immediate family member carries the diagnosis of a speciic condition known to be treatable by hemopoietic transplantation (Chap. 56, p. 1 075).

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P reconcept i o n a l a n d P renatal C a re Margulies R, Miller L: Fruit size as a model for teaching irst trimester uterine sizing in bimanual examination. Obstet Gynecol 98(2):34 1 , 200 1 Martin ]A, Hamilton BE, Sutton PO, et al: Births: inal data for 2006. Natl Vital Stat Rep 5 (7) : 1 , 2009 McCauley ME, van den Broek N, Dou L, et al: Vitamin A supplementation during pregnancy for maternal and newborn outcomes. Cochrane Database Syst Rev 1 O: CD008666, 20 1 5 McDuie RS ] r, Beck A, Bischof K , et al: Efect of frequency of prenatal care visits on perinatal outcome among low-risk women. A randomized con­ trolled trial. ]AMA 275: 847, 1 996 Metz TO, Stickrath EH: Marijuana use in pregnancy and lactation: a review of the evidence. Am ] Obstet Gynecol 2 1 3 (6) : 6 1 , 20 1 5 Michalowicz BS, Hodges ]S, DiAngelis A], et al: Treatment of periodontal disease and the risk of preterm birth. N Engl ] Med 35 5 : 1 88 5 , 2006 Molloy AM, Kirke PN, Troendle ]F, et al: Matenal vitamin B I 2 status and risk of neural tube defects in a population with high neural tube defect preva­ lence and no folic acid fortiication. Pediatrics 1 23(3):9 1 7, 2009 Montagnana M, Trenti T, Aloe R, et al: Human chorionic gonadotropin in pregnancy diagnostics. Clin Chim Acta 4 1 2 ( 1 7- 1 8) : 1 5 1 5, 20 1 1 Morgan ]L, Baggari S R, McIntire DO, et al: Pregnancy outcomes after ante­ partum tetanus, diphtheria, and acellular pertussis vaccine. Obstet Gynecol 1 2 5 (6) : 1 433, 20 1 5 Mozurkewich EL, Luke B , Avni M , e t al: Working conditions and adverse pregnancy outcome: a meta-analysis. Obstet Gynecol 95:623, 2000 Murray N, Homer CS, Davis GK, et al: he clinical utility of routine urinalysis in pregnancy: a prospective study. Med ] Aust 1 77:47 , 2002 Newman RB, Goldenberg RL, Moawad AH, et al: Occupational fatigue and preterm premature rupture of membranes. Am ] Obstet Gynecol 1 84:438, 200 1 Noren L, b stgaard S, Johansson G, et al: Lumbar back and posterior pelvic pain during pregnancy: a 3-year follow-up. Eur Spine ] 1 1 :267, 2002 Nossier SA, Naeim NE, EI-Sayed NA, et al: he efect of zinc supplementation on pregnancy outcomes: a double-blind, randomized cotrolled trial, Egypt. Br ] Nutr 1 1 4(2) :274, 20 1 5 Ota E , Mori R, Middleton P , e t al: Zinc supplementation for improving preg­ nancy and infant outcome. Cochrane Database Syst Rev 2:CD000230, 20 1 5 Patel MV, Nuthalapaty FS, Ramsey PS, et al: Pica: a neglected risk factor for preterm birth . Obstet Gynecol 1 03:68S, 2004 Patnode CD, Henderson ]T, hompson ]H, et al: Behavioral counseling and pharmacotherapy interventions for tobacco cessation in adults, including pregnant women: a review of reviews for the U.S. Preventive Services Task Force. Ann Intern Med 1 63(8) :608, 20 1 5 Partridge S , Balayla ], Holcroft CA, et al: Inadequate prenatal care utilization and risks of infant mortality and poor birth outcome: a retrospective analysis of 28,729,765 U.S. deliveries over 8 years. Am ] Perinatol 29( 1 0) :787, 20 1 2 Phupong V , Hanprasertpong T : Interventions for heartburn i n pregnancy. Coch rane Database Syst Rev 9 :CDO 1 1 3 79, 20 1 5 Pitkin M : Calcium metabolism in pregnancy and the perinatal period: a review. Am ] Obstet Gynecol 1 5 1 :99, 1 98 5 Pollak K T , Oncken CA, Lipkus 1 M , e t a l : Nicotine replacement and behavioral therapy for smoking cessation in pregnancy. Am ] Prev Med 33(4):297, 200 Poskus T, Buzinskiene 0, Drasutiene G, et al: Haemorrhoids and anal issures during pregnancy and after childbirth: a prospective cohort study. B]OG 1 2 1 ( 1 3) : 1 666, 20 1 4 Power M L , Wilson E K , Hogan S O , e t a l : Patterns o f preconception, prena­ tal and postnatal care for diabetic women by obstetrician-gynecologists. ] Reprod Med 5 8 ( 1 -2) :7, 20 1 3 Pritchard ]A, Scott DE: Iron demands during pregnancy. In Hallberg L, Harwerth HG, Vannotti A (eds): Iron Deficiency: Pathogenesis, Clinical Aspects, Therapy. New York, Academic Press, 1 970 Read ]S, lebanof A: Sexual intercourse during pregnancy and preterm delivery: efects of vaginal microorganisms. Am ] Obstet Gynecol 1 68: 5 1 4, 1 993 Rink BD, Norton ME: Screening for fetal aneuploidy. Semin Perinatol 40( 1 ): 35, 2 0 1 6 Rumbold A , Ota E, Nagata C, e t a l : Vitamin C supplementation in pregnancy. Cochrane Database Syst Rev 9:CD0040 2, 20 1 5 Ryan ET, Wilson ME, Kain KC: Illness after international travel. N Engl ] Med 347:505, 2002 Sa Roriz Fonteles C, Zero DT, Moss ME, et al: Fluoride concentrations in enamel and dentin of primary teeth after pre- and postnatal luoride expo­ sure. Caries Res 39:505, 2005 Sagedal LR, Overby NC, Bere E, et al: Lifestyle intervention to limit gesta­ tional weight gain: the Norwegian Fit for Delivery randomized controlled trial. B]OG 1 240):97, 20 1 7

Salam A, Zuberi N F , Bhutta ZA: Pyridoxine (vitamin BG) supplementation during pregnancy or labour for maternal and neonatal outcomes. Cochrane Database Syst Rev 6:CD000 1 9, 20 1 5 Sayle AE, Savitz DA, Thorp ]M ]r, et al: Sexual activity during late pregnancy and risk of preterm delivery. Obstet Gynecol 97:283, 200 1 Schau berger CW, Rooney BL, Brimer LM: Factors that inluence weight loss in the puerperium. Obstet Gynecol 9:424, 1 992 Schrag S]: Maternal immunization to prevent neonatal group B streptococcal disease. Obstet Gynecol 1 27(2) : 1 99, 20 1 6 Scott DE, Pritchard ]A, Satin AS, e t al: Iron deficiency during pregnancy. In Hallberg L, Harwerth HG, Vannotti A (eds): Iron Deiciency: Pathogenesis, Clinical Aspects, Therapy. New York, Academic Press, 19 0 Screnci M, Murgi E, Valle V, et al: Sibling cord blood donor program for hematopoietic cell transplantation: the 20-year experience in the Rome Cord Blood Bank. Blood Cells Mol Dis 57:7 1 , 20 1 6 Sibai BM, Villar MA, Bray E : Magnesium supplementation dring pregnancy: a double-blind randomized controlled clinical trial. Am ] Obstet Gynecol 1 6 1 : 1 1 5, 1 989 Siddique ], Lauderdale OS, VanderWeele T], et al: Trends in prenatal ultra­ sound use in the United States. Med Care 47: 1 1 29, 2009 Siu AL, U.S. Preventive Services Task Force: Behavioral and pharmacotherapy interventions for tobacco smoking cessation in adults, including pregnant women: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 1 63(8):622, 20 1 5 Smith CA: Efects of maternal under nutrition upon the newborn infant in Holland 0 944- 1 945). Am ] Obstet GynecoI 30:229, 1 947 Smith MW, Marcus PS, Wurtz LD: Orthopedic issues in pregnancy. Obstet Gynecol Surv 63: 1 03, 2008 Spierings EL, Sabin TO: De novo headache during pregnancy and puerperium. N eurologist 2 1 ( 1 ) : 1 , 20 1 6 Spindel ER, McEvoy CT: The role o f nicotine i n the efects of maternal smok­ ing during pregnancy on lung development and childhood respiratory dis­ ease: impl ications for dangers of E-cigarettes. Am ] Respir Crit Care Med 1 93(5):486, 20 1 6 Staruch M, Kucharcyzk A , Zawadzka K , e t al: Sexual activity during pregnancy. Neuro Endocrinol Lett 3 0 ) :53, 20 1 6 Stein Z , Susser M, Saenger G, e t al: Nutrition and mental performance. Sci­ ence 1 78:708, 1 972 Stephens TV, Payne M, Ball Ro, et al: Protein requirements of healthy preg­ nancy women during early and late gestation are higher than current recom­ mendations. J Nutr 1 45 ( 1 ) : 3, 20 1 5 Stewart RD, Nelson DB, Adhikari EH, et al: he obstetrical and neonatal impact of maternal opioid detoxiication in pregnancy. Am ] Obstet Gyne­ col 209:267.e 1 , 20 1 3 Sugarman SO: Cases in vaccine court-legal battles over vaccines and autism. N Engl ] Med 257: 1 275, 200 Tan Pc, Yow CM, Omar SZ: Efect of coital activity on onset of labor in women scheduled for labor induction. Obstet Gynecol 1 1 0: 820, 200 Taylor CM, Golding ], Emond AM: Adverse efects of maternal lead levels on birth outcomes in the ALSPAC study: a prospective birth cohort study. B]OG 1 22 (3) :322, 20 1 5 hompson W, Price C, Goodson B , et al: Early thimerosal exposure and neuropsychological outcomes at 7 to 1 0 years. N Engl ] Med 257: 1 28 1 , 2007 Till SR, Everetts 0, Haas OM: Incentives for increasing prenatal care use by women in order to improve maternal and neonatal outcomes. Cochrane Database Syst Rev 1 2:CD0099 1 6, 20 1 5 Tong T , Dietz PM, Morrow B , e t al: Trends i n smoking before, during, and after pregnancy-pregnancy risk assessment monitoring system, United States, 40 sites, 2000-20 1 0. MMWR 62(6) : 1 , 20 1 3 Tozzi AE, Bisiacchi P , Tarantino V, e t al: Neuropsychological performance 1 0 years after immunization i n infancy with thimerosal-containing vaccines. Pediatrics 1 23 (2) :475, 2009 U.S. Department of Health and Human Services: Reducing tobacco use: a report of the Surgeon General. Atlanta, U.S. Department of Health and H uman Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Oice on Smoking and Health, 2000 U.S. Environmental Protection Agency: Fish: what pregnant women and parents need to know. 20 14. Available at: http://www.fda.gov/Food/FoodborneIllness­ Contaminants/Metals/ucm393070.htm. Accessed September 1 9, 20 1 6 U . S . Preventive Services Task Force: Recommendation statement: clinical guidelines: folic acid for the prevention of neural tube defects. Ann Intern Med 1 50:626, 2009 Villar ] , Baaqeel H , Piaggio G, et al: WHO atenatal care randomised trial for the evaluation of a new model of routine antenatal care. Lancet 357: 1 5 5 1 , 200 1

P re nata l C a re Vintzileos M, Ananth CV, Smulian JC, et al: Prenatal care and black-white fetal death disparity in the United States: heterogeneity by high-risk condi­ tions. Obstet Gynecol 99:483, 2002 Wang S M , Dezinno P, Maranets I, et al: Low back pain during pregnancy: prevalence, risk facrors, and outcomes. Obstet Gynecol 1 04:65, 2004 Washington State Health Care Authority: Ultrasonography (ultrasound) in pregnancy: a health technology assessmenr. 20 1 0. Available at: http://www. hta.hca. wa.gov/ documen ts/i naLreporcul trasound. pdf. Accessed Septem­ ber 1 9, 20 1 6 West KP: Vitamin A deiciency disorders i n children and women. Food Nun Bull 24:578, 2003 Widen EM, Whyatt vl, Hoepner A, et al: Excessive gestational weight gain is associated with long-term body fat and weight retent ion at 7 y postpartum

in African American and Dominican mothers with underweight, normal, and overweight prepregnancy BM!. Am J Clin NLltr 1 02(6) : 1 460, 2 0 1 5 Wilcox AJ, Baird DD, Dunson D , et al: Natural limits o f pregnancy testing in relation to the expected menstrual period. JAMA 286: 1 759, 200 1 Wilson DL, Barnes M, Ellett L, et al: Decreased sleep eiciency, increased wake after sleep onset and increased cortical arousals in late pregnancy. Aust N Z J Obstet Gynaecol 5 1 ( 1 ) :38, 20 1 1 Worthen N, Bustillo M: Efect of urinary bladder fullness on fundal height measurements. Am J Obstet Gynecol 1 38:759, 1 980 XU J , Kochanek KD, Murphy S L: Deaths: inal data for 2007. Nat Stat Vit Rep 58( 1 9) : 1 , 20 1 0 Zaman K , Roy E , Arifeen S E , e t al: Efectiveness o f maternal inluenza immu­ nization in mothers and infants. N Engl J v Ied 359( 1 5) : 1 5 5 5 , 2008

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Feta l I m a g i n g

SONOGRAPHY IN OBSTETRICS . . . . . . . . . . . . . . . . . . . . 1 82 TEC H N OLOGY AND SAF ETY . . . . . . . . . . . . . . . . . . . . . . 1 82 G ESTATIONAL AGE ASSESSMENT . . . . . . . . . . . . . . . . . 1 83 FI RST-TRIMESTER SONOGRAPHY . . . . . . . . . . . . . . . . . . 1 85 S ECON D- AND TH IRD-TRIM ESTER SONOGRAPHY . . . . 1 86 CERVICAL LENGTH ASSESSMENT .

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NORMAL AND ABNORMAL F ETAL ANATOMY. . . . . . . . 1 9 1 DOPPLER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 1 3 MAG N ETIC RESONANCE IMAGI NG . . . . . . . . . . . . . . . . . 2 1 5

After discovey of the Roentgen ray and the demonstration of the various uses to which it might be put, it was thought possible that it might also aord a valuable method ofinves­ tigating the shape and size of the pelvis. - ] . Whitridge Williams ( 1 903) X-ray techniques were j ust on the horizon when the first edition of this textbook was published. he first application focused on the maternal pelvis without attention to the fetus. hus, congenital abnormalities were routinely not discovered until birth. Subsequent radiographic eforts to evaluate the fetus were later replaced by ultrasonography and more recently by magnetic resonance (MR) imaging, techniques which have become increasingly sophisticated. he subspecialty of fetal medicine has developed only because of these advances, and today's practitioner can hardly imagine obstetrical care without them.

SONOGRAPHY IN OBSTETRICS Prenatal sonography can be used to accurately assess gestational age, fetal number, viability, and placental location, and it can aid diagnosis of many fetal abnormalities. With improvements in resolution and image display, anomalies are increasingly detected in the irst trimester, and Doppler is used to manage pregnancies complicated by growth impairment or anemia. he American College of Obstetricians and Gynecologists (20 1 6) recommends that prenatal sonography be performed in all pregnancies and considers it an important part of obstetrical care in the United States. • Technology and Safety

The real-time image on the ultrasound screen is produced by sound waves that are relected back from fluid and tissue inter­ faces of the fetus, amnionic fluid, and placenta. Sector array transducers contain groups of piezoelectric crystals working simultaneously in arrays. These crystals convert electrical energy into sound waves, which are emitted in synchronized pulses. Sound waves pass through tissue layers and are reflected back to the transducer when they encounter an interface between tis­ sues of diferent densities. Dense tissue such as bone produces high-velocity reflected waves, which are displayed as bright echoes on the screen. Conversely, luid generates few relected waves and appears dark. Digital images generated at 50 to more than 1 00 frames per second undergo postprocessing that yields the appearance of real-time imaging. Ultrasound refers to sound waves traveling at a frequency above 20,000 hertz (cycles per second) . Higher-frequency transducers yield better image resolution, whereas lower fre­ quencies penetrate tissue more efectively. Transducers use wide-bandwidth technology to perform within a range of frequencies. In early pregnancy, a 5- to 1 0-megahertz (MHz) transvaginal transducer usually provides excellent resolution,

Feta l l ma g i ng

because the early fetus is close to the transducer. And, in the first and second trimesters, a 4- to 6-MHz transabdomi­ nal transducer is similarly close enough to the fetus to yield precise images. By the third trimester, however, a lower fre­ quency 2- to 5-MHz transducer may be needed for tissue penetration-particularly in obese patients-and this can lead to compromised resolution. Feta I Safety

Sonography should be performed o nly for a valid medical indi­ cation, using the lowest possible exposure setting to gain neces­ sary information-the AAA principle-as low as reasonably 4chievable. Examinations are performed only by those trained to recognize fetal abnormalities and artifacts that may mimic pathology, using techniques to avoid ultrasound exposure beyond what is considered safe for the fetus (American College of Obstetricians and Gynecologists, 20 1 6; American Institute of Ultrasound in Medicine, 20 1 3b) . No causal relationship has been demonstrated between diagnostic ultrasound and any rec­ ognized adverse efect in human pregnancy. The International Society of Ultrasound in Obstetrics and Gynecology (20 1 6) further concludes that there is no scientifically proven associa­ tion between ultrasound exposure in the first or second trimes­ ters and autism spectrum disorder or its severity. All sonography machines are required to display two indices: the thermal index and the mechanical index. The thermal index is a measure of the relative probability that the examination may raise the temperature, potentially high enough to induce injury. That said, fetal damage resulting from commercially available ultrasound equipment in routine practice is extremely unlikely. The potential for temperature elevation is higher with longer examination time and is greater near bone than in soft tissue. heoretical risks are higher during organogenesis than later in gestation. The thermal index for soft tissue, Tis, is used before 1 0 weeks' gestation, and that for bone, ib, is used at or beyond 1 0 weeks' (American Institute of Ultrasound in Medi­ cine, 20 1 3b) . The thermal index is higher with pulsed Doppler applications than with routine B-mode scanning (p. 2 1 3) . In the first trimester, if pulsed Doppler is clinically indicated, the thermal index should be ;0.7, and the exposure time should be as brief as possible (American Institute of Ultrasound in Medicine, 20 1 6) . To document the embryonic or fetal heart rate, motion-mode (M-mode) imaging is used instead of pulsed Doppler imaging. The mechanical index is a measure of the likelihood of adverse efects related to rarefactional pressure, such as cavi tation­ which is relevant only in tissues that contain air. Microbubble ultrasound contrast agents are not used in pregnancy for this reason. In mammalian tissues that do not contain gas bodies, no adverse efects have been reported over the range of diagnostically relevant exposures. Because fetuses cannot contain gas bodies, they are not considered at risk. The use of sonography for any nonmedical purpose, such as "keepsake fetal imaging," is considered contray to responsible medical practice and is not condoned by the Food and Drug Administration (20 1 4) , the American Institute of Ultrasound in Medicine (20 1 2, 20 1 3b) , or the American College of Obste­ tricians and Gynecologists (20 1 6) .

Operator Safety

The reported prevalence of work-related musculoskeletal dis­ comfort or injury among sonographers approximates 70 percent Ganga, 20 1 2; Roll, 20 1 2) . The main risk factors for injury dur­ ing transabdominal ultrasound examinations are awkward pos­ ture, sustained static forces, and various pinch grips used while maneuvering the transducer (Centers for Disease Control and Prevention, 2006) . Maternal habitus can be contributory because more force is oten employed when imaging obese patients. The following guidelines may help avert injury: 1 . Position the patient close to you on the examination table. As a result, your elbow is close to your body, shoulder abduc­ tion is less than 30 degrees, and your thumb is facing up. 2. Adjust the table or chair height so that your forearm is paral­ lel to the floor. 3. If seated, use a chair with back support, support your feet, and keep ankles in neutral position. Do not lean toward the patient or monitor. 4. Face the monitor squarely and position it so that it is viewed at a neutral angle, such as 1 5 degrees downward. 5 . Avoid reaching, bending, or twisting while scanning. 6. Frequent breaks may prevent muscle strain. Stretching and strengthening exercises can be helpful. • Gestational Age Assessment

The earlier that sonography is performed, the more accurate the gestational age assessment. Specific criteria for "re-dating" a pregnancy, that is, reassigning the gestational age and estimated date of delivery using initial sonogram findings, are shown in Table 1 0- 1 . The only exception to revising the gestational age based on early sonography is if the pregnancy resulted from assisted reproductive technology, in which case accuracy of ges­ tational age assessment is presumed. Sonographic measurement of the crown-rump length (CRL) is the most accurate method to establish or conirm gestational

TABLE 1 0- 1 . Sonog ra p h i c Gestational Age Assessment Gestational Age

5 d >7 d >7 d >10 d >14 d >21 d

HC HC HC HC

AC AC AC AC

FL FL FL FL

aSonog ra p h i c gestati o n a l a g e s h o u l d be used when t h e LM P-d e rived gestat i o n a l age d iffers from t h a t o bta i n e d w i t h sonog ra phy by the t h reshold va l ue. AC a bdom i na l ci rcu mference; B P O b i pa r i etal d i a m eter; C R L crown-ru m p l ength; FL fem u r length; HC h ead c i rcu mference; LM P l a st m e n strual period. Mod ified from American Col lege of Obstetri c i a n s a nd Gyn eco lo g i sts, 20 1 7 b. =

=

=

=

=

=

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1 84

The Feta l Patient

FIGURE 1 0-1 The measu red crown-ru m p length in this 1 2-week 3-day fetus a pproxi mates 6 cm.

age (Appendix, p. 1 263) . As noted, transvaginal imaging typi­ cally yields higher resolution images. The CL is measured ' in the midsagittal plane with the embryo or fetus in a neu­ tral, nonlexed position so that its length can be measured in a straight line (Fig. 1 0- 1 ) . The measurement should include

neither the yolk sac nor a limb bud. The mean of three discrete measurements is used. Until 1 3 6/7 weeks' gestation, the CL is accurate to within 5 to 7 days (American College of Obstetri­ cians and Gynecologists, 20 1 7b) . Starting at 1 4°/ weeks, equipment software formulas calculate estimated gestational age and fetal weight from measurements of the biparietal diameter, head and abdominal circumference, and femur length (Fig. 1 0-2) . The estimates are most accurate when multiple parameters are used but may over- or underes­ timate fetal weight by up to 20 percent (American College of Obstetricians and Gynecologists, 20 1 6) . Various nomograms for other fetal structures, including the cerebellar diameter, ear length, ocular distances, thoracic circumference, and lengths of kidney, long bones, and feet, may be used to address speciic questions regarding organ system abnormalities or syndromes (Appendix, p. 1 266) . The biparietal diameter (BPD) most accurately reflects ges­ tational age, with a variation of 7 to 1 0 days in the second trimester. The BPD is measured perpendicular to the midline falx in the transthalamic view, at the level of the thalami and cavum septum pellucidum (CSP) (see Fig. 1 0-2A) . Calipers are placed from the outer edge of the skull in the near ield to the inner edge of the skull in the far field. he head circumference (HC) is also measured in the trans thalamic view. An ellipse is

FIGURE 1 0-2 Feta l biometry. A. Tra nsth a l a m i c view. A tra nsverse (axial) image of the head is obta i ned at the level of the cavum sept u m pell ucid u m (arrows) a nd thalami (asterisks). The biparieta l dia mete r is measu red perpendicu lar to the sag itta l m i d l i ne, from the outer edge of the sku l l i n the nea r field to the i n ner edge of the sku l l i n t h e fa r field. B y convention, t h e near field is that which i s closer to the sonog ra p h ic tra nsd ucer. The head circu mference is measu red circu mferentia l ly a round the outer border of the sku l l. B. Fem u r length. T h e fem u r is measured perpendiCUlar t o the femora l shaft, from each dia physea l end, excl uding the epi physis. C. Abdominal ci rcu mference. This is a transverse mea s u rement at the level of the stomach (5). The J-sha ped structu re (arrowheads) i n d icates the con­ fl uence of the u m b i l ical vei n and the right porta l vein. Idea l ly, o n ly one rib is visible on each side of the a bdomen, i n d icati ng that the i mage was not taken at a n oblique a ng le.

Feta l l m a g i n g

placed around the outer edge of the skull or the circumference is calculated using BPD and occipital-frontal diameter (OFD) values. he cephalic index, which is the BPD divided by the OFD, is normally 70 to 86 percent. If the head shape is lattened-dolichocephay, or rounded­ brachycephay, the HC is more reliable than the BPD. hese head shape variants may be normal or can be secondary to fetal position or oligohydramnios. But, dolichocephaly can occur with neural-tube defects, and brachycephaly may be seen in fetuses with Down syndrome. lso, with abnormal skull shape, craniosynostosis and other craniofacial abnormalities are a con­ sideration. he femur length (FL) correlates well with both BPD and gestational age. It is measured with the beam perpendicular to the long axis of the shat. Calipers are placed at each end of the calcified diaphysis and exclude the epiphysis. For gestational age estimation, it has a variation of 7 to 1 1 days in the second trimes­ ter (see Fig. 1 O-2B). A femur measurement that is < 2. 5th per­ centile for gestational age or that is shortened to :;90 percent of that expected based on the measured BPD is a minor marker for Down syndrome (Chap. 1 4, p.287). he normal range for the FL to abdominal circumference (AC) ratio is generally 20 to 24 per­ cent. A dramatically foreshortened FL or a FL-to-AC ratio below 1 8 percent prompts evaluation for a skeletal dysplasia (p. 2 1 0) . O f biometric parameters, A C is most afected b y fetal growth. Thus, for gestational age estimation, AC has the great­ est variation, which can reach 2 to 3 weeks in the second trimester. To measure the AC, a circle is placed outside the fetal skin in a transverse image that contains the stomach and the confluence of the umbilical vein with the portal sinus (see Fig. 1 0-2C) . The image should appear as round as possible and ideally contains no more than 1 rib on each side of the abdo­ men. he kidneys should not be visible in the image. Variability of the sonographic gestationl age estimate increases with advancing gestation. Accordingly, pregnancies not imaged prior to 22 weeks to conirm or revise gestational age are considered suboptimaly ated (American College of Obstetricians and Gynecologists, 20 1 7a) . Although the estimate is improved by averaging multiple parameters, if one parameter difers

TABLE 1 0-2. S o m e I n d ications for First-Tri m ester Ultrasou n d Exa m ination

Confi rm a n i ntra u terine p reg n a n c! Eva l u ate a suspected ectop ic p reg n a n cy Defi ne the c a u s e of vag i n a l bleed i n g Eva l uate pelvic pa i n Est i m ate g estationa l age Diag nose o r eva l uate m u lt ifeta l gestations C o n fi rm ca rdiac activity Ass i st c h o ri o n i c vi l l u s sa m p l ing, em bryo tra n sfer, and l oca l izat i o n a n d re m ova l of a n i ntra uteri n e device Assess for certa i n feta l a n o ma l i es, such as a ne n cepha ly, i n h ig h-risk ' atients Eva l u ate m atern a l pe lvic m a sses a n d/or uterine a bnor m a I ities Measu re n u c h a l tra n s l ucency /hen pa rt of a scree n i n g p rog ra m for feta l a neu ploidy Eva l uate s u s oected gestati o n a l trophoblastic d i sease

Mod i fied from the American I n s titute of U ltrasound i n

Med i c i n e, 2 0 1 3a .

significantly from the others, consideration should be given to excluding it from the calculation. he outlier may result from poor visibility, but it could also indicate a fetal abnormality or growth problem. Reference tables such as the one in the Appendix (p. 1 264) may be used to estimate fetal weight percentiles. • First-Trimester Sonography

Indications for sonography before 1 4 weeks' gestation are listed in Table 1 0-2. Early pregnancy can be evaluated using trans­ abdominal or transvaginal sonography, or both. he compo­ nents listed in Table 1 0-3 should be assessed. First-trimester sonography can reliably diagnose anembryonic gestation, embryonic demise, ectopic pregnancy, and gestational tro­ phoblastic disease. he irst trimester is also the ideal time to evaluate the uterus, adnexa, and cul-de-sac. Determination of

TABLE 1 0-3. Com po n e nts of Sta ndard U ltraso u n d Exa m i nation by Tri m ester First Tri mester

Second and Third Tri mester

Gestationa l sac s i ze, l ocation, a nd n u m be r E m b ryo a n d/or yo l k s a c identification Crown-ru m p l e ngth Feta l n u m ber, i n c l u d i ng a m n ion i city a n d chorionicity of m u ltieta l gestations E m b ryon i c/feta l card ia c activity Assessment of e m b ryon i /feta l a natomy a ppropriate fo r the fi rst ri mester Eva l uation of the maternal u terus, a d nexa, a n d cu l-de-sac Eva l uat"on of the feta l n u c h a l reg i on, with conside ration of feta l :cha l tra n s l ucenry a ssessm ent

Feta l n u m ber, i n c l u d i n g a m n io n i city a nd chorionicity of m u ltifeta l g estations Feta l ca rd iac activity Feta l p resentation P lacental l ocation, a p peara n ce, a nd relatio n s h i p t o tie i nterna l cervica l os, with docu m entati o n of placental c o rd i nsertion s ite when tech n ic a l l y possi ble A m n i o n ic fl u id vol u me Gestati o n a l age a ssessment Feta l wei g h t estimation Feta l a natom ica l su rvey, i n c l u d i ng docu m entation of tec h n ical l i m i tations Eva l uation of the maternal uterus, adnexa, a n d cervix w h e n a p propriate

Mod i fied fro m the Ame rica n I n stitute of U ltraso u n d in M ed i c i ne, 20 1 3a .

1 85

1 86

The Feta l Pat i e n t

chorionicity in a multifetal gestation is most accurate in the first trimester (Chap. 45, p. 868) . n intrauterine gestational sac is reli­ ably visualized with transvaginal sonog­ raphy by 5 weeks, and an embryo with cardiac activity by 6 weeks (Fig. 1 0-3) . The embryo should b e visible transvagi­ nally once the mean sac diameter has reached 25 mm-otherwise the gesta­ tion is anembyonic. Cardiac motion is usually visible with transvaginal imaging when the embryo length reaches 5 mm. In embryos 30 kg/m 2 M u l ti feta l gestation (Cha p. 45, p. 864) Abnormal serum a l pha-fetoprotei n or estriol leve l s Teratogen expo s u re N u c h a l t ra n sl ucency meas u re m e n t ::3 .0 m m

increased risk for fetal geneticich romosomal abnormal ity i n cu rrent preg nancy P a re nta l car r i a g e of genetic/ch romoso mal a b normal ity Ma te rnal age ::3 5 at d e l ivery Abnormal a neu ploidy scree n i n g test resu l t M i nor aneu plnidy marker (on stc m d a rd sonogram) N uc h a l tra n s l ucency m ea s u re ment ::3 .0 mm Other condition affecting the fetus Congen ita l i nfection (Cha ps. 64 a n d 65) Drug d ependence A l l o i m m u n ization (Ch a p. 1 5, p. 30 1 ) A m n i o n i c fl u i d a bnormal ity (Ch a p. 1 1 , p. 2 2 7)

Mod i fied from Jax, 20 1 4, 20 1 5 .

gestational age. Oligohydramnios indicates an amnionic fluid volume below normal range, and subjective crowding of the fetus is often noted. Hydramnios-also called poyhydramnios­ defines a volume above a given normal threshold. Amnionic luid volume is usually assessed semiquantitatively. Measurements include either the single deepest vertical luid pocket or the sum of the deepest vertical pockets from each of four equal uterine quadrants-the amnionic luid index (Phelan, 1 987) . Reference ranges have been established for both measurements from 1 6 weeks' gestation onward. he single deepest vertical pocket is

normally between 2 and 8 cm, and the amnionic luid index normally ranges between 8 and 24 cm. A further discussion and images are provided in Chapter 1 1 (p. 227) .

Cervica l Le ngth Assessment Evaluation of the relationship between the placenta and the internal cervical os is an essential component of the standard sonogram. Abnormalities of the placenta and umbilical cord are reviewed in Chapter 6 (p. 1 1 1 ) . Although the cervix may be imaged transabdominally (Fig. 1 0-4) , this is often limited

FIGURE 1 0-4 A. Tra nsa bdom i n a l i mage of the cervix depicting the i ntern a l os a nd extern a l as. B. Tra nsva g i n a l i m a g i n g p rovides a m o re accu rate eva l u ation of the cervix a n d should be used for medical decision-ma ki n g . I n this image, a rrowheads mark the endocervica l canal. (Used with perm ission from Dr. E m i ly Ad h i ka ri.)

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The Feta l Patient

TABLE 1 0-8. C riteria for Tra n sva g i n a l Eva l u ation of the Cervix Imaging the Cervix Maternal b l a d d e r s h o u ld be em pty. Tra n sd u cer is i nserted u nd e r rea l -t i m e observation, identiying m i d sag itta l pla ne, i nten a l os, a nd then extenal os, w h i l e keeping t h e i nternal os i n vi ew. I nternal os, externa l os, a n d entire endocervica l canal s h o u l d be v i s i b l e. The i nternal os may a p pea r as a s m a l l tri a n g u l a r i n dentation at t h e j u n ction o f t h e a m n io n ic cavity a nd endoce rvical ca n a l . I mage i s e n l a rged so that t h e cervix fi l l s a p p roxi m ately 7 5 % o f t h e screen. Anterior a n d posterior width of the cervix s h o u l d be a pproxi mately eq u a l . Tra n sd ucer i s p u l led b a c k s l i g htly u nti l the i mage beg i n s t o b l u r, e n s u r i n g that p ressu re is n ot placed on the cervix, then i n serted o n ly enough to restore a clear i mage. I mages s h o u l d be o bta i n ed with and without fu n d a l o r su p ra p u b i c pressu re, to assess for dyna m i c cha nge-or shorte n i ng on rea l -t i m e i ma g i n g . Measuring t h e Cervix Ca l i pers a re pl aced where a nterior and posterior wa l l s of cervix m eet. Endocervica l ca n a l a ppea rs as a fa i nt, l i near echodensity. If ca nal has a c u rved conto u r, a stra ight l i ne between the i nte rna l a n d external os w i l l d eviate from the path of the end ocervica l ca n a l . If m i d po i nt o f t h e l i n e betwee n the i nterna l a n d external c a n a l d eviates b y � 3 m m from the e ndocervica l c a n a l , measure the cervica l l ength i n two l i near seg ments. F u n ne l i ng, s l u d g e (de b r i s), or dyna m i c cha nge is noted . At least th ree sepa rate i mages a re mea s u red d u ri ng a period of at least 3 m i n utes to a l l ow for dyn a m i c c h a n g e. Visual izatio n of cervical s h orten i n g on rea l-ti me i ma g i ng, with or without fu n d a l or s u pra p u b i c pressu re, ra i ses preterm b i rth r i s ks. Shortest cervica l l e ngth i mage that meets a l l criteria s h o u l d be u sed .

Mod ified fro m l a m s, 20 1 3.

by technical factors that include maternal habitus, cervical posi­ tion, or shadowing by the fetal presenting part. In addition, the maternal bladder or pressure from the transducer may artifi­ cially elongate the appearance of the cervix. As a result, values from transabdominal or transvaginal measurement of the cervix can difer significantly. If the cervix appears shortened or if it cannot be ade­ quately visualized during transabdominal evaluation, trans­ vaginal assessment is considered (American Institute of Ultrasound in Medicine, 20 1 3b) . Only cervical length mea­ surements obtained transvaginally at or beyond 1 6 weeks' gestation are considered sufficiently accurate for clinical decision-making (see F ig. 1 0-4) . A foreshortened cervix is associated with an elevated risk for preterm birth, particu­ larly in the setting of prior preterm birth, and the degree of risk rises proportionally with the degree of cervical shorten­ ing (Chap. 42, p. 8 1 5) . T o measure the cervix transvaginally, the imaging criteria shown in Table 1 0-8 are followed. he endocervical canal should be visible in its entirety, and images ideally are obtained over several minutes to allow for dynamic change. During examination, visible funneling or debris is sought. F unnel­ ing is a protrusion of amnionic membranes into a portion of the endocervical canal that has dilated (Fig. 1 0-5 ) . F un­ neling is not an independent predictor of preterm birth, however, it is associated with cervical shortening, and trans­ vaginal assessment is recommended if a funnel is suspected transabdominally. The cervical length is measured distal

to the funnel, because the base of the funnel becomes the functional internal os. If the cervix is dilated, as with cer­ vical insuiciency, the membranes may prolapse through the endocervical canal and into the vagina, producing an

FIGURE 1 0-5 Tra nsva g i n a l image depicti ng a foreshortened cervix with fu n neling. F u n neling is a protrusion of a m nionic mem­ branes i nto a portion of the endocervical ca nal that h a s d i lated . The d ista l protruding edge of the fu n nel becomes the fu nctional i nternal os (left arrow). Thus, the measu red cervical length, which l ies between the a rrows, should not i nclude the fu n nel. (U sed with perm ission from Dr. E m i ly Ad h i ka ri.)

Feta l l ma g i ng

FIGURE 1 0-6 The tra nsventric u l a r view depicts the lateral ven­ tricles, which conta i n the echoge n ic choroid plexus (CP). The late ra l ventricle is mea s u red at t h e atrium (arrows), which is t h e confl u­ e nce of the temporal a n d occi pita l horns. A norma l mea s u rement is between 5 a nd 1 0 m m throug hout the second a n d t h i rd trimes­ ters. The atria measu red 6 m m i n this 2 1 -week fetu s . hourglass appearance. Sludge or debris represents an aggre­ gate of particulate matter within the amnionic sac, close to the internal os. In pregnancies at risk for preterm birth, sludge is associated with a further increased risk.

NORMAL AND ABNORMAL FETAL ANATOMY Many fetal anomalies and syndromes may be characterized with targeted sonography, and selected abnormalities are dis­ cussed subsequently. This list is not intended to be compre­ hensive but covers abnormalities commonly detected with standard sonography and those that are potentially amenable to fetal therapy. Sonographic features of chromosomal abnor­ malities are reviewed in Chapters 1 3 and 1 4, and fetal therapy is discussed in Chapter 1 6.

FIGURE 1 0-7 Tra n scerebe l l a r view of the posterior fossa, dem­ onstrati n g measurement of the cerebe l l u m (+), cisterna mag n a (x), a n d n ucha l fold thickness (backet). Ca re is ta ke n not t o a n g le obliq uely down the spine, which may a rtificia l l y i ncrease the n uchal fold measurement. cerebellar diameter in millimeters is roughly equivalent to the gestational age in weeks (Goldstein, 1 987) . The cisterna magna normally measures between 2 and 1 0 mm. Efacement of the cisterna magna is present in the Chiari II maormation, dis­ cussed later (p. 1 93). Imaging of the spine includes evaluation of the cervical, thoracic, lumbar, and sacral regions (Fig. 1 0-8 ) . Representa­ tive spinal images for record keeping are often obtained in the sagittal or coronal plane, but real-time imaging of each spinal segment in the transverse plane is more sensitive for anomaly detection. Transverse images demonstrate three ossifi c ation centers. The anterior ossiication center is the vertebral body, and the posterior paired ossification centers represent the

• Brain and Spine

Standard sonographic evaluation of the fetal brain includes three transverse (axial) views. The transthalamic view is used to measure the BPD and HC and includes the midline falx, cavum septum pellucidum (CSP) , and thalami (see Fig. 1 0- IA) . The CSP is the space between the two laminae that separate the frontal horns of the lateral ventricles. Inability to visualize a normal CSP may indicate a midline brain abnormality such as agenesis of the corpus callosum, lobar holoprosencephaly, or septo-optic dysplasia (de Morsier syndrome) . The transventricu­ lar view includes the lateral ventricles, which contain the echo­ genic choroid plexus (Fig. 1 0-6) . The ventricles are measured at their atrium, which is the confluence of the temporal and occipital horns. The transcerebellar view is obtained by angling the transducer back through the posterior fossa (Fig. 1 0-7) . In this view, the cerebellum and cisterna magna are measured, and between 1 5 and about 20 weeks, the nuchal skinfold thickness may also be measured. From 1 5 until 22 weeks' gestation, the

FIGURE 1 0-8 Normal feta l spine. In this sag itta l i mage of a 2 1 -week fetu s, the cervical (, thoracic (, l u m ba r (, a n d sacral spine (5) a re depicted. Arrows denote the p a ra l le l rows of pa i red posterior ossification centers-representi n g the j u n ction of verte­ bra l l a m i n a a n d ped icles.

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The Feta l Patient

FIGURE 1 0-9 Anencepha ly/acra nia. A. Acra n ia . Th i s l l -week fetus has a bsence of the cra n i u m, with protrusion of a d i sorg a n ized mass of bra i n tissue that resembles a "shower ca p" (arrows) a nd a cha racteristic tria n g u l a r facial a p peara nce. B. Anencepha ly. This sag itta l image shows the absence of forebra i n a n d cra n i u m a bove the sku l l base a n d orbit. The long wh ite a rrow points to the feta l orbit, a nd the s hort wh ite a rrow indicates the nose. j unction of vertebral laminae and pedicles. Ossiication of the spine proceeds in a cranial-caudal fashion, such that ossification of the upper sacrum (5 1 -52) is not generally visible sonographi­ cally before 1 6 weeks' gestation, and ossification of the entire sacrum may not be visible until 2 1 weeks (De Biasio, 2003) . Thus, detection of some spinal abnormalities can be challeng­ ing in the early second trimester. If a brain or spinal abnormality is identifi e d, targeted sonog­ raphy is indicated. he International Society of Ultrasound in Obstetrics and Gynecology (2007) has published guidelines for a "fetal neurosonogram." Fetal MR imaging may also be helpful (p. 2 1 7) . N e u ra l-Tu be Defects

hese defects include anencephaly, myelomeningocele (also called spina bifi d a), cephalocele, and other rare spinal fusion (or schisis) abnormalities. hey result from incomplete closure of the neural tube by the embryonic age of 26 to 28 days. heir birth prevalence is 0.9 in 1 000 in the United States and most of Europe and 1 .3 in 1 000 in the United Kingdom (Cragan, 2009; Dolk, 20 1 0) . Many neural-tube defects can be prevented with folic acid supplementation. When isolated, neural-tube defect inheritance is multifactorial, and the recurrence risk without periconceptional folic acid supplementation is 3 to 5 percent (Chap. 1 3 , p. 270) . Screening for neural-tube defects with maternal serum alpha-fetoprotein (MSAFP) has been ofered routinely as part of prenatal care since the 1 980s (Chap. 1 4, p. 283) . Women currently have the option of neural-tube defect screening with MSAFP, sonography, or both (American College of Obstetri­ cians and Gynecologists, 20 1 6) . Serum screening is generally performed between 1 5 and 20 weeks' gestation. And, if using an upper threshold of 2 . 5 multiples of the median (MoM) , the anticipated detection rate is at least 90 percent for fetal anencephaly and 80 percent for myelomeningocele. Targeted sonography is the preferred diagnostic test, and in addition to characterizing the neural-tube defect, it may identiy other

abnormalities or conditions that also result in MSAFP elevation (Table 1 4-6, p. 283) . Anencephay is characterized by absence of the cranium and telencephalic structures above the level of the skull base and orbits (Fig. 1 0 9) . Acrania is absence of the cranium with protrusion of disorganized brain tissue. Both are uniformly lethal and are generally considered together, with anencephaly as the fi n al stage of acrania (Bronshtein, 1 99 1 ) . These anoma­ lies are often diagnosed in the late first trimester, and with adequate visualization, virtually all cases may be diagnosed in the second trimester. Inability to image the BPD raises sus­ picion. The face often appears triangular, and sagittal images readily demonstrate absence of the ossified cranium. Hydram­ nios from impaired fetal swallowing is common in the third trimester. Cphaocee is the herniation of meninges through a cranial defect, tpically located in the midline occipital region (Fig. 1 0- 10). -

FIGURE 1 0-1 0 Encepha locele. Th i s tra nsverse i m a g e depicts a l a rge defect in the occi pita l reg ion of the cra n i u m (arrows) thro u g h w h i c h meninges and bra i n t i s s u e h ave hern iated.

Feta l l ma g i n g

FIGURE 1 0-1 1 Myelomen ingocele , I n this sag itta l image of a l u m bosacral myelomeningocele, the a rrowheads i n d icate nerve roots with i n the a nechoic hern iated sac. The overlyi n g skin is vis­ i ble a bove the level of the spinal defect but a bru ptly stops at the defect (arrow) ,

the sac may be easier to image in the sagittal plane, transverse images more readily demonstrate separation or splaying of the laterl processes. Detection of spina bifida is aided by two characteristic cranial fi n dings (Nicolaides, 1 9 86) . Scalloping of the frontal bones is termed the lemon sign, and anterior curvature of the cerebellum with efacement of the cisterna magna is the banana sign (Fig. 1 0- 1 2) . These indings are manifestations of the Chi­ ari II malformation, also called the Arnold-Chiari maorma­ tion. This develops when downward displacement of the spinal cord pulls a portion of the cerebellum through the foramen magnum and into the upper cervical canal. Ventriculomegay is another frequent associated sonographic finding, particularly after midgestation. More than 80 percent of infants with open spina bifi d a require ventriculoperitoneal shunt placement. A small BPD is often present as well. Children with spina biida require multidisciplinary care to address problems related to the defect, therapeutic shunting, and deicits in swallowing, bladder and bowel function, and ambulation. Fetal myelome­ ningocele surgery is discussed i n Chapter 1 6 (p. 3 1 9) . Ve ntric u l o mega ly

When brain tissue herniates through the skull defect, the anomaly is termed an encephaocee. Herniation of the cerebellum and other posterior fossa structures constitutes a Chiari II maomaion. Asso­ ciated hydrocephalus and microcephaly are common, and survivors have a high incidence of neurological deficits and intellectual dis­ ability. Cephalocele is an important feature of the autosomal reces­ sive Meckel-Guber syndrome, which includes cystic renal dysplasia and polydactyly. A cephalocele not located in the occipital midline rises suspicion for amnionic-band sequence (Chap. 6, p. 1 1 6). Spina bia is a defect in the vertebrae, typically the dorsal arches, with exposure of the meninges and spinal cord. The birth prevalence approximates 1 in 2000 (Cragan, 2009; Dolk, 20 1 0) . Most cases are open spina bia-the defect includes the skin and sot tissues. Herniation of a meningeal sac containing neural elements is termed a myelomeningocele (Fig. 1 0- 1 1 ) . When only a meningeal sac is present, the defect is a meningocele. Although

Characterized by distention of the cerebral ventricles by cere­ brospinal luid (CSF) , this finding is a nonspecifi c marker of abnormal brain development (Pilu, 20 1 1 ) . The atrium nor­ mally measures between 5 and 1 0 mm fro m 1 5 weeks' gestation until term (see Fig. 1 0-6) . Mild ventriculomegaly is diagnosed when the atrial width measures 1 0 to 1 5 mm (Fig. 1 0- 1 3) , and overt or severe ventriculomegaly when it exceeds 1 5 mm. The larger the atrium, the greater the likelihood of an abnormal outcome (Gaglioti, 2009; J06, 2008) . CSF is produced within the ventricles by the choroidplexus, which is composed of loose connective tissue surrounding an epithelium-lined capillary core. he choroid plexus often appears to dangle within the ventricle when severe ventriculomegaly is present. Ventriculomegaly may be caused by various genetic and envi­ ronmental insults. It may be due to other central nervous system (CNS) abnormalities-such as Dandy-Walker malformation or

FIGURE 1 0-1 2 Cra n i a l fi ndi ngs i n myelomen i ngocele, A. I mage of a feta l head at the level of the latera l ventricles d e m o n strates inward bowi ng or sca l loping of the fronta l bones (arrows)-the lemon sig n. B. I mage of a feta l head at the level of the posterior fossa shows a nterior c u rvature of the cerebe l l u m (arrows) with effacement of the cisterna mag na-the banana sig n.

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The Feta l Patient

FIGURE 1 0-1 3 Ventricu lomega ly. I n this tran sverse view of the cra n i u m , the wh ite l i ne depicts measurement of the atri u m of the latera l ventricle, which measured 1 2 m m, con sistent with mild ven­ triculomega ly.

FIGURE 1 0- 1 4 Agenesis of the corpus ca l losum. Th is image dem­ on strates a "teard rop" sha ped ventricle with m i ld ventriculomegaly (dotted line) a nd latera l ly d i splaced frontal horns (arrow). A normal cav u m septum pel l ucid u m can not be visual ized .

holoprosencephaly, to an obstructive process-such as aqueduc­ tal stenosis, or to a destructive process-such as porencephaly or an intracranial teratoma. Initial evaluation includes a targeted examination of fetal anatomy, testing for congenital infections such as cytomegalovirus and toxoplasmosis, and chromosomal microarray analysis, which is described in Chapter 1 3 (p. 27 1 ) . Fetal MR imaging should b e considered t o assess for associated abnormalities that may not be detectable sonographically. Prognosis is generally determined by etiology, severity, and rate of progression. However, even with mild-appearing and iso­ lated ventriculomegaly, prognosis can vary widely. In a systematic review of nearly 1 500 mild-to-moderate cases, 1 to 2 percent were associated with congenital infection, 5 percent with aneuploidy, and 1 2 percent with neurological abnormality (Devaseelan, 20 1 0) . A neurological abnormality was significantly more com­ mon if ventriculomegly progressed with advancing gestation.

Holop rosencepha ly

Agenesis of the Corpus Ca l l os u m

The corpus callosum i s the major iber bundle connecting recip­ rocal regions of the cerebral hemispheres. With complete agen­ esis of the corpus callosum, a normal cavum septum pellucidum cannot be visualized sonographically. Also, the frontal horns are displaced laterally, and the atria show mild enlargement poste­ riorly-such that the ventricle has a characteristic "teardrop" appearance (Fig. 1 0- 1 4) . Callosal dysgenesis involves only the caudal portions-the body and splenium-and consequently may be more diicult to detect prenatally. In population-based studies, agenesis of the corpus callosum has a prevalence of 1 in 5000 births (Glass, 2008; Szabo, 20 1 1 ) . I n a review o f apparently isolated cases, fetal MR imaging iden­ tiied additional brain abnormalities in more than 20 percent (Sotiriadis, 20 1 2) . If the anomaly was still considered isolated following MR imaging, normal developmental outcome was reported in 75 percent of cases, but severe disability occurred in 1 2 percent. Agenesis of the corpus callosum is associated with other anomalies, aneuploidy, and more than 200 genetic syndromes. Thus, genetic counseling can be challenging.

In early normal brain development, the prosencephalon or forebrain divides as it becomes the telencephalon and dien­ cephalon. With holoprosencephaly, the prosencephalon fails to divide completely into two separate cerebral hemispheres and underlying paired diencephalic structures. Main forms of holoprosencephaly are a continuum that contains, with decreasing severity, alobar, semilobar, and lobar types. In the most severe form-alobar holoprosencephay-a single mono­ ventricle, with or without a covering mantle of cortex, sur­ rounds fused central thalami (Fig. 1 0- 1 5) . In semilobar holoprosencephay, partial separation of the hemispheres occurs. Lobar holoprosencephay is characterized by a variable degree of fusion of frontal structures and should be considered when a normal CSP cannot be seen. Diferentiation into two cerebral hemispheres is induced by prechordal mesenchyme, which is also responsible for diferentiation of the midline face. Thus, holoprosencephaly may be associated with anomalies of the orbits and eyes­ hypotelorism, cyclopia, or micro-ophthalmia; lips-median cleft; or nose-ethmocephaly, cebocephaly, or arhinia with proboscis (see Fig. 1 0- 1 5) . The birth prevalence o f holoprosencephaly is only 1 in 1 0,000 to 1 5 ,000. However, the abnormality has been iden­ tiied in nearly 1 in 250 early abortuses, which attests to the extremely high in-utero lethality (Orioli, 20 1 0; Yamada, 2004) . The alobar form accounts for 40 to 75 percent of cases, and 30 to 40 percent have a numerical chromosomal abnor­ mality, particularly trisomy 1 3 (Orioli, 20 1 0; Solomon, 20 1 0) . Conversely, two thirds o f trisomy 1 3 cases are found to have holoprosencephaly. Fetal karyotype or chromosomal microar­ ray analysis should be ofered when this anomaly is identiied. Da ndy-Wa l ker Ma lformation -Verm ian Agenesis

This posterior fossa abnormality is characterized by agenesis of the cerebellar vermis, posterior fossa enlargement, and eleva­ tion of the tentorium. Sonographically, luid in the enlarged

Feta l l m a g i ng

(Th) encircled b y a monoventricle () with a coveri n g m a ntle (M) o f cortex. T h e m id l i n e fa lx is a bsent. (Rep roduced with permission from Rafael Levy, ROMS.) B. I n t h i s profi le view of the face, a soft tissue mass-a proboscis (arrow), protrudes from the reg ion of the forehea d .

FIGURE 1 0-1 5 Alobar holoprosencephaly. A. Tra n sverse cra n ial image of a fetu s with alobar holoprosencepha ly, depicting fused tha l a m i

cisterna magna visibly communicates with the fourth ventricle through the cerebellar vermis defect, with visible separation of the cerebellar hemispheres (Fig. 1 0- 1 6) . The birth prevalence approximates 1 in 1 2,000 (Long, 2006) . Associated anomalies and aneuploidy are common. These include ventriculomegaly in 30 to 40 percent, other anomalies in approximately 50 per­ cent, and aneuploidy in 40 percent (Ecker, 2000; Long, 2006) . Dandy-Walker malformation is also associated with numerous genetic and sporadic syndromes, congenital viral infections, and teratogen exposure, all of which greatly afect the prog­ nosis. Thus, the initial evaluation mirrors that for ventriculo­ megaly (p. 1 93). Inerior vermian agenesis, also called Dandy- Walker variant, is a term used when only the inferior portion of the vermis is absent. But, even when vermian agenesis appears to be partial

FIGURE 1 0- 1 6 Dandy-Wa l ker ma lformation. This tra nscerebe l l a r i mage demonstrates agenesis o f the cerebel l a r vermis. T h e cerebel­ lar hemispheres (+) a re widely sepa rated by a fl u id col lection that con nects the 4th ventricle (asterisk) to the e n l a rged cisterna magna (eM).

and relatively subtle, the prevalence of associated anomalies and aneuploidy is still high, and the prognosis is often poor (Ecker, 2000; Long, 2006) . S c h ize n ce p h a ly an d Pore n ce p h a ly

Schizencephaly is a rare brain abnormality characterized by clefts in one or both cerebral hemispheres, typically involv­ ing the perisylvian fissure. The cleft is lined by heterotopic gray matter and communicates with the ventricle, extending through the cortex to the pial surface (Fig. 1 0- 1 7) . Schizen­ cephaly is believed to be an abnormality of neuronal migra­ tion, which explains its typically delayed recognition until after midpregnancy (Howe, 20 1 2) . It is associated with absence of the cavum septum pellucidum, resulting in the frontal horn communication shown in the image below.

FIGURE 1 0-1 7 Sch izencepha ly. Th i s tran sverse image of the feta l head shows a large cleft that extends from the rig ht latera l ven ­ tricle t h ro u g h t h e cortex. Beca use the borders of t h e cleft a re sepa­ rate, the defect is termed open-lipped. (U sed with permission from Michael Davidson, ROMS.)

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The Feta l Patient

FIGURE 1 0-1 8 Sacrococcygea l teratom a . Sonog raph ica l ly, this tumor a p pears as a solid a nd/or cystic mass that a rises from the a nterior sacru m a n d tends to extend i n feriorly and externa l ly as it g rows. In this i mage, a 7 x 6 cm i n h omogeneous solid mass is vis­ i ble below the norma l-a ppea ri n g sacru m . There is a l so an intern a l component t o t h e tu m o r. In contrast, porencephaly is a cystic space within the brain that is lined by white matter and may or may not communi­ cate with the ventricular system. It is generally considered to be a destructive lesion and may develop following intracranial hemorrhage in the setting of neonatal alloimmune thrombocy­ topenia or following death of a monochorionic co-twin (Fig. 45-20, p. 878). Fetal MR imaging should be considered when either of these CNS anomalies is identiied. Sacrococcygea l Te rato ma

his germ cell tumor is one of the most common tumors in neonates, with a birth prevalence of approximately 1 in 28,000 (Derikx, 2006; Swamy, 2008) . It is thought to arise from the totipotent cells along Hensen node, anterior to the coccyx. Classification of sacrococcygeal teratoma (SCT) includes four types (Altman, 1 974) . Type 1 is predominantly external with a minimal presacral component; type 2 is predominantly exter­ nal but with a significant intrapelvic component; type 3 is pre­ dominantly internal but with abdominal extension; and type 4 is entirely internal with no external component. he tumor histological type may be mature, immature, or malignant. Sonographiclly, SCT appears as a solid and/or cystic mass that arises rom the anterior sacrum and usually extends inferiorly and externally as it grows (Fig. 1 0- 1 8) . Solid components oten have varying echogenicity, appear disorganized, and may enlarge rapidly with advancing gestation. Internal pelvic components may be more challenging to visualize, and fetal MR imaging should be considered. Hydramnios is frequent, and hydrops may develop from high-output cardiac failure, either as a consequence of tumor vascularity or secondary to bleeding within the tumor and resultant anemia. Mentioned throughout this chapter, hydrops is more ully described in Chapter 1 5 (p. 309). Fetuses with tumors > 5 cm oten require cesarean delivery, and classical hysterotomy may be needed (Gucciardo, 201 1) . s shown in Figure 1 6-3 (p. 320), fetal surgery is suitable for some SCT cases.

FIGURE 1 0- 1 9 M i d l i ne face. Th i s view demonstrates the i nteg rity of the u pper l i p.

Ca u d a l Reg ression Seq ue nce-Sacra l Ag enesis

his rare anomaly is characterized by absence of the sacral spine and often portions of the lumbar spine. It is approximately 25 times more common in diabetic pregnancies (Garne, 20 1 2) . Sonographic indings include a spine that appears abnormally short, lacks normal lumbosacral curvature, and terminates abruptly above the level of the iliac wings. Because the sacrum does not lie between the iliac wings, they are abnormally close together and may appear "shield-like." here may also be abnormal positioning of the lower extremities and lack of nor­ mal local soft tissue development. Caudal regression should be diferentiated from sirenomelia, which is a rare anomaly char­ acterized by a single fused lower extremity that occupies the midline. • Face and Neck

Normal fetal lips and nose are shown in Figure 1 0- 1 9 . A fetal profile is not a required component of standard examination but may be helpful in identiying cases of micrognathia-an abnormally small j aw (Fig. 1 0-20) . Micrognathia should be considered in the evaluation of hydramnios (Chap. 1 1 , p . 227) . Use of the ex-utero intrapartum treatment (EI) procedure for severe micrognathia is discussed in Chapter 1 6 (p. 327) . Fac i a l C l efts

here are three main types of clefts. he irst type, clt lip and palate, always involves the lip, may also involve the hard palate, can be unilateral or bilateral, and has a birth prevalence that approximates 1 in 1 000 (Cragan, 2009; Dolk, 20 1 0) . If iso­ lated, the inheritance is multifactorial-with a recurrence risk of 3 to 5 percent for one prior afected child. If a cleft is visible in the upper lip, a transverse image at the level of the alveolar ridge may demonstrate that the defect also involves the primary palate (Fig. 1 0-2 1 ) . In one systematic review o f low-risk pregnancies, cleft lip was identiied so no graphically in only about half of cases

Feta l l mag i ng

FIGURE 1 0-20 Feta l profi le. A. Th is image depicts a normal feta l profile. B. This fetus has severe m icrog nathia, wh ich creates a severely

recessed c h i n .

(Maarse, 20 1 0) . Approximately 40 percent of those detected in prenatal series are associated with other anomalies or syn­ dromes, and aneuploidy is common (Maarse, 20 1 1 ; Oferdal, 2008) . The rate of associated anomalies is highest for bilateral defects that involve the palate. Using data from the Utah Birth Defect Network, Walker and associates (200 1 ) identified aneu­ ploidy in 1 percent with cleft lip alone, 5 percent with unilat­ eral cleft lip and palate, and 1 3 percent with bilateral cleft lip and palate. It is reasonable to ofer fetal chromosomal microar­ ray analysis when a cleft is identiied. he second type of cleft is isolated clt palate. I t begins at the uvula, may involve the soft palate, and occasionally involves the hard palate-but does not involve the lip. The birth preva­ lence approximates 1 in 2000 (Dolk, 20 1 0) . Identiication of isolated cleft palate has been described using specialized 2- and 3-dimensional sonography (Ramos, 20 1 0; Wilhelm, 20 1 0) . However, i t is not expected t o b e visualized during a standard sonographic examination (Maarse, 20 1 1 ; Oferdal, 2008) . A third type of cleft is median clt lp, which is found in association with several conditions. hese include agenesis of the primary palate, hypotelorism, and holoprosencephaly.

Median clefts may also be associated with hypertelorism and frontonasal hyperplasia, formerly called the median clt ace syndrome. Cysti c Hygroma

This venolymphatic malformation is characterized by luid­ illed sacs that extend from the posterior neck (Fig. 1 0-22) . Cystic hygromas may b e diagnosed as early as the irst trimes­ ter and vary widely in size. They are believed to develop when lymph from the head fails to drain into the j ugular vein and accumulates instead in jugular lymphatic sacs. Their birth prev­ alence approximates 1 in 5 000. B ut, reflecting the high in-utero lethality of the condition, the first-trimester incidence exceeds 1 in 300 (Malone, 2005). Up to 70 percent of cystic hygromas are associated with aneuploidy. When cystic hygromas are diagnosed in the irst trimester, trisomy 2 1 is the most common aneuploidy, followed by 45,X and trisomy 1 8 (Kharrat, 2006; Malone, 2005) . First­ trimester fetuses with cystic hygromas are ive times more likely to be aneuploid than fetuses with a thickened nuchal trans­ lucency. When cystic hygromas are diagnosed in the second trimester, approximately 75 percent of aneuploid cases are 45,X- Turner syn­ drome Gohnson, 1 993; Shulman, 1 992) . Even in the absence of aneuploidy, cys­ tic hygromas confer a significantly greater risk for other anomalies, particularly car­ diac anomalies that are flow-related. These include hypoplastic let heart and coarc­ tation of the aorta. Cystic hygromas also may be part of a genetic syndrome. One is Noonan yndrome, an autosomal domi­ nant disorder that shares several features with Turner syndrome, including short stature, lymphedema, high-arched palate, and oten pulmonary valve stenosis. FIGURE 1 0-21 Cleft l i p/pal ate. A. This fetus has a pro m i nent u n i latera l (left-sided) cleft Large cystic hygromas are usually asso­ l i p. B. Tra nsverse view of the pa late i n the same fetus demonstrates a defect i n the a lveolar ciated with hydrops fetalis, rarely resolve, ridge (arrow), The tongue ) is a l so visi ble.

1 97

1 98

The Feta l Patient

FIGURE 1 0-22 Cystic hyg romas. A. This 9-week fetus with a cystic hyg rom a (arrow) was later found to have Noonan syn d rome. B. Massive m u ltiseptated hyg rom a s (arrowheads) in the setting of hyd rops feta l i s at 1 5 weeks' gestation.

and carry a poor prognosis. Small hygromas may undergo spon­ taneous resolution, and provided that fetal karyotype and echo­ cardiography results are normal, the prognosis may be good. The likelihood of a nonanomalous liveborn neonate with normal karyotype following identiication of first-trimester hygroma is approximately 1 in 6 (Kharrat, 2006; Malone, 2005) . • Thorax

he lungs appear homogeneous and surround the heart. In the four-chamber view of the heart, they comprise approximately two thirds of the area, with the heart occupying the remaining third. The thoracic circumference is measured at the skin line in a transverse plane at the level of the four-chamber view. In cases of suspected pulmonary hypoplasia secondary to a small thorax, such as with severe skeletal dysplasia, comparison with a reference table may be helpul (Appendix, p. 1 266) . Vari­ ous abnormalities may appear so no graphically as cystic or solid space-occupying lesions or as an efusion outlining the heart or lung(s) . Fetal therapy for thoracic abnormalities is discussed in Chapter 1 6 (p. 324) .

Sonographically, left-sided CDH typically shows dextropo­ sition of the heart toward the right side of the thorax and a cardiac axis pointing toward the midline (Fig. 1 0-23) . Asso­ ciated findings include the stomach bubble or bowel peristal­ sis in the chest and a wedge-shaped mass-the liver-located anteriorly in the left hemithorax. Liver herniation complicates at least 50 percent of cases and is associated with a 30-percent reduction in the survival rate (Mullassery, 20 1 0) . With large lesions, impaired swallowing and mediastinal shift may result in hydramnios and hydrops, respectively. Eforts to reduce neonatal mortality rates and need for extracorporeal membrane oxygenation (ECMO) have focused on indicators such as the sonographic lung-to-head ratio, M R imaging measurements o f lung volume, and the degree of liver herniation Gani, 20 1 2; Oluyomi-Obi, 20 1 6; Worley, 2009) . These and fetal therapy for CDH are reviewed in Chapter 1 6 (p. 323) .

Cong e n ital Dia p h rag matic Hern i a

This is a defect in the diaphragm through which abdominal organs herniate into the thorax. It is let-sided in approximately 75 percent of cases, right-sided in 20 percent, and bilateral in 5 percent (Gallot, 2007) . he prevalence of congenital diaphrag­ matic hernia (CDH) is 1 in 3000 to 4000 births (Cragan, 2009; Dolk, 20 1 0) . Associated anomalies and aneuploidy are found in 40 percent of cases (Gallot, 2007; Stege, 2003). With suspected CDH, targeted sonography and fetal echocardiography should be performed, and fetal chromosomal microarray analysis should be ofered. In population-based series, the presence of an asso­ ciated abnormality reduces the overall survival rate of neonates with CDH from approximately 50 percent to about 20 percent (Colvin, 2005; Gallot, 2007) . If there are no associated abnor­ malities, the major causes of neonatal mortality are pulmonary hypoplasia and pulmonary hypertension.

FIGURE 1 0-23 Congenita l d i a p h rag matic hernia. I n this tra ns­ verse view of the thorax, the heart is sh ifted to the fa r rig ht side of the chest by a let-sided dia p h ra g matic hernia conta i n i n g stomach (5), l iver (, a nd bowel (B).

Feta l l m a g i n g

Congen ita l Cysti c Adenomato id Malformation

This abnormality represents a hamartomatous overgrowth of terminal bronchioles that communicates with the tracheo­ bronchial tree. It is also called congenital pulmonay airway maormation (CPM), based on an understanding that not all histopathological types are cystic or adenomatoid (Aziz­ khan, 2008; Stocker, 1 977, 2002) . The estimated prevalence is 1 in 6000 to 8000 births, and this rate is rising because of improved sonographic detection of milder cases (Burge, 20 1 0; Duncombe, 2002) . Sonographically, congenital cystic adenomatoid malforma­ tion (CCA M) is a well-circumscribed thoracic mass that may appear solid and echogenic or may have one or multiple vari­ ably sized cysts (Fig. 1 0-24) . It usually involves one lobe, has blood supply from the pulmonary artery, and drains into the pulmonary veins. Lesions with cysts : 5 mm are generally

termed macrocystic, and lesions with cysts < 5 mm are termed microcystic (Adzick, 1 985). In a review of 645 CCM cases, the overall survival rate exceeded 95 percent, and 30 percent of cases demonstrated apparent prenatal resolution. The other 5 percent of cases­ typically very large lesions with associated mediastinal shift­ were complicated by hydrops, and the prognosis was poor (Cavoretto, 2008) . CCAMs often become less conspicuous with advancing gestation. However, a subset of CCAMs dem­ onstrates rapid growth between 1 8 and 26 weeks' gestation. Corticosteroid therapy has been used for large microcystic lesions to forestall growth and potentially ameliorate hydrops (Curran, 20 1 0; Peranteau, 20 1 6) . If a large dominant cyst is present, thoracoamnionic shunt placement may lead to hydrops resolution. Fetal therapy for CCAM is discussed in Chapter 1 6 (p. 324) . Pul monary Sequestration

Also called a bronchopulmonary sequestration, this abnormal­ ity is an accessory lung bud "sequestered" from the tracheo­ bronchial tree, that is, a mass of nonfunctioning lung tissue. Most cases diagnosed prenatally are extralobar, which means they are enveloped in their own pleura. Overall, however, most sequestrations present in adulthood and are intralobar-within the pleura of another lobe. Extralobar pulmonary sequestra­ tion is considered signifi c antly less common than CCAM, and no precise prevalence has been reported. Lesions have a left­ sided predominance and most often involve the left lower lobe. Of cases, 10 to 20 percent are located below the diaphragm, and associated anomalies have been reported in approximately 10 percent of cases (Yildirim, 2008). Sonographically, pulmonary sequestration presents as a homogeneous, echogenic thoracic mass (Fig. 1 0-2 5A) . Thus, it may resemble a microcystic CCAM. However, the blood supply is from the systemic circulation-from the aorta rather than the pulmonary artery (see Fig. 1 0-25B) . In 5 to 1 0 per­ cent with pulmonary sequestration, a large ipsilateral pleural efusion develops, and without treatment, this may result in pulmonary hypoplasia or hydrops (see Fig. 1 0-25C,D). Thera­ peutic thoracoamnionic shunting of efusions is discussed in Chapter 16 (p. 324) . Hydrops may also result from medias­ tinal shift or high-output cardiac failure due to the left-to­ right shunt imposed by the mass. In the absence of a pleural efusion, the reported survival rate exceeds 95 percent, and 40 percent of cases demonstrate apparent prenatal resolution (Cavoretto, 2008) . Con ge n ita l H i g h Ai rway Obstruction Seq uence

FIGURE 1 0-24 Tra n sverse (A) and sag itta l (8) images of a 26-week fetu s with a very l a rge left-sided microcystic congen ita l cystic adenomatoid malformation (CCAM). The mass ( ) fi l l s the thorax and has shifted the heart to the far right side of the chest, with development of ascites (asterisks). Fortu nately, the mass d i d not conti n ue t o g row, t h e ascites resolved, and t h e neonate wa s del ivered at term and d id wel l fol l owi n g resection.

This rare anomaly usually results from laryngeal or tracheal atresia. The normal egress of lung fluid is obstructed, and the tracheobronchial tree and lungs become massively distended. Sonographically, the lungs appear brightly echogenic, the bron­ chi are dilated, the diaphragm is flattened or everted, and the heart is compressed (Fig. 1 0-26). Venous return is impaired and ascites develops, typically followed by hydrops. In one review of 1 1 8 cases, associated anomalies were identiied in more than 50 percent (Sanford, 20 1 2) . Congenital high airway obstruc­ tion sequence (CHAOS) is a feature of the autosomal recessive

1 99

200

The Feta l Patient

FIGURE 1 0-25 Pulmonary seq uestration. A. Th is tra n sverse i mage at the level of the 4-c h a m ber view of the hea rt depicts a pul monary seq uestration i nvolving the left lower lobe in a 25-week fetus. Mass effect leads to dextroposition of the hea rt to the right side of the chest. B. A sag itta l i mage shows the p u l monary seq uestration s u ppl ied by a bra nch of the abdo m i n a l aorta . C. Over the next 3 weeks, a large i psi­ l atera l pleura l effusion develops (asterisk), res u lting in mediasti n a l s h ift a nd dextroposition of the heart to the fa r rig ht thorax. D. Fol lowi n g placement of a double-pigta i l s h u nt t h ro u g h the chest wa l l a n d i nto t h e effusion, t h e effu sion dra i ned a n d t h e l u n g s i g n ifica ntly reex­ panded. Arrows poi nts to coi l s of the pigta i l s h u nt. (U sed with permission from Dr. E l a i ne D u ryea.) Fraser syndrome and has been associated with the 22q 1 1 .2 dele­ tion syndrome. In some cases, the obstructed airway spontane­ ously perforates, which potentially confers a better prognosis. he EIT procedure has significantly improved outcome in selected cases (Chap. 1 6, p. 327) . Heart

FIGURE 1 0-26 Congen ita l h i g h a i rway o bstruction seq uence (CHAOS). The l u ng s a ppea r brig htly echogenic, a nd one is ma rked by an "L." The bronchi, one of which is noted by an a rrow, a re d i l ated with fl u i d . F l attening a nd eversion of the d i a p h ra g m i s common, as i s ascites (asterisks).

Cardiac malformations are the most common class of congen­ ital anomalies, and their overall prevalence is 8 in 1 000 births (Cragan, 2009) . Almost 90 percent of cardiac defects are mul­ tifactorial or polygenic in origin, another 1 to 2 percent result from a single-gene disorder or gene-deletion syndrome, and 1 to 2 percent stem from exposure to a teratogen such as isotretinoin, hydantoin, or maternal diabetes. Based on data from population-based registries, approximately 1 in 8 live­ born and stillborn neonates with a congenital heart defect has a chromosomal abnormality (Dolk, 20 1 0; Hartman, 2 0 1 l ) . O f chromosomal abnormalities associated with cardiac anom­ alies, trisomy 2 1 accounts for more than 50 percent of cases. Others are trisomy 1 8, 22q 1 1 .2 deletion, trisomy 1 3, and

Feta l l m ag i ng

monosomy X (Hartman, 20 1 1 ) . Of these aneuploid fetuses, 50 to 70 percent also have extracardiac anomalies. Chromo­ somal micro array analysis should be ofered when cardiac defects are found. Traditionally, detection of congenital cardiac anomalies is more challenging than for anomalies of other organ systems. Routine second-trimester sonography identiies approximately 40 percent of those with major cardiac anomalies before 22 weeks' gestation, and specialized sonography may identiy 80 percent (Romosan, 2009; Trivedi, 20 1 2) . For selected anoma­ lies, prenatal detection may improve neonatal survival. his may be particularly true for ductal-dependent lesions-those requiring prostaglandin infusion after birth to keep the duc­ tus arteriosus open (Franklin, 2002; Mahle, 200 1 ; Tworetzky, 200 1 ) .

L

Basic Ca rd iac Exa m i nation

Standard cardiac assessment includes a four-chamber view, evaluation of rate and rhythm, and evaluation of the left and right ventricular outlow tracts (Figs. 1 0-27 and 1 0-28A-C) . Examination o f the cardiac outflow tracts aids detection of abnormalities that might not be appreciated in the four-cham­ ber view. hese include tetralogy of Fallot, transposition of the great vessels, and truncus arteriosus. he our-chamber view is a transverse image of the fetal tho­ rax at a level immediately above the diaphragm. It allows evalu­ ation of cardiac size, position in the thorax, cardiac axis, atria and ventricles, foramen ovale, atrial septum primum, interven­ tricular septum, and atrioventricular valves (see Fig. 1 0-27) . he atria and ventricles should be similar in size, and the apex of the heart should form a 45-degree angle with the left anterior chest wall. Abnormalities of cardiac axis are frequently encoun­ tered with structural cardiac anomalies and occur in more than a third (Shipp, 1 995) . The lt ventricular oulow tract view is a transverse image j ust above the diaphragm and demonstrates that the ascending aorta arises entirely from the left ventricle. The inteventricular septum is shown to be in continuity with the anterior wall of the aorta, and the mitral valve in continuity with the posterior wall of the aorta (see Fig. 1 0-28B). Ventricular septal defects and outflow tract abnormalities are often visible in this view (Fig. 1 0-29) . The right ventricular oulow tract view shows the right ven­ tricle giving rise to the pulmonary artery (see Fig. 1 0-28C) . Together, the left and right outflow tract views demonstrate the normal perpendicular orientation of the aorta and pulmonary artery, and the comparable size of these great arteries. Struc­ tures visible in the right ventricular outlow tract view include the right ventricle and the main pulmonary artery, which sub­ sequently branches into the right and left pulmonary arteries. hese structures are also visible in the short axis view, shown in Figure 1 0-28E. Feta l Echoca rd iog ra phy

This is a specialized examination of fetal cardiac structure and function designed to identiy and characterize abnormalities. Guidelines for its performance have been developed collabora­ tively by the American Institute of Ultrasound in Medicine,

A

FIGURE 1 0-27 The fou r-cham ber view. A. Diagram demonstrat­

ing meas u rement of the cardiac axis from the fou r-chamber view of the feta l heart. B. Sonog ra m of the fou r-ch a m ber view at 2 2 weeks' gestation shows t h e normal sym metry o f t h e atria a n d ven­ tricles, normal position of the m itra l a nd triscu s pid va lves, p u l m o­ n a ry vei n s enteri ng the left atri u m, a nd desce n d i n g aorta (Ao). L left; LA left atri u m; LV left ventricle; R rig ht; RA rig ht atri u m; RV rig ht ventricle. =

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American College of Obstetricians and Gynecologists, Society for Maternal-Fetal .Medicine, American Society of Echocar­ diography, and American College of Radiology. Echocardiog­ raphy indications include suspected fetal cardiac anomaly, extracardiac anomaly, or chromosomal abnormality; fetal arrhythmia; hydrops; thick nuchal translucency; monocho­ rionic twin gestation; irst-degree relative to the fetus with a congenital cardiac defect; in vitro fertilization; maternal anti­ Ro or anti-La antibodies; exposure to a medication associated with cardiac defects; and maternal metabolic disease associ­ ated with cardiac defects-such as pregestational diabetes or phenylketonuria (American Institute of Ultrasound in Medi­ cine, 20 1 3a) . Components of the examination are listed in

201

Feta l l m a g i n g

TABLE 1 0-9. Components of Feta l Echoca rd iog ra p hy Basic imaging parameters Eva I uation of atria Eva l uati on of ventricles Eva l uation of g reat vesse l s Ca rd iac a n d viscera l situs Atrioventricu l a r j u n ctions Ventri c u l o a rteria l j u n ctions Scann ing planes, g ray sca le Four-cha m ber view Left ve ntricu l a r o utflow tract R i g ht ve ntri c u l a r o utfl ow tract Th ree-vessel and trachea view Short-axis view, l ow (ventricles) Short-axis view, h i g h (outflow tracts) Aortic a rch Ducta l a rch S u perior a n d i n ferior ve na cavae Color Doppler eva l uation Syste m ic vei n s (ve n a cavae a nd d u ctus ve nosu sd) P u l mona ry ve i n s Fora men ova l e Atrioventric u l a r va lvesa Atr i a l a n d ve ntri c u l a r septae Aor t i c a n d p u l m o na ry va lvesa Ductus a rterios u s Aortic a rch U m bi l ic a l a rtery and vei n (optiona l)a Cardiac rate and rhyt h m assessment

aPu lsed-wave Do ppler sonography shou ld be used as a n adj u n ct to eva l uate these structu res. Ca rd iac b i o m etry a n d fu nction a l assessm ent are optio n a l b u t s h o u l d b e conside red for s u s pected struct u ra l/ fu nctional a b n o r m a l i ties. Ada pted fro m the American I n stitute of U ltrasound i n Med i c i n e, 2 0 1 3 b.

Table 1 0-9, and examples of nine required gray-scale imaging views are shown in Figure 1 0-28 . Examples of selected cardiac anomalies are reviewed below. Ve ntric u l a r Septa l Defect. This is the most common con­

genital cardiac anomaly and is found in approximately 1 in 300 births (Cragan, 2009; Dolk, 20 1 0) . Even with adequate visualization, the prenatal detection rate of ventricular septal defect (VSD) is low. A defect may be appreciated in the mem­ branous or muscular portion of the interventricular septum in the four-chamber view, and color Doppler demonstrates flow through the defect. Imaging of the left ventricular out­ flow tract may show discontinuity of the interventricular sep­ tum as it becomes the wall of the aorta (see Fig. 1 0-29) . Fetal VSD is associated with other abnormalities and aneuploidy, and chromosomal microarray analysis should be ofered. hat said, the prognosis for an isolated defect is good. More than a third of prenatally diagnosed VSDs close in utero, and another third close in the irst year of life (Axt-Fliedner, 2006; Paladini, 2002) . Endoca rdial Cushion Defect. This is also called an atrioven­ tricular (A ) septal dect or A V canal dect. It has a prevalence of approximately 1 in 2 500 births and is associated with tri­ somy 2 1 in more than half of cases (Christensen, 20 1 3 ; Cra­ gan, 2009; Dolk, 20 1 0) . The endocardial cushions are the crux of the heart, and defects jointly involve the atrial septum pri­ mum, interventricular septum, and medial leaflets of the mitral and tricuspid valves (Fig. 1 0-30) . Approximately 6 percent of cases occur with heterotaxy syndromes, that is, those in which the heart and/or abdominal organs are on the incorrect side. Endocardial cushion defects associated with heterotaxy can have comorbid conduction system abnormalities resulting in third-degree AV block, which confers a poor prognosis (Chap. 1 6, p . 3 1 6) .

Hypoplastic Let Heart Synd rome. This anomaly i s found in approximately 1 in 4000 births (Cragan, 2009; Dolk, 20 1 0) . Sonographically, the let side of the heart may appear "illed-in" or the let ventricle may be so small and attenuated that a ventricular chamber is diicult to appreciate (Fig. 1 0-3 1 ) . There may b e n o visible let ventricular inlow or outflow, and reversal of low may be documented in the aortic arch. Although this anomaly was once considered a lethal prognosis, 70 per­ cent of afected infants may now survive to adulthood (Feinstein, 20 12) . Post­ natal treatment consists of a three-stage palliative repair or cardiac transplanta­ tion. Still, morbidity remains high, and developmental delays are common (Lloyd, 20 1 7; Paladini, 20 1 7) . This is a ductal-dependent lesion for which FIGURE 1 0-30 Endoca rd i a l cushion defect. A. During ventricular systole, the l atera l leaflets neonatal administration of prostaglan­ of the m itra l a n d triscuspid va lves come together in the midl ine. But the atrioventricular va lve din therapy is essential. Fetal therapy plane is a bnormal, a com mo n atri u m (A) is observed, a n d there is a visible defect (arrow) i n for hypoplastic left heart is discussed in t h e interventricular sept u m . B . D u ri n g d iastolic fi l l i ng, ope n i n g o f t h e atrioventricu l a r va lves more clea rly demonstrates the a bsence of their media l leaflets. Chapter 16 (p. 326) .

203

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The Feta l Patient

FIGURE 1 0-28 Feta l echocard iog ra p hy g ray-sca le imaging planes. A. Four-c h a m ber view. B. Left ventricular outflow tract view. The wh ite a rrow i l l u strates the mitra l va lve beco m i n g the wa l l of the aorta . The arrow with asterisk ma rks the interventricu l a r septum becoming the opposing aortic wa l l . C. Right ventricu l a r outflow tract view. D. Th ree vessel a nd trachea view. E. High s hort-axis view (outflow tracts). F. Low short-axis view (ventricles). G. Aortic a rc h view. H. Ductal a rch view. I. Su perior a nd inferior vena cavae views. Ao aorta; IVC inferior vena cava; LA left atri u m; LV left ventricle; PA p u l monary a rtery; RA rig ht atri u m; RV rig ht ventricle; SVC s u pe rior vena cava. =

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FIGURE 1 0-29 Ventricular septa l defect. A. l n t h i s fou r-ch a m ber view o f a 22-week fetus, a d efect (arrow) is noted in the su perior (mem­ branous) portion of the interventri c u l a r septu m . B . T h e left-ventricu lar outflow tract view o f t h e same fetus demonstrates a brea k (arrow) i n con­ t i n u ity between the i nterve ntri c u l a r septu m and the a nterior wa l l of the aorta.

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204

The Feta l Patient Tetralogy of Fallot. This anomaly occurs

in approximately 1 in 3000 births (Cra­ gan, 2009; Dolk, 20 1 0; Nelson, 20 1 6) . I t includes a ventricular septal defect; an overriding aorta; a pulmonary valve abnormality, typically stenosis; and right ventricular hypertrophy (Fig. 1 0-32) . h e last does not present before birth. Due to the location of the ventricular septal defect, the four-chamber view may appear normal. Following postnatal repair, the 20-year survival rates exceed 95 per­ cent (Knott-Craig, 1 998). However, cases with pulmonay atresia have a more complicated course. There is also a variant in which the pulmonary valve is absent. These afected fetuses are at risk for hydrops and for tracheomalacia from compression of the trachea by an enlarged pulmonary artery. Ca rd iac Rha bdomyoma. his is the

most common cardiac tumor. Approxi­ mately 50 percent of cases are associated with tuberous sclerosis, an autosomal dominant disease with multiorgan sys­ tem manifestations. Tuberous sclerosis is caused by mutations in the hamartin FIGURE 1 0-31 Hypoplastic left heart syndrome. A. In this 4-ch a m ber view at 1 6 weeks, the ( TSCl) and tuberin ( TSC2) genes. let ve ntricle (L) appears "fi l led in" and is Sign ificantly smaller than the right ventricle (R). The Cardiac rhabdomyomas appear as tricuspid va lve () is open, whereas the mitra l va lve a p pears closed (asterisk). B. Color Dop­ well-circumscribed echo genic masses, pler depicts flow from the rig ht atri u m to the rig ht ventricle on ly, and left ventricular fi l l i n g is usually within the ventricles or out­ not visi ble. C. The left ventricu l a r outflow tract view demonstrates ma rked na rrowing of the low tracts. They may be single or aorta (Ao). RV rig ht ventricle; LA let atri u m . D. The tiny ci rcle (a rrow) i n this s hort axis view multiple; may grow in size during ges­ is the hypoplastic aortic root. (Used with perm ission from Rafael Levy, ROMS.) tation; and occasionally, may lead to inlow or outfl o w obstruction. In cases without obstruction or large tumor size, the prognosis is relatively good from a cardiac standpoint, because the tumors tend to regress after the neonatal period. Because extracardiac findings of tuberous sclerosis may not be apparent with prenatal sonography, MR imaging may be considered to evaluate fetal CNS anatomy (p. 2 1 7) . =

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M-Mode

FIGURE 1 0-32 Tetra logy of Fa l lot. This i mage s h ows a ventricu l a r septa l defect with a n overrid i ng aorta i n a fetu s with tetra logy of F a l l ot. The a rrow poi nts to the aortic va lve. The left ve ntricle (LV) a n d rig ht ventricle (R) a re labeled.

Motion-mode or M-mode imaging is a linear display of car­ diac cycle events, with time on the x-axis and motion on the y-axis . It is often used to measure embryonic or fetal heart rate (Fig. 1 0-3 3) . If an abnormality of heart rate or rhythm is identiied, M-mode imaging permits separate evaluation of atrial and ventricular waveforms. Thus, it is particularly useful for characterizing arrhythmias and their response to treatment (Chap . 1 6, p. 3 1 6) . M-mode can also be used to assess ventricular function and atrial and ventricular outputs. Prematu re Atrial Contractions. Also called atrial extrasystoles, these are the most common fetal arrhythmia and a frequent

Feta l l m a g i ng

pause that follows the premature contrac­ tion. PACs sometimes occur with an atrial septal aneurysm but are not associated with major structural cardiac abnormali­ ties. Older case reports describe an associ­ ation with maternal cafeine consumption and with hydralazine (Lodeiro, 1 989; Oei, 1 989) . In approximately 2 percent of cases, afected fetuses are later identi­ fied to have a supraventricular tachycar­ dia (S) that requires urgent treatment (Copel, 2000) . Accordingly, pregnancies with fetal PACs are often followed with fetal heart rate assessment as often as every 1 to 2 weeks until ectopy resolves. T reat­ ment of fetal SVT and other arrhythmias is discussed in Chapter 1 6 (p. 3 1 6) . • Abdominal Wall

he integrity of the abdominal wall is assessed at the level of the cord insertion dur­ ing the standard examination (Fig. 1 0-3 5) . Ventral wall defects include gastroschisis, omphalocele, and body stalk anomaly. finding. They represent cardiac conduction system immaturity and typically resolve later in gestation or in the neonatal period. Gastroschisis is a full-thickness abdominal wall defect located Premature atrial contractions (PACs) may be conducted and to the right of the umbilical cord insertion. Bowel herniates thus sound like an extra beat. However, they are more com­ through the defect into the amnionic cavity (Fig. 1 0-36) . he monly blocked, and with handheld Doppler they sound like a prevalence is approximately 1 in 2000 births Oones, 20 1 6 ; Nel­ dropped beat. As shown in Figure 1 0-34, the dropped beat may son, 20 1 5) . Gastroschisis is the one major anomaly more com­ be demonstrated with M-mode evaluation as a compensatory mon in fetuses of younger mothers, and the average maternal age is 20 years (Santiago-Munoz, 2 007) . Coexisting bowel abnormalities such as jjunal atresia are found in approximately 1 5 percent of cases (Nelson, 20 1 5 ; Over­ cash, 20 1 4) . Gastroschisis is not associ­ ated with aneuploidy, and the survival rate is 90 to 95 percent (Kitchanan, 2000; Nelson, 20 1 5 ; Nembhard, 2 00 1 ) . Fetal-growth restriction complicates gastroschisis in 1 5 to 40 percent of cases (Overcash, 2014; Santiago-Munoz, 2 007) . Growth restriction does not appear t o be associated with adverse outcomes such as longer hospitalization or higher mortal­ ity rate (Nelson, 20 1 5; Overcash, 20 1 4) . However, earlier gestational age at deliv­ ery does pose a risk for adverse outcome with gastroschisis, and planned delivery at 36 to 37 weeks does not confer neonatal benefit (Al-Kaf, 20 1 6; Overcash, 20 1 4; South, 20 1 3) . Omphalocele complicates 1 in 3000 to 5000 pregnancies (Canield, 2006; D olk, FIGURE 1 0-34 M-mode. I n this i mage, there i s norm a l concord a n ce between atrial (A) 20 1 0) . It forms when the lateral ectome­ a n d ventricular contractions (). Movement of the tricuspid valve en is a lso shown. There i s sodermal folds fail to meet in the mid­ a l so a prematu re atrial contraction (arrow) a n d a su bseq uent ea rly ventricu lar contraction, fol l owed by a compensatory pause. line. This leaves the abdominal contents

FIGURE 1 0-33 M-mode, or motion mode, i s a l i nea r display of the events of the ca rdiac cycle, with time on the x-axis a n d motion on the y-axis. M-mode is used commonly to mea s u re the feta l hea rt rate, as in t h is 1 2-week fetus.

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The Feta l Patient

FIGURE 1 0-35 Normal ventra l wa l l . Tra n sverse view of the a bdo­ men i n a second-trimester fetus with a n i ntact a nterior a bdominal wa l l a n d normal cord i n sertion. covered only by a two-layered sac of amnion and peritoneum into which the umbilical cord inserts (Fig. 1 0-37) . More than half of cases are associated with other major anomalies or aneu­ ploidy. Omphalocele also is a component of syndromes such as Beckwith-Wiedemann, cloacal exstrophy, and pentaloy of Cantrell. Smaller defects confer greater risk for aneuploidy (De Veciana, 1 994) . Chromosomal microarray analysis should be ofered in all cases of omphalocele. Body stalk anomay, also known as limb-body-wall complex or cyllosoma, is a rare, lethal anomaly characterized by abnormal formation of the body wall. Typically, no abdominal wall is vis­ ible, and the abdominal organs extrude into the extraamnionic coelom. here is close approximation or fusion of the body to the placenta, and the umbilical cord is extremely short. Acute-angle scoliosis is another feature. Amnionic bands are often identified.

FIGURE 1 0-37 Om phalocele. Tra nsverse view of the a bdomen showi ng a n o m phalocele a s a l a rg e a bdominal wa l l defect with exteriorized l iver covered by a thin mem bra ne. • Gastrointestinal Tract

he stomach is visible in nearly all fetuses after 1 4 weeks' gesta­ tion. If the stomach is not seen during initial evaluation, the examination is repeated, and targeted sonography should be considered. Nonvisualization of the stomach may be secondary to impaired swallowing in the setting of oligohydramnios or to underlying causes such as esophageal atresia, a craniofacial anomaly, or a CNS or musculoskeletal abnormality. Fetuses with hydrops may also have impaired swallowing. he bowel, liver, gallbladder, and spleen can be identiied in many second- and third-trimester fetuses. Bowel appearance changes with fetal maturation. Occasionally, it may be bright or echogenic, which may indicate small amounts of swallowed intraamnionic blood, especially with comorbid MSAFP eleva­ tion. Bowel that appears as bright as fetal bone confers a slightly greater risk for underlying gastrointestinal malformations, for cystic ibrosis, for trisomy 2 1 , and for congenital infection such as cytomegalovirus (Fig. 1 4-3, p. 287) . Gastroi ntest i n a l Atresia

FIGURE 1 0-36 Gastroschisis. This 1 8-week fetus has a fu l l­ thickness ventra l wa l l defect to the rig ht of the cord i n se rtion (arrowhea), t h rough which mu ltiple s ma l l bowel loops (B) have herniated i nto the a m n ionic cavity.

Bowel atresia is characterized by obstruction and proximal bowel dilation. In general, the more proximal the obstruction, the more likely it is to lead to hydramnios. At times, hydram­ nios from proximal small-bowel obstruction can be suiciently severe to result in maternal respiratory compromise or preterm labor and may necessitate amnioreduction (Chap. 1 1 , p. 230) . Esophageal atresia occurs in approximately 1 in 4000 births (Cragan, 2009; Pedersen, 20 1 2) . It may be suspected when the stomach cannot be visualized and hydramnios is present. hat said, in up to 90 percent of cases, a concomitant tracheo­ esophageal istula allows luid to enter the stomach, such that prenatal detection is problematic. More than half have associ­ ated anomalies or genetic syndromes. Multiple malformations are present in 30 percent of cases, and aneuploidy such as tri­ som) 1 8 or 2 1 , in 10 percent (Pedersen, 20 1 2) . Cardiac, uri­ nary tract, and other gastrointestinal abnormalities are the most frequently associated anomalies. Approximately 1 0 percent of

Feta l l ma g i n g

FIGURE 1 0-38 Duodenal atresia. The double-bubble sign rep re­ sents d istension of the stomach (5) a nd the first part of the d uo­ den u m (0), as seen on this axia l abdominal i ma ge. Demonstrati n g conti n u ity between the stomach a n d proximal duoden u m con­ fi rms that the second "bubble" is the proximal d uode n u m .

FIGURE 1 0-39 Normal feta l kid neys. The kid neys a re vis i b l e adjacent t o the feta l s p i ne in this 2 9-week fetus. W i t h adva n c i ng gestation, a rim of peri neph ric fat aids visu a l ization of the kid n ey m a rgins. A physiolog ica l a mo u nt of u ri ne is visi ble in the rena l pel­ ves and is ma rked i n one kid ney by a n a rrow.

cases of esophageal atresia occur as part of the VACTERL asso­ ciation, which is yertebral defects, !nal atresia, £ardiac defects, !racheo�sophageal istula, renal anomalies, and limb abnormali­ ties (Pedersen, 20 1 2) . Duodenal atresia is found i n approximately 1 in 1 0,000 births (Best, 20 1 2; Dolk, 20 1 0) . It is characterized by the sonographic double-bubble sin, which represents distention of the stomach and the irst part of the duodenum (Fig. 1 0-3 8). This finding is usually not present before 22 to 24 weeks' gestation. Demonstrat­ ing continuity between the stomach and proximal duodenum confirms that the second "bubble" is the proximal duodenum. Approximately 30 percent of afected fetuses have an associated chromosomal abnormality or genetic syndrome, particularly tri­ somy 2 1 . Of cases without a genetic abnormality, a third have associated anomalies, most commonly cardiac defects and other gastrointestinal abnormalities (Best, 20 1 2). Obstructions in the more distal small bowel usually result in multiple dilated loops that may have enhanced peristaltic activity. Large-bowel obstructions and anal atresia are less readily diagnosed by sonography, because hydramnios is not a typi­ cal feature and the bowel may not be signiicantly dilated. A transverse view through the pelvis may show an enlarged rectum as an anechoic structure between the bladder and the sacrum.

pelvis. With application of Doppler, the bladder is outlined by the two superior vesical arteries as they become the umbilical arteries of the umbilical cord (Fig. 1 0-40 and Chap. 6, p. 1 1 7) . The fetal ureters and urethra are not visible sonographically unless abnormally dilated. The placenta and membranes are the major sources of amni­ onic fluid early in pregnancy. However, after 1 8 weeks' gesta­ tion, most of the luid is produced by the kidneys (Chap. 1 1 , p . 225). Fetal urine production rises from 5 mLlhr at 20 weeks to approximately 50 mLlhr at term (Rabinowitz, 1 989) . Nor­ mal amnionic luid volume in the second half of pregnancy suggests urinary tract patency with at least one functioning kid­ ney. But, unexplained oligohydramnios suggests a urinary tract defect or placental perfusion abnormality.

• Kidneys and Urinary Tract

The fetal kidneys are visible adjacent to the spine, frequently in the fi r st trimester and routinely by 1 8 weeks' gestation (Fig. 1 0-3 9) . he length of the kidney approximates 20 mm at 20 weeks and grows by about 1 . 1 mm each week thereafter (Chitty, 2003) . With advancing gestation, the kidneys become relatively less echogenic, and a rim of perinephric fat aids visu­ alization of their margins. he fetal bladder is readily visible in the second trimester as a round, anechoic structure in the anterior midline of the

FIGURE 1 0-40 Normal feta l bladder. The normal feta l bladder is rea d i ly visible as a rou nd, fl u id-fi l led structure in the a nterior pelvis, outl i ned by the two s u perior vesica l a rteries as they become t h e u m bi l ical a rteries of t h e u m bilical cord.

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The Feta l Patient

FIGURE 1 0-41 Ren a l pelvis d i latation. This com mon fi n d i n g i s identified i n 1 to 5 percent of preg na ncies. A. l n this 34-week fetu s with m i l d ren a l pelvis di latation, the a nterior-posterior d iameter of the ren a l pelvis measured 7 mm in the tra nsverse plane. B. Sag itta l i mage of the kid n ey in a 32-week fetu s with severe ren a l pelvis d i l atation secondary to u reteropelvic j u n ction o bstruction. The a rrow points to one of the rou nded ca lyces. Renal Pe lvis D i l atation

This finding is present in 1 to 5 percent of fetuses. It is also called urinary tract dilatation or hydronephrosis. In 40 to 90 percent of cases, it is transient or physiological and does not represent an underlying abnormality (Ismaili, 2003; Nguyen, 20 1 0) . In approximately a third of cases, a urinary tract abnor­ mality is conirmed in the neonatal period. Of these, uretero­ pelvic junction (UP]) obstruction and vesicoureteral relux UR) are the most frequent. he fetal renal pelvis is measured anterior to posterior in a transverse plane, and calipers are placed on the inner border of the fluid collection (Fig. 1 0-4 1 ) . Although various thresholds have been deined, the pelvis is typically considered dilated if it exceeds 4 mm in the second trimester or 7 mm at approxi­ mately 32 weeks' gestation (Reddy, 20 1 4) . Typically, the second-trimester threshold is used to identiy pregnancies that warrant subsequent third-trimester evaluation. he Society for Fetal Urology categorized renal pelvis dilata­ tion based on a metaanalysis of more than 1 00,000 screened pregnancies (Table 1 0- 1 0) (Lee, 2006; Nguyen, 20 1 0) . he degree of dilatation correlates with the likelihood of an under­ lying abnormality. Other suggestive indings of pathology

TABLE 1 0- 1 0. Risk for Postnata l U r i n a ry Abnorm a l ity Accord i n g to Deg ree of Ren a l Pelvis Di l atationa Dilatation

M i ld Moderate Severe

Second Trimester

4 to < 7 m m 7 to � 1 0 m m > 1 0 mm

Third Tri mester

7 to 1 5 mm

aSociety for Feta l U rology Classifi catio n . Mod ified from Lee, 2006; Ng uyen, 20 1 0.

Postnatal Abnormal ity

1 2% 45% 88%

include calyceal dilatation, cortical thinning, or dilatation else­ where along the urinary tract. Mild pyelectasis in the second trimester is associated with a slightly greater risk for Down syndrome and is considered a soft marker for this (Fig. 1 4-3, p. 287) . U reteropelvic Junction Obstruction. This condition is the

most common abnormality associated with renal pelvis dilata­ tion. The birth prevalence is 1 in 1 000 to 2000, and males are afected three times more often than females (Williams, 2007; Woodward, 2002) . Obstruction is generally functional rather than anatomical, and it is bilateral in up to a fourth of cases. he likelihood of ureteropelvic junction obstruction rises from 5 percent with mild renal pelvis dilatation to more than 50 percent with severe dilatation (Lee, 2006) . D u p l i cated Ren a l Col lecti ng System. In this anatomical anomaly, the upper and lower poles of the kidney-called moieties-are each drained b) a separate ureter (Fig. 1 0-42) . Duplication i s found i n approximately 1 in 4000 pregnan­ cies, is more common in females, and is bilateral in 1 5 to 20 percent of cases (James, 1 99 8 ; Vergani, 1 998; Whitten, 200 1 ) . Sonographically, an intervening tissue band separates two distinct renal pelves . Development of hydronephrosis or ureteral dilatation may occur due to abnormal implan­ tation of one or both ureters within the bladder-a rela­ tionship that refl e cts the anatomical Weigert-Meyer rule. The upper pole ureter may develop obstruction from a uretero­ cele within the bladder, whereas the lower pole ureter has a shortened intravesical segment that predisposes to vesico­ ureteral reflux (see Fig. 1 0-42B) . Thus, both moieties may become dilated from diferent etiologies, and both are at risk for loss of function.

Renal Ag enesis

The prevalence of bilateral renal agenesis is approximately in 8000 births, whereas that of unilateral renal agenesis is 1 in

Feta l l ma g i ng

FIGURE 1 0-42 D u pl icated renal col lecti n g system. The upper a n d lower moieties of the kid ney a re each d ra i ned by a sepa rate u reter. A. Ren a l pelvis d i l atation is visible in both the u pper (U) a n d lower (L) pole moieties, which a re sepa rated by an i nterve n i n g b a n d of ren a l tissue (arrowhead). B . T h e bladder, encirc led b y t h e h i g h l i g hted u m bi l ical a rteries, conta i n s a u reterocele (arrowhead ) . 1 000 births (Cragan, 2009; Dolk, 20 1 0; Sheih, 1 989; Wiesel, 2005). When a kidney is absent, color Doppler imaging of the descending aorta demonstrates absence of the ipsilateral renal artery (Fig. 1 0-43) . In addition, the ipsilateral adrenal gland typically enlarges to ill the renal fossa, termed the ying down adrenal sin (Hofman, 1 992) . As with other fetal anomalies, amniocentesis for chromosomal microarray analysis should be considered. If renal agenesis is bilateral, no urine is produced, and the resulting anhydramnios leads to pulmonary hypoplasia, limb contractures, and a distinctively compressed face. When this combination results from renal agenesis, it is called Poter syn­ drome, after Dr. Edith Potter, who described it in 1 946. When these abnormalities result from severely decreased amnionic luid volume from another etiology, such as bilateral multicys­ tic dysplastic kidney or autosomal recessive polycystic kidney

disease, it is called Poter sequence. he prognosis for these abnormalities is extremely poor. M u lticystic Dys p l a stic Kid ney

This severe form of renal dysplasia results in a nonfunction­ ing kidney. The nephrons and collecting ducts do not form normally, such that primitive ducts are surrounded by ibro­ muscular tissue, and the ureter is atretic (Hains, 2009). S ono­ graphically, the kidney contains numerous smooth-walled cysts of varying size that do not communicate with the renal pelvis and are surrounded by echogenic cortex (Fig. 1 0-44) . Unilateral multicystic dysplastic kidney (MCDK) has a prev­ alence of 1 in 4000 births. Contralateral renal abnormalities are present in 30 to 40 percent-most frequently vesicoureteral relux or ureteropelvic j unction obstruction (Schreuder, 2 009) . Nonrenal anomalies have been reported in 2 5 percent of cases,

FIGURE 1 0-43 Ren a l agenesis. A. l n this coronal i m a ge of the feta l abdomen, color Doppler shows the cou rse of the abdom i na l aorta. The u ltraso u n d bea m is perpendicular to the aorta, demonstrati n g a bsence of the ren a l a rteries bi latera lly. B. This coronal image of a fetus with u n i latera l ren a l agenesis shows the a d renal g la n d (arrowheads) fi l l i n g the rena l fossa, termed the "lyi n g-down" a d renal sig n . The a d renal g la nd has a hypoechoic cortex a nd hyperechoic med u l l a .

209

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The Feta l Patient

FIGURE 1 0-44 M u lticystic dysplastic kid neys. Coronal view of the fetal abdomen demonstrates ma rkedly e n l a rged kid neys conta in­ i n g mu ltiple cysts of va rying s izes that do not com m u n icate with a ren a l pelvis. and cystic dysplasia may occur as a component of many genetic syndromes (Lazebnik, 1 999; Schreuder, 2009) . If MCDK is isolated and unilateral, the prognosis is generally good. Bilateral MCDK is found in approximately 1 in 1 2,000 births. It is associated with severely decreased amnionic luid volume starting early in gestation. his leads to Potter sequence and a poor prognosis (Lazebnik, 1 999) . Polycystic Kid ney D isease

Of the hereditary polycystic diseases, only the infantile form of autosomal recessive poyystic kidney disease (APD) may be reliably diagnosed prenatally. ARPKD is a chronic, progressive disease of the kidneys and liver that results in cystic dilatation of the renal collecting ducts and in congenital hepatic ibro­ sis (Turkbey, 2009) . he carrier frequency of a disease-causing mutation in the PHDI gene approximates 1 in 70, and the disease prevalence is 1 in 20,000 (Zerres, 1 998). he phenotypic variability of ARPKD ranges from lethal pulmonary hypoplasia at birth to presentation in late childhood or even adulthood with predominantly hepatic manifestations. Sonographically, infantile ARPKD displays abnormally large kidneys that ill and distend the fetal abdomen and have a solid, ground-glass texture. Severe oligohydramnios confers a poor prognosis. Autosomal dominant poyystic kidney disease ADPD), which is far more common, usually does not manifest until adulthood (Chap. 53, p. 1 03 1 ) . Even so, some fetuses with AD PKD have mild renal enlargement and enhanced renal echogenicity in the setting of normal amnionic luid volume. he diferential diagnosis for these findings includes several genetic syndromes, aneuploidy, or normal variant. Bladder Outlet O bstruction

Distal obstruction of the urinary tract is more frequent in male fetuses, and the most common etiology is posterior urethral valves. Characteristically, the bladder and proximal urethra are dilated, termed the "keyhole" sign, and the bladder wall is thick (Fig. 1 0-4 5) . Oligohydramnios, particularly before

FIGURE 1 0-45 Posterior u reth ra l va lve. In this 1 9-week fetus with severe bladder outlet obstruction, the b ladder is d i lated and thick­ wa l led, with d i l atation of the proxi m a l u rethra that resem bles a "keyhole." Adjacent to the bladder is a n e n l a rged kid ney with evi­ dence of cystic dysplasia, conferring a poor prog nosis. midpregnancy, portends a poor prognosis because of pulmonary hypoplasia. Unfortunately, the outcome may be poor even with normal amnionic fluid volume. Evaluation includes a careful search for associated anomalies, which may occur in 40 percent of cases, and for aneuploidy, which has been reported in 5 to 8 percent (Hayden, 1 988; Hobbins, 1 984; Mann, 20 1 0) . If nei­ ther are present, afected male fetuses with severe oligohydram­ nios who have fetal urinary electrolytes suggesting a potentially favorable prognosis may be fetal therapy candidates. Evaluation and treatment of fetal bladder outlet obstruction is discussed in Chapter 16 (p. 325). • Skeletal Abnormalities

The 20 1 5 revision of the Nosology and Classification of Genetic Skeletal Disorders includes an impressive 436 skeletal anomalies in 42 groups, characterized by genetic abnormalities, phenotypic features, or radiographic criteria (Bonafe, 20 1 5) . h e two types o f skeletal dysplasias are osteochondrodyspasias­ the generalized abnormal development of bone and/or cartilage, and dysostoses-which are abnormalities of individual bones, for example, poydacyy. In addition to these maormations, skel­ etal abnormalities include dormations, as with some cases of clubfoot, and disruptions such as limb-reduction defects. S ke leta l Dysplasias

The prevalence of skeletal dysplasias approximates 3 in 1 0,000 births. Two groups account for more than half of all cases: the ibroblast growth octor 3 (FGF3) chondrodysplasia group and the osteogenesis impeecta and decreased bone density group. Each occurs in 0.8 in 1 0 ,000 births (Stevenson, 20 1 2) . Evaluation o f a pregnancy with suspected skeletal dyspla­ sia includes a survey of every long bone, as well as the hands and feet, skull size and shape, clavicles, scapulae, thorax, and spine. Reference tables are used to determine which long bones are afected and ascertain the degree of shortening (Appendix,

Feta l l m a g i ng

p. 1 267) . Involvement of all long bones is termed micromelia, whereas predominant involvement of only the proximal, inter­ mediate, or distal long bone segments is termed rhizomelia, meso melia, and acromelia, respectively. he degree of ossiica­ tion should be noted, as should presence of bowing or frac­ tures. Each of these may provide clues to narrow the diferential diagnosis and occasionally suggest a specific skeletal dysplasia. Many, if not most, skeletal dysplasias have a genetic compo­ nent, and knowledge of specific mutations has advanced dra­ matically (Bonafe, 20 1 5) . lthough precise characterization may elude prenatal diag­ nosis, it is frequently possible to determine whether a skeletal dysplasia is lethal. Lethal dysplasias show profound long bone shortening, with measurements < 5 th percentile, and display femur length-to-abdominal circumference ratios below 1 6 per­ cent (Nelson, 20 1 4; Rahemtullah, 1 997; Ramus, 1 998). Gen­ erally, other sonographic abnormalities are evident. Pulmonary FIGURE 1 0-46 Osteogenesis i m perfecta. Type I la, which is l ethal, hypoplasia is suggested by a thoracic circumference < 80 per­ is cha racterized by such profound lack of sku l l ossification that gentle pressure on the materna l a bdomen from the u ltraso u n d cent of the abdominal circumference value, by a thoracic cir­ tra n sd ucer resu lts i n visible deformation (flatte n i n g ) o f the s k u l l cumference 50 percent of the thoracic circumference value (Appendix, p. 1 266) . Afected pregnancies also may develop hydramnios and/or hydrops (Nelson, 20 1 4) . Other features include multiple in-utero fractures and ribs that h e FGFR3 chondrodysplasias include achondroplasia and appear "beaded." Inheritance is autosomal dominant, such that thanatophoric dysplasia. Achondroplasia, also called heterozygous all cases result from either new mutations or gonadal mosaicism achondroplasia, is the most common nonlethal skeletal dyspla­ (Chap. 1 3, p. 264). Another skeletal dysplasia that results in sia. An impressive 98 percent of cases are due to a speciic point severe hypomineralization is hypophosphatasia, which has an mutation in the FGFJ gene. It has an autosomal dominant autosomal recessive inheritance. inheritance, and 80 percent of cases result from a new muta­ C l u bfoot-Ta l i pes Eq u i nova rus tion. Achondroplasia is characterized by long bone shortening that is predominantly rhizomelic, an enlarged head with frontal his disorder is notable for a deformed talus and shortened bossing, depressed nasal bridge, exaggerated lumbar lordosis, Achilles tendon. he afected foot is abnormally fixed and and a trident configuration of the hands. Intelligence is typi­ positioned with equinus (downward pointing) , varus (inward cally normal. Sonographically, the femur and humerus mea­ rotation), and forefoot adduction. Most cases are considered surements may not lie below the 5 th percentile until the early malformations, with a multifactorial genetic component. third trimester. hus, this condition is usually not diagnosed However, an association with environmental factors and with until late in pregnancy. In homozygotes, which represent 2 5 early amniocentesis suggests that deformation also plays a role percent of the ofspring of heterozygous parents, the condition (Tredwell, 200 1 ) . Sonographically, the footprint is visible in is characterized by greater long bone shortening and is lethal. the same plane as the tibia and ibula (Fig. 1 0-47) . he other major class of FGFR3 dysplasias, thanatophoric h e prevalence o f clubfoot approximates 1 i n 1 000 births, dysplasia, is the most common lethal skeletal disorder. It is char­ and the male:female ratio is 2: 1 (Carey, 2003; Pavone, 2 0 1 2) . acterized by severe micromelia, and afected fetuses-particu­ Clubfoot i s bilateral i n approximately 50 percent o f afected individuals, and associated anomalies are present in at least 50 larly those with type II-may develop a characteristic cloverleaf skull deformity (Kleeblattschade) due to craniosynostosis. More percent of all cases (lv fammen, 2004; Sharma, 20 1 1 ) . Frequently than 99 percent of cases may be confirmed with genetic testing. Osteogenesis impeecta represents a group of skeletal dysplasias typiied by hypomineralization. here are mul­ tiple types, and more than 90 percent of cases are characterized by a muta­ tion in the COLIAI or COLIA2 gene. Type IIa, also called the perinatal form, is lethal. It displays a profound lack of skull ossification, such that gentle pres­ sure on the maternal abdomen from FIGURE 1 0-47 Foot position. A. N o r m a l fetal lower leg, demonstrating n o r m a l positi o n of the ultrasound transducer results in the foot. B. With ta l i pes eq u i n ova rus, the foot "print" is visible in the same p l a n e as the tibia visible skull deformation (Fig. 1 0-46) . a n d fi bula.

21 1

21 2

The Feta l Patient

associated anomalies include neural­ tube defects, arthrogryposis, and myo­ tonic dystrophy and other genetic syndromes. In cases with associated anomalies, aneuploidy is found in approximately 30 percent. In contrast, the rate is < 4 percent when club­ foot appears isolated (Lauson, 20 1 0; Sharma, 20 1 1 ) . hus, a careful search for associated structural abnormalities is warranted, and chromosomal microar­ ray analysis may be considered. L i m b-Red u ctio n Defects

FIGURE 1 0-48 Tra nsverse l i m b-red uction defect. A. At 1 8 weeks' gestation, o n ly a rud i­ Documentation of the arms and legs is menta ry h a nd was visi ble. B. By 24 weeks, the rad i u s a n d u l na were normal in size a nd a component of the standard examina­ a p pearance, a n d s m a l l rud i m enta ry d i g its were evident. tion. he absence or hypoplasia of all or part of one or more extremities is a limb-reduction dect. he birth prevalence is 4 to 8 in 1 0,000 in "real time," 3-D imaging is static and obtained by processing (Kucik, 20 12; Stoll, 20 1 0; Vasluian, 20 1 3) . Approximately half a volume of stored images. With our-dimensional (4-DJ sonog­ of these are isolated defects, up to on� third occur as part of a raphy, also known as real-time 3-D sonography, rapid recon­ recognized syndrome, and individuals in the remaining cases struction of the rendered images conveys the impression that have other coexisting anomalies (Stoll, 20 1 0; Vasluian, 20 1 3) . the scanning is in real time. Upper extremities are afected more frequently than lower ones. For 4-D imaging, one application known as spatiotemporal Of categories, a terminal transverse limb dect lacks part or all image co rrelatio n-S TIC improves visualization of cardiac anat­ of a distal limb to create a stump (Fig. 1 0-48) . his is more omy. During an automated sweep over the heart, the STIC common than a longitudinal dect, which is complete or par­ application acquires a volume that includes thousands of 2D tial absence of the long bone(s) on only one side of a given images captured at a rate as high as 1 50 frames per second extremity. (Devore, 2003) . These individual images are obtained at difer­ Absence of an entire extremity is termed amelia. Phocomelia, ent locations in the heart but at the same point in time. These associated with thalidomide exposure, is an absence of one or views are subsequently arranged according to their spatial and more long bones with the hands or feet attached to the trunk temporal domains. his permits display of an ordered sequence (Chap. 1 2, p. 246) . Limb-reduction defects are associated of volume sets in a continuous cine loop (or video clip) of the with numerous genetic syndromes, such as Roberts syndrome, cardiac cycle (Yeo, 20 1 6) . For example, after obtaining a volume an autosomal recessive condition characterized by tetraphoco­ sweep over the cardiac apex, an application such as Fetal Intel­ melia. A clubhand dormiy, usually from an absent radius, ligent Navigation Echocardiography (FINE) can be applied to is associated with trisomy 1 8 and is also a component of the thrombocytopenia-absent radius syndrome (Fig. 1 3-5B, p. 258). Limb-reduction defects may occur in the setting of a disrup­ tion such as amnionic-band sequence (Chap. 6, p. 1 1 6) . hey have also been associated with chorionic villus sampling when performed before 1 0 weeks' gestation (Fig. 1 4-6, p. 294) . THREE - AND FOU R- DIMEN SIONAL SONOGRAPHY During the past two decades, three-dimensional (3-D) sonog­ raphy has gone from a novelty to a standard feature of most modern ultrasound equipment (Fig. 1 0-49) . 3-D sonography is not routiney used during a standard examination nor consid­ ered a required modality. However, it may be a component of specialized evaluations. Most 3-D scanning uses a special transducer developed for this purpose. After a region of interest is identiied, a 3-D vol­ ume is acquired that can be rendered to display axial, sagittal, coronal, or oblique images. Sequential "slices" may be gener­ ated, similar to computed tomographic (CT) or MR images. Unlike two-dimensional (2-D) scanning, which appears to be

FIGURE 1 0-49 Feta l face. Su rface rendered th ree-d i mensional i mage of a normal feta l face a n d hand at 32 weeks.

Feta l l m a g i ng

display videos of each of the diferent cardiac views shown in Fig. 1 0-28 (Garcia, 20 1 6) . It is hoped that such technology may eventually improve detection of fetal cardiac anomalies. For selected anomalies, such as those of the face and skel­ eton, for tumors, and for some cases of neural-tube defects, 3-D sonography can add useful information (American College of Obstetricians and Gynecologists, 20 1 6; Goncalves, 2005) . That said, comparisons of 3-D and conventional 2-D sonography for the diagnosis of most congenital anomalies have not demon­ strated better overall detection rates (Goncalves, 2006; Reddy, 2008) . The American College of Obstetricians and Gynecolo­ gists (20 1 6) concludes that proof of a clinical advantage of 3-D sonography for prenatal diagnosis is generally lacking.

DOPPLER hen sound waves strike a moving target, the frequency of the waves reflected back is shifted in proportion to the velocity and direction of that moving target-a phenomenon known as the Doppler sht. Because the magnitude and direction of the frequency shift depend on the relative motion of the moving target, Doppler can help evaluate low within blood vessels. The Doppler equation is shown in Figure 1 0-50. n important component of the equation is the angle of insonation, abbreviated as theta (8) . This is the angle between the sound waves from the transducer and low within the vessel. Measurement error becomes large when 8 is not close to zero, in other words, when blood fl o w is not coming directy toward or away from the transducer. For this reason, ratios are often used to compare diferent waveform components, allowing cosine 8 to cancel out of the equation. Figure 1 0-5 1 is a schematic of the Doppler waveform and describes the three ratios commonly used. he simplest is the systolic-diastolic ratio (SID ratio), which compares the maximal (or peak) systolic low with end-diastolic flow to evaluate downstream impedance to flow. Currently, two types of Doppler modalities are available for clinical use. Continuous-wave Doppler equipment has two separate types of crystals-one transmits high-frequency sound waves, and

�

anSducer

, ,

fd

=

2 fo

VC�S e

I ,

,

Artery

FIGURE 1 0-50 Doppler equation. U ltrasound emanating from the transducer with i n itia l frequency fo strikes blood moving at velocity v. Reflected frequency fd is dependent on a ng l e e between bea m of sou nd a n d vessel .

S D $-D S S-D M ean

=

=

=

SID Ratio Resistance index Puls ati l ity i ndex

FIGURE 1 0-51 Doppler systol ic-d iasto l i c waveform i n d ices of blood flow velocity. S represents the pea k systo l ic flow or velocity, a nd D i n d icates the end-d iastolic flow or velocity. The mean, which is the ti me-average mea n velocity, i s ca lcu lated from computer­ d i g itized waveforms. another continuously captures signals. In M-mode imaging, continuous-wave Doppler is used to evaluate motion through time, however, it cannot image individual vessels. Pulsed-wave Doppler uses only one crystal, which transmits the signal and then waits until the returning signal is received before transmitting another one. It allows precise targeting and visualization of the vessel of interest. Pulsed-wave Dop­ pler can be conigured to allow color-low mapping-such that blood flowing toward the transducer is displayed in red and that flowing away from the transducer appears in blue. Vari­ ous combinations of pulsed-wave Doppler, color-flow Doppler, and real-time sonography are commercially available. • U mbilical Artery

Umbilical artery Doppler has been subjected to more rigorous assessment than any previous test of fetal health. he umbili­ cal artery difers from other vessels in that it normally has for­ ward low throughout the cardiac cycle. Moreover, the amount of low during diastole increases as gestation advances, and this reflects decreasing placental impedance. As a result, the SID ratio normaly declinesrom approximatey 4. 0 at 20 weeks ' gestation, to generaly less than 3. 0 ter 30 weeks ' and inaly to 2. 0 at term. Because of downstream impedance to low, more end-diastolic low is observed at the placental cord insertion than at the fetal ventral wall. hus, abnormalities such as absent or reversed end­ diastolic low will appear first at the fetal cord insertion site. The International Society of Ultrasound in Obstetrics and Gynecol­ ogy recommends that umbilical artery Doppler measurements be made in a free loop of cord (Bhide, 20 1 3) . H owever, assess­ ment close to the ventral wall insertion may optimize measure­ ment reproducibility when low is diminished (Berkley, 20 1 2) . The waveform i s considered abnormal i f the SID ratio is > 95th percentile for gestational age. In extreme cases of growth restriction, end-diastolic flow can become absent or even

21 3

214

The Feta l Patient

reversed (Fig. 44-8, p. 8 54) . Such reversal of end-diastolic flow has been associated with greater than 70-percent obliteration of the small muscular arteries in placental tertiary stem villi (Kingdom, 1 997; Morrow, 1 989). As described in Chapter 44 (p. 854), umbilical artery Dop­ pler aids management of fetal-growth restriction and has been associated with improved outcome in these cases (American College of Obstetricians and Gynecologists, 20 1 5) . It is not recommended for complications other than growth restriction. Similarly, its use for growth-restriction screening is not advised (Berkley, 20 1 2) . Abnormal umbilical artery Doppler findings should prompt a complete fetal evaluation, if not already done, because abnormal measurements are associated with major fetal anomalies and aneuploidy (Wenstrom, 1 99 1 ) .

Doppler waveform is characterized by high diastolic low veloc­ ities and markedly turbulent flow. Greater resistance to flow and development of a diastolic notch are associated with later development of gestational hypertension, preeclampsia, and fetal-growth restriction. Zeeman and coworkers (2003) also found that women with chronic hypertension who had elevated uterine artery impedance at 1 6 to 20 weeks' gestation were at greater risk to develop superimposed preeclampsia. However, the technique, best testing interval, and defining criteria for this indication have not been standardized. As the predictive value of uterine artery Doppler testing is considered to be low, its use for screening or for clinical decision-making is not recom­ mended in either high-risk or low-risk pregnancies (Sciscione, 2009) .

• Ductus Arteriosus

• Middle Cerebral Artery

Doppler evaluation of the ductus arteriosus has been used pri­ marily to monitor fetuses exposed to indomethacin and other nonsteroidal antiinlammatory agents (NSAIDs) . Indometh­ acin, which is used by some for tocolysis, may cause ductal constriction or closure, particularly when used in the third tri­ mester (Huhta, 1 987) . The resulting increased pulmonary flow can cause reactive hypertrophy of the pulmonary arterioles and eventual development of pulmonary hypertension. In a review of 1 2 randomized controlled trials involving more than 200 exposed pregnancies, Koren and coworkers (2006) reported that NSAIDs raised the odds of ductal constriction 1 5-fold. When these agents are indicated, their duration is typically lim­ ited to less than 72 hours. And, women taking NSAIDs are closely monitored so that these can be discontinued if ductal constriction is identified. Fortunately, ductal constriction is often reversible after NSAID discontinuation. • Uterine Artery

Uterine blood low is estimated to rise from 50 mLlmin early in gestation to 500 to 750 mLlmin by term. he uterine artery

Doppler interrogation of the middle cerebral artery (MCA) has been investigated and applied clinically for fetal anemia detec­ tion and fetal-growth restriction evaluation. Anatomically, the path of the MCA is such that flow often approaches the trans­ ducer "head-on," allowing for accurate determination of low velocity (Fig. 1 0-52) . he M CA is imaged in an axial view of the head at the base of the skull, ideally within 2 mm of the internal carotid artery origin. Velocity measurement is optimal when the insonating angle is close to zero, and no more than 30 degrees of angle correction should be used. In general, veloc­ ity assessment is not performed in other fetal vessels, because a larger insonating angle is needed and confers significant mea­ surement error. When fetal anemia is present, the peak systolic velociy is enhanced due to greater cardiac output and decreased blood viscosity (Segata, 2004) . This has permitted the reliable, nonin­ vasive detection of fetal anemia in cases of blood-group alloim­ munization. Mari and colleagues (2000) demonstrated that an MCA peak systolic velocity threshold of 1 .50 MoM could reliably identiy fetuses with moderate or severe anemia. As discussed in Chapter 1 5 (p. 303), MCA peak systolic velocity has replaced

FIGURE 1 0-52 Middle cerebra l a rtery (MCA) Doppler. A. Color Doppler of the circle of Wi l l is, demonstrating the correct location to sa m ple the MCA. B. The waveform demonstrates a peak systolic velocity exceed i n g 70 cm/sec i n a 32-week fetu s with severe feta l a nemia second­ a ry to Rh a l l oi m m u n ization.

Feta l l ma g i n g

invasive testing with amniocentesis as the preferred test for fetal anemia detection (Society for Maternal-Fetal Medicine, 20 1 5) . MCA Doppler has also been studied a s a n adjunct i n evalu­ ation of fetal-growth restriction. Fetal hypoxemia is believed to result in increased blood flow to the brain, heart, and adre­ nal glands, leading to greater end-diastolic low in the MCA. his phenomenon, "brain-sparing," is actually a misnomer, as it is not protective for the fetus but rather is associated with perinatal morbidity and mortality (Bahado-Singh, 1 999; Cruz­ Martinez, 20 1 1 ) . The utility ofMCA Doppler to aid the timing of delivery is uncertain. It has not been evaluated in random­ ized trials or adopted as standard practice in the management of growth restriction (American College of Obstetricians and Gynecologists, 20 1 5 ; Berkley, 20 1 2) . • Ductus Venosus

he ductus venosus is imaged as it branches from the umbilical vein at approximately the level of the diaphragm. Fetal position poses more of a challenge in imaging the ductus venosus than it does with either the umbilical artery or the middle cerebral artery. he waveform is biphasic and normally has forward flow through­ out the cardiac cycle. The irst peak reflects ventricular systole, and the second is ventricular diastolic illing. These are followed by a nadir during atrial contraction-termed the a-wave. It is believed that Doppler indings in preterm fetuses with growth restriction show a progression in which umbilical artery Doppler abnormlities are followed by ones in the middle cerebral artery and then in the ductus venosus. However, manifestations of these abnormalities vary widely (Berkley, 20 1 2) . With severe fetal-growth restriction, cardiac dysfunction may lead to low in the a-wave that is decreased, absent, and eventually reversed, along with pulsatile low in the umbilical vein (Fig. 1 0-53). Ductus venosus abnormalities have potential t o iden­ tiy preterm growth-restricted fetuses that are at greatest risk for adverse outcomes (Baschat, 2003, 2004; Bilardo, 2004; Figueras, 2009) . As noted by the Society for Maternal-Fetal Medicine, however, they have not been suiciently evaluated in randomized trials (Berkley, 20 1 2) . In sum, Doppler assessment of vessels other than the umbilical artery has not been shown to improve perinatal outcome, and thus their role in clinical practice remains uncertain (American College of Obstetricians and Gynecologists, 20 1 5) .

FIGURE 1 0-53 Venous Doppler a bn o rma l ities. A. Reversa l of a-wave flow i n the ductus venosus. Arrows depict a-waves below the baseli ne. This fi nding may be identified with ca rdiac dysfu nc­ tion in the setting of severe feta l-g rowth restriction. B. Pu lsati le flow in the u m bi l ica l vei n . The u nd u lating u m b i l ical venous wave­ form below the baseline i nd icates tricuspid reg u rg itation. Above the base l i n e is the u m bi l ica l a rtery waveform, in which there is no visible e nd-d iastolic flow. Beca u se the ven o u s waveform is below the base l i n e in this image, it is not possible to determ i ne whether the u m b i l ica l a rtery end-diastolic flow i s reversed.

MAGN ETIC RESONANCE IMAGING Image resolution with MR is oten superior to that with sonog­ raphy because it is not as hindered by bony interfaces, maternal obesity, oligohydramnios, or an engaged fetal head. Thus, it can serve as an adjunct to sonography in evaluating suspected fetal abnormalities. Examples include complex abnormalities of the fetal CNS, thorax, gastrointestinal system, genitourinary system, and musculoskeletal system. MR has also been used in the evalu­ ation of maternal pelvic masses and placental invasion. MR imag­ ing, however, is not portable, it is time-consuming, and its use is generally limited to referral centers with expertise in fetal imaging. To guide clinical use, the American College of Radiology and Society for Pediatric Radiology (20 1 5) have developed

a practice guideline for fetal MR imaging. This document acknowledges primacy of sonography as the preferred screen­ ing modality. Moreover, it recommends that fetal MR imaging be used for problem solving to ideally contribute to prenatal diagnosis, counseling, treatment, and delivery planning. Spe­ cific indications for fetal MR imaging are listed in Table 1 0- 1 1 and are discussed subsequently. • Safety

MR imaging uses no ionizing radiation, but theoretical con­ cerns include the efects of luctuating electromagnetic ields and high sound-intensity levels. The strength of the magnetic

215

21 6

The Feta l Patient

TABLE 1 0-1 1 . Feta l Conditions for Which Mag netic Reso n a n ce I mag i n g May Be I n d icateda Brain and spine

Agenesis of the corpus cal losurn

Ventriculomegaly

Cavum sept u m pel lucid u m a bnorma l ities H o l o p rosencepha Iy Poste rior fossa a b n o r m a l ities Cerebral cortical ma lformation o r m i g ratio n a l a b norm a l ities Ce p h a l ocel e S o l i d o r cyJti c m a sses Vasc u l a r ma lfo rmations Hyd ra n encephaly I nfarction. Hemorrhage Monochorio n i c twi n p reg n a ncy compl ications N e u ra l -t u be defects Sacrococcygea l terato ma Sacra l a g e n esis (ca u d a l reg ressi on) S i renomelia Verteb ra l a n o m a l ies Fa m i ly h i s Lory conferring a risk for b ra i n a n o m a ly

Skull, face, and neck

Ve nolym phatic ma Iformations H e m a n g iomas Go iter Terato mas Facia l clefts Other a bnorm a l ities with pote ntial a i rway obstruction

Thorax Congen ital cystic adenomatoid ma lformation Extra lobar p u l mo n a ry seq uestration B ronchogenic cyst or congen ita l lobar overi nflation D i a p h rag matic hernia Efusions Med i a st i n a l ma sses Assess ment for eso phageal atresia Eva l uation of p u l monary hypoplasia secondary to d iaphrag matic hernia, ol igohyd ra m n ios, chest mass, or ske!eta l dysplasia

Abdomen, pelvis, and retroperitoneum Abdo m i nopelvic cystic mass eva l uation Tu mor eva l uation (sacrococcygeal terato ma, n e u robl astoma, hema ngioma, s u prare n a l or re n a l m a sses) Complex genito u r i n a ry a n o m a l ies (bladder outl et o bstruction synd romes, bladder exstrophy, cloaca l exstrophy) Assess re n a ! a n omal ies with o l igohyd ra m n ios Diag nose bowel a n o m a l i e s (a norectal m a lfor mat ions, complex o bstructions)

Com plications of monochorionic twins Deter m i ne vascu l a r a n atomy prior to la ser t reatment Assess m o rbid ity ater d eath of a m o nocho rionic co-twi n Eva l u ate conjoi ned twi ns

Fetal surgery assessment Feta l bra i n a n atomy before a n d after s u rg ical i ntervention A n o m a l ies for which feta l s u rgery is p l a n ned aln some cases, magnetic resona nce

(MR)

imaging is i n d icated

o n ly if the a n omaly is su spec ed but ca n not be adequately cha racterized sonog ra phical ly, vvhich i s assessed on a case-by­ case basis.

Data from Am erica n Col lege of Radio logy, 20 1 5 .

field is measured in tesLa (), and most imaging studies dur­ ing pregnancy are performed using 1 . 5 T. A few preliminary studies advocate the use of 3 T for fetal imaging to potentially improve signal-to-noise ratios and thus image clarity (Victoria, 20 1 6) . For safety, all clinical examinations must adhere to the speciic absorption rate, which is regulated by the Food and Drug Administration, and the ALARA principle should be fol­ lowed. Thus, for routine clinical examinations, the lower ield strength of 1 . 5 T is recommended (Prayer, 20 1 7) . Human and tissue studies support the safety o f fetal MR imaging. Repetitive exposure of human lung fibroblasts to a static 1 . 5-T magnetic ield does not afect cellular prolifera­ tion (Wiskirchen, 1 999) . Fetal heart rate patterns have been evaluated before and during MR imaging, and no signiicant diferences were observed (Vadeyar, 2000) . Children exposed to MR as fetuses do not show a greater incidence of disease or disability when tested at age 9 months or 3 years (Baker, 1 994; Clements, 2000) . Glover and associates ( 1 995) attempted to mimic the sound level experienced by the fetal ear by having an adult volun­ teer swallow a microphone while the stomach was illed with a liter of luid to represent the amnionic sac. Sound intensity was attenuated at least 30-dB from the body surface to the fluid­ filled stomach and reduced the sound pressure from 1 20 dB to below 90 dB. This level is considerably less than the 1 35 dB experienced from vibroacoustic stimulation used in ante­ partum well-being assessments (Chap. 1 7, p. 337) . Cochlear function testing in infants exposed to 1 . 5-T MR imaging as fetuses showed no hearing impairment (Reeves, 20 1 0) . he American College o f Radiology (20 1 3) concludes that based on available evidence, MR imaging has no documented deleterious efects on the developing fetus. Therefore, MR imag­ ing can be performed in pregnancy if data are needed to care for the fetus or mother. Health-care providers who are pregnant may work in and around an MR unit, but it is recommended that they not remain in the MR scanner magnet room-known as Zone IV-while an examination is in progress. Gadolinium-based MR contrast agents are gadolinium (Gd3 +) chelates. These contrast agents readily enter the fetal circulation and are excreted via fetal urination into amnionic luid, where they may remain for an indeterminate period before being ingested and reabsorbed. he longer the gadolinium-che­ late molecule remains in a protected space such as the amnionic sac, the greater the potential for dissociation of the toxic Gd3 + ion. Accordingly, gadolinium contrast should be avoided dur­ ing pregnancy because of this potential for dissociation. Routine use of gadolinium is not recommended unless there are over­ whelming potential benefits (American College of Radiology, 20 1 3) . In adults with renal disease, this contrast agent has been associated with development of nephrogenic systemic fibrosis, a potentially severe complication. • Technique

Before MR examination, all women complete a written safety questionnaire that includes information about metallic implants, pacemakers, or other metal- or iron-containing devices that may alter the study (American College of Radiology, 20 1 3) .

Fetal l m a g i n g

Iron supplementation may cause artifact in the colon but does not usually afect the resolution of fetal images. In more than 4000 MR procedures performed at Parkland Hospital in preg­ nancy during the past 1 5 years, maternal anxiety secondary to claustrophobia and/or fear of MR equipment has developed in less than 1 percent of our patients. To reduce maternal anxiety in this small group, a single oral dose of diazepam, 5 to 1 0 mg, or lorazepam, 1 to 2 mg, may be given. To begin an MR examination, women are placed in a supine or left lateral decubitus position. A torso coil is used in most circumstances to send and receive the radiofrequency pulses, but a body coil can be used alone to accommodate large mater­ nal habitus. A series of three-plane localizers, or scout views, are obtained relative to the maternal coronal, sagittal, and axial planes. he gravid uterus is imaged in the maternal axial plane (7-mm slices, 0 gap) with a T2-weighted fast acquisition. Typically, these may be a single-shot fast spin echo sequence (SSFSE) , half-Fourier acquisition single-shot turbo spin echo (HASTE) , or rapid acquisition with relaxation enhancement (AE) , depending on the brand of machine. Next, a fast T 1 -weighted acquisition such as spoiled gradient echo (SPGR) is performed (7-mm thickness, 0 gap) . hese large-field-of-view acquisitions through the maternal abdomen and pelvis are par­ ticularly good for identiying fetal and maternal anatomy. Orthogonal images of targeted fetal or maternal structures are then obtained. In these cases, 3- to 5-mm slice thickness, o gap T2-weighted acquisitions are performed in the coro­ nal, sagittal, and axial planes. Depending on the anatomy and underlying suspected abnormality, T 1 -weighted images can be performed to evaluate for subacute hemorrhage, fat, or location of normal structures that appear bright on these sequences, such as liver and meconium in the colon (Brugger, 2006; Zaretsky, 2003b) . Short Tl inversion recovey (STIR) and frequency-selective fat-saturated T2-weighted images may provide diferentiation in cases in which the water content of the abnormality is simi­ lar to that of the normal structure. An example is a thoracic mass compared with normal lung. Difusion-weighted imaging may be employed to evaluate for restricted difusion, which can be seen in ischemia, cellular tumors, or clotted blood (Brugger, 2006; Zaretsky, 2003b) . Our series also includes an axial brain 3- to 5-mm T2-weighted sequence to obtain head biometry for gestational age estimation using the biparietal diam­ eter and head circumference (Reichel, 2003) .

national Society of Ultrasound in Obstetrics and Gynecology were visible at 30 weeks' gestation (Millischer, 20 1 3) . he aorta and pulmonary artery were the most diicult to evaluate. Zaretsky and coworkers (2003a) similarly found that with the exclusion of cardiac structures, fetal anatomical evaluation was possible in 99 percent of cases. Centra I Ne rvous System

For intracranial anomalies, very fast T2-weighted images pro­ duce excellent tissue contrast, and eSF-containing structures are hyperintense or bright. This allows exquisite detail of the poste­ rior fossa, midline structures, and cerebral cortex. T 1 -weighted images are used to identiy hemorrhage. eNS biometry obtained with MR imaging is comparable with that obtained using sonography (Twickler, 2002) . Nomo­ grams have been published for m ultiple intracranial structures, including corpus callosum and cerebellar vermis lengths (Garel, 2004; Tilea, 2009) . MR imaging provides valuable added information for cere­ bral abnormalities suspected sonographically (Benacerraf, 2007; Li, 20 1 2) . In early studies, MR imaging changed the diagnosis in 40 to 50 percent of cases and afected management in 1 5 to 5 0 percent (Levine, 1 999b; Simon, 2000; Twickler, 2 003) . Additional information is more likely to be gained when the examination is performed beyond 24 weeks' gestation. More recently, Griiths and associates (20 1 7) reported that M R evaluation o f suspected fetal brain anomalies identified addi­ tional indings in nearly 50 percent and changed prognosis in 20 percent. Fetuses with a cerebral abnormality may have a signiicant lag in cortical development. Levine and colleagues ( l 999a) demon­ strated that MR imaging accurately portrays cerebral gyration and sulcation patterns (Fig. 1 0-54) . Sonography permits limited evaluation of subtle migrational abnormalities, and MR imaging provides greater accuracy, particularly later in gestation. For ventriculomegaly, fetal MR imaging is selected to help identiy associated underlying eNS dysmorphology (p. 1 93) . In cases of septo-optic dysplasia, MR imaging may confi r m absence of the septum pellucidum and display hypoplastic

• Fetal Anatomical Evaluation

Whenever a fetal abnormality is identiied, indings from the afected organ and other organ systems should be thoroughly char­ acterized. Accordingly, a fetal anatomical survey is generally completed during each MR examination. In a recent prospective study, nearly 95 percent of the anatomical components recommended by the Inter-

FIGURE 1 0-54 Axi a l images of the fetal brain at 23 weeks' gestation (A) a nd at 33 weeks (8) demonstrate the normal gyration and sulcation progression d u ri n g feta l develop­

ment. These i mages were obta ined using a H a lf Fourier Acq uisition Single Shot Tu rbo Spin Echo (HASTE) sequence beca use it is relative ly motion insensitive.

21 7

218

The Feta l Patient

optic tracts (Fig. 1 0-5 5) . In other fetuses, M R imaging can also assist with identiy­ ing agenesis or dysgenesis of the corpus callosum and characterizing migrational abnormalities (Benacerraf, 2007; Li, 20 1 2; Twickler, 2003) . Another fetal MR imaging indica­ tion is evaluation of suspected intraven­ tricular hemorrhage (IVH) . Fetal IVH risk factors include atypical-appearing ventriculomegaly, neonatal alloimmune thrombocytopenia, and a monochorionic multifetal gestation complicated by demise of one fetus or by severe twin-twin transu­ FIGURE 1 0-55 Septo-optic dyspla sia. Axial (A) a n d coro n a l (B) i mages at 30 weeks' ges­ sion syndrome (Hu, 2006) . If hemorrhage tation confirm a bsence of the cavum sept u m pel l ucid u m (arrowheads) i n both. There is is seen, MR imaging characteristics may a l so associated mild ventriculomegaly (arrow). indicate which structures are involved and approximately when bleeding occurred. In oligohydramnios or maternal obesity, MR imaging may add the setting of congenital fetal infections, ,1R imaging can delin­ value (Caire, 2003). Hawkins and coworkers (2008) found eate the variable degrees of neural parenchymal abnormality and that lack of signal in a contracted fetal bladder on T2-weighted subsequent maldevelopment (Soares de Oliveira-Szejnfeld, 20 1 6) . sequences was associated with lethal renal abnormalities Aside from cerebral structure, suspected spinal dysraphisms, (F ig. 1 0-5 8) . Diferences in signal characteristics between including neural-tube defects, can also be further characterized meconium in the fetal colon and urine in the bladder may per­ for surgical planning. Figure 1 0-5 6 demonstrates a complex mit deinition of cystic abdominal abnormalities (Farhataziz, skin-covered dysraphism with associated tethering of the spinal 2005) . Given the predictable pattern of meconium accumula­ cord. his terminal myelocystocele will benefit from early inter­ tion within the gastrointestinal tract and high signal intensity vention following delivery. on T 1 -weighted sequences, MR imaging is a complementary Thorax tool in diagnosing gastrointestinal abnormalities and complex cloacal malformations (Furey, 20 1 6) . Peritoneal calciications Many thoracic abnormalities are readily seen with targeted sonog­ related to meconium peritonitis are more readily apparent raphy. MR imaging, however, may help delineate the location and size of space-occupying thoracic lesions and quantiy remaining lung tissue volumes. MR imaging can aid in characterizing the type of congenital cystic adenomatoid mal­ formation and in visualizing the blood sup­ ply of pulmonary sequestration (p. 200). With congenital diaphragmatic hernia, MR imaging can help veriy and quantiy the abdominal organs within the thorax. his includes the volume of herniated liver and compressed lung tissue volumes (Fig. 1 0-57) (Debus, 20 1 3; Lee, 20 1 1 ; Mehollin-Ray, 20 1 2) . Also in fetuses with diaphragmatic hernia, MR imaging can assist in identiying other organ-system abnormalities, which may greatly afect fetal prognosis (Kul, 20 1 2) . MR imaging simi­ larly is used for chest evaluation in skeletal dysplasia and to measure lung volumes in pregnancies with prolonged oligohydram­ nios secondary to renal disease or rup­ tured membranes (Messerschmidt, 20 1 1 ; Zaretsky, 2005). Abdomen

When sonographic viewing of fetal abdominal abnormalities is limited by

FIGURE 1 0-56 Term i n a l myelocystocele, 36 weeks' gestation. A. In this sag itta l T2-weig hted i mage, the s p i n a l cord is tethered, expa n d i n g i nto the term i n a l cyst (arrow). B. Seen in this Tl -weig hted i mage, the m e n i ngocele a nd term i n a l cyst a re covered by s u bcuta neous fat (arrows) a nd ski n .

Feta l l ma g i ng

sonographically, whereas pseudocysts and resultant abnormalities of meco­ nium migration are better delineated with MR imaging . • Adjunct to Fetal Therapy

FIGURE 1 0-57 A. Coro n a l i m a g e of n o r m a l l u n g s on a ba l a n ced seq u e n ce at 29 weeks' g estat i o n . The l iver (L) and sto m a c h (5) l ie below the d i a p h ra g m . B. Left-sided co n g e n ita l d i a p h ra g matic h e r n i a (C DH) (dotted ellipse) seen on b a l a n ced seq u e n ce at 3 3 weeks. C. The T1 -we i g h ted seq u e n ce confi r m s the s u bd i a p h ra g matic position of the l iver and bette r d e l i n eates t h e s m a l l bowe l (arrow) a n d m econ i u m-conta i n i n g colon (arrowhead) t h a t h ave h e rn iated i nto t h e ch est. D. Another i m a g e of a left-sided C D H at 22 weeks d e m o n strates no n o r m a l l u n g , the heart (H) d i s p l a ced i nto the rig ht chest, and an e levated l iver (dotted

ellipse) .

As indications for fetal therapy have grown, MR imaging is used preop­ eratively to outline abnormalities. At some centers, before laser ablation of placental anastomoses for twin-twin transfusion syndrome, MR imaging is performed to assess the fetal brain for IVH or periventricular leukoma­ lacia (Chap. 4 5 , p. 878) (Hu, 2006; Kline-Fath, 2007) . Because of its pre­ cision in visualizing brain and spine indings in cases of myelomeningo­ cele, it is often used preoperatively. For sacrococcygeal teratomas, if fetal surgery is considered, MR imaging may identiY tumor extension into the fetal pelvis (Avni, 2002; Neu­ bert, 2004; Perrone, 20 1 7) . With a fetal neck mass for which an EIT is considered, M R imaging may help delineate the lesion extent and its efect on the oral cavity, hypo­ pharynx, and trachea (Hirose, 2003; Lazar, 20 1 2; Ogamo, 2005; Shi­ raishi, 2000) . Finally, vfR imaging can also calculate a j aw index when an EIT procedure may be needed for severe micrognathia (MacArthur, 20 1 2; Morris, 2009) . Fetal therapy is discussed in Chapter 1 6 (p. 327) .

FIGURE 1 0-58 A. Sag ittal short T1 i nversion recovery (STI R) i mage t h rou g h a fetus with posterior u reth ral va lve at 23 weeks' g estation. Notice the cha racteristic di lation of t h e posterior u reth ra (arrowhead). B. At 31 weeks, a coronal image shows prog ress ion of severe hyd ro­ nephrosis, cystic cha nges in the pa ren chyma, hyd rou reter, a n d a n hyd ra m n ios. The l u n g s (L) show a decreased sig n a l a nd a re s m a l l . C. A n axia l ba la nced seq uence shows a d istended b ladder (B) with thickened wa l l (arrows) .

219

220

The Feta l Patie nt • Placenta

The clinical importance of identiying women with placenta accreta is discussed in Chapter 4 1 (p. 777) . Sonography is gen­ erally used to identiy placental invasion into the myometrium, however, MR evaluation is an adjunct for indeterminate cases. Findings concerning for invasion include dark intraplacental bands on T2-weighted images, focal bulging, and placental heterogeneity (Leyendecker, 20 1 2) . When used in a comple­ mentary role, MR imaging sensitivity is high for detection of placental invasion, although the depth of invasion is diicult to predict. Clinical risk factors and sonographic indings should be taken into account when interpreting MR placental images. • Emerging Concepts

Of these, MR difusion tensor imaging and tractography may allow urther understanding of neural development and more precise defi n ition of abnormality and pathology (Kasprian, 2008; Mitter, 20 1 5) . Automatic and semiautomated extraction of quantitative data from MR imaging volumetric acquisitions of fetal brain and placenta may enable subanalyses of massive data­ sets not previously possible with laborious manual segmentation (Tourbier, 20 1 7; Wang, 20 1 6) . Using multiparametric MR of the placenta in vivo will expand our understanding of function and pathology without risk to mother or fetus. Last, although echocardiography will always be paramount in fetal heart assess­ ment, MR imaging may contribute to volumetric cardiac analysis and will urther evaluation of the aorta, which is oten diicult to completely examine sonographically (Lloyd, 20 1 7) .

Avni FE, Guibaus L, Robert Y, et al: MR imaging of fetal sacrococcygeal tera­ toma: diagnosis and assessment. AJR Am J Roentgenol 1 78 ( 1 ) : 1 79, 2002 Axt-Fliedner R, Schwarze A, Smrcek J , et al: Isolated ventricular septal defects dated by color Doppler imaging: evolution during fetal and first year of postnatal life. Ultrasound Obstet Gynecol 27:266, 2006 Azizkhan RG, Crombleholme TM: Congenital cystic lung disease: contempo­ rary antenatal and postnatal management. Pediatric Surg Int 24:643, 2008 Bahado-Singh RO, Kovanci E, Jefres A, et al: he Doppler cerebroplacental ratio and perinatal outcome in intrauterine growth restriction. Am J Obstet GynecoI 1 80 (3):750, 1 999 Baker PN, Johnson IR, Harvey PR, et al: A three-year follow-up of children imaged in utero with echo-planar magnetic resonance. Am J Obstet Gynecol 1 70 : 32, 1 994

Baschat A: Doppler application in the delivery timing of the preterm growth­

restricted fetus: another step in the right direction. Ultrasound Obstet

Baschat A: Relationship between placental blood low resistance and precor­ GynecoI 23 : 1 1 1 , 2004

dial venous Doppler indices. Ultrasound Obstet Gynecol 22:56 1 , 2003

Benacerraf BR, Shipp TO, Bromley B, et al: What does magnetic resonance imaging add to the prenatal sonographic diagnosis of ventriculomegaly? J Ultrasound Med 26: 1 5 1 3, 2007 Berkley E, Chauhan SP, Abuhamad A: Society for Maternal-Fetal Medicine Clinical Guideline: Doppler assessment of the fetus with intrauterine Best E , Tennant PWG, Addor M , et al: Epidemiology of small intestinal growth restriction. Am J Obstet Gynecol 206(4) :300, 20 1 2

atresia in Europe: a register-based study. Arch Dis Child Fetal Neonatal Ed 97(5) :F353 , 20 1 2

Bhide A, Acharya G , Bilardo CM, et al: ISUOG Practice Guidelines: use o f Dop­ pier ultrasonography in obstetrics. Ultrasound Obstet Gynecol 4 1 (2):233, 20 1 3 Bilardo CM, Wolf H , Stigter RH, e t al: Relationship between monitor­ ing parameters and perinatal outcome in severe, early intrauterine growth restriction. Ultrasound Obstet Gynecol 23: 1 1 9, 2004 Bonafe L, Cormier-Daire V, Hall C, et al: Nosology and classification of genetic skeletal disorders: 20 1 5 revision. Am J Med Genet 1 67A( 1 2) :2869, 20 1 5 Bromley B , Shipp TO, Lyons J , et al: Detection of fetal structural anomalies in a basic first-trimester screening program for aneuploidy. J Ultrasound Med 3 3 ( 1 0) : 1 737, 20 1 4 Bronshtein M , Ornoy A : Acrania: anencephaly resulting from secondary degeneration of a closed neural tube: two cases in the same family. J Clin Ultrasound 1 9 (4):230, 1 99 1 Brugger PC, Stuhr F , Lindner C , et al: Methods o f fetal MR: beyond

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225

C H A PT E R 1 1

Am n ion ic Fl u id

NORMAL AMNIONIC F L U I D VOLUME . . . . . . . . . . . . . . . 225 PHYSIOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

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SONOGRAPH IC ASSESSMENT .

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HYDRAMN IOS . . . . . . . . . OLIGOHYDRAM NIOS .

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BORDERLINE OLIGOHYDRAM N I OS . . . . . . . . . . . . .

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NORMAL AMNIONIC FLUID VOLUME Amnionic luid volume increases from approximately 3 0 mL at 10 weeks to 200 mL by 16 weeks and reaches 800 m L by the mid-third trimester (Brace, 1 989; Magann, 1 997) . The luid is approximately 98-percent water. A full-term fetus contains roughly 2800 mL of water and the placenta another 400 mL, such that the term uterus holds nearly 4 liters of water (Modena, 2004) . Abnormally decreased luid volume is termed oligohydramnios, whereas abnormally increased luid volume is termed hydramnios or poyhydramnios. • Physiology

It is generaly agreed that amniotic luid represents in great part a transudation from the matenal vesses, but many authorities consider that a portion of it is derivedrom uri­ nay secretion ofthe oetus. J Whitridge Williams ( 1 903) -

.

At the time Williams wrote this, the fetal kidney was thought by many to be nonfunctional. Since that time, however, much has been learned of this complex multifunctional liquor amnii. mnionic fluid serves several roles during pregnancy. Fetal breathing of amnionic fl u id is essential for normal lung growth, and fetal swallowing permits gastrointestinal (GI) tract development. Amnionic fluid also creates a physical space for fetal movement, which is necessary for neuromusculoskeletal maturation. It further guards against umbilical cord compres­ sion and protects the fetus from trauma. Amnionic luid even has bacteriostatic properties. Abnormalities of volume may result from fetal or placental pathology-indicating a problem with luid production or its circulation. These volume extremes may be associated with increased risks for adverse pregnancy outcome.

Early in pregnancy, the amnionic cavity is fi l led with luid that is similar in composition to extracellular luid. During the first half of pregnancy, transfer of water and other small molecules takes place across the amnion-transmembranous low; across the fetal vessels on placental surface-intramembranous low; and transcutaneous low-across fetal skin. Fetal urine produc­ tion begins between 8 and 1 1 weeks' gestation, but it does not become a major component of amnionic luid until the second trimester, which explains why fetuses with lethal renal abnormalities may not manifest severe oligohydramnios until after 1 8 weeks. Water transport across the fetal skin continues until keratinization occurs at 22 to 25 weeks. This explains why extremely preterm neonates can experience signiicant luid loss across their skin. With advancing gestation, four pathways play a major role in amnionic luid volume regulation (Table 1 1 - 1 ) . First, fetal urination is the primary source of amnionic luid in the second half of pregnancy. By term, fetal urine production may exceed 1 liter per day, and the entire amnionic luid volume is recir­ culated on a daily basis. Fetal urine osmolality is similar to that of amnionic luid and significantly hypotonic to that of mater­ nal and fetal plasma. Speciically, the osmolality of maternal

226

The Feta l Patient

TABLE 1 1 -1 . A m n io n i c F l u id Vol u me Reg u lation i n Late P reg na ncy Effect on Volume

Pathway

Feta l u ri nation Feta l swa l l owi n g Feta l l u ng fl u id secretion I ntra mem b ra no u s flow across feta l vessels on the p lacental su rface Transmembra nous fiow across a m n ionic mem brane

Approximate Dai ly Volume ( m L)

P rod u ction Resorption P rod uction Resorption

1 000 750 350 400

Resorption

M i n i ma l

Data from Mag a n n , 2 0 1 1 ; Modena, 2004; Moore, 20 1 0.

and fetal plasma approximates 280 mOsm/mL, whereas that of amnionic fluid is about 260 mOsm/L. The hypotonicity of amnionic luid accounts for significant intramembranous fluid transfer across and into fetal vessels on the placental surface. This transfer reaches 400 mL per day and is a second regulator of fluid volume (Mann, 1 996) . In the setting of maternal dehy­ dration, the resultant increase in maternal osmolality favors fluid transfer from the fetus to the mother, and then from the amnionic luid compartment into the fetus (Moore, 20 1 0) . n important third source o f amnionic fluid regulation is the respiratory tract. Approximately 3 5 0 mL of lung fluid is produced daily late in gestation, and half of this is immediately swallowed. Last, fetal swallowing is the primary mechanism for amnionic luid resorption and averages 500 to 1 000 mL per day (Mann, 1 996) . Impaired swallowing, secondary to either a central nervous system abnormality or GI tract obstruction, can result in an impressive degree of hydramnios. The remain­ ing pathways are transmembranous and transcutaneous low, which together account for a far smaller proportion of fluid transport in the second half of pregnancy. • Measurement

F rom a practical standpoint, the actual volume of amnionic luid is rarely measured outside of the research setting. That said, direct measurement and dye-dilution methods of luid quantifi c ation have contributed to our understanding of nor­ mal physiology. These measurements have further been used to validate sonographic fluid assessment techniques. Dye dilution involves injecting a small quantity of a dye such as aminohip­ purate into the amnionic cavity under sonographic guidance and then sampling the amnionic fluid to determine the dye concentration and hence to calculate the volume. Brace and Wolf ( 1 989) reviewed 1 2 studies done through the 1 960s in which amnionic fluid volume was assessed using these measurement techniques. Although fluid volume increased across gestation, they found that the mean value did not change significantly between 22 and 39 weeks-it was approximately 750 mL. There was considerable variation at each week of gestation, especially in the mid-third trimester, when the 5 th percentile was 300 mL and the 95th percentile nearly 2000 mL. In contrast, Magann and colleagues ( 1 997) , using dye-dilution measurements, found that amnionic fluid volume rose with advancing gestation. Specifically, the aver­ age fluid volume was approximately 400 mL between 22 and

30 weeks, doubling thereafter to a mean of 800 mL. he vol­ ume remained at this level until 40 weeks and then declined by approximately 8 percent per week. The two reports difered in the regression methodology employed, and despite difer­ ent conclusions, both identiied a wide normal range, particu­ larly in the third trimester. This normal variation is similarly observed sonographically. • Sonographic Assessment

Amnionic fluid volume evaluation is a component of every standard sonogram performed in the second or third trimester (Chap. 1 0, p. 1 88). It may be measured using either of two semi-quantitative techniques, the single deepest pocket of fluid or the amnionic fluid index (API) , which was described by Phelan and associates ( 1 987) . Both measurements are reproducible and, in the setting of a fluid abnormality, can be followed serially over time to assess trends and to aid communication among providers. For these reasons, semiquantitative assessment of amnionic luid is preferred to qualitative or subjective estima­ tion (American College of Obstetricians and Gynecologists, 20 1 6) . Using either technique, a fluid pocket must be at least 1 em in width to be considered adequate. Fetal parts or loops of umbilical cord may be visible in the pocket, but they are not included in the measurement. Color Doppler is generally used to veriY that umbilical cord is not within the measurement. S i n g l e Deepest Pocket

his is also called the largest or maximal vertical pocket of amni­ onic fluid. he ultrasound transducer is held perpendicular to the floor and parallel to the long axis of the woman. Then, while scanning in the sagittal plane, the largest vertical pocket of luid is identified and measured. The single deepestpocket mea­ surement is considered normal f above 2 cm and less than 8 cm, with values below and above this range indicating oligohydram­ nios and hydramnios, respectivey. hese thresholds are based on data from Chamberlain and associates ( 1 984) and correspond to the 3rd and 97th percentiles. When evaluating twin pregnan­ cies and other multi fetal gestations, a single deepest pocket of amnionic fl u id is assessed in each gestational sac, again using a normal range of more than 2 em to less than 8 em (Hernandez, 20 1 2; Society for Maternal-Fetal Medicine, 20 1 3) . The fetal biophysical profile similarly uses a single deepest vertical pocket threshold of more than 2 em to indicate normal amnionic luid volume. This is discussed further in Chapter 1 7 (p. 337) .

Amnionic Fluid

A m n io n ic F l u id I ndex

... Moore, 1 990 ... Machado, 2007 -- Hinh , 2005 30 �----�-------�------�28 Mild hydramnios 26 24 22 E > ;' 20 97.5th percentile ) 0 1 8 .� 16 Q -

As with the single deepest luid pocket measurement, the ultra­ sound transducer is held perpen­ dicular to the loor and parallel to the long axis of the woman. The uterus is divided into four equal quadrants-the right and left upper and lower quadrants, :J = 14 respectively. The AFI is the sum > ·c 1 2 50th percentile of the single deepest pocket from 0 ·c 1 0 . each quadrant. The intraobserver E . . . --- . . . . . 8 « -... . . • • variability of the AFI approxi­ • • • • • 2.5th percentile 6 mates 1 cm, and the interob­ 4 server variability is about 2 cm. 2 Variations are larger when luid 0 volumes are above the normal 1 6 1 8 20 22 24 26 28 30 32 34 36 38 40 42 range (Moore, 1 990; Rutherford, Weeks' gestation 1 987) . A useful guideline is that FIGURE 1 1 -1 A m n ionic fl uid index (AFI) accord i n g to gestationa l-age-specific and threshol d the AFI approximates three times val ues. The b l u e cu rves represent the 25th, 50th, a n d 975th AFI percenti le val ues, based on the the single deepest pocket of fluid nomogram by M oo re ( 1 990). Red and tan cu rves represent 5 0th percentile val ues for AFI from (Hill, 2003) . Machado (2007) a n d fro m H i n h a n d Ladinsky (2005), res pectively. The l ig ht b l u e and yel low s haded Determination of whether the bars i n d icate t h reshold values u sed to defi ne hyd ra m n ios a n d oligohyd ra m n ios, res pectively. AFI is normal may be based on either a static numerical threshold or a gestational age-specific percentile reference range. he AFI is generally considered normal ifgreater than 5 cm and below 24 or 25 cm. Values outside these ranges indicate oligohydramnios and hydramnios, respectively. The upper threshold of 24 cm is used in consensus documents (American College of Obstetricians and Gynecologists, 20 1 6; Reddy, 20 1 4) . The 25-cm threshold is oten applied in research studies (Khan, 20 1 7; Luo, 20 1 7; Pri-Paz, 20 1 2) . Moore and Cayle ( 1 990) have provided normal curves for AFI values based on a cross-sectionl evaluation of nearly 800 uncomplicated pregnancies. he mean AFI was found to be between 12 and 1 5 cm from 16 weeks until 40 weeks' gestation. Other investigators have published nomograms with similar mean values (Hinh, 2005; Machado, 2007) . Figure 1 1 - 1 depicts these AFI nomogram reference values in relation to com­ monly used thresholds for hydramnios and oligohydramnios. -

HYDRAMN IOS This is an abnormally increased amnionic luid volume, and it complicates 1 to 2 percent of singleton pregnancies (Dashe, 2002; Khan, 20 1 7; Pri-Paz, 20 1 2) . It is more frequently noted in multifetal gestations (Hernandez, 20 1 2) . Hydramnios may be suspected if the uterine size exceeds that expected for ges­ tational age. The uterus may feel tense, and palpating fetal small parts or auscultating fetal heart tones may be diicult. An extreme example is shown in Figure 1 1 -2. Hydramnios may be urther categorized according to degree. Such categorization is primarily used in research studies to stratiy risks. Several groups have termed hydramnios as mid if the AFI is 25 to 29.9 cm; moderate, if 30 to 34.9 cm; and severe, if 35 cm or more (Lazebnik, 1 999; Luo, 20 1 6; Odibo, 20 1 6; Pri-Paz, 20 1 2) . Mild hydramnios is the most common, comprising

FIGURE 1 1 -2 Severe hyd ra m n ios-55 00 mL of a m n ionic fl u id was measured at del ivery.

227

228

The Feta l Patient

hydropic fetus and placenta. he underlying pathophysiology in such cases is complex but is frequently related to a high cardiac­ output state. Severe fetal anemia is a classic example. Because the etiologies of hydramnios are so varied, hydramnios treatment also difers and is tailored in most cases to the underlying cause. Co n g e n ita l Anomal ies

FIGURE " -3 Sonog ra m of severe hyd ra m n ios at 35 weeks in a preg n a ncy complicated by feta l aq ued ucta l stenosis. Thi s pocket of a m n i o n ic fl u id measures > 1 5 cm, and the a m n io n ic fl u i d i ndex mea s u red nearly 50 cm.

approximately two thirds of cases; moderate hydramnios accounts for about 20 percent; and severe hydramnios for approximately 1 5 percent. Using the single deepest pocket of amnionic fluid, mild hydramnios is defined as 8 to 9.9 cm, moderate as 1 0 to 1 1 .9 cm, and severe hydramnios as 1 2 cm or more (Fig. 1 1 -3) . In general, severe hydramnios i s far more likely t o have a n under­ lying etiology and to have consequences for the pregnancy than mild hydramnios, which is frequently idiopathic and benign. • Etiology

Underlying causes ofhydramnios include fetal anomalies-either structural abnormalities or genetic syndromes-in approximately 1 5 percent, and diabetes in 1 5 to 20 percent (Table 1 1 -2) . Con­ genital infection, red blood cell alloimmunization, and placental chorioangioma are less frequent etiologies. Infections that may present with hydramnios include cytomegalovirus, toxoplas­ mosis, syphilis, and parvovirus. Hydramnios is oten a compo­ nent of hydrops etalis, and several of the above causes-selected anomalies, infections, and alloimmunization-may result in a

Selected anomalies and the likely mechanism by which they cause hydramnios are shown in Table 1 1 -3 . Many of these abnormalities are depicted and discussed in Chapter 1 0. Because of this association, targeted sonography is indicated whenever hydramnios is identiied. If a fetal abnormality is encountered concurrent with hydramnios, amniocentesis with chromosomal microarray analysis should be ofered, because the aneuploidy risk is signiicantly elevated (Dashe, 2002; Pri-Paz, 20 1 2) . Importantly, the degree o f hydramnios correlates with the likelihood of an anomalous infant (Lazebnik, 1 999; Pri-Paz, 20 1 2) . At Parkland Hospital, the prevalence of an anomalous neonate was approximately 8 percent with mild hydramnios, 1 2 percent with moderate hydramnios, and more than 3 0 percent with severe hydramnios (Dashe, 2002) . Even if no abnormal­ ity was detected with targeted sonography, the likelihood of a major anomaly identified at birth was 1 to 2 percent if hydram­ nios was mild or moderate and 1 0 percent if hydramnios was severe. he overall reported risk that an underlying anomaly will be discovered ater delivery has ranged from 9 percent in the neonatal period to 28 percent among infants followed to 1 year of age (Abele, 20 1 2; Dorleijn, 2009) . he anomaly risk is particularly high with hydramnios coexistent with fetal-growth restriction (Lazebnik, 1 999). Although amnionic luid volume abnormalities are associated with fetal malformations, the converse is not usually the case. In the Spanish Collaborative Study of Congenital Malforma­ tions that included more than 27,000 anomalous infants, only 4 percent of pregnancies were complicated by hydramnios, and another 3 percent with oligohydramnios (Martinez-Frias, 1 999) . Dia betes M e l l itus

he amnionic luid glucose concentration is higher in dia­ betic women than in those without diabetes, and the AFI may

TABLE " -2. Hyd ra m n ios: P reva lence a nd Associated Etiologies-Va l ues in Percent Golan ( 1 993) n 1 49 =

Many ( 1 995) n 275 =

Biggio ( 1 999) n 370 =

Dashe (2002) n 672 =

Pri - Paz (20 1 2) n 655 =

2

Preval ence A m nionic fl uid i ndex M i ld 25-29.9 cm Moderate 3 0-34.9 cm Severe > 35 cm

72 20 8

66 22 12

64 21 15

82 1 1a 7

52 38a 18

Etiology

I d iopath i c Feta l a nomaly Dia betes

65 19 15

69 1 5a 18

72 8 20

aA sig n iicant correlation was identified between severity of hyd ra m nios and l i kelihood of a n a nomalous i nfa nt.

Am n io n i c F l u id

TABLE 1 1 -3. Selected Anoma l ies and M echa n i s m for Hyd ra m n ios Mechan ism

Anomaly Examples

I m pa i red swa l lowi ng (C N S)

Anencephaly Hyd ra nencep h a l y H o l oprosencephaly C l eft l i p/pa l ate Microg n ath ia N eck venolymphatic a bnorm a l ity C HAOSa D i a p h ra g m atic h e r n i aa Cystic adenomatoid m a l formation? Pu l mo n a r seq uestrati o na E bste i n a n o m a l ya Tetralogy of Fa l l et with a bsent p u l monary a lvea Thyroto/icos is� Card i o m 'a pathy, myoca rd itisa Ta chya rrhyth m iaa: tna i fl u tter, a tria l fi bri l l a tion, su praventric u l a r tachycard ia Bradya rrhyt h m iaa. heart b l ock Esophagea l atresia Duoden a l atresia U reteropelvic j u n ction obstruction ("pa radoxi ca l h y d ra m n i os") Baarte r synd rome Arth rog rypos is, a k i nesia seq u e nce Myoto n i c d ystro phy Sacrococcyg eal tera tomaa Mesoblastic neph romaa Placenta l chorioa n g l omaG

I m pa i red swa l l owi ng (cr a n iofacial) Tracheal com p ression or o bstru cti on Thoracic etiology (med i a sti n a l s h i ft)

H ig h-output card iac state

F u n cti ona l card iac etiology Ca rd i a c a r rhyth m i a G I obstruction Rena l - U ri n a ry N e u rolog i ca l o r m u scu l a r eti o l ogy N eopl astic etiology

a Poses risk for hyd ro ps. C H AOS con g e n ita l h i g h-a i rway o bstruction seq ue nce; GI =

correlate with the amnionic fluid glucose concentration (Dashe, 2000; Spellacy, 1 973; Weiss, 1 985). Such findings support the hypothesis that maternal hyperglycemia causes fetal hypergly­ cemia, with resulting fetal osmotic diuresis into the amnionic luid compartment. hat said, rescreening for gestational dia­ betes in pregnancies with hydramnios does not appear to be beneicial, provided that the second-trimester glucose tolerance test result was normal (F rank Wolf, 20 1 7) . M u ltifeta l Gestation

Hydramnios is generally deined in multifetal gestations as a single deepest amnionic luid pocket measuring 8 cm or more. It may be further characterized as moderate if the single deepest pocket is at least 1 0 cm and severe if this pocket is at least 1 2 cm. In a review of nearly 2000 twin gestations, H ernandez and colleagues (20 1 2) identifi e d hydramnios in 1 8 percent of both monochorionic and dichorionic pregnan­ cies. As in singletons, severe hydramnios was more strongly associated with fetal abnormalities. In monochorionic ges­ tations, hydramnios of one sac and oligohydramnios of the other are diagnostic criteria for twin-twin transfusion syn­ drome (TTTS) , discussed in Chapter 45 (p. 878) . Isolated hydramnios of one sac also may precede the development of this syndrome (Chon, 20 1 4) . In the absence of TTTS, hydramnios does not generally raise pregnancy risks in non­ anomalous twins (Hernandez, 20 1 2) .

=

gastro i n test i n a l .

I d io pathic Hyd ra m n ios

his accounts for up to 70 percent of cases of hydramnios and is thus identified in as many as 1 percent of pregnancies (Panting-Kemp, 1 999; Pri-Paz, 20 1 2; Wiegand, 20 1 6). Idiopathic hydramnios is rarely identiied during midtrimester sonography and is oten an incidental inding later in gestation. he gesta­ tional age at sonographic detection usually lies between 32 and 35 weeks (Abele, 20 1 2; Odibo, 20 1 6; Wiegand, 20 1 6) . Although it is a diagnosis of exclusion, an underlying fetal abnormality may subsequently become apparent with advancing gestation, particu­ larly if the degree of hydramnios becomes severe. In the absence of an etiology, idiopathic hydramnios is mild in approximately 80 percent of cases, and resolution is reported in more than a third of afected pregnancies (Odibo, 20 1 6; Wiegand, 20 1 6). Mild, idiopathic hydramnios is most commonly a benign finding, and associated pregnancy outcomes are usually good. • Complications

Unless hydramnios is severe or develops rapidly, maternal symptoms are infrequent. With chronic hydramnios, luid accumulates gradually, and a woman may tolerate excessive abdominal distention with relatively little discomfort. Acute hydramnios, however, tends to develop earlier in pregnancy. It may result in preterm labor before 28 weeks or in symptoms that become so debilitating as to necessitate intervention.

229

230

The Feta l Patient

Symptoms may arise from pressure exerted within the over­ distended uterus and upon adjacent organs. When distention is excessive, such as that shown in Figure 1 1 -2, the mother may sufer dyspnea and orthopnea to such a degree that she may be able to breathe comfortably only when upright. Edema may develop as a consequence of major venous system compression by the enlarged uterus, and it tends to be most pronounced in the lower extremities, vulva, and abdominal wall. Rarely, oliguria may result from ureteral obstruction by the enlarged uterus (Chap. 53, p. 1 037) . Maternal complications such as these are typically associated with severe hydramnios from an underlying etiology. Maternal complications associated with hydramnios include placental abruption, uterine dysfunction during labor, and postpartum hemorrhage. Placental abruption is fortunately infrequent. It may result from the rapid decompression of an overdistended uterus that follows fetal-membrane rupture or therapeutic amnioreduction. With prematurely ruptured mem­ branes, a placental abruption occasionally occurs days or weeks after amniorrhexis. Uterine dysfunction consequent to overdis­ tention may lead to postpartum atony and, in turn, postpartum hemorrhage. • Pregnancy Outcomes

Some outcomes more common with hydramnios include birth­ weight > 4000 g, cesarean delivery, and importantly, perinatal mortality. Pregnancies with idiopathic hydramnios are associ­ ated with birthweights exceeding 4000 g in nearly 25 percent of cases, and the likelihood appears to be greater if the hydram­ nios is moderate or severe (Luo, 20 1 6 ; Odibo, 20 1 6; Wiegand, 20 1 6) . A rationale for this association is that larger fetuses have higher urine output, by virtue of their increased volume of dis­ tribution, and fetal urine is the largest contributor to amnionic luid volume. Cesarean delivery rates are also higher in preg­ nancies with idiopathic hydramnios, with reported rates of 35 to 5 5 percent (Dorleijn, 2009; Khan, 20 1 7; Odibo, 20 1 6) . An unresolved question i s whether hydramnios alone raises the risk for perinatal mortality. Some studies have found no increase in stillbirth or neonatal death rates with idiopathic hydramnios, whereas others show a greater risk (Khan, 20 1 7; Pilliod, 20 1 5 ; Wiegand, 20 1 6) . Using birth certificate data from the state of California, Pilliod and coworkers (20 1 5) iden­ tified hydramnios in 0.4 percent of singleton, nonanomalous pregnancies, and afected pregnancies had significantly greater stillbirth rates. At 37 weeks, the stillbirth risk was sevenfold higher in pregnancies with hydramnios. By 40 weeks, this risk was more than tenfold higher-66 per 1 0,000 births compared with 6 per 1 0,000 without hydramnios. isks appear to be compounded when a growth-restricted fetus is identiied with hydramnios (Erez, 2005). The com­ bination also has a recognized association with trisomy 1 8 . When an underlying cause is identified, degree o f hydramnios has been associated with likelihood of preterm delivery, small­ for-gestational age newborn, and perinatal mortality (Pri-Paz, 20 1 2) . However, idiopathic hydramnios is generally not associ­ ated with preterm birth (Magann, 20 1 0; Many, 1 995; Panting­ Kemp, 1 999) .

• Management

s previously noted, treatment is directed to the underlying cause.

Occasionally, severe hydramnios may result in early preterm labor or the development of maternal respiratory compromise. In such cases, large-volume amniocentesis-termed amnioreduc­ tion may be needed. he technique is similar to that for genetic amniocentesis, described in Chapter 1 4 (p. 292) . One diference is that it is generally done with a larger needle, 1 8- or 20-gauge, and uses either an evacuated container bottle or a larger syringe. Approximately 1 000 to 2000 mL of luid is slowly withdrawn over 20 to 30 minutes, depending on the severity of hydramnios and gestational age. he goal is to restore amnionic fluid volume to the upper normal range. Hydramnios severe enough to neces­ sitate amnioreduction almost invariably has an underlying cause, and subsequent amnioreduction procedures may be required as oten as weekly or even semiweekly. In a review of 1 38 singleton pregnancies requiring amniore­ duction for hydramnios, a fetal GI malformation was identified in 20 percent, a chromosomal abnormality or genetic condi­ tion in almost 30 percent, and a neurological abnormality in 8 percent (Dickinson, 20 1 4) . In only 20 percent of cases was the hydramnios idiopathic. he initial amnioreduction procedure in this series was performed at 3 1 weeks' gestation, and the median gestational age at delivery was 36 weeks. Complica­ tions within 48 hours of amnioreduction included deliveY in 4 percent and ruptured membranes in 1 percent. here was no instance of chorioamnionitis, placental abruption, or bradycar­ dia requiring delivery (Dickinson, 20 1 4) . -

OLIGOHYDRAMNIOS his is an abnormally decreased amount of amnionic luid. Oligohydramnios complicates approximately 1 to 2 percent of pregnancies (Casey, 2000; Petrozella, 20 1 1 ) . When no measur­ able pocket of amnionic fluid is identiied, the term anhydram­ nios may be used. Unlike hydramnios, which is often mild and often confers a benign prognosis in the absence of an underly­ ing etiolo) , oligohydramnios is always a cause for concern, as discussed on page 23 1 . The sonographic diagnosis ofoligohydramnios is usualy based on an API less than 5 cm or a single deepest pocket of amnionic luid below 2 cm (American College of Obstetricians and Gynecolo­ gists, 20 1 6) . Using the Moore nomogram, an API threshold of 5 em is below the 2.5th percentile throughout the second and third trimesters (see Fig. 1 1 - 1 ) . Either criterion is considered acceptable. However, use of API rather than single deepest pocket will identiy more pregnancies as having oligohydramnios, with­ out evidence of improvement in pregnancy outcomes (Kehl, 20 1 6; Nabhan, 20 1 0) . When evaluating multifetal pregnancies for TTTS, a single deepest pocket below 2 em is used to define oligohydramnios (Society for Maternal-Fetal Medicine, 20 1 3) . • Etiology

Pregnancies complicated by oligohydramnios include those in which the amnionic luid volume has been severely diminished since the early second trimester and those in which the fluid

Am n io n i c F l u id

agenesis, bilateral multicystic dysplastic kidney, unilateral renal agenesis with contralateral multicystic dysplastic kidney, and the infantile form of autosomal recessive poycystic kidney dis­ ease. Urinary abnormalities may also result in oligohydramnios because of fetal bladder outlet obstruction. Examples of this are posterior urethral valves, urethral atresia or stenosis, or the mega­ cystis microcolon intestinal hypoperistalsis syndrome. Complex fetal genitourinary abnormalities such as persistent cloaca and sireno­ melia similarly may result in a lack of amnionic luid. Many of these renal and urinary abnormalities are discussed and depicted in Chapter 1 0 (p. 208) . If no amnionic luid is visible beyond the mid-second trimester due to a genitourinary etiology, the prognosis is extremely poor unless fetal therapy is an option. Fetuses with bladder-outlet obstruction may be candidates for vesicoamnionic shunt placement (Chap. 1 6, p. 325).

volume was normal until near-term or even full-term. The prognosis depends heavily on the underlying cause and thus varies. Whenever oligohydramnios is diagnosed, it becomes an important consideration in clinical management. Early-Onset O l i gohyd ra m n ios

When amnionic fluid volume is abnormally decreased from the early second trimester, it may reflect a fetal abnormality that precludes normal urination, or it may represent a placental abnormality suiciently severe to impair perfusion. In either circumstance, the prognosis is poor. Ruptured membranes should be excluded, and targeted sonography is performed to assess for fetal and placental abnormalities. O l i g o hyd ra m n ios after M i d preg na ncy

When amnionic luid volume becomes abnormally decreased in the late second or in the third trimester, it is very often associ­ ated with fetal-growth restriction, with a placental abnormality, or with a maternal complication such as preeclampsia or vascu­ lar disease (Table 1 1 -4) . The underlying cause in such cases is frequently uteroplacental insuiciency, which can impair fetal growth and reduce fetal urine output. Exposure to selected med­ ications has also been linked with oligohydramnios as discussed subsequently. Investigation of third-trimester oligohydramnios generally includes evaluation for ruptured membranes and sonog­ raphy to assess fetal growth. Umbilical artery Doppler studies are recommended if growth restriction is identiied (Chap. 1 0, p. 2 1 3) . Oligohydramnios is commonly encountered in late­ term and postterm pregnancies (Chap. 43, p. 837) . Magann and coworkers ( 1 997) found that amnionic luid volume decreased by approximately 8 percent per week beyond 40 weeks.

Med ication

Oligohydramnios has been associated with exposu re to drugs that block the renin-angiotensin system. These include angiotensin-converting enzyme (ACE) inhibitors, angioten­ sin-receptor blockers, and nonsteroidal antiinlammatory drugs (NSAIDs) . When taken in the second or third tri­ mester, ACE inhibitors and angiotensin-receptor blockers may create fetal hypotension, renal hypoperfusion, and renal ischemia, with subsequent anuric renal failure (Bullo, 2 0 1 2; Guron, 2000) . Fetal skull bone hypoplasia and limb contrac­ tures have also been described (Schaefer, 2003) . NSAID s can be associated with fetal ductus arteriosus constriction and with lower fetal urine production . In neonates, their use may result in acute and chronic renal insuiciency (Fanos, 2 0 1 1 ) . These agents are discussed i n Chapter 1 2 (p. 24 1 ) . • Pregnancy Outcomes

Con gen ita l Anoma l i es

By approximately 18 weeks, the fetal kidneys are the main con­ tributor to amnionic luid volume. Selected renal abnormalities that lead to absent fetal urine production include bilateral renal

Oligohydramnios is associated with adverse pregnancy out­ comes. Casey and colleagues (2000) found that an AFI � 5 em

TABLE 1 1 -4. P reg na ncy Outco mes in Women Diag nosed with Oligohyd ra m n ios between 24 and 34 Weeks' Gestation Factor

Major m a lformation Sti l l bi rth Gestat i o n a l age at d e l iverya P reterm b i rth, s ponta n eo u sa P rete rm b i rth, i nd i cateda Cesa rea n d e l ive ry for nonreass u r i n g fetal statu sa B i rthwe i g h t < 1 0th percenti lea < 3 rd percenti lea N eo nata l d eatha

AFI � 5 em

AFI 8 to 24 em

42 (25) 8 (5) 35. 1 ± 3.3 49 (42) 2 3 20) 1 0 (9)

634 (2) 1 33 « 1 ) 3 9.2 ± 2.0 1 698 (6) 405 (2) 1 083 (4)

6 1 (53) 43 (37) 1 (1)

3 388 ( 1 2) 1 1 30 (4) 24 « 1 )

(n

=

1 66)

(n

=

28, 1 85)

P Value < .00 1 < .00 1 < .00 1 < .00 1 < .00 1 < .00 1

< .00 1 < .00 1 < .OO l b

Data expressed as No. (%) a nd mean ± sta n d a rd deviation. aAnoma l o u s i n fa nts excl u ded. bTh i s d i ffe ren ce was no longer s i g n ificant after a dj u stment fo r gestational age at del ivery. Data fro m Petrozel la, 20 1 1 .

23 1

232

The Fetal Patient

complicated 2 percent of pregnancies undergoing sonography at Parkland Hospital ater 34 weeks' gestation. Fetal malforma­ tion rates were elevated in those with oligohydramnios. Even in their absence, rates of stillbirth, growth restriction, nonreassUf­ ing heart rate pattern, and meconium aspiration syndrome were higher than in nonafected pregnancies. Petrozella and associates (20 1 1 ) similarly reported that an AFI :;5 em identiied between 24 and 34 weeks was associated with increased risks for stillbirth, spontaneous or medically indicated preterm birth, heart rate pattern abnormalities, and growth restriction (see Table 1 1 -4) . In one metaanalysis comprising more than 1 0,000 pregnan­ cies, women with oligohydramnios had a twofold greater risk for cesarean delivery for fetal distress and a ivefold higher risk for an Apgar score I

Cell-free fetal DNA Real-time quantitative PCR

genotyping

Detection of sing le-gene disorders

determination

Massive ly parallel genomic seq uencing Trisomy 2 1 , 1 8 , and 1 3 screening

FIGURE 1 3-1 4 Cel l-free DNA is actu a l ly de rived from a poptotic trophoblast. T h e D N A is isolated from materna l plasma, a n d rea l-ti me qua ntitative polymerase c h a i n reaction (PCR) may be u sed to ta rget specific reg ions or seq uences. Th is may be used for Rh D genotyping, detection of patern a l ly i n herited sing le-gene d isorders, or feta l sex determi nation. Scree n i n g for a utosoma l trisom ies a n d sex ch romo­ soma l a neu ploid ies is performed using whole-genome seq uencing, chromosome selective or ta rgeted sequencing, a n d a n a lysis of s i n g l e n ucleotide polymorphisms.

273

274

The Feta l Patient

a screening option in those at greater risk for fetal autosomal trisomy (American College of Obstetricians and Gynecologists, 20 1 7b; Society for Maternal-Fetal Medicine, 20 1 5) . Unfortunately, cell-free DNA screens do not yield a result in 4 to 8 percent of cases. This may be due to assay failure, high assay variance, or low fetal fraction (Norton, 20 1 2; Perga­ me nt, 20 1 4; Quezada, 20 1 5) . Such pregnancies carry a greater risk for fetal aneuploidy. In addition, results may not relect the fetal DNA complement but rather may indicate conined placental mosaicism, early demise of an aneuploid cotwin, maternal mosaicism, or rarely occult maternal malignancy (Bianchi, 20 1 5 ; Curnow, 20 1 5; Grati, 20 1 4b; Wang, 20 1 4) . Recommendations for counseling are discussed in Chapter 1 4 (p. 285). Feta l Sex Determ i nation. From the standpoint of genetic

disease, fetal sex determination may be clinically useful if the fetus is at risk for an X-linked disorder. It may also be ben­ eficial if the fetus is at risk for congenital adrenal hyperplasia because maternal corticosteroid therapy may be avoided if the fetus is male (Chap. 1 6, p. 3 1 7) . In a metaanalysis of more than 6000 pregnancies by Devaney and associates (20 1 1 ) , the sensitivity of cell-free DNA testing for fetal sex determination approximated 95 percent between 7 and 1 2 weeks' gestation and improved to 99 percent after 20 weeks. The test speciic­ ity was 99 percent at both time periods, suggesting that cell­ free fetal DNA is a reasonable alternative to invasive testing in selected cases. tion, nearly 40 percent of fetuses of h D-negative women are themselves h D negative. Fetal h D genotype assessment from maternal blood can eliminate administration of anti-D immune globulin in these pregnancies, thereby reducing cost and poten­ tial risk. With h D alloimmunization, early identification of an h D-negative fetus might avoid unnecessary middle cerebral artery Doppler assessment or amniocentesis. Evaluation using cell-free DNA is done using real-time PCR to target several exons of the HD gene. These are typically exons 4, 5 , and 7. h D-genotyping is performed routinely with cell-free DNA in Denmark and the Netherlands (Clausen, 20 1 2; de Haas, 20 1 6) . In a population-based study of more than 2 5 ,000 h D-negative women screened at 27 weeks, the false-negative rate-in which h D-negative status was missed-was only 0.03 percent. The false-positive rate-in which h immune globulin would be given unnecessarily-was less than 1 per­ cent (de Haas, 20 1 6) . Similar results were reported from the United Kingdom, although the false-negative rate was higher in the irst trimester (Chitty, 20 1 4) . Investigators concluded that false-negative screening results might increase the alloimmuni­ zation risk, but by less than 1 case per million births (Chitty, 20 1 4) . h D alloimmunization is discussed in Chapter 1 5 (p. 30 1 ) . Rh D Genotype Evaluation. In a predominantly white popula­

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those with pregnancies at risk for speciic genetic disorders. he goal of prenatal diagnosis is to provide accurate information regarding short- and long-term prognosis, recurrence risk, and potential therapy, thereby improving patient counseling and optimizing outcomes. Management of an afected pregnancy, including whether a woman would elect pregnancy termination, may be incorporated into the discussion of screening and testing options. However, nondirective counseling is central to prenatal diagnosis. his practice provides the patient with unbiased knowledge regard­ ing a diagnosis and preserves her autonomy (Flessel, 20 1 1 ) . Fetal imaging of congenital anomalies is discussed in Chapter 1 0, and pregnancy termination is discussed in Chapter 1 8.

. . 295

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Carul examination should ordinariy lead to a correct diag­ nosis ofhydrocephalus in the last weeks ofpregnancy. In many cases the dormiy can be detected by external papation. -]. Whitridge Williams ( 1 903) In the initial edition of Williams Obstetrics, very few fetal disorders could be identiied before delivery. Now, more than 1 00 years later, prenatal diagnosis has become a separate field of its own. Strictly speaking, prenatal diagnosis is the science of identiying congenital abnormalities, aneuploidies, and other genetic syndromes in the fetus. It encompasses the diagnosis of structural malformations with specialized sonography; routine screening tests for aneuploidy and neural-tube defects; diag­ nostic tests such as karyotyping and chromosomal microarray analysis performed on chorionic villi and amniocentesis speci­ mens; and additional screening and diagnostic tests ofered to

More than 40 years ago, Brock ( 1 972, 1 973) observed that pregnancies complicated by neural-tube defects had higher lev­ els of alpha-fetoprotein (AFP) in maternal serum and amni­ onic luid. his formed the basis for the irst maternal serum screening test for a fetal condition. The beginning of wide­ spread serum screening came in 1 977, after a collaborative trial from the United Kingdom established the association between elevated maternal serum AFP levels (MSAFP) and fetal open neural-tube defects (Wald, 1 977) . When screening was per­ formed at 1 6 to 1 8 weeks' gestation, detection approached 90 percent for pregnancies with fetal anencephaly and 80 percent for those with myelomeningocele (spina biida) . hese sensi­ tivities are comparable to current testing (American College of Obstetricians and Gynecologists, 20 1 6a) . The terms level I and level II sonography were coined in this context. In the California MSAFP Screening Program of the 1 980s and early 1 990s, women received serum screening prior to sonography, and those with an elevated MSAFP level would undergo level I sonography to identiy an incorrect gestational age, mulrifetal gestation, or fetal demise (Filly,

278

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1 993). A third of pregnancies with an elevated MSAFP level had one of these three etiologies. Although birth defects were occasionally detected during level I sonography, this was not the expectation. If level I sonography did not identiy an etiol­ ogy for the MSAFP level elevation, amniocentesis would be ofered. Then, only if the amnionic luid AFP concentration were elevated would the woman undergo level II sonography. his more detailed and comprehensive survey of fetal anatomy was performed to detect and characterize the fetal abnormality. If the amnionic fluid AFP level was elevated, an assay for amnionic luid acetylcholinesterase was concurrently per­ formed. his capitalized on the tendency of acetylcholinesterase to leak directly from exposed neural tissue into the amnionic luid. The presence of both analytes in the amnionic luid was considered diagnostic for neural-tube defects (American Col­ lege of Obstetricians and Gynecologists, 20 1 6a) . The overall sensitivity of amniocentesis to diagnose open neu­ ral-tube defects approximates 98 percent, with a false-positive rate of 0.4 percent (Milunsky, 2004) . Importantly, other fetal abnormalities are associated with elevated amnionic fluid AFP levels and positive assay results for acetylcholinesterase. These include ventral wall defects, esophageal atresia, fetal teratoma, cloacal exstrophy, and skin abnormalities such as epidermolysis bullosa. hus, by current standards, these amnionic luid ana­ lytes would be considered ancillary screening tests, understand­ ing that a positive result would prompt additional fetal imaging. With current imaging technology, most neural-tube defects are detected with sonography, and targeted sonography is the diagnostic test of choice (Dashe, 2006) . Pregnant women now have the option of neural-tube defect screening with either MSAFP or sonography (American College of Obstetri­ cians and Gynecologists, 20 1 6c) . Although level II is used as a synonym for targeted sonography, the former might best be removed from our lexicon. Namely, today's targeted sonogra­ phy includes a much more comprehensive evaluation of fetal anatomy (Chap. 1 0, p. 1 87) . As MSAFP screening was being adopted, the designation «advanced maternal age" (AMA) became popular. A 1 979 National Institutes of Health Consensus Development Con­ ference recommended advising pregnant women who were 35 years and older about the possibility of amniocentesis for fetal karyotyping. he threshold was based on the greater risk for selected fetal chromosomal abnormalities with increasing maternal age and on the assumption that at that time, the loss rate attributable to amniocentesis was equivalent to the fetal Down syndrome risk at maternal age 35. Notaby, this is no longer the case, as discussed later (p. 293) . Serum aneuploidy screening soon became available for women who would be younger than 35 at delivery. In 1 984, Merkatz and colleagues reported that MSAFP levels were lower in pregnancies with trisomies 2 1 and 1 8 at 1 5 to 2 1 weeks' gestation. Maternal age was incorporated into the calculation, such that a speciic risk could be assigned (DiMaio, 1 987; New England Regional Geneties G roup, 1 989). The MSAFP screen detected approximately 25 percent of cases of fetal tri­ somy 2 1 when the threshold ratio for a positive result was set at 1 :270. This ratio relects the approximate second-trimester risk for Down syndrome at maternal age 3 5 . This trisomy 2 1

18

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E 10 D ) ii 8 12

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4 2 0 1 982 1 986 1 990 1 994 1 998 2002 2006 201 0 201 4

Year F IG U R E 1 4- 1 Trends in the percentage of births to women aged 35 to 44 yea rs. (Data from the Centers for Disease Control a nd Prevention, 20 1 5.)

risk threshold and the associated 5-percent false-positive rate became standards that remain in use in some laboratories today. For more than a decade after its introduction, serum aneu­ ploidy screening was intended for women younger than 35, because it simply did not have suicient sensitivity to be ofered to women who had higher a priori risk. This is also no lon­ ger the case. And, because the prevalence of fetal aneuploidy rises sharply with maternal age, the positive-predictive value of all aneuploidy screening tests-whether analyte-based or cell­ free DNA tests-is higher in women aged 35 years or older. Women 35 and older now make up more than 1 5 percent of deliveries in the United States (Fig. 1 4- 1 ) . At Parkland Hospi­ tal, this age group accounts for half of births with Down syn­ drome (Hussamy, 20 1 7) .

SCREENING FOR ANEUPLOIDY Aneuploidy is the presence of one or more extra chromo­ somes, usually resulting in trisomy, or loss of a chromosome­ monosomy. Data from population-based registries that include births, fetal deaths, and pregnancy terminations indicate an overall prevalence of 4 such abnormalities per 1 000 births (Wellesley, 20 1 2) . Aneuploidy accounts for more than 50 percent of first-trimester abortions, about 20 percent of second-trimester losses, and 6 to 8 percent of stillbirths and early-childhood deaths (Reddy, 20 1 2; Stevenson, 2004; Wou, 20 1 6) . Of recognized pregnancies with chromosomal abnor­ malities, trisomy 2 1 composes approximately half of cases; tri­ somy 1 8 accounts for 15 percent; trisomy 1 3 , for 5 percent; and the sex chromosomal abnormalities-45 ,X, 47,XX, 47,Y, and 47,XY-for approximately 1 2 percent (Wellesley, 20 1 2) . The risk for fetal trisomy increases with maternal age, par­ ticularly after age 35 (Fig. 1 3-2, p. 255). When counseling, a provider includes specific maternal-age-related aneuploidy risks (Tables 1 4- 1 and 1 4-2) . Other important fetal aneuploidy risk factors include a numerical chromosomal abnormality or structural chromosomal rearrangement in the woman or her partner-such as balanced translocation-or a prior pregnancy with autosomal trisomy or triploidy. Broadly speaking, there are two types of aneuploidy screen­ ing tests, those that are traditional or analyte-based and those that are cell-free DNA-based. All pregnant women should be

P renata l Dia g nosis

TABLE 1 4- 1 . Mate r n a l Age-Rel ated Risk for Down Syn d rome and Any Aneu ploidy at M idtri m ester and at Term in S i n g l eton Preg n a ncies Down Synd rome Age

35 36 37 38 39 40 41 42 43 44 45

Any Aneuploidy

--

Midtrimester

Term

M idtrimester

Term

1 /250 1 / 1 92 1 / 1 49 1 /1 1 5 1 /89 1 /69 1 /5 3 1 /4 1 1 /3 1 1 /2 5 1 /1 9

1 /385 1 /303 1 /227 1 / 1 75 1 /1 37 1 / 1 06 1 /8 1 1 /64 1 /50 1 /38 1 /30

1 /1 32 1 / 1 05 1 /83 1 /65 1 /5 3 1 /40 1 13 1 1 /25 1 /1 9 1 /1 5 1 /1 2

1 /204 1 / 1 67 1 /1 30 1 / 1 03 1 /8 1 1 /63 1 /50 1 /39 1 /30 1 /24 1 /1 9

Data fro m Hook EB, Cross P K, Sch rei nemac hers DM: C h ro m osomal a b normal ity rates at a m n i ocentesis a n d i n l ive-born i nfa nts, JAMA. 1 983 Apr 1 5;249( 1 5):2034-2038.

ofered aneuploidy screening or diagnostic testing early in preg­ nancy (American College of Obstetricians and Gynecologists, 20 1 6c) . Considerations prior to screening are as follows: 1 . Has the patient elected screening? At least 20 percent of women elect not to receive aneuploidy screening, even when finan­ cial barriers are removed. Fewer than 40 percent of women with a positive screening result elect prenatal diagnosis (Dar, 20 1 4; Kuppermann, 20 1 4) . 2. ould the patient preer prenatal diagnosis? Diagnostic test­ ing is safe and efective, and chromosomal microarray TABLE 1 4-2. Matern a l Age-Related Risk fo r Down Syn d rome a nd Any Aneu ploidy at M i dtrimester a nd at Term in Dizygotic Twi n Preg n a n ciesa Down Syndrome Age

32 33 34 35 36 37 38 39 40 41 42

Any Aneuploidy

--

Midtrimester

Term

M idtrimester

Term

1 /256 1 /206 1 / 1 60 1 /1 25 1 /98 1 177 1 /60 1 /47 1 /3 7 1 /29 1 /2 3

1 /409 1 13 1 9 1 /2 5 7 1 / 1 99 1 /1 53 1 /1 1 8 1 /92 1 172 1 /5 6 1 /44 1 /3 3

1 / 1 49 1/1 1 6 1 /9 1 1 17 1 1 /56 1 /44 1 /35 1 /2 7 1 /2 1 1 /1 7 1 /1 3

1 /1 7 1 1/1 51 1 / 1 26 1 /1 01 1 /82 1 /67 1 /54 1 /44 1 /3 5 1 /28 1 /22

aRisk a p pl ies to one o r both fetu ses. Data from Meyers C, Adam R, D u ng a n J, et al: A n e u p l o idy i n twi n gestations: when is mate rn a l age adva n ced? O bstet Gyneco l . 1 997 Feb;89(2):248-25 1 .

analysis provides information about genetic conditions that screening tests and karyotyping alone currently do not (American College of Obstetricians and Gynecolo­ gists, 20 1 6b) . This is discussed further on page 29 1 and in Chapter 13 (p. 27 1 ) . 3 . Is this a multetal gestation? All traditional (analyte-based) aneuploidy screening tests are significantly less efective in multifetal gestations, and cell-free DNA screening is not cur­ rently recommended with multifetal gestations (p. 2 8 5 ) . 4. What method will b e used o r neural-tube deect screening? Whenever a patient elects an aneuploidy screening test that does not include second-trimester serum analytes, screening for neural-tube defects should be performed sep­ arately, either with MSAFP assessment or with sonography (American College of Obstetricians and Gynecologists, 20 1 6c) . 5 . Does theetus have a major anomay? If so, diagnostic testing is recommended rather than screening. The American College of Obstetricians and Gynecologists (20 1 6c) has airmed that screening for aneuploidy should be an informed patient choice, with an underlying foundation of shared decision making that its her clinical circumstances, val­ ues, interests, and goals. Elements of counseling prior to aneu­ ploidy screening are listed in Table 1 4-3 . • Statistical Considerations

Aneuploidy screening can be challenging because the test char­ acteristics of each option may vary with maternal age and with whether the test is analyte-based or cell-free DNA-based. The test sensitivity is the detection rate-that is, the proportion of aneuploid fetuses identiied by the screening test. Its converse, the false-negative rate, is the percentage of cases that the test is expected to miss. A first-trimester screening test with a sensitiv­ ity of 80 percent is expected to miss 1 in 5 cases. The sensitivity of screening tests for Down syndrome has increased steadily during the past 30 years, from just 25 percent with serum AFP alone to more than 90 percent with integrated or sequential screening. Another key characteristic is the false-positive rate, the percentage of unafected pregnancies that will "falsely" screen positive. This approximates 5 percent for fi r st-trimester screen­ ing, quadruple-marker screening, or integrated screening options (Baer, 20 1 5 ; Kazerouni, 20 1 1 ; Malone, 2005b; Nor­ ton, 20 1 5) . The converse of false-posi tive rate is speciici ty­ analyte-based screens will be reassuring in approximately 95 percent of unafected pregnancies. lthough test sensitivity has improved, the false-positive rate has been held constant for many diferent aneuploidy screening tests (Table 1 4-4) . Both statistics are relevant for counseling. An additional con­ sideration is that with all analyte-based screening tests, women 35 and older have higher rates of positive results (Kazerouni, 20 1 1 ; Malone, 2005b). Importantly, neither sensitivity nor false-positive rate con­ veys individual risk. he statistic that patients and providers usually consider to be the test result is the positive-predictive value, which is the proportion of those with a positive screening result who actually have an aneuploid fetus. It may be expressed

279

280

The Feta l Patient

TABLE 1 4-3. A n e u p loidy Screen i ng Cou nsel i n g Elements

1 . All pregnant women have 3 options: screen i ng, d iagnostic testing, and no screening or testing. The pu rpose of a scree n i n g test i s to provide i nformation, n ot t o d i ctate a cou rse of action. Diag nostic test i n g is safe a n d effective a nd p rovides i n formation that screen i n g does not. 2. The d iference between a scree n i n g test and a d iagnostic test. Screen i ng eva l uates whether the p reg n a n cy is at i ncreased r i s k a nd est i m ates deg ree of risk. Detect i o n rate, fa l se-negative rate, a n d fa l se-positive rate a re provid ed . Cel l-free D N A scree n i ng d oes n ot a l ways provid e a resu lt. I rrevers i b l e m a nagement deci s i on s s h o u l d not be based on screen i n g test res u lts. With a positive scree n i n g res u lt, a d i a g n osti c test is reco m m en d ed if the pati e nt wants to know whether the fetu s is affected . 3. Basic i nformation is provided a bout each condition covered by the screening test (preva lence, associated a b normal ities, prog nosis), and scree n i ng test l i m itations. A benefit of d ia g nosis i ncl u des earl i e r i d entification of associated a b no rm a l ities. In case of trisomy 1 8 o r 1 3, d ia g nosis may affect preg na n cy m a n a g e m ent if compl ications a rise such as g rowth restriction or n o n reassu ring feta l heart rate. With sex c h ro mosome a n e u p l o i d i es, p h e n otypic express ion va ries w i d e ly. Seve ra l a re so m i l d they wo u l d oth e rwise not be d ia g nosed . 4. The patient's a priori risk for fetal aneu ploidy may affect her screening test options or election. Age-rel ated risk i nfo rmation may be fou n d in refe re nce ta b l es. If a patient has had a prior fetu s with a utoso m a l tri somy, robe son i a n tra n s l ocation, or other c h romoso m a l a b n o r rn a l ity, a d d it i o n a l eva l uation a n d cou n se l i n g a re s u g g ested. Mod ified with perm ission from Das h e JS: A n e u ploidy scree n i n g i n preg n a n cy, Obstet Gynecol . 20 1 6 J u l ; 1 28( 1 ) : 1 8 1 - 1 94.

as a l :X ratio or as a percentage. he positive-predictive value is directly afected by disease prevalence, so it is much higher for women aged 35 years and older than for younger women (Table 1 4-5) . Positive-predictive values can also be reported for cohorts of pregnancies. For example, the positive-predictive

value reported in a research trial is the proportion of women with positive screening results who have afected fetuses (see Table 1 4-4) . Negative-predictive value is the proportion of those with a negative screening test result who have unafected (euploid) fetuses. Because the prevalence of aneuploidy is so

TABLE 1 4-4. Cha racteristics of Scree n i n g Tests for Trisomy 2 1 in Singletons Detection Rate

False-Positive Rate

PositivePredictive Va l uea

Quadruple screen: AFP, hCG, estriol, i n h i b i n

80-82%

5%

3%

F i rst-tri mester screen: NT, hCG, PAP P-A F i rst-tri mester NT a l o n e

80-84% 64-70%

5% 5%

3-4%

I ntegrated scree n i ng

94-96%

5%

5%

Sequential screening: Stepwise Conti ngent

92% 91%

5.1 % 4.5%

5% 5%

99%

0. 1 % 4-8%

Ta b l e 1 4-5 4%

Screening Test

Cell -free DNA screen ing: Positive res u l t Low fetal fraction or no res u l t

aThe positive-pred i ctive va l u e represents the overa l l popu lation stud ied a n d can not be a p pl ied to a ny i n d i vi d u a l patient. AFP = a l p ha-fetop rote i n ; hCG = h u ma n chorionic g o nadotro p i n; NT = n u c h a l tra n s l u ce n cy; PA.P P-A = preg n a ncy-associ ated plasma prote i n A. Data from Baer, 20 1 5; Gil, 20 1 5; Ma lone, 200S b; j\lorton, 20 1 5; Perga ment, 20 1 4; Quezada, 20 1 5; Dashe, 20 1 6.

P ren ata l D i a g nosis

TABLE 1 4-5. Positive-Pred ictive Va l u e of Cel l -Free D N A Scree n i ng for Autosomal Triso m i es a n d Se lected Sex C h romosome Abnorma l ities, Accord i n g to Matern a l Age Materna l Age

Trisomy 21

Trisomy 18

Trisomy 1 3

45,X

47,XXY

20 25 30 35 40 45

48% 51% 61% 79% 93% 98%

1 4% 5% 21% 3 9% 69% 90%

6% 7% 1 0% 21% 50% NA

41 % 41 % 41% 41% 41 % 41%

29% 29% 29% 30% 5 2% 77%

N A = not ava i l a ble; �� I PT = n o n-i nvasive prenata l test. Pos itive-predictive va l u es were o bta i ned u s i ng the N I PT/Cel 1 F ree DNA Scree n i ng P red ictive Va l u e Ca l c u lator fro m the Pe rinata l Q u a l ity Fou nd ation, 20 1 7. Ca l c u l ations a re based on p reva l e n ce at 1 6 weeks' g estation u s i ng sensitivities and s pecific ities from G i l , 20 1 5 .

low, the negative-predictive value of all aneuploidy screening tests generally exceeds 99 percent (Gil, 20 1 5; Norton, 20 1 5) . • Traditional Aneuploidy Screening Tests

hese screening tests have multiple markers or analytes and are also called conventional or traditional to diferentiate them from cell-free DNA-based screening. There are three categories: irst-trimester screens, second-trimester screens, and combina­ tions of irst- and second-trimester screens. If the test has a irst­ trimester component, it almost always includes a measurement of the sonographic nuchal translucency, which is discussed in the next section. Each maternal serum analyte is measured as a concentra­ tion-for example, nanograms per milliliter of AFP. he con­ centration is converted to a multiple of the median (MoM) by adjusting for maternal age, maternal weight, and gestational age. he nuchal translucency measurement increases with crown-rump length (CRL) , and thus its value is adjusted for CRL and also reported as an MoM. The AFP analyte is further adjusted for maternal race and ethnicity and for presence of diabetes, which all afect the calculation of neural-tube defect risk rather than of aneuploidy risk (Greene, 1 988; Huttly, 2004) . Reporting these results as an MoM of the unafected population normalizes the distribution of analyte levels and permits comparison of results from diferent laboratories and populations. he analyte-based aneuploidy screening result is based on a composite likelihood ratio, and the maternal age-related risk is multiplied by this ratio. his principle similarly applies to modiication of fetal Down syndrome risk by selected sono­ graphic markers, which are discussed later on page 286. Each woman is provided with a speciic risk for trisomy 2 1 and for trisomy 1 8-or in the irst trimester, for trisomy 1 8 or 1 3 in some cases. he result is expressed as a ratio that represents the positive-prediCtive value. Importantly, each screening test also has a predetermined value at which or above which it is deemed "positive" or abnor­ mal. For second-trimester tests, this threshold has traditionally been set at the risk for fetal Down syndrome in a woman aged

35 years-approximately 1 in 270 in the second trimester (see Table 1 4- 1 ) . he threshold selected for a positive screen relects the laboratory requirement but is somewhat problematic, as it may bear no relationship to patient preference. However, a pos­ itive screening result may afect whether the patient is deemed "high risk," receives formal genetic counseling, and is ofered diagnostic testing with chorionic villus sampling or amn iocen­ tesis. Thus, it behooves the provider to discuss the patient's preferences prior to screening. F i rst-Trim ester A n e u ploidy Scre en i ng

Also called combined irst-trimester screening, this test com­ bines two maternal serum analytes, human chorionic gonad­ otropin (hCG) and pregnancy-associated plasma protein A (PAPP-A) , with the sonographic measurement of the nuchal translucency (NT) . It is performed between 1 1 and 14 weeks' gestation. In cases of fetal Down syndrome, the irst-trimester serum free 3-hCG level is higher and the PAPP-A level is lower. With trisomy 1 8 and trisomy 1 3, levels of both analytes are lower (Cuckle, 2000; Malone, 2005b) . Nuchal Transl ucency. his is the maximum thickness o f the subcutaneous translucent area between the skin and soft tissue overlying the fetal spine at the back of the neck (Fig. 1 4-2) . An increased NT thickness is not a fetal abnor­ mality but rather is a marker that confers i ncreased risk. It is measured in the sagittal plane and is valid when the CRL value lies between 38 to 45 mm and 84 mm, with the lower limit varying according to the laboratory. Speciic criteria for NT measurement are listed in Table 1 0-4 (p. 1 86). When­ ever possible, it is helpful to diferentiate increased NT from cystic hygroma, which is a venolymphatic malformati o n that appears as a septated hypoechoic space behind the n eck, extending along the length of the back (Fig. 1 0-22, p. 1 98 ) . Cystic hygroma confers a ivefold increased aneuploidy risk when identiied in the irst trimester (Malone, 2005a) . In addition to aneuploidy, an increased NT thickness is asso­ ciated with other genetic syndromes and various birth defects, especially fetal cardiac anomalies (Simpson, 2007) . And, if the NT measurement reaches 3 mm or more, the aneuploidy risk

28 1

282

The Feta l Patient

3-hCG and PAPP-A levels are approximately double the sin­ gleton values (Vink, 20 1 2) . Even with speciic curves, a normal dichorionic cotwin will tend to normalize screening results, and thus, the aneuploidy detection rate is at least 1 5-percent lower (Bush, 2005) . Maternal age afects the performance of first-trimester aneu­ ploidy screening. Prospective trials have demonstrated Down syndrome detection rates of 67 to 75 percent in women younger than 35 years at delivery, which are 1 0 percent lower than the overall detection rates in these studies (Malone, 2005b; Wap­ ner, 2003) . Among women older than 35 at delivery, Down syndrome detection reached 90 to 95 percent, albeit at a higher false-positive rate of 1 5 to 22 percent. U n explai ned Abnormal ities of Fi rst-Tri mester Ana­ Iytes. There is a signiicant association between serum PAPP­

FIGURE 1 4-2 Sagittal i mage of a normal, 1 2-week fetus demon­ strati n g correct ca l i per placement (+) for n uchal tra n s l ucency mea­ s u rement. The feta l nasal bone and overlyi n g ski n a re i nd icated. The nasal tip and the 3 rd a nd 4th ventricles (asterisk), which a re other l a n d m a rks that should be visi ble in the nasal bone i mage, a re a l so shown. (U sed with perm ission from Dr. Michael Za retsky.)

is unlikely to normalize using serum analyte assessment (Com­ stock, 2006) . Because of this, if the NT measurement is at least 3 mm or exceeds the 99th percentile, the patient should receive counseling and be ofered targeted sonography with fetal echo­ cardiography. In addition, she should be ofered cell-free DNA screening and prenatal diagnosis (American College of Obste­ tricians and Gynecologists, 20 1 6c) . The NT must be imaged and measured with a high degree of precision for aneuploidy detection to be accurate. This has led to standardized training, certiication, and ongoing quality review programs. In the United States, training, credentialing, and monitoring are available through the Nuchal Translucency Quality Review program of the Perinatal Quality Foundation and through the Fetal Medicine Foundation. Efficacy of F i rst-Tri mester Scree n i n g . Before first-trimester screening became widely adopted, four large prospective tri­ als were conducted, together including more than 1 00,000 pregnancies (Reddy, 2006) . When the false-positive rate was set at 5 percent, the overall rate for trisomy 2 1 detection was 84 percent, comparable to quadruple-marker screening (see Table 1 4-4) . he detection rate is approximately 5 percent higher if performed at 1 1 weeks' compared with 1 3 weeks' gestation, and slightly lower-80 to 82 percent-when cases with cystic hygroma are analyzed separately (Malone, 2005a) . In a recent multicenter trial, first-trimester screening detected approximately 80 percent of fetuses with trisomy 2 1 , 8 0 percent with trisomy 1 8, and 5 0 percent with trisomy 1 3 (Norton, 20 1 5) . As an isolated marker, NT detects approximately two thirds of fetuses with Down syndrome, with a false-positive rate of 5 percent (Malone, 2005b) . However, NT is generally used as an isolated marker only in screening for multifetal gestations, in which serum screening is less accurate or may not be avail­ able. he NT distribution is similar in twins and singletons (Cleary-Goldman, 2005) . In twin pregnancies, serum free

A levels below the 5th percentile and preterm birth, growth restriction, preeclampsia, and fetal demise (Cignini, 20 1 6; D ugof, 2004; Jellife-Pawlowski, 20 1 5) . S imilarly, low levels of free 3-hCG have been associated with fetal demise (Goetzl, 2004) . he sensitivity and positive-predictive values of isolated markers are generally too low to make them clinically useful as screening tests. There has been renewed interest in low-dose aspirin for pre­ vention of early preeclampsia in women identified as at risk based on mean arterial pressure, uterine artery Doppler values, and PAPP-A levels. However, these observations are prelimi­ nary (Park, 20 1 5) . Second-Tr i m ester Aneu pl oidy Screen i n g

Currently, the only second-trimester multiple marker test widely used in the United States is the quadruple marker or "quad" screening test. It is performed from 1 5 to 21 weeks' gestation, and inclusive gestational age ranges vary according to individual laboratories. Pregnancies with fetal Down syn­ drome are characterized by lower maternal serum AFP, higher hCG, lower unconjugated estriol, and higher dimeric inhibin levels. When the quad screen was initially described, the Down syndrome detection rate approximated 70 percent. But, by the early 2000s, the reported detection rate in two large prospec­ tive trials had improved to 8 1 to 83 percent, with a 5-percent screen-positive rate (Malone, 2005b; Wald, 1 996, 2003) . The improved detection rate is attributable, at least in part, to accu­ rate gestational age assessment with sonography. In a review of more than 500,000 pregnancies receiving quadruple-marker screening through the statewide California Prenatal Screening Program, trisomy 2 1 detection was 78 percent with sonographic gestational age assessment but only 67 percent when the screen was calculated based on last menstrual period alone (Kazerouni, 20 1 1 ) . As with first-trimester screening, aneuploidy detection rates are lower in younger women and higher in women older than 35 years at delivery. If second-trimester serum screening is used in twin pregnancies, aneuploidy detection rates are sig­ nificantly lower (Vink, 20 1 2) . With trisomy 1 8 , the levels of the first three analytes are all decreased, and inhibin is not part of the calculation. Trisomy 1 8 detection is similar to that for Down syndrome, with a false-positive rate of only 0.5 percent (Benn, 1 999).

P re n ata l Diag nosis

Although the quadruple-marker screening test is used to screen for Down syndrome and trisomy 1 8, pregnancies with other chromosomal abnormalities may be identiied as well. The California Prenatal Screening Program found that the quadruple-marker screen result was abnormal in 96 percent of those with triploidy, in 75 percent with Turner syndrome (45,X) , in 44 percent with trisomy 1 3, and in more than 40 percent of those with other major chromosomal abnormalities (Kazerouni, 20 1 1 ) . Although a speciic risk for these aneuploi­ dies cannot be provided based on the test result, the informa­ tion may be relevant for women considering amniocentesis. Quadruple-marker screening ofers no beneit over irst­ trimester screening from the standpoint of trisomy 2 1 or tri­ somy 1 8 detection. As a stand-alone test, it is generally used if women do not begin care until the second trimester or if irst-trimester screening is not available. In 20 1 1 , women who initiated prenatal care beyond the irst trimester made up nearly 25 percent of pregnancies in the United States. As subsequently discussed, combining irst- and second-trimester screening yields an even greater aneuploidy detection rate. Maternal Serum AFP Elevation : Neu ra l-Tu be Defect Screen­ ing. All p regnant women are ofered screening for fetal

open neural-rube defects in the second trimester, either with MSAFP screening or with sonography (American College of Obstetricians and Gynecologists, 20 1 6c) . Measurement of the MSAFP concentration between 1 5 and 20 weeks' ges­ tation has been ofered as part of routine prenatal care for more than 30 years. Because AFP is the major protein in fetal serum, analogous to albumin in a child or adult, the normal concentration gradient between fetal plasma and maternal serum is on the order of 5 0 , 000: 1 . Defects in fetal integument, such as neural-tube and ventral-wall defects, permit AFP to leak into the amnionic fluid, resulting in dramatically increased maternal serum levels. he AFP value rises by about 1 5 percent per week during the screening win­ dow (Knight, 1 992) . he MoM is generally recalculated if the irst-trimester CRL or second-trimester biparietal diam­ eter difers from the stated gestational age by more than 1 week. Using an MSAFP level of 2.5 MoM as the upper limit of normal, the neural-tube defect detection rate is at least 90 per­ cent for anencephaly and 80 percent for spina biida, with a screen-positive rate of 3 to 5 percent (American College of Obstetricians and Gynecologists, 20 1 6a; Milunsky, 2004) . Higher screening threshold values are used in twin pregnancies (Cuckle, 1 990) . Virtually all cases of anencephaly and many cases of spina biida may be detected or suspected during a standard second-trimester sonographic examination (Dashe, 2006) . Most centers now use targeted sonography as the primary method to evaluate elevated MSAFP levels and as the prenatal diagnos­ tic test of choice for neural-tube defects (Chap. 1 0, p. 1 92) . If targeted sonography is not available and myelomeningo­ cele cannot be excluded, amniocentesis may be considered for measurement of amnionic luid AFP and acetylcholinesterase levels. That said, we recommend additional imaging prior to establishing the diagnosis, with the understanding that other

TABLE 1 4-6. Conditions Associated w ith a n Elevated M SA F P Concentration

U n d e resti m ated gestationa l age M u ltifetal g estation Feta l d eath N e u ra l-tu be d efect Ga strosch i s i s O m pha loce le Cystic hyg ro m a Esophagea l or i ntest i na l obstruction Liver n ecrosis Ren a l a no m a l ies-polycystic kid neys, rena l agenesis, co ngen ital n e p h rosis, u ri n a ry tra ct o bstruct i o n C l oaca l exstrophy Osteogenesis i m pe rfecta Sac rococcygea l teratoma Con g e n ita l ski n abnormal ity P i l o n i d a l cyst C h o ri oa ng i oma of pl acenta Pl a ce nta i n tervi l l ous t h ro m bosis P l acenta l a bru ption O l i g oh yd ra m n ios P reecla m psia Feta l-g rowth restri ction Mater n a l h e patoma or terato m a MSAFP

=

m aternal seru m a l p ha-fetop rote i n .

abnormalities or conditions can result in elevation of these amnionic luid analytes (Table 1 4-6) . Sonographic indings characteristic of fetal neural-tube defects are reviewed in Chap­ ter 1 0 (p. 1 92) . Fetal surgery for myelomeningocele is discussed in Chapter 1 6 (p. 3 1 9) . U nexpla i ned Abnormal ities of Second-Tri mester Ana lytes.

he positive-predictive value of an elevated MSAFP value is only 2 percent. Approximately 98 percent of pregnancies with an MSAFP level exceeding 2.5 MoM have an etiology other than a neural-tube defect. hus, counseling is indicated not only to inform the patient about the beneits and limita­ tions of targeted sonography for the diagnosis of neural-tube defects but also to review the numerous other conditions. Some of these include fetal anomalies, placental abnormalities, and adverse outcomes associated with MSAFP level elevation (see Table 1 4-6) . he likelihood of one of these abnormalities or of an adverse pregnancy outcome in the absence of a recog­ nized abnormality rises in proportion to the AFP level. Adverse outcomes include fetal-growth restriction , preeclampsia, pre­ term birth, fetal demise, and stillbirth. More than 40 percent of pregnancies may be abnormal if the MSAFP level is greater than 7 MoM (Reichler, 1 994) . Second-trimester elevation of either hCG or dimeric inhibin alpha levels also shows signiicant association with adverse preg­ nancy outcomes. he outcomes reported are similar to those associated with MSAFP level elevation. Moreover, the likeli­ hood of adverse outcome is augmented when levels of several markers are elevated (Dugof, 2005).

283

284

The Feta l Patient

Many of these complications are assumed to result from placental damage or dysfunction. However, the sensitivity and positive-predictive values of these markers are considered too low to be useful for screening or management. No speciic pro­ gram of maternal or fetal surveillance has been found to favor­ ably afect pregnancy outcomes (Dugof, 20 1 0) . At Parkland Hospital, prenatal care for these women is not altered unless a specific complication arises. Despite the extensive list of pos­ sible adverse outcomes, it is reassuring that most women with unexplained elevation of these analytes have normal outcomes. Low Materna l Serum Estriol Level. A maternal serum estriol level

less than 0.25 MoM has been associated with two uncommon but important conditions. he irst, Smith-Lemli-Opitz syndrome, is an autosomal recessive condition resulting from mutations in the 7-dehydrocholesterol reductase gene. It is characterized by abnormalities of the central nervous system, heart, idney, and extremities; with ambiguous genitalia; and with fetal-growth restriction. For this reason, the Society for Maternal-Fetal Medicine has recommended that sonographic evaluation be per­ formed if an unconjugated estriol level is 1 80 beats per minute (bpm) ; bradyarrhythmia, heart rate < 1 1 0 bpm; and ectopy, typically pre­ mature atrial contractions. If these are identiied, fetal M-mode sonography is performed to measure the atrial and ventricular rates and to clariY the relationship between atrial and ventricular beats, thereby diagnosing the type of rhythm disturbance. P remat u re Atria l Contracti o n s

This is by far the most common arrhythmia and is identiied in 1 to 2 percent of pregnancies (Hahurij, 20 1 1 ; Strasburger, 20 1 0) . Generally a benign inding, premature atrial contrac­ tions represent immaturity of the cardiac conduction system, and they typically resolve later in gestation or in the neona­ tal period. If the premature atrial contraction is conducted, it sounds like an extra beat when auscultated with handheld Dop­ pler or fetoscope. However, premature atrial contractions are more commonly blocked and sound like dropped beats. In general, premature atrial contractions are not associated with major structural cardiac abnormalities, although they sometimes occur with an atrial septal aneurysm. As shown in Figure 1 0-34 (p. 205), M-mode evaluation demonstrates that the dropped beat is a compensatory pause following the prema­ ture atrial contraction. They may occur as frequently as every other beat, known as blocked atrial bigeminy. This results in an auscultated fetal ventricular rate as low as 60 to 80 bpm. Unlike other causes of bradycardia, atrial bigeminy is benign and does not require treatment (Strasburger, 20 1 0) .

31 6

The Feta l Pati ent

Approximately 2 percent of fetuses with premature atrial contractions are later found to have a supraventricular tachycar­ dia (Copel, 2000; Srinivasan, 2008) . Given the importance of identiying and treating supraventricular tachyarrhythmias, a fetus with premature atrial contractions is often monitored with heart rate assessment every 1 to 2 weeks until the ectopy resolves. This requires neither sonography nor fetal echocardiography, as the rate and rhythm may be easily ascertained with handheld Doppler. Tac hyarrhyt h m ia s

The two most common tachyarrhyth­ mias are supraventricular tachycardia (ST) and atrial lutter. SVT is charac­ terized by an abrupt increase in the fetal heart rate to 1 80 to 300 bpm with 1 : 1 atrioventricular concordance. he typi­ cal range is 200 to 240 bpm. ST may FIGURE 1 6- 1 Atri a l fl utter. In this M-mode i mage at 28 weeks' gestation, ca l i pers mark the ventri c u l a r rate, which is approxi m ately 225 bpm. There a re two atrial beats (A) for develop secondary to an ectopic focus or each ventri c u l a r beat (), such that the atrial rate is a pprox i m ately 450 bpm with 2:1 to an accessory atrioventricular pathway atrioventric u l a r block. leading to a reentrant tachycardia. Atrial lutter is characterized by a much higher many cases, additional agents are needed, particularly i f hydrops atrial rate, generally 300 to 500 bpm, with varying degrees of has developed. SVT is generally more likely than atrial flutter atrioventricular block. As a result, the ventricular rate in a fetus to convert to a normal rhythm. With either arrhythmia, how­ with atrial flutter may range from below normal to approxi­ ever, the overall neonatal survival rate now exceeds 90 percent mately 250 bpm (Fig. 1 6- 1 ) . In contrast, fetal sinus tachycardia (Ekman-Joelsson, 20 1 5; Jaeggi, 20 1 1 ; van der Heijden, 20 1 3) . typically presents with a gradual heart rate rise to a rate that is only slightly above normal. With this, readily discernible Bradya rrhyt h m ia causes may be maternal fever or hyperthyroidism, or rarely, The most common etiology of pronounced fetal bradycardia is fetal anemia or infection. If a fetal tachyarrhythmia is identified, it is important to congenital heart block. Approximately 50 percent of cases occur determine whether it is sustained-deined as present for at least in the setting of a structural cardiac abnormality involving the conduction system. hese include heterotaxy, in particular lt­ 50 percent of the time. It may be necessary to monitor the fetal heart rate for 1 2 to 24 hours upon initial detection, and atrial isomerism; endocardial cushion deect; and less commonly corrected transposition of the great vessels (Srinivasan, 2008) . then periodically to reassess (Srinivasan, 2008) . Unsustained or intermittent tachyarrhythmias generally do not require treat­ he prognosis of heart block secondary to a structural cardiac anomaly is extremely poor, and fetal loss rates exceed 80 per­ ment, provided that fetal surveillance is reassuring. cent (Glatz, 2008; Strasburger, 20 1 0) . Sustained fetal tachyarrhythmia with ventricular rates exceed­ I n a structurally normal heart, 8 5 percent of atrioventric­ ing 200 bpm impairs ventricular illing to a degree that the risk for hydrops is significant. With atrial flutter, lack of coordinated ular block cases develop secondary to transplacental passage atrioventricular contractions may further compound this risk. of maternal anti-SSA/Ro or anti-SSB/La antibodies (Buyon, Maternal administration of antiarrhythmic agents that cross the 2009) . Many of these women have, or subsequently develop, placenta may convert the rhythm to normal or lower the baseline systemic lupus erythematosus or other connective tissue dis­ ease (Chap. 59, p. 1 1 42) . he risk of third-degree heart block heart rate to forestall heart failure. Therapy may require dosages at the upper end of the therapeutic adult range. Thus, a maternal with these antibodies is small-only about 2 percent. But, the electrocardiogram is obtained before and during therapy. risk may reach 20 percent if a prior infant has been afected. Immune-mediated congenital heart block confers a mortality Antiarrhythmic medications most commonly used include digoxin, sotalol (Betapace) , flecainide (Tambocor) , and pro­ rate of 20 to 30 percent, requires permanent pacing in two thirds of surviving children, and also poses a risk for cardio­ cainamide (Pronestyl) . heir selection depends on the type of tachyarrhythmia as well as provider familiarity and experience myopathy (Buyon, 2009) . If associated with efusions, brady­ arrhythmias, or endocardial ibroelastosis, neonatal status may with the drug. Traditionally, digoxin has been the initial pre­ ferred treatment, although it may poorly transfer to the fetus progressively worsen after birth (Cuneo, 2007) . after hydrops has developed. Many centers now use lecainide Initial research eforts focused on maternal corticosteroid or sotalol as first-line therapy Gaeggi, 20 1 1 ; Shah, 20 1 2) . I n therapy to potentially reverse fetal heart block or forestall it.

Feta l The ra py

Friedman and colleagues (2008, 2009) conducted a prospective multicenter trial of pregnancies with anti-SSA/Ro antibodies­ the PR Interval and Dexamethasone (PRIDE) study. Weekly sonographic surveillance was performed, and heart block was treated with maternal oral dexamethasone 4 mg daily. Unfortu­ nately, progression from second- to third-degree block was not prevented with maternal dexamethasone therapy, and third­ degree atrioventricular block was irreversible. In rare cases, there was a potential benefit in reversing irst-degree atrioventricular block. However, irst-degree block did not generally progress even without treatment. In a subsequent review of 1 56 preg­ nancies with isolated second- or third-degree fetal heart block, dexamethasone therapy similarly did not afect disease progres­ sion, need for pacemaker in the neonatal period, or overall sur­ vival rates (Izmirly, 20 1 6) . hus, dexamethasone use cannot be recommended for this indication. More recent eforts have turned to potential therapy with hydroxychloroquine (Plaquenil) , a mainstay of treatment for systemic lupus erythematosus (Chap. 59, p. 1 1 42) . In a multi­ center review of more than 250 pregnancies in women whose prior pregnancies had been complicated by neonatal lupus, recurrence of congenital heart block was signiicantly lower if the woman had been treated with hydroxychloroquine during pregnancy (Izmirly, 20 1 2) . Research in this area is ongoing. Maternal terbutaline has also been given to increase the fetal heart rate in cases with sustained bradycardia of any cause in which the fetal heart rate is below 55 bpm. Reversal of hydrops with this therapy has been reported (Cuneo, 2007, 20 1 0) . • Congenital Adrenal Hyperplasia

Several autosomal recessive enzyme deiciencies cause impaired fetal synthesis of cortisol from cholesterol by the adrenal cortex. his results in congenital adrenal hyperplasia (CAH) . CAH is the most common etiology of androgen excess in females with 46,X disorders of sex development, formerly female pseudo­ hermaphroditism (Chap. 3, p. 4 1 ) . Lack of cortisol stimulates adrenocorticotrophic hormone (ACTH) secretion by the ante­ rior pituitary, and the resulting androstenedione and testos­ terone overproduction leads to virilization of female fetuses. Sequelae may include formation of labioscrotal folds, persis­ tence of a urogenital sinus, or even creation of a penile urethra and scrotal sac. More than 90 percent ofCAH cases are caused by 2 1 -hydrox­ ylase deficiency, which is found in classic and nonclassic forms. he incidence of classic CAH approximates 1 : 1 5000 births overall and is higher in selected populations. For example, it has been reported in approximately 1 :300 Yupik Eskimos (Nimkarn, 20 1 0) . Among those with classic CAH, 75 percent are at risk for salt-wasting adrenal crises and require postnatal treatment with mineralocorticoids and glucocorticoids to pre­ vent hyponatremia, dehydration, hypotension, and cardiovas­ cular collapse. The remaining 25 percent with classic CAH have the simple virilizing ype and also require glucocorticoid supplementation. As discussed in Chapter 32 (p. 6 1 4) , all states mandate newborn screening for CAH. he eicacy of maternal dexamethasone treatment to suppress fetal androgen overproduction and either obviate or

ameliorate virilization of female fetuses has been recognized for more than 30 years (David, 1 984; New, 20 1 2) . Prenatal corti­ costeroid therapy is considered successful in 80 to 85 percent of cases (Miller, 20 1 3; Speiser, 20 1 0) . The alternative is con­ sideration of postnatal genitoplasty, a complex and somewhat controversial surgical procedure (Braga, 2009) . he tpical preventive regimen is oral dexamethasone given to the mother at a dosage of 20 Lg/kg/d-up to 1 .5 mg per day, divided in three doses. The critical period for external genitlia development is 7 to 1 2 weeks' gestation, and treatment to pre­ vent virilization should be initiated by 9 wees-bore it is known whether the etus is at risk. Because this is n autosomal recessive condition, ffected females mke up only 1 in 8 at-risk conceptions. Typically, carrier parents are identified after the birth of an afected child. Molecular genetic testing is clinically available, initially using sequence analysis of the CP21A2 gene, which encodes the 2 1 -hydroxylase enzyme (Nimkarn, 20 1 6) . If this is uninformative, gene-targeted deletion/duplication analy­ sis is performed, and additional testing such as whole exome sequencing may be considered (Chap. 1 3, p. 272) . A goal of prenatal diagnosis is to limit dexamethasone expo­ sure in males and in unafected females. Prenatal diagnosis with molecular genetic testing may be performed on chorionic villi-at 10 to 12 weeks' gestation-or on amniocytes after 1 5 weeks. Cell-free DNA testing of maternal serum has potential to replace invasive tests such as chorionic villus sampling and amniocentesis for CAH (Chap. 1 3 , p. 273). Determinatio n of fetal gender using cell-free fetal DNA has at least 95-percent sensitivity when performed at or beyond 7 weeks' gestation (Devaney, 20 1 1 ) . In the research setting, cell-free DNA testing using hybridization probes lanking the CP21A2 gene can be efective as early as 5 617 weeks' gestation (New, 20 1 4) . Maternal treatment with dexamethasone has become a topic of signiicant controversy. The Endocrine Society recommends that treatment be given only in the context of research protocols (Miller, 20 1 3; Speiser, 20 1 0) . It should be noted that if therapy is initiated shortly before 9 weeks, the dose of dexamethasone used is not considered to have significant teratogenic poten­ tial because organogenesis of major organs has already taken place (McCullough, 20 1 0) . Ongoing concerns, however, focus on the potential efects of either excess endogenous androgens or excess exogenous dexamethasone on the developing brain . Although maternal dexamethasone has been used for many years to prevent virilization of female fetuses with CAH, long­ term safety data are relatively limited. • Congenital Cystic Adenomatoid

Malformation Sonographically, this malformation is a well-circumscribed lung mass that may appear solid and echogenic or may have one or multiple variably sized cysts (Fig. 1 0-24, p. 1 99) . Lesions with cysts � 5 mm are termed macrocystic, whereas microcystic lesions have smaller cysts or appear solid (Adzick, 1 985) . Also called congenital pulmonary airway malformation (CPAM), it represents a hamartomatous overgrowth of terminal bronchi­ oles. Therapy for macrocystic congenital cystic adenomatoid malformation (CCAM) is discussed later (p. 324) .

317

318

The Feta l Patient

Occasionally, a microcystic CCAM may demonstrate rapid growth, generally between 1 8 and 26 weeks' gestation. he mass may become so large that it causes mediastinal shift, which may compromise cardiac output and venous return, resulting in hydrops (Cavoretto, 2008) . A CCAM-volume ratio (CVR) has been used to quantiy size and risk for hydrops in these severe cases (Crombleholme, 2002) . his ratio is an esti­ mate of the CCAM volume (length X width X height X 0. 52) divided by the head circumference. In a series of 40 pregnan­ cies with microcystic CCAM, the mean CVR was 0.5 at 20 weeks' gestation, peaking in size at 1 .0 at 26 weeks, followed by a pronounced decline prior to delivery (Macardle, 20 1 6) . A third o f fetuses had n o increase i n mass size. I n the absence of a dominant cyst, a CVR exceeding 1 .6 is associated with a hydrops risk as high as 60 percent. However, CCAM growth resulting in hydrops develops in fewer than 2 percent of cases if the initial CVR is below 1 .6 (Ehrenberg-Buchner, 20 1 3; Peran­ teau, 20 1 6) . Importantly, a CVR in the range of 1 .6 indicates that the mass essentially fills the thorax, and thus it is not unex­ pected that ascites or hydrops may develop. If the CVR exceeds 1 .6 or if signs of hydrops develop, cortico­ steroid treatment has been used in an efort to improve outcome. Regimens include dexamethasone-6.25 mg every 1 2 hours for four doses, or betamethasone- 1 2 . 5 mg intramuscularly every 24 hours for two doses. Following a single course of cortico­ steroids, hydrops resolved in approximately 80 percent of cases, and 90 percent of treated fetuses survived (Loh, 20 1 2; Peranteau, 20 1 6) . Recently, multiple courses of steroids-generally two­ have been advocated for fetuses with large CCAM lesions and with persistent or worsening hydrops or ascites despite a single course of medication (Derderian, 20 1 5; Peranteau, 20 1 6) . • Thyroid Disease

Identification of fetal thyroid disease is rare and usually prompted by sonographic detection of a fetal goiter. If a goiter is found, determination of fetal hyper- or hypothyroidism is essential, and thyroid hormone levels may be measured in amni­ onic luid or fetal blood. Traditionally, fetal blood sampling, described in Chapter 14 (p. 294) , is preferred to amniocentesis for guiding treatment, although data are limited (Abuhamad, 1 99 5 ; Ribault, 2009) . Goals of therapy are correction of the physiological abnormality and diminished goiter size. The goi­ ter may compress the trachea and esophagus to such a degree

that severe hydramnios or neonatal airway compromise may develop. Hyperextension of the fetal neck by a goiter can create labor dystocia. Feta l Thyrotoxicosis

Untreated fetal thyrotoxicosis may present with goiter, tachy­ cardia, growth restriction, hydramnios, accelerated bone matu­ ration, and even heart failure and hydrops (Huel, 2009; Peleg, 2002) . The cause is usually maternal Graves disease with trans­ placental passage of IgG thyroid-stimulating immunoglobulins. Fetal blood sampling may confirm the diagnosis (Duncombe, 200 1 ; Heckel, 1 997; Srisupundit, 2008) . Conirmed fetal thyrotoxicosis is followed by maternal antithyroid treatment. During this, if the mother develops hypothyroidism, she is given supplemental levothyroxine (Hui, 20 1 1 ) . Fetal Hypothyroidism

I n a woman receiving medication for Graves disease, transpla­ cental passage of methimazole or propylthiouracil may cause etal hypothyroidism (Bliddal, 20 1 1 a) . Other potential causes of fetal hypothyroidism resulting in goiter include transplacental passage of thyroid peroxidase antibodies, fetal thyroid dyshor­ monogenesis, and maternal overconsumption of iodine supple­ ments (Agrawal, 2002; Overcash, 20 1 6) . Goitrous hypothyroidism may lead to hydramnios, neck hyperextension, and delayed bone maturation. If the mother is receiving antithyroid medication, discontinuation is generally recommended, along with intraamnionic levothyroxine injection. Numerous case reports describe intraamnionic levothyroxine treatment. However, optimal dosage and frequency have not been established, and reported dosages range from 50 to 800 �g every 1 to 4 weeks (Abuhamad, 1 995; Bliddal, 20 1 1 b; Ribault, 2009) .

SURGICAL TH ERAPY Also called maternaletal surgery, these procedures are ofered for selected congenital abnormalities in which the likelihood of fetal deterioration is so great that delaying treatment until after delivery would risk fetal death or substantially greater postnatal morbidity. Open fetal surgef) is a highly specialized interven­ tion performed at relatively few centers in the United States and for only a few fetal conditions. Criteria for consideration of fetal surgery are listed in Table 1 6- 1 . In many cases, data regarding the safety and eicacy of these procedures are limited.

TABLE 1 6-1 . G u i d i ng Pri n c i p les for Feta l Surg ica l Procedures Accu rate prenatal d i a g n osis for t h e defect is ava i l a bl e, with stag i n g if a pp l ica ble The defect a ppears isolated, with n o evi dence of other a bnormal i ty or u nderly i n g genetic syn d rome that wou l d s i g n ifica ntly worse n su rviva l o r q u a l ity o f l ife The defect res u lts i n a h i g h l i ke l i h ood of death or i r reve rsi ble o rg a n destruction, and postnata l th era py is i nadequate The p roced u re i s tec h n ica l ly fea S i ble, and a m u ltid isci p l i n a ry tea m i s in a g ree ment regard i n g the treatment p l a n Maternal risks from the p roced u re a re wel l d ocu mented a n d co nsid ered accepta ble Th e re i s com p rehensive parenta l co u n sel i ng It is recom m e nded that there be a n a n i ma l model for the defect a n d p roced u re Data fro m Deprest, 20 1 0; H a r r i so n , 1 982; Vrecen a k, 20 1 3; Wa l s h, 201 1 .

Fetal T h e ra py

TABLE 1 6-2. Sel ected Feta l Abnormal ities Amena b l e to Feta l S u rgery Open Feta l Surgery

Myelomen i n gocele Con g e n ita l cysti c adeno mato i d ma lfo rmation ((CAM) Extra lobar p u l m o n a ry seq u estration Sacrococcygeal terato ma Fetoscopic Surgery

Twi n-tw i n tra nsfu s i o n : laser of place nta l a nastomoses D i a p h rag matic hern ia : feta l e n doscopic tracheal occ l u s i o n (F ETO) Poster i or u reth ra l va lves: cystoscopic laser Con g e n ita l h i g h a i rway obstruction : voca l cord laser A m n i o n i c band re lease Percuta neous Proced u res

Sh u nt th era py Posterior- u reth ra l va lves/bladder outlet o bstructi o n Pleu ra l effu sion : chylothorax o r seq u estration Do m i n ant cyst in CCAM Radiofreq u e ncy a b lation Twi n-reve rsed a rterial pe rfu s i o n (TRAP) seq uence Monochor i o n i c twi n s with severe a nomaly i n 1 twi n Chorioa n g ioma Feta l i ntraca rd iac catheter proced u res Aortic or p u l m o n i c va l v u l o p l asty for stenosis Atrial septosto my fo r hypo plastic left hea rt with restrictive atrial sept u m Ex-Utero I ntra partum Treatment (EXIT) Proced ures

Con g e n ita l d i a p h ra g matic hern ia after F ETO Congen ita l h i g h a i rway o bstruction sequence (CHAOS) Seve re m i c rog nath ia Tu mors i nvo l v i n g neck o r a i rway EXIT-to-resection : resecti o n of feta l thoracic or med iasti n a l mass EX IT-to-extracorpo rea l m e m b ra n e oxygenation (E(MO): co ngen ita l d i a p h ra g matic hernia

he Agency for Healthcare Research and Quality stresses that when considering fetal surgery, the overriding concern must be maternal and fetal safety. Accomplishing the fetal goals of the procedure is secondary (Walsh, 20 1 1 ) . Some abnormalities amenable t o fetal surgical treatment, antepartum or intrapartum, are shown in Table 1 6-2. An over­ view of these procedures, their indications, and complications is provided here to assist with initial patient evaluation and counseling. Additional content is also found in Cunningham and Gilstrap s Operative Obstetrics, 3rd edition. • Open Fetal Surgery

These procedures require extensive preoperative counseling and multidisciplinary care. he mother must undergo general endotracheal anesthesia to suppress both uterine contractions and fetal responses. Using intraoperative sonographic guid­ ance to avoid the placental edge, a low-transverse hysterotomy

incision is made with a stapling device that seals the edges for hemostasis. To replace amnionic fluid losses, warmed l uid is continuously infused into the uterus thorough a rapid infusion device. he fetus is gently manipulated to permit pulse oxim­ etry monitoring and to establish venous access, in case l uids or blood are emergently needed. The surgical procedure is then performed. After completion, the hysterotomy is closed and tocolysis begun. Tocolysis typically includes intravenous mag­ nesium sulfate for 24 hours, oral indomethacin for 48 hours, and, at some centers, oral nifedipine until delivery (Wu, 2 009) . Prophylactic antibiotics are also administered and generally continued for 24 hours following the procedure. Cesarean delivery is needed later in gestation and for all future deliveries. R i s ks

Morbidities associated with fetal surgery are well characterized. In a review of 87 open procedures, Golombeck and cowork­ ers (2006) reported the following morbidities: pulmonary edema-28 percent, placental abruption-9 percent, blood transfusion-13 percent, premature rupture of membranes-52 percent, and preterm delivery-33 percent. Wilson and associ­ ates (20 1 0) reviewed subsequent pregnancy outcomes following open fetal surgery and reported that 14 percent of women expe­ rienced uterine rupture and 14 percent had uterine dehiscence. Morbidities identiied in the recent Management ofMyelomenin­ gocele Study (MOMS) are shown in Table 1 6-3 (Adzick, 20 1 1 ) . Other potential risks include maternal sepsis and fetal death dur­ ing or following the procedure, particularly if hydrops is present. Mye l o m e n i n goce l e S u rg ery

Even with postnatal repair, children with myelomeningocele gen­ erally have varying degrees of paralysis, bladder and bowel dys­ function, developmental delays, and brainstem dysfunction from the Arnold-Chiari II malformation (Chap. 1 0, p. 1 93). Damage is postulated to result from abnormal embryonic neurulation and from ongoing exposure of neural elements to amnionic luid (Adzick, 20 1 0 ; Meuli, 1 995, 1 997) . Fetal myelomeningocele meets the criteria listed in Table 1 6- 1 and is the first nonlethal birth defect for which fetal surgery has been ofered (Fig. 1 6-2) . I n preliminary reports, infants following antepartum defect repair were more likely to have reversal of the Arnold-Chiari II malformation and were less likely to require ventriculoperito­ neal shunt placement (Bruner, 1 999; Sutton, 1 999) . S purred by this, the randomized, multicenter MOMS trial was con­ ducted (Adzick, 20 1 1 ) . Criteria for trial participation included: ( 1 ) a singleton fetus at 1 9. 0 to 25.9 weeks' gestation; (2) an upper myelomeningocele boundary between T1 and S 1 con­ irmed by fetal magnetic resonance (MR) imaging; (3) evidence of hindbrain herniation; and (4) a normal karyotype and no evidence of a fetal anomaly unrelated to the myelomeningocele. Women at risk for preterm birth or placental abruption, those with a contraindication to fetal surgery, and women with body mass index > 35 kg/m 2 were excluded. he MOMS indings demonstrated improved early childhood outcomes in the prenatal surgery cohort (see Table 1 6-3) . Children who had undergone prenatal surgery were twice as likely to walk independently by 30 months. hey had signiicantly less hindbrain herniation and were only half

319

320

The Feta l Patient

TABLE 1 6-3. Benefits a n d R i s ks of Feta l Myelomen i ngocele S u rgery versus Postnata l Repa i r

Benefits (Primary Outcomes)

Peri nata l d eath o r s h u nt by 1 2 m o nthsa S h u nt placement by 1 2 months Com posite developmenta l sco rea,b H i n d b ra i n hern iation (any) Bra i n stem ki n ki ng (a ny) I ndependent wa l ki n g (30 months)

Fetal Surgery (n = 78)

Postnatal Surgery (n = 80)

P val ue

68% 40% 1 49 ± 5 8 64% 20% 42%

98% 82% 1 23 ± 5 7 96% 48% 21%

< 0.00 1 < 0.00 1 0.007 < 0.00 1 < 0.00 1 0.0 1

6% 6% 9% 21% 34 ± 3

0 0 1% 4% 37 ± 1

0 .03 0.03 0.03 0.00 1 < 0.00 1

79% 46% 1 3%

1 5% 5% 0

< 0.00 1

Risks

Maternal p u l monary edema P lacental a b r u ption Maternal tra n sfu s i o n at d e l ive ry 01 igo hyd ra m n ios Gestation a l age at del ivery P rete rm b i rth

0 0 l

5

:

10

1 20

500

� > 400 E .. ) � � II 300

11 ­ - )

E � �

� m 200 ) = . _

1 00

18

20

22

24

26

� �

.,

,....

State 1 F

4

" i.

...-... .. , .. � j. "1 � ..I�.. ·{l r �""

State 2 F

..... .'!'�,

F I G U R E 1 7- 1 Feta l bladder vol u me mea s u re me nts together with fetal heart rate ( F H R) va riation record ed i n relation to 1 F or 2F behavior states. State 1 F feta l heart rate has a na rrow ba ndwidth con sistent with q u iet sleep. State 2 F heart rate shows wide oscil­ lation of the base l i n e consistent with active sleep. (Mod ified with permission fro m Oosterhof H, vd Stege JG, La nder M, et al: U ri n e prod uction rate is re lated t o behaviou ra l states i n the near term h u ma n fetus, Br J Obstet Gynaeco l. 1 993 Oct; l 00(1 0):920-922.)

28

30

32

34

Gestational age (weeks)

36

38

40

FIGURE 1 7-2 G ra p h depicts averages of feta l move ments cou nted d u ri n g 1 2-hour periods (mea n ± SEM). (Data from Sadovsky, 1 979a.)

Sadovsky and coworkers ( 1 979b) classiied fetal move­ ments into three categories according to both maternal per­ ceptions and independent recordings using piezoelectric sensors. Weak, strong, and rolling movements were described, and their relative contributions to total weekly movements throughout the last half of pregnancy were quantiied. As pregnancy advances, the rate of weak movements decreases, more vigorous movements increase for several weeks, and then rates of these subside at term. Presumably, declining amni­ onic luid and space account for diminished activity at term. Figure 1 7-2 shows fetal movements during the last half of ges­ tation in 1 27 pregnancies with normal outcomes. he mean number of weekly movements calculated from 1 2-hour daily recording periods rose from approximately 200 at 20 weeks' gestation to a maximum of 575 movements at 32 weeks. Fetal movements then declined to an average of 282 at 40 weeks. Normal weekly maternal counts of fetal movements ranged between 50 and 950. Count showed large daily variations, with included counts as low as 4 to 10 per 1 2-hour period in normal pregnancies. • Clinical Application

20

1 00

600

Diminished fetal activity may be a harbinger of impending fetal death (Sadovsky, 1 973) . To quantiy fetal movement, clinical methods include use of a uterine contraction tocodynamom­ eter, visualization with sonography, and maternal subjective perceptions. Most, but not all, investigators report excellent correlation between maternally perceived fetal motion and movements documented by instrumentation. For example, Rayburn ( 1 980) found that 80 percent of all movements observed dur­ ing sonographic monitoring were perceived by the mother. In contrast, Johnson and colleagues ( 1 992) reported that beyond 36 weeks, mothers perceived only 16 percent of fetal body movements . Fetal motions lasting more than 20 seconds were more likely to be identified than shorter episodes. Although several fetal-movement counting protocols have been used, neither the optimal number of movements nor the ideal dura­ tion for counting them has been defi n ed. For example, in one method, perception of 1 0 fetal movements in up to 2 hours is considered normal (Moore, 1 989). Commonly, women may

Feta l Assessment

present in the third trimester complaining of subjectively reduced fetal movement. Harrington and associates ( 1 998) reported that 7 percent of nearly 6800 women presented with a complaint of decreased fetal movement. Fetal heart rate monitoring tests were employed if sonographic scans for fetal growth or Doppler velocimetry were abnormal. Preg­ nancy outcomes for women who complained of decreased fetal movement were not significantly diferent from those for women without this complaint. Scala and colleagues (20 1 5) reported that 6 percent of women at term reported decreased fetal movements at 36 weeks or more. Women with two or more episodes of reduced fetal movements had greater risks of growth-restricted newborns and abnormal Doppler uter­ ine artery low studies. However, stillbirth rates were not increased. Measurement of the myocardial performance index did not improve accuracy (Ho, 20 1 7) . Grant and coworkers ( 1 989) performed a n unparalleled investigation of maternally perceived fetal movements and pregnancy outcome. More than 68,000 pregnancies were ran­ domly assigned between 28 and 32 weeks' gestation. Women in the fetal movement arm of the study were instructed by specially employed midwives to record the time needed to feel 1 0 movements each day. his required an average of 2.7 hours each day. Women in the control group were informally asked about movements during prenatal visits. Reports of decreased fetal motion were evaluated with tests of fetal well-being. Antepartum death rates for otherwise normal singleton fetuses were similar in the two study groups. Despite the count­ ing policy, most stillborn fetuses were dead by the time the mothers reported for medical attention. Importantly, rather than concluding that maternal perceptions of fetal activity were meaningless, these investigators concluded that informal maternal perceptions were as valuable as formally recorded fetal movement. Saastad and associates (20 1 1 ) reported a total of 1 076 women who were randomly assigned to standardized fetal movement counting from gestational week 28 versus no count­ ing. Growth-restricted fetuses were identiied before birth sig­ niicantly more often when fetal movement counting was used. he rate of I -minute Apgar scores :;3 was signiicant reduced (0.4 versus 2.3 percent) when counting was used. Also, War­ rander and coworkers (20 1 2) described placental pathology in pregnancies complicated by diminished fetal movements. Decreased movement was associated with various placental abnormalities including infarction.

FETAL BREATH ING After decades of uncertainty as to whether the fetus nor­ mally breathes, Dawes and coworkers ( 1 972) showed small inward and outward flows of tracheal fluid in fetal sheep, indicating thoracic movement. These chest wall movements difered from those following birth in that they were discon­ tinuous. Another interesting feature of fetal respiration was paradoxical chest wal movement ( Fig. 1 7-3) . In the newborn or adult, the opposite occurs . One interpretation of the para­ doxical respiratory motion might be coughing to clear amni­ onic fluid debris. Although the physiological basis for the

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breathing relex is not completely understood, such exchange of amnionic fluid appears to be essential for normal lung development (Chap. 7, p. 1 33). Dawes ( 1 974) identiied two types of respiratory movements . The irst are gasps or sighs, which occurred at a frequency of 1 to 4 per minute. The sec­ ond, irregular bursts of breathing, occurred at rates up to 240 cycles per minute. hese latter rapid respiratory movements were associated with rapid eye movement. Badalian and asso­ ciates ( 1 993) studied the maturation of normal fetal b reath­ ing using color low and spectral Doppler analysis of nasal fluid low as an index of lung function. hey suggested that fetal respiratory rate declined in conjunction with increased respiratory volume at 33 to 36 weeks and coincidental with lung maturation. Many investigators have examined fetal breathing move­ ments using sonography to determine whether chest wall move­ ments might reflect fetal health. Several variables in addition to hypoxia were found to afect fetal respiratory movements. These included hypoglycemia, sound stimuli, cigarette smok­ ing, amniocentesis, impending preterm labor, gestational age, the fetal heart rate itself, and labor-during which it is normal for respiration to cease. Because fetal breathing movements are episodic, interpreta­ tion of fetal health when respirations are absent may be tenu­ ous. Patrick and associates ( 1 980) performed continuous 24-hour observation using sonography to characterize fetal breathing patterns during the last 1 0 weeks of pregnancy. A total of 1 224 hours of fetal observation in 5 1 pregnancies were collected, and

333

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The Feta l Patient

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F IG U R E 1 7-4 The percentage of time spent breat h i n g by 1 1 fetu ses at 3 8 to 39 weeks. There is a sign ifica nt i ncrease i n feta l breat h i n g activity after breakfast. Breathing activity d i m i n ished d u r­ i n g the day a nd reached its m i n i m u m between 20:00 a n d 24:00 h o u rs. There was a sig n ificant i ncrease in the percentage of time s pent breathing between 04:00 a n d 07:00 hours, when mothers were as leep. (Ada pted with permission from Patrick J, Ca m p bell K, Carmichael L, et a l : Patterns of h u m a n feta l breath i n g d u ring the last 1 0 weeks of preg n a n cy, Obstet Gynecol . 1 980 J u l;56(1 ):24-30.)

Figure 1 7-4 displays the percentages of time spent breathing near term. Clearly, there is diurnal variation, because breathing substantively diminishes during the night. In addition, breath­ ing activity increases somewhat following maternal meals. Total absence of breathing was observed in some of these normal fetuses for up to 1 22 minutes, indicating that fetal evaluation to diagnose absent respiratory motion may require long periods of observation. The potential for breathing activity to be an important marker of fetal health is unfulilled because of the multiplic­ ity of factors that normally afect breathing. Most clinical applications have included assessment of other fetal biophysi­ cal indices, such as heart rate. As discussed subsequently, fetal breathing has become a component of the biophysical proile.

cord compression, suggesting oligohydramnios, which is often a concomitant of placental insuiciency. Ray and colleagues ( 1 972) used this concept in 66 compli­ cated pregnancies and developed the oytocin challenge test, which was later called the contraction stress test. Intravenous oxytocin is used to stimulate contractions, and the criterion for a positive test result, that is, an abnormal result, is uniform repetitive late fetal heart rate decelerations. These reflected the uterine contrac­ tion waveform and had an onset at or beyond the contraction acme. Such late decelerations could be the result of uteroplacen­ tal insuiciency. In their study, the tests were generally repeated on a weekly basis, and the investigators concluded that negative contraction stress test results, that is, normal results, forecasted fetal health. A major disadvantage is that the average contraction stress test requires 90 minutes to complete. To perform the test, the fetal heart rate and uterine contrac­ tions are recorded simultaneously with an external monitor. If at least three spontaneous contractions of 40 seconds or longer are present in 1 0 minutes, no uterine stimulation is necessary (Ameri­ can College of Obstetricians and Gynecologists, 20 1 6). Con­ tractions are induced with either oxytocin or nipple stimulation if there are fewer than three in 1 0 minutes. For oxytocin use, a dilute intravenous inusion is initiated at a rate of 0.5 mU/min and doubled every 20 minutes until a satisfactory contraction pattern is established (Freeman, 1 975). The results of the contraction stress test are interpreted according to the criteria shown in Table 1 7- l . Nipple stimulation to induce uterine contractions is usually successful for contraction stress testing (Huddleston, 1 984) . One method involves a woman rubbing one nipple through her clothing for 2 minutes or until a contraction begins. This 2-minute nipple stimulation ideally will induce a pattern of three contractions per 1 0 minutes. If not, after a 5-minute interval, she is instructed to retry nipple stimulation to achieve the desired pattern. If this is unsuccessful, then dilute oxytocin may be used. Advantages include reduced cost and shortened testing times. Some have reported unpredictable uterine hyper­ stimulation and fetal distress, whereas others did not find exces­ sive activity to be harmful (Frager, 1 987; Schellpfefer, 1 985).

CONTRACTION STRESS TESTING As amnionic luid pressure rises with uterine contractions, myo­ metrial pressure exceeds collapsing pressure for vessels coursing through uterine muscle. his ultimately lowers blood flow to the intervillous space. Brief periods of impaired oxygen exchange result, and if utero placental pathology is present, these elicit late fetal heart rate decelerations (Chap. 24, p. 466) . Contractions also may produce a pattern of variable decelerations as a result of

NONSTRESS TESTS Freeman ( 1 975) and Lee and colleagues ( 1 975) introduced the nonstress test to describe fetal heart rate acceleration in response to fetal movement as a sign of fetal health. This test involved the use of Doppler-detected fetal heart rate acceleration coincident with fetal movements perceived by the mother. By the end of the 1 970s, the nons tress test had become the primary method of testing fetal

TABLE 1 7-1 . Criteria for I nterpretation of the Contraction Stress Test Negative: no late or s i g n ificant va riable d ecel e rations Positive: late decelerations fol l owi ng 5 0% o r m o re of contractions (even if the contraction fre q u e n cy is fewer than th ree in

1 0 m i n utes) Equivocal-suspicious: i nterm itten t late dece l e rati o n s or s i g n ifi ca nt va ria ble decelerations Equ ivoca l - hypersti m u latory: feta l heart rate decelerat ions that occ u r i n the p resence of contractio n s more freq uent than eve ry 2 m i n utes or last i n g longer than 90 seconds U nsatisfactory: fewer than th ree contractions i n 1 0 m i n utes o r a n u n i nterpreta ble traci n g

Feta l Assess ment

health. he nonstress test was easier to perform, and normal results were used to urther discriminate false-positive contraction stress tests. Simplistically, the nons tress test is primarily a test of etal condition, and it difers from the contraction stress test, which is considered a test of uteropacental onction. Currently, nons tress testing is the most widely used primary testing method for assess­ ment of fetal well-being. It has lso been incorporated into the biophysical profile testing system, subsequently discussed. • Fetal Heart Rate Acceleration

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£ 30 Autonomic inluences are mediated by sympathetic or para­ .� ) sympathetic impulses from brainstem centers to normally raise 20 ) ) or slow the fetal heart rate. Beat-to-beat variability is also under :J D 10 the control of the autonomic nervous system (Matsuura, 1 996) . L Consequently, pathological loss of fetal heart rate acceleration 0 36 40 24 32 28 16 20 may be seen in conjunction with signiicantly decreased beat­ Weeks' gestation to-beat variability (Chap. 24, p. 462) . Loss of such reactivity, however, is most commonly associated with sleep cycles. It also FIGURE 1 7-5 Percentage of fetuses tlith at least one acceleration may be caused by central depression from medications or ciga­ of 1 5 bpm s u stained for 1 5 seco nds concu rrent with feta l move­ rette smoking Oansson, 2005). ment. (Red rawn from P i l l a i M, Ja mes 0: The development of feta l heart rate patterns d u ri n g normal preg n a ncy, Obstet Gynecol . 1 990 The nonstress test is based on the hypothesis that the heart Nov;76(5 Pt 1 ):8 1 2-8 1 6.) rate of a fetus that is not acidemic as a result of hypoxia or neurological depression will temporarily accelerate in response to fetal movement. Fetal movements during testing are identi­ • Normal Nonstress Tests ied by maternal perception and recorded. As hypoxia develops, Criteria to define normal nons tress test results difer. They these fetal heart rate accelerations diminish (Smith, 1 988). vary regarding the number, amplitude, and duration of accel­ Gestational age inluences acceleration or reactivity of the fetal erations and the test duration. he definition recommended heart rate. Pillai and James ( 1 990b) studied the development of by the American College of Obstetricians and Gynecologists fetal heart rate acceleration patterns during normal pregnancy. The (20 1 6) requires two or more accelerations peaking at 1 5 bpm percentage of body movements that is accompanied by accelera­ or more above baseline, each lasting 1 5 seconds or more, and all tions and the amplitude of these accelerations both increase with occurring within 20 minutes of beginning the test (Fig. 1 7-6) . gestational age (Fig. 1 7-5). Guinn and colleagues ( 1 998) studied I t i s also recommended that accelerations with o r without fetal nons tress test results between 25 and 28 weeks' gestation in 1 88 movements be accepted, and that a 40-minute or longer trac­ normal fetuses. Only 70 percent of these normal fetuses demon­ ing-to account for fetal sleep cycles-should be performed strated the required 1 5 beats per minute (bpm) or more of heart before concluding that fetal reactivity is insuicient. Miller and rate acceleration. Lesser degrees of acceleration, that is, 1 0 bpm, occurred in 90 percent of the fetuses. The National Institute of Child NONSTR ESS TEST Health and Human Development Fetal Monitoring Workshop defined normal acceleration based on gesta­ tional age (Macones, 2008) . In fetuses at or beyond 32 weeks' gestation, the acceleration acme is 1 5 bpm or more above the baseline rate, and the accel­ eration lasts 1 5 seconds or longer but less than 2 minutes. Before 32 weeks, normal accelerations are defined as having an acme that is 10 bpm or more above baseline for 1 0 seconds or longer. Cousins and associates (20 1 2) compared the Workshop cri­ teria recommended before 32 weeks, that is, 1 0 bpm/ 1 0 seconds, with standard 1 5 bpm/ 1 5 seconds criteria in a randomized trial of 1 43 women. FIGURE 1 7-6 Reactive nonstress test. In the u p per panel, notice the i ncrease of feta l hea rt rate They found no diferences in perina­ by more than 1 5 beats/min for longer t h a n 1 5 seconds fol lowi ng feta l move m ents, wh ich a re tal outcomes. i nd icated by the vertica l ma rks (lower panen.

335

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The Feta l Patient

coworkers ( 1 996b) reviewed outcomes in fetuses with nons tress tests consid­ ered as nonreactive because there was only one acceleration. hey concluded that one acceleration was j ust as reliable as two in predicting healthy fetal status. Although a normal number and amplitude of accelerations seems to reflect fetal well-being, their absence does not invariably predict fetal compromise. Indeed, some investigators have reported 90-percent or higher false-positive rates (Devoe, 1 986) . Because healthy fetuses may not move for periods of up to 75 minutes, some have considered that a longer duration of nonstress testing might increase the positive-predictive value of an abnormal, that is, nonreactive, test (Brown, 1 98 1 ) . In this scheme, either the test became reactive during a period up to 80 minutes or the test remained non­ reactive for 1 20 minutes, which indicated that the fetus was very ill. Not only do deinitions of normal nonstress test results difer, but the repro­ ducibility ofinterpretations is problematic (Hage, 1 985). Thus, although nonstress testing is popular, the reliability of test interpretation needs improvement. • Abnormal Nonstress Tests

L 240 . I I ! L ..� .. I i ' -- - -... . .. -+-210 --�r -- j- �I � fl+-+-+-35 1 0 mIU/mL. If the initial 3-hCG level exceeds the set discriminatory level and no evidence for an IUP is seen with TVS, then ectopic preg­ nancy is a concern. The diagnosis is narrowed in most cases to a failing IUP, a recent complete abortion, or an ectopic pregnancy. Early multifetal gestation also remains a possibility. Without clear evidence for ectopic pregnancy, serial 3-hCG level assessment is reasonable, and a level is checked 48 hours later. This averts unnecessary methotrexate administration and avoids harming an early normal multifetal pregnancy. With greater concern for an ectopic gestation, D&C is another option to distinguish an ectopic from a failing IUP. I mportantly, patient factors greatly influence these decisions. Levels below the Discriminatoy Zone. If the initial 3-hCG level is below the set discriminatory value, pregnancy location is often not technically discernible with TVS. With these P ULs, serial 3-hCG level assays are done to identiY patterns that indi­ cate either a growing or failing IUP. Levels that rise or fall out­ side these expected parameters increase the concern for ectopic pregnancy. hus, appropriately selected women with a possible ectopic pregnancy, but whose initial 3-hCG level is below the discriminatory threshold, are seen 2 days later for further evalu­ ation. Trends in levels aid diagnosis.

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With early normal progressing IUPs, Barnhart and cowork­ ers (2004b) reported a 53-percent 48-hour minimum rise with a 24-hour minimum rise of 24 percent. Seeber and associates (2006) found an even more conservative minimal 35-percent 48-hour rise in normal IUPs. With multifetal gestation, this same anticipated rate of rise is expected (Chung, 2006) . Despite these guidelines, Silva and colleagues (2006) caution that a third of women with an ectopic pregnancy will have a 53-percent rise at 48 hours. They further reported that no single pattern char­ acterizes ectopic pregnancy and that approximately half of ecto­ pic pregnancies will show decreasing �-hCG levels, whereas the other half will have increasing levels. Also, despite a declining �-hCG level, a resolving ectopic pregnancy may rupture. With a failing IUP, patterned rates of �-hCG level decline can also be anticipated. Following spontaneous abortion, rates decline by 2 1 to 35 percent at 48 hours and 68 to 84 percent at 7 days. Of note, these ranges relect that �-hCG percent­ ages drop faster if the initial �-hCG level is higher (Barnhart, 2004a) . With resolving PULs, Butts and coworkers (20 1 3) found greater rates of decline that ranged from 35 to 50 percent at 48 hours and 66 to 87 percent at 7 days for starting hCG values between 250 and 5000 mIU/mL. In pregnancies without these expected rises or falls in �-hCG levels, distinction between a nonliving IUP and an ectopic pregnancy may be aided by additional �-hCG levels (Zee, 20 1 4) . Again delay is balanced against the risk from rupture. D&C is an option and provides a quicker diagnosis balanced against normal pregnancy interruption. Before curettage, a sec­ ond TVS examination may be indicated and may display new informative indings. Serum Progestero n e

A single serum progesterone measurement may clariy the diag­ nosis in a few cases (Stovall, 1 989, 1 992) . A value exceeding 25 ng/mL excludes ectopic pregnany with 92-percent sensi­ tivity (Lipscomb, 1 999a; Pisarska, 1 998). Conversely, values 1 00,000 mIU/mL, uterine size that is large for gestational age, theca-lutein cysts >6 cm, and slow decline in 3-hCG levels (Berkowitz, 2009; Kang, 20 1 2; Wolfberg, 2005) .

GESTATIONAL TROPHOBLASTIC NEOPLASIA This group includes invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. These tumors almost always develop with or after some form of recognized pregnancy. Half follow hydatidiform mole, a fourth follow miscarriage or tubal pregnancy, and another fourth develop after a preterm or term pregnancy (Goldstein, 2 0 1 2) . Although these four tumor types are histologically distinct, they are usually diagnosed solely by persistently elevated serum 3-hCG levels because tissue is infrequently available for s tudy. Criteria to diagnose postmolar GTN are shown in Table 20-3 . • Clinical Findings

hese placental tumors are characterized clinically by their aggressive invasion into the myometrium and propensity to metastasize. he most common inding with GTN is irregular bleeding associated with uterine subinvolution. The bleeding may be continuous or intermittent, with sudden and sometimes massive hemorrhage. Myometrial perforation from trophoblastic growth may cause intraperitoneal hemorrhage. In some women, lower genital tract metastases are evident, whereas in others only distant metastases are found with no trace of uterine tumor. • Diagnosis, Staging, and Prognostic Scoring

Consideration for the possibility of GTN i s the most important factor in its recognition. Unusually persistent bleeding ater any type of pregnancy should prompt measurement of serum 3-hCG

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Early P reg n a n cy Co m pl ications

TABLE 20-3. C riteria for Diagnosis of Gestation a l Trophoblastic Neoplasia

1 . P l atea u of se r u m �-hCG level (± 1 0 pe rce nt) for fo u r meas u re m e nts d u ri n g a pe riod of 3 wee ks o r l o n g e r-days 1 , 7, 1 4, 2 1 2 . R i se of ser u m �-hCG level > 1 0 pe rce nt d u ri ng t h ree wee kly consecutive meas u re ments o r l o n ger, d u r i n g a period of 2 weeks or m ore-days '1 , 7, 1 4 3. Seru m �-hCG level re ma i n s detecta b l e for 6 m o nths o r m o re 4. H i sto l og ica l c riteria for chorioca rc i n o m a • Histological Classification

levels and consideration for diagnostic curettage if levels are ele­ vated. Uterine size is assessed along with careful examination for lower genital tract metastases, which usually appear as bluish vas­ cular masses (Cagayan, 20 1 0) . Tissue diagnosis is unnecessary, thus biopsy is not required and may cause significant bleeding. Once the diagnosis is veriied, in addition to a baseline serum J-hCG level and hemogram, a search for local disease and metastases includes tests of liver and renal function, trans­ vaginal sonography, chest CT scan or radiograph, and brain and abdominopelvic CT scan or MR imaging. Less commonly, positron-emission tomographic (PET) scanning and cerebro­ spinal luid J-hCG level determination are used to identiy metastases (Lurain, 20 1 1 ) . GTN i s staged clinically using the system o f the International Federation of Gynecology and Obstetrics (FIGO) (2009) . his includes a modiication of the World Health Organization (WHO) ( 1 983) prognostic index score, with which scores of 0 to 4 are given for each of the categories shown in Table 20-4. Women with WHO scores of 0 to 6 are considered to have low-risk disease, whereas those with a score :::7 are considered in the high-risk group.

Again, it is stressed that the diagnosis of trophoblastic neo­ plasias is usually made by persistently elevated serum J-hCG levels without conirmation by tissue study. Clinical staging is assigned without regard to histological indings, even if avail­ able. Still, there are distinct histological types, described next. I nvas ive Mole

These are the most common trophoblastic neoplasms that fol­ low hydatidiform moles, and almost all invasive moles arise from partial or complete moles. Previously known as chorioad­ enoma destruens, invasive mole is characterized by extensive tis­ sue invasion by trophoblast and whole villi . There is penetration deep into the myometrium, sometimes with involvement of the peritoneum, adjacent parametrium, or vaginal vault. Although locally aggressive, invasive moles are less prone to metastasize. Gestationa l Chorioca rcino m a

his is the most common type of trophoblastic neoplasm to follow a term pregnancy or a miscarriage, and only a third of

TABLE 20-4. I nternational Federation of Gynecology a n d Obstetrics (FIGO) Sta g i ng and Diagnostic Scoring System for

Gestational Trophoblastic Neoplasia Anatomical Staging

Stage Stage Stage Stage

I II III IV

Di sease confi ned to the uterus GTN exte nds outside o f t h e uterus b u t i s l i m ited t o t h e gen ita l structu res (ad nexa, vag i na, b road l i g a ment) GTN extends to the l u n g s, with or without known gen ita l tract i nvolvement All other metastatic sites

Mod ified World Hea lth Organ ization (WHO) P rog nostic Scori ng Systema Scoresb

Age (yea rs) Antecedent p reg na ncy I nterva l after i nd ex p reg nancy (mo) P retreatment se r u m J-hCG ( m I U/m l) la rgest t u m o r s ize (incl u d i ng uterus) Site of metastases N u m ber o f m etastases P revious fa i led chemothera py d ru g s

0

< 40 Mole 12 :::1 0 5 Liver, bra i n >8 :::2

aAda pted by FIGO. blow risk = WHO score of 0 to 6; h i g h risk = WHO score of :::7. J-hCG = beta h u m a n chor i o n i c gonadotropi n ; GI = g astro i ntest i n a l ; GTN = gestational tropho blast i c neoplasia . Ada pted with perm ission fro m FIGO Comm ittee on Gynecologic O n co l ogy: C u rrent F IGO sta g i n g for ca ncer of the vag i na, fa l lo p i a n tu be, ova ry, and gestational trophoblastic neoplas ia, I nt J Gynaecol Obstet 2009 Apr; l 05 ( 1 ):3-4.

Gestational Trophob la stic D i sease

chemotherapy (Baergen, 2006) . For higher-risk stage I and for later stages, adjuvant multidrug chemotherapy is also given (Schmid, 2009) . Ep ith e l ioid Tro p ho b lastic Tu mor

This rare tumor develops from chorionic-type intermediate trophoblast. he uterus is the main site of involvement, and bleeding and low hCG levels are typical fi n dings (Scott, 2 0 1 2) . Primary treatment i s hysterectomy because this tumor is rela­ tively resistant to chemotherapy. Metastatic disease is common, and combination chemotherapy is employed (Davis, 20 1 5) . • Treatment

A

FIGURE 20-5 Metastatic cho rioca rci noma. A. Chest rad iograph demonstrates widespread metastatic lesions. B. Autopsy speci men with mu ltiple hemorrha g i c hepatic metastases. (U sed with perm i s­ sion from Dr. Michael Con ner.)

cases follow a molar gestation (Soper, 2006) . Choriocarcinoma is composed of cells rem iniscent of early cytotrophoblast and syncytiotrophoblast, however, it contains no villi. his rapidly growing tumor invades both myometrium and blood vessels to create hemorrhage and necrosis. Myometrial tumor may spread outward and become visible on the uterine surface as dark, irregular nodules. Metastases often develop early and are generally blood-borne ( Fig. 20-5) . The most common sites are the lungs and vagina, but tumor may travel to the vulva, kidneys, liver, brain, ovaries, and bowel. Bleeding can com­ plicated these metastases (Fatema, 20 1 6; Wei, 20 1 6; Zhang, 20 1 7) . Choriocarcinomas are commonly accompanied by ovar­ ian theca-lutein cysts. Placenta l Site Trophobl astic Tu mor

This rare tumor arises from intermediate trophoblasts at the pla­ cental site. hese tumors have associated serum �-hCG levels that may be only modestly elevated. However, they produce variant forms of hCG, and identiication of a high propor­ tion of free �-hCG is considered diagnostic. Treatment of pla­ cental site trophoblastic tumor by hysterectomy is preferred because these locally invasive tumors are usually resistant to

Women with GTN are best managed by oncologists, and some evidence supports treatment in centers specializing in GTN (Kohorn, 20 1 4) . The prognosis is excellent with rare excep­ tions, and patients are routinely cured even in the presence of widespread disease. Chemotherapy alone is usually the primary treatment. Although controversial, some also consider a sec­ ond uterine evacuation to be an adjuvant therapeutic option in some GTN cases to avoid or minimize chemotherapy (Pezeshki, 2004; van Trommel, 2005) . In other cases, suction curettage may infrequently be needed to resolve bleeding or remove a sub­ stantial amount of retained molar tissue. In speciic cases, hys­ terectomy may be primary or adjuvant treatment (Clark, 2 0 1 0) . Single-agent chemotherapy protocols are usually suicient for nonmetastatic or low-risk metastatic neoplasia (Lawrie, 20 1 6) . In their review of 1 08 women with low-risk disease, Abrao and col­ leagues (2008) reported that monotherapy protocols with either methotrexate or actinomycin D were equally efective compared with a regimen containing both. In general, methotrexate is less toxic than actinomycin D (Chan, 2006; Secki, 20 1 0) . Regimens are repeated until serum �-hCG levels are undetectable. Combination chemotherapy is given for high-risk disease, and reported cure rates approximate 90 percent (Lurain, 2 0 1 0) . Several regimens have been used with success. One i s EMA-CO, which includes �toposide, methotrexate, gctinomycin D, �yclo­ phosphamide, and Oncovin (vincristine) . In selected cases, adjuvant surgical and radiotherapy may also be employed (Hanna, 20 1 0) . Frequent causes of death include hemorrhage from metastatic sites, respiratory failure, sepsis, and multiorgan failure due to widespread chemoresistant disease (Lybol, 20 1 2; Neubauer, 20 1 5) . With either low- o r high-risk disease, once serum � -hCG levels are undetectable, serosurveillance is continued for 1 year. During this time, efective contraception is crucial to avoid any teratogenic efects of chemotherapy to the fetus and to mitigate conusion from rising �-hCG levels caused by superimposed pregnany (Secki, 20 1 0; Williams, 20 1 4) . For those who con­ ceive despite this within the surveillance year following treatment, pregnancy may continue since most will have a favorable outcome (Tse, 20 1 2; Woolas, 1 998) . Importantly, this group is advised of the low but important risk of delayed diagnosis if tumor recurs during the pregnancy (Blagden, 2002; Tuncer, 1 999b) . A small number of women during surveillance, despi te no evidence of metastases, will be found to have very low �-hCG levels that plateau. This phenomenon is called quiescent hCG

395

396

Ea rly P reg n a n cy Compl i cati o n s

and presumably is caused by dormant trophoblast. Close obser­ vation without therapy is recommended, but 20 percent will eventually have recurrent active and progressive trophoblastic neoplasia (Ngu, 20 14) .

SU BSEQU ENT PREGNANCY Women with prior hydatidiform mole generally do not have impaired fertility, and their pregnancy outcomes are usually normal Qoneborg, 20 1 4; Matsui, 20 1 1 ; Sebire, 2003) . One concern is the 2-percent risk for developing trophoblastic dis­ ease in a subsequent pregnancy, which was described earlier. Sonographic evaluation is recommended in early pregnancy, and subsequently if indicated. Women who have successfully completed GTN chemother­ apy are advised to delay pregnancy for 1 2 months. Fertility and pregnancy outcomes are typically normal, and congenital anom­ aly rates are not increased (Berkowitz, 2000; Tse, 20 1 2) . One exception is an unexplained higher stillbirth rate of 1 . 5 percent compared with a background rate of 0.8 percent (Vargas, 20 1 4) . After hydatidiform mole o r GTN treatment, i n subsequent pregnancy, the placenta or products of conception are sent for pathological evaluation at delivery. A serum 3-hCG level is measured 6 weeks postpartum (Lurain, 20 1 0) .

REFERENCES Abrao A, d e Andrade ]M, Tiezzi D G , e t a l : Treatment for low-risk gestational trophoblastic disease: comparison of single-agent methotrexate, dactinomy­ cin and combination regimens. Gynecol Oncol 1 08 : 1 49, 2008 Altman AD, Bently B, Murray S, et al: Maternal age-related rate of gestational trophoblastic disease. Obstet Gynecol 1 1 2:244, 2008 American College of Obstetricians and Gynecologists: Diagnosis and treatment of gestational trophoblastic disease. Practice Bulletin No. 53, June 2004, Reairmed 20 1 6 Baergen N , Rutgers ]L, Young RH, e t al: Placental site trophoblastic tumor: a study of 55 cases and review of the literature emphasizing factors of prog­ nostic significance. Gynecol Oncol 1 00:5 1 1 , 2006 Bandy LC, Clarke-Pearson DL, Hammond CB: Malignant potential of gesta­ tional trophoblastic disease at the extreme ages of reproductive life. Obstet Gynecol 64(3):395, 1 984 Banet N, DeScipio C, Murphy M , et al: Characteristics of hydatidiform moles: analysis of a prospective series with p57 immunohistochemistry and molecular genotyping. Mod PathoI 27(2) :238, 2 0 1 4 Benirschke K , Burton G], Baergen N (eds): Molar pregnancies. In Pathology of the Human Placenta, 6th ed. New York, Springer, 20 1 2, p 687 Berkowitz RS, Goldstein DP: Current management of gestational trophoblas­ tic diseases. Gynecol Oncol 1 1 2 (3):654, 2009 Berkowitz RS, Tuncer ZS, Bernstein MR: Management of gestational tropho­ blastic diseases: subsequent pregnancy experience. Semin Oncol 27(6) :678, 2000 Blagden SP, Foskett A, Fisher A, et al: he efect of early pregnancy follow­ ing chemotherapy on disease relapse and foetal outcome in women treated for gestational trophoblastic tumours. Br ] Cancer 86( 1 ) :26, 2002 Cagayan MS: Vaginal metastases complicating gestational trophoblastic neo­ plasia. ] Reprod Med 5 5 (5-6) :229, 20 1 0 Castrillon D H , S u n 0, Weremowicz S, e t al: Discrimination o f complete hyda­ tidiform mole from its mimics by immunohistochemistry of the paternally imprinted gene product p57KIP2. Am ] Surg PathoI 25 ( 1 0) : 1 22 5 , 200 1 Chan KK, Huang Y, Tam F, et al: Single-dose methotrexate regimen in the treatment of low-risk gestational trophoblastic neoplasia. Am ] Obstet GynecoI 1 95 : 1 282, 2006 Clark RM, Nevadunsky NS, Ghosh S, et al: The evolving role of hysterectomy in gestational trophoblastic neoplasia at the New England Trophoblastic Disease Center. ] Reprod Med 5 5 (5-6) : 1 94, 20 1 0 Cormano ] , Mackay G , Holschneider C : Gestational trophoblastic disease diagnosis delayed by the hook efect. Obstet GynecoI 1 26(4) : 8 1 1 , 20 1 5

Dantas PRS, Maesd. I , Filho ]R, e t al: Does hormonal contraception during molar pregnancy follow-up influence the risk and clinical aggressiveness of gestational trophoblastic neoplasia after controlling for risk factors? Gynecol Oncol September 1 6 , 20 1 7 [Epub ahead of print] Davis MR, Howitt BE, Quade B], et al: Epithelioid trophoblastic tumor: a single institution case series at the New England Trophoblastic Disease Cen­ ter. Gynecol Oncol 1 37(3):456, 20 1 5 Delmis ] , Pfeifer 0 , Ivanisecvic M , e t al: Sudden death from trophoblastic embolism in pregnancy. Eur ] Obstet Gynecol Reprod Bioi 92:22 5 , 2000 de Medeiros SF, Norman RJ : Human chorionic gonadotrophin protein core and sugar branches heterogeneity: basic and clinical insights. Hum Reprod Update 1 5 ( 1 ) :69, 2009 Drake D, Rao GG, McIntire DO, et al: Gestational trophoblastic disease among Hispanic women: a 2 1 -year hospital-based study. Gynecol Oncol 1 03: 8 1 , 2006 Eagles N, Sebire N], Short 0, et al: Risk of recurrent molar pregnancies fol­ lowing complete and partial hydatidiform moles. H um Reprod 30(9) :2055, 20 1 5 Elias M , Goldstein DP, Berkowitz RS: Complete hydatidiform mole in women older than age 50. ] Reprod Med 5 5 (5-6) :208, 20 1 0 Elias K M , Shoni M , Bernstein M , e t al: Complete hydatidiform mole in women aged 40 to 49 years. ] Reprod Med 57(5-6) :254, 2 0 1 2 Eysbouts K , Bulten ] , Ottevanger P B , e t al: Trends in incidence for ges­ tational trophoblastic disease over the last 20 years in a population-based study. Gynecol Oncol 140( 1 ) :70, 20 1 6 Fatema N , Arora NV, l Abri FM, e t al: Pancreatic and hepatic metastasis of an undiagnosed choriocarcinoma: an exceptional cause of haemoperitoneum in young women-report of a rare case. Case Rep Oncol 9 (3):633, 20 1 6 FIGO Committee on Gynecologic Oncology: Current FIGO staging for can­ cer of the vagina, fallopian tube, ovary, and gestational trophoblastic neo­ plasia. Int ] Gynaecol Obstet 1 05:3, 2009 Fowler 0], Lindsay I , Seck! M], et al: Routine pre-evacuation ultrasound diag­ nosis of hydatidiform mole: experience of more than 1 000 cases from a regional referral center. Ultrasound Obstet Gynecol 27( 1 ) : 56, 2006 Goldstein DP, Berkowitz RS: Current management of gestational trophoblas­ tic neoplasia. Hematol Oncol Clin North Am 26( 1 ) : 1 1 1 , 20 1 2 Gueye M, Kane-Gueye S M , Ndiaye-Gueye M D , e t al: Gestational tropho­ blastic neoplasia after achieving a nondetectable serum human chorionic gonadotrophin level. B]OG 1 2 1 ( 1 1 ) : 1 4 1 5, 20 1 4 Hankins G O , Wendel G O , Snyder R, e t al: Trophoblastic embolization dur­ ing molar evacuation: central hemodynamic observations. Obstet Gynecol 63:368, 1 987 Hanna RK, Soper ]T: The role of surgery and radiation therapy in the manage­ ment of gestational trophoblastic disease. Oncologist 1 5 (6) : 593, 20 1 0 Harvey A , Mitchell H D , Stenman U H , e t al: Diferences i n total human chorionic gonadotropin immunoassay analytical specificiry and ability to measure human chorionic gonadotropin in gestational trophoblastic disease and germ cell tumors. ] Reprod Med 5 5 (7-8):28, 2 0 1 0 Hassadia A , Kew F M , Tidy]A, et al: Ectopic gestational trophoblastic disease: a case series review. ] Reprod Med 57(7-8):297, 20 1 2 ]oergensen MW, Niemann I , Rasmussen A , e t al: Triploid pregnancies: genetic and clinical features of 1 58 cases. Am ] Obstet GynecoI 2 1 1 (4):370.e 1 , 20 1 4 ]oneborg U , Eloranta S, Johansson L, et al: Hydatidiform mole and subse­ quent pregnancy outcome: a population-based cohort study. Am ] Obstet GynecoI 2 1 1 (6) :68 1 .e 1 , 20 1 4 Kang WD, Choi HS, Kim S M : Prediction o f persistent gestational trophoblas­ tic neoplasia: the role of hCG level and ratio in 2 weeks after evacuation of complete mole. Gynecol OncoI 1 24 (2):250, 20 1 2 Kerkmeijer LG, Massuger LF, Ten Kate-Booij M], e t al: Earlier diagnosis and serum human chorionic gonadotropin regression in complete hydatidiform moles. Obstet Gynecol 1 1 3:326, 2009 Kofinas ]0, Kruczek A, Sample ] , et al: Thyroid storm-induced multi-organ failure in the setting of gestational trophoblastic disease. ] Emerg Med 4 8 ( 1 ) : 3 5 , 20 1 5 Kohorn EI: Worldwide survey o f the results o f treating gestational trophoblas­ tic disease. ] Reprod Med 59(3-4) : 1 4 5 , 20 1 4 Lakovschek Ie, Streubel B , Ulm B : Natural outcome of trisomy 1 3 , trisomy 1 8 , and triploidy ater prenatal diagnosis. Am ] Med Genet A 1 5 5A(1 1 ) :262, 20 1 1 Lawler SO, Fisher A, Dent J: A prospective genetic study of complete and partial hydatidiform moles. Am ] Obstet Gynecol 1 64 : 1 270, 1 9 9 1 Lawrie TA, Alazzam M , Tidy ], e t al: First-line chemotherapy i n low-risk ges­ tational trophoblastic neoplasia. Cochrane Database Syst Rev 6:CD007 1 02, 20 1 6 Lee C , Smith H O , Kim S]: Epidemiology. In Hancock BW, Seck! M], Berkowitz RS, et al (eds): Gestational trophoblastic disease, 3rd ed. London, International Society for the Study of Trophoblastic Disease, 20 1 1 , p 57. Available at: http://www.isstd.org/index.html. Accessed April 23, 2 0 1 6

Gestational Tro p h o b l a stic D i sease Upata F, Parkash V, Talmor M, et al: Precise DNA genotyping diagnosis of hydatidiform mole. Obstet GynecoI 1 1 5 (4):784, 20 1 0 Lurain JR: Gestational trophoblastic disease I : epidemiology, pathology, clin­ ical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole. Am J Obstet Gynecol 203(6) : 53 1 , 20 1 0 Lurain JR: Gestational trophoblastic disease II: classification and management of gestational trophoblastic neoplasia. Am J Obstet Gynecol 204 ( 1 ) : 1 1 , 20 1 1 Lybol C, Centen DW, homas CM, et al: Fatal cases of gestational tropho­ blastic neoplasia over four decades in the Netherlands: a retrospective cohort study. BJOG 1 1 9 ( 1 2) : 1 465, 20 1 2 Mangili G , Garavaglia E , Cavoretto P , e t al: Clinical presentation o f hydatidi­ form mole in northern Italy: has it changed in the last 20 years? Am J Obstet GynecoI 1 98 (3):302.e 1 , 2008 Massardier J , Golfner F , Journet D, et al: Twin pregnancy with complete hyda­ tidiform mole and coexistent fetus obstetrical and oncological outcomes in a series of 1 4 cases. Eur J Obstet Gynecol Reprod BioI 1 43:84, 2009 Matsui H, Iitsuka Y, Suzuka K, et al: Subsequent pregnancy outcome in patients with spontaneous resolution of HCG after evacuation of hydatidi­ form mole: comparison between complete and partial mole. Hum Reprod 1 6(6) : 1 274, 2 0 1 1 Merchant SH, Amin MB, Viswanatha DS, et al: p57KIP2 immunohistochem­ istry in early molar pregnancies: emphasis on its complementary role in the diferential diagnosis of hydropic abortuses. Hum Pathol 36: 1 80, 2005 Neubauer NL, Strohl E, Schink Jc, et al: Fatal gestational trophoblastic neoplasia: an analysis of treatment failures at the Brewer Trophoblastic Disease Center from 1 979-20 1 2 compared to 1 962- 1 978. Gynecol Oncol 1 38 (2) :339, 20 1 5 Ngan HY, Seck! MJ, Berkowitz RS, et al: Update on the diagnosis and manage­ ment of gestational trophoblastic disease. Int J Gynaecol Obstet 1 3 1 Suppl 2:S 1 23 , 20 1 5 Ngu SF, Chan KK: Management of chemoresistant and quiescent gestational trophoblastic disease. Curr Obstet Gynecol Rep 3:84, 20 1 4 Niemann I , Petersen LK, Hansen ES, et al: Diferences i n current clinical fea­ tures of diploid and triploid hydatidiform mole. BJOG 1 1 4 : 1 273, 2007 Pezeshki M , Hancock BW, Silcocks P: he role of repeat uterine evacuation in the management of persistent gestational trophoblastic disease. Gynecol Oncol 9 5 (3):423, 2004 Schmid P, Nagai Y, Agawal R: Prognostic markers and long-term outcome of placental-site trophoblastic tumours: a retrospective obsevational study. Lancet 374(9683):48, 2009 Schorge JO, Goldstein DP, Bernstein MR, et al: Recent advances in gestational trophoblastic disease. J Reprod Med 45 :692, 2000 Scott EM, Smith L, Desouki MM, et al: Epithelioid trophoblastic tumor: a case report and review of the literature. Case Rep Obstet Gynecol 20 1 2 : 862472, 20 1 2 Sebire NJ, Fisher A , Foskett M , e t al: Risk of recurrent hydatidiform mole and subsequent pregnancy outcome following complete or partial hydatidi­ form molar pregnancy. BJOG 1 1 0 ( 1 ) :22, 2003 Sebire N], Foskett M, Fisher A, et al: Risk of partial and complete hydatidi­ form molar pregnancy in relation to maternal age. BJOG 1 09:99, 2002a Sebire NJ, Foskett M, Parainas FJ, et al: Outcome of twin pregnancies with complete hydatidiform mole and healthy co-twin. Lancet 3 5 9:2 1 6 5 , 2002b Sebire NJ, Foskett M, Short D, et al: Shortened duration of human chori­ onic gonadotrophin surveillance following complete or partial hydatidiform

mole: evidence for revised protocol of a UK regional trophoblastic disease unit. BJOG 1 1 4 (6) : 60, 2007 Sebire NJ, Lindsay I , Fisher A: Overdiagnosis of complete and partial hyda­ tidiform mole in tubal ectopic pregnancies. Int J Gynecol Pathol 24 (3) :260, 2005 Seck! MJ, Sebire NJ, Berkowitz RS: Gestational trophoblastic disease. Lancet 376(9742) : 7 1 7, 20 1 0 Smith H O , Wiggins C , Verschraegen CF, e t al: Changing trends i n gestational trophoblastic disease. J Reprod Med 5 1 :777, 2006 Soper JT: Gestational trophoblastic disease. Obstet Gynecol 1 08 : 1 76, 2006 Sun SY, Melamed A, Goldstein DP, et al: Changing presentation of complete hydatidiform mole at the New England Trophoblastic Disease Center over the past three decades: does early diagnosis alter risk for gestational tropho­ blastic neoplasia? Gynecol Oncol 1 3 8 ( 1 ) :46, 20 1 5 Tidy JA, Gillespie M, Bright N , et al: Gestational trophoblastic disease: a study of mode of evacuation and subsequent need for treatment with che­ motherapy. Gynecol Oncol 78 pp. 309, 2000 Tse Y, Chan KK, Tam F: 20-year experience of managing profuse bleeding in gestational trophoblastic disease. J Reprod Med (5): 397, 200 Tse Y, Ngan HY: Gestational trophoblastic disease. Best Pract Res Clin Obstet GynaecoI 26(3) :3 57, 20 1 2 Tuncer ZS, Bernstein MR, Goldstein DP, e t al: Outcome o f pregnancies occurring before completion of human chorionic gonadotropin follow-up in patients with persistent gestational trophoblastic tumor. Gynecol Oncol 73 (3) :345, 1 999a Tuncer ZS, Bernstein MR, Goldstein DP, et al: Outcome of pregnancies occur­ ring within 1 year of hydatidiform mole. Obstet Gynecol 94(4) : 5 8 8 , 1 999b van Trommel NE, Massuger LF, Verheijen H, et al: he curative efect of a second curettage in persistent trophoblastic disease: a retrospective cohort survey. Gynecol Oncol 99:6, 2005 Vargas R, Barroilhet LM, Esselen K, et al: Subsequent pregnancy outcomes after complete and partial molar pregnancy, recurrent molar pregnancy, and gestational trophoblastic neoplasia: an update from the New England Tro­ phoblastic Disease Center. J Reprod Med 59(5-6) : 1 88, 2 0 1 4 Wang Q, Fu J, Hu L , e t al: Prophylactic chemotherapy for hydatidiform moleto prevent gestational trophoblastic neoplasia. Cochrane Database Syst Rev 9: CD007289, 2 0 1 7 Wee L , Jauniaux E: Prenatal diagnosis and management o f twin pregnancies complicated by a co-existing molar pregnancy. Prenat Diagn 25 (9) :772, 2005 Wei H, Zhang T, Uu B, et al: Choriocarcinoma of unknown origin with mul­ tiple organ metastasis and cerebral hemorrhage: a case report and literature review. Oncol Lett 1 1 (6):3749, 20 1 6 Williams ] , Short D, Dayal L , e t al: Efect o f early pregnancy following che­ motherapy on disease relapse and fetal outcome in women treated for gesta­ tional trophoblastic neoplasia. J Reprod Med 59 (5-6) :248-54, 20 1 4 Wolfberg AJ, Berkowitz RS, Goldstein DP: Postevacuation hCG levels and risk of gestational trophoblastic neoplasia in women with complete molar pregnancy. Obstet Gynecol 1 06(3): 548, 2005 Woolas RP, Bower M, Newlands ES, et al: Influence of chemotherapy for gesta­ tional trophoblastic disease on subsequent pregnancy outcome. BJO G 1 05 : 1 032, 1 998 World Health Organization Scientific Group: Gestational trophoblastic disease. WHO Tech Rep Ser 692: 1 , 1 983 Zhang W, Uu B, Wu J, et al: Hemoptysis as primary manifestation in three women with choriocarcinoma with pulmonary metastasis: a case series. J Med Case Rep 1 1 ( 1 ) : 1 1 0, 20 1

397

400

C H A PT E R 2 1

P hys i o l ogy of La bo r

MATERNAL AND F ETAL COMPARTMENTS . . . . . . . . . . 400 SEX STEROI D HORMO N E ROLE .

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PROSTAGLAN D I NS ROLE . . . . . . . . . . . . . . . . . .

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. . . 402

PHASE 1 : UTER I N E QUI ESCENCE AND C ERVICAL SOFTENING . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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.

. . . 403

.

PHASE 2: PREPARATION FOR LABOR . . . . . . . . . . . . . . . 408 PHASE 3: LABOR. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 1 1 UTEROTONINS IN PARTURITION PHASE 3 . . . . . . . . . . . 4 1 6 PHASE 4: TH E PUERPERIUM . . .

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From time immemorial inquiring minds have sought an explanation or theact that labour usualy ensues about 280 days after the appearance of the last menstrual perio, but thus ar no satiactory universal cause has been discovered. -J. Whitridge Williams ( 1 903) The importance of labor physiology was highlighted in the irst edition of Wiliams Obstetrics, in which an entire section was devoted to the topic. Given the science at that time, those nine chapters were concerned with the mechanics of labor and delivery. However, the current understanding of labor includes a wide spectrum of preparedness even before the first regular contractions. Labor is the last few hours of human pregnancy. It is char­ acterized by forceful and painful uterine contractions that efect cervical dilation and cause the fetus to descend through the birth canal. Extensive preparations take place in both the uterus

and cervix long before this. During the irst 36 to 38 weeks of normal gestation, the myometrium is in a preparatory yet unre­ sponsive state. Concurrently, the cervix begins an early stage of remodeling yet maintains structural integrity. Following this prolonged uterine quiescence, a transitional phase follows dur­ ing which myometrial unresponsiveness is suspended and the cervix undergoes ripening, efacement, and loss of structural cohesion. The physiological processes that regulate parturition-the bringing forth of young-and the onset of labor continue to be deined. Three general contemporaneous theories describe labor initiation. Viewed simplistically, the irst is the functional loss of prenancy maintenanceactors. he second focuses on synthesis of actors that induce parturition. The third suggests that the mature fetus is the source of the initial signalor parturition commence­ ment. Current research supports a model that draws from all three themes. However, labor onset clearly represents the cul­ mination of a series of biochemical changes in the uterus and cervix. hese result from endocrine and paracrine signals ema­ nating from both mother and fetus. Their relative contributions vary between species, and it is these diferences that complicate elucidation of the exact factors that regulate human parturition. When parturition is abnormal, then preterm- labor, dystocia, or postterm pregnancy may result. Of these, preterm labor remains the major contributor to neonatal mortality and morbidity.

MATERNAL AND F ETAL COM PARTMENTS

• Uterus

The myometrial layer of the uterus is composed of bundles of smooth muscle cells surrounded by connective tissue. In contrast to skeletal or cardiac muscle, the smooth muscle cell is not ter­ minally diferentiated and therefore is readily adaptable to envi­ ronmental changes. Varied stimuli such as mechanical stretch, inlammation, and endocrine and paracrine signals can modulate

Physiology of Labor

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Amnionic flU

Amnion I

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Chorion

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r-----�--�- --�����-�1

Prostaglandin

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' Chorio ic Mesenchyme

---I--Decidua

Myometriu m

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FIGURE 21 -1 The a m nion synthesizes prosta g l a ndi ns, a n d late i n preg nancy, synthesis is a u g mented by increased phospho l i pa se A2 a n d prosta g l a n d i n H synthase, type 2 (PGHS-2) activity. During preg na ncy, t h e tra n s port o f prosta g l a n d i n s from t h e a m nion t o maternal tis­ sues is l i m ited by expression of the i nactivating enzymes, prosta g l a nd i n dehyd rogenase (PG D H), i n the chorion. During la bor, PGDH l evels decli ne, and a m n ion-derived p rosta g l a nd i n s ca n i nfl uence mem b ra n e rupture a n d uterine contractil ity. The role of decid u a l activation i n partu rition i s u nclear but may i nvolve loca l progesterone meta bol i s m a nd hig her prosta g l a n d i n receptor concentrations, thus e n h a n c i n g uterine prosta g l a n d i n actions a n d cytokine prod uctio n. (Redrawn fro m Smith R: Partu rition. N Engl J M e d . 2 0 0 7 J a n 1 8;356(3):27 1 -283.) the transition of the smooth muscle cell among phenotypes that provide cell growth, proliferation, secretion, and contractility. In addition to this phenotypic plasticity, several smooth mus­ cle qualities confer advantages for uterine contraction eiciency and fetal delivery. First, the degree of smooth muscle cell short­ ening with contractions may be one order of magnitude greater than that attained in striated muscle cells. Second, forces can be exerted in smooth muscle cells in multiple directions. his difers from the contraction force generated by skeletal muscle, which is always aligned with the axis of the muscle fi b ers. hird, smooth muscle is not organized in the same manner as skeletal muscle. In myometrium, the thick and thin ilaments are found in long, random bundles throughout the cells. his plexiform arrangement aids greater shortening and force-generating capac­ ity. Last, greater multidirectional force generation in the uterine fundus compared with that of the lower uterine segment per­ mits versatility in expulsive force directionality. Lining the thick muscular uterine walls, the endometrium is transformed by pregnancy hormones and is then termed decidua. Composed of stromal cells and maternal immune cells, the decidua serves to maintain the pregnancy via unique immu­ no regulatory functions that suppress inlammatory signals dur­ ing gestation. However, at the end of pregnancy, decidual activation ensues. With this, the decidua transitions to induce inflammatory signals and withdraw active immunosuppression, which contribute to parturition initiation. During pregnancy, the cervix has multiple functions that include: ( 1 ) maintenance of barrier function to protect the reproductive tract from infection, (2) maintenance of cervi­ cal competence despite greater gravitational forces as the fetus grows, and (3) orchestration of extracellular matrix changes that allow progressively greater tissue compliance. In nonpregnant women, the cervix is closed and firm, and its consistency is similar to nasal cartilage. By the end of pregnancy, the cervix is easily distensible, and its consistency is similar to the lips of the oral cavity. Observations in three­ dimensional sonography and magnetic resonance imaging show increases in the cross-sectional area of the cervical canal and in the cervical stroma from early to late pregnancy (House,

2009; Lang, 20 1 0) . Concurrent with expansion of the stroma, the cervical epithelia proliferate and exert a pregnancy-sp ecific immunoprotection. • Placenta

In addition to providing the exchange of nutrients and waste between mother and fetus, the placenta is a key source of ste­ roid hormones, growth factors, and other mediators that main­ tain pregnancy and potentially aid the transition to parturition. The fetal membranes-amnion and chorion and adjacent decidua-make up an important tissue shell around the fetus that serves as a physiological, immunological, and metabolic shield to protect against untimely parturition initiation. he amnion provides virtually all of the fetal membranes' tensile strength to resist membrane tearing and rupture (Chap. 5, p. 95). This avascular tissue is highly resistant to penetration by leukocytes, microorganisms, and neoplastic cells (Fig. 2 1 - 1 ) . I t also constitutes a selective filter to prevent fetal particulate­ bound lung and skin secretions from reaching the maternal compartment. In this manner, maternal tissues are protected from amnionic fluid constituents that could prematurely accel­ erate decidual or myometrial activation or could promote adverse events such as amnionic luid embolism. The chorion is a primarily protective tissue layer and pro­ vides immunological acceptance. It is also enriched with enzymes that inactivate uterotonins, which are agents that stim­ ulate contractions. Inactivating enzymes include prostaglan­ din dehydrogenase, oxytocinase, and enkephalinase (Cheung, 1 990; Germain, 1 994) .

SEX STEROID HORMO N E ROLE In many species, the role of sex steroid hormones is clear- estro­ gen promotes and progesterone inhibits the events leading to parturition. nd, the removal of progesterone, that is, progester­ one withdrawa, directly precedes progression of parturition. In addition, providing progesterone to some species will delay partu­ rition via a decline in myometrial activity and continued cervical

40 1

402

La bor

Esterified arachidonic acid in phospholipid stores

competency (Challis, 1 994). In humans, however, it seems most likely that both estrogen and progesterone are components of a broader molecular system that maintains uterine quiescence. Plasma levels of estrogen and progesterone in normal preg­ nancy are enormous and in great excess of the ainity constants for their receptors. For this reason, it is diicult to comprehend how relatively subtle changes in the ratio of their concentrations could modulate physiological processes during pregnancy. The teleological evidence, however, for an increased progesterone­ to-estrogen ratio in the maintenance of pregnancy and a decline in this ratio for parturition is overwhelming. In all species stud­ ied, including humans, administration of the progesterone­ receptor antagonists miepristone (RU-48) or onapristone will promote some or all key features of parturition. These include cervical ripening, greater cervical distensibility, and augmented uterine sensitivity to uterotonins (Bygdeman, 1 994; Chwalisz, 1 994b; Wolf, 1 993) . The exact role of estrogen in regulation of human uterine quiescence and cervical competency is less well understood. hat said, estrogen can advance progesterone responsiveness and, in doing so, promote uterine quiescence. At the end of pregnancy, estrogen aids processes that mediate uterine activa­ tion and cervical ripening. Both progesterone and estrogen bind to nuclear receptors that regulate gene transcription in a cell- and context-speciic pattern. Two nuclear receptors for estrogen are estrogen recep­ tor a (ERa) and estrogen receptor 3 (ER3). Nuclear recep­ tor isoforms of the progesterone receptor (PR-A and PR-B) are encoded by difering transcripts from a single gene (Patel, 20 1 5) .

Phospholipase A2 or Phospholipase C with diacylglycerol lipases Arachidonic acid

Prostaglandin H 2 synthase types 1 or 2 (PGHS-1 and PGHS-2 ) PGH2

Prostaglandin isomerases

11\ 11\

Prostaglandins

1 5-hydroxyprostaglandin dehydrogenase (PGDH)

Inactive prostaglandin metabolites FIGURE 21 -2 Overview of the prosta g l a n d i n biosynthetic

PROSTAGLANDINS ROLE Prostaglandins are lipid molecules with varied hormone-like actions. In parturition, they play a prominent role in myome­ trial contractility, relaxation, and inlammation. Prostaglandins interact with a family of eight diferent G-protein-coupled receptors (p. 406) , several of which are expressed in myome­ trium and cervix (Konopka, 20 1 5 ; Myatt, 2004) . The major synthetic pathways involved in prostaglandin bio­ synthesis are shown in Figure 2 1-2. Prostaglandins are produced using plasma membrane-derived arachidonic acid, which usually is released by the action of phospholipase A2 or C. Arachidonic acid can then act as substrate for both type 1 and 2 prostaglandin H synthase (PGHS- l and -2) , which are also called cyclooxy­ genase- l and -2 (COX- l and -2) . Both PGHS isoforms convert arachidonic acid to the unstable prostaglandin G 2 and then to prostaglandin H 2 . hese enzymes are the target of many nonste­ roidal antiinlammatory drugs (NSAIDs) . Indeed, the tocolytic actions of speciic NSAIDs, as discussed in Chapter 42 (p. 826) , were considered promising until they were shown to have adverse fetal efects (Loudon, 2003; Olson, 2003, 2007). Through prostaglandin isomerases, prostaglandin H 2 is con­ verted to active prostaglandins. These include prostaglandins E2 (PGEJ , F 2x (PGF 2x), and 1 2 (PGI2) . Isomerase expression is tissue-speciic and thereby controls the relative production of various prostaglandins. Another important control point for prostaglandin activity is its metabolism, which most often is

pathway.

through the action of 1 5-hydroxyprostaglandin dehydrogenase (PGDH). Expression of this enzyme is up regulated during preg­ nancy in the uterus and cervix, which provides the important ability to rapidly inactivate prostaglandins (Giannoulias, 2002; Kishore, 20 1 4) . Thus, myometrial responses to prostaglandins stem from a balance between prostaglandin synthesis versus metabolism, from the relative expression of various prostaglan­ din receptors, or from a switch in receptor-signaling pathways (Kandola, 20 1 4; Lyall, 2002; Olson, 2007; Smith, 200 1 ) . It is entirely possible that prostanoids contribute to myometrial relaxation at one stage of pregnancy and to myometrial contrac­ tions after parturition initiation (Myatt, 2004) . In addition to the myometrium, the amnion synthesizes sev­ eral bioactive pep tides and prostaglandins that cause myometrial relaxation or contraction (see Fig. 2 1 - 1 ) . Late in pregnancy, amnionic prostaglandin biosynthesis is increased, and phospho­ lipase A2 and PGHS-2 show greater activity Oohnson, 2002). Accordingly, many hypothesize that prostaglandins regulate events leading to parturition. The amnion is likely the major source for amnionic fluid prostaglandins, and their role in the activation of cascades that promote membrane rupture is clear. he influence of amnion-derived prostaglandins on uterine qui­ escence and activation, however, is less delineated. his is because prostaglandin transport from the amnion through the chorion to access maternal tissues is limited by expression of PGDH.

Physiol ogy o f La bor

1

Importantly, the phases of parturition should not be confused with the clinical stages of labor, that is, the first, second, arturition and third stages-which make up phase Contractile Uterine Uterine Uterine 3 of parturition (Fig. 2 1 -4) . unresponsiveness, preparedness contraction, involution, Beginning even before implanta­ cervical softening cervical dilation, for labo, cervical repai, tion, a remarkably efective period of cervical fetal and placenta breast feeding ripening expUlsion (three myometrial quiescence is imposed. This Conception stages of labor) phase 1 normally comprises 95 p ercent I nitiation of of pregnancy and is characterized by Onset of partu rition Delivery of uterine smooth muscle tranquility with labor conceptus Fertility maintenance of cervical structural integ­ restored rity (Fig. 2 1 -5) . All manner of molecular FIGURE 21 -3 The phases of partu rition. systems-neural, endocrine, paracrine, and autocrine-are likely called to implement and coordinate a state of PHASE 1 : UTERI N E QUIESCENCE AND relative uterine unresponsiveness. Moreover, a complementary CERVICAL SOFTENING "fail-safe" system that protects the uterus against agents that As shown in Figure 2 1 -3, parturition can be arbitrarily divided could perturb the tranquility of phase 1 also must be in place. During phase 1 , the myometrial cells undergo a phenotypic into four overlapping phases that correspond to the major physiological transitions of the myometrium and cervix during modification to a noncontractile state, and uterine muscle is pregnancy (Casey, 1 993, 1 997; Challis, 2000; Word, 2007) . rendered unresponsive to natural stimuli. Concurrently, the These phases of parturition include: ( 1 ) a prelude to it, (2) uterus must initiate extensive changes in its size and vascu­ the preparation for it, (3) the process itself, and (4) recovery. larity to accommodate fetal growth and prepare for uterine contractions. he myometrial unre­ sponsiveness of phase 1 continues until Stages of Labor near the end of pregnancy. That said, 1 st some low-intensity myometrial con­ Contractions and Fetal descent Placenta tractions are felt during the quiescent cervical di latation and delivery delivery phase, but they do not normally cause cervical dilation. hese contractions are common toward the end of preg­ I nancy, especially in multiparas, and are 10 10 : Phase of referred to as Braxton Hicks contractions or alse labor (Chap. 4, p. 50). I The quiescence of phase 1 likely - 8 E 8 stems from: ( 1 ) actions of estrogen and � progesterone via intracellular receptors, C 0 (2) myometrial-cell plasma membrane I = m :- 6 6 receptor-mediated increases in cyclic � adenosine monophosphate (cMIP), C (3) generation of cyclic guanosine j ) monophosphate (cGMP) , and (4) 4 '; - 4 . other systems, including modiication D U of myometrial-cell ion channels.

Phase Processes of labor

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FIGURE 2 1 -4 Com posite of the average dilation cu rve for labor i n n u l liparous wo men. The curve is based o n a n a lysis of data derived from a la rge, nearly consecutive series of women. The first stage is d ivided i nto a relatively flat latent phase a nd a ra pidly prog ress ive active phase. I n the active pha se, there a re three identifiable pa rts: an acceleration phase, a l i nea r phase of maxi m u m s lope, a n d a deceleration phase. (Redrawm from F ried man EA: La bor: C l i n ica l Eva l u ation and Management, 2nd ed. New York, Appleton-Centu ry-Crofts, 1 978.)

• Myometrial Relaxation

and Contraction

The balance between myometrial relax­ ation and contraction is controlled by steroid- and peptide-hormone tran­ scriptional regulation of key genes and their protein products. Quiescence is achieved in part by: ( 1 ) diminished intracellular crosstalk and reduced intra­ cellular Ca2 + ( [Ca2 +J levels; (2) ion­ channel regulation of cell membrane

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Prostaglandins Oxytocin CRH? I nflammatory cell activation Estrogen Relaxin

Oxytocin I nflammatory cel l activation

• Myometrium is major site of action

• Cervix is major site

• Both are sites of action

FIGURE 21 -5 The key factors thought to reg u l ate the phases of h u m a n pa rtu rition. C R H h u ma n chorionic gonadotropin; PAF

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platelet-activati n g factor; PGDH

potential; (3) activation of the uterine endoplasmic reticulum stress-unfolded protein response; and (4) uterotonin degrada­ tion. In contrast, contractility results from: ( 1 ) enhanced inter­ actions between the actin and myosin proteins; (2) heightened excitability of individual myometrial cells; and (3) promotion of intracellular crosstalk that allows synchronous contractions to develop. Acti n-Myos i n I nteractions

Actin and myosin proteins are essential to muscle contraction. For this, actin must be converted from a globular to a ilamen­ tous form. Indeed, a potential mechanism for maintenance of relaxation is the promotion of actin into a globular form rather than into ibrils, which are required for contraction (Fig. 2 1 -6) . Moreover, actin must b e attached t o the cytoskeleton a t focal points in the cell membrane to allow tension to develop. Actin must partner with myosin, which is composed of multiple light and heavy chains. The coupling of myosin and actin activates adenosine triphosphatase (ATPase), hydrolyzes adenosine triphosphate, and generates force. This interaction is brought about by enzymatic phosphorylation of the 20-kDa light chain of myosin (Stull, 1 998). his is catalyzed by the enzyme myosin light-chain kinase, which is activated by calcium. Calcium b inds to calmodulin, a calcium-binding regulatory protein, which in turn binds to and activates myosin light­ chain kinase. hus, logically, uterine relaxation ordinarily is promoted by conditions that lower concentrations of (Ca2 +)i. In contrast,

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agents that prompt contraction act on myometrial cells to aug­ ment (Ca2 +)i levels. Or, they allow an inlux of extracellular calcium through ligand- or voltage-regulated calcium channels (see F ig. 2 1 -6) . Voltage-gated ion channels open, additional calcium ions move into the cell, and cellular depolarization follows. For example, prostaglandin F 2ex and oxytocin bind their respective receptors during labor to open ligand-activated calcium channels. Activation of these receptors also releases calcium from the sarcoplasmic reticulum to lower electronega­ tivity within the cell. Additionally, greater localization of non­ selective cation channels on the cell membrane promotes Ca2 + entry (Ying, 20 1 5) . The rise in (Ca2 +)i levels is often transient. B ut, contractions can be prolonged by inhibition of myo­ sin phosphatase, an enzyme which dephosphorylates myosin (Woodcock, 2004) . Reg u l ation of Mem bra n e Potentia l s

As j ust noted, myocyte excitability i s regulated in part by changes in the electrochemical potential gradient across the plasma membrane. Before labor, myocytes maintain a relatively high interior electro negativity. Maintenance of a hyperpolar­ ized membrane potential attenuates smooth muscle cell excita­ tion and is regulated by ion channels. Consistent with the importance of myometrial quiescence, numerous potassium channels control membrane potential. One key regulator is the large-conductance voltage- and Ca2 +­ activated K channel (BKeJ (Perez, 1 993) . In normal physiol­ ogy, the myometrial BKca channel plays dual and opposing

Physio logy of La bor

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Ca++ FIGURE 21 -6 Uterine myocyte relaxation and contraction. A. Uterine relaxation is maintai ned by factors that increase myocyte cyclic adenosine monophosphate (cAMP) levels. This activates protein kinase A (PKA) to promote phosphodiesterase activity with dephosphorylation of myosi n lig ht-cha in kinase (MLCK). Other processes serve to mainta in actin in a globular form a n d thus t o prevent the fibril formation necessary for contrac­ tions. B. Uterine contractions result from reversal of these sequences. Actin now assu mes a fibrillar form, a nd ca lci u m enters the cel l to comb i ne with ca lmod u l i n to form complexes. These complexes activate MLCK to bring about phosphorylation of the myosin light chains. Th is generates ATPase activity to cause sliding of myosin over the actin fi brils, which is a uteri ne contraction. AC adenylyl cyclase; Ca 2 + calcium; DAG diacylglycerol; Gs and GQ G-receptor proteins; I P3 inositol tri phosphate; LC20 light chain 20; PIP3 phosphatidyli nositol 3,4,5-tri phosp hate; PLC phosphol ipase C; R-PKA inactive protein kinase. (Redrawn from Smith R: Pa rtu rition. N Engl J Med. 2007 Jan 1 8;356(3):271 -283.) =

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roles to maintain a balance between uterine quiescence and contractility. The B ca channel is abundantly expressed in the myometrium. For most of pregnancy, opening the BKca chan­ nel allows potassium to leave the cell to maintain interior elec­ tronegativity, thus preventing voltage-gated Ca2 + inlux and contraction. Enhancing B ca channel opening results in myo­ metrial relaxation, whereas inhibition of the B ca channel aug­ ments myometrial contractility. he ability of B ca channel to regulate calcium dynamics and ultimately uterine contractility from early to late gestation may result from temporal changes in expression of the B ca channel and/or Bca interacting part­ ners (Wakle-Prabagaran, 20 1 6) . Myo metri a l G a p J u nctions

Cellular signals that control myometrial contraction and relax­ ation can be efectively transferred between cells through inter­ cellular junctional channels. Communication is established between myocytes by gap junctions, which aid the passage of electrical or ionic coupling currents as well as metabolite coupling. The transmembrane channels that make up the gap junctions consist of two protein "hemi-channels" (Saez, 2005) . These connexons are each composed of six connexin subunit proteins (Fig. 2 1 -7) . Of these, connexin-43 is expressed in

myometrium, and concentrations rise near labor onset. Pairs of connexons establish a conduit between coupled cells for the exchange of small molecules that can be nutrients, waste, metabolites, second messengers, or ions. Optimal numbers and types of gap junctions are believed to be important for electrical myometrial synchrony. Progesterone maintains uterine quiescence in part by mech­ anisms that lower expression of various key proteins needed for contractility. hese contraction-associated proteins (CAPs) include the oxytocin receptor, prostaglandin F receptor, and connexin-43. At the end of pregnancy, increased stretch along with greater estrogen dominance raises CAP levels. Integration of diverse regulatory pathways culminates in released inhibition of connexin-43 and oxytocin receptor levels to promote greater uterine contractility (Nadeem, 20 1 6; Renthal, 20 1 0; Williams, 20 1 2b) . E n d o p l a s m i c Reticu l u m Stress Respo n se

As another potential mechanism, progesterone main tains uterine quiescence through support of myometrial caspase 3, which is an anticontractile agent Qeyasuria, 2009) . his protein degrades both actin and the speciic gap junction protein, con­ nexin-43 (Kyathanahalli, 20 1 5) .

405

406

La bor

Cell 1 membrane

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l

In mice, myometrial caspase 3 activation is regulated by a pregnancy-induced endoplasmic reticulum stress response (ERSR). As background, the endoplasmic reticulum aids protein fold­ ing and transport. Functional irregularities cause misfolded proteins to accumulate and trigger the ERSR. he ERSR and its unolded-protein response (UPR) are cellular mechanisms that work to maintain homeostasis in the face of stimuli, such as stretch and inlammation. Prolonged ERSR promotes caspase 3 activation to preserve quiescence despite these stimuli.

Cell 2 membrane

G-Prote in-Co u p l ed Rece ptors

Various cell surface receptors directly regulate myocyte contrac­ tility. Discussions thus far have described ion channel-linked receptors that regulate intracellular Ca2 + and membrane poten­ tial. In addition, numerous G-protein-coupled receptors appear to be modified during the phases of parturition. Several of these are present in myometrium and associated with Gos-mediated activation of adenylyl cyclase to yield higher cAMP levels. These receptors together with appropriate ligands may act with sex steroid hormones to maintain uterine quiescence (Price, 2000; Sanborn, 1 998) . Examples are the LH receptor and corticotro­ pin-releasing hormone receptor 1 (CRHR 1 ) , both described in this section (Fig. 2 1 -8) . Other G-protein-coupled myometrial receptors, instead, are associated with G-protein-mediated acti­ vation of phospholipase C, which remember releases arachi­ donic acid. Ligands for the G-protein-coupled receptors include numerous neuropeptides, hormones, and autacoids. Many of these are available to the myometrium during pregnancy in high concentration via endocrine or autocrine mechanisms. 3-Adrenoreceptors are prototypical examples of cAMP sig­ naling causing myometrium relaxation. 3-Adrenergic receptors mediate Gs-stimulated increases in adenylyl cyclase, elevated

No passage of /� large molecules through closed channels

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Interacting plasma membranes

FIGURE 21 -7 The prote i n s u b u n its of g a p ju nction c h a n n els a re ca l led con nexins. Six con n ex i n s form a hemichannel (con nexon), a n d two con nexon s (one from each ce l l ) form a g a p j u n ction chan­ nel. Con nexon s and g a p j u nction chan nels ca n be formed from one or more con nexin proteins. The com position of the g a p j u nc­ tion ch a n n e l is i m porta nt for these chan nels' selectivity with rega rd to passage of molecules a nd com m u nication between cel ls. A Agonist

B

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FIGURE 2 1 -8 G-protein-coupled receptor signal tra nsduction pathways. A. Receptors cou pled to heterotrimeric guanosine-triphosphate (GTP)-binding proteins (G proteins) a re i ntegral transmem brane proteins tl 13t transduce extracellular sig nals to the cel l interior. G-protei n-coupled receptors exh ibit a common structu ra l motif consisting of seven membra ne-span ning regions. B. Receptor occupation promotes interaction between the receptor and the G protein on the i nterior su rface of the membrane. This induces an exchange of guanosine diphosphate (GOP) for GTP on the G protein Q subu nit and dissociation of the Q subunit from the 31 heterodimer. Depending on its isoform, the GTP-Q subunit com plex med iates intracellular sig naling either indirectly by acti ng on effector molecules such as adenylyl cyclase (AC) or phospholipase C (PLC), or directly by reg ulating ion channel or kinase fu nction. cAMP cyclic adenosi ne monophosphate; DAG diacylg lycerol; I P3 inositol triphosphate. =

=

=

Physiology of Labor

levels of cAMP, and myometrial cell relaxation. The rate-lim­ iting factor is likely the number of receptors expressed and the level of adenylyl cyclase expression. Agents binding to these receptors have been used for tocolysis of preterm labor and include ritodrine and terbutaline (Chap. 42, p. 826) . LH and hCG hormones share the same receptor, and this G-protein-coupled receptor has been found in myometrial smooth muscle and blood vessels (Ziecik, 1 992) . Levels of myometrial LH-hCG receptors during pregnancy are greater before than during labor. Chorionic gonadotropin acts to acti­ vate adenylyl cyclase by way of a plasma membrane receptor G's-linked system. This lessens contraction frequency and force and lowers the number of tissue-speciic myometrial cell gap junctions (Ambrus, 1 994; Eta, 1 994) . hus, high circulating levels of hCG may be one mechanism of uterine quiescence. In the mouse, variations in FSH-receptor density also regulate myometrial contractile activity (Stilley, 20 1 6) . Prostaglandin E2 mediates its diverse cellular efects through four G-protein-coupled receptors. Speciically, prostaglandin E receptors 1 through 4 (EP ,-EP4) are expressed in the myo­ metrium during pregnancy and with labor onset (Astle, 2005; Leonhardt, 2003) . EP 2 and EP4 act through G's to raise cAMP levels and maintain myometrial cell quiescence but switch to a G'q/ 1 1 calcium-activating pathway during labor (Kandola, 20 1 4) . EP] and EP3 receptors act through G'q and G'i to aug­ ment intracellular Ca2 + and contractility. he peptide hormone relaxin binds to the G-protein-coupled receptor named reaxin amiy peptide receptor 1 (FP1). Binding activates adenylyl cyclase in uterine smooth muscle cells. Adenylyl cyclase in turn prevents increased intracellular Ca2 + and thus pro­ motes uterine quiescence (Downing, 1 993; Meera, 1 995). There are two separate human relaxin genes, designated HI and H2. Of these, HI is primarily expressed in the decidua, trophoblast, and prostate, whereas H2 is primarily expressed in the corpus luteum. Relaxin in plasma of pregnant women is believed to originate exclusively from corpus luteum secretion. Plasma levels peak at approximately 1 ng/mL between 8 and 1 2 weeks' gestation. Thereater, they decline to lower levels that persist until term. Corticotropin-releasing hormone (CRH) is synthesized in the placenta and hypothalamus. Discussed on page 4 1 0, CRH plasma levels rise dramatically during the inal 6 to 8 weeks of normal pregnancy and are implicated in mechanisms that con­ trol the timing of human parturition (Smith, 2007; Wadhwa, 1 998) . CRH appears to promote myometrial quiescence during most of pregnancy but then aids myometrial contractions with parturition onset. Studies suggest that these opposing actions are achieved by diferential actions of CRH via its receptor CRHR1 . I n nonlaboring myometrium at term, the interaction of CRH with its CRHR1 receptor activates the Gs-adenylate cyclase­ cAMP signaling pathway. his results in inhibition of inositol triphosphate (IP3) and stabilization of (Ca2 +)j levels (You, 20 1 2). However, in term laboring myometrium, (Ca2 +)j concentrations are augmented by CRH activation of G proteins Gq and Gi and prompts stimulation of IP3 production and greater contractility. Cyc l i c G u a n o s i n e Monophosp hate

As just described, cAvIP is an important mediator of myome­ trial relaxation. However, activation of guanylyl cyclase raises

intracellular cyclic guanosine monophosphate (cGMP) levels. This also promotes smooth muscle relaxation (Word, 1 993) . Intracellular cGMP levels are increased in the pregnant myo­ metrium and can be stimulated by atrial natriuretic peptide (ANP) , brain natriuretic peptide (BNP) receptors, and nitric oxide (Telfer, 200 1 ) . All of these factors and their receptors are expressed in the pregnant uterus. Accelerated Uteroto n i n Deg rad ation

In addition to pregnancy-induced compounds that promote myometrial cell refractoriness, the activity of enzymes that degrade or inactivate endogenously produced uterotonins are strikingly increased in phase 1 . Some of these degrading enzymes and their respective targets include PGDH and prostaglandins; enkephalinase and endothelins; oxytocinase and oxytocin; diamine oxidase and histamine; catechol O-methyltransferase and catecholamines; angiotensinases and angiotensin-II ; and platelet-activating factor (PAF) and PAF acetylhydrolase. Levels of several of these enzymes decrease late in gestation (Germain, 1 994) . • Decidua

To ensure uterine quiescence, the synthesis in the decidua of prostaglandins, in particular PGF 2', is markedly suppressed. Suppression of prostaglandin production here persists through­ out most of pregnancy, and suppression withdrawal is a prereq­ uisite for parturition (Norwitz, 20 1 5) . Phase 1 o f parturition also promotes a n environment of immune tolerance to protect the fetus. Namely, decidual stro­ mal cells proactively ensure that fetal antigens do not elicit a maternal immune response. his stems from a reduced capacity to attract T cells. This limited ability derives in part from epi­ genetic silencing of T cell-attracting inlammatory chemokine genes (Erlebacher, 20 1 3; Nancy, 20 1 2; PrabhuDas, 20 1 5) . • Cervical Softening

The initial stage of cervical remodeling-termed sotening­ begins in phase 1 of parturition. It is characterized by greater tissue compliance, yet the cervix remains irm and unyielding. Hegar ( 1 895) irst described palpable softening of the lower uterine segment at 4 to 6 weeks' gestation, and this sign was once used to diagnose pregnancy. Clinically, the maintenance of cervical anatomical and structural integrity is essential for pregnancy to continue to term. Preterm cervical dilation, struc­ tural insuiciency, or both may forecast delivery. Cervical softening results from increased vascularity, cellu­ lar hypertrophy and hyperplasia, and slow, progressive com­ positional and structural changes in the extracellular matrix (Mahendroo, 20 1 2; Myers, 20 1 5 ; Word, 2007) . Key to matrix changes, collagen, which is the main structural protein in the cervix, undergoes conformational changes that alter tissue stif­ ness and flexibility (Zhang, 20 1 2) . Speciically, collagen pro­ cessing and the number or type of stable covalent cross-links between collagen triple helices is altered. Mature cross-links between newly synthesized collagen monomers are reduced due to diminished expression and activity of the cross-link-forming

407

408

La bo r

enzymes beginning in early pregnancy (Akins, 20 1 1 ; Drewes, 2007; Yoshida, 20 1 4) . hese enzymes are lysyl hydroxylase and lysyl oxidase. Together, these early pregnancy changes contrib­ ute to greater tissue compliance. Clinical evidence for the importance ofmatrix changes to cer­ vical sotening is supported by in vivo mechanical evaluation of the cervix (Badir, 20 1 3; Parra-Saavedra, 201 1 ) . he prevalence of cervical insuiciency is also higher in those with inherited defects in the synthesis or assembly of collagen or elastic ibers (Anum, 2009; Hermanns-Le, 2005 ; Rahman, 2003; Wang, 2006) . Examples are Ehlers-Danlos and Marfan syndromes, dis­ cussed in Chapter 59 (p. 1 1 5 1 ) . Concurrent with matrix remod­ eling in the sotening period, genes involved in cervical dilation and parturition are actively repressed (Hari Kishore, 20 1 2) .

PHASE 2: PREPARATION FOR LABOR To prepare for labor, the myometrial tranquility of phase 1 of parturition must be suspended-so-called uterine awakening or activation. This phase 2 of parturition is a progression of uterine changes during the last few weeks of pregnancy. Importantly, shifting events associated with phase 2 can cause either preterm or delayed labor. • Progesterone Withdrawal

Key factors in uterine activation are depicted in Figure 2 1 -5 . In species that exhibit progesterone withdrawal, parturition pro­ gression to labor can be blocked by administering progesterone to the mother. Whether progesterone administration in the absence of classic progesterone withdrawal in pregnant women can delay the timely onset of parturition or prevent preterm labor continues to be investigated. he possibility that pro­ gesterone-containing injections or vaginal suppositories may prevent preterm labor has been studied in several randomized trials conducted during the past 1 5 years. hese are discussed in Chapter 42 (p. 8 1 6) , and their use in preventing recurrent preterm birth continues to be debated (Norman, 20 1 6) . Classic progesterone withdrawal resulting from decreased secretion does not occur in human parturition. However, a mechanism for progesterone inactivation, whereby the myome­ trium and cervix become refractory to progesterone's inhibitory actions, is supported by studies using progesterone-receptor antagonists. Mifepristone is a classic steroid antagonist, acting at the level of the progesterone receptor. Although less efective in inducing abortion or labor in women later in pregnancy, mifepristone appears to have some efect on cervical ripening and on increasing myometrial sensitivity to uterotonins (Ber­ kane, 2005; Chwalisz, 1 994a) . The diverse mechanisms by which functional progester­ one withdrawal or antagonism is achieved is an active area of research. These include: ( 1 ) changes in the relative expression of the nuclear progesterone-receptor isoforms, PR-A, PR-B, and PR-C; (2) diferential interaction of PR-A and PB-B with enhancers and inhibitors of gene expression; (3) alterations in PR activity through changes in the expression of coactivators or corepressors that directly influence receptor function; (4) local inactivation of progesterone by steroid-metabolizing enzymes

or synthesis of a natural antagonist; and (5) microRNA regu­ lation of progesterone-metabolizing enzymes and transcrip­ tion factors that modulate uterine quiescence (Condon, 2003; Mahendroo, 1 999; Mesiano, 2002; Nadeem, 20 1 6; Renthal, 20 1 0; Williams, 20 1 2a) . Taken together, these observations support the concept that multiple pathways exist for a func­ tional progesterone withdrawal. • Myometrial Changes

Phase 2 myometrial changes prepare it for labor contractions. his results from a shit in the expression of key proteins that control uterine quiescence to an expression of contraction-associated pro­ teins, described earlier (p. 405) (Renthal, 20 1 5) . Of these CAPs, myometrial oxytocin receptors and gap junction proteins, such as connexin-43, markedly rise in number. These CAPs increase uterine irritability and responsiveness to uterotonins. Another critical change in phase 2 is formation of the lower uterine segment from the isthmus. With this development, the fetal head often descends to or even through the pelvic inlet­ so-called lightening. he abdomen commonly undergoes a shape change, sometimes described by women as "the baby dropped." It is also likely that the lower segment myometrium is unique from that in the upper uterine segment, resulting in distinct roles for each near term and during labor. This is supported by human studies that demonstrate diferential expression of pros­ taglandin receptors and CAPs within the upper- and lower-seg­ ment myometrial regions (Astle, 2005; Blanks, 2003; Sparey, 1 999) . Near term, elevated expression of the HoA13 gene in the lower myometrial segment compared with the upper seg­ ment also induces CAP expression and regionalized contractil­ ity of the lower segment (Li, 20 1 6) . Oxytoci n Rece ptors

Because of its long-standing application for labor induction, it seemed logical that oxytocin must play a central role in spon­ taneous human labor. Myometrial oxytocin receptor levels do rise during phase 2 of parturition, and the level of oxytocin receptor mRNA in human myometrium at term is greater than that found in preterm myometrium (Wathes, 1 999). However, it is unclear whether oxytocin plays a role in the early phases of uterine activation or whether its sole function is in the expulsive phase of labor. Most studies of regulation of myometrial oxyto­ cin receptor synthesis have been performed in rodents. Disrup­ tion of the oxytocin receptor gene in the mouse does not afect parturition. This suggests that, at least in this species, multiple systems likely ensure that parturition occurs. Progesterone and estradiol appear to be the primary regu­ lators of oxytocin receptor expression. Estradiol treatment in vivo or in myometrial explants raises myometrial oxytocin receptor concentrations. This action, however, is prevented by simultaneous treatment with progesterone (Fuchs, 1 983) . Pro­ gesterone also may act within the myometrial cell to enhance oxytocin receptor degradation and inhibit oxytocin activation of its receptor at the cell surface (Bogacki, 2002) . hese data indicate that one of the mechanisms whereby progesterone maintains uterine quiescence is through inhibition of a myo­ metrial oxytocin response.

Physiology of La bor • Cervical Ripening

Before contractions begin, the cervix must undergo extensive remodeling. his eventually leads to the cervix yielding and dilating from forceful uterine contractions. Cervical modii­ cations during phase 2 principally involve connective tissue changes-termed cervical ripening. The transition from the softening to the ripening phase begins weeks or days before labor. During this transformation, the cervical matrix changes its total amounts of gycosaminogycans, which are large linear polysaccharides, and proteogycans, which are proteins bound to these glycosaminoglycans. Many of the processes that aid cervical remodeling are controlled by the same hormones regulating uterine function. That said, the molecular events of each are varied because of diferences in cellular composition and physiological require­ ments. For example, the hormone relaxin regulates myometrial quiescence. It also regulates cervical ripening, but through cell proliferation and modulation of extracellular matrix compo­ nents (Park, 2005; Soh, 20 1 2) . The uterine corpus is predomi­ nantly smooth muscle. In contrast, the cervix has a high ratio of ibroblasts to smooth muscle cells, and extracellular matrix contributes significantly to overall tissue mass. Recent studies in the nonpregnant human cervix report a spatial gradient of smooth muscle cells. Specifically, smooth muscle cells make up approximately 50 percent of stromal cells at the internal os but only 10 percent at the external os (Vink, 20 1 6) . Cervical Co n n ective Ti ssue Col lagen. The cervix is an extracellular-matrix-rich tissue.

Constituents of the matrix include type I, III, and IV collagen, matricellular proteins, glycosaminoglycans, proteoglycans, and

Collagen fiber

Fibril Collagen cross links

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Tightly packed fibrils

Before cervical ripening

During cervical ripening

Collagen fiber cross section

elastic ibers. Of these, collagen is largely responsible for the structural disposition of the cervix. During collagen assembly, multiple collagen triple-helical molecules are cross-linked to one another by the actions of lysyl oxidase to form ibrils. In addition, ibril size, packing, and organization determine the strength and mechanical properties of the cervix. These p rop­ erties are regulated in part by collagen-binding proteoglycans such as decorin or biglycan, as well as matricellular proteins such as thrombospondin 2 ( Fig. 2 1 -9) . Higher turnover o f collagen during pregnancy likely allows the gradual replacement of mature cross-linked collagen ibrils with poorly cross-linked ibrils, which yield greater collagen disorganization. his increased turnover, rather than loss of collagen to achieve cervical remodeling, is supported by mouse and human studies that document no changes in collagen con­ tent between nonpregnant states and term pregnancy (Akins, 20 1 1 ; Myers, 2008; Read, 2007; Yoshida, 20 1 4) . In further support, polymorphisms or mutations in genes required for collagen assembly are associated with an elevated incidence of cervical insuiciency (Anum, 2009; Rahman, 2003; Warren, 2007) . Glycosa mi nog lyca ns and Proteog lyca ns. Hyaluronan is a high-molecular-weight polysaccharide that functions alone, whereas most other glycosaminoglycans (GAGs) complex with proteins to form proteoglycans. Hyaluronan is a hydrophilic, space-illing molecule, and thus greater hyaluronan production during cervical ripening is thought to increase viscoelasticity, hydration, and matrix disorganization. Hyaluronan synthesis is carried out by hyaluronan synthase isoenzymes, and expres­ sion of these enzymes is elevated in the cervix during ripening (kgul, 20 1 2 ; Straach, 2005). Although not well deined, changes in proteoglycan composition are also suggested to accompany cervical rip­ ening. At least three small leucine­ rich proteoglycans are expressed in the cervix-decorin, biglycan, and ibromodulin (Westergren-Thorsson, 1 998). In other connective tissues, decorin interacts with collagen to reg­ ulate the packing, order, and strength of collagen fibrils (see Fig. 2 1 -9) (Ameye, 2002) . In addition to the cer­ vix, these proteoglycans are expressed in the fetal membranes and uterus.

Loosely packed fibrils Col lagen fiber cross section

FIGURE 21 -9 The col lagen fiber a rch itecture is reorga n ized in phases 1 a nd 2 of partu rition to a l low a g ra d u a l i ncrease in mecha n ical com pliance of the cervix, A collagen fi ber is made up of m a ny fi bri ls, F i b ri l s ize a nd packi ng a re reg u lated i n pa rt by sma l l proteog lyca ns such as , , decorln and by the denS ity of col lagen cross-links, I n phase 1 , fi bril s ize i s u n iform a nd fi bri l s a re v eil org a n iz,ed : a l tho u g h a dec l i n e in cross-l i n k dens ity aids soften i ng , D u ri n g cervica l ripen i n g , , IS I n p h a s e 2, fi bri l size l e s s u niform, a n d spacing between col l agen fi brils a n d fi bers is g reater a nd disorg a n ized,

I nfl a m matory Cha n ges. In phase 2, resident immune cells are localized to the cervical stroma, although a func­ tional role for these cells in this phase of remodeling has been challenged. M icroarray studies comparing gene expression patterns at term both before and after cervical ripening show little rise in proinflammatory gene expression. In contrast, p roin­ flammatory and immunosuppressive

409

41 0

La bor

gene expression in the cervix after delivery increases markedly compared with that during cervical ripening (Bollapragada, 2009; Hassan, 2006, 2009) . Further, detailed studies in mice provide evidence that leukocyte migration but not activation takes place before labor. Once labor is underway, activation of neutrophils, pro inflammatory M 1 macrophages, and tis­ sue repair M2 macrophages in the cervix is augmented. This suggests a role for inlammatory cells in postpartum cervical remodeling and repair (Mahendroo, 20 1 2) .

hydramnios. Although the mechanisms causing preterm birth in these two examples are debated, a role for uterine stretch must be considered. Cell signaling systems that are inluenced by stretch to regu­ late the myometrial cell continue to be defined. his process­ mechanotransduction-may include activation of cell-surface receptors or ion channels, transmission of signals through extracellular matrix, or release of autocrine molecules that act directly on myometrium (Shynlova, 2007; Young, 20 1 1 ) .

I n d u ction o f Cervical R i pe n i n g

Feta l E n d ocri ne Cascades

No therapies prevent premature cervical ripening. In contrast, treatment to promote cervical ripening for labor induction includes direct application of prostaglandins PGE2 and PGF 2'. Prostaglandins likely modiy extracellular matrix structure to aid ripening. Although the role of prostaglandins in the normal physiology of cervical ripening remains unclear, this property is useful clinically to assist labor induction (Chap. 26, p. 505) . In some nonhuman species, the cascades of events that allow cervical ripening are induced by dropping serum progesterone concentrations. And in humans, administration of progester­ one antagonists causes cervical ripening.

The ability of the fetus to provide endocrine signals that initiate parturition has been demonstrated in several species. However, evidence suggests that it is not regulated in the same manner in humans. hat said, the human fetal hypothalamic-pituitary­ adrenal-placental axis is considered a critical component of nor­ mal parturition. Moreover, premature activation of this axis is considered to prompt many cases of pre term labor (Challis, 2000, 200 1 ) . As in the sheep, steroid products of the human fetal adrenal gland are believed to have efects on the placenta and membranes that eventually transform the myometrium from a quiescent to a contractile state. A key component in the human may be the unique ability of the placenta to produce large amounts of CRH (Fig. 2 1 - 1 0) . A CRH hormone that i s identical to maternal and fetal hypothalamic CRH is synthesized by the placenta in relatively large amounts (Grino, 1 987; Saijonmaa, 1 988). However, unlike hypothalamic CRH, which is under glucocorticoid neg­ ative feedback, cortisol instead stimulates placental CRH pro­ duction. This ability makes it possible to create a feed-forward endocrine cascade that does not end until delivery. Maternal plasma CRH levels are low in the first trimes­ ter and rise from midgestation to term. In the last 1 2 weeks, CRH plasma levels rise exponentially, peak during labor, and then fall precipitously after delivery (Frim, 1 988; Sasaki, 1 987) . Amnionic luid CRH concentrations similarly increase in late gestation. CRH is the only trophic hormone-releasing

E n d ocervica l Epithel ia

In addition to matrix changes, during pregnancy, endocervical epithelial cells proliferate such that endocervical glands account for a signiicant percentage of cervical mass. he endocervical canal is lined with mucus-secreting columnar and stratified squamous epithelia. These cells form both a mucosal barrier and a tight j unctional barrier that protect against microbial invasion (Akgul, 20 1 4; Blaskewicz, 20 1 1 ; Timmons, 2007) . The mucosal epithelium recognizes and deters pathogen inva­ sion via expression of toll-like receptors that identiy pathogens and via antimicrobial pep tides and protease inhibitors. In addi­ tion, these epithelia express signals to underlying immune cells when a pathogenic challenge exceeds their protective capacity (Wira, 2005). • Fetal Contributions to Parturition

It is intriguing to envision that the mature human fetus pro­ vides the signal to initiate parturition, and evidence for fetal signaling is mounting (Mendelson, 20 1 7) . The fetus may give signals through blood-borne agents that act on the placenta or through secretion into the amnionic luid.

. . - - - - - -

- -

Maternal estrogens

Uteri n e Stretch

Fetal growth is an important component in uterine activa­ tion in phase 2 of parturition. With uterine activation, stretch is required for induction of specific CAPs. Namely, stretch increases expression of connexin-43 and oxytocin receptors. Levels of gastrin-releasing peptide, a stimulatory agonist for smooth muscle, are also augmented by stretch in the myome­ trium (Tattersall, 20 1 2) . Clinical clues for a role o f stretch come from the observa­ tion that multifetal pregnancies carry a much greater risk for preterm labor than singleton ones. And, preterm labor is also signiicantly more common in pregnancies complicated by

FIGU RE 2 1 - 1 0 The placenta l-fetal a d renal endocri ne cascade. In late gestation, placenta l corticotropi n-releas i n g hormone (CRH) sti m u lates feta l a d renal prod u ction of dehyd roepi a nd rosterone sul­ fate (DH EA-S) a n d cortisol. The latter sti m u lates prod uction of pla­ centa l CRH, which leads to a feed-forwa rd cascade that enha nces adre n a l steroid hormone prod uction. ACTH a d renocorticotropic hormone. =

Physio logy of Labor

factor to have a speciic serum binding protein. During most of pregnancy, CRH-binding protein (CRH-BP) binds most maternal circulating CRH , and this inactivates it (Lowry, 1 993). During later pregnancy, however, CRH-BP levels in both maternal plasma and amnionic luid decline, leading to markedly greater levels of bioavailable CRH (Perkins, 1 99 5 ; Petraglia, 1 997) . In pregnancies in which the fetus can be considered "stressed" from various complications, concentrations of CRH in fetal plasma, amnionic luid, and maternal plasma are greater than those seen in normal gestation (Berkowitz, 1 996; McGrath, 2002) . he placenta is the likely source of this elevated CRH concentration. For example, placental CRH content is four­ fold higher in placentas from women with preeclampsia than in those from normal pregnancies (Perkins, 1 995). Placental CRH is thought to play several roles in parturition regulation. It may enhance fetal cortisol production to provide positive feedback so that the placenta produces more CRH. Late in pregnancy-phase 2 or 3 of parturition-modiication in the CRH receptor favors a switch from cAMP formation to increased myometrial cell calcium levels via protein kinase C activation (You, 20 1 2) . Oxytocin acts to attenuate CRH­ stimulated accumulation of cAMP in myometrial tissue. CRH acts to augment myometrial contractile force in response to PGF 2: (Benedetto, 1 994) . Finally, CRH stimulates fetal adrenal Cwsteroid synthesis, thereby increasing substrate for placental aromatization. Some have proposed that the rising CRH level at the end of gestation relects a etal-placental clock (McLean, 1 995). CRH concentrations vary greatly among women, and the rate of rise in maternal CRH levels is a more accurate predictor of pregnancy outcome than is a single measurement (Leung, 200 1 ; McGrath, 2002) . In this regard, the placenta and fetus, through endocrinological events, inluence the timing of partu­ rition at the end of normal gestation. Feta l L u n g S u rfacta nt a n d P l atel et-Activati n g Factor

Surfactant protein A (SP-A) produced by the fetal lung is required for lung maturation. SP-A is expressed by the human amnion and decidua, is p resent in the amnionic luid, and prompts signaling pathways in human myometrial cells (Garcia-Verdugo, 2008; Lee, 20 1 0; Snegovskikh, 20 1 1 ) . he exact mechanisms by which SP-A activates myometrial con­ tractility in women, however, remain to be clarifi e d. One mode may be its efects on prostaglandins. Namely, SP-A selectively inhibits prostaglandin F 2: in the term decidua, but SP-A levels drop in the amnionic luid at term (Chaiworapongsa, 2008) . In addition to SP-A, the fetal lung makes the uterotonic agent platelet-activating factor (Frenkel, 1 996; Toyoshima, 1 995). This factor and SP-A play a role in fetal-maternal signaling for parturition (Gao, 20 1 5) . Feta l-Mem bra ne S e nesce nce

Toward the end of pregnancy, fetal membranes undergo physi­ ological aging termed cellular senescence (Menon, 20 1 6) . In human fetal membranes and animal models, stretch and oxida­ tive stress induce senescent fetal membrane to manifest a form of sterile inflammation termed senescent-associated secretory

phenotype (SASP) . This in turn propagates inlammatory sig­ nals that further weaken the fetal membrane and activate sig­ nals in the decidua and myometrium to initiate parturition. hus, as the functional necessity of fetal membranes declines at term, they are able to promote signals that contribute to parturition initiation. Feta l Anoma l i es a n d Delayed Pa rtu rition

Some evidence shows that pregnancies with markedly dimin­ ished estrogen production may be associated with prolonged gestation. These "natural experiments" include women with inherited placental sulfatase deiciency and fetal anencephaly with adrenal hypoplasia. The broad range of gestational length seen with these disorders, however, calls into question the exact role of estrogen in human parturition initiation. Other fetal abnormalities that prevent or severely reduce the entry of fetal urine or lung secretions into amnionic fluid do not prolong human pregnancy. Examples are renal agenesis and pulmonary hypoplasia, respectively. Thus, a fetal signal through the paracrine arm of the fetal-maternal communication system does not appear to be mandated for parturition initiation. Some brain anomalies of the fetal calf, fetal lamb, and some­ times the human fetus delay the normal timing of parturition. More than a century ago, Rea ( 1 898) observed an association between fetal anencephaly and prolonged human gestation. Malpas ( 1 933) extended these observations and described a pregnancy with an anencephalic fetus that was prolonged to 374 days-53 weeks. He concluded that the association between anencephaly and prolonged gestation was attributable to anomalous fetal brain-pituitary-adrenal function. Indeed, the adrenal glands of the anencephalic fetus are very small and, at term, may be only 5 to 1 0 percent as large as those of a nor­ mal fetus. This is caused by developmental failure of the fetal zone that normally accounts for most of fetal adrenal mass and production of C wsteroid hormones (Chap. 5, p. 1 04) . S uch pregnancies are associated with delayed labor and suggest that the fetal adrenal glands are important for the timely onset of parturition.

PHASE 3: LABOR This phase is synonymous with active labor, which is custom­ arily divided into three stages. These compose the commonly used labor graph shown in Figure 2 1 -4. he irst stage b egins when spaced uterine contractions of suicient frequency, inten­ sity, and duration are attained to bring about cervical thinning, termed facement. Several uterotonins may be important to the success of this stage of active labor (see F ig. 2 1 -5) . These have been shown to stimulate smooth muscle contraction through G-protein coupling. This labor stage ends when the cervix is fully dilated-about 1 0 cm-to allow passage of the term-sized fetus. The irst stage of labor, therefore, is the stage of cervical eacement and dilation. The second stage begins when cervical dilation is complete and ends with delivery. Thus, the second stage of labor is the stage ofetal expulsion. Last, the third stage begins immediately after delivery of the fetus and ends with the delivery of the placenta. Thus, the third stage of labor is the stage ofplacental separation and expulsion.

41 1

41 2

La bor

Active segment I I

Body Anat. I .O. Hist. I .O. ---E . O. ------N O N P R E G NANT UTERUS

PREGNANT UTERUS AT TERM

UTERUS I N LABOR NORMAL EARLY FI RST STAG E

E .O. �

Active segment

Pathological retraction ring (Sandi)

I

I I I

Passive segment

Obliterated 1 . 0.

--- E .O.-"

UTERUS IN LABOR NORMAL SECOND STAG E

UTERUS IN LABOR ABNORMAL SECOND STAG E - DYSTOCIA

FIGURE 21 -1 1 Seq uence of development of the segments and rings i n the uterus at term a nd i n la bor. Note comparison between the uterus of a n o n preg nant woman, the uterus at term, and the uterus d u ri n g la bor. The passive lower uterine seg ment is derived from the isth m u s, a nd the physiolog ical retraction ri n g develops at the j u nction of the u pper and lower uterine seg ments. The pathological retrac­ tion r i n g develops from the physio log ica l ring. Anat. 1.0. a nato m ical i ntern a l os; E.O. external os; H ist. 1 .0. h istolog ica l i nternal os; P h . R.R. p hysiological retraction ri ng. =

=

=

=

• First Stage: Clinical Onset of Labor

Uter i n e La bor Contractions

In some women, forceful uterine contractions that efect deliv­ ery begin suddenly. In others, labor initiation is heralded by spontaneous release of a small amount of blood-tinged mucus from the vagina. his extrusion of the mucus plug that had previously illed the cervical canal during pregnancy is referred to as "show" or "bloody show." Its passage indicates that labor is already in progress or likely will ensue in hours to days. Unique among physiological muscular contractions, those of uterine smooth muscle during labor are painful. Several possible causes have been suggested: ( 1 ) hypoxia of the contracted myo­ metrium-such as that with angina pectoris; (2) compression of nerve ganglia in the cervix and lower uterus by contracted interlocking muscle bundles; (3) cervical stretching during dila­ tion; and (4) stretching of the peritoneum overlying the fundus. Of these, compression of nerve ganglia in the cervix and lower uterine segment by the contracting myometrium is an especially attractive hypothesis. Paracervical infiltration with local anesthetic usually produces appreciable pain relief with contractions (Chap. 25, p. 490) . Uterine contractions are involuntary and, for the most part, independent of extrauter­ ine control. Neural blockade from epidural analgesia does not diminish their frequency or intensity. In other examples, myo­ metrial contractions in paraplegic women and in women after bilateral lumbar sympathectomy are normal but painless. Mechanical stretching of the cervix enhances uterine activ­ ity in several species, including humans. his phenomenon is the Ferguson relex (Ferguson, 1 94 1 ) . Its exact mechanism is unclear, and release of oxytocin has been suggested but not proven. Manipulation of the cervix and "stripping" the fetal membranes is associated with a rise in blood levels of prosta­ glandin F 2. metabolites. The interval between contractions narrows gradually from approximately 1 0 minutes at the onset of irst-stage labor to as little as 1 minute or less in the second stage. Periods of relaxation between contractions, however, are essential for fetal welfare. Unremitting contractions compromise uteroplacental blood fl o w suiciently to cause fetal hypoxemia. In active-phase labor, the duration of each contraction ranges from 30 to 90 seconds

and averages 1 minute. Contraction intensity varies appreciably during normal labor. Speciically, amnionic fluid pressures gen­ erated by contractions during spontaneous labor average 40 mm Hg, but vary from 20 to 60 mm Hg (Chap. 24, p. 479) . Disti nct Lower and U pper Uteri ne Segments. During active labor, the anatomical uterine divisions that were initiated in phase 2 of parturition become increasingly evident (Figs. 2 1 - 1 1 and 2 1 - 1 2) . By abdominal palpation, even before membrane rupture, the two segments can sometimes be diferentiated. he upper segment is firm during contractions, whereas the lower segment is softer, distended, and more passive. This mechanism is imperative because if the entire myometrium, including the lower uterine segment and cervix, were to contract simultane­ ously and with equal intensity, the net expulsive force would markedly decline. hus, the upper segment contracts, retracts, and expels the fetus. In response to these contractions, the

--Active

-

--

II

/

segment

0evel of internal cervical os Cervix Passive segment

/

..... .. . -, - Level of external cervical os

-�-- Vagina

FIGURE 21 -1 2 The uterus at the time of vag i n a l del ivery. The active u pper seg ment retracts a ro u n d the presenti n g part as the fetu s descends through the birth ca n a l . In the passive lower seg­ ment, there is considerably less myometria l tone.

Physiology of La bo r

softened lower uterine segment and cervix dilate and thereby form a greatly expanded, thinned-out tube through which the fetus can pass. he myometrium of the upper segment does not relax to its original length after contractions. Instead, it becomes relatively fixed at a shorter length. The upper active uterine segment con­ tracts down on its diminishing contents, but myometrial ten­ sion remains constant. he net efect is to take up slack, thus maintaining the advantage gained in expulsion of the fetus. Concurrently, the uterine musculature is kept in irm contact with the uterine contents. As the consequence of retraction, each successive contraction commences where its predecessor left of. hus, the upper part of the uterine cavity becomes slightly smaller with each successive contraction. Because of the successive shortening of the muscular fibers, the upper active segment becomes progressively thickened throughout first- and second-stage labor (see Fig. 2 1 - 1 1 ) . This process continues and results in a tremendously thickened upper uterine segment immediately after delivery. Clinically, it is important to understand that the phenomenon of upper segment retraction is contingent on a decrease in the vol­ ume of its contents. For this to happen, particularly early in labor when the entire uterus is virtually a closed sac with only mini­ mal cervical dilation, the musculature of the lower segment must stretch. This permits a greater portion of the uterine contents to occupy the lower segment. The upper segment retracts only to the extent that the lower segment distends and the cervix dilates. Relaxation of the lower uterine segment mirrors the same gradual progression of retraction. Recall that after each contrac­ tion of the upper segment, the muscles do not return to their previous length, but tension remains essentially the same. By comparison, in the lower segment, successive lengthening of the fibers with labor is accompanied by thinning, normally to only a few millimeters in the thinnest part. s a result of the lower segment thinning and concomitant upper segment thickening, a boundary between the two is marked by a ridge on the inner uterine surface-the physiological retraction ring. When the thin­ ning of the lower uterine segment is extreme, as in obstructed labor, the ring is prominent and forms a pathological retraction ring. This abnormal condition is also known as the Bandl ring, which is discussed further in Chapter 23 (p. 455). Changes in Uterine Shape. Each contraction gradually elon­

gates the ovoid uterine shape and thereby narrows the horizon­ tal diameter. This change in shape has important efects on the labor process. First, there is greater etal xis pressure, that is, the smaller horizontal diameter serves to straighten the fetal vertebral column. This presses the upper pole of the fetus firmly against the fundus, whereas the lower pole is thrust farther downward. The lengthening of the ovoid shape has been estimated at 5 to 10 cm. Second, with lengthening of the uterus, the longitudinal muscle ibers are drawn taut. As a result, the lower segment and cervix are the only parts of the uterus that are flexible, and these are pulled upward and around the lower pole of the fetus. Anci l l a ry Fo rces

After the cervix is dilated fully, the most important force in fetal expulsion is produced by maternal intraabdominal pressure.

Contraction of the abdominal muscles simultaneously with forced respiratory eforts with the glottis closed is referred to as pushing. The force is similar to that with defecation, b ut the intensity usually is m uch greater. The importance of intraab­ dominal pressure is shown by the prolonged descent during labor in paraplegic women and in those with a dense epidural block. And, although increased intraabdominal pressure is nec­ essary to complete second-stage labor, pushing accomplishes little in the first stage. It exhausts the mother, and its associated elevated intrauterine pressures may be harmful to the fetus. Cervica l Cha nges

s the result of contraction forces, two fundamental changes­

efacement and dilation-occur in the ripened cervix. For an average-sized fetal head to pass through the cervix, its canal must dilate to a diameter of approximately 10 cm. At this time, the cervix is said to be completely or ully dilated. Although there may be no fetal descent during cervical efacement, most commonly the presenting fetal part descends somewhat as the cervix dilates. Cervical facement is "obliteration" or "taking up" of the cervix. It is manifest clinically by shortening of the cervical canal from a length of approximately 3 cm to a mere circular oriice with almost paper-thin edges. The muscular fi b ers at the level of the internal cervical os are pulled upward, or "taken up," into the lower uterine segment. The condition of the exter­ nal os remains temporarily unchanged (Fig. 2 1 - 1 3) . Mu ltipara

Primigravida

A

B

-;,

!

c

FIGURE 21 -1 3 Schematic showi n g effacement and d i lation.

A. Before la bor, the pri m i g ravid cervix i s long a n d u n d i lated in con­

trast to that of the m U ltipara, which has d i lation of the interna l a n d externa l o s . B. A s efacement beg i n s, t h e m u ltipa rous cervix s hows d i lation a nd fu n neling of the i nternal os. Th is is less appa rent i n the pri m i g ravid cervix. C. A s complete efacement is achieved i n the pri m i g ravid cervix, d i lation is m i n i m a l . The reverse is true i n the m u ltipa ra .

41 3

41 4

La bor

Efacement may be compared to a funneling process in which the whole length of a narrow cylinder is converted into a very obtuse, fl a ring funnel with a small distal circular open­ ing. Because of growing myometrial activity during uterine preparedness for labor, appreciable efacement of a softened cervix sometimes is accomplished before active labor begins. Efacement causes expulsion of the mucous plug as the cervical canal is shortened. Because the lower segment and cervix have less resistance during a contraction, a centrifugal pull is exerted on the cervix and creates cervical dilation (Fig. 2 1 - 1 4) . As uterine contrac­ tions cause pressure on the membranes, the hydrostatic action of the amnionic sac in turn dilates the cervical canal like a wedge. The process of cervical efacement and dilation causes formation of the orebag of amnionic luid. This is the leading portion of fluid and amnionic sac located in front of the pre­ senting part. In the absence of intact membranes, the pressure of the presenting fetal part against the cervix and lower uterine segment is similarly efective. Early rupture of the membranes does not retard cervical dilation so long as the presenting fetal part is positioned to exert pressure against the cervix and lower segment. Referring back to Figure 2 1 -4, recall that cervical dilation is divided into latent and active phases. The active phase is subdivided further into the acceleration phase, the phase of maximum slope, and the deceleration phase (Friedman, 1 978) . The duration of the latent phase is more variable and sensitive to extraneous factors. For example, sedation may prolong the latent phase, and myometrial stimulation shortens it. The latent phase duration has little bearing on the subsequent course of labor, whereas the characteristics of the accelerated phase are usually predictive of labor outcome. The first stage ends when cervical dilation is complete. • Second Stage: Fetal Descent

In many nulliparas, engagement of the head is accomplished before labor begins. hat said, the head may not descend fur­ ther until late in labor. In the descent pattern of normal labor, a typical hyperbolic curve is formed when the station of the fetal head is plotted as a function of labor duration. Station describes descent of the fetal biparietal diameter in relation to a line drawn between maternal ischial spines (Chap. 22, p. 436) . Active descent usually takes place after dilation has pro­ gressed for some time (Fig. 2 1 - 1 5) . During second-stage labor, the speed of descent is maximal and is maintained until the presenting part reaches the perineal floor (Friedman, 1 978) . In nulliparas, the presenting part typically descends slowly and steadily. In multiparas, however, particularly those of high par­ ity, descent may be rapid. • Pelvic Floor Changes

he birth canal is supported and functionally closed by the pel­ vic loor (Chap. 2, p. 2 1 ) . The most important component of the loor is the levator ani muscle and the ibromuscular con­ nective tissue that covers its upper and lower surfaces. he bio­ mechanical properties of these structures and of the vaginal wall

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External cervical os A

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95th percentile) had a 1 6-percent rate of second-stage labor lasting 3 hours (95th percen­ tile). his compared with a 4.5-percent rate of prolonged second stages in women with irst-stage labors lasting �

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Birthweight

F I G U R E 23-5 Birthweig ht d i stribution of 362 n ewborns born by cesa rea n del ivery after a fa i led forceps attem pt at Parkla n d Hos­ pital from 1 989-1 999. O n ly 1 2 percent (n 44) of the newborns weig hed >4000 g (dark bars). =

F I G U R E 23-6 Face presentation. The occi put is the longer end of the head lever. The chin is di rectly posterior. Vag i n a l del ivery is i m possible u n less the chin rotates a nteriorly.

A b n o rm a l La bo r

anterior even in late labor (Duf, 1 98 1 ) . If not, the fetal brow (bregma) is pressed against the maternal symphysis pubis. his position precludes lexion of the fetal head necessary to negoti­ ate the birth canal. hus, a mentum posterior presentation is undeliverable except with a very preterm fetus. Face presentation is diagnosed by vaginal examination and palpation of facial features. A breech may be mistaken for a face presentation. Namely, the anus may be mistaken for the mouth, and the ischial tuberosities for the malar promi­ nences. Digital diferentiation is described in Chapter 28 (p. 540) . Radiographically, demonstration of the hyperex­ tended head with the facial bones at or below the pelvic inlet is characteristic. Cruikshank and White ( 1 973) reported an incidence of 1 in 600, or 0. 1 7 percent. As shown in Table 22- 1 (p. 422) , among more than 70,000 singleton newborns delivered at Parkland Hospital, approximately 1 in 2000 had a face presentation at delivery. Etio logy

Causes of face presentations are numerous and include con­ ditions that favor extension or prevent head lexion. Preterm fetuses, with their smaller head dimensions, can engage before conversion to vertex position (Shafer, 2006) . In exceptional instances, marked enlargement of the neck or coils of cord

\

around the neck may cause extension. Bashiri and associates (2008) reported that fetal malformations and hydramnios were risk factors for face or brow presentations. Anencephalic fetuses naturally present by the face. Extended neck positions develop more frequently when the pelvis is contracted or the fetus is very large. In a series of 1 4 1 face presentations studied b y Hellman and coworkers ( 1 950) , the incidence of inlet contraction was 40 percent. his high incidence of pelvic contraction should be kept in mind when considering management. High parity is a predisposing factor for face presentation (Fuchs, 1 985). In these cases, a pendulous abdomen permits the back of the fetus to sag forward or laterally, often in the same direction in which the occiput points. his promotes extension of the cervical and thoracic spine. M ec h a n i sm of La bor

Face presentations rarely are observed above the pelvic inlet. Instead, the brow generally presents early and is usually con­ verted to present the face after further extension of the neck during descent. he mechanism of labor in these cases consists of the cardinal movements of descent, internal rotation, and flexion, and the accessory movements of extension and exter­ nal rotation (Fig. 23-7) . Descent is brought about by the same factors as in cephalic presentations. Extension results from the

450�

FIGURE 23-7 Mecha n i s m of l a bor for right mentoposterior position with su bseq uent rotation of the mentu m a nteriorly a nd del ivery.

45 1

452

La bor

relation of the fetal body to the delected head, which is con­ verted into a two-armed lever, the longer arm of which extends from the occipital condyles to the occiput. When resistance is encountered, the occiput must be pushed toward the back of the fetus while the chin descends. The objective of internal rotation of the face is to bring the chin under the symphysis pubis. Only in this way can the neck traverse the posterior surface of the symphysis pubis. If the chin rotates directly posteriorly, the relatively short neck cannot span the anterior surface of the sacrum, which measures about 1 2 cm in length. Moreover, the fetal brow (bregma) is pressed against the maternal symphysis pubis. This position precludes lexion necessary to negotiate the birth canal. Hence, as discussed earlier, birth of the head from a mentum posterior position is impossible unless the shoulders enter the pelvis at the same time, an event that is impossible except when the fetus is extremely small or macerated. Internal rotation results from the same factors as in vertex presentations. After anterior rotation and descent, the chin and mouth appear at the vulva, the undersurface of the chin presses against the symphysis, and the head is delivered by lexion. The nose, eyes, brow (bregma), and occiput then appear in succession over the anterior margin of the perineum. ter birth of the head, the occiput sags backward toward the anus. Next, the chin rotates externally to the side toward which it was originally directed, and the shoulders are born as in cephalic presentations. Edema may sometimes significantly distort the face. At the same time, the skull undergoes considerable molding, mani­ fested by an increase in length of the occipitomental diameter of the head. M a n a g e m e nt

In the absence of a contracted pelvis and with efective labor, successful vaginal delivery usually will follow. Fetal heart rate monitoring is probably better done with external devices to avoid damage to the face and eyes. Because face presentations among term-size fetuses are more common when there is some degree of pelvic inlet contraction, cesarean delivery frequently is indicated. Attempts to convert a face presentation manu­ ally into a vertex presentation, manual or forceps rotation of a persistently posterior chin to a mentum anterior position, and internal podalic version and extraction are dangerous and should not be attempted. Low or outlet forceps delivery of a mentum anterior face presentation can be completed and is described in Chapter 29 (p. 562) . • Brow Presentation

This rare presentation is diagnosed when that portion of the fetal head between the orbital ridge and the anterior fontanel presents at the pelvic inlet. As shown in Figure 23-8 , the fetal head thus occupies a position midway between full lexion (occiput) and extension (face) . Except when the fetal head is small or the pelvis is unusually large, engagement of the fetal head and subsequent delivery cannot take place as long as the brow presentation persists. The causes of persistent brow presentation are the same as those for face presentation. A brow presentation is commonly

F I G U R E 23-8 B row posterior presentation.

unstable and often converts to a face or an occiput presentation (Cruikshank, 1 973) . The presentation may be recognized by abdominal palpation when both the occiput and chin can be palpated easily, but vaginal examination is usually necessary. The frontal sutures, large anterior fontanel, orbital ridges, eyes, and root of the nose are felt on vaginal examination, but neither the mouth nor the chin is palpable. With a very small fetus and a large pelvis, labor is generally easy. With a larger fetus, it is usually diicult. his is because engagement is impossible until there is marked molding that shortens the occipitomental diameter or more commonly, until the neck either lexes to an occiput presentation or extends to a face presentation. The considerable molding essential for vagi­ nal delivery of a persistent brow characteristically deforms the head. he caput succedaneum is over the forehead, and it may be so extensive that identiication of the brow by palpation is impossible. In these instances, the forehead is prominent and squared, and the occipitomental diameter is diminished. In transient brow presentations, the prognosis depends on the ultimate presentation. If the brow persists, prognosis is poor for vaginal delivery unless the fetus is small or the birth canal is large. Principles of management are the same as those for a face presentation. • Transverse Lie

In this position, the long axis of the fetus is approximately per­ pendicular to that of the mother. When the long axis forms an acute angle, an oblique lie results. The latter is usually only tran­ sitory, because either a longitudinal or transverse lie commonly results when labor supervenes. For this reason, the oblique lie is called an unstable lie in Great Britain.

Abnorma l Labor

Eti ology

Some of the more common causes of transverse lie include: ( 1 ) abdominal wall relaxation from high parity, (2) preterm fetus, (3) placenta previa, (4) abnormal uterine anatomy, (5) hydram­ nios, and (6) contracted pelvis. Women with four or more deliveries have a tenfold inci­ dence of transverse lie compared with nulliparas. A relaxed and pendulous abdomen allows the uterus to fall forward, delecting the long axis of the fetus away from the axis of the birth canal and into an oblique or transverse position. Placenta previa and pelvic contraction act similarly. A transverse or oblique lie occa­ sionally develops in labor from an initial longitudinal position. M ec h a n i s m of La bor

Spontaneous delivery of a fully developed newborn is impossible with a persistent transverse lie. After rupture of the membranes, if labor continues, the fetal shoulder is forced into the pelvis, and the corresponding arm frequently prolapses (Fig. 23- 1 0). After some descent, the shoulder i s arrested b y the margins of the pelvic inlet. As labor continues, the shoulder is impacted irmly in the upper part of the pelvis. he uterus then con­ tracts vigorously in an unsuccessful attempt to overcome the obstacle. With time, a retraction ring rises increasingly higher and becomes more marked. With this neglected transverse lie, the uterus will eventually rupture. Even without this complica­ tion, morbidity is increased because of the frequent association F I G U R E 23-9 Leopold ma neuver performed on a woman with a feta l tra n sverse l ie, right acromiodorsoa nterior position.

In a transverse lie, the shoulder is usually positioned over the pelvic inlet. The head occupies one iliac fossa, and the breech the other. This creates a shoulder presentation in which the side of the mother on which the acromion rests determines the des­ ignation of the lie as right or let acromial. And because in either position the back may be directed anteriorly or poste­ riorly, superiorly or inferiorly, it is customary to distinguish varieties as dorsoanterior and dorsoposterior (Fig. 23-9) . A transverse lie i s usually recognized easily, often by inspec­ tion alone. The abdomen is unusually wide, whereas the uterine fundus extends to only slightly above the umbilicus. No fetal pole is detected in the fundus, and the ballottable head is found in one iliac fossa and the breech in the other. The position of the back is readily identifiable. When the back is anterior, a hard resistance plane extends across the front of the abdomen. When it is posterior, irregular nodulations representing fetal small parts are felt through the abdominal wall. On vaginal examination, in the early stages of labor, if the side of the thorax can be reached, it may be recognized by the "gridiron" feel of the ribs. With further dilation, the scapula and the clavicle are distinguished on opposite sides of the tho­ rax. The position of the axilla indicates the side of the mother toward which the shoulder is directed. Transverse lie was found once in 322 singleton deliveries (0.3 percent) at both the Mayo Clinic and the University of Iowa Hospital (Cruikshank, 1 973; Johnson, 1 964) . This is remarkably similar to the incidence at Parkland Hospital of approximately 1 in 335 singleton fetuses.

F I G U RE 23-1 0 Neglected shou lder presentation. A th ick mus­ cular ba nd for m i n g a patho logical retraction ring has developed j ust a bove the t h i n lower uteri ne seg ment. The force generated d u ring a uteri ne contraction is d i rected centri peta l l y at a nd a bove the level of the patholog ica l retraction r i n g . Th is serves to stretch fu rther and possibly to rupt u re the t h i n l ower seg ment below the retraction ri ng.

453

454

Labor

with placenta previa, the increased likelihood of cord prolapse, and the necessity for major operative eforts. If the fetus is small-usually < 800 g-and the pelvis is large, spontaneous delivery is possible despite persistence of the abnor­ mal lie. The fetus is compressed with the head forced against its abdomen. A portion of the thoracic wall below the shoulder thus becomes the most dependent part, appearing at the vulva. he head and thorax then pass through the pelvic cavity at the same time. he fetus, which is doubled upon itself and thus sometimes referred to as condupLicato corpore, is expelled.

\

'

M a n a g e me nt

Active labor in a woman with a transverse lie is usually an indi­ cation for cesarean delivery. Before labor or early in labor, with the membranes intact, attempts at external version are worth­ while in the absence of other complications. If the fetal head can be maneuvered by abdominal manipulation into the pelvis, it should be held there during the next several contractions in an attempt to ix the head in the pelvis. With cesarean delivery, because neither the feet nor the head of the fetus occupies the lower uterine segment, a low transverse incision into the uterus may lead to diicult fetal extraction. his is especially true of dorsoanterior presentations. herefore, a vertical hysterotomy incision is often indicated .

A

I

I �--

!

/

\

\

I

I

.

• Compound Presentation

With this, an extremity prolapses alongside the presenting part, and both present simultaneously in the pelvis (Fig. 23- 1 1 ) . Goplerud and Eastman ( 1 953) identiied a hand o r arm pro­ lapsed alongside the head once in every 700 deliveries. Much less common was prolapse of one or both lower extremities alongside a cephalic presentation or a hand alongside a breech. At Parkland Hospital, compound presentations were identiied in only 68 of more than 70,000 singleton fetuses-an incidence of approximately 1 in 1 000. Causes of compound presentations are conditions that prevent complete occlusion of the pelvic inlet by the fetal head, including preterm labor. In most cases, the prolapsed part should be left alone, because most often it will not interfere with labor. If the arm is prolapsed alongside the head, the condition should be observed closely to ascertain whether the arm retracts out of the way with descent of the presenting part. If it fails to retract and if it appears to prevent descent of the head, the prolapsed arm should be pushed gently upward and the head simultaneously downward by fundal pressure. In general, rates of perinatal mortality and morbidity are increased as a result of concomitant preterm delivery, prolapsed cord, and traumatic obstetrical procedures. Serious inj ury to the forearm is rare (Kwok, 20 1 5; Tebes, 1 999) .

COMPLICATIONS WITH DYSTOCIA

• Maternal Complications

Dystocia, especially if labor is prolonged, is associated with a higher incidence of several common obstetrical and neonatal complications. Inection, either intrapartum chorioamnionitis or postpartum pelvic infection, is more common with desultory

F I G U R E 23-1 1 Com pou nd presentation. A. The left h a n d is lying i n front of the vertex. With fu rther l a bor, the h a nd a nd a rm may retract from the b i rth canal, a n d the head may then descend nor­ m a l ly. B. Photog ra ph of a s m a l l 34-week fetu s with a com pou nd presentation that del ivered u n eventfu l ly with the h a nd presenting fi rst. (Used with permission from Dr. El izabeth Mosier.)

and prolonged labors. Pospartum hemorrhage rates from atony are increased with prolonged and augmented labors. Uterine tears with hysterotomy also occur at greater incidence if the fetal head is impacted in the pelvis. Uterine rupture is another risk. Abnormal thinning of the lower uterine segment creates a serious danger during prolonged labor, particularly in women of high parity and in those with a prior cesarean delivery. When disproportion is so pronounced that there is no engagement or descent, the lower uterine seg­ ment becomes increasingly stretched, and rupture may follow. In such cases, the normal contraction ring is usually exaggerated, like that shown in Figure 23- 1 0. Such pathological retraction rings are localized constrictions of the uterus that develop in association with prolonged obstructed

Abnorma l L a b o r 4 5 5

labors. Seldom encountered today, the pathological retraction ring o/Bandl is associated with marked stretching and thinning of the lower uterine segment. In contemporary practice, after birth of a irst twin, a pathological ring may still develop occasionally as an hourglass constriction of the uterus. he band may be seen clearly as a uterine indentation and signifies impending rupture of the lower uterine segment. he ring can sometimes be relaxed and delivery efected with appropriate general anesthesia, but occasionally prompt cesarean delivery ofers a better prognosis for the second twin (Chap. 45, p. 890). Fistula ormation may result from dystocia, as the presenting part is irmly wedged into the pelvic inlet. Tissues of the birth canal lying between the leading part and the pelvic wall may be subjected to excessive pressure. Because of impaired circula­ tion, necrosis can result and become evident several days after delivery as vesicovaginal, vesicocervical, or rectovaginal istulas. Most often, pressure necrosis follows a very prolonged second stage. Such fistulas are rarely seen today except in undeveloped countries. Pelvicloor injuy during pregnancy and childbirth has gained recent attention. The pelvic floor is exposed to direct compres­ sion from the fetal head and to downward pressure from mater­ nal expulsive eforts. These forces stretch and distend the pelvic floor, resulting in functional and anatomical alterations in the muscles, nerves, and connective tissues. Accumulating evidence suggests that such efects on the pelvic floor during childbirth can afect urinary or anal continence and pelvic support. hese relationships are discussed in Chapter 30 (p. 5 68) . Lower extremiy nerve injuy in the mother can follow prolonged second-stage labor. Wong and colleagues (2003) reviewed neurological injury involving the lower extremities in association with labor and delivery. The most common mecha­ nism is external compression of the common fibular (formerly common peroneal) nerve. This is usually caused by inappro­ priate leg positioning in stirrups, especially during prolonged second-stage labor. hese and other injuries are discussed in Chapter 36 (p. 66 1 ) . Fortunately, symptoms resolve within 6 months of delivery in most women. • Perinatal Complications

Similar to the mother, the incidence of peripartum fetal sep­ sis rises with longer labors. Caput succedaneum and molding develop commonly and may be impressive (Fig. 22- 1 6, p. 43 1 ) (Buchmann, 2008). Mechanical trauma such as nerve inj ury, fractures, and cephalohematoma are also more frequent and are discussed further in Chapter 33 (p. 627) .

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Amorosa L F , Amorosa JH, Wellman O S , e t a l : Management o f pelvic injuries in pregnancy. Orthop Clin North Am 44(3) : 30 1 , 20 1 3 Bashiri A , Burstein E , Bar-David J, e t a l : Face and brow presentation: indepen­ dent risk factors. ] Matern Fetal Neonatal Med 2 1 (6) : 3 5 7, 2008 Bleich AT, Alexander ]M, McIntire DO, et al: An analysis of second-stage labor beyond 3 hours in nulliparous women. Am ] PerinatoI 29:7 1 7, 20 1 2 Buchman n E], Libhaber E : Sagittal suture overlap i n cephalopelvic dispropor­ tion: blinded and non-participant assessment. Acta Obstet Gynecol Scand 87(7) :73 1 , 2008 Caldeyro-Barcia R, Alvarez H, Reynolds SR: A better understanding of uterine contractility through simultaneous recording with an internal and a seven channel external method. Surg Obstet Gynecol 9 1 :64 1 , 1 9 50 Chen HY, H uang SC: Evaluation of midpelvic contraction. Int Surg 67: 5 1 6, 1 982 Cheng YW, Hopkins LM, Caughey AB: How long is too long: does a pro­ longed second stage of labor in nulliparous women afect matenal and neo­ natal outcomes? Am ] Obstet GynecoI 1 9 1 (3) : 933, 2004 Cheng YW, Shafer BL, Bryant AS , et al: Length of the irst stage of labor and associated perinatal outcomes in nulliparous women. Obstet Gynecol 1 1 6( 5 ) : 1 1 27, 20 1 0 Cibils LA, Hendricks C H : Normal labor i n vertex presentation. Am J Obstet GynecoI 9 1 :38 5 , 1 965 Cohen W: InAuence of the duration of second stage labor on perinatal outcome and puerperal morbidity. Obstet Gynecol 49 :266, 1 977 Cohen W, Friedman EA: Management of Labor. Baltimore, University Park Press, 1 983 Cohen WR, Friedman EA: Misguided guidelines for managing labor. Am J Obstet Gynecol 2 1 2(6):753.e l , 20 1 5a Cohen WR, Friedman EA: Perils of the new labor management guidelines. Am J Obstet Gynecol 2 1 2(4) :420, 20 1 5b Cruikshank DP, White CA: Obstetric malpresentations: twenty years' experi­ ence. Am J Obstet Gynecol 1 1 6: 1 097, 1 973 Duf P: Diagnosis and management of face presentation. Obstet Gynecol 57: 1 0 5 , 1 98 1 Eller We, Mengert WF: Recognition of mid-pelvic contraction. Am ] Obstet Gynecol 53:252, 1 947 Ferguson ]E, Newberry YG, DeAngelis GA, et al: he fetal-pelvic index has minimal utility in predicting fetal-pelvic disproportion. Am J Obstet Gyne­ col 1 79: 1 1 86, 1 998 Floberg ] , Belfrage P, Ohlsen H : I nAuence of pelvic outlet capacity on labor. A prospective pelvimetry study of 1 ,429 unselected primiparas. Acta Obstet Gynecol Scand 66: 1 2 1 , 1 987 Fraser WD, Marcoux 5, Krauss I , et al: Multicenter, randomized, controlled trial of delayed pushing for nulliparous women in the second stage of labor with continuous epidural analgesia. Am J Obstet Gynecol 1 82 : 1 1 6 5 , 2000 Friedman E: The graphic analysis of labor. Am ] Obstet Gynecol 68: 1 568, 1 954 Friedman EA: Labor. Clinical Evaluation and Management, 2nd ed. New York, Appleton-Cen tury-Crofts, 1 9 8 Friedman EA: Prim igravid labor; a graphicostatistical analysis. Obstet Gynecol 6(6) : 567, 1 9 5 5 Friedman EA, Sachtleben MR: Station of the fetal presenting part 1 1 : effect o n t h e course of labor. Am ] Obstet Gynecol 93: 530, 1 965 Friedman EA, Sachtleben M R: Station of the fetal presenting part IV: arrest of descent in n ulliparas. Obstet Gynecol 4 : 1 29, 1 976 Fuchs K, Peretz BA, Marcovici R, et al : The grand multipara-is it a problem? Int J Gynaecol Obstet 73:32 1 , 1 98 5 Gambling D R , Sharma S K , Ramin S M , e t al : A randomized study of com­ bined spinal-epidural analgesia versus intravenous meperidine during labor: impact on cesarean delivery rate. Anesthesiology 89(6): 1 336, 1 998 Goplerud ], Eastman N]: Compound presentation: survey of 65 cases. Obstet Gynecol 1 : 59, 1 9 53 Grobman WA, Bailit ], Lai Y, et al: Association of the duration of active push­ ing with obstetric outcomes. Obstet Gynecol 12 (4): 667, 20 1 6 Handa VL, Laros RK: Active-phase arrest in labor: predictors of cesarean deliv­ ery in a nulliparous population. Obstet Gynecol 81 :758, 1 993 Hannah M, Ohlsson A, Farine 0, et al : International Term PROM Trial: a RCT of induction of labor for prelabor rupture of membranes at term. Am J Obstet Gynecol 1 74:303, 1 996 Hannah ME, Hodnett ED, Willan A, et al: Prelabor rupture of the membranes at term: expectant management at home or in hospital? Obstet Gynecol 96: 533, 2000 Hansen S L, Clark SL, Foster JC: Active pushing versus passive fetal descent in the second stage of labor: a randomized controlled trial. Obstet Gynecol 99:29, 2002 Harper LM, Caughey AB, Roehl A, et al : Deining an abnormal irst stage of labor based on maternal and neonatal outcomes. m J Obstet Gynecol 2 1 0(6) : 536.e l , 2 0 1 4

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Labor Hauth )C, Hankins GO, Gilstrap LC III: Uterine contraction pressures achieved in parturients with active phase arrest. Obstet Gynecol 78 :344, 1 99 1 Hauth )C, Hankins GO, Gilstrap LC III, et al: Uterine contraction pressures with oxytocin induction/augmentation. Obstet GynecoI 68:305, 1 986 Hellman LM, Epperson )W, Connally F: Face and brow presentation: the experience of the Johns Hopkins Hospital, 1 896 to 1 948. Am ) Obstet Gynecol 59:83 1 , 1 9 50 Hendricks CH, Quilligan E), Tyler AB, et al: Pressure relationships between intervillous space and amniotic fluid in human term pregnancy. Am ) Obstet Gynecol 77: 1 028, 1 95 9 Hillis OS: Diagnosis of contracted pelvis b y the impression method. Surg Gynecol Obstet 5 1 : 8 57, 1 930 Johnson CE: Transverse presentation of the fetus. )MA 1 87:642, 1 964 Kaltreider OF: Criteria of midplane contraction. Am ) Obstet GynecoI 63:392, 1 9 52 Korhonen U, Taipale P, Heinonen S: Fetal pelvic index to predict cephalopel­ vic disproportion-a retrospective clinical cohort study. Acta Obstet Gynecol Scand 94(6) :6 1 5 , 20 1 5 Kwok CS, Judkins CL, Sherratt M : Forearm injury associated with compound presentation and prolonged labour. ) Neonatal Surg 4 (3) :40, 20 1 5 Larks SO: Electrohysterography. Springfield, Thomas, 1 960 Laughon SK, Berghella V, Reddy UM, et a1: Neonatal and maternal outcomes with prolonged second stage of labor. Obstet Gynecol 1 24 ( 1 ) :57, 20 1 4 Le Ray C , Audibert F , Goinet F , et al: When to stop pushing: efects of duration of second-stage expulsion eforts on maternal and neonatal out­ comes in nulliparous women with epidural analgesia. Am ) Obstet Gynecol 20 1 (4) :36 1 .e 1 , 2009 Leveno K) , Nelson DB, McIntire DO: Second-stage labor: how long is too long? Am ) Obstet Gynecol 2 1 4(4) :484, 20 1 6 Mahon TR, Chazotte C , Cohen WR: Short labor: characteristics and outcome. Obstet Gynecol 84:47, 1 994 Manyonda IT, Shaw DE, Drife )0: he efect of delayed pushing in the sec­ ond stage of labor with continuous lumbar epidural analgesia. Acta Obstet Gynecol Scand 69:29 1 , 1 990 Marte K, Voutsos L: Reduction in the cesarean delivery rate after obstetric care consensus guideline implementation. Obstet Gynecol 1 28 (6) : 1 44 5 , 20 1 6 Martin )A, Hamilton BE, Osterman M), et al: Births: final data for 20 1 3. Nat! Vital Stat Rep 64( 1 ) : 1 , 20 1 5 McCarthy S : Magnetic resonance imaging in obstetrics and gynecology. Magn Reson Imaging 4:59, 1 986 Mengert F: Estimation of pelvic capaciry. )1A 1 38 : 1 69, 1 948 Menticoglou SM, Manning F, Harman C, et 1: Perinatal outcomes in relation to second-stage duration. Am ) Obstet Gynecol 1 73:906, 1 995a Menticoglou SM, Perlman M , Manning FA: High cervical spinal cord injury in neonates delivered with forceps: report of 1 5 cases. Obstet Gynecol 86:589, 1 995b Moore MM, Shearer DR: Fetal dose estimates for CT pelvimetry. Radiology 1 7 1 :265, 1 989 Mozurkewich E, Chilimigras ) , Koepke E, et al: Indications for induction of labour: a best-evidence review. B)OG 1 1 6(5) :626, 2009 Mueller P: About the prognosis for delivery with a narrow pelvis. Arch Gyn­ aekoI 27:3 1 1 , 1 885 Nelson DB, McIntire DO, Leveno K): Relationship of the length of the first stage of labor to the length of the second stage. Obstet GynecoI 1 22:27, 20 1 3 Olah KS, Neilson ) : Failure to progress in the management of labour. B)OG 1 0 1 : 1 , 1 994 Passos F, Cardose K, Coelho M , et a1: Antibiotic prophylaxis in premature rupture of membranes at term. Obstet GynecoI 1 20: 1 045, 20 1 2

Pattinson RC, Cuthbert A , Vannevel V : Pelvimetry for fetal cephalic presenta­ tions at or near term for deciding on mode of delivery. Cochrane Database Syst Rev 3:CD000 1 6 1 , 20 1 7 Peleg 0 , Hannah ME, Hodnett ED, e t 1 : Predictors of cesarean delivery after prelabor rupture of membranes at term. Obstet Gynecol 93: 1 03 1 , 1 999 Plunkett BA, Lin A, Wong CA, et a1: Management of the second stage of labor in nulliparas with continuous epidural analgesia. Obstet Gynecol 1 02: 1 09, 2003 Reynolds SR, Heard 00, Bruns P, et 1: A multichannel strain-gauge tocody­ namometer: an instrument for studying patterns of uterine contractions in pregnant women. Bull Johns Hopkins Hosp 82:446, 1 948 Rosenbloom )1, Stout M), Tuuli MG, et al: New labor management guidelines and changes in cesarean delivery patterns. m ) Obstet Gynecol October 1 4, 20 1 7 [Epub ahead of print] Roshanfekr 0, Blakemore K), Lee ), et 1: Station at onset of active labor in nul­ liparous patients and risk of cesarean delivery. Obstet Gynecol 93:329, 1 999 Rouse D), Owen ) , Hauth ]C: Active-phase labor arrest: oxytocin augmenta­ tion for at least 4 hours. Obstet Gynecol 93:323, 1 999 Rouse D), Weiner S), Bloom SL, et a1: Second-stage labor duration in nullipa­ rous women: relationship to maternal and perinatal outcomes. Am ) Obstet GynecoI 201 (4) :357.e 1 , 2009 Satin A), Maberry lC, Leveno ), et al: Chorioamnionitis: a harbinger of dystocia. Obstet Gynecol 79:9 1 3 , 1 992 Shafer BL, Cheng W, Vargas ]E, et a1: Face presentation: predictors and delivery route. Am ] Obstet Gynecol 1 94(5):elO, 2006 Sharma SK, McIntire DO, Wiley ) , et al: Labor analgesia and cesarean delivery: an individual patient meta-analysis of nulliparous women. Anesthesiology 1 00( 1 ) : 1 42, 2004 Sheiner E, Levy A, Mazor M: Precipitate labor: higher rates of maternal com­ plications. Eur ] Obstet Gynecol Reprod BioI 1 1 6 ( 1 ) :43, 2004 Sporri S , Hanggi W, Brahetti A, et a1: Pelvimetry by magnetic resonance imag­ ing as a diagnostic tool to evaluate dystocia. Obstet Gynecol 89:902, 1 997 Stark DO, McCarthy SM, Filly A, et a1: Pelvimetry by magnetic resonance imaging. Am ) RadioI 1 44:947, 1 98 5 Tebes C C , Mehta P, Calhoun DA, e t 1: Congenital ischemic forearm necrosis associated with a compound presentation. ] Matern Fetal Med 8:28 1 , 1 999 Thoms H : he obstetrical signiicance of pelvic variations: a study of 450 pri­ miparous women. Bl] 2:2 1 0, 1 937 Thorp )M )r, Pahel-Short L, Bowes WA )r: The Mueller-Hillis maneuver: can it be used to predict dystocia? Obstet Gynecol 82:5 1 9, 1 993 Thurnau GR, Scates DH, Morgan M A: he fetal-pelvic index: a method of identiying fetal-pelvic disproportion in women attempting vaginal birth after previous cesarean delivery. Am ) Obstet Gynecol 1 65 : 3 53 , 1 99 1 Vallier A, Cureton BA, Schubeck 0 : Pregnancy outcomes ater pelvic ring injury. ) Orthop Trauma 26(5) :302, 20 1 2 Wilson-Leedy ] G , DiSilvestro A), Repke ]T, e t al: Reduction i n the cesar­ ean delivery rate after Obstetric Care Consensus guideline implementation. Obstet GynecoI 1 28 ( 1 ) : 1 4 5 , 20 1 6 Wong CA, Scavone BM, Dugan S , e t 1 : Incidence o f postpartum lumbosacral spine and lower extremiry nerve injuries. Obstet Gynecol 1 0 1 :279, 2003 World Health Organization: Partographic management of labour. Lancet 343: 1 399, 1 994 Zaretsky MV, Alexander ]M, McIntire DO, et al: Magnetic resonance imaging pelvimetry and the prediction of labor dystocia. Obstet Gynecol 1 06: 9 1 9, 2005 Zhang ) , Landy H), Branch OW, et al: Contemporary patterns of spontane­ ous labor with normal neonatal outcomes. Obstet Gynecol 1 1 6: 1 28 1 , 20 1 0 Zhang ], Troendle ] F , Yancey MK: Reassessing the labor curve i n nulliparous women. m ) Obstet GynecoI 1 87(4): 824, 2002

457

C H A PT E R 24

I nt ra pa rt u m Assess m e nt

ELECTRONIC FETAL MON ITORI NG

. . . . . . . . . . . . . . . . .

OTH ER I NTRAPARTU M ASSESSMENT TECH N IQUES . NON REASSURING FETAL STATUS

. . . . . . . . . . . . . . . . .

MECONIUM I N THE AMNIONIC F L U I D

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FETAL H EART RATE PAIERNS A N D BRAIN I NJ U RY . C U RRENT RECOMMEN DATIONS .

. .

. .

. . . . . . . . . . . . . . . . . .

INTRAPARTUM SURVEILLANCE OF UTERINE ACTIVIY

. . .

457 470

became used in most pregnancies. Now, more than 85 percent of all live births in the United States undergo electronic fetal monitoring (Ananth, 20 1 3) .

472 474 476 478 478

To study the orces exerted by labour, a rubber bag was inserted into the uterus which was connected with a manom­ eter. In this way it wasound that the intra-uterine pressure, in the intervals between the contractions, was represented by a column of mercury 20 millimeters high, 5 of which were due to the toniciy ofthe wals and 15 to its contents. During the pains, however, the mercury rose consideraby, reaching a height offrom 80 to 250 milimeters. -J. Whitridge Williams ( 1 903) Little is written in the first edition of this textbook concern­ ing monitoring of the fetus during labor. Much later, peri­ odic auscultation of the fetal heartbeat with a fetoscope was adopted. These practices were eclipsed in the late 1 960s and early 1 970s by the development of electronic fetal monitoring (Hon, 1 958). It was hoped that the continuous graph-paper portrayal of the fetal heart rate was potentially diagnostic in assessing pathophysiological events afecting the fetus. When fi r st introduced, electronic fetal heart rate monitoring was used primarily in complicated pregnancies but gradually

ELECTRONIC FETAL MONITORI NG

• Internal (Direct) Electronic Monitoring

Direct fetal heart measurement is accomplished by attaching a bipolar spiral electrode directly to the fetus (Fig. 24- 0 . The wire electrode penetrates the fetal scalp, and the second pole is a metal wing on the electrode. The electrical fetal cardiac signal-P wave, QRS complex, and T wave-is ampliied and

B1 F

F

F

M

F

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F I G U R E 24- 1 I ntern a l electron ic feta l monito ring. Schematic representation of a bipolar electrode attached to the feta l sca l p for detection of fetal QRS com p lexes (F). Also shown is the maternal hea rt a n d co rresponding electrical complex (M) that is detected.

458

La bor

fed into a cardiotachometer for heart rate calculation. he peak R-wave voltage is the portion of the fetal electrocardiogram (ECG) most reliably detected. n example of the method of fetal heart rate processing employed when a scalp electrode is used is shown in Figure 24-2. Time (t) in milliseconds between fetal R waves is fed into a car­ diotachometer, where a new fetal heart rate is set with the arrival of each new R wave. As also shown in Figure 24-2, a premature atrial contraction is computed as a heart rate acceleration because the interval (t2) is shorter than the preceding one (t1 ) . he phe­ nomenon of continuous R-to-R wave fetal heart rate computa­ tion is known as beat-to-beat variabiliy. Electrical cardiac complexes detected by the electrode include those generated by the mother. However, the ampli­ tude of the maternal ECG signal is diminished when recorded through the fetal scalp electrode and is masked by the fetal ECG. Shown in Figure 24-3 are simultaneous recordings of maternal chest wall ECG signals and fetal scalp electrode ECG signals. This fetus is experiencing premature atrial contrac­ tions, which cause the cardiotachometer to rapidly and errati­ cally seek new heart rates, resulting in the "spiking" shown in the standard fetal monitor tracing. Importantly, when the fetus is dead, the maternal R waves are still detected by the scalp electrode as the next best signal and are counted by the cardiotachometer (Fig. 24-4) .

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F I G U R E 24-2 Schematic representation of feta l electroca rd io­ g ra phic sig nals used to com pute conti n u i n g beat-to-beat hea rt rate with sca l p electrodes , Ti me i nterva l s (tI l t 21 t3) in m i l l i seconds between successive fetal R waves a re u sed by a ca rdiotachometer to compute i n stantaneous feta l hea rt rate , ECG electroca rd io­ g ra m; PAC prematu re atria l contraction, =

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Although membrane rupture may be avoided, external monitoring does not provide the precision of fetal heart rate measurement aforded by internal monitoring (Nunes, 20 1 4) . In some women-for example, those who are obese-external monitoring may be dif­ icult (Brocato, 20 1 7) . With external monitoring, the fetal heart rate is detected through the mater­ nal abdominal wall using the ultrasound Doppler principle. Ultrasound waves undergo a shift in frequency as they are reflected from moving fetal heart valves and from pulsatile blood ejected during systole (Chap. 1 0, p. 2 1 3) . he unit consists of a transducer that emits ultrasound and a sensor to detect a shift in frequency of the reflected sound. The transducer is placed on the mater­ nal abdomen at a site where fetal heart action is best detected. A coupling gel must be applied because air conducts ultrasound waves poorly. he device is held in position by an elastic belt. Correct positioning enhances difer­ entiation of fetal cardiac motion from maternal arterial pulsations (Neilson, 2008) .

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I ntrapartu m Assessment

brought together investigators with exper­ tise in the ield to propose standardized, unambiguous deinitions for interpreta­ tion of fetal heart rate patterns during labor. This workshop reconvened in 2008 . he deinitions proposed as a result of this second workshop are used in this chapter and have been adopted by the American College of Obstetricians and Gynecolo­ I -�-����---L�--- 30 ---� gists (20 1 7 a) (Table 24- 1 ) . Importantly, Maternal heart rate Dyi ng fetus interpretation of electronic fetal heart rate --" --- .---, -, -, - -,- 1 00---., -.. data is based on the visual pattern of the I 80 heart rate as portrayed on chart recorder I graph paper. Thus, the choice of vertical I 40 and horizontal scaling greatly afects the appearance of the fetal heart rate. Scal­ ing factors recommended by the NICHD Workshop are 30 beats per minute (beats/ FIGURE 24-4 P lacenta l a bruption. In the u pper panel, the feta l sca l p electrode fi rst detected the heart rate of the dying fetus. After feta l death, the maternal electroca rd io­ min or bpm) per vertical cm (range, 30 to g ram com plex is d etected a nd recorded. The second panel disp lays a n a bsence of uteri ne 240 bpm) and 3 cm/ min chart recorder contractions. paper speed. Fetal heart rate variation is falsely displayed at the slower 1 cm/ min Ultrasound Doppler signals are edited electronically before paper speed compared with that of the smoother baseline fetal heart rate data are printed onto monitor paper. Relected recorded at 3 cm/min. hus, pattern recognition can be con­ ultrasound signals from moving fetal heart valves are analyzed siderably distorted depending on the scaling factors used. through a microprocessor that compares incoming signals with the most recent previous signal. This process, called autocorrela­ • Baseline Fetal Heart Activity tion, is based on the premise that the fetal heart rate has regular­ ity, whereas "noise" is random and without regularity. Several This refers to the modal characteristics that prevail apart from fetal heart motions must be deemed electronically acceptable periodic accelerations or decelerations associated with uterine by the microprocessor before the fetal heart rate is printed. contractions. Descriptive characteristics of baseline fetal heart Such electronic editing has greatly improved the tracing qual­ activity include rate, beat-to-beat variabili, etal arrhythmia, ity of the externally recorded fetal heart rate. Other features of and distinct patterns such as sinusoidal or saltatory fetal heart current fetal monitors include the capability to monitor twin rates. fetuses, monitor concurrent maternal heart rate, display the Rate fetal ECG, and record maternal pulse oximetry values. Many fetal monitors are capable of interfacing with archival storage With increasing fetal maturation, the heart rate decreases. This systems, which obviates maintaining actual paper tracings. continues postnatally such that the average rate is 85 bpm by Technological advances now allow fetal heart rate moni­ age 8 years (Tintinalli, 20 1 6) . Pillai and James ( 1 990) reported toring from a remote, centralized location. Theoretically, the that the baseline fetal heart rate declined an average of 24 bpm ability to monitor several patients simultaneously was hoped to between 1 6 weeks' gestation and term, or approximately 1 bpm improve neonatal outcomes. That said, only one study on cen­ per week. his normal gradual slowing of the fetal heart rate tralized fetal monitoring has been reported. Anderson and col­ is thought to correspond to maturation of parasympathetic leagues (20 1 1 ) measured the ability of 1 2 individuals to detect (vagal) heart control (Renou, 1 969) . critical signals in fetal heart rate tracings on one, two, or four The baseline fetal heart rate is the approximate mean rate monitors. The results showed that detection accuracy declined rounded to increments of 5 bpm during a 1 0-minute tracing as the number of displays increased. segment. In any 1 0-minute window, the minimum interpreta­ ble baseline duration must be at least 2 minutes. If the baseline fetal heart rate is less than 1 1 0 bpm, it is termed bradycardia. • Fetal Heart Rate Patterns If the baseline rate is greater than 1 60 bpm, it is called tachy­ cardia. The average fetal heart rate is considered the result of The interpretation of fetal heart rate patterns can be problem­ tonic balance between accelerator and decelerator influences atic without deinitions and nomenclature. In one example, on pacemaker cells. In this concept, the sympathetic system Blackwell and colleagues (20 1 1 ) asked three .1aternal-Fetal is the accelerator influence, and the parasympathetic system is Medicine specialists to independently interpret 1 54 fetal heart the decelerator factor mediated by vagal slowing of heart rate rate tracings. Interobserver agreement was poor for the most (Dawes, 1 985). Heart rate also is under the control of arte­ ominous tracings and moderate for less severe patterns. rial chemoreceptors such that both hypoxia and hypercapnia The National Institute of Child Health and Human Devel­ can modulate rate. More severe and prolonged hypoxia, with a opment (NICHD) Research Planning Workshop ( 1 997) 60

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The mean F H R rou n ded to i nc rements of 5 b p m d u ri n g a 1 O-m i n seg m ent, exc l u d i n g : -Period ic or e p isod i c c h a n g e s -Periods o f marked F H R va ria b i l ity -Seg ments of ba se l i n e that d ifer by more than 25 b p m Th e basel i n e m u st be for a m i n i m u m o f 2 m i n i n a ny 1 O-m i n seg ment or the base l i ne for that t i m e period i s i ndeterm i n ate. I n t h i s case, o n e m a y refer t o the p r i o r 1 O-m i n wi n dow for determ i n ation of base l i n e. Normal F H R base l i n e: 1 1 0- 1 60 b p m Tachyca rd ia: F H R base l i nes i s g reater than 1 60 beats per m i n ute Bradyca rdia: F H R base l i n e i s l ess than 1 1 0 beats per m i n ute F l uctuations i n the base l i n e F H R that a re i r reg u la r i n a m p l itude a n d freq u ency Va ria b i l ity i s vis u a l ly q u a ntified a s the a m p l itude of pea k-to-troug h in beats per m i n ute -Absent: a m p l itude ra n g e u n detecta ble -M i n i m a l : a m p l itude ra n g e detecta ble but 5 beats per m i n utes o r fewer -Moderate (normal) : a m p l itude ra nge 6-25 beats per m i n ute -Ma rked: a m p l itude ra n g e g reater than 25 beats per m i n ute A visua l ly a ppa rent a bru pt i nc rease (on set to pea k i n l ess t h a n 30 seco nds) i n the F H R A t 3 2 wee ks o f gestation a n d beyond, a n accel eration h a s a pea k o f 1 5 b p m or m o re a b ove base l i ne, with a d u ration of 1 5 sec or more b ut less than 2 m i n utes from on set to retu rn Before 3 2 weeks, an a cceleration has a pea k of 1 0 bpm or more a bove base l i ne, with a d u ration of 1 0 seconds or m ore but less tha n 2 m i n utes fro m o n set to ret u rn P rolonged accel e ration l a sts 2 m i n utes or more but l ess t h a n 1 0 m i n utes i n d u ration If a n acceleration lasts 1 0 m i n utes o r lon ger, it i s a base l i ne c h a nge Vi s u a l l y a ppa rent u s ua l ly sym m etrica l g radual decrease a n d ret u rn of the F H R a ssociated with a ute ri n e contra ction A g radual FHR decrease i s defi ned a s from the o n set to the F H R n a d i r of 30 seconds or more The decrease i n F H R is ca l c u l ated from the onset to the n a d i r of the dece leration The nad i r of the decele rat i o n occu rs at the same time as the pea k of the contractio n I n most cases the o n set, n ad i r, a n d recovery o f t h e decel e ration a re coi ncident w i t h the beg i n n i n g, pea k, and end i ng of the cont raction, res pectively Vi s u a l l y a ppa rent u s u a l ly sym m etrica l grad u a l decrease a n d retu rn of the F H R associated with a uteri ne contraction A g radual FHR decrease i s defi n ed a s from the o nset to the F H R nadir of 30 seconds o r more The decrease i n F H R is ca l c u l ated from the o n set to the nad i r of the d ece leration The decel eration i s delayed in ti m i n g, with the n a d i r of the deceleration occ u rring after the peak of the contraction I n most cases the o n set, nad i r, a n d recovery of the deceleration occ u r after the beg i n n i ng, pea k, a n d e nd i ng o f the contractio n , respectively Vi s u a l l y a pparent a bru pt decrease i n FHR A n abrupt FHR decrease i s defi n ed as from the o n set of the decel eration to the beg i n n i n g of the FHR nadir of less tha n 3 0 seco nds The decrease i n FHR i s ca l c u l ated from the o n set to the n a d i r of the d ecel eration The decrease in F H R is 1 5 beats per m i n u te or g reater, lasti n g 1 5 seco nds or g reater, a nd l ess than 2 m i n utes i n d u ration When va riable dece l e rati o n s a re associated with uterine contraction, their on set, depth, a n d d u ration com m o n ly va ry with su ccessive uteri n e contractions Vi s u a l l y a p pa rent decrease in the F H R bel ow the base l i n e Decrease i n F H R fro m the basel i ne that i s 1 5 beats per m i n ute or more, a n d l ess than 2 m i n utes i n d u ration If a deceleratio n l a st 1 0 m i n utes o r lon ger, it is a ba se l i n e cha nge Vi s u a l ly a p pa re nt, s m ooth , s i n e wave-line u nd u l ati ng pattern i n FHR base l i ne with a cyc l e frequency of 3-5 per m i n ute w h i c h persists for 20 m i n utes or more

F H R = feta l hea rt rate. Data fro m Maco nes, 2008.

I ntra pa rt u m Asse s s m e nt

210

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F I G U R E 24-5 Feta l bradyca rd ia measu red with a sca l p electrode (upper paneD in a preg n a ncy compl icated by placenta l a bruption

and su bseq uent fetal death. Concu rrent uterine contractions a re shown in the lower panel.

rising blood lactate level and severe metabolic acidemia, induces a prolonged fall in heart rate (hakor, 2009) . Bradyca rd ia. In the third trimester, the normal mean baseline fetal heart rate has generally been accepted to range between 1 20 and 1 60 bpm. B ut, pragmatically, a rate between 1 00 and 1 1 9 bpm, in the absence of other changes, usually is not considered to represent fetal compromise. Such low but potentially normal baseline heart rates also have been attributed to head compres­ sion from occiput posterior or transverse positions, particularly during second-stage labor (Young, 1 976) . Such mild bradycar­ dias were observed in 2 percent of monitored pregnancies and averaged approximately 50 minutes in duration. Freeman and associates (2003) have concluded that bradycardia within the range of 80 to 1 20 bpm and with good variability is reassuring. Interpretation of rates less than 80 bpm is problematic, and such rates generally are considered nonreassuring. Some causes of fetal bradycardia include congenital heart block and serious fetal compromise 0aeggi, 2008; Larma, 2007) . Figure 24-5 shows bradycardia in a fetus dying from placental abruption. Maternal hypothermia under general anesthesia for repair of a cerebral aneurysm or during maternal cardiopulmonary bypass for open-heart surgery can also cause fetal bradycardia. Sustained fetal bradycardia in the setting of severe pyelonephritis and maternal hypothermia also has been reported (Hankins, 1 997) . Involved fetuses apparently are not harmed by several hours of such bradycardia. Tachycardia. Fetal tachycardia is deined as a baseline heart

rate greater than 1 60 bpm. The most common explanation for fetal tachycardia is maternal fever from chorioamnionitis, although fever from any source can produce this. In some cases, fetal tachycardia may precede overt maternal fever (Gilstrap,

F I G U R E 24-6 Schematic representation of short-term beat-to­ beat va ria b i l ity measu red by a feta l sca l p electrode. t time i nter­ va l betwee n successive feta l R waves. (Ada pted with perm ission from Klava n M, Laver AT, Boscola MA: C l i n ica l concepts of feta l hea rt rate m o n itori ng. Wa ltham, Hewlett-Packa rd, 1 977.) =

1 987) . Fetal tachycardia caused by maternal infection typically is not associated with fetal compromise unless there are associ­ ated periodic heart rate changes or fetal sepsis. Other causes of fetal tachycardia include fetal compromise, cardiac arrhythmias, and maternal administration of parasym­ pathetic inhibiting (atropine) or sympathomimetic (terbuta­ line) drugs. Prompt relief of the compromising event, such as correction of maternal hypotension caused by epidural analge­ sia, can result in fetal recovery. he key feature to distinguish fetal compromise in association with tachycardia seems to be concomitant heart rate decelerations. Wandering Baseline. This baseline rate is unsteady and "wan­

ders" between 1 20 and 1 60 bpm (Freeman, 2003) . This rare find­ ing is suggestive of a neurologically abnormal fetus and may occur as a preterminal event. In contrast, changes of the normal baseline are common in labor and do not predict morbidity (Yang, 20 1 7) . Beat-to-Beat Va ria b i l ity

Baseline variability is an important index of cardiovascular function and appears to be regulated largely by the autonomic nervous system (Kozuma, 1 997) . That is, a sympathetic and parasympathetic "push and pull" mediated via the sinoatrial node produces moment-to-moment or beat-to-beat oscillation of the baseline heart rate. Such heart rate change is deined as baseline variability. Variability can be further analyzed over the short term and long term, although these terms have fallen out of use. Short-term variabiliy relects the instantaneous change in fetal heart rate from one beat-or R wave-to the next. This variability is a measure of the time interval between cardiac systoles (Fig. 24-6) . Short-term variability can most reliably be determined to be normally present only when electrocardiac cycles are measured directly with a scalp electrode. Long-term variability is used to describe the oscillatory changes during 1 minute and result in the waviness of the baseline (Fig. 24-7) . 1 35

1 25 F I GURE 24-7 Schematic representation of long-term beat-to-beat varia bility of the fetal heart rate ra n g i n g between 1 25 a nd 1 35 bpm. (Ada pted with permission from Klava n M, Laver AT, Boscola MA: Clinica l concepts of feta l heart rate monitorin g . Wa ltha m, Hewlett­ Packa rd, 1 977.)

46 1

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La bor

he normal frequency of such waves is three to ive cycles per minute (Freeman, 2003) . It should be recognized that precise quantitative analysis of both short- and long-term variability presents several frus­ trating problems due to technical and scaling factors (Parer, 1 985). hus, most clinical interpretation is based on visual analysis with subjective judgment of the smoothness or latness of the baseline. According to Freeman and associates (2003), no evidence suggests that the distinction between short- and long-term variability has clinical relevance. Similarly, the NICHD Workshop ( 1 997) did not recommend diferentiating short- and long-term variability because in actual practice they are visually determined as a unit. The workshop panel defined baseline variability as those baseline luctuations of two cycles per minute or greater. They recommended the criteria shown in Figure 24-8 for quantifi c ation of variability. Normal beat­ to-beat variability was accepted to be 6 to 25 bpm. I n crea sed Va ria b i l ity. Several physiological and pathological processes can afect beat-to-beat variability. Greater variability accompanies fetal breathing and body movements (Dawes, 1 98 1 ; Van Geijn, 1 980) . Pillai and James ( 1 990) reported increased baseline variability with advancing gestation. Up to 30 weeks, baseline characteristics were similar during both fetal rest and activity. After 30 weeks, fetal inactivity was asso­ ciated with diminished baseline variability, but fetal activity enhanced it. Last, the baseline fetal heart rate becomes more physiologically ixed (less variable) as the rate rises. This phe­ nomenon presumably relects less cardiovascular physiologi­ cal wandering as beat-to-beat intervals shorten with a higher heart rate. Decreased Va ria b i l ity. A common cause of diminished beat­ to-beat variability is administration of analgesic drugs dur­ ing labor (Chap. 2 5 , p. 487) . Various central nervous system depressant drugs can cause transient diminished beat-to-beat variability. Included are narcotics, barbiturates, phenothiazines, tranquilizers, and general anesthetics. Corticosteroids also dampen variability (Knaven, 20 1 7) . As one specifi c example, variability regularly diminishes within 5 to 1 0 minutes fol­ lowing intravenous meperidine administration, and the efects may last up to 60 minutes or longer (Hill, 2003; Petrie, 1 993) . Butorphanol given intravenously has similar efects (Schucker, 1 996) . And, chronically administered buprenorphine sup­ presses fetal heart rate and movement (Jansson, 20 1 7) . Magnesium suate, widely used i n the United States for tocolysis or management of hypertensive gravidas, is associated with diminished beat-to-beat variability. In a study of nearly 250 term gestations, magnesium sulfate administration led to decreased variability but without evidence of adverse neonatal efects (Duy, 20 1 2) . Others have echoed these fi n dings (Hal­ lak, 1 999; Lin, 1 988). With magnesium sulfate tocolysis of preterm labor, variability was also diminished in most reviewed studies (Nensi, 20 1 4 ; Verdurmen, 20 1 7) . O f greatest concern, diminished beat-to-beat variability can be an ominous sign indicating a seriously compromised fetus. Paul and coworkers ( 1 975) reported that loss of variability in combination with decelerations was associated with etal

acidemia. Decreased variability was deined as an excursion of the baseline of ; 5 bpm (see Fig. 24-8) . Severe maternal acidemia can also lower fetal beat-to-beat variability, for example, in a mother with diabetic ketoacidosis. According to Dawes ( 1 985), metabolic acidemia that causes depression of the fetal brainstem or the heart itself creates the loss of variability. hus, diminished beat-to-beat variability, when it relects fetal compromise, likely relects acidemia rather than hypoxia. Indeed, mild degrees of fetal hypoxemia have been reported actually to enhance variability, at least initially (Murotsuki, 1 997) . Reduced baseline heart rate variabiliy is the single most reli­ able sign ofetal compromise. Smith and coworkers ( 1 988) per­ formed a computerized analysis of beat-to-beat variability in growth-restricted fetuses before labor. Diminished variability (;4.2 bpm) maintained for 1 hour was diagnostic of develop­ ing acidemia and imminent fetal death. In contrast, Samuelof and associates ( 1 994) evaluated variability in 2200 consecutive deliveries and concluded that variability by itself could not be used as the only indicator of fetal well-being. They also warned that good variability should not be interpreted as necessarily reassuring. Blackwell and associates (20 1 1 ) found that even experts often disagreed as to whether variability was absent or minimal (;5 bpm) . In sum, beat-to-beat variability is afected by fetal physiol­ ogy, and its meaning difers depending on the clinical setting. Decreased variability in the absence of decelerations is unlikely to reflect fetal hypoxia (Davidson, 1 992) . A persistently flat fetal heart rate baseline-absent variability-within the nor­ mal baseline rate range and without decelerations may relect a previous fetal insult that has resulted in neurological damage (Freeman, 2003). Ca rd iac Arrhyth m ia

When fetal cardiac arrhythmias are irst suspected using elec­ tronic monitoring, indings can include baseline bradycardia, tachycardia, or most commonly in our experience, abrupt base­ line spiking (Fig. 24-9) . An arrhythmia can only be documented, practically speaking, when scalp electrodes are used. Some fetal monitors can be adapted to output the scalp electrode signals into an ECG recorder. Because only a single lead is obtained, analysis and interpretation of rhythm and rate disturbances are severely limited. Southall and associates ( 1 980) studied fetal cardiac rate and rhythm disturbances in 934 normal pregnancies between 30 and 40 weeks. Arrhythmias, episodes of bradycardia < 1 00 bpm, or tachycardia > 1 80 bpm were encountered in 3 percent. Most supraventricular arrhythmias are of little signiicance during labor unless there is coexistent fetal heart failure as evidenced by hydrops. Many supraventricular arrhythmias disappear in the immediate neonatal period, although some are associated with structural cardiac defects (Api, 2008) . Intermittent base­ line bradycardia is frequently due to congenital heart block. Conduction defects, most often complete atrioventricular (AV) block, usually are found in association with maternal connec­ tive tissue diseases (Chap. 59, p. 1 1 42) . Antepartum evaluation of the fetus with an identiied arrhythmia and potential treat­ ment options are discussed in Chapter 1 6 (p. 3 1 5) .

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FIGURE 24-8 Grades of baseline feta l heart rate va ria bility shown in the fol lowing five panels. 1 . U ndetecta ble, a bsent va riabil ity. 2. M i n i m a l va riabil ity, ;5 b p m . 3 . Moderate (normal) va ria bility, 6 t o 2 5 bpm. 4 . Ma rked varia bility, >25 b p m . 5. Sinusoidal pattern. Th is differs from va ri­ a b i l ity in that it has a smooth, sinel ike pattern of reg u l a r fl uctuation and is excl uded i n the definition of feta l heart rate va riabil ity. (Adapted with perm ission from Nation a l I n stitute of Child Health and H u m a n Development Resea rch Planning Workshop, 1 997.)

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F I G U R E 24-9 I nternal feta l monitori ng at term demonstrated occa s ion a l a b r u pt beat-to-beat feta l hea rt rate spiking due to erratic extrasystoles shown in the correspon d i n g feta l electroca r­ diogra m. The normal newborn was del ivered sponta neously a nd had normal cardiac rhythm in the n u rsery.

Most fetal arrhythmias without comorbid fetal hydrops are inconsequential during labor, but they may hinder interpreta­ tion of fetal heart rate tracings. Sonographic evaluation of fetal anatomy and echocardiography can be useful. Generally, in the absence of fetal hydrops, neonatal outcome is not measurably improved by pregnancy intervention. At Parkland Hospital, intrapartum fetal cardiac arrhythmias, especially those associated with clear amnionic fluid, are typically managed conservatively. S i n u s o i d a l Heart Rate

A true sinusoidal pattern such as that shown in panel 5 of Figure 24-8 can be observed with fetal intracranial hemor­ rhage, with severe fetal asphyxia, and with severe feral anemia. he last may stem from anti-D alloimmunization, fetomaternal hemorrhage, twin-twin transusion syndrome, fetal parvoviral infection, or vasa previa with bleeding. Insigniicant sinusoidal patterns have been reported following administration of meperi­ dine, morphine, alphaprodine, and butorphanol (Angel, 1 984; Egley, 1 99 1 ; Epstein, 1 982) . Shown in Figure 24- 1 0 is a sinu­ soidal pattern seen with maternal meperidine administration. An important characteristic of this pattern when due to narcotics is the sine frequency of 6 cycles per minute. A sinusoidal pattern also has been described with chorioamnionitis, fetal distress, and umbilical cord occlusion (lvlurphy, 1 99 1 ) . Young ( 1 980a) and Johnson ( 1 98 1 ) with their coworkers concluded that intrapar­ tum sinusoidal fetal heart patterns were not generally associated with fetal compromise. hus, management is usually dictated by the clinical setting. Modanlou and Freeman ( 1 982), based on their extensive review, proposed adoption of a strict definition: 1 . Stable baseline heart rate of 1 20 to 1 60 bpm with regular oscillations 2. Amplitude of 5 to 1 5 bpm (rarely greater)

F I G U R E 24- 1 0 S i n u soida l feta l hea rt rate pattern associated with maternal i ntravenous meperid ine ad m i n istration. Sine waves a re occ u rring at a rate of 6 cycles per m i n u te.

3. Long-term variability frequency of 2 to 5 cycles per minute 4. Fixed or flat short-term variability 5. Oscillation of the sinusoidal waveform above or below a baseline 6. Absent accelerations. Although these criteria were selected to deine a sinusoidal pattern that is most likely ominous, they observed thar the pat­ tern associated with alphaprodine is indistinguishable. Other investigators have proposed a classiication of sinusoidal heart rate patterns into mild-amplitude 5 to 1 5 bpm, intermedi­ ate-1 6 to 24 bpm, and major-::2 5 bpm to quantiy fetal risk (Murphy, 1 99 1 ; Neesham, 1 993). Some have defined intrapartum sine wavelike baseline varia­ tion with periods of acceleration as pseudosinusoidal. Murphy and colleagues ( 1 99 1 ) reported that pseudosinusoidal patterns were seen in 1 5 percent of monitored labors. Mild pseudosi­ nusoidal patterns were associated with use of meperidine and epidural analgesia. Intermediate pseudosinusoidal patterns were linked to fetal sucking or transient episodes of fetal hypoxia caused by umbilical cord compression. Egley and associates ( 1 99 1 ) reported that 4 percent of fetuses demonstrated sinu­ soidal patterns transiently during normal labor. hese authors observed patterns persisting for up to 90 minutes in some cases. The pathophysiology of sinusoidal patterns is unclear, in part due to various deinitions. There seems to be general agreement that antepatum sine wave baseline undulations portend severe fetal anemia. Still, few anti-D alloimmunized fetuses develop this pat­ tern (Nicolaides, 1 989) . The sinusoidal pattern has been reported to develop or disappear ter fetal transusion (Del Valle, 1 992; Lowe, 1 984). Ikeda and associates ( 1 999) proposed that the pat­ tern is related to waves of arterial blood pressure, reflecting oscil­ lations in the baroreceptor-chemoreceptor feedback mechanism. • Periodic Fetal Heart Rate Changes

These refer to deviations from baseline that are temporally related to uterine contractions. Acceleration refers to a rise in fetal heart rate above baseline, and deceleration is a drop below the baseline rate. The nomenclature most commonly used in the United States is based on the timing of the deceleration in rela­ tion to contractions-thus, eary, late, or variable. he waveform

I nt ra p a rt u m Asses s m ent

of these decelerations is also significant for pattern recognition. In early and late decelerations, the slope of fetal heart rate change is gradual, resulting in a curvilinear and uniform or symmetrical waveform. With variable decelerations, the slope of fetal heart rate change is abrupt and erratic, giving the waveform a jag­ ged appearance. The NICHD Workshop ( 1 997) proposed that decelerations be defined as recurrent if they accompanied � 5 0 percent o f contractions in any 20-minute period. Another system now used less often to describe decelera­ tions is based on the pathophysiological events considered most likely to underlie the pattern. In this system, early decelera­ tions are termed head compression, late decelerations are termed uteroplacental insuiciency, and variable decelerations are cord compression patterns.

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hese are abrupt heart rate increases above the fetal heart rate base­ line and defined by n onset-to-peak rise within 30 seconds (Amer­ ican College of Obstetricians and Gynecologists, 20 1 7a) . At 32 weeks' gestation and beyond, an acceleration has a peak � 1 5 bpm above baseline. Its duration is � 15 sec but 7 or with normal arterial blood acid-base values was not consistent with an acute hypoxic-ischemic event.

TABLE 24-2. Th ree-Tier F eta l Hea rt Rate

I n terpretation System Category I-Normal

I ncl ude a l l of the fo l lowi n g : Basel i n e rate: 1 1 0- 1 60 bpm • Base l i n e FHR varia b i l ity: moderate • Late o r va ric ble decel era tio ns: a bsent • Ea rly dece lerations: p resent o r a bsent • Accelerations: present o r a bsent •

I n c l ude a l l F H R trac i n g s n ot categorized a s Category I or I I I . Category I I tracings m a y re present a n a p prec i a b l e fraction of those encountered i n cli nical ca re. Exa m ples i nc l u de a n y of the fol lowi n g : Base l i n e rate • Bradyca rd ia n ot acco m p a n ied by a bsent base l i n e va ria b i l ity • Ta chyca rd ia Base l i ne F H R varia b i l ity • M i n i ma l base l i n e va ria b i l ity Absent basel i ne va ria b i l ity n ot acco m p a n i ed by recu rrent decelerations • Ma rked base l i n e va ria b i l i ty Acce lerations • Absence of i n d uced accelerations after feta l sti m u l ation Period ic or episod i c decelerations • Recu rrent va riable d ecel e rations acco m pa n i ed by m i n i ma l or m oderate basel i n e va ri a b i l ity • Prolong ed deceleration : 2 m i n but < 1 0 m i n • Recu rre nt l ate decelerations vvith moderate base l i n e va ria b i l ity • Va riable decelerati o n s with other cha racteristi cs, s u c h as slow retu rn t o ba sel i n e, "overs hoots," or "sh o u l d e rs" Category I I-I ndeterm i nate

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I nclude e ither: Absent basel i ne F H R va riabil ity a n d any of the fo l lowi ng : Recu rrent late decelerati o n Recu rrent va ri a b l e deceie rati o n s Bradyca rdia • S i n usoidal patten •

bpm beats per m i n ute; F H R feta l heart rate. Reproduced with perm ission from Macones GAl H a n ki ns G O, Spong CY, et al: The 2008 National I nstitute of Child Hea lth and H u man Development workshop report on electronic feta l mon itoring: u pdate on defi n itions, i nterpretation, and research g u idelines, Obstet Gynecol. 2008 Sep; 1 1 2(3):66 1 -666. =

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Sholapurkar (20 1 2) challenged the validity of the three­ tier system because most abnormal fetal heart rate patterns fall into the indeterminate category II. It was further sug­ gested that this resulted from most fetal heart rate decelera­ tions being inappropriately classiied as variable decelerations due to cord compression. A group of 1 9 experts led by Clark (20 1 3) observed that more than 80 percent of fetuses have

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F H R patterns in tier II. hey proposed a management algo­ rithm for these fetuses, however, their hypothetical algorithm was not clinically tested. Parer and King (20 1 0) compared this situation in the United States with that of other countries in which a consensus on clas­ siication and management has been reached by several profes­ sional societies. Some of these include the Royal College of Obstetricians and Gynaecologists, the Society of Obstetricians and Gynaecologists of Canada, the Royal Australian and New Zealand College of Obstetricians and Gynaecologists, and the Japan Society of Obstetrics and Gynecology. These authors fur­ ther comment that the NICHD three-tier system is inadequate because category II-an indeterminate FHR pattern-contains a vast heterogenous mixture of patterns that prevents develop­ ment of a management strategy. Parer and Ikeda (2007) had previously proposed a color­ coded ive-tier system for both F H R interpretation and management. Two subsequent reports have compared the five- and three-tier systems. Bannerman and associates (20 1 1 ) found that the two systems were similar in fetal heart rate interpretations for tracings that were either very normal or very abnormal. Coletta and coworkers (20 1 2) found that the ive-tier system had better sensitivity than the three-tier sys­ tem. Elliott and colleagues (20 1 0) used computerization to measure the performance of a ive-tier classiication system but failed to successfully analyze and categorize 2472 fetal heart recordings. It is apparent that, after 50 years of continuous electronic fetal heart rate monitoring use, there is not a consensus on interpretation and management recommendations for FHR patterns (Parer, 20 1 1 ) . • Meconium in the Amnionic Fluid

Obstetricians have long realized that meconium during labor is problematic in the prediction of fetal distress or asphxia. Indeed, although 1 2 to 22 percent of labors are complicated by meconium, only a few are linked to neonatal mortality. In an investigation from Parkland Hospital, meconium was found to be a "low-risk" obstetrical hazard because the perinatal mortal­ ity rate attributable to meconium was only 1 death per 1 000 live births (Nathan, 1 994) . Three theories regarding fetal passage of meconium may explain, in part, the tenuous connection between its detec­ tion and neonatal mortality. First, fetuses may pass meconium in response to hypoxia, and meconium therefore signals fetal compromise (Walker, 1 953) . Second, in utero passage of meco­ nium may represent normal gastrointestinal tract maturation under neural control (Mathews, 1 979) . A inal theory posits that meconium passage follows vagal stimulation from com­ mon but transient umbilical cord entrapment with resultant increased bowel peristalsis (Hon, 1 96 1 ) . Ramin and associates ( 1 996) studied almost 8000 pregnan­ cies with meconium-stained amnionic fluid delivered at Park­ land Hospital. Meconium aspiration syndrome was signiicantly associated with fetal acidemia at birth. Other signiicant corre­ lates of aspiration included cesarean delivery, forceps to expe­ dite delivery, intrapartum heart rate abnormalities, depressed

Apgar scores, and need for assisted ventilation at delivery. Anal­ ysis of the type of fetal acidemia based on umbilical blood gases suggested that the fetal compromise associated with meconium aspiration syndrome was an acute event. his is because most acidemic fetuses had abnormally increased PC02 values rather than a pure metabolic acidemia. Dawes and coworkers ( 1 972) observed that such hypercar­ bia in fetal lambs induces gasping and resultant increased amni­ onic fluid inhalation. Jovanovic and Nguyen ( 1 989) observed that meconium gasped into the fetal lungs caused aspiration syndrome only in asphyxiated animals. Ramin and colleagues ( 1 996) hypothesized that the patho­ physiology of meconium aspiration syndrome includes, but is not limited to, fetal hypercarbia, which stimulates fetal res­ piration leading to aspiration of meconium into the alveoli. Lung parenchymal injury is secondary to acidemia-induced alveolar cell damage. In this pathophysiological scenario, meconium in amnionic fl u id is a fetal environmental haz­ ard rather than a marker of preexistent compromise. This proposed pathophysiological sequence is not all-inclusive, because it does not account for approximately half of the cases of meconium aspiration syndrome in which the fetus is not acidemic at birth. Thus, it was concluded that the high incidence of meco­ nium observed in the amnionic fluid during labor often rep­ resents fetal passage of gastrointestinal contents in conjunction with normal physiological processes. lthough normal, such meconium becomes an environmental hazard when fetal aci­ demia supervenes. Importantly, such acidemia occurs acutely, and therefore meconium aspiration is unpredictable and likely unpreventable. Moreover, Greenwood and colleagues (2003) showed that clear amnionic fluid was also a poor predictor. In a prospective study of 8394 women with clear amnionic fl u id, they found that clear fl u id was an unreliable sign of fetal well­ being. G rowing evidence indicates that many newborns with meconium aspiration syndrome have suffered chronic hypoxia befo re birth (Ghidini, 200 1 ) . B lackwell and asso­ ciates (200 1 ) found that 60 percen t of neonates diagnosed with meconium aspiration syndrome had umbilical artery blood p H ::7 . 2 0 , implying that the syndrome was unre­ lated to the neonatal condition at delivery. S imilarly, markers of chronic hypoxia, s uch as elevated fetal erythro­ poietin levels and i ncreased nucleated red blood cell counts in newborns, suggest that chronic hypoxia is involved in many meconium aspiration syndrome cases (Dollberg, 200 1 ; J azayeri, 2000) . In the recent past, routine obstetrical management of a newborn with meconium-stained amnionic fluid included intrapartum suctioning of the oropharynx and nasopharynx. In 2005 , management guidelines were signiicantly modiied. Now, the American College of Obstetricians and Gynecologists (20 1 7c) recommends that newborns with meconium-stained amnionic fl u id, regardless of their vigor, should no longer rou­ tinely receive intrapartum suctioning. Suctioning is reserved for those with airway obstruction. hey also recommend that an appropriately credentialed team with full resuscitation skills be available (Chap. 32, p. 607) .

I ntra part u m Assessment

TABLE 24-3. Some Res uscitative Measu res for Category II or Category I I I Traci ngs Interventionsb Fetal Heart Rate Abnormalitya

Rec u rrent late decelerations Prolonged decelerat i o n s o r b radyca rd ia M i n i m a l o r a bsent FHR va ria b i l i ty

Latera l d ec u b itus pos itio n i ng; ad m i n i ster maternal oxyge n ; i ntravenou s fl u i d bol u s; red u ce u terine contract i o n freq uency

Tachysystol e with categ ory I I or I I I trac i n g

Disconti n ue oxytoci n o r prosta g l a n d i ns; G ive tocolyti cs: terbuta l i ne, mag nes i u m s u l fate

Recu rrent va r i a b l e decelerations Prolonged decel erati o ns o r bra dyca rd ia

Reposition mother; a m n i oi nfu s i o n ; with cord prola pse, ma n u a l ly elevate the presenting part w h i l e pre pa ri n g for i m med iate del ivery

aSi m u lta neo u s eva l u ation of the sus pected ca u se(s) is a l s o an i m porta n t step i n ma nagement of a bnormal F H R t ra c i n g s . T h e combi nation o f m u lt i p l e i n terventions S i m u lta n eously m a y be appropriate a nd potenti a l ly m o re effective t h a n d o i n g t h e m i n d ivid u a l ly o r seria l ly. FHR feta l h ea rt rate. =

• Management Options

Principal management options for variant fetal heart rate pat­ terns consist of correcting any fetal insult, if possible. Sugges­ tions are listed in Table 24-3 . he woman is moved to a lateral position, and supplemental oxygen is provided by mask. Cor­ recting maternal hypotension caused by regional analgesia and discontinuing oxytocin both serve to improve uteroplacental perfusion. Vaginal examination excludes a prolapsed cord or impending delivery. Simpson and James (2005) assessed the beneits of three maneuvers in 52 women with fetal oxygen saturation sensors already in place. They used intravenous hydration-500 to 1 000 mL of lactated Ringer solution given over 20 minutes; lateral versus supine positioning; and admin­ istration of supplemental oxygen at l O Ll min using a nonre­ breathing mask. Each of these maneuvers signiicantly raised fetal oxygen saturation levels. Toco lysis

Terbutaline sulfate given to relax the uterus can be a temporiz­ ing maneuver in the management of nonreassuring fetal heart rate patterns during labor. A single 250-�g intravenous or subcutaneous injection is used to inhibit uterine contractions and thereby improve fetal oxygenation. Cook and Spinnato ( 1 994) described their 1 0-year experiences with terbutaline tocolysis in 368 pregnancies. Such resuscitation improved fetal scalp blood pH values, although all fetuses underwent cesarean delivery. hese investigators concluded that although the studies were small and rarely randomized, most reported favorable results with terbutaline tocolysis for nonreassuring patterns. Small intravenous doses of nitroglycerin-60 to 1 80 �g-also have been reported to be beneicial (Mercier, 1 997) . Bullens and associates (20 1 5) concluded in their review that tocolysis was beneicial. Still, the American College of Obstetricians and Gynecologists (20 1 7b) cites that evidence is insuicient to recommend tocolysis for nonreassuring fetal heart rate patterns. Amn ioi nfu s i o n

Miyazaki and Taylor ( 1 983) infused saline through an intrauter­ ine pressure catheter in laboring women who had either vari­ able or prolonged decelerations attributed to cord entrapment.

Such therapy improved the heart rate pattern in half of the women studied. Later, .Miyazaki and Nevarez ( 1 985) randomly assigned 96 nulliparas in labor with cord compression p atterns and found that those who were treated with amnioinfusion required cesarean delivery for fetal distress less often. Based on many of these early reports, transvaginal amnioinfusion has been extended into three clinical areas (Dad, 20 1 6) . hese include: ( 1 ) treatment of variable or prolonged decelerations; (2) prophylaxis for women with oligohydramnios, as with pro­ longed ruptured membranes; and (3) attempts to dilute or wash out thick meconium (Chap. 33, p. 620) . Many diferent amnioinusion protocols have been reported, but most provide a 500- to 800-mL bolus of warmed normal saline followed by a continuous inusion of approximately 3 mLimin (Owen, 1 990; Pressman, 1 996). In another study, Rinehart and colleagues (2000) gave either a 500-mL bolus of normal saline at room temperature alone or a similar bolus plus a continuous inu­ sion at 3 mLimin. heir study included 65 women with variable decelerations, and the investigators found neither method to be superior. Wenstrom and associates ( 1 995) surveyed use of mnioin­ usion in teaching hospitals in the United States. The procedure was used in 96 percent of the 1 86 centers surveyed, and it was estimated that 3 to 4 percent of llwomen delivered at these centers received such inusion. Potential complications of mnioinusion are sum­ marized in Table 24-4.

TABLE 24-4. Compl ications Associated with Amnioinfusion from a Su rvey of 1 86 Obstetrica l U n its Complication

Uteri n e hype rto n us Abnorm a l feta l hea rt rate tra c i n g Chorioa m n i o n itis Cord prola pse Uterine ru ptu re Maternal ca rdiac or resp i ratory com p ro m ise Pl acenta l a b ru ption Maternal death Data from We n strom, 1 995.

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For variable decelerations, Hofmeyr and Lawrie (20 1 2) reviewed the efects of amnioinfusion in the management of fetal heart rate patterns associated with umbilical cord compression . They concluded that amnioinfusion appeared to be useful in reducing the occurrence of variable decelerations, improving neonatal outcome, and lowering cesarean delivery rates. The American College of Obstetricians and Gynecolo­ gists (20 1 6) has concluded that amnioinfusion is a reasonable approach in the treatment of repetitive variable decelerations regardless of meconium status. For oligohydramnios, amnioinfusion has been used prophy­ lactically to avoid intrapartum fetal heart rate patterns from cord occlusion. Nageotte and coworkers ( 1 99 1 ) found that this resulted in signiicantly fewer and less severe variable decelerations in labor. However, the cesarean delivery rate or condition of term newborn was not improved. In a ran­ domized investigation, Macri and colleagues ( 1 992) studied prophylactic amnioinfusion in 1 70 term and postterm preg­ nancies complicated by both thick meconium and oligohy­ dramnios. Amnioinfusion significantly reduced meconium aspiration syndrome rates and cesarean delivery rates for fetal distress. In contrast, Ogundipe and associates ( 1 994) ran­ domly assigned 1 1 6 term pregnancies with an amnionic luid index < 5 cm to receive prophylactic amnioinfusion or stan­ dard obstetrical care. Overall cesarean delivery rates, delivery rates for fetal distress, or umbilical cord acid-base studies did not difer significantly between groups. For meconium-stained amnionic luid, Pierce and associates (2000) reviewed 1 3 prospective trials of intrapartum amnioin­ fusion for 1 924 women with meconium-stained fluid. In the amnioinfusion group, newborns were signiicantly less likely to have meconium below the vocal cords, and meconium aspira­ tion syndrome rates were lower. he cesarean delivery rate was also reduced in the amnioinfusion group. Similar results were reported by Rathore and coworkers (2002) . In contrast, several investigators were not supportive of amnioinfusion for meconium staining. For example, Usta and associates ( 1 995) reported that amnioinfusion was not feasi­ ble in half of women with moderate or thick meconium who were randomized to this treatment. These investigators were

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unable to demonstrate improved neonatal outcomes with this treatment. Spong and coworkers ( 1 994) also concluded that although prophylactic amnioinfusion did dilute meconium, it did not improve perinatal outcome. Last, F raser and colleagues (2005) randomized amnioinfusion in 1 998 women with thick meconium-stained amnionic fluid in labor and found no ben­ eits. Hofmeyr and associates (20 1 4) reported mixed results from their review. Because of these indings, the American College of Obstetricians and Gynecologists (20 1 6) does not recommend amnioinfusion to dilute meconium-stained amni­ onic fluid. • Fetal Heart Rate Patterns and Brain Injury

Studies that have attempted to correlate fetal heart rate patterns with brain injury primarily have examined infants identiied in medicolegal actions. Phelan and Ahn ( 1 994) reported that among 48 fetuses later found to be neurologically impaired, a persistent nonreactive fetal heart rate tracing was already pres­ ent at the time of admission in 70 percent. They concluded that fetal neurological injury occurred predominately before arrival to the hospital. When they looked retrospectively at heart rate patterns in 209 brain-injured newborns, they concluded that there was not a single unique pattern associated with fetal neu­ rological injury (Ahn, 1 996) . Graham and associates (2006) reviewed the world literature published between 1 966 and 2006 on the efect of fetal heart rate monitoring to prevent perinatal brain injury and found no beneit. Fetal heart rate patterns necessary for perinatal brain dam­ age have been studied in experimental animals. .1yers ( 1 972) described the efects of complete and partial asphyxia in rhe­ sus monkeys. Complete asphyxia was produced by total occlu­ sion of umbilical blood low that led to prolonged deceleration (Fig. 24-26) . Fetal arterial pH did not drop to 7.0 until approx­ imately 8 minutes after complete cessation of oxygenation and umbilical low. At least 1 0 minutes of such prolonged decelera­ tion was required before there was evidence of brain damage in surviving fetuses. Myers ( 1 972) also produced partial asphyxia in rhesus mon­ keys by impeding maternal aortic blood flow. This resulted in

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FI G U R E 24-26 Prolonged deceleration i n a rhesu s m o n key shown with blood pressu re a n d biochem ica l c h a n g e s d u ring tota l occl usion of u m b i l ica l cord blood flow. (Data from Myers, 1 972.)

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analgesia was used in 5 5 percent. The length of the second stage, even in those lasting up to 6 hours or more, was not related to neonatal outcome. These results were attributed to careful use of electronic monitoring and scalp pH measurements. These investigators concluded that there is no compelling reason to intervene with a possibly diicult forceps or vacuum extraction because a certain number of hours have elapsed. They observed, however, that after 3 hours in the second stage, delivery by cesarean or other operative method increased progressively. By 5 hours, the prospects for spontaneous delivery in the subse­ quent hour were only 1 0 to 1 5 percent. Newer guidelines have been promoted by the Consensus Com­ mittee (20 1 6) for second-stage labor. These recommend allowing a nullipara to push for at least 3 hours and a multipara to push for at least 2 hours before second-stage labor arrest is diagnosed. One caveat is that maternal and fetal status should be reassuring. These authors provide options to these times before cesarean deliv­ ery is performed. Namely, longer durations may be appropriate as long as progress is documented. Also, a specific maximal length of time spent in second-stage labor beyond which ll women should undergo operative delivery has not been identiied. Intuitively, the goal to lower cesarean delivery rates is best balanced with one to ensure neonatal safety. And, it is prob­ lematic that no robust data on neonatal outcomes support the safety of allowing prolonged second-stage labor. Data from many evaluations reveal that serious newborn consequences attend second-stage labors longer than 3 hours (Allen, 2009; Bleich, 20 1 2; Laughon, 20 1 4; Leveno, 20 1 6; Rosenbloom, 20 1 7) . Other data, when adjusted for labor variables, show no diference in neonatal complications for these longer second stages (Cheng, 2004; Le Ray, 2009; Rouse, 2009) . Grobman and colleagues (20 1 6) have argued that the absolute number of such adverse outcomes is small and "overall outcomes remain good." That said, some of the complications are severe. Thus, to fully ascertain specifi c efect of these guidelines on morbidity rates, randomized controlled trials are needed. It is possible that prolonged first-stage labor presages that with the second stage. Nelson and associates (20 1 3) studied the rela­ tionships between the lengths of the irst and second stages of labor in 1 2,523 nulliparas at term delivered at Parkland Hospi­ tal. The second stage signiicantly lengthened concomitantly with increasing irst-stage duration. The 95th percentile was 1 5.6 and 2.9 hours for the first and second stages, respectively. Women with irst stages lasting longer than 1 5 .6 hours (> 95th percetile) had a 1 6-percent rate of second-stage labor lasting 3 hours (95th percen­ tile) . his compared with a 4.5-percent rate of prolonged second stages in women with irst-stage labors lasting 5 contractions i n a 1 0-minute period. It should always be qualiied by the pres­ ence or absence of fetal heart rate abnormalities. 2. Uterine hypertonus, hyperstimulation, and hypercontractiliy are terms no longer deined, and their use is not recom­ mended. Because uterine tachysystole associated with fetal compro­ mise may develop when prostaglandins are used with preexisting spontaneous labor, such use is not recommended. If tachysystole

I nd uction and A u g m e ntation of La bor

follows the 1 0-mg insert, its removal by pulling on the tail of the surrounding net sac will usually reverse this efect. Irrigation to remove the gel preparation has not been shown to be helpful. The manufacturers recommend caution when these prep­ arations are used in women with ruptured membranes. This concern is also extended to women with glaucoma or asthma. However, in a review of 1 89 women with asthma, dinopros­ tone was not associated with asthma worsening or exacerbation (Towers, 2004) . Other contraindications listed by the manu­ facturers include a history of dinoprostone hypersensitivity, suspicion of fetal compromise or cephalopelvic disproportion, unexplained vaginal bleeding, women already receiving oxyto­ cin, those with six or more previous term pregnancies, those with a contraindication to vaginal delivery, or women with a contraindication to oxytocin or who may be endangered by prolonged uterine contractions, for example, those with a his­ tory of cesarean delivery or uterine surgery. Ad m i n i stration. PGE2 preparations should only be adminis­ tered in or near the delivery suite. Moreover, uterine activity and fetal heart rate should be monitored (American College of Obstetricians and Gynecologists, 20 1 6) . These guidelines stem from the risk of uterine tachysystole. When contractions begin, they are usually apparent in the irst hour and show peak activ­ ity in the irst 4 hours. According to manufacturer guidelines, oxytocin induction that follows prostaglandin use for cervical ripening should be delayed for 6 to 1 2 hours following PGE2 gel administration or for at least 30 minutes after removal of the vaginal insert.

Prosta g l a n d i n E ,

Misoprostol-Cytotec-is a synthetic prostaglandin EI (PGE1) that is approved as a 1 00- or 200-�g tablet for peptic ulcer prevention. It has been used "of label" for preinduction cervi­ cal ripening and may be administered orally or vaginally. he tablets are stable at room temperature. Although widespread, the of-label use of misoprostol has been controversial (Wagner, 2005; Weeks, 2005). Specifically, G. D. Searle & Company notiied physicians that misoprostol is not approved for labor induction or abortion (Cullen, 2000) . Still, the American College of Obstetricians and Gynecologists (20 1 6) reairmed its recommendation for use of the drug because of proven safety and eicacy. It currently is the preferred prostaglandin for cervical ripening at Parkland Hospital. In one review of 234 women administered misoprostol, no instances of asthma exacerbation were associated with its use, and the risk of this was calculated to be 50 percent EAS tear; and (3c) EAS plus internal anal sphincter (lAS) tears.

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A

8

F I G U R E 27- 1 2 M a n u a l re mova l of placenta. A. One hand g rasps the fu n d u s a n d the other hand is i n serted i nto the uterine cavity a n d the fi ngers a re swept from side to side a s they a re adva nced. B. When the placenta detaches, it is g rasped and re moved .

38

2

4

3b

3c

F I G U R E 27- 1 3 1 . Fi rst-deg ree peri neal laceration: i nj u ry to o n ly the vag i n a l e pith e l i u m or peri nea l ski n . 2. Second-deg ree laceration: i nj u ry to peri neum that spares the a n a l s p h i n cter com plex but i nvolves the peri nea l m u scles, which a re the b u l bospongiosus and su perficial tra n sverse peri nea l mu scles. 3a. Th i rd-deg ree laceration: 50 percent of the EAS i s torn, but the i nternal a n a l sphincter (lAS) rem a i n s i ntact. 3c. Th ird-deg ree laceratio n : EAS and lAS a re torn. 4. Fourth-deg ree laceration: the peri neal body, entire anal s p h i n cter com plex, a nd a norecta l mucosa a re l acerated . (Reproduced with per­ m i ssion from Kenton K, Muel ler M: Episiotomy a n d obstetric a n a l s p h i n cter lacerations. I n Yeoma n s ER, H offma n B L, Gi lstra p LC I I I, et al (eds) : C u n n i n g h a m and Gilstra p's Operative Obstetrics, 3 rd ed. New York, McGraw- H i l i Ed ucatio n, 201 7.)

Vag i nal Del ivery

hird- and fourth-degree lacerations are considered obstetrical anal sphincter injuries (OASIS) , and their combined incidence varies from 0.5 to 5 percent (Blondel, 20 1 6; Friedman, 20 1 5) . Risk factors for these more complex lacerations include nullipar­ ity, midline episiotomy, persistent OP position, operative vaginal delivery, Asian race, short perineal length, and increasing fetal birthweight (Ampt, 20 1 3; Dua, 2009; Gurol-Urganci, 20 1 3 ; Landy, 20 1 1 ) . Mediolateral episiotomy i s protective i n most, but not all, studies Ganga, 20 1 4; Raisanen, 20 1 1 ; Shmueli, 20 1 6) . Morbidity rates rise as laceration severity increases. Compared with simpler lacerations, anal sphincter injuries are associated with greater blood loss and puerperal pain. Wound disruption and infection rates are other risks (Goldaber, 1 993; Lewicy-Gaupp, 20 1 5). Stock and coworkers (20 1 3) reported that approximately 7 percent of 909 OASIS lacerations had complications. Long term, anal sphincter injuries are linked with approximately doubled rates of fecal incontinence compared with vaginl delivery without OASIS (Evers, 20 1 2; Gyhagen, 20 1 4) . Data on long-term dyspa­ reunia are limited, and rates are increased in some but not all stud­ ies (MoS, 2008; Otero, 2006; Salim, 2014; Sundquist, 20 1 2) . T o ensure appropriate repair, identiication and correct cat­ egorization is essential. Diagnosis rates of OASIS improve with clinical experience (ndrews, 2006) . Intrapartum endoanal ultrasound, performed in research studies, also boosts detection, and rates of clinically occult tears in primiparas range from 6 to 1 2 percent (Corton, 20 1 3; Faltin, 2005; Ozyurt, 20 1 5) . hat said, few data currently support routine intrapartum endoanal sonography, and the American College of Obstetricians and Gynecologists (20 1 6b) does not recommended i t (Walsh, 20 1 5) . Women with a prior OASIS have a higher recurrence rate compared with multiparas without prior OASIS (Baghestan, 20 1 2; Edozien, 20 14; Elfaghi, 2004) . That said, the risk mir­ rors that of primiparas in the general population and is low (Basham, 20 1 3 ; Boggs, 20 1 4; Priddis, 20 1 3) . Fetal macrosomia and operative vaginal delivery are notable risks in this cohort of parturients and can influence counseling in future pregnan­ cies. Speciically, patients may choose to deliver by cesarean to avoid repeat OASIS. his consideration may be most pertinent for those with prior postpartum anal incontinence, with OASIS complications requiring corrective surgery, or with psychological trauma (American College of Obstetricians and Gynecologists, 20 1 6b) . However, planned cesarean delivery is balanced against its associated operative risks discussed in Chapter 30 (p. 568) .

mirror those found with second-degree laceration, and their repairs are analogous. The midline episiotomy begins at the fourchette, incises the perineal body in the midline, and ends well before the external anal sphincter is reached. he incision length varies from 2 to 3 cm depending on perineal length and degree of tissue thinning. The mediolateral episiotomy begins at the midline of the fourchette and is directed to the right or left at an angle 60 degrees of the midline (Fig. 27- 14) . This angle accounts for perineal anatomy distortion during crowning and ultimately yields an incision 45 degrees of the midline for sutur­ ing (El-Din, 20 14; Kalis, 20 1 1 ) . The lateral episiotomy begins at point 1 to 2 cm lateral from the midline. It too is angled toward either the right or the left ischial tuberosity. Before episiotomy, analgesia may be provided by existing labor regional analgesia, by bilateral pudendal nerve blockade, or by local infiltration of I -percent lidocaine. Some instead advo­ cate 2.5-percent lidocaine-prilocaine cream (EMLA cream) , but this requires application an hour before expected delivery, which may be logistically diicult (Franchi, 2009; Kargar, 20 1 6) . I f episiotomy is performed unnecessarily early, incisional bleeding may be considerable before delivery. If it is performed too late, lacerations will not be prevented. Typically, episiot­ omy is completed when the head is visible during a contraction to a diameter of approximately 4 cm, that is, crowning. When used in conjunction with forceps delivery, most perform an epi­ siotomy after application of the blades. Few data directly compare midline and mediolateral types. As noted, midline episiotomy has a greater likelihood of associated anal sphincter lacerations (Coats, 1 980; de Leeuw, 200 1 ) . Short­ term rates of self-perceived pain and dyspareunia are similar or increased with mediolateral episiotomy (Fodstad, 20 1 3, 2 0 1 4; Sartore, 2004) .

• Episiotomy

Types

In contrast to spontaneous lacerations, perineotomy is intended incision of the perineum. Episiotomy is incision of the puden­ dum-the external genital organs. In common parlance, how­ ever, the term episiotomy often is used synonymously with perineotomy, a practice that we follow here. Obstetrical text­ books and organizational guidelines difer considerably in their description of episiotomy techniques. Kalis and associates (20 1 2) have presented a classifi c ation, and we agree with the need for terminology standardization. Midline and mediolateral episiotomies are the two main types and vary by the angle of perineal incision. Involved structures

--�F I G U R E 27- 1 4 A mediolatera l episiotomy is cut as the ba by's head crowns. Fingers a re insinuated between the peri neum a n d head. T h e i ncision beg ins i n the m id l i n e a n d is d irected toward the i psi latera l ischia l tu berosity at a n a ng l e 60 deg rees of the mid l i ne. (Reproduced with permission from Kenton K, Mueller M: Episiotomy and obstetric anal sphi ncter lacerations. In Yeom a n s ER, Hoffm a n BL, Gilstra p L C I I I , e t a l (eds): C u n n i n g h a m a n d G i l stra p's Operative Obstetrics, 3 rd ed. New York, McGraw- H i l i Ed u cation, 20 1 7.)

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Even fewer studies compare lateral episiotomy to either medio­ lateral or midline. One randomized trial compared lateral and mediolateral tpes in nulliparas. Groups did not difer in pain scores, in sexual qulity of life, or in vaginal or perineal trauma, including OASIS (Karbanova, 2014a,b; Necesalova, 20 1 6) . The authors also reported that mediolateral episiotomies required less time and suture for the repair. Thus, among the three, mediolateral episiotomy may be the preferred incision to reduce OASIS rates. I nd icati o n s

In the past, routine episiotomy was practiced to avoid a ragged laceration and to limit postoperative pain and anal sphinc­ ter injury rates. But, a Cochrane review of randomized trials showed lower rates of severe perineal/vaginal trauma in women

A

c

managed with a restrictive, that is, selective use of episiotomy for spontaneous delivery rather than with routine episiotomy Qiang, 20 1 7) . Importantly, this review did not discern between midline and mediolateral episiotomies. The American College of Obstetricians and Gynecologists (20 1 6b) has concluded that restricted use of episiotomy is pre­ ferred to routine use. We are of the view that the procedure should be applied selectively for appropriate indications. Thus, episiotomy can be considered for indications such as shoulder dys­ tocia, breech delivery, fetal macrosomia, operative vaginal deliv­ eries, persistent OP positions, markedly short perineal length, and other instances in which failure to perform an episiotomy will result in signiicant perineal rupture. The final rule is that there is no substitute for surgical judgment and common sense.

B

o

F I G U R E 27-1 5 Med iolatera l episiotomy repair. A. The vag inal epithel i u m and deeper tissues a re closed with a sing le, contin uous, locking sutu re. The angle seems less acute now (a pproximately 45°) since the perineum is no longer distended. B. Ater the vag i n a l component of the laceration is repaired, deeper peri nea l tissues a re reapproxi mated by a sing le, conti n uous, nonlocki ng sutu re. Small episiotomies may not require this deeper layer. C. With a similar contin uous, non locki ng techniq ue, the su perficial transverse perineal and b u l bospongiosus muscles are reap­ proxi mated. D. Last, the perineal skin is closed using a su bcuticu lar stitch . (Reproduced with permission from Kenton K, M ueller M: Episiotomy and o bstetric anal sphincter lacerations. In Yeomans ER, Hoffma n BL, Gilstrap LC I I I, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3 rd ed. New York, McGraw-Hili Ed ucation, 201 7.)

Vag i n a l Del ivery

With this new approach, epIsIotomy rates have dropped. Oliphant and coworkers (20 1 0) used the National Hospital Discharge Survey to analyze episiotomy rates between 1 979 and 2006 in the United States. hey noted a 75-percent decline in the age-adjusted episiotomy rate. In the United States in 20 1 2 episiotomy was performed in approximately 12 percent of vaginal births (Friedman, 20 1 5) . • Laceration and Episiotomy Repairs

Typically, perineal repairs are deferred until the placenta has been delivered. his policy permits undivided attention to the signs of placental separation and delivery. A further advantage is that the repair is not interrupted or disrupted by placenta deliv­ ery. his is especially true if manual removal must be performed. The major disadvantage is continuing blood loss until the repair is completed. Direct pressure from an applied gauze sponge will help to limit this volume.

A

c

For suitable repair, an understanding of perineal support and anatomy is necessary and is discussed in Chapter 2 (p. 1 9) . Adequate analgesia is imperative, and women without regional analgesia can experience high levels of pain during perineal suturing. Again, locally injected lidocaine can be used solely or as a supplement to bilateral pudendal nerve blockade. In those with epidural analgesia, additional dosing may be necessary. First-degree lacerations do not always require repair, and sutures are placed to control bleeding or restore anatomy. Here, few data guide suture selection, and ine-gauge absorbable or delayed-absorbable suture or adhesive glue is suitable. Second-degree laceration correction as well as midline and mediolateral episiotomy repairs include similar steps. Namely, these close the vaginal epithelium and reapp roxi­ mate the bulbospongiosus and supericial transverse perineal muscles during restoration of the perineal body ( Figs. 2 7- 1 5 and 27- 1 6) . For this, most studies support a continuous

B

D

F I G U R E 27- 1 6 Midline episiotomy repair. A. An a nchor stitch is placed a bove the wou nd a pex to beg i n a running, locki n g closure with 2-0 suture to close the vag i n a l epithe l i u m a nd deeper tissues a nd rea pprox i mate the hymeneal ri ng. B. A tra nsition stitch red i rects s u t u r­ ing from the vag i n a to the peri neu m . C. The superficial tra n sverse peri neal a n d b u l bos po ngiosus m uscles a re rea pproxi mated u s i ng a conti n uous, non locki ng tech n i q u e with the same length of sutu re. This aids restoration of the peri neal body for long-term su pport. D. The

conti n uous suture is then ca rried u pward a s a s u bcuticu lar stitch. The fi nal knot is tied proxim a l to the hymeneal ring. (Reproduced with perm ission from Kenton K, Mueller M : E pisiotomy a nd obstetric anal sphi ncter lacerations. I n Yeomans E R, Hoffm a n BL, G i lstrap LC I I I, et al (eds): C u n n i n g h a m and G i l strap's Operative Obstetrics, 3 rd ed. New York, McGraw- H i l i Ed ucation, 20 1 7.)

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Del ivery

suturing method, which is faster than placing interrupted sutures and, with few exceptions, yields less pain (Grant, 200 1 ; Kettle, 20 1 2; Kindberg, 2008; Valenzuela, 2009) . Blunt needles are suitable and likely decrease the incidence of needle-stick injuries (El-Refaie, 20 1 2; Mornar, 2008). Com­ monly used suture materials are 2-0 polyglactin 9 1 0 (Vicryl) or chromic catgut. With the former, a decrease in postsur­ gical pain and lower risk of wound dehiscence are cited as major advantages Q allad, 20 1 6; Kettle, 20 1 0) . Closures with traditional polyglactin 9 1 0, however, occasionally require removal of residual suture from the repair site because of pain or dyspareunia. This disadvantage may be reduced by using a rapidly absorbed polyglactin 9 1 0 (Vicryl Rapide) (Bharathi, 20 1 3; Kettle, 2002; Leroux, 2006) . For third-degree laceration repair, two methods are avail­ able to repair the external anal sphincter. The irst is an end­ to-end technique, which we prefer, and is shown in Figure 27- 1 7. Initially, the cut ends of the external anal sphincter, which often retract, are isolated and brought to the midline. I mportantly, the strength of this closure is derived from the connective tissue surrounding the sphincter-often called the capsule-and not the striated muscle. Thus, serial interrupted

sutures incorporate sphincter fibers and perisphincter connec­ tive tissue, to bring sphincter ends together. here are few evidence-based data to guide suture selection for sphincter repair, but delayed-absorbable material can provide sustained tensile strength during healing. This theory is supported by the above study by J all ad and coworkers (20 1 6) , which showed higher perineal breakdown rate following OASIS repair with chromic gut. With the overlapping technique, the ends of the external anal sphincter are brought to the midline and lie atop one another. This method is only suitable for type 3c lacerations-those involving the external and internal anal sphincter. Two rows of mattress sutures travel through both sphincter ends to recre­ ate the anal ring. In comparing the two methods, neither yields superior long-term anatomical or functional results (Farrell, 20 1 2; Fernando, 20 1 3; Fitzpatrick, 2000) . Also with type 3c lacerations, the lAS is repaired before the EAS and is described next. With fourth-degree laceration repairs, the torn edges of the rectal mucosa are reapproximated (Fig. 27- 1 8) . At a point 1 cm proximal to the wound apex, sutures are placed approximately 0.5 cm apart in the rectal muscularis and do not enter the anorectal lumen. Clinicians oten use 4-0 polyglactin 9 1 0 or chromic gut for this running suture line. Some recom­ mend a second reinforcing layer above this (Hale, 2007) . If this is not done, then the next layer to cover the anorec­ tal mucosa is formed by reapproxima­ tion of the internal anal sphincter. his running, nonlocking closure is com­ pleted with 3-0 or 4-0 suture (see Fig. 27- 1 8B). Following any repair, needle and sponge counts are reconciled and recorded in the delivery note. Superior For reduction of infectious mor­ Posterior capsule bidity associated with anal sphincter lacerations, a single dose of antibiotic at the time of repair is recommended by the American College of Obste­ tricians and Gynecologists (20 1 6c) . Inferior Anterior his practice is supported by evi­ dence (Buppasiri, 20 1 4; Duggal, 2008; Lewicky-Gaupp, 20 1 5 ; Stock, 20 1 3) . A single dose of a second­ generation cephalosporin is suitable, or clindamycin for penicillin-allergic Figure of eight women. With OASIS, postopera­ tively, stool softeners are prescribed F I G U R E 27- 1 7 In overview, with end-to-end a pproxi mation of the external anal sphincter (EAS), for a week, and enemas and supposi­ a sutu re is placed through the EAS muscle, and four to six simple i nterru pted 2-0 or 3-0 sutu res of polyg lactin 9 1 0 a re placed at the 3, 6, 9, and 1 2 o'clock positions through the perisphincter con­ tories are avoided. nective tissue. To begin, disrupted ends of the striated EAS muscle and ca psule a re identified and Unfortunately, normal function is g rasped. The first suture is placed posteriorly to maintai n clear exposu re. Another suture is then not always ensured even with correct placed i nferiorly at the 6 o'clock position. The sphincter muscle fibers a re next reapposed by a and complete surgical repair. Some fig u re-of-eight stitch. Last, the remainder of the fascia is closed with a stitch placed a nterior to the women may experience continuing sphincter cyli nder and again with once placed su perior to it. (Reprod uced with perm ission from fecal incontinence caused by injury Kenton K, Mueller M: Episiotomy a nd obstetric anal sphi ncter lacerations. In Yeomans ER, Hofman to the innervation of the pelvic Boor BL, Gi lstrap LC I I I, et al (eds): Cunningham and Gilstra p's Operative ObstetriCS, 3 rd ed. New York, McGraw-Hili Ed ucation, 20 1 7.) musculature (Roberts, 1 990) .

I�

Vag i nal Del ivery

A

B

F I G U R E 27- 1 8 A. Sutu ring of the a norectal mucosa beg i ns above the laceration a pex using a conti n uous, non locki ng method with fine­ gauge a bsorba ble sutu re such as 3-0 or 4-0 chromic g ut or polyg lacti n 9 1 0. Sutu res a re placed through the anorectal s u bmucosa approxi­ mately 0.5 cm apart down to the a n a l verge. B. A second rei nforci ng layer uses 3-0 delayed-absorba ble suture in a conti n uous, nonlocking fashion. This incorporate the torn ends of the internal a nal sphincter (lAS), which can be identified as the glistening white fibrous structure lyi ng between the anal ca nal subm ucosa a nd the fibers of the external anal sphincter. I n many cases, the lAS retracts latera lly a nd m u st be soug ht and retrieved for repa ir. (Reprod uced with permission from Kenton K, Mueller M: Episiotomy a n d obstetric anal sphi ncter lacerations. I n Yeoma n s ER, Hofman BL, Gilstra p LC I I I, et al (eds): Cu n n ingham and Gilstrap's Operative Obstetrics, 3 rd ed. New York, McGraw-Hili Ed ucation, 201 7.)

• Perineal Laceration Care

Initially, locally applied ice packs help reduce swelling and allay discomfort (de Souza Bosco Paiva, 20 1 6) . In subsequent days, warm sitz baths aid comfort and hygiene. Additionally, a small squirt botde of warm water can cleanse the site after voiding or stooling. For pain, topical application of 5-percent lidocaine ointment was not efective in relieving episiotomy or perineal laceration discomfort in one randomized trial (Minassian, 2002) . Oral analgesics containing codeine provide considerable relie. For lesser degree of discomfort, NSAID tablets can be given. Because pain may signal a large vulvar, paravaginal, or ischio­ rectal fossa hematoma or perineal cellulitis, these sites should be examined carefully if pain is severe or persistent. Manage­ ment of these complications is discussed in Chapters 37 and 4 1 (pp. 674 and 764). In addition to pain, urinary retention may complicate episiotomy recovery (Mulder, 20 1 2, 20 1 6) . Its management is described in Chapter 36 (p. 660) . For those with second-degree lacerations or anal sphinc­ ter tears, intercourse is usually proscribed until after the irst puerperal visit at 6 weeks. Compared with women with intact perineum, those with perineal trauma show higher rates of delayed intercourse at 3 and 6 months, but not at 1 year (McDonald, 20 1 5 ; Rldestad, 2008; Signorello, 200 1 ) .

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539

C H A PT E R 2 8

B reec h De l ive ry

C LASSIFICATION OF BREECH PRESENTATIONS . . . . . . . 539 DIAGNOSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 540 ROUTE OF DELIVERY . . . . . . . . . . . . . . . . . . . . . . . . . . . . 540 LABOR AND DELIVERY MANAGEMENT . . . . . . . . . . . . . 543 PARTIAL BREECH EXTRACTION . . . . . . . . . . . . . . . . . . . 544 TOTAL BREECH EXTRACTION . . . . . . . . . . . . . . . . . . . . . 548

extremities and buttocks. With a frank breech, lower extremi­ ties are flexed at the hips and extended at the knees, and thus the feet lie close to the head (F ig. 28- 1 ) . With a complete breech, both hips are lexed, and one or both knees are also lexed (Fig. 28-2) . With an incomplete breech, one or both hips are extended. As a result, one or both feet or knees lie below the breech, such that a foot or knee is lowermost in the birth canal (Fig. 28-3) . A footling breech is an incomplete breech with one or both feet below the breech.

EXTERNAL CEPHALIC VERSION. . . . . . . . . . . . . . . . . . . . 549

The essential prerequisite or the successful peormance of breech extraction lies in the complete dilatation of the cer­ vix and the absence of any serious mechanical obstacle. It is true that in a certain number ofcases extraction through an impeecty dilated cervix is possible, but this is usualy fected ony at the cost ofdeep cervical tears. -J . Whitridge Williams ( 1 903) Near term, the fetus typically has spontaneously assumed a cephalic presentation. Conversely, if the fetal buttocks or legs enter the pelvis before the head, the presentation is breech. This fetal lie is more common remote from term, as earlier in pregnancy each fetal pole has similar bulk. At term, breech pre­ sentation persists in approximately 3 to 5 percent of singleton deliveries (Cammu, 20 1 4; Lyons, 20 1 5 ; Macharey, 20 1 7) .

CLASSIFICATION OF BREECH PRESENTATIONS he categories of frank, complete, and incomplete breech pre­ sentations difer in their varying relations between the lower

F IG U R E 28- 1 Fra n k breech presentatio n .

540

Delive ry

F I G U R E 28-2 Com plete breech presentatio n .

Of term breech fetuses, the neck may be extremely hyperex­ tended in perhaps 5 percent, and the term stargazingetus is used (Cimmino, 1 975). With these, fetal or uterine anomalies may be more prevalent and are sought if not previously identified (Phelan, 1 983). With this hyperextension, vaginal delivery can result in injury to the cervical spinal cord. hus, if identified at term, this is an indication for cesarean delivery (Westgren, 1 98 1) . hat said, flexion itself may be implicated, s cses of spinal cord injury have been reported following uneventul cesarean delivery of such fetuses (Hernandez-Marti, 1 984). With transverse lie and similar hyperextension of the fetal neck, the term iyingetus is applied.

DIAG NOSIS

• Risk Factors

Understanding the clinical settings that predispose to breech pre­ sentation can aid early recognition. Other than early gestational age, risk factors include extremes of amnionic fluid volume, mul­ tifetal gestation, hydrocephaly, anencephaly, structural uterine abnormalities, placenta previa, pelvic tumors, and prior breech delivery. One study found that following one breech delivery, the recurrence rate for a second breech presentation was 1 0 percent, and for a subsequent third breech it was 28 percent (Ford, 20 1 0) . • Examination

Leopold maneuvers to ascertain fetal presentation are discussed in Chapter 22 (p. 424) . With the irst maneuver, the hard, round fetal head occupies the fundus. he second maneu­ ver identifies the back to be on one side of the abdomen and the small parts on the other. With the third maneuver, if not engaged, the softer breech is movable above the pelvic inlet.

F I G U RE 28-3 I ncom plete breech presentation.

After engagement, the fourth maneuver shows the breech to be beneath the symphysis. he accuracy of this palpation var­ ies (Lydon-Rochelle, 1 993; Nassar, 2006) . hus, with sus­ pected breech presentation-or any presentation other than cephalic-sonographic evaluation is indicated. During cervical examination with a frank breech, no feet are appreciated, but the fetal ischil tuberosities, sacrum, and anus are usually palpable. Ater urther fetal descent, the external genitalia may also be distinguished. When labor is prolonged, the fetal but­ tocks may become markedly swollen, rendering digital diferentia­ tion of a face and breech diicult. In some cases, the anus may be mistaken for the mouth and the ischial tuberosities for the malar eminences. With careul examination, however, the inger encounters muscular resistance with the anus, whereas the hard, less yielding jaws are felt through the mouth. The finger, upon removal from the anus, may be stained with meconium. The mouth and malar eminences form a triangular shape, whereas the ischial tuberosities and anus lie in a straight line. With a complete breech, the feet may be felt alongside the buttocks. In footling presentations, one or both feet are inferior to the buttocks. The fetal sacrum and its spinous processes are palpated to establish position. As with cephalic presentations, fetal position is designated to reflect the relations of the fetal sacrum to the maternal pelvis. Positions include left sacrum anterior (LSA) , right sacrum anterior (RSA) , left sacrum posterior (LSP) , right sacrum posterior (RSP) , and sacrum transverse (ST) .

ROUTE OF DELIVERY Multiple factors aid determination of the best delivery route for a given mother-fetus pair. These include fetal characteristics,

B reech D e l ivery

maternal pelvic dimensions, coexistent pregnancy complications, provider experience, patient preference, hospital capabilities, and gestational age. Compared with their term counterparts, preterm breech fetuses have distinct complications related to their small size and immaturity. For example, rates of head entrapment, birth trauma, and perinatal mortality can be greater. Accordingly, separate dis­ cussions of term and preterm breech fetuses are more appropriate. • Term Breech Fetus Current obstetrical thinking regarding vaginal delivery of the term breech fetus has been tremendously inluenced by results of the Term Breech Trial (Hannah, 2000) . his trial included 1 04 1 women randomly assigned to planned cesarean and 1 042 to planned vaginal delivery. In the planned vaginal delivery group, 57 percent were actually delivered vaginally. Planned cesarean delivery was associated with a lower risk of perinatal mortality compared with planned vaginal delivery-3 per 1 000 versus 1 3 per 1 000. Cesarean delivery was also associated with a lower risk of "serious" neonatal morbidity- 1 .4 versus 3.8 percent. Short­ term maternal morbidity was similar between groups. Critics of the Term Breech Trial emphasize that fewer than 1 0 percent of candidates underwent radiological pelvimetry. Also, most of the outcomes included in the "serious" neonatal morbidity composite did not actually portend long-term infant disability (Whyte, 2004) . Since that trial, however, additional data favoring cesarean delivery has come from the World Health Organization (Lum­ biganon, 20 1 0) . From their evaluation of more than 1 00,000 deliveries from nine participating Asian countries, they reported improved perinatal outcomes for the term breech fetus with planned cesarean compared with planned vaginal delivery. Other studies have evluated neonatal outcome with cesarean delivery and also found lowered neonatal morbidity and mortality rates (Hartnack Tharin, 20 1 1 ; Lyons, 20 1 5; Rietberg, 2005; Vistad, 20 1 5) . From their metaanalysis, Berhan and Haileamlak (20 1 6) calculate absolute risk of perinatal mortality to be 0.3 percent and of fetal birth trauma or neurological morbidity to be 0.7 percent. In contrast, other studies support vaginal delivery as a suit­ able option at term (Hofmeyr, 20 1 5a) . he Presentation et Mode dAccouchement-PEMODA study-which translates as presentation and mode of delivery-showed no diferences in corrected neonatal mortality rates and neonatal outcomes according to delivery mode (Goinet, 2006) . his French pro­ spective observational study involved more than 8000 women with term breech singletons. Strict criteria were used to select 2526 of these for planned vaginal delivery, and 71 percent of that group were delivered vaginally. Similarly, data from the Lille Breech Study Group in France showed no excessive mor­ bidity in term breech singletons delivered vaginally provided strict fetal biometric and maternal pelvimetry parameters were applied (Michel, 20 1 1 ) . Other smaller studies support these findings as long as guidelines are part of the selection process (Alarab, 2004; Giuliani, 2002; Toivonen, 20 1 2) . Long-term evidence i n support o f vaginal breech delivery comes from Eide and associates (2005). These investigators analyzed intel­ ligence testing scores of more than 8000 men delivered breech and

found no diferences in intellectual performance in those undergo­ ing vaginal or cesarean delivery. Also, a 2-year follow up from the Term Breech trial showed similar risks for death and for neurode­ velopmental delay between delivery groups (Whyte, 2004). Despite evidence on both sides of the debate, at least in the United States, rates of planned vaginal delivery attempts con­ tinue to decline. And as predicted, the number of skilled pro­ viders able to safely select and vaginally deliver breech fetuses continues to dwindle (Chinnock, 2007) . Moreover, o bvious medicolegal concerns make physician training in such deliver­ ies diicult. In response, some institutions have developed birth simulators to improve resident competence in vaginal breech delivery (Deering, 2006; Maslovitz, 2007) . • Preterm Breech Fetus

In contrast to the term breech fetus, there are no randomized trials regarding delivery of the preterm breech fetus. Moreover, study comparisons are oten made diicult by lumping, splitting, or overlapping of preterm gestational age groups. All that said, it would appear that for the preterm breech fetus, planned cesar­ ean delivery confers a survival advantage compared with planned vaginal delivery. Reddy and associates (20 1 2) reported data from deliveries between 24 and 32 weeks' gestation. For breech fetuses within these gestational ages, attempting vaginal delivery yielded a low success rate, and those completed were associated with higher neonatal mortality rates compared with planned cesar­ ean delivery. Other investigations have reported similar findings (Bergenhenegouwen, 20 14; Demirci, 20 1 2; Muhuri, 2006) . For preterm fetuses in younger subgroups-23 to 28 weeks­ the data are more conflicting, and some studies describe no improved survival rate with planned cesarean delivery (Bergen­ henegouwen, 20 1 5; Kayem, 20 1 5; Thomas, 20 1 6) . For periviable etuses, deined by them as 20 to 25 6/7 weeks, a consensus work­ shop of perinatal organizations concluded that "available data do not consistently support routine cesarean delivery to improve perinatal mortality or neurological outcomes for early preterm infants" (Raju, 20 1 4). A subsequent joint statement by the Amer­ ican College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine (20 1 7) suggested consideration for cesarean delivery for periviable fetuses beginning at 23 °/7 weeks, with a recommendation for cesarean delivery at 25 °1 weeks. For more mature preterm breech fetuses, that is, between 32 and 37 weeks, again there are sparse data to guide delivery route selection. Bergenhenegouwen and coworkers (20 1 5) studied more than 6800 breech deliveries in a subgroup between 32 and 37 weeks. With planned cesarean delivery, they found similar perinatal mortality rates but less composite mortality and severe morbidity. It appears in this subgroup that fetal weight rather than gestational age is likely more important. he Maternl-Fetal Nfedicine Com­ mittee of the Society of Obstetricians and Gynaecologists of Can­ ada (SOGC) states that vaginal breech delivery is reasonable when the estimated fetal weight is >2500 g (Kotaska, 2009) . There are especial concerns for delivery of the second noncephalic-presenting twin fetus that are discussed in Chapter 45 (p. 888). In the United States, all these findings shape practice, and cesarean delivery is almost uniformly favored for the preterm breech fetus for which resuscitation is planned.

54 1

542

Del ivery • Delivery Complications

Increased rates of maternal and perinatal morbidity can be antic­ ipated with breech presentations. For the mother, with either cesarean or vaginal delivery, genital tract laceration can be prob­ lematic. With cesarean delivery, added stretching of the lower uterine segment by forceps or by a poorly molded fetal head can extend hysterotomy incisions. With vaginal delivery, especially with a thinned lower uterine segment, delivery of the atercom­ ing head through an incompletely dilated cervix or application of forceps may cause vaginal wall or cervical lacerations, and even uterine rupture. Manipulations may also extend an episiotomy, create deep perineal tears, and increase infection risks. Anesthesia suicient to induce appreciable uterine relaxation during vaginal delivery may cause uterine atony and in turn postpartum hemor­ rhage. Maternal death is rare, but rates appear higher in those with planned cesarean delivery for breech presentation-a case fatality rate of 0.47 maternal deaths per 1 000 births (Schutte, 2007) . Last, the risks associated with vaginal breech delivery are balanced against general cesarean delivery risks described in Chapter 30 (p. 568). Long-term, cesarean risks include those associated with repeated hysterotomy or with vaginal birth ater cesarean-VBAC-further described in Chapter 3 1 (p. 593) . For the fetus, prematurity and its complications are frequently comorbid with breech presentation. Rates of congenital anoma­ lies are also greater (Cammu, 20 14; Mostello, 20 1 4) . Compared with cephalic presentation, umbilical cord prolapse is more fre­ quent with breech fetuses (Behbehani, 20 1 6; Obeidat, 20 1 0) . Birth trauma can include fractures o f the humerus, clavicle, and femur (Canpolat, 20 1 0; Matsubara, 2008) . In some cases, trac­ tion may separate scapular, humeral, or femoral epiphyses (Lam­ rani, 20 1 1 ) . Trauma is more common with vaginal births, but fetal trauma is also seen with cesarean deliveries. Rare traumatic injuries may involve soft tissues. Brachial plexus injury and paralysis is one example (Foad, 2008) . The spinal cord may be injured or even severed, or vertebrae frac­ tured, especially if great force is employed (Vialle, 2007) . Hematomas of the sternocleidomastoid muscles occasionally develop after delivery but usually disappear spontaneously. Last, genital injury may follow breech delivery (Saroha, 20 1 5) . Some perinatal outcomes may b e inherent t o the breech position rather than delivery. For example, development of hip dysplasia is more common in breech compared with cephalic presentation and is unafected by delivery mode (de H undt, 20 1 2; Fox, 20 1 0; Ortiz-Neira, 20 1 2) . • Imaging Techniques

In many fetuses-especially those that are preterm-the breech is smaller than the atercoming head. Moreover, unlike cephalic presentations, the head of a breech-presenting fetus does not undergo appreciable molding during labor. Thus, if vaginal deliv­ ery is considered, fetal size, type of breech, and degree of neck lexion or extension are evaluated. In addition, pelvic dimensions are assessed to avoid head entrapment from cephalopelvic dispro­ portion. Sonography and fetal pelvimetry are options. Sonographic fetal evaluation will have been performed in most cases as part of prenatal care. If not, gross fetal abnormalities, such as hydrocephaly or anencephaly, can be rapidly ascertained

with sonography. This will identiy many fetuses not suitable for vaginal delivery. It will also help to ensure that a cesarean delivery is not performed under emergency conditions for an anomalous fetus with no chance of survival. Head flexion can usually also be determined sonographi­ cally, and for vaginal delivery, the fetal head should not be extended (Fontenot, 1 997; Rojansky, 1 994) . If imaging is uncertain, then simple two-view radiography of the maternal abdomen is useful to define fetal head inclination. Sonographic identification of a nuchal arm may warrant cesarean delivery to avoid neonatal harm (Sherer, 1 989). he accuracy of fetal weight estimation by sonography is not altered by breech presentation (McNamara, 20 1 2) . Although variable, many protocols use fetal weights > 2500 g and < 3800 to 4000 g or evidence of growth restriction as exclusion crite­ ria for planned vaginal delivery (Azria, 20 1 2; Kotaska, 2009) . Similarly, a biparietal diameter (BPD) >90 to 1 00 mm is often considered exclusionary (Giuliani, 2002; Roman, 2008) . Pelvimetry assesses the maternal bony pelvis before vaginal delivery, and one-view computed tomography (CT) , magnetic resonance (MR) imaging, or plain film radiography is suitable. Comparative data among these modalities for pelvimetry are lack­ ing, but CT is favored due to its accuracy, low radiation dose, and widespread availability (homas, 1 998). At Parkland Hospital, we use CT pelvimetry when possible to assess the critical dimensions of the pelvis (Chap. 2, p. 30) . Although variable, some suggest specific measurements to permit a planned vaginal delivery: inlet anteroposterior diameter : 1 0. 5 cm; inlet transverse diameter : 1 2.0 cm; and midpelvic interspinous distance : 1 0.0 cm (Azria, 20 1 2; Vendittelli, 2006). Some have recommended maternal­ fetal biometry correlation. Appropriate values include: the sum of the inlet obstetrical conjugate minus the fetal BPD is : 1 5 mm; the inlet transverse diameter minus the BPD is :25 mm; and the midpelvis interspinous distance minus the BPD is :0 mm (Michel, 20 1 1) . With MR imaging, Hofmann and colleagues (20 1 6) found vaginal delivery success rates of 79 percent in selected candidates if the interspinous distance exceeded 1 1 cm. • Decision-Making Summary

Currently, the American College of Obstetricians and Gyne­ cologists (20 1 6b) recommends that "the decision regarding the mode of delivery should depend on the experience of the health-care provider" and that "planned vaginal delivery of a term singleton breech fetus may be reasonable under hospital­ specific protocol guidelines." These guidelines have been echoed by other obstetrical organizations (Kotaska, 2009; Royal Col­ lege of Obstetricians and Gynaecologists, 2006) . Risks versus beneits are weighed and discussed with the patient. If possible, this is preferably done before admission. A diligent search is made for other complications, actual or anticipated, that might warrant cesarean delivery. Common circumstances are listed in Table 28- 1 . For a favorable outcome with any breech deliv­ ery, at the very minimum, the birth canal must be suiciently large to allow passage of the fetus without trauma. he cervix must be fully dilated, and if not, then a cesarean delivery nearly always is the more appropriate method of delivery if suspected fetal compromise develops.

B reech Del ivery

TABLE 28-1 . Factors Favoring Cesarean Del ivery of the

Breech Fetus

Lack of operator experie n ce Pat ient req uest for cesa rea n del ivery La rge fetu s: > 3 800 to 4000 g Apparently h ea lthy a nd via b l e p r eterm fetus either with active l a bo r o r with i nd i cated delivery Seve re feta l -g rowth restriction Feta l a n o m a l y i nco m patible with vag i n a l del ive ry Prior peri nata l death or neonatal b i rth tra u m a I ncomp lete o r foot l i n g breech p resentation Hyperextended h ead Pelvic contraction o r u nfavora ble pelvic shape dete r m i n ed c l i n i ca l ly or with pelvimetry Prior cesa rea n d e l ivery

LABOR AND DELIVERY MANAGEMENT

• Vaginal Delivery Methods

The conduct of both labor and delivery difer between cephalic and breech presentations. First, breech labor in general proceeds more slowly, but steady cervical progress is a positive indicator of adequate pelvic proportions (Lennox, 1 998) . Vaginal breech delivery is accomplished by one of three methods. With sponta­ neous breech delivery, the fetus is expelled entirely without any traction or manipulation other than support of the newborn. With partial breech extraction, the fetus is delivered spontane­ ously as far as the umbilicus, but the remainder of the body is delivered by provider traction and assisted maneuvers, with or without maternal expulsive eforts. With total breech extraction, the entire fetal body is extracted by the provider. • Labor Induction and Augmentation

As with many other aspects of breech position, induction or augmentation of labor is controversial. Here again, data are limited and mostly retrospective. With labor induction, Burgos and coworkers (20 1 7) reported equivalent vaginal delivery rates compared with spontaneous labor. With induction, however, they reported higher rates of neonatal intensive care unit admis­ sion. But, others have found similar perinatal outcome and cesarean delivery rates Qarniat, 20 1 7; Marzouk, 20 1 1 ) . Finally, others described greater cesarean delivery rates with induction but similar neonatal outcomes (Macharey, 20 1 6) . I n many studies, successful vaginal delivery i s associated with orderly labor progression. hus, some protocols avoid augmen­ tation for the breech-presenting fetus, whereas others recom­ mend it only for hypotonic contractions (Alarab, 2004; Kotaska, 2009) . In women with a viable fetus, at Parkland Hospital, we attempt amniotomy induction but prefer cesarean delivery instead of pharmacological labor induction or augmentation.

• Labor Management

On arrival to the labor unit, surveillance offetal heart rate and uter­ ine contractions begins, and immediate recruitment of necessary staf includes: ( 1 ) a provider skilled in the art of breech extraction,

(2) an associate to assist with the delivery, (3) anesthesia personnel who can ensure adequate analgesia or anesthesia when needed, and (4) an individual trained in newborn resuscitation. For the mother, intravenous access is obtained. his allows, if needed, emergency induction of anesthesia or maternal resuscitation following hemor­ rhage from lacerations or from uterine atony. At admission, the status of the membranes and progression of labor are assessed. Knowledge regarding cervical dilatation, cervical efacement, and presenting part station is essential for preparation. If labor is too far advanced, pelvimetry may be unsafe if fetal expulsion in the radiology department is a pos­ sibility. This alone, however, should not force the decision for cesarean delivery. As mentioned, stepwise labor progression itself is a good indicator of pelvic adequacy (Biswas, 1 993) . Sonographic assessment, described earlier, is completed. Ulti­ mately, the choice of abdominal or vaginal delivery is based on factors discussed earlier and listed in Table 28- 1 . During labor, one-on-one nursing is ideal because of cord prolapse risks, and physicians must be readily available for such emergencies. Guidelines for monitoring the high-risk fetus are applied (Chap. 24, p. 478). For first-stage labor, while most clini­ cians prefer continuous electronic monitoring, the fetal heart rate is recorded at a minimum of every 1 5 minutes. A scalp electrode can be safely aixed to the buttock, but genitalia are avoided. If a nonreassuring fetal heart rate pattern develops, then a decision must be made regarding the necessity of cesarean delivery. When membranes rupture, either spontaneously or arti­ ficially, the cord prolapse risk is appreciable and is increased when the fetus is small or when the breech is not frank. There­ fore, vaginal examination is performed immediately following rupture, and special attention is directed to the fetal heart rate for the irst 5 to 1 0 minutes thereafter. For women in labor with a breech presentation, continu­ ous epidural analgesia is advocated by some. This may increase the need for labor augmentation and prolong second-stage labor (Chadha, 1 992; Confino, 1 985). hese potential disadvantages are weighed against the advantages of better pain relief and increased pelvic relaxation should extensive manipulation be required. Anal­ gesia must be suicient for episiotomy, for breech extraction, and for Piper forceps application. Nitrous oxide plus oxygen inhala­ tion can provide further relief from pain. If general anesthesia is required, it must be induced quickly.

• Spontaneous Breech Delivery

Similar to vertex delivery, spontaneous expulsion of a breech fetus entails sequential cardinal movements. First, engagement and descent of the breech usually take place with the bitro­ chanteric diameter in one of the oblique pelvic diameters. The anterior hip usually descends more rapidly than the posterior hip, and when the resistance of the pelvic Boor is met, internal rotation of 45 degrees usually follows, bringing the anterior hip toward the pubic arch and allowing the bitrochanteric diameter to occupy the anteroposterior diameter of the pelvic outlet. If the posterior extremity is prolapsed, however, it, rather than the anterior hip, rotates to the symphysis pubis. After rotation, descent continues until the perineum is dis­ tended by the advancing breech, and the anterior hip appears at the vulva. By lateral lexion of the fetal body, the posterior

543

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De l i ve ry

F I G U R E 28-4 The h i ps of the fra n k breech a re deliveri n g over the peri n e u m . The a nterior hip u s u a l ly del ivers fi rst.

hip then is forced over the perineum, which retracts over the fetal buttocks, thus allowing the fetus to straighten out when the anterior hip is born (Fig. 28-4) . he legs and feet follow the breech and may be born spontaneously or require aid. After the birth of the breech, there is slight external rotation, with the back turning anteriorly as the shoulders are brought into relation with one of the oblique diameters of the pelvis. The shoulders then descend rapidly and undergo internal rota­ tion, with the bisacromial diameter occupying the anteropos­ terior plane. Immediately following the shoulders, the head, which is normally sharply flexed on the thorax, enters the pelvis in one of the oblique diameters and then rotates to bring the posterior portion of the neck under the symphysis pubis. The head is then born in flexion. The breech may engage in the transverse diameter of the pelvis, with the sacrum directed anteriorly or posteriorly. he mechanism oflabor in the transverse position difers only in that internal rotation is through an arc of 90 rather than 45 degrees. Infrequently, rotation renders the back of the fetus to lie pos­ teriorly instead of anteriorly. Such rotation is prevented if pos­ sible. Although the head can be delivered by allowing the chin and face to pass beneath the symphysis, the slightest traction on the body may cause extension of the head, which increases the diameter of the head that must pass through the pelvis.

F I G U R E 28-5 To del iver the left leg, two fi ngers of the provider's left hand a re placed beneath and pa ra l l el to the fem u r. The thigh is then slig htly a bd u cted a nd pressu re from the fi ngertips i n the popl itea l fossa should i nd uce knee flexion a n d bring the foot with i n reach. The foot is then g rasped to gently del iver the enti re leg outside the vag i na. A similar proced u re is fol lowed on the rig ht. (Fi g u res 28-5 though 28-8: Reprod uced with perm ission from Yeo m a n s ER: Vag i n a l breech del ivery. In Yeo m a n s E R, Hoffma n B L, G i l strap LC I I I , et al (eds): C u n n i n g h a m a nd G i l strap's Operative Obstetrics, 3 rd ed. New (ork, McGraw-H i l i Ed ucation, 201 7.)

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.

J

�

• Partial B reech Extraction

With breech delivery, successively larger and less compressible parts are born. Thus, spontaneous expulsion is the exception, and vaginal delivery typically requires skilled provider partici­ pation for the fetus to navigate the birth canal. Noteworthy clinical pearls are provided by Yeomans (20 1 7) in the third edition of Cunningham and Gilstrap s Operative Obstetrics. First, with all breech deliveries, unless the perineum is con­ siderably lax, an episiotomy is made and is an important adjunct to delivery. As discussed in Chapter 27 (p. 529), mediolateral episiotomy may be preferred for its lower associated risk of anal

F I G U R E 28-6 To del iver the body, thu mbs a re placed over the sacrum, and each index fi nger wra ps over the top of the corre­ spo n d i n g fetal i l iac c rest. Gentle downwa rd traction is appl ied u ntil the sca pu las a re clearly visi ble. (Reprod uced with permission from Yeoma n s ER: Vag i n a l breech del ivery. In Yeo m a n s E R, Hofm a n BL, Gi lstrap LC I I I, et a l (eds): C u n n i n g h a m a nd G i l strap's Operative Obstetrics, 3 rd ed. New York, McGraw- H i l i Ed ucation, 20 1 7.)

B reech Delivery

A

B

F I G U R E 28-7 A. After del ivery of the fi rst a rm, 1 80-deg ree rotation of the fetal body brings the sacru m to a rig ht sacru m tra n sverse (RST) position. B. F i ng ers of the provider's h a n d extended over the right shou lder a n d pa ra l lel to the h u merus. These sweep the a rm downwa rd across the c hest a n d o ut. (Reprod u ced with perm ission from Yeo m a n s ER: Vag i n a l b reech del ivery. I n Yeomans ER, Hoffma n BL, G i l stra p LC I I I, et al (eds): C u n n i ng h a m a n d Gi lstra p's Operative Obstetrics, 3 rd ed. New York, McGraw- H i l i Education, 20 1 7.)

sphincter lacerations. Ideally, the breech is allowed to deliver spontaneously to the umbilicus. Delivery of the breech draws the umbilicus and attached cord into the pelvis. Therefore, once the breech has passed beyond the vaginal introitus, the abdo­ men, thorax, arms, and head must be delivered promptly either spontaneously or assisted. The posterior hip will deliver, usually from the 6 o'clock posi­ tion, and oten with suicient pressure to evoke passage of thick meconium (see Fig. 28-4) . he anterior hip then delivers, fol­ lowed by external rotation to a sacrum anterior position. The mother is encouraged to continue to push as the fetus descends until the legs are accessible. The legs are sequentially delivered by splinting the femur with the operator's fingers positioned parallel to the long axis of the femur, and by exerting pressure upward and laterally to sweep each leg away from the midline (Fig. 28-5) . Following delivery o f the legs, the fetal bony pelvis is grasped with both hands. The fingers should rest on the anterior supe­ rior iliac crests and the thumbs on the sacrum. his minimizes the chance of fetal abdominal soft-tissue injury ( Fig. 28-6) . Maternal expulsive eforts are again used i n conjunction with downward traction to afect delivery. A cardinal rule in successul breech extraction is to employ steady, gentle, downward traction until the lower halves of the scapulas are delivered, making no attempt at delivery of the shoul­ ders and arms until one axilla becomes visible. It makes little dif­ ference which shoulder is delivered irst, and two methods are suitable for their delivery. In the first method, with the scapulas visible, the trunk is rotated either clockwise or counterclocwise to bring the anterior shoulder and arm into view (Fig. 28-7) . Dur­ ing delivery of the arm, fingers and hand are aligned parallel to the humerus and act to splint and prevent humeral fracture. he body of the fetus is then rotated 1 80 degrees in the reverse direction to bring the other shoulder and arm into position for delivery.

he second method is employed if trunk rotation is unsuc­ cessful. With this maneuver, the posterior shoulder is delivered first. For this, the feet are grasped in one hand and drawn upward over the inner thigh of the mother (Fig. 28-8) . The

F I G U R E 28-8 I nfrequently, the posterior a rm must be delivered first. For this, the lower h a lf of the fetal body is raised up and over the maternal g roin. The provider's fi ngers a re i nserted u nder the posterior shou lder and a l ig ned with the hu merus. (Reprod uced with permission from Yeoma n s ER: Vag i n a l breech delivery. In Yeoma ns ER, Hoffma n BL, G i l strap LC I I I, et al (eds): Cunningham a nd Gilstrap's Operative Obstetrics, 3 rd ed. New York, McGraw-Hili Education, 201 7.)

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Del ivery

hand enters over the shoulder, fingers are aligned parallel to the long axis of the humerus, and the fetal arm is swept upward. The posterior shoulder slides out over the perineal margin and is usually followed by the arm and hand. Then, by depressing the body of the fetus, the anterior shoulder emerges beneath the pubic arch, and the arm and hand usually follow spontaneously. After both shoulders are delivered, the back of the fetus tends to rotate spontaneously to the symphysis. Delivery of the head may then be accomplished. N uc h a l Arm

During delivery, one or both fetal arms occasionally may lie across the back of the neck and become impacted at the pelvic inlet. With such a nuchal arm, delivery is more diicult and can be aided by rotating the fetus through a half circle in such a direction that the friction exerted by the birth canal will draw the elbow toward the face (Fig. 28-9) . With a right nuchal arm, the body should be rotated counterclockwise, which rotates the fetal back toward the maternal right. With a left nuchal arm, the rota­ tion is clockwise. If rotation fails to free the nuchal arm, it may be necessary to push the fetus upward to a roomier part of the pelvis. If the rotation is still unsuccessul, the nuchal arm oten is extracted by hooking a inger(s) over it and forcing the arm over the shoulder, and down the ventral surface for delivery of the arm. In this event, fracture of the humerus or clavicle is common. Del ive ry of the Aftercom i n g Head

F I G U R E 28-9 Red uction of a rig ht n uchal arm is accomplished by rotati ng the fetal body 1 80 deg rees cou nterclockwise, which directs the feta l back to the maternal rig ht. Friction exerted by the birth ca nal will d raw the el bow toward the face. (Reprod uced with permission from Yeomans ER: Vaginal breech delivery. In Yeomans ER, Hoffman BL, Gilstrap LC I I I, et al (eds): Cunni ngham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Ed ucation, 201 7.)

Mauriceau Maneuver. The fetal head is normally extracted with

forceps or by one of several maneuvers. With any of these tech­ niques, hyperextension of the fetal neck is avoided. With the Mauriceau maneuver, the index and middle inger of one hand are applied over the maxilla, to flex the head, while

A

the fetal body rests on the palm of the same hand and forearm (Fig. 28- 1 0) . Fetal legs straddle the forearm. Two ingers of the other hand then are hooked over the fetal neck and grasp the shoulders. Downward traction is concurrently applied until the suboccipital region appears under the symphysis. Gentle suprapubic pressure simultane­ ously applied by an assistant helps keep the head flexed. The body then is slightly elevated toward the maternal abdomen, and the mouth, nose, brow, and eventually the occiput emerge successively over the perineum. With this maneuver, the pro­ vider uses both hands simul­ taneously to exert continuous downward gentle traction while balancing forces between the fetal neck and maxilla to avoid neck hyperextension.

B

FIGURE 28-1 0 A. Del ivery of the aftercoming head u s i n g the Mau ricea u maneuver. Note that as the fetal head is bei n g del ivered, flexion of the head is mai nta i ned by su pra p u bic pressu re provided by an assistant. B. P ressu re on the maxi l l a is appl ied S i m u ltaneously by the operator as upward and outwa rd traction is exerted .

Forceps. Specialized forceps can be used to deliver the aftercoming head. Piper for­ ceps, shown in Figure 28- 1 1 , or Laufe-Piper forceps may be applied electively or when the Mauriceau maneuver cannot be accomplished easily. The blades

Breech Del ive ry

B

A

c

F I G U R E 28- 1 1 Piper forceps for del ivery of the aftercom i n g head. A. The fetal body is held elevated using a wa rm towel a nd the left blade of forceps is a p p l ied to the aftercom i n g head. B. The rig ht blade is a ppl ied with the body sti l l elevated. C. Forceps del ivery of the afterco m­ ing head. Note the di rection of move ment s hown by the a rrow.

of the forceps are not applied to the aftercoming head until it has been brought into the pelvis by gentle traction, combined with suprapubic pressure, and is engaged. Suspension of the body of the fetus in a towel efectively holds the fetus up and helps keep the arms and cord out of the way as the forceps blades are applied. Because the forceps blades are directed upward from the level of the perineum, some choose to apply them from a one-knee kneeling position. Piper forceps have a downward arch in the shank to accommodate the fetal body and lack a pelvic curve. This shape permi ts direct application of the cephalic curve of the blade along the length of the maternal vagina and fetal parietal bone. The blade to be placed on the maternal left is held in the provider's left hand. The right hand

slides between the fetal head and left maternal vaginal sidewall to guide the blade inward and around the parietal bone. he opposite blade mirrors this application. Once in place, the blades are articulated, and the fetal body rests across the shanks. The head is delivered by pull­ ing gently outward and slightly raising the handle simultane­ ously. This rolls the face over the perineum, while the occiput remains beneath the symphysis until after the brow delivers. Ideally, the head and body move in unison to minimize neck hyperextension. Mod ified Prague Maneuver. Rarely, the back of the fetus fails to rotate to the symphysis. The fetus still may be delivered using the modiied Prague maneuver. With this, two fingers of one

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Del ive ry

F I G U R E 28- 1 2 Del ivery of the afte rco m i n g head u s i n g the modi­ fied Pra g u e m a ne uver necessitated by fa i l u re of the feta l tru n k to rotate a nteriorly.

hand grasp the shoulders of the back-down fetus from below while the other hand draws the feet up and over the maternal abdomen (Fig. 2 8- 1 2) .

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Head Entrapment. his emergency reflects either an incom­ pletely dilated cervix or cephalopelvic disproportion. First, especially with a small preterm fetus, an incompletely dilated cervix can constrict around the neck and impede delivery of the aftercoming head. At this point, signiicant cord compres­ sion must be assumed, and time management is essential. With gentle traction on the fetal body, the cervix, at times, may be manually slipped over the occiput. If unsuccessful, then Diihrssen incisions may be necessary (Fig. 28- 1 3) . General anesthesia with halogenated agents or intravenous nitroglycerin is another option to aid lower uterine segment relaxation. As an extreme measure, replacement of the fetus higher into the vagina and uterus, followed by cesarean delivery, can rescue an entrapped breech fetus. This Zavaneli maneuver is classically performed to relieve intractable shoulder dystocia (Sandberg, 1 988). However, case reports also have described its use for an entrapped aftercoming head (Sandberg, 1 999; Steyn, 1 994) . In cases with cephalopelvic disproportion and arrest of aftercoming head, the Zavanelli maneuver or symphysiotomy are options (Sunday-Adeoye, 2004; Wery, 20 1 3) . Using local analgesia, symphysiotomy surgically divides the intervening symphyseal cartilage and much of its ligamentous support to widen the symphysis pubis up to 2.5 cm (Basak, 20 1 1 ) . Lack of provider training and potentially serious maternal pelvic or urinary tract injury explain its rare use in the United States. That said, if cesarean delivery is not possible, symphysiotomy may be lifesaving for both mother and baby (Hofmeyr, 20 1 2) .

• Total Breech Extraction

Com p lete or I ncomplete Breech

At times, total extraction of a complete or incomplete breech may be required. A hand is introduced through the vagina, and both fetal feet are grasped. he ankles are held with the middle fi n ger lying between them. With gentle traction, the feet are brought through the introitus (Fig. 28- 1 4) . As the legs

)

)

I

F IGUR E 28- 1 3 D u h rssen incision bei n g cut at 2 o'clock, which is followed by a second i ncision at 10 o'clock. I nfreq uently, a n addi­ tional i ncision is req u i red at 6 o'clock. The incisions a re so p la ced as to m i n i m ize bleed i n g from the latera l ly located cervica l bra n ches of the uteri ne a rtery. After del ivery, the i ncisions a re re pai red as descri bed i n C h a pter 4 1 (p. 763).

1

t

I

F I G U R E 28- 1 4 Com plete breech extraction beg i n s with traction on the feet and a n kl es.

B reech Del ivery

begin to emerge through the vulva, downward gentle traction is continued. As the legs emerge, successively higher portions are grasped, first the calves and then the thighs. When the breech appears at the vaginal outlet, gentle traction is applied until the hips are delivered. The thumbs are then placed over the sacrum and the fingers over the iliac crests. Breech extraction is then completed, as described for partial breech extraction (p. 544) . If only one foot can be grasped, it can be brought down into the vagina and held with the appropriate hand, right hand for right foot and left hand for left foot (Yeomans, 20 1 7) . With the irst foot secure, the opposite hand is introduced, passed upward along the leg, and guided to locate the other foot. If the remaining hip is extended, the second foot is usually eas­ ily grasped and brought down. If the hip is lexed and knee extended, a finger is hooked into that groin, and traction will bring the lower half of the fetus down until the leg can be reached. For cesarean delivery, these total breech extraction maneuvers can be used to deliver a complete, incomplete, or footling breech through the hysterotomy incision. Fra n k B reech

During complete extraction of a frank breech, moderate trac­ tion is exerted by a finger in each groin and aided by a generous episiotomy. Once the breech is pulled through the introitus, the steps described for partial breech extraction are then completed (p. 544) . These maneuvers are also used during cesarean delivery of a frank breech through a hysterotomy incision. Rarely during vaginal delivery, a frank breech will require decomposition inside the uterine cavity. Attributed to Pinard ( 1 889) , this procedure converts a frank breech into a footling breech. It is accomplished more readily if the membranes have ruptured only recently. It becomes extremely diicult if amnionic luid is scant and the uterus is tightly contracted around the fetus. Pharmacological relaxation by general anesthesia or intravenous magnesium sulfate, nitroglycerin, or a betamimetic agent may be required. To begin, two ingers are carried up along one leg to externally rotate the hip by pressing on the medial side of the thigh parallel to the femur. Simultaneously, pressure in the popli­ teal fossa should prompt spontaneous knee flexion, which brings the corresponding foot into contact with the back of the provid­ er's hand. he fetal foot then may be grasped and brought down.

EXTERNAL CEPHALIC VERSION With version, fetal presentation is altered by physically substi­ tuting one pole of a longitudinal presentation for the other, or converting an oblique or transverse lie into a longitudinal presentation. Manipulations performed through the abdomi­ nal wall that yield a cephalic presentation are termed external cephalic version. Manipulations accomplished inside the uterine cavity that yield a breech presentation are designated intenal podalic version. This latter procedure is reserved for delivery of a second twin and described in Chapter 45 (p. 890) . • Indications

External cephalic version (ECy) reduces the rate of noncephalic presentation at birth (Hofmeyr, 20 1 5b) . For breech fetuses near

term, the American College of Obstetricians and Gynecologists (20 1 6a,b) recommends that version be ofered and attempted whenever possible. Its success rate averages about 60 percent (de H undt, 20 1 4) . For women with a transverse lie, the overall success rate is significantly higher. In general, ECV is attempted before labor in a woman who has reached 37 weeks' gestation. Before this time, breech pre­ sentation still has a high likelihood of correcting spontaneously. And, if ECV is performed too early, time may allow a rever­ sion back to breech (Bogner, 20 1 2) . Last, if attempts at version cause a need for immediate delivery, complications of iatro­ genic late-preterm delivery generally are not severe. Absolute contraindications to external version are few. It is contraindicated if vaginal delivery is not an option, such as with placenta previa. Another is multifetal gestation. Relative contraindications are early labor, oligohydramnios or rupture of membranes, known nuchal cord, structural uterine abnor­ malities, fetal-growth restriction, and prior abruption or its risks (Rosman, 20 1 3) . While many consider a prior cesarean delivery a contraindication, a few small studies found ECV was not asso­ ciated with uterine rupture (Burgos, 20 1 4; Keepanasseril, 20 1 7; Weill, 20 1 7) . At Parkland Hospital, we do not attempt version in these women. More data from clinical studies are needed. Several factors can improve the chances of a successful attempt. These include multiparity, unengaged presenting part, nonanterior placenta, nonobese patient, and abundant amni­ onic fluid (Kok, 2009, 20 1 1 ; Velzel, 20 1 5). To augment the last parameter, Burgos and coworkers (20 1 4) administered a preprocedural 2-L intravenous luid bolus. While this improved amnionic luid volume, it did not increase version success rates. • Complications

Patient counseling includes a discussion regarding small but real risks for placental abruption, preterm labor, and fetal com­ promise. Rarely, uterine rupture, fetomaternal hemorrhage, alloimmunization, amnionic luid embolism, and even death may also complicate attempts at external version. hat said, fetal deaths are rare, serious complication rates are typically very low, and emergent cesarean rates are 0 . 5 percent or less (Grootscholten, 2008; Rodgers, 20 1 7) . And even after success­ ful EC, several reports suggest that the cesarean delivery rate does not completely revert to the baseline for vertex presenta­ tions. Specifically, dystocia, malpresentation, and nonreassur­ ing fetal heart patterns may be more common in these fetuses completing successful version (Chan, 2004; de Hundt, 20 1 4; Vezina, 2004) . • Technique

ECV should be carried out in an area that has ready access to a facility equipped to perform emergency cesarean deliv­ ery (American College of Obstetricians and Gynecologists, 20 1 6a) . Because of the risk for surgical intervention, intra­ venous access is obtained, and patients abstain from eating for 6 or more hours. Sonographic examination is perfo rmed to conirm nonvertex presentation, document amnionic fl u id volume adequacy, exclude obvious fetal anomalies if not done previously, and identiy placental location and fetal spine

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orientation. Preprocedural external monitoring is performed to assess fetal heart rate reactivity. Anti-D immune globulin is given to Rh-D negative women. Tocolysis and regional anal­ gesia may be elected, and rationale for these is provided in subsequent sections. he woman is placed in left lateral tilt to aid utero placental perfusion, and Trendelenburg positioning helps during eleva­ tion of the breech. D uring the procedure, we prefer to monitor fetal heart motion sonographically. An abundant abdominal coating of ultrasound gel permits this and also minimizes pain­ ful skin friction (Vallikkannu, 20 1 4) . A forward roll o f the fetus usually i s attempted fi r st. One or two providers may participate, and one hand grasps the head. he fetal buttocks are then elevated from the maternal pelvis and displaced laterally (Fig. 28- 1 5) . The buttocks are then gen­ tly guided toward the fundus, while the head is simultaneously directed toward the pelvis. If the forward roll is unsuccessful, a backward flip is attempted. ECV attempts are discontinued for excessive discomfort, persistently abnormal fetal heart rate, or after multiple failed attempts. Failure is not always absolute. Ben-Meir and colleagues (2007) reported a spontaneous ver­ sion rate of 7 percent among 226 failed versions-2 percent among nulliparas and 13 percent among multiparas. If ECV is successful, a nonstress test is repeated until a normal test result is obtained. If version is completed before 39 weeks' gestation, then awaiting spontaneous labor and fetal maturity is preferred. In some studies, immediate labor induc­ tion is linked to higher cesarean delivery rates (Burgos, 20 1 5; Kuppens, 20 1 3) .

• Tocolysis

To relax the uterus prior to an ECV attempt, existing evidence supports the use of tocolysis (American College of Obstetri­ cians and Gynecologists, 2 0 1 6a) . Most data support the use of the beta-mimetics terbutaline and ritodrine (Cluver, 20 1 5) . In one such trial, Fernandez and coworkers ( 1 996) reported that the success rate with subcutaneous terbutaline-52 percent­ was significantly higher than without-27 percent. Our policy at Parkland Hospital is to administer 250 I1g of terbutaline subcutaneously to most women before attempted ECV. When maternal tachycardia-a known side efect of terbutaline-is noted, the attempt is begun. Data are limited and, in some cases nonsupportive, for alternate agents that include calcium­ channel blockers, such as nifedipine; nitric oxide donors, such as nitroglycerin; the oxytocin-receptor antagonist atosiban; and another betamimetic salbutamol (Burgos, 20 1 0; Hilton, 2009; Kok, 2008; Vani, 2009; Velzel, 20 1 7; Wilcox, 20 1 1 ) . • Conduction Analgesia

Epidural analgesia coupled with tocolysis has been reported to increase version success rates compared with tocolysis alone (Goetzinger, 20 1 1 ; Magro-Malosso, 20 1 6) . Moreover, rates of complications that include fetal heart rate aberrations, emer­ gency cesarean delivery, or placental abruption were not greater with regional analgesia. Of randomized trials, spinal and epi­ dural have both shown success (Khaw, 20 1 5 ; Weiniger, 20 1 0) . Currently, the superior technique and best drugs to administer are unclear. In contrast, from limited data, intravenous seda­ tion does not appear to improve success rates (Burgos, 20 1 6; Khaw, 20 1 5) . • Moxibustion

This is a traditional Chinese medicine technique that burns a cigarette-shaped stick of ground Artemisia vugaris-which is also known as mugwort or in Japanese as moxa. At the BL 67 acupuncture point, the stick is directly placed against the skin or indirectly heats an acupuncture needle at the site to increase fetal movement and promote spontaneous breech version (Ewies, 2002) . It is performed usually between 33 and 36 weeks' gesta­ tion to permit a trial of ECV if not successful. Results from ran­ domized controlled studies are conflicting (Bue, 20 1 6; Coulon, 20 1 4; Coyle, 20 1 2 ; Sananes, 20 1 6; Vas, 20 1 3) .

REFERENCES

FIGURE 28-1 5 External cepha lic version. With a n attem pted for­ wa rd rol l, clockwise pressure is exerted against the fetal poles.

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Fontenot T, Campbell B, Mitchell-Tun E, et al: Radiographic evaluation of breech presentation: is it necessary? Ultrasound Obstet Gynecol 1 0:338, 1 997 Ford JB, Roberts CL, Nassar N, et al: Recurrence of breech presentation in consecutive pregnancies. BJOG 1 1 7(7):830, 20 1 0 Fox AE, Paton RW: he relationship between mode of delivery and develop­ mental dysplasia of the hip in breech infants: a four-year prospective cohort study. J Bone Joint Surg Br 92( 1 2) : 1 695, 20 1 0 Giuliani A , Scholl WMJ , Basver A , e t al: v lode o f delivery and outcome of 699 term singleton breech deliveries at a single center. Am J Obstet Gynecol 1 87 : 1 694, 2002 Goetzinger KR, Harper LM, Tuuli MG, et al: Efect of regional anesthesia on the success rate of external cephalic version: a systematic review and meta­ analysis. Obstet Gynecol 1 1 8 (5) : 1 1 37 , 201 1 Goinet F, Carayol M, Foidart JM, et al: Is planned vaginal delivery for breech presentation at term still an option? 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Del ive ry Macharey G, Ulander VM, Heinonen S, et al: Induction of labor in breech presentations at term: a retrospective observational study. Arch Gynecol Obstet 293 (3) : 549, 20 1 6 Magro-Malosso ER, Saccone G , D i Tommaso M , e t al: Neuraxial analgesia to increase the success rate of external cephalic version: a systematic review and meta-analysis of randomized controlled trials. Am J Obstet Gynecol 2 1 5 (3) :276, 20 1 6 Marzouk P , Arnaud E , Oury JF, et al: Induction o f labour and breech presen­ tation: experience of a French maternity ward. [French] . J Gynecol Obstet Bioi Reprod (Paris) 40(7) :668, 20 1 1 Maslovitz S, Barkai G , Lessing JB, et al: Recurrent obstetric management mis­ takes identiied by simulation. Obstet Gynecol 1 09 (6) : 1 29 5 , 2007 Matsubara S, Izumi A, Nagai T, et al: Femur fracture during abdominal breech delivery. Arch Gynecol Obstet 278(2) : 1 95 , 2008 McNamara JM, Odibo AO, Macones GA, et al: The efect of breech presentation on the accuracy of estimated fetal weight. Am J PerinatoI 29(5):353, 20 1 2 Michel S , Drain A , Closset E , e t al: Evaluation o f a decision protocol for type of delivery of infants in breech presentation at term. Eur J Obstet Gynecol Reprod Bioi 1 5 8 (2) : 1 94, 20 1 1 Mostello 0 , Chang JJ, Bai F, et al: Breech presentation at delivery: a marker for congenital anomaly? J Perinatol 34 ( 1 ) : 1 1 , 20 1 4 Muhuri PK, Macdorman M F , Menacker F : Method o f delivery and neonatal mortaliry among very low birth weight infants in the United States. Matern Child Health J 1 0:47, 2006 Nassar N , Roberts CL, Cameron CA, et al: Diagnostic accuracy of clinical examination for detection of non-cephalic presentation in late pregnancy: cross sectional analytic study. BMJ 333 : 578, 2006 Obeidat N , Zayed F , Alchalabi H , et al: Umbilical cord prolapse: a l O-year retrospective study in two civil hospitals, North Jordan. J Obstet Gynaecol 30(3) :257, 20 1 0 Ortiz-Neira CL, Paolucci EO, Donnon T : A meta-analysis o f common risk factors associated with the diagnosis of developmental dysplasia of the hip in newborns. Eur J RadioI 8 1 (3) :e344, 20 1 2 Phelan JP, Bethel M , DeVore G , et al: Use o f ultrasonography i n the breech presentation with hyperextension of the fetal head. J Ultrasound Med 2 (8) :373, 1 983 Pinard A: On version by external maneuvers. In Traite du Palper Abdominal. Paris, Lauwereyns, 1 889 Raju TN, Mercer BM, Burchfield OJ, et al: Periviable birth: executive sum­ mary of a joint workshop by the Eunice Kennedy Shriver National Insti­ tute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Academy of Pediatrics, and merican College of Obstetricians and Gynecologists. Obstet GynecoI 1 23 (5) : 1 083, 20 1 4 Reddy U M , Zhang J, S u n L , e t al: Neonatal mortality b y attempted route of delivery in early preterm birth. Am J Obstet Gynecol 207(2) : 1 1 7.e 1 , 20 1 2 Rietberg CC, Elferink-Stinkens PM, Visser G H : The efect o f the Term Breech Trial on medical intervention behaviour and neonatal outcome in he Neth­ erlands: an analysis of 3 5 ,453 term breech infants. BJOG 1 1 2 (2) :205, 2005 Rodgers R, Beik N , Nassar N, et al: Complications of external cephalic version: a retrospective analysis of 1 1 2 1 patients at a tertiary hospital in Sydney. BJO G 1 24(5) :767, 20 1 Rojansky N, Tanos V, Lewin A, et al: Sonographic evaluation of fetal head extension and maternal pelvis in cases of breech presentation. Acta Obstet Gynecol Scand 73:607, 1 994 Roman H, Carayol M, Watier L, et al: Planned vaginal delivery of fetuses in breech presentation at term: prenatal determinants predictive of elevated risk of cesarean delivery during labor. Eur J Obstet Gynecol Reprod Bioi 1 3 8 ( 1 ) : 1 4, 2008 Rosman AN, Guijt A, Vlemmix F, et al: Contraindications for external cephalic version in breech position at term: a systematic review. Acta Obstet Gynecol Scand 92 (2) : 1 37, 20 1 3 Royal College o f Obstetricians and Gynaecologists: h e management o f breech presentation. RCOG Green Top Guidelines, No. 20b. London, 2006 Sananes N, Roth GE, issi GA, et al: Acupuncture version of breech pre­ sentation: a randomized sham-controlled single-blinded trial. Eur J Obstet Gynecol Reprod Bioi 204:24, 20 1 6 Sandberg E C : The Zavanelli maneuver: 1 2 years o f recorded experience. Obstet GynecoI 93:3 1 2, 1 999

Sandberg EC: he Zavanelli maneuver extended: progression of a revolutionary concept. Am J Obstet Gynecol 1 5 8 (6 Pt 1 ) : 1 347, 1 988 Saroha M , Batra P, Dewan P, et al: Genital injuries i n neonates following breech presentation. J Neonatal Perinatal Med 8 (4):42 1 , 20 1 5 Schutte JM, Steegers A, Santema JG, et al: Maternal deaths after elective cesarean section for breech presentation in the Netherlands. Acta Obstet Gynecol Scand 86(2) :240, 2007 Sherer OM, Menashe M, Palti Z, et al: Radiologic evidence of a nuchal arm in the breech-presenting fetus at the onset of labor: an indication for abdomi­ nal delivery. Am J PerinatoI 6(3) :353, 1 989 Steyn W, Pieper C: Favorable neonatal outcome after fetal entrapment and partially successful Zavanelli maneuver i n a case of breech presentation. Am J Perinatol l l :348, 1 994 Sunday-Adeoye 1M, Okonta P, Twomey 0: Symphysiotomy at the Mater Misericordiae Hospital Afikpo, Ebonyi State of Nigeria ( 1 982- 1 999) : a review of 1 0 1 3 cases. J Obstet GynaecoI 24(5 ) : 5 2 5 , 2004 Thomas PE, Petersen SG, Gibbons K: he influence of mode of birth on neo­ natal survival and maternal outcomes at extreme prematurity: a retrospective cohort study. Aust N Z J Obstet Gynaecol 56( 1 ) :60, 20 1 6 homas SM, Bees NR, Adam EJ: Trends i n the use o f pelvimetry techniques. Clin RadioI 5 3 (4) :293, 1 998 Toivonen E, Palomaki 0, Huhtala H , et al: Selective vaginal breech delivery at term-still an option. Acta Obstet Gynecol Scand 9 1 ( 1 0) : 1 1 77, 20 1 2 Vallikannu N , Nadzratulaiman N , Omar SZ, e t al: Talcum powder or aqueous gel to aid external cephalic version: a randomised controlled trial. BMC Pregnancy Childbirth 1 4:49, 20 1 4 Vani S , Lau SY, Lim BK, e t al: Intravenous salbutamol for external cephalic version. Int J Gynecol Obstet 1 04 ( 1 ) :28, 2009 Vas J, Aranda-Regules JM, Modesto M, et al: Using moxibustion in primary healthcare to correct non-vertex presentation: a multicentre randomised controlled trial. Acupunct Med 3 1 ( 1 ) : 3 1 , 2 0 1 3 Velzel J , Vlemmix F , Opmeer B e , e t a l : Atosiban versus fenoterol a s a uterine relaxant for external cephalic version: a randomised controlled trial. BMJ 26:356, 20 1 7 Velzel J , d e Hundt M , Mulder FM, et al: Prediction models for successful external cephalic version: a systematic review. Eur J Obstet Gynecol Reprod BioI 1 95 : 1 60 , 20 1 5 Vendittelli F , Pons Je, Lemery 0 , et al: h e term breech presentation: neonatal results and obstetric practices in France. Eur J Obstet Gynecol Reprod BioI 1 2 5 (2) : 1 76, 2006 Vezina Y, Bujold E, Varin J, et al: Cesarean delivery after successful external cephalic version of breech presentation at term: a comparative study. Am J Obstet Gynecol 1 90:763, 2004 Vialle R, Pietin-Vialle C, Ilharreborde B, et al: Spinal cord injuries at birth: a multicenter review of nine cases. J Matern Fetal Neonatal Med 20(6) :43 5 , 2007 Vistad I, Klungs0yr K, Albrechtsen S, et al: Neonatal outcome of singleton term breech deliveries in N otway from 1 99 1 to 2 0 1 1 . Acta Obstet Gynecol Scand 94(9) :997, 20 1 5 Weill Y, Pollack N : he eicacy and safery o f external cephalic version after a previous caesarean delivery. Aust N Z J Obstet Gynaecol 57(3) :323, 20 1 7 Weiniger CF, Ginosar Y , Elchalal U , e t al: Randomized controlled trial of external cephalic version in term multiparae with or without spinal analge­ sia. Br J Anaesth 1 04(5):6 1 3, 20 1 0 Wery E , L e Roch A , Subtil 0: Zavanelli maneuver performed in a breech pre­ sentation. Int J Gynaecol Obstet 1 20(2) : 1 93, 20 1 3 Westgren M , Grundsell H , Ingemarsson I , et al: Hyperextension of the fetal head in breech presentation. A study with long-term follow-up. BJOG 88(2) : 1 0 1 , 1 98 1 Whyte H , Hannah ME, Saigal S , et al: Outcomes o f children at 2 years after planned cesarean birth versus planned vaginal birth for breech presentation at term: the International Randomized Term Breech Trial. Am J Obstet GynecoI 1 9 1 (3) : 864, 2004 Wilcox CB, Nassar N, RobertS CL: Efectiveness of nifedipine tocolysis to facil­ itate external cephalic version: a systematic review. BJOG 1 1 8 (4) :423, 20 1 1 Yeomans ER: Vaginal breech delivery. In Yeomans ER, Hofman BL, Gilstrap LC I I I , et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hill Education, 20 1 7

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C H A PT E R 2 9

O pe ra t ive Va g i n a l De l ive ry

I N DICATIONS

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CLASSIFICATION A N D PREREQU ISITES

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MORBIDITY

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TRIAL OF OPERATIVE VAG INAL DELIVERY

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TRAI NING

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VACUUM EXTRACTION

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FORCEPS DELIVERY

The most important function oforceps is traction exercised or the purpose ofdrawing the head through the genital tract. In not a ew cases, however, particulary in occipito-posterior presentations, its employment as a rotator is attended by most happy results. -J. Whitridge Williams ( 1 903) Operative deliveries are vaginal deliveries accomplished with the use of forceps or a vacuum device. Once either is applied to the fetal head, outward traction generates forces that aug­ ment maternal pushing to deliver the fetus vaginally. he most important function of both devices is traction. In addition, for­ ceps may also be used for rotation, particularly from occiput transverse and posterior positions. According to the birth certiicate data from the National Vital Statistics Report, forceps- or vacuum-assisted vaginal delivery was used for 3.2 percent of births in the United States in 20 1 4. his is a decline from 9.0 percent in 1 990 (Hamil­ ton, 20 1 5) . For these deliveries, a vacuum is disproportionately selected, and the vacuum-to-forceps delivery ratio is nearly 5: 1 (Merriam, 20 1 7) . In general, most of these attempts are

successful. In 2006, only 0.4 percent of forceps trials in the United States and 0.8 percent of vacuum extraction attempts failed to result in vaginal delivery (Osterman, 2009) .

INDICATIONS If it is technically feasible and can be safely accomplished, ter­ mination of second-stage labor by traction instruments is indi­ cated in any condition threatening the mother or fetus that is likely to be relieved by delivery. Some fetal indications include nonreassuring fetal heart rate pattern and premature placen­ tal separation (Schuit, 20 1 2) . In the past, forceps delivery was believed to be somewhat protective of the fragile preterm infant head. However, outcomes for neonates who weigh 500 to 1 500 g do not signiicantly difer if delivered spontaneously or by outlet forceps (Fairweather, 1 98 1 ; Schwartz, 1 983). Some maternal indications include heart disease, pulmonary compromise, intrapartum infection, and certain neurological conditions. The most common are exhaustion and prolonged second-stage labor. However, a speciic maximum length beyond which all women should be considered for operative vaginal delivery has not been identiied (American College of Obstetricians and Gynecologists, 20 1 6) . Operative delivery i s generally performed from either a low or outlet station. Additionally, forceps or vacuum deliv­ ery should not be used electivey until the criteria for an o utlet delivery have been met. In these circumstances, operative deliv­ ery is a simple and safe operation, although with some risk of maternal lower reproductive tract injury (Yancey, 1 999) .

CLASSIF ICATION AND PREREQUISITES Classiication for operative vaginal delivery is summarized in Table 29- 1 . I t emphasizes that the two most important discriminators of risk for both mother and neonate are station and rotation. Station is measured in centimeters, -5 to 0 to + 5 .

554

De l ive ry

TABLE 29-' . Operative Vag i n a l Del ivery Prereq u i s ites a n d Classification Accord i ng to Station a n d Rotationa

Procedure

Criteria

Outlet forceps

Sca l p is v i s i b l e at the i ntroitus without sepa r at i n g the l a b i a Feta l s ku l l h a s r e a c h e d p e l v i c fl oor Feta l head i s at or o n peri n e u m Head i s O A o r O P or Head is right or l eft OA or OP pos iti o n but rotation ;45 deg rees

Low for ceps (2 types)

Lea d i n g poi nt of feta l s ku l l is at station � + 2 (a) Rotation is ;45 deg rees, or (b) Rotation is > 45 deg rees

M idfo rceps

cm,

a n d n ot on the pelvic floo r, a n d :

Station is betwee n 0 a nd +2 c m

Prerequ isites

E n g ag ed head Vertex p resentationb,c Known feta l head position C P D n ot s u s pected Feta l weig ht est i m ated

Expe r i e n ced operator R u pt u red m e m b ra nes Co m pl etely d i l ated ce r vix Adeq u ate a n esthes ia E m ptied mate r n a l bladder

N o feta l coag u l o pathy N o feta l de m i ne ra l izati o n d i so rder Wi l l i n g ness to a ba n d o n OVD I nformed consent com pleted

aClassifi cation for the vacu u m del ivery system is the same as for forceps except that vac u u m is used for traction but not rotation. bFo rce ps, b u t n ot va c u u m extracto r , may be u sed for del ive ry of a face presentation with mentum a nte rior. ( P i pe r forceps m ay be used to del iver the head d ur i ng b reech del ivery. C P D cep h a l opelvic d is pr o portion; OA occ i p ut a nterior; OP occ i put poste rior; OVD ope rative vag i n a l del ivery. =

=

=

Zero station relects a line drawn between the ischial spines. Deliveries are categorized as outlet, low, and midpelvic pro­ cedures. High orceps, in which instruments are applied above 0 station, have no place in contemporay obstetrics. Once station and rotation are assessed, several prerequisites are met and are listed in Table 29- 1 . For vacuum extraction, fetuses should also be at least 34 weeks' gestation, and although infrequently used in the United States, fetal scalp blood sam­ pling should not have been recently performed. Of requisites, ascertaining correct head position is essential, and the anatomy of the fetal skull is described in Figure 29- 1 . In unclear cases, sonography is useful to identiy fetal orbits and nasal bridge to aid orientation (Malvasi, 20 1 4) .

=

Regional analgesia or general anesthesia is preferable for low forceps or midpelvic procedures, although pudendal blockade may prove adequate for outlet forceps. As discussed in Chapter 25 (p. 495), regional analgesia during labor does not appear to increase the risk for operative delivery (Halpern, 2004; Marucci, 2007; Wassen, 20 1 4) . The bladder i s emptied to provide additional pelvic space and minimize bladder trauma. Urinary retention and bladder dysunc­ tion are oten short-term efects of forceps and vacuum deliveries (Mulder, 20 1 2; Pifarotti, 20 1 4) . Notably, episiotomy and epi­ dural analgesia, both common associates, are also identified risks for urinary retention. Symptoms are brief and typically resolve with 24 to 48 hours of passive Foley catheter bladder drainage. Occipital bone ---­ Lambdoid suture Posterior fontanel ---

Parietal bone

--­

Vertex

Parietal bone Sagittal suture

----

Biparietal diam.eter

=

9.5 cm

Lambdoid

Occipital bone Occiput

Anterior fontanel Coronal suture

Frontal bone --Frontal suture

Temporal suture

--­"-

--/ .=

-7 '

FIGURE 29- 1 Feta l head (A, B) at term s howi ng fonta nels, sutures, and va rious di mensions.

A

B

Operative Va g i na l D e l ive ry

MORBI D ITY There is an increased risk of certain morbidities for both mother and fetus when operative delivery is employed. In general, these are related to the ease with which the delivery is accomplished. • Maternal Morbidity

In general, a higher station and/or greater degrees of rotation increase the chance of maternal or fetal injury. Morbidity is most properly compared with morbidity from cesarean deliv­ ery, and not with that from spontaneous vaginal delivery. his is the most appropriate comparator because the alternative to indicated operative delivery is cesarean delivery. For example, postpartum wound or uterine infection is more frequent in women following cesarean compared with operative vaginal delivery (Bailit, 20 1 6; Halscott, 20 1 5) . Moreover, in a study of more than 1 million births, Spiliopoulos and associates (20 1 1 ) reported cesarean delivery, but not operative vaginal delivery, as a risk for peripartum hysterectomy. Lacerations

he very conditions that lead to indications for operative deliv­ ery also increase the need for episiotomy and the likelihood of lacerations (de Leeuw, 2008). That said, forceps and vacuum deliveries are associated with higher rates of third- and fourth­ degree lacerations as well s vaginal wall and cervical lacerations (Gurol-Urganci, 20 1 3; Hirayama, 20 1 2; Landy, 20 1 1 ; Pergiali­ otis, 20 1 4) . These appear to occur more frequently with forceps compared with vacuum extraction, and especially if there is a midline episiotomy (Kudish, 2006; O'Mahony, 20 1 0) . Haga­ dorn-Freathy and coworkers ( 1 99 1 ) reported a 1 3-percent rate of third- and fourth-degree episiotomy extensions and vaginal lacerations for outlet forceps, 22 percent for low forceps with less than 45-degree rotation, 44 percent for low forceps with more than 45-degree rotation, and 37 percent for midforceps deliveries. In an efort to lower rates of third- and fourth-degree lacera­ tions, and coincident with overall eforts to reduce routine episiot­ omy use, many advocate only indicated episiotomy with operative delivery. If episiotomy is required, a protective efect against these more extensive perineal lacerations may be aforded by mediolat­ eral episiotomy (de Leeuw, 2008; de Vogel, 20 1 2; Hirsch, 2008). Early disarticulation of forceps and cessation of maternal pushing during disarticulation can also be protective. Last, these injuries are more common with an occiput posterior position (Damron, 2004) . Thus, manual or forceps rotation to an occiput anterior position and then subsequent traction delivery may decrease rates of lower reproductive tract injury (Bradley, 20 1 3) . Pelvic F l o o r D isord e rs

his term encompasses urinary incontinence, anal inconti­ nence, and pelvic organ prolapse. Operative vaginal delivery has been suggested as a possible risk for each of these. Proposed mechanisms include structural compromise and/or pelvic loor denervation secondary to forces exerted during delivery. Parity and speciically vaginal delivery are risk factors for urinary incontinence (Gyhagen, 2 0 1 3 ; Rortveit, 2003) . But, many studies do not support an increased risk compared with

vaginal delivery alone (Gartland, 20 1 6; Leijonhuvud, 2 0 1 1 ; MacArthur, 20 1 6; Tahtinen, 20 1 6) . Evidence linking anal incontinence with operative vaginal delivery is conlicting. Some studies show that anal sphincter disruption caused by higher-order episiotomy, but not delivery mode, is the main etiological factor strongly associated with anal incontinence (BoIs, 20 1 0; Evers, 20 1 2; Nygaard, 1 997) . In con­ trast, others directly link operative delivery with this complica­ tion (Dolan, 20 1 0; Marthur, 20 1 3) . But, these studies may not be incongruous-recall that operative delivery is associated with increased rates of higher-order episiotomy. Importantly, several studies and reviews have not found cesarean delivery to be protec­ tive for anal incontinence (Nelson, 20 1 0) . Last, evidence linking pelvic organ prolapse with operative delivery also indicates mixed results (Gyhagen, 20 1 3; Handa, 20 1 2; Vo1l0yhaug, 20 1 5) . • Perinatal Morbidity

Ac ute Perinata l I nj u ry

hese injuries are more frequent with operative vaginal deliv­ ery than with cesarean delivery or spontaneous vaginal deliv­ ery. Injuries may be seen with either method. hey are more common with vacuum extraction, and types associated with this device include cephalohematoma, subgaleal hemorrhage, retinal hemorrhage, neonatal jaundice secondary to these hemorrhages, shoulder dystocia, clavicular fracture, and scalp lacerations. Cephalohematoma and subgaleal hemorrhage are both extracra­ nial lesions described in Chapter 33 (p. 628) . Forceps-assisted vaginal delivery has higher rates of facial nerve injury, brachial plexus injury, depressed skull fracture, and corneal abrasion (merican College of Obstetricians and Gynecologists, 20 1 5 ; Demissie, 2004; Dupuis, 2005). For intracranial hemorrhage, some studies have associated vacuum extraction with higher rates, whereas others show similar rates with either of the two methods (Towner, 1 999; Wen, 200 1 ; Werner, 20 1 l ) . Comparing operative vaginal with cesarean delivery, rates of extracranial hematoma, skull fracture, facial nerve or brachial plexus injury, retinal hemorrhage, and facial or scalp lacera­ tion are lower with cesarean deliveY, and shoulder dystocia is eliminated. Importantly, however, fetal acidemia rates are not increased with operative delivery (Contag, 20 1 0; Walsh, 2 0 1 3) . Intracranial hemorrhage rates are similar among newborns deliv­ ered by vacuum extraction, forceps, or cesarean delivery during labor (Towner, 1 999). But, these rates are higher than among those delivered spontaneously or by cesarean delivery before labor. These authors suggest that the common risk factor for intracranial hemorrhage is abnormal labor. Werner and associ­ ates (20 1 1 ) , in their evaluation of more than 1 50,000 singleton deliveries, reported that forceps-assisted delivery was associated with fewer total neurological complications compared with vac­ uum-assisted or cesarean delivery. However, as a subset, subdural hemorrhage was signiicantly more frequent in both instrumental cohorts compared with neonates in the cesarean delivery group. Comparing rotational operative delivery and second-stage cesarean delivery, maternal and neonatal morbidity rates are similar (Aiken, 20 1 5 ; Bahl, 20 1 3; Stock, 20 1 3) . For example, in their large series, Tempest and associates (20 1 3) found similar morbidity rates among malpositioned fetuses d uring

555

556

Del ivery

second-stage labor that underwent Kielland rotation, rotational vacuum extraction, or emergency cesarean delivery. Comparing midforceps and cesarean delivery, reports of neo­ natal morbidity rates are from older studies and are conflicting. In the study by Towner and colleagues ( 1 999) , similar risks were reported for intracranial hemorrhage. Bashore and associates ( 1 990) observed comparable Apgar scores, cord blood acid-base values, neonatal intensive care unit admission, and birth trauma between these two. In another study, however, Robertson and coworkers ( 1 990) reported signiicantly higher rates of these adverse outcomes in the midforceps group. Hagadorn-Freathy and colleagues ( 1 99 1 ) reported an increased risk for facial nerve palsy-9 percent-with midforceps delivery. In a recent report comparing low and midforceps procedures, Ducarme and coworkers (20 1 5) found comparable morbidity rates. Mech a n i s m s of Acute I nj u ry

he types of fetal injury with operative delivery can usually be explained by the forces exerted. In cases of cephalohematoma or subgaleal hemorrhage, suction and perhaps rotation during vacuum extraction may lead to a primary vessel laceration. Intra­ cranial hemorrhage may result from skull fracture and vessel lac­ eration or from vessel laceration alone due to exerted forces. With facial nerve palsy, one of the forceps blades may compress the nerve against the facial bones. he higher rates of shoulder dystocia seen with vacuum extraction may result from the angle of traction. With the vacuum, this angle creates vector forces that actually pull the anterior shoulder into the symphysis pubis (Caughey, 2005) . To explain brachial plexus injury, Towner and Ciotti (2007) proposed that as the fetal head descends down the birth canal, the shoulders may stay above the pelvic inlet. Thus, similar to shoulder dystocia at the symphysis, this "shoul­ der dystocia at the pelvic inlet" is overcome by traction forces but with concomitant stretch on the brachial plexus. Lo ng-Te rm I nfa nt Morbid ity

Evidence regarding long-term neurodevelopmental outcomes in children born by operative delivery is reassuring. In an older study, Seidman and colleagues ( 1 99 1 ) evaluated more than 52,000 Israeli Defense Forces dratees at age 17 years and found that regard­ less of delivery mode, rates of physical or cognitive impairments were similar. Wesley and associates ( 1 992) noted similar intelli­ gence scores among 5-year-olds following spontaneous, forceps, or vacuum deliveries. Murphy and coworkers (2004) found no asso­ ciation between forceps delivery and epilepsy in a cohort of more than 2 1 ,000 adults. In their epidemiological review, O'Callaghan and colleagues (20 1 1 ) found no association between cerebral palsy and operative delivery. Last, Bahl and associates (2007) noted that the incidence of neurodevelopmental morbidity was similar in those undergoing successul forceps delivery, failed forceps with cesarean delivery, or cesarean delivery without forceps. Data regarding midforceps deliveries are for the most part reassuring. Broman and coworkers ( 1 975) reported that infants delivered by midforceps had slightly higher intelligence scores at age 4 years compared with those of children delivered sponta­ neously. Using the same database, however, Friedman and asso­ ciates ( 1 977, 1 984) analyzed intelligence scores at or after age 7 years. They concluded that children delivered by midforceps

had lower mean intelligence quotients compared with those delivered by outlet forceps. In yet another report from this database, Dierker and colleagues ( 1 986) compared long-term outcomes of children delivered by midforceps with those deliv­ ered by cesarean after dystocia. he strength of this study is the appropriateness of the control group. hese investigators reported that delivery by midforceps was not associated with neurodevelopmental disability. Last, Nilsen ( 1 984) evaluated 1 8-year-old men and found that those delivered by Kielland forceps had higher intelligence scores than those delivered spontaneously, by vacuum extraction, or by cesarean.

TRIAL OF OPERATIVE VAGI NAL DELIVERY If an attempt to perform an operative delivery is expected to be diicult, then it should be considered a trial. Moving the woman to an operating room for this attempt, which could be followed by immediate cesarean delivery if operative delivery fails, has merit. If forceps cannot be satisfactorily applied, then the procedure is stopped and either vacuum extraction or cesar­ ean delivery is performed. With the former, if the fetus does not descend with traction, the trial should be abandoned and cesarean delivery performed. With such caveats, cesarean delivery after an attempt at operative vaginal delivery was not associated with adverse neo­ natal outcomes if there was a reassuring fetal heart rate tracing (Alexander, 2009) . A similar study evaluated 1 22 women who had a trial of midcavity forceps or vacuum extraction in a set­ ting with full preparations for cesarean delivery (Lowe, 1 987) . Investigators found no significant diference in immediate neo­ natal or maternal morbidity compared with that of 42 women delivered for similar indications by cesarean but without such a trial. Conversely, in 6 1 women who had "unexpected" vacuum or forceps failure in which there was no prior preparation for immediate cesarean delivery, neonatal morbidity was higher. Some factors associated with operative delivery failure are persistent occiput posterior position and birthweight >4000 g (Ben-Haroush, 2007; Verhoeven, 20 1 6) . However, Palatnik and associates (20 1 6) found that risk factors poorly predicted success. In general, to avert morbidity with failed forceps or vacuum delivery, the American College of Obstetricians and Gynecologists (20 1 5) cautions that these trials should be attempted only if the clinical assessment suggests a successful outcome. We also emphasize proper training. Sequential instrumentation most often involves an attempt at vacuum extraction followed by one with forceps. his most likely stems from the higher completion rate with forceps com­ pared with vacuum extraction noted earlier. This practice signif­ icantly increases risks for fetal trauma (Dupuis, 2005; Gardella, 200 1 ; Murphy, 20 1 1 ) . Because of these adverse outcomes, the American College of Obstetricians and Gynecologists (20 1 5) recommends against the sequential use of instruments unless there is a "compelling and j ustifiable reason. "

TRAINING As the rate of operative vaginal delivery has declined, so have opportunities for training (Fitzwater, 20 1 5 ; Kyser, 20 1 4) . In

Operative Vag i na l D e l i ve ry

Fenestrated blade Right

Toe

branch Overlapping

Handle

-Simpson forceps

Sliding lock Pelvic curve

Let branch

shank

Luikart forceps

FIGURE 29-2 S i m pson forceps have fenestrated blades, pa ra l l e l sha n ks, a nd E n gl i s h lock. T h e cepha l i c cu rve acco m m odates t h e feta l h ead.

F I G U R E 29-3 Luika rt forceps have pseudofenestrated blad es, overla pp i n g s h a n ks, s l id i n g lock, to ngue g roove ha nd les. The pelvic c u rve is ma rked i n this exa m ple by the black l i ne.

many programs, training in even low and outlet forceps proce­ dures has reached critically low levels. For residents completing training in 20 1 5 , the Accreditation Council for Graduate Med­ ical Education reported a median of only five forceps deliveries, and that for vacuum deliveries was 1 6. Because traditional hands-on training has evolved, residency programs should have readily available skilled operators to teach these procedures by simulation as well as through actual cases (Skinner, 20 1 7; Spong, 20 1 2) . And, the efectiveness of simulation training has been reported (Dupuis, 2006, 2009; Leslie, 2005). In one program, maternal and neonatal morbid­ ity rates with operative delivery decreased after the implemen­ tation of a formal education program that included a manikin and pelvic model (Cheong, 2004) . In another, a 59-percent increase in forceps deliveries over 2 years was related to a single experienced and proactive instructor assigned to teach forceps to residents in labor and delivery (Solt, 20 1 1 ) .

the right and left branches and stabilize the instrument. They can be located at the end of the shank nearest to the handles (English lock) , at the ends of the handles (pivot lock), or along the shank (sliding lock) . Although varied in design, handles, when squeezed, raise compression forces against the fetal head. hus, forces to consider include traction and compression. • Blade Application and Delivery

Forceps blades grasp the head and are applied according to fetal head position. If the head is in an occiput anterior (OA) posi­ tion, two or more fingers of the right hand are introduced inside the left posterior portion of the vulva and then into the vagina beside the fetal head. he handle of the left branch is grasped between the thumb and two fingers of the left hand (Fig. 2 9-4) .

FORCEPS DELIVERY

• Design

Forceps refers to the paired instrument, and each member of this pair is called a branch. Branches are designated left or right according to the side of the maternal pelvis to which they are applied (Fig. 29-2) . Each branch has four components: blade, shank, lock, and handle (Fig. 29-3) . Each blade has a toe, a heel, and two curves. Of these, the outward cephalic curve con­ forms to the round fetal head, whereas the upward pelvic curve corresponds more or less to the curve of the birth canal. Some blades have an opening within or a depression along the blade surface and are termed enestrated or pseudoenestrated, respec­ tively. True fenestration reduces the degree of head slippage during forceps rotation. Disadvantageously, it can increase fric­ tion between the blade and vaginal wall. With pseudo fenestra­ tion, the forceps blade is smooth on the outer maternal side but indented on the inner fetal surface. he goal is to reduce head slipping yet improve the ease and safety of application and removal of forceps compared with pure fenestrated blades. In general, fenestrated blades are used for a fetus with a molded head or for rotation. In most situations, however, despite these subtle diferences any are appropriate. he blades are connected to shanks, which may be parallel or overlapping. Locks are found on all forceps and help to connect

F I G U R E 29-4 F o r O A or LOA positions, t h e left h a n d l e o f t h e for­ ceps is held in the left hand. The blade is i ntrodu ced into the l eft side of the pelvis between the fetal head a nd the fi ngers of the operator's right hand.

557

55 8

Del ivery

) FIGURE 29-5 I n sertion a rc of the blade. I m porta ntly, the t h u m b o f t h e rig ht h a n d , g u id es t h e blade d u ring placement, as shown i n Fig u re 29-6.

he blade tip is then gently passed into the vagina between the fetal head and the palmar surface of the ingers of the right hand (Fig. 29-5) . For application of the right blade, two or more in­ gers of the left hand are introduced into the right posterior por­ tion of the vagina to serve as a guide for the right blade. his blade is held in the right hand and introduced into the vagina. With each blade, the thumb is positioned behind the heel, and most of the insertion force comes from this thumb (Fig. 29-6) . I f the head i s positioned i n a let OA (LOA) o r right OA (ROA) position, then the lower of the two blades is typically placed irst. Mter positioning, the branches are articulated. he blades are constructed so that their cephalic curve is closely adapted to the sides of the fetal head (Fig. 29-7) . The fetal head i s perfectly grasped only when the long axis o f the blades corresponds t o the occipitomental diameter (see Fig. 29- 1 ) . As a result, most of the blade lies over the lateral face. If the fetus is in an OA positi� n, then the concave arch of the blades is directed toward the sagittal suture. If the fetus is in an occiput posterior (OP) position, then the concave arch is directed toward the midline face. Suboptimal blade placement can increase morbidity (Ramphul, 20 1 5) . For OA position, appropriately applied blades are equidistant from the sagittal suture, and each blade is equidistant from its adjacent lambdoidal suture. In the OP position, the blades are equidistant from the mid­ line of the face and brow. Also for OP position, blades are symmetrically placed relative to the sagittal suture and each coronal suture. Applied in this way, the forceps should not slip, and traction may be applied most advantageously. With most forceps, if one blade is applied over the brow and the other over the occiput, the instrument cannot be locked, or if locked, the blades will slip of when traction is applied (Fig. 29-8) . With both branches i n place, i t should b e an easy matter to articulate the handles, engage the lock, and correct asynclitism if present. Asynclitism is resolved by pulling and/or pushing each branch along the long axis of the instrument until the

F I G U R E 29-6 In a p p lying the second blade, insertional force is generated m a i n ly by the th u m b. (Reprod uced with perm ission from Yeom a n s ER: Operative vag i na l del ivery. I n Yeo m a n s E R, Hoff­ m a n BL, G i l stra p LC I I I, et a l (ed s): Cu n n i n g h a m a n d G i l stra p's Oper­ ative Obstetrics, 3 rd ed. New York, McGraw- H i l i Ed ucation, 20 1 7.)

inger guards align. If necessary, rotation to OA position is per­ formed before traction is applied (Fig. 29-9) . When it is certain that the blades are placed satisfactorily, then gentle, intermittent, downward and outward traction is exerted concurrent with maternal eforts until the perineum

8

F I G U R E 29-7 A. The forceps a re sym metrica l ly placed a n d a rticu l ated . B. T h e vertex is OA. (Reproduced with permission from Yeomans ER: Operative vag i n a l del ivery. In Yeoma ns E R, Hoffma n BL, G i l strap L C I I I, e t a l (ed s): C u n n i ng h a m a n d G i l stra p's Operative Obstetrics, 3 rd ed. New York, McGraw- H i l i Ed ucation, 201 7.)

Operative Vag i na l Del ivery

B

B. With i ncorrect placement, b lades tend to s l i p of with traction.

F I G U R E 29-8 I ncorrect a p p l ication of forceps. A. One blade over the occiput a n d the other over the brow. Forceps ca n not be locked.

begins to bulge. When the head is at 0 to + 2 of + 5 sta­ tion, the initial direction of traction is quite posterior, almost toward the Roor. With head descent, the vector of forces changes continuously (Fig. 29- 1 0) . As a teaching tool for this, a Bill axis traction device can be attached over the finger guards of most forceps. he instrument has an arrow and indicator line. When the arrow points directly to the line, traction is

A

B FIGURE 29-9 A. If LOA, the vertex is rotated (arrow) fro m t h is position to OA (B). (Re prod uced with permission from Yeo m a n s E R: Operative vag i na l del ivery. I n Yeom a n s E R , Hoffman BL, G i lstra p LC I I I, et al (eds): C u n n i n g h a m a n d G i l stra p's Operative Obstetrics, 3 rd ed. New York, McGraw- H i l i Ed ucation, 201 7.)

F I G U R E 29- 1 0 With low forceps, the direction of gentle traction for del ivery of the head is i n d icated (arrow). The vector c h a nges with feta l descent.

559

560

Del ivery

along the path of least resistance. With traction, as the vulva is distended by the occiput, an episiotomy may be performed if indicated. Additional horizontal traction is applied, and the handles are then gradually elevated. As the handles are raised, the head is extended. D uring the b irth of the head, mecha­ nisms of spontaneous delivery should be simulated as closely as possible. The force produced by the forceps on the fetal skull is a function of both traction and compression by the forceps, as well as friction produced by maternal tissues. It is impos­ sible to ascertain the amount of force exerted by forceps for an i ndividual patient. Traction should therefore be inter­ mittent, and the head should be allowed to recede between contractions, as in spontaneous labor. Except when urgently indicated, as in severe fetal bradycardia, delivery should be suiciently slow, deliberate, and gentle to prevent undue head compression. It is preferable to apply traction only with each uterine contraction. Maternal pushing will aug­ ment these eforts. After the vulva has been well distended by the head, the delivery may be completed in several ways. Some clinicians keep the forceps in place to control the head. If this is done, however, the blade volume adds to vulvar distention, thus

increasing the likelihood of laceration or necessitating a large episiotomy. To prevent this, the forceps may be removed, and delivery is then completed by maternal pushing (Fig. 29- 1 1 ) . Importantly, i f blades are disarticulated and removed too early, the head may recede and lead to a prolonged delivery. Delivery in some cases may be aided by addition of the modiied Ritgen maneuver. • Occiput Posterior Positions

Prompt delivery may at times become necessary when the small occipital fontanel is directed toward one of the sacro­ iliac synchondroses. In these right OP (ROP) or left OP (LOP) positions, the fetal head is often imperfectly lexed. With OP positions, second-stage labor can be lengthened. In these cases, the head may spontaneously deliver OP, may be manually or instrumentally rotated to an OA position, or may be delivered OP by forceps or vacuum. With manual rotation, an open hand is inserted into the vagina. The palm straddles the sagittal suture of the fetal head. The opera­ tor's ingers wrap around one side of the fetal face and thumb extends along the other side. If the occiput is ROP, rotation is clockwise to bring it to an ROA or OA position (Fig. 29- 1 2) .

B FIGURE 29-1 1 Bra nches a re re moved in the o pposite order from that i n which they were orig i n a l ly pl aced . The fi ng ers of the rig ht ha nd, covered by a sterile towel, bolster the peri n e u m . The th u m b is placed d i rectly on the head to prevent sudden eg ress. (Reproduced with permission from Yeomans ER: Operative vag i n a l del ivery. I n Yeo m a n s E R, Hoffm a n B L , G i l stra p LC I I I, e t a l (eds): C u n n i n g h a m a nd G i l stra p's Operative Obstetrics, 3 rd ed. New York, McG raw- H i l i Ed ucation, 20 1 7.)

I

/� (, '. _ .V\.. IA...._./ . ..

�

_ /'

F I G U R E 29- 1 2 A. M a n u a l rotation using the left ha nd, pa l mup, to rotate from ROP. B. The head is flexed and destatio ned d u ri ng clockwise rotation to reach an OA pOSition. (Reprod u ced with permission from Yeomans ER: Operative vag i n a l del ivery. I n Yeomans ER, H ofm a n BL, G i l stra p L C I I I, et a l (eds): C u n n i n g h a m a n d Gilstra p's Operative Obstetrics, 3 rd e d . New York, McGraw-H i l i Education, 201 7.)

Operative Va g i na l D e l ivery

With LOr position, rotation is counterclockwise. hree actions are performed simultaneously between contractions. The irst is fetal head fl e xion to provide a smaller diameter for rotation and subsequent descent. Second, slight destationing of the fetal head moves the head to a level in the maternal pelvis with suf­ ficient room to complete the rotation. Importantly, destation­ ing should not be confused with disengaging the fetal head, which is proscribed. Concurrently, some prefer to also place the other hand externally on the corresponding side of the maternal abdomen to pull the fetal back up toward the midline in syn­ chrony with the internal rotation. Le Ray and colleagues (2007, 20 1 3) reported a success rate of greater than 90 percent with manual rotation. Barth (20 1 5) provides an excellent summary of this technique. Manual rotations are most easily completed in multiparas. If manual rotation cannot be easily accomplished, application of forceps blades to the head in the posterior position and delivery from an or position may be the safest procedure. In many cases, the cause of a persistent or position and of the diiculty in accomplishing rotation is an anthropoid pelvis. his archi­ tecture opposes rotation and predisposes to posterior delivery (Fig. 2- 1 7, p. 3 1 ) . With forceps delivery from an o r position, downward and outward traction is applied until the base of the nose passes under the symphysis (Fig. 29- 1 3) . he handles are then slowly elevated until the occiput gradually emerges over the upper margin of the perineum. he forceps are directed downward again, and the nose, mouth, and chin successively emerge from the vulva. or delivery causes greater distention of the vulva, and a large episiotomy may be needed. or deliveries have a higher incidence of severe perineal lacerations and extensive episi­ otomy compared with OA positions (de Leeuw, 2008; Pearl, 1 993) . Also, newborns delivered from or positions have a higher incidence ofErb and facial nerve palsies, 1 and 2 percent, respectively, than those delivered from OA positions. As expected, rotations to OA ultimately decrease perineal delivery trauma (Bradley, 20 1 3) . Last, for forceps rotations from an o r to OA position, the Kielland instruments are preferred because they have a less pro­ nounced pelvic curve (Fig. 2 9- 1 4) . Cunningham and Gilstrap s

F I G U R E 29-1 3 Outlet fo rce ps del ivery from an OP positio n . The head should be flexed ater the breg ma passes u nder the sym physis.

A

Sliding lock

B F I G U R E 29- 1 4 Kie l land forceps. The cha racteristic features a re m i n i ma l pelvic c u rvatu re (A), s l i d i n g lock (8), a nd l ig ht weig ht.

Operative Obstetrics, 3rd edition, ofers a more detailed descrip­ tion of this Kielland forceps procedure (Yeomans, 20 1 7) . • Occiput Transverse Positions

With occiput transverse (OT) positions, rotation is required for delivery. With experienced operators, high success rates with minimal maternal morbidity can be achieved (Burke, 20 1 2; Stock, 20 1 3) . Either standard forceps, such as Simpson, or spe­ cialized forceps, such as Kielland, are employed. With Kielland forceps, each handle has a small knob, and branches are placed so that this knob faces the occiput. he station of the fetal head must be accurately determined to be at, or preferably below, the level of the ischial spines, especially in the presence of extreme molding. Kielland described two methods of applying the anterior blade. In our example, placement with a left OT (LOT) posi­ tion is described. With the wandering method, the anterior blade is first introduced into the posterior pelvis (Fig. 2 9- 1 5) . The blade i s then arched around the face to a n anterior posi­ tion. To permit this sweep of the blade, the handle is held close to the maternal left buttock throughout the maneuver. he sec­ ond blade is introduced directly posteriorly, and the branches are locked. After checking the application, the handles of the Kielland forceps are pulled slightly to the patient's right to increase fetal head lexion and create a smaller diameter for rotation. he irst and second fingers of the left hand are placed over the inger guards with the palm against the handles. his palm faces the maternal left. Concurrently, the first two ingers of the opera­ tor's right hand are placed against the anterior lambdoid suture. he fetal head is then destationed approximately 1 cm. For rotation in a counterclockwise direction, the wrist of the left hand supinates, to direct this palm upward. Simultaneously, two ingers of the right hand press on the edge of the right pari­ etal bone that borders the lambdoid suture. This ensures that the fetal head turns with the blades and does not slip. he second type of blade application introduces the anterior blade with its cephalic curve directed upward to curve under

561

562

Del ive ry

A

B

c

F I G U R E 29- 1 5 A. Appl ication of the right bra nc h of the Kiel land forceps to a head in LOT position. The knob on t h i s branch (colored blue) will u lti mate ly face the occi put. B. The rig ht bra n c h is wa ndered to its fi nal position beh i nd the sym physis. C. I nsertion of the left branch of the Kie l l a n d forceps d i rectly posterior along the h o l l ow of the sacrum. Th is bra nc h is i n serted to the materna l rig ht of the a nterior bra nch to aid i n engaging the sliding lock. (Reprod u ced with permission from Yeomans ER: Operative vag inal del ivery. I n Yeomans ER, Hoffman BL, G i l stra p LC I I I, et al (eds): Cu n n i ng ha m and G i l strap's Operative Obstetrics, 3 rd ed. New York, McG raw- H i l i Education, 20 1 7.)

the symphysis. After it has been advanced far enough toward the upper vagina, it is turned on its long axis through 1 80 degrees to adapt the cephalic curvature to the head. With either application, after rotation completion, the oper­ ator may choose from two acceptable methods for delivery. In one, the operator applies traction on the Kielland forceps using a bimanual grip described previously for conventional forceps (p. 559). When the posterior fontanel has passed under the subpubic arch, the handles can be elevated to the horizon­ tal. Raising the handles above the horizontal may cause vagi­ nal sulcus tears because of the reverse pelvic curve (Dennen, 1 95 5) . Alternatively, the Kielland forceps can be removed after rotation and replaced with conventional forceps. With this approach, moderate traction is first employed to seat the head before switching instruments. • Face Presentations

With a mentum anterior face presentation, forceps can be used to efect vaginal delivery. The blades are applied to the sides of the head along the occipitomental diameter, with the pelvic curve directed toward the neck. Downward traction is exerted until the chin appears under the symphysis. hen, by an upward movement, the face is slowly extracted, with the nose, eyes, brow, and occipur appearing in succession over the anterior margin of the perineum. Forceps should not be applied to the mentum posterior presentation because vaginal delivey is impossible except in vey smalttuses.

Vacuum devices contain a cup, shaft, handle, and vacuum generator. Vacuum cups may be metal or hard or soft plastic, and they may also difer in their shape, size, and reusability. In the United States, nonmetal cups are generally preferred, and there are two main types. he soft cup is a pliable bell-shaped dome, whereas the rigid type has a firm flattened mushroom­ shaped cup and circular ridge around the cup rim (Table 29-2) . When compared, rigid mushroom cups generate significantly more traction force (Hofmeyr, 1 990; Muise, 1 993) . With or positions or with asynclitism, the flatter cup also permits improved placement at the flexion point, which is typically less accessible with these head positions. The trade-of is that the flatter cups have higher scalp laceration rates. Thus, many manufacturers recommend soft bell cups for more straightfor­ ward OA deliveries. Several investigators have compared outcomes with various rigid and soft cups. Metal cups provide higher success rates but greater rates of scalp injuries, including cephalohematomas

f f - � . --

A

:0

VAC U U M EXTRACTION

• Vacuum Extractor Desig n

With vacuum delivery, suction i s created within a cup placed on the fetal scalp such that traction on the cup aids fetal expul­ sion. In the United States, vacuum extractor is the preferred term, whereas in Europe it is commonly called a ventouse (Fig. 29- 1 6) . heoretical beneits of this tool compared with forceps include simpler requirements for precise positioning on the fetal head and avoidance of space-occupying blades within the vagina, thereby mitigating maternal trauma.

B F I G U R E 29- 1 6 Vac u u m del ivery systems. A. The Kiwi OmniCup conta i n s a hand held vacuu m-generati ng p u m p, which is attached via flexi ble t u b i n g to a rigid plastic m u s h room c u p. B. The Mityvac Mystic II MitySoft Bell Cup has a soft bel l cup attac hed by a semirigid shaft to a handheld p u m p.

Operative Vag i na l Del ivery

TABLE 29-2. Vac u u m Cups for Operative Vag i na l Delivery

Cup Style

Manufacturer

+

Soft Bel l C u p

GentleVac Kiwi P roCu p Mityvac M itySoftBe l 1 Pea rl Edge Be l l C u p Sec u re C u p Soft To uch Te nder Tou c h Te nder To u c h U ltra Ve lvet Toucha Reusa ble vac u u m del ivery c u pa

Posterior fonta n e l le

- _ ... _ -

OB Scientific Cl i n ica l I n n ovatio n s CooperS u rg ica l CooperS u rg i c a l Uta h Med ica l P rod u cts Uta h Medica l P roducts Uta h Med ical P rod u cts Uta h Med ica l Prod u cts Uta h Medical P rod u cts CooperS u rg ica l

3 em I

I

I

\ \

6 em

I

/

/

..

/

\ \\ .... ..

o

,

\

\

\

\ I

I

" ------,/ //� +

I I I

-; -_ _ _ _

Flexion poi nt Cup perimeter

Anterior fontanelle

Rigid Mushroom C u p

F lex Cup Mityvac M-Style S u pe r M-Style M ityvac M-Sel ectb Kiwi O m n i C u pb Kiwi O m n i-MT Kiwi O m n i-C C u pc

Uta h Med ica l P rod u cts Coope rS u rg ica l CooperS u rg ica l CooperS u rg i ca l Cl i n i ca l I n novati ons C l i n ica l I n n ovations C l i n ical I n n ovations

"Reusa ble c u ps. bSu ita ble for occ i put posterior positions o r asyn c l i t i s m . ( F o r extractions t h ro u g h a hyste rotomy i nc i s i o n d u ri ng cesa rea n d e l ivery.

(O'Mahony, 20 1 0) . In another study, Kuit and coworkers ( 1 993) found that the only advantage of the soft cups was a lower incidence of scalp inj ury. hey reported a 1 4-percent episiotomy extension rate with both rigid and pliable cups. In a review, Vacca (2002) concluded that there were fewer scalp lacerations with the soft cup, but that the rate of cephalohe­ matomas and subgaleal hemorrhage was similar between soft and rigid cups. Importantly, high-pressure vacuum generates large amounts of force regardless of the cup used (Duchon, 1 998) . Aside from the cup, the shaft that connects the cup and han­ dle may be lexible or semiflexible. Tubing-like flexible shafts may be preferred for OP positions or asynclitic presentation to permit better seating of the cup. Last, the vacuum generator may be handheld and actuated by the operator or may be held and operated by an assistant. • Technique

An important step in vacuum extraction is proper cup place­ ment over the lexion point. his pivot point maximizes traction, minimizes cup detachment, lexes but averts twisting the fetal head, and delivers the smallest head diameter through the pel­ vic oudet. This improves success rates, lowers fetal scalp injury rates, and lessens perineal trauma because the smallest fetal head diameter distends the vulva (Baskett, 2008) . The lexion point is found along the sagittal suture, approxi­ mately 3 cm in front of the posterior fontanel and approximately

FIGURE 29- 1 7 Drawi ng demonstrates correct cup placement a t t h e flexion point. A l o n g the sag itta l sutu re, t h i s s pot l i e s 3 cm fro m the posterior fonta nel a n d 6 cm from the a nterior fonta nel.

6 cm from the anterior fontanel. Because cup diameters range from 5 to 6 cm, when properly placed, the cup rim lies 3 cm from the anterior fontanel (Fig. 29- 1 7) . Placement of the cup more anteriorly on the fetal cranium-near the anterior fonta­ nel-should be avoided as it leads to cervical spine extension during traction unless the fetus is small. Such placement also delivers a wider fetal head diameter through the vaginal open­ ing. Last, asymmetrical placement relative to the sagittal suture may worsen asynclitism. For elective use, cup placement in OA positions is seldom diicult. In contrast, when the indication for delivery is failure to descend caused by occipital malposition­ with or without asynclitism or deflexion-cup positioning can be diicult. During cup placement, maternal soft tissue entrapment predisposes the mother to lacerations and virtually ensures cup dislodgement, colloquially called a "pop of. " Thus, the entire cup circumference should be palpated both before and after the vacuum has been created and again prior to traction to exclude such entrapment. Gradual vacuum creation is advocated by some and is generated by increasing the suction in increments of 0.2 kg/cm 2 every 2 minutes until a total negative pressure of 0.8 kg/cm 2 is reached (Table 29-3 ) . hat said, other studies have shown that negative pressure can be increased to 0.8 kg/cm2 in < 2 minutes without a signiicant diference in eicacy or in maternal and fetal outcomes (Suwannachat, 20 1 1 , 20 12) . TABLE 29-3. Vac u u m P ress u re Conversions

mm Hg

cm Hg

1 00 200 300 400 500 600

10 20 30 40 50 60

inches Hg

3.9 7.9 1 1 .8 1 5 .7 1 9.7 23.6

I b/in 2

kg/cm 2

1 .9 3.9 5.8 7.7 9.7 1 1 .6

0. l 3 0.2 7 OA 1 0.54 0.68 0.82

563

564

Del ivery

Once suction is created, the instrument handle is grasped, and traction is initiated. Similar to forceps delivery, traction angles mirror that in Figure 29- 1 0. Eforts are intermittent and coordinated with maternal expulsive eforts. Manual torque to the cup is avoided as it can cause cup displacement or cepha­ lohematomas and, with metal cups, "cookie-cutter"-type scalp lacerations. hus, OA oblique positions are corrected not by rotation, but solely by downward outward traction. During pulls, the operator should place the nondominant hand within the vagina, with the thumb on the extractor cup and one or more ingers on the fetal scalp. So positioned, descent of the presenting part can be j udged and the traction angle can be adjusted with head descent. In addition, the relationship of the cup edge to the scalp can be assessed to help detect cup separation. Between contractions, some physicians will lower the suc­ tion levels to decrease rates of scalp injury, whereas others will maintain suction in cases with a nonreassuring fetal heart rate to aid rapid delivery. No diferences in maternal or fetal out­ come were noted if the level of vacuum was decreased between contractions or if an efort was made to prevent fetal loss of station (Boill, 1 997) . Once the head is extracted, the vacuum pressure is relieved and the cup removed. Vacuum extraction should be considered a trial. Without early and clear evidence of descent toward delivery, an alter­ native delivery approach should be considered. As a general guideline, progressive descent should accompany each traction attempt. Neither data nor consensus are available regarding the number of pulls required to efect delivery, the maximum number of cup pop-ofs that can be tolerated, or optimal total duration of the procedure. Some manufacturers have recom­ mendations regarding these in their instructional literature (Clinical Innovations, 20 1 6; CooperSurgical, 20 1 1 ) . During a vacuum extraction trial, cup dislodgement due to technical failure or less than optimal placement should not be equated with dislodgement under ideal conditions of exact cup placement and optimal vacuum maintenance. hese cases may merit either additional attempts at placement or, alternatively, a trial of forceps (Ezenagu, 1 999; Williams, 1 99 1 ) . he least desirable cases are those in which traction without progress or multiple disengagements occur following correct cup applica­ tion and appropriate traction. As with forceps, clinicians should embrace a willingness to abandon attempts at vacuum extrac­ tion if satisfactory progress is not made (American College of Obstetricians and Gynecologists, 20 1 5) .

REFERENCES Accreditation Council for Graduate Medical Education: Obstetrics and Gynecology Case Logs. 20 1 5 . Available at: http://www.acgme.org/Portals/ 0/PDFs/220_NationaLReport_Program_Version.pdf. Accessed May 1 1 , 20 1 6 Aiken AR, Aiken CE, Alberry M S , e t al: Management o f fetal malposition in the second stage of labor: a propensity score analysis. Am ] Obstet Gynecol 2 1 2 (3) : 3 5 5 .e 1 , 20 1 5 Alexander ]M, Leveno K], Hauth ]C, et al: Failed operative vaginal delivery. Obstet GynecoI 1 1 4(5) : 1 0 1 7, 2009 American College of Obstetricians and Gynecologists, Society for Maternal­ Fetal Medicine: Safe prevention of the primary cesarean delivery. Obstetric Care Consensus No. 1 , March 2014, Reairmed 2 0 1 6

American College o f Obstetricians and Gynecologists: Operative vaginal deliv­ ery. Practice Bulletin No. 1 54, November 20 1 5 Bahl R, Patel R, Swingler R, et al: Neurodevelopmental outcome at 5 years after operative delivery in the second stage of labor: a cohort study. Am ] Obstet GynecoI 1 97: 147, 2007 Bahl R, Van de Venne M , Macleod M, et al: Maternal and neonatal morbidity in relation to the instrument used for mid-cavity rotational operative vaginal delivery: a prospective cohort study. B]OG 1 20 ( 1 2) : 1 526, 20 1 3 Bailit ]L, Grobman WA, Rice IM, e t al: Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medi­ cine Units Network. Am ] Obstet GynecoI 2 1 4(5):63 8 .e 1 , 2016 Barth H ]r: Persistent occiput posterior. Obstet GynecoI 1 2 5 (3):695, 20 1 5 Bashore A , Phillips W H ]r, Brinkman C R III: A comparison o f the morbidity ofmidforceps and cesarean delivety. Am ] Obstet GynecoI 1 62 (6) : 1 428, 1 990 Baskett TF, Fanning CA, Young DC, et al: A prospective observational study of 1 000 vacuum assisted deliveries with the OmniCup device. ] Obstet Gyn­ aecol Can 30 (7) : 5 73 , 2008 Ben-Haroush A, Melamed N, Kaplan B, et al: Predictors of failed operative vaginal delivery: a single-center experience. Am ] Obstet Gynecol 1 97:308. e 1 , 2007 Bofill ]A, Rust OA, Schorr S], et al: A randomized trial of two vacuum extrac­ tion techniques. Obstet Gynecol 89(5 Pt 1 ) :758, 1 997 BoIs EM, Hendriks E], Berghmans BC, et al: A systematic review of etiologi­ cal factors for postpartum fecal incontinence. Acta Obstet Gynecol Scand 89(3) :302, 2 0 1 0 Bradley MS, Kaminski R], Streitman D C , e t al: Efect o f rotation o n perineal lacerations in forceps-assisted vaginal deliveries. Obstet Gynecol l 22( 1 ) : 1 32, 20 1 3 Broman SH, Nichols PL, Kennedy WA: Preschool IQ: prenatal and early developmental correlates. Hillsdale, L. Erlbaum Associates, 1 975 Burke N , Field K, Mujahid F, et al: Use and safety of Kielland's forceps in cur­ rent obstetric practice. Obstet Gynecol 1 20 (4) :766, 20 1 2 Caughey A B , Sandberg PL, Zlatnik M G , et al: Forceps compared with vacuum. Rates of neonatal and maternal morbidity. Obstet Gynecol 1 06:908, 2005 Cheong YC, Abdullahi H, Lashen H , et al: Can formal education and train­ ing improve the outcome of instrumental delivery? Eur ] Obstet Gynecol 1 1 3 : 1 39, 2004 Clinical Innovations: Kiwi complete vacuum delivery system instruc­ tions for use. Available at: http://clinicalinnovations.com/wp-content/ uploads/20 1 5/03/Kiwi-IFU.pdf. Accessed May 1 3 , 20 1 6 Contag SA, Clifton RG, Bloom SL, e t al: Neonatal outcomes and operative vaginal delivery versus cesarean delivery. Am ] PerinatoI 27(6):493, 20 1 0 CooperSurgical: Mityvac vacuum-assisted delivery. 2 0 1 1 . Available at: http:// www. coopersurgical.com/Products/DetaiIlMi tyvac-Vacuum -Assisted­ Delivery-Pumps-and-Accessories. Accessed May 1 3 , 20 1 6 Damron D P , Capeless EL: Operative vaginal delivery: a comparison o f forceps and vacuum for success rate and risk of rectal sphincter injury. Am ] Obstet Gynecol 1 9 1 : 907, 2004 de Leeuw ]W, de Wit C, Kuijken ]P, et al: Mediolateral episiotomy reduces the risk for anal sphincter injury during operative vaginal delivery. B]OG 1 1 5 : 1 04, 2008 Demissie K, Rhoads GG, Smulian ]C, et al: Operative vaginal delivery and neonatal and infant adverse outcomes: population based retrospective analy­ sis. BM] 329 (7456) :24, 2004 Dennen EH: Forceps Delivery. Philadelphia, F .A. Davis Company, 1 9 55 de Vogel ] , van der Leeuw-van Beek A, Gietelink 0, et al: The efect of a medio­ lateral episiotomy during operative vaginal delivery on the risk of developing obstetrical anal sphincter injuries. Am ] Obstet GynecoI 206(5) :404, 20 1 2 Dierker L], Rosen M G , Thompson K , e t al: Midforceps deliveries: long-term outcome of infants. Am ] Obstet Gynecol 1 54:764, 1 986 Dolan LM, Hilton P: Obstetric risk factors and pelvic loor dysfunction 20 years ater first delivery. Int Urogynecol ] Pelvic Floor Dysfunct 2 1 :535, 20 1 0 Ducarme G , Hamel ]F, Bouet PE, e t al: Maternal and neonatal morbidity after attempted operative vaginal delivery according to fetal head station. Obstet GynecoI 1 26 (3) : 52 1 , 20 1 5 Duchon MA, DeMund MA, Brown RH : Laboratory comparison of modern vacuum extractors. Obstet Gynecol 72: 1 5 5, 1 998 Dupuis 0, Moreau R, Pham MT: Assessment of forceps blade orientations during their placement using an instrumented childbirth simulator. B]OG 1 1 6 (2):327, 2009 Dupuis 0, Moreau R, Silveira R, et al: A new obstetric forceps for the training of junior doctors: a comparison of the spatial dispersion of forceps blade trajectories between junior and senior obstetricians. m ] Obstet Gynecol 1 94: 1 524, 2006 Dupuis 0, Silveira R, Dupont C, et al: Comparison of "instrument-associated" and "spontaneous" obstetric depressed skull fractures in a cohort of 68 neo­ nates. Am ] Obstet GynecoI 1 92 ( 1 ) : 1 6 5 , 2005

Operative Va g i nal D e l i ve ry Evers EC, Blomquist J L, McDermott KC, et al: Obstetrical anal sphincter laceration and anal incontinence 5- 1 0 years after childbirth. Am J Obstet GynecoI 207(5):425.e 1 , 20 1 2 Ezenagu LC, Kakaria R , Bofill JA: Sequential use o f instruments a t operative vaginal delivery: is it safe? Am J Obstet Gynecol 1 80 : 1 446, 1 999 Faiweather 0 : Obstetric management and follow-up of the very low-birth­ weight infant. J Reprod Med 26:387, 1 9 8 1 Fitzwater JL, Owen J , Ankumah NA, e t al: Nulliparous women i n the second stage of labor: changes in delivery outcomes berween rwo cohorts from 2000 and 20 1 1 . Obstet GynecoI 1 26( 1 ) : 8 1 , 20 1 5 Friedman A, Sachtleben MR, Bresky PA: Dysfunctional labor, 1 2. Long-term efects on the fetus. Am J Obstet GynecoI 1 27:779, 1 977 Friedman EA, Sachtleben-Murray M R, Dahrouge 0, et al: Long-term efects of labor and delivery on ofspring: a matched-pair analysis. Am J Obstet Gynecol 1 5 0:94 1 , 1 984 Gardella C, Taylor M, Benedetti T, et al: The efect of sequential use of vacuum and forceps for assisted vaginal delivery on neonatal and maternal outcomes. Am J Obstet Gynecol 1 8 5 (4):896, 200 1 Gartland 0, MacArthur C, Woolhouse H, et al: Frequency, severiry and risk factors for urinary and faecal incontinence at 4 years postpartum: a prospec­ tive cohort. BJOG 1 23(7) : 1 203, 20 1 6 Gurol-Urganci I , Cromwell DA, Edozien LC, e t al: hird- and fourth-degree perineal tears among primiparous women in England between 2000 and 20 1 2: time trends and risk factors. BJOG 1 20 ( 1 2) : 1 5 1 6, 20 1 3 Gyhagen M , Bullarbo M , Nielsen T , e t al: The prevalence o f urinary inconti­ nence 20 years after childbirth: a national cohort study in singleton primipa­ rae after vaginal o r caesarean delivery. BJOG 1 20: 1 44, 20 1 3 Hagadorn-Freathy AS, Yeomans ER, Hankins GO: Validation o f the 1 988 ACOG forceps classiication system. Obstet Gynecol 77:356, 1 99 1 Halpern SH, Muir H , Breen W, e t al: A multicenter randomized controlled trial comparing patient-controlled epidural with intravenous analgesia for pain relief in labor. Anesth Analg 99(5) : 1 532, 2004 Halscott TL, Reddy UM, Landy HJ, et al: Maternal and neonatal outcomes by attempted mode of operative delivery from a low station in the second stage of labor. Obstet GynecoI 1 26 (6) : 1 265, 20 1 5 Hamilton BE, Martin JA, Osterman MJ, et al: Births: final data for 2 0 1 4. Nat! Vital Stat Rep 64 ( 1 2) : 1 , 20 1 5 Handa L, Blomquist JL, McDermott KC, et al: Pelvic floor disorders after vaginal birth: efect of episiotomy, perineal laceration, and operative birth. Obstet Gynecol 1 1 9 (2 Pt 1 ) :233, 20 1 2 Hirayama F , Koyanagi A , Mori R, e t al: Prevalence and risk factors for third­ and fourth-degree perineal lacerations during vaginal delivery: a multi­ country study. BJOG 1 1 9 (3) :340, 20 1 2 Hirsch E , Haney EI, Gordon TE, e t al: Reducing high-order perineal laceration during operative vaginal delivery. Am J Obstet GynecoI 1 98 (6) :668 .e 1 , 2008 Hofmeyr GJ, Gobetz L, Sonnendecker EW, et al: New design rigid and soft vacuum extractor cups: a preliminary comparison of traction forces. BJOG 97(8):68 1 , 1 990 Kudish B, Blackwell S , Mcneeley SG, et al: Operative vaginal delivery and mid­ line episiotomy: a bad combination for the perineum. Am J Obstet Gynecol 1 9 5 (3):749, 2006 Kuit JA, Eppinga HG, Wallenburg HCS, et al: A randomized comparison of vacuum extraction delivery with a rigid and a pliable cup. Obstet Gynecol 82:280, 1 993 Kyser L, Lu X, Santillan 0 , et al: Forceps delivery volumes in teaching and nonteaching hospitals: are volumes suicient for physicians to acquire and maintain competence? Acad Med 89 ( 1 ) :7 1 , 20 1 4 Landy HJ, Laughon S K, Bailit J L, et al: Characteristics associated with severe perineal and cervical lacerations during vaginal delivery. Obstet Gynecol 1 1 7(3) :627, 2 0 1 1 Leijonhuvud A, Lundholm C, Cnattingius S, et al: Risks of stress urinary incontinence and pelvic organ prolapse surgery in relation to mode of child­ birth. Am J Obstet GynecoI 204( 1 ) :70.e 1 , 20 1 1 Le Ray C, Deneux-haraux C, Khireddine I, et al: Manual rotation to decrease operative delivery in posterior or transverse positions. Obstet Gynecol 1 22(3) :634, 20 1 3 Le Ray C , Serres P , Schmitz T, e t al: Manual rotation i n occiput posterior or transverse positions. Obstet Gynecol 1 1 0: 873, 200 Leslie KK, Dipasqule-Lehnerz P, Smith M: Obstetric forceps training using visual feedback and the isometric strength testing unit. Obstet Gynecol 1 05:377, 2005 Lowe B: Fear of failure: a place for the trial of instrumental delivery. BJOG 94:60, 1 987 MacArthur C, Wilson 0, Herbison P, et al: Faecal incontinence persisting after childbirth: a 1 2-year longitudinal study. BJOG 1 20(2) : 1 69, 20 1 3 MacArthur C, X ilson 0 , Herbison P , e t al: Urinary incontinence persisting after childbirth: extent, delivery history, and efects in a 1 2-year longitudinal cohort study. Prolong Study Group. BJOG 1 23(6) : 1 022, 20 1 6

Malvasi A, Tinelli A, Barbera A, et al: Occiput posterior position diagnosis: vaginal examination or intrapartum-sonography? A clinical review. J Matern Fetal Neonatal Med 27(5 ) : 520, 20 1 4 Marucci M , Cinnella G , Perchiazzi G , e t al: Patient-requested neuraxial analge­ sia for labor: impact on rates of cesarean and instrumental vaginal delivery. Anesthesiology 1 06(5) : 1 035, 2007 Merriam A, Ananth CV, Wright JD, et al: Trends in operative vaginal delivery, 2005-20 1 3 : a population-based study. BJOG 1 24(9) : 1 365, 20 1 7 Muise L , Duchon A , Brown R H : he efect of artificial caput o n perfor­ mance of vacuum extractors. Obstet GynecoI 8 1 (2) : 1 70, 1 993 Mulder F, Schofelmeer M, Hakvoort R, et al: Risk factors for postpartum urinary retention: a systematic review and meta-analysis. BJOG 1 1 9 ( 1 2) : 1440, 20 1 2 Murphy O J , Libby G , Chien P, e t al: Cohort study of forceps delivery and the risk of epilepsy in adulthood. Am J Obstet Gynecol 1 9 1 :392, 2004 Murphy OJ, Macleod M, Bahl R, et al: A cohort study of maternal and neona­ tal morbidiry in relation to use of sequential instruments at operative vaginal delivery. Eur J Obstet Gynecol Reprod Bioi 1 56 ( 1 ) : 4 1 , 20 1 1 Nelson L, Furner SE, Westercamp M, et al: Cesarean delivery for the preven­ tion of anal incontinence. Cochrane Database Syst Rev 2 :CD006756, 20 1 0 Nilsen ST: Boys born by forceps and vacuum extraction examined at 1 8 years of age. Acta Obstet Gynecol Scand 63: 549, 1 984 Nygaard IE, Rao SS, Dawson JD: Anal incontinence after anal sphincter disruption: a 30-year retrospective cohort study. Obstet Gynecol 8 9 : 896, 1 99 O'Callaghan ME, MacLennan AH, Gibson CS, et al: Epidemiologic associa­ tions with cerebral palsy. Obstet GynecoI 1 1 8(3): 576, 20 1 1 O'Mahony F, Hofmeyr GJ, Menon V: Choice of instruments for assisted vagi­ nal delivery. Cochrane Database Syst Rev 1 1 :CD005455, 20 1 0 Osterman MJ, Martin JA, Menacker F : Expanded health data from the new birth certificate, 2006. Nat! Vital Stat Rep 58(5) : 1 , 2009 Palatnik A, Grobman WA, Hellendag MG, et al: Predictors of failed operative vaginal delivery in a contemporary obstetric cohort. Obstet Gynecol 1 27 (3): 50 1 , 20 1 6 Pearl M L, Roberts J M , Laros RK, e t al: Vaginal delivery from the persistent occiput posterior position: influence on maternal and neonatal morbidiry. J Reprod Med 3 8 : 9 5 5 , 1 993 Pergialiotis V, Vlachos 0, Protopapas A, et al: Risk factors for severe perineal lacerations during childbirth. Int J Gynaecol Obstet 1 2 5 ( 1 ) :6, 20 1 4 Pifarotti P , Gargasole C , Folcini C , e t al : Acute post-partum urinary reten­ tion: analysis of risk factors, a case-control study. Arch Gynecol Obstet 289(6) : 1 249, 20 1 4 Ramphul M, Kennelly MM, Burke G , e t al: Risk factors and morbidiry asso­ ciated with suboptimal instrument placement at instrumental delivery: observational study nested within the Instrumental Delivery & Ultrasound randomised controlled trial ISRCTN 72230496. BJOG 1 22 (4) : 5 5 8 , 20 1 5 RobertSon PA, Laros RK, Zhao L : Neonatal and maternal outcome i n low­ pelvic and mid-pelvic operative deliveries. Am J Obstet Gynecol 1 62 : 1 436, 1 990 Rorrveit G, Dalrveit AK, Hannestad YS, et al: Urinary incontinence after vagi­ nal delivery or cesarean section. N Engl J Med 348:9000, 2003 Schuit E, Kwee A, Westerhuis ME, et al : A clinical prediction model to assess the risk of operative delivery. BJOG 1 1 9(8) : 9 1 5 , 20 1 2 Schwartz DB, Miodovnik M , Lavin J P Jr: Neonatal outcome among low birth weight infants delivered spontaneously or by low forceps. Obstet Gynecol 62:283, 1 983 Skinner S , Davies-Tuck M, Wallace E, et al: Perinatal and maternal outcomes after training residents in forceps before vacuum instrumental birth. Obstet Gynecol 1 30( 1 ) : 1 5 1 , 20 1 7 Seidman OS, Laor A , Gale R , e t al: Long-term efects of vacuum and forceps deliveries. Lancet 337: 1 5 83, 1 9 9 1 Solt I , Jackson S, Moore T , e t al: Teaching forceps: the impact o f proactive faculry. Am J Obstet Gynecol 204(5) :448. e 1 , 20 1 1 Spiliopoulos M, Kareti A, Jain NJ, et al: Risk of peripartum hysterectomy by mode of delivery and prior obstetric history: data from a population-based study. Arch Gynecol Obstet 283(6) : 1 26 1 , 20 1 1 Spong CY, Berghella V, Wenstrom KD, et al: Preventing the first cesarean delivery: summary of a Joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medi­ cine, and American College of Obstetricians and Gynecologists X orkshop. Obstet GynecoI 1 20(5): 1 1 8 1 , 20 1 2 Stock SJ, Josephs K , Farquharson S , e t al: Matenal and neonatal outcomes of successful Kielland's rotational forceps delivery. Obstet GynecoI 1 2 1 (5): 1 032, 20 1 3 Suwannachat B , Laopaiboon M , Tonmat S , e t al: Rapid versus stepwise appli­ cation of negative pressure in vacuum extraction-assisted vaginal delivery: a multicentre randomised controlled non-inferiority trial. BJOG 1 1 8 ( 1 0): 1 247, 20 1 1

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De l ive ry Suwannachat B, Lumbiganon P, Laopaiboon M: Rapid versus stepwise nega­ tive pressure application for vacuum extraction assisted vaginal delivery. Cochrane Database Syst Rev 8:CD006636, 20 1 2 Tahtinen RNf, Cartwright R , Tsui JF, et al: Long-term impact o f mode of delivery on stress urinary incontinence and urgency urinary incontinence: a systematic review and meta-analysis. Eur Urol 70( 1 ) : 1 48, 20 1 6 Tempest N, Hart A, Walkinshaw S , et al : A re-evaluation of the role of rota­ tional forceps: retrospective comparison of maternal and perinatal outcomes following diferent methods of birth for malposition in the second stage of labor. BJOG 1 20 ( 1 0) : 1 2 7, 20 1 3 Towner 0 , Castro NlA, Eby-Wilkens E , et al: Efect o f mode o f delivery in nulliparous women on neonatal intracranial injuY. N Engl J /Ied 34 1 : 1 09, 1 999 Towner DR, Ciotti MC: Operative vaginal delivery: a cause of birth injury or is it? Clin Obstet Gynecol 50(3): 563, 2007 Vacca A: Vacuum-assisted delivery. Best Pract Res Clin Obstet Gynaecol 1 6: 1 7, 2002 Verhoeven CJ, Nuij C, Janssen-RolfCR, et al: Predictors for failure of vacuum­ assisted vaginal delivery: a case-control study. Eur J Obstet Gynecol Reprod Bioi 200:29, 20 1 6 Voll0yhaug I , M0rkved S , Salvesen 0 , et al: Forceps delivery i s associated with increased risk of pelvic organ prolapse and muscle trauma: a cross-sectional

study 1 6-24 years after irst delivery. Ultrasound Obstet Gynecol 46(4) : 487, 20 1 5 Walsh CA, Robson M , McAulife FM: Mode of delivery at term and adverse neonatal outcomes. Obstet Gynecol 1 2 1 ( 1 ) : 1 22, 20 1 3 Wassen MM, H ukkelhoven CW, Scheepers He, e t al: Epidural analgesia and operative delivery: a ten-year population-based cohort study in The Nether­ lands. Eur J Obstet Gynecol Reprod Bioi 1 83: 1 2 5 , 20 1 4 Wen SW, Liu S , Kramer MS, et al: Comparison o f maternal and infant out­ comes between vacuum extraction and forceps deliveries. Am J Epidemiol 1 53 (2) : 1 03, 200 1 Werner EF, Janevic TM, IIIuzzi J, et al: Mode of delivery in nulliparous women and neonatal intracranial injury. Obstet Gynecol 1 1 8(6): 1 239, 20 1 1 Wesley B, Van den Berg B , Reece EA: The effect of operative vaginal delivery on cognitive development. Am J Obstet Gynecol 1 66:288, 1 992 Williams MC, Knuppel A, O' Brien WF, et al: A randomized comparison of assisted vaginal delivery by obstetric forceps and polyethylene vacuum cup. Obstet Gynecol 78:789, 1 99 1 Yancey MK, Pierce B , Schweitzer 0 , et al: Observations o n labor epidural analge­ sia and operative delivery rates. Am J Obstet Gynecol 1 80(2 Pt 1 ) :353, 1 999 Yeomans ER: Operative vaginal delivery. I n Yeomans ER, Hofman B L, Gil­ strap LC I I I , et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hili Education, 20 1 7

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I n some instances, abdominal hysterectomy is indicated following delivery. When performed at the time of cesarean delivery, the operation is termed cesarean hysterectomy. If done within a short time after vaginal delivery, it is termed pospar­ tum hysterectomy. Peripartum hysterectomy is a broader term that combines these two. In most cases, hysterectomy is total, but supracervical hysterectomy is an option. The adnexa are not usually removed. In most instances, a simple or type I hysterec­ tomy is performed. However, for women with invasive cervical cancer, radical hysterectomy removes the uterus, parametrium, and proximal vagina to achieve tumor excision with negative margins. Also, for cases of placenta percreta that extend toward the pelvic sidewall, similar radical excision of the parametrium may be needed.

CESAREAN DELIVERY IN THE U N ITED STATES ?he anterior suace of the uterus is opened longitudinaly along its midline. ?his is best accomplished by making an incision a ew centimetres long with a scapel, and then rap­ idy enlarging it with the scissors to 1 6 or 18 centimetres. ?he membranes are then rupture, the child is seized by one oot and rapidy extracted ] Whitridge Williams ( 1 903) -

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From the above description, cesarean technique has evolved during the past century. For example, preference for classical hysterotomy has given way to low transverse incision. Evi­ dence-based data now guide many surgical steps and are pre­ sented throughout this chapter. Of deinitions, cesarean delivey defines the birth of a fetus via laparotomy and then hysterotomy. This defi n ition is not applied to removal of the fetus from the abdominal cavity in the case of uterine rupture or with abdominal pregnancy. Rarely, hysterotomy is performed in a woman who has just died or in whom death is expected soon-postmortem or perimortem cesarean delivery (Chap. 47, p. 93 1 ) .

In the United S tates, the cesarean delivery rate rose from 4.5 percent in 1 970 to 32.9 percent in 2009. Following this peak, the rate has trended slightly downward, and it was 32.0 per­ cent in 20 1 5 (Martin, 20 1 7) . Some indications for perform­ ing cesarean delivery are shown in Table 30- 1 . More than 85 percent of these operations are performed for four reasollS­ prior cesarean delivery, dystocia, fetal jeopardy, or abnormal fetal presentation. The latter three compose the main i ndi­ cations for primary cesarean delivery (Barber, 20 1 1 ; B oyle, 20 1 3) . The reasons for persistently significant cesarean rates are not completely understood, but some explanations include the fol­ lowing: 1 . Women are having fewer children, thus, a greater percent­ age of births are among nulparas, who are at increased risk for cesarean delivery. 2. The average maternal age is rising, and older women, especially n ulliparas , have a higher risk of cesarean delivery.

568

Del ivery

TABLE 30- 1 . Some I n dications for Cesa rea n Del ivery

Maternal

Prior cesare a n del ive ry Abnormal pl a ce n tati o n Mate rna req uest Prior classical hysterotomy U n known u terine sca r type Uteri n e i ncision d e h i sce n ce Prior fu l i-th ickness myomectomy Gen ita l tract obstructive mass I nvasive cervica l cance r P ri o r trachelecto my Perma n ent cerclage P rior pelvic reco n structive s u rgery Prior s i g n ifica nt peri neal t ra u ma Pelvic d eform ity H SV o r H IV i n fection Ca rdiac or pu l mo n a ry d isease Cerebra l a n e u rysm o r a rteriovenous ma l fo rmation Patho l ogy req u i ri n g concurre n t i ntraabd o m i n a l s u rg e ry Peri m o rtem cesa rea n d e l i lery Maternal-Fetal

Fetal

N o n reass u r i n g feta l status Ma I p resentation Macrosom ia Con g e n ita l a no m a ly Abnormal u m b i l i ca l cord Doppler study Throm bocytope n ia Prior neonata l b i rth t ra u m a =

CESAREAN DELIVERY RISKS To provide accurate informed consent, understanding both maternal and neonatal risks and beneits with surgery is essen­ tial. In broad terms, cesarean delivery has higher maternal surgi­ cal risks for the current and subsequent pregnancies compared with spontaneous vaginal birth. his is balanced against lower rates of perineal injury and short-term pelvic floor disorders. For the neonate, cesarean delivery ofers lower rates of birth trauma and stillbirth but greater rates of initial respiratory di­ iculties. • Maternal Mortality and Morbidity

Ceph a l o pelvic d i s p roportion Fai l ed operative va g i na l delivery Placenta p revia o r placenta l abru ption

H IV h u m a n i m m u n odeficiency vi rus; H SV s i m p lex v i rus.

1 0. Elective cesarean deliveries are increasingly being performed for various indications that include maternal request, con­ cern for pelvicloor injury associated with vaginal birth, and reduction ofetal injury rates. 1 1 . Assisted reproductive technoloy is more widely used than in the past and is associated with greater cesarean delivery rates (Reddy, 2007) . 1 2. Mapractice litigation related to fetal injury during sponta­ neous or operative vaginal delivery continues to contribute to the present cesarean delivery rate.

=

h erpes

3. he use of electronic etal monitoring is widespread. This practice is associated with an increased cesarean delivery rate compared with intermittent fetal heart rate auscul­ tation. Fetal distress accounts for only a minority of all cesareans. In many more cases, concern for an abnormal or "nonreassuring" fetal heart rate tracing prompts cesarean delivery. 4. Most fetuses presenting breech are now delivered by cesarean. 5. he frequency of operative vaginal delivery has declined. 6. Rates of labor induction continue to rise, and induced labor, especially among nulliparas, raises the cesarean delivery rate. 7. Obesi, which is a cesarean delivery risk, has reached epidemic proportions. 8. Rates of cesarean delivery in women with preeclampsia have increased, whereas labor induction rates for these patients have declined. 9. he rate of vaginal birth ater cesarean- BAC-has decreased from a high of 28 percent in 1 996 and was 1 1 percent in 20 1 4 (Hamilton, 20 1 5) .

For the mother, death attributable solely to cesarean delivery is rare in the United States. Even so, numerous studies attest to increased mortality risks. Clark and colleagues (2008), in a review of nearly 1 . 5 million pregnancies, found maternal mor­ tality rates of 2.2 per 1 00,000 cesarean deliveries compared with 0.2 per 1 00,000 vaginal births. In a metaanalysis of 203 studies, Guise and coworkers (20 1 0) reported a maternal mor­ tality rate of 1 3 per 1 00,000 with elective repeat cesarean deliv­ ery compared with 4 per 1 00,000 women undergoing a trial of labor after prior cesarean. Similar to mortality rates, the frequencies of some maternal complications are increased with all cesarean compared with vaginal deliveries. Villar and associates (2007) reported that maternal morbidity rates increased twofold with cesarean com­ pared with vaginal delivery. Principal among these are infection, hemorrhage, and thromboembolism. In addition, anesthetic complications, which also rarely include death, have a greater incidence with cesarean compared with vaginal delivery (Chees­ man, 2009; Hawkins, 20 1 l ) . Adjacent organs infrequently may be injured, which is described in detail on page 583. Women who undergo a cesarean delivery are much more likely to be delivered by a repeat operation in subsequent pregnancies. For women undergoing subsequent cesarean, the maternal risks j ust described are even greater (Cahill, 2006; Marshall, 20 1 1 ; Silver, 2006) . As an advantage, cesarean delivery is associated with lower rates of urinary incontinence and pelvic organ prolapse than is vaginal birth (Glazener, 2 0 1 3 ; Gyhagen, 20 1 3a,b; Handa, 2 0 1 1 ; Leijonhuvud, 20 1 1 ) . Rates of anal incontinence appear uninluenced by delivery route (Fritel, 2007; Nelson, 20 1 0) . Protective advantages persist to some degree over time, but cesarean delivery is not totally protective. Moreover, longitudinal studies suggest that initial pelvic floor advantages

Cesa rea n Del ive ry a n d Peri pa rt u m Hysterectomy

gained from cesarean delivery are lost as women age (Dolan, 20 1 0; MacArthur, 201 1 , 20 1 3; Nelson, 20 1 0) . To address this, the National Institutes of Health (2006) held a conference on cesarean delivery on maternal request. It summarized that stress urinary incontinence rates after elective cesarean delivery are lower than those following vaginal delivery. However, the dura­ tion of this protection is unclear, particularly in older and mul­ tiparous populations. This same panel considered the evidence implicating vaginal delivery in other pelvic loor disorders to be weak and not favoring either delivery route. • Neonatal Morbidity

Cesarean delivery is associated with a lower rate of fetal trauma (Linder, 20 1 3; Moczygemba, 20 1 0) . lexander and colleagues (2006) found that fetal injury complicated 1 percent of cesar­ ean deliveries. Skin laceration was most common, but others included cephalohematoma, clavicular fracture, brachial plexop­ athy, skull fracture, and facial nerve palsy. Cesarean deliveries following a failed operative vaginal delivery attempt had the highest injury rate, whereas the lowest rate-0. 5 percent­ occurred in the elective cesarean delivery group. hat said, Worley and colleagues (2009) noted that approximately a third of women who were delivered at Parkland Hospital entered spontaneous labor at term, and 96 percent of these delivered vaginally without adverse neonatal outcomes. Some evidence shows higher asthma and allergy rates in those delivered by cesarean. With the hope to improve neona­ tal microbiota, swabbing the newborn mouth with a gauze that was incubated in the maternal vagina 1 hour before surgery is described in preliminary studies. However, the American College of Obstetricians and Gynecologists (20 1 7 e) does not encourage this practice due to few data and the potential for transmission of harmful organisms. • Cesarean Delivery on Maternal Request

Some women request elective cesarean delivery. Data regard­ ing the true incidence of cesarean delivey on matenal request (CDMR) are poor. Rate estimates range from 1 to 8 percent in the United States (Barber, 20 1 1 ; Declercq, 2005; Gossman, 2006; Menacker, 2006) . Reasons for the request include pelvic floor protection, con­ venience, fear of childbirth, and reduced risk of fetal injury. Data to address these concerns are slowly accruing. One study of more than 66,000 Chinese parturients compared outcomes of those who elected planned vaginal or primary cesarean deliv­ ery (Liu, 20 1 5). Short-term serious maternal morbidity and neonatal mortality rates were similar. For the newborns, rates of birth trauma, infection, and hypoxic ischemic encephalopathy were low in both groups but statistically lower with cesarean delivery. Respiratory distress syndrome rates were greater in the CMDR cohort. A smaller study comparing these two routes of delivery support these findings (Larsson, 20 1 1 ) . he debate surrounding CDMR includes these medical points, the concept of informed free choice by the woman, and the autonomy of the physician in ofering CMDR. Dur­ ing the National Institutes of Health panel (2006) cited above,

participants noted that most of the maternal and neonatal outcomes examined had insuicient data to permit recom­ mendations. Despite this, the panel was able to draw a few conclusions, which are echoed by the American College of Obstetricians and Gynecologists (20 1 7a) . Namely, CMDR should not be performed before 39 weeks' gestation unless fetal lung maturity is conirmed. Cesarean delivery is ideally avoided in women desiring several children because of placental implan­ tation abnormalities and cesarean hysterectomy risks. F inally, CMDR should not be motivated by the unavailability of efec­ tive pain management.

PATIENT PREPARATION

• Delivery Availability

No nationally recognized standard of care currently dictates the acceptable time interval to begin cesarean delivery. Previously, a 30-minute decision-to-incision interval was recommended. In studying this, Bloom and coworkers (200 1 ) found that 69 per­ cent of 7450 cesareans performed in labor commenced more than 30 minutes after the decision to operate. In a second study, Bloom and colleagues (2006) evaluated cesarean deliveries per­ formed for emergency indications. They reported that failure to achieve a cesarean delivery decision-to-incision time of less than 30 minutes was not associated with a negative neonatal outcome. A subsequent systematic review echoed this ind­ ing (ToIcher, 20 1 4). Despite this, when faced with an acute, catastrophic deterioration in fetal condition, cesarean delivery usually is indicated as rapidly as possible, and thus purposeful delays are inappropriate. he American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (20 1 7) recommend that facilities giving obstetrical care should have the ability to initiate cesarean delivery in a time frame that best incorporates maternal and fetal risks and beneits. • I nformed Consent

Obtaining informed consent is a process and not merely a med­ ical document (American College of Obstetricians and Gyne­ cologists, 2 0 1 5). The conversation should enhance a woman's awareness of her diagnosis and contain a discussion of medical and surgical care alternatives, procedure goals and limitations, and surgical risks. For women with a prior cesarean delivery, the option of a trial of labor should be included for suitable candidates. lso, in those desiring permanent sterilization or intrauterine device insertion, consenting for these can be com­ pleted concurrently. n informed patient may decline a particular recommended intervention, and a woman's decision-making autonomy must be respected. In the medical record, clinicians should docu­ ment her reasons for refusal and should note that the inter­ vention's value and the health consequences of not proceeding with it have been explained. For Jehovah's Witnesses, informed consent discussions regarding blood products ideally begin early in pregnancy. Acceptable blood products vary widely among individual women, and a preoperative checklist of approved products

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allows superior preparation (Hubbard, 20 1 5; H usarova, 20 1 6) . In general, red cells, white cells, platelets, and plasma are viewed as primary blood components and are eschewed. However, certain clotting factors or cell fractions may be accept­ able (Lawson, 20 1 5) . Before and after surgery, iron, folate, and, if necessary, erythropoietin are accepted agents to help maxi­ mize hemoglobin levels. Perioperatively, phlebotomy should be limited, and pediatric collection tubes are preferable. Intraop­ erative options include treatment of atony to limit blood loss; topical hemostatic agents, tranexamic acid, and desmopressin to promote clot formation; red blood cell salvage or acute nor­ movolemic hemodilution to provide autologous donation; and controlled hypotensive anesthesia, uterine artery embolization, occlusive vascular balloons, and temporary aortic compression for uncontrolled bleeding (Belfort, 20 1 1 ; v lason, 20 1 5) . • Timing of Scheduled Cesarean Delivery

Adverse neonatal sequelae from neonatal immaturity with elec­ tive delivery before 39 completed weeks are appreciable (Clark, 2009; Tita, 2009) . To avoid these, assurance of fetal maturity before scheduled elective surgery is essential as outlined by the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (20 1 7) and discussed in Chapter 3 1 (p. 597) . To assist with this and other components of cesarean delivery planning, the American College of Obste­ tricians and Gynecologists (20 1 1 , 20 1 4b) has created Patient Safety Checklists to be completed before the planned surgery. • Preoperative Care

If cesarean delivery is scheduled, a sedative may be given at bedtime the night before surgery. In general, no other seda­ tives, narcotics, or tranquilizers are administered until after the fetus is born. In one small randomized trial, no benefits were gained from a presurgical enema (Lurie, 20 1 2) . Solid food intake is stopped at least 6 to 8 hours before the procedure. Uncomplicated patients may have moderate amounts of clear liquids up to 2 hours before surgery (American Society of Anes­ thesiologists, 20 1 6) . his comports with Enhanced Recovery After Surgery (ERAS) protocols that strive to maintain anabolic homeostasis and advocate clear carbohydrate drinks up to 2 hours before scheduled surgery and early postoperative feed­ ing (Ljungqvist, 20 1 7) . Although evidence supports an ERAS approach for many procedures, data specifically addressing this for cesarean delivery are scarce (Wrench, 20 1 5) . The woman scheduled for repeat cesarean delivery typically is admitted the day of surgery and evaluated by the obstetri­ cal and anesthesia teams. Recently performed hematocrit and indirect Coombs test are reviewed. If the latter is positive, then availability of compatible blood must be ensured. As discussed in Chapter 25 (p. 490) , regional analgesia is preferred for cesarean delivery. An antacid is given shortly before regional analgesia or induction of general anesthesia. One example is Bicitra, 30 mL orally in a single dose. This min­ imizes the lung injury risk from gastric acid aspiration. Once the woman is supine, a wedge beneath the right hip and lower back creates a left lateral tilt to aid venous return and avoid

hypotension. Data are insuicient to determine the value of fetal monitoring before scheduled cesarean delivery in women without risk factors. Our practice is to obtain a 5-minute tracing prior to elective cases. At minimum, fetal heart sounds should be documented in the operating room prior to surgery. Of urther preparations, hair removal at the surgical site does not lower surgical site infection (SSI) rates (Kowalski, 20 1 6) . However, if hair is obscuring, i t is removed the day o f surgery by clipping, which is associated with fewer SSIs than shaving (Tan­ ner, 20 1 1 ) . Chemical depilation the night before surgery com­ pared with clipping has similar SSI rates (Lefebvre, 201 5). An electrosurgical grounding pad is placed near the surgical incision and typically on the lateral thigh. n indwelling bladder catheter is typically placed at Parkland Hospital to collapse the bladder away from the hysterotomy incision, to avert urinary retention secondary to regional analgesia, and to allow accurate postopera­ tive urine measurement. Small studies show that catheterization may be withheld in hemodynamically stable women to minimize urinary infections (Abdel-Aleem, 20 14; Li, 20 1 1 ; Nasr, 2009) . he risk of venous thromboembolism is increased with pregnancy and almost doubled in those undergoing cesarean delivery Oames, 2006) . Accordingly, for all women not already receiving thromboprophylaxis, the American College of Obste­ tricians and Gynecologists (20 1 7d) recommends initiation of pneumatic compression hose before cesarean delivery. These are usually discontinued once the woman ambulates. Recom­ mendations between organizations vary, and the American College of Chest Physicians suggests only early ambulation for women without risk factors who are undergoing cesarean deliv­ ery (Bates, 20 1 2) . For women already receiving prophylaxis or those with increased risk factors, they support escalation of prophylaxis. Last, the Royal College of Obstetricians and Gyn­ aecologists (20 1 5) are the most conservative and suggest phar­ macological prophylaxis for the largest proportion of patients. hese various methods and recommendations are discussed in Chapter 52 and are shown in Table 52-6 (p. 1 020) . Some women scheduled for cesarean delivery have concur­ rent comorbidity that requires specific management in anticipa­ tion of surgery. Among others, these include insulin-requiring or gestational diabetes, coagulopathy or thrombophilia, chronic corticosteroid use, and signiicant reactive airway disease. Surgi­ cal preparations are discussed in the respective chapters cover­ ing these topics. • I nfection Prevention

Anti biotic Prophylaxis

Cesarean delivery is considered a clean contaminated case, and postoperative febrile morbidity is common. Numerous good­ quality trials show that a single dose of an antibiotic given at the time of cesarean delivery signiicantly decreases infectious mor­ bidity (Smaill, 20 1 4) . Although more obvious for women under­ going unscheduled cesarean delivery, this practice also pertains to women undergoing elective surgery (American College of Obste­ tricians and Gynecologists, 20 1 6) . Depending on drug allergies, most recommend a single intravenous dose of a 3-lactam antibi­ otic-either a cephalosporin or extended-spectrum penicillin. A 1 -g dose of cefazolin (Ancd) is an eicacious and cost-efective

Cesarean Del ivery a nd Peri part u m H ysterectomy

choice. Additional doses are considered in cases with blood loss > 1 500 mL or with duration longer than 3 hours. Recommen­ dations for the best dose in obese parturients are conflicting (Ahmadzia, 20 1 5; Maggio, 20 1 5; Swank, 20 1 5; Young, 20 1 5) . One recent pharmacokinetic analysis showed suicient tissue levels with a 2-g dose for cesarean deliveries lasting 1 .5 hours. Authors recommended consideration for redosing in obese women if surgeries were longer (Grupper, 20 1 7) . A growing body o f evidence supports extending the anti­ biotic spectrum (Andrews, 2003; Tita, 2008) . One large ran­ domized trial added azithromycin, 500 mg intravenously, to standard prophylaxis prior to cesarean delivery for women in labor or with ruptured membranes (Tita, 20 1 6) . Rates of wound infection and endometritis were signiicantly lower in the extended-spectrum group compared with those in the stan­ dard prophylaxis cohort. In pregnant women with a history of infection with meth­ icillin-resistant Staphylococcus aureus (MRSA) , a single dose of vancomycin added to the standard prophylaxis for cesarean deliveries can be elected. Decolonization plays a limited role but may be considered prior to a p lanned cesarean delivery in women with known MRSA colonization (American College of Obstetricians and Gynecologists, 20 1 6) . Signifi c ant penicillin o r cephalosporin allergy, which mani­ fests by anaphylaxis, angioedema, respiratory distress, or urti­ caria, merits prophylaxis with a single 600-mg intravenous dose of clindamycin combined with a weight-based dose of an ami­ noglycoside as an alternative. A 900-mg clindamycin dose is used for obese patients. Antibiotic administration before surgical incision lowers postoperative infection rates without adverse neonatal efects compared with drug administration after umbilical cord clamp­ ing (Mackeen, 20 1 4b; Sullivan, 2007; Witt, 20 1 1 ) . Prophylaxis is ideally administered within the 60 minutes prior to the start of planned cesarean delivery. For emergent delivery, antibiotics are given as soon as feasible. Preoperative preparation of the abdominal wall skin is efec­ tive to prevent wound infection. Either chlorhexidine or povi­ done-iodine solutions are suitable (Hadiati, 20 14; Ngai, 20 1 5; Springel, 20 1 7) . In studies that found a diference, chlorhexi­ dine was favored, and this is our practice (Menderes, 20 1 2; Tuuli, 20 1 6a) . In addition, preoperative vaginal cleansing with a povidone-iodine scrub has been evaluated in small random­ ized trials (Haas, 20 1 4; Caissutti, 20 1 7) . Some showed lower rates of metritis, especially for those with ruptured membranes or active labor, but not lower rates of wound infection (Haas, 20 1 0; Memon, 20 1 1 ; Yildirim, 20 1 2) . Some recommend preoperative vaginal cleansing, bur we do not do this at Parkland Hospital. Antibiotic prophylaxis against infective endocarditis is not rec­ ommended for most cardiac conditions-exceptions are women with cyanotic heart disease, prosthetic valves, or both (American College of Obstetricians and Gynecologists, 20 1 6) . Regimens selected for routine cesarean infection prophylaxis will also serve as appropriate endocarditis coverage (Chap. 49, p. 965) . Other Preventions

Glycemic control in diabetics lowers wound infection rates and is emphasized in Chapter 57 (p. 1 1 05). Smoking is another

modiiable risk, and its mitigation i s especially helpful for mor­ bidly obese women (Alanis, 20 1 0; Avila, 20 1 2; Shree, 2 0 1 6) . Intraoperative normothermia lowers wound infection rates in general surgery and is a Surgical Care Improvement Project measure (Kurz, 1 996; he Joint Commission, 20 1 6) . his tenet might logically be extrapolated to cesarean delivery, although deinitive studies are lacking (Carpenter, 20 1 2) . Perioperative supplementation with high-concentration inspired oxygen does not lower wound infection rates (Duggal, 20 1 3; Klingel, 2 0 1 3) . • Surgical Safety

he Joint Commission (20 1 3) established a protocol to pre­ vent surgical errors. For cesarean delivery, all relevant docu­ ments are veriied immediately before surgery, and a "time out" is completed. The "time out" requires attention of the entire team to confirm that the patient, site, and procedure are cor­ rect. Important discussions also include introduction of the patient-care team members, veriication of prophylactic anti­ biotics, estimation of procedure length, and communication of anticipated complications. Additionally, requests for special instrumentation should be addressed preoperatively to p revent potential patient compromise and intraoperative delays. An instrument, sponge, and needle count before and after surgery is crucial to surgical safety. If counts are not reconciled, radiographic imaging for retained foreign objects is obtained (American College of Obstetricians and Gynecologists, 20 1 4a) .

CESAREAN DELIVERY TECH N IQU E With minor variations, surgical performance of cesarean deliv­ ery is comparable worldwide. Most steps are founded on evi­ dence-based data, and these have been reviewed by Dahlke and associates (20 1 3) . As with all surgery, a clear understanding of relevant anatomy is essential, and this is described and illus­ trated in Chapter 2 (p. 1 4) . • Laparotomy

In obstetrics, a suprapubic transverse incision or a midline ver­ tical one is chosen for laparotomy. Transverse abdominal entry is by either Pfannenstiel or Maylard incisions. Of all these, the Pfannenstiel incision is selected most frequently for cesarean delivery. Transverse incisions follow Langer lines of skin tension. Thus, compared with vertical ones, Pfannenstiel incisions ofer superior cosmesis and lower incisional hernia rates. Use of the Pfannenstiel incision, however, is often discouraged for cases in which a large operating space is essential or in which access to the upper abdomen may be needed. With transverse inci­ sions, because of the layers created during incision of the inter­ nal and external oblique aponeuroses, purulent fluid can collect between these. Therefore, some favor a midline vertical incision for cases with high infection risks. Emergent entry is typically faster with vertical incision during primary and repeat cesarean delivery (Wylie, 20 1 0) . Last, neurovascular structures, which include the ilioinguinal and iliohypogastric nerves and superi­ cial and inferior epigastric vessels, are often encountered with

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transverse inCISIons. Logically, bleeding, wound hematoma, and neurological disruption may more frequently complicate these incisions compared with vertical ones. he best incision for the morbidly obese parturient is unclear (Smid, 20 1 6) . As discussed in Chapter 48 (p. 943), our preference with very obese women is a periumbilical midline vertical incision. he Maylard incision difers mainly from the Pfannenstiel in that the bellies of the rectus abdominis muscle are transected horizontally to widen the operating space. It is technically more diicult due to its required m uscle cutting and isolation and ligation of the inferior epigastric arteries, which lie laterally to these muscle bellies. Once access is gained, metal handheld retractors provide exposure for hysterotomy. A few small randomized studies have evaluated postcesarean wound infection rates with a disposable plastic barrier retractor (Alexis-O) . Results showing benefi t are contradictory (Hinkson, 20 1 6; Scolari Childress, 20 1 6; he­ odoridis, 20 1 1 ) . Tra n sverse I nc i s i o n s

muscle either bluntly or sharply until the superior border of the symphysis pubis is reached. Next, the superior fascial edge is grasped and again, separation of fascia from the rectus muscle is completed. Blood vessels coursing between the sheath and muscles are clamped, cut, and ligated, or they are coagulated with an electrosurgery blade. Meticulous hemostasis is impera­ tive to lower rates of incisional hematoma and infection. he fascial separation progresses cephalad and laterally to create a semicircular area above the transverse incision with a radius of approximately 8 cm. This will vary depending on fetal size. he rectus abdominis and pyramidalis muscles are then separated in the midline, irst superiorly and then inferiorly, by sharp and blunt dissection to expose the transversalis fascia and peri­ toneum. he transversalis fascia and preperitoneal fat are bluntly dis­ sected away to reach the underlying peritoneum. The perito­ neum near the upper end of the incision is opened carefully, either bluntly or by elevating it with two hemostats placed approximately 2 cm apart. his upper site lowers cystotomy risks. The tented fold of peritoneum between the clamps is examined and palpated to ensure that omentum, bowel, or bladder is not adjacent. he peritoneum is then incised. The peritoneal incision is extended superiorly to the upper pole of the fascial dissection and downward to just above the peritoneal relection over the bladder. Importantly, in women with prior intraabdominal surgery, including cesarean delivery, omentum or bowel may be adhered to the undersurface of the perito­ neum. In women with obstructed labor, the bladder may be pushed cephalad almost to the level of the umbilicus.

With the Pfannenstiel incision, the skin and subcutaneous tissue are incised using a low, transverse, slightly curvilinear incision. his is made at the level of the pubic hairline, which is typically 3 cm above the superior border of the symphysis pubis. The incision is extended laterally suiciently to accom­ modate delivery-1 2 to 1 5 cm is typical. Sharp dissection is continued through the subcutaneous layer to the fascia. The supericial epigastric vessels can usu­ ally be identiied halway between the skin and fascia, several centimeters from the midline, and are coagulated. If lacerated, these may be suture ligated with 3-0 plain gut suture or coagulated with an electro surgical blade. he fascia is then incised sharply at the Uterus midline. he anterior abdominal fascia is typically composed of two visible layers, the aponeurosis from the external oblique muscle and a fused layer containing apo­ neuroses of the internal oblique and transverse abdominis muscles. Ideally, the two layers are individually incised during lateral extension of the fascial inci­ sion. The inferior epigastric vessels usu­ ally lie outside the lateral border of the rectus abdominis muscle and beneath the :� �-Vesicoute rine fused aponeuroses of the internal oblique se rosa and transverse abdominis muscles. hus, although infrequently required, extension ;Bladder of the fascial incision further laterally may cut these vessels. With extension, these vessels are best identiied and coagulated or ligated to prevent bleeding and vessel retraction. Once the fascia is incised, the infe­ rior fascial edge is grasped with Kocher clamps and elevated by an assistant as the operator separates the fascial sheath F I G U R E 30-1 The loose peritoneum a bove the bladder reflection is g rasped with forceps from the underlying rectus abdominis a nd i ncised with Metzen ba u m sci ssors, _ _ _

_

__ _ _

_

_ _ _ _ __

Cesarean Del ivery a n d Peri pa rt u m Hysterecto my

M i d l i ne Ve rtica l I ncision

This incision begins 2 to 3 cm above the superior margin of the symphysis. It should suiciently long to allow fetal deliv­ ery, and 1 2 to 1 5 cm is typical. Sharp or electrosurgical blade dissection through the subcutaneous layers ultimately exposes the anterior rectus sheath. A small opening is made sharply with scalpel in the upper half of the linea alba. Placement here helps avoid potential cystotomy. Index and middle in­ gers are placed beneath the fascia to elevate it, and the fascial incision is extended irst superiorly and then inferiorly with scissors. Midline separation of the rectus muscles and pyrami­ dalis muscles and peritoneal entry are similar to those with the Pfannenstiel incision.

Vesicouterin e serosa

-.:- Myometri u m

• Hysterotomy

Most often, the lower uterine segment is incised transversely as described by Kerr in 1 92 1 . Occasionally, vertical incision conined solely to the lower uterine segment may be elected (Kronig, 1 9 1 2) . In contrast, a classical incision begins as a low-vertical incision, which is then extended cephalad into the active portion of the uterine corpus. Last, a fundal or even pos­ terior incision may be selected for cases with placental accrete syndromes. Low Tra n sverse Cesa rea n I nc i s i o n

F I G U R E 30-2 T h i s peritoneal e d g e is elevated a nd incised lateral ly.

bladder is gently separated from the underlying lower uterine segment with blunt or sharp dissection within this vesicouter­ ine space (Fig. 30-3) . This bladder lap creation efectively moves the bladder away from the planned hysterotomy site. It also helps prevent bladder laceration if an unintended inferior hysterotomy extension occurs during fetal delivery. In general, this caudad separation of bladder does not exceed 5 cm and usually is less. However, in instances in which cesar­ ean hysterectomy is planned or anticipated, extended caudad dissection is recommended to aid total hysterectomy and decrease the risk of cystotomy.

For most cesarean deliveries, this incision is preferred. Com­ pared with a classical incision, it is easier to repair, causes less incision-site bleeding, and promotes less bowel or omentum adherence to the myometrial incision. Located in the inactive segment, it also is less likely to rupture during a subsequent pregnancy. Before any hysterotomy, the surgeon palpates the fundus to identiy degrees of uterine rotation. The uterus may be rotated so that one round ligament is more anterior and closer to the midline. In such cases, the uterus can be Vesicoute rin e manually reoriented and held to permit serosa centering of the incision. This avoids inci­ sion extension into and laceration of the adjacent uterine artery. A moist sponge may be used to pack protruding bowel away from the operative ield. he relection of peritoneum at the upper margin of the bladder and overly­ ing the lower uterine segment is grasped in the midline with forceps and incised transversely with scissors (Fig. 30- 1 ) . Fol­ lowing this initial incision, scissors are inserted between peritoneum and lower uterine segment. Open scissors are pushed laterally from the midline on each side. This transverse peritoneal incision extends almost the full length of the lower uterine "{ segment. As the lateral margin on each side is approached, the scissors are directed slightly cephalad (Fig. 30-2) . The lower F I G U RE 30-3 Cross section shows b l u nt dissection of the bladder of the uterus to expose the lower uterine seg ment. edge of peritoneum is elevated, and the

! f,

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Some surgeons do not create a bladder lap. The main advan­ tage is a shorter skin incision-to-delivery time. However, data supporting this practice are limited (O'Neill, 20 14; Tuuli, 20 1 2) .

F I G U R E 30-4 The myometr i u m is i ncised with s h a l low strokes to avoid cutting the fetal head.

Uteri ne I ncision. The uterus i s entered through the lower uter­ ine segment. Digital palpation to find the physiological border between irmer upper segment myometrium and the more flex­ ible lower segment can guide placement. The bladder flap inci­ sion can also serve as a guide, and a hysterotomy site near this line is often selected. For women with advanced or complete cervical dilatation, the hysterotomy is placed relatively higher. Failure to adjust increases the risk of lateral extension of the incision into the uterine arteries. It may also lead to incision of the cervix or vagina rather than the lower uterine segment. Such incisions into the cervix can distort postoperative cervical anatomy. The uterus can be incised by various techniques. Each is ini­ tiated by using a scalpel to transversely incise the exposed lower uterine segment for 1 to 2 cm in the midline (Fig. 30-4) . Repet­ itive shallow strokes avoid fetal laceration. As the myometrium thins, a fingertip can then bluntly enter the uterine cavity. Once the uterus is opened, the hysterotomy is lengthened by simply spreading the incision, using lateral and slightly upward pres­ sure applied with each index inger (Fig. 30-5) . Some evidence also supports widening the lower-uterine-segment incision instead with ingers pulling in opposition in a cephalocaudad direction (Cromi, 2008; Xodo, 20 1 6) .

Amnionic sac

_

�.

f

f " .

F I G U R E 30-5 After enteri ng the uteri ne cavity, the i ncision is extended latera l ly with fi n gers or with ba ndage scissors (inset).

Cesa rea n Delive ry and Peripa rt u m Hysterectomy

Alternatively, if the lower uterine segment is thick and unyielding, cutting laterally and then slightly upward with ban­ dage scissors will lengthen the incision. Importantly, when scis­ sors are used, the index and midline fingers of the nondominant hand should be insinuated beneath the myometrium and above fetal parts to prevent fetal laceration. Comparing blunt and sharp expansion of the initial uterine incision, blunt stretch is associ­ ated with fewer unintended incision extensions, shorter operative time, and less blood loss. However, the rates of infection and need for transfusion do not difer (ASIClOglu, 20 1 4; Saad, 20 1 4) . The uterine incision i s made large enough t o allow delivery of the fetus without tearing into the uterine vessels that course along the lateral uterine margins. If the placenta is encountered in the incision line, it must be either detached or incised. Pla­ cental function is thereby compromised, and thus delivery is performed expeditiously. At times, a l ow transverse hysterotomy is selected but pro­ vides inadequate room for delivery. In such instances, one cor­ ner of the hysterotomy incision is extended cephalad into the contractile portion of the myometrium-a J incision. If this is completed bilaterally, a U incision is formed. Last, some prefer instead to extend in the midline-a T incision. As expected, each has higher intraoperative blood loss (Boyle, 1 996; Pat­ terson, 2002) . Moreover, as these extend into the contractile portion, a trial of labor is more likely to be complicated by uterine rupture in future pregnancies. Delivey of the Fetus. In a cephalic presentation, a hand is slipped into the uterine cavity between the symphysis and fetal head. The head is elevated gently with the ingers and palm through the inci­ sion. Once the head enters the incision, delivery may be aided by modest transabdominal fundal pressure (Fig. 30-6) . After a long labor with cephalopelvic disproportion, the fetal head may be tightly wedged in the birth canal. Release of an impacted fetal head raises the risk of hysterotomy exten­ sion, of associated blood loss, and of fetal skull fracture. In

I ncision in lower uterine segment

I F I G U R E 30-6 Del ivery of the fetal h ead.

this situation, there are three considerations for delivery. F irst, a "push" method may be used. With this, upward pressure exerted by a hand in the vagina by an assistant will help to dislodge the head and allow its delivery above the symphysis . If this i s anticipated, a patient in frog-leg position may allow easier vaginal access. Second, as an alternative, a "pull" method grasps the fetal legs to bring them through the hysterotomy. he fetus is then delivered by traction as one would complete a breech extraction. Support for this latter approach comes only from small random­ ized trials and retrospective cohort studies (Berhan, 20 1 4 ; J eve, 20 1 6; Nooh, 20 1 7) . A low vertical hysterotomy incision, which will give more room for the "pull" technique, may be selected. If a low transverse incision has already been made, then this can be extended to a J-, U-, or T-incision as previously discussed. The third method is use of the "fetal pillow," which is a distensible intravaginal balloon that when inflated, elevates the fetal head. The device is available outside the United S tates, but evidence for its eicacy is limited (Safa, 20 1 6; Seal, 2 0 1 6) . Conversely, i n women without labor, the fetal head may be unmolded and without a leading cephalic point. The round head may be diicult to lift through the uterine incision in a relatively thick lower segment that is unattenuated by labor. In such instances, either forceps or a vacuum device may b e used to deliver the fetal head (Fig. 30-7) . fter head delivery, a inger should b e passed across the fetal neck to determine whether it is encircled by one or more umbilical cord loops. If present, these are slipped over the head. The head is rotated to an occiput transverse position, which aligns the fetal bisacromial diameter vertically. The sides of the head are grasped with two hands, and gentle downward traction is applied until the anterior shoulder enters the hys­ terotomy incision (Fig. 30-8 ) . Next, by upward movement, the posterior shoulder is delivered. During delivery, abrupt or powerful force is avoided to avert brachial plexus injury. With steady outward traction, the rest of the body then readily fol­ lows. Gentle fundal pressure may aid this. With some exceptions, current American Heart Associa­ tion neonatal resuscitation recommendations eschew suction­ ing immediately following birth, even with meconium p resent (Wyckof, 20 1 5) . A fuller discussion of this and delayed umbil­ ical cord clamping is found in Chapter 27 (p. 5 1 8) . he umbil­ ical cord is clamped, and the newborn is given to the team member who will conduct resuscitative eforts as needed. Comparing elective cesarean under neuraxial anesthesia and spontaneous vaginal deliveries, studies show that the need for neonatal resuscitation is not practically signiicant between the two (Atherton, 2006; Gordon, 2005; Jacob, 1 997) . he American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (20 1 7) recommend that "a qualiied person who is skilled in neonatal resuscitation should be in the delivery room." At Parkland Hospital, pediatric nurse practitioners attend uncomplicated, scheduled cesarean deliver­ ies. Notably, as anticipated neonatal risks rise, so too should the resuscitative skills of the attendants (Wyckof, 20 1 5) . T o promote breastfeeding, the American College o f Obste­ tricians and Gynecologists (20 1 7b) recommends skin-to-skin contact between newborn and mother in the delivery room.

575

576

Del ivery

A

B

Although most randomized trials focus on vaginal birth, several small studies support such contact following cesarean delivery, and this our practice (Moore, 20 1 6; Stevens, 2 0 1 4) . After birth, a n intravenous infusion containing two ampules or 20 units of oxytocin per liter of crystalloid is infused at 1 0 mLlmin. Some prefer higher infusion dosages, however, non­ dilute boluses are avoided because of associated hypotension (Roach, 20 1 3) . Once the uterus contracts satisfactorily, the rate can be reduced. An alternative is carbetocin-a longer-acting oxytocin derivative that is not available in the United States­ that provides suitable, albeit more expensive, hemorrhage pro­ phylaxis Qin, 20 1 6) . Ergot-alkaloids are second-tier agents and carry hypertensive side efects. Carboprost, a I S-methyl derivative of prostaglandin F 2> is another second-tier agent used to treat uterine atony. Some but certainly not all studies

indicate that misoprostol appears to perform similarly to oxy­ tocin (Chaudhuri, 20 1 4; Conde-Agudelo, 20 1 3) . Finally, some recommend the use of tranexamic acid added to a standard oxy­ tocin infusion to decrease blood loss (Simonazzi, 20 1 6; Wang, 20 1 5) . Its antifibrinolytic action and efects on thromboembo­ lism rates in pregnant surgical patients are unclear. Larger trials are needed before widespread use. Additional discussions of all these agents are found in Chapter 4 1 (p. 759) .

Delivey of the Placenta. he uterine incision is observed for any vigorously bleeding sites. These should be quickly clamped with Pennington or ring forceps. Although some surgeons may prefer , manual removal of the placenta, spontaneous delivery prompted by some cord traction may reduce the risk of operative blood loss and infection (Anorlu, 2008; Baksu, 2005). Fundal massage may

A

B

FIGURE 30-7 A. The first cesarea n forceps blade is placed. B. Slight u pwa rd and outward traction is used to l it the head through the incision.

F I G U R E 30-8 The a nterior (A) and then the posterior (B) s h o u lder a re del ivered .

Cesa rea n Del ivery a nd Peri pa rt u m Hyste rectomy

begin as soon as the fetus is delivered to hasten placental separation and delivery (Fig. 30-9) . Immediately after delivery and quick gross inspection of the placenta, the uterine cavity is suctioned and wiped out with a gauze sponge to remove avulsed membranes, vernix, and clots. In the past, double-gloved fingers or ring forceps placed through the hysterotomy incision were used to dilate an ostensibly closed cervix. his practice does not reduce infection rates fro m poten­ tial hematometra and is not recommended (Kirscht, 20 1 7; Liabsuetrakul, 20 1 1 ) .

Lower uterine segm ent Uterin e incision

Uterine Repa i r. Ater placental delivery, the uterus is lited through the incision and onto the draped abdominal wall, and the fundus is covered with a moistened laparotomy P lacenta sponge. We favor this and believe a relaxed, atonic uterus can be recognized quickly and massage applied. Incision and bleeding points are more easily visualized and repaired, espe­ F I G U R E 30-9 P lacenta b u l g i n g thro u g h the uteri n e i ncision as the uterus contracts. A cially if there have been extensions. Adnexal hand gently m a ssages the fu n d u s to h e l p aid s pontaneous place nta l separation . exposure is superior, and thus, tubal steriliza­ tion is easier. Instead, some clinicians prefer Traditionally, the peritoneum in the anterior cul-de-sac is to close the hysterotomy with the uterus in situ. Comparing approximated with a continuous 2-0 chromic catgut suture these two approaches, febrile morbidity, pain, and blood loss line. Multiple randomized trials suggest that omission of this are not signiicantly diferent (Walsh, 2009; Zaphiratos, 20 1 5) . step causes no postoperative complications (Grundsell, 1 998; Before hysterotomy closure, previously clamped large vessels Irion, 1 996; Nagele, 1 996) . If tubal sterilization is to be per­ may be ligated separately or incorporated within the running formed, it is completed as described in Chapter 39 (p. 702) . incision closure. IUD insertion, if planned, is completed prior to hysterotomy closure (Chap. 3 8 , p. 685). One angle of the uterine incision is grasped to stabilize and maneuver the inci­ sion. he uterine incision is then closed with one or two layers of continuous 0- or no. 1 absorbable suture (Fig. 30- 1 0) . Chro­ mic catgut suture is used by many, but some prefer synthetic delayed-absorbable polyglactin 9 1 0 (Vicryl) . In subsequent pregnancy, neither suture type has been shown superior by mitigating against greater rates of adverse pregnancy out­ comes such as uterine incision rupture (CORONIS Collabora­ tive Group, 20 1 6) . Single-layer closure is typically faster and is not associated with higher rates of infection or transfusion (CAESAR Study Collaborative Group, 20 1 0; Dodd, 20 1 4; Roberge, 20 1 4) . Moreover, most studies observed that the num­ ber of layers does not significantly afect complication rates in the next pregnancy (Chapman, 1 997; CORONIS Collaborative Group, 20 1 6; Durnwald, 2003; Roberge, 20 1 1 ) . A t Parkland Hospital, we use a one-layer uterine closure with chromic catgut. he initial suture is placed just beyond one angle of the uterine incision. A continuous, locking suture line for hemostasis is then performed, with each suture pen­ etrating the full thickness of the myometrium. he suture line then extends to a point just beyond the opposite incision angle. If approximation is not satisfactory after a single layer or if bleeding sites persist, then more sutures are required. Either another layer of running suture is placed to achieve approxima­ tion and hemostasis, or individual bleeding sites can be secured F I G U RE 30-1 0 The cut edges of the uteri ne incision a re a p proxi­ mated with a ru n n i ng, locki n g s u t u re. with targeted figure-of-eight or mattress stitches.

577

578

Del ive ry

Ad h e s i o n s

Following cesarean delivery, adhesions commonly form within the vesicouterine space or between the anterior abdominal wall and uterus. And, with each successive pregnancy, the percent­ age of afected women and adhesion severity rise (Morales, 2007; Tulandi, 2009) . Adhesions can signifi c antly lengthen incision-to-delivery time and total operative time (Rossouw, 20 1 3; Sikirica, 20 1 2) . Although occurring infrequently, rates of cystotomy and bowel injury are also increased because of adhesive disease (Rahman, 2009; Silver, 2006) . Intuitively, scarring can be reduced by handling tissues deli­ cately, achieving hemostasis, and minimizing tissue ischemia, infection, and foreign-body reaction. Most recent data on short­ and long-term outcomes show no benefi t to peritoneal closure (CAESAR Study Collaborative Group, 20 1 0; CORONIS Col­ laborative Group, 20 1 3 , 20 1 6; Kapustian, 20 1 2) . Similarly, most studies show no benefit from placement of an adhesion barrier at the hysterotomy site (Edwards, 20 1 4; Kiefer, 20 1 6) . A bd o m i n a l Closure

Any laparotomy sponges are removed, and the paracolic gut­ ters and cul-de-sac are gently suctioned of blood and amni­ onic fl u id. Some surgeons irrigate the gutters and cul-de-sac, especially in the presence of infection or meconium. Routine irrigation in low-risk women, however, leads to greater intra­ operative nausea but not to lower postoperative infection rates (Eke, 20 1 6; Viney, 20 1 2) . Prior t o abdominal closure, correct sponge and instrument counts are verified. he rectus abdominis muscle bellies are allowed to fall into place. With signifi c ant diastasis, the rectus muscles may be approximated with one or two figure-of-eight sutures of 0 or no. 1 chromic gut suture. The overlying rectus fascia is closed by a continuous, nonlocking technique with a delayed-absorbable suture. In patients with a higher risk for infection, there may be theoretical value in selecting a mono­ ilament suture here rather than braided material. The subcutaneous tissue usually need not be closed if it is less than 2 em thick. With thicker layers, however, closure is recommended to minimize seroma and hematoma forma­ tion, which can lead to wound infection and/or disruption (Bohman, 1 992; Chelmow, 2004) . One recent metaanalysis found lower rates of seroma formation and of developing any wound complication with closure, but hematoma and wound infection rates were unafected (Pergialiotis, 20 1 7) . Addition of a subcutaneous drain does not prevent significant wound complications (Hellums, 2007; Ramsey, 2005) . Skin is closed with a running subcuticular stitch of 4-0 delayed-absorbable suture, with adhesive glue, or with sta­ ples. In comparison, final cosmetic results and infection rates appear similar, skin suturing takes longer, but wound separa­ tion rates are higher with metal staples (Basha, 20 1 0; Figueroa, 20 1 3 ; Mackeen, 20 1 4a, 20 1 5) . Poliglecaprone 25 (NIonocryl) or polyglactin 9 1 0 (Vieryl) are both suitable (Tuuli, 20 1 6b) . Outcomes with 2-octyl cyanoacrylate adhesive (Dermabond) were equivalent to sutures for Pfannenstiel incisions (Daykan, 20 1 7; Siddiqui, 20 1 3) . A sterile thin abdominal wound dress­ ' ing is suicient. In morbidly obese women, application of

a prophylactic negative-pressure device atop the closed skin incision to prevent seroma and subsequent infection does not appear to lower wound complication rates (Hussamy, 20 1 8; Smid, 20 1 7) . joel-Coh e n a n d M isgav La dach Tech n iq u e s

The Pfannenstiel-Kerr technique j ust described has been used for decades. More recently, Joel-Cohen and Misgav Ladach techniques have been added (Holmgren, 1 999). These difer from traditional Pfannenstiel-Kerr entry mainly by their initial incision placement and greater use of blunt dissection. he Joel-Cohen technique creates a straight 1 0-cm transverse skin incision 3 em below the level of the anterior superior iliac spines (Olofson, 20 1 5) . he subcutaneous tissue layer is opened sharply 2 to 3 em in the midline. This is carried down, with­ out lateral extension, to the fascia. A small transverse incision is made in the fascia, and curved Mayo scissors are pushed laterally on each side and beneath intact subcutaneous fat to incise the fascia. With this incision completed, an index finger from each hand is inserted between the rectus abdominis muscle bellies and beneath the fascia. One finger is moved cranially and the other caudally, in opposition, to separate the bellies and further open the fascial incision. hen, a finger from each hand hooks under each belly to stretch the muscles laterally. The peritoneum is entered sharply, and this incision is sharply extended cephalo­ caudad. Entry with the Misgav Ladach technique difers in that the peritoneum is entered bluntly (Holmgren, 1 999). Modiications to the Joel-Cohen method abound. For emer­ gency delivery, we begin along a line somewhat lower on the abdomen. For speed, we extend the fascial incision bluntly by hooking index fingers in the fascial incision's lateral angles and pulling laterally (Hofmeyr, 2009; Olofson, 20 1 5) . Index fin­ gers insinuated between the rectus bellies then move cephalo­ caudad in opposition to stretch the incision. Blunt index-finger dissection enters the peritoneum, and again, cranial and cau­ dad opposing stretch opens this layer. Last, all the layers of the abdominal wall are grasped manually and pulled laterally in opposition to further open the operating space. These techniques have been associated with shorter opera­ tive times and with lower rates of intraoperative blood loss and postoperative pain (Mathai, 20 1 3) . They may, however, prove diicult for women with anterior rectus fibrosis and peritoneal adhesions (BoIze, 20 1 3) . C l a s s i ca l Cesa rea n I n cision Ind ications. This incision is usually avoided because it encom­ passes the active upper uterine segment and thus is prone to rupture with subsequent pregnancies. Some indications stem from diiculty in exposing or safely entering the lower uterine segment. For example, a densely adhered bladder from previous surgery is encountered; a leiomyoma occupies the lower uter­ ine segment; the cervix has been invaded by cancer; or massive maternal obesity precludes safe access to the lower uterine seg­ ment. A classical incision is also preferred for placenta previa with anterior implantation, especially those complicated by pla­ centa accrete syndromes. In extreme cases of this, the typical classical hysterotomy may be placed even higher in the uterine body or posteriorly to avoid the placenta. As such, fetuses with

Cesa rea n Del ive ry a nd Peripa rt u m Hysterectomy

cephalic presentation are then delivered in a manner similar to total breech extraction (Chap. 28, p. 548) . In other instances, fetal indications dictate the need. Trans­ verse lie ofa largeetus, especially if the membranes are ruptured and the shoulder is impacted in the birth canal, usually neces­ sitates a classical incision. A fetus presenting as a back-down transverse lie is particularly diicult to deliver through a trans­ verse uterine incision. In instances when the fetus is very small and breech, a classical incision may be preferable (Osmundson, 20 1 3) . In such cases, the poorly developed lower uterine seg­ ment provides inadequate space for the manipulations required for breech delivery. Or, less commonly, the small fetal head may become entrapped by a contracting uterine fundus following membrane rupture. Last, with multiple fetuses, a classical inci­ sion again may provide suitable room for extraction of fetuses that may be malpositioned or preterm (Osmundson, 20 1 5) . Uterine I ncision and Repai r. A vertical uterine incision is initi­ ated with a scalpel beginning as low as possible and preferably within the lower uterine segment (Fig. 30- 1 1 ) . If adhesions, insuicient exposure, a tumor, or placenta percreta preclude development of a bladder flap, then the incision is made above the level of the bladder. Once the uterus is entered with a scal­ pel, the incision is extended cephalad with bandage scissors until it is long enough to permit delivery of the fetus. With scissor use, the fingers of the nondominant hand are insinuated between the myometrium and fetus to prevent fetal laceration. As the incision is opened, numerous large vessels that bleed pro­ fusely are commonly encountered within the myometrium. The remainder of fetal and placental delivery mirrors that with a low transverse hysterotomy. For incision closure, one method employs a layer of 0- or no. 1 chromic catgut with a running stitch to approximate the

FIGURE 30-1 1 An initial sma l l vertical hysterotomy incision is made in the lower uterine seg ment. F i n gers a re i n s i n uated between the myometrium and fetus to avoid feta l laceration. Scissors exten d the incision cepha lad as needed for del ivery. (Reprod uced with permis­ sion from Johnson DD: Cesa rea n del ivery. I n Yeomans ER, Hoffma n BL, Gilstrap L C I I I, e t a l (eds): Cu n n i n g ham a n d Gilstra p's Operative Obstetrics, 3 rd ed. New York, McGraw-Hili Education, 201 7.)

deeper length of the incision (Fig. 30- 1 2) . he outer layer of myometrium is then closed along its length with similar suture and with a running suture line. To achieve good approximation and to prevent the suture from tearing through the myometrium,

F IG U RE 30- 1 2 Classical i ncision clos u re. The deeper h a lf (left) a nd su perficial half (middle) of the i ncision are closed in a ru n n i n g fas h i o n . T h e serosa is t h e n closed (right) . (Reprod uced with perm ission from Joh nson D D : Cesa rea n delivery. I n Yeom a n s E R, Hoffm a n B L, G i l stra p LC I I I, et al (eds): C u n n i n g h a m a n d Gilstra p's Operative Obstetrics, 3 rd ed. New York, McGraw- H i l i Ed u cation, 201 7.)

5 79

580

De l ivery

it is helpul to have an assistant compress the uterus on each side of the wound toward the midline as each stitch is placed.

PERI PARTUM HYSTERECTOMY

• I nd ications

Hysterectomy is most commonly performed to arrest or prevent hemorrhage from intractable uterine atony or abnormal placen­ tation (Bateman, 20 1 2; Hernandez, 20 1 2; Owolabi, 20 1 3) . It is more often completed during or after cesarean delivery but may be needed following vaginal birth. If all deliveries are con­ sidered, the peripartum hysterectomy rate in the United States approximates 1 per 1 000 births and has risen signiicantly dur­ ing the past few decades (Bateman, 20 1 2; Govindappagari, 20 1 6) . D uring a 25-year period, the rate of peripartum hys­ terectomy at Parkland Hospital was 1 .7 per 1 000 births (Her­ nandez, 20 1 2) . Most of this rise is attributed to the increasing rates of cesarean delivery and its associated complications in subsequent pregnancy (Bateman, 20 1 2; Bodelon, 2009; Flood, 2009; Orbach, 20 1 1 ) . Of hysterectomies, approximately one half to two thirds are total, whereas the remaining cases are supracervical (Rossi, 20 1 0; Shellhaas, 2009) . Major complications of peripartum hysterectomy include greater blood loss and risk of urinary tract damage. Blood loss is usually appreciable because hysterectomy is being performed for hemorrhage that frequently is torrential, and the procedure itself is associated with substantial bleeding. lthough many cases with hemorrhage cannot be anticipated, those with abnormal implan­ tation are oten identiied antepartum. Preoperative prepara­ tions for placenta accreta are discussed in Chapter 4 1 (p. 78 1 ) and have also been outlined by the Society for Maternal-Fetal

F I G U R E 30- 1 4 The posterior l eaf of the broad l iga ment adjacent to the uterus is perforated j ust beneath the fa l lopian tu be, utero­ ova ria n ligaments, and ova rian vessels.

( F I G U R E 30- 1 3 The rou nd ligaments a re cla m ped, dou bly l igated, and tra nsected bilatera l ly.

F I G U R E 30- 1 5 The uteroova rian l igament and fa l lopian tube are c l a m ped and cut. The latera l ped icle is doubly l igated .

Cesa rea n Delive ry a nd Peri part u m Hystere cto my

Medicine (20 1 0) and American College of Obste­ tricians and Gynecologists (20 1 7c) . An important factor afecting the cesarean hysterectomy complication rate is whether the operation is performed electively or emergently. With anticipated or planned cesarean hysterec­ tomy, rates of blood loss, blood transfusion, and urinary tract complications are lower that with emergent procedures (Briery, 2007; Glaze, 2008) .

!

Anterior uterus

• Hysterectomy Technique

Total or supracervical hysterectomy is performed using standard operative techniques. Adequate exposure is essential, but initially, placement of a self-retaining retractor such as a Balfour is not necessary. Rather, satisfactory exposure is obtained with cephalad traction on the uterus by an assistant, along with handheld Richardson or Deaver retractors. he bladder lap is deflected downward to the level of the cervix if possible to permit total hysterectomy. In cases in which cesarean hysterectomy is planned or strongly sus­ pected, extended bladder flap dissection is ide­ ally completed before initial hysterotomy. Later attempts at bladder dissection may be obscured by bleeding, or excess blood may be lost while this dissection is performed. After cesarean delivery, the placenta is typi­ cally removed. In cases of placenta accrete syndrome for which hysterectomy is already planned, the placenta is usually left undisturbed in situ. In either situation, if the hysterotomy incision is bleeding appreciably, it can be sutured or Pennington or sponge forceps can be applied for hemostasis. If bleeding is minimal, neither maneuver is necessary. he round ligament is divided close to the uterus between clamps, and each pedicle is ligated (Fig. 30- 1 3) . Either 0 or no. 1 suture can be used in either chromic gut or delayed­ absorbable material. he anterior leaf of the broad ligament is incised downward to meet the former bladder flap incision. he posterior leaf of the broad ligament adjacent to the uterus is bluntly or sharply perforated just beneath the fal­ lopian tube, uteroovarian ligament, and ovarian vessels (Fig. 30- 1 4) . hese structures together are then divided between sturdy clamps placed close to the uterus (Fig. 30- 1 5) . he lateral pedicle is doubly ligated. The medial clamp remains and is removed later with the entire uterine specimen. he posterior leaf of the broad ligament is incised toward the uterosacral ligaments (Fig. 30- 1 6) . Next, the bladder and attached peritoneal flap are further deflected and dissected as needed. If the bladder flap is unusually adhered, as it may be after previous hysterotomy incisions, careful sharp dissection may be necessary (Fig. 30- 1 7) .

:

�

�-- Uterine

Poste rior l eaf of broad ligament

Uterosacral ligam n�s

\

vessels

\

\

F I G U RE 30- 1 6 The posterior leaf of the broad l i g a ment is d ivided i nferiorly towa rd the uterosacra l liga ment.

£' L i}

/

-

� ") "

Vi I

. , {,/

:(; �

,

y ', , )---

� � '\ -

k7{ .I " 40 weeks Low-ve rtical i n cision U n kn ow n i ncision La bor i n d u ction Med ical d isease M u lt i p l e prior cesa rea n del iveries E d u cation < 1 2 yea rs S ho rt i nterdel ivery i nterva l Liabi l ity concern s

Class ical or T i nc i s ion P rior r u pt u re Patient refusal Tra n sfu ndal s u rg e ry Obstetrica l contra i nd ication, e.g ., p revia I nadequate fa c i l ities

aMost consider these a bsol ute contra i n d i cations. EGA est i mated g estatio n a l a g e. =

DELIVERY ROUTE RISKS As evidence mounted that the risk of uterine rupture might be greater than expected, the American College of Obstetricians and Gynecologists ( 1 988, 1 998, 1 999, 2 0 1 7a) issued updated Practice Bulletins supporting labor trials but also urging a more cautious approach. It is problematic that both options have risks and beneits to mother and fetus but that these are not always congruent. • Maternal Risks

Rates of uterine rupture and associated complications clearly are increased with TO LAC. Uterine rupture typically is classified as either ( 1 ) complete, when all layers of the uterine wall are sepa­ rated, or (2) incomplete, when the uterine muscle is separated but the visceral peritoneum is intact. Incomplete rupture is also commonly referred to as uterine dehiscence. It is these risks that underpin most of the angst in attempting TOLAC. Despite this, some have argued that these factors should weigh only minimally in the decision because their absolute risk is low. One systematic review by Guise and colleagues (20 1 0) concluded that the risk of uterine rupture was significantly elevated in women undergo­ ing TOLAC-absolute risk of 0.47 percent and relative risk of 20.7-compared with those choosing ERCD. he Maternal-Fetal Medicine Units Network conducted a prospective study at 1 9 academic centers (Landon, 2004) . The outcomes of nearly 1 8,000 women attempting TOLAC were compared with more than 1 5 ,000 gravidas undergoing ERCD. The absolute risk of uterine rupture was 0.7 percent compared with no reported uterine ruptures in the ERCD cohort (Table 3 1 -2) . .10st studies suggest that the mater­ nal mortaliy rate does not difer significantly between these two groups (Landon, 2004; Mozurkewich, 2000) . But, the aforementioned systematic review by Guise (20 1 0) found the

risk of maternal death to be signiicantly reduced for women undergoing TOLAC compared with ERCD. In a retrospective Canadian cohort study, the maternal death rate for women undergoing ERCD was 5 .6 per 1 00,000 cases compared with 1 .6 per 1 00,000 for those attempting TOLAC (Wen, 2005) . Estimates of maternal morbidiy are also conflicting. he review by Guise (20 1 0) observed no significant diferences in the risk of hysterectomy or transfusion. But, another metaanalysis reported that women undergoing TOLAC were approximately half as likely to require a blood transfusion or hysterectomy compared with those undergoing ERCD (Mozurkewich, 2 000) . Conversely, in the Network study, investigators observed that the risks of transfusion and infection were significantly greater for women attempting TOLAC (Landon, 2004) . This disparity is also found among other studies. Notably, compared with a successful TOLAC, the risk of these major complications was ivefold greater with an attempted vaginal delivery that failed (Babbar, 20 1 3; Rossi, 2008) . • Fetal and Neonatal Risks

TOLAC is associated with significantly higher perinatal mortal­ iy rates compared with ERCD. he perinatal rate with TOLAC is 0. 1 3 compared with 0.05 percent for ERCD, and the neonatal mortality rates are 0. 1 1 versus 0.06 percent, respectively (Guise, 20 1 0) . In another study of nearly 25,000 women with a prior cesarean delivery, the vaginal-delivery-related perinatal death risk was 1 .3 per 1 000 among 1 5,5 1 5 women electing TOLAC. Although this absolute risk is small, it is 1 1 times greater than the risk found in 90 1 4 women with ERCD (Smith, 2002) . TOLAC also appears to be associated with a higher risk of hypoxic ischemic encephalopathy (HIE) than ERCD. The Net­ work study reported the incidence of HIE at term to be 46 per 1 00,000 TOLACs compared with zero cases in women under­ going ERCD (Landon, 2004) .

593

594

De l ivery

N I C H D Materna l-Feta l Med icine U n its Network, 1 999-2002

TABLE 3 1 -2. Com p l ications in Women with a Prior Cesarean Del ivery E n rol l ed i n the

Complication

Trial of Labor Group n = 1 7,898 No. (%)

Uteri n e r u pt u re Uteri n e d e h i scence Hyste rectomy Th ro m boe m bo l i c d i sease Tra n sfu s i o n Uteri ne i nfection Maternal death Antepart u m sti l l bi rtha 3 7-38 weeks �39 weeks I n tra pa rtu m sti l l b i rtha Term H I Ea Te rm neonata l d eatha

1 24 1 19 41 7 304 51 7 3

(0.7) (0. 7) (0.2) (0.04) ( 1 .7) (2.9) (0.02)

18 16 2 12 13

(0.4) (0.2) (0.08) (0.08)

Elective Repeat Cesarean Group n = 1 5,801 No. (%)

0 76 47 10 1 58 285 7

(0.5) (0.3 ) (0. 1 ) ( 1 .0) ( 1 .8) (0.04)

8 (0. 1 ) 5 (0. 1 ) 0 0 7 (0.05)

Odds Ratio (95% (I)

p

value

NA ( 1 .04- 1 .85) (0.5 1 - 1 . 1 7) (0.24- 1 .62) ( 1 .4 1 -2.08) ( 1 .40- 1 .87) (0. 1 0- 1 .46)

< .00 1 .03 .2 2 .32 < .00 1 < .00 1 .2 1

2.93 ( 1 .27-6. 75) 2.70 (0.99-7.38) NA NA 1 .82 (0.73-4.57)

.008 .07 NS < .00 1 .1 9

1 .38 0.77 0.62 1 .7 1 1 .62 0.38

aDe n o m i nator i s 1 5,338 for the trial of labor g ro u p a n d 1 5,0 1 4 for the el ective repeat cesa rea n del ivery g ro u p. CI confiden ce i nterva l; H I E hypoxic ischemic e n cephalopathy; NA not applica ble; N IC H D National I n stitute of C h i l d Health a n d H u m a n Development; NS n ot s i g n ifica nt. Ada pted fro m La n d o n , 2004. =

=

=

=

In the systematic review, the absolute risk of transient tachy­ pnea ofthe newborn was slightly higher with ERCD compared with TOAC-4.2 versus 3.6 percent (Guise, 20 1 0) . But, neonatal bag and mask ventilation were used more often in newborns delivered following TOAC than in those delivered by ERCD-5 .4 versus 2.5 percent. Finally, there are no signii­ cant diferences in 5-minute Apgar scores or neonatal intensive care unit admission rates for newborns delivered by TO AC compared with those delivered by ERCD. Birth trauma from lacerations is more commonly seen in neonates born by ERCD.

CAN DI DATES FOR TRIAL OF LABOR Few high-quality data are available to guide selection of TOAC candidates. In a population-based cohort study of 4 1 ,450 women delivering in California hospitals, Gregory and colleagues (2008) reported a TOAC success rate of 74 percent when no maternal, fetal, or placental complications were present. Several algorithms and nomograms have been developed to aid prediction, but none has demonstrated reasonable prognostic value (Grobman, 2007b, 2008, 2009; Macones, 2006; Metz, 20 1 3; Srinivas, 2007). A pre­ dictive model for failed trial of labor, however, was found to be somewhat predictive of uterine rupture or dehiscence (Stanhope, 20 1 3) . Despite these limitations for precision, several points are pertinent to candidate evaluation and are described in the next sections. Current recommendations of the American College of Obstetricians and Gynecologists (20 1 7a) are that most women with one previous low-transverse hysterotomy are candidates, and if appropriate, they should be counseled regarding TOAC and ERCD options. Although not our practice, those with two prior low-transverse incisions may be considered.

=

• Prior Uterine I ncision

Prior I ncision Type

he type and number of prior cesarean deliveries are overrid­ ing factors in recommending TOAC. Women with one prior low-transverse hysterotomy have the lowest risk of symptom­ atic scar separation (Table 3 1 -3) . The highest risks are with prior vertical incisions extending into the fundus, such as that

TABLE 3 1 -3. Types of Prior Uterine I ncisions and

Esti mated Risks for Uteri ne Rupture Prior Incision

C l a ssical T-s h a ped Low-ve rticala One l ow-tra n sverse M u ltiple l ow-tra n sverse P r i o r prete rm cesa rea n del ivery P rior u teri n e ru pt u re Lowe r seg ment U p per uterus

Estimated Rupture Rate (%)

2-9 4-9 1 -7 0.2-0.9 0.9- 1 .8 " i n c reased" 2-6 9-32

aSee text for defi n ition . Data fro m the American Co l l ege of Obstetricians a n d Gynecolog i sts, 20 1 7a; Ca h i l l, 20 1 O b; Chau han, 2002; La ndon, 2006; Macones, 2005a,b; M a rt i n , 1 997; M i l ler, 1 994; Sciscione, 2008; Soci ety for Maternal-Feta l Med ici ne, 20 1 2; Ta h see n , 20 1 0.

Prior Cesa rea n D e l ivery

delivery occurred at term. hey observed uterine rupture in 1 .8 percent in the prior periviable group versus 0.4 percent in the prior term group. Of the uterine ruptures in the periviable group, half were in women whose prior uterine incision was described as low transverse. Harper and associates (2009) did not confirm these findings. There are also special considerations for women with u terine malformations who have undergone cesarean delivery. Earlier reports suggested that the uterine rupture risk in a subsequent pregnancy was greater than the risk in those with a prior low­ transverse hysterotomy and normally formed uterus (Ravasia, 1 999). But, in a study of 1 03 women with miillerian duct anomalies, there were no cases of uterine rupture (Erez, 2007) . Given the wide range of risk for uterine rupture associated with the various uterine incision types, it is not surprising that most fellows of the American College of Obstetricians and Gynecologists consider the type of prior incision to be the most important factor when considering a TOLAC (Coleman, 2005). Prior I ncision Closu re

F I G U R E 3 1 -3 Ru ptu red vertica l cesa rean delivery sca r (arrow) iden­ tified at time of repeat cesa rea n del ivery ea rly in la bor. The two black asterisks to the left ind icate some sites of densely adhered omentum.

shown in Figure 3 1 -3 . Importantly, in some women, a classical scar will rupture before labor onset, and this can happen sev­ eral weeks before term. In a review of 1 57 women with prior classical cesarean delivery, one woman had a complete uterine rupture before labor onset, whereas 9 percent had a uterine dehiscence (Chauhan, 2002) . he risk of uterine rupture in women with a prior vertical incision that did not extend into the fundus is unclear. Martin ( 1 997) and Shipp ( 1 999) and their coworkers reported that these low-vertical uterine incisions did not have an increased risk for rupture compared with low-transverse incisions. The American College of Obstetricians and Gynecologists (20 1 7a) concluded that although evidence is limited, women with a prior vertical incision in the lower uterine segment without fundal extension may be candidates for TOLAC. This is in contrast to prior classical or T-shaped uterine incisions, which are considered by most as contraindications to labor. Although there are few indications for a primary classical incision, 53 percent of women undergoing cesarean delivery between 24 °/7 weeks and 2 5 6r weeks have such an incision (Osmundson, 20 l 3) . By 28 weeks' gestation, the risk drops to 35 percent and declines to < 10 percent by 32 weeks. he like­ lihood of classical uterine incision is also increased by nonce­ phalic presentations. In those instances-for example, preterm breech fetus with an undeveloped lower segment-the "low vertical" incision almost invariably extends into the active seg­ ment. Prior preterm cesarean delivery may result in a twofold increased risk for rupture (Sciscione, 2008) . This may be in part explained by the greater likelihood with a preterm fetus of upward uterine incision extension. Lannon and coworkers (20 1 5) compared 456 women with a prior periviable cesarean delivery with more than 1 0,000 women whose prior cesarean

As discussed in Chapter 30 (p. 577), the low-transverse hys­ terotomy incision can be sutured in either one or two layers. A metaanalysis by Roberge and colleagues (20 1 4) compared single- versus double-layer closure and locking versus unlocking suture for uterine closure. They reported that rates for uter­ ine dehiscence or uterine rupture for these closures did not difer signiicantly. Single-layer closure and locked irst layer, however, was associated with a reduced myometrial thickness during subsequent sonographic measurement. In contrast, Ben­ nich and coworkers (20 1 6) reported that a double-layer closure did not increase the residual myometrial thickness when saline contrast sonography was done several months postpartum. At Parkland Hospital, we routinely close the lower-segment inci­ sion with one running, locking suture line. N u m ber of Prior Cesa rea n I n cisions

At least three studies report a doubling or tripling of the rupture rate in women with two compared with one prior transverse hysterotomy (.1acones, 2005a; Miller, 1 994; Tahseen, 2 0 1 0) . In contrast, analysis of the Network database b y Landon and associates (2006) did not conirm this. Instead, they reported an insigniicant diference in the uterine rupture rate in 975 women with multiple prior cesarean deliveries compared with 1 6,9 1 5 women with a single prior operation-0.9 versus 0.7 percent, respectively. As discussed on page 599, other seri­ ous maternal morbidity increases along with the number of prior cesarean deliveries (Marshall, 20 1 1 ) . I ma g i n g of Prior I n c isio n

Sonographic measurement of a prior hysterotomy incision has been used to predict the likelihood of rupture. Large defects in a nonpregnant uterus forecast a greater risk for subsequent rupture (Osser, 201 1 ) . Naji and coworkers (20 l 3a,b) found that the residual myometrial thickness decreased as pregnancy progressed and that rupture correlated with a thinner scar. In a systematic review, women with a prior low-transverse cesar­ ean incision underwent third-trimester sonographic evaluation ( Jastrow, 20 1 0a) . Investigators concluded that the thickness of the lower uterine segment was a strong predictor for a u terine

595

596

Del ive ry

scar defect in women with prior cesarean delivery. They deined this segment as the smallest measurement between urine in the maternal bladder and amnionic luid. hat said, they could not ind an ideal threshold value to recommend TOLAC. his same group subsequently recruited 1 85 6 women contemplat­ ing vaginal birth after a single low-transverse incision, and they sonographically measured lower uterine segment thick­ ness by between 34 weeks and 39 weeks G as trow, 20 1 6) . hey grouped women into three risk categories for uterine rupture during TOLAC based on the measured segment value: high risk < 2.0 mm; intermediate risk 2.0-2.4 mm; and low risk � 2 . 5 mm. he TOAC rates were 9, 42, and 6 1 percent in the three categories, respectively. Of the 984 TOLACs, there were no symptomatic uterine ruptures. Overall, data are limited, and this evaluation is currently not part of our routine practice. • Prior Uterine Rupture

Women who have previously sustained a uterine rupture are at greater risk for recurrence. As shown in Table 3 1 -3, those with a previous low-segment rupture have up to a 6-percent recur­ rence risk, whereas prior upper segment uterine rupture confers a 9- to 32-percent risk (Reyes-Ceja, 1 969; Ritchie, 1 97 1 ) . Fox and associates (20 1 4) reported 1 4 women with prior uterine rupture and 30 women with prior uterine dehiscence. In 60 subsequent pregnancies, they reported no uterine ruptures or severe complications if women were managed in a standardized manner with cesarean delivery prior to labor onset. • I nterdelivery Interval

Magnetic resonance imaging studies of myometrial heal­ ing suggest that complete uterine involution and restoration of anatomy may require at least 6 months (Dicie, 1 997) . To explore this further, Shipp and coworkers (200 1 ) examined the relationship between interdelivery interval and uterine rupture in 2409 women with one prior cesarean delivery. There were 29 women with a uterine rupture- l .4 percent. Interdelivery intervals :;1 8 months were associated with a threefold greater risk of symptomatic rupture during a subsequent TOLAC compared with intervals > 1 8 months. Similarly, Stamilio and associates (2007) noted a threefold augmented risk of uterine rupture in women with an interpregnancy interval 4000 g, and 2.4 percent for >4250 g. Similarly, Jastrow and colleagues (20 1 Ob) in a retrospective report of 2586 women with a prior low-transverse uterine incision, observed an elevated risk for a failed trial of labor, uterine rupture, shoulder dystocia, and perineal laceration associated with rising birthweights. Con­ versely, Baron and coworkers (20 1 3) did not ind higher uterine rupture rates with birthweights > 4000 g. With a preterm fetus, women who attempt a TOLAC have higher VBAC rates and lower rupture rates (Durnwald, 2006; Quinones, 2005). Data supporting external cephalic version (ECV) for breech presentation are limited and are derived from small studies (Burgos, 20 1 4; Weill, 20 1 7) . From thes;, ECV success and adverse event rates appear comparable to women without prior cesarean. The American College of Obstetricians and Gynecol­ ogists (20 1 6) acknowledges this lack of robust data. At Park­ land Hospital, we do not attempt ECV in those with a prior cesarean delivery. • Multifetal Gestation

Twin pregnancy does not appear to increase the risk of uter­ ine rupture. Ford and associates (2006) analyzed 1 850 women with twins and reported a 45-percent successful VBAC rate and a rupture rate of 0.9 percent. Similar studies by Cahill (2005) and Varner (2007) and their colleagues reported rupture rates of 0.7 to 1 . 1 percent and VBAC rates of 75 to 85 percent. According to the American College of Obstetricians and Gyne­ cologists (20 1 7a) , women with twins and a prior low-transverse hysterotomy can safely undergo TO LAC. • Maternal Obesity

Prior vaginal delivery, either before or after a cesarean birth, improves the prognosis for a subsequent vaginal delivery with either spontaneous or induced labor (Aviram, 20 1 7; Grinstead, 2004; Hendler, 2004; Mercer, 2008) . Prior vaginal delivery also lowers the risk of subsequent uterine rupture and other morbidities (Cahill, 2006; Hochler, 20 1 4 ; Zelop, 1 999) .

Multiple studies have reported an inverse relationship between prep regnancy body mass index (BMI) and VBAC rates. Hibbard and coworkers (2006) reported the following rates: 85 percent with a normal BMI, 78 percent with a BMI between 25 and 30, 70 percent with a BMI between 30 and 40, and 6 1 percent with a BMI �40. Similar findings were reported by Juhasz and associates (2005) .

• Prior Cesarean Delivery Indication

• Fetal Death

Women with a nonrecurring indication-for example, breech presentation-have the highest VBAC rate of nearly 90 percent (Wing, 1 999) . Those with a prior cesarean delivery for fetal

Most women with a prior cesarean delivery and fetal death in the current pregnancy would prefer a vaginal delivery. Although fetal concerns are obviated, available data suggest that maternal

Prior Cesa rea n Del ivery

risks are increased. Nearly 46,000 women with a prior cesarean delivery in the Network database had a total of209 fetal deaths at an average gestational age of32.8 weeks (Ramirez, 20 1 0) . There were 1 58 women who elected TOLAC, with a VBAC rate of 87 percent. In the entire TOLAC group, the uterine rupture rate was 2.4 percent. Of the 1 1 6 women who underwent an induc­ tion of labor, there were five uterine ruptures (3.4 percent) .

LABOR AND DELIVERY CONSIDERATIONS

• Timing

The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine (20 1 7b) recommend delaying nonmedically indicated deliveries until 39 completed weeks of gestation or beyond. As shown in Figu re 3 1 -4, sig­ niicant and appreciable adverse neonatal morbidity has been reported with elective delivery before 39 completed weeks (Chiossi, 20 1 3 ; Clark, 2009) . Thus, if ERCD is planned, it is essential that the fetus be mature. The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (20 1 7) have estab­ lished the following guidelines for timing an elective cesarean delivery, and accurate gestational dating is suitable using any of these criteria. 1 . Sonographic measurements taken before 20 weeks' gestation support a gestational age :39 weeks. 2. Fetal heart sounds have been documented for 30 weeks by Doppler ultrasound. 3. A positive serum or urine �-human chorionic gonadotropin (hCG) test result has been documented for :36 weeks. • Intrapartum Care

Because of uterine rupture risks for women undergoing TOLAC, the American Academy of Pediatricians and the American College 20

Any adverse outcome RDS or TTN • Sepsis • •

15 c

� 10 D

..

of Obstetricians and Gynecologists (20 1 7) recommend that such trials be undertaken only in facilities with staf immediately avail­ able to provide emergency care. Moreover, these centers s hould have a plan and resources for managing uterine rupture. Some argue that these provisions deny women full access to choices. For example, in an earlier survey of Ohio hospitals, 1 5 percent of Level I, 63 percent of Level II, and 1 00 percent of Level III institutions met these requirements (Lavin, 2002) . Moreover, an obstetrical anesthesia workforce survey reported that due to staf­ ing limitations, TOLAC was allowed in only 8 8 percent of hos­ pitals with : 1 500 annual deliveries, in 59 percent of those with 500 to 1 499 deliveries, and in 43 percent of those with < 500 deliveries (Traynor, 20 1 6) . In some cases, women choose to attempt TOLAC at a birthing center or at home (Shields, 2 0 1 7) . • Cervical Ripening and Labor Sti mulation

Labor induction is associated with a higher failure rate dur­ ing TOLAC. The risks for uterine rupture, however, are less clear with induction or augmentation, with the exception of prostaglandin E1-misoprostol-which is contraindi­ cated (American College of Obstetricians and Gynecolo gists, 20 1 7a) . Although most institutions are not so conservative, we do not induce or augment labor pharmacologically in women electing TOLAC at Parkland Hospital. Instead, we attempt induction only by amniotomy. Other considerations are to avoid induction or augmentation in women with an unknown prior incision type, an unfavorabl e cervix, or preg­ nancy > 40 weeks. Oxytocin

Induction or augmentation of labor with oxytocin has been implicated in increased rates of uterine rupture in women under­ going TOLAC (Zelop, 1 999) . In the Network study reported by Landon and colleagues (2004), uterine rupture was more fre­ quent in women induced with oxytocin alone-I . l percent­ than in those in spontaneous labor-O.4 percent. Augmentation of labor was associated with uterine rupture in 0.9 percent. Among women in this trial without a prior vaginal delivery, the uterine rupture risk associated with oxytocin induction was 1 .8 percent-a fourfold greater risk compared with spontane­ ous labor (Grobman, 2007a) . In contrast, in one case-control study, induction was not associated with a higher risk for rup­ ture (Harper, 2 0 1 2a). Cahill (2008) and Goetzl (200 1 ) and their coworkers reported a dose-related risk of rupture with oxytocin. Prosta g l a n d i n s

5

o --37 40 38 39 42 41 G estational age (weeks) F I G U R E 3 1 -4 Neonata l m o rbid ity rates seen with 1 3,258 elective repeat cesa rea n del iveries. Any adverse outcome incl udes death. Sepsis incl udes suspected a nd proven. RDS respi ratory di stress synd rome; IN tra nsient tachypnea of the newborn. (Data from Tita AT, La ndon MB, Spong CY, et a l : Ti m i n g of elective repeat cesa rea n del ivery at te rm a n d neonata l o utcomes. N Engl J Med 360(2): 1 1 1 , 2009.) =

=

Various prostaglandin preparations commonly employed for cervical ripening or labor induction are discussed in Chapter 26 (p. 506). s a group, their safe use in women with a prior cesarean delivery is unclear because of conlicting data. With misoprostol (PGE1 ) , Wing and colleagues ( 1 998) compared it versus oxytocin for labor induction in women with a prior cesarean delivery. They terminated their trial after two of the irst 1 7 women assigned to misoprostol developed a uterine rupture. Other studies confirmed this, and most con­ sider misoprostol to be contraindicated (American College of Obstetricians and Gynecologists, 20 1 7 a) .

597

598

Del ivery

Of other prostaglandins, studies to evaluate their use for induction are contradictory. Ravasia and coworkers (2000) compared uterine rupture in 1 72 women given PGE2 gel with 1 544 women in spontaneous labor. The rupture rate was signif­ icantly greater in women treated with PGE2 gel-2.9 percent compared with 0.9 percent in those with spontaneous labor. Lydon-Rochelle and associates (200 1 ) found similar results. However, in the Network study cited previously, the uterine rupture rate was 1 .4 percent when any prostaglandin was used in combination with oxytocin (Landon, 2004) . But, in the subgroup of 227 women in whom labor was induced with a prostaglandin alone, there were no ruptures. Similar findings were reported with intravaginal prostaglandins, which were not associated with a greater uterine rupture risk (Macones, 2005b) . These latter investigators, along with Kayani and col­ leagues (2005 ) , found that sequential use of a prostaglandin followed by oxytocin was associated with a threefold greater risk of rupture compared with spontaneous labor.

• Uterine Scar Exploration

Following VBAC, some clinicians routinely document the integrity of a prior scar by placing a hand through the dilated cervix and along the inner surface of the lower uterine segment. But routine uterine exploration is considered by others to be unnecessary. In a longitudinal study of 3469 women who had a VBAC, seven uterine dehiscences and one uterine rupture yielded an overall event rate of 0.23 percent (Silberstein, 1 998). They concluded that transcervical evaluation need only be per­ formed in symptomatic patients. Currently, the benefi t s of routine scar evaluation in the asymptomatic woman are unclear, however, surgical correction of a dehiscence is necessary if significant bleeding is encoun­ tered. Our practice is to routinely examine these prior hyster­ otomy sites. Any decision for laparotomy and repair takes into consideration the extent of the tear, whether the peritoneal cav­ ity has been entered, and the presence of active bleeding.

UTERIN E SCAR RUPTURE

M ec h a n i c a l M ethods

Studies concerning the use of a transcervical Foley catheter for cervical ripening and induction of labor in women with a prior cesarean delivery are limited (Ben-Aroya, 2002; Jozwiak, 20 1 4) . I n a retrospective study o f 2479 women with prior cesarean delivery, the uterine rupture risk using a transcervical Foley cath­ eter for labor induction ( 1 .6 percent) was not significantly greater than that with spontaneous labor ( 1 . 1 percent) or with using amniotomy with or without oxytocin ( 1 .2 percent) (Bujold, 2004) . In contrast, Hofman (2004) described 1 38 women who underwent preinduction cervical ripening with a Foley catheter compared with 536 women who entered labor spontaneously. They observed a significant and inordinately high uterine rupture risk during labor following Foley catheter cervical ripening com­ pared with spontaneous onset of labor-6.5 versus 1 .9 percent. • Epidu ral Analgesia

• Diagnosis

Progress of labor in women attempting TOLAC is similar to normal labor, and no speciic pattern presages uterine rupture (Graseck, 20 1 2; Harper, 20 1 2b; Sondgeroth, 20 1 7) . Before hypovolemic shock develops, symptoms and physical findings in women with uterine rupture may appear bizarre unless the possibility is kept in mind. For example, hemoperitoneum from a ruptured uterus may result in diaphragmatic irritation with pain referred to the chest. This may direct one to a diagnosis of pulmonary or amnionic fluid embolism instead of uterine rupture. As shown in Figure 3 1 -5, the most common sign of uterine rupture is a nonreassuring fetl heart rate pattern with variable decelerations that may evolve into late decelerations and bradycardia. In 36 cases of such rupture during TOLAC, there were fetal signs of uterine rupture in 24, maternal signs in eight, and a combination of maternal and fetal in three (Holmgren, 20 1 2) . Few women experience cessation of contractions follow­ ing uterine rupture, and the use of intrauterine pressure cath­ eters does not assist reliably in the diagnosis (Rodriguez, 1 989) .

Concerns that epidural analgesia for labor might mask the pain of uterine rupture have not been veriied. Fewer than 1 0 percent of women with scar separation experience pain and bleeding, and fetal heart rate decelerations are the most likely sign (ieser, i -� . ,1 t= t • 2002) . That said, Cahill and coworkers i I , (20 1 0a) documented that more frequent leo 1/ t t \ (� -\ "i episodes of epidural dosing were associ­ -t � V \ A ated with increasing uterine rupture rates. t � -. ,\ t -. V \/ VBAC rates are similar, and in some J 0 + � -w 60 \_IlY cases higher, among women with labor r - : bO , -i ,. t I , .� epidural analgesia compared with those using other forms of analgesia (Aviram, 20 1 7; Shmudi, 20 1 7) . Perhaps related, almost a fourth of VBAC deliveries were completed with either forceps or vacuum (Inbar, 20 1 7) . he merican Academy of Pediatrics and the American College of Obstetricians and Gynecologists (20 1 7) F I G U R E 3 1 -5 Feta l hea rt rate tracing in a wom a n whose uterus ruptured d u ring labor have concluded that epidural analgesia wh i le pushing. The r u pture apparently sti m u lated a reflex push, after which uterine tone d i m i n is hed a n d feta l bradyca rd ia worsened. may safely be used during TOLAC. FHR-240-bpm

FHR-240-bpm

�

2 1 0-180 150

1 2090

30

--LUA-0-1mHg

�J

210

150 •

120

�

30

T

Prior Cesa rea n Del ivery

In some women, the clinical appearance of uterine rupture mirrors that of placental abruption. In most, however, there is remarkably little appreciable pain or tenderness. Also, because most women in labor are treated for discomfort with either narcotics or epidural analgesia, pain and tenderness may not be readily apparent. The condition usually becomes evident because of fetal distress and occasionally because of maternal hypovolemia from concealed hemorrhage. If the fetal presenting part has already entered the pelvis with labor, loss of station may be detected by pelvic examination. If the fetus is partly or totally extruded from the uterine rupture site, abdominal palpation or vaginal examination may be help­ ful to identiY the presenting part, which will have moved away from the pelvic inlet. A irm contracted uterus may at times be felt alongside the fetus. Sonography may be helpful. • Decision-to-Delivery Time

With rupture and expulsion of the fetus into the peritoneal cavity, the chances for intact fetal survival are dismal, and reported mortality rates range from 50 to 75 percent. Fetal condition depends on the degree to which placental implantation remains intact, although this can change within minutes. With rupture, the only chance of fetal survival is aforded by immedi­ ate delivery-most often by laparotomy-otherwise, hypoxia is inevitable. If rupture is followed by total placental separation, then very few neurologically intact fetuses will be salvaged. Thus, even in the best ofcircumstances, someetal outcomes wil be impaire. he Utah experiences are instructive here (Holmgren, 20 1 2) . Of the 35 laboring patients with uterine rupture, the decision-to-delivery time was < 1 8 minutes in 1 7, and none of these infants had an adverse neurological outcome. Of the 1 8 born > 1 8 minutes from decision time, the three infants with long-term neurological impairments were delivered at 3 1 , 40, and 42 minutes. There were no deaths, thus severe neonatal neurological morbidity developed in 8 percent of this group of 35 women with uterine rupture. In a study using the Swedish Birth Registry, Kaczmarczyk and coworkers (2007) found that the risk of neonatal death following uterine rupture was 5 percent. In the Network study cited earlier, seven of the 1 1 4 uterine ruptures associated with TOAC-6 percent-were complicated by development of neonatal HIE (Spong, 2007) . Maternal deaths from uterine rupture are uncommon. Of 2.5 million women who gave birth in Canada between 1 99 1 and 200 1 , there were 1 898 cases of uterine rupture, and four of these-0.2 percent-resulted in maternal death (Wen, 2005) . In other regions of the world, however, maternal mortality rates are much higher. From rural India, the maternal mortality rate asso­ ciated with uterine rupture was 30 percent (Chatterjee, 2007) . • Management

With complete rupture during TOAC, hysterectomy may be required. In selected cases, however, suture repair with uterine preservation may be performed. Sheth ( 1 968) described out­ comes from a series of 66 women in whom repair of a uterine rupture was elected rather than hysterectomy. hirteen of the 41 mothers who did not have tubal sterilization had a total of

599

2 1 subsequent pregnancies. Uterine rupture recurred in four of these-approximately 20 percent. Usta and associates (2007) reported similar results. In another study, however, women with a uterine dehiscence were not more likely to have a subse­ quent uterine rupture (Baron, 20 1 4) .

M U LTI PLE REPEAT CESAREAN DELIVERI ES Because of the aforementioned concerns with TOAC, most women in the United States undergo ERCD. his choice has several signiicant maternal complications, and rates of these rise in women who have multiple repeat operations. The inci­ dences of some common complications for women with one prior transverse cesarean delivery who undergo an ERCD were shown in Table 3 1 -2. Of note, half of cesarean hysterectomies done at Parkland Hospital are in women with one or more prior cesarean deliveries (Hernandez, 20 1 3) . The Network addressed issues o f increased morbidity i n a cohort of 30, 1 32 women who had from one to six repeat cesar­ ean deliveries (Silver, 2006) . he rates of some of the more frequent or serious complications are depicted in Figure 3 1 -6. In addition, rates of bowel or bladder injury, admission to an intensive care unit or need for ventilator therapy, and maternal mortality, as well as operative and hospitalization length, showed significantly rising trends. Similar results have been reported by others (Nisenblat, 2006; Usta, 2005) . More diicult to quantiY are risks for bowel obstruction and pelvic pain from peritoneal 8

• •

7

C

•

•

6

•

Wound/uterine infection Placenta previa Transfusion Hysterectomy Placenta accreta

) u

m 5 S

�

c 0

.� 4 .. E

2

0 u

� )

:

3

2

O -� Fourth � Fifth Third First Second

(620 1 )

( 1 5,808)

(6324)

( 1 452)

(347)

Number of repeat cesarean deliveries (Number of women)

F I G U R E 3 1 -6 Maternal-Feta l Medicine U n its Network: rates of some com p l icatio ns with i ncreas i ng n u m ber of repeat cesa rea n del iveries. (Data from Si lver RM, La ndon M B, Rouse OJ, e t a l : M ater­ n a l morbid ity associated with m U ltiple repeat cesa rea n deliveries. Obstet Gynecol 207:1 2 26, 2006.)

600

Del ivery

TABLE 3 1 -4. Some Recommendations of P rofessional Societies Conce rn i n g a Trial of Labor to Attempt VBAC

America n Co l lege of O bstetrici a n s a n d Gynecologists (20 l 7a)

Society of O bstetrici a n s a n d Gyna eco l og ists of Canada (2005)

=

cesa rea n d e l i very; VBAC

Facil ities

Offer to m ost wom e n with one p rior l ow-tra n sverse i ncision; consider for t.IO prior low-tra n sverse i ncisions

Safest with a b i l ity for i m med iate cesa rea n d e l i very; patients should be a l l owed to accept i ncreased risk when n ot ava i la b l e S h o u l d del iver i n h ospita l i n which ti mely cesa rea n d e l ivery is ava i la ble; a p p roxi m ate timefra me of 30 m i n utes

Offer to worne n with one prior tra n sverse l ow­ seg ment cesa re a n del ivery; with > 1 prior CD then VBAC l i kely s uccessfu l but i ncreased risks

Roya l College of O bstetrici a n s a n d Gynaecol o g i sts (2007)

CD

Counseling

Discuss VB,\C o ption with wom e n with p rior l ow-seg ment cesa re a n del ivery; d e c i s i o n between o bstetrician and patient =

Other

S u ita b l e del i very su ite with conti n uo u s ca re and m o n itori n g ; i m m ed iate cesa re a n del ivery capa b i l ity

Not precl uded: twi n s, macr o so m ia, prior l ow­ vertical or u n kn ow n type o f i ncision

Oxytoci n or Foley catheter i nd u ction safe, but p rosta g l a n d i ns s h o u l d not be u sed; macrosom ia, d i a betes, postterm p reg n a n cy, twi n s a re n ot contrai n d ications Caution with twi ns and macroso m ia

vag i na l b i rth afte r cesa rea n .

adhesive disease, both of which increase with each successive cesarean delivery (Andolf, 20 1 0; Mankuta, 20 1 3) . Cook and colleagues (20 1 3) from the United Kingdom Obstet­ ric Surveillance System (UKOSS) described adverse sequelae of women with ive or more cesarean deliveries. These women had signiicantly higher rates of morbidity. Namely, the major hemor­ rhage rate increased 1 8-fold; visceral damage, 1 7-fold; critical care admissions, I S-fold; and delivery 1 p rior tra n sverse C D, u n know n i ncision, twi n s, macrosomia Labor and delivery

Cauti o n s for i nd u ction-u nfavo ra b l e cervix, h i g h station Consider AROM Avoid prosta g l a n d i n s Respect oxytoci n-know w h e n t o q u it Bewa re of a bn o rm a l l a bor p rogress Res pect EFM pattern a bn orma l ities Know when to a ba ndon a trial of labor ACOG American Col l ege of Obstetricia n s and Gynecologists; AROM a rtificial ru ptu re of m e m bra nes; CD cesare a n delivery; EFM electro n i c fetal m o n i oring . =

=

=

=

Prior Cesarean Del ivery

REFERENCES American Academy o f Pediatrics, American College of Obstetricians and Gynecologists: Guidelines for Perinatal Care, 8th ed. Elk Grove Village, 20 1 7 American College o f Obstetricians and Gynecologists: Guidelines for vaginal delivery ater a previous cesarean birth. Committee Opinion No. 64, Octo­ ber 1 98 8 American College of Obstetricians a n d Gynecologists: Vaginal delivery after previous cesarean birth. Committee Opinion No. 1 43, October 1 994 American College of Obstetricians and Gynecologists: Vaginal birth ater previous cesarean delivery. Practice Bulletin No. 2, October 1 998 American College of Obstetricians and Gynecologists: Vaginal birth after previous cesarean delivery. Practice Bulletin No. 5 , ] uly 1 999 American College of Obstetricians and Gynecologists: External cephalic version. Practice Bulletin No. 1 6 1 , February 20 1 6 American College o f Obstetricians and Gynecologists: Vaginal birth after cesarean delivery. Practice B ulletin No. 1 84, November 20 1 7a merican College of Obstetricians and Gynecologists, Society for Maternal­ Fetal Medicine: Nonmedically indicated early-term deliveries. Committee Opinion No. 56 1 , April 20 1 3, Reairmed 20 1 7b Andolf E, Thorsell M, Kallen K: Cesarean delivery and risk for postoperative adhesions and intestinal obstruction: a nested case-control study of the Swedish Medical Birth Registry. Am ] Obstet Gynecol 203 :406.e l , 20 1 0 Aviram A , Hadar E , Gabbay-Benziv R, e t al: Successful tolac i n a population with a high success rate-what are the diferences? Abstract No. 923. Am ] Obstet GynecoI 2 1 6:S 526, 20 1 7 Babbar S , Chauhan S , Hammas I , e t al: Failed trial of labor after cesarean delivery: indications for failure and peripartum complications. Abstract No. 8 1 8 , Am ] Obstet Gynecol 208 (1 Suppl) : S342, 20 1 3 Barger M K, Dunn ]T, Bearman S , e t al: A survey o f access to trial o f labor in California hospitals in 20 1 2. BMC Pregnancy Childbirth 1 3 :83, 20 1 3 Baron ] , Weintraub AY, Eshkoli T , et al: h e consequences o f previous uterine scar dehiscence and cesarean delivery on subsequent births. Int ] Gynaecol Obstet 1 26(2) : 1 20 , 20 1 4 Baron ], Weintraub A , Sergienko R , e t al: Is vaginal delivery o f a macrosomic infant after cesarean section really so dangerous? Abstract No. 799, Am ] Obstet Gynecol 208 ( 1 Suppl) :S33 5 , 20 1 3 Ben-Aroya Z , Hallak M, Segal 0, e t al: Ripening o f the uterine cervix i n a post-cesarean parturient: prostaglandin E2 versus Foley catheter. ] Matern Fetal Neonatal Med 1 2 ( 1 ) :42 2002 Bennich G , Rudnicki M, Wilken-Jensen C, et al: Impact of adding a second layer to a single unlocked closure of a cesarean uterine incision: randomized controlled trial. Ultrasound Obstet GynecoI 47(4) :4 1 7, 20 1 6 Bonanno C , Clausing M, Berkowitz R : VBAC: a medicolegal perspective. Clin Perinatol 38: 2 1 7, 20 1 1 Bujold E, Blackwell SC, Gauthier R]: Cervical ripening with transcervical Foley catheter and the risk of uterine rupture. Obstet Gynecol 1 03 ( 1 ) : 1 8 2004 Bujold E, Gauthier R] : Should we allow a trial of labor after a previous cesarean for dystocia in the second stage of labor? Obstet Gynecol 98:652, 200 1 Burgos ], Cobos P, Rodriguez L, et al: Is external cephalic version at term con­ traindicated in previous caesarean section? A prospective comparative cohort study. B]OG 1 2 1 :230, 20 1 4 Cahill A , Stamilio O M , Pare E, e t al: Vaginal birth ater cesarean (VBAC) attempt in twin pregnancies: is it safe? Am ] Obstet Gynecol 1 93: 1 050, 2005 Cahill AG, Odibo AO, Allswroth ]E, et al: Frequent epidural dosing as a marker for impending uterine rupture in patients who attempt vaginal birth after cesarean delivery. Am ] Obstet Gynecol 202 :355.e 1 , 20 1 0a Cahill AG, Stamilio DM, Odibo A, et al: Is vaginal birth after cesarean (VBAC) or elective repeat cesarean safer in women with a prior vaginal delivery? Am ] Obstet Gynecol 1 9 5 : 1 1 43, 2006 Cahill AG, Tuuli M, Odibo AO, et al: Vaginal birth ater caesarean for women with three or more prior caesareans: assessing safety and success. B]OG 1 1 7:422, 20 1 Ob Cahill AG, Waterman BM, Stamilio DM, et al: Higher maximum doses of oxytocin are associated with an unacceptably high risk for uterine rupture in patients attempting vaginal birth after cesarean delivery. Am ] Obstet Gynecol 1 99:32.e 1 , 2008 Chatterjee SR, Bhaduri S: Clinical analysis of 40 cases of uterine rupture at Durgapur Subdivisional Hospital: an observational study. ] Indian Med Assoc 1 05 : 5 1 0, 2007 Chauhan SP, Magann EF, Wiggs CD, et al: Pregnancy after classic cesarean delivery. Obstet Gynecol 1 00:946, 2002 Cheng Y, Snowden ], Cottrell E, et al: Trends in proportions of hospitals with VBAC: impact of ACOG guidelines. Am ] Obstet Gynecol 21 0:S24 1 , 20 1 4 Chiossi G, Lai Y , Landon M B , e t al: Timing o f delivery and adverse outcomes in term singleton repeat cesarean deliveries. Obstet Gynecol 1 2 1 : 56 1 , 20 1 3

Clark SL, Miller DO, Belfort A, et al: Neonatal and maternal outcomes associated with elective term delivery. Am ] Obstet Gynecol 200 (2) : 1 56. e l , 2009 Coleman VH, Erickson K, Schulkin ] , et al: Vaginal birth after cesarean deliv­ ery. ] Reprod Med 50:26 1 , 2005 Cook ], ]avis S, Knight M , et al: Multiple repeat caesarean section in the UK: incidence and consequences to mother and child. A national, prospective, cohort study. B]OG 1 20( 1 ) : 8 5 , 20 1 3 Cragin E : Conservatism i n obstetrics. N Y Med ] 1 04 : 1 , 1 9 1 6 Dicle 0 , Kiiciikler C , Pirnar T : Magnetic resonance imaging evaluation of inci­ sion healing after cesarean sections. Eur Radiol 7:3 1 , 1 997 Durnwald CP, Rouse 0], Leveno K], et al: he Maternal-Fetal Medicine Units Cesarean Registry: safety and eicacy of a trial of labor in preterm pregnancy after a prior cesarean delivery. Am ] Obstet Gynecol 1 9 5 : 1 1 1 9, 2006 Eastman N]: Williams Obstetrics, 1 0th ed. Appleton-Century-Crofts, New York, 1 9 50 Erez 0, Dulder 0, Novack L, et al: Trial of labor and vaginal birth after cesar­ ean section in patients with uterine millerian anomalies: a population-based study. Am ] Obstet Gynecol 1 96: 537.e 1 , 2007 Ford M, Bateman BT, Simpson LL: Vaginal birth ater cesarean delivery in twin gestations: a large, nationwide sample of deliveries. Am ] Obstet Gynecol 1 9 5 : 1 1 38 , 2006 Fox NS, Gerber RS, Mourad M, et al: Pregnancy outcomes in patients with prior uterine rupture or dehiscence. Obstet GynecoI 1 23 (4) :785, 2 0 1 4 Goetzl L , Shipp TO, Cohen A , et al: Oxytocin dose and the risk o f uterine rupture in trial of labor ater cesarean. Obstet Gynecol 97:38 1 , 200 1 Graseck AS, Odibo AO, Tuuli M, et al: Normal first stage of labor in women undergoing trial oflabor after cesarean delivery. Obstet GynecoI 1 1 9 (4) :732, 20 1 2 Gregory KD, Korst LM, Fridman M , e t a l : Vaginal birth ater cesarean: clinical risk factors associated with adverse outcome. Am ] Obstet Gynecol 1 98:4 52. e 1 , 2008 Grinstead ], Grobman WA: Induction of labor after one prior cesarean: predic­ tors of vaginal delivery. Obstet Gynecol 1 03 : 534, 2004 Grobman WA, Gilbert S, Landon MB, et al: Outcomes of induction o f labor after one prior cesarean. Obstet Gynecol 1 09 :262, 2007a Grobman WA, Lai Y, Landon MB, et al: Can a prediction model for vaginal birth after cesarean also predict the probability of morbidity related to a trial of labor? Am ] Obstet Gynecol 200( 1 ) : 56.e 1 , 2009 Grobman WA, Lai Y, Landon MB, et al: Development of a nomogram for predic­ tion of vaginal birth ater cesarean delivery. Obstet Gynecol 1 09:806, 2007b Grobman WA, Lai Y, Landon MB, et al: Prediction of uterine rupture asso­ ciated with attempted vaginal birth ater cesarean delivery. Am ] Obstet GynecoI 1 99:30.e 1 , 2008 Guise ]M, Denman MA, Emeis C, et al: Vaginal birth after cesarean: new insights on maternal and neonatal outcomes. Obstet Gynecol 1 1 5 : 1 267, 20 1 0 Hamilton BE, Martin ]A, Osterman M], e t al: Births: inal data for 20 1 4. Nat! Vital Stat Rep 64( 1 2) : 1 , 20 1 5 Hamilton BE, Martin ]A, Osterman M]: Births: preliminary data for 20 1 5 . Nat! Vital Stat Rep 65(3) : 1 , 20 1 6 Harper LM, Cahill AG, Boslaugh S , e t al: Association o f induction o f labor and uterine rupture in women attempting vaginal birth after cesarean: a survival analysis. Am ] Obstet Gynecol 206: 5 1 .e 1 , 20 1 2a Harper LM, Cahill AG, Roehl A, et al: he pattern of labor preceding uterine rupture. Am ] Obstet GynecoI 207(3) : 2 1 0.e 1 , 20 1 2b Harper LM, Cahill AG, Stamilio DM, et al: Efect of gestational age at the prior cesarean delivery on maternal morbidity in subsequent VBAC attempt. Am ] Obstet GynecoI 200(3):276.e 1 , 2009 Hendler I, Bujold E: Efect of prior vaginal delivery or prior vaginal birth after cesarean delivery on obstetric outcomes in women undergoing trial of labor. Obstet Gynecol 1 04(2) :2 3, 2004 Hernandez ]S, Wendel GO, Sheield ]S: Trends in emergency peripartum hys­ terectomy at a single institution: 1 988-2009. Am ] PerinatoI 30:36 5 , 20 1 3 Hibbard ]U, Gilbert S , Landon M B , e t al: Trial o f labor o r repeat cesarean delivery in women with morbid obesity and previous cesarean delivery. Obstet Gynecol 1 08: 1 2 5 , 2006 Hochler H, Yafe H, Schwed P, et al: Safety of a trial of labor after cesarean delivery in grandmultiparous women. Obstet GynecoI 1 23:304, 20 1 4 Hofman MK, Sciscione A, Srinivasana M , et al: Uterine rupture in patients with a prior cesarean delivery: the impact of cervical ripening. Am ] Perina­ toI 2 1 (4):2 1 7, 2004 Holmgren C, Scott ]R, Porter TF, et al: Uterine rupture with attempted vagi­ nal birth after cesarean delivery. Obstet Gynecol 1 1 9:725, 20 1 2 Inbar R, Mazaaki S , Kalter A , e t al: Trial of labour after caesarean (TO LAC) is associated with increased risk for instrumental delivery. ] Obstet Gynaecol 37( 1 ) :44, 20 1 7

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De l ivery Jastrow N, Chailet N, Roberge S, et al: Sonographic lower uterine segment thickness and risk of uterine scar defect: a systematic review. J Obstet Gyn­ aecol Can 32(4):32 1 , 20 1 0a Jastrow N, Demers S, Chaillet N, et al: Lower uterine segment thickness to prevent uterine rupture and adverse perinatal outcomes: a multicenter pro­ spective study. Am J Obstet Gynecol 2 1 5 (5) :604.e 1 , 20 1 6 Jastrow N , Demers S , Gauthier Rl, e t al: Adverse obstetric outcomes i n women with previous cesarean for dystocia in second stage labor. Am J Perinatol 30: 1 3 , 20 1 3 Jastrow N , Robere S , Gauthier RJ , et al: Efect o f birth weight on adverse obstetric outcomes in vaginal birth after cesarean delivery. Obstet Gynecol 1 1 5 (2):338, 20 1 0b Jozwiak M, Van De Lest H, Burger NB, et al: Cervical ripening with Foley catheter for induction of labor after cesarean section: a cohort study. Acta Obstet Gynecol Scand 93:296, 20 1 4 Juhasz G , Gyami C , Gyami P, e t al: Efect of body mass index and exces­ sive weight gain on success of vaginal birth after cesarean delivery. Obstet Gynecol l O6:74 1 , 2005 Kaczmarczyk M , Span�n P, Terry P, et al: Risk factors for uterine rupture and neonatal consequences of uterine rupture: a population-based study of suc­ cessive pregnancies in Sweden. BJOG 1 1 4: 1 208, 2007 Kayani SI, lfirevic Z: Uterine rupture after induction of labour in women with previous caesarean section. BJOG 1 1 2:45 1 , 2005 Kieser E, Baskett TF: A 1 0-year population-based study of uterine rupture. Obstet Gynecol 1 00:749, 2002 Landon MB, Hauth Jc, Leveno KJ , et al: Maternal and perinatal outcomes associated with a trial of labor after prior cesarean delivery. N Engl J Med 3 5 1 :258 1 , 2004 Landon MB, Leindecker S, Spong CY, et al: he Iv fFMU Cesarean Registry: factors afecting the success of trial of labor after previous cesarean delivery. Am J Obstet Gynecol 1 93 : 1 0 1 6, 2005 Landon MB, Spong CY, Thon E, et al: Risk of uterine rupture with a trial of labor in women with multiple and single prior cesarean delivery. Obstet Gynecol 1 08: 1 2, 2006 Lannon SM, Guthrie A, Vanderhoeven JP, et al: Uterine rupture risk after periviable cesarean delivery. Obstet Gynecol 1 2 5 : 1 095, 20 1 5 Lavin JP, DiPasquale L, Crane S, et al: A state-wide assessment of the obstetric, anesthesia, and operative team personnel who are available to manage the labors and deliveries and to treat the complications of women who attempt vaginal birth after cesarean delivery. Am J Obstet Gynecol 1 87:6 1 1 , 2002 Leeman Uvl, Beagle M, Espey E, et al: Diminishing availability of trial of labor ater cesarean delivery in New Mexico hospitals. Obstet GynecoI 1 22:242, 20 1 3 Lydon-Rochelle M, Holt VL, Easterling TR, e t al: Risk o f uterine rupture during labor among women with a prior cesarean delivery. N Engl J Med 345:3, 200 1 Macones GA, Cahill A, Pare E, et al: Obstetric outcomes in women with two prior cesarean deliveries: is vaginal birth after cesarean delivery a viable option? Am J Obstet GynecoI 1 92: 1 223, 2005a Macones GA, Cahill AG, Stamilio DM, et al: Can uterine rupture in patients attempting vaginal birth ater cesarean delivery be predicted? Am J Obstet Gynecol 1 9 5 : 1 1 48, 2006 Macones GA, Peipert J, Nelson DB, et al: Maternal complications with vagi­ nal birth after cesarean delivery: a multicenter study. Am J Obstet Gynecol 1 93 : 1 656, 2005 b Mankuta D , Mansour M, Alon SA: Ivlaternal a n d fetal morbidity d u e to abdominal adhesions after repeated cesarean section. Abstract No. 792, Am J Obstet Gynecol 208 ( 1 Suppl):S332, 20 1 3 Marshall NE, F u R , Guise JM: Impact o f multiple cesarean deliveries o n mater­ nal morbidity: a systematic review. Am J Obstet GynecoI 205 :262.e 1 , 2 0 1 1 Martin IN, Perry KG, Roberts WE, et al: The care for trial of labor in the patients with a prior low-segment vertical cesarean incision. Am J Obstet Gynecol 1 77: 1 44, 1 997 McMahon MJ, Luther ER, Bowes WA J r, et al: Comparison of a trial of labor with an elective second cesarean section. N Engl J Med 335 :689, 1 996 Mercer BM, Gilbert S , Landon MB, et al: Labor outcomes with increasing number of prior vaginal births after cesarean delivery. Obstet Gynecol 1 1 1 :285, 2008 Metz TD, Stoddard GJ, Henry E, et al: Simple, validated vaginal birth after cesarean delivery prediction model for use at the time of admission. Obstet Gynecol 1 22 : 57 1 , 20 1 3 Miller DA, Diaz FG, Paul RH: Vaginal birth after cesarean: a 1 0-year experi­ ence. Obstet GynecoI 84(2) :255, 1 994 Mozurkewich EL, Hutton EK: Elective repeat cesarean delivery versus trial of labor: a meta-analysis of the literature from 1 989 to 1 999. Am J Obstet Gynecol 1 83 (5) : 1 1 87, 2000 Naji 0 , Daemen A, Smith A, et al: Changes in cesarean section scar dimen­ sions during pregnancy: a prospective longitudinal study. Ultrasound Obstet Gynecol 4 1 (5):5 56, 20 1 3a

Naji 0, Wynants L, Smith A, et al: Predicting successful vaginal birth after cesarean section using a model based on cesarean scar features examined using transvaginal sonography. Ultrasound Obstet Gynecol 41 (6) :672, 20 1 3b National Institutes of Health: Consensus Development Conference of Cesar­ ean Childbirth, September 1 980. N I H Pub No. 82-2067, Bethesda, NIH, 1 98 1 National Institutes o f Health Consensus Development Conference Panel: National Institutes of Health Consensus Development conference state­ ment: Vaginl birth after cesarean: new insights. March 8-1 0, 20 1 0. Obstet Gyneco1 1 1 5 : 1 2 9, 20 l O Nisenblat V, Barak S , Griness OB, e t al: l laternal complications associated with multiple cesarean deliveries. Obstet Gynecol l O8:2 1 , 2006 Osmundson SS, Garabedian MJ, Lyell OJ: Risk factors for classical hyster­ otomy by gestational age. Obstet Gynecol 1 22:845, 2 0 1 3 Osser OV, Valentin L : Clinical importance of appearance o f cesarean hyster­ otomy scar at transvaginal ultrasonography in nonpregnant women. Obstet Gynecol 1 1 7:525, 201 1 Pauerstein CJ: Once a section, always a trial of labor? Obstet Gynecol 28:273, 1 966 Pauerstein CJ, Karp L, Muher S: Trial of labor after low segment cesarean sec­ tion. S Med J 62:925, 1 969 Peaceman v!, Gersnoviez R, Landon MB, et al: he MFMU cesarean registry: impact of fetal size on trial of labor success for patients with previous cesar­ ean for dystocia. Am J Obstet Gynecol 1 9 5 : 1 1 27, 2006 Quinones IN, Stamilio OM, Pare E , et al: he efect of prematurity on vaginal birth after cesarean delivery: success and maternal morbidity. Obstet Gyne­ col 1 05 : 5 1 9, 2005 Ramirez MM, Gilbert S, Landon MB, et al: Mode of delivery in women with antepartum fetal death and prior cesarean delivery. Am J Perinatol 27: 825, 20 1 0 Ravasia OJ, Brain PH, Pollard JK: Incidence o f uterine rupture among women with mullerian duct anomalies who attempt vaginal birth after cesarean delivery. Am J Obstet Gynecol 1 8 1 : 8 7, 1 999 Ravasia OJ, Wood SL, Pollard J K: Uterine rupture during induced trial of labor among women with previous cesarean delivery. Am J Obstet Gynecol 1 83 : 1 1 76, 2000 Reyes-Ceja L, Cabrera R, Insfran E, et al: Pregnancy following previous uterine rupture: study of 1 9 patients. Obstet Gynecol 34:387, 1 969 Ritchie EH: Pregnancy after rupture of the pregnant uterus: a report of 36 pregnancies and a study of cases reported since 1 932. J Obstet Gynaecol Br Commonw 78 :642, 1 97 1 Roberge S , Demers S, Bergella V, et a l : Impact o f single- v s double-layer clo­ sure on adverse outcomes and uterine scar defect: a systematic review and metaanalysis. Am J Obstet Gynecol 2 1 1 :453, 20 1 4 Rodriguez M H , Masaki 0 1 , Phelan J P , e t al: Uterine rupture: are intrauterine pressure catheters useful in the diagnosis? Am J Obstet Gynecol 1 6 1 :666, 1 989 Rosenstein MG, Kuppermann M , Gregorich SE, et al: Association between vaginal birth after cesarean delivery and primary cesarean delivery rates. Obstet Gynecol 1 22: l O 1 0, 20 1 3 Rossi AC, D'Addario V : Maternal morbidity following a trial o f labor after cesarean section vs elective repeat cesarean delivery: a systematic review with metaanalysis. Am J Obstet Gynecol 1 99 (3):224, 2008 Royal College of Obstetricians and Gynaecologists: Birth after previous caesar­ ean birth. Green-top Guideline No. 45, February 2007 Sachs BP, Koblin C, Castro A, et al: The risk of lowering the cesarean-deliv­ ery rate. N Engl J Med 340: 5 , 1 999 Sciscione AC, Landon MB, Leveno KJ, et al: Previous preterm cesarean deliv­ ery and risk of subsequent uterine rupture. Obstet Gynecol 1 1 1 :648, 2008 Scott J R: Vaginal birth after cesarean delivery: a common-sense approach. Obstet Gynecol 1 1 8:342, 201 1 Sheth SS: Results of treatment of rupture of the uterus by suturing. J Obstet Gynaecol Br Commonw 7 5 : 5 5 , 1 968 Shields M , Zwerling B , Cheng W: Outcomes of hospital versus out-of­ hospital birth in vaginal birth after cesarean. Abstract No. 827. Am J Obstet Gynecol 2 1 6:S474, 20 1 7 Shipp TO, Zelop CM, Repke JT, e t al: Interdelivery interval and risk o f symp­ tomatic uterine rupture. Obstet Gynecol 97: 1 75 , 200 1 Shipp TO, Zelop CM, Repke JT, et al: Intrapartum uterine rupture and dehis­ cence in patients with prior lower uterine segment vertical and transverse incisions. Obstet Gynecol 94:735, 1 999 Shmueli A, Salman L, Nassie 01, et al: he intriguing association between epi­ dural anesthesia and mode of delivery among women in trial of labor after cesarean delivery. Abstract No. 949. Am J Obstet Gynecol 2 1 6:S536, 20 1 7 Silberstein T , Wiznitzer A , Katz M, e t al: Routine revision o f uterine scar after cesarean section: has it ever been necessary? Eur J Obstet Gynecol Reprod BioI 78:29, 1 998

Prior Cesa rea n Del ive ry Silver M , Landon MB, Rouse 0], et al: Maternal morbidity associated with multiple repeat cesarean deliveries. Obstet Gynecol 207: 1 226, 2006 Smith GC, Pell ]P, Cameron AD, et al : Risk of perinatal death associated with labor after previous cesarean del ivery in uncomplicated term pregnancies. ]AMA 287:2684, 2002 Society for Matenal-Fetal Medicine: Counseling and management of women with prior classical cesarean delivery. Conremp OB/GYN 57(6) :26, 20 1 2 Society o f Obstetricians and Gynaecologists o f Canada: SOGC clinical practice guidelines. Guidelines for vaginal birth after previous caesarean birth. Num­ ber 1 5 5 (replaces guideline Number 1 47) , February 200 5 . Int ] Gynaecol Obstet 89 (3) :3 1 9, 2005 Sondgeroth KE, Stout M] , Tuuli MG, et al: Does uterine resting tone have any cli nical value in trial of labor (TOLAC)? Abstract No. 829. Am ] Obstet Gynecol 2 1 6:5475, 20 1 Spong CY, Landon MB, Gilbert 5, et al: Risk of uterine rupture and adverse perinatal outcome at term after cesarean delivery. Obstet Gynecol 1 1 0:80 1 , 2007 Srinivas SK, Stamilio OM, Stevens E], et al: Predicting failure of a vaginal birth attempt after cesarean delivery. Obstet Gynecol 1 09: 800, 2007 Stamilio OM, DeFranco E, Pare E, et al: Short inrerpregnancy inrerval. Risk of uterine rupture and complications of vaginal birth after cesarean delivery. Obstet Gynecol 1 1 0, 1 075, 2007 Stanhope T, El-Nasher 5 , Garrett A, et al: Prediction of uterine rupture or dehiscence during trial of labor after cesarean delivery: a cohort study. Abstract No. 82 1 , Am ] Obstet Gynecol 208 ( 1 Suppi) :S343, 20 1 3 Tahseen 5 , Griiths M : Vaginal birth after two caesarean sections (VBAC-2)­ a systematic review with meta-analysis of success rate and adverse outcomes of VBAC-2 versus VBAC- 1 and repeat (third) caesarean sections. B]OG 1 1 7:5, 20 1 0

Tita AT, Landon MB, Spong CY, et al: Timing of elective repeat cesarean delivery at term and neonatal outcomes. N Engl ] Med 3 6 0 ( 2 ) : I l l , 2009 Traynor A], Aragon M, Ghosh 0, et al: Obstetric Anesthesia Workforce Sur­ vey: a 30-year update. Anesth Analg 1 22(6) : 1 939, 20 1 6 Uddin SFG, Simon E: Rates and success rates o f trial oflabor ater cesarean deliv­ ery in the United States, 1 990-2009. Maten Child Health ] 1 7: 1 309, 20 1 3 Usta 1 M , Hamdi MA, Abu M usa A, e t al: Pregnancy outcome i n patients with previous uterine rupture. Acta Obstet Gynecol 86: 1 72, 2007 Usta 1M, Hobeika EM, Abu-Musa A, et al : Placenra previa-accreta: risk fac­ tors and complications. Am ] Obstet Gynecol 1 93: 1 045, 2005 Varner MW, Thon E, Spong CY, et al: Trial of labor after one previous cesar­ ean del ivery fo r multifetal gestation. Obstet Gynecol 1 1 0:8 1 4, 2007 Weill Y, Pol lack RN : The eicacy and safety of external cephalic vers ion after a previous caesarean del ivery. Aust N Z ] Obstet Gynaecol 5 7 ( 3 ) :323, 20 1 7 Wen SW, Huang L, Liston R, et al: Severe maternal morbidity i n Canada, 1 99 1 -200 1 . CMA] 1 73:759, 2005 Wing DA, Lovett K, Paul RH: Disruption of prior uterine incision following misoprostol for labor induction in women with previous cesarean delivery. Obstet Gynecol 91 :828, 1 998 Wing DA, Paul RH: Vaginal birth after cesarean section: selection and manage­ ment. Clin Obstet GynecoI 42:836, 1 999 Zelop CM , Shipp TO, Repke ]T, et al : Outcomes of trial of labor following previous cesarean delivery among women with fetuses weighing > 4000 g. Am ] Obstet Gynecol 1 8 5 : 903, 200 1 Zelop CM, Shipp TO, Repke ]T, et al: Uterine rupture during induced or augmented labor in gravid women with one prior cesarean delivery. Am ] Obstet Gynecol 1 8 1 :882, 1 999

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C H A PT E R 3 2

The Newborn

TRANSITION TO AIR BREATH ING . . . . . . . . . . . . . . . . . . 606 CARE IN THE DELIVERY ROOM . . . . . . . . . . . . . . . . . . . . 607 EVALUATION OF NEWBORN CON DITION . . . . . . . . . . . 6 1 0

and immediately available for every resuscitation (Wyckof, 20 1 5) . This team should not be on call at home or in a remote area of the hospital. Moreover, team training through frequent simulation practice is recommended for all who may be called to attend deliveries (Perlman, 20 1 5) .

PREVENTIVE CARE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 1 3 ROUTI N E N EWBORN CARE . . . . . . . . . . . . . . . . . . . . . . . 6 1 4

Normaly the newy born child begins to cry almost imme­ diatey ater its exit from the vulva. This act indicates the establishment of respiration, which is accompanied by important modications in the circulatory system. -J. Whitridge Williams ( 1 903) In most instances at delivery, the newborn is healthy and vigor­ ous, but at times, special care may be needed. For this reason, the American Academy of Pediatrics and the American Col­ lege of Obstetricians and Gynecologists (20 1 7b) recommend that every birth should be attended by at least one qualified individual. This person should be skilled in the initial steps of newborn care and positive-pressure ventilation, and their only responsibility is management of the newborn. his usually is a pediatrician, nurse practitioner, anesthesiologist, nurse anesthe­ tist, or specially trained nurse. However, in their absence, the responsibility for neonatal resuscitation falls to the obstetrical attendant. hus, obstetricians should be well versed in measures for immediate care of the newborn. The number and qualiications of personnel who attend the delivery will vary depending on the anticipated risk, the num­ ber of babies, and the hospital setting. A qualiied team with full resuscitation skills should be present for high-risk deliveries

TRANSITION T O A I R BREATH I N G Immediately following birth, the newborn must promptly con­ vert from placental to pulmonary gas exchange. Pulmonary vascular resistance must fall, pulmonary perfusion must rapidly rise, and unique fetal vascular shunts must begin to close to separate the systemic and pulmonary circulations (Rudolph, 1 979) . These shunts include the patent ductus arteriosus and patent foramen ovale, described in Chapter 7 (p. 1 29) . Lung aeration is not only critical for pulmonary gas exchange. Recent studies suggest that it is signiicantly responsible for initiating cardiovascular changes at birth (Hooper, 20 1 6) . I n utero, the fetal lungs are illed with amnionic luid, which must be cleared quickly for air breathing. This clearance occurs through various means, and the contributions of these mecha­ nisms may depend on gestational age and mode of delivery. First, a large release of fetal adrenaline late in labor stimulates pulmonary epithelial cells to stop secreting and instead to start reabsorbing lung liquid as a result of sodium-channel activation (te Pas, 2008) . The contribution of this mechanism is unlikely to be major, as blockade of the receptors for sodium channel activation reduces or delays but does not prevent lung liquid clearance at birth (O'Brodovich, 1 990) . As a second method, mechanical forces aid lung fluid clearance during labor. Early reports described compression of the fetal thorax and abdomen as they passed through the birth canal leading to lung liquid expulsion (Karl berg, 1 962; Saunders, 1 978) . By this mechanism, up to a third of lung liq­ uid is expelled in a jet of luid from the nose and mouth once the respiratory tract is exposed to the lower outside pressure.

The Newborn

However, it may be that uterine contractions force a change in fetal posture leading to compression of the thorax and increased intrathoracic pressures. his prompts expulsion of lung liquid early in labor more so than the "vaginal squeeze" theory (Lines, 1 997; te Pas, 2008; Vyas, 1 98 1 ) . In a third mechanism, a significant amount of lung liq­ uid is cleared after birth (Hooper, 20 1 6) . In animal studies, most lung aeration occurs during inspiration-within three to ive breaths after birth. But, no liquid clears between breaths (Hooper, 2007) . Speciically, the transpulmonary pressure gra­ dient during inspiration promotes movement of fluid into the interstitial tissue. From here, it is gradually cleared, probably by the pulmonary circulation and lymphatic vessls. It is possible for lung interstitial tissue pressure to rise to a point that luid can actually move back into the airspaces during expiration unless positive end-expiratory pressure opposes liquid reentry (Siew, 2009a,b) . This may be a contributing factor in the devel­ opment of transient tachypnea ofthe newborn. As fluid is replaced by air, compression of the pulmonary vasculature is reduced considerably, and in turn, resistance to blood flow is lowered. With the fall in pulmonary arterial blood pressure, the ductus arteriosus normally closes. High, negative intrathoracic pressures are required to permit the initial entry of air into the fluid-illed alveoli. Normally, from the irst breath after birth, progressively more residual air accumulates in the lung. And, with each successive breath, lower pulmonary opening pressure is required. In the normal mature newborn, by approximately the ifth breath, pressure­ volume changes achieved with each respiration are very similar to those of the adult. hus, the breathing pattern shifts from shallow episodic inspirations characteristic of the fetus to regu­ lar, deeper inhalations (Chap. 1 7, p. 333). As a last mechanism, surfactant, which is synthesized by the type II pneumocytes, lowers alveolar surface tension and helps maintain lung inlation by preventing alveolar collapse. Insuf­ icient surfactant, which is common in preterm neonates, leads promptly to respiratory distress syndrome (Chap. 34, p. 636) . In utero, umbilical venous retun is the main source of pre­ load for the left ventricle, particularly as fetal pulmonary blood flow is very low due to high pulmonary vascular resistance and is unable to provide suicient venous return to maintain left ventricular output (Hooper, 20 1 5) . Clamping the umbilical cord reduces preload for the left ventricle and thus reduces cardiac output. Until the lungs aer­ ate and pulmonary blood low increases, the reduced cardiac output will manifest as bradycardia. If cord clamping is delayed until after the lungs have aerated, the transition is smoother and cardiac ouput does not fall (Bhatt, 20 1 3) . This understand­ ing has led to interest in delayed (physiological) cord clamping, especially if it can be done after successful infl a tion of the lung. Randomized trials are currently underway. CARE I N TH E DELIVERY ROOM The International Liaison Committee on Resuscitation (ILCOR) updated its scientiic review for neonatal delivery room care and resuscitation (Perlman, 20 1 5) . The ILCOR sci­ entiic review is used by the American Academy of Pediatrics

and the American Heart Association to develop the neonatal resuscitation guidelines for North America (Wyckof, 20 1 5). • Immediate Care

Before and during delivery, careful consideration must be given to several determinants of neonatal well-being. hese include: ( 1 ) maternal health status; (2) prenatal complications, includ­ ing any suspected fetal malformations; (3) gestational age; (4) labor complications; (5) duration of labor and ruptured mem­ branes; (6) type and duration of anesthesia; (7) diiculty of delivery; and (8) medications given during labor and thei r dos­ ages, administration routes, and timing. When risk factors are present, neonatal resuscitation provid­ ers should be present for the delivery. This team readies equip­ ment, ensures that adequate personnel are present, delegates roles and responsibilities, and considers contingency plans to stabilize the newborn. Four questions a neonatal provider will ask pertain to expected gestional age, amnionic fluid color, fetal number, and additional fetal risks. Several conditions are associated with a nonvigorous presentation. These may include immaturity, hypoxemia or acidosis from any cause, sepsis syn­ drome, recent drugs administered to the mother, and central nervous system developmental abnormalities. Those related to the respiratory tract are lung abnormalities, upper airway obstruction, pneumothorax, and meconium aspiration. • Umbilical Cord Clamping

Ideally, obstetrical and pediatric teams discuss plans regarding umbilical cord management. Delayed cord clamping provides transfusion of placental blood to the newborn. In term infants, delay of cord clamping by 30 to 60 seconds raises hemoglo­ bin levels at birth, improves iron stores during infancy, and enhances neurodevelopment at 4 years of age (Katheria, 2 0 1 7) . As discussed in Chapter 33 ( p . 625) , the only reported nega­ tive outcome of delayed cord clamping is hyperbilirubinemia, leading to a higher rate of phototherapy (American College of Obstetricians and Gynecologists, 20 1 7a) . In preterm neonates, delayed cord clamping reduces rates of blood transfusion, intra­ ventricular hemorrhage, and necrotizing enterocolitis. Delayed cord clamping should be performed in preterm and term newborns who do not require resuscitation at birth (American Academy of Pediatrics, 20 1 7 a; American College of Obstetricians and Gynecologists, 20 1 7a; Perlman, 2 0 1 5) . here should b e n o delay i f a newborn requires resuscitation or if the placental circulation is disrupted by abruption, cord avulsion, or bleeding placenta previa or vasa previa. • Newborn Resuscitation

Approximately 1 0 percent of newborns require some degree of active resuscitation to stimulate breathing, and 1 percent need extensive care. Perhaps not coincidentally, the risk of death for newborns delivered at home compared with those delivered in hospitals is increased two- to threefold (American College of Obstetricians and Gynecologists, 20 1 7 d) . When deprived of adequate gas exchange, either before or after birth, neonates demonstrate a well-deined sequence of

607

608

The N ewborn

�!j

Irregular gasping

Rapid breathing � A n � A � A Primary � V V j V V V �a

apnea

Heart rate (bpm)

D

MAP 1m H9)Time

F I G U R E 32-1 P hysiological changes associated with primary a nd secon d a ry a p nea in the newborn. bpm beats per m i n ute; H R hea rt rate; M A P mea n a rterial press u re. (Ada pted with permission from Kattwi n kel J: Textbook of Neonata l Resuscitation, 6th ed. El k Grove V i l l ag e, American Academy of Ped iatrics a nd American Hea rt Association, 2 0 1 0.) =

=

=

events leading to apnea (Fig. 32- 0 . With oxygen deprivation and carbon dioxide (C02) elevation, there is a transient period of rapid breathing, and if it persists, breathing stops, which is termed primay apnea. This stage is accompanied by a fall in heart rate and loss of neuromuscular tone. Simple stimula­ tion will usually reverse primary apnea. If oxygen deprivation and asphyxia persist, however, the newborn will develop deep gasping respirations, followed by seconday apnea. This latter stage is associated with a further decline in heart rate, fall in blood pressure, and loss of neuromuscular tone. Neonates in secondary apnea will not respond to stimulation and will not spontaneously resume respiratory eforts. Unless ventilation is assisted, death follows. Clinically, primary and secondary apneas are indistinguish­ able, and thus, secondary apnea must be assumed. And, when a response to stimulation is not immediate, resuscitation with efec­ tive ventilation of the apneic newborn must be started quickly. • Resuscitation Protocol I n it i a l Assessment

Immediately after birth and usually during the delay for umbil­ ical cord clamping, newborn tone, respiratory efort, and heart rate are evaluated (Fig. 32-2) . :Most term neonates are vigorous by 1 0 to 30 seconds after birth (Ersdal, 20 1 2) . For these, initial steps of warming the newborn can be done on the mother's chest or abdomen. Direct skin-to-skin contact with the mother and drying and covering the newborn with a warm blanket will help maintain euthermia (36.5 to 37. 5°C) . A vigorously crying newborn does not require routine oral suctioning (Carrasco, 1 997; Gungor, 2006) . Instead, bulb suctioning to remove secretions is best reserved for those who cannot clear secretions on their own due to apnea or copious secretions. Additional routine care steps include drying, gentle stimulation by rub­ bing the newborn's back, and continued observation during the transition period. If not vigorous or if preterm, the neonate is carried to a prewarmed radiant warmer for the initial newborn care steps.

The initial wet birth blanket is removed to allow newborn dry­ ing. Cold stress is associated with multiple neonatal morbidi­ ties and mortality. Preterm infants are particularly vulnerable, and special steps to maintain euthermia include providing a warmer delivery room (> 25°C) , covering the neonatal head with either a plastic or wool hat, application of polyethylene plastic "ponchos" or wraps to slow evaporative heat losses, use of chemically activated thermal mattresses to reduce conductive heat loss, and administration of warm, humidified respiratory gases during respiratory stabilization (Perlman, 20 1 5) . A t the radiant warmer, newborns must b e positioned to maximally open the airway, with mild extension of the neck. If the newborn is apneic or has copious secretions that it can­ not clear, a bulb syringe or suction catheter may be used to clear the mouth and then the nose. Routine intubation and suctioning of meconium-stained amnionic luid is no longer recommended for the nonvigorous newborn (American Col­ lege of Obstetricians and Gynecologists, 20 1 7b; Perlman, 20 1 5) . Intubation and suction are reserved for suspected air­ way obstruction. After completion of the initial stabilization steps, apnea, gasping respirations, or heart rate � 1 00 beats per minute (bpm) should prompt immediate administration of positive­ pressure ventilation with room air (Fig. 32-3) . his should be started by 60 seconds of life, if not sooner, once the initial steps are completed. M a s k Ve nti lation

Assisted ventilation by facemask at a rate of 40 to 60 breaths per minute is recommended. Oxygen saturation is monitored by pulse oximetry. Supplemental oxygen can be given in gradu­ ated, rising percentages to maintain oxygen saturation values within a normal range per minute of life. Adequate ventila­ tion is best indicated by an improved heart rate. Colorimetric end-tidal carbon dioxide (ETC02) monitoring placed between the positive-pressure device and facemask serves as a helpful adjunct for detection of successful gas exchange during mask ventilation (Weiner, 20 1 6) . I f the heart rate remains � 1 00 bpm after 5 to 1 0 positive pressure breaths, the attempted ventilation is inadequate and corrective steps must be taken. These can be remembered by the pneumonic M R. SOPA (Table 32- 1 ) . The two most common problems are mask leak due to an inefective seal and malposi­ tion of the airway (Schmolzer, 20 1 1 ) . If corrective steps do not improve the heart rate, either intubation with an endotracheal tube or placement of a laryngeal mask airway is required. Alte r n ative A i rway

If mask ventilation is inefective or prolonged, an alternative airway is placed. For tracheal intubation, a laryngoscope with a straight blade-size 0 for a preterm newborn and size 1 for a term neonate-is used. Gentle cricoid pressure may be use­ ful. An increasing heart rate and ETC0 2 detection after several breaths are the primary methods of conirming intubation of the trachea and not the esophagus. One can also look for sym­ metrical chest wall motion; auscultate for equal breath sounds, especially in the axillae; and auscultate for the absence of breath sounds or gurgling over the stomach.

The Newborn

Once in place, the tube is used for tracheal suction­ ing only for a suspected obstructed airway. Otherwise, an appropriate positive-pressure device is attached to the endotracheal tube. Air pufs are delivered at a rate of 40 to 60 per minute with a force adequate to sta­ bilize the heart rate. In term infants, opening pres­ sures of 30 to 40 cm H 2 0 typically will expand the alveoli without causing barotrauma. Once the lung is inflated, less pressure is typically needed (20 to 25 cm H 2 0) . For preterm infants, pressures of 20 to 2 5 cm H 2 0 are typically used. An increase in heart rate and peripheral oxygen saturation (Sp0 2 ) levels within acceptable ranges reflect a positive response.

Counseling Tea m briefing Equipment check

Term? Good tone? Breathing/crying?

y es l nfant with mother -____..�l . Routine care

No Warm, maintain temperature Position airway Clear secretions Dry, stim ulate

�

>

'E

Positive-pressure ventilation Sp02 monitor Consider ECG monitor

C h est Com pres s i o n s

Position, clear airway Sp02 monitor Supplementary O2 prn Consider C PAP

--+1 Post resuscitation care

Team debriefing

Check chest movement Ventilation corrective steps ETT or laryngeal mask prn

I ntubate Chest compressions Coordinate with PPV 1 00% O2 ECG monitor Consider UVC

Most commonly, efective ventilation is all that is required to stabilize the newborn in the delivery room. If the heart rate remains < 60 bpm despite ventilation corrective steps, including placement of tracheal tube, chest compressions are initiated. Once the tracheal tube has been secured, compressions are done from the head of the bed rather than the side so that space is opened up for a provider to have umbilical venous access. When compressions are initiated, the oxygen concentration is increased to 1 00 percent. With the two-thumb com­ pression method, hands encircle the chest, while the thumbs depress the sternum. Compressions are deliv­ ered on the lower third of the sternum at a depth suf­ icient to generate a palpable pulse. This is typically one third of the anterior-posterior diameter of the chest. Compared with other techniques, this method ofers less provider fatigue over time, yields higher generated perfusion pressures, and lessens hand malpositioning that could cause traumatic injury (Kapadia, 20 1 2) . A 3: 1 compressions-to-ventilation ratio i s recom­ mended, and 90 compressions and 30 breaths achieve approximately 1 20 events each minute. Coordinated chest compressions and ventilations should continue until the spontaneous heart rate is � 60 bpm.

IV epinephrine Consider hypovolemia Consider pneumothorax

FIGURE 32-2 Algorithm for resusc itation of the n ewborn based on the I nternational Liaison Com m ittee on Resuscitation scientific review a nd recom mended by the America n Academy of Ped iatrics and America n Heart Association (Perl m a n, 20 1 5; Wyckoff, 20 1 5). bpm beats per m i n ute; CPAP = conti nuous positive a i rway pres­ sure; ECG = electroca rd iogram; ETT = endotracheal tu be; HR hea rt rate; IV intravenous; P PV = positive-pressure venti lation; Sp02= peri pheral oxyge n satu ration; UVC u m bi l ical venous catheter. =

=

=

=

F I G U R E 32-3 Correct use of bag-a nd-mask ventilation. The head should be i n a sniffi ng pos ition with the tip of the nose poi n t i n g to the cei l i ng. The neck should not be hyperextended.

609

61 0

The Newbor n

TABLE 32-1 . Venti l ation Corrective Ste ps (MR. SOPA) M-Mask a dj u stment R-Repos ition a i rway S-S uction mouth a n d nose O-Open the mouth P-Press u re i nc rease A-Adva n ced a i rway

Check the sea l of the mask a n d rea pply if needed . Make s u re t h e n ew born is tru ly i n the open a i rway (m i l d exte n s i o n ) positi o n . Remove obstruct i n g secretions. I n a n effort to a c h i eve a good sea l, providers someti mes accidenta l ly cl ose the mouth . The h ig her res i sta nce of the narrow-d ia meter nasa l passages w i l l l i m it efective ve nti lation . Try i n cr ea s i n g the i nflation pressu re. If a l l prior steps fa i l to a c h i eve chest rise, i ntu bate or place a l a ryngea l m a s k.

Data from Wei n e r , 20 1 6.

E p i n e p h ri n e

Intravenously administered epinephrine is indicated if the heart rate remains ;60 bpm after adequate ventilation and chest compressions. The recommended intravenous dose is 0.0 1 to 0.03 mg/kg. Epinephrine may be given through the endotracheal tube if venous access has not been established, but its action is less reliable (Kapadia, 20 1 7) . If given through the endotracheal tube, higher doses are employed-0.05 to 0. 1 mg/kg. D i sconti n u a tio n of Res u scitation

ILCOR concludes that it is reasonable to discontinue resusci­ tative eforts for a neonate who remains without a heartbeat despite at least 1 0 minutes of continuous and adequate resusci­ tative eforts. Notably, the decision to continue or discontinue resuscitative eforts must be individualized (Perlman, 20 1 5). EVALUATION OF N EWBORN CONDITION • Apgar Score

he scoring system described by Dr. Virginia Apgar in 1 953 remains a useul clinical tool to classiY newborn health imme­ diately after birth and to assess the efectiveness of resuscitative

measures (American Academy of Pediatrics, 20 1 7) . s shown in Table 32-2, each of five easily identiiable characteristics­ heart rate, respiratory efort, muscle tone, relex irritability, and color-is assessed and assigned a value of 0, 1 , or 2. In the cur­ rently recommended expanded form, concurrent resuscitation interventions are also recorded over time. he total score, based on the sum of the five components, is determined in all neonates at 1 and 5 minutes ater delivery. In those with a score < 7, the score may be calculated at urther 5-minute intervals until a 20-minute Apgar score is assigned or resuscitation eforts are halted. In an analysis of more than 1 50,000 newborns delivered at Parkland Hospital, Casey and associates (200 1 b) assessed the signiicance of the 5-minute score for predicting survival dur­ ing the first 28 days of life. They found that in term neonates, the risk of neonatal death was approximately 1 in 5000 for those with Apgar scores of 7 to 1 0. his risk compares with a mortality rate of 25 percent for term newborns with 5-minute scores ;3. Low 5-minute scores were comparably predictive of neonatal death in preterm neonates. These investigators con­ cluded that the Apgar scoring system remains relevant for the prediction of neonatal survival. There have been attempts to use Apgar scores to define asphxial injury and to predict subsequent neurological

TABLE 32-2. 20-M i n ute Expa nded Apg a r Score Sign

0 point

1 point

2 point

Color Heart rate Reflex i rrita bility

B l u e or pa le Absent No response

Ac rocya n otic < 1 00/m i n G r i m ace

M uscle tone Respi ration

Limp Absent

Some fl exi o n Wea k cry; hypove nti lation

Com p l etely p i n k > 1 OO/m i n Cry or active with d rawa l Active motion Good, cryi n g

1 min

5 min

10 min

1 5 min

20 m i n

10

15

20

Tota l Comments:

Resuscitation M i n utes Oxygen PPV/CPAP ETT Chest compressions Epinephrine

5

CPAP = conti n uo u s positive a i rway pressu re; En = e n d otracheal tu be; P PV = pos itive-pressu re venti lati o n . Data fro m Wei ner, 20 1 6.

The Newborn

outcome-uses for which the Apgar score was never intended (Chap. 33, p. 624) . Such associations are diicult to mea­ sure with reliability given that both asphyxial injury and low Apgar scores are infrequent outcomes. For example, according to United States birth certiicate records for 20 1 0, only 1 .8 percent of newborns had a 5-minute score below 7 (Martin, 20 1 2) . Similarly, in a population-based study of more than 1 million term newborns in Sweden between 1 988 and 1 997, the incidence of 5-minute Apgar scores of �3 approximated 2 per 1 000 (Thorngren-Jerneck, 200 1 ) . Previously, many groups established erroneous definitions of asphyxia based solely on low Apgar scores. hese prompted the American College of Obstetricians and Gynecologists and American Academy of Pediatrics (20 1 7f) to issue a series of joint opinions with important caveats regarding Apgar score limitations. Certain elements of the Apgar score are partially dependent on the physiological maturity of the newborn, and a healthy, preterm neonate may receive a low score only because of immaturity. Other influencing factors include fetal malformations, maternal medications, and infection. Therefore, it is inappropriate to use an Apgar score alone to diagnose asphyxia. Moreover, the Apgar score alone cannot establish hypoxia as the cause of cerebral palsy, as discussed in Chapter 33 (p. 624) . • U m bilical Cord Blood Acid-Base Studies

Blood taken from umbilical vessels may be used for acid-base studies to assess the metabolic status of the neonate. Blood collection is performed following delivery by immediately isolating a 1 0- to 20-cm segment of cord with two clamps placed near the neonate and another two clamps positioned nearer the placenta. The cord is then cut between the two proximal clamps and then the two distal clamps (Blickstein, 2007) . Arterial blood is drawn from the isolated cord segment into a 1 - to 2-mL commercially prepared plastic syringe containing lyophilized heparin or a similar syringe that has been flushed with a heparin solution containing 1 000 U/mL. Once sampling is completed, the needle is capped and the syringe transported, on ice, to the laboratory. Although eforts should be made for prompt transport, neither the pH nor partial pressure of CO 2 (pC0 2 ) values change signifi c antly in blood kept at room temperature for up to 60 minutes (Lynn, 2007) . Mathematical models have been developed that allow reasonable prediction of birth acid-base status in properly collected cord blood samples analyzed as late as 60 hours after delivery (Chauhan, 1 994) . Acid-base measurements can show signiicant variances between diferent analyzing devices (vlokarami, 20 1 2) . • Fetal Acid-Base Physiology

he fetus produces both carbonic and organic acids. Carbonic acid (H 2 C03) is formed by oxidative metabolism of CO 2 . he fetus usually rapidly clears CO 2 through the placental circula­ tion. If CO 2 clearance is lowered, then carbonic acid levels rise. This often follows impaired placental exchange. When H 2 C03

accumulates in fetal blood and organic acids do not concur­ rently rise, the result is respiratoy acidemia. In contrast, organic acids primarily include lactic and 3-hydroxybutyric acids. Levels of these increase with persistent placental exchange impairment, and they result from anaero­ bic glycolysis. These organic acids are cleared slowly from fetal blood. When they accumulate, without a concurrent increase in H 2 C03, the result is metabolic acidemia. With the develop­ ment of metabolic acidemia, bicarbonate (HC03 -) levels drop because it is used to bufer the organic acid. A rise in H2C03 concentrations accompanied by greater organic acid levels, relected by decreased HC03 - levels, causes mixed respiratoy­ metabolic acidemia. In the fetus, respiratory and metabolic acidemia and ulti­ mately tissue acidosis are most likely part of a progressively worsening continuum. his is diferent from adult pathophys­ iology, in which distinct conditions result either in respira­ tory acidosis-for example, pulmonary disease, or in metabolic acidosis-for example, diabetes. In the fetus, the placenta serves as both the lungs and, to a certain degree, the kidneys. One principal cause of fetal acidemia is a drop in uteroplacental perfusion. This creates retention of CO 2 , that is, respiratory acidemia, and if protracted and severe enough, yields a mixed or metabolic acidemia. Assuming that maternal pH and blood gases are normal, the actual pH of fetal blood is dependent on the proportion of carbonic and organic acids and the amount of bicarbonate, which is the major bufer in blood. This can best be illustrated by the Henderson-Hasselbalch equation: HC03pH = pK + I og [base] or , pH = pK + I og --"H 2 C03 [acid] -

For clinical purposes, HC03 - represents the metabolic component and is reported in mEq/L. The H 2 C03 concentra­ tion reflects the respiratory component and is reported as the pC0 2 in mm Hg. Thus: pH

=

pK

+

metabolic (HC03 - mEq/L) respiratory (Peo 2 mm Hg)

I og ----�-�-��

The result of this equation is a pH value. Because pH is a logarithmic term, it does not give a linear measure of acid accumulation. For example, a change in hydrogen ion concen­ tration associated with a fall in pH from 7.0 to 6.9 is almost twice that which is associated with a fall in pH from 7.3 to 7.2. For this reason, the change in base-termed delta base- ofers a more linear measure of the degree of accumulation of meta­ bolic acid (Armstrong, 2007) . The delta base is a calculated number used as a measure of the change in bufering capacity of bicarbonate (HC03 -). he formula for calculating the base excess (BE) is as follows: BE = 0.02786

X

pC02

X l O(pH

- 6. 1 )

X

1 3.77

X

pH - 1 24.58

Shown in Figure 32-4 is a nomogram developed from which these can be calculated if only two parameters are known. For example, the HC03 - concentration declines with a metabolic acidemia as it is consumed to maintain a normal pH. A base deicit develops when the HC03 - concentration drops below

61 1

61 2

The N ewborn

HC03mEq/L 25

PC02 mm Hg 25

Base excess

o

mEq/L

20

30

pH 7.4

35

7.3

15

40

7.2

50

7.0 6.9

9 8

0

6.8

:

6.7

? ,

15

0

7 5

6

0 , 0

E

60 70 80

6.6

90

D

:

1 00 1 10 1 20

FIGURE 32-4 Nomogram for determining the delta base. (Adapted with permission from Siggaard­ Anderson 0: Blood acid-base alig n ment nomogram, Scand J ( l i n La b I nvest. 1 963; 1 5:2 1 1 -7.)

TABLE 32-3. U m b i l ical Cord B l ood

Values Arterial Blood pH Pco2 (mm H g ) H C03 - (m Eq/L) Base excess (m Eq/L) Venous Blood pH PC02 (mm H g ) H C03 - (m Eq/L) Base excess (m Eq/L)

pH

• Clinical Significance

of Acidemia

7. 1 10

normal levels, and a base excess occurs when HC03 - values are above normal. Importantly, a mixed respira­ tory-metabolic acidemia with a large base deicit and a low HC03 -, for example 1 2 mmollL, is more often associated with a depressed neonate than is a mixed acidemia with a mini­ mal base deficit and a more nearly normal HC03 - level.

Fetal oxygenation and pH generally decline during the course of normal labor. Normal umbilical cord blood pH and blood gas values at delivery in term newborns are summarized in Table 32-3 . Similar values have been reported for preterm neonates (Dick­ inson, 1 992; Ramin, 1 989; Riley, 1 993) . he lower limits of normal pH in the newborn have been found to range from 7.04 to 7. 1 0 (horp, 1 996) . Thus, these values should be considered to deine neonatal acide­ mia. Even so, most fetuses will tol­ erate intrapartum acidemia with a pH as low as 7.00 without incurring neurological impairment (Freeman, 1 988; Gilstrap, 1 989) . That said, in a study of newborns with a pH < 7.0 from Parkland Hospital, there were

a n d Blood Gas Va l ues i n Normal Term Newborns

Ram i n, 1 989a Spontaneous Del ivery n = 1 292c 7.28 (0.07) 49.9 ( 1 4.2) 2 3 . 1 (2.8) - 3 .6 (2.8)

Riley, 1 993b Spontaneous Delivery n 3522c =

7.2 7 (0.069) 50.3 ( 1 1 . 1 ) 22.0 (3 .6) - 2. 7 (2.8) 7.34 (0.063) 40.7 (7.9) 2 1 .4 (2.5) -2.4 (2)

aNewborns of sel ected women with u ncom p l i cated vag i na l d e l iveries. b Newbo rns of u n se l ected women with vag i n a l d e l iveries. (Data shown as mean (SO). d Oata shown as ra n g e with 2.5 or 97.5 perce nti le. eCesa rea n del ive ry- l a bo r not stated. F rom Centers for D i sease Control a n d P revention, 2 0 1 2; Watson, 2006.

Kotaska, 20 1 Ob S pontaneous Del ivery n = 303d

Kotaska, 201 0e Cesarean Delivery n = 1 89d

7.3 1 (7.06-7.44) 4 1 (24.9-70.9)

7.34 (7. 1 0-7.42) 44 (29. 1 -70.2)

7.26 (7.0 1 -7.3 9) 5 1 (30.9-85 .8)

7.3 (7.05-7.39) 54 (37.5 -79.5)

The Newborn

inordinate proportions of neonatal deaths-8 percent, intensive care admissions-39 percent, intubations-1 4 percent, and seizures-1 3 percent (Goldaber, 1 99 1 ) . And, in a study from Oxford of more than 5 1 ,000 term newborns, the incidence of neonatal encephalopathy in those with a birth pH < 7.0 was 3 percent (Yeh, 20 1 2) . Even those with who had normal S-minute Apgar scores but an arterial cord pH values < 7.0 had a signifi­ cantly higher risk of morbidity that included respiratory distress, neonatal intensive care unit admission, and sepsis (Sabol, 20 1 6) . The speed o f acidemia resolution after birth i s associated with outcome (Casey, 200 1 a) . Res p i rato ry Acid e m i a

Acute interruption in placental gas exchange is accompanied by subsequent CO2 retention and respiratory acidemia. The most common antecedent factor is transient umbilical cord compres­ sion. Generally, respiratory acidemia is not harmful to the fetus (Low, 1 994) . he degree to which pH is afected by pC02-the respira­ tory component of the acidosis-can be calculated. First, the upper normal neonatal pC02 of about 50 mm Hg is subtracted from the cord blood gas pC02 value. Each additional 1 0 mm Hg pC02 increment will lower the pH by 0.08 units (Eisen­ berg, 1 987) . hus, in a mixed respiratory-metabolic acidemia, the benign respiratory component can be calculated. As an example, acute cord prolapse during labor prompts cesarean delivery of a neonate 20 minutes later. The umbilical artery blood gas pH was 6.95 and the pC0 2 was 90 mm Hg. The degree to which the cord compression and subsequent impair­ ment of CO2 exchange afected the pH is calculated using the relationship given earlier and shown below. 90 mm Hg - 50 mm Hg To correct pH: (40

-

1 0)

X

=

40 mm Hg excess CO2

0.08 = 0.32; 6.95 + 0'. 32

=

acidemia may be so severe that it causes subsequent neuro­ logical impairment-hypoxic-ischemic encephalopathy (Chap. 33, p. 62 1 ) . In fact, a fetus without such acidemia cannot by defi n ition have sufered recent hypoxic-induced injury. hat said, severe metabolic acidosis is poorly predictive of subse­ quent neurological impairment in the term neonate (King, 1 998; Socol, 1 994) . In very-Iow-birthweight neonates, that is, those < 1 000 g, newborn acid-base status may be more closely linked to intraventricular hemorrhage and possibly long-term neurological outcome (Lavrijsen, 2005 ; Salhab, 2005; Victory, 2003) . Casey and coworkers (200 1 b) described the association between metabolic acidemia, low Apgar scores, and neonatal death in term and preterm newborns. Regarding term neonates, the risk of neonatal death was more than 3200-fold greater in term neonates with metabolic acidemia and 5-minute scores ;3 compared with those with a 5-minute Apgar score ::7. • Recommendations for Cord Blood Gas

Determinations

In some centers, cord gas analysis is performed in all neonates at birth (Casey, 200 1 b; Sabol, 20 1 6) . Cost-efectiveness analysis for universal cord blood gas measurements suggest beneit and potential cost savings (White, 20 1 0, 20 1 6) . It seems reasonable to obtain cord blood gas determinations for intrapartum cases of cesarean delivery for fetal compromise, abnormal fetal heart rate tracing, fever, and low 5-minute Apgar score. Multifetal gestation and severely growth-restricted fetuses are others. Although umbilical cord acid-base blood determinations are poorly predictive of either immediate or long-term adverse neurological outcome, they provide the most objective evidence of the fetal metabolic status at birth.

7.27

Therefore, the pH before cord prolapse was approximately 7.27, well within normal limits. Thus, the low pH resulted from respiratory acidosis. Meta bo l i c Ac i d e m i a

The fetus begins to develop metabolic acidemia when oxygen deprivation is suiciently long and severe to require anaero­ bic metabolism for cellular energy needs. Low and associates ( 1 997) defined fetal acidosis as a base deicit ::1 2 mmoUL, and severe fetal acidosis as a base deicit ::1 6 mmoUL. In the Parkland study of more than 1 50 ,000 newborns cited earlier, metabolic acidemia was defined using umbilical cord blood gas thresholds that were two standard deviations below the mean (Casey, 200 1 b) . Thus, metabolic acidemia was an umbilical artery blood pH < 7.00 accompanied by a pC02 ;76.3 mm Hg, with higher values indicating a respiratory component; HC03- concentration ; 1 7. 7 mmoUL; and base defi c it ::1 0.3 mEq/L. From the standpoint ofpossible neurological injury, the American College of Obstetricians and Gynecologists (20 1 4) defines metabolic acidosis as umbilical arterial pH 20 mg/ dL (Eggert, 2006) . Concomitant glucose-6-phosphate deiciency worsens hyperbilirubinemia (Chang, 20 1 7) . In approximately 1 5 per­ cent of term newborns, bilirubin levels cause clinically visible skin yellowing termed physiological jaundice (Burke, 2009) . As expected, in preterm neonates, the bilirubin elevation is greater and more prolonged. Acute B i l i ru b i n Encepha l o pathy a nd Kern i cte r u s

Excessive serum bilirubin levels can be neurotoxic for newborns (Dijk, 20 1 2; Watchko, 20 1 3) . he pathogenesis is complex, and toxicity has two forms. Acute bilirubin encephalopathy is encoun­ tered in the irst days of life and is characterized by hypotonia, poor feeding, lethargy, and abnormal auditory-evoked responses (Kaplan, 20 1 1) . Immediate recognition and treatment' will usu­ ally mitigate progressive neurotoxicity. he chronic form is termed kernicterus. With this, neurotoxicity follows bilirubin deposition and staining of the basal ganglia and hippocampus and is further characterized by profound neuronal degeneration. Survivors have spasticity, muscular incoordination, and varying

degrees of mental deiciencies (Frank, 20 1 7) . Although there is a positive correlation between kernicterus and unconjugated bilirubin levels above 1 8 to 20 mg/dL, it can develop at much lower concentrations, especially in very preterm neonates (Sgro, 20 1 1 ) . Continuing hemolysis is a risk factor for kernicterus (EI Houchi, 20 1 7; Vandborg, 20 1 2) . Prevention a n d Treatment

Various forms of phototherapy are used to prevent and treat neonatal hyperbilirubinemia (Ree, 20 1 7) . These «bili-lights" emit a spectrum of 460 to 490 nm, which augments bilirubin oxidation to enhance its renal clearance and lower serum levels. Sunlight iltered to remove ultraviolet light has been used in resource-poor countries (Slusher, 20 1 5) . Light that penetrates the skin also increases peripheral blood low, which further enhances photo-oxidation. It is problematic that available devices are not standardized (Bhutani, 2 0 1 1 ) . Another advan­ tage is that exchange transfusions are seldom required with phototherapy. Studies in both preterm and term newborns attest to phototherapy eicacy (Watchko, 20 1 3) . A Neonatal Research Network study reported that aggressive phototherapy in low-birthweight neonates reduced rates of neurodevelop­ mental impairment (Newman, 2006) . Similar reductions were reported from Canada after implementation of 2007 guidelines (Sgro, 20 1 6) . For term newborns, the American Academy o f Pediatrics and the American College of Obstetricians and Gynecologists (20 1 7) stress early detection and prompt phototherapy to pre­ vent bilirubin encephalopathy. Despite these measures, biliru­ bin encephalopathy persists, and this is somewhat related to early hospital discharges (Gazzin, 2 0 1 1 ; Kaplan, 20 1 1 ; Sgro, 20 1 1 ) . According to Burke and coworkers (2009), hospitaliza­ tions for kernicterus in term newborns were 5 . 1 per 1 00,000 in 1 988. Since then, however, this rate has dropped to 0.4 to 2.7 cases per 1 00,000 births (Watchko, 20 1 3) . This may be due in part to legislation, discussed in Chapter 36 (p. 662), to minimize brief postpartum hospital stays. • Hemorrhagic Disease of the Newborn

his disorder is characterized by spontaneous internal or exter­ nal bleeding beginning any time after birth. Most hemor­ rhagic disease results from abnormally low levels of the vitamin K-dependent clotting factors-V, VII , IX, X, prothrombin, and proteins C and S (Zipursky, 1 999) . Newborns whose mothers took anticonvulsant drugs are at higher risk because these suppress maternal hepatic synthesis of some of these fac­ tors. Classic hemorrhagic disease is usually apparent 2 to 5 days after birth in neonates not given vitamin K prophylaxis at delivery (Busield, 20 1 3) . Delayed hemorrhage may occur at 2 to 1 2 weeks in exclusively breastfed infants because breast milk contains little vitamin K. Other causes of neonatal hemor­ rhage not related to vitamin K include hemophilia, congenital syphilis, sepsis, thrombocytopenia purpura, erythroblastosis, and intracranial hemorrhage. The American Academy of Pediatrics and the American Col­ lege of Obstetricians and Gynecologists (20 1 7) recommend routine prophylaxis for hemorrhagic disease with a 0.5- to

D iseases a n d I nj u ries of the Term Newborn

1 -mg dose of vitamin K\ (phytonadione) given intramuscu­ larly. Oral administration is not efective, and maternal vita­ min K administration results in very little transport to the fetus (Sankar, 20 1 6) . • Thromboctopenia

Abnormally low platelet concentrations in term newborns may be due to various etiologies such as immune disorders, infec­ tions, drugs, or inherited platelet defects, or they may be part of a congenital syndrome (American College of Obstetricians and Gynecologists, 20 1 6b) . In many, thrombocytopenia is an extension of a fetal disorder such as infection with B 1 9 par­ vovirus, cytomegalovirus, toxoplasmosis, and others discussed in Chapters 64 and 65. Neonatal thrombocytopenia has been reported with maternal antiretroviral therapy for human immu­ nodeiciency virus (HIV) infection (Smith, 20 1 6) . Term new­ borns admitted to NICUs, especially those with sepsis, have accelerated platelet consumption (Eissa, 20 1 3) . I m m u ne Th ro m bocyto pe n ia

In women with an autoimmune disorder such as systemic lupus erythematosus or immunological thrombocytopenia, maternal antiplatelet IgG is transferred to the fetus and can cause acceler­ ated platelet destruction. Most cases are mild, and platelet levels usually reach a nadir at 48 to 72 hours. Maternal corticosteroid therapy generally has no efect on fetal platelets. Fetal blood sampling for platelet determination is seldom necessary, and platelets are usually adequate to prevent fetal hemorrhage dur­ ing delivery (Chap. 56, p. 1 086) . A l l o i m m u ne Thro m bocyto pe n ia

Alloimmune thrombocytopenia (AIT) or neonatal alloimmune thrombocytopenia (NAIT) is caused by maternal-fetal platelet antigen disparity. If maternal alloimmunization is stimulated, then transplacental antiplatelet IgG antibodies cause severe fetal thrombocytopenia and severe bleeding (Winkelhorst, 20 1 7) . his i s considered i n detail i n Chapter 1 5 (p. 307) . Preec l a m p s i a Synd ro m e

Maternal platelet function and destruction can be severely afected in women with severe preeclampsia. That said, fetal or neonatal thrombocytopenia is rarely caused by the preeclampsia syndrome even when the mother has severe thrombocytopenia. Findings from the large study of mother-infant pairs delivered at Parland Hospital dispelled earlier reports of an association of neonatal thrombocytopenia with preeclampsia (Pritchard, 1 987) . Instead, neonatal thrombocytopenia was found to be associated with preterm delivery and its numerous complica­ tions (Chap. 34, p. 636) . I NJ U RI ES OF THE N EWBOR N Birth injuries can potentially complicate any delivery. hus, although some are more likely associated with operative deliv­ ery by forceps or vacuum, others are seen with otherwise uncomplicated vaginal or cesarean delivery. In this section, some injuries are discussed in general, but specifi c injuries are

TABLE 33-4. I ncid e n ce of M ajor a n d M i nor Bi rth Tra u m a-N ova Scotia, 1 988-2001 Birth Trauma (Rate per 1 000) Majora Minorb

Type of Delivery (Trauma Rate per 1 000)

N u m ber

Spontaneous ( 1 4)

88,324

1 .2

13

Assisted Vacu u m (7 1 ) Forceps (58)

3 1 75 1 0,478

3.7 5.2

67 53

Failed assisted Vacu u m ( 1 05) Forceps (56)

609 714

8.3

1 00 50

Cesa rea n (8.6) Labor ( 1 2) No l a bor ( 1 .2)

1 6, 1 32 1 0)3 1 540 1

OJ 0.4 0.2

8.3 1 1 .9 1 .1

1 1 9,432

1 .6

18

All ( 1 9.5)

7.0

aMajor tra u m a = depressed sku l l fractu re, i ntracra n i a l hemorrhage, brach i a l pl exopathy, o r com b i nation . b M i n o r tra u ma l i n e a r s ku l l fractu re, other fra ctu res, fac i a l pa l sy, ce pha loh emato ma, o r combi nation . Data from Baskett, 2007. =

described elsewhere in connection with their associated obstet­ rical complications. • I ncidence

In three population studies that included more than 8 mil­ lion term newborns, the overall incidence of birth trauma was 20 to 26 per 1 000 deliveries (Baskett, 2007; Linder, 20 1 2; Moczygemba, 20 1 0) . Data from Nova Scotia show an overall trauma risk of 1 9. 5 per 1 000 deliveries (Table 33-4) . Only 1 .6 cases of major trauma per 1 000 were found, and these rates were highest with failed forceps or vacuum delivery and low­ est with cesarean delivery without labor. hus, most traumatic injuries were minor, and these had an incidence of 1 8 per 1 000 deliveries. Trauma associated with cesarean delivery from a vIaternal­ Fetal Medicine Units Network study was described by Alexan­ der and coworkers (2006) . There were 400 injuries identiied from a total of 37, 1 00 operations-a rate of 1 1 per 1 000 cesar­ ean deliveries. Although skin lacerations predominated-7 per 1 000-more serious injuries in these 400 infants included 88 cephalohematomas, 1 1 clavicular fractures, 1 1 facial nerve pal­ sies, nine brachial plexopathies, and six skull fractures. • Cranial I njuries

Traumatic head injuries that are associated with labor or delivery can be external and obvious, such as a skull or man­ dibular fracture; they can be intracranial; and in some, they are covert. The fetal head has considerable plasticity and can undergo appreciable molding. Rarely, severe molding can result in tearing of veins. hese may be the bridging cortical veins

62 7

628

The N ewborn

that empty into the sagittal sinus, the internal cerebral veins, the vein of Galen, or those of the tentorium itself. As a result, intracranial, subdural, and even epidural hemorrhage can be seen after an apparently uneventful vaginal delivery (Scheibl, 20 1 2) . Bleeding may also be asymptomatic. Conversely, sub­ galeal hemorrhages associated with forceps of vacuum delivery can be life threatening (Doumouchtsis, 2008; Swanson, 20 1 2) . I n rare severe head trauma cases, fetal brain tissue can embolize to the heart or lungs (Cox, 2009) . I nt ra c ra n ia l H e morrhage

Most aspects of neonatal intracranial hemorrhage are related to gestational age. Speciically, most hemorrhage in the preterm neonate results from hypoxia and ischemia. However, in term newborns, trauma is the most frequent cause. Some varieties are shown in Table 33-5. Importanty, in some newborns, a puta­ tive cause is notound. Intracranial hemorrhage is asymptomatic in many cases. The reported incidence varies, but it is highest with operative deliveries-both vaginal and cesarean deliver­ ies. In the study by Moczygemba and colleagues (20 1 0) , for more than 8 million singleton deliveries, the overall intracra­ nial hemorrhage rate approximated 0.2 per 1 000 births. In another study, Werner and associates (20 1 l ) cited a combined incidence in more than 1 20,000 nulliparous singleton opera­ tive deliveries of 0. 1 2 percent, or about 1 in 750 procedures. he rates of intracranial hemorrhage were 1 :385 with vacuum delive) ; 1 : 5 1 5 with forceps, and 1 : 1 2 1 0 with cesarean delivery. In another study, its incidence was nearly 1 percent following vacuum-assisted deliveries (Simonson, 2007) . According to the American College of Obstetricians and Gynecologists (20 1 5) , the incidence of intracranial hemor­ rhage from birth trauma has been substantively lowered by elimination of diicult instrumented vaginal deliveries. This

was veriied in a report of carefully conducted Kielland forceps deliveries (Burke, 20 1 2) . The prognosis after hemorrhage depends o n its location and extent (see Table 33-5) . For example, subdural and subarach­ noid hemorrhage seldom results in neurological abnormalities, whereas large hematomas are serious. Any bleeding into the parenchyma from intraventricular or intracerebellar hemor­ rhage often causes serious permanent damage or death. Peri­ ventricular hemorrhage rarely causes the type of sequelae that are common in those born preterm (Chap. 34, p. 639) . Newborns who have traumatic subdural or infratentorial hemorrhage tears will have neurological abnormalities from the time of birth (Volpe, 1 995). Those most severely afected have stupor or coma, nuchal rigidity, and opisthotonos that worsen over minutes to hours. Some newborns who are born depressed appear to improve until about 1 2 hours of age, when drowsiness, apathy, feeble cry, pallor, failure to nurse, dyspnea, cyanosis, vomiting, and convulsions become evident. Spontaneous intracranial hemorrhage has also been docu­ mented in healthy term neonates (Rutherford, 20 1 2; Shah, 20 1 6) . In a prospective MR imaging study, Whitby and coworkers (2004) found that 6 percent of those delivered spon­ taneously and 28 percent of those delivered by forceps had a subdural hemorrhage. None of these had clinical indings, and hematomas resolved by 4 weeks in all infants. Extra c ra n i a l Hemato m a s

These blood collections accumulate outside the calvarium and are categorized as a cephalohematoma or subgaleal hemorrhage (Fig. 33-2) . From its most superficial surface inward, the scalp is composed of skin, subcutaneous tissue, galea aponeurotica, subgaleal space, and calvarium periosteum. The galea aponeuro­ tica is dense fibrous tissue, whereas the subgaleal space contains

TABLE 33-5. Major Types of Neonatal I ntracra n i a l Hemorrhage Type

Etiology and Neuropathogenesis

Clinical Outcomes

S u bd u ra l

Tra u m a-te ntorial, fa lx, or ven o u s (si n u s) lacerat i o n ca u s i ng h e m atoma

U n com mon but potenti a l ly serious; sym ptom onset is va r i a b l e depe n d i n g on hematoma expa n s ion, but u s u a l ly < 24 hou rs: i rrita b i l ity, lethargy, a n d b ra i n stem com pression Common but a l most a l ways ben i g n

Poss i b ly d ue to t ra u m a o r hypoxia-excl udes SAH P r i m a ry associated with s u bd u ra l , i ntraventricu l a r, i ntracerebral s u ba rac h noid (AVM, a ne u rysm), o r i ntracerebe l l a r h e morrhage Tra u m a a n d perhaps hypoxia-most cases in preter m I ntracere be l l a r i nfa nts I nt rave ntri c u l a r Tra u m a and hypoxia (no d i scern i b l e cause i n 2 5 percent)-hemorrhage usua l ly from choroid p l exus Tra u ma with e p i d u ra l or i ntracerebra l h emorrhage M i scella neous Hemo rrhag i c i nfa rction-e m bo l i s m o r th rom bos i s i n a rtery o r ve i n Coag u lopath i es-t h rom bocytopen i a o r i n herited factor defi c i e n cies Vasc u l a r defect-a n e u rysm or AVM AVM a rteriovenous malformation; SAH Data from Vol pe, 1 995 . =

=

s u ba ra c h n o i d h e morrhage.

U n common but serious U n common but serious; sym ptoms as for s u bd u ra l h e morrhage Depends on cause

Di seases a n d I nj u ries of the Te rm Newborn

Caput s uccedane u m

�

Scalp I Edema

Scalp S u bgaleal h e m o rrhage

Galeal aponeurosis

I

/

S ubgaleal s pace Periosteu m Parietal bone

Galeal aponeurosis

I _.,-,_, �

/

�iii;i q����Lj

S u bgaleal space Perioste u m

Galeal apo n e u rosis Cephalohem atom a

I

S u bgaleal s pace Periosteu m

I

newborns delivered by vacuum extraction (Simonson, 2007) . In the Network study of cesarean delivery outcomes cited above, the incidence of cephalohematoma was 2.4 per 1 000 operations (Alexander, 2006) . Others have reported lower incidences, although cephalohematoma is more common with vacuum compared with forceps deliveries-0.8 versus 2.7 per 1 000 operative deliveries (Werner, 20 1 1 ) . Subgaleal hemorrhage results from laceration o f one of the emissary veins, with bleeding between the galea aponeurotica and the skull periosteum (Shah, 20 1 6) . Although most com­ mon with operative deliveries, cases with spontaneous vaginal delivery have been described (Uu, 20 1 7) . Because of its loose areolar tissue and large surface area, significant blood volumes can collect in this potential space and can extend from the neck to the orbits and laterally to the temporal fascia above the ears (Modanlou, 20 1 6) . Resulting hypotension can lead to signii­ cant morbidity, and cited mortality rates range from 12 to 1 8 percent (Chang, 2007; Kilani, 2006) . S ku l l Fractu res

Parietal bone

�����

FIGURE 33-2 Schematic of extracra n ial lesions in the neonate that i nclude caput succed a n e u m , subga lea l hemorrhage, a n d cep halohematoma.

loose, ibroareolar tissue. Traversing across the subgaleal space are large, valveless emissay veins, which connect the dural sinuses inside the skull with supericial scalp veins. Both the galea aponeurotica and subgaleal space span across the occipital, parietal, and frontal bones. In contrast, periosteum invests each individual skull bone and does not cross suture lines. Cephalohematomas are cranial subperiosteal hematomas. These develop from shearing forces during labor and delivery that lacerate the emissary or diploic veins. Fortunately, the densely adhered periosteum impedes rapid enlargement and limits inal hematoma size. Hemorrhage can be over one or both parietal bones, but palpable edges can be appreciated as the blood reaches the limits of the periosteum. These hemato­ mas must be diferentiated from caput succedaneum, also shown in Figure 33-2. A cephalohematoma may not be apparent until hours after delivery, when bleeding suicient to raise the peri­ osteum has occurred. After it is identiied, it often grows larger and persists for weeks or even months, and bleeding may be suicient to cause anemia as discussed on page 625 . By con­ trast, with caput succedaneum, swelling of the scalp is from soft-tissue edema that overlies the periosteum. The caput is maximal at birth, rapidly grows smaller, and usually disappears within hours or a few days. Occasionally it becomes infected, and an abscess may form (Kersten, 2008) . Cephalohematomas are common, and in the study from Nova Scotia shown in Table 33-3, these accounted for 80 per­ cent of traumatic injuries with an incidence of 1 6 per 1 000 (Baskett, 2007) . They rarely develop in the absence of birth trauma, and an I I -percent incidence was reported in 9 1 3 term

These are rare but are especially worrisome because of their asso­ ciation with the serious intracranial hemorrhages. Volpe ( 1 99 5) considers three types of skull injuries to be fractures-linear and depressed fractures and occipital osteodiastasis. In a French study of nearly 2 million deliveries from 1 990 to 2000, the incidence of skull fractures was reported to be 3.7 per 1 00,000 births, and 75 percent were associated with instrumented vaginal deliveries (Dupuis, 2005). These are occasionally seen with spontaneous or cesarean delivery (Fig. 33-3) . These latter fractures are more common when the head is tightly wedged in the pelvis. In such cases, there are at least three possible causes. A fracture may result from skull compression against the sacral promontory, by hand pressure used to lift the head at cesarean delivery, or from transvaginally applied upward hand pressure by an assistant. Fractures are managed with surgical decompression, although spontaneous resolution can follow (Basaldella, 20 1 1 ) .

F I G U R E 33-3 Depressed sku l l fracture evident i m m ediately after cesa rea n del ivery. Labor had prog ressed, and the head was deep i n t h e pelvis. Dislodg ment o f t h e head from t h e b i rth ca nal was per­ formed by a n assista nt using m a n u a l pressu re u pward throug h the vagina. (U sed with perm ission from Dr. Ki m berly M Spoonts.)

629

630

The N ewborn

• Spinal Cord Injury

Overstretching of the spinal cord and associated hemorrhage and edema are rare. They are usually caused by excessive lon­ gitudinal or lateral traction of the spine or by torsion during delivery. In some cases, vertebrae are fractured or dislocated. Menticoglou and associates ( 1 995) described 1 5 neonates with this type of high cervical spinal cord injury and found that all of the injuries were associated with forceps rotations. Spinal cord injury also can occur during breech delivery. Ross and cowork­ ers (2006) described C5-6 vertebral dislocation associated with a Zavanelli maneuver done because of shoulder dystocia (Chap. 27, p. 523). • Peripheral Nerve Injuries

Traumatic injuries to nerves can be serious and distressing, especially if permanent. Injury can involve a single nerve, or it can afect a nerve root, plexus, or trunk (Volpe, 1 995). Bra c h i a l P l exopathy

Inj uries to the brachial plexus are relatively common. hey are identiied in 1 to 3 per 1 000 term births (Baskett, 2007; Lindqvist, 20 1 2; Wall, 20 1 4) . In the study reported by Moc­ zygemba and colleagues (20 1 0) , the incidence of brachial nerve injury was 1 . 5 per 1 000 vaginal deliveries and 0. 1 7 per 1 000 cesarean deliveries. he incidence among 366,408 neonates born at Parkland Hospital was 3 . 5 per 1 000 births (Wall, 20 1 4) . Breech delivery and shoulder dystocia are risks for this trauma. However, severe plexopathy may also occur without risk factors (Torki, 20 1 2) . With plexopathy, the injury damages the nerve roots that supply the brachial plexus-C5_8 and T , . With hemorrhage and edema, axonal function may be temporarily impaired, but the recovery chances are good. However, with avulsion, the prog­ nosis is poor. In 90 percent of cases, damage to the C5-6 nerve roots causes Erb or Duchenne paraysis (Volpe, 1 995). Injuries with breech delivery are normally of this type, whereas the more extensive lesions follow diicult cephalic deliveries (Ubachs, 1 995). The C5-6 roots join to form the upper trunk of the plexus, and injury leads to paralysis of the deltoid, infraspinatus, and lexor muscles of the forearm. he afected arm is held straight and internally rotated, the elbow is extended, and the wrist and ingers lexed. Finger function usually is retained. Because lateral traction on the fetal head is frequently employed to efect deliv­ ery of the shoulders in normal vertex presentations, most cases of Erb paralysis follow deliveries that do not appear diicult. Damage to the C8-T, roots supplying the lower plexus results in Klumpke paraysis, in which the hand is laccid. Total involvement of all brachial plexus nerve roots results in laccid­ ity of the arm and hand, and with severe damage, there may also be Horner syndrome. Because of its importance, the American College of Obste­ tricians and Gynecologists (20 1 4a) convened a task force to review extant studies. his Task Force concluded that shoul­ der dystocia cannot be accurately predicted, but in most cases, axonal death does not occur and the prognosis is good. Lindqvist and associates (20 1 2) reported complete recovery in 86 percent of children with C5-6 trauma, which was the most

F I G U R E 33-4 Left facial nerve i nj u ry. Th i s was a l most com pletely resolved two d ays after del ivery.

common injury, and in 38 percent of those with C5-7 dam­ age. However, those with global C5-8-T, inj uries always had permanent disability. Associated clavicular fracture is some­ what protective (Wall, 20 1 4) . Surgical exploration and pos­ sible repair may improve function if there is persistent paralysis (Malessy, 2009) . Fac i a l Pa ra lys i s

Trauma to the facial nerve commonly occurs as it emerges from the stylomastoid foramen, and this can cause facial paralysis (Fig. 33-4) . The incidence, which ranges from 0.2 to 7.5 per 1 000 term births, is likely inluenced by the vigor with which the diagnosis is sought (Al Tawil, 20 1 0; Moczygemba, 20 1 0) . Facial paralysis may b e apparent a t delivery o r may develop shortly after birth. It most frequently is associated with uncom­ plicated vaginal delivery. However, in one series, a fourth of cases followed cesarean delivery (Alexander, 2006; Al Tawil, 20 1 0) . Facial nerve damage is likely more common with low forceps (Levine, 1 984) . It is possible that damage is caused by pressure exerted by the posterior blade when forceps have been placed obliquely on the fetal head. In these cases, forceps marks indicate the cause of injury. Spontaneous recovery within a few days is the rule, however, permanent paralysis has been described (Al Tawil, 20 10). • Fractures

Most long-bone fractures follow diicult deliveries, however, this is not always the case. At minimum, palpation of the clavi­ cles and long bones is indicated for all newborns after a diicult delivery. Crepitation or unusual irregularity should prompt radiographic examination. Clavicular ractures are common, unpredictable, and una­ voidable complications of normal birth. heir incidence aver­ ages 5 to 1 0 per 1 000 live births (Linder, 20 1 2; Moczygemba, 20 1 0) . Other than female gender, no speciic risk factors­ including birthweight and mode of delivery-have been iden­ tiied. Clavicular fractures protect against brachial plexopathy when there is shoulder dystocia (Wall, 20 1 4) .

D i seases and I nj u ries of t h e Te r m Newborn

HumeraLractures are infrequent, and 70 percent follow an uneventful birth (Turpenny, 1 993). Others are associated with diicult delivery of the shoulders in cephalic deliveries and of an extended arm in breech deliveries. Radiographically, they are often of the greenstick type, although complete fractures and distal humeral epiphyseal fractures can occur (harakan, 20 1 6) . FemoraLractures are rare and usually are associated with vag­ inal breech delivery. hey occasionally follow cesarean delivery, and in one report, they were bilateral (Cebesoy, 2009) . Because most breech-presenting fetuses now undergo cesarean delivery, most of these fractures are associated with this mode (Alexan­ der, 2006; Cebesoy, 2009) . MandibuLar .ractures have been reported, are rare, and have been reviewed by Vasconcelos and coworkers (2009) . he rare cases of cervicaL vertebraL disLocation in fetuses delivered as breech or after the Zavanelli maneuver were discussed earlier (Ross, 2006) . Finally, ribractures are occasionally encountered (Khan, 20 1 6) .

talipes equinovarus (clubfoot) , scoliosis, and hip dislocation (Miller, 1 98 1 ) . Talipes and other positional foot abnormalities are associated with membrane rupture from early amniocentesis between 1 1 and 1 3 weeks' gestation (Chap. 14, p. 293).

REFERENCES

hlin K, Himmelmann K , Hagberg G, e t a l : Cerebral palsy and perinatal infec­ tion in children born at term. Obstet Gynecol 1 22:4 1 , 2 0 1 3 Ahlin K , Himmelmann K , Nisson S, et al: Antecedents of cerebral palsy according to severity of motor impairment. Acta Obstet Gynecol Scand 95(7) :793, 20 1 6 kin MA, Coban D , Doganay S , e t al: I ntrahepatic and adrenal hemorrhage as a rare cause of neonatal anemia. J Perinat Med 39(3):353, 2 0 1 1 Al Tawil K, Saleem N, Kadri H, et al: Traumatic facial nerve palsy in new­ borns: is it always iatrogenic? Am J Perinatol 27:7 1 1 , 20 1 0 Alexander J M , Leveno KJ , Hauth J, et al: Fetal injury associated with cesarean delivery. Obstet Gynecol 1 08:885, 2006 Alfirevic Z, Devane D , Gyte GM, et al: Continuous cardiotocography (CTG) as a form of electronic fetal monitoring (EFM) for fetal assessment during labour. Cochrane Database System Rev 2:CD006066, 20 1 7 American Academy o f Pediatrics, American College o f Obstetricians and Gyne­ cologists: Guidelines for perinatal care, 8th ed. Elk Grove Village, MP, • Muscle I njuries 20 1 7 American Academy o f Pediatrics, American College o f Obstetricians and Gyne­ Sternocleidomastoid muscle injury in the past was usually seen cologists: Neonatal encephalopathy and cerebral palsy. Defining the patho­ with vaginal breech delivery. Hematomas of the muscle or the genesis and pathophysiology. Elk Gtove Village, MP, 2003 American College of Obstetricians and Gynecologists: Neonatal brachial plexus fascial sheath may resolve slowly with cicatricial contraction. palsy. Report of the American College of Obstetricians and Gynecologists' Task With normal neck growth, the less-elastic damaged muscle Force on Neonatal Brachial Plexus Palsy. Obstet Gynecol 1 23 (4) :902, 20 14a does not elongate appropriately. As a result, the head is gradu­ American College of Obstetricians and Gynecologists: Neonatal encepha­ lopathy and neurologic outcome, second edition. Repon of the Ameri­ ally turned toward the side of the injuy-torticoLis. can College of Obstetricians and Gynecologists' Task Force on Neonatal Encephalopathy. Obstet GynecoI 1 23 (4):896, 20 1 4b American College of Obstetricians and Gynecologists: Operative vaginal deliv­ • Soft Tissue Injuries ery. Practice Bulletin No. 1 54, November 20 1 5 American College o f Obstetricians and Gynecologists: Amnioinfusion does Conceivably, any fetal organ or part could be injured with either not prevent meconium aspiration syndrome. Committee Opinion N o . 346, vaginal or cesarean delivery. Some of these include subcapsu­ October 2006, Reairmed 20 1 6a lar hepatic hematomas that presented as inguinal and scrotal American College of Obstetricians and Gynecologists: hrombocytopenia in pregnancy. Practice Bulletin No. 1 66, September 20 1 6b hematoma. In such cases, ecchymoses of the inguinal region American College of Obstetricians and Gynecologists: Approaches to limit are termed StabLer sign, and those of the scrotum are termed intervention during labor and birth. Committee Opinion No. 687, Febru­ Bryant sign (Heyman, 20 1 1 ; Saroha, 20 1 5) . hymic gland trau­ ary 20 1 7a American College of Obstetricians and Gynecologists: Delayed cord clamping matic hemorrhage in those with underlying hyperplasia or cyst after birth. Committee Opinion No. 684, January 20 1 7b has been described before, during, and after delivery (EHinger, American College of Obstetricians and Gynecologists: Delivery of a newborn 2007; Saksenberg, 200 1 ) . Inj uries to the sixth cranial nerve with meconium-stained amniotic fluid. Committee Opinion No. 689, March 20 1 7c with resultant lateral rectus ocular muscle paralysis have also American College of Obstetricians and Gynecologists: I ntrapartum fetal hean been reported (Galbraith, 1 994) . rate monitoring: nomenclature, interpretation, and general management principles. Practice Bulletin No. 1 06, J uly 2009, Reairmed 2 0 1 7d American College of Obstetricians and Gynecologists, American Academy of • Congenital Deformity I nJ"uries Pediatrics: Neonatal Encephalopathy and Neurologic Outcome, 2 nd ed. Washington, ACOG, 20 1 4c Several injuries create morphological defects sustained long American College of Obstetricians and Gynecologists, American Academy of before delivery. One is the amnionic band syndrome caused Pediatrics: The Apgar score. Committee Opinion No. 644, October 20 1 7e American College of Obstetricians and Gynecologists, American Society of when a free strip of amnion forms a focal ring around an Addiction Medicine: Opioid use disorder in pregnancy. Committee Opin­ extremity or digit. Eventually, deformation or amputation may ion No. 1 1 , August 20 1 7f ---resyltc-€ al ly, th� mpHtat� pa�... ithin.--A'lTH-'''r� , riw f T , haudhari B , eased risk for respirathe uterus. he genesis of such bands is debated and discussed tory distress among white, male, late preterm and term infants. J Perinatol 32( 1 0) :750, 20 1 2 in Chapter 6 (p. 1 1 6) . A similar anomaly is a Limb-reduction Avagliano L, Marconi AM, Candiani \ 1 , et al: Thrombosis o f the umbilical deect associated with chorionic villus sampling performed vessels revisited. An observational study of 3 1 7 consecutive autopsies at a single institution. Hum PathoI 41 :97 1 , 20 1 0 before 9 weeks' gestation (Chap. 1 4, p. 294) . Azzopardi D, Strohm B , Marlow N, et al : Efects of hypothermia for perinatal Various congenital postural anomalies form when a normally asphyxia on childhood outcomes. N Engl J Med 37 1 (2) : 1 40, 2014 developed fetal structure becomes deformed by intrauterine Barbu D, Men 1, Kruger M, et al: Evidence of fetal central nervous system mechanical factors. Examples of the latter include chronic oliinjury in isolated congenital hean defects: microcephaly at birth. Am J Obstet Gynecol 20 1 ( 1 ) :43.e 1 , 2009 gohydramnios, as well as restricted fetal movement imposed by Basaldella L, Marton E, Bekelis K, et al: Spontaneous resolution of atraumatic an abnormally shaped or small uterine cavity or by the presence intrauterine ping-pong fractures in newborns delivered by cesarean section. J Child Neurol 26: 1 1 49, 20 1 1 of additional fetuses. Some mechanical deformations include

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The N ewborn Redline RW: Placental pathology: a systematic approach with clinical correla­ tions. Placenta 22:S86, 2008 Ree 1M, Smits-Wintjens E, van der Bon ]G, et al: Neonatal management and outcome in alloimmune hemolytic disease. Expert Rev Hematol 1 0 (7) :607, 20 1 7 Reuter S , Moser C , Baack M : Respiratory distress i n the newborn. Pediatr Rev 35 ( 1 0) :4 1 7, 2 0 1 4 Richey S , Ramin S M , Bawdon E, et al: Markers of acute and chronic asphyxia in infants with meconium-stained amniotic fluid. Am ] Obstet Gynecol 1 72 : 1 2 1 2, 1 99 5 Robinson M N , Peake L], Ditchield M R, et a l : Magnetic resonance imaging indings in a population-based cohort of children with cerebral palsy. Dev Med Child Neurol 5 1 ( 1 ) :39, 2008 Ross MG, Beall MH: Cervical neck dislocation associated with the Zavanelli maneuver. Obstet Gynecol 1 08 :737, 2006 Rossi AC, Vanderbilt 0, Chmait RH: Neurodevelopmental outcomes after laser therapy for twin-twin transfusion syndrome: a systematic review and meta-analysis. Obstet Gynecol 1 1 8 (5) : 1 1 45 , 20 1 1 Rutherford v lA, Ramenghi A, Cowan FM: Neonatal stroke. Arch Dis Child Fetal Neonatal Ed 97(5 ) :F377, 20 1 2 Saksenberg V , Bauch B , Reznik S : Massive acute thymic haemorrhage and cerebral haemorrhage in an intrauterine fetal death. ] Clin Pathol 54:796, 200 1 Sankar M], Chandrasekaran A, Kumar P, et al: Vitamin K prophylaxis for prevenrion of vitamin K deficiency bleeding: a systematic review. ] Perinatol 36 (Suppl 1 ) :S29, 20 1 6 Saroha M , Batra P , Dewan P , e t al: Genital injuries i n neonates following breech presentation. ] Neonatal Perinatal Med 8 (4):42 1 , 20 1 5 Scheibl A, Calderon EM, Borau M] , et al: Epidural hematoma. ] Pediatr Surg 47(2) :e l 9, 20 1 2 Sgro M , Campbell 0 , Barozzino T , e t al: Acute neurological indings i n a national cohort of neonates with severe neonatal hyperbilirubinemia. ] Peri­ natoI 3 1 (6) :392, 201 1 Sgro M, Kandasamy S, Shah V, et al: Severe neonatal hyperbilirubinemia decreased after the 2007 Canadian guidelines. ] Pediatr 1 7 1 :43, 20 1 6 Shah NA, Wusthof C]: I ntracranial hemorrhage i n the neonate. Neonatal Netw 3 5 (2):6 , 20 1 6 Shankaran S, Branes P O , Hintz SR, e t al: Brain injury following trial o f hypo­ thermia for neonatal hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 97(6) : F398, 20 1 2 Shatrov ]G, Birch Sc, Lam FT, e t al : Chorioamnionitis and cerebral palsy: a meta-analysis. Obstet Gynecol 1 1 6:387, 20 1 0 Silva M, Smith RN, Lehmann CU, e t al: Neonatal nucleated red blood cells and the prediction of cerebral white matter injury in preterm infants. Obstet Gynecol 1 07:5 50, 2006 S imonson C, Barlow P, Dehennin N , et al: Neonatal complications of vacuum­ assisted delivery. Obstet Gynecol 1 1 0: 1 89, 2007 Singh BS, Clark RH, Powers RJ, et al: Meconium aspiration syndrome remains a significant problem in the NICU: outcomes and treatment patterns in term neonates admitted for intensive care during a ten-year period. ] Peri­ natol 29 (7) :497, 2009 S lusher TM, Olusanya BO, Vreman H], et al: A randomized trial of photother­ apy with filtered sunlight in Mrican neonates. N Engl ] Med 373 ( 1 2) : 1 1 1 5 , 20 1 5 Smith C, Weinberg A, Forster ]E, et al : Maternal lopinavir-ritonavir is associ­ ated with fewer adverse events in infants than nelfinavir or atazanavir. Infect D is Obstet Gynecol 20 1 6:984804 1 , 20 1 6 Smithers-Sheedy H , McInryre S , Gibson C , e t al: A special supplement: ind­ ings from the Australian Cerebral Palsy Register, birth years 1 993 to 2006. Dev Med Child Neurol 5 8 (Suppl 2) : 5 , 20 1 6 Spruij t M , Steggerda S , Rath M , e t al: Cerebral injury i n twin-twin transfusion syndrome treated with fetoscopic laser surgery. Obstet Gynecol 1 20( 1 ) : 1 5 , 20 1 2 Stanley F], Blair E : Why have we failed to reduce the frequency o f cerebral palsy? Med ] Aust 1 54:623, 1 99 1 Stoknes M, Andersen GL, Dahlseng M O , e t al: Cerebral palsy and neona­ tal death in term singletons born small for gestational age. Pediatrics 1 30(6):e l 629, 20 1 2 Strijbis E M , Oudman I , van Essen P , e t al: Cerebral palsy and the application of the inrernational criteria for acute intrapartum hypoxia. Obstet Gynecol 1 07: 1 357, 2006 Stuart A, Olausson PO, Kallen K: Apgar scores at 5 minutes after birth in relation to school performance at 16 years of age. Obstet Gynecol 1 1 8 (2 Pt 1 ) :20 1 , 20 1 1 Swanson AE, Veldman A, Wallace EM, et al: S ubgaleal hemorrhage: risk fac­ tors and outcomes. Acta Obstet Gynecol Scand 91 (2):260, 20 1 2

Tagin A , Woolcott CG, Vincer M], e t al: Hypothermia for neonatal hypoxic ischemic encephalopathy: an updated systematic review and meta-analysis. Arch Pediatr Adolesc v Ied 1 66(6) : 5 5 8, 20 1 2 Takenouchi T , Kasdorf E, Engel M , et al : Changing pattern of perinatal brain injury in term infants in recent years. Pediatr Neurol 46(2): 1 06, 20 1 2 hacker SB, Stroup OF, Peterson HB: Eicacy and safety o f intrapartum elec­ tronic fetal monitoring: an update. Obstet Gynecol 86:6 1 3 , 1 99 5 harakan S], Lee R], White M, e t al: Distal humeral epiphyseal separation i n a newborn. Orthopedics 39(4) :e764, 20 1 6 horngren-]erneck K , Herbst A: Perinatal factors associated with cerebral palsy in children born in Sweden. Obstet Gynecol 1 08 : 1 499, 2006 Tolia VN, Patrick SW, Bennett MM, et al: Increasing incidence of the neonatal abstinence syndrome in U.S. neonatal ICUs. N Engl ] Med 372(22) :2 1 1 8 , 20 1 5 Torfs CP, van den Berg B , Oechsli FW, et al: Prenatal and perinatal factors in the etiology of cerebral palsy. ] Pediatr 1 1 6:6 1 5 , 1 990 Torki M, Barton L, Miller 0, et al: Severe brachial plexus palsy in women without shoulder dystocia. Obstet Gynecol 1 20(3) :539 , 20 1 2 Turpenny PO, Nimmo A : Fractured clavicle o f the newborn i n a population with a high prevalence of grand-multiparity: analysis of78 consecutive cases. B]OG 1 00:338, 1 993 Ubachs ]M, Sloof AC, Peeters LL: Obstetric antecedents of surgically treated obstetric brachial plexus injuries. B]OG 1 02:8 1 3, 1 995 Vain NE, Szyld EG, Prudent LM, et al: Oropharyngeal and nasopharyngeal suctioning of meconium-stained neonates before delivery of their shoulders: multicentre, randomized controlled trial. Lancet 364:597, 2004 Vandborg PK, Hansen BM, Greisen G , et al: Follow-up of neonates with total serum bilirubin levels �25 mg/dL: a Danish population-based study. Pedi­ atrics 1 30 ( 1 ) :6 1 , 20 1 2 Vasconcelos BC, Lago CA, Nogueira RV, e t al: Mandibular fracture in a pre­ mature infant: a case report and review of the literature. ] Oral Maxillofac Surg 67( 1 ) :2 1 8 , 2009 Villamor E, Tedrof K, Peterson M, et al: Association between matenal body mass index in early pregnancy and incidence of cerebral palsy. ]AMA 3 1 7(9) :925, 20 1 7 Volpe JJ: Neurology of the Newborn, 3 rd ed. Philadelphia, Saunders, 1 99 5 Wall L B , Mills ] K, Leveno K], e t al : Incidence and prognosis of neonatal brachial plexus palsy with and without clavicle fractures. Obstet Gynecol 1 23 (6) : 1 288, 20 1 4 Walsh B, Boylan G , Dempsey E , e t al: Association o f nucleated red blood cells and severity of encephalopathy in normothermic and hypothermic infants. Acta Paediatr 1 02(2):e64, 20 1 3 Walsh B H , Bovian GB, Murray OM: Nucleated red blood cells and early EEG: predicting Sarnat stage and two year outcome. Early H um Dev 87( 5):33 5 , 201 1 Walsh BH, Neil ], Morey ], et al: he frequency and severity of magnetic reso­ nance imaging abnormalities in infants with mild neonatal encephalopathy. ] Pediatr 1 87:26, 20 1 7 Wambach ]A, Wegner 0], Depass K , e t al: Single ABCA3 mutations increase risk for neonatal respiratory distress syndrome. Pediatrics 1 30(6) :e 1 5 75, 20 1 2 Watchko ] F , Tiribelli C : Bilirubin-i nduced neurologic damage-mechanisms and management approaches. N Engl ] Med 369:2 1 , 20 1 3 Wayock CP, Meserole RL, Saria S , e t al : Perinatal risk factors for severe injury in neonates treated with whole-body hypothermia for encephalopathy. Am ] Obstet GynecoI 2 1 1 ( 1 ) :4 1 .e l , 20 1 4 Wenstrom KD, Andrews W, Maher ]E: Amnioinfusion survey: prevalence, protocols, and complications. Obstet Gynecol 86: 572, 1 995 Wener EF, ]anevic TM, Illuzzi ] , et al: Mode of delivery in nulliparous women and neonatal intracranial injury. Obstet Gynecol 1 1 8 (6): 1 239, 201 1 Whitby EH, Griiths PO, Rutter S, et al: Frequency and natural history of subdural haemorrhages in babies and relation to obstetrical factors. Lancet 363: 846, 2004 Wiberg N , Kallen K, Herbst A, et al: Relation between umbilical cord blood pH, base deicit, lactate, 5-minute Apgar score and development of hypoxic ischemic encephalopathy. Acta Obstet Gynecol Scand 89: 1 263, 20 1 0 Wiklund LM, Uvebrant P , Flodmark 0: Computed tomography a s a n adjunct in etiological analysis of hemiplegic cerebral palsy, 1 . Children born pre­ term. Neuropediatrics 22: 50, 1 99 1 a Wiklund LM, Uvebrant P, Flodmark 0: Computed tomography as an adjunct in etiological analysis of hemiplegic cerebral palsy, 2. Children born at term. Neuropediatrics 22: 1 2 1 ) 1 99 1 b Williams ]W: Obstetrics: a Text-book for the Use of Students and Practitio­ ners. New York, Appleton, 1 903 Winkelhorst 0 , Murphy MF, Greinacher A, et al: Antenatal managemet in fetal and neonatal alloimmune thrombocytopenia: a systematic review. Blood 1 29( 1 1 ) : 1 538, 20 1 7

Di seases a nd I nj u ries of the Term Newborn Wiswell TE, Tuggle JM, Turner BS: Meconium aspiration syndrome: have we made a diference? Pediatrics 85:7 1 5 , 1 990 World Health Organization: Guidelines on Basic Newborn Resuscitation. Geneva, World Health Organization, 20 1 2 Wu YW, Bauer A , Ballard A , et al: Erythropoietin for neuroprotec­ tion in neonatal encephalopathy: safety and pharmacokinetics. Pediatrics 1 30(4):683, 20 1 2 W u W, Croen A , Shah SJ, e t al : Cerebral palsy i n a term population: risk factors and neuroimaging findings. Pediatrics 1 1 8 :69 1 , 2006 Wu W, Plum TN, Danielsen B, et al: Nighttime delivery and risk of neonatal encephalopathy. Am J Obstet GynecoI 204( l ) :37.e 1 , 20 1 1

Wyckof M H , Aziz K, Escobedo MB, et al: Part 1 3 : Neonatal resuscitation: 20 1 5 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Pediatrics 1 36 (Suppl 2): S I 96, 20 1 5 Yaish HM, Christensen RD, Lemmons RS: Neonatal nonimmune hemolytic anemia. Curr Opin Pediatr 29 ( 1 ) : 1 2, 20 1 7 Yeh P , Emary K , Impey L: The relationship between umbilical cord arterial pH and serious adverse neonatal ourcome: analysis of 5 1 , 5 1 9 consecurive validated samples. BlOG 1 1 9 (7) : 824, 20 1 2 Zipursky A : Prevention o f vitamin K deficiency bleeding in newborns. B r J Haematol 1 04:430, 1 999

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The Preterm Newborn

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!he prognosis or the child depends, of course, upon the degree of development, as wel as the pathological condi­ tion or which premature delivery is undertaken. Generaly speaking, in the case ofchildren born bore the thiry-second week, the chances ofsurviving are vey small. -]. Whitridge Williams ( 1 903) At the time of this textbook's irst edition, preterm delivery of a living newborn was frequently followed by neonatal death. Contrast this with today's technological advances that have advanced the threshold of viability to 22 to 24 weeks' gestation. Even so, the preterm newborn is susceptible to various serious medical complications both early and later in life (Table 34- 1 ) . A less commonly cited cause o f morbidity and mortality is congenital malformations, which are much more prevalent in preterm births. These complications of prematurity can be placed in perspec­ tive in terms of overall neonatal outcomes. In 2009, two thirds of all infant deaths in the United States were in the 1 2 per­ cent born before 37 weeks (Mathews, 20 1 3) . Fortunately, dur­ ing the past decade, rates of preterm birth have declined from

approximately 12 percent in 2007 to 10 percent in 20 1 4. This is in part due to a decline in births to teen mothers (Ferre, 20 1 6) .

RESPI RATORY DISTRESS SYNDROME The seminal complication of the preterm newborn is respiratory distress syndrome (DS). This results from immature lungs that are unable to sustain necessary oxygenation. Resulting hypoxia is an underlying associated cause of neurological damage such as cerebral palsy. In addition, hyperoxia, a side efect of DS treat­ ment contributes to morbidities such as bronchopulmonary ' dysplasia, pulmonary hypertension, necrotizing enterocolitis, periventricular leukomalacia, and retinopathy of prematurity. • Etiopathogenesis

To provide blood gas exchange immediately following delivery, the lungs must rapidly fill with air while being cleared of fluid. Concurrently, pulmonary arterial blood low must rise remark­ ably. Although some of the luid is expressed as the chest is com­ pressed during vaginal delivery, most is absorbed through the

TABLE 34-1 . Co m p l i cations of Prematu rity Respi ratory d i stress syn d rome (ROS) Hya l i n e mem bra n e d i sea se ( H M O) B ronchopu l mo n a ry dysplasia (BPO) P n e u mothorax P n e u m o n ia/sepsis Patent d uctu s a rterios u s (P OA) Necrotizi ng enterocol itis (N EC) Retinopathy of prematu rity (RO P) I ntrave ntric u l a r hemorrhage (IVH) Periventricu l a r l e u komalac i a (PVL) Cerebra l pa l sy (CP)

The P rete rm N ewborn

pulmonary lymphatics via complex mechanisms described in Chapter 32 (p. 606) . Suicient surfactant, synthesized by type II pneumocytes, is essential to stabilize the air-expanded alveoli. It lowers surface tension and thereby prevents lung collapse during expiration (Chap. 7, p. 1 33) . If surfactant is inadequate, hyaline membranes form in the distal bronchioles and alveoli, and RDS develops. Although respiratory distress syndrome is generally a disease of preterm neonates, it does develop in term newborns, especially with sepsis or meconium aspiration. In these cases, surfactant can be inactivated by inlammation andlor presence of meconium (Chap. 33, p. 6 1 9) . With inadequate surfactant, alveoli are unstable, and low pressures cause collapse at end expiration. Pneumocyte nutri­ tion is compromised by hypoxia and systemic hypotension. Par­ tial persistence of the fetal circulation may lead to pulmonary hypertension and a relative right-to-Ieft shunt. Eventually, alveolar cells undergo ischemic necrosis. When oxygen therapy is initiated, the pulmonary vascular bed dilates, and the shunt reverses. Protein-filled fl u id leaks into the alveolar ducts, and the cells lining the ducts slough. Hyaline membranes composed of ibrin-rich protein and cellular debris line the dilated alveoli and terminal bronchioles. he epithelium underlying the membrane becomes necrotic. At autopsy, with hematoxylin-eosin staining of lung tissue, these membranes appear amorphous and eosino­ philic, like hyaline cartilage. Because of this, respiratory distress syndrome is also termed hyaline membrane disease. • Clinical Course

In typical RDS, tachypnea develops, the chest wall retracts, and expiration is accompanied by nostril flaring and by grunting­ in an attempt to provide a positive end-expiratory pressure to prevent lung collapse. Shunting of blood through nonven­ tilated lung contributes to hypoxemia and to metabolic and respiratory acidosis. Poor peripheral circulation and systemic hypotension may be evident. The chest radiograph shows a difuse reticulogranular infiltrate and an air-illed tracheobron­ chial tree air bronchogram. As discussed further in Chapter 33 (p. 6 1 9) , respiratory insuiciency can also be caused by sepsis, pneumonia, meco­ nium aspiration, pneumothorax, persistent fetal circulation, heart failure, and malformations involving thoracic structures, such as diaphragmatic hernia. Common mutations in surfactant protein production and the phospholipid transporter (ABCA3) contribute to RDS (Beers, 20 1 7; Tredano, 2003; Wert, 2009) . -

• Treatment

An important factor inluencing survival is neonatal intensive care. Although hypoxemia prompts supplemental oxygen, excess oxygen can damage the pulmonary epithelium, retina, and other immature tissues. Despite this, advances in mechani­ cal ventilation technology have improved neonatal survival rates. For example, continuous positive airway pressure (CPAP) prevents the collapse of unstable alveoli. This allows high inspired-oxygen concentrations to be reduced, thereby mini­ mizing its toxicity. In an attempt to minimize the need for tra­ cheal intubation and intermittent positive-pressure ventilation,

CPAP has been studied in well-designed multicenter trials (Morley, 2008; SUPPORT Study Group, 20 1 0b) . An initial CPAP strategy with subsequent selective surfactant use is a beneficial alternative to immediate intubation and surfactant for many neonates of extremely early gestational age (American Academy of Pediatrics, 20 1 4) . Mechanical ventilation has undoubtedly improved survival rates but is an important factor in the genesis of chronic lung dis­ ease of prematurity-bronchopulmonary dypasia (BPD). Namely, mechanical ventilation places a newborn at risk for barotrauma and volutrauma. Moreover, hyperoxia can create reactive oxy­ gen species that trigger inflammation. Infection can also be con­ tributory. In afected newborns, alveolar and pulmonary vascular development is disrupted and leads to hypoxia, hypercarbia, and chronic oxygen dependence (Davidson, 20 1 7; Kair, 20 1 2) . As prevention, hightequency oscilatory ventilation has been evaluated. However, beneits and risks varied considerably between studies (Cools, 20 1 5) . Treatment o f the ventilator-dependent neonate with gluco­ corticoids was also used previously to prevent BPD. he Ameri­ can Academy of Pediatrics now recommends against routine steroid use because of limited beneits and greater rates of impaired motor and cognitive function and school performance in exposed neonates (Doyle, 20 1 4a,b; Watterberg, 20 1 0) . I n other eforts for BPD prevention, early animal studies demonstrated significant improvements in lung function with weeks of inhaled nitric oxide (McCurnin, 2005) . Despite ini­ tial enthusiasm, clinical trials failed to demonstrate a consis­ tent benefi t . A National Institutes of Health (NIH) consensus statement and the American Academy of Pediatrics (20 1 4) con­ cluded that the available data do not support its use to prevent or treat BPD (Cole, 20 1 1 ) . Caeine has been used widely to treat apnea o f prematu­ rity, but it also has bronchodilatory efects. One large random­ ized trial of cafeine versus placebo showed lower BPD rates, improved neurodevelopmental outcomes during early child­ hood, and good evidence of safety up to 1 1 years (Schmidt, 2006, 20 1 2, 20 1 7) . This therapy is now widely used for new­ borns weighing ; 1 250 g. The antioxidant vitamin A is necessary for normal lung growth and the integrity of respiratory tract epithelial cells. Preterm newborns have low vitamin A levels at birth, and this has been associated with a greater risk of developing BPD. Ran­ domized trials support the use of vitamin A to achieve a mod­ est reduction in BPD rates for very-Iow-birthweight neonates weighing < 1 500 g (Darlow, 20 1 6) . S u rfa cta nt Prophy l a x i s a n d Rescue

Exogenous surfactant products are delivered via endotracheal tube to help prevent RDS . They contain biological or ani­ mal surfactants such as bovine-Survanta, calf-Inasu , or porcine- Curosu f Synthetic surfactants such as irst-generation Exosuf and second-generation Suaxin R are equivalent but not superior to animal-derived surfactant (Moya, 2007) . In a Cochrane review, Ardell and coworkers (20 1 5) found that animal-derived surfactants led to better outcomes than syn­ thetic surfactants, which do not contain important surfactant proteins. here are currently no synthetic surfactants available.

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Surfactant replacement was established decades ago as an efective and safe therapy for RDS. Treatment reduces rates of mortality and pneumothorax and improves survival without BPD (Polin, 20 1 4). It has been used for prophyxis of preterm, at-risk newborns and for rescue of those with established disease. Given together, antenatal corticosteroids and surfactant result in an even greater reduction in the overall death rate. However, randomized trials indicate that in populations with high use of antenatal ste­ roids and routine use of CPP in the delivery room, prophylac­ tant surfactant is no longer beneficial and is associated with more risk of death or BPD (Rojas-Reyes, 20 1 2; Sardesai, 20 1 7) . Explo­ ration of diferent, less invasive ways to deliver rescue surfactant to spontaneously breathing preterm neonates is currently underway. Potential routes include surfactant application into the pharynx, surfactant nebulization, or application via laryngeal mask or via a thin catheter placed in the trachea (Kribs, 20 1 6). • Prevention

A nten ata l Corti costeroi d s

The N I H ( 1 994, 2000) has concluded that a single course of antenatal corticosteroid therapy reduces RDS and intraventricu­ lar hemorrhage rates in preterm neonates born between 24 and 34 weeks' gestation (p. 640) . he American College of Obste­ tricians and Gynecologists (20 1 6a) considers all women at risk for preterm birth in this gestational-age range to be potential candidates for therapy. It also may be considered for pregnant women starting at 23 weeks' gestation who are at risk of preterm delivery within 7 days. his is discussed further is Chapter 42 (p. 823) . More recently, administration of antenatal corticoste­ roids to women at risk for late-preterm delivery (34 to 36 weeks' gestation) was found to significantly reduce the rate of neonatal respiratory complications (Gyami-Bannerman, 20 1 6) . A m n i ocentesis t o Assess Feta l L u n g M atu rity

In some instances, when gestational age is uncertain, knowledge of fetal lung maturity may inluence plans for delivery. One example is the woman with a prior classical cesarean delivery in whom repeat operation is planned and gestational age cannot be confi r med. Several tests are used to ensure fetal pulmonary maturity by analysis of amnionic fluid obtained by sonographi­ cally guided amniocentesis. At Parkland Hospital, we still find an occasional indication for such testing, however, the American College of Obstetricians and Gynecologists (20 1 7 a, b) counsels against its use in most of these cases. Instead the College recom­ mends late-term delivery at "4 1 weeks' gestation" using the best clinical estimate of gestational age (Chap. 1 0, p. 1 83). If amniocentesis is elected, luid acquisition is similar to that described for second-trimester amniocentesis (Chap. 1 4, p. 292) . Complications requiring urgent delivery are rare (Zalud, 2008) . Following analysis, the probability of RDS developing in a given newborn depends on the test used and fetal gestational age. Importantly, administration of corticoste­ roids to induce pulmonary maturation has variable efects on some of these tests. Varner and colleagues (20 1 3) have provided a review of testing options. Of biochemical tests, the labor-intensive lecithin-sphingo­ myelin (LIS) ratio for many years was the gold-standard test.

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F I G U R E 34-1 Cha nges in mea n concentrations of lecith i n a nd sphi ngomye l i n in a m n ionic fl uid d u ri ng gestation i n norma l preg na ncy. (Mod ified with perm ission from G l uc k L, Ku lovich MV: Lecithin-sph i ngomye l i n ratios in a m n iotic fl uid in normal a nd a b nor­ m a l preg nancy, Am J Obstet Gynecol. 1 973 Feb 1 5; 1 1 5 (4):539-546.)

Dipalmitoylphosphatidylcholine (DPPC), that is, lecithin, and phingomyelin are surfactant components. Before 34 weeks, both are present in amnionic fluid in similar concentrations. At 32 to 34 weeks, the concentration of lecithin relative to sphingomy­ elin begins to rise (Fig. 34- 1) . The risk of neonatal RDS is slight whenever the concentration of lecithin is at least twice that of sphingomyelin-LIS ratio >2 (Gluck, 1 97 1 ) . Previously, RDS was thought to develop despite an LIS ratio > 2 in newborns of women with diabetes. Some recommend that phosphatidygycerol, another surfactant phospholipid, be documented in amnionic fluid of these women. Based on current evidence, it is unclear if either diabetes, per se, or its level of control causes false-positive phospholipid test results for fetal lung maturity (De Luca, 2009) . Of biophysical tests, the luorescence poariation test is an automated assay that measures the surfactant-to-albumin ratio in uncentriuged amnionic luid and gives results in less than an hour. Investigators found the TDx-FLM to be equal or superior to the LIS ratio, foam stability index, or phosphatidylglycerol assess­ ment. his included testing in diabetic pregnancies (Karcher, 2005 ; Varner, 20 1 3) . he modified TDx-FLM Il is used by many hospitals as their primary test of pulmonary maturity. Thresholds vary by gestational age (Bennasar, 2009). he oam stabiliy or shake test relies on the ability of surfactant in amnionic luid, when mixed appropriately with ethanol, to generate stable foam at the air-liquid interface (Clements, 1 972) . Problems include errors caused by slight contamination and frequent false-negative test results. Of other tests, the Lumadex-FSI test, luorescent poaria­ tion (microviscomery), and amnionic luid absorbance at 650-nm waveength have all been used with variable success. The lamelar body count is a rapid, simple, and accurate method of assessing fetal lung maturity and is comparable to TDx-FLM and LIS ratio accuracy (Karcher, 2005; Varner, 20 1 3).

N ECROTIZING ENTEROCOLITIS This newborn bowel disorder has clinical findings that include abdominal distention, emesis, ileus, bilious gastric aspirates,

The P rete rm Newborn

and bloody stools. here is often radiological evidence of pneumatosis intestinalis-bowel wall gas derived from invading bacteria. Other classic imaging fi n dings include hepatobiliary gas and pneumoperitoneum. Bowel perforation may prompt resection. Necrotizing enterocolitis (NEC) is seen primarily in low-birthweight newborns but occasionally is encountered in mature neonates. Various hypothesized causes include peri­ natal hypotension, hypoxia, sepsis, umbilical catheterization, exchange transfusions, blood transfusions, and the feeding of cow milk and hypertonic solutions (Neu, 20 1 0) . he patho­ physiology is thought to be multifactorial, and genetic disposi­ tion, intestinal immaturity, imbalance in microvascular tone, abnormal microbial colonization in the intestine, exposure to enteral feeds, and highly immunoreactive intestinal mucosa play potential roles (Caplan, 20 1 7; Neu, 20 1 0) . Medical treatment includes abdominal decompression, bowel rest, broad-spectrum antibiotics, and parenteral nutri­ tion. Surgery is reserved for neonates with intestinal perforation or deteriorating clinical or biochemical status. Possible surgical procedures include drain placement, exploratory laparotomy with resection of diseased bowel, or enterostomy with creation of a stoma (Neu, 20 1 0) .

RETI NOPATHY OF PREMATU RITY By 1 950, this condition, formerly known as retrolentalibropla­ sia, became the largest single cause of blindness in this country. Mter the discovery that the disease resulted from hyperoxemia, its frequency declined but began to rise again with the increas­ ing survival rates of extremely pre term newborns. Normally, the fetal retina vascularizes centrifugally from the optic nerve starting at approximately the fourth month and con­ tinues until shortly after birth. During vascularization, excessive oxygen induces severe retinal vasoconstriction with endothelial damage and vessel obliteration. his is followed by subsequent aberrant neovascularization, in which the new vessels penetrate the retina and extend into the vitreous. Here, they are prone to leak proteins or burst with subsequent hemorrhage. Adhesions can form to detach the retina. Vascular endothelial growth fac­ tor (VEGF) plays an important role in normal angiogenesis and is up regulated during retinopathy of prematurity (ROP) devel­ opment (Sharma, 20 1 7) . his understanding has opened new avenues of treatment with anti-VEGF therapies. Precise levels of hyperoxemia that can be sustained without causing ROP are unknown. Mter birth, there is a "relative" hyperoxia compared with in utero oxygen content, even in new­ borns not exposed to higher inspired oxygen concentrations. To better understand the oxygen saturation threshold neces­ sary to minimize ROP without raising rates of other adverse outcomes, the Neonatal Research Network performed a ran­ domized trial of oxygenation in 1 3 1 6 neonates born between 24 and 27 weeks' gestation (SUPPORT Study Group, 20 1 0a) . he two target ranges of oxygen saturation were 85 to 89 per­ cent in one arm and 9 1 to 95 percent in the other arm. hese targets were both commonly employed in neonatal intensive care units. Death before discharge occurred signiicantly more frequently in the lower-oxygen saturation group-20 versus 1 6 percent. However, severe ROP among survivors developed

signiicantly less often in the lower-oxygen saturation group8.6 versus 1 7. 9 percent.

B RAIN DISORDERS Central nervous system inj ury usually creates diferent neu­ roanatomical sequelae in preterm newborns compared with those at term (Chap. 33, p. 62 1 ) . In preterm neonates, cerebral lesions detected by neuroimaging include intraventricular hem­ orrhage, cerebellar hemorrhage, periventricular hemorrhagic infarction, cystic periventricular leukomalacia, and difuse white matter injury. All of these are strongly associated with adverse neurodevelopmental outcomes (Kwon, 20 1 4) . Cranial sonography remains the preferred approach for detecting frequently occurring brain abnormalities and acute events. It is readily available and reliable for detecting common abnormalities and monitoring brain growth. Because cystic inju­ ries may take 2 to 5 weeks to evolve, serial scans are obtained dur­ ing this time. In those whose findings are transient and resolve in the neonatal period, prognosis is improved compared with infants whose lesions remain and evolve. At the same time, how­ ever, between 4 and 10 percent of prematurely born children may develop cerebral palsy (CP) in the absence of lesions. Put another way, 90 to 96 percent of preterm newborns with CP have cerebral lesions that are detectable using cranial sonography. • I ntracranial Hemorrhage

here are ive major categories of intracranial hemorrhage in the neonate (Volpe, 2008) . Primay subarachnoid hemorrhage is more common in those born preterm and is frequently benign. Cerebelar hemorrhage is also more frequent in preterm neonates and is increasingly recognized as a cause of serious sequelae. Intraventricular hemorrhage IVH) is almost exclusively seen in preterm newborns, is relatively common, and can have seri­ ous efects. Subdural hemorrhages are more frequent in term newborns and can be serious. Miscelaneous intraparenchymal hemorrhage is also more frequent in those born at term and is of variable concern. • Periventricular-I ntraventricular Hemorrhage

In preterm infants, the germinal matrix capillary network is fragile for several reasons. First, the subependymal germinal matrix provides poor support for the vessels coursing through it. Second, venous anatomy in this region causes stasis and con­ gestion, which makes vessels susceptible to bursting if intravas­ cular pressure rises. Third, vascular autoregulation is impaired in the preterm neonate (Matsuda, 2006; Verhagen, 20 1 4) . I f fragile capillaries i n the germinal matrix rupture, blood escapes into surrounding tissues and may extend into the ven­ tricular system and brain parenchyma. This type of hemorrhage is common in preterm neonates, especially those born before 32 weeks. However, it can also develop at later gestational ages and even in term neonates. Most hemorrhages develop within 72 hours of birth, but they have been observed as late as 24 days (Whitelaw, 20 l l ) . Because IVH usually is recognized within 3 days of delivery, its genesis is often erroneously attributed to

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birth events. It is important to realize that prelabor IVH can also occur (Achiron, 1 993; Nores, 1 996) . The pathogenesis of IVH is multifactorial and includes hypoxic-ischemic events, carbon dioxide elevations, anatomical factors, blood pressure instability, coagulopathy, genetic fac­ tors, and many others (McCrea, 2008; Ment, 20 1 6) . Moreover, preterm birth is frequently associated with infection, which fur­ ther predisposes to endothelial activation, platelet adherence, and thrombi (Redline, 2008) . Respiratory distress and mechan­ ical ventilation are commonly associated factors (Sarkar, 2009) . lmost half of hemorrhages are clinically silent. Most small germinal matrix hemorrhages and those confined to the cere­ bral ventricles resolve without impairment. But, nearly half do show some sign of neurological impairment (Patra, 2006) . Survivors of extensive periventricularlintraventricular hemor­ rhage can have major neurodevelopmental handicaps (Mukerji, 20 1 5) . Large lesions can result in hydrocephalus or in degen­ erated cystic areas termed periventricular leukomalacia (PVL) , discussed below. Importantly, the extent of PVL correlates with CP risk (Bassan, 2006) . I n c i d e n ce a n d Severity

Ventricular hemorrhage incidences depends on gestational age at birth. From the Neonatal Research Network, approximately 65 percent of all neonates born before 28 weeks' gestation dem­ onstrated some evidence of hemorrhage or PVL (Stoll, 20 1 0) . h e incidence ranged from 6 0 percent in those born a t 2 3 weeks to only 23 percent in those at 28 weeks. Importantly, grade IV intraventricular hemorrhage was documented in 2 1 percent of 23-week-old neonates but in only 3 percent of those at 28 weeks. The severity of IVH can be assessed by neuroimaging studies. Papile and coworkers ( 1 978) devised the most widely used grading scheme to quantiY the extent of a lesion and estimate prognosis: •

• •

•

Grade I-hemorrhage limited to the germinal matrix Grade II-intraventricular hemorrhage Grade Ill-hemorrhage with ventricular dilation Grade IV-parenchymal extension of hemorrhage.

Ante n ata l Corticostero i d s

If given at least 24 hours before delivery, corticosteroids pre­ vent or reduce the incidence and severity of IVH (Wei, 20 1 6) . A Consensus Development Conference o f the N I H ( 1 994) concluded that such therapy reduced rates of mortality, RDS, and IVH in preterm neonates born between 24 and 32 weeks' gestation. A second consensus statement by the NIH (2000) recommended that repeated courses of corticosteroids not be given (Chap. 42, p. 823) . Subsequently, the Maternal-Fetal Medicine Units Network reported that repeated corticosteroid courses were associated with some improved preterm neonatal outcomes, but also with reduced birthweight and increased risk for fetal-growth restric­ tion (Wapner, 2006) . Surveillance of this cohort through age 2 to 3 years found that children exposed to repeated versus single­ dose steroid courses did not difer signiicantly in physical or neurocognitive measures (Wapner, 2007) . It was worrisome, however, that there was a nonsignifi c ant 5 .7-fold relative risk of CP in infants exposed to multiple steroid courses.

At the same time, the 2-year follow-up of the Australian Col­ laborative Trial was reported by Crowther and coworkers (2007) . In more than 1 1 00 newborns, the incidence of CP was almost identical4.2 versus 4.8 percent-in those given repeated ver­ sus single-course steroids, respectively. More recently, it was reported that for those born before 28 weeks' gestation, if 1 0 days or more had passed since betamethasone administration, the incidence of severe IVH was higher (Liebowitz, 20 1 6) . h e most recent recommendations from the American Col­ lege of 0 bstetricians and Gynecologists (20 1 6a) are for a single course of corticosteroids for pregnant women between 24°/ weeks and 33 6/ weeks' gestation who are at risk for preterm delivery. They further note that those given their initial course more than 1 4 days prior and who have imminent risk of pre­ term delivery may receive a second "rescue" course. Antenatal corticosteroids are "considered" for 23 °/ to 23 6/7 weeks and not recommended for pregnancies < 23 weeks (American College of Obstetricians and Gynecologists, 20 1 7c) . Other Preventive Method s

Although antenatal magnesium suate for those at risk for pre­ term delivery does not reduce the incidence ofIVH, it does ofer protection from neurodevelopmental impairment (Crowther, 2007; Doyle, 2009) . The American College of Obstetricians and Gynecologists (20 1 6b) recommends its use for this indica­ tion, as discussed further in Chapter 42 (p. 824) . he eicacy of antenatal vitamin K and phenobarbital, as well as postnatal phenobarbital, have not been shown to consistently reduce the incidence of IVH (Crowther, 20 1 0a,b; Smit, 20 1 3). Although vitamin E reduced IVH rates, the associated risk for sepsis was increased (Brion, 2003) . One metaanalysis of the many ran­ domized trials of postnatal indomethacin showed a reduction in IVH rates, but no improvement in rates of death or neurode­ velopmental impairment (Fowlie, 20 1 0) . h e beneits o f cesarean delivery compared with vaginal birth to lower IVH rates remains controversial. One metaanal­ ysis reported that cesarean delivery for very-Iow-birthweight neonates had no efect on rates of severe IVH but did reduce overall IVH rates (Barzilay, 20 1 6) . Delayed cord clamping compared with immediate cord clamping has been reported to reduce the risk for IVH in preterm newborns (Rabe, 20 1 2) . • Periventricular Leukomalacia

This pathological description refers to cystic areas deep in brain white matter that develop after hemorrhagic or ischemic infarc­ tion. Tissue ischemia leads to regional necrosis. Because brain tissue does not regenerate and the preterm neonate has minimal gliosis, these irreversibly damaged areas appear as echolucent cysts in neuroimaging studies. Generally, they require at least 2 weeks to form but may develop as long as 4 months after the initial insult. hus, their presence at birth may help to deter­ mine the timing of an inciting event.

CEREBRAL PALSY This term refers to a group of conditions that are characterized by chronic movement or posture abnormalities that are cerebral

The P rete rm Newborn

in onglll, arise early in life, and are nonprogressive (Nelson, 2003) . Epilepsy and mental retardation frequently accom­ pany CP. Its cause(s) are diferent in preterm and term infants (Chap. 33, p. 622) . CP is commonly classified by the type of neurological dys­ function-spastic, dyskinetic, or ataxic-as well as the num­ ber and distribution of limbs involved-quadriplegia, diplegia, hemiplegia, or monoplegia. The major types and their frequen­ cies were categorized by Freeman ( 1 988) and Rosen ( 1 992) and their associates: •

•

• • •

Spastic quadrplegia, which has a strong association with developmental retardation and seizure disorders-20 percent Diplegia, which is common in preterm or low-birthweight neonates-30 percent Hemiplegia-30 percent Choreoathetoid ypes-I S percent Mixed varieties.

• I ncidence

According to the Centers for Disease Control and Prevention (20 1 6), the prevalence of CP in the United States approxi­ mates 3 in 1 000 children. In some countries, the incidence has risen because advances in care of very preterm newborns have improved their survival but not their neurological progno­ sis (O'Callaghan, 20 1 1 ) . For example, Moster and coworkers (2008) presented long-term follow-up of more than 900,000 births in Norway. he CP rate was 0. 1 percent in nonanoma­ lous term newborns but was 9. 1 percent in those born at 23 to 27 weeks. • Risks

Pe r i n ata l I nfection/I nfla m m a t i o n

PL is associated with infection and infl a mmation. Zupan and colleagues ( 1 996) studied 753 infants born between 24 and 32 weeks, 9 percent of whom developed PVL. Those born before 28 weeks, those who had infl a mmatory events during the last days to weeks before delivery, and those who had both were at highest risk. In another study, PVL was strongly associated with prolonged membrane rupture, chorioamnionitis, and neonatal hypotension (Perlman, 1 996) . Bailis and coworkers (2008) reported that chronic-and not acute-placental inlammation was associated with PVL. Fetal infection may be a key element in the pathway between preterm birth and CP (Burd, 20 1 2; Leviton, 20 1 0) . As discussed i n Chapter 4 2 (p. 8 1 0) , chorioamnionitis i s a major cause of spontaneous preterm delivery. In the pathway proposed in Figure 34-2, antenatal reproductive tract infec­ tion evokes the production of cytokines such as tumor necrosis factor and interleukins- 1 , -6, and -8. hese in turn stimulate prostaglandin production and preterm labor. Preterm fetal intracranial blood vessels are susceptible to rupture and dam­ age, and the cytokines that stimulate preterm labor also have direct toxic efects on oligodendrocytes and myelin. Vessel rup­ ture, tissue hypoxia, and cytokine-mediated damage result in massive neuronal cell death. Glutamate is released, stimulating membrane receptors to allow excess calcium to enter the neu­ rons. High intracellular calcium levels are toxic to white mat­ ter, and glutamate may be directly toxic to oligodendrocytes (hwaja, 2008) . Many studies have shown that infection and cytokines can directly damage the immature brain (Chau, 20 1 4; Yoon, 1 997a) . Tumor necrosis factor and interleukin-6 were more frequently found in the brains of infants who died with PVL

I nt raventri c u l a r H e morrhage

Various clinical and pathological data link CP with associated severe IVH (grade III or IV) and resulting PVL. In one study of nearly 1 500 neonates born before ;28 weeks, the rate of CP was fivefold greater in those who had grade III or IV hemor­ rhage compared with those who sufered no IVH (Bolisetty, 20 1 4) .

Maternal or intrauterine infection LPS Cytokines �

1

Ischemia

Preterm newborns are most susceptible to brain ischemia and PVL. Before 32 weeks' gestation, the vascular anatomy of the brain is composed of two systems. One penetrates into the cortex-the ventrieulopedal system. The other reaches down to the ventricles, but then curves to flow outward-the ven­ trieulofugal system (Weindling, 1 99 5 ) . There are no vascular anastomoses connecting these two systems. As a result, the area between these systems, through which the pyramidal tracts pass near the lateral cerebral ventricles, is a watershed area vulnerable to ischemia. Vascular insuiciency before 32 weeks leading to ischemia would afect this watershed area first. Resulting damage of the pyramidal tracts may cause spastic diplegia. After 32 weeks, vascular flow shifts toward the cortex, and hypoxic injury after this time primarily dam­ ages the cortical region.

Periventricular leukomalacia

Preterm birth

Cerebral palsy F I G U R E 34-2 Schematic representation of the hypothesized pathway between materna l or i ntra uteri ne i nfection and preterm birth o r periventricular leukoma lacia. Both potentia l ly lead to cere­ bral pa lsy. LPS l i popolysaccha ride; PG prosta g l a n d i n . =

=

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(Yoon, 1 997b) . Cytokines are strongly linked to white matter lesions even when organisms cannot be demonstrated (Yoon, 2000) . Andrews and colleagues (2008) provided data that raise ques­ tions regarding a higher incidence of adverse neurodevelopmen­ tal outcomes related to exposure to chorioamnionitis. In a cohort born between 23 and 32 weeks, they studied several surrogate indicators and direct markers of in utero infl a mmation. These included clinical findings, cytokine levels, histological findings, and microbial culture results. Infants undergoing comprehensive psychoneurological testing had similar incidences of CP, intel­ ligence quotient (IQ) scores < 70, or both, regardless of these markers. The researchers interpreted their findings to support current practices that employ eforts to delay delivery with pre­ term pregnancies in the absence of overt intrauterine infection. Importantly, this does not apply to preterm pregnancy in which clinical chorioamnionitis is diagnosed. Of 3094 singletons born before 33 weeks' gestation, 1 5 percent had evidence of clinical chorioamnionitis (Soraisham, 2009) . Compared with nonin­ fected infants, cases complicated by infection had significantly higher rates of early-onset sepsis-4.8 versus 0.9 percent-and of IH-22 versus 1 2 percent. • Prevention-Neuroprotection

The beneits of antenatal magnesium sulfate and corticoste­ roids have already been described. Few specific treatments have been identified to reduce or prevent brain injury in the vulnerable preterm newborn. One potential neuroprotective therapy is with erythropoiesis stimulating agents (ESAs) such as erythropoietin and darbepoetin. In addition to stimulating erythropoiesis, ESAs are protective in the developing brain in animal models (Wassink, 20 1 7) . Preliminary clinical studies are encouraging, and large trials are now underway (Beirer, 20 1 4) .

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Barzilay E, Gadot Y, Koren G. Safety of vaginal delivery in very low birth­ weight vertex singletons: a meta-analysis. J Matern Fetal Neonatal Med 29(22) :3724, 20 1 6 Bassan H , Venson CB, Limperopoulos C , et al: Ultrasonographic features and severity scoring of periventricular hemorrhagic infarction in relation to risk factors and outcome. Pediatrics 1 1 7 : 2 1 1 1 , 2006 Beers MF, Mulugeta S: he biology of the ABCA3 lipid transporter in lung health and disease. Cell Tissue Res 367(3) :48 1 , 20 1 7 Beirer R , Peceny MC, Hartenberger C H , e t al: Erythropoietin concentrations and neurodevelopmental outcome in preterm infants. Pediatrics 1 1 8:63 5 , 2006 Bennasar M , Figueras F, Palacio M et al: Gestational age-specific cutof levels of TDx-FLM II for the prediction of neonatal respiratory distress syndrome. Fetal Diagn Ther 2 5 :392, 2009 Bolisetty S, Dhawan A, Abdel-Latif M, et al: I ntraventricular hemorrhage and neurodevelopmental outcomes in extreme preterm infants. Pediatrics 1 33 ( 1 ) : 5 5 , 20 1 4 Brion LP, Bell EF, Raghuveer TS: Vitamin E supplementation for prevention of morbidity and mortality in preterm infants. Cochrane Database Syst Rev 4: CD003665, 2003 Burd I, Balakrishnan B, Kannan S: Models of fetal brain injury, intrauterine inlammation, and preterm birth. Am J Reprod I mmunol 67(4) : 287, 20 1 2 Caplan MS, Fanarof A. Necrotizing enterocolitis: a historical perspective. Semin PerinatoI 4 1 (l ) : 2, 201 Centers for Disease Control and Prevention : Data and statistics for cerebral palsy. 20 1 6 . Available at: https:llwww.cdc.gov/ncbddd/cp/data.html. Octo­ ber 23, 20 1 7 Chau V , McFadden DE, Poskitt KJ, e t al: Chorioamnionitis i n the pathogen­ esis of brain injury in preterm infants. Clin PerinatoI 4 1 ( 1 ) : 83, 20 1 4 Clements JA, Platzker ACG , Tierney O F , e t al: Assessment o f the risk o f respi­ ratory distress syndrome by a rapid test for surfactant in amniotic fluid. N Engl J Med 286: 1 07 , 1 972 Cole FS, Alleyne C, Barks JD et al: N I H Consensus Development Conference statement: inhaled nitric-oxide therapy for premature infants. Pediatrics 1 27:363, 201 1 Cools F, Ofringa M, Askie LM: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants. Cochrane Database Syst Rev 3 :CDOOO 1 04, 20 1 5 Crowther CA, Crosby DO, Henderson-Smart OJ: Phenobarbital prior to pre­ term birth for preventing neonatal periventricular haemorrhage. Cochrane Database Syst Rev 1 :CDOOO 1 64, 20 1 Oa Crowther CA, Crosby DO, Henderson-Smart OJ: Vitamin K prior to preteI'm birth for preventing neonatal peri ventricular haemorrhage. Cochrane Data­ base Syst Rev 1 : CD000229, 20 1 0b Crowther CA, Doyle LW, Haslam RR, et al: Outcomes at 2 years of age after repeat doses of antenatal corticosteroids. N Engl J Med 357: 1 1 9, 2007 Darlow BA, Graham PJ, Rojas-Reyes MX: Vitamin A supplementation to pre­ vent mortality and short- and long-term morbidity in very low birth weight infants. Cochrane Database Syst Rev 8:CD00050 1, 20 1 6 Davidson LM, Berkelhamer S K: Bronchopulmonary dysplasia: chronic lung disease of infancy and long-term pulmonary outcomes. J Clin Med 6 ( 1 ) , 20 1 7 D e Luca AK, Nakazawa CY, Azevedo BC, e t al: Influence o f glycemic control on fetal lung maturity in gestations afected by diabetes or mild hyperglyce­ mia. Acta Obstet Gynecol Scand 8 8 (9) : 1 036, 2009 Doyle LW, Crowther CA, Middleton P, et al: Antenatal magnesium sulfate and neurologic outcome in preterm infants: a systematic review. Obstet Gynecol 1 1 3: 1 327, 2009 Doyle LW, Ehrenkranz A, Halliday HL: Early « 8 days) postnatal cortico­ steroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 5 : CDOO I 1 46, 20 1 4a Doyle LW, Ehrenkranz A, Hall iday HL: Late (> days) postnatal corticoste­ roids for chronic lung disease in preterm infants. Cochrane Database Syst Rev 5:CDOO I 1 45 , 20 1 4b Ferre C, Callaghan W, Olson C et al: Efects of maternal age and age-speciic preterm birth rates on overall preterm birth rates-United States, 2007 and 20 1 4 . MMWR 65 : 1 1 8 1 , 20 1 6 Fowlie PW, Davis PG, McGuire W : Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Data­ base Syst Rev 7:CD000 1 74, 20 1 0 Freeman JM, Nelson KB: Intrapartum asphyxia and cerebral palsy. Pediatrics 82:240, 1 988 Gl uck L, Kulovich MV: Lecithin-sphingomyel i n ratios in amniotic fl uid in normal and abno rmal p regnancy. Am J Obs tet G ynecol 1 1 5 : 5 3 9 , 1 973 Gluck L, Kulovich MV, Borer RC J r, et al: Diagnosis of the respiratory distress syndrome by amniocentesis. Am J Obstet Gynecol 1 09:440, 1 97 1

The P rete rm New born Gyami-Bannerman C, Thon EA, Blackwell Sc, et al: Antenatal betamethasone for women at risk for late preterm delivery. N Engl J Med 3 4( 1 4) : 1 3 1 1 , 20 1 6 Kair LR, Leonard DT, Anderson J M : Bronchopulmonary dysplasia. Pediatr Rev 33 (6) :255, 20 1 2 Karcher R , Sykes E , Batton D , e t al : Gestational age-speciic predicted risk of neonatal respiratory distress syndrome using lamellar body count and sur­ factant-to-albumin ratio in amniotic fluid. Am J Obstet Gynecol 1 93 : 1 680, 2005 Khwaja 0, Volpe JJ : Pathogenesis of cerebral white matter injury of prematu­ rity. Arch Dis Child Fetal Neonatal Ed 93(2) : F 1 53, 2008 Kribs A: Minimally invasive surfactant therapy and noninvasive respiratory support. Clin Perinatol 43 (4) : 5 5 , 20 1 6 Kwon SH, Vasung L, Ment L R e t al: The role o f neuroimaging i n predict­ ing neurodevelopmental outcomes of preterm neonates. Clin Perinatol 4 1 ( 1 ) :257, 20 1 4 Leviton A , Allred E N , Kuban KC, e t a l : Microbiologic and histologic char­ acteristics of the extremely preterm infant's placenta predict white matter damage and later cerebral palsy. The ELGAN study. Pediatr Res 67: 9 5 , 20 1 0 Liebowitz M , Clyman R: Antenatal betamethasone: a prolonged time interval from administration to delivery is associated with an increased incidence of intraventricular hemorrhage before 28 weeks gestation. J Pediatr 1 77: 1 1 4, 20 1 6 Mathews TJ, MacDorman M F : Infant mortality statistics from the 2009 period linked birth/infant death data set. Natl Vital Stat Rep 6 1 (8): 1 , 20 1 3 Matsuda T , Okuyama K , Cho K , e t al: Cerebral hemodynamics during the induction of antenatal periventricular leukomalacia by hemorrhagic hypo­ tension in chronically instrumented fetal sheep. Am J Obstet Gynecol 1 94: 1 057, 2006 McCrea HJ, Ment LR: he diagnosis, management, and postnatal preven­ tion of intravetricular hemorrhage in the preterm neonate. Clin Perinatol 3 5 (4):7 7, 2008 McCurnin DC, Pierce A, Chang LY, et al : Inhaled NO improves early pulmonary function and modifies lung growth and elastin deposition in a baboon model of neonatal chronic l ung disease. Am J Physiol Lung Cell Mol Physiol 288:L540, 2005 Ment LR, Aden U, Bauer CR, et al: Genes and environment in neonatal intra­ ventricular hemorrhage. Semin PerinatoI 39(8): 592, 20 1 6 Morley J, Davis PG, Doyle L W e t al: Nasal CPAP o r intubation a t birth for very preterm infants. N Engl J Med 358 :700, 2008 Moster D , Lie RT, Markestad T: Long-term medical and social consequences of preterm birth. N Engl J Med 359:262, 2008 Moya F, Sinha S , Gadzinowski j , et al: One year follow-up of very preterm infants who received lucinactat for prevention of respiratory distress syn­ drome: results from 2 multicenter randomized controlled trials. Pediatrics 1 1 9 (6) : e 1 36 1 , 2007 Mukerji A, Shah V, Shah PS: Periventricularlintraventricular hemorrhage and neurodevelopmental ourcomes: a meta-analysis. Pediatrics 1 36(6) : 1 1 32, 20 1 5 National Institutes o f Health: Antenatal corticosteroids revisited: repeat courses. NIH Consensus Statement 1 7(2) : 1 , 2000 National Institutes of Health: The efects of corticosteroids for fetal maturation on perinatal outcomes. NIH Consensus Statement 1 2 (2): 1 , 1 994 Nelson KB: Can we prevent cerebral palsy? N Engl J Med 349: 1 765, 2003 Neu j, Walker WA: Necrotizing enterocolitis. N Engl j Med 364:255, 20 1 0 Nores j , Roberts A , Carr S : Prenatal diagnosis and management o f fetuses with intracranial hemorrhage. Am j Obstet Gynecol 1 74:424, 1 996 O'Caliaghan ME, MacLennan AH , Gibson CS, et al: Epidemiologic associa­ tions with cerebral palsy. Obstet Gynecol 1 1 8: 576, 20 1 1 Papile LA, Burstein J , Burstein R, et al: Incidence and evolution of subependy­ mal and intraventricular hemorrhage: a study of infants with birth weights less than 1 500 gm. J Pediatr 92: 529, 19 8 Patra K, Wilson-Costello D, Taylor H G , et al: Grades I-II intraventricular hemorrhage in extremely low birth weight infants: efects on neurodevelop­ ment. J Pediatr 1 49: 1 69, 2006 Perlman ]M, Risser R, Broyles RS: Bilateral cystic leukomalacia in the prema­ ture infant: associated risk factors. Pediatrics 97:822, 1 996 Polin A, Carlo WA, Committee on Fetus and Newborn of the American Academy of Pediatrics: Surfactant replacement therapy for preterm and term neonates with respiratory distress. Pediatrics 1 33( 1 ) : 1 56, 20 1 4 Rabe H, Diaz-Rossello JL, Duley L, e t a l : Efect of timing of umbilical cord clamping and other strategies to influence placental transfusion at pre­ term birth on maternal and infant outcomes. Cochrane Database Syst Rev 8: CD003248 , 20 1 2 Redline RW: Placental pathology: a systematic approach with clinical correla­ tions. Placenta 22:S86, 2008 Rojas-Reyes MX, Morley CJ, Soli R: Prophylactic versus selective use of sur­ factant in preventing morbidity and mortality in preteI'm infants. Cochrane Database Syst Rev 3:CD000 5 1 0, 20 1 2

Rosen MG, Dickinson JC: he incidence of cerebral palsy. Am J Obstet Gyne­ col 1 67:4 1 7, 1 992 Sardesai S, Biniwale M, Wertheimer F, et al: Evolution of surfactant therapy for respiratory distress syndrome: past, present, and future. Pediatr Res 8 1 ( 1-2) : 240, 20 1 7 Sarkar S , Bhagat I , Dechert R, e t al: Severe intraventricular hemorrhage i n pre­ term infants: comparison of risk factors and short-term neonatal morbidities between grade 3 and grade 4 intraventricular hemorrhage. Am J Perinatol 26:4 1 9 , 2009 Schmidt B, Anderson Pj, Doyle LW, et al: Survival without disability to age 5 years after neonatal cafeine therapy for apnea of prematurity. JAMA 307(3) :275, 20 1 2 Schmidt B, Roberts RS, Anderson PJ, e t al: Academic performance, motor fu nction, and behavior 1 1 years after neonatal cafeine citrate therapy for apnea of prematuri ty: an I I -year follow-up of the CAP Randomized Clini­ cal Trial. JAMA Pediatr 1 1 (6) : 564, 20 1 7 Schmidt B , Roberts RS, Davis P , e t al: Cafeine therapy for apnea o f prematu­ rity. N Engl J Med 354 (20) : 2 1 1 2, 2006 Sharma M, VanderVeen D : Identiication and treatment of retinopathy of pre­ maturity: update 201 7. New Reviews 1 8 (2) :e8 5 , 20 1 7 Smit E , Odd D , Whitelaw A : Postnatal phenobarbital for the prevention of intraventricular haemorrhage in preteI'm infants. Cochrane Database SYSt Rev 8 : CDOO I 69 1 , 20 1 3 Soraisham AS, Singhal Nalini, McMillan D D , e t al: A multicenter study on the clinical outcome of chorioamnionitis in preterm infants. Am j Obstet Gynecol 200: 3 2.e 1 , 2009 Stoll Bj , Hansen NI, Bell EF et al: Neonatal outcomes of extremely pre­ term infants from the NICHD Neonatal Research Network. Pediatrics 1 26(3) :443, 20 1 0 SUPPORT Study Group o f the Eunice Kennedy Shriver NICHD Neonatal Research Network, Carlo WA, Finer NN, et al: Target ranges of oxygen saturation in extremely preterm infants. N Engl j Med 362(2 1 ) : 1 9 59, 2 0 1 0a SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Finer NN, Carlo WA, et al: Early CPAP versus sur­ factant in extremely preterm infants. N Engl j Med 3 62(2 1 ) : 1 970, 20 1 0b Tredano M, Griese M, De Blic J, et al: Analysis of 40 sporadic or familial neonatal and pediatric cases with severe unexplained respiratory distress: relationship to S FTPB. Am J Med Genet A 1 1 9 :324, 2003 Varner S , Sherman C, Lewis D et al: Amniocentesis for fetal lung maturity: will it become obsolete? Rev Obstet Gynecol 6(3/4): 1 26, 20 1 3 Verhagen EA, H ummel LA, Bos AF, e t al : Near-infrared spectroscopy t o detect absence of cerebrovascular autoregulation in p reteI'm infants. Clin Neuro­ physiol 1 2 5 ( 1 ) :47, 20 1 4 Volpe J J : Neurology of the Newborn, 5 th ed. Philadelphia, Saunders, 2 008 Wapner Rj , Sorokin Y, Mele L, et al: Long-term outcomes after repeated doses of antenatal corticosteroids. N Engl J Med 357: 1 1 90, 2007 Wapner RJ, Sorokin Y, Thom EA, et al: Single versus weekly courses of ante­ natal corticosteroids: evaluation of safety and eicacy. Am J Obstet Gynecol 1 9 5 :633, 2006 Wassink G , Davidson jO, Dhillon SK, et al: Partial white and grey matter pro­ tection with prolonged infusion of recombinant human erythropoietin after asphyxia in preterm fetal sheep. J Cereb Blood Flow Metab 37(3 ) : 1 080, 20 1 Watterberg KL, American Academy of Pediatrics Committee on Fetus and Newborn: Policy statement-postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia. Pediatrics 1 26(4) : 800, 20 1 0 Wei JC, Catalano R, Proit J , et al: Impact of antenatal steroids o n intraventricu­ lar hemorrhage in very-low-birth weight infants. j Perinatol 36(5) :352, 2 0 1 6 Weindling M: Periventricular haemorrhage and periventricular leukomalacia. BJOG 1 02(4) :278, 1 995 Wert SE, Whitsett JA, Nogee LM : Genetic disorders of surfactant dysfunction. Pediatr Dev Pathol 1 2(4) :253, 2009 Whitelaw A: Core concepts: intraventricular hemorrhage. NeoReviews 1 2(2) :e94, 20 1 1 Yoon B H , Kim Cj, Romero R, et al: Experimentally induced intrauterine infection causes fetal brain white matter lesions in rabbits. Am j Obstet Gynecol 1 77:797, 1 997a Yoon B H , Romero R, Kim CJ, et al: High expression of tumor necrosis factor­ alpha and interleukin-6 in periventricular leukomalacia. Am J Obstet Gyne­ col 1 77:406, 1 997b Yoon BH, Romero R, Park JS, et al: Fetal exposure to an intra-amniotic inflam­ mation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol 1 82:6 5 , 2000 Zalud I, Janas S: Risks of third trimester amniocentesis. J Reptod Med 5 3 ( 1 ):45, 2008 Zupan V, Gonzalez P, Lacaze-Masmonteil T, et al: Periventricular leukomala­ cia: risk factors revisited. Dev Med Child NeuroI 38: 1 06 1 , 1 996

643

644

C H A PT E R 3 5

St i l l birth

DEFIN ITION O F FETAL MORTALITY . . . . . . . . . . . . . . . . 645 CAUSES OF F ETAL DEATH . . . RISK FACTORS . . . . . . . .

.

.

.

.

. . . . . . . . . . . . . . . . . . . . 645

. . . . . . . . . . . . . . . . . . . . . . 646

EVALUATION OF TH E STI LLBORN F ETUS . . . . . . . . . . . . 646 PSYCHOLOGICAL ASPECTS . . . . . . . . . . . . . . . . . . . . . . . 648 PRIOR STILLBIRTH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648 CHANGES IN STI LLBI RTH RATES . . . . . . . . . . . . . . . . . . . 649

In the latter months ofpregnancy, the disappearance ofoe­ tal movements usualy directs the attention of the patient to the possibiliy ofoetal death. The diagnosis of this condi­ tion, however, can be considered absolute ony after repeated examinations, when one hasailed to hear theoetal heart or perceive the movements of the child. -J. Whitridge Williams ( 1 903)

his compilation was considered a call to action after the rec­ ognition that an estimated 2.65 million stillbirths occur each year and that 98 percent of stillborn fetuses are from low- and middle-income countries ( The Lanceis Stillbirth Series Steering Committee, 20 1 l a-). Unfortunately, progress in improving these rates has been slow, as outlined in The Lancet's subsequent five-part progress report, which emphasized the need for dedi­ cated leadership, measured efects of interventions, and inves­ tigation into knowledge gaps ( The Lancets Ending Preventable Stillbirths Series Study Group, 20 l 6a-e) . In the United States, an estimated 1 million fetal losses are reported each year, and most occur before 20 weeks' ges­ tation. Fetal mortality data from the National Vital Statistics system are usually presented for fetal deaths after the 20-week threshold (MacDorman, 20 1 5) . Using this definition, numbers of fetal deaths in the United States in 20 1 3 slightly surpassed numbers of infant deaths (Fig. 35- 1 ) . As shown in Figure 35-2, Fetal deaths

Infant deaths

Under age 28 days

33.8%

In Williams' time, absolute documentation of fetal death was frustrating for both patient and obstetrician. Now, sonography provides prompt conirmation, which allows expedient induc­ tion of labor and delivery. However, epidemiologically, defin­ ing and reporting fetal deaths was-and continues to be-a challenge. In response, eforts to standardize the deinition of stillbirth and analyze varying reports for application into clini­ cal practice and public health policy are now being empha­ sized. Moreover, stillbirth research and prevention within the United States and abroad has expanded. Global public health eforts were stimulated in part by a six-part series in The Lancet.

24.9%

1 6. 1 %

FI G U RE 35- 1 Percent d i stribution o f feta l deaths a t 2 0 weeks' gestation or more and of i nfa nt deaths: U n ited States, 201 3 . (Data from MacDorma n M F, Reddy U M, Si lver RM: Trends in sti l l b i rth by gestation a l age in the U n ited States, 2006-2 0 1 2, O bstet Gynecol . 201 5 Dec; 1 26(6): 1 1 46- 1 1 50.)

Sti l l b i rth 0.7 0.6 0.5

�

)

0.4

: 0.3

0.2 0. 1 0.0

.1 -" -.... . -_.. .. . .. -1 .... .. . .. . -. .. ". 1

20

24

36 28 32 Gestational age (weeks)

40

FIGURE 35-2 Prospective feta l morta l ity rate per 1 000 births by weeks of gestation: U n ited States, 20 1 3. (Redrawn from MacDorman MF, Reddy UM, Silver RM: Trends i n sti l l birth by gestation a l age in the U n ited States, 2006-20 1 2, Obstet Gynecol. 20 1 5 Dec; 1 26(6): 1 1 46- 1 1 50.)

fetal death rates are highest at the earliest and latest gestational ages, which suggests etiological diferences.

DEF I N ITION OF FETAL MORTALITY he current definition of fetal death adopted by the Cen­ ters for Disease Control and Prevention National Center for Health Statistics is based on a deinition recommended by the World Health Organization (MacDorman, 20 1 5) . It states that "Fetal death means death prior to complete expulsion or extraction .rom the mother of a product of human conception irrespective of the duration of pregnancy and which is not an induced termination ofpregnancy. The death is indicated by the act that after such expulsion or extraction, the etus does not breathe or show any other evidence of lie such as beating of the heart, pulsation of the umbilical cor, or deinite movement of voluntary m uscles. Heartbeats are to be distinguishedrom tran­ sient cardiac contractions; respirations are to be distinguished .rom fleeting respiratory eorts or gasps. " Reporting requirements for fetal deaths in the United States are determined by each state, and thus, criteria difer signii­ cantly (Chap. 1 , p. 3) . Most states mandate reporting of deaths of fetuses that are 20 weeks' gestation or older or have a mini­ mum birthweight of 350 g (roughly equivalent to 20 weeks) or some combination of these two. However, several states require reporting of fetal deaths at all periods of gestation, and one sets the threshold at 16 weeks. lternatively, two states require reporting of deaths for fetuses with birthweights of 500 g, which approximates that at 22 weeks. here is substantial evidence that not all fetal deaths for which reporting is required are actually recorded (MacDorman, 20 1 5) . This is most likely for those at earlier gestational ages. Comparisons of rates among countries are limited by incomplete fetal death data. Namely, internationally, less than 5 percent of neonatal deaths have formalized docu­ mentation ( The Lancet's Ending Preventable Stillbirths Series Study Group, 20 1 6d) . Further, comparative analyses using birthweight versus gestational age among countries do not provide equivalent results. For example, in the United States, if stillbirth would be deined by a birthweight � 500 g, the stillbirth rate would be reduced by 40 percent compared with

2000

2005

201 0

201 3

F I G U R E 35-3 Feta l morta l ity rates by period of g estation: U n ited States, 2000-20 1 3. (Data from MacDorm a n M F, Reddy UM, S i l ver RM: Trends in sti l l b i rth by gestational age in the U n ited States, 2006-20 1 2, O bstet Gynecol . 201 5 Dec; 1 26(6): 1 1 46- 1 1 50.)

a 22-week-age deined cohort (Blencowe, 20 1 6) . To address nomenclature diferences, some have called for changes to the current deini tion a oseph, 20 1 5 ) . Overall, fetal mortality rates i n the United States have remained relatively unchanged since 2006. However, the infant mortality rate has declined 1 1 percent, and both rates are now essentially equal (MacDorman, 20 1 5) . Three fetal mortality epochs are gen­ erally described: early (less than 20 completed weeks' gestation); intermediate (20 to 27 weeks) ; and late (28 weeks or more) . The fetal mortality rate at 20 to 27 weeks in 20 1 3 declined 3 percent from the prior year. Between 2006 and 20 1 2, rates were essen­ tially unchanged in this age group. The late fetal mortality rate has been relatively unchanged since 2006 (Fig. 3 5-3) .

CAUSES O F FETAL DEATH The Eunice Kennedy Shriver National I nstitute of Child Health and Human Development (NICHD) created the Stillbirth Collaborative Research Network to ascertain stillbirth causes in racially and geographically diverse populations in the United States. From this, the Stillbirth Collaborative Research Net­ work Writing Group (20 1 1 b) examined reasons for death at 20 weeks' gestation or later between 2006 and 2008 in 59 ter­ tiary care and community hospitals in ive states. Standardized evaluations included autopsy, placental histology, and testing of maternal or fetal bloodltissues, including fetal karyotyping. Evaluations were performed in 5 00 women with 5 1 2 stillbirths. Of these losses, 83 percent were before labor. Causes of still­ birth were divided into eight categories shown in Table 3 5 - 1 . hese categories were then classified as probable, possible, or unknown. As an example, diabetes was considered a probable cause if the fetus had diabetic embryopathy with lethal anoma­ lies or the mother had diabetic ketoacidosis. It was a possible cause if the mother had poor glycemic control and the fetus had abnormal growth. Overal, a probable or possible source was identiied in 76percent ofcases. This Network study is unprecedented in the United S tates for several reasons. It was a population-based cohort of

645

646

The N ewborn

TABLE 35-1 . Ca u ses of 5 1 2 Sti l l bi rths i n the Sti l l b i rth Col la borative Research Network Study Cause Obstetrical com p l i catio n s P la cental a bn o r m a l ities Feta l ma lformations I nfection U m bi l ical cord a bn o r m a l ities H ype rte n s ive d i so rd e rs Med i ca l com p l i cations U ndeterm i n ed

Percent 29 24 14 13 10 9 8 24

Examples A b r u ption, m u ltifeta l g estati on, ru ptu red m e m branes at 20-24 weeks U te r o p l acental i n s ufficiency, maternal vascu l a r d i sorders Major structural a bnorma l ities and/or genetic abnormalities I nvolvi n g the fetu s or pl acenta P rola pse, strictu re, t h ro m bosis P reec l a m ps i a, c h ro n ic hyperte n s i o n D i a b etes, a nti phosph o l i pid a nti body syn d ro m e N o t a p p l icable

Percentages a re ro u n ded a n d tota l more tha n 1 00 p e rcent beca use so me sti l l bi rths had more t h a n one ca use. Overa l l , a ca use was i d e ntified i n 76 percent of sti l l b i rth s. Data from Sti l l b i rth Col l a bo rative Resea r c h N etwork Writi ng G ro u p, 20 1 1 b.

stillbirths, in which all underwent systematic and thorough evaluation. Each assigned cause of fetal death is reasonably straightforward and comprehensible except for "placental abnormalities. " This category contains "uteroplacental insuf­ ficiency" and a few other less clearly defined placental entities. his aside, the leading reasons for fetal death were obstetrical and primarily included abruption, multifetal gestation compli­ cations, and spontaneous labor or ruptured membranes before viability. Importantly, this study illustrated that systematic evaluation may identiy a likely cause in approximately three fourths of stillbirths. his rate is considerably higher than those in most prior analyses and serves to emphasize the importance of careful examination.

RISK FACTORS Many factors are associated with an increased risk of stillbirth. Among others, these include advanced maternal age; African­ American race; smoking; illicit drug use; maternal medical diseases-such as overt. diabetes or chronic hypertension; assisted reproductive technology; nulliparity; obesity; and prior adverse pregnancy outcomes-such as prior preterm birth or growth-restricted newborn (Reddy, 20 1 0; Varner, 20 1 4) . Two major studies have assessed whether stillbirth risk factors could be identiied either before or shortly after preg­ nancy confirmation. In the first, Reddy and colleagues (20 1 0) analyzed data from the NICHD Consortium on Safe Labor. Briely, the pregnancy outcomes of 206,969 women delivered between 2002 and 2008 at 1 9 hospitals in the United States were analyzed. When the distribution of stillbirths according to gestational age was studied, the tragedy of stillbirth occurred primarily in term pregnancies. hese investigators concluded that their results did not support routine antenatal surveillance for any demographic risk factors. The second analysis of stillbirth risk factors was included in the Stillbirth Collaborative Research Network study described earlier. he validity of stillbirth prediction was assessed based on risks identifi e d in early pregnancy. Th e y found that preg­ nancy factors known at the start of pregnancy accounted for only a small proportion of stillbirth risk. Except for prior stillbirth or pregnancy loss from causes such as preterm birth

or fetal-growth restriction, other risks had limited predictive value (Stillbirth Collaborative Research Network Writing Group, 20 1 1 a) . he importance of prior stillbirth as a risk for recurrence has been emphasized by Sharma and associ­ ates (2006) . Specifi c ally, the stillbirth risk was ivefold higher in women with a prior stillbirth. From another report, prior preterm birth, fetal-growth restriction, preeclampsia, and pla­ cental abruption were strongly associated with subsequent stillbirth (Rasmussen, 2009) . Table 3 5-2 lists estimates of stillbirth risk according to maternal factors.

EVALUATION OF TH E STI LLBORN FETUS Determining the cause of fetal death aids maternal coping, helps assuage any perceived guilt, permits more accurate coun­ seling regarding recurrence risk, and may prompt therapy or intervention to prevent a similar outcome in subsequent preg­ nancies (American College of Obstetricians and Gynecologists, 20 1 6a) . Identification of inherited syndromes also provides useful information for other family members. • Clinical Examination

Important tests in stillbirth evaluation are neonatal autopsy, chromosomal analysis, and examination of the placenta, cord, and chorioamnionic membranes (Pinar, 20 1 4) . Page and coworkers (20 1 7) found placental pathology and fetal autopsy to be the most useful. One algorithm from the American Col­ lege of Obstetricians and Gynecologists (20 1 6a) is shown in Figure 3 5-4. Findings are documented in the medical record, and relevant prenatal events are delineated. Photographs are taken whenever possible, and a full radiograph of the fetus­ a etogram-may be performed. Postnatal magnetic resonance (MR) imaging or sonography may be especially important in providing anatomical information if parents decline a full autopsy (McPherson, 20 1 7; Shruthi, 20 1 7) . • Laboratory Eva luation

If autopsy and chromosomal studies are performed, up to 35 percent of stillborn fetuses are discovered to have major

Sti l l b i rth

TABLE 35-2. Estimated Maternal Risk Factors a n d of S t i l l b i rt h

Condition

Risk

Estimated Rate of Stil l birth ( per 1 000 births)

ORa

6.4 4.0-5.5

1 .0 0.86

6-25

1 .5-2.7

9-5 1 1 2-29

1 .2-4.0 1 .8-4.4

6- 1 0 6-35 40- 1 5 0 1 5-200 1 2-20 1 8-40 1 2-30 1 0- 1 5

1 .2-2.2 1 . 7 -7.0 6-20 2.2-30 2 .2-3 .0 2 .8-5 .0 1 .8-4.4 1 .7-3.0

1 2- 1 5 1 3- 1 8 1 0- 1 3

1 .9-2 . 7 2. 1 -2.8 1 .6-2.0

1 2-30 9-20

2-4.6 1 .4-3 .2

12 34

1 .0-2.8 2 .8-3 . 7

1 1 -1 4 1 1 -2 1 1 2- 1 4

1 .8-2.2 1 .8-3 . 3 2 .0-2.2

A l l p reg n a n c i es Low- r i s k p reg na ncies Hype rte n s ive d i sorders C h ronic hypertension PIH Mild Severe Dia betes D i et a l o n e I n s u l i n + d iet SLE Ren a l d i sease Thyroi d d i sease Th rom bo p h i l ia Chol estasis of preg n a n cy S m o k i n g > 1 0 ciga rettes O bes ity B M I 2 5-29.9 kg/m 2 B M I > 30 Education « 1 2 yr vs ::1 2 yr) Prior I UG R « 1 0%) Prior sti l l bi rth M u ltifeta l g e statio n Twi n s Tri p l ets Mate r n a l age 3 5-39 yr ::4 0 yr Black wo m e n com pared with wh ite wom e n

aOdd s ratio of the factor being present compared with the risk factor bei n g a bsent. body mass i ndex; I U G R i ntra u te r i n e g rowth BMI restriction; P I H = preg n a n cy-i n d uced hypertension; SLE = syste m i c l u pus e rythem atosus. Ada pted from F retts, 2005. =

=

structural anomalies (Faye-Petersen, 1 999) . Approximately 20 percent have dysmorphic features or skeletal anomalies, and 8 percent have chromosomal abnormalities (Pauli, 1 994; Saller, 1 995) . In the absence of anatomic dysmorphology, up to 5 per­ cent of stillborn fetuses will have a chromosomal abnormality (Korteweg, 2008) . Although the American College of Obste­ tricians and Gynecologists (20 1 6a) previously recommended karyotyping all stillborn fetuses, technological advancements of high-resolution, whole-genome sequencing-such as with chro­ mosomal microarray anaysis ()-are now replacing stan­ dard karyotyping for chromosomal analysis of stillborn fetuses

I nspect fetus a n d placenta:

Weight, head circumference, and length of fetus Weight of placenta Photographs of fetus and placenta Frontal and profile photographs of whole body, face, extremities, palms, and any abnormalities Document finding and abnormalities Obtain consent from parents for cytologic specimens:

Obtain cytologic specimens with sterile techniques and instruments Acceptable cytologic specimens (at least one) - Amniotic fluid obtained by amniocentesis at time of prenatal diagnosis of demise: paticularly valuable if delivery is not expected imminently - Placental block (1 x 1 ) cm taken from below the cord insertion site on the unfixed placenta - Umbilical cord segment (1 .5 cm) - Internal fetal tissue specimen, such as costochondral junction or patella; skin is not recommended Place specimens in a sterile tissue culture medium of lactated Ringer's solution and keep at room temperature when transported to cytology laboratory Obta i n parental consent for fetal autopsy

Fetal autopsy and placental pathology (may include fetal whole-body X-ray)

)

If no consent is given for autopsy, send placenta alone for pathology

F I G U R E 3 5-4 F l ow c h a rt for fetal a nd p l a ce nta l eva l u ation. (Mod ified with perm ission from ACOG P ractice B u l leti n No. 1 02: management of stil l birth, Obstet Gyneco l . 2009 M a r; 1 1 3 (3):748-761 .)

(Chap. 1 3, p. 27 1 ) . CMA does not require dividing cells and is reported to be more useful in the evaluation of fetal death. his is especially true because the culturing of macerated fetal tissue is frequently unsuccessful (Reddy, 20 1 2) . Both the American College of Obstetricians and Gynecologists (20 1 6c) and the Society for Maternal-Fetal Medicine (20 1 6) now endorse the use of CMA for stillborn fetuses. Appropriate consent must be obtained to take fetal samples, including tissue or luid obtained postmortem by needle aspira­ tion. As recently outlined by the American College of Obstetri­ cians and Gynecologists (20 1 6c) , any type of fetal or placental tissue or amnionic fluid can be submitted for genetic testing by CMA. Contamination with maternal tissue or blood is ideally avoided. If fetal blood cannot be obtained from the umbilical cord or by cardiac puncture, the American College of Obstetri­ cians and Gynecologists (20 1 6a) recommends at least one of the following samples: ( 1 ) a placental block measuring about 1 X 1 cm taken below the cord insertion site in the unfixed specimen; (2) umbilical cord segment approximately 1 . 5 cm long; or (3) internal fetal tissue specimen such as costochondral junction or patella. Tissue is washed with sterile saline before

647

648

The Newborn

being placed in lactated Ringer solution or sterile cytogenetic medium. Notably, placement in formalin or alcohol kills viable cells. If conventional karyotyping is the only test available and the timing of death is recent, amnionic luid can be obtained by amniocentesis, as those cells obtained in a sterile fashion provide a greater likelihood of cell growth and eventual result compared with tissue obtained after delivery. Maternal blood is obtained for Kleihauer-Betke staining; for antiphospholipid antibody and lupus anticoagulant testing if indicated; and for serum glucose measutement to exclude overt diabetes (Silver, 20 l 3) . I n cases with signifi c ant growth restriction, with a fam­ ily or personal history of thrombosis, or with severe placental pathology, testing for factor V Leiden mutation, prothrombin mutation, antithrombin level, and protein C and S activity may provide some information that could afect future pregnancy management (American College of Obstetricians and Gynecol­ ogists, 20 1 6a) . Our interpretation of relevant placental pathol­ ogy includes derangements that stem from maternal vessel obstruction, which are described in Chapter 6. Although some have recommended routine evaluation of heritable thrombo­ philias, no evidence supports the clinical or financial eiciency of screening in an unselected population. Silver and colleagues (20 1 6) , with data from the Stillbirth Collaborative Research Network, found that most maternal and fetal thrombophilias were not associated with stillbirth and recommended against routine testing. • Autopsy

Parents are ofered and encouraged to allow a full autopsy. That said, valuable information can still be obtained from limited studies. Pinar and coworkers (20 1 2) described the autopsy pro­ tocol used by the Stillbirth Collaborative Research Network. As an alternative, gross external examination combined with photography, radiography, MR imaging, bacterial cultures, and selective use of chromosomal and histopathological studies often aids determination. A complete autopsy is more likely to yield valuable data. An analysis of 400 consecutive fetal deaths in Wales showed that autopsy altered the presumed cause of death in 1 3 percent and provided new information in another 26 percent (Cartlidge, 1 995). Other investigators have found that autopsy results changed the recurrence risk estimates and parental counseling in 25 to 50 percent of cases (Faye-Petersen, 1 999; Silver, 2007) . For example, Miller and associates (20 1 6) recently demon­ strated that placental examination with autopsy altered future medical management in 45 percent of cases. According to the survey by Goldenberg and coworkers (20 1 3) , most hospitals do not audit stillbirths. In other centers, however, maternal records and autopsy findings are reviewed on a monthly basis by a stillbirth committee composed of obstetricians, maternal-fetal medicine specialists, neonatolo­ gists, clinical geneticists, and perinatal pathologists. If possible, the cause of death is assigned based on available evidence. Most importantly, parents are then contacted and ofered counseling regarding the reason for the death, the potential recurrence risk, and possible strategies to avoid recurrence.

PSYCHOLOGICAL ASPECTS Fetal death is psychologically traumatic for a woman and her family. Further stressors are an interval of more than 24 hours between the diagnosis of fetal death and labor induction, not seeing her infant for as long as she desires, having no tokens of remembrance, and poor communication (Radestad, 1 996; Siassakos, 20 1 7) . The importance of seeing and holding a still­ born fetus for parental psychological well-being was recently summarized by Kingdon and colleagues (20 1 5) . As discussed in Chapter 6 1 (p. 1 1 76) , a woman experiencing a stillbirth or early miscarriage is at increased risk for depression and should be closely monitored (Nelson, 20 1 3) . Nuzum and coworkers (20 1 4) reported that few obstetrical providers receive formal training in perinatal bereavement care. At Parkland Hospital, this care includes time with the infant, keepsake items, photographs, chaplaincy consultation, and bereavement support information. Care is coordinated through a dedicated nursing team ailiated with labor and delivery.

PRIOR STI LLBIRTH Table 35-3 lists an outlined approach for women with prior still­ birth. Importantly, these recommendations are based primarily on limited or inconsistent scientiic evidence or on expert opin­ ions. Unfortunately, few studies address management of afected women. Those with modiiable risk factors for stillbirth, such as hypertension or diabetes, warrant speciic prevention strategies. Given that obesity has been identiied as a risk factor for stillbirth and other obstetrical complications, preconceptional weight loss would seem prudent. Logically, women with a prior fetal death due to placental vascular events, that is, placental insuiciency, are also at increased risk for subsequent adverse perinatal out­ comes (Monari, 20 1 6) . According to Reddy (2007) , because almost half of fetal deaths are associated with growth restriction, fetal sonographic anatomical assessment beginning at midpreg­ nancy is recommended. his is followed by serial growth studies beginning at 28 weeks. Supplementation with vitamin C or E in pregnancy has not been demonstrated to reduce the risk of fetal death (Rumbold, 20 1 5a,b) . Weeks and associates ( 1 995) evaluated fetal biophysical test­ ing in 300 women whose only indication was prior stillbirth. There was one subsequent stillbirth, and only three fetuses had abnormal testing results before 32 weeks. Notably, no relation­ ship was found between the gestational age of the previous still­ born fetus and the incidence or timing of abnormal test results or fetal jeopardy in the subsequent pregnancy. These investigators concluded that antepartum surveillance should begin at 32 weeks or later in the otherwise healthy woman with a history of still­ birth. This recommendation is supported by the American Col­ lege of Obstetricians and Gynecologists (20 1 6a) with the caveat that it increases the iatrogenic preterm delivery rate. Although fetal movement counting strategies are routinely employed as described in Chapter 1 7 (p. 332) , few data guide its use in clini­ cal practice for those with a prior stillbirth (Mangesi, 20 1 5) . Delivery a t 39 weeks' gestation i s recommended. Labor induction is suitable, and cesarean delivery is elected for those with a contraindication to induction. his timing minimizes

Sti l l b i rth

TABLE 35-3. Ma nagement of S u bseq uent Preg nancy after Sti l l bi rth Preconceptional or I n itial Prenatal Visit Deta i l ed medical and obstetrica l h i story Review eva l uation of prior sti l l bi rth Dete r m i nation of rec u rrence risk Discuss recu rre nce of comorbid o bstetric co m p l i cations Smoking cessation P reconcept i o n a l we i g ht loss in o bese wo men Genetic cou nse l i ng if fa m i ly g e n etic cond ition exi sts Dia betes screen Th rombop h i l ia scree n : a nti phos p h o l i pid a nti bod ies (o nly if h i story i n d i cates) S u p port and reass u ra nce First Trimester Dat i n g sonog ra p hy F i rst-tri meste r screen : p reg n a n cy-a ssoci ated plasma prote i n A, h u ma n chori o n i c gonadotropin, and n u c h a l tra n s l ucenc/ S u p port a n d reass ura nce Second Trimester Feta l sonog ra p h ic a nato m i c a l s u rvey at 1 8-20 weeks' g estation Materna l ser u m scree n i n g (q u a d ru ple) or s i n g l e-ma rker a l p h a fetop rotei n if fi rst-t r i mester scree n i n g el ecteda Pos s i b l e uteri n e a rtery Dopp l e r stud ies at 2 2-24 weeks' gestationa S u pport a n d reass u ra nce Th i rd Trimester Sonog ra p h i c scree n i n g for feta l -g rowth restriction, sta rt i n g at 28 wee ks Kic k cou nts sta rt i n g at 28 weeks Ante part u m feta l s u rvei l la nce sta rti n g at 32 weeks or 1 -2 weeks earl ier than prior sti l l b i rth S u p port and reassura nce Del ivery Elective i n d u ction at 39 wee ks Del i ve ry before 39 wee ks on ly with docu mented fetal l u ng matu rity by a m n i ocentes i s aprovides risk modifi cation but d oes n o t a lter ma nagement. Mod ified fro m Red dy, 2007.

fetal mortality rates, although the degree of risk reduction may be greater for older women (Page, 20 1 3) .

CHANGES I N STI LLBI RTH RATES Following declines between 2000 and 2006, the United States fetal mortality rate has been relatively unchanged since 2006 (MacDorman, 20 1 5) . Interpretation of these fetal mortality rates in the context of changing national healthcare strategies has spawned considerable debate. One example is the efort to prevent non-medically indicated deliveries before 39 weeks

and its subsequent efect on term stillbirth rates. he value of this practice for neonatal outcome is described in Chapter 26 (p. 504) . To analyze whether implementation of this "39week rule" has altered the term stillbirth rate, Nicholson and coworkers (20 1 6) examined data from 45 states and the Dis­ trict of Columbia during a 7-year period. The proportion of births before 39 weeks progressively declined from 2007 and 20 1 3, but the term stillbirth rate rose. his suggested that the 39-week rule may cause unintended harm. MacDorman and associates (20 1 5) also evaluated trends in stillbirth rates by gestational ages in the United States between 2006 and 20 1 2. They used a "traditional stillbirth rate, " which was calculated using a denominator composed of the live-birth number plus the stillbirth number at a given gestational age. They found increased rates at 24 to 27, 34 to 36, and 38 weeks' gesta­ tion. Alternatively, no diferences were found in "prospective stillbirth rates. " These rates were calculated using a denomi­ nator composed of the number of women who are pregnant at a given gestational age for weeks 2 1 through 42. he dis­ crepancies in stillbirth rates appear to be primarily due to the decline in the number of births in the preterm and early-term gestational ages. To summarize, implementation of the 39-week rule has reduced the number of elective births before 39 weeks' gesta­ tion, although an unintended consequence may be an increase in term stillbirths-especially among women with medical complications. he importance of induction at less than 39 weeks in pregnant women with complications to prevent still­ birth is underscored by Little and colleagues (20 1 5) . These authors performed a retrospective multistate analysis of early­ 6 term deliveries (37°/7 to 38 /7 weeks) from 2005 to 20 1 1 . They noted a decline in the number of early-term deliveries during this time but not a signiicant change in the term stillbirth rates. There was, however, a 25-percent rise in the rate of term, singleton stillbirths among women with diabetes, and this was attributed to clinicians misapplying early-term delivery policies to high-risk women. Undoubtedly, continued surveillance of stillbirth rates is warranted for both high- and low-risk preg­ nancies at a state and national level.

REFERENCES American College of Obstetricians a n d Gynecologists: Management of still­ birth. Practice Bulletin No. 1 02, March 2009, Reairmed 20 1 6a American College of Obstetricians and Gynecologists: M icroarrays and next-gen­ eration sequencing technology: the use of advanced genetic diagnostic tools in obstetrics and gynecology. Committee Opinion No. 682, December 20 1 6b American College of Obstetricians and Gynecologists: Prenatal diagnostic test­ ing for genetic disorders. Practice Bulletin No. 1 62 , May 20 1 6c Blencowe H, Cousens 5, Bianchi JF, et al: National, regional, and worldwide estimates of stillbirth rates in 20 1 5 , wi th trends from 2000: a systematic analysis. Lancet Glob Health 4(2):e98, 20 1 6 Cartlidge P H , Stewart J H : Efect o f changing the stillbirth deinition o n evalu­ ation of perinatal mortality rates. Lancet 346:486, 1 99 5 Faye-Petersen O M , Guinn DA, Wenstrom K D : Value of perinatal autopsy. Obstet Gynecol 94(6) : 9 1 5, 1 999 FrettS RC: Etiology and prevention of stillbirth. Am J Obstet Gynecol 1 93 (6) : 1 923, 2005 Goldenberg L, Farrow V, McClure EM, et l: Stillbirth: knowledge and prac­ tice among U.S. obstetrician-gynecologists. Am J Perinatol 30(l 0):8 1 3 , 20 1 3 Joseph KS, Kinniburgh B , Hutcheon JA, e t al: Rationalizing deinitions and procedures for optimizing clinical care and public health in fetal death and stillbirth . Obstet GynecoI 1 2 5 (4) :784, 20 1 5

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The Newborn Kingdon C, Givens JL, O'Donnell E, et al: Seeing and holding Baby: system­ atic review of clinical management and parental outcomes ater stillbirth. B irth 42(3) : 206, 20 1 5 Korteweg FJ, Bouman K, Erwich J , e t al: Cytogenetic analysis after evaluation of 750 fetal deaths. Obstet Gynecol 1 1 1 :865, 2008 Little SE, Zera CA, Clapp A , et al: A multi-state analysis of early-term delivery trends and the association with term stillbirth. Obstet Gynecol 1 26 (6) : 1 1 3 8, 20 1 5 MacDorman M F , Gregory EC: Fetal and perinatal mortaliry, United States, 20 1 3 . Natl Vital Stat Rep 64(8) : 1 , 20 1 5 MacDorman MF, Reddy UM, Silver M : Trends i n stillbirth by gestational age in the United States, 2006-20 1 2 . Obstet GynecoI 1 26(6): 1 1 46, 20 1 5 Mangesi L, Hofmeyr GJ, Smith V, et al: Fetal movement counting for assess­ ment of fetal wellbeing. Cochrane Database Syst Rev 1 O:CD004909, 20 1 5 McPherson E, Nestoridi E, Heinke D , et al: Alternatives to autopsy for fetl and early neonatal (perinatal) deaths: insights from the Wisconsin stillbirth ser­ vice program. Birth Defects Res September 1 2, 20 1 7 [Epub ahead of print] Miller ES, Minturn L, Linn R, et al: Stillbirth evaluation: a stepwise assessment of placental pathology and autopsy. Am J Obstet Gynecol 2 1 4: 1 1 5 , 20 1 6 Monari F , Pedrielli G , Vergani P , e t al: Adverse perinatal outcome i n subse­ quent pregnancy after stillbirth by placental vascular disorders. PLoS One 1 1 (5):e0 1 5576 1 , 20 1 6 Nelson D B , Freeman MP, Johnson N L, e t al: A prospective study o f post­ partum depression in 1 7,648 parturients. J Matern Fetal Neonatal Med 26( 1 2) : 1 1 5 5 , 20 1 3 Nicholson JM, Kellar LC, Ahmad S , e t al: U S term stillbirth rates and the 39-week rule: a cause for concern? Am J Obstet Gynecol 2 1 4:62 1 , 20 1 6 Nuzum D , Meaney S , O'Donoghue K : h e impact o f stillbirth on consultant obstetrician gynaecologists: a qualitative study. BJOG 1 2 1 : 1 020, 20 1 4 Page JM, Christiansen-Lindquist L , horsten V , e t al: Diagnostic Tests for Evaluation of Stillbirth: Results From the Stillbirth Collaborative Research Network. Obstet Gynecol 1 29 (4):699, 20 1 7 Page JM, Snowden JM, Cheng W, e t al: h e risk o f stillbirth and infant death by each additional week of expectant management stratiied by maternal age. Am J Obstet GynecoI 209(4) :375.e 1 , 20 1 3 Pauli M , Reiser CA: Wisconsin Stillbirth Service Program: I I . Analysis of diagnoses and diagnostic categories in the irst 1 ,000 referrals. Am J Med Genet 50: 1 3 5 , 1 994 Pinar H, Goldenberg L, Koch MA, et al: Placental indings in singleton still­ births. Obstet Gynecol 1 23:325, 20 1 4 Pinar H , Koch A, Hawkins H , e t al: The stillbirth collaborative research network postmortem examination protocol. Am J Perinatol 29: 1 87, 20 1 2 Radestad I , Steineck G , Nordin C, et al: Psychological complications after stillbirth-influence of memories and immediate management: population based study. BMJ 3 1 2 : 1 5 05, 1 996 Rasmussen S, Irgens LM, Skjaerven R, et al: Prior adverse pregnancy outcome and the risk of stillbirth. Obstet Gynecol 1 1 4(6) : 1 2 59, 2009 Reddy UM: Prediction and prevention of recurrent stillbirth. Obstet Gynecol 1 1 0 : 1 1 5 1 , 2007 Reddy UM, Laughon SK, Sun L, et al: Prepregnancy risk factors for antepar­ tum stillbirth in the United States. Obstet Gynecol 1 1 6: 1 1 1 9, 20 1 0 Reddy UM, Page GP, Saade G R, e t al: Karyotype versus microarray testing for genetic abnormalities after stillbirth. N Engl J Med 367(23) :2 1 8 5 , 20 1 2 Rumbold A , Ota E , Hori H , e t al: Vitamin E supplementation i n pregnancy. Cochrane Database Syst Rev 9:CD004069, 20 1 5a

Rumbold A, Ota E, Nagata C, et al: Vitamin C supplementation in pregnancy. Cochrane Database Syst Rev 9: CD004072, 20 1 5b Saller DN Jr, Lesser KB, Harrel U, et al: he clinical utility of the perinatal autopsy. JAMA 273:663, 1 995 Sharma PP, Salihu HM, Oyelese Y, et al: Is race a determinant of stillbirth recurrence? Obstet Gynecol 1 07 (2 Pt 1 ) :39 1 , 2006 Shruthi M, Gupta N , Jana M, et al: Comparative study of conventional and virtual autopsy using postmortem MRI in the phenotypic characterization of stillbirths and malformed fetuses. Ultrasound Obstet Gynecol March 1 3, 20 1 7 [Epub ahead of print] Siassakos D , Jackson S, Gleeson K, et al: ll bereaved parents are entitled to good care after stillbirth: a mixed-methods multicentre study (INSIGHT) . BJOG J uly 3 1 , 20 1 7 [Epub ahead of print] Silver M: Fetal death. Obstet Gynecol 1 09: 1 53, 2007 Silver RM, Parker CB, Reddy UM, et al: Antiphospholipid antibodies i n still­ birth. Obstet GynecoI 1 22 (3) :64 1 , 20 1 3 Silver R M , Saade GR, Thorsten V , et al: Factor V Leiden prothrombin G202 1 0A, and methylene tetrahydrofolate reductase mutations and still­ birth: the Stillbirth Collaborative Research Network. Am J Obstet Gynecol 2 1 5 :468, 20 1 6 Society for Maternal-Fetal Medicine: h e use o f chromosomal micro array for prenatal diagnosis. Sociery for Maternal-Fetal Medicine (SMFM) Consult Series No. 4 1 , October 20 1 6 Stillbirth Collaborative Research Network Writing Group: Association between stillbirth and risk factors known at pregnancy conirmation. JAMA 306(22) :2469, 20 1 1 a Stillbirth Collaborative Research Network Writing Group: Causes of death among stillbirths. JAMA 306(22) :2459, 20 1 1 b The Lancet's Ending Preventable Stillbirths Series Study Group: Stillbirths: eco­ nomic and psychosocial consequences. Lancet 387:604, 20 1 6a The Lancet's Ending Preventable Stillbirths Series Study Group: Stillbirths: ending preventable deaths by 2030. Lancet 387:703, 20 1 6b The Lancet's Ending Preventable Stillbirths Series Study Group: Stillbirths: progress and uninished business. Lancet 387: 574, 20 1 6c The Lancet's Ending Preventable S tillbirths Series S tudy G roup: S tillbirths: rates, risk factors, and acceleration towards 2030. Lancet 387: 5 87 , 2 0 1 6d The Lance's Ending Preventable Stillbirths Series Study Group: Stillbirths: recall to action in high-income countries. Lancet 387: 69 1 , 20 1 6e The Lancet's Stillbirths Series Steering Committee: Stillbirths: how can health systems deliver for mothers and babies? Lancet 377: 1 6 1 0, 20 l l a The Lancet's Stillbirths Series Steering Committee: Stillbirths: the vision for 2020. Lancet 3 7: 1 798, 20 1 1 b The Lancet's Stillbirths Series Steering Committee: Stillbirths: the way forward in high-income countries. Lancet 3 7: 1 703, 20 1 1 c The Lancet's Stillbirths Series Steering Committee: Stillbirths: what diference can we make and at what cost? Lancet 37 : 1 523, 20 1 1 d The Lancet's Stillbirths Series Steering Committee: Stillbirths: where? When? Why? How to make the data count? Lancet 377: 1 448, 20 1 1 e The Lancet's Stillbirths Series Steering Committee: Stillbirths: why they matter. Lancet 377: 1 3 53, 20 1 1 f Varner JW, Silver M , Rowland Hogue CJ, et al: Association between still­ birth and illicit drug use and smoking during pregnancy. Obstet Gynecol 1 23 : 1 1 3, 20 1 4 Weeks JW, Asrat T , Morgan M A, e t al: Antepartum surveillance for a history of stillbirth: when to begin? Am J Obstet Gynecol 1 72 :486, 1 995

652

C H A PT E R 3 6

The P uerperi u m

REPRODUCTIVE TRACT I NVOLUTION . . . . . . . . . . . . . . . 652 PLACENTAL SITE I NVOLUTION . . . . . . . . . . . . . . . . . .

654

U RI NARY TRACT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

654

PERITO N E U M AND ABDOM INAL WALL . . . . . . . . . . . . . 655 BLOOD AND BLOOD VOLU ME . . . . . . . . . . . . . . . . . . . . 655 LACTATION A N D BREASTFEEDING . . . . . . . . . . . . . . . . 656 HOSPITAL CARE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659 HOME CAR E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663

Although the changes occurring during the puerperium are considered as physiological, they border vey closey upon the pathological, in as much as under no other circumstances does such marked and rapid tissue metabolism occur without a departure rom a condition ofhealth. -J. Whitridge Williams ( 1 903) The word puerperium is derived from Latin-puer, child + parus, bringing forth. Currently, it defines the time following delivery during which pregnancy-induced maternal anatomi­ cal and physiological changes return to the nonpregnant state. Its duration is understandably inexact, but is considered to be between 4 and 6 weeks. Although much less complex com­ pared with pregnancy, the puerperium has appreciable changes as stated above by Williams ( 1 903) , and some of these may be either bothersome or worrisome for the new mother. Kanotra and colleagues (2007) analyzed challenges that women faced

from 2 to 9 months following delivery. The Pregnancy Risk Assessment Surveillance System-PRAMS-of the Centers for Disease Control and Prevention (20 1 6) listed concerns of new mothers that are shown in Table 36- 1 . At least a third of these women felt the need for social support, and 25 percent had concerns with breastfeeding.

REPRODUCTIVE TRACT I NVOLUTION • Birth Canal

Return of the tissues in the birth canal to the nonpregnant state begins soon ater delivery. he vagina and its outlet gradually dimin­ ish in size but rarely regain their nulliparous dimensions. Rugae begin to reappear by the third week but are less prominent than before. he hymen is represented by several small tags of tissue, which scar to form the mytom caunces. The vaginal epithelium reflects the hypoestrogenic state, and it does not begin to proliferate until 4 to 6 weeks. This timing is usually coincidental with resumed ovarian estrogen production. Lacerations or stretching of the perineum dur­ ing delivery can lead to vaginal outlet relaxation. Some damage to the pelvic loor may be inevitable, and parturition predisposes to urinary incontinence and pelvic organ prolapse. • Uterus

The massively increased uterine blood fl o w necessary to main­ tain pregnancy is made possible by signiicant hypertrophy and remodeling of pelvic vessels. After delivery, their caliber gradually diminishes to approximately that of the prepregnant state. Within the puerperal uterus, larger blood vessels become obliterated by hyaline changes. They are gradually resorbed and replaced by smaller ones. Minor vestiges of the larger vessels, however, may persist for years. During labor, the margin of the dilated cervix, which cor­ responds to the external os, may be lacerated. The cervical opening contracts slowly, and for a few days immediately after

The Pu erperi u m

20

TABLE 36-1 . Preg na ncy Risk Assessment Survei l la nce System-PRAMSa Concerns Ra ised by Women in the F i rst 2-9 Months Postpa rt u m Concerns Need for soc i a l s u pport B reastfeed i n g issues I n adeq uate ed ucation a bout n ewborn ca re H e l p with postpart u m depress ion Perceived n eed for exte nded hospital stay Need for maternal insura nce coverage postpartum

Percent 32

24

21 10 8 6

aCe nters for D isease Control a nd P reve ntion, 2 0 1 6. Data fro m Ka notra 5, D'Angelo 0, P h a res TM, et a l : Cha l l e n ges fa ced b y n ew mothers i n t h e ea rly postpa r­ t u m period: an a n a lys i s of co m ment data from the 2000 P reg na ncy R i s k Assess ment Mon ito r i n g System (P RAMS) s u rvey. Mate rn C h i l d Health J 1 1 (6) :549, 200 7.

labor, it readily admits two ingers. By the end of the first week, this opening narrows, the cervix thickens, and the endocervical canal re-forms. The external os does not completely resume its pregravid appearance. It remains somewhat wider, and typi­ cally, ectocervical depressions at the site of lacerations become permanent. These changes are characteristic of a parous cervix (Fig. 36- 1 ) . Cervical epithelium also undergoes considerable remodeling. This actually may be salutary because almost half of women have regression of high-grade dysplasia following delivery (Ahdoot, 1 998; Kaneshiro, 2005). Ater delivery, the fundus of the contracted uterus lies slightly below the umbilicus. It consists mostly of myometrium covered by serosa and internally lined by decidua. The markedly attenuated lower uterine segment contracts and retracts, but not as forceully as the uterine corpus. During the next few weeks, the lower seg­ ment is converted from a clearly distinct substructure large enough to accommodate the fetal head to a barely discernible uterine isth­ mus located between the corpus and internal cervical os. Imme­ diately postpartum, the anterior and posterior walls, which lie in close apposition, are each 4 to 5 cm thick (Buhimschi, 2003). At this time, the uterus weighs approximately 1 000 g. Myometrial involution is a truly remarkable feat of destruc­ tion or deconstruction that begins as soon as 2 days ater deliv­ ery (Williams, 1 93 1 ) . The total number of myocytes does not decrease appreciably-rather, their size decreases markedly. As emphasized by Hytten ( 1 995), the quality of studies that describe the degree of decreasing uterine weight postpartum are

FIGURE 36-1 Com mo n a ppea ra nce of n u l l i pa rous (A) a nd parous (8) cervices.

)

18

15

13

�

) )

E

:

;

10

)

U

10

9

�

7.6 AP diameter

5 2

3

4

5

1 2.8 1 2.4 1 2 Cavity length 8 6 6.7 6.4 •

6

Days postpartum

7

8

9

FIGURE 36-2 Sonog ra p h i c measu rements of uterine i nvol ution d u ring the first 9 days postpa rtu m. AP anteroposterior. (Data from Hytten F: The C l i n ical Physiology of the Puerperi u m . London, Fa rrand Press, 1 995.) =

poor. Best estimates show that the uterus weighs approximately 500 g by 1 week postpartum, about 300 g by 2 weeks, and at 4 weeks, involution is complete and the uterus weighs approxi­ mately 1 00 g. Ater each successive delivery, the uterus is usually slightly larger than before the most recent pregnancy. Sonog ra p h i c F i n d i n g s

Uterine involution and rapid dissipation of size progresses in the first week ( Fig . 36-2) . Sonographically, the uterus and endometrium return to pregravid size by 8 weeks postpartum (Bae, 20 1 2; Steinkeler, 20 1 2) . In a study of 42 normal puer­ peras, Tekay and Jouppila ( 1 993) identiied fl u id in the endo­ metrial cavity in 78 percent of women at 2 weeks, 52 percent at 3 weeks, 30 percent at 4 weeks, and 1 0 percent at 5 weeks. Belachew and coworkers (20 1 2) used three-dimensional sonog­ raphy and visualized intracavitary tissue matter in a third on day 1 , in 95 percent on day 7, in 87 percent on day 1 4, and in 28 percent on day 28. By day 56, the small cavity was empty. Sohn and associates ( l 9��) described Doppler ultrasound results showing continuously increasing uterine artery vascular resistance during the first 5 days postpartum. Weintraub and colleagues (20 1 3) posited that uterine involution may be difer­ ent in preeclamptic women because they more likely had early diastolic notches seen on uterine artery velocimetry. Decid u a a nd E n do metri a l Reg e n e ration

Because separation of the placenta and membranes involves the spongy layer, the decidua basalis is not sloughed. The in situ decidua varies markedly in thickness, it has an irregular jagged border, and it is infiltrated with blood, especially at the placental site. Within 2 or 3 days ater delivery, the remaining decidua becomes diferenti­ ated into two layers. he superficial layer becomes necrotic and is sloughed in the lochia. The basal layer adjacent to the myome­ trium remains intact and is the source of new endometrium. Endometrial regeneration is rapid, except at the placental site. Within a week or so, the free surface becomes covered by epithe­ lium, and Sharman ( 1 953) identified ully restored endometrium in all biopsy specimens obtained from the 1 6th day onward. His­ tological endometritis is part of the normal reparative process.

653

654

The Puerperi u m

vforeover, microscopic inflammatory changes characteristic of acute salpingitis are seen in almost half of women between 5 and 1 5 days, however, these findings are not thought to reflect infec­ tion (Andrews, 1 95 1 ) . C l i n ica l As pects

Afterpa i n s. Several clinical findings arise with uterine invo­

lution. In primiparas, the uterus tends to remain tonically contracted following delivery. In multiparas, it often con­ tracts vigorously at intervals and gives rise to aterpains, which are similar to but milder than labor contractions. hese are more pronounced as parity increases and worsen when the newborn suckles, likely because of oxytocin release (Holdcroft, 2003) . Usually, afterpains decrease in intensity and become mild by the third day. We have encountered unusually severe and persistent afterpains in women with postpartum uterine infections. Loc h ia . Early in the puerperium, sloughing of decidual tissue results in a vaginal discharge of variable quantity. he discharge is termed lochia and contains erythrocytes, shredded decidua, epithelial cells, and bacteria. For the irst few days ater delivery, there is blood suicient to color it red lochia rubra. Ater 3 or 4 days, lochia becomes progressively pale in color-lochia serosa. ter approximately the 1 0th day, because of an admixture of leukocytes and reduced fluid content, lochia assumes a white or yellow-white color-lochia alba. he average duration of lochial discharge ranges from 24 to 36 days (Fletcher, 20 1 2) . Because of this expected leukocyte component, saline preparations of lochia for microscopic evaluation in cases of suspected puerperal metri­ tis are typically uninformative and not recommended. -

• Placental Site I nvolution

Complete extrusion of the placental site takes up to 6 weeks. Immediately after delivery, the placental site is approximately palm-sized. Within hours of delivery, it normally contains many thrombosed vessels that ultimately undergo organization. By the end of the second week, it is 3 to 4 cm in diameter. Placental site involution is an exfoliation process, which is prompted in great part by undermining of the implantation site by new endometrial proliferation (Williams, 1 93 1 ) . Thus, involution is not simply absorption in situ. Exfoliation consists of both extension and "downgrowth" of endometrium from the margins of the placental site, as well as development of endometrial tissue from the glands and stroma left deep in the decidua basalis after placental separation. Anderson and Davis ( 1 968) concluded that placental site exfoliation results from sloughing of infarcted and necrotic supericial tissues followed by a remodeling process. S u b i nvo l ution

In some cases, uterine involution is hindered because of infection, retained placental fragments, or other causes. Such subinvolution is accompanied by varied intervals of prolonged lochia as well as irregular or excessive uterine bleeding. During bimanual examina­ tion, the uterus is larger and soter than would be expected. With bleeding, pelvic sonography may help exclude retained placenta or, less-commonly, vascular malformations as the source (lraha,

20 1 7) . Methylergonovine (Methergine), 0.2 mg orally every 3 to 4 hours for 24 to 48 hours, is recommended by many, but its eicacy is questionable. If there is infection, antimicrobial ther­ apy usually leads to a good response. In an earlier study, Wager and coworkers ( 1 980) reported that a third of these late cases of postpartum metritis are caused by Chamydia trachomatis. For mild infection, empirical therapy with azithromycin or doxycy­ cline usually prompts resolution regardless of bacterial etiology. At our institution, common oral options taken for 7 to 1 0 days include doxycycline, 1 00 mg twice daily; azithromycin, 500 mg twice daily; or ampicillin-clavulanate (Augmentin) , 875 mg twice daily. Serious metritis is treated with intravenous broad-spectrum antibiotics listed in Table 37-2. Another cause of subinvolution is incompletely remodeled uteroplacental arteries (Andrew, 1 989; Kavalar, 20 1 2) . hese noninvoluted vessels are illed with thromboses and lack an endothelial lining. Perivascular trophoblasts are also identi­ ied in the vessel walls, which suggests an aberrant interaction between uterine cells and trophoblasts. Late Postpa rtu m Hemorrhage

Seconday pospartum hemorrhage is deined as bleeding 24 hours to 1 2 weeks ater delivery. Clinically worrisome uterine hem­ orrhage develops within 1 to 2 weeks in perhaps 1 percent of women. Such bleeding most oten is the result of abnormal invo­ lution of the placental site. It occasionally is caused by retention of a placental fragment or by a uterine artery pseudoaneurysm. Usually, retained products undergo necrosis with ibrin deposi­ tion and may eventually form a so-called placental poyp. As the eschar of the polyp detaches from the myometrium, hemorrhage may be brisk. As discussed in Chapter 56 (p. 1 090), delayed postpartum hemorrhage may also be caused by von Willebrand disease or other inherited coagulopathies (Lipe, 20 1 1 ) . I n our experiences, few women with delayed hemorrhage are found to have retained placental fragments. hus, we and others do not routinely perform curettage (Lee, 1 98 1 ) . Another concern is that curettage may worsen bleeding by avulsing part of the implantation site. Thus, in a stable patient, if sonographic examination shows an empty cavity, then oxytocin, methyler­ gonovine, or a prostaglandin analogue is given. Suitable dosing is found in Table 20-2 (p. 392) . Antimicrobials are added if uterine infection is suspected. If large clots are seen in the uter­ ine cavity with sonography, then gentle suction curettage is con­ sidered. Otherwise curettage is carried out only if appreciable bleeding persists or recurs after medical management. U RI NARY TRACT Normal pregnancy-induced glomerular hyperiltration persists during the puerperium but returns to prepregnancy baseline by 2 weeks (Hladunewich, 2004) . Dilated ureters and renal pelves return to their prep regnant state by 2 to 8 weeks postpartum. Because of this dilated collecting system, coupled with residual urine and bacteriuria in a traumatized bladder, symptomatic urinary tract infection remains a concern in the puerperium. Funnell and colleagues ( 1 954) used cystoscopy immedi­ ately postpartum and described varying degrees of submuco­ sal hemorrhage and edema. Bladder trauma is associated most

The Puerpe ri u m

closely with labor length and thus to some degree is a normal accompaniment of vaginal delivery. Postpartum, the bladder has an increased capacity and a relative insensitivity to intra­ vesical pressure. hus, overdistention, incomplete emptying, and excessive residual urine are frequent (Buchanan, 20 1 4; Mulder, 20 1 4) . Acute urinary retention is also more common with narcotic analgesia (Kandadai, 20 1 4) . heir management is discussed on page 660. It is unusual for urinary incontinence to manifest during the puerperium. hat said, much attention has been given to the potential for subsequent development of urinary incontinence and other pelvic loor disorders in the years following delivery. A more detailed discussion is found in Chapter 30 (p. 568).

PERITO N EUM AND ABDOM I NAL WALL The broad and round ligaments require considerable time to recover from stretching and loosening during pregnancy. As a result of ruptured elastic ibers in the skin and prolonged disten­ tion by the pregnant uterus, the abdominal wall remains soft and laccid. If the abdomen is unusually labby or pendulous, an ordinary girdle is often satisfactory. n abdominal binder is another temporary measure. Several weeks are required for these structures to return to normal, and recovery is aided by exercise. hese may be started anytime following vaginal delivery. Ater cesarean delivery, a 6-week interval to allow fascia to heal and abdominal soreness to diminish is reasonable. Silvery abdominal striae commonly develop as striae graviarum (Chap. 4, p. 53) . Except for these, the abdominal wall usually resumes its prep reg­ nancy appearance. When muscles remain atonic, however, the abdominal wall also remains lax. Marked separation of the rectus abdominis muscles-diastasis recti-may result.

BLOOD AND BLOOD VOLU M E • Hematological a n d Coagulation Changes

Marked leukocytosis and thrombocytosis may occur dur­ ing and after labor. The white blood cell count sometimes reaches 30,000/�L, with the increase predominantly due to granulocytes. There is a relative lymphopenia and an abso­ lute eosinopenia. Normally, during the irst few postpartum days, hemoglobin concentration and hematocrit luctuate moderately. We routinely check these on the irst postpar­ tum day or earlier if indicated. If they fall much below the levels present just before labor, a considerable amount of blood has been lost. By the end of pregnancy, l aboratory values that assess coagulation are altered (Kenny, 20 1 4) . These changes are discussed in Chapter 4 (p. 59) and listed in the Appendix (p. 1 2 56). Many persist variably in the puerperium. For exam­ ple, a markedly increased plasma ibrinogen level is maintained at least through the irst week and hence so is an elevated sedi­ mentation rate. Hypercoagulability appears to be greater and is relected by the likelihood of deep-vein thrombosis and pul­ monary embolism in the 12 weeks following childbirth (Kamel, 20 1 4) . his is depicted in Figu re 36-3 and is discussed further in Chapter 52 (p. 1 004) .

30 '

�

2 0

s c

25 20

� 15

) u � c E e

-

10

c

I J

5

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

0-3

_ _ _ _ _ _

_ _ _ _ _ _ _

1

_ _ _ _ _ _

I

_ _ _ _ _

- -I

7-9 1 0-1 2 1 3-1 5 1 6-1 8 4-6 Weeks after childbirth

FIGURE 36-3 Risk of deep-vein thrombosis or pu l monary embolism fol lowi ng c h i l d birth. (Data from Ka m e l H , N avi S, Srira m N, et a l : Risk of a Th rom botic Event after the 6-week postpartu m period. N E n g l J M e d 3 70: 1 307, 201 4.)

• Pregnancy-Induced Hypervolemia

When the amount of blood attained by normal pregnancy hypervolemia is lost as postpartum hemorrhage, the woman almost immediately regains her nonpregnant blood volume (Chap. 4 1 , p. 756) . If less has been lost at delivery, blood volume generally nearly returns to its nonpregnant level by 1 week after delivery. Cardiac output usually remains elevated for 24 to 48 hours postpartum and declines to nonpregnant val­ ues by 1 0 days (Robson, 1 987) . Heart rate changes follow this pattern, and blood pressure similarly returns to nonpregnant values ( F ig. 36-4). Correspondingly, systemic vascular resistance remains in the lower range characteristic of pregnancy for 2 days postpartum and then begins to steadily increase to nor­ mal nonpregnant values (Hibbard, 20 1 4) . Despite this, Morris and coworkers (20 1 5) found that reduced arterial stifness per­ sists following pregnancy. They suggest a signiicant favorable

1 25

J

I

E E

1 00 75

Systolic I-�� r I-:� L I __+ 1 20 1 1 2 1 1 1 20 I I I 1 1 4 1I 1 1 51 -18 86

88 E

90 E

72 ! 71 1 Diastolic

74 !

75!

MAP 86 (

o

(

2 3 Days postpartum

91 E

89 �

76! � 73 4

5

FIGURE 36-4 During the early puerperium, blood pressure norm a l ly rises toward non preg nant val ues. MAP

=

mea n arterial pressure.

655

656

The P u e rperi u m

efect o f pregnancy o n maternal cardiovascular remodeling, which may represent a mechanism by which preeclampsia risk is reduced in subsequent pregnancies. • Postpartum Diuresis

Normal pregnancy is associated with an appreciable increase in extracellular sodium and water retention, and postpartum diuresis is a physiological reversal of this process. Chesley and coworkers ( 1 959) demonstrated a decrease in sodium space of approximately 2 L during the fi r st week postpartum. his also corresponds with loss of residual pregnancy hypervolemia. In preeclampsia, pathological retention of luid antepartum and its diuresis postpartum may be prodigious (Chap. 40, p. 744) . Postpartum diuresis results in relatively rapid weight loss of 2 to 3 kg, which is additive to the 5 to 6 kg incurred by deliv­ ery and normal blood loss. Weight loss from pregnancy itself is likely to be maximal by the end of the second week postpartum. It follows that any residual increased weight compared with prepregnancy values probably represents fat stores that will per­ sist. According to Schauberger and associates ( 1 992) , women approach their self-reported prepregnancy weight 6 months after delivery but still retain an average surplus of 1 .4 kg (3 Ib) .

LACTATION AND BREASTFEEDING • Breast Anatomy and Secretory Products

Each mature mammary gland or breast is composed of 1 5 to 25 lobes. hey are arranged radially and are separated from one another by varying amounts of fat. Each lobe consists of several lobules, which in turn are composed of numerous alveoli. Each alveolus is provided with a small duct that joins others to form a single larger duct for each lobe as shown in Figure 36-5. These lacterous ducts open separately on the nipple, where they may be distinguished as minute but dis­ tinct orifi c es. he alveolar secretory epithelium synthesizes the various milk constituents. After delivery, the breasts begin to secrete colostrum, which is a deep lemon-yellow liquid. It usually can be expressed from the nipples by the second postpartum day. Compared with mature milk, colostrum is rich in immunological components and contains more minerals and amino acids (Ballard, 20 1 3) . It also has more protein, much o f which i s globulin, but less sugar and fat. Secretion persists for 5 days to 2 weeks, with gradual conversion from "transitional" to mature milk by 4 to 6 weeks. The colostrum content of immunoglobulin A (IgA) ofers the newborn protection against enteric pathogens. Other host resistance factors found in colostrum and milk include complement, macrophages, lymphocytes, lactoferrin, lactoper­ oxidase, and lysozymes. Mature milk is a complex and dynamic biological luid that includes fat, proteins, carbohydrates, bioactive factors, miner­ als, vitamins, hormones, and many cellular products (Table 36-2) . The concentrations and contents o f human milk change even during a single feed and are inluenced by maternal diet and by newborn age, health, and needs. A nursing mother eas­ ily produces 600 mL of milk daily, and maternal gestational

F I G U R E 36-5 Schematic of the a lveo l a r a n d d ucta l system d u r­ i ng lactation. N ote the myoepithelial fi bers (M) that surround the outside of the u ppermost a lveo l u s. The secretions from the g l a n­ d u l a r elements a re extruded i nto the l u men of the a lveol i (A) a nd ejected by the myoepithelial cel l s i nto the d ucta l system (0), which e m pties t h rough the n i pple. Arterial blood s u pply to the a lveol u s i s identified b y t h e u p per rig ht a rrow a nd venous d rai nage b y the a rrow beneath.

TABLE 36-2. Average Com position of H u m a n B reast M i l k Fat Tota l Fatty Acids P U FA Cholesterol

g/1 00 m L 4.2 Trace 0.6 0.0 1 6

Protein Tota l Case i n a-Lacta l b u m i n Lactoferri n

g/1 00 m L 1 .1 OJ OJ 0.2

Ca rbohyd rate Lactose O l i gosacc h a rides

g/ 1 00 m L

P U FA

=

7

0.5

Polyu n saturated fatty acids.

The Puerp e r i u m

weight gain has little impact on its quantity or quality. Milk is isotonic with plasma, and lactose accounts for half of the osmotic pressure. Essential amino acids are derived from blood, and nonessential amino acids are derived in part from blood or synthesized in the mammary gland. Most milk proteins are unique and include alpha-lactalbumin, beta-lactoglobulin, and casein. Fatty acids are synthesized in the alveoli from glucose and are secreted by an apocrine-like process. Most vitamins are found in human milk, but in variable amounts. Vitamin K is virtually absent, and thus, an intramuscular dose is given to the newborn (Chap. 33, p. 626) . Vitamin D content is low22 IU/mL, and newborn supplementation is also recommended by the American Academy of Pediatrics (Wagner, 2008) . Whey is milk serum and has been shown to contain large amounts of interleukin-6 (Saito, 1 99 1 ) . Human milk has a whey-to-casein ratio of 60:40, considered ideal for absorption. Prolactin appears to be actively secreted into breast milk. Epidermal growth octor (EGF) has been identiied, and because it is not destroyed by gastric proteolytic enzymes, it may be absorbed to promote growth and maturation of newborn intes­ tinal mucosa (McCleary, 1 99 1 ) . O ther critical components in human milk include lactoferrin, melatonin, oligosaccharides, and essential fatty acids. • Endocrinology of Lactation

The precise humoral and neural mechanisms involved in lacta­ tion are complex. Progesterone, estrogen, and placental lacto­ gen, as well as prolactin, cortisol, and insulin, appear to act in concert to stimulate the growth and development of the milk­ secreting apparatus (Stuebe, 20 1 4) . With delivery, the mater­ nal serum levels of progesterone and estrogen decline abruptly and profoundly. This drop removes the inhibitory inluence of progesterone on alpha-lactalbumin production and stimulates lactose synthase to increase milk lactose. Progesterone with­ drawal also allows prolactin to act unopposed in its stimulation of alpha-lactalbumin production. Activation of calcium-sensing receptors (CaSR) in mammary epithelial cells downregulates parathyroid hormone-related protein (PTHrP) and increases calcium transport into milk (Vanhouten, 20 1 3) . Serotonin is also produced in mammary epithelial cells and has a role in maintaining milk production (Collier, 20 1 2) . The intensity and duration of subsequent lactation are controlled, in large part, by the repetitive stimulus of nursing and emptying of milk from the breast. Prolactin is essential for lactation, and women with extensive pituitary necrosis­ Sheehan syndrome�o not lactate (Chap. 58, p. 1 1 33) . Although plasma prolactin levels fall after delivery to levels lower than during pregnancy, each act of suckling triggers a rise in levels (Pang, 2007) . Presumably a stimulus from the breast curtails the release of dopamine, also known as prolactin-inhib­ iting octor, from the hypothalamus. In turn, this transiently induces increased prolactin secretion. The posterior pituitary secretes oxytocin in pulsatile fashion. This stimulates milk expression fro m a lactating breast by caus­ ing contraction of myoepithelial cells in the alveoli and small milk ducts (see Fig. 36-5) . Milk ejection, or letting down, is a relex initiated especially by suckling, which stimulates the

posterior pituitary to liberate oxytocin . he reflex may even be provoked by an infant cry and can be inhibited by maternal fright or stress (Stuebe, 20 1 4) . • Immunological Consequences

of Breastfeeding

Human milk contains several protective immunological sub­ stances, including secretory IgA and growth factors. The anti­ bodies in human milk are speciically directed against maternal environmental antigens such as Escherichia coli (Iyengar, 2 0 1 2) . According to the Centers for Disease Control and Preven tion (Perrine, 20 1 5) , breastfeeding decreases the incidence of ear, respiratory, and gastrointestinal infections; necrotizing entero­ colitis; and sudden infant death syndrome. Much attention has been directed to the role of maternal breast milk lymphocytes in neonatal immunological processes. Milk contains both T and B lymphocytes, but the T lympho­ cytes appear to difer from those found in blood. Speciically, milk T lymphocytes are almost exclusively composed of cells that exhibit speciic membrane antigens. These memory T cells appear to be an avenue for the neonate to beneit from the maternal immunological experience. • Nursing

Human milk is ideal food for newborns in that it provides age­ speciic nutrients, immunological factors, and antibacterial sub­ stances. Milk also contains factors that act as biological signals for promoting cellular growth and diferentiation. A list of the advantages of breastfeeding is shown in Table 36-3 . For both mother and infant, the beneits of breastfeeding are long-term. For example, women who breastfeed have a lower risk of breast and reproductive cancer, and their children have increased adult intelligence independent of a wide range of possible con­ founding factors (J ong, 20 1 2; Kramer, 2008). Breastfeeding is associated with decreased postpartum weight retention ( Baker, 2008) . In addition, rates of sudden-infant-death syndrome are signiicantly lower among breastfed infants. Bartek and col­ leagues (20 1 3) estimate that a 90-percent breastfeeding rate for 1 2 months would save more than $3 billion annually in excess infant and maternal morbidity costs. For all these reasons, the TABLE 36-3. Adva ntages of B rea stfeed i n g N utriti onal I m m u nolog ical Deve l opmenta l Psycholog i ca l Socia l Econom ical Envi ron menta l O pti m a l g rowth a n d development Decrease risks for ac ute a n d c h ro n i c d i sea ses Data from America n Acad emy of Pediatrics a n d the American Col lege of Obstetrici a n s a n d Gyneco logists: G u id e l i nes for Peri natal Ca re, 8th ed, E l k G rove Vi l la ge, AAP, 20 1 7.

657

658

The P u e rperi u m

TABLE 36-4. Ten Steps t o S u ccessfu l B rea stfeed i n g 1 . H ave a written breastfeed i n g pol icy t h a t i s reg u l a rly com m u n i cated to a l l health-ca re staff 2. Tra i n a l l staf i n ski l l s n ecessa ry to i m p l e m e nt t h i s pol icy 3 . I nfor m a l l preg n a nt wom e n a bout the beneits a n d m a nagement o f b reastfeed i ng 4. Help mothers i nitiate breastfeedi ng with i n an hour of birth 5 . S h ow m others how to brea stfeed a nd how to s u sta i n lactation, eve n i f they s h o u l d b e sepa rated from thei r i nfa nts 6. Feed n ewborns not h i n g but b reast m i l k, u n less m ed i ­ ca l l y i n d icated, a nd u nd e r n o c i rc u m sta n ces p rovi de b reast m i l k s u bstitutes, feed i n g bottl es, or paCiiers free of c h a rg e or at low cost 7 . P ra ctice room i ng-i n, w h i c h a l l ows mothers and new­ borns to rem a i n tog ether 24 h o u rs a day 8. E n co u ra g e breastfeed i ng on d e m a n d 9. G ive no a rtiicial paCiiers t o breastfeed i n g n ewborns 1 0. H e l p sta rt breastfeed i n g s u pport g ro u ps and refer m others to them Ada pted with perm ission from World Health Orga n izati o n : P rotect i n g , p romoti ng a n d s u pport i n g b reast-feed i n g : the spec i a l role of matern ity services. Geneva, World H ea lth Org a n ization, 1 989.

American Academy of Pediatrics (20 1 7) and American College of Obstetricians and Gynecologists (20 1 6a, 20 1 7b) supports the World Health Organization (20 1 1 ) recommendations of exclusive breastfeeding for up to 6 months. The Surgeon General of the u.S. Department of Health and Human Services (20 1 1 ) lists some barriers to breastfeeding and suggests practical means of overcoming them. Educational ini­ tiatives that include father and peer counseling may improve these rates (Pisacane, 2005; Wolfberg, 2004) . The Baby Friendy Hospital Initiative is an international program to increase rates of exclusive breastfeeding and to extend its duration. It is based on the World Health Organization ( 1 989) Ten Steps to Success­ ul Breaseeding (Table 36-4) . Worldwide, almost 20,000 hos­ pitals are designated as "baby-friendly," however, only 1 0 to 1 5 percent of hospitals in the United States are so designated (Centers for Disease Control and Prevention, 20 1 4; Perrine, 20 1 5) . Forrester-Knauss and coworkers (20 1 3) described success­ ul trends toward exclusive breastfeeding in Switzerland during 9 years in which a Baby-Friendly Hospital Initiative was imple­ mented. In a large population-based study done in the United States, fewer than two thirds of term neonates were exclusively breastfed at the time of discharge (McDonald, 20 1 2) . Various individual resources available are available for breastfeeding mothers that include online information from the American Academy of Pediatrics (http://www.aap.org) and La Leche League International (http://ww. llli.org) . • Care of Breasts

The nipples require little attention other than cleanliness and attention to skin issures. Fissured nipples render nursing

painful, and they may have a deleterious influence on milk pro­ duction. These cracks also provide a portal of entry for pyogenic bacteria. Because dried milk is likely to accumulate and irritate the nipples, washing the areola with water and mild soap is help­ ful before and ater nursing. When the nipples are irritated or fissured, some recommend topical lanolin and a nipple shield for 24 hours or longer. Although specific evidence supporting this practice is lacking, nipple pain usually subsides by 1 0 days (Dennis, 20 1 4) . If issuring is severe, the newborn should not be permitted to nurse on the afected side. Instead, the breast is emptied regularly with a pump until the lesions are healed. Poor latching of the neonate to the breast can create such issures. For example, the newborn may take into its mouth only the nipple, which is then is forced against the hard palate during suckling. Ideally, the nipple and areola are both taken in to evenly dis­ tribute suckling forces. Moreover, the force of the hard palate against the lactiferous sinuses aids their eicient emptying, while the nipple is thereby positioned closer to the soft palate. • Contraindications to Breastfeeding

Nursing is contraindicated in women who take street drugs or do not control their alcohol use; have an infant with galacto­ semia; have human immunodeiciency virus (HIV) infection; have active, untreated tuberculosis; take certain medications; or are undergoing breast cancer treatment (American Academy of Pediatrics, 20 1 7; Faupel-Badger, 20 1 3) . Breastfeeding has been recognized for some time as a mode of H IV transmission and is proscribed in developed countries in which adequate nutrition is otherwise available. Other viral infections do not contraindi­ cate breastfeeding. For example, with maternal cytomegalovirus infection, both virus and antibodies are present in breast milk. And, although hepatitis B virus is excreted in milk, breastfeed­ ing is not contraindicated if hepatitis B immune globulin is given to the newborns of afected mothers. Maternal hepatitis C infection is not a contraindication because breastfeeding has not been shown to transmit infection (Society for Maternal­ Fetal Medicine, 20 1 7) .Women with active herpes simplex virus may sucle their infants if there are no breast lesions and if particular care is directed to hand washing before nursing. • Drugs Secreted in Milk

Most drugs given to the mother are secreted in breast milk, although the amount ingested by the infant typically is small. Many factors influence drug excretion and include plasma concentration, degree of protein binding, plasma and milk pH, degree of ionization, lipid solubility, and molecular weight (Rowe, 20 1 3) . The ratio of drug concentration in breast milk to that in maternal plasma is the milk-to-plasma drug-concentration ratio. Ideally, to minimize infant exposure, medication selection should favor drugs with a shorter half­ life, poorer oral absorption, and lower lipid solubility. If mul­ tiple daily drug doses are required, then each is taken by the mother ater the closest feed. Single daily-dosed drugs may be taken j ust before the longest infant sleep interval-usually at bedtime (Spencer, 2002) . Only a few drugs are absolutely contraindicated while breastfeeding (Berlin, 20 1 3; Bertino, 20 1 2) . Cytotoxic drugs

The Puerperi u m

may interfere with cellular metabolism and potentially cause immune suppression or neutropenia, afect growth, and at least theoretically, increase the risk of childhood cancer. Examples include cyclophosphamide, cyclosporine, doxorubicin, metho­ trexate, and mycophenolate. If a medication presents a con­ cern, then the importance of therapy should be ascertained. It should be determined whether there is a safer alternative or whether neonatal exposure can be minimized if the medication dose is taken immediately after each breastfeeding (American Academy of Pediatrics, 20 1 7) . Finally, recreational drugs such as marijuana and alcohol should be avoided (American College of Obstetricians and Gynecologists, 20 1 7 a) . Data on individual drugs are available through the National Institutes of Health website, LactMed, which can be found at toxnet.nlm.nih.gov. Radioactive isotopes of copper, gallium, indium, iodine, sodium, and technetium rapidly appear in breast milk. Con­ sultation with a nuclear medicine specialist is recommended before performing a diagnostic study with these isotopes (Chap. 46, p. 908) . he goal is to use a radionuclide with the shortest excretion time in breast milk. The mother should pump her breasts before the study and store enough milk in a freezer to feed the infant. After the study, she should pump her breasts to maintain milk low but discard all milk produced dur­ ing the time that radioactivity is present. his ranges from 15 hours to 2 weeks, depending on the isotope used. Impor­ tantly, radioactive iodine concentrates and persists in the thyroid. Its special considerations are discussed in Chapter 63 (p. 1 20 1 ) . • Breast Engorgement

his is common in women who do not breastfeed. It is typified by milk leakage and breast pain, which peak 3 to 5 days after delivery (Spitz, 1 998). Up to half of afected women require analgesia for breast pain relief, and as many as 1 0 percent report severe pain for up to 1 4 days. Evidence is insuicient to irmly support any speciic treat­ ment (Mangesi, 20 1 6) . hat said, breasts can be supported with a well-itting brassiere, breast binder, or sports bra. Cool packs and oral analgesics for 1 2 to 24 hours aid discomfort. Pharma­ cological or hormonal agents are in general not recommended to suppress lactation. Fever caused by breast engorgement was common before the renaissance of breastfeeding. In one study, Almeida and Kitay ( 1 9 86) reported that 1 3 percent of puerperas had fever from engorgement that ranged from 37. 8 to 39°C. Fever seldom persists for longer than 4 to 1 6 hours . The incidence and severity of engorgement and of the fever associated with it are much lower if women breastfeed. Other causes of fever, especially those due to infection, must be excluded. Of these, mastitis is infection of the mammary parenchyma. I t is relatively common in lactating women and is discussed in Chapter 37 (p. 675 ) . • Other Issues with Lactation

With inverted nipples, lactiferous ducts open directly into a depression at the center of the areola. With these depressed nipples, nursing is diicult. If the depression is not deep, milk sometimes can be drawn out by a breast pump. If instead the

nipple is greatly inverted, daily attempts are made during the last few months of pregnancy to draw or "tease" the nipple out with the fingers. Extra breasts-poymastia, or extra nipples-poythelia, may develop along the former embryonic mammary ridge. Also termed the milk line, this line extends from the axilla to the groin bilaterally. In some women, rests of accessory breast tissue can be found in the mons pubis or vulva (Wagner, 20 1 3) . In the general population, the incidence of accessory breast tissue ranges from 0.22 to 6 percent (Loukas, 2 007) . hese breasts may be so small as to be mistaken for pigmented moles, or if without a nipple, for lymphadenopathy or lipoma. Polymastia has no obstetrical signifi c ance, although occasion­ ally enlargement of these accessory breasts during pregnancy or engorgement postpartum may result in patient discomfort and anxiety. Galactocele is a milk duct that becomes obstructed by inspis­ sated secretions. The amount is ordinarily limited, but an excess may form a luctuant mass-a galactocele-that may cause pressure symptoms and have the appearance of an abscess. It may resolve spontaneously or require aspiration. Among individuals, the volume of milk secreted varies markedly. This depends not on general maternal health b ut on breast glandular development. Rarely, there is complete lack of mammary secretion-agalactia. Occasionally, mammary secre­ tion is excessive-poygalactia.

HOSPITAL CARE For 2 hours after delivery, blood pressure and pulse are taken every 1 5 minutes, or more frequently if indicated. Temperature is assessed every 4 hours for the first 8 hours and then at least every 8 hours subsequently (American Academy of Pediatrics, 20 1 7) . The amount of vaginal bleeding is monitored, and the fundus palpated to ensure that it is well contracted. If relax­ ation is detected, the uterus should be massaged through the abdominal wall until it remains contracted. U terotonics are also sometimes required. Blood can accumulate within the uterus without external bleeding. his may be detected early by uter­ ine enlargement during fundal palpation in the irst postdeliv­ ery hours. Because the likelihood of signiicant hemorrhage is greatest immediately postpartum, even in normal births, the uterus is closely monitored for at least 1 hour after delivery. Postpartum hemorrhage is discussed in Chapter 4 1 (p. 758). If regional analgesia or general anesthesia was used for labor or delivery, the mother should be observed in an appropriately equipped and stafed recovery area. Women are out of bed within a few hours after delivery. n attendant should be present for at least the irst time, in case the woman becomes syncopal. he many conirmed advantages of early ambulation include fewer bladder complications , less frequent constipation, and reduced rates of puerperal venous thromboembolism. As discussed on page 6 5 5 , deep-vein thrombosis and pulmonary embolism are common in the puerperium (see Fig. 36-3) . In an audit of puerperal women at Parkland Hospital, the frequency of venous thromboembo­ lism was found to be 0.008 percent after a vaginal birth and

659

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The P u e rperi u m

0.04 percent following cesarean delivery. We attribute this low incidence to early ambulation. Risk factors and other measures to diminish the frequency of thromboembolism are discussed in Chapter 52 (p. 1 004) . here are no dietary restrictions for women who have been delivered vaginally. Two hours after uncomplicated vaginal delivery, a woman is allowed to eat. With breastfeeding, the level of calories and protein consumed during pregnancy are increased slightly as recommended by the Food and Nutrition Board of the National Research Council (Chap. 9, p. 1 67) . If the mother does not breastfeed, dietary requirements are the same as for a nonpregnant woman. We recommend oral iron supplementation for at least 3 months after delivery and hema­ tocrit evaluation at the first postpartum visit. As noted earlier, profound drops in estrogen levels follow removal of the placenta. Reminiscent of the menopause, post­ partum women may experience hot lushes, especially at night. Importantly, the patient 's temperature is assessed to diferenti­ ate these physiological vasomotor events from infection. In women with migraines, dramatic hypoestrogenism may trigger headaches. Importantly, severe headaches should be dif­ ferentiated from spinal headache or hypertensive complications. Care varies depending on migraine severity. Mild headaches may respond to analgesics such as ibuprofen or acetamino­ phen. lternatively, M idrin combines isometheptene mucate, which is a sympathomimetic agent; dichloralphenazone, which is a mild sedative; and acetaminophen and is compatible with breastfeeding. For more severe headaches, oral or systemic nar­ cotics can be used. I nstead of Midrin, a triptan, such as sumat­ riptan (Imitrex), can efectively relieve headaches by causing intracranial vasoconstriction. • Perineal Care

he woman is instructed to clean the vulva from anterior to posterior-the vulva toward the anus. A cool pack applied to the perineum may help reduce edema and discomfort during the irst 24 hours if there is a perineal laceration or an episi­ otomy. Most women also appear to obtain a measure of relief from the periodic application of a local anesthetic spray. Severe

perineal vaginal, or rectalpain always warrants carul inspection and papation. Severe discomfort usually indicates a problem,

such as a hematoma within the irst day or so and infection ater the third or fourth day (Chap. 37, p. 674 and Chap. 4 1 , p . 764) . Beginning approximately 2 4 hours after delivery, moist heat as provided by warm sitz baths can be used to reduce local discomfort. Tub bathing after uncomplicated delivery is allowed. The episiotomy incision normally is firmly healed and nearly asymptomatic by the third week. Rarely, the cervix, and occasionally a portion of the uterine body, may protrude from the vulva following delivery. his is accompanied by variable degrees of anterior and posterior vagi­ nal wall prolapse. Symptoms include a palpable mass at or past the introitus, voiding diiculties, or pressure. Puerperal proci­ dentia typically improves with time as the weight of the uterus lessens with involution. As a temporizing measure in those with pronounced prolapse, the uterus can be replaced and held in position with a suitable pessary.

Hemorrhoidal veins are often congested at term. Thrombo­ sis is common and may be promoted by second-stage pushing. Treatment includes topically applied anesthetics, warm soaks, and stool-softening agents. Nonprescription topical prepara­ tions containing corticosteroids, astringents, or phenylephrine are often used, but no randomized studies support their eicacy compared with conservative management. • Bladder Function

In most delivery units, intravenous luids are inused during labor and for an hour or so ater delivery. Oxytocin, in doses that have an antidiuretic efect, is typically inused postpartum, and rapid bladder filling is common. Moreover, both bladder sensation and capability to empty spontaneously may be diminished by local or conduction analgesia, by trauma to the bladder, by episiotomy or lacerations, or by operative vaginal delivery. Thus, urinary reten­ tion and bladder overdistention is common in the early puerpe­ rium. he incidence in more than 5500 women studied with a bladder scanner was 5. 1 percent (Buchanan, 20 1 4) . In another study, Musselwhite and coworkers (2007) reported retention in 4.7 percent of women who had labor epidural analgesia. Risk fac­ tors that increased the likelihood of retention were primiparity, cesarean delivery, perineal laceration, oxytocin-induced or aug­ mented labor, operative vaginal delivery, catheterization during labor, and labor duration > 1 0 hours. Prevention of bladder overdistention demands observation ater delivery to ensure that the bladder does not overill and that it empties adequately with each voiding. he enlarged blad­ der can be palpated suprapubically, or it is evident abdominally indirectly as it elevates the fundus above the umbilicus. he use of an automated bladder scanner sonography system has been studied to detect high bladder volumes and thus postpartum urinary retention (Buchanan, 20 1 4; Van Os, 2006) . If a woman has not voided within 4 hours ater delivery, it is likely that she cannot. If she has trouble voiding initially, she also is likely to have further trouble. n examination for perineal and genital-tract hematomas is completed. With an overdistended bladder, an indwelling catheter should be left in place until the factors causing retention have abated. Even without a demonstrable cause, it usually is best to leave the catheter in place for at least 24 hours. his prevents recurrence and allows recovery of normal bladder tone and sensation. When the catheter is removed, a voiding trial is completed to demonstrate an ability to void appropriately. If a woman cannot void after 4 hours, she should be catheterized and the urine volume measured. If more than 200 mL, the bladder is not functioning appropriately, and the catheter is left for another 24 hours. Although rare, if retention persists after a second voiding trial, an indwelling catheter and leg bag can be elected, and the patient returns in 1 week for an outpatient voiding trial. Intermittent sel-catheterization is another option (Mulder, 20 1 7) . During a voiding trial, i f less than 200 m L o f urine is obtained, the catheter can be removed and the bladder sub­ sequently monitored clinically as described earlier. Harris and coworkers ( 1 977) reported that 40 percent of such women develop bacteriuria, and thus a single dose or short course of

The Puerpe r i u m

antimicrobial therapy against uropathogens is reasonable after the catheter is removed. • Pain, Mood, and Cognition

Discomfort and its causes following cesarean delivery are con­ sidered in Chapter 30 (p. 585). During the irst few days after vaginal delivery, the mother may be uncomfortable because of afterpains, episiotomy and lacerations, breast engorgement, and at times, postdural puncture headache. Mild analgesics contain­ ing codeine, aspirin, or acetaminophen, preferably in combina­ tions, are given as frequently as every 4 hours during the irst few days. It is important to screen the postpartum woman for depres­ sion (American College of Obstetricians and Gynecologists, 20 1 6b) . It is fairly common for a mother to exhibit some degree of depressed mood a few days after delivery. Termed pospartum blues, this likely is the consequence of several fac­ tors. hese include emotional letdown that follows the excite­ ment and fears experienced during pregnancy and delivery, discomforts of the early puerperium, fatigue from sleep depri­ vation, anxiety over the ability to provide appropriate newborn care, and body image concerns. In most women, efective treat­ ment includes anticipation, recognition, and reassurance. This disorder is usually mild and self-limited to 2 to 3 days, although it sometimes lasts for up to 1 0 days. Should these moods persist or worsen, an evaluation for symptoms of major depression is done (Chap. 6 1 , p. 1 1 76) . Suicidal or infanticidal ideation is dealt with emergently. Because major postpartum depression recurs in at least a fourth of women in subsequent pregnancies, some recommend pharmacological prophylaxis beginning in late pregnancy or immediately postpartum. Last, postpartum hormonal changes in some women may afect brain function. Bannbers and colleagues (20 1 3) com­ pared a measure of executive function in postpartum women and controls and observed a functional decline in postpartum subjects.

common (24 percent) , followed by femoral neuropathies ( 1 4 percent) . A motor deicit accompanied a third o f injuries. Nul­ liparity, prolonged second-stage labor, and pushing for a long duration in the semi-Fowler position were risk factors. The median duration of symptoms was 2 months, and the range was 2 weeks to 1 8 months. Nerve injuries with cesarean delivery include the iliohypo­ gastric and ilioinguinal nerves (Rahn, 20 1 0) . These are dis­ cussed further in Chapter 2 (p. 1 5) . • Musculoskeletal I njuries

Pain in the pelvic girdle, hips, or lower extremities may follow stretching or tearing injuries sustained at normal or diicult delivery. Magnetic resonance (MR) imaging is often infor­ mative (Miller, 20 1 5) . One example is the piriformis m uscle hematoma shown in Figure 36-6 . Most injuries resolve with antiinlammatory agents and physical therapy. Rarely, there may be septic pyomyositis such as with iliopsoas muscle abscess (Nelson, 20 1 0; Young, 20 1 0) . Separation o f the symphysis pubis or one o f the sacroiliac synchondroses during labor leads to pain and marked interfer­ ence with locomotion (Fig. 36-7) . Estimates of the frequency of this event vary widely from 1 in 600 to 1 in 30,000 deliveries (Reis, 1 932; Taylor, 1 986) . In our experiences, symptomatic separations are uncommon. heir onset of pain is often acute during delivery, but symptoms may manifest either antepar­ tum or up to 48 hours postpartum (Snow, 1 997) . In suspected cases, radiography is typically selected. The normal distance of the symphyseal joint is 0.4 to 0.5 cm, and symphyseal separa­ tion > 1 cm is diagnostic for diastasis. Treatment is generally conservative, with rest in a lateral decubitus position and an appropriately itted pelvic binder (Lasbleiz, 20 1 7) . Surgery is occasionally necessary in some symphyseal separations of more than 4 cm (Kharrazi, 1 997) . The recurrence risk is high in sub­ sequent pregnancy, and Culligan and coworkers (2002) recom­ mend consideration for cesarean delivery.

• Neuromusculoskeletal Problems

Obstetrica l N e u ro path ies

Pressure on branches of the lumbosacral nerve plexus during labor may manifest as complaints of intense neuralgia or cramp­ like pains extending down one or both legs as soon as the head descends into the pelvis. If the nerve is injured, pain may continue after delivery, and variable degrees of sensory loss or muscle paralysis can result. In some cases, there is footdrop, which can be secondary to injury at the level of the lumbosa­ cral plexus, sciatic nerve, or common fibular (peroneal) nerve (Bunch, 20 1 4) . Components of the lumbosacral plexus cross the pelvic brim and can be compressed by the fetal head or by forceps. The common ibular nerves may be externally com­ pressed when the legs are positioned in stirrups, especially dur­ ing prolonged second-stage labor. Obstetrical neuropathy is relatively infrequent. Wong and associates (2003) evaluated more than 6000 puerperas and found that approximately 1 percent had a conirmed nerve injury. Lateral femoral cutaneous neuropathies were the most

FIGURE 36-6 I n h o mogeneous mass of the rig ht p i riformis m u sc l e consistent w i t h a he mato m a (yellow cursor measurements) is c o m ­ pared w i t h t h e norma l-appea ring left pi riformis m uscle (yellow arrow),

66 1

662

The P u e rperi u m

Hospital-stay length following labor and delivery is now reg­ ulated by federal law (Chap. 32, p. 6 1 6) . Currently, the norms are hospital stays up to 48 hours following uncomplicated vaginal delivery and up to 96 hours following uncomplicated cesarean delivery (American Academy of Pediatrics, 20 1 7; Blumenfi e ld, 20 1 5) . Earlier hospital discharge is acceptable for appropriately selected women if they desire it . • Contraception

F I G U R E 36-7 P u bic symphysea l sepa ration fou nd o n the fi rst postpartu m d ay fol lowi ng vag i n a l del ivery of a 2840-g newborn. The patient had pa i n over the pubic bone a nd pa i n with a m bu la­ tion. A s h uffl i ng gait was noted, a nd she had d ifficu lty with leg ele­ vation when s u pi ne. The patient was treated with physica l thera py a nd a n a lgesics. A pelvic bi nder was a p p l ied, a n d a rol l i n g wa l ker was provided. She i m proved q u ickly a n d was d ischarged home o n postoperative day S .

I n rare cases, fractures of the sacrum or pubic ramus are caused by even uncomplicated deliveries (Alonso-Burgos, 2007; Speziali, 20 1 5) . As discussed in Chapter 5 8 (p. 1 1 29), the lat­ ter are more likely with osteoporosis associated with heparin or corticosteroid therapy (Cunningham, 2005). In rare bur serious cases, bacterial osteomyelitis-osteitis pubis-can be devastat­ ing. Lawford and coworkers (20 1 0) reported such a case that caused massive vulvar edema. • Immunizations

he D-negative woman who is not isoimmunized and whose newborn is D-positive is given 300 -1g of anti-D immune glob­ ulin shortly after delivery (Chap. I S , p. 305). Women who are not already immune to rubella or varicella are excellent candi­ dates for vaccination before discharge (Swamy, 20 1 5). hose who have not received a tetanus/diphtheria or inluenza vaccine should be given these (American College of Obstetricians and Gynecologists, 20 1 7c) . Morgan and colleagues (20 1 5) reported that implementation of a best-practices alert in the electronic medical record was associated with a tetanus/diphtheria immu­ nization rate of 97 percent at Parkland Hospital. Vaccination is also discussed in Chapter 9 (p. 1 7 1 ) . • Hospital Discharge

Following uncomplicated vaginal delivery, hospitalization is seldom warranted for more than 48 hours. A woman should receive instructions concerning anticipated normal physi­ ological puerperal changes, including lochia patterns, weight loss from diuresis, and milk let-down. She also should receive instructions concerning fever, excessive vaginal bleeding, or leg pain, swelling, or tenderness. Persistent headaches, shortness of breath, or chest pain warrant immediate concern.

During the hospital stay, a concerted efort is made to provide family planning education. Various forms of contraception are discussed throughout Chapter 38 and sterilization procedures in Chapter 39. Women not breastfeeding have return of menses usually within 6 to 8 weeks. At times, however, it is diicult clinically to assign a speciic date to the first menstrual period after deliv­ ery. A minority of women bleed small to moderate amounts intermittently, starting soon after delivery. Ovulation occurs at a mean of 7 weeks, but ranges from 5 to 1 1 weeks (Perez, 1 972) . hat said, ovulation before 28 days has been described (Hytten, 1 995). hus, conception is possible during the artii­ cially deined 6-week puerperium. Women who become sexualy active during the puerperium, and who do not desire to conceive, should initiate contraception. Kelly and associates (2005) reported that by the third month postpartum, 58 percent of adolescents had resumed sexual intercourse, but only 80 percent of these were using contraception. Because of this, many recommend long-acting reversible contraceptives-LARC (Baldwin, 20 1 3) . Women who breastfeed ovulate much less frequently com­ pared with those who do not, but variation is great. Tim­ ing of ovulation depends on individual biological variation and the intensity of breastfeeding. Lactating women may first menstruate as early as the second or as late as the 1 8th month after delivery. Campbell and Gray ( 1 993) analyzed daily urine specimens to determine the time of ovulation in 92 lactating women. As shown in Figure 36-8, breastfeeding in general delays resumption of ovulation, although as already empha-

1 00 75 -

::

8 50 ..

) .

25

10

20

30

40

50

Weeks postpartum

60

70

FIGURE 36-8 Cumu lative proportio n of breastfeed ing women who ovulated d u ri n g the first 70 weeks fol l owing del ivery. (Data from Campbell OM, Gray RH: Cha racteristics and determi n a nts of postpartum ova ria n fu nction in women in the U n ited States. Am J Obstet Gynecol 1 69:5S, 1 993.)

Th e Puerperi u m

sized, it does not invariably forestall it. Other fi n dings in their study included the following: 1 . Resumption of ovulation was frequently marked by return of normal menstrual bleeding. 2. Breastfeeding episodes lasting 1 5 minutes seven times daily delayed ovulation resumption. 3. Ovulation can occur without bleeding. 4. Bleeding can be anovulatory. 5. The risk of pregnancy in breastfeeding women was approxi­ mately 4 percent per year. For the breastfeeding woman, progestin-only contraceptives, such as progestin pills, depot medroxyprogesterone, or proges­ tin implants, do not afect the quality or quantity of milk. Suc­ cess with the progesterone-releasing vaginal ring has also been described (Carr, 20 1 6) . hese may be initiated any time during the puerperium. Estrogen-progestin contraceptives likely reduce the quantity of breast milk, but under the proper circumstances, they too can be used by breastfeeding women. hese hormonal methods are discussed in Chapter 38.

HOME CARE • Coitus

No evidence-based data guide resumption of coitus after delivery, and practices are individualized (Minig, 2009) . After 2 weeks, coitus may be resumed based on desire and comort. Barrett and colleagues (2000) reported that almost 90 per­ cent of 484 primiparous women resumed sexual activity by 6 months. And although 65 percent of these reported problems, only 1 5 percent discussed them with a health-care provider. Intercourse too soon may be unpleasant, if not frankly pain­ ful, and this may be related to episiotomy incisions or severe lacerations. In a study of women without an episiotomy, only 0.4 percent of those with a first- or second-degree tear had dyspareunia (Ventolini, 20 1 4) . Conversely, in primipa­ ras with an episiotomy, 67 percent had sexual dysfunction at 3 months, 3 1 percent at 6 months, and 1 5 percent at 1 2 months (Chayachinda, 20 1 5) . Dyspareunia was also common follow­ ing cesarean delivery (McDonald, 20 1 5) . Postpartum, the vulvovaginal epithelium is thin, and very little lubrication follows sexual stimulation. his stems from the hypoestrogenic state following delivery, which lasts until ovula­ tion resumes. It may be particularly problematic in breastfeeding women who are hypoestrogenic for many months postpartum (Palmer, 2003). For treatment, small amounts of topical estrogen cream can be applied daily for several weeks to vulvar tissues. Additionally, vaginal lubricants may be used with coitus. This same thinning of the vulvovaginal epithelium can lead to dysuria. Topical estrogen can again be ofered once cystitis is excl uded. • Late Maternal Morbidity

Taken together, major and minor maternal morbidity are sur­ prisingly common in the months following childbirth. In a survey of 1 249 British mothers followed for up to 1 8 months,

TABLE 36-5. P uerpera l M o rb i d ity Reported by 8 Weeks Morbidity Fati g u e B reast problems Anemia Backache Hem orrhoids Headache " B l u es" Con sti pati o n Sutu re brea kd own Vag i n a l d i scharg e

PercentQ 59 36 25 24 23 22

21

20 16 15

Gi n 8 7 percent of a l l wome n , at l east o n e sym ptom wa s re ported . Data from Glazener CM, Abda l l a M, Stroud P, et a l : Post nata l maternal m o rbid ity: extent, ca u ses, prevent i o n a n d treatment. BJOG 1 02:282, 1 995.

3 percent required hospital readmission within 8 weeks (Gla­ zener, 1 995; hompson, 2002) . Milder health problems during the first 8 weeks were reported by 87 percent (Table 3 6-5 ) . Moreover, almost three fourths continued to have various problems for up to 1 8 months. Practitioners should be aware of these potential issues in their convalescing patients. • Follow-Up Care

By discharge, women who had an uncomplicated vaginal deliv­ ery can resume most activities, including bathing, driving, and household functions. Jimenez and Newton ( 1 979) tabulated cross-cultural information on 202 societies from various interna­ tional geographical regions. Following childbirth, most societies did not restrict work activity, and approximately half expected a return to full duties within 2 weeks. Wallace and coworkers (20 l 3) reported that 80 percent of women who worked during pregnancy resume work by 1 year ater delivery. Despite this, Tulman and Fawcett ( 1 988) reported that only half of mothers regained their usual level of energy by 6 weeks. Women who delivered vaginally were twice as likely to have normal energy levels at this time compared with those with a cesarean delivery. Ideally, the care and nurturing of the infant should be provided by the mother with ample help from the father. The American Academy of Pediatrics and the American Col­ lege of Obstetricians and Gynecologists (20 1 7) recommend a postpartum visit between 4 and 6 weeks. his has proven quite satisfactory to identiy abnormalities beyond the immediate puerperium and to initiate contraceptive practices. REFERENCES Ahdoot 0, Van Nostrand M , Nguyen NJ , et al: he efect of route o f deliv­ ery on regression of abnormal cervical cytologic indings in the postpartum period. Am J Obstet Gynecol 1 78 : 1 1 1 6, 1 998 Almeida 00 Jr, Kitay DZ: Lactation suppression and puerperal fever. m J Obstet Gynecol 1 54:940, 1 9 86 Alonso-Burgos A, Royo P, Diaz L, et al: Labor-related sacral and pubic frac­ tures. J Bone Joint Surg 89:396, 2007

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The P ue rperi u m American Academy of Pediatrics: Breastfeeding and the use of human milk. Pediatrics 1 29 (3) :e827, 20 1 2 American Academy o f Pediatrics, American College o f Obstetricians and Gyne­ cologists: Guidelines for Perinatal Care, 8th ed. Elk Grove Village, AAP, 20 1 7 American College o f Obstetricians and Gynecologists: Breastfeeding i n under­ served women: increasing initiation and continuation of breastfeeding. Committee Opinion No. 570, August 20 1 3 , Reairmed 20 1 6a American College of Obstetricians and Gynecologists: Screening for perinatal depression. Committee Opinion No. 630, May 20 1 5 , Reairmed 20 1 6b American College of Obstetricians and Gynecologists: Marijuana use during pregnancy and lactation. Committee Opinion No. 722, October 20 1 7a American College of Obstetricians and Gynecologists: Optimizing support for breastfeeding as part of obstetric practice. Committee Opinion No. 658, February 20 1 6, Reairmed 20 1 7b American College of Obstetricians and Gynecologists: Update on immuniza­ tionand pregnancy: tetanus, diphtheria, and pertussis vaccination. Commit­ tee Opinion No. 7 1 8 , September 20 1 7c Anderson R, Davis J: Placental site involution. Am J Obstet Gynecol 1 02 :23, 1 96 8 Andrew A C , Bulmer I N , Wells M, e t a l : Subinvolution of the uteroplacental arteries in the human placental bed. Histopathology 1 5 :395, 1 98 9 Andrews MC: Epithelial changes in the puerperal fallopian tube. A m J Obstet Gyneco1 62:28, 1 9 5 1 Bae H S , m KH, O h MJ, e t al: Postpartum uterine involution: sonographic changes in the endometrium between 2 and 6 weeks postpartum related to delivery mode and gestational age at delivery. Ultrasound Obstet Gynecol 3 9(6) :727, 20 1 2 Baker JL, Gamborg M , Heitmann BL, e t al: Breastfeeding reduces postpartum weight retention. Am J Clin Nutr 8 8 (6) : 1 543, 2008 Baldwin MK, Edelman AB: he efect of long-acting reversible contraception on rapid repeat pregnancy in adolescents: a review. J Adolesc Health 52(4 Suppl):S47, 20 1 3 Ballard 0, Morrow L : Human milk composition: nutrients and bioactive factors. Pediatr Clin North Am 60( 1 ) :49, 20 1 3 Bannbers E , Gingnell M , Engman J , e t al: Prefrontal activity during response inhibition decreases over time in the postpartum period. Behav Brain Res 24 1 : 1 32 , 20 1 3 Barrett G , Pendry E , Peacock J , et al: Women's sexual health after childbirth. BJOG 1 07: 1 8 6 , 2000 Bartek MC, Stuebe M , Schwarz EB, et al: Cost analysis of maternal disease associated with suboptimal breastfeeding. Obstet Gynecol 1 22: 1 1 1 , 20 1 3 Belachew J , Axelsson 0 , Mulic-Lutvica A , e t al: Longitudinal study o f the uter­ ine body and cavity with three-dimensional ultrasonography in the puerpe­ rium. Acta Obstet Gynecol Scand 9 1 ( 1 0) : 1 1 84, 20 1 2 Berlin C M Jr, van den Anker IN: Safety during breastfeeding: drugs, foods, environmental chemicals, and maternal infections. Semin Fetal Neonatal Med 1 8 ( 1 ) : 1 3, 20 1 3 Bertino E , Varalda A , D i Nicola P , e t al: Drugs and breastfeeding: instructions for use. J Matern Fetal Neonatal Med 25 (Supp1 4) :78, 20 1 2 Blumenfield J, El-sayed Y, Lyell DJ, e t al: Risk factors for prolonged postpar­ tum length of stay following cesarean delivery. Am J Perinatol 32:825, 20 1 5 Buchanan J , Beckmann M : Postpartum voiding dysfunction: identiying the risk factors. Aust N Z J Obstet Gynaecol 54( 1 ) :4 1 , 20 1 4 Buhimschi CS, Buhimschi A , Malinow M , e t al: Myometrial thickness during human labor and immediately postpartum. Am J Obstet Gynecol 1 88 : 5 5 3 , 2003 Bunch K, Hope E: An uncommon case of bilateral peroneal nerve palsy fol­ lowing delivery: a case report and review of the literature. Case Rep Obstet Gyneco1 20 1 4:746480, 20 1 4 Campbell O M , Gray RH: Characteristics and determinants o f postpartum ovarian function in women in the United States. Am J Obstet Gynecol 1 69 : 5 5 , 1 993 Carr SL, Gaield ME, Dragoman MV, et al: Safety of the progesterone-releas­ ing vaginal ring (PVR) among lactating women. Contraception 94(3) :253, 20 1 6 Centers for Disease Control and Prevention: Breastfeeding Report Card­ United States, 20 1 4. Available at: http://ww.cdc.gov/breastfeeding/data/ reportcard.htm. Accessed March 27, 20 1 6 Centers for Disease Control and Prevention: PRAMS , the Pregnancy Risk Assessment Monitoring System. 20 1 6. Available at: http://ww. cdc.gov/ PRAMS/index.htm. Accessed March 27, 20 1 6 Chayachinda C , Titapant V, Ungkanungdecha A: Dyspareunia and sexual dys­ function ater vaginal delivery in hai primiparous women with episiotomy. J Sex Med 1 2 ( 5) : 1 27 5 , 20 1 5 Chesley LC, Valenti C , Uichano L : Alterations i n body fluid compartments and exchangeable sodium in early puerperium. Am J Obstet Gynecol 77: 1 0 54, 1 95 9

Collier RJ, Hernandez LL, Horseman N D : Serotonin a s a homeostatic regula­ tor of lactation. Domest Anim Endocrino1 43(2) : 1 6 1 , 20 1 2 Culligan P, Hill S , Heit M : Rupture of the symphysis pubis during vaginal delivery followed by two subsequent uneventful pregnancies. Obstet Gyne­ col 1 00 : 1 1 1 4, 2002 Cunningham FG: Screening for osteoporosis. N Engl J Med 353( 1 8) : 1 975, 2005 Dennis CL, Jackson K, Watson J: Interventions for treating painful nipples among breastfeeding women. Cochrane Database Syst Rev 1 2:CD007366, 20 1 4 Faupel-Badger JM, Arcaro F, Balkam J], e t al: Postpartum remodeling, lacta­ tion, and breast cancer risk: summary of a National Cancer Institute-spon­ sored workshop. J Nat! Cancer Inst 1 0 5 (3) : 1 66, 20 1 3 Fletcher S, Grotegut CA, James AH: Lochia patterns among normal women: a systematic review. J Womens Health (Larchmt) 2 1 ( 1 2) : 1 290, 20 1 2 Forrester-Knauss C , Merten S, Weiss C, e t al: The Baby-Friendly Hospital Initiative in Switzerland: trends over a 9-year period. J Hum Lact 29(4) : 5 1 0, 20 1 3 Funnell JW, Klawans AH, Cottrell TL: h e postpartum bladder. Am J Obstet Gyneco1 67: 1 249, 1 954 Glazener CM, Abdalla M, Stroud P, et al: Postnatal maternal morbidity: extent, causes, prevention and treatment. BJOG 1 02:282, 1 99 5 Harris E, homas L, H u i GW: Postpartum suveillance for urinary tract infection: patients at risk of developing pyelonephritis after catheterization. South Med J 70: 1 273, 1 977 Hibbard JU, Schrof SG, Cunningham FG: Cardiovascular alterations in nor­ mal and preeclamptic pregnancy. In Taylor N, Roberts JM, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amster­ dam, Academic Press, 20 1 4 Hladunewich A, Lafayette A, Derby G C , e t al: The dynamics o f glomerular iltration in the puerperium. Am J Physiol Renal Physiol 286:F496, 2004 Holdcrot A, Snidvongs S, Cason A, et al: Pain and uterine contractions during breast feeding in the immediate post-partum period increase with parity. Pain 1 04:589, 2003 Hytten F : he Clinical Physiology of the Puerperium. London, Farrand Press, 1 99 5 Iraha Y , Okada M , Toguchi M, et a l : Multimodality imaging in secondary postpartum or postabortion hemorrhage: retained products of conception and related conditions. J pn J Radiol October 1 9, 20 1 7 [Epub ahead of print] Iyengar SR, Walker WA: Immune factors in breast milk and the development of atopic disease. J Pediatr Gastroenterol Nutr 5 5 (6):64 1 , 20 1 2 Jimenez M H , Newton N: Activity and work during pregnancy and the post­ partum period: a cross-cultural study of 202 societies. Am J Obstet Gynecol 1 3 5 : 1 7 1 , 1 979 Jong DE, Kikkert HR, Fidler V, et al: Efects of long-chain polyunsaturated fatty acid supplementation of infant formula on cognition and behavior at 9 years of age. Dev Med Child Neurol 54( 1 2) : 1 1 02, 20 1 2 Kamel H , Navi B, Sriram N , e t al: Risk o f a thrombotic event after the 6-week postpartum period. N Engl J Med 370: 1 307, 20 1 4 Kandadai P, Kandadai V , Saini J , e t al: Acute urinary retention after cesarean delivery: a case-control study. Female Pelvic Med Reconstr Surg 20(5) :276, 20 1 4 Kaneshiro BE, Acoba J D , Holzman J , e t al: Efect o f delivery route o n natural history of cervical dysplasia. Am J Obstet Gynecol 1 92(5): 1 452, 2005 Kanotra S, D'Angelo 0, Phares TM, et al: Challenges faced by new mothers in the early postpartum period: an analysis of comment data from the 2000 Pregnancy Risk Assessment Monitoring System (PRAMS) survey. Matern Child Health J 1 1 (6) : 549, 2007 Kavalar R, Arko D, Fokter Dovnik N, et al: Subinvolution of placental bed vessels: case report and review of the literature. Wien Klin Wochenschr 1 24 ( 1 9-20):725 , 20 1 2 Kelly LS, Sheeder J , Stevens-Simon C: Why lightning strikes twice: postpartum resumption of sexual activity during adolescence. J Pediatr Adolesc Gynecol 1 8:327, 2005 Kenny LC, McCrae R, Cunningham FG: Platelets, coagulation, and the liver. In Taylor N, Roberts JM, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 20 1 4 Kharrazi FD, Rodgers B , Kennedy JG, et a l : Parturition-induced pelvic dis­ location: a report oHour cases. J Orthop Trauma 1 1 :277, 1 997 Kramer MS, Aboud F, Mironova E, et al: Breastfeeding and child cognitive development: new evidence from a large randomized trial. Arch Gen Psy­ chiatry 6 5 (5): 578, 2008 Lasbleiz J, Sevestre FX, Moquet PY: Using an elastic band device after a severe obstetric pubic symphyseal separation: clinical and imaging evaluation. Obstet Gynecol 1 30(3):62 5 , 20 1 7 Lawford M , Scott K , Lust K : A case o f massive vulvar oedema due t o septic pubic symphysitis complicating pregnancy. Aust N Z J Obstet Gynaecol 50(6) : 576, 20 1 0

The P u e r pe ri u m Lee CY, Madrazo B, Drukker B H : Ultrasonic evaluation of the postpartum uterus in the management of postpartum bleeding. Obstet Gynecol 58 :227, 1 98 1 Lipe BC, Dumas MA, Ornstein DL: Von Willebrand disease i n pregnancy. Hematol Oncol Clin North Am 2 5 (2):335, 201 1 Loukas M, Clarke P, Tubbs RS: Accessory breasts: a historical and current perspective. Am Surg 73 (5):525, 2007 Mangesi L, Zakarija-Grkovic I: Treatments for breast engorgement during lac­ tation. Cochrane Database Syst Rev 6:CD006946, 20 1 6 McCleary MJ: Epidermal growth factor: a n important constituent o f human milk. J H um Lact 7: 1 23 , 1 9 9 1 McDonald EA, Gartland D, Small R , et al: Dyspareunia and childbirth: a ptospective cohort study. BJOG 1 22 :672, 20 1 5 McDonald SD, Pullenayegum E , Chapman B , e t al: Prevalence and pre­ dictors of exclusive breastfeeding at hospital discharge. Obstet Gynecol 1 1 9 (6) : 1 1 7 1 , 20 1 2 Miller JM, Low LK, Zielinski R, et al: Evaluating maternal recovery from labor and delivery: bone and levator ani injuries. Am J Obstet Gynecol 2 1 3 : 1 88 e 1 , 20 1 5 Minig L , Trimble EL, Sarsotti C, e t al: Building the evidence base for postop­ erative and postpartum advice. Obstet Gynecol 1 1 4(4) :892, 2009 Morgan JL, Baggari S R, Chung W, et al : Association of a Best-Practice Alert and prenatal administration with tetanus toxoid, reduced diphtheria tox­ oid, and acellular pertussis vaccination rates. Obstet Gynecol 1 26(2):333, 20 1 5 Morris EA, Hale SA, Badger GJ , et al: Pregnancy induces persistent changes in vascular compliance in primiparous women. Am J Obstet Gynecol 2 1 2 (5) :633.e 1 , 20 1 5 Mulder FE, Hakvoort A, de Bruin JP, et al: Comparison of clean intermit­ tent and transurethral indwelling catheterization for the treatment of overt urinary retention after vaginal delivery: a multicentre randomized controlled clinical trial. Int Urogynecol J August 30, 20 1 7 [Epub ahead of print] Mulder FE, Hakvoort A, Schofelmeer MA, et al: Postpartum urinary reten­ tion : a systematic review of adverse efects and management. Int Urogynecol J 25 ( 1 2) : 1 605, 20 1 4 Musselwhite KL, Faris P , Moore K , e t al: Use o f epidural anesthesia and the risk of acute postpartum urinary retention. Am J Obstet Gynecol 1 96:472, 2007 Nelson DB, Manders DB, Shivvers SA: Primary iliopsoas abscess and preg­ nancy. Obstet Gynecol 1 1 6(2 Pt 2):479, 20 1 0 Palmer AR, Likis F E : Lactational atrophic vaginitis. J Midwifery Womens Health 48:282, 2003 Pang W, Hartmann PE Initiation of human lactation: secretory diferentia­ tion and secretory activation. J Mammary Gland Bioi Neoplasia 1 2:2 1 1 , 2007 Perez A, Vela P, Masnick GS, et al: First ovulation after childbirth: the efect of breastfeeding. Am J Obstet Gynecol 1 1 4: 1 04 1 , 1 9 2 Perrine CG, Galuska DA, Dohack JL, et al: Vital signs: improvements in maternity care policies and practices that support breastfeeding-United States, 2007-20 1 3 . MMWR 64 : 1 1 1 2 , 20 1 5 Pisacane A, Continisio GI, Aldinucci M , e t al: A controlled trial o f the father's role in breastfeeding promotion. Pediatrics 1 1 6:e494, 2005 Rahn DO, Phelan ]N, Roshanravan SM, et al: Anterior abdominal wall nerve and vessel anatomy: clinical implications for gynecologic surgery. Am ] Obstet Gynecol 202(3):234.e 1 , 20 1 0 Reis A , Baer J L , Arens A , e t al: Traumatic separation o f the symphysis pubis during spontaneous labor: with a clinical and x-ray study of the normal sym­ physis pubis during pregnancy and the puerperium. Surg Gynecol Obstet 55 :336, 1 932 Robson SC, Dunlop W, H unter S: Haemodynamic changes during the early puerperium. BM] (Clin Res Ed) 294: 1 065, 1 987 Rowe H , Baker T, Hale W: Maternal medication, drug use and breastfeeding. Pediatr Clin North Am 6 ( 1 ) :275, 20 1 3 Saito S , Maruyama M , Kato Y, e t al: Detection o f IL-6 i n human milk and its involvement i n IgA production. J Reprod ImmunoI 20:267, 1 99 1 Schauberger CW, Rooney BL, B rimer LM: Factors that influence weight loss in the puerperium. Obstet Gynecol 79:424, 1 992 Sharman A: Postpartum regeneration of the human endometrium. J Anat 87: 1 , 1 953 Snow RE, Neubert AG: Peripartum pubic symphysis separation: a case series and review of the literature. Obstet Gynecol Surv 52:438, 1 997

Society for Maternal-Fetal Medicine, Hughes B L, Page CM, et al: Hepatitis C in pregnancy: screening, treatment, and management. Am J Obstet Gynecol August 4, 20 1 7 [Epub ahead of print] Sohn C, Fendel H, Kesternich P: Involution-induced changes in arterial uter­ ine blood flow [German] . Z Geburtshilfe PerinatoI 1 92:203, 1 98 8 Spencer JP, Gonzalez L S III, Barnhart DJ : Medications in t h e breast-feeding mother. Am Fam Physician 65(2): 1 70, 2002 Speziali A, Tei MM, Placella G, et al: Postpartum sacral stress fracture. Case Rep Orthop 20 1 5 :704393, 20 1 5 Spitz M , Lee NC, Peterson HB: Treatment for lactation suppression: little progress in one hundred years. Am ] Obstet Gynecol 1 79: 1 4 8 5 , 1 99 8 Steinkeler J, Coldwell BJ , Warner MA: Ultrasound of the postpartum uterus. Ultrasound Q 28 (2) :97, 20 1 2 Stuebe M : Enabling women to achieve their breastfeeding goals. Obstet Gynecol 1 23:643, 20 1 4 Swamy G, Heine RP: Vaccinations for pregnant women. Obstet Gynecol 1 2 5 : 2 1 2, 20 1 5 Taylor RN, Sonson RD : Separation of the pubic symphysis. An underrecog­ nized peripartum complication. J Reprod Med 31 :203, 1 986 Tekay A, Jouppila P: A longitudinal Doppler ultrasonographic assessment of the alterations in peripheral vascular resistance of uterine arteries and ultra­ sonographic indings of the involuting uterus during the puerperium. Am J Obstet Gynecol 1 68 ( 1 Pt 1 ) : 1 90, 1 993 hompson JF, Roberts CL, Currie M, et al: Prevalence and persistence of health problems after childbirth: associations with parity and method of birth. Birth 29:83, 2002 Tulman L, Fawcett J: Return of functional ability after childbirth. N u rs Res 37:77, 1 98 8 U . S . Department of Health a n d H uman Services. Executive summary: t h e Sur­ geon General's call to action to support breastfeeding. 20 1 1 . Available at: http://ww. s urgeongeneral.gov/library/calls/breastfeeding/executivesum­ mary. pdf. Accessed March 27, 20 1 6 Van O s AF, Van der Linden PJ: Reliability o f a n automatic ultrasound sys­ tem in the post partum period in measuring urinary retention. Acta Obstet Gynecol Scand 8 5 :604, 2006 Vanhouten IN, Wysolmerski JJ: he calcium-sensing receptor in the breast. Best Prac Res Clin Endocrinol Metab 27(3)403, 20 1 3 Ventolini G, Yaklic J L, Galloway M L, e t al: Obstetric vulvar lacerations and postpartum dyspareunia. ] Reprod Med 59( 1 1 - 1 2) : 560, 20 1 4 Wager GP, Martin D H , Koutsky L , e t al: Puerperal infectious morbidity: rela­ tionship to route of delivery and to antepartum Chlamydia trachomatis infec­ tion . Am J Obstet GynecoI 1 38 : 1 028, 1 980 Wagner CL, Greer F R, American Academy of Pediatrics Section on Breastfeed­ ing: Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics 1 22(5): 1 1 42, 2008 Wagner IJ, Damitz A, Carey E, et al: Bilateral accessory breast tissue of the vulva: a case report introducing a novel labiaplasty technique. Ann Plast Surg 70(5): 549, 20 1 3 Wallace M , Saurel-Cubizolles M], EDEN mother-child cohort study group: Returning to work one year after childbirth: data from the mother-child cohort EDEN. Matern Child Health ] 1 7(8) : 1 432, 20 1 3 Weintraub AY, Aricha-Tamir B , Steiner N , et al: Postpartum uterine artery Doppler velocimetry among patients following a delivery complicated with preeclampsia. Hypenens Pregnancy 32(4):450, 20 1 3 Williams JW: Obstetrics. New York, D . Appleton, 1 903 Williams JW: Regeneration of the uterine mucosa after delivery with especial reference to the placental site. Am J Obstet Gynecol 22:664, 1 93 1 Wolfberg A], Michels KB, Shields W, e t al: Dads as breastfeeding advocates: results from a randomized controlled trial of an educational intervention. Am J Obstet GynecoI 1 9 1 :708, 2004 Wong CA, Scavone BM, Dugan S, et al: Incidence of postpartum lumbosacral spine and lower extremity nerve injuries. Obstet Gynecol 1 0 1 : 279, 2 003 World Health Organization: Exclusive breastfeeding for six months best for babies everywhere. 201 1 . Available at: http://www.who.int/mediacentre/news/state­ menrs/20 1 1 1breastfeeding..,20 1 1 01 1 5/en.l Accessed March 2 , 20 1 6 World Health Organization: Protecting, promoting and supporting breast­ feeding: the special role of maternity services. Geneva, World Health Orga­ nization, 1 989 Young OM, Werner E, Sfakianaki AK: Primary psoas muscle abscess after an uncomplicated spontaneous vaginal delivery. Obstet Gynecol 1 1 6(2 Pt 2): 4 , 20 1 0

665

666

C H A PT E R 3 7

P uerpera l Com p l i cat ion s

PUERPERAL FEVER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666 UTERINE INFECTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667 ABDOM INAL I NCISIONAL IN FECTIONS . . . . . . . . . . . . . 670 ADN EXAL ABSCESSES AND PERITONITIS . . . . . . . . . . . 671 PARAM ETRIAL PH LEGMON . . . . . . . . . . . . . . . . . . . . . . 672 SEPTIC PELVIC THROMBOPHLEBITIS . . . . . . . . . . . . . . . 673 PERI NEAL I N FECTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . 674 TOXIC SHOCK SYN DROME . . . . . . . . . . . . . . . . . . . . . . . 675 BREAST INF ECTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675

One cannotail to be impressed with the very large propor­ tion ofpatients whose troubles have originated rom ibrile aictions during the puerperium, which in many cases were cleary due to the neglect of aseptic precautions on the part of the obstetrician or midwe. -J. Whitridge Williams ( 1 903) Although the woman who recently gave birth is susceptible to several potentially serious complications, pelvic infection contin­ ues to be the most important source of maternal morbidity and mortality. Other infections include mastitis and breast abscesses. hat said, puerperal complications include many of those encoun­ tered during pregnancy. For example, as discussed in Chapter 52 (p. 1 004) , venous thromboembolism during the short 6-week puerperium is as frequent as during all 40 antepartum weeks. Other puerperal issues and care are discussed in Chapter 36.

PUERPERAL PELVIC I N F ECTION Traditionally, the term puerperal iniction describes any bacte­ rial infection of the genital tract after delivery. hese infections as well as preeclampsia and obstetrical hemorrhage formed the lethal triad of maternal death causes before and during the 20th century. Fortunately, because of efective antimicrobials, maternal mortality from infection has become uncommon. Creanga and associates (20 1 7) reported results from the Preg­ nancy Mortality Surveillance System, which contained 2009 pregnancy-related maternal deaths in the United States from 20 1 1 through 20 1 3. Infection caused 1 2.7 percent of preg­ nancy-related deaths and was the second leading cause. In a similar analysis of the North Carolina population from 1 99 1 through 1 999, Berg and colleagues (2005) reported that 40 percent of infection-related maternal deaths were preventable. • Puerperal Fever

Several infective and noninfective factors can cause puerperal fever-a temperature of 38.0°C ( 1 00.4°F) or higher. Most persistent ivers ater childbirth are caused by genital tract inic­ tion. Using this conservative deinition of fever, Filker and Monif ( 1 979) reported that only about 20 percent of women febrile within the fi r st 24 hours after vaginal delivery were sub­ sequently diagnosed with pelvic infection. his was in con­ trast to 70 percent of those after cesarean delivery. It must be emphasized that spiking fevers of 39°C or higher that develop within the first 24 hours postpartum may be associated with virulent pelvic infection caused by group A streptococcus, discussed on page 667. Other causes of puerperal fever include breast engorgement; infections of the urinary tract, of perineal lacerations, and of epi­ siotomy or abdominal incisions; and respiratory complications ater cesarean delivery (Nlaharaj , 2007) . Approximately 1 5 per­ cent of women who do not breastfeed develop postpartum fever

P u e rpera l Co m p l i ca t i o n s

from breast engorgement. As discussed in Chapter 36 (p. 659) , the incidence o f fever i s lower i n breastfeeding women. "Breast fever" rarely exceeds 39°C in the irst few postpartum days and usually lasts < 24 hours. Urinary inections are uncommon post­ partum because of the normal diuresis encountered then. Acute pyelonephritis has a variable clinical picture. The irst sign of renal infection may be fever, followed later by costovertebral angle ten­ derness, nausea, and vomiting. Atelectasis following abdominal delivery is caused by hypoventilation and is best prevented by coughing and deep breathing on a ixed schedule following sur­ gery. Fever associated with atelectasis is thought to stem from normal flora that proliferate distal to obstructing mucus plugs. • Uterine I nfection

Postpartum uterine infection or puerperal sepsis has been called variously endometritis, endomyometritis, and endoparametritis. Because infection involves not only the decidua but also the myometrium and parametrial tissues, we prefer the inclusive term metritis with pelvic celulitis. Pred i s po s i n g Fa cto rs

The route of delivery is the single most signiicant risk factor for the development of uterine infection (Burrows, 2004; Koroukian, 2004) . In the French Confidential Enquiry on Maternal Deaths, Deneux-haraux and coworkers (2006) cited a nearly 25-fold increased infection-related mortality rate with cesarean versus vaginal delivery. Rehospitalization rates for wound complications and metritis were increased significantly in women undergoing a planned primary cesarean delivery compared with those having a planned vaginal birth (Declercq, 2007). Women delivered vaginally at Parkland Hospital have a I ­ to 2-percent incidence o f metritis. For women at high risk for infection because of membrane rupture, prolonged labor, and multiple cervical examinations, the frequency of metritis after vaginal delivery is 5 to 6 percent. I f intrapartum chorioamnion­ itis is present, the risk of persistent uterine infection increases to 1 3 percent (Maberry, 1 99 1 ) . These igures are similar to those reported from a cohort of more than 1 1 5,000 women by the Maternal Fetal Medicine Units Network in whom the overall pelvic infection rate approximated 5 percent (Grobman, 20 1 5) . Because o f the significant morbidity following hysterotomy, single-dose perioperative antimicrobial prophylxis is recom­ mended for all women undergoing cesarean delivery (American College of Obstetricians and Gynecologists, 20 1 6b) . Antimicro­ bial prophylaxis has done more to decrease the incidence and severity of postcesarean delivery infections than any other inter­ vention in the past 30 years. Such practices decrease the puer­ peral pelvic infection risk by 65 to 75 percent (Smaill, 20 1 0) . he magnitude of the risk is exemplified from earlier reports that predate antimicrobial prophylaxis. Cunningham and asso­ ciates ( 1 978) described an overall incidence of 50 percent in all women undergoing cesarean delivery at Parland Hospital. Impor­ tant risk factors for infection following surgery included prolonged labor, membrane rupture, multiple cervical examinations, and internal fetal monitoring. Women with all these factors who were not given perioperative prophylaxis had a 90-percent serious post­ cesarean delivery pelvic infection rate (DePalma, 1 982).

It is generally accepted that pelvic infection is more frequent in women of lower socioeconomic status (Maharaj, 2007) . Except in extreme cases usually not seen in this country, it is likely uncommon that anemia or poor nutrition predispose to infection. Bacterial colonization of the lower genital tract with certain microorganisms-for example, group B streptococcus, Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma urea­ yticum, and Gardnerela vaginalis-has been associated with an increased postpartum infection risk (Andrews, 1 99 5 ; Jacobsson, 2002; Watts, 1 990). Other factors associated with an increased infection risk include general anesthesia, cesarean delivery for multifetal gestation, young maternal age and nulliparity, pro­ longed labor induction, obesity, and meconium-stained amni­ onic fl u id (Acosta, 20 1 2; Leth, 20 1 1 ; Siriwachirachai, 20 1 4; Tsai, 2 0 1 1 ) . M ic ro b i o logy

Most female pelvic infections are caused by bacteria indig­ enous to the genital tract. Over the past 25 years, there have been reports of group A 3-hemolytic streptococcus causing toxic shock-like syndrome and life-threatening infection (Castagnola, 2008; Nathan, 1 994) . Prematurely ruptured membranes are a prominent risk factor in these infections (Anteby, 1 999). In reviews by Crum (2002) and Udagawa ( 1 999) and their col­ leagues, women in whom group A streptococcal infection was manifested before, during, or within 1 2 hours of delivery had a maternal mortality rate of almost 90 percent and fetal mortality rate > 50 percent. In the past 1 0 years, skin and sot-tissue infec­ tions due to community-acquired methicillin-resistant Staphylo­ coccus aureus (A-MRSAJ have become common (Chap. 64, p. 1 223) . Although this variant is not a frequent cause of puerperal metritis, it is oten implicated in abdominal incisional infections (Anderson, 2007; Patel, 2007) . Rotas and coworkers (2007) reported a woman with episiotomy cellulitis from CA-MRSA and hematogenously spread necrotizing pneumonia. Common Pathogens. Bacteria responsible for most female genital tract infections are listed in Table 37- 1 . Most o f these infections are polymicrobial, which enhances bacterial synergy.

TABLE 37- 1 . Bacteria Com mo n ly Respon s i b l e for

Female Genita l I nfections Aerobes

G ra m-positive cocc i-g rou p A, B, a n d D streptococci, ente rococc us, Staphylococcus aureus, Staphylococcus epidermidis G ra m - n eg at i ve b a cteri a-Escherichia coll� Klebsiella, Proteus G ra m -va ri a bl e-Gardnerella vaginalis Oth ers

Mycoplasma a nd Chlamydia, Neisseria gonorrhoeae Anaerobes

Cocci-Peptostreptococcus a n d Peptococcus spec i es Oth ers-Clostridium, Bacteroides, Fusobacterium, Mobiluncus

667

668

The P u erperi u m

Other factors that promote virulence are hematomas and devi­ talized tissue. Although the cervix and vagina routinely harbor such bacteria, the uterine cavity is usually sterile before rupture of the amnionic sac. As the consequence of labor and delivery and associated manipulations, the amnionic fluid and uterus become contaminated with anaerobic and aerobic bacteria. Intraamnionic cytokines and C-reactive protein are also mark­ ers of infection (Combs, 20 1 3; Marchocki, 20 1 3) . In stud­ ies done before the use of antimicrobial prophylaxis, Gilstrap and Cunningham ( 1 979) cultured amnionic fluid obtained at cesarean delivery in women in labor with membranes ruptured more than 6 hours. All had bacterial growth, and on average, each specimen contained 2 . 5 organisms. Anaerobic and aero­ bic organisms were identified in 63 percent, anaerobes alone in 30 percent, and aerobes alone in only 7 percent. Anaerobes included Peptostreptococcus and Peptococcus species in 45 per­ cent, Bacteroides species in 9 percent, and Clostridium species in 3 percent. Aerobes included Enterococcus in 1 4 percent, group B streptococcus in 8 percent, and Escherichia coli in 9 percent of isolates. Sherman and coworkers ( 1 999) later showed that bacterial isolates at cesarean delivery correlated with those taken from women with metritis at 3 days postpartum. Group B strep­ tococci, E coli, and enterococci are some of the more common blood culture isolates with metritis (Cape, 20 1 3; O'Higgins, 20 1 4) . Although important because of the severity of infections they cause, clostridial species rarely cause puerperal infections (Chong, 20 1 6) . h e role o f other organisms i n the etiology o f these infections is unclear. Observations of Chaim and colleagues (2003) suggest that when cervical colonization of U ureayticum is heavy, it may contribute to the development of metritis. To add evidence to these observations, Tita and associates (20 1 6) recently reported that azithromycin-based extended-spectrum antimicrobial pro­ phylaxis reduced postoperative cesarean delivery infections from 12 to 6 percent compared with j-Iactam agents given alone. Chlamydial infections have been implicated in late-onset, indo­ lent metritis (Ismail, 1 985). Finally, Jacobsson and associates (2002) reported a threefold risk of puerperal infection in a group of Swedish women in whom bacterial vaginosis was identified in early pregnancy (Chap. 65, p. 1 245). Bacterial C u l t u res. Routine genital tract cultures obtained before treatment serve little clinical use and add significant costs. Similarly, routine blood cultures seldom modiy care. In two earlier studies done before perioperative prophy­ laxis was used, blood cultures were positive in 1 3 percent of women with postcesarean metritis at Parkland Hospital and 24 percent in those at Los Angeles County Hospital (Cun­ ningham, 1 978; DiZerega, 1 979) . In a later Finnish study, Kankuri and associates (2003) identified bacteremia in only 5 percent of almost 800 women with p uerperal sepsis. Blood cultures might be reasonable in women with exceedingly high temperature spikes that may signiy virulent infection with group A streptococci. Pathogenesis a n d C l i n i ca l Cou rse

Puerperal infection following vaginal delivery primarily involves the placental implantation site, decidua and adjacent

myometrium, or cervicovaginal lacerations. The pathogenesis of uterine infection following cesarean delivery is that of an infected surgical incision. Bacteria that colonize the cervix and vagina gain access to amnionic fluid during labor. Postpartum, they invade devitalized uterine tissue. Parametrial cellulitis next follows with infection of the pelvic retroperitoneal fibroareolar connective tissue. With early treatment, infection is contained within the parametrial and paravaginal tissue, but it may extend deeply into the pelvis. Fever is the most important criterion or the diagnosis ofpost­ partum metritis. Intuitively, the degree of fever is believed proportional to the extent of infection and sepsis syndrome. Temperatures commonly are 38 to 39°C. Chills that accom­ pany fever suggest bacteremia or endotoxemia. Women usu­ ally complain of abdominal pain, and parametrial tenderness is elicited on abdominal and bimanual examination. Leukocyto­ sis may range from 1 5 ,000 to 30,000 cells/�L, but recall that delivery itself increases the leukocyte count (Hartmann, 2000) . Although an ofensive odor may develop, many women have foul-smelling lochia without evidence for infection, and vice versa. Some other infections, notably those caused by group A j-hemolytic streptococci, may be associated with scant, odor­ less lochia (Anderson, 20 1 4) . Treat m e nt

I f nonsevere metritis develops following vaginal delivery, then treatment with an oral or intramuscular antimicro­ bial agent may be suicient (Meaney-Delman, 20 1 5) . For moderate to severe infections, however, intravenous therapy with a broad-spectrum antimicrobial regimen is indicated. Improvement follows in 48 to 72 hours in nearly 90 percent of women treated with one of several regimens discussed below. Persistent fever after this interval mandates a careful search for causes of refractory pelvic infection. hese include a parametrial phlegmon-an area of intense cellulitis; an abdominal incisional or pelvic abscess or infected hematoma; and septic pelvic thrombophlebitis. I n our experience, per­ sistent fever is seldom due to antimicrobial-resistant bacteria or due to drug side efects. he woman may be discharged home after she has been afebrile for at least 24 hours, and further oral antimicrobial therapy is not needed (French, 2004; Nlackeen, 20 1 5) . Choice of Ant i m icrobia ls. Although therapy is empirical, ini­ tial treatment following cesarean delivery is directed against ele­ ments of the mixed lora shown in Table 37- 1 . For infections following vaginal delivery, as many as 90 percent of women respond to regimens such as ampicillin plus gentamicin. In contrast, anaerobic coverage is included for infections following cesarean delivery (Table 37-2) . In 1 979, DiZerega and colleagues compared the efective­ ness of clindamycin plus gentamicin with that of penicillin G plus gentamicin for treatment of pelvic infections following cesarean delivery. Women given the clindamycin-gentamicin regimen had a 95-percent response rate, and this regimen is still considered by most to be the standard by which others are measured (F rench, 2004; Mackeen, 20 1 5) . Because enterococ­ cal cultures may be persistently positive despite this standard

P u e rpera l C o m p l i cations

TABLE 37-2. Antim i c ro b i a l Regi mens for Pelvic I nfecti o n s Fol l owi n g Cesa rea n Del ivery Re i men

Comments

C l i nda myc i n + g enta m i c i n

"Gold sta n d a rd," 90-97% eficacy, once-d a i ly g enta m ic i n dosing accepta b l e PLUS Am pici l l i n added t o reg i me n w i t h sepsis synd rome o r suspected enterococcal i nfection Genta m i c i n s u bstitute for ren a l i n s ufi ciency P i peraci l l i n , p i pe raci l l i n tazobacta m, a m p i ci l l i n/su l bacta m, ticarci l l i n/c lavu l a n ate Cefoteta n, cefoxiti n , cefotaxi me Added to other reg i me n s for s u spected Staphylococcus aureus i nfectio n s Metro n idazo l e has exce l l ent a n aerobic coverag e

Cli ndamyci n + aztreon a m Extended-s pectru m pen i ci l l i n s Cepha lospori n s Va n comyc i n Metro n idazole + a m pi ci l l i n + g e nta m i c i n Ca rba penems

I m i pe ne mlc i la stati n, m e ropenem, e rta penem reserved for s peci a l i nd i catio n s

therapy, some add ampicillin t o the clindamycin-gentamicin regimen, either initially or if there is no response by 48 to 72 hours (Brumfi e ld, 2000) . Many authorities recommend that serum gentamicin levels be periodically monitored. At Parkland Hospital, we do not routinely do so if the woman has normal renal function. Once­ daily dosing and multiple-dosing with gentamicin both pro­ vide adequate serum levels, and either method has similar cure rates (Livingston, 2003) . Because of potential nephrotoxicity and ototoxicity with gentamicin in the event of diminished glomerular iltration, some have recommended a combination of clindamycin and a second-generation cephalosporin to treat such women. Others recommend a combination of clindamy­ cin and aztreonam, which is a monobactam compound with activity similar to the aminoglycosides. The spectra of 3-lactam antimicrobials include activity against many anaerobic pathogens. Some examples include cephalosporins such as cefoxitin, cefotetan, cefotaxime, and ceftriaxone, as well as extended-spectrum penicillins such as piperacillin, ticarcillin, and mezlocillin. 3-Lactam antimicrobi­ als are inherently safe and, except for allergic reactions, are free of major toxicity. The 3-lactamase inhibitors clavulanic acid, sulbactam, and tazobactam have been combined with ampicil­ lin, amoxicillin, ticarcillin, and piperacillin to extend their spec­ tra. Metronidazole has superior in vitro activity against most anaerobes. This agent given with ampicillin and an aminogly­ coside provides coverage against most organisms encountered in serious pelvic infections. Metronidazole is also used to treat Clostridium dficile colitis. lmpenem and similar antimicrobials are in the carbape­ nem family. hese ofer broad-spectrum coverage against most organisms associated with metritis. Imipenem is used in com­ bination with cilastatin, which inhibits its renal metabolism. Preliminary indings with ertapenem indicated suboptimal out­ comes (Brown, 20 1 2) . It seems reasonable from both a medical and an economic standpoint to reserve these drugs for serious nonobstetrical infections. Vancomycin is a glycopeptide antimicrobial active against gram-positive bacteria. It is used in lieu of 3-lactam therapy for a patient with a type 1 allergic reaction and given for suspected infections due to Staphylococcus aureus and to treat C diicile colitis (Chap. 54, p. 1 048) .

Perio perative Pro p hylaxis

The use of periprocedural antimicrobial prophylaxis is com­ mon in obstetrics. Even so, no rigorous studies have evalu­ ated providing prophylaxis following operative vaginal delivery or manual removal of the placenta (Chongsomchai, 20 1 4; Liabsuetrakul, 20 1 7) . But, as discussed, antimicrobial prophylaxis at the time of cesarean delivery has remarkably reduced the postoperative pelvic and wound infection rates. Numerous studies have shown that prophylactic antimicro­ bials reduce the pelvic infection rate by 70 to 80 percent (Chelmow, 200 1 ; Dinsmoor, 2009; Smaill, 2 0 1 4) . he observed benefi t applies to both elective and nonelective cesarean delivery and also includes a reduction in abdominal incision infection rates. Single-dose prophylaxis with a 2-g dose of ampicillin or a first-generation cephalosporin is ideal. Both equal the eicacy of broad-spectrum agents or multiple-dose regimens (Ameri­ can College of Obstetricians and Gynecologists, 20 1 6b) . For obese women, evidence supports a 3-g dose of cefazolin to reach optimal tissue concentrations (Swank, 20 1 5 ) . Extended­ spectrum prophylaxis with azithromycin added to standard single-dose prophylaxis further reduced postcesarean metritis rates (Sutton, 20 1 5 ; Ward, 20 1 6) . As noted earlier, Tita and colleagues (20 1 6) reported that postoperative uterine infec­ tion was decreased from 1 2 to 6 percent with the addition of azithromycin to cefazolin. Women known to be colonized with MRSA are given vancomycin in addition to a cephalosporin (Chap. 64, p. 1 223). It is controversial whether the infection rate is lowered further if the antimicrobial is given before the skin incision compared with after umbilical cord clamping (Baaqeel, 20 1 3; Macones, 20 1 2; Sun, 20 1 3) . The American College of Obste­ tricians and Gynecologists (20 1 6b) has concluded that the evidence favors predelivery administration. Abdominal p reop­ erative skin preparation with chlorhexidine-alcohol is superior to iodine-alcohol for preventing surgical-site infections (Tuuli, 20 1 6) . Additive salutary efects may be gained by preoperative vaginal cleansing with povidone-iodine rinse or application of metronidazole gel (Haas, 20 1 4; Reid, 20 1 1 ; Yildirim, 2 0 1 2) . Other Method s of Prophylaxis. Several studies have addressed

the value of prenatal cervicovaginal cultures. These are obtained

669

670

The P u e rperi u m

i n the hope o f identiying pathogens that might b e eradicated to decrease incidences of preterm labor, chorioamnionitis, and puerperal infections. Unfortunately, treatment of asymptomatic vaginal infections has not been shown to prevent these com­ plications. Carey and coworkers (2000) reported no beneficial efects for women treated for asymptomatic bacterial vaginosis. Klebanof and colleagues (200 1 ) reported a similar postpartum infection rate in women treated for second-trimester asymp­ tomatic Trichomonas vaginalis infection compared with that of placebo-treated women. Technical maneuvers done to alter the postpartum infec­ tion rate have been studied with cesarean delivery. For example, allowing the placenta to separate spontaneously compared with removing it manually lowers the infection risk. However, chang­ ing gloves by the surgical team after placental delivery does not (Atkinson, 1 996). Exteriorizing the uterus to close the hyster­ otomy may decrease febrile morbidity (Jacobs-Jokhan, 2004). Postdelivery mechanical lower segment and cervical dilatation has not been shown to be efective (Liabsuetrakul, 20 1 1 ) . No diferences were found in postoperative infection rates when single- and two-layer uterine closures were compared (Hauth, 1 992) . Similarly, infection rates are not appreciatively afected by closure versus nonclosure of the peritoneum (Bamigboye, 20 1 4 ; Tulandi, 2003). Importantly, although closure of sub­ cutaneous tissue in obese women does not lower the wound infection rate, it does decrease the wound separation incidence (Chelmow, 2004) . Similarly, skin closure with staples versus suture has a higher incidence of noninfectious skin separation (Mackeen, 20 1 2; Tuuli, 20 1 1 ) . • Complications of Uterine

and Pelvic I nfections In more than 90 percent of women, metritis responds to antimicrobial treatment within 48 to 72 hours. In some of the remainder, any of several complications may arise. These include wound infections, complex pelvic infections such as phlegmons or abscesses, and septic pelvic thrombophlebitis ( Jaiyeoba, 20 1 2) . As with other aspects of p uerperal infections, the incidence and severity of these complications are remark­ ably decreased by perioperative antimicrobial prophylaxis. • Abdominal Incisional Infections

Wound infection is a common cause of persistent fever in women treated for metritis. Incisional infection risk factors include obesity, diabetes, corticosteroid therapy, immunosup­ pression, anemia, hypertension, and inadequate hemostasis with hematoma formation. If prophylactic antimicrobials are given, the incidence of abdominal wound infection following cesarean delivery ranges from 2 to 1 0 percent depending on risk factors (Andrews, 2003; Chaim, 2000) . From our experiences at Parkland Hospital, the incidence is closer to 2 percent. Incisional abscesses that develop following cesarean deliv­ ery usually cause persistent fever or fever that begins on about the fourth day. In many cases, antimicrobials had been given to treat pelvic infection, yet fever persisted. The wound is

J

"

�.....�./ .. -

c: - �

�

"

I

))

F I G U R E 37-1 Secondary a bd o m i n a l wou n d clos u re tech niq ue. (Reproduced with permi ssion from Worley KC: Postoperative com­ plications. In Yeoma n s ER, Hoffma n BL, Gi l stra p LC I I I, et a l (eds): C u n n i ng h a m a nd G i l stra p's Operative Obstetrics, 3 rd ed. N ew York, McGraw H i l l Ed ucation, 2 0 1 7.)

erythematous and drains pus. Although organisms that cause wound infections are generally the same as those isolated from amnionic luid at cesarean delivery, hospital-acquired patho­ gens may also be causative (Owen, 1 994) . Treatment includes antimicrobials and surgical drainage and debridement of devitalized tissue. his typically requires spinal analgesia or general anesthesia. The fascia is carefully inspected to document integrity. Local wound care there­ after is completed twice daily. Before each dressing change, procedural analgesia is tailored to wound size and location, and oral, intramuscular, or intravenous dosage routes are suit­ able. Topical lidocaine may also be added. Necrotic tissue is removed, and the wound is repacked with moist gauze. At 4 to 6 days, healthy granulation tissue is typically present, and secondary en bloc closure of the open layers can usually be accomplished (Wechter, 2005) . As shown in Figure 37- 1 , a polypropylene or nylon suture of appropriate gauge enters 2 to 3 cm from one wound edge. It crosses the wound to incorporate the full wound thickness and emerges 3 cm from the other wound edge. hese are placed in series to close the opening. In most cases, sutures may be removed on postpro­ cedural day 1 0. Vac u u m-Assi sted Wou nd C l os u re

his system was designed to apply negative pressure to a foam­ wound interface that would promote wound healing. The tech­ nique is variably referred to as vacuum-assisted closure-VAC; topical negative pressure-TNP; and negative-pressure wound

P u e rpe ra l Compl ications

therapy-NPWT. Several systems are available and widely accepted despite meager formal evidence for clinical eicacy (Echebiri, 20 1 5 ; Rouse, 20 1 5 ; Swift, 20 1 5) . In obstetrics, disrupted and infected abdominal wounds are a major indica­ tion for vacuum-assisted closure. Closure of perineal wounds resulting from infected episiotomies, hematomas, or abscesses is another (Aviki, 20 1 5) . hese devices are also used for the "open surgical abdomen," which is occasionally encountered in obstetrics. Negative-pressure wound therapy has also been used to prevent wound infections in those closed to heal by primary intention. Very few randomized trials have compared vacuum-assisted wound closure with conventional wound care (Semsarzadeh, 20 1 5) . Likewise, its cost efectiveness has not been thoroughly studied, although provider time is decreased substantially (Lewis, 20 1 4) . From their review, Moues and colleagues (20 1 l ) are more circumspect about its use for disrupted abdominal wounds because of scarce data. Other reviewers conclude that vacuum therapy is the most eicient method of temporary abdominal closure for patients with open abdominal wounds (Bruhin, 20 1 4; Quyn, 20 1 2) . Wo u n d De h i scence

Wound disruption or dehiscence refers to separation of the fascial layer. This is a serious complication and requires sec­ ondary closure of the incision in the operating room. McN ee­ ley and associates ( 1 998) reported a fascial dehiscence rate of approximately 1 per 300 operations in almost 9000 women undergoing cesarean delivery. Other than wound infection, obesity may be a risk factor (Subramaniam, 20 1 4) . Most dis­ ruptions manifested on about the fifth postoperative day and were accompanied by a serosanguinous discharge. Two thirds of 27 fascial dehiscences identified in this study were associated with concurrent fascial infection and tissue necrosis. • Necrotizing Fasciitis

This uncommon, severe wound infection is associated with high mortality rates. In obstetrics, necrotizing fasciitis may involve abdominal incisions, or it may complicate episiotomy or other perineal lacerations. As the name implies, tissue necro­ sis is significant. Of the risk factors for fasciitis summarized by Owen and Andrews ( 1 994) , three of these-diabetes, obesity, and hypertension-are relatively common in gravidas. Like pel­ vic infections, these wound complications usually are polymi­ crobial and are caused by organisms that make up the normal vaginal lora. In some cases, however, infection is caused by a single virulent bacterial species such as group A O-hemolytic streptococcus (Anderson, 20 1 4; Rimawi, 20 1 2) . Occasionally, necrotizing infections are caused by rarely encountered patho­ gens (Chong, 20 1 6; Swartz, 2004) . Goepfert and coworkers ( 1 997) reviewed their experiences with necrotizing fasciitis. Nine cases complicated more than 5000 cesarean deliveries, a frequency of 1 . 8 per 1 000. In two women, the infection was fatal. In another report, Schorge and colleagues ( 1 998) described ive women with fasciitis following cesarean delivery. None of these women had predisposing risk factors, and none died.

F I G U R E 3 7-2 Necrotizing fasci itis i nvolvi n g t h e a bd o m i n a l wa l l a n d Pfa n nenstiel i ncision. The s k i n ra pidly beca me d u s ky a n d g a n g renous, a n d p u s is seen exud i n g from the left a n g l e o f t h e incision. Exte n sive debridement a n d s u p po rtive thera py were lifesavi n g .

Infection may involve skin, supericial and deep subcu­ taneous tissues, and any of the abdominopelvic fascial layers (Fig. 37-2) . In some cases, muscle is also involved-myoosciitis. Although some virulent infections-for example, those caused by group A O-hemolytic streptococci-develop early postpar­ tum, most of these necrotizing infections do not cause symp­ toms until 3 to 5 days after delivery. Clinical findings vary, and it is frequently diicult to diferentiate more innocuous superi­ cial wound infections from an ominous deep fascial one. A high index of suspicion, with surgical exploration if the diagnosis is uncertain, may be lifesaving (Goh, 20 1 4) . We aggressively pursue early exploration. Certainly, if myofasciitis progresses, the woman may become ill from septicemia (Chap. 47, p. 92 1 ) . Early diagnosis, surgical debridement, antimicrobials, and intensive care are paramount to successfully treat necrotiz­ ing soft-tissue infections (Gallup, 2002; Goh, 20 1 4) . Surgery includes extensive debridement of all infected tissue, leaving wide margins of healthy bleeding tissue. This may include extensive abdominal or vulvar debridement with unrooing and excision of abdominal, thigh, or buttock fascia. Death is virtu­ ally universal without surgical treatment, and rates approach 25 percent even if extensive debridement is performed. With extensive resection, synthetic mesh may ultimately be required later to close the fascial incision (Gallup, 2002; McNeeley, 1 998) . • Adnexal Abscesses and Peritonitis

An ovarian abscess rarely develops in the puerperium. These are presumably caused by bacterial invasion through a rent in the ovarian capsule (Wetchler, 1 985). The abscess is usually unilat­ eral, and women typically present 1 to 2 weeks after delivery. Rupture is common, and peritonitis may be severe. Peritonitis is infrequent following cesarean delivery. It almost invariably is preceded by metritis, especially cases with uterine incisional necrosis and dehiscence. However, it may stem from

671

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The Puerperi u m

a ruptured adnexal abscess or an inadvertent intraoperative bowel injury. Peritonitis is rarely encountered ater vaginal delivery, and many such cases are due to virulent strains ofgroup A 3-hemolytic streptococci or similar organisms. Importantly in postpartum women, abdominal rigidity may not be prominent with puerperal peritonitis because of physiological abdominal wall laxity from pregnancy. Pain may be severe, but frequently, the irst symptoms of peritonitis are those of adynamic ileus. Marked bowel disten­ tion may develop, which is unusual ater uncomplicated cesarean delivery. If the infection begins in an intact uterus and extends into the peritoneum, antimicrobial treatment alone usually suf­ ices. Conversely, peritonitis caused by uterine incisional necrosis as discussed subsequently, or from bowel perforation, must be treated promptly with surgical intervention . • Parametrial Phleg mon

For some women in whom metritis develops following cesarean delivery, parametrial cellulitis is intensive and forms an area of induration-a phlemon-within the leaves of the broad liga­ ment (Fig. 37-3) . hese infections are considered when fever persists longer than 72 hours despite intravenous antimicrobial therapy (Brown, 1 999; DePalma, 1 982) . Phlegmons are usually unilateral, and they frequently are limited to the parametrium at the base of the broad ligament.

F I G U R E 37-4 Pelvic com puted tomography sca n showing necro­ sis of the uteri n e i ncision with gas in the myometri u m (arrows). There is also a l a rge rig ht-sided para metrial a bscess (a).

If the inflammatory reaction is more intense, cellulitis extends along natural lines of cleavage. he most common form of extension is laterally along the broad ligament, with a ten­ dency to extend to the pelvic sidewall. Occasionally, posterior extension may involve the rectovaginal septum, producing a firm mass posterior to the cervix. In most women with a phlegmon, clinical improvement follows continued treatment with a broad-spectrum antimicrobial regimen. Typically, fever resolves in 5 to 7 days, but in some cases, it persists longer. Absorption of the induration may require several days to weeks. In some women, severe cellulitis of the uterine incision may ultimately lead to necrosis and separation (Treszezamsky, 20 1 1 ) . Extrusion of purulent material as shown i n Figure 37-4 causes intraabdominal abscess formation and peritonitis as described above. Surgery is reserved for women in whom uterine inci­ sional necrosis is suspected because of ileus and peritonitis. For most, hysterectomy and surgical debridement are needed and are predictably diicult because the cervix and lower uterine segment are involved with an intense inflammatory process that extends to the pelvic sidewall. he adnexa are seldom involved, and one or both ovaries can usually be conserved. Blood loss is often appreciable, and transfusion is usually necessary. I ma g i n g Stu d i es

FIGU RE 37-3 Left-sided pa ra metri a l ph legmon: cel l u l itis ca u ses i n d u ration in the para metri u m a djacent to the hysterotomy i nci­ sion. (Reproduced with perm ission from Worley KC: Postoperative com plications. I n Yeomans E R, Hofman B L, Gilstra p LC I I I, et al (eds): C u n n i n g h a m a nd G i l strap's Operative Obstetrics, 3 rd ed. New York, McG raw H i l l Ed ucation, 2 0 1 7.)

Persistent puerperal infections can be evaluated using com­ puted tomography (CT) or magnetic resonance (MR) imaging. Brown and associates ( 1 99 1 ) used CT imaging in 74 women in whom pelvic infection was refractory to antimicrobial therapy given for 5 days. hey found at least one abnormal radiological inding in 75 percent of these women, and in most, these were nonsurgical lesions. In most cases, imaging can be used to dis­ suade surgical exploration. Uterine incisional dehiscence such as shown in Figure 37-4 can sometimes be confirmed based on CT scanning images. hese indings must be interpreted within the clinical context because apparent uterine incisional defects thought to represent edema can be seen even after uncompli­ cated cesarean delivery (Twickier, 1 99 1 ) . Shown in Figure 37-5

P u e rpera l Compl ications

percutaneous drainage may be required to efectively treat it (Shahabi, 2002; Swanson, 2008). • Septic Pelvic Thrombophlebitis

Suppurative thrombophlebitis was a frequent complication in the preantibiotic era, and septic embolization was com­ mon. However, with the advent of antimicrobial therapy, the mortality rate and need for surgical therapy for these infec­ tions diminished. Septic phlebitis arises as an extension along venous routes and may cause thrombosis as shown in Figure 37-6. Lymphangitis often coexists. he ovarian veins may then become involved because they drain the upper uterus and there­ fore the placental implantation site. The experiences of Witlin and Sibai ( 1 995) and Brown and coworkers ( 1 999) suggest that puerperal septic thrombophlebitis is likely to involve one or F I G U R E 37-5 Necrotic hysterotomy i nfection. Severe cel l u l itis of both ovarian venous plexuses. In a fourth of women, the clot the uteri ne i n cision resu lted in dehiscence with s u bseq uent lea k­ extends into the inferior vena cava and occasionally to the renal age into the peritoneal cavity. Hysterectomy was req u i red for suf­ vein. ficient debridement of necrotic tissue. The incidence of septic phlebitis has varied in several reports. In a 5-year survey of 45,000 women who were delivered at Parkland Hospital, Brown and associates ( 1 999) found an inci­ is a necrotic hysterotomy incision that leaked into the perito­ dence of septic pelvic thrombophlebitis in 1 per 9000 gravidas neal cavity. following vaginal delivery and 1 per 800 after cesarean delivery. Occasionally, a parametrial phlegmon may suppurate, form­ he overall incidence of 1 per 3000 deliveries was similar to ing a fluctuant broad ligament mass that may point above the the 1 per 2000 reported by Dunnihoo and colleagues ( 1 99 1 ) . inguinal ligament. hese abscesses can dissect anteriorly as In large studies o f women with cesarean delivery, the incidence shown in Figure 37-4 and be amenable to CT-directed needle was 1 in 400 to 1 in 1 000 surgeries (Dotters-Katz, 2 0 1 7; Rouse drainage. Occasionally they dissect posteriorly to the rectovagi­ 2004) . Chorioamnionitis, endometritis, and wound complica­ nal septum, where surgical drainage is easily efected by colpot­ tions were other risks. omy. A psoas abscess is rare, and despite antimicrobial therapy, Women with septic thrombo­ phlebitis usually have symptomatic improvement with antimicrobial ,-- I nferior vena cava treatment, however, they continue to have fever. Although pain occasion­ ally is noted in one or both lower --- Ovarian vein quadrants, patients are usually asymp­ tomatic except for chills. As shown in --- Common iliac vein Figure 37-7, the diagnosis can be con­ firmed by pelvic CT or MR imaging (Klima, 2008) . Using either, Brown and colleagues ( 1 999) found that 20 percent of 69 women with metritis -�- External iliac vein who had fever despite > 5 days of appropriate antimicrobial therapy J--- I nternal i liac vein had septic pelvic thrombophlebitis. It has been disproven that intrave­ nous heparin causes fever to dissipate .. .. ., -J --t ... --- Uterine vei n with septic phlebitis (Brown, 1 986; Witlin, 1 995) . And although Gar­ cia and coworkers (2006) and Klima and Snyder (2008) advocate heparin therapy, we do not recommend anti­ coagulation. In a randomized study of 14 women by Brown and associates FIGURE 37-6 Septic pelvic th rombophl ebitis: uteri ne a n d parametrial i nfection may extend ( 1 999) , the addition of heparin to to a ny pelvic vessel as wel l as the i nferior vena cava. The clot i n the right com mo n i l iac vei n antimicrobial therapy for septic pel­ extends from the uteri ne a n d interna l i l iac vei n s a n d into t h e inferior vena cava . T h e ova ria n vic thrombophlebitis did not hasten vei n septic t h rom bosis extends h a l fway to the vena cava.

673

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The P u e rperi u m

With infection, however, dehiscence is a concern. Ramin and colleagues ( 1 992) reported an episiotomy dehiscence rate of 0.5 percent at Parkland Hospital-80 percent of these were infected. Uygur and associates (2004) reported a I -percent dehiscence rate and attributed two thirds to infection. No data suggest that dehiscence is related to faulty repair. When the anal sphincter is disrupted at delivery, the subse­ quent infection rate is higher and is likely influenced by intra­ partum antimicrobial treatment (Buppasiri, 20 1 4; Stock, 20 1 3) . Lewicky-Gaupp and colleagues (20 1 5) reported a 20-percent infection rate. Infection of a fourth-degree laceration can be even more serious. Goldaber and coworkers ( 1 993) described fourth-degree lacerations in 390 parturients, of whom 5 .4 per­ cent had morbidity. In these women, 2.8 percent had infec­ tion and dehiscence, 1 .8 percent had only dehiscence, and 0.8 percent only infection. Although life-threatening septic shock is rare, it may still occur as a result of an infected episiotomy. Occasionally also, necrotizing fasciitis develops as discussed on page 67 1 . Pathogenesis a n d C l i n ica l Cou rse

FIGURE 37-7 Septic ova ri a n vei n throm bosis-contrast-en h anced computed tomog raphy sca n. A. E n l a rged right ova ria n vei n fi l led with low-density thrombus (black arrow). Contrast is seen in u reter (white arrow). R lower pole, rig ht kid ney. B. Coronal i mage demon­ strates e n larged right ovaria n vei n fi l led with low-density throm bus (arrows). (Reproduced with perm ission from Worley KC: Postopera­ tive complications. I n Yeomans ER, Hoffma n BL, Gilstrap LC III, et al (eds): C u n n i ng h a m and Gilstra p's Operative Obstetrics, 3 rd ed. New York, McGraw H i l l Ed ucation, 201 7.) =

recovery or improve outcome. Certainly, no evidence supports long-term anticoagulation. • Perineal I nfections

Episiotomy infections are not common because the operation is performed much less frequently now than in the past (Ameri­ can College of Obstetricians and Gynecologists, 20 1 6a) . Rea­ sons for this are discussed further in Chapter 27 (p. 530). In an older study, Owen and Hauth ( 1 990) described only 1 0 episiotomy infections in 20,000 women delivered vaginally.

Episiotomy dehiscence is most commonly associated with infection. Other factors include coagulation disorders, smok­ ing, and human papillomavirus infection (Ramin, 1 994) . Local pain and dysuria, with or without urinary retention, are fre­ quent symptoms. Ramin and colleagues ( 1 992) , evaluating a series of 34 women with episiotomy dehiscence, reported that the most common indings were pain in 65 percent, purulent discharge in 65 percent, and fever in 44 percent. In extreme cases, the entire vulva may become edematous, ulcerated, and covered with exudate. Vaginal lacerations may also become infected directly or by extension from the perineum. he epithelium becomes red and swollen and may then become necrotic and slough. Parame­ trial extension can lead to lymphangitis. Cervical lacerations are common but seldom are noticeably infected, which may manifest as metritis. Deep lacerations that extend directly into the base of the broad ligament may become infected and cause lymphangitis, parametritis, and bacteremia. Treatment. Infected episiotomies are managed similar to other

infected surgical wounds. Drainage is established, and in most cases, sutures are removed and the infected wound debrided. In women with obvious cellulitis but no purulence, close observa­ tion and broad-spectrum antimicrobial therapy alone may be appropriate. With dehiscence, local wound care is continued along with intravenous antimicrobials. Early Repai r of I nfected Episiotomy. Hauth and colleagues ( 1 986) were the irst to advocate early episiotomy repair after infection subsided, and other studies have confirmed the ei­ cacy of this approach. Hankins and coworkers ( 1 990) described early repair in 3 1 women with an average duration of 6 days from dehiscence to repair. All but two had a successful repair. Each of the two women with failures developed a pinpoint rec­ tovaginal istula that was treated successfully with a small rectal lap. With episiotomy dehiscence due to infection, Ramin and coworkers ( 1 992) reported successful early repair in 32 of

P u e rpe ra l Com pl i cations

TABLE 37-3. Preoperative Protocol for Ea rly Repa i r of Episiotomy Deh i scence Open wou nd, remove sutu res, beg i n i ntrave n o u s a n t i m icro b i a l s Wou nd care S itz bath severa l times d a i ly r hyd rothera py Adeq u ate a n a lgesia or a n esthes ia-reg i o n a l a na l g es i a or g e nera l a nesthesia may be necessa ry for t h e fi rst few debridem ents Scru b wou nd twice daily with a povidone-iod i ne sol ution Debride n ecrotic tissue Clos u re when afe b r i l e a n d p i n k, healthy g ra n u l ation tissue pred o m i nates Bowel p reparation for fou rth-deg ree repa i r

3 4 women (94 percent) , and Uygur and colleagues (2004) noted a similarly high percentage. Rarely, intestinal diversion may be required to allow healing (Rose, 2005). Before performing early repair, diligent preparation is essential as outlined in Table 37-3 . The surgical wound must be properly cleaned and cleared of infection. Once the surface of the episiotomy wound is free of infection and exudate and covered by pink granulation tissue, secondary repair can be accomplished. The tissue must be adequately mobilized, with special attention to identiy and mobilize the anal sphincter muscle. Secondary closure of the episiotomy is accomplished in layers, as described for primary episiotomy closure (Chap. 27, p. 53 1 ) . Postoperative care includes local wound care, stool softeners, and nothing per vagina or rec­ rum until healed. • Toxic Shock Syndrome This acute febrile illness with severe multisystem derangement has a case-fatality rate of 1 0 to 1 5 percent. Fever, headache, mental confusion, difuse macular erythematous rash, subcuta­ neous edema, nausea, vomiting, watery diarrhea, and marked hemoconcentration are usual fi n dings. Renal failure followed by hepatic failure, disseminated intravascular coagulopathy, and circulatory collapse may follow in rapid sequence. During recovery, the rash-covered areas undergo desquamation. For some time, Staphylococcus aureus was recovered from almost all aHicted persons. Specifically, a staphylococcal exotoxin, termed toxic shock syndrome toxin-l ( TSST-l) , was found to cause the clinical manifestations by provoking profound endo­ thelial injury. A very small amoun t of TSST- 1 has been shown to activate T cells to create a "cytokine storm" as described by Que (2005) and Heying (2007) and their coworkers. During the 1 990s, sporadic reports of virulent group A 3-hemolytic streptococcal infection began to appear (Ander­ son, 20 1 4) . Heavy colonization or infection is complicated in some cases by streptococcal toxic shock syndrome, which is produced when pyrogenic exotoxin is elaborated. Serotypes M I and M3 are particularly virulent (Beres, 2004; Okumura, 2004) . Finally, almost identical indings of toxic shock were

reported by Robbie and associates (2000) in women with Clos­ tridium sordellii colonization. Thus, in some cases of toxic shock syndrome, infection is not apparent and colonization of a mucosal surface is the pre­ sumed source. At least 1 0 to 20 percent of pregnant women have vaginal colonization with S aureus. And Clostridium petingens and sordellii are cultured from 3 to 1 0 percent of asymptomatic women (Chong, 20 1 6) . Thus, it is not surprising that the disease develops in postpartum women when growth of vaginal bacteria is luxuriant (Chen, 2006; Guerinot, 1 982) . Delayed diagnosis and treatment may be associated with maternal mortality (Schummer, 2002) . Crum and colleagues (2002) described a neonatal death following antenatal toxic shock syndrome. Principal therapy is supportive, while allow­ ing reversal of capillary endothelial injury. Ant�microbial ther­ apy that includes staphylococcal and streptococcal coverage is given. With evidence of pelvic infection, antimicrobial therapy must also include agents used for polymicrobial infections. Women with these infections may require extensive wound debridement and possibly hysterectomy. Because the toxin is so potent, the mortality rate is correspondingly high (Hotch­ kiss, 2003) . BREAST I N F ECTIONS Parenchymal infection of the mammary glands is a rare ante­ partum complication but is estimated to develop in up to a third of breastfeeding women (Barbosa-Cesnik, 2003). Exclud­ ing breast engorgement, in our experiences, as well as that of Lee and associates (20 1 0) , the incidence of mastitis is much lower and probably approximates 3 percent. No evidence sup­ ports any of several prophylactic measures to prevent breast infection (Crepinsek, 20 1 2) . Risk factors include diiculties in nursing, cracked nipples, and oral antibiotic therapy (Branch­ Elliman, 20 1 2; Mediano, 2 0 1 4) . Symptoms of suppurative mastitis seldom appear before the end of the first week postpar­ tum and, as a rule, not until the third or fourth week. Infection almost invariably is unilateral, and marked engorgement usu­ ally precedes inlammation. Symptoms include chills or actual rigors, which are soon followed by fever and tachycardia. Pain is severe, and the breast(s) becomes hard and red (Fig. 37-8) . Approximately 1 0 percent o f women with mastitis develop an abscess. Detection of fluctuation may be diicult, and sonogra­ phy is usually diagnostic. • Etiology

Staphylococcus au reus, especially MRSA, is the most com­ monly isolated organism in breast infections. Matheson and coworkers ( 1 988) found it in 40 percent of women with mas­ titis. O ther commonly isolated organisms are coagulase-neg­ ative staphylococci and viridans streptococci. The immediate source of organisms that cause mastitis is almost always the infant's nose and throat. Bacteria enter the breast through the nipple at fi s sures or small abrasions. he infecting organ­ ism can usually be cultured from milk. Toxic shock syndrome from mastitis caused by S aureus has been reported (Demey, 1 989; Fujiwara, 200 1 ) .

675

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F I G U R E 37-8 P uerpera l mastitis with b reast a bscess. A. P hoto­ g ra ph shows i n d u rated, erythematous skin overlying a rea of rig ht b reast i nfection. B. Sonog ra p h ic picture of this 5-cm abscess. (Used with perm ission from Dr. E m i ly Ad h i kari.)

At times, suppurative mastitis reaches epidemic levels among nursing mothers. Such outbreaks most often coincide with the appearance of a new strain of antibiotic-resistant staphylococ­ cus. A contemporaneous example is CA-MRSA, which has rap­ idly become the most commonly isolated staphylococcal species in some areas (Berens, 20 1 0; Klevens, 2007) . At Parkland Hos­ pital from 2000 to 2004, Laibl and associates (2005) reported that a fourth of CA-MRSA isolates were from pregnant or postpartum women with puerperal mastitis. Hospital-acquired MRSA may cause mastitis when the newborn becomes colo­ nized ater contact with nursery personnel who are colonized (Centers for Disease Control and Prevention, 2006) . Staford and colleagues (2008) found a higher incidence of recurrent abscess in those with CA-MRSA-associated mastitis. • Management

Provided that appropriate therapy for mastItiS is started before suppuration begins, the infection usually resolves within 48 hours. As discussed, abscess formation is more

common with S aureus infection (Matheson, 1 988) . Most recommend that milk be expressed from the afected breast onto a swab and cultured before therapy is begun. B acterial identification and antimicrobial sensitivities provide infor­ mation mandatory for a successful program of nosocomial infection surveillance (Lee, 20 1 0) . The most efective treatment has not been reported Oahan­ far, 20 1 3) . hus, the initial antimicrobial choice is influenced by the current experience with staphylococcal infections at a given institution. Dicloxacillin, 500 mg orally four times daily, may be started empirically. Erythromycin is given to women who are penicillin sensitive. If the infection is caused by resistant, penicillinase-producing staphylococci or if resistant organisms are suspected while awaiting the culture results, then vancomycin, clindamycin, or trimethoprim-sulfamethoxazole is given (Sheield, 20 1 3) . Although clinical response may be prompt, treatment is recommended for 1 0 to 14 days. Marshall and coworkers ( 1 975) demonstrated the impor­ tance of continued breastfeeding. hey reported that of 65 women with mastitis, the only three who developed abscesses were among the 1 5 women who quit breastfeeding. Vigorous milk expression may be suicient treatment alone (homsen, 1 984) . Sometimes the infant will not nurse on the inlamed breast. his probably is not related to any changes in the milk taste but is secondary to engorgement and edema, which can make the areola harder to grip. Pumping can alleviate this. When nursing bilaterally, it is best to begin suckling on the uninvolved breast. This allows let-down to commence before moving to the tender breast. In resource-poor countries, breastfeeding in women infected with the human immunodeficiency virus (HIV) is not contra­ indicated. In the setting of mastitis or breast abscess, it is rec­ ommended to stop feeding from the infected breast. his is because HIV RNA levels increase in afected breast milk. These levels return to baseline after symptoms resolve (Semrau, 20 1 3) . • Breast Abscess

In a population-based study of nearly 1 .5 million Swedish women, the incidence of breast abscess was 0. 1 percent (Kvist, 2005) . An abscess should be suspected when defervescence does not follow within 48 to 72 hours of mastitis treatment or when a mass is palpable. Again, sonographic imaging is valuable. Breast abscesses can be large, and in one case report, 2 L of pus were released (Martic, 20 1 2) . Traditional therapy is surgical drainage, which usually requires general anesthesia. he incision ideally is placed along Langer skin lines for a cosmetic result (Stehman, 1 990) . In early cases, a single incision over the most dependent portion of luctuation is usually suicient. Multiple abscesses, however, require several incisions and disruption of loculations. The resulting cavity is loosely packed with gauze, which should be replaced at the end of 24 hours by a smaller pack. A more recently used technique that is less invasive is sono­ graphically guided needle aspiration using local analgesia. his has an 80- to 90-percent success rate (Geiss, 20 1 4; Schwarz, 200 1 ) . In a randomized trial, Naeem and colleagues (20 1 2) compared surgical drainage and aspiration. They found aspiration resulted in quicker healing at 8 weeks, 77 versus 93 percent, respectively.

Puerpera l C o m p l i cations

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The P u erperi u m Grobman WA, Bailit ]L, Rice MM, e t al: Racial and ethnic disparities i n mater­ nal morbidity and obstetric care. Obstet GynecoI 1 2 5 (6) : 1 460, 20 1 5 Guerinot GT, Gitomer SD, Sanko SR: Postpartum patient with toxic shock syndrome. Obstet Gynecol 5 9:43S, 1 982 Haas DM, Morgan S , Contreras K: Vaginal preparation with antiseptic solution before cesarean section for preventing postoperative infections. Cochrane Database Syst Rev 1 2:CD007892, 20 1 4 Hankins G D , Hauth ]C, Gilstrap LC, e t al: Early repair o f episiotomy dehis­ cence. Obstet Gynecol 75:48, 1 990 Hartmann KE, Barrett E, Reid VC, et al: Clinical usefulness of white blood cell count after cesarean delivery. Obstet Gynecol 96:295, 2000 Hauth ]C, Gilstrap LC III, Ward SC, et al: Early repair of an external sphincter ani muscle and rectal mucosal dehiscence. Obstet Gynecol 67:806, 1 986 Hauth ]C, Owen ], Davis RO: Transverse uterine incision closure: one versus two layers. Am ] Obstet GynecoI 1 67: 1 1 08, 1 992 Heying R, van de Gevel ], Que YA, et al: Fibronectin-binding proteins and clumping factor A in Staphylococcus aureus experimental endocarditis: FnBPA is suicient to activate human endothelial cells. hromb Haemost 97:6 1 7, 2007 Hotchkiss RS, Karl IE: The pathophysiology and treatment of sepsis. N Engl ] Med 348:2, 2003 Ismail MA, Chandler AE, Beem ME: Chlamydial colonization of the cervix in pregnant adolescents. ] Reprod Med 30: 549, 1 9 85 ]acobs-]okhan D , Hofmeyr G: Extra-abdominal versus i ntra-abdominal repair of the uterine incision at caesarean section. Cochrane Database Syst Rev 4:CD0000 8 5 , 2004 ]acobsson B , Pernevi P, Chidekel L, et al: Bacterial vaginosis in early pregnancy may predispose for preterm birth and postpartum endometritis. Acta Obstet Gynecol Scand 8 1 : 1 006, 2002 ]ahanfar S, Ng q , Teng CL: Antibiotics for mastitis in breastfeeding women. Cochrane Database Syst Rev 2 :CD005458, 20 1 3 ]aiyeoba 0 : Postoperative infections i n obstetrics and gynecology. Clin Obstet Gynecol 5 5 (4) :904, 20 1 2 Kankuri E, Kurki T , Carlson P , e t al: Incidence, treatment and outcome of peripartum sepsis. Acta Obstet Gynecol Scand 82 :730, 2003 Klebanof MA, Carey ]C, Hauth ]C, et al: Failure of metronidazole to prevent preterm delivery among pregnant women with asymptomatic Trichomonas vaginalis infection. N Engl ] Med 345 :487, 200 1 Klevens M , Morrison MA, Nadle ] , et al: Invasive methicillin-resistant Staph­ ylococcus aureus infections in the United States. ]AMA 298: 1 763, 2007 Klima DA, Snyder TE: Postpartum ovarian vein thrombosis. Obstet Gynecol 1 1 1 :43 1 , 2008 Koroukian SM: Relative risk of postpartum complications in the Ohio Medic­ aid population: vaginal versus cesarean delivery. Med Care Res Rev 6 1 : 203, 2004 Kvist LJ, Rydhstroem H: Factors related to breast abscess after delivery: a pop­ ulation-based study. BJOG 1 1 2: 1 070, 2005 Laibl VR, Sheield JS, Roberts S, et al: Clinical presentation of community­ acquired methicillin-resistant Staphylococcus aureus in pregnancy. Obstet Gynecol 1 06:46 1 , 2005 Lee IW, Kang L, Hsu HP, et al: Puerperal mastitis requiring hospitalization during a nine-year period. Am ] Obstet Gynecol 203(4) :332, 20 1 0 Leth A , Uldbjerg N , Norgaard M , e t al: Obesity, diabetes, and the risk of infections diagnosed in hospital and post-discharge infections ater cesarean section: a prospective cohort study. Acta Obstet Gynecol Scand 90(5):50 1 , 20 1 1 Lewis LS, Convery PA, Bolac CS, et al: Cost of care using prophylactic nega­ tive pressure wound vacuum on closed laparotomy incisions. Gynecologic Oncology 1 32 (3) :684, 20 1 4 Liabsuetrakul T , Choobun T , Peeyananjarassri K , e t al: Antibiotic prophylaxis for operative vaginal delivery. Cochrane Database Syst Rev 8:CD0044 5 5 , 20 1 7 Liabsuetrakul T , Peeyananjarassri K : Mechanical dilatation o f the cervix a t non­ labour caesarean section for reducing postoperative morbidity. Cochrane Database Syst Rev I I :CD0080 1 9, 20 1 1 Livingston ]c, Llata E, Rinehart E, et al: Gentamicin and clindamycin therapy in postpartum endometritis: the eicacy of daily dosing versus dosing every 8 hours. Am ] Obstet GynecoI 1 88 : 1 49, 2003 Lewicky-Gaupp C, Leader-Cramer A, Johnson LL, et al: Wound complications after obstetric anal sphincter injuries. Obstet Gynecol 1 25 ( 5) : 1 088, 20 1 5 Maberry MC, Gilstrap LC ITI, Bawdon RE, et al: Anaerobic coverage for intra­ amnionic infection: matenal and perinatal impact. Am J Perinatol 8:338, 1 99 1 Mackeen AD, Berghella V, Larsen ML: Techniques and materials for skin clo­ sure in caesarean section. Cochrane Database Syst Rev I I :CD003 57 , 20 1 2 Mackeen AD, Packard RE, Ota E , e t al: Antibiotic regimens for postpartum endometritis. Cochrane Database Syst Rev 2:CDOO 1 067, 20 1 5

Macones GA, Cleary L, Parry S, et al: The timing of antibiotics at cesarean: a randomized controlled trial. Am J PerinatoI 29 (4) :273, 20 1 2 Maharaj D : Puerperal pyrexia: a review. Part II: Obstet Gynecol Surv 62:400, 2007 Marchocki Z, O' Donoghue M, Collins K, et al: Clinical signiicance of elevated high-sensitivity C-reactive protein in amniotic fluid obtained at emergency caesarean section. Am ] Obstet Gynecol 208 ( 1 ) S 3 1 4, 20 1 3 Marshall BR, Hepper ]K, Zirbel CC: Sporadic puerperal mastitis-an infec­ tion that need not interrupt lactation. ]AMA 344: 1 3 77, 1 975 Martic K, Vasilj 0: Extremely large breast abscess in a breastfeeding mother. ] H um Lact 2 8 (4) :460, 20 1 2 Matheson I , Aursnes I , Horgen M , e t al: Bacteriological indings and clinical symptoms in relation to clinical outcome in puerperal mastitis. Acta Obstet Gynecol Scand 67:723, 1 988 McNeeley SG ]r, Hendrix SL, Bennett SM, et al: Synthetic graft placement in the treatment of fascial dehiscence with necrosis and infection. Am ] Obstet Gynecol 1 79: 1 430, 1 998 Meaney-Delman D, Bartlett A, Gravett MG, et al: Oral and intramuscular treatment options for early postpartum endometritis in low-resource set­ tings: a systematic review. Obstet GynecoI 1 25 (4) :789, 20 1 5 Mediano P , Fernandez L , Rodriguez JM, et al: Case-control study of risk fac­ tors for infectious mastitis in Spanish breastfeeding women. BMC Preg­ nancy Childbirth 1 4 : 1 9 5, 20 1 4 Moues CM, Heule F, Hovius SE: A review o f topical negative pressure therapy in wound healing: suicient evidence? Am ] Surg 20 1 (4) : 544, 2 0 1 1 Naeem M, Rahimnajjad MK, Rahimnajjad NA, et al: Comparison of incision and drainage against needle aspiration for the treatment of breast abscess. Am Surg 78 ( 1 1 ) : 1 224, 20 1 2 Nathan L , Leveno K]: Group A streptococcal puerperal sepsis: historical review and 1 990s resurgence. Infect Dis Obstet Gynecol 1 :252, 1 994 O'Higgins AC, Egan AF, Murphy Oc, et al: A clinical review of maternal bacteremia. Int Gynaecol Obstet 1 24(3):226, 20 1 4 Okumura K , Schrof R , Campbell R , e t al: Group A streptococcal puerperal sepsis with retroperitoneal involvement developing in a late postpartum woman: case report. Am Surg 70:730, 2004 Owen ] , Andrews W: X'ound complications after cesarean section. Clin Obstet Gynecol 27:842, 1 994 Owen J, Hauth JC: Episiotomy infection and dehiscence. In Gilstrap LC III, Faro S (eds): I nfections in Pregnancy. New York, Liss, 1 990, p 61 Patel M , Kumar A, Stamm AM, et al: USA300 genotype community-asso­ ciated methicillin-resistant Staphylococcus aureus as a cause of surgical site infection. ] Clin Microbiol 45 ( 1 0) :343 1 , 2007 Que YA, HaeAiger ]A, Piroth L, et al: Fibrinogen and ibronectin binding cooperative for valve infection and invasion i n Staphylococcus aureus experi­ mental endocarditis. ] Exp Med 20 1 : 1 627, 2005 Quyn A], Johnston C, Hall D, et al: he open abdomen and temporary abdominal closure systems-historical evolution and systematic review. Colorectal Dis 1 4(8) :e429, 20 1 2 Ramin SM, Gilstrap LC: Episiotomy and early repair of dehiscence. Clin Obstet Gynecol 37: 8 1 6, 1 994 Ramin SM, Ramus R, Little B, et al: Early repair of episiotomy dehiscence associated with infection. Am J Obstet Gynecol 1 67: 1 1 04, 1 992 Reid VC, Hartmann E, McMahon M, et al: Vaginal preparation with povi­ done iodine and postcesarean infectious morbidity: a randomized controlled trial. Obstet GynecoI 97: 1 47, 20 1 1 Rimawi B H , Soper DE, Eschenbach DA: Group A streptococcal infections in obstetrics and gynecology. Clin Obstet Gynecol 5 5 (4) : 864, 20 1 2 Robbie A , Dummer S , Booth NA, et al: Plasminogen activator inhibitor 2 and urokinase-type plasminogen activator in plasma and leucocytes in patients with severe sepsis. Br ] Haematol 1 09:342, 2000 Rose CH, Blessitt L, Araghizadeh F : Episiotomy dehiscence that required intestinal diversion. Am J Obstet Gynecol 1 93: 1 759, 2005 Rotas M , McCalla S , Liu C, et al: Methicillin-resistant Staphylococcus aureus necrotizing pneumonia arising from an infected episiotomy site. Obstet Gynecol 1 09: 533, 2007 Rouse D]: Prophylactic negative pressure wound therapy. Obstet Gynecol 1 25 : 297, 20 1 5 Rouse DJ, Landon M , Leveno KJ , et al: The Maternal-Fetal Medicine Units cesarean registry: chorioamnionitis at term and its duration-relationship to outcomes. m ] Obstet Gynecol 1 9 1 :2 1 1 , 2004 Schorge JO, Granter SR, Lerner LH, et al: Postpartum and vulvar necrotizing fasciitis: early clinical diagnosis and histopathologic correlation. ] Reprod Med 43:586, 1 998 Schummer W, Schummer C: Two cases of delayed diagnosis of postpartal strep­ tococcal toxic shock syndrome. Infect Dis Obstet Gynecol 1 0:21 7, 2002 Schwarz RJ, Shrestha R: Needle aspiration of breast abscesses. Am J Surg 1 82: 1 1 7, 200 1

P u erpera l Co m p l ications Semrau K, Kuhn L, Brooks DR, et al: Dynamics of breast milk HIV- 1 RNA with unilateral mastitis or abscess. ] Acquir Immune Defic Syndr 62(3):348, 20 1 3 Semsarzadeh NN, Tadisina KK, Maddox ] , et al: Closed incision negative­ pressure therapy is associated with decreased surgical-site infections: a meta­ analysis. Plast Reconstr Surg 1 36(3):592, 20 1 5 Shahabi S , Klein ]P, Rinaudo PF: Primary psoas abscess complicating a normal vaginal delivery. Obstet Gynecol 99:906, 2002 Sheield ]S: Methicillin-resistant Staphylococcus aureus in obstetrics. Am ] Peri­ nato I 30(2) : 1 25, 20 1 3 Sherman 0 , Lurie S , Betzer M , e t al: Uterine flora at cesarean and its relation­ ship to postpartum endometritis. Obstet Gynecol 94:787, 1 999 Siriwachirachai T, Sangkomkamhang US, Lumbiganon P, et al: Antibiotics for meconium-stained amniotic fluid in labour for preventing matenal and neonatal infections. Cochrane Database Syst Rev 1 1 :CD007772, 2 0 1 4 Smaill FM, Grivell M : Antibiotic prophylaxis versus n o prophylaxis for preventing infection after cesarean section. Cochrane Database Syst Rev 1 0:CD007482, 2 0 1 4 Staford I , Hernandez ], Laibl V , e t al: Community-acquired methicillin-resis­ tant Staphylococcus aureus among patients with puerperal mastitis requiring hospitalization. Obstet GynecoI 1 1 2(3) : 533, 2008 Stehman FB: Infections and inflammations of the breast. In Hindle WH (ed): Breast Disease for Gynecologists. Norwalk, Appleton & Lange, 1 990, p 1 5 1 Stock L , Basham E , Gossett D R, et al: Factors associated with wound com­ plications in women with obstetric and sphincter injuries (OASIS). Am ] Obstet Gynecol 208(4) :327.e 1 , 20 1 3 Subramaniam A , ]auk VC, Figueroa 0 , e t al: Risk factors for wound disruption following cesarean delivery. ] Matern Fetal Neonatal Med 27( 1 2) : 1 237, 20 1 4 Sun ], Ding M , Liu ] , et al: Prophylactic administration of cefazolin prior to skin incision versus antibiotics at cord clamping in preventing postcesarean infectious morbidity: a systematic review and meta-analysis of randomized controlled trials. Gynecol Obstet Invest 75(3) : 1 75 , 20 1 3 Sutton AL, Acosta EP, Larson KB, e t al : Perinatal pharmacokinetics o f azithro­ mycin for cesarean prophylaxis. Am ] Obstet GynecoI 2 1 2 (6) : 8 1 2 .e l , 20 1 5 Swank ML, Wing DA, Nicolau DP, e t al: Increased 3-gram cefazolin dosing for cesarean delivety prophylaxis in obese women. Am ] Obstet Gynecol 2 1 3(3) :4 1 5 . e 1 , 20 1 5 Swanson A , Lau KK, Kornman T , e t al: Primary psoas muscle abscess i n preg­ nancy. Aust N Z ] Obstet Gynaecol 48 (6):607, 2008 Swartz MN: Cellulitis. N Engl ] Med 350:904, 2004 Swift SH, Zimmerman MB, Hardy-Fairbanks A]: Efect of Single-use negative pressure wound therapy on postcesarean infections and wound complica­ tions for high-risk patients. ] Reprod Med 60(5-6) : 2 1 1 , 20 1 5

Tita AT, Szychowski ]M, Boggess K, et al: Adjunctive azithromycin prophy­ laxis for cesarean delivery. N Engl ] Med 375 ( 1 3) : 1 23 1 , 20 1 6 Thomsen AC, Espersen T , Maigaard S : Course and treatment o f milk stasis, noninfectious inflammation of the breast, and infectious mastitis in nursing women. Am ] Obstet GynecoI 1 49:492, 1 984 Treszezamsky AD, Feldman 0, Sarabanchong VO: Concurrent postpartum uterine and abdominal wall dehiscence and Streptococcus anginosus i n fection. Obstet GynecoI 1 1 8 (2) :449, 20 1 1 Tsai PS, Hsu CS, Fan YC: General anaesthesia is associated with increased risk of surgical site infection after cesarean delivery compared with neuraxial anaesthesia: a population-based study. Br ] Anaesth 1 07(5):757, 20 1 1 Tulandi T, Al-]aroudi 0: Nonclosure of peritoneum: a reappraisal. Am ] Obstet Gynecol 1 89: 609, 2003 Tuuli MG, Liu ] , Stout M], et al: A randomized trial comparing skin antiseptic agents at cesarean delivery. N Engl ] Med 3 4(7) :647-5 5, 20 1 6 Tuuli MG, Rampersad \1, Carbone ]F, et al: Staples compared with subcu­ ticular suture for skin closure after cesarean delivety: a systematic review and meta-analysis. Obstet Gynecol 1 1 7(3):682, 20 1 1 Twickler OM, Setiawan AT, Harrell RS, et al: CT appearance of the pelvis after cesarean section. A]R Am ] Roentgenol 1 56:523, 1 9 9 1 Udagawa H , Oshio Y , Shimizu Y : Serious group A streptococcal i n fection around delivery. Obstet Gynecol 94: 1 53, 1 999 Uygur 0, Yesildaglar N , Kis S, et al: Early repair of episiotomy dehiscence. Aust N Z ] Obstet Gynaecol 44:244, 2004 Ward E, Duf P: A comparison of 3 antibiotic regimens for prevention of postcesarean endometritis: an historical cohort study. Am ] Obstet Gynecol 2 1 4(6) :75 1 .e 1 , 20 1 6 Watts D H , Krohn A , H illier SL, e t al: Bacterial vaginosis as a risk factor for post-cesarean endometritis. Obstet Gynecol 75:52, 1 990 Wechter ME, Pearlman MD, Hartmann KE: Reclosure of the disrupted lapa­ rotomy wound. A systematic review. Obstet Gynecol 1 06:376, 200 5 Wetchler S], Dunn L]: Ovarian abscess. Report of a case and a review of the literature. Obstet Gynecol Surv 40:476, 1 985 Widin AG, Sibai BM: Postpartum ovarian vein thrombosis ater vaginal delivery: a report of 1 1 cases. Obstet Gynecol 85:775, 1 995 Worley KC: Postoperative complications. In Yeomans ER, Hofman BL, Gil­ strap LC I I I , et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hill Education, 20 1 7 Yildirim G, Gungorduk K , Asicioglu 0 , e t al: Does vaginal preparation with povidone-iodine prior to cesarean delivery reduce the risk of endometritis? A randomized controlled trial. ] Maten Fetal Neonatal Med 2 5 ( 1 1 ) :23 1 6, 20 1 2

679

680

C H A PT E R 3 8

Contra cept ion

I NTRAUTERINE DEVICES . . . . . . . . . . . . . . . . . . . . . . . . . 681 PROGESTI N IM PLANTS . . . . . . . . . . . . . . . . . . . . . . . . . . 685 PROGESTI N - ONLY CONTRACEPTIVES . . . . . . . . . . . . . . 689 HORMONAL CONTRACEPTIVES . . . . . . . . . . . . . . . . . . . 689 BARRIER M ETHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693 FERTILITY AWARENESS- BASED M ETHODS . . . . . . . . . . 695 SPERMICIDES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695 EMERGENCY CONTRACEPTION . . . . . . . . . . . . . . . . . . . 696 PU ERPERAL CONTRACEPTION . . . . . . . . . . . . . . . . . . . . 697

From the evidence available, it appears to be toleraby sat­ iactoriy demonstrated that in women who copulate at requent intervals the tube must be regarded as a species of receptaculum seminis, in which spermatozoa are always present and waiting or the ovum, and that ertilization usualy occurs in the tubes and ony rarey in the uterus. -J. Whitridge Williams ( 1 903) Nearly half of all pregnancies each year in the United States are unintended (Finer, 20 1 6) . hese may follow contracep­ tive method failure or stem from lack of contraceptive use. In 20 1 1 to 20 1 3, 7 percent of sexually active fertile women in the United States not pursuing pregnancy did not use any birth control method (Daniels, 20 1 5) . For those seeking contraception, efective contraceptive methods are available and variably selected (Table 3 8- 1 ) . With these methods, estimated failure rates of perfect and typical use during the irst year difer widely. To reflect these failure rates, the World Health Organization (WHO) has grouped methods into eicacy tiers (see Table 38- 1 ) . Implants and

TABLE 38-1 . Contraceptive Fa i l u re Rates D u r i n g the Fi rst Yea r of Method U se i n Women i n the U n ited States Methoda

Perfect Use

Typical Use

Top Tier: Most Effective I ntra ute r i n e devices: Levo norg estre l system T 380A copper Levo norgestrel i mpla nts Female steri l ization Ma l e steri l ization

0.2 0.6 0.05 0.5 0. 1

0.2 0.8 0.05 0.5 0.1 5

Second Tier: Very Effective Com b i nation p i l l Vag i na l r i n g Patch D M PA P rogesti n-o n l y p i l l

OJ OJ OJ 0.2 OJ

9 9 9 6 9

Th i rd Tier: Effective Condom Male Female Dia p h ra g m with sper m icides Fert i l ity-awa reness Sta n d a rd days Two day Ovu lation Sym ptotherma I

2 5 6

18 21 12 24

5 4 3 0.4

Fourth Tier: Least Effective Sper m i cides Sponge P a ro u s wo men N u l l i pa ro u s women

18

28

20 9

24 12

No WHO Category With d rawal No contraception

4 85

22 85

aMethods organ ized accord i n g to tiers of efficacy. DMPA de pot medroxyprog estero ne acetate; WHO Wo rld Health Org a n ization. Data from Tru ssel l, 20 1 1 a. =

=

Contraception

intrauterine devices are found in the top tier. They efectively lower unintended pregnancy rates and are considered long-act­ ing reversible contraception (ARC) . he American College of Obstetricians and Gynecologists (20 1 7 c) recognizes these tiers, recommends counseling on al options, and encourages highly efective LARC for appropriate candidates. No contraceptive method is completely without side efects, but contraception usually poses less risk than pregnancy. However, some disorders or medications can raise the risks from certain contraceptives. The World Health Organization (20 1 5) has provided and updated evidence-based guidelines, termed Medical Eigibiliy Criteria, for the use of all highly efective reversible contraceptive methods by women with vari­ ous health conditions. Individual countries have subsequently modiied these guidelines. The United States Medical Eligibiliy Criteria (US MEC) was updated in 20 1 6 by the Centers for Disease Control and Prevention (Curtis, 20 1 6b) . These docu­ ments are available at: http://ww. cdc.govlreproductivehealth/ U nin tendedPregnancy/ Contraception_Guidance.h tm. In the United States MEC, reversible contraceptive meth­ ods are organized into six groups by their similarity: com­ bination hormonal contraceptives (CHCs) , progestin-only pills (POPs) , depot medroxyprogesterone acetate (DMPA) , implants, levonorgestrel-releasing intrauterine system (LNG­ IUS) , and copper intrauterine devices (Cu-IUDs) . For a given health condition, each method is categorized 1 through 4 (T able 38-2) . he score describes the safety proile for a typi­ cal woman with that condition: ( 1 ) no restriction of method use, (2) method advantages outweigh risks, (3) method risks outweigh advantages, and (4) method poses an unacceptably high health risk. lternatively, depending on the underlying disorder or patient desire, male or female sterilization may be a preferred or recommended permanent contraceptive method (American College of Obstetricians and Gynecologists, 20 1 7b) . hese options are fully discussed in Chapter 39. I NTRAUTER I N E DEVICES Globally, 1 4 percent of reproductive-aged women use intra­ uterine contraception, and in the United States, 1 0 percent of contracepting women use this method (Buhling, 20 1 4; Daniels, 20 1 5) . he five intrauterine devices (IUDs) currently approved for use in the United States are chemicaly active and continually elute either copper or levonorgestrel. These all have a T-shaped frame of polyethylene that is compounded with barium to render them radiopaque. Of devices, Mirena and Liletta both measure 32 X 32 mm and contain a 52-mg levonorgestrel-releasing cylinder reservoir in the stem of the T (Fig. 38- 1 ) . Two trailing strings that are tan (Mirena) or blue (Liletta) are attached to the distal stem to aid eventual device removal. Skyla-known as Jaydess in some countries-contains 1 3. 5 mg of levonorgestrel. It has smaller dimensions-28 X 30 mm-and was sized to more appropriately it a nullipa­ rous uterus (Gemzell-Danielsson, 20 1 2) . yleena has the same dimensions but contains 1 9. 5 mg of the same progestin. Two trailing strings of Skyla are tan, and those of yleena are blue. Skyla and yleena can be diferentiated from Mirena and

Liletta visually and sonographically by a silver ring near the j unction of their stem and arms. Mirena and yleena are cur­ rently approved for 5 years of use following insertion, whereas Skyla and Liletta are approved for 3 years. he third device, the T380A IUD named ParaGar, is wound with copper, and two strings extend from the stem base. Originally blue, the strings are now white. It is currently approved for 1 0 years of use following insertion (Teva Wom­ en's Health, 20 1 4) . In addition t o these ive currently marketed IUDs, women may retain discontinued brands. A Lippes Loop has two "S" shapes stacked one on the other. he Dalkon Shield has a crab form, whereas a Copper 1 mirrors that number. Progestasert is an early T-shaped progestin-releasing IUD. Last, various metal­ eluting ring devices are common in Asia. • Contraceptive Action

All these IUDs are efective. Failure rates are well below 1 per­ cent and similar overall to those of tubal sterilization (Thon­ neau, 2008; Trussell, 20 1 1 b) . heir mechanisms have not been precisely deined, but prevention of fertilization is now favored. With the LNG-IUS, long-term progestin release leads to endometrial atrophy, which hinders normal implantation (Silverberg, 1 986) . Moreover, progestins create scant viscous cervical mucus that obstructs sperm motility (Apter, 20 1 4; Moraes, 20 1 6) . Within the uterus, an intense local endome­ trial inlammatory response is induced, especially by copper­ containing devices. Cellular and humoral components of this inlammation are expressed in endometrial tissue and in luid illing the uterine cavity and fallopian tubes. These lead to decreased sperm and egg viability (Ortiz, 2007) . Also, in the unlikely event that fertilization does occur, the same inlamma­ tory actions are directed against the blastocyst. Also, with the Cu-IUD speciically, copper levels rise in the cervical mucus of users and act to decrease sperm motility and viability ( Jecht, 1 973) . he above efects are considered primary for contra­ ception because ovulation inhibition is inconsistent with the LNG-IUS and lacking with the Cu-IUD (Nilsson, 1 984) .

FIGURE 38-1 I ntrauterine devices ( I U Ds). A. ParaGard T 380A cop­ per I U D. B. Mirena levonorgestrel-releasing i ntra uterine syste m .

(Reproduced with perm ission from Stua rt G S : Contraception a nd sterilizatio n. In Hoffm a n B L, Schorge JO, Bradshaw KD, et a l : Wil­ liams Gynecology, 3 rd ed. New York, McGraw- H i l i Education, 2 0 1 6.)

68 1

682

The P u e rperi u m

TABLE 38-2. Contra i nd ications a n d Ca utions with Specific Contraceptive Methods 1

2

=

=

no method restrictions method benefits outweigh risks

3 4

=

=

method risks outweigh benefits method poses an unacceptably high health risk

In this ta ble, a blank space ind icates the method is category 1 or 2 Condition Postpa rtu m < 2 1 d / < 30 d 2 1 -42 d Postpregna ncy i nfection Smoking & age ::3 5 yr Act ive b reast ca ncer B reast cancer d isease free ::5 yr M u l t i p l e ca rd iova scu l a r risks Wel l -control led or m i l d CHTN Systo l i c BP ::1 60 or d i asto l i c BP ::1 00 Va scu l a r d i sease Com p l i cated heart va lve d i sease Peri pa rt u m card io myopathy Acute or prior TEe Th ro m bop h i l i a S u rgery with long i m mobi l ization MS with i m mo b i l ization DM > 20 yr or vasc u l a r d i sease DM with e n d-org a n d i sease M a l a bsorptive bariatric s u rgery I nfl a m matory bowel d i sease Ci rrhosis (severe, decompensated) Live r t u m o rs9 Sym pto matic g a l l b l adder d i sease CHC - related cholestasis At risk for GC/CT Di storted uterine cavity GTD s u rve i l l a nce Fosa m p ren avi r Enzyme-inducing a nticonvu lsants h La motrig i n e Rifa m p i n/rifa buti n

CHCa

POP

DMPA

Implants LNG-IUS

Cu-I U D

4/3 2/3 b 4 3/4c 4 3 3/40 3 4 4 4 3/4d 3/4 d 4 4 3 3/4 d 3/4d 3f 2/3 d 4 4 3

4 3

4 3 3

4 3

4 3

3 3

3 3

4

3 3

3

3 3

3 3

3 3

3 3 4 4

3 4 4

3 3

3

3 3

3 Sta rtlContinue (S/C) i

Condition

SIC

SIC

SIC

SIC

SIC

Cu rrent r h istory of I S H D Stroke M i g ra i ne with a u ra U nexp l a i n ed vag i n a l b l eed i n gl Cervica l ca n ce r before treatment GTD s u rvei l l a nce Cu rrent P I D or cervicitis Rheu matoid a rth ritis Acute v i ra l h epatitis Pelvic t u be rcu losis

4 4 4

2/3 2/3 2/3

3

2/3 2/3 2/3 3

2/3

SLE & positive or u n known A PAs

4

2/3 3

2/3 k

2/3 4/2 4/2 4/2 4/2

4/2 4/2 4/2 4/2

4/3

4/3

4/2 3

3

3

3

3

SLE & severe thro m bocytope n i a Com pl icated sol i d-org a n tra n s p l a n t

3

SIC

4

3/2 3/2

3/2

Contraception

aCo m b i nati on hormone cont racepti o n (CHC) g ro u p i n cl u d es p i l l s, vag i n a l r i n g , a n d patch . bAssoci ated risks that i nc rease category score i nc l u d e: age : 3 5 , tra n sfu s i o n at d e l i ve ry, B M I : 30, postpa rt u m hemorrhage, cesa rea n d e l i very, smoki ng, preec l a m ps i a . (S moking : 1 5 c i g a rettes/day i n creases risk category to 4 i n t h i s age g ro u p. d R i s k categ ory score is mod ified by assoc i ated risk facto rs a n d d i sease severity. e l n c l u d i n g s u perfi c i a l t h rom bos is. fOra l agents o n l y. R i n g a n d patch a re category 1 . g Be n i g n hepatic adenoma o r he patoce l l u l a r ca ncer. Foca l n od u la r hyperplasia co m pat i b l e w i t h h o r m o n e u se. hThese i n cl ude phe nyto i n, barbitu rates, ca rbamaze p i n e, oxcarbaze p i n e, pri m idone, to p i ra m ate. l i n those methods u n der Sta rt/Conti n u e col u m ns, the fi rst U S M EC n u m be r refers to whet h e r a method m ay b e i n itiated i n a n afected patient. For pati e n ts who i n itia l ly develop the c o n ­ d ition wh i l e u s i n g a s pec ifi c m ethod, the second n u m ber refe rs t o risks for conti n u i n g that method. J P rior to eva l uati o n . kThose on c h ro n i c corticoste roids a n d at r i s k for b o n e fra ctu re. A I DS acq u i red i m m u n odefi c i e n cy syn d rome; APA a nt i p h o s p h o l i pid a nt i bod i es; ARV a nti retrov i ra l; BP blood pressu re; B M I body mass i n dex; C HTN ch ro n i c hyperte n s i o n ; Cu- I U D copper i ntra uteri n e device; DM d ia betes m e l l itus; D M PA de pot med roxyp ro­ gestero ne a cetate; GC/CT gono rrhea/chla myd i a l i nfecti o n ; GTD g estati o n a l trophobl as­ tic d isease; I S H D isch e m i c heart d i sease; LNG-I US levon orgestrel-re l e a s i n g i ntra uteri n e system; MS m u lti ple scl e rosis; PI p r otea se i n h i bitor; P I D pelvic i nfl a m matory d isease; progesti n-only pil ls; SLE system l u pus erythematosus; VTE venous throm boem bol ism. POP Com pi led from Cu rtis, 2 0 1 6b; Merc k, 20 1 5; Teva Wo m e n 's Health, 20 1 4. =

=

=

=

=

=

=

=

=

=

=

=

=

=

=

=

=

=

• Method-Specific Adverse Efects Ecto p i c Preg n a n cy

Contraindications to IUD use are few and shown in Table 38-2. In the past, IUDs were perceived to increase the risk of ectopic pregnancy, but this has since been clariied. Speciically, IUDs provide efective contraception and lower the absolute num­ ber of ectopic pregnancies by half compared with the rate in noncontracepting women (World Health Organization, 1 985, 1 987) . But, the I UD mechanisms of action are more efective in preventing intrauterine implantation. hus, if an I UD fails, a higher proportion of pregnancies are likely to be ectopic (Back­ man, 2004; Furlong, 2002) . Lost Device

Expulsion of an IUD from the uterus is most common dur­ ing the first month. hus, women are examined approximately 1 month following I UD insertion, usually after menses, to identiy the tails trailing from the cervix. Following this, a woman is instructed to palpate the strings each month after menses. Regardless of I UD type, the cumulative 3-year expul­ sion rate approximates 1 0 percent (Madden, 20 1 4; Simonatto, 20 1 6) . This rate is higher in those :;2 5 years Qatlaoui, 20 1 7) . I f the tail of a n I U D cannot b e visualized, the device may have been expelled, may have perforated the uterus, or may be malpositioned. Alternatively, the device may be nor­ mally positioned with its tails folded within the endocervi­ cal canal or uterine cavi ty. To investigate, after excluding pregnancy, a cytological brush can be twirled within the

=

endocervical canal to entangle the strings and bring them gently into the vagina. If unsuccessful, the uterine cavity is probed gently with a Randall stone clamp or with a special­ ized rod with a terminal hook to snare the strings or device. One should not assume that a device has been expelled unless it was seen. Thus, if tails are not visible and the device is not felt by gentle probing of the uterine cavity, transvaginal sonography can be used to ascertain if the device lies within the uterus. lthough traditional sonography will document IUD position adequately in most cases, three-dimensional sonography ofers improved visualization, especially with the LNG-IUS (Moschos, 20 1 l ) . If sonography is inconclusive or if no device is seen, then a plain radiograph of the abdomino­ pelvis is taken. Computed tomography (CT) scanning or, less commonly, magnetic resonance (MR) imaging is an alternative (Boortz, 20 1 2) . It is safe to perform MR imaging at 1 . 5 and 3 Tesla (T) with an IUD in place (Ciet, 20 1 5) . Pe rfo rati o n

During uterine sounding or IUD insertion, the uterus may be perforated, which is identiied by the tool traveling farther than the expected uterine length based on initial bimanual exami­ nation. Rates approximate 1 per 1 000 insertions, and risks include puerperal insertion, lactation, provider inexperience, and extremes of uterine lexion (Harrison-Woolrych, 2003; Heinemann, 20 1 5). Although devices may migrate sponta­ neously into and through the uterine wall, most perforations occur, or at least begin, at the time of insertion (Ferguson, 20 1 6) .

683

684

The P u erperi u m

With acute perforation, the fundus i s the more common site, and bleeding is typically minimal due to myometrial con­ traction around the puncture hole. If no brisk or persistent bleeding is noted from the os following instrument or device removal, then patient observation alone is reasonable. Rarely, acute lateral perforations may lacerate the uterine artery, and subsequent brisk bleeding may prompt laparoscopy or lapa­ rotomy for control. Following any perforation, although this is not irmly evidence-based, a single dose of broad-spectrum antibiotic may mitigate infection. With chronic perforation, a device can penetrate the muscu­ lar uterine wall to varying degrees. A patient may be asymptom­ atic but abdominal pain, uterine bleeding, or missing strings can be clues (Kaislasuo, 20 1 3) . hose with a predominantly intrauterine location are usually managed by hysteroscopic IUD removal. In contrast, devices that have nearly or com­ pletely perforated through the uterine wall are more easily removed laparoscopically. Notably, an extrauterine Cu-IUD frequently induces an intense local inlammatory reaction and adhesions (Kho, 20 1 4) . Laparotomy may be necessary, and bowel preparation is considered. Sigmoid and bladder perfora­ tions and small-bowel obstruction have been reported remote from insertion (Sano, 20 1 7; Xu, 20 1 5 ; Zeino, 20 1 1 ) . M e n stru a l C h a n g e s

Dysmenorrhea and bleeding irregularities can complicate IUD use (Aoun, 20 1 4; Grunloh, 20 1 3) . These can be treated with some degree of success by nonsteroidal antiinlammatory drugs (NSAIDs) or tranexamic acid, which is an antiibrino­ lytic (Godfrey, 20 1 3; Madden, 20 1 2; S0rdal, 20 1 3) . Of the two I UDs, heavy bleeding more often complicates Cu-IUD use and may cause iron-deiciency anemia, for which oral iron salts are given. With the LNG-IUS, irregular spotting for up to 6 months after placement often gives way to progressive amen­ orrhea, which is reported by 30 percent of women after 2 years and by 60 percent after 1 2 years (Ronnerdag, 1 999) . his is frequently associated with improved dysmenorrhea.

if any, increase in infertility rates in these low-risk patients (H ubacher, 200 1 ) . The American College of 0 bstetricians and Gynecologists (20 1 5c, 2 0 1 6a) recommends that women at low risk for STDs, including adolescents, be considered good can­ didates for IUDs. he IUD is also safe and efective in women infected with human immunodeiciency virus (HIV) and may be used in others who are immunosuppressed (Centers for Dis­ ease Control and Prevention, 20 1 5 ; Tepper, 20 1 6a) . If infection does develop, it may take several forms and typically requires broad-spectrum antimicrobials. Pelvic inlam­ matoy disease (PID) without abscess is treated with antibiot­ ics on an outpatient or inpatient basis, depending on infection severity. here are theoretical concerns that a coexistent IUD may worsen the infection or delay resolution. A provider may choose to remove an IUD in this setting, although some evidence supports allowing a device to remain during treatment in those hospitalized with mild or moderate PID (Centers for Disease Control and Prevention, 20 1 5; Tepper, 20 1 3) . If infec­ tion fails to improve during 48 to 72 hours of treatment, the device is removed. Tuboovarian abscess can complicate PID and is treated aggressively with intravenous broad-spectrum antibi­ otics and IUD removal. Last, septic abortion mandates immedi­ ate uterine evacuation and antibiotics. Actinomyces israelii is a gram-positive, slow-growing, anaero­ bic indigenous vaginal bacterium that rarely causes suppurative infection. Some have found it more frequently in the vaginal lora or on the Pap smears of IUD users (Curtis, 1 98 1 ; Kim, 20 1 4) . Current recommendations advise that an asymptomatic woman may retain her IUD and does not require antibiotic treatment (American College of Obstetricians and Gynecolo­ gists, 20 1 7c; Lippes, 1 999; Westhof, 2007a) . However, if signs or symptoms of infection develop in a woman who harbors Actinomyces species, then the device is removed and antibiotics are given. Early indings with infection include fever, weight loss, abdominal pain, and abnormal uterine bleeding or dis­ charge. Actinomyces species are sensitive to antibiotics with gram-positive coverage, notably the penicillins.

I nfection

Preg n a ncy with an I U D

he risk of upper genital tract device-related infection is greatest during the irst months following IUD insertion (Farley, 1 992; Turok, 20 1 6) . Pathogens include Neisseria gonorrhoeae, Chla­ mydia trachomatis, and vaginal lora. Women at risk for sexually transmitted diseases (STDs) should be screened either before or at the time of I UD insertion (Centers for Disease Control and Prevention, 20 1 5; Sufrin, 20 1 2) . That said, device inser­ tion need not be delayed while awaiting sexually transmitted disease or Pap test results in asymptomatic women (Birgisson, 20 1 5) . If these bacteria are subsequently found and the patient is without symptoms, then the IUD may remain and treatment prescribed as detailed in Chapter 65 (p. 1 240) . Importantly, routine antimicrobial prophylaxis before insertion is not rec­ ommended (Grimes, 20 1 2; Walsh, 1 998). And the American Heart Association does not recommend bacterial endocarditis prophylaxis with insertion (Nishimura, 20 1 4) . Mter the irst month, infection risk is not increased i n IUD users who would otherwise be at low risk of sexually transmit­ ted infections. Correspondingly, IUDs appear to cause little,

For women who conceive while using an IUD, ectopic pregnancy should be excluded. With intrauterine pregnancy, if the tail is seen, it should be grasped and the IUD removed by gentle out­ ward traction. his action reduces complications such as abor­ tion, chorioamnionitis, and preterm birth (Fulkerson Schaefer, 20 1 7; Kim, 20 1 0) . Speciically, in one cohort, a 54-percent abor­ tion rate and 1 7-percent preterm delivery rate was noted if the device remained in situ. More favorably, rates of 25 percent and 4 percent, respectively, resulted from prompt Cu-IUD removal (Tatum, 1 976) . Few data guide management with the LNG-IUS, and most practice extrapolates from copper devices. If the tail is not visible, attempts to locate and remove the device may result in abortion. Although not our practice, some case reports and small series describe sonography or hysteros­ copy to assist in diicult device removals (Perez-Medina, 20 1 4; Schiesser, 2004) . Ater fetal viability is reached, it is unclear whether it is better to remove an IUD whose strings are visible and accessible or to leave it in place. Fetal malformation rates are not greater with a device let in situ (Tatum, 1 976; Vessey, 1 979) .

Co ntra ce ption

Second-trimester miscarriage with an IUD in place is more likely to be infected (Vessey, 1 974) . Sepsis may be fulminant and fatal. Pregnant women with a device in utero who demon­ strate any evidence of pelvic infection are treated with broad­ spectrum antibiotics and prompt uterine evacuation. Because of these risks, a woman should be given the option of early pregnancy termination if the device cannot be removed early in pregnancy. Last, in women who give birth with a device in place, appropriate steps should be taken at delivery to identiy and remove the IUD. • IUD Insertion

Ti m i n g

T o reduce expulsion rates and perforation risks, I U D insertion has traditionally followed complete uterine involution-at least 6 weeks after delivery. Women delivered at Parkland Hospital are seen 3 weeks postpartum, and IUDs are inserted 6 weeks postpartum or sooner if involution is complete. Alternatively, immediately ater miscarriage, surgical abortion, or delivery, an IUD may be inserted in the absence of overt infec­ tion (Lopez, 20 1 5a; Okusanya, 20 1 4). Also, "immediate" inser­ tion 1 week ater mifepristone and completed medical abortion has been described (Saav, 20 1 2; Shimoni, 20 1 1 ) . The risk of IUD expulsion is slightly higher if it is placed immediately following any of these recent pregnancies (Whitaker, 20 1 7) . However, in studies, the number of women in immediate-placement groups who ultimately receive and retain an IUD is greater than in groups scheduled for traditionally timed placement, some of whose mem­ bers do not return for insertion (Bednarek, 20 1 1 ; Chen, 20 1 0) . With immediate insertion, techniques depend o n uterine size. After irst-trimester evacuation, the IUD can be placed using the manufacturer's standard instructions. If the uterine cavity is larger, the IUD can be placed using ring forceps with sonographic guidance (Drey, 2009; Fox, 20 1 1 ) . Immediately following vaginal o r cesarean delivery, a n I UD can be placed by a hand, by its inserter tube, or by ring forceps (Levi, 20 1 5 ; Xu, 1 996) . With any of these methods, the arms of the IUD need not be folded into the inserter tube prior to insertion. During cesarean delivery placement, the hand or inserter travels through the unsutured open hysterotomy to deposit the device at the fundus. A second hand cupping the outer fundus can provide back pressure and stabilize the uterus during insertion. Strings are then gently directed toward the cervix. For instrumented insertion following vaginal delivery, the clinician resterilizes the vulva and changes gloves after pla­ cental delivery but before perineal repairs. he anterior lip of the loppy cervix is held with ring forceps. A second ring for­ ceps grasp the IUD stem and guides it through the uterine cavity to the fundus. For manual insertion following vaginal delivery, the provider secures the IUD between the index and middle fingers to deposit the device. In either case, back pres­ sure against the fundus by an abdominal hand can guide posi­ tioning (Stuart, 20 1 7; The ACQUIE Project, 2008 ) . For placement not related t o pregnancy, insertion near the end of normal menstruation, when the cervix is usually softer and somewhat more dilated, may be easier and also helps exclude early pregnancy. But, insertion is not limited to this

time. For the woman who is sure she is not pregnant and does not want to be pregnant, insertion is done at any time. Tec h n i q u e

Before insertion, contraindications are sought. Candidates are counseled, and written consent obtained. n oral NSAID , with or without codeine, can be used to allay cramps ater insertion (Ngo, 20 1 5) . But NSAIDs, misoprostol, or even paracervical blockade do not consistently decrease discomfort experienced during device placement (Bednarek, 20 1 5; Hubacher, 2006; Mody, 20 1 2; Pergialiotis, 20 14) . Of topical lidocaine products, 2-percent gel is inefective, but a newer gel and a spray both show promise (Aksoy, 20 1 6; Lopez, 20 1 5b; Tornblom-Paulander, 20 1 5) . Bimanual pelvic examination delineates uterine position and size. Abnormalities are evaluated, as they may contraindi­ cate insertion. Mucopurulent cervicitis or signiicant vaginitis is appropriately treated and resolved before IUD insertion. The cervical surface is cleansed with an antiseptic solution, and sterile instruments and a sterile IUD are used. A tenaculum is placed on the cervical lip, and the canal and uterine cavity are straightened by applying gentle outward traction. The cav­ ity is then probed by a uterine sound to identiy its direction and depth. Speciic steps of ParaGard and Mirena insertion are shown in Figures 38-2 and 38-3 and outlined in their respec­ tive package inserts. Following insertion, only the threads should be visible trail­ ing from the cervix. These are trimmed to allow 3 to 4 cm to protrude into the vagina, and their length is recorded. If improper device positioning is suspected, placement should be confirmed, using sonography if necessary. I f the IUD is not positioned completely within the uterus, it is removed and replaced with a new device. An expelled or partially expelled device should not be reinserted. PROGEST I N IMPLANTS • Etonogestrel l mplant

Contraception can be provided by thin, pliable progestin­ containing cylinders that are implanted subdermally and release hormone over many years. One of these, Nepanon is a single-rod implant with 68 mg of etonogestrel covered by an ethylene vinyl acetate copolymer cover. The implant is placed subdermally on the medial surface of the upper arm 8 to 1 0 cm from the elbow in the biceps groove and is aligned with the long axis of the arm. It may be used as contraception for 3 years, removed, and then replaced at the same site or in the opposite arm (Merck, 20 1 6a). Nexplanon is radiopaque, and its inserter device is designed to assist with subdermal positioning and avert deeper place­ ment. This device replaced Implanon, which is not radiopaque. A misplaced Implanon may be identiied with sonography using a 1 0- to I S-MHz linear array transducer (Shulman, 2006) . In some cases, MR imaging may be required if supplemental information is needed despite sonography (Correia, 20 1 2) . Both implants are similarly shaped and pharmacologically iden­ tical. They are highly efective, and the mechanism of action for progestin-only products is described later (p. 689) (Croxatto, 1 998; Mommers, 20 1 2) . Implanon is safe and still approved by

685

686

The P uerperi u m

-.--- --_ . .

I U D --:

--+- I nserter tube

-- Flange 1 .5 cm

from cervix --- SI ide r

- Slider moved

back -- Handle

--- Strings in cleft

B

A

I nserter tube advanced After slider moved back, inserter tube removed

f... :::-Flange

abuts cervix

Slider ­ moved back

_

c

o

Strings released from cleft

F I G U R E 38-2 I n sertion of the Mirena i ntrauterine system . I n itial ly, t h reads from behi n d the slider a re fi rst released to hang freely. The s l ider fou nd o n the h a n d l e s h o u l d be positioned at the top of the handle nearest the device. The IUD arms a re oriented horizonta l ly. A fla nge o n the outside o f the i n se rter t u be is positioned from t h e I U D t i p t o reflect the depth fou n d with uteri n e sou n d i n g . A. As both free threads a re p u l led, the Mirena I U D is d rawn i nto the i nserter tu be. The threads a re then tig htly fixed from below i nto the hand le's cleft. I n these depic­ tions, the i nserter t u be has been foreshortened. The i nserter tube is g ently i n serted i nto the uteru s u ntil the fla nge l ies 1 .5 to 2 cm from the external cervica l os to a l low the a rm s to open. B. While holding the i nserter steady, the IUD arms a re released by p u l l i n g the slider back to reach the raised horizontal mark on the h a n d l e, but n o fu rther. C. The i n serter i s then gently g u ided i nto the uterine cavity u ntil its fla nge touches the cervix. D . The device is released by hold i n g the i nserter fi rmly i n position and p u l l i ng the slider down all the way. The threads will be released a utomatica l ly from the clet. The i n se rter may then be removed, and IUD stri ngs tri m med. (Reproduced with permission from Stua rt GS: Contraception and steri l ization. I n Hoffm a n B L, Schorge JO, Bradshaw KD, et al: Wi l l i a m s Gynecology, 3 rd ed. New York, McG raw-H i l i Ed ucation, 201 6.)

Contraception

Base of -�-----H;� -- �� IUD

-_

_ _ _

Tip of inserter rod

I nserter ---I tube

=:-:Flange

A

c

B

o

F I G U R E 38-3 I n sertion of ParaGard T 380A. The uterus is sou nded, a n d the I U D is loaded i nto its inserter tube not more t h a n 5 m i n utes before i n sertion. A b l u e plastic fla nge on the outside of the in serter t u be is positioned from the IUD tip to reflect uteri n e depth. The I U D a rms s h o u l d lie i n the same p l a ne as the flat portion o f the oblong b l u e fla nge. A . The i nserter tu be, with the I U D loaded, i s passed into the endo metrial cavity. A long, solid, wh ite i n serter rod a buts the base of the I U D. When the blue fla nge contacts the cervix, i n sertion stops. B. To release the IUD a rms, the sol id wh ite rod with i n the i n serter t u be i s held steady, while the i nserter t u be i s withdrawn n o more than 1 cm. C. The i n serter tu be, not the i n serter rod, is the n carefu l ly moved u pwa rd towa rd the top of the uterus u ntil s l ig ht resista nce is felt. At no time d u ri n g i n sertion is the i n serter rod a dva n ced forwa rd. D. First, the solid w h ite rod a nd then the i n serter tu be a re withdrawn i n d i­ vid u a l ly. At com pletion, only the threads should be visible protru d i n g from the cervix. These a re trim med to a l low 3 to 4 c m to extend i nto the vag i na. (Reprod u ced with perm ission from Stu a rt GS: Contraception a nd steril ization. I n Hoffma n BL, Schorge JO, Bradshaw KD, et a l : Wi l l i a m s Gynecology, 3 rd e d . New York, McGraw- H i l i Ed u cation, 201 6.)

687

688

The P u e rpe r i u m

the Food and Drug Administration (FDA), but i t i s n o longer distributed by the manufacturer.

Second, nonpalpable devices are not uncommon and require radiological imaging for localization. As an adjunct, one group adopted the hook-wire tagging method used in breast tumor surgery to allow deep-lying implants to be marked prior to extraction (Nouri, 20 1 3) . If imaging fails to locate an implant, etonogestrel blood level determination can help veriy that the implant is indeed in situ. his special assay must be coordinated with the manufacturer ( 1-877-467-5266) .

• Levonorgestrel l mplants

he irst progestin implants contained levonorgestrel (LNG) , and systems are still available outside the United States. Jadelle, originally named Norplant-2, provides LNG and contracep­ tion for 5 years through two subdermally implanted Silastic rods. Ater this time, rods may be removed and if desired, new rods inserted at the same site (Bayer Group, 20 1 5) . Jadele is approved by the FDA, however, it is not marketed or distrib­ uted in the United States. Sino-implant II is a two-rod system with the same amount ( 1 50 mg) of LNG and same mechanism of action as Jadele but provides 4 years of contraception. Sino­ implant II is manufactured in China and approved for use by 20 countries in Asia and Mrica (FHI 360, 20 1 2) . Like the etonogestrel implant, these systems are placed sub­ dermally on the inner arm approximately 8 cm from the elbow and have similar removal steps. Implants vary regarding their insertion technique, and manufacturer instructions should be consulted. Both implant systems are highly efective (Sivin, 1 998; Steiner, 20 1 0) . h e forerunner o f these implants was the Norpant System, which provided LNG in six Silastic rods implanted subdermally. The manufacturer stopped distributing the system in 2002. Few data compare the LNG and etonogestrel implants. In one, eicacy and discontinuation rates by 2.5 years of use were similar (Bahamondes, 20 1 5) .

• I mplant Insertion

Ti m i n g

For those not currently using hormonal contraception, the etonogestrel implant is ideally inserted within 5 days of menses onset. With LNG-releasing implants, contraception is estab­ lished within 24 hours if inserted within the first 7 days of the menstrual cycle (Sivin, 1 997; Steiner, 20 1 0) . For transitioning methods, an implant is placed on the day of the first placebo combination oral contraceptive (COC) pill; on the day that the next depot-medroxyprogesterone injection would be due; or within 24 hours of taking the last POP (Merck, 20 1 6a) . In women certain that they are not pregnant, insertion at other times of the cycle is followed by alternative contraception for 7 days. Related to pregnancy, an implant may be inserted before discharge following delivery or abortion (Sothornwit, 20 1 7) . N ex p l a n on I n sertion Tec h n iq u e

With the patient lying down, her nondominant arm, forearm, and hand are outstretched on the bed with the inner aspects of each exposed upward, and the elbow is flexed. The insertion site is marked with a sterile pen 8 to 1 0 cm proximal to the medial condyle of the humerus. A second mark is placed 4 cm proximally and delineates the inal path of the implant. he Nex­ planon is inserted using sterile technique. The area is cleansed aseptically, and a I -percent lidocaine anesthetic track is injected beneath the sin along the planned insertion path. The implant is then placed as shown in Figure 38-4. Ater placement, both

• Method-Specific Adverse Efects

Unscheduled bleeding is common with progestin-only meth­ ods and described on page 689. Device-specific adverse efects derive mainly from malpositioning. First, branches of the medial antebrachial cutaneous nerve can be injured during implant or needle insertion that is too deep or during exploration for a lost implant. Clinically, numbness and paresthesia over the antero­ medial aspect of the forearm are noted (Wechselberger, 2006) .

A

B

c

o

F I G U R E 38-4 Nexpla no n i nsertion. A sterile pen m a rks the i n se rtion site, which is 8 to 1 0 cm prox i m a l to the med i a l h u mera l condyle. A secon d m a rk is placed 4 cm prox i m a l ly a lo n g the a rm 's long axis. The a rea is c lea ned a septica l ly, a nd a l -percent l idoca i n e a nesthetic track i s i njected a l ong the p l a n ned i n se rtion path. A. The i nsertion device is g rasped at its g ri pper bu bbles fou n d o n either side, a n d the need le ca p i s removed outwa rd. The device ca n be seen wit h i n the n eed le bore. The need le bevel then pierces the ski n at a 30-deg ree a ng le. B. O n ce the complete bevel is su bcuta neous, the need le is q u ickly a n g led downwa rd to lie horizontal ly. C. I m porta ntly, the ski n is tented u pwa rd by the need le as the need le i s slowly adva n ced horizonta l ly and s u bderm a l ly. D. Once the n eed le is completely i nserted, the lever on the top of the device is p u l led backwa rd towa rd the operator. Th i s retracts the need le and thereby deposits the i m p l a nt. The device is then lifted away from the ski n. After placement, both patient a n d o pe rator should pal pate the 4-cm i m pla nt.

Contra ce ption

patient and provider should palpate and identiY both ends of the 4-cm implant. To minimize bruising at the site, a pressure ban­ dage is created around the arm and is removed the following day. With implant extraction, the removal site is irst cleansed with antiseptic. he proximal end of the implant is depressed with a finger to allow the distal end to bulge up toward the skin. Ater anesthetizing the skin over this bulge, the skin is incised 2 mm toward the elbow along the long axis of the arm. he proximal butt of the implant is then pushed toward this incision. Once vis­ ible, the distal end of the implant is grasped with a hemostat and removed. If present, supericial adhesions surrounding an implant may be dissected away with hemostat tips placed into the incision. PROGESTIN -ONLY CONTRACEPTIVES • Actions a nd Side Efects

Progestin-only contraceptives include the implants just described, injectables, and pills. s their primary contraceptive action, these progestins suppress luteinizing hormone (LH) and in turn block ovulation. As other efects, cervical mucus is thickened to retard sperm passage, and atrophy renders the endometrium unfavor­ able for implantation. Fertility is restored rapidly following ces­ sation of progestin-only contraception. n exception is DMPA, as described on page 693 (Mansour, 20 1 l ) . For all progestin-only methods, irregular o r heavy uterine bleeding is a distinct disadvantage. It is the most frequently reported adverse event leading to method discontinuation. Often, counseling and reassurance is suicient. Troublesome bleeding may be improved by one to two cycles of combination oral contraceptives, by a 1 - to 3-week course of estrogen alone, or by a short course of NSAIDs combined with the established method (Abdel-Aleem, 20 1 3) . Fortunately, with prolonged use, progestins induce endometrial atrophy, which leads to sus­ tained amenorrhea. For the well-counseled patient, this is often an advantage. Most progestin-only contraceptive methods do not signii­ cantly afect lipid metabolism, glucose levels, hemostatic factors, liver function, thyroid function, or blood pressure (DorRinger, 2002) . However, the increased low-density lipoprotein (LDL) cholesterol and decreased high-density lipoprotein (HDL) cho­ lesterol levels seen with DMPA may be less desirable for women with cardiac or vascular disease risks (Kongsayreepong, 1 993) . Progestin-only methods do not impair milk production and are an excellent choice for lactating women. here are no increased risks ofgenital tract, liver, or breast neoplasia (Samson, 20 1 6; Wilailak, 20 1 2; World Health Organization, 1 99 1 a,b, 1 992) . Weight gain and bone fracture are not prominent side efects of this contraceptive group, except for depot progester­ one, discussed on page 693 (Lopez, 20 1 2a, 20 1 3a) . Functional ovarian cysts develop with a greater frequency in women using progestin-only agents, although they do not usually necessitate intervention (European Society of Human Reproduction and Emblyology, 200 1 ; Hidalgo, 2006; Nahum, 20 1 5) . Last, an association between depression and DMPA or POPs is unclear (Civic, 2000; Pagano, 20 1 6; Svendal, 20 1 2; Westhof, 1 995). Women with depression may be prescribed these methods, but surveillance following initiation is reasonable.

• Progestin Contraindications

These methods are ideal for most women, but contraindica­ tions and cautions are associated with a few conditions listed in Table 38-2. Current breast cancer and pregnancy are the only two absolute contraindications. In a few instances, manufac­ turer restrictions difer from the US MEC. First, manufacturer prescribing information lists thrombosis or thromboembolic disorders as contraindications (Merck, 20 1 6a; Pizer, 20 1 5a,b) . However, for individuals with these disorders, US MEC considers progestin-containing methods category 2. Moreover, evidence does not link progestin-only methods with throm­ boembolism, stroke, or cardiovascular disease (Mantha, 20 1 2; Tepper, 20 1 6b; World Health Organization, 1 998) . Second, for many progestin products, manufacturers note prior ectopic pregnancy as a contraindication. his is secondary to proges­ terone's efect of slowing fallopian tube motility and thereby delaying fertilized egg transport to the endometrial cavity. hat said, efective contraception lowers pregnancy rates over­ all. Thus, for those with prior ectopic pregnancy, US MEC considers progestin injectables and implants category 1 , and progestin-only pills are category 2. HORMONAL CONTRACEPTIVES These currently are available in forms that contain both estro­ gen and progestin or contain only progestin. Progestin-only injectables and pills are considered very efective, yet second­ tier agents, due to the need for increased patient compliance. Similarly, products containing both estrogen and progestin, often termed combination hormonal contraception (CHC) , are considered in this tier. These may be supplied as pills, transvagi­ nal rings, or transdermal patches. • Combination Hormonal Contraceptives

Mechanism of Action

Actions of combination hormonal contraceptives are multiple, but the most important efect is suppression of hypothalamic gonadotropin-releasing factors. his in turn blocks pituitary secretion of follicle-stimulating hormone (FSH) and luteiniz­ ing hormone (LH) and thereby inhibits ovulation. The pro­ gestin component of CHCs provides ovulation prevention by suppressing LH; it thickens cervical mucus and thereby retards sperm passage; and it renders the endometrium unfavorable for implantation. Estrogen blocks ovulation by suppressing FSH release. To promote cycle control, estrogen stabilizes the endometrium, which prevents intermenstrual bleeding-also known as breakthrough bleeding. The net efect is an extremely efective yet highly reversible method (Mansour, 20 1 1 ) . • Combination Oral Contraceptive Pills

Co m position

hese pills are the most frequently used reversible birth control method in the United States. In a 2006 to 20 1 0 survey, 1 6 per­ cent of contracepting women in the United States were using these (Daniels, 20 1 5) . COCs are marketed in a wide variety

689

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The P u e rperi u m

o f estrogen and progestin combinations. lvlost are available as generics, and the FDA (20 1 6) confirms the bioequivalence of COC generics. The merican College of Obstetricians and Gynecologists (20 1 5a) supports the use of either branded or generic preparations. Pharmacologically, ethinyl estradiol is the most com­ mon estrogen present in COC formulations in the United States. Less frequently, mestranol or estradiol valerate is used. Unwanted efects most often attributed to the estrogen com­ ponent include breast tenderness, weight gain, nausea, and headache. COCs also contain one of several progestins that are struc­ turally related to progesterone, testosterone, or spironolactone. hus, these progestins bind variably to progesterone, androgen, glucocorticoid, and mineralocorticoid receptors. hese aini­ ties explain many pill-related side efects and are often used to compare one progestin with another. Most progestins used in COCs are related to testoster­ one and may impart androgenic side afects such as acne and adverse HDL and LDL levels. To avoid these efects, antian­ drogenic progestins have been introduced and include dienogest and nomegestroL acetate. he latter is used in a COC approved outside the United States. Despite these pharmacological dif­ ferences, the true advantage of one progestin over another is less apparent clinically (Lawrie, 2 0 1 1 ; Moreau, 2007) . Another progestin, drospirenone, is structurally similar to spironolactone. he doses in currently marketed COCs have efects similar to 25 mg of this diuretic (Seeger, 2007) . Drospirenone displays antiandrogenic activity, provides an antialdosterone action to minimize water retention, and has antimineralocorticoid properties that may, in theory, cause potassium retention and hyperkalemia (Krattenmacher, 2000) . hus, it is avoided in women with renal or adrenal insuiciency or with hepatic dysfunction. Moreover, serum potassium level monitoring is recommended in the first month for patients chronically treated concomitantly with any drug associated with potassium retention. hese include NSAIDs, angiotensin­ converting enzyme (ACE) inhibitors, angiotensin II antago­ nists, heparin, aldosterone antagonists, and potassium-sparing diuretics (Bayer HealthCare Pharmaceuticals, 20 1 5) . Since the development o f COCs, their estrogen and proges­ tin content has dropped remarkably to minimize adverse efects. Currently, the lowest acceptable dose is limited by the ability to prevent pregnancy and to avoid unacceptable breakthrough bleeding. hus, the daily estrogen content varies from 1 0 to 50 1g of ethinyl estradiol, and most contain 3 5 j.1g or less. In a few COCs, inert placebo pills have been replaced by tablets containing iron. These have the suix Fe added to their name. In addition, Beyaz has a form of folate-levomefolate calcium-within both its active and placebo pills. With COCs termed monophasic piLs, the progestin dose remains constant throughout the cycle. In others, the dose fre­ quently is varied, and term biphasic, triphasic, or quadriphasic piL is used depending on the number of dose changes within the cycle. In some formulations, the estrogen dose also var­ ies. In general, phasic pills were developed to reduce the total progestin content per cycle without sacrificing contraceptive eicacy or cycle control. he theoretical advantage of a lower

total progesterone dose per cycle, however, has not been borne out clinically (Moreau, 2007) . Cycle control also appears to be comparable among mono- through triphasic pills (van Vliet, 20 1 1 a,b,c) . Ad m i n i stration

Hormones are taken daily for a specified time (2 1 to 81 days) and then replaced by placebo for a speciied time (4 to 7 days) , which is called the "pill-free interval. " During these pill-free days, withdrawal bleeding is expected. With the trend toward lower estrogen doses to minimize side efects, follicular development and ovulation may occur. To counter this, the active-pill duration in some formulations is extended to 24 days. In comparison, these 24/4 regimens per­ form similarly to higher-estrogen-dose 2 1 /7 regimens (Anttila, 20 1 1 ; Marr, 20 1 2) . Alternatively, longer durations o f active hormone, designed to minimize the number of withdrawal episodes, have similar eicacy and safety proiles as more traditional administration (Edelman, 20 1 4) . These extended-cycle products produce a 1 3-week cycle, that is, 1 2 weeks of hormone use, followed by a week for withdrawal menses. The product Amethyst provides continuous active hormone pills for 365 days each year. Such extended or continuous regimens may be especially suited for women with significant menstrual symptoms (Mendoza, 20 1 4) . For general initiation, women ideally begin COCs o n the first day of a menstrual cycle. In such cases, a supplementary contraceptive method is unnecessary. With the more tradi­ tional "Sunday start," women begin pills on the irst Sunday that follows menses onset, and an additional method is needed for 1 week to prevent conception. If menses begin on a Sunday, then pills are begun that day and no supplemental method is required. Alternatively, with the "quick start" method, COCs are started on any day, commonly the day prescribed, regard­ less of cycle timing. An additional method is used during the first week (Westhof, 2002, 2007b) . If the woman is unknow­ ingly already pregnant during quick start initiation, COCs are not teratogenic (Lammer, 1 986; Rothman, 1 978; Savolainen, 1 9 8 1 ) . However, a missed menses following COC initiation should prompt pregnancy testing. Similar same-day initiation can be implemented with the contraceptive vaginal ring or patch (Murthy, 2005; Schafer, 2006) . For maximum eiciency, pills are best taken at the same time each day. If one dose is missed, the missed pill is taken immedi­ ately; the scheduled dose for that day is taken on time; and then daily pills are continued. If two or more doses are missed, the most recent missed pill is taken immediately; the scheduled dose for that day is taken on time; and an efective barrier technique used for 7 days while daily pills are then continued (Curtis, 20 16a). If with­ drawal bleeding fails to occur during the pill-free interval, a woman should continue her pills but seek attention to exclude pregnancy. With initiation of COCs, spotting or bleeding is common. It does not relect contraceptive failure and typically resolves within one to three cycles. If unscheduled bleeding persists, those with bleeding during the fi r st part of a pill pack may ben­ eit from an increase in the estrogen dose, whereas those with bleeding during the second part may improve with a higher progestin dose (Nelson, 20 1 1 ) .

Contraception

• Method-Specific Efects

Altered Drug Eficacy

Some drugs decrease COC efectiveness, and choosing another contraceptive method is preferable. However, if a COC is selected for concurrent use in these instances, a preparation containing a minimum of 30 �g ethinyl estradiol is ideally chosen. Conversely, some COCs interfere with the actions of certain drugs (see Table 38-2) . In obese women, COCs are efective (Lopez, 20 1 6) . Some studies point to lowered hormone bioavailability, but over­ all eicacy remains high (Nakajima', 20 1 6; Westhof, 20 1 0; Yamazaki, 20 1 5) . With the transdermal patch method, how­ ever, evidence is more robust that obesity may alter pharmaco­ kinetics and lower eicacy, as discussed on page 692. Meta bol i c C h a n g e s

Combination oral contraceptives alter lipid synthesis and in general raise serum levels of triglycerides and of total cho­ lesterol, H DL, and very-low density lipoprotein (VLDL) cholesterol. Estrogen lowers LDL cholesterol concentrations . Oral contraceptives are not atherogenic, and their efect on lipids is clinically inconsequential for most women (Wallach, 2000) . In women with dyslipidemias, limited data suggest that COCs increase the risk for myocardial infarction and minimally so for venous thromboembolism or stroke (Drago­ man, 20 1 6) . For those with multiple additional risk factors for vascular disease, alternative contraceptive methods are recommended. With COCs, protein metabolism is afected, and estrogens boost hepatic production of various globulins. First, fibrinogen and many of the clotting factor levels rise in direct proportion to the estrogen dose and may lead to thrombosis. Angiotensino­ gen production is also augmented by COCs, and its conversion by renin to angiotensin I may be associated with "pill-induced hypertension," discussed subsequently. Last, COCs elevate sex hormone-binding globulin (SHBG) levels, which in turn lower concentrations of bioavailable testosterone and lessen andro­ genic side efects. Regarding carbohydrate metabolism, current low-dose for­ mulations have minimal efects in women who do not have diabetes (Lopez, 20 1 4) . And, the risk of developing diabetes is not increased (Kim, 2002) . For diabetic women, COCs may be used in nonsmokers with disease duration < 20 years and without associated vascular disease, nephropathy, retinopathy, or neuropathy (Curtis, 20 1 6b) . Of other metabolic changes, thyroid-binding globulin and thyroid-stimulating hormone (TSH) levels are elevated, but free plasma thyroxine (FT4) levels are unchanged (Raps, 20 1 4) . Studies have not supported a connection between COCs and weight gain (Gallo, 20 1 4) . Ca rd iova sc u l a r Effects

Despite increased plasma angiotensinogen (renin substrate) levels, women using low-dose COC formulations rarely develop clini­ cally significant hypertension (Chasan-Taber, 1 996). However, it is common practice for patients to return 8 to 1 2 weeks ater COC initiation for evaluation of blood pressure and other symptoms.

During initial contraception selection, a history of gesta­ tional hypertension does not preclude subsequent COC use. Among women with well-controlled hypertension, COC use is linked to greater risks than nonusers for stroke, acute myo­ cardial infarction, and peripheral arterial disease, and in these women, COCs are considered US MEC category 3 (Curtis, 20 1 6b) . Severe forms of hypertension, especially those with end-organ involvement, preclude COC use. For nonsmoking women younger than 35, the risk of stroke is extremely low (World Health Organization, 1 996) . COCs are associated with a small increased risk for ischemic stroke (Chan, 2004; Lidegaard, 20 1 2) . Rates increase signiicantly for women who have hypertension, who smoke, or who have migraine headaches with visual aura or other focal neurological changes and use COCs (MacClellan, 2007; Tepper, 20 1 6c) . The evidence for stroke risk in migraineurs without aura i s less clear (Etminan, 2005; Schurks, 2009) . COC initiation may be considered for women with preexisting migraines without aura if they are otherwise healthy, younger, normotensive nonsmok­ ers. For women with prior stroke, COCs should not be consid­ ered due to risks for repeat events. For women with prior myocardial infarction, COCs should not be considered. Also, in women with multiple cardiovas­ cular risk factors, which include smoking, hypertension, older age, and diabetes, the risk for myocardial infarction outweighs the beneits of this method. However, for those without these risks, low-dose oral contraceptives are not associated with an increased risk of myocardial infarction (Margolis, 2007; World Health Organization, 1 997) . The risks for deep-vein thrombosis and pulmonary embolism are increased in women who use COCs (Stadel, 1 98 1 ) . These clearly are estrogen-dose related, and rates have substantively declined with lower-dose formulations containing 1 0 to 35 �g of ethinyl estradiol. he general-population risk of venous throm­ boembolism (VTE) is 4 to 5 events per 1 00,000 woman-years. he incidence ofVTE with COC use increases three- to fivefold compared with nonusers (Shaw, 20 1 3; van Hylckama Vlieg, 2009). Obesity raises the VTE risk, which is compounded by COCs (Horton, 20 1 6; Suchon, 20 1 6) . Accordingly, in an obese woman, COCs are considered a US MEC category 2. VTEs are signiicantly increased in women older than 35 years who smoke, and COCs are not recommended. Those most at risk for VTE include women with thrombophilias (ESHRE Capri Workshop Group, 20 1 3) . Nloreover, COC use during the month before a major operative procedure appears to double the risk for postop­ erative VTE (Robinson, 1 99 1 ) . Thus, the merican College of Obstetricians and Gynecologists (20 1 6d) recommends balanc­ ing the risks ofVTE and the degree of postoperative immobility with the risk of unintended pregnancy during the 4 to 6 weeks required to reverse the thrombogenic efects of COCs before surgery. In the early puerperium, VTE risks are also increased, and COCs are not recommended for women within the irst 4 weeks after delivery. Certain progestins within COC are linked with greater rates of thromboembolism. A slightly higher VTE risk with drospirenone-containing COCs has been shown in two stud­ ies. In response, an assessment of benefi t s and VTE risks in users of these pills has been emphasized (Food and Drug

69 1

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The P u erperi u m

Administration, 20 1 2; Jick, 20 1 1 ; Parkin, 20 1 1 ) . Desogestrel and gestodene are also implicated and carry similarly elevated risks (Stegeman, 20 1 3; Vinogradova, 20 1 5) . N eo p l a s i a

Most studies indicate that COCs overall are not associated with an increased risk of cancer (Cibula, 20 1 0) . In fact, a protective efect against ovarian and endometrial cancer has been shown (Collaborative Group on Epidemiological Studies of Ovarian Cancer, 2008; Tsilidis, 20 1 1 ) . As an exception, the relative risk of cervical dysplasia and cervical cancer is higher in current COC users, but this declines after use is discontinued. Follow­ ing 1 0 or more years, risk returns to that of never users (Inter­ national Collaboration of Epidemiological Studies of Cervical Cancer, 2007) . It is unclear whether COCs contribute to breast cancer development. Major studies show no risk or a small risk among current users, which drops with time following ces­ sation (Collaborative Group on Hormonal Factors in Breast Cancer, 1 996; Hannaford, 2007; Marchbanks, 2002) . Although COC use in the past was linked to development of hepatic ocal nodular hyperplasia and benign hepatic adenoma, large studies do not support this (Heinemann, 1 998). Moreover, no evidence supports concern for greater risk of hepatocellular cancer (Maheshwari, 2007) . For women with known tumors, COCs may be used in those with focal nodular hyperplasia, but avoided in those with benign hepatic adenoma and hepatocellu­ lar carcinoma (Kapp, 2009b) . Rates of colorectal cancer appear to be reduced in ever users (Bosetti, 2009; Luan, 20 1 5) . Othe r Effects

Cholestasis and cholestatic jaundice are uncommon, but they resolve when COCs are discontinued. In women who have active hepatitis, COCs should not be initiated, but these may be continued in women who experience a flare of their liver disease while already taking COCs. Use of progestin-only con­ traception in these women is not restricted. Moreover, there is no reason to withhold COCs from women who have recovered. Mild compensated cirrhosis does not limit the use of COCs or progestin-only methods. But in those with severe decompen­ sated disease, all hormonal methods are avoided (Kapp, 2009a) . Chloasma, which is hyperpigmentation of the face and fore­ head, is more likely in women who demonstrated such a change during pregnancy (Chap. 4, p. 53) . This is less common with low­ dose estrogen formulations. Although previously used for treating unctional ovarian cysts, low-dose COC formulations have been shown to have no efects related to cyst resolution or prevention (European Society of Human Reproduction and Embryology, 200 1 ; Grimes, 20 1 4) . Many noncontraceptive beneits are associated with COC use (American College of Obstetricians and Gynecologists, 20 1 6c) . And indeed, COCs may be used for these efects, even in those without contraceptive needs. Dysmenorrhea and heavy menstrual bleeding lessen with COC use. Another action is to improve androgenic conditions such as acne and hirsutism. For women with premenstrual dysphoric disorder (PMDD), several studies have shown symptom improvement in those who use the drospirenone-containing COC Yaz (Lopez, 20 1 2b; Pearl­ stein, 2005 ; Yonkers, 2005) .

• Transdermal Patch

he Ortho Evra patch contains ethinyl estradiol and the proges­ tin norelgestromin. It has an inner layer containing an adhesive and hormone matrix, and a water-resistant outer layer. Thus, women can wear the patch in bathtubs, showers, swimming pools, saunas, and whirlpools without decreased eicacy. he patch may be applied to buttocks, upper outer arm, lower abdomen, or upper torso, but the breasts are avoided. Because the hormones are combined with the adhesive, improper skin adherence will lower hormone absorption and eicacy. here­ fore, if a patch is so poorly adhered that it requires reinforce­ ment with tape, it should be replaced. Initiation of the patch is the same as for COCs, and a new patch is applied weekly for 3 weeks, followed by a patch-free week to allow withdrawal bleeding. Although a patch is ideally worn no longer than 7 days, hormone levels remain in an efec­ tive range for up to 9 days. This afords a 2-day window for patch-change delays (Abrams, 200 1 ) . I n general, the transdermal patch and vaginal ring produce metabolic changes, side efects, and eicacy rates comparable to those with COC pills. However, the patch has been associ­ ated with a higher thromboembolism risk in some but not all studies (Cole, 2007; Jick, 20 1 0; Lidegaard, 20 1 1 ) . In response, the Food and Drug Administration (20 1 5 b) approved labeling for the patch to state that the risk for VTE may be increased compared with other COCs, and relative risk estimates range from 1 .2 to 2.2. Obesity-90 kg or greater-may be associ­ ated with a higher risk for patch contraceptive failure ( Janssen Pharmaceuticals, 20 1 5 ; Zieman, 2002) . Finally, application­ site reaction and breast tenderness are more frequent during initial cycles in patch wearers (Urdl, 2005) . • Transvaginal Ring

The NuvaRing is yet another form of combination hormonal contraception and is a lexible intravaginal ring. he ring is constructed of ethinyl vinyl acetate, and it measures 54 mm in diameter and 4 mm in cross section (Fig. 38-5) . During

F I G U R E 38-5 NuvaRing: estrogen-progesti n-releasing vag i n a l contraceptive ring.

Contra c e ption

insertion, the ring is compressed and threaded into the vagina, but no specific final orientation within the vagina is required. Its core releases ethinyl estradiol and the progestin etonogestrel, which are absorbed across the vaginal epithelium. Before being dispensed, the rings are refrigerated, and once dispensed, their shelf life is 4 months. he ring is placed within 5 days of menses onset and, after 3 weeks of use, is removed for 1 week to allow withdrawal bleeding. Contraception will still be aforded if a ring is left in place for a fourth week (Merck, 20 1 6b). Patient satisfaction is high with this method, although vagi­ nitis, ring-related events, and leukorrhea are more common (Lopez, 20 1 3b; Oddsson, 2005) . Despite this, no deleterious afect on lower reproductive tract or endometrial epithelia has been found (Lete, 20 1 3; Veres, 2004) . A ring may be used con­ currently with vaginal medications or with a tampon (Haring, 2003; Verhoeven, 2004a,b) . Approximately 70 percent of part­ ners feel the ring during intercourse (Dieben, 2002) . If this is bothersome, the ring may be removed for intercourse but should be replaced within 3 hours to maintain eicacy. • Injectable Progestin Contraceptives

Both intramuscular depot medroxyprogesterone acetate-Depo­ Provera (DMPA)- 1 50 mg every 3 months, and norethisterone enanthate, 200 mg every 2 months, are injectable progestin con­ traceptives used worldwide. Of the two, DMPA is available in the United States. DMPA is injected into the deltoid or gluteus muscle, but massage is avoided to ensure that the drug is released slowly. lternatively, a subcutaneous version, depo-subQ provera 1 04, is also available and is injected into the subcutaneous tissue of the anterior thigh or abdomen every 3 months. DMPA is efective, and as with other progestin-only methods, contraception is provided by ovulation inhibition, greater cervi­ cal mucus viscosity, and creation of an endometrium unfavorable for ovum implantation. Initial injection is given within the irst 5 days following menses onset. Serum levels suicient for con­ traception are observed by 24 hours. Thus, no additional con­ traceptive method is required for initiation within this window. Alternatively, limited data support a "quick weart," or initiation of DMPA regardless of cycle day. If so implemented, investiga­ tors recommend an initial negative pregnancy test result before injection, a supplemental contraceptive method during the 7 days following injection, and a second pregnancy test after 3 to 6 weeks to identiy an early pregnancy (Rickert, 2007; Sneed, 2005). Pregnancies conceived during DMPA use are not associ­ ated with a higher risk of fetal malformation (Katz, 1 985). For women who present for intramuscular DMPA reinjection more than 13 weeks or for subcutaneous DMPA reinjection more than 14 weeks ater the prior dose, the manufacturer recommends exclusion of pregnancy before reinjection (Pfizer, 20 1 5a,b) .

Similar to other progestin-only contraceptive, irregular menstrual bleeding is common, and a fourth of women dis­ continued DVIPA in the irst year because of this (Cromer, 1 994) . Unique to DMPA, prolonged anovulation can follow discontinuation, which results in delayed fertility resumption. After injections are stopped, a fourth of patients do not resume regular menses for up to 1 year (Gardner, 1 970) . Accordingly, DMPA may not be ideal for women who plan to use birth control only brieRy before attempting conception. As with other progestins, DMPA has not been associ­ ated with cardiovascular events or stroke in otherwise healthy women. However, in those with severe hypertension, a higher risk of stroke has been found in DMPA users (World Health Organization, 1 998) . Moreover, the US MEC authors express concerns regarding hypoestrogenic efects and reduced HDL levels from DMPA in women with vascular disease or m ultiple risks for cardiovascular disease. Weight gain is generally attributed to DMPA, and these increases are comparable between the two depot forms (Bahamondes, 200 1 ; Vickery, 20 1 3; Westhof, 2007c) . In long-term users, loss of bone mineral density is also a p oten­ tial problem (Petitti, 2000; Scholes, 1 999). In 2004, the FDA added a black box warning to DMPA labeling, which notes that this concern is probably most relevant for adolescents, who are building bone mass, and perimenopausal women, who will soon have increased bone loss during menopause. That said, World Health Organization ( 1 998) and American Col­ lege of Obstetricians and Gynecologists (20 1 6b) believe that DMPA should not be restricted in those high-risk groups. And, it seems prudent to reevaluate overall risks and bene­ its during extended use. It is somewhat reassuring that bone loss appears to be reversible after discontinuation of therapy, although reversal is still not complete after 1 8 to 24 m onths (Clark, 2006; Scholes, 2002) . • Progestin-Only Pills

So-called mini-pils are progestin-only contraceptives that are taken daily. hese contraceptives have not achieved widespread popularity and are used by only 0.4 percent of reproductive-aged American women (Hall, 20 1 2) . Unlike COCs, they do not reliably inhibit ovulation. Rather, their efectiveness depends more on cervical mucus thickening and endometrial atrophy. Because mucus changes are not sustained longer than 24 hours, mini-pills should be taken at the same time every day to be maximally efective. If a progestin-only pill is taken even 4 hours late, a supplemental form of contraception must be used for the next 48 hours. Progestin-only pills are contraindicated in women with known breast cancer or pregnancy. Other cau­ tions are listed in Table 38-2.

Act i o n s a n d S i d e Efects

Injected progestins ofer the convenience of a 3-month dos­ ing schedule, contraceptive eicacy comparable with or better than COCs, and minimal to no lactation impairment. Iron­ deiciency anemia is less likely in long-term users because of amenorrhea, which develops in up to 50 percent after 1 year and in 80 percent after 5 years.

BARRIER METHODS • Male Condom

For many years, male and female condoms, vaginal diaphragms, and periodic abstinence have been used for contraception with variable success (see Table 38-2) . When used properly, condoms

693

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Th e P uerpe r i u m

B F I G U R E 38-6 FC2 Female Condom i n sertion a n d positio n i n g . A. The i n ner ring is squeezed for i n sertion. The sheath is i nserted s i m i l a rly to a d i a p h rag m . B. The i n ner ring is pu shed i nwa rd with a n i ndex fi nger.

provide considerable but not absolute protection against a broad range of sexually transmitted diseases, including HIV (Eaton, 20 1 4) . Contraceptive eicacy of the male condom is enhanced appreciably by a reservoir tip and probably by the addition of a spermicide. Such agents, as well as those used for lubrication, should be water-based because oil-based products degrade latex condoms and diaphragms. For individuals sensitive to latex, condoms made from lamb intestines are efective, but they do not provide infection pro­ tection. Fortunately, nonallergenic condoms have been devel­ oped that are made of polyurethane or of synthetic elastomers. Polyurethane condoms are efective against STDs but have a higher breakage and slippage rate compared with latex con­ doms (Gallo, 2 0 1 2a) .

jelly or cream. The spermicide is applied into the dome cup and along the device rim. The diaphragm is then positioned so that the cup faces the cervix and that the cervix, vaginal forni­ ces, and anterior vaginal wall are partitioned efectively from the remainder of the vagina and the penis. I n this fashion, the centrally placed spermicide is held against the cervix. When appropriately positioned, one rim is lodged deep in the poste­ rior vaginal fornix, and the opposite rim its behind the inner surface of the symphysis and immediately below the urethra (Fig. 3 8-7) . If a diaphragm is too small, it will not remain in place. If it is too large, it is uncomfortable when forced into position. A coexistent cystocele or uterine prolapse typically leads to instability and expulsion. Because size and spring

• Female Condom

The only female condom available in the United States is mar­ keted as the FC2 Female Condom. It is a synthetic nitrile sheath with one lexible polyurethane ring at each end. Its open ring remains outside the vagina, whereas its closed internal ring is fi t ted under the symphysis like a diaphragm (Fig. 38-6) . The female condom can be used with both water-based and oil­ based lubricants. Male condoms should not be used concur­ rently because simultaneous use may cause friction that leads to condom slipping, tearing, and displacement. Following use, the female condom outer ring should be twisted to seal the condom so that no semen spills. As an added value, the female condom may ofer some protection against STDs (Minnis, 2005). • Diaphragm Plus Spermicide

The diaphragm consists of a circular latex dome of variable diameter supported by a circumferential latex-covered metal spring. It is efective when used in combination with spermicidal

F I G U RE 38-7 A d ia p h ra g m in place c reates a p hysical ba rrier between the vagina a nd cervix.

Contrace ption

flexibility must be individualized, the diaphragm is itted by providers and available only by prescription. For use, the diaphragm and spermicide can be inserted hours before intercourse. If more than 6 hours elapse, the diaphragm can remain but additional spermicide is placed in the upper vagina for maximum protection. Spermicide is reapplied before each subsequent coital episode. The diaphragm is not removed for at least 6 hours after intercourse. Because toxic shock syn­ drome has been described following its use, it may be worth­ while to remove the diaphragm at 6 hours, or at least the next morning, to minimize this rare event. Diaphragm use is associ­ ated with a slightly greater rate of urinary infections, presumably from urethral irritation by the ring under the symphysis. • Cervical Cap

FemCap is currently the only available cervical cap in the United States. Made of silicone rubber, it has a sailor-cap shape with a dome that covers the cervix and a lared brim, which allows the cap to be held in place by the muscular walls of the upper vagina. Available in 22-, 26-, and 30-mm sizes, it is used with a spermicide applied once at insertion to both sides of the dome cup. For contraception, it should remain in place for 6 hours following coitus and may remain for up to 48 hours. Even with proper itting and correct use, pregnancy rates with this method are higher that with the diaphragm (Gallo, 2 0 1 2b; Mauck, 1 999). FERTI LITY AWAREN ESS - BASED METHODS These family planning methods attempt to identiY the fertile days each cycle and advise sexual abstinence during these days. Their major drawback is their limited eicacy, which is shown in Table 38- 1 . Common forms of these fertility awareness­ based (FAB) methods include Standard Days, Temperature Rhythm, Cervical Mucus, and Symptothermal Methods. Some smartphone applications aim to assist these practices (Fehring, 20 1 3) . h e Standard Days Method counsels women to avoid unpro­ tected intercourse during cycle days 8 through 1 9. For suc­ cessful use, women must have regular monthly cycles of 26 to 32 days. hose who use this method can mark a calendar or can use Cycle-Beads, which is a ring of counting beads, to keep track of their days. he Temperature Rhythm Method relies on a sustained O.4°F rise in the basal body temperature, which usually precedes ovu­ lation. For maximum eicacy, the woman must abstain from intercourse from'the irst day of menses through the third day after the temperature increase. he Cervical Mucus Method, also called the Two-Day Method or Billings Method, relies on awareness of vaginal "dryness" and "wetness. " hese reflect changes in the amount and quality of cervical mucus at diferent times in the menstrual cycle. With the Billings Method, abstinence is required from the beginning of menses until 4 days after slippery mucus is identified. With the Two-Day Method, intercourse is consid­ ered safe if a woman did not note mucus on the day of planned intercourse or the day prior.

he Symptothermal Method combines changes in cervical mucus-onset of fertile period; changes in basal body tempera­ ture-end of fertile period; and calculations to estimate the time of ovulation. This method is more complex to learn and apply, but it does not appreciably improve eicacy. SPERMICI DES These contraceptives are marketed variously as creams, j ellies, suppositories, fi l ms, and aerosol foam. \10st can be purchased without a prescription. They are considered a less efective method (see Table 38- 1 ) . If pregnancy does occur, they are not teratogenic (Briggs, 20 1 5) . Typically, spermicides function by providing a p hysi­ cal barrier to sperm penetration and a chemical spermicidal action. The active ingredient is nonoxynol-9 or octoxynol-9. Although these are spermicidal, they do not provide STD protection. Ideally, spermicides must be deposited high in the vagina in contact with the cervix shortly before intercourse. Their duration of maximal efectiveness is usually no more than 1 hour, and thereafter, they must be reinserted before repeat intercourse. Douching is avoided for at least 6 hours after coitus. • Contraceptive Sponge

The Today contraceptive sponge is an over-the-counter, one­ size-fits-all device. The nonoxynol-9-impregnated polyure­ thane disc is 2 . 5 cm thick and 5 . 5 cm wide and has a dimple on one side and satin loop on the other (Fig. 38-8 ) . The sponge can be inserted up to 24 hours prior to intercourse, and while in place, it provides contraception regardless of coital frequency. It should remain in place for 6 hours after intercourse. Pregnancy is prevented primarily by the spermi­ cide nonoxynol-9 and to a lesser extent by covering the cervix and absorbing semen.

F IG U RE 38-8 Today s po nges. The sponge is moistened with ta p water a nd gently sq ueezed to c reate light suds. It is then posi­ tioned with the d i m p le d i rectly agai nst the cervix. The fa bric l oop tra i l s within the vag i n a and ca n be hooked with a fi nger to later extract the sponge.

695

696

The P u e rperi u m

TABLE 38-3. Methods Ava i l a b l e for Use a s Emergency Contraception Method

Form ulation

P rogestin-Only P i l l P l a n B On e-Step Next C h o i ce One Dose

1 50 mg LNG

PRM P i l l Ella

3 0 mg u l i pri sta l a cetate

COC P i l l s b,c Ogestrel C rysel l e, Low-Ogestrel E n p resse (ora nge), Trivora (pi n k) Levora, Seaso n a l e Avia n e, LoSeason i q u e (ora nge)

0.05 0.03 0.0 3 0.03 0.02

mg mg mg mg mg

EE EE EE EE EE

+ 0.5 m g norgestrel + O J m g n o rgestrel + 0. 1 25 m g L N G + 0. 1 5 m g LNG + 0. 1 mg LNG

Pills per Dose

N u mber of Dosesa

2

2 2 2 2 2

4 4

4

5

Copper-Contai n i ng I U D P a ra g a rd T 380A a Doses ta ken 1 2 h o u rs a pa rt if m u lt i p l e. b Oth e r COC bra n d s with for m u lations identica l to those a bove m ay a l so be u sed . (Use of a n a ntiemetic agent before ta k i n g the med icati o n w i l l lessen t h e risk of n a u sea, w h i c h is a com mon side effect. com b i nati on ora l contraceptive; EE eth i nyl estra d i ol; I U D i ntra uterine device; LNG COC levonorgestrel ; PRM p rogesterone-receptor modu lato r. =

=

=

=

=

Although the sponge is possibly more convenient than the diaphragm or condom, it is less efective than either (Kuyoh, 20 1 3) . Most common causes for method discontinuance are pregnancy, irritation, discomfort, or vaginitis (Beckman, 1 989) . Although toxic shock syndrome has been reported with the contraceptive sponge, it is rare, and evidence suggests that the sponge may actually limit production of the responsible staphy­ lococcal exotoxin (Remington, 1 987) . Still, it is recommended that the sponge not be used during menses or the puerperium. EMERGENCY CONTRACEPTION Following unprotected sexual intercourse, many women present for contraceptive care. Several emergency contracep­ tion (EC) regimens substantially lower the likelihood of an unwanted pregnancy when used correctly. Current meth­ ods include COCs, progestins, progesterone antagonists, and copper-containing IUDs (Table 38-3) . Overall, the IUD is most efective, and ulipristal acetate is the most eicient oral regimen (American College of Obstetricians and Gynecologists, 20 1 7a) . Patients can obtain information regarding emergency contraception by calling 1 -888-NOT-2-LATE or accessing The Emergency Contraception Website: http://not-2-late.com. • Hormonal Emergency Contraception

Except for allergy to a particular component, no conditions in the US MEC contraindicate hormonal EC methods. With progestin-only regimens, levonorgestrel is taken as a single, one­ time 1 . 5-mg dose (Arowojolu, 2002) . his is now recommended

instead of two 0.75-mg doses separated by 1 2 or 24 hours (Ngai, 2005) . Dosing begins ideally within 72 hours of unprotected coitus but may be given up to 1 20 hours. Notably, the single­ dose regimen is available over-the-counter without a prescription to all reproductive-aged women (Food and Drug Administration, 20 1 3, 20 1 5a) . One progesterone-receptor modulator currently available for EC is ulipristal acetate and is marketed as Ela. It is taken as a single 30-mg tablet up to 1 20 hours after unprotected inter­ course (Brache, 20 1 0; Watson, 20 1 0) . Also known as the Yuzpe method, this older E C method pro­ vides a minimum of 1 00 jLg of ethinyl estradiol and 0 . 5 mg of levonorgestrel in each of two doses. As shown in Table 38-3, a suicient dose may be achieved by two or more pills. he first dose is taken ideally within 72 hours of intercourse but may be given up to 1 20 hours. The initial dose is followed 1 2 hours later by a second equivalent dose. The major mechanism with all hormonal regimens is inhibi­ tion or delay of ovulation. Of oral methods, failure rates are low­ est with ulipristal ( 1 to 2 percent) and greatest with the Yuzpe method (2 to 3.5 percent) (Cleland, 20 1 4) . IfEC fails to prevent pregnancy or is mistimed, no associations with major congenital malformation or pregnancy complications have been noted with these hormonal methods (Jatlaoui, 20 1 6; Levy, 20 1 4) . With EC administration, nausea and vomiting can b e an important side efect (American College of Obstetricians and Gynecologists, 20 1 5b; Gemzell-Danielsson, 20 1 3) . Accord­ ingly, an oral antiemetic may be prescribed at least 1 hour before each dose (Rodriguez, 20 1 3) . If a woman vomits within 2 hours of a dose, the dose is repeated.

Contraception

• Copper-Contai ning Intrauterine Devices

For women who are candidates, Cu-IUD insertion is the most efective emergency contraceptive method and provides an efective 1 0-year method of contraception (Cheng, 20 1 2) . If an IUD is placed up to 5 days after unprotected coitus, the failure rate approximates only 0. 1 percent (Cleland, 20 1 2; Wu, 20 1 0) . PUERPERAL CONTRACEPTION For mothers who are nursing exclusively, ovulation during the irst 10 weeks after delivery is unlikely. Nursing, however, is not a reliable method of family planning for women whose infants are on a daytime-only feeding schedule. Moreover, waiting for first menses involves a risk of pregnancy, because ovulation usu­ ally antedates menstruation. Certainly, after the fi r st menses, contraception is essential unless the woman desires pregnancy. As shown in Table 38-2, all methods may be suitable for nursing mothers after the initial weeks, during which throm­ boembolism risks are still great. With all hormonal methods, very small quantities are excreted in breast milk, but no adverse efects on infants have been reported (Phillips, 20 1 5 ; World Health Organization, 1 988) . Although not robust, some older studies link decreased infant weight gain or milk volume with early initiation of combination oral contraceptives before 6 weeks postpartum (Lopez, 20 1 5c; Tepper, 20 1 6a) . REFERENCES Abdel-Aleem H , d'Arcangues C, Vogelsong M , e t a l : Treatment of vaginal bleeding irregularities induced by progestin only contraceptives. Cochrane Database Syst Rev 1 0:CD003449, 20 1 3 Abrams LS, Skee OM, Wong FA, et al: Pharmacokinetics of norelgestromin and ethinyl estradiol from two consecutive contraceptive patches. J Clin PharmacoI 4 1 : 1 232, 200 1 Aksoy H, Aksoy U, Ozyurt S, et al: Lidocaine 1 0% spray to the cervix reduces pain during intrauterine device insertion: a double-blind randomised con­ trolled trial. J Fam Plann Reprod Health Care 42(2) :83, 20 1 6 American College of Obstetricians and Gynecologists: Brand versus generic oral contraceptives. Committee Opinion No. 375, August 200 , Reairmed 20 1 5a American College of Obstetricians and Gynecologists: Emergency contracep­ tion . Practice Bulletin No. 1 52, September 20 1 5b American College of Obstetricians and Gynecologists: Increasing access to contraceptive implants and intrauterine devices to reduce unintended preg­ nancy. Committee Opinion No. 642, October 20 1 5c American College of Obstetricians and Gynecologists: Adolescents and long-acting reversible contraception: implants and intrauterine devices. Committee Opinion No. 539, October 20 1 2, Reairmed 20 1 6a American College of Obstetricians and Gynecologists: Depot medroxyproges­ terone acetate and bone efects. Committee Opinion No. 602, June 20 14, Reairmed 20 1 6b American College of Obstetricians and Gynecologists: Noncontraceptive use of hormonal contraceptives. Practice B ulletin No. 1 1 0, January 20 1 0, Reaf­ irmed 20 1 6c American College of Obstetricians and Gynecologists: Prevention of deep vein thrombosis and pulmonary embolism. Practice Bulletin No. 84, August 2007, Reairmed 20 1 6d American College of Obstetricians and Gynecologists: Access to emergency contraception. Committee Opinion No. 707, July 20 1 7a American College of Obstetricians and Gynecologists: Beneits and risks of sterilization. Practice B ulletin No. 1 33 , February 20 1 3 , Reairmed 20 1 7b American College of Obstetricians and Gynecologists: Long-acting reversible contraception: implants and intrauterine devices. Practice B ulletin No. 1 86, November 20 1 7c Anttila L, Bachmann G, Hernadi L, et a1: Contraceptive eicacy of a combined oral contraceptive containing ethinyl oestradiol 20 !lg/drospirenone 3 mg administered in a 24/4 regimen: a pooled analysis of four open-label studies. Eur J Obstet Gynecol Reprod BioI 1 5 5 (2) : 1 80, 201 1

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=

Ronnerdag M , Odlind V: Health efects o f long-term use of the intrauterine levonorgestrel-releasing system. Acta Obstet Gynecol Scand 78:7 1 6, 1 999 Rothman KJ, Louik C: Oral contraceptives and birth defects. N Engl J Med 299:522, 1 978 Saav I, Stephansson 0, Gemzell-Danielsson K: Early versus delayed insertion of intrauterine contraception ater medical abortion-a randomized con­ trolled trial. PLoS One 7( 1 1 ) :e48948, 20 1 2 Samson M, Porter N , Orekoya 0 , e t al: Progestin and breast cancer risk: a systematic review. Breast Cancer Res Treat 1 5 5 ( 1 ) :3, 20 1 6 Sano M, Nemoto K , Miura T , e t al: endoscopic treatment o f intrauterine device migration into the bladder with stone formation. J Endourol Case Rep 3 ( 1 ) : 1 05, 20 1 7 Savolainen E , Saksela E , Saxen L : Teratogenic hazards of oral contraceptives ana­ lyzed in a national malformation register. Am ] Obstet GynecoI 1 40:52 1 , 1 98 1 Schafer ]E, Osborne LM, Davis AR, e t al: Acceptability and satisfaction using Quick Start with the contraceptive vaginal ring versus an oral contraceptive. Contraception 73(5):488, 2006 Schiesser M , Lapaire 0, Tercanli S, et al: Lost intrauterine devices during preg­ nancy: maternal and fetal outcome after ultrasound-guided extraction. An analysis of 82 cases. Ultrasound Obstet Gynecol 23:486, 2004 Scholes 0, LaCroix AS, Ichikawa LE, et al: Injectable hormone contraception and bone density: results from a prospective study. Epidemioloy 1 3: 58 1 , 2002 Scholes 0, LaCroix AS, Ott SM, et al: Bone mineral density in women using depot medroxyprogesterone acetate for contraception. Obstet Gynecol 93:233, 1 999 Schurks M , Rist PM, Bigal ME, et al: Migraine and cardiovascular disease: systematic review and meta-analysis. BM] 339:b39 1 4 , 2009 Seeger JD, Loughlin ], Eng PM, et al: Risk of thromboembolism in women taking ethinylestradiolldrospirenone and other oral contraceptives. Obstet Gynecol 1 1 0: 5 87, 2007 Shaw A, Edelman AB: Obesity and oral contraceptives: a clinician's guide. Best Pract Res Clin Endocrinol Metab 27( 1 ) : 5 5 , 20 1 3 Shimoni N , Davis A, Ramos ME, et al: Timing of copper intrauterine device insertion after medical abortion: a randomized controlled trial. Obstet Gynecol 1 1 8 (3):623, 201 1 Shulman LP, Gabriel H: Management and localization strategies for the non­ palpable Implanon rod. Contraception 73:325, 2006 Silverberg SG, Haukkamaa M, Arko H, et al: Endometrial morphology during long-term use of levonorgestrel releasing intrauterine devices. Int J Gynecol Pathol 5 : 235, 1 986 Simonatto P, Bahamondes MV, Fernandes A, et al: Comparison of rwo cohorts of women who expulsed either a copper-intrauterine device or a levonorgestrel-releasing intrauterine system. J Obstet Gynaecol Res 42(5 ) : 5 54, 20 1 6 Sivin I , Campodonico 1 , Kiriwat 0 , e t al: The performance o f levonorgestrel rod and Norplant contraceptive implants: a 5 year randomized study. H um Reprod 1 3 ( 1 2) :33 1, 1 99 8 Sivin I, Viegas 0, Campodonico I, et a l : Clinical performance of a new rwo-rod levonorgestrel contraceptive implant: a three-year randomized study with Norplant implants as controls. Contraception 5 5 (2) :73, 1 99 Sneed R, Westhof C, Morroni C, et al: A prospective study of immediate initiation of depot medroxyprogesterone acetate contraceptive injection. Contraception 71 (2) :99, 2005 S0rdal T, Inki P, Draeby J, et al: Management of initial bleeding or spotting ater levonorgestrel-releasing intrauterine system placement: a randomized controlled trial. Obstet Gynecol 1 2 1 (5) :934, 20 1 3 Sothornwit J , Werawatakul Y, Kaewrudee S , e t al: Immediate versus delayed postpartum insertion of contraceptive implant for contraception. Cochrane Database Syst Rev 4 :CDO l 1 9 1 3 , 20 1 7 Stadel BV: Oral contraceptives and cardiovascular disease. N Engl J Med 305:6 1 2, 1 9 8 1 Stegeman B H , d e Bastos M, Rosendaal F R , e t al: Diferent combined oral contraceptives and the risk of venous thrombosis: systematic review and net­ work meta-analysis. BM] 347:f5298, 20 1 3 Steiner M, Lopez M, Grimes 0 , e t al: Sino-implant (II)-a levonorgestrel releasing two-rod implant: systematic review of the randomized controlled trials. Contraception 8 1 (3) 1 97, 20 1 0 Stuart GS: Contraception and sterilization. I n Hofman B L, Schorge JO, Brad­ shaw KD, et al: Williams Gynecology, 3rd ed. New York, McGraw-Hill Education, 20 1 6 Stuart GS: Puerperal sterilization. I n Yeomans ER, Hofman BL, Gilstrap LC III, et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hill Education, 20 1 7 Suchon , AJ Frouh F, Henneuse A , e t al: Risk factors for venous thromboem­ bolism in women under combined oral contraceptive. The PILi Genetic Risk Monitoring (PILGRIM) Study. Thromb Haemost 1 1 5 ( 1 ) : 1 3 , 20 1 6

Contraception Sufrin CB, Postlethwaite 0, Armstrong A , et al: Neisseria gonorrhea and Chlamydia trachomatis screening at intrauterine device insertion and pelvic inflammatory disease. Obstet GynecoI 1 20 (6) : 1 3 1 4 , 20 1 2 Svendal G , Berk M , Pasco JA, e t al: The use o f hormonal contraceptive agents and mood disorders in women. J Afect Disord 1 40( 1 ) : 92, 20 1 2 Tatum HJ, Schmidt F H , Jain AK: Management and outcome o f pregnancies associated with Copper-T intrauterine contraceptive device. Am J Obstet Gynecol 1 26:869, 1 976 Tepper NK, Curtis KM , Nanda K, et al: Safety of intrauterine devices among women with H IV: a systematic review. Contraception 94(6) :7 1 3, 20 1 6a Tepper NK, Phillips SJ, Kapp N, et al: Combined hormonal contraceptive use among breastfeeding women: an updated systematic review. Contraception 94(3) :262 20 1 6b Tepper N K, Steenland MW, Gaield ME, et al: Retention of intrauterine devices in women who acquire pelvic inflammatory disease: a systematic review. Contraception 87(5) :65 5, 20 1 3 Tepper N K, Whiteman M K, Marchbanks PA, e t al: Progestin-only contracep­ tion and thromboembolism: a systematic review. Contraception 94(6) :678, 20 1 6c Tepper NK, Whiteman MK, Zapata LB, et al: Safety of hormonal contra­ ceptives among women with migraine: a systematic review. Contraception 94(6) :630, 20 1 6d Teva Women's Health: ParaGard T 380A intrauterine copper contraceptive: prescribing information, 20 1 4. Available at: http://paragard.com/Pdf/Para­ Gard-PLpdf. Accessed October 1 0, 20 1 6 h e ACQUIRE Project: The Postpartum Intrauterine Device: a Training Course for Service Providers. New York, EngenderHealth, 2008 honneau PF, Almont TE: Contraceptive eicacy of intrauterine devices. Am J Obstet GynecoI 1 98 :248, 2008 Tornblom-Paulander S, Tingaker BK, Werner A, et al: Novel topical formula­ tion of lidocaine provides signiicant pain relief for intrauterine device inser­ tion: pharmacokinetic evaluation and randomized placebo-controlled trial. Ferril Steril 1 03 (2):422, 20 1 5 Trussell J : Contraceptive eicacy. I n Hatcher A , Trussell J , Nelson AL, et al (eds): Contraceptive Technology, 20th ed. New York, Ardent Media, 20 1 1 a Trussell J: Contraceptive failure in the United States. Contraception 70:89, 20 1 1 b Tsilidis KK, Allen NE, Key TJ, et al: Oral contraceptive use and reproductive factors and risk of ovarian cancer in the European Prospective Investigation into Cancer and Nutrition. Br J Cancer 1 05 (9): 1 436, 20 1 1 Turok O K, Eisenberg DL, Teal SB, et al: A prospective assessment of pel­ vic infection risk following same-day sexually transmitted infection testing and levonorgestrel intrauterine system placement. Am J Obstet Gynecol 2 1 5 (5 ) :599 .e l , 20 1 6 Urdl W, Apter 0, Alperstein A , e t al: Contraceptive eicacy, compliance and beyond: factors related to satisfaction with once-weekly transdermal compared with oral contraception. Eur J Obstet Gynecol Reprod Bioi 1 2 1 :202, 2005 van H ylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, et al: The venous thrombotic risk of oral contraceptives, efects of oestrogen dose and proges­ togen type: results of the MEGA case-control study. BMJ 339:b292 1 , 2009 Van Vliet A, Grimes DA, Helmerhorsr FM, et al: Biphasic versus monophasic oral contraceptives for contraception. Cochrane Database Syst Rev 6:CD002032, 2006, Reairmed 20 1 1 a Van Vliet HA, Grimes DA, Lopez LM, et al: Triphasic versus monopha­ sic oral contraceptives for contraception. Cochrane Database Syst Rev 1 1 :CD0035 53 , 20 1 1 b Van Vliet HA, Raps M, Lopez LM, et al: Quadriphasic versus monopha­ sic oral contraceptives for contraception. Cochrane Database Syst Rev 1 l :CD009038, 20 1 1 c Veres S, Miller L, Burington B: A comparison between the vaginal ring and oral contraceptives. Obstet Gynecol 1 04 : 5 5 5 , 2004 Verhoeven CH, Dieben TO: he combined contraceptive vaginal ring, NuvaR­ ing, and tampon co-usage. Contraception 69(3): 1 97, 2004a Verhoeven CH, van den Heuvel MW, Mulders TM, et al: The contracep­ tive vaginal ring, NuvaRing, and antimycotic co-medication. Contraception 69 (2) : 1 29, 2004b Vessey MP, Johnson B , Doll R, et al: Outcome of pregnancy in women using intrauterine devices. Lancet 1 :49 5, 1 974 Vessey MP, Meisler L, Flavel R, et al: Outcome of pregnancy in women using diferent methods of contraception. Br J Obstet Gynaecol 86:548, 19 9 Vickery Z, Madden T, Zhao Q, et al: Weight change at 1 2 months in users of three progestin-only contraceptive methods. Contraception 88(4) :503, 20 1 3 Vinogradova Y , Coupland C , Hippisley-Cox J : Use o f combined oral contra­ ceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD data-bases. BMJ 350:h2 1 3 5, 20 1 5 Wallach M , Grimes DA (eds): Modern Oral Contraception. Updates from he Contraception Report. Totowa, Emron, 2000

Walsh T, Grimes 0 , Frezieres R, et al: Randomised controlled trial o f prophy­ lactic antibiotics before insertion of intrauterine devices. IUD Study Group. Lancet 3 5 1 : 1 005, 1 998 Watson: Ella prescribing information. 2 0 1 0 . Available at: http://www.accessdata. fda.govldrugsatfda_docs/labell20 1 01022474s0001bl.pdf. Accessed December 27, 20 1 6 Wechselberger G , Wolfram 0, Piilzl P , e t al: Nerve injury caused by removal of an implantable hormonal contraceptive. Am J Obstet Gynecol 1 95 ( 1 ) :323, 2006 Westhof C: IUDs and colonization or infection with Actinomyces. Contracep­ tion 75 :S48, 2007a WesthofC, Heartwell S, Edwards S, et al: Initiation of oral contraceptive using a quick start compared with a conventional start: a randomized controlled trial. Obstet Gynecol 1 09: 1 270, 2007b Westhof C, Jain J K, Milson, et al: Changes in weight with depot medroxypro­ gesterone acetate subcutaneous injection 1 04 mg/0.65 mL. Contraception 75:26 1 , 2007c Westhof C, Kerns J, Morroni C, et al: Quick start: novel oral contraceptive initiation method. Contraception 66: 1 4 1 , 2002 WesthofC, Wieland 0, Tiezzi L: Depression in users of depo-medroxyproges­ terone acetate. Contraception 5 1 (6):3 5 1 , 1 995 Westhof CL, Torgal AH , Mayeda ER, et al: Pharmacokinetics of a combined oral contraceptive in obese and normal-weight women. Contraception 8 1 (6) :474, 20 1 0 Whitaker AK, Chen BA, Borgatta L : Society o f Family Planning Guidelines: postplacental insertion of intrauterine devices. Contraception October 5, 20 1 7 [Epub ahead of print) Wilailak S, Vipupinyo C, Suraseranivong V, et al: Depot medroxyprogester­ one acetate and epithelial ovarian cancer: a multicentre case-control study. BJOG 1 1 9 (6) :672, 20 1 2 World Health Organization: A multinational case-control study o f ectopic pregnancy. Clin Reprod Ferril 3: 1 3 1 , 1 98 5 World Health Organization: Acute myocardial infarction and combined oral contraceptives: results of an international multi-center case-control study. Lancet 349 : 1 202, 1 997 World Health Organization: Cardiovascular disease and use of oral and injectable progestogen-only contraceptives and combined injectable con­ traceptives. Resulrs of an international, multicenter, case-control study. Contraception 57:3 1 5 , 1 998 World Healrh Organization: Depot-medroxyprogesterone acetate (DMPA) and risk of endometrial cancer. Int J Cancer 49: 1 86, 1 99 1 a World Health Organization: Depot-medroxyprogesterone acetate (DMPA) and risk of invasive squamous cell cervical cancer. Contraception 45(4): 299, 1 992 World Health Organization: Depot-medroxyprogesterone acetate (DMPA) and risk of liver cancer. Int J Cancer 49(2) : 1 82, 1 99 1 b World Health Organization: Efects of hormonal contraceptives o n breast milk composition and infant growth. S tud Fam Plann 1 9/36 1 , 1 98 8 World Health Organization: Ischaemic stroke a n d combined oral contracep­ tives: results of an international, multi-center case-control study. Lancet 348:498, 1 996 World Health Organization: Mechanism of action, safety and eicacy o f intra­ uterine devices. Technical Reporr No. 753, Geneva, Switzerland, WHO, 1 987 World Health Organization: vledical Eligibility for Contraceptive Use, 5 th ed. Geneva, World Health Organization, 20 1 5 Wu S , Godfrey EM, Wojdyla 0 , et al: Copper T380A intrauterine device for emergency contraception: a prospective, multicentre, cohort clinical trial. BJOG 1 1 7( 1 0) : 1 205, 20 1 0 X U JX, Remedios E , Duthie A , et al: Intrauterine contraceptive device: cause o f small bowel obstruction and ischaemia. A N Z J Surg May 2 6 , 20 1 5 [Epub ahead of print) XU JX, Rivera R, Dunson TR, et al: A comparative study of two techniques used in immediate postplacental insertion (IPPI) of the Copper T-380A IUD in Shanghai, People's Republic of China. Contraception 54 ( 1 ) :3 3 , 1 996 Yamazaki M, Dwyer K, Sobhan M, et al: Efect of obesity on the efectiveness of hormonal contraceptives: an individual participant data meta-analysis. Contraception 92(5) :445, 20 1 5 Yonkers A , Brown C , Pearlstein TB, e t al: Eicacy of a new low-dose oral contraceptive with drospirenone in premenstrual dysphoric disorder. Obstet Gynecol 1 06:492, 2005 Zeino MY, Wietfeldt ED, Advani V, et al: Laparoscopic removal of a copper intrauterine device from the sigmoid colon. JSLS 1 5 (4) : 568, 20 1 1 Zieman M, Guillebaud J, Weisberg E, et al: Contraceptive eicacy and cycle control with the Orrho Evra/Evra transdermal system: the analysis of pooled data. Fertil Steril 77:S 1 3 , 2002

701

702

C H A PT E R 3 9

Steri l ization

P U ERPERAL TUBAL STERI LIZATION . . . . . . . . . . . . . . .

.

702

NON P U ERPERAL TU BAL STERILIZATION . . . . . . . . . . . . 704 LONG-TERM COMPLICATIONS . . . . . . . . . . . . . . . . . . . . 704 TRAN SCERVICAL STERI LIZATION . . . . . . . . . . . . . . . . . . 705 VASECTOMY . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

.

. . . . . 706

In order, therore, to render a woman permanenty ster­ ile by an operation upon the tubes, they must be excised by wedge-shaped incisions at the cornua of the uterus and the wounds closed by sutures. -J. Whitridge Williams ( 1 903) Sterilization is a popular choice of contraception for millions of men and women. Among women using contraception, one third rely on either male or female sterilization (Daniels, 20 1 5) . This procedure is indicated i n those requesting sterilization and who clearly understand its permanence and its diicult and often unsuccessful reversal. All persons considering sterilization should also be counseled regarding alternative contraceptive choices (American College of Obstetricians and Gynecologists, 20 1 7a,c) . Female sterilization is usually accomplished by occlusion, excision, or division of the fallopian tubes. Puerperal steril­ ization procedures follow cesarean or vaginal delivery and approximately 7 percent of all live births in the United States (Moniz, 20 1 7) . Nonpuerperal tubal sterilization is done at a time unrelated to recent pregnancy and is also termed interval sterilization.

PU ERPERAL TUBAL STERI LIZATION • Timing

For several days postpartum, the uterine fundus lies at the level of the umbilicus, and fallopian tubes are accessible directly beneath the abdominal wall. Moreover, abdominal laxity allows easy repositioning of the incision over each uterine cornu. On our service, puerperal tubal ligation is performed by a surgical team dedicated to this role the morning after delivery. This timing minimizes hospital stay but lowers the likelihood that postpartum hemorrhage would complicate recovery fol­ lowing surgery. In addition, the status of the newborn can be better ascertained before surgery. In contrast, some prefer to perform sterilization immediately following delivery and use neuraxial analgesia already placed for labor. In this model, bar­ riers to sterilization can be lessened by designating these post­ partum surgeries as urgent, especially in high-volume labor and delivery units, which usually prioritize limited operating-room availability for intrapartum procedures (American College of Obstetricians and Gynecologists, 20 1 6; Potter, 20 1 3) . • Technique

Various techniques are now used to disrupt tubal patency. In general, a midtubal segment of fallopian tube is excised, and the severed ends seal by fi b rosis and peritoneal regrowth. Commonly used methods of puerperal sterilization include the Parkland, Pomeroy, and modiied Pomeroy techniques (American College of Obstetricians and Gynecologists, 20 1 7a) . Less often, Filshie clips are used (Madari, 2 0 1 1 ) . I rving and Uchida techniques o r Kroener fimbriectomy are rarely used because of their increased required dissection or unfavorably high failure rates. Also, in the absence of uterine or other pelvic disease, hysterectomy solely for sterilization at the time of cesarean delivery, early in the puerperium, or even remote from pregnancy is diicult to j ustiy. It carries

Ste ri l ization

signifi c antly increased surgical morbidity compared with tubal sterilization. Evidence suggests that the fallopian tube may be the origin of pelvic serous carcinomas, especially those of the ovary. With this knowledge, the Society of Gynecologic Oncologists (20 1 3) and American College of Obstetricians and Gynecologists (20 1 7b) recommend consideration of salpingectomy to lower cancer risks. Speciically, for women at average risk of ovarian cancer, risk-reducing salpingectomy should be discussed and considered with patients at the time of abdominal or pelvic surgery, at hysterectomy, or in lieu of tubal ligation. Spinal analgesia is typically selected for cases scheduled for the fi r st postpartum day. If done more proximate to delivery, the same epidural catheter used for labor analgesia can be used for sterilization analgesia. Notably, for those with preeclampsia, HELLP (hemolysis, �levated liver enzyme levels, low 2latelet count) syndrome, or gestational thrombocytopenia, platelet levels should be > 1 00,000 for spinal blockade (Chap. 25, p. 496) . General anesthesia may be less desirable due to residual pregnancy-related airway vulnerabilities (Bucklin, 2003) . The bladder is emptied before surgery to avoid its laceration. A full bladder can also push the fundus above the umbilicus. A small infraumbilical incision is ideal for several reasons. As noted, the fundus in most cases lies near the umbilicus. Second, the umbilicus usually remains the thinnest portion of the ante­ rior abdominal wall and requires less subcutaneous dissection to reach the linea alba fascia. hird, an infraumbilical incision ofers fascia with suicient integrity to provide a closure that has mini­ mal risk for later incisional hernia. Last, incisions that follow the natural curve of the lower umbilical skin fold yield suitable cos­ mesis. A 2- to 4-cm transverse or vertical skin incision is usually suicient for normal-weight women. For obese women, a 4- to 6-cm incision may be needed for adequate abdominal access. Beneath this incision, the subcutaneous tissue is bluntly separated to reach the linea alba fascia. For this, an Allis clamp can be opened and closed as downward pressure is exerted. Similarly, the blades of two army-navy retractors both pulling in downward yet opposite directions can part the subcutaneous layer. Clearing this fatty tissue away from the fascia isolates the fascia for incision and for later closure without intervening fat, which may impede wound healing. he fascial incision may be transverse or vertical and follows the same orientation of the skin incision. For this, once the linea alba is reached, it is grasped with two Allis clamps-one placed on either side of the planned fascial incision. The purchase of tissue with each clamp should be substantial and creates a small roll of fascia to be incised. Often, the peritoneum is incorporated simultaneously and entered. If not, the peritoneum is grasped with two hemostats and sharply cut. Others may prefer to bluntly enter with a single index finger. Notably, if the initial fascial inci­ sion is too small, it can be extended with curved Mayo scissors. Adequate exposure is critical, and army-navy or appendiceal retractors are suitable. For obese women, a slightly larger inci­ sion and narrow deeper retractors may be required. If bowel or omentum is obstructing, Trendelenburg position can help displace these cephalad. Digitally packing with a single, moist, fanned-out piece of surgical gauze can also be used, but a hemostat should always be attached to the distal end to avert

A

B F I G U RE 39- 1 Parkland method. A. An avascu lar site in the mesosa l pinx adjacent to the fa l lopian tube is perforated with a sma l l hemostat. The jaws are opened t o sepa rate t h e fa l l opian tube from the a djacent mesosa lpinx for approximately 2.5 c m . B. The freed fa llopian tube is l igated proximally a nd d ista l ly with O-c h romic sutu re. The intervening seg ment of a pproxi mately 2 cm is exci sed, and the excision site is inspected for hemostasis. Th is method was designed to avoid the in itial intimate proxi m ity of the cut ends of the fa l lopian tube i n herent with the Pomeroy proced u re. (Reprod u ced with permission from Hoffman BL, Corton MM: S u rg e ries fo r b e n i g n gynecologic cond itions. I n Hoffm a n BL, Schorge J O , B radshaw KD, et a l : Wi l l iams Gynecology, 3 rd ed. New York, McGraw- H i l i Education, 201 6.)

its retention. At times, tilting the entire table to the opposite side of the tube being exposed assists tube isolation. he fallopian tube is identiied and grasped at its midportion with a Babcock clamp, and the distal fimbria conirmed. his prevents confusing the round ligament with the midportion of the tube. A common reason for sterilization failure is ligation of the wrong structure, typically the round ligament. Therefore, identiication and isolation of the distal tube prior to ligation is necessary. Whenever the tube is inadvertently dropped, it is mandatory to repeat this identification process. Surgical steps for ligation are outlined in Figures 39- 1 and 39-2 .

703

704

The P u e rperi u m

With salpingectomy and cesarean delivery, total blood loss rates were not statistically higher (Powell, 20 1 7; Shinar, 20 1 7) . After surgery, diet i s given as tolerated. Ileus i s infrequent and should prompt concern for bowel injury, albeit rare. Most women have an uncomplicated course and are discharged on the first postoperative day. NONPUERPERAL TU BAL STERILIZATION

F I G U RE 39-2 Pomeroy method. During l igation of a m idseg ment tubal loo p, plain catg ut is u sed to ensu re pro m pt a bsorption of the l igature a nd s u bseq uent separation of the severed tubal ends. (Reprod uced with perm ission from Hoffm a n BL, Corton MM: S u r­ geries for benign gynecolog i c cond itions. I n Hoffma n B L, Schorge JO, Bradshaw KD, et a l : Wi l l i a m s Gynecology, 3 rd ed. New York, McGraw- H i l i Ed ucation, 2 0 1 6.)

Steps of salpingectomy are shown in Figure 39-3 . he umbilical incision generally will need to be larger to allow an adequate view of the tube and mesosalpinx and to place clamps. With total salpingectomy, the entire mesosalpinx must be divided to free the fallopian tube. In two small cohorts undergoing salpingectomy ater vaginal birth, surgical times were longer than for tubal occlusion, and in one report, blood loss was increased (Danis, 20 1 6; Powell, 20 1 7) .

A

These techniques and other modiications basically consist of (1) ligation and resection at laparotomy as described earlier for puerperal sterilization; (2) application of permanent rings, clips, or inserts to the fallopian tubes by laparoscopy or hysteroscopy; or (3) electrocoagulation of a tubal segment, usually through a laparoscope. A detailed description and illustration of these can be found in Wiliams Gynecoloy, 3rd edition (hompson, 20 1 6) . In the United States, a laparoscopic approach t o interval tubal sterilization is the most common. The procedure is fre­ quently performed in an ambulatory surgical setting under gen­ eral anesthesia. In almost all cases, the woman can be discharged within several hours. Minilaparotomy using a 3-cm suprapubic incision is also popular, especially in resource-poor countries. Major morbidity is rare with either minilaparotomy or lapa­ roscopy. lthough not often used, the peritoneal cavity can be entered through the posterior vaginal fornix via colpotomy to perform tubal interruption. LONG-TERM COMPLICATIONS • Contraceptive Failure

Pregnancy following sterilization is infrequent. The Collabora­ tive Review of Sterilization (CREST) study followed 1 0,863 women who had undergone tubal sterilization from 1 978 through 1 986 (Peterson, 1 996) . he cumulative failure rate for the various tubal procedures was 1 8.5 per 1 000 or approximately

B

F I G U RE 39-3 A. With s a l pi ngectomy, the mesosa l p i n x is seq uenti a l ly c l a m ped, c ut, a n d l igated. B. At the cornu, c l a m ps a re placed across the fa l lopian t u be a nd its adjacent mesosa l pi nx prior to t u b a l transection. (Reproduced with perm ission from Stuart GS: Puerpera l steril iza­ tion. In Yeomans ER, Hoffm a n B L, G i l strap, I I I, et al (ed s): C u n n i ng h a m a nd G i l stra p's Operative Obstetrics, 3 rd ed. New York, McGraw- H i l i , 2 0 1 7.)

Steril ization

0 . 5 percent. The study found puerperal sterilization to be highly efective. The 5-year failure rate was 5 per 1 000, and for 1 2 years, it was 7 per 1 000. Puerperal sterilization fails for two major reasons. First, sur­ gical errors occur and include transection of the round ligament or only partial transection of the tube. For this reason, both tubal segments are submitted for pathological confirmation. Second, a fistulous tract or spontaneous reanastomosis may form between the severed tubal stumps. Approximately 30 percent ofpregnancies that follow a failed tubal sterilization procedure are ectopic. his rate is 20 percent for those following a postpartum procedure (Peterson, 1 996, 1 997) . hus, any symptoms of pregnancy in a woman after tubal sterilization must be investigated, and an ectopic preg­ nancy excluded. • Other Efects

Overall, risks for ovarian cancer decline and for breast cancer are unafected following sterilization (Gaudet, 20 1 3; Pearce, 20 1 5) . Women who have undergone tubal sterilization are highly unlikely to subsequently have salpingitis (Levgur, 2000) . For menorrhagia and intermenstrual bleeding following tubal sterilization, most studies of the risk have found no association (DeStefano, 1 985; Peterson, 2000; Shy, 1 992) . Less objective but important psychological sequelae of steril­ ization have also been evaluated. In the CREST study, Costello (2002) found that tubal ligation did not change sexual interest or pleasure in 80 percent of women. In most of the 20 percent of women who did report a change, positive efects were 1 0 to 1 5 times more likely. Invariably, a number of women express regrets regarding sterilization, and this is especially true if it is performed at a younger age (Curtis, 2006; Kelek:i, 2005) . In the CREST study, Jamieson (2002) reported that 7 percent of women who had undergone tubal ligation had regrets by 5 years. his is not limited to their own sterilization, because 6. 1 percent of women whose husbands had undergone vasectomy had similar regrets. • Tubal Sterilization Reversal

No woman should undergo tubal sterilization believing that subsequent fertility is guaranteed either by surgery or by assisted reproductive techniques. Both approaches are technically dif­ icult, expensive, and not always successful. In general, preg­ nancy rates after tubal reversal favor women with age younger than 35 years, with 7 cm of remaining tube, with a short time from antecedent sterilization, and with isthmic-isthmic repairs. With reanastomosis via laparotomy, rates of live births range from 44 to 82 percent (Deieux, 20 1 1 ; Malacova, 20 1 5) . The rate of ectopic pregnancy is 2 to 1 0 percent after reanastomo­ sis (American Society for Reproductive Medicine, 20 1 5) . With reanastomosis to reverse Essure sterilization, only 27 percent of women had subsequent live births (Monteith, 20 1 4) . TRANSCERVICAL STERI LIZATION Devices can be inserted via hysteroscopy to occlude the proximal fallopian tubes. he Essure micro insert has a ine stainless-steel

F I G U R E 39-4 Essure m icroinsert placement hysteroscopica l l y a nd i n g rowth of tissue. (Reprod u ced with perm ission from Thom pson M, Kho K: M i n i m a l ly invasive surgery. I n Hoffm a n B L, Schorge J O, Bradshaw KD, et a l (eds): Wi l l iams Gynecology, 3 rd ed. New York, McGra w- H i l l, 2 0 1 6.)

inner coil enclosed in polyester fibers and an expandable outer coil of Nitinol-a nickel and titanium alloy (Fig. 39-4) . he outer coil expands after placement, allowing the inner fibers to expand. These synthetic fi b ers incite a chronic inflammatory response to prompt local tissue ingrowth that leads to complete tubal lumen occlusion. For hysteroscopic placement, sedation, paracervical block, or both may be used, and in-oice insertion is often elected. Devices cannot be placed in all women , and some do not tolerate the procedure while awake (DuY, 2005) . Bilateral placement is achieved in 8 1 to 98 percent of cases on a first attempt (la Chapelle, 20 1 5) . Since the introduction of Essure, cited adverse events include abnormal bleeding, perforation of the uterus or fallopian tubes from device migration, and allergy or hypersensitivity reac­ tions, especially to the nickel component (Al-Sai, 20 1 3 ; IIao, 20 1 5) . Some events resulted in device removal that requires abdominal surgery (Casey, 20 1 6; Lazorwitz, 20 1 7) . To provide more information of the risks and beneits, the Food and Drug Administration (20 1 6) has drafted a black box warning and patient-decision checklist to aid counseling. Because complete tubal blockage is not 1 00 percent, it must be conirmed by hysterosalpingography (HSG) 3 months fol­ lowing surgery (Bayer Healthcare, 2002) . With such confir­ mation, eicacy rates for these devices reach 98 to 99 percent (Chudnof, 20 1 5 ; Munro, 20 1 4) . In real-world settings, preg­ nancies following transcervical sterilization are most frequently attributed to conception before insertion or HSG and to non­ compliance with HSG or its misinterpretation. Although data are limited to small case series, pregnancies conceived with Essure in place do not appear to be at increased risk from the device (Arora, 20 1 4; Veersema, 20 1 4) . Another insert, Adiana, also stimulates tissue ingrowth for tubal occlusion using a cylindrical, nonabsorbent silicone elas­ tomer matrix. However, for inancial reasons, production of this device has now been discontinued by the manufacturer

705

706

The P u e rperi u m

Vasectomy i s safer than tubal ster­ ilization because it is less invasive and is performed with local analgesia (American College of Obstetricians and Gynecologists, 20 1 7a) . In a review to compare the two, Hendrix and associ­ ates ( 1 999) found that, compared with vasectomy, female tubal sterilization ,--- Left seminal vesicle has a 20-fold increased complication --- Left vas deferens Prostate ----... rate, a 1 0- to 37-fold failure rate, and costs three times as much. Right vas deferens One disadvantage is that steriliza­ Incision on left side of tion following vasectomy is not imme­ scrotum, and in tunica diate. Complete release of sperm stored V2" of duct removed in the reproductive tract beyond the I ncision on "+ _ right side interrupted vas deferens takes approxi­ Ends are sealed mately 3 months or 20 ejaculations. Epididymis The American Urological Association recommends a postprocedural semen .... . ----. Testis analysis at 8 to 1 6 weeks to document sterility (Sharlip, 20 1 2) . During the period before azoospermia is docu­ mented, another form of contraception should be used. F I G U R E 39-5 Anatomy of male reprod uctive system showing proced u re for vasectomy. The failure rate for vasectomy during the first year i s 9.4 per 1 000 proce­ dures and 1 1 .4 per 1 000 at 2, 3 , and 5 years Qamieson, 2004) . (Hologic, 20 1 2) . hat said, patients with these inserts may be Failures result from unprotected intercourse too soon after liga­ encountered and can consider their device efective. tion, incomplete occlusion of the vas deferens, or recanalization lthough not currently available in the United States, quin­ (Awsare, 2005; Deneux-haraux, 2004) . acrine pellets cause sclerosis at the tubal ostia. Placement at the Other than regrets, long-term consequences are rare. One is uterine fundus with an IUD-type inserter method allows pellet troublesome chronic scrotal pain, which develops in up to 1 5 migration into the tubal ostia. Of drawbacks, prior cancer asso­ percent of men (Leslie, 2007; vlanikandan, 2004) . Previous ciations have been disproved (Sokal, 20 1 Oa,b) . Eicacy appears concerns for atherogenesis, immune-complex mediated disease, enhanced by technique modification. In one early cohort of testicular cancer, and prostate cancer have been allayed by a 1 33 5 treated women, pregnancy rates at 1 0 years were 1 2 per­ cent (Sokal, 2008) . Following insertion technique improve­ number of investigators (Bernal-Delgado, 1 998; Giovannucci, 1 992; Goldacre, 1 983; M0ller, 1 994) . ment, a 2-year failure rate of 1 .2 percent was calculated by Reanastomosis of the vas deferens can be completed most Lippes (20 1 5) . efectively using microsurgical techniques. In general, concep­ tion rates following reversal are adversely afected by longer VASECTOMY duration from vasectomy, poor sperm quality found at reversal, and type of reversal procedure required (American Society for Currently, up to a half million men in the United States Reproductive Medicine, 2008) . undergo vasectomy each year (Barone, 2006; Eisenberg, 20 1 0) . And 5 percent o f women rely o n this method for contracep­ tion (Daniels, 20 1 5) . For sterilization, the vas deferens lumen REFERENCES is disrupted to block the passage of sperm from the testes. Most Al-Safi ZA, Shavell VI, Hobson DT, et al: Analysis of adverse events with commonly, a no-scapel vasectomy (NS) accomplishes this with Essure hysteroscopic sterilization reported to the Manufacturer and User one specialized instrument that grasps the vas deferens and sur­ Facility Device Experience database. J Minim Invasive Gynecol 20 (6) :825, 20 1 3 rounding skin together. A second dissector tool punctures the American College o f Obstetricians and Gynecologists: Access to postpartum skin and then isolates the vas (Rogers, 20 1 3) . As clariied by the sterilization. Committee Opinion No. 5 30, July 20 1 2, Reairmed 20 1 6 American Urological Association, minimaly invasive vasectomy American College o f Obstetricians and Gynecologists: Benefits and risks of includes any vas isolation procedure, including the no-scalpel sterilization. Practice Bulletin No. 1 33 , February 20 1 3 , Reairmed 20 1 7a American College of Obstetricians and Gynecologists: Salpingectomy technique, which uses a skin incision measuring :;1 cm and for ovarian cancer prevention. Committee Opinion No. 620, J anuary requires minimal vas dissection (Fig. 3 9-5) (Sharlip, 20 1 2) . 20 1 5b, Reairmed 20 1 7b Compared with conventional vasectomy that employs incisions American College of Obstetricians and Gynecologists: Sterilization of women: ethical issues and considerations. Committee Opinion No. 695, Apri > 1 cm and greater dissection, the no-scalpel technique is associ­ 20 l 7c ated with fewer minor surgical complications, but each is equally American Society for Reproductive Medicine: Vasectomy reversal. Fertil Steril 90:S78, 2008 efective (Cook, 20 1 4) . � -

-

---

Ste r i l ization American Society for Reproductive Medicine: Role of tubal surgety in the era of assisted reproductive technology: a committee opinion. Fertil Steril 1 03 (6):e37, 20 1 5 Arora P , Arora RS, Cahill 0 : Essure for management o f hydrosalpinx prior to in vitro fertilisation-a systematic review and pooled analysis. B]OG 1 2 1 (5): 527, 20 1 4 Awsare N , Krishnan ] , Boustead G B , e t al: Complications o f vasectomy. Ann R Coli Surg Engl 8 :406, 2005 Barone A , Hutchison PL, Johnson CH, et al: Vasectomy in the Unites States, 2002. ] U rol 1 76:232, 2006 Bayer Healthcare: Essure: instruction for use. 2002. Available at: http://www. hcp.essure-us.com/ assets/ pdf/Link%20 Essure%20 I FU. pdf. Accessed April 28, 20 1 6 Benal-Delgado E , Latour-Perez ], Pradas-Arnal F , e t al: The association between vasectomy and prostate cancer: a systematic review of the literature. Fertil Steril 0:20 1 , 1 998 Bucklin BA: Postpartum tubal ligation: timing and other anesthetic consider­ adons. Clin Obstet Gynecol 46(3) :657, 2003 Casey ], Aguirre F, Yunker A: Outcomes of laparoscopic removal of the Essure sterilization device for pelvic pain: a case series. Contraception 94(2): 1 90, 20 1 6 Chudnof SG, Nichols J E ]r, Levie M : Hysteroscopic Essure inserts for per­ manent contraception: extended follow-up results of a phase I I I multicenter international study. J Minim Invasive Gynecol 22(6):95 1 , 20 1 5 Cook A , Pun A , Gallo MF, e t al: Scalpel versus no-scalpel incision for vasec­ tomy. Cochrane Database SYSt Rev 3 : CD004 1 1 2, 2 0 1 4 Costello C, H illis S, Marchbanks P, et al: he efect o f interval tubal steriliza­ don on sexual interest and pleasure. Obstet Gynecol 1 00:3, 2002 Curtis M, Mohllajee AP, Peterson H B : Regret following female sterilization at a young age: a systematic review. Contraception 3:205, 2006 Daniels K, Daugherty ], Jones ], et al: Current contraceptive use and varia­ tion by selected characteristics among women aged 1 5-44: United States, 2 0 1 1 -20 1 3 . Nat! Health Stat Report 86: 1 , 20 1 5 Danis RB, Della Badia CR, Richard SD: Postpartum permanent sterilization: could bilateral salpingectomy replace bilateral tubal ligation? J Minim Inva­ sive GynecoI 23(6):928, 20 1 6 Deieux X , Morin Surroca M, Faivre E , e t al: Tubal anastomosis after tubal sterilization: a review. Arch Gynecol Obstet 83(5) : 1 1 49, 201 1 Deneux-Tharaux C, Kahn E, Nazerali H, et al: Pregnancy rates after vasectomy: a survey of U.S. urologists. Contraception 69:40 1 , 2004 DeStefano F, Perlman ]A, Peterson H B , et al: Long term risk of menstrual disturbances after tubal sterilization. Am J Obstet GynecoI 1 52:835, 1 985 DuY S, Marsh F, Rogerson L, et al: Female sterilization: a cohort con­ trolled comparative study of Essure versus laparoscopic sterilization. BJOG 1 1 2 : 1 5 22, 2005 Eisenberg ML, Lipshultz LI : Estimating the number of vasectomies performed annually in the United States: data from the National Survey of Family Growth. J Urol 1 84(5) :2068, 20 10 Food and Drug Administration: Labeling for permanent hysteroscopically­ placed tubal implants itended for sterilization. 20 1 6. Available at: http:// ww.fda.gov/downloads/MedicaIDevices/DeviceRegulationandGuidance/ GuidanceDocuments/UCM488020. pdf. Accessed April 28, 20 1 6 Gaudet MM, Patel AV, Sun J, et al: Tubal sterilization and breast cancer incidence: results from the cancer prevention study II nuuition cohort and meta-analysis. Am J Epidemiol 1 7(6):492, 20 1 3 Giovannucci E , Tosteson TD, Speizer FE, e t al: A long-term study o f mortality in men who have undergone vasectomy. N Engl ] Med 326: 1 392, 1 992 Goldacre ]M, Holford TR, Vessey MP: Cardiovascular disease and vasectomy. N Engl ] Med 308:805, 1 983 Hendrix NW, Chauhan SP, Morrison JC Sterilization and its consequences. Obstet Gynecol Surv 54: 66, 1 999 Hofman B L, Corton MM: Surgeries for benign gynecologic conditions. In Hofman BL, Schorge JO, Bradshaw KD, et al: Williams Gynecology, 3 rd ed. New York, McGraw-Hill Education, 20 1 6 Hologic: Hologic announces second quarter iscal 20 1 2 operating results. 20 1 2. Available online at: ile:///C/Users/bhofm/Downloads/Hologic-Announces­ Second-Quarter-Fiscal-20 1 2-0perating-Results. pdf. Accessed May 1 9, 20 1 6 Jamieson DJ, Costello C, Trussell ] , et al: The risk of pregnancy after vasec­ tomy. Obstet Gynecol 1 03 : 848, 2004 Jamieson DJ, Kaufman SC, Costello C, et al: A comparison of women's regret after vasectomy versus tubal sterilization. Obstet Gynecol 99: I 073, 2002 Kelek:i S, Erdemoglu E, Kuduk S, et al: Risk factors for tubal ligation: regret and psychological efects. Impact of Beck Depression Inventoty. Contraception 7 1 :4 1 , 2005 la Chapel Ie CF, Veersema S, Brolmann HA, et al: Efectiveness and feasibil­ ity of hysteroscopic sterilization techniques: a systematic review and meta­ analysis. Ferril Steril 1 03 (6) : 1 5 1 6, 20 1 5

Lazorwitz A, Tocce K: A case series of removal of nickel-titanium sterilization microinserts from the uterine cornua using laparoscopic electrocautety for salpingectomy. Contraception 96(2) :96, 20 1 7 Leslie TA, I lling RO, Cranston DW, et al: h e incidence of chronic scrotal pain after vasectomy: a prospective audit. BJU Int 1 00: 1 330, 2007 Levgur M, Duvivier R: Pelvic inAammatory disease after tubal sterilization: a review. Obstet Gynecol Surv 55:4 1 , 2000 Lippes J : Quinacrine sterilization (QS): time for reconsideration. Contracep­ tion 92(2):9 1 , 20 1 5 Madari S , Varma R, Gupta J : A comparison o f the modified Pomeroy tubal ligation and Filshie clips for immediate postpartum sterilisation: a systematic review. Eur ] Contracept Reprod Health Care 1 6(5):34 1 , 20 1 1 Malacova E , Kemp-Casey A, Bremner A, et al: Live delivety outcome after tubal sterilization reversal: a population-based study. Ferril Steril 1 04(4) :92, 20 1 5 Manikandan R , Srirangam SJ, Pearson E , e t al: Early and late morbidity after vasectomy: a comparison of chronic scrotal pain at 1 and 10 years. BJU Int 93:57 1 , 2004 Mao ] , pfeifer S , Schlegel P, et al: Safety and eicacy of hysteroscopic steriliza­ tion compared with laparoscopic sterilization: an observational cohort study. BM] 3 5 1 :h5 1 62, 20 1 5 M01ler H , Knudsen LB, Lynge E : Risk o f testicular cancer after vasectomy: cohort study of over 73,000 men. BM] 309:29 5, 1 994 Moniz MH, Chang T, Heisler M, et al : I npatient postpartum long-acting reversible conuaception and sterilization in the United States, 2008-20 1 3 . Obstet Gynecol 1 29 (6) : 1 078, 20 ] Monteith CW, Berger GS, Zerden ML: Pregnancy success after hysteroscopic sterilization reversal. Obstet Gynecol 1 24(6) : 1 1 83 , 2 0 1 4 Munro M G , Nichols ]E, Levy B, e t al: Hysteroscopic sterilization: l O-year retrospective analysis of worldwide pregnancy reportS. ] Minim Invasive Gynecol 2 1 (2):245, 20 1 4 Pearce C L , Stram D O , Ness RB, e t al: Population distribution o f lifetime risk of ovarian cancer in the United States. Cancer Epidemiol Biomarkers Prev 24(4) :67 1 , 20 1 5 Peterson HB, ]eng G , Folger SG, e t al: he risk o f menstrual abnormalities after tubal sterilization. N Engl ] Med 343: 1 68 1 , 2000 Peterson HB, Xia Z, Hughes ]M, et al: The risk of ectopic pregnancy after tubal sterilization. U.S. Collaborative Review of Sterilization Working Group. N Engl J Med 336( 1 1 ) :762, 1 997 Peterson HB, Xia Z, Hughes ]M, et al: The risk of pregnancy after tubal ster­ ilization: findings from the U.S. Collaborative Review of Sterilization. m ] Obstet Gynecol 1 4: 1 1 6 1 , 1 996 Potter JE, Stevenson A], White K, et al: Hospital variation in postpartum tubal sterilization rates in California and Texas. Obstet Gynecol 1 2 1 ( 1 ) : 1 52 , 20 1 3 Powell CB, Alabaster A, Simmons S , e t al: Salpingectomy for sterilization: change in practice in a large integrated health care system, 20 1 1 -20 1 6. Obstet Gynecol 1 30(5):96 1 , 20 1 7 Rogers M D , Kolettis PN: Vasectomy. Urol Clin North A m 40(4) :559, 20 1 3 Sharlip 1 0 , Belker AM , Honig S , et al : Vasectomy: AUA guideline. Outcomes of microsurgical vasovasostomy fo r vasectomy reversal: a meta-analysis and systematic review. ] Urol 1 88(6 Suppi):2482, 20 1 2 Shinar S , Blecher Y, Alpern S , e t al: Total bilateral salpingectomy versus partial bilateral salpingectomy for permanent sterilization during cesarean delivety. Arch Gynecol Obstet 295(5): 1 1 85, 20 1 7 Shy KK, Stergachis A , Grothaus LG, e t al: Tubal sterilization and risk o f sub­ sequent hospital admission for menstrual disorders. Am ] Obstet Gynecol 1 66: 1 698, 1 992 Society of Gynecologic Oncologists: SGO Clinical Practice Statement: Salpin­ gectomy for ovarian cancer prevention. Available at: https://www.sgo.org/ cl inical-practice/gu idel i nes/sgo-cl inical-p ractice-statemen t -sal pi ngecto my­ for-ovarian-cancer-prevention.l Accessed December 1 3, 20 1 3 Sokal D C , Hieu d o T , Loan NO, e t al: Contraceptive efectiveness o f two insertions of quinacrine: results from 1 0-year follow-up in Vietnam. Con­ traception 8 :6 1 , 2008 Sokal DC, Trujillo V, Guzman SC, et al: Cancer risk after sterilization with transcervical quinacrine: updated indings from a Chilean cohort. Contra­ ception 8 1 ( 1 ) : 5 , 20 10a Sokal DC, Vach TH, Nanda K, Quinacrine sterilization and gynecologic cancers: a case-control study in northen Vietnam. Epidemiology 21 (2): 1 64, 2 0 1 Ob Stuart GS: Puerperal sterilization. In Yeomans ER, Hofman BL, Gilstrap, I I I , e t a l (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd e d . New York, McGraw-Hill, 20 1 Thompson M, Kho K: Minimally invasive surgery. In Hofman BL, Schorge JO, Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGraw-Hill, 20 1 6 Veersema S , Mijatovic V, Dreyer K , e t al: Outcomes o f pregnancies i n women with hysteroscopically placed micro-inserts in situ. ] M inim Invasive Gyne­ col 2 1 (3) :492, 20 1 4

707

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C H A PT E R 40

H yperten s ive D i sorders

TERMI NOLOGY AND DIAGNOSIS . . . . . . . . . . . . . . . . . . 7 1 0 I NCIDENCE AND RISK FACTORS . . . . . . . . . . . . . . . . . . . 7 1 3 ETIOPATHOGENESIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 1 3 PATHOPHYSIOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 1 7 PREDICTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 725 PREVENTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 726 PREECLAMPSIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 728 ECLAMPSIA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 734 MANAG EMENT CONSI DERATIONS . . . . . . . .

.

. . . . . . . . 738

LONG -TERM CONSEQUENCES . . . . . . . . . . . . . . . . . . . . 744

An eclamptic convulsion sometimes occurs without warning, "like a boltfrom a clear sky ': in women who are apparenty in peect health. In the majoriy of cases, however, the out­ break is precededor a longer or shorter period by premoni­ toy symptoms indicative of toxemia ofpregnancy, among the more common being oedema, headache, epigastric pain, and possiby disturbances of vision. - J. Whitridge Williams ( 1 903) At the time of this textbook's irst edition, it was accepted that "toxemia" preceded most cases of eclampsia. he central role of hypertension had not yet been discovered, and after many years, it became apparent that preeclampsia was a syndrome of which

hypertension was only one important facet. Still, the mecha­ nisms by which pregnancy incites or aggravates hypertension remain unsolved. Indeed, hypertensive disorders remain among the most signiicant and intriguing unsolved problems in obstet­ rics. hese disorders complicate 5 to 1 0 percent of all pregnan­ cies, and together they are one of the deadly triad-along with hemorrhage and infection-that contributes greatly to mater­ nal morbidity and mortality rates. Of hypertensive disorders, the preeclampsia syndrome, either alone or superimposed on chronic hypertension, is the most dangerous. As subsequently discussed, new-onset hypertension during pregnancy-termed gestational hypertension-is followed by signs and symptoms of preeclampsia almost half the time, and preeclampsia is identi­ ied in 4 to 5 percent of all pregnancies (Martin, 20 1 2) . h e World Health Organization (WHO) systematically reviews maternal mortality worldwide, and in developed coun­ tries, 1 6 percent of maternal deaths were attributed to hyper­ tensive disorders (han, 2006) . In the United States from 2 0 1 1 to 20 1 3, 7.4 percent of2009 pregnancy-related maternal deaths were caused by preeclampsia or eclampsia (Creanga, 20 1 7) . A similar rate was 1 0 percent in France from 2003 through 2007 (Saucedo, 20 1 3) . Importantly, more than half of these hyper­ tension-related deaths were deemed preventable (Berg, 2005). TERMINOLOGY AND DIAGNOSIS To update and codiy the terminology and classiication of hypertensive disorders of pregnancy, a Task Force of the American College of Obstetricians and Gynecologists (20 1 3) has provided evidence-based recommendations for clinical practice. The previous basic classiication was retained and describes four types of hypertensive disease: 1 . Preeclampsia and eclampsia syndrome 2. Chronic hypertension of any etiology 3. Preeclampsia superimposed on chronic hypertension

Hyperte n s ive D i s o rders

4. Gestational hypertension-definitive evidence for the pre­ eclampsia syndrome does not develop and hypertension resolves by 1 2 weeks postpartum. Importantly, this classification diferentiates the preeclamp­ sia syndrome from other hypertensive disorders because it is potentially more ominous. • Diagnosis of Hypertensive Disorders Hypertension is diagnosed empirically when appropriately taken blood pressure exceeds 1 40 mm Hg systolic or 90 mm Hg diastolic. Korotkof phase V is used to define diastolic pres­ sure. Previously, incremental increases of 30 mm Hg systolic or 1 5 mm Hg diastolic above blood pressure values taken at midpregnancy had also been used as diagnostic criteria, even when absolute values were < 1 40/90 mm Hg. These incremen­ tal changes are no longer used to define hypertension, but it is recommended that such women be observed more closely because eclamptic seizures develop in some whose blood pres­ sures have stayed below 1 40/90 mm Hg (Alexander, 2006) . Also, a sudden rise in mean arterial pressure but still in a nor­ mal range-"delta hypertension"-may signiy preeclampsia (Macdonald-Wallis, 20 1 2; Zeeman, 2007) . • Concept of "Delta Hypertension"

he systolic and diastolic blood pressure levels of 1 40/90 mm Hg have been arbitrarily used since the 1 950s to define "hyper­ tension" in nonpregnant individuals. However, these levels were selected by insurance companies to characterize a group of middle-aged men. It seems more realistic to deine normal­ range blood pressures that fall between an upper and lower limit for a particular population-such as young, healthy, pregnant women. A schematic example using arbitrary mean arterial blood pressure readings is shown in Figure 40- 1 . Data curves for both women show blood pressure measurements near the

... Patient A ... Patient B )

..

:J ) ) )

, C 0 0 ..

m

�

8

16

:

9 5 th � 5 0t h :�5th

24

Weeks' gestation

32

40

F I G U R E 40- 1 Schematic shows normal reference ra nges for mean a rterial b lood pressu re cha nges across preg nancy. Patient A (blue) has mea n bl ood pressu res near the 20th percentile throughout preg n a n cy. Patient B (red) has a s i m i l a r pattern with mea n pres­ s u res at the 25th percentile u nt i l a pprox i m ately 36 weeks when her blood press u re beg i n s to rise. By term, it is su bsta ntively higher and i n the 75th percenti le, but she is sti l l consid ered "n ormoten sive."

25th percentile until 32 weeks. These begin to rise in patient B, who by term has substantively higher blood pressures. How­ ever, her pressures are still < 1 40/90 mm Hg, and thus she is considered to be "normotensive. " We use the term delta hyper­ tension to describe this rather acute rise in blood pressure. Some of these women will go on to have obvious preeclampsia, and some even develop eclamptic seizures or HELLP (hemolysis, devated liver enzyme levels, low 2latelet count) syndrome while still normotensive. • Gestational Hypertension

his diagnosis is made in women whose blood pressures reach 1 40/90 mm Hg or greater for the irst time after midpregnancy, but in whom proteinuria is not identiie. Almost half of these women subsequently develop preeclampsia syndrome. Even so, when blood pressure increases appreciably, it is dangerous to both mother and fetus to ignore this rise only because protein­ uria has not yet developed. As Chesley ( 1 985) emphasized, 1 0 percent o f eclamptic seizures develop before overt proteinuria can be detected. Finally, gestational hypertension is reclassiied by some as transient hypertension if evidence for preeclampsia does not develop and the blood pressure returns to normal by 1 2 weeks postpartum. • Preeclampsia Syndrome

Preeclampsia is best described as a pregnancy-speciic syndrome that can aect virtualy evey organ system. In addition, it her­ alds a higher incidence of cardiovascular disease later in life (p. 744) . Although preeclampsia is much more than simply gesta­ tional hypertension with proteinuria, appearance of proteinuria remains an important diagnostic criterion. Thus, proteinuria is an objective marker and relects the system-wide endothelial leak that characterizes the preeclampsia syndrome. In some women with the preeclampsia syndrome, neither overt proteinuria nor fetal-growth restriction are features (Sibai, 2009) . Because of this, the Task Force (20 1 3) suggests other diagnostic criteria, which are shown in Table 40- 1 . Evidence of multiorgan involvement may include thrombocytopenia, renal dysfunction, hepatocellular necrosis, central nervous system perturbations, or pulmonary edema. • I ndicators of Preeclampsia Severity

The markers listed in Table 40- 1 are also used to classiy pre­ eclampsia syndrome severity. lthough many use a dichoto­ mous "mild" and "severe" classiication, the Task Force (20 1 3) discourages the use of "mild preeclampsia." It is problematic that there are criteria for the diagnosis of "severe" preeclamp­ sia, but the default classiication is either implied or specii­ cally termed as " mild," "less severe," or " nonsevere" (Alexander, 2003; Lindheimer, 2008b) . here are no generally agreed-on criteria for "moderate" preeclampsia-an elusive third category. We use the criteria listed in Table 40-2, which are categorized as "severe" versus "nonsevere. " Some symptoms are considered o minous. Headaches or visual disturbances such as scotomata can precede eclampsia, which is a convulsion not attributable to another cause. The

71 1

71 2

Obstet rica l Com pl icati o n s

TABLE 40- 1 . Classification a n d D i a g n os i s o f P reg n a n cy-Associated Hypertension Condition

Criteria Req u i red

Gestational hypertension

B P > 1 40/90 mm H g after 20 weeks in previously normote n s i ve women

P reecla m psia: Hypertension p l u s P rote i n u ria

•

•

•

2300 m g/24 h, or U ri ne p rotei n : c reat i n i n e ratio 20.3, or D i pstick 1 + pers i ste nta or

Throm bocytope n i a Ren a l i n sufficie ncy Live r i nvolvement Cere b ra l sym ptoms P u l m o n a ry edema

•

•

•

•

Platelet cou nt < 1 OO,OOO/ .LL C reat i n i n e level > 1 . 1 m g/d L or d o u b l i n g of basel i ne b Seru m tra n sa m i nase l eve l sc twice normal H eadac he, visual d i stu rba nces, convu l sions

a Recom me n ded o n ly if sol e ava i l a b l e test. b N o prior re n a l d i sease. CAST (as pa rtate tra n sa m i nase) or A LT (a la n i ne tra n sa m i na se). BP b l ood pressu re. Modified with perm ission from A me ri ca n Col leg e of Obstet ri c i a n s a n d Gynecologists; Task Force on Hypertension i n P reg n a ncy: Hyperte nsion i n p re g n a n cy. Report o f t h e America n Col lege o f Obstetricians a n d Gynecologi sts' T a s k Force o n Hyperte n s i o n i n Preg na ncy, O bstet Gyneco l . 2 0 1 3 Nov; 1 22 (S) : 1 1 22-3 1 =

seizures are generalized and may appear before, during, or after labor. The proportion that develops seizures later, after 48 hours postpartum, approximates 1 0 percent (Sibai, 2005; Zwart, 2008) . Another symptom, epigastric or right upper quad­ rant pain, frequently accompanies hepatocellular necrosis, isch­ emia, and edema that ostensibly stretches Glisson capsule. This characteristic pain is frequently accompanied by elevated serum TABLE 40-2. I n d icators of Severity of Gestational Hypertens ive Disordersa Abnormality

Nonsevereb

Severe

D ia sto l i c B P Systo l i c BP P rote i n u riac Headache V i s u a l d i stu rba n ces U pper a bdom inal pain Ol i g u ria Convulsion (eclampsia) Seru m c reati n i ne Throm bocytopen ia ( < 1 OO,OOO/ L L) Seru m tra n s a m i nase el evation Fetal-g rowth restriction P u l m o n a ry edema Gestat i o n a l age

< 1 1 0 m m Hg < 1 60 m m Hg None to pos itive Absent Absent A bsent Absent Absent Normal Absent

� 1 1 0 mm Hg � 1 60 m m Hg None to pos itive P resent P resent P resent P resent P resent E l evated P resent

Minimal

Ma rked

Absent Absent Late

P resent Present Early

aCom pa re with criteria i n Ta b l e 40- 1 . b l n c l u d es " m i ld " and "moderate" hyperte n s i o n not specifi­ ca l ly d efi n ed . cMost d i sreg a rd deg rees of p rote i n u ria to c l a ssify n o nsevere or severe. BP b lood pressu re. =

hepatic transaminase levels. Finally, thrombocytopenia also sig­ nifies worsening preeclampsia. It represents platelet activation and aggregation as well as microangiopathic hemolysis. Other factors indicative of severe preeclampsia include renal or cardiac involvement, obvious fetal-growth restriction, and early-onset disease. he more profound these signs and symptoms, the less likely it is that they can be temporized, and the more likely that deliv­ ery will be required. A caveat is that dierentiation between non­ severe and severe gestational hypertension or preeclampsia can be misleading because what might be apparenty mild disease may progress rapidy to severe disease. • Preeclampsia Superimposed on

Chronic Hypertension

Regardless of its cause, any chronic hypertensive disorder predisposes a woman to develop superimposed preeclamp­ sia syndrome. Chronic underlying hypertension is diagnosed in women with documented blood pressures > 1 40/90 mm Hg before pregnancy or before 20 weeks' gestation, or both. Hypertensive disorders can create diicult problems with diag­ nosis and management in women who are not irst seen until after midpregnancy. This is because blood pressure normally drops during the second and early third trimesters in both nor­ motensive and chronically hypertensive women (see Fig. 40- 1 ) . Thus, a woman with previously undiagnosed chronic vascular disease who is seen before 20 weeks frequently has blood pres­ sures within normal range. During the third trimester, how­ ever, as blood pressures return to their originally hypertensive levels, it may be diicult to determine whether hypertension is chronic or induced by pregnancy. Even a careful search for evi­ dence of preexisting end-organ damage may be futile, as many of these women have mild disease and no evidence of ventricu­ lar hypertrophy, retinal vascular changes, or renal dysfunction.

Hype rte nsive Disorders

In some with chronic hypertension, blood pressure rises to obviously abnormal levels, typically after 24 weeks' gestation. If new-onset or worsening baseline hypertension is accompanied by new-onset proteinuria or other indings listed in Table 40- 1 , then superimposed preeclampsia is diagnosed. Compared with "pure" preeclampsia, superimposed preeclampsia commonly develops earlier in pregnancy. It also tends to be more severe and more often is accompanied by fetal-growth restriction. he same criteria shown in Table 40-2 are also used to further char­ acterize severity of superimposed preeclampsia. I NCIDENCE AND RISK FACTORS Young and nulliparous women are particularly vulnerable to developing preeclampsia, whereas older women are at greater risk for chronic hypertension with superimposed preeclampsia. he incidence is markedly inluenced by race and ethnicity-and thus by genetic predisposition. In one study by the Maternal-Fetal Medicine Units (MFMU) Network, the incidence of preeclamp­ sia was 5 percent in white, 9 percent in Hispanic, and 1 1 per­ cent in African-American women (Myatt, 20 1 2a,b) . In addition, black women have greater morbidity (Shahul, 20 1 5) . In several worldwide studies reviewed by Staf and coworkers (20 1 5) , the incidence of preeclampsia in nulliparous populations ranged from 3 to 1 0 percent. he incidence of preeclampsia in multiparas also varies and ranges from 1 .4 to 4 percent (Fisher, 20 1 5) . Bartsch and associates (20 1 6) extracted data from more than 25 million pregnancies and calculated relative risks for several clinical factors shown in Table 40-3. Others include the metabolic syndrome and hyperhomocysteinemia (Karu­ manchi, 20 1 6a; Masoudian, 20 1 6; Scholten, 20 1 3) . Pregnan­ cies with a male fetus are also at slightly higher risk a askolka,

TABLE 40-3. Selected C l i n ical Risk Facto rs for

Preec l a m psia

Risk Factor SLE N u l l i pa rity Age > 3 5 Prior sti l l b i rth C KD ART B M I > 30 M u ltifeta l Prior a b ru ption Dia betes Prior preecla m psia CHTN APA

Preg nancies ( m i llions) 2 .43 2 .98 5 .24 0.063 0.97 1 .46 5 .92 7.3 1 0.29 2.55 3 . 72 6.59 0.22

Pooled U nadjusted Relative Risk (95% 0) 2.5 ( 1 .0-6.3) 2 . 1 ( 1 .9-2 .4) 1 .2 ( 1 . 1 - 1 .3) 2 .4 ( 1 .7-3 .4) 1 .8 ( 1 .5-2. 1 ) 1 .8 ( 1 .6-2 . 1 ) 2 .8 (2 .6-3 . 1 ) 2 .9 (2.6-3 . 1 ) 2 .0 ( 1 .4-2 .7) 3 .7 (3. 1 -4.3) 8.4 (7. 1 -9.9) 5 . 1 (4.0-6.5) 2 .8 ( 1 .8-4.3)

APA a nti phosphol i p i d a nti body; ART assisted rep ro­ d u ctive tech nology; B M I body mass i ndex; C HTN c h ro n i c hyperte nsion; CKD c h ronic kid ney d isease; SLE syste m i c l u pu s e ryth e m atosu s. Data from Ba rtsch, 2 0 1 6. =

=

=

=

=

=

20 1 7) . Although smoking during pregnancy causes various adverse pregnancy outcomes, ironically, it carries a reduced risk for hypertension during pregnancy (Bainbridge, 2005; Kraus, 20 1 4) . Other factors are human immunodeficiency virus (HIV) seropositivity and sleep-disordered breathing (Facco, 20 1 7; Sansone, 20 1 6) . For eclampsia, the incidence has declined i n areas where health care is more readily available. In the United States in 1 998, it afected 1 in 3250 births (Ventura, 2000) . Except for Iceland, which has an extremely low rate, in countries with adequate resources the incidence averages 1 in 2000 to 3000 deliveries (Andersgaard, 2006; Jaatinen, 20 1 6; O'Connor, 20 1 3; Royal College of Obstetricians and Gynaecologists, 2006; Zwart, 2008). ETIOPATHOGENESIS Any satisfactory theory concerning the origins of preeclampsia must account for the observation that gestational hypertensive disorders are more likely to develop in women with the follow­ ing characteristics: • •

•

•

Are exposed to chorionic villi for the irst time Are exposed to a superabundance of chorionic villi, as with twins or hydatidiform mole Have preexisting conditions associated with endothelial cell activation or inflammation, such as diabetes, obesity, cardio­ vascular or renal disease, immunological disorders, or heredi­ tary inluences Are genetically predisposed to hypertension developing dur­ ing pregnancy.

A fetus is not a requisite for preeclampsia to develop. And, although chorionic villi are essential, they need not be intrauter­ ine. For example, preeclampsia can develop with an abdominal pregnancy (Worley, 2008) . Regardless ofprecipitating etioloy, the cascade of events leading to the preeclampsia syndrome is char­ acterized by abnormalities that result in systemic vascular endothe­ lial damage with resultant vasospasm, transudation ofplasma, and ischemic and thrombotic sequelae. • Phenotypic Expression of

Preeclampsia Syndrome

he preeclampsia syndrome varies widely in its clinical pheno­ typic expression. But, at least two major subtypes are diferenti­ ated by whether or not remodeling of uterine spiral arterioles by endovascular trophoblasts is defective. his concept has given rise to the "two-stage disorder" theory of preeclampsia patho­ genesis. According to Redman and coworkers (20 1 5a) , stage 1 is caused by faulty endovascular trophoblastic remodeling that downstream causes the stage 2 clinical syndrome. Importantly, stage 2 can be modified by preexisting maternal conditions that are also manifest by endothelial cell activation or inlammation and are listed in the third prior bullet. Such staging is artiicial, and it seems logical that preeclamp­ sia syndrome presents clinically as a spectrum of worsening disease. Moreover, evidence is accruing that many "isoforms" exist as discussed subsequently. Examples include diferences in

71 3

714

Obstetrical Com p l ications

maternal and fetal characteristics, placental indings, and early­ versus late-onset disease (Phillips, 20 1 0; Valensise, 2008; van der Merwe, 20 1 0) . • Etiology

n imposing number of mechanisms have been proposed to explain the cause of preeclampsia. Those currently considered important include: 1 . Placental implantation with abnormal trophoblastic inva­ sion of uterine vessels 2. Immunological maladaptive tolerance between maternal, paternal (placental) , and fetal tissues 3. Maternal maladaptation to cardiovascular or inlammatory changes of normal pregnancy 4. Genetic factors including inherited predisposing genes and epigenetic inluences. A b n o r m a l Tro p h o b l a stic I nva s i o n

Discussed in Chapter 5 (p. 88), normal implantation is char­ acterized by extensive remodeling of the spiral arterioles within the decidua basalis (Fig. 40-2) . Endovascular trophoblasts replace the vascular endothelial and muscular linings to enlarge the vessel diameter (Zhou, 1 997) . The veins are invaded only superficially. In some cases of preeclampsia, however, trophoblastic inva­ sion may be incomplete. With this, decidual vessels, but not myometrial vessels, become lined with endovascular tropho­ blasts. The deeper myometrial arterioles thus do not lose their endothelial lining and musculoelastic tissue, and their mean external diameter is only half that of corresponding vessels in normal placentas (Fisher, 20 1 5) . In general, the magnitude of defective trophoblastic invasion correlates with the severity of the hypertensive disorder (Madazli, 2000) . And importantly,

/

it is more prevalent in women with early-onset preeclampsia (Khodzhaeva, 20 1 6) . cMahon and associates (20 1 4) found that lower levels of soluble antiangiogenic growth factors may be involved in this faulty endovascular remodeling. From placental electron microscopy studies, early preeclamp­ tic changes include endothelial damage, insudation of plasma constituents into vessel walls, proliferation of myointimal cells, and medial necrosis (De Wolf, 1 980). Hertig ( 1 945) referred to lipid accumulation in myointimal cells and macrophages as atherosis. These indings are more common in placentas from women diagnosed with preeclampsia before 34 weeks (Nelson, 20 1 4b). Acute placental vascular atherosis may also identiy a group of women at greater risk for later atherosclerosis and car­ diovascular disease (Staf, 20 1 5) . In pregnancy, the abnormally narrow lumen of spiral arterioles likely impairs placental blood fl o w. Diminished perfusion and a hypoxic environment even­ tually lead to release of placental debris or microparticles. At this point, these changes incite a systemic inlamma­ tory response, which is stage 2 of the preeclampsia syndrome (Lee, 20 1 2; Redman, 20 1 2) . Defective placentation is posited to further cause the susceptible woman to develop gestational hypertension, the preeclampsia syndrome, preterm delivery, a growth-restricted fetus, and/or placental abruption (Brosens, 20 1 1 ; Labarrere, 20 1 7; Nelson, 20 1 4b) . I m m u no l og i ca l Factors

IVlaternal immune tolerance to paternally derived placental and fetal antigens is discussed in Chapter 5 (p. 95). Loss of this tolerance is another cited theory for preeclampsia (Erlebacher, 20 1 3) . Certainly, the histological changes at the maternal­ placental interface are suggestive of acute graft rejection. Inferential data also suggest that preeclampsia is an immune­ mediated disorder. For example, the risk of preeclampsia is appreciably enhanced in circumstances in which formation of blocking antibodies to placental antigenic sites might be

Anchoring villi

�" I

.. ) -

�-

Syncytiotrophoblast Cytotrophoblast

Interstitial extravillous trophoblast Endovascular extravillous trophoblast NORMAL

PREECLAMPSIA

FIGURE 40-2 Schematic representation of normal placenta l i m pla ntation shows proliferation of extravi l lous trophoblasts from an a nchor­ i n g vi l l us. These trophoblasts i nvade the decidua a n d extend i nto the wa l l s of the spira l a rteriole to rep lace the e ndothe l i u m a nd muscular wa l l to create a d i lated low-resista nce vessel. With preecl a m psia, defective i m pla ntation is characterized by incomplete i nvasion of the s p i ra l a rteriol a r wa l l b y extravil lous trophoblasts. T h i s resu lts i n a s m a l l-ca l i ber vessel with h i g h resista nce t o flow.

Hypertens ive D i s o rd e rs

impaired. In this scenario, the irst pregnancy would carry a higher risk. Tolerance dysregulation might also explain an ele­ vated risk when the paternal antigenic load is increased, that is, with two sets of paternal chromosomes-a "double dose." Namely, women with molar pregnancies have a high incidence of early-onset preeclampsia. Women with a trisomy 1 3 fetus also have a 30- to 40-percent incidence of preeclampsia. hese women have elevated serum levels of antiangiogenic factors. he gene for one of these factors, soluble ins-like tyrosine kinase 1, is on chromosome 1 3 (Bdolah, 2006) . Conversely, women previ­ ously exposed to paternal antigens, such as a prior pregnancy with the same partner, are "immunized" against preeclampsia. his phenomenon is not as apparent in women with a prior abortion (Strickland, 1 986) . Multiparas impregnated by a new consort have a greater risk of preeclampsia (Mostello, 2002) . Redman and colleagues (20 1 5a) reviewed the possible role of immune maladaptation in preeclampsia pathophysiology. In women destined to be preeclamptic, extravillous trophoblasts early in pregnancy express reduced amounts of immunosup­ pressive nonclassic human leukocyte antigen G (HLA G) . Black women more commonly have the 1 597�C gene allele that fur­ ther predisposes to preeclampsia (Loisel, 20 1 3) . hese changes may contribute to the defective placental vascularization in stage 1 of the preeclampsia syndrome. As discussed in Chapter 4 (p. 59) , T-helper (h) lymphocytes during normal pregnancy are produced so that type 2 activity is increased in relation to type 1-so-called ype 2 bias (Redman, 20 1 2, 20 1 5a) . h2 cells pro­ mote humoral immunity, whereas Th 1 cells stimulate inlamma­ tory cytoine secretion. Beginning in the early second trimester in women who develop preeclampsia, Th 1 action is increased. Endot h e l i a l C e l l Activati o n

Inflammatory changes are believed to be a continuation of stage 1 alterations. In response to ischemia or other inciting causes, placental factors are released and begin a cascade of events (Davidge, 20 1 5) . Thus, antiangiogenic and metabolic factors and other inflammatory leukocyte mediators are thought to provoke systemic endothelial cell injury, which is used synony­ mously here wit h endothelial cel activation or dyfunction. Endothelial cell dysfunction may result from an extreme activated state of leukocytes in the maternal circulation (Faas, 2000; Gervasi, 200 1 ) . Briefl y , cytokines such as tumor necrosis factor-a (TNF-a) and the interleukins may contribute to the systemic oxidative stress associated with preeclampsia. This is characterized by reactive oxygen species and free radicals that lead to formation of self-propagating lipid peroxides (Manten, 2005). hese peroxides in turn generate highly toxic radicals that injure systemic vascular endothelial cells, modiy nitric oxide production by these cells, and interfere with prostaglan­ din balance. Other consequences of oxidative stress include production of the lipid-laden macrophage foam cells seen in placental atherosis, activation of systemic microvascular coagu­ lation manifested by thrombocytopenia, and greater systemic capillary permeability relected by edema and proteinuria. Genetic Factors

Preeclampsia appears to be a multifactorial, polygenic disorder. In one study of almost 1 .2 million Swedish births, a genetic

TABLE 40-4. Genes with Poss i ble Associations with Preec la m psia Syndrome Gene (Polymorphism)

F unction Afected

MTH FR (C677D

Methylene tetra hyd rofol ate red u ctase Fa ctor VLelden A n g iotensi n og e n H u ma n leu kocyte a nti gens En d oth e l i a l n itric ox i d e Prot h rombi n (factor I I) A n g ioten s i n-converti ng enzy m e Cytotoxic T- Iym phocytea ssociated protei n L i pop rote i n l i pase Seri ne peptidase i n h i bitor Decrea sed m ethylation

F5 (Le iden) AGT (M23 5T) H L A (Va rious) NOS3 (G l u 298 Asp) F2 (G202 1 OA) ACE (IIDd1l ntron 1 6) CTLA4 LPL SERPI N E 1 G N A promoter

Data from B u u rma, 2 0 1 3 ; Sta i nes- U ri a s, 20 1 2; Triche, 20 1 4; Wa rd, 2 0 1 4; Ye, 20 1 6.

association for gestational hypertension and for preeclampsia was found (Nilsson, 2004) . Ward and Taylor (20 1 5) cite an incident risk for preeclampsia of 20 to 40 percent for daugh­ ters of preeclamptic mothers; 1 1 to 37 percent for sisters of preeclamptic women; and 22 to 47 percent for twins. E thno­ racial factors are important, as evidenced by the high incidence of preeclampsia in African-American women. It may be that Latina women have a lower incidence because of interactions of American Indian and white race genes (Shahabi, 20 1 3) . h e hereditary predisposition for preeclampsia likely s tems from interactions of literally hundreds of inherited genes­ both maternal and paternal-that control myriad enzymatic and metabolic functions throughout every organ system (Triche, 20 14). Plasma-derived factors may induce some of these genes in preeclampsia (Mackenzie, 20 1 2) . Thus, the clini­ cal manifestation in any given woman with the preeclampsia syndrome will occupy a spectrum. In this regard, phenotypic expression will difer among similar genotypes depending on interactions with environmental components (Yang, 20 1 3) . Hundreds of genes have been studied for their possible asso­ ciation with preeclampsia (Buurma, 20 1 3; Sakowicz, 2 0 1 6; Ward, 20 1 5) . Several that may have a significant association with the syndrome are listed in Table 40-4. However, because of the complex phenotypic expression of preeclampsia, it is doubtful that any one candidate gene will be found responsible. Indeed, Majander and associates (20 1 3) have linked preeclamp­ sia predisposition to even etal genes on chromosome 1 8. • Pathogenesis

Va sospasm

The concept of vasospasm with preeclampsia has been advanced for a century (Volhard, 1 9 1 8) . Systemic endothelial activation causes vasospasm that elevates resistance to produce subsequent hypertension. Concurrently, systemic endothelial cell injury promotes interstitial leakage, and blood constituents, including

715

71 6

Obstetrical Compl ications

platelets and ibrinogen, are deposited subendothelially. Endo­ thelial j unctional proteins are also disrupted, and the suben­ dothelial region of resistance arteries undergoes ultrastructural change (Suzuki, 2003; Wang, 2002) . The much larger venous circuit is similarly involved. With diminished blood low because of maldistribution from vasospasm and interstitial leakage, ischemia of the sur­ rounding tissues can lead to necrosis, hemorrhage, and other end-organ disturbances characteristic of the syndrome. One important clinical correlate to this is the markedly attenu­ ated blood volume seen in women with severe preeclampsia (Zeeman, 2009) . E n d oth e l i a l Cel l I nj u ry

Inj ury to systemic endothelial cells is now a centerpiece of preeclampsia pathogenesis (Davidge, 20 1 5) . In this scheme, protein factor(s)-likely placental-are secreted into the maternal circulation and provoke activation and dysfunction of the systemic vascular endothelium. Many facets of the clini­ cal syndrome of preeclampsia are thought to result from these widespread endothelial cell changes. Intact endothelium has anticoagulant properties. lso, systemic endothelial cells, by releasing nitric oxide, blunt the response of vascular smooth muscle to agonists. Inj ured or acti­ vated endothelial cells may produce less nitric oxide and may secrete substances that promote coagulation and greater sensi­ tivity to vasopressors. Further evidence of endothelial activa­ tion includes the characteristic changes in glomerular capillary endothelial morphology, greater capillary permeability, and elevated blood concentrations of substances associated with endothelial activation. Likely, multiple factors in the plasma of preeclamptic women combine to exert these vasoactive efects (Myers, 2007; Walsh, 2009) . I nc rea sed Pressor Res ponses

As discussed in Chapter 4 (p. 63), pregnant women nor­ mally develop refractoriness to infused vasopressors (Abdul­ Karim, 1 96 1 ) . Women with early preeclampsia, however, have enhanced vascular reactivity to infused norepinephrine and angiotensin II (Raab, 1 956; Talledo, 1 968) . Moreover, increased sensitivity to angiotensin II clearly precedes the onset of gestational hypertension (Gant, 1 974) . Paradoxically, women who develop preterm preeclampsia have lower circulat­ ing levels of angiotensin II (Chase, 20 1 7) . Several prostaglandins are thought t o be central to pre­ eclampsia syndrome pathophysiology. Specifically, the blunted pressor response seen in normal pregnancy is at least par­ tially due to diminished vascular responsiveness mediated by endothelial prostaglandin synthesis. For example, compared with normal pregnancy, endothelial prostacyclin (PGI 2 ) pro­ duction is lower in preeclampsia. This action appears to be mediated by phospholipase A2 (Davidge, 20 1 5). At the same time, thromboxane A2 secretion by platelets is increased, and the prostacyclin:thromboxane A2 ratio declines. The net result favors greater sensitivity to infused angiotensin II and, ultimately, vasoconstriction (Spitz, 1 988) . hese changes are apparent as early as 22 weeks' gestation in gravidas who later develop preeclampsia (Chavarria, 2003) .

Nitric oxide is a potent vasodilator synthesized from I-argi­ nine by endothelial cells. Inhibition of nitric oxide synthesis raises mean arterial pressure, lowers heart rate, and reverses the pregnancy-induced refractoriness to vasopressors. In humans, nitric oxide likely is the compound that maintains the normal low-pressure vasodilated state characteristic of fetoplacental per­ fusion (Myatt, 1 992; Weiner, 1 992) . he efects of nitric oxide production in preeclampsia are unclear. It appears that the syndrome is associated with decreased endothelial nitric oxide synthase expression, thus resulting in lower nitric oxide activity (Davidge, 20 1 5) . Endothelins are 2 1 -amino-acid pep tides and potent vaso­ constrictors. Endothelin- 1 (ET- 1 ) is the primary isoform produced by human endothelium (Karumanchi, 20 1 6b) . Plasma ET- 1 levels are elevated in normotensive pregnant women, but women with preeclampsia have even higher lev­ els (Ajne, 2003 ) . According to Taylor and Roberts ( 1 999) , the placenta is not the source of increased ET - 1 concentra­ tions, and they likely arise from systemic endothelial activa­ tion. Interestingly, treatment of preeclamptic women with magnesium sulfate lowers ET - 1 concentrations (Sagsoz, 2003 ) . And, in animal studies, sildenafil reduces ET- 1 con­ centrations (Gillis, 20 1 6) . A n g i og e n i c a n d Anti a n g i og e n i c Prote i n s

Placental vasculogenesis i s evident b y 2 1 days after conception. The list of pro- and antiangiogenic substances involved in pla­ cental vascular development is extensive, and the families of vascular endothelial growth factor (VEGF) and angiopoietin are the most studied. Angiogenic imbalance describes excessive amounts of antiangiogenic factors, which are thought to be stimulated by worsening hypoxia at the uteroplacental inter­ face. Trophoblast of women destined to develop preeclampsia overproduces at least two antiangiogenic pep tides that enter the maternal circulation (Karumanchi, 20 1 6a) . First, soluble ins-like yrosine kinase i {sFlt-i} is a receptor for VEGF . As depicted in Figure 40-3, elevated maternal sFlt- 1 levels inactivate and reduce circulating free placental growth factor (PIGF) and VEGF concentrations, leading to endothelial dysfunction (Maynard, 2003). Importantly, sFlt- 1 levels begin to rise in maternal serum months before preeclampsia is evident (Fig. 40-4) . These high levels in the second trimester are asso­ ciated with a doubling of the risk for preeclampsia (Haggerty, 20 1 2) . This divergence from normal levels appears to develop even sooner with early-onset preeclampsia (Vatten, 20 1 2) . These factors are also operative i n pregnancies complicated by fetal-growth restriction (Herraiz, 20 1 2) . A second antiangiogenic peptide, soluble endoglin (sEng) , inhibits various transforming growth factor beta (TGF-3) iso­ forms from binding to endothelial receptors (see Fig. 40-3) . Endoglin is one of these receptors. Decreased binding to endo­ glin diminishes endothelial nitric oxide-dependent vasodilata­ tion. Serum levels of sEng also begin to rise months before clinical preeclampsia develops (Haggerty, 20 1 2) . Interestingly, metformin reduces antiangiogenic secretion from human tis­ sues (Brownfoot, 20 1 6) . In one systematic review, third-trimester elevation of sFlt- 1 levels and lower PIGF concentrations correlate with

Hyperte ns ive D i s o rd e rs

=

Preeclampsia

Normal

SEng .� \

..0��

1Y

�

V�GF

Endothelial dysfunction impaired relaxation

Endothelial health relaxation

F I G U R E 40-3 Schematic o f the receptor blocki ng action of s Flt- 1 (so l u ble fms-l i ke tyrosine ki nase 1 ) a nd sol u ble endog l i n (sEng).

preeclampsia development after 25 weeks' gestation (Widmer, 2007) . Subsequently, Haggerty and coworkers (20 1 2) reported that doubling of expressions of sFlt- 1 and sEng increased the preeclampsia risk by 39 and 74 percent, respectively. The cause

1 600 :J

E ) S c o

.C� � c o

PE NT

1 400

1 200

8-1 2

1 5-1 8

23-26

400 :J E )

S c 0

.C� )

)

c 0

)

NT

300 PE

200 1 00

O --8-1 2 23-26 1 5-1 8 Weeks' gestation

F I G U R E 40-4 Angiogenic a nd a ntiangiogen ic factors i n nor­ motensive (N) a nd preecl a m ptic (PE) women across preg n a n cy. Both pa i rs of factors a re sig n ifica ntly divergent by 23 to 26 weeks' gestation. s F lt sol u ble fms-l i ke tyrosine kinase 1 ; PIGF placenta l growth factor. (Data from Myatt, 2 0 1 3 .) =

PATHOPHYSIOLOGY Evidence for preeclampsia manifestation begins early in preg­ nancy with covert pathophysiological changes that gain momen­ tum across gestation and eventually become clinically apparent. Unless delivery supervenes, these changes ultimately lead to multiorgan involvement with a clinicl spectrum ranging from meager findings to one of cataclysmic deterioration. As discussed, these are thought to be a consequence of endothelial dysfunction, vasospasm, and ischemia. Although the many maternal conse­ quences of the preeclampsia syndrome are usually described in terms of individual organ systems, they frequently are multiple and overlap . • Cardiovascular System

)

1 000

of placental overproduction of anti angiogenic proteins remains an enigma. here is a racial-eth­ nic diference in their secretion (Yang, 20 1 6) . Concentrations of the soluble forms are not higher in fetal circulation or amnionic fl u id of preeclamptic women, and their levels in maternal blood dis­ sipate after delivery (Staf, 2007) . Clinical research aims to employ antiangiogenic proteins in the prediction and diagnosis of preeclampsia. One prelimi­ nary report described therapeutic apheresis to reduce sFlt- 1 levels (Thadhani, 20 1 6) .

=

Cardiovascular disturbances are common with preeclampsia syndrome. hese are related to: ( 1 ) greater cardiac afterload caused by hypertension; (2) cardiac preload, which is reduced by a pathologically diminished volume expansion during preg­ nancy and which is increased by intravenous crystalloid or oncotic solutions; and (3) endothelial activation leading to interendothelial extravasation of intravascular fluid into the extracellular space and, importantly, into the lungs. • Hemodynamic Changes and

Cardiac Function

The cardiovascular aberrations of pregnancy-related hyper­ tensive disorders vary depending on several modifiers. These factors include preeclampsia severity, hypertension severity, presence of underlying chronic disease, and the part of the clinical spectrum in which these are studied. In some women, these cardiovascular changes may precede hypertension (De Paco, 2008; Easterling, 1 990; Khalil, 20 1 2; Melchiorre, 2 0 1 3) . Nevertheless, with the clinical onset o f preeclampsia, cardiac outpur declines, due at least in part to greater peripheral resis­ tance. When assessing cardiac function in preeclampsia, con­ sideration is given to echocardiographic measures of myocardial function and to clinically relevant ventricular function.

71 7

Hyperte n sive D i s o rd e rs

blood loss incurred at delivery. Anemia may also partially result from greater erythrocyte destruction as subsequently described. • Maternal Thrombocytopenia

The platelet count is routinely measured in women with any form of gestational hypertension. Decreased platelet concentra­ tions with eclampsia were described more than 1 00 years ago. The frequency and intensity of thrombocytopenia vary and are dependent on the severity and duration of the preeclampsia syn­ drome (Heilmann, 2007; Hupuczi, 2007) . Overt thrombocy­ topenia-deined by a platelet count < 1 00,000/�L-indicates severe disease (see Table 40-2) . In general, the lower the platelet count, the higher the rates of maternal and fetal morbidity and mortality (Leduc, 1 992) . In most cases, delivery is advisable because worsening thrombocytopenia usually ensues. Mter delivery, the platelet count may continue to decline for the irst day or so. It then usually rises progressively to reach a normal level within 3 to 5 days. As discussed later (p. 722), in some instances with HELLP syndrome, the platelet count continues to fall after delivery. If these do not reach a nadir until 48 to 72 hours, then preeclampsia syndrome may be incorrectly attrib­ uted to one of the thrombotic microangiopathies discussed in Chapter 56 (p. 1 088) . Myriad other platelet alterations are attributed to the pre­ eclampsia syndrome. hese were reviewed by Kenny and coworkers (20 1 5) and include platelet activation with increased .-degranulation producing �-thromboglobulin, factor 4, and enhanced clearance. Paradoxically, in most studies, in vitro plate­ let aggregation is reduced compared with the normal increase that is characteristic of pregnancy. This likely is due to platelet "exhaustion" following in vivo activation. Although the cause is unknown, immunological processes or simply platelet deposi­ tion at sites of endothelial damage may be implicated. Levels of platelet-bound and circulating platelet-bindable immunoglobu­ lins are elevated, which suggests platelet surface alterations. Abnormally low platelets do not develop in the fetuses or neonates born to preeclamptic women despite severe mater­ nal thrombocytopenia (Kenny, 20 1 5 ; Pritchard, 1 987) . Thus, maternal thrombocytopenia in a hypertensive woman is not a etal indication or cesarean delivery. • Hemolysis

Severe preeclampsia is frequently accompanied by hemolysis, which manifests as elevated serum lactate dehydrogenase levels and reduced haptoglobin levels. Other evidence comes from schizocytosis, spherocytosis, and reticulocytosis in peripheral blood (Cunningham, 1 985; Pritchard, 1 954, 1 976) . hese derangements result in part from microangiopathic hemoysis caused by endothelial disruption with platelet adherence and ibrin deposition. Cunningham and coworkers ( 1 995) pos­ tulated that erythrocyte morphology was partially caused by serum lipid alterations. Related, substantively decreased long­ chain fatty acid content is found in erythrocytes of preeclamp­ tic women (Mackay, 20 1 2) . Mter early reports o f hemolysis and thrombocytopenia with severe preeclampsia, descriptions were added of abnor­ mally elevated serum liver transaminase levels that indicated

hepatocellular necrosis (Chesley, 1 978) . Weinstein ( 1 982) referred to this combination of events as the HELLP syn­ drome-and this term now is used worldwide. Also, facets of the HELLP syndrome are included in criteria that diferenti­ ate severe from nonsevere preeclampsia (see Table 40-2 ) . he HELLP syndrome is discussed further in that section (p. 722) . • Coagulation Changes

Subtle changes consistent with intravascular coagulation , and less often erythrocyte destruction, commonly are found with preeclampsia and especially eclampsia (Cunningham, 20 1 5; Kenny, 20 1 5) . Some of these changes include elevated factor VIII consumption, increased levels of ibrinopeptides A and B and of D-dimers, and reduced levels of regulatory proteins­ antithrombin I I I and proteins C and S. Coagulation aberra­ tions generally are mild and are seldom clinically signiicant (Kenny, 20 1 5 ; Pritchard, 1 984) . Unless placental abruption is comorbid, plasma ibrinogen levels do not difer remarkably from levels found in normal pregnancy. Fibrin degradation products such as D-dimers are minimally elevated. As pre­ eclampsia worsens, so do abnormal indings with thromboelas­ tography (Pisani-Conway, 20 1 3) . Despite these changes, routine laboratory assessments of coagulation, such as prothrombin time (PT) , activated partial thromboplastin time (aPTT) , and plasma ibrinogen level, are not required in the management of pregnancy-associated hypertensive disorders. • Endocrine and Hormonal Alterations

Plasma levels of renin, angiotensin II, angiotensin 1-, aldoste­ rone, deoxycorticosterone, and atrial natriuretic peptide (ANP) are substantively augmented during normal pregnancy. ANP is released during atrial wall stretching from blood volume expan­ sion, and it responds to cardiac contractility (Chap. 4, p. 63) . Levels of serum ANP rise in pregnancy, and its secretion is further enhanced in women with preeclampsia (Luft, 2009) . Levels of its precurs or-proatrial natriuretic peptide-are also increased in preeclampsia (Sugulle, 20 1 2) . Vasopressin levels are similar in nonpregnant, normally pregnant, and preeclamptic women even though the metabolic clearance is elevated in the latter two (Durr, 1 999) . • Fluid and Electrolyte Alterations

In women with severe preeclampsia, the volume of extracel­ lular luid, manifest as edema, is usually much greater than that in normal pregnant women. As discussed, the mecha­ nism responsible for pathological luid retention is endothe­ lial inj ury (Davidge, 20 1 5) . In addition to generalized edema and proteinuria, these women have reduced plasma oncotic pressure. his reduction creates a iltration imbalance and further displaces intravascular luid into the surrounding interstitium. Electrolyte concentrations do not difer appre­ ciably in women with preeclampsia compared with those of normal pregnant women. Following an eclamptic convulsion, the serum pH and bicar­ bonate concentration are lowered due to lactic acidosis and compensatory respiratory loss of carbon dioxide. he intensity

719

720

Obstetrica l Com p l ications

of acidosis relates to the amount of lactic acid produced­ metabolic acidosis-and the rate at which carbon dioxide is exhaled-respiratory acidosis. • Kidney

During normal pregnancy, renal blood flow and glomerular filtration rate rise appreciably (Chap. 4, p. 65). With pre­ eclampsia, several reversible anatomical and pathophysiologi­ cal changes ensue. Of clinical importance, renal perfusion and glomerular iltration are reduced. Levels that are much less than normal nonpregnant values are infrequent and are the conse­ quence of severe disease. Most of the decrement in glomeru­ lar filtration is from higher renal aferent arteriolar resistance that may be elevated up to fivefold (Conrad, 20 1 5; Comelis, 2 0 1 1 ) . Morphological changes are characterized by glomerular endotheliosis, which blocks the barrier that allows filtration. Diminished iltration causes serum creatinine levels to rise to values seen in nonpregnant individuals, that is, 1 mg/ mL, and sometimes higher (Lindheimer, 2008a) . Abnormal values usu­ ally begin to normalize 1 0 days or later after delivery (Comelis, 20 1 1 ; Spaan, 20 1 2a) . In most preeclamptic women, the urine sodium concentra­ tion is elevated. Urine osmolality rises, urine:plasma creatinine ratio is elevated, and fractional excretion of sodium is low, which all indicated that a prerenal mechanism is involved. Sodium-containing crystalloid infusion raises left ventricular illing pressure, and although oliguria temporarily improves, rapid infusions may cause clinically apparent pulmonary edema. Intensive intravenous fluid therapy is not indicated as "treatment" for preeclamptic women with oliguria unless urine output is diminished from hemorrhage or luid loss from vom­ iting or fever. Plasma uric acid concentration is typically elevated in pre­ eclampsia. The elevation exceeds that attributable to the reduction in glomerular filtration rate and likely is also due to enhanced tubu­ lar reabsorption (Chesley, 1 945). At the same time, preeclampsia is associated with diminished urinary excretion of calcium, perhaps because of greater tubular reabsorption (Taufield, 1 987). Protei n u ria

As shown in Table 40- 1 , detection of proteinuria helps to establish the diagnosis of preeclampsia. Abnormal protein excretion is empirically deined by 24-hour urinary excretion exceeding 300 mg; a urine protein: creatinine ratio � 0 . 3 ; or persistent protein values of 30 mg/ dL ( 1 + dipstick) in ran­ dom urine samples. Although worsening or nephrotic-range proteinuria has been considered by most to be a sign of severe disease, this does not appear to be the case (Airoldi, 2007) . Certainly, this concept was not accepted by the 20 1 3 Task Force. Problematically, the optimal method of establishing abnor­ mal levels of either urine protein or albumin remains to be defined. For a 24-hour quantitative specimen, the "consensus" threshold value used is � 300 mg/24 h (American College of Obstetricians and Gynecologists, 20 1 3) . Using a urinary pro­ tein excretion threshold of 1 65 mg in a 1 2-hour sample shows equivalent eicacy (Stout, 20 1 5 ; Tun, 20 1 2) .

Determination o f urinary protein:creatmme ratio may supplant the cumbersome 24-hour quantiication (Kyle, 2008; Morris, 20 1 2) . Chen and associates (2008) found that clean-catch and catheterized urine specimens correlate well. In one systematic review, random urine protein:creatinine ratios below 1 30 to 1 50 mg/g, that is, 0. 1 3 to 0. 1 5 , indicate a low likelihood of proteinuria exceeding 300 mg/ d (Papanna, 2008) . Ratios < 0.08 or > 1 . 1 9 have negative- or positive-pre­ dictive values of 86 and 96 percent, respectively (Stout, 20 1 3) . However, midrange ratios, that is, 300 mg/g o r 0.3, have poor sensitivity and specificity. Thus, many recommend that with midrange ratio values, 24-hour protein excretion should be quantifi e d. With urine dipstick assessment, determinations depend on urine concentration and are notorious for false-positive and -negative results. hus, assessment may show a dipstick value of 1 + to 2+ from concentrated urine specimens from women who excrete < 300 mg/ d. Importantly, proteinuria may develop late, and some women may already be delivered or have had an eclamptic convulsion before it appears. For example, 1 0 to 1 5 percent of women with HELLP syndrome do not have proteinuria at presentation (Sibai, 2004) . In one report, 1 7 percent of eclamptic women did not have proteinuria by the time of seizures (Zwart, 2008) . A natom ica l C h a nges

Sheehan and Lynch ( 1 973) frequently found changes identifi­ able at autopsy by light and electron microscopy in the kidneys of eclamptic women. Glomeruli are enlarged by approximately 20 percent, they are "bloodless," and capillary loops variably are dilated and contracted. Endothelial cells are swollen-termed glomerular capillay endotheliosis (Spargo, 1 959). Endothelial cells are often so swollen that they block or partially block the capillary lumens (Fig. 40-7) (Hecht, 20 1 7) . Homogeneous sub­ endothelial deposits of proteins and fi b rin-like material are seen. Endothelial swelling may result from angiogenic protein "withdrawal" caused by the complexing of free angiogenic proteins with a compatible circulating antiangiogenic protein receptor (see Fig. 40-3) . The angiogenic proteins are crucial for podocyte health, and their inactivation leads to podocyte dys­ function and endothelial swelling (Conrad, 20 1 5; Karumanchi, 2009) . Also, eclampsia is characterized by greater excretion of these epithelial podocytes (Wagner, 20 1 2; White, 20 1 4) . Acute K i d n ey I nj u ry

Although mild degrees of acute kidney injury are encountered, clinically apparent acute tubular necrosis is almost invariably induced by comorbid hemorrhage with hypovolemia and hypo­ tension (Chap. 4 1 , p. 755) . his is usually caused by severe obstetrical bleeding-especially placental abruption-coupled with inadequate blood replacement. Drakeley and cowork­ ers (2002) described 72 women with preeclampsia and renal failure. Half had HELLP syndrome, and a third had placen­ tal abruption. In one review of 1 83 women with HELLP syn­ drome, 5 percent had kidney injury (Haddad, 2000) . Of those with renal injury, half had placental abruption, and most had postpartum hemorrhage. Last, irreversible renal cortical necrosis develops rarely (Chap. 53, p. 1 037) .

718

Obstetrical C o m p l ications Myoca rd i a l Fu nction

Of women with preeclampsia, serial echo cardiographic studies document diastolic dysfunction in 40 to 45 percent (Guirguis, 20 1 5; Melchiorre, 20 1 2) . With this dysfunction, ventricles do not properly relax and cannot ill properly. In some of these women, functional diferences persist up to 4 years after deliv­ ery (Evans, 20 1 1 ; Orabona, 20 1 7) . Diastolic dysfunction stens from ventricular remodeling, which is judged to be an adaptive response to maintain normal contractility despite the increased afterload of preeclampsia. High levels of antiangiogenic proteins may be contributory (Shahul, 20 1 6) . In the otherwise healthy pregnant woman, these changes are usually clinically incon­ sequential. But when combined with underlying ventricular dysfunction-for example, concentric ventricular hypertrophy from chronic hypertension-further diastolic dysfunction may cause cardiogenic pulmonary edema (Wardhana, 20 1 7) . his is discussed further in Chapters 47 (p. 9 1 8) and 49 (p. 964) . Ve ntri c u l a r Fu nction

Despite the relatively high frequency of diastolic dysfunction with preeclampsia, clinical cardiac function in most afected women is appropriate (Hibbard, 20 1 5) . In some preeclamp­ tic women, cardiac troponin levels are slightly elevated, and amino-terminal pro-brain natriuretic peptide (Nt pro-BNP) levels are elevated with severe preeclampsia (Pergialiotis, 20 1 6; Zachary, 20 1 7) . Importantly, both normally pregnant women and those with preeclampsia syndrome can have nor­ mal or slightly hyperdynamic ventricular function (Fig. 40-5) . hus, both have a cardiac output that i s appropriate for left­ sided illing pressures. Filling pressures are dependent on the volume of intravenous fluids. Thus, aggressive hydration results in overtly hyperdynamic ventricular function. his is

accompanied by elevated pulmonary capillary wedge pres­ sures, and pulmonary edema may develop despite normal ventricular function . This is because of an alveolar endothe­ lial-epithelial leak, and it is compounded by decreased oncotic pressure from a low serum albumin concentration. In sum, aggressive fluid administration to otherwise normal women with severe preeclampsia substantially elevates normal left­ sided filling pressures and raises a physiologically normal car­ diac output to hyperdynamic levels. • Blood Volume

Hemoconcentration is a hallmark of eclampsia. This concept was precisely quantiied by Zeeman and colleagues (2009) , who expanded the prior observations of Pritchard and associates ( 1 984) . hey showed in eclamptic women that the normally expected pregnancy blood volume expansion is severely cur­ tailed (Fig. 40-6) . Women of average size have a blood volume of 3000 mL, and during the last several weeks of a normal pregnancy, this averages 4500 mL. With eclampsia, however, much or all of the anticipated 1 500 mL excess is lost. Such hemoconcentration results from generalized vasospasm that follows endothelial activation and leakage of plasma into the interstitial space. In women with preeclampsia, and depending on its severity, hemoconcentration is usually not as marked. hese changes have substantial clinical consequences. Impor­ tantly, women with severe hemoconcentration are unduly sensi­ tive to blood loss at delivery that otherwise may be considered normal. Vasospasm and endothelial leakage of plasma persist for a variable time ater delivery as the endothelium is restored to normalcy. u this takes place, vasoconstriction reverses, and s the blood volume reexpands, the hematocrit usully falls. Importanty} a substantive cause of this all in hematocrit} however} is usualy the D D • D

1 20 110

6000

Hyperdynamic

1 00 5000

f E

E 9 �

;

90

:J

s

80

E

I

70 60

Depressed

5

10

15

20

3000

0

2000

-

30 o

> 0 0 0

5 j

50 40

25

30

PCWP (mm Hg) F I G U R E 40-5 Ventricu l a r fu nction i n norma l ly preg nant women (striped area) and i n women with eclam psia (boxed area) is pl ot­ ted on a Bra u nwa l d ventricular fu nction c u r e. Normal va lues a re from C l a rk ( 1 989), a nd those for ecl a m psia a re from H a n ki n s ( 1 984). PCWP p u l mo n a ry ca p i l l a ry wedge pressu re; LVSWI left ven­ tricu l a r stroke work i n dex. =

4000

I

0

.J

o

Nonpregnant Term pregnant Eclampsia 1 st pregnancy Normotensive 2nd pregnancy

=

1 000

0

Normal controls

Eclampsia

F I G U R E 40-6 Tota l blood vol u mes in normote nsive women compared with those with ecla m psia. The vertica l extensions a re one sta ndard deviation from the mea n . I n ecl a m ptic women, blood vo l u me is m i n i m a l ly i ncrea sed compared with a su bsequent nor­ motensive preg nancy. (Data from Zeeman, 2009.)

Hypertensive Disord e rs

Liver involvement with pre­ eclampsia may clinically d isplay Pedicel at least three manifestations. Narrow First, pain is considered a sign of interspace severe disease. It typically mani­ V fests by moderate-to-severe right upper quadrant or midepigas­ tric pain and tenderness. Such Endothelial women usually have elevated swelling serum aspartate transaminase (AST) or alanine transaminase (ALT) levels. In some cases, however, the amount of hepatic Basement tissue involved with infarction Swollen fenestra membrane fenestra may be surprisingly extensive yet still clinically insignificant (N el­ son, 20 1 7) . In our experiences, P R E EC LA M PS I A NORMAL infarction may be worsened by F I G U R E 40-7 Schematic s howi n g g l omeru l a r ca p i l l a ry endothel iosis. The capi l l a ry o f t h e norma l hypotension from obstetrical g l omeru l u s shown on the left h a s wide endothelial fen estrations, a nd the ped icels ema nating hemorrhage, and it occasion­ from the podocytes a re widely spaced (arrow). The i l l ustration on the right is of a g lomeru l u s with ally causes hepatic failure-also c h a nges i nd u ced by the preecla m psia syndrome. The endothel ial cel l s a re swo l l e n a nd their fenes­ called shock liver (Alexander, tra e n a rrowed, as a re the ped icels that now a but each other. 2009; Yoshihara, 20 1 6) . Second, elevations of serum AST and ALT levels are markers for severe preeclampsia. Values • Liver seldom exceed 500 U/L, but levels reaching more than 2000 The characteristic hepatic lesions with eclampsia are regions of U/L have been reported (Chap. 5 5 , p. 1 058) . In general, serum periportal hemorrhage in the liver periphery (Hecht, 20 1 7) . concentrations inversely follow platelet levels, and they both However, lesions as extensive as those shown i n Figure 40-8 are usually normalize within 3 days following delivery. unusual. Sheehan and Lynch ( 1 973) described that some degree As a third presentation, hemorrhagic infarction may extend of hepatic infarction accompanied hemorrhage in almost half of to form a hepatic hematoma. This in turn can extend to form women who died with eclampsia. hese findings corresponded a subcapsular hematoma that may rupture. Computed tomog­ with reports during the 1 960s that described elevated serum raphy (CT) scanning or magnetic resonance (MR) imaging hepatic transaminase levels. Along with the earlier observations greatly aids diagnosis (Fig. 40-9) . Unruptured hematomas by Pritchard and associates ( 1 954), who described hemolysis are probably more common than clinically suspected and are and thrombocytopenia with eclampsia, this constellation of more likely to be found with HELLP syndrome. Although hemolysis, hepatocellular necrosis, and thrombocytopenia was later termed HELLP syndrome.

FIGURE 40-8 Gross l iver specimen from a woman with preeclamp­ sia who d ied from aspiration pneumonitis. Periporta l hemorrhagic necrosis was seen m icroscopical ly. (Reproduced with perm ission from Cu n n in g h am FG: Liver d isease compl icating pregnancy. Wi l l iams Obstetrics, 1 9th ed. (Suppl 1 ), Norwa l k, Appleton & La nge, 1 993.)

F I G U R E 40-9 Abdomi n a l T i m a g i n g perfo rmed postpartum i n a woman with severe H ELLP syndrome a n d rig ht-u pper q uadra nt pai n . A l a rge subca psular hematoma (asterisk) is seen confl uent with i ntra hepatic infa rction and hematoma (arrowhead). N u merous fla me­ shaped hemorrhages a re seen at the hematoma interface (arrows).

721

722

Obstetrical Com p l i cations

once considered a surgical condition, current management of a hepatic hematoma usually consists of observation unless bleed­ ing is ongoing. In some cases, however, prompt surgical inter­ vention or angiographic embolization may be lifesaving. In one review of 1 80 cases of hepatic hematoma or rupture, 94 percent of afected gravidas had HELLP syndrome, and in 90 percent of the total, the capsule had ruptured (Vigil-De Gracia, 20 1 2) . The maternal mortality rate was 2 2 percent, and the perinatal mortality rate was 3 1 percent. In rare cases, liver transplanta­ tion is necessary (Hunter, 1 995; Wicke, 2004) . Acute fatty liver of pregnancy is sometimes confused with preeclampsia (Nelson, 20 1 3; Sibai, 2007a) . It too has an onset in late pregnancy, and often there is accompanying hyperten­ sion, elevated serum transaminase and creatinine levels, and thrombocytopenia. However, the hallmark of acute fatty liver is significant liver dysfunction, and Table 5 5 - 1 (p. 1 059) high­ lights these clinical diferences. Last, no convincing data link pancreatic involvement with preeclampsia syndrome (Sheehan, 1 973) . Thus, the occasional case of concurrent hemorrhagic pancreatitis is likely unrelated (Lynch, 20 1 5; Swank, 20 1 2) . In our experiences from Parkland Hospital, amylase levels were seldom elevated in preeclamptic women (Nelson, 2 0 1 4a) . H E L L P Syn d rome

There is no universally accepted strict deinition of HELLP syndrome, and thus its incidence varies by investigator. In the previously noted study of 1 83 women with HELLP syndrome, 40 percent had adverse outcomes, and two mothers died (Had­ dad, 2000) . Complications included eclampsia in 6 percent, placental abruption-1 0 percent, acute kidney injury-5 percent, and pulmonary edema- 1 0 percent. Stroke, hepatic hematoma, coagulopathy, acute respiratory distress syndrome, and sepsis were other serious complications. Women with preeclampsia and HELLP syndrome typically have worse outcomes than preeclamptic women without the HELLP constellation (Kozic, 20 1 1 ; Martin, 20 1 2, 20 1 3) . I n one review of693 women with HELLP syndrome, 1 0 percent had concur­ rent eclampsia (Keiser, 20 1 1 ) . Sep and associates (2009) described a significantly higher risk for complications in women with HELLP syndrome compared with those with "isolated preeclampsia." These included eclampsia- 1 5 versus 4 percent; preterm birth-93 versus 78 percent; and perina­ tal mortality rate-9 versus 4 percent, respectively. Because of these marked clinical diferences, it has been postulated that HELLP syndrome has a dis­ tinct pathogenesis (Reimer, 20 1 3; Vaught, 20 1 6) .

FIGURE 40- 1 0 Th is a utopsy bra i n slice shows a fata l hypertensive hemorrhage i n a pri m igravida with ecl a m psia.

N e u ro a n ato m i ca l Les i o n s

From early anatomical descriptions, brain pathology accounted for only about a third of fatal cases such as the one shown in Figure 40- 1 0. In fact, most deaths were from pulmonary edema, nd brain lesions were coincidental. Thus, lthough gross intracere­ bral hemorrhage was seen in up to 60 percent of eclamptic women, it was fatal in only half of these (Melrose, 1 984; Richards, 1 988; Sheehan, 1 973). s shown in Figure 40- 1 1 , other principal lesions found at autopsy of eclamptic women were cortical and subcorti­ cal petechial hemorrhages. The classic microscopic vascular lesions consist of fibrinoid necrosis of the arterial wall and perivascular micro infarcts and hemorrhages. Other frequently described major lesions include subcortical edema, multiple nonhemorrhagic areas of "sotening" throughout the brain, and hemorrhagic areas in the

Pia -arach noid

---Cortical

r�---

Subcortical

• Brain

Headaches and visual symptoms are common with severe preeclampsia, and associated convulsions deine eclampsia. The earliest anatomical descrip­ tions of brain involvement came from autopsy specimens, but CT and MR imaging and Dop­ pler studies have added many important insights.

F I G U RE 40- 1 1 Com posite i l l ustration showi n g l ocatio n of cerebral hemorrhages a nd petechiae in women with ecl a m psia. I n se rt shows the level of the bra i n from which the m a i n i mage was constructed. (Data from Shee h a n , 1 973.)

Hyperte n s ive Disord e rs

white matter (Hecht, 20 1 7) . here also may be hemorrhage in the basal ganglia or pons, sometimes with rupture into the ventricles. Cere b rova scu l a r Pat h o p hys i o l ogy

Clinical, pathological, and neuroimaging findings have led to two general theories to explain cerebral abnormalities with eclampsia. Importantly, endothelial cell dysfunction that characterizes the preeclampsia syndrome likely is a key in both. The first theory suggests that in response to acute and severe hypertension, cere­ brovascular overregulation leads to vasospasm (Trommer, 1 988). In this scheme, diminished cerebral blood low is hypothesized to result in ischemia, cytotoxic edema, and eventually tissue infarc­ tion. Little objective evidence supports this mechanism. he second theory is that sudden elevations in systemic blood pressure exceed the normal cerebrovascular autoregula­ tory capacity (Hauser, 1 988; Schwartz, 2000) . Regions of forced vasodilation and vasoconstriction develop, especially in arterial boundary zones. At the capillary level, disruption of end-capillary pressure causes increased hydrostatic pressure, hyperperfusion, and extravasation of plasma and red cells through endothelial tight-junction openings. his leads to vasogenic edema. he recent description of a central nervous system lymphatic vascu­ lature lends credibility to this theory (Louveau, 20 1 5) . h e most likely mechanism i s a combination o f the two. hus, a preeclampsia-associated interendothelial cell leak devel­ ops at blood pressure (hydraulic) levels much lower than those that usually cause vasogenic edema and is coupled with a loss of upper-limit autoregulation (Fugate, 20 1 5; Zeeman, 2009) . With imaging studies, these manifest as the posterior reversible encepha­ lopathy syndrome (Fig. 40- 1 2) (Fugate, 20 1 5; Hinchey, 1 996) . he lesions of this syndrome principally involve the posterior brain-the occipital and parietal cortices. But, in at least a third of cases, other areas are involved (Edlow, 20 1 3; Zeeman, 2004a) .

F I G U R E 40- 1 2 Cra n i a l m a g n etic-resona nce i ma g i ng i n a n u l­ l i pa ra with ecl a m psia. Multilobe T2- F LA I R h i g h-sig n a l lesions a re a p pa rent. F LA I R fl u id-atten uated i nversion recovery. (Used with perm ission from Dr. Gerda Zeema n .) =

Cere b ra l B l ood Flow

Autoregulation is the mechanism by which cerebral blood flow remains relatively constant despite alterations in cerebral perfu­ sion pressure. Remember that cerebral perfusion pressure is the diference between mean arterial pressure and intracranial pres­ sure. In nonpregnant individuals, this autoregulation protects the brain from hyperperfusion when mean arterial pressures rise to as high as 1 60 mm Hg. hese are pressures far greater than those seen in all but a very few women with eclampsia. Thus, to explain eclamptic seizures, it was theorized that autoregu­ lation must be altered by pregnancy. Studies by Cipolla and colleagues (2007, 2009, 20 1 5) have convincingly shown that autoregulation is unchanged across pregnancy in rodents. But, some investigators have provided evidence of impaired auto­ regulation in women with preeclampsia aanzarik, 20 1 4; van Veen, 20 1 3) . Zeeman and associates (2003) showed that cerebral blood flow during the irst two trimesters of normal pregnancy is similar to nonpregnant values. But during the last trimester, low signifi­ cantly drops by 20 percent. his group also found greater cerebral blood low in this trimester in women with severe preeclampsia compared with that in normotensive pregnant women (Zeeman, 2004b). Taken together, these fi n dings suggest that eclampsia occurs when cerebral hyperperfusion forces capillary luid inter­ stitially because of endothelial damage. This leak leads to perivas­ cular edema characteristic of the preeclampsia syndrome. N e u ro l o g i c a l M a n ifestatio n s

Several neurological manifestations typiy the preeclamp­ sia syndrome. Each signiies severe involvement and requires immediate attention. First, headache and scotomata are thought to arise from cere­ brovascular hyperperusion that has a predilection for the occipi­ tal lobes. Up to 75 percent of women have headaches, and 20 to 30 percent have visual changes preceding eclamptic convulsions (Sibai, 2005; Zwart, 2008). The headaches may be mild to severe and intermittent to constant. In our experiences, they are unique in that they do not usually respond to traditional analgesia, but they frequently improve ater magnesium sulfate infusion. Convulsions are diagnostic for eclampsia. These are caused by excessive release of excitatory neurotransmitters-espe­ cially glutamate; massive depolarization of network neurons; and bursts of action potentials (Meldrum, 2002) . Clinical and experimental evidence suggests that extended seizures can cause signiicant brain injury and later brain dysfunction. Blindness is rare with preeclampsia alone, but it complicates eclamptic convulsions in up to 1 5 percent of women (Cun­ ningham, 1 995). Blindness may develop up to a week or more following delivery (Chambers, 2004) . There are at least two ypes of blindness, as discussed subsequently. Generalized cerebral edema may develop and is usually mani­ fest by mental status changes that vary from confusion to coma. This situation is particularly dangerous because fatal transtento­ rial herniation can result. Last, women with eclampsia have been shown to have some cognitive decline when studied 5 to 1 0 years following an eclamptic pregnancy. This is discussed further in the inal sec­ tion (p. 745).

723

724

Obstetrical Com p l ications N e u ro i m a g i n g Stud ies

With CT imaging, localized hypodense lesions at the gray- and white-matter j unction, primarily in the parietooccipital lobes, are typically found in eclampsia. Such lesions may also be seen in the frontal and inferior temporal lobes, the basal ganglia, and thalamus (Brown, 1 988). These hypodense areas correspond to petechial hemorrhages and local edema. Edema of the occipi­ tal lobes or difuse cerebral edema may cause symptoms such as blindness, lethargy, and confusion (Cunningham, 2000) . Widespread edema can appear as marked compression or even obliteration of the cerebral ventricles. S uch women may develop signs of impending life-threatening trans tentorial herniation. Several MR imaging acquisitions are used to study eclamptic women. Common findings are hyperintense T2 lesions-namely, posterior reversible encephalopathy syndrome (PRES)-in the subcortical and cortical regions of the parietal and occipital lobes (see Fig. 40- 1 2) . Also, the basal ganglia, brainstem, and cerebel­ lum are relatively commonly involved (Brewer, 20 1 3; Zeeman, 2004a) . Again, these lesions represent focal cerebral edema. Although these PRES lesions are almost universal in women with eclampsia, their incidence in women with preeclampsia approximates 20 percent (Mayama, 20 1 6) . Lesions are more likely in women who have severe disease and who have neuro­ logical symptoms. And although usully reversible, a fourth of these hyperintense lesions represent cerebral infarctions that have persistent indings (Loureiro, 2003; Zeeman, 2004a) . Vi s u a l C h a nges a n d B l i n d ness

Scotomata, blurred vision, or diplopia are common with severe preeclampsia and eclampsia. hese usually improve with mag­ nesium sulfate therapy and/or lowered blood pressure. Blind­ ness is less common, is usually reversible, and may arise from three potential areas. These are the visual cortex of the occipital lobe, the lateral geniculate nuclei, and the retina. In the retina, pathological lesions may be ischemia, infarction, or detachment (Handor, 20 1 4; Roos, 20 1 2) . Occipital blindness i s also called amaurosis-from the Greek dimming. With imaging, afected women usually have evidence of extensive occipital lobe vasogenic edema. Of 1 5 women cared for at Parkland Hospital, occipital blindness lasted from 4 hours to 8 days, but it resolved completely in all cases (Cun­ ningham , 1 995). Rarely, extensive cerebral infarctions may result in total or partial visual defects. Blindness from retinal lesions is caused either by serous reti­ nal detachment or rarely by retinal infarction, which is termed Purtscher retinopathy ( Fig. 40- 1 3) . Serous retinal detachment is usually unilateral and seldom causes total visual loss. In fact, asymptomatic serous retinal detachment is relatively common with preeclampsia (Saito, 1 998). I n most cases of eclampsia­ associated blindness, visual acuity subsequently improves. However, if blindness is caused by retinal artery occlusion, vision may be permanently impaired (Lara-Torre, 2002; Mose­ man, 2002; Roos, 20 1 2) . Cere b ra l Edema

Clinical manifestations suggesting widespread cerebral edema are worrisome. During 1 3 years at Parkland Hospital, 1 0 of 1 75 women (6 percent) with eclampsia were diagnosed with

F I G U R E 40- 1 3 Purtscher reti nopathy caused by choroida l isch­ emia a n d i nfa rction i n preecl a m psia syn d rome. Ophth a l moscopy s hows scattered yel l owish, opaq u e lesions of the retina (arrows). (Reprod u ced with permission from Lam OS, Chan W: I mages in c l i n ica l medicine. Choroidal ischemia in p reecl a m psia. N Engl J Med 344(1 0):739, 200 1 .)

symptomatic cerebral edema (Cunningham, 2000) . Symptoms ranged from lethargy, confusion, and blurred vision to obtun­ dation and coma. In most cases, symptoms waxed and waned. Mental status changes generally correlated with the degree of involvement seen with CT and MR imaging studies. These women are very susceptible to sudden and severe blood pressure elevations, which can acutey worsen the already widespread vaso­ genic edema. Thus, careful blood pressure control is essential. In the 10 women with generalized edema, three became comatose and had imaging indings of transtentorial herniation, from which one died. Consideration is given for treatment with mannitol or dexamethasone. • Uteroplacental Perfusion

Compromised utero placental perfusion is almost certainly a major culprit in the greater perinatal morbidity and mortal­ ity rates seen with preeclampsia (Harmon, 2 0 1 5) . Defects in endovascular trophoblastic invasion with the preeclampsia syndrome were discussed earlier (p. 7 1 4) . hus, measurement of uterine, intervillous, and placental blood low would likely be informative. Attempts to assess these in humans have been hampered by several obstacles that include inaccessibility of the placenta, the complexity of its venous eiuent, and the need for radioisotopes or invasive techniques. Measurement of uterine artery blood low velocity has been used to estimate resistance to uteroplacental blood low (Chap. 1 7, p. 339) . Vascular resistance is estimated by com­ paring arterial systolic and diastolic velocity waveforms. By the completion of placentation, impedance of uterine artery blood low is markedly decreased, but with abnormal placentation, abnormally high resistance persists (Everett, 20 1 2; Ghidini, 2008; Napolitano, 20 1 2) . Earlier studies were done to assess this by measuring peak systolic:diastolic velocity ratios from uterine and umbilical arteries in preeclamptic pregnancies. In

Hyperten s ive Disorders

some cases, but certainly not all, there was higher resistance (Fleischer, 1 986; Trudinger, 1 990) . Another Doppler waveform-uterine artery "notching"­ has been associated with elevated risks for preeclampsia or fetal-growth restriction (Groom, 2009) . In the MFMU Net­ work study reported by Myatt and colleagues (20 1 2a) , how­ ever, notching had a low predictive value except for early-onset severe disease. Resistance in uterine spiral arteries has also been measured. Impedance was higher in peripheral than in central vessels-a "ring-like" distribution (Matijevic, 1 999) . Mean resistance val­ ues were greater in all women with preeclampsia compared with those in normotensive controls. One study used MR imaging and other techniques to assess placental perfusion ex vivo in myometrial arteries removed from women with preeclampsia or fetal-growth restriction (Ong, 2003) . In both conditions, myometrial arteries exhibited endothelium-dependent vasodi­ latory response. Moreover, other pregnancy conditions are also associated with increased resistance (Urban, 2007) . One major adverse efect, fetal-growth restriction, is discussed in Chapter 44 (p. 847) . de Almeida Pimenta and colleagues (20 1 4) assessed placen­ tal vascularity using a three-dimensional power Doppler his­ togram and described a placental vasculariy index. This index value was reduced in women with any pregnancy-associated hypertensive disorders- 1 l . 1 percent compared with 1 5 .2 per­ cent in normal controls. Despite these indings, evidence for compromised uteropla­ cental circulation is found in only a few women who go on to develop preeclampsia. Indeed, when preeclampsia develops during the third trimester, only a third of women with severe disease have abnormal uterine artery velocimetry (Li, 2005) . In

a study of 50 women with HELLP syndrome, only a third had abnormal uterine artery waveforms (Bush, 200 1 ) . In general, the extent of abnormal waveforms correlates with severity of fetal involvement (Ghidini, 2008 ; Groom, 2009) . PREDICTION Various biological markers implicated in the preeclampsia syn­ drome have been measured to help predict its develop ment. Although most have been evaluated in the irst half of preg­ nancy, some have been tested as predictors of severity in the third trimester (Chaiworapongsa, 20 1 3; Lai, 20 1 3 ; Mosim ann, 20 1 3) . Others have been used to forecast recurrent preeclamp­ sia (Demers, 20 1 4; Eichelberger, 20 1 5) . Some of these tests are listed in Table 40-5, which is by no means all inclusive. Overall, these eforts have resulted in testing strategies with poor sensitivity and with poor positive-predictive values for pre­ eclampsia (Conde-Agudelo, 20 1 5; Odibo, 20 1 3) . Currenty, no screening tests or preecampsia are predictaby reliable, vali, and economical However, combinations of tests, some yet to be ade­ quately evaluated, may be promising (Gallo, 20 1 6; Olsen, 20 1 2) . • Vascular Resistance Testing a nd

Placental Perfusion

Most tests in this category are cumbersome, time consuming, and overall inaccurate. To evaluate blood pressure changes, three tests assess the blood pressure rise in response to a s timu­ lus. In one, women at 28 to 32 weeks' gestation rest in the left lateral decubitus position and then roll to the supine posi­ tion. With this rol-over test, increased blood pressure with this maneuver signifies a positive test. he isometric exercise

TABLE 40-5. P red ictive Tests for Development of the P reecla m psia Syn d rome

Testing Related To:

Exa mples

Placenta l perfusio n/vascu l a r resi sta nce

Rol l -over test, isometric h a nd g ri p or cold p ressor test, pressor res ponse to aero b i c exerc i s e, a ng iote n s i n-I I i n fu s ion, m id t r i m ester mea n a rteri a l pressu re, platelet a n g iote n s i n - I I b i n d i n g, re n i n, 24- h o u r a m b u l atory b l ood p ressure m o n itoring, ute r i n e a rtery r feta l tra n sc ra n i a l Doppler veloc i m etry H u ma n chorionic gonadotro p i n ( h CG), a l pha-fetoprotei n (AF P), estriol, preg na n cy-a ssociated protei n A (PAPP A), i n h i b i n A, a ctivi n A, pl acenta l prote i n 1 3, procal cito n i n, corticotropi n ­ relea s i n g hormone, A d i si nteg r i n , A DAM- 1 2, kisspepti n Serum u ric acid, m icroa l b u m i n u ria, u ri na ry ca lci u m or ka l l i krei n, m i crotra n sferri n u ria, N-acetyl-3-g l ucosa m i n ida se, cystati n C, podocytu ria, podoca lyx i n P l ate let cou nt a n d activation, fi bro n ect i n , e ndoth e l i a l ad h esion m o lecu les, prosta g l a n d i n s, prostacycl i n, M M P-9, t h rom boxa ne, C-reactive protein, cyto ki n es, en dothe l i n , n e u roki n i n B, homocystei n e, l i pi d s, i n s u l i n res ista n ce, resist i n , a ntiphos p h o l i pi d a n t i bodies, p l a s m i nog e n a ctivator- i n h i bitor ( PAl), lept i n , p-selecti n, a n g iogenic a nd a nt i a n g iogen i c factors such a s pl acenta l g rowth factor (PIG F), vasc u l a r endot h e l i a l g rowth factor (VEGF), fm s-l i ke tyros i ne ki nase recepto r- 1 (sFlt- 1 ), e n d og l i n Antith rom bi n-I I I (AT-3), atria l n atri u retic peptide (AN P), 32- m i c rog lo bu l i n , h a ptog lobi n, tra n sferrin, ferritin, 2 5 - hyd roxyvita m i n 0, g en etic marke rs, cell-free feta l DNA, ser u m and u ri n e proteom ics a n d meta bol o m i c markers, hepatic a m i n otra n sferases

Feta l-placenta l u n it endocri ne dysfu nction Ren a l dysfu nction Endoth e l i a l dysfu n ction/ oxida nt stress

Oth e rs

ADAM 1 2 ADAM meta l lo pe ptidase doma i n 1 2; MMP matrix m eta l loprotei nase. Ada pted from Conde-A g u delo, 2 0 1 5, Duckworth, 20 1 6. =

=

725

726

Obstetrica l Com pl i cations

test employs the same principle by squeezing a handball. The angiotensin 11 infusion test is performed by giving incremen­ tally i ncreasing doses intravenously, and the hypertensive response is quantiied. In an updated metaanalysis, sensitivi­ ties of all three tests were reported to range from 55 to 70 percent, and specifi c ities approximated 85 percent (Conde­ Agudelo, 20 1 5) . Uterine artey Doppler velocimety i s posited to relect faulty trophoblastic invasion of the spiral arteries. his failure results in diminished placental perfusion and upstream greater uterine artery resistance. Increased uterine artery velocimetry determined by Doppler ultrasound in the first two trimesters might provide indirect evidence of this process and thus serve as a predictive test for preeclampsia (Dar, 20 1 0; Groom, 2009) . Elevated low resistance results in an abnormal vessel waveform represented by an exaggerated diastolic notch. hese indings have value for pre­ diction of fetal-growth restriction but not preeclampsia (Ameri­ can College of Obstetricians and Gynecologists, 20 1 5) . Several low velocity waveforms have been investigated for preeclampsia prediction, however, none is suitable for clinical use (Conde­ Agudelo, 20 1 5; Kleinrouweler, 20 1 2; Myatt, 20 1 2a) .

Several serum analytes have been proposed to help predict pre­ eclampsia (see Table 40-5) . Newer ones are continually added. In general, none of these tests are clinically beneicial for hyper­ tension prediction.

are elevated, the substantive overlap with levels i n normotensive pregnant women stultiies their predictive value. Markers of oxidative stress were also hoped to predict pre­ eclampsia. Namely, associated higher levels of lipid peroxides coupled with decreased antioxidant activity raised this pos­ sibility. Other markers include iron, transferrin, and ferritin; resistin; hyperhomocysteinemia; blood lipids, including triglyc­ erides, free fatty acids, and lipoproteins; and antioxidants such as ascorbic acid and vitamin E (Christiansen, 20 1 5 ; Conde­ Agudelo, 20 1 5 ; D'Anna, 2004; Mackay, 20 1 2; Mignini, 2005) . However, these have not been found to be predictive. Last, an imbalance in antiangiogenic factors is linked to pre­ eclampsia etiopathogenesis. For example, serum levels ofVEGF and PIGF begin to drop before clinical preeclampsia develops. And, recall from Figure 40-4 that at the same time, levels of some antiangiogenic factors, such as sFlt- 1 and sEng, begin to rise (Karumanchi, 20 1 6a; Maynard, 2008) . With some of these factors, sensitivities for all cases of preeclampsia ranged from 30 to 50 percent, and specificity approximated 90 percent (Conde-Agudelo, 20 1 5) . heir predictive accuracy is higher for early-onset preeclampsia (Redman, 20 1 5b; Tsiakkas, 20 1 6) . Determination o f the sFlt- l IPIGF ratio in women admitted near 37 weeks' gestation to exclude preeclampsia was useful as a predictive factor (Baltajian, 20 1 6; Zeisler, 20 1 6a,b) . These results suggest a clinical role for preeclampsia prediction, espe­ cially later in pregnancy (Ducworth, 20 1 6; Gallo, 20 1 6) . They may also predict adverse pregnancy outcomes in women with lupus and comorbid anti phospholipid antibodies (Kim, 20 1 6) .

• Renal Function Tests

• Other Markers

• Fetal-Placental Unit Endocrine Function

Hyperuricemia likely results from reduced uric acid clearance from diminished glomerular filtration, increased tubular reab­ sorption, and decreased secretion. Cnossen and coworkers (2006) reported that its sensitivity to detect preeclampsia ranged from 0 to 5 5 percent, and speciicity was 77 to 95 percent. Isolated gestational proteinuria is a risk factor for preeclamp­ sia Qayaballa, 20 1 5; Morgan, 20 1 6; Yamada, 20 1 6) . As a pre­ dictive test for preeclampsia, microalbuminuria has sensitivities that range from 7 to 90 percent and specificities that span 29 to 97 percent (Conde-Agudelo, 20 1 5) . • Endothelial Dysfunction a nd Oxidant Stress

Endothelial activation and infl a mmation are major participants in the pathophysiology of the preeclampsia syndrome. As a result, compounds such as those listed in Table 40- 5 are found to be elevated in circulating blood of afected women, and some have been assessed for their predictive value. First, ibronectins are high-molecular-weight glycoproteins released from endothelial cells and extracellular matrix follow­ ing endothelial injury. However, in one systematic review, nei­ ther cellular nor total ibronectin levels were clinically useful to predict preeclampsia (Leeflang, 2007) . Thrombocytopenia and platelet dysfunction are integral features of preeclampsia. Platelet activation causes augmented destruction and lower concentrations. Mean platelet volume rises because of platelet immaturity (Kenny, 20 1 5) . Although markers of coagulation activation, described earlier (p. 7 1 9) ,

As discussed in Chapter 1 3 (p. 273), cell-free DNA (cfDNA) can be detected in maternal plasma. It is hypothesized that cDNA is released in preeclampsia by accelerated apoptosis of cytotrophoblasts (DiFederico, 1 999). One MFMU Network study found no correlation between total cfDNA levels and preeclampsia (Silver, 20 1 7) . Proteomic, metabolomic, and transcriptomic technologies can be employed to study serum and urinary proteins and cel­ lular metabolites. These have opened new vistas for preeclamp­ sia prediction, and preliminary studies indicate that these may become useful (Bahado-Singh, 20 1 3; Carty, 20 1 1 ; Ma, 20 14; Myers, 20 1 3) . PREVENTION Various strategies used to prevent or modiy preeclampsia severity have been evaluated. Some are listed in Table 40-6. In general, none of these has been found to be convincingly and reproducibly efective. • Dietary and Lifestyle Modifications

Dietary "treatment" for preeclampsia has produced some inter­ esting abuses (Chesley, 1 978) . A low-salt diet was one of the earliest research eforts to prevent preeclampsia (De Snoo, 1 937) . This was followed by years of inappropriate diuretic therapy. Although these practices were discarded, it ironically

Hypertensive D isord e rs

TABLE 40-6. Some Methods to P revent Preec l a m psia That Have Been Eva luated in Ra n d o m ized Trials Dieta ry m a n i pu lation-low-sa lt d i et, ca lci u m o r fi s h o i l s u ppleme ntation Exercise-physical activity, stretc h i n g Cardiovascular drugs-d i u retics, anti hypertensive d ru g s Antioxida nts-a scorb ic acid (vita m i n C ) , a-tocopherol (vita m i n E), vita m i n D Antithrom botic drugs-low-dose a s p i ri n , a s p i r i n/ d i pyridamo le, a s p i ri n + h e pa ri n, a s p i r i n + keta nseri n Mod ified fro m Staff, 20 1 5 .

was not until relatively recently that the irst randomized trial was done and showed that a sodium-restricted diet was inefec­ tive in preventing preeclampsia (Knuist, 1 998). Regular exercise during pregnancy is linked to a lower risk of developing preeclampsia (Barakat, 20 1 6; Morris, 20 1 7) . Also, in one systematic review, a trend toward risk reduction with exer­ cise was noted (Kasawara, 20 1 2) . Only a few studies have been randomized, and thus, more research is needed (Staf, 2 0 1 5) . Somewhat related, Abenhaim and coworkers (2008) reported a retrospective cohort study of 677 nonhypertensive women hospitalized for bed rest because of threatened preterm delivery. When outcomes of these women were compared with those of the general obstetrical population, bed rest was associated with a signiicantly reduced relative risk-0.27-of developing pre­ eclampsia. From two small randomized trials, prophylactic bed rest for 4 to 6 hours daily at home was successful in signiicantly lowering the incidence of preeclampsia in women with normal blood pressures (\1eher, 2006) . Calcium supplementation has been studied in several trials, including one by the National Institute of Child Health and Human Development (NICHD) that included more than 4500 low-risk nulliparas (Levine, 1 997) . Calcium supplemen­ tation did not prevent preeclampsia or pregnancy-associated hypertension. In one metaanalysis, increased calcium intake in high-risk women lowered the risk for preeclampsia (Patrelli, 20 1 2) . However, in aggregate, most of these trials have shown that unless women are calcium deficient, supplementation has no salutary efects (Sanchez-Ramos, 20 1 7; Staf, 20 1 5) . Cardioprotective aty acids found in some fatty fishes are plentiful in diets of Scandinavians and American Eskimos. Because supplementation with these fatty acids likely prevents inflammatory-mediated atherogenesis, it was posited that they might also prevent preeclampsia. Unfortunately, randomized trials conducted thus far have shown no such beneits from ish oil supplementation (Makrides, 2006; Olafsdottir, 2006; Zhou, 20 1 2) . • Antihypertensive Drugs

Because of the putative efects of sodium restriction for pre­ eclampsia prevention, diuretic therapy became popular with the introduction of chlorothiazide in 1 957 (Finnerty, 1 958; Flowers, 1 962) . In one metaanalysis of nine randomized trials

with more than 7000 pregnancies, women given diuretics had a lower incidence of edema and hypertension but not of pre­ eclampsia (Churchill, 2007) . Because women with chronic hypertension are at high risk for preeclampsia, several random­ ized trials have evaluated various antihypertensive drugs to reduce the incidence of superimposed preeclampsia (Chap. 50, p. 980) . A critical analysis of these trials by Staf and coworkers (20 1 5) failed to demonstrate benefits for this goal. • Antioxidants

Data imply that an imbalance between oxidant and antioxi­ dant activity plays a role in preeclampsia pathogenesis . Thus, naturally occurring antioxidants-vitamins C, D, and E­ might reduce such oxidation. Several randomized studies have assessed antioxidant vitamin supplementation for women at high risk for preeclampsia (Poston, 2006; Rumbold, 2006; Villar, 2009) . he Combined Antioxidant and Preeclampsia Prediction Studies (CAPPS) by the MFMU Network included almost 1 0 ,000 low-risk nulliparas (Roberts, 20 1 0) . None of these studies showed reduced preeclampsia rates in women provided vitamins C and E compared with those given placebo. Statins were proposed to prevent preeclampsia because they stimulate hemoxygenase- 1 expression, which inhibits sFlt- 1 release. Preliminary animal data suggest that statins may pre­ vent hypertensive disorders of pregnancy (Lewis, 20 1 7) . The MFMU Network plans a randomized trial to test pravastatin for this purpose (Costantine, 20 1 3, 20 1 6) . Meormin inhibits hypoxic inducible actor 1 . b y lowering mitochondrial electron transport chain activity. It reduces sFlt- 1 and sEng activity and thus has potential to prevent preeclampsia (Brownfoot, 20 1 6) . However, clinical studies are lacking. • Antithrombotic Agents

As noted earlier (p. 7 1 5) , preeclampsia is characterized by vaso­ spasm, endothelial cell dysfunction, and inlammation, as well as activation of platelets and the coagulation-hemostasis system. Other sequelae include placental infarction and spiral artery thrombosis (Nelson, 20 1 4b) . Thus, antithrombotic agents have been evaluated to reduce the incidence of preeclampsia. Low-molecular-weight heparin for prophylaxis has been stud­ ied in several randomized trials. Rodger and colleagues (20 1 6) performed a metaanalysis using individual patient data from 963 women. The risk for recurrent preeclampsia, abruption, or fetal-growth restriction was similar in women receiving h eparin or placebo. Aspirin, in low oral doses of 50 to 1 50 mg daily, efec­ tively inhibits platelet thromboxane A2 biosynthesis but has minimal efects on vascular prostacyclin production (Wallen­ burg, 1 986) . Still, several clinical trials have shown l imited benefi t s in preeclampsia prevention. For example, a random­ ized trial from the MFMU Network found that risks for adverse outcomes were not significantly reduced with aspirin therapy (Caritis, 1 998). Some combined reports, however, are more favorable. The Paris Collaborative Group perfo rmed a metaanalysis that included 3 1 randomized trials involv­ ing 32,2 1 7 women (Askie, 2007) . For women assigned to receive antiplatelet agents, the relative risk for preeclampsia,

727

728

O bstetrica l Com p l i cations

superimposed preeclampsia, preterm delivery, or any adverse pregnancy outcome was significantly decreased by 1 0 per­ cent. Other metaanalyses report marginal benefits of low-dose aspirin for prevention of severe preeclampsia (Roberge, 20 1 2; Villa, 20 1 3) . Recently, one randomized trial of more than 1 600 women at high risk for preterm preeclampsia provided low-dose aspirin from 1 1 to 1 4 weeks' gestation until 36 weeks to prevent recurrence. The rate of preterm recurrence was 1 .6 percent in the aspirin group compared with 4.3 percent in the placebo arm ( Rolnik, 20 1 7) . In recent dueling metaanalyses, Roberge and colleagues (20 1 7) found that aspirin prophylaxis initiated before 1 6 weeks' gestation was associated with a signiicant risk reduction­ about 60 percent-for preeclampsia and fetal-growth restriction. Moreover, they found a dose-response efect. At the same time, Meher and associates (20 1 7) performed an individual partici­ pant data metaanalysis and reported a much lower-about 1 0 percent-risk reduction that was significant whether therapy was initiated before or after 1 6 weeks. Meanwhile, the U.S. Preventive Services Task Force recom­ mends low-dose aspirin prophylaxis for women at high risk for preeclampsia (Henderson, 20 1 4) . Because of this, the American College of Obstetricians and Gynecologists (20 1 6b) issued a Practice Advisory that recommends low-dose aspirin be given between 1 2 and 28 weeks' gestation to help prevent preeclamp­ sia in high-risk women. This includes those with a history of preeclampsia and those with twins, chronic hypertension, overt diabetes, renal disease, and autoimmune disorders. These results have also raised the question as to whether al pregnant women should be given aspirin (Mone, 20 1 7) . At this time, our answer is "no." Low-dose aspirin coupled with heparin mmgates throm­ botic sequelae in women with lupus anticoagulant (Chap. 59, p. 1 1 45). Because of a similarly high prevalence of placental thrombotic lesions found with severe preeclampsia, trials have assessed the possible merits of such treatments for women with prior preeclampsia. In two randomized trials, women with a history of early-onset preeclampsia were given an aspirin ther­ apy or an enoxaparin plus aspirin regimen (Groom, 20 1 7; Had­ dad, 20 1 6) . Outcomes were similar. From their reviews, Sergis and associates (2006) reported better pregnancy outcomes in women with prior severe preeclampsia given low-molecular­ weight heparin plus low-dose aspirin compared with those given low-dose aspirin alone. Similar indings were reported by de Vries and coworkers (20 1 2) .

The basic management objectives for any pregnancy compli­ cated by preeclampsia are: ( 1 ) termination of pregnancy with the least possible trauma to mother and fetus, (2) birth of a healthy newborn that subsequently thrives, and (3) complete restoration of health to the mother. In many women with pre­ eclampsia, especially those at or near term, all three objectives are served equally well by induction of labor. One of the most important clinical questions or succesul management is precise knowledge ofetal age. • Early Diagnosis of Preeclampsia

Traditionally, the frequency of prenatal visits is increased dur­ ing the third trimester, and this aids early detection of pre­ eclampsia. Women without overt hypertension, but in whom eary developing preeclampsia is suspected during routine prenatal visits, are seen more frequenty. For many years at Parkland Hospital, women with new-onset diastolic blood pressures > 80 mm Hg but < 90 mm Hg or with sudden abnormal weight gain of more than 2 pounds per week have, at minimum, returned for visits at 7 -day intervals. Outpatient surveillance is continued unless overt hypertension, proteinuria, headache, visual disturbances, or epigastric pain supervenes. Women with overt new-onset hypertension-either dia­ stolic pressures �90 mm Hg or systolic pressures � 1 40 mm Hg-are admitted to determine if the increase is due to pre­ eclampsia, and if so, to evaluate its severity. • Evaluation

With hospitalization, a systematic evaluation is instituted to include: •

•

•

•

PREECLAMPSIA Pregnancy complicated by gestational hypertension is managed based on its severity, presence of preeclampsia, and gestational age. Preeclampsia cannot always be diagnosed definitively. hus, the Task Force (20 1 3) recommends more frequent pre­ natal visits if preeclampsia is "suspected." Increases in systolic and diastolic blood pressure can be either normal physiological changes or signs of developing patholoy. Heightened surveil­ lance permits more prompt recognition of ominous changes in blood pressure, critical laboratory findings, and clinical signs and symptoms (Macdonald-Wallis, 20 1 5) .

•

Detailed examination, which is coupled with daily scrutiny for clinical indings such as headache, visual disturbances, epigastric pain, and rapid weight gain Daily weight measurement Quantification of proteinuria or urine protein:creatmme ratio on admittance and at least every 2 days thereafter Blood pressure readings with an appropriate-size cuf every 4 hours, except between 2400 and 0600 unless previous read­ ings are elevated Measurements of plasma or serum creatinine and hepatic transaminase levels and a hemogram that includes a platelet count. The frequency of testing is determined by hyperten­ sion severity. Although some recommend measurement of serum uric acid and lactate dehydrogenase levels and coag­ ulation studies, their value has been questioned (Conde­ Agudelo, 20 1 5 ; Thangaratinam, 2006) . Evaluation of fetal size and well-being and amnionic luid volume, by either physical examination or sonography.

Reduced physical activity throughout much of the day is likely beneficial, but as the 20 1 3 Task Force concluded, absolute bed rest is not desirable. Ample protein and calories are included in the diet, and sodium and fluid intake are not limited or forced. In sum, goals of evaluation include early identification of preeclampsia or worsening of the syndrome and development of a management plan for timely delivery. Fortunately, many cases are suiciently mild and near enough to term that they

Hypertens ive D i s o rders

can be managed conservatively until labor commences sponta­ neously or until the cervix becomes favorable for labor induc­ tion. Complete abatement 0/ al signs and symptoms, however, is uncommon until ater delivery. If severe preeclampsia is diag­ nosed using the criteria in Table 40-2, further management is subsequently described. • Consideration for Delivery

Termination o/pregnancy is the ony cureor preeclampsia. Head­ ache, visual disturbances, or epigastric pain are indicative that convulsions may be imminent, and oliguria is another ominous sign. Severe preeclampsia demands anticonvulsant and often antihypertensive therapy, followed by delivery. Treatment for eclampsia is identical. The prime objectives are to forestall con­ vulsions, to prevent intracranial hemorrhage and serious dam­ age to other vital organs, and to deliver a healthy newborn. his is true even when the cervix is unfavorable (Tajik, 20 1 2) . Labor induction is carried out, usually with preinduc­ tion cervical ripening with a prostaglandin or osmotic dilator (Chap. 26, p. 505). Concerns stemming from an unfavorable cervix, a perceived sense of urgency because of preeclampsia severity, and a need to coordinate neonatal intensive care have led some to advocate cesarean delivery. Alexander and colleagues ( 1 999) reviewed 278 singleton liveborn neonates weighing 750 to 1 500 g delivered of women with severe preeclampsia at Parkland Hospital. I n half of the women, labor was induced, and the remainder underwent cesarean delivery without labor. Induction was successful in accomplishing vaginal delivery in a third, and it was not harmful to very-low-birthweight neonates. Others have reported similar observations (Alanis, 2008; Roland, 20 1 7) . However, whenever it appears that induction almost certainly will not succeed or attempts have failed, then cesarean delivery is indicated. For a woman near term, with a soft, partially efaced cervix, even a milder degree of preeclampsia probably carries more risk to the mother and her fetus-newborn than does induction of labor (Tajik, 20 1 2) . A randomized trial of 756 women with mild preeclampsia supported delivery after 37 weeks' gestation (Koopmans, 2009) . When the fetus is preterm, the tendency is to temporize in the hope that additional weeks in utero will reduce the risk of neonatal death or serious morbidity from prematurity. Such a policy certainly is justified in milder cases. Assessments of fetal well-being and placental function are performed, especially when the fetus is immature. Most recommend frequent perfor­ mance of nonstress testing or biophysical proiles to assess fetal well-being (American College of Obstetricians and Gynecolo­ gists, 20 1 6a) . Several tests can be used to provide evidence of lung maturity (Chap. 34, p. 638). An sFlt- l IPlGF ratio 7 gl dL or to liberal trans­ fusions to maintain the hemoglobin level at 1 0 to 1 2 gl dL. he 30-day mortality rate was similar- 1 9 versus 23 percent in the restrictive versus liberal groups, respectively (Hebert, 1 999) . Transfusion therapy in nonpregnant patients with septic shock had similar mortality rates when 7 g/dL was compared with 9 gl dL as targets for transfusions (Holst, 20 1 4) . he number of units transused in a given woman to reach a target hematocrit depends on her body mass and on expectations ofadditional blood loss. B l oo d Co m po n e nt Prod u cts

Contents and efects of transfusion of various blood compo­ nents are shown in Table 4 1 -8 . Compatible whole blood is ideal

Obstetrica l Hemo rrhage

TABLE 41 -8. Blood P roducts Com monly Tra nsfused in Obstetrica l Hemorrhage Product

Vol u me per U n it

Contents per U nit

Efect on Hemorrhage

Whole blood

About 5 00 m L; Hct �40 percent

R BCs, pl a s m a, 600-700 mg fi bri nogen, no p l atel ets

Packed RBCs

2 50-300 m L; H ct 5 5 -80 percent About 250 m L; 30-m i n ute thaw About 1 5 m L, frozen

RBCs, m i n i ma l fi bri nogen, no p l ate lets Co l l oid, 600-700 mg fi bri nogen, no p l atelets O n e u n it � 200 mg fi bri nogen, o t h e r clott i n g factors, no p latelets One u n it ra i ses platelet co u nt a bout 5 000/�L; s i n g le-donor a p h eres is bag p referable

Resto res blood vol u m e a n d fi b r i n ogen, i n crea ses H ct 3 -4 vo l u m e perce nt per u n it I ncreases Hct 3-4 vo l u m e perce nt pe r u n it Resto res c i rc u lat i n g vo l u me a n d fi b r i nogen 1 5-20 u n its or 3-4 g wi l l i ncrea s e basel i n e fi bri nogen 1 50 m g/d L 6- 1 0 u n its tra nsfu sed: s i n g le-d o n o r bag p referable to ra i se p l atel ets � 3 0,000/�L

�

F resh-frozen plasma (FFP) Cryopreci pitate P l atelets

Hct

=

About 50 m L, stored at roo m tem peratu re

hem atocrit; RBCs

=

�

red blood ce l l s.

or treatment ofhypovolemiarom catastrophic hemorrhage. It has a shelf life of 40 days, and 70 percent of the transfused red cells function for at least 24 hours following transfusion. One unit raises the hematocrit by 3 to 4 volume percent. Important for obstetrical hemorrhage, whole blood replaces many coagulation factors in obstetrics-especially fibrinogen-and its plasma treats hypovolemia. A collateral derivative is that women with severe hemorrhage are resuscitated with fewer blood donor exposures than with packed red cells and components (Shaz, 2009) . Evidence supports the preferable use of whole blood for mas­ sive hemorrhage, including our experiences at Parkland Hospi­ tal (Alexander, 2009; Hernandez, 20 1 2) . Of more than 66,000 deliveries, women with obstetrical hemorrhage treated with whole blood had signiicantly lower incidences of renal failure, acute respiratory distress syndrome, pulmonary edema, hypo­ ibrinogenemia, intensive care unit admissions, and maternal death compared with those given packed red cells and compo­ nent therapy. Freshly donated whole blood has also been used successfully for life-threatening massive hemorrhage at combat support hospitals (Murdock, 20 1 4; Stubbs, 20 1 6) . In most institutions today, however, whole blood i s rarely available. hus, most women with obstetrical hemorrhage and ongoing massive blood loss are given packed red cells and crys­ talloid. In these instances, no data support a 1 : 1 plasma: red cell transfusion ratio. As subsequently discussed, many institutions use massive tranfusion protocols designed to anticipate all facets of massive obstetrical hemorrhage. These "recipes" commonly contain a combination of red cells, plasma, cryoprecipitate, and platelets (Cunningham, 20 1 5 ; Pacheco, 2 0 1 1 ; Shields, 2 0 1 l ) . Several studies have assessed plasma:red cell ratio with mas­ sive transfusion protocols used in civilian trauma units and military combat hospitals (Borgman, 2007; Gonzalez, 2007; Hardin, 20 14; Johansson, 2007) . Patients undergoing mas­ sive transfusion-deined as 1 0 or more units of blood-had much higher survival rates as the ratio of plasma to red cell units neared 1 : 1 .4, that is, one unit of plasma given for each 1 .4 units of packed red cells. By way of contrast, the highest mortality group had a ratio of 1 : 8 . Most of these studies ound

that component replacement is rarey necessay with acute replace­ ment of5 to 1 0 units ofpacked red cels. F rom the foregoing, when red cell replacement exceeds five units or so, evaluation of platelet count, clotting studies, and plasma fibrinogen concentration is reasonable. In the woman with obstetrical hemorrhage, the platelet count should be main­ tained > 50,000/�L by the infusion of platelet concentrates. A fibrinogen level < 1 50 mg/dL or a suiciently prolonged PT or PTT in a woman with surgical bleeding is an indication for replacement. Fresh-frozen plasma is administered in doses of 1 0 to 1 5 mLlkg, or alternatively, cryoprecipitate is infused (see Table 4 1 -8) . D i l utiona l Coa g u l o pathy

A major drawback of treatment for massive hemorrhage with crystalloid solutions and packed red blood cells is depletion of platelets and clotting factors. his can lead to a dilutional coagu­ lopathy that is clinically indistinguishable from DIe (Hossain, 20 1 3) . Thrombocytopenia is the most frequent coagulation defect found with blood loss and multiple transfusions (Counts, 1 9 9). In addition, packed red cells have only very small amounts of soluble clotting factors, and stored whole blood is deicient in platelets and in factors V, VIII, and XI. As discussed, massive replacement with red cells only and without factor replacement can also cause hypoibrinogenemia and prolongation of the PT and PTT. Because many causes of obstetrical hemorrhage also cause consumptive coagulopathy, the distinction between dilu­ tional and consumptive coagulopathy can be confusing. Fortu­ nately, treatment for both is similar. Type a n d Screen ve rs u s C rossm atch

A blood type and antibody screen should be performed for any woman at significant risk for hemorrhage. Screening involves mixing maternal serum with standard reagent red cells that carry antigens to which most of the common clinically signii­ cant antibodies react. Crossmatching involves the use of actual donor erythrocytes rather than the standardized red cells. This process is eicient, and only 0.03 to 0.07 percent of patients

789

790

Obstetrica l Co m p l ications

identiied as having no antibodies are subsequently found to have antibodies (Boral, 1 979) . Importanty, administration of screened blood rarey results in adverse clinical sequelae. Pac ked Red B l ood Ce l l s

One unit of packed erythrocytes i s derived from o n e unit of whole blood to have a hematocrit of 55 to 80 volume per­ cent. One unit will increase the hematocrit by 3 to 4 volume percent. Plate l ets

With surgical delivery or with lacerations, platelet transfusions are considered with ongoing obstetrical hemorrhage when the platelet count falls below 50,000/�L (Kenny, 20 1 5). In the nonsurgical patient, bleeding is rarely encountered if the platelet count is 1 0,000/�L or higher (Murphy, 20 1 0) . The preferable source of platelets is one "bag" obtained by single-donor apher­ esis. This contains the equivalent of six units from six indi­ vidual donors. Depending on maternal size, each single-donor apheresis six-unit bag raises the platelet count by approximately 20,000/�L (Schlicter, 20 1 0) . If these bags are not available, then individual-donor platelet units are used, and six to eight such units are generally transfused one at a time. Importantly, the donor plasma in platelet units must be compatible with recipient erythrocytes. Further, because some red blood cells are invariably transfused along with the platelets, only units from D-negative donors should be given to D-nega­ tive recipients. If it is necessary to give these, however, adverse sequelae are unlikely (Lin, 2002) . Fresh - Frozen P l a s m a

This component is prepared by separating plasma from whole blood and then freezing it. Approximately 30 minutes are required for frozen plasma to thaw. It is a source of all stable and labile clotting factors, including fibrinogen. Thus, it is often used for treatment of women with consumptive or dilu­ tional coagulopathy. Plasma is not appropriateor use as a volume expander in the absence of speciic clotting actor deiciencies. It should be considered in a bleeding woman with a fibrinogen level < 1 50 mg/dL or with an abnormal PT or PTT. An alternative to frozen plasma is liquid plasma (LQP). This never-frozen plasma is stored at 1 to 6°C for up to 26 days, and in vitro, it appears to be superior to thawed plasma (Matijevic, 20 1 3) , . C ryo p re c i p itate a n d Fi bri n og e n C o n ce ntra te

Each unit of cryoprecipitate is prepared from one unit of fresh-frozen plasma. Each 1 0- to 1 5-mL unit contains at least 200 mg of fi b rinogen along with factor VIII:C, fac­ tor VIII:von Willebrand factor, factor XIII, and ibronectin (American Association of Blood Banks, 20 1 4) . It is usually given as a "pool" or "bag" using an aliquot of ibrinogen con­ centrate taken from 8 to 1 20 donors. Cryoprecipitate is an ideal source of ibrinogen when levels are dangerously low and there is oozing from surgical incisions. Another alternative is virus-inactivated ibrinogen concentrate. Each gram of this raises the plasma fibrinogen level approximately 40 mg/ dL (Ahmed, 20 1 2 ; Kikuchi, 20 1 3) .

Recom b i n a n t Activated Fa cto r VI I

This synthetic vitamin K-dependent protein is available as NovoSeven. It binds to exposed tissue factor at the site of injury to generate thrombin that activates platelets and the coagula­ tion cascade. Since its introduction, rFVIla has been used to help control hemorrhage from surgery, trauma, and obstetri­ cal causes (Goodnough, 20 1 6; Murakami, 20 1 5) . Most Level I trauma centers include it in their massive transfusion protocols, and it is included in the one used at Parkland Hospital. Impor­ tantly, rFVIIa will not be efective if the plasma fibrinogen level is < 50 mg/dL or the platelet count is < 30,000/�L. One major concern with rFVIla use is arterial-and to a lesser degree venous-thrombosis. In a review of 35 random­ ized trials with nearly 4500 subjects, arterial thromboembolism developed in 55 percent (Levi, 20 1 0a) . A second concern is that it was found to be only marginally efective (Pacheco, 20 1 1 ) . Tra n exa m i c Acid

This antiibrinolytic drug has been used for traumatic and obstet­ rical hemorrhage. Tranexamic acid inhibits clot lysis to help fore­ stall bleeding by preventing plasmin from degrading ibrin. Its use has been associated with a higher incidence of renal cortical necrosis (F rimat, 20 1 6) . The evidence supporting its use as an adjunct in obstetrical hemorrhage is limited, and its routine use for prophylaxis is not recommended American College of Obste­ tricians and Gynecologists, 20 1 7d; Pacheco, 20 1 7) . M a s s ive Tra n sfu sion Protocols

These function to speed blood product delivery to the bedside or operating room, which permits product infusion early in the resuscitation process. he rationale is to prevent adverse efects of aggressive resuscitation solely with crystalloid and packed red blood cells. That said, it is not necessary to acti­ vate massive transfusions until at least four to ive units of red cells have been given within 2 hours or so. Once activated, red cells, plasma, platelets, and fibrinogen are given by protocol in amounts shown in Table 4 1 -9. Some protocols include rFVIIa and others include tranexamic acid. As expected, studies attesting to the superiority for sur­ vival with massive transfusion protocols are limited. Most TABLE 41 -9. Parkland Hospital Obstetrical Massive Tra nsfusion Protocol Round No.

PRBC 5 U n its

FFP 3 U n its X

x

2

X

3

4

X

X

X

X

X

X

X

X

X

X

X

5

X

X

7

X

X

6

X X

8

Pits 6-pack

Cryo 1 U nit

X

X

Cryo c ryopreci pitate; F F P fresh froze n p l a s ma; Pits P l atelets; P R BC packet red bl ood cel ls; rVl l a reco m b i n a nt activated factor VI I (NovoSeven) . =

=

=

=

=

rVl la 2 mg X X X X

Obstetrica l H e m o rrhage

reports describe nonpregnant trauma victims, but some obser­ vational studies address obstet­ rical hemorrhage (Green, 20 1 6; Pacheco, 20 1 6) . More data with use of these protocols is needed. Vi scoe l a stic Assays

Normal coagu l ation

mm

mm

CT

60 40

60 40

20

20

20

20

40 60

40 60

Thromboelastography (TEG) and rotational thromboelastometry 50 min 40 30 20 50 min 10 30 40 20 10 (ROTEM) are point-of-care tests that assess coagulation in whole B F I BTEM A EXTEM blood during massive transfu­ F I G U R E 4 1 -32 TEG/ROTEM based viscoe lastic assays of coag u lation p rofi les i n a preg nant sions. These tests work by ana­ woman. A. EXTEM c l ot profi le: CT clotting time; A5-20 clot a m pl ified at 5, 1 0, 1 5, 20 m i n ; lyzing both clot formation and M C F maxi m u m c l ot fi rm ness. B. F I BTEM c l ot p rofi l e showi n g excel lent fi brin-based clot q ua l­ breakdown in a whole blood sam­ ity. (Reprod uced with permission from Solomon C, Col l is R E, Col l i n s PW: Haemostatic monitor­ ing d u ring postpa rtu m haemorrhage a n d i m pl ications for ma nagement, Br J A naesth. 2 0 1 2 ple from a given patient. Testing Dec; 1 09(6) :85 1 -863.) produces a proile of coagulation dynamics, and displayed values indicate the speed and quality of the cell salvage group-2.5 versus 3.5 percent, but this was not clot formation (Fig. 4 1 -32) . hese assays provide information a signiicant diference (han, 20 1 7) . Similar to prior reports, regarding time to clot formation, clot strength, and fi b rinolysis. no cases of amnionic luid embolism were reported. Currently, they guide blood product replacement in trauma, liver transplant, and cardiac surgery patients. Studies of TEG Tra nsfu s i o n C o m p l ications and ROTEM techniques in pregnant women have conirmed the hypercoagulable state of pregnancy and provide reference Of serious known risks, transfusion of an incompatible blood ranges for use in this population (Butwick, 20 1 5 ; de Lange, component may result in acute hemolysis. If severe, this can 20 1 4; Solomon, 20 1 2) . cause DIC, acute kidney injury, and death. Preventable errors Although these point-of-care tests appear promising, they also responsible for most of such reactions frequently include mis­ have several limitations. For example, they cannot be used to labeling of a specimen or incorrectly transfusing a patient not detect disorders of primary hemostasis (Solomon, 20 1 2) . Addi­ slated for those products. The rate of such errors in the United tionally, these tests cannot diagnose coagulopathies stemming States is estimated to be 1 in 1 4,000 units, but these events are from platelet dysfunction or antiplatelet drugs. A major draw­ likely underreported (Lerner, 20 1 0) . A transfusion reaction is back is the risk of misinterpretation when tests are used by inade­ characterized by fever, hypotension, tachycardia, dyspnea, chest quately trained personnel. Further study is necessary before these or back pain, lushing, severe anxiety, and hemoglobinuria. tests are widely applied for treatment of obstetrical hemorrhage. Immediate supportive measures include stopping the transfu­ sion, treating hypotension and hyperkalemia, provoking diure­ To p ica l H emo static Age nts sis, and alkalinizing the urine. Transfusion-related acute lung injury (TAIl) is the most Several agents can be used to control persistent surgical oozing. common cause of transfusion-related mortality. The syndrome These were recently reviewed by Miller and colleagues (20 1 5) . is characterized by severe dyspnea, hypoxia, and noncardiogenic Other than for cesarean hysterectomy, these are seldom used i n pulmonary edema that develop within 6 hours of transfusion obstetrical hemorrhage. (Peters, 20 1 5) . TRALI is estimated to complicate at least 1 in Ce l l Sa lva g e a n d A uto l og o u s Tra nsfu s i o n 1 2,000 transfusions (Carson, 20 1 7) . Although the pathogenesis is incompletely understood, injury to the pulmonary capillaries Preoperative patient phlebotomy and autologous blood storage for may arise from anti-human leukocyte antigen (HA) and neu­ transfusion has been disappointing. Exceptions are women trophil (HNA) antibodies in donor plasma (Lerner, 20 1 0) . A with a rare blood type or with unusual antibodies. Most have delayed form ofTRALI has been reported to begin 6 to 72 hours concluded that autologous transfusions are not cost efective following transfusion (Marik, 2008) . Management is supportive (Etchason, 1 995; Pacheco, 20 1 1 , 20 1 3) . and may include mechanical ventilation (Chap. 47, p. 9 1 9) . Intraoperative blood salvage with reinfusion i s considered to Bacterial inection from transfusion o f a contaminated blood be a safe intervention in obstetrical patients. As discussed in component is unusual because organism growth is discouraged Chapter 30 (p. 569) , this practice may be helpful for women by refrigeration. The most often implicated contaminants of declining transfusion. Prior concern centered on amnionic fluid red cells include Yersinia, Pseudomonas, Serratia, Acinetobacter, contamination and embolism (Dhariwal, 20 1 4; Goucher, 20 1 5 ; and Escherichia species. The more important risk is from bacte­ Pacheco, 20 1 1 ) . A recent randomized trial involving 3028 rial contamination of platelets, which are stored at room tem­ women compared routine cell salvage use against routine care, in perature. Current estimates are that 1 in 1 000 to 2000 platelet which salvage was employed only for bleeding indications. he units are contaminated. Death from transfusion-related sepsis rate of nonautologous donor blood transfusion was reduced in =

=

=

79 1

792

Obstetrical C o m p l ications

is 1 per 1 7,000 for single-donor platelets and 1 per 6 1 ,000 for apheresis-donor packs (Lerner, 20 1 0) . iral inection risks from transfusion have been curtailed. he risk of HIV or hepatitis C virus infection in screened blood is estimated to be 1 case per 1 to 2 million units transfused (Carson, 20 1 7; Stramer, 2004) . The risk for HIV-2 infection is less. Other viral infections include hepatitis B transmission, which is esti­ mated to be < 1 per 1 00,000 transused units / Qackson, 2003) . Because of its high prevalence, cytomegalovirus-infected leukocytes are often transfused. hus, precautions are taken for immunosuppressed recipients, keeping in mind that this includes the fetus. Also, risks for transmitting West Nile virus, human T-lymphotropic virus type I, parvovirus B 1 9, and toxoplasmosis are slight (American Association of Blood Banks, 20 1 3; Foroutan-Rad, 20 1 6) . Finally, Zika virus has emerged as another relevant transfusion-trans­ F I G U R E 4 1 -33 Uteri ne a rtery l igation. The suture goes t h ro u g h the latera l uterine mitted infection (Motta, 20 1 6) . The Food and wa l l a nteriorly, cu rves a ro u n d posteriorly, then re-enters a nteriorly. When tied, it encompasses the uteri ne a rtery. Drug Administration (20 1 6) revised recom­ mendations for collection of all whole blood series, the failure rate was 20 percent (Kaya, 20 1 6) . From their components to include testing for Zika virus. This practice has review, Sathe and coworkers (20 1 6) reached similar conclusions. been airmed by the Centers for Disease Control and Preven­ Some unique complications can rarely follow compression tion (20 1 6) . sutures (Matsubara, 20 1 3) . Most involve variations of uterine ischemic necrosis with peritonitis (Gottlieb, 2008; Joshi, 2004; • Adj unctive Surgical Procedu res Ochoa, 2002; Treloar, 2006) . In one case, total uterine necro­ Several invasive procedures can help arrest postpartum hemor­ sis followed B-Lynch sutures that were placed in combination rhage. A report from the Agency for Healthcare Research and with bilateral ligation of uterine, uteroovarian, and round liga­ Quality concluded that most studies addressing these methods ment arteries (Friederich, 2007) . In most cases, subsequent are of poor quality (Likis, 20 1 5) . In one study of 6660 women pregnancies are uneventful if compression sutures are used (n, with postpartum hemorrhage, 4.4 percent underwent an inva­ 20 1 3) . A few women, however, with B-Lynch or Cho sutures sive procedure, and 1 . 1 percent had a hysterectomy (Kayem, developed uterine wall defects (Akoury, 2008) . Another long­ 20 1 6) . he failure rate of conservative measures was 1 5 percent term complication is uterine cavity synechiae (Alouini, 20 1 1 ; in surgical and embolization procedures. Ibrahim, 20 1 3; Poujade, 20 1 1 ) .

\

Uteri n e Artery Ligation

I nte r n a l I l ia c A rtery Ligation

The technique for unilateral or bilateral uterine artery ligation is used primarily for lacerations at the lateral part of a h) ster­ otomy incision (Fig. 4 1 -33) . In our experiences, this procedure is less helpful for hemorrhage from uterine atony.

For years, ligation of one or both internal iliac arteries has been used to reduce pelvic hemorrhage. Drawbacks are that the pro­ cedure may be technically diicult and is only successful half of the time (American College of Obstetricians and Gynecolo­ gists, 20 1 7d) . It is not particularly helpful for abating hemor­ rhage with postpartum atony (Clark, 1 985). For ligation, adequate exposure is obtained by opening the peritoneum over the common iliac artery and dissecting down to the bifurcation of the external and internal iliac arteries (Fig. 4 1 -3 5) . Branches distal to the external iliac arteries are palpated to veriY pulsations at or below the inguinal area. liga­ tion of the internal iliac artery 5 cm distal to the common iliac bifurcation will usually avoid the posterior division branches (Bleich, 2007) . The areolar sheath of the artery is incised lon­ gitudinally, and a right-angle clamp is carefully passed j ust beneath the artery from lateral to medial. Care must be taken not to perforate contiguous large veins, especially the internal

Uter in e Co m p ression Sutures

his surgical technique uses a no. 2 chromic suture to com­ press the anterior and posterior uterine walls together (B-Lynch, 1 997) . Because they give the appearance of suspenders, they are also called braces (Fig. 4 1 -34) . Several modiications of the B-Lynch technique have been described (Cho, 2000; Hayman, 2002; Matsubara, 20 1 3 ; Nelson, 2007) . Indications vary for its application, and this will afect the success rate. For example, B-Lynch (2005) cited 948 cases with only seven failures. Con­ versely, Kayem and associates (20 1 1 ) described 2 1 1 women who had an overall failure rate of 25 percent, which did not difer between B-Lynch sutures and their modiications. In another

O bstetrical H e m orrhage

A

c

D

F I G U R E 4 1 -34 Uterine com pression sutu re or "bra ce." The B-Lync h suture tech n iq u e is i l l u strated from a n a nterior view of the uterus i n F i g u res A, B, a n d 0 a n d a posterior view i n Fig u re C. T h e n u m bers denote the seq uentia l path of t h e suture and a re s hown i n more t h a n o n e fig u re. Step 1 . Beg i n n i ng below t h e i ncision, the need le pierces t h e lower uteri ne seg ment t o e nter the uterine cavity. Step 2 . The need le exits the cavity a bove the i ncision. The sutu re then loops u p a nd a ro u n d the fu n d u s to the posterior uteri n e surface. Step 3 . The need le pierces the posterior uteri ne wa l l to reenter the ute ri n e cavity. The suture then traverses to the opposite side with i n the cavity. Step 4. The need le exits the uteri n e cavity t h ro u g h the posterior uteri ne wa l l . From the back of the uterus, the s utu re loops up a nd a round the fu n d u s to the front of the uterus. Step 5. The needle pierces the myo m etri u m a bove the i ncision to reenter t h e uterine c avity. Step 6. The need l e exits below the i ncision a n d the sutu res at points 1 a nd 6 a re tied below the incision. The hysterotom y i n c ision is then closed i n the u s u a l fas h i o n .

iliac vein. Suture-usually nonabsorbable-is passed under the artery with a clamp, and the vessel is then securely ligated. he most important mechanism of action with internal iliac artery ligation is an 8 5-percent reduction in pulse pres­ sure in those arteries distal to the ligation (Burchell, 1 968) . his converts an arterial pressure system into one with pressures approaching those in the venous circulation. his creates vessels more amenable to hemostasis via pressure and clot formation. Even bilateral internal iliac artery ligation does not appear to interfere with subsequent reproduction. Nizard and colleagues

(2003) reported follow-up in 1 7 women who had bilateral artery ligation. From a total of 21 pregnancies, 1 3 were nor­ mal, three ended with miscarriage, three were terminated, and two were ectopic. A n g i og ra ph ic E m b o l ization

This modality is now used for many causes of intractable hem­ orrhage when surgical access is diicult. In more than 500 women reported, embolization was 90-percent efective (Gron­ vall, 20 1 4; Lee, 20 1 2; Poujade, 20 1 2; Zhang, 20 1 5) . After his

793

794

Obstetrica l Com p l ications

if all other measures have failed, especially in low-resource areas (Dildy, 2006; Howard, 2002) . The pack is constructed of a sturdy sterile plastic bag that is illed with gauze rolls that are unwound and knotted together. Suicient rolls are used to pro­ vide enough volume to fill the pelvis. he pack is introduced transabdominally with the stalk exiting the vagina. Mild trac­ tion is applied by tying the stalk to a I -liter fluid bag, which is hung over the foot of the bed. The umbrella pack is removed vaginally after 24 hours. REFERENCES

F I G U R E 41 -35 Ligation o f the r i g h t i nternal i l iac a rtery. U nem­ bal med cadaveric d issection shows the right-a n g l e cla m p passing u nderneath t h e a nterior d ivision of the i nterna l i l iac a rtery j u st d is­ ta l to its posterior d ivision. (Used with permission from Dr. M a rl e n e Corton.)

review, Rouse (20 1 3) concluded that embolization can be used to arrest refractory postpartum hemorrhage. Other reports have been less enthusiastic. Fertility is not impaired, and many subsequent successful pregnancies have been reported (Chauleur, 2008; Fiori, 2009; Kolomeyevskaya, 2009) . An important caveat or these procedures is that women with hemodynamic instabiliy related to active bleeding should not be removed rom the operating room. Complications of embolization are relatively uncommon but can be severe. Case reports detail instances of iatrogenic iliac artery rupture, uterine ischemic necrosis, and uterine infection (Gronvall, 20 1 4; Katakam, 2009; Nakash, 20 1 2) . Finally, l-hunyan and coworkers (20 1 2) described a woman with massive buttock necrosis and paraplegia following bilateral internal iliac artery embolization. In a few instances, massive blood loss and diicult surgical dissection is anticipated. The use of balloon-tipped catheters preoperatively inserted into the iliac or uterine arteries was described earlier in management of placenta accrete syndromes (p. 78 1 ) . Pelvic Pac k i n g

For significant bleeding refractory to suture or topical hemostats, pelvic packing with gauze and termination of the operation may be considered. Rolls of gauze are packed to provide constant local pressure. This may serve as a tem­ porizing step prior to interventional embolization. In other cases, packing alone may be left for 24 to 48 hours. If the patient is stable and bleeding appears to have stopped, pack­ ing is removed. The umbrela or parachutepack uses a similar concept (Logoth­ etopulos, 1 926) . Although seldom used today, it can be lifesaving

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803

C H A PT E R 42

Prete rm B i rt h

DEFIN ITION OF PRETERM BIRTH

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803

PRETERM B I RTH RATE TREN DS

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804

PRETERM N EWBORN MORBI DITY

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805

CAUSES OF PRETERM BIRTH

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809

CONTRI BUTI NG FACTORS

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81 2

DIAGNOSIS

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814

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81 5

MANAGEMENT OF PRETERM PREMATU RE RUPTU RE OF MEMBRANES MANAGEMENT OF PRETERM LABOR WITH I NTACT MEMBRANES

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PRETERM B I RTH PREVENTION

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81 9

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.

822

It is generaly admitted that there exists in the medulla a centre or uterine contractions, which can be stimulated by an excess of carbon dioxide in the bloo, by anaemia and the presence of various toxic substances; and it seems highy probable that the requency ofpremature labour in cases of renal insuiciency and eclampsia may be due to the action of metabolic poisons upon the centre. -J. Whitridge Williams ( 1 903) In this textbook's first edition, very little was mentioned regard­ ing preterm birth. Indeed, preterm birth was not incorporated as a stand-alone topic until the 1 3th edition in 1 966. And, this content totaled only three sentences that cited use ofisoxsuprine

as a tocolytic agent. In contrast, present-day research now pro­ duces more than 3000 articles published annually. Data derive from study of animal models, translational research, clinical trials, and genetic investigations. Despite eforts, elucidating the biology of human parturition and the subsequent efo rts to prevent preterm birth remain elusive (Martin, 20 1 7) . DEFI N ITION OF PRETERM BI RTH Low birthweight deines neonates who are born too small. Pre­ term or premature birth describes neonates who are born too early. With respect to gestational age, a newborn may be pre­ term, term, or postterm. With respect to size, a newborn may be normally grown and appropriate or gestational age; undersized, thus, smaLor gestational age; or overgrown and consequently, large or gestational age. Small for gestational age categorizes newborns whose birthweight is < 1 0th percentile for gestational age. Other frequently used terms have included etal-growth restriction or intrauterine growth restriction. he term large for gestational age describes newborns whose birthweight is > 90th percentile for gestational age. The term appropriate or gesta­ tional age designates newborns whose weight is between the 1 0th and 90th percentiles. Thus, neonates born before term can be small or large for gestational age, but still preterm by deinition. Low birthweight refers to neonates weighing 1 500 to 2500 g; vey low birth­ weight are those between 1 000 and 1 500 g; and extremey low birthweight refers to those between 500 and 1 000 g. Before the 1 5th edition of this textbook, a preterm or prema­ ture newborn was deined by a birthweight < 2500 g. With that edition, preterm neonates were considered to be those delivered before 37 completed weeks, that is, < 36 6r weeks (Pritchard, 1 976) . This defi n ition, which has now been in use for more than 40 years, was fi r st promulgated in 1 976 by the World Health Organization (WHO) and the International Federation

804

Obstetrica l Comp l i cations

TABLE 42- 1 . I nfa nt Morta l ity Rates in the U n ited States i n 201 3 Live Births No. (%)

I nfant Deaths (per 1 000 births)

Total i nfants

3 ,932, 1 8 1 ( 1 00)

2 3 ,446 (6)

Gestational age: < 34 weeks 34-36 weeks < 3 7 wee ks 3 7-38 wee ks 3 9-4 1 wee ks ::4 2 weeks

1 3 3,503 (3) 3 1 3,858 (8) 447,361 ( 1 1 ) 974, 1 62 (25) 2,29 1 ,468 (5 8) 2 1 5 ,5 1 0 (5)

1 3,284 2 268 1 5,552 2933 42 1 8 515

( 1 00) (7) (3 5) (3) (2) (2)

Data from Matth ews, 20 1 5 .

of Gynecology and Obstetrics (FIGO) . The defi n ition derived from a statistical analysis of gestational age distribution at birth (Steer, 2005). Importantly, the denotation lacks a spe­ cific functional basis and should be clearly distinguished from the concept of prematuriy. Prematurity represents incomplete development of various organ systems at birth. For example, the lungs are particularly afected, leading to the respiratory distress syndrome (RDS) (Chap. 34, p. 636) . In 20 1 3 in the United States, 23,446 infants died in their first year of life, and a third of infants died from preterm-related causes (Matthews, 20 1 5) . Gestational age at delivery and the risk of neonatal morbidity and mortality are inversely related (Frey, 20 1 6) . Namely, neonates born in the early-preterm period make up the smallest proportion of births, but these infants experi­ ence disproportionately higher rates of prematurity-related complications (Table 42- 1 ) . Beginning in 2005, i n recognition that neonates born between 34°/7 weeks and 366/7 weeks experience morbidities and mortality characteristic of premature newborns, preterm births were subdivided. Those before 33 6/ weeks are labeled eary pre­ term, and those occurring between 34 and 36 completed weeks are late preterm. Indeed, compared with births at 39°/ weeks through 40 617 weeks, these late-preterm infants experience morbidities that are also associated with prematurity (Spong, 20 1 3) . Recently, this concept has expanded to births 37°/7 weeks through 38 6/ weeks, which are now defined as eary term, and those 39 °/7 weeks through 40 6/ weeks, which are deined as term. his revised terminology has led some to redefine a short gestation as those < 39 °/ weeks. By doing so, more than a third of live births in the United States in 20 1 5 would be defi n ed as having a shortened period of gestation (Martin, 20 1 7) . One implication is that only 65 percent of births in the United States occurred during the optimal 39 to 4 1 weeks' gestation. This emphasizes the realization that fetal maturation in humans is a continuum that is completed later in human pregnancy than previously appreciated. As a result, adverse neonatal sequelae from neonatal immaturity with elective delivery before 39 completed weeks are appreciable (Reddy, 2009; Tita, 2009) . This knowledge resulted in the development and application of the "39-week rule" to deter nonmedically indicated deliveries

before 39 weeks (Spong, 20 1 1 ) . An unintended consequence of this health-care strategy has been a rise in stillbirth rates in the United States. One concern is that the rule may be misapplied to gestations with true medical indications for early delivery (Hill, 20 1 7; Nicholson, 20 1 6) . Spong (20 1 6) has emphasized the need to perform necessary obstetrical interventions when indicated. PRETERM BI RTH RATE TRENDS • Methodology

In the United States, the preterm birth rate rose slightly from 9.57 percent in 20 1 4 to 9.63 percent for 20 1 5 (Martin, 20 1 7) . This marks the irst rise i n this percentage since 2007. Although concerning, some argue that the drop in preterm birth rates from 2007 to 20 1 4 reflected systematic bias associated with changes in obstetrical dating (Frey, 20 1 6) . Speciically, beginning with the 20 1 4 data year, the National Vital Statistics Reports from the National Center for Health Statistics transitioned to a new standard for estimating newborn gestational age for birth certificate completion (Martin, 20 1 5) . The new measure-obstetrical estimate o f gestational age at delivery-replaced calculations based on the date of the last normal menses (Chap. 44, p. 846) . As shown in Figure 42- 1 , these measures difer and do not provide equivalent absolute numerical comparisons of preterm birth rates. For example, the 20 1 5 obstetrical estimate-based preterm birth rate was 9.6 per­ cent compared with the last menstrual period-based rate of 1 1 .3 percent (Martin, 20 1 7) . hus, current national data are now not directy comparable to previousy reported rates ofpreterm birth due to diering gestational age caculation methodologies. he national data are now reported starting with year 2007, which coincides with the year that this information became available.

14 1 2. 68

• LMP

Obstetric estimate

12 10

C

J J

8

-

J ..

6 4 2 0

2007

2009

20 1 1

201 3

F I G U R E 42-1 Percentage of preterm b i rths in the U n ited States accord i n g to method of assessment of gestation a l age. LM P date of last norma l menses. (Ada pted with permission from Martin J A, Osterman MJ, Kirmeyer SE, et al: Measuring gestation a l age in vita l statistics data: tra nsitioning to the o bstetric estimate. Natl Vita l Stat Rep. 201 5 J u n 1 ;64(5 ) : 1 -20.) =

P reterm B i rth

• Trend Factors

Ferre and colleagues (20 1 6) using National Vital Statistics Sys­ tem data showed that the overall reduction of preterm birth before 20 1 4 was in part due to the changes in maternal age dis­ tribution. Speciically, teen birth rates declined. This translated into a drop in preterm birth rates over the same epoch and could explain the lower infant mortality rates (Callaghan, 20 1 7) . One disturbing aspect o f preterm birth rate trends in the United States is persistent racial and ethnic disparities. Rates of preterm birth among black women are markedly elevated above those for white and Hispanic women in every year recorded (Martin, 20 1 7) . Moreover, rates of births before 32 completed weeks in black women are higher than those in white and His­ panic women combined. Some investigators attribute this dis­ parity to socioeconomic circumstances (Collins, 2007; Leveno, 2009) . Internationally, the rates of preterm birth in the United States are also higher compared with those in other indus­ trialized countries (Ananth, 2009; Delnord, 20 1 7; Martin, 20 1 7) . PRETERM N EWBORN MORBIDITY Newborns born before 37 weeks sufer various morbidities, largely due to organ system immaturity (Table 42-2) . hat said, remarkable strides have been made in neonatal survival for those born preterm. his is especially true for neonates born after 28 weeks. In a study of more than 1 8,000 newborns weighing between 400 and 1 500 g or aged between 22 and 32 weeks' gestation, survival rates were analyzed as a func­ tion of both birthweight and gestational age (Fanarof, 2007) . Mter achieving a birthweight of : 1 000 g or a gestational age of 28 weeks for females, or 30 weeks for males, survival rates reach 95 percent.

• Threshold of Viability

Births once considered to be "abortuses" because the fetus weighed < 500 g are now classified as live births. In the United States in 20 1 4 , 5 863 live births < 500 g were recorded (Martin, 20 1 7) . For those newborns delivered before 33 weeks' gesta­ tion, perinatal and neonatal care has advanced tremendously. As a result, the threshold of viability, which is the lower limit of fetal maturation compatible with extrauterine survival, has been reassessed. Currently, the threshold of viability lies between 20 and 26 weeks' gestation. Neonates born in this periviable period have been described as fragile and vulnerable because of their immature organ sys­ tems. Many of these are described in Chapter 34 (p. 639) and include brain injury from hypoxic-ischemic injury and sepsis. In this setting, hypoxia and sepsis start a cascade of events that lead to brain hemorrhage, to white-matter inj ury that causes periventricular leukomalacia, and to poor subsequent brain growth eventuating in neurodevelopmental impairment. Asso­ ciated morbidities include intellectual disability, cerebral palsy, blindness, seizures, and spastic quadriparesis that can result in the need for a lifetime of medical care (Annas, 2004) . Because active brain development normally occurs throughout the sec­ ond and third trimesters, those born < 2 5 weeks are believed to be especially vulnerable to brain injury. To clariY obstetrical care of these fetuses, the Society for Maternal-Fetal Medicine, the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD), the American Academy of Pediatrics, and the American College of Obstetricians and Gynecologists convened a joint workshop in 20 1 3 (Raj u, 20 1 4) . he executive summary statement from this meeting served as the underpinnings for an Obstetric Care Consensus document from the American College of Obstetri­ cians and Gynecologists (20 1 7 e) .

TABLE 42-2. Major Short- a n d Long-Te rm Problems i n Very-Low- B i rthwe i g h t I nfa nts Organ or System

Short-Term Problems

Long-Term Problems

Pu l mona ry

Respi ratory d i stress syndrome, air leak, bronchopul monary dysplasia, a p nea of prematu rity Hyperbi l i ru bi n e m ia, feed i n g i nto l e ra nce, necrotizi ng e nteroco l itis, g rowth fa i l u re Hosp ital-acq u i red i nfection, i m m u n e deficie ncy, peri nata l i n fection I ntrave ntri c u l a r hemorrhage, periventri c u l a r l e u koma lacia, hyd roce p h a l u s Ret i n o pathy o f p rematu rity

B ronchop u l mona ry dyspla sia, reactive a i rway d i sease, a sth m a Fa i l u re t o th rive, s hort-bowel synd rom e, c h o lesta s i s Respi ratory syn cyt i a l virus i nfect i o n , bro n c h i o l i t i s Cerebra l pa l sy, hyd rocep h a l u s, cerebra l atro p hy, n e u rodeve l o p m e nta l d e lay, hea ring loss B l i n d ness, ret i n a l deta c h m e nt, myo pia, stra bi s m u s P u l m o n a ry hypertens ion, hyperte n sion i n a d u lthood Hypertension in a d u lthood

Gastroi ntesti n a l r n utritional I m m u n olog ical Centra l n ervo u s system Ophtha l molog ical Ca rd iova scu l a r Ren a l Hematolog ical Endocrinological

Hypotension, patent d u ctus a rteriosus, p u l monary hypertension Wa te r a nd el ectrolyte i m ba l a n ce, aci d-base d i stu rba nces Iatrog e n i c a ne m ia, need fo r freq u e nt tra n sfu s i ons, a n e m ia of p remat u r ity Hypog lyce m i a , tra n siently low t hyroxi ne leve ls, cortisol deficiency

Data from Eic henwald, 2008.

I m pa i red g l u cose reg u lation, i ncreased i ns u l i n resi sta nce

805

806

Obstetrica l Co m p l ications 1 00

TABLE 42 -3. Outcomes at 2V2 Yea rs Corrected Age by Gestational Age at B i rth in Sweden, 2004-2007

80 E

60

D

40

) o

.

Gestational Age (wk)

• Ishii (20 1 3) • Stoll (20 1 0)

• Rysavy (20 1 5)

20

Outcome

22

23

24

25

26

Total

Liveborn i n fa nts

51

01

1 44

205

206

707

Su rvived to 1 year (%) Per c nt disabledo N o d i sabi l i ty Mild Mod erate Sever e

10

53

67

82

85

70

0 40 20 40

30 19 30 21

34 33 21

44 29

49 34 10 7

42 31

(no. ) o -22

24

23

25

Weeks' gestation

F I G U R E 42-2 Neonatal s u rviva l rates a ccord i n g to condition at b i rth a n d gestation a l age. I s h i i (20 1 3) data c u rve reflects l iveborn s u rviva l rates; Sto l l (20 1 0) c u rve reflects l iveborn s u rviva l rates; Rysavy (20 1 5) c u rve reflects overa l l s u rviva l rates.

Perivi a bl e N eo n ata l S u rviva l

he Obstetric Care Consensus summary provides a review of outcomes for those born in the periviable period. Delivery before 23 weeks typically results in death, and survival rates approximate only 5 percent (Fig. 42-2) . Among those that live, morbidity is nearly universal. Notably, the authors highlight the wide variation in practices regarding active resuscitation and suggest that these variations may explain the difering perinatal outcomes among diferent institutions. An important caveat, however, is ascertainment bias. For example, the mean survival rate is 45 percent if the denominator is all live births compared with 72 percent if the denominator is only newborns admitted to neonatal intensive care (Guillen, 20 1 1 ) . Another source of bias is use of multicenter datasets with considerable diferences in obstetrical and early neonatal interventions, particularly at 22 and 23 weeks' gestation (Stoll, 20 1 0) . T o evaluate contemporaneous outcomes o f neonates born at 22 to 24 weeks, the NICHD Neonatal Research Network reported both survival and neurodevelopmental outcomes assessed across consecutive birth-year epochs of 2000 to 2003, 2004 to 2007, and 2008 to 20 1 1 in infants aged 18 to 22 months (Younge, 20 1 7) . The percentage of infants who survived rose signiicantly from 30 percent in 2000 to 2003 to 36 percent in 2008 to 20 1 1 . he percentage of infants who survived without neurodevelopmental impairment also significantly grew from 1 6 percent to 2 0 percent during the same time period (Fig. 42-3) . Although rates o f survival without neurodevelopmental impair­ ment increased over time among infants born at 23 and • % of infants who died

Epoch 1 (2000 - 2003)

o

20

60 Percent

40

80

1 00

11

C l i n ica l M a n a g ement

he Obstetric Care Consensus document also addresses man­ agement options based on the clinical characteristics of a given pregnancy. Nonmodiiable factors are fetal gender, weight, and plurality. Potentially modifiable antepartum and intrapartum factors include the location of delivery, intent to intervene % of infants who survived without neu rodevelopmental impairment Epoch 3 (2008 - 201 1 )

Epoch 2 (2004 - 2007)

60 Percent

40

16

24 weeks, only 1 percent of infants born at 22 weeks survived without neurodevelopmental impairment (Younge, 20 1 7) . Somewhat similar results were published from Sweden (Serenius, 20 1 3) . his report details a national population­ based prospective study of all neonates born before 27 weeks. Shown in Table 42-3 are the survival and disability rates for 707 Swedish infants born alive from 22 to 26 weeks' gestation between 2004 and 2007 in Sweden. Compared with rates in the United States, rates of survival without neurodevelopmen­ tal impairment were higher in the Swedish cohort for infants born at 24 weeks during 2004 to 2007.

neurodevelopmental impairment

20

17

'1 0

apercentage with d i sa bi l ity at 2 V2 yea rs corrected age. The overa l l rate of d i sa b i l ities i n cl udes perfo rm a n ce on the Bayley III assess m e nts, me nta l deve l op m e nt d e l ay, cerebra l palsy. a n d v i s u a l a n d hea r i n g d i sab i l ities. Data fro m Sere n i u s F, I a l l e n K, B l e n n ow M, et a l : N e u rodevelopmenta l outcome i n extremely p reter m i n fa nts at 2 . 5 yea rs after active perinata l ca re i n Sweden, JAMA 201 3 May 1 ;309( 1 7): '1 8 1 0- 1 820.

• % of infants who su rvived with

o

13

80

1 00

o

20

60 Percent

40

80

1 00

F I G U R E 42-3 Mortal ity a nd neurodevelopmenta l o utcomes at 1 8 to 22 months of corrected age by birth epoch in neonates born at 22 to 24 weeks. (Data from You nge N, Goldstei n RF, Ba n n eM, et a l : Surviva l and neurodevelopmenta l outcomes a mong periviable i nfa nts, N Engl J Med. 20 1 7 Feb 1 6;376(7):6 1 7-628.)

P reterm B i rth

TABLE 42-4. General G u idel i nes for Obstetrical I nterventions for Th reatened and I m m i nent Periv i a b l e Del ivery Neonata l a ssess m e nt for resu scitation Corticostero i d ther a py Magnesi u m s u l fate neu rop rotection Tocolysis Antim icrobia l thera py for P P ROM Cont i n uous EFM GBS prophylaxis Cesa rea n d e l ivery for fetal i nd i cation Agg ressive r es u scitation

4000 g. And, although almost 70 percent of low-birthweight neonates are born preterm, the balance of low-birthweight newborns accounted for approxi­ mately 3 percent of term births in 20 1 5 (Martin, 20 1 7). Between 1 990 and 2006, the proportion of newborns with birthweights < 2500 g grew by more than 20 percent when the rate peaked at 8.3 percent (Martin, 20 1 2) . his trend toward smaller babies has slowed since the mid- to late-2000s and might partly be explained by the concurrent movement toward fewer deliver­ ies prior to 39 weeks' gestation (Richards, 20 1 6) . In contrast, between 1 990 and 2006, the incidence of birthweights >4000 g declined approximately 30 percent to a nadir of 7.6 percent in 20 1 0 (Martin, 20 1 2) . This trend away from the upper extreme is diicult to explain because it coincides with the epidemic preva­ lence of obesity, a known cause of macrosomia (Morisaki, 20 1 3) . F ETAL GROWTH

When inants are of large size and abundant, they may mechanicaly throw out offunction so great a portion ofthe placenta as seriousy to inteere with the nutrition of the oetus, and sometimes cause its death. Excessive development of the oetus can usualy be traced to prolongation ofpreg­ nancy, large size of one or both parents, advancing age, or multipariy of the mother. - J. Whitridge Williams ( 1 903) he concept of excessive or impaired fetal growth was not con­ sidered in detail by Williams in his irst edition. Abnormally diminished fetal growth was attributed to placental lesions and fetal infections. Conversely, a large fetus was of obvious concern because of associated dystocia. Currently, fetal-growth disorders at both ends of the spectrum are major problems in obstetrics. Nearly 20 percent of the almost 4 million neonates born in the United States are at the low and high extremes of fetal growth.

• Pathophysiology

Human fetal growth is characterized by sequential patterns of tissue and organ growth, diferentiation, and maturation. How­ ever, the "obstetrical dilemma" postulates a conlict between the need to walk upright-requiring a narrow pelvis-and the need to think-requiring a large brain, and thus a large head. Some speculate that evolutionary pressures restrict growth late in pregnancy (Mitteroecker, 20 1 6) . Thus, the ability to growth restrict may be adaptive rather than pathological. Fetal growth has been divided into three phases. The initial phase of hyperplasia occurs in the irst 16 weeks and is charac­ terized by a rapid increase in cell number. The second phase, which extends up to 32 weeks' gestation, includes both cellular hyperplasia and hypertrophy. After 32 weeks, fetal mass accrues by cellular hypertrophy, and it is during this phase that most fetal fat and glycogen are accumulated. The corresponding

Feta l-G rowth D i so rd e rs 80

60

§

l 0

5

40

.. c

� 20

e )

0

20

25

30

35

40

45

Gestational age at last ultrasound (weeks) F I G U R E 44-1 I nc rements i n feta l weight g a i n in g ra m s per day from 24 to 42 weeks' gestation. The black l i n e represents the mea n a n d the outer b l u e li nes depict ±2 sta n d a rd deviations. (Data from pregna ncies m a naged at Parkl a n d Hos pita l.)

fetal-growth rates during these three phases are 5 g/d at 1 5 weeks' gestation, 1 5 to 20 g/d at 24 weeks', and 30 to 35 g/d at 34 weeks' (Williams, 1 982). As shown in Figre 44- 1 , the velocity of fetal growth varies considerably. Fetal development is determined by maternal provision of substrate and placental transfer of these, whereas fetal growth potentil is governed by the genome. The precise cellular and molecular mechanisms by which normal fetal growth ensues are incompletely understood. That said, considerable evidence sup­ port an important role for insulin and insulin-like growth factors (IGFs) in regulation offetal growth and weight gain (Luo, 20 1 2) . hese growth factors are produced b y virtually all fetal organs and are potent stimulators of cell division and diferentiation. Other hormones implicated in fetal growth have been iden­ tified, particularly hormones derived from adipose tissue. These hormones are known broadly as adipokines and include leptin, the protein product of the obesiy gene. Fetal leptin concentra­ tions rise during gestation, and they correlate both with birth­ weight and with neonatal fat mass (Brifa, 20 1 5; Logan, 20 1 7; Simpson, 20 1 7) . Other adipokines possibly involved include adiponectin, ghrelin, follistatin, resistin, visfatin, vaspin, omen­ tin- I , apelin, and chemerin. Fetal growth is also dependent on an adequate supply of nutrients. As discussed in Chapter 7 (p. 1 38), both exces­ sive and diminished maternal glucose availability afect fetal growth. Reduced maternal glucose levels may result in a lower birthweight. Still, growth-restricted neonates do not typically show pathologically low glucose concentrations in cord blood (Pardi, 2006) . Fetal-growth restriction in response to glucose deprivation generally results only after long-term severe mater­ nal caloric deprivation (Lechtig, 1 975). Conversely, excessive glycemia produces macrosomia. Vary­ ing levels of glucose afect fetal growth via insulin and its associated IGFs. he Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study Cooperative Research Group (2008) found that elevated cord C-peptide levels, which relect fetal hyperinsulinemia, are associated with greater birthweight. his relationship was noted even in women with maternal glucose

levels below the threshold for diabetes. Overgrowth does occur in the fetuses of euglycemic women. Its etiology is thus likely more complicated than merely dysregulated glucose metabo­ lism (Catalano, 20 1 1 ) . Genetic factors, including genomic imprinting and epigenetic modifi c ations via gene methylation, are also important and emphasize the potential role of inheri­ tance (Begemann, 20 1 5 ; Nawathe, 20 1 6) . Excessive transfer o f lipids may also lead to fetal overgrowth (Higa, 20 1 3) . Free or nonesteriied fatty acids in maternal plasma may be transferred to the fetus via facilitated diusion or ater liberation of fatty acids from triglycerides by trophoblastic lipases (Gil-Sinchez, 20 1 2) . Generally speaking, lipolytic activity is augmented in pregnancy, and fatty acid levels are increased in nonobese women during the third trimester (Diderholm, 2005). Independent of prepregnancy body mass index (BMI), higher free fatty acid levels during the latter half of pregnancy correlate with birthweight (Crume, 20 1 5) . Other studies have correlated mater­ nal triglyceride levels with birthweight (Di Cianni, 2005; Vrijkotte, 20 1 1 ) . Greater intake of certain fatty acids, particularly omega-3, is also associated with greater birthweight (Calabuig-Navarro, 20 1 6) . Placental fatty acid metabolism and transfer may be dys­ regulated in fetal-growth restriction and in maternal conditions associated with fetal overgrowth. For example, levels of endo­ thelial lipase are reduced with deicient fetal growth, and this enzyme is overexpressed in placentas of women with diabetes (Gauster, 2007, 20 1 1 ) . Others have reported that diabetes and obesity are associated with altered placental lipid-transport gene expression (Radaelli, 2009) . Obesity is also linked with greater expression of fatty acid binding/transport proteins within the trophoblast (Myatt, 20 1 6; Scifres, 20 1 1 ) . he end result of these alterations is an abnormal accumulation of lipids that can result in pathological placental inlammation and dysfunction (Calabuig-Navarro, 20 1 6; Myatt, 20 1 6; Yang, 20 1 6) . mino acids undergo active transport, which explains the normally higher fetal concentrations compared with mater­ nal levels. In growth restriction, this pattern is reversed. One possible mechanism is altered transport of these amino acids. Remember, amino acids that reach the fetus must first cross the microvillus membrane at the maternal interface. Amino acids then traverse the trophoblastic cell, and inally cross the basal membrane into fetal blood (Chap. 5, p. 90). In human placentas, fetal growth correlates with peroxisome proliferator activator receptor gamma (PPAR-,) activity, which governs placental regulation of L-type amino acid (AT) receptors 1 and 2 (Chen, 20 1 5b) . Additional modulation is from rap amy­ cin complex (mTORC) 1 and 2 receptors (Rosario, 20 1 3) . Pla­ cental mTORC activity is reduced in fetal-growth restriction. Others have shown that increasing birthweight and maternal BMI are linked to expression and activity of particular amino­ acid transporters at the microvillus membrane (Jansson, 20 1 3) . • Normal Birthweight

Normative data for fetal growth based on birthweight vary with ethnicity and geographic region. Accordingly, researchers have developed fetal-growth curves using various populations and geographic locations throughout the United States (Brenner, 1 976; Ott, 1 993; Overpeck, 1 999; Williams, 1 975) . Because

845

846

Obstetrica l Com p l i cations

TABLE 4-1 . 20 1 1 Gestati o n a l Age B i rthweight (g) Percentiles for 3,252,0 1 1 S i n g leton Live B i rths i n the U n ited States Age (wk)

5th

1 0th

Percentile 50th

90th

95th

24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

539 540 580 650 740 84 1 952 1 080 1 23 2 1 41 4 1 63 2 1 87 1 21 1 7 2353 2564 2737 2863 2934 294 1

567 584 637 71 9 822 939 1 068 1 214 1 380 1 5 73 1 793 2030 2270 2500 2706 2877 3005 3 082 3099

680 765 872 997 '1 1 3 8 '1 2 90 1 45 5 1 63 5 1 83 3 2053 2296 2 549 2 7 97 3025 321 9 3 3 74 3499 3600 3686

850 938 1 080 1 260 1 462 1 672 1 883 2 1 01 233 1 2579 2846 31 1 9 3380 361 2 3 799 3 94 1 4057 4 1 67 4290

988 997 1 1 80 1 46 7 1 78 7 2070 2294 2483 2664 286 1 3093 3 345 3 5 94 381 8 3995 4 1 25 4232 4340 4474

F rom D u ryea, 20 1 4, with perm i ss i o n ,

these curves are based on speciic ethnic or regional groups, they do not represent the entire population. To address this, birthweights such as those shown in Table 4- 1 are derived nationwide in the United States. Shown in Figure 4-2 are growth curves rom more thn 3.2 million mothers with singleton livebon neonates in the United States during 1 99 1 and 201 1

(Duryea, 20 14). hese current curves plot birthweight against a ges­ tational age based on n obsteical estimate, formed in part by sonog­ raphy. hese curves are thought to be more accurate and reflect more precise pregnancy dating. Older curves used gestational age derived rom a last menstrual period. Comparing birthweights rom 1 99 1 to data from 20 1 1 , the more recent growth curves indicate that the earlier assessments overestimated birthweihts in the ase of preterm birth. In particular, the 50th percentile for fetal growth that previ­ ously corresponded to 31 to 32 weeks' gestation now corresponds to 33 to 34 weeks' when improved obstetrical dating is used. The curves by Alexander ( 1 996) and Duryea (20 1 4) and their associates are most accurately termed a population rerence, rather than a standard. A population reference incorporates pregnancies of varying risks, along with the resulting outcomes, both nor­ mal and abnormal. In contrast, a stanard incorporates normal pregnancies with normal outcomes. Because population refer­ ences include preterm births, which are more likely to be growth restricted, it has been argued that the associated birthweight data overestimate deficient fetal growth (Mayer, 20 1 3; Zhang, 20 1 0) . One recent project sought t o define regional standards i n eight countries and was based on data from optimal maternal health and socioeconomic conditions. Growth trajectories from the International Fetal and Newborn Growth Consortium for the 2 1 st Century-INTERGROWTH 2 1 were similar in these eight: China, India, Kenya, Brazil, Oman, Italy, the United Kingdom, and the United States (Villar, 20 1 4) . However, an international standard based on the healthiest women is of questionable value (Hanson, 20 1 5) . • Fetal Growth versus Birthweight

Most of what is known regarding normal and abnormal human fetal growth is actually based on birthweights that are assem­ bled as references for fetal growth at particular gestational ages. his is problematic, however, because birth­ 5,000 weight does not deine the rate of fetal growth. By last menstrual period Indeed, such b irthweight curves reveal comBy obstetrical estimate promised growth only at the extreme of impaired growth. hus, they cannot be used 4,000 to identiy the fetus that fails to achieve an expected size but whose birthweight is above the 1 0th percentile. For example, a fetus with 3,000 . a birthweight in the 40th percentile may not ) have achieved its genomic growth potential .�. for a birthweight in the 80th percentile. : 2,000 m The rate or velociy of fetal growth can be estimated by serial sonographic anthro­ pometry. For example, Milovanovic (20 1 2) 1 ,000 demonstrated that the growth rate of intrinsically small-for-gestational-age (SGA) new­ borns (those below the 1 0th percentile) � o -approximates that of appropriate-for-gesta­ 22 38 24 30 32 34 36 40 26 42 44 28 tional-age neonates. However, diminished Gestational age (weeks) growth velocity may be linked to perinatal F I G U R E 44-2 Fetal-g rowth c u rves for births in the U n ited States i n 20 1 1 . C u rves morbidity and adverse postnatal metabolic va ry depe n d i n g o n whether gestation a l age was ca lcu lated from the last menstrual changes that are independent of birthweight. period o r from a n i m proved obstetrical esti mate, derived i n part using sonog ra phy. Recently, Sovio and colleageus (20 1 5) demon­ (Mod ified with perm ission from Duryea EL, Hawkins JS, Mci ntire DO, et al: A revised strated that growth velocity of the abdominal birth weight reference for the U n ited States. Obstet Gynecol. 20 1 4 J u l ; 1 24(1 ) : 1 6-22.) -

-

�

Feta l-Growth Diso rd e rs

circumference in the lowest decile distinguishes SGA newborns who sufer increased morbidity. Conversely, an excessive fetal­ growth velocity, particularly of the abdominal circumference­ which may be correlated with increased hepatic blood low-is associated with an overgrown neonate (American College of Obstetricians and Gynecologists, 20 1 6a) . Several conditions or disorders can adversely afect the nor­ mal growth of a fetus. It is important clinically to distinguish between fetal-growth restriction and constitutional low birth­ weight. FETAL-G ROWTH RESTRICTION • Definition

Lubchenco and coworkers ( 1 963) published detailed compari­ sons of gestational ages with birthweights to derive norms for expected fetal size at a given gestational week. Battaglia and Lubchenco ( 1 967) then classiied smalor-gestational-age neo­ nates as those whose weights were below the 1 0th percentile for their gestational age. Low-birthweight newborns who are small for gestational age are often designated as having etal­ growth restriction. Such infants were shown to be at increased risk for neonatal death. For example, the mortality rate of SGA neonates born at 38 weeks was 1 percent compared with 0.2 percent in those with appropriate birthweights. Importantly, many neonates with birthweights < 1 0th percen­ tile are not pathologically growth restricted, but instead are small simply because of normal biological factors. s many as 70 per­ cent of such SGA infants have normal outcomes and are thought to be appropriately grown when maternal ethnic group, parity, weight, and height are considered (Unterscheider, 20 1 5) . These small but normal infants also do not show evidence of the postna­ tal metabolic derangements commonly associated with deficient fetal growth. Moreover, intrinsically SGA newborns remain sig­ nificantly smaller during surveillance to 2 years compared with appropriate-for-gestational age neonates, but they do not show diferences in measures of metabolic risk (Milovanovic, 20 1 2) . Because o f these disparities, other classifications have been developed. Usher and McLean ( 1 969) suggested that fetal growth standards should be based on mean weights-for-age, with normal limits deined by ±2 standard deviations. This def­ inition would limit SGA infants to 3 percent of births instead of 1 0 percent. In a population-based analysis of 1 22,754 births at Parkland Hospital, McIntire and colleagues ( 1 999) showed this definition to be clinically meaningful. Also, as shown in Figure 44-3 , most adverse outcomes are in newborns smaller than the 3rd percentile. The importance of this cut-of has been independently confi r med in a prospective study by Unters­ cheider and colleagues (20 1 3a) . More recently, individual or customized fetal-growth poten­ tial is proposed to replace a population-based threshold. In this model, a fetus that deviates from its individual optimal size at a given gestational age is considered either overgrown or growth restricted (Chiossi, 20 1 7) . Such optimal projections are based on maternal race or ethnicity. But, the superiority of custom­ ized growth curves has not been established (Chiossi, 20 1 7; Costantine, 20 1 3; Grobman, 20 1 3; Zhang, 20 1 1 ) .

C ) )

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-

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70

30

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1 50

80

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u

1 75

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10 > 10 10 9

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FIGURE 44-3 Relationship between birthweight percentile a nd peri nata l morta l ity and morbid ity rates in 1 560 smal l-for-gestational­ age fetuses. A prog ressive increase i n both morta l ity a nd morbid ity rates is observed as birthweight percenti le decreases .. (Data from Man ning, 1 995.)

• Symmetrical versus Asymmetrical

G rowth Restriction

Campbell and Thoms ( 1 977) described the use of the sono­ graphically determined head-to-abdomen circumerence ratio (HCIA) to diferentiate growth-restricted fetuses. Those who were symmetrical were proportionately small, and those who were asymmetrical had disproportionately lagging abdominal growth compared with head growth. The onset or etiology of a particular fetal insult is hypothetically linked to either type of growth restriction. In the instance of symmetrical growth restric­ tion, an early insult could result in a relative decrease i n cell number and size. For example, early global insults such as those from chemical exposure, viral infection, or cellular maldevelop­ ment with aneuploidy may cause a proportionate reduction of both head and body size. Asymmetrical growth restriction m ight follow a later pregnancy insult such as placental insuiciency from hypertension. In this variation, resultant diminished glu­ cose transfer and hepatic storage would primarily afect cell size and not number. Thereby, fetal abdominal circumference­ which relects liver size-would be reduced. B ra i n S pa r i n g

Such somatic growth restriction is proposed to result from pref­ erential shunting of oxygen and nutrients to the brain. This allows normal brain and head growth, that is-brain spa ring. Accordingly, the ratio of brain weight to liver weight during the last 1 2 weeks-usually about 3 to I-may be increased to 5 to 1 or more in severely growth-restricted infants. Because of b rain­ sparing efects, asymmetrical fetuses were thought to be pref­ erentially protected from the full efects of growth restriction. Considerable evidence has since accrued that fetal growth patterns are much more complex. For example, fetuses with

847

848

Obstetrica l Co m pl ications

aneuploidy typically have disproportionately large head sizes and thus are asymmetricaLy growth restricted, which is contrary to contemporaneous thinking (Nicolaides, 1 99 1 ) . Moreover, most preterm neonates with growth restriction due to pre­ eclampsia and associated utero placental insuiciency are found to have more symmetrical growth impairment-again, a depar­ ture from accepted principles (Salaia, 1 995) . More evidence of the complexity of growth patterns was presented by Dashe and associates (2000) . These investigators analyzed 8722 consecutive liveborn singletons who had under­ gone sonographic examination within 4 weeks of delivery. Although only 20 percent of growth-restricted fetuses demon­ strated sonographic head-to-abdomen asymmetry, these fetuses were at greater risk for intrapartum and neonatal complications. Symmetrically growth-restricted fetuses were not at increased risk for adverse outcomes compared with those appropriately grown. These investigators concluded that asymmetrical fetal­ growth restriction represented signiicantly disordered growth, whereas symmetrical growth restriction more likely represented normal, genetically determined small stature. Other data further challenge the concept of brain sparing. Roza and associates (2008) found that fetuses with circula­ tory redistribution-brain sparing-had a higher incidence of later behavioral problems. In another study, evidence of brain sparing was found in half of 62 growth-restricted fetuses with birthweights < 1 0th percentile and who showed abnormal middle cerebral artery Doppler low studies (Figueras, 2 0 1 1 ) . Compared with controls, these neonates had significantly lower neurobehavioral scores in multiple areas, suggesting profound brain injury. Zhu and coworkers (20 1 6) prospectively com­ pared late-onset growth restriction in 1 4 fetuses with that in 26 non-growth-restricted fetuses using magnetic resonance imag­ ing to analyze hemodynamic flow. Despite the concept of brain sparing, growth-restricted infants had significantly smaller brains than controls. he complex efects of such insults-with respect to timing and severity-on brain structure, connectiv­ ity, and neurobehavioral outcomes have been recently reviewed by Miller and colleagues (20 1 6) . • Placental Abnormal ities

Fetal-growth restriction is one of the "major obstetrical syn­ dromes" associated with defects in early placentation (Brosens, 20 1 5) . Rogers and coworkers ( 1 999) concluded that implan­ tation-site disorders may be both a cause and consequence of hypoperfusion at the placental site. This comports with the asso­ ciation of certain placental angiogenic factors with pregnancy hypertensive disorders (Chap. 40, p. 7 1 6) . Thus, it may be that placentas from pregnancies complicated by hypertension elabo­ rate these angiogenic factors in response to placental-site hypo­ perfusion, whereas pregnancies complicated by fetal-growth restriction without hypertension do not Qeyabalan, 2008) . Mechanisms leading to abnormal trophoblastic invasion are likely multifactorial, and both vascular and immunologi­ cal etiologies have been proposed. For example, atriaL natri­ uretic peptide converting enzyme, also known as corin, plays a critical role in trophoblastic invasion and remodeling of the uterine spiral arteries (Cui, 20 1 2) . hese processes are impaired

in corin-deficient mice, which also develop evidence of pre­ eclampsia. Moreover, mutations in the gene for corin have been reported in women with preeclampsia (Chen, 20 1 5a) . Several immunological abnormalities are associated with fetal­ growth restriction. This raises the prospect of maternal rejection of the " paternal semiallograft." Rudzinski and colleagues (20 1 3) studied C4d, a component of complement that is associated with humoral rejection of transplanted tissues. They found this to be highly associated with chronic villitis-88 percent of cases versus only 5 percent of controls-and with reduced placen­ tal weight. In a study of 1 0,204 placentas, chronic villitis was associated with placental hypoperfusion, fetal acidemia, and fetal-growth restriction and its sequelae (Greer, 20 1 2) . im and coworkers (20 1 5) extensively reviewed chronic inflammatory placental lesions and their association with fetal-growth restric­ tion, preeclampsia, and preterm birth. • Perinatal Morbidity and Mortality

Several short-term and long-term adverse sequelae are linked with fetal-growth restriction. First, perinatal morbidity and mortality rates are substantive (see Fig. 44-3) . Rates of stillbirth and adverse neonatal outcomes that include birth asphyxia, meconium aspiration, hypoglycemia, and hypothermia are all increased, as is the prevalence of abnormal neurological develop­ ment. This is true for both term and preterm growth-restricted newborns. In one analysis of nearly 3000 newborns born before 27 weeks' gestation, those weighing < 1 0th percentile had a nearly fourfold higher risk of neonatal death or neurodevel­ opmental impairment and a 2.6-fold increased risk of cerebral palsy compared with non-SGA neonates (De Jesus, 20 1 3) . In another analysis of more than 9 1 ,000 uncomplicated pregnan­ cies, newborns with weights < 5th percentile had a higher risk of low 5-minute Apgar score, respiratory distress, necrotizing enterocolitis, and neonatal sepsis than appropriate-weight neo­ nates. The risks of stillbirth and neonatal death were sixfold and fourfold higher, respectively .\1endez-Figueroa, 20 1 6) . The most severely growth-impaired newborns also have the worst outcomes. In one study of more that 44,561 neonates, only 14 percent of those weighing < 1 st percentile at birth survived to discharge (Griin, 20 1 5) . For those infants who survive, the risks of adverse neurodevelopmental outcomes are substantial, especially for growth-impaired fetuses with either brain sparing or a major birth defect (Meher, 20 1 5 ; Nelson, 2 0 1 5b) . Poor motor, cognitive, language and attention, and behavioral outcomes in growth-restricted newborns unfortu­ nately persist into early childhood and adolescence (Baschat, 20 1 4; Levine, 20 1 5 ; Rogne, 20 1 5) . • Long-Term Sequelae Feta l U n derg rowth

Barker ( 1 992) hypothesized that aduLt mortality and morbid­ ity are related to fetal and infant health. This includes both under- and overgrowth. In the context of fetal-growth restric­ tion, numerous reports describe a relationship between subop­ timal fetal nutrition and an increased risk of subsequent adult hypertension, atherosclerosis, type 2 diabetes, and metabolic

Feta l-G rowth D i s o rd e rs

derangement (Burton, 20 1 6; J ornayvaz, 20 1 6) . he degree to which low birthweight mediates adult disease is controversial, as weight gain in early life also appears important (Breij , 20 1 4; Kerhof, 20 1 2; McCloskey, 20 1 6) . Mounting evidence suggests that fetal-growth restriction may afect organ development, particularly that of the heart. Indi­ viduals with low birthweight demonstrate cardiac structural changes and dysfunction persisting through childhood, adoles­ cence, and adulthood. In one study, 80 infants who were born SGA before 34 weeks' gestation were compared at 6 months with 80 normally grown children (Cruz-Lemini, 20 1 6) . The heart in the SGA children had a more globular ventricle that resulted in systolic and diastolic dysfunction. In another study, echocardiog­ raphy in 4 1 8 adolescents showed that low birthweight was asso­ ciated with a thicker let ventricular posterior wall (Hietalampi, 20 1 2) . In their review, Cohen and colleagues (20 1 6) concluded, however, that these findings have unclear long-term signiicance. Deficient fetal growth is also associated with postnatal structural and functional renal changes. In a review by Luyckx and Brenner (20 1 5) , birthweight abnormalities were evaluated for linkage with disordered nephrogenesis, renal dysfunction, chronic kidney disease, and hypertension. Both low and high birthweight, as well as maternal obesity and gestational diabe­ tes, afect in-utero development of the kidney and its health into adulthood. However, other variables that include child­ hood nutrition, acute kidney injury, excessive childhood weight gain, and obesity also worsen long-term renal function. Feta l Overg rowth

Particularly in women with diabetes and elevated cord blood levels of IGF- 1 , fetal overgrowth is associated with greater neonatal fat mass and morphological heart changes. Pedersen ( 1 9 54) irst proposed that hyperglycemia leads to fetal hyperin­ sulinemia and fetal overgrowth. This has been extended to organ dysmorphia, for example, increased interventricular septal thick­ ness in neonates of mothers with gestational diabetes (nan, 20 1 1 ; Garcia-Flores, 20 1 1 ) . he cardiopulmonary vasculature is also adversely afected by diabetes in pregnancy. In 3277 cases of persistent pulmonary hypertension of the newborn (PPHN) , maternal obesity, diabetes, and both deficient and excessive fetal growth were independent risk factors (Steurer, 20 1 7) . Long­ term consequences of fetal overgrowth from obesity and dia­ betes are discussed in Chapters 48 (p. 94 1 ) and 57 (p. 1 097) . • Accelerated Lung Maturation

Numerous reports have described accelerated fetal pulmonary maturation in complicated pregnancies associated with growth restriction (Perelman, 1 985). One possible explanation is that the fetus responds to a stressed environment by augmenting adre­ nal glucocorticoid secretion, which leads to accelerated fetal lung maturation (Laatikainen, 1 988). Although this concept pervades modern perinatal thining, evidence to support it is negligible. To examine this hypothesis, Owen and associates ( 1 990) analyzed perinatal outcomes in 1 78 women delivered because of hypertension. hey compared these with outcomes in new­ borns of 1 59 women delivered because of spontaneous preterm labor or ruptured membranes. They concluded that a "stressed"

pregnancy did not confer an appreciable survival advantage. Similar findings were described by Friedman and colleagues ( 1 995) in women with severe preeclampsia. Two studies from Parkland Hospital also substantiate that the preterm infant accrues no apparent advantages from fetal-growth restriction (McIntire, 1 999; Tyson, 1 99 5 ) . • Risk Factors a n d Etiologies

Risk factors for impaired fetal growth include potential abnor­ malities in the mother, fetus, and placenta. hese three "com­ partments" are depicted in Figure 44-4 . Some of these factors are known causes of fetal-growth restriction and may afect more than one compartment. For instance, cytomegalovirus infections can afect the fetus directly. In contrast, bacterial infections such as tuberculosis may have signiicant maternal efects that lead to poor fetal growth. Similarly, malaria, a pro­ tozoal infection, is a recognized cause of fetal-growth restric­ tion (Briand, 20 1 6) . Importantly, many causes of diminished fetal growth are prospectively considered risk factors, because impaired fetal growth is not consistent in all afected women. C o n stitutiona l ly S ma l l Mothers

It is axiomatic that small women typically have smaller new­ borns. As discussed subsequently, both prepregnancy weight and gestational weight gain modulate this risk. Durie and colleagues (20 1 1 ) showed that the risk of delivering an SGA neonate was highest among underweight women who gained less weight than recommended by the Institute of Medicine (Chap. 9, p. 1 66) . Also, both maternal and paternal size inlu­ ences birthweight. In a Swedish study of 1 37,538 term births, it was estimated that the maternal and paternal birthweights explained 6 and 3 percent of variance in birthweight, respec­ tively (Mattsson, 20 1 3) . Gestatio n a l Wei g h t G a i n a nd N u t rition

In the study by Durie (20 1 1 ) cited above, gestational weight gain during the second and third trimesters that was less than

/

Woma n

Poor gestational weight gain Constitutionally small Poor nutrition Social deprivation Eating disorders

Fetal malformations

Infection

Maternal medical conditions

Genetic abnormalities or multifetal gestation

Placental or cord abnormalities

Placenta

F I G U R E 44-4 Risk factors and causes of i m pa i red feta l g rowth centeri n g on the mother, her fetus, a n d the placenta .

849

850

O bstetrical Com pl ications

that recommended by the Institute of Medicine was associated with SGA neonates in women of all weight categories except class II or III obesity. Conversely, excessive gestational weight gain was associated with an overgrown newborn in all weight categories (Blackwell, 20 1 6) . As perhaps expected, eating disorders are linked with signifi­ cantly higher risks for low birthweight and preterm birth (Micali, 20 1 6) . Marked weight gain restriction ater midpregnancy should not be encouraged even in obese women (Chap. 48, p. 94 1 ) . Even so, it appears that food restriction to < 1 500 kcal/d adversely afects fetal growth minimally (Lechtig, 1 975) . The best documented efect of famine on fetal growth was in the Hunger Winter of 1 944 in Holland. For 6 months, the Ger­ man occupation army restricted dietary intake to 500 kcal/d for civilians, including pregnant women. This resulted in an average birthweight decline of only 250 g (Stein, 1 975) . It is unclear whether undernourished women may beneit from micronutrient supplementation. In one study, almost 32,000 Indonesian women were randomly assigned to receive micronutrient supplementation or only iron and folate tablets (Prado, 20 1 2) . Ofspring of those receiving the supplement had lower risks of early infant mortality and low birthweight and had improved childhood motor and cognitive abilities. Con­ versely, Liu and coworkers (20 1 3) randomly assigned 1 8,775 nulliparas to folic acid alone; folic acid and iron; or folic acid, iron, and 1 3 other micronutrients. Folic acid and iron, with or without the additional micro nutrients, resulted in a 30-per­ cent reduction in risk of third-trimester anemia. But, supple­ mentation did not afect other maternal or neonatal outcomes. A Cochrane database review of 1 9 trials involving 1 38,538 women concluded that supplementation of iron and folic acid improved birth outcomes, including lower risks of low birth­ weight and SGA (Haider, 20 1 7) . he importance of antena­ tal vitamins and trace metals is further discussed in Chapter 9 (p. 1 68) . Exercise in pregnancy may be beneficial for optimal fetal growth. One metaanalysis of 28 studies involving 5322 women concluded that exercise reduces the risk of fetal overgrowth without raising the risk of poor growth (Wiebe, 20 1 5) . Another metaanalysis concluded that aerobic exercise did not result in low-birthweight neonates (Di Mascio, 20 1 6) . Soc i a l I ssues

The efect of social deprivation on birthweight is intercon­ nected with lifestyle factors such as smoking, alcohol or other substance abuse, and poor nutrition. With appropriate modiy­ ing interventions, women with psychosocial factors were sig­ niicantly less likely to deliver a low-birthweight infant and also had fewer preterm births and other pregnancy complications (Coker, 20 1 2) . Women who are immigrants may be a t particular risk for poor fetal growth. In one study of 56,443 singleton pregnancies in Rotterdam, social deprivation was associated with adverse perinatal outcomes that included SGA newborns (Poeran, 20 1 3) . That said, a similar linkage was not found in socially deprived women of non-Western origin. The efect of immi­ gration, however, is complex and dependent on the population studied (Howell, 20 1 7; Sanchez-Vaznaugh, 20 1 6) .

Va s c u l a r a n d Ren a l D i sease

Especially when complicated by superimposed preeclampsia, chronic vascular disease commonly causes growth restriction (Chap. 50, p. 980) . In a study of more than 2000 women, vascular disease as evidenced by abnormal uterine artery Dop­ pler velocimetry early in pregnancy was associated with higher rates of preeclampsia, SGA neonates, and delivery before 34 weeks (Groom, 2009). Using Washington state birth certii­ cate data, Leary and colleagues (20 1 2) found that maternal isch­ emic heart disease was linked to SGA infants in 25 percent of 1 86 births. Roos-Hesselink and coworkers (20 1 3) described similar pregnancy outcomes in 25 women with ischemic heart disease. Chronic renal insuiciency is frequently associated with underlying hypertension and vascular disease. Nephropathies are commonly accompanied by restricted fetal growth (Cun­ ningham, 1 990; Feng, 20 1 5; Saliem, 20 1 6) . hese relation­ ships are considered further in Chapter 53 (p. 1 034) . Preg estatio n a l D i a betes

Fetal-growth restriction in the newborns of women with diabetes may be related to congenital malformations or may follow substrate deprivation from advanced maternal vascular disease (Chap. 57, p. 1 1 00). Also, the likelihood of restricted growth increases with worsening White classification, particularly nephropathy (Klemetti, 20 1 6) . hat said, the prevalence of serious vascular disease associ­ ated with diabetes in pregnancy is low, and the primary efect of overt diabetes, especially type 1 , is fetal overrowth. For example, in a prospective study of 682 consecutive pregnancies complicated by diabetes, women with type 1 diabetes were significantly more likely than women with type 2 diabetes to have a neonate weighing above the 90th and 97.7th percentiles (Murphy, 20 1 1). Addition­ ally, women with type 1 diabetes were significantly less likely to deliver an SGA newborn. In a recent study of 375 term single­ ton pregnancies complicated by type 1 diabetes, the risk of fetal overgrowth correlated with rising third-trimester glycemic values (Cyganek, 20 1 7) . Nearly a fourth of neonates were macrosomic. And, third-trimester hemoglobin Al c and fasting glucose values were independent predictors for the risk of macrosomia. C h ro n i c H ypoxia

Conditions associated with chronic uteroplacental hypoxia include preeclampsia, chronic hypertension, asthma, mater­ nal cyanotic heart disease, smoking, and high altitude. When exposed to a chronically hypoxic environment, some fetuses have signiicantly reduced birthweight. In more than 1 .8 million births in Austria, the birthweight declined 1 50 g for each 1 000meter rise in altitude (Waldhoer, 20 1 5). In 63,620 Peruvian live births, the mean birthweight was significantly decreased at higher compared with lower altitudes-3065 g ± 475 g versus 3280 g ± 525 g (Gonzales, 2009) . In this study, the rate of birth weights < 2500 g was 6.2 percent at low altitudes, and it was 9.2 percent at high altitudes. In contrast, the rate of birthweights >4000 g was 6.3 percent at low altitudes and 1 .6 percent at high altitudes. Anemia

In most cases, maternal anemia does not restrict fetal growth. Exceptions include sickle-cell disease and some other inherited anemias (Desai, 20 1 7; Thame, 20 1 6) . Importantly, curtailed

F eta l-Growth Disorders

maternal blood-volume expansion is linked to fetal-growth restriction (de Haas, 20 1 7; Stott, 20 1 7) . This is further dis­ cussed in Chapter 40 (p. 7 1 8) . Anti p h o s p h o l i p i d Syn d ro m e

Adverse obstetrical outcomes including fetal-growth restric­ tion have been associated with three species of antiphospho­ lipid antibodies: anticardiolipin antibodies, lupus anticoagulant, and anti-32 gycoprotein-I antibodies. Mechanistically, a "wo­ hit" hypothesis suggests that initial endothelial damage is then followed by intervillous placental thrombosis. More specifi­ cally, oxidative damage to certain membrane proteins such as 32 glycoprotein-I is followed by antiphospholipid antibody binding, which leads to immune complex formation and ulti­ mately to thrombosis (Giannakopoulos, 20 1 3) . his syndrome is considered in detail in Chapters 52 (p. 1 008) and 59 (p. 1 1 43) . Pregnancy outcomes in women with these antibodies may be poor and include fetal-growth restriction and fetal demise (Cer­ vera, 20 1 5) . he primary autoantibody that predicts obstetrical antiphospholipid syndrome appears to be lupus anticoagulant (Yelnik, 20 1 6) . I nfert i l ity

It is controversial whether pregnancies in women with prior infertility with or without treatment have an increased risk of SGA newborns (Zhu, 2007) . Dickey and colleagues (20 1 6) compared birthweight curves for singletons conceived by in vitro fertilization to the birthweight curves of Duryea (20 1 4) , described o n page 846. hey found n o reduction i n fetal growth. Kondapalli and Perales-Puchalt (20 1 3) reviewed pos­ sible links between low birthweight and infertility with its vari­ ous interventions and concluded that any association remains unexplained for singletons. P l a ce nta l , Cord, a n d Uteri ne A b n o r m a l ities

Several placental abnormalities may cause poor fetal growth. These are discussed further throughout Chapter 6 and include chronic placental abruption, extensive infarction, chorioangi­ oma, velamentous cord insertion, placenta previa, and umbili­ cal artery thrombosis. Growth failure in these cases is presumed secondary to uteroplacental insuiciency. Abnormal placental implantation leading to endothelial dysfunction may also limit fetal growth (Brosens, 20 1 5) . This pathology is implicated in pregnancies complicated by preeclampsia (Chap. 40, p. 7 1 4) . If the placenta is implanted outside the uterus, the fetus is usu­ ally growth restricted (Chap. 1 9, p. 383) . Finally, some uter­ ine malformations have been linked to impaired fetal growth (Chap. 3, p. 44) . M u ltifeta l Gestation

Pregnancy with two or more fetuses is more likely to be compli­ cated by diminished growth of one or more fetuses compared with that of normal singletons. This is illustrated in Figure 44-5 and discussed in Chapter 45 (p. 872) . Dru g s with Te ratogenic a n d Feta l Effects

Several drugs and chemicals are capable oflimiting fetal growth. Some are teratogenic and afect the fetus before organogenesis is

4000

Singletons

3500

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: ) '5 � :: ::

s

3000 2500 2000 1 500 1 000 500 0

20

40 25 30 35 Gestational age at d e l ivey (weeks)

45

F I G U R E 44-5 B i rthweight a n d gestatio n a l age relationships i n m u ltifeta l g estations without m a lformations del ivered a t Pa r k l a nd Hospita l .

complete. Some exert-or continue to exert-fetal efects after embryogenesis ends at 8 weeks. Many of these are considered in detail in Chapter 1 2, and examples include anticonvulsants and antineoplastic agents. Cigarette smoking, opiates and related drugs, alcohol, and cocaine may also cause growth restriction, either primarily or by decreasing maternal food intake. he link with cafeine use and fetal-growth restriction remains specu­ lative (American College of Obstetricians and Gynecologists, 20 1 6b) . In contrast, Cyganek and colleagues (20 1 4) studied growth restriction in pregnancies complicated by renal and liver transplants and concluded that common immunosup­ pressive drugs-prednisone, azathioprine, cyclosporine A, and tacrolimus-did not significantly afect fetal-growth rates. Mate rn a l a n d Feta l I nfections

Viral, bacterial, protozoan, and spirochetal infections have been implicated in up to 5 percent of fetal-growth restriction cases and are discussed throughout Chapters 64 and 65. The best known of these are rubela and cytomegalovirus inection. Both promote calcifications in the fetus that are associated with cell death, and infection earlier in pregnancy correlates with worse outcomes. Toda and colleagues (20 1 5) described a Vietnamese epidemic in which 39 percent of 292 term newborns with con­ genital rubella syndrome were low birthweight. In one study of 238 primary cytomegalovirus infections, no severe cases were observed when infection occurred after 14 weeks' gestation (Picone, 20 1 3) . hese investigators later identified sonographic findings in 30 of 69 cases of congenital infection, and growth restriction was noted in 30 percent of these 30 cases (Picone, 20 14). Tuberculosis and syphilis have also both been associated with poor fetal growth. Both extrapulmonary and pulmonary tuber­ culosis are linked with low birthweight (Chap. 5 1 , p. 995) . Sobhy (20 1 7) analyzed 1 3 studies that included a total of 3384 women with active tuberculosis. The odds ratio was 1 .7 for low birthweight. The etiology is uncertain, however, the adverse efects on maternal health, compounded by efects of poor nutrition and poverty, are important Gana, 20 1 2) . Congenital syphilis is more common, and paradoxically, the placenta is almost always larger and heavier due to edema and perivascular

85 1

852

O bstetrical Com p l i cations

inflammation (Chap. 65, p. 1 237) . Congenital syphilis is strongly linked with preterm birth and thus low-birthweight newborns (Sheield, 2002) . Toxoplasma gondii can also cause congenital infection, and Paquet and Yudin (20 1 3) describe its classic association with fetal-growth restriction. Capobiango (20 1 4) described 3 1 Bra­ zilian pregnancies complicated by congenital toxoplasmosis. Only 1 3 percent were treated antepartum for toxoplasmosis, and low birthweight complicated nearly 40 percent of all the pregnancies. Congenital maaria also causes low birthweight and poor fetal growth. Briand and colleagues (20 1 6) emphasize the importance of prophylaxis early in pregnancy for women at risk. Co n g e n ita l M a lformations

In a study of more than 1 3,000 fetuses with major structural anomalies, 22 percent had accompanying growth restriction (Khoury, 1 988). In one study of 1 1 1 pregnancies complicated by fetal gastroschisis, a third had birthweights < 1 0th percentile (Nelson, 20 1 5a) . As a general rule, the more severe the malfor­ mation, the more likely it is that the fetus will be SGA. This is especially evident in fetuses with chromosomal abnormalities or those with serious cardiovascular malformations. C h ro m osoma l A n e u p l o i d ies

Depending on which chromosome is redundant, fetuses with autosomal trisomies may display poor fetal growth. For exam­ ple, in trisomy 21, fetal-growth restriction is generally mild. By contrast, fetal growth in trisomy 18 is virtually always signifi­ cantly limited. he crown-rump length in fetuses with trisomy 1 8 and 1 3 , unlike that with trisomy 2 1 , is typically shorter than expected (Bahado-Singh, 1 997; Schemmer, 1 997) . By the second trimester, long-bone measurements usually are below the 3rd percentile. In one group of 1 74 children with trisomy 1 3, the mean birthweight with trisomy 1 3 was 2500 g, and in 254 children with trisomy 1 8, it was 1 800 g (Nelson, 20 1 6) . Poor fetal growth also complicates Turner syndrome, and the severity correlates with increasing haploinsuiciency of the short arm of the X chromosome (Fiot, 20 1 6) . In contrast, poor growth is not characteristic of an increased number of X chromosomes (Ottesen, 20 1 0; Wigby, 20 1 6) . As discussed in Chapter 1 3 (p. 263), aneuploidic patches in the placenta­ conined placental mosaicism (CPM)-is a recognized cause of fetal-growth restriction. Evidence suggests that aneuploidy afecting both the cytotrophoblast and mesenchymal core of the placenta, which is type 3 CPM, is associated with fetal­ growth restriction (Toutain, 20 1 0) . First-trimester prenatal programs that screen for fetal aneu­ ploidy ' may incidentally identiy pregnancies at risk for fetal­ growth restriction unrelated to karyotype. In their analysis of 80 1 2 women, the risk for growth restriction was higher in eukaryotic fetuses with extremely low free 3-human chori­ onic gonadotropin (3-hCG) and pregnancy-associated plasma protein-A (PAPP-A) levels (Krantz, 2004) . From her review, Dugof (20 1 0) concluded that a low PAPP-A level is strongly associated with poor fetal growth, but studies of free 3-hCG are conflicting. Second-trimester analytes, including elevated alpha-fetopro­ tein and inhibin A levels and low unconjugated serum estriol

concentrations, are significantly associated with birthweight below the 5th percentile. An even greater risk of poor growth is linked with certain combinations of these analytes. Still, these markers are poor screening tools for complications such as fetal­ growth restriction due to low sensitivity and positive-predictive values (Dugof, 20 1 0) . Nuchal translucency is also not predic­ tive of fetal-growth restriction. he role of all these markers in aneuploidy screening is discussed in Chapter 1 4 (p. 28 1 ) . • Fetal-Growth Restriction Recognition

Identification of the inappropriately growing fetus remains a challenge. Eary establishment of gestational age, ascertainment of maternal weight gain, and careful measurement of uterine fundal growth throughout pregnancy will identiy many cases of abnormal fetal growth in low-risk women. Risk factors, including a prior growth-restrictedetus, raise the recurrence risk to nearly 20 percent (American College of Obstetricians and Gynecologists, 2 0 1 5). In women with risk factors, serial sono­ graphic evaluation is considered. Although examination fre­ quency varies depending on indications, an initial early dating examination followed by an examination at 32 to 34 weeks, or when otherwise clinically indicated, will identiy many growth­ restricted fetuses. Even so, deinitive diagnosis frequently cannot be made until delivery. U te r i n e Fu n d a l H e ig ht

According to one systematic review, insuicient evidence sup­ ports the utility of fundal height measurement to detect fetal­ growth restriction (Robert Peter, 20 1 5). Nonetheless, carefully performed serial fundal height measurements are recommended as a simple, safe, inexpensive, and reasonably accurate screening method to detect growth-restricted fetuses. As a screening tool, its principal drawback is imprecision. Haragan and coworkers (20 1 5) reported sensitivities of 7 1 and 43 percent for detect­ ing excessive or deficient fetal growth. Specificities were 85 and 66 percent, respectively. he method used by most for fundal height measurement is described in Chapter 9 (p. 1 64) . Between 1 8 and 30 weeks' gestation, the uterine fundal height in centimeters coincides within 2 weeks of gestational age. Thus, if the measurement is more than 2 to 3 cm from the expected height, inappropriate fetal growth is suspected and sonography is considered. Sonogra p h i c M ea s u re m e n t

One supporting point for routine sonographic evaluation of all pregnancies is the opportunity to diagnose growth restric­ tion. Typically, such routine screening incorporates an early initial sonographic examination-usually at 1 6 to 20 weeks' gestation. Increasingly, a first-trimester examination is added to establish gestational age and identiy anomalies. Some then recommend repeat sonographic evaluation at 32 to 34 weeks to evaluate fetal growth. First-trimester sonography has limited accuracy to predict SGA newborns. For example, Croverro and associates (20 1 7) reported detection rates of 35 and 42 percent with false-posi­ tive rates of 5 and 10 percent, respectively. From nearly 9000 screened pregnancies, Tuuli and colleagues (20 1 1 ) concluded

Feta l-G rowth Disorders 7000 6000 : 5000 n

'5 � 4000

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2

3000

) i E 2000

J

;

w

1 000 O ---� o 1 000 2000 3000 4000 5000 6000 7000

Birthweight (g)

F I G U R E 44-6 Correl ation of sonog ra ph i c feta l wei g ht esti mation u s i ng a bd o m i n a l circu mference (A C) a nd actual birthweig ht. (Data from p reg n a ncies ma naged at Pa rkla nd Hos pita l.)

that second-trimester sonography is superior to first-trimester scans for predicting SGA neonates. At Parkland Hospital, we provide midpregnancy sonographic screening examination of all pregnancies. Additional sonographic evaluations of fetal growth are performed as clinically indicated. With sonography, the most common method for identiy­ ing poor fetal growth is estimation of weight using multiple fetal biometrical measurements. Combining head, abdomen, and femur dimensions provides optimum accuracy, whereas little incremental improvement is gained by adding other biometrical measurements (Platz, 2008) . Of the dimensions, femur length measurement is technically the easiest and the most reproducible. Biparietal diameter and head circumference measurements are dependent on the plane of section and may also be afected by deformative pressures on the skull. Last, abdominal circumference measurements are more variable. However, these are most frequently abnormal with fetal-growth restriction because soft tissue predominates in this dimension ( Fig. 44-6) . Shown in Figure 44-7 is an example of a severely growth-restricted newborn. Some studies have reported a significant predictive value for small abdominal circumference with respect to lagging fetal growth. One study screened nearly 4000 pregnancies using either clinically indicated or universal sonography in the third trimester (Sovio, 20 1 5) . Universal sonography raised the rate of detection of SGA from 20 percent to 57 percent. Importantly, however, the neonatal morbidity rate was increased only if the abdominal circumference growth velocity was in the lowest decile. Sonographic estimates of fetal weight and actual weight may be discordant by 20 percent or more, leading to both false-pos­ itive and false-negative indings. Dashe and associates (2000) studied 8400 live births at Parkland Hospital in which fetal sonographic evaluation had been performed within 4 weeks of delivery. They reported that 30 percent of growth-restricted fetuses were not detected. In a study of 2 5 86 women with low-risk pregnancies randomly assigned to sonography at 32 or 36 weeks' gestation, sensitivity to identiy grow restriction was improved at the later gestational age (Roma, 20 1 5) . Still, nearly

F I G U R E 44-7 A 3 6-week newborn with severe fetal-g rowth restriction. (U sed with permission from Dr. Rox a n e Holt.)

40 percent of cases of growth restriction deined as birthweight 8 em in one sac and oligohydramnios defined by a largest vertical pocket < 2 em in the other twin is found. Only 1 5 percent of pregnancies complicated by lesser degrees of luid imbalance progress to TTTS (Huber, 2006) . Although growth discordance or growth restriction may be found with TTTS, these per se are not considered diagnostic criteria. Organizations that include the American College of Obste­ tricians and Gynecologists (20 1 6) , Society for Maternal-Fetal Medicine (20 1 3) , and North American Fetal herapy Network (Emery, 20 1 5) recommend sonography surveillance of pregnan­ cies at risk for TTTS. To aid earlier identification of amnionic luid abnormalities and other complications of monochorionic twins, these examinations begin at approximately 16 weeks' gestation, and subsequent studies are considered every 2 weeks. Once identiied, TTTS is typically classiied by the Quintero ( 1 999) staging system (Fig. 4 5-2 1 ) : •

•

•

• •

Stage I-discordant amnionic fluid volumes as described in the earlier paragraph, but urine is still visible sonographically within the bladder of the donor twin Stage II-criteria of stage I, but urine is not visible within the donor bladder Stage III-criteria of stage II and abnormal Doppler studies of the umbilical artery, ductus venosus, or umbilical vein Stage IV-ascites or frank hydrops in either twin Stage V-demise of either fetus.

In addition to these criteria, evidence suggests that cardiac function of the recipient twin correlates with fetal outcome (Crombleholme, 2007) . Although fetal echocardiographic ind­ ings are not part of the Quintero staging system, many centers routinely perform fetal echocardiography for TTTS. heo­ retically, earlier diagnosis of cardiomyopathy in the recipient twin may identiy pregnancies that would beneit from early

intervention. One system for evaluating cardiac function-the myocardial peormance index (MPI) or Tei index-is a Dop­ pler index of ventricular function calculated for each ventricle (Michelfelder, 2007) . lthough scoring systems that include assessment of cardiac function have been developed, their usefulness to predict outcomes remains controversial (Society for Maternal-Fetal Medicine, 20 1 3) . Ma nagement and Prog nosis. h e prognosis for mulrifetal gestations complicated by TTTS is related to Quintero stage and gestational age at presentation. More than three fourths of stage I cases have been reported to remain stable or regress without intervention. Conversely, outcomes in those identi­ ied at stage III or higher are much worse, and the perinatal loss rate is 70 to 1 00 percent without intervention (Society for Maternal-Fetal Medicine, 20 1 3) . At Parkland Hospital, among expectantly managed pregnancies with TTTS, most had early disease at diagnosis, and 50 percent of stage I cases progressed (Duryea, 2 0 1 6) . Several therapies are available for TTTS and include amnio­ reduction, laser ablation of vascular placental anastomoses, selective feticide, and septosromy. Described further in Chap­ ter 1 1 (p. 230), amnioreduction describes needle drainage of excess amnionic fluid. Septostomy is intentionally creating a hole in the dividing amnionic membrane but has largely been abandoned as treatment (Society for Maternal-Fetal Medicine, 20 1 3) . Comparative data from randomized trials for some of these other techniques are discussed below. The Eurofetus trial included 1 42 women with severe TTTS diagnosed before 26 weeks. Participants were randomly assigned to laser ablation of vascular anastomoses or to serial amniore­ duction (Senat, 2004) . A higher survival rate to age 6 months for at least one twin was found in pregnancies undergoing laser ablation-76 versus 5 1 percent, respectively. Moreover, analyses of randomized studies confirm better neonatal outcomes with laser therapy compared with selective amnioreduction (Roberts, 2008; Rossi, 2008, 2009) . In contrast, Crombleholme and asso­ ciates (2007) , in a randomized trial of 42 women, found equiva­ lent rates of 30-day survival of one or both twins treated with either amnioreduction or selective fetoscopic laser ablation-75 versus 65 percent, respectively. Furthermore, evaluation of

FIGURE 45-21 A. Sonog ram of stage I ms at 1 9 weeks' gestation. Oligohyd ra m nios in the donor twi n sac ca uses the mem bra n e to essentia l ly wra p around the "stuck twi n " and suspend it from the a nterior uteri ne wa l l . B. In this same preg na n cy, hyd ra m n ios is seen in the reci pient twi n sac. The mea s u red pocket exceeds 1 0 cm. C. Stage I I ms i n a donor twi n at 1 7 weeks' gestation . Color Doppler high lig hts the a rteries that outl i n e the feta l bladder, which conta i ns no urine.

879

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Obstetrica l Com pl ications

twins from the Eurofetus trial through 6 years of age did not demonstrate an additional survival benefit beyond 6 months or improved neurological outcomes in those treated with laser (Salomon, 20 1 0) . At this time, laser ablation of anastomoses is preferred for severe TTTS (stages II-IV) . Optimal therapy for stage I disease is controversial. After laser therapy, close ongoing surveillance is necessary. Robyr and colleagues (2006) reported that a fourth of 1 0 1 pregnancies treated with laser required additional invasive ther­ apy because of either recurrent TTTS, or middle cerebral artery (MCA) Doppler evidence of anemia or polycythemia. Recently, in a comparison of selective laser ablation of individual anas­ tomoses versus ablation of the entire surface of the chorionic plate along the vascular equator, Baschat and coworkers (20 1 3) found that equatorial photocoagulation reduced the likelihood of recurrence. Selective fetal reduction has generally been considered if severe amnionic luid and growth disturbances develop before 20 weeks. In such cases, both fetuses typically will die without intervention. Any substance injected into one twin may afect the other twin because of shared circulations. hus, for the fetus chosen for reduction, feticidal techniques include methods that occlude the umbilical vein or umbilical cord of using radiofre­ quency ablation, fetoscopic ligation, or coagulation with laser, monopolar, or bipolar energy (Challis, 1 999; Chang, 2009; Parra-Cordero, 20 1 6) . Even after these procedures, however, the risks to the remaining fetus are still appreciable (Rossi, 2009) . This topic is further discussed on page 89 1 . Twi n A n e m ia-Po lycythe m i a Seq u e n ce

This form of chronic fetofetal transfusion, referred to as TAPS, is characterized by significant hemoglobin diferences between donor and recipient twins. However, TAPS lacks the discrep­ ancies in amnionic luid volumes typical of TTTS (Slaghekke, 20 1 0) . It is diagnosed ante natally by M CA peak systolic veloc­ ity (PSV) > 1 . 5 multiples of the median (MoM) in the donor and < 1 .0 MoM in the recipient twin (Society for Maternal­ Fetal Medicine, 20 1 3) . The spontaneous form of TAPS report­ edly complicates 3 to 5 percent of monochorionic pregnancies, and it occurs in up to 1 3 percent of pregnancies after laser photocoagulation of the placenta. Spontaneous TAPS usually occurs after 26 weeks' gestation, and iatrogenic TAPS develops within 5 weeks of a procedure (Lewi, 20 1 3) . Although a staging system has been proposed by Slaghekke and colleagues (20 1 0) , further studies are necessary t o better elucidate the natural his­ tory of TAPS and its management. In brief, evidence of fetal compromise or greater diferences in MCA PSV between twins raise the stage. Twi n Reversed -A rterial- Perfu s i on Seq u e n ce

lso known as an acardiac twin, this is a rare but serious com­ plication of monochorionic multifetal gestation. n estimated incidence is 1 case in 35,000 births. In the classic twin reversed­ arterial-perfusion (TRAP) sequence, there is a normally formed donor twin that shows features of heart failure and a recipient twin that lacks a heart (acardius) and other structures. In one theory, the TRAP sequence is caused by a large artery-to-artery placental shunt, often also accompanied by a vein-to-vein shunt

F I G U R E 45-22 Twi n reversed-a rteria l-pe rfusion seq uence. In the TRAP seq uence, there is u s u a l ly a norm a l ly formed donor twi n that has featu res of heart fa i l u re, a n d a reci pient twi n that lac ks a heart. It has been hypothesized that the TRAP seq uence is caused by a l a rg e a rtery-to-artery placenta l s h u nt, often a l so accompanied by a vei n-to-vei n s h u nt. With i n the si ng le, sha red placenta, perfusion pressure of the donor twi n overpowers that i n the reci pient twi n , w h o thus receives reverse blood fl ow from i t s twi n s i b l i ng. The "used" a rterial b lood that reaches the recipient twi n preferenti a l ly goes to its i l iac vessels a n d thus perfuses o n ly the lower body. This disrupts g rowth a nd development of the u pper body.

(Fig. 4 5-22) . Within the single, shared placenta, arterial perfu­ sion pressure of the donor twin exceeds that in the recipient twin, who thus receives reverse blood low containing deoxy­ genated arterial blood from its cotwin (Lewi, 20 1 3) . his "used" arterial blood reaches the recipient twin through its umbilical arteries and preferentially goes to its iliac vessels. Thus, only the lower body is perfused, and therefore disrupted growth and development of the upper body results. In these cases, failed head growth is called acardius acephalus; a partially developed head with identifiable limbs is called acardius myelacephalus; and failure of any recognizable structure to form is acardius amorphous, which is shown in Figure 45-23 (Faye-Petersen, 2006) . Because of this vascular connection, the normal donor twin must not only support its own circulation but also pump blood through the underdeveloped acardiac recipient. This may lead to cardiomegaly and high-output heart failure in the nor­ mal twin (Fox, 2007) . In the past, the mortality rate among the pump twins exceeded 50 percent. This stemmed largely from complications of prematurity or from a prolonged high-output state leading to cardiac failure (Dashe, 200 1 ) . Risk appears to be directly related to size of the acardiac twin. One sonographic method to estimate acardiac twin size uses the volume of an ellipse: length X width X height x \/6. When the acardiac twin volume is < 50 percent of that of the pump twin, expectant management may be reasonable given the inherent risks of fetal interven­ tion (Chap. 1 5, p. 326) (Jelin, 20 1 0) . When the volume of the

M u ltifeta l Preg n a n cy

Diagnosis is usually made in the first half of pregnancy. Sonographically, a normal-appearing twin is accompanied by its cotwin, which is a large placenta containing multiple small anechoic cysts (Fig. 20-4, p. 3 9 1 ) . Often, these pregnancies are terminated, but pregnancy continuation is increasingly adopted. First, the pregnancy prognosis is not as poor as pre­ viously thought, and live birth rates range between 20 and 40 percent (Dolapcioglu, 2009; McNamara, 20 1 6) . Second, the risk of persistent trophoblastic disease is similar whether the pregnancy is terminated or not (Massardier, 2009; Sebire, 2002) . That said, given the limited number of cases, robust data for irm recommendations are lacking. Importantly, com­ plications of expectant management include vaginal bleeding, hyperemesis gravidarum, thyrotoxicosis, and early-onset pre­ eclampsia (McNamara, 20 1 6) . Many of these complications result in preterm birth with its attendant adverse perinatal sequelae as well as perinatal loss. Logically, close surveillance is needed for those continuing the pregnancy. FIGURE 45-23 Photog ra p h of an a ca rdiac twi n weig h i n g 475 g ra ms. The u nderd eveloped h ead i s i n d i cated by the black a rrow, and its d eta i l s a re shown in the i n set. A yel l ow c l a m p is seen on its u m b i l ica l cord. Its via ble donor cotwin wa s delivered vag i n a l ly at 36 weeks a nd weighed 2325 g ra m s. (Used with perm ission from Dr. M ichael D. H nat.)

acardiac twin is large, however, treatment has generally been ofered. Radiofrequency ablation (RFA) is the preferred modal­ ity of therapy, and contemporary reports now suggest improved perinatal outcomes. he North American Fetal Therapy Net­ work reviewed their experiences with 98 cases from 1 998 to 2008 in which RFA of the umbilical cord was performed (Lee, 20 1 3) . Median gestational age at delivery was 37 weeks, and 80 percent of neonates survived (Lee, 20 l 3) . he average ges­ tational age at the time of the RFA was 20 weeks, and the estimated acardius-to-pump twin volume on average was 90 percent. Major complications were prematurely ruptured mem­ branes and preterm birth. Interestingly, TRAP sequences can also occur within mono­ amnionic pregnancies. he perinatal outcomes of such pregnan­ cies appear to be worse than that of monochorionic diamnionic cases. Sugibayashi and associates (20 1 6) in a review of 40 cases recently reported that pump twin survival following RFA was 88 percent in monochorionic diamnionic pregnancies but only 67 percent in monoamnionic pregnancies. • Hydatidiform Mole with Coexisting

Normal Fetus

his unique gestation contains one normal fetus, and its cotwin is a complete molar pregnancy. Reported prevalence rates range from 1 in 22,000 to 1 in 1 00,000 pregnancies (Dolapcioglu, 2009) . It must be diferentiated from a partial molar pregnancy, in which an anomalous singleton fetus­ usually triploid-is accompanied by molar tissue (Fig. 20-4, p. 39 1 ) . At times, a twin pregnancy may occur with a normal twin in one sac and a partial mole in the other sac (McN amara, 20 1 6) .

DISCORDANT GROWTH OF TWI N F ETUSES Fetal size inequality develops in approximately 1 5 percent of twin gestations and may relect pathological growth restric­ tion in one fetus (Lewi, 20 1 3; Miller, 20 1 2) . Generally, as the weight diference within a twin pair rises, the perinatal mortality rate increases proportionately. If it develops, restricted growth of one twin fetus, often termed selective etal-growth restriction, usually develops late in the second and early third trimester. Earlier discordancy indicates higher risk for fetal demise in the smaller twin. Speciically, when discordant growth is identified before 20 weeks, fetal death occurs in approximately 20 percent of the growth-restricted fetuses (Lewi, 20 1 3) . • Etiopathogenesis

he cause of birthweight inequality in twin fetuses is often unclear, but the etiology in monochorionic twins likely difers from that in dichorionic twins. Because the single placenta is not always equally shared in monochorionic twins, these twins have greater rates of discordant growth outside of TTTS than dichorionic twins. Discordancy in monochorionic twins is usually attributed to placental vascular anastomoses that cause hemodynamic imbalance between the twins. Reduced pressure and perfusion of the donor twin can cause diminished placental and fetal growth. Even so, unequal placental sharing is prob­ ably the most important determinant of discordant growth in monochorionic twins (Lewi, 20 1 3) . Occasionally, monochori­ onic twins are discordant in size because they are discordant for structural anomalies. Discordancy in dichorionic twins may result from various factors. Dizygotic fetuses may have diferent genetic growth potential, especially if they are of opposite genders. Second, because the placentas are separate and require more implanta­ tion space, one placenta might have a suboptimal implantation site. Bagchi and associates (2006) observed that the incidence of severe discordancy is twice as great in triplets as it is in twins. This fi n ding lends credence to the view that in utero crowding is a factor in multifetal growth restriction. Placental pathology

88 1

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O bstetrica l Com pl ications

may play a role as well. In one study of 668 twin placentas, a strong relationship between histological placental abnormalities and birthweight discordancy was observed in dichorionic, but not monochorionic, twin pregnancies (Kent, 20 1 2) . • Diagnosis

Size discordancy between twins can be determined sonographi­ cally. hat said, diferences in crown-rump length are not reliable predictors for birthweight discordance (Miller, 20 1 2) . hus, most begin surveillance for discordancy ater the first trimester. One common method uses sonographic fetal biom­ etry to compute an estimated weight for each twin (Chap. 1 0, p. 1 84) . The weight of the smaller twin is then compared with that of the larger twin. hus, percent discordancy is calculated as the weight of the larger twin minus the weight of the smaller twin, then divided by the weight of the larger twin. Alterna­ tively, given that abdominal circumference (AC) relects fetal nutrition, some use the sonographic AC value of each twin. With these methods, some diagnose selective fetal-growth restriction if the AC measurements difer more than 20 mm or if the estimated fetal weight diference is 20 percent or more. That said, several diferent weight disparities between twins have been used to deine discordancy. Accumulated data sug­ gest that weight discordancy greater than 25 to 30 percent most accurately predicts an adverse perinatal outcome. At Parkland, Hollier and coworkers ( 1 999) retrospectively evaluated 1 370 delivered twin pairs and stratiied twin weight discordancy in 5-percent increments within a range of 1 5 to 40 percent. They found that the incidence of respiratory distress syndrome, intraventricular hemorrhage, seizures, periventricular leukoma­ lacia, sepsis, and necrotizing enterocolitis rose directly with the degree of weight discordancy. Rates of these conditions grew substantially if discordancy exceeded 25 percent. The relative risk of fetal death increased significantly to 5.6 if discordancy was more than 30 percent and rose to 1 8.9 if it was greater than 40 percent. • Management

Seria l Sonogra phy

Sonographic monitoring of twin growth has become a mainstay in management. Monochorionic twins are generally monitored more frequently. his is because their risk of death is higher-3.6 percent versus 1 . 1 percent-and the risk of neurological dam­ age in the surviving twin is substantial compared with those risks in dichorionic twins (Hillman, 20 1 1 ; Lee, 2008) . Thorson and colleagues (20 1 1 ) retrospectively analyzed 1 08 monochori­ onic twin pregnancies and found that a sonographic evaluation interval > 2 weeks was associated with a higher Quintero stage at the time of TTTS diagnosis. hese indings have led some to recommend serial sonographic examination every 2 weeks in monochorionic twins (Simpson, 20 1 3; Society for Maternal­ Fetal Medicine, 20 1 3) . However, there have been no random­ ized trials of the optimal frequency of sonographic surveillance in monochorionic twin pregnancies. At Parkland Hospital, monochorionic twins undergo sonographic evaluation to assess interval growth every 4 weeks. In addition, a specific ultrasound

examination to search for TTTS is completed at each interven­ ing 2-week mark between these sonograms. For dichorionic pregnancies, a recent report suggests that sonographic evaluation every 2 weeks would identiY more abnormalities prompting delivery (Corcoran, 20 1 5) . It has yet to be determined if this practice would improve perinatal out­ comes. At our institution, dichorionic twins are sonographi­ cally evaluated every 6 weeks. Feta l S u rve i l l a n ce

Depending on the degree of discordancy and the gestational age, fetal surveillance may be indicated, especially if one or both fetuses exhibit restricted growth. Nonstress testing, biophysical profi l e, and umbilical artery Doppler assessment have all been recommended in the management of twins. However, none has been assessed in appropriately sized prospective trials (Miller, 20 1 2) . If discordancy i s identiied i n a monochorionic twin preg­ nancy, umbilical artery Doppler studies in the smaller fetus may help guide management (Gratac6s, 2007) . Namely, inves­ tigators have correlated umbilical artery Doppler results with placental indings and with the degree of selective fetal-growth restriction to predict fetal outcome (Gratac6s, 20 1 2) . hese correlations have yielded categories of selective fetal-growth restriction. Type I is characterized by positive end-diastolic low, a smaller degree of weight discordance, and a relatively benign clinical course. Type II displays persistently absent end-diastolic fl o w in the smaller twin and carries a high risk of deterioration and demise. Type III is intermittently absent or reversed end-diastolic fl o w. Because of large artery-to-artery anastomoses associated with the placentas in this category, type III is associated with a lower risk of deterioration than type II. In all evaluated cases, unequally shared placenta was noted to some degree. With uncomplicated dichorionic multifetal gestations, use of antepartum surveillance has not improved perinatal out­ comes. In sum, the American College of Obstetricians and Gynecologists (20 1 6) recommends that antepartum testing be performed in multi fetal gestations for indications similar to those for singleton fetuses (Chap. 1 7, p. 33 1 ) . At Parkland, all women with twin discordancy : 2 5 percent undergo daily monitoring as an inpatient. Data are limited to establish the optimal timing of delivery of twins for size discor­ dancy alone. For those at advanced gestational ages, delivery can be pursued. F ETAL DEMISE • Death of One Fetus

At any time during multifetal pregnancy, one or more fetuses may die, either simultaneously or sequentially. Causes and inci­ dence of fetal death are related to zygosity, chorionicity, and growth concordance. In some pregnancies, one fetus dies remote from term, but pregnancy continues with one or more live fetuses. When this occurs early in pregnancy, it may manifest as a vanish­ ing twin, discussed on page 87 1 . In a slightly more advanced

M u ltifeta l Preg n a n cy

FIGURE 45-24 This fetus pa pyraceus is a ta n ovoid mass com­ pressed agai nst the feta l membranes. Anatomical pa rts can be identified a s m a rked. Demise of this twi n had been noted d u ri n g so nogra phic exa m i n ation performed at 1 7 weeks' g estation. Its via b l e cotwin del ivered at 40 weeks. (U sed with perm ission from Dr. Michael V. Za retsky.)

gestation, fetal death may go undetected until delivery. In this case, delivery of a normal newborn is followed by expulsion of a dead fetus that is barely identiiable. It may be compressed appreciably-'tus compressus, or it may be lattened remarkably through desiccation-'tus papyraceus (Fig. 45-24) . As shown i n Figure 4 5-2 5 , the risk o f stillbirth i s related to gestational age in all twins but is much higher for monochori­ onic twin pregnancies before 32 weeks' gestation. In a review of 9822 twin pregnancies, Morikawa and associates (20 1 2) reported that 2 . 5 percent of monochorionic diamnionic twins

30 §

9 = c

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Monochorionic diamnionic Dichorionic diamnionic

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o 22 24 26 28 30 32 34 36 38 Gestational week

FIGURE 45-25 P rospective risk of sti l l bi rth among women who reached a g iven gestational week (per 1 000 women). (Reproduced with permission from Morikawa M, Yamada 1, Ya mada T, et a l : P ro­ spective risk of sti l l b i rth: monochorionic d i a m n iotic twi n s vs d icho­ rion ic twi ns, J Peri nat Med. 2 0 1 2 J a n 1 0;40(3):245-249.)

greater than 22 weeks had a death of one or both twins. This compared with 1 .2 percent of dichorionic twins. In this same review, women with monochorionic diamnionic twins who lost one twin were 16 times more likely to experience death of the cotwin than women with dichorionic twins who lost one twin. Other investigations have found similar trends (Danon, 20 1 3; Hillman, 20 1 1 ; Mahony, 20 1 1 ) . Other factors that afect the prognosis for the surviving twin include gestational age at the time of the demise and duration between the demise and delivery of the surviving twin. With a vanishing twin, the risk of death after the irst trimester is not increased for the survivor. However, when a fetus dies in the second trimester or later, the efect of gestational age at the time of death and the mortality risk to the cotwin are less clear. In an analysis by Hillman and colleagues (20 1 1 ) , cotwin demise rates were unafected regardless of whether the irst death occurred at 1 3 to 27 weeks' gestation or at 28 to 34 weeks. In cases with the death of one twin after the irst trimester, however, the odds of spontaneous and iatrogenic preterm delivery of the remain­ ing living twin were increased (Hillman, 20 1 1 ) . Preterm birth was ive times more likely in monochorionic twin gestations complicated by demise of one twin between 28 and 33 weeks' gestation. If the fetus died after 34 weeks, preterm delivery rates were similar. The neurological prognosis for a surviving cotwin depends almost exclusively on chorionicity. In their comprehensive review, Ong and coworkers (2006) found an 1 8-percent rate of neurological abnormality in twins with monochorionic placen­ tation compared with only 1 percent in those with dichorionic placentation. In another review, in twin pregnancies compli­ cated by a single fetal demise before 34 weeks, a ivefold higher risk of neurodevelopmental morbidity was identiied in mono­ chorionic twins compared with dichorionic twins. If the one fetus died after 34 weeks, the likelihood of neurological deicits was essentially the same between monochorionic and dichori­ onic twin pregnancies (Hillman, 20 1 1 ) . Later i n gestation, the death o f one o f multiple fetuses could theoretically trigger coagulation defects in the mother. Only a few cases of maternal coagulopathy after a single fetal death in a twin pregnancy have been reported. This is probably because the surviving twin is usually delivered within a few weeks of the demise (Eddib, 2006) . That said, we have observed transient, spontaneously corrected consumptive coagulopathy in multi­ fetal gestations in which one fetus died and was retained in utero along with its surviving twin. he plasma ibrinogen con­ centration initially decreased b ut then increased spontaneously, and the level of serum ibrinogen-ibrin degradation products increased initially but then returned to normal levels. At deliv­ ery, the portions of the placenta that supplied the living fetus appeared normal. In contrast, the part that had once provided for the dead fetus was the site of massive ibrin deposition . M a n a gement

Decisions should be based on gestational age, the cause of death, and the risk to the surviving fetus. First-trimester losses require no additional surveillance for this speciic indication. If the loss occurs after the irst trimester, the risk of death or dam­ age to the survivor is largely limited to monochorionic twin

883

884

Obstetrical Com pl ications

gestations. Morbidity in the monochorionic twin survivor is almost always due to vascular anastomoses, which often cause the demise of one twin followed by sudden hypotension in the other (p. 878) . For this reason, if one fetus of a monochorionic twin gestation dies ater the first trimester but before viability, pregnancy termination can be considered (Blickstein, 20 1 3) . Occasionally, death o f one but not all fetuses results from a maternal complication such as diabetic ketoacidosis or severe preeclampsia with abruption. Pregnancy management is based on the diagnosis and the status of both the mother and sur­ viving fetus. If the death of one dichorionic twin is due to a discordant congenital anomaly in the irst trimester, it should not afect the surviving twin. S ingle fetal death during the late second and early third trimesters presents the greatest risk to the surviving twin. Although the risks of subsequent death or neurological dam­ age to the survivor are comparatively higher for monochori­ onic twins at this gestational age, the risk of preterm birth is equally increased in mono- and dichorionic twins (Ong, 2006) . Delivery generally occurs within 3 weeks of diagnosis of fetal demise, thus antenatal corticosteroids for survivor lung matu­ rity should be considered (Blickstein, 20 1 3) . Regardless, unless the intrauterine environment is hostile, the goal is to prolong the preterm pregnancy. Timing of elective delivery after conservative management of a late second- or early third-trimester single fetal death is debatable. Dichorionic twins can probably be safely delivered at term. Monochorionic twin gestations are more diicult to manage and are often delivered between 34 and 37 weeks' ges­ tation (Blickstein, 20 1 3) . In cases of single fetal death at term, especially when the etiology is unclear, most opt for delivery instead of expectant management. The American College of Obstetricians and Gynecologists (20 1 6) also endorse an indi­ vidualized approach to such cases. • I m pending Death of One Fetus

During antepartum surveillance tests of well-being, abnormal results in one twin, but not the other, pose a particular dilemma. Delivery may be the best option for the compromised fetus yet may result in death from immaturity of the cotwin. If fetal lung maturity is conirmed, salvage of both the healthy fetus and its jeopardized sibling is possible. Unfortunately, ideal manage­ ment if twins are immature is problematic but should be based on the chances of intact survival for both fetuses. Often the compromised fetus is severely growth restricted or anomalous. Thus, performing amniocentesis for fetal chromosomal analysis in women of advanced maternal age carrying twin pregnancies is advantageous, even for those who would continue their preg­ nancies regardless of the diagnosis. Chromosomal abnormality identification in one fetus allows rational decisions regarding interventions. PRENATAL CARE With prenatal management of multifetal pregnancy, primary goals aim to prevent or interdict complications as they develop. A major imperative is to prevent preterm delivery of markedly

immature neonates. At Parkland Hospital, women with multi­ fetal gestations are seen every 2 weeks beginning at 22 weeks' gestation. A digital cervical examination is performed at each visit to screen for cervical shortening or dilation. Identification of other unique complications discussed earlier may also lead to interventions including admission or early delivery. • Diet

long with more frequent prenatal VISItS, the maternal diet should provide additional requirements for calories, protein, minerals, vitamins, and essential fatty acids. he Institute of Medicine (2009) recommends a 37- to 54-lb weight gain for women with twins and a normal BMI. In their review, Good­ night and Newman (2009) endorse supplementation of micro­ nutrients such as calcium, magnesium, zinc, and vitamins C, D, and E. his is based on upper intake levels from the Food and Nutrition Board of the Institute of Medicine. he daily recommended augmented caloric intake for women with twins is 40 to 45 kcal/kg/d. Diets contain 20 percent protein, 40 per­ cent carbohydrate, and 40 percent fat divided into three meals and three snacks daily. • Sonography

As noted earlier (p. 882), serial sonographic examinations are usually performed throughout the third trimester to search for abnormal fetal growth and assess amnionic fluid volume. Asso­ ciated oligohydramnios may indicate utero placental pathology and should prompt further evaluation of fetal well-being. That said, quantiYing amnionic luid volume in multifetal gesta­ tion is sometimes diicult. Some measure the deepest vertical pocket in each sac or assess the luid subjectively. Magann and coworkers (2000) compared subjective assessment and several objective methods of assessing amnionic fluid volume in 23 sets of twins. They found all methods to be equally poor in predict­ ing abnormal volumes in diamnionic wins. At Parkland Hos­ pital, the single deepest vertical pocket is measured in each sac. A measurement < 2 em is considered oligohydramnios, and a measurement > 8 cm is considered hydramnios (Duryea, 20 1 7; Hernandez, 20 1 2) . • Antepartum Fetal Surveillance

Of surveillance methods, the nons tress test or biophysical pro­ file is often selected for twin or higher-order multifetal gesta­ tions. Because of the complex complications associated with these gestations and the potential technical diiculties in dif­ ferentiating fetuses during antepartum testing, the usefulness of these methods appears limited. According to DeVoe (2008) , the few exclusive studies of nonstress testing in twins suggest that the method performs the same as in singleton pregnancies. Elliott and Finberg ( 1 995) used the biophysical profile as the primary method for monitoring higher-order multifetal gestations. They reported that four of 24 monitored pregnan­ cies had a poor outcome despite reassuring biophysical proile scores. Although biophysical testing is commonly performed in multifetal gestations, there are insuicient data to determine its eicacy (DeVoe, 2008) .

Similar indings have been reported with the addition of umbilical artery Doppler velocimetry in twins with concordant growth. For example, when umbilical artery Doppler velocime­ try was added to management compared with fetal testing based on fetal-growth parameters alone in the absence of growth dis­ cordance, perinatal outcomes were not improved (Giles, 2003) . Likewise, Hack and associates (2008) investigated the utility of umbilical artery Doppler velocimetry in 67 uncomplicated monochorionic twin gestations and did not ind diferences in mortality rates using pulsatility indices of the umbilical artery. All testing schemes have high false-positive rates in single­ tons, and data suggest that testing in multifetal gestations per­ forms no better. In cases of abnormal testing in one twin and normal results in another, iatrogenic preterm delivery remains a major concern. Options are similar to those described in the management of impending fetal death (p. 884) . PRETERM BIRTH Preterm labor is common in multifetal pregnancies and may complicate up to 50 percent of twin, 75 percent of triplet, and 90 percent of quadruplet pregnancies (Elliott, 2007) . Similar to singleton preterm labor, intraamnionic infection is docu­ mented in approximately one third of twin pregnancy cases (Oh, 20 1 7) . I n twins, the proportion o f preterm births varies widely from 40 to 70 percent (Giufre, 20 1 2) . For example, black women have disparately higher risks for preterm delivery (Grant, 20 1 7) . • Prediction of Preterm Birth

A major goal of multi fetal prenatal care is accurate prediction of women likely to experience preterm delivery. Within the past decade, cervical length has been shown to be a potent pre­ dictor of preterm labor and delivery. To and associates (2006) so no graphically measured cervical length in 1 1 63 twin preg­ nancies at 22 to 24 weeks' gestation. Rates of preterm delivery before 32 weeks were 66 percent in those with cervical lengths of 1 0 mm; 24 percent for lengths of 20 mm; and only 1 percent for 40 mm. In one review, Conde-Agudelo and coworkers (20 1 0) concluded that a cervical length < 20 mm was most accurate for predicting birth before 34 weeks, with a speciicity of 97 percent and positive likelihood ratio of 9.0. Kindinger and colleagues (20 1 6) noted that prediction depended on both cervical length and gestational age at ascertainment. One study compared serial cervical length measurements with a single midgestation measurement. hese authors found that multiple assessments were more accurate to determine the risk of pre term twin birth in asymptomatic women (Melamed, 20 1 6a) . In another study, a change in cervical length :0.2 cm identified pregnancies at risk for delivery before 35 weeks (Moroz, 20 1 7) . Interestingly, a closed internal os by digital examination was found to be as predictive of postponed deliv­ ery as was the combination of a normal sonographically mea­ sured cervical length and negative fetal fibronectin test result (McMahon, 2002) . Unfortunately, cervical length assessment in twin pregnancies has not been associated with improved outcomes (Gordon, 20 1 6) .

• Prevention of Preterm Birth

M u ltifeta l P reg n a n cy

Several schemes have been evaluated to prevent preterm labor and delivery. In recent years, some have been shown to decrease the risk of preterm delivery, but only in subgroups of singleton pregnancies. In general, most have been disappointingly inef­ fective for both singleton and multifetal pregnancies (American College of Obstetricians and Gynecologists, 20 1 6) . Bed Rest

The bulk of evidence suggests that routine hospitalization does not prolong multifetal pregnancy. In one metaanaly­ sis, the practice did not reduce the risk of preterm birth or perinatal mortality (Crowther, 2 0 1 0) . At Parkland Hospital, elective hospitalization was compared with outpatient manage­ ment, and no advantages were found (Andrews, 1 99 1 ) . I mpor­ tantly, however, almost half of women managed as outpatients required admission for specifi c indications such as hypertension or threatened preterm delivery. Limited physical activity, early work leave, more frequent health-care visits and sonographic examinations, and structured maternal education regarding preterm delivery risks have been advocated to reduce pre term birth rates in women with mul­ tiple fetuses. However, little evidence suggests that these mea­ sures substantially change outcome. Pro p hylactiC Toco lys i s

his has not been studied extensively in multifetl pregnancies. In one review of prophylactic oral beta-mimetic therapy that included 374 twin pregnancies, treatment did not reduce the rate of twins delivering before 37 or before 34 weeks' gestation (Ymasmit, 20 1 5) . In light of the Food and Drug Administration warning against the use of oral terbutaline because of maternal side efects, the prophylactic use of beta-mimetic drugs in multi­ fetal gestations seems unwarranted. I ntra m uscu l a r Prog este ro n e Thera py

lthough somewhat efective in reducing recurrent preterm birth in women with a singleton pregnancy, weekly injections of 1 7 alpha-hydroxyprogesterone caproate ( 1 7-OHP-C) are not efec­ tive for multifetal gestations (Caritis, 2009; Rouse, 2007) . hese results were corroborated in a randomized trial of 240 twin preg­ nancies (Combs, 20 1 1 ) . Moreover, women carrying twins and having a cervical length < 36 mm (25th percentile) did not ben­ eit despite their greater risk for preterm birth (Durnwald, 2 0 1 0) . Senat and colleagues (20 1 3) assigned 1 65 asymptomatic women with twins and a cervical length or = 30 weeks. Am J Obstet Gynecol 1 74( 1 Pt 1 ) :66, 1 996 Kim HS, Kim MK, Oh JW, et al : Placental transfer of dexamethasone in twin pregnancy compared to singleton pregnancy. Abstract No. 662. Am J Obstet GynecoI 2 1 6 ( 1 ) :S388, 20 1 7 Kim JH, Park SW, Lee JJ: Birth weight reference for triples i n Korea. J Korean Med Sci 25:900, 20 1 0 Kindinger LM, Poon LC, Cacciatore S , e t al: h e efect o n gestational age and cervical length measurements in the prediction of spontaneous preterm birth in twin pregnancies: an individual patient level meta-analysis. BJOG 1 23 (6) :877, 20 1 6 Klein K , Rode L , Nicolaides KH, e t al: Vaginal micronized progesterone and risk of preterm delivery in high-risk twin pregnancies: secondary analysis of a placebo-controlled randomized trial and meta-analysis. Ultrasound Obstet Gynecol 38(3):28 1 , 20 1 1 Knox G, Morley 0 : Twinning in Yoruba women. J Obstet Gynaecol Br Emp 67:98 1 , 1 960 Kuleva M, Youssef A, Maroni E, et al: Maternal cardiac unction in normal twin pregnancy: a longitudinal study. Ultrasound Obstet Gynecol 38:575, 20 1 1 Kulkarni AD, Jamieson DJ, Jones HW ]r, et al: Fertility treatments and mul­ tiple births in the United States. N Engl J Med 369(23):22 1 8, 20 1 3 Langer B , Boudier E , Gasser B , e t al: Antenatal diagnosis o f brain damage in the survivor after the second trimester death of a monochorionic monoam­ niotic co-twin: case report and literature review. Fetal Diagn her 1 2:286, 1 997 Lantieri T, Revelli A, Gaglioti P, et al: Superfetation after ovulation induction and intrauterine insemination performed during an unknown ectopic preg­ nancy. Reprod Biomed Online 20(5) :664, 20 1 0 Lappen JR, Hackney ON, Bailit J L: Maternal and neonatal outcomes of attempted vaginal compared with planned cesarean delivery in triplet gesta­ tions. Am J Obstet Gynecol 2 1 5 (4):493.e 1 , 20 1 6 Lee H , Bebbington M , Crombleholme TM, e t al: The North American Fetal herapy Network Registry data on outcomes of radiofrequency ablation for twin-reversed arterial perfusion sequence. Fetal Diagn her 33(4) :224, 20 1 3 Lee HC, Gould J B , Boscardin W] , e t al: Trends in cesarean delivery for twin births in the United State 1 995-2008. Obstet Gynecol 1 1 8 ( 5) : 1 095, 20 1 1 Lee YM, Clery-Goldman J, haker HM, et al: ntenatal sonographic predic­ tion of twin chorionicity. Am J Obstet Gynecol 1 95 (3):863, 2006 Lee YM, Wylie BJ, Simpson LL, et al: Twin chorionicity and the risk of still­ birth. Obstet Gynecol I I I :30 1 , 2008 LeFevre ML, Bain RP, Ewigman BG, et al: A randomized trial of prenatal ultrasonographic screening: impact on maternal management and out­ comes. RADIUS (Routine Antenatal Diagnostic Imaging with Ultrasound) Study Group. Am J Obstet Gynecol 1 69 (3):483, 1 993 Leftwich H K, Zaki MN, Wilkins 1, et al: Labor patterns in twin gestations. Am J Obstet Gynecol 209 (3) :254.e 1 , 20 1 3 Legro RS, B rzyski RG, Diamond MP, e t al: The Pregnancy i n Polycystic Ovary Syndrome II study: baseline characteristics and efects of obesity from a mul­ ticenter randomized clinical trial. Ferti! Steril 1 0 1 ( 1 ) :258e.8, 20 1 4 Leung Y , Tam H , Leung T N , e t al: Efect o f twin-to-twin delivery interval on umbilical cord blood gas in the second twins. BJOG 1 09 ( 1 ) :63, 2002 Leveno KJ, Quirk JG, Whalley P], et al: Fetal lung maturation in twin gesta­ tion. Am ] Obstet Gynecol 1 48:405, 1 984 Lewi L, Deprest J, Hecher K: The vascular anastomoses in monochorionic twin pregnancies and their clinical consequences. Am J Obstet Gynecol 208 ( 1 ) : 1 9, 20 1 3 Lewi L , Gratacos E , Ortibus E , e t al: Pregnancy and infant outcome o f 80 consecutive cord coagulations in complicated monochorionic multiple preg­ nancies. Am J Obstet Gynecol 1 94(3):782, 2006 Liem S, Schuit E, Hegerman M, et al : Cervical pessaries for prevention of pre­ term birth in women with a multiple pregnancy (ProTWIN): a multicenter, open-label randomised controlled trial. Lancet 382(990 1 ) : 1 34 1 , 20 1 3 Livingston JC, Livingston LW , Ramsey R , e t al: Second-trimester asynchro­ nous multi fetal delivery results in poor perinatal outcome. Obstet Gynecol 1 03:77, 2004 Lopriore E, Oepkes D: Neonatal morbidity in twin-twin transfusion syn­ drome. Early Hum Dev 87: 595, 20 1 1 Lorenz JM: Neurodevelopmental outcomes of twins. Semin Perinatol 36(3):20 1 , 20 1 2 Lucovnik M , Blickstein I , Lasic M , e t al: Hypertensive disorders during mono­ zygotic and dizygotic twin gestations: a population-based study. Hypertens Pregnancy 1 3 5 (4) : 542, 20 1 6

M u ltifeta l P reg na ncy Luke B, Brown M B : Maternal morbidity and infant death in twin vs triplet and quadruplet pregnancies. Am J Obstet Gynecol 1 98:40 l .e 1 , 2008 MacDonald-Wallis C, Lawlor DA, Fraser A, et al: Blood pressure change in normotensive, gestational hypertensive, preeclamptic, and essential hyper­ tensive pregnancies. Hypertension 59: 1 24 1 , 20 1 2 Magann E F , Chauhan SP, Whitworth NS, e t al: Determination of amniotic luid volume in twin pregnancies: ultrasonographic evaluation versus opera­ tor estimation. Am J Obstet Gynecol 1 82: 1 606, 2000 Mahony BS, Mulcahy C, McCaulife F, et al: Fetal death in twins. Acta Obstet Gynecol Scand 9 0 ( 1 1 ) : 1 274, 20 1 1 Manning FA (ed) : Fetal biophysical profile scoring. In Fetal Medicine: Prin­ ciples and Practices. Notwalk, Appleton & Lange, 1 99 5 Martin JA, Hamilton B E , Osterman MJ , e t al: Births: inal data for 20 1 5 . Nat! Vital Stat Rep 66( 1 ) : 1 , 20 1 7 Massardier J , Golfner F , Journet 0, e t al: Twin pregnancy with complete hyda­ tidiform mole and coexistent fetus obstetrical and oncological outcomes in a series of 14 cases. Eur J Obstet Gynecol Reprod Bioi 1 43:84, 2009 Iatthews T], MacDorman MF, Thoma ME: Infant mortality statistics from the 20 1 3 period linked birth/infant death data set. Narl Vital Stat Rep 64(9 1 ) : 1 , 20 1 5 Maynard SE, Moore Simas TA, Solitro MJ, et al: Circulating angiogenic fac­ tors in singleton vs multiple gestation pregnancies. Am J Obstet 1 98 :200. e l , 2008 McClamrock HD, J ones HW, Adashi EY: Ovarian stimulation and intrauter­ ine insemination at the quarter centennial: implications for the multiple births epidemic. Ferril Steril 97(4) :802, 20 1 2 McElrath TF, Notwitz ER, Robinson IN, e t al: Diferences i n TDx fetal lung maturity assay values between twin and singleton pregnancies. Am J Obstet Gynecol 1 82: 1 1 1 0, 2000 McHugh K, Kiely EM, Spitz L: Imaging of conjoined twins. Pediatr Radiol 36:899, 2006 McLennan AS, Gyami-Bannerman C, Ananth CV, et al: The role of maternal age in twin pregnancy outcomes. Am J Obstet Gynecol 21 7(l ) : 80.e l , 20 1 7 McMahon KS, Neerhof MG, Haney EI, e t al: Prematurity i n multiple gesta­ tions: identiication of patients who are at low risk. Am J Obstet Gynecol 1 86: 1 1 37, 2002 McNamara HC, Kane SC, Craig JM, et al: A review of the mechanisms and evidence for typical and atypical twinning. Am ] Obstet Gynecol 2 1 4(2) : 1 72, 20 1 6 McPherson JA, Odibo 0 , Shanks AL, e t al: Impact o f chorionicity o n risk and timing of intrauterine fetal demise in twin pregnancies. Am ] Obstet GynecoI 207: 1 90.e 1 , 20 1 2 Melamed N , Pittini A , Hiersch L , e t al: D o serial measurements of cervical length improve the prediction of preterm birth in asymptomatic women with twin gestations? Am J Obstet GynecoI 2 1 5 (5):6 1 6.e 1 , 20 1 6a Melamed N, Shah ], Yoon EW, et al: he role of antenatal corticosteroids in twin pregnancies complicated by preterm birth. Am J Obstet Gynecol 2 1 5 (4) :482.e l , 20 1 6b Mhyre ]M: Maternal mortality. Curr Opin Anesthesiol 25 :277, 20 1 2 Michelfelder E , Gotrliebson W, Border W , e t al: Early manifestations and spec­ trum of recipient twin cardiomyopathy in twin-twin transfusion syndrome: relation to Quintero stage. Ultrasound Obstet Gynecol 30:965, 2007 M iller J, Chauhan SP, Abuhamad AZ: Discordant twins: diagnosis, evaluation and management. Am J Obstet GynecoI 206( l ) : 1 0, 2 0 1 2 Morikawa M , Yamada T , Yamada T , e t al : Prospective risk of stillbirth: mono­ chorionic diamniotic twins vs dichorionic twins. J Perinat Med 40:245, 20 1 2 Moroz LA, Brock CO, Govidappagari 5 , et al: Association between change in cervical length and spontaneous preterm birth in twin pregnancies. Am J Obstet Gynecol 2 1 6(2) : 1 59.e l , 20 1 7 Muggli EE, Halliday ]L: Folic acid and risk o f twinning: a systematic review of the recent literature, J uly 1 994 to July 2006. MJA 1 86(5) :243, 2007 Muleba N, Dashe N, Yost 0, et al: Respiratory morbidity among second-born twins. Presented at the 25th Annual Meeting of the Sociey for Maternal Fetal Medicine, February 7- 1 2, 2005 Mutchinick OM, Luna-Munoz L, Amar E, et al : Conjoined twins: a world­ wide collaborative epidemiological study of the international clearinghouse for birth defects surveillance and research. Am J Med Genet C Semin Med Genet 1 5 7C( 4) :274, 201 1 Newman RB, Krombach 5, Myers MC, et al: Efect of cerclage on obstetrical outcome in twin gestations with a shortened cervical length. Am J Obstet Gynecol 1 86:634, 2002 Nicolaides KH, Syngelaki A, Poon LC, et al: Cervical pessary placement for prevention of preterm birth in unselected twin pregnancies: a randomized controlled trial. Am J Obstet Gynecol 2 1 4( l ) : 3 .e l , 20 1 6 Norman ]E, Mackenzie F , Owen P , et al: Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a randomised, double-blind, placebo-controlled study and meta-analysis. Lancet 373:2034, 2009

Nylander PP: Biosocial aspects of multiple births. ] Biosoc Sci 3:29, 1 97 1 Nylander PP: Serum levels o f gonadotropins i n relation to multiple pregnancy in Nigeria. B]OG 80:65 1 , 1 973 O'Brien P, Nugent M , Khalil A: Prenatal diagnosis and obstetric management. Semin Pediatr Surg 24 (5):203, 20 1 5 Odibo AO, Cahill AG, Goetzinger KR, et al : Customized growth charts for twin gestations to optimize identiication of small-for-gestational age fetuses at risk of intrauterine fetal death. Ultrasound Obstet GynecoI 4 1 :637, 20 1 3 Oh K] , Hong ]S, Romero R, et al: The frequency and clinical significance of intra-amniotic inlammation in twin pregnancies with preterm labor and intact membranes. J Matern Fetal Neonatal Med October 1 , 20 1 7 [Epub ahead of print] Olusanya BO, Solanke OA: Perinatal correlates of delayed childbearing in a developing country. Arch Gynecol Obstet 285(4) : 95 1 , 20 1 2 Ong 55, Zamora J , Khan KS, et al: Prognosis for the co-twin following single­ twin death: a systematic review. BJOG 1 1 3 :992, 2006 Painter IN, Willemsen G, Nyholt 0, et al: A genome wide linkage scan for dizygotic twinning in 525 families of mothers of dizygotic twins. Human Reprod 2 5 (6) : 1 569, 20 1 0 Pakrashi T, Defranco A: The relative proportion of preterm births complicated by premature rupture of membranes in multifetal gestations: a population-based study. Am J PerinatoI 30:69, 20 1 3 Parra-Cordero M , Bennasar M , Martinez ]M, e t al: Cord occlusion i n mono­ chorionic twins with early selective intrauterine growth restriction and abnormal umbilical artery doppler: a consecutive series of 90 cases. Fetal Diagn Ther 3 9 (3) : 1 86, 20 1 6 Peigne M , Andrieux ] , Deruelle P , e t al: Quintuplets after a transfer o f two embryos following in vitro fertilization: a proved superfecundation. Fertil Steril 9 5 (6) : 2 1 24.e 1 3, 201 1 Pettit KE, Merchant 1, Machin GA, et al: Congenital heart defects in a large, unselected cohort of monochorionic twins. J Perinatol 33 :467, 20 1 3 Post A, Heyborne K: Managing monoamniotic twin pregnancies. C1in Obstet Gynecol 58(3):643, 20 1 5 Prefumo F , Cabassa P , Fichera A, et al: Preliminary experience with microwave ablation for selective feticide in monochorionic twin pregnancies. Ultra­ sound Obstet GynecoI 4 1 :469, 20 1 3 Prefumo F, Fichera A , Pagani G, e t al: The natural history of monoamniotic twin pregnancies: a case series and systematic review of the literature. Prenat Diagn 3 5 (3):274, 20 1 5 Pritchard JA: Changes i n blood volume during pregnancy. Anesthesiology 26: 393, 1 965 PROSPECT: A trial of pessary and progesterone for preterm prevention in twin gestation with a short cervix, May 20 1 7. Available at: https:llclinicaltri­ als.gov/ct2/show/NCT025 1 8594. Accessed October 30, 20 1 7 Quarello E , Molho M , Ville Y : Incidence, mechanisms, and patterns o f fetal cerebral lesions in twin-to-twin transfusion syndrome. ] Matern Fetal Neo­ natal Med 20:589, 2007 Quigley MM, Cruikshank DP: Polyhydramnios and acute renal failure. ] Reprod Med 1 9 :92, 1 977 Quinn KH, Cao CT, Lacoursiere Y, et al: Monoamniotic twin pregnancy: continuous inpatient electronic fetal monitoring-an impossible goal? Am J Obstet Gynecol 204: 1 6 1 , 20 1 1 Quintero A, Morales ) , Allen MH, et al: Staging of twin-twin transfusion syndrome. J Perinatol 1 9: 5 50, 1 999 Rana 5, Hacker MR, Modest AM, et al: Circulating angiogenic factors and risk of adverse maternal and perinatal outcomes in twin pregnancies with sus­ pected preeclampsia: novelty and signiicance. Hypertension 60:45 1 , 20 1 2 Ray B , Platt MP: Mortality o f twin and singleton livebirths under 3 0 weeks' gestation: a population-based study. Arch Dis Child Fetal Neonatal Ed 94(2) : F 1 40, 2009 Rayburn WF, Lavin ]P J r, Miodovnik M, et al: Multiple gestation: time interval between delivery of the irst and second twins. Obstet Gynecol 63:502, 1 984 Razavi AS, Chasen ST, Chambers F, et al: Maternal morbidity associated with labor induction in twin gestations. Abstract No. 733 Am ] Obstet Gynecol 2 1 6:5427, 20 1 7 Rebarber A, Roman AS, Istwan N , et al: Prophylactic cerclage in the manage­ ment of triplet pregnancies. Am ] Obstet Gynecol 1 93 : 1 1 93 , 2005 Record RG, McKeown T, Edwards ]H: An investigation of the diference in measured intelligence between twins and single births. Ann Hum Genet 34( 1 ) : 1 1 , 1 970 Reddy UM, Abuhamad AZ, Levine 0, et al: Fetal imaging: executive sum­ mary of a joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Institute of Ultrasound in Medicine, American College of Obstetricians and Gynecologists, American College of Radiology, Society for Pediatric Radi­ ology, and Society of Radiologists in Ultrasound Fetal Imaging workshop. Obstet Gynecol 1 23 (5): 1 070, 20 1 4

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Obstetrical C o m p l ications Reddy U M , Branum M , Klebanof A : Relationship of maternal body mass index and height to twinning. Obstet GynecoI 1 05 (3): 593, 2005 Roberts D, Dalziel 5 : Antenatal corticosteroids for accelerating fetal lung matu­ ration for women at risk of preterm birth. Cochrane Database Syst Rev 3 :CD004454, 2006 Roberts D , Gates 5, Kilby M , et aI: Interventions for twin-twin transfusion syndrome: a Cochrane review. Ultrasound Obstet GynecoI 3 1 :70 1 , 2008 Robyr R, Lewi L, Salomon LJ, et I: Prevdence and management of late fetal complications following successful selective laser coagulation of chorionic plate anastomoses in twin-to-twin transfusion syndrome. Am J Obstet Gynecol 1 94:796, 2006 Rode L, Klein K, Nicolaides KH, et al: Prevention of preterm delivery in twin gestations (PREDICT): a multicenter, randomized, placebo-controlled trial on the efect of vaginal micronized progesterone. Ultrasound Obstet Gyne­ col 38 :272, 20 1 1 Roman A, Papanna R, Johnson A, et aI: Selective reduction in complicated monochorionic pregnancies: radiofrequency ablation vs bipolar cord coagu­ lation. Ultrasound Obstet Gynecol 36:37, 20 1 0 Roman A , Rochelson B , Martinelli P , e t aI: Cerclage i n twin pregnancy with dilated cervix between 16 to 24 weeks of gestation: retrospective cohort study. m J Obstet GynecoI 2 1 5 ( 1 ) :98.e 1 , 20 1 6 Roman AS, Saltzman D H , Fox N , e t al: Prophylactic cerclage i n the manage­ ment of twin pregnancies. m J PerinatoI 30(9) :75 1 , 20 1 3 Romero R, Conde-Agudelo A, EI-Refaie W, et aI: Vaginal progesterone decreases preterm birth and neonatal morbidity and mortality in women with a twin gestation and a short cervix: an updated meta-analysis of indi­ vidual patient data. Ultrasound Obstet GynecoI 49(3):303, 20 1 7 Ronalds GA, D e Stavola BL, Leon DA: he cognitive cost o f being a twin: evidence from comparisons within families in the Aberdeen children of the 1 9 50s cohort study. BMJ 33 1 (7528): 1 306, 2005 Rossi AC, D'Addario V: Laser therapy and serial amnioreduction as treatment for twin-twin transfusion syndrome: a metaanalysis and review of literature. m J Obstet Gynecol 1 98 : 1 47, 2008 Rossi AC, D'Addario V: Umbilical cord occlusion for selective feticide in com­ plicated monochorionic twins: a systematic review of literature. Am J Obstet GynecoI 200(2) : 1 23 , 2009 Rossi AC, Mullin PM, Chmait RH: Neonatal outcomes of twins according to birth order, presentation and mode of delivery: a systematic review and meta-analysis. BJOG 1 1 8 (5 ) : 523, 20 1 1 Rothman KJ: Fetal loss, twinning and birthweight ater orl contraceptive use. N Engl J Med 297:468, 1 977 Rouse DJ, Caritis SN, Peaceman M , et al: A trial of 1 7alpha-hydroxyprogesterone caproate to prevent prematurity in twins. N Engl J Med 357:454, 2007 Rouse DJ, Skopec GS, Zlatnik FJ : Fundal height as a predictor of preterm twin delivery. Obstet GynecoI 8 1 :2 1 1 , 1 993 Salem SY, Kibel M, Asztalos E, et al: Neonatal outcomes of low-risk, late­ preterm twins compared with late-preterm singletons. Obstet Gynecol 1 30 (3) : 5 82 , 2 0 1 7 Salomon LJ, O rtqviast L, Aegerter P, et aI: Long-term developmental follow-up of infants who participated in a randomized clinical trial of amniocentesis vs laser photocoagulation for the treatment of twin-to-twin transfusion syn­ drome. m J Obstet Gynecol 203(5) :444.e l , 20 1 0 Schmitz T , Prunet C , Azria E , e t aI: Association between planned cesarean delivery and neonatal mortality and morbidity in twin pregnancies. Obstet GynecoI 1 29 (6):986, 20 1 7 Sebire NJ, Foskett M , Paradinas FJ, et al: Outcome o f twin pregnancies with complete hydatidiform mole and healthy co-twin. Lancet 359:2 1 65 , 2002 Senat MV, Deprest J, Boulvain M , et al: Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome. N Engl J Med 3 5 1 : 1 36, 2004 Senat MV, Porcher R, Winer N, et al: Prevention of preterm delivery by 1 7a1pha-hydroxyprogesterone caproate in asymptomatic twin pregnancies with a short cervix: a randomized controlled trial. Am J Obstet Gynecol 208 (3) : 1 94.e 1 , 20 1 3 Shen 0 , Samuelof A, Beller U , et I : Number of yolk sacs does not predict amnionicity in early first-trimester monochorionic multiple gestations. Ultrasound Obstet Gynecol 27( 1 ) :53, 2006 Shub A, Walker SP: Planned early delivery versus expectant management of monoamniotic twins. Cochran Database Syst Rev 4:CD008820, 20 1 5 Simpson LL: Ultrasound in twins: dichorionic and monochorionic. Semin PerinatoI 37(5) :348 , 20 1 3 Slaghekke F , Kist ] , Oepkes D , e t al: Twin anemia-polycythemia sequence: diagnostic criteria, classiication, perinatal management and outcome. Fetal Diagn Ther 27(4) : 1 8 1 , 20 1 0 Smith Gc, Fleming M , White IR: Birth order o f twins and risk o f perinatal death related to delivety in England, Northern Ireland, and Wales, 1 9942003: retrospective cohort study. BMJ 334(7593) : 576, 2007

Society for Maternl-Fetal Medicine, Simpson LL: Twin-twin transusion syn­ drome. Am J Obstet Gynecol 208 ( 1 ) :3, 20 1 3 Sparks TN, Norton ME, Flessel M , e t aI: Observed rate o f Down syndrome in twin pregnancies. Obstet GynecoI 1 28 (5): 1 1 27, 20 1 6 Spencer R: Parasitic conjoined twins: externl, internal (fetuses i n fetu and teratomas), and detached (acardiacs) . Clin Anat 1 4:428, 200 1 Spencer R: Theoretical and analytical embryology of conjoined twins: part I : embryogenesis. Clin Anat 1 3:36, 2000 Sperling L, Kiil C, Larsen LU, et I: Naturlly conceived twins with mono­ chorionic placentation have the highest risk of fetal loss. Ultrasound Obstet Gynecol 28 :644, 2006 Spitz L: Seminars in pediatric surgery: The management of conjoined twins: the great Ormond Street experience. Preface. Semin Pediatr Surg 24(5):20 1 , 20 1 5 Stein W, Misselwitz B , Schmidt 5 : Twin-to-twin delivery time interval: influ­ encing factors and efect on short term outcome of the second twin. Acta Obstet Gynecol Scand 87(3):346, 2008 Strandskov HH, Edelen EW, Siemens GJ: Analysis of the sex ratios among single and plural births in the total white and colored U.S. populations. m J Phys Anthropol 4:49 1 , 1 946 Sugibayashi R, Ozawa K, Sumie M: et aI: Forty cases of twin reversed arterial perfusion sequence treated with radio frequency ablation using the multistep coagulation method: a single-center experience. Prenat Diagn 36(5) :437, 2016 Sunderam 5, Kissin D M , Crawford SB, e t al: Assisted reproductive technology surveillance-United States, 20 1 4. MMWR 66(6) : 1 , 20 1 7 Szymusik I , Kosinska-Kaczynska K , Bomba-Opon D , e t al: IVG versus spon­ taneous twin pregnancies-which are at higher risk of complications? J Matern Fetal Neonatal Med 25 ( 1 2) :2725, 20 1 2 Talauliker VS, Arulkumaran 5 : Reproductive outcomes after assisted concep­ tion. Obstet Gynecol Surv 67(9) : 566, 20 1 2 Tan L , Goon SM, Salmon Y, e t I : Conjoined twins. Acta Obstet Gynecol Scand 50:373, 1 97 1 Tannuri A , Batatinha J , Velhote M , e t aI: Conjoined twins-twenty years' experience at a reference center in Brazil. Clinics 68(3):37 1 , 20 1 3 Taylor M , Rebarber A, Saltzman DH, e t aI: Induction o f labor i n twin com­ pared with singleton pregnancies. Obstet Gynecol 1 20(2) :297, 20 1 2 horngren-Jerneck K , Herbst A : Low 5-minute Apgar score: a population­ based register study of 1 million term births. Obstet GynecoI 98 ( 1 ) :65, 200 1 horson HL, Ramaeker DM, Emery ST: Optimal interval for ultrasound sur­ veillance in monochorionic twin gestations. Obstet Gynecol 1 1 7 ( 1 ) : 1 3 1 , 20 1 1 To MS, Fonseca EB, Molina FS, et al: Maternal characteristics and cervical length in the prediction of spontaneous early preterm delivery in twins. m J Obstet GynecoI 1 94(5) : 1 360, 2006 Trivedi N, Gillett R: he retained twinltriplet following a preterm delivery­ an analysis of the literature. Aust N Z J Obstet GynaecoI 38:46 1 , 1 998 Turpin R, Lejeune J , Lafourcade J , et I: Presumption of monozygotism in spite of sexul dimorphism: Y male subject and haploid X neuter subject. C R Hebd Seances Acad Sci 252:2945, 1 96 1 Varner MW, Leindecker S , Spong CY, e t al: h e Maternal-Fetal Medicine Unit Cesarean Registry: trial of labor with a twin gestation. m J Obstet Gynecol 1 93 : 1 35, 2005 Vintzileos AM, Ananth CV, Kontopoulos E, et al: Mode of delivety and risk of stillbirth and infant mortality in triplet gestations: United States, 1 995 through 1 998. m J Obstet Gynecol 1 92:464, 2005 Vora NL, Ruthazer R, House M, et al: Triplet ultrasound growth parameters. Obstet GynecoI 1 07:694, 2006 Wada H, Nunogami K, Wada T, et aI: Difuse brain damage caused by acute twin-twin transfusion during late pregnancy. Acta Paediatr Jpn 40:370, 1 998 Walker MC, Murphy E, Pan 5, et I: Adverse maternal outcomes in multife­ tal pregnancies. BJOG I l l : 1 294, 2004 Waller DK, Tita TN, Annegers JF: Rates of twinning before and ater fortii­ cation of foods in the U.S. with folic acid, Texas, 1 996 to 1 998. Paediatr Perinat EpidemioI 1 7(4):378, 2003 Wen SW, Demissie K, Yang , et al: Maternal morbidity and obstetric com­ plications in triplet pregnancies and quadruplet and higher-order multiple pregnancies. m J Obstet Gynecol 1 9 1 :254, 2004 White C, Wyshak G: Inheritance in human dizygotic twinning. N Engl J Med 2 7 1 : 1 003, 1 964 Wolfe MD, de la Torre L, Moore LE, et al: Is the protocol for induction of labor in singletons applicable to twin gestations? J Reprod Med 58(304) : 1 37, 20 1 3 Yamasmit W , Chaithongwongwatthana 5 , Tolosa JE, e t al: Prophylactic oral betamimetics for reducing preterm birth in women with a twin pregnancy. Cochrane Database Syst Rev 1 2:CD004733, 20 1 5

M u ltifeta l P re g na ncy Yang Q, Wen SW, Chen Y, et al: Occurrence and clinical predictors of opera­ tive delivery for the vertex second twin after normal vaginal delivery of the irst twin. Am J Obstet Gynecol 1 92 ( 1 ) : 1 78, 2005a Yang Q, Wen SW, Chen Y, et al: Neonatal death and morbidity in vertex­ nonvertex second twins according to mode of delivery and birth weight. Am J Obstet GynecoI 1 92(3) :840, 2005b Yeomans ER: Delivery of twin gestations. I n Yeomans ER, Hofman BL, Gil­ strap LC I I I , et al (eds): Cunningham and Gilstrap's Operative Obstetrics, 3rd ed. New York, McGraw-Hill Education, 20 1 7 Yinon Y , Mazkereth R, Rosentzweig N , e t l : Growth restriction as a determinant of outcome in preterm discordant twins. Obstet Gynecol 1 05 ( 1 ) : 80, 2005

Young BC, Wylie BJ: Efects of twin gestation on maternal morbidity. Semin Perinatol 36(3) : 1 62, 20 1 2 Zech NH, Wisser J , Natalucci G , et al: Monochorionic-diamniotic twins dis­ cordant in gender form a naturally conceived pregnancy through postzygotic sex chromosome loss in a 4 Y zygote. Prenat Diagn 28:759, 2008 Zhao DP, de Villiers SF, Slaghekke F, et al: Prevalence, size, number and localization of vascular anastomoses in monochorionic placentas. Placenta 34:589, 20 1 3 Zwijnenburg PJ, Meijiers-Heijboer H , Boomsma D I : Identical but not the same: the value of discordant monozygotic twins in genetic research. Am J Med Genet B Neuropsychiatr Genet 1 53B(6) : 1 1 34, 20 1 0

897

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C H A PT E R 46

Genera l Con s i deration s a n d M atern a l Eva l u ation

MEDICATIONS AND S U RGERIES . . . . . . . . . . . . . . . . . . . 90 1 LAPAROSCOPIC S U RGERY . . . . . . . . . . . . . . . . . . . . . . . 90 1 RADIOG RAPHY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 904 DIAGNOSTIC RADIATION . . . . . . . . . . . . . . . . . . . . . . . . 906 SONOGRAPHY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 909 MAG N ETIC RESONANCE I MAGING . . . . . . . . . . . . . . . . . 909

Obstetricians should have a working knowledge o f the wide-ranging medical disorders common to childbearing-aged women. Many of these are within the purview of the general obstetrician. Other disorders, however, will warrant consultation, and still others require a multidisciplinary team. The latter may include maternal-fetal medicine specialists, hospitalists, inter­ nists and medical subspecialists, surgeons, anesthesiologists, and numerous other disciplines (Levine, 20 1 6) . The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine (20 1 4, 20 1 7b) has redefined aspects of maternal care and proposed required levels of specialized care. It should be axiomatic that a woman must never be penal­ ized because she is pregnant. To ensure this, several questions should be addressed: •

As a rule, al diseases which subject the organism to a con­ siderable strain are much more serious when occurring in a pregnant woman. -J. Whitridge Williams ( 1 903)

•

•

•

As reviewed by Williams in 1 903, pregnant women are suscep­ tible to any medical and surgical disorder that can afect child­ bearing-aged women. Some of these, especially those that are chronic, more often precede pregnancy. But, they can acutely complicate an otherwise normal pregnancy. Of estimates, one managed-care population had an overall antenatal hospital­ ization rate of 1 0. 1 per 1 00 deliveries (Gazmararian, 2002) . Approximately one third was for nonobstetrical conditions that included renal, pulmonary, and infectious diseases. In another study from the 2002 Nationwide Inpatient Sample, the injury hospitalization rate was 4. 1 women per 1 000 deliveries (Kuo, 2007) . Last, approximately 1 in every 635 pregnant women will undergo a nonobstetrical surgical procedure (Corneille, 20 1 0; Kizer, 20 1 1 ) .

What management would be recommended if the woman were not pregnant? If the proposed management is diferent because the woman is pregnant, can this be j ustiied? What are the risks versus benefi t s to the mother and her fetus, and are they counter to each other? Can an individualized management plan be devised that bal­ ances beneits versus risks of any alterations?

Such an approach allows individualized care for women with most medical and surgical disorders complicating pregnancy. MATERNAL PHYSIOLOGY AND LABORATORY VALU ES Pregnancy induces physiological changes in virtually all organ sys­ tems. In turn, results of numerous laboratory tests are altered, and some values would, in the nonpregnant woman, be considered abnorml. Conversely, some may appear to be within a normal range but are decidedly abnormal for the gravida. These changes may ampliy or obuscate evaluation of coexisting conditions. he wide range of pregnany efects on normal physiology and

Genera l Co nsiderati o n s a nd Maternal Eva l uation

laboratory values are discussed in the chapters that follow in this section and are listed in the Appendix (p. 1 255) . M EDICATIONS AND SURGERIES • Pregnancy Outcomes

Fortunately, most medications needed to treat frequently encountered illnesses complicating pregnancy can be given with relative safety. That said, notable exceptions are considered in Chapter 1 2 and throughout this text. Regarding surgery, the risk of an adverse pregnancy out­ come is not appreciably increased in most women who undergo an uncomplicated operative procedure. With complications, however, risks likely are increased. For example, perforative appendicitis with feculent peritonitis has significant maternal and perinatal morbidity and mortality rates even if surgical and anesthetic techniques are flawless. Conversely, procedure­ related complications may adversely afect outcomes. For exam­ ple, a woman who has uncomplicated removal of an inflamed appendix may sufer aspiration of acidic gastric contents dur­ ing tracheal intubation or extubation. Still, compared with nonpregnant women undergoing similar procedures, pregnant women do not appear to have excessive complications (Silvestri, 20 1 1 ) . In a study of the American College of Surgeons' National Surgical Quality Improvement Program, outcomes in pregnant women were compared with matched nonpregnant controls (Moore, 20 1 5) . The investigators reported similar out­ comes in the two cohorts, each with 2539 patients. In a smaller study, however, women undergoing nonobstetrical surgery after 23 weeks' gestation had a high rate of subsequent preterm delivery (Baldwin, 20 1 5) . The most extensive data regarding anesthetic and surgical risks for the gravida and her fetus are from the Swedish Birth Registry and described by Mazze and Kallen ( 1 989) . The efects on pregnancy outcomes of 5405 nonobstetrical surgical pro­ cedures performed in 720,000 pregnant women from 1 973 to 1 98 1 were analyzed. For approximately half of these pro­ cedures, general anesthesia was used and commonly involved nitrous oxide supplemented by another inhalation agent or intravenous medications. These procedures were performed in 4 1 percent of women in the first trimester, 35 percent in the second, and 24 percent in the third. Overall, 25 percent were abdominal operations, and 20 percent were gynecological or urological procedures. Laparoscopy was the most frequently performed operation, and appendectomy was the most com­ mon second-trimester procedure. • Peri natal Morbidity

Excessive perinatal morbidity associated with nonobstetrical surgery is attributable in many cases to the disease itself rather than to adverse efects of surgery and anesthesia. he Swed­ ish Birth Registry again provides valuable data (Table 46- 1 ) . Importantly, the incidences of congenital malformations or of stillbirths were not significantly diferent from those of non­ exposed control newborns. However, incidences of low birth­ weight, preterm birth, and neonatal death in infants born to women who had undergone surgery were significantly greater.

TABLE 46-1 . Bi rth Outcomes in 5405 P regna nt Wom e n U ndergoing N o n o bstetrical Su rgery Outcome

Rate

Maj o r m a lformation Sti l l b i rth Neonata l death by 7 days P reter m < 3 7 wk B i rthwe i g ht < 1 500 g B i rt hwei g ht < 2500 g

1 .9% 7 per 1 000 1 0.5 per 1 000 7.5% 1 .2% 6.6%

p va luea

NS NS < 0.05 < 0.05 < 0.05 < 0.05

aCo m pa red with 720,000 preg n a ncies in women without s u rg e ry. NS n ot s i g n ifi cant. Data fro m Mazze, 1 989. =

Increased neonatal death rates were largely due to preterm birth. In two other studies, the preterm delivery rate in women undergoing nonobstetrical surgery was also elevated (Baldwin, 20 1 5; Hong, 2006) . Rates of fetal abnormalities with maternal surgery in early pregnancy do not appear increased. Kallen and Mazze ( 1 990) scrutinized 572 operations performed at 4 to 5 weeks' gesta­ tion and reported a nonsignificant relationship with elevated neural-tube defect rates. In a similar study from a Hungarian database, Czeizel and colleagues ( 1 998) found no evidence that anesthetic agents were teratogenic. LAPAROSCOPIC SURG E RY Laparoscopy has become the most common first-trimester pro­ cedure used for diagnosis and management of several surgical disorders. In 20 1 7, the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) updated its recommendations concerning laparoscopy use in pregnant women (Table 46-2) . Information regarding surgical approach selection i n preg­ nancy comes from the American College of Surgeons data­ base (Silvestri, 20 1 1 ) . During the 5-year period ending in 2009, almost 1 300 pregnant women were studied who had undergone either appendectomy or cholecystectomy. Open appendectomy was performed in 36 percent of 857 gravi­ das compared with only 1 7 percent of those not pregnant. Of those undergoing cholecystectomy, an open procedure was used in 1 0 percent of 436 pregnant women compared with 5 percent of nonpregnant women. No randomized tri­ als compare laparoscopic with open surgery, however, most reviews report equally satisfactory outcomes (Bunyavejchevin, 20 1 3; Cox, 20 1 5 ; Fatum, 200 1 ) . The most frequently per­ formed procedures were cholecystectomy, adnexal surgery, and appendectomy. For adnexal mass surgery in pregnancy, laparoscopy is preferred, and several studies conirm its relative safety (Daykan, 20 1 6; Hoover, 20 1 1 ; Webb, 20 1 5) . At first, 26 to 28 weeks became the upper gestational-age limit recom­ mended, but as experience has accrued, many now describe laparoscopic surgery performed in the third trimester (Kizer, 20 1 1 ) . In one report of 59 gravidas undergoing laparoscopic cholecystectomy or appendectomy, a third were > 26 weeks'

901

902

Med i ca l and S u rg ica l Com pl ications

TABLE 46-2. Some G u id e l i nes fro m the Society of A merica n Gastroi ntest i n a l E ndoscopic S u rgeons (SAGES) for La pa roscopic S u rg ery i n P reg n a nt Wom e n Ind ications-sa me a s for non preg n a n t wom e n Ad n ex a l mass exc i s ion I nvestigation of acute a bdom i na l processes A p pend ectomy, cholecystectomy, neph rectomy, a d re n a l ecto my, s p l en ecto my Tech n iq u e Pos ition: latera l rec u m bent Entry: open tech n i q u e, ca refu l Veress n eed le, o r optical troca r; fu n d a l h e i g ht may a lter i n se rtion s ite selection Troca rs: d i rect v i s u a l ization for placement; fu n d a l h e i g ht may a lter i n se rtion site selection CO2 i n s ufl ation pressures: 1 0- 1 5 mm H g M o n itori n g : capnog ra phy i ntraoperatively, F H R a ssess ment pre- a n d postoperatively Perioperative pneu matic com pression devices and early postoperative a m bu lation CO2 = ca rbon d ioxide; FHR = feta l heart rate. Data from Pea rl, 20 1 7.

gestation (Rollins, 2004) . No serious adverse sequelae are linked to these procedures. In addition, laparoscopic sple­ nectomy, adrenalectomy, and nephrectomy have also been described in pregnant women (Asizare, 20 1 4; Dong, 20 1 4; Gernsheimer, 2007; Miller, 20 1 2; Stroup, 2007) . • Hemodynamic Efects

Abdominal insulation for laparoscopy causes hemodynamic changes that are summarized in Table 46-3 . Reedy and associ­ ates ( 1 995) studied baboons at the human equivalent of 22 to 26 weeks' gestation. No substantive physiological changes were found with insulation pressures of 1 0 mm Hg, but 20 mm Hg caused significant maternal cardiovascular and respiratory changes after 20 minutes. hese included increased respiratory rate, respiratory acidosis, diminished cardiac output, and increased pulmonary artery and capillary wedge pressures.

In women, cardiorespiratory changes are generally not severe if insulation pressures are kept below 1 5 mm Hg. With noninvasive hemodynamic monitoring in women at midpreg­ nancy, the cardiac index decreased 26 percent by 5 minutes of insulation and 2 1 percent by 1 5 minutes (Steinbrook, 200 1 ) . Despite this, mean arterial pressures, systemic vascular resis­ tance, and heart rate did not change significantly. • Obesity

Laparoscopic surgery frequently is ideal for the obese woman (Sisodia, 20 1 5) . However, some outcomes may be adversely afected in obese gravidas compared with normal-weight patients. Of these, higher conversion rates to laparotomy, longer operating times, and longer hospitalizations have been reported. Also, adequate ventilation is more diicult, and greater pneumoperitoneal pressures are needed to create

TABLE 46-3. Physiolog i ca l Effects of CO2 I n s uflation of the Peritoneal Cavity System

Efectsa

Mechan isms

Respi ratory Ca rd iovascu la r

I ncreased PC02 ; decreased p H I ncreased : heart rate; syste m ic vasc u l a r res i sta n ce; p u l m o n a ry, central venous, and mean a rteria l pressu res Decreased ca rd iac output Decrea sed s p l a nc h n i c flow with hypoperfu s i o n of l iver, k i d n eys, a nd gastroi ntest i n a l o rg a n s Decreased ven o u s ret u rn from lower extre m ities I ncreased cereb ra l blood flow

CO2 a bsorption Hypercarbia a n d i ncreased i nt ra a bd o m i na l pressu re

B lood flow

Decreased venous ret u rn I nc reased i ntraa bdo m i n a l p ress u re I n c reased i ntraabd o m i n a l p ressu re Hyperca rbia poss i bly from s h u nt i n g due to s p l a nch n ic ta m ponade

a Effects i ntens ified when i n s ufflation press u re > 20 mm H g i n baboons (Reedy, 1 995). b Data p r i m a r i l y from a n i ma l stu d ies. CO2 =ca rbon d i oxi de; CSF = cerebrosp i n a l fl u id; PC0 2 = pa tial p ressure of CO2, Data from O'Rou rke, 2 006; Reynolds, 2003 .

}

Possible Maternal-Fetal Efects Hyperca rbia, acidosis Uteroplacental hypoperfu s ionpos s i b l e feta l hypoxia, acidosis, a n d hypoperfusion b As a bove

As a bove I ncreased CSF pressu re b

Genera l Con s i de rations a nd Maternal Eva l uation

suitable operating space. here is anatomical distortion of the abdominal wall with displaced landmarks. Finally, the risk of developing hernias at port sites is greater. • Perinatal Outcomes

Because precise efects of laparoscopy in the human fetus are unknown, animal studies are informative. In early studies of pregnant ewes, various investigators reported that uteroplacen­ tal blood low declines when intraperitoneal insulation pres­ sure exceeded 1 5 mm Hg (Barnard, 1 995; Hunter, 1 995) . This was the result of decreased perfusion pressure and increased placental vessel resistance (see Table 46-3) . The previously cited baboon studies by Reedy and coworkers ( 1 995) produced similar findings. Perinatal outcomes in women are limited to observational studies. Reedy and colleagues ( 1 997) used the updated Swed­ ish Birth Registry database to analyze a 20-year period with more than 2 million deliveries. Of 2 1 8 1 laparoscopic proce­ dures, most were performed during the irst trimester. Perina­ tal outcomes for these women were compared with those of all women in the database and those undergoing open surgical procedures. These investigators confirmed the earlier indings of an increased risk of low birthweight, preterm delivery, and fetal-growth restriction. Diferences were not found, however, in outcomes of women undergoing laparoscopy versus lapa­ rotomy. n observational study of 262 women undergoing surgery for an adnexal mass noted similar findings (Koo, 20 1 2) . • Technique

The following description is an overview of laparoscopic tech­ niques in pregnancy. For a detailed description refer to Chapter 1 5 in Cunningham and Gistrap s Operative Obstetrics, 3rd edition (Kho, 20 1 6) .

Preparation for laparoscopy difers little from that used for laparotomy. Bowel cleansing is not needed but may aid visu­ alization and manipulations by emptying the large intestine. N asogastric or orogastric decompression reduces the risk of stomach trocar puncture and aspiration. Aortocaval compres­ sion is avoided by a left-lateral tilt. Positioning of the lower extremities in boot-type stirrups maintains access to the vagina for fetal sonographic assessment or manual uterine displace­ ment. Intrauterine manipulators are logically avoided. Most reports describe the use of general anesthesia after tra­ cheal intubation with monitoring of end-tidal carbon dioxide­ EtC0 2 (Hong, 2006; Ribic-Pucelj , 2007) . With controlled ventilation, EtC0 2 is maintained at 30 to 35 mm Hg. Beyond the irst trimester, technical modifications of standard pelvic laparoscopic entry are required to avoid uterine puncture or laceration (Fig. 46- 1 ) . Many recommend open enuy tech­ niques to avoid perforations of the uterus, pelvic vessels, and adnexa (Kizer, 20 1 1 ; Koo, 20 1 2) . The abdomen is incised at or above the umbilicus, and the peritoneal cavity entered under direct visualization (Fig. 46-2) . At this point, the cannula is then connected to the insulation system, and a 1 2-mm Hg pneu­ moperitoneum is created. The initial insulation should be con­ ducted slowly to allow for prompt assessment and reversal of any untoward pressure-related efects. Gas leakage around the can­ nula is managed by tightening the surrounding skin with a towel clamp. Insertion of secondary trocars into the abdomen is most safely performed under direct laparoscopic viewing. Single-port surgery has also been described (Dursun, 20 l 3) . In more advanced pregnancies, direct entry through a left upper quadrant port in the midclavicular line, 2 cm beneath the costal margin, may better avoid the fundus (Donkervoort, 20 1 1 ; Stepp, 2004) . Known as Palmer point, this entry site is also used in gynecological laparoscopy because visceroparietal adhesions infrequently form here (Vilos, 2007) .

F I G U R E 46- 1 Preg n a nt uterus at 1 0, 20, a n d 36 weeks' gestation depicti ng d istortion of other i ntra peritonea l o rg a n s. (Reprod uced with perm ission from Kho KA: Diag n ostic a nd operative l a pa roscopy. I n Yeomans ER, Hoffm a n BL, Gilstra p LC I I I , et a l (eds): Cu n n i ng h a m and G i l stra p's Operative Obstetrics 3 rd ed, New York McGraw-H i l i Education, 201 7.)

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Medical a n d S u rg ica l Com pl icat i o n s

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B

c

F I G U R E 46-2 Open entry tec h n i q u e for la paroscopic i n strument placement. A. Fascia g rasped with two A l l i s c l a m ps a n d e levated prior to s h a rp incision. B. Two fascial stitches i ncorporate the peritoneum and fascia. C. These fascial sutures a re wra pped a round holders of the H a sson c a n n u l a to a n c hor it i n place. (Reproduced with perm ission from Kho KA: Diagnostic and operative la pa roscopy. I n Yeomans ER, Hoffma n BL, G i l strap LC I I I, et a l (ed s): C u n n i n g h a m a n d G i l strap's O pe rative Obstetrics 3 rd ed, New York McGraw- H i l i Ed ucation, 20 1 7.)

Gasless laparoscopy is a less commonly selected alternative approach that uses a rod with intraabdominal fan-blade-shaped retractors. When opened, these allow the abdominal wall to be lifted upward. It avoids the typical laparoscopic cardiovascular changes because the pneumoperitoneum is created by retrac­ tion rather than insuiation (Phupong, 2007) . • Complications

Risks inherent to any abdominal endoscopic procedure are probably increased slightly during pregnancy. The obvious unique complication is perforation of the pregnant uterus with either a trocar or Veress needle (Azevedo, 2009; Kizer, 20 1 1 ; Mala, 20 14). hat said, reported complications are infrequent (Fatum, 200 1 ; Koo, 20 1 2) . One Cochrane database review noted a need for randomized trials to deduce comparative benefi t s and risks of laparoscopy versus laparotomy during pregnancy (Bunyavejchevin, 20 1 3) . Pragmatically, this seems unfeasible, and common sense should dictate the approach. RADIOG RAPHY Imaging modalities are used as adjuncts for diagnosis and therapy during pregnancy. Options include sonography, radi­ ography, and magnetic resonance (MR) imaging. Of these, radiography is the most problematic. Inevitably, some radio­ graphic procedures are performed before recognition of early pregnancy, usually because of trauma or serious illness. For­ tunately, most diagnostic radiographic procedures are associ­ ated with minimal fetal risks. As with drugs and medications, however, these procedures may lead to litigation if pregnancy outcome is adverse. And, x-ray exposure may lead to a needless therapeutic abortion because of patient or physician anxiety. Since 2007, the American College of Radiology (ACR) has addressed the growing concern of radiation dose in all ields of medicine (Amis, 2007) . Some of its goals were to limit expo­ sure through radiation safety practices and promote lifelong

accumulated records of exposures in any given patient. Task Force recommendations included additional considerations for special radiosensitive populations, such as children and pregnant and potentially pregnant women. At our institutions, special rec­ ommendations are made for gravidas. Radiation exposure values and duration are recorded and monitored in high-exposure areas such as computed tomography (CT) and luoroscopy. • Ionizing Radiation

he term radiation literally refers to energy transmission and thus is often applied not only to x-rays, but also to microwaves, ultrasound, diathermy, and radio waves. Of these, x-rays and gamma rays have short wavelengths with very high energy and are ionizing radiation forms. The other four energy forms have rather long wavelengths and low energy (Brent, 1 999b, 2009) . Ionizing radiation refers to waves or particles-photons-of sig­ niicant energy that can change the structure of molecules such as those in DNA or that can create free radical or ions capable of secondarily damaging tissue (Hall, 1 99 1 ; National Research Council, 1 990) . Methods of measuring the efects of x-rays are summarized in Table 46-4. The standard terms used are exposure TABLE 46-4. Some Measu res of Ion izing Rad iation Exposu re

Dose

N u m ber of ions p rod u ced by x-rays per kg of a i r U n it roentgen (R) Amount of energy deposited per kg of tissue Modern u n it g ray (Gy) ( 1 Gy 1 00 rad) Trad itiona l u n it rad Amount of e n e rgy deposited per kg of tissue n o r m a l ized for biolog ical effectiveness Modern u n it si evert (Sv) (1 Sv 1 00 rem) Trad itio n a l u n it re m =

Re lative effective dose

=

General Co n s i d e rations a n d Maternal Eva l uation

(in air), dose (to tissue), and reative fictive dose (to tissue) . In the range of energies for diagnostic x-rays, the dose is now expressed in grays (Gy) , and the relative efective dose is expressed in sieverts (Sv) . hese can be used interchangeably. For consistency, all doses discussed subsequently are expressed in contemporane­ ously used units of gray ( 1 Gy 1 00 rad) or sievert ( 1 Sv 1 00 rem) . To convert, 1 Sv 1 00 rem 1 00 rad. As noted, the biological efects of x-rays are caused by an electrochemical reaction that can damage tissue. According to Brent ( 1 999a, 2009), x- and gamma-radiation at high doses can create two types of biological efects and reproductive risks in the fetus. These are deterministic eicts and stochastic focts, which are both described in the next sections. =

=

=

=

• Deterministic Efects

One potential harmful efect of radiation exposure is determin­ istic, which may result in abortion, growth restriction, congeni­ tal malformations, microcephaly, or mental retardation. hese deterministic efects are threshold efects, and the threshold level is the NOAEL-No Observed Adverse Eict Level (Brent, 2009) . lthough controversial, the NOEL concept supports that there is no risk below a threshold dose (0.05 Gy or 5 rad) . It also suggests that the threshold for gross fetal malformations is more likely to be 0.2 Gy (20 rad) . The harmful deterministic efects of ionizing radiation have been extensively studied for cell damage with resultant disordered embryogenesis. These have been assessed in animal models, as well as in Japanese atomic bomb survivors and the Oxford Survey of Childhood Cancers (Sorahan, 1 995). Addi­ tional sources have confirmed prior observations and provided more information (Groen, 20 1 2) . One is a 2003 Interna­ tional Commission on Radiological Protection publication that describes biological fetal efects from prenatal irradiation. Another is the Biological Efects of Ionizing Radiation-BEIR II Phase 2 report of the National Research Council (2006) , which discusses health risks from exposure to low levels of ion­ izing radiation. A n i m a l Stu d ies

In the mouse model, the lethality risk is highest during the pre­ implantation period-up to 1 0 days postconception (Kanter, 20 1 4) . This is likely due to blastomere destruction caused by chromosomal damage (Hall, 1 99 1 ) . During organogenesis, high-dose radiation-1 Gy or 1 00 rad-is more likely to cause malformations and growth restriction and less likely to have lethal efects in the mouse. Studies of brain development sug­ gest efects on neuronal development and a window of cortical sensitivity in early and midfetal periods. That said, acute low­ dose ionizing radiation appears to have no deleterious efects (Howell, 20 1 3) . H u m a n Data

Data on adverse human efects of high-dose ionizing radiation mostly derive from the atomic bomb survivors of Hiroshima and Nagasaki (Greskovich, 2000; Otake, 1 987) . The International Commission on Radiological Protection (2003) confirmed initial studies showing that the increased risk of severe mental

retardation was greatest between 8 and 1 5 weeks' gestation. There may be a lower-threshold dose of 0.3 Gy (30 rad) , which is a range similar to the window of cortical sensitivity in the mouse model discussed earlier. he mean decrease in intelligence quo­ tient (IQ) scores was 25 points per Gy or 1 00 rad. here appears to be linear dose response, but it is not clear whether there is a threshold dose. Most estimates err on the conservative side by assuming a linear nonthreshold hypothesis. In a study of fetuses exposed to low radiation doses, Choi and colleagues (20 1 2) did not find an increased risk for congenital anomalies. Finally, an increased risk of mental retardation in humans < 8 weeks' or > 25 weeks' gestation has not been documented, even with doses exceeding 0 . 5 Gy or 50 rad (International Commission on Radiological Protection, 2003) . Reports have described high-dose radiation used to treat women for malig­ nancy, menorrhagia, and uterine myomas. Dekaban ( 1 968) described 22 infants with microcephaly, mental retardation, or both following exposure in the fi r st half of pregnancy to an estimated 2 . 5 Gy or 250 rad. S u m m a ry of Fetal Rad iation Expo s u re

From 8 to 1 5 weeks, the fetus is most susceptible to radiation­ induced mental retardation. It has not been resolved whether this is a threshold or nonthreshold linear function of dose. he Committee on Biological Efects ( 1 990) estimates the risk of severe mental retardation to be as low as 4 percent for 0. 1 Gy ( 1 0 rad) and as high as 60 percent for 1 . 5 G y ( 1 50 rad). But recall that these doses are 2 to 1 00 times higher than those considered maximal from diagnostic radiation. Importantly, cumulative doses from multiple procedures may reach the harmful range, especially at 8 to 1 5 weeks' gestation. At 1 6 to 25 weeks, the risk is less. And again, there is no proven risk before 8 weeks or after 25 weeks. I mportantly, embryofetal risks from low-dose diagnostic radiation appear to be minimal. Current evidence suggests that risks for malformations, growth restriction, or abortion are not increased from a radiation dose of less than 0.05 Gy (5 rad) . Indeed, Brent (2009) concluded that gross congenital malformations would not be increased with exposure to less than 0 . 2 Gy (20 rad) . Because diagnostic x-rays seldom exceed 0. 1 Gy ( 1 0 rad) , Strzelczyk and associates (2007) concluded that these procedures are unlikely to cause deterministic efects. As emphasized by Groen and coworkers (20 1 2) , 0. 1 Gy is the radiation equivalent to that from more than 1 000 chest x-rays! • Stochastic Efects

These efects refer to random, presumably unpredictable onco­ genic or mutagenic efects of radiation exposure. Stochastic efects concern associations between fetal diagnostic radiation exposure and increased risk of childhood cancers or genetic dis­ eases. According to Doll and Wakeford ( 1 997) , as well as the National Research Council (2006) BEIR VII Phase 2 report, excess cancers can result from in utero exposure to doses as low as 0.0 1 Sv or 1 rad. Stated another way by Hurwitz and col­ leagues (2006), the estimated risk of childhood cancer follow­ ing fetal exposure to 0.03 Gy or 3 rad doubles the background risk of 1 in 600 to that of 2 in 600.

905

906

Med ica l a nd S u rg ica l Co m pl icatio n s

In one report, in utero radiation exposure was determined for 1 0 solid cancers in adults from age 1 7 to 45 years. here was a dose-response relationship as previously noted at the 0. 1 Sv or 1 0 rem threshold. hese cancers likely are associated with a complex series of interactions between DNA and ionizing radiation. They also make it more problematic to predict can­ cer risk from low-dose radiation of less than 0. 1 Sv or 1 0 rem. Importantly, below doses of 0. 1 to 0.2 Sv, there is no convinc­ ing evidence of a carcinogenic efect (Brent, 2009, 20 1 4; Pres­ ton, 2008; Strzelczyk, 2007) . • X-Ray Dosimetry

Estimates of dose to the uterus and embryo for various frequently used radiographic examinations are summarized in Table 46-5 . Imaging of maternal body parts farthest from the uterus results in a very small dose of radiation scatter to the embryo or fetus. The size of the woman, radiographic technique, and equipment performance are other variables (Wagner, 1 997) . hus, data in the table serve only as guidelines. When the radiation dose for a specific individual is required, a medical physicist should be consulted. Brent (2009) recommends consulting the Health Physics Society website (ww. hps.org) to view some examples of questions and answers posed by patients exposed to radiation. • Therapeutic Radiation

he Radiation Therapy Committee Task Group of the American Association of Physics in Medicine (Stovall, 1 995) emphasizes careful individualization of radiotherapy for the pregnant woman (Chap. 63, p. 1 1 9 1 ) . For example, in some cases, shielding of the fetus and other safeguards can be employed (Fenig, 200 1 ; Nuyttens, 2002) . In other instances, the fetus will be exposed to dangerous radiation doses, and a carefully designed plan must be improvised (Prado, 2000) . Examples include models that estimate the fetal dose given during maternal brain radiotherapy

or tangential breast irradiation (Mazonakis, 1 999, 2003) . The harmful efects of radiotherapy on future fertility and pregnancy outcomes were reviewed by Wo and Viswanathan (2009) and others and are detailed in Chapter 63 (p. 1 1 92) . • Diagnostic Radiation R a d i og ra p h s

T o estimate fetal risk, approximate x-ray dosimetry must be known. According to the merican College of Radiology, no single diagnostic procedure results in a radiation dose signii­ cant enough to threaten embryo-fetal well-being (Hall, 1 99 1 ) . F o r standard radiographs, dosimetry i s presented in Table 46-5. In pregnancy, the AP-view chest radiograph is the most commonly used study, and fetal exposure is excep­ tionally small-0.0007 Gy or 70 mrad. With one abdominal radiograph, because the embryo or fetus is directly in the x-ray beam, the dose is higher-O. OO 1 Gy or 1 00 mrad. he stan­ dard intravenous pyelogram may exceed 0.005 Gy or 500 mrad because of several exposures. The one-shot pyelogram described in Chapter 53 (p. 1 030) is useful when urolithiasis or other causes of obstruction are unproven by sonography but still sus­ pected. Most "trauma series," such as radiographs of an extrem­ ity, skull, or rib series, deliver low doses because of the fetal distance from the target area (Shakerian, 20 1 5) . F l u o roscopy a n d Ang iogra phy

Dosimetry calculations are much more diicult with these pro­ cedures because of variations in the number of radiographs obtained, total fluoroscopy time, and luoroscopy time in which the fetus is in the radiation field. As shown in Table 46-6, the range is variable. he Food and Drug Administration (FDA) limits the exposure rate for conventional fluoroscopy such as barium studies, however, special-purpose systems such as angi­ ography units have the potential for much higher exposure.

TABLE 6-5. Dose to the Uterus for Com mon Rad iolog i c P roced u res Study

View

Sku W Chest Mam mog ra m d L u m bosacra l s p i n ee Abdomene I ntravenous pye l og ra m e H i p b (s i n g le)

AP, PA, Lat AP, PN, Latd Cc, Lat AP, Lat AP 3 views AP Lat

Dosea per View (mGy)

No. Films b

Dose (mGy)

4. 1 1 .5 4.0 3 .4 1 .0 5.5

< 0 .0005 0.0002-0.0007 0.0007 -0.002 1 .76-3.6 0.8- 1 .63 6.9- 1 4

2 .0

1 -2

< 0.000 1 < 0.000 1 -0.0008 < 0.0003-0.0005 1 . 1 4-2.2

0.7- 1 .4 0 . 1 8-0.5 1

aCa l c u l ated for x-ray bea m s with half-va l u e layers ra n g i n g from 2 to 4 mm a l u m i n u m eq u iva lent u s i n g the methodo logy of Rose nstei n, 1 988. b Based on data a nd methods reported by Laws, 1 978. (Entra n ce expos u re data from Conway, 1 989. d Est i m ates based on com pi lation of a bove data . eBased on N EXT data reported i n Nati onal Cou nci l on Rad iation P rotection and Measu rements, 1 989. AP a n terior-posterior; CC cra n i a l -ca u d a l ; Lat l atera l; PA posterior-a nterior. =

=

=

=

General Co n s i d e rations a nd Maternal Eva l uation

TABLE 46-6. Est i mated X-Ray Doses to the Uterus/ E m bryo from Common F l uo roscopic P roced u res

Procedu re

Cerebra l a n g iog ra ph l Card iac a n g i og ra p hy b ,( S i n g le-vessel PTCA b,c Dou ble-vessel PTCA b,c U pper gastroi ntest i n a l series d Ba r i u m swa l low ,e Bari u m enema b,f,9

Dose to Uterus (mGy)

Fl uoroscopic Exposure in Seconds (SO)

< 0. 1 0.65 0.60 0.90 0.56 0.06 20-40

223 ( ± 1 1 8) 1 02 3 (± 952) 1 1 86 (± 593) 1 36 1 92 289-3 1 1

aWa g ner, 1 997. C a l c u lations based on data of Gorson, 1 984. c F i nci, 1 987. d S u l e i m a n , 1 99 1 . eBased on fe male data from Rowley, 1 987. fAssu m es em bryo i n rad iation fie l d for entire exa m i nation. 9Bed n a rek, 1 983. PTCA = percuta neous tra n s l u m i n a l coro n a ry a ng i oplasty; S D = sta n d a rd deviati o n .

Angiography and vascular embolization may occasion­ ally be necessary for trauma and for serious maternal disor­ ders, especially renal disease (Wortman, 20 1 3) . As before, a greater distance from the embryo or fetus lowers the exposure and risk. Co m puted Tom o g ra p hy

These x-ray images are usually performed by obtaining a spi­ ral of 360-degree images that are postprocessed in multiple planes. Of these, the axial image remains the most commonly obtained . .Multidetector CT (MDCT) images are now stan­ dard for common clinical indications. The most recent detec­ tors have 1 6 or 64 channels, and multidetector protocols may result in increased dosimetry compared with traditional CT imaging. Several imaging parameters have an efect on exposure (Brenner, 2007) . These include pitch, kilovoltage, tube current, collimation, number of slices, tube rotation, and total acquisi­ tion time. If a study is performed with and without contrast, the dose is doubled because twice as many images are obtained. Fetal exposure is also dependent on factors such as maternal size as well as fetal size and position. And as with plain radiog­ raphy, the closer the target area is to the fetus, the greater the delivered dose. Cranial CT scanning is the most commonly performed study in gravidas. It is used for neurological disorders as discussed in Chapter 60 (p. 1 1 56) and with eclampsia as noted in Chapter 40 (p. 724) . Nonenhanced CT scanning is commonly used to detect acute hemorrhage within the epidural, subdural, or sub­ arachnoid spaces (Fig. 46-3) . Because of the distance from the fetus, radiation dosage is negligible (Goldberg-Stein, 20 1 2). Abdominal procedures are more problematic. Hurwitz and associates (2006) employed a 1 6-channel multidetector

F I G U R E 46-3 A 3 7-yea r-old with intra pa rt u m ecl a m psia at term. A n i mage from a noncontrast c o m p uted tomogra phy head study demonstrates a large left-sided frontopa rieta l tem pora l i ntra pa­ renchym a l hematoma (H) with i ntraventric u l a r extension (arrow­ heads). The m i d l i ne (arrow) is shifted to the right d ue to mass effect from the hematoma. (Reproduced with perm ission from Kho KA: Diag n ostic a n d operative lapa roscopy. In Yeomans ER, Hoffma n B L, G i l stra p LC I I I, et a l (eds): Cu n n i n g ha m a nd G i lstra p's Opera tive O bstetrics 3 rd ed, New York McGraw- H i l i Ed u cation, 20 1 7.)

scanner to calculate fetal exposure at 0 and 3 months' gesta­ tion using a phantom model. Calculations were made for three commonly requested procedures in pregnant women (Table 46-7) . he pulmonary embolism protocol has the same dosim­ etry exposure as the ventilation-perfusion (V/Q) lung scan discussed on page 908. Because of the pitch used, the appen­ dicitis protocol has the highest radiation exposure, however, it is very useful clinically when MR imaging is not available. Using a similar protocol in 67 women with suspected appen­ dicitis, Lazarus and coworkers (2007) reported sensitivity of 92 percent, specificity of 99 percent, and a negative-predictive value of 99 percent. Here, dosimetry was markedly decreased compared with standard appendiceal imaging because of a dif­ ferent pitch. his is discussed further in Chapter 54 (p. 1 052) . Last, for suspected urolithiasis, the multidetector-scan protocol is used if sonography is nondiagnostic. Using a similar proto­ col, White and colleagues (2007) identifi e d urolithiasis in 1 3 o f 2 0 women at an average o f 26. 5 weeks. Finally, as shown in

TABLE 46-7. Esti mated Rad iation Dosimet ry with , 6-Cha n nel M u lti detector Co m puted­ Tomog ra p h i c (M DCT) I ma g i n g Protocol s

Protocol P u l m o n a ry e m bolism Ren a l stone Append ix Data from H u rwitz, 2006.

Dosimetry (mGy) 3 Months' Gestation Preim plantation 0.20-0.47 8- 1 2 1 5- 1 7

0.6 1 -0.66 4-7 20-40

907

908

Med ica l a n d S u rg ica l Com pl ications

because of increasingly faster acquisition times (Brown, 20 1 4) . Others have reported a higher use rate for CT angiography and emphasize that dosimetry is similar to that with V/Q scintigra­ phy (Brenner, 2007; Greer, 20 1 5; Hurwitz, 2006) . Controver­ sies on this topic continue, recognizing that fetal radiation doses are lower with CT angiography compared with the V/Q scan, but maternal chest radiation doses are substantially higher with CT scanning (van Mens, 20 1 7) . We prefer MDCT scanning initially for suspected pulmonary embolism (Chap. 52, p. 1 0 1 6) . C T pelvimetry i s used b y some before attempting breech vaginal delivery (Chap. 28, p. 542) . he fetal dose approaches 0.0 1 5 Gy or 1 . 5 rad, but use of a low-exposure technique may reduce this to 0.0025 Gy or 0.25 rad. Rad iogra p h i c Contra st Age nts

hese can be given intravenously or taken orally. Intravenous contrast agents are considered category B by the FDA. The types of intravenous contrast employed for imaging today are iodin­ ated and low osmolality, thus, they cross the placenta to the fetus. With water-soluble iodinated contrast, no cases of neo­ natal hypothyroidism or other adverse efects have been docu­ mented (American College of Radiology, 20 1 5). Oral contrast preparations, typically containing iodine or barium, have mini­ mal systemic absorption and are unlikely to afect the fetus. N uc l ea r Med i c i n e Stu d ie s

F I G U R E 46-4 Th is woman i n her third trimester was i nvolved i n a hig h-speed motor vehicle accident. A. Maxi m u m i ntensity projec­ tion acqu i red for materna l i nd ications rea d i ly identifies fetal sku l l fractu res (arrows). B . 3-D reformatted CT i mage i n a bone a lgorith m demonstrates the feta l skeleton from d a t a a c q u i red d u ring the matern a l exa m i nation. Agai n, the a rrow ma rks one fracture site. (Reprod uced with permission from Bai ley AA, Twickler OM: Peri­ operative i m a g i ng. In Yeomans ER, Hoffm a n BL, Gi lstra p LC I I I, et al (eds): C u n n i n g ha m and Gilstrap'S Operative Obstetrics 3 rd ed. New York: McGraw- H i l i Education; 201 7. Photo contri butor: Dr. Travis Brow n i ng .)

Figure 46-4, abdominal tomography is performed if indicated in the pregnant woman with severe trauma (Matzon, 20 1 5 ; Shakerian, 20 1 5) . Most experience with chest CT scanning is with suspected pulmonary embolism. The most recent recommendations for its use in pregnancy from the Prospective Investigation of Pul­ monary Embolism Diagnosis-PIOPED-II investigators were summarized by Stein and associates (2007) . They found that pulmonary scintigraphy-the V/Q scan-was recommended at that time for pregnant women by 70 percent of radiologists and chest CT angiography by 30 percent. Indeed, scintigraphy is still recommended by the American Thoracic Society for gravi­ das with a normal chest x-ray (Leung, 20 1 2) . hat said, most agree that multidetector-CT angiography has improved accuracy

hese studies are performed by "tagging" a radioactive element to a carrier that can be injected, inhaled, or swallowed. For example, the radioisotope technetium-99m may be tagged to red blood cells, sulfur colloid, or pertechnetate. he method used to tag the agent determines fetal radiation exposure. he amount of placental transfer is obviously important, but so is renal clearance because of fetal proximity to the maternal blad­ der. Measurement of radioactive technetium is based on its decay, and the units used are the curie (Ci) or the becquerel (Bq) . Dosimetry is usually expressed in millicuries (mCi) . he efective tissue dose is expressed in sievert units (Sv) with con­ version as discussed in Table 46-4: 1 Sv = 1 00 rem = 1 00 rad. Depending on the physical and biochemical properties of a radioisotope, an average fetal exposure can be calculated (Wagner, 1 997; Zanzonico, 2000) . Commonly used radio­ pharmaceuticals and estimated absorbed fetal doses are given in Table 46-8 . The radionuclide dose should be kept as low as possible (Adelstein, 1 999; Zanotti-Fregonara, 20 1 7) . Exposures vary with gestational age and are greatest earlier in pregnancy for most radiopharmaceuticals. One exception is the later efect of iodine- 1 3 1 on the fetal thyroid (Wagner, 1 997) . Discussed earlier, some still use the ventilation-perfusion lung scan for suspected pulmonary embolism. It is also used if CT angiography is nondiagnostic. Perfusion is measured with injected 99T c-macroaggregated albumin, and ventilation is measured with inhaled xenon- 1 27 or xenon- 1 33. Fetal expo­ sure with either is negligible (Chan, 2002; 110untford, 1 997) . Thyroid scanning with iodine- 1 23 or iodine- 1 3 1 seldom is indicated in pregnancy. With trace diagnostic doses used, how­ ever, fetal risk is minimal. Importantly, therapeutic radioiodine in doses to treat Graves disease or thyroid cancer may cause fetal thyroid ablation and cretinism.

Genera l Considerations a nd Maternal Eva l uation

TABLE 6-8. Rad iopha rmaceuticals Used in N uclea r Med icine Studies Estimated Activity Adm inistered per Examination (meW 20 m C i 99mTC DTPA

Study B ra i n

Weeks' Gestation b 4000 9

Preeclampsia

Birthweight >4500 9

FIGURE 48-5 I ncidence of selected preg na ncy outcomes in 1 6, 1 02 women e n rol led in the FASTER (Fi rst- a n d Second-Tri mester Eva l uation of Risk) trial accord i n g to BMI. (Data from Weiss, 2004.)

normal-weight women. LDL-III predominance is a hallmark of ectopic liver fat accumulation that is typical of NAFLD. At Parkland Hospital, we are now frequently encountering obese gravidas who have NAFLD and evidence of steatohepatitis manifest by elevated serum hepatic transaminase levels. In rare cases, liver biopsy is necessary to exclude other causes. In addition to these metabolic complications, quality-of-life measures are also negatively afected by obesity during preg­ nancy (Amador, 2008; Ruhstaller, 20 1 7) . One systematic review found significantly higher risks of depression in overweight and obese women during and after pregnancy (Molyneaux, 20 1 4) . Obese women were also significantly more likely t o experience anxiety during pregnancy. • Perinatal Morta lity

Stillbirths are more prevalent as the degree of obesity accrues (Ovesen, 20 1 1 ; Schummers, 20 1 5) . In a review of almost 1 00

: )

)

..

0.85

J 0.80 E -

20

)

S ) ) : ) 0

'3 E

• Perinatal Morbidity

Both fetal and neonatal complications are increased in obese women. Two important and interrelated cofactors that

30 -

studies, obesity was the highest ranking modifiable risk factor for stillbirth (Flenady, 20 1 l ) . In super-morbidly obese com­ pared with normal-weight gravidas, Yao and associates (20 1 4) found 5.7 and l 3.6-fold higher stillbirth rates at 39 and 4 1 weeks' gestation, respectively. Remarkably, 2 5 percent of term stillbirths in this study involved obese women. Chronic hyper­ tension with superimposed preeclampsia associated with obe­ sity is one cause of excessive stillbirths. Evaluating perinatal death rates, Lindam and coworkers (20 1 6) reported that high maternal BMI in early pregnancy was a risk factor. The risk of neonatal death is also greater for obese women 0ohansson, 20 1 4; Meehan, 20 1 4) . Finally, Cnattingius and Villamor (20 1 6) noted that accruing weight between preg­ nancies is a risk factor for perinatal mortality, whereas weight loss between pregnancies for overweight women lowers this risk.

• Obese • Normal-weight

S > 0.75 c w >

10

.J

E >

.J

O ---�

0.70

I

0.65 0.60

---� 1 2-1 6

Body mass i ndex (kg/m 2)

FIGURE 48-6 Hyperg lyce m ia a n d Adverse Preg na ncy Outcome (HAPO) study: freq uency of preecla m psia accord i n g to BMI. (Data from the HAPO Study Cooperative Research Group, 2008.)

26-30 Pregnancy (weeks)

32-36

3 mos Postpartum

FIGURE 48-7 Geometric c h a nges of ve ntricu l a r remod e l i n g left across preg nancy i n obese a nd normal-weight wo men. LVM ventricu l a r mass, LVEDV left ventricular end-d iastolic volu me. (Data from Stewart, 2 0 1 6.) =

=

Obesity

contribute to excessive rates of perinatal morbidity are chronic hypertension and diabetes, both of which are associated with maternal obesity. hese comorbidities each may play a role in the higher rates of fetal-growth restriction and indicated pre­ term birth that are seen in obese women (Schummers, 20 1 5) . Pregestational diabetes also raises the birth defect rate, and ges­ tational diabetes is complicated by excessive numbers of large­ for-gestational-age and macrosomic fetuses (Chap. 44, p . 857) . Even when diabetes i s not considered, the prevalence of macrosomic newborns is greater in obese women (Kim, 20 1 6; Ovesen, 20 1 1 ; Schummers, 20 1 5) . he group from Metro­ Health Medical Center in Cleveland has extensively studied prepregnancy obesity, gestational weight gain, and diabetes and their relationship to adverse pregnancy outcomes and to greater newborn weight and fat mass (Catalano, 2009, 20 1 5; Lassance, 20 1 5 ; Ma, 20 1 6; Yang, 20 1 6) . Although each of these variables is associated with larger and more corpulent newborns, pre­ pregnancy BMI and its efect on inflammation and placental gene expression has the strongest influence on the prevalence of macrosomic neonates. Rates of birth defects are also higher with comorbid obesity (Stothard, 2009) . For neural-tube defects, elevated risks of 1 .2-, 1 .7-, and 3. I -fold are found in overweight, obese, and severely obese women, respectively (Rasmussen, 2008) . he National Birth Defect Prevention Study reported a correlation between BMI and congenital heart defects (Gilboa, 20 1 0) . However, this may be related to diabetes as a cofactor (Biggio, 20 1 0) . Importantly, obesity is detrimental t o the accuracy o f obstetri­ cal sonographic examination and to antepartum identiication of birth defects (Adekola, 20 1 5 ; Dashe, 2009; Weichart, 20 1 1 ) . • Long-Term Ofspring Morbidity

Obese women beget obese children, who themselves become obese adults. Catalano and coworkers (2009) studied ofspring at a mean age of 9 years and found a direct association with maternal prepregnancy obesity and childhood obesity. hey also reported associations with central obesity, elevated sys­ tolic blood pressure, increased insulin resistance, and lipid abnormalities-all elements of the metabolic syndrome. Reyn­ olds and associates (20 1 3) reported higher rates of cardiovascu­ lar disease and all-cause mortality in 37,709 adult ofspring of overweight and obese mothers. Similar cardiometabolic health efects in ofspring were echoed by Gaillard and colleagues (20 1 6) . Other data support that excessive maternal weight gain in pregnancy may predict obesity in adult ofspring (Lawrence, 20 1 4; Reynolds, 20 1 0) . Last, rates of glucose intolerance and metabolic syndrome are higher among ofspring of obese women (Gaillard, 20 1 6; Tan, 20 1 5) . he potential biological mechanisms of these associations are unclear. But such studies raise the possibility ofetal program­ ming, that is, the fetal environment may lead to adverse adult health outcomes. Elucidation is limited by insuicient data on potential maternal and genetic predisposing factors and on the environment of the infant and child in relation to diet and activ­ ity. he science of epigenetics has provided some support for the possibility that perturbations of the maternal-fetal environment can adversely alter postdelivery events (Kitsiou-Tzeli, 20 1 7) . Also

possible are contributions of the maternal-child environment sub­ sequent to birth (Gluck, 2009) . These and other factors regarding fetal programming are discussed in Chapter 44 (p. 849) . ANTEPARTUM MANAGEMENT • Maternal Weight Gain

The I nstitute of Medicine (2009) has updated its previous maternal weight gain determinants (Table 9-4, p. 1 66) . For overweight women, weight gain of 1 5 to 25 pounds is sug­ gested. For obese women, the Institute advocates a gain of 1 1 to 20 pounds. Intuitively, maternal weight must increase suf­ iciently to provide for fetal and placental tissue accrual and for amnionic fluid and maternal blood volume expansion. Thus, maternal weight loss is during pregnancy is discouraged. The American College of Obstetricians and Gynecologists (20 1 5) endorses these Institute guidelines. However, these recommendations were issued without irm scientifi c evidence to support them, and their value remains unproven (Rasmussen, 20 1 0) . For example, recent studies dif­ fer with respect to the efect of insuicient weight gain for obese women. Bodnar and colleagues (20 1 6) reported no greater risk for low-birthweight or small-for-gestational-age newborns among 47,494 obese women who had inadequate weight gain during pregnancy. Bogaerts and associates (20 1 5) found that even weight loss among obese women did not yield poor fetal growth. In contrast, however, Hannaford and coworkers (20 1 7) reported that obese women who gained less than the Institute recommendations were almost three times more likely to deliver a small-for-gestational-age neonate. Another study similarly found an almost twofold greater risk among obese women who lost weight during pregnancy (Cox Bauer, 20 1 6) . Apart from inadequate weight gain, excessive gestational weight gain may portend greater risks for the obese mother. Berggren and coworkers (20 1 6) noted that overweight and obese women accrued maternal fat rather than lean mass with excessive gestational weight gain. From another analysis, overall higher rates of hypertensive disorders, cesarean delivery, and fetal overgrowth as well as lower rates of spontaneous preterm birth and fetal undergrowth were found among women gain­ ing more than recommended Oohnson, 20 1 3) . However, when analyzed according to BMI category, significantly higher rates of preeclampsia, cesarean delivery, and fetal overgrowth were identified among the 1 937 overweight women, but not for the 1 445 obese women, who gained excess weight. During pregnancy, overweight and obese women gain more weight than recommended compared with normal-weight grav­ idas (Endres, 20 1 5) . Moreover, overweight and obese women have excessive postpartum weight retention at 1 year, and one third retain at least 20 pounds more than their prepregnancy weight. • Dietary I ntervention

Several dietary interventions can help limit and achieve the weight-gain targets listed in the previous section. Options include lifestyle interventions and physical activity. In one ran­ domized trial of exercise in 300 overweight women, risks for

941

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Med ical a n d S u rg ica l C o m p l icat i o n s

gestational diabetes were lowered (Wang, 20 1 7) . That said, in another trial, 75 overweight women were randomly assigned to routine care or to a 1 6-week moderate-intensity stationary cycling program starting after midpregnancy. NIaternal and neonatal outcomes did not difer between groups (Seneviratne, 20 1 6) . Also, a Cochrane database analysis of 1 1 ,444 women suggests that lifestyle interventions confer only a modest reduc­ tion in maternal weight gain, and their benefits for fetal over­ growth, cesarean delivery rate, and adverse neonatal outcome are not significant (Muktabhant, 20 1 5) . Regarding neonatal outcomes, the poor success of lifestyle interventions during pregnancy has been attributed to their late introduction, that is, after early gene expression within the placenta has already been programmed (Catalano, 20 1 5) . • Prenatal Care

Close prenatal monitoring detects most early signs of diabetes or hypertension. Standard screening tests for fetal anomalies are suicient, while remembering the sonographic limitations for fetal anomaly detection in this group. Accurate fetal growth surveillance in obese women usually requires serial sonographic assessment. Antepartum external fetal heart rate monitoring is likewise more diicult. I NTRAPARTU M MANAGEMENT Obese women are at increased risk for multiple labor or intra­ partum complications. These include postterm pregnancy or labor abnormalities (Carpenter, 20 1 6) . In one study of 1 43,5 1 9 women, the odds of spontaneous labor at term in obese women was approximately half that of normal-weight women (Deni­ son, 2008) . In an analysis of more than 5000 parturients, 2 women with a Bh11 > 30 kg/m had a longer duration of and slower early progression in first-stage labor (Norman, 20 1 2) . • Labor I nduction

Compared with normal-weight women, obese women are twice as likely to undergo labor induction (Denison, 2008) . Unfor­ tunately, obese women are also twice as likely to experience a failed induction, and this risk rises with greater degrees of obesity (Wolfe, 20 1 1 ) . In a retrospective analysis of 470 nul­ liparous women with a BMI > 30 kg/m2 and an unfavorable cervix, those who underwent labor induction at 39 weeks' gestation were compared with those expectantly managed beyond 39 weeks (Wolfe, 20 1 4) . Two thirds of pregnancies expectantly managed either labored or had spontaneously ruptured membranes. Compared with this cohort, those who underwent planned labor induction had an elevated cesarean delivery rate-26 versus 40 percent. Moreover, their new­ borns were more frequently admitted to the neonatal intensive care unit-6 versus 1 8 percent. Conversely, Lee and associ­ ates (20 1 6) reviewed statistics from 74,725 deliveries in obese women and reported that elective induction at 37 to 39 weeks in nulliparas and especially multiparas was actually associated with a lower cesarean delivery rate. hese conflicting results highlight the diiculties faced by obstetrical providers as they

contemplate the seemingly competing interests of the fetus and the obese mother. To address this, the Maternal-Fetal Medicine Units Network is conducting a randomized trial of planned labor induction at 39 weeks' gestation in nulliparous women. • Anesthesia Risks

Obese women present anesthesia challenges that include dii­ cult epidural and spinal analgesia placement and complications from failed or diicult intubations. Evaluation of super-mor­ bidly obese gravidas by the anesthesiologist is recommended during prenatal care or upon arrival to the labor unit (American College of Obstetricians and Gynecologists, 20 1 7) . Although the rationale for antepartum anesthesia consultation and early epidural analgesia access seems logical, little published data truly demonstrates benefits from these practices (Eley, 20 1 6) . Regional analgesia for morbidly obese women is associated with longer neuraxial procedure times and more failed place­ ment attempts (Tonidandel, 20 1 4) . Importantly, however, spi­ nal analgesia in obese women for cesarean delivery does not appear to have benefits over combined spinal-epidural. For example, Ross and colleagues (20 1 4) compared single-shot spinal analgesia with combined spinal-epidural analgesia and found that both methods could be placed with equal expedi­ ency and function similarly in morbidly obese patients. Obese women who undergo regional analgesia that is com­ plicated by relative hypotension more frequently have neonates with umbilical artery cord blood acidemia, probably due to delayed delivery. Edwards and colleagues (20 1 3) studied 5742 obese women and found that pH significantly dropped, and base deficit rose, with increasing BMI. The rate of pH 1 40/90 mm Hg-to be 34 percent in blacks, 29 percent in whites, and 2 1 percent in Mexican Americans. For many years, the Joint National Committee has pro­ mulgated guidelines for diagnosis, classification, and manage­ ment of chronic hypertension. In 2008, the National Heart, Lung, and Blood Institute discontinued these guidelines, and the Joint National Committee 8 GNC 8) was instead asked to provide an evidence-based review Games, 20 1 4) . Findings per­ tinent to caring for young women with chronic hypertension are summarized in Table 5 0- 1 . • Treatment and Benefits for

Nonpregnant Adults

Proven benefits accrue with treatment of otherwise normal adults who have sustained hypertension. Numerous studies evaluating many combinations of antihypertensive therapy

have been conducted. I mportantly, these trials evaluated monotherapy versus combination therapeutic regimens and their ethnospecific beneits. Most evaluated cardiovas­ cular outcomes, but many also confirmed risk reductions in rates of cerebrovascular accident, renal insuficiency, and mortality. Because of these incontrovertible beneits, the JNC 8 recommends the management outlined in Table 5 0- 1 . Thus, even for mildly elevated blood pressure, interven­ tions to reduce these sequelae are beneficial (SPRINT Research Group, 20 1 5). Moreover, antihypertensive therapy in non­ pregnant reproductive-aged women with sustained diastolic pressures ::90 mm Hg is considered standard. Not clear from these observations, however, is what constitutes the best man­ agement for women being treated who contemplate pregnancy, for those undergoing treatment who become pregnant, or for those first identified to have chronic hypertension during preg­ nancy (August, 20 1 5). In these women, the benefits and safety of instituting antihypertensive therapy are less clear, as subsequently discussed on page 98 1 . • Preconceptional Counseling

Women with chronic hypertension are ideally counseled before pregnancy. The duration of hypertension, degree of blood pres­ sure control, and current therapy are ascertained. hose women who require multiple medications for control or those who are poorly controlled carry greater risk for adverse pregnancy outcomes. Home measurement devices are checked for accu­ racy. General health, daily activities, and dietary habits are also assessed (Table 50-2) . For hypertensive women with disease lasting longer than 5 years or with comorbid diabetes, cardiovascular and renal func­ tion is assessed (August, 20 1 5; Gainer, 2005) . Women with evidence for organ dysfunction or those with prior adverse events such as a stroke, myocardial infarction (MI), arrhyth­ mias, or ventricular failure are at markedly higher risk for a recurrence or worsening dysfunction during pregnancy. Renal function is evaluated by serum creatinine measurement. Also, if

TABLE 50-1 . Eig hth Joint Nationa l Com m ittee (J NC 8}-20 1 4 C h ronic Hypertension Guideli nes and Recommendations Evidence-based reco m mendations fro m ra ndom ized contro l l ed tri a l s Defi n itions for hyperten sion a n d prehyperten s i o n n ot a d d ressed Lifestyle mod ifi cati o n s endorsed from the Lifestyle Work G ro u p (Ecke l , 20 1 3) Recom mend selection a mong fou r specific med ication c l a sses: a n g i oten s i n-converting e nzyme i n h i bitors (ACE-I), a n g i otensi n-receptor blocke rs (ARB), ca l c i u m-c h a n n e l blocke rs, or d i u retics: Gene ra l popu lation: 0.3), proteinuria is further quantified with a 24-hour urine collec­ tion (Hladunewich, 20 1 1 ; Kuper, 20 1 6; Morgan, 20 1 6a) . The Working Group Report on High Blood Pressure in Pregnancy (2000) of the National Heart, Lung, and Blood Institute con­ cluded that the risks of fetal loss and accelerated renal disease deterioration are increased if the serum creatinine level is above 1 .4 mg/dL (Chap. 53, p. 1 034) . Although pregnancy is considered by many to be contrain­ dicated in women with severe, poorly controlled hypertension, there is no consensus. Certainly, women who maintain persis­ tent diastolic pressures ::1 1 0 mm Hg despite therapy; require multiple antihypertensives; have a serum creatinine level > 2 mg/ dL; or have a history of prior stroke, MI, or cardiac failure must be counseled as to the marked risks to themselves and to their pregnancy outcome.

DIAGNOSIS AND EVALUATION I N PREGNANCY he hypertensive disorders that uniquely complicate pregnancy are discussed in Chapter 40 (p. 7 1 0). Women are diagnosed with chronic hypertension if it is documented to precede preg­ nancy or ifhypertension is identified before 20 weeks' gestation. Evidence also supports that prehypertension may herald adverse outcomes similar to those in women with chronic hyperten­ sion (Rosner, 20 1 7) . In some women without overt chronic hypertension, a history of repeated pregnancies complicated by gestational hypertension, with or without the preeclampsia syn­ drome, may be elicited. Each is a risk marker for latent chronic hypertension, and this is especially so for preeclampsia, and in particular early-onset preeclampsia. In many ways, gestational hypertension is analogous to gestational diabetes in that such women have a chronic hypertensive diathesis, in which heredity and environment play a major role. Although uncommon, secondary causes of hypertension are always a possibility in afected women. Thus, consideration is given to underlying chronic renal disease, connective-tissue disease, primary aldosteronism, Cushing syndrome, pheochro­ mocytoma, and myriad other causes. That said, most pregnant women with antecedent hypertension will have otherwise uncomplicated disease.

=

U n ited States Depart m e n t

• Associated Risk Factors

Several factors increase the likelihood that pregnant women will have chronic hypertension. hree of those most frequently cited are ethnicity, obesity, and diabetes. As previously dis­ cussed, chronic hypertension has a population incidence that is highest in black women and lowest in Mexican-American women (Kotchen, 20 1 5) . Related to this, hundreds of blood pressure-related phenotypes and genomic regions have been identified, including candidate genes for preeclampsia and chronic hypertension (Cowley, 2006; Ward, 20 1 5) . The metabolic syndrome i s a clinical cluster that includes hypertension, high blood sugar, excess fat at the waist, and abnormal cholesterol or triglyceride levels. This constellation is a risk marker for superimposed preeclampsia and for persistent postpartum hypertension Qeyabalan, 20 1 5; Spaan, 20 1 2) . This is not surprising because obesity may increase the prevalence of chronic hypertension tenfold (Chap. 48, p. 938). In addition, obese women are more likely to develop superimposed pre­ eclampsia. Diabetes is also prevalent in chronically hyperten­ sive women, and its interplay with obesity and preeclampsia is overwhelming (Leon, 20 1 6) . In aforementioned study from the Nationwide Patient Sample, the most frequent comor­ bidities associated with chronic hypertension were pregesta­ tional diabetes-6.6 percent, thyroid disorders-4. 1 percent, and collagen-vascular disease-0.6 percent (Bateman, 2 0 1 2) . Similar comorbidities were described b y Cruz and associates (20 1 1 ) . • Efects o f Pregnancy on

Chronic Hypertension

Blood pressure drops in early pregnancy in most women with chronic hypertension, and it rises again during the third tri­ mester (Fig. 50- 1 ) . According to studies by Tihtonen and coworkers (2007) , women with chronic hypertension have per­ sistently elevated vascular resistance and possibly reduced intra­ vascular volume expansion. Adverse outcomes in these women are dependent largely on whether superimposed preeclamp­ sia develops. This may be related to observations reported by Hibbard and colleagues (2005 , 20 1 5) that arterial mechanical properties are most marked in women with superimposed pre­ eclampsia.

977

978

Med ica l a n d S u rg ical Co m p l i cations

1 60 ; 1 40 : E

. 1 20

Chronic hypertension

)

..

:l n n

�

o

C o o

ii

1 00 80 60 40 ---� 35 40 10 20 30 15 25 Gestational age (weeks)

FIGURE 50- 1 Mea n systol i c a nd d iastol i c b l ood pressu res a c ross preg na ncy in 1 07 u ntreated c h ron ica lly hype rten sive women (yellow) com pa red with b l ood pressu res a c ross p re g n a ncy in 4589 healthy n u l l i p a ras (blue). (Data from August, 20 1 5; Levi n e, 1 997; Sibai, 1 990a.)

ADVERSE PREGNANCY EFFECTS Chronic hypertension is associated with several adverse mater­ nal and perinatal outcomes listed in Table 50-3. In sum, these adversities are directly related to severity and duration of hypertension before pregnancy and whether superimposed pre­ eclampsia develops, especially early in gestation. Importantly, in women with mild chronic hypertension, outcomes are also related to blood pressure levels during pregnancy. At this time, however, there are no proven benefits of "tight" versus "less­ tight" control of chronic hypertension during pregnancy, as discussed later (p. 982) (Magee, 20 1 5) . • Maternal Morbidity and Mortality

Most women whose chronic hypertension is well controlled with therapy before pregnancy will do well. Even these women, however, are at increased risk for adverse outcomes. Compli­ cations are more likely with severe baseline hypertension and

TABLE 50-3. Some Adverse Efects of C h ro n i c Hypertension on Maternal a n d Peri n ata l Outcomes Materna l

Peri natal

S u pe ri m posed p reec l a m psia H ELLP synd rome P la centa l a b r u ption Stroke Acute kid n ey i n j u ry Hea rt fa i l u re Hyperte n sive c a rd iomyopathy Myoca rd i a l i nfa rction Mate r n a l d eath

Sti l l b i rt h G rowth restriction Preterm d e l ivery Neonata l death Neonata l morbidity

H ELLP h e molYSiS, elevated l iver enzy m e l eve l s, l ow platelet cou nt. =

especially with documented end-organ damage (Czeizel, 20 1 1 ; Odibo, 20 1 3) . In a study of pregnancy outcomes in nearly 30,000 chronically hypertensive women, Gilbert and associates (2007) reported markedly increased rates of maternal morbid­ ity that included stroke, pulmonary edema, and renal failure. hese observations were verified in the report from the Nation­ wide Patient Sample by Bateman and colleagues (20 1 2) . In this latter study, hypertension complications included stroke-2.7 per 1 000, acute renal failure-5 .9 per 1 000, pulmonary edema- 1 . 5 per 1 000, mechanical ventilation-3. 8 per 1 000, and in-house maternal mortality-O.4 per 1 000. he contribu­ tion of hypertension to pregnancy-related strokes is discussed in Chapter 60 (p. 1 1 60) and to hypertensive and idiopathic peripartum cardiomyopathy in Chapter 49 (p. 963) . Pregnancy-aggravated hypertension may be due to ges­ tational hypertension or to superimposed preeclampsia. In either instance, blood pressures can be dangerously elevated. As emphasized by Clark and Hankins (20 1 2) , systolic pres­ sure :::1 60 mm Hg or diastolic pressure :::1 1 0 mm Hg will rapidly cause renal or cardiopulmonary dysfunction or cere­ bral hemorrhage. With superimposed severe preeclampsia or eclampsia, the maternal prognosis is poor unless the pregnancy is ended. Placental abruption is a common and serious com­ plication (Chap. 4 1 , p. 767) . In addition to hypertensive heart failure mentioned above, aortic dissection was described by Weissman-Brenner and coworkers (2004) and is discussed in Chapter 49 (p. 967) . In aggregate, chronic hypertension is associated with a five­ fold risk for maternal death (Gilbert, 2007) . his is emphasized by the report by Creanga and colleagues (20 1 5) describing 3358 pregnancy-related deaths in the United States from 2006 through 20 1 0. Hypertensive disorders, including chronic hypertension and preeclampsia syndrome, accounted for 9.4 percent of these deaths. Undoubtedly related were other causes of death such as cardiovascular conditions- 1 4.6 per­ cent, cerebrovascular conditions-6.2 percent, and cardio­ myopathy- 1 1 .8 percent. Moodley (2007) reported similar indings with 3406 maternal deaths from South Africa. • Superimposed Preeclampsia

Because superimposed preeclampsia is not precisely defined in women with chronic hypertension, the reported incidence varies from 1 3 to 40 percent (American College of Obstetri­ cians and Gynecologists, 20 1 3; Bramham, 20 1 6; Kim, 20 1 6b; Moussa, 20 1 7) . August and colleagues (20 1 5) posit that this predilection may stem from similar genetic, biochemical, and metabolic abnormalities. For example, the risk for superim­ posed preeclampsia is directly related to the severity of baseline hypertension (Ankumah, 20 1 4; Morgan, 20 1 6b) . In a Mater­ nal-Fetal Medicine Units (MFMU) Network trial, Caritis and coworkers ( 1 998) identiied superimposed preeclampsia in 25 percent of hypertensive gravidas. he rate was 29 percent in a California database study (Yanit, 20 1 2) . And, women whose hypertension becomes severe enough to warrant chronic anti­ hypertensive therapy during pregnancy are at inordinately high risk for superimposed preeclampsia (Morgan, 20 1 6a) . And, this risk is even higher if there is baseline proteinuria. Finally, and

C h ro n i c Hypertension

;

1 15

• Preeclampsia • No preeclampsia

:

E 1 00 S )

; 1 05

) ) )

. � 1 00 ; :: I c I )

E

95

90 0

5

10

15

20

25

30

35

40

women at high risk for preeclampsia (Henderson, 20 1 4) . The recommendation to initiate 8 1 mg between 1 2 and 28 weeks' gestation and continue therapy until delivery was adopted by the American College of Obstetricians and Gynecologists (20 1 6b) . In addition to chronic hypertension, indications for aspirin prophylaxis for those at high-risk of preeclampsia include a history of preeclampsia, multifetal gestation, diabetes, renal disease, and autoimmune disease. Antioxidants to prevent preeclampsia have been studied. Spinnato and coworkers (2007) randomly assigned 3 1 1 women with chronic hypertension to treatment with vitamins C and E or with a placebo. A similar number in both groups developed preeclampsia-1 7 versus 20 percent, respectively.

Gestational age (weeks)

FIGURE 50-2 Blood press u re trends in treated, c h ronica l ly hyper­ tensive women with a nd without s u peri m posed preeclampsia. Mean materna l pressu res (MAPs) at entry (p 0.002) and throug hout gesta­ tion (p < 0.00 1 ) a re sig n ifica ntly d iferent for each g roup. MAP nad ir at 23.3 weeks (95% CI, 22.5-24. 1 ) for su perim posed preeclampsia versus 26.4 weeks (95% CI, 22.5-27.6) for those without preec l a m psia is sign ificant (3. 1 weeks, 95% (I, 2.3-4.3). (Data from Morg a n , 2 0 1 6a.) =

shown in Figure 5 0-2, chronically hypertensive women des­ tined to develop severe superimposed preeclampsia have higher initial blood pressures that nadir earlier than those of women who do not develop severe disease. Thus far, clinical prognostic and predictive tests for super­ imposed preeclampsia have been disappointing (Conde­ Agudelo, 20 1 5) . Di Lorenzo and colleagues (20 1 2) studied serum markers for Down syndrome to predict preeclampsia and calculated a sensitivity of 60 percent, with a 20-percent false-positive rate. Similar results were found using antian­ giogenic factors to discriminate among chronic hyperten­ sion, gestational hypertension, and preeclampsia (Costa, 20 1 6; Sibai, 2008) . According to Anton and coworkers (20 1 3) , microRNA assays may prove valuable as predictors of pregnancy-associated hypertension. Prevention

Trials of various medications to prevent preeclampsia in women with chronic hypertension have generally been disappointing and show little or no benefit. Low-dose aspirin has been evaluated most frequently (Mol, 20 1 6; Sta, 20 1 5). In the MFMU Net­ work study by Caritis ( 1 998) cited above, the incidence of super­ imposed preeclampsia, fetal-growth restriction, or both is similar in women given low-dose aspirin or placebo. Using the same database, Moore and associates (20 1 5) found that early admin­ istration of low-dose aspirin « 1 7 weeks' gestation) resulted in a significant 4 1 -percent lower frequency of superimposed pre­ eclampsia in chronically hypertensive women-1 8 versus 3 1 percent. Duley (2007) and Meads (2008) and their colleagues performed systematic reviews and noted that low-dose aspirin was beneicial in some high-risk women. Moderate beneits were also found from a metaanalysis by Askie and coworkers (2007). In a secondary analysis, Poon and associates (20 1 7) noted that aspirin was inefective to reduce the incidence of preterm preeclampsia. he U.S . Preventive Services Task Force recommends treatment with low-dose aspirin for chronically hypertensive

• Placental Abruption

Chronic hypertension augments the risk two- to threefold for premature placental separation. he general obstetrical popula­ tion risk is 1 in 200 to 300 pregnancies, and this rises to 1 in 60 to 1 20 pregnancies in women with chronic hypertension (Ankumah, 20 1 4; Cruz, 20 1 1 ; Magee, 20 1 5) . he abruption risk is elevated further if the woman smokes. Most abrup­ tions are in women with worsening gestational hypertension or superimposed preeclampsia. The abruption risk is highest with severe hypertension, and Vigil-De Gracia and colleagues (2004) reported it to be 8.4 percent. From medical record data from the Norwegian Birth Registry, folic acid and/or multivi­ tamin supplements slightly lowered the abruption incidence in women with chronic hypertension (Nilsen, 2008) . • Perinatal Morbidity and Mortal ity

Rates of almost all adverse perinatal outcomes are greater in women with chronic hypertension than in nonafected controls. As expected, for the entire group of hypertensive women, those who developed preeclampsia have substantially higher adverse outcome rates compared with those without preeclampsia. As shown in Figure 50-3, adverse outcome rates rise incremen­ tally with rising blood pressures. Evidence also supports that chronic hypertension-treated or untreated-is associated with 55 50 45 40 35 E ) 30 J ; 25 . 20 15 10 5 0

• • • •

Preterm birth P reeclampsia SGA « 1 0%) Perinatal motality

< 1 40/ 90 (n 478)

1 40-1 50/90-99 (n 221 )

=

=

1 5 1 -1 59/1 00- 1 09 (n 60) =

Blood pressure (mm Hg)

FIGURE 50-3 F requency of selected adve rse m atern a l and perina­

La ! uu Lcomes by blood p ressure stratification i n women with m i l d

c h ro n i c hypertension. S G A Ankumah, 2 0 1 4.)

=

s m a l l for gestation a l a g e . (Data fro m

979

980

Med ical a n d S u rg ical Com pl icati o n s

congenital anomalies. Bateman and coworkers (20 1 5) from the Medicaid Analytic Extract cited earlier found an elevated risk for severe congenital malformations-especially cardiac defects. Moreover, severe hypertension and fetal esophageal atresia or stenosis have been associated (Binhidy, 20 1 1 ; Van Gelder, 20 1 5) . The stillbirth frequency with chronic hypertension i s sub­ stantively greater in most reports (Chap. 3 5 , p. 646) . In the Nationwide Patient Sample study, the stillbirth rate was 1 5 . 1 per 1 000 births (Bateman, 20 1 2) . This is similar to that of 1 8 per 1 000 from a Norwegian study by Ahmad and cowork­ ers (20 1 2) and of 24 per 1 000 births from a Network study reported by Ankumah and colleagues (20 1 4) and described on page 982. Low-birthweight neonates are also common. hey are due to fetal-growth restriction, preterm delivery that is largely clinically indic�ted, or both (see Fig. 5 0-3) . In the California database study noted earlier, a fourth of fetuses were delivered preterm (Yanit, 20 1 2) . These and other studies attest to the elevated risk for fetal­ growth restriction, and the incidence averages 20 percent. Zetterstrom and coworkers (2006) reported a 2.4-fold risk for fetal-growth restriction in 2754 chronically hypertensive Swed­ ish women compared with the risk in normotensive women. Broekhuijsen and associates (20 1 2) found a 1 .3-fold increased risk for 1 609 Dutch nulliparas with chronic hypertension com­ pared with that in normotensive controls. As with other com­ plications, fetal-growth dysfunction is more likely in chronically hypertensive women who develop superimposed preeclampsia. In one study, the incidence of growth-restricted fetuses born to women with superimposed preeclampsia was almost 50 per­ cent compared with only 2 1 percent in chronically hypertensive women without preeclampsia (Chappell, 2008) . Finally, women with chronic hypertension severe enough to warrant treatment had an I I -percent incidence of fetal-growth restriction to a degree yielding birthweights ; 3rd percentile (Morgan, 20 1 6a) . For all of these reasons, neonates born to these women have a correspondingly high rate of intensive-care nursery admission. All of these adverse perinatal efects of chronic hypertension contribute to the greater perinatal mortality rate, which is three­ to fourfold higher than the rate in nonafected gravidas (American College of Obstetricians and Gynecologists, 20 1 3). In the Net­ work study by Ankumah (20 1 4) referenced in Figure 50-3, the perinatl death rate was 3 1 per 1 000 births with mild hyperten­ sion, 72 per 1 000 births with moderate disease, and 1 00 per 1 000 births in women with severe chronic hypertension. And, in the study from Parkland Hospital by Morgan (20 1 6a), the perinatal mortality rate was 32 per 1 000 births in women who were treated for their chronic hypertension. Again, as expected, the highest rates are in women who develop superimposed preeclampsia, for whom the risk doubled from 4 to 8 percent. Finally, if diabetes coexists with chronic hypertension, then preterm delivery, fetal­ growth restriction, and perinatal mortality rates are increased even more (Gonzalez-Gonzalez, 2008; Yanit, 20 1 2) .

MANAGEMENT DURING PREGNANCY he diagnosis of chronic hypertension in pregnancy should be confi r med. The American College of Obstetricians and

Gynecologists (20 1 3) recommends use of ambulatory moni­ toring to exclude suspected white-coat hypertension before initiating antihypertensive therapy. Goals for chronic hyper­ tension management include rate reductions of adverse mater­ nal or perinatal outcomes just discussed. Treatment is targeted to prevent moderate or severe hypertension and to delay or dampen the severity of pregnancy-aggravated hypertension. To some extent, these goals can be achieved pharmacologically. Blood pressure self-monitoring is encouraged, but for accuracy, automated devices must be properly calibrated (Brown, 2004; Staessen, 2004) . Personal health modification includes dietary counseling and reduction of behaviors such as tobacco, alcohol, cocaine, or other substance use (see Table 5 0-2) . A low-sodium diet is not required (American College of Obstetricians and Gynecologists, 20 1 3) . Some women-especially those with long-term o r untreated hypertension-have complications that increase the risk of adverse pregnancy events. For example, in one study, a fourth of gravidas with chronic hypertension also had concentric ven­ tricular hypertrophy (Ambia, 20 1 7; Kim, 20 1 6a) . Thus, if not already accomplished, assessment during pregnancy is done for the cardiovascular and renal systems (Morgan, 20 1 6a,b) . • Antihypertensive Drugs

As concluded by the American College of Obstetricians and Gynecologists (20 1 3 , 20 1 6a) , treatment of hypertension dur­ ing pregnancy has included every drug class, but information is still limited regarding safety and eicacy (Czeizel, 20 1 1 ; Pody­ mow, 20 1 1 ) . lthough many studies indicate greater perinatal adverse efects in gravidas requiring treatment, it is still not known whether this is due to cause or efect (Orbach, 20 1 3) . The following summary o f antihypertensive drugs i s abstracted from several sources, including the 2016 Physicians ' Desk Rf erence. Many of these drugs are also discussed throughout Chapter 1 2 (p. 24 1 ) and have been reviewed by Umans and associates (20 1 5) . Ad re n e rg i c- Recepto r Blocking Age nts

PeripheraLy acting 3-adrenergic-receptor blockers cause a gen­ eralized decline in sympathetic tone and decreased cardiac output. Examples are propranolol, metoprolol, and atenolol. Labetalol is a popular and commonly used QJ3-adrenergic blocker that is considered safe. Some adrenergic-blocking drugs act centraLy by reducing sympathetic outflow to efect a generalized decreased vascular tone. These include clonidine and a-methyldopa. Drugs in this class most frequently used in pregnancy to treat hypertension are methyldopa or an a- or 3-receptor blocking agent such as labetalol. Ca l c i u m-C h a n n e l Blocking Ag e nts

hese drugs are divided into three subclasses based on their modiication of calcium entry into cells and interference with binding sites on voltage-dependent calcium channels. Com­ mon agents include nifedipine-a dihydropyridine, and verapamil-a phenylalkyl amine derivative. These agents have negative inotropic efects and thus can worsen ventricular dys­ function and congestive heart failure. Theoretically, they may

C h ro n ic H ypert e n s i o n

potentiate the vasoactive actions of magnesium sulfate that is given for eclampsia neuroprophylaxis. Although data are lim­ ited regarding their use during pregnancy, they appear to be safe therapy for chronic hypertension (Briggs, 20 1 5 ; Umans, 20 1 5) . D i u retics

hiazide diuretics are sulfonamides, and these were the first drug group used to successfully treat chronic hypertension (Beyer, 1 982) . hese agents and loop-acting diuretics such as furosemide are commonly used in nonpregnant hypertensive patients. In the short term, they provide sodium and water diuresis with volume depletion. But with time, there is sodium escape, and volume depletion is partially corrected. Some aspect of lowered peripheral vascular resistance likely contributes to their efectiveness in reducing long-term morbidity (Umans, 20 1 5) . Thiazide drugs may b e mildly diabetogenic, and expected vol­ ume expansion may be curtailed in pregnant women. Sibai and colleagues ( 1 984) showed that plasma volume expanded only about 20 percent over time in hypertensive pregnant women who continued diuretic therapy compared with a 50-percent expansion in women who discontinued treatment. lthough perinatal outcomes were similar in these women, such concerns have led to practices of withholding diuretics as irst-line therapy for chronic hypertension, particularly after 20 weeks' gestation (Working Group Report, 2000) . Even so, in a Cochrane review, Churchill and associates (2007) reported no diferences in peri­ natal outcomes in 1 836 nonhypertensive women randomly assigned to a thiazide diuretic or placebo for primary preeclamp­ sia prevention. Overall, thiazide diuretics are considered safe in pregnancy (Briggs, 20 1 5) . But for preeclampsia treatment, they are considered to be inefective (Umans, 20 1 5) . Va sod i lators

Hydralazine relaxes arterial smooth muscle and has been used parenterally for decades to safely treat severe peripartum hyper­ tension (Chap. 40, p. 739) . Oral hydralazine mono therapy for chronic hypertension is not generally used because of its weak antihypertensive efects and resultant tachycardia. It may be an efective adjunct for long-term use with other antihyperten­ sives, especially if there is chronic renal insuiciency. In one study, vasodilator treatment of chronically hypertensive women was associated with a twofold rise in rates of low-birthweight and growth-restricted neonates (S u, 20 1 3) . Ang iote n s i n-Co nve rti ng Enzyme I n h i bitors

These drugs inhibit the conversion of angiotensin-I to the potent vasoconstrictor angiotensin-II. They can cause severe fetal malformations when given in the second and third trimes­ ters. These include oligohydramnios, hypocalvaria, and renal dysfunction (Chap. 1 2, p. 24 1 ) . Some preliminary studies also suggest teratogenic efects, and because of this, they are not recommended at any time during pregnancy (Briggs, 20 1 5 ; Podymow, 20 1 1 ) . Angiotensin-receptor blockers act i n a similar manner. But, instead of blocking the production of angiotensin-II, they inhibit binding to its receptor. They are presumed to have the

same fetal efects as angiotensin-converting enzyme inhibitors and thus are also contraindicated. • Antihypertensive Treatment in Pregnancy Seve re C h ro n i c Hyperte n s i o n

The prognosis for pregnancy outcome with chronic hyperten­ sion is somewhat dependent on the severity of disease ante­ dating pregnancy. This may be related to indings that many women with severe hypertension have renal disease-as either cause or efect (Cunningham, 1 990; Morgan, 20 1 6a) . It fol­ lows that women whose hypertension is severe enough to require antihypertensive therapy are at inordinately high risk for superimposed preeclampsia. Sibai and coworkers ( 1 986) described outcomes fro m 44 pregnancies in women whose blood pressure at 6 to 1 1 weeks' gestation was 2 1 70/ 1 1 0 mm Hg. All were given oral treat­ ment with a-methyldopa and hydralazine to maintain pres­ sures < 1 60/ 1 1 0 mm Hg. Of the 44 pregnancies, superimposed preeclampsia developed in half, and all adverse perinatal out­ comes were in this group. Moreover, all neonates of women in the superimposed group were delivered preterm, nearly 80 percent were also growth restricted, and 48 percent sufered perinatal death. Conversely, those women with severe chronic hypertension who did not develop superimposed preeclampsia had reasonably good outcomes. There were no perinatal deaths, and only 5 percent of fetuses were growth restricted. Webster and colleagues (20 1 7) found labetalol and nifedipine to be equally efective for chronic hypertension in pregnant women. Morgan and coworkers (20 1 6a) reported 447 women whose chronic hypertension required treatment beginning prior to 20 weeks. More than half of these women developed superim­ posed severe preeclampsia. he rate of preeclampsia was 53 per­ cent for those whose 24-hour protein excretion was 300 mg/day, 79 percent developed severe preeclampsia. M i l d or M o d e rate Hyperte n s i o n

Continuing prepregnancy antihypertensive treatment during pregnancy is debatable for those with mild or moderate hyper­ tension. Although blood pressure reduction certainly beneits the mother long term, it at least theoretically can reduce utero­ placental perfusion. In older observational reports, most preg­ nancy outcomes in women with mild to moderate hypertension generally were good without treatment and unless superim­ posed preeclampsia developed (Chesley, 1 978; Umans, 20 1 5) . Newer data are accruing that address potential salutary efects on pregnancy outcomes by simply lowering blood pres­ sure. Earlier studies were relatively small and had widely vary­ ing inclusion and outcome criteria. In a Cochrane review of 49 of these studies that included a total of 4723 women with mild to moderate hypertension, Abalos and coworkers (20 1 4) conirmed that the risk for subsequent severe hypertension was lowered with therapy. Compared with untreated women , the frequencies of superimposed preeclampsia, eclampsia, abrup­ tion, preterm birth, fetal-growth restriction, and perinatal or maternal mortality did not difer. This latter Cochrane review raised concerns for fetal-growth restriction with 3-blocking

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TABLE 50-4. Selected P reg n a n cy O utcomes in Women with C h ro n i c Hyperte n s i o n Treated D u ri ng P reg nancy w i t h and without Basel i ne P rote i n u riaa Outcome S u pe ri m posed p reec l a m psia Abru ption EGA at d e l ivery (mea n ) b ; 3 0 weeks ; 34 weeks ; 3 7 weeks B i rthwe i g ht (mean) b ; 3 rd percent i l e ; 1 0th perce n t i l e Peri nata l morta l ity

Baseline Proteinuriaa

No Proteinu ria

P-value

79% 0 3 5. 1 ± 4.3 wks 1 8% 34% 48% 2379 ± 1 028 g 20% 41 % 36/1 000

49% 1% 3 7 .2 ± 3 .3 wks 6% 1 7% 26% 28 1 4 ± 807 g 9% 22% 3 1 / 1 000

0.05 . H ELLP hemolys i s, el evated l iver enzyme leve ls, low platelet cou nt. Data from Mag ee, 2 0 1 5 . =

C h ron i c Hypert e n s ion

also mandatory for women with prior adverse outcomes such as strokes, MIs, and evidence for cardiac or renal dysfunction. With end-organ dysfunction, treatment to diastolic pressure level ;90 mm Hg is reasonable to mitigate further organ damage. For most women with mild to moderate hypertension, the College recommends that treatment be withheld as long as systolic blood pressure is < 1 60 mm Hg and diastolic blood pressure is < 1 05 mm Hg. Some find it reasonable to begin antihypertensive treatment in otherwise healthy pregnant women with persistent systolic pressures > 1 5 0 mm Hg or dia­ stolic pressures of 95 to 1 00 mm Hg or greater (August, 20 1 5 ; Working Group Report, 2000) . At Parkland Hospital we initi­ ate treatment with antihypertensive agents for blood pressures of 1 50/ 1 00 mm Hg or higher. Our preferred regimens include monotherapy with a 3-blocking drug such as labetalol or a calcium-channel blocking agent such as amlodipine. For women in the first half of pregnancy, therapy with a thiazide diuretic seems reasonable. This is especially true in black women, in whom there is a high prevalence of salt-sensitive chronic hypertension. It is controversial whether or not women who present early in pregnancy and who are already taking antihypertensive drugs should continue to take these (Rezk, 20 1 6) . According to the American College of Obstetricians and Gynecologists (20 1 3) and the Society for Maternal-Fetal Medicine (20 1 5) , for women with mild t o moderate hypertension, i t i s reasonable to discontinue medications during the irst trimester and to restart them if blood pressures approach the severe range. Our practice at Parkland Hospital is to continue treatment if the woman is already taking drugs when she presents for prenatal care. Exceptions are discontinuation of angiotensin-converting enzyme inhibitors and receptor blockers. Some women will have persistently worrisome hyperten­ sion despite usual therapy (Samuel, 20 1 1 ; Sibai, 1 990a) . I n these women, primary attention i s given t o the likelihood o f pregnancy-aggravated hypertension, with or without super­ imposed preeclampsia. Other possibilities include inaccurate blood-pressure measurements, suboptimal treatment, and antagonizing substances such as chronic ingestion of nonsteroi­ dal antiinlammatory drugs (NSAIDs) (Moser, 2006; Sowers, 2005 ) . • Pregnancy-Aggravated Hypertension or

Superimposed Preeclampsia

As discussed, the frequency of superimposed preeclampsia for women with chronic hypertension varies depending on the study population and hypertension severity (Ankumah, 20 1 4) . Importantly, i n 4 0 t o 50 percent o f chronically hypertensive women, superimposed preeclampsia develops before 37 weeks (Chappell, 2008; Harper, 20 1 6) . This proportion is even higher in women who required hypertension treatment during preg­ nancy (Morgan, 20 1 6a) . The diagnosis may be diicult to make, especially in women with hypertension who have underlying renal disease with chronic proteinuria (Cunningham, 1 990; Morgan, 20 1 6b) . As discussed in Chapter 40 (p. 7 1 2) , conditions that support

the diagnosis of superimposed preeclampsia include worsening hypertension, new-onset proteinuria, neurological symp toms such as severe headaches and visual disturbances, generalized edema, oliguria, and certainly, convulsions or pulmonary edema. Making the diagnosis based on worsening proteinuria in women with baseline proteinuria is problematic. Supporting laboratory abnormalities are rising serum creatinine or hepatic transaminase levels, thrombocytopenia, or any of the facets of HELLP (hemolysis, �levated liver enzyme levels, low 2latelet count) syndrome. For women with chronic hypertension and superimposed preeclampsia with severe features, magnesium sulfate for maternal neuroprophylaxis is recommended (Ameri­ can College of Obstetricians and Gynecologists, 20 1 3) . S evere hypertension is treated as described in Chapter 40 (p. 738 ) . Some pregnant women with chronic hypertension have worsening hypertension with no other findings of superim­ posed preeclampsia. This is most commonly encoun tered near the end of the second trimester. In the absence of other supporting criteria for superimposed preeclampsia, this likely represents the higher end of the normal blood-pressure curve shown in Figure 50- 1 . In such women, if preeclampsia can be confidently excluded, it is reasonable to begin or to increase the dose of antihypertensive therapy. • Fetal Assessment

Women with well-controlled chronic hypertension who have no complicating factors can generally be expected to have a good pregnancy outcome. Because even those with mild hypertension have a greater risk of superimposed preeclampsia and fetal-growth restriction, serial antepartum assessment of fetal well-being is recommended by many. That said, accord­ ing to the American College of Obstetricians and Gynecolo­ gists (20 1 3) , with the exception of sonographic fetal-growth monitoring, described in Chapter 44 (p. 852), no conclusive data address either benefit or harm associated with various antepartum surveillance strategies. • Expectant Management of Early-Onset

Preeclampsia

Given that many women with chronic hypertension develop superimposed preeclampsia before term, considerations for expect­ ant management may be reasonable in some cases. In a study from Magee-Women's Hospital, 4 1 careully selected women with a median gestational age of 3 1 .6 weeks were expectantly managed (Samuel, 20 1 1) . Despite liberal criteria to mandate delivery, 1 7 percent developed either placental abruption o r pulmonary edema. The latency period was extended by a mean of 9.7 days. There were no perinatal deaths, however, salutary outcomes were similar. These investigators recommend randomized trials to study expect­ ant management before this becomes usual care. • Delivery

For chronically hypertensive women who have complications such as fetal-growth restriction or superimposed preeclamp­ sia, the decision to deliver is made by clinical j udgment. The route of delivery is dictated by obstetrical factors. Certainly,

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most women with superimposed severe preeclampsia are better delivered even when the fetus is markedly preterm. Increased risk for placental abruption, cerebral hemorrhage, and peripar­ tum heart failure attend delivery delays (Cunningham, 1 986, 2005 ; Martin, 2005). For women with chronic hypertension without preeclamp­ sia, expectant management at later gestational ages was reported recently by H arper and colleagues (20 1 6) . They concluded that expectant management beyond 39 weeks' gestation was associ­ ated with an increasing incidence of severe preeclampsia and that plan ned delivery before 37 weeks was associated with a rise in rates of adverse neonatal outcomes. For women with mild to moderate chronic hyperten­ sion who continue to have an uncomplicated pregnancy, the merican College of Obstetricians and Gynecologists (20 1 3) recommends delivery not be pursued until 3 8 °17 weeks. The consensus committee indings by Spong and associates (20 1 1 ) recommend consideration for delivery a t 38 t o 39 weeks, that is, :::37 completed weeks. A trial of labor induction is prefer­ able, and many of these women respond favorably and will be delivered vaginally (Alexander, 1 999; Atkinson, 1 995) . • I ntrapa rtum Considerations

For women with severe preeclampsia, peripartum manage­ ment is the same as described in Chapter 40 (p. 729) . Epi­ dural analgesia for labor and delivery is optimal with the caveat that it is not given to treat hypertension (Lucas, 200 1 ) . hat said, women with severe superimposed preeclampsia are more sensitive to the acute hypotensive efects of epidural analgesia (Vricella, 20 1 2) . Also in this group, magnesium sulfate neu­ roprophylaxis is initiated for prevention of eclampsia. Severe hypertension-diastolic blood pressure :::1 1 0 mm Hg or sys­ tolic pressure :::1 60 mm Hg-is treated with either intravenous hydralazine or labetalol. Some prefer to treat women when the diastolic pressure reaches 1 00 to 1 05 mm Hg. Vigil-De Gra­ cia and colleagues (2006) randomly assigned 200 women to intravenous hydralazine or labetalol to acutely lower severe high blood pressure in pregnancy. Outcomes were similar except for significantly more maternal palpitations and tachycardia with hydralazine and signiicantly more neonatal hypotension and bradycardia with labetalol. • Postpartum Care

In most respects, postpartum observation, prevention, and management of adverse complications are similar in women with severe chronic hypertension and in those with severe pre­ eclampsia-eclampsia. For persistent severe hypertension, con­ sideration is given for a cause such as pheochromocytoma or Cushing disease (Sibai, 20 1 2) . And, in women with chronic end-organ damage, certain complications are more common. These include cerebral or pulmonary edema, heart failure, renal dysfunction, or cerebral hemorrhage, especially within the irst 48 hours after delivery (Martin, 2005 ; Sibai, 1 990b, 20 1 2) . hese frequently are preceded by sudden elevations­ "spikes"-of mean arterial blood pressure and of the systolic component (Cunningham, 2000, 2005).

Following delivery, as maternal peripheral resistance rises, left ventricular workload also grows. This elevation is further aggravated by appreciable and pathological amounts of inter­ stitial luid that are mobilized to be excreted as endothelial dis­ ruption from preeclampsia resolves. In these women, sudden hypertension-either moderate or severe-may exacerbate dia­ stolic dysfunction, cause systolic dysfunction, and lead to pul­ monary edema (Cunningham, 1 986; Gandhi, 200 1 ) . Prompt hypertension control, along with furosemide-evoked diuresis, usually quickly resolves pulmonary edema. he antihypertensive regimen given antepartum can be restarted in the puerperium. It is also possible in many women to forestall postpartum hypertension by administering intrave­ nous or oral furosemide to augment the normal postpartum diuresis. In one study, 20-mg oral furosemide given daily for 5 days to postpartum women with severe preeclampsia aided blood pressure control (Ascarelli, 2005). Daily weights are helpful in this regard. On average, a woman should weigh 1 5 pounds less immediately after delivery. Excessive extracellular fluid can then be estimated. Other studies are in progress to determine aspects of postpartum blood pressure management (Cursino, 20 1 5) . Some evidence supports that chronic ingestion ofNSAIDs in the puerperium elevates blood pressure in women with severe preeclampsia (Vigil-De Gracia, 20 1 7) . his may not be prob­ lematic if these drugs are given only as needed (Wasden, 20 1 4) . Women with chronic hypertension have special consider­ ations for contraceptive and sterilization choices. These are dis­ cussed in detail throughout Chapters 38 and 39. • Long-Term Prognosis

Ultimately, women with chronic hypertension are at high risk for lifetime cardiovascular complications, especially when accompanied by diabetes, obesity, and the metabolic syn­ drome. Recent evidence also suggests that these women are at greater risk to develop cardiomyopathy remote from pregnancy (Behrens, 20 1 6) .

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C h ro n ic Hypert e n s ion 20 1 6b. Available at: http://ww.acog.org/About-ACOG/News-Room/ Practice-Advisories/Practice-Advisory-Low-Dose-Aspirin-and-Prevention­ of-Preeclampsia-Updated-Recommendations. Accessed January 5, 20 1 7 Ankumah NA, Cantu J , Jauk V , e t al: Risk o f adverse pregnancy outcomes in women with mild chronic hypertension before 20 weeks of gestation. Obstet Gynecol 123(5):966, 20 1 4 Anton L , Olarerin-George AO, Schwartz N, et al: miR-2 1 0 inhibits tropho­ blast invasion and is a serum biomarker for preeclampsia. Am J Pathol 1 83(5): 1 437, 20 1 3 Ascarelli MH, Johnson V , McCreary H , et al: Postpartum preeclampsia man­ agement with furosemide: a randomized clinical trial. Obstet Gynecol 1 0 5 ( 1 ) :29, 2005 Askie LM, Duley L, Henderson-Smart OJ, et al: Antiplatelet agents for pre­ vention of pre-eclampsia: a meta-analysis of individual patient data. Lancet 369(9575) : 1 79 1 , 2007 Atkinson MW, Guinn 0, Owen J, et al: Does magnesium sulfate afect the length of labor induction in women with pregnancy-associated hyperten­ sion? Am J Obstet GynecoI 1 73(4) : 1 2 1 9, 1 995 August P, Jeyabalan A, RobertS JM: Chronic hypertension and pregnancy. In: Taylor N, RobertS JM, Cunningham FG, et al (eds): Chesley's Hyperten­ sive Disorders in Pregnancy. Amsterdam, Academic Press, 20 1 5 Banhidy F, Acs N, Puh6 EH, et al: Chronic hypertension with related drug treatment of pregnant women and congenital abnormalities in their of­ spring: a population-based study. Hypertens Res 34(2) :257, 20 1 1 Bateman BT, Bansil P, Hernandez-Diaz S, et al: Prevalence, trends, and out­ comes of chronic hypertension: a nationwide sample of delivery admissions. Am J Obstet Gynecol 206(2) : 1 34.e 1 , 20 1 2 Bateman BT, H uybrechts KF, Fischer MA, et al: Chronic hypertension in pregnancy and the risk of congenital malformations: a cohort study. Am J Obstet Gynecol 2 1 2:337.e 1 , 20 1 5 Behrens 1 , Basit S , Lykke JA, et al: Association between hypertensive disorders of pregnancy and later risk of cardiomyopathy. JAMA 3 1 5 ( 1 0): 1 026, 20 1 6 Beyer KH: Chlorothiazide. J Clin Pharmacol 1 3: 1 5 , 1 982 Bramham K, Hladunewich A , Jim B, et al: Pregnancy and kidney disease. NephSAP Nephrology Assessment Program 1 5 ( 1 ) : 1 , 20 1 6 Briggs GG, Freeman RK: Drugs i n Pregnancy and Lactation, 1 0th ed. Phila­ delphia, Lippincott Williams & Wilkins, 20 1 5 Broekhuijsen K , Langeveld J , van den Berg P , et al: Maternal and neonatal outcomes in pregnancy in women with chronic hypertension. Am J Obstet GynecoI 206:S344, 20 1 2 Brown M , McHugh L , Mangos G , et al: Automated self-initiated blood pres­ sure or 24-hour ambulatory blood pressure monitoring in pregnancy? BJOG 1 1 1 :38, 2004 Caritis S, Sibai B, Hauth J, et al: Low-dose aspirin to prevent preeclampsia in women at high risk. N Engl J Med 338( 1 1 ) :70 1 , 1 998 Centers for Disease Control and Prevention: Vital signs: prevalence, treatment, and control of hypertension-United States, 1 999-2002 and 2005-2008. MMWR 60(4) : 1 , 20 1 1 Chappell LC, Enye S, Seed P, et al: Adverse perinatal outcomes and risk factors for preeclampsia in women with chronic hypertension: a prospective study. Hypertension 5 1 (4) : 1 002, 2008 Chesley LC: Superimposed preeclampsia or eclampsia. In Chesley LC (ed): Hyper­ tensive Disorders in Pregnancy. New York, Appleton-Century-Crots, 1 978 Churchill 0, Beevers GO, Meher S, et al: Diuretics for preventing pre-eclamp­ sia. Cochrane Database Syst Rev 1 :CD00445 1 , 200 Clark SL, Hankins GO: Preventing maternal death. 10 clinical diamonds. Obstet Gynecol 1 1 9(2):360, 20 1 2 ClinicalTrials.gov: Chronic Hypertension and Pregnancy (CHAP) Project. 20 1 6. Available at: https:llclinicaltrials.gov/ct2/show/NCT022994 1 4 . Accessed JanualY 5, 20 1 7 Conde-Agudelo A, Romero R, RobertS ltvl: Tests to predict preeclampsia. In Taylor N, RobertS JM, Cunningham FG, et al (eds): Chesley's Hyper­ tensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 20 1 5 Costa A, Hoshida MS, Alves A , et al: Preeclampsia and superimposed pre­ eclampsia: the same disease? he role of angiogenic biomarkers. Hypertens Pregnancy 3 5 (2): 1 39, 20 1 6 Cowley AW Jr: he genetic dissection o f essential hypertension. Nat Rev Genet 7:829, 2006 Creanga A, Berg CJ, Syverson C, et al: Pregnancy-related mortality in the United States, 2006-20 1 0. Obstet Gynecol 1 25 ( 1 ) : 5 , 20 1 5 Cruz MO, Gao W, Hibbard JU: Obstetrical and perinatal outcomes among women with gestational hypertension, mild preeclampsia, and mild chronic hypertension. Am J Obstet GynecoI 205 :260.e l , 20 1 1 Cunningham FG: Severe preeclampsia and eclampsia: systolic hypertension is also important. Obstet Gynecol 1 0 5: 237, 2005 Cunningham FG, Cox SM, Harstad W , et al: Chronic renal disease and pregnancy outcome. Am J Obstet Gynecol 1 63:453, 1 990

Cunningham FG, Pritchard JA, Hankins GO, et al: Idiopathic cardiomyopathy or compounding cardiovascular events? Obstet GynecoI 67: 1 57, 1 986 Cunningham FG, Twickler 0: Cerebral edema complicating eclampsia. Am J Obstet Gynecol 1 82 ( 1 ) :94, 2000 Cursino T, Katz L, Coutinho I, et al: Diuretics vs. placebo for postpartum blood pressure control in preeclampsia (DIUPRE): a randomized clinical trial. Reprod Health 1 2: 66, 20 1 5 Czeizel AE, Banhidy F : Chronic hypertension in pregnancy. Curr Opin Obstet Gynecol 23(2):76, 20 1 1 Di Lorenzo G, Ceccarello M, Cecotti V, et al: First trimester maternal serum PIGF, free b-hCG, PAPP-A, PP- 1 3, uterine artery Doppler and maternal history for the prediction of preeclampsia. Placenta 33(6):495 , 20 1 2 Duley L, Henderson-Smarr OJ, Meher S , et al: Antiplatelet agents for pre­ venting pre-eclampsia and its complications. Cochrane Database Syst Rev 2:CD004659, 2007 Eckel RH, Jakicic JM, Ard JD, et al: 20 1 3 AHAIACC guidelines on lifestyle management to reduce cardiovascular risk: a report of the American College of CardiologylAmerican Heart Association Task Force on Practice Guide­ lines. Circulation 1 29(25 Suppl 2):S76, 20 1 3 Forouzanfar M H , Liu P , Roth GA, e t al: Global burden o f hypertension and sysrolic blood pressure of at least 1 1 0 to 1 1 5 mm Hg, 1 990-20 1 5. JM1A 3 1 7: 1 65, 20 1 7 Gainer J , Alexander J , Mclntire 0 , et al: Maternal echocardiogram findings in pregnant patients with chronic hypertension. Presented at the 25th Annual Meeting of the Society for Maternal-Fetal Medicine, Reno, February 7-1 2, 2005 Gandhi SK, Powers JC, Nomeir A, et al: The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 344 ( 1 ) : 1 7, 200 1 Gilbert M, YoungAL, Danielsen B: Pregnancy-outcomes in women with chronic hypertension: a population-based study. J Reprod Med 52( 1 1 ) : 1 046, 2007 Gonzalez-Gonzalez NL, Ramirez 0, Mozas J, et al: Factors inluencing preg­ nancy outcomes in women with type 2 versus type 1 diabetes mellitus. Acta Obstet Gynecol Scand 8 7 ( 1 ) :43, 2008 Gruppo di Studio Iperrensione in Gravidanza: Nifedipine versus expectant management in mild to moderate hypertension in pregnancy. BJOG 1 05 (7) : 7 1 8, 1 998 Harper LM, Biggio JR, Anderson S, et al: Gestational age of delivery in pregnan­ cies complicated by chronic hypertension. Obstet Gynecol 1 27(6): 1 1 0 1 , 20 1 6 Henderson JT, Whitlock EP, O'Connor E , et al: Low-dose aspirin for preven­ tion of morbidity and mortality from preeclampsia: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med 1 60 ( 1 0): 695, 2 0 1 4 Hibbard J U , Korcarz C E , Nendaz GG, e t a l : The arterial system in pre-eclamp­ sia and chronic hypertension with superimposed pre-eclampsia. BJOG 1 1 2 (7) :897, 2005 Hibbard JU, Shrof SG, Cunningham FG: Cardiovascular alterations in pregnancy and preeclamptic pregnancy. In Taylor RN, Roberts J M , Cun­ ningham FG, et al (eds): Chesley's Hypertensive Disorders in Pregnancy. Amsterdam, Academic Press, 20 1 5 Hladunewich MA, Schaefer F : Proteinuria in special populations: pregnant women and children. Adv Chronic Kidney Dis 1 8 (4):267, 20 1 1 James PA, Oparil S, Carter BL, et al: 20 1 4 evidence-based guidelines for the management of high blood pressure in adults. Report from the panel mem­ bers appointed to the Eighth Joint National Committee ONC 8). JAMA 3 1 1 (5): 507, 20 1 4 Jeyabalan A , Hubel CA, Roberts J M : Metabolic syndrome and preeclampsia. In Taylor RN, RobertS JM, Cunningham FG, et al (eds): Chesley's Hyper­ tensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 20 1 5 Kim MJ, Seo J , Cho Kl, et al: Echocardiographic assessment of structural and hemodynamic changes in hypertension-related pregnancy. J Cardiovasc Ultrasound 24:28, 20 1 6a Kim SA, Park JB: OS 23-03 Midtrimester risk prediction of superimposed pre-eclampsia in pregnant women with chronic hypertension. J Hypertens 34 Suppl 1 :e24 1 , 20 1 6b Kotchen TA: Hypertensive vascular disease: In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 1 9th ed. New York, McGraw-Hill Education, 20 1 5 Kuper SG, Tita AT, Youngstrom ML, et al: Baseline renal function tests and adverse outcomes in pregnant patients with chronic hypertension. Obstet Gynecol 1 28:93, 20 1 6 Leon MG, Moussa HN, Longo M , et al: Rate of gestational diabetes mellitus and pregnancy outcomes in patients with chronic hypertension. Am J Peri­ natoI 33(8) :74 5 , 20 1 6 Levine RJ, Hauth JC, Curet LB, et al: Trial of calcium to prevent preeclampsia. N Engl J Med 33 (2):69, 1 99 Lindheimer MD, Taylor RN, Roberts JM et al: Introduction, history, contro­ versies, and deinitions. In Taylor RN, Roberts JM, Cunningham FG, et al

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Med ical a nd S u rg ica l Com p l i cations (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 20 1 5 Lucas M), Sharma SK, McIntire DD, et al: A randomized trial of labor analge­ sia in women with pregnancy-induced hypertension. Am ) Obstet Gynecol 1 85 (4):970, 200 1 Magee A, von Dadelszen P, Rey E, et al: Less-tight versus tight control of hypertension in pregnancy. N Engl ) Med 3 2 (5) :407, 20 1 5 Martin ) N )r, Thigpen BD, Moore RC, et al: Stroke and severe preeclampsia and eclampsia: a paradigm shift focusing on systolic blood pressure. Obstet Gynecol 1 05 (2):246, 2005 Meads CA, Cnossen )S, Meher S, et al: Methods of prediction and prevention of pre-eclampsia: systematic reviews of accuracy and efectiveness literature with economic modelling. Health Technol Assess 1 2(6): 1 , 2008 Mol BW, Roberts CT, Thangaratinam S, et al: Pre-eclampsia. Lancet 387( 1 0022) :999, 20 1 6 Moodley ): Maternal deaths due to hypertensive disorders i n pregnancy: Saving Mothers report 2002-2004. Cardiovasc ) Afr 1 8:358, 2007 Moore GS, Allshouse A, Post AL. et al: Early initiation of /ow-dose aspirin for reduction in preeclampsia risk in high-risk women: a secondary analysis of the MFMU high-risk aspirin study. ) Perinatol 35 (5) :328, 20 1 5 Morgan )L, Nelson DB, RobertS SW, et al: Blood pressure profiles across pregnancy in women with chronic hypertension. Am ) PerinatoI 33( 1 2): 1 1 28, 20 1 6a Morgan )L, Nelson DB, Roberts SW, et al: The association of baseline pro­ teinuria and adverse pregnancy outcomes in pregnant women with treated chronic hypertension. Obstet Gynecol 1 28:270, 20 1 6b Moser M, Setaro )F: Resistant or diicult-to-control hypertension. N Engl ) Med 355:385, 2006 Moussa HN, Leon MG, Marti A, et al: Pregnancy outcomes in women with preeclampsia superimposed on chronic hypertension with and without severe features. Am ) PerinatoI 34(4) :403, 20 1 7 Nilsen R M , Vollset SE, Rasmussen SA, et al: Folic acid and multivitamin supplement use and risk of placental abruption: a population-based registry study. Am ) Epidemiol 1 67(7) :867, 2008 Odibo I, Zilberman D, Apuzzio ), et al: Utiliry of posterior and septal wall thickness in predicting adverse pregnancy outcomes in patients with chronic hypertension. Abstract No. 624, Am ) Obstet Gynecol 208:S265, 20 1 3 Orbach H, Matok I , Gorodischer R , et al: Hypertension and antihyperten­ sive drugs in pregnancy and perinatal outcomes. Am ) Obstet Gynecol 208(4) :30 1 .e 1 , 20 1 3 Physicians' Desk Reference, 70th ed. Chestertown, PDR Network, 20 1 6 Podymow T , August P: Antihypertensive drugs i n pregnancy. Semin Nephrol 3 1 ( 1 ) :70, 20 1 1 Poon LC, Wright D, Rolnik DL, et al: Aspirin for evidence-based preeclampsia prevention trial: efect of aspirin in prevention of preterm preeclampsia in sub­ groups of women according to their characteristics and medical and obstetrical history. Am ) Obstet Gynecol August 4, 20 1 7 [Epub ahead of print] Rezk M, Eliakwa H, Gamal A, Emara M: Maternal and fetal morbidiry follow­ ing discontinuation of antihypertensive drugs in mild to moderate chronic hypertension: a 4-year observational study. Pregnancy Hypertens 6:29 1 , 20 1 6 Rosner )Y, Gutierrez M, Dziadosz M, e t al: Prehypertension i n early preg­ nancy: what is the signiicance? Am ) PerinatoI 34(2) : 1 l 7, 20 1 7 Samuel A, Lin C, Parviainen K, et al: Expectant management o fpreeclmpsia super­ imposed on chronic hypertension. ) Matern Fetal Neonatal Med 24(7) :907, 20 1 1 Sibai BM: Etiology and management of postpartum hypertension-preeclamp­ sia. Am ) Obstet Gynecol 206(6) :470, 20 1 2 Sibai BM, Anderson G D : Pregnancy outcome o f intensive therapy in severe hypertension in irst trimester. Obstet Gynecol 67(4) : 5 1 7, 1 986 Sibai BM, Grossman A, Grossman HG: Efects of diuretics on plasma vol­ ume in pregnancies with long-term hypertension. Am ) Obstet Gynecol 1 50 (7) :83 1 , 1 984 Sibai BM, Koch vA, Freire S, et al: Serum inhibin A and angiogenic factor levels in pregnancies with previous preeclampsia andlor chronic hyperten­ sion: are they useful markers for prediction of subsequent preeclampsia? Am ) Obstet Gynecol 1 99(3):268.e 1 , 2008 Sibai BM, Mabie We, Shamsa F, et al: A comparison of no medication versus methyldopa or labetalol in chronic hypertension during pregnancy. Am ) Obstet Gynecol 1 62(4):960, 1 990a Sibai BM, Villar A, Mabie BC: Acute renal failure in hypertensive disorders of pregnancy. Pregnancy outcome and remote prognosis in thirry-one con­ secutive cases. Am ) Obstet GynecoI 1 62 (3) : 7, 1 990b

Sociery for Maternal-Fetal Medicine: SMFM statement: beneit of antihyper­ tensive therapy for mild-to-moderate chronic hypertension during preg­ nancy remains uncertain. Am ) Obstet GynecoI 2 1 3 ( 1 ):3, 20 1 5 Sowers ) R, White WB, Pitt B , et al: he efects of cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory therapy on 24-hour blood pressure in patients with hypertension, osteoarthritis, and rype 2 diabetes mellitus. Arch Intern Med 1 6 5 (2) : 1 6 1 , 2005 Spaan JJ, Sep S) , van Balen VL, et al: Metabolic syndrome as a risk factor for hypertension after preeclampsia. Obstet Gynecol 1 20 (2 Pt 1 ) :3 1 1 , 20 1 2 Spinnato )A 2nd, Freire S , Pinto ESilva )L, et al: Antioxidant therapy to prevent preeclampsia: a randomized controlled trial. Obstet Gynecol 1 1 O( 6): 1 3 1 1 , 2007 Spong CY, Mercer BM, D'lton M, et al: Timing of indicated late-preterm and early-term birth. Obstet Gynecol 1 1 8 (2 Pt 1 ) :323, 20 1 1 SPRINT Research Group, Wright )T )r, Williamson )D, et al: A random­ ized trial of intensive versus standard blood-pressure control. N Engl ) Med 373(22) :2 1 03, 20 1 5 Staessen )A, Den Hond E , Celis H , et al: Antihypertensive treatment based on blood pressure measurement at home or in the physician's oice: a random­ ized controlled trial. JAMA 2 9 1 (8):955, 2004 Staf CA, Sibai BM, Cunningham FG: Prevention of preeclampsia and eclamp­ sia. In Taylor RN, Roberts )M, Cunningham FG, et al (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 20 1 5 Su CY, Lin HC, Cheng HC, et al: Pregnancy outcomes of anti-hypertensives for women with chronic hypertension: a population-based study. PLoS One 8(2) :e53844, 20 1 3 Tihtonen K , Koobi T , Huhtala H , e t al: Hemodynamic adaptation dur­ ing pregnancy in chronic hypertension. Hypertens Pregnancy 26(3) :3 1 5 , 2007 Umans )G, Abalos E, Cunningham FG: Antihypertensive treatment. In Taylor RN, Roberts )M, Cunningham FG, et al (eds): Chesley's Hypertensive Dis­ orders in Pregnancy, 4th ed. Amsterdam, Academic Press, 20 1 5 Van Gelder MM, Van Bennekom CM, Louik C , e t al: Maternal hypertensive disorders, antihypertensive medication use, and the risk of birth defects: a case control-study. B)OG 1 22(7) : 1 002, 20 1 5 Vigil-De Gracia P , Lasso M, Montufar-Rueda C: Perinatal outcome i n women with severe chronic hypertension during the second half of pregnancy. Int ) Gynaecol Obstet 8 5 (2): 1 39, 2004 Vigil-De Gracia P, Lasso M, Ruiz E, et al: Severe hypertension in pregnancy: hydralazine or labetalol a randomized clinical trial. Eur ) Obstet Gynecol Reprod BioI 1 28( 1 -2) : 1 57, 2006 Vigil-De Gracia P, Solis V, Ortega N: Ibuprofen versus acetaminophen as a post-partum analgesic for women with severe pre-eclampsia: randomized clinical study. ) Matern Fetal Neonatal Med 30( 1 1 ) : 1 279, 20 1 7 Vricella LK, Louis )M, Mercer BM, e t al: Epidural-associated hypotension is more common among severely preeclamptic patients in labor. Am ) Obstet GynecoI 207(4):335.e 1 , 20 1 2 Ward K , Taylor RN: Genetic factors in the etiology o f preeclampsia/eclamp­ sia. In Taylor RN, Roberts )M, Cunningham FG, et al (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 20 1 5 Wasden SW, Ragsdale ES, Chasen ST, et al: Impact of non-steroidal anti­ inflammatory drugs on hypertensive disorders of pregnancy. Pregnancy Hypertens 4:259, 20 1 4 Webster LM, Myers )E, Nelson-Piercy C , e t al: Labetalol versus nifedipine as antihypertensive treatment for chronic hypertension in pregnancy: a ran­ domized controlled trial. Hypertension 70:9 1 5, 20 1 7 Weissman-Brenner A , Schoen R, Divon MY: Aortic dissection i n pregnancy. Obstet Gynecol 1 03: 1 1 1 0, 2004 Working Group Report on High Blood Pressure in Pregnancy: Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am ) Obstet Gynecol 1 83:S 1 , 2000 Yanit E, Snowden )M, Cheng W, et al: he impact of chronic hypertension and pregestational diabetes on pregnancy outcomes. Am ) Obstet Gynecol 207(4) :333.e 1 , 20 1 2 Zetterstrom K , Lindeberg SN, Haglund B , e t al: Chronic hypertension as a risk factor for ofspring to be born small for gestational age. Acta Obstet Gynecol Scand 8 5 (9): 1 046, 2006

987

C H A PT E R 5 1

P u l mon ary D i sorders

. . . . . . . . . . . . . . . . . . . . . . 988

ASTHMA . . . . . . . . . . . . .

.

ACUTE BRONCH ITIS . . .

. .

.

.

.

.

. . . . . . . . . . . . . . . .

PNEUMONIA. . . . . . . . . . . . . . . . . . . . . . . . . . . .

.

.

. . . . . 99 1

. . . . . . 992

TUBERCULOSIS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 995 SARCOIDOSIS. . . . . . . . . . . . . . . . . . . . . . .

.

.

. . . . . . . . . 997

CYSTIC FI BROSIS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 997 CARBON MONOXI DE POISON I N G. . . . . . . . . . . . . . . . . 999

A lung which is partialy destroyed or thrown out offunction may suice or the respiration of a normal individual, but be unable to respond to the added demands ofpregnancy, particulary in the latter months, when the enlarged uterus restricts the mobiliy of the diaphragm. -J. Whitridge Williams ( 1 903) As indicated by the above, it has long been appreciated that women in advanced pregnancy tolerate lung disease poorly. Nevertheless, pulmonary disorders are frequently encountered during pregnancy. Chronic asthma or an acute exacerbation is the most common and afects up to 8 percent of pregnant women. Moreover, asthma along with community-acquired pneumonia accounted for almost 1 0 percent of nonobstetri­ cal antepartum hospitalizations in one managed care plan (Gazmararian, 2002) . Pneumonia is also a frequent postpartum complication requiring readmission (Belfort, 20 1 0) . These and other pulmonary disorders are superimposed on several impor­ tant pregnancy-induced changes of ventilatory physiology. For example, pregnant women, especially those in the last trimester,

are susceptible to complications of severe acute pneumonitis as evidenced by the disparate number of maternal deaths during infl u enza pandemics. The important and sometimes marked changes in the respira­ tory system induced by pregnancy are reviewed in Chapter 4 (p. 64), and values for associated tests can be found in the Appendix (p. 1 260) . Lung volumes and capacities that are measured directly to assess pulmonary pathophysiology may be signiicantly altered. In turn, these change gas concentrations and acid-base values in blood. Some of the physiological alterations induced by preg­ nancy were summarized by Wise and associates (2006) : 1 . ital capaciy and inspiratory capaciy increase by approxi­ mately 20 percent by late pregnancy. 2. Expiratory reserve volume decreases from 1 300 mL to approx­ imately 1 1 00 mL. 3. idal volume increases approximately 40 percent as a result of respiratory stimulation by progesterone. 4. Minute ventilation increases 30 to 40 percent due to increased tidal volume. As a result, arterial P02 increases from 1 00 to 1 05 mm Hg. 5. Increasing metabolic demands cause a 30-percent rise in carbon dioxide (C02) production. But, because of its concom­ itantly increased difusion capacity and hyperventilation, the arterial Peo2 decreases from 40 to 32 mm Hg. 6. Residual volume decreases approximately 20 percent from 1 500 mL to approximately 1 200 mL. 7. Chest wal compliance is reduced by a third by the expanding uterus and increased intraabdominal pressure. This causes a 1 0- to 25-percent decrease in functional residual capaci­ the sum of expiratory reserve and residual volumes. In a longitudinal cohort study, Grindheim and colleagues (20 1 2) also showed that forced vital capacity and peak expi­ ratory flow rose progressively across pregnancy after 1 4 to 16 weeks' gestation. The end result of these pregnancy-induced changes is substantively increased ventilation due to deeper but

988

Med ical a n d S u rg ical Co m p l ications

not more frequent breathing. hese are thought to be stimu­ lated by basal oxygen consumption as it rises incrementally from 20 to 40 mLimin in the second half of pregnancy.

ergonovine exacerbate asthma, these commonly used obstetri­ cal drugs should be avoided if possible. • Clinical Course

ASTHMA Reactive airway disease is seen frequently in young women and therefore oten complicates pregnancy. Asthma prevalence grew steadily in many countries beginning in the mid- 1 970s but may have plateaued in the United States with a prevalence in adults of approximately 1 0 percent (Barnes, 20 1 5; Centers for Disease Con­ trol and Prevention, 20 1 Oc, 20 1 3). The estimated asthma preva­ lence during pregnancy ranges between 4 and 8 percent, and this appears to be rising (Kelly, 20 1 5; Racusin, 20 1 3) . Finally, evidence is accruing that fetal and neonatal environmental exposures may contribute to the origins or mitigation of asthma (Grant, 20 1 6; Litonjua, 20 1 6; Spiegel, 20 1 6). • Pathophysiology

Asthma is a chronic inlammatory airway syndrome with a major hereditary component. Increased airway responsiveness and persistent subacute inflammation are associated with poly­ morphism genes on chromosomes 5q that include cytokine gene clusters, 3-adrenergic and glucocorticoid receptor genes, and the T-cell antigen receptor gene (Barnes, 20 1 5) . Asthma is etiologically and clinically heterogeneous, and an environmental allergic stimulant such as influenza or cigarette smoke serves as a promoter for susceptible individuals (Bel, 20 1 3) . h e hallmarks o f asthma are reversible airway obstruction from bronchial smooth muscle contraction, vascular conges­ tion, tenacious mucus, and mucosal edema. Mucosal inlam­ mation is characterized by infiltration with eosinophils, mast cells, and T lymphocytes. hese causes airway inflammation and increased responsiveness to numerous stimuli that include irritants, viral infections, aspirin, cold air, and exercise. Several inflamma­ tory mediators produced by these and other cells include hista­ mine, leukotrienes, prostaglandins, cytokines, IgE, and many others. Importantly, because F-series prostaglandins and

Pulmonary unction changes are more pronounced in asthmatics compared with healthy women (Zairina, 20 1 5). Asthma mani­ festations range from mild wheezing to severe bronchoconstric­ tion, which obstructs airways and decreases airflow. his lowers the forced expiratory volume in 1 second/forced vital capacity (FEVJFVC) ratio and the peak expiratory flow (PEF) . The work of breathing progressively increases, and patients note chest tight­ ness, wheezing, or breathlessness. Subsequent alterations in oxy­ genation primarily reflect ventilation-perfusion mismatching because the distribution of airway narrowing is uneven. Varied manifestations of asthma have led to a simple classii­ cation that considers severity, onset, and duration of symptoms (Table 5 1 - 1 ). With persistent or worsening bronchial obstruc­ tion, clinical stages progress as shown in Figure 5 1 - 1 . Hypoxia initially is mitigated by hyperventilation, which maintains arterial P02 within a normal range but lowers Peo2 ' creating respiratory alkalosis. As airway narrowing worsens, ventilation-perusion defects increase, and arterial hypoxemia ensues. With severe obstruction, ventilation becomes impaired as fatigue causes early CO2 retention. Because of hyperventilation, this may only be seen initially as an arterial Peo2 returning to the normal range. With continuing obstruction, respiratory failure follows from fatigue. Although these changes are generally reversible and well tolerated by the healthy nonpregnant individual, even early asthma stages may be dangerous for the pregnant woman and her fetus. This is because smaller functional residual capacity and increased pulmonary shunting render the woman more susceptible to hypoxia and hypoxemia. Effects of Preg na ncy on Ast h m a

Pregnancy has an unpredictable efect on underlying asthma. In their review of six prospective studies of more than 2000 gravidas, Gluck and Gluck (2006) reported that approxi­ mately a third each improved, remained unchanged, or clearly

TABLE 5 1 -1 . Classification of Ast h m a Severity Severity Persistent Component

I ntermittent

Mild

Moderate

Severe

Sym pto m s Noctu rna l awa ken i n g s S h o rt-acti n g 3-a g o n i st for sym pto m s I nterference with normal activity L u n g fu nction

; 2 day/wk ; 2 x/mo ; 2 day/wk

>2 day/wk, not d a i ly 3 -4 x /mo ::2 day/wk, but not > 1 x /day M i nor l i m itation

Da i l y > 1 x /wk, not n i g htly Da i ly

Th rou g hout day Often 7 x /wk Severa l times d a i ly

Some l i m itatio n

Extremely l i m ited

::80% p red i cted Norma l

60-80% pred i cted Red uced 5%

< 60% pred icted Red uced > 5 %

•

•

F EV1 F EV/FVC

None N o r m a l betwee n exace rbations > 80% pred icted Norma l

F EV forced exp i ratory vol u me; FVC forced vital capacity. F ro m N atio n a l Heart, Lung, a n d B l ood I n stitute, 2007. =

=

P u l m o n a ry D i s o rd e rs

" ,

Mild respiratory alkalosis ,'

Mabie and coworkers ( 1 992) reported an 1 8-fold increased exacerbation risk following cesarean versus vaginal delivery.

FEV1 - 65-80% P02 NORMAL PC02 decreased

Preg n a ncy Outco me

Continuing airway

obstruction

Respiratory alkalosis

" .

FEV 1 - 50-65% P02 slightly decreased PC02 decreased

" ,

FEV 1 - 35-50% P02 decreased PC02 NORMAL

" ,

FEV1 < 35% P02 decreased PC02 HIGH Acidosis

Ventilatoy failure ,(

Danger zone

,'

Ventilatoy failure

Respiratory failure

F I G U R E 5 1 - 1 Cli nical stages of a st h ma. F EV1 vol u me in 1 second.

=

forced expi ratory

worsened. Exacerbations are more common with severe disease (Ali, 20 1 3) . In a study by Schatz and associates (2003), baseline severity correlated with asthma morbidity during pregnancy. With mild disease, 1 3 percent of women had an exacerbation and 2.3 percent required admission; with moderate disease, these numbers were 26 and 7 percent; and for severe asthma, 52 and 27 percent. Others have reported similar observations (Charlton, 20 1 3 ; Hendler, 2006) . Finally, morbidity rates are disproportionately increased in black compared with white women. Up to 20 percent of women with mild or moderate asthma have been reported to have an intrapartum exacerbation (Schatz, 2003) . Conversely, Wendel and associates ( 1 996) reported exacerbations at the time of delivery in only 1 percent of women.

Women with asthma have had improved pregnancy outcomes during the past 20 years. he incidence of spontaneous abortion in women with asthma may be slightly increased (Blais, 2 0 1 3) . Maternal and perinatal outcomes for nearly 30,000 pregnan­ cies in asthmatic women are shown in Table 5 1 -2. Findings are not consistent among these studies. For example, in some, but not all, the incidences of preeclampsia, preterm labor, growth­ restricted infants, and perinatal mortality are slightly increased (Murphy, 20 1 1 ) . Other reports cited a small rise in the incidence of placental abruption and previa, preterm rupture of mem­ branes, and gestational diabetes (Getahun, 2006; Wang, 2 0 14). But, in a European report of 37,585 pregnancies of women with asthma, the risks for most obstetrical complications were not increased (Tata, 2007) . Finally, Cossette and coworkers (20 1 3) reported a nonsigniicant trend between perinatal complications and increasing inhaled-corticosteroid dosage. Increased morbidity appears to be signiicantly linked to severe disease, poor control, or both. In the study by the Mater­ nal-Fetal Medicine Units (MFMU) Network, delivery before 37 weeks ' gestation was not increased among the 1 687 pregnancies of asthmatic women compared with those of 8 8 1 controls (Dom­ browski, 2004a) . But for women with severe asthma, the rate was increased approximately twofold. In a prospective evaluation of 656 asthmatic pregnant women and 1 052 pregnant controls, Triche and coworkers (2004) found that women with moderate to severe asthma, regardless of treatment, are at increased risk of preeclampsia. Finally, the MFMU Network study suggests a direct relationship of baseline pregnancy FEV] with birthweight and an inverse relationship with rates of gestationl hypertension and preterm delivery (Schatz, 2006) . Maternal morbidity includes life-threatening complica­ tions from status asthmaticus. his causes muscle fatigue with respiratory arrest, pneumothorax, pneumomediastinum, acute cor pulmonale, and cardiac arrhythmias. Not surprisingly, maternal and perinatal mortality rates rise substantively when mechanical ventilation is required.

TABLE 51 -2. Materna l and Peri nata l Outcomes in P regnancies Com plicated by Asthma Perinata l Outcomes (%) Study

No.

Gestationa l Hypertensiona

Growth Restriction

Preterm Del ivery

L i u (200 1 ) Dom b rows ki (2004a) Mendola (20 1 3) Cossette (20 1 3)

2 1 93 1 73 9 1 7,044 73 76

13 1 2. 2 b 1 0.2c NS

12 7. 1 b NS 1 3 .5c

10 1 6b 1 4.8c 9.5c

Approx i mate average

28,3 5 2

--1 1

--1 1

--1 3

al ncl udes p reecla m psia synd romes. b l n c id e n ce n ot s i g n ificantly d iferent com pa red with co ntrol g ro u p o r g e nera l o bstetrical pop u latio n . cl ncid ence s i g n ifi ca ntly g reater than control g ro u p or g e n e ra l obstetrica l po p u lation. NS not stated . =

989

990

Medical a nd S u rg ica l Com pl ications Feta I Effects

As discussed, with reasonable asthma control, perinatal out­ comes are generally good. In the Network study cited above, rates of adverse neonatal sequelae caused by asthma were not signiicantly increased (Dombrowski, 2004a) . he caveat is that severe asthma was uncommon in this closely monitored group. When respiratory alkalosis develops, earlier animal and human studies suggest that fetal hypoxemia develops well before the alkalosis compromises maternal oxygenation (Rolston, 1 974) . It is hypothesized that the fetus is jeopardized by decreased uterine blood flow, decreased maternal venous return, and an alkaline-induced letward shit of the oxyhemoglobin dissocia­ tion curve (Chap. 47, p. 920) . The fetal response to maternal hypoxemia is decreased umbil­ ical blood fl o w, increased systemic and pulmonary vascular resis­ tance, and decreased cardiac output. Observations by Bracken and colleagues (2003) confirm that the incidence of fetal-growth restriction increases with asthma severity. Because the fetus may be seriously compromised as asthma severity increases, the need for aggressive management is underscored. Monitoring the fetal response is, in efect, an indicator of maternal status. Possible teratogenic or adverse fetal efects of drugs given to control asthma have been a concern. Several reports show a slightly greater risk for varied abnormalities such as cleft lip and palate and autism spectrum disorders. However, not all studies have veriied this (Eltonsy, 20 1 6; Gidaya, 20 1 6; Mur­ phy, 20 1 3b; Wang, 20 1 4) . It is worrisome that up to half of these women discontinue essential treatment between 5 and 1 3 weeks' gestation (Enriquez, 2006) . • Clinical Eva luation

he subjective severity of asthma frequently does not corre­ late with objective measures of airway function or ventilation. Although clinical examination can also be an inaccurate predic­ tor, useful signs include labored breathing, tachycardia, pulsus paradoxus, prolonged expiration, and use of accessory muscles. S igns of a potentially fatal attack include central cyanosis and altered consciousness. Arterial blood gas analysis provides objective assessment of maternal oxygenation, ventilation, and acid-base status. With this information, the severity of an acute attack can be assessed (see Fig. 5 1 - 1 ) . That said, in a prospective evaluation, Wen­ del and associates ( 1 996) found that routine arterial blood gas analysis did not help to manage most pregnant women who required admission for asthma control. If used, the results must be interpreted in relation to normal values for pregnancy. For example, a Pco2 > 3 5 mm Hg with a pH < 7.35 is consis­ tent with hyperventilation and CO2 retention in a pregnant woman. Pulmonary function testing should be routine in the man­ agement of chronic and acute asthma. Sequential measurement of the FEV1 or of the peak expiratoy low rate-PEFR-is the best measure of severity. n FEV1 less than 1 L, or less than 20 percent of predicted value, correlates with severe disease defined by hypoxia, poor response to therapy, and a high relapse rate. The PEFR correlates well with the FEVl , and it can be mea­ sured reliably with inexpensive portable meters. It is advanta-

geous for each woman to determine her own baseline when asymptomatic to compare with values when symptomatic. • Management of Chronic Asthma

Asthma management by an experienced team produces the most salutary outcomes (Bonham, 20 1 7; Lim, 20 14; Wendel, 1 996) . Management guidelines include: 1 . Patient education-general asthma management and its efect on pregnancy. 2 . Environmental precipitating factors-avoidance or control. Viral infections that include the common cold are frequent triggering events (Ali, 20 1 3; Murphy, 20 1 3a) . 3 . Objective assessment of pulmonary function and fetal status-monitor with PEFR or FEVl . 4. Pharmacological therapy-in appropriate combinations and doses to provide baseline control and treat exacerbations. Compliance may be a problem, and periodic medication reviews are helpful (Sawicki, 20 1 2) . I n general, women with moderate t o severe asthma ideally measure and record either their FEV1 or PEFR twice daily. The FEVl ideally is > 80 percent of predicted. For PEFR, predicted values range from 380 to 5 5 0 L/min. Each woman has her own baseline value, and therapeutic adjustments can be made using this (American College of Obstetricians and Gynecolo­ gists, 20 1 6a; Rey, 2007) . Treatment depends on disease severity. No therapeutic regimen for management of pregnant asthmatics is universally accepted (Bain, 20 1 4). 3-Agonists help abate bronchospasm, and corticosteroids treat infl a mmation . Regimens recommended for outpatient management are listed in Figure 5 1 -2 . For mild asthma, inhaled 3-agonists as needed are usually suicient. For persistent asthma, inhaled corticosteroids are administered every 3 to 4 hours. The goal is to reduce the use of 3-agonists for symptomatic relie. A case-control study from Canada with a cohort of more than 1 5,600 nonpregnant women with asthma showed that inhaled corticosteroids reduced hospitalizations by 80 percent (Blais, 1 998). At Parkland Hospital, Wendel and

LABA Low-dose

les

Low-dose

les

oes

LABA

LABA

High-dose

High-dose

les

les

Short-acti ng �-agonist for symptoms Mild

Mild

intermittent persistent

Moderate

Severe

Very severe

persistent

persistent

persistent

FIGURE 5 1 -2 Stepwise a pproach to asthma treatment. ICS inhaled corticosteroids; LABA long-acting 3-agonists; OCS ora l coticoste­ roids. (Modified from Barnes PJ: Asthma. In Kasper D, Fauci A, Hauser SL, et al (eds): Harrison's Pri nciples of I nternal Medicine, 1 9th ed. New York, McGraw-Hili Ed ucation, 20 1 5, p 1 669.) =

=

=

P u l m o n a ry D i s o rders

colleagues ( 1 996) achieved a 5 5-percent reduction in readmis­ sions for severe exacerbations with inhaled steroids. heophylline has been used less frequently since inhaled corticosteroids became available. Minimal beneit is gained with use of these compounds and they have a high rate of side efects. However, some theophylline derivatives are considered useful for oral maintenance therapy if the initial response to inhaled corticosteroids and 3-agonists is not optimal (Dom­ browski, 2004b) . Antileukotrienes inhibit leukotriene synthesis and include zileuto n, zairlukast, and montelukast. hese drugs are given orally or by inhalation for prevention, but they are not efec­ tive for acute disease (Barnes, 20 1 5). For maintenance, they are used in conjunction with inhaled corticosteroids to allow minimal dosing. Approximately half of asthmatics will improve with these drugs. hese agents are not as efective as inhaled corticosteroids, and there is little experience with their use in pregnancy (Fanta, 2009) . Cromones include cromoyn and nedocromil which inhibit mast cell degranulation. They are inefective for acute asthma and are used primarily to treat childhood asthma. • Management of Acute Asthma

Treatment of acute asthma during pregnancy is similar to that for the nonpregnant asthmatic. Importantly, the threshold for hospitalization is signiicantly lower. Intravenous (IV) hydra­ tion may help clear pulmonary secretions, and supplemental oxygen is given by mask. The therapeutic aim is to maintain the P02 > 60 mm Hg, and preferably normal, along with 90to 95-percent oxygen saturation. Baseline pulmonary function testing includes FEV) or PEFR. Continuous pulse oximetry and electronic fetal monitoring, depending on gestational age, may provide useful information. Antibiotics are not given unless there is concomitant pneumonitis, which is caused by the same organisms discussed on page 992 (Terraneo, 20 1 4) . First-line therapy for acute asthma includes a short-acting 3 -adrenergic agonist, such as terbutaline, albuterol, isoetha­ rine, epinephrine, isoproterenol, or metaproterenol, which is given subcutaneously, taken orally, or inhaled. In severely ill women, these drugs can be given IV (Barnes, 20 1 5) . They bind to speciic cell-surface receptors and activate adenylyl cyclase to increase intracellular cyclic AMP and modulate bronchial smooth muscle relaxation. Long-acting preparations are used for outpatient therapy. If not previously given for maintenance, inhaled corticoste­ roids are commenced. A nebulized anticholinergic drug may be added if the response at this point is unsatisfactory (Barnes, 20 1 5) . Also, for severe exacerbations, IV magnesium sulfate or theophylline may prove eicacious. Corticosteroids are given early to all patients with severe acute asthma. Unless the response to bronchodilator and inhaled corticosteroid therapy is prompt, oral or parenteral corticosteroids are given (Lazarus, 20 1 0) . One regimen is oral prednisone or prednisolone or IV methylprednisolone in a dose of 30 to 45 mg daily for 5 to 1 0 days without tapering (Barnes, 20 1 5) . Because their onset of action is several hours, corticosteroids are given initially along with 3-agonists for severe acute asthma.

At this juncture, further management depends on the sever­ ity and response to therapy. If initial therapy with 3-agonists is associated with improvement of FEV, or PEFR to above 70 percent of baseline, then discharge can be considered. Some women may beneit from longer observation. Alternatively, for the woman with obvious respiratory distress, or if the FEV) or PEFR is SO mm Hg. hus, the alveolar-arterial oxygen tension diference is a more

useful indicator of disease. More than S6 percent of patients with acute pulmonary embolism will have an alveolar-arterial diference > 20 mm Hg (Lockwood, 20 1 2) . Even with massive pulmonary embolism, signs, symptoms, and laboratory data to support the diagnosis may be deceptively nonspecifi c . • Massive Pulmonary Embolism

his is defined as embolism causing hemodynamic instability (Tapson, 200S) . Acute mechanical obstruction of the pulmo­ nary vasculature causes increased vascular resistance and pulmo­ nary hypertension followed by acute right ventricular dilation. In otherwise healthy patients, significant pulmonary hyperten­ sion does not develop until 60 to 75 percent of the pulmonary vascular tree is occluded (Guyton, 1 954) . Moreover, circulatory collapse requires 75- to SO-percent obstruction. This is depicted schematically in Figure 52-4 and emphasizes that most acutely symptomatic emboli are large and likely a saddle embolism. hese are suspected when the pulmonary artery pressure is sub­ stantively increased as estimated by echocardiography. If there is evidence of right ventricular dysfunction, the mortality rate approaches 25 percent. This compares with a I -percent rate without such dysfunction (Kinane, 200S) . It is important in these cases to infuse crystalloids carefully and to support blood pressure with vasopressors. As discussed on page l O I S, oxygen treatment, endotracheal intubation, and mechan­ ical ventilation are completed preparatory to thrombolysis, filter placement, or embolectomy (Tapson, 200S) . • Diagnosis

In most cases, recognition of a pulmonary embolism requires a high index of suspicion that prompts objective evaluation. Exposure of the mother and fetus to ionizing radiation is a con­ cern when investigating a suspected pulmonary embolism dur­ ing pregnancy. However, this concern is largely overruled by the hazards of missing a potentially fatal diagnosis. Moveover, erroneously assigning a diagnosis of pulmonary embolism to a pregnant woman is also fraught with problems. It unnecessar­ ily exposes the mother and fetus to the risks of anticoagulation treatment and will impact delivery plans, future contracep­ tion, and thromboprophylaxis during subsequent pregnancies. herefore, investigations should aim at diagnostic certainty (Konstantinides, 20 1 4) . I n 20 1 1 , the American horacic Society and the Society of Thoracic Radiology developed an algorithm-shown in Figure 52-5 for the diagnosis of pulmonary embolism during pregnancy (Leung, 20 1 l ) . In addition to compression ultra­ sonography, which was previously discussed (p. 1 0 1 0) , the algorithm includes computed-tomographic pulmonary angi­ ography (CTPA) and ventilation-perfusion scintigraphy. Co m pu ted To mogra p h ic P u l m o n a ry A n g iogra p hy

Multidetector computed tomography with pulmonary angiog­ raphy is currently the most commonly employed technique used for pulmonary embolism diagnosis in nonpregnant patients (Bourjeily, 20 1 2; Pollack, 20 1 1 ) . he technique is described further in Chapter 46 (p. 907) , and an imaging example is

Th rom boe m bolic D i sorders

Pulmonary tru n k Diameter 3 cm ; total area =

Right lobar arteries (3)

=

9 cm2

Right and left pulmonary artery Dia. 1 .5 cm each ; total area 9 cm2 =

---\

Left lobar arteries (2)

Lobar arteries (5) Dia. 8 m m each ; total area 1 3 cm2 =

Segmental arteries (1 9) Dia. 6 m m each ; total area 36 cm2 =

Subsegmental arteries (65) Dia. 4 mm each ; total area 8 1 7 cm2 =

FIGURE 52-4 Schematic of p u l m on a ry a rterial c i rcu lation. N ote that the cross-sectio n a l a rea of the p u l m o n a ry tru n k and the com b i n ed p u l mo n a ry a rteries is 9 c m 2 . A l a rge saddle embol ism cou l d occ l ude 50 to 90 percent of the p u l m o n a ry tree, ca u s i ng hemody n a m i c i n sta­ b i l ity. As the a rteries give of distal b ra n ches, the tota l s u rface a rea ra pidly i n c reases, that is, 1 3 cm 2 for the combi ned five lobar a rteries, 36 cm 2 for the com b i ned 1 9 seg menta l a rteries, a nd more than 800 c m 2 for the total 65 su bseg menta l a rterial b ra n ches. Th u s, h emodyn a m ic i nsta b i l ity is less l i kely with e m bo l i past the lobar a rteries. (Data from S i n g h a l S, Henderson R, Horsfield K, et a l : Morphometry of the h u m a n p u l m o n a ry a rterial tree, Circ Res. 1 973 Aug;3 3 (2): 1 90- 1 97.)

Suspected P E in preg nancy

f

Leg sym pto ms

I

Present

+

Absent

l

N egative C U S ---------------� . � CXR

I

+

Positive

I

N egative

Treat

Abnormal

Normal

Positive

Positive

Tech n ical ly

Negative

i n adeq u ate

Stop

l

Nondiag nostic ( -. CTPA .. ----------- V/0

t

Treat

C U S , CTPA

�

Stop

FIGURE 52-5 The America n Thoracic Society and Society of Thoracic Rad iology d iag nostic a lgorithm for suspected p u l m o n a ry embolism computed tomog ra phic p u l monary a ngiography; C U S com pression u ltrasonogra phy; CXR c hest x-ray; PE d u ring preg n a n cy. CTPA p u l m o n a ry e m bolism; V/O ventilation/perfusion sci ntig ra phy. (Mod ified with pe rmission from Leu n g AN, B u l l TM, jaesc h ke R, et a l : An oficia l America n Thora c i c Society/Society of Thoracic Radiology C l i n ical P ractice G u idel i n e: Eva l uation of suspected p u l mo n a ry e m bo l i s m in preg n a n cy, Am j Respir Crit Care Med. 20 1 1 Nov 1 5; 1 84( 1 0) : 1 200- 1 208.) =

=

=

=

=

1 01 7

1 01 8

Med i ca l a n d S u rg i ca l Compl ications

results. Speciically, the proportion of indeterminate results for both approximated 20 percent. By way of comparison, about a fourth of the nonpregnant population had indeterminate stud­ ies. The investigators attributed this diference to the younger age of the pregnant patients. Similarly, one systematic review concluded that both CTPA and lung scintigraphy seem appro­ priate for exclusion of pulmonary embolism during pregnancy (van Mens, 20 1 7) . I ntravascu l a r P u l m o n a ry A n g i o g ra p hy

F I G U R E 52-6 Axial i mage o f the c hest from a fou r-c h a n nel m u l ­ tidetector s p i ra l com puted tomog ra phic sca n performed ater ad m i n istration of intravenous contrast. There is e n ha ncement of the p u l m o n a ry a rtery with a l a rge thro m b u s on the rig ht (arrow) consistent with p u l monary embol ism. (Reprod u ced with perm is­ sion from Dr. Michael Landay.)

shown in Figure 5 2-6. The estimated fetal radiation exposure averages 0.45 to 0.6 mGy. he estimated maternal breast dose is 1 0 to 70 mGy (Waksmonski, 20 1 4) . Bourjeily and colleagues (20 1 2) performed a follow-up study of 3 1 8 pregnant women who had a negative CTPA performed for a suspected pulmonary embolism. All were seen 3 months following their initial presentation or at 6 weeks postpartum. None of these women were subsequently diagnosed with a thromboembolism. CTPA has many advantages, but we find that the higher resolution allows detection of previously inaccessible smaller distal emboli that have uncertain clinical significance. Similar observations have been reported by others (Anderson, 2007; Hall, 2009) . Also, the hyperdynamic circulation and aug­ mented plasma volume associated with pregnancy leads to a higher number of nondiagnostic studies compared with non­ pregnant patients (Ridge, 20 1 1; Scarsbrook, 2006) . Venti lati o n-Perfu s ion S c i nt i g ra p hy-Lu n g Sca n

his technique involves a small dose of radiotracer such as intravenously administered technetium-99m-macroaggregated albumin. There is negligible fetal and maternal breast radiation exposure-0. 1 to 0.4 mGy. The scan may not provide a dei­ nite diagnosis because many other conditions can cause perfu­ sion defects. Examples are pneumonia or local bronchospasm. Chan and coworkers (2002) found that a fourth of ventilation­ perfusion scans in pregnant women were nondiagnostic. In these instances, CTPA is preferred (Tromeur, 20 1 7) . T o compare the performance o f lung scintigraphy and CTPA, Revel and colleagues (20 1 1 ) evaluated 1 37 pregnant women with suspected pulmonary embolism. he two modali­ ties performed comparably and had no signiicant diferences between the proportions of positive, negative, or indeterminate

his requires catheterization of the right side of the heart and is considered the reference test for pulmonary embolism. With newer generation multidetector CT scanners, however, the role of invasive pulmonary angiography has been questioned. his is especially true given the higher radiation exposure for the fetus (Konstantinides, 20 1 4; Kuriakose, 20 1 0) . Other detractions are that it can be time consuming, uncomfortable, and asso­ ciated with dye-induced allergy and renal failure. Indeed, the procedure-related mortality rate approximates 1 in 200 (Stein, 1 992) . It is reserved for confirmation when less invasive tests are equivocal. • Management

Immediate treatment for pulmonary embolism is full antico­ agulation similar to that for deep-vein thrombosis as discussed on page 1 0 1 2. Several complementary procedures may be indicated. Ven a Cava l F i l te rs

The woman who has very recently sufered a pulmonary embo­ lism and who must undergo cesarean delivery presents a par­ ticularly serious problem. Reversal of anticoagulation may be followed by another embolus, and surgery while ully anticoagu­ lated frequently results in life-threatening hemorrhage or trouble­ some hematomas. In these cases, placement of a vena caval ilter should be considered before surgery (Marik, 2008) . Moreover, in the very infrequent circumstances in which heparin therapy fails to prevent recurrent pulmonary embolism from the pelvis or legs, or when embolism develops from these sites despite heparin treatment, a vena caval ilter may also be indicated. Such filters can also be used following massive emboli in patients who are not candidates for thrombolysis (Deshpande, 2002) . he device is inserted through either the jugular or femoral vein and can be inserted during labor Jamjute, 2006) . Routine filter placement has no added advantage to heparin given alone (Decousus, 1 998) . Retrievable ilters may be used as short-term protection and then removed 1 to 2 weeks later (Liu, 20 1 2) . From their systematic review, Harris and associates (20 1 6) found that complication rates in pregnant women with vena caval filters are comparable to those in nonpregnant patients. T h ro m bolys i s

Compared with heparin, thrombolytic agents provide more rapid lysis of pulmonary clots and improvement of pulmonary hypertension (Tapson, 2008) . Konstantinides and cowork­ ers (2002) studied 256 nonpregnant patients receiving hepa­ rin for an acute submassive pulmonary embolism. hey also

Th ro m boem bolic D i s o rders

were randomly assigned to a placebo or the recombinant tissue plasminogen activator alteplase. hose given the placebo had a threefold greater risk of death or treatment escalation compared with those given alteplase. Agnelli and associates (2002) per­ formed a metaanalysis of trials involving 46 1 nonpregnant patients. They reported that the risk of recurrence or death was significantly lower in patients given thrombolytic agents and heparin compared with those given heparin alone- 1 0 versus 1 7 percent. Importantly, however, there were ive-2 percent-fatal bleeding episodes in the thrombolysis group and none in the heparin-only group. In their review, Leonhardt and colleagues (2006) identiied 28 reports of tissue plasminogen activator use during pregnancy. Ten cases were for thromboembolism. Complication rates were similar to those in nonpregnant patients, and the authors con­ cluded that such therapy should not be withheld during preg­ nancy if indicated. However, Akazawa and Nishida (20 1 7) reviewed 1 3 cases of systemic thrombolytic therapy adminis­ tered during the irst 48 hours after delivery. Blood transfusion was required in five of the eight cesarean deliveries, including three cases of hysterectomy and two cases of hematoma removal. E m bo l ecto my

Given the eicacy of thrombolysis and filters, surgical embo­ lectomy is uncommonly indicated. Published experience with emergency embolectomy during pregnancy is limited to case reports (Colombier, 20 1 5 ; Saeed, 20 1 4) . From their review, Ahearn and associates (2002) found that although the opera­ tive risk to the mother is reasonable, the stillbirth rate is 20 to 40 percent.

TH ROMBOPROPHYLAXI S Most recommendations regarding thromboprophylaxis during pregnancy stem from consensus guidelines. In one review of guidelines for thromboprophylaxis in pregnancy, the authors concluded that there is a lack of overall agreement about which women should be ofered thromboprophylaxis or ofered test­ ing for thrombophilias (Okoroh, 20 1 2) . Bates and associates (20 1 6) also conducted a review of guidelines for obstetrically associated VTE. hey summarized that evidence-based rec­ ommendations are based largely on observational studies and extrapolated from data in nonpregnant patients. Similarly, a Cochrane review concluded that evidence is insuicient for firm recommendations regarding thromboprophylaxis during pregnancy (Bain, 20 1 4) . h e confusion that has ensued has provided fertile ground for litigators. Cleary-Goldman and associates (2007) surveyed 1 5 1 fellows of the American College of Obstetricians and Gynecolo­ gists and reported that intervention without a clear indication is common. Table 52-6 lists several consensus recommendations for thromboprophylaxis. In some cases, more than one option is listed, thus illustrating the confusion that currently reigns. • Prior Venous Thromboembolism

In general, either antepartum surveillance or heparin prophy­ laxis is recommended for women with prior TE but without

a recurrent risk factor, including no known thrombophilia. The study by Tengborn and coworkers ( 1 989) , however, suggested that such management may not be efective. hey reported out­ comes in 87 pregnant Swedish women who had prior throm­ boembolic disease and were not tested for thrombophilias. Despite unfractionated heparin prophylaxis, which was usually 5000 U twice daily, three of 20 women ( 1 5 percent) developed antepartum recurrence. his compared with eight of 67 women ( 1 2 percent) not given heparin. Brill-Edwards and colleagues (2000) prospectively studied 1 25 pregnant women with a single prior VTE. Antepartum hep­ arin was not given, but anticoagulant therapy was given for 4 to 6 weeks postpartum. Six women had a recurrent venous throm­ bosis-three antepartum and three postpartum. here were no recurrences in the 44 women without a known thrombophilia or whose prior thrombosis was associated with a temporary risk factor. These findings imply that prophylactic heparin may not be required for these two groups of women. In contrast, and as shown in Table 52-6, women with a prior thrombosis in association with a thrombophilia or in the absence of a tempo­ rary risk factor generally should be given both antepartum and postpartum prophylaxis (Connors, 20 1 7) . D e Stefano and coworkers (2006) studied 1 1 04 nonpreg­ nant women who had a irst-episode VTE before the age of 40 years. After excluding those with antiphospholipid antibodies, 88 women were identiied who subsequently had a total of 1 5 5 pregnancies and who were not given anti thrombotic prophy­ laxis. There were 1 9 women (22 percent) who had a subsequent pregnancy- or puerperium-related VTE. Of 20 women whose original thrombosis was associated with a transient risk factor­ not including pregnancy or oral contraceptive use-there were no recurrences during pregnancy, but two during the p uerpe­ rium. hese data also suggest that for women with a prior VTE, anti thrombotic prophylaxis during pregnancy could be tailored according to the circumstances of the original event. It is important to emphasize that VTE may recur despite anti­ thrombotic prophylaxis. Galambosi and associates (20 1 4) stud­ ied 270 women during 369 pregnancies who had at least one previous VTE. A total of 28 women ( l 0.4 percent) sufered a recurrent VTE. Twelve of these recurrences occurred early in pregnancy before the initiation of antithrombotic prophylaxis, and 1 6 occurred despite prophylactic use of LMWH. Our practice at Parkland Hospital for many years for women with a history of prior VTE was to administer subcutaneous UFH, 5 000 to 7500 units two to three times daily. With this regimen, the recurrence of documented deep-vein thrombosis embolization was rare. Beginning approximately 1 0 years ago, we have successfully used 40 mg enoxaparin given subcutane­ ously daily for thromboprophylaxis. • Cesarean Delivery

The risk for deep-vein thrombosis and especially for fatal throm­ boembolism rises manyfold in women following cesarean com­ pared with that ater vaginal delivery. When considering that a third of women giving birth in the United States yearly undergo cesarean delivery, pulmonary embolism is understandably a major cause of maternal mortality (Creanga, 20 1 7). hat said, the "lack

1 01 9

1 020

Med i ca l a n d S u rg ical Com pl i cations

TABLE 52-6. Some Recom mendations for Th ro m bopro phylaxis d u ri n g P regna ncy Pregna ncy ACCp b

ACOGa

Postpartu m ACCpb

Clinica l Scenario

ACOGa

Prior single VTE R i s k factor no longer p resent

Su rve i l la n ce o n l y

S u rve i l l a nce o n l y

Postpa rt u m a nticoag u lationC "Su rve i l la nce o n l y acknowledged by some experts."

P reg n a n cy- o r estrog enrelated o r no known association (i d iopat h i c) and not rece i v i n g long-term t h e ra py

P rophylact i c U F H r LMWH or "Su rve i l l a n ce o n l y acknowledged by some experts"

P rophylactic or i ntermed i ate-dose LMWH

Postpa rt u m a nticoag u lationC

Receivi n g l o ng-term warfa r i n

NSS

NSS

Assoc iated with a h i g hrisk t h ro m bo p h i l i a d and not rece i v i n g long-term a nticoa g u lation or a n affected fi rst -d eg ree relat ive Associated with a lowrisk t h ro m bop h i l iae and not rece i v i n g treatment

P rophylactic, i ntermed i ate-, r adj u sted-dose LMWH r UFH

Adj u sted-dose LMWH o r 7 5 % of a therapeutic dose of LMWH NSS

P rophylactic o r i ntermed iate-d ose L M W H or U F H o r s u rve i l l a n ce o n l y

NSS

Two or more prior VTEs with or without thromboph i l i a NSS Not receivi n g lon g-term P rophylactiC or therapeutic-dose thera py U F H or LMWH

Receivi n g l o ng-te rm a nticoag u l ation

No prior VTE H ig h-ri s k t h ro m bop h i l ia d

Positive fa m i ly h i sto ry TE and h o m ozyg ous factor V Leiden or p rot h ro m b i n 202 1 OA m utati o n

P rophylactic or i ntermed iatedose LMWH or wa rfa r i n target I N R 2.0-3 .0 x 6 wee ks Prophylacti c or i ntermed iatedose LMWH or wa rfa r i n ta rget I N R 2.0-3 .0 x 6 weeks Res u m e long-te rm a nticoag u l ation

Postpa rt u m a nticoa g u lationC or i nte rmed iateor adj u sted-dose LMWH or U F H x 6 weeksc

P rophylactic or i ntermed iatedose LMWH or wa rfa r i n ta rget I N R 2.0-3 .0 x 6 weeks

Postpa rtu m a nticoa g u l ationc or i ntermed iate-d ose LMWH or U F H

P rophylactic o r i ntermed iatedose LMWH or wa rfa r i n ta rget I N R 2 .0-3.0 x 6 weeks

Postpart u m a nticoa g u l ationc or thera peutic -dose LMWH or UFH x 6 weeks

P rop hylactic or i ntermed iatedose LMWH or wa rfa r i n ta rget I N R 2 .0-3.0 x 6 weeks Res u m ption of long-term a nt i coag u l ation

Thera peutic-dose LMWH or U F H

Adj u sted-dose LMWH o r 7 5 % of a thera peutic dose of LMWH

Resu m ption of longterm a nticoa g u lation

S u rve i l l a n ce o n l y or p rophylactic o r i ntermed i ate-dose LMWH or U F H

P rophylactic r i ntermed iate-dose LMWH

Postpa rt u m a nticoag u lation.

NSS

P rophylactic or i ntermed iate-d ose LMWH

NSS

I nter m ed iatedose LMWH o r wa rfa r i n ta rget I N R 2.0-3.0 x 6 wee ks P ro p hylactiC or i ntermed iatedose LMWH or wa rfa r i n ta rg et I N R 2.0-3.0 x 6 weeks

Th rom boe m bo l i c Disorders

TABLE 52-6. Conti n ued Pregnancy ACCp b

ACOGa

Postpa rtu m ACCp b

Clinical Scenario

ACOGa

Negative fa m i ly h i story fE a n d homozyg ous factor V Leiden or p roth rom b i n 202 1 OA m utation

S u rvei l l a nce o n ly or p rophylactic LMWH or UFH

S u rvei l l a nce only

Postpa rtu m a nticoa g u lation(

Pos itive fa m i ly h i story fE a n d low- r i s k t h rom boph i l iase

S u rve i l l a nce o n ly

S u rvei l l a nce o n l y

Postpa rtu m a nticoa g u lationC or i ntermed iate-dose LMWH or U F H

Low-risk t h rom bop h i l i ae

S u rve i i la nce o n ly

S u rvei l l a nce o n ly if no fa m i ly h i story

S u rve i l lance o n ly; postpa rtu m a nt i coa g u lation with add itional risk factorsf

NSS

P rop hylactic a nti coag u lationC; referra l to s pecia l i st9

NSS

P rophylactic- or i ntermed i atedose U F H or p rophylactic-dose LMWH, both g iven with 75- 1 00 mg/ day a s p i r i n h

P rop hylactic h epa r i n p l us low-dose a s p i r i n x 6 wee ks if prior rec u rrent p reg n a n cy l oss r sti l l b i rth9

NSS

Antiphospholipid antibodies H i story of fE P ro p hylactic a n ti coag u l ation with U FH or LMWH (? p l u s l ow-dose asp i r i n) No prior fE Su rvei l l a nce o n l y or p rophylact i c LMWH or U F H or p rophylactic LMWH or U F H p l u s lowdose a s p i r i n if prior recu rrent p reg n a n cy l oss or sti l l b i rth

P ro p hylact i c- o r i n termed iated ose LMWH or wa rfa ri n targ et I N R 2 .0-3.0 x 6 weeks P rop hylactic or i nte rmediated ose LMWH or in wo m e n n ot p rote i n C or S deficie n t, wa rfa r i n targ et I N R 2 .0-3 .0 S u rvei l l a n ce o n l y if n o fa m i ly h i story

aAmerica n Col l ege of Obstetricians and Gynecologists, 20 1 7a, c. b American Co l lege of Chest PhYSici a n s (Bates, 20 1 2) . (Postpa rtu m treatment levels s h ould be � a nte pa rtu m treatm ent. d Antithro m b i n defi c i e n cy; d o u bly h eterozyg ous or homozyg ous fo r p roth ro m b i n 202 1 OA a n d factor V Le i d e n . eHeterozyg ous factor V Le iden o r p rot h ro m b i n 202 1 OA; p rote i n S o r C defi c i e n cy. fF i rst-deg ree relative with fE at < 50 yea rs; other maj o r t h rom bot i c r i s k factors, e.g., obesity, p rol onged i m m o b i l ity. 9Women with a n t i p h os p h o l i pi d syn d rome s h o u l d not use estrogen-conta i n i n g contracept ives. hTreatment is reco m me n d ed if the d i agnosis of a nt i phosphol i pid syn d rome is ba sed on three or more prior p reg na n cy losses. low-molec u l a r-we i g ht hepa r i n; NSS not s pecifica l ly stated; U F H u nfracti onated hepari n; LMWH ve nous t h rom boe m bo l i s m . fE P rop hylactic, i ntermed i ate-, a n d adj u sted-dose reg i m e n s a re l i sted i n Ta b l e 5 2-5 (p. 1 0 1 3). =

=

=

=

of high quality data" described earlier by Bates and colleagues (20 1 6) creates considerable variation in the current recommen­ dations promulgated by the American College of Obstetricians and Gynecologists, the Royal College of Obstetricians, and the American College of Chest Physicians (Palmero la, 20 1 6) . In 20 1 1 , the American College o f Obstetricians and Gyne­ cologists (20 1 7b) recommended placement of pneumatic

compression devices before cesarean delivery for all women not already receiving thromboprophylaxis. his recommen­ dation was based primarily on consensus and expert opinion. For patients undergoing cesarean delivery with additional risk factors for thromboembolism, both pneumatic compression devices and UFH or LMH may be recommended. he Col­ lege stipulated that cesarean delivery in an emergency setting

1 02 1

1 022

Med ical a n d S u rg ica l Com p l ications

should not be delayed because of the time necessary to imple­ ment thromboprophylaxis. Implementation of this strategy by the Hospital Corporation of America, the largest for-profit obstetrical health care delivery system in the United States, was associated with a reduction in deaths from pulmonary embo­ lism from 7 of 45 8 ,097 cesarean births to 1 of 465 ,880 cesarean births (Clark, 20 1 1 , 20 1 4) . In 20 1 6, the National Partnership for Maternal Safety pub­ lished several consensus recommendations for the prevention of maternal TE (D'lton, 20 1 6) . These recommendations included expanded use of antenatal prophylaxis for women hos­ pitalized 3 days or longer, expanded use of prophylaxis during and after vaginal delivery, and expanded use of pharmacological prophylaxis to most women after cesarean delivery. In response, Sibai and Rouse (20 1 6) expressed concern that these new rec­ ommendations derive from sparse data of questionable appli­ cability to obstetrical patients. They called for better quality evidence to measure the benefi t s, harms, and costs of increased pharmacological thromboprophylaxis. As aptly expressed by Macones (20 1 7) , "an intervention, such as increased postcesar­ ean pharmacologic thromboprophylaxis, where there are legiti­ mate concerns about eicacy and safety, requires a much higher degree of evidence before a national guideline is implemented. " We agree with these sentiments.

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Med ica l and S u rg ica l Co m p l ications Women's Health o f the Society o f hrombosis and Haemostasis (GTH). Vasa 4 5 (2) : 1 03, 20 1 6 U u Y, S un Y, Zhang S , e t al: Placement o f a retrievable inferior vena cava ilter for deep venous thrombosis in term pregnancy. J Vasc Surg 5 5 : 1 042, 20 1 2 Lockwood C : hrombosis, thrombophilia, and thromboembolism: clinical updates in women's health care. American College of Obstetricians and Gynecologists Vol. VI, No. 4, October 2007, Reairmed 20 1 2 Lockwood CJ: Inherited thrombophilias i n pregnant patients: detection and treatment paradigm. Obstet Gynecol 99:333, 2002 Lopez-Quesada E, Vilaseca A Lailla JM: Plasma total homocysteine in uncomplicated pregnancy and in preeclampsia. Eur J Obstet Gynecol Reprod Bioi 1 08:45, 2003 Louis-Jacques AF, Maggio L, Romero ST: Prenatal screening for thrombophil­ ias. Clin Lab Med 36(2):42 1 , 20 1 6 Macones GA: Patient safety i n obstetrics. More evidence, less emotion. Obstet Gynecol 1 03 (2) :25 , 20 1 7 MacCallum P , Bowles L , Keeling 0: Diagnosis and management o f heritable thrombophilias. BMJ 349:g438 , 20 1 4 Magnani HN: n analysis o f clinical outcomes of 9 1 pregnancies i n 8 3 women treated with danaparoid (Orgaran). hromb Res 1 25 :297, 20 1 0 Marik PE, Plante A : Venous thromboembolic disease and pregnancy. N Engl J Med 359:2025, 2008 McDonnell BP, Glennon K, McTiernan A, et al: Adjustment of therapeutic LMWH to achieve specific target anti-FXa activity does not afect outcomes in pregnant patients with venous thromboembolism. J Thromb Thromboly­ sis 43( 1 ) : 1 05, 20 1 7 Morikawa M, Yamada T , Yamada T , et al: Changes i n D-dimer levels after cesarean section in women with singleton and twin pregnancies. hromb Res 1 28:e33, 2 0 1 1 Mueller MJ, Lebherz TB: Antepartum thrombophlebitis. Obstet Gynecol 34:867, 1 969 Murphy N, Broadhurst 01, Khashan AS, et al: Gestation-speciic n-dimer ref­ erence ranges: a cross-sectional study. BJOG 1 22(3) :395, 20 1 5 Nelson-Piercy C, Powrie R, Borg J-Y, et al: Tinzaparin use in pregnancy: an international, retrospective study of the safety and eicacy proile. Eur J Obstet Gynecol Reprod Bioi 1 59:293, 20 1 1 Okoroh E, Azonobi I , Grosse S, et al: Prevention of venous thromboembolism in pregnancy. J Women Health 2 1 :6 1 1 , 20 1 2 Overcash RT, Somers AT, LaCoursiere DY: Enoxaparin dosing after cesarean delivery in morbidly obese women. Obstet GynecoI 1 25 (6) : 1 37 1 , 20 1 5 Paidas MJ, Triche EW, James AH, et al: Recombinant human antithrombin in pregnant patients with hereditaty antithrombin deficiency: integrated analy­ sis of clinical data. Am J Perinatol 33(4):343, 20 1 6 Palmerola KL.D'Alton ME, Brock CO, et al: A comparison of recommen­ dations for pharmacologic thromboembolism prophylaxis ater caesarean delivety from three major guidelines. BJOG 1 23:2 1 57, 20 1 6 Pierangeli SS, Leader B , Barilaro G , e t al: Acquired and inherited thrombo­ philia disorders in pregnancy. Obstet Gynecol Clin North Am 38:27 1 , 20 1 1 Pollack CV, Schreiber 0, Goldhaber SZ, et al: Clinical characteristics, manage­ ment, and outcomes of patients diagnosed with acute pulmonary embolism in the emergency department. JACC 57:700, 20 1 1 Quinlan OJ, McQuillan A, Eikelboom JW: Low-molecular-weight heparin compared with intravenous unfractionated heparin for treatment of pulmo­ naty embolism: a meta-analysis of randomized, controlled trials. Ann Intern Med 1 40: 1 43, 2004 Revel MP, Cohen S, Sanchez 0, et al: Pulmonary embolism during pregnancy: diagnosis with lung scintigraphy or CT angiography? Radiology 258:590, 20 1 1 Rheaume M , Weber F, Durand M, et al: Pregnancy-related venous throm­ boembolism risk in asymptomatic women with antithrombin deficiency: a systematic review. Obstet GynecoI 1 27(4) :649, 20 1 6 Ridge CA, Mhuircheartaigh IN, Dodd JD, et al: Pulmonary CT angiogra­ phy protocol adapted to the hemodynamic efects of pregnancy. AJR Am J RoentgenoI 1 97: 1 058, 20 1 1 Roach RE, Ufering WM, van Hylckama Vlieg A, et al: he risk of venous thrombosis in individuals with a history of superficial vein thrombosis and acquired venous thrombotic risk factors. Blood 1 22 (26) :4264, 20 1 3 Robertson L, Wu 0 , Langhorne P , et al: hrombophilia i n pregnancy: a sys­ tematic review. Br J HaematoI 1 32: 1 7 1 , 2005 Rodger M A, Hague WM, Kingdom J, et al: Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): a multinational open-label randomized trial. Lancet 84(9955): 1 673, 20 1 4 Rodger M A, Kahn SR, Cranney A , et al: Long-term dalteparin i n pregnancy not associated with a decrease in bone mineral density: substudy of a ran­ domized controlled trial. J hromb Haemost 5 : 1 600, 2007 ,

Rodie VA, Thomson AJ, Stewart FM, et al: Low molecular weight heparin for the treatment of venous thromboembolism in pregnancy: a case series. BJOG 1 09: 1 020, 2002 Sabadell J, Casellas M, Alijotas-Reig J, et al: Inherited antithrombin deficiency and pregnancy: maternal and fetal outcomes. Eur J Obstet Gynecol Reprod Bioi 1 49:47, 20 1 0 Saccone G , Berghella V, Maruotti GM, et al: Antiphospholipid antibody pro­ file based obstetric outcomes of primary anti phospholipid syndrome: the PREGNANTS study. Am J Obstet GynecoI 2 1 6(5):525 .e 1 , 20 1 7 Saeed G , Moller M , Neuzner J , et al: Emergent surgical pulmonary embolec­ tomy in a pregnant woman: case report and literature review. Tex Heart Inst J 4 1 (2) : 1 88, 20 1 4 Said JM, Higgins JR, Moses EK, et al: Inherited thrombophilia polymorphisms and pregnancy outcomes in nulliparous women. Obstet Gynecol 1 1 5: 5 , 20 1 0a Said JM, Ignjatovic V, Monagle PT, et al: Altered reference ranges for protein C and protein S during early pregnancy: implications for the diagnosis of protein C and protein S deficiency during pregnancy. Thromb Haemost 1 03:984, 20 1 0b Sanson BJ, Lensing AW, Prins MH, et al: Safety oflow-molecular-weight hepa­ rin in pregnancy: a systematic review. hromb Haemost 8 1 :668, 1 999 Scarsbrook AF, Evans AL, Owen AR, et al: Diagnosis of suspected venous thromboembolic disease in pregnancy. Clin RadioI 6 1 : 1 , 2006 Seguin J, Weatherstone K, Nankervis C: Inherited antithrombin III deficiency in the neonate. Arch Pediatr Adolesc Med 1 48:389, 1 994 Seligsohn U , Lubetsky A: Genetic susceptibility to venous thrombosis. N Engl J Med 344: 1 222, 200 1 Shanbhag S, Pai N, Ghosh K, et al: Letters to the editor. Prenatal diagnosis in a family with purpura fulminans. Blood Coagul Fibrinolysis 26:350, 20 1 5 Sharpe CJ, Crowther A Webert E, et al: Cerebral venous thrombosis dur­ ing pregnancy in the setting of type I antithrombin deficiency: case report and literature review. Transf Med Rev 25:6 1 , 20 1 1 Sibai BM, Rouse OJ: Pharmacologic thromboprophylaxis in obstetrics: broader use demands better data. Obstet GynecoI 1 28 (4):68 1 , 20 1 6 Silver vI, Saade GR, Thorsten V, et al: Factor V Leiden, prothrombin G202 1 0A, and methylene tetrahydrofolate reductase mutations and still­ birth: the Stillbirth Collaborative Research Network. Am J Obstet Gynecol 2 1 5(4):468.e1 , 20 1 6 Silver M , Zhao Y, Spong CY, et al: Prothrombin gene G202 1 0A mutation and obstetric complications. Obstet Gynecol 1 1 5: 1 4 , 20 1 0 Singhal S , Henderson R , Horsield K , e t al: Morphometry o f the human pul­ monary arterial tree. Circ Res 33: 1 90, 1 973 Smith MP, Norris A, Steer PJ, et al: Tinzaparin sodium for thrombosis treat­ ment and prevention during pregnancy. Am J Obstet GynecoI 1 90:495, 2004 Stein PO, Athanasoulis C, Alavi A, et al: Complications and validity of pulmo­ nary angiography in acute pulmonary embolism. Circulation 85 :462, 1 992 Stephenson ML, Serra E, Neeper JM, et al: A randomized controlled trial of difering doses of postcesarean enoxaparin thromboprophylaxis in obese women. J Perinatol 36(2):95, 20 1 6 Stewart A: Warfarin-induced skin necrosis treated with protein C concentrate (human). Am J Health-Syst Pharm 67:90 1 , 20 1 0 Tanimura K , Ebina Y , Sonoyama A , et al: Argatroban therapy for heparin­ induced thrombocytopenia during pregnancy in a woman with hereditary antithrombin deficiency. J Obstet Gynaecol Res 38:749, 20 1 2 Tapson VF: Acute pulmonary embolism. N Engl J Med 358: 1 037, 2008 Tengborn L, Bergqvist 0, Matzsch T, et al: Recurrent thromboembolism in pregnancy and puerperium: is there a need for thromboprophylaxis? Am J Obstet Gynecol 1 60:90, 1 989 Tromeur C, van der Pol LM, Klok FA, et al: Pitfalls in the diagnostic management of pulmonaty embolism in pregnancy. Thromb Res 1 5 1 Suppl 1 :S86, 201 7 van Mens TE, Scheres LJ, de Jong PG, et al: Imaging for the exclusion of pulmo­ nary embolism in pregnancy. Cochrane Database Syst Rev 1 :CDO 1 1 053, 20 1 7 van Wijk F H , Wolf H, Piek J11, e t al: Administration o f low molecular weight heparin within two hours before caesarean section increases the risk of wound haematoma. BJOG 1 09:955, 2002 Virchow R: Gesammelte Abhandlungen zur wissenschaftlichen Medizin. Frankfurt, Medinger Sohn & Co., 1 856 Waksmonski CA: Cardiac imaging and functional assessment I pregnancy. Semin PerinatoI 38 (5) :240, 20 1 4 Waldman M , Sheiner E , Vardi IS: Can we profile patients at risk for thrombo­ embolic events after delivery: a decade of follow up. Am J Obstet Gynecol 208:S234, 20 1 3 Walker MC, Garner PR, Keely EJ, et al: Changes i n activated protein C resis­ tance during normal pregnancy. Am J Obstet Gynecol 1 77: 1 62, 1 997 Wells PS, Anderson D R, Rodger M, et al: Evaluation ofD-dimer in the diag­ nosis of suspected deep-vein thrombosis. N Engl J Med 349: 1 227, 2003 ,

1 02 5

C H A PT E R 5 3

Ren a l and Urin ary Tra ct D i sorders

PREGNANCY- I N DUCED U RI NARY TRACT CHANGES . . 1 025 U RI N ARY TRACT INFECTIONS . . . . . . . . . . . . . . . . . . . . 1 026 NEPHROLITH IASIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 030 PREGNANCY AFTER RENAL TRANSPLANTATION . . . . 1 030 POLYCYSTIC KIDNEY DISEASE . . . . . . . . . . . . . . . . . . . 1 03 1 GLOM ERULAR DISEASES . . . . . . . . . . . . . . . . . . . . . . . . 1 032

PREGNANCY- I N DUCED URI NARY TRACT CHANGES Significant changes in both structure and function within the urinary tract during normal pregnancy are discussed in Chap­ ter 4 (p. 65) . he kidneys become larger, and dilatation of the right renal calyces and ureters can be striking (Fig. 5 3- 1 ) . Some dilatation develops before 1 4 weeks and likely stems

CHRONIC KI D N EY DISEASE . . . . . . . . . . . . . . . . . . . . . . 1 034

20

ACUTE KI DNEY I NJ U RY . . . . . . . . . . . . . . . . . . . . . . . . . 1 036 LOWER GENITAL TRACT LESIONS . . . . . . . . . . . . . . . . . 1 037

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W 3 E l 0 B )

In rare instances in patients suiringfrom pyelitis, the preg­ nant uterus may so compress the ureter as to cause a dam­ ming back of the purulent discharge, and thus give rise to a pyelonephritis. -]. Whitridge Williams ( 1 903)

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Left kidney

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Renal and urinary tract disorders are frequently encountered in pregnancy. Some precede pregnancy-one example being nephrolithiasis. In some women, pregnancy-induced changes may predispose to development or worsening of urinary tract disorders-an example is the markedly increased risk for pyelo­ nephritis, described above by Williams. Finally, some renal pathology is unique to pregnancy, such as preeclampsia. With good prenatal care, however, most women with these disorders will likely have no long-term sequelae.

o ��� 4 6 8 1 0 1 2 1 4 1 6 1 8 20 20 20 20 20 20 20 20 20 38 40 Weeks of pregnancy

FIGURE 53-1 The 50th, 75th, and 90th percentiles for matern a l ren a l cal icea l diameters measured u s i n g sonography i n 1 395 preg­ n a nt women from 4 to 42 weeks' gestation. (Red rawn from Fa u ndes A, Bricola-Filho M, Pi nto e Si lva JC: Di latation of the u rinary tract d u r­ ing preg na ncy: proposa l of a c u rve of maxim a l ca l i cea l dia meter by gestational age. Am J Obstet Gynecol 1 78: 1 082, 1 998.)

1 026

Med ical a nd S u rg ical Com p l ications

from progesterone-induced relaxation of the muscularis. More marked dilatation is apparent beginning in midpregnancy because of more distal ureteral compression, especially on the right side (Faundes, 1 998) . There is also some vesicoureteral relux during pregnancy. Because of these physiological changes, the risk of upper urinary infection rises. Also, imaging studies done to evaluate urinary tract obstruction may occasionally be erroneously interpreted. Evidence of functional renal hypertrophy becomes appar­ ent very soon ater conception. Glomeruli are larger, although cell numbers do not grow (Strevens, 2003). Pregnancy-induced intrarenal vasodilatation develops, and both aferent and eferent resistances decline. This leads to greater efective renal plasma fl o w and glomerular fi l tration (Helal, 20 1 2; Hussein, 20 1 4) . B y 1 2 weeks' gestation, the glomerular filtration rate (GFR) is already augmented 20 percent above nonpregnant values (Hla­ dunewich, 2004) . Ultimately, plasma low and GFR rise by 40 and 65 percent, respectively. Consequently, serum concentra­ tions of creatinine and urea drop substantively across preg­ nancy, and values within a nonpregnant normal range may be abnormal for pregnancy (Appendix, p. 1 257). Other alterations include those related to maintaining normal acid-base homeo­ stasis, osmoregulation, and fluid and electrolyte retention. • Assessment of Renal Function During

Pregnancy

Urinalysis results are essentially unchanged during pregnancy, except for occasional glucosuria. Although protein excretion normally rises, it seldom reaches levels that are detected by usual screening methods. Higby and colleagues ( 1 994) reported 24-hour protein excretion in pregnancy to be 1 1 5 mg/d with a 95-percent confidence level of 260 mg/d. Values did not sig­ niicantly difer by trimester (Fig. 4- 1 4, p. 67) . Albumin con­ stitutes only a small part of total protein excretion and ranges from 5 to 30 mg/d. Airoldi and Weinstein (2007) concluded that proteinuria must exceed 300 mg/ d to be considered abnor­ mal. Many consider 500 mg/d to be important with gestational hypertension. Investigators have correlated a urinary protein­ to-creatinine ratio of :0.3 in a spot urine sample-ideally from a irst morning void-with a 24-hour protein excretion rate of :300 mg (Kuper, 20 1 6) . In one study, 3 percent o f 4 5 8 9 nulliparas screened before ' 20 weeks had idiopathic hematuria, deined as 1 + or greater blood on urine dipstick (Stehman-Breen, 2002) . These women had a twofold risk of developing preeclampsia. In another study of 1 000 women screened during pregnancy, the inci­ dence of dipstick hematuria was 1 5 percent (Brown, 2005) . Most women had only trace levels of hematuria, and the false­ positive rate was 40 percent. If the serum creatinine level in pregnancy persistently exceeds 0.9 mg/dL (75 LmollL) , then intrinsic renal disease is suspected. In these cases, some determine the creatinine clear­ ance as an estimate of the GFR. Of other assessment tools, sonography provides imaging of renal size, relative consistency, and elements of obstruction (see Fig. 53- 1 ) . Magnetic resonance (MR) imaging of renal masses provides excellent anatomic infor­ mation (Putra, 2009) . Full-sequence intravenous pyelography is

not done routinely, but injection of contrast media with one or two abdominal radiographs may be indicated by the clinical situation. The usual clinical indications for cystoscopy are fol­ lowed. Ureteroscopy is another available tool when indicated. Although renal biopsy is relatively safely performed during pregnancy, it usually is postponed unless results may change therapy. From a review of 243 biopsies in pregnant women, the incidence of complications was 7 percent-this compares with 1 percent in postpartum women (Piccoli, 20 1 3) . Some consider biopsy for rapid deterioration of renal function with no obvious cause or for symptomatic nephrotic syndrome (Lindheimer, 2007 a) . We and others have found biopsy helpful in selected cases to direct management (Chen, 200 1 ; Piccoli, 20 1 3) . In one series, renal biopsy in 1 2 normal pregnant volunteers showed that five had slight to moderate glomerular endothelio­ sis (Strevens, 2003) . Recall this is the histopathological lesion that is putatively typical of preeclampsia and is characterized by ibrin deposition within the glomerular endothelium leading to capillary occlusion. In contrast, all 27 women with protein uric hypertension had endotheliosis, and in all but one, it was mod­ erate to severe. • Pregnancy after Unilateral Nephrectomy

In these cases, if the remaining kidney is normal, renal func­ tion becomes augmented. However, women who have donated a kidney have a higher frequency of gestational hypertension or preeclampsia in subsequent pregnancy-I I versus 5 percent compared with non-donors (Garg, 20 1 5) . Otherwise, women with one normal kidney most often have no diiculty in preg­ nancy. Moreover, kidney donation does not lead to long-term adverse consequences. That said, thorough functional evalua­ tion of the remaining kidney is essential (Ibrahim, 2009) .

U R INARY TRACT I N F ECTIONS These infections are the most frequent bacterial infections com­ plicating pregnancy. Although asymptomatic bacteriuria is the most common, symptomatic infection includes cystitis, or it may involve the renal calyces, pelvis, and parenchyma to cause pyelonephritis. Organisms that cause urinary infections are those from the normal perineal lora. Approximately 90 percent of Escherichia coli strains that cause nonobstructive pyelonephri­ tis have adhesins such as P- and S-imbriae. These are cell-sur­ face protein structures that enhance bacterial adherence and, thereby, virulence (Foxman, 20 1 0; Hooton, 20 1 2) . Data suggest that pregnant women have more severe sequelae from urosepsis. One possible underlying factor is the T -helper cell-Th 1 /h2 ratio-reversal of normal pregnancy, which is discussed in Chapter 4 (p. 59). Other perturbations of cytokine or of adhesin expression may be contributory (Chaemsaithong, 20 1 3; Sledzinska, 20 1 1 ). But even if pregnancy itself does not enhance these virulence factors, urinary stasis, vesicoureteral relux, and diabetes predispose to symptomatic upper urinary infections (Czaja, 2009) . In the puerperium, several risk factors predispose to urinary infections. Bladder sensitivity to intravesical fluid tension is often diminished due to labor trauma or epidural analgesia.

Re n a l a n d U ri n a ry Tract D i so rders

Bladder sensations can also be obscured by discomfort from vaginal or perineal injury. Normal postpartum diuresis may worsen bladder overdistention, and catheterization to relieve retention often leads to urinary infection. Postpartum pyelo­ nephritis is treated in the same manner as antepartum renal infections (McDonnold, 20 1 2) . • Asymptomatic Bacteriuria

This refers to persistent, actively multiplying bacteria within the urinary tract in asymptomatic women. he incidence during pregnancy is similar to that in nonpregnant women. It var­ ies from 2 to 7 percent, and it is characteristically population dependent. he highest incidence is in African-American mul­ tiparas with sickle-cell trait, and the lowest is in aluent white women of low parity. Asymptomatic infection is also more common in diabetics (Schneeberger, 20 1 4) . Bacteriuria i s typically present at the first antepartum visit. An initial positive urine culture result done as a part of prenatal care should prompt treatment. After this, fewer than 1 percent of women develop a urinary tract infection (Whalley, 1 967) . A clean-voided specimen containing more than 1 00,000 organ­ isms/mL is diagnostic. It may be prudent to treat when lower concentrations are identified, because pyelonephritis devel­ ops in some women despite colony counts of only 20,000 to 50,000 organisms/mL (Lucas, 1 993) . Most studies indicate that if asymptomatic bacteriuria is not treated, approximately 25 percent of infected women will develop symptomatic infection during pregnancy (Smaill, 20 1 5) . In a more recent study, only 2.4 percent of treated women developed pyelonephritis (Kazemier, 20 1 5) . Eradica­ tion of bacteriuria with antimicrobial agents prevents most of these serious infections. The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (20 1 7) , as well as the U.S. Preventive Services Task Force (2008 ) , recommend screening for bacteriuria at the first pre­ natal visit. Standard urine cultures may not be cost efective when the prevalence is low. Less expensive screening tests such as the leukocyte esterase/nitrite dipstick are cost efec­ tive when the prevalence is ;2 percent (Rogozinska, 20 1 6; Rouse, 1 995) . Also, a dipstick culture technique has excel­ lent positive- and negative-predictive values (Mignini, 2009) . With this, a special agar-coated dipstick is first placed into urine and then also serves as the culture plate. Because of a high prevalence-5 to 8 percent-at Parkland Hospital, most women are screened by traditional urine culture. Susceptibil­ ity determination is not necessary because initial treatment is empirical (Hooton, 20 1 2) . I n some but not all studies, covert bacteriuria has been asso­ ciated with preterm or low-birthweight infants. It is even more controversial whether eradication of bacteriuria decreases these complications. Evaluating a cohort of 25,746 mother-infant pairs, Schieve and coworkers ( 1 994) reported urinary tract infection to be associated with greater risks for low-birthweight infants, preterm delivery, pregnancy-associated hypertension, and anemia. hese fi n dings vary from those of others (Gilstrap, 1 98 1 b; Whalley, 1 967) . Notably, in most studies, cohorts with asymptomatic infection are not evaluated separately from those

with acute renal infection (Banhidy, 2007) . One Cochrane database review noted insuicient data to answer this question (Smaill, 20 1 5) . Treatment

Bacteriuria responds to empirical treatment with any of several antimicrobial regimens listed in Table 5 3- 1 . Although selec­ tion can be based on in vitro susceptibilities, in our extensive experience, empirical oral treatment for 1 0 days with nitro­ furantoin macrocrystals, 1 00 mg at bedtime, is usually efec­ tive. Satisfactory results are also achieved with a 7-day oral course of nitrofurantoin, 1 00 mg given twice daily (Lumbiga­ non, 2009) . Single-dose antimicrobial therapy is less success­ ful (Widmer, 20 1 5) . The important caveat is that, regardless of regimen given, the recurrence rate is approximatey 30 percent. This may indicate covert upper tract infection and the need for longer therapy. hus, after initial therapy, periodic sur­ veillance is necessary to prevent recurrent urinary infections (Schneeberger, 20 1 5) . For recurrent bacteriuria, we have had success with nitrofu­ rantoin, 1 00 mg orally at bedtime for 2 1 days (Lucas, 1 994) . For women with persistent or frequent bacteriuria recurrences, suppressive therapy for the remainder of pregnancy can be given. We routinely use nitrofurantoin, 1 00 mg orally at bed­ time. This drug may rarely cause an acute pulmonary reaction that dissipates on its withdrawal (Boggess, 1 996) .

TABLE 53-1 . Ora l Antim icro b i a l Age nts U sed for Treatment of P reg n a n t Wom e n with Asym ptomatic Bacte r i u ria Single-dose treatment Amoxici l l i n, 3 9 A m p ic i l l i n, 2 9 Cep h a losporin, 2 9 N itrofu ra nto i n , 200 mg Tri met h o p ri m-su lfa methoxazole, 3 2 0/ 1 600 mg 3-day course Amoxi c i l l i n, 5 00 m g th ree ti mes d a i ly A m p i ci l l i n , 2 5 0 mg fou r ti mes d a i ly Cepha los pori n, 250 mg fou r ti mes d a i ly C i p rofl oxac i n, 2 5 0 mg twi ce d a i ly Levofloxac i n, 250 or 500 mg d a i ly N itrofu ra nto i n , 50 to 1 00 mg fou r t i mes d a i ly or 1 00 mg twice d a i ly Tri met h o p r i m-su lfa methoxazole, 1 60/800 m g twice d a i ly Other N itrofu ra ntoi n, 1 00 m g fo u r ti mes d a i ly for 1 0 days N itrofu ra nto i n , 1 00 mg twice d a i ly for 5 to 7 d ays N itrofu ra ntoi n, 1 00 mg at bedtime for 1 0 days Treatment fa i l u res N itrofu ra ntoi n, 1 00 mg fou r ti mes d a i ly fo r 2 1 days Su ppression for bacterial persistence or recurrence N itrofu ra nto i n , 1 00 mg at bedtime fo r p re g n a ncy re ma i n d e r

1 02 7

1 028

Med ica l a n d S u rg ical Co m p l ications

• Cystitis and U reth ritis

Lower urinary infection during pregnancy may develop with­ out antecedent covert bacteriuria (Harris, 1 98 1 ) . Cystitis pro­ duces dysuria, urgency, and frequency, but with few associated systemic indings. Pyuria and bacteriuria are usually found. Microscopic hematuria is common, and occasionally there is gross hematuria from hemorrhagic cystitis. Although cystitis is usually uncomplicated, the upper urinary tract may become involved by ascending infection. Almost 40 percent of pregnant women with acute pyelonephritis have preceding symptoms of lower tract infection (Gilstrap, 1 98 1 a) . Women with cystitis respond readily t o any o f several regi­ mens. Most of the 3-day regimens listed in Table 53- 1 are usu­ ally 90-percent efective (Fihn, 2003) . Single-dose therapy is less efective, and if it is used, concomitant pyelonephritis must be confidently excluded. Lower urinary tract symptoms with pyuria accompanied by a sterile urine culture may stem from urethritis caused by Chlamydia trachomatis. Mucopurulent cervicitis usually coex­ ists, and azithromycin therapy is efective (Chap. 65, p. 1 240) . • Acute Pyelonephritis

Renal infection is one of the most frequent serious medical com­ plications of pregnancy. Data from the 2006 Nationwide Inpa­ tient Sample showed that nearly 29,000 pregnancy-associated hospitalizations were for acute pyelonephritis Qolley, 20 1 2) . I n one hospital-system database o f nearly 5 5 0,000 births, its incidence was 0 . 5 percent (Wing, 20 1 4) . Importantly, pyelo­ nephritis is a leading cause of septic shock during pregnancy (Snyder, 20 1 3) . In one Parkland Hospital Obstetrical Intensive Care Unit review, 1 2 percent of antepartum admissions were for sepsis syndrome caused by renal infections (Zeeman, 2003). Urosepsis may be related to an increased incidence of cerebral palsy in preterm infants Qacobsson, 2002) . Fortunately, afected mothers sufer no serious long-term sequelae (Raz, 2003) . C l i n i ca l F i n d i n g s

Renal infection develops more frequently in the second tri­ mester, and nulliparity and young age are risks (Hill, 2005).

Pyelonephritis is unilateral and right-sided in more than half of cases, and it is bilateral in a fourth. Fever and shaking chills usually develop rather abruptly, and patients have aching pain in one or both lumbar regions. Anorexia, nausea, and vomiting may worsen dehydration. Tenderness usually can be elicited by percussion in one or both costovertebral angles. he dif­ ferential diagnosis includes, among others, labor, chorioam­ nionitis, adnexal torsion, appendicitis, placental abruption, or infarcted leiomyoma. Evidence of the sepsis syndrome is com­ mon (Chap. 47, p. 92 1 ) . I f this infection i s suspected, a urine sample obtained by catheterization may be preferred to avoid obscuring contamina­ tion from the lower genital tract. he urinary sediment contains many leukocytes, frequently in clumps, and numerous bacteria. Bacteremia is demonstrated in 1 5 to 20 percent of these women. E coli is isolated from urine or blood in 70 to 80 percent of infections, Klebsiela pneumoniae in 3 to 5 percent, Enterobacter or Proteus species in 3 to 5 percent, and gram-positive organ­ isms, including group B Streptococcus and Staphylococcus aureus, in up to 1 0 percent of cases (Hill, 2005 ; Wing, 2000) . Plasma creatinine is monitored because early studies reported that 20 percent of pregnant women developed acute kidney injury. More recent findings, however, show this to be only 5 percent if aggressive fluid resuscitation is provided (Hill, 2005). Follow-up studies have demonstrated that this endotoxin-induced damage is reversible long term. s shown in Figure 5 3-2, varying degrees of respiratory distress syndrome from endotoxin-induced alveolar injury are manifest in up to 2 percent of women (Cunningham, 1 987; Snyder, 20 1 3; Wing, 20 1 4) . Uterine activity from endotoxin i s common and i s related to fever severity (Graham, 1 993). In one study, women with pyelonephritis averaged five contractions per hour at admis­ sion, and this decreased to two per hour within 6 hours of intravenous luid and antimicrobial administration (Millar, 2003) . Notably, 3-agonist therapy for tocolysis increases the likelihood of respiratory insuiciency from permeability edema (Lamont, 2000) . The incidence of pulmonary edema in women with pyelonephritis who were given 3-agonists was reported to be 8 percent-a fourfold increase over that expected (Towers, 1 99 1 ) .

F I G URE 53-2 A series of a nterior-posterior projection chest rad iographs of i m p rovi ng acute respi ratory distress syndrome (ARDS) i n a second-tri mester p reg n a nt woma n with severe pyeloneph ritis. A. A n extensive i nfi ltrative process a nd complete obl iteration o f the d i a phrag m (white arrows) i s seen . B. I m proved aeration of l u ng fields bilatera l ly is n oted a s pleura l d i sease resolves (arrows). c. M a rked ly i m proved vis u a l ization of the lung fields with res i d u a l plate l i ke atelectasis a nd normal a p peara n ce of the d ia p h ragm.

Re n a l a n d U ri n a ry Tract Di sorders

TABLE 53-2. Management of the P re g n a nt Woman with Acute Pyel oneph ritis Hosp ital i ze patient Obta i n u ri n e and poss i bly blood c u lt u res Eva l u ate he mog ra m , se ru m creati n i ne, a nd electrolytes Mon itor vita l s i g n s freque ntly, i n c l u d i n g u ri n a ry outp utco nsider i ndwe l l i n g catheter Esta b l i s h u ri n a ry output �50 m L/h r with i n trave n o u s c rysta l l o i d sol ution Ad m i n i ster i ntrave n o u s a n t i m i c robi a l t hera py (see text) Obta i n ch est rad i ograph if there is dys pnea or tac hypnea Repeat hemato logy a nd c h e m i stry stu d ies i n 48 h o u rs C h a n g e to o ra l a n t i m icro b i a l s when afebri l e Discharg e w h e n afebrile 24 h o u rs, consider a n t i m i cr o b i a l th era py for 7 t o 1 0 days Repeat u ri ne c u lt u re 1 to 2 weeks after a n t i m icrobia l thera py com pleted Mod ified from Lucas, 1 994; S heffield, 2005.

Endotoxin-induced hemoysis is common, and approximately a third of these women with pyelonephritis develop anemia (Cox, 1 99 1 ) . With recovery, hemoglobin regeneration is nor­ mal, and acute infection does not afect erythropoietin produc­ tion (Cavenee, 1 994) . Ma n a g e m ent

One scheme for management of acute pyelonephritis is shown in Table 5 3-2. Urine cultures are taken, but prospective trials show that blood cultures are of limited clinical utility (Gomi, 20 1 5; Wing, 2000) . We obtain blood cultures if the tempera­ ture is > 39°C. Intravenous hydration to ensure adequate urinay ouput is the cornerstone of treatment. Antimicrobials are also begun promptly with the caveat that they may initially worsen endotoxemia from bacterial lysis. Surveillance for worsening sepsis syndrome includes serial monitoring of urinary output, blood pressure, pulse, temperature, and oxygen saturation. High fevers are lowered with a cooling blanket and acetaminophen. his is especially important in early pregnancy because of pos­ sible teratogenic efects from hyperthermia. Antimicrobial therapy usually is empirical, and ampicillin plus gentamicin; cefazolin or ceftriaxone; or an extended-spec­ trum antibiotic are all 95-percent efective in randomized trials (Sanchez-Ramos, 1 995; Wing, 1 998, 2000). Fewer than half of E coli strains are sensitive to ampicillin in vitro, but cephalospo­ rins and gentamicin generally have excellent activity. Serum cre­ atinine levels are monitored if nephrotoxic drugs are given. Initial treatment at Parkland Hospital is ampicillin plus gentamicin. Some recommend suitable substitutes if bacterial studies show in vitro resistance. With any of the regimens discussed, response is usually prompt, and 95 percent of women are afebrile by 72 hours (Hill, 2005; Sheield, 2005). ter discharge, most recom­ mend oral therapy for a total of 7 to 14 days (Hooton, 20 1 2) . Persistent I nfection. Generally, intravenous hydration and antimicrobial therapy are followed by stepwise defervescence of approximately 1 °F per day. With persistent spiking fever or

lack of clinical improvement by 48 to 72 hours, urinary tract obstruction, another complication, or both are considered. In these women, renal sonography is recommended to search for obstruction, which is manifest by abnormal ureteral or pyelo­ caliceal dilatation (Seidman, 1 998) . Although most women with continuing infection have no evidence of obstruction, some are found to have calculi. Although renal sonography will detect hydronephrosis, stones are not always seen in preg­ nancy (Butler, 2000; Maikranz, 1 987). If stones are strongly suspected despite a nondiagnostic sonographic examination, a plain abdominal radiograph will identiy nearly 90 percent. Another option is the modifi e d one-shot intravenous pyelo­ gram-a single radiograph obtained 30 minutes after contrast injection-which usually provides adequate imaging (Butler, 2000) . In some women, MR imaging may disclose the cause of persistent infection (Spencer, 2004) . Even without urinary obstruction, persistent infection can be due to an intrarenal or perinephric abscess or phlegmon (Cox, 1 988; Rai, 20 1 2) . Obstruction relief i s important, and o n e method i s cystoscopic placement of a double-J ureteral stent (Rodriguez, 1 988) . Because these stents are usually left in place until after deliv­ ery, they frequently become encrusted and require replacement. We have found that percutaneous nephrostomy is preferable because the stents are more easily replaced. Finally, surgical removal of stones may be required in some women (p. 1 030) . Outpatient Management. This is sometimes done for non­

pregnant women with uncomplicated pyelonephritis (Hooton, 20 1 2) . Outpatient management was described in 92 pregnant women who were first given in-hospital intramuscular ceftri­ axone, two 1 -g doses 24 hours apart (Wing, 1 999) . After this, only a third of the group was considered suitable for outpatient therapy, and these women were randomly assigned either to discharge home and oral antimicrobials or to continued hospi­ talization with intravenous therapy. A third of the outpatient management group was unable to adhere to the treatment regi­ men and required readmission. his suggests that outpatient management is applicable to very few gravidas. Recurrent urinary tract infection-either covert or symptom­ atic-develops in 30 to 40 percent of women following comple­ tion of pyelonephritis treatment (Cunningham, 1 973) . Unless other measures are taken to ensure urine sterility, nitrofurantoin, 1 00 mg orally at bedtime given for the remainder of the preg­ nancy, reduces bacteriuria recurrence (Van Dorsten, 1 987) . • Reflux Nephropathy

Vesicoureteral reflux in early childhood can cause recurrent uri­ nary tract infections, and subsequent chronic interstitial nephri­ tis is attributed to chronic pyelonephritis. Moreover, high-pressure sterile reflux impairs normal renal growth. Combined, this leads to patchy interstitial scarring, tubular atrophy, and loss of nephron mass and is termed relux nephropathy. In some cases­ especially those with staghorn calculi-xanthogranulomatous pyelonephritis causes suppurative destruction of renal tissue. In adults, long-term complications of chronic pyelonephri­ tis include hypertension, which may be severe (Beck, 20 1 5 ; Diamond, 20 1 2) .

1 029

1 030

Med ical and S u rg ical Com p l i cations

Perhaps half of women with reflux nephropathy were treated during childhood for renal infections. Many also had surgical correction of reflux as children, and these women commonly have bacteriuria when pregnant (Mor, 2003). In the other half of women with relux nephropathy, a clear history of recurrent cystitis, acute pyelonephritis, or obstructive disease is lacking. Reports describing 939 pregnancies in 379 women with reflux nephropathy indicate that impaired renal function and bilateral renal scarring were associated with increased maternal complica­ tions (EI-Khatib, 1 994; Jungers, 1 996; Kohler, 2003). Chronic renal disease and pregnancy outcome are discussed on page 1 034.

N EPHRO LITHIASIS Kidney stones develop in up to 9 percent of women during their lifetime with an average age of onset in the third decade (Curhan, 20 1 5) . Calcium salts make up approximately 90 percent of stones, and hyperparathyroidism should be excluded. Although calcium oxalate stones in young nonpregnant women are most common, most stones in pregnancy-65 to 75 percent-are calcium phosphate or hydroxyapatite (Ross, 2008; Tan, 20 1 3) . Patients who have a stone typically form another one every 2 to 3 years. One study found pregnancy was a risk factor for stone formation (Reinstatler, 20 1 7) . Contrary t o past teachings, a low-calcium diet promotes stone formation. Thiazide diuretics diminish stone formation. In general, obstruction, infection, intractable pain, and heavy bleeding are indications for stone removal, discussed later. • Stone Disease During Pregnancy

he incidence of stone disease complicating pregnancy varies. At the low end, the incidence was 0.3 admissions per 1 000 preg­ nancies at Parkland Hospital (Butler, 2000). In an Israeli study, the incidence in nearly 220,000 pregnancies was 0.8 per 1 000 (Rosenberg, 20 1 1 ) . In Washington state, the incidence was 1 .7 per 1 000 pregnancies (Swartz, 2007) . Bladder stones are rare, but recurrent infection and labor obstructed by stones have been reported (Ait Benkaddour, 2006; Ruan, 20 1 1 ) . Data are conflicting whether women with kidney stones have an increased risk for low-birthweight and preterm newborns. In one study of 2239 women with nephrolithia­ sis compared with normal controls, stones were associated with a signiicantly elevated preterm delivery rate- l 0.6 ver­ sus 6.4 percent (Swartz, 2007) . The more recent nationwide study from Taiwan also found 20- to 40-percent increases in rates of low birthweight and pre term birth (Chung, 20 1 3) . I n contrast, a study from Hungary reported that pregnancy outcomes, including preterm delivery, were similar in women with stones and normal controls (Banhidy, 2007) . Compa­ rable conclusions were drawn from the Israeli study discussed above (Rosenberg, 20 1 1 ) . D ia g n o s i s

Pregnant women may have fewer symptoms with stone pas­ sage because of urinary tract dilatation (Hendricks, 1 99 1 ; Tan, 20 1 3) . hat said, more than 90 percent of pregnant women with symptomatic nephrolithiasis present with pain.

Gross hematuria is less common than in afected nonpregnant women. It was a presenting symptom in 23 percent of women described by Butler and associates (2000) . In another study, however, only 2 percent had gross hematuria (Lewis, 2003). Sonography is usually selected to visualize stones, but many are not detected because hydronephrosis may obscure indings (Iv1cAleer, 2004) . Transabdominal color Doppler sonography to detect presence or absence of ureteral "jets" of urine into the bladder may exclude obstruction (Asrat, 1 998). If the ureter is abnormally dilated but no stone is seen, then other imaging studies are indicated. While helical computed tomography (CT) scanning is the preferred imaging method for nonpregnant individuals, the associated x-ray exposure has led some to recommend MR imaging as a second-line test in pregnancy (Masselli, 20 1 5) . Thus CT scanning is usually avoided during pregnancy if possible (Curhan, 20 1 5 ; Masselli, 20 1 5) . If it is used, the slices can be tailored as needed. White and colleagues (2007) recommend unenhanced helical CT and cite an average fetal radiation dose to be 7 mGy. M a n a g ement

Treatment depends on symptoms and gestational age (Semins, 20 1 4) . Intravenous hydration and analgesics are given. In up to half of women with symptomatic stones, infection will be identiied, and this is treated vigorously as described earlier (p. 1 029) . Although stones infrequently cause symptomatic obstruction during pregnancy, persistent pyelonephritis should prompt a search for obstruction due to nephrolithiasis. Urinary obstruction with concomitant infection is an emergency-"pus under pressure" (Curhan, 20 1 5) . Approximately 65 t o 80 percent of symptomatic women will improve with conservative therapy, and the stone usually passes spontaneously (Tan, 20 1 3) . Others require an invasive procedure such as ureteral stenting, ureteroscopy, percutaneous nephrostomy, transurethral laser lithotripsy, or basket extrac­ tion (Butler, 2000; Johnson, 20 1 2; Semins, 20 1 4) . Removal by a flexible basket via cystoscopy, although used less often than in the past, is still a reasonable consideration for pregnant women. In one study, 623 various procedures were performed in 2239 symptomatic pregnant women, but less than 2 percent required surgical exploration (Swartz, 2007) . Of other treatments, the need for fluoroscopy limits the utility of percutaneous nephro­ lithotomy (Toth, 2005) . Extracorporeal shock-wave lithotripsy is contraindicated in pregnancy.

PREGNANCY AFTER RENAL TRANSPLANTATION Following transplantation, the I -year graft survival rate is 95 percent for grafts from living donors and 89 percent for those from deceased donors. Survival rates approximately doubled between 1 988 and 1 996, due in large part to the introduction of cyclosporine and muromonab-CD3 (OKT3 monoclonal antibody) to prevent and treat organ rejection. Since then, mycophenolate mofetil and tacrolimus have further reduced acute rejection episodes, however, the former is consid­ ered teratogenic (Briggs, 20 1 4) . he National Transplant Preg­ nancy Registry reports that 23 percent of fetuses exposed to

R e n a l a n d U r i n a ry Tract D i s o rd e rs

mycophenolate had birth defects (Coscia, 20 1 0) . Importantly, resumption of renal function after transplantation promptly restores fertility in reproductive-aged women (Hladunewich, 20 1 1 ; Rao, 20 1 6) . But, more than half of transplant recipients in one study reported that they were not counseled regarding contraception (French, 20 1 3). • Pregnancy Outcomes

Women after transplantation do better with pregnancy than those with end-stage renal disease receiving dialysis (Saliem, 20 1 6) . In one review of 2000 pregnancies in transplant recipi­ ents, most were treated with cyclosporine and tacrolimus, and approximately 75 percent of pregnancies resulted in a live birth (Coscia, 20 1 0) . Studies from other countries describe similar outcomes (Bramham, 20 1 3; Wyld, 20 l 3) . In a study from Uruguay, 62 percent of liveborns were preterm (Orihuela, 20 1 6) . Two other reports also cited a high prevalence of pre­ term delivery (Erman Akar, 20 1 5; Stoumpos, 20 1 6) . Notably, the incidence of fetal malformations was not increased, except in those who took mycophenolate mofetil (Coscia, 20 1 0) . The incidence o f preeclampsia i s increased i n all transplant recipients (Brosens, 20 l 3) . In the UK National Cohort Study, the incidence of preeclampsia was 22 percent (Bramham, 20 1 3) . From their review, Josephson and McKay (20 1 1 ) cite an incidence of a third of pregnancies but question the validity of this frequency. Importantly, in some cases, rejection is dif­ ficult to distinguish from preeclampsia. hat said, the incidence of rejection episodes approximates 2 to 5 percent (Bramham, 20 1 3; Orihuela, 20 1 6) . Viral infections-especially those by poyomavirus hominis 1, also called BK virus, are frequent. In kidney transplant recipients, this virus can cause nephropathy and graft loss, and afected patients generally have an asymp­ tomatic decline in renal function (Wright, 20 1 6) . Gestational diabetes is also found in approximately 5 percent of transplant recipients. Both are likely related to immunosuppression ther­ apy. Similar outcomes are reported by other investigators (Al Duraihimh, 2008; Cruz Lemini, 2007; Ghafari, 2008) . Several requisites should be satisfied by renal transplanta­ tion patients before attempting pregnancy G osephson, 20 1 1 ; Lopez, 20 1 4) . First, women should be i n good general health for at least 1 to 2 years after transplantation. Also, renal func­ tion should be stable and without severe renal insuiciency. Thus, serum creatinine is 1 .4 mg/ dL and 24-hour protein excretion > 1 g/d are associated with the shortest renal survival times following pregnancy (Imbas­ ciati, 2007) .

C H RO N IC KIDN EY DISEASE his describes a pathophysiological process that can progress to end-stage renal disease. he National Kidney Founda­ tion describes six stages of chronic kidney disease defi n ed by decreasing GFR. It progresses from stage O-GFR >90 mLi 2 2 min/ 1 .73 m to stage 5-GFR < 1 5 mLimin/ 1 .73 m . Several diseases can worsen renal function, and many result from one of the glomerular diseases discussed earlier. hose that most frequently lead to end-stage disease requiring dialysis and kid­ ney transplantation and their approximate percentages include: diabetes, 35 percent; hypertension, 25 percent; glomerulone­ phritis, 20 percent; and polycystic kidney disease, 1 5 percent (Abboud, 20 1 0; Bargman, 20 1 5) . .Most reproductive-aged women with these diseases have varying degrees of renal insuiciency, proteinuria, or both. To counsel regarding fertility and pregnancy outcome, the degree of renal functional impairment and of associated hypertension are assessed. Successful pregnancy outcome in general may be more related to these two factors than to the speciic under­ lying renal disorder. A general prognosis can be estimated by considering women with chronic renal disease in arbitrary cat­ egories of renal function (Davison, 20 1 1 ) . hese include nor­ mal or mild impairment--deined as a serum creatinine < 1 . 5 mg/ dL; moderate impairment-deined as a serum creatinine 1 . 5 to 3.0 mg/dL; and severe renal insuiciencydeined as a serum creatinine > 3 . 0 mg/dL. Although some have suggested adopting the classification of the National Kidney Foundation, others recommend using the older categories (Davison, 20 1 1 ; Piccoli, 20 1 Oa, 20 1 1 ) . Thus, the obstetrician is ideally familiar with both. • Pregnancy and Chronic Renal Disease

Most women have relatively mild renal insuiciency, and its severity along with any underlying hypertension is prognostic of pregnancy outcome. Renal disease with comorbidities secondary to a systemic disorder-for example, diabetes or systemic lupus erythematosus-portends a worse prognosis (Davison, 20 1 1 ; Koh, 20 1 5) . For all women with chronic renal disease, the inci­ dences of hypertension and preeclampsia, preterm and growth­ restricted newborns, and other problems are high (Kendrick, 20 1 5) . Despite these, the National High Blood Pressure Educa­ tion Program (2000) concluded that the prognosis has substan­ tively improved since the 1 980s. his has been verified by several reviews (Hladunewich, 20 1 6a; Nevis, 20 1 1 ; Ramin, 2006) . Loss of renal tissue is associated with compensatory intrare­ nal vasodilation and hypertrophy of the surviving nephrons. he resultant hyperperfusion and hyperiltration eventually dam­ age surviving nephrons to cause nephrosclerosis and worsening renal function . With mild renal insuiciency, pregnancy causes

c l c ) c J 0 . Ow c

75

@ g 50 � J � E O

-

-

.. c :=

�

o � :J

g

> 0

E 0 u

-

25

m e

J � J �

o �-� Normal Eclampsia Mildpregnancy

moderate CRI

Severe CRI

F I G U R E 53-4 Blood vol u me expa nsion i n 44 normally preg nant women at term compared with 29 who had ecl a m psia; 1 0 with moderate c h ro n ic renal insufficiency (CRI)-seru m creati n i ne 1 .5 to 2.9 mg/d L; a nd fou r with severe CRI-serum creati n i ne �3.0 mg/d L . (Data from C u n n i n g h a m , 1 990; Zeema n, 2009.)

greater augmentation of renal plasma low and GFR (Baylis, 2003; Helal, 20 1 2) . With progressively declining renal func­ tion, there is little, if any, augmented renal plasma low. In one study, only half of women with moderate renal insuiciency demonstrated a pregnancy-augmented GFR, and women with severe disease had no increase (Cunningham, 1 990) . Importanty, severe chronic renal insuiciency curtails normal pregnancy-induced hypervolemia. Blood volume expansion during pregnancy is related to disease severity and correlates inversely with serum creatinine concentration. As shown in Figure 5 3-4, women with mild to moderate renal dysfunction have normal blood volume expansion that averages 5 5 percent. With severe renal insuiciency, however, volume expansion averages only 25 percent, which is similar to that seen with hemoconcentration from eclampsia. In addition, these women have variable degrees of chronic anemia due to intrinsic renal disease. Ren a l D i sease with Preserved Fu n ction

In some women, although glomerular disease has not yet caused renal dysfunction, incidences of pregnancy complications are still increased. As shown in Table 5 3-4, these problems are less frequent than in cohorts of women with moderate and severe renal insuiciency. Two earlier studies illustrate this. In one describing 1 23 pregnancies in women with biopsy-proven glomerular disease, only a few of the women had renal dys­ function, yet 40 percent developed obstetrical or renal compli­ cations (Surian, 1 984). In another study of 395 pregnancies in women with preexisting glomerulonephritis and minimal renal insuiciency, impaired renal function developed in 1 5 percent during pregnancy, and 60 percent had worsening proteinuria (Packham, 1 989) . Only 12 percent had antecedent chronic hypertension, however, more than half of the 395 pregnan­ cies were complicated by hypertension. he perinatal mortality rate was 1 40 per 1 000, but even without early-onset or severe hypertension or nephrotic-range proteinuria, the perinatal

Re n a l a nd U r i n a ry Tract D i s o rders

TABLE 53-4. Co m p l ications (Percent) Associated with C h ron ic Ren a l Disease During P reg n a n cy

Complication C h ro n i c HTN Gestational HT�1 Worse n i n g ren a l fu ncti on Perm a nent dysfu n ction P reterm d e l ive ry Feta I -g rowth restriction Peri n ata l morta l ity

Preserved Fu nction

Renal I nsuficiency Moderate and Severe Severe

25 20-50 8- 1 5

30-70 30-50 0-43

50 75 26-35

4-5

1 0-20

35

7 8- 1 4

30-60 30-38

73-89 57

5- 1 4

4-7

hyperte n s i o n . HTN Data fro m Al suwa ida, 2 0 1 1 ; C u n n i n g h am, 1 990; Fa rwe l l , 2 0 1 3; Feng, 20 1 5 ; I m basciati, 2 007; Maruotti, 20 1 2; Nevis, 2 0 1 1 ; Packha m, 1 989; P icco l i, 201 Oa, 2 0 1 1 ; Stettl e r, 1 992; S u ri a n , 1 984; Trevisa n, 2004. =

death rate was 50 per 1 000. Importantly, in 5 percent of these women, worsening renal function was permanent. C h ro n ic Re n a l I n s uffi c i e n cy

In women with chronic kidney disease who also have renal insuiciency, adverse outcomes are generally directly related to the degree of renal impairment. Outcomes of women with moderate versus severe renal insuiciency are usually not sepa­ rated (Table 53-5) . hat said, Piccoli and associates (20 1 0a) described 9 1 pregnancies complicated by stage 1 chronic kid­ ney disease. Primarily because of hypertension, 33 percent were delivered preterm, and 1 3 percent had fetal-growth restriction. Alsuwaida and colleagues (20 1 1 ) reported similar observations. Other investigators have described pregnancies complicated by moderate or severe renal insuiciency (Cunningham, 1 990; Imbasciati, 2007; Zhang, 20 1 5) . Despite a high incidence of chronic hypertension, anemia, preeclampsia, preterm delivery,

5000 4500 4000 § 3500 E 3000 .� 2500 � 2000 l 1 500 1 000 500

90th

o ---� 20

40 35 30 25 Gestational age (weeks)

45

FIGURE 53-5 Birthweight percentiles of i nfa nts born to 29 women at Pa rkl a n d Hospital with m i l d to moderate ren a l i n s uf­ ficiency-seru m creati n i ne 1 .4 to 2.4 mg/d L (black poin ts) a n d severe rena l i n sufficiency-serum creati n i ne � 2. 5 mg/d L (red points). (Data from C u n n i ng ha m , 1 990; Stettl e r, 1 992. Growth curves a re those reported by Alexa nder, 1 996.)

and fetal-growth restriction, perinatal outcomes were generally acceptable. As shown in Figure 5 3-5 , fetal growth is frequently impaired and related to renal dysfunction severity. • Management

Prenatal care is tailored for women with chronic renal disease. Frequent monitoring of blood pressure is paramount, and serum creatinine levels, protein/creatinine ratio, and 24-hour protein excretion are quantiied as indicated. Bacteriuria is treated to decrease the risk of pyelonephritis and urther nephron loss. Protein-rich diets are recommended Gim, 20 1 6; Lindheimer, 2000) . In some women with anemia from chronic renal insui­ ciency, a response is seen with recombinant erythropoietin, how­ ever, hypertension is a common side efect. Serial sonography is performed to follow fetal growth. he diferentiation between worsening hypertension and superimposed preeclampsia is prob­ lematic. Preliminary data indicate that the angiogenic biomark­ ers placental growth factor (PIGF) and its soluble antiangiogenic receptor (sFlt- l ) may be useful to separate chronic from gesta­ tional hypertension. This is described in Chapter 40 (p. 7 1 6) .

TABLE 53-5. Outcomes i n 1 79 Preg nancies i n Wom e n U n dergoing Dia lysis Pregnancies Delivery Birthweight (wk) (g)

Pregnancy Outcomes (%) Perinatal Hypertension Hydram nios Mortal ity

Survivi ng I nfants

Study

N

Chao (2002) Ta n (2006) Chou (2008) Luders (20 1 0) S h a h i r (20 1 3) Jes udason (20 1 4)

13 11 13 52 13 77

32 31 31 33 NS 34

1 540 1 3 90 1510 1 555 2 1 30 1 750

72 36 57 67 1 9a NS

46 18 71 40 14 NS

31 18 50 13 22 20

69 82 50 87 78 80

1 79

-32

- 1 600

-50

-44

- 25

- 80

Approxi mate avera g es apreec la m psia on ly. not stated . NS =

1 035

1 036

Med i ca l a n d S u rg ica l Com p l ications

• Long-Term Efects

In some women, pregnancy may accelerate chronic renal dis­ ease progression by increasing hyperfiltration and glomerular pressure to worsen nephrosclerosis (Baylis, 2003; Helal, 20 1 2) . his i s more likely i n women with severe chronic renal insuf­ iciency (Abe, 1 99 1 ; Jones, 1 996) . For example, Jungers and associates ( 1 995) reported few long-term pregnancy-related adverse efects in 360 women with chronic glomerulonephritis and antecedent normal renal function. However, at 1 year after pregnancy, Jones and Hayslett ( 1 996) reported that 1 0 per­ cent of such women with moderate or severe renal insuiciency had developed end-stage renal failure-stage 5 chronic kidney disease. In a study from Parkland Hospital, we found that 20 percent of pregnant women with similar insuiciency had developed end-stage renal failure by a mean of 4 years (Cun­ ningham, 1 990) . Similar indings in women with a median follow-up of 3 years were described by Imbasciati and cowork­ ers (2007) . By this time, end-stage disease was apparent in 30 percent of women whose serum creatinine was ::l .4 mg/dL and who had proteinuria > 1 g/d. Chronic proteinuria is also a marker for subsequent development of renal failure. In another report from Parkland Hospital, 20 percent of women with chronic proteinuria discovered during pregnancy progressed to end-stage renal failure within several years (Stettler, 1 992) . • Dialysis During Pregnancy

Signiicantly impaired renal function is accompanied by sub­ fertility that may be corrected with chronic renal replacement therapy-either hemodialysis or peritoneal dialysis (Hladune­ wich, 20 1 6b; Shahir, 20 1 3). Not unexpectedly, these preg­ nancies can be complicated. In one review of 1 3 1 cases, mean fetal birthweights were higher in women who conceived while undergoing dialysis-1 530 g versus 1 24 5 g-than in women who conceived before starting dialysis (Chou, 2008) . his was also true for 77 pregnancies described by J esudason and coworkers (20 1 4) . Similar outcomes from several reports are shown in Table 53-5. Outcomes are similar with either hemodialysis or perito­ neal dialysis. hus, for the woman already undergoing either method, it seems reasonable to continue that method with con­ sideration for its increasing frequency. In the woman who has never been dialyzed, the threshold for initiation during preg­ nancy is unclear. Lindheimer and colleagues (2007a) recom­ mend dialysis when serum creatinine levels are between 5 and 7 mg/ dL. Because it is imperative to avoid abrupt volume changes that cause hypotension, dialysis frequency may be extended to five to six times weekly (Reddy, 2007) . Certain protocols emphasize attention to replacement of substances lost through dialysis Qim, 20 1 6) . Multivitamin doses are doubled, and calcium and iron salts are provided along with suicient dietary protein and calories. Chronic anemia is treated with erythropoietin. To meet pregnancy changes, extra calcium is added to the dialysate along with less bicarbonate. Maternal complications are common and include severe hyper­ tension, placental abruption, heartailure, and sepsis. In a review of 90 pregnancies in 78 women, as well as those shown in Table 53-5, high incidences of maternal hypertension and anemia,

preterm and growth-restricted infants, stillbirths, and hydram­ nios were reported (Piccoli, 20 1 0b) .

ACUTE KI DNEY I NJ U RY Previously termed acute renalailure, acute kidney injury (AKI) is now used to describe suddenly impaired kidney function with retention of nitrogenous and other waste products normally excreted by the kidneys (Waikar, 20 1 5) . Severe AKI associated with pregnancy is less frequent today. For example, in a 6-year period, the overall incidence at the Mayo Clinic was 0.4 per­ cent (Gurrieri, 20 1 2) . It is even less common for women who require dialysis-1 case per 1 0,000 births (Hildebrand, 20 1 5) . But, i t still occasionally causes signiicant obstetrical morbidity, and women who require acute dialysis have increased maternal mortality rates (Kuklina, 2009; Van Hook, 20 1 4) . Outcomes are available from four older studies comprising a total of 266 women with renal failure (Drakeley, 2002; Nzerue, 1 998; Sibai, 1 990; Turney, 1 989) . Nearly 70 percent had preeclamp­ sia, 50 percent had obstetrical hemorrhage, and 30 percent had a placental abruption. Almost 20 percent required dialysis, and the maternal mortality rate was 1 5 percent. lthough obstetrical cases of AKI that require dialysis have become less prevalent, acute renal ischemia is still often associ­ ated with severe preeclampsia and hemorrhage (Gurrieri, 20 1 2; Jim, 20 1 7) . Particularly contributory are HELLP (hemolysis, devated liver enzymes, low .latelet levels) syndrome and pla­ cental abruption (Audibert, 1 996; Drakely, 2002) . Septicemia is another frequent comorbidity, especially in resource-poor countries (Acharya, 20 1 3; Srinil, 20 1 1 ; Zeeman, 2003) . AKI is also common in women with acute fatty liver of pregnancy (Sibai, 2007) . Some degree of renal insuiciency was found in virtually all of 52 such women cared for at Parkland Hospi­ tal (Nelson, 20 1 3) . Another woman from Parkland Hospital developed AKI from dehydration caused by severe hyperemesis gravidarum at 1 5 weeks (Hill, 2002) . Other causes include thrombotic micro angiopathies (Balofsky, 20 1 6; Ganesan, 20 1 1 ) (Chap. 56, p . 1 088). • Diagnosis and Management

In most women, AKI develops postpartum, thus manage­ ment is usually not complicated by fetal considerations. An abrupt rise in serum creatinine level is most often due to renal ischemia. Oliguria is an important sign. In obstetri­ cal cases, both prerenal and intrarenal factors are often con­ tributory. For example, with total placental abruption, severe hypovolemia from massive hemorrhage is common, and pre­ existent renal ischemia from preeclampsia is often comorbid. I n addition, disseminated intravascular coagulopathy may be contributory. When azotemia is evident and severe oliguria persists, some form of renal replacement treatment is indicated. Hemofiltra­ tion or dialysis is initiated before marked deterioration occurs. Hemodynamic measurements are normalized. Importantly, medication doses are adjusted, and magnesium sulfate, iodin­ ated contrast agents, aminoglycosides, and nonsteroidal antiin­ lammatory drugs (NSAIDs) are prominent examples (Waikar,

Ren a l a n d U ri n a ry Tract D i sorders

20 1 5) . Early dialysis appears to reduce the maternal mortality rate appreciably and may enhance the extent of renal function recovery. With time, renal function usually returns to normal or near normal. • Prevention

AKI in obstetrics is most often due to acute blood loss, espe­ cially that associated with preeclampsia. hus, it may often be prevented by the following means: 1 . Prompt and vigorous volume replacement with crystalloid solutions and blood in instances of massive hemorrhage, such as in placental abruption, placenta previa, uterine rup­ ture, and postpartum uterine atony (Chap. 4 1 , p. 788) . 2. Delivery or termination of pregnancies complicated by severe preeclampsia or eclampsia, and careful blood transfu­ sion if loss is more than average (Chap. 40, p . 7 1 8) . 3. Close observation for early signs o f sepsis syndrome and shock in women with pyelonephritis, septic abortion, cho­ rioamnionitis, or sepsis from other pelvic infections (Chap. 47, p. 92 1 ) . 4 . Avoidance o f loop diuretics t o treat oliguria before ensuring that blood volume and cardiac output are adequate for renal perfusion. 5 . Judicious use of vasoconstrictor drugs to treat hypotension, and only after it has been determined that pathological vaso­ dilatation is the cause. Irreversible ischemic renal failure caused by acute cortical necrosis is rare now in obstetrics (F rimat, 20 1 6) . Before wide­ spread availability of dialysis, it complicated a fourth of obstet­ rical renal failure cases (Griinfeld, 1 987; Turney, 1 989) . Most cases followed placental abruption, preeclampsia-eclampsia, and endotoxin-induced shock. O nce common with septic abor­ tion, this is a rare cause in this country today (Lim, 20 1 1 ; Srinil, 20 1 1 ) . Histologically, the lesion appears to result from throm­ bosis of segments of the renal vascular system. he lesions may be focal, patchy, conluent, or gross. Clinically, renal cortical necrosis follows the course of AKI, and its diferentiation from acute tubular necrosis is not possible during the early phase. he prognosis depends on the extent of the necrosis. Recovery of function is variable, and stable renal insuiciency may result (Lindheimer, 2007a) . • Obstructive Renal Fai lure

Rarely, bilateral ureteral compression by a very large pregnant uterus is greatly exaggerated. Resultant ureteral obstruction in turn may cause severe oliguria and azotemia. An extreme example is shown in Figure 53-6. In their series of 1 3 obstruc­ tion cases, Brandes and Fritsche ( 1 99 1 ) described one woman with twins who developed anuria and a serum creatinine level of 1 2.2 mg/dL at 34 weeks' gestation. After amniotomy, urine flow resumed at 500 mL/hr, and her serum creatinine levels rapidly dropped to normal range. Eckford and Gingell ( 1 99 1 ) described 1 0 women in whom ureteral obstruction was relieved by stenting. he stents were left in place for a mean of 1 5 . 5 weeks and removed 4 to 6 weeks postpartum. Others have reported similar experiences (Sadan, 1 994; Satin, 1 993) .

FIGURE 53-6 A. Mag netic resona nce i mage i n a coronal p l a ne o f a preg nant wom a n with u nilatera l hydronephrosis ca u sed by u retera l obstruction. The serum creati n i ne level was 8 mg/d L a n d decreased to 0.8 mg/d L ater a percuta neous nephrostomy t u be was p l a ced. B. Let kid ney (arrow) and associated hyd ronephrosis (asterisk) a re aga i n noted in this axia l plane i mage from the same patient.

Partial ureteral obstruction may be accompanied by fluid reten­ tion and significant hypertension. When the obstructive uropa­ thy is relieved, diuresis ensues and hypertension dissipates. In our experience, women with previous urinary tract surgery for reflux are more likely to have such obstructions.

LOWER GEN ITAL TRACT LESIONS • Urethral Diverticulum

Although infrequently complicating pregnancy, this type of diverticulum originates from an enlarging paraurethral gland abscess that ruptures into the urethral lumen. As infection clears, the remaining dilated diverticular sac and its ostium into the urethra persist. Urine collecting within and dribbling from the sac, pain, a palpable mass, and recurrent urinary infec­ tions may be associated fi n dings. In general, a diverticulum is managed expectantly during pregnancy. Rarely, drainage may be necessary, or surgery required (Iyer, 20 1 3) . If additional antepartum evaluation is needed, MR imaging is preferred for its superior soft tissue resolution and ability to deine complex diverticula (Dwarkasing, 20 1 1 ; Pathi, 20 1 3) . • Urogenital Tract Fistulas

Fistulas found during pregnancy likely existed previously, but in rare cases, they form during pregnancy. In developed coun­ tries, vesicovaginal or cervicovaginalistula following a McDon­ ald cerclage has been reported (Massengill, 20 1 2; Zanconato, 20 1 5) . These fistulas may also form with prolonged obstructed labor that is more often seen in resource-poor countries (Cow­ gill, 20 1 5) . In these cases, the genital tract is compressed between the fetal head and bony pelvis. Brief pressure is not signiicant, but prolonged pressure leads to tissue necrosis with subsequent fistula formation (Wall, 20 1 2) . Vesicouterine istulas can develop after prior vaginal or cesarean delivery (DiMarco,

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2006; Harfouche, 20 1 4; Manjunatha, 20 1 2) . Rarely, vesi­ cocervical istula can follow cesarean delivery or may form if the anterior cervical lip is compressed against the symphysis pubis (Dudderidge, 2005 ) . Finally, an ileouterine istula from a degenerating posterior wall fibroid tumor has been described (Shehata, 20 1 6) .

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Med ica l a n d S u rg ica l Com pl ications Luders C, Martins MC, Titak SM, et al: Obstetric outcome in pregnancy women on long-term dialysis: a case series. Am ] Kidney Dis 56( 1 ) : 77, 20 1 0 Lumbiganon P , Villar ] , Laopaiboon M , e t al: One-day compared with 7-day nitrofurantoin for asymptomatic bacteriuria in pregnancy. Obstet Gynecol 1 1 3:339, 2009 Maikranz P, Coe FL, Parks ], et al: Nephrolithiasis in pregnancy. Am ] Kidney Dis 9:354, 1 987 Manjunatha YC, Sonwalkar P: Spontaneous antepartum vesicouterine istula causing severe oligohydramnios in a patient with a previous cesarean deliv­ ery. ] Ultrasound Med 3 1 (8) : 1 294, 20 1 2 Maruotti GM, Sarno L , Napolitano R , e t al: Preeclampsia i n women with chronic kidney disease. ] Matern Fetal Neonatal Med 25(8) : 1 367, 20 1 2 Masselli G , Weston M , Spencer ]: he role of imaging i n the diagnosis and man­ agement of renal stone disease in pregnancy. Clin Radiol 70( 1 2) : 1 462, 20 1 5 Massengill ]c, Baker TM, Von Pechmann WS, et al: Commonalities of cerclage-related genitourinary istulas. Female Pelvic Med Reconstr Surg 1 8(6) :362, 20 1 2 McAleer S], Loughlin KR: Nephrolithiasis and pregnancy. Curr Opin Urol 14: 1 23, 2004 McDonnold M , Friedman A, Raker C, et al: Is postpartum pyelonephritis asso­ ciated with the same maternal morbidity as antepartum pyelonephritis? ] Matern Fetal Neonatal Med 25(9) : 1 709, 20 1 2 Mignini L , Carroli G, Abalos E , e t al: Accuracy o f diagnostic tests to detect asymptomatic bacteriuria during pregnancy. Obstet Gynecol 1 1 3 ( 1 ) :346, 2009 Millar LK, DeBuque L, Wing DA: Uterine contraction frequency during treat­ ment of pyelonephritis in pregnancy and subsequent risk of preterm birth. ] Perinat Med 3 1 :4 1 , 2003 Mor Y, Leibovitch I, Zalts R, et al: Analysis of the long-term outcome of surgi­ cally corrected vesicoureteric relux. B]U Int 92:97, 2003 Moretti ME, Sgro M, Johnson DW, et al: Cyclosporine excretion into breast milk. Transplantation 75:2 1 44, 2003 National High Blood Pressure Education Program: Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am ] Obstet GynecoI 1 83 ( 1 ):S l , 2000 Nelson DB, Yost NP, Cunningham FG: Acute fatty liver of pregnancy: clini­ cal outcomes and expected durations of recovery. Am ] Obstet Gynecol 209(5):456.e 1 , 20 1 3 Nevis IF, Reitsma A, DominicA, et al: Pregnancy outcomes i n women with chronic kidney disease: a systematic review. Clin ] Am Soc NephroI 6:2587, 20 1 1 Nzerue CM, Hewan-Lowe K, Nwawka C: Acute renal failure in pregnancy: a review of clinical outcomes at an inner city hospital from 1 986-1 996. ] Natl Med Assoc 90:486, 1 998 Orihuela S, Nin M, San Roman S, et al: Successful pregnancies in kidney trans­ plant recipients: Experience of the National Kidney Transplant Program from Uruguay. Transplant Proc 48(2) :643, 20 1 6 Packham DK, North A, Fairley KF, e t al: Primary glomerulonephritis and pregnancy. Q ] Med 7 1 :537, 1 989 Pathi SD, Rahn DD, Sailors ]L, et al: Utility of clinical parameters, cystoure­ throscopy, and magnetic resonance imaging in the preoperative diagnosis of urethral diverticula. Int Urogynecol ] 24(2):3 1 9 , 20 1 3 Piccoli G B , Attini R, Vasario E , e t al: Pregnancy and chronic kidney disease: a challenge in all CKD stages. Clin ] Am Soc Nephrol 5:844, 20 1 0a Piccoli GB, Conijn A, Attini R, et al: Pregnancy in chronic kidney disease: need for a common language. ] Nephrol 24(03)282, 20 1 1 Piccoli GB, Conijn A, Consiglio V, et al: Pregnancy in dialysis patients: is the evidence strong enough to lead us to change our counseling policy? Clin ] Am Soc Nephrol 5:62, 20 1 0b Piccoli GB, Daidola G, Attini R, et al: Kidney biopsy in pregnancy: evidence for counseling? A systematic narrative review. B]OG 1 20(4) :4 1 2, 20 1 3 Putra LG, Minor TX, Bolton DM, e t al: Improved assessment o f renal lesions in pregnancy with magnetic resonance imaging. Urology 74:535, 2009 Rai ], Smith RB: Acute lobar nephronia in pregnancy: a rarely reported entity in obstetric renal medicine. Arch Gynecol Obstet 286(3) :797, 2 0 1 2 Ramin S M , Vidaef AC, Yeomans ER, e t al: Chronic renal disease in preg­ nancy. Obstet Gynecol 108(6) : 1 53 1 , 2006 Rao S, Ghanta M , Moritz M], et al: Long-term functional recovery, quality of life, and pregnancy after solid organ transplantation. Ied Clin North Am 1 00(3) :6 1 3, 20 1 6 Raz R , Sakran W , Chazan B, e t al: Long-term follow-up o f women hospitalized for acute pyelonephritis. Clin Infect Dis 37: 1 0 14, 2003 Reddy SS, Holley ]L: Management of the pregnant chronic dialysis patient. Adv Chronic Kidney Dis 14: 1 46, 2007 Reinstatler L, Khaleel S, Pais VM ] r: Association of pregnancy with stone for­ mation among women in the United States: a NHANES analysis 2007 to 20 1 2. ] Urol February 24, 20 1 7 [Epub ahead of print]

Rocha A, Cardoso A, Malheiro ], et al: Pregnancy ater kidney transplantation: grat, mother, and newborn complications. Transplant Proc 45(3): 1 088, 20 1 3 Rodriguez PN, Klein AS: Management o f urolithiasis during pregnancy. Surg Gynecol Obstet 1 66: 1 03, 1 988 Rogozinska E, Formina S, Zamora ] , et al: Accuracy of onsite tests to detect asymptomatic bacteriuria in pregnancy. Obstet Gynecol 1 28:495, 20 1 6 Rosenberg E , Sergienko R , Abu-Ghanem S: Nephrolithiasis during pregnancy: characteristics, complications, and pregnancy outcome. World ] Urol 29(6) :743, 20 1 1 Ross AE, Handa S, Lingeman ]E, et al: Kidney stones during pregnancy: an investigation into stone composition. Urol Res 36:99, 2008 Rouse D], Andrews W, Goldenberg L, et al: Screening and treatment of asymptomatic bacteriuria of pregnancy to prevent pyelonephritis. A cost­ efectiveness and cost beneit analysis. Obstet GynecoI 86: 1 1 9, 1 995 Ruan ]M, Adams SR, Carpinito G, et al: Bladder calculus presenting as recur­ rent urinary tract infections: a late complication of cervical cerclage place­ ment: a case report. ] Reprod Med 56(3-4) : 1 72, 20 1 1 Sadan 0, Berar M , Sagiv R, et al: Ureteric stent in severe hydronephrosis of pregnancy. Eur ] Obstet Gynecol Reprod BioI 56:79, 1 994 Saliem S, Patenaude V, Abenhaim HA: Pregnancy outcomes among renal transplant recipients and patients with end-stage renal disease on dialysis. ] Perinat Med 44(3) :32 1 , 20 1 6 Sanchez-Ramos L , Mlpine K], Adair CD, e t al: Pyelonephritis in pregnancy: once a day ceftriaxone versus multiple doses of cefazolin. A randomized double-blind trial. Am ] Obstet Gynecol 1 72: 1 29, 1 995 Satin A], Seiken GL, Cunningham FG: Reversible hypertension in pregnancy caused by obstructive uropathy. Obstet GynecoI 8 1 :823, 1 993 Schieve A, Handler A, Hershow R, et al: Urinary tract infection during preg­ nancy: its association with maternal morbidity and perinatal outcome. Am ] Public Health 84:405 , 1 994 Schneeberger C, Geerlings SE, Middleton P, et al: Interventions for preventing recurrent urinary tract infection during pregnancy. Cochrane Database Syst Rev 7:CD009279, 20 1 5 Schneeberger C , Kazemier BM, Geerlins SE: Asymptomatic bacteriuria and urinary tract infections in special patient groups: women with diabetes mel­ litus and pregnant women. Curr Opin Infect Dis 27: 1 06, 20 1 4 Seidman D S , Soriano D, Dulitzki M , e t al: Role o f renal ultrasonography in the management of pyelonephritis in pregnant women. ] Perinatol 1 8:98, 1 998 Semins M], Matlaga BR: Kidney stones during pregnancy. Nat Rev Urol 1 1 (3): 1 63, 20 1 4 Shahir AK, Briggs N , Katsoulis ] , e t al: n observational outcomes study from 1 966-2008, examining pregnancy and neonatal outcomes from dialysed women using data from theANZDATA Registry. Nephrology 1 8 (4):276, 20 1 3 Sheield ] S , Cunningham F G : Urinary tract infection in women. Obstet Gynecol 1 06: 1 085, 2005 Shehata A, Hussein N, El Halwagy A, et al: Ileo-uterine istula in a degener­ ated posterior wall ibroid after caesarean section. Clin Exp Reprod Med 43( 1 ) : 5 1 , 20 1 6 Sibai BM: Imitators o f severe preeclampsia. Obstet Gynecol 1 09:956, 2007 Sibai BM, Villar A , Mabie BC: Acute renal failure in hypertensive disorders of pregnancy. Pregnancy outcome and remote prognosis in thirry-one con­ secutive cases. Am ] Obstet Gynecol 1 62 (3) :777, 1 990 Sledzinska A, Mielech A, Krawczyk B, et al: Fatal sepsis in a pregnant woman with pyelonephritis caused by Escherichia coli bearing Dr and P adhesions: diagnosis based on postmortem strain genotyping. B]OG 1 1 8(2):266, 20 1 1 Smail! FM, Vazquez ]C: Antibiotics for asymptomatic bacteriuria in preg­ nancy. Cochrane Database Syst Rev 8:CD000490, 20 1 5 Snyder CC, Barton ]R, Habli M , e t al: Severe sepsis and septic shock i n preg­ nancy: indications for delivery and maternal and perinatal outcomes. ] Matern Fetal Neonatal Med 26(5): 503, 20 1 3 Spencer ]A, Chahal R, Kelly A, e t al: Evaluation o f painful hydronephrosis in pregnancy: magnetic resonance urographic patterns in physiological dilata­ tion versus calculous obstruction. ] U rol 1 7 1 :256, 2004 Srinil S, Panaput T: Acute kidney injury complicating septic unsafe abortion: clinical course and treatment outcomes of 44 cases. ] Obstet Gynaecol Res 37( 1 1 ) : 1 525, 20 1 1 Stehman-Breen CO, Levine R], Qian C, et al: Increased risk of preeclamp­ sia among nulliparous pregnant women with idiopathic hematuria. Am ] Obstet Gynecol 1 8 :703, 2002 Stettler RW, Cunningham FG: Natural history of chronic proteinuria compli­ cating pregnancy. Am ] Obstet GynecoI 1 67: 1 2 1 9, 1 992 Stoumpos S, McNeill SH, Gorrie M, et al: Obstetric and long-term kidney outcomes in renal transplant recipients: a 40 year single-centre study. Clin Transplant 30(6) :673, 20 1 6 Stratta P, Canavese C , Quaglia M: Pregnancy in patients with kidney disease. Nephrol 1 9 : 1 35, 2006

R e n a l a n d U ri n a ry Tract Diso rders Strevens H, Wide-Swensson D, Hansen A, et al: Glomerular endotheliosis in normal pregnancy and pre-eclampsia. BJOG 1 1 0:83 1 , 2003 Sturgiss SN, Davison JM: Efect of pregnancy on long-term function of renal allografts. Am J Kidney Dis 26:54, 1 995 Su X, Lv J, Liu Y, et al: Pregnancy and kidney outcomes in patients with IgA nephropathy: a cohort study. Am J Kidney Dis 70:762, 2 0 1 7 Surian M, Imbasciati E, Cosci P, e t al: Glomerular disease and pregnancy: a study of 1 23 pregnancies in patients with primary and secondary glomerular diseases. Nephron 36: 1 0 1 , 1 984 Swartz A, Lydon-Rochelle MT, Simon D, et al: Admission for nephroli­ thiasis in pregnancy and risk of adverse birth outcomes. Obstet Gynecol 1 09(5) : 1 099, 2007 Tan LK, Kanagalingam D, Tan HK, et al: Obstetric outcomes in women with end­ stage renal failure requiring renal dialysis. Int J Gynaecol Obstet 94: 1 7, 2006 Tan K, Cha DY, Gupta M: Management of stones in abnormal situations. Urol Clin North Am 40( 1 ) :79, 20 1 3 Toth C , Toth G , Varga A , et al: Percutaneous nephrolithotomy i n early preg­ nancy. Int Urol NephroI 37: 1 , 2005 Towers CV, Kaminskas CM, Garite TJ, et al: Pulmonary injury associated with antepartum pyelonephritis: can patients at risk be identified? Am J Obstet Gynecol 1 64:974, 1 9 9 1 Trevisan G, Ramos J G , Martins-Costa S, e t al: Pregnancy i n patients with chronic renal insuiciency at Hospital de Clinicas of Porto Alegre, Brazil. Ren Fail 26:29, 2004 Turney JH, Ellis CM, Parsons FM: Obstetric acute renal failure 1 956- 1 987. BJOG 96:679, 1 989 U.S. Preventive Services Task Force. Screening for asymptomatic bacteriuria in adults. Reairmation recommendation statement. 2008. Available at: http://ww.uspreventiveservicestaskforce.org/ uspstf08/ asym ptbact/asbactrs. htm. Accessed September 22, 20 1 6 Van Dorsten J P , Lenke RR, Schifrin B S : Pyelonephritis in pregnancy: the role of in-hospital management and nitrofurantoin suppression. ] Reprod Med 32:897, 1 987 Van Hook JW: Acute kidney injury during pregnancy. Clin Obstet Gynecol 5 (4):85 1-6 1 , 20 1 4 Waikar S S , Bonventre J\\1: Acute kidney injury. I n Kasper D L , Fauci AS, Hauser SL, et al (eds) : Harrison's Principles of Internal Medicine, 1 9th ed. New York, McGraw-Hill Education, 20 1 5 Wall LL: Preventing obstetric fistulas i n low-resource countries: insights from a Haddon matrix. Obstet Gynecol Surv 67(2) : 1 1 1 , 20 1 2

%alley PJ: Bacteriuria o f pregnancy. A m J Obstet Gynecol 97:723, 1 967 White WM, Zite NB, Gash J, et al: Low-dose computed tomography for the evaluation of flank pain in the pregnant population. J Endourol 2 1 ( 1 1 ) : 1 255, 2007 Widmer M, Lopez 1 , Gulmezoglu AM, et al: Duration of treatment for asymptomatic bacteriuria during pregnancy. Cochrane Database Syst Rev I I :CD00049 1 , 20 1 5 Wing DA, Fassett MJ, Getahun D : Acute pyelonephritis i n pregnancy: an 1 8-year retrospective analysis. Am J Obstet Gynecol 2 1 0 (3) : 2 1 9 . e l , 20 1 4 Wing DA, Hendershott CM, Debuque L, et al: A randomized trial o f three antibiotic regimens for the treatment of pyelonephritis in pregnancy. Am J Obstet Gynecol 92:249, 1 998 Wing DA, Hendershott CM, Debuque L, et al: Outpatient treatm ent of acute pyelonephritis in pregnancy after 24 weeks. Obstet Gynecol 94:683, 1 999 Wing DA, Park AS, DeBuque L, et al: Limited clinical utiliry of blood and urine cultures in the treatment of acute pyelonephritis during pregnancy. Am J Obstet GynecoI 1 82 : 1 437, 2000 Wright A], Gill JS: Strategies to prevent BK virus infection in kidney transplant recipients. Curr Opin Infect Dis 29(4) :353, 2 0 1 6 Wyatt RJ, Julian BA: IgA nephropathy. N Engl J Med 368(25) :2402, 2 0 1 3 Wyld M L, Clayton PA, Jesudason S , et al: Pregnancy outcomes for kidney transplant recipients. Am J Transplant 1 3 :3 1 73, 20 1 3 Zanconato G , Bergamini V , Baggio S , e t al: Successful pregnancy outcomes after laparoscopic cerclage in a patient with cervicovaginal fistula. Case Rep Obstet GynecoI 20 1 5 :784025, 20 1 5 Zeeman GG, Cunningham GC, Pritchard JA: h e magnitude of hemoconcen­ tration with eclampsia. Hypertens Pregnancy 28(2) : 1 27, 2009 Zeeman GG, Wendel GO Jr, Cunningham FG: A blueprint for obstetric criti­ cal care. Am J Obstet Gynecol 1 88:532, 2003 Zhang n, Ma X, Hao L, et al: A systematic review and meta-analysis of out­ comes of pregnancy in CKD and CKD outcomes in pregnancy. Cli n J Soc Nephrol 1 0 ( 1 1 ) : 1 964, 20 1 5 Zhao C , Zhao J , Huang Y, et al: New-onset systemic lupus erythematosus dur­ ing pregnancy. Clin Rheumatol 32(6) : 8 1 5, 20 1 3 Zhou J, Pollak MR: Polycystic kidney disease and other inherited disorders of tubule growth and development. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 1 9th ed. New York, McGraw-Hill Education, 20 1 5

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G a stroi n test i n a l D i sorders

GEN ERAL CONSI DERATIONS . . . . . . . . . . . . . . . . . . . . 1 042 U PPER GASTROI NTESTINAL TRACT DISORDERS . . . . . 1 043 HYPEREMESIS G RAVI DARUM . . . . . . . . . . . . . . . . . . . . 1 043 GASTROESOPHAGEAL REFLUX DISEASE . . . . . . . . . . . 1 046 PEPTIC U LCER DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . 1 047 SMALL BOWEL A N D COLON DISORDERS . . . . . . . . . . 1 047 ACUTE DIARRH EA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 047 I N FLAMMATORY BOWEL DISEASE . . . . . . . . . . . . . . . . 1 048 I NTESTI NAL OBSTRUCTION . . . . . . . . . . . . . . . . . . . . . 1 05 1 APPEN D ICITIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 052

The diagnosis of acute appendicitis is more dficult than at other times, as the enlarged uterus renders it almost impos­ sible to explore the right iliac region satiactoriy. -J. Whitridge Williams ( 1 903) hese words summarize that during normal pregnancy, the gastrointestinal tract and its appendages undergo remarkable anatomical, physiological, and functional alterations. hese changes, which are discussed in detail in Chapter 4 (p. 68) , can appreciably alter clinical findings normally relied on for diagnosis and treatment of gastrointestinal disorders such as appendicitis. Moreover, as pregnancy progresses, gastrointestinal symptoms become more diicult to assess. Physical findings are often obscured by a large uterus that displaces abdominal organs and can alter the location and intensity of pain and tenderness.

GENERAL CONSI DERATIONS • Diagnostic Techniques E n d oscopy

Fiberoptic endoscopic instruments have revolutionized diagno­ sis and management of most gastrointestinal conditions, and these are particularly well suited for pregnancy. Endoscopy in pregnancy is associated with a slightly increased risk for preterm birth, but this is likely due to the disease itself (Ludvigsson, 20 1 7) . With endoscopy, the esophagus, stomach, duodenum, and colon can be inspected (Cappell, 20 1 1 ; Savas, 20 1 4) . The proximal jejunum can also be studied, and the ampulla of Vater cannulated to perform endoscopic retrograde cholangiopancrea­ tography-ERCP (Akcakaya, 20 1 4; Fogel, 20 1 4) . Preliminary data suggest that postendoscopic pancreatitis following gallstone removal may have a higher incidence in pregnant women (Inam­ dar, 20 1 6) . Experience in pregnancy with videocapsule endoscopy for small-bowel evaluation remains limited (Storch, 2006) . Upper gastrointestinal endoscopy is used for management as well as diagnosis of several problems. Common bile duct explo­ ration and drainage are used for choledocholithiasis as described in Chapter 5 5 (p. 1 070) . It is also used for sclerotherapy and for placement of percutaneous endoscopic gastrostomy (PEG) tubes. Several concise reviews have been provided (Cappell, 20 1 1 ; Fogel, 20 1 4; Gilinsky, 2006) . For visualization of the large bowel, lexible sigmoidoscopy can be used safely in pregnant women (Siddiqui, 2006). Coonoscopy is indispensible for viewing the entire colon and distal ileum to aid diagnosis and management of several bowel disorders. Except for the midtrimester, reports of colonoscopy during pregnancy are limited, but most results indicate that it should be performed if indicated (Cappell, 20 1 0, 20 1 1 ; De Lima, 20 1 5) . Bowel prepara­ tion is completed using polyethylene glycol electrolyte or sodium phosphate solutions. With these, serious maternal dehydration that may cause diminished uteroplacental perusion should be avoided.

Gastro i ntest i n a l Di sord e rs N o n i nva s i ve I m a g i n g Tec h n iq u es

he obvious ideal technique for gastrointestinal evaluation during pregnancy is abdominal sonography. Because com­ puted tomography (CT) use is limited in pregnancy due to radiation exposure, magnetic resonance (MR) imaging is now commonly used to evaluate the abdomen and retroperitoneal space (handelwal, 20 1 3) . One example is magnetic resonance cholangiopancreatography-MRCP (Oto, 2009) . Another is magnetic resonance enterography-MRE (Stern, 20 1 4) . These and other imaging modalities, and their safe use in pregnancy, are considered in more detail in Chapter 46. Lapa roto my and La pa roscopy

Surgery is lifesaving for certain gastrointestinal conditions­ perforative appendicitis being the most common example. Laparo­ scopic procedures have replaced traditional surgical techniques for many abdominal disorders during pregnancy. hese are shown in detail with descriptions of surgical technique in Chapter 46 (p. 903) and in Cunningham and Gilstrap 5 Operative Obstetrics, 3rd edition (Kho, 20 1 6). Guidelines for diagnosis, treatment, and use of laparoscopy for surgical problems during pregnancy have been provided by the Society of American Gastrointestinal and Endoscopic Surgeons-SAGES (Pearl, 20 1 7). • Nutritional Support

Specialized nutritional support can be delivered enteraly, usu­ ally via nasogastric tube feedings, or parenteraly with nutrition given by venous catheter access, either peripherally or centrally. When possible, enteral alimentation is preferable because it has fewer serious complications (Bistrian, 20 1 2; Stokke, 20 1 5) . I n obstetrical patients, very few conditions prohibit enteral nutrition as a first efort to prevent catabolism. For extreme cases, such as recalcitrant hyperemesis gravidarum, percutane­ ous endoscopic gastrostomy with a jejunal port (PEG-J tube) has been described (Saha, 2009) . he purpose ofparenteraleeding, or hyperalimentation, is to provide nutrition when the intestinal tract must be quiescent. Central venous access is necessary for total parenteral nutrition because its hyperosmolarity requires rapid dilution in a high­ fl o w vascular system. hese solutions provide 24 to 40 kcall kg/ d, principally as a hypertonic glucose solution. Various conditions may prompt total parenteral nutrition during pregnancy (Table 54- I ) . Not surprisingly, gastrointesti­ nal disorders are the most common indication, and in the many studies cited, feeding duration averaged approximately 33 days. Importantly, complications of parenteral nutrition are fre­ quent, and they may be severe (Guglielmi, 2006) . n early report of 26 pregnancies described a 50-percent rate of complications, which included pneumothorax, hemothorax, and brachial plexus injury (Russo-Stieglitz, 1 999). he most frequent serious compli­ cation is catheter sepsis, and Folk (2004) reported a 25-percent incidence in 27 women with hyperemesis gravidarum. Although bacterial sepsis is most common, Candia septicemia has been described (Paranyuk, 2006) . he Centers for Disease Control and Prevention has updated its detailed guidelines to prevent catheter-related sepsis, and these serve to lessen the dangers of serious infections (O'Grady, 20 1 1 ) . Perinatal complications are

TABLE 54-1 . Some Co nd itions Treated with Entera l or Pa rentera l N utrition D u r i n g P reg na ncya Ach a lasia Anorexia n e rvosa Append i ce a l ru ptu re Bowe l obstruction B u rn s Chol ecystitis C ro h n d i sease D i a betic g a stropathy Esophagea l i nj u ry Hype remesis g ravi d a r u rn J ej u noi lea l bypass M a l i g n a n cies Osto my o bstru ction Pancreatit i s Preecl a m psia syn d rome S h ort g u t syndrome Stroke U l cerative co l iti s aOisorders a re l i sted a l pha betica lly. Data from Fol k, 2004; G u g l i e l m i, 2006; M a n liadeva n, 2 0 1 5; Og u ra, 2003; Porter, 20 1 4; R u sso-Stie g l itz, 1 999; Saha, 2 009; S p i l iopo u l os, 2 0 1 3 .

uncommon, however, fetal subdural hematoma caused by mater­ nal vitamin K deiciency has been described (Sakai, 2003) . Appreciable morbidity is also associated with long-term use of a peripheraly inserted central catheter (PICC). Infection is the most common serious long-term complication (Holmgren, 2008; Ogura, 2003). In a series of 84 such catheters inserted in 66 preg­ nant women, Cape and coworkers (20 1 4) reported a 56-percent complication rate, of which bacteremia was the most frequent. From a review of 48 reports of nonpregnant adults, Turcotte and associates (2006) concluded that peripherally placed cath­ eters provided no advantages compared with centrally placed ones. Still, for short-term nutrition lasting a few weeks, it seems reasonable that PICC placement has a greater beneit-versus­ risk ratio (Bistrian, 20 1 2) .

U PPER G ASTROINTESTINAL TRACT DISORDERS • Hyperemesis Gravidaru m

Mild to moderate nausea and vomiting are especially common in pregnant women until approximatel) 1 6 weeks' gestation (Chap. 9, p. 1 74) . In a small but signifi c ant proportion of these, however, it is severe and unresponsive to simple dietary modiication and antiemetics. Severe unrelenting nausea and vomiting hyperemesis gravidarum-is deined variably as being suiciently severe to produce weight loss, dehydration, keto­ sis, alkalosis from loss of hydrochloric acid, and hypokalemia. Acidosis develops from partial starvation. I n some women, transient hepatic dysfunction develops, and biliary sludge accu­ mulates (Matsubara, 20 1 2) . Other causes should be considered -

1 043

1 044

Med ical a n d S u rg ic a l Com p l i cations

because ultimately hyperemesis gravidarum is a diagnosis of exclusion (Benson, 20 1 3) . Study criteria have not been homogeneous, thus reports of population incidences vary. here does, however, appear to be an ethnic or familial predilection (Grjibovski, 2008) . In population-based studies from California, Nova Scotia, and Norway, the hospitalization rate for hyperemesis gravidarum was 0.5 to 1 percent (Bailit, 2005 ; Fell, 2006; Vikanes, 20 1 3) . Up t o 2 0 percent of those hospitalized in a previous pregnancy for hyperemesis will again require hospitalization (Dodds, 2006; Trogstad, 2005 ) . In general, obese women are less likely to be hospitalized for this (Cedergren, 2008) . The etiopathogenesis of hyperemesis gravidarum is unknown and is likely multifactorial. It apparently is related to high or rapidly rising serum levels of pregnancy-related hormones. Puta­ tive culprits include human chorionic gonadotropin (hCG), estrogen, progesterone, leptin, placental growth hormone, pro­ lactin, thyroxine, and adrenocortical hormones (Verberg, 2005). More recently implicated are other hormones that include ghre­ lins, leptin, nesfatin- 1 , and peptide Y (3-36) (Albayrak, 20 1 3; Gungor, 20 1 3) . Superimposed o n this hormonal cornucopia are an imposing number of biological and environmental factors. Moreover, in some but not all severe cases, interrelated psychological compo­ nents play a major role (Christodoulou-Smith, 20 1 1 ; McCarthy, 20 1 1 ) . Other factors that increase the risk for admission include hyperthyroidism, previous molar pregnancy, diabetes, gastroin­ testinal illnesses, some restrictive diets, and asthma and other allergic disorders (Fell, 2006; Mullin, 20 1 2) . n association of Helicobacter pylori infection has been proposed, but evidence is not conclusive (Goldberg, 2007) . Chronic marijuana use may cause the similar cannabinoid hyperemesis syndrome (Alaniz, 20 1 5; Andrews, 20 1 5) . And for unknown reasons-perhaps estrogen­ related-a female fetus increases the risk by 1 .5-fold (Schif, 2004; Tan, 2006; Veenendaal, 20 1 1 ) . Finally, some but not all studies have reported an association between hyperemesis gravi­ darum and preterm labor, placental abruption, and preeclampsia (Bolin, 20 1 3 ; Vandraas, 20 1 3; Vikanes, 20 l 3) . Com pi i cat i o n s

Vomiting may be prolonged, frequent, and severe, and a list of potentially fatal complications is given in Table 54-2. Various TABLE 54-2. Some Serious and Life-Th reate n i n g

Compl i cations o f Reca l citrant Hyperemesis G ravid a ru m

Acute k i d ney i nj u ry-may req u i re d i a lys i s Depress ion-ca use vers u s efect? Dia p h ra g matic r u ptu re Esophag ea l ru ptu re- Boerhaave syn d rome Hypoprot h ro m b i n e m ia-vita m i n K deficie n cy Hypera l i me n tation co m pl ications Ma l l ory-Wei ss tea rs-bleed i n g , pneu mothorax, pneu momed iasti n u m , pneu moperica rd i u m R h a bdomyolys i s Wer n i c ke e n ce p h a lopathy-th i a m i n e deficiency

degrees of acute kidney injury from dehydration are encountered (Nwoko, 20 1 2) . An extreme example was a woman we cared for who required 5 days of dialysis when her serum creatinine level rose to 1 0.7 mg/dL (Hill, 2002) . One complication from continuous retching is a Mallory-Weiss tear. Others are pneu­ mothorax, pneumomediastinum, diaphragmatic rupture, and gastroesophageal rupture-Boerhaave syndrome (American Col­ lege of 0 bstetricians and Gynecologists, 20 1 5 ; Chen, 20 1 2) . A t least two serious vitamin deiciencies have been reported with hyperemesis in pregnancy. One is Wernicke encephalopathy from thiamine deiciency that has been recognized with increas­ ing frequency (Di Gangi, 20 1 2; Palacios-vIarques, 20 1 2) . In two reviews, ocular signs, confusion, and ataxia were common, but only half had this triad (Chiossi, 2006; Selitsky, 2006) . With this encephalopathy, an abnormal electroencephalogram (EEG) may be seen, and usually MR imaging shows findings (Vaknin, 2006; Zara, 20 1 2) . At least three maternal deaths have been described, and long-term sequelae include blindness, con­ vulsions, and coma (Selitsky, 2006). he second is vitamin K deicieny that has been reported to cause maternal coagulopathy and fetal intracranial hemorrhage, as well as vitamin K embry­ opathy (Kawamura, 2008; Lane, 20 1 5; Sakai, 2003). M a n a gement

One algorithm for management of nausea and vomiting of pregnancy is shown in Figure 5 4- 1 . Most women with mild Mild

I

Dietary management; Ginger extract; Vitamin 86 plus doxylamine, diphenhydramine, or dimenhydrinate

I Moderate

I

Promethazine, prochlorperazine, trimethobenzamide, chlorpromazine, metoclopramide, or ondansetron (oral, rectal, parenteral)

I

I Severe

I

Intravenous hydration with thiamine; Parenteral: metoclopramide, promethazine, or ondansetron

1

Intractable

I

Enteral or parenteral nutrition F I G U RE 54- 1 Algorith m for outpatient and i n patient manage­ ment of hyperemeSis gravidarum.

Gastro i ntesti n a l Di s o rd e rs

TABLE 54-3. Med ications for Gastric Disorders in P reg n a n cy Med ication (Bra nd Name)

Usual Dosing

Route(s)

At bedti me; u p to 4 times d a i ly Every 6 h r 1 2 .5-25 m g 5 - 1 0 ( 2 5 P R) m g Every 8 h r 8 mg Every 6 h r 5- 1 5 mg

PO

Options for Nausea and Vom iting Antihistamine

Doxy l a m i ne + pyridox i ne (Dicleg i s)a Ph en othiazin es

P rometh azi n e (Phe nergan)C P roc h l o rperazi ne (Com paz i n e)C Serotonin an tagonist

Ondan setron (Zofra n) b

Benzamides

Metoclopra m ide (Reg l a n) b

1 M, IV, P O , PR 1 M, IV, PO, P R

IV, PO

1 M, IV, PO

Oral Options for Gastroesophageal Refl ux (GERD)

H2 receptor antagonists

Ra n it id i ne (Za ntac) b C i m etid i ne (Taga met) b N izatid i n e (Axid) b Famoti d i n e ( Pepcid) b

1 5 0 mg twice da i ly 400 mg 4 ti mes da i ly for u p to 1 2 wks 800 mg twice da i ly for u p to 1 2 wks 1 5 0 mg twi ce d a i ly 20 mg twice d a i ly up to 6 wks

Proton-pump inhibitors

Pa ntoprazo l e (Protonix) b La nsoprazo l e (Prevacid) b Omeprazole (Prilosec, Zegeridr Dex l a n soprazole (Dex i l a nt)C

40 15 20 30

mg mg mg mg

d a i ly for u p to 8 wks d a i ly for up to 8 wks d a i ly for 4-8 wks d a i ly for up to 4 wks

aFood and Drug Ad m i n i stration category A. b Food and Drug Ad m i n i stration category B. (Food a n d Drug Ad m i n i stration category C.

to moderate symptoms respond as outpatients to any of sev­ eral irst-line antiemetic agents (Clark, 20 1 4; Matthews, 20 1 4) . One that i s becoming a mainstay i s Diclegis-a combination of doxylamine ( 1 0 mg) plus pyridoxine ( 1 0 mg) . It has been proven safe and efective (Briggs, 20 1 5 ; Koren, 20 1 4) . The usual dose is two tablets orally at bedtime. If relief is insuf­ ficient, then additional doses, first in the morning, and then in the morning and midafternoon can be added each day to the bedtime dose. At our institution, for cost savings, we prescribe these two agents individually: Unisom (doxylamine) Y2 of a 50-mg tablet plus a 25-mg vitamin B 6 tablet. The same gradu­ ated dosing is used but does not exceed three total daily doses. Ondansetron (Zofran) also does not appear to be teratogenic. It was slightly more eicacious than a combination of doxylamine and pyridoxine in a randomized trial (Oliveira, 20 1 4; Pasternak, 20 1 3) . Its drawbacks include potential maternal efects from prolonged QT-interval and serotonin syndrome (Koren, 20 1 4) . When simple measures fail, intravenous crystalloid solutions are given to correct dehydration, ketonemia, electrolyte dei­ cits, acid-base imbalances, and hypokalemia. No benefi t s are gained by infusing 5-percent dextrose along with crystalloids (Tan, 20 l 3) . Thiamine, 1 00 mg, is given to prevent Wernicke encephalopathy (Giugale, 20 1 5 ; Niebyl, 20 1 0) . his is usually diluted in 1 L of the selected crystalloid and infused at the maintenance rate desired for patient hydration. If vomiting persists after rehydration and failed outpatient management, hospitalization is recommended (American College

of Obstetricians and Gynecologists, 20 1 5) . Day care has also been shown to be efective in one randomized study (McCar­ thy, 20 1 4) . Intravenous hydration is continued and antiemet­ ics such as promethazine, prochlorperazine, chlorpromazine, or metoclopramide are given parenterally (Table 54-3) . The bulk of evidence is that treatment with glucocorticosteroids is not efective (Yost, 2003) . Because of their putative teratoge­ nicity, they are not routinely recommended (American College of Obstetricians and Gynecologists, 20 1 5) . With persistent vomiting after hospitalization, appropriate steps should be taken to exclude possible underlying diseases as a cause of hyperemesis. That said, in one study, endoscopy did not change management in 49 women (Debby, 2008) . Other potential causes of vomiting include gastroenteritis, cholecys­ titis, pancreatitis, hepatitis, peptic ulcer, and pyelonephritis. In addition, severe preeclampsia and fatty liver are more likely after midpregnancy. And although clinical thyrotoxicosis has been implicated as a cause of hyperemesis, it is more likely that abnormally elevated serum thyroxine levels are a surrogate for higher-than-average serum hCG levels (Sun, 20 1 4) . This is discussed further in Chapter 5 (p. 1 00). In our experiences, serum free thyroxine levels normalize quickly with hydration and emesis treatment. With treatment, most women will have a salutary response and may be sent home with antiemetic therapy. Their read­ mission rate is 25 to 35 percent in most prospective studies. If associated psychiatric and social factors contribute to the

1 045

1 046

Med ical a n d Su rg ical Com pl ications

illness, the woman usually improves remarkably while hospi­ talized (Swallow, 2004) . That said, symptoms may relapse in these women, and some go on to develop posttraumatic stress syndrome (Christodoulou-Smith, 20 1 1 ; McCarthy, 20 1 1 ) . For some women, hyperemesis can be an indication for elective ter­ mination (Poursharif, 2007) . In the small percentage of women who continue to have recalcitrant vomiting after intensive therapy, consideration is given for enteral nutrition (p. 1 043) . Stokke and associates (20 1 5) described successful use of nasojejunal feeding for up to 4 1 days in 1 07 such women. Use of sonography to conirm correct placement of the tube has been described (Swartzlander, 20 1 3) . Percutaneous endoscopic gastrostomy with a jejunal port has also been reported (Saha, 2009; Schrag, 2007) . A ran­ domized trial failed to show any advantages from early enteral feeding (Grooten, 20 1 7) . I n our experiences, only a very few women will require parenteral nutrition (Yost, 2003) . In a study of 5 99 women, however, Peled and coworkers (20 1 4) reported that 20 percent required central venous access to be established for nutrition. • Gastroesophageal Reflux Disease

Symptomatic reflux is seen in up to 1 5 percent of nonpregnant individuals (Kahrilas, 20 1 5) . he spectrum of sequelae includes esophagitis, stricture, Barrett esophagus, and adenocarcinoma. The main symptom of relux is heartburn, or pyrosis, which is especially common in pregnancy. Its prevalence rose from 26 percent in the irst trimester to 36 percent in the second and 5 1 percent in the third trimesters (Malfertheiner, 20 1 2) . The retrosternal burning sensation stems from esophagitis caused by gastroesophageal relux related to relaxation of the lower esophageal sphincter. Reflux symptoms usually respond to tobacco and alcohol abstinence, small meals, head of the bed elevation, and avoid­ ance of postprandial recumbency. So-called "trigger" foods are also avoided and usually include fatty foods, tomato-based foods, and cofee. Oral antacids are first-line therapy. If severe symp­ toms persist, sucralfate (Carafate) is given along with a proton­ pump inhibitor or an H2-receptor antagonist (see Table 54-3) . Both classes are generally safe for use in pregnancy (Briggs, 20 1 5; Mahadevan, 2006b) . Of these, a 1 -g sucralfate tablet is taken orally 1 hour before each of the three meals and at bedtime for up to 8 weeks. Antacids are not used within Y2 hour before or after sucralfate doses. If relief is not attained, then endoscopy should be considered. Misoprostol is contraindicated because it stimulates labor (Chap. 26, p. 508). In nonpregnant patients, surgical fundoplication is per­ formed (Kahrilas, 20 1 5) . Although the procedure is not done during pregnancy, Biertho and colleagues (2006) described 25 women who had undergone laparoscopic Nissen fundoplica­ tion before pregnancy. Only 20 percent had relux symptoms during pregnancy. • H iatal Hernia

he older literature is informative regarding hiatal hernias in pregnancy. Upper gastrointestinal radiographs performed in 1 95 women in late pregnancy showed that 20 percent of 1 1 6

multiparas and 5 percent of 79 nulliparas had a hiatal hernia (Rigler, 1 935). Of 1 0 women studied postpartum, hernia per­ sisted in three at 1 to 1 8 months. he relationship of hiatal hernia with reflux esophagitis, and thus symptoms, is not clear. One study demonstrated no rela­ tionship between reflux and hernia and showed that the lower esophageal sphincter functioned efectively even when displaced intrathoracically (Cohen, 1 97 1 ) . Nevertheless, during preg­ nancy, these hiatal hernias may cause vomiting, epigastric pain, and bleeding from ulceration. Schwentner (20 1 1 ) reported severe herniation requiring surgical repair in a woman with a 1 2-week gestation. Curran and coworkers ( 1 999) described a 30-week pregnancy complicated by gastric outlet obstruction from a paraesophageal hernia. • Diaphragmatic Hernia

These are caused by herniations of abdominal contents through either the foramen of Bochdalek or vforgagni. Fortunately, they rarely complicate pregnancy. Kurzel and associates ( 1 988) reviewed the outcomes of 1 8 pregnant women with such a her­ nia and who developed acute obstruction. Because the maternal mortality rate was 45 percent, they recommend repair during pregnancy even if a woman is asymptomatic. Herniation has been reported in one pregnant woman from a previous trau­ matic diaphragmatic defect and in another who had antire­ lux surgery in early pregnancy (Brygger, 20 1 3; Flick, 1 999). Several case reports also describe spontaneous diaphragmatic rupture from increased intraabdominal pressure during delivery (Chen, 20 1 2; Sharifah, 2003) . • Achalasia

his is a rare motility disorder in which the lower esophageal sphincter does not relax properly with swallowing. There is also nonperistaltic contraction activity of the esophageal muscula­ ris to cause symptoms (Kahrilas, 20 1 5 ; Khudyak, 2006) . The defect is caused by inflammatory destruction of the myenteric (Auerbach) plexus within smooth muscle of the lower esopha­ gus and its sphincter. Postganglionic cholinergic neurons are unafected, thus, sphincter stimulation is unopposed. Symp­ toms are dysphagia, chest pain, and regurgitation. Barium swallow radiography demonstrates bird beak or ace of spades narrowing at the distal esophagus. Endoscopy is performed to exclude gastric carcinoma, and manometry is confirmatory. If dilatation of the esophagus and medical therapy does not pro­ vide relief, myotomy is considered (Torquati, 2006) . During pregnancy, normal relaxation of the lower esopha­ geal sphincter in women with achalasia theoretically should not occur. Even so, in most women, pregnancy does not seem to worsen achalasia. One report of 20 afected preg­ nant women found no excessive relux esophagitis (Mayberry, 1 987) . Khudyak and coworkers (2006) reviewed 35 cases and described most women as symptom free, although esophageal dilatation was needed in a few. A maternal death was reported at 24 weeks' gestation associated with perforation of a 1 4-cm diameter megaesophagus (Fassina, 1 995). Management of achalasia includes soft diet and anticholin­ ergic drugs. With persistent symptoms, other options include

Gastro i ntest i n a l Di sord e rs

nitrates, calcium-channel antagonists, and botulinum toxin A injected locally (Hooft, 20 1 5 ; Kahrilas, 20 1 5) . Balloon dila­ tation of the sphincter may be necessary, and 85 percent of nonpregnant patients respond to this. Satin ( 1 992) and Fiest ( 1 993) and their associates reported successful use of pneu­ matic dilatation in pregnancy. One caveat is that esophageal per­ oration is a serious complication of dilatation. Spiliopoulos and colleagues (20 1 3) described a 29-week pregnant woman with achalasia treated for 1 0 weeks with parenteral nutrition. Surgi­ cal correction was performed postpartum. • Peptic Ulcer Disease

he lifetime prevalence of acid peptic disorders in women is 1 0 percent (Del Valle, 20 1 5) . Erosive ulcer disease involves the stomach and duodenum. Gastroduodenal ulcers may be caused by chronic gastritis from H pylori, or they develop from nonsteroidal antiinlammatory drug (NSAID) use. Neither is common in pregnancy (McKenna, 2003; Weyermann, 2003) . Acid secretion is also important, and thus underlies the ei­ cacy of antisecretory agents (Suerbaum, 2002). Gastroprotec­ tion during pregnancy probably originates from physiological changes that include reduced gastric acid secretion, decreased motility, and considerably increased mucus secretion (Hyt­ ten, 1 99 1 ) . Despite this, ulcer disease may be underdiagnosed because of frequent treatment for reflux esophagitis (Mehta, 20 1 0) . In the past 50 years at Parkland Hospital, during which time we have cared for more than 500,000 pregnant women, we have encountered very few who had proven ulcer disease. Perforation is rare (Goel, 20 1 4) . Before appropriate therapy was commonplace, Clark ( 1 953) studied 3 1 3 pregnancies in 1 1 8 women with ulcer disease and noted a clear remission dur­ ing pregnancy in almost 90 percent. However, beneits were short lived. Symptoms recurred in more than half by 3 months postpartum and in almost all by 2 years. The mainstay of management is eradication of H pylori and prevention of NSAID-induced disease. Antacids are usually self-prescribed, but irst-line therapy is with HTreceptor block­ ers or proton-pump inhibitors (Del Valle, 20 1 5) . Sucraote is the aluminum salt of sulfated sucrose that inhibits pepsin. It provides a protective coating at the ulcer base. Approximately 1 0 percent of the aluminum salt is absorbed, and it is consid­ ered safe for pregnant women (Briggs, 20 1 5) . With active ulcers, a search for H pylori i s undertaken. Diagnostic aids include the urea breath test, serological test­ ing, or endoscopic biopsy. If any of these yield positive results, combination antimicrobial and proton-pump inhibitor therapy is indicated. Several efective oral treatment regimens do not include tetracycline and can be used during pregnancy. hese 1 4-day regimens include amoxicillin, 1 000 mg twice daily plus clarithromycin, 250 to 500 mg twice daily, plus metronidazole, 500 mg twice daily given along with the proton-pump inhibi­ tor omeprazole (Del Valle, 20 1 5) . • Upper Gastrointestinal Bleeding

In some women, persistent vomiting is accompanied by worrisome upper gastrointestinal bleeding. Occasionally, a peptic ulceration is the source. However, most of these women have small linear

mucosal tears near the gastroesophageal junction Mallo y- Weiss tears, described earlier. Bleeding usually responds promptly to conservative measures, including iced-saline irrigations, topical antacids, and intravenously administered HTblockers or proton­ pump inhibitors. Transfusions may be needed, and if bleeding persists, then endoscopy is usually indicated (O'Mahony, 2007) . With sustained retching, the less common, but more serious, esophageal rupture Boerhaave syndrome-may develop from greatly increased esophageal pressure. -

-

SMALL BOWEL AND COLON DISORDERS The small bowel has diminished motility during pregnancy. Using a nonabsorbable carbohydrate, Lawson ( 1 985) showed that small bowel mean transit times were 99, 1 25 , and 1 37 minutes in each trimester, compared with 75 minutes when nonpregnant. In a study cited by Everson ( 1 992) , mean tran­ sit time for a mercury-illed balloon from the stomach to the cecum was 58 hours in term pregnant women compared with 52 hours in nonpregnant women. Muscular relaxation of the colon is accompanied by increased absorption of water and sodium that predisposes to consti­ pation. This complaint is reported by almost 40 percent of women at some time during pregnancy (Everson, 1 992) . Such symptoms are usually only mildly bothersome, and preventive measures include a high-iber diet and bulk-forming lxatives. Wald (2003) has reviewed treatment options. We have encoun­ tered several pregnant women who developed megacolon from impacted stool. These women almost invariably had chronically abused stimulatory laxatives. • Acute Diarrhea

he estimated monthly prevalence of diarrhea among adults is 3 to 7 percent (DuPont, 20 1 4). Diarrhea can be classiied as acute « 2 weeks), persistent (2 to 4 weeks) , and chronic (>4 weeks). Most cases of acute diarrhea are caused by infectious agents, and a third result from foodborne pathogens. The large variety of viruses, bacteria, helminths, and protozoa that cause diarrhea in adults inevitably also alict pregnant women. Some of these are discussed in Chapter 64. Evaluation of acute diarrhea depends on its severity and duration. Some indications for evaluation include profuse watery diarrhea with dehydration, grossly bloody stools, fever > 38°C, duration >48 hours without improvement, recent antimicrobial use, and diarrhea in the immunocompro­ mised patient (Camilleri, 20 1 5; DuPont, 20 1 4) . Cases of mod­ erately severe diarrhea with fecal leukocytes or gross blood may best be treated with empirical antibiotics rather than evaluation. Some features of the more common acute diarrheal syndromes and their treatment are shown in Table 54-4. The mainstay of treatment is intravenous hydration using normal saline or Ringer lactate with potassium supplemen­ tation in amounts to restore maternal blood volume and to ensure uteroplacental perfusion. Vital signs and urine output are monitored for signs of sepsis syndrome. For moderately severe nonfebrile illness without bloody diarrhea, antimobility agents such as loperamide (Imodium) may be useful. Bismuth subsalicylate (Pepto-Bismol) may also alleviate symptoms.

1 04 7

1 048

Med i ca l and S u rg ical Co m p l ications

TABLE 54-4. Etio logy, C l i n ical Featu res, and Treatment of Com mo n Acute Dia rrheal Synd romes Agents

I ncubation

Emesis

Pa i n

Fever

Diarrhea

Toxin producers

1 -72 h r

3-4+

1 -2 +

0- 1 +

3-4 + , watery

Treatment

1 . Staphylococcus

1 . None

2. C perfringens

2. None

3 . E coli (en terotoxin)

3 . C i p rofloxac i n

4. B cereus

4. None

Enteroad herent

1 -8 days

0- 1 +

1 -3 +

0-2 +

1 . E coli

1 -2 + , watery,

m u shy

1 . C i p rofloxac i n

2 . Giardia

2. Ti n i dazole

3 . H e l m i nt h s

3 . As detected

Cytotoxin prod ucers

1 -3 days

0- 1 +

3-4+

1 -2 +

1 . C difficile

1 -3 + , watery,

then bloody

1 . Metro n idazole

2 . E coli (hemorrha g i c)

2. None

I nfla m matory 1 -3 d ays

Minimal

1 -3 +

3-4+

2-3 +

1 -3 + , watery

1 . Rotavirus

1 . None

2. Norovirus

2. None 1 - 1 1 days

Variable

0-3 +

2-4 +

3-4+

3 . Salmonella

1 -4 + watery or

bloody

3. C i p rofloxaci n

4. Campylobacter

4. Azith romyci n

5. Vibrio

5. Doxycycl i ne 1 -8 days

Severe

0- 1 +

3-4+

3 -4+

1 -2 + , bloody

6. Shigella 7. E coli

6. Ci profloxac i n 7. C i p rofloxa c i n 8. Metro n i d azol e

8. Entamoeba histolytica B cereus

=

Bacillus cereus; C difficile

=

Clostridium difficile; C perfringens

=

Clostridium perfringens; E coli

=

Escherichia coli.

Data from Ca m i l l e ri, 2 0 1 5; Du Pont, 2 0 1 4.

Judicious use of antimicrobial agents is warranted. For moderate to severely ill women, some recommend empirical treatment with ciprofloxacin, 500 mg twice daily for 3 to 5 days. Speciic pathogens are treated as needed when identiied (see Table 54-4) . Syndromes for which treatment is usually unnecessary include those caused by Escherichia coli, staphy­ lococcal species, Bacilus cereus, and Norwalk-like virus. Severe illness caused by Salmonela spp is treated with ciprofloxacin or trimethoprim-sulfamethoxazole; by Campylobacter spp with azithromycin; by Clostridium diicile with oral metronidazole or vancomycin; and by Giardia spp and Entamoeba histoytica with metronidazole (DuPont, 20 1 4; Rocha-Castro, 20 1 6) . Clostridium Difficile I n fection

his anaerobic gram-positive bacillus is transmitted by the fecal-oral route. It is the most frequent nosocomial infection in the United S tates. In 20 1 1 , 4 5 3,000 cases of C dicile and 29,000 associated deaths were reported by the Centers for D isease Control and Prevention (CDC) (Lessa, 20 1 5) . he most important risk factor is antibiotic use, and the highest risk is with aminopenicillins, clindamycin, cephalosporins, and luoroquinolones. O ther risk factors include inlam­ matory bowel disease, i mmunosuppression, advanced age, and gastrointestinal surgery. Most cases are hospital-acquired, however, community-acquired cases are becoming common

(Leler, 20 1 5) . With severe colitis, the infection-related mor­ tality rate is 5 percent. Diagnosis is by enzyme immunoassay for toxins in the stool, or by DNA-based tests that identiy toxin genes. Only patients with diarrhea should be tested, and posttreatment testing is not recommended. Prevention is by soap-and-water hand washing, and infected individuals are isolated. Treatment is oral vanco­ mycin or metronidazole. The risk of recurrence after an ini­ tial episode is 20 percent. Fecal microbial transplantation may become standard for recurrent clostridial colitis. • I nflammatory Bowel Disease

Two presumably noninfectious forms of intestinal inlamma­ tion are ulcerative colitis and Crohn disease. Diferentiation between these is important because treatment difers. That said, they both share common features, and sometimes are indis­ tinguishable if Crohn disease involves the colon. he salient clinical and laboratory features shown in Table 54-5 permit a reasonably confident diagnostic diferentiation in most cases. he etiopathogenesis is enigmatic in both, but a genetic predis­ position is suspected. Inlammation is thought to result from dysregulated mucosal immune function in response to com­ mensal microbiota, with or without an autoimmune compo­ nent (Friedman, 20 1 5) .

G a st ro i ntesti nal D isord e rs

TABLE 54-5. Some S h a red and Diferentiating C h a racteristics of I nfla m m atory Bowel Di sea se Croh n Disease

U lcerative Col itis Shared Characteristics Hered itary Other

More than 1 00 d isea se-assoc i ated genetic loci-a t h i rd s h a red; Jewish p red o m i na nce; fa m i l ia l i n 5- 1 0% o f cases; Tu rner syn d rome; i m m u ne dysreg u l ation C h ro n i c a nd i nterm itte nt with exacerbations a n d rem i ss ions; extra i ntesti n a l m a n ifestations: arth ritis, erythema nodosu m, uveitis Diferentiating Characteristics

Major sym ptoms Bowel involvement

Endoscopy Serum a nti bod ies Compl ications Management

Dia rrh ea, tenes m u s, recta l bl eed i n g , cra m p i n g pain; c h ron ic, i nte rmittent Mucosa and submucosa of large bowel ; usually beg i n s a t rectum (40% p roctitis on ly); continuous d i sease G ra n u l a r a n d fri a b l e e rythematous m ucosa; recta l i nvo lvement Anti neutrop h i l cyto p l a s m i c (pAN CA) 70% Toxic megacolon; strictu res; a rth ritis; cancer (3-5%) Med ica l; p roctocol ectomy cu rative -

Fibroste notic-recu rre nt RLQ co l icky pa i n ; fever F istu l izi ng-cuta n eo u s, b l a d d e r, i nterenteric Deep layers s m a l l a n d la rg e bowe l ; com monly tra n sm u ra l ; d i sconti n uous i nvolvement; strictu res a nd fi stu las Patchy; rectu m spared; peria n a l i nvolve ment A nti-S cerevisiae - 5 0% F i st u l a s; a rth ritis; toxic megacolon Medical; seg mental a n d fi st u l a resection

RLQ rig ht l owe r q u a d ra nt; S cerevisiae Saccharomyces cerevisiae. Data from F ried m a n, 2 0 1 5 ; Lichten stei n , 2009; Podolsky, 2002. =

=

U l cerative Col itis

This is a mucosal disorder with inflammation confined to the superficial luminal layers of the colon. It typically begins at the rectum and extends proximally for a variable distance. In approx­ imately 40 percent of cases, disease is conined to the rectum and rectosigmoid, but 20 percent have pancolitis. For unknown reasons, prior appendectomy protects against development of ulcerative coli tis (Friedman, 20 1 5) . Endoscopic indings include mucosal granularity and friability that is interspersed with muco­ sal ulcerations and a mucopurulent exudate (Fig. 54-2) . Major symptoms o f ulcerative colitis include diarrhea, rectal bleeding, tenesmus, and abdominal cramps. The disease can be acute or intermittent and is characterized by exacerbations and remissions. Toxic megacolon and catastrophic hemorrhage are particularly dangerous complications that may necessitate col­ ectomy. Extraintestinal maniestations include arthritis, uveitis,

and erythema nodosum. Another serious problem is that the risk of colon cancer approaches 1 percent per year. With either ulcerative colitis or Crohn disease, there is also concern for pos­ sible increased risks for venous thromboembolism (Kappelman, 20 1 1 ; Novacek, 20 1 0) . Cro h n D i sease

Also known as regional enteritis, Crohn ileitis, and granulo­ matous colitis, Crohn disease has more protean manifestations than ulcerative colitis. It involves not only the bowel mucosa but also the deeper layers, and sometimes involvement is transmural (see Fig. 54-2). Lesions can be seen throughout the entire gas­ trointestinal tract, from the mouth to the anus, but it typically is segmental (Friedman, 20 1 5) . Approximately 30 percent of patients have small-bowel involvement, 25 percent have isolated colonic involvement, and 40 percent have both, usually with the terminal ileum and colon involved. Perianal fistulas and abscesses develop in a third of those with colonic involvement. Symptoms depend on which bowel segment(s) is involved. Thus, complaints may include lower-right-sided cramping abdominal pain, diarrhea, weight loss, low­ grade fever, and obstructive symptoms. The disease is chronic with exacerbations and remissions, and importantly, it cannot be cured medically or surgically. Approxi­ mately a third of patients require surgery within the first year ater diagnosis, and thereater, 5 percent per year. Reactive F I G U R E 54-2 Ca u ses of colitis. A. C h ro n ic u l cerative col itis with d iffuse u lcerations a n d arthritis is common, and the gastrointesti­ exudates. B. Cro h n col itis with deep u l cers. (Reprod u ced with perm ission from S o n g LM nal cancer risk, although not as great as. with Topazian M: Gastointesti n a l endoscopy. Kasper DL, Fauci AS, Hauser SL, et al (eds): Ha rrison's Princi ples of I ntern a l Medici ne, 1 9th ed. New York: McGraw- H i l i Ed ucation; 2 0 1 5 .) ulcerative colitis, is increased substantially.

1 049

1 050

Med i ca l a n d S u rg ical Com p l ications I nfl a m matory Bowel D i sease a n d Fert i l ity

Subfertility is commonly linked to chronic medical disease, but 1VIahadevan (2006a) cited a normal fertility rate for infl a mma­ tory bowel disease unless severe disease warranted surgery. Sim­ ilarly, Alstead (2003) reported that decreased female fertility from active Crohn disease returned to normal with remission. For women requiring surgical resection, laparoscopic anas­ tomosis has a higher subsequent fertility rate (Beyer-Berjot, 20 1 3) . With colectomy, however, even though fertility is improved, up to half of women will be persistently infertile (Bartels, 20 1 2) . Sexual function and fertility are only modestly afected by ileal pouch-anal anastomosis (Hor, 20 1 6) . Subfer­ tility may also be partially due to sulfasalazine, which causes reversible sperm abnormalities (Feagins, 2009) . I nfl a m m atory Bowe l D i sease a n d Preg n a n cy

Because ulcerative colitis and Crohn disease are relatively common in young women, they are encountered with some frequency in pregnancy. In this regard, a few generalizations can be made. First, consensus supports that pregnancy does not increase the likelihood of an inlammatory bowel disease flare (.1ahadevan, 20 1 5) . Indeed, in a 1 0-year surveillance of women in the European Collaborative on Infl a mmatory Bowel Disease, the likelihood of a lare during pregnancy was decreased compared with the preconceptional rate (Riis, 2006) . Although most women with quiescent disease in early pregnancy do not have relapses, when a lare develops, it may be severe. lso, active disease in early pregnancy increases the likelihood of poor pregnancy outcome, which is discussed sub­ sequently. In general, most usual treatment regimens may be continued during pregnancy. Diagnostic evaluations should be undertaken if needed to direct management, and surgery should be performed if indicated. For women who successfully complete pregnancy, about half experience improvement in their health-relate.d q uali ty of life (Ananthakrishnan, 20 1 2) . At first glance, i t appears that adverse pregnancy outcomes are increased with infl a mmatory bowel disease (Boyd, 20 1 5 ; Cornish, 20 1 2; Getahun, 20 1 4) . Initially, this was attributed to the fact that most studies included women with either form of disease. Specifically, Crohn disease was noted to be linked to excessive morbidity (Dominitz, 2002; Stephansson, 20 1 0) . But, according t o Reddy (2008) and others, these adverse outcomes were in women with severe disease and multiple recurrences. Indeed, in the prospective European case-control ECCO-EpiCom study of 332 pregnant women with infl a mma­ tory bowel disease, Bortoli and coworkers (20 1 1 ) found similar outcomes in women with ulcerative colitis or Crohn disease compared with normally pregnant women. Importantly, peri­ natal mortality rates are not appreciably increased. Ulcerative Col itis and Preg nancy. Ulcerative colitis does not signiicantly alter the course of pregnancy in afected women. In one review of 755 pregnancies, colitis that was quiescent at conception worsened in approximately a third of pregnancies (Fonager, 1 998) . In women with active disease at the time of conception, approximately 45 percent worsened, 25 percent remained unchanged, and only 25 percent improved. hese observations are similar to those previously described in an

extensive review by Miller ( 1 986) and a later report from Oron and colleagues (20 1 2) . Osteoporosis i s a signiicant complication in up t o a third of these women, and thus vitamin D-800 IU daily-and cal­ cium-1 200 mg daily-are given. Folic acid, 4 mg orally daily, is recommended preconceptionally and during the first trimes­ ter for neural-tube defect prevention. his high dose counter­ acts the antifolate actions of sulfasalazine. Flares may be caused by psychogenic stress, and reassurance is important. Management for colitis for the most part mirrors that out­ side of pregnancy. Treatment of active colitis and maintenance therapy incorporate drugs that deliver 5-aminosalicyclic acid (5-ASA) or mesalamine. Suasalazine (Azuidine) is the proto­ type, and its 5-ASA moiety inhibits prostaglandin synthase in colonic mucosa. Others include olsalazine (Dipentum), balsala­ zide (Colazal), and delayed-release 5-ASA derivatives (Apriso, Asacol Pentasa, Lialda). Glucocorticoids are given orally, par­ enterally, or by enema for moderate or severe disease that does not respond to 5-ASA. However, these latter drugs are not given for maintenance therapy. Recalcitrant disease is man­ aged with immunomodulating drugs, including azathioprine, 6-mercaptopurine, or cyclosporine, which appear relatively safe in pregnancy (Briggs, 20 1 5 ; Mozafari, 20 1 5) . Importantly, methotrexate is contraindicated in pregnancy. In the past, biological therapy was reserved for recalcitrant moderate to severe disease. Because of their considerable ei­ cacy, these medications are now frequently given initialy for severe disease to prevent future complications. These agents are antibodies against tumor necrosis factor-alpha (TNF-alpha) . Those approved for treatment of ulcerative colitis include inf liximab (Rem icade) , adalimumab (Hum ira), and golinumab (Simponi). These drugs are administered intravenously or sub­ cutaneously. Several studies indicate that they are safe for use in pregnancy, although there are concerns that their discon­ tinuance may prompt a relapse (Torres, 20 1 5) . Another worry is that they may cause immunosuppression in the neonate (Brams, 20 1 6; Diav-Citrin, 20 1 4; Gisbert, 20 l 3) . Colorectal endoscopy i s performed a s indicated (Katz, 2002) . During pregnancy, colectomy and ostomy creation for fulmi­ nant colitis may be needed as a lifesaving measure, and it has been described during each trimester. Dozois (2006) reviewed 42 such cases and found that, in general, outcomes have been good in recent reports. Most women underwent partial or complete colectomy, but Ooi and colleagues (2003) described decompression colostomy with ileostomy in a 1 0- and a 1 6-week pregnancy. Parenteral nutrition discussed on page 1 043 is occa­ sionally necessary for women with prolonged exacerbations. For women with an ileal pouch and an anal anastomosis performed before pregnancy, sexual function and fertility are improved (Cornish, 2007) . Disadvantages that temporarily worsen in pregnancy include frequent bowel movements, fecal incontinence, and pouchitis. he last is an inflammatory con­ dition of the ileoanal pouch probably due to bacterial prolif­ eration and stasis. Pouchitis usually responds to cephalosporins or metronidazole. In one rare case, adhesions to the growing uterus led to ileal pouch perforation (Aouthmany, 2004) . Women who have had a prior proctocolectomy and ileal pouch-anal anastomosis can be safely delivered vaginally

Gastro i n test i na l Disorders

(Ravid, 2002) . Hahnloser (2004) reviewed routes of delivery in women with 235 pregnancies before and 232 pregnancies after ileoanal pouch surgery. Functional outcomes were similar, and it was concluded that cesarean delivery should be reserved for obstetrical indications. Postcesarean delivery ileoanal pouch obstruction has been described (Malecki, 20 1 0) . To reiterate, ulcerative colitis likely has minimal adverse efects on pregnancy outcome. Modigliani (2000) reviewed perinatal outcomes in 2398 pregnancies and reported them to be not substantively diferent from those in the general obstetrical population. Speciically, the incidences of spontane­ ous abortion, preterm delivery, and stillbirth were remarkably low. In a population-based cohort study of 1 07 women from Washington state, perinatal outcomes, with two exceptions, were similar to those of 1 308 normal pregnancies (Dominitz, 2002) . One exception was an inexplicably increased incidence of congenital malformations. These authors and others also describe a cesarean delivery rate that was substantially increased compared with that for normal controls (Mahadevan, 20 1 5) . he previously described ECCO-EpiCom study reported simi­ lar outcomes in 1 87 gravidas with ulcerative colitis compared with normal pregnant controls (Bortoli, 20 1 1 ) . Crohn Disease a n d Preg na ncy. I n general, Crohn disease activity during pregnancy is related to its status around the time of conception. In a cohort study of 279 pregnancies in 1 86 women whose disease was inactive at conception, a fourth relapsed during pregnancy (Fonager, 1 998) . In 93 with active disease at conception, however, two thirds either remained active or worsened. Miller ( 1 986) had described similar fi n dings from his earlier review, as did Oron and associates (20 1 2) . Calcium, vitamin D , and folic acid supplementation mirror that for ulcerative colitis. For maintenance during asymptom­ atic periods, no regimen is universally efective. Suasalazine is efective for some, but the newer 5-ASA formulations are better tolerated. Prednisone therapy may control moderate to severe lares but is less efective for small-bowel involvement. Immunomodulators such as azathioprine, 6-mercaptopurine, and cyclosporine are used for active disease and for mainte­ nance. These appear relatively safe during pregnancy (Briggs, 20 1 5 ; Chande, 20 1 5) . As discussed in Chapter 1 2 (pp. 242 and 244) , methotrexate, mycophenolate mofetil, and mycophenolic acid are contraindicated in pregnancy (Briggs, 20 1 5; Food and Drug Administration, 2008) . As with ulcerative colitis, treatment with antitumor necrosis factor monoclonal antibodies is often used initially for active Crohn disease and maintenance (Casanova, 20 1 3; Cominelli, 20 1 3; Friedman, 20 1 5) . These biological compounds include inliximab, adalimumab, certolizumab (Cimzia), natalizumab (Tysabri), and vedolizumab (Enyvio). As discussed on page 1 050, this class of immunomodulators is considered safe in pregnancy (Briggs, 20 1 5 ; Clowse, 20 1 5) . heir discontinuance may be followed by a relapse (Torres, 20 1 5) . Endoscopy or conservative surgery is indicated for compli­ cations. Patients with small-bowel involvement are more likely to require surgery for complications that include istulas, stric­ tures, abscesses, and intractable disease. An abdominal surgical

procedure was required during 5 percent o f pregnancies described by Woolfson ( 1 990) . Parenteral hyperalimentation has been used successfully during severe recurrences (Russo­ Stieglitz, 1 999) . hose with an ileal loop colostomy may have signiicant problems. Women with a perianal istula-unless these are rectovaginal-usually can undergo vaginal delivery without complications (Forsnes, 1 999; Takahashi, 2007) . As discussed, the likelihood is greater that Crohn disease is associated with adverse pregnancy outcomes compared with ulcerative colitis (Stephansson, 20 1 0) . Outcomes are probably related to disease activities. In a case-control Danish study, Norgard (2007) reported a twofold risk of preterm births. Dominitz (2002) reported a two- to threefold increased risk for preterm delivery, low birthweight, fetal growth restriction, and cesarean delivery in 1 49 women with Crohn disease. Recall, however, that the prospective ECCO-EpiCom study found outcomes to be similar to those for normal pregnancies. • Ostomy and Pregnancy

A colostomy or an ileostomy can be problematic during preg­ nancy because of its location (Hux, 20 1 0) . In a report of 82 pregnancies in 66 women with an ostomy, stomal dyfunction was common, but it responded to conservative management in most cases (Gopal, 1 98 5 ) . Surgical intervention was necessary, however, in three of six women who developed bowel obstruc­ tion and in another four with ileostomy prolapse almost 1 0 percent overall. I n this older study, only a third o f 8 2 women underwent cesarean delivery, but Takahashi (2007) described six of seven cesarean deliveries in women with Crohn disease and a stoma. Although adhesions usually are involved with an obstructed ileostomy, the enlarging uterus may act to obstruct (Porter, 20 1 4) . Finally, Farouk and coworkers (2000) reported that pregnancy did not worsen long-term ostomy function. -

• I ntestinal Obstruction

The incidence of bowel obstruction is not increased during pregnancy, although it generally is more diicult to diagnose. Meyerson ( 1 995) reported a 20-year incidence of 1 in 1 7,000 deliveries at two Detroit hospitals. In one study, adhesive dis­ ease leading to small-bowel obstruction was the second most common cause of an acute abdomen in pregnancy following appendicitis-1 5 versus 30 percent, respectively (Unal, 20 1 1 ) . Approximately half o f cases are due t o adhesions from previ­ ous pelvic surgery that includes cesarean delivery (Al-Sunaidi, 2006; Andolf, 20 1 0; Lyell, 20 1 1 ) . Another 25 percent of bowel obstruction cases are caused by volvulus-sigmoid, cecal, or small bowel. hese have been reported in late pregnancy or early puerperium (Bade, 20 1 4; Biswas, 2006; l Maksoud, 20 1 5) . Small-bowel obstruction has been reported in preg­ nancy following the currently popular Roux-en-Y gastric bypass for weight loss (Bokslag, 20 1 4; Wax, 20 1 3) . Intussusception is occasionally encountered (Bosman, 20 1 4 ; Harma, 20 1 l ) . Bowel obstruction subsequent to colorectal surgery for can­ cer was increased threefold in women who had open versus laparoscopic surgery (Haggar, 20 1 3) . Finally, Serra and col­ leagues (20 1 4) described a massive ventral hernia with intes­ tinal obstruction.

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Med i ca l a n d S u rg ica l Comp l ications

• Colonic Pseudo-obstruction

Also known as Ogilvie syndrome, pseudo-obstruction is caused by adynamic colonic ileus. It is characterized by massive abdominal distention with cecal and right-hemicolon dilata­ tion. Approximately 1 0 percent of all cases are associated with pregnancy, and its frequency has been reported as high as 1 in 1 500 deliveries (Reeves, 20 1 5) . he syndrome usually develops postpartum-most commonly after cesarean delivery-but it has been reported antepartum (Tung, 2008) . Rarely, the large bowel may rupture (Singh, 2005 ) . Treatment with an intrave­ nous infusion of neostigmine, 2 mg, usually results in prompt decompression (Song, 20 1 5) . In some cases, colonoscopic decompression is performed, and laparotomy is needed for perforation (De Giorgio, 2009; Rawlings, 20 1 0) . • Appendicitis

F I G U RE 54-3 Cha racteristic "bent i n ner tu be" seen w i t h sigmoid volvu l u s o n a bd o m i n a l rad iog ra p h . (Reprod uced with perm ission from Song LM, Topazia n M : Gastoi ntest i n a l e ndoscopy. Kasper D L, Fauci AS, H a user S L, et al (eds): Ha rrison's Princi ples of I nternal Medicine, 1 9th ed. New York: McGraw- H i l i Ed ucation; 201 5 .)

Most cases of intestinal obstruction during pregnancy result from pressure of the growing uterus on intestinal adhesions. According to Davis and Bohon ( 1 983) , this more likely occurs around midpregnancy when the uterus becomes an abdomi­ nal organ; in the third trimester when the fetal head descends; or immediately postpartum when uterine size acutely shrinks. Perdue ( 1 992) reported that 98 percent of afected pregnant women had either continuous or colicky abdominal pain, and 80 percent had nausea and vomiting. Abdominal tenderness was found in 70 percent, and abnormal bowel sounds noted in only 55 percent. Plain abdominal radiographs following soluble contrast showed evidence of obstruction in 90 percent of women (Fig. 5 4-3) . Plain radiographs, however, are less accurate for diagnosing small-bowel obstruction, and we and others have found that CT and MR imaging can be diagnostic (Biswas, 2006; Essilie, 2007; McKenna, 2007) . Colonoscopy can be both diagnostic and therapeutic for colonic volvulus (Dray, 20 1 2; Khan, 20 1 2) . During pregnancy, mortality rates with obstruction can be excessive because of diicult and thus delayed diagnosis, reluc­ tance to operate during pregnancy, and the need for emergency surgery (Firstenberg, 1 998; Shui, 20 1 1 ) . In an older report of 66 pregnancies, Perdue and associates ( 1 992) described a 6-percent maternal mortality rate and 26-percent fetal mortal­ ity rate. Two of the four women who died were in late preg­ nancy, and they had bowel perforation from sigmoid or cecal volvulus caused by adhesions.

The lifetime incidence for appendicitis ranges from 7 to 1 0 percent (Flum, 20 1 5) . hus, i t i s not surprising that an evalua­ tion for possible appendicitis is relatively common during preg­ nancy. heilen and colleagues (20 1 5) studied 1 7 1 such women during a 5-year period, but only 12 women ultimately were found to have pathologically confirmed appendicitis. After clinical and imaging evaluation, the frequency of suspected appendicitis is much lower and that of confirmed appendicitis in more than 8 million women ranged from 1 in 1 000 to 1 in 5 500 births (Abbasi, 20 14; Hee, 1 999; Mazze, 1 99 1 ) . I t i s repeatedly-and appropriately-emphasized that preg­ nancy makes the diagnosis of appendicitis more diicult. Nau­ sea and vomiting accompany normal pregnancy, but also, as the uterus enlarges, the appendix commonly moves upward and outward from the right lower quadrant (Baer, 1 932; Erkek, 20 1 5; Pates, 2009) . Another often-stated reason for late diag­ nosis is that some degree of leukocytosis accompanies normal pregnancy. For these and other reasons, pregnant women­ especially those late in gestation-frequently do not have clini­ cal findings "typical" for appendicitis. Thus, it commonly is confused with cholecystitis, labor, pyelonephritis, renal colic, placental abruption, or uterine leiomyoma degeneration. Most reports indicate increasing morbidity and mortality rates with advancing gestational age. nd as the appendix is progressively delected upward by the growing uterus, omen­ tal containment of infection becomes increasingly unlikely. It is indisputable that appendiceal perforation is more common dur­ ing later pregnancy (Abbasi, 20 1 4) . In the studies by Andersson (200 1 ) and Ueberrueck (2004) , the incidence of perforation was approximately 8, 1 2, and 20 percent in successive trimesters. D i a g n os i s

Persistent abdominal pain and tenderness are the most repro­ ducible fi n dings. Right-lower quadrant pain is the most frequent, although pain migrates upward with appendiceal dis­ placement CMourad, 2000) . For initial evaluation, sonographic abdominal imaging is reasonable in suspected appendicitis, even if to exclude an obstetrical cause of pain (Butala, 20 1 0) . hat said, graded compression sonography is diicult because of cecal displacement and uterine imposition (Pedrosa, 2009) . Appen­ diceal computed tomography is more sensitive and accurate than

Gastroi ntesti n a l Disord e rs

F I G U R E 54-4 Anterior-posterior m a g n etic resona nce image of a peri a ppend icea l a bscess in a m i dtri mester preg n a n cy. The a bscess is a pproxi m ately 5 x 6 cm, and the a ppend i cea l l u men (arow) is visible wit h i n the rig ht-lower q u a d ra nt m ass. The g ravid uterus is seen to the right of this mass.

sonography to conirm suspected appendicitis (Katz, 20 1 2; Raman, 2008) . Specifi c views can be designed to diminish fetal radiation exposure (Chap. 46, p. 907) . It is generally accepted that when available, MR imaging is the preferred modality for evaluation of suspected appendicitis in pregnancy (Fig. 5 4-4) . MR imaging has high diagnostic yield and accu­ racy, and it also provides alternative diagnoses (Fonseca, 20 1 4; Theilen, 20 1 5) . One metaanalysis cited positive- and negative­ predictive values for MR imaging of 90 and 99.5 percent, respectively (Blumenfeld, 20 1 1 ) . Burke and associates (20 1 5) reported similar indings. Using a decision-analysis model, CT and MR imaging were found to be cost efective (Kasten berg, 20 1 3) . This was verified in the clinical study of more than 7000 cases reported by Fonseca and coworkers (20 1 4) . M a n a g e ment

When appendicitis is suspected, treatment is prompt surgical exploration. Although diagnostic errors may lead to removal of a normal appendix, surgical evaluation is preferable to post­ poned intervention and generalized peritonitis (Abbasi, 20 1 4) . I n earlier reports, the diagnosis was veriied i n only 6 0 to 70 percent of pregnant women. As indicated above, however, with CT and MR imaging, these igures have improved (Blumen­ feld, 20 1 1 ; Theilen, 20 1 5) . Still and importantly, the accuracy of diagnosis is inversely proportional to gestational age. Currently, laparoscopy is almost always used to treat sus­ pected appendicitis during the irst two trimesters. In a report from a Swedish database of nearly 2000 laparoscopic appen­ dectomies, perinatal outcomes were similar to those of more than 1 500 open laparotomies done before 20 weeks' gestation (Reedy, 1 997) . Conversely, in their review, Wilasrusmee and coworkers (20 1 2) reported a higher rate of fetal loss with lapa­ roscopy. Authors of a more recent systematic review indicate that the level of evidence is not strong enough to demonstrate a preferred approach to appendectomy. They concede that lap­ aroscopy may be associated with a higher risk of miscarriage

(Walker, 20 1 4) . It has evolved that in many centers, laparo­ scopic appendectomy is also performed in most cases during the third trimester (Donkervoort, 20 1 1 ) . This is encouraged by the Society of American Gastrointestinal and Endoscopic Surgeons (Pearl, 20 1 7; Soper, 20 1 1 ) . That said, most are of the opinion that laparoscopic surgery in pregnancy after 26 weeks' gestation should be performed only by the most experienced endoscopic surgeons (Parangi, 2007) . Before exploration, intravenous antimicrobial therapy is begun, usually with a second-generation cephalosporin or third­ generation penicillin. Unless there is gangrene, perforation, or a periappendiceal phlegmon, antimicrobial therapy can usually be discontinued after surgery. Without generalized peritonitis, the prognosis is excellent. Seldom is cesarean delivery indicated at the time of appendectomy. Uterine contractions are common, and although some clinicians recommend tocolytic agents, we do not. De Veciana ( 1 994) reported that tocolytic use substantially increased the risk for pulmonary-permeability edema caused by sepsis syndrome (Chap. 47, p. 9 1 7) . Anti m ic ro b i a l ve rsu s S u rg ic a l Treatm e nt

Because of European studies, some have advocated that many cases of appendicitis can be treated successfully with intrave­ nous antimicrobials alone (Flum, 20 1 5; J 00, 20 1 7) . At this time, we discourage this practice until appropriate studies have been done with pregnant women. In one study, 6 percent of pregnant women with appendicitis were treated medically, and these gravidas had "considerably" elevated risks for septic shock, peritonitis, and venous thromboembolism compared with surgically managed cases (Abbasi, 20 1 4) . P reg n a ncy Outcomes

Appendicitis increases the likelihood of abortion or preterm labor, especially if peritonitis has developed. In two studies, spontaneous labor after 23 weeks ensued with greater frequency following surgery for appendicitis compared with surgery for other indications (Cohen-Kerem, 2005; Mazze, 1 99 1 ) . In one study, the fetal loss rate was 22 percent if surgery was performed after 23 weeks' gestation. Two large population-based studies attest to the adverse outcomes from appendicitis in pregnancy. From the California Inpatient File of 3 1 33 pregnant women undergoing surgery for suspected appendicitis, the fetal loss rate was 23 percent, and it was doubled-6 versus 1 1 percent-with simple versus complicated disease (McGory, 2007). A nation­ wide study from Taiwan found that risks for low birthweight and preterm delivery rose 1 . 5- to 2-fold when outcomes in 908 women with acute appendicitis were compared with those of controls (Wei, 20 1 2) . Long-term complications are not common. The possible link between sepsis and neonatal neurological inj ury has not been veriied (Mays, 1 995) . Finally, appendicitis during preg­ nancy does not appear to be associated with subsequent infertil­ ity (Viktrup, 1 998) .

REFERENCES Abbasi N, Patenaude V, Abenhaim HA: Management and outcomes of acute appendicitis in pregnancy-population-based study of over 7000 cases. BlOC 1 2 1 ( 1 2): 1 509, 2014

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Ogura ]M, Francois E, Perlow ]H, et al: Complications associated with peripherally inserted central catheter use during pregnancy. Am ] Obstet GynecoI 1 88 : 1 223, 2003 Oliveira LG, Capp SM, You B , et al: Ondansetron compared with doxyl­ amine and pyridoxine for treatment of nausea in pregnancy. Obstet Gynecol 1 24(4) :735, 20 1 4 O'Mahony S : Endoscopy i n pregnancy. Best Pract Res Clin Gastroenterol 2 1 :893, 2007 Ooi BS, Remzi FH, Fazio W: Turnbull-blowhole colostomy for toxic ulcer­ ative colitis in pregnancy: report of two cases. Dis Colon Rectum 46: 1 1 1 , 2003 Oron G, Yogev Y, Shkolnik S, et al: Inflammatory bowel disease: risk factors for adverse pregnancy outcome and the impact of maternal weight gain. ] VIatern Fetal Neonatal Med 25 ( 1 1 2):2256, 20 1 2 Oto A , Ernst R, Ghulmiyyah L , e t al: h e role o f MR cholangiopancreatog­ raphy in the evaluation of pregnant patients with acute pancreaticobiliary disease. Br ] Radiol 82(976) :279, 2009 Palacios-Marques A, Delgado-Garcia S, Martin-Bayon T, et al: Wernicke's encephalopathy induced by hyperemesis gravidarum. BM] Case Rep June 8, 20 1 2 Parangi S , Levine D , Henry A , e t al: Surgical gastrointestinal disorders during pregnancy. Am ] Surg 1 93:223, 2007 Paranyuk Y, Levin G, Figueroa R: Candida septicemia in a pregnant woman with hyperemesis receiving parenteral nutrition. Obstet Gynecol 1 0 :535, 2006 Pasternak B, Svanstr6m M, Henrik A: Ondansetron in pregnancy and risk of adverse fetal outcomes. N Engl ] Med 368:8 1 4, 20 1 3 Pates ]A, Avendanio TC, Zaretsky MV, e t al: h e appendix i n pregnancy: confirming historical observations with a contemporary modaliry. Obstet Gynecol 1 1 4(4) :805, 2009 Pearl ]P, Price R, Tonkin E, et al: SAGES guidelines for the use of laparos­ copy during pregnancy. Surg Endosc 3 1 ( 1 0):3767, 20 1 7 Pedrosa I , Lafornara M , Pandharipande PV, e t al: Pregnant patients suspected of having acute appendicitis: efect of MR imaging on negative laparotomy rate and appendiceal perforation rate. Radiology 250(3) : 49, 2009 Peled Y, Melamed N, Hiersch L, et al: he impact of total parenteral nutrition support on pregnancy outcome in women with hyperemesis gravidarum. ] Matern Fetal Neonatal Med 27( 1 1 ) : 1 1 46, 20 1 4 Perdue PW, Johnson HW ]r, Staford PW: Intestinal obstruction complicating pregnancy. Am ] Surg 1 64:384, 1 992 Podolsky DK: Inflammatory bowel disease. N Engl ] Med 347(6) :4 1 7, 2002 Porter H, Seeho S: Obstructed ileostomy in the third trimester of pregnancy due to compression from the gravid uterus: diagnosis and management. BM] Case Rep August 1 9, 20 1 4 Poursharif B , Korst LM, Macgibbon W , e t al: Elective pregnancy termination in a large cohort of women with hyperemesis gravidarum. Contraception 76:45 1 , 2007 Prefontaine E, Sutherland LR, Macdonald ] K, et al: Azathioprine or 6-mercap­ topurine for maintenance of remission in Crohn's disease. Cochrane Data­ base Syst Rev 1 :CD000067, 2009 Raman SS, Osuagwu FC, Kadell B, et al: Efect of CE on false positive diagno­ sis of appendicitis and perforation. N Engl ] Med 358:972, 2008 Ravid A, Richard CS, Spencer LM, et al: Pregnancy, delivery, and pouch func­ tion after ileal pouch-anal anastomosis for ulcerative colitis. Dis Colon Rec­ tum 45: 1 283, 2002 Rawlings C: Management of postcaesarian Ogilvie's syndrome and their subse­ quent outcomes. Aust N Z ] Obstet Gynaecol 50(6) :5 3, 20 1 0 Reddy D , Murphy S], Kane SV, e t al: Relapses o f inflammatory bowel disease during pregnancy: in-hospital management and birth outcomes. Am ] Gas­ troenterol 1 03: 1 203, 2008 Reedy MB, Kallen B, Kuehl T]: Laparoscopy during pregnancy: a study of five fetal outcome parameters with use of the Swedish Health Registry. Am ] Obstet Gynecol 1 77:673, 1 997 Reeves M, Frizelle F , Wakeman C, et al: Acute colonic pseudo-obstruction in pregnancy. ANZ ] Surg 8 5 ( 1 0) :728, 20 1 5 Rigler LG, Eneboe ]B: Incidence of hiatus hernia i n pregnant women and its significance. ] Thorac Surg 4:262, 1 935 Riis L, Vind I , Politi P, et al: Does pregnancy change the disease course? A study in a European cohort of patients with inflammatory bowel disease. Am ] GastroenteroI 1 0 1 : 1 539, 2006 Rocha-Castro ], Kronbauer K, Daile ], et al: Characteristics of bacterial acute diarrhea among women. Int ] Gynaecol Obstet 1 32(3) :302, 20 1 6 Russo-Stieglitz E , Levine AB, Wagner BA, e t al: Pregnancy outcome in patients requiring parenteral nutrition. ] Matern Fetal Med 8: 1 64, 1 999 Saha S, Loranger D, Pricolo V, et al: Geeding jejunostomy for the treatment of severe hyperemesis gravidarum: a case series. ] Parenter Enteral Nutr 33(5): 529, 2009

Gastroi ntestinal D isorders Sakai M, Yoneda S, Sasaki Y, et al: Maternal total parenteral nutrition and fetal subdural hematoma. Obstet Gynecol 1 0 1 : 1 1 42, 2003 Satin AJ, Twickler D, Gilstrap LC: Esophageal achalasia in late pregnancy. Obstet Gynecol 79:8 1 2, 1 992 Savas N: Gastrointestinal endoscopy in pregnancy. World J Gastroenterol 20(4 1 ) : 1 524 1 , 20 1 4 Schif MA, Reed S D , Daling JR: The sex ratio o f pregnancies complicated by hospitalisation for hyperemesis gravidarum. BJOG 1 1 1 :27, 2004 Schrag SP, Sharma R, Jaik NP, et al: Complications related to percutane­ ous endoscopic gastrostomy (PEG) tubes: a comprehensive clinical review. J Gastrointest Liver Dis 1 6:407, 2007 Schwentner L, Wulf C, Kreienberg R, et al: Exacerbation of a maternal hia­ tus hernia in early pregnancy presenting with symptoms of hyperemesis gravidarum: case report and review of the literature. Arch Gynecol Obstet 283(3):409, 20 1 1 Selitsky T, Chandra P, Schiavello HJ: Wernicke's encephalopathy with hyper­ emesis and ketoacidosis. Obstet Gynecol 1 07:486, 2006 Serra AE, Fong A, Chung H: A gut-wrenching feeling: pregnancy complicated by massive ventral hernia with bowel obstruction. Am J Obstet Gynecol 2 1 1 ( 1 ) :79, 20 1 4 Sharifah H, Naidu A , Vimal K : Diaphragmatic hernia: a n unusual cause o f postpartum collapse. BJOG 1 1 0:70 1 , 2003 Shui LH, Rafi J, Corder A, et al: Mid-gut volvulus and mesenteric vessel thrombosis in pregnancy: case report and literature review. Arch Gynecol Obstet 283 (Suppl 1 ) :39, 20 1 1 Siddiqui U, Denise-Proctor D: Flexible sigmoidoscopy and colonoscopy dur­ ing pregnancy. Gastrointest Endosc Clin North Am 1 6:59, 2006 Singh S, Nadgir A, Bryan M: Post-cesarean section acute colonic pseudo­ obstruction with spontaneous perforation. Int J Gynaecol Obstet 89: 1 44, 2005 Song LM, Topazian M: Gastrointestinal endoscopy. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 1 9th ed. New York, McGraw-Hill Education, 20 1 5, p 1 947 Soper NJ: SAGES' guidelines for diagnosis, treatment, and use of laparoscopy for surgical problems during pregnancy. Surg Endosc 25:3477, 20 1 1 Spiliopoulos D, Spiliopoulos M, Awala A: Esophageal achalasia: an uncommon complication during pregnancy treated conservatively. Case Rep Obstet GynecoI 2 0 1 3 (639698) : 1 , 20 1 3 Stephansson 0, Larsson H, Pedersen L , e t al: Crohn's disease i s a risk factor for preterm birth. Clin Gastroenterol Hepatol 8(6) : 509, 20 1 0 Stern M D , Kopylov U , Ben-Horin S, e t al: Magnetic resonance enterography in pregnant women with Crohn's disease: case series and literature review. BMC Gastroenterol 14: 1 46, 20 1 4 Stokke G, Gjelsvik BL, Flaatten KT, e t al: Hyperemesis gravidarum, nutri­ tional treatment by nasogastric tube feeding: a 1 0-year retrospective cohort study. Acta Obstet Gynecol Scand 94(4):359, 20 1 5 Storch 1 , Barkin JS: Contraindications to capsule endoscopy: do any still exist? Gastrointest Endosc Clin North Am 1 6:329, 2006 Suerbaum S, Michetti P: Helicobacter pylori infection. N Engl J Med 347: 1 1 75, 2002 Sun S, Qiu X, Zhou J: Clinical analysis of 65 cases of hyperemesis gravi­ darum with gestational transient thyrotoxicosis. J Obstet Gynaecol Res 40 (6) : 1 567, 2 0 1 4 Swallow BL, Lindow SW, Masson A , e t al: Psychological health in early preg­ nancy: relationship with nausea and vomiting. ] Obstet GynaecoI 24:28, 2004 Swartzlander TK, Carlan SJ, Locksmith G, et al: Sonographic conirmation of the correct placement of a nasoenteral tube in a woman with hyperemesis gravidarum: case report. J Clin Ultrasound 4 1 (Suppl 1 ) : 1 8, 20 1 3 Takahashi K , Funayama Y, Fukushima K , e t al: Pregnancy and delivery in patients with enterostomy due to anorectal complications from Crohn's dis­ ease. Int ] Colorectal Dis 22:3 1 3, 200 Tan PC, Jacob R, Quek KF, et al: he fetal sex ratio and metabolic, biochemi­ cal, haematological and clinical indicators of severiry of hyperemesis gravi­ darum. B]OG 1 1 3:733, 2006

Tan P C , Norazilah MJ, Omar S Z : Dextrose saline compared with normal saline rehydration of hyperemesis gravidarum: a randomized controlled trial. Obstet Gynecol 1 2 1 (2 Pt l ) :29 1 , 20 1 3 Theilen L H , Mellnick VM, Longman E , e t al: Utiliry o f magnetic resonance imaging for suspected appendicitis in pregnant women. Am J Obstet Gyne­ col 1 2 (3):345, 20 1 5 Torquati A , Luti R, Khaitan L, e t al: Heller myotomy vs Heller myotomy plus Dor fundoplication: cost-utility analysis of a randomized trial. Surg Endosc 20:389, 2006 Torres J, Boyapati RK, Kennedy NA, et al: Systematic review of efects of with­ drawal of immunomodulators or biologic agents from patients with infl a m­ matory bowel disease. Gastroenterology 149(7) : 1 7 1 6, 20 1 5 Trogstad LI, Stoltenberg C , Magnus P , e t al: Recurrence risk i n hyperemesis gravidarum. BJOG 1 1 2 : 1 64 1 , 2005 Tung CS, Zighelboim I, Gardner MO: Acute colonic pseudo Obstruction com­ plicating twin pregnancy. J Reprod Med 53:52, 2008 Turcotte S, Dube S, Beauchamp G: Peripherally inserted central venous cath­ eters are not superior to central venous catheters in the acute care of surgical patients on the ward. World J Surg 30: 1 603, 2006 Ueberrueck T, Koch A, Meyer L, et al: Ninety-four appendectomies for sus­ pected acute appendicitis during pregnancy. World J Surg 28:508, 2004 Unal A, Sayherman SE, Ozel L, et al: Acute abdomen in pregnancy requiring surgical management: a 20-case series. Eur J Obstet Gynecol Reprod BioI 1 59 ( 1 ):87, 20 1 1 Vaknin Z, Halperin R, Schneider D, et al: Hyperemesis gravidarum and non­ speciic abnormal EEG indings. J Reprod Med 51 :623, 2006 Vandraas KF, Vikanes AV, Vangen S, et al: Hyperemesis gravidarum and birth outcomes-a population-based cohort study of 2.2 million births in the Nor­ wegian Birth Registry. BJOG 1 20 ( 1 3) : 1 654, 20 1 3 Veenendaal MV, van Abeelen AF, Painter RC, e t al: Consequences of hyper­ emesis gravidarum for ofspring: a systematic review and meta-analysis. BJOG 1 1 8(1 1 ) : 1 302, 201 1 Verberg MF, Gillott JD, Fardan NA, et al: Hyperemesis gravidarum, a litera­ ture review. Hum Reprod Update 1 1 : 5 2 , 2005 Vikanes AV, Stoer NC, Magnus P, et al: Hyperemesis gravidarum and preg­ nancy outcomes in the Norwegian mother and child cohort-a cohort study. BMC Pregnancy Childbirth 1 3 : 1 69, 20 1 3 Viktrup L , Hee P: Fertility and long-term complications four to nine years after appendectomy during pregnancy. Acta Obstet Gynecol Scand 77:746, 1 998 Wald A: Constipation, diarrhea, and symptomatic hemorrhoids during preg­ nancy. Gastroenterol Clin North Am 32:309, 2003 Walker HG, I Samaraee A, Mills SJ, et al: Laparoscopic appendicectomy in pregnancy: a systematic review of the published evidence. Int J Surg 1 2 ( 1 1 ) : 1 235, 2014 Wax JR, Pinette MG, Cartin A: Roux-en-Y gastric bypass-associated bowel obstruction complicating pregnancy-an obstetrician's map to the clinical mineield. m J Obstet GynecoI 208(4) :265, 20 1 3 Wei PL, Keller J], Liang H H , e t al: Acute appendicitis and adverse preg­ nancy outcomes: a nationwide population-based study. J Gastrointest Surg 16(6): 1 204, 20 1 2 Weyermann M , Brenner H, Adler G, e t al: Helicobacter pylori infection and the occurrence and severity of gastrointestinal symptoms during pregnancy. Am ] Obstet Gynecol 1 89:526, 2003 Wilasrusmee CSukrat B, McEvoy M , et al: Systematic review and meta-analysis of safety laparoscopic versus open appendectomy for suspected appendicitis in pregnancy. Br J Surg 99( 1 1 ) : 1 470, 2 0 1 2 Woolfson K , Cohen Z , McLeod RS: Crohn's disease and pregnancy. Dis Colon Rectum 33:869, 1 990 Yost NP, McIntire DD, Wians FH Jr, et al: A randomized, placebo-controlled trial of corticosteroids for hyperemesis due to pregnancy. Obstet Gynecol 1 02: 1 250, 2003 Zara G, Codemo V, Palmieri A, et al: Neurological complications in hypereme­ sis gravidarum. Neurol Sci 33( 1 ) : 1 33, 20 1 2

1 0S j

1 058

C H A PT E R 5 5

Hepat i c, B i l i ary, an d Pan creati c D i sorders

I NTRAHEPATIC CHOLESTASIS OF PREGNANCY. . . . . . 1 059 ACUTE FATY LIVER OF PREGNANCY . . . . . . . . . . . . . 1 060 .

VIRAL H EPATITIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 062 NONALCOHOLIC FATY LIVER DISEASE . . . . . . . . . . . 1 067 CI RRHOSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 067 ACETAMINOPHEN OVERDOSE H EPATOTOXICITY. . . . 1 068 H E PATIC ADENOMA .

.

. . . . . . . . . . . . . . . . . . . . . . . . . 1 069

GALLBLADDER DISORDERS . . . . . . . . . . . . . . . . . . . . . 1 069 PANCREATIC DISORDERS . . . . . . . . . . . . . . . . . . . . . . . 1 070

Prenancy is comparativey seldom complicated by jaundice. Notwithstanding the act that in most cases the jaundice disappears without treatment, too avorable a prognosis should not be ventured, or the reason that now and again the condition may represent the initial symptom of acute yellow atrophy ofthe liver. -J. Whitridge Williams ( 1 903) Even though Williams only mentions acute hepatic fatty meta­ morphosis, in practice, disorders of the liver, gallbladder, and pancreas together comprise a formidable list of complications that may arise in pregnancy. Some stem from preexisting con­ ditions and some are unique to gestation. The relationships of several of these with pregnancy can be fascinating, intriguing, and challenging.

H EPATIC DISORDERS Customarily, liver diseases complicating pregnancy are placed into three general categories. he first includes those specifi­ cally related to pregnancy that resolve either spontaneously or following delivery. Examples are intrahepatic cholestasis and acute fatty liver, both discussed in the next sections. Also, hepatic dysfunction from hyperemesis gravidarum may involve the liver. Mild hyperbilirubinemia with elevated serum trans­ aminase levels is seen in up to half of afected women requiring hospitalization. However, these levels seldom exceed 200 U/L (Table 5 5- 1 ) . Liver biopsy may show minimal fatty changes. Hyperemesis gravidarum is discussed in detail in Chapter 54 (p. 1 043) . Another in this first category is hepatocellular dam­ age with preeclampsia-the HELLP syndrome-which is char­ acterized by hemolysis, �levated serum liver enzyme levels, and low 2latelet counts. hese changes are discussed in detail in Chapter 40 (p. 72 1 ) . The second category involves acute hepatic disorders that are coincidental to pregnancy, such as acute viral hepatitis. The third category includes chronic liver diseases that predate preg­ nancy, such as chronic hepatitis, cirrhosis, or esophageal varices. I mportantly, several normal pregnancy-induced physiologi­ cal changes induce appreciable liver-related clinical and labora­ tory manifestations (Chap. 4, p. 68, and Appendix, p. 1 257) . Findings such as elevated serum alkaline phosphatase levels, pal­ mar erythema, and spider angiomas, which might suggest liver disease, are common during normal pregnancy. Metabolism is also afected, due to altered expression of the cytochrome P450 system. This alteration is mediated by higher levels of estrogen, progesterone, and other pregnancy hormones. For example, hepatic CYF IA2 expression declines, whereas that of CYF2D6 and CYF3A4 rises. Importantly, cytochrome enzymes are expressed in many organs besides the liver, most notably the

H e patic, B i l ia ry, a n d Pa n c reatic Disorders

TABLE 55- 1 . C l i n ical a n d La boratory F i n d i n g s with Acute Liver Diseases i n Preg nancy Hepatic Disorder

Onset i n Pregnancy

Clinical Findings

Hyperemesis Chol esta s i s

Early Late

Fatty l ive r

Late

P reec l a m psia H e patitis

M i d to late Va riable

Severe N&V P ru ritus, j a u nd ice Moderate N&V, ± HTN, l iver fa i l u re H A, HTN J a u nd ice

Renal

Hematological and Coag ulation

AST (U/L)

Bili (mg/dL)

Cr (mg/dL)

Hct

Plat

Fib

DD

PT

Hemolysis

N L-300 N L-200

N L-4 1 -5

i NL

ii NL

NL NL

NL NL

NL NL

NL NL

No No

2 00-800

4- 1 0

iii

iii

11

111

i

ii

iii

N L-300 2000+

1 -4 5 -20

i NL

i i

11 1

NL NL

i NL

NL

i-i i No

i

i ncrea sed leve l s; 1 decrea sed leve ls; AST aspa rtate tra n sa m i na se; Bili b i l i ru b i n; Cr c reat i n i n e; D D D-d i m e rs; i fi bri nogen; HA headache; Hct h e m atoc rit; HTN hypertension; N&V n a u sea and vo m i t i n g ; NL normal; Fib P l at plate l ets; PT p rot h ro m b i n t i m e. =

=

=

=

=

=

=

=

=

=

=

=

=

=

placenta. The net efect is complex and likely influenced by gestational age and organ of expression (Isoherranen, 20 1 3) . Despite all o f these functional changes, n o major hepatic histo­ logical changes are induced by normal pregnancy. • I ntrahepatic Cholestasis of Pregnancy

his condition has been called recurrent jaundice of pregnancy, cholestatic hepatosis, and icterus gravidarum and is characterized by pruritus, icterus, or both. It may be more common in multifetal pregnancy, and there is a significant genetic influence (Lausman, 2008; Webb, 20 1 4) . Because of this, its incidence varies by popu­ lation. For example, cholestasis is infrequent in North America, with an overall incidence approximating 1 case in 500 to 1 000 pregnancies. But, its rate nears 5.6 percent among Latina women in Los Angeles (Lee, 2006) . Historically, indigenous women from Chile and Bolivia also have a relatively high incidence. For unknown reasons, this incidence has declined since the 1 970s and is now less than 2 percent (Reyes, 20 1 6) . In other countries, for example Sweden, China, and Israel, the incidence varies from 0.25 to 1 . 5 percent (Glantz, 2004; Luo, 20 1 5; Sheiner, 2006). Path o g e n e s i s

The cause of obstetrical cholestasis is unclear, but changes in various sex steroid levels are implicated. However, current research focuses on the numerous mutations in the many genes that control hepatocellular transport systems. Examples include mutations of the ABCB4 gene, which encodes multidrug resis­ tance protein 3 (vlDR3) associated with progressive amilial intrahepatic cholestasis, and errors of the ABCBll gene, which encodes a bile-salt export pump (Anzivino, 20 1 3; Dixon, 20 1 4) . Other potential gene products are the farnesoid X receptor and transporting ATPase encoded by A TP8Bl (Abu-Hayyeh, 20 1 6; Davit-Spraul, 20 1 2) . Some drugs that similarly decrease cana­ licular transport of bile acids aggravate the disorder. We have encountered impressive cholestatic jaundice in gravidas taking azathioprine following renal transplantation. Whatever the inciting cause(s) , bile acids are cleared incom­ pletely and accumulate in plasma. Hyperbilirubinemia results

from retention of conjugated pigment, but total plasma con­ centrations rarely exceed 4 to 5 mg/ dL. Alkaline phosphatase levels are usually elevated even more than in normal preg­ nancy. Serum transaminase levels are normal to moderately elevated but seldom exceed 250 U/L (see Table 55- 1 ) . Liver biopsy shows mild cholestasis with bile plugs in the hepato­ cytes and canaliculi of the centrilobular regions, but without inflammation or necrosis. These changes disappear after deliv­ ery but often recur in subsequent pregnancies or with estrogen­ containing contraceptives. C l i n i ca l P resentati o n

Pruritus develops in late pregnancy, although it occasionally manifests earlier. Constitutional symptoms are absent, and gen­ eralized pruritus shows predilection for the soles. Skin changes are limited to excoriations from scratching. Biochemical tests may be abnormal at presentation, but pruritus may precede laboratory indings by several weeks. Approximately 1 0 percent of women have jaundice. With normal liver enzymes, the diferential diagnosis of pruritus includes other skin disorders (Table 62- 1 , p. 1 1 85). Findings are unlikely to stem from preeclamptic liver disease if blood pressure elevation or proteinuria is absent. Sonography may be warranted to exclude cholelithiasis and biliary obstruc­ tion. Moreover, acute viral hepatitis is an unlikely diagnosis because of the usually low serum transaminase levels seen with cholestasis. Conversely, chronic hepatitis C is associated with a significantly increased risk of cholestasis, which may be as high as 20-fold among women who test positively for hepatitis C RNA (Marschall, 20 1 3) . M a n a g e m e nt

Pruritus may be troublesome and is thought to result from elevated serum bile salt concentrations. Antihistamines and topical emollients may provide some relie. Although cholestyr­ amine is reported to be efective, this compound also lowers absorption of fat-soluble vitamins, which may lead to vitamin K defi c iency. Fetal coagulopathy with subsequent intracranial

1 05 9

, 060

Med ica l a n d S u rg i ca l Com p l ications

hemorrhage and stillbirth have been reported (Matos, 1 997; Sadler, 1 995). A recent metaanalysis suggests that ursodeoxycholic acid relieves pruritus, lowers bile acid and serum enzyme levels, and may reduce certain neonatal complications. hese include preterm birth, fetal distress, respiratory distress syndrome, and neonatal intensive care unit (NICU) admission (Bacq, 20 1 2) . Kondrackiene and associates (2005) randomly assigned 84 symptomatic women to receive either ursodeoxycholic acid ($ to 1 0 mg/kg/d) or cholestyramine. hey reported superior relief with ursodeoxycholic acid-67 versus 1 9 percent, respec­ tively. Similarly, Glantz and coworkers (2005) found superior beneits to women randomly assigned to ursodeoxycholic acid versus dexamethasone. he American College of Obstetricians and Gynecologists (20 1 5) has concluded that ursodeoxycholic acid relieves pruritus and improves fetal outcomes, although evidence for the latter is not compelling.

bile acid levels. For instance, Brouwers and coworkers (20 1 5) reported high rates of spontaneous preterm birth ( 1 9 percent), meconium- stained amnionic fluid (48 percent), and perinatal death ( 1 0 percent) with bile acids levels > 1 00 ILmollL despite active management leading to earlier delivery. Kawakita and colleagues (20 1 5) found a similar stillbirth link. In particular, among 233 women followed with cholestasis of pregnancy, there were four stillbirths, all of which were among women with bile acid levels > 1 00 LmollL. Gao and associates (20 1 4) implicated bile acids in cardiac dysfunction. Namely, in an ex­ vivo preparation of cardiac myocytes, cholic acid lowered the beating rates in a dose-dependent manner, while increasing intracellular calcium levels. Intriguingly, studies have shown prolongations in the PR interval during fetal echocardiography among afected women (Rodriguez, 20 1 6; Strehlow, 20 1 0) .

Preg n a ncy O utco mes

The most frequent cause of acute liver failure during pregnancy is acute fatty liver-also called acuteaty metamorphosis or acute yellow atrophy. It is characterized by accumulation of microve­ sicular fat that literally "crowds out" normal hepatocytic func­ tion (Fig. 5 5 - 1 ) . Grossly, the liver is small, soft, yellow, and greasy. In its worst form, the incidence approximates 1 case in 1 0,000 pregnancies (Nelson, 20 1 3) . Fatty liver recurring in subsequent pregnancy is rare, but a few cases have been described (Usta, 1 994) .

Earlier reports describe excessive adverse pregnancy outcomes in women with cholestatic jaundice. That said, data accrued during the past two decades are ambiguous concerning increased perina­ tal mortality rates and whether close fetal surveillance is preventa­ tive. Several studies also illustrate this. In one evaluation of 693 Swedish women, perinatal mortality rates were slightly increased, but only in mothers with severe disease (Glantz, 2004) . Sheiner and coworkers (2006) described no diferences in perinatal out­ comes in 376 afected pregnancies compared with their overall obstetrical population. However, rates of labor induction and cesarean delivery in afected women signiicantly rose. Lee and associates (2009) described two cases of sudden fetal death not predicted by nonstress testing. In another study of 1 0 1 afected women, no term fetuses died, but 87 percent of women under­ went labor induction, ostensibly to avoid adverse outcomes (Rook, 2 0 1 2) . Nonetheless, neonatal complications developed in a third of the pregnancies, particularly respiratory distress, fetal distress, and meconium-stained amnionic luid. These problems were noted more frequently in those with higher total bile acid levels. Herrera and coworkers (20 1 7) reported similar results. Finally, Wikstrom Shemer and colleagues (20 1 3) reported outcomes in 5477 women with cholestasis from a database of 1 ,2 1 3,668 births. They described novel associations of cholestasis with preeclampsia and gestational diabetes. Although neonates were more likely to have a low 5-minute Apgar score and to be large for gestational age, the stillbirth rate was not increased. This was thought to reflect higher induction and preterm birth rates. Thus, by this time, many had now recommended early labor induction to avoid stillbirth. Relecting this, at Parkland Hospital, some maternal-fetal specialists ofer induction at 38 weeks, whereas others suggest 39 weeks. As discussed, some evidence supports that high serum bile acid levels may contribute to fetal death. Bile acids typically remain < 1 0 ILmol/L throughout normal pregnancy (Egan, 20 1 2) . Elevated levels have been associated with meconium passage and stillbirth. For example, in the prior study of 693 Swedish women, stillbirths were limited to women with bile acid levels > 40 ILmollL (Glantz, 2004) . More recent data indicate that adverse outcomes are associated with even higher

• Acute Fatty Liver of Pregnancy

Etio pathogenesis

Although much has been learned about this disorder, interpre­ tation of conflicting data has led to incomplete but interesting observations. For example, some if not most cases of maternal fatty liver are associated with recessively inherited mitochon­ drial abnormalities of fatty acid oxidation. These are similar to those in children with Reye-like syndromes. Several muta­ tions have been described for the mitochondrial trifunctional

F I G U RE 55-1 Acute fatty l iver of p reg n a n cy. C ross section of the l iver from a wom a n who died as the res u lt of p u l mo n a ry aspiration a nd respi ratory fa i l u re. The l iver has a g reasy yel l ow a ppea ra nce, which was present throughout the entire speci men. I n set: Electron photomicrogra ph of one swollen hepatocyte conta i n i n g n u mer­ ous microvesic u l a r fat d roplets (*) . The nuclei (N) rem a i n ce ntered wit h i n the cel l, in contrast to the case with macrovesicular fat deposition. (Used with perm ission from Dr. Don Wheeler.)

H e patic, B i l ia ry, a n d Pa n c reati c Di sord e rs

protein enzyme complex that catalyzes the last oxidative steps in the pathway. The most common are the G1528C and E474Q mutations of the gene on chromosome 2 that codes for long-chain-3-hydroxyacyl-CoA-dehydrogenase-known as LCHAD. here are other mutations for medium-chain acyl­ CoA dehydrogenase-MCAD, as well as for carnitine palmito­ yltransferase 1 (CPT 1 ) defi c iency (Santos, 2007; Ylitalo, 2005) . Sims and coworkers ( 1 995) observed that some homozygous LCHAD-deicient children with Reye-like syndromes had het­ erozygous mothers with fatty liver. This was also seen in women with a compound heterozygous fetus. Although some conclude that ony heterozygous LCHAD-deicient mothers are at risk when their fetus is homozygous, this is not always true (Baskin, 20 1 0) . There i s a controversial association between fatty acid 3-oxidation enzyme defects and severe preeclampsia-especially in women with HELLP syndrome (Chap. 40, p. 72 1 ) . Most of these observations derive from retrospective study of mothers delivered of a child who later developed Reye-like syndrome. For example, one case-control study compared 50 mothers of children with a fatty-acid oxidation defect and 1 250 mothers of matched control infants (Browning, 2006) . During their pregnancy, 1 6 percent of mothers with an afected child devel­ oped liver problems compared with only 0.9 percent of control women. Problems included HELLP syndrome in 1 2 percent and fatty liver in 4 percent. Despite these indings, the clini­ cal, biochemical, and histopathological findings are suiciently disparate to suggest that severe preeclampsia, with or with­ out HELLP syndrome, and fatty liver are distinct syndromes (American College of Obstetricians and Gynecologists, 20 1 5 ; Sibai, 2007). C l i n ica l Fi n d i n g s

Acute fatty liver almost always manifests late i n pregnancy. Nelson and colleagues (20 1 3) described 5 1 afected women at Parkland Hospital with a mean gestational age of 37 weeks (range 3 1 .7 to 40.9). Almost 20 percent were delivered at 34 weeks' gestation or earlier. Of these 5 1 women, 4 1 percent were nulliparous, and two thirds carried a male fetus. From other data, 1 0 to 20 percent of cases are in women with a mul­ tifetal gestation (Fesenmeier, 2005; Vigil-De Gracia, 20 1 1 ) .

Fatty liver has a clinical spectrum o f severity. In the worst cases, symptoms usually develop over several days. Persistent nausea and vomiting are major complaints, and degrees of mal­ aise, anorexia, epigastric pain, and progressive jaundice vary. Perhaps half of afected women have hypertension, p rotein­ uria, and edema, alone or in combination-signs suggestive of preeclampsia. As shown in Tables 5 5- 1 and 5 5-2 , degrees of moderate to severe liver dysfunction are manifest by hypofi­ brinogenemia, hypoalbuminemia, hypocholesterolemia, and prolonged clotting times. Serum bilirubin levels usually are < 1 0 mgl dL, and serum transaminase levels are modestly ele­ vated and usually < 1 000 U/L. In almost all severe cases, profound endothelial cell activa­ tion with capillary leakage causes hemoconcentration, acute kidney injury, ascites, and sometimes pulmonary permeability edema (Bernal, 20 1 3) . With severe hemoconcentration, utero­ placental perfusion is reduced and this, along with maternal acidosis, can cause fetal death even before presentation for care. Both maternal and fetal acidemia are associated with a high incidence of fetal jeopardy and a concordantly high cesarean delivery rate. Hemolysis can be severe and evidenced by leukocytosis, nucleated red cells, mild to moderate thrombocytopenia, and elevated serum levels of lactic acid dehydrogenase (LDH). Because of hemoconcentration, however, the hematocrit is often within the normal range. The peripheral blood smear demonstrates echinocytosis, and hemolysis is thought to stem from efects of hypocholesterolemia on erythrocyte membranes (Cunningham, 1 985). The degree of clotting dysfunction also varies and can be serious and life threatening, especially if operative delivery is undertaken. Coagulopathy is caused by diminished hepatic pro­ coagulant synthesis, although some evidence supports increased consumption from disseminated intravascular coagulopathy. As shown in Table 55-2, hypoibrinogenemia sometimes is profound. Of 5 1 women with fatty liver cared for at Parkland Hospital, almost a third had a plasma fibrinogen level nadir to < 1 00 mg/dL (Nelson, 20 1 4) . Modest level elevations of serum D-dimers or fibrin-split products indicate an element of con­ sumptive coagulopathy. Although usually modest, occasionally thrombocytopenia is marked (see Table 5 5-2) . Again, among the

TABLE 55-2. Laboratory F i n d i ngs in 2 1 5 Women with Acute Fatty Liver of P regna ncy Most Abnormal Laboratory Val ues Mean ± 1 SD (range)a 3 Platelets ( 1 0 /.LL) Creatinine (mg/dL)

Series

No.

Fibrinogen (mg/d L)

Pe rei ra ( 1 997) Fese n m e i e r (2005) Vi g i l-De G racia (20 1 1 ) N e l son (20 1 3) X iong (20 1 5) Z h a n g (20 1 6)

32 16 35 51 25 56

ND ND 1 36 ± 80 1 47 ± 96 (2 7-400) ND 246 ± 1 86

1 23 (26-262) 8 8 (22-226) 86 99 ± 68 (9-385) 82 ( 1 6-242) 1 45 ± 75

2.0 ± 0.8 (0.7-5.0) 2.4 (0.8-5 .9) 1 .4 ± 0.9

99 (25-9 1 1 ) 692 ( 1 22-3 1 95 ) 2 80 ± 236 449 ± 3 75 (53-2245) 3 8 5 ( 1 0-2 1 44) 260 ± 23 7

215

1 40

1 02

2.5

330

Est i mated avera g e

2.7 ( 1 . 1 -8.4) 3.3 (0.5-8.6)

AST (U/L)

a F i b ri nogen and p l atelet va l ues l i sted reflect the nad i r fo r each pat i e nt, whereas creati n i n e a nd AST va l ues refl ect pea k va l u es for each patient. AST aspa rtate tra n s a m i na se; N O not done. =

=

1 06 1

1 062

Med ical and S u rg i c a l Co m p l i cations

group from Parkland Hospital, 20 percent had platelet counts < 1 00,000/�L and 1 0 percent had platelet counts < 50,000/�L (Nelson, 2 0 1 4) . Various liver imaging techniques have been used t o confirm the diagnosis, however, none are particularly reliable. Specii­ cally, Castro and associates ( 1 996) reported poor sensitivity for conirmation by sonography-three of 1 1 patients, computed tomography (CT)-five of 1 0, and magnetic resonance (MR) imaging-none of ive. Similarly, in a prospective evaluation of the Swansea criteria proposed by Ch'ng and coworkers (2002), only a quarter of women had classic sonographic findings that include maternal ascites or an �chogenic hepatic appearance (Knight, 2008). Our experiences are similar (Nelson, 20 1 3) . The syndrome typically continues to worsen after diagnosis. Hypoglycemia is common, and obvious hepatic encephalopa­ thy, severe coagulopathy, and some degree of renal failure each develop in approximately half of women. Fortunately, delivery arrests liver function deterioration. We have encountered several women with a orme fruste of this disorder. Clinical involvement is relatively minor and laboratory aberrations-usually only hemolysis and a decreased plasma fibrinogen level-herald the syndrome. hus, the spec­ trum of liver involvement varies from milder cases that go unnoticed or are attributed to preeclampsia, to overt hepatic failure with encephalopathy. M a n a gement

Intensive supportive measures and good obstetrical care are essential. In some cases, the fetus may already be dead when the diagnosis is made, and the route of delivery is less problematic. Oten, living fetuses tolerate labor poorly. Because significant procrastination in efecting delivery may increase maternal and fetal risks, we prefer a trial of labor induction with close fetal sur­ veillance. Although some recommend cesarean delivery to hasten hepatic healing, this increases maternal risk when coagulopathy is severe. Nonetheless, cesarean delivery is common, and rates approach 90 percent. Transfusions with whole blood or packed red cells, along with fresh-frozen plasma, cryoprecipitate, and platelets, are usually necessary if surgery is performed or if obstet­ rical lacerations complicate vaginal delivery (Chap. 4 1 , p. 788) . Hepatic dysfunction resolves postpartum. It usually normal­ izes within a week, and in the interim, intensive medical sup­ port may be required. Two associated conditions can be seen around this time. Perhaps a fourth of women have evidence for transient diabetes insipidus. This presumably stems from elevated vasopressinase concentrations caused by diminished hepatic production of its inactivating enzyme. Finally, acute pancreatitis develops in approximately 20 percent. With supportive care, recovery usually is complete. lvIater­ nal deaths are caused by sepsis, hemorrhage, aspiration, renal failure, pancreatitis, and gastrointestinal bleeding. Two women died in the series from Parkland Hospital. One was an encepha­ lopathic woman who aspirated before intubation during trans­ fer to our care. The other was in a woman with massive liver failure and nonresponsive hypotension (Nelson, 20 1 3) . I n some centers, other measures have included plasma exchange and even liver transplantation (Fesenmeier, 2005; Franco, 2000; Martin, 2008) .

Mate r n a l a n d Peri nata l O utco mes

Although maternal mortality rates with acute fatty liver of preg­ nancy have approached 75 percent in the past, the contempo­ raneous outlook is much better. From his review, Sibai (2007) cites an average mortality rate of 7 percent. He also cited a 70-percent preterm delivery rate and a perinatal mortality rate of 1 5 percent, which in the past was nearly 90 percent. At Park­ land Hospital, the maternal and perinatal mortality rates dur­ ing the past four decades have been 4 percen t and 1 2 percent, respectively (Nelson, 20 1 3) . • Acute Viral Hepatitis

Although most viral hepatitis syndromes are asymptomatic, during the past 30 years, acute symptomatic infections have become even less common in the United States (Daniels, 2009) . There are at least ive distinct types of viral hepatitis: A (HAV) , B (HBV), D (HDV) caused by the hepatitis B-associated delta agent, C (HCV) , and E (HEV) . he clinical presentation is similar in all, and although the viruses themselves probably are not hepatotoxic, the immunological response to them causes hepatocellular necrosis (Dienstag, 20 1 5a,b) . Acute infections are most often subclinical and anicteric. When they are clinically apparent, nausea and vomiting, head­ ache, and malaise may precede jaundice by 1 to 2 weeks. Low­ grade fever is more common with hepatitis A. By the time jaundice develops, symptoms are usually improving. Serum transaminase levels vary, and their peaks do not correspond with disease severity (see Table 55- 1 ) . Peak levels that range from 400 to 4000 U/L are usually reached by the time jaundice develops. Serum bilirubin values typically continue to rise, despite falling serum transaminase levels, and peak at 5 to 20 mgl dL. Any evidence for severe disease should prompt hospitaliza­ tion. These include persistent nausea and vomiting, prolonged prothrombin time, low serum albumin level, hypoglycemia, high serum bilirubin level, or central nervous system symp­ toms. In most cases, however, clinical and biochemical recov­ ery is complete within 1 to 2 months in all cases of hepatitis A, in most cases of hepatitis B, but in only a small proportion of cases of hepatitis C. When patients are hospitalized, their feces, secretions, bed­ pans, and other articles in contact with the intestinal tract should be handled with glove-protected hands. Extra precau­ tions, such as double gloving during delivery and surgical procedures, are recommended. Due to significant exposure of health-care personnel to hepatitis B, the Centers for Disease Control and Prevention (CDC) (20 1 6a) recommend active and passive vaccination, described later. There is no vaccine for hepatitis C, so recommendations are for postexposure serosur­ veillance only. Acute hepatitis has a case-fatality rate of 0. 1 percent. For patients ill enough to be hospitalized, it may reach 1 percent. Most fatalities are due to fulminant hepatic necrosis, which in later pregnancy may resemble acute fatty liver. In these cases, hepatic encephalopathy is the usual presentation, and the mortality rate is 80 percent. Approximately half of patients with fulminant disease have hepatitis B infection, and co-infection with the delta agent is common.

H e pati c, B i l i a ry, a n d Pa n c reatic Disorders

• Chronic Viral Hepatitis

which may persist for several months. During convlescence, IgG antibody predominates, and it persists and provides subsequent immunity. here is no chronic stage of hepatitis A. Management of hepatitis A in pregnancy includes a bal­ anced diet and diminished physical activity. Women with less severe illness may be managed as outpatients. In developed countries, the efects of hepatitis A on pregnancy outcomes are not dramatic (American College of Obstetricians and Gyne­ cologists, 20 1 5 , 20 1 6) . Both perinatal and maternal mortal­ ity rates, however, are substantively increased in resource-poor countries. Hepatitis A virus is not teratogenic, and transmission to the fetus is negligible. Preterm birth rates may be increased, and neonatal cholestasis has been reported (Urganci, 2003) . Although hepatitis A RNA has been isolated in breast milk, no cases of neonatal hepatitis A have been reported secondary to breastfeeding (Daudi, 20 1 2) . Preventatively, vaccination during childhood with fon­ inactivated hepatitis viral vaccine is more than 90-percent efective. HAV vaccination is recommended by the American College of Obstetricians and Gynecologists (20 1 6) and the Advisory Committee on Immunization (Kim, 20 1 5a) for high­ risk adults. This category includes behavioral and occupational populations and travelers to high-risk countries. These coun­ tries are listed in the CDC (20 1 6c) Health Information for International Travel "yellow book," which is available on the CDC website. Passive immunization for the pregnant woman recently exposed by close personal or sexual contact with a person with hepatitis A is provided by a 0.02 mLlkg dose of immune globulin (Kim, 20 1 5a) . Victor and colleagues (2007) reported that a single dose of HAV vaccine given in the usual dosage within 2 weeks of contact with an afected person was as efective as immune serum globulin to prevent hepatitis A. In both groups, HAV developed in 3 to 4 percent.

The CDC (20 1 6b) estimated that more than 4 million Americans were living with chronic viral hepatitis. Although most chroniclly infected persons are asymptomatic, approximately 20 percent develop cirrhosis within 1 0 to 20 years (Dienstag, 20 1 5b) . When present, symptoms are nonspecific and usually include fatigue. In some patients, cirrhosis with liver failure or bleeding varices may be the presenting inding. Indeed, asymptomatic chronic viral hepatitis as a group remains the leading cause of liver cancer and the most frequent reason for liver transplantation. Chronic viral hepatitis is usually diagnosed serologically (Table 55-3) . With persistently abnormal biochemical tests, liver biopsy usually discloses active inlammation, continuing necro­ sis, and fibrosis that may lead to cirrhosis. Chronic hepatitis is classiied by cause; by grade, defined by histological activity; and by stage, which is the degree of progression (Dienstag, 20 1 5b) . Most young women with chronic viral hepatitis either are asymptomatic or have only mild liver disease. For seroposi­ tive asymptomatic women, there usually are no problems with pregnancy. With symptomatic chronic active hepatitis, preg­ nancy outcome depends primarily on disease and ibrosis sever­ ity, and especially on the presence of portal hypertension. he few women whom we have managed have done well, but their long-term prognosis is poor. Accordingly, they should be coun­ seled regarding possible liver transplantation as well as abortion and sterilization options. • Hepatitis A

Vaccination has reduced the incidence of hepatitis by 95 percent since 1 995. In 20 1 4, the rate was 0.4 per 1 00,000 individuals (Centers for Disease Control and Prevention, 20 1 6b) . his 27-nm RNA picornavirus is transmitted by the fecal-oral route, usually by ingestion of contaminated food or water. The incubation period is approximately 4 weeks. Individuals shed virus in their feces, and during the relatively brief period of viremia, their blood is also infectious. Signs and symptoms are oten nonspecific and usually mild, although jaundice develops in most patients. Symptoms usu­ ally last less than 2 months, although 1 0 to 1 5 percent of patients may remain symptomatic or relapse for up to 6 months (Dienstag, 20 1 5a) . Early serological testing identifies IgVl anti- AV antibody,

• Hepatitis B

This double-stranded DNA virus is found worldwide. It is endemic in Africa, Central and Southeast Asia, China, Eastern Europe, the Middle East, and certain areas of South America, where preva­ lence rates reach 5 to 20 percent. The World Health Organiza­ tion (WHO) (2009) estimates that more than 2 billion people worldwide are infected with HBV, and of these, 370 million have

TABLE 55-3. S i m pl ified Diagnostic Approach i n Patients with Hepatitis Diag nosis Ac ute hepatitis A Acute hepatiti s B C h ro n i c hepatitis B Ac ute hepatiti s A with c h ro n i c B Ac ute hepatitis A a n d B Ac ute hepatiti s C

H BsAg

Serological Test IgM Anti-HAV IgM Anti-H Bc

Anti-HCV

+ +

+ + +

+

+

+

+

+ +

HAV h e patitis A v i r u s; H B c hepatitis B core; H BsAg h e patitis B s u rface a ntigen; H CV h e patitis C virus. Co m p i led from the Ce nters for D isease Control a nd P revention, 20 1 6b; Diensta g , 20 1 5a . =

=

=

=

1 063

1 064

Med ica l a nd S u rg ica l Co m pl i catio n s

chronic infection. The CDC (20 1 6b) estimated nearly 1 8, 1 00 cases of acute hepatitis B in the United States in 20 1 4. This is a substantial decline since vaccination was introduced in the 1 980s. he hepatitis B virus is transmitted by exposure to blood or body fluids from infected individuals. In endemic countries, vertical transmission, that is, from mother to fetus or newborn, accounts for at least 35 to 50 percent of chronic H BV infec­ tions. In low-prevalence countries such as the United States, which has a prevalence < 2 percent, the more frequent mode of HBV transmission is by sexual transmission or by sharing contaminated needles. H BV can be transmitted in any body luid, but exposure to virus-laden serum is the most eicient. Acute hepatitis B develops after an incubation period of 30 to 1 80 days with a mean of 8 to 1 2 weeks. At least half of acute infections are asymptomatic. If symptoms are present, they are usually mild and include anorexia, nausea, vomiting, fever, abdominal pain, and jaundice. Acute H BV accounts for half of cases of fulminant hepatitis. Symptoms completely resolve within 3 to .4 months in more than 90 percent of patients. Figure 5 5-2 details the sequence of the various HBV antigens and antibodies in acute infection. The first serologi­ cal marker to be detected is the hepatitis B surface antigen (HBsAg) , often preceding the increase in transaminase levels. As HBsAg disappears, antibodies to the surface antigen develop (anti-H Bs) , marking complete resolution of disease. Hepatitis B core antigen is an intracellular antigen and not detectable in serum. However, anti -HBc is detectable wi thin weeks of HBsAg appearance. The hepatitis Be antigen (HBeAg) is present during times of high viral replication and often correlates with detect­ able HBV DNA. After acute hepatitis, approximately 90 per­ cent of adults recover completely. The 1 0 percent who remain chronically infected are considered to have chronic hepatitis B. Chronic HBV infection is oten asymptomatic but may be clinically suggested by persistent anorexia, weight loss, fatigue, and

Jaundice IL t ALT I �� HBeAg I - HB e I I1[=�A�n�ti� IgG Anti- HBc __-'

__-'

- - - - -

o

4

8

- -

x

=ll J J

- - - -

52

1 2 1 6 20 24 28 32 36

1 00

Weeks after exposure

FIGURE 55-2 Seq uence of various a ntigens and a ntibod ies in acute hepatitis B. ALT a l a n i ne transaminase; a nti-HBc a nti body to hepatitis B core antigen; a nti-HBe a nti body to hepatitis B e a nti­ gen; a nti-HBs anti body to hepatitis B s u rface a ntigen; H BeAg hepatitis B e a ntigen; H BsAg hepatitis B s u rface a ntigen. (Repro­ d uced with perm ission from Dienstag J L: Acute viral hepatitis. I n Kasper DL, Fauci AS, Hauser SL, e t a l (eds): Ha rrison's Princi ples of I nterna l Medici ne, 1 9th ed. New York, McGraw-H i l i Ed ucation, 20 1 5). =

=

=

=

=

=

hepatosplenomegaly. Extrahepatic manifestations may include arthritis, generalized vasculitis, glomerulonephritis, pericarditis, myocarditis, transverse myelitis, and peripheral neuropathy. One risk factor for chronic disease is age at acquisition. It is more than 90 percent in newborns, 50 percent in young children, and less than 1 0 percent in immunocompetent adults. Another risk is an immunocompromised state such as those with human immuno­ deiciency virus (HIV) infection, transplant recipients, or per­ sons receiving chemotherapy. Chronically infected persons may be asymptomatic carriers or have chronic disease with or without cirrhosis. Patients with chronic disease have persistent HBsAg serum positivity. he patients with evidence of high viral replica­ tion-HBV DNA with or without HBeAg-have the highest likelihood of developing cirrhosis and hepatocellular carcinoma. The WHO considers hepatitis B to be second only to tobacco among human carcinogens. HBV DNA has been found to be the best correlate of liver injury and disease progression risk. Preg n a n cy a n d H e patiti s B

Hepatitis B infection is not a cause of excessive maternal mor­ bidity and mortality. It is often asymptomatic and found only on routine prenatal screening (Stewart, 20 1 3) . A review of data from the National Inpatient Sample reported a modest increase in preterm birth rates in HBV-positive mothers but no efect on fetal growth restriction or preeclampsia rates (Reddick, 20 1 1 ) . Others have shown similar results (Chen, 20 1 5) . Transplacental viral infection is uncommon, and Towers and associates (200 1 ) reported that viral DNA i s rarely found i n amnionic luid or cord blood. Interestingly, HBV DNA has been found in the ovaries of HBV-positive pregnant women, although this may not be a significant factor in perinatal transmission Gin, 20 1 6b) . The highest HBV DNA levels were found in women who trans­ mitted the virus to their fetuses (Dunkelberg, 20 1 5; Society for Maternal-Fetal Medicine, 20 1 6) . I n the absence o f HBV immunoprophylaxis, 1 0 to 2 0 per­ cent of women positive for HBsAg transmit viral infection to their infant. This rate increases to almost 90 percent if the mother is HBsAg and HBeAg positive. Immunoprophylaxis and hepatitis B vaccine given to newborns of HBV-infected mothers has decreased transmission dramatically and prevented approx­ imately 90 percent of infections (Smith, 20 1 2) . But, women with high HBV viral loads-1 06 to 1 0 8 copies/ mL-or those who are HBeAg positive still have approximately a 1 0-percent vertical transmission rate, regardless of immunoprophylaxis (Yi, 20 1 6) . The Society for Maternal-Fetal Medicine (20 1 6) recommends antiviral therapy to decrease vertical transmission in women at highest risk because of high HBV DNA levels. Although lami­ vudine, a cytidine nucleoside analogue, signiicantly lowers the risk of fetal HBV infection in women with high HBV viral loads, recent data indicate that lamivudine may be less efective in the third trimester. Moreover, it is associated with the development of resistant mutations and is no longer recommended at a first­ line agent. Newer drugs include the adenosine nucleoside ana­ logue tenofovir and the thymidine analogue telbivudine. Both are associated with a lower risk of resistance than lamivudine (Ayres, 20 1 4; Yi, 20 1 6) . Tenofovir has been recommended as the irst-line agent during pregnancy by the Society for Maternal-Fetal Medi­ cine (20 1 6) . These antiviral medications appear safe in pregnancy

Hepatic, B i l i a ry, and P a n c reatic Disord e rs

and are not associated with higher rates of congenital malforma­ tions or adverse obstetrical outcomes (Brown, 20 1 6) . Hepatitis B immunoglobulin (HBIG) given antepartum to women at highest risk of transmission is also cost-efective (Fan, 20 1 6) . Newborns of seropositive mothers are given H B I G very soon after birth. This is accompanied by the first of a three­ dose hepatitis B recombinant vaccine. H ill and colleagues (2002) applied this strategy in 369 infants and reported that the 2.4-percent transmission rate was not increased with breast­ feeding if vaccination was completed. Although virus is present in breast milk, the incidence of transmission is not lowered by formula feeding (Shi, 20 1 l ) . he American Academy of Pedi­ atrics and the American College of Obstetricians and Gyne­ cologists (20 1 7) does not consider maternal HBV infection a contraindication to breastfeeding. For high-risk mothers who are seronegative, hepatitis B vac­ cine can be given during pregnancy. he eicacy is similar to that for nonpregnant adults, and overall seroconversion rates approach 95 percent after three doses (Stewart, 20 1 3) . he tra­ ditional vaccination schedule of 0, 1 , and 6 months may be diicult to complete during pregnancy, and compliance rates decline after delivery. Sheield and coworkers (20 1 1 ) reported that the three-dose regimen given prenatally-initially and at 1 and 4 months-resulted in seroconversion rates of 56, 77, and 90 percent, respectively. This regimen was easily completed during routine prenatal care. • Hepatitis 0

Also called delta hepatitis, this is a defective RNA virus that is a hybrid particle with an HBsAg coat and a delta core. he virus must co-infect with hepatitis B either simultaneously or secondarily. It cannot persist in serum longer than hepatitis B virus. Transmission is similar to hepatitis B. Chronic co­ infection with B and D hepatitis is more severe and accelerated than with HBV alone, and up to 75 percent of afected patients develop cirrhosis. HDV infection is detected by the presence of anti-HDV and HDV DNA. Neonatal transmission is unusual, as neonatal HBV vaccination usually prevents delta hepatitis. • Hepatitis C

This is a single-stranded RNA virus, and transmission occurs via blood and body luids, although sexual transmission is inei­ cient. Up to a third of anti-HCV positive persons have no iden­ tifiable risk factors (Dienstag, 20 1 5b) . Screening for HCV is recommended for H IV-infected individuals, persons with injec­ tion drug use, hemodialysis patients, children born to mothers with HCV, persons exposed to HCV-positive blood or body fluids, persons with unexplained elevations in transaminase val­ ues, and recipients of blood or transplants before July 1 992. Prenatal screening is recommended for high-risk women, and in the United States, seroprevalence rates reach 1 to 2.4 percent (American College of Obstetricians and Gynecologists, 20 1 6; Arshad, 20 1 1 ) . It is higher in women who are infected with HIV. Santiago-Munoz and associates (2005) found that 6.3 percent of HIV-infected pregnant women at Parkland Hospital were co-infected with hepatitis B or C.

Acute HCV infection is usually asymptomatic or yields mild symptoms. Only 1 0 to 1 5 percent develop jaundice. he incubation period ranges from 1 5 to 1 60 days with a mean of 7 weeks. Transaminase levels are elevated episodically during the acute infection. Hepatitis C RNA testing is now preferred for HCV diagnosis. RNA levels may be found even before elevations of transaminase and anti-HCV levels. Speciically, anti-HCV antibody is not detected for an average of 1 5 weeks and in some cases up to a year (Dienstag, 20 1 5a) . Nearly 80 to 90 percent of patients with acute HCV will be chronically infected. Although most remain asymptomatic, approximately 20 to 30 percent progress to cirrhosis within 20 to 30 years. Transaminase values fluctuate, and HCV RNA levels vary over time. Liver biopsy reveals chronic disease and fibrosis in up to 50 percent, however, these indings are oten mild. Overall, the long-term prognosis for most patients is excellent. Preg n a n cy a nd Hepatiti s C

As expected, most pregnant women diagnosed with HCV have chronic disease. HCV infection was initially thought to have limited pregnancy efects. However, more recent reports have chronicled modestly increased fetal risks for low birthweight, NICU admission, preterm delivery, and mechanical ventilation (Berkley, 2008; Pergam, 2008; Reddick, 20 1 l ) . In some women, these adverse outcomes may have been inluenced by concurrent high-risk behaviors associated with HCV infection. he primary adverse perinatal outcome is vertical transmis­ sion of HCV infection to the fetus-infant. This is higher in mothers with viremia (Indolfi , 20 1 4; Joshi, 20 1 0) . Airoldi and Berghella (2006) cited a rate of 1 to 3 percent in HCV-positive, RNA-negative women compared with 4 to 6 percent in those who were RNA-positive. In a report from D ublin, the vertical transmission rate in 545 HCV-infected women was 7. I -percent in RNA-positive women compared with none in those who were RNA-negative (McMenamin, 2008) . Some have found an even greater risk when the mother is co-infected with HIV (Snidjew­ ind, 20 1 5 ; Tovo, 20 1 6) . Invasive prenatal diagnostic procedures have not been reported to increase transmission to the fetus. However, Rae and Sheield (20 1 4) note that few studies have addressed this possibility, and they recommend avoiding tra­ versing the placenta during amniocentesis. Approximately two thirds of prenatal transmission cases occur peripartum. HCV genotype, invasive prenatal procedures, breastfeeding, and deliv­ ery mode are not associated with mother-to-child transmission. That said, invasive procedures such as internal electronic fetal heart rate monitoring are avoided. HCV infection is not a con­ traindication to breastfeeding. No licensed vaccine is available for HCV prevention. The chronic HCV infection treatment has traditionally included alpha interferon (standard and pegylated) , alone or in com­ bination with ribavirin. This regimen is contraindicated in pregnancy because of the teratogenic potential of ribavirin in animals (Joshi, 20 1 0) . he initial 5-year review of the Ribavirin Pregnancy Registry found no evidence for human teratogenic­ ity. However, the registry has enrolled fewer than half of the necessary numbers to allow a conclusive statement to be made (Roberts, 20 1 0) . The development and study of direct-acting and host-targeted antiviral drugs in the past decade shows great

1 065

1 066

Medical a n d S u rg i ca l Co m p l ications

promise for chronic hepatitis C management (Liang, 20 1 3; Lok, 20 1 2; Poordad, 20 1 3) . Current interferon-free, ribavirin-free regimens are being evaluated, although no data are available for pregnant women. • Hepatitis E

This water-borne RNA virus usually is enterically transmitted by contaminated water supplies. Hepatitis E is probably the most common cause of acute hepatitis (Hoofnagle, 20 1 2) . It causes epidemic outbreaks in third-world countries with substantial morbidity and mortality rates. Pregnant women have a higher case-fatality rate than nonpregnant individuals. In a metaanaly­ sis of nearly 4000 subjects from Asia and Africa, Jin and cowork­ ers (20 1 6a) reported maternal and fetal case-fatality rates of 2 1 and 34 percent, respectively. Fulminant hepatitis, although rare overall, is more common in gravidas and contributes to the increased mortality rates. An altered innate immune response to incipient hepatitis E infection during pregnancy, afecting macrophage function and toll-like receptor signaling, may be a factor in the development of fulminant hepatitis (Sehgal, 20 1 5) . A recombinant HEV vaccine has been developed and licensed in China. It is > 95 percent efective for 1 2 months after vac­ cination. Long-term eicacy is 87 percent, and protective titers are maintained for up to 4.5 years (Zhang, 20 1 5) . Preliminary data from inadvertently vaccinated pregnant women show no adverse maternal or fetal events (Wu, 20 1 2) . At this time, it is unclear if this Chinese-licensed vaccine is efective in other areas of the world where other genotypes predominate. Geno­ type 4 is most common in China, and types 2 and 3 are more common in the Americas. A Food and Drug Administration (FDA) approved vaccine is not available at this time. Hepatitis E is found worldwide, and although the highest prevalence is in east Asia, the CDC (20 1 5) lists Mexico as a highly endemic country. Seroprevalence rates vary by age and geography, but overall seroprevalence rates of 1 0 percent have been reported. Durango State has the highest rate (37 percent) (Fierro, 20 1 6) . • Hepatitis G

Hepatitis G is the former name of an RNA flavivirus now known as HPvG or human pegivirus. This blood-borne infec­ tion of the liver, spleen, bone marrow, and mononuclear cells of the peripheral blood does not actually cause hepatitis (Chivero, 20 1 5) . It is thought to infect 750 million people worldwide, with up to two times that many with evidence of past infection. It may modulate the immune response, particularly during co­ infection with HIV. Currently, no treatment aside from basic blood and body luid precautions is recommended. Vertical transmission (to the fetus/infant) and horizontal transmission (to peers) has been described (Trinks, 20 1 4) . • Autoimmune Hepatitis

his is a generally progressive chronic hepatitis that is impor­ tant to distinguish from other forms . Autoimmune hepatitis is more common in women and frequently coexists with other types of autoimmune disease, particularly autoimmune thy­ roid disease and Sjogren syndrome. Symptoms are typical of

acute and chronic hepatitis, but one quarter may be asymptom­ atic. Rates of cirrhosis vary worldwide, but in western countries autoimmune hepatitis is more common and is characterized by multiple autoimmune antibodies such as antinuclear antibod­ ies (ANA) and anti-smooth muscle antibody. Type 2 autoim­ mune hepatitis has an even higher prevalence in females and typically a more aggressive presentation. he incidence peaks in childhood and adolescence, before peak reproductive years. Treatment employs corticosteroids, alone or combined with azathioprine. Failure to respond to these two agents is more fre­ quent in those with type 2 disease, and nearly all women with type 2 disease require more intensive therapy that is sustained long term (Vierling, 20 1 5) . In some patients with progres­ sive disease and cirrhosis, hepatocellular carcinoma develops. In general, autoimmune hepatitis-especially when severe­ increases the risk of adverse pregnancy outcomes. Westbrook and coworkers (20 1 2) reported the outcomes of 8 1 pregnancies in 5 3 women. A third had a flare, and these were more common in those not taking medication and those with active disease in the year before conception. Maternal and fetal com­ plications were higher among women with cirrhosis, particularly with respect to the risks of death or need for liver transplantation during the pregnancy or within 1 2 months postpartum. From one Swedish national database analysis, frequencies of preterm birth, low birthweight, and diabetes were higher, but not those of preeclampsia or cesarean delivery (Stokkeland, 20 1 6) . Danielsson Borssen (20 1 6) reported stable or mild disease in 84 percent of 58 women who delivered 1 00 newborns. Nearly a fourth of cases were delivered before 38 weeks, and a postpartum flare developed in a third. Cirrhosis was present in 40 percent, and these women experienced more complications during pregnancy. • I ron and Copper Overload

Chronic hepatitis and cirrhosis can result from iron and copper overload. Iron overload may stem from a primary cause that is generally inherited, such as hereditary hemochromatosis, or originates secondary to complications of certain hemoglobin­ opathies. Many of the gene mutations underlying hereditary hemochromatosis involve hepcidin and result in dysregulated iron transport (Chap. 4 p. 58) . Some of these mutations are more common in certain populations originating from north­ ern Europe (Pietrangelo, 20 1 6; Salgia, 20 1 5) . Cardiomyopa­ thy, diabetes, joint disease, and skin changes can coexist with liver disease. Pregnancy outcomes associated with iron overload in hereditary hemochromatosis are driven by the degree of liver dysfunction, although higher iron levels may afect birthweight (Dorak, 2009) . A form of neonatal hemochromatosis that does not afect the mother is now thought to be alloimmune and is called ges­ tational aloimmune liver disease (Anastasio, 20 1 6) . With this, maternal autoantibodies cross to the fetus and mediate dysfunc­ tion of iron homeostasis, although the antigenic target of these alloantibodies remains unclear. It is associated with significant neonatal morbidity and mortality, and frequently recurs in sub­ sequent pregnancies. In these cases, antepartum treatment with intravenous immunoglobulin (IVIG) may improve outcomes (Feldman, 20 1 3; Roumiantsev, 20 1 5) .

Hepatic, B i l i a ry, a n d Pa n c reatic Disord e rs

Copper overload leading to chronic hepatitis and cirrhosis is Wilson disease. This systematic condition can also manifest with cardiomyopathy, renal disease, neuropsychiatric symp­ toms, and certain endocrine abnormalities. A Kayser-Fleischer ring surrounding the iris is highly speciic, but a suspected diagnosis generally requires genetic analysis. Autosomal reces­ sive mutations of the A TP7B gene underlie this disorder. his gene codes for the P-type ATPase involved in copper transport to ceruloplasmin and bile (Bandman, 20 1 5) . With Wilson disease, infertility may b e present, but preg­ nancy outcomes among afected women who do conceive are inluenced by disease severity. Malik and colleagues (20 1 3) reported four cases in pregnancy, and three had associated ges­ tational hypertension or preeclampsia. Maternal and neonatal outcomes were good, and the authors review chelation therapy with penicillamine and zinc sulfate in pregnancy. he American College of Gastroenterology states that few data guide which of the various chelating agents is best (Tran, 20 1 6) . These include penicillamine, zinc, and trientine, and any theoretical risks are outweighed by the risks of discontinuing therapy. he latter include not only hepatic decompensation, but also injury to the placenta and fetal liver. Accordingly, the American College of Gastroenterology recommends that pregnant women should continue their chelation therapy, although a dose reduction of 25 to 50 percent should be considered to promote wound heal­ ing in the event of a surgical delivery. As a reminder, copper ions regulate the activity of proteins essential to wound repair. • Nonalcoholic Fatty Liver Disease

his condition is frequently comorbid with obesity and is the most common chronic liver disease in the United States (Diehl, 20 1 7) . Its most severe form-nonacoholic steatohepati­ tis (NASH)-is an increasingly recognized condition that may occasionally progress to hepatic cirrhosis. Nonalcoholic fatty liver disease (NAFLD) is a macrovesicular fatty liver condition that resembles alcohol-induced liver injury but is seen without this substance abuse. Obesity, type 2 diabetes, and hyperlipidemia­ syndrome X-frequently coexist (Chap. 48 p. 938) . The current hypothesis suggests that these conditions may interact with other unknown etiological agents to cause multiple insults or "hits" leading to hepatic injury. For example, half of persons with type 2 diabetes have NAFLD, and insulin resistance has been postu­ lated to act as one possible "hit" (Buzzetti, 20 1 6) . Browning and associates (2004) used MR spectroscopy to determine the preva­ lence ofNAFLD in Dallas County and found that approximately a third of adults were afected. This varied by ethnicity, with 45 percent of Hispanics, 33 percent of whites, and 24 percent of blacks being afected. Most people-80 percent-found to have steatosis had normal liver enzymes. In a study of obese adolescents undergoing bariatric surgery, more than a third had fatty liver without hepatitis, whereas an additional 20 percent had borderline or definite NASH (Xanthakos, 20 1 5) . Liver damage follows a progressive continuum from NAFLD to NASH and then to hepatic ibrosis that may progress to cir­ rhosis (Goh, 20 1 6) . Still, in most persons, the disease is usu­ ally asymptomatic, and it is a frequent explanation for elevated serum transaminase levels found in blood donors and during

other routine screening. Indeed, NAFLD is the cause of ele­ vated asymptomatic transaminase levels in up to 90 percent of cases in which other liver disease is ultimately excluded. It also is the most common cause of abnormal liver tests among adults in this country. Currently, weight loss along with con trol of diabetes and dyslipidemia is the only recommended treatment. Fatty liver iniltration is probably much more common than realized in obese and diabetic gravidas. During the past decade, we encountered an increasing number of pregnant women with these disorders. Once severe liver injury, that is, acute fatty liver of pregnancy, is excluded, gravidas with fatty liver iniltra­ tion have no greater rates of adverse outcomes relative to liver involvement compared with pregnant women of similar weight. That said, some emerging data indicate that this condition may portend adverse pregnancy outcomes. In 1 1 0 pregnancies with NAFLD from the Swedish Medical Birth and the National Patient Registries, risks of gestational diabetes, preeclampsia, pre­ teI'm birth, and low-birthweight newborns were two- to threefold greater than in unafected women (Hagstrom, 201 6) . Yarrington and associates (20 1 6) reported a high rate of gestational diabetes among nonobese women without liver disease, alcohol use, or diabetes, and who had elevated alanine transaminase levels in the irst trimester. s the obesity endemic worsens, adverse efects of this liver disorder on pregnancy will be clarified. • Cirrhosis

Irreversible chronic liver injury with extensive fibrosis and regenerative nodules is the inal common pathway for several disorders. Laennec cirrhosis from chronic alcohol exposure is the most frequent cause in the general population. But in young women-including pregnant women-most cases are caused by postnecrotic cirrhosis from chronic hepatitis B and C. Many cases of cryptogenic cirrhosis are now known to be caused by NAFLD (Goh, 20 1 6) . Clinical manifestations of cirrhosis include jaundice, edema, coagulopathy, metabolic abnormali­ ties, and portal hypertension with gastroesophageal varices and with splenomegaly that may cause thrombocytopenia. The inci­ dence of deep-vein thromboembolism is increased (S0gaard, 2009) . The prognosis is poor, and 75 percent have progressive disease that leads to death in 1 to 5 years. Women with symptomatic cirrhosis frequently are infertile. hose who become pregnant generally have poor outcomes. Common complications include transient hepatic failure, vari­ ceal hemorrhage, preterm delivery, fetal growth restriction, and maternal death (Tan, 2008) . Outcomes are generally worse if esophageal varices coexist. Another potentially fatal complication of cirrhosis arises from associated splenic artery aneurysms. Up to 20 percent of ruptures occur during pregnancy, and 70 percent of these rupture in the third trimester (Palatnik, 20 1 7; Tan, 2008 ) . In a review of 32 gravidas with aneurysm rupture, the mean aneu­ rysm diameter was 2.25 cm, and in half of cases, the diameter was 1 50 1g/mL, treatment is given (Smilk­ stein, 1 988) . If plasma determinations are not available, empiri­ cal treatment is given if the ingested amount exceeded 7.5 g. An oral loading dose of 1 40 mg/kg of N-acetylcysteine is fol­ lowed by 1 7 maintenance doses of 70 mg/kg every 4 hours for 72 hours of total treatment time. Both the oral and an equally eicacious IV dosing regimen have been reviewed by Hodgman and Garrard (20 1 2) . he drug has been reported to reach thera­ peutic concentrations in the fetus (Wiest, 20 1 4) . After 1 4 weeks' gestation, the fetus has some cytochrome P450 activity necessary for metabolism of acetaminophen to the toxic metabolite. Riggs and colleagues ( 1 989) reported fol­ low-up data from the Rocky Mountain Poison and Drug Cen­ ter in 60 women sufering overdose. he likelihood of maternal and fetal survival was better if the antidote was given soon after overdose. At least one 33-week fetus appears to have died as a direct result of hepatotoxicity 2 days after maternal inges­ tion. In another case, Crowell and associates (2008) reported a case of acetaminophen overdose at 32 weeks' gestation. The woman had taken 9.75 grams of acetaminophen approximately 1 . 5 hours prior to arrival. With treatment, the patient survived and went on to deliver a healthy term neonate. • Focal Nodular Hyperplasia

This benign lesion of the liver is characterized in most cases by a well-delineated accumulation of normal but disordered hepatocytes that surround a central stellate scar. hese usually can be diferentiated from hepatic adenomas by magnetic reso­ nance (vIR) or computed tomographic (CT) imaging. Except in the rare situation of unremitting pain, surgery is rarely indi­ cated, and most women remain asymptomatic during preg­ nancy. In one review of 20 cases in Germany, no woman had related complications during pregnancy (Rifai, 20 1 3) . hree women showed 20-percent tumor growth; in 1 0 patients, the tumor decreased in size; and the remaining seven were unchanged across pregnancy. Ramirez-Fuentes and associates (20 1 3) studied 44 lesions with MR imaging in 30 women. Of the lesions, 80 percent were unchanged in size, and most of the remainder decreased in size. They concluded that size changes were unrelated to pregnancy, combination oral con­ traceptive (COC) use, or menopause. Notably, this lesion is not a contraindication to estrogen-containing contraceptives (Chap. 38, p. 692) .

He patic, B i l i a ry, a nd Pa n c reatic D i s o rders TABLE 55-4. Preg na ncy Compl i cations (%) in 5 5 8 P reg na ncies after Liver Tra n spla ntation Series

No.

Preeclampsia/ Hypertension

Cesarean Delivery

Rejection

J a i n (2003) Nagy (2003) C h r i sto pher (2006) Coscia (20 1 0) J a b i ry-Zien iewicz (20 1 1 ) B l u m e (20 1 3) We i g hted Ave rage:

49 38 71 28 1 39 62 540

2-8 21 1 3-28 22-3 3 8-26 6 1 6-28

45 46 28 32 79 30 38

24 17 17 6 8 13 10

• Hepatic Adenoma

- This is an uncommon benign neoplasm but has a 5-percent risk of malignant transformation and a significant risk of rupture-asso­ ciated hemorrhage, particularly in pregnancy. s just discussed, adenomas can usually be diferentiated from focal nodular hyper­ plasia by MR or CT imaging. Adenomas have a 9: 1 predomi­ nance among women and are strongly linked with COC use. The rupture risk progresses with lesion size, and surgery is generally recommended for tumors measuring > 5 cm (Agrawal, 20 1 5) . Tran and colleagues (20 1 6) recommend sonographic surveil­ lance of hepatic adenomas during pregnancy. In one review of 27 cases in pregnany, 23 became apparent in the third trimester .nd puerperium (Cobey, 2004) . Bleeding complicated no tumors measuring 200 mg/dL plus classic signs and symptoms such as polydipsia, polyuria, and unexplained weight loss, or those with a fasting glucose level > 1 25 mg/dL are considered by the ADA (20 1 7a) and the World Health Organization (20 1 3) to have overt diabetes first detected in pregnancy. Women with only minimal metabolic derangement may be more diicult to identiY. To diagnose overt diabetes in pregnancy, he International Association of Diabetes and Preg­ nancy Study Groups (IADPSG) Consensus Panel (20 1 0) rec­ ognizes the threshold values found in Table 57-4 for fasting or random plasma glucose and glycosylated hemoglobin (HbA1 J levels at prenatal care initiation. The ADA (20 1 7a) and the World Health Organization (20 1 3) now also consider a plasma glucose level > 200 mg/dL measured 2 hours after a 75 g oral glucose load to be diagnostic. No consensus has been reached as to whether such testing should be universal or limited to those women classiied as high risk. Regardless, the tentative diagnosis of overt diabetes during pregnancy based on these thresholds should be conirmed postpartum. isk factors for impaired carbohydrate metabolism in pregnant women include a strong familial history of diabetes, prior delivery of a large newborn, persistent glucosuria, or unexplained fetal losses. • I m pact on Pregnancy

With overt diabetes, the embryo, fetus, and mother frequently experience serious complications directly attributable to diabetes.

Peterson and colleagues (20 1 5) estimate that thousands of these complications might be prevented each year by preconceptional care for improved glycemic control. The likelihood of successful outcomes with overt diabetes, however, is not simply related to glucose control. The degree of underlying cardiovascular or renal disease may be more important. Thus, advancing stages of the White classification, seen in Table 57-2, are inversely related to favorable pregnancy outcomes. Shown in Table 57-5 are data that chronicle the deleterious pregnancy outcomes with overt diabetes. hese maternal and fetal complications are described in the following sections. Feta I Efects

Spontaneous Abortion. Several studies have shown that early miscarriage is associated with poor glycemic control (Chap. 1 8, p. 347) . Up to 25 percent of diabetic gravidas have an early pregnancy loss (Galindo, 2006; Rosenn, 1 994) . hose whose HbA1c concentrations were > 1 2 percent or whose prepran­ dial glucose concentrations were persistently > 1 20 mg/dL had an elevated risk. Bacon and associates (20 1 5) reviewed 89 pregnancies in women with maturity-onset diabetes of the young (MODy), which is a monogenic form of diabetes. hese investigators found that only women with the causative glu­ cose kinase gene (GCK) mutation were more likely to have a miscarriage. These women are characterized by hyperglycemic variability that is diicult to control.

TABLE 57-3. P roposed Classifi cation System for Dia betes i n P reg n a n cy Gestational diabetes: d i a betes d ia g nos d d u ri n g p reg na ncy that is n ot c l ea rly overt (type 1 or type 2) d i a betes Type 1 Dia betes: Dia betes resu lti ng from �-ce l l destruction, u s u a l ly l ead i n g to a bsol ute i n s u l i n deficiency a. Without va scu l a r com pl ications b. With vasc u l a r com p l i cations (speciy wh ich)

Type 2 Dia betes: Dia betes from i nadeq uate i n s u l i n secretion i n the face of i nc rea sed i n su l i n resi sta nce a. Without vascu l a r com p l i cations b. With vascu l a r com p l icat i o n s (speciy wh i ch)

Other types of dia betes: g e n etic i n o ri g i n, associated with p a n creatic d i sease, d rug-ind uced, o r c h e m i ca l ly i n d uced Data fro m American D i a betes Association, 20 1 7a.

1 099

1 1 00

Med ical a n d S u rg ica l Com pl i cations

TABLE 57-4. Diagnosis of Overt Dia betes i n P reg n a n cya Measure of G lycemia

Threshold

Fa sti n g plasma g l u cose H e m og l o b i n A l e Ra ndom p l a s m a g l u cose

At l ea st 7.0 m mollL ( 1 26 m g/d L) At lea st 6.5% At least 1 1 . 1 m mol/L (200 mg/d L) p l u s confi rmation

aApply to wom e n without known d i a betes a ntedati n g preg nancy. The deci sion to perfo rm blood testi n g for eva l u ation of g lyce m i a o n a l l p reg n a n t women r o n ly on wo m e n with c h a racte ristics i nd icati ng a h i g h ris k fo r d i a betes is ba sed on the backg round fre q u e n cy of a b n o r m a l g l u cose m eta bo l i s m i n the popu lation a nd o n l ocal c i rcu msta n ces. Data from I nternatio n a l Association of Dia betes a n d P reg na ncy Study G ro u ps Conse n s u s P a n e l , 2 0 1 0.

Preterm Del ivery. Overt diabetes is an undisputed risk factor for preterm birth. Eidem and associates (20 1 1 ) analyzed 1 307 births in women with type 1 diabetes from the Norwegian NIedi­ cal Birth Registry. More than 26 percent were delivered preterm compared with 6.8 percent in the general obstetrical population. Moreover, almost 60 percent were indicated preterm births, that is, due to obstetrical or medical complications. In one review of more than 500,000 California births, 1 9 percent of women with pregestational diabetes had a preterm birth compared with 9 percent in controls (Yanit, 20 1 2) . In the Canadian study shown in Table 57-5, the incidence of preterm birth was 28 percent. Ma lformations. he incidence of major malformations in women with type 1 diabetes is at least doubled and approxi­ mates 1 1 percent Qovanovic, 20 1 5). These account for almost half of perinatal deaths in diabetic pregnancies. As shown in Table 57-6, cardiovascular malformations accounted for more than half of the anomalies. In a cohort study of more than 2 million births in Canada, the risk of an isolated cardiac defect was ivefold higher in women with type 1 diabetes (Uu, 20 1 3) . he caudal regression sequence, described in Chapter 1 0 (p. 1 96) , is a rare malformation frequently associated with maternal diabetes (Garne, 20 1 2) . Poorly controlled diabetes, both preconceptionally and early in pregnancy, is thought to underlie this elevated severe­ malformation risk. s shown in Figure 57-2, increased maternal

TABLE 57-5. P reg na ncy Outcomes of B i rths in Nova Scotia from 1 988 to 2002 in Women with a n d without Pregestational Dia betes

Factor

Dia betic (n = S 1 6) %

Gestational hypertension Preterm b i rt h Macrosom ia Feta I-g rowth restriction Sti l l b i rth Peri n ata l death

Nondiabetic (n = l S0, S98) %

P

value

9

< .00 1

28 45 5

5 13 10

< .00 1 < .00 1 < .00 1

0.4 0.6

Altered Fetal Growth. Diminished growth may result from congenitl malformations or from substrate deprivation due to advanced maternal vascular disease. That said, fetal overgrowth is more typical of pregestational diabetes. Maternal hyperglycemia prompts fetal hyperinsulinemia, and this in turn stimulates exces­ sive somatic growth. Except for the brain, most fetal organs are afected by the macrosomia that characterizes the fetus of a dia­ betic woman. Newborns such as the one shown in Figure 57-3 are described as being anthropometrically diferent from other large­ for-gestational age (LGA) neonates (Catalano, 2003; Durnwald, 2004) . Speciically, those whose mothers are diabetic have exces­ sive fat deposition on the shoulders and trunk, which predisposes to shoulder dystocia or cesarean delivery. he incidence of macrosomia rises signiicantly when mean maternal blood glucose concentrations chronically exceed 1 30 mg/dL (Hay, 20 1 2) . Hammoud and coworkers (20 1 3)

TABLE 57-6. Maj o r Congenital A n o m a l ies i n 36,345 N eonates Born to Women with Dia betes between 2004 a nd 2 0 1 1 Organ System

28

1 .0 1 .7

HbA[c levels and major malformations clearly correlate. To explain this, at least three interrelated molecular chain reactions have been linked to maternal hyperglycemia (Reece, 20 1 2) . hese include alterations in cellular lipid metabolism, excess produc­ tion of toxic superoxide radicals, and activation of programmed cell death. In their review of molecular mechanisms underlying diabetic embryopathy, Yang and colleagues (20 1 5) suggest that these cellular responses to oxidative stress represent potential therapeutic targets to prevent diabetes-induced embryopathy.

.06 .004

Tota l Card iac M u scu los keleta l U ri n a ry CNS GI Other

Type 2 DM n = 41 66

GDM n = 3 1 ,700

55 38 1 3

454 272 31 28 13 30 80

2203 1 1 29 23 1 260 64 1 64 355

11

CNS ce ntra l nervo us system; OM d i a betes m e l l itu s; gestational d i a betes; G I g a stroi ntesti n a l . GDM Data from Jova noviC, 20 1 5 . =

=

Data from Ya ng, 2006.

�pe 1 DM n = 482

=

=

D i a betes Mel l itus

24

25 : )

) ..

) .

700

27

30

600

21

20 15

� 15 � 12

1 1 .7

10 5

5

2/1 7

3/1 9

6-6.9

7-7.9

) 0 �

300 3

n

o

6 5 0 z

�8

FIGURE 57-2 The freq uency of m ajor congenita l ma lformations i n newborns of women with pregestational diabetes stratified by hemog lobin Ale level s at first prenatal visit. (Data from Gali ndo A, Burg u i llo AG, Azriel S, et al: Outcome of fetuses i n women with pre­ gestational dia betes mellitus, J Peri nat Med. 2006;34(4):323-33 1 .)

reported that the macrosomia rates for Nordic women with type 1 , type 2, or gestational diabetes were 35 percent, 28 per­ cent, and 24 percent, respectively. As shown in Figure 57-4, the birthweight distribution of neonates of diabetic mothers is skewed toward consistently heavier birthweights. In the study by Hammoud and colleagues (20 1 3) , fetal growth profiles from 897 sonographic examinations in 244 women with diabetes were compared with 843 examina­ tions in 1 45 control women. he abdominal circumference grew disproportionately larger in the diabetic groups. Analy­ sis of head circumference/abdominal circumference (HC/AC) ratios shows that this disproportionate growth occurs mainly

' ..

FIGURE 57-3 Th is 6050-g macrosomic i nfa nt was born to a woma n with gestation a l d i a betes.

z 9

400 .

u

0 6.4 percent at delivery was independently associated with urgent cesarean delivery. This suggests that tighter glycemic control during the third trimester might reduce late fetal compromise and cesar­ ean delivery for fetal indications (Miailhe, 20 1 3) . The cesarean delivery rate for women with overt diabetes has remained at approximately 80 percent for the past 40 years at Parkland Hospital. Reducing or withholding the dose of long-acting insulin to be given on the day of delivery is recommended. Regular insu­ lin should be used to meet most or all of the insulin needs of the mother during this time, because insulin requirements typically drop markedly after delivery. We have found that continuous insulin infusion by calibrated intravenous pump is most sat­ isfactory (Table 57- 1 0) . Throughout labor and after delivery,

the woman should be adequately hydrated intravenously and given glucose in suicient amounts to maintain normoglyce­ mia. Capillary or plasma glucose levels are checked frequently, especially during active labor, and regular insulin is adminis­ tered accordingly. Puerperi u m

Often, women may require virtually no insulin for the irst 24 hours or so postpartum. Subsequently, insulin requirements may luctuate markedly during the next few days. Infection must be promptly detected and treated. When appropriate, oral agents can be restarted. Counseling in the puerperium should include a discussion of birth control. Efective contraception is especially important in women with overt diabetes to allow optimal glucose control before subsequent conception. G ESTATIONAL DIABETES In the United States in 20 1 0, almost 5 percent of gravidas were afected by gestational diabetes (DeSisto, 20 1 4) . World­ wide, its prevalence difers according to race, ethnicity, age, and body composition and by screening and diagnostic cri­ teria. There continue to be several controversies pertaining to the diagnosis and treatment of gestational diabetes. A National Institutes of Health (NIH) Consensus Development Confer­ ence (20 1 3) was convened to study this. he American College of Obstetricians and Gynecologists (20 1 7a) has also updated its recommendations. These two authoritative sources provide an analysis of the issues surrounding the diagnosis and bolster the approach to identiying and treating women with gesta­ tional diabetes. The word gestational implies that diabetes is induced by pregnancy-ostensibly because of exaggerated physiological changes in glucose metabolism (Chap. 4, p. 56) . Gestational diabetes is deined as carbohydrate intolerance of variable sever­ ity with onset or first recognition during pregnancy (American College of Obstetricians and Gynecologists, 20 1 7a) . This dei­ nition applies whether or not insulin is used for treatment and undoubtedly includes some women with previously unrecog­ nized overt diabetes. Use of the term gestational diabetes has been encouraged to communicate the need for enhanced surveillance and to

TABLE 57- 1 0. I n s u l i n Ma nagement Duri ng Labor a n d Del ivery • • • •

• •

U s u a l dose of i ntermed i ate-acti ng i n s u l i n is g ive n at bedti m e. Morn i ng dose of i n su l i n is withheld . I ntravenous i nfusion of n o r m a l sa l i ne is beg u n . Once active labor beg i n s or g l ucose levels decrease t o less t h a n 7 0 mg/d L, t h e i nfu sion is cha nged from sa l i ne t o 5 % dextrose a n d del ivered at a rate o f 1 00- 1 50 cc/h (2 . 5 m g/kg/m i n) t o achieve a g l ucose level of a p proxi mately 1 00 mg/d L. G l ucose leve l s a re checked h o u rly u s i n g a bedside m eter a l l owi ng for adj u stment in the i n s u l i n or g l ucose i nfu sion rate. Reg u l a r (short-acti ng) insulin is admin istered by i ntravenous i nfusion at a rate of 1 .25 U/h if g l u cose levels exceed 1 00 mg/d L.

Data from Cou sta n DR. Delive ry: ti m i ng, mode, and ma nageme nt. I n : Reece EA, Co u sta n DR, Ga bbe SG, ed itors. Dia betes in wo men: adolescence, p reg n a n cy, a n d men opa use. 3 rd ed. P h i la d e l p h i a (PA): L i p p i ncott W i l l i a m s & Wil ki ns; 2004; a n d Jova novic L , Pete rso n CM. M a n agement o f the preg na nt, i n s u l i n-dependent d i a betic wo m a n . Dia betes Ca re 1 980;3 :63-8.

1 1 07

1 1 08

Med ical a nd S u rg i cal Co m pl ications

stimulate women to seek further testing postpartum. The most important perinatal correlate is excessive fetal growth, which may result in both maternal and fetal birth trauma. he likelihood of fetal death with appropriately treated gestational diabetes is not diferent from that in the general population. Importantly, more than half of women with gestational diabetes ultimately develop overt diabetes in the ensuing 20 years. And, as discussed on page 1 097, evidence is mounting for long-range complications that include obesity and diabetes in their ofspring.

TABLE 57-1 1 . Th reshold Va l ues for D i a g n osis of Gestational Dia betes Plasma Glucose Fasti n g 1 -h r OGTI 2-h r OGTI

• Screening and Diagnosis

Glucose Concentration Thresholda m mol/l mg/dL 5. 1 1 0.0 8.5

Above Threshold (%) Cumulative

92 1 80 1 53

aOne or more of these va l ues from a 7 5 -g OGTI m u st be eq u a l ed or exceeded for the d i ag nosis of g estational d i a betes. b i n a d d ition, 1 . 7% of pa rticipa nts i n the i n it i a l cohort we re u n b l i nded beca use of fa sti ng plasma g l u cose l eve ls > 5 .8 m mol/L ( 1 05 mg/d L) or 2-h r OGTI va l ues > 1 1 . 1 m mollL (200 mg/d L), bri n g i n g t h e tota l to 1 7.8%. o ra l g l u cose tolera n ce test. OGI Data fro m I nternationa l Association of D i a betes a n d P reg n a n cy Study G rou ps, 20 1 0.

Despite almost 50 years of research, there is still no agreement regarding optimal gestational diabetes screening. The diiculty in achieving consensus is underscored by the controversy fol­ lowing publication of the single-step approach espoused by the International Association of Diabetes and Pregnancy Study Groups Consensus Panel (20 1 0) and shown in Table 57- 1 1 . his strategy was greatly influenced by results of the Hypo­ glycemia and Pregnancy Outcomes (HAPO) Study, described later. Although the ADA (20 1 7a) supports this new scheme, the American College of Obstetricians and Gynecologists (20 1 7a) continues to recommend a two-step approach to screen and diagnose gestational diabetes. Similarly, the NIH Consensus Development Conference in 20 1 3 concluded that evidence is insuicient to adopt a one-step approach. he recommended two-step approach begins with either uni­ versal or risk-based selective screening using a 50-g, I -hour oral glucose challenge test. Participants in the Fifth International

=

Workshop Conferences on Gestational Diabetes endorsed use of selective screening criteria shown in Table 57- 1 2. Conversely, the American College of Obstetricians and Gynecologists (20 1 7a) recommends universal screening of pregnant women using a laboratory-based blood glucose test. It is suggested that attempts to identiy the 1 0 percent of women who should not be screened would add unnecessary complexity. Screening should

TABLE 57-1 2. Risk-Based Recom mended Scree n i n g Strategy for Detecti n g G DMa GDM risk assessment: s h o u l d be a scerta i ned at the fi rst p re nata l visit Low Risk: B lood g l u cose test i n g not routi nely req u i red if all t h e fol lowi n g a re p resent: Mem ber of an eth n i c g ro u p with a low preva l e n ce of G D M No known d ia betes i n fi rst-deg ree relatives Age < 25 yea rs We i g ht n or ma l before p reg n a ncy Wei g ht n or ma l at b i rth No h i story of a b n o r m a l g l ucose meta bol i s m No h i story o f poor o bstetrical outcome Average Risk: Perfor m blood g l u cose testi n g at 24 to 28 weeks u s i n g either: Two-step proced u re: 5 0-g o ra l g l u cose c h a l l e n g e test (GCT), fo l lowed by a d iag nostic 1 00-g OGI for those meet i n g the t h reshold va l ue i n the GCT One-ste p proced u re: d ia g nostic 1 00-g OGTI pe rfo rm ed on a l l s u bjects H igh Risk: Perform blood g l ucose test i n g as soon as fea s i b l e, u s i n g the proced u res descri bed a bove, if one or m o re of these a re p resent: Seve re obesity Strong fa m i ly h istory of type 2 d ia betes P revious h istory of G DM, i m pa i red g l u cose meta bo l i s m , or g l ucos u ria If G DM i s not d ia g n osed, bl ood g l u cose test i n g should be re peated at 24 to 28 weeks' g estation or at a ny time sym ptom s or s i g n s suggest hyperg lyce m i a aCriteria o f the Fifth I ntenati o n a l Workshop-Confe re n ce on Gestationa l D i a betes. G DM g estationa l d i a betes m e l l it u s; OGTI ora l g l ucose tolerance test. Reproduced with per m i ss i o n from Metzger B E, Cou sta n DR, the Org a n iz i n g Com m ittee: S u m m a ry a n d reco m m e ndations of the Fou rth I nte rnational Workshop-Confe re nce o n Gestational Dia betes M e l l itus, Dia betes Care. 1 998 Aug; 2 1 S u ppI 2:B 1 6 1 -B 1 67 . =

8.3 1 4.0 1 6. 1 b

=

Dia betes M e l l itus

be performed beween 24 and 28 weeks' gestation in those women not known to have glucose intolerance earlier in preg­ nancy. This 50-g screening test is followed by a dianostic 1 00-g, 3-hour oral glucose tolerance test (OGT) if screening results meet or exceed a predetermined plasma glucose concentration. For the 50-g screen, the plasma glucose level is measured 1 hour ater a 50-g oral glucose load without regard to the time of day or time oflast meal. In a recent review, the pooled sensitiv­ ity for a threshold of 1 40 mg/dL ranged from 74 to 83 percent depending on 1 00-g thresholds used for diagnosis (van Leeuwen, 20 1 2) . Sensitivity estimates for a 50-g screen threshold of 1 35 mg/dL improved only slightly to 78 to 85 percent. Importantly, speciicity dropped from a range of 72 to 85 percent for 1 40 mg/dL to 65 to 8 1 percent for a threshold of 1 3 5 mg/dL. Using a threshold of 1 30 mg/dL marginally improves sensitivity with a further decline in speciicity (Donovan, 20 1 3) . That said, in the absence of clear evidence supporting one cutof value over another, the American College of Obstetricians and Gynecolo­ gists (20 1 7a) sanctions using any one of the three 50-g screen thresholds. At Parkland Hospital, we continue to use 1 40 mg/dL as the screening threshold to prompt the 1 00-g test. Justiication for screening and treatment of women with ges­ tational diabetes was strengthened by the study by Crowther and coworkers (2005). They assigned 1 000 women with gestational diabetes between 24 and 34 weeks' gestation to receive dietary advice with blood glucose monitoring plus insulin therapy-the intervention group-or to undergo routine prenatal care. Women were diagnosed as having gestational diabetes if their blood glu­ cose was > 1 00 mg/ dL ater an overnight fast and was between 1 40 and 1 98 mg/dL 2 hours ater ingesting a 75-g glucose solu­ tion. Women in the intervention group had a signiicantly lower risk of a composite adverse outcome that included perinatal death, shoulder dystocia, fetal bone fracture, and fetal nerve palsy. Mac­ rosomia deined by birthweight ::4 000 g complicated 1 0 percent of deliveries in the intervention group compared with 2 1 percent in the routine prenatal care group. Cesarean delivery rates were almost identical in the two study groups. Slightly diferent results were reported by the Maternal­ Fetal Medicine Units Network randomized trial of 958 women (Landon, 2009) . Dietary counseling plus glucose monitoring was compared with standard obstetrical care in women with mild gestational diabetes to reduce perinatal morbidity rates. Mild gestational diabetes was identiied in women with fast­ ing glucose levels < 95 mg/dL. hey reported no diferences in rates of composite morbidity that included stillbirth; neonatal hypoglycemia, hyperinsulinemia, and hyperbilirubinemia; and birth trauma. Importantly, secondary analyses demonstrated a 50-percent reduction in macrosomia, fewer cesarean deliveries, and a signiicant decrease in shoulder dystocia rate-1 . 5 versus 4 percent-in treated versus control women. Based largely on these two landmark studies, the U.S. Pre­ ventive Sevices Task Force (20 1 4) now recommends universal screening in low-risk women after 24 weeks' gestation. How­ ever, the Task Force concluded that evidence is insuicient to assess the balance of benefits versus harms of screening before 24 weeks. For screening, the optimal OGTT ro identiy gesta­ tional diabetes has not been agreed upon. The World Health Organization (20 1 3) and the ADA (20 1 7a) recommend the

TABLE 57-1 3. Diag nosis of G DM U s i n g Th reshold G l ucose Va l ues from 1 00-g Ora l G l ucose Tolera n ce Testa,b � Carpenter-Coustan d

Ti me

Fast i n g 1 -h r 2-h r 3-h r

(mg/dL)

(mmoI/L)

(mg/dL)

1 05 1 90 1 65 1 45

5.8 1 0.6 9.2 8.0

95 1 80 1 55 1 40

(mmoI/L) 5.3 1 0. 0 8.6 7.8

aTh e test should be perform ed when the patient i s fa sti n g . bTwo or more o f t h e ve nous plasma g l u cose concentra ­ tions l isted a re met or exceeded for a positive d i a g nos i s. (Se r u m g l ucose leve l . d Ser u m or p l a s m a g l ucose l eve l . N D DG Nati o n a l D i a betes Data G ro u p. Data from America n Dia betes Association, 20 1 7a; Ferra ra, 2002. =

75-g, 2-hour OGTT, but acknowledge that the diagnosis can be accomplished using the two-step strategy. In the United States, however, the 1 OO-g, 3-hour OGTT performed after an overnight fast is recommended by the American College of Obstetricians and Gynecologists (20 1 7a) . Proposed criteria for interpreta­ tion of the diagnostic 1 00-g OGTT are shown in Table 5 7- 1 3 . In a secondary analysis of the Maternal-Fetal Medicine Units Network treatment trial, Harper and colleagues (20 1 6) showed that women diagnosed with either the National Diabetes Data Group (NDDG) or the Carpenter-Co us tan criteria beneited from treatment. However, the number needed to treat to pre­ vent a shoulder dystocia was higher for the Carpenter-Cous tan criteria. At Parkland Hospital we continue to use the NDDG criteria for diagnosis. Criteria for the 75-g OGTT recom­ mended are shown in Table 57- 1 1 . The H yperg lyce m i a a n d Adverse Preg na ncy O utco m e Study

This was a 7-year international epidemiological study of 23,325 pregnant women at 15 centers in nine countries (HAPO Study Cooperative Research Group, 2008) . The investigation ana­ lyzed the association of various levels of glucose intolerance during the third trimester with adverse infant outcomes in women with gestational diabetes. Between 24 and 32 weeks' gestation, the general population of pregnant women under­ went a 75-g OGTT after an overnight fasting. Blood glucose levels were measured fasting and then 1 and 2 hours after glu­ cose ingestion. Caregivers were blinded to results except for women whose glucose levels exceeded values that required treatment and removal from the study. Glucose values at each of these three time posts were stratiied into seven categories (Fig. 57-6) . hese values were then correlated with rates for birthweight > 90th percentile (LGA) , primary cesarean deliv­ ery, neonatal hypoglycemia, and cord-serum C-peptide lev­ els > 90th percentile. Odds of each outcome were calculated using the lowest category-for example, fasting plasma glucose :;7 5 mg/dL-as the referent group. Their indings in general supported the supposition that increasing plasma glucose levels were associated with increasing adverse outcomes. Ecker and

1 1 09

1 1 10

Med i ca l a n d S u rg ica l Co m p l i cations

diagnosis rates but not with reduced macrosomia rates compared with a two­ step approach. Remarkably, they identi­ fied a higher primary cesarean delivery rate associated with adoption of the IADPSG recommendations. he ADA (20 1 3, 20 1 7a) initially recommended adopting this new approach, however, based on benefits inferred from trials in women identiied using a two-step approach described on page 1 1 08, they now concede that data support a two­ step strategy as well.

30 25 C ) � ) 20

:

. c 15 ) J " � 10 )

« � ..J

5

Glucose levels - Fasting

;

75

; 1 05

75-79

80-84

85-89

90-94

95-99

:: 1 00

N I H Con s e n s u s Deve l o p m ent Confe re n ce

Prompted b y the disparate recommen­ dations, the NIH Consensus Devel­ opment Conference on Diagnosing F I G U R E 57-6 Hyperg lycemia a nd Adverse P reg na n cy Outcome (HAPO) Study. The fre­ Gestational Diabetes Mellitus (20 1 3) q u ency of n ewborn b i rthweig ht ::9 0th percentile for gestational age plotted agai nst g l u cose was convened. his conference included l a rge levels fasti n g a nd at 1 - and 2-hr i nterva ls fol lowi n g a 75-g ora l g l ucose load. LGA input from a m ultidisciplinary planning for gestational age. (Reprod uced with permission from HAPO Study Cooperative Research committee, a systematic evidence review Group, Metzge r BE, Lowe LP, et al: Hyperg lycem i a a nd adverse preg nancy outcomes, N E n g l J M e d . 2008 May 8;358( 1 9) : 1 99 1 -2002.) by the Agency for Healthcare Research and Quality Evidence-Based Practice Center, expert testimony, and a nonbiased panel to produce Greene (2008) concluded that it would be diicult to show the overall report. he panel concluded that there were poten­ that treating lesser degrees of carbohydrate intolerance would tial beneits to worldwide standardization. However, it found provide any meaningful improvements in clinical outcomes. insuicient evidence to adopt a one-step diagnostic process such We agree that changes in criteria are not j ustiied until clinical as the one proposed by the IADPSG. Moreover, as mentioned trials prove benefits. his position was also endorsed by the previously, after consideration of these indings, the American 20 1 3 NIH Consensus Development Conference. College of Obstetricians and Gynecologists (20 1 7a) continues I nternati o n a l Association of Dia betes to recommend a two-step screening and diagnostic approach to a n d P reg n a n cy Stu d y G ro u p gestational diabetes diagnosis. he College noted no significant improvements in maternal or perinatal outcomes that would h e IADPSG sponsored a workshop conference o n the diag­ ofset the tripling of gestational diabetes incidence that would nosis and classiication of gestational diabetes in 2008. After derive from the one-step approach. We applaud this decision. reviewing the results of the HAPO study, a panel developed recommendations for the diagnosis and classiication of hyper­ glycemia during pregnancy. This panel allowed for the diagno­ • Maternal and Fetal Efects sis of overt diabetes during pregnancy as shown in Table 57-4. Adverse consequences of gestational diabetes difer from those It also recommended a single-step approach to the diagnosis of pregestational diabetes. Unlike in women with overt diabetes, of gestational diabetes using the 75-g, 2-hour OGTT. hresh­ women with gestational diabetes do not appear to have fetuses with olds for fasting, 1 - , and 2-hour values based on mean glucose substantially higher rates of anomalies than the general obstetrical concentrations from the entire HAPO study cohort were con­ population (Sheield, 2002) . In a study of more than 1 million sidered. hese glucose level thresholds were derived using an women from the Swedish Medical Birth Registry, major malfor­ arbitrary 1 .75 odds ratio of outcomes such as LGA birthweight mation rates were marginally elevated in fetuses of gestational dia­ and cord serum C-peptide levels > 90th percentile. Only one betics compared with those of nondiabetic controls-2.3 versus of these thresholds, shown in Table 5 7- 1 1 , would need to be 1 .8 percent (Fadl, 20 1 0) . The stillbirth rate was not greater in this met or exceeded to make the diagnosis of gestational diabetes. study. Similarly, the stillbirth rate was not increased in an analysis It is estimated that implementation of these recommenda­ by Jovanovic and associates (20 1 5) of more than 800,000 preg­ tions would raise the prevalence of gestational diabetes in the nancies from 2005 through 20 1 1 . In contrast, and not unexpect­ United States to 1 7. 8 percent! Said another way, the number edly, women with elevated fasting glucose levels have elevated rates of women with mild gestational diabetes would grow almost of unexplained stillbirths similar to those of women with overt threefold with no evidence of treatment benefit (Cundy, diabetes. This increasing risk with progressive maternal hypergly­ 20 1 2) . Feldman and coworkers (20 1 6) evaluated the imple­ cemia emphasizes the importance of identiying women with evi­ mentation of the IADPSG paradigm in a before-ater analysis dence of preexisting diabetes early in pregnancy (see Table 57-4). that included more than 6000 women. he new strategy was Similar to women with overt diabetes, adverse maternal efects associated with a significant increase in gestational diabetes - 1 hour

- 2 hour

;

90

1 06-1 32 1 33-1 55 1 56-1 7 1 9 1 -1 08

1 72-1 93 1 94-2 1 1

::2 1 2

1 09-1 25 1 26-1 39 1 40-1 57 1 58-1 77

:: 1 78

=

Dia betes M e l l it u s

associated with gestational diabetes include a higher frequency of hypertension and cesarean delivery. Feta l Macroso m ia

he primary efect attributed to gestational diabetes is exces­ sive fetal size or macrosomia that is variably defined and dis­ cussed further in Chapter 44 (p. 857) . The perinatal goal is to avoid diicult delivery from macrosomia and concomitant birth trauma associated with shoulder dystocia. In a retrospec­ tive analysis of more than 80,000 vaginal deliveries in Chinese women, Cheng and associates (20 1 3) calculated a 76-fold greater risk for shoulder dystocia in newborns weighing : 4200 g compared with the risk in those weighing < 3500 g. Impor­ tantly, however, the odds ratio for shoulder dystocia in women with diabetes was < 2 . Although gestational diabetes is certainly a risk factor, it accounts for onl) a small number of pregnancies complicated by shoulder dystocia. he excessive shoulder and trunk fat that commonly character­ izes the macrosomic newborn of a diabetic mother theoretically predisposes such neonates to shoulder dystocia or cesarean deliv­ ery (Durnwald, 2004; McFarland, 2000). Landon and associates (20 1 1 ) identified shoulder dystocia in approximately 4 percent of women with mild gestational diabetes compared with < 1 percent of women with a 50-g glucose screen result < 1 20 mg/dL. In a ptospective study of fetal adipose measurements, however, Buh­ ling and coworkers (20 1 2) demonstrated no diferences between measurements in 630 ofspring of women with gestational diabe­ tes and 1 42 without diabetes. he authors attributed this negative inding to successful treatment of gestational diabetes. Extensive evidence supports that insulin-like growth factors also play a role in fetal-growth regulation (Chap. 44, p. 845). hese proinsulin-like polypeptides are produced by virtually all fetal organs and are potent stimulators of cell diferentiation and division. Luo and coworkers (20 1 2) reported that insulin­ like growth factor- 1 strongly correlated with birthweight. he HAPO study investigators also reported dramatic increases in cord-serum C-peptide levels with rising maternal glucose levels following a 75-g OGTT. C-peptide levels above the 90th per­ centile were found in almost a third of newborns in the high­ est glucose categories. Other factors implicated in macrosomia include epidermal growth factor, ibroblast growth factor, platelet-derived growth factor, leptin, and adiponectin (Grissa, 20 1 0; Loukovaara, 2004; Mazaki-Tovi, 2005). Neonata l H ypog l yce m i a

Hyperinsulinemia may provoke severe hypoglycemia within minutes of birth, but only three fourths of these episodes occur in the irst 6 hours (Harris, 20 1 2) . he deinition of neona­ tal hypoglycemia is controversial, with recommended clinical thresholds ranging from 35 to 45 mg/dL. An NIH workshop conference on neonatal hypoglycemia supported using a thresh­ old of 35 mg/dL in term newborns but cautioned that this practice is not strictly evidence based (Hay, 2009) . Newborns described by the HAPO study (2008) had an incidence of clini­ cal neonatal hypoglycemia that rose with increasing maternal OGTT result values deined in Figure 57-6. The frequency varied from 1 to 2 percent, but it was as high as 4.6 percent in women with fasting glucose levels : 1 00 mg/ dL. Similarly,

Cho and colleagues (20 1 6) , analyzed more than 3000 Korean women who underwent a 50-g OGTT and found that neonates born to women with a screening result : 200 mg/dL were 84 times more likely to have hypoglycemia than those b orn to women with a result < 1 40 mg/dL. he risk of neonatal hypo­ glycemia correlates with umbilical cord C-peptide levels. But, importantly, the risk also rises with birthweight, independent of a maternal diabetes diagnosis (Mitanchez, 20 1 4) . Maternal Obesity. I n women with gestational diabetes, mater­ nal body mass index (BMI) is an independent and more substan­ tial risk factor for fetal macrosomia than is glucose intolerance (Ehrenberg, 2004; Mission, 20 1 3) . Stuebe and associates (20 1 2) completed a secondary analysis of women with either untreated mild gestational diabetes or normal glucose tolerance testing results. They found that higher BMI levels were associated with rising birthweight, regardless of glucose levels. In one analysis of more than 600,000 pregnant women, gestational diabetes, compared with obesity or gestational weight gain, contrib­ uted the least to the population-attributable fraction of LGA neonates (Kim, 20 1 4) . he highest fraction of LGA neonates was attributable to maternal obesity plus excessive gestational weight gain. Similarly, Egan and colleagues (20 1 4) found that excessive gestational weight gain is common in women with gestational diabetes and confers an additive risk for fetal mac­ rosomia. Weight distribution also seems to play a role because the risk of gestational diabetes is greater with maternal truncal obesity. Suresh and colleagues (20 1 2) veriied that increased maternal abdominal subcutaneous fat thickness as measured by sonography at 1 8 to 22 weeks' gestation correlated with BMI and was a better predictor of gestational diabetes.

• Management

Women with gestational diabetes can be divided into two functional classes using fasting glucose levels. Pharmacologi­ cal methods are usually recommended if diet modiication does not consistently maintain the fasting plasma glucose levels < 9 5 mg/dL or the 2-hour postprandial plasma glucose < 1 20 mg/dL (American College of Obstetricians and Gyne­ cologists, 20 1 7a) . Whether pharmacological treatment should be used in women with lesser degrees of fasting hyperglycemia is unclear. here have been no controlled trials to identiy ideal glucose targets for fetal risk prevention. On the other hand, the HAPO study (2008) did demonstrate increased fetal risk at glucose levels below the threshold used for diagnosis of dia­ betes. The Fifth International Workshop Conference recom­ mended that fasting capillary glucose levels be kept ; 9 5 mg/ dL (Metzger, 2007) . In a systematic review, Hartling and colleagues (20 1 3) con­ cluded that treating gestational diabetes resulted in a signiicantly lower incidence of preeclampsia, shoulder dystocia, and macroso­ mia. For example, the calculated risk ratio was 0.50 for delivering a newborn >4000 g ater treatment. These investigators caution that the attributed risk for these outcomes is low, especially when glucose values are only moderately elevated. Importantly, they were unable to demonstrate an efect on neonatal hypoglycemia or on future metabolic outcomes in the ofspring.

1111

11 12

Med ical a nd S u rg ica l Com pl i cations D ia betic D iet

Nutritional instructions generally include a carbohydrate­ controlled diet suicient to maintain normoglycemia and avoid ketosis. On average, this includes a daily caloric intake of 30 to 35 kcallkg. Moreno-Castilla and associates (20 1 3) randomly assigned 1 52 women with gestational diabetes to either a 40- or a 5 5-percent daily carbohydrate diet and found no diference in insulin levels and pregnancy outcomes. he American Col­ lege of Obstetricians and Gynecologists (20 1 7 a) suggests that carbohydrate intake be limited to 40 percent of total calories. The remaining calories are apportioned to give 20 percent as protein and 40 percent as fat. The most appropriate dietary approach for women with ges­ tational diabetes has not been established. One metaanalysis of trials of low-glycemic index diets found that diets higher in complex carbohydrates and dietary iber reduced the risk of macrosomia and likelihood of insulin use in women with gestational diabetes (Wei, 20 1 6) . That said, there clearly are limitations to what can be accomplished with various dietary approaches alone. Most and Langer (20 1 2) found that insulin was efective in reducing the risk of excessive birthweight in ofspring of obese women with gestational diabetes. Casey and colleagues (20 1 5 b) also found that dietary treatment alone for morbidly obese women with mild gestational diabetes did not reduce neonatal fat mass or LGA birthweights. Exerc i se

Few trials have evaluated exercise speciically for women with gestational diabetes. he American College of Obstetricians and Gynecologists (20 1 7a,b) recommends regular physical activity that incorporates aerobic and strength-conditioning exercise during pregnancy and extends this to women with gestational diabetes. Two recent metaanalyses demonstrate that structured exercise programs during pregnancy diminish weight gain during pregnancy and even reduce the risk of developing gestational diabetes (Russo, 20 1 5; Sanabria-Martinez, 2 0 1 5). Exercise during pregnancy in woman with gestational diabetes also lowers glucose levels Qovanovic-Peterson, 1 989) . G l u cose M o n itori n g

Hawkins and colleagues (2008) compared outcomes in 3 1 5 women with diet-treated gestational diabetes who used personal glucose monitors with those of 6 1 5 gestational diabetics who were also diet-treated but who underwent intermittent fasting glucose evaluation during weekly obstetrical visits. Women using daily blood-glucose self monitoring had significantly fewer macrosomic newborns. They also gained less weight after diagnosis than women evaluated during clinic visits only. hese indings support the common practice of blood-glucose self monitors for women with diet-treated gestational diabetes. Postprandial surveillance for gestational diabetes has been shown to be superior to preprandial surveillance (DeVeciana, 1 995). At Parkland Hospital, we reviewed the impact of chang­ ing to postprandial monitoring in women with diet-treated gestational diabetes and demonstrated a signiicant reduction in maternal weight gain per week-0.63 lb/week to 0.45 lb/week­ in women managed with a postprandial monitoring schema. The merican College of Obstetricians and Gynecologists

(20 1 7a) and the ADA (20 1 7b) recommend glucose assessment four times daily. The first check is performed fasting, and the remainder are done 1 or 2 hours ater each meal. I n s u l i n Treatment

Historically, insulin has been considered standard therapy in women with gestational diabetes when target glucose levels can­ not be consistently achieved through nutrition and exercise. It does not cross the placenta, and tight glycemic control can typi­ cally be achieved. Insulin therapy is typically added if fasting levels persistently exceed 95 mg/ dL in women with gestational diabetes. The American College of Obstetricians and Gynecol­ ogists (20 1 7 a) also recommends that insulin be considered in women with I -hour postprandial levels that persistently exceed 1 40 mg/dL or those with 2-hour levels > 1 20 mg/dL. Impor­ tantly, all of these thresholds are extrapolated from recommen­ dations for managing women with overt diabetes. If insulin is initiated, the starting dose is typically 0.7 to 1 .0 units/kg/d and is given in divided doses (American College of Obstetricians and Gynecologists, 20 1 7a) . A combination of intermediate-acting and short-acting insulin may be used, and dose adjustments are based on glucose levels at particular times of the day. At Parkland Hospital, the starting daily dose is divided so that two thirds is given in the morning before break­ fast and one third in the evening before dinner. In the morn­ ing dose, one third is regular insulin and two thirds are NPH (neutral protamine Hagedorn) . For the evening dose, one half is regular insulin and the other half is NPH. Insulin instruc­ tion for these women is accomplished either in a specialized outpatient clinic or during a short hospital stay. As shown in Table 57-8, insulin analogues such as insulin aspart and insulin lispro have a more rapid onset of action than regular insulin and theoretically could be helpful in postprandial glucose man­ agement. Experience with these analogues with gestational dia­ betes is limited, and Singh and coworkers (2009) were unable to demonstrate a beneit compared with conventional insulins. Ora l Hypog lycem i c Agents

Insulin is the preferred first-line agent for persistent hypergly­ cemia in women with gestational diabetes. However, both the American College of Obstetricians and Gynecologists (20 1 7 a) and the ADA (20 1 7b) acknowledge that several studies support the safety and eicacy of either glyburide (Micronase) or met­ formin (Glucophage) (Langer, 2000; Nicholson, 2009; Rowan, 2008) . Balsells and colleagues (20 1 5) performed metaanalyses of trials comparing both agents to insulin or to each other. In the seven trials comparing glyburide with insulin, glyburide was associated with higher birthweight, more macrosomia, and more frequent neonatal hypoglycemia. In the six trials compar­ ing metformin with insulin, metformin was associated with less maternal weight gain, more ?reterm birth, and less severe neo­ natal hypoglycemia. On average from all trials, treatment fail­ ures occurred in 6 percent of women treated with glyburide and 34 percent of those treated with metformin. In the two studies comparing oral hypoglycemic agents with each other, metfor­ min treatment was associated with less maternal weight gain, lower birthweight, and less macrosomia. In contrast to trials of each agent compared with insulin, treatment failure rates of

Dia betes M e l l itus

both agents in these two studies were equivalent. Importantly, in a randomized trial of glyburide treatment as an adjunct to diet therapy in 395 women with mild gestational diabetes, Casey and coworkers (20 1 5a) did not identiy any signifi c ant improvements in pregnancy outcomes in women treated with glyburide. Concerns have emerged regarding potential adverse out­ comes among women treated with glyburide. First, like metfor­ min, glyburide crosses the placenta and reaches concentrations in the fetus that are more than two thirds of maternal lev­ els (Caritis, 20 1 3) . Additionally, a study of more than 9000 women with gestational diabetes treated with either insulin or glyburide showed a signiicant rise in rates of neonatal intensive care unit admission, respiratory distress, and neonatal hypogly­ cemia associated with glyburide use (Castillo, 20 1 5) . Metformin reaches fetal serum concentrations similar to maternal levels. However, in one study of 75 1 women with gestational diabetes who were randomly assigned to metformin or insulin treatment, short-term perinatal adverse events did not difer between groups (Rowan, 2008) . Outcomes included neonatal hypoglycemia, respiratory distress syndrome, photo­ therapy, birth trauma, 5-minute Apgar score .7, and preterm birth. Overall growth of ofspring at age 2 years also did not difer (Rowan, 20 1 1 ) . Nevertheless, the fat distribution in chil­ dren exposed to metformin showed a tendency toward a more favorable pattern. From a smaller randomized metformin trial, at 1 8 months, ofspring exposed to metformin were slightly heavier, but markers of early motor or language development did not difer compared with those in ofspring exposed to insulin (Ijas, 20 1 5) . The Food and Drug Administration has not approved gly­ buride and metformin use for treatment of gestational diabetes. However, the American College of Obstetricians and Gyne­ cologists (20 1 7 a) recognizes both as reasonable choices for second-line glycemic control in women with gestational dia­ betes. Because long-term outcomes have not been fully stud­ ied, the committee recommends appropriate counseling, which includes disclosing the limitations in current safety data. • Obstetrical Management

In general, for women with gestational diabetes who do not require insulin, early delivery or other interventions are seldom required. here is no consensus regarding the value or timing of antepartum fetal testing. It is typically reserved for women with pregestational diabetes because of the greater stillbirth risk. The American College of Obstetricians and Gynecologists (20 1 7a) endorses fetal surveillance in women with gestational diabetes and poor glycemic control. At Parkland Hospital, women with gestational diabetes are routinely instructed to perform daily fetal kick counts in the third trimester (Chap. 1 7, p. 332) . Insulin-treated women are ofered inpatient admission after 34 weeks' gestation, and antepartum monitoring is performed three times each week. Women with gestational diabetes and adequate glycemic control are managed expectantly. Elective labor induction to prevent shoulder dystocia compared with spontaneous labor remains controversial. Alberico and colleagues (20 1 7) recently

described their truncated randomized trial of 425 women with gestational diabetes that compared labor induction between 38 and 39 weeks' and expectant management until 4 1 weeks' ges­ tation. Although underpowered, this G INEXMAL Trial dem­ onstrated no clinically meaningful diference in the cesarean delivery rate between the induction and expectant management groups-1 2.6 versus 1 1 .8 percent. However, with early labor induction, neonatal hyperbilirubinemia rates were signiicantly higher, and ironically, there was a nonsigniicant threefold greater shoulder dystocia rate. In a retrospective cohort study of 8392 Canadian women with gestational diabetes, Melamed and coworkers (20 1 6) found that routine delivery at 38 or 39 weeks was associated with a lower rate of cesarean delivery but with an elevated rate of neonatal intensive care unit admis­ sion. The American College of Obstetricians and Gynecologists (20 1 7a) recommends that routine labor induction in women with diet-treated gestational diabetes should not occur before 39 weeks' gestation. At Parkland Hospital, women with diet­ treated gestational diabetes are not electively induced for this indication. However, those treated with insulin are delivered at 38 weeks' gestation. Elective cesarean delivery to avoid brachial plexus i nj uries in overgrown fetuses is another important issue. The American College of Obstetricians and Gynecologists (20 1 7a) has con­ cluded that data are insuicient to determine whether cesar­ ean delivery in women with gestational diabetes whose fetuses have a sonographically estimated weight �4500 g should be performed to avoid risk of birth trauma. From their system­ atic review, Garabedian and coworkers (20 1 0) estimated that as many as 588 cesarean deliveries in women with gestational diabetes and an estimated fetal weight of �4500 g would be necessary to avoid one case of permanent brachial plexus palsy. Scifres and colleagues (20 1 5) , in their retrospective analysis of 903 women with gestational diabetes who underwent so no­ graphic evaluation within 1 month of delivery, demonstrated that sonographic estimates of fetal weight typically overdiag­ nosed fetuses as being LGA. Only 22 percent of women esti­ mated to have an LGA fetus actually delivered an overgrown newborn. Still, the American College of Obstetricians and Gynecologists (20 1 6a) acknowledges that prophylactic cesarean delivery may be considered in diabetic women with an esti­ mated fetal weight �4500 g. • Postpartum Evaluation

Recommendations for postpartum evaluation are based on the 50-percent likelihood of women with gestational diabetes developing overt diabetes within 20 years (O'Sullivan, 1 982) . The Fifth International Workshop Conference on Gestational Diabetes recommended that women diagnosed with gesta­ tional diabetes undergo postpartum evaluation with a 75-g OGTT (Metzger, 2007) . These recommendations are shown in Table 5 7- 1 4 along with the classification scheme of the ADA (20 1 7b) . Eggleston and colleagues (20 1 6) reviewed insurance claim data from 2000 to 20 1 3 and found that only 24 percent of women with a pregnancy complicated by gestational diabetes underwent postpartum screening within a year, and less than half of those underwent a 75-g OGTT. he American College

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Med ica l a n d S u rg ical Co m p l ications

TABLE 57-1 4. F ifth I nternational Works h o p-Conference: Meta bolic Assessments Recom mended after P reg na ncy with Gestational Dia betes Time Postd e l ive ry ( 1 - 3 d) Early postpart u m (6- 1 2 wk) 1 -yr postpa rt u m A n n u a l ly Tria n n u a l l y P repreg n a n cy

Test

Purpose

Fa sti ng or ra n d o m plasma g l u cose 75-g, 2-h r OGI 75-g, 2 - h r OGTI Fa sti ng p l a s m a g l ucose 75-g, 2-h r OGTI 75-g, 2-h r OGTI

Detect pers i ste nt, overt d i a betes Postpa rtu m classification of g l u cose m eta bo l i s m Assess g l u cose meta bol i s m Assess g l u cose meta bol i s m Assess g l u cose meta bol i s m ClaSSify g l ucose meta bol i s m

Classification of the American Diabetes Association (20 1 3)

Fasti ng < 1 00 m g/d L 2 h r < 1 40 m g/d L H e m og l o b i n A 1 c < 5 .7%

1 00- 1 25 m g/d L 2 h r � 1 40- 1 99 mg/d L 5 .7-6.4%

� 1 26 mg/d L 2 hr � 200 mg/d L �6.5%

OGTI ora l g l u cose tolera n ce test. Data from A merican Dia betes Association, 20 1 3, 20 1 7a; Metzge r, 2007. =

of Obstetricians and Gynecologists (20 1 7a) recommends either a fasting glucose or the 75-g, 2-hour OGTT at 4 to 1 2 weeks postpartum for the diagnosis of overt diabetes. he ADA (20 1 7a) recommends testing at least every 3 years in women with a history of gestational diabetes but normal postpartum glucose screening. Women with a history of gestational diabetes are also at risk for cardiovascular complications associated with dyslipid­ emia, hypertension, and abdominal obesity-the metabolic syn­ drome (Chap. 48, p. 937) . In a study of 47,909 parous women, Kessous and coworkers (20 1 3) evaluated subsequent hospitaliza­ tions due to cardiovascular morbidity. hey found that almost 5000 women with gestational diabetes were 2.6 times more likely to be hospitalized for cardiovascular morbidity. Another study evaluated 483 women between 5 and 1 0 years ater being diagnosed with mild gestational diabetes (Varner, 20 1 7) . Inves­ tigators found no increased risk for developing metabolic syn­ drome associated with additional pregnancies. However, risk for subsequent diabetes rose almost fourfold if gestational diabetes complicated at least one subsequent pregnancy. • Recurrent Gestational Diabetes

In a metaanalysis of published reports from 1 973 through 20 1 4, the pooled gestational diabetes recurrence rate was 48 percent (Schwartz, 20 1 5) . Rates in primiparas were lower (40 percent) than in multiparas (73 percent) . The same group of investigators identified maternal BMI, insulin use, fetal mac­ rosomia, and weight gain between pregnancies as additional risk factors for gestational diabetes recurrence (Schwartz, 20 1 6) . Thus, lifestyle behavioral changes that include weight control and exercise between pregnancies would seem likely to prevent gestational diabetes recurrence. Gueli and colleagues (20 1 6) were unable to demonstrate a lower recurrence rate in women randomized to an exercise program that started before 1 4 weeks' gestation in a subsequent pregnancy. Conversely, Ehrlich and colleagues (20 1 1 ) found that prepregnancy loss of

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Donovan L, Hartling L, Muise M, et al: Screening tests for gestational diabetes: a systematic review for the U.S. Preventive Services Task Force. An n Intern Med 1 5 9 (2) : 1 1 5 , 20 1 3 Durnwald C , Huston-Presley L , Amini S , et al: Evaluation o f body composi­ tion of large-for-gestational-age infants of women with gestational diabetes mellitus compared with women with normal glucose levels. Am ] Obstet Gynecol 1 9 1 : 804, 2004 Ecker ]L, Greene MF: Gestational diabetes-setting limits, explorin g treat­ ment. N Engl ] Med 3 5 8 ( 1 9) :206 1 , 2008 Egan vl, Dennedy MC, Al-Ramli W: ATLANTIC-DIP: excessive gestational weight gain and pregnancy outcomes i n women with gestational or pregesta­ tional diabetes mellitus. ] Clin Endocrinol Metab 99( 1 ) :2 1 2, 20 1 4 Eggleston E M , LeCates RF, Zhang F, e t al: Variation i n postpartum glycemic screening in women with a history of gestational diabetes mellitus. 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Medical a n d S u rg ica l Com p l i cations Hammoud NM, Visser GH, Peterst SA, e t al: Fetal growth profiles of macro­ somic and non-macrosomic infants of women with pregestational or gesta­ tional diabetes. Ultrasound Obstet GynecoI 4 1 (4) :390, 20 1 3 Hanson U , Persson B : Outcome o f pregnancies complicated b y type 1 insulin­ dependent diabetes in Sweden: acute pregnancy complications, neonatal mortality and morbidity. Am J Perinatol 1 0 :330, 1 993 HAPO Study Cooperative Research Group: Hyperglycemia and adverse preg­ nancy outcomes. N Engl J Med 35 8:206 1 , 2008 Harper LM, Mele L, Landon MB, et al: Carpenter-Coustan compared with National Diabetes Data Group criteria for diagnosing gestational diabetes. Obstet Gynecol 1 27(5): 893, 20 1 6 Harris D L, Weston PJ, Harding JE: I ncidence o f neonatal hypoglycemia i n babies identified a s at risk. J Pediatr 1 6 1 ( 5 ) : 787, 20 1 2 Hartling L , Dryden DM, Guthrie A , et al: Benefits and harms o f treating ges­ tational diabetes mellitus: a systematic review and meta-analysis for the U.S. Preventive Services Task Force and the National I nstitutes of Health Oice of Medical Applications of Research. Ann I ntern Med 1 59(2) : 1 23, 20 1 3 Hawkins JS, Lo JY, Casey BM, e t al: Diet-treated gestational diabetes: compari­ son of early versus routine diagnosis. m J Obstet Gynecol, 1 98:287, 2008 Hawthorne G : Maternal complications in diabetic pregnancy. Best Pract Res Clin Obstet Gynaecol 25 ( 1 ) :77, 20 1 1 Hay W: Care of the infant of the diabetic mother. Curr Diab Rep 1 2 :4, 20 1 2 Hay W, Raju TN, Higgins RD, et al: Knowledge gaps and research needs for understanding and treating neonatal hypoglycemia: workshop report from Eunice Kennedy Shriver National Institute of Child Health and Human Development. J Pediatrics 1 5 5 ( 5 ) :6 1 2, 2009 H il l JB, Sheield JS, McIntire DD, et al: Acute pyelonephritis in pregnancy. Am J Obstet Gynecol 1 0 5 ( l ) : 1 8 , 2005 How HY, Sibai B , Lindheimer M, et al: Is early-pregnancy proteinuria associ­ ated with an i ncreased rate of preeclampsia in women with pregestational diabetes mellitus? Am J Obstet GynecoI 1 90:775, 2004 H uang H, He J, Johnson D, et al: Deletion of placental growth factor pre­ vents diabetic retinopathy and is associated with Akt activation and H I F 1 a­ VEG F pathway inhibition. Diabetes 64(3) : 1 067, 20 1 5 Huang T, Kelly A, Becker SA, et al: Hypertrophic cardiomyopathy in neo­ nates with congenital hyperinsulinism. rch Dis Child Fetal Neonatal Ed 98(4) :F35 1 , 20 1 3 Idris N , Wong SF, homae M , et al: Inluence o f polyhydramnios o n perinatal outcome in pregestational diabetic pregnancies. Ultrasound Obstet Gynecol 36(3 ) :338, 20 1 0 Ijas H , Vaarasmaki M , Saarela T , e t al: A follow-up o f a randomised study of metformi n and insulin in gestational diabetes mellitus: growth and develop­ ment of the children at the age of 1 8 months. BJOG 1 22( ) :994, 20 1 5 I n ternational Association of Diabetes and Pregnancy Study Groups Consensus Panel: Recommendations on the diagnosis and classiication of hyperglyce­ mia in pregnancy. Diabetes Care 33(3) , 20 1 0 Jensen DM, Damm P , Ovesen P , et al: Microalbuminuria, preeclampsia, and preterm delivery in pregnant women with type 1 diabetes. Diabetes Care 33:90, 20 1 0 Johnston RC, Gabby L , Tith T, et al: Immediate postpartum glycemic control and risk of surgical site infection. J Matern Fetal Neonatal Med 30(3):267, 20 1 7 Jovanovic L , Liang Y, Weng W , e t al: Trends i n the incidence o f diabetes, its clinical sequelae, and associated costs in pregnancy. Diabetes Metab Res Rev 3 1 (7):707, 20 1 5 Jovanovic-Peterson L, Durak EP, Peterson CM : Randomized trial of diet ver­ sus diet plus cardiovascular conditioning on glucose levels in gestational dia­ betes. Am J Obstet GynecoI 1 6 1 :4 1 5 , 1 989 Kessous R, Shoham-Vardi I , Pariente G, et al: An association between gesta­ tional diabetes mellitus and long-term maternal cardiovascular morbidity. Heart 99: 1 1 1 8 , 20 1 3 Kim C , Ferrara A , McEwen LN, e t al: Preconception care i n managed care: the translating research into action for diabetes study. Am J Obstet Gynecol 1 92 : 227, 2005 Kim SY, Sharma AJ, Sappenield W, et al: Association of maternal body mass index, excessive weight gain, and gestational diabetes mellitus with large-for­ gestational-age births. Obstet GynecoI 1 23 (4) :737, 20 1 4 Kitzmiller J L, Block J M , Brown F M , e t al: Managing preexisting diabetes for pregnancy. Diabetes Care 3 1 (5) : 1 060, 2008 Krakowiak P, Walker CK, Bremer A, et l: Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. Pediatrics 1 29 : e l 1 2 1 , 20 1 2 Landon M B , Catalano PM, Gabbe SG: Diabetes mellitus. I n Gabbe SG, Niebyl J R, Simpson JL (eds): Obstetrics: Normal and Problem Pregnancies, 4th ed. Philadelphia, Churchill Livingstone, 2002 Landon M B , Mele L, Spong CY, et al: The relationship between maternal gly­ cemia and perinatal outcome. Obstet Gynecol 1 1 7 (2) :2 1 8, 20 1 1

Landon M B , Spong CY, Thon E, et al: A multicenter, randomized treatment trial of mild gestational diabetes. N Engl J Med 36 1 ( 1 4) : 1 339, 2009 Langer 0, Conway DL, Berkus MD, et al: A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 343: 1 1 34, 2000 Lauenborg J , Mathiesen E, Ovesen P, et al: Audit on stillbirths in women with pregestational type 1 diabetes. Diabetes Care 26(5): 1 38 5 , 2003 Leinonen PJ, Hiilesmaa VK, Kaaja RJ: Maternal mortality i n type 1 diabetes. Diabetes Care 24(8) : 1 50 1 , 200 1 Little SE, Zara CA, Clapp vIA, et al: A multi-state analysis of early-term delivery trends and the association with term stillbirth. Obstet Gynecol 1 26(6) : 1 1 38, 20 1 5 Liu S , Joseph KS , Lisonkova S , et al: Association between maternal chronic conditions and congenital heart defects: a population-based cohort study. Circulation 1 28 (6) : 5 83, 20 1 3 Loukovaara M , Leinonen P , Teramo K , e t al: Diabetic pregnancy associated with increased epidermal growth factor in cord serum at term. Obstet Gyne­ col 1 03 :240, 2004 Luo Zc, Nuyt AM, Delvin E, et al: Maternal and fetal IGF- 1 and IGF- 1 1 levels, fetal growth, and gestational diabetes. J Clin Endocrinol Metab 9 : 1 720, 20 1 2 Marschalek J , Farr A , Kiss H , e t al: Risk o f vaginal infections a t early gestation in patients with diabetic conditions during pregnancy: a retrospective cohort study. PLoS O ne 1 1 (5):e0 1 5 5 1 82, 20 1 6 Martin JA, Hamilton BE, Osterman MJ, e t al: Births: final data for 20 1 5 . Natl Vital Stat Rep 66 ( 1 ) : 1 , 20 1 7 Mathiesen ER, Ringholm L , Feldt-Rasmussen B , e t al: Obstetric nephrology: pregnancy in women with diabetic nephropathy-the role of antihyperten­ sive treatment. Clin J Am Soc Nephrol : 208 1 , 20 1 2 Mazaki-Tovi S , Kanety H , Pariente C, et al: Cord blood adiponectin i n large­ for-gestational age newborns. Am J Obstet Gynecol 1 93: 1 238, 2005 McCance D R, Holmes VA, Maresh MJ, et al: Vitamins C and E for preven­ tion of preeclampsia in women with type 1 diabetes (DAPIT): a randomised placebo-controlled trial. Lancet 3 6:259, 20 1 0 McElvy SS, Demarini S , Miodovnik M , e t al: Fetal weight and progression of diabetic retinopathy. Obstet Gynecol 97: 5 87, 200 1 v IcFariand MB, Langer 0, Fazioni E, et al : Anthropometric and body com­ position diferences in large-for-gestational age, but not appropriate-for­ gestational age infants of mothers with and without diabetes mellitus. J Soc Gynecol Investig 7:23 1 , 2000 Melamed N , Ray JG, Geary M, et al: Induction of labor before 40 weeks is associated with lower rate of cesarean delivery in women with gestational diabetes mellitus. m J Obstet GynecoI 2 1 4(3) :364.e 1 , 20 1 6 Metzger BE, Buchanan TA, Coustan DR, e t al: Summary and recommenda­ tions of the Fith International Workshop-Conference on Gestational Dia­ betes. Diabetes Care 30(SuppI 2) :S25 1 , 2007 Miailhe G , Le Ray C, Timsit J, et al: Factors associated with urgent cesarean delivery in women with type 1 diabetes mellitus. Obstet Gynecol 1 2 1 :983, 20 1 3 Middleton P , Crowther CA, Simmonds L : D iferent intensities of glycaemic control for pregnant women with pre-existing diabetes. Cochrane Database Syst Rev 5 :CD008 540, 20 1 6 Mission J F , Marshall NE, Caughey AB: Obesiry i n pregnancy: a big problem and getting bigger. Obstet Gynecol Sur 88(5) :389, 20 1 3 Mitanchez D , Burguet A , Simeoni U : Infants born to mothers with gestational diabetes mellitus: mild neonatal efects, a long-term threat to global health. J Pediatr 1 64(3) :445 , 20 1 4 Moreno-Castilla C, Hernandez M, Bergua M , e t a l : Low-carbohydrate diet for the treatment of gestational diabetes mellitus. Diabetes Care 36:2233, 20 1 3 Most 0 , Langer 0 : Gestational diabetes: maternal weight gain i n relation to fetal growth, treatment modality, BMI and glycemic control. J Matern Fetal Med 2 5 ( 1 1 ) :24 58, 20 1 2 National Institutes o f Health: N I H Consensus Development Conference on Diagnosing Gestational Diabetes Mellitus. 20 1 3 . Available at: https:llcon­ sensus. nih.gov/20 1 3/gdm.htm. Accessed November 1 1 , 2 0 1 7 Nicholson W, Bolen S , Witkop CT, e t a l : Beneits and risks of oral diabetes agents compared with insulin in women with gestational diabetes. Obstet Gynecol 1 1 3( 1 ) : 1 93, 2009 O'Sullivan J B : Body weight and subsequent diabetes mellitus. JAMA 248 :949, 1 982 Owen CG, Martin RM, Whincup PH, et al: Does breastfeeding inluence risk of type 2 diabetes in later life? A quantitative analysis of published evidence. Am J Clin N utr 84: 1 043, 2006 Patel EM, Goodnight H, James AH, et al: Temporal trends in maternal medical conditions and stillbirth. Am J Obstet Gynecol 2 1 2(5) :673.e 1 , 20 1 5 Pedersen J : he Pregnant Diabetic and Her Newborn, 2nd ed. Baltimore, Williams & Wilkins, 1 977

Dia betes M e l l itus Pedersen ], M0lsted-Pedersen L, Andersen B: Assessors of fetal perinatal mor­ tality in diabetic pregnancy. Analysis of 1 332 pregnancies in the Copenha­ gen series, 1 946- 1 972. Diabetes 23:302, 1 974 Persson M, Norman M, Hanson U: Obstetric and perinatal outcomes in type I diabetic pregnancies. Diabetes Care 32:2005, 2009 Peterson C, Grosse SO, Li R, et a1: Preventable health and cost burden of adverse birth outcomes associated with pregestational diabetes in the United State. Am ] Obstet Gynecol 2 1 2 ( 1 ) :74.e 1 , 201 5 Pociot F, Lernmark A: Genetic risk factors for type 1 diabetes. Lancet 387(1 0035):233 1 , 20 1 6 Powers AC: Diabetes mellitus. I n : Longo DL, Fauci AS , Kaspar DL, e t a l (eds): Harrison's Principles of Internal Medicine, 1 8th ed. McGraw-H ili, New York, 20 1 2 Rasmussen L , Laugesen CS, Ringholm L , e t al: Progression o f diabetic reti­ nopathy during pregnancy in women with type 2 diabetes. Diabetologia 53: 1 076, 20 1 0 Reece A : Diabetes-induced birth defects: what do w e know? What can w e do? CUff Diab Rep 1 2:24, 20 1 2 Renault KM , Carlsen EM, N0gaard K , e t al: Intake o f carbohydrates during pregnancy in obese women is associated with fat mass in the newborn of­ spring. Am ] Clin Nutr 1 02(6) : 1 47 5 , 20 1 5 Reutens AT: Epidemiology of diabetic kidney disease. Med Clin North Am 97: 1 , 20 1 3 Rewers M, Ludvigsson ] : Environmental risk factors for type 1 diabetes. Lancet 387( 1 003 5) :2340 , 20 1 6 Ringholm L , Vestgaard M , Laugesen CS, e t al: Pregnancy-induced increase in circulating IGF-1 is associated with progression of diabetic retinopathy in women with type 1 diabetes. Growth Horm IGF Res 2 1 :25, 20 1 1 Roeder A, Moore TR, Ramos GA: Insulin pump dosing across gestation in women with well-controlled type 1 diabetes mellitus. Am ] Obstet Gynecol 207:324.e 1 , 20 1 2 Rolo LC, Nardozza LMM, J unior EA, e t al: Reference curve of the fetal ven­ tricular septum area by the STIC method: preliminary study. Arq Bras Car­ diol 96(5) :386, 2 0 1 1 Rosenn B, Miodovnik M, Combs CA, et al: Glycemic thresholds for spontane­ ous abortion and congenital malformations in insulin-dependent diabetes mellitus. Obstet Gynecol 84: 5 1 5 , 1 994 Rowan ]A, Hague WM, Wanzhen G , et al: Metformin versus insulin for the treatment of gestational diabetes. N Engl ] Med 358 :2003, 2008 Rowan ]A, Rush EC, Obolonkin V, et al: Metformin in gestational diabetes: the ofspring follow-up (MiG TOFU) : body composition at 2 years of age. Diabetes Care 34 ( 1 0) :2279, 20 1 1 Russell NE, Foley M, Kinsley BT, et al: Efect of pregestational diabetes mel­ litus on fetal cardiac function and structure. Am ] Obstet Gynecol 1 99:3 1 2 . e 1 , 2008 Russo LM, Nobles e, Ertel A, et al: Physical activity interventions in preg­ nancy and risk of gestational diabetes mellitus: a systematic review and meta­ analysis. Obstet Gynecol 1 2 5 (3) : 5 76, 20 1 5 Salvesen DR, Brudenell M], Nicolaides KH: Fetal polycythemia and thrombo­ cytopenia in pregnancies complicated by maternal diabetes mellitus. Am ] Obstet Gynecol 1 66: 1 287, 1 992 Salvesen DR, Brudenell M] , Snijders ]M, et al: Fetal plasma erythropoietin in pregnancies complicated by maternal diabetes mellitus. Am ] Obstet Gyne­ col 1 68:88, 1 993 Sanabria-Martinez G, Garda-Hermoso A, Poyatos-Le6n R, et al: Efectiveness of physical activity interventions on preventing gestational diabetes mellitus and excessive maternal weight gain: a meta-analysis. B]OG 1 22(9) : 1 1 67, 20 1 5 Saudek CD: Progress and prom ise of diabetes research. ]AMA 287:2582, 2002 Schwartz N, Nachum Z, Green MS: Risk factors of gestational diabetes mel­ litus recurrence: a meta-analysis. Endocrine 53(3) :662, 20 1 6

Schwartz N, Nachum Z, Green M S : The prevalence of gestational diabetes mellitus recurrence-efect of ethnicity and parity: a metaanalysis. Am ] Obstet GynecoI 2 1 3 (3) :3 1 O, 20 1 5 Scifres CM, Feghali M, Dumont T, et al: Large-for-gestational-age ultrasound diagnosis and risk for cesarean delivery in women with gestational diabetes mellitus. Obstet Gynecol 1 26(5 ) : 978, 20 1 5 Sheield ]S, Buder-Koster EL, Casey BM, et al: Maternal diabetes mellitus and infant malformations. Obstet Gynecol 1 00:925, 2002 Sheiner E, Mazor-Drey E, Levy A: Asymptomatic bacteriuria during preg­ nancy. ] Matern Fetal Neonatal Med 22(5) :423, 2009 Sibai BM, Caritis S, Hauth ], et al: Risks of preeclampsia and adverse neonatal outcomes among women with pregestational diabetes mellitus. Am ] Obstet Gynecol 1 82:364, 2000 Sibai BM, Viteri OA: Diabetic ketoacidosis in pregnancy. Obstet Gynecol 1 23 ( 1 ) : 1 67, 20 1 4 Singh S R, Ahmad F, Lai A , e t al: Eicacy and safety o f insulin analogues for the management of diabetes mellitus: a meta-analysis. CMA] 1 80(4) :3 8 5 , 2009 Stewart ZA, Wilinska ME, Hartnell S , et al: Closed-loop insulin delivery preg­ nancy in women with type 1 diabetes. N Engl ] Med 375 (7):644, 2 0 1 6 Stuebe AM, Landon MB, Lai Y , e t al: Maternal BMI, glucose tolerance, and adverse pregnancy outcomes. Am ] Obstet Gynecol 207:62.e. 1 , 20 1 2 Suresh A, Liu A, Poulton A, et a1: Comparison o f maternal abdominal s u bcuta­ neous fat thickness and body mass index as markers for pregnancy outcomes: a stratiied cohort study. Aust N Z ] Obstet Gynecol 52:420, 20 1 2 U.S. Preventive Services Task Force: Gestational diabetes mellitus, screening. 20 1 4. Available at: https:llwww.uspreventiveservicestaskforce.org/Page/ Documen t/U pdateS ummaryF inall gestational-diabetes-melli tus-screeni ng. Accessed November 1 1 , 20 1 7 Van Leeuwen M , Louwerse MD, Opmeer Be, et al: Glucose challenge test for detecting gestational diabetes mellitus: a systematic review. B]OG 1 1 9 (4):393, 20 1 2 Varner MW, Rice M M , Landon M B , e t al: Pregnancies after the diagnosis of mild gestational diabetes mellitus and risk of cardiometabolic disorders. Obstet GynecoI 1 29 (2):273, 20 1 7 Vestgaard M , Ringholm L, Laugesen CS, e t al: Pregnancy-induced sight­ threatening diabetic retinopathy in women with type 1 diabetes. Diabet Med 27:43 1 , 20 1 0 Vidaef AC, Yeomans ER, Ramin SM: Pregnancy i n women with renal disease. Part I I : speciic underlying renal conditions. Am ] Perinatol 2 5 :399 , 2008 Vink ]Y, Poggi SH, Ghidini A: Amniotic fluid index and birth weight: is there a relationship in diabetics with poor glycemic control? Am ] Obstet Gynecol 1 9 5 : 848, 2006 Wang PH, Lau ], Chalmers TC: Meta-analysis of efects of intensive blood-glucose control on late complications of type 1 diabetes. Lancet 34 1 : 1 306, 1 993 Wei ], Heng W, Gao ]: Efects of low glycemic index diets on gestational diabetes mellitus: a meta-analysis of randomized controlled clinical trials. Medicine (Baltimore) 9 5 (22):e3792, 2 0 1 6 White P: Classiication of obstetric diabetes. Am ] Obstet Gynecol 1 30:228, 19 8 World Health Organization: Diagnostic criteria and classification of hypergly­ cemia irst detected in pregnancy. Geneva, WHO, 20 1 3 Yang ] , Cummings EA, O'Connell C , e t al: Fetal and neonatal outcomes of diabetic pregnancies. Obstet Gynecol 1 08:644, 2006 Yang P, Reece EA, Wang F, et al: Decoding the oxidative stress hypothesis in diabetic embryopathy through proapoprotic kinase signaling. Am ] Obstet Gynecol 2 1 2(5): 569, 20 1 5 Yanit KE, Snowden ]M, Cheng W, e t al: he impact o f chronic hypertension and pregestational diabetes on pregnancy outcomes. Am ] Obstet Gynecol 207:333, 20 1 2 Young EC, Pires M, Marques L , e t al: Efects of pregnancy o n the onset and progression of diabetic nephropathy and of diabetic nephropathy on preg­ nancy outcomes. Diabetes Metab Syndr 5: 1 3 7, 20 1 2

1117

1 1 18

C H A PT E R 5 8

En d ocrine D i sorders

THYROI D PHYSIOLOGY AND PREGNANCY . . . . . . . . . 1 1 1 8 HYPERTHYROIDISM . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 20 HYPOTHYROI DISM . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 23 S U BCLIN ICAL HYPOTHYROIDISM. . . . . . . . . . . . . . . . . 1 1 24 IODI N E DEFICIENCY . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 26 CONGEN ITAL HYPOTHYROIDISM . . . . . . . . . . . . . . . . . 1 1 27 POSTPARTUM THYROI DITIS . . . . . . . . . . . . . . . . . . . . . 1 1 27 NODULA R THYROID DISEASE . . . . . . . . . . . . . . . . . . .

.

1 1 28

PARATHYROID DISEASE . . . . . . . . . . . . . . . . . . . . . . . . 1 1 28 ADRENAL GLA N D DISORDERS . . . . . . . . . . . . . . . . . . . 1 1 30 PITU ITARY DISORDERS . . . . . . . . . . . . . . . . .

.

. . . . . . . 1 1 32

In a smal number ofcases the thyroid gland increases mark­ edy in size, though we are ignorant as to its signicance. -J. Whitridge Williams ( 1 903) In 1 903, little was known of many endocrine disorders. Still, endocrinopathies seem particularly closely related to pregnancy because of its gestational proclivity for prodigious hormone secretion. This is best illustrated by placental lactogen in dia­ betes, the most common endocrinopathy encountered in preg­ nancy (Chap. 57, p. 1 097) . Pregnancy is also interrelated with some endocrinopathies that are at least partially due to autoim­ mune dysregulation. Clinical manifestations of this result from

complex interplay among genetic, environmental, and endog­ enous factors that activate the immune system against targeted cells within endocrine organs. An extraordinary example of these interactions comes from studies that implicate maternal organ engraftment by fetal cells that were transferred during pregnancy. These cells later provoke antibody production, tissue destruction, and autoimmune endocrinopathies. THYRO I D DISORDERS Taken in aggregate, disorders of the thyroid gland are com­ mon in young women and thus frequently encountered in pregnancy. Maternal and fetal thyroid function are intimately related, and drugs that afect the maternal thyroid also afect the fetal gland. Moreover, thyroid autoantibodies have been associated with increased rates of early pregnancy wastage. Also, uncontrolled thyrotoxicosis and untreated hypothyroidism are both associated with adverse pregnancy outcomes. Finally, evi­ dence suggests that the severity of some autoimmune thyroid disorders may be ameliorated during pregnancy, only to be exacerbated postpartum . • Thyroid Physiology and Pregnancy

Maternal thyroid changes are substantial, and normally altered gland structure and function are sometimes confused with thy­ roid abnormalities. These alterations are discussed in detail in Chapter 4 (p. 69), and normal serum hormone level values are found in the Appendix (p. 1 258) . First, maternal serum concentrations of thyroid binding globulin are increased concomitantly with total or bound thyroid hormone levels (Fig. 4- 1 6, p. 70) . Second, thyrotropin, also called thyroid­ stimulating hormone (TSH) , currently plays a central role in screening and diagnosis of many thyroid disorders. Notably, TSH receptors are cross stimulated, albeit weakly, by massive quantities of human chorionic gonadotropin (hCG) secreted

Endocr i n e Disorders

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O ---L 0.0 10 20 40 30 o Gestational age (weeks) FIGURE 58- 1 Gestationa l age specific va l ues for serum thyroid sti m u lating hormone (TSH) leve l s (black lines) and free thyroxi n e (T4) levels (blue lines). Data were derived from 1 7,298 women tested d u ri n g preg n a n cy. For each color, the d a rk solid l i nes represent the 50th percenti le, whereas the u pper a n d lower l ight l i nes represent the 2 5th and 975th percenti les, respectively. (Data from Ca sey, 2005; Dashe, 2005.)

by placental trophoblast. Because TSH does not cross the pla­ centa, it has no direct fetal efects. During the irst 1 2 weeks of gestation, when maternal hCG serum levels are maximal, thyroid hormone secretion is stimulated. he resulting greater serum free thyroxine (T4) levels act to suppress hypothalamic thyrotropin-releasing hormone (TRH) and in turn limit pituitary TSH secretion (Fig. 5 8- 1 ) . Accordingly, TRH is undetectable in maternal serum. Conversely, in fetal serum, beginning at midpregnancy, TRH becomes detectable, but levels are static and do not increase. hroughout pregnancy, maternal thyroxine is transferred to the fetus (American College of Obstetricians and Gynecolo­ gists, 20 1 7) . Maternal thyroxine is important for normal fetal brain development, especially before the onset of fetal thyroid gland function (Bernal, 2007; Korevaar, 20 1 6) . And, even though the fetal gland begins concentrating iodine and syn­ thesizing thyroid hormone after 12 weeks' gestation, maternal thyroxine contribution remains important. In fact, maternal sources account for 30 percent of thyroxine in fetal serum at term (horpe-Beeston, 1 99 1 ) . Still, developmental risks associ­ ated with maternal hypothyroidism after midpregnancy remain poorly understood (Morreale de Escobar, 2004; Sarkhail, 20 1 6) . • Autoimmunity a n d Thyroid Disease

w 0 0

Most thyroid disorders are inextricably linked to autoantibod­ ies against nearly 200 thyrocyte components. These antibodies variably stimulate thyroid function, block function, or cause thyroid inlammation that may lead to follicular cell destruc­ tion. Often, these efects overlap or even coexist. Thyroid-stimulating autoantibodies, also called thyroid­ stimulating immunoglobulins (TSls), bind to the TSH recep­ tor and activate it, causing thyroid hyperfunction and growth. Although these antibodies are identiied in most patients with classic Graves disease, simultaneous production of thyroid­ stimulating blocking antibodies may blunt this efect Qameson,

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FIGURE 58-2 I ncidence in percent of a ntithyroid peroxidase a nti­ bod ies i n 1 6,407 women who a re norm a l or euthyroid, i n 233 with isolated maternal hypothyrox i n e m i a (1M H), i n 598 with s u bcl i n ical hypothyroidism (SCH), a nd i n 1 34 with overt hypothyroidism. (Data from Casey, 2007).

20 1 5) . Thyroidperoxidase (TPO) is a thyroid gland enzyme that normally functions in the production of thyroid hormones. Thyroid peroxidase antibodies, previously called thyroid micro­ somal autoantibodies, are directed against TPO and, as shown in Figure 5 8-2, have been identiied in 5 to 1 5 percent of all pregnant women (Abbassi-Ghanavati, 20 1 0; Sarkhail, 20 1 6) . These antibodies have been associated i n some studies with early pregnancy loss and preterm birth (Negro, 2006; Korev­ aar, 20 1 3; Plowden, 20 1 7; Thangaratinam, 20 1 l ) . In another study with more than 1 000 TPO antibody-positive pregnant women, the risk for preterm birth was not elevated, however, the risk for placental abruption was greater (Abbassi-Ghana­ vati, 20 1 0) . These women are also at high risk for postpartum thyroid dysfunction and at lifelong risk for permanent thyroid failure (Andersen, 20 1 6; Jameson, 20 1 5) . Feta l M i croc h i m e r i s m

Autoimmune thyroid disease is much more common in women than in men. One intriguing explanation for this disparity is fetal-to-maternal cell traicking (Greer, 20 1 l ) . Fetal cells are known to enter maternal circulation during pregnancy. When fetal lymphocytes enter maternal circulation, they can live for more than 20 years. Stem cell interchange can lead to engraft­ ment in several maternal tissues and is termed etal microchi­ merism. In some cases, this may involve the thyroid gland (Bianchi, 2003; Boddy, 20 1 5 ; Khosrotehrani, 2004) . A high prevalence of Y-chromosome-positive cells has been identiied using luorescence in situ hybridization (FISH) in the thyroid glands of women with Hashimoto thyroiditis-60 percent, or with Graves disease-40 percent (Renne, 2004) . In another study of women giving birth to a male fetus, Lepez and col­ leagues (20 1 l ) identiied signiicantly more circulating male mononuclear cells in those with Hashimoto thyroiditis. I roni­ cally, such microchimerism may have a protective role for auto­ immune thyroid disorders (Cirello, 20 1 5) .

1 1 19

1 1 20

Med i ca l a n d S u rg ica l Co m p l ications

TABLE 58-1 . I nci dence of Overt Hyperthyro i d i s m i n Preg n a n cy Study

Cou ntry

Wa n g (20 1 1 )a Va i dya (2007)a Laza r u s (2007) b Casey (2006r Andersen (20 1 6r,d

C h i na U n ited K i n g d o m U n ited K i n g d o m U n ited States Denmark

I ncidence 1% 0.7% 1 .7% 0.4% 0.4-0.7%

aScree n ed i rl t h e fi rst tri mester. b Screened at 9- 1 5 weeks. (Screened before 20 weeks. d D i a g n osed i n ea rly versus later preg n a ncy.

• Hyperthyroidism

The incidence of thyrotoxicosis or hyperthyroidism in preg­ nancy is varied and complicates between 2 and 1 7 per 1 000 births when gestational-age appropriate TSH threshold values are used (Table 5 8- 1 ) . Because normal pregnancy simulates some clinical findings similar to thyroxine excess, clinically mild thyrotoxicosis may be diicult to diagnose. Suggestive indings include tachycardia that exceeds that usually seen with normal pregnancy, thyromegaly, exophthalmos, and failure to gain weight despite adequate food intake. Laboratory testing is confirmatory. TSH levels are markedly depressed, while serum free T4 (IT4) levels are elevated Qameson, 20 1 5) . Rarely, hyper­ thyroidism is caused by abnormally high serum triiodothyro­ nine (T3) levels-so-called Trtoxicosis. Thyrotoxicosis a n d Preg na ncy

he overwhelming cause of thyrotoxicosis in pregnancy is Graves disease, an organ-speciic autoimmune process associated with thyroid-stimulating TSH-receptor antibodies as previously dis­ cussed '(De Leo, 20 1 6) . Because these antibodies are specifi c to Graves hyperthyroidism, such assays have been proposed for diagnosis, management, and prognosis in pregnancies compli­ cated by hyperthyroidism (Barbesino, 20 1 3) . At Parkland Hos­ pital, these receptor antibody assays are generally reserved for cases in which fetal thyrotoxicosis is suspected. With Graves disease, during the course of pregnancy, hyperthyroid symp­ toms may initially worsen because ofhCG stimulation but then subsequently diminish with drops in receptor antibody titers in the second half of pregnancy (Mestman, 20 1 2 ; Sarkhail, 20 1 6) . Amino and coworkers (2003) have found that levels o f blocking antibodies also decline during pregnancy. Treatment. Thyrotoxicosis during pregnancy can nearly always

be controlled by thionamide drugs. Propylthiouracil (PTU) has been historically preferred because it partially inhibits the conversion of T4 to T3 and crosses the placenta less readily than methimazole. he latter has also been associated with a rare methimazole embryopathy, characterized by esophageal or choanal atresia as well as aplasia cutis, a congenital skin defect. yoshihara and associates (20 1 2, 20 1 5) analyzed outcomes in Japanese women with irst-trimester hyperthyroidism and found a twofold increased risk of major fetal malformations in pregnancies exposed to methimazole compared with either

PTU or potassium iodide. Speciically, seven of nine cases with aplasia cutis and the only case of esophageal atresia were in the group of methimazole-exposed fetuses. here have also been reports of a PTU-associated embryopathy (Andersen, 20 1 4) . In 2009, the Food and Drug Administration issued a safety alert on PTU-associated hepatotoxicity. his warning prompted the American Thyroid Association and the American Associa­ tion of Clinical Endocrinologists (20 1 1 ) to recommend PTU therapy during the first trimester followed by methimazole beginning in the second trimester. he obvious disadvantage is that this might lead to poorly controlled thyroid function. Accordingly, at Parkland Hospital, we continue to prescribe PTU treatment throughout pregnancy. Transient leukopenia can be documented in up to 10 percent of women taing antithyroid drugs, but this does not require therapy cessation (American College of Obstetricians and Gyne­ cologists, 20 1 7) . In approximately 0.3 percent, however, agranu­ loytosis develops suddenly and mandates drug discontinuance (Thomas, 20 1 3) . It is not dose related, and because of its acute onset, serial leukocyte counts during therapy are not helpul. Thus, fever or sore throat develops, women are instructed to discon­ tinue medication immediatey and reportor a complete blood count. herapy may have other side efects. First, as noted, hepato­ toxicity is a possibility and develops in approximately 0. 1 per­ cent of treated women. Serial measurement of hepatic enzyme levels does not prevent fulminant PTU-related hepatotoxicity. Second, approximately 20 percent of patients treated with PTU develop antineutrophil cytoplasmic antibodies NC). Despite this, only a small percentage of these subsequently develops serious vasculitis (Kimura, 20 1 3) . Finally, although thion­ amides have the potential to cause fetal complications, these are uncommon. In some cases, thionamides may even be thera­ peutic for the fetus, because TSH-receptor antibodies cross the placenta and can stimulate the fetal thyroid gland to cause thy­ rotoxicosis and goiter. The initial thionamide dose is empirical. For nonpregnant patients, the American hyroid Association recommends that methimazole be used at an initial higher daily dose of 1 0 to 20 mg orally followed by a lower maintenance dose of 5 to 1 0 mg. If PTU is selected, a dose of 50 to 1 50 mg orally three times daily may be initiated depending on clinical severity (Bahn, 20 1 1 ) . At Parkland Hospital, we usually initially give 300 or 450 mg of PTU daily in three divided doses for pregnant women. Occasionally, daily doses of 600 mg or higher are nec­ essary. As discussed, we generally do not transition women to methimazole during the second trimester. he goal is treatment with the lowest possible thionamide dose to maintain thyroid hormone levels slightly above or in the high normal range, while TSH levels remains suppressed (Bahn, 20 1 1 ) . Serum free T4 concentrations are measured every 4 to 6 weeks. Subtotal thyroidectomy can be performed after thyrotoxicosis is medically controlled. This seldom is done during pregnancy but may be appropriate for the very few women who cannot adhere to medical treatment or in whom drug therapy proves toxic (Stagnaro-Green, 20 1 2a) . Surgery is best accomplished in the second trimester. Potential drawbacks of thyroidectomy include inadvertent resection of parathyroid glands and injury to the recurrent laryngeal nerve.

E n docrine Disorders

Thyroid ablation with therapeutic radioactive iodine is con­ traindicated during pregnancy. The necessary doses may also cause fetal thyroid gland destruction. Thus, when radioactive iodine is given unintentionally, many clinicians recommend abortion. Any exposed fetus must be carefully evaluated, and the incidence of fetal hypothyroidism depends on gestational age and radioiodine dose (Berlin, 200 1 ) . There is no evidence that radioiodine given before pregnancy causes fetal anomalies if enough time has passed to allow radiation efects to dissipate and if the woman is euthyroid (Ayala, 1 998). The International Commission on Radiological Protection has recommended that women avoid pregnancy for 6 months after radioablative therapy (Brent, 2008) . Moreover, during lactation, the breast also concentrates a substantial amount of iodine. This may pose neonatal risk due to 13 1 I-containing milk ingestion and mater­ nal risk from significant breast irradiation. To limit the latter, a delay of 3 months after breastfeeding cessation will more reli­ ably ensure complete breast involution. Preg na ncy Outcome. Women with thyrotoxicosis have preg­ nancy outcomes that largely depend on whether metabolic control is achieved. For example, excess thyroxine may cause miscarriage or preterm birth (Andersen, 20 1 4; Sheehan, 20 1 5) . In untreated women o r i n those who remain hyperthyroid despite therapy, incidences of preeclampsia, heart failure, and adverse perinatal outcomes are higher (Table 58-2) . A prospec­ tive cohort study from China showed that women with clini­ cal hyperthyroidism had a 1 2-fold greater risk of delivering an infant with hearing loss (Su, 20 1 1 ) . Feta l a n d N eo nata l Efects

In most cases, the perinate is euthyroid. In some, however, hyper- or hypothyroidism can develop with or without a goi­ ter (Fig. 5 8-3) . Clinical hyperthyroidism develops in up to 1 percent of neonates born to women with Graves disease (Barbesino, 20 1 3 ; Fitzpatrick, 20 1 0) . If fetal thyroid disease is TABLE 58-2. Pregna ncy Outcomes in Women with Overt Thyrotoxicos i s Treated and Euthyroida n 380

U ncontrol led Thyrotoxicosisa n 90

40 ( 1 0%) 1 0

1 5 ( 1 7%) 7 (8%) 1

5 1 ( 1 6%) 37 ( 1 1 %) 0/5 9

29 (32%) 1 5 ( 1 7%) 6/33 ( 1 8%)

4 2

0 0

=

Maternal Outcome P reec l a m psia Heart fa i l u re Death Perinata l Outcome P reterm del ivery G rowth restriction Sti l l b i rth Thyrotoxicos i s Hypothyroi d i s m Goiter

=

2

a Data prese nted as n (%). Data from Davis, 1 989; Kri p l a n i, 1 994; Luewan, 20 1 1 ; Med ici, 20 1 4; M i l l a r, 1 994.

F I G U RE 58-3 Term hypothyroid neonate del ivered of a wo m a n with a 3-year h istory o f thyrotoxicosis that rec u rred at 26 weeks' gestation. The mother was g iven met h i m azole 30 mg ora l ly d a i ly a n d wa s euthyroid at del ivery.

suspected, nomograms are available for sonographically mea­ sured thyroid volume (Gietka-Czernel, 20 1 2) . The fetus o r neonate who was exposed to excessive maternal thyroxine may have any of several clinical presentations. First, goitrous thyrotoxicosis is caused by placental transfer of thyroid­ stimulating immunoglobulins. Nonimmune hydrops and fetal demise have been reported with fetal thyrotoxicosis (Nachum, 2003; Stulberg, 2000) . The best predictor of perinatal thyro­ toxicosis is presence of thyroid-stimulating TSH-receptor anti­ bodies in women with Graves disease (Nathan, 20 1 4) . This is especially true if their levels are more than threefold higher than the upper normal limit (Barbesino, 20 1 3) . In a study of 72 pregnant women with Graves disease, Luton and associ­ ates (2005) reported that none of the fetuses in 31 low-risk mothers had a goiter, and all were euthyroid at delivery. Low risk was defined as no requirement for antithyroid medica­ tions during the third trimester or an absence of antithyroid antibodies. Conversely, in a group of 4 1 women who either were taking antithyroid medication at delivery or had thyroid receptor antibodies, 1 1 fetuses-27 percent-had sonographic evidence of a goiter at 32 weeks' gestation. Seven of these 1 1 fetuses were determined to be hypothyroid, and the remain­ ing fetuses were hyperthyroid. In response to these results, the merican Thyroid Association and American Association of Clinical Endocrinologists (20 1 1 ) recommend routine evalu­ ation of TSH-receptor antibodies between 22 and 26 weeks' gestation in women with Graves disease. he American College of Obstetricians and Gynecologists (20 1 7) , however, does not recommend such testing. If the fetus is thyrotoxic, maternal thionamide drugs are adjusted even though maternal thyroid function may be within the targeted range (Mestman, 20 1 2) . lthough usually short-lived, neonatal thyrotoxicosis may require short-course antithyroid drug treatment (Levy-Shraga, 20 1 4 ; Nathan, 20 14) .

1 1 21

1 1 22

Medical a nd S u rg ical Co m p l ications

A second presentation is goitrous hypothyroidism caused by fetal exposure to maternally administered thionamides (see Fig. 5 8-3). Although there are theoretical neurological implications, reports of adverse fetal efects seem to have been exaggerated. Available data indicate that thionamides carry an extremely small risk for causing neonatal hypothyroidism (Momotani, 1 997; O'Doherty, 1 999) . For example, in at least 239 treated thyrotoxic women shown in Table 5 8- 1 , evi­ dence of hypothyroidism was found in only four newborns. Furthermore, at least four long-term studies report no abnor­ mal intellectual and physical development of these children (Mestman, 1 998). If maternal hypothyroidism developed, the fetus can be treated by a reduced maternal antithyroid medication dose and injections of intraamnionic thyroxine if necessary. A third presentation, nongoitrous hypothyroidism, may develop from transplacental passage of maternal TSH-receptor blocking antibodies (Fitzpatrick, 20 1 0; Gallagher, 200 1 ) . And finally, etal thyrotoxicosis after maternal thyroid gland ablation, usually with 1 3 1 1 radioiodine, may result from transplacental thyroid-stimulating antibodies. In one report of early fetal exposure to radioiodine, neonatal thyroid studies indicated transient hyperthyroidism from maternal transfer of stimulat­ ing antibodies (Tran, 201 0) . Feta l Diagnosis. Evaluation of fetal thyroid function is some­ what controversial. Although the fetal thyroid volume can be measured sonographically in women taking thionamide drugs or in those with thyroid-stimulating antibodies, most inves­ tigators do not currently recommend this routinely (Cohen, 2003; Luton, 2005) . Kilpatrick (2003) recommends umbili­ cal cord blood sampling and fetal antibody testing only if the mother has previously undergone radioiodine ablation. Because fetal hyper- or hypothyroidism may cause hydrops, growth restriction, goiter, or tachycardia, fetal blood sampling may be appropriate if these are identified (Brand, 2005) . he Endo­ crine Society clinical practice guidelines recommend umbilical cord blood sampling only when the diagnosis of fetal thyroid disease cannot be reasonably ascertained based on clinical and sonographic data (Garber, 20 1 2) . Diagnosis and treatment are considered further in Chapter 1 6 (p. 3 1 8) . Thyroid Sto rm a n d Hea rt Fa i l u re

Both of these are acute and life-threatening in pregnancy. hy­ roid storm is a hypermetabolic state and is rare in pregnancy. In contrast, pulmonary hypertension and heart failure from cardiomyopathy caused by the profound myocardial efects of thyroxine are common in pregnant women (Sheield, 2004) . As shown in Table 58-2, heart failure developed in 8 percent of 90 women with uncontrolled thyrotoxicosis. In these women, cardiomyopathy is characterized by a high-output state, which may lead to a dilated cardiomyopathy (Fadel, 2000; Klein, 1 998) . The pregnant woman with thyrotoxicosis has minimal cardiac reserve, and decompensation is usually precipitated by preeclampsia, anemia, sepsis, or a combination of these. For­ tunately, thyroxine-induced cardiomyopathy and pulmonary hypertension are frequently reversible (Sheield, 2004; Siu, 2007; Vydt, 2006) .

Management. Treatment is similar for thyroid storm and heart failure and should be carried out in an intensive care area that may include special-care units within labor and delivery (American College of Obstetricians and Gynecologists, 20 1 7) . Shown i n Figure 5 8-4 i s our stepwise approach t o medical management of thyroid storm or thyrotoxic heart failure. An hour or two ater initial thionamide administration, iodide is given to inhibit thyroidal release of T3 and T4. It can be given intravenously as sodium iodide or orally as either saturated solution of potassium iodide (SSKI) or Lugol solution. With a history of iodine-induced anaphylaxis, lithium carbonate, 300 mg every 6 hours, is given instead. Most authorities rec­ ommend dexamethasone, 2 mg intravenously every 6 hours for four doses, to further block peripheral conversion of T4 to T3. If a 3 -blocker drug is given to control tachycardia, its efect on heart failure must be considered. Propranolol, labetalol, and esmolol have all been used successfully. Coexisting severe pre­ eclampsia, infection, or anemia should be aggressively managed before delivery is considered. Hypere m es i s G ravi d a r u m a n d Gestationa l Tra n s ient Thyrotoxicos i s

Transient biochemical features of hyperthyroidism may be observed in 2 to 15 percent of women in early pregnancy (Fitz­ patrick, 20 1 0) . Many women with hyperemesis gravidarum have abnormally high serum thyroxine levels and low TSH levels (Chap. 54, p. 1 045). his results from TSH-receptor stimulation from massive-but normal for pregnancy­ concentrations of hCG. This transient condition is also termed gestational transient thyrotoxicosis. Even if associated with hyper­ emesis, antithyroid drugs are not warranted (American College of Obstetricians and Gynecologists, 20 1 7) . The degree of hCG level elevation does not correlate with thyroxine and TSH val­ ues, which become more normal by midpregnancy (Nathan, 2 0 1 4 ; Yoshihara, 20 1 5) . Thyrotoxicosis a n d Gestati o n a l Tro p h o b l a stic Disease

he prevalence of increased thyroxine levels in women with a molar pregnancy ranges between 2 5 and 65 percent (Hersh­ man, 2004) . As discussed, abnormally high hCG levels lead to overstimulation of the TSH receptor. Because these tumors are now usually diagnosed early, clinically apparent hyperthyroid­ ism has become less common. With molar evacuation, serum free T4 levels usually normalize rapidly in parallel with declin­ ing hCG concentrations. This is discussed further in Chapter 20 (p. 39 1 ) . • Subclinical Hyperthyroidism

hird-generation TSH assays with an analytical sensitivity of 0.002 mU/mL permit identiication of subclinical thyroid disorders. These biochemically defined extremes usually rep­ resent normal biological variations but may herald the earli­ est stages of thyroid dysfunction. Subclinical hyperthyroidism is characterized by an abnormally low serum TSH concentra­ tion in concert with normal thyroxine hormone levels (Surks, 2004) . Long-term efects of persistent subclinical thyrotoxicosis include osteoporosis, cardiovascular morbidity, and progression

E n d ocrine D i s o rders

Start thionamides and consider heart rate control

I Thionamides: Heart rate control (if necessary):

PTU 1 000 mg PO/NGT load then 200 mg every 6 hr PO/NGT

Propranolol 1 0-40 mg PO every 4-6 h r

After 1 -2 hours of thionamide therapy start iodine: Sodium iodide 500-1 000 mg IV every 8 hr or

Potassium iodide 5 gtt PO every 8 hr or

Lugol solution 1 0 gtt PO every 8 hr or

if iodine anaphylaxis history, Lithium carbonate 300 mg PO every 6 hr

Consider corticosteroid therapy for 24 hours: Dexamethasone 2 mg IV every 6 hr or

Hydrocortisone 1 00 mg IV every 8 hr F I G U R E 58-4 One m a nagement method for thyroid storm o r thyrotoxic hea rt fa i l u re. gtt tu be; PO

=

ora l ly; PTU

=

=

d rops; I V

=

i ntraven o u s; NGT

=

nasogastric

pro pyl t h i o u ra c i l .

to overt thyrotoxicosis or thyroid failure. Casey and Leveno (2006) reported that subclinical hyperthyroidism was found in 1 .7 percent of pregnant women. Importantly, subclinical hyperthyroidism was not associated with adverse pregnancy outcomes. In separate retrospective analyses of almost 25,000 women who underwent thyroid screening throughout preg­ nancy, Wilson and colleagues (20 1 2) and Tudela and cowork­ ers (20 1 2) also found no relationship between subclinical hyperthyroidism and preeclampsia or gestational diabetes. Treatment of subclinical hyperthyroidism is unwarranted in pregnancy because antithyroid drugs may afect the fetus. hese women may beneit from periodic surveillance, and approxi­ mately half eventually have normal TSH concentrations. • Hypothyroidism

Overt or symptomatic hypothyroidism, as shown in Table 5 8-3, has been reported to complicate between 2 and 1 2 per 1 000 pregnancies. It is characterized by insidious nonspeciic clini­ cal indings that include fatigue, constipation, cold intolerance, muscle cramps, and weight gain. A pathologically enlarged thy­ roid gland depends on the etiology of hypothyroidism and is

more likely in women in areas of endemic iodine deiciency or those with Hashimoto thyroiditis. Other indings include edema, dry skin, hair loss, and prolonged relaxation phase of deep tendon relexes. Clinical or overt hypothyroidism is con­ irmed when an abnormally high serum TSH level is accom­ panied by an abnormally low thyroxine level. Subclinical

TABLE 58-3. Freq uency of Overt H ypothyroid ism i n Pregnancy Study

Country

Wa n g (20 1 1 )a Clea ry-Gol d m a n (2008)a Va idya (2007)d Ca sey (200S) b Ande rsen (20 1 6) d

China U n ited States U n ited K i n g d o m U n ited States Den m a r k

aScreened d u ri n g fi rst tri mester. b Screened before 20 weeks. ( I n c l udes those t reated before p reg n a n cy. d D i a g nosed in ea rly versus l ater p reg n a ncy.

I ncidence 0.3% 0.3% 1 .0% 0.2% 1 .2%

1 1 23

1 1 24

Med i ca l a nd S u rg ica l Com p l icat i o n s

hypothyroidism, discussed later, is defined by an elevated serum TSH level and normal serum thyroxine concentration Qame­ son, 20 1 5) . Sometimes included in the spectrum of subclinical thyroid disease are asymptomatic individuals with high levels of anti-TPO or anti thyroglobulin antibodies. Autoimmune euthy­ roid disease represents a new investigative frontier in screening and treatment of thyroid dysfunction during pregnancy. Overt H ypothyro i d i s m a n d P reg n a ncy

he most common cause of hypothyroidism in pregnancy is H ashimoto thyroiditis, characterized by glandular destruc­ tion from autoantibodies, particularly anti-TPO antibodies. Another cause is postablative Graves disease. Clinical identiica­ tion of hypothyroidism is especially diicult during pregnancy because many of the signs or symptoms are also common to pregnancy itself. Thyroid analyte testing should be performed on symptomatic women or those with a history of thyroid dis­ ease (American College of Obstetricians and Gynecologists, 20 1 7) . Severe hypothyroidism during pregnancy is uncommon, probably because it is often associated with infertility and higher spontaneous abortion rates (De Groot, 20 1 2) . Even women with treated hypothyroidism undergoing in vitro fertil­ ization have a significantly lower chance of achieving pregnancy (Scoccia, 20 1 2) . Treatment. The American hyroid Association and American Association of Clinical Endocrinologists (20 1 1 ) recommend replacement therapy for overt hypothyroidism beginning with levothyroxine in doses of 1 to 2 ILg/kgl d or approximately 1 00 Lg daily. Women who are athyreotic after thyroidectomy or radioiodine therapy may require higher doses. Surveillance is with TSH levels measured at 4- to 6-week intervals, and the thyroxine dose is adjusted by 25- to 50-lLg increments until TSH values become normal. Pregnancy is associated with an increased thyroxine requirement in approximately a third of supplemented women (Abalovich, 20 1 0; Alexander, 2004) . The increased demand in pregnancy is believed to be related to augmented estrogen production (Arafah, 200 1 ) . Greater thyroxine requirements begin a s early as 5 weeks' gestation. In a randomized trial that provided an increased levothyroxine dose at pregnancy confi r mation in 60 mothers, Yassa and coworkers (20 1 0) found that a 29- to 43-percent increase in the weekly dose maintained serum TSH values < 5 .0 mUlL during the first trimester in all women. Impor­ tantly, however, this increase caused TSH suppression in more than a third of women. Signifi c ant hypothyroidism may develop early in women without thyroid reserve, such as those with a previous thyroidectomy, those with prior radioiodine ablation, or those undergoing assisted reproduc­ tive techniques (Alexander, 2004; Loh, 2009) . Anticipatory 2 5-percent increases in thyroxine replacement at pregnancy conirmation will reduce this likelihood. All other women with hypothyroidism should instead undergo TSH testing at initiation of prenatal care. Preg na ncy Outcome with Overt Hypothyroidism. Obser­ vational studies, although limited, indicate that excessive adverse perinatal outcomes are associated with overt thyroxine

TABLE 58-4. Preg nancy C o m p l i cations in 440 Women with Hypothyro i d i s m

Compl ications P reec l a m psia P lace nta l a bru ption Card i ac dysfu n ction B i rthwe i g ht < 2000 ga, b Sti l i bi rthsC

Hypothyroidism (%) Overt Subcli nical 1 1 2) (n 328) (n =

32 8 3 33 9

=

8 1 2 32 3c

a p reterm or term del iveries were the o n l y o utcomes reported by Aba l ovich, 2002. blow b i rthwe i g h t a n d sti l l b i rth were o utcomes re ported by SU, 20 1 1 . COn e i n fa nt d i ed from syp h i l i s. Data from Aba l ovich, 2002; Davis, 1 988; leu ng, 1 993; M a n n i stb, 2009; Su, 20 1 1 .

deficiency (Table 5 8-4) . Preterm birth rates, for example, are higher (Sheehan, 20 1 5) . With appropriate replacement ther­ apy, however, rates of adverse efects are not increased in most reports (Bryant, 20 1 5 ; Matalon, 2006; Tan, 2006) . In one dissenting study, however, risks for some pregnancy complica­ tions were greater even in women taking replacement therapy (Wikner, 2008) . Most experts agree that adequate hormone replacement during pregnancy minimizes the risk of adverse outcomes and most complications. Fetal and Neonatal Efects. Undoubtedly, maternal and fetal thyroid abnormalities are related. In both, thyroid unction is dependent on adequate iodide intake, and its deiciency early in pregnancy can cause both maternal and fetal hypothyroidism. And, as discussed, maternal TSH-receptor-blocking antibod­ ies can cross the placenta and cause fetal thyroid dysunction. Rovelli and colleagues (20 1 0) evaluated 1 29 neonates born to women with autoimmune thyroiditis. They found that 28 per­ cent had an elevated TSH level on the third or fourth day of life, and 47 percent of these had TPO antibodies on day 1 5. Still, autoantibodies were undetectable at 6 months of age. It seems paradoxical that despite these transient laboratory findings in the neonate, TPO and anti thyroglobulin antibodies have little or no efect on etal thyroid function (Fisher, 1 997) . Indeed, prevalence of fetal hypothyroidism in women with Hashimoto thyroiditis is estimated to be only 1 in 1 80,000 newborns (Brown, 1 996) .

• Subclinical Hypothyroidism

Although common in women, the incidence of subclinical hypothyroidism varies depending on age, race, dietary iodine intake, and serum TSH thresholds used to establish the diagnosis Qameson, 20 1 5) . In two large studies totaling more than 25 ,000 pregnant women screened in the first half of pregnancy, subclini­ cal hypothyroidism was identified in 2.3 percent (Casey, 2005; Cleary-Goldman, 2008) . he rate of progression to overt thyroid failure is afected by TSH level, age, other disorders such as dia­ betes, and presence and concentration of antithyroid antibodies.

E n d ocri ne Disorders

Diez and Iglesias (2004) prospectively followed 93 nonpreg­ nant women with subclinical hypothyroidism for 5 years and reported that in a third, TSH values became normal. In the other two thirds, those women whose TSH levels were 1 0 to 1 5 mUlL developed overt disease at a rate of 1 9 per 1 00 patient years. Those women whose TSH levels were < 1 0 mUIL devel­ oped overt hypothyroidism at a rate of 2 per 1 00 patient years. Regarding screening for subclinical hypothyroidism in non­ pregnant individuals, the U.S. Preventative Services Task Force also reports that nearly all patients who develop overt hypothy­ roidism within 5 years have an initial TSH level > 1 0 mUlL (Helfand, 2004; Karmisholt, 2008) . For gravidas, in a 20-year follow-up study of 5805 women who were screened in early pregnancy, only 3 percent developed thyroid disease. Of the 224 women identified with subclinical hypothyroidism during pregnancy, 1 7 percent developed thy­ roid disease in the next 20 years, and most of these had either TPO or thyroglobulin antibodies during pregnancy (Mannisto, 20 1 0) . hus, the likelihood of progression to overt hypothy­ roidism during pregnancy in otherwise healthy women with subclinical hypothyroidism seems remote. S u bc l i n i ca l H ypothyroid i s m a n d Preg na ncy

Earlier studies were suggestive that subclinical hypothyroidism might be associated with adverse pregnancy outcomes. In 1 999, interest was heightened by two studies indicating that undiag­ nosed maternal thyroid hypofunction may impair fetal neuro­ psychological development. In one study, Pop and associates ( 1 999) described 22 women with free T4 levels < 1 0th percentile whose ofspring were at higher risk for impaired psychomotor development. In the other study, Haddow and coworkers ( 1 999) retrospectively evaluated children born to 48 untreated women whose serum TSH values were > 98th percentile. Some had diminished school performance, reading recognition, and intel­ ligent quotient (IQ) scores. Although described as "subclinically hypothyroid," these women had an abnormally low mean serum free thyroxine level, and thus, many had overt hypothyroidism. To further evaluate any adverse efects, Casey and colleagues (2005) identiied subclinical hypothyroidism in 2.3 percent of 1 7,298 women screened at Parkland Hospital before midpreg­ nancy. hese women had small but signiicantly higher incidences of preterm birth, placental abruption, and neonates admitted to the intensive care nursery compared with euthyroid women. In another study of 1 0,990 similar women, however, Cleary­ Goldman and associates (2008) did not ind such associations. Other studies subsequently conirmed a link between sub­ clinical thyroid function and adverse outcomes (Chen, 20 1 7; Maraka, 20 1 6) . One included 24,883 women screened through­ out pregnancy and showed an almost twofold greater risk of severe preeclampsia (Wilson, 20 1 2) . In an analysis of the same cohort, a consistent relationship was shown between rising TSH levels and the risk for gestational diabetes (Tudela, 20 1 2) . Finally, Nelson and colleagues (20 1 4) found a n elevated risk for diabetes and stillbirth. Lazarus and colleagues (20 1 2) reported the indings of the international multicenter Controlled Antenatal Thyroid Screening (CATS) study. his study evaluated prenatal thy­ roid screening and randomized treatment of both subclinical

hypothyroidism and isolated maternal hypothyroxinemia. They reported that ofspring IQ scores at age 3 years were not supe­ rior in the treated pregnancies. Despite these indings, the unanswered question concerned whether treatment of subclinical hypothyroidism would miti­ gate any or all of these reported adverse outcomes. To address this, the Maternal-Fetal Medicine Units Network screened more than 97,000 pregnant women for thyroid disorders and reported that 3.3 percent had subclinical hypothyroid­ ism. hese 677 women were randomly assigned to thyroxine replacement therapy or placebo. As reported by Casey and col­ leagues (20 1 7) , and shown in Table 5 8-5 , maternal adverse pregnancy outcomes or cognitive development in the ofspring at 5 years did not difer between groups. Annual developmental testing scores and behavioral and attention-deicit hyperactivity disorder results also did not difer. Screening in Preg nancy. Because of the findings in the stud­ ies from 1 999 cited above, some professional organizations began to recommend routine prenatal screening and treatment for subclinical hypothyroidism. Consequent to the Lazarus study, however, clinical practice guidelines from the Endocrine Society, the American hyroid Association, and the American Association of Clinical Endocrinologists uniformly recom­ mended screening only those at greater risk during pregnancy (De Groot, 20 1 2; Garber, 20 1 2) . his has been and still is the recommendation of the American College of Obstetricians and Gynecologists (20 1 7) . he indings of Casey and colleagues (20 1 7) further buttress these recommendations.

• Isolated Maternal Hypothyroxinemia

Women with low serum free T4 values but a normal-range TSH level are considered to have isolated matenal hypothyroxinemia. Its incidence in two large trials was l .3 to 2. 1 percent (Casey, 2007; Cleary-Goldman, 2008) . As shown in Figure 58-2, unlike in subclinical hypothyroidism, these women had a low preva­ lence of antithyroid antibodies. Evolution of the knowledge of this thyroid disorder was similar to that seen with subclinical hypothyroidism. Initial studies reported that ofspring of women with isolated hypo­ thyroxinemia had neurodevelopmental diiculties (Kooistra, 2006; Pop, 1 999, 2003) . In another study, Casey and col­ leagues (2007) found no higher risks for other adverse perinatal outcomes compared with those of euthyroid women. Also, the aforementioned CATS study did not ind improved neurode­ velopmental outcomes in women with isolated hypothyroxin­ emia who were then treated with thyroxine (Lazarus, 20 1 2) . h e randomized trial conducted b y the Maternal-Fetal Med­ icine Units Network also provided data to settle this question. Casey and colleagues (20 1 7) noted no higher rates of adverse outcomes between groups and found that early thyroxine treat­ ment ofered no beneits (see Table 58-5). • Euthyroid Autoimmune Thyroid Disease

Autoantibodies to TPO and thyroglobulin have been identi­ ied in 6 to 20 percent of reproductive-aged women (Than­ garatinam, 20 1 l ) . Most who test positive for such antibodies,

1 1 25

1 1 26

Medical a n d S u rg ica l Co m p l icati o n s

TABLE 58-5. P reg na ncy a n d Peri n ata l Outcom es Accord i n g to Diag nosis a n d Treatment Group of Thyroid Disordersa Outcome Maternal EGA at d e l ivery (weeks) P reterm b i rt h < 34 weeks Placenta l a bru ption P reecla m ps i a Dia betes Perinatal and Child hood Sti l l b i rth Neonata l death N I C U a d m i ss i o n B i rthwe i g ht < 1 0th centi l e I Q med i a n (25th, 75th percenti l e)

Subcli nical Hypothyroidism Thyroxine Placebo 39. 1 ± 2 . 5 9. 1 % 0.3% 6.5% 7 .4%

3 8.9 ± 3 . 1 1 0.9% 1 .5% 5 .9%

39.0 ± 2.4 3 .8% 1 .1 % 3 .4% 8.0%

38.8 ± 3. 1 2 .7% 0.8% 4.2% 9.2%

1 2/ 1 000

2 1 / 1 000 311 000 6 .2 % 8. 1 % 94 (85 , 1 07)

8/1 000 4/1 000 1 1 .8% 8.8% 94 (83, 1 0 1 )

1 91'1 000 4/1 000 1 1 .9% 7.8% 9 1 (82, 1 0 1 )

0

8.6% 9.8% 97 (85, 1 05)

dFor a l l com pa r i so n s, p > 0.05 . esti mated gestat i o n a l a ge; IQ EGA Data from Casey, 2 0 1 7 . =

=

6.5%

i n te l l i g e n ce q uotient; [l ICU

however, are euthyroid. That said, such women carry a two- to ivefold increased risk for early pregnancy loss (Stagnaro-Green, 2004; hangaratinam, 20 1 1 ) . he presence of thyroid antibod­ ies has also been associated with preterm birth (Stagnaro-Green, 2009) . In a randomized treatment trial of 1 1 5 euthyroid women with TPO antibodies, Negro and coworkers (2006) reported that treatment with levothyroxine astoundingly reduced the preterm birth rate from 22 to 7 percent. Contrarily, Abbassi­ Ghanavati and associates (20 1 0) evaluated pregnancy outcomes in more than 1 000 untreated women with TPO antibodies and did not ind an increased risk for preterm birth compared with the risk in 1 6,000 euthyroid women without antibodies. hese investigators, however, did find a threefold greater risk of pla­ cental abruption in these women. As with nonpregnant subjects with TPO antibodies, these women are also at increased risk for progression of thyroid disease and postpartum thyroiditis (Jameson, 20 1 5; Stagnaro­ Green, 2 0 1 2a) . Currently, universal screening for the thyroid autoantibodies is not recommended by any professional organi­ zation (De Groot, 20 1 2; Stagnaro-Green, 20 l l a, 20 1 2a) . • Iodine Deficiency

Isolated Hypothyroxinemia Thyroxine Placebo

Decreasing iodide fortification of table salt and bread products in the United States during the past 25 years has led to occa­ sional iodide defi c iency (Caldwell, 2005; Hollowell, 1 998) . Importantly, the most recent National Health and Nutrition Examination Survey indicated that, overall, the United States population remains iodine suicient (Caldwell, 20 1 l ) . Even so, experts agree that iodine nutrition in vulnerable popula­ tions, such as pregnant women, requires continued monitoring. In 20 1 1 , the Oice of Dietary Supplements of the National Institutes of Health sponsored a workshop to prioritize iodine

=

neonatal i nte n s ive care u n i t.

research. Participants emphasized the decline in median urinary iodine levels to 1 25 Lg/L in pregnant women and the serious potential efects on developing fetuses (Swanson, 20 1 2) . Dietary iodine requirements are higher during pregnancy due to augmented thyroid hormone production, increased renal losses, and fetal iodine requirements. Adequate iodine is requisite for fetal neurological development beginning soon after conception, and abnormalities are dependent on the degree of deficiency. he World Health Organization (WHO) has estimated that 38 million children are born every year at risk of lifelong brain damage associated with iodine deiciency (Alipui, 2008) . Although it is doubtful that mild diciency causes intel­ lectual impairment, supplementation does prevent fetal goiter (Stagnaro-Green, 20 1 2b) . Severe diciency, on the other hand, is frequently associated with damage typically encountered with endemic cretinism (Delange, 200 1 ) . It is presumed that moderate deiciency has intermediate and variable efects. Ber­ bel and associates (2009) began daily supplementation in more than 300 pregnant women with moderate deiciency at three time periods-4 to 6 weeks, 1 2 to 1 4 weeks, and after deliv­ ery. They found improved neurobehavioral development scores in ofspring of women supplemented with 200 ILg potassium iodide very early in pregnancy. Similarly, Velasco and cowork­ ers (2009) found improved Bayley Psychomotor Development scores in ofspring of women supplemented with 300 ILg of iodine daily in the irst trimester. In contrast, Murcia and col­ leagues (20 1 1 ) identified lower psychomotor scores in 1 -year­ old infants whose mothers reported daily supplementation of more than 1 50 ILg. To address this, randomized controlled trial of iodine supplementation in mildly to moderately iodine­ deficient pregnant women in India and hailand is nearing completion (Pearce, 20 1 6) .

E n d ocrine Disord ers

Regarding daily iodine intake, the Institute of Medicine (200 1 ) recommends 220 �g/d during pregnancy and 290 �g/d during lactation (Chap. 9, p. 1 68). he Endocrine Society recommends an average iodine intake of 1 50 �g/d in repro­ ductive-aged women, and this should be increased to 250 �g during pregnancy and breastfeeding (De Groot, 20 1 2) . The American Thyroid Association has recommended that 1 50 �g of iodine be added to prenatal vitamins to achieve this average daily intake (Becker, 2006) . According to Leung and coworkers (20 1 1 ) , however, only 5 1 percent of the prenatal multivitamins in the United States contain iodine. It has even been suggested that because most cases of maternal hypothyroxinemia world­ wide are related to relative iodine deficiency, supplementation may obviate the need to consider thyroxine treatment in such women (Gyami, 2009) . However, without evidence of benefi t , it is hard to justiy the cost of iodine supplementation of large numbers of pregnant women in areas with mild iodine dei­ ciency (Pearce, 20 1 6) . Importantly, experts caution against oversupplementa­ tion. Teng and associates (2006) contend that excessive iodine intake-deined as > 300 �g/d-may lead to subclinical hypo­ thyroidism and autoimmune thyroiditis. he Endocrine Soci­ ety, in accordance with the WHO, advises against exceeding twice the daily recommended intake of iodine, or 500 �g/ d (De Groot, 20 1 2; Leung, 20 1 1 ) . • Congenital Hypothyroidism

Universal newborn screening for neonatal hypothyroidism was introduced in 1 974 and is now required by law in all states (Chap. 32, p. 6 1 4) . This develops in approximately 1 in 3000 newborns and is one of the most preventable causes of mental retardation (LaF ranchi, 20 1 1 ) . Developmental disorders of the thyroid gland such as agenesis and hypoplasia account for 80 to 90 percent of these cases. he remainder is caused by hereditary defects in thyroid hormone production (Moreno, 2008) . Early and aggressive thyroxine replacement is critical for newborns with congenital hypothyroidism. Still, some neonates identified by screening programs who were treated promptly will exhibit cognitive deicits into adolescence (Song, 200 1 ) . herefore, i n addition to timing o f treatment, the severity of congenital hypothyroidism is an important factor in long-term cognitive outcomes. Olivieri and colleagues (2002) reported that 8 percent of 1 420 newborns with congenital hypothyroid­ ism also had other major congenital malformations. • Postpartum Thyroiditis

Transient autoimmune thyroiditis is consistently found in approximately 5 to 1 0 percent of women during the first year after childbirth (Nathan, 20 1 4; Stagnaro-Green, 2 0 1 1 b, 20 1 2a) . Postpartum thyroid dysfunction with an onset within 1 2 months includes hyperthyroidism, hypothyroidism, or both. The propensity for thyroiditis antedates pregnancy and is directly related to increasing serum levels of thyroid auto­ antibodies. Up to 50 percent of women who are thyroid-anti­ body positive in the irst trimester will develop postpartum thyroiditis (Stagnaro-Green, 20 1 2a) . In a Dutch study of 82 women with type 1 diabetes, postpartum thyroiditis developed

in 1 6 percent and was threefold higher than in the general population (Gallas, 2002) . Importantly, 46 percent of those identified with overt postpartum thyroiditis had TPO anti­ bodies in the fi r st trimester. C l i n i ca l M a n ifesta t i o n s

In clinical practice, postpartum thyroiditis is diagnosed infre­ quently because it typically develops months after delivery and causes vague and nonspeciic symptoms (Stagnaro-Green, 2004) . he clinical presentation varies, and classically two clinical phases that may develop in succession are recognized. The first and earliest is destruction-induced thyrotoxicosis with symptoms from excessive release of hormone from glandular disruption. The onset is abrupt, and a small, painless goiter is common. Although there may be many symptoms, only fatigue and palpitations are more frequent in thyrotoxic women com­ pared with normal controls. This thyrotoxic phase usually lasts only a few months. hionamides are inefective, and if symp­ toms are severe, a 3-blocking agent may be given. he second and usually later phase between 4 and 8 months postpartum is hypothyroidism from thyroiditis. hyromegaly and other symp­ toms are common and more prominent than during the thyro­ toxic phase. hyroxine replacement at doses of25 to 75 �g/d is typically given for 6 to 1 2 months. Stagnaro-Green and associates (20 1 1 b) reported postpartum surveillance results in 4562 Italian gravidas who had been screened for thyroid disease in pregnancy. Serum TSH and anti-TPO anti­ body levels were measured again at 6 and 1 2 months. Overall, two thirds of 1 69 women (3.9 percent) with postpartum thyroid­ itis were identiied to have hypothyroidism only. The other third were diagnosed with hyperthyroidism. Only 14 percent of all women demonstrated the "classic" biphasic progression described above. These indings are consistent with data compiled from 20 other studies between 1 982 and 2008 (Stagnaro-Green, 20 1 2a) . Importantly, women who experience either type of post­ partum thyroiditis have a 20- to 30-percent risk of eventually developing permanent hypothyroidism, and the annual pro­ gression rate is 3.6 percent (Nathan, 20 1 4) . Women at greater risk for developing hypothyroidism are those with higher titers of thyroid antibodies and higher TSH levels during the initial hypothyroid phase. Others may develop subclinical disease, but half of those with thyroiditis who are positive for TPO antibodies develop permanent hypothyroidism by 6 to 7 years (Stagnaro-Green, 20 1 2a) . n association between postpartum thyroiditis and postpar­ tum depression has been proposed but remains unresolved. Lucas and coworkers (200 1 ) found a 1 .7-percent incidence of postpar­ tum depression at 6 months in women with thyroiditis as well as in controls. Pederson and colleagues (2007) found a signiicant correlation between abnormal scores on the Edinburgh Postnatal Depression Scale and total thyroxine values in the low normal range during pregnancy in 3 1 women. Similarly unsettled is the link between depression and thyroid antibodies. Kuijpens and associates (200 1 ) reported that TPO antibodies were a marker for postpartum depression in euthyroid women. In a random­ ized trial, however, Harris and coworkers (2002) reported no diference in postpartum depression in 342 women with TPO antibodies who were given either levothyroxine or placebo.

1 1 27

1 1 28

Med ica l a nd S u rg i c a l Co m p l icat i o n s

• Nodular Thyroid Disease

hyroid nodules can be found in 1 to 2 percent of reproduc­ tive-aged women (Fitzpatrick, 20 1 0) . Management of a pal­ pable thyroid nodule during pregnancy depends on gestational age and mass size. Small nodules detected by sensitive sono­ graphic methods are more common during pregnancy in some populations. Kung and associates (2002) used high-resolution sonography and found that 1 5 percent of Chinese women had nodules larger than 2 mm in diameter. Almost half were mul­ tiple, and the nodules usually enlarged modestly across preg­ nancy and did not regress postpartum. Biopsy of those > 5 mm3 that persisted at 3 months usually showed nodular hyperplasia, and none were malignant. In most studies, 90 to 95 percent of solitary nodules are benign (Burch, 20 1 6) . Evaluation o f thyroid nodules during pregnancy should be similar to that for nonpregnant patients. As discussed in Chap­ ter 46 (p. 908) , radioiodine scanning in pregnancy is usually not recommended (American College of Obstetricians and Gynecologists, 20 1 7) . Sonographic examination reliably detects nodules > 5 mm, and their solid or cystic structure also is determined. According to the American Association of Clinical Endocrinologists, sonographic characteristics associated with malignancy include hypoechogenic pattern, irregular margins, and microcalcifications (Gharib, 2005 ) . Fine-needle aspiration (FNA) is an excellent assessment method, and histological tumor markers and immunostaining are reliable to evaluate for malignancy (Hegedus, 2004) . If the FNA biopsy shows a fol­ licular lesion, surgery may be deferred until after delivery. Evaluation of thyroid cancer involves a multidisciplinary approach (Fagin, 20 1 6) . Most thyroid carcinomas are well dif­ ferentiated and pursue an indolent course. Messuti and cowork­ ers (20 1 4) provided evidence that persistence or recurrence of these tumors may be more common in pregnant women. When thyroid malignancy is diagnosed during the first or second tri­ mester, thyroidectomy may be performed before the third tri­ mester (Chap. 63, p. 1 20 1 ) . In women without evidence of an aggressive thyroid cancer or in those diagnosed in the third trimester, surgical treatment can be deferred to the immediate puerperium (Gharib, 20 1 0) . PARATHYROID DISEASE The function of parathyroid hormone (PTH) is to maintain extracellular fluid calcium concentration. his 84-amino acid hormone acts directly on bone and kidney and indirectly on small intestine through its efects on synthesis of vitamin D ( l ,25-(OH)2D) to increase serum calcium (Potts, 20 1 5) . Secretion is regulated b y serum ionized calcium concentra­ tion through a negative feedback system. Cacitonin is a potent parathyroid hormone that acts as a physiological parathyroid hormone antagonist. The interrelationships between these hor­ mones, calcium metabolism, and PTH-relatedprotein produced by fetal tissue are discussed in Chapter 4 (p. 7 1 ) . O f fetal demands, calcium requirements reach 300 mg/d in late pregnancy and 30 g for the entire gestation. These needs and greater renal calcium loss from augmented glomerular iltra­ tion substantively raise maternal calcium demands. Pregnancy

is associated with a twofold rise in serum concentrations of 1 ,25-dihydroxyvitamin D, which increases gastrointestinal cal­ cium absorption. he efectuating hormone is probably of pla­ cental and decidual origin because maternal PTH levels are low normal or decreased during pregnancy (Cooper, 20 1 1 ; Molitch, 2000) . Total serum calcium levels decline with serum albumin concentrations, but ionized calcium levels remain unchanged. Vargas Zapata and colleagues (2004) have suggested a role for insulin-like growth factor- 1 (IGF- 1 ) in maternal calcium homeostasis and bone turnover. • Hyperparathyroidism

Hypercalcemia is caused by hyperparathyroidism or cancer in 90 percent of cases (Potts, 20 1 5) . Because many automated laboratory systems include serum calcium measurement, hyper­ parathyroidism has changed from being a condition deined by symptoms to one that is discovered on routine screening (Pallan, 20 1 2) . It has a reported prevalence of 2 to 3 per 1 000 women, but some have estimated the rate to be as high as 1 4 per 1 000 when asymptomatic cases are included. Almost 80 percent are caused by a solitary adenoma, and another 1 5 percent by hyper­ functioning of all four glands. In the remainder, a malignancy as the cause of increased serum calcium levels is usually obvious. Of note, PTH produced by tumors is not identical to the natu­ ral hormone and may not be detected by routine assays. In most patients, the serum calcium level is elevated to within only 1 to 1 . 5 mg/dL above the upper normal limit. This may help to explain why only 20 percent of those who have abnor­ mally elevated levels are symptomatic (Bilezikian, 2004) . In a fourth, however, symptoms become apparent when the serum calcium level continues to rise. Hypercacemic crisis manifests as stupor, nausea, vomiting, weakness, fatigue, and dehydration. All women with symptomatic hyperparathyroidism should be surgically treated (Potts, 20 1 5) . Indications for parathyroid­ ectomy include a serum calcium level 1 .0 mg/dL above the upper normal range, a calculated creatinine clearance < 60 mLi min, reduced bone density, or age > 50 years (Bilezikian, 2009) . Those not meeting these criteria should undergo annual serum calcium and creatinine level measurement and bone density assessment every 1 to 2 years (Pallan, 20 1 2) . H yp e r p a rathyro i d i s m i n P reg n a ncy

In their review, Schnatz and Thaxton (2005) found fewer than 200 reported cases of hyperparathyroidism complicating pregnancy. As in nonpregnant patients, parathyroid adenoma is the most common etiology. Ectopic parathyroid hormone production and rare cases of parathyroid carcinoma have been reported in pregnancy (Montoro, 2000; Saad, 20 1 4) . Symp­ toms include hyperemesis, generalized weakness, renal calculi, and psychiatric disorders. Occasionally, pancreatitis is the pre­ senting disorder (Cooper, 20 1 1 ; Hirsch, 20 1 5) . Pregnancy theoretically improves hyperparathyroidism because of signiicant calcium shunting to the fetus and aug­ mented renal excretion (Power, 1 999) . When the "protective efects" of pregnancy are withdrawn, however, postpartum hypercalcemic crisis is a significant danger. his life-threatening complication can be seen with serum calcium levels greater than

E n docri ne D i s o rd e rs

1 4 mgl dL and is characterized by nausea, vomiting, tremors, dehydration, and mental status changes (Malekar-Raikar, 20 1 1 ) . Early reports described excessive stillbirths and preterm deliveries in pregnancies complicated by hyperparathyroid­ ism. More recent reports, however, described lower rates of stillbirth, neonatal death, and neonatal tetany (Kovacs, 2 0 1 1 ) . Other fetal complications include miscarriage, · fetal-growth restriction, and low birthweight (Chamarthi, 20 1 1 ) . Schnatz (2005) reported a 25-percent incidence of preeclampsia. Management in Pregnancy. Surgical removal of a symptomatic parathyroid adenoma is preferable. This should prevent fetal and neonatal morbidities and postpartum parathyroid crises (Kovacs, 20 1 1) . Elective neck exploration during pregnancy is usually well tolerated, even in the third trimester (Hirsch, 20 1 5; Schnatz, 2005; Stringer, 20 1 7) . In at least two cases, a mediastinal adenoma was removed at midpregnancy (Rooney, 1 998; Saad, 20 1 4) . Medical management may b e appropriate i n asymptomatic pregnant women with mild hypercalcemia (Hirsch, 20 1 5) . If so, patients are careully monitored in the puerperium for hypercal­ cemic crisis. Initial medical management might include cacito­ nin to decrease skeletal calcium release, or oral phosphate, 1 to 1 .5 g daily in divided doses, to bind excess calcium. For women with dangerously elevated serum calcium levels or those who are mentally obtunded with hypercacemic crisis, emergency treatment is instituted. Diuresis with intravenous normal saline is begun so that urine low exceeds 1 50 mLlhr. Furosemie is given in conven­ tional doses to block tubular calcium reabsorption. Importantly, hypokalemia and hypomagnesemia should be prevented. Adjunc­ tive therapy includes mithramycin, which inhibits bone resorption. Neonata l Efects. Normally, cord blood calcium levels are higher than maternal levels (Chap. 7, p. 1 39) . With maternal hyperparathyroidism, abnormally elevated maternal and thus fetal levels further suppress fetal parathyroid function. Because of this, newborn calcium levels rapidly drop after birth, and 1 5 to 25 percent of these neonates develop severe hypocalcemia with or without tetany (Molitch, 2000) . Neonatal hypopara­ thyroidism caused by maternal hyperparathyroidism is usually transient and is treated with calcium and 1 ,25-dihydroxyvita­ min D3 (calcitriol) . he latter will not be efective in preterm infants, however, because the intestinal vitamin D receptor is not suiciently expressed (Kovacs, 2 0 1 1 ) . Neonatal tetany or seizures should stimulate an evaluation for maternal hyperpara­ thyroidism (Beattie, 2000; Ip, 2003) .

gluconate or calcium lactate in doses of 3 to 5 g/d; and a low­ phosphate diet. Fetal risks from large doses of vitamin D have not been established. During treatment, the therapeutic chal­ lenge in women with known hypoparathyroidism is manage­ ment of blood calcium levels. It is possible that the greater calcium absorption typical of pregnancy will result in lower calcium requirements or that the fetal demand for calcium will result in greater need. he goal during pregnancy is to maintain a corrected calcium level in the low normal range. • Pregnancy-Associated Osteoporosis

In most gravidas, even with their remarkably increased calcium requirements, it is uncertain whether pregnancy causes osteopenia (Kaur, 2003; To, 2003) . In one study of 200 pregnant women in which bone mass was measured, Kraemer and colleagues (20 1 1 ) demonstrated a decline in bone density during pregnancy. Women who breastfed, carried twin pregnancies, or had a low body mass index were at higher risk of bone loss. From their review, Thomas and Weisman (2006) cite a 3- to 4-percent average reduction in bone mineral density during pregnancy. Lactation also represents a period of negative calcium balance that is corrected through maternal skeletal resorption. Feigenberg and coworkers (2008) found cortical bone mass reductions using ultrasound in young primiparas in the puerperium compared with nulligravid controls. Rarely, some women develop idiopathic osteoporosis while preg­ nant or lactating (Hellmeyer, 2007) . The most common symptom of osteoporosis is back p ain in late pregnancy or postpartum. Other symptoms are hip pain, either unilateral or bilateral, and diiculty in weight bearing until the woman is nearly immobilized (Maliha, 20 1 2) . In more than half of women, no apparent reason for osteopenia is found. Some known causes include heparin (unfractionated only) , prolonged bed rest, and corticosteroid therapy (Cun­ ningham, 2005; Galambosi, 20 1 6) . In a few cases, overt hyper­ parathyroidism or thyrotoxicosis eventually develops. Treatment is problematic and includes calcium and vita­ min D supplementation and standard pain management. Shown in Figure 58-5 is a hip radiograph from a woman

• Hypoparathyroidism

The most common cause of hypocalcemia is hypoparathyroid­ ism that usually follows parathyroid or thyroid surgery. Hypo­ parathyroidism is estimated to follow up to 7 percent of total thyroidectomies (Shoback, 2008) . It is characterized by facial muscle spasms, muscle cramps, and paresthesias of the lips, tongue, fingers, and feet. This can progress to tetany and seizures (Potts, 20 1 5) . Chronically, hypocalcemic pregnant women may also have a fetus with skeletal demineralization resulting in mul­ tiple bone fractures in the neonatal period (Alikasifoglu, 2005) . Maternal treatment includes calcitriol, dihydrotachysterol, or large vitamin D doses of 50,000 to 1 50,000 U/d; calcium

FIGURE 58-5 Anteroposterior p l a i n hip rad iog raph of a 25-ye a r­ old wo man at 26 weeks' gestation. She com p l a i ned of left h i p a n d knee pain a n d prog ressive wea kness. Tra n sient osteoporosis of the left fe m u r responded over 3 months to physical therapy combi ned with vita m i n 0 and ca l c i u m supplementation .

1 1 29

1 1 30

Med i c a l a n d S u rg ica l Co m p l i cations

treated at Parkland Hospital during the third trimester for transient osteoporosis of pregnancy. For women with preg­ nancy-associated osteopenia, long-term surveillance indicates that although bone density improves, these women and their ofspring may have chronic osteopenia (Carbone, 1 99 5 ) . Related, prenatal supplementation of normal women with cholecalciferol, 1 000 IU / d, did not increase ofspring bone mineral content, although it did ensure maternal vitamin D repletion (Cooper, 20 1 6) . ADRENAL GLAND DISORDERS Pregnancy has profound efects on adrenal cortical secretion and its control or stimulation. These interrelationships were reviewed by Lekarev and New (20 1 1 ) and are discussed in detail in Chapter 4 (p. 7 1 ) . • Pheochromoctoma

Pheochromocytomas are chromain tumors that secrete cat­ echolamines and usually are located in the adrenal medulla, although 1 0 percent are located in sympathetic ganglia. They are called the 1 0-percent tumor because approximately 1 0 per­ cent are bilateral, 1 0 percent are extraadrenal, and 1 0 percent are malignant. These tumors can be associated with medullary thyroid carcinoma and hyperparathyroidism in some of the autosomally dominant or recessive multiple endocrine neopla­ sia syndromes, as well as in neurofi b romatosis and von Hippel­ Lindau disease (Neumann, 20 1 5) . These tumors complicate approximately 1 per 50,000 pregnancies (Quartermaine, 20 1 7) . Notably, they are found in 0 . 1 percent of hypertensive patients (Abdelmannan, 20 1 1 ) . However, they are more commonly found at autopsy but with infrequent clinical recognition . Symptoms are usu­ ally paroxysmal and manifest as hypertensive crisis, seizure disorders, or anxiety attacks. Hypertension is sustained in 60 percent of patients, but half of these also have paroxysmal crises. Other symptoms during paroxysmal attacks are head­ aches, profuse sweating, palpitations, chest pain, nausea and vomiting, and pallor or flushing. The standard screening test is quantification of meta­ nephrines and catecholamine metabolites in a 24-hour urine specimen (Neumann, 20 1 5) . Diagnosis is established by mea­ surement of a 24-hour urine collection with at least two of three assays for free catecholamines, metanephrines, or vanil­ lylmandelic acid (VMA) . Determination of plasma catechol­ amine levels is the most sensitive test. In nonpregnant patients, adrenal localization is usually successful with either computed tomography (CT) or magnetic resonance (MR) imaging. For most cases, preferred treatment is laparoscopic adrenalectomy (Neumann, 20 1 5) .

TABLE 58-6. Outcomes of P reg n a ncies Com p l i cated by Pheoch romocytoma a n d Reported in Fou r Contiguous Epochs

D i a g nosis A ntep a rtu m Postpa rtu m A utopsy Mate r n a l death Fet a l wastage

51 36 12 16 26

83 14 2 4 11

70 23 7 12 17

73 28

8 17

are now lower but still formidable. I n their review of 77 cases, Biggar and Lennard (20 1 3) reported that antepartum diagnosis is the most important determinant of maternal mortality risk. That said, Salazar-Vega and colleagues (20 1 4) described good outcomes in women diagnosed after delivery. Diagnosis of pheochromocytoma in pregnancy is simi­ lar to that for nonpregnant patients. MR imaging is the pre­ ferred technique because it almost always locates adrenal and extraadrenal pheochromocytomas (Fig. 5 8-6) . In many cases, the principal challenge is to diferentiate preeclampsia from the hypertensive crisis caused by pheochromocytoma. Grim­ bert and colleagues ( 1 999) diagnosed two pheochromocytomas during 56 pregnancies in 30 women with von Hippel-Lindau disease.

P h eoc h ro m ocyto m a Co m p l icati n g P reg n a n cy

These tumors are rare but result in dangerous pregnancy com­ plications. Geelhoed ( 1 983) provided an earlier review of 89 cases in which 43 mothers died. Maternal death was much more common if the tumor was not diagnosed antepartum-58 ver­ sus 1 8 percent. As seen in Table 5 8-6, maternal mortality rates

F I G U RE 58-6 Coro n a l mag netic resona nce image taken in a 32-week preg n a nt wom a n shows a rig ht-sided pheoc h romocy­ tom a (arrow) a nd its position relative to the l iver a bove it.

Endoc r i n e D i s o rders M a n a g e me nt

Immediate control of hypertension and symptoms with an .-adrenergic blocker such as phenoxybenzamine is impera­ tive. he dose is 1 0 to 30 mg, two to four times daily. After .-blockade is achieved, 3-blockers may be given for tachycar­ dia. In many cases, surgical exploration and tumor removal are performed during pregnancy, preferably during the second trimester (Biggar, 20 1 3; Dong, 20 1 4) . Successful laparoscopic removal of adrenal tumors has become the norm (Miller, 20 1 2; Zuluaga-G6mez, 20 1 2) . If diagnosed later in pregnancy, either planned cesarean delivery with tumor excision or postpartum resection is appropriate. Recurrent tumors are troublesome, and even with good blood pressure control, dangerous peripartum hypertension may develop. We have cared for three women in whom recur­ rent pheochromocytoma was identiied during pregnancy. Hypertension was managed with phenoxybenzamine in all three. Two newborns were healthy, but a third was stillborn in a mother with a massive tumor burden who was receiving phenoxybenzamine, 1 00 mg daily. In all three women, tumor was resected postpartum. • Cushing Syndrome

his syndrome is rare and the female:male ratio is 3: 1 (Arit, 20 1 5) . Most cases are iatrogenic from long-term corticosteroid treatment. Cushing disease refers to bilateral adrenal hyperplasia stimulated by corticotropin-producing pituitary adenomas. Cor­ ticotropin is also called adrenocorticotropic hormone (ACTH) . Most adenomas are microadenomas measuring < 1 em, and half measure < 5 mm. Rarely, abnormal secretion of hypothalamic corticotropin-releasing factor may cause corticotropic hyper­ plasia. Such hyperplasia may also be caused by nonendocrine tumors that produce polypeptides similar to either corticotro­ pin-releasing factor or corticotropin. Less than a fourth of cases of Cushing syndrome are corticotropin independent, and most of these are caused by an adrenal adenoma. Tumors are usually bilateral, and half are malignant. Occasionally, associated andro­ gen excess may lead to severe virilization. he typical cushingoid body habitus is caused by adipose tissue deposition that characteristically results in moon acies, a builo hump, and truncal obesiy. Fatigability and weakness, hypertension, hirsutism, and amenorrhea are each encountered in 75 to 85 percent of nonpregnant patients (Hatipoglu, 20 1 2) . Personality changes, easy bruisability, and cutaneous striae are common. Up to 60 percent may have impaired glucose toler­ ance. Diagnosis can be diicult and is suggested by elevated plasma cortisol levels that cannot be suppressed by dexametha­ sone or by elevated 24-hour urine free cortisol excretion (Arit, 20 1 5 ; Loriaux, 20 1 7) . Neither test is totally accurate, and each is more diicult to interpret in obese patients. Serum corti­ cotropin levels and CT and MR imaging are used to localize pituitary and adrenal tumors or hyperplasia. C u s h i n g Syn d ro m e a n d Preg n a n cy

Because most women have corticotropin-dependent Cushing syndrome, associated androgen excess may cause anovulation,

TABLE 58-7. Mater n a l a n d Peri nata l Com p l i cations i n Preg n a ncies Com p l i cated by Cush i n g Syn d ro m e Compl ication Materna l Hyperte n s i o n D i a betes Preec l a m psia Osteo porosi s/fractu re Psyc h i atri c d i sorders Ca rd i a c fa i l u re Morta l ity Perinatal Feta l-g rowth restri cti o n P rete rm d e l i very Sti l l b i rth Neonata l death

I ncidence (%) 68 25 15 5

4 3 2

21

43

6

2

Data fro m L i n dsay, 2005.

and pregnancy is rare. In their review, Lekarev and New (20 1 1 ) identiied fewer than 1 40 reported cases of Cushing syndrome in pregnancy. These difer compared with nonpregnant women in that half are caused by corticotropin-independent adrenal adenomas (Kamoun, 20 1 4; Lacroix, 20 1 5) . Approximately 30 percent of cases are from a pituitary adenoma, and 1 0 percent from adrenal carcinomas. All reports stress diiculties in diag­ nosis because of pregnancy-induced increases in plasma cortisol, corticotropin, and corticotropin-releasing factor levels. Measure­ ment of24-hour urinary free cortisol excretion is recommended, with consideration for the normal elevation seen in pregnancy. Pregnancy outcomes in women with Cushing syndrome are listed in Table 5 8-7. Heart failure is common during preg­ nancy and is a major cause of maternal mortality (Buescher, 1 992) . Hypercortisolism in pregnancy may also cause poor wound healing, osteoporotic fracture, and psychiatric compli­ cations (Kamoun, 20 1 4) . Long-term medical therapy for Cushing syndrome usually is inefective, and deinitive therapy is resection of the pituitary or adrenal adenoma or bilateral adrenalectomy for hyperplasia (Lacroix, 20 1 5 ; Motivala, 20 1 1 ) . During pregnancy, manage­ ment of hypertension in mild cases may suice until delivery. In their review, Lindsay and associates (2005) described pri­ mary medical therapy in 20 women with Cushing syndrome. Most were successfully treated with meyrapone as an interim treatment until deinitive surgery after delivery. A few cases were treated with oral ketoconazole. However, because this drug also blocks testicular steroidogenesis, treatment during p reg­ nancy with a male fetus is worrisome. Miepristone, the noreth­ indrone derivative used for abortion and labor induction, has shown promise for treating Cushing disease but should not be used in pregnancy for obvious reasons. If necessary, pituitary adenomas can be treated by transsphenoidal resection (Boscaro, 200 1 ; Lindsay, 2005). Unilateral adrenalectomy has been safely performed in the early third trimester and can also be curative (Abdelmannan, 20 1 1 ) .

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Med i ca l a n d S u rg ic a l Compl ications

• Adrenal I nsuficiency-Addison Disease

Primary adrenocortical insuiciency is rare because more than 90 percent of total gland volume must be destroyed for symptoms to develop. Autoimmune adrenalitis is the most common cause in the developed world, but tuberculosis is a more frequent etiology in resource-poor countries (Arit, 20 1 5 ; Kamoun, 2 0 1 4) . The incidence has been cited as being as high as 1 in 3000 births in Norway (Lekarev, 20 1 1 ) . In the United States, the prevalence was 1 per 1 0,000 to 20,000 pregnancies (Schneiderman, 20 1 7) . here is an increased incidence of con­ current H ashimoto thyroiditis, primary ovarian insuiciency, type 1 diabetes, and Graves disease. These poyglandular auto­ immune syndromes also include pernicious anemia, vitiligo, alo­ pecia, nontropical sprue, and myasthenia gravis. Untreated adrenal hypofunction frequently causes infer­ tility, but with replacement therapy, ovulation is restored. If untreated, symptoms often include weakness, fatigue, nausea and vomiting, and weight loss. Because serum cortisol levels are increased during pregnancy, the inding of a low value should prompt a cosyntropin test to document the lack of response to infused corticotropin (Salvatori, 2005) . In a large Swedish cohort study, 1 1 88 women with Addison disease were compared with more than 1 1 ,000 age-matched controls who delivered between 1 973 and 2006 (Bjornsdottir, 20 1 0) . Women diagnosed with adrenal insuiciency within 3 years of delivery were signiicantly more likely to deliver pre­ term, to deliver a low-birthweight newborn, and to undergo cesarean delivery. Others have reported similar adverse out­ comes (Quartermaine, 20 1 7) . Most pregnant women with Addison disease are already taking glucocorticoid and miner­ alocorticoid replacement drugs. hese should be continued and women observed for evidence of either inadequate or excessive corticosteroid replacement (Lebbe, 20 1 3) . During labor, deliv­ ery, and postpartum, or after a surgical procedure, corticoste­ roid replacement must be increased appreciably to approximate the normal adrenal response-the so-called stress dose. Hydro­ cortisone, 1 00 mg, is usually given intravenously every 8 hours for 48 hours. It is important that shock from causes other than adrenocortical insuiciency-for example, hemorrhage or sep­ sis-be recognized and treated promptly. • Primary Aldosteronism

Hyperaldosteronism is caused by an adrenal adenoma-Conn syndrome-in approximately 75 percent of cases. Idiopathic bilateral adrenal hyperplasia makes up the remainder, except for rare cases of adrenal carcinoma (Abdelmannan, 20 1 1 ; Eschler, 20 1 5) . Findings include hypertension, hypokalemia, and muscle weakness. High serum or urine levels of aldosterone confirm the diagnosis. In normal pregnancy, as discussed in Chapter 4 (p. 72) , progesterone blocks aldosterone action, and thus there are very high aldosterone levels (Appendix, p. 1 25 8 ) . Accordingly, the diagnosis of hyperaldosteronism during pregnancy can be diicult. Since renin levels are suppressed in pregnant women with hyperaldosteronism, a plasma aldosterone-to-renin activity ratio may be helpful for diagnosis (Kamoun, 20 1 4) . Hypertension worsens as pregnancy progresses, and medical

management includes potassium supplementation and anti­ hypertensive therapy. In many cases, hypertension responds to spironolactone, but 3-blockers or calcium-channel blockers may be preferred because of the potential fetal antiandrogenic efects of spironolactone. Mascetti and coworkers (20 1 1 ) reported successful use of amiloride i n a pregnant woman. Use of eplerenone, a selective aldosterone-receptor antagonist, has also been reported (Cabassi, 20 1 2) . Laparoscopic tumor resection is curative (Eschler, 20 1 5 ; M iller, 20 1 2) . PITU ITARY DISORDERS The pituitary enlarges impressively during pregnancy, predomi­ nately from lactotrophic cellular hyperplasia induced by estro­ gen stimulation (Chap. 4, p. 68) . Several pituitary disorders can also complicate pregnancy. • Prolactinomas

These adenomas are found often in nonpregnant women since the advent of widely available serum prolactin assays. Serum levels < 25 pg/mL are considered normal in nonpregnant women (Nlotivala, 20 1 1 ) . Adenoma symptoms and indings include amenorrhea, galactorrhea, and hyperprolactinemia. Tumors are classiied arbitrarily by their size measured by CT or MR imaging. A micro adenoma is :;1 0 mm, and a macroad­ enoma is > 1 0 mm. Treatment for microadenomas is usually with bromocriptine, a dopamine agonist and powerful prolac­ tin inhibitor, which frequently restores ovulation. For suprasel­ lar macroadenomas, most recommend surgical resection before pregnancy is attempted (Araujo, 20 1 5) . I n a pooled analysis o f more than 750 pregnant women with prolactinomas, only 2.4 percent with microadenomas devel­ oped symptomatic enlargement during pregnancy (Molitch, 2 0 1 5). Symptomatic enlargement of macroadenomas, however, is more frequent and was found in 2 1 percent of 238 pregnant women. Schlechte (2007) also reported that 1 5 to 35 percent of suprasellar macroadenomas have tumor enlargement that causes visual disturbances, headaches, and diabetes insipidus. Nonfunctioning adenomas can also cause symptoms of pitu­ itary expansion in pregnancy (Lambert, 20 1 7) . Pregnant women with microadenomas should be queried regularly for headaches and visual symptoms. Those with mac­ roadenomas are followed more closely and have visual field test­ ing during each trimester. CT or MR imaging is recommended only if symptoms develop ( Fig. 5 8-7) . Serial serum prolactin levels serve little use because of normal rises during pregnancy (Appendix, p. 1 259) . Symptomatic tumor enlargement should be treated immediately with a dopamine antagonist. he safety of bromocriptine in pregnancy is well established. The safety profi l e is less well known for cabergoline, which is increas­ ingly used in nonpregnant women because it is better tolerated and more efective. Cabergoline is generally considered safe for use in pregnancy (Araujo, 20 1 5 ; Auriemma, 20 1 3) . Lebbe and colleagues (20 1 0) described 1 00 pregnancies exposed to cabergoline and found no adverse efects. Similar indings were reported in 85 exposed Japanese pregnant women (Ono, 20 1 0) . Surgery is recommended for women with no response.

Endocrine D i s o rd e rs

because of an increased metabolic clearance rate stimulated by placentl vasopressinase (Lindheimer, 1 994). By this same mecha­ nism, subclinicaL diabetes inspidus may become symptomatic or cases of transient diabetes inspidus may be encountered during pregnancy (Bellastella, 20 1 2; Robertson, 20 1 5) . he prevalence of vasopressinase-induced diabetes insipidus is estimated at 2 to 4 per 1 00,000 pregnancies (Wallia, 20 l 3) . In our experiences, a s described i n Chapter 5 5 (p. 1 062) , transient secondary diabetes insipidus is more likely encoun­ tered with acute atty Liver ofpregnancy (Nelson, 20 l 3) . This probably is due to altered vasopressinase clearance because of hepatic dysfunction. • Sheehan Synd rome

FIGURE 58-7 Magnetic resona nce imaging of a pitu itary adenoma: Sag ittal Tl -weig hed i mage demonstrates a hyperintense sel l a r a nd su prasellar mass (arrow). N ote the layeri ng of complex fl uid within the mass, which was found d u ri n g surgery to be hemorrhage. (Used with perm ission from Dr. April Bai ly.)

• Acromegaly

his is caused by excessive growth hormone, usually from an acidophilic or a chromophobic pituitary adenoma. In normal pregnancy, pituitary growth hormone levels decrease as placen­ tal epitopes are secreted. Diagnosis is confirmed by elevated IGF- 1 serum levels (Katznelson, 20 1 4) . Fewer than 1 00 cases of acromegaly have been reported during pregnancy (Cheng, 20 1 2; Dias, 20 1 3; Motivala, 20 1 1 ) . Pregnancy is probably rare in women with acromegaly because half are hyperprolactin­ emic and anovulatory. During pregnancy, afected women are at marginally greater risk for gestational diabetes and hyperten­ sion (Caron, 20 1 0; Dias, 20 l 3) . Management i s similar to that for prolactinomas, with close monitoring for symptoms of tumor enlargement. Dopamine agonist therapy is less efective than for prolactinomas. And, transsphenoidal resection, generally considered irst-line treat­ ment outside of pregnancy, may be necessary for symptomatic tumor enlargement during pregnancy (Motivala, 20 1 1 ) . Guven and associates (2006) reported a case of pituitary apoplexy necessitating emergent transsphenoidal adenoma resection and cesarean delivery at 34 weeks. S uccessful treatment of preg­ nant women with the somatostatin-receptor ligand octreotide and with the GH analogue pegvisomant has also been reported (Dias, 20 1 3; Fleseriu, 20 1 5) . • Diabetes Insipidus

The vasopressin deficiency evident in diabetes insipidus is usu­ ally due to agenesis or destruction of the neurophypophysis (Robertson, 20 1 5) . True diabetes insipidus is a rare complica­ tion of pregnancy. Diabetes insipidus therapy is intranasal administration of a syn­ thetic analogue of vasopressin, desmopressin, which is 1 -deamino8-D-arginine vasopressin (DDAP) . Ray ( 1 998) reviewed 53 cases in which DDAP was used during pregnancy with no adverse sequelae. Most women require increased doses during pregnancy

Sheehan ( 1 937) reported that pituitary ischemia and necrosis associated with obstetrical blood loss could result in hypo­ pituitarism. With modern methods of hemorrhagic shock treatment, Sheehan syndrome is now seldom encountered (Feinberg, 2005; Pappachan, 20 1 5 ; Robalo, 20 1 2) . Afected women may have persistent hypotension, tachycardia, hypo­ glycemia, and lactation failure. Because deficiencies of some or all pituitary-responsive hormones may develop after the initial insult, Sheehan syndrome can be heterogenous and may not be identified for years (Tessnow, 20 1 0) . In one cohort study of 60 women from Costa Rica with Sheehan syndrome, the average time to diagnosis was 1 3 years (Gei-Guardia, 20 1 1 ) . Because adrenal insuiciency is the most life-threatening complication, adrenal function should be immediately assessed in any woman suspected of having Sheehan syndrome. Mter glucocorticoid replacement, subsequent analyses and replacement of thyroid, gonadal, and growth hormones is considered. • Lymphocytic Hypophysitis

This rare autoimmune pituitary disorder is characterized by massive iniltration by lymphocytes and plasma cells with parenchymal destruction of the gland. vIany cases are tem­ porally linked to pregnancy (Foyouzi, 20 1 1 ; Honegger, 20 1 5; Melmed, 20 1 5) . here are varying degrees of hypopituitarism or symptoms of mass efect, including headaches and visual ield defects. A sellar mass is seen with CT or MR imaging. A mass accompanied by a modestly elevated serum prolactin level-usually < 1 00 pgl mL-suggests lymphocytic hypophy­ sitis. In contrast, levels > 200 pg/mL are encountered with a prolactinoma. he etiology is unknown, but nearly 30 percent have a history of coexisting autoimmune diseases including Hashimoto thyroiditis, Addison disease, type 1 diabetes, or pernicious anemia. Treatment is with glucocorticoids and pitu­ itary hormone replacement. he disease may be self-limited, and a careful withdrawal of hormone replacement is attempted after inflammation subsides (Foyouzi, 20 1 1 ; Melmed, 20 1 5). REFERENCES Abalovich I, Alcaraz G, Kleiman-Rubinsztein ] , et al: he relationship of preconception thyrotropin levels to requirements for increasing the levo­ thyroxine dose during pregnancy in women with primary hypothyroidism. Thyroid 20( 1 0) : 1 1 5, 20 1 0

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E ndocrine Disorders Robertson GL: Disorders of the neurohypophysis. In Kasper L, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 1 9th ed. New York, McGraw-Hill Education, 20 1 5 Rooney DP, Traub AI, Russell CF], et al: Cure of hyperparathyroidism i n pregnancy b y sternotomy a n d removal of a mediastinal parathyroid ade­ noma. Postgrad Med ] 74:233, 1 998 Rovelli R, Vigone M , Giovanettoni C, et al: Newborns of mothers afected by autoimmune thyroiditis: the importance of thyroid function monitoring i n the irst months of life. Ital ] Pediatr 36:24, 20 1 0 Saad AF, Pacheco LD, Costantine MM: Management o f ectopic parathyroid adenoma in pregnancy. Obstet GynecoI 1 24:478, 20 1 4 Salazar-Vega ]L, Levin G , Sanso G : Pheochromocytoma associated with preg­ nancy: unexpected favourable outcome in patients diagnosed after delivery. ] Hypertens 32(7) : 1 45 8 , 20 1 4 Salvatori R : Adrenal insuiciency. ]AMA 294:248 1 , 2005 Sarathi V, Lila A, Bandgar T, et al: Pheochromocytoma and pregnancy: a rare but dangerous combination. Endocr Pract 1 6(2): 300, 20 1 0 Sarkhail P , Mehran L , Askari S , e t al: Maternal thyroid function and autoim­ munity in 3 trimesters of pregnancy and their ofspring's thyroid function. Horm Metab Res 48:20, 20 1 6 Schlechte ]A: Long-term management o f prolactinomas. ] Clin Endocrinol Metab 92:286 1 , 2007 Schnatz PF, haxton S : Parathyroidectomy in the third trimester of pregnancy. Obstet Gynecol Surv 60:672, 2005 Schneiderman M, Czuzoj-Shulman N , Spence AR, et al : Maternal and neona­ tal outcomes of pregnancies in women with Addison's disease: a population­ based cohort study on 7.7 millions births. B]OG 1 24 : 1 772, 20 1 7 Scoccia B , Demir H , Kang Y, et al: In viro fertilization pregnancy rates in levothyroxine-treated women with hypothyroidism compared to women without thyroid dysfunction disorders. TIlyroid 22(6) : 63 1 , 20 1 2 Sheehan HL: Post-partum necrosis of the anterior pituitary. ] Pathol Bacteriol 45 : 1 89, 1 937 Sheehan PM, Nankervis A, Araujo ] linior E, et al: Maternal thyroid disease and preterm birth: systematic review and meta-analysis. ] Clin Endocrinol Metab 1 00( 1 1 ):4325, 20 1 5 Sheield ]S, Cunningham FG: Thyrotoxicosis and heart failure that complicate pregnancy, Am ] Obstet Gynecol 1 90 :2 1 1 , 2004 Shoback 0: Hypoparathyroidism . N Engl ] Med 359:39 1 , 2008 Siu CW, Zhang XH, Yung C, et al: Hemodynamic changes in hyperthyroidism­ related pulmonary hypertension: a prospective echocardiographic study. ] Clin Endocrinol Metab 92: 1 736, 2007 Song SI, Daneman D , Rovet ]: he inluence of etiology and treatment factors on intellectual outcome in congenital hypothyroidism. ] Dev Behav Pediatr 22:3 6, 200 1 Stagnaro-Green A: Maternal thyroid disease and preterm delivery. ] Clin Endo­ crinol Metab 94:2 1 , 2009 Stagnaro-Green A: Overt hyperthyroidism and hypothyroidism during preg­ nancy. Clin Obstet Gynecol 54(3) :478, 20 1 1 a Stagnaro-Green A, Glinoer 0: Thyroid autoimmunity and the risk of miscar­ riage. Baillieres Best Pract Res Clin Endocrinol Metab 1 8: 1 6 , 2004 Stagnaro-Green A, Pearce E: hyroid disorders in pregnancy. Nat Rev Endo­ crinol 8:650, 20 1 2a Stagnaro-Green A, Schwartz A, G ismondi R, et al: High rate of persistent hypothyroidism i n a large-scale prospective study of postpartum thyroiditis i n southern Italy. ] Clin Endocrinol Metab 96(3):652, 20 1 1 b Stagnaro-Green A, Sullivan S, Pearch EN: Iodine supplementation during pregnancy and lactatio n . ]AMA 308 (23) :2463, 20 1 2b Stringer KM, Gough ], Gough I R: Primary hyperparathyroidism during preg­ nancy: management by minimally invasive surgery based on ultrasound localization. ANZ ] Surg 87( 1 0) : E 1 34, 20 1 7 Stulberg RA, Davies GAL: Maternal thyrotoxicosis and fetal nonimmune hydrops. Obstet Gynecol 95: 1 036, 2000 Su PY, Huang K, Hao ]H, et al: Maternal thyroid function in the first rwenry weeks of pregnancy and subsequent fetal and infant development: a pro­ spective population-based cohort study in China. ] Clin Endocrinol Metab 96( 1 0) : 3234, 20 1 1 Surks MI, Ortiz E, Daniels GH, et al: Subclinical thyroid disease: scientiic review and guidelines for diagnosis and management. ]AMA 29 1 (2) :228, 2004

Swanson CA, Zimmerman M B , Skeaf S, et al: Summary of an N I H workshop to identiy research needs to improve the monitoring of iodine status i n the United States and to inform the DRI l -3. ] Nutr 142: 1 1 75S, 20 1 2 Tan TO, Cheng W, Caughey AB: Are women who are treated for hypothy­ roidism at risk for pregnancy complications? Am ] Obstet Gynecol 1 94 :e l , 2006 Teng W, Shan Z, Teng X, et al: Efect of iodine i ntake on thyroid diseases i n China. N Engl ] Med 3 54:2783, 2006 Tessnow A, Wilson ]: The changing face of Sheehan's syndrome. Am ] Med Sci 340(5):402, 20 1 0 Thangaratinam S , Tan A, Knox E , e t al: Association berween thyroid autoan­ tibodies and miscarriage and preterm birth: meta-analysis of evidence. BM] 342:d26 1 6, 2 0 1 1 Thomas M, Weisman SM: Calcium supplementation during pregnancy and lactation : efects on the mother and the fetus. Am ] Obstet Gynecol 1 94:937, 2006 Thomas S K, Sheield ]S, Roberts SW: Thionamide-induced neutropenia and ecthyma in a pregnant patient with hyperthyroidism. Obstet Gynecol 1 22:940, 20 1 3 Thorpe-Beeston ]G, Nicolaides KH, Snij ders RJ, e t al: Thyroid function i n small for gestational age fetuses. Obstet Gynecol 77: 70 1 , 1 99 1 To W, Wong MW, Leung TW: Relationship berween bone mineral density changes in pregnancy and maternal and pregnancy characteristics: a longi­ tudinal study. Acta Obstet Gynecol Scand 82:820, 2003 Tran P, DeSimone S , Barrett M , et al: 1- 1 3 1 treatment of Graves' disease in an unsuspected irst trimester pregnancy; the potential for adverse efects on the fetus and a review of the current guidelines for pregnancy screeni ng. Int ] Pediatr EndocrinoI 20 1 0:858359, 20 1 0 Tudela CM, Casey BM, McIntire D D , e t al: Relationship o f subclinical thyroid disease to the incidence of gestational diabetes. Obstet Gynecol 1 1 9(5): 983, 20 1 2 Vaidya B, Anthony S , Bilous M , e t al: Detection of thyroid dysfunction in early pregnancy: universal screening or targeted high-risk case finding? ] Clin Endocrinol Metab 9 2 ( 1 ) : 203, 2007 Vargas Zapata CL, Donangelo CM, Woodhouse LR, et al: Calcium homeo­ stasis during pregnancy and lactation in Brazilian women with low calcium intakes: a longitudinal study. Am ] Clin Nutr 80:4 1 7, 2004 Velasco I, Carreira M, Santiago P, et al: Efect of iodin e prophylaxis during pregnancy on neurocognitive development of children during the first rwo years of life. ] Clin Endocrinol Metab 94:3234, 2009 Vydt T, Verhelst ], De Keulenaer G : Cardiomyopathy and thyrotoxicosis: tachycardiomyopathy or thyrotoxic cardiomyopathy? Acta Cardiol 6 1 : 1 1 5 , 2006 Wallia A, Bizhanova A, Huang W, et aI: Acute diabetes insipidus mediated by vasopressinase after placental abruption. ] Clin Endocrinol Metab 9 8 : 88 1 , 20 1 3 Wang W, Teng W, Shan Z , e t al: h e prevalence o f thyroid disorders d uring early pregnancy in China: the beneits of universal screening i n the irst trimester of pregnancy. Eur ] Endocrinol 1 64(2) : 263, 20 1 1 Wikner BN, Sparre LS, Stiller CO, et al: Maternal use of thyroid hormones i n pregnancy a n d neonatal outcome. Acta Obstet Gynecol Scand 87(6) : 6 1 7, 2008 Wilson KL, Casey BM, McIntire DO, et al: Diagnosis of subcli nical hypo­ thyroidism early i n pregnancy is a risk factor for the development of severe preeclampsia. Clin Thyroidol 24(5) : 1 5 , 20 1 2 Yassa L , Marqusee E , Fawcett R , e t al: hyroid hormone early adjustment in pregnancy (the THERAPy) trial. ] Clin Endocrinol Metab 95 (7) :3234, 20 1 0 Yoshihara A, Noh ]Y, Mukasa K, at el: Serum human chorionic gonadotropin levels and thyroid hormone levels in gestational transient thyrotoxicosis: is the serum hCG level useful for diferentiating berween active Graves' disease and GTT? Endocr ] 62(6) : 5 57, 20 1 5 Yoshihara A, Noh ]Y, Yamaguchi T, e t al: Treatment o f Graves disease with antithyroid drugs i n the irst trimester of pregnancy and the prevalence of congenital malformation. ] Clin Endocrinol Metab 9 : 2396, 20 1 2 Zuluaga-Gomez A , Arrabal-Polo A, Arrabal-Martin M , e t al: Management of pheochromocytoma during pregnancy: laparoscopic adrenalectomy. Am Surg 8(3) : E 1 56, 20 1 2

1 1 37

1 1 38

C H A PT E R 5 9

Con nective Ti ss ue D i sorders

IMMUNE- M EDIATED CONN ECTIVE TISSUE DISEASES. . 1 1 38 SYSTEMIC LUPUS ERYTHEMATOSUS . . . . . . . . . . . . . . 1 1 39 ANTI PHOS P HOLIPID SYN DROM E . . . . .

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are more prevalent in women, for example, systemic lupus erythematosus (SLE) and rheumatoid arthritis. Second are the inherited disorders of bone, skin, cartilage, blood vessels, and basement membranes. Some examples include Marfan syn­ drome, osteogenesis imperfecta, and Ehlers-Danlos syndrome.

R H EU MATOID ARTHRITIS . . . . . . . . . . . . . . . . . . . . . . . 1 1 46 SYSTEMIC SCLEROSIS-SCLERODERMA . . . . . . . . . . . 1 1 48 VASC U LITIS SYN DROMES . . . . . . . . . . . . . . . . . . . . . . . 1 1 49 INFLAMMATORY MYOPATH IES . .

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. . . . . . . 1 1 50

H EREDITARY CONN ECTIVE TISSUE DISORDERS . . . . . 1 1 5 1

Owing to the great vasculariy incident to pregnancy, the var­ ious pelvicjoints always show a somewhat increased motiliy. In rare instances, particulary when the pelvis is contracted in the lower portion, spontaneous rupture ofthe symphysis pubis or one or both sacro-iliac joints has been observe. -]. Whitridge Williams ( 1 903) The principal concerns in the 1 st edition of Williams Obstetrics with disorders of the joints were the obstructed pelvis caused by rickets. There is no mention of the arthritides complicating pregnancy. And of course, immune-mediated disease had not yet been elucidated. Connective tissue disorders, which are also termed collagen vascular disorders, have two basic underlying causes. First are the immune-complex diseases in which connective tissue damage is caused by deposition of immune complexes. Because these are manifest by sterile inflammation-predominately of the skin, joints, blood vessels, and kidneys-they are referred to as rheumatic diseases. Many of these immune-complex diseases

I M M U N E - M EDIATED CON N ECTIVE TISS U E DISEASES hese disorders can be separated into those associated with and those without autoantibody formation. The rheumatoid actor (F) is an autoantibody found in many autoimmune inflam­ matory conditions such as SLE, rheumatoid arthritis, systemic sclerosis (scleroderma) , mixed connective tissue disease, der­ matomyositis, polymyositis, and various vasculitis syndromes. he F-seronegative spondyloarthropathies are strongly associated with expression of the human leukocyte antigen B27 (HLA­ B27) antigen and include ankylosing spondylitis, psoriatic arthritis, Reiter disease, and other arthritis syndromes. Pregnancy may mitigate activity in some of these syndromes as a result of the immunosuppression that also allows successful engraftment of fetal and placental tissues. These changes are discussed in detail in Chapters 4 (p. 5 8) and 5 (p. 95). One example is pregnancy-induced predominance ofT2 helper cells compared with cytokine-producing T 1 helper cells (Keeling, 2009) . Pregnancy hormones also alter immune cells. Namely, estrogens upregulate and androgens downregulate T-cell response, and progesterone is immunosuppressive (Cutolo, 2006; Haupl, 2008a; Robinson, 20 1 2) . In contrast, immune-mediated disease may contribute to obstetrical complications. One longitudinal cohort study found that unrecognized autoimmune systemic rheumatic disorders are associated with significant risk for preeclampsia and fetal­ growth restriction (Spinillo, 20 1 6) . In this study, the preva­ lence of unrecognized rheumatic arthritis was 0.4 percent, and was 0.3 percent each for SLE, Sjogren syndrome, and antiphos­ pholipid syndrome.

Con n ective Ti ssue D i s o rd e rs

Last, some immune-mediated diseases may either be caused or activated as a result of prior pregnancies. To explain, fetal cells and free fetal DNA are detectable in maternal blood beginning early in pregnancy (Simpson, 20 1 3 ; Sitar, 2005; Waldorf, 2008) . Fetal cell microchimerism is the persistence of fetal cells in the maternal circulation and in organs fol­ lowing pregnancy. These fetal cells may become engrafted in maternal tissues and stimulate autoantibodies. This raises the possibility that fetal cell micro chimerism leads to the predilec­ tion for autoimmune disorders among women (Adams, 2004) . Evidence for this includes fetal stem cells engrafted in tissues in women with autoimmune thyroiditis and systemic sclero­ sis Gimenez, 200 5 ; S;ivatsa, 200 1 ) . Such microchimerism has also been described in women with SLE and those with rheu­ matoid arthritis-associated HLA alleles (da Silva, 20 1 6; Lee, 20 1 0; Rak, 2009a) . Conversely, engrafted maternal cells may provoke autoimmune conditions in a woman's ofspring (Ye, 20 1 2; Stevens, 20 1 6) . SYSTEMIC LUPUS ERYTH EMATOSUS Lupus is a heterogeneous autoimmune disease with a complex pathogenesis that results in interactions between susceptibility genes and environmental factors (Hahn, 20 1 5) . Immune system abnormalities include overactive B lymphocytes that are respon­ sible for autoantibody production. hese result in tissue and cellular damage when autoantibodies or immune complexes are directed at one or more cellular nuclear components (Tsokos, 20 1 1 ) . In addition, immunosuppression is impaired, including regulatory T-cell function (Tower, 20 1 3) . Some autoantibodies produced in patients with SLE are shown in Table 59- I . Almost 90 percent of SLE cases are in women, and its prevalence in those of childbearing age approximates 1 in 500 (Lockshin, 2000) . Accordingly, the disease is encountered rela­ tively frequently during pregnancy. The 1 0-year survival rate is 70 to 90 percent (Tsokos, 2 0 1 1 ) . Infection, lupus lares, end­ organ failure, hypertension, stroke, and cardiovascular disease account for most deaths.

Genetic inluences are implicated by a higher concordance with monozygotic compared with dizygotic twins-25 versus 2 percent, respectively. Moreover, frequency in patients with one afected family member is 1 0 percent. he relative risk of disease rises if there is inheritance of the "autoimmunity gene" on chromosome 16 that predisposes to SLE, rheumatoid arthritis, Crohn disease, and psoriasis. Susceptibility genes such as HA-Al, -B8, -D3, -DBl, and - TET3 explain only a portion of the genetic herita­ bility (Tsokos, 20 1 1 ; Yang, 20 1 3) . Interestingly, even maternal exposure to fetal genes elevates susceptibility to SLE development. A case-control study found that a child's HLA-DRB 1 genotype increases the risk of SLE in the mother (Cruz, 20 1 6) . Further­ more, neonatal lupus erythematosus has been reported in an infant conceived via oocyte donor to a mother with autoimmune disease with circulating anti-Ro and anti-La antibodies (Chiou, 20 1 6) . • Clinical Manifestations and Diagnosis

Lupus is notoriously variable in its presentation, course, and outcome (Table 59-2) . Findings may be conined initially to one organ system, and others become involved later. O r, the disease may irst be multisystem. Frequent fi n dings are mal­ aise, fever, arthritis, rash, pleuropericarditis, photosensitivity, anemia, and cognitive dysfunction. At least half of patients have renal involvement. SLE is also associated with declines in atten­ tion, memory, and reasoning (Hahn, 20 1 5; Kozora, 2008) . Identification of antinuclear antibodies (ANA) is the best screening test, however, a positive result is not speciic for SLE. For example, low titers are found in normal individuals, other autoimmune diseases, acute viral infections, and chronic inlammatory processes. Several drugs can also cause a posi­ tive reaction. Antibodies to double-stranded DNA (dsDNA) and to Smith (Sm) antigens are relatively speciic for SLE, whereas other antibodies are not (see Table 5 9- 1 ) . Although hundreds of autoantibodies have been described in SLE, only a few have been shown to participate in tissue injury (Sherer, 2004; Tsokos, 20 1 1 ) . Currently, micro array proiles are being developed for more accurate SLE diagnosis (Putterman, 20 1 6) .

TABLE 59-1 . Some Autoa nti bodies Produced i n Pati ents with System i c L u p u s Erythematos u s (SLE) Anti body

Preva lence (%)

Anti n uc l e a r (ANA) A nti-d s D N A Anti-Sm (S m ith) Anti- R N P Anti-Ro (SS-A)

84-98 62-70 25-38 3 3-40 3 0-49

A nti-La (SS- B) Anti h istone A nti phosphol i pid

1 0-35 70 2 1 -50

Antieryth rocyte A n t i p l atelet

Best scree n i n g test, m u ltiple a ntibod ies; a secon d n egative test m a kes S L E u n l i ke ly H i g h titers S LE-specific; may correlate with d i sea se activity, n e p h ritis, a n d va scu l it i s Spec ific for S L E Not S L E-specifi c, h i g h titers associated w i t h rheu matic syn d ro mes Not SLE-speci fi c; associated with si cca syn d ro m e, pred i s poses to cuta neous l u p u s, neonata l l u pus with hea rt b l ock, red u ced risk of n e p h ritis Associ ated with a nti-Ro Com m on in d ru g - i n d uced l u pu s L u p u s a nticoa g u l a nt a nd a ntica rd i o l i p i n a nti bod ies associated with th ro m bos is, feta l l oss, th rom bocytopen ia, va lvu l a r heart d i sease; fa lse-positive test fo r syp h i l i s D i rect Coo m b s test, may deve l o p he mo lysis Th rom bocyto p e n i a i n 1 5%; poor cl i n ica l test

60 30

dsDNA d o u b le-stra nded D N A; R N P Data from Arbu ckle, 2003; Ha h n , 20 1 5 . =

Cli n ical Associations

=

ribon u c l eo p rote i n .

1 1 39

1 1 40

Med ical a nd S u rg ic a l Com p l ications

TABLE 59-2. Some C l i n ica l Man ifestations of System i c Lupus E rythematosus Organ System

Clinical Manifestations

Syste m i c M u scu l oskeleta l H e m atological

Fat i g ue, m a l a i se, fever, wei g ht l oss Art h ra l g i as, mya l g i as, polyarth ritis, myo pathy A n e m i a , h e m o lys i s, l e u kope n ia, t h rom bocytopen ia, l u p u s a nticoag u l a nt, sp lenomeg a ly M a l a r (butterfly) rash, d i scoid rash, p h otosensitivity, ora l u l ce rs, a l opec i a, skin rashes Cog n itive dysfu ncti o n , mood d i sorder, hea dache, seizu res, stro ke P l e u ritis, pericard itis, myoca rd itis, e ndoca rd itis, p n e u m o n itis, p u l m o n a ry hyperte n s i o n P rote i n u ri a , n e p h rotic syn d rome, re n a l fa i l u re N a u sea, pa i n , d i a rrhea, a bn o r m a l l iver enzyme level s Th rom bosis: venous ( 1 0%), a rteri a l (5%) Co nj u n ctivitis, s icca syn d rome

Cuta neous N e u ro l og ica l Card io p u l mo n a ry Rena l Gastro i ntesti n a I Vasc u l a r Ocu l a r

Percent 95 95 85 80 60 60 30-50 40 15 15

Modifi ed from Kasper, 2 0 1 5 .

Anemia develops frequently, and there may be leukopenia and thrombocytopenia. Proteinuria and casts are found in the half of patients with glomerular lesions. Lupus nephritis can also cause renal insuiciency, which is more common if there are anti phospholipid antibodies (Moroni, 2004) . Other labora­ tory indings include false-positive syphilis serology, prolonged partial thromboplastin time, and higher RF levels. Elevated serum D-dimer concentrations often follow a lare or infection, but unexplained persistent elevations are associated with a high risk for thrombosis (Wu, 2008) . The diagnostic criteria for SLE are listed in Table 59-3 . If any four or more of these 1 1 criteria are present, serially or TABLE 59-3. C l i n ica l Criteria for Classification of System i c Lupus Erythematosu s Clinica l Ma n ifestations Ski n Oral u l ce rs Alopecia Synovitis Re n a l : p rote i n u ria, ca sts, biopsy N e u ro l og ica l : se i z u res, psychosis, mye l itis, n e u ro path i es, confu s i o n a l state Hemo lytic a ne m i a Leu ko pe n i a or lym p h o pe n i a Th rom b ocytope n i a I m m u nolog ica l Manifestations ANA Anti-d sDNA Anti-Sm Anti p h osphol i p i d Hypoco m p le me n te m i a Di rect Coom bs a nti n u c l ea r a nti bod ies; d s D N A d o u b l e-stra nded ANA DNA; S m = S m ith . Data from H a h n, 2 0 1 5; H och berg, 1 997. =

=

simultaneously, the diagnosis of lupus is made. Importantly, numerous drugs can induce a lupus-like syndrome. These include proton-pump inhibitors, thiazide diuretics, antifun­ gals, chemotherapeutics, statins, and antiepileptics. Drug­ induced lupus is rarely associated with glomerulonephritis and usually regresses when the medication is discontinued (Lauri­ naviciene, 20 1 7) . • Lupus and Pregnancy

Of nearly 1 6.7 million pregnancies from 2000 to 2003 in the United States, 1 3,555 were complicated by lupus-an incidence of approximately 1 in 1 250 pregnancies (Clowse, 2008) . Dur­ ing pregnancy, lupus improves in a third of women, remains unchanged in a third, and worsens in the remaining third. Thus, in any given pregnancy, the clinical condition can worsen or lare without warning (Hahn, 20 1 5 ; Khamashta, 1 997) . Petri ( 1 998) reported a 7-percent risk of major morbidity during pregnancy. In a cohort of 1 3, 5 5 5 women with SLE during pregnancy, the maternal mortality and severe morbidity rate was 325 per 1 00,000 (Clowse, 2008 ) . In a review of 1 3 studies with 1 7 maternal deaths attributable to SLE and lupus nephritis, all occurred in those with active disease (Ritchie, 20 1 2) . Results of a prospective cohort study of 385 women are shown in Figure 59- 1 . During the past several decades, pregnancy outcomes in women with SLE have improved remarkably. For most women with inactive or mild/moderate SLE, pregnancy outcomes are relatively favorable. Women who have conined cutaneous lupus do not usually have adverse outcomes (Hamed, 20 1 3) . However, newly diagnosed SLE during pregnancy tends to be severe (Zhao, 20 1 3) . In general, pregnancy outcome is best in women for whom : ( 1 ) lupus activity has been quiescent for at least 6 months before conception; (2) there is no lupus nephritis manifest by proteinuria or renal dysfunction; (3) anti phospho­ lipid syndrome or lupus anticoagulant is absent; and (4) super­ imposed preeclampsia does not develop (Peart, 20 14; Stojan, 20 1 2; Wei, 20 1 7; Yang, 20 1 4) .

Co n nective Tissue D i s o rders Lu p u s ve rs u s Preec l a m ps i a- Ecla m ps i a

25 o SLE (n 385) o SLE, low risk (n =

20

• Controls (n

C 15 ) u

;

.

=

=

1 29)

1 98)

10 5

Any adverse outcome

Perinatal death

Preterm birth Fetal-growth restriction « 36 wks)

F I G U R E 59-1 F req uency of a dverse p reg nancy outcomes. A l l wom e n with system ic l u pus erythematosus (SLE) i n t h e PROM ISSE study a re compared with a su bset of low-risk SLE patients a nd with control patients without SLE. ( Data from Buyon, 201 5.)

Chronic hypertension complicates up to 30 percent of pregnan­ cies in women with SLE (Egerman, 2005). Also, as mentioned, preeclampsia is common, and superimposed preeclampsia is encountered even more often, and earlier, in those with nephritis or antiphospholipid antibodies (Bertsias, 2008) . Pre­ eclampsia and lupus nephritis share features of hypertension, proteinuria, edema, and renal function deterioration. How­ ever, the management is distinct, as lupus nephritis is treated with immunosuppression, and severe preeclampsia/eclampsia requires delivery (Lazzaroni, 20 1 6) . It may be diicult, if not impossible, to diferentiate lupus lare with nephropathy from severe preeclampsia if the kidney is the only involved organ (Petri, 2007) . Central nervous system involvement with lupus may culminate in convulsions similar to those of eclampsia. One proposed schema for diferentiating the two is shown in Table 59-4. Management for preeclampsia-eclampsia is described in Chapter 40 (p. 728).

Lu p u s N e p h ritis

Active nephritis is associated with adverse pregnancy outcomes, although these have improved remarkably and especially if dis­ ease remains in remission (Moroni, 2002, 2005; Stojan, 20 1 2) . O f complications, women with renal disease have a high inci­ dence of gestational hypertension and preeclampsia. Of 80 gravidas with SLE reported by Lockshin ( 1 989) , 63 percent of women with preexisting renal disease developed preeclamp­ sia compared with only 14 percent of those without underly­ ing renal disease. In a review of 309 pregnancies complicated by lupus nephritis, 30 percent sufered a lare, and 40 percent of these had associated renal insuiciency (Moroni, 2005). he maternal mortality rate was 1 .3 percent. These indings were corroborated in a subsequent prospective study (Moroni, 20 1 6b) . In addition, a third of the 1 1 3 pregnancies were deliv­ ered preterm (Imbasciati, 2009; Moroni, 20 1 6a) . Wagner and coworkers (2009) compared outcomes of 58 women with 90 pregnancies and found that active nephritis was linked with a signiicantly higher incidence of maternal complications-57 versus 1 1 percent. Most recommend continuation during pregnancy of immu­ nosuppressive therapy for nephritis. New-onset nephritis or severe renal lare is treated aggressively with intravenous cor­ ticosteroids and consideration of immunosuppressive drugs or intravenous immunoglobulin (Lazzaroni, 20 1 6) .

• Management During Pregnancy

Lupus management consists primarily of monitoring fetal well-being and maternal clinical and laboratory status (Lateef, 20 1 2) . Pregnancy-induced thrombocytopenia and proteinuria resemble SLE disease activity, and the identiication of a lupus lare is confounded by the increased facial and palmar erythema of normal pregnancy (Lockshin, 2003) . For SLE activity monitoring, various laboratory techniques have been recommended, but interpretation may be challeng­ ing. The sedimentation rate may be misleading because of pregnancy-induced hyperibrinogenemia. Serum complement levels are also normally increased in pregnancy (Appendix, p. 1 259). And, although falling or low levels of complement components C3, C4, and CH 5 0 are more likely to be associated with active disease, higher levels provide no assurance against disease activation. Our experiences and those of others suggest that clinical manifestations of disease and complement levels correlate poorly (Lockshin, 1 995; Varner, 1 983). Serial hematological studies may detect changes in disease activity. Hemolysis is characterized by a positive Coombs test, anemia, reticulocytosis, and unconjugated hyperbilirubinemia. hrombocytopenia, leukopenia, or both may develop. Accord­ ing to Lockshin and Druzin ( 1 995), chronic thrombocytopenia

TABLE 59-4. Some Distinctions between Lupus Fla re and P reecla m psia Synd rom e Factor

Lupus

Preeclam psia

C l i n ical fi n d i n g s

Fatig ue, h eadac h e, extra-ren a l s i g n s (rash, serositis, a rth ritis) N orma l or h i g h HemolytiC P resent N o rm a l or h i g h Norm a l Decreased

Headaches, confusion, v i s u a l c h a nges, co nvu l s i o n s High Absent P resent N ormal or h i g h N o r m a l or h i g h Normal

B l ood press u re Anemia P rote i n u ria Creati n i ne Tra n s a m i n ases Co m p l e m e n t

Data fro m A n d reol i, 20 1 2.

1 1 41

1 1 42

Med ica l a n d S u rg ica l Com p l ications

in early pregnancy may be due to antiphospholipid antibodies. Later, thrombocytopenia may indicate preeclampsia. Urine is tested frequently to detect new-onset or worsen­ ing proteinuria. The fetus is closely observed for adverse efects such as growth restriction and oligohydramnios. Many recom­ mend screening for anti-SS-A (anti-Ro) and anti-SS-B (anti-La) antibodies, because of associated fetal complications described subsequently. Antepartum, the fetus is surveilled as outlined by the American College of Obstetricians and Gynecologists (20 1 6a) and described in Chapter 1 7 (p. 33 1 ) . Unless hyper­ tension or evidence of fetal compromise or growth restriction develops, pregnancy is allowed to progress to term. Peripartum corticosteroids in "stress doses" are given to women who are taking these drugs or who recently have done so.

• Perinatal Mortal ity a n d Morbidity

Adverse perinatal outcome rates are signiicantly elevated in pregnancies complicated by SLE. Among these are preterm delivery, fetal-growth restriction, stillbirth, and neonatal lupus syndrome (Madazli, 20 1 4; Phansenee, 20 1 7) . Perina­ tal outcome rates worsen in mothers with a lupus flare, sig­ nificant proteinuria, or renal impairment and in those with chronic hypertension, preeclampsia, or both (Lazzaroni, 20 1 6) . Adverse outcomes are also more common i n women with neu­ ropsychiatric lupus (de Jesus, 20 1 7) . Reasons at least partially responsible for adverse fetal consequences include decidual vasculopathy with placental infarction and decreased perfusion (Hanly, 1 988).

P h a rmacolog ica l Treatment

N e on ata l L u p u s Syn d ro m e

here is no cure for SLE, and complete remissions are rare. Approximately a fourth of pregnant women have mild disease, which is not life threatening, but may be disabling because of pain and fatigue. Arthralgia and serositis can be managed by nonsteroidal antiinflammatory drugs (NSAIDs) . However, chronic or large intermittent dosing is avoided due to related oligohydramnios or ductus arteriosus closure (Chap. 1 2, p . 24 1 ) . Low-dose aspirin can be used throughout gestation. Severe disease is managed with corticosteroids such as pred­ nisone, 1 to 2 mg/kg/d orally. Mter the disease is controlled, this dose is tapered to a daily morning dose of 1 0 to 1 5 mg. Corticosteroid therapy can lead to gestational diabetes. I mmunosuppressive agents such as azathioprine are ben­ eicial for active disease. These are usually reserved for lupus nephritis or disease that is corticosteroid resistant. Azathio­ prine has a good safety record during pregnancy (Fischer-Betz, 20 1 3; Petri, 2007) . Its recommended daily oral dose is 2 to 3 mg/kg. Teratogenic medications to be avoided include mycophenolate mofetil, methotrexate, and cyclophosphamide (Gotestam Skorpen, 20 1 6) . However, cyclophosphamide can be considered in the second or third trimester for severe dis­ ease (Lazzaroni, 20 1 6) . In some situations, mycophenolate is the only treatment that achieves disease stability. In these cases, counseling is essential regarding fetal risks described in Chapter 1 2 (p. 244) (Bramham, 20 1 2) . Antimalarials reduced dermatitis, arthritis, and fatigue (Hahn, 20 1 5) . Although these agents cross the placenta, hydroxychloroquine is not associated with congenital mal­ formations. Because of the long half-life of antimalarials and because discontinuing therapy can precipitate a lupus lare, most recommend their continuation during pregnancy (Borden, 200 1 ) . 'When severe disease supervenes-usually a lupus lare­ high-dose glucocorticoid therapy is given. Petri (2007) rec­ ommends pulse therapy consisting of methylprednisolone, 1 000 mg given intravenously over 90 minutes daily for 3 days, then a return to maintenance doses if possible. In nonpregnant subjects, antihypertensive therapy oten includes an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker. For pregnancy, these should be changed to safer fetal options such as calcium-channel blockers, alpha methyldopa, or labetalol (Cabiddu, 20 1 6) .

This is characterized by newborn skin lesions-lupus dermati­ tis; a variable number of hematological and systemic derange­ ments; and occasionally congenital heart block (Hahn, 20 1 5) . Cutaneous manifestations can b e present i n 3 0 to 40 percent of infants and appears at 4 to 6 weeks of age (Silverman, 20 1 0) . hese are usually associated with anti-SS-A and SS-B antibod­ ies, and approximately 40 percent of women with SLE are posi­ tive for these (Buyon, 20 1 5) . Thrombocytopenia and hepatic involvement are seen in 5 to 1 0 percent of afected infants. In a review of outcomes in 9 1 infants born to women with lupus, eight of these were possibly afected-four had deinite neonatal lupus and four had possible disease (Lockshin, 1 988) . Cutaneous lupus, thrombocytopenia, and autoimmune hemo­ lysis are transient and clear within a few months (Zuppa, 20 1 7) . This is not always so for congenital heart block, discussed next. In subsequent ofspring, the recurrence risk for neonatal lupus may near 25 percent Qulkunen, 1 993) . Con g e n ita l H ea rt Block

Fetal and neonatal heart block results from difuse myocardi­ tis and ibrosis in the region between the atrioventricular (A) node and bundle of His. Congenital heart block develops almost exclusively in fetuses of women with antibodies to the SS-A or SS-B antigens (Buyon, 1 993) . Even in the presence of such antibodies, however, the incidence of fetal myocarditis is only 2 to 3 percent but rises to 20 percent with a prior afected child (Bramham, 20 1 2; Lockshin, 1 988). Fetal cardiac monitoring is performed between 18 and 26 weeks' gestation in pregnancies with either of these antibodies. The cardiac lesion is permanent, and a pacemaker is generally necessary. Long-term prognosis is poor. Of 325 infants with cardiac neonatal lupus, nearly 20 per­ cent died, and of these, one third was stillborn (Izmirly, 20 1 1 ) . Maternal administration of corticosteroids, plasma exchange, or intravenous immunoglobulin does not reduce the risk of congenital heart block. Maternal corticosteroid administration for treatment congenital heart block is controversial, is cur­ rently not recommended, and is discussed further in Chapter 1 6 (p. 3 1 6) . Although this therapy to treat fetal heart block has not been studied in randomized trials, some evidence suggests that early fetal exposure to the mother's corticosteroid treatment for SLE may mitigate fetal myocarditis. Namely, Shinohara and coworkers ( 1 999) reported no heart block in 26 neonates whose

Con n ective Tiss u e Disorde rs

mothers received corticosteroids before 1 6 weeks' gestation as part of SLE maintenance therapy. By contrast, 1 5 of 6 1 neo­ nates with heart block were born to women in whom corticoste­ roid therapy was begun after 1 6 weeks for an SLE exacerbation. There are reports that maternal treatment with hydroxychlo­ roquine (Plaquenil) is associated with a lower incidence of fetal heart block (Izmirly, 20 1 2) . Research in this area is ongoing. • Long-Term Prognosis a nd Contraception The survival rate for women with SLE is 95 percent at 5 years, 90 percent at 1 0 years, and 78 percent at 20 years (Hahn, 20 1 5) . In general, women with lupus and chronic vascular or renal disease may limit family size because of morbidity asso­ ciated with the disease and greater risks for adverse perinatal outcomes. For contraception, combination oral contraceptives did not increase the incidence of lupus lares in two large multi­ center trials (Petri, 2005; Sanchez-Guerrero, 2005). Progestin­ only implants and injections provide efective contraception with no known efects on lupus lares (Sammaritano, 20 1 4) . Concerns that intrauterine device (IUD) use and immunosup­ pressive therapy lead to greater infection rates in these patients are not evidenced-based. Notably, comorbid antiphospholipid antibodies are a contraindication to hormonal methods. Tubal sterilization may be advantageous and is performed with great­ est safety postpartum or whenever SLE is quiescent.

ANTI PHOSPHOLI PID SYNDROME his syndrome is an autoantibody-mediated acquired thrombo­ philia with recurrent thrombosis or pregnancy morbidity as part of its clinical constellation (Moutsopoulos, 20 1 5) . Speciically, antiphospholipid syndrome (APS) is diagnosed in women with persistently positive serum tests for antiphospholipid antibodies and with arterial and/or venous thromboses or obstetrical mor­ bidity. Antibodies include lupus anticoagulant, anti cardiolipin antibody, and anti-3 2 glycoprotein-I antibody. Phospholipids are the main lipid constituents of cell and organelle membranes. There are proteins in plasma that asso­ ciate noncovalently with these phospholipids. Antiphospho­ lipid antibodies are directed against these phospholipids or phospholipid-binding proteins (Giannakopoulos, 20 1 3; Tsokos, 20 1 1 ) . his antibody group may be ofIgG, IgM, and IgA classes, alone or in combination. Antiphospholipid antibodies are most common with SLE, other connective tissue disorders, and APS. However, a small proportion of otherwise normal women and men have low levels of these antibodies. The stimulus for autoantibody production is unclear, but it possibly is due to a preceding infection. he pathophysiol­ ogy encountered is mediated by one or more of the following: ( 1 ) activation of various procoagulants, (2) inactivation of natu­ ral anticoagulants, (3) complement activation, and (4) inhibition of syncytiotrophoblast diferentiation (Tsokos, 20 1 1 ) . Clinically, these actions lead to arterial or venous thromboses or to preg­ nancy morbidity. Virtually every organ system may be afected. Central nervous system involvement is one of the most prominent clinical manifestations. In addition to cerebro­ vascular arterial and venous thrombotic events, there may be

psychiatric features and even multiple sclerosis (Binder, 2 0 1 0) . Renovascular involvement may lead t o renal failure that can be diicult to diferentiate from lupus nephritis (D'Cruz, 2 009) . Peripheral and visceral thromboses are also a feature. For example, Ahmed and associates (2009) reported a postpartum woman who developed spontaneous cecal perforation follow­ ing a mesenteric vessel infarction. O bstetrical complications encompass recurrent pregnancy loss and placental dysfunction relected by fetal-growth restriction, stillbirth, preeclampsia, and preterm birth. Treatment using aspirin, anticoagulation, and close monitoring has increased live birth rates to more than 70 percent in these women (Schreiber, 20 1 6) . A small proportion o f these patients develop the catastrophic antiphospholipid antibody syndrome (CAPS) or Asherson syn­ drome. his is deined as a rapidly progressive thromboembolic disorder simultaneously afecting three or more organ systems or tissues (Schreiber, 20 1 6) . It has a high mortality rate from activation of a cytokine storm. In half of cases, a "triggering" event is identiied. • Specific Antiphospholipid Antibodies

As mentioned, several antibodies in APS are directed against a speciic phospholipid or phospholipid-binding protein: 1 . 32-Gycoprotein I-also known as apolipoprotein H-is a phospholipid-binding plasma protein that inhibits pro­ thrombinase activity within platelets and inhibits plate­ let aggregation (Giannakopoulos, 20 1 3) . hus, its normal action is to limit procoagulant binding and thereby prevent coagulation cascade activation. Logically, antibodies directed against this glycoprotein would reverse its anticoagulant activity and promote thrombosis. This is important fro m an obstetrical viewpoint because 3 2 -glycoprotein I is expressed in high concentrations on the syncytiotrophoblast surface. Complement activation may contribute to its pathogen­ esis (Avalos, 2009; Tsokos, 20 1 1 ) . Teleologically, this seems appropriate because the decidua intuitively should be a criti­ cal area to prevent coagulation that might lead to intervillous space thrombosis. Another possibility is that 3 2 -glycoprotein I may be involved in implantation, and this glycoprotein may result in pregnancy loss via an inlammatory mecha­ nism (Iwasawa, 20 1 2; Meroni, 2 0 1 1 ) . 2 . Lupus anticoagulant (LAC) i s a heterogeneous group o f anti­ bodies directed against phospholipid-binding proteins. This antibody group induces prolongation in vitro of the pro­ thrombin, partial thromboplastin, and Russell viper venom times. hus, paradoxically, this so-called anticoagulant is actually powerfully thrombotic in vivo. 3. Anticardiolipin antibodies (ACAs) are directed against one of the many phospholipid cardiolipins found in mitochondrial membranes and platelets. • Antibodies against Natural Anticoagulants

Some anti phospholipid antibodies are also directed against the natural anticoagulant proteins C and S (Robertson, 2006) . Another is directed against the anticoagulant protein annexin V, which is expressed in high concentrations by syncytiotrophoblast

1 1 43

1 1 44

Med i ca l a n d S u rg ica l Co m p l i cati o n s

TABLE 59-5. S o m e C l i n ical Featu res o f Antiphospho l i pid Syndrome Ven o u s t h ro m bosis-thro m boem bol i sm, t h ro m bo p h l e b itis, l ived o reticu l aris Arte r i a l th ro m bosis-stroke, tra n s i e nt i s c h e m ic attac k, L i b m a n-Sacks ca rd iac vegetations, myoca rd i a l i s c h e m ia, d i sta l extrem ity a n d visce ra l t h ro m bo s i s a nd g a n g rene H em atolog ica l -t h rom bocytopen i a, a uto i m m u n e hemolyti c a ne m i a Oth e r- n e u ro l og ica l m a n ifestat i o n s, m i g ra i n e h eadaches, e p i l e psy; re n a l a rtery, ve i n, or g l o m e ru l a r t h ro m bosis; a rt h ritis a n d a rth ra lg i a Preg n a n cy-preec l a m ps i a syn d ro m e, recu rre nt m i sca rriage, p rete rm d e l ivery, feta l-g rowth restrict i o n, feta l death Data fro m G i a n n a ko p o u l os, 2 0 1 3; M o utsopo u los, 20 1 5 .

(Giannakopoulos, 20 1 3) . Testing for these other antibodies is not recommended (American College of Obstetricians and Gynecologists, 20 1 7) . However, some studies have evaluated these nonconventional antiphospholipid antibodies in women who clinically meet APS criteria but do not have the classic antibody proile. In one study, treatment of women with these nonconventional antibodies ofered some beneits, such as a lower pregnancy loss rate (Mekinian, 20 1 6) . Clinical features shown i n Table 5 9-5 provide indications for testing. By international consensus, APS is diagnosed based on laboratory and clinical criteria found in Table 1 8-5 (p. 353) . First, one o f two clinical criteria-which are vascular throm­ bosis or certain pregnancy morbidity-must be present. With laboratory criteria, elevated levels of LAC, ACA, and anti-3z­ glycoprotein I should be conirmed on two occasions 1 2 weeks apart. he diagnosis can be further stratified based on the num­ ber of these tests that are positive (Miyakis, 2006) . Tests for LAC are nonspeciic coagulation tests. he partial thromboplastin time is generally prolonged because the antico­ agulant interferes with conversion of prothrombin to thrombin in vitro. Tests considered more speciic are the dilute Russell vper venom test and the platelet neutralization procedure. here is currently disagreement as to which of these two is best for screening. If either is positive, then identiication of LAC is conirmed. Branch and Khamashta (2003) recommend conservative inter­ pretation of results based on repeated tests from a reliable labora­ tory that are consistent with each clinical case. Only approximately 20 percent of patients with PS have a positive LAC assay alone. Thus, ACA enzyme-linked immunosorbent assay (ELISA) testing should also be performed. Eforts have been made to standardize ACA assays, however, these remain without international stan­ dards (Adams, 20 1 3) . For each APS test, interlaboratory variation can be large, and agreement between commercial kits is poor. • Pregnancy and Antiphosphol ipid Antibodies

As noted, nonspecifi c low levels of antiphospholipid antibod­ ies are identified in approximately 5 percent of normal adults (Branch, 20 1 0) . When Lockwood and coworkers ( 1 989) irst studied 737 normal pregnant women, they reported that 0.3 percent had LAC and 2.2 percent had elevated concentra­ tions of either IgM or IgG ACAs. Subsequent investigations confirmed this, and taken together, they totaled almost 4000 normal pregnancies with an average prevalence for antiphos­ pholipid antibodies of 4.7 percent. This is similar to that

for normal nonpregnant individuals (Harris, 1 99 1 ; Yasuda, 1 99 5 ) . I n women with high ACA levels, and especially when AC is identiied, risks for decidual vasculopathy, placental infarc­ tion, fetal-growth restriction, early-onset preeclampsia, and recurrent fetal death are increased (Saccone, 20 1 7) . Some of these women, like those with SLE, also have a high incidence of venous and arterial thromboses, cerebral thrombosis, hemo­ lytic anemia, thrombocytopenia, and pulmonary hypertension (American College of Obstetricians and Gynecologists, 20 1 7; Clowse, 2008) . In 1 9 1 LAC-negative women with APS, women with antibodies to cardiolipin and 32-glycoprotein I had signii­ cantly higher miscarriage rates than if either one alone was posi­ tive (Liu, 20 1 3) . Women with higher titers tend to have more adverse outcomes (Hadar, 20 1 7) . Preg n a n cy Patho physiology

It is not precisely known how antiphospholipid antibodies cause damage, but it is likely that their actions are multifactorial. Plate­ lets may be damaged directly by antiphospholipid antibody or indirectly by binding 3 2-glycoprotein I, which causes platelets to be susceptible to aggregation (Giannakopoulos, 20 1 3). One theory proposes that phospholipid-containing endothelial cell or syncytiotrophoblast membranes may be damaged directly by the antiphospholipid antibody or indirectly by antibody binding to either 3z-glycoprotein l or annexin V (Rand, 1 997, 1 998). his prevents the cell membranes from protecting the syncytiotropho­ blast and endothelium. This exposes the basement membrane, to which damaged platelets can adhere and form a thrombus. Pierro and associates ( 1 999) reported that antiphospholipid antibodies decreased decidual production of the vasodilat­ ing prostaglandin E2. Diminished protein C or S activity and greater prothrombin activation may also be contributory (Zan­ gari, 1 997) . Evidence also supports that thrombosis with APS stems from activation of the tissue factor pathway (Amengual, 2003) . Finally, uncontrolled placental complement activation by anti phospholipid antibodies may play a role in fetal loss and growth restriction (Holers, 2002) . Complications from APS cannot be completely explained by thrombosis alone. Animal models suggest that efects are due to inflammation rather than thrombosis (Cohen, 20 1 1 ) . Some investigators hypothesize that APS-associated clotting is triggered as a "second hit" from innate inflammatory immune responses. These investigators recommend treatment with anti­ inlammatory agents (Meroni, 20 1 1 ) .

Co n n ective Tissue D i s o rd e rs

Adverse Preg n a ncy Outcomes

Overall, antiphospholipid antibodies are generally associated with higher rates of fetal wastage (Chap. 1 8, p. 353). In most early reports that describe these outcomes, however, women were included because they had had repeated adverse outcomes. Both antibody prevalence and miscarriage are common-recall that the incidence of antiphospholipid antibodies in the general obstetrical population is about 5 percent and early pregnancy loss approximates 20 percent. Accordingly, current data are too limited to conclude the exact risks for adverse efects of these antibodies on pregnancy outcomes. Fetal deaths, however, are more characteristic with APS than are first-trimester miscar­ riages (Oshiro, 1 996; Roque, 2004) . Moreover, women with higher titers have worse obstetrical outcomes compared with those with low titers (Hadar, 20 1 7; Nodler, 2009) . When otherwise unexplained fetal deaths are examined, the data are mixed. One study measured ACA levels in 309 pregnancies with fetal death and found no diferences in their frequency compared with levels in 6 1 8 normal preg­ nancies (Haddow, 1 99 1 ) . In another of women with recur­ rent pregnancy loss, those with antiphospholipid antibodies had a higher rate of preterm delivery (Clark, 2007) . In a case-control study of 5 82 stillbirths and 1 547 live births, a three- to fivefold higher risk for stillbirth was found in women with elevated ACA and anti-3rglycoprotein I levels (Silver, 20 1 3) . In women with antiphospholipid antibodies, adverse outcomes are more common in the presence of: ( 1 ) all three classic anti phospholipid antibody types, (2) comorbid SLE or systemic autoimmune diseases, and (3) prior thrombosis and pregnancy morbidity. Logistic regression found the prob­ ability of pregnancy failure was 93 percent with two or more antiphospholipid antibody types but was 63 percent for those with only one (Rufatti, 20 1 1 ) . Th ro m bo s i s P revention i n P reg n a ncy

Because of study heterogeneity, current treatment recommen­ dations for women with antiphospholipid antibodies can be confusing. Therapy is directed at thrombosis prevention. As discussed, antiphospholipid antibodies are immunoglobulins that may be of G, M, or A classes. Those directed against the phospholipids (PL) are termed GPL, MPL, and APL, respec­ tively. During testing, these are reported as semiquantified phospholipid binding-unit levels and expressed as negative, low-positive, medium-positive, or high-positive (American College of Obstetricians and Gynecologists, 20 1 7) . Of the three, higher titers for GPL and MPL anticardiolipin antibod­ ies are clinically important, whereas low-positive titers are of questionable clinical signiicance. As discussed in Chapter 52 (p. 1 008) , women with prior thromboembolic events who have antiphospholipid antibodies are at risk for recurrence in subsequent pregnancies. For these women, prophylactic anticoagulation with heparin throughout pregnancy and then for 6 weeks postpartum with either heparin or warfarin is recommended (American College of Obstetri­ cians and Gynecologists, 20 1 7) . For those without prior throm­ boembolic events, recommendations for management from the American College of Obstetricians and Gynecologists (20 1 7)

and the American College of Chest Physicians (Bates, 20 1 2) vary and are listed in Table 52-6 (p. 1 020) . Some acceptable schemes include close antepartum maternal observation with or without prophylactic or intermediate-dose heparin, and some form of postpartum anticoagulation for 4 to 6 weeks. Scias­ cia and coworkers (20 1 6) have presented preliminary salutary results with treatment with hydroxychloroquine. Several trials have questioned the need for heparin for women with antibodies but no history of thrombosis (Branch, 20 1 0) . lthough this is less clear, some recommend that women be treated if they have medium- or high-positive ACA titers or LAC activity and a prior second- or third-trimester fetal death not attributable to other causes (Dizon-Townson, 1 998; Lockshin, 1 995). Some report that women with recur­ rent early pregnancy loss and medium- or high-positive titers of antibodies may beneit from therapy (Robertson, 2006) . Described earlier (p. 1 1 43) , catastrophic antiphospholipid syndrome is treated aggressively with full anticoagulation, high-dose corticosteroids, plasma exchange, and/or intravenous immunoglobulins (Cervera, 20 1 0; Tenti, 20 1 6) . If needed, rituximab may be added (Sukara, 20 1 5) . Due to the risk of fetal-growth abnormalities and stillbirth, serial sonographic assessment of fetal growth and antepartum testing in the third trimester is recommended by the American College of Obstetricians and Gynecologists (20 1 6a, 20 1 7) . S pecific Th e ra py i n Preg n a ncy

here are other agents used to treat pregnant women with APS, but with no prior thromboembolic event. Aspirin, in doses of 60 to 80 mg orally daily, blocks conversion of arachidonic acid to thromboxane A2 while sparing prostacyclin production. This reduces synthesis of thromboxane A2, which usually causes platelet aggregation and vasoconstriction, and simultaneously spares prostacyclin, which normally has the opposite efect. There appear to be no major side efects from low-dose aspirin other than a slight risk of small-vessel bleeding during surgi­ cal procedures. Low-dose aspirin does not reduce adverse preg­ nancy outcomes in anti phospholipid antibody-positive women without the complete APS syndrome (Amengual, 20 1 5) . I ts use is recommended for women with SLE or APS (American Col­ lege of Obstetricians and Gynecologists, 20 1 6b) . Unractionated heparin is given subcutaneously in dosages of 5000 to 1 0,000 units every 1 2 hours. Some prefer low­ molecular-weight heparin, such as 40 mg enoxaparin (Lovenox) once daily (Kwak-Kim, 20 1 3) . With therapeutic dosing, mea­ surement of heparin levels may be useful because clotting tests can be altered by LAC. he rationale for heparin therapy is to prevent venous and arterial thrombotic episodes. Hepa­ rin therapy also prevents thrombosis in the microcirculation, including the decidual-trophoblastic interface (Toglia, 1 996) . As discussed, heparin binds to 3rglycoprotein I, which coats the syncytiotrophoblast. This prevents binding of ACAs and anti-3rglycoprotein I antibodies to their surfaces, which likely prevents cellular damage (Tsokos, 20 1 1 ) . Heparin also binds to antiphospholipid antibodies in vitro and likely in vivo. Aspi­ rin plus heparin therapy is the most eicacious regimen (de Jesus, 20 1 4) . However, heparin therapy is associated with sev­ eral complications that include bleeding, thrombocytopenia,

1 1 45

1 1 46

Med ica l a nd S u rg ica l Com p l ications

TABLE 59-6. P reg na ncy O utcomes (%) i n 750 Women Treated for the Antiphosph o l i pid Synd rome-the PREGNA NTS Study

Outcome Live b i rth Sti l l b i rth P reec l a m psiaa

TriplePositive 20) (n

Double-Positive LAC N egative 90) (n

LAC Alone 54) (n

ACA Alone (n 458)

Anti-�2 G lycoprotei n (n 1 28)

30 45 55

43 34 54

80 7 11

56 21 34

48 30 48

=

=

a ntica rd i o l i p i n a nti bod ies; LAC ACA a N o nsevere on ly. Data from Saccone, 2 0 1 7. =

=

=

=

=

l u p u s a nticoag u la nt.

osteopenia, and osteoporosis. A description of various heparins and their adverse efects is found in Chapter 52 (p. 1 0 1 2) . Corticosteroids generally should not b e used with primary APS-that is, without an associated connective tissue disor­ der. For women with SLE or those being treated for APS who develop SLE, corticosteroid therapy is indicated (Carbone, 1 999) . In such cases of seconday APS seen with SLE, the dose of prednisone should be maintained at the lowest efective level to prevent lares. Intravenous immunoglobulin therapy (NIG) is controversial and has usually been reserved for women with overt disease­ including CAPS or heparin-induced thrombocytopenia or both (Alijotas-Reig, 20 1 3) . It is used when other first-line therapies have failed, especially in the setting of preeclampsia and fetal­ growth restriction. IlG is administered by some in doses of 0.4 g/kgld for 5 days-total dose of 2 g/kg. This is repeated monthly, or it is given as a single dose of 1 g/kg each month. Treatment is expensive, as one course costs more than $ 1 0,000. A recent lit­ erature review found no beneits from adding IlG to low-dose aspirin and low-molecular-weight heparin (Tenti, 20 1 6) . And, a Cochrane review found no improvement in the live birth rate for immunotherapy given to women with recurrent pregnancy loss (Wong, 20 1 4) . Trials are needed before application of this expensive and cumbersome therapy becomes widespread. Immunosuppression with hydroxychloroquine may be benefi­ cial with APS by reducing the risk of thrombosis and improv­ ing pregnancy outcomes in women with APS (Mekinian, 20 1 5 ; Sciascia, 20 1 6) . Hydroxychloroquine is commonly used with low-dose aspirin in the treatment of women with antiphospho­ lipid antibodies and SLE. Statins have been examined due to their protective efects on endothelium. In a small trial in 21 women with APS who devel­ oped fetal-growth restriction or preeclampsia, the addition of pravastatin to low-dose aspirin and low-molecular-weight hepa­ rin improved placental blood flow, preeclampsia features, and pregnancy outcomes (Lekou, 20 1 6) . Larger trials are needed. Treatment Effi ca cy

Fetal loss is common in women with APS if untreated (Rai, 1 995). Even with treatment, recurrent fetal loss rates remain at 20 to 30 percent (Branch, 2003; Empson, 2005; Ernest, 20 1 1 ) . Shown in Table 59-6 are pregnancy outcomes from 750 treated women with primary APS-the PREGNANTS

study (Saccone, 20 1 7) . Participants were treated with low-dose aspirin and prophylactic low-molecular-weight heparin starting in the irst trimester. Importantly, some women with SLE and antiphospholipid antibodies have normal pregnancy outcomes without treatment. Also, it is emphasized that women with LAC and prior bad pregnancy outcomes have had liveborn neonates without treatment. In a manner similar to neonatal lupus syndrome (p. 1 1 42), up to 30 percent of newborns demonstrate passively acquired antiphospholipid antibodies, and thus there is concern for their adverse neonatal efects (N alii, 20 1 7) . One group found higher rates of learning disabilities in these children (Tincani, 2009) . Simchen and colleagues (2009) reported a fourfold greater risk for perinatal strokes. Of 1 4 1 newborns followed in a Euro­ pean registry, the rate of preterm birth was 1 6 percent; low birthweight, 1 7 percent; and later behavioral abnormalities in 4 percent of the children. here were no cases of neonatal thrombosis (Motta, 20 1 2) . A 7-year study of 26 women who had APS with 36 pregnancies reported three cases of autism spectrum disorder, all associated with persistent neonatal anti­ � 2 _g1ycoprotein- 1 IgG antibodies (Abisror, 20 1 3) . RHEUMATO I D ARTH RITIS This chronic inflammatory disease stems from immunological dysunction, and iniltrating T cells secrete ctokines to cause inflammation, polyarthritis, and systemic symptoms. he cardinal feature is inflammatory synovitis that usually involves the periph­ eral joints. he disease has a propensity for cartilage destruction, bony erosions, and joint deformities. Pain, aggravated by move­ ment, is accompanied by swelling and tenderness. Extraarticular manifestations include rheumatoid nodules, vasculitis, and pleuro­ pulmonary symptoms. Other complaints are fatigue, anorexia, and depression. he American College of Rheumatology criteria for rheumatoid arthritis diagnosis are shown in Table 59-7. A score of 6 or greater ulills the requirements for definitive diagnosis. The worldwide prevalence of rheumatoid arthritis is 0.5 to 1 percent, women are afected three times more often than men, and peak onset is from 25 to 55 years (Shah, 20 1 5) . There is a genetic predisposition, and heritability is estimated at 1 5 to 30 percent (McInnes, 20 1 1 ) . Genome-wide associated studies have identified more than 30 loci involved in rheumatoid arthritis pathogenesis (Kurka, 20 1 3) . There is an association with the

Co n n ective Tis s u e Disord e rs

TABLE 59-7. Criteria for Classificati o n of Rheumatoid Art h ritis Factor

Criteria

Joint involvement

1 l a rge-sho u lder, e l bow, h i p, knee, a n kl e 2 - 1 0 l a rge 1 -3 s m a l l-MCP, P I P, t h u m b I P, MTP, wrists 4- 1 0 s m a l l > 1 O-at least 1 s m a l l

Serolog ica l testing

Acute-phase reacta nts D u ration of sym ptoms

Score o

2

3

5

N egative RF a n d n egative ACPA Low-pos itive RF or a nti-CC P H ig h-positive RF or a nti-CCP

o

N or m a l CRP a n d ESR Abnormal CRP or ESR

o

Less than 6 weeks 6 weeks or longer

o

2 3

1

cyc l ic citru l l i nated peptides; ACPA = ant i-citru l l i n ated peptide a nt i body; CCP C-reactive protei n; ESR e ryth rocyte sed i me ntation rate; I P i nterpha l a n­ CRP gea l j o i nt; MCP = m etaca rpo p h a l a ngeal j o i nt; MTP = m etata rso p h a l a ngeal joi nt; PIP proxi m a l i n terp h a l a n g e a l j o i nt; RF rheu m atoid fa ctor. Criteria esta b l is hed in col l a boration with the America n Col leg e of R h e u matology a n d the E u ro pea n League Aga i nst Rheu matism. A score ::: 6 fu lfi l l s criteria for diagnosis. Data from Aleta ha, 2 0 1 0; S h a h , 20 1 5 . =

=

=

=

class II major histocompatibility complex molecule HLA­ DR4 and HLA-DRB 1 alleles (McInnes, 20 1 1 ; Shah, 20 1 5) . Pregnancy provides a protection against rheumatoid arthritis development, and this may be related to HLA-disparate fetal microchimerism (Guthrie, 20 1 0) . Of other inluences, cigarette smoking raises the risk of rheumatoid arthritis (Papadopoulos, 2005). • Management

Treatment is directed at pain relief, inlammation reduction, protection of articular structures, and preservation of function. Physical and occupational therapy and self-management instruc­ tions are essential. Until recently, aspirin and other NSAIDs were the cornerstone of therapy, but they do not retard disease progression. According to Shah and St. Clair (20 1 5) , methotrex­ ate has become the preferred disease-modiying antirheumatic drug (DMARD). NSAIDs serve as adjunctive therapy but are important to pregnancy because methotrexate is contraindicated. Conventional NSAIDs nonspeciically inhibit both cyclooxygen­ ase- 1 (COX- I ) , which is an enzyme critical to normal platelet function, and COX-2, which mediates inflammatory response mechanisms. Because gastritis with acute bleeding is an unwanted side efect common to conventional NSAIDs, the more specific COX-2 inhibitors have been recommended. However, their long-term use is associated with higher risk for myocardial infarc­ tion and major vascular events (Patrono, 20 1 6) . In one systematic review, a higher rate o f cardiac malforma­ tions was found in newborns exposed to NSAIDs in the first trimester (Adams, 20 1 2) . In addition, NSAIDs are associated with early spontaneous abortions, ductus arteriosus constric­ tion, and neonatal pulmonary hypertension. Thus, risks versus beneits of these medications must be considered.

=

=

Glucocorticoid therapy in low-to-moderate doses is given to achieve more rapid symptom control. Of these, prednisone, 7.5 mg orally daily for the first 2 years of active disease, substan­ tively reduces progressive joint erosions (Kirwan, 1 995; Shah, 20 1 5). The American College of Rheumatology recommends several DMARDs that may reduce or prevent joint damage (Singh, 20 1 6) . Lelunomide, like methotrexate, is teratogenic (Briggs, 20 1 5) (Chap . 1 2, p. 24 1 ) . Sulfasalazine and hydroxy­ chloroquine are safe for use in pregnancy (Pardett, 2 0 1 1 ) . These, combined with COX-2 inhibitors and with relatively low-dose prednisone-7. 5 to 20 mg daily-usually success­ fully treat flares. In one review of drug exposure, a fourth of women with rheumatoid arthritis took a DMARD within 6 months of conception (Kuriya, 20 1 1 ) . During pregnancy, 4 percent of 393 pregnant women were given a category D or X medication. Methotrexate was the most common2.9 percent. Biological DMARDs have revolutionized the treatment of rheumatoid arthritis. These include tumor necrosis factor alpha (TNF-.) inhibitors-infliximab, adalimumab, golimumab, certolizumab, and etanercept (Shah, 20 1 5) . Their use in preg­ nancy is limited, and fetal safety is a concern (Mako!, 2 0 1 1 ; Ojeda-Uribe, 20 1 3) . I n one drug-exposure review, 1 3 percent of 393 women were given a biological cytokine-inhibiting DMARD-primarily etanercept (Kuriya, 20 1 1 ) . In another review of 300 exposures, no fetal efects were noted (Berthelot, 2009). A prospective study of 38 women found similar results (Hoxha, 20 1 7) . In 74 women exposed to adalimumab during pregnancy, no risks were identified (Burmester, 20 1 7) . There is also little known regarding pregnancy efects of anakinra, an interleukin- 1 receptor antagonist, or of rituximab, an antago­ nist to the B-cell CD20 antigen.

1 1 47

1 1 48

Med i ca l a nd S u rg ica l C o m p l i cations

• Pregnancy a nd Rheumatoid Arthritis

In up to 90 percent of women with rheumatoid arthritis, their disease will improve during pregnancy (de .Man, 2008) . Animal studies suggest this may be due to regulatory T-cell alterations (Munoz-Suano, 20 1 2) . Even so, some women develop disease during pregnancy, and others become worse (Nelson, 1 997) . A downside to this respite during pregnancy is that post­ partum exacerbation is common (0stensen, 2007) . This may stem from postpartum alterations in innate immunity (Haupl, 2008b) . In one review, a postpartum flare was more common if women were breastfeeding (Barrett, 2000a) . These same inves­ tigators followed 1 40 women with rheumatoid arthritis during 1 to 6 months postpartum (Barrett, 2000b) . There was only a modest fall in objective disease activity, and only 1 6 percent had complete remission. They observed that although overall disease actually did not exacerbate postpartum, the mean num­ ber of infl a med joints rose signiicantly. Some studies report a protective efect of pregnancy against developing new-onset rheumatoid arthritis. In a case-control study of 88 afected women, there was a protective efect of pregnancy in the long term, but the likelihood of new-onset rheumatoid arthritis was increased sixfold during the irst 3 postpartum months (Silman, 1 992) . Pikwer and colleagues (2009) reported a significant reduction in the risk of subse­ quent arthritis in women who breastfed longer than 1 2 months. hese indings may reflect the interference of sex hormones with several putative processes involved in arthritis pathogen­ esis, including immunoregulation (Haupl, 2008a,b) . First, Unger and associates ( 1 983) reported that amelioration of rheumatoid arthritis correlated with serum levels of pregnancy­ associated apha2-gycoprotein. his compound has immuno­ suppressive properties. Second, Nelson and coworkers ( 1 993) noted that amelioration of disease was associated with a dispar­ ity in HLA class II antigens between mother and fetus. They s�ggested that the maternal immune response to paternal HLA antigens may play a role in pregnancy-induced remission of arthritis. In addition to monocyte activations, there also may be T-lymphocyte activation (Forger, 2008). • Juvenile Rheumatoid Arthritis

This group of diseases is the most frequent cause of chronic arthritis in children and persists into adulthood. In 76 preg­ nancies of 5 1 afected Norwegian women, pregnancy had no efects on clinical presentation, but disease activity usually became quiescent or remained so during pregnancy (0stensen, 1 99 1 ) . Postpartum flares were common as was discussed for rheumatoid arthritis. Joint deformities often developed in these women, and 1 5 of 20 cesarean deliveries were done for con­ tracted pelves or joint prostheses. Results from a summary of 39 Polish women with j uvenile rheumatoid arthritis were similar (Musiej-Nowakowska, 1 999) . This arthritis portends few adverse pregnancy outcomes. The risk for preterm birth is increased, but later fetal development is normal (Mohamed, 20 1 6; Rom, 20 1 4; Wallenius, 2 0 1 4) . Dis­ ease severity in early pregnancy was predictive of preterm deliv­ ery and fetal-growth restriction in a cohort study (Bharti, 20 1 5) . nother study o f 1 90 pregnancies followed from first trimester to

delivery found patients with low disease activity scores in the first trimester were likely to have low disease activity or remission in the third trimester (Ince-Askan, 20 1 7) . In a study of 1 807 births, Remaeus and associates (20 1 7) reported increased incidences of preterm birth, fetal-growth restriction, and preeclampsia. Primary treatment of symptomatic women during preg­ nancy is with aspirin and NSAIDs. These are used with appro­ priate concerns for irst-trimester efects, impaired hemostasis, prolonged gestation, premature ductus arteriosus closure, and persistent pulmonary circulation. Low-dose corticosteroids are also prescribed as indicated. Gold compounds have been administered in pregnancy (Almarzouqi, 2007) . Immunosuppressive therapy with azathioprine, cyclophos­ phamide, or methotrexate is not routinely used during preg­ nancy. Only azathioprine is considered during early pregnancy because the other agents are teratogens (Briggs, 20 1 5) . As dis­ cussed on page 1 1 47, DMARDs including sulfasalazine and hydroxychloroquine are acceptable for use in pregnancy. If the cervical spine is involved, particular attention is war­ ranted during pregnancy. Subluxation is common, and preg­ nancy, at least theoretically, predisposes to this because of joint laxity. Importantly, there are anesthesia concerns during endo­ tracheal intubation. Following pregnancy in women with rheumatoid arthritis and its j uvenile form, contraceptive counseling may include combination oral contraceptives. These are a logical choice because of their efectiveness and their potential to improve disease (Farr, 20 1 0) . That said, all methods of contraception are appropriate. SYSTEMIC SCLEROSIS -SCLERODERMA This is a chronic multisystem connective tissue disorder of unknown etiology. It is characterized by microvascular dam­ age, immune system activation leading to inlammation, and excessive deposition of collagen in the skin and often in the lungs, heart, gastrointestinal tract, and kidneys. It is uncom­ mon, displays a 5-to- 1 female dominance, and typically afects those aged 30 to 50 years (Meier, 20 1 2; Varga, 20 1 5) . This strong prevalence o f scleroderma i n women and its greater incidence in the years following childbirth give credence to the hypothesis that microchimerism is involved as discussed earlier (p. 1 1 39) (Lambert, 20 1 0) . Artlett and coworkers ( 1 998) demonstrated Y-chromosomal DNA in almost half of women with systemic sclerosis compared with only 4 percent of controls. Rak and colleagues (2009b) identiied male microchimerism in peripheral blood mononuclear cells more frequently in women with limited versus diuse scleroderma-20 versus 5 percent. • Clinical Course

The hallmark is overproduction of normal collagen. In the more benign form-Limited cutaneous systemic sclerosis-progression is slow. With diuse cutaneous systemic sclerosis, skin thickening progresses rapidly, and skin fibrosis is followed by gastrointesti­ nal tract ibrosis, especially the distal esophagus (Varga, 20 1 5) . Pulmonary interstitial fibrosis along with vascular changes may cause pulmonary hypertension, which develops in 1 5 percent

Co n n ective Ti ssue D i s o rders

of patients. Antinuclear antibodies are found in 95 percent of patients, and immunoincompetence often develops. Raynaud phenomenon, which includes cold-induced epi­ sodic digital ischemia, is seen in 95 percent of patients, and there may also be swelling of the distal extremities and face. Half of patients have symptoms from esophageal involve­ ment, especially fullness and epigastric burning pain. Pulmo­ nary involvement is frequent and causes dyspnea. The 1 0-year cumulative survival rate is 70 percent in those with pulmo­ nary fibrosis, and pulmonary arterial hypertension is the main cause of death Goven, 20 1 0; Varga, 20 1 5) . Women with lim­ ited cutaneous disease such as the CEST syndrome-falcinosis, Baynaud phenomenon, .sophageal involvement, .clerodacyy, and .elangiectasia-have milder disease. Overlap syndrome refers to systemic sclerosis with features of other connective tissue disorders. Mixed connective tissue disease is a term used for the syndrome involving features of SLE, systemic sclerosis, polymyositis, rheumatoid arthritis, and high titers of anti-ribonucleoprotein (RNP) antibodies (see Table 59- 1 ) . he disorder is also termed undierentiated connective tissue disease (Spinillo, 2008) . Although systemic sclerosis is incurable, treatment directed at end-organ involvement can sometimes relieve symptoms and improve function. Renal involvement and hypertension are often comorbid. At times, ACE inhibitors may be required for blood pressure control despite their known teratogenicity. Scleroderma renal crisis develops in up to a fourth of these patients and is characterized by obliterative vasculopathy of the renal cortical arteries. his leads to renal failure and malignant hypertension. Interstitial restrictive lung disease is common and frequently becomes life threatening. Associated pulmonary hypertension is treated with bosentan or sildenail (Chap. 49, p. 960) . • Pregnancy and Systemic Sclerosis

The prevalence of scleroderma in pregnancy approximates 1 in 22,000 pregnancies (Chakravarty, 2008) . These women usually have stable disease during gestation if their baseline unction is good. As perhaps expected, dysphagia and reflux esophagitis are aggravated by pregnancy (Steen, 1 999). Dysphagia results from loss of esophageal motility due to neuromuscular dysunction. A decrease in amplitude or disappearance of peristaltic waves in the lower two thirds of the esophagus is seen using manometry. Symptomatic treatment for reflux is described in Chapter 54 (p. 1 046). Women with renal insuiciency and malignant hyperten­ sion have a higher incidence of superimposed preeclampsia. With rapidly worsening renal or cardiac disease, pregnancy ter­ mination should be considered. As discussed, renal crisis is life threatening and is treated with ACE inhibitors, but it does not improve with delivery (Gayed, 2007) . Pulmonary hypertension usually contraindicates pregnancy. Vaginal delivery may be anticipated, unless the soft tissue thickening wrought by scleroderma produces dystocia requir­ ing cesarean delivery. Tracheal intubation for general anes­ thesia has special concerns because of limited ability of these women to open their mouths widely (Sobanski, 20 1 6) . Because of esophageal dysfunction, aspiration is also more likely, and

epidural analgesia is preferable. Warming the delivery room and intravenous fluids, extra blankets, and socks and gloves are recommended to improve impaired circulation from Raynaud phenomenon. If corticosteroids were used frequently, stress doses of hydrocortisone are recommended (Sobanski, 20 1 6) . Maternal and fetal outcomes correlate with underlying dis­ ease severity. In a review of 2 1 4 gravidas with systemic sclerosis, 45 percent had difuse disease. Major complications included renal crisis in three and greater rates of preterm birth (Steen, 1 989, 1 999) . Chung and coworkers (2006) also reported elevated rates of preterm delivery, fetal-growth restriction, and perinatal mortality. A multicenter study of 1 09 pregnan­ cies from 25 centers reported higher rates of preterm delivery, fetal-growth restriction, and very-low-birthweight newborns (Taraborelli, 20 1 2) . hese are likely related to placental abnor­ malities that include decidual vasculopathy, acute atherosis, and infarcts (Sobanski, 20 1 6) . Scleroderma may b e associated with subfertility (Bernatsky, 2008; Lambe, 2004) . For women who do not choose preg­ nancy, several reversible contraceptive methods are acceptable. However, hormonal agents, especially combination oral con­ traceptives, probably should not be used, especially in women with pulmonary, cardiac, or renal involvement. Due to the often unrelenting progression of systemic sclerosis, permanent sterilization is also considered. VASCULITIS SYN DROMES Inlammation and damage to blood vessels may be primary or caused by another disease. Immune-complex deposition is presumed to underlie most cases (Langford, 20 1 5). Primary types include poly­ arteritis nodosa, temporal or giant-cell arteritis, Takayasu arteritis, Henoch-Schonlein purpura, Behyet syndrome, and cutaneous or hypersensitivity arteritis (Goodman, 20 1 4). Small vessel vasculiti­ des such as granuomatosis with poyangiitis and eosinophilic granuo­ matosis with poyangiitis have antibodies directed against proteins in the cytoplasmic granules of leukocytes-antineutrophil ytopsmic antibodies-NA (Pagnox, 201). • Polyarteritis Nodosa

This necrotizing vasculitis of small and medium-sized arteries is characterized clinically by myalgia, neuropathy, gastrointestinal disorders, hypertension, and renal disease (Goodman, 2 0 1 4) . O f cases, approximately a third is associated with hepatitis B antigenemia (Langford, 20 1 5) . Symptoms are nonspecifi c , and fever, weight loss, and malaise are present in more than half of cases. Diagnosis is made by biopsy, and treatment consists of high-dose prednisone plus cyclophosphamide. Vasculitis due to hepatitis B antigenemia responds to antivirals, glucocorticoste­ roids, and plasma exchange (Chap. 5 5 , p. 1 063) . Only a few reports describe polyarteritis nodosa associated with pregnancy. Of 1 2 afected gravidas, polyarteritis first manifested during pregnancy in seven, and it was rapidly fatal by 6 weeks postpartum (Owen, 1 989) . he diagnosis was not made until autopsy in six of the seven women. Four women continued pregnancy, which resulted in one stillborn and three successful outcomes.

1 1 49

1 1 50

Med i c a l a nd S u rg ical Compl i cations

• Granulomatosis with Polyangiitis

Formerly Wegener granulomatosis, this is a small-vessel nec­ rotizing granulomatous vasculitis afecting the upper and lower respiratory tract and kidney (Pagnoux, 20 1 6) . Disease frequently includes sinusitis and nasal disease-90 percent; pulmonary infi l trates, cavities, or nodules-85 percent; glo­ merulonephritis-75 percent; and musculoskeletal lesions-65 percent (Sneller, 1 995). At least 90 percent have polyangiitis (Langford, 20 1 5) . It is uncommon and usually encountered after age 50. Koukoura and associates (2008) reviewed 36 cases in association with pregnancy and found a higher preterm birth rate. In another report, a second woman had disease-related pneumonitis, but pregnancy did not appear to afect disease activity (Pagnoux, 20 1 1 ) . Because subglottic stenosis is found in up to a fourth of patients, the anesthesia team is ideally con­ sulted antepartum (Engel, 20 1 1 ) . Corticosteroids are standard treatment, but azathioprine, cyclosporine, and IVIG therapy may also be used. For severe disease in the late second or third trimester, cyclophosphamide in combination with prednisolone seems acceptable. • Takayasu Arteritis

Also called pulseless disease, this is a chronic inflammatory arte­ ritis afecting large vessels (Goodman, 20 1 4) . Unlike temporal arteritis, which develops almost exclusively after age 5 5 , the onset of Takayasu arteritis is almost always before age 40. It is associated with abnormal angiography of the upper aorta and its main branches and with upper extremity vascular impair­ ment. Death usually results from congestive heart failure or cerebrovascular events. Computed tomography or magnetic resonance angiography can detect this disorder before the development of severe vascular compromise. Takayasu arteritis may respond symptomatically to corticosteroid therapy, how­ ever, it is not curative. Surgical bypass or angioplasty improves survival rates. Comorbid severe renovascular hypertension, cardiac invol­ vement, or pulmonary hypertension worsen pregnancy prog­ nosis (Singh, 20 1 5) . Hypertension is relatively common and should be carefully controlled. Blood pressure is most accu­ rately measured in the lower extremity. Overall, the prognosis for pregnancy is good Oohnston, 2002) . A study of 58 women with Takayasu arteritis found an elevated risk of pregnancy­ related hypertension and preeclampsia but overall favorable maternal and fetal outcomes (Gudbrandsson, 20 1 7) . A study of 52 patients comparing obstetrical outcomes before and ater diagnosis reported higher rates of obstetrical complications after diagnosis. These included preeclampsia, preterm birth, and fetal-growth restriction or death (Comarmond, 20 1 5) . Involvement o f the abdominal aorta portends worse perinatal outcome (Sharma, 2000) . Vaginal delivery is preferred, and epidural analgesia has been advocated for labor and delivery. • Other Vasculitides

Henoch-Schonlein purpura is uncommon after childhood. Tay­ abali and associates (20 1 2) reviewed 20 pregnancies compli­ cated by this vasculitis and described cutaneous lesions in three

fourths. Approximately half had arthralgias. For Beh;et disease, Gungor and colleagues (20 1 4) described 298 pregnancies in 94 women and found higher miscarriage rates and smaller babies compared with healthy controls. Formerly Churg-Strauss vas­ culitis, eosinophilic granulomatosis with polyangiitis is rare in pregnancy Oennette, 20 1 3) . Hot and associates (2007) described a pregnant woman who responded to IVIG therapy. Corradi and associates (2009) described an afected 3 5-year­ old woman at term whose necrotizing vasculitis involved the heart, and she subsequently underwent cardiac transplantation. Edwards (20 1 5) described one woman who developed postpar­ tum relapses of this vasculitis in each of two pregnancies. I N F LAMMATORY MYOPATHI ES These are acquired and potentially treatable causes of skeletal muscle weakness with a prevalence of 1 in 1 00,000 persons (Dalakas, 20 1 2) . There are three major groups: polymyositis, dermatomyositis, and inclusion-body myositis, which all pres­ ent with progressive asymmetrical muscle weakness. They have a variable association with connective tissue diseases, malig­ nancy, drugs, systemic autoimmune disease such as Crohn dis­ ease, and viral, bacterial, and parasitic infections. Poymyositis is a subacute inflammatory myopathy that is frequently associated with one of the autoimmune connective tissue disorders. Dermatomyositis manifests as a characteristic rash accompanying or preceding weakness. Laboratory findings include elevated muscle enzyme levels in serum and an abnor­ mal electromyogram. Conirmation is by biopsy, which shows perivascular and perimysial inlammatory infiltrates, vasculitis, and muscle iber degeneration. It usually develops alone but can overlap with systemic sclerosis or mixed connective tissue disease. Prevailing theories suggest that the syndromes are caused by viral infections, autoimmune disorders, or both. Impor­ tantly, approximatey 15 percent of adults who develop derma­ tomyositis have an associated malignant tumor. The timing of myositis and tumor appearance may be separated by several years. he most common sites of associated cancer are breast, lung, stomach, and ovary. The disease usually responds to high-dose corticosteroid therapy, immunosuppressive drugs such as azathioprine or methotrexate, or IVIG (Dalakas, 2 0 1 2; Linardaki, 20 1 1 ) . Experiences i n pregnancy are garnered mostly from case series and reviews. Chen and colleagues (20 1 5) found 1 7 women with polymyositis/ dermatomyositis in an Australian population-based cohort of births. These women had higher rates of hypertension (23 percent), antepartum hemorrhage ( 1 1 percent), cesarean delivery (88 percent), and preterm birth (35 percent) . Another series of 60 women with dermatomyositis and 38 with polymy­ ositis found that in 80 percent, pregnancy had no adverse efect on their disease. Similar results have been reported by others (Missumi, 20 1 5; Pinal-Fernandez, 20 1 4) . Rosenzweig and col­ leagues ( 1 989) reviewed 24 pregnancy outcomes in 1 8 women with primary disease. Of these, a fourth had an exacerbation in the second or third trimester. In 1 2 in whom disease became manifest first during pregnancy, half of the eight pregnancies resulted in perinatal death, and one woman died postpartum.

C o n n ective Tissue D i s o rders

From their review, Doria and associates (2004) concluded that pregnancy outcome was related to dermatomyositis activity and that new-onset disease was particularly aggressive. H EREDITARY CON N ECTIVE TISSU E DISORDERS Numerous inherited mutations involve genes that encode for structural proteins of bone, skin, cartilage, blood vessels, and basement membranes. Although connective tissues contain many complex macromolecules such as elastin and more than 30 proteoglycans, the most common constituents are ibrillar collagen types I, II, and III. Various mutations, some reces­ sively and some dominantly inherited, result in clinical syn­ dromes that include Marfan and Ehlers-Danlos syndromes, osteogenesis imperfecta, chondrodysplasias, and epidermoly­ sis bulla. Of concern during pregnancy is the predilection for these disorders to result in aortic aneurysms (Schoenhof, 20 1 3) . • Marfan Syndrome

This is an autosomal dominant connective tissue disorder that has a population prevalence of 1 in 3000 to 5000 (Prockop, 20 1 5) . Marfan syndrome afects both sexes equally. The syn­ drome is due to abnormal fibrillin-a constituent of elastin­ caused by any of several diferent mutations in the FENI gene (Biggin, 2004) . Located on chromosome 1 5q2 1 , the FENI gene has a high mutation rate, and there are many mild, sub­ clinical cases. A 5 0-percent risk of disease transmission to the ofspring exists, however, the ability to predict disease severity in progeny is limited by the lack of distinct genotype-phe­ notype correlation and large clinical variability. Currently, preimplantation and prenatal diagnoses are limited to the 80 percent of cases in which the mutation in the FBNI gene is known (Smok, 20 1 4) . In severe disease, there i s degeneration o f the elastic lamina in the media of the aorta. his weakness predisposes to aor­ tic dilation or dissecting aneurysm, which appears more com­ monly during pregnancy (Curry, 20 1 4; Roman, 20 1 6) . Marfan syndrome complicating pregnancy is discussed in more detail in Chapter 49 (p. 967) . • Ehlers-Dan los Syndrome

This disease is characterized by various connective tissue changes, including skin hyperelasticity. In the more severe types, rupture of any of several arteries can cause either stroke or bleeding. There are several disease types based on skin, joint, or other tissue involvement. Some are autosomal dominant, some recessive, and some X-linked (Solomons, 20 1 3) . Their aggregate prevalence approximates 1 in 5000 births (Prockop, 20 1 5) . Types I, II, and III are autosomally dominant, and each accounts for approximately 30 percent of cases. Type IV is uncommon but is known to predispose to preterm delivery, maternal great-vessel rupture, postpartum bleeding, and uter­ ine rupture (Pepin, 2000) . In most, the underlying molecular defect afects collagen or procollagen.

In general, women with Ehlers-Danlos syndrome reportedly have a higher frequency of preterm rupture of membranes, pre­ term delivery, and antepartum and postpartum hemorrhage (Volkov, 2006) . That said, a recent cohort study of 3 1 4 women reported no greater risk of adverse pregnancy outcome, includ­ ing preterm birth (Sundelin, 20 1 7) . Several cases of spontane­ ous uterine rupture have been described (Rudd, 1 983) . Tissue fragility makes episiotomy repair and cesarean delivery diicult. Hurst and colleagues (20 1 4) surveyed 1 769 respondents of the Ehlers-Danlos National Foundation and found a preterm birth rate of 25 percent and infertility rate of 44 percent. A mater­ nal and fetal death from spontaneous rupture of the right iliac artery has been reported (Esaka, 2009) . Bar-Yosef and associ­ ates (2008) described a newborn with multiple congenital skull fractures and intracranial hemorrhage caused by Ehlers-Danlos type VIIC. • Osteogenesis I mperfecta

This disorder has a prevalence of 1 in 20,000 births for type I and 1 in 60,000 for type II. It is characterized by brittle bones and afected patients often have blue sclerae, hearing loss, mul­ tiple prior bone fractures, and dental abnormalities. There are up to 1 5 subtypes based on the causative gene and clinical picture, which ranges from mild to severe (Van Dijk, 20 1 0) . Genetic inheritance includes autosomal dominant, autosomal recessive, and sporadic patterns. Type I is the mildest form, and the typical mutation afects the COLIA I gene (Sykes, 1 990) . Type II is typically lethal in utero (Prockop, 20 1 5) . Women with osteogenesis imperfecta, most commonly type I, may have successful pregnancies. hat said, several risks in pregnancy include fractures, complications related to scoliosis with restrictive lung disease, micrognathia, brittle teeth, an unstable cervical spine, uterine rupture, and cepha­ lopelvic disproportion. A retrospective cohort of 295 . women with osteogenesis imperfecta found greater risks of antepartum hemorrhage, abruption, fetal-growth restriction, congenital malformations, and preterm birth (Ruiter-Ligeti, 20 1 6) . It is not unusual for afected women to enter pregnancy having had 20 to 30 prior fractures. Most require minimal treatment other than management of the fractures and consideration of bisphosphonates to decrease bone loss. Depending on the type of osteogenesis imperfecta, the fetus may be afected and may also sufer fractures in utero or dur­ ing delivery (Chap. 1 0, p. 2 1 0) . Prenatal diagnosis is available in many situations, if desired, and in utero stem cell therapy is being evaluated (Couzin-Frankel, 20 1 6) . REFERENCES Abisror N , Mekinian A, Lachassinne E, et al: Autism spectrum disorders in babies born to mothers with antiphospholipid syndrome. Semin Arthritis Rheum 43(3) :348, 20 1 3 Adams K , Bombardier C , van der Heijde OM: Safety o f pain therapy during pregnancy and lactation in patients with inflammatory arthritis: a systematic literature review. J Rheumatol Suppl 90:59, 20 1 2 Adams KM, Nelson JL: Microchimerism: a n investigative frontier i n autoim­ munity and transplantation. JAMA 29 1 : 1 1 27, 2004 Adams M: Measurement of lupus anticoagulants: an update on quality in labo­ ratory testing. Semin Thromb Hemost 39(3) :267, 20 1 3

1 1 51

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Med ical a n d S u rg ical Co m pl i catio n s Lockshin M D , Sammaritano L R : Rheumatic disease. In Barron W M , Lind­ heimer MD (eds): Medical Disorders During Pregnancy, 3rd ed. St. Louis, Mosby, 2000 Lockwood CJ, Romero R, Feinberg RF, et al: The prevalence and biologic sig­ niicance of lupus anticoagulant and anticardiolipin antibodies in a general obstetric population. Am J Obstet Gynecol 1 6 1 :369, 1 989 Madazli R, Yuksel MA, Oncul M, et al: Obstetric outcomes and prognostic factors of lupus pregnancies. Arch Gynecol Obstet 289:49, 20 1 4 Makol A , Wright K , Amin S : Rheumatoid arthritis and pregnancy: safety con­ siderations in pharmacological management. Drugs 7 1 ( 1 5) : 1 973, 20 1 1 McInnes IB, Scherr G : The pathogenesis of rheumatoid arthritis. N Engl J Med 365 (23) :2205, 20 1 1 Meier FM, Frommer W, Dinser R, et al: Update on the proile of the EUSTAR cohort: an analysis of the EULAR Scleroderma Trials and Research group database. Ann Rheum Dis 7 1 (8): 1 3 5 5 , 20 1 2 Mekinian A , Bourrienne M e , Carbillon L , e t al: Non-conventional antiphos­ pholipid antibodies in patients with clinical obstetrical APS : prevalence and treatment eicacy in pregnancies. Semin Arthritis Rheum 46(2):232, 20 1 6 Mekinian A , Lazzaroni M G , Kuzenko A , e t al: The eicacy o f hydroxychloro­ quine for obstetrical outcome in anti-phospholipid syndrome: data from a European multicenter retrospective study. Autoimmun Rev 1 4(6) :498, 20 1 5 Meroni PL, Borghi MO, Raschi E , e t al: Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol 7(6) :330, 2 0 1 1 Missumi LS, Souza F H , Andrade JQ, et al: Pregnancy outcomes in derma­ tomyositis and polymyositis patients. Rev Bras Reumatol 5 5 (2) : 9 5 , 20 1 5 Miyakis S , Lockshin MD, Atsumi T, et al: International consensus statement on an update of the classiication criteria for deinite antiphospholipid syn­ drome (APS) . J hromb Haemost 4:295, 2006 Mohamed MA, Goldman C, EI-Dib M , et al: Maternal juvenile rheumatoid arthritis may be associated with preterm birth but not poor fetal growth. J Perinatol 36(4) :268, 20 1 6 Moroni G, Doria A , Giglio E , e t al: Fetal outcome and recommendations of pregnancies in lupus nephritis in the 2 1 st centuly. A prospective multicenter study. J Autoimmun 74:6, 20 1 6a Moroni G, Doria A, Giglio E, et al: Maternal outcome in pregnant women with lupus nephritis. A prospective multicenter study. J Autoimmun 74: 1 94, 20 1 6b Moroni G, Ponticelli e Pregnancy after lupus nephritis. Lupus 1 4: 8 9 , 2005 Moroni G, Quaglini S , Bani G, et al: Pregnancy in lupus nephritis. Am J Kidney Dis 40:7 1 3 , 2002 Moroni G, Ventura D, Riva P, et al: Antiphospholipid antibodies are associ­ ated with an increased risk for chronic renal insuiciency in patients with lupus nephritis. Am J Kidney Dis 43:28, 2004 Morra M, Bofa MC, Tincani A, et al: Follow-up of babies born to mothers with anti phospholipid syndrome: preliminary data from the European neo­ natal registry. Lupus 2 1 (7) : 76 1 , 20 1 2 Moutsopoulos H M , Vlachoyiannopoulos PG: Antiphospholipid syndrome I n Kasper DL, Fauci AS, Hauser SL, e t al (eds): Harrison's Principles o f Inter­ nal Medicine, 1 9th ed. New York, McGraw-Hili, 20 1 5 Munoz-Suano A , Kallikourdis M , Sarris M , e al: Regulatory T cells protect from autoimmune arthritis during pregnancy. J Autoimmun 38 (2-3) :J 1 03, 20 1 2 Musiej-Nowakowska E , Ploski R: Pregnancy and early onset pauciarticular juvenile chronic arthritis. Ann Rheum Dis 58:475, 1 999 Nalli e, Iodice A, Andreoli L, et al: Long-term neurodevelopmental outcome of children born to prospectively followed pregnancies of women with systemic lupus erythematosus and/or antiphospholipid syndrome. Lupus 26: 5 52, 20 1 7 Nelson JL, Hughes A, Smith AG, et al: Maternal-fetal disparity i n HLA class II alloantigens and the pregnancy-induced amelioration of rheumatoid arthritis. N Engl J Med 329:466, 1 993 Nelson JL, 0stensen M : Pregnancy and rheumatoid arthritis. Rheum Dis C1in North Am 23: 1 95 , 1 997 Nodler J, Moolamalla S R, Ledger EM, et al: Elevated antiphospholipid anti­ body titers and adverse pregnancy outcomes: analysis of a population-based hospital dataset. BMC Pregnancy Childbirth 9 ( 1 ) : 1 1 , 2009 Ojeda-Uribe M , Afif N, Dahan E, et al: Exposure to abatacept or rituximab in the irst trimester of pregnancy in three women with autoimmune diseases. Clin Rheumatol 32(5):695, 20 1 3 Oshiro BT, Silver M , Scorr JR, e t al: Antiphospholipid antibodies and fetal death. Obstet Gynecol 87:489, 1 996 0stensen M : Pregnancy in patients with a history of juvenile rheumatoid arthritis. Arthritis Rheum 34:88 1 , 1 99 1 0stensen M, Villiger P M : h e remission o f rheumatoid arthritis during preg­ nancy. Semin I mmunopathol 29: 1 8 5, 2007 Owen J, Hauth Je Polyarteritis nodosa in pregnancy: a case report and brief literature review. Am J Obstet Gynecol 1 60:606, 1 989

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Con n ective Tiss u e D i s o rders Rudd NL, Nimrod C, Holbrook A, et al: Pregnancy complications in type IV Ehlers-Danlos syndrome. Lancet 1 (83 1 4-5): 50, 1 98 3 Rufatti A , Tonello M , Visentin MS, e t a l : Risk factors for pregnancy failure i n patients with anti-phospholipid syndrome treated with conventional thera­ pies: a multicentre, case-control study. Rheumatology 50(9) : 1 684, 20 1 1 Ruiter-Ligeti J , Czuzoj-Shulman N, Spence AR, et al: Pregnancy outcomes in women with osteogenesis imperfecta: a retrospective cohort study. J Perina­ toI 36 ( 1 0) : 828, 20 1 6 Saccone G , Maruotti GM, Berghella V, et al: Obstetric outcomes i n pregnant women with primary anti phospholipid syndrome according to the antibody proile: the PREGNANTS study. Abstract No. 62, Am J Obstet Gynecol 2 1 6:S45, 20 1 7 Sammaritano LR: Contraception i n patients with systemic lupus erythematosus and antiphospholipid syndrome. Lupus 23( 1 2) : 1 242, 20 1 4 Sanchez-Guerrero J , Uribe AG, Jimenez-Santana L, e t a l : A trial of cotracep­ tive methods in women with systemic lupus erythematosus. N Engl J Med 353:2539, 2005 Schoenhof F, Schmidli J, Czerny M, et al: Management of aortic aneurysms in patients with connective tissue disease. J Cardiovasc Surg 54( 1 suppl 1): 1 2 5, 20 1 3 Schreiber K , Hunt BJ: Pregnancy and antiphospholipid syndrome. Semin Thromb Hemost 42(7) :780, 2 0 1 6 Sciascia S, Hunt BJ, Talavera-Garcia E, e t al: The impact of hydroxychloro­ quine treatment on pregnancy outcome in women with anti phospholipid antibodies. Am J Obstet GynecoI 2 1 4 (2):273.e 1 , 20 1 6 Shah A , St. Clair EW: Rheumatoid arthritis. I n Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles ofInternal Medicine, 1 9th ed. New York, McGraw-Hill, 20 1 5 Sharma BK, Jain S , Vasishta K: Outcome o f pregnancy i n Takayasu arteritis. Int J Cardiol 75:S 1 59 , 2000 Sherer Y, Gorstein A, Fritzler MJ, et al: Autoantibody explosion in systemic lupus erythematosus: more than 1 00 diferent antibodies found in S LE patients. Semin Arthritis Rheum 34(2):50 1 , 2004 Shinohara K, Miyagawa S , Fujita T, et al : Neonatal lupus erythematosus: results of maternal corticosteroid therapy. Obstet Gynecol 93:952, 1 999 Silman A, Kay A, Brennan P: Timing of pregnancy in relation to the onset of rheumatoid arthritis. Arthritis Rheum 3 5 : 1 52, 1 992 Silver M , Parker CB, Reddy UM, et al: Antiphospholipid antibodies in still­ birth. Obstet Gynecol 1 22(3) :64 1 , 20 1 3 Silverman E, Jaeggi E: Non-cardiac manifestations o f neonatal lupus erythema­ tosus. Scand J Immunol 72:223, 20 1 0 Simchen MJ, Goldstein G , Lubetsky A, e t al: Factor V Leiden and anti phos­ pholipid antibodies in either mothers or infants increase the risk for perina­ tal arterial ischemic stroke. Stroke 40( 1 ) :65, 2009 Simpson JL: Cell-free fetal DNA and maternal serum analytes for monitoring embryonic and fetal status. Fertil Steril 99(4) : 1 1 24, 20 1 3 Singh JA, Saag KG, Bridges SL ]r , e t aI: 20 1 5 American College o f Rheumatol­ ogy Guideline for the management of rheumatoid arthritis. Arthritis Care Res (Hoboken) 6 8 ( 1 ) : 1 , 20 1 6 Singh N, Tyagi S , Tripathi R , e t al: Maternal and fetal outcomes i n pregnant women with Takayasu aortoarteritis: does optimally timed intervention in women with renal artery involvement improve pregnancy outcome? Taiwan ] Obstet Gynecol 54(5): 597, 20 1 5 Sitar G , Brambati B , Baldi M , et al: he use o f non-physiological conditions to isolate fetal cells from maternal blood. Exp Cell Res 302: 1 53, 2005 Smok DA: Aortopathy in pregnancy. Semin Perinatol 3 8 (5) :295, 20 1 4 Sneller M C : Wegener's granulomatosis. ]AMA 273 : 1 288, 1 995 Sobanski V, Launay D, Depret S, et al: Special considerations in pregnant systemic sclerosis patients. Expert Rev Clin Im munol 1 2 ( 1 1 ) : 1 1 6 1 , 20 1 6 Solomons ] , Coucke P , Symoens S , e t al: Dermatosparaxis (Ehlers-Danlos type VIIC) : prenatal diagnosis following a previous pregnancy with unex­ pected skull fractures at delivery. Am ] Med Genet A 1 6 1 (5): 1 1 22, 20 1 3 Spinillo A , Beneventi F, Epis OM, e t al: h e efect o f newly diagnosed undifferentiated connective tissue disease on pregnancy outcome. Am ] Obstet GynecoI 1 99 (6) :632.e 1 , 2008 Spinillo A, Beneventi F, Locatelli E, et al: The impact of unrecognized auto­ immune rheumatic diseases on the incidence of preeclampsia and fetal growth restriction: a longitudinal cohort study. BMC Pregnancy Childbirth 1 6 ( 1 ) :3 1 3, 2 0 1 6 Srivatsa B, Srivatsa S, Johnson K , e t al : Microchimerism o f presumed fetal origin in thyroid specimens from women: a case-control study. Lancet 3 58 :2034, 2001 Steen VD: Pregnancy in women with systemic sclerosis. Obstet Gynecol 94: 1 5 , 1 999 Steen VD, Conte C, Day N, et al : Pregnancy in women with systemic sclerosis. Arthritis Rheum 32: 1 5 1 , 1 989

Stevens M . Maternal microchimerism in health and disease. Best Pract Res Clin Obstet GynecoI 3 1 : 1 2 1 , 20 1 6 Stojan G , Baer AN: Flares o f systemic lupus erythematosus during pregnancy and the puerperium: prevention, diagnosis and management. Expert Rev Clin I mmunol 8 ( 5):439, 20 1 2 Sukara G, Baresic M , Sen tic M , e t al: Catastrophic antiphospholipid syndrome associated with systemic lupus erythematosus treated with rituximab: case report and a review of the literature. Acta Reumatol Port 40(2) : 1 69 , 20 1 5 Sundelin HE, Stephansson 0 , Johansson K, e t al: Pregnancy outcome i n joint hypermobility syndrome and Ehlers-Danlos syndrome. Acta Obstet Gynecol Scand 96( 1 ) : 1 1 4, 20 1 7 Sykes B , Ogilvie D, Wordsworth P , e t al: Consistent linkage o f dom inantly inherited osteogenesis imperfecta to the type I collagen loci: COL I A I and COU A2. Am ] Hum Genet 46(2) :293, 1 990 Taraborelli M, Ramoni V, Brucato A, et al: Brief report: successful pregnancies but a higher risk of preterm births in patients with systemic sclerosis: an Italian multicenter study. Arthritis Rheum 64(6) : 1 970, 20 1 2 Tayabali S , Andersen K , Yoong W : Diagnosis and management o f Henoch­ Sch6nlein purpura in pregnancy: a review of the literature. Arch Gynecol Obstet 286(4) :825, 20 1 2 Tenti S , Cheleschi S , Guidelli G M , e t al: Intravenous immunoglobulins and antiphospholipid syndrome: how, when and why? A review of the literature. Autoimmun Rev 1 5 (3):226, 20 1 6 Tincani A , Rebaioli CB, Andreoli L , e t al: Neonatal efects o f maternal anti phospholipid syndrome. Curr Rheumatol Rep 1 1 ( 1 ) :70, 2009 Toglia M R, Weg ]G: Venous thromboembolism during pregnancy. N Engl ] Med 33 5 : 1 08, 1 996 Tower C, Mathen S, Crocker I, et al: Regulatory T cells in systemic lupus ery­ thematosus and pregnancy. Am J Reprod Immunol 69(6) : 5 8 8 , 20 1 3 Tsokos GC: Systemic lupus erythematosus. N Engl ] Med 365 (22) :2 1 1 0, 20 1 1 Unger A, Kay A, Griin A], et al: Disease activity and pregnancy associated beta2-glycoprotein in rheumatoid arthritis. BM] 286:750, 1 98 3 Van Dijk F S , Pals G , Van Rijn RR, e t a l : Classification of osteogenesis imper­ fecta revisited. Eur ] Med Genet 53 ( 1 ) : 1 , 20 1 0 Varga ]: Systemic sclerosis (scleroderma) and related disorders. I n Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 1 9th ed. New York, McGraw-Hill, 20 1 5 Varner MW, Meehan RT, Syrop CH, et al: Pregnancy i n patients with sys­ temic lupus erythematosus. Am ] Obstet Gynecol 1 45 : 1 025, 1 983 Volkov N, Nisenblat V, Ohel G, et al: Ehlers-Danlos syndrome: insight on obstetric aspects. Obstet Gynecol Surv 62: 5 1 , 2006 Wagner S, Craici I , Reed 0, et al: Maternal and foetal outcomes in pregnant patients with active lupus nephritis. Lupus 1 8 (4)342, 2009 Waldorf M , Nelson ]L: Autoimmune disease during pregnancy and the microchimerism legacy of pregnancy. Immunol Invest 37:63 1 , 2008 Wallenius M , Salvesen A, Daltveit AK, et al: Rheumatoid arthritis and out­ comes in first and subsequent births based on data from a national birth registry. Acta Obstet Gynecol Scand 93 (3) : 302, 20 1 4 Wei S , Lai K , Yang Z , e t al: Systemic lupus erythematosus and risk o f preterm birth: a systematic review and meta-analysis of observational studies. Lupus 26: 563, 20 1 7 Wong LF, Porter TF, Scott ]R: I mmunotherapy for recurrent miscarriage. Cochrane Database Syst Rev 1 O:CDOOO 1 1 2, 20 1 4 Wu H , Birmingham OJ, Rovin B, et al: D-dimer level and the risk for thrombosis in systemic lupus erythematosus. Clin ] Am Soc Nephrol 3 : 1 628, 2008 Yang H , Liu H , Xu D, et al: Pregnancy-related systemic lupus erythematosus: clinical features, outcome and risk factors of disease flares-a case control study. PLoS One 9(8): e l 04375, 20 1 4 Yang W , Tang H , Zhang Y , e t al: Meta-analysis followed b y replication identi­ ies loci in or near CDKN I B, TET3, CD80, DRAM l , and ARI D5B as associated with systemic lupus erythematosus in Asians. Am ] Hum Genet 92 ( 1 ) :4 1 , 20 1 3 Yasuda M, Takakuwa K , Tokunaga A , e t al: Prospective studies o f the associa­ tion between anticardiolipin antibody and outcome of pregnancy. Obstet Gynecol 86: 5 5 5 , 1 995 Ye Y, van Zyl B, Varsani H, et al: Maternal microchimerism in muscle biop­ sies from children with juvenile dermatomyositis. Rheumatology (Oxford) 5 1 (6):987, 20 1 2 Zangari M , Lockwood CJ, Scher J , et al: Prothrombin activation fragment ( F 1 .2) is increased in pregnant patients with antiphospholipid antibodies. Thromb Res 85: 1 77, 1 997 Zhao C, Zhao J , Huang Y, et al: New-onset systemic lupus erythematosus dur­ ing pregnancy. Clin Rheumatol 32(6) :8 1 5 , 20 1 3 Zuppa A, Riccardi R , Frezza A , e t al: Neonatal lupus: follow-up i n infants with anti SSA/Ro antibodies and review of the literature. Autoimmun Rev 1 6:42 , 20 1 7

1 1 55

1 1 56

C H A PT E R 60

Neurolog i ca l D i sorders

CENTRAL NERVOU S SYSTEM I MAGING . . . . . . . . . . . . 1 1 56 H EADACHE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 57 S EIZURE DISORDERS . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 58 CEREBROVASCULA R DISEASES . . . . . . . . . . . . . . . . . . 1 1 60 DEMYELI NATI NG OR DEGENERATIVE DISEASES . . . . . 1 1 64 NEU ROPATH I ES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 66 SPINAL CORD I NJ U RY . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 67 I DIOPATH IC I NTRACRANIAL HYPERTENSION . . . . . . . 1 1 68 MATERNAL VENTRICULA R S H U NTS . . . . . . . . . . . . . . . 1 1 68 MATERNAL BRAIN DEATH . . . . . . . . . . . . . . . . . . . . . . . 1 1 68

Epilepsy appears to have no fect on pregnancy, though at the time oflabour it may be mistaken or eclampsia by inex­ perienced observers. f the attacks are requent the patient should be put upon large doses ofpotassium bromide and treatedjust as at other times. -J. Whitridge Williams ( 1 903) Although several neurological diseases are relatively common in women of childbearing age, less than two pages were devoted to Diseases of the Nervous System in this textbook's first edition. In the past, some may have precluded pregnancy, however, few do so now. Most encountered during pregnancy are the same as for nonpregnant women, however a few neurological disorders may be seen more frequently in pregnant women. Examples are Bell palsy, specific types of strokes, and benign intracranial

hypertension or pseudotumor cerebri. Neurovascular disorders are an important cause of maternal mortality and accounted for nearly 7 percent of maternal deaths in the United States from 20 1 1 through 20 1 3 (Creanga, 20 1 7) . Many neurological disorders frequently precede pregnancy. fost women with chronic neurological disease who become pregnant will have successful outcomes, but some disorders have speciic risks. Conversely, other women will have new­ onset neurological symptoms during pregnancy, and these often must be distinguished from pregnancy complications. Psychi­ atric disorders can also manifest with cognitive and neuromus­ cular abnormalities and should be considered in the evaluation. CENTRAL N ERVOUS SYSTEM I MAG I N G Computed tomography (CT) and magnetic resonance (MR) imaging assist in the diagnosis, classification, and management of many neurological and psychiatric disorders. As discussed in Chapter 46 (p. 907), these imaging methods can be used safely during pregnancy. CT scanning is often used when rapid diag­ nosis is necessary and is excellent for detecting recent hemor­ rhage. Because it does not use radiation, MR imaging is oten preferred and is particularly helpful to diagnose demyelinating diseases, arteriovenous malformations, congenital and develop­ mental nervous system abnormalities, posterior fossa lesions, and spinal cord diseases. Whenever either test is done, the woman with advanced pregnancy should be positioned in a left lateral tilt with a wedge under one hip to prevent hypotension and to diminish aortic pulsations, which may degrade the image. Cerebral angiography with contrast injection, usually via the femoral artery, is a valuable adjunct to the diagnosis and treat­ ment of some cerebrovascular diseases. Fluoroscopy delivers more radiation but can be performed with abdominal shield­ ing. Positron emission tomography (PET) and functional M R imaging (fMI) have not been evaluated for use in pregnant patients (Chiapparini, 20 1 0) .

N e u rolog ica l D i s o rd ers

H EADAC H E I nfection,

In one national survey i n the United States i n 20 1 2, 1 7 per­ cent of those aged 1 8 to 44 years reported a severe headache or migraine within the past 3 months (Blackwell, 20 1 4) . Burch and coworkers (20 1 5) reported that 24 percent of nonpregnant women in this age group were similarly afected. Of pregnant women presenting with headache who received a neurologi­ cal consultation, two thirds were due to primary disorders, with over 90 percent due to migraine. Of the other third due to secondary conditions, over half were due to hypertensive disorders (Robbins, 20 1 5) . Interestingly, Aegidius and associ­ ates (2009) reported a decline in the rate of all headache types during pregnancy in nulliparas, especially during the third tri­ mester. The classifi c ation by the International Headache Society (20 l 3) is shown in Table 60- 1 . In pregnant women, primary headaches are more common than those stemming from second­ ary causes (Digre, 20 1 3; Sperling, 20 1 5) . Migraine headaches are those most likely to be afected by the hormonal changes of pregnancy (Pavlovic, 20 1 7) . The incidences of severe headache causes in pregnancy are shown in Figure 60- 1 . • Tension-Type Headache

These are the most frequent cause of all headaches. Charac­ teristic features include muscle tightness and mild-to-moderate pain in the back of the neck and head that can persist for hours. Neurological disturbances or nausea are typically absent. The pain usually responds to rest, massage, application of heat or ice, antiinlammatory medications, or mild tranquilizers. Hos­ pital admission is seldom necessary. • Migra i ne Headache

The term migraine describes a periodic, sometimes incapacitat­ ing neurological disorder with episodic attacks of severe head­ ache and autonomic nervous system dysfunction (Goadsby, 20 1 5) . The International Headache Society (20 l 3) classifies

TABLE 60- 1 . Headache Cla ssification Primary M i g ra i n e Tensio n-type Tri g e m i n a l ce p h a l a l g i a Oth e r Secondary Tra u ma Va scu l a r d i sor d e rs Su bsta nce a bu se I nfecti o n Di sorders o f homeosta s i s Cra n i ofac i a l d i sorders Psyc h i atric d i sorders Data from I nternat i o n a l Headache Soci ety, 20 1 3 .

Stroke, Pituitary,

2.1 %

2.8%

3.6% �

• • •

Other headache, (tension

59% 37% Without aura, 24 Chronic, 6%

M igraine,

With aura,

6% 3%)

F I G U RE 60-1 I n cidences of headache ca u ses i n 1 40 consecutive p reg n a nt women for whom in-hospital n e u ro l og y consu ltatio n was req u ested. (Data from Robbins, 2 0 1 5 .)

three migraine types based on chronicity and on the presence or absence of an aura. 1 . Migraine without aura-formerly termed common migraine­ is characterized by a unilateral throbbing headache, nausea and vomiting, or photophobia . 2. Migraine with aura-formerly termed classic migraine-has similar symptoms preceded by premonitory neurological phenomena such as visual scotoma or hallucinations. A third of patients have this type of migraine, which sometimes can be averted if medication is taken at the first premonitory sign. 3. Chronic migraine is defi n ed by a migraine headache occur­ ring at least 1 5 days each month for more than 3 months. These are the most common reason for admission for head­ ache evaluation and management. Migraines may begin in childhood, peak in adolescence, and tend to diminish in both frequency and severity with advancing years. According to Lip­ ton and associates (2007), their annual prevalence is 1 7 percent in women and 6 percent in men. Another 5 percent of women have probable migraine, that is, they have all criteria but one (Silberstein, 2007) . Speciic polymorphisms have been identi­ fied that modulate the risk of migraines (Chen, 20 1 5; Schiirks, 20 1 0) . hese headaches are especially common in young women and have been linked to hormone levels (Charles, 20 1 7; Pav­ lovic, 20 1 7) . They are frequently encountered during pregnancy. Sensory sensitivity with migraines is likely caused by mono­ aminergic sensory control systems in the brainstem and hypo­ thalamus (Goadsby, 201 5). his exact pathophysiology is uncertain, but they occur when neuronal dysfunction leads to decreased cortical blood How, activation of vascular and menin­ geal nociceptors, and stimulation of trigeminal sensory neurons (Brandes, 2007; D'Andrea, 20 1 0) . A predilection for the poste­ rior circulation has been described (Kruit, 2004) . Migraines­ especially those with aura in young women-are associated with increased risk for ischemic strokes. The risk is greater in those who smoke or use combination oral contraceptives. M i g ra i n e in P reg na n cy

The prevalence of migraine headaches in the first trimester is 2 percent (Chen, 1 994) . Most migraineurs have improvement

1 1 57

1 1 58

Med i ca l a n d S u rg ica l Compl ications

during pregnancy (Kvisvik, 20 1 1 ) . Still, migraines-usually those with an aura-occasionally appear for the first time dur­ ing pregnancy. Pregnant women with preexisting migraine symptoms may have other symptoms suggestive of a more seri­ ous disorder, and new neurological symptoms should prompt a complete evaluation (Detsky, 2006; Heaney, 20 1 0) . Although conventional thinking has been that migraine headaches do not pose increased maternal or fetal risks, several recent studies have refuted this (Allais, 20 1 0) . In these, rates of preeclampsia, gestational hypertension, preterm birth, and other cardiovascular morbidities, including ischemic stroke, were increased (Grossman, 20 1 7; Wabnitz, 20 1 5) . Bushnell and coworkers (2009) identiied an incidence of migraines during pregnancy of 1 85 per 1 00,000 deliveries. Of diagnoses associated in these gravid migraineurs, risks were signiicantly higher for stroke, 1 6-fold; myocardial infarction, ivefold; heart disease, twofold; venous thromboembolism, twofold; and preeclampsia/gestational hypertension, twofold. M a n a g e m e nt

Data are limited regarding non pharmacological management in pregnancy such as biofeedback techniques, acupuncture, and transcranial magnetic stimulation (Airola, 20 1 0; Dodick, 20 1 0) . Efective medications include nonsteroidal antiinlam­ matory drugs (NSAIDs), and most migraine headaches respond to simple analgesics such as ibuprofen, acetaminophen, or Mid­ rin, especially if given early. Severe migraines are vexing for the patient and her caregiv­ ers. Multitargeted drug therapy is necessary in most cases for migraine relief (Gonzalez-Hernandez, 20 1 4) . Headaches are treated aggressively with intravenous hydration and parenteral antiemetics and opioids for immediate pain relie. Although a 2-g infusion of magnesium sulfate has gained favor in the past few years, a metaanalysis reported no beneits (Choi, 20 1 4) . Ergotamine derivatives are potent vasoconstrictors and are avoided in pregnancy because of their uterotonic efects (Briggs, 2 0 1 5). Triptans are serotonin 5-HT I Bl2 0-receptor agonists that efectively relieve headaches by causing intracranial vasocon­ striction (Contag, 20 1 0) . They also relieve nausea and vomit­ ing and greatly reduce the need for analgesics. Triptans can be given as an oral tablet, injection, rectal suppository, or intra­ nasal spray. hey are best used in combination with NSAIDs (Goadsby, 20 1 5) . The greatest experience is with sumatriptan (Imitrex) , and although not studied extensively in pregnancy, it appears to be safe (Briggs, 20 1 5 ; Nezvalova-Henriksen, 20 1 0) . However, i n one follow-up study a t 3 6 months o f children exposed to triptans in pregnancy, Wood and colleagues (20 1 6) found neurodevelopment diferences, including emotionality and activity problems. Some women will beneit from peripheral nerve blocks, and Govindappagari and coworkers (20 1 4) described their experiences with 13 pregnant women. For women with fre­ quent migraine headaches, oral prophylactic therapy is war­ ranted. Amitriptyline (Elavil) , 1 0 to 1 75 mg daily; propranolol (Inderal), 40 to 1 20 mg daily; or metoprolol (Lopressor, Top­ rol), 25 to 1 00 mg daily, have been used with success (Contag, 20 1 0; Goadsby, 20 1 5 ; Lucas, 2009) .

• Cluster Headache

This rare primary headache disorder is characterized by severe uni­ lateral lancinating pain radiating to the face and orbit, lasting 1 5 to 1 80 minutes, and occurring with autonomic symptoms and agita­ tion. Pregnancy does not afect symptom severity. Afected women should avoid tobacco and lcohol. Acute mnagement includes 1 00-percent oxygen therapy and sumatriptan given as a 6-mg dose subcutaneously (VanderPluym, 20 1 6) . If recurrent, prophylaxis is administered using a calcium-channel blocking agent. SEIZURE DISORDERS The Centers for Disease Control and Prevention reported that the prevalence of epilepsy in adults in 2005 was 1 .65 percent­ thus over 1 million American women of childbearing age are afected (Kobau, 2008) . After headaches, seizures are the next most prevalent neurological condition encountered in preg­ nancy, and they complicate 1 in 200 births (Brodie, 1 996; Yerby, 1 994) . Importantly, epilepsy accounted for 5 percent of maternal deaths in the United Kingdom for the 2 0 1 1 to 20 1 3 triennium (Knight, 20 1 5) . • Pathophysiology

A seizure is deined as a paroxysmal disorder of the central ner­ vous system characterized by an abnormal neuronal discharge with or without loss of consciousness. Some identiiable causes of convulsive disorders in young adults include head trauma, alcohol- and other drug-induced withdrawals, cerebral infec­ tions, brain tumors, biochemical abnormalities, and arterio­ venous malformations. A search for these is prudent with a new-onset seizure disorder in a pregnant woman. he diagnosis of idiopathic epilepsy is one of exclusion. Epilepsy encompasses diferent syndromes whose cardinal feature is a predisposition to recurrent unprovoked seizures. he International League Against Epilepsy Commission on Classiication and Terminology recently updated the following deinitions (Fisher, 20 1 4) . Foc a l Seiz u res

These originate in one localized brain area and afect a corre­ spondingly localized area of neurological unction. They are believed to result from trauma, abscess, tumor, or perinatal fac­ tors, although a speciic lesion is rarely demonstrated. Focal sei­ zures without dyscognitiveeatures start in one region of the body and progress toward other ipsilateral areas of the body, producing tonic and then clonic movements. Simple seizures can afect sen­ sory unction or produce autonomic dysfunction or psychologi­ cal changes. Cognitive function is not impaired, and recovery is rapid. Focal seizures with dyscognitive eatures are oten preceded by an aura and followed by impaired awareness manifested by sudden behavioral arrest or motionless stare. Involuntary move­ ments such as picking motions or lip smacking are common. Genera l ized S e izu res

These involve both brain hemispheres and may be preceded by an aura before an abrupt loss of consciousness. There is a strong hereditary component. In generalized tonic-clonic seizures, loss

N e u ro l og ical D i so rders

of consciousness is followed by tonic contraction of the mus­ cles and rigid posturing, and then by clonic contractions of all extremities while the muscles gradually relax. Return to con­ sciousness is gradual, and the patient may remain confused and disoriented for several hours. Absence seizures-also called petit mal seizures-are a form of generalized epilepsy that involve a brief loss of consciousness without muscle activity and are characterized by immediate recovery of consciousness and ori­ entation. • Preconceptional Counseling

Women with epilepsy ideally are counseled before pregnancy and relevant points are presented also in Chapter 8 (p. 1 48). Folic acid supplementation with 0.4 mg per day is begun at least 1 month before conception. The dose is increased to 4 mg when the woman taking antiepileptic medication becomes pregnant. hese medications are assessed and adjusted with a goal of mono therapy using the least teratogenic medication. If this is not feasible, then attempts are made to reduce the num­ ber of medications used and to use them at the lowest efective dose (Patel, 20 1 6) . Medication withdrawal should be consid­ ered if a woman is seizure free for 2 years or more. • Epilepsy During Pregnancy

The major pregnancy-related risks to women with epilepsy are fetal malformations and increased seizure rates. Seizure con­ trol is the main priority to avoid its attendant morbidity and mortality risks. Early studies described worsening seizure activ­ ity during pregnancy, however, this is less so now because of more efective drugs. Contemporary studies cite higher rates of seizure activity in only 20 to 30 percent of pregnant women (Mawer, 20 1 0; Vajda, 2008) . Women who are seizure free for at least 9 months before conception will likely remain so during pregnancy (Harden, 2009b) . Greater seizure frequency is often associated with decreased and thus subtherapeutic anticonvulsant serum levels, a lower seizure threshold, or both. An impressive number of pregnancy­ associated alterations can result in sub therapeutic serum levels. These include nausea and vomiting, slower gastroin­ testinal motility, antacid use that diminishes drug absorption, pregnancy hypervolemia ofset by protein binding, induction of hepatic enzymes such as cytochrome oxidases, placental enzymes that metabolize drugs, and increased glomerular il­ tration that hastens drug clearance. Importantly, some women discontinue medication because of teratogenicity concerns. Finally, the seizure threshold can be afected by pregnancy­ related sleep deprivation and by hyperventilation and pain during labor. Preg n a ncy Co m p l icatio n s

Women with epilepsy have a small increased risk of pregnancy complications that include spontaneous abortion, hemorrhage, hypertensive disorders, preterm birth, fetal-growth restriction, and cesarean delivery (Harden, 2009b; Viale, 20 1 5) . Impor­ tantly, MacDonald (20 1 5) also reports a tenfold higher mater­ nal death rate, and, as mentioned earlier, epilepsy accounted for 5 percent of maternal deaths in the United Kingdom.

Postpartum depression rates are also reportedly higher in epi­ leptic women (Turner, 2009) . Finally, children of epileptic mothers have a 1 0-percent risk of developing a seizure disorder. E m b ryofeta l Ma lformati o n s

For years, it was diicult to separate efects of epilepsy from those of its therapy as the primary cause of fetal malforma­ tions. As discussed in Chapter 8 (p. 1 48) , it is now believed that untreated epilepsy is not associated with an elevated fetal malformation rate (Thomas, 2008) . That said, the fetus of an epileptic mother who takes certain anticonvulsant medications has an indisputably greater risk for congenital malformations. Moreover, mono therapy is associated with a lower birth defect rate compared with multiagent therapy. hus, if necessary, increasing monotherapy dosage is at least initially preferable to adding another agent (Buhimschi, 2009) . Specifi c drugs, when given alone, increase the malformation rate (Chap. 1 2, p. 240) . Some of these are listed in Table 60-2 . Phenytoin and phenobarbital increase the major malformation rate two- to threefold above baseline (Perucca, 2005; Thomas, 2008) . Valproate is a particularly potent teratogen, which has a dose-dependent efect and raises the malformation risk four- to eightfold (Eadie, 2008; lein, 20 1 4; Wyszynski, 2005) . Val­ proate is also associated with lower cognitive performance (Kas­ radze, 20 1 7) . In general, with polytherapy, the risk rises with each drug added. A metaanalysis of 3 1 studies found lamotrig­ ine and levetiracetam to carry the lowest risk of malformations (Weston, 20 1 6) . M a n a g e m e nt i n Preg n a ncy

The American Academy of Neurology and the American Epi­ lepsy Society have guidelines regarding treatment in pregnant women (Harden, 2009a-c) . The major goal is seizure preven­ tion. To accomplish this, treatment for nausea and vomiting is provided, seizure-provoking stimuli are avoided, and medi­ cation compliance is emphasized. The fewest necessary anti­ convulsants are given at the lowest dosage efective for seizure control. Although some providers routinely monitor serum drug levels, these concentrations may be unreliable because of altered protein binding. Free or unbound drug levels, although perhaps more accurate, are not widely available. Importantly, there is no evidence that such monitoring improves seizure con­ trol (Adab, 2006) . For these reasons, drug levels may be most informative if measured following seizures or if noncompliance is suspected. For women taking anticonvulsant drugs, a targeted so no­ graphic examination at midpregnancy is recommended by some to search for anomalies. Testing to assess fetal well-being is generally not indicated for women with uncomplicated epi­ lepsy. For women desiring to breastfeed, data regarding the safety of the various anticonvulsant medications are limited. That said, no obvious deleterious efects, such as long-term cogni­ tive issues, have been reported (Briggs, 20 1 5; Harden, 2009c) . Of birth control methods, oral contraceptive pill failure rates are higher with some of the anticonvulsant agents, especially lamotrigine. Thus, other more reliable methods should be con­ sidered (Chap. 38, p. 680) .

1 1 59

1 1 60

Med ical a n d S u rg i c a l Co m p l i cations

TABLE 60-2. Teratogenic Effects of Com mo n A ntico nvu l sa nt Med ications Embryofetal Risksa

Drug (Brand Name)

Abnormalities Descri bed

Affected

Va l p roate (Depa kote)

Neu ra l-t u be defects, clefts, card iac a n o m a l ies; a ssociated deve l o p mental delay Feta l hydanto i n synd rome-cra n iofac i a l a no m a l ies, fi ngerna i l hypo p l a s i a , g rowth d eficiency, deve lo p mental d e l ay, ca rd i a c a n o m a l i es, cl efts Feta l hyda ntoi n syn d ro m e, as a bove; s p i n a b i fida

1 0% with mo nothera py; h i g h e r with polyt hera py 5-1 1 %

Yes

1 -2%

Yes

1 0-20%

Sugg ested

La m otrig i ne (La m icta l)

C l efts, ca rd iac a n o m a l i es, u ri n a ry tract m a lformations I ncreased risk for cl efts (Reg i st ry d ata)

Suggested

Top i ra m ate (Topamax)

C l ets

Leveti raceta m (Ke pp ra)

Theoret i ca l-skeleta l a b n o r m a l ities; i m pa i red g rowth in a n i ma l s

Up to 1 % (4- to 1 0-fold h i g her t h a n expected) 2-3% ( 1 5- to 2 0-fo l d h i g he r t h a n expected) P re l i m i na ry observations

P henyto i n (Di l a nt i n )

Carba mazepi ne; oxca rbaze p i n e (Teg retol; Tri l epta l) Phenobarbita l

Yes

Suggested Suggested

a R i s k categories from B r i g g s, 20 1 5; Food a n d Drug Ad m i n i stration, 2 0 1 1 ; H a rden, 2009b; H o l mes, 2008; H u nt, 2008.

CEREBROVASCULAR DISEASES Abnormalities of the cerebrovascular circulation include strokes-both ischemic and hemorrhagic, as well as anatomical anomalies, such as arteriovenous malformations and aneurysms. Cerebral ischemia is caused by reduction in blood low that lasts longer than several seconds. Early, neurological symptoms may manifest. Ater a few minutes, however, infarction often follows. Hemorrhagic stroke is caused by bleeding directly into or around the brain. It produces symptoms by its mass efect, by toxic efects of blood, or by increasing intracranial pressure. Of strokes in pregnant women, roughly half are ischemic and the other half hemorrhagic (Zofkie, 20 1 8) . h e current obesity endemic i n this country, along with con­ comitant increases in rates of heart disease, hypertension, and diabetes, has increased the prevalence of strokes (Centers for Disease Control and Prevention, 20 1 2) . Women have higher lifetime risk of stroke than men and greater associated mortality rates (Martinez-Sanchez, 20 1 1 ; Roger, 20 1 2) . Moreover, preg­ nancy increases the immediate and lifetime risk of both isch­ emic and hemorrhagic stroke (Jamieson, 20 1 0; lung, 20 1 0) . Stroke is relatively uncommon i n pregnant women, occur­ ring in 1 0 to 40 per 1 00,000 births, but it contributes dis­ parately to maternal mortality rates (Lefert, 20 1 6; Miller, 20 1 6; Yoshida, 20 1 7) . he incidence is rising as measured by pregnancy-related hospitalizations for stroke (Callaghan, 2008; Kukiina, 20 1 1 ) . Importantly, most are associated with hyper­ tensive disorders or heart disease. Of the pregnancy-related mortality rate in the United States, 6.6 percent is due to cere­ brovascular accidents, and 7.4 percent is associated with pre­ eclampsia (Creanga, 20 1 7) . Of maternal deaths after 42 days postpartum, 9.8 percent were attributable to cerebrovascular accidents.

• Risk Factors

Most strokes in pregnancy manifest either during labor and delivery or in the puerperium. In a study of 2850 pregnancy­ related strokes, approximately 1 0 percent developed ante­ partum, 40 percent intrapartum, and almost 50 percent postpartum (James, 2005 ) . In contrast, Lefert (20 1 6) reports a timing of 45 percent antepartum, 3 percent intrapartum, and 53 percent postpartum in 1 45 women. Several risk factors­ unrelated and related to pregnancy-have been reported from studies that included more than 10 million pregnancies. These include age; migraines, hypertension, obesity, and diabetes; cardiac disorders such as endocarditis, valvular prostheses, and patent foramen ovale; and smoking. hose related to pregnancy include hypertensive disorders, gestational diabetes, obstetrical hemorrhage, and cesarean delivery. Byar, the most common risk actors are pregnancy-associated hypertensive disorders. A third of strokes are associated with gestational hypertension, and hyper­ tensive women compared with normotensive counterparts have a three- to eightfold greater risk of stroke (Scott, 20 1 2; Wang, 20 1 1 ) . Women with preeclampsia undergoing general anesthesia may be at higher risk of stroke compared with those given neuraxial anesthesia (Huang, 20 1 0) . Another risk factor for peripartum stroke is cesarean delivery, which raises the risk 1 . 5-fold compared with vaginal delivery (Lin, 2008) . Pregnancy-induced efects on cerebrovascular hemodynam­ ics include enhanced autoregulation that maintains blood low despite changes in systemic blood pressure (van Teen, 20 1 6) . Although cerebral blood low decreases b y 2 0 percent from mid­ pregnancy until term, it increases signiicantly with gestational hypertension (Zeeman, 2003, 2004b) . Such hyperperfusion at least intuitively would be dangerous for women with certain vascular anomalies.

Neu rolog ica l D i s o rd e rs

Hypertensive

S u bcortical

hemorrhage

i nfarction

• Ischemic Stroke

Acute occlusion or embolization of an intracranial blood vessel causes cerebral ischemia, which may result in death of brain tissue (Fig. 60-2) . he more common associated conditions and etiolo­ gies of ischemic stroke are shown in Table 60-3 . A transient ischemic attack (TIA) is caused by reversible ischemia, and symptoms usually last less than 24 hours. Approximately 1 0 percent of these patients have a stroke by 1 year (Amarenco, Embolism or 20 1 6) . Patients with a stroke usually have a sud­ t h rombosis den onset of severe headache, hemiplegia or other neurological deicits, or occasionally seizures. I n contrast, focal neurological symptoms accom­ panied by an aura usually signiy a irst-episode S u bcortical migraine (Liberman, 2008). --�i nfarction Evaluation of an ischemic stroke includes echo­ cardiography and cranial imaging with CT, MR, or angiography. Serum lipids are measured with the caveat that their values are distorted by normal pregnancy (Appendix, p. 1 259) . Tests to detect antiphospholipid antibodies and lupus anticoagu­ lant are performed. These underlie up to a third of ischemic strokes in otherwise healthy young women (Chap. 59, p. 1 1 43) . Also, sickle-cell syndromes are evaluated when indicated (Buonanno, 20 1 6) . With a thorough evaluation, most causes of Cortical vei n embolism can be identifi e d, although treatment is th ro m bosis not always available. Some of these include cardiac­ FIGURE 60-2 I l l ustrations of a b ra i n showing various types of strokes seen in associated embolism, vasculitis, or vasculopa­ preg nancy: ( 1 ) su bcortical i n fa rctio n (preec l a m psia), (2) hypertensive hemor­ thy such as Moyamoya disease (Ishimori, 2006; rhage/ (3) a ne u rysm, (4) e m bolism or thro m bosis in m id d le cerebra l a rtery, Miyakoshi, 2009; Simolke, 1 99 1 ) . Outcomes of (5) a rteriovenous ma lformation, and (6) cortical vei n throm bosis. embolic strokes were reported to be favorable and similar to those of nonpregnant women (Lefert, 20 1 6) . hrombolysis for ischemic stroke during pregnancy has been reported (Tversky, 20 1 6) . TABLE 60-3. Some Associated Di sorders or Ca u ses of Ischemic and H emorrhagic Strokes D u r i n g Preg n a n cy or the Puerperi u m Ischemic Stroke

Hemorrhagic Stroke

Preecl a m ps i a syn d ro m e Arterial t h ro m bo s i s Ve nous t h ro m bosis L u p u s a nti coag u l a nt Anti phospholi pid a nti bod ies Th rom bop h i l ia s M i g ra i n e i n d u ced P a radoxical e m bo l u s Card ioem b o l i c Sickle hemog l o b i n o pathy Arteri a l d i ssection Vasc u l itis Moya moya d i sease Coca i ne, a m pheta m i nes

C h ro n i c hyperte n s i o n Preec l a m psia syn d ro m e A rteriovenous ma lformation Sacc u l a r a neu rysm Ang i oma Coca ine, metha m pheta m i nes Vascu l opathy

From Sm ith, 20 1 5; Yager, 2 0 1 2.

P reec l a m ps i a S y n d r o m e

In reproductive-age women, a significant proportion ofpregnancy­ related ischemic strokes are caused by gestational hypertension and preeclampsia (Jeng, 2004; Miller, 20 1 6). s shown in Figure 60-2, areas of subcortical perivascular edema and petechial hemorrhage may progress to cerebral infarction (Aukes, 2007, 2009; Zee­ man, 2004a). Although these are usually clinically manifest by an eclamptic convulsion, a few women will sufer a symptomatic stroke from a larger cortical infarction (Chap. 40, p. 734). Other conditions with findings similar to preeclampsia include thrombotic microangiopathies (Chap. 56, p. 1 088) and the reversible cerebral vasoconstriction syndrome (Chap. 40, p. 744) . The latter, also termed pospartum angiopathy, can cause exten­ sive cerebral edema with necrosis and widespread infarction with areas of hemorrhage (Edlow, 20 1 3; Katz, 20 1 4; Miller, 20 1 6) . Cere b ra l E m b o l i s m

These strokes usually involve the middle cerebral artery (see Fig. 60-2) . he diagnosis can be made with conidence only after thrombosis and hemorrhage have been excluded and is

1 1 61

1 1 62

Med ical a n d S u rg ica l Co m p l ications

more certain if an embolic source is identifi e d. Hemorrhage may be more diicult to exclude because embolization and thrombosis are both followed by hemorrhagic infarction. Par­ adoxical embolism is an uncommon cause, even considering that more than a fourth of adults have a patent foramen ovale through which right-sided venous thromboemboli are deported (Scott, 20 1 2) . Foraminal closure may not improve outcomes in these patients, however, this procedure has been performed during pregnancy (Dark, 20 1 1 ) . Assorted cardioembolic causes of stroke include arrhythmias-especially atrial ibrillation, val­ vular lesions, mitral valve prolapse, mural thrombus, infective endocarditis, and peripartum cardiomyopathy. Management of embolic stroke in pregnancy consists of sup­ portive measures and antiplatelet therapy. Thrombolytic ther­ apy and anticoagulation in pregnancy are controversial issues (U, 20 1 2) . Cereb ra l A rtery Th ro m bos i s

Most thrombotic strokes afect older individuals and are caused by atherosclerosis, especially of the internal carotid artery. Many are preceded by one or more TIAs. hrombolytic ther­ apy with a recombinant tissue plasminogen activator (rt-PAj is recommended. Alteplase is one of these and given within the irst 3-hour window if there is measurable neurological deficit and if neuroimaging has excluded hemorrhage. his recombi­ nant enzyme can be used in pregnancy. A principal risk is hem­ orrhagic transformation of an ischemic stroke in 3 to 5 percent of treated patients (Smith, 20 1 5; van der Worp, 2007) . Cere b ra l Ve n o u s Th ro m bosis

In one study in the United States, 7 percent of cerebral venous thromboses were associated with pregnancy (Wasay, 2008). But, in the Nationwide Inpatient Sample of more than 8 million deliv­ eries, James and associates (2005) reported that venous thrombo­ sis caused only 2 percent of pregnancy-related strokes (Saposnik, 201 1 ) . here are numerous predisposing causes, and for gravidas, late pregnancy and the puerperium are times of greatest risk. Thrombosis of the lateral or superior sagittal venous sinus usually occurs in the puerperium and often in association with preeclampsia, sepsis, or thrombophilia (see Fig. 60-2) . It is more common in patients with inherited thrombophilias or antiphospholipid antibodies (Chaps. 52, p. 1 006 and 59, p. 1 1 43) . Headache is the most frequent presenting symptom, neurological defi c its are common, and up to a third of patients have convulsions (Wasay, 2008) . he diagnosis is made using MR venography (Saposnik, 20 1 1 ) . Management includes anticonvulsants for seizures, and although heparinization is recommended by most, its eicacy is controversial (Saposnik, 20 1 1 ; Smith, 20 1 5) . Antimicrobials are given if there is septic thrombophlebitis, and fibrinolytic therapy is reserved for those women failing systemic anticoagu­ lation. The acute prognosis for venous thrombosis in pregnant women is better than in nonpregnant subjects, and mortality rates are less than 1 0 percent (McCaulley, 20 1 1 ) . I n women with a prior cerebral venous thrombosis, one sys­ tematic review found only one recurrence in 2 1 7 pregnancies and five noncerebral venous thrombotic events in 1 86 pregnancies (Aguiar de Sousa, 20 1 6) . In a study of 52 women on prophylactic

anticoagulation with prior cerebral venous thrombosis, there were no cases of recurrent thrombosis or bleeding, however 24 percent had late obstetrical complications (Martinelli, 20 1 6) . Rec u rrence R i s k o f I sc h e m i c Stroke

Women with prior ischemic stroke have a low risk for recur­ rence during a subsequent pregnancy unless a specific, persistent cause is identiied. During a 5-year follow-up of 373 women with arterial ischemic strokes, there were 1 87 pregnancies in 1 25 women. Thirteen women had a recurrent ischemic stroke, and of these, only two were associated with pregnancy. The authors concluded that the risk of stroke recurrence is low and a pre­ vious ischemic stroke is not a contraindication to pregnancy (Lamy, 2000) . In one study of 1 770 nonpregnant women with anti phospholipid-related ischemic stroke, investigators reported no diference in the recurrence risk as long as preventative treat­ ment was given with warfarin or aspirin (Levine, 2004) . Currently, no irm guidelines define prophylaxis in preg­ nant women with a stroke history (Helms, 2009) . The Ameri­ can Heart Association stresses the importance of controlling risk factors such as hypertension and diabetes (Furie, 20 1 l ) . Women with anti phospholipid syndrome o r certain cardiac conditions should be considered for prophylactic anticoagula­ tion as discussed in Chapter 49 (p. 954) and 52 (p. 1 008) . • Hemorrhagic Stroke

The two distinct categories of spontaneous intracranial bleed­ ing are intracerebral and subarachnoid hemorrhage. The symp­ toms of a hemorrhagic stroke are similar to those of an ischemic stroke, and their diferentiation is only possible with CT or MR imaging (Morgenstern, 20 1 0; Smith, 20 1 5) . I nt ra ce re b ra l H e morrhage

Bleeding into the brain parenchyma most often is caused by spontaneous rupture of small vessels previously damaged by chronic hypertension (see Fig. 60-2) . Thus, pregnancy-associated hemorrhagic strokes such as the one shown in Figure 60-3 are

F I G U R E 60-3 A 3 7-year-old g ravida with i ntra pa rtum ecl a m psia at term. A noncontrast com puted tomography axial head i mage demon strates a l a rge i ntra parenchyma l hemorrhage.

N e u rological D i s o rders

oten associated with chronic hypertension and superimposed preeclampsia (Cunningham, 2005; Martin, 2005) . Because of its location, this type of hemorrhage has much higher morbidity and mortality rates than does subarachnoid hemorrhage (Smith, 20 1 5) . Pressure-induced rupture causes bleeding into the puta­ men, thalamus, adjacent white matter, pons, and cerebellum. In the 28 women described by Martin and associates (2005), half died and most survivors had permanent disabilities. his cau­ tions for the importance of proper management for gestational hypertension-especially systolic hypertension-to prevent cerebrovascular pathology (Chap. 40, p. 738) . S u ba ra c h n o i d H e m o r r h a g e

In a study of 639 cases of pregnancy-related subarachnoid hem­ orrhage from the Nationwide Inpatient Sample, the incidence was 5.8 per 1 00,000 pregnancies, with half occurring post­ partum (Bateman, 20 1 2) . A remarkably similar incidence was reported in Japanese women (Yoshida, 20 1 7) . hese bleeds are more likely caused by an underlying cerebrovascular malforma­ tion in an otherwise norml patient (see Fig. 60-2) . Ruptured saccular or "berry" aneurysms cause 80 percent of all subarach­ noid hemorrhages. The remaining cases are caused by a ruptured arteriovenous malformation, coagulopathy, angiopathy, venous thrombosis, infection, drug abuse, tumors, or trauma. Such cases are uncommon, and a ruptured aneurysm or angioma or bleed­ ing from a vascular mlformation has an incidence of 1 in 75,000 pregnancies. Although this frequency is not diferent from that in the general population, the mortality rate during pregnancy is reported to be as high as 35 percent (Yoshida, 20 1 7) . Intracranial Aneurysm. Approximately 1 to 2 percent o f adults have this lesion (Lawton, 20 1 7) . Fortunately, only a small per­ centage rupture. he rate approximates 0. 1 percent for aneurysms < 1 0 mm and 1 percent for those > 1 0 mm (Smith, 20 1 5) . Most aneurysms identified during pregnancy arise from the circle of Willis, and in 20 percent of case, there are multiple lesions. Preg­ nancy does not raise the risk for aneurysmal rupture. However, because of their high prevalence, they are more likely to cause subarachnoid bleeding than other etiologies (Hirsch, 2009; Tiel Groenestege, 2009) . A systematic review of 44 women with 50 aneurysms in pregnancy reported that 72 percent ruptured dur­ ing pregnancy, and 78 percent of these did so during the third trimester (Barbarite, 20 1 6) . his proclivity for rupture late in pregnancy was also reported by Yoshida and colleagues (20 1 7) . The cardinal symptom o f a subarachnoid hemorrhage from an aneurysm rupture is sudden severe headache that is accom­ panied by visual changes, cranial nerve abnormalities, focal neurological deicits, and altered consciousness. Patients typi­ cally have signs of meningeal irritation, nausea and vomiting, tachycardia, transient hypertension, low-grade fever, leukocy­ tosis, and proteinuria. Prompt diagnosis and treatment may prevent potentially lethal complications. The American Heart Association recommends noncontrast cranial CT imaging as the irst diagnostic test, although MR imaging may be superior (Connolly, 20 1 2; Smith, 20 1 5) . Treatment o f subarachnoid hemorrhage includes bed rest, analgesia, and sedation, with neurological monitoring and strict blood pressure control. Repair of a potentially accessible aneurysm

during pregnancy depends in part on the risk of recurrent hem­ orrhage versus the surgical risks. At least in nonpregnant patients, the risk of subsequent bleeding with conservative treatment is 20 to 30 percent for the irst month and then 3 percent per year. The risk of rebleeding is highest within the irst 24 hours, and recurrent hemorrhage leads to death in 70 percent. Early repair after the sentinel hemorrhage is done by surgi­ cal clipping of the aneurysm. Also, an endovascular coil can be placed using luoroscopic angiography, while attempting to limit fetal radiation exposure. Barbarite and colleagues (20 1 6) report lower complication rates with coil embolization than clipping. For unruptured aneurysms, surgical management resulted in a third fewer complications than no treatment. For gravidas remote from term, repair without hypotensive anes­ thesia seems optimal. For women near term, cesarean delivery followed by aneurysm repair is a consideration, and we have successfully done this in several cases. For aneurysms repaired either before or during pregnancy, most allow vaginal delivery iflabor ensues remote from aneurys­ mal repair. Problems arise in defining "remote," and although some recommend 2 months, the time for complete healing is unknown. For women who survive subarachnoid hemor­ rhage, but in whom surgical repair is not done, we agree with Cartlidge (2000) and recommend against bearing down-put another way, we favor cesarean delivery. Arteriovenous Malformations. hese are

congenital focal abnormal conglomerations of dilated arteries and veins with sub arteriolar disorganization (see Fig. 60-2) . hey lack capil­ laries and have resultant arteriovenous shunting. Although unclear, the risk of bleeding may rise with gestational age. When arteriovenous malformations (AVMs) bleed, half do so into the subarachnoid space, whereas half are intraparenchymal with subarachnoid extension (Smith, 2 0 1 5). hey are uncom­ mon and are estimated to occur in 0.0 1 percent of the general population. Of 65 identiied cases of AVM in pregnancy, 83 percent ruptured during pregnancy or postpartum, and more than 80 percent of these ruptured in the second or third tri­ mester. Hemorrhage upon presentation is associated with poor maternal outcome (Lu, 20 1 6) . Bleeding does not appear to b e more likely during preg­ nancy. lthough these malformations are correspondingly rare during pregnancy, AVM bleeding accounted for 1 7 percent of hemorrhagic strokes in one study (Yoshida, 20 1 7) . At Parkland Hospital in a 33-year period during which there were about 466,000 births, 57 women had a CVA, and five of these strokes were due to a bleeding AM (Simolkie, 1 99 1 ; Zokie, 20 1 8). Treatment of AVMs in nonpregnant patients is largely indi­ vidualized. No consensus guides whether all accessible lesions should be resected. Factors include AVM symptoms; its anat­ omy and size; presence of an associated aneurysm, which is found in up to 60 percent of cases; and especially, prior AVM bleeding. Mter hemorrhage, the risk of recurrent bleeding in unrepaired lesions is 6 to 20 percent within the first year, and 2 to 4 percent per year thereater (Friedlander, 2007; Smith, 20 1 5) . The mortality rate with a bleeding AVM is 1 0 to 2 0 percent. In pregnancy, the decision to operate is usually based on neurosurgical considerations, and Friedlander (2007)

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recommends strong consideration for treatment if bleeding occurs. Because of the high risk of recurrent hemorrhage from an unresected or inoperable lesion, we favor cesarean delivery. DEMYELINATING OR DEG E N ERATIVE DISEASES The demyelinating diseases are neurological disorders charac­ terized by immune-mediated focal or patchy destruction of myelin sheaths accompanied by an infl a mmatory response. The degenerative diseases are multifactorial and are characterized by progressive neuronal death. • Multiple Sclerosis

In the United States, multiple sclerosis (MS) is second only to trauma as a cause of neurological disability in middle adulthood (Hauser, 20 1 5b). The disease afects women twice as often as men, and it usually begins in the 20s and 30s. he familial recurrence rate of MS is 1 5 percent, and the incidence in of­ spring is increased I S-fold. Studying California deliveries, Fong and colleagues (20 1 8) reported that 0.03 percent of deliveries were complicated by MS between 200 1 and 2009. The demyelinating characteristic of this disorder results predominately from T cell-mediated autoimmune destruction of oligodendrocytes that synthesize myelin. here is a genetic susceptibility and likely an environmental trigger such as expo­ sure to certain bacteria and viruses. Of these, Chlamydophila pneumoniae, human herpesvirus 6, or Epstein-Barr virus are implicated (Frohman, 2006; Goodin, 2009) . There are four clinical types of MS: 1. Relapsing-remitting MS accounts for initial presentation in 85 percent of afected individuals. With it, unpredictable recur­ rent episodes of focal or multifocal neurological dysfunction

usually are followed by full recovery. Over time, however, relapses lead to persistent deficits. 2. Secondary progressive MS disease is relapsing-remitting dis­ ease that begins to pursue a progressive downhill course after each relapse. All patients likely develop this type eventually. 3. Primary progressive MS accounts for 1 5 percent of cases. With it, disability gradually progresses from the time of ini­ tial diagnosis. 4. Progressive-relapsing MS refers to primary progressive vIS with apparent relapses. Classic findings of MS include sensory loss, visual symp­ toms from optic neuritis, weakness, paresthesias, and a host of other neurological symptoms. Almost 75 percent of women with isolated optic neuritis develop MS within 1 5 years. Clini­ cal diagnosis is confirmed by MR imaging and cerebrospinal fluid analysis. In greater than 95 percent of cases, MR imag­ ing shows characteristic multifocal white matter plaques that represent discrete areas of demyelination (Fig. 60-4) . Their appearance and extent are less helpful for predicting treatment response. Similarly, identification of serum antibodies against myelin oligodendrocyte glycoprotein and myelin basic protein is not predictive of recurrent disease activity (Kuhle, 2007) . Efects of Preg n a n cy

The PRegnancy In Multiple Sclerosis-PlMS-study was a European prospective multicenter study in which 254 preg­ nancies were described (Vukusic, 2006) . Relapse risk was reduced 70 percent during pregnancy, but with a significantly greater relapse rate postpartum. This may be related to higher pregnancy-induced numbers of T-helper lymphocytes and an increased T2/T l ratio (Airas, 2008) . In a metaanalysis of women with more than 1 200 pregnancies complicated by lvIS, their relapse rate was 0.4 per year before pregnancy; 0.26 per year during pregnancy; and this increased to 0.7 per year

FIGURE 60-4 Mag netic resona nce c ra n ial i mages from a woman with m U ltiple sclerosis. A. T2-weig hted axia l i mage s hows bright signal abnorm a l ities i n wh ite matter, typical for m u ltiple sclerosis. B. Sag itta l T2-FLAIR i mage shows hyperintense a reas wit h i n the corpus cal losum that a re representative of demye l i nation i n m u lti p l e sclerosis. (Reproduced with permission from Ha user SL, Goodi n DS: Mu ltiple Sclerosis and other demyel i nati n g diseases. I n Kasper DL, Fauci AS, Ha user SL, et a l (eds): Ha rrison's Pri n ci p les of I nterna l Med icine, 1 9th ed. McGraw- H i l i, New York, 201 5 b.)

Neu rolog ical D i s o rders

after delivery (Finkelsztejn, 20 1 1 ) . Bove and associates (20 1 4) reached similar conclusions after a systematic review. Factors associated with postpartum relapse include a high relapse rate before pregnancy, relapses during pregnancy, and a high MS disability score (Portaccio, 20 1 4; Vukusic, 2006) . Breastfeed­ ing has no apparent efect on postpartum relapses (Hellwig, 20 1 5 ; Portaccio, 20 1 1 ) . Efects o f M u lt i p l e S c l e ro s i s o n Preg n a ncy

With uncomplicated disease, there are usually no adverse efects on pregnancy ourcome (Bove, 20 1 4) . Some women may become fatigued more easily, those with bladder dysfunction are predisposed to urinary infection, and women with spinal lesions at or above T6 are at risk for autonomic dysrelexia. In one study of 449 pregnancies in afected women, the labor induction rate was higher, and second-stage labor was longer (Dahl, 2006) . he greater induction rate and elective opera­ tions contributed to the overall higher cesarean delivery rate. In an analysis of 649 afected women, the mean birthweight was lower but the perinatal mortality rate was similar compared with that of controls (Dahl, 2005) . Other studies have cor­ roborated that MS does not significantly afect obstetrical and neonatal outcomes (Finkelsztejn, 20 1 1 ; Fong, 20 1 8) . Ma n a g e m e n t i n P reg n a ncy

Goals are to arrest acute or initial attacks, employ disease­ modiying agents, and provide symptomatic relief. Some treatments may need to be modiied during pregnancy. Acute or initial attacks are treated with high-dose intravenous methylprednisolone-500 to 1 000 mg daily for 3 to 5 days, followed by oral prednisone for 2 weeks. Plasma exchange may be considered. Symptomatic relief can be provided by analge­ sics; carbamazepine, phenytoin, or amitriptyline for neurogenic pain; baclofen for spasticity; :Tadrenergic blockade for bladder neck relaxation; and cholinergic and anticholinergic drugs to stimulate or inhibit bladder contractions. Several disease-modiying therapies can be used for relaps­ ing MS or for exacerbations. Examples include in terferons 3 1 a (Rebi), 3 1 b (Betaseron) , and glatiramer acetate (Copaxone) , which lower relapse rates by a third (Rudick, 20 1 l ) . Data con­ cerning safety in pregnancy are limited but overall reassuring (Amato, 20 1 0; Salminen, 20 1 0) . In clinical trials, natalizumab (Tysabri) , an :4-integrin antagonist, especially when combined with interferon 3 1 a, significantly reduced MS clinical relapse rates (Polman, 2006; Rudick, 2006) . In a review of 35 preg­ nancies, irst-trimester drug exposure did not worsen outcomes (Hellwig, 20 1 1 ) . If these drugs are used in pregnancy, the neo­ nate should be monitored for thrombocytopenia and anemia (Alroughani, 20 1 6) . Fetal exposure i n 89 pregnancies to ingolimod (Gilenya) , another immune-modulating drug, was associated with six fetal malformations and nine spontaneous losses. Because of this and associated animal teratogenicity, its use in pregnancy is not rec­ ommended. Due to its prolonged persistence, contraception is recommended for 2 months ater drug cessation (Alroughani, 20 1 6; Karlsson, 20 1 4) . Prevention o f relapses postpartum i s aforded b y treatment with intravenous immunoglobulin (II G) , given in a dose of

0.4 g/kg daily for 5 days during weeks 1 , 6, and 1 2 (Argyriou, 2008) . • Huntington Disease

his adult-onset neurodegenerative disease stems from an auto­ somal dominant expanded CAG trinucleotide repeat within the Huntington gene on chromosome 4. It is characterized by choreoathetotic movements, progressive dementia, and psychi­ atric manifestations. Because the mean age of onset is 40 years, Huntington disease rarely complicates pregnancy. Prenatal diagnosis is discussed in Chapter 14 (p. 288) . Prenatal screen­ ing is controversial, and because this usually is a late-onset adult disease, extensive counseling is important (Schulman, 20 1 5) . • Myasthenia G ravis

This autoimmune-mediated neuromuscular disorder afects approximately 1 in 7500 persons. It is more common in women, and its incidence peaks in their 20s and 30s. he eti­ ology is unknown, but genetic factors likely play a role. Most patients demonstrate antibodies to the acetylcholine receptor, although 1 0 to 20 percent are seronegative (Drachman, 2 0 1 5) . he latter often have antibodies to muscle-specific tyrosine kinase (MuSK) , which regulates assembly of the acetylcholine receptor subunits at the neuromuscular junction (Pal, 20 1 l ) . Cardinal features o f myasthenia are weakness and easy fatigability of facial, oropharyngeal, extraocular, and limb muscles. Deep tendon reflexes are preserved. Cranial muscles are involved early and disparately, and diplopia and ptosis are common. Facial muscle weakness causes diiculty in smiling, chewing, and speaking. In 85 percent of patients, the weakness becomes generalized. Other autoimmune diseases may coexist, and hypothyroidism should be excluded. The clinical course is marked by exacerbations and remissions, especially when it first becomes clinically apparent. Remissions are not always com­ plete and are seldom permanent. Systemic diseases, concurrent infections, and even emotional upset may precipitate exacerba­ tions, of which there are three types: 1 . Myasthenic crises-characterized by severe muscle weakness, inability to swallow, and respiratory muscle paralysis. 2. Rtactory crises-characterized by the same symptoms but unresponsive to the usual therapy. 3. Cholinergic crisesexcessive cholinergic medication leads to nausea, vomiting, muscle weakness, abdominal pain, and diarrhea. All three of these can be life threatening, but a refractory crisis is a medical emergency. Those with bulbar myasthenia are at particular risk because they may be unable to swallow or even ask for help. M a n a ge m e n t

Myasthenia is manageable but not curable. Oral pyridostigmine is the first-line treatment. Thymectomy is recommended but post­ poned until ater pregnancy (Sanders, 20 1 6) . Anticholinesterase medications improve symptoms by impeding acetylcholine deg­ radation but seldom produce normal muscle function. Ironically,

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overdose is manifest by increased weness-cholinergic crisis­ that may be diicult to diferentiate from myasthenic symptoms. Most of those refractory to anticholinesterase therapy respond to immunosuppressive therapy with glucocorticoids, azathioprine, or cyclosporine in pregnancy. When short-term, rapid clinical improvement is needed-such as for a surgical procedure or a myasthenic crisis-high-dose IVIG or plasma exchange is usually efective (Barth, 20 1 1 ; Cortese, 20 1 1 ; Sanders, 20 1 6) . Mya st h e n ia a n d P reg n a ncy

Because the greatest period of risk is within the first year fol­ lowing diagnosis, postponing pregnancy until there is sustained improvement is reasonable. Antepartum management of myas­ thenia includes close observation with liberal rest and prompt treatment of infections (Heaney, 20 1 0; Kalidindi, 2007) . Women in remission who become pregnant while taking corti­ costeroids or azathioprine should continue these. hymectomy has been successfully performed during pregnancy in refractory cases (Ip, 1 986) . Acute onset of myasthenia or its exacerbation demands prompt hospitalization and supportive care. Plasma­ pheresis and high-dose IVIG are options for emergency situa­ tions (Drachman, 20 1 5) . Although pregnancy does not appear t o afect the overall course of myasthenia, fatigue common to most pregnancies may be exacerbated, and the expanding uterus may compro­ mise respiration. Maternal hypotension or hypovolemia are ideally avoided as they can trigger crises. he clinical course of myasthenia during pregnancy is unpredictable, and frequent hospitalizations are the norm. Up to a third of women have worsening myasthenia during pregnancy, and exacerbations occur equally in all three trimesters (Djelmis, 2002; Pod­ ciechowski, 2005) . In women with stable disease, most will remain stable throughout pregnancy but likely worsen in the first few months postpartum (Sanders, 20 1 6) . Myasthenia gravis has no significant adverse efects on pregnancy outcomes (Wen, 2009) . Preeclampsia is a concern because magnesium sulfate may precipitate a severe myasthenic crisis (Hamaoui, 2009; Heaney, 20 1 0) . Although phenytoin use is also problematic in this regard, its adverse efects are less troublesome. hus, many choose it for neuroprophylaxis in women with severe preeclampsia. Because smooth muscle is unafected, most women have normal labor. Oxytocin is given for the usual indications, and cesarean delivery is reserved for obstetrical indications. Narcot­ ics may cause respiratory depression, and close observation and respiratory support are essential during labor and delivery. Cura­ riform drugs are avoided-examples include magnesium sulfate discussed above, muscle relaxants used with general anesthesia, and aminoglycosides. Neuraxial analgesia is accomplished with amide-type local agents. Regional analgesia is preferred unless there is signiicant bulbar involvement or respiratory compro­ mise (Almeida, 20 1 0; Blichfeldt-Lauridsen, 20 1 2) . During second-stage labor, some women may have impaired voluntary expulsive eforts that may warrant operative vaginal delivery. Neon ata l Efects

As discussed above, 80 percent of mothers with myasthenia gra­ vis have anti-acetylcholine-receptor immunoglobulin G (IgG)

antibodies. These and anti-MuSK antibodies cross transpla­ centally, and the fetus can be afected. Poor fetal swallowing may yield hydramnios (Heaney, 20 1 0) . Similarly, 1 0 to 20 per­ cent of neonates manifest myasthenia symptoms (Jovandaric, 20 1 6) . Transient symptoms usually include a feeble cry, poor suckling, and respiratory distress. Symptoms usually respond to cholinesterase inhibitors and resolve within a few weeks as maternal IgG antibodies clear. NEUROPATH I ES Peripheral neuropathy is a general term used to describe disor­ ders of peripheral nerve(s) from various sources. Poyneuropa­ thies can be axonal or demyelinating as well as acute, subacute, or chronic (Amato, 20 1 5) . hese are often associated with systemic diseases such as diabetes, with drug or environmental toxin exposure, or with genetic disease. Mononeuropathies are relatively common in pregnancy and signiY focal involvement of a single nerve trunk. These imply local causation such as trauma, compression, or entrapment. Traumatic pudendal, obturator, femoral, and common fibular mononeuropathies are usually caused by childbirth and are dis­ cussed in Chapter 36 (p. 66 1 ) . • Guillain-Barre Syndrome

In 75 percent of cases, this acute demyelinating polyradiculo­ neuropathy has clinical or serological evidence for an acute infec­ tion. Commonly associated are infections with Campylobacter jjuni, cytomegalovirus, Zika virus, and Epstein-Barr virus; surgical procedures; and immunizations (Haber, 2009; Hauser, 20 1 5a; Pacheco, 20 1 6) . Guillain-Barre syndrome is thought to be immune-mediated from antibodies formed against nonself antigens. Demyelination causes sensory and motor conduction blockade, and remyelination yields recovery in most cases. Clinical features include areflexic paralysis-usually ascending-with or without sensory disturbances. Autonomic dysfunction is common . The full syndrome develops over 1 to 3 weeks. Some manifest as chronic inlammatoy demyelinating poyneuropathy, and our experiences indicate that this may be relatively common in these young women. Guillain-Barre syndrome is not more common in preg­ nancy, and its clinical course mirrors that for nonpregnant individuals. After an insidious onset, paresis and paralysis most oten continue to ascend to cause ventilatory weakness. Management is supportive and incorporates venous thrombo­ embolism prophylaxis, pressure ulcer prevention, and enteral nutrition. In the worsening phase, patients are hospitalized, and a fourth requires ventilatory assistance. IVIG or plasma­ pheresis is beneficial if begun within 1 to 2 weeks of motor symptoms, however, neither decreases mortality rates (Cortese, 20 1 1 ; Gwathmey, 20 1 1 ; Pritchard, 20 1 6) . Up to 1 0 percent of patients deteriorate after initial improvement on therapy, and retreatment with 2 g/kg IVIG over 5 days is recommended. Although most patients recover fully within several months to a year, the mortality rate is 5 percent, mainly due to pulmo­ nary complications and arrhythmias (Hauser, 20 1 5a; Pacheco, 20 1 6) .

N e u rological D i s o rd e rs

into the shoulder (Katz, 2002) . Symptoms are bilateral in 80 percent of gravidas, and 10 percent have evidence for severe denervation (Seror, 1 998) . Diferential diagnosis includes cer­ vical radiculopathy of C6-C7 and de Quervain tendonitis . he latter is caused by swelling of the conjoined tendons and their sheaths near the distal radius. Nerve conduction studies may be helpful for clariication (Alfonso, 20 1 0) . I n pregnancy, the reported incidence o f carpal tunnel syn­ drome is 7 to 43 percent and varies greatly because the range of symptoms is marked (Meems, 20 1 5 ; Padua, 20 1 0) . Symp­ tomatic treatment with a splint applied to a slightly lexed wrist during sleep lightens pressure and usually provides relief. Although symptoms typically are self-limited, occasionally sur­ gical decompression and corticosteroid injections are necessary (Keith, 2009; Shi, 20 1 1 ) . Symptoms may persist in more than half of patients at 1 year and in a third at 3 years (Padua, 2 0 1 0) . F I G U R E 60-5 Be l l facial nerve p a l sy developing on the day of cesa rea n del ivery for d ichorionic twi ns. Th is wom a n was treated with pred n isone a n d a ntivi ral medication, a nd the pa lsy had a l m ost resolved 3 weeks postpa rtu m .

• Bell Palsy

his disfiguring palsy is usually a mononeuropathic acute facial paralysis that is relatively common in reproductive-aged women (Fig. 60-5) . It has a female predominance, and preg­ nant women carry a fourfold risk compared with nonpregnant women (Cohen, 2000; Heaney, 20 1 0) . The disease is character­ ized by facial nerve inlammation and often is associated with reactivation of herpes simplex virus or herpes zoster virus. Bell palsy usually has an abrupt and painful onset with maximum weakness by 48 hours. In some cases, hyperacusis and loss of taste accompany paralysis (Beal, 20 1 5) . Manage­ ment includes supportive care with facial muscle massage and eye protection against corneal lacerations from drying. here is general consensus that prednisone, 1 mg/kg given orally daily for 5 days, will improve outcomes and shorten the recov­ ery period (Salinas, 20 1 6; Sullivan, 2007) . It is controversial whether addition of an antiviral medication will add benefits (de Almeida, 2009; Gagyor, 20 1 5 ; Quant, 2009) . It is unclear if pregnancy alters the prognosis for spontane­ ous facial palsy recovery. Gillman and associates (2002) found that only half of pregnant women recovered to a satisfactory level after 1 year, compared with approximately 80 percent of nonpregnant women and men. Some prognostic markers for incomplete recovery are bilateral palsy, recurrence in a subse­ quent pregnancy, greater percentage of nerve function loss, and a faster rate of loss (Cohen, 2000; Gilden, 2004) . Other than a ivefold greater rate for gestational hypertension or preeclamp­ sia, women with Bell palsy do not have increased adverse preg­ nancy outcomes rates (Katz, 20 1 1 ; Shmorgun, 2002) . • Carpal Tunnel Syndrome

This syndrome results from compression of the median nerve and is the most frequent mononeuropathy in pregnancy (Padua, 20 1 0) . Symptoms include burning, numbness, or tin­ gling along the inner half of one or both hands. Others are wrist pain and numbness extending into the forearm and sometimes

SPI NAL CORD I NJ U RY According to the National Spinal Cord Inj ury Statistical C enter (20 1 7) , there are approximately 1 7,000 new spinal cord inju­ ries each year. he average age is 42 years, and males account for 80 percent of new cases. Cord injury severity determines the short- and long-term prognosis as well as that for pregnancy. For women, many have altered sexual function and transient hypothalamic pituitary hypogonadism. hat said, pregnancy is not uncommon if menstruation resumes (Bughi, 2008). I n a review of nearly 2000 women in the National Spinal Cord Inj ury Database, 2 percent reported pregnancy in the prior 1 2 months (Iezzoni, 20 1 5) . Gravidas with spinal cord inj ury have an increased fre­ quency of pregnancy complications that include preterm and low-birthweight neonates. Recent observations in nonpregnant women note that the vaginal microbiota is altered in these women (Pires, 20 1 6) . Perhaps related, most have asymptom­ atic bacteriuria with sporadic symptomatic urinary infections. Bowel dysfunction causes constipation in more than half, and anemia and pressure-necrosis skin lesions are also common. Two serious and life-threatening events can complicate spi­ nal cord injuries. First, if the cord is transected above T 10' the cough reflex is impaired, respiratory function may be compro­ mised, and pneumonitis from covert aspiration can be serious. Pulmonary function tests are considered to assess this risk, and some women may need ventilatory support in late pregnancy or in labor. Second, women with lesions above T 5-T6 are at risk for auto­ nomic dysrlexia. With this, stimuli from structures innervated below the level of the spinal lesion lead to massive, disordered sympathetic stimulation. Abrupt catecholamine release can cause vasoconstriction with severe hypertension and symptoms that include throbbing headaches, facial fl u shing, sweating, bradycardia, tachycardia, arrhythmias, and respiratory distress . Dysrelexia can be precipitated by various stimuli. hese include urethral catheterization, bladder distention from urinary reten­ tion, rectal or cervical stretch during digital examinations, uter­ ine contractions and cervical dilation, or any manipulatio n of other pelvic structures (American College of Obstetricians and Gynecologists, 20 1 6; Krassioukov, 2009) . In one report, 1 2 of

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Med ica l a n d S u rg ica l C o m p l i cat i o n s

1 5 women at risk for autonomic dysreflexia sufered at least one episode during pregnancy (Westgren, 1 993) . Because uterine contractions are not afected by spinal cord lesions, labor is usually easy-even precipitous, and compara­ tively painless. If the lesion is below T 1 2 ' uterine contractions are felt normally. For lesions above T 1 2 , the risk of out-of­ hospital delivery is substantial and can be minimized by teach­ ing women to palpate for uterine contractions. This is especially important because up to 20 percent of women deliver preterm (Westgren, 1 993) . Some recommend tocodynamometry and weekly cervical examinations beginning at 28 to 30 weeks. Another reasonable option that we frequently employ at Park­ land Hospital is elective hospitalization after 36 to 37 weeks' gestation (Hughes, 1 99 1 ) . Spinal o r epidural analgesia extending t o T I O prevents auto­ nomic dysrelexia and should be instituted at the start of labor. If there are severe symptoms before epidural placement, steps are taken to abolish the provoking stimulus. A parenteral antihyper­ tensive agent such as hydralazine or labetalol is given. Labor and vaginal delivery with epidural or spinal analgesia is preferable and will minimize autonomic dysrelexia (Kuczkowski, 2006) . Operative vaginal delivery is frequently necessary. IDIOPATH IC I NTRACRA N IAL HYPERTENSION Also known as pseudotumor cerebri, this disorder is typified by increased intracranial pressure without hydrocephalus. The cause is unknown, but it may result from overproduction or under absorption of cerebrospinal luid (CSF) . Symptoms include headache in at least 90 percent of cases, visual disturbances such as loss of a visual field or central visual acuity in 70 percent, and commonly occurring papilledema that may be sight-threatening (Evans, 2000; Heaney, 20 1 0) . Other complaints are stif neck, back pain, pulsatile tinnitus, and cranial nerve palsies. he syndrome is oten found in young women and is preva­ lent in those who are obese, who recently gained weight, or both (Fraser, 20 1 1 ) . Along with symptoms, other criteria for diagnosis include elevated intracranial pressure > 25 em H20, normal CSF composition, normal cranial CT or MR imaging indings, pap­ illedema, and no evidence for systemic disease. If papilledema is not present, other criteria are required (Friedman, 20 1 3) . I diopathic intracranial hypertension i s usually self-limited. Visual defects can be prevented by lowering the CSF pressure, and agents include acetazolamide to reduce fluid production, furosemide, or topiramate. Corticosteroids are now rarely used. Surgical intervention is occasionally necessary and is accom­ plished by either lumboperitoneal shunting of spinal fluid or optic nerve sheath fenestration. It is controversial if pregnancy is a risk factor for idiopathic intracranial hypertension. Certainly, symptoms may first appear in pregnancy, and women previously diagnosed may become symptomatic. Symptoms usually develop by midpreg­ nancy, tend to be self-limited, and usually resolve postpartum. Pregnancy does not alter management. Some recommend serial visual fi e ld testing to forestall permanent vision loss. In a report of 1 6 pregnant women, visual ield loss developed in four, and it became permanent in one (Huna-Baron, 2002) . Visual ield loss is often coincident with the development of

papilledema, for which acetazolamide is given. Lee and asso­ ciates (2005) reported successful treatment of 1 2 pregnant women. Although outmoded for treatment of nonpregnant individuals, repeated lumbar punctures are generally successful in providing temporary relief throughout pregnancy. In some pregnant women, surgical therapy becomes necessary, and we and others have had promising results with optic nerve sheath fenestration (hambisetty, 2007) . Pregnancy complications are likely due to associated obesity and not to intracranial hypertension. In a review of 54 pregnan­ cies, rates of adverse perinatal outcomes were not elevated (Katz, 1 989) . he route of delivery depends on obstetrical indications, and conduction analgesia is safe (Aly, 2007; Karmaniolou, 20 1 1 ) . MATERNAL VENTRICULAR SHUNTS Pregnancies in women with previously placed ventricular shunts for obstructive hydrocephalus usually have satisfactory out­ comes (Landwehr, 1 994) . Shunts may be ventriculoperitoneal, ventriculoatrial, or ventriculopleural. Partial obstruction of a shunt is common, especially late in pregnancy (Schiza, 20 1 2) . In one report o f 1 7 such pregnancies, neurological complica­ tions were reported in 1 3 (Wisof, 1 99 1 ) . Findings included headaches in 60 percent, nausea and vomiting in 35 percent, lethargy in 30 percent, and ataxia or gaze paresis, each in 20 percent. Most symptoms respond to conservative management. However, if CT scanning during symptom evaluation discloses acute hydrocephaly, then the shunt is tapped or pumped several times daily. In some cases, surgical revision is necessary and may be emergently indicated (Murakami, 20 1 0) . Another shunting procedure is placement o f an endoscopic third ventriculostomy for hydrocephalus (de Ribaupierre, 2007) . With this, a small hole is created in the loor of the third ventricle to allow CSF to low directly into lower cisterns. One report described successful results in ive pregnant women who under­ went endoscopic ventriculostomy (Rifaud, 2006) . In a review, however, reproductive function and miscarriage rates were found to significantly worsen in these women (Bedaiwy, 2008). Vaginal delivery is preferred in women with shunts, and unless there is a meningomyelocele, conduction analgesia is permitted. Antimicrobial prophylaxis is indicated if the perito­ neal cavity is entered for cesarean delivery or tubal sterilization. MATERNAL B RAIN D EATH Brain death is rare in obstetrics. Life-support systems and par­ enteral alimentation for up to 1 5 weeks while awaiting delivery have been described (Hussein, 2006; Powner, 2003; Souza, 2006) . Some women were treated with aggressive tocolysis and antimicrobial therapy. In one review of 1 7 women with persis­ tent vegetative state who were given various levels of support, fi v e women died after delivery, and most of the others remained in their vegetative state (Chiossi, 2006) . With a diagnosis of brain death using the uniform Deter­ mination of Death Act definition, there are no published reports of neurological recovery (Wijdicks, 20 1 0) . Few insti­ tutional brain-death policies address pregnancy (Lewis, 20 1 6) . The ethical, inancial, and legal implications, both civil and

N e u rolog i c a l D i s o rders

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PSYCHOLOGICAL ADJ U STME NTS TO PREGNANCY . . 1 1 73 MAJOR DEPRESSION . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 75 BI POLAR AND RELATED DISORDERS . . . . . . . . . . . . . . 1 1 78 ANXI ETY DISORDERS. . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 79 SCHIZOPHRENIA S PECTRU M DISORDERS . . . . . . . . . . 1 1 80 EATING DISORDERS. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 80 PERSONALITY D I SORDERS . . . . . . . . . . . . . . . . . . . . . . 1 1 8 1

h e insaniy ofpregnancy is usualy a manestation ofauto­ intoxication, and may be accompanied by melancholic or maniacal symptoms. It usualy persists throughout gestation, but disappears shorty ater labour, unless the patient has an hereditary tendency to mental derangement. -]. Whitridge Williams ( 1 903) The subject of mental illness was only briely addressed by Williams in 1 903, when it appears that acute puerperal psy­ choses were manifestations of eclampsia or sepsis. More than 1 00 years later, we have learned that pregnancy and the puer­ perium are at times suiciently stressful to provoke mental ill­ ness. Such illness may represent recurrence or exacerbation of a preexisting psychiatric disorder, or it may signal the onset of a new condition. his 25th edition of Williams Obstetrics marks only the second edition with a focused chapter dedicated to psychiatric illnesses. To emphasize the rising national interest, American College of 0 bstetricians and Gynecologists President Dr. Gerald F. Joseph Jr. declared postpartum depression as an initiative in 2009.

Psychiatric disorders during pregnancy are associated with less prenatal care, substance use, poor obstetrical and neonatal outcomes, and higher rates of postpartum psychiatric illness (Frieder, 2008) . Despite these known risks, obstetrical provid­ ers often are reluctant to confront or fail to identiy some of these mental health issues during pregnancy. For example, Lyell and colleagues (20 1 2) found that the diagnosis of depression was not documented in nearly half of the records of depressed women. Yet, perinatal mood disorders can have far-reaching consequences beyond the immediate efect on maternal mental health and social function by adversely afecting the mother­ child relationship (Weinberg, 1 998). lso, suicide is a primary cause of death among women during the perinatal period in the United States, and major depression is among the strongest predictors of suicidal ide­ ation (Melville, 20 1 0) . Between 2004 and 20 1 2, self-harm, sui­ cide, or drug overdose was the leading cause of maternal death in Colorado (Metz, 20 1 6) . In a 1 0-year analysis of Washington state hospitalizations, Comtois and associates (2008) studied 355 women with a postpartum suicide attempt. Substance abuse was linked with a sixfold higher and prior psychiatric hospital­ ization with a 27-fold greater risk for suicide. These rates rose further if there were multiple hospitalizations. Also of note, 54 percent of pregnancy-associated suicides involve intimate­ partner conlict (Palladino, 2 0 1 1 ) . PSYCHOLOGICAL ADJ U STMENTS TO PREGNANCY Biochemical factors and life stressors can markedly inluence mental health and mental illness during the perinatal period. Intuitively, pregnancy exacerbates some coexisting psychologi­ cal disorders. Namely, an increased risk for mood disorders is linked with pregnancy-related shifts in sex steroid and mono­ amine neurotransmitter levels, dysfunction of the hypothalamic­ pituitary-adrenal axis, thyroid dysfunction, and alterations in

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Med ica l a n d S u rg ical Com p l ications

immune response (Yonkers, 20 1 1 ) . These changes, coupled with familial clustering of depression cases, suggest that there may be a subgroup of women at risk for developing a unipolar major depressive disorder during pregnancy. Women respond in various ways to stressors of pregnancy, and some express persistent concerns regarding fetal health, child care, lifestyle changes, or fear of childbirth pain. Anxiety, sleep disorders, and unctional impairment are common (Romero, 20 1 4; Vythilingum, 200S) . However, according to Littleton and coworkers (2007), anxiety symptoms in pregnancy are associ­ ated with psychosocial variables similar to those for nonpregnant women. he level of perceived stress is significantly higher for women whose fetus is at high risk for a malformation, for those with preterm labor or delivery, and for those with other medi­ cal complications (Alder, 2007; Ross, 2006) . Hippman and col­ leagues (2009) screened for depression in S l women who had an increased risk for a fetus with aneuploidy. Half of these women had a positive depression screening score, whereas only 2.4 per­ cent of those with a normal pregnancy did so. Several steps can be taken to diminish psychological stress in the event of a poor obstetrical outcome. For example, follow­ ing a stillbirth, Gold (2007) encouraged parental contact with the newborn and provision of photographs and other infant memorabilia. Addressing associated sleep disorders also seems reasonable Quulia Paavonen, 20 1 7; Romero, 20 1 4) . • The Puerperium

This is a particularly stressful time for women, and risks for mental illness are increased. Up to 1 5 percent of women develop a nonpsychotic postpartum depressive disorder within 6 months of delivery (Tam, 2007; Yonkers, 20 1 1 ) . A few have a psychotic illness following delivery, and half of these manifest a bipolar disorder. Depressive disorders are more likely in women with obstetrical complications such as severe preeclampsia or fetal-growth restriction, especially if associated with early deliv­ ery. Houston and coworkers (20 1 5) found that expectations at delivery also increased the risk for postpartum depression. Importantly, stressors beyond those directly related to the pregnancy can raise perinatal depression rates. Tarney and col­ leagues (20 1 5) identified spouse deployment as a factor for postpartum depression in a study at Womack Army Medical Center. But, among women with a history of bipolar disorder, these elements play a lesser role in the development of mania or depression (Yonkers, 20 1 1 ) . M ate r n ity B l ues

Also called pospartum blues, this is a time-limited period of heightened emotional reactivity experienced by half of women within the irst week after parturition. Prevalence estimates for the blues range from 26 to S4 percent depending on diagnostic criteria (O'Hara, 20 1 4) . his emotional state generally peaks on the fourth or ifth postpartum day and normalizes by day 1 0 (O'Keane, 20 1 1 ) . h e predominant mood i s happiness, but afected moth­ ers are more emotionally labile. hey also may have insomnia, weepiness, depression, anxiety, poor concentration, and irri­ tability. Mothers may be transiently tearful for several hours and then recover completely, only to be tearful again the next

day. Supportive treatment is indicated, and afected women are reassured that the dysphoria is transient and most likely due to biochemical changes. They should be monitored for develop­ ment of depression and other severe psychiatric disturbances. • Perinatal Evaluation and Screening

Both the American College of Obstetricians and Gynecologists (20 1 6a) and the United States Preventative Services Task Force now recommend screening at least once during the perinatal period for depression and anxiety (Siu, 20 1 6) . Identiication of psychiatric disorders in pregnancy can be challenging because changes in behavior and mood are often attributed to preg­ nancy. To diferentiate these, Yonkers (20 1 1 ) recommends assessment of cognitive symptoms-for example, loss of con­ centration. Excessive symptoms of anxiety and insomnia-even during periods of infant sleep-can also suggest postpartum depression. Speciic factors for depression are reviewed and include a prior personal or family history of depression. Universal-screening programs for depression continue to evolve (Venkatesh, 20 1 6) . At Parkland Hospital, mental illness screening is generally done at the irst prenatal visit using a brief risk-based query and again postpartum using a universal­ applied screening tool for postpartum depression. Questions search for psychiatric disorders, related therapy, prior or cur­ rent use of psychoactive medications, and current symptoms. Women with a history of sexual, physical, or verbal abuse; substance abuse; and personality disorders are also at greater risk for depression (man, 2007; Janssen, 20 1 2) . History of neglect and abuse are especially powerful antecedents of depres­ sion in adolescent pregnancy (Meltzer-Brody, 20 1 4) . Smok­ ing and nicotine dependence and obesity also raise rates of all mental disorders in pregnancy (Goodwin, 2007; Molyneaux, 20 1 4) . Finally, because eating disorders may be exacerbated by pregnancy, afected women are followed closely (p. l 1 S0) . Several screening instruments shown in Table 6 1 - 1 are avail­ able and have been validated for use during pregnany and the puerperium. Use of one of these screening tools is encouraged because symptom- or risk-based screening alone may be insuf­ icient (American College of Obstetricians and Gynecologists, 20 1 6a) . Cerimele and colleagues (20 1 3) found that obstetri­ cians and gynecologists failed to identiY 60 percent of depressed women in clinical practice. As mentioned earlier, at Parkland Hospital, all women are screened during their irst postpartum visit using the Edinburgh Postnatal Depression Scale (EPDS). In an analysis of more than 1 7,000 women, 6 percent had scores that indicated either minor or major depressive symptoms, and 1 2 women had thoughts of self-harm (Nelson, 20 1 3) . Similarly, Kim and coworkers (20 1 5) assessed suicidal ideation in more than 22,000 women screened using the EPDS both during preg­ nancy and postpartum. They found rates of depression as high as 3.4 percent during the puerperium. A small fraction of those with thoughts of self-harm had a credible plan, intent, and means for attempted suicide. Obviously, suicidal ideation warrants prompt psychiatric consultation for evaluation and management. Screening for perinatal depression without appropriate subsequent treatment is insuicient (American College of Obstetricians and Gynecologists, 20 1 6a) . hat said, mecha­ nisms to ensure adequate ensuing care can be problematic. In

Psych iatric D is o rders

TABLE 61 - 1 . Depression Scree n i n g Tool sa

Screening Tool

Items

Ed i n bu rg h Postnata l Depression Sca le Patient H ea lth Q u estion na i re 9 Center for Epidemiolog ic Studies Depression Sca le

Ti me to Complete (min) Ava i lable Resou rces Online b

10

50 percent of untreated early syphilis cases and in 1 0 percent of late latent disease (Fiumara, 1 975; Hollier, 200 1 ) . • Clinical Manifestations

M ate r n a l Syp h i l i s

This i s staged according to clinical features and disease duration. 1 . Primary syphilis is diagnosed by its characteristic chancre, which develops at the inoculation site. This solitary, painless

F I G U R E 65-3 Condyloma lata. (Reprod uced with perm ission from Horsager R, Roberts S, Roger V, et a l (eds): Wi l l iams Obstetrics 24th Edition Study G u ide, New York, McGraw H i l l Education, 20 1 4; Photo contributor: Dr. Jonath a n Wi l l ms.)

lesion typically has a raised, firm border and a red, smooth ulcerated base without signiicant pus ( Fig. 65- 1 ) . Nonsup­ purative lymphadenopathy may develop. A chancre will usu­ ally resolve spontaneously in 2 to 8 weeks, even if untreated. Multiple lesions, if found, are predominantly in HIV- 1 co­ infected women. 2. Secondary syphilis stems from dissemination of spirochetes to afect multiple organ systems. Manifestations develop 4 to 1 0 weeks after the chancre appears and include dermatologi­ cal abnormalities in up to 90 percent of women. A difuse macular rash, plantar and palmar targetlike lesions, patchy alopecia, and mucous patches may be seen (Fig. 65-2) . Con­ dylomata lata are flesh-colored papules and nodules found on the perineum and perianal area (Fig. 65-3) . These papules are teeming with spirochetes and are highly infectious. Most women with secondary syphilis also express constitutional symptoms such as fever, malaise, headache, and myalgias.

F I G U R E 65-2 Secondary syph i l is. A. Ta rget lesions on the pa l ms. B. Mucous patches a round the nose a n d mouth. (U sed with perm ission from Dr. Dev i n Macias.)

Sex ua l ly Tra n s m itted I nfecti o n s

Hepatitis, nephropathy, ocular changes, anterior uveitis, and periostitis can also develop. 3. Latent syphilis develops when primary or secondary syphilis is not treated but clinical manifestations still resolve. It is identified instead by serological testing. Eary latent syphilis is subclinical disease acquired within the preceding 1 2 months. Disease diagnosed beyond 1 2 months is either late latent syphilis or latent syphilis of unknown duration. 4. Tertiary syphilis is a slowl) progressive disease afecting any organ system but is rarely seen in reproductive-aged women. Co n g e n ita l Syp h i l i s

Without screening and treatment, approximately 7 0 percent of infected women will have an adverse pregnancy outcome (Hawkes, 20 1 l ) . Maternal infection can lead to preterm labor, fetal death, fetal-growth restriction, or fetal infection (Gomez, 20 1 3) . Because of immune incompetence prior to midpreg­ nancy, the fetus generally does not manifest the immunological inlammatory response characteristic of clinical disease before this time (Silverstein, 1 962) . Once fetal syphilis develops, how­ ever, it manifests as a continuum. Fetal hepatic abnormalities are followed by anemia and thrombocytopenia, then ascites and hydrops (Hollier, 200 1 ) . Stillbirth remains a major complica­ tion (Lawn, 20 1 6; Su, 20 1 6) . he newborn may have jaundice with petechiae or purpuric skin lesions, lymphadenopathy, rhinitis, pneumonia, myocarditis, nephrosis, or long-bone involvement ( Fig. 65-4) . With syphilitic infection, the placenta becomes large and pale (see Fig. 65-4) . Microscopically, villi lose their characteris­ tic arborization and become thicker and clubbed. Sheield and colleagues (2002c) described these villi in more than 60 per­ cent of syphilitic placentas. Blood vessels markedly diminish in number, and in advanced cases, they almost entirely disappear as a result of endarteritis and stromal cell proliferation. Likely related, Lucas and coworkers ( 1 99 1 ) demonstrated increased vascular resistance in uterine and umbilical arteries of infected

pregnancies. h e cord may also show evidence o f infection. I n a study o f 25 untreated women, Schwartz and associates ( 1 995) reported that necrotizing funisitis was present in a third. • Diagnosis

The United States Preventative Services Task Force recom­ mends that clinicians screen all pregnant women for syphilis to prevent congenital infection (Wolf, 2009) . Testing is ideally performed at the irst prenatal visit. In populations with a high prevalence of syphilis, serological testing is repeated in the third trimester and again at delivery (Workowski, 20 1 5) . Treponema pallidum cannot b e cultured from clinical speci­ mens. However, direct diagnosis of early-stage disease from lesion exudate, tissue, or body luid can be completed by dark­ ield microscopic examination, by polymerase chain reaction (PCR) , or by direct fluorescent antibody tests for T pallidum (DFA-TP) (Tsang, 20 1 5) . hese methods are not widely available and are less sensitive for blood specimens (Grange, 20 12; Henao­ Martinez, 20 1 4) . hus, in practice, diagnoses are mainly derived from clinical indings coupled with serological blood testing. Serological testing is used for diagnostic and for screening purposes. here are two types. If the irst of these is positive, then the second type is also performed. his combination identifies infection and clariies disease stage. Traditionally, the first type is nontreponemal testing, and either the Venereal Disease Research Laboratory (VDRL) or the rapid plasma reagin (RPR) is selected. Both tests measure patient immunoglobulin M and G (IgM and IgG) antibodies formed against cardiolipin that is released from damaged host cells and possibly also from treponemes. Nota­ bly, these same antibodies can also be produced in response to other acute events that include recent vaccination, febrile illness, and pregnancy itself or in response to chronic conditions such as intravenous drug abuse, systemic lupus erythematosus, aging, leprosy, or cancer. As such, these all serve as potential sources of false-positive results (Larsen, 1 995). Conversely, seroconversion occurs at around 3 weeks, but can take up to 6 weeks (Peeling,

F I G U R E 65-4 Congenita l syp h i l is. A. Fetog ra m of a sti l l born i nfa nt i nfected with syp h i l i s showing the "moth-eaten" a ppea ra nce of the fe m u rs (arrow) . B. E n l a rged hyd ro p i c placenta of a syp h i l is-i nfected neonate.

1 23 7

1 238

Med i c a l a nd S u rg ica l Co m pl icatio n s

2004). Thus, women with very early primary syphilis can have initially false-negative serological test results. With positive nontreponemal test results, findings are quan­ tified and expressed as titers. Because titers reflect disease activity, they increase during early syphilis and often exceed levels of 1 :32 in secondary syphilis. Following treatment of primary and secondary syphilis, serological testing at 3 to 6 months usually confirms a fourfold drop in VDRL or RPR titers (Rac, 20 1 4a) . Because VDRL titers do not correspond directly to RPR titers, consistent use of the same test for surveillance is recom­ mended. hose with treatment failure or reinfection may lack this expected decline. Importantly, some successfully treated patients may still exhibit persistently low-level positive titers, which are referred to as "serofast." his state is more likely in older individuals, those with lower initial nontreponemal anti­ body titers, and those with later stages of syphilis (Seia, 20 1 5) . The second type o f serological testing is trep0 nemal-specic. It seeks patient antibodies formed specifically against T pali­ dum. he antibodies detected by treponemal assays appear up to a few weeks earlier than those detected by nontreponemal tests (Levett, 20 1 5) . Tests includes the fluorescent treponemal­ antibody absorption tests (FTA-ABS) , the T palidum passive particle agglutination (TP-PA) test, and various immunoassays (Association of Public Health Laboratories, 20 1 5) . O/note, these treponemal-speciic tests generaly remain positive throughout lie. Each of the serological tests has limitations including false­ positive and -negative results. Traditionally, nontreponemal tests have been used for screening in the United States, and results are then conirmed by a specific treponemal test. Within the past several years, some laboratories have implemented a reverse screening algorithm, namely, screening first with a treponemal­ specific test (Binnicker, 20 1 2; Centers for Disease Control and Prevention, 20 1 1 ) . Both approaches are efective if there is a program for appropriate screening, follow-up, and treatment. In contrast to these tests, rapid "point-of-care" (POC) syphilis screening of blood or serum samples is being devel­ oped (Singh, 20 1 5 ; Tucker, 20 1 0) . hese may be best used for women with limited prenatal care. Most tests are treponemal­ specifi c , and positive POC results can then be confirmed by a laboratory nontreponemal test. In hard-to-reach populations, some countries immediately treat women with positive POC results. This practice, however, risks overtreating previously cured women who still have residual persistent treponemal antibodies. his limitation may be overcome by newer POC dual tests, which simultaneously assess nontreponemal and treponemal antibodies (Causer, 20 1 5) .

Following maternal diagnosis, sonographic evaluation is performed for fetuses > 20 weeks' gestation to search for signs of congenital syphilis. Rac and associates (20 1 4b) noted that 3 1 percent of infected women diagnosed at � 1 8 weeks' gesta­ tion had abnormal fetal sonographic indings. Hepatomegaly, placental thickening, hydramnios, ascites, hydrops fetalis, and elevated middle cerebral artery Doppler velocimetry measure­ ments are indicative of fetal infection. Before 20 weeks, treat­ ment is highly successful, and sonographic findings are rare (Nathan, 1 997) . For fetuses of viable age with sonographic findings, ante­ partum fetal heart rate monitoring prior to treatment is rec­ ommended. Spontaneous late decelerations or a nonreactive tracing likely reflects an extremely ill fetus that may poorly tolerate a Jarisch-Herxheimer reaction, described next. In this extreme case, consultation with a neonatologist regarding a plan of delaying treatment, pursuing delivery, and then treat­ ing in the nursery is a consideration (Wendel, 2002) . • Treatment

Syphilis therapy during pregnancy is given to eradicate mater­ nal infection and to prevent or treat congenital syphilis. Paren­ teral penicillin G remains the preferred treatment for all stages of syphilis during pregnancy (Table 65- 1 ) . During pregnancy, authorities recommend that a second dose of benzathine peni­ cillin G be given 1 week after the initial dose. Such treatment is also given for women with concomitant HIV infection (Workowski, 20 1 5) . Benzathine penicillin G is highly efective for early maternal infection. In a study of 340 pregnant women so treated, Alex­ ander and associates ( 1 999) reported six cases-1 .8 percent-of congenital syphilis. Four of these six neonates were from a group of 75 women with secondary syphilis. The other two were identi­ fied in those delivered from a group of 1 02 women with early latent syphilis. Congenital syphilis was generally confined to neo­ nates of women treated ater 26 weeks and is likely related to the duration and severity of fetal infection. Sheield and coworkers (2002b) reported that high maternal serological titers, preterm delivery, and delivery shortly ater antepartum therapy are all risks for failure of maternal treatment to prevent neonatal infection. here are no proven alternatives to penicillin therapy during pregnancy. Erythromycin and azithromycin may be curative for the mother, but because of limited transplacental passage, these drugs do not prevent all congenital disease (Berman, 2004; Wendel, 1 988; Zhou, 2007) . Moreover, in several countries,

TABLE 65-1 . Reco m m e nded Treatment for Preg n a nt Women with Syph i l i s Category

Treatment

Early syp h i l i sa

Benzath i ne p e n i ci l l i n G, 2.4 m i l l io n u n its as a s i n g le i njection-some reco m mend a secon d d ose 1 week l ater Benzat h i n e p e n i ci l l i n G, 2 4 m i l l io n u n its i nt ra m u sc u larly weekly for t h ree doses

More t h a n l -yea r d u rationb

.

a p r i m a ry, seconda ry, a n d ea rly l atent syp h i l i s o f l e s s tha n 1 -yea r d u ra tio n . bLatent syp h i l i s of u n kn own or more t h a n 1 -yea r d u ration; tertia ry syp h i l i s. M i ssed doses a re n ot accepta b l e for preg n a n t w o m e n , a nd those who m i ss a ny d ose o f thera py m u st repeat the fu l l cou rse o f thera py. Data from Workows ki, 2 0 1 5 .

Sexu a l ly Tra n s m itted I n fect i o n s

macrolide-resistant strains of T pallidum are now prevalent (Stamm, 20 1 5) . Cephalosporins may prove useful, but data are limited (Liang, 20 1 6) . Tetracyclines, including doxycycline, are efective but generally not recommended during pregnancy, because of the risk for fetal deciduous-teeth discoloration. All women with syphilis are ofered counseling and testing for HIV and other STDs. Following syphilis treatment, serolog­ ical testing to detect treatment failures is done at 3 to 6 months and usually confi r ms a fourfold drop in VDRL or RPR titers. During pregnancy, serological titers can be checked monthly in women at high risk for reinfection (Workowski, 20 1 5) . I n some instances, a woman may present without symp­ toms but describes recent sexual contact with a person who has been diagnosed with syphilis. She should be evaluated clinically and serologically. If her partner is diagnosed and their sexual contact occurred within the preceding 90 days, the gravida is treated presumptively for early syphilis, even if serological test results are negative. his accounts for early infection but before seroconversion. If contact was earlier than 90 days ago, treat­ ment is based on serological results (Workwoski, 20 1 5) . Pe n ic i l l i n Reacti o n s

Women with a history of penicillin allergy should have either an oral stepwise penicillin-dose challenge or skin testing per­ formed to confirm the risk of immunoglobulin E (IgE)­ mediated anaphylaxis. If conirmed, penicillin desensitization, shown in Table 65-2, is recommended and then followed by benzathine penicillin G treatment (Wendel, 1 985).

TABLE 65-2. Pen ici l l i n Allergy-Ora l Desensitization Protocol for Patie nts with a Positive Ski n Test Penici llin V Suspension Dosea 1 2 3 4 5 6 7 8 9

10

11 12 13 14

Amountb (units/m L)

mL

Units

Cu m ulative Dose (un its)

1 000 1 000 ·1 000 1 000 1 000 1 000 1 000 1 0,000 1 0,000 1 0,000 SO,OOO 80,000 SO,OOO SO,OOO

0. 1 0.2 0.4 O.S 1 .6 3.2 6.4 1 .2 2.4 4.S 1 .0 2.0 4.0 8.0

1 00 200 400 800 1 600 3 200 6400 1 2,000 24,000 4S,OOO 80,000 1 60,000 3 20,000 640,000

1 00 3 00 700 1 5 00 3 1 00 6300 1 2, 700 24,700 4S,700 96,700 1 76,700 3 36,700 656,700 1 ,296,700

al nte rva l between d oses: 1 5 m i n utes. E l a psed ti me: 3 h o u rs and 45 m i n utes. C u m u l ative dose: 1 . 3 m i l l ion u n its. Observation period : 30 m i n utes before pa rentera l a d m i n i stration of pen ici l l i n . bThe s pecific a m o u nt of d r u g was d i l uted i n a pproxi mately 30 mL of water and a d m i n i stered o ra l ly. Fro m We ndel, 1 985, with perm i ssion .

Distinct from allergy, a Jarisch-Herxheimer reaction devel­ ops following penicillin treatment in most women with pri­ mary syphilis and approximately half with secondary infection. Uterine contractions, mild maternal temperature elevation, decreased fetal movement, and fetal heart rate decelerations are findings. Reaction treatment is supportive with antipyretics as needed, hydration, and oxygen supplementation (Klein, 1 990) . In a study of 50 gravidas who received benzathine penicillin for syphilis, Myles and associates ( 1 998) reported a 40-p ercent incidence of Jarisch-Herxheimer reactions. Of the 3 1 women monitored electronically, 42 percent developed regular uterine contractions, and 39 percent developed variable decelerations. All contractions resolved within 24 hours of therapy. Accord­ ingly, for fetuses of viable age, some recommend administering the irst dose of antibiotic in labor and delivery and with con­ tinuous fetal monitoring for at least 24 hours (Rae, 20 1 7) . Oth­ ers recommend this only if sonographic signs of fetal syphilis, described earlier, are found (Duf, 20 1 4; Wendel, 2002) . If this second plan is elected, patients are counseled on reaction signs and encouraged to seek evaluation if they develop. GONORRHEA Of notiiable STDs, infections caused by Neisseria gonorrhoeae are the second most common. The incidence of gonorrhea in the United States has continued to rise since 2009, and in 20 1 5 , the rate was 1 24 cases per 1 00,000 persons (Centers for Disease Control and Prevention, 20 1 6c) . he highest rates in women of any ethnicity were in those aged 1 5 to 24 years. In pregnant women, its prevalence approximates 0.6 percent (Blatt, 20 1 2) . In most pregnant women, infection is limited to the lower genital tract-the cervix, urethra, and periurethral and vestibular glands. Acute salpingitis is rare in pregnancy. But, pregnant women account for a disproportionate number of disseminated gonococcal infections (Bleich, 20 1 2) . Gonococcal infection can have deleterious efects i n any tri­ mester. Untreated gonococcal cervicitis is associated with septic abortion as well as infection after voluntary abortion ( Burk­ man, 1 976) . Preterm delivery, prematurely ruptured mem­ branes, chorioamnionitis, and postpartum infection are more frequent in women with gonococcal infection (lger, 1 988; Johnson, 20 1 1 ) . Vertical transmission o f gonorrhea is predominantly due to fetal contact with vaginal infection during birth. he pre­ dominant sequela is gonococcal ophthalmia neonatorum, which can lead to corneal scarring, ocular perforation, and blindness. Transmission rates are high and approximate 40 percent (Laga, 1 986) . Accordingly, as discussed in Chapter 32 (p. 6 1 3) , ocular prophylaxis is provided to newborns (Mabry-Hernandez, 2 0 1 0) . • Screening and Treatment

Pregnant women who live in high-prevalence areas or who are at risk for gonorrhea should undergo irst-trimester screening. Risk factors include age �25 years; prior gonococcal infection; other STDs; prostitution; new or multiple sexual partners; drug abuse; black, Hispanic, or American Indian or laska Native ethnicity; and inconsistent condom use (American Academy of

1 23 9

1 240

Med i ca l a n d S u rg ica l Co m p l ications

1 -g oral dose of azithromycin is also provided for chlamydial co-infection (Workowski, 20 1 5) .

Pediatrics, 20 1 7) . For women who test positive, screening for syphilis, chlamydial infection, and H IV should precede treat­ ment, if possible. Gonococcal infection is a marker for con­ comitant chlamydial infection. Thus, if chlamydial testing is unavailable, presumptive chlamydial therapy is given to women treated for gonorrhea. Screening for gonorrhea in women is by culture or nucleic acid ampliication tests (NAATs) . NAATs have replaced cul­ ture in most laboratories, and kits are available for specific col­ lection from the vagina, en docervix, or urine. Of these, vaginal or cervical samples are preferred, as urine collection may detect up to 1 0 percent fewer infections (Papp, 20 1 4) . If used, the initial urine stream, not midstream, is collected. NAATs are also recommended for diagnosis of rectal or pharyngeal disease, but participating laboratories must be CLIA (Clinical Labora­ tory Improvement Amendments) compliant with required test modifi c ations. Culture is also available for these anatomical sites. Rapid POC tests for gonorrhea, although available, do not yet reach the sensitivity or specificity of culture or NAAT and have not been rigorously studied in pregnant women (Herbst de Cortina, 20 1 6) . Gonorrhea treatment has evolved during the past decade due to the ability of N gonorrhoeae to rapidly develop antimicrobial resistance. The current treatment for uncomplicated gonococ­ cal infection during pregnancy is 250 mg of cetriaxone intra­ muscularly plus 1 g of azithromycin orally (Workowski, 20 1 5) . h e latter provides another drug with a diferent mechanism of action against N gonorrhoeae and treats chlamydial co-infections. Patients are instructed to abstain from sexual intercourse for 7 days ater they and their sexual partners have completed treat­ ment. u an alternative regimen, a single, 400-mg oral dose of cefixime plus 1 g of azithromycin should be reserved for situations that preclude cetriaxone treatment. With cephalosporin allergy, a 240-mg intramuscular dose of gentamicin can be coupled with a 2-g oral azithromycin dose. Repeat testing is recommended in the third trimester for any woman treated for gonorrhea in the first trimester and for any uninfected woman who is at high risk for gonococcal infection (American Academy of Pediatrics, 20 1 7) . Treatment i s recommended for sexual contacts. Expedited therapy, discussed on page 1 24 1 , is a less-desirable option due to the now-preferred injectable regimen.

Chlamydia trachomatis is an obligate intracellular bacterium that has several serotypes, including those that cause lympho­ granuloma venereum. The most commonly encountered strains are those that attach only to columnar or transitional cell epi­ thelium and cause cervical infection. It is the most common reportable STD in the United States, and the overall chla­ mydial infection rate among women was 646 cases per 1 00,000 females in 20 1 5 (Centers for Disease Control and Prevention, 20 1 6c) . Most pregnant women have asymptomatic infection, but a third have urethral syndrome, urethritis, or Bartholin gland infection (Peipert, 2003) . Mucopurulent cervicitis may be due to chlamydial or gonococcal infection or both. Other chlamyd­ ial infections not usually seen in pregnancy are endometritis, salpingitis, reactive arthritis, and Reiter syndrome. The role of chlamydial infection in pregnancy complications remains controversial. A few studies have reported a direct asso­ ciation between C trachomatis and miscarriage, whereas most show no correlation (Baud, 20 1 1 ; Coste, 1 99 1 ; Paukku, 1 999). It is disputed whether untreated cervical infection increases the risk of preterm delivery, preterm ruptured membranes, low birthweight, or perinatal mortality (Andrews, 2000, 2006; BIas, 2007; Johnson, 20 1 1 ; Moodley, 20 1 7; Silva, 20 1 1 ) . Chlamydial infection has not been associated with a greater risk of chorio­ amnionitis or with peripartum pelvic infection (Berman, 1 987; Gibbs, 1 987) . However, delayed postpartum uterine infection has been described by Hoyme and associates ( 1 986) . The syn­ drome, which develops 2 to 3 weeks postpartum, is distinct from early postpartum metritis. It is characterized by vaginal bleeding or discharge, low-grade fever, and uterine tenderness. Infection poses a higher risk to the newborn than to the mother. Vertical transmission leads to infection in 8 to 44 percent of neonates delivered vaginally from afected women (Rosenman, 2003) . Of neonatal infections, conjunctivitis is the most common (Chap. 32, p. 6 1 3) . Perinatal transmission to newborns can also cause pneumonia.

• Disseminated Gonococcal I nfections

• Screening and Treatment

Gonococcal bacteremia may cause disseminated infections that manifest as petechial or pustular skin lesions, arthralgias, or septic arthritis. For treatment of septic arthritis, the CDC recommends ceftriaxone, 1 g intramuscularly or intravenously (IV) every 24 hours plus a single 1 -g oral dose of azithromy­ cin (Workowski, 20 1 5) . Treatment is continued for 24 to 48 hours ater clinical improvement, and therapy is then changed to an oral agent to complete 1 week of therapy. Prompt recog­ nition and antimicrobial treatment will usually yield favorable outcomes in pregnancy (Bleich, 20 1 2) . Meningitis and endo­ carditis rarely complicate pregnancy, but they may be fatal (Bataskov, 1 99 1 ; Burgis, 2006) . For gonococcal endocarditis, ceftriaxone 1 to 2 g IV every 1 2 hours should be continued for at least 4 weeks, and for meningitis, 1 0 to 1 4 days. A single

CHLAMYDIAL I N F ECTIONS

Currently, the U.S. Preventive Services Task Force (LeFevre, 20 1 4) as well as the American Academy of Pediatrics and American College of Obstetricians and Gynecologists (20 1 7) recommend chlamydia screening for all women at the irst prenatal visit. he College further suggests testing in the third trimester for those treated in the irst trimester; all women aged ;25 years; and those aged �25 years with behavioral factors, which mirror those for women at risk for gonorrhea. In one review of repeat chlamydial infections among women, the rein­ fection rate was 14 percent, and most recurred within the first 8 to 1 0 months (Hosenfeld, 2009) . Diagnosis is made predominantly by culture or NAAT. Cul­ tures are more expensive and less accurate than newer NAATs (Greer, 2008) . Of samples for NAAT, vaginal or cervical

Sexu a l ly Tra n s m itted I n fections

TABLE 65-3. O ra l Treatment of Chlamydia trachomatis I nfections D u r i n g P reg n a ncy Regi men

Drug and Dosage

P referred

Azit h romyci n , 1 9 as a s i ng l e dose

Alternative

A moxici l l i n, 500 mg th ree t i mes d a i ly fo r 7 d or

E ryt h romyc i n ba se, 5 00 mg fou r times d a i ly for 7 d or

E ryt h romyci n ethylsucc i nate, 800 mg fou r ti mes d a i l y fo r 7 d or

E ryt h romyc i n ba se, 250 mg fo u r t i mes d a i ly for 1 4 d or

E ryth romyc i n ethyl succ i nate, 400 mg fo u r ti mes d a i l y for 1 4 d Data from Workowski, 20 1 5 .

samples are preferred, as urine collection may detect up to 1 0 percent fewer infections (Papp, 20 1 4; Wiesenfeld, 20 1 7) . However, Roberts and associates (20 1 1 ) evaluated NAAT of urine speci­ mens compared with cervical secretions in more than 2000 pregnant women and found them to be equivalent. As with gonorrhea, the irst portion of the urine stream is collected. Currently recommended treatment regimens for chlamydial infections are shown in Table 65-3 . Azithromycin is irst-line treatment and is safe and efective in pregnancy. The luoroqui­ nolones and doxycycline are usually avoided in pregnancy, and erythromycin estolate is contraindicated because of drug-related hepatotoxicity. Chlamydial testing is repeated 3 to 4 weeks after therapy completion and ,gain 3 months after treatment. I n high-risk individuals, third-trimester rescreening i s recom­ mended (Workowski, 20 1 5) . Exped ited Pa rtn e r Thera py

To prevent STD transmission, guidelines for expedited part­ ner therapy (EPT) have been created by the Centers for Dis­ ease Control and Prevention (2006a) and are endorsed by the American College of Obstetricians and Gynecologists (20 1 5) . With EPT, a prescription is provided to the diagnosed patient for their partner. It is delivered by the patient to their partner without medical assessment of the partner or professional coun­ seling. EPT ideally does not replace traditional strategies, such as standard patient referral with screening for other STDs. EPT is acceptable for treatment of sexual contacts with chlamydial infection. In light of new guidelines that recom­ mend injectable ceftriaxone, EPT for gonorrhea is less desirable unless the partner will otherwise not seek treatment (Centers for Disease Control and Prevention, 20 1 6a) . Fewer data are available to assess this strategy for trichomoniasis (Kissinger, 2006; Schwebke, 20 1 0) . EPT is not recommended for syphilis (Workowski, 20 1 5) . Although sanctioned by the CDC, EPT is not legal i n several states. \{oreover, the risk of litigation in the event of adverse outcomes may be elevated when a practice has uncertain legal status or is outside formally accepted community practice stan­ dards (Centers for Disease Control and Prevention, 2006a) . The legal status of EPT in each of the 50 states can be found at: http://ww. cdc.gov/std/ept/legal!default.htm.

• Lymphogranuloma Venereum

L] , L2 ,

and L3 serovars of C trachomatis cause ymphogranuloma venereum (LG). he primary genital infection is transient, is seldom recognized, and is not linked with vertical transmission to the fetus. It can be confused with chancroid. Classically, mat­ ted inguinal adenitis may develop on either side of the inguinal ligament to give rise to the "groove sign." At times, these nodes may suppurate. Ultimately, the lymphatics of the lower genital tract and perirectal tissues may be involved. Here, sclerosis and fi b rosis can cause vulvar elephantiasis and severe rectal stricture. Fistula formation involving the rectum, perineum, and vulva may also evolve. For treatment during pregnancy, erythromycin base, 5 00 mg orally four times daily, is given for 2 1 days (Workowski, 20 1 5) . Some authorities instead use szithromycin, 1 g orally weekly for 2 1 days, although data regarding eicacy are scarce. H ERPES SIM PLEX VIRUS his virus poses a disproportionately higher risk to the newborn than to the mother. hus, strategies in pregnancy aim to curb rates of vertical transmission. • Adult Disease

Two types of herpes simplex viruses are distinguished based on immunological diferences. Yet, the two viruses have sig­ niicant DNA sequence homology, and thereby, prior infec­ tion with one type attenuates a primary infection with the other. Type 2 HSV is recovered almost exclusively from the genital tract and is usually transmitted by sexual contact. Type 1 is responsible for most nongenital infections and typically is acquired in childhood. However, more than half of new cases of genital herpes in adolescents and young adults are now caused by HSV- 1 infection (Bernstein, 20 1 3) . his rise in the prevalence of HSV- 1 genital disease is thought to stem from an increase in oral-genital sexual practices. Another explana­ tion is that HSV- 1 acquisition has declined in childhood as a result of improved living conditions and hygiene (Bradley, 20 1 4; Xu, 2007) . Without prior exposure, this renders young

1 24 1

1 242

M ed i c a l a nd S u rg ical Co m p l i cations

people without HSV- l antibodies susceptible to genital acquisi­ tion of HSV- l or -2. Genital herpes simplex virus afects an estimated 50 mil­ lion adolescents and adults (Workowski, 20 1 5) . Most women are unaware of their infection, but HSV-2 seroprevalence among non-Hispanic white females in the United States was 1 5 .3 from 2007 to 20 1 0 and among black females, it was 53 percent (Fanfair, 20 1 4; Schulte, 20 1 4) . In one study of nearly 1 6,000 pregnant women from 2000 to 20 1 0, the overall serop­ revalence of HSV-2 was 16 percent, and for HSV- l , it was 66 percent (Delaney, 20 1 4) . Seronegative pregnant women have a 4 to 5 percent risk to acquire HSV- l or -2 during pregnancy (Brown, 1 997; Kulhanjian, 1 992) . For those who are H SV- l seropositive, acquisition risk for HSV-2 approximates 2 percent (Brown, 1 997) . C l i n i c a l M a n ifestations

Once transmitted by contact, HSV- l or -2 replicates at the entry site. Following mucocutaneous infection, the virus moves retrograde along sensory nerves. It then remains latent in cra­ nial nerves or dorsal spinal ganglia, but recurrences are com­ mon. HSV infections may be categorized into three groups. First episode primary inection describes the case in which H SV- l or 2 is isolated from a lesion in the absence of HSV- l or -2 serological antibodies. The typical incubation period of 6 to 8 days (range 1 to 26 days) may be followed by a papular eruption with itching or tingling, which then becomes pain­ ful and vesicular. Multiple vulvar and perineal lesions may or may not coalesce, and then ulcerate (Fig. 6 5-5) . Associated inguinal adenopathy can be severe. Many women do not pres­ ent with typical lesions. Instead, a pruritic or painful abraded area or knife-cut may be found. Cervical involvement is com­ mon, although it may be inapparent clinically. Transient sys­ temic influenza-like symptoms are frequent and are presumably caused by viremia. Some cases are severe enough to require hos­ pitalization. Hepatitis, encephalitis, or pneumonia infrequently

F I G U RE 65-5 First-episode pri m a ry g e n ital herpes s i m plex virus i n fection. Vesicles a nd kn ife-cut lesions a re i n d icated by a rrows. S m a l l u lcers ri m the a n us. S i m i l a r lesions can typica l ly be seen o n the v u lva .

develop, and disseminated disease is rare. After 2 to 4 weeks, all signs and symptoms of infection disappear. Instead of these classic symptoms, the percentage of asymptomatic primary HSV-2 genital infections may be as high as 90 percent (Fan­ fair, 20 1 3) . First episode nonprimay inection i s diagnosed when one HSV type is isolated from a lesion in a woman who has only the other serological HSV-type antibody present. In general, compared with primary infection, nonprimary infections are characterized by fewer lesions, less pain, fewer systemic mani­ festations, and briefer duration of lesions and viral shedding. This is likely because of some immunity from cross-reacting antibodies, for example, from childhood-acquired HSV- l infection. Recurrent disease is characterized by isolation of HSV- l or -2 from the genital tract in women with the same serotype antibodies. During the latency period, in which viral particles reside in nerve ganglia, reactivation is common and mediated through poorly understood stimuli. The resulting lesions gener­ ally are fewer in number, are less tender, and shed virus for a shorter period than those of primary infection. Typically, they recur at the same sites. Genital disease recurrences are more fre­ quently caused by HSV-2 compared with HSV- l . Recurrences are most frequent in the irst year after initial infection, and rates slowly decline subsequently (Benedetti, 1 999) . Gravidas with a known prior history of genital HSV often experience recurrences (Sheield, 2006) . Asymptomatic viral shedding is defined by the absence of clin­ ical findings. Most infected women shed virus intermittently over time, and most HSV transmission to a partner occurs dur­ ing these periods of asymptomatic viral shedding. • Vertical Transmission

he virus can be passed to the fetus/neonate by three routes: ( 1 ) peripartum in 85 percent, (2) postnatal in 1 0 percent, or (3) intrauterine in 5 percent Qames, 20 1 5) . As discussed in Chapter 1 8 (p. 347) , evidence does not suggest an obvious link between HSV infection and miscarriage (Zhou, 20 1 5) . Peripartum transmission i s b y far the more frequent route of infection, and the fetus is exposed to virus shed from the cervix or lower genital tract. HSV- l or -2 invades the uterus following membrane rupture or is transmitted by contact at delivery. The newborn is mainly infected, but rare cases of maternal endo­ metritis have . been described (Hollier, 1 997; McGill, 20 1 2) . Neonatal manifestations vary. First, infection may b e localized to the skin, eye, or mouth-SEM disease-in approximately 40 percent of cases. Second, central nervous system disease with encephalitis is seen in 30 percent. Last, disseminated dis­ ease with involvement of multiple major organs is found in 32 percent. Localized infection is usually associated with a good outcome. Conversely, even with acyclovir treatment, dissemi­ nated infection has a mortality rate of nearly 30 percent (Corey, 2009; Kimberlin, 20 1 1 ) . Of disseminated or cerebral infection survivors, serious developmental and central nervous system morbidity is seen in 20 to 50 percent. The neonatal infection rate is 0 . 5 to 1 per 1 0,000 births in the United States (Flagg, 2 0 1 1 ; Mahnert, 2007) . Most infected

Sex u a l l y Tra n s m itted I nfections

newborns are born to mothers with no reported history of HSV infection (Gardella, 20 1 0) . The risk of neonatal infection cor­ relates with the presence of HSV in the genital tract, the HSV type, invasive obstetrical procedures, and stage of maternal infection (Brown, 2005, 2007) . For example, neonates born to women who acquire genital HSV near the time of delivery have a 30- to 50-percent risk of infection. This is attributed to higher viral loads and the lack of transplacental protective antibodies (Brown, 1 997, 2000) . Women with recurrent HSV have less than a I -percent risk of neonatal infection (Pasternak, 20 1 0; Prober, 1 987) . Postpartum transmission is uncommon and passed to the newborn by contact with an infected mother, family member, or health-care worker. The clinical presentation mirrors that with peripartum transmission. In utero transmission of HSV- l or HSV-2 is rare and is part of the TORCH (roxoplasmosis, Qther, rubella, �ytomegalovi­ rus, herpes virus) collection of infections. Intrauterine HSV infection classically leads to disease involving the skin (blisters, scarring), the central nervous system (hydranencephaly, micro­ cephaly, intracranial calcification) , or the eyes (chorioretini­ tis, microphthalmia) (Hutto, 1 987) . Bone and viscera can be involved (Marquez, 20 1 1 ) . If seen sonographically, indings should prompt viral serological testing as described next. PCR analysis of an amniocentesis sample is another potential tool (Diguet, 2006) . • Diagnosis

Several organizations recommend against routine serological HSV screening in asymptomatic gravidas (American College of Obstetricians and Gynecologists, 20 1 6b; Workowski, 20 1 5 ; U.S. Preventive Services Task Force, 20 1 6) . However, for those with a clinically suspicious lesion, a diagnosis should be con­ irmed by laboratory testing. Available HSV tests are either virological or type-speciic serological tests. Direct virological tests are can be performed on a specimen from the mucocutaneous lesion. PCR or culture of the sample is a testing option. Of the two, PCR assays are more sensitive, the results generally are available in 1 to 2 days, and specimen handling is easier. In contrast, for viral culture, the sensitivity of HSV isolation is relatively low as vesicular lesions ulcerate and then crust. Also, results sometimes are not available for 7 to 14 days (Strick, 2006) . Regardless of the test performed, HSV viral types should be diferentiated (LeGof, 20 1 4) . Importantly, a negative culture or PCR result does not exclude infection. In contrast, false-positive results are rare. Serological assays are available to detect antibodies produced against speciic HSV glycoproteins, G l and G2. These proteins evoke type-speciic antibody responses to HSV- l and HSV-2 infection, respectively, and they reliably diferentiate the two. IgG antibodies develop 1 to 2 weeks after a primary infection and then persist. This permits conirmation of clinical infection and identiication of asymptomatic carriers. Providers should request type-speciic glycoprotein G-based assays when serol­ ogy is being performed. Sensitivity approaches 90 to 1 00 per­ cent, and speciicity is 99 to 1 00 percent (Wald, 2002) . IgM antibody detection is not a useful test.

• Management

In nonpregnant patients, antiviral therapy with acyclovir, vala­ cyclovir, or famciclovir is used to treat irst-episode genital herpes. Oral or parenteral preparations attenuate clinical infec­ tion and viral shedding duration. Suppressive therapy is also an option to limit recurrent infections and to reduce heterosexual transmission (Corey, 2004) . In pregnant women, acyclovir is safe (Briggs, 20 1 5) . Through 1 999, the manufacturers o f acyclovir and valacyclovir maintained a registry of outcomes following exposure to these drugs during pregnancy. More than 700 neonates exposed dur­ ing the irst trimester were evaluated, and there were no adverse efects attributable to acyclovir (Stone, 2004) . At this time, data are insuicient regarding famciclovir exposure, although a pregnancy registry is being maintained ( 1 -888-669-6682) . For a primary outbreak during pregnancy, women may be given antiviral therapy to attenuate and decrease the duration of symptoms and viral shedding (Table 65-4) . Women with HIV co-infection may require a longer duration of treatment. Those with severe or disseminated HSV are given IV acyclovir, 5 to 1 0 mg/kg every 8 hours for 2 to 7 days until clinically improved. This is followed by oral antiviral drugs to complete at least 1 0 days of total therapy (Workowski, 20 1 5) . For intense discomfort, oral analgesics and topical anesthetics may provide some relief, and comorbid urinary retention is treated with an indwelling bladder catheter. For recurrent HSV infections during pregnancy, antiviral treatment is provided mainly for symptom relief (see Table 65-4) . Although uncommon, acyclovir resistance has been reported, pre­ dominantly with HSV-2 and in immunocompromised patients (Andrei, 20 1 3) . During pregnancy, amniocentesis, percutaneous cord blood sampling, or transabdominal chorionic villus sampling may be performed even with active genital lesions. With active lesions, however, internal electronic monitoring during labor is not rec­ ommended. T ranscervical procedures may best be delayed until lesions have resolved (American College of Obstetricians and Gynecologists, 20 1 6b) . • Peripartum Shedding Prophylaxis

To diminish vertical transmission risks, cesarean delivery is indi­ cated for women with active genital lesions or prodromal symp­ toms (American College of Obstetricians and Gynecologists, 20 1 6b) . Several studies have shown that acyclovir or valacyclo­ vir suppression initiated at 36 weeks' gestation for gravidas with recurrences during pregnancy lowers the number of HSV out­ breaks at term. The goal is to decrease the need for cesarean deliv­ ery (Hollier, 2008) . his suppressive therapy will also decrease viral shedding (Scott, 2002; Sheield, 2006; Watts, 2003). One systematic review evaluated acyclovir prophylaxis given from 36 weeks to delivery to women with HSV recurrence during pregnancy. Sheield and colleagues (2003) found that suppressive therapy was associated with signiicantly lower rates of clinical HSV recurrence, cesarean deliveries for HSV recurrences, total HSV detection, and asymptomatic shedding. Subsequent stud­ ies using valacyclovir suppression have shown similar results (Andrews, 2006; Sheield, 2006) . Because of these studies, the

1 243

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Med ical a n d S u rg i cal C o m p l ications

TABLE 65-4. Ora l Antivi ra l Medications for Herpesvirus I nfection i n P reg n a n cya Indication

Pregna ncy Recom mendation

Pri m a ry or fi rst e p i sode i n fection

Acyclovir, 400 m g t h ree ti mes da i ly for 7- 1 0 d

Sym pto m ati c recu rre nt i nfecti o n (epi sod ic thera py)

or

Va l acyclovir, 1 9 twice d a i ly for 7-1 0 d ays

Acycl ov i r, 400 mg th ree t i m es d a i l y for 5 days or

Acyc l ov i r, 800 mg twice d a i ly for 5 d ays or

Acycl ovi r, 800 mg three ti mes d a i ly for 2 d or

Va l a cyclovir, 5 00 mg twice d a i ly for 3 days or

Da i ly s u p p ress i o n

Va l acyc l ov i r, 1 9 once d a i ly for 5 days

Acyclovir, 400 mg three ti mes daily from 36 weeks until del ivery or

Va lacycl ovi r, 500 mg twi ce d a i ly from 36 weeks u nt i l del ivery F a m c i cl ov i r not preferred d u ri ng preg na n cy d u e to fewer safety d ata. Data fro m Workows ki, 20 1 5 .

American College of Obstetricians and Gynecologists (20 1 6b) recommends viral therapy at or beyond 36 weeks for women who had primary genital herpes infection or active recurrent genital herpes during pregnancy. It is unclear whether suppres­ sion is needed for women with outbreaks before but not during pregnancy. Notably, despite maternal antiviral suppression, several cases of atypical neonatal herpes infection have been reported (Pinninti, 20 1 2) . O n presentation for delivery, a woman with a history of HSV should be questioned regarding prodromal symptoms such as vulvar burning or itching. A careful examination of the vulva, vagina, and cervix is performed, and women without gen­ ital lesions may proceed with labor and delivery. Use of a fetal scalp electrode can raise the transmission risk. But, electrode placement is reasonable if needed in the absence of active lesions (American College of Obstetricians and Gynecologists, 20 1 6b) . Suspicious lesions should be cultured or PCR tested. Cesar­ ean delivery is indicated for women with genital lesions or pro­ dromal symptoms. It is not recommended for women with a history of HSV infection but no active genital disease at the time of delivery. Moreover, an active lesion in a nongenital area is not an indication for cesarean delivery. Instead, an occlusive dressing is placed, and vaginal delivery is allowed. With preterm ruptured membranes, no evidence suggests that external lesions cause ascending fetal infection. Major and associ­ ates (2003) described expectant management of preterm prema­ ture membrane rupture in 29 women at gestational ages < 3 1 weeks. There were no cases o f neonatal HSV, and the maximum infection risk was calculated to be 1 0 percent. Antiviral treat­ ment is recommended. For women with a clinical recurrence at delivery, there is not an absolute duration of membrane rupture beyond which the fetus would not beneit from cesarean delivery (merican College of Obstetricians and Gynecologists, 20 1 6d) . Women with active HSV may breastfeed if there are no active breast lesions. Strict hand washing is essential. Valacyclovir and

acyclovir may be used for symptomatic maternal lesions during breastfeeding, as drug concentrations in breast milk are low. One study found the acyclovir concentration to be only 2 percent of that used for therapeutic dosing of the neonate (Sheield, 2002a) . CHANCROID Haemophilus ducryi can cause painul, nonindurated genital ulcers termed sot chancres. At times, these are accompanied by painul suppurative inguinal lymphadenopathy. Although com­ mon in some developing countries, only 1 1 cases were reported in the United States in 20 1 5 (Centers for Disease Control and Pre­ vention, 20 1 6c) . Appropriate media are not widely accessible, and no Food and Drug Administration (FDA)-cleared PCR test is yet available. Instead, painul genital ulcer(s) and negative screening for syphilis or HSV leads to a presumptive diagnosis. Treatment in pregnancy is azithromycin, 1 g orally as a single dose; erythro­ mycin base, 500 mg orally three times daily for 7 days; or cetriax­ one, 250 mg in a single intramuscular dose (Workowski, 20 1 5). HUMAN PAPILLOMAVIRUS This is a common STD, and more than 40 types infect the geni­ tal tract. In the United States from 2005 to 2006, the overall HPV prevalence was 40 percent in females aged 1 4 to 59 years (Liu, 20 1 6) . Prevalence is highest in younger women, and some of this seroprevalence now relects HPV vaccination in this age group (Brouwer, 20 1 5) . Most reproductive-aged women become infected within a few years of becoming sexually active, and most infections are asymptomatic and transient. High-risk types are those with the most oncogenic potential. Of these, HPV types 1 6 and 1 8 are oten associated with dysplasia (Chap. 63, p. 1 1 93). Mucocutaneous external genital warts termed con­ dyloma acuminata are usually caused by types 6 and 1 1 .

Sex u a l ly Tra n s m itted I n fecti o n s

For unknown reasons, genital warts frequently increase in number and size during pregnancy. hese lesions may some­ times grow to fill the vagina or cover the perineum, thus mak­ ing vaginal delivery or episiotomy diicult. Maternal HPV infection does not appear to be related to preterm labor (Sub­ ramaniam, 20 1 6) . • Condyloma Acuminata Treatment

Genital wart eradication during pregnancy is usually not neces­ sary unless they are symptomatic. herapy is directed toward debulking symptomatic warts yet minimizing treatment toxic­ ity to the mother and fetus. Several agents are available, but no deinitive evidence supports superiority of one over another (Workowski, 2 0 1 5). Response to treatment during pregnancy may be incomplete, but lesions frequently improve or regress rapidly following delivery. Trichloroacetic or bichloracetic acid, 80- to 90-percent solu­ tion, applied topically weekly, is an efective regimen for external warts. Some prefer cyotherapy, laser ablation, or surgical excision. Agents not recommended in pregnancy because of concerns for maternal and fetal safety include podophyllin resin, podoilox solution or gel, imiquimod cream, and sinecatechins. There are three vaccines available for long-term prevention. Gardasil (HPV4) is a quadrivalent vaccine against HPV types 6, 1 1 , 1 6, and 1 8 . his is being replaced by Gardasil 9 (HPV9), a nonavalent vaccine that protects against all the types in HPV4 plus types 3 1 , 33, 45, 52, and 5 8 . Cervarix (HPV2) is a biva­ lent vaccine against HPVs 1 6 and 1 8. One of these vaccines is selected and given as a three-dose series on a schedule of 0, 1 -2, and 6 months for those aged 1 5 to 26 years. A two-dose regimen, given at 0 and again at 6 to 1 2 months, is now recom­ mended for girls aged 9 to 1 4 years (Meites, 20 1 6) . Vaccines are licensed for females aged 9 to 26 years, and the target age is 1 1 to 1 2 years. he vaccines are not recommended for pregnant women, however, inadvertent exposures do occur. No adverse pregnancy outcomes are associated with the vaccines (Moreira, 20 1 6; Panagiotou, 20 1 5; Vichnin, 20 1 5) . If a woman is found to be pregnant after starting the vaccination series, the remain­ ing doses are delayed and given after delivery (American Col­ lege of Obstetricians and Gynecologists, 20 1 7a) . Women who are breastfeeding may receive the vaccine. • Neonatal Infection

Vertical transmission rates ofHPV to the newborn are minimal. Juvenile-onset recurrent respiratory papillomatosis QoRRP) is a rare, benign neoplasm of the larynx. It can cause hoarseness and respiratory distress in children and is most often caused by HPV 6 or 1 1 . Risks for infection are maternal genital HPV infection and longer labors (Niyibizi, 20 1 4) . Many newborns are likely exposed to HPV, but few develop JoRRP (Silverberg, 2003; Smith, 2004; Tenti, 1 999). For example, the national incidence of JoRRP in 2006 in the United States ranged from 0.5 to 1 per 1 00,000 children (Marsico, 20 1 4) . The beneit of cesarean delivery to decrease transmission risk is unknown, and thus it is currently not recommended solely to prevent HPV transmission (Workowski, 20 1 5). HPV vaccination may ultimately decrease JoRRP rates in the uture (Matys, 20 1 2) .

VAG I N ITIS Pregnant women frequently develop increased vaginal dis­ charge. his may be a physiological discharge, described in Chapter 4 (p. 5 1 ) , but should be diferentiated from symptom­ atic vaginitis, which is also common in pregnancy. Fortunately, vaginitis is prevented in part by normal vaginal lora. To better understand this, studies of the composition and function of the normal vaginal microflora are currently underway with the Vaginal H uman Microbiome Project (Huang, 20 1 4) .

• Bacterial Vaginosis Diagnosis

Not an infection in the ordinary sense, bacterial vaginosis (BY) is a maldistribution of normal vaginal flora. With BV, num­ bers of lactobacilli are decreased, and anaerobic bacteria spe­ cies are overrepresented. hese anaerobes include Gardnerela, Prevotela, Mobiluncus, and Bacteroides species; Atopobium vagi­ nae; and BV-associated bacteria, provisionally named BVAB 1 , BVAB2, and BVAB3. hese last three are newly recognized bacteria found in women with BV (Fredricks, 2005). Molecular ribosomal RNA gene sequencing techniques have greatly aided this understanding of the vaginal lora, also called the vaginal m icro biota. Five types of vaginal microbiota exist, referred to as communiy state ypes (eSTs). And, a woman can be categorized to one of these ive CSTs based on her vaginal microbiota composition (Ravel, 20 1 1 ) . Researchers have begun to quantiy the risk of BV by these CST groups. Speciically, CSTs I, II, III, and V are rich in lactobacilli. In contrast, CST IV is a heterogeneous microbiota of strict anaerobes and is asso­ ciated with BV. CSTs vary racially, and CST IV is also the most common in asymptomatic, healthy black women (Fett­ weis, 20 1 4) . Pregnancy-related changes in vaginal microbiota are also being defined and may hold keys to adverse BV-related pregnancy outcomes, discussed subsequently (Romero, 20 1 4) . O f childbearing-aged women i n the United States, nearly 30 percent have BV. In black women, the prevalence approximates 50 percent (llsworth, 2007) . Most women are asymptomatic, but a foul, thin vaginal discharge is a typical complaint. Associated risk factors are douching, multiple partners, smoking, and altered host immunity (Desseauve, 20 1 2; Koumans, 2007; Murphy, 20 1 6) . For clinical diagnosis of BV, three of the four following cri­ teria are present: ( 1 ) vaginal pH >4.5; (2) a thin, milky, non­ inlammatory vaginal discharge; (3) > 20 percent clue cells seen microscopically; and (4) a fishy odor ater addition of 1 0-percent potassium hydroxide to vaginal secretion samples (Amsel, 1 983) . The last is described as a positive "whif test." Likewise, alka­ linity of seminal fluid and blood are responsible for foul-odor complaints ater intercourse and with menses in afected women. Clue cells are vaginal epithelial cells containing many attached bacteria, which create a poorly deined stippled cellular border (Fig. 65-6) . he higher vaginal pH stems from diminished acid production by lactobacilli. Similarly, Trichomonas vaginalis infec­ tion is also associated with anaerobic overgrowth and resultant elaborated amines. hus, women diagnosed with BV should have no microscopic evidence of trichomoniasis (see Fig. 65-6) .

1 245

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M ed ica l and S u rg ical Co m pl i cati o n s

F I G U R E 65-6 A . Bacterial vag inosis. M i c roscopy revea ls severa l s q u a m o u s cel l s heavily studded with bacteria. C l u e cel l s a re covered to the extent that cel l borders a re b l u rred a n d n uclei a re not vis i b l e (arrows). B. Trichomonads (arrows). (Reprod u ced with perm ission from McCord E, Ra h n DO, Hoffm a n BL: Gynecologic i n fection. In Hoffm a n B L, Schorge JO, Bradshaw KD, et a l (ed s): Wi l l iams Gynecology, 3 rd ed. N ew York, McG raw H i l l Ed ucation, 20 1 6. P hoto contributors: La u ri Ca m p a g n a a nd Mercedes Pineda, W H N P.)

The Nugent score, used primarily in research studies rather than clinical practice, is a system employed for diagnosing BV (Nugent, 1 9 9 1 ) . During microscopic examination of a gram­ stained vaginal discharge smear, scores are calculated by assess­ ing bacteria staining and morphology. Treatment

Several adverse pregnancy-related health outcomes associated with BV are preterm birth, premature rupture of the mem­ branes, and postpartum endometritis (Hillier, 1 995; Leitich, 2003; Watts, 1 990) . It also increases susceptibility to STDs, including HIV (Atashili, 2008; Brotman, 20 1 0) . For women at low risk for preterm birth, however, treatment of BV does not reduce preterm birth rates (Brocklehurst, 20 1 3; Carey, 2000) . For high-risk women, evidence is conlicting. Currently, the American College of Obstetricians and Gynecologists (20 1 6c) , CDC, and U.S. Preventive Services Task Force do not rec­ ommend routine BV screening of asymptomatic gravidas-at either high or low risk for pre term delivery-to prevent pre­ term birth (Nygren, 2008; Workowski, 20 1 5) . Treatment is reserved for symptomatic women. Preferred drugs are metronidazole, 500 mg twice daily orally for 7 days; metronidazole 0.75-percent gel, one applicator intravaginally, daily for 5 days; or clindamycin 2-percent cream, one applicator intravaginally nightly for 7 days. Alternatives are clindamycin, 300 mg orally twice daily for 7 days, or 1 00-mg clindamycin ovules placed intravaginally nightly for 3 days (Workowski, 20 1 5) . It is still debated whether BV is a sexually transmitted infection. But, treatment of a male partner does not appear to lower recurrence rates (Amaya-G uio, 20 1 6) . • Trichomoniasis D i a g nosis

Vaginitis caused by Trichomonas vaginalis is common, and its prevalence in the United States approximates 3 percent in nonpregnant and pregnant women (llsworth, 2009; Satter-

white, 20 1 3) . The prevalence is higher in those older than 30 years compared with younger women. Risks include black race, douching, and greater number of lifetime sexual partners (Sut­ ton, 2007) . Among women, frequent sites of infection include the urethra, endocervix, and vagina. Symptomatic vaginitis is characterized by yellow purulent discharge, pruritus, vulvovagi­ nal erythema, and colpitis macularis, which is often termed a "strawberry cervix" and reflects a patchy, maculoerythematous ectocervix (W0Iner-Hanssen, 1 989) . Trichomonads are flagellated, pear-shaped, motile organ­ isms that are somewhat larger than leukocytes. These parasites can readily be seen microscopically moving briskly in a sample mixed on a slide with saline. Prompt inspection ofvaginal secre­ tions is advantageous because trichomonads slow with cooling. At times, T vaginalis may be found incidentally on a Pap test slide. Both of these microscopic slide tests have low diagnostic sensitivity that approximates only 60 percent (Krieger, 1 988; Wiese, 2000) . And, Pap tests can yield false-positive results. Thus, Pap test trichomonad indings warrant wet-prep micros­ copy or other diagnostic confirmation (American College of Obstetricians and Gynecologists, 20 1 7 c) . Of other tests, culture is expensive, lengthy, and sensitivities are 75 to 95 percent (Asso­ ciation of Public Health Laboratories, 20 1 6; Huppert, 2007) . Laboratory NAAT analysis of a vaginal, endocervical, or urine sample is available, is completed in minutes to hours, and ofers superior sensitivity of 95 to 1 00 percent (Schwebke, 20 1 1 ; Van Der Pol, 20 1 4) . Rapid POC testing is also available but may sacriice sensitivity for speed. The OSOi Trichomonas Rapid Test provides results in 1 0 minutes, is suitable for oice use, and has sensitivities of 88 to 98 percent (Herbst de Cortina, 20 1 6) . Treatment

Metronidazole, administered orally in a single 2-g dose, is efec­ tive in eradicating T vaginalis. For those with HIV infection, treatment instead with metronidazole 500 mg orally twice daily for 7 days improves eicacy. Because of the high rate of reinfection among women treated for trichomoniasis, retesting

Sex u a l ly Tra n s m itted I nfections

for T vaginalis is recommended for all sexually active women within 3 months following initial treatment (Workowski, 20 1 5) . Metronidazole, an FDA category B drug, is not teratogenic or fetotoxic, but has displayed some tumorigenicity in animal stud­ ies (Briggs, 20 1 5; Czeizel, 1 998) . For this reason, the manufac­ turer recommends against its use during the irst trimester (Pfizer, 20 1 6) . Fewer data are available for tinidazole, which is a category C drug, and thus metronidazole is preferred. vletronidazole and tinidazole have similar chemical structures, and those allergic to metronidazole may also react to tinidazole. For allergic patients, metronidazole desensitization is efective, and one scheme is out­ lined in the study by Helms and coworkers (2008). With post­ partum breastfeeding, feeds are delayed for 24 hours following the last oral metronidazole dose per manufacturer prescribing infor­ mation. For tinidazole, the delay is 72 hours. Perinatal transmission of trichomoniasis by direct contact in the birth canal is rare but may lead to neonatal respiratory or genital infection (Bruins, 20 1 3; Trintis, 20 1 0) . Some studies have linked trichomonal infection with preterm birth. A few other studies implicate this infection with preterm premature rupture of membranes and small-for-gestational age newborns (Silver, 20 14). However, treatment did not lower preterm birth rates in a randomized study by Klebanof and colleagues (200 1 ) . Also, i n this study, but not one b y Mann and coworkers (2009) , treatment for trichomoniasis was associated instead with a higher preterm birth rate. In sum, treatment for symptomatic women is reasonable and outlined above. For most asymptomatic women during preg­ nancy, screening is not recommended. However, for pregnant women with HIV infection, screening at the first prenatal visit and prompt treatment are encouraged. his is because T vaginalis infection in pregnant women with HIV may be a risk factor for vertical HIV transmission (Gumbo, 20 1 0; Workowski, 20 1 5). , • Candidiasis

Candida albicans or other candidal species can be identified by culture from the vagina during pregnancy in approximately 20 percent of women. A link between candidiasis and preterm birth is not robust (Cotch, 1 998; Kiss, 2004; Roberts, 20 1 5) . hus, asymptomatic colonization requires no treatment. he organism, however, can create an extremely profuse, irritating discharge. For symptoms, efective treatment is a 1 00-mg miconazole vaginal suppository or a 2-percent butoconazole, I -percent clotrimazole, 2-percent miconazole, or 0.4-percent terconazole cream, any of which is used daily for 7 days. A shorter, 3-day regimen is daily 2-percent clotrimazole, 4-percent miconazole, or 0 . 8-percent tioconazole cream, or daily 200-mg miconazole or 80-mg terconazole suppository (Workowski, 20 1 5) . In some women, infection is likely to recur and require repeated treat­ ment during pregnancy. In these cases, symptomatic infection usually subsides after pregnancy (Sobel, 2007) . For treatment, the American College of Obstetricians and Gynecologists (20 1 7 c) and the CDC recommend topical rather than oral azoles for symptoms. As discussed urther in Chapter 1 2 (p. 24 1 ) , oral fluconazole is generally not considered teratogenic, but in 20 1 6, the FDA released a safety alert regarding a possible link with miscarriage (M0Igaard-Nielsen, 20 1 6) .

H U MAN I MMUNODEFICIENCY VIRUS • Etiopathogenesis and Epidemiology

Causative agents of acquired immunodeficiency syndrome (AIDS) are RNA retroviruses termed human immunodiciency viruses, HIV-J and HIV-2. Most cases worldwide are caused by H IV- l infection. Sexual intercourse is the major mode of transmission. he virus also is passed by blood, and infected mothers may infect their fetuses during labor and delivery or by breast milk. he primary determinant of transmission is the plasma H IV- l viral load. For sexual transmission, the viral H IV envelope binds to mucosal dendritic cells. These cells then present the viral par­ ticle to specific T lymphocytes. These lymphocytes are defined phenotypically by their cluster ofdierentiation 4 (CD4) glyco­ protein surface antigens. The CD4 site serves as a receptor for the virus. Once infected, CD4 T lymphocytes may die, and the common denominator of clinical illness with AIDS is pro­ found immunodeficiency that gives rise to various opportunis­ tic infections and neoplasms. In the United States, the CDC (20 1 6c) estimated that more than 1 .2 million individuals were infected in 20 1 3, and new cases numbered more than 39,000. Approximately 8500 women with HIV give birth annually in the United S tates. However, the estimated number of perinatally acquired H IV cases has decreased dramatically, and the perinatal transmis­ sion rate in 20 1 3 was 1 .8 percent (Centers for Disease Control and Prevention, 2 0 1 6b, 20 1 7) . his is predominantly due to the implementation of prenatal HIV testing and antiretroviral therapy (ART) for the woman and then her neonate. • Clinical Manifestations

he incubation period from exposure to clinical disease aver­ ages 3 to 6 weeks. Acute HIV infection is similar to many other viral syndromes and usually lasts less than 1 0 days. Common symptoms, if any, include fever, fatigue, rash, headache, lymph­ adenopathy, pharyngitis, myalgias, nausea, and diarrhea. After symptoms abate, the level of viremia usually decreases to a set point, and patients with the highest viral burden at this time progress more rapidly to AIDS and death (Fauci, 2007) . Accord­ ing to the CDC, AIDS is defined by a CD4 T-cell count < 200 cells/lLL, by CD4 T-cells comprising < 14 percent of ali lympho­ cytes, or one of several AIDS-defining illnesses (Schneider, 2008; Selik, 20 1 4) . Route of infection, the pathogenicity of the infect­ ing viral strain, the initial viral inoculum, and the immunological status of the host all afect the rapidity of progression. • Prenatal HIV Screening

he CDC (2006b) and the American College of Obstetricians and Gynecologists (20 1 6e) recommend prenatal HIV screen­ ing using an opt-out approach. his means that a woman is notiied that HIV testing is included in a comprehensive set of antenatal tests, but that testing may be declined. Women are given information regarding HIV but are not required to sign a specific consent. hrough the use of such opt-out strategies, H IV testing rates have increased. Specifi c state laws concerning

1 24 7

1 248

M ed i ca l a n d S u rg ical Compl i cati ons

screening vary and can be found at: ww. cdc.gov/hiv/policies/ law/states/testing.html. Repeat testing during the third trimester, preferably before 36 weeks' gestation, is considered for all pregnant women. Retesting is recommended for those at risk for acquiring HIV or for women in high-risk areas, namely, those with rates of HIV infection of 1 per 1 000 pregnant women screened (Workowski, 20 1 5) . At-risk factors include injection drug use, prostitution, a suspected or known H IV-infected sexual partner, multiple sexual partners, or a diagnosis of another STD (American Col­ lege of Obstetricians and Gynecologists, 20 1 6e) . he initial laboratory screening test for H IV is an antigen/ antibody combination immunoassay that detects antibodies against HIV- 1 and HIV-2 and detects HIV- 1 p24 antigen (Centers for Disease Control and Prevention, 20 1 4) . Antibody can be detected in most patients within 1 month of infection, and thus, antibody serotesting may not exclude early infection. Instead, for acute primary HIV infection, identiication of viral p24 core antigen or viral RNA is possible. No further testing is required for specimens that are negative on the initial immuno­ assay unless a known exposure to HIV has occurred. As shown in Figure 65-7, specimens with a "reactive" (that is, a positive) antigen/antibody combination immunoassay result should be tested with an antibody immunoassay that diferen­ tiates H IV- 1 antibodies from HIV-2 antibodies. The HIV- 1 / H IV-2 antibody diferentiation immunoassay is resulted as positive or negative for HN- 1 antibodies, for HN-2 antibodies, or for H IV antibodies, undiferentiated. If these two serial

immunoassays are discordant, an H IV- 1 NAAT-qualitative or quantitative H IV RNA test-is performed (Centers for Dis­ ease Control and Prevention, 20 1 4) . Women with undocumented H IV status at delivery should have a fourth-generation H IV antigen/antibody combination screening test performed on a blood sample. A negative screen­ ing test result does not need confirmation. However, in cases of recent HIV exposure, consideration is given to peripartum interventions to reduce perinatal transmission despite negative HIV testing. Repeat interval testing is recommended to exclude very early infection not identified with the initial screen. With a positive fourth-generation HIV testing result, peripartum and neonatal interventions to reduce perinatal transmission are initi­ ated. This includes avoidance of breastfeeding, although breast milk may be stored until confirmatory test results are available. Interventions can be discontinued if confirmatory testing is neg­ ative. To confirm a positive result from any initial H IV test, the laboratory testing algorithm in Figure 65-7 should be used and begins with the antigen/antibody combination immunoassay. • Vertical Transmission

Viral burden and neonatal infection rates are directly related. In one cohort, neonatal infection was 1 percent with < 400 copies/mL, and it was 23 percent when maternal viral RNA levels were >30,000 copies/mL (Cooper, 2002) . Among 26 1 5 infants born to mothers taking ART before conception and during pregnancy, there were no cases of vertical transmission with maternal viral loads < 50 copies/ mL at delivery (Mandelbrot, 20 1 5) . Transmis­ HIV- 1 /2 antigen/antibody combination immunoassay sion of H IV infection, however, has been observed at all HIV RNA levels, including I those that were nondetectable by current . assays. Transplacental H IV transmission (+) (-) Negative for H IV-1 and H IV-2 can occur early, and the virus has even antibodies and p24 antigen been identifi e d in specimens from elective abortion (Lewis, 1 990) . Kourtis and col­ H IV- 1 /H IV-2 antibody differentiation immunoassay leagues (200 1 ) estimated that 20 percent of vertical transmission occurs before 36 weeks' gestation, 50 percent in the days H IV-1 (+) H IV-1 (-) H IV-1 (+) H IV-2 (-) H I V-2 (+) H I V-2 (+) before delivery, and 30 percent intrapar­ tum. Transmission rates for breastfeeding may be as high as 30 to 40 percent and H IV-1 NAAT are associated with increasing H IV viral I burden (Kourtis, 2006, 2007; Slyker, 20 1 2) . In nonpregnant individuals, con­ H IV-1 NAAT (+) H IV-1 NAAT (-) comitant STDs and horizontal H IV trans­ Acute H IV- 1 infection Negative for H IV-1 mission are linked. Evidence also supports that vertical transmission rates may be F I G U R E 65-7 Algorit h m for H IV testi ng. In the pathway colored l ig ht- b l u e, for specimens increased by comorbid STDs (Schulte, that a re reactive on the i n itial a ntigen/a nti body com bi n ation i m m u noassay a n d nonreac­ 200 1 ; Watts, 20 1 2) . tive or i ndeterm i nate o n the H IV- 1 /H IV-2 a ntibody d iferentiation i m m u n oassay, a n ucleic

!

+

a cid a m pl ification test (NAAT) is i m pleme nted . A positive H IV- 1 N AAT resu lt a n d nonreac­ tive H IV- 1 /H IV-2 antibody d ifferentiation i m m u noa ssay res u lt i nd i cate la boratory evidence for acute H IV- 1 infectio n . A positive H IV- 1 N AAT resu l t and indetermi n ate H IV- 1 /H IV-2 a nti body d iferentiation i m m u noassay result i n d icate the presence of H IV- 1 i nfecti on con­ fi rmed by H IV- 1 NAAT. A negative H IV- 1 N AAT res u lt a n d n o n reactive o r i n determ i nate H IV- 1 /H IV-2 a nti body d ifferentiation i m m u noassay result i nd icate a fa l se-positive result o n the i n itial a ntigen/a nti body com b i nation i m m u noassay. (Reprod u ced with perm ission from Centers for Disease Control a nd Prevention, 201 4.)

• Antepartum Care

Pregnant women with HIV infection need special attention and are seen in consultation by physicians with special interest in this field. An additional resource is the National

Sexu a l ly Tra n s m itted I nfections

Perinatal H IV Hotline (1-888-448-8765), which is a federally unded service that provides free antepartum, intrapartum, or post­ partum consultation to providers. At Parkland Hospital, an HIV­ infected pregnant woman is initially assessed with the following: •

•

• •

• •

•

•

Standard prenatal laboratory surveys that include serum cre­ atinine, complete blood count, and bacteriuria screening Plasma H IV RNA quantification-"viral load"-CD4 T-cell count, and antiretroviral resistance testing Serum hepatic aminotransferase levels HSV- 1 and 2, cytomegalovirus, toxoplasmosis, and hepatitis B and C serological screening Baseline chest radiograph Tuberculosis testing with puriied protein derivative (PPD) skin testing, or interferon-gamma release assay Evaluation of need for pneumococcal, hepatitis A, hepatitis B, T dap, and influenza vaccines Sonographic evaluation to establish gestational age.

During pregnancy, the risk of HIV transmission does not appear to be increased with amniocentesis or other invasive diag­ nostic procedures in women receiving efective ART resulting in viral suppression (Floridia, 20 1 7) . For women not receiving ART, the risk rises approximately twofold (Mandelbrot, 1 996) . If amniocentesis is performed, eforts are taken to avoid passing through the placenta (Panel on Treatment of HI V-Infected Preg­ nant Women and Prevention of Perinatal Transmission, 20 1 6) . A n t i retrovi ra l Thera py

In overview, the ideal strategy to suppress viral load and mini­ mize vertical HIV transmission includes: ( 1 ) preconceptional ART, (2) antepartum ART, (3) intrapartum continuation of the antepartum oral ART regimen plus IV zidovudine, and (4) newborn ART prophylxis. ART is recommended for all HIV­ infected pregnant women, and it should be initiated as early in pregnancy as possible. Treatment reduces the risk of perinatal transmission regardless of CD4 T-cell count or HIV RNA level. Adherence is essential because the risk of viral drug resistance is lessened. As for nonpregnant adults, pregnant women are treated with at least three antiviral agents. The Panel on Treatment of HI V-Infected Pregnant Women and Prevention of Perinatal Transmission (20 1 6) has issued guide­ lines for four diferent scenarios during pregnancy (Table 65-5) . h e following paragraphs summarize these recommendations. First, women already taking ART at pregnancy onset are encouraged to continue the regimen if viral suppression is ade­ quate. Didanosine, stavudine, and full-dose ritonavir, which difers from ritonavir-boosted agents, are exceptions due to preg­ nancy toxicity but not teratogenicity. Second, women who have never received antiretroviral therapy-antiretroviral nai've-are given ART regardless of trimester. In general, the starting regimen comprises two nucleoside reverse transcriptase inhibitors plus either a rito­ navir-boosted protease inhibitor or an integrase inhibitor. hird, women who have previously received antiretrovi­ ral therapy but are currently not taking medications should undergo H IV resistance testing because prior ART use raises their risk of drug resistance. Typically, ART is initiated prior to receiving results of these drug-resistance tests. In this case,

initial ART selection should factor results of prior resistance testing, if available; prior ART regimen; and current ART preg­ nancy guidelines, that is, those for ART-naive women. Drug­ resistance testing may then modiy the initial regimen. For these three categories of women taking antepartum ART, therapy surveillance is outlined in Table 65- 5 . Most patients with adequate viral response have at least a I -log viral load decline within 1 to 4 weeks after starting therapy. For those who fail to achieve this decline, options include review of drug resistance study results, confi r mation of regimen compli­ ance, and ART modiication. During labor and delivery, oral medications can be taken with sips of water. Additionally, IV zidovudine is given to women with an HIV RNA viral load > 1 000 copies/ mL or who have an unknown viral load near delivery. At Parkland Hospital, we administer intrapartum IV zidovudine to all HIV-positive women, regardless of viral load. A 2 mg/kg load is infused over 1 hour followed by zidovudine 1 mg/kg/hr until delivery. In this instance, for gravidas already taking antepar­ tum oral zidovudine, their oral dose can be held, and IV drug is instead administered. H IV-infected women undergoing a scheduled cesarean delivery are given IV zidovudine as a load­ ing dose followed by 2 more hours of continuous maintenance therapy-a total of 3 hours of infused zidovudine. he fourth group includes women who present in labor and who are taking no medications. hese women are given IV zid­ ovudine intrapartum as just described. • Delivery Planning

During labor, artificial membrane rupture, fetal scalp electrode placement, episiotomy, and operative vaginal delivery are reserved for clear obstetrical indications (Mandelbrot, 1 996; Peters, 20 1 6) . Labor augmentation i s used when needed to shorten the interval to delivery to further lower the transmission risk. Delayed cord clamping in preterm neonates is acceptable. Neuraxial analgesia is suitable. Postpartum hemorrhage is best managed with oxyto­ cin and prostaglandin analogues. Methylergonovine (Methergine) and other ergot alkaloids adversey interact with reverse transcriptase and protease inhibitors to cause severe vasoconstriction. In some cases, cesarean delivery lowers H IV prenatal trans­ mission (European Mode of Delivery Collaboration, 1 999; International Perinatal HIV Group, 1 999). The American College of Obstetricians and Gynecologists (20 1 7b) recom­ mends that scheduled cesarean delivery be discussed and rec­ ommended for H IV-infected women with HIV- 1 RNA loads > 1 000 copies/mL. Scheduled delivery is recommended at 38 weeks' gestation in these women to avert spontaneous labor. For women with HIV RNA levels � 1 000 copies/mL, data are insuicient to predict similar beneits, and scheduled cesar­ ean delivery is unlikely to confer additional risk reduction for women already taking ART and achieving viral suppression (Briand, 20 1 3; Jamieson, 2007; Read, 2005) . Vaginal delivery in this group may be elected. However, if cesarean delivery is instead chosen for a well-counseled woman in this group, it should be performed at 39 weeks. Similarly, cesarean delivery performed for obstetrical indications in this lower-viral-Ioad group should be done at 39 weeks when possible.

1 249

1 250

Med ical a nd S u rg ica l Co m p l i cati o n s

TABLE 65-5. Recom mendations for H IV Antiv i ra l D r u g U se D u r i n g Preg nancy Clinical Scenario

Recommendations

Ta ki ng ART a nd becomes preg n a nt

Conti n u e cu rrent m ed ication if vi r a l s u p p ression adequate and patient to lerati ng

ART na'(ve

I n itiate ART: com b i n e two N RTls with either a ritonavir-boosted PI or a n i nteg rase i n h i bitor - Prefer red N RTI d u a l co m b i nati o n s: a bacavir/l a m ivud i ne, tenofovi r d i so prox i l fu ma rate (TD F)!emtricita bi n e, or TDF/l a m ivu d i ne. If a bacavi r is u sed, H LA-B�'5 70 1 testi ng is com p leted to ide ntified pote n t i a l hype rse n s itivity reacti o n - Preferred P I : ataza navi r/rito navi r or d a r u navi r/ritonavi r - P referred i ntegrase i n h i b itor: ra lteg ravi r

Prior ART use but not cu rrently I n itiate ART with reg i me n based on prior thera py h i story a n d "esi sta nce test i n g No ART use a nd presents i n labor IV ZDV (see I ntra p a rtu m Ca re) Ante part u m ca re

See a ntepa rtu m scree n i n g test l i st (p. 1 249) ART s h o u l d be i n itiated as ea rly as possi b l e For t hose with H IV RNA l evels > 500- '1 000 copies/m L, o r d e r H IV a nt i retrovi ra l d rug­ res ista nce tes t i n g but do n ot d e l ay ART i n itiation awa i t i n g res u lts Re peat H IV RNA levels 2-4 weeks after i n itiati ng (o r c h a n g i ng) A RT d rugs; month ly unti l RNA l eve l s a re u n detecta ble; t h e n at l east every 3 mo; and fi n a l ly at 34-36 weeks' gestation for d e l ivery p l a n n i ng C D4+ cou nt s h o u l d be m o n itored at the i n itial visit a n d every 3 -6 mo

I ntra p a rt u m ca re

If H IV R N A level > 1 000 co p i es/ m L or is u n known before l a bor o r ROM, p l a n cesa rea n del ivery at 38 weeks' gestati o n If H IV RNA levels > 1 0 0 0 o r i s u n known but la bor or ROM h a s e n s ued, ben efits o f cesa rea n d e l ivery a re u nc l ea r a n d l a bor p l a n s a re i nd ivid u a l i zed If H IV RNA level :;1 000 copi es/m L, vag i n a l delivery is perm itted; cesa rea n d e l ivery not ro utinely recom m e n ded Sta rt IV ZDV if H IV RNA l evel > 1 000 copies/m L nea r del ivery o r is u n kn ow n . Dos i ng is 2 mg/kg IV load ove r 1 h r, then 1 mg/kg/hr u nt i l del ive ry. IV Z DV s h o u l d beg i n 3 h r befo re sched u l ed cesa rea n del ivery Those ta king ora l a ntepa rtu m ART s h o u l d take t h i s d u r i n g l a bor w it h s i ps of water

a nti retrovi ra l thera py; N RTI n u cleoside reverse t ra n scri pta se i n h i bitor; ROM = ru ptu re of m e m b ra nes; ART ZDV zidovud i ne. Ada pted fro m the P a n e l on Treatment of H IV-I nfected P reg n a nt Wo men a n d P reve ntion of Perinatal Tra n s m ission, 20 1 6. De partment of Health a n d H u ma n Services. =

=

=

• Postpartum Care

Vertical transmission is increased by breastfeeding, and it gen­ erally is not recommended for H IV-positive women in the United States, where formula is readily available (Read, 2003) . In nutritionally deprived countries, where infectious disease and malnutrition are primary causes of infant death, the World Health Organization (20 1 6) recommends exclusive breastfeeding during the first 6 to 1 2 months. he Panel on Treatment of HI V-Infected Pregnant Women and Prevention of Perinatal Transmission (20 1 6) strongly rec­ ommends that ART regimens not be discontinued postpartum but continued lifelong for the advantages of viral suppression. Ideally, all those planning pregnancy should be receiving ART and have a plasma viral load below detectable levels before conception. As one benefit, interpregnancy viral load suppres­ sion is associated with less vertical transmission in a subsequent pregnancy (French, 20 1 4; Mandelbrot, 20 1 5; Stewart, 20 1 4; Townsend, 20 1 4) . Reassuringly, for those seeking subsequent pregnancy, when ART is available, repeated pregnancy in a

healthy woman with HIV has no signiicant efect on disease progression (Calvert, 20 1 5) . Linkage to general HIV care post­ partum is critical to maintain viral suppression (Swain, 20 1 6) . For women who do not have H IV infection, but whose partner is seropositive, current guidance supports the use of highly active antiretroviral therapy with viral suppression in the infected partner (treatment as prevention) , and consideration of antiretroviral preexposure prophylaxis (PreP) for the HIV­ negative partner. The well-counseled couple can consider peri­ ovulatory condomless intercourse, or uterine insemination or in vitro fertilization after sperm washing for assisted conception (Brooks, 20 1 7; Kawwass, 20 1 7) . If, instead, pregnancy is undesired, efective contraception is discussed (Chap. 38, p. 680) . Counseling also includes education for decreasing high-risk sexual behaviors to prevent transmission and to decrease other STD acquisition. Similarly, women with HIV have unique gynecological issues, such as genital neoplasia, which require special attention (American College of Obstetri­ cians and Gynecologists, 20 1 6a; Werner, 20 1 6) .

Sexua l ly Tra n s m itted I nfections

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1 25 5

APPEN DIX

I . S E R U M A N D B LOOD CONSTITUE NTS . . . . . . . . . . . . . . . 1 255 II. MATERNAL ECHOCARDIOGRAPHIC MEASU REMENTS I I I . F ETA L S O N O G R A P H I C M EA S U R E M ENTS . . .

.

.

. . 1 26 1

. . . . . . . . 1 262

A P P E N D I X I. Seru m and Blood Constituents H EMATO LOGY

Erythropoietin b (U/L) Ferritin b (n g/m L) Folate, red blood cell (ng/m L) Folate, seru m (ng/m L) Haptoglobin (mg/m L) Hemoglobin b (g/d L) Hematocriti J (%) I ron, tota l binding capacity (TI BC) b (.Lg/d L) I ron, serum b (Lg/d L) Mean corpuscular hemog lobin (MCH) (pg/c e l l ) Mea n corpuscular vol u me (MCV) ( x m 3 ) Platelet ( x 1 09/ L) Mean platelet vol u m e (M PV) (Lm3) Red blood cell count (RBC) ( x 1 OO/m m3) Red cel l d istri bution width ( RDW) (%) Wh ite blood cell count (WBC) ( x 1 03/m m3) Neutrophils (x 1 03/m m3) Lym phocytes ( x 1 03/m m3) Monocytes ( x 1 03/m m3) Eosi nophils (x 1 03/m m3) Basophils ( x 1 03/m m3) Tra nsferri n (mg/d L) Tra nsferrin, sat u ration without i ron (%) Tra nsferrin, sat u ration with i ron (%)

Non preg nant Adu lta

1 st Trimester

2nd Trimester

3 rd Tri mester

4-2 7 1 0- 1 5 0d 1 5 0-450

1 2-25 6- 1 30 1 3 7-589

8-67 2-230 94-828

1 4-2 2 2 0- 1 1 6 1 09-663

5 .4- 1 8.0 2 5-250 1 2- 1 5.8d 3 5 .4-44.4 2 5 1 -406

2 .6- 1 5 .0 1 30 ± 43 1 1 .6- 1 3 .9 3 1 .0-4 1 .0 2 78-403

0.8-24.0 1 1 5 ± 50 9.7-1 4.8 30.0-39.0 Not re ported

1 .4-20.7 1 3 5 ± 65 9.5- 1 5 .0 28.0-40.0 359-609

7, 43, 45, 46, 5 3 , 58, 7 2 26A 1 0, 45, 47, 5 8, 62 6, 7, 1 0, 42, 45 5 8, 66 62

41 - 1 4 1 2 7-3 2

72- 1 43 30-32

44- 1 78 30-3 3

30- 1 93 2 9-32

1 0, 62 42

79-93

8 1 -96

82-97

8 1 -99

6, 42, 45, 5 8

1 65-4 1 5 6.4- 1 1 .0

1 74-39 1 7.7- 1 0.3

1 55-409 7.8- 1 0.2

1 46-429 8.2- 1 0.4

4, 6, 1 6, 42, 45 42

4.00-5 .20

3 .42-4 . 5 5

2.8 1 -4.49

2 . 7 1 -4.43

6, 42, 45, 5 8

< 1 4. 5

1 2.5 - 1 4. 1

1 3 .4- 1 3 .6

1 2 .7- 1 5 .3

42

3.5-9. 1

5 . 7- 1 3 .6

5 .6- 1 4.8

5 .9- 1 6.9

6, 9, 42, 45 , 5 8

1 .4-4.6 0.7-4.6 0. 1 -0. 7 0-0.6 0-0.2 200-400c 22-46b

3.6- 1 0. 1 1 . 1 -3.6 0. 1 - 1 . 1 0-0.6 0-0. 1 2 54-344 N ot re ported

3 .8- 1 2.3 0.9-3 .9 0. 1 - 1 . 1 0-0.6 0-0 . 1 220-44 1 1 0-44

3.9- 1 3 . 1 1 .0-3.6 0. 1 - 1 .4 0-0.6 0-0. 1 288-5 3 0 5-37

4, 6, 9, 42 4, 6, 9, 42 6, 9, 42 6, 9 6, 9 3 9, 42 47

2 2-46b

Not reported

1 8-92

9-98

47

References 7, 1 0, 47

� l Q 3� 42, 45, 4� 62, 70 45, 46, 72

1 256

Append ix

COAGU LATION

Antithrombin I I I, fu nctional (%) D-Dimer (1g/m L) Factor V (%) Factor VII (%) Factor VIII (%) Factor IX (%) Factor XI (%) Factor X I I (%) Fibri nogen (mg/d L) Fibronectin (mg/L) Homocysteine (1mol/L) I nternational norma l ized ratio (l N R) Partial throm boplastin ti me, activated (a PTI) (sec) Prothrombin time ( PT) (sec) Protei n C, fu nctional (%) Protei n 5, total (%) Protei n 5, free (%) Protei n 5, fu nctional activity (%) Throm bin time (TI) (sec) Thrombomod u l i n (ng/m L) Tissue plas m inogen activator (ng/m L) Tissue plasmi nogen activator i n h i b itor- 1 ( ng/m L) von Wil lebrand d isease von Wi l l ebrand factor antigen (%) ADAMT5- 1 3, von Wi l lebra nd cleaving protease (%)

Nonpreg nant Ad u lta

1 st Tri mester

2nd Tri mester

3rd Trimester

References

70- 1 3 0

89- 1 1 4

78- 1 26

82- 1 1 6

1 5, 1 6, 39A

0.22-0.74 50- 1 5 0 50- 1 50 50- 1 50 50- 1 50 50- 1 50 50- 1 5 0 233-496 290 ± 85 4.4- 1 0.8 0.9- 1 .049

0.05-0.95 75-95 1 00- 1 46 90-2 1 0 1 03- 1 72 80- 1 2 7 78- 1 24 244-5 1 0 3 7 7 ± 3 09 3.34- 1 1 0.86- 1 .08

0.3 2- 1 .29 72-96 95- 1 5 3 97-3 1 2 1 54-2 1 7 82- 1 44 90- 1 5 1 2 9 1 -538 3 1 5 ± 295 2.0-26.9 0.83- 1 .02

0. 1 3- 1 .7 60-88 1 49-2 1 1 0 1 43-3 5 3 1 64-23 5 65- 1 23 1 29- 1 94 3 0 1 -696 3 34 ± 2 5 7 3 .2-2 1 .4 0 .80- 1 .09

1 6, 25, 25C, 35, 39A, 4 1 A, 5 1 40 16 1 6, 40 16 16 16 1 6, 25, 25C, 39A, 4 1 A, 42, 5 1 27A 43, 45, 46, 5 3 , 7 2 1 5, 41 A

26.3-39.4

2 3.0-3 8.9

22.9-38. 1

22.6-35 .0

1 5 , 1 6, 4 1 A, 42

1 2.7- 1 5 .4

9.7- 1 3 .5

9.5- 1 3 .4

9.6- 1 2.9

1 6, 4 1 A, 42

70- 1 30 70- 1 40 70- 1 40 65- 1 40

78- 1 2 1 3 9- 1 05 34- 1 3 3 5 7-95

83- 1 3 3 27- ·1 0 1 1 9- 1 1 3 42-68

67- 1 3 5 3 3- 1 0 1 20-65 1 6-42

1 5, 24, 40 1 6, 24, 40 24, 40 40

1 7 .7 ± 2.8 2.7 ± 3. 1 1 .6- 1 3h

1 6. 1 ± 1 .5 4.3 ± 1 .3 1 .8-6.0

1 5 .4 ± 2.7 4.2 ± 1 .2 2.36-6.6

1 6.5 ± 2 .4 3 .6 ± 1 .3 3 .34-9.20

27A 27A 1 5, 1 6, 25C

4-43

1 6- 3 3

36-55

6 7-92

1 6, 25C

75- 1 2 5

62-3 1 8

90-247

84-422

39A, 44A, 73

40- 1 701

40- 1 60

22- 1 3 5

3 8- 1 05

39A, 44A

Serum a n d Bl ood Constitue nts

BLOOD C H E M ICAL CONSTITUTE NTS

Non pregnant Ad u lta Alanine a m i n otra nsferase (ALT) ( U/L) Albu m i n (g/d L) A l ka l ine phosphatase ( U / L) Al pha-1 antitrypsin (m g/d L) Alpha-fetoprotei n (n g/m U Ammonia (�M) Amylase (U/L) Anion gap ( m m o l/L) Aspa rtate a m i n otra n sferase (AST) (U/L) Bicarbonate (m m o l/L) B i l i ru bin, tota l (mg/d L) B i l i ru bin, u n conj ugated (mg/d L) Biliru b i n, conj ugated (mg/d U Bile acids (�mo l/L) CA- 1 25 (�g/m L) Ca lcium, ion ized (mg/d L) Ca lci um, total (mg/d L) Ceru lopla s m i n (m g/d L) Chloride (m Eq/L) Creati n i n e ( mg/d L) Gam ma-gl utamyl tra nspeptidase (GGT) ( U /L) Lactate dehydrogenase ( U /L) Li pase (U/L) Magnes i u m (m g/d L) Osmolal ity (mOs m/kg H2O) Phosphate (mg/d L) Potass i u m (m Eq/L) Prea l b u m i n (m g/d L) Protei n, tota l (g/d L) Sod i u m (m Eq/L) Urea n itrogen (m g/d L) Uric acid (mg/d L)

7-4 1 4. 1 -5 .3 3 3-96

d

1 00-200

1 st Trimester

2nd Trimester

3 rd Trimester

References

3-30

2-33

2-25

5, 3 9, 42, 70

3 . 1 -5 . 1 1 7-88

2.6-4.5 2 5 - 1 26

2.3-4.2 38-229

3, 5, 26, 2 9, 3 9, 42, 7 2 3, 5, 3 9, 42, 70

225-323

273-3 9 1

3 27-487

42

" 1 3 0-400

" 1 30-590

39B

3 1 ± 3.2 20-96 7- 1 6 1 2-38

24-83 1 3- 1 7 3-23

1 6-73 1 2-1 6 3-33

2 7.3 ± 1 .6 1 5-8 1 1 2- 1 6 4-32

31A 32, 3 9, 42, 68 42 5, 3 9, 42, 70

2 2-30 0.3- 1 .3 0.2-0.9

20-24 0. 1 -0.4 0. 1 -0.5

20-24 0. 1 -0.8 0. 1 -0.4

20-24 0.1 - 1 . 1 0 . 1 -0.5

42 5, 39 5, 42

0. 1 -0.4

0-0. 1

0-0. 1

0-0 . 1

5

0.3-4.BJ 7.2-27 4.5-5 .3 8.7- 1 0.2 2 5-6 3 1 02 - 1 09 0.5-0.9d 9-58

0-4.9 2 .2-268 4.5-5 . 1 8.8- 1 0.6 30-49 1 0 1 - 1 05 0.4-0.7 2-23

0-9. 1 1 2-25 . 1 4.4-5.0 8.2-9.0 40- 5 3 97- 1 09 0.4-0.8 4-22

0- 1 1 .3 1 6.8-43 .8 4.4-5 .3 8.2-9.7 43-78 97- 1 09 0.4-0.9 3-26

5, 1 4 3A, 3 0A, 67A 2 6, 42, 48, 56 3, 29, 3 9, 42, 48, 5 6, 6 3 42, 44 20, 3 9, 42 39, 42, 45 5, 42, 39, 70

1 1 5-2 2 1

78-433

80-447

82-5 24

42, 2 9, 3 9, 70

3-43 1 .5-2.3 275-295 2 .5-4.3 3 .5-5.0 1 7-34 6.7-8.6 1 36- 1 46 7-20 2.5-5.6d

2 1 - 76 1 .6-2.2 2 75-280 3 . 1 -4.6 3 .6-5 .0 1 5-27 6.2-7.6 1 3 3- 1 48 7-1 2 2 .0-4.2

26- 1 00 1 .5-2.2 2 76-289 2.5-4.6 3 .3-5.0 20-27 5. 7-6.9 1 29- 1 48 3-1 3 2 .4-4.9

41-1 1 2 1 . 1 -2.2 2 78-280 2.8-4.6 3 .3-5 . 1 1 4-23 5.6-6.7 1 30- 1 48 3- 1 1 3 . 1 -6.3

32 3, 26, 29, 3 9, 42, 48, 63 1 7, 63 3, 26, 3 3 , 3 9, 42 20, 26, 29, 3 9, 42, 63, 66 42 26, 29, 42 1 7, 26, 29, 3 9, 42, 63, 66 20, 3 9, 42 1 7, 39, 42

1 257

1 258

Appe n d ix

M ETABOLIC A N D E N DOCRI N E TESTS

Aldosterone (ng/d L) Angiotensi n-converting enzyme (ACE) (U/L) Cortisol (19/d L) Hemog lobin AlC (%) Parathyroid hormone (pg/m L) Parathyroi d hormonerelated protein ( p m o l/L) Ren i n, plasma activity (ng/m L/ h r) Thyroid sti m u lating hormone (TSH) (.1I U/m L) Thyroxi ne-bi nding globu l i n (mg/d L) Thyroxi ne, free (T4) (ng/d L) Thyroxi n e, tota l (T4) (.1g/d L) Tri iodothyroni ne, free (fT3 ) (pg/m L) Tri iodothyronine, tota l (T3 ) (ng/d L)

Non preg nant Adu lta

1 st Tri m ester

2 nd Trimester

3rd Tri mester

References

2-9 9-67

6- 1 04 1 -3 8

9- 1 04 1 -36

1 5- 1 0 1 1 -3 9

2 1 , 34, 69 20, 54

0-2 5 4-6 8-5 1

7- 1 9 4-6 1 0- 1 5

1 0-42 4-6 1 8-25

1 2-50 4-7 9-26

42, 69 48, 49, 5 9 3

< l .3e

0.7-0.9

1 .8-2.2

2 .5-2.8

3

0.3-9.0e

N ot re ported

7.5-54.0

5 .9-5 8.8

20, 34

0.34-4.25

0.60-3 .40

0.37-3 .60

0.38-4.04

39, 42, 5 7

1 .3-3.0

1 .8- 3. 2

2.8-4.0

2 .6-4.2

42

0.8- 1 . 7

0.8- 1 .2

0.6- 1 .0

0 . 5-0.8

42, 5 7

5 .4- 1 1 .7

6.5- 1 0. 1

7 . 5 - 1 0.3

6. 3-9. 7

29, 42

2.4-4.2

4. 1 -4.4

4.0-4.2

N ot reported

57

77- 1 35

97- 1 49

1 1 7- 1 69

1 23- 1 62

42

Non preg nant Adu lta

1 st Tri m ester

2nd Tri mester

3rd Tri mester

References

70- 1 40 63-1 60 20- 1 00

1 1 2- 1 99 1 1 6- 1 46 3 2 -47

1 65-22 1 7 5 - 1 45 3 5-44

1 30-240 7 1 -1 33 2 9-42

2, 30, 42 2, 42 42

2 79-966 0.4- 1 .0

1 1 8-438 N ot reported

1 30-656 Not reported

99-5 26 0.9- 1 .3

45, 72 64

25-45

20-65

72-1 60

60- 1 1 9

3, 48

0.5-5 .0e

1 .2 - 1 .8

1 . 1 - 1 .5

0.7-0.9

60

1 4-80

1 8-27

1 0-2 2

1 0- 1 8

3, 60

5-1 8

7- 1 3

1 0- 1 6

1 3-23

42

75- 1 20

5 7-88

5 1 -80

50-77

2, 42, 5 8

VITAM I N S A N D M I N E RALS

Copper (1g/d L) Selen i u m (.19/L) Vita m i n A (reti nol) (1g/d L) Vita m i n B 1 2 (pg/m L) Vita m i n C (ascorbic acid) (mg/d L) Vita m i n � 1 ,25-d i hyd roxy (pg/m L) Vita m i n 0, 24,25-d i hydroxy (ng/m L) Vita m i n 0, 25-hydroxy (ng/m L) Vita m i n E (x-tocop herol) (1g/m L) Zinc (.1g/d L)

Seru m a n d B l ood Const i t u e nts

AUTO I M M U N E A N D I N F LAM MATORY M E DI ATO RS

(3 com p lement ( m g /d L) C4 com plement (mg/d L) C-reactive protein (CRP) (mg/U Erythrocyte sed imentation rate (ESR) (m m/h r) IgA (mg/d L) IgG (mg/d L) IgM (mg/d U

Non preg nant Ad u lta

1 st Tri mester

2nd Trimester

3 rd Trimester

References

83- 1 7 7 1 6-47 0.2- 3.0

62-98 1 8-36 N ot re ported

7 3 - 1 03 1 8-34 0.4-20.3

77- 1 1 1 22·-32 0.4-8. 1

42 42 28

0-20d

4--5 7

7-47

1 3-70

71

70-3 50 700- 1 700 50-300

95-243 98 1 - 1 267 78-232

99-2 3 7 8 1 3- 1 1 3 1 74-2 1 8

1 1 2-250 678-990 85-269

42 42 42

Non preg nant Ad u le

1 st Trimester

2nd Trimester

3 rd Trimester

References

1 .3-6.8e

2 .0- 1 6.5

0.9-7.8

0.8-6. 5

52

< 20-443 dJ < 1 -20d 0-20 d 1 8- 1 1 4d

1 88--2497 8-48 36-2 1 3 3 9- 1 3 1

1 2 78-7 1 92 1 1 0-330 2 1 4-7 1 7

6 1 3 7-3460 99-342 1 3 7-3 72 2 1 6-724

1 .3 , 5 2 1 3, 52 3, 1 3, 38, 49 1 , 52

6 - 86 d 0.6- 1 O.6d.e

25 .7-2 1 1 .4 5 .2-28.5

34. 3-242.9 5 .2-28.5

62.9-308.6 1 5 .5-84

52 52

Non preg nant Adu lta

1 st Trimester

2nd Trimester

3 rd Tri mester

References

< 200 40-60 < 1 00 6-40e < 1 50 1 1 9-240

1 4 1 -2 1 0 40-78 60- 1 5 3 1 0- 1 8 40- 1 5 9 1 1 1 - 1 50

1 76-299 52-87 77- 1 84 1 3-23 75-382 1 42-253

2 1 9-349 48-87 1 0 1 -2 24 2 1 -36 1 3 1 -453 1 45-262

8, 1 8, 3 1 , 42 8, 1 8, 3 1 , 42, 55 8, 1 8, 3 1 , 42, 5 5 31 8, 1 8, 3 1 , 3 9, 42, 5 5 1 8, 3 9, 49

52- 1 63

58-81

66- 1 88

85-2 38

1 8, 3 9, 49

Non preg nant Ad u lta

1 st Trimester

2nd Tri mester

3rd Trimester

References

Not re ported

N ot reported

28. 1 -70. 1

N ot reported

11

22 ± 1 0

22 ± 1 0

32 ± 1 5

31 ± 21

1 2A

3 9-238d < 6k 50 ± 26 0-0.08

2 7-83 Not reported 60 ± 45 N ot reported

25-75 Not reported 60 ± 40 Not re ported

1 3- 1 0 1 1 .8-2 .4 43 ± 34 0-0.064 (i ntra pa rt u m )

4 1 , 42 41 1 2A 36, 65

SEX H O R M O N E S

Dehyd roepiandrosterone su lfate ( D H EAS) (�mol/L) Estrad iol (pg/m U Progesterone (ng/m L) Prolactin (ng/m L) Sex hormone binding g l o b u l i n ( n m o l/L) Testosterone ( n g/d L) 1 7-Hydroxyprogesterone ( n m o l/L)

L I P I DS

Cholesterol, tota l (mg/d U HDL-cholesterol (mg/d L) LDL-cholesterol (mg/d L) VLDL-cholesterol (mg/dL) Trig lycerides (mg/d L) Apoli poprotei n A-I ( mg/d L) Apo l i poprotein B (mg/d U

CARDIAC

Atrial natriu retic peptide (AN P) ( p g / m L) B-type natri u retic peptide ( B N P) (pg/m U Creati n e ki nase (U/U Creatine ki nase-MB (U/L) NT-pro-BN P (pg/m L) Troponin I ( n g/m L)

1 25 9

1 260

A p pe n d ix

B LOOD GAS

Bicarbonate (HC0 3 -) (m Eq/L) Peo2 ( m m Hg) P02 ( m m H g ) pH

Nonpregnant Adu lta

1 st Trimester

2nd Trimester

3rd Trimester

References

22-26

N ot reported

N ot reported

1 6-22

23

38-42 90- 1 00 7.38-7.42 (a rte ria l)

N ot reported 93- 1 00 7.36-7.5 2 (ve n o u s)

N ot reported 90-98 7 .40-7. 5 2 (ve n o u s)

25-33 92- 1 07 7.4 1 -7. 5 3 (ven o u s) 7.39-7.45 (arterial)

23 23, 67 23, 26

Non preg nant Adu lta 492-696d,=

1 st Trimester

2nd Trimester

3rd Tri mester

References

696-985

6 1 2- 1 1 70

595-945

1 9, 22

1 06- 1 32 d

1 3 1 - 1 66

1 3 5 - 1 70

1 1 7- 1 82

1 9, 22, 5 0

1 6.9-24.1 ' 5 00-800

1 4.7-2 1 .6 3 26-975

1 4.3-2 1 .9 278- 1 066

1 7. 1 -2 5 . 1 2 3 8- 1 034

1 9, 22, 5 0 61

< 30

5-1 5

4- 1 8

3-22

2 7, 6 1

< 7. 5 e

1 .6-5 .2

0.3-6.9

0.8-4.2

66

9 1 - 1 30

69- 1 40

5 5- 1 36

5 0- 1 66

22, 66

8.8- 1 4e

1 0.6- 1 1 .6

1 0. 3- 1 1 .5

1 0.2- 1 1 .4

61

2 5 - 1 00e

1 7- 3 3

1 0-38

1 1 -3 5

66

< 1 50

1 9- 1 4 1

47- 1 86

46- 1 85

27

1 00-260e

5 3 -2 1 5

34-2 1 3

3 7- 1 49

1 7, 66

RENAL F U N CTION TESTS

Effective renal plasma flow ( m L/m i n) G lomeru lar fi ltration rate (GFR) ( m Um i n) Fi ltration fraction (%) Osmolarity, u r i n e (mOs m/kg) 24-hr a l b u m i n excretion (mg/24 h r) 24-hr calci u m excretion ( m mo1/24 h r) 24- hr creat i n i n e clearance (m L/m i n) 24-hr creat i n i n e excretion ( m m o 1/24 h r) 24-hr potassi u m excretion ( m m o 1/24 h r) 24-hr protein excretion (mg/24 h r) 24-hr sod i u m excretion ( m mol/24 h r)

a U n less othe rwise s pecified, a l l n o r m a l refe rence va l u es a re fro m the seventee nth ed ition of Harrison 's Principles of Internal Medicine (37).

bRa nge i ncl udes refe re nces with and without i ron s u p p l e m e ntation . (Refere n ce va l ues a re fro m Laboratory Reference Handbook, Path o l ogy Depa rtme nt, Parkl a n d Hospita l , 2005 . dNorm a l refe rence ra n g e is s pecifi c ra nge for fem a les. =Refe rence va l u e s a re from the 1 5th ed ition of Harrison 's Principles of Intenal Medicine ( 1 2). fRange i s for pre m e n o p a u s a l fem a les and varies by m e n st ru a l cycle p hase. 9 Reference va l ues a re fro m Cerneca et a l : Coag u l ation a n d fi b r i n olysis cha nges i n nor m a l preg na ncy i ncreased levels of procoag u l a nts a nd red uced leve l s of i n h i b itors d u ri ng p reg n a n cy i n d uce a hype rcoa g u l a b l e state, com bi ned with a reactive fi brino lysis ( 1 5). h Reference va l ues a re fro m Cerneca et a l and C h o i et al: Tissue p l a s m i n ogen a ctivato r leve l s change with plasma fi bri nogen concentrations d u ri n g p reg n a ncy ( 1 5, 1 6) . ' Reference va l ues a re from Ma n n u cci e t a l : C h a nges i n h e a lt h a n d d i sease o f t h e meta l loprotease t h a t cleaves von W i l l e bra n d facto r (44A). j Refe rence va l ues a re fro m Bacq et a l : Liver fu n ction tests i n n o r m a l p reg nancy: a prospective study of 1 02 p reg n a n t wo men a n d 1 02 m atch ed contro l s (5) . kRefe rence va l ues a re fro m Lei serowitz et a l : Creat i n e ki n ase a n d its MB i soenzyme in the t h i rd tri mester a n d t h e peri partu m period (4 1 ) . ' Refe rence va l u es a re from D u n lop: Seri a l c h a nges i n ren a l h a e m odyna m ics d u ri n g norm a l h u m a n preg na ncy ( 1 9) . Appendix cou rtesy of D r. M i na Abbassi-G h a n avati a n d D r. La u ra G. Greer.

Matern a l Echoca rd iog ra ph ic Measurements

A P P E N D I X I I . Mate rna l Ech oca rd i o g ra p h ic Measurements Preg na ncy 1 st Trimester

2nd Tri mester

3rd Tri mester

Postpa rt u m

Geometry IVSd ( m m) LVE D D ( m m) LVESD ( m m ) PWd RVT LV m a s s (g) LV mass (g/m2)

7 .3 ± 1 .0 45 -47.8 28-30 6.3 ± 0.7 0.26-0.36 1 1 1 -1 21 66 ± 1 3

7.4 ± 1 . 1 47-48.9 2 9- 3 0. 1 6.6 ± 0.7 0.27-0 . 3 7 1 2 1 - 1 35 70 ± 1 2

7.8 ± 1 .2 47-49.6 3 0-30.8 6.9 ± 1 .0 0.28-0.38 1 36- 1 5 1 76 ± 1 6

7. 1 ± 0.9 46-48.8 2 8-30.6 6. 1 ± 0.6 0.2 5-0.35 1 1 4- 1 1 9 67 ± 1 1

Systol ic fu nction FS (%) SW th i cken i ng (%) PW t h i c ke n i n g (%) VCFC (ci rc/sec) ESS (g/cm2)

3 7-38 47 ± 1 7 66 ± 1 6 1 . 1 5-0.3 59 ± 9

76-78 53 ± 1 6 72 ± 1 6 1 . 1 8-0. 1 6 53 ± 1 1

80-85 51 ± 15 74 ± 1 6 1 . 1 8-0. 1 2 52 ± 1 1

6 7-69 54 ± 1 9 71 ± 14 1 . 1 8-0. ·1 2 66 ± 1 2

75-76 0.85 ± 0. 1 3 0.5 ± 0.09 1 76 ± 44 90 ± 1 9 263 ± 50 454 ± 1 2 1

76-78 0.84 ± 0. 1 6 0.5 ± 0.1 1 88 ± 40 79 ± 1 8 2 7 6 ± 43 4 1 2 ± 79

80-85 0.77 ± 0 . 1 5 0.55 ± 0. 1 1 93 ± 3 3 72 ± 1 6 282 ± 37 3 75 ± 63

6 7-69 0.77 ± 0. 1 1 0.46 ± 0. 1 2 0 1 ± 48 69 ± 1 0 288 ± 48 523 ± 88

Left Ventricle

Diastolic fu nction Hea rt rate M it ra l E wave (m/sec) Mitra l A wave (m/sec) Decel e ration t i m e (ms) IVRT (ms) E wave d u ration (ms) E and A wave d u ration (ms)

Va l ues a re ra nges o r mea n s ± S D. ci rcu mferen ce; d d iasto l i c; ESS = end-systo l ic wa l l stress; FS fra ct i o n a l s ho rte n i ng; IVRT i sovol u m i c relaxati o n C i rc i nterventricular septu m-d iastole; LV let ventricle; LVEDD left ventricu l a r end-diasto l ic d i mension; LVES D = time; IVSd let ventri c u l a r end-systo l i c d i me n s ion; PW posterior wa l l; RWT re l at ive wa l l t h i cke n i ng; SW = septa l wa l l; VCFC rate-adj u sted mea n ve locity of c i rcu mfe rentia l fi ber th icken i ng. Data from Savu (62A) a n d Vita re l l i ( 7 1 A) . =

=

=

=

=

=

=

=

=

=

1 26 1

1 262

A p pe n d ix

A P P E N DIX I I I . Fetal Sonogra p h i c Mea s u rements TA B L E 1 1 1-1 . Mean Gestational Sac Dia meter and Crown-Ru m p Length a n d Correspond i ng Menstrual Age Menstrual A g e (day) 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84

Menstrua l Age (wk) 4J 4.6 4.9 5. 1 5 .4 5.7 6.0 6J 6.6 6.9 7. 1 7.4 7.7 8.0 8.3 8.6 8.9 9. 1 9.4 9.7 1 0.0 1 0J 1 0.6 1 0.9 1 1 .1 1 1 .4 1 1 .7 1 2.0

Gestational Sac S ize (mm) 3 5 6 8 10 12 14 16 18 20 22 24 26 27 29 31 33 35 37 39 41 43 45 47 49

5 '1

53

Crown-Ru m p Length (em)

0.2 OJ5 0.5 0.7 0.9 1 .0 1 .2 1 .4 1 .6 1 .8 2.0 2 .2 2 .4 2 .6 2.9 3.1 3 .4 3.7 4.0 4.2 4.6 5 .0 5 .4

Data from Nyberg, 1 992; Had lock, 1 992; Robi nson; 1 975; Daya, 1 99 1 .

Feta l So n o g ra p h ic Mea s u re m ents

TABLE 1 1 1 - 2. Mea n Gestational Age Percenti les Co rrespo n d i n g to Crown -Ru m p Length (C RL) Mea s u rements Gestational Age (wk)

Gestational Age (wk)

--

CRL (m m) 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29

� 5th

50th

6 + 5 6+6 7 + 1 7 + 2 7 + 3 7 +4 7 + 5 8 8+ 1 8 + 2 8 + 3 8+4 8 + 5 8+6 8+6 9 9+ 1 9 + 2 9 + 3 9+4

7 + 3 7+4 7 + 5 8 8+4 8 + 2 8 + 3 8+4 8 + 5 8 + 6 9 9+ 1 9 + 2 9+3 9+4 9+ 5 9+6 10

10 + 1 10 + 2

95th 8 8 8 8 8 9

9

+ + + +

2 3 4 6

+ 1 9+2 9 + 3 9+4 9+5 9+6 10 10 + 1 10 + 2 10 + 3 10 + 4 10 + 5 10 + 5 10 + 6

Percentile

CRL (m m)

5th

50th

95th

30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

9 + 5 9 + 5 9 + 6 10 10 + 1 10 + 2 10 + 2 10 + 3 10 + 4 10 + 5 10 + 5 10 + 6 11 11 1 "1 + 1 11 + 2 11 + 2 11 + 3 11 +4 11 +4

10 + 2 10 + 3 10 + 4 10 + 5 10 + 6 10 + 6 11 11 + 1 11 +2 11 +2 11 + 3 11 +4 11 +4 11 +5 11 +6 11 +6 12 12 + 1 12 + 1 11 +2

11 11 + 1 11 + 2 11 + 2 11 + 3 11 + 4 11 + 5 11 + 6 11 + 6 12 12 + 1 12+ 1 12+ 2 12 + 3 12 + 3 12 + 4 12 + 5 12 + 5 12 + 6 13

1 263

1 264

A p pe n d i x

TA B L E 1 1 1-3. Feta l Wei g ht Percenti les Accord i n g to Gestati o n a l Age Fetal Weight Percenti les (g)

G est a t"lona I Age (wk)

3rd

1 0th

50th

90th

97th

10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

26 34 43 54 69 87 1 09 1 35 1 66 204 247 298 357 424 5 00 5 86 681 787 903 1 029 1 1 63 1 306 1 45 7 1 61 3 1 773 1 936 2098 2259 24 1 4 2563 2 700 2825 2935

29 37 48 61 77 97 1 21 1 50 1 85 227 275 331 3 97 472 556 652 758 8 76 1 005 1 1 45 1 294 1 454 1 62 1 1 795 1 97 3 2 1 54 2335 25 1 4 2687 2852 3 004 3 1 44 3 266

35 45 58 73 93 1 17 1 46 1 81 223 273 331 3 99 478 5 68 670 785 91 3 1 05 5 1 21 0 1 3 79 1 5 59 1 75 1 1 95 3 2 1 62 2377 2595 281 3 3028 3 2 36 3435 361 9 3787 3934

41 53 68 85 1 09 1 37 1 71 21 2 26 1 319 387 467 559 664 784 91 8 1 068 1 2 34 1 41 5 1 61 3 1 824 2048 2285 2529 2781 3 026 3291 3 542 3 785 40 1 8 4234 4430 4602

44 56 73 92 1 17 1 47 1 83 227 280 342 41 5 500 599 71 2 840 984 1 1 45 1 32 3 1 51 7 '1 729 1 95 5 2 1 96 2449 271 1 298 1 3254 3 5 28 3797 4058 4307 4538 4749 4933

Ada pted with perm ission fro m H a d l oc k, 1 99 1 .

Feta l Sonogra ph i c Mea s u re m e nts

TABLE 1 1 1-4. Smoothed B i rth Weight Percenti les for Twins with Dichorionic Placentation S moothed B i rth Weight Percenti les GA (wk) 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

5th

1 0th

50th

90th

95th

477 538 606 684 771 870 980 1 1 02 1 235 1 3 74 1515 1 65 3 1 78 1 1 892 1 989 2079 2 1 67 2258 2352

513 5 78 65 2 735 829 935 1 054 1 1 86 1 328 1 477 1 630 1 778 1 91 6 2035 2 1 39 2236 233 1 2428 2530

632 71 2 803 906 1 02 1 1 1 52 1 298 1 460 1 63 5 1819 2007 2 1 90 2359 2506 2634 2753 2870 2990 31 1 5

757 853 962 1 085 1 223 1 3 79 1 5 54 1 748 1 958 2 1 79 2403 2622 2825 3 00 1 3 1 55 3297 3437 358 1 373 1

80 1 903 1 01 8 1 1 48 1 294 1 45 9 1 645 1 850 2072 2306 2543 2 775 2989 3 1 76 3339 3489 3637 3 790 3 948

GA gestationa l age. Rep rod u ced with pe rmission from Ananth, 1 998. =

TABLE 1 1 1-5. Smoothed B i rth Wei g ht Percenti les for Twi ns with Monochorionic Placentati o n Smoothed B i rth Weight Percentiles GA (wk)

5th

1 0th

50th

90th

95th

23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

392 456 5 30 61 5 71 3 823 944 1 072 1 204 1 335 1 45 7 1 562 1 646 1 728 1 83 1 1 95 7 2 1 00 2255 2422

43 1 501 582 676 784 904 1 03 7 1 1 78 1 3 23 1 467 1 60 1 1 71 6 1 808 1 899 20 1 2 2 1 50 2307 2478 266 1

533 620 720 836 970 1 1 19 1 282 1 45 7 1 63 7 1814 1 980 2 1 23 223 7 2 349 2489 2660 2854 3 065 3292

648 753 875 1017 1 1 78 1 360 1 5 59 1 77 1 1 990 2205 2407 2580 271 9 2855 3025 3233 3469 3 726 400 1

683 794 922 1 07 2 1 242 1 43 3 1 643 1 867 2097 2325 2537 2 720 2866 3009 3 1 89 3408 3657 3927 42 1 7

Re p rod u ced with perm ission from Ana nth, 1 998.

1 265

1 266

Appendix

TABLE 1 1 1 -6. Feta l Thoracic Circu mfere n ce Measu rements (cm) Accord i n g to Gestational Age G esta t·lana I Age (wk) 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40

Predictive Percentiles No.

2.5

5

10

25

50

75

90

95

97.5

6 22 31 21 20 30 18 21 27 20 25 24 24 24 27 24 28 27 25 20 23 22 21 7 6

5 .9 6.8 7.7 8.6 9.6 1 0.4 1 1 .3 1 2.2 1 3.2 1 4. 1 1 5 .0 1 5 .9 1 6.8 1 7.7 1 8.6 1 9.5 20.4 2 1 .3 22.2 23.1 24.0 24.8 25.9 26.8 2 7 .7

6.4 7.3 8.2 9.1 1 0.0 1 1 .0 1 1 .9 1 2 .8 1 3.7 1 4.6 1 5 .5 1 6.4 1 7.3 1 8.2 1 9. 1 20.0 20.9 2 1 .8 2 2 .8 23.7 24.6 25.5 26.4 27.3 28.2

7.0 7.9 8.8 9.7 1 0.6 1 1 .6 1 2 .5 1 3 .4 1 4.3 1 5 .2 1 6. 1 1 7.0 1 7 .9 1 8.8 1 9. 7 20.6 2 1 .5 22.5 2 3 .4 24.3 25.2 2 6. 1 2 7.0 27.9 28.8

8.0 8.9 9.8 1 0.7 1 1 .7 1 2.6 1 3 .5 1 4.4 1 5 .3 1 6.2 1 7. 1 1 8.0 1 8.9 1 9.8 20.7 2 1 .6 22.6 2 3 .5 24.4 25.3 26.2 27.1 28.0 28.9 29.8

9. 1 1 0.0 1 '1 .0 1 1 .9 1 2.8 1 3 .7 1 4.6 1 5 .5 1 6.4 1 7.3 1 8.2 1 9. 1 20.0 2 1 .0 2 1 .9 22.8 23.7 24.6 2 5 .5 26.4 27.3 28.2 29. 1 30.0 30.9

1 0.3 1 1 .2 1 2. 1 1 3 .0 1 3 .9 1 4.8 1 5 .7 1 6.6 1 7.5 1 8.4 1 9.3 20.2 2 1 .2 22.1 23 .0 2 3 .9 24.8 25.7 26.6 27.5 28.4 29.3 30.2 31 .1 32.1

1 1 .3 1 2.2 1 3. 1 1 4.0 1 5 .0 1 5 .8 1 6.7 1 7.6 1 8.5 1 9.4 20.3 2 1 .3 22.2 23.1 24.0 24.9 2 5 .8 26.7 2 7 .6 28.5 29.4 30.3 3 1 .2 32.2 33.1

1 1 .9 1 2.8 1 3 .7 1 4.6 1 5 .5 1 6.4 1 7.3 1 8.2 1 9. 1 20.0 2 1 .0 2 1 .9 2 2.8 23.7 24.6 25.5 26.4 27.3 28.2 29. 1 30.0 30.9 3 1 .9 3 2.8 33.7

1 2 .4 1 3 .3 1 4.2 1 5. 1 1 6.0 1 6.9 1 7.8 1 8.8 1 9.7 20.6 2 1 .5 22.4 23.3 24.2 25.1 26.0 26.9 2 7.8 28.7 29.6 30.6 3 1 .5 32.4 33.3 34.2

Re p r od uced with perm ission from Ch itka ra, 1 987.

Feta l Sonog ra p h ic Meas u re m e nts

TA B L E 1 1 1-7. Length o f Feta l L o n g B o n e s ( m m ) Accord i n g t o Gestational Age H u merus Percenti le

U l na Percentile

Rad i u s Percenti le

Femur Percentile

Tibia Percentile

---

---

---

---

---

Fi bula Percent i l e

Week

5

50

95

5

50

95

5

15

95

5

50

95

5

50

95

5

50

95

15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40

11 12 19

18 21 24 27 29 32 34 36 38 41 43 45 46 48 50 52 53 55 56 57 58 60 61 61 62 63

26 25 29 30 36 36 40 40 45 46 51 49 51 52 56 56 59 59 62 62 65 63 64 66 69 69

10

16 19 21 24 26 29 31 33 35 37 39 41 43 44 46 47 49 50 52 53 54 55 56 57 57 58

22 24 32 30 32 32 36 37 43 41 44 44 48 48 51 54 59 58 60 59 61 61 62 63 66 65

12 9 11 14 20 2 '1 25 24 26 27 31 30 33 33 36 34 34 37 41 39 38 41 45 45 46 46

15 18 20 22 24 27 29 31

19 21 29 26 29 28 32 34 39 38 40 41 45 45 47 49 53 51 51 53 57 54 53 53 54 54

11 13 20 19 23 22 27 29 35 34 38 39 45 45 49 49 53 53 56 57 61 61 64 62 64 66

19 22 25 28 31 33 36 39 41 44 46 49 51 53 56 58 60 62 64 65 67 69 71 72 74 75

26 24 29 31 38 39 45 44 48 49 54 53 57 57 62 62

5 7 15 14 19 19 24 25 30 28 31 33 39 38 40 41 46 46 49 47 48 49 52 54 58 58

16 19 22 24 27 29 32 34 36 39 41 43 45 47 49 51 52 54 56 57 59 60 61 62 64 65

27 25 29 29 35 35 39 39 43 45 50 49 51 52 57 56 58 59 62 64 69 68 71 69 69 69

10 6 7 10 18 18 24 21 23 26 33 32 35 36 40 38 40 40 43 46 51 51 55 54 55 54

14 17 19 22 24 27 29 31 33 35 37 39 41 43 45 47 48 50 51 52 54 55 56 57 58 59

18 22 31 28 30 30 34 37 44 41 42 43 47 47 50 52 57 56 59 56 57 56 58 59 62 62

18

22 23 28 28 32 31 35 36 42 41 44 44 47 47 5 50 52 53 57

55 56 56

8 11 13 20 21 25 24 27 29 34 34 37 37 40 38 39 40 43 44 47 47 49 48 49 50

Rep rod u ced with permission fro m Jea nty, 1 983,

32

34 36 37 39 40 42 43 44 45 46 47 48 48 49 49 50 50

67

67 71 70

73 74 77 79 83 81

1 26 7

1 268

Appe n d ix

TA B L E 1 1 1-8. O c u l a r Parameters Accord i n g to Gestational Age B i nocu lar Distance (mm)

I nterocu l a r Distance (mm)

---

---

Age (wk)

5th

50th

95th

5th

50th

95th

15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40

15 17 19 22 24 26 28 30 31 33 35 36 38 39 41 42 43 45 46 47 48 49 50 50 51 52

22 25 27 29 31 33 35 37 39 41 42 44 45 47 48 50 51 52 53 54 55 56 57 58 59 59

30 32 34 37 39 41 43 44 46 48 50 51 53 54 56 57 58 60 61 62 63 64 65 65 66 67

6 6 6 7 7 8 8 9 9 10 10 11 11 12 12 13 13 14 14 15 15 16 16 17 17 18

10 10 11 11

14 15 15 16 16 17 17 18 18 19 19 20 20 21 21 22 22 23 23 24 24 25 25 26 26 26

Ada pted with perm ission from Romero R , 1 988.

12

12 13 13 14 14 15 15 16 16 17 17 18 18 19 19 20 20 21 21 22 22

Ocu lar Diam eter (mm) 5th 4 5

50th

5

6 7 8

7 8 8 9 10 10 11 12 12 13 13 14 14 14 15 15 15 16 1 16 16 16

9 10 11 12 12 13 13 14 14 15 15 16 16 17 17 17 18 18 18 18 19 19

6

9

95th 9 9

10 11 12 13 13 14 15 15 16 16 17 17 18 18 19 19 19 20 20 20 21 21 21 21

Feta l Sonogra p h ic Measure ments

TA BLE 1 1 1-9. Tra nsverse Cerebe l l a r Diameter Measurements Accord i n g to Gestational Age Cerebel l u m Diam eter (mm)

G esta t"lona I Age (wk)

10

15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39

10 14 16 17 18 18 19 21 22 22 23 25 26 27 29 31 32 33 32 33 31 36 37 40 52

25 12 16 16 17 18 19 20 23 23 24 2 1 .5 28 28.5 30 32 32 35 36 36 38 37 29 37 40 52

50 14 16 17 18 19 19 22 23 24 25 28 29 30 31 34 35 38 38 40 40 40.5 43 45 48.5 52

Ada pted with permission from Go ldste i n, 1 987.

75 15 16 17 18 19 20 23 24 25 27 28 30 31 32 36 37 39 40 43 41 43 52 52 52 55

.

90 16 17 18 19 22 22 24 24 26 28 29 32 32 34 38 40 43 42 44 44 47 55 55 55 55

1 269

1 270

Appe n d ix

TA BLE 1 1 1-1 0. Reference Va l u es for U m b i l ical Artery Doppler I n d ices

16 17 18 19 20 21 22 23 24 25 26 27 28 29

30 31 32 33 34 35 36 37 38 39 40 41 42

0.70 0.69 0.68 0.67 0.66 0.65 0.64 0.63 0.62 0.6 1 0.60 0.59 0.58 0.57 0.56 0.5 5 0.54 0.53 0.52 0.5 1 0.50 049 0.47 0.46 0 45 0.44 0.43 .

3. 39 3.27 3.1 6 3 .06 2 .97 2 .88 2.79 2.7 1 2.64 2.57 2.50 2 44 2.38 2.32 2.26 2.2 1 2.1 6 2.1 1 2 .07 2 .03 1 .98 1 . 94 1 .90 1 .87 1 .83 1 .80 1 .76

5.1 2 4 . 86 4.63 4.4 1 4.2 2 4 . 04 3 .88 3 . 73 3 .59 3 .46 3 34 3 .22 3.1 2 3 .02 2 .93 2 .84 2.76 2 .68 2 .6 1 2.54 2 47 2 .4 1 2.35 2.30 2 . 24 2.1 9 2. 1 4

0.80 0.79 0.78 0.77 0.76 0.75 0 74 0.73 0.72 0.7 1 0.70 0.69 0.68 0.67 0.66 0.65 0.64 0.63 0.62 0.6 1 0.60 0.59 0.57 0.56 0.55 0.54 0.53 .

.

.

0.90 0.89 0.88 0.87 0.86 0.85 0 . 84 0.83 0.82 0.8 1 0.80 0.79 0.78 0.77 0.76 0.75 0 . 74 0.73 0.72 0.7 1 0.70 0.69 0.67 0.66 0.65 0.64 0.63

1 0. 50 9 46 8.6 1 7.90 7. 30 6.78 6.3 3 5 . 94 5 .59 5 .28 5 .0 1 4.76 4 53 4.3 3 4. '1 4 3 .97 3 .8 1 3 .66 3.53 3 40 3.29 3. 1 8 3 .08 2 .98 2 .89 2.8 1 2.73 .

.

GA gestati o n a l age. Ada pted with perm i ss i o n from Kofn a s A D, 1 992. =

A P P E N D I X R E F E RE N C E S Acromite MT, Mantzoros CS, Leach E , et al: Androgens i n preeclamp­ sia. m J Obstet Gynecol 1 80 :60, 1 999 2. Alvarez S1, Castanon SG, Ruata MLC, et al : Updating of normal levels of copper, zinc and selenium in serum of pregnant women. J Trace Elem Med BioI 2 1 (S l ) :49, 200 2A. Ananth CV, Vintzileos, Shen-Schwarz S, et al: Standards of birth weight in rwin gestations. Obstet Gynecol 91 :9 1 7, 1 998 3. Ardawi MSM, Nasrat HAN, BA'Aqueel HS: Calcium-regulating hormones and parathyroid hormone-related peptide in normal human pregnancy and postpartum: a longitudinal study. Eur J Endocrinol 1 3 :402, 1 997 3A. Aslam N, Ong C, Woelfer B, et al: Serum CA ] 25 at 1 1 - 1 4 weeks of gestation in women with morphologically normal ovaries. BJOG 1 07(5): 689, 2000 4. Aziz Karim S, Khurshid M, Rizvi JH, et al: Platelets and leucocyte counts in pregnancy. J Pak Med Assoc 42:86, 1 992 5 . Bacq Y , Zarka 0, Brechot JF, e t a l : Liver function tests in normal preg­ nancy: a prospective study of 1 02 pregnant women and 1 02 matched controls. Hepatology 23: 1 030, 1 996 6. Balloch AJ, Cauchi MN: Reference ranges for haematology parameters in pregnancy derived from patient populations. Clin Lab HaematoI 1 5 :7, 1 993 1.

7.

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57.

65.

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IN DEX Note: Page references for igures are indicated by , for tables by

22q 1 1 .2 microdeletion syndrome, 260-26 1 39-week rule, 648-649, 804 45,X (Turner syndrome) , 39, 259 cystic hygroma, 1 9 euploid abortion, 347 fetal-growth restriction, 352 monosomy, 258 46,XX disorders of sex development, 39t, 40-4 1 46,X gonadal dysgenesis, 40 46,XX ovotesticular, 40 46,X testicular, 40 androgen excess, 40-4 1 ovarian development, 40 46,XY disorders of sex development, 39, 39t 46,XY gonadal dysgenesis, 39-40 androgen production or action, 40 mixed gonadal dysgenesis, 40 partial gonadal dysgenesis, 40 pure gonadal dysgenesis, 40 testicular regression, 40 47,XXY (Klinefelter syndrome), 39, 259-260 47,yy, 260 A

ABCD4 gene, 1 0 59 ABCDIl gene, 1 059 Abdominal circumference (AC) ratio, sonography, 1 85 Abdominal imaging, fetal M Rl , 2 1 8-2 1 9, 2 1 9/ Abdominal incisional infections, postpartum, 670-67 1 , 670/ vacuum-assisted wound closure, 670-67 1 wound dehiscence, 67 1 Abdominal pregnancy, 383-384 Abdominal wall, 53 diastasis recti, 53 striae gravidarum, 53 Abdominal wall imaging, fetal normal and anomalies body-stalk anomaly, 206 gastroschisis, 205, 206/ jujenal atresia, 205 normal, 205, 206/ omphalocele, 20 5-206, 206/ sonography, 205-206 body stalk anomaly, 206 ABO blood group incompatibility, 302, 303 Abortion, 346-364 anticoagulation, 1 0 1 5 coagulopathies, 787 definition, 346 elective, 357 euploid, 347 nomenclature, 346-347 partial birth, 363 postabortal contraception, 364 septic, 347 from IUD, 684

t.

Abortion (Cont.): therapeutic, 357 tubal, 372 Abortion, induced, 3 5 7-364 classiication, 357 consequences, 364 deinition, 346, 3 5 7 irst-trimester methods, medical, 361-362, 362t irst-trimester methods, surgical, 358-36 1 complications, 360-36 1 hygroscopic dilators, 358-3 59, 3 5 8/ misoprostol, 3 5 9 preoperative preparation, 3 5 8-3 59, 3 5 8] 3 5 9/ vacuum aspiration, 3 5 9-360, 360/ second-trimester methods, 362-364 dilation and evacuation, 362-363 dilation and extraction, 363 fetal and placental evaluation, 364 intact D & E, 363 medical, 363-364 in U.S. legal influences, 357-3 58 provider availability, 358 rate, 4, 3 5 7 Abortion, midtrimester, 353-357 cevical insuiciency, 354-3 57 (See aso Cervical insuiciency) incidence and etiology, 353-354, 354t management, 354 Abortion, spontaneous (miscarriage), 347 alcohol, 348 anembryonic, 347 cafeine, 348 cancer, 348 clinically silent vs. apparent, 347 deinition, 346, 347 embryonic, 347 irst-trimester, 347-352 clinical classiication anti-D immunoglobulin, 352 complete, 349, 350t incomplete, 349 inevitable, 3 5 1 missed, 349-3 5 1 , 350] 350t septic, 35 1 -3 5 2 threatened, 348-349, 349t fetal factors, 347 incidence, 347 maternal factors, 347-348 paternal factors, 348 pathogenesis, 347 multifetal pregnancy, 8 7 1 nutrition, 348 occupational and environmental factors, 348 pregestational diabetes, 1 099 recurrent, 347, 352-353, 352t, 353t smoking, 348

Abortion ratio, 357 Abortus, deined, 3 Abrupt baseline spiking, 462, 464/ Abruption, placental, 76 -773. See aLso Placental abruption Abruptio placentae. See Placental abruption Absence seizures, 1 1 5 9 Abuse physical, 925-926, 926t sexual, 926, 926t Acardiac myelacephalus, 880 Acardiac twin, 880-8 8 1 , 880] 88 1/ fetoscopic radiofrequency ablation for, 326 Acardius acephalus, 880 Acardius amorphus, 880, 8 8 1/ Acceleration, fetal heart rate, 464, 465 nonstress tests, 335, 335/ Accelerator influences, fetal heart fate, 459, 460t Accidents. See aLso Trauma automobile, 926-927, 927/ Accrete syndromes, 777-782. See aLso Morbidly adherent placenta ACE-inhibitor fetopathy, 24 1 Acetaminophen overdose hepatotoxicity, 1 06 8 Achalasia, 1 046- 1 047 Achondrodysplasia, 2 1 1 Acid-base equilibrium, maternal, 65 Bohr efect, 65 physiological dyspnea, 65 respiratory efort, 65 Acid-base physiology, fetal, 6 1 1 -6 1 2, 6 1 2/ Acid-base studies neonatal encephalopathy, 62 1 umbilical cord blood, 6 1 1 , 6 1 2t umbilical cord blood gas determinations, 613 Acidemia fetal clinical signiicance, 6 1 2-6 1 3, 6 1 2t metabolic, 6 1 1 mixed respiratory-metabolic, 6 1 1 nomogram, 6 1 1 -6 1 2, 6 1 2/ respiratory, 6 1 1 newborn, 6 1 2-6 1 3, 6 1 2t metabolic, 6 1 3 respiratory, 6 1 3 Acitretin, teratogenicity, 245-246 Acne vulgaris, 1 1 87 Acoustic stimulation tests, fetal, 335, 337 Acrania, sonography, 1 92/ Acromegaly, 1 1 33 Acromelia, 2 1 1 Actin-myosin interactions, parturition, 404, 405/ Actinomyces israeLii, I U D infection, 684 Activated factor VII , recombinant, for hemorrhage, 790 Activated protein C, 60, 60t

1 273

1 274

I n dex Activated protein C resistance thrombophilia, 1 00 5/ 1 006t, 1 007 Active management of labor, 438 Active phase, labor, 432, 432/ 433-434, 433/ abnormalities, 433-434 disorders, neuraxial analgesia, 445-446, 445t prolongation, 442-446 Active-phase arrest, 442, 443-444, 443/ 443t oxytocin for, 5 1 0-5 1 1 Active-phase prolongation, labor, 442-446 6-cm rule vs. 4-cm, 444 background, 444t-446t, 445-446, 445/ 446/ arrest disorder, 442, 443-444, 443/ 443t Obstetric Care Consensus Committee, 444, 444/ protraction disorder, 442 , 443 , 443t, 444 Sae Prevention 0/the Primay Cesarean Delivey, 442 second-stage descent disorders, 446-447 Activin, placental, 99t, 1 02 Acute chest syndrome, with sickle-cell disease, 1 082 Acute cortical necrosis, 1 037 placental abruption, 772 Acute fatty liver of pregnancy, 722, 1 060-1 062, 1 060/ 1 06 1 t diabetes insipidus, 1 1 33 Acute fatty metamorphosis, 1 060-1 062, 1 060/ 1 06 1 t Acute kidney injury (AKI) , 1 036-1 037 criteria and incidence, 1 036 diagnosis and management, 1 036-1 037 etiology, 1 036 obstructive renal failure, 1 037, 1 037/ placental abruption, 7 2 preeclampsia, 720, 1 036 prevention, 1 037 Acute myocardial infarction, 968-969, 969/ Acute respiratory distress syndrome (ARDS), 9 1 8-92 1 clinical course, 9 1 9, 9 1 9/ criteria, 9 1 8 definitions, 9 1 8 etiopathogenesis, 9 1 8-9 1 9, 9 1 8t extracorporeal membrane oxygenation, 920 management, 9 1 9 mechanical ventilation, 9 1 9-92 1 extracorporeal membrane oxygenation, 920 fetal oxygenation, 920, 920/ IV luids, 920-92 1 long-term outcomes, 92 1 positive end-expiratory pressure, 920 Acute tubular necrosis, in preeclampsia, 720 Acute yellow atrophy, 1 060- 1 062, 1 060/ 1 06 1 t Acyclovir, for herpes simplex virus, 1 243, 1 244t Adalimumab for Crohn disease, 1 05 1 for rheumatoid arthritis, 1 1 47 for ulcerative colitis, 1 050 Adamantanes, 1 2 1 4 Addison disease, placental estrogen biosynthesis, 1 06 Addisonian pernicious anemia, 10 8 Adenomyosis, 1 1 9 Adenovirus, 1 2 1 6 Adhesions, from cesarean delivery, 578 intestinal obstruction from, 1 0 5 1 - 1 0 52, 1 052/

Adiana insert, 705- 06 Adipocytokines, 5 1 , 936. See aso speciic ypes Adipokines, 845, 936. See also speciic ypes Adiponectin, 5 1 , 56 Admission for birth, fetal monitoring, low-risk pregnancies, 469-4 0 Adnexal abscesses, postpartum, 67 1 Adnexal cysts, 1 200 Adnexal mass, asymptomatic, in pregnancy, 1 1 98- 1 1 99 Adrenal cortical hypoplasia, fetal, placental estrogen biosynthesis, 1 05 Adrenal crisis, salt-wasting, 3 1 7 Adrenal gland disorders, 1 1 30- 1 1 32 adrenal insuiciency, 1 1 32 aldosteronism, primary, 1 1 32 Cushing syndrome, 1 1 3 1 , 1 1 3 1 t pheochromocytoma, 1 1 30- 1 1 3 1 , 1 1 30/ 1 1 30t Adrenal glands, fetal, 1 37 Adrenal glands, fetal-placental interactions, 1 04- 1 06 estriol synthesis, placental, 1 0 5 estrogen production, fetal conditions on, 1 0 5 anencephalic fetus, 1 05 fetal adrenal cortical hypoplasia, 1 05 fetal demise, 1 05 fetal erythroblastosis, 1 05 fetal-placental sulfatase deiciency, 1 05 trisomy 2 1 , 1 0 5 estrogen production, maternal conditions on, 1 0 5- 1 06 Addison disease, 1 06 androgen-producing tumors, 1 06 glucocorticoid treatment, 1 05- 1 06 fetal adrenal steroid precursor, 1 0 5 Adrenal glands, maternal, 7 1 -72 aldosterone, 72 androgens, 72 androstenedione, 72 dehydroepiandrosterone sulfate, 2 testosterone, 72 cortisol, 7 1 -72, 7 1/ adrenocorticotropic hormone, 7 1 -72, 1/ tissue refractoriness, 72 transcortin, 7 1 deoxycorticosterone, 72 transcortin, 7 1 Adrenal insuiciency, 1 1 32 Adrenal steroid precursor, fetal, 1 05 Adrenocorticotropic hormone (ACTH) fetal, 1 36 maternal, 7 1 -72, 7 1/ Adynamic ileus, 672 Afordable Care Act (ACA), 6, 7 Afibrinogenemia, 1 09 1 African American women, maternal mortality, 6, 6/ Afterpains, 654 Agalactia, 659 Age, maternal for childbirth, trends, 278, 2 8/ on fetal trisomy risk, 278, 2 9t, 280t autosomal, 255, 2 5 5/ on multifetal pregnancies, 866, 866/ on placental abruption, 769-7 0 on placenta previa risk, 7 5 on preconceptual care, 1 5 1 , 1 5 1/

Age, paternal, 1 52 advanced autosomal dominant inheritance, 265 ETproto-oncogene, 265 on trisomy 2 1 , 265 on preconceptual care, 1 52 Agenesis of corpus callosum, sonography, 1 94, 1 94/ Air breathing, newborn transition to, 606-607 Air bronchogram, 63 Air travel, pregnancy, 1 1 Airway conductance, in pregnancy, 64 Ajo, teratogenicity, 248t Alagille syndrome, 26 1 t ALARA principle, 1 83 Alcock canal, 22 Alcohol fetal alcohol syndrome, 1 62, 239-240, 239t, 240/ miscarriage, 348 prenatal use, 1 62 teratogenicity, 1 62, 239-240, 239t, 240/ Aldosterone, maternal, 72 Aldosteronism, primary, 1 1 32 Algae, hygroscopic dilator, 358, 358/ Alglucerase enzyme replacement, 1 080 Allelic heterogeneity, 264-265 All-fours maneuver, 522 All-heal, teratogenicity, 248t Alloimmune thrombocytopenia (AIT), 307-308, 308t, 1 087 �tal, 307-308, 308t 1 087 newborn, 627, 1 087 Alloimmunization CDE (Rh) blood group incompatibility, 30 1 -302, 302t detection, 30 1 , 30 1 t grandmother efect, 302 to minor antigens, 302-303 ABO blood group incompatibility, 302, 303 Kell autoimmunization, 302-303 recurrent pregnancy loss, 353 red cell, 300, 30 1 -306 (See also Red cell alloimmunization) Alobar holoprosencephaly, 1 94 Aloe, teratogenicity, 248t Alopecia. See Telogen eluvium Alpha-fetoprotein (AFP). See Maternal serum alpha-fetoprotein (MSAFP) 1 6.-H ydroxydehydroepiandrosterone ( l 6-0HDHEA) , 1 0 5 1 7-Alpha hydroxyprogesterone caproate ( l 7-0HP-C) , 7 .-methyldopa, for chronic hypertension in pregnancy, 980 .-thalassemias, 1 084- 1 08 5 , 1 08 5 t carrier screening, 290 Alteplase for cerebral artery thrombosis, 1 1 62 for pulmonary embolism, 1 0 1 9 Amaurosis, i n preeclampsia, 24 Ambiguous genitalia, 38-39 Ambrisentan, teratogenicity, 243 Ambulatory uterine monitoring, preterm birth, 8 1 4 Amebiasis, 1 22 - 1 228 Amino acids fetal, 1 39 maternal, on fetal growth, 845 Aminoglycosides, teratogenicity, 242 Amitryptaline, for migraine, 1 1 5 8

I ndex Amniocentesis, 29 1 -293 complications, 293 early, 293 for fetal lung maturity, 638, 638/ indications, 2 9 1 -292 for infection detection, preterm labor with intact membranes, 822 multifetal pregnancy, 292-293 for neural-tube defect diagnosis, 2 8 technique, 292, 292, 292t time to complete, 292 Amniochorion, 1 1 6-1 1 7 amnionic sheet, 1 1 7 amnion nodosum, 1 1 6- 1 1 7 amniotic band sequence, 1 1 6 chorioamnionitis, 1 1 6 funisitis, 1 1 6 limb-body wall complex, 1 1 6 Amniogenic cells, 96 Amnioinfusion for fetal heart rate decelerations from cord entrapment, 475-476, 4 5t variable decelerations, 476 for meconium aspiration syndrome, 476, 620 for meconium-stained amnionic luid, 4 6 for oligohydramnios, 476 Amnion, 95-97 anatomy, 9 5-96, 96/ circulation, 94, 94/ development, 96 histogenesis, 96-97 amnion epithelial cells, 96-97 amnion mesenchymal cells, 97 metabolic functions, 97 physiology, 40 1 , 40 1/ prostaglandin synthesis, 40 1 , 40 1/ tensile strength, 97 Amnion epithelial cells, 96-97 Amnion luid absorbance, 650-nm wavelength, 638 Amnionic band sequence, 1 1 6, 1 93 Amnionic luid, 96, 225-232 forebag, 4 1 4, 4 1 7/ hydramnios, 1 89, 225, 226-230 (See also Hydramnios) meconium-stained (See Meconium-stained amnionic luid) normal, 225-227 measurement, 226 physiology, 225-226, 226t sonographic assessment, 226-227 amnionic luid index, 1 89, 226, 227, 227/ single deepest pocket, 226 oligohydramnios, 1 89, 225, 230-232 (See also Oligohydramnios) sources, 207 spectral analysis, for alloimmunization, 304 Amnionic luid embolism, 785-787 clinical outcomes, 787 diagnosis, 78 5-786, 786t pathophysiology, 786-787, 786/ precipitous labor and delivery, 448 Amnionic luid index (AFI), 1 89, 22 sonographic assessment, 1 89, 226, 227, 227/ Amnionic luid volume, 1 88- 1 8 9 on fetal activity, 332 fetal-growth restriction, 853 sonographic assessment, 1 88- 1 89 Amnionic sheet, 1 1 Amnion mesenchymal cells, 9

Amnion nodosum, 1 1 6-1 1 7 Amnion sac, 96 Amnioreduction, 230 Amniotic band sequence, 1 1 6 Amniotomy, for labor induction and augmentation, 504, 5 1 1-5 12, 5 1 1 t Amoxicillin, for Lyme disease, 1 225 Amphetamines, teratogenicity, 247 Ampicillin for group B Streptococcus, 1 222 for listeriosis, 1 220 Anabolic steroids, teratogenicity, 243 Anal canal, 2 1 -22, 2 1/ Analgesia, labor multifetal pregnancy, 888 narcotic, 487, 487t nitrous oxide, 488 parenteral butorphanol, 488 eicacy and safety, 488 fentanyl, 487t, 488 meperidine and promethazine, 48 -488, 487t nalbuphine, 488 remifentanil, 488 Analgesia, neuraxial, 490-497 for cesarean delivety, 575 combined spinal-epidural, 493, 497 continuous lumbar epidural block, 487f, 493-497 (See also Epidural block, continuous lumbar) continuous spinal, 493, 49 epidural (See Epidural block, obstetric) spinal (subarachnoid) block, 490-492 cesarean delivery, 49 1 complications, 49 1 -492, 49 1 t contraindications, 492, 492t vaginal delivery, 490-49 1 Analgesia, obstetric, 48 5-498. See also speciic ypes

and indications cardiovascular disorders, 49 1 , 953, 962 cesarean delivery, local iniltration, 497-498,

497/ conduction with bleeding disorders, 1 09 1 for extenal cephalic version, 5 5 0 o n maternal mortality, 486 obstetrical anesthesia services, 486, 486t pain relief principles, 486-48 , 48 1 postpartum, 500 with preeclampsia-eclampsia, 743 regional, 488-490 anesthetic agents, 488, 489t cardiovascular toxicity, 489 central nervous system toxicity, 489 paracervical block, 490 pudendal block, 489-490, 489t, 490/ systemic toxicity, management, 489 Anal sphincter complex, 2 1f, 22 Anatomic survey, fetal, sonography standard, 1 8 7 , 1 88t targeted components, 1 87, 1 88t indications, 1 87, 1 89t Anatomy, fetal, imaging Doppler, 2 1 3-2 1 5 (See also Doppler imaging, fetal) magnetic resonance imaging, 2 1 5-220 (See also Magnetic resonance imaging (MRl))

Anatomy, fetal, imaging (Cont: abdomen, 2 1 8-2 1 9, 2 1 9/ central nervous system, 2 1 7-2 1 8, 2 1 7f, 2 1 8/ characterization, 2 1 7 thorax, 2 1 8, 2 1 9/ sonography, 1 9 1 -2 1 3 (See also speciic anatomic

sites) 3-D and 4-D, 2 1 2-2 1 3, 2 1 2/ abdominal wall, 205-206 brain and spine, 1 9 1 - 1 96 face and neck, 1 96-1 9 8 gastrointestinal tract, 206-207 heart, 200-205 kidneys and urinary tract, 207-2 1 0 skeletal abnormalities, 2 1 0-2 1 2 thorax, 1 98-200 Anatomy, maternal, 1 4-3 1 abdominal wall, anterior, 1 4- 1 6, 1 5/ blood supply, 1 4- 1 5 , 1 5/ fascia, 1 4 innervation, 1 5- 1 6, 1 5/ skin, 1 4 subcutaneous layer, 1 4 generative organs, external, 1 6-23 hymen, 1 7- 1 8 perineum, 1 8, 1 9-23 (See also Perineum, anatomy) vagina, 1 8- 1 9, 1 8/ vulva (pudenda), 1 6- 1 7, 1 7j(See also Vulva) generative organs, internal, 23-28 blood supply, pelvic, 24f, 2 5-27, 26/(See aLso Blood supply, pelvic) fallopian tubes, 2 8, 29/ innervation, pelvic, 27-28, 27/(See aLso Innervation, pelvis) ligaments, 24-25 , 24f, 2 5/ broad, 24f, 2 5 cardinal, 25, 2 5/ infundibulopelvic, 24f, 2 5 round, 24-25, 24f, 2 5/ uteroovarian, 24f, 28 uterosacral, 24, 24f, 25, 2 5/ lymphatics, pelvic, 27 ovaries, 24f, 28 uterus, 23-24, 23/ cervix, 23-24, 24/ endometrium, 24, 24/ myometrium, 24, 24j myometrium, in labor, 400-40 1 intraperitoneal organ distortion, 903, 903/ musculoskeletal pelvic, 29-3 1 bones, 29, 30/ joints, 29 pelvic shapes, 3 1 , 3 1/ planes and diameters, 30-3 1 , 30/ midpelvis and pelvic outlet, 30, 30/ pelvic inlet, 30, 30/ urinary tract, lower, 28-29 bladder, 28-29 ureter, 29 Androgen-insensitivity syndrome (AID) , 40 Androgen-producing tumors, on placental estrogen biosynthesis, 1 06 Androgens, maternal, 72 androstenedione, 72 dehydroepiandrosterone sulfate, 72 testosterone, 72 Androstenedione, 72

1 275

1 2 76

I ndex Anembryonic gestation, 1 86 Anembryonic miscarriage, 34 Anemia aplastic and hypoplastic, 1 080- 1 08 1 pregnancy, 1 080 pregnancy, after bone marrow transplantation, 1 080- 1 08 1 Diamond-Blackfan, 1 080 Fanconi, 1 080 fetal, 300-306 causes, 300 hemolytic disease of the fetus and newborn, 300 incidence and course, 300 red cell alloimmunization, 300, 3 0 1 -306 (See aso Red cell alloimmunization) hemolytic, 10 8- 1 080 autoimmune hemolysis, 10 8 bacterial toxins, 1 079 drug-induced hemolysis, 1 078- 1 079 erythrocyte enzyme deiciencies, 1 080 erythrocyte membrane defects, inherited, 1 079- 1 080 hereditary spherocytosis, 1 079 paroxysmal nocturnal hemoglobinuria, 1 079 pregnancy-associated, 1 079 hereditary nonspherocytic, 1 080 marernal, 1 07 5- 1 08 1 from blood loss, 1 077 with chronic disease, 1 077 deinition and incidence, 1 075- 1 076, 1 076, 1 076t in fetal-growth restriction, 850-85 1 iron-deiciency, 1 076- 1 077, 1 077/ megaloblastic, 1 077- 1 078 on pregnancy outcomes, 1 076 newborn, 625-626 spherocytic, 1 079 Anencephaly, fetal estrogen biosynthesis, placental, 1 0 5 imaging, 1 92, 1 92/ Anesthesia, obstetric, 90 1 , 9 0 1 t. See also specic

ypes cardiovascular disorders, 49 1 , 953, 962 deaths, anesthesia-related, 485, 485t on fetus, 486 general, 498-500 aspiration, 499-500 extubation, 499 failed intubation, 498-499 induction and intubation, 498 inhalational anesthetics, 499 patient preparation, 498 labor, muirifetal pregnancy, 888 in obese, 942 obstetrical anesthesia services, 486, 486t pain relief principles, 486-487, 487/ with preeclampsia-eclampsia, 743 regional, 488-490 (See aso Regional analgesia, obstetric) Aneuploidy deinition, 254, 278 erythrocytes, 1 3 1 fetal, 8 cell-free DNA screening, 8 screening, prenatal, 1 65 fetal-growth restriction, 852 incidence, 254, 254, 278

Aneuploidy screening, 278-288 cell-free DNA, 2 3-2 4, 284-286 vs. analyte-based screening, 28 5-286 historical perspective, 284 indications, 285 limitations, 2 8 5 low-risk pregnancies, 285 screening performance, 284-285 secondary screening, 285 counseling elements, 279, 280t false-positive rate, 279, 280t sonographic, 286-288 applications and importance, 286, 286t irst-trimester, 282, 288 second-trimester markers, "soft signs," 286-288, 287, 287t clinodactyly, 287/ echogenic fetal bowel, 287-288, 287/ echogenic intracardiac focus, 286-287, 287/ nuchal skinfold, 286, 287/ renal pelvis dilatation, 28 , 287/ "sandal-gap," 287/ statistical considerations, 277-279 false-positive rate, 279, 280t individual risk, 279-280 negative-predictive value, 280-28 1 positive-predictive value, 280, 280t, 28 1 t sensitivity, 279 test types and choice, 276-277 traditional tests, 2 8 1 -284 composite likelihood ratio, 28 1 irst-trimester, 28 1 -282 eicacy, 282 nuchal translucency, 2 8 1 -282, 282/ nuchal translucency, crown-rump length on, 28 1 unexplained abnormalities, 282 multiple analytes, 28 1 multiple of the median, 2 8 1 predetermined positive value, 28 1 second-trimester, 282-284 California Prenatal Screening Program, 282-283 detection rates, 282 estriol level, 284 integrated screening, 280t, 284 maternal serum AFP and neural-tube defects, 283, 283t quadruple, marker, 282-283 sequential screening, 280t, 284 unexplained abnormalities, 283-284 Aneurysm Charcot-Bouchard, 738-739 intracranial, 1 1 63 intracranial berry, 1 032 umbilical artery, 1 20 Angelman syndrome imprinting, 268, 268t micro deletions, 26 1 t Angiogenic proteins, pregnancy-related hypertension, 7 1 6-7 1 7, 7 1 7/ Angiographic embolization, for hemorrhage, 93-794 Angiography cerebral, 1 1 56 in pregnancy, 906-907, 907t pulmonary intravascular, for pulmonary embolism, 1 0 1 8 multi detector CT, 907, 1 0 1 6- 1 0 1 8 , 1 0 1 8/ radiation, in pregnancy, 906-907, 907t

Angiotensin-converting enzyme (ACE) inhibitors management, in pregnancy, 98 1 oligohydramnios, 23 1 teratogenicity, 24 1 , 98 1 Angiotensin II, 63 parturition, 4 1 Angiotensin I I infusion test, 26 Angiotensin-receptor blockers oligohydramnios, 23 1 teratogenicity, 24 1 , 98 1 Anhydramnios, 230 Anidulafungin, for pneumonia, 995 Anomalies, fetal. See also specic ypes delayed parturition, 4 1 1 sonographic detection irst-trimester, 1 86, 1 86t second- and third-trimester, 18 - 1 88 vaginal delivery, 525 Anorexia nervosa, 1 52, 1 1 80- 1 1 8 1 Antelexion, uterine, 46 Antenatal testing summary, 340-34 1 Antepartum fetal surveillance multifetal pregnancy, 884-8 85 normal test, stillbirth rates, 34 1 , 34 1 t Anterior clavicle fracture, deliberate, vaginal delivery, 5 23 Anthrax bioterrorism, 1 228 Antiangiogenic proteins preeclampsia, 1 6- 1 7, 71 , 726 pregnancy-related hypertension, 7 1 6-7 1 7, 7 1 7/ Ant32 glycoprotein-I, fetal-growth restriction, 85 1 Antibody-mediated immunity, maternal, 59 Anticardiolipin antibodies (ACAs) , 1 1 43 Anticoagulants. See aso specic ypes continuous lumbar epidural block and, 496 natural, antibodies against antiphospholipid syndrome, 1 1 43- 1 1 44 for surgically corrected heart disease, 247, 954-95 5 An ticoagulation abortion and, 1 0 1 5 continuous lumbar epidural block and, 496 for deep-vein thrombosis, 1 0 1 2- 1 0 1 5 complications, 1 0 1 5 delivery and, 1 0 1 5- 1 0 1 6 heparin-induced osteoporosis, 1 0 1 5 heparin-induced thrombocytopenia, 1 008, 1015 low-molecular-weight heparin, 1 0 1 3- 1 0 1 4, 1 0 1 3t newer agents, 1 0 1 5 unfractionated heparin, 1 0 1 2- 1 0 1 3, 1 0 1 3t delivery and, 1 0 1 5- 1 0 1 6 for surgically corrected heart disease, 247, 954-9 5 5 Anticonvulsants, teratogenicity, 1 1 60t Anti-D alloimmunization prevention, 300, 305-306 Anti-D immune globulin, 300, 305-306 septic abortion, 352 Antidiuretic hormone (ADH ) , maternal, 69 Antiepileptic medications, teratogenicity, 240-24 1 , 240/ carbamazepine, 240 hydantoin, 240, 240/ phenobarbital, 240 phenytoin, 240 topiramate, 240 valproic acid, 240

I n dex Antifungals. See also specic ypes teratogenicity, 24 1 Antihistamines, oral, 1 1 88 Antihypertensive drugs, for preeclampsia. See also

specic ypes mild-to-moderate hypertension, 730 prevention, 727 Antiinlammatory agents. See also specic ypes teratogenicity lelunomide, 24 1 NSAIDs, 24 1 Antimicrobial agents. See aso specic ypes for preterm labor with intact membranes, 825 for preterm premature rupture of membranes, 822 teratogenicity, 242 aminoglycosides, 242 chloramphenicol, 242 nitrofurantoin, 242 sulfonamides, 242 tetracyclines, 242 Antimiillerian hormone (AMH), 38 Antineoplastic agents. See also specic ypes teratogenici ty cyclophosphamide, 242 methotrexate, 242-243 tamoxifen, 243 trastuzumab, 243 Antioxidants. See aso specic ypes for preeclampsia prevention, 727 Antiphospholipid antibodies. See aso specic ypes anticardiolipin antibodies, 1 1 43 �Tglycoprotein-I, 1 1 43 lupus anticoagulant, 1 1 43 pregnancy loss, recurrent, 353 thromboprophylaxis, 1 02 1 t Antiphospholipid syndrome (APS), 1 1 43-1 1 46 antibodies against natural anticoagulants,

1 1 43-1 1 44 catastrophic, 1 1 43 clinical and laboratory criteria, 353t, 1 1 44, 1 1 44t etiopathogenesis, 1 1 43 fetal-growth restriction, 8 5 1 pregnancy and antiphospholipid antibodies,

1 1 44- 1 1 46 adverse outcomes, 1 1 45 pathophysiology, 1 1 44 therapy, pregnancy-speciic, 1 1 45-1 146 thrombosis prevention, 1 1 45 treatment eicacy, 1 1 46, 1 1 46t pregnancy loss, recurrent, 353 thrombophilias, 1 008 Antipsychotics, teratogenicity, 245 Anriretroviral na'ive, 1 250 Antiretroviral therapy (ART), antepartum, for H IV, 1 249, 1 250t Antithrombin deiciency thrombophilia, 1 006t, 1 007 Antithrombotics. See also specic ypes for preeclampsia prevention, 27-728 Antiviral agents. See also specic ypes teratogenici ty efavirenz, 243 endothelin-receptor antagonists, 243 ribavirin, 243 Andey-Bixler syndrome, 24 1 Anxiety disorders, 1 1 79-1 1 80 Aorta, diseases of, 967-968 aortic coarctation, 968 aortic dissection, 967 Marfan syndrome, 967-968

Aortic coarctation, 968 Aortic dissection, 967 Aortic insuiciency, 956t, 958 Aortic stenosis, 956t, 957-958 Aortic valvuloplasty, fetal, intracardiac catheter procedures, 326 Apgar score, 6 1 0-6 1 1 , 6 1 0t cerebral palsy, 624, 624t Apixaban, 1 0 1 5 Aplastic anemia, 1 080- 1 0 8 1 pregnancy, 1 080 pregnancy, ater bone marrow transplantation,

1 080- 1 08 1 Appendicitis, 1 052- 1 053, 1 053/ Appropriate for gestational age, 803 Aqueductal stenosis, 1 94 Arabian pessary, 825 Arachnoiditis, from spinal block, 492 Arcuate uterus, 44/ 45 Arginine vasopressin. See Vasopressin Arias-Stella reaction, 5 1 Arnold-Chiari malformation, imaging, 1 93 Arrest (labor) active-phase, 442, 443-444, 443/ 443t oxytocin for, 5 1 0-5 1 1 disorders, 434, 442, 443-444, 443/ 443t transverse, 43 1 Arrhythmias, 965-967 bradyarrhythmias, 966 deinition, 3 1 5 fetal, 462-464, 464/ baseline, 462-464, 464/ abrupt baseline spiking, 462, 464/ therapy for, 3 1 5-3 1 7 bradyarrhythmia, 3 1 6-3 1 7 premature atrial contractions, 3 1 5-3 1 6 tachyarrhythmias, 3 1 6, 3 1 6/ incidence, 965 mechanisms, 965-966 prolonged QT interval, 967 supraventricular tachycardias, 966-967 ventricular tachycardia, 967 Arrhythmogenic right ventricular dysplasia, 964 Artemisinin, for malaria, 1 227 Arteriovenous malformations (AVM) , 1 1 63- 1 1 64 Arteriovenous oxygen diference, maternal,

65 Artery-to-artery anastomoses, monochorionic twins, 877-8 8, 877/ Artesunate, for malaria, 1 227 Ascorbic acid. See Vitamin C Asherman syndrome after abortion curettage, irst-trimester, 36 1 recurrent pregnancy loss, 352 Asherson syndrome, 1 1 43 Ashkenazi Jewish descent carrier screening, 29 1 genetic screening, prenatal, 1 65 preconceptual care, 1 5 1 Asphyxia neonatorum, 62 1 Aspiration general anesthesia, obstetric, 499-500 vacuum, 359-360, 360/ Aspirin for antiphospholipid syndrome, 1 145 for lupus, 1 1 42 on preeclampsia risk, 27-728 for rheumatoid arthritis, 1 1 47 Assault, sexual, 926, 926t

Assessment, fetal, 3 3 1 -34 1 . See aso specic ypes acoustic stimulation tests, 337 antenatal testing summary, 340-341 biophysical proile, 337-33 9 components and scores, 337-338, 338t, 339/ interpretation, 338, 338t modiied, 338-339 breathing, 333-334, 333/ 334/ contraction stress testing, 334, 334t Doppler velocimetry, 339-340 heart rate (See also Heart rate tests, fetal) contraction stress testing, 334, 334t nonstress tests, 334-337 movements, 33 1 -333 clinical application, 332-333 physiology, 33 1 -332, 332/ Assessmen t, intrapartum, 457-48 1 . See also specic

ypes Doppler velocimetry, 472 electronic fetal monitoring, 457-470 fetal electrocardiography, 47 1-472, 472/ fetal pulse oximetry, 47 1 , 47 1/ fetal scalp blood sampling, 470, 470/ nonreassuring fetal status, 472-478 scalp stimulation, 470 uterine activity, surveillance of, 478-48 1 (See also Uterine activity, intrapartum surveillance) vibroacoustic stimulation, 470-47 1 Assisted reproductive technologies (ART), 9 ectopic pregnancy risk, 372 placenta previa, 775 preconceptual care, 1 5 1 - 1 5 2 Asthma, 988-99 1 clinical course, 988, 988t, 989/ clinical evaluation, 989/ 990 fetal efects, 990 management acute asthma, 9 9 1 chronic asthma, 990-99 1 , 990/ labor and delivery, 99 1 status asthmaticus and respiratory failure, 99 1 pathophysiology, 988 pregnancy on, 988-989 on pregnancy outcome, 989, 989t Astute clinical model, 237 Asymmetrical growth restriction, 847 Asymptomatic adnexal mass, in pregnancy, 1 1 98-1 1 99 Asymptomatic bacteriuria, 1 027, 1 02 t Asynclitism, 42 , 429/ anterior, 427, 429/ posterior, 427, 429/ Atelectasis, after abdominal delivery, 667 Atenolol, for chronic hypertension in pregnancy, 980 Atherosis, 7 1 4 Atopic eruption o f pregnancy, 1 1 85t, 1 1 86 Atosiban, for preterm labor, 827 A TP8Bl gene, 1 059 Atrial extrasystoles, 204-205, 205/ Atrial lutter, fetal, therapy for, 3 1 6 Atrial natriuretic peptide (ANP) maternal, 63 in preeclampsia, 7 1 9 serum and blood tests, 1 259t Atrial natriuretic peptide (ANP) converting enzyme, on fetal-growth restriction, 848 Atrial septal defects (ASDs), 9 5 8 Atrial septostomy, fetal, intracardiac catheter procedures, 326

1 27 7

1 278

I n dex Atrioventricular (AV) septal defects, 959 fetal, sonography, 203, 203/ Attitude, fetal, 422-423, 422/ Atypical glandular cells of undetermined signiicance, 1 1 92- 1 1 93 Augmentation, labor. See Labor augmentation Autism spectrum diseases, newborn, 625 Autocorrelation, 4 5 8 Autoimmune adrenalitis, 1 1 32 Autoimmune disorders, maternal remission, 59 Autoimmune hemolysis, 1 078 Autoimmune hepatitis, 1 066 Autoimmune mediators, serum and blood constituents, 1 259t Autoimmunity, thyroid disease and, 1 1 1 9 , 1 1 1 9/ fetal microchimerism, 1 1 1 9 Autoimmunization, Kell, 302-303 Autologous blood storage, 79 1 Autologous transfusion, for hemorrhage, 9 1 Automobile accidents, 926-92 , 927/ on pregnancy, 1 7 1 Autonomic dysrelexia, 1 1 67- 1 1 68 Autoregulation cerebrovascular, 73, 1 1 60 cerebral blood low, 723 hypertensive disorders, 723 preterm neonate, 639 hypovolemic shock, 788 thyroid gland, 57 Autosomal dominant inheritance, 264t, 265 advanced paternal age, 265 codominant genes, 265 expressivity, 265 penetrance, 265 Autosomal dominant polycystic kidney disease (ADPKD) , 2 1 O Autosomal monosomy, 347 Autosomal recessive inheritance, 264t, 265-266 consanguinity, 266 enzyme deficiencies, 265 heterozygous carrier, 265 inborn errors of metabolism, 265-266 phenylketonuria, 265-266 Autosomal recessive polycystic kidney disease (ARPKD) , 2 1 0 Autosomal trisomies, 254-25 8 etiology, 254-25 5 incidence, 254, 254/ other, 258 risk maternal age on, 2 5 5 , 2 5 5/ after pregnancy with autosomal trisomy, 256 trisomy 13 (Patau syndrome), 1 94, 1 9 5f 257-258 trisomy 1 8 (Edwards syndrome), 257, 258/ trisomy 2 1 (Down syndrome), 256-25 , 256f 257/ AV canal defect, fetal sonographic, 203, 203/ Awa, teratogenicity, 248t Azath ioprine for Crohn disease, 1 0 5 1 for lupus, 1 1 42 for ulcerative colitis, 1 0 50 Azelaic acid, 1 1 87 Azithromycin for gonorrhea, 1 240 for shigellosis, 1 220

B B 1 9 parvovirus, 1 2 1 6 Baby Friendly Hospital Initiative, 658 Bacillus anthracis, 1 228 Back pain from continuous lumbar epidural block, 495 in pregnancy, 1 74- 1 75 Bacterial endocarditis, 965 Bacterial infections, 1 220- 1 22 5 . See also speciic

ypes

group A Streptococcus, 1 220 group B Streptococcus, 1 220- 1 222, 1 22 1f 1 222/ Hansen disease, 1 224- 1 22 5 listeriosis, 1 223- 1 224, 1 224/ Lyme disease, 1 225 NIRSA, 1 222- 1 223, 1 223/ salmonellosis, 1 224 shigellosis, 1 224 from transfusions, 79 1 -792 tuberculosis, 1 22 5 Bacterial vaginosis, 1 245- 1 246, 1 246/ preterm birth, 8 1 3 Bacteriuria, asymptomatic, 1 027, 1 027t Bakri balloon, 76 1 , 76 1/ Bakri balloon tamponade for paracervical hematoma, 65 placenta previa, 7 7 for uterine inversion, 62 Bakri postpartum balloon, 76 1 , 761/ Balloon tamponade for esophageal varices, 1 068 for paracervical hematoma, 765 for placenta previa, 777 for uterine atony, 76 1 , 761/ for uterine inversion, 762 Balsalazide, for ulcerative colitis, 1 0 50 Banana sign, 1 93, 1 93/ Bandl rang, 4 1 3 Barker hypothesis, 1 66 Barrier methods, 693-695 cervical cap, 695 condom female, 694, 694/ male, 682t-683t, 693-694 diaphragm plus spermicide, 694-69 5 , 694/ Bartholin glands, 1 7 , 1 7f 1 9-20, 1 9/ Basalis layer, 83, 84/ Basal plate, placenta, I I I Batdedore placenta, 1 1 8 B cells, fetal, 1 37 B-cell tumors, 1 202- 1 203 Beading, 5 1 Beat-to-beat variability, fetal, 335, 458, 46 1 -462, 46 1f 463/ decreased, 462 deinition, 458 increased, 462 long-term, 46 1 , 46 1/ short-term, 46 1 , 461/ Becker muscular dystrophy, X-linked inheritance, 266 Beckwi th-Wiedemann syndrome imprinting, 268, 268t omphalocele, 206 Beh:et disease, 1 1 50 Bell palsy, 1 1 6 , 1 1 6 1 Benign hepatic adenoma, oral cotraceptives, 692

Benzathine penicillin G, for syphilis, 1 238, 1 238t Benzoyl peroxide, 1 1 8 Berger disease, 1 032 Bernard-Soulier syndrome, 1 086 Berry aneurysm, intracranial, 1 032 ruptured, 1 1 63 Beta-carotene, 246 Beta interferons, for multiple sclerosis, 1 1 6 5 Betamethasone, for lung maturation, 1 34 Betamethasone dipropionate, dermatological, 1 1 88 Beta-thalassemia, carrier screening, 290 )2-glycoprotein- 1, 1 1 43 )-adrenergic receptor agonists, for preterm labor, 826 )-adrenergic receptor blockers for chronic hypertension in pregnancy, 980 for cystic fibrosis, 998 )-adrenoceptors, parturition, 404 )-human chorionic gonadotropin () -hCG) hydatidiform mole, 3 9 1 multifetal pregnancies, 870 )-thalassemias, 1 085-1 086 Beyaz, 690 Bicarbonate, in preeclampsia, 7 1 9-720 Bicornuate uterus, 4f, 45 Bilobate placenta, 1 1 2 Bimanual uterine compression, for uterine atony, 760, 760/ Biophysical proile, fetal, 337-339 components and scores, 337-338, 338t, 339/ interpretation, 338, 338t modiied, 338-339 Bioteque cup pessary, preterm birth prevention, 886 Bioterrorism athrax, 1 228 other agents, 1 228 smallpox, 1 228 Biparietal diameter (BPD), 1 84- 1 8 5 , 1 84/ Biphasic pills, 690 Bipolar disorder, 1 1 78- 1 1 79 Birth. See also speciic topics deinition, 3 home, 8 live, 3 preterm, 802-828 (See also Preterm birth) Birth canal, puerperium, 652 Birth canal injuries, 763-767 hematomas, puerperal, 764-765 classiication and risks, 764 , 765/ clinical course and management, 764-765 diagnosis, 764, 765/ lacerations cervical, 763-764 postpartum care, 5 27-529, 528/ vulvovaginal, 763 uterine rupture, 765-767 management and outcomes, 767 pathogenesis, 766-767, 767/ predisposing factors, 765-766, 66 t Birth certiicate, 2, 3t Birth defects. See also Congenital malformations;

speciic ypes etiology, 234, 235/ incidence, 234, 235/ from medications, 234, 234t, 235/ Birth rate, 3

I n dex Birthweight definition, 3 extremely low, 3, 803 vs. fetal growth, 846-847 high empirical macrosomia, 857, 857t macrosomia, 857 on shoulder dystocia risk, 520-52 1 low, 3, 4, 4t, 803 multifetal pregnancy, 8 2, 8 2/ 873/ normal, 845-846, 846/ 846t prior cesarean delivery, 596 very low, 3, 803 Bishop score, 436 for preinduction cervical ripening assessment,

505-506, 505t Black cohosh, teratogenicity, 248t Bladder fetal congenital abnormalities, 4 1 normal, imaging, 207, 207/ maternal, 28-29, 68 labor, 438 Bladder and perineal abnormalities, 41 bladder exstrophy, 4 1 clitoral anomalies, 4 1 cloacal exstrophy, 4 1 epispadias, 4 1 hymenal anomalies, 4 1 Bladder exstrophy, 4 1 Bladder function, maternal after cesarean delivery, 585-586 hospital care, puerperium, 660-66 1 after spinal block, 492 Bladder oudet obstruction, 2 1 0 Blastocyst, 87/ 88 development, 1 2 5 fertilization, 87/ 88 inner cell mass, 87/ 88 trophectoderm, 87/ 88 trophoblasts, 8 , 88 Blastomere, 8 -88, 8 f biopsy, 295, 295/ Blastomycosis pneumonia, 995 Bleeding. See also Hemorrhage breakthrough, hormonal contraceptives, 689 sentinel bleed, placenta previa, 775 upper gastrointestinal tract, 1 047 upper GI disorders, 1 04 Blindness, preeclampsia and eclampsia, 723, 724,

724/ Blocked atrial bigeminy, fetal, 3 1 5 Blood constiruents, 1 25 5 t- 1 260t (See also Serum and blood constituents) hematological and coagulation changes, 655, 655/ Blood component products, for hemorrhage,

788-789, 789t Blood low, uteroplacental, 50-5 1 fundamentals, 50 regulation, 50-5 1 Blood low disruption, placental fetal fetal thrombotic vasculopathy, 1 1 4/ 1 1 5 subamnionic hematoma, 1 1 5 villous vascular lesions, 1 1 5 maternal, 1 1 4-1 1 5 hematoma, 1 1 4-1 1 5, 1 1 4/ infarction, 1 1 4

Blood low disruption, placental (Cont.: intervillous thrombosis, 1 1 4 maternal loor infarction, 1 1 4 perivillous ibrin deposition, 1 1 4, 1 1 4/ Blood gas, tests, 1 260t Blood loss, obstetrical. See also Hemorrhage, obstetrical anemia from, 10 7 delivery with preeclampsia-eclampsia, 743 by type of delivery, 756, 756/ estimation, 758 Blood pressure. See also Hypertension; Hypertensive disorders of pregnancy; Hypotension oral contraceptives on, 69 1 Blood pressure, maternal, 60, 62-63, 62/ hypotension, supine, 63 multifetal pregnancies, 87 1 Blood replacement, for hemorrhage, obstetrical,

788-792 blood component products, 788-789, 789t cell salvage and autologous transfusion, 79 1 cryoprecipitate and fibrinogen concentrate,

789t, 790 dilutional coagulopathy, 789 fresh-frozen plasma, 790 massive transfusion protocols, 789, 790- 9 1 ,

790t packed red blood cells, 789t, 90 platelets, 789t, 790 recombinant activated factor II, 790 topical hemostatic agents, 79 1 tranexamic acid, 790 transfusion complications, 9 1 -792 type and screen vs. crossmatch, 789-790 viscoelastic assays, 79 1 , 79 1/ whole blood, 788-789, 789t Blood sampling, fetal, 294-295, 295/ scalp, 470, 470/ Blood supply abdominal wall, anterior, 1 4- 1 5 , 1 5/ pelvic, 24/ 25-27, 26/ internal iliac artery branches, 26/ 27 ovarian artery, 26, 26/ Sampson artery, 26, 26/ uterine artery, 25-26, 26/ veins, 26 Blood transfusion, fetal, for red cell alloimmunization, 304-305 Blood volume fetal estimation, 307 fetoplacental, 1 3 1 matenal, 57-5 8, 58/ eclampsia on, 1 8-7 1 9, 1 8/ erythroid hyperplasia, 58 estimation, 307 hypertensive disorders of pregnancy,

7 1 8-7 1 9, 7 1 8/ hypervolemia, 5 -58, 58/ total, calculating, 756, 56t puerperium hemarological and coagulation changes, 655,

655/ postpartum diuresis, 656 pregnancy-induced hypervolemia, 655-656,

655/ Bloody show, 5 1

Blue cohosh, teratogenicity, 248t Blunt trauma, 927 Body mass index (BM!), 9 3 6 . See also Birthweight; Obesity; Weight undernutrition, severe prenatal, 1 66 weight gain recommendations, 1 65-1 66, 1 66t weight retention after pregnancy, 1 66-1 67,

1 67/ Body size, fetopelvic disproportion, 450, 450/ Body stalk anomaly, 206 Boerhaave syndrome, 1 044, 1 04 Bohr efect, 65 Bone marrow transplantation, for sickle-cell hemoglobinopathies, 108 1 Bone morphogenetic protein 1 5 (BMP- 1 5) , 8 1 ovulation, 8 1/ 82 Bones, pelvic, 29, 30/ " Borderline" AFI, 232 "Borderline" oligohydramnios, 232

Borrelia burgdoreri, 1 22 5 Bosentan, teratogeniciry, 243 Bowel, fetal, echogenic, 287-288, 287/ Bowel obstruction, 1 05 1 Bowel tract injury, from peripartum hysterectomy,

585 Braces, for hemorrhage, 792, 793/ Brachial plexopathy, newborn, 630 Brachycephaly, 1 84 Bradyarrhythmias, 966 definition, 3 1 5 fetal, 459, 46 1 , 46 1/ therapy for, 3 1 6-3 1 7 Brain eclamptic seizures on, 45 stroke types, 1 1 6 1 , 1 1 6 1/ Brain, pregnancy-related hypertension on,

722-724 cerebral blood low, 23 cerebrovascular pathophysiology, 723, 723/ neuroanatomical lesions, 722-723, 722/ neuroimaging srudies, 724 neurological manifestations, 723 visual changes and blindness, 724, 724/ Brain and spine imaging, fetal, magnetic resonance imaging, 1 28- 1 29, 1 29/ Brain and spine imaging, fetal, sonography,

1 9 1 - 1 96 agenesis of corpus callosum, 1 94, 1 94/ causal regression sequence, sacral agenesis, 1 96 components evaluated, 1 9 1 - 1 92 Dandy-Walker malformation, vermian agenesis,

1 93, 1 94-1 95 , 1 9 5/ holoprosencephaly, 1 94, 1 95/ neural-rube defects, 1 92- 1 93 amnionic-band sequence, 1 93 anencephaly, 1 92, 1 92/ cephalocele, 1 92-1 93, 1 92/ Chiari I I I malformation, 1 93 encephalocele, 1 93 Meckel-Gruber syndrome, 1 93 spina biida, 1 93 , 1 93/(See also Spina bi ida, fetal sonography) sacrococcygeal teratoma, 1 96, 1 96/ schizencephaly and porencephaly, 1 95-1 96,

1 95/ transcerebellar view, 1 9 1 , 1 9 1/ transthalamic view, 1 9 1 transventricular view, 1 9 1 , 1 9 1/ ventriculomegaly, 1 9 1/ 1 93- 1 94, 1 94/

1 279

1 280

I n dex Brain death, maternal, 93 1 , 1 1 68- 1 1 69 Brain disorders. See also specic ypes preterm newborn, 639-640 intracranial hemorrhage, 639 periventricular-intraventricular hemorrhage, 639-640 periventricular leukomalacia, 640 Brain imaging, fetal magnetic resonance imaging, 2 1 7-2 1 8, 2 1 7/ sonography (See Brain and spine imaging, fetal, sonography) Brain injury, fetal heart rate patterns, 476-47 , 476/ Brain natriuretic peptide (BNP) amnion epithelial cells, 97 maternal, 63 serum and blood tests, 1 259t Brain sparing, 847-848 Braunwald ventricular function, 6 1 , 6 1f 949 Braxton Hicks contractions, 50, 403 molding, 43 1 , 43 1/ BR2 gene mutations, 1 200 Breakthrough bleeding, hormonal contraceptives, 689 Breast abscess, 676 Breast carcinoma, 1 200- 1 2 0 1 Breast engorgement, lactation, 659 Breastfeeding, 656-659 advantages, 65 -65 8, 657t breast anatomy and secretory productions, 656-657, 656f 656t care, 658 engorgement, 659 contraindications, 658 drugs in milk, 658-659 immunological consequences, 657 inverted nipples, 659 nursing, 657-6 58, 657t, 658t successful, ten steps, 658, 658t Breast infections, 675-676, 676/ Breasts, maternal, 53 colostrum, 53 gigantomastia, 5 2f 5 3 glands o f Montgomery, 53 Breathing fetal, 1 34, 333-334, 333f 334/ maternal capacity, in pregnancy, 64 Breech delivery, 539-5 50. See also Delivery, breech Breech presentation, 422, 422f 422t, 425/ See also Delivety, breech irst twin, multifetal pregnancy, 889 Breus mole, 1 1 5 Broad ligament, 24f 2 5 Bronchitis, acute, 99 1 -992 Bronchopulmonary dysplasia, 637 Bronchopulmonary sequestration, 1 99, 200/ Brow presentation, 422, 422f 422t fetopelvic disproportion, 452, 452/ Bryant sign, 63 1 BT-Cath, 76 1 , 761/ Bulbospongiosus muscle, 1 9-20, 1 9f 20, 20/ Bulimia nervosa, 1 52, 1 1 80-1 1 8 1 Burkitt lymphoma, 1 203 Burns, 930-9 3 1 electrical and lightning injuries, 930-9 3 1 mortality rates, 9 3 0 , 930/ Butoconazole, for candidiasis, 1 247 Butorphanol, for labor, 488

C Cafeine excess, miscarriage, 348 i n pregnancy, 1 74 for respiratory distress syndrome, preterm newborn, 637 Calcification, placenta, 1 1 5 Calcitonin, 1 1 28 for hyperparathryoidism, 1 1 29 maternal, 1 Calcitriol, for hypoparathyroidism, 1 1 29 Calcium fetal, 1 39 fetal demands, 1 1 28 maternal, 57 parturition, 404 Calcium, supplements on preeclampsia risk, 727 pregnancy and lactation, 1 67t, 1 68 Calcium-channel blockers for chronic hypertension, in pregnancy, 980-98 1 for preterm labor, 827 Calcium gluconate, for hypoparathyroidism, 1 1 29 Calcium lactate, for hypoparathyroidism, 1 1 29 California Prenatal Screening Program, 282-283 Callosal dysgenesis, 1 94 Calmodulin, parturition, 404 Calories, for pregnancy, 1 67, 1 67/ Cancer, 1 1 90- 1 204. See aso Neoplastic disorders;

speciic ypes Cancer antigen 1 25 (CA l 25), 1 1 98 Cancer therapy, i n pregnancy, 1 1 9 1 - 1 1 92. See also

speciic ypes chemotherapy, 1 1 9 1 diagnostic imaging, 1 1 9 1 fertility and pregnancy after, 1 1 92 molecular, 1 1 9 1 radiation, 1 1 9 1 surgery, 1 1 9 1 targeted, 1 1 9 1- 1 1 92 Candida vaginitis, 1 247 Candidiasis (Candida albicans), 1 247 vulvovaginal, pregnancy treatment, 24 1 Cannabinoid hyperemesis syndrome, 1 044 CAOS. See Chronic abruption-oligohydramnios sequence Caput succedaneum, 43 1 , 43 f vs. cephalohematoma, 629 dystocia, 43 1 , 43 1f 4 5 5 Carbamazepine, teratogenicity, 240 , 1 1 60t Carbetocin, after cesarean delivery, 576 Carbohydrate metabolism, maternal, 5 5-56, 5 5/ accelerated starvation, 56 insulin resistance, 56 Carbon dioxide (C02) production, in pregnancy, 98 Carbon monoxide, 999 poisoning, 999- 1 000 Carboprost after cesarean delivery, 576 for uterine atony, 760 Cardiac arrhythmia. See Arrhythmia; speciic ypes Cardiac chemistry, serum and blood constituents, 1 259t Cardiac examination, sonographic, 20 1 , 20 1/-202/ four-chamber view, 20 1 , 20 If 202/ left ventricular outflow tract view, 20 1 , 202/ other views, 20 1 , 202/ right ventricular outflow tract view, 20 1 , 202/

Cardiac function, maternal, 60 multifetal pregnancies, 87 1 pregnancy-related hypertension, 7 1 7-7 1 8 Cardiac magnetic resonance (CMR) imaging, 949, 95 1 Cardiac natriuretic peptides, maternal, 63 atrial natriuretic peptide, 63, 7 1 9, 1 259t brain natriuretic peptide, 63, 97, 1 2 59t Cardiac output, maternal, 60, 6 1 -62 Cardiac plasticity, 6 1 Cardiac rhabdomyoma, 204 Cardiac surgery, in pregnancy, 9 5 5 Cardinal ligament, 25, 2 5/ Cardinal movements of labor, 427, 428/ Cardiogenic hydrostatic edema, 9 1 8 Cardiogenic pulmonary edema, 9 1 7 Cardiomyopathies maternal, 962-964 arrhythmogenic right ventricular dysplasia, 964 classification, 962 dilated, 963 hypertrophic, 962-963 peripartum, 963-964, 963/ primary vs. secondary, 962 restrictive cardiomyopathy, 964 Takotsubo cardiomyopathy, 964 neonatal, with maternal pregestational diabetes, 1 1 02 Cardiopulmonary resuscitation (CPR) , for trauma cesarean delivery, 93 1 incidence, 93 1 maternal brain death, 93 1 , 1 1 68-1 1 69 Cardiovascular disorders, 948-969. See aso speciic

ypes aorta, diseases of, 967-968 arrhythmias, 965-967 cardiomyopathies, 962-964, 963/ congenital heart disease, 9 5 8-960, 960/ diagnosis, heart disease, 949-9 5 1 classiication, functional heart disease, 9 5 1 , 952t clinical indings, 949, 950t diagnostic studies, 949-95 1 cardiovascular MR imaging, 9 5 1 echocardiography, 95 1 electrocardiogram, 949, 950/ radiography, 9 5 1 preconceptual counseling, 9 5 1 , 953t systolic low murmurs, 949, 950/ heart failure, 964-965 infective endocarditis, 965, 966t ischemic heart disease, 968-969, 969/ management, peripartum, 95 1 -954 analgesia and anesthesia, 49 1 , 953, 962 intrapartum heart failure, 962 labor and delivery, 9 1 6, 953 NYHA class I & II, 95 1 -952 NYHA class I I I & V, 952-9 53 puerperium, 9 1 7, 962-963 physiological considerations, pregnancy, 948-949 cardiovascular physiology, 60, 948-949, 949t ventricular function, 6 1f 949 pulmonary hypertension, 960-962, 96 1 t surgically corrected heart disease, 24 , 9 54-9 5 5 , 954t valvular heart disease, 9 5 5-9 58, 956f 956t valvular lesions, 1 032

I ndex Cardiovascular physiology, in pregnancy, 60,

948-949, 949t Cardiovascular system, fetal, 1 29-1 3 1 circulatory changes at birth, 1 3 1 fetal circulation, 1 29- 1 3 1 , 1 30/ fetoplacental blood volume, 1 3 1 Cardiovascular system, maternal, 60-64 cardiac function, 60 cardiac natriuretic peptides, 63 atrial natriuretic peptide, 63, 7 1 9, 1 259t brain natriuretic peptide, 63, 97, 1 259t cardiac output, 60, 6 1 -62 circulation and blood pressure, 60, 62-63, 62/ hypotension, supine, 63 endothelin, 63 heart, 60-6 1 Braunwald ventricular function, 6 1 , 6 1/ 949 cardiac sounds, 6 1 , 950/ diastolic murmur, 6 1 , 950/ left ventricular mass, 6 1 , 6 1/ plasticiry, 6 1 heart rate, 60 hemodynamic function, late pregnancy, 6 1/

62, 62t nitric oxide, 63--64 preeclampsia on, 7 1 7 prostaglandins, 63 prostacyclin, 63 prostaglandin £2' 63 renin, angiotensin II, and plasma volume, 63 ventricular performance, 60, 6 1/ Carneous degeneration, 1 1 96 Carpal tunnel syndrome, 1 1 67 Carrier, heterozygous, autosomal recessive inheritance, 265 Carrier screening, prenatal, for genetic disorders,

288-2 9 1 Ashkenazi Jewish descent, 2 9 1 cystic ibrosis, 2 8 9 , 289t ethnicity-based, 288, 289t expanded carrier, 288 founder efect, 288 goal, 288 panethnic, 288 sickle hemoglobinopathies, 290 spinal muscular atrophy, 289-290 Tay-Sachs disease, 290-29 1 thalassemias alpha-, 290 beta-, 290 Case-control studies, teratogens, 237 Case reports, teratogens, 237 Case series, teratogens, 23 Caspofungin, for pneumonia, 995 Catastrophic antiphospholipid antibody syndrome (CAPS), 1 1 43, 1 1 45 Category A-O drugs and medications, 238,

238t Causal regression sequence, sacral agenesis, 1 96 CD4 T lymphocyte subpopulations, 59 CD£ (Rh) blood group incompatibility, 301-302,

302t Cefazolin, for group B Streptococcus, 1 222 Ceixime, for gonorrhea, 1 240 Cefotaxime, for Lyme disease, 1 225 Ceftriaxone for gonorrhea, 1 240 for Lyme disease, 1 22 5 for shigellosis, 1 220

Cefuroxime, for Lyme disease, 1 22 5 Cell-free DNA, 2 7 3 , 273/ fetal sex determination, 274 h 0 genotype evaluation, 274 Cell-free DNA screening, aneuploidy, 8, 273-274,

284-286

analyte-based screening, 285-286 historical perspective, 284 indications, 285 limitations, 285 low-risk pregnancies, 285 screening performance, 284-285 secondary screening, 285 Cell salvage, for hemorrhage, 79 1 Cellular adhesion molecules (CAMs) , implantation, vs.

88 Cellular senescence, 4 1 1 Central nervous system (CNS) eclamptic seizures on, 745 fetal, 1 28-1 29 brain, 1 28-1 29, 1 29/ spinal cord, 1 29 maternal, 72-73 eyes, 73 Kruckenberg spindles, 73 memory, 72-73 sleep, 73 Central nervous system (CNS) imaging fetal magnetic resonance imaging, 2 1 -2 1 8, 2 1 7/

2 1 8/ sonography, 1 9 1 - 1 96 (See also Brain and spine imaging, fetal, sonography) maternal, 1 1 56 Cephalic-cephalic presentation, multifetal pregnancy, 888 Cephalic index, 1 84 Cephalic-noncephalic presentation, multifetal pregnancy, 888-889, 889t Cephalic pole, 422 Cephalic presentation, 422, 422/ 422t Cephalocele, fetal sonography, 1 92-1 93, 1 92/ Cephalohematoma, newborn, 628-629, 629/ Cephalopelvic disproportion, 442-443 Cerclage. See also Cevical cerclage McDonald, 355, 3 5 5/ cervicovaginal istula after, 1 037 emergency or rescue, 825 vesicovaginal istula after, 1 037 Shirodkar, 3 5 5 , 3 56/ Cerebellum fetal sonography, 1 9 1 , 1 9 1/ transverse diameter, by gestational age,

1 269t newbon, preterm hemorrhage, 639 Cerebral angiography, 1 1 56 Cerebral artery thrombosis, 1 1 62 Cerebral blood flow, pregnancy-related hypertension on, 723, 1 1 60 Cerebral edema, eclampsia, 23 Cerebral embolism, 1 1 6 1-1 1 62 , 1 1 6 1/ Cerebral hemorrhage, eclampsia, 722,

722/ Cerebral palsy Apgar scores, 624, 624t deinition, 640-64 1 heart rate monitoring, intrapartum fetal,

623-624

Cerebral palsy (Cont: incidence and epidemiological correlates,

622-623, 623/ 623t neuroimaging, 624-625 newborn, 622-624 nucleated red blood cells and lymphocytes, 624 preterm newborn, 640-642 incidence, 64 1 neuroprotection, 642 risks, 64 1 -642 types, 622, 642 umbilical cord blood gas studies, 624 Cerebral venous thrombosis, 1 1 62 Cerebrospinal fluid (CSF) , choroid plexus, 1 93 Cerebrovascular diseases, 1 1 60-1 1 64 etiopathogenesis, 1 1 60 hemorrhagic stroke, 1 1 6 1 t, 1 1 62-1 1 64 intracerebral hemorrhage, 1 1 6 1/ 1 1 62-1 1 63 ,

1 1 62/ subarachnoid hemorrhage, 1 1 6 1/ 1 1 6 3 arteriovenous malformations, 1 1 63- 1 1 64 intracranial aneurysm, 1 1 63 incidence, 1 1 60 ischemic stroke, 1 1 6 1 - 1 1 62 , 1 1 6 1/ 1 1 6 1 t cerebral artery thrombosis, 1 1 62 cerebral embolism, 1 1 6 1 - 1 1 62, 1 1 6 1/ cerebral venous thrombosis, 1 1 62 preeclampsia syndrome, 1 1 6 1 recurrence risk, 1 1 62 obesity epidemic in, 1 1 60 risk factors, 1 1 60- 1 1 6 1 Cerebrovascular system, pregnancy-related hypertension on, 723, 23/ Certolizumab for Crohn disease, 1 05 1 for rheumatoid arthritis, 1 1 47 Cervical cancer, 1 1 92- 1 1 95 endocervical polyp, 1 1 92- 1 1 93 epithelial neoplasia, 1 1 93-1 1 94, 1 1 94t invasive cervical cancer, 1 1 94-1 1 95, 1 1 9 5/ Cervical cap, 695 Cervical cerclage, 45 preterm birth prevention, 8 1 5-8 1 6, 8 1 6/ multifetal pregnancy, 886 rescue cervical insuiciency, midtimester abortion,

355 preterm birth prevention, multifetal pregnancy, 886 preterm labor with intact membranes, 825 transabdominal, 356, 35 f vaginal, 3 5 5-356, 3 5 5/ 3 56/ Cervical conization, 1 1 93-1 1 94 Cervical dilation, 4 1 1 , 4 1 4, 4 1 4/ 435 duration of labor curves, 445 , 445/ rate of change, by stage, 445 , 445t Cervical efacement, 4 1 1 , 4 1 3-4 1 4, 4 1 3/ 43 5 Cervical eversion, 5 1 , 5 1/ Cervical "favorability," for ripening preinduction,

505-506 Cervical insuiciency, midtrimester abortion, 354-357 clinical presentation and diagnosis, 3 54 complications, 356-357 etiology, 354 presurgical preparation, 354-3 5 5 rescue cerclage, 3 5 5 surgical indications, 354 transabdominal cerclage, 3 56, 357/ vaginal cerclage, 3 5 5-356, 3 5 5/ 356/

1 28 1

1 282

I n d ex Cervical intraepithelial neoplasia (CIN), 1 1 93-1 1 94, 1 1 94t abnormal cytology and histology, 1 1 93, 1 1 94t cervical conization, 1 1 93- 1 1 94 human papillomavirus, 1 1 93 Cervical lacerations, 763-764 Cervical Mucus Method, 695 Cervical os, 23-24 Cervical pessaries, for preterm labor with intact membranes, 825 Cervical pregnancy, 382-383, 382/ Cervical ripening, 409-4 1 0 with cesarean delivelY, prior, 597-598 connective tissue collagen, 409, 409/ glycosaminoglycans and proteoglycans, 409, 409/ inflammatory changes, 409-4 1 0 deinition, 503 endocervical epithelia, 4 1 0 induction, 4 1 0 methods, 508-5 1 2 mifepristone o n , 408 Cervical ripening, preinduction, 505-508 agents and regimens, 505, 505t cervical "favorability," 5 05-506 mechanical techniques, 5 07-508 hygroscopic cervical dilators, 508 transcervical catheter, 508, 508/ pharmacological techniques, 506-507 nitric oxide donors, 507 prostaglandin El, 507 prostaglandin E2, 506-507, 506/ Cervical softening, 407-408 Cervical stroma, 24 Cervical vertebral dislocation, newborn, 63 1 Cervicitis, mucopurulent Chlamydia, 1 028, 1 240 Cervicoisthmic cerclage, 356, 357/ Cervicovaginal fistula, 1 037 Cervix, 23-24, 24f 5 1 , 5 1/ abnormalities, Mullerian, 42-43 assessment, labor, 435-436 cervical length assessment, sonography, 1 89- 1 9 1 , 1 89f 354 management, preterm birth, 8 1 5 screening, universal, 7-8 conglutinated, 1 1 94 examination, labor, 435 funneling, 354 incompetent, midtrimester abortion, 354 infections, prenatal testing, 1 63 labor changes, 403f 4 1 2-4 1 3 , 4 1 2/ consistency, 436 fetal station, 436 position, 436 nulliparous vs. parous, 653, 653/ pregnancy, 40 1 preterm birth, changes, 8 1 4 puerperium, 653, 653/ spontaneous preterm labor, dysfunction, 8 1 0 strawberry, 1 246 transvaginal sonographic evaluation, 1 90- 1 9 1 , 1 90f 1 90t unfavorable, defined, 840 Cesarean delivery. See Delivery, cesarean Cesarean delivery on maternal request (CDMR), 569 Cesarean hysterectomy, 567

Cesarean-scar pregnancy (CSP) , 3 8 1 -382, 382/ placenta accreta, 7 8 Cetirizine, 1 1 8 8 Chadwick sign, 5 2 Chancroid, 1 244 Charcot-Bouchard aneurysm, 38- 39 Chemerin, 5 1 Chemical constituents, serum and blood, 1 257t Chemoreceptors, arterial, on fetal heart rate, 459-46 1 Chemotherapy, in pregnancy, 1 1 9 1 Chest compressions, newborn resuscitation, 609 Chest wall compliance, in pregnancy, 64, 64f 987 Chest wall movement, fetal, paradoxical, 333, 333/ Chiari malformations, fetal sonography Chiari II, 1 93 Chiari III, 1 93 Chickenpox, 1 2 1 2 Chlamydia (Chlamydia trachomatis), 1 240- 1 24 1 , 1 24 1 t conjunctivitis, newborn, 6 1 4 expedited partner therapy, 1 24 1 IUD infection, 684 lymphogranuloma venereum, 1 24 1 mucopurulent cervicitis, 1 028, 1 240 in pregnancy complications, 1 240 prenatal testing, 1 63 screening and treatment, 1 240-1 24 1 , 1 24 1 t urethritis, 1 028, 1 240 Chloasma, 53 oral contraceptives, 692 Chloramphenicol, teratogenicity, 242 Chloroquine, for malaria, 1 227 Chlorthiazide, on preeclampsia risk, 72 Cholangitis, ascending, 1 070 Cholecystitis, 1 069 medical vs. surgical management, 1 070 in pregnancy, 1 069-1 070 Cholelithiasis, 1 069, 1 070/ endoscopic retrograde cholangiopancreatography for, 1 070 medical vs. surgical management, 1 070 in pregnancy, 1 069- 1 0 0 Cholestasis, from oral contraceptives, 692 Cholestatic jaundice, from oral contraceptives, 692 Cholesterol biosynthesis, H MG-CoA reductase, 1 03 serum and blood, 1 259t Cholinergic crisis, myasthenia gravis, 1 66, 1 1 65 Chorangiocarcinoma, 1 1 5 Chorangioma, 1 1 5-1 1 6, 1 1 6/ Chorangiomatosis, 1 1 5 Chorangiosis, 1 1 5 Chorioadenoma destruens, 394 Chorioamnionitis, 1 1 6 on cerebral palsy risk, 642 labor disorders, 447 preterm premature rupture of membranes, 8 2 1 -822 Chorioangioma, 1 1 5- 1 1 6, 1 1 6/ Chorion, 89, 90-9 5 , 1 26/ development, 90, 9 1/ chorion frondosum, 90 chorion laeve, 90 physiology, 40 1 , 40 1/ Chorion fro ndosum, 90, 293 Chorionic cavity. See Gestational sac

Chorionicity, multifetal pregnancies, determining, 86 -869, 868t placental examination, 865f 869, 869/ sonographic, 867-869, 868f 869/ Chorionic plate, placenta, I I I Chorionic villi, 90, 90f 389/ Langerhans cells, 90 primary villous stalks, .90 secondary villi, 90 tertiary vill i , 90 Chorionic villus sampling (CVS), 293-294, 293f 294/ Chorion laeve, 90 Choroid plexus, cerebrospinal fluid production, 1 93 Christmas disease, 1 089-1 090 Chromosomal abnormalities, 254-264. See also

speciic ypes chromosomal mosaicism, 263-264 chromosome number, 254-260 chromosome structure, 260-263 incidence and relative proportion, 254, 254/ nomenclature, standard, 254, 2 5 5 t recurrent pregnancy loss, 3 5 2 spontaneous abortion, 347 Chromosomal inversions paracentric, 263, 263/ pericentric, 263, 263/ Chromosomal microarray analysis (CMA), 254, 27 1 -272, 272/ clinical applications, 272 prenatal, 260 Chromosomal mosaicism, 263-264 confined placental, 263-264 gonadal, 264 Chromosomal ovotesticular disorders of sex development, 39 Chromosomal translocations, 26 1 -262 reciprocal, 26 1 -262, 262/ Robertsonian, 262 Chromosome number abnormalities, 254-260 autosomal trisomies, 2 54-258 (See also Trisomies, autosomal) monosomy, 2 5 8 polyploidy, 2 5 9 diandric triploidy, 2 5 9 digynic triploidy, 259 tetraploid pregnancies, 259 sex chromosome abnormalities, 2 5 8-2 59 45,X, 39, 258, 2 59, 347, 352 47,XXX, 259 47,xXY, 39, 259-260 47,yy, 260 Chromosome structure abnormalities, 260-263 chromosomal inversions paracentric, 263 , 263/ pericentric, 263, 263/ chromosomal translocations, 26 1-262 reciprocal, 26 1 -262, 262/ Robertsonian, 262 deletions and duplications, 260-26 1 , 260/ 22q 1 1 . 2 microdeletion syndrome, 260-26 1 microdeletions, 260 microduplications, 260 isochromosomes, 262-263 ring chromosome, 263 Chronic abruption-oligohydramnios sequence (CAOS), 232, 768, 3 Chronic hypertensive diathesis, 977

I ndex Chronic inlammatory demyelinating polyneuropathy, 1 1 66 Chronic kidney disease (CKD), 1 034-1 036 classification, 1 034- 1 036 criteria, 1 034 long-term efects, 1 036 management, 1 03 5 pregnancy and, 1 034-1 035 chronic renal insuiciency, 1 035, 1 035/ 1 03 5 t dialysis, 1 036 renal disease with preserved function, 1 034- 1 035, 1 034t Chronic renal insuiciency, 1035, 1 035/ 1035t Churg-Strauss vasculitis, 1 1 50 Chylothorax, percutaneous fetal surgery, 324-325, 324/ Cigarette smoking. See Smoking Circulation, maternal, 60, 62-63, 62/ Circulatory disturbances, placenta, 1 1 3-1 1 5 fetal blood low disruption fetal thrombotic vasculopathy, 1 1 4/ 1 1 5 subamnionic hematoma, 1 1 5 villous vascular lesions, 1 1 5 maternal blood low disruption, 1 1 4-1 1 5 hematoma, 1 1 4-1 1 5 , 1 1 4/ infarction, 1 1 4 intervillous thrombosis, 1 1 4 maternal loor infarction, 1 1 4 perivillous fibrin deposition, 1 1 4, 1 1 4/ Circumcision, 1 6 1/ 6 1 5-6 1 6 Circum marginate placenta, 1 1 3, 1 1 3/ Circumvallate placenta, 1 1 3, 1 1 3/ Cirrhosis, 1 06 Class X, 238, 238t Clavicle fracture deliberate anterior, vaginal delivery, 523 newborn, 630 Cleft lip imaging, fetal, 1 96-1 97, 1 9 f Cleft palate imaging, fetal, 1 96- 1 97, 1 97/ Cleidotomy, for shoulder dystocia, 523 Clem. See embryofetus; Cucurbita pepo Clindamycin for bacterial vaginosis, 1 245 for malaria, 1 227 Clinodacryly, second-trimester aneuploid screening, 287/ Clitoris, 1 7, 1 7/ 1 9, 1 9/ 20, 20/ anomalies, 4 1 Cloacal exstrophy, 4 1 omphalocele, 206 Clobetasole propionate, 1 1 88 Clofazi mine, for Hansen disease, 1 224 Clonidine, for chronic hypertension in pregnancy, 980 Close calls, 6 Closing volume, 64 Clostridium dificile, 1 048 Clostridium peringens hemolytic anemia, 1 079 septic abortion, 3 5 1 toxic shock syndrome, postpartum, 675 Clostridium sordellii septic abortion, 3 5 1 toxic shock syndrome, postpartum, 675 Clotrimazole, for candidiasis, 1 24 Clubfoot, 2 1 1 -2 1 2, 2 1 1/ 63 1 Clubhand deformiry, 2 1 2 Cluster headache, 1 1 58

Coagulation activation normal, 83, 784/ pathological, 784 preeclampsia and eclampsia on, 7 1 9 pregnancy-induced changes, 783 puerperium, 655, 655/ serum and blood constituents, 1 256t serum and blood tests, 1 256t Coagulation and fibrinolysis, maternal, 59-60, 784/ factor XIII, 60 hemostasis, 59, 60t platelets, 60 procoagulants, 59-60, 60t regulatory proteins, 60, 1 005/ activated protein C, 60, 60t Coagulation cascade, thrombophilias on, 1 005, 1 005/ Coagulation defects, inherited, 1 089- 1 09 1 conduction analgesia and, 1 09 1 factor VI I I deficiency, 1 090 factor X (Stuart-Prower factor) deiciency, 1 090- 1 09 1 factor X I deiciency, 1 0 9 1 factor X I I deficiency, 1 09 1 factor XI I I deficiency, 1 09 1 hemophilias A and B , 1 089-1 090 von Willebrand disease, 1 090 Coagulation defects, placenta previa, 75 Coagulation factors fetal, 1 33 puerperium, 655 Coagulopathies, obstetrical, 782-78 coagulation, activation of normal, 783, 784/ pathological, 784 diagnosis, 784-785 disseminated intravascular coagulation, 782-7 83 management, comorbid conditions abortion, 787 amnionic fluid embolism, 8 5-787 clinical outcomes, 787 diagnosis, 785-786, 786t pathophysiology, 86-787, 786/ fetal death and delayed delivery, 785 placental abruption, 785 preeclampsia, eclampsia, and HELLP, 85 purpura fulminans, 787 sepsis syndrome, 78 management, general, 785 pregnancy-induced changes, 783 sepsis syndrome, 87 Cocaine placental abruption, 770 teratogeniciry, 248 Coccidioidomycosis pneumonia, 995 Codominant genes, autosomal dominant inheritance, 265 Cognition pregestational diabetes on, long-term development, 1 1 02 puerperium, hospital care, 66 1 Cohort studies, teratogens, 23 Cohosh, teratogeniciry, 248t Coiling, umbilical cord, 1 1 7 Coitus pregnancy, I 1 puerperium, 663

Cold-agglutinin disease, 1 078 Collagen I , 97 Collagen II, 9 Collagens, 97 amnion tensile strength, 97 cervical ripening, 409, 409/ Colles fascia, 1 9, 1 9/ Colonic pseudo-obstruction, 1 052 Colonoscopy, 1 042 Colony-stimulating factor (CSF- l ) , blastocyst, 88 Colorectal cancer, 1 204 Colostomy, pregnancy and, 1 05 1 Colostrum, 53, 656 Combined spinal epidural (CSE) analgesia vs. meperidine, for nullipara in spontaneous labor at term, 445-446, 445 t obstetric, 493/ 497 Communiry, 1 245 Communiry-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) , 1 223 pneumonia, 992-994, 993t Communiry-acquired pneumonia (CAP), 992 Communiry state rypes (CSTs) , 1 245 Complement factors, maternal, C3 and C4, 59, 1 259t Complete abortion, 349, 350t Complete androgen-insensitiviry syndrome (CArS), 40 Complete breech presentation, 422, 422f 539, 540/ Complications, medical and surgical. See also speciic ypes imaging in pregnancy, 9 1 1 , 9 1 1 t incidence, 900 laparoscopic surgery, 90 1 -904 (See also Laparoscopic surgery, in pregnancy) magnetic resonance imaging, 909-9 1 1 maternal physiology and laboratory values, 900-90 1 medications and surgeries perinatal morbidiry, 90 1 , 90 1 t pregnancy outcomes, 90 1 radiography, 904-909 sonography, 909 Composite likelihood ratio, aneuploidy screening, 28 1 Compound presentation, 454, 454/ fetopelvic disproportion, 454, 454/ Compression ultrasonography, for deep-vein thrombosis, 1 0 1 0- 1 0 1 1 , 1 0 1 2/ Compressor urethrae muscle, 20, 20/ Computed tomography (CT) . See also specic indications appendix, 1 05 2-1 053, 1 053/ cancer, in pregnancy, 1 1 9 1 central nervous system, 1 1 56 multidetector CT pulmonary angiography, 907, 1 0 1 6-1 0 1 8, 1 0 1 8/ in pregnancy, 907-908, 907/ 90 t, 908/ diagnostic, 907-908, 90 f 907t, 908/ Conceptive history, prenatal, 1 6 1 Condom female, 694, 694/ male, 682t-683t, 693-694 Conduction analgesia with bleeding disorders, 1 09 1 for extenal cephalic version, 550 Conduplicato corpore, 454 Condyloma acuminata, 1 244- 1 245

1 283

1 284

I n d ex Condyloma lata, 1 236- 1 237, 1 236/ Confined placental mosaicism (CPM), 263-264, 852 Congenital adrenal hyperplasia (CAH), fetal, therapy for, 3 1 7 Congenital cystic adenomatoid malformation (CCAM) , 1 99, 1 99/ fetal, therapy for, 3 1 7-3 1 8 thoracic shunts for, 325 Congenital deformity injuries, newborn, 63 1 .

See aso speciic ypes Congenital diaphragmatic hernia (CDH), 1 98, 1 98/ fetoscopic surgety, 323-324, 323/ Congenital genital tract anomalies, recurrent pregnancy loss, 353 Congenital genitourinary anomalies, 33-46. See also Genitourinary anomalies, congenital Congeni tal heart block, 3 1 6 systemic lupus erythematosus, 1 1 43 Congenital heart disease, 9 58-960 atrial septal defects, 958 atrioventricular septal defects, 959 cyanotic heart disease, 959 Eisenmenger syndrome, 958-959, 960, 960/ incidence, 958 outcomes, 958 persistent (patent) ductus arteriosus, 959 ventricular septal defects, 958-959 Congenital high airway obstruction sequence (CHAOS) , 1 99-200, 200/ ex-utero intrapartum treatment for, 327 Congenital hypothyroidism, 1 1 27 Congenital malformations fetal-growth restriction, 852 multifetal pregnancy, 8 7 1 -8 2 Congenital pulmonary airway malformation (CPAW) , 1 99, 1 99/ 3 1 7-3 1 8 Congenital rubella syndrome, 237 Congenital varicella syndrome, 1 2 1 2- 1 2 1 3, 1 2 1 3/ Conglutinated cervix, 1 1 94 Conization, cervical, 1 1 93- 1 1 94 Conjoined rwins, 875-876, 875/-877/ spectrum, 875/ Conjunctivitis, newborn, 6 1 4 Connective tissue, cervical ripening collagen, 409, 409/ glycosaminoglycans and proteoglycans, 409, 409/ inflammatory changes, 409-4 1 0 Connective tissue disorders, 1 1 3 8- 1 1 5 1 . See also

specic disorders anti phospholipid syndrome, 1 1 43- 1 1 46 hereditary connective tissue disorders, 1 1 5 1 Ehlers-Danlos syndrome, 1 1 5 1 'Iarfan syndrome, 1 1 5 1 osteogenesis imperfecta, 1 1 5 1 immune-mediated connective tissue diseases,

1 1 38-1 1 3 9 classiication, 1 1 3 8 fetal cell microchimerism, 1 1 39 obstetrical complications, 1 1 38 pregnancy, 1 1 3 8 RF-seronegative spondyloarthropathies, 1 1 38 rheumatoid factor, 1 1 38 inflammatory myopathies, 1 1 50-1 1 5 1 rheumatoid arthritis, 1 1 46-1 1 48 systemic lupus erythematosus, 1 1 39-1 1 43 systemic sclerosis, scleroderma, 1 1 48- 1 1 49 undiferentiated connective tissue disease, 1 1 49 vasculitis syndromes, 1 1 49-1 1 50

Connexins, 405, 406/ Connexons, 405, 406/ Consanguinity, autosomal recessive inheritance, 266 Consistency, 436 Constitutionally small mothers, in fetal-growth restriction, 849 Consumptive coagulopathy, 782 placental abruption, 77 1 Contiguous gene syndrome, 260 Contingent sequential screening, 280t, 284 Continuous lumbar epidural block, 487/ 493-497. See aso Epidural block, continuous lumbar Continuous positive airway pressure (CPAP), for respiratory distress syndrome, preterm newborn, 637 Continuous spinal analgesia, labor, 493/ 497 Continuous-wave Doppler, 2 1 3 Contraception, 680-697. See aso speciic ypes barrier methods, 693-695 cervical cap, 695 condom female, 694, 694/ male, 682t-683t, 693-694 diaphragm plus spermicide, 694-695, 694/ emergency, 696-697, 696t copper-containing I UDs, 696t, 697 hormonal, 696, 696t failure rates, 680-68 1 , 680t fertility awareness-based methods, 680t, 695 Cervical Mucus Method, 695 Standard Days Method, 695 Symptothermal Method, 695 Temperature Rhythm vlethod, 695 hormonal contraceptives, 689-693 (See aso Contraceptives, hormonal) intrauterine devices, 68 1-685 (See aso Intrauterine devices (IUDs)) long-acting reversible, 68 1 Medical Eligibility Criteria, 68 1 overview, 680-68 1 , 682t-683t postabortal, 364 progestin implants, 685-689 (See also Progestin implants) progestin-only contraceptives, 689 actions and side efects, 689 contraindications, 682t-683t, 689 puerperal, 662-663, 66/ 682t-683t, 697 with sickle-cell hemoglobinopathies, 1 083 spermicides, 695-696 contraceptive sponge, 680t, 695, 695/ Contraceptives, hormonal, 689-693 combination hormonal, mechanism of action, 689 combination oral, 689-690 injectable progestin, 693 method-specific efects altered drug eicacy, 682t-683t, 69 1 cardiovascular, 69 1 -692 chloasma, 692 cholestasis and cholestatic jaundice, 692 metabolic, 69 1 neoplasia, 692 noncontraceptive benefits, 692 progestin-only pills, 682t-683t, 693 transdermal patch, 692 transvaginal ring, 692-693, 692/ Contracted inlet, 448-449 Contracted midpelvis, 449 Contracted outlet, 449

Contraction-associated proteins (CAPs), 405 parturition, 405 Contraction stress test, 334, 334t Contrast agents, in pregnancy, 908, 9 1 0-9 1 1 gadolinium-based, 2 1 6 Conventional vasectomy, 06 Convulsions in eclampsia, 723 (See aso Eclampsia; Magnesium sulfate) from spinal block, 492 Cooley anemia, 1 08 5 Copper fetal , 1 39 overload, 1 067 serum and blood testing, 1 2 5 8t Copper intrauterine devices (Cu-IUDs), 68 1 -685. See aso Intrauterine devices (IUDs) emergency contraception, 696t, 697 insertion, 685, 687/ Copy number variant, 254 Cord blood banking, prenatal, 1 75 Cord-blood stem-cell transplantation, for sickle-cell hemoglobinopathies, 1 08 1 Cord compression patterns, fetal heart rate, 465 Cord loops, 1 1 9- 1 20 Cordocentesis, 294-295, 295/ Cord strictures, 1 1 9 Corin, on fetal-growth restriction, 848 Cornual resection, for interstitial pregnancy, 380,

380/ Coronavirus infection, 1 2 1 6, 1 2 1 9 Cor pulmonale, cystic ibrosis, 998 Corpus callosum agenesis, imaging, 1 94, 1 94/ Corpus luteum, luteal phase, 8 1/ 82-83, 82/ Cortical necrosis, acute, 1 037 placental abruption, 772 Corticosteroids. See also specic ypes antenatal, for preterm infants, 638 for antiphospholipid syndrome, 1 1 46 for fetal lung maturation preterm labor with intact membranes,

823-824 preterm premature rupture of membranes,

822 for HELLP syndrome, 733, 734/ teratogenicity, 244 Corticotropin. See Adrenocorticotropic hormone (ACTH) Corticotropin-releasing hormone (CRH) fetal macrosomia, 1 38 parturition, 4 1 0-4 1 1 , 4 1 0/ parturition, 407 placental, 99t, 1 0 1 Cortisol, 1 258t amnion mesenchymal cells, 97 fetal lung maturation, 1 34 parturition, 4 1 0-4 1 1 , 4 1 0/ maternal, 7 1 -72, 7 1/ adrenocorticotropic hormone, 1- 2, 1/ tissue refractoriness, 72 transcortin, 7 1 Cosmeceuticals, teratogenicity, 246 Counseling preconceptual (See Preconceptual counseling) on pregnancy outcomes, 1 46-1 4 Couvelaire uterus, 77 1 , 772/ Coxsackievirus infection, 1 2 1 6

I ndex Cranial injuries, newborn, 627-629 extracranial hematomas, 628-629, 629/ intracranial hemorrhage, 628, 628t skull fractures, 629, 629/ Craniosynostosis, 1 85 C-reactive protein, maternal, 59, 1 259t CREST syndrome, 1 1 49 Cri-du-chat syndrome, 26 1 t Crista dividens, 1 3 0-1 3 1 Critical care and trauma, 9 1 5-925. See also speciic ypes acute respiratory distress syndrome, 9 1 8-92 1 cardiopulmonaty resuscitation, 9 3 1 envenomation, 93 1 obstetrical intensive care, 9 1 5-9 1 7 hemodynamic changes i n pregnancy, 9 1 7, 9 1 7t obstetrical critical care, 9 1 6, 9 1 6t organization, critical care, 9 1 5, 9 1 6t pulmonary artery catheter, 9 1 6-9 1 7 pulmonary edema, acute, 9 1 7-9 1 8 sepsis syndrome, 92 1-925 thermal injury, 930-93 1 electrical and lightning injuries, 930-93 1 mortaliry rates, 930, 930/ 'rauma, 925-930 Crizanlizumab, for sickle-cell hemoglobinopathies, 1 08 1 Crohn disease, 1 049, 1 049/ classiication, 1 048, 1 049t etiopathogenesis, 1 048 fertility and, 1 050 pregnancy and, 1 0 5 1 Crowning, 5 1 7 Crown-rump length (CRL), 1 83-1 84, 1 84, 1 86/ on nuchal translucency, 28 1 pregnancy loss, early, 350 Cryoprecipitate, for hemorrhage, 789t, 790 Cryptococcosis pneumonia, 995 Cryptogenic cirrhosis, 1 067 Cucurbita pepo. See Clem Culdocentesis, for ectopic pregnancy, 376, 377/ Cushing disease, 1 1 3 1 Cushing syndrome, 1 1 3 1 , 1 1 3 1 t Cyanotic heart disease, 959 Cyclic guanosine monophosphate (cGMP), parturition, 40 Cyclooxygenase 1 (COX- I ) , 402 Cyclooxygenase 2 (COX-2), 402 menstruation, 85 Cyclophosphamide for lupus, 1 1 42 teratogenicity, 242, 1 1 42 Cyclosporine for Crohn disease, 1 0 5 1 for pemphigoid gestationis, 1 1 86 for ulcerative colitis, 1 050 Cyllosoma, 206 CPl7Al, 1 03 CP2lAI, 3 1 Cyst hepatic, 1 032 umbilical cord, 1 1 8 pseudocysts, 1 1 8 true, 1 1 8 Cystic ibrosis, 997-999 carrier screening, 289, 289t compound heterozygosity, 289 diagnosis, 997-998 genetics, 997

Cystic ibrosis (Cont: homozygosity, 289 lung transplantation, 999 management, 998-999 meconium peritonitis, 998 pathophysiology, 998 preconceptual counseling, 998 pregnancy outcome, 999, 999t screening, 998 Cystic ibrosis transmembrane conductance regulator (CFTR), 997 Cystic ibrosis transmembrane conductance regulator gene (CTFR), 289 allelic heterogeneity, 264-265 carrier screening, 289, 289t Cystic hygroma, fetal sonographic, 1 97- 1 98 , 1 98/ Cystitis, 1 027t, 1 028 Cystotomy repair, after peripartum hysterectomy, 583-584, 584/ Cytogenetic analysis, 270 Cytokines. See also speciic ypes in insulin resistance, 936-93 spontaneous preterm labor, origin, 8 1 1 Cytomegalovirus (CMV) infection, 1 2 1 0- 1 2 1 2, 1 2 1 1/ diagnosis, prenatal, 1 2 1 1 - 1 2 1 2, 1 2 1 1/ fetal-growth restriction, 8 5 1 fetal infection, 1 2 1 0- 1 2 1 1 , 1 2 1 1/ management and prevention, 1 2 1 2 maternal infection, 1 2 1 0 Cytotec. See Misoprostol Cytotrophoblasts, 88, 89/ D

Dabigatran, 1 0 1 5 D alloimmunization prevention, anti-D-immune globulin for, 300, 305-306 Danazol, teratogenicity, 243 Dandy-Walker malformation, 1 93 Dandy-Walker variant, 1 95 imaging, 1 93, 1 94-1 95, 1 9 5/ D-antigen alloimmunization, erythrocyte, 95 Dapsone, for Hansen disease, 1 224 D-dimer screening, for deep-vein thrombosis, 1 0 1 1- 1 0 1 2 Death. See also Mortality; speciic ypes fetal, 3 infant, 3 maternal direct, 3 indirect, 3 maternal brain, 93 1 , 1 1 68-1 1 69 neonatal early, 3 late, 3 non maternal, 4 pregnancy-associated, 4 Death rate fetal, 3, 4, 5/ maternal, 4 neonatal, 3, 4, 5/ Decelerations, fetal heart rate, 464-469 early, 464-466, 465/ head compression, 465-466, 465/ inluences, 459, 460t late, 466, 466/ uteroplacental insuiciency, 465 , 466 postterm pregnancy, 836, 836/ prolonged, 468-469, 468/-469/ variable, 466-468, 466-468/

Decidua, 80, 85-87, 86, 40 1 decidualization, 85 dysfunctional, morbidly adherent placenta, 780 hemochorial placentation, 8 5 histology, 86-87, 86/ parturition, 407 prolactin, 87 puerpera, 653 structure, 85-86, 86/ Decidua basalis, 86, 86/ Decidua capsularis, 85, 86/ Decidual cast, 349, 373/ Decidual immune cells, 95 Decidual macrophages, 95 Decidual reaction, 5 1 -52 Decidua natural killer cells (dNK), 9 1 , 95 Decidua parietalis, 86, 86/ Decleration phase, labor, 432, 432/ Deep-vein thrombosis, 1 0 1 0- 1 0 1 6 cli nical presentation, 1 0 1 0 diagnosis, 1 0 1 0-1 0 1 2 algorithm, 1 0 1 0, 1 0 1 1/ compression ultrasonography, 1 0 1 0-1 0 1 1 , 1 0 1 2/ D-dimer screening, 1 0 1 1 - 1 0 1 2 magnetic resonance imaging, 1 0 1 1 labor and delivery, 1 0 1 4 management, anticoagulation, 1 0 1 2-1 0 1 5 abortion and, 1 0 1 5 complications, 1 0 1 5 delivery and, 1 0 1 5- 1 0 1 6 heparin-induced osteoporosis, 1 0 1 5 heparin-induced thrombocytopenia, 1 008, 1015 low-molecular-weight heparin, 1 0 1 3- 1 0 14, 1 0 l 3t newer agents, 1 0 1 5 unfractionated heparin, 1 0 1 2-1 0 1 3, 1 0 1 3t warfarin, 1 0 1 4- 1 0 1 5 oral contraceptives, 69 1 Deibrination syndrome, 782 Deibulation, 525, 525/ Dehydroepiandrosterone (DHEA), placental, 1 03-104, 1 04/ Dehydroepiandrosterone sulfate (DHEA-S), 72 fetal, parturition, 4 1 0/ placental, 1 03-1 04, 1 04/ serum and blood, 1 259t Deletions, chromosomal, 260-26 1 , 260/ 22q 1 1 .2 microdeletion syndrome, 260-26 1 cardiovascular disorders, 9 1 6, 953 microdeletions, 260 Delivery. See aso specic ypes and topics with anticoagulation, 1 0 1 5- 1 0 1 6 and deep-vein thrombosis, 1 0 1 4 asthma on, 99 1 fetal-growth restriction, 856 gestational diabetes, 1 1 1 3 with H IV, maternal, 1 249 with hypertension, chronic, 983-984 placenta and membranes, 4 1 5-4 1 6, 4 1 5, 4 1 6/ with preeclampsia, 729 delayed, 730- 33, 732, 732t, 733/ (See also under Preeclampsia) glucocorticoids, for lung maturation, 733, 733t with pregestational diabetes, 1 1 06-1 1 0 , 1 1 07t for preterm labor with intact membranes, 827

1 28 5

1 286

I n dex Delivery (Cont.): for preterm premature rupture of membranes, 8 1 9-82 1 with sickle-cell hemoglobinopathies, 1 083 of triplets or higher-order gestation, 890-89 1 Delivery, breech, 539-5 50. See aso Breech presentation cesarean delivery, factors, 542, 543t classiication, 539-540 complete, 539, 540/ frank, 539, 539/ incomplete, 539, 540/ stargazing fetus, 540 complications, 542 decision-making summary, 542, 543t diagnosis examinations, 540 risk factors, 540 extenal cephalic version, 549-5 50 complications, 549 conduction analgesia, 550 indications, 549 moxibustion, 550 technique, 549-5 50, 550/ tocolysis, 550 lying fetus, 540 imaging, 542 route of delivery, 540-54 1 preterm breech fetus, 541 term breech fetus, 54 1 Delivery, breech, labor and delivery management, 543-549 labor induction and augmentation, 543 labor management, 543 partial breech extraction, 544-548 delivery of aftercoming head Diihrssen incision, 548, 548/ forceps, 546-547, 547/ Mauriceau maneuver, 546, 546/ modified Prague maneuver, 547-548, 548/ symphysiotomy, 548 Zavanelli maneuver, 548 nuchal arm, 546, 546/ spontaneous breech delivery, 543-544, 544/ total breech extraction, 548-549 complete breech, 548-549, 548/ frank breech, 544, 549 incomplete breech, 548-549 vaginal methods, 543 Delivery, cesarean, 567-57 1 analgesia continuous lumbar epidural block on rates of, 495, 496/ local iniltration, 497-498, 497/ spinal block, 4 9 1 breech presentation, factors, 542, 543t deinition, 567 elective elective repeat cesarean delivery, 592 for overgrowth, fetal, 859 incidence, U.S., 567-568 indications, 567-568, 568t morbidly adherent placenta, 78 1-782 multifetal pregnancy, 547f 890 obese, 942-943 patiet preparation, 569-571 delivery availability, 569 infection prevention, 570-57 1

Delivery, cesarean (Cont.): informed consent, 569-570 preoperative care, 5 0 surgical safety, 5 1 timing, 570 perimonem, 9 3 1 placental abruption, 772 placenta previa, 7 7 postmortem or peri mortem, 567 postoperative care, 585-586 euvolemia evaluation, 585 hospital care until discharge ambulation and wound care, 586 analgesia, vital signs, IV luids, 585 bladder and bowel function, 585-586 hospital discharge, 586 recovery suite, 585 postterm, 838, 838f 840, 84 1 prior, on D & E, 363 rate, 4, 4t, 8 risks, 568-569 maternal mortality and morbidity, 568-569 on matenal request, 569 neonatal morbidity, 569 terminology, 567 thromboprophylaxis, 1 0 1 9- 1 022, 1 020t trauma, 929-930 Delivery, cesarean, prior, 5 9 1 -600 candidates, trial of labor, 594-597 cesarean delivery indication, prior, 596 fetal death, 596-597 fetal size and lie, 596 interdelivery interval, 596 multifetal gestational, 596 obesity, maternal, 596 uterine incision, prior, 594-596 closure, 595 imaging, 595-596 number, 595 type, 594-595, 5 94t, 595/ uterine rupture, prior, 596 vaginal delivery, prior, 596 controversy, history, 5 9 1-592, 592/ delivery route risks, 593-594 fetal and neonatal, 5 94-595 maternal, 594, 595t factors, 592, 593t labor and delivery considerations, 597-598 cervical ripening and labor stimulation, 597-59 8 epidural analgesia, 5 9 8 intrapartum care, 597 timing, 597, 597/ uterine scar exploration, 598 multiple repeat cesarean deliveries, 599-600, 599/ placenta previa, 775 uterine scar rupture, 598-599, 598/ vaginal birth after cesarean, 20 1 8, 600, 600f 600t Delivery, cesarean, technique, 571-580 hysterotomy, 573-580 abdominal closure, 578 adhesions, 578 classical cesarean incision, 578-580 indications, 5 8-579 uterine incision and repair, 579-580, 579/

Delivery, cesarean, technique (Cont.): incision, low transverse cesarean, 572/-577f 573-578 fetus delivery, 575-576, 575-576/ placenta delivery, 576-5 7, 577/ uterine, 574-575, 574/ uterine repair, 57 , 577/ Joel-Cohen technique, 578 Misgav Ladach technique, 578 laparotomy, 5 1-573 midline vertical incision, 5 3 transverse incisions, 571-572 Delivery, delayed coagulopathies, 785 preeclampsia, 730-733, 732t, 733t Delivery, multifetal pregnancy, 887-8 9 1 cesarean, 547f 890 route breech presentation, irst twin, 889 cephalic-cephalic presentation, 888 cephalic-noncephalic presentation, 888-889, 889t timing, 887-888 triplet or higher-order gestation, 890-8 9 1 vaginal birth after cesarean delivery, 890 vaginal delivery, second twin, 889-890, 890/ Delivery, placenta, 525-526, 526/ Delivery, vaginal, 5 1 6-533 anomalous fetuses, 525 female genital mutilation, 524-525, 525t home birth, 524 invasive cervical cancer, 1 1 95 multifetal pregnancy, second twin, 889-890, 890/ occiput anterior position, 5 1 7-5 1 9 cord clamping, 5 1 8-5 1 9 delivery o f head, 5 1 7-5 1 8, 5 1 7/ delivery of shoulder, 5 1 8, 5 1 8/ modiied Ri tgen maneuver, 5 1 7, 5 1 7/ occiput transverse position, 5 1 9 operative, 553-564 perinatal laceration care, 533 persistent occiput posterior position, 43 1 , 5 1 9-520 delivery, 5 1 9-520 morbidity, 5 1 9 placental abruption, 772-773 postpartum care, immediate, 527-533 birth canal lacerations, 527-529, 528/ episiotomy, 529-53 1 , 529/ fundamentals, 527 laceration and episiotomy repairs, 530/-533f 53 1 -532 preparation, 5 1 6 prior pelvic reconstructive surgery, 525 shoulder dystocia, 43 1 , 520-524 (See aso Shoulder dystocia, vaginal delivery) spinal block for, 490-49 1 third stage of labor, 525-527 management, general, 526 management, uterotonic, 526-527 ergonovine and methylergonovine, 527 misoprostol, 527 oxytocin, high-dose, 527 manual removal, 527, 528/ placenta delivery, 525-526, 526/ vacuum extraction, 562-564 technique, 563-564, 563f 563t vacuum extractor design, 562-563, 562f 563t water birth, 524

I n d ex Delivery, vaginal, operative, 553-564 classiication and prerequisites, 5 53-5 54, 554/ 5 54t forceps delivery, 557-562 blade application and delivery, 5 57-560, 5 5 /-559/ design, 5 57, 55 / face presentations, 561 forceps, 557, 557/ occiput posterior positions, 560-56 1 , 560-56 1/ occiput transverse positions, 561-562, 562/ incidence, 553 indications, 553 mechanisms of acute injury, perinatal, 556 morbidity, 5 5 5-556 maternal, 5 5 5 lacerations, 5 5 5 pelvic loor disorders, 5 5 5 perinatal acute perinatal injury, 5 5 5-556 infant morbidity, long-term, 556 mechanisms of acute injury, 556 training, 5 56-5 57 trial of, 556 Delivery room care, newborn, 607-6 1 0 immediate, 607 resuscitation protocol, 607-608, 608/ alternative ailway, 608-609 chest compressions, 609 discontinuation of resuscitation, 6 1 0 epinephrine, 6 1 0 initial assessment, 608, 609/ mask ventilation, 608, 609/ 6 1 0t umbilical cord clamping, 607 Delta hepatitis, 1 065 Delta hypertension, 71 1 , 7 1 1/ Delta sign, 868-869, 868/ Demyelinating diseases, 1 1 64-1 1 66 deinition, 1 1 64 multiple sclerosis, 1 1 64- 1 1 65 , 1 1 64/ Dendritic cells, fetal-maternal interface, 9 5 Dental care, in pregnancy, 1 7 1 Deoxycorticosterone, 72 Depo-Provera (DM PA) , 693 Depression. See aLso Major depression fetal-growth restriction, 1 1 74 major, 1 1 75-1 1 78 preeclampsia, 1 1 74 screening, perinatal, 1 1 74- 1 1 75, 1 1 75t Dermatologic disorders, 1 1 84-1 1 88 not speciic to pregnancy, 1 1 86-1 1 88 acne vulgaris, 1 1 87 erythema nodosum, 1 1 87 hidradenitis suppurativa, 1 1 88 neuroibromatosis, 1 1 88 psoriasis and pustular psoriasis, 1 1 87, 1 1 87/ pyoderma faciale, 1 1 88 pyogenic granuloma, 1 1 87-1 1 88, 1 1 8 / rosacea fulminans, 1 1 88 pregnancy-speciic dermatoses, 1 1 84-1 1 86 atopic etuption of pregnancy, 1 1 85t, 1 1 86 intrahepatic cholestasis of pregnancy, 1 1 84 pemphigoid gestation is, 1 1 84- 1 1 86, 1 1 8 5/ 1 1 85t pruritic urticarial papules and plaques of pregnancy, 1 1 85t, 1 1 86, 1 1 86/ treatment, 1 1 88 Dermatomyositis, 1 1 50-1 1 5 1

Descent, fetal, 427, 436 delivery, placenta and membranes, 4 1 5-4 1 6, 4 1 5/ 4 1 6/ pelvic loor changes, 2 1 , 4 1 4-4 1 5 second-stage disorders, 446-447 Desmopressin, for diabetes insipidus, 1 1 33 Development and physiology. See Embryofetal development; Embryonic development; Fetal development and physiology; I mplantation and placental development; speciic ypes Dexamethasone, for lung maturation, 1 34 Diabetes insipidus, 1 1 33 transient, 1 062 Diabetes mellitus, 1 097- 1 1 1 4. See a/so Gestational diabetes; Pregestational diabetes; speciic ypes classiication etiological, 1 097, 1 098t in pregnancy, 1 098, 1 098/ in pregnancy, White, 1 098, 1 099t inheritance, with maternal pregestational diabetes, 1 1 02-1 1 03 medical history, 1 47- 1 48, 1 48/ pregestational diabetes, 1 098- 1 1 07 Diabetic gastropathy, 1 1 04 Diabetic ketoacidosis, 1 1 04, 1 1 05t Diabetic nephropathy, 1 1 03 Diabetic neuropathy, 1 1 04 Diabetic retinopathy, 1 1 03-1 1 04 Diagnosis, prenatal, 277-296. See a/so Prenatal diagnosis Diagnostic radiation, in pregnancy, 906-909 CT, 907-908, 907/ 907t, 908/ luoroscopy and angiography, 906-907, 907t nuclear medicine studies, 908-909, 909t radiographic contrast agents, 908 radiographs, 906 Dialysis, in pregnancy, 1 036 Diamond-Blackfan anemia, 1 080 Diandric triploidy, 259 Diaphragm, maternal, 64, 64/ Diaphragmatic hernia, 1 046 Diaphragm plus spermicide, 694-695, 694/ Diarrhea, acute, 1 047- 1 048, 1 048t Diastasis recti, 53, 655 Diastolic murmur, 61, 950/ Diastolic notch, 2 1 4, 26 Diathesis, chronic hypertensive, 9 7 Diclegis, for hyperemesis gravidarum, 1 045 Didephys virginiana, 44. See Virgil Dienogest, 690 Diet, maternal for depression, 1 1 78 for gestational diabetes, 1 1 1 2 for hypoparathyroidism, 1 1 29 in multifetal pregnancy, 884 for obesity, maternal, 94 1-942 preconceptual care, 1 52 for preeclampsia prevention, 726-727 vegetarian, 1 52 Dietary reference intakes, pregnancy and lactation, 1 67, 167t Diethylstilbestrol (DES) cervical insuiciency, 354 Mullerian abnormalities, 42 tract abnormalities, 43/ 45 teratogenicity, 243-244 DiGeorge/Shprintzen syndrome, 26 1 t

Digestive enzymes, fetal, 1 35 Digestive system, fetal, 1 34- 1 3 5 . See a/so Gastrointestinal tract, fetal Digynic triploidy, 259 Dihydrotachysterol, for hypoparathyroidism, 1 1 29 Dilapan-S, 358, 358/ Dilated cardiomyopathies, 963 Dilation, cervical, 4 1 1 , 4 1 4, 4 1 4/ 43 5 curves average nulliparous, 432, 432/ duration of labor, 445, 445/ rate of change, by stage, 445 , 445t Dilational division, labor, 432, 432/ Dilation and curettage (0 & C) , 359, 360/ Dilation and evacuation (D & E) , 362-363 intact, 363 Dilation and extraction (0 & X), 363 Dilators Hank, 359 Hegar, 359, 360/ hygroscopic, 358-359, 3 5 8/ for cervical ripening, 508 osmotic, 3 5 8-359, 3 5 8/ Pratt, 359 Dilurional coagulopathy, 789 Dinoprostone, for induced abortion, 362t Dipalmitoylphosphatidylcholine (DPPC, PC) , surfactan t, 1 34 amniocentesis assessment, 638, 638/ Diphenhydramine, 1 1 88 Direct maternal death, 3 Direct monitoring, fetal, 4 57-458, 457/-459/ Discordant growth, twin fetuses, 8 8 1 -882 diagnosis, 882 etiopathogenesis, 8 8 1 -882 management fetal surveillance, 882 serial sonography, 882 Disease-modiying antirheumatic drugs (DMARDs), for rheumatoid arthritis, 1 1 47 Disloyalty. See Williams Obstetrics Disseminated gonococcal infections, 1 240 Disseminated intravascular coagulation (DIC) , 782 in pregnancy, 782-783 Diuresis, postpartum, 656 Diuretics, for hypertension in pregnancy chronic, 981 preeclampsia-eclampsia, 740 Dizygotic twins mechanisms, 864 vs. monozygotic twins, 864 DMPA. See Depot medroxyprogesterone acetate DNA triplet repeat expansion, anticipation, 267-268, 26 t fragile X syndrome, 267-268 Dolichocephaly, 1 84, 1 85 Doppler equation, 2 1 3, 2 1 3/ Doppler imaging, fetal, 2 1 3-2 1 5 continuous-wave, 2 1 3 Doppler equation, 2 1 3, 2 1 3/ Doppler shift, 2 1 3 ductus arteriosus, 2 1 4 ductus venosus, 2 1 5 , 2 1 5/ heart monitoring, 4 5 8-45 9 middle cerebral artery, 2 1 4-2 1 5, 2 1 4/ pulsed-wave, 2 1 3 systolic-diastolic (SID) ratio, 2 1 3 systolic-diastolic (SID) waveform, 2 1 3 , 2 1 3/ technology, 2 1 3, 2 1 3/

1 287

1 288

I n dex Doppler imaging, fetal (Cont): umbilical artery, 2 1 3-2 1 4, 854/ uterine artery, 2 1 4 Doppler shift, 2 1 3 Doppler velocimetry, fetal, 339-340 blood Bow, for anemia, 2 14-2 1 5 ductus venosus, 340 fetal-growth restriction, 853-854, 854/ intrapartum, 472 middle cerebral artery, 300, 303-304, 304, 340 umbilical artery velocimetry, 339-340 uterine artery, 340, 726 Double-bubble sign, 20 , 207/ Double decidual sign, 1 59, 1 59/ Double-outlet right ventricle, 957 Down syndrome. See Trisomy 2 1 (Down syndrome) Doxycycline for Lyme disease, 1 225 for malaria, 1 22 Drospirenone, 690 Drug-induced hemolysis, 1 078-1 079 Drugs, recreational (illicit). See also speciic ypes fetal-growth restriction, 8 5 1 preconceptual care, 1 52 prenatal, 1 62 teratogenici ty amphetamines, 247 cocaine, 248 marijuana, 249 opioids-narcotics, 248-249 phencyclidine, 249 toluene, 249 Duchenne muscular dystrophy, X-linked inheritance, 266 Duchenne paralysis, newborn, 630 Ductus arteriosus, fetal Doppler imaging, 2 1 4 Ductus venosus, fetal Doppler imaging, 2 1 5, 2 1 5/ Doppler velocimetry, 340 Diihrssen incision, for partial breech extraction, 548, 548/ Duke criteria, 965 Duncan mechanism, 4 1 6, 758 Duodenal atresia, 207, 207/ Duplicated renal collecting system, 208, 209/ Duplications, chromosome, 260-26 1 , 260/ microduplications, 260, 26 1 t Duration, normal labor, 434 Dysfibrinogenemia, 1 09 1 Dysgenetic testis, 38 Dysostoses, 2 1 0 Dyspnea, maternal physiological, 6 5 Dystocia, 44 1-455. See also speciic topics cesarean delivery for, 446, 446, 446t complications maternal, 453, 454-455 istula formation, 455 hemorrhage, 454 infection, 454 lower extremity nerve injury, 455, 66 1 pelvic Boor injury, 455 uterine rupture, 453, 454-455 uterine tears with hysterectomy, 454 perinatal caput succedaneum and molding, 43 1 , 43 1, 455 mechanical trauma, 455 descriptors, 44 1-442, 44 1 t fetopelvic disproportion, 448-454

Dystocia (Cont.): compound presentation, 454, 454/ historical, 44 1 mechanisms, 442 precipitous labor and delivery, 448 prematurely ruptured membranes at term, 447448 uterine dysfunction, 443 E

Eagle-Barrett syndrome, 325 Early neonatal death, 3 Early pregnancy loss, 346-347 Eastern European descent carrier screening, 29 1 genetic screening, prenatal, 1 65 preconceptual care, 1 5 1 Eating disorders, 1 52 , 1 1 80-1 1 8 1 fetal-growth restriction, 850 Ebola virus infection, 1 2 1 9 Ebstein anomaly, 959, 1 1 79 Eccentric cord insertion, 1 1 8 Echinacea, teratogenicity, 248t Echocardiography, 20 1 -205, 95 1 . See aso speciic disorders cardiac rhabdomyoma, 204 components, 202-203, 203t endocardial cushion defect, 203, 203/ hypoplastic left heart syndrome, 203, 204/ maternal measurements, 1 26 1 t M-mode, 204-205, 205/ premature atrial contractions, 204-205, 205/ specialized examination, 20 1 -203 tetralogy of Fallot, 204, 20/ ventricular septal defect, 202, 203 Echogenic fetal bowel, 287-288 , 287/ Echogenic intracardiac focus, 286-287, 287/ Echovirus infection, 1 2 1 6 Eclampsia, 734-738. See aso Hypertensive disorders of pregnancy clinical findings, 734-735, 734/ coagulopathies, 785 cognitive decline after, 723 continuous lumbar epidural block and, 496-497 edema, 735, 735/ fetal heart rate, 735, 735/ management, 736 magnesium sulfate, for convulsions, 736-738, 736t, 737, 738t (See aso Magnesium sulfate, for eclampsia seizures) on maternal and fetal risk, 734 vs. systemic lupus erythematosus, 1 1 4 1 , 1 1 4 1 t Ectocervix, 24 Ectopic pregnancy, 349, 3 7 1 -384 abdominal, 383-384 acute vs. chronic, 372 causes, 37 1 cervical, 382-383, 382/ cesarean scar, 38 1 -382, 382/ decidual cast, 373, 373/ interstitial, 380-38 1 , 380, 38 1/ other sites, 384 ovarian, 384 tubal, 37 1 -380 (See also Tubal pregnancy) Eczema, 1 1 8 5 t, 1 1 86 Edema. See speciic ypes Edwards syndrome. See Trisomy 1 8 (Edwards syndrome) Efavirenz, teratogenicity, 243 Efacement, cervical, 4 1 1 , 4 1 3-4 14, 4 1 3, 435

Ehlers-Danlos syndrome, 1 1 5 1 Eisenmenger syndrome, 958-959, 960, 960/ Elective abortion, 357. See also Abortion, induced Elective repeat cesarean delivery (ERCD) , 592. See also Delivery, cesarean, prior Electrical injuries, 930-93 1 Electrical shock, 1 52 Electric vacuum aspiration (EVA) , 359-360, 360/ Electrocardiogram (ECG), 949, 950/ fetal, 457-458 , 457/-459, 47 1 -472, 472/ beat-to-beat variability, 458 Electroconvulsive therapy (ECT), for depression, 1 1 78 Electrolyte and mineral metabolism, maternal, 57 calcium, 57 iodine, 57 magnesium, 57 phosphate, 57 sodium and potassium, 57 Wolf-Chaikof efect, 57 Electrolytes eclamptic convulsion on, 7 1 9-720 pregnancy-related hypertension on, 7 1 9-720 Electromagnetic ields, 1 52 Electronic fetal monitoring, 457-470 baseline heart activity, 459-464, 460t (See aso uner Heart rate monitoring, fetal electronic) complications, 48 1 external (indirect), 458-459 heart rate patterns, 459, 460t admission, low-risk pregnancies, 469-470 computerized interpretation, 470 second-stage labor, 469 internal (direct), 457-458, 457/-459/ intrapartum, labor, 436 periodic fetal heart rate changes, 464-469 trauma, 930 Embolectomy, for pulmonary embolism, 1 0 1 9 Embolism, pulmonary, 1 0 1 6- 1 0 1 9. See aso Pulmonary embolism oral contraceptives, 69 1 Embolization. See also specic ypes angiographic, for hemorrhage, 793-794 Embryofetal development, placenta in, 1 39-1 4 1 intervillous space, 1 39-1 40 placental transfer, 1 40- 1 4 1 , 1 40t mechanisms, 1 40 oxygen and carbon dioxide transfer, 1 40-14 1 , 1 40/ selective transfer and facilitated difusion, 1 4 1 Embryofetal energy and nutrition, 1 37-1 39 Embryofetus. See Clem Embryogenesis embryonic development, 1 25-128 (See aso Embryonic development) gestational age, 1 24- 1 25, 1 24/ Embryology external genitalia, 35, 37/ genital tract, 33-35, 34/ gonads, 35, 36/ urinary system, 33, 34/ Embryonic development, 1 25-1 28 embryonic period, 1 26-1 28, 1 26, 1 27/ overview, 1 25 , 1 25/ teratogenicity, 236, 236/ zygote and blastocyst development, 1 2 5 Embryonic miscarriage, 347 Emergency contraception, 696-697, 696t copper-containing IUDs, 696t, 697 hormonal, 696, 696t

I n dex Emissary veins, 629 Employment, on pregnancy, 1 70 Encephalocele, fetal sonography, 1 93 Encephalopathy, neonatal, 620-622 neuroimaging, 624-625 Endocardial cushion defect echocardiography, 203, 203/ fetal, therapy for, 3 1 6 Endocarditis gonococcal, 1 240 infective, 965, 966t Libman-Sacks, 957 Endocervical canal, 24 Endocervical epithelia, cervical ripening, 4 1 0 Endocervical polyp, 1 1 92- 1 1 93 Endocrine cascades, fetal, parturition phase 2, 4 1 0-4 1 1 , 4 1 0/ Endocrine disorders, 1 1 1 9- 1 1 33. See aso speciic ypes adrenal gland disorders, 1 1 30-1 1 32, 1 1 30/ 1 1 3 1 t parathyroid disease, 7 1 , 1 1 28-1 1 30, 1 1 29/ pituitary disorders, 1 1 32-1 1 33, 1 1 33/ thyroid disorders, 1 1 1 9- 1 1 28 (See aso Thyroid disorders; specic ypes) Endocrine system. See aso speciic gLands and hormones fetal, 1 36-1 37 adrenal glands, 1 37 immunological system B cells, 1 37 immunoglobulin A, 1 37 immunoglobulin G, 1 37 immunoglobulin M, 1 3 lymphocytes and monocytes, 1 3 7 pituitary gland, 1 36 thyroid gland, 1 36- 1 3 7 maternal, 68-72 adrenal glands, 7 1 -72 parathyroid glands, 7 1 pituitary gland, 68-69 pregnancy-related hypertension on, 7 1 9 thyroid gland, 69-7 1 , 70/ Endocrine tests, serum and blood, 1 258t. See aLso speciic ypes Endoglin, soluble (sEng), in preeclampsia, 7 1 6, 7 1 7/ Endometrial carcinoma, 1 1 97 Endometrial cycle, 83-8 5 menstruation, 84/ 85 proliferative phase, 83-84, 83/ secretory phase, 84-85 , 84/ Endometrial invasion, placenta, 9 1 Endometrial lesions, 1 1 9 Endometriosis, 1 1 97 Endometritis, postpartum, 667-6 0, 667t Endometrium, 24, 24/ basalis layer, 83, 84/ functionalis layer, 83-84, 84/ histology changes, cyclical, 80, 8 1/ preovulatory, 84 puerpera, regeneration, 653-654 Endomyometritis, postpartum, 667-670, 667t Endoparametritis, postpartum, 667-670, 66 t Endoplasmic reticulum stress response (ERSR) , parturition, 405-406 Endosalpinx, 28, 52 Endoscopic retrograde cholangiopancreatography (ERCP), 1 042, 1 070 Endoscopic tracheal occlusion, fetoscopic surgery, 323-324, 323/

Endothelial cell activation, hypertensive disorders, 7 1 5 injury, pregnancy-related hypertension, 7 1 6 preeclampsia, dysfunction, 725t, 726 Endothelin, 63, 7 1 6. See aLso speciic ypes Endothelin- 1 (ET- l ) parturition, 4 1 7 i n preeclampsia, 7 1 6 Endothelin-receptor antagonists, teratogenicity, 243 Endotoxin-induced hemolysis, 1 029 Endovascular trophoblasts, 88, 89/ Energy fetal, 1 37-1 3 9 (See aso Nutrition, fetal) fetal demands, on mother, 55, 55t Engagement, 427, 429/ Engorgement, breast, lactation, 659 Enhanced Recovery After Surgery (ERAS) protocols, for cesarean delivety, 570 Entamoeba histoytica, 1 227- 1 228 Enteral nutrition for gastrointestinal disorders, 1 043, 1 043t for hyperemesis gravidarum, 1 046 Enterovirus infections, 1 2 1 6 Envenomation, 93 1 Environmental exposures. See aso Teratogens miscarriage, 348 preconceptual care, 1 52 Enzyme deiciencies, autosomal recessive inheritance, 265 Ephedra, teratogenicity, 248t Epidermal growth factor (EGF) in breast milk, 657 endometrial cycle, 84 Epidural block, continuous lumbar, 487/ 493-49 on cesarean delivery rates, 495, 496/ complications back pain, 495 higher or total spinal blockage, 494 hypotension, 494 inefective analgesia, 494 maternal fever, 494-495 miscellaneous, 495 contraindications anticoagulation, 496 severe preeclampsia-eclampsia, 496-497 thrombocytopenia, 496 on fetal heart rate, 495 on labor, 495, 495t safety, 496 technique, 493-494, 494t timing, 495-496 Epidural block, obstetric, 492-493, 493/ with cesarean delivery, prior, 598 for external cephalic version, 550 Epigastric vessels, 1 4-1 5 , 1 5/ Epigenetics, 94 1 Epilepsy. See Seizure disorders Epinephrine, for newborn resuscitation, 6 1 0 Episiotomy indications, 530-53 1 infections, 674-6 5, 6 5t lateral, 529-530 mediolateral, 529-530, 529/ midline, 529-530 postpartum care, 529-53 1 , 529/ repair early, 674-675, 675t postpartum, 530-533/ 53 1-532

Episiotomy (Cont: end-to-end approximation, anal sphincter, 532, 532/ fourth-degree lacerations, 532, 533/ mediolateral episiotomy, 530/ 53 1 midline repair, 53 1-532, 5 3 1/ overlapping technique, 532 second-degree lacerations, 530/-53 1/ 53 1-532 third-degree lacerations, 532, 532/ types, 529-530 Epispadias, 4 1 Epstein-Barr virus mononucleosis, autoimmune hemolysis from, 1 078 Erb paralysis, newborn, 630 Ergonovine for labor, third-stage, 527 for uterine atony, 759 Ergot-oxytocin, for uterine atony, 60 Erythema infectiosum, 1 2 1 6 Erythema migrans, 1 225 Erythema nodosum, 997, 1 1 87 Erythroblastosis fetalis, 300 estrogen biosynthesis, placental, 1 05 Erythrocyte fetal, 1 3 1 placenta, D-antigen alloimmunization, 9 5 Erythrocyte enzyme deiciencies, 1 080 Erythrocyte membrane defects, inherited, 1 079- 1 080 Erythrocyte sedimentation rate (ESR), 59, 1 259t Erythroid hyperplasia, 58 Erythromycin, for lymphogranuloma venereum, 1 24 1 Erythropoiesis, fetal, 1 3 1 Erythropoietin recombinant, 1 077 serum, fetal maturity on, 1 3 1 Esophageal atresia, 206 Esophageal varices, 1 068 Essure microinsert, 705, 705/ Estimated date of confinement (EDC), 1 2 5 Estimated gestational age, postterm pregnancy, 8 3 5 Estradiol on endometrial cycle proliferative phase, 83-84 secretory phase, 84 endometrial invasion, 9 1 ovarian-endometrial cycle, 83 serum and blood, 1 259t Estriol low maternal serum, second-trimester, 284 synthesis, placental, 1 0 5 Estrogen, matenal dehydroepiandrosterone sulfate precursor, 1 04, 1 04/ on endometrial cycle, 83-84 in labor, 402 luteal phase, 83 ovarian cycle, 82, 82/ ovarian-endometrial cycle, 83 Estrogen biosynthesis, placental, 1 03- 1 04 biosynthesis, 1 03-1 04, 1 04/ directional secretion, 1 04 fetal conditions on, 105 anencephalic fetus, 1 05 fetal adrenal cortical hypoplasia, 1 05 fetal demise, 105 fetal erythroblastosis, 105

1 289

1 290

I n dex Estrogen biosynthesis, placental (Cont.: fetal-placental sulfatase deficiency, 1 0 5 trisomy 2 1 , 1 0 5 maternal conditions o n , 1 05-1 06 Addison disease, 1 06 androgen-producing tumors, 1 06 glucocorticoid treatment, 1 05- 1 06 Estrogen receptor . (ER.) in labor, 402 ovarian-endometrial cycle, 83 Estrogen receptor 3 (ER3) in labor, 402 ovarian-endometrial cycle, 83 Etanercept, for rheumatoid arthritis, 1 147 Ethacridine lactate, for induced abortion, 363 Ethanol. See Alcohol Ethnicity maternal mortality, 6, 6/ pregnancy rates by, 4 Ethyl alcohol. See Alcohol Etonogestrel implant, 685-688 Euploid abortion, 347 Euthyroid autoimmune thyroid disease, 1 1 25- 1 1 26 Evaluation, newborn condition, 6 1 0-6 1 3 acidemia, clinical significance, 6 1 2-6 1 3, 6 1 2t Apgar score, 6 1 0-6 1 1 , 6 1 0t fetal acid-base physiology, 6 1 1-6 1 2, 6 1 2/ umbilical cord blood acid-base studies, 6 1 1 Evans syndrome, 1 078 Evening primrose oil, teratogenicity, 248t Exercise for gestational diabetes, 1 1 1 2 in preconceptual care, 1 52 on preeclampsia risk, 727 in pregnancy, 1 70, 1 70t Expedited partner therapy (EPT), for chlamydia, 1 24 1 Expiratory reserve volume, 64 in pregnancy, 64, 65f, 987 Explusion, labor, 43 1 Expressivity, autosomal dominant inheritance, 265 Expulsive force abnormalities, 442-44 labor disorders fetal station, labor onset, 447 prolongation, active-phase, 442-446 6-cm rule, background, 444t-446t, 445-446, 445f, 446/ 6-cm rule, vs. 4-cm, 444 arrest disorder, 442, 443-444, 443f, 443t Obstetric Care Consensus Committee, 444, 444/ protraction disorder, 442, 443, 443t, 444 Sae Prevention 0/the Primay Cesarean Delivey, 442 second-stage descent disorders, 446-44 prolongation, latent-phase, 442, 443t prolongation disorder, 443t pushing eforts, matenal, 447 uterii1e dysfunction, risks, 447 uterine dysfunction, 442 fundal dominance, 442 hypertonic uterine, 442 hypotonic uterine, 442 incoordinate, 442 Extension, labor, 429, 430/ External anal sphincter (EAS), 2 1f, 22

External cephalic version (ECV), 549-550 complications, 549 conduction analgesia, 550 indications, 549 moxibustion, 550 technique, 549-550, 550/ tocolysis, 550 External (indirect) electronic monitoring, 458-459 External genitalia. See also speciic sites embryology, 35, 37/ External parasitic twins, 8 5f, 876 External rotation, labor, 428, 429-43 1 Extraamnionic saline infusion (EASI), for labor induction, 508, 508/ Extracellular luid, in preeclampsia, 7 1 9 Extrachorial placentation, 1 1 3, 1 1 3/ Extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome, 920, 994 for cardiovascular disorders, 965 for congenital diaphragmatic hernia, 1 9 8 critical care and trauma, 920 EXIT to, 328 for meconium aspiration syndrome, 620 Extracranial hematomas, newborn, 628-629, 629/ Extravillous trophoblasts, 88, 89/ Extremely low birthweight, 3, 803 Ex-utero intrapartum treatment (EXIT), 3 1 9t, 327-328, 32 f, 327t Eye infection prophylaxis, newborn, 6 1 3-6 1 4 Eyes, maternal, 73 of Texas are upon you. See Williams Obstetrics F

Face and neck, fetal sonography, 1 96-1 98 cystic hygroma, 1 97-1 98, 1 9 8/ facial clefts, 1 96-1 97, 1 97/ micrognathia, 1 96, 1 97/ normal, 1 96, 1 96f, 1 97/ Face presentation, 422, 422, 422t fetopelvic disproportion, 450-454, 4 5 1/ etiology, 45 1 fundamentals, 450-45 1 , 45 1/ labor mechanisms, 45 1 -452, 45 1/ management, 452 forceps delivety, 561 left and mentum anterior, 425/ Facial cleft imaging, fetal, 1 96-1 97, 1 97/ Facial nerve Bell palsy, 1 1 67, 1 1 67/ trauma, newborn, 630, 630/ Facial paralysis, newborn, 630, 630/ Factor V Leiden mutation, 1 005, 1 006t, 1 00 See also Thrombophilias Factor V Leiden mutation thrombophilia, 1 005f, 1 006t, 1 007 Factor VIII deficiency, 1 090 Factor VIII inhibitors, 1 090 Factor IX inhibitors, 1 090 Factor X deficiency, 1 090- 1 09 1 Factor X I deficiency, 1 09 1 Factor XII deficiency, 1 09 1 Factor XIII, 60 Factor XIII deficiency, 1 09 1 Failure to progress, 442, 443 Fallopian tubes, 28, 29f, 52 endosalpinx, 28, 52 Mullerian abnormalities, 45 ectopic pregnancy, 37 1 -3 2 myosalpinx, 28, 52 torsion, 52

Fallot tetralogy, 959 False knots (umbilical cord), 1 1 9 False labor, 50, 403, 432 Family history, preconceptual care, 1 49, 1 50/ Family planning services, 9 Fanconi anemia, 1 080 FAST scan, for trauma, 929, 929/ Fatigue, in pregnancy, 1 75 Fat metabolism, maternal, 56-57 adiponectin, 56 ghrelin, 56-57 hyperlipidemia, 56 leptin, 56 visfatin, 5 Fatty acids cardioprotective, on preeclampsia risk, 727 placental metabolism, on fetal growth, 845 FBN} gene, 1 1 5 1 FC2 female condom, 694, 694/ Feeding, newborn, 6 1 5 Female genital mutilation, vaginal delivery, 524-525, 525t FemCap, 695 Femoral artery, 1 4-1 5 , 1 5/ Femoral fractures, newborn, 63 1 Femur length (FL), sonography, 1 85 Fentanyl, for labor, 487t, 488 Ferguson reflex, 4 1 2 Ferning, 5 1 Ferrous fumarate, 1 077 Ferrous gluconate, 1 077 Ferrous sulfate, 1 077 Fertility after cancer therapy, 1 1 92 inlammatory bowel disease on, 1 050 leiomyomas on, 1 1 97 rate, defined, 3 Fertility awareness-based methods Cervical Mucus Method, 695 Standard Days Method, 695 Symptothermal Method, 695 Temperature Rhythm Method, 695 Fertilization, 87-88, 87f, 1 24/ blastocyst, 87f, 88 blastomeres, 87-88 , 87/ morula, 87, 88 zygote, 87-88, 87/ Fetal adrenal cortical hypoplasia, placental estrogen biosynthesis, 105 Fetal adrenal gland-placental interactions, 1 04-1 06. See also Adrenal glands, fetal-placental interactions Fetal age, 1 6 1 , 1 66- 1 67 Fetal alcohol syndrome, 1 62, 239-240, 239t, 240/ Fetal alloimmune thrombocytopenia (FNAIT), 307-308, 3080 108 Fetal assessment, 3 3 1 -34 1 . See also Assessment, fetal; speciic assessments; speciic ypes Fetal attitude, 422-423, 422/ Fetal axis pressure, 4 1 3 Fetal blood sampling, 294-295, 295/ scalp, 470, 470/ Fetal body size, fetopelvic disproportion, 450, 450/ Fetal cell microchimerism, 1 1 39 Fetal death definition, 3 rate, 3, 4, 5/

I ndex Fetal demise estrogen biosynthesis, placental, 1 05 multifetal pregnancy, 882-884 death of one fetus, 882-888, 883/ death of one fetus, impending, 884 pregestational diabetes, unexplained, 1 1 0 1- 1 1 02 Fetal descent. See Descent, fetal Fetal development and physiology, 1 28- 1 37, 845 cardiovascular system, 1 29- 1 3 1 circulatory changes at birth, 1 3 1 fetal circulation, 1 29- 1 3 1 , 1 30/ fetoplacental blood vol ume, 1 3 1 cetral nervous system, 1 28-1 29 brain, 1 28-1 29, 1 29/ spinal cord, 1 29 digestive system, 1 34- 1 35 digestive enzymes, 1 3 5 liver, 1 35 meconium, 1 3 5 pancreas, 1 3 5 stomach emptying, 1 3 5 swallowing, 1 34- 1 3 5 endocrine gland development, 1 36-1 37 adrenal glands, 1 37 immunological system B cells, 1 37 immunoglobulin A, 1 37 immunoglobulin G, 1 37 immunoglobulin M, 1 37 lymphocytes and monocytes, 1 37 pituitary gland, 1 36 thyroid gland, 1 36- 1 3 energy and nutrition, 13 - 1 39 amino acids, 1 39 free fatry acids and triglycerides, 1 38 glucose and fetal growth, 1 3 8 fetal macrosomia, 1 38 glucose transport, 1 38 heavy metals, placental sequestration, 1 3 9 ions and trace metals, 1 39 leptin, 1 3 8 proteins, 1 39 vitamins, 1 39 fetal period epochs, gestational weeks, 1 28, 1 6 1 1 2, 1 28, 1 28/ 1 6, 1 28 20, 1 28 24, 1 28 28, 1 28 32 and 36, 1 28 40, 1 28 hemopoiesis, 1 3 1 - 1 3 3 coagulation factors, 1 33 fetal hemoglobin, 1 3 1 - 1 33, 920/ hemoglobin and gestational age, 1 3 1 , 1 32/ plasma proteins, 1 33 platelets, 1 3 1 , 1 32/ multifetal pregnancy, long-term, 8 3 musculoskeletal system, 1 37 respiratory system, 1 33-1 34 anatomical maturation, 1 33 breathing, 1 34 corticosteroids and lung maturation, 1 34 pulmonary surfactant, 1 33- 1 34, 1 34/ respi ratory distress syndrome, 1 33 urinary system, 1 35- 1 36

Fetal disorders, 300-3 1 3. See also specic ypes anemia, fetal, 300-306 hemorrhage, fetomaternal, 302t, 306-307, 306/ hydrops fetalis, 300, 309-3 1 2 mirror syndrome, 3 1 2-3 1 3 thrombocytopenia, fetal, 30 -309 Fetal distress, 472. See also Nonreassuring fetal status postterm pregnancy, 837-838, 838/ Fetal D NA in maternal circulation, 273-274 cell-free DNA, 273, 273/ aneuploidy screening, 2 3-274 fetal sex determination, 274 Rh D genotype evaluation, 2 4 Fetal endoscopic tracheal occlusion (FET), 323-324, 323/ Fetal erythroblastosis, placental estrogen biosynthesis, 1 0 5 Fetal expulsion stage, 4 1 1 Fetal factor XIII, 1 33 Fetal ibrinogen, 1 33 Fetal ibronectin (fFN) amnion epithelial cells, 96 preterm birth, 8 1 4 Fetal growth, 844-847 birthweight, normal, 845-846, 846f, 846t vs. birthweight, 846-84 insulin and insulin-like growth factors, 845 phases, 845-846, 845/ velociry, 846-847 Fetal-growth disorders, 847-859 incidence, 844 overgrowth, 1 38, 856-8 59 (See also Macrosomia) pregestational diabetes, 1 1 00- 1 1 0 1 , 1 1 0 1/ Fetal growth potential customized, 847 genomic, 845, 846 Fetal-growth restriction, 847-8 56 brain sparing, 847-848 deinition, 847 depression, 1 1 74 early-onset, 854 with hypertension, 983 intrauterine, preterm birth, 803 long-term sequelae fetal overgrowth, 849 fetal undergrowth, 848-849 lung maturation, accelerated, 849 management, 8 54-856 algorithm, 855, 8 5 5/ deliveY timing, 8 5 5-856 labor and delivery, 4 8, 608, 8 56 near-term fetus, 8 5 5f, 856 remote from term, 8 5 5f, 856 morbidity and mortality, perinatal, 847, 847f, 848 placental abnormalities, 848 postterm pregnancy, 838-839 preterm birth, 803 prevention, 854 recognition, 852-856 amnionic luid volume measurement, 853 Doppler velocimettY, 853-8 54, 854/ early, 852 prior growth-restricted fetus, 8 52 sonographic measurement, 852-853, 853/ uterine fundal height, 852 risk factors and etiologies, 849-852 anemia, 850-85 1 antiphospholipid syndrome, 85 1

Fetal-growth restriction (Cont: chromosomal aneuploidies, 852 congenital malformations, 852 constitutional small mothers, 849 drugs and teratogens, 8 5 1 gestational weight gain and nutrition, 849-850 hypoxia, chronic, 850 infections, 85 1 -852 infertility, 85 1 multifetal gestation, 8 5 1 , 85 1f, 872, 8 2/ placental, cord, and uterine abnormalities, 85 1 pregestational diabetes, 8 5 0 social issues, 850 vascular and renal diseases, 850 from seizure disorders, 1 1 5 9 selective, twins, 88 1 symmetrical vs. asymmetrical, 847-848 three compartments, 849, 849/ umbilical artery Doppler, 2 1 3-2 14, 854/ Fetal head molding Braxton Hicks contractions, 43 1 , 43 1/ dystocia, 43 1 , 43 1J, 455 shape changes, 43 1 , 43 1/ size, fetopelvic disproportion, 450, 450/ Fetal hydantoin syndrome, 240, 240/ Fetal imaging. See Imaging, fetal; specic ypes Fetal Intelligent Navigation Echocardiography (FINE), 2 1 2-2 1 3 Fetal lie, 42 1-422, 422/ with cesarean delivery, prior, 596 longitudinal, 422, 422/ oblique, 422, 452 transverse abnormal labor, 452-454 etiology, 453 management, 454 mechanism of labor, 453-454, 454/ position and presentation, 452-453 neglected, 453 normal labor, 422, 422t, 425/ Fetal-matenal interface decidual immune cells, 95 decidual macrophages, 95 decidua natural killer cells, 95 dendritic cells, 95 human leukocyte antigens, 95 immunogenicity, trophoblasts, 95 natural killer cells, 95 T cells, maternal, 95 Fetal measurements, sonography, 1 83- 1 84, 1 262t-1 270t birthweight, smoothed percentiles for twins with dichorionic placentation, 1 265t with monochorionic placentation, 1 26 5 t cerebellar diameter, transverse, b y gestational age, 1 269t crown-rump length and menstrual age, 1 83-1 84, 1 84f, 1 86f, 1 263t gestational sac diameter and, 1 262t gestational sac diameter, mean, 1 262t long bone length, by gestational age, 1 267 t ocular parameters, by gestational age, 1 268t thoracic circumference, by gestational age, 1 266t umbilical artery Doppler indices, reference values, 1 2 Ot weight by gestational age, 1 264t

1 29 1

1 292

I ndex Fetal-membrane senescence, 4 1 1 Fetal movements, 3 3 1 -333 clinical application, 332-333 physiology, 33 1-332, 332/ Fetal-pelvic index, 450 Fetal period, for teratogenicity, 236, 236/ Fetal period epochs, gestational weeks, 1 28, 1 6 1 1 2, 1 28, 1 2 8/ 1 6, 1 28 20, 1 28 24, 1 28 28, 1 28 32 and 36, 1 28 40, 1 28 Fetal pillow, 575 Fetal-placental clock, 4 1 1 Fetal-placental sulfatase deficiency, placental estrogen biosynthesis, 1 05 Fetal-placental unit endocrine function, 725t, 726 Fetal position (presentation), 423-424, 423/-425/ See aso Delivery, vaginal; speciic positions breech, 422, 422, 422t, 425/ cesarean delivery, 542, 543t first rwin, multifetal pregnancy, 889 cephalic, 422, 422f, 422t compound, 454, 454/ deinition, 422 face, 422, 422f, 422t fetopelvic disproportion, 450-454, 45 1/ (See also Fetopelvic disproportion) forceps delivery, 5 6 1 left and mentum anterior, 425/ multifetal pregnancy, 888 shoulder, 422, 422t, 425/ vertex, 422, 422t left occiput anterior, 423f, 427 left occiput posterior, 423f, 43 1 left occiput transverse, 427, 430/ right occiput anterior, 423, 427 right occiput posterior, 424, 430, 43 1 right occiput transverse, 424, 427 Fetal programming, 1 66, 94 1 Fetal pulse oximetry, 47 1 , 47 1/ Fetal scalp blood sampling, 470, 470/ Fetal station, 4 1 4, 4 1 5, 436 labor onset, expulsive disorders, 447 Fetal thrombotic vasculopathy, 1 1 4, 1 1 5 Fetal warfarin syndrome, 247, 247/ Fetomaternal hemorrhage, 306-307 causes, 302, 302t clinical presentation and diagnosis, 306 incidence, 306, 306/ laboratory tests, 307, 307/ quantifi c ation, 307 with red cell alloimmunization, 302, 302t Fetopelvic disproportion, 443, 448-454 brow presentation, 452, 452/ compound presentation, 454, 454/ face presentation, 450-454, 45 1/ etiology, 45 1 fundamentals, 450-45 1 , 4 5 1/ labor mechanisms, 4 5 1 -452, 45 1/ management, 452 fetal body and head size, 450, 450/ pelvic capacity, 448-449 contracted inlet, 448-449 contracted midpelvis, 449 contracted outlet, 449

Fetopelvic disproportion (Cont.): pelvic capacity estimation, 449-450 pelvic fractures, 449 transverse lie, 452-454, 453/ etiology, 453 management, 454 mechanism of labor, 453-454, 454/ neglected, 453 position and presentation, 452-453 Fetopelvic proportion, 443 Fetoscopic surgery, 321-324. See also Surgery, fetoscopic Fetotoxic agents, 234, 234t, 238-249. See also Teratogens Fetus compressus, 883, 883/ Fetus-in-fetu, 875, 876 Fetus papyraceus, 883, 883/ Fever, maternal from continuous lumbar epidural block, 494-495 puerperal, 666-667 Fibrinogen, fetal, 1 33 Fibrinogen concentrate, for hemorrhage, 789t, 790 Fibrin stabilizing factor, 60, 1 33 Fibroblast growth factor, fetal macrosomia, 1 38 Fibroblast growth actor receptor 3 (FGF3) gene advanced paternal age, 265 chondrodysplasia, 2 1 0-2 1 1 phenotypic heterogeneity, 265 Fibroids, 1 1 95-1 1 97, 1 1 96f, 1 1 9 I Fibronectin, fetal (FN) amnion epithelial cells, 96 preterm birth, 8 1 4 Fifth disease, 1 2 1 6 Filgrastim, for cancer, 1 1 9 1 First-trimester screening, aneuploidy sonographic, 282, 288 traditional tests, 28 1-282 eicacy, 282 nuchal translucency, 28 1 -282, 282/ nuchal translucency, crown-rump length on, 28 1 unexplained abnormalities, 282 First-trimester sonography, 1 85- 1 86 components assessed, 1 85-1 86, 1 85 t fetal anomaly detection, 1 86, 1 86t indications, 1 85, 1 85 t nuchal translucency, 1 86, 1 86t Fistula cervicovaginal, 1 037 ileouterine, 1 03 8 maternal formation, dystocia, 4 5 5 urogenital tract, 1 037- 1 038 vesicouterine, 1 037- 1 038 Flexible sigmoidoscopy, 1 042 Flexion, labor, 429, 429/ Flexion point, 563, 563/ Fluconazole for candidiasis, 1 247 teratogenicity, 24 1 Fluid therapy. See aso speciic disorders for hemorrhage, 788 for preeclampsia, 40 Fluorescence in situ hybridization (FISH), 270-27 1 , 27 1/ chromosome abnormalities, 254, 255t Fluorescence polarization test, 638 Fluoride, pregnancy and lactation, 1 67t, 1 68

Fluoroquinolones for salmonellosis, 1 220 for shigellosis, 1 220 Fluoroscopy, in pregnancy, 906-907, 907t Flying fetus, 540 Foam stability test, 638 Focal nodular hyperplasia, 1 068 oral contraceptives, 692 Focal placenta accreta, 778, 779 Focal seizures, 1 1 58 Foley balloon tamponade, for placenta previa, 777 Folic acid deficiency, in megaloblastic anemia, 1 077- 1 078 supplements, for neural-tube defect prevention, 1 28-1 29, 1 69 Folinic acid, for toxoplasmosis, 1 226 Follicles, 8 1 Follicle-stimulating hormone (FSH) fetal, 1 36 maternal ovarian cycle, 8 1-82, 82/ ovarian-endometrial cycle, 80, 8 1/ Follistatin, blastocyst, 88 Fontanels, at term, 554, 5 54/ Fontan repair, 959 Food and Drug Administration (FDA) drug and medication categories, 238, 238t Footling breech presentation, 422, 422/ Forced vital capacity, 64 Forceps delivery, 557-562 blade application and delivery, 557-560, 557/-559/ design, 557, 557/ face presentations, 5 6 1 forceps, 5 5 7 , 557/ occiput posterior positions, 560-56 1 , 560/-561/ occiput transverse positions, 561-562, 562/ for partial breech extraction, 546-547, 547/ Forebag, amnionic fluid, 4 1 4, 4 1 7/ 46,X disorders of sex development, 39t, 40-41 46,X gonadal dysgenesis, 40 46,X ovotesticular, 40 46,X testicular, 40 androgen excess, 40-4 1 ovarian development, 40 46,XY disorders of sex development, 39, 39t 46,XY gonadal dysgenesis, 39-40 androgen production or action, 40 mixed gonadal dysgenesis, 40 partial gonadal dysgenesis, 40 pure gonadal dysgenesis, 40 testicular regression, 40 Four-chamber view, cardiac imaging, 20 1 , 20 1, 202/ Fractures, newborn, 630-63 1 Fragile X mental retaration 1 (FMRl) gene, 267-268 Fragile X syndrome DNA triplet repeat expansion, 267-268 X-linked inheritance, 266, 267 Frank breech presentation, 422, 422, 539, 539/ total breech extraction, 544, 549 Frankenhauser plexus, 27, 28 Fraser syndrome, congenital high airway obstruction sequence, 1 99-200, 200/ Fraternal rwins, mechanisms, 864

I n dex Free fatty acids, fetal, 1 38 Fresh-frozen plasma, for hemorrhage, 790 Fulminant hepatic necrosis, 1 062 Functional divisions, labor, 432, 432/ Functionalis layer, 83-84, 84/ Functional M R imaging (MI), 1 1 56 Functional residual capacity, 64, 65/ Fundal dominance, 442 expulsive force, uterine dysfunction, 442 Fundal height fetal-growth restriction, 852 prenatal, 1 64- 1 65 Fungal infections, disseminated, 1 228 Fungal pneumonia, 994-995 Funic presentation, 1 20 Funic soule, 1 65 Funisitis, 1 1 6 Funneling, cervical, 354 Furosemide for hyperparathtyoidism, 1 1 29 for persistent severe postpartum hypertension, 743-744 G

Gadolinium-based contrast agents, 2 1 6 Galactocele, 659 Gallbladder, maternal, 68 Gallbladder disorders cholelithiasis and cholecystitis, 1 069, 1 070/ endoscopic retrograde cholangiopancreatography, 1 070 gallbladder disease in pregnancy, 1 069- 1 070 medical vs. surgical management, 10 0 Gallstones, 1 069, 1 070/ Gap j unctions, myometrial, parturition, 405, 406/ Garden heliotrope, teratogenicity, 248t Garlic, teratogenicity, 248t Gaskin maneuver, 522 Gasps, fetal, 333, 333/ Gastric cancer, 1 204 Gastric emptying time, maternal, 68 Gastroesophageal reflux disease (GERD), 1 046 Gastrointestinal atresia, 206-207 Gastrointestinal disorders, maternal, 1 042- 1 053 diagnostic techniques endoscopy, 1 042 laparotomy and laparoscopy, 1 043 noninvasive imaging, 1 043 nutritional support, 1 043 nutritional support, 1 043, 1 043t small bowel and colon disorders, 1 047- 1 053 appendicitis, 1 052- 1 053, 1 053/ Clostridium diicile infection, 1 048 colonic pseudo-obstruction, 1 052 diarrhea, acute, 1 047- 1 048, 1 048t inflammatory bowel disease, 1 048-1 05 1 , 1 048t intestinal obstruction, 1 05 1 - 1 052, 1 052/ ostomy and pregnancy, 1 0 5 1 upper GI tract disorders, 1 043-1 047 achalasia, 1 046-1 047 bleeding, 1 047 diaphragmatic hernia, 1 046 gastroesophageal reflux disease, 1 046 hiatal hernia, 1 046 hyperemesis gravidarum, 1 043-1 046 (See also Hyperemesis gravidarum) peptic ulcer disease, 1 047

Gastrointestinal tract, physiology fetal, 1 34-1 35 digestive enzymes, 1 3 5 liver, 1 3 5 meconium, 1 35 pancreas, 1 35 stomach emptying, 1 3 5 swallowing, 1 34-1 3 5 maternal, 6 8 gallbladder, 68 gastric emptying time, 68 hemorrhoids, 68 liver, 68 pyrosis, 68 Gastrointestinal tract cancer, 1 204 Gastrointestinal tract imaging, fetal sonography, 206-207 double-bubble sign, 207, 207/ duodenal atresia, 207, 207/ gastrointestinal atresia, 206-20 normal, 206 Gastroschisis, fetal sonographic, 205, 206/ Gaucher disease, 1 080 Gender gonadal, 38 phenotypic, 38 Gender assignment, 4 1 Gene microarray techniques, prenatal, 8 Generalized pustular psoriasis of pregnancy, 1 1 87, 1 1 87/ Generalized tonic-clonic seizures, 1 1 58- 1 1 59 GeneReview database, 253 Genetic diseases. See also speciic diseases andgenes incidence, 253 preconceptual care, 1 49-1 5 1 Eastern European and ] ewish descent, 1 5 1 family history, 1 49, 1 50/ neural-tube defects, 1 49 phenylketonuria, 1 49-1 50, 1 49t thalassemias, 1 50-1 5 1 Genetic heterogeneity, 264 Genetics, 253-274. See also speciic topics chromosomal abnormalities, 254-264 deinition, 253 genomics, obstetric, 253-254 inheritance, modes of, 264-270 pregnancy-related hypertension, 7 1 5 , 1 St Genetics Home Reference (GHR) , 254 Genetic Testing Registry (GTR) , 253, 288 Genetic tests, 270-274 chromosomal microarray analysis, 271-272, 272/ clinical applications, 272 cytogenetic analysis, 270 fetal DNA in maternal circulation, 273-274 cell-free DNA, 273, 273/ aneuploidy screening, 273-274 fetal sex determination, 274 Rh D genotype evaluation, 274 luorescence in situ hybridization, 270-27 1 , 27 1/ prenatal screening, 1 65 whole exome sequencing, 2 2-273 whole genome sequencing, 272-273 Genitalia. See also speciic ypes ambiguous, 38-39 embryology, external, 35, 37/ Genital tract. See also speciic anatomic structures and disorders embryology, 33-35, 34/

Genital tract anomalies, maternal. See aso speciic ypes recurrent pregnancy loss, 353 Genitourinary anomalies, congenital, 33-46. See also speciic ypes bladder and perineal abnormalities, 4 1 genitourinary tract embryology, 33-37, 34, 37/ Mullerian abnormalities, 4 1 -45, 42t, 43/ sex development disorders, 38-4 1 , 39t uterine flexion, 46, 46/ Genitourinary tract embryology anomalies, 33-3 external genitalia, 35, 3 f genital tract, 33-35 , 34/ gonads, 35, 36/ urinary system, 33, 34/ Genomic copy variant, 260 Genomics deinition, 253 obstetric, 253-254 technology, 8 Gentamicin for gonorrhea, 1 240 for listeriosis, 1 220 Gestational age, 1 24- 1 25, 1 24/ assessment, 1 83-1 85, 1 83 t abdominal circumference ratio, 1 85 biparietal diameter, 1 84-1 85, 1 84/ cephalic index, 1 84 crown-rump length, 1 83-1 84, 1 84{, 186f, 1 262t femur length, 1 85 suboptimally dated, 1 8 5 thoracic circumference, 1 266t estimated newborn, 6 1 4-6 1 5 postterm pregnancy, 835 Naegele rule, 1 25 , 1 6 1 Gestational alloimmune liver disease, 1 066 Gestational diabetes, 1 098, 1 1 07- 1 1 1 4 definition, 1 1 07- 1 1 08 incidence, 1 1 07 laboratory tests, prenatal, 1 65 management, 1 1 1 1- 1 1 1 3 diet, 1 1 1 2 exercise, 1 1 1 2 fundamentals, 1 1 1 1 glucose monitoring, 1 1 1 2 insulin treatment, 1 1 1 2 obstetrical, 1 1 1 3 oral hypoglycemic agents, 1 1 1 2- 1 1 1 3 postpartum evaluation, 1 1 4t, 1 1 1 3-1 1 1 4 recurrent, 1 1 1 4 maternal and fetal efects, 1 1 1 0 fetal macrosomia, 1 1 1 1 fundamentals, 1 1 OOt, 1 1 1 0- 1 1 1 1 maternal obesity, 1 1 1 1 neonatal hypoglycemia, 1 1 1 1 obesity, 939 prenatal care, 1 65 screening and diagnosis, 1 1 08-1 1 1 0 Hyperglycemia and Adverse Pregnancy Outcome study, 1 1 09-1 1 1 0, 1 1 1 0/ International Association of Diabetes and Pregnancy Study Group, 1 1 1 0 NIH Consensus Development Conference, 1 1 10 risk-based recommended screening strategy, 1 1 08- 1 1 09, 1 1 08t threshold glucose values for diagnosis, 1 1 08, 1 1 08t glucose tolerance test, 1 1 09, 1 1 09t

1 293

1 294

I nd ex Gestational hypertension, 1 1 . See a/so Hypertensive disorders of pregnancy Gestational sac, 86, 1 59 definition, 349 sonography, 349 threatened abortion, 349 Gestational thrombocytopenia, 1 086 Gestational transient thyrotoxicosis, 1 1 22 Gestational trophoblastic disease, 388-396. See a/so speciic ypes classiication, 388 deinition, 396 gestational trophoblastic neoplasia, 393-396 hydatidiform mole, 388-393 subsequent pregnancy, 396 Gestational trophoblastic neoplasia (GTN), 393-396 clinical indings, 393 deinition, 388 diagnosis, staging, and prognostic scoring, 393-394, 394t etiology, 393 histological classiication, 394-395 epithelioid trophoblastic tumor, 395 gestational choriocarcinoma, 394-395, 395/ invasive mole, 388, 394 placental site trophoblastic tumor, 395 subsequent pregnancy, 396 treatment, 395-396 Ghrelin, 56-5 Gigantomastia, 52, 53 Ginger, teratogenicity, 248t Ginkgo bi/oba, teratogenicity, 248t Ginseng, teratogenicity, 248t Glands of Montgomety, 53 Glatiramer acetate, for multiple sclerosis, 1 1 65 Glomerular capillary endotheliosis, 720, 72 1/ Glomerular diseases, 1 032- 1 034, 1 033t acute nephritic syndromes, 1 032- 1 033, 1 032t glomerulonephritis, 1 032 nephrotic syndromes, 1 032t, 1 033-1 034, 1 033/ patterns, 1 032, 1 032t Glomerular endotheliosis, in preeclampsia, 720 Glomerular iltration rate (GFR) , 65-66, 65, 1 026, 1 034 tests, 1 260t Glomerulonephritis, 1 032 chronic, 1 032 rapidly progressive, 1 032 Glucocorticoids. See a/so speciic ypes for colitis, 1 050 in estrogen biosynthesis, placental, 1 05-1 06 for lung maturation, 1 34 with preeclampsia, 733, 33t with preterm labor, multifetal pregnancy, 886 Glucose, maternal on fetal growth, 1 38, 845 fetal macrosomia, 1 3 8 glucose transport, 1 38 monitoring, gestational diabetes, 1 1 1 2 Glucose-6-phosphate dehydrogenase (G6PD) deiciency, 1 080 Glucose transport, fetal, 1 3 8 Glucose transport proteins (GLUTs), fetal, 1 3 8 Glucosuria, maternal, 66 Glyceryl trinitrate, for preinduction cervical ripening, 507 Glycosaminoglycans (GAGs), cervical ripening, 409, 409/

Goitrous hypothyroidism, fetal and neonatal, 1 1 22 Goitrous thyrotoxicosis, fetal and neonatal, 1 1 2 1 , 1 1 2 1/ Golinumab for colitis, 1 050 for rheumatoid arthritis, 1 1 47 Gonadal dysgenesis, 3 8 Gonadal gender, 3 8 Gonadal mosaicism, 264 Gonadotropin-releasing hormone (GnRH), placental, 99t, 1 0 1 Gonadotropins ovulation, 8 1, 82 rwinning, 867 Gonads. See also speciic ypes embryology, 3 5 , 36/ Gonococcal infections, 1 239- 1 240 disseminated, 1 240 Gonorrhea, 1 239-1 240 disseminated gonococcal infections, 1 240 incidence, 1 239 newborn, 6 1 3 screening and treatment, 1 239-1 240 Goodpasture syndrome, 1 032 G-protein-coupled receptors, parturition, 406-407, 406/ Grandmother efect (theory), 302 Granulomatosis with polyangiitis, 1 1 50 Gravida, 1 60 Greater vestibular glands, 1 7, 1 7/ Group A Streptococcus infections, 1 220 Group B Streptococcus infections, 1 220- 1 222, 1 22 1, 1 222/ laboratory tests, prenatal, 1 65 maternal and perinatal infection, 1 220 prophylaxis intrapartum antimicrobial, 1 22 1 - 1 222, 1 222, 1 222t perinatal infections, 1 220- 1 22 1 , 1 22 1/ vaccine, GBS, 1 22 1 Growth, fetal. See Fetal growth Growth diferentiation factor 9 (GDF9), 8 1 ovulation, 8 1f, 8 2 Growth disorders, fetal, 844-859. See a/so Fetal­ growth disorders; specic ypes Growth hormone (GH) fetal, 1 36 maternal, 69 Growth hormone-releasing hormone (GHRH), placental, 99t, 1 0 1 Growth hormone variant (hGH-V), placental, 99t, 1 02 Growth potential, fetal customized, 847 genomic, 845, 846 Guanylyl cyclase, parturition, 407 Guillain-Barre syndrome, 1 1 66 H Hrreceptor blockers, for peptic ulcer disease, 1 047 Hadegan, 235 Haemophi/us ducreyi, 1 244 Haemophilus inluenzae pneumonia, 992-994, 993t Hair, maternal, 54 hair growth periods, 54 telogen eluvium, 54 Hank dilator, 359 Hansen disease, 1 224- 1 225 Hantavirus infection, 1 2 1 6

Hantavirus pulmonary syndrome, 1 2 1 3 Haultain incision, 762 Head, fetal compression, on heart rate, 465 molding Braxton Hicks contractions, 43 1 , 4 3 1/ dystocia, 43 1 , 43 1, 455 shape changes, 43 1 , 43 1/ size, fetopelvic disproportion, 450, 450/ Headache, 1 1 57-1 1 58, 1 1 5 f classiication, 1 1 57, 1 1 57/ cluster, 1 1 58 incidence, 1 1 57, 1 1 57/ management, 1 1 58 migraine, 1 1 57 in pregnancy, 1 1 57-1 1 58 in preeclampsia, 723 in pregnancy, 1 74-1 75 tension-type, 1 1 57 Head-to-abdomen circumference ratio (HC/AC), 847 Health-care-associated pneumonia (HCAP), 992 Health status, prenatal, 1 6 1-163 Heart, fetal, 200-205 cardiac examination, basic, 20 1 , 20 1-202/ four-chamber view, 20 1 , 20 I, 202/ left ventricular outlow tract view, 20 1 , 202/ other views, 20 1 , 202/ right ventricular outflow tract view, 20 1 , 202/ echocardiography, 201-205 cardiac malformations, 200-20 1 cardiac rhabdomyoma, 204, 204/ components, 202-203, 203t echogenic intracardiac focus, 286-287, 287/ endocardial cushion defect, 203, 203/ hypoplastic left heart syndrome, 203, 204/ M-mode, 204-205, 205/ premature atrial contractions, 204-205, 205/ specialized examination, 20 1-203 tetralogy of Fallot, 204, 204/ ventricular septal defect, 202, 203 normal, 1 98 Heart, maternal, 60-61 Braunwald ventricular function, 6 1 , 6 1, 949 diastolic murmur, 6 1 left ventricular mass, 6 1 , 6 1/ plasticity, 6 1 Heart activity, baseline fetal, 459-464. See also Heart rate monitoring, fetal electronic Heart block congenital, 3 1 6 systemic lupus erythematosus, 1 1 43 Heartburn, 68, 1 046 in pregnancy, 1 74 Heart disease. See also Cardiovascular disorders surgically corrected, 954-955 anticoagulation, 247, 954-955 cardiac surgery in pregnancy, 955 heart transplantation, pregnancy after, 955 valve replacement before pregnancy, 954, 954t Heart examination, sonographic, 20 1 , 20 1/-202/ Heart failure, 964-965 diagnosis, 964-965 etiology, 964 intrapartum, 962 management, 965 preeclampsia, 964 thyroid storm and, 1 1 22, 1 1 23/

I n dex Heart rate, fetal, 459-46 1 . See also Nonreassuring fetal status, intrapartum assessment continuous lumbar epidural block on, 495 contraction stress testing, 334, 334t decelerations, postterm pregnancy, 838, 838/ in eclampsia, 73 5, 73 5/ measurements, 332, 332/ nonreassuring fetal status, 472-4 8 (See also Nonreassuring fetal status, intrapartum assess men t) deinition, 4 2-473 diagnosis, 473-474, 4 3t Heart rate, maternal, 60, 1 26 1 t Heart rate monitoring, fetal electronic, baseline, 457-470 accelerator inAuences, 459, 460t admission, low-risk pregnancies, 469-4 0 baseline heart activity, 459-464 beat-to-beat variability, 335, 458, 46 1 -462, 46 1f, 463/ decreased, 462 increased, 462 cardiac arrhythmia, 462-464, 464/ abrupt baseline spiking, 462, 4641 definition, 459, 460t rate, 459-46 1 accelerator inAuences, 459, 460t bradycardia, 459, 46 1 , 46 1/ chemoreceptors on, 459-46 1 decelerator inAuences, 459, 460t sinusoidal, 464, 464/ tachycardia, 46 1 wandering baseline, 461 sinusoidal heart rate, 464, 464/ wandering baseline, 46 1 beneits, 477 bradycardia, 459, 46 1 , 46 1/ cerebral palsy, 623-624 chemoreceptors on, 459-46 1 complications, 48 1 computerized interpretation, 470 decelerator inAuences, 459, 460t extenal (indirect), 458-459 heart rate patterns, 459, 460t brain injury, 476-477, 476/ second-stage labor, 469, 469/ cord compression, 465, 469, 469/ internal (direct), 457-458, 457-459/ non reassuring fetal status, recommendations, 478, 478t periodic changes, 464-469 accelerations, 335, 335f, 464, 465 decelerations, 464-469 early, 464-466, 465/ head compression, 465-466, 465/ late, 466, 466/ prolonged, 468-469, 468/-469/ uteroplacental insuiciency, 465, 466 variable, 466-468, 466/-468/ deinition, 464 nomenclature, 464-465 recommendations, current, 478, 478t sinusoidal, 464, 464/ tachycardia, 46 1 wandering baseline, 46 1 Heart rate tests, fetal contraction stress, 334, 334t nonstress, 334-337 abnormal, 336, 336f, 337/

Heart rate tests, fetal (Cant.): acceleration, 335, 335/ acoustic stimulation, 337 beat-to-beat variability, 335 decelerations during, 336-33 deinition, 334 false-normal, 337 incidence of use, 334-335 interval between testing, 336 normal, 335-336, 335/ Heart sounds fetal, 1 65 maternal, 6 1 , 950/ Heart transplantation, pregnancy after, 955 Heart valves. See Valvular heart disease Heavy metals, placental sequestration, 1 39 Hegar dilator, 359, 360/ Helicobacter pylori, 1 047 HELLP syndrome clinical presentation, 72 1 coagulopathies, 785 deinition, 7 1 9, 722 hepatocellular damage, 1 058 liver in, 72 1 -722, 72 1/ pregnancy-associated hemolysis, 1 079 vs. thrombotic microangiopathies, 1 088- 1 089, 1 089t Hematocrit fetal, 1 3 1 maternal, 58 Hematological changes maternal, 57-58 hemoglobin concentration and hematocrit, 58 iron metabolism, 58 hepcidin, 58 iron requirements, 58, 58/ puerperium, 655, 655/ Hematological disorders fetal, thrombocytopenia, 1 087 maternal, 1 075- 1 09 1 (See also specic ypes) anem�� 1 0 5- 1 0 8 1 hemoglobinopath ies, 1 08 1- 1 084 inherited coagulation defects, 1 089- 1 0 9 1 platelet disorders, 1 086- 1 08 9 polycythemias polycythemia vera, 1 08 1 secondaty polycythemia, 1 08 1 thalassemia syndromes, 1 084- 1 086 thrombophilias, 1 09 1 newborn, 625-62 anemia, 625-626 hemorrhagic disease of the newborn, 626-627 hyperbilirubinemia, 626 polycythemia and hyperviscosity, 626 thrombocytopenia, 627 Hematology, serum and blood constituents, 1 255t Hematoma cord, 1 20 extracranial, newborn, 628-629, 629/ massive subchorion ic, 1 1 5 maternal, 1 1 4-1 1 5, 1 1 4/ piriformis muscle, 66 1 , 66 1/ puerperal, 764-765, 65/ classiication and risks, 764, 765/ clinical course and management, 764-765 diagnosis, 764, 65/ subamnionic, 1 1 5

Hematuria, 66 idiopathic, 1 026 Hemochorial placentation, 8 5 Hemochromatosis, neonatal, 1 066- 1 067 Hemoconcentration in eclampsia, 7 1 8-7 1 9, 7 1 8/ in preeclampsia, 7 1 8, 7 1 8/ Hemodynamics, matenal invasive monitoring, for preeclampsia-eclampsia, 740 late pregnancy, 6 1f, 62, 62t pregnancy changes, intensive care, 9 1 , 9 1 7t pregnancy-related hypertension on, 71 -7 1 8 myocardial function, 7 1 8 ventricular function, 7 1 8, 7 1 8/ Hemoglobin fetal, 1 3 1- 1 33, 920/ gestational age and, 1 3 1 , 1 32/ maternal concentration, 58 total hemoglobin mass, 65 Hemoglobin A, 1 32 Hemoglobin C, 1 083, 1 084t Hemoglobin C-3-thalassemia, 1 083, 1 084t Hemoglobin E, 1 084 Hemoglobin F fetal, 1 32- 1 33 function , 1 32 Hemoglobin H disease, 1 085 Hemoglobinopath ies, 1 08 1 - 1 084 hemoglobin C and C-3-thalassemia, 1 083, 1 084t hemoglobin E, 1 084 hemoglobinopathy in the newborn, 6 1 4, 1 084 prenatal diagnosis, 270, 1 084 sickle-cell hemoglobinopathies, 108 1 - 1 083 sickle-cell trait, 1 083 Hemoglobinopathy in the newborn, 6 1 4, 1 084 Hemoglobin SC, 265 , 1 082, 1 082t Hemolysis autoimmune, 1 0 8 drug-induced, 1 078- 1 079 microangiopathic, 7 1 9 after preeclampsia, 7 1 9 pregnancy-associated, 1 079 pregnancy-induced, 1 079 Hemolytic anemias, 1 078- 1 080 autoimmune hemolysis, 1 078 bacterial toxins, 1 079 drug-induced hemolysis, 1 078- 1 079 erythrocyte enzyme deiciencies, 1 080 erythrocyte membrane defects, inherited, 1 0 9- 1 080 paroxysmal nocturnal hemoglobin uria, 1 079 pregnancy-associated, 1 079 Hemolytic disease of the fetus and newborn (H DFN) , 300 Hemolytic uremic syndrome (HUS) , 1 088- 1 089, 1 089t Hemophilia A, 1 089-1 090 X-linked inheritance, 266 Hemophilia B, 1 089- 1 090 Hemopuiesis, fetal, 1 3 1 - 1 33 coagulation facrors, 1 33 fetal hemoglobin, 1 3 1 - 1 33 , 920/ hemoglobin and gestational age, 1 3 1 , 1 32/ plasma proteins, 1 33 platelets, 1 3 1 , 1 32/

1 29 5

1 296

I nd ex Hemorrhage, fetomaternal, 306-307, 930 causes, 302, 302t clinical presentation and diagnosis, 306 incidence, 306, 306/ laboratory tests, 307, 307/ quantiication, 307 with red cell alloimmunization, 302, 302t Hemorrhage, obstetrical, 5 5- 87. See also speciic topics; speciic ypes after abortion, surgical, 361 anemia from, 1 077 birth canal injuries, 763- 67 cervical lacerations, 763-764 puerperal hematomas, 764-765 , 765/ uterine rupture, 765-767, 766t, 67/ vulvovaginal lacerations, 763 blood loss estimation, 758 coagulopathies, 782-787 deinition and incidence, 755, 756-75 , 756, 756t dystocia, 454 hemostasis mechanisms, normal, 7 5 5 incidence, 7 5 5 morbidly adherent placenta, 777-782 placental abruption, 67- 73 placenta previa, 773-777 postpartum, 758 late (secondary), 392t, 654, 758 quantiication, 307 risks, 757, 757, 757t timing antepartum, 75 -75 8 postpartum, 7 5 8 uterine atony, 758-76 1 uterine inversion, 6 1-763 Hemorrhage management, obstetrical, 787-794 blood replacement, 788-792 (See aso Blood replacement, for hemorrhage, obstetrical) fluid resuscitation, 788 fundamentals, 787 hypovolemic shock, 788 surgical procedures, adjunctive, 792-794 angiographic embolization, 793-794 internal iliac artery ligation, 792-793, 794/ pelvic packings, 794 uterine artery ligation, 792, 792/ uterine compression sutures, 792, 793/ Hemorrhagic disease of the newborn, 626-627 Hemorrhagic stroke, 1 1 6 1 t, 1 1 62-1 1 64 intracerebral, 1 1 6 1, 1 1 62- 1 1 63, 1 1 62/ subarachnoid, 1 1 6 1, 1 1 63 arteriovenous malformations, 1 1 63-1 1 64 intracranial aneurysm, 1 1 63 Hemorrhoids, 68 in pregnancy, 1 75 Hemostasis, 59, 60t mechanisms, normal, 7 5 5 Hemostatic agents, topical, for hemorrhage, 79 1 Henoch-Schonlein purpura, 1 032, 1 1 50 Heparin with low-dose aspirin, on preeclampsia risk, 728 postpartum venous thrombosis, 1 0 1 4- 1 0 1 5 Heparin-induced osteoporosis, 1 0 1 5 Heparin-induced thrombocytopenia (HIT), 1 008, 1015 Hepatic. See also Liver entries Hepatic adenoma, 1 069 oral contraceptives, 692

Hepatic adenoma, benign, oral contraceptives, 692 Hepatic cysts, 1 032 Hepatic disorders, 1 058-1 069. See also specic ypes acetaminophen overdose hepatotoxiciry, 1 068 acute fatry liver of pregnancy, 1 060-1 062, 1 060, 1 06 1 t autoimmune hepatitis, 1 066 cirrhosis, 1 067 classiication, 1 058, 1 059t clinical and laboratory indings, 1 058, 1 059t focal nodular hyperplasia, 1 068 gestational alloimmune liver disease, 1 066 HELLP syndrome, 1 05 8 hepatic adenoma, 1 069 hepatitis, 1 062-1 066 (See also Hepatitis) intrahepatic cholestasis of pregnancy, 1 0591 060 iron and copper overload, 1 066- 1 067 liver transplantation, 1 069, 1 069t nonalcoholic fatry liver disease, 1 067 portal hypertension and esophageal varices, 1 068 pregnancy-induced physiology, 1 058- 1 059 Wilson disease, 1 067 Hepatic necrosis, fulminant, 1 062 Hepatitis, 1 062- 1 066 acute viral, 1 0 59t, 1 062 autoimmune, 1 066 chronic viral, 1 063, 1 063t copper overload, 1 067 iron overload, 1 066 Hepatitis A, 1 063 vaccination, 1 063 Hepatitis B , 1 063- 1 065, 1 064/ vaccination, newborn, 6 1 4, 1 065 Hepatitis C, 1 065-1 066 Hepatitis D, 1 065 Hepatitis G, 1 066 Hepatocellular cancer, 1 204 Hepcidin, 5 8 in iron-deiciency anemia, 1 076 Herbal remedies, teratogeniciry, 247, 248t Hereditary connective tissue disorders, 1 1 5 1 Ehlers-Danlos syndrome, 1 1 5 1 Marfan syndrome, 1 1 5 1 osteogenesis imperfecta, 1 1 5 1 Hereditary nonspherocytic anemia, 1 080 Hereditary spherocytosis, 1 079 Hernia diaphragmatic, 1 046 hiatal, 1 046 Heroin abuse prenatal care, 1 62 teratogeniciry, 248-249 Herpes gestationis, 1 1 84-1 1 86, 1 1 8 5, 1 1 85t Herpes simplex virus (HSV), 1 24 1 - 1 244 adult disease, 1 24 1- 1 242, 1 242/ diagnosis, 1 243 management, 1 243, 1 244t shedding prophylaxis, peripartum, 1 243-1 244 vertical transmission, 1 242- 1 243 Herpes zoster, 1 2 1 2 Heterogeneiry allelic, 264-265 genetic, 264 locus, 264 phenorypic, 265 Heteroplasmy, 267 Heterotaxy, 3 1 6

Heterotopic pregnancies. See also Tubal pregnancy incidence, 371 Heterozygous achondrodysplasia, 2 1 1 Heterozygous carrier, autosomal recessive inheritance, 265 Hiatal hernia, 1 046 Hidradenitis suppurativa, 1 1 88 High-densiry lipoprotein (HDL) cholesterol Depo-Provera on, 689 oral contraceptives, 69 1 serum and blood, 1 259t High-frequency oscillatory ventilation, for respiratory distress syndrome, preterm newborn, 637 Hip dislocation, newborn, 63 1 Hispanic women, maternal mortaliry, 6, 6/ Histoplasmosis pneumonia, 995 Hodgkin disease, 1 202, 1 202t Hofbauer cells, 93 Holoprosencephaly, sonography, 1 94, 1 9 5/ Homan sign, 1 0 1 0 Home birth, 8 vaginal delivery, 5 24 Home care, puerperium coitus, 663 follow-up care, 663 maternal morbidiry, late, 663, 663t Homoplasmy, 267 Horizontal transmission, 1 209. See also speciic inections Hormonal contraceptives. See Contraceptives, hormonal Hormones. See also speciic ypes pregnancy-related hypertension on, 7 1 9 Hormones, placental, 98- 1 04, 99t. See aso speciic hormones activin, 99t, 1 02 estrogen production, 1 03- 1 04 biosynthesis, 1 03-1 04, 1 04/ directional secretion, 1 04 human chorionic gonadotropin, 98- 1 00 biological functions, 1 00 biosynthesis, 98, 99t concentrations, 99- 1 00, 99/ levels, abnormal, 1 00 regulation, 1 00 human placental lactogen, 99t, 1 00- 1 0 1 biosynthesis, 1 00- 1 0 1 metabolic actions, 1 0 1 hypothalamic-like releasing hormones corticotropin-releasing hormone, 99t, 1 0 1 gonadotropin-releasing hormone, 99t, 1 0 1 growth hormone-releasing hormone, 99t, 101 thyrotropin, 99t, 1 0 1 inhibin, 99t, 1 02 leptin, 1 02 neuropeptide Y, 99t, 102 parathyroid hormone-related protein, 99t, 1 02 pituitary-like hormones, growth hormone variant, 99t, 1 02 production rates, 98, 98t progesterone production, 1 02-1 03, 1 03/ relaxin, 1 00 Horner syndrome, newborn, 630 Hospital-acquired methicillin-resistant Staphylococcus aureus (HA-MRSA), 1 223 Hospital-acquired pneumonia (HAP), 992

I nd ex Hospital discharge, newborn, 6 1 6 Hospitalist, Ob/Gyn, 8 Human chorionic gonadotropin (hCG). See also 3-human chorionic gonadotropin (3-hCG) embryonic period, 1 26 luteal phase, 82, 83 maternal, 69, 70/ parturition, 407 placental, 98-1 00 biological functions, 1 00 biosynthesis, 98, 99t concentrations, 99- 1 00, 99/ levels, abnormal, 1 00 regulation, 1 00 pregnancy detection, early, 346 pregnancy tests, 1 58- 1 59, 1 5 8/ Human immunodeiciency virus (HIV) , 1 24 1 250, 1 248, 1 250t antepartum care, 1 248- 1 249 antiretroviral therapy, 1 249, 1 250t clinical manifestations, 1 247 delivery planning, 1 249 etiopathogenesis and epidemiology, 1 247 postpartum care, 1 250 prenatal screening, 1 24 -1 248, 1 248/ vertical transmission, 1 248 Human leukocyte antigens (HLAs) , fetal-maternal interface, 95 Human papillomavirus (HPV) , 1 244- 1 24 5 cervical intraepithelial neoplasia, 1 1 93 condyloma acuminata, 1 244, 1 245 condyloma acuminata treatment, 1 245 incidence, 1 244 neonatal infection, 1 245 vaccine, 1 245 Human placental lactogen (PL) fetal, 1 38 placental, 99 t, 1 00- 1 0 1 biosynthesis, 1 00- 1 0 1 metabolic actions, 1 0 1 Humeral fractures, newborn, 63 1 H untington disease, 1 1 65 Huntington procedure, 762 Hyaline membrane disease, 637 Hydantoin, teratogenicity, 240, 240/ Hydatidiform mole, 388-393 3-hCG , 39 1 clinical findings, 390-3 9 1 , 3 9 1/ coexisting normal fetus, 88 1 complete, 388, 389 diagnosis, 3 9 1 -392, 3 9 1/ epidemiology and risk factors, 389 historical findings, 388-389, 389/ management, 392-393, 392t partial, 388, 389 pathogenesis, 389-390, 389, 390t subsequent pregnancy, 396 rwin pregnancy, 390 Hydralazine, for hypertension chronic, 98 1 preeclampsia-eclampsia, 739, 739/ Hydramnios, 1 89, 225, 226-230 categorization, 227-228, 228t clinical presentation, 227, 227f, 228/ complications, 229-230 etiology, 228-229 congenital anomalies, 228, 229t diabetes mellitus, 228-229

Hydramnios (Cont: idiopathic hydramnios, 229, 230 multifetal gestation, 229 management, 230 m ulti fetal p regnancies, 871 myasthenia gravis, 1 1 66 pregestational diabetes, 1 1 02 pregnancy outcomes, 230 severe, 227, 227, 228, 228t Hydrocephaly, 1 93 . See also Ventriculomegaly Hydrops fetalis, 228, 300, 309-3 1 2 diagnostic evaluation, 3 1 0, 3 1 1 t, 3 1 2/ immune hydrops, 309 isolated efusion or edema, 3 1 0-3 1 2 mirror syndrome, 3 1 2-3 1 3 non immune hydrops, 309-3 1 1 pathogenesis, proposed, 309, 3 1 0/ 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, cholesterol biosynthesis, 1 03 H ydroxychloroquine for malaria, 1 227 for rheumatoid arthritis, 1 1 47 1 5-Hydroxyprostaglandin dehydrogenase (PGDH), menstruation, 85 Hydroxyurea, for sickle-cell hemoglobinopathies, 1081 Hygroscopic dilators, 3 58-359, 358/ for cervical ripening, 508 Hymen, 1 7- 1 8 Hymenal anomalies, 4 1 Hymenal ring, 20, 20/ Hyperalimentation, for gastrointestinal disorders, 1 043 Hyperbilirubinemia, newborn, 6 1 5, 626 pregestational diabetes, 1 1 02 Hypercalcemic crisis, 1 1 28, 1 1 29 Hypercoiled umbilical cord, 1 1 7 Hyperemesis gravidarum, 1 74, 1 043- 1 046 complications, 1 044, 1 044t criteria, 1 043- 1 044 etiopathogenesis, 1 044 gestational transient thyrotoxicosis, 1 1 22 management, 1 044- 1 046, 1 044, 1 045t pregestational diabetes, 1 1 04 Hyperglycemia, maternal on birthweight, 845 fetal pathology and, 147 preconceptual care, 1 47- 1 48 on pregnancy outcomes, 939, 940/ Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, 1 1 09- 1 1 1 0, 1 1 1 0/ Hyperhomocysteinemia, 1 005, 1 00--1 008 Hyperinsulinemia. See also Diabetes mellitus; Gestational diabetes; Pregestational diabetes on birthweight, 845 Hyperlipidemia, 56 Hyperparathyroidism, 1 1 28-1 1 29 Hyperpigmentation, matenal, 53 chloasma, 53 linea alba, 53 Hyperreactio luteinalis, 52, 1 1 99 Hyperstimulation, uterine, 480-48 1 Hypertension idiopathic intracranial, 1 1 68 multifetal pregnancy, 8�2-873 with obesiry, 939, 940/ portal, 1 068 pulmonary, 960-962

Hypertension, chronic, 975-984 adverse pregnancy efects, 978-980, 978t morbidity and mortality maternal, 978 perinatal, 979-980, 979/ placental abruption, 979 preeclampsia prevention, 979 superimposed, 978-979, 979/ blood pressure range, 975 defi n ition and classification, 976 diagnosis and evaluation, 977 guidelines and recommendations, 976, 976t incidence, 975 management, in pregnancy, 980-984 antihypertensive drugs, 980-9 8 1 ACE inhibitors, teratogenicity, 98 1 adrenergic-receptor blocking agents, 980 calcium-channel blockers, 980-98 1 diuretics, 98 1 vasodilators, 98 1 antihypertensive treatment in pregnancy, 981-983 mild or moderate hypertension, 98 1 -982, 982t recommendations, therapy, 982-983 severe chronic hypertension, 98 1 "tight control," 982, 982t delivery, 983-984 diagnosis, confirmation, 980 expectant, early-onset preeclampsia, 983 fetal assessment, 983 intrapartum considerations, 984 postpartum care, 984 pregnancy-aggravated hypertension, 983 prognosis, long-term, 984 metabolic syndrome, 9'7 monality, 975-976 preconceptual counseling, 976-977, 977t pregnancy on, 977, 978/ pregnancy-related hypertension, 744-745 risk factors, 977 treatment and benefits, nonpregnant adults, 9:6, 976t Hypertension management, severe, 738-740 diuretics, 740 hydralazine, 739, 739/ labetalol, 739 nifedipine, 740 other antihypertensive agents, 740 Hypertensive disorders of pregnancy, 7 1 0-745 eclampsia, 734-738 (See also Eclampsia) etiopathogenesis, 7 1 3-7 1 7 cascade of events, 7 1 3 etiology, 7 1 4-7 1 5 endothelial cell activation, 7 1 5 immunological factors, 7 1 4-7 1 5 trophoblastic invasion, 7 1 4, 7 1 4/ genetic factors, 7 1 5, 7 1 5t pathogenesis angiogenic and antiangiogenic proteins, 7 1 6-7 1 -, 7 1 7/ endothelial cell injury, 7 1 6 pressor responses, increased, 7 1 6 vasospasm, 7 1 5-7 1 6 phenotypic expression, preeclampsia syndrome, 7 1 3-7 1 4 incidence and risk facrors, - 1 3, 7 1 3t long-term consequences, -44-745

1 29 7

1 298

I n dex Hypertensive disorders of pregnancy (Cont.: cardiovascular morbidity, 744-745 central nervous system sequelae, 45 future pregnancies, 744 morbidity and mortality, 744, 745 t renal sequelae, 745 morbidity and mortality, maternal, 7 1 0 , 978 multifetal pregnancy, 8 2-873 oral contraceptives, 69 1 pathophysiology, 7 1 7-725 blood volume, 7 1 8-7 1 9, 7 1 8/ brain, 722-724 cerebral blood flow, 723 cerebrovascular, 723, 723/ neuroanatomical lesions, 722-723, 722/ neuroimaging studies, 724 neurological, 723 visual changes and blindness, 724, 724/ cardiovascular system, 7 1 7 coagulation changes, 7 1 9 endocrine and hormonal, 7 1 9 luid and electrolyte, 7 1 9-720 hemodynamic changes and cardiac function, 7 1 7-7 1 8 myocardial function, 7 1 8 ventricular function, 7 1 8, 7 1 8/ hemolysis, 7 1 9 kidney, 7 20, 72 1/ liver, 72 1 -722, 72 1/ thrombocytopenia, maternal, 7 1 9 utero placental perfusion, 724-725 placental abruption, 770 prediction, 725-726 endothelial dysfunction and oxidant stress, 725t, 726 fetal-placental unit endocrine function, 725t, 726 other markers, 726 renal function tests, 725t, 726 tests, 725, 725 t vascular resistance testing and placental perfusion, 725-726, 725t preeclampsia, 728-734 (See aso Preeclampsia) preexisting hypertension management, 983 prevention, 726-728 antihypertensive drugs, 727 antioxidants, 727 anti thrombotic agents, 727-728 dietary and lifestyle modiications, 726-727 methods, 727t with superimposed chronic hypertension, 979 stroke risk, 1 1 60 terminology and diagnosis, 7 1 0-7 1 1 cri teria, 7 1 1 delta hypertension, 7 1 1 , 7 1 1/ gestational hypertension, 71 1 preeclampsia syndrome, 7 1 1 , 7 1 2t severity indicators, 7 1 1 -7 1 2, 7 1 2t superimposed on chronic hypertension, 7 1 2-7 1 3 transient hypertension, 7 1 1 Hypertensive disorders of pregnancy, management, 738-744 analgesia and anesthesia, 743 blood loss at delivery, 743 fluid therapy, 740 hemodynamic monitoring, invasive, 740 neuroprophylaxis (magnesium sulfate), 74 1 -743 indications, 742

Hypertensive disorders of pregnancy, management (Cont: randomized trials, 74 1-742, 4 1 t selective vs. universal prophylaxis, 742-743, 742t persistent severe postpartum hypertension, 743 furosemide for, 743-744 plasma exchange, 744 plasma volume expansion, 740, 74 1 t pulmonary edema, 740 reversible cerebral vasoconstriction syndrome, 744 severe hypertension, 738-740 diuretics, 740 hydralazine, 739, 739/ labetalol, 739 nifedipine, 740 other antihypertensive agents, 740 Hyperthyroidism, 1 1 20-1 1 22 diagnosis, fetal, 1 1 22 fetal and neonatal efects, 1 1 2 1 - 1 1 22, 1 1 2 1/ hyperemesis gravidarum and gestational transient thyrotoxicosis, 1 1 22 subclinical, 1 1 22-1 1 23 thyroid storm and heart failure, 1 1 22, 1 1 23/ thyrotoxicosis gestational transient thyrotoxicosis, 1 1 22 pregnancy, 1 1 20-1 1 2 1 , 1 1 2 1 t Hypertonic uterine dysfunction, 442 Hypertrophic cardiomyopathies, 962-963 Hyperuricemia, preeclampsia, 726 Hyperviscosity, newborn, 626 Hypervolemia. See also Blood volume maternal, 57-58, 58/ multifetal pregnancies, 870-87 1 pregnancy-induced, 65 5-656, 655/ 1 034, 1 034/ Hypocalcemia, neonatal, pregestational diabetes, 1 1 02 Hypocoiled umbilical cord, 1 1 7 Hypodysibrinogenemia, 1 0 9 1 H ypoibrinogenemia coagulopathies, 784 familial , 1 09 1 management, 789 Hypogastric nerves, 27/ 28 Hypoglycemia, neonatal gestational diabetes, 1 1 1 1 pregestational diabetes, 1 1 02 Hypoparathyroidism, 1 1 29 Hypophosphatasia, 2 1 1 Hypoplastic anemia, 1 080- 1 0 8 1 pregnancy, 1 080 ater bone marrow transplantation, 1 080- 1 08 1 Hypoplastic left heart syndrome echocardiography, 203, 204/ Fontan repair, 959 pregnancy after, 959-960 Hypotension, maternal from continuous lumbar epidural block, 494 from spinal block, 49 1 supine, 63 Hypothalamic-like releasing hormones, placental corticotropin-releasing hormone, 99t, 1 0 1 gonadotropin-releasing hormone, 9 9 t, 1 0 1 growth hormone-releasing hormone, 99t, 101 thyrotropin, 99t, 1 0 1

Hypothyroidism fetal and neonatal goitrous, 1 1 22 nongoitrous, 1 1 22 maternal, 1 1 23-1 1 24, 1 1 23t, 1 1 24t classiication, 1 1 23-1 1 24 congenital, 1 1 27 fetal, therapy for, 3 1 8 postpartum thyroiditis, 1 1 27 subclinical, 1 1 24- 1 1 25 , 1 1 26t Hypothyroxinemia, isolated maternal, 1 1 25 Hypotonic uterine dysfunction, 442 Hypovolemic shock management, 788 placental abruption, 771 Hypoxia, chronic, fetal-growth restriction, 850 Hypoxic inducible factor, metformin on, 727 Hypoxic-ischemic encephalopathy (HIE), newborn, 477, 620-622 with cesarean delivery, prior, 593 cr�eti� 62 1-622, 622t prevention, 622 Hyrd anastomosis, 1 1 8 Hysterectomy, peripartum, 567, 580-586 bowel injury, 585 cesarean, 567 complications, 580-5 8 1 incidence, 580 indications, 580-582 for morbidly adherent placenta, 781-782 for placenta accreta, 363 for placenta previa, 7 7 postoperative care, 585-586 euvolemia evaluation, 585 hospital care until discharge ambulation and wound care, 586 analgesia, vital signs, IV fluids, 585 bladder and bowel function, 585-586 hospital discharge, 586 recovery suite, 585 radical, 567 technique, 582-583 bladder dissection, 58 1 , 58 f broad ligament, 580/ 58 1 , 5 8 1/ fundamentals, 58 1-582 round ligaments, 580/ 58 1 salpingo-oophorectomy, 583 supracervical hysterectomy, 583 total hysterectomy, 582-583 cardinal ligaments, 582, 582/ curved clamp, 582, 583/ running-lock suture, vaginal wall edges, 583, 583/ uterine vessels, 582, 582/ uteroovarian ligament and fallopian tube, 580/ 58 1 urinary tract injury, 583-584 cystotomy repair, 583-584, 584/ ureteral, 584, 584/ uterine tears with, 454 Hysterotomy, cesarean delivery, 567, 573-580 abdominal closure, 578 adhesions, 578 classical cesarean incision, 578-580 indications, 578-579 uterine incision and repair, 579-580, 579/ incision, low transverse cesarean, 572/-5 7/ 573-578 fetus delivery, 575-576, 575/-576/

I n dex Hysterotomy, cesarean delivery (Cont.): placenta delivery, 576-5 7, 57 f uterine, 574-575, 574/ uterine repair, 577, 5 7/ Joel-Cohen technique, 578 Misgav Ladach technique, 578

Idiopathic intracranial hypertension, 1 1 68 Idiopathic thrombocytopenic purpura (ITP) fetal, 308-309 maternal, 1 086-1 087 newborn, 62 IgA nephropathy, 1 032 Ileostomy pregnancy and, 1 05 1 prolapse, 1 05 1 Ileouterine fistula, 1 03 8 Ileus, adynamic, 672 Iliohypogastric nerve, 1 5- 1 6, 1 5/ Ilioinguinal nerves, 1 5- 1 6, 1 5/ Imaging. See specic ypes and topics Imaging, fetal (sonography), 1 82-220. See also Sonography 3D and 40, 2 1 2-2 1 3 Fetal Intelligent Navigation Echocardiography, 2 1 2-2 1 3 spatiotemporal image correlation, 2 1 2 technology and mechanisms, 2 1 2, 2 1 2/ 3D and 40 sonography, 2 1 2-2 1 3 Doppler, 2 1 3-2 1 5 (See aso Doppler imaging, fetl) fetal anatomy, normal and abnormal, 1 9 1 -2 1 2 (See also Anatomy, fetal, sonography) magnetic resonance imaging, 2 1 5-220 obstetric, 1 82-1 9 1 (See also Sonography, obstetric) Imaging, in pregnancy, 9 1 1 , 9 1 1 t. See also specic ypes Imiglucerase therapy, 1 080 Immigrants, fetal-growth restriction, 850 Immune maladaptation, in preeclampsia, 7 1 5 Immune-mediated connective tissue diseases, 1 1 3 8-1 1 39 classiication, 1 1 38 fetal cell microchimerism, 1 1 39 obstetrical complications, 1 1 38 pregnancy, 1 1 38 RF-seronegative spondyloarthropathies, 1 1 38 rheumatoid factor, 1 1 38 Immune thrombocytopenia (ITP) fetal, 308-309 maternal, 1 086- 1 087 newborn, 627 Immune tolerance, matenal, in preeclampsia, 7 1 4- 1 5 Immunizations, maternal. See Vaccines, matenal Immunogeniciry, trophoblast, fetal-maternal interface, 95 Immunoglobulin A (IgA) fetal, 1 3 maternal, serum and blood, 1 259t Immunoglobulin G (IgG) fetal, 1 37 maternal, serum and blood, 1 2 59t Immunoglobulin M (IgM) fetal, 1 37 maternal, serum and blood, 1 259t Immunological system, fetal, 137 Immunological system, maternal, 58-59 antibody-mediated immuniry, 59 autoimmune disorders, remission, 59

Immunological system, maternal (Cont.): CD4 T lymphocyte subpopulations, 59 leukocytes and lymphocytes, 59 complement factors C3 and C4, 59, 1 259t C-reactive protein, 59 erythrocyte sedimentation rate, 59 inlammatory markers, 59 leukocyte alkaline phosphatase, 59 procalcitonin, 59 major histocompatibility complex, 5 9 platelets, 60 regulatory proteins, 60, 1 005/ spleen, 60 tolerance, maternal-fetal, 58-59 Immunology fetal and newborn, 1 209- 1 2 1 0 maternal pregnancy-induced changes, 1 209 pregnancy-related hypertension, 7 1 4-7 1 5 Immunosuppressants, teratogenicity corticosteroid, 244 mycophenolate mofetil, 244 Impetigo herpetiformis, 1 1 8-, 1 1 87/ Implanon, 685-688 Implantation, 88, 1 24/ Implantation and placental development, 80- 1 06. See also speciic topics amnion, 95-97, 96/ decidua, 80, 8 5-87, 86/ fetal adrenal gland-placental interactions, 1 04-1 06 hormones, placental, 98-1 04, 99 t implantation and early trophoblast formation, 87-90 (See also Trophoblast formation, early) ovarian-endometrial cycle, 80-85 placenta and chorion, 90-95 umbilical cord, 97, 98/ 1 30/ Imprincin� 268, 268t Angelman syndrome, 268, 268t Prader-Willi syndrome, 268, 268t Inborn errors of metabolism, autosomal recessive inheritance, 265-266 Incest consanguinity, autosomal recessive inheritance, 266 definition, 266 Incompetent cervix, midtrimester abortion, 354 Incomplete abortion, 349 Incomplete breech presentation, 539, 540/ total breech extraction, 548-549 Incontentia pigmenti, X-linked inheritance, 266 Incoordinate uterine dysfunction, 442 Incoordination, uterine contractions, 480 Indirect Coombs test, 1 60t, 301 Indirect electronic monitoring, 458-459 Indirect maternal death, 3 Individual risk, aneuploidy screening, 279-280 Indomethacin, for periventricular-intraventricular hemorrhage prevention, 640 Induced abortion. See Abortion, induced Induction, labor, 503-5 1 2. See also Labor induction Inertia uteri, 503 Inevitable abortion, 3 5 1 Infant mortality rate, 3 Infarction acute myocardial, 968-969, 969/ placental matenal, 1 1 4 maternal loor, 1 1 4

Infectious diseases, 1 209- 1 228. See also speciic ypes after abortion, surgical, 3 6 1 bacterial, 1 220- 1 225 bioterrorism, 1 228 breast, 675-676, 676/ etiology, 1 209, 1 2 1 0/ fetal, fetal-growth restriction, 85 1-852 immunology, maternal and fetal, 1 209- 1 2 1 0 fetal and newbon, 1 209- 1 2 1 0 pregnancy-induced changes, 1 209 labor, spontaneous preterm, 8 1 0-8 1 1 maternal dystocia, 454 fetal-growth restriction, 8 5 1 -8 52 pregestational diabetes, 1 1 04 mycotic, 1 228 perinatal on cerebral palsy risk, 64 1-642 on periventricular leukomalacia, 64 1 preterm birth an tibiotic prophylaxis, 8 1 3 bacterial vaginosis, 8 1 3 prevention, for cesarean delivery, 570-57 1 protozoal, 1 225- 1 228 puerperal, sepsis syndrome, 923-925, 925/ 925t septic abortion, 35 1-352 sexually transmitted diseases, 1 23 5-1 250 (See also Sexually transmitted diseases (STDs)) from transfusions, 7 9 1 -792 transmission, 1 209 travel precautions, 1 228 viral, 1 2 1 0- 1 220 wound, in obese, 943 Infective endocarditis, 965, 966t Inferior hypogastric plexus, 27/ 28 Inferior vermian agenesis, 1 9 5 Infertiliry ectopic pregnancy risk with, 372 fetal-growth restriction, 8 5 1 Infertility therapy multifetal pregnancy, 864 twinning, 867 Inlammatory bowel disease (IBD), 1 048- 1 0 5 1 classiication, 1 048, 1 049t Crohn disease, 1 049, 1 049/ etiopathogenesis, 1 048 fertility and, 1 050 pregnancy and, 1 050- 1 05 1 ulcerative colitis, 1 049, 1 049/ Inlammatory gene, cervical ripening, 409-4 1 0 Inlammatory markers. See also specic ypes matenal, 59 Inflammatory mediators, serum and blood constituents, 1 259t Inlammatory myopathies, 1 1 5 0- 1 1 5 1 I nlammatory responses, spontaneous preterm labor, 8 1 0-8 1 1 Inlammatory tightrope, 85 Inliximab for Crohn disease, 1 0 5 1 for rheumatoid arthritis, 1 1 47 for ulcerative colitis, 1 050 Inluenza pneumonia, 994 Inluenza vaccine, 1 2 1 4 Inluenza virus infection, 1 2 1 3- 1 2 14, 1 2 1 4t Infundibulopelvic ligament, 24/ 25 Inhalational anesthetics, in obstetrics, 499

1 299

1 300

I ndex Inheritance, modes of, 264-270 autosomal dominant, 264t, 265 advanced paternal age, 265 codominant genes, 265 expressivity, 265 penetrance, 265 autosomal recessive, 264t, 265-266 consanguinity, 266 enzyme deficiencies, 265 heterozygous carrier, 265 inborn errors of metabolism, 265-266 phenylketonuria, 265-266 DNA triplet repeat expansion, anticipation, 267-268, 267t fragile X syndrome, 26 -268 imprinting, 268, 268t ngelman syndrome, 268, 268t Prader-Willi syndrome, 268, 268t mitochondrial, 266-267 multifactorial inheritance, 268-270, 268t cardiac defects, 269-270, 953t neural-tube defects, 270 threshold trait, 269, 269/ phenotype-genotype relationship, 264-265 heterogeneity, 264-265 uniparental disomy, 268, 269/ X-linked, 264t, 266 Y-linked, 266 Inherited coagulation defects, 1 089- 1 09 1 . See also Coagulation defects, inherited Inherited thrombocytopenia, 1 086 Inhibin, placental, 99t, 1 02 Inhibin B, ovarian cycle, 82 Injuries. See also specic ypes maternal (See Critical care and trauma) newborn, 627-63 1 (See also Newborn injuries; specic ypes) Inlet, contracted, 448-449 Inner cell mass, blastocyst, 87j 88, 1 2 5 Innervation abdominal wall, anterior, 1 5- 1 6, 1 5/ pelvis, 27-28, 2 f hypogastric nerves, 27j 28 inferior hypogastric plexus, 27j 28 parasympathetic, 27j 28 splanchnic nerves, 27j 28 superior hypogastric plexus, 27j 28 sympathetic, 2 , 27/ utetovaginal plexus, 27j 28 vesical plexus, 27j 28 Insertion, umbilical cord, 1 1 8, 1 1 8/ Inspiratory capacity, 64 in pregnancy, 64, 65j 987 Insulin fetal growth, 845 gestational diabetes, 1 1 1 2 pregestational diabetes monitoring, 1 1 06, 1 1 06t treatment, 1 1 05- 1 1 06, 1 1 05t Insulin-like growth factors fetal growth, 845 fetal macrosomia, 1 3 8 Insulin resistance, 93 . See also Diabetes cytokines, 936-93 maternal, 56 Intact D & E, 363 Integrins, implantation, 88 Intellectual disabiliry, newborn, 625

Intensive care, obstetrical, 9 1 5-9 1 7 hemodynamic changes i n pregnancy, 9 1 , 9 1 7t obstetrical critical care, 9 1 6, 9 1 6t organization, critical care, 9 1 5, 9 1 6t pulmonary artery catheter, 9 1 6-9 1 7 Intercostal nerves, 1 5-16, 1 5j 1 6/ Interferon inducible protein- l 0, decidual natural killer cells, 9 1 Interferons 3 , for multiple sclerosis, 1 1 65 Interleukin-6 (IL-6) , amnion mesenchymal cells, 97 Interleukin-8 (IL-8) amnion epithelial cells, 96 amnion mesenchymal cells, 97 decidual natural killer cells, 9 1 menstruation, 8 5 Internal anal sphincter (lAS), 2 1j 22 Internal iliac artery branches, 26j 27 ligation, for hemorrhage, 792-793, 794/ Internal (direct) monitoring, fetal, 457-458, 457/-459/ Internal rotation, labor, 429, 430/ Interstitial pneumonitis, 997 Interstitial pregnancy, 380-3 8 1 , 380j 3 8 1/ Interstitial trophoblasts, 88, 89/ Interval between pregnancies cesarean delivery, prior, and trial of labor, 596 preterm birth, 8 1 3 Intervillous thrombosis, 1 1 4 Intestinal obstruction, 1 0 5 1 - 1 052, 1 052/ Intimate-partner violence preconceptual care, 1 52- 1 53 prenatal, 1 62-1 63 Intoxicating pepper, teratogenicity, 248t Intracardiac catheter procedures, fetoscopic, 326-327 Intracerebral hemorrhage, 1 1 6 1j 1 1 62- 1 1 63, 1 1 62/ Intracranial aneurysm, 1 1 63 Intracranial berry aneurysm, 1 032 Intracranial hemorrhage newborn, 628, 628t preterm labor with intact membranes, prevention, 827-828 preterm newborn, 639 Intradecidual sign, 1 59 Intrahepatic cholestasis of pregnancy, 1 0 59-1 060, 1 1 84 I ntramembranous Bow, 225, 226t Intraoperative blood salvage with reinfusion, 79 1 Intraparenchymal hemorrhage, preterm newborn, 639 Intrapartum amnioinfusion, for meconium aspiration syndrome, 476, 620 Intrapartum assessment, 457-48 1 . See also Assessment, intrapartum; specic ypes Intrapartum Doppler velocimetry, 4 2 Intrauterine devices (IUDs) , 68 1 -685 approved devices, 68 1 , 681/ contraceptive action, 68 1 insertion, 685, 686/-687/ method-specific adverse efects, 683-685 contraindications, 682t-683t ectopic pregnancy, 683 infection, 684 lost device, 683 menstrual changes, 684 perforation, 683-684 pregnancy, 684-685

Intrauterine growth restriction, 803 Intravascular pulmonary angiography, for pulmonary embolism, 1 0 1 8 Intravenous immunoglobulin (IV1G) for antiphospholipid syndrome, 1 1 46 for Crohn disease, 1 1 65 for pemphigoid gestationis, 1 1 86 Intravenous pyelography, 1 026 Intraventricular hemorrhage (IH) magnetic resonance imaging, 2 1 8, 2 1 8/ on periventricular leukomalacia, 64 1 preterm newborn, 639 cerebral palsy, 64 1 Invasion, early, 89-90, 89j 1 26/ chorion, 89, 1 26/ syncytiotrophoblast, 89-90 trophoblastic lacunae, 90 Invasive cervical cancer, 1 1 94-1 1 95 , 1 1 95/ Invasive mole, 388, 394 Inverted nipples, 659 In-vitro fertilization (IVF), 9, 1 5 1 Iodide, fetal, 1 39 Iodine, maternal, 5 deficiency, 1 1 26-1 1 27 pregnancy and lactation, 1 67t, 168 status, 71 Ionizing radiation, pregnancy and, 904-905, 904t Ions. See also Electrolyte and mineral metabolism, maternal; Electrolytes fetal, 1 39 overload, 1 066- 1 06 Iron, maternal metabolism, 58 hepcidin, 58 pregnancy and lactation, 1 67t, 1 68 requirements, 58, 58/ Ischemia, brain, cerebral palsy, 64 1 Ischemic heart disease, 968-969, 969/ fetal-growth restriction, 8 50 incidence, 968 myocardial infarction, in pregnancy, 968-969, 969/ after pregnancy-related hypertension, 745 prior, pregnancy with, 969 Ischemic stroke, 1 1 6 1 - 1 1 62, 1 1 6 1j 1 161t cerebral artery thrombosis, 1 1 62 cerebral embolism, 1 1 6 1 - 1 1 62, 1 1 6 1/ cerebral venous thrombosis, 1 1 62 preeclampsia syndrome, 1 1 6 1 recurrence risk, 1 1 62 Ischioanal fossae, 2 1 , 2 1/ Ischiocavernous muscles, 1 9j 20, 20/ Ischiopubic ramus, 1 9, 1 9j 20, 20/ Ischiorectal fossae, 2 1 , 2 1/ Isochromosomes, 262-263 Isodisomy, 268 Isolated cleft palate, 1 97 Isolated maternal hypothyroxinemia, 1 1 25 Isometric exercise test, 25-726 Isosorbide mononitrate, for preinduction cervical ripening, 507 Isotretinoin, teratogenicity, 245 J

Jadeli levonorgestrel implants, 688 J arisch-Herxheimer reaction, 1 239

I n dex J aydess intrauterine device, 68 1 . See also Intrauterine devices (IUDs) Jeryl-Lynn vaccine, 1 2 1 4 Jewish descent carrier screening, 29 1 genetic screening, prenatal, 1 65 preconceptual care, 1 5 1 J incision, for cesarean delivery, 575 Joel-Cohen technique, 578 Joints, pelvic, 29 Jujenal atresia, fetal sonographic, 205 Juvenile rheumatoid arthritis, 1 1 48 K

Kallman syndrome, 26 1 t Karyorype nomenclature, 2 54, 2 5 5 t Kava (kawa) , teratogenicity, 248t Kell autoimmunization, 302-303 Kernicterus, preventing, 1 33 Ketoconazole, for Cushing syndrome, 1 1 3 1 Keyhole sign, 2 1 0, 2 1 O, 325 Kidney disease, chronic, 1 034- 1 036 Kidneys. See also Renal entries Kidneys, fetal, 1 3 5- 1 36 Kidneys, maternal, 65-67, 66t glomerular filtration rate, 65-66, 65/ injury, acute (See Acute kidney injury (AKI)) normal, imaging, 207, 207/ preeclampsia on, 745 pregnancy-related hypertension on, 720, 72 1/ acute kidney injury, 720 anatomical changes, 720 proteinuria, 720 renal function tests, 66 renal plasma flow, 65-66, 65/ size, 65, 66t urinalysis, 66-67, 67/ urine protein, measuring, 67 Kidneys and urinary tract, fetal sonography, 207-2 1 0 bladder outlet obstruction, 2 1 0 duplicated renal collecting system, 208, 209/ multicystic dysplastic kidney, 209-2 1 0, 2 1 0/ normal, 207, 20 f polycystic kidney disease, 2 1 0 renal agenesis, 208-209, 209/ renal pelvis dilatation, 208, 208f, 208t ureteropelvic j unction obstruction, 208 Kidney stones, 1 030 Kielland forceps, 561-562, 561, 562/ Kisspeptin, 837 Kleihauer-Betke (KB) test, 30 Klinefelter syndrome, 39, 259-260 Klumpke paralysis, newborn, 630 Knots, umbilical cord, 1 1 9 Koplik spots, 1 2 1 5 Kruckenberg spindles, 73 Kruckenberg tumors, 1 204 Kyleena intrauterine device, 68 1 . See also Intrauterine devices (IUDs) L

Labetalol for chronic hypertension, in pregnancy, 980 for hypertension with preeclampsia-eclampsia, 739 Labia majora, 1 6, 1 7/ Labia minora, 1 6-1 , 1 7/ Labium minus, 20, 20/

Labor. See also speciic ypes and topics asthma on, 991 cardiovascular disorders, 9 1 6, 953 continuous lumbar epidural block on, 495, 495t with deep-vein thrombosis and anticoagulation, 1014 diagnosis, radiography, 426-427 false, 50, 403, 432 fetal-growth restriction, 856 gestational diabetes, 1 1 1 3 identification, 435 postterm pregnancy, 841-842 preterm labor with intact membranes, 827 sickle-cell hemoglobinopathies, 1 083 stages, 403f, 4 1 1 trial of, 443 Labor, abnormal, 441-455 dystocia, 44 1-442, 44 1 t (See also Dystocia) dystocia, complications maternal, 453, 454-455 fistula formation, 455 hemorrhage, 454 infection, 454 lower extremity nerve injury, 455, 66 1 pelvic floor injury, 455 uterine rupture, 453, 454-455 uterine tears with hysterectomy, 454 perinatal caput succedaneum and molding, 43 1 , 43 1f, 455 mechanical trauma, 455 expulsive force abnormalities, 442-44" (See also Expulsive force abnormalities) fetopelvic disproportion, 448-454 (See also Fetopelvic disproportion) precipitous labor and delivery, 448 prematurely ruptured membranes at term, 447-448 Labor, multifetal pregnancy, 887-889 analgesia and anesthesia, 888 fetal presentation, evaluation, 888 labor induction or stimulation, 888 preparations, 887 timing of delivery, 887-888 Labor, normal, 43 1 -434 definition, 4 3 1 -432 duration, 434 first stage, 432-434 active phase, 432, 432, 433-434, 433/ active phase, abnormalities, 433-434 decleration phase, 432, 432/ dilatation curve, average, nulliparous, 432, 432/ functional divisions, 432, 432/ latent phase, 432-433, 433/ prolonged, 433 phase of maximum slope, 432, 432/ onset, 43 1 -432, 432/ second stage, 434 summary, 434 Labor, physiology, 400-4 1 7 labor initiation theories, 400 maternal and fetal compartments placenta, 40 1 , 40 1/ uterus, 400-40 1 phase 1 , uterine quiescence and cervical softening, 403-408 cervical softening, 407-408

Labor, physiology (Cont.: decidua, 407 myometrial relaxation and contraction, 403-40 actin-myosin interactions, 404, 405/ balance and quiescence, control, 403-404 cyclic guanosine mono phosphate, 407 endoplasmic reticulum stress response, 405-406 G-protein-coupled receptors, 406-407, 406/ membrane potential regulation, 404-405, 405/ myometrial gap j unctions, 405, 406/ uterotonin degradation, accelerated, 407 quiescence, 403 phase 2, preparation for labor, 408-4 1 1 cervical ripening, 409-4 1 0 connective tissue, 409-4 1 0, 409/ endocervical epi thelia, 4 1 0 induction, 4 1 0 fetal contributions anomalies and delayed parturition, 41 1 endocrine cascades, 4 1 0-4 1 1 , 4 1 0/ fetal-membrane senescence, 4 1 1 lung surfactant and platelet-activating factor, 4 1 1 uterine stretch, 4 1 0 myometrial changes, 408 oxytocin receptors, 408 progesterone withdrawal, 408 phase 3, labor, 4 1 1-4 1 6 first stage, clinical onset, 4 1 1-4 1 4 ancillary forces, 4 1 2 cervical changes, 403f, 4 1 2-4 1 3 , 4 1 2/ uterine labor contractions, 4 1 1-4 1 2, 4 1 1/ pelvic loor changes, 2 1 , 4 1 4-4 1 5 second stage, fetal descent, 4 1 4, 4 1 5/ third stage, delivery of placenta and membranes, 4 1 5-4 1 6, 4 1 5f, 4 1 6/ phase 3, parturition, uterotonins, 4 1 6-4 1 7 angiotensin II, 4 1 7 endothelin- l , 4 1 7 oxytocin, 4 1 6 prostaglandins, 4 1 6-4 1 , 4 1 :/ phase 4, puerperium, 4 1 7, 526 phases, parturition, 403, 403f, 404/ prostaglandins, 402, 403/ sex steroid hormone, 40 1-402 stages, 403, 403/ Labor, spontaneous preterm cervical dysfunction, 8 1 0 cytokines, origin, 8 1 1 infecrion, 8 1 0-8 1 1 inflammatory responses, 8 1 0-8 1 1 maternal-fetal stress, 809-8 1 0 uterine distention, 809 vaginal m icrobiota, 8 1 1 Labor, third stage, 525-527 management, general, 526 management, uterotonic, 526-527 ergonovine and methylergonovine, 527 misoprostol, 527 oxytocin, high-dose, 5 27 manual removal, 527, 528/ placenta delivery, 525-526, 526/

1 30 1

1 302

I n dex Laboratory tests, prenatal. See also speciic ypes and indications complications, medical and surgical, 900-9 0 1 initial evaluation, 1 60t, 1 63 subsequent visits gestational diabetes, 1 65 group B streptococcal infection, 1 65 neural-tube defect and genetic screening, 1 65 Labor augmentation. See also Labor induction for breech delivery, 543 with cesarean delivery, prior, 597-598 deinition, 503 methods, 508-5 1 2 amniotomy, 504, 5 1 1-5 1 2, 5 l l t oxytocin, 5 09-5 l l , 509t prostaglandin Ej , 508-509 multifetal pregnancy, 888 Labor disorders, expulsive force active-phase prolongation, 442-446 6-cm rule, background, 444t-446t, 445-446, 445, 446/ 6-cm rule, vs. 4-cm, 444 arrest disorder, 442, 443-444, 443f, 443t Obstetric Care Consensus Committee, 444, 444/ protraction disorder, 442, 443, 443t, 444 Sae Prevention 0/the Primay Cesarean Delivey, 442 second-stage descent disorders, 446-447 fetal station, labor onset, 447 latent-phase prolongation, 442, 443t prolongation disorder, 443t pushing eforts, maternal, 447 uterine dysfunction, risks, 447 Labor induction, 503-5 1 2 for breech delivery, 543 cervical ripening, preinduction, 505-508 with cesarean delivery, prior, 597-598 defi n ition, 503 elective, 504 factors in success of, 504-505 incidence, 503 indications, 503 methods, 508-5 1 2 amniotomy, 504, 5 1 1 -5 1 2, 5 1 1 t membrane stripping, 5 1 2, 840 oxytocin, 509-5 1 1 , 509t prostaglandin Ej, 508-509 multifetal pregnancy, 888 obese, 942 postterm pregnancy, 840 vs. fetal testing, 840-84 1 , 84 1 t prophylactic, for fetal overgrowth, 858-859 risks, 504 techniques, 504 Labor management, normal, 434-438 active management of labor, 438 Emergency Medical Treatment and Labor Act, 434 evaluation, initial, 435-436 cervical assessment, 435-436 cervical examination, 435 laboratory studies, 436 ruptured membranes, 435 irst-stage labor, 436-438 general examination, 436 infrapartum fetal monitoring, 436 IV fluids, 437 maternal monitoring, 436-437 maternal position, 437

Labor management, normal (Cont: oral intake, 437 pain relief, 436 rupture of membranes, 437-438 urinary bladder function, 438 Guidelines or Perinatal Care, 434 ideal, viewpoints, 434 identiication oflabor, 435 nurse/patient ratios, 434, 434t partograph, 439 protocols, 438439 second-stage labor, 438 Labor mechanisms, normal, 42 1-43 1 . See also Labor mechanisms diagnosis, 424-427 Leopold maneuvers, 424-425, 426/ sonography and radiography, 426-427 vaginal examination, 426, 42 f fetal attitude, 422-423, 422/ fetal head shape changes, 43 1 , 43 1/ fetal lie, 42 1 -422, 422/ longitudinal, 422, 422/ oblique, 422 transverse, 422, 422t, 425/ fetal position, 423-424, 423/-425/(See also Fetal position (presentation)) occiput anterior presentation, 423f, 427-43 1 cardinal movements of labor, 42 , 428/ descent, 427 engagement, 427, 429/ synclitism and asynclitism, 427, 429/ explusion, 43 1 extension, 429, 430/ external rotation, 428, 429-43 1 lexion, 429, 429/ internal rotation, 429, 430/ occiput posterior presentation, 43 1 pelvic loor changes, 42 1 Lacerations maternal cervical, 763-764 postpartum repairs, 530/-533, 53 1-532 after vaginal delivery, operative, 555 vulvovaginal, 763 perinatal care, 533 Lactate, fetal, 1 38 Lactation and breastfeeding, 656-659 agalactia, 659 breast anatomy and secretory productions, 656-657, 656, 656t breast care, 658 breast engorgement, 659 contraindications, to breastfeeding, 658 drugs in milk, 658-659 endocrinology, 657 lactation, 657 galactocele, 659 immunological consequences, 657 inverted nipples, 659 milk line, 659 nursing, 657-658, 657t, 658t polygalactia, 659 polymastia, 659 polythelia, 659 Lactiferous ducts, 656, 656/ Lactobacillus acidophilus, vaginal, 52 Laennec cirrhosis, 1 067 Lambda sign, 868-869, 868/ Lamellar body count, 638

Laminaria algae, hygroscopic dilator, 358, 358/ Lamotrigine, teratogeniciry, 1 1 60t Langer-Gledion syndrome, 26 1 t Langerhans cells, 90 Langer lines, 14 Laparoscopic adjustable silicone gastric banding (LASGB), 944-945 , 944t Laparoscopic surgery, in pregnancy, 9 0 1 -904 complications, 904 gastrointestinal disorders, 1 043 ges tati o n ti m i ng, 901-902 GI endoscopic surgery, 9 0 1 -902, 902t hemodynamic efects, 902 obesiry, 902-903 perinatal outcomes, 903 prevalence, 90 1 surgical approach, 9 0 1 technique, 903-904, 903, 904/ Laparotomy cesarean delivery, 5 7 1 -5 3 midline vertical incision, 573 transverse incisions, 57 1 -572 gastrointestinal disorders, 1 043 Large-bowel obstruction, fetal sonographic, 207 Large-for-gestational age, 803. See also Macrosomia gestational diabetes, 1 1 1 1 pregestational diabetes, 1 1 00- 1 1 0 1 , 1 1 0 1/ Last menstrual period (LMP), gestational age and, 1 24, 1 24/ Late neonatal death, 3 Latent phase, labor, 432-433, 433/ prolongation, 433, 442, 443t Lead, teratogeniciry, 244 Lead screening, prenatal, 1 70-1 7 1 Lecithin-sphingomyelin (LIS) ratio, 638, 638/ Lelunomide, teratogeniciry, 241 Left-atrial isomerism, 3 1 6 Left occiput anterior (LOA), 423, 427 Left occiput posterior (LOP) , 423, 43 1 Left occiput transverse (LOT), 42, , 430/ Left ventricular mass, 6 1 , 6 1/ Left ventricular outflow tract, cardiac imaging, 20 1 , 202/ Legionella pneumonia, 992-994, 993t Leiomyomas, uterine, 1 1 95-1 1 97, l l 96, l l 97/ cesarean delivery with, 578 placental abruption, 770 placenta previa, 75 recurrent pregnancy loss, 352-353 Leiomyomatosis peritonealis disseminata, 1 1 96 Lemon sign, 1 93, 1 93/ Lenalidomide, teratogeniciry, 247 Leopold maneuvers, 424-425, 426, 453, 453, 540 Leprosy, 1 224- 1 225 Leptin, 5 1 , 56 fetal, 1 38, 845 placental, 1 02 Letting down, 657 Leucovorin, for tubal pregnancy, 377t, 378 Leukemia inhibitory factor (LIF) , blastocyst, 88 Leukemias, 1 203 Leukocyte alkaline phosphatase, 59 Leukocytes and lymphocytes, maternal, 59 complement factors C3 and C4, 59, 1 259t C-reactive protein, 59 erythrocyte sedimentation rate, 59 inlammatory markers, 59 leukocyte alkaline phosphatase, 59 procalcitonin, 59

I n d ex Levator ani muscles, 20, 20/ labor, 4 1 5 Levetiracetam, teratogenicity, 1 1 60t Levonorgestrel implants, 688 Levonorgescrel-releasing intrauterine system (LNGIUS), 68 1-685. See also Intrauterine devices (IUDs) Liability, medical, 8 Libman-Sacks endocarditis, 957 Lie, fetal, 42 1 -422, 422/ with cesarean delivety, prior, 596 longitudinal, 422, 422/ oblique, 422 transverse (See also Transverse lie) abnormal labor, 452-454, 453/ neglected, 453 normal labor, 422, 422t, 425/ Lifestyle for hypertension, chronic adult population, 976t pregnancy, 976, 9 7t for preeclampsia prevention, 726-727 preterm birth and, 8 1 2 Ligaments, pelvic, 24-25 , 24! 25/ broad, 24! 25 cardinal, 25, 25/ infundibulopelvic, 24! 25 round, 24-25, 24! 25/ uteroovarian, 24! 28 uterosacral, 24, 24! 25, 25/ Lightening, 408 Lightning injuries, 930-93 1 Liletta intrauterine device, 68 1 . See also Intrauterine devices ( IUDs) Limb-body wall complex, 1 1 6, 206 Limb-reduction defects, 2 1 2, 2 1 2! 294! 63 1 with chorionic villus sampling, 294, 294/ Linea alba, 53 Lipids. See also speciic lipid disorders excessive transfer, fetal overgrowth, 845 serum and blood tests, 1 259t Lipoprotein lipase, fetal, 1 38 Liquid plasma (LQP), 790 Listeriosis (Listeria monoytogenes), 1 223- 1 224, 1 224/ Lithium, teratogenicity, 244-245, 1 1 79 Live birth, 3 Liver. See also Hepatic entries clinical and laboratoty indings, 1058, 1 059t fetal, 1 3 5 maternal, 6 8 eclampsia and preeclampsia o n , 72 1-722, 72 1/ pregnancy-induced physiology, 1 058- 1 059 Liver disorders, 1 058- 1 069. See also Hepatic disorders; speciic ypes Liver transplantation, 1 069, 1 069 t Lobar holoprosencephaly, 1 94 Lochia, 654 Lochia alba, 654 Lochia rubra, 654 Lochia serosa, 654 Locus heterogeneity, 264 Long-acting reversible contraception (LARC), 68 1 Long-acting thyroid stimulators (LATS) , fetal, 1 36 Long bone length, by gestational age, 1 267 t Long-chain polyunsaturated fatty acids, placentalfetal transfer, 1 3 8 Longitudinal lie, 422, 422-425! 422t, 423-424 Longitudinal limb-reduction defect, 2 1 2, 2 1 2/ Long QT syndrome, 967

Looping, cardiac tube, 1 29 Loops, umbilical cord, 1 1 9- 1 20 Loratidine, 1 1 88 Low birthweight, 3 , 803 multifetal pregnancy, 872, 872! 873/ rates, U.S., 4, 4t Low-density lipoprotein (LDL) cholesterol Depo-Provera on, 689 fetal, 1 05 oral contraceptives, 69 1 placental uptake and use, 1 38 serum and blood, 1 259t Lower extremity nerve injury, matenal, dysrocia, 455, 66 1 Low-lying placenta, 774 Low-molecular-weight heparin (LMWH) for cardiovascular disease, 9 54-955 for deep-vein thrombosis, 1 0 1 3- 1 0 14, 1 0 1 3t dosing and monitoring, 1 0 1 4 on preeclampsia risk, 727 safety, 1 0 14 Luikart forceps, 5 57, 557/ Lumadex-FSI test, 638 Lung. See also Pulmonary entries Lung compliance, 64 Lung maturation betamethasone for, 1 34 dexamethasone for, 1 34 fetal-growth restriction, accelerated, 849 glucocorticoids for, 1 34, 33, 733t, 886 Lung transplantation, for cystic fibrosis, 999 Lupus anticoagulant (LAC) antiphospholipid syndrome, 1 143 fetal-growth restriction, 85 1 Lupus nephritis, 1 14 1 Luteal-phase defect, recurrent pregnancy loss, 353 Luteinization, 82-83 Luteinizing hormone (LH) fetal, 1 36 maternal luteal phase, 82! 83 ovarian cycle, 82, 82/ ovarian-endometrial cycle, 80, 8 1/ ovulation, 8 1! 82 parturition, 407 Luteoma, pregnancy, 1 1 99 Lying down sign, 209 Lyme disease, 1 225 Lymphadenopathy, 997 Lymphatics, pelvic, 27 Lymphocytes cerebral palsy, 624 fetal, 1 37 maternal, 59 Lymphocytic hypophysitis, 1 1 33 Lymphogranuloma venereum, 1241 Lymphomas Hodgkin disease, 1 202, 1 202t non-Hodgkin lymphomas, 1 202- 1 203, 1 202t Lyonization, 1 080 M

M 1 macro phages, 9 1 M 2 macrophages, 9 1 Macitentan, teratogenicity, 243 Mackenrodt ligament, 25, 2 5/ Macrophages decidual, 95 M 1 and M2, 9 1

Macrosomia, 1 38, 856-859 birthweight distribution, 85 corticotropin-releasing hormone, 1 38 definition, 8 57 diagnosis, 858 erroneous, 858 empirical birthweight, 857, 85' t fetal-growth restriction, 849 ibroblast growth facror, 1 38 gestational diabetes, 1 1 1 1 glucose, 1 3 8 hyperglycemia, 845 incidence, 8 57 insulin-like growth factors, 1 38 management, 858-859 cesarean delivery, elective, 859 labor induction, prophylactic, 858-8 5 9 morbidity, maternal and perinatal, 857-858, 858t posrrerm pregnancy, 837! 839 pregestational diabetes, 1 1 00- 1 1 0 1 , 1 1 0 1/ risk factors, 857, 857t size, 856-85Magnesium, maternal, 57 pregnancy and lactation, 1 67t, 1 68 Magnesium sulfate for eclampsia seizures, 736-738, 736t anticonvulsant and neuroprotective efects, 737 dosage, 736, 736t, 737/ fetal and neonatal efects, 738 maternal safery and eicacy, 738, 738 t o n myometrial contractility, 737-738 as neuroprophylaxis, 74 1- 43 indications, 742 randomized trials, 74 1-742, 74 1 t selective vs. universal prophylaxis, 742-743, 742t pharmacology and toxicology, 737 for migraine, 1 1 58 for preterm delivery risks, 640 for preterm labor, 826 for preterm labor with intact membranes, 824-825, 824t Magnetic resonance cholangiopancreatography (MRCP), 1 043 Magnetic resonance enterography (MRE), 1 043 Magnetic resonance imaging (MRI) , 2 1 5-220, 909-9 1 1 . See also specic indications adjunct, to fetal therapy, 2 1 9 cancer, i n pregnancy, 1 1 9 1 central nervous system, 1 1 56 contrast agents, 9 1 0-9 1 1 gadolinium-based, 2 1 6 for deep-vein thrombosis, 1 0 1 1 emerging concepts, 220 fetal anatomic evaluation, 2 1 7-2 1 9 abdomen, 2 1 8-2 1 9 , 2 1 9/ central nervous system, 2 1 7-2 1 8, 2 1 7! 2 1 8/ characterization, 2 1 7 thorax, 2 1 8, 2 1 9/ fetal indications, 9 1 0! 9 1 1 image resolution, 2 1 5 indications, 2 1 5 , 2 1 6t maternal indications, 9 1 0! 9 1 1 multifetal pregnancy, 870 placenta, 220 practice guidelines, 2 1 5 safety, 2 1 5-2 16, 9 1 0 short T1 inversion recovery, 2 1 7 technique, 2 1 6-2 1 7

1 303

1 304

I n dex Ma huang, teratogenicity, 248t Major depression, 1 1 5- 1 1 78. See also Depression etiology, 1 1 76 incidence, 1 1 75 postpartum, 1 1 76-1 1 77 pregnancy and, 1 1 75- 1 1 6 symptoms, 1 1 75, 1 1 76t treatment algorithm, 1 1 77, 1 1 7/ drug, 1 1 76- 1 1 78, 1 1 76t electroconvulsive therapy, 1 1 78 fetal and neonatal efects, 1 1 78 Major histocompatibility complex (MHC) , maternal, 5 9 Malaria, 1 226- 1 227, 1 227/ congenital, fetal-growth restriction, 852 Malformations. See aLso specic ypes embryofetal seizure disorders, 1 1 59 from seizure disorders, 1 1 59 pregestational diabetes, 1 1 00, 1 1 00t, 1 1 0 1/ Malignant gestational trophoblastic disease, 388, 393-396. See also Gestational trophoblastic neoplasia (GTN) Malignant melanoma, 1 203-1 204 Mallory-Weiss tears, 1 044, 1 047 Management of Myelomeningocele Study (MOMS) , 3 1 9-32 1 Mandibular fractures, newborn, 63 1 Manual vacuum aspiration (MVA), 3 59-360, 360/ Marfan syndrome, 967-968, 1 1 5 1 Margina cord insertion, 1 1 8 Marginal previa, 774. See aLso Placenta previa Marijuana, teratogenicity, 249 Mask of pregnancy, 53 Mask ventilation, newborn resuscitation, 608, 609f 6 1 0t Massive perivillous fibrin deposition, 1 14 Massive subchorionic hematomas, 1 1 5 Massive transfusion protocols, 789, 790- 9 1 , 790t Mastitis, 659, 675-676, 676/ Maternal age childbirth, trends, 278, 278/ on fetal trisomy risk, 278, 279t, 280t autosomal, 255, 255/ in multifetal pregnancies, 866, 866/ on placental abruption, 769-770 on placenta previa risk, 775 on preconceptual care, 1 5 1 , 1 5 1/ Maternal anatomy. See Anatomy, maternal Maternal blood volume (MBV), estimation, 307 Maternal-fetal stress, spontaneous preterm labor, 809-8 1 0 Maternal loor infarction, 1 1 4 Maternal monitoring, labor, 436437 Maternal morbidity. See Morbidity, maternal Maternal mortality. See Mortality, maternal Maternal mortality ratio, 4, 5-6, 5/-6/ Maternal physiology. See Physiology, maternal Maternal position, labor, 437 Maternal serum alpha-fetoprotein (MSAFP), 1 92 elevation, neural-tube defects and, 283, 283t historical perspective, 277-278 morbidly adherent placenta, 779 placenta previa, 775 targeted sonography, 278 ultrasonography, 277-278 Maternal ventricular shunts, 1 1 68 Maternity blues, 1 1 74

Matrix metalloprotease ( v IMP) family endometrial invasion, 9 1 menstruation, 85 Mauriceau maneuver, 546, 546/ Maximal vertical pocket, 226 Maximum breathing capacity, 64 Maximum slope, phase of, 432, 432/ Mayer-Rokitansky-Klister-Hauster (MRKH) syndrome, 42 May-Hegglin anomaly, 1 086 Maylard incision, for cesarean delivery, 572 McDonald cerclage, 3 5 5 , 3 5 5/ cervicovaginal istula after, 1 037 emergency or rescue, 825 vesicovaginal fistula after, 1 037 MCP- 1 , amnion mesenchymal cells, 97 McRoberts maneuver, 5 2 1 -522, 5 2 1-522/ Mean sac diameter, early pregnancy loss, 350 Measles, mumps, rubella (MMR) vaccine, 1 2 14, 1 2 1 5- 1 2 1 6 Measles virus infection, 1 2 1 4- 1 2 1 5 Measurements, fetal, 1 83-1 84, 1 84f 1 86f 1 262t- 1 270t. See also Fetal measurements, sonography Mechanical index, sonography, 1 83 Mechanotransduction, 4 1 0 Meckel-Gruber syndrome, 1 93 Meconium, 1 35 postterm pregnancy, 837f 84 1 , 848 Meconium aspiration syndrome fetal, 1 35, 474 newborn, 620 postterm pregnancy, 836t, 838, 840, 84 1-842 Meconium peritonitis, 998 :Meconium-stained amnionic l uid, 474 amnioinfusion for, 476 amnionic luid embolism, 785 intrahepatic cholestasis of pregnancy, 1 060 labor, 474 membrane rupture, 437 prostaglandin E2 administration, vaginal, 507 suctioning, newborn, 608 occiput anterior delivery, 5 1 8 routine, not recommended, 474 uterine infection, 667 Median cleft face syndrome, 1 97 Median cleft lip, 1 97 Medicaid, 7 Medical and surgical complications. See also specic ypes general considerations, 900-9 1 1 (See aLso Complications, medical and surgical) incidence, 900 Medical Eligibility Criteria, 6 8 1 Medical history, preconceptual care, 1 47-1 49 diabetes mellitus, 1 47- 1 48, 148/ epilepsy, 1 48-1 49, 1 48 t immunizations, 1 49 Medications, in pregnancy birth defects, 234, 234t, 235/(See aso Teratogens) counseling, 238-239 FDA, letters and labels, 238, 238t risk information, presenting, 238-239 perinatal morbidity, 90 1 , 9 0 1 t pregnancy outcomes, 90 1 use, 234-235, 234t counseling, 238-239 teratogenicity criteria, 235-236, 235t, 236/ V Iegaloblastic anemia, 1 077- 1 078

Meiosis, pericentric or paracentric inversion, 263, 263/ Melasma gravidarum, 5 3 Membrane potential regulation, parturition, 404-405, 405/ Membrane repair, for preterm premature rupture of membranes, 3 5 1 , 822 Membrane rupture, labor, 435, 437438 Membrane stripping, for labor induction, 5 1 2 postterm pregnancy, 840 Memory, 2-73 Mendelian disorder, 264, 264t. See aLso specic ypes Meningitis gonococcal, 1 240 from spinal block, 492 Meningocele, sonography, 1 93 Menstrual age, 1 24-1 25 , 1 24/ Naegele rule, 1 25, 1 6 1 Menstrual history, prenatal, 1 6 1 Menstruation, last, gestational age and, 1 24, 1 24/ Meperidine vs. combined spinal epidural analgesia, for nullipara in spontaneous labor at term, 445-446, 445t for labor, 487488, 487t 6-Mercaptopurine for Crohn disease, 1 0 5 1 for ulcerative colitis, 1 050 Mercury, teratogenicity, 244 Mesomelia, 2 1 1 Metabolic acidemia fetal, 6 1 1 newborn, clinical significance, 6 1 2-6 1 3, 6 1 2t Metabolic changes, maternal, 54-5 carbohydrate metabolism, 5 5-56, 5 5/ accelerated starvation, 56 insulin resistance, 56 electrolyte and mineral metabolism, 57 energy demands and metabolic rate, 55, 55t fat metabolism, 56-57 hyperlipidemia, 56 leptin, 56 protein metabolism, 55 water metabolism, 54-55, 5 5/ weight gain, 54, 54t Metabolic rate, maternal, 55, 55t Metabolic syndrome, 937, 938t gestational diabetes, 1 1 1 4 with hypertension, chronic, 977 Metabolic tests, serum and blood, 1 258t Metallothionein- 1 , fetal, l 39 Metals heavy, placental sequestration, 1 39 trace fetal, 1 3 9 pregnancy and lactation, 1 67t, 1 68 Metformin, on preeclampsia risk, 727 Methergine, for uterine atony, 759-760 Methicillin-resistant StaphyLococcus aureus (MRSA), 1 222- 1 223, 1 223/ breast infections, 675-676 cesarean delivery with histoty of, 571 Methotrexate (MTX) for abortion, induced, 36 1-362, 362t teratogenicity, 242-243 for tubal pregnancy, 377-3 8, 377t vs. surgery, 379-380 a-Methyldopa, for chronic hypertension in pregnancy, 980

I ndex Methylergonovine for labor, third-stage, 527 for uterine atony, 59 Methylprednisolone, for lupus, 1 1 42 Metoprolol for chronic hypertension, in pregnancy, 980 for migraine, 1 1 58 Metritis with pelvic cellulitis, postpartum, 66 -6 0, 667t Metronidazole for amebiasis, 1 228 for bacterial vaginosis, 1 245 for trichomoniasis, 1 246- 1 24 Metyrapone, for Cushing syndrome, in pregnancy, 1 131 Micafungin, for pneumonia, 995 Miconazole, for candidiasis, 1 24 Microabscesses, listeriosis, 1 224, 1 224/ Microangiopathic hemolysis, 7 1 9 Microcephaly, 1 84 chromosomal, 258, 266 infection, 1 1 20, 1 2 1 5, 1 2 1 9, 1 225 malformation, 1 93 radiation, 905 Microchimerism, fetal, 95 connective tissue disorders, 1 1 39 placental "barrier" breaks, 9 5 systemic sclerosis, 1 1 48 thyroid disease and autoimmunity, 1 1 1 9 Microdeletions, 260 Microdeletion syndromes, 260, 26 1 t Microduplications, 260, 261 t Micrognathia, fetal sonographic, 1 96, 1 97/ ex-utero intrapartum treatment for, 327 Microinvasive disease, 1 1 9 5 Micromelia, 2 1 1 Microparticles, in preeclampsia, 7 1 4 MicroRNA species, o n vascular remodeling and uterine blood Row, 5 1 Microvesicometry, 638 Middle cerebral artery (MCA) Doppler imaging, 2 1 4-2 1 5, 2 1 4/ Doppler velocimetry, fetal, 300, 303-304, 304, 340 Midpelvis, 30, 30/ contracted, 449 measurements, average, 449 Mifepristone (RU-486), 1 1 3 1 for abortion, induced irst-trimester, 361-362, 362t second-trimester, 362t, 363 on cervical ripening, 408 on parturition, 402 Migraine headache, 1 1 57 in pregnancy, 1 1 57- 1 1 58 Milk, human breast, 656-657, 656, 656t drugs secreted in, 658-659 immunological consequences, 65 nursing, 657-65 8, 657t, 658t Milk ejection, 657 Milk line, 659 Milk-to-plasma drug-concentration ratio, 658 Miller-Dieker syndrome, 261 t Minerals. See aso speciic mineras intake, pregnancy and lactation, 1 67t, 1 68 metabolism, maternal, 57 serum and blood tests, 1 258t \ lini-pills, 682t-683t, 693 Minute ventilation, in pregnancy, 64, 987 miR 1 7-92 cluster, 51 -

Mirena intrauterine system, 68 1 -685. See also I ntrauterine devices (IUDs) device, 68 1 , 68 1/ insertion, 685, 686/ Mirror image twins, 875 Mirror syndrome, 3 1 2-3 1 3 Miscarriage. See Abortion, spontaneous (miscarriage) Misgav Ladach technique, 578 Misoprostol, 507. See also Prostaglandin EI (PGEI) for abortion, induced irst-trimester, 36 1-362, 362t second-trimester, 362t, 363 for abortion surgery, 359 for cervical ripening preinduction, 507 for trial oflabor after cesarean section, 550 for labor induction and augmentation, 508-509 third-stage, 52 for urerine atony, 760 Missed abortion, 349-35 1 , 350, 350t Mithramycin, for hyperparathryoidism, 1 1 29 Mitochondrial inheritance, 266-267 Mitral insuiciency, 956t, 957 Mitral stenosis, 95 5-957, 956t management, 956-957, 956/ pathophysiology, 955-957 pregnancy ourcomes, 956 Mitral valve prolapse, 957 Mixed gonadal dysgenesis, 39 Mixed respiratory-metabolic acidemia, fetal, 6 1 1 M-mode echocardiography, 204-205, 205/ MMP-9, endometrial invasion, 9 1 MMR vaccine, 1 2 1 4 Modes o f inheritance, 264-270. See also Inheritance, modes of Modiied Prague maneuver, 54 -548, 548/ Modiied Ritgen maneuver, 5 1 , 5 1 7/ Molding, fetal head, 43 1 , 43 1/ Braxton Hicks contractions, 43 1 , 43 1/ dystocia, 43 1 , 43 1, 455 Mole. See also specic ypes Breus, 1 1 5 hydatidiform, 388-393 invasive, 388, 394 Molecular therapy. See also speciic ypes in pregnancy, 1 1 9 1 \lometasone furoate, 1 1 88 Monoamnionic twins, 873-875, 874/ Monochorionic twins, vascular anastomoses, 8 6-88 1 artery-to-artery anastomoses, 877-878, 87 1 connection number, size, and direction, 8 7, 877/ hydatidiform mole with coexisting normal fetus, 88 1 twin anemia-polycythemia sequence, 880 twin reversed-arterial-perfusion sequence, 880-88 1 , 880, 88 1/ twin-to-twin transfusion syndrome, 877, 878-880 diagnosis, 879, 879/ fetal brain damage, 878, 878/ management and prognosis, 879-880 Quintero staging, 879, 879/ Monoclonal antibodies, for cancer, 1 1 9 1 -1 1 92 \ lonocyte chemotactic protein-l (MCP- I ) , menstruation, 8 5 Monocytes, fetal, 1 37 Monogenic disorder, 264, 264t. See also speciic ypes Monophasic pills, 690

Monosomy, 258 autosomal, 347 deinition, 254 Monosomy X, euploid abortion, 347 Monozygotic twins, 864 genesis, 864, 865/ mechanisms, 864 Mons pubis, 1 6, 1 7/ Mood, puerperium, 661 Mood disorders, 1 1 75-1 1 80 anxiety disorders, 1 1 79- 1 1 80 bipolar and related disorders, 1 1 78-1 1 79 major depression, 1 1 75-1 1 78 postpartum psychosis, 1 1 79 Morbidity, fetal, trauma-related, 927 Morbidity, infant, operative vaginal delivery, 556 Morbidity, long-term of-spring, maternal obesity on, 941 Morbidity, maternal cesarean delivery, 568-569 hypertension, chronic, in pregnancy, 978 hypertensive disorders of pregnancy, 9 8 late, puerperium, 663, 663t obesity-associated, 938, 938/ overgrowth, fetal, 857-858, 8 58t placental abruption, 69, 769t severe, 6, 7 t Morbidity, multifetal pregnancy fetal, 863-864 maternal, 864 Morbidity, newborn, preterm birth, 805-809, 805t late-preterm birth, 807-809 distriburion, 807-808, 807/ neonatal morbidity rates, 808-809, 808t neonatal mortality rates, 808-809, 808/ obstetrical complications, 808, 808/ threshold of viability, 805-807 clinical management, 806-80 , 807 t deinition, 805 periviable neonatal survival, 806, 806/, 806t periviable period, 805 Morbidity, perinatal fetal-growth restriction, 847, 847f, 848 hypertension, chronic, 979-980, 979/ medications, 90 1 obesity, 940-94 1 overgrowth, fetal, 857-8 58, 858t postterm pregnancy, 836, 836t surgery, 90 1 , 90 1 t systemic lupus erythematosus, 1 1 42- 1 1 4 3 Morbidly adherent placenta, 777-782 classiication, 778-779, 778, 779/ clinical presentation and diagnosis, 780-7 8 1 , 780, 78 1/ etiopathogenesis, 777- 78 incidence, 779 management, 8 1 -782 cesarean delivery and hysterectomy, 78 1 -782 conservative, 82 delivery timing, 78 1 postoperative prophylactic catheterization, 78 1 transfer for delivery, 78 1 , 78 1 t placenta previa, 75 pregnancy outcomes, 82, 783t risk factors, 779- 80, 780/ Moning sickness, 1 4 Morphine, for labor, 487t, 488

1 30 5

1 306

I nd ex Mortality, fetal. See also Stillbirth coagulopathies, 85 deinition, 645 rates, 645 , 645/ trauma-related, 927 Mortality, infant, 804, 804t preterm birth, 804, 804t rate, 3 Mortality, maternal cesarean delivery, 568-569 direct, 3 hypertension, chronic, in pregnancy, 978 hypertensive disorders of pregnancy, 978 indirect, 3 matenal mortality ratio, 4, 5-6, 5/-6/ placental abruption, 769, 769t suicide, 1 1 73 Mortality, multifetal pregnancy fetal, 863-864 maternal, 864 Mortality, perinatal cesarean delivery, prior, 593 fetal-growth restriction, 847, 847, 848 hypertension, chronic, 979-980, 979/ measures, 4, 4, 5/ obesity, 940 postterm pregnancy, 836, 836, 836t systemic lupus erythematosus, 1 1 42-1 1 43 congenital heart block, 1 1 43 neonatal lupus syndrome, 1 1 42- 1 1 43 Mortality measures, infant deaths, 4-5 Mortality rate fetal, thermal injury, 930, 930/ infant, 3 maternal, 4, 5-6, 5/-6/ thermal injury, 930, 930/ neonatal, 3 perinatal, 3, 4, 4/ Mortality ratio, maternal, U. S., 4, 5-6 common causes, 5, 5/ by ethnicity and race, 6, 6/ rates, 5 by state, 5-6, 5/ Morula, 87, 88 Mosaicism, chromosomal, 263-264 confined placental, 263-264 gonadal, 264 Mothers, constitutionally small, in fetal-growth restriction, 849 Movements, fetal, 3 3 1 -333 clinical application, 332-333 physiology, 3 3 1 -332, 332/ Moxibustion, for external cephalic version, 550 MRKH syndrome, 42 Mucopurulent cervicitis, Chlamydia, 1 028, 1 240 Mucus plug, 5 1 \ lullerian abnormalities, 4 1 -45, 42t cervical, 42-43 diethylstilbestrol, 42, 43, 45 fallopian tube, 45 Mullerian agenesis, 42, 43/ principal deformities, 4 1 -42 recurrent pregnancy loss, 353 uterine, 43-45 arcuate uterus, 44, 45 bicornuate uterus, 44, 45 cerclage treatment, 45 discovery, 43 imaging, 43-44, 44/

Mullerian abnormalities (Cont): septate uterus, 44, 45 unicornuate uterus, 44 uterine didelphys, 44-45 vaginal, 42 Mullerian agenesis, 42, 43/ Mullerian-inhibiting substance (MIS), 38 Multicystic dysplastic kidney (MCDK) , 209-2 1 0, 2 1 0/ Multidetector CT (MDCT) in pregnancy, 908 pulmonary angiography, pulmonary embolism, 907, 1 0 1 6- 1 0 1 8, 1 0 1 8/ Multifactorial inheritance, 268-270, 268t cardiac defects, 269-270, 953t neural-tube defects, 270 threshold trait, 269, 269/ Multifetal gestation. See Multifetal pregnancy Multifetal pregnancy, 863-892 amniocentesis, 292-293 delivery, 887-89 1 breech presentation, irst twin, 889 cephalic-cephalic presentation, 888 cephalic-noncephalic presentation, 888-889, 889t cesarean, 547, 890 timing, 887-888 triplet or higher-order gestation, 890-891 vaginal birth after cesarean delivery, 890 vaginal delivery, second twin, 889-890, 890/ diagnosis, 869-870 abdominal radiography, 870 clinical evaluation, 869-870 magnetic resonance imaging, 870 sonography, 870, 870/ discordant growth, twin fetuses, 88 1 -882 diagnosis, 882 etiopathogenesis, 88 1-882 management fetal surveillance, 882 serial sonography, 882 fetal complications, unique, 873-88 1 monoamnionic twins, 873-875, 874/ monochorionic twins and vascular anastomoses, 8 6-88 1 artery-to-artery anastomoses, 8 7-878, 877/ connection number, size, and direction, 877, 877/ hydatidiform mole with coexisting normal fetus, 8 8 1 twin anemia-polycythemia sequence, 880 twin reversed-arterial-perfusion sequence, 880-8 8 1 , 880f, 88 1/ twin-to-twin transfusion syndrome, 87 , 878-880 (See also Twin-to-twin transfusion syndrome (TTTS)) twinning, unique and aberrant, 875-876 conjoined twins, 875-876, 875/-877/ external parasitic twins, 875, 876 fetus-in-fetu, 875, 876 fetal demise, 882-884 death of one fetus, 882-888, 883/ death of one fetus, impending, 884 fetal-growth restriction, 85 1 , 8 5 1, 8 2, 872/ hydramnios, 229 incidence, 863 infertility therapy, 864 mechanisms, 864-869

Multifetal pregnancy (Cont.): chorionicity, determining, 867-869, 868t placental examination, 865, 869, 869/ sonographic, 867-869, 868, 869/ dizygotic vs. monozygotic twinning, 864 sex ratios, 867 superfecundation, 865, 866/ superfetation, 864-865 twinning factors, 865-867 monozygotic, genesis, 864, 865/ zygosity, determining, 867 morbidity and mortality fetal, 863-864 maternal, 864 physiological adaptations, maternal, 870-8 7 1 pregnancy complications, 87 1 -873 congenital malformations, 871-872 development, long-term infant, 873 hypertension, 872-873 low birthweight, 872, 872, 873/ spontaneous abortion, 871 prenatal care, 884-885 diet, 884 fetal surveillance, antepartum, 884-885 sonography, 884 preterm birth, 8 1 2, 873, 885-887 delayed delivery of second twin, 887 prediction, 885 preterm labor, treatment, 886 preterm premature rupture of membranes, 8 1 9-822, 886-887 prevention bed rest, 885 cervical cerclage, 886 pessary, 886 progesterone therapy, 1M, 885 progesterone therapy, vaginal, 885-886 tocolysis, prophylactic, 885 selective reduction, 89 1 termination, 89 1 -892 Multilobate placenta, 1 1 2 Multipara, 1 6 1 placenta previa risk, 775 Multiple analytes, aneuploidy screening, 28 1 Multiple endocrine neoplasia syndromes, 1 1 30 Multiple of the median (MoM) , 281 Multiple sclerosis, 1 1 64-1 1 65, 1 1 64/ Mumps virus infection, 1 2 1 4 Murmur diastolic, 6 1 , 950/ systolic low, 949, 950/ Musculoskeletal anatomy, pelvic, 29-3 1 bones, 29, 30/ joints, 29 pelvic shapes, 3 1 , 3 1/ planes and diameters, 30-3 1 , 30/ mid pelvis and pelvic outlet, 30, 30/ pelvic inlet, 30, 30/ Musculoskeletal injuries. See also speciic ypes hospital care, puerperium, 66 1-662, 661, 662/ muscle injuries, newborn, 63 1 Musculoskeletal system, development and physiology fetal, 1 37 maternal, 72 Myasthenia gravis, 1 1 65- 1 1 66 Myasthenic crisis, 1 1 65 Mycobacterium leprae, 1 224- 1 225 Mycophenolate embryopathy, 244

I n dex Mycophenolate mofetil for lupus, 1 1 42 teratogeniciry, 244 Mycoplasma pneumonia, autoimmune hemolysis from, 1 078 Mycotic infections, 1 228 Myelination, fetal central nervous system, 1 29 Myelocystocele, fetal magnetic resonance imaging, 2 1 8, 2 1 8/ M yelo men ingocele fetal endoscopic repair, 324 open fetal surgery, 3 1 9-32 1 , 320/ 320t sonography, 1 93, 1 93/ surgery, open fetal, 3 1 9-32 1 , 320/ 320t Myocardial function, pregnancy-related hypertension on, 7 1 8 Myocardial infarction acute, 968-969, 969/ in pregnancy, 968-969, 969/ Myocardial performance index (MPI), twin-to-twin transfusion syndrome, 879 Myoclonus-dystonia, imprinting, 268, 268t Myocytes, uterus arrangement, 50 Myofascitis, postpartum, 67 1 Myometrial gap junctions, parturition, 405, 406/ Myometrium, 24, 24/ involution, puerperium, 653 labor, 400-40 1 parturition, 408 oxytocin receptors, 408 parturition, relaxation and contraction, 403-407 actin-myosin interactions, 404, 405/ balance and quiescence, control, 403-404 cyclic guanosine monophosphate, 407 endoplasmic reticulum stress response, 405-406 G-protein-coupled receptors, 406-407, 406/ membrane potential regulation, 404-405, 405/ myometrial gap junctions, 405, 406/ uterotonin degradation, accelerated, 407 Myopathies, inflammatory, 1 1 50-1 1 5 1 Myosalpinx, 28, 52 Myosin light-chain kinase, parturition, 404 Myrtiform caruncles, 654 Myxomatous degeneration, 957 N N -acerylcysteine, 1 068 Naegele rule, 1 25 , 1 6 1 Nalbuphine, for labor, 488 Nasal physiology, 64-65 Natalizumab for Crohn disease, 105 1 for multiple sclerosis, 1 1 65 National Birth Defects Prevention Study (NBDPS), 237 National Vital Statistics System, U.S., 2 Natural-killer-cell neoplasms, 1 202- 1 203 Natural killer cells (NKCs) decidua, 9 1 , 95 fetal-maternal interface, 9 5 Nausea, i n pregnancy, 1 74. See also Hyperemesis gravidarum N ear misses, 6 Neck, fetal sonography anomalies, 1 96-1 98, 1 98/ normal, 1 96, 1 96/ 1 97/ Necrotizing enterocolitis, 638-639

Necrotizing fasciitis, postpartum, 67 1 , 67 1/ Needle-through technique, 493/ 497 Negative-predictive value, aneuploidy screening, 280-28 1 Negative-pressure wound therapy (NPWT), 670-67 1 , 943 Neglected transverse lie, 453 Neisseria gonorrhoeae, 1 239- 1 240 disseminated infection, 1 240 IUD infection, 684 newborn infection, 6 1 3 prenatal testing, 1 63 Neonatal abstinence syndrome, 9, 625 Neonatal alloimmune thrombocytopenia (NAIT), 307-308, 308t, 1 087 Neonatal behavioral syndrome, 245 Neonatal death early, 3 late, 3 rate, 3, 4, 5/ Neonatal encephalopathy, 620-622 neuroimaging, 624-625 Neonatal lupus syndrome, 1 1 42 Neonatal mortaliry rate, 3 Neonatal sepsis, group B Streptococcus, 1 220 Neonate postterm, 3 preterm, 3 term, 3 Neoplastic disorders, 1 1 90-1 204. See aso speciic ypes breast carcinoma, 1 200- 1 20 1 cancer therapy, 1 1 9 1 -1 1 92 gastrointestinal tract cancer, 1 204 leukemias, 1 203 lymphomas Hodgkin disease, 1 202, 1 202t non-Hodgkin lymphomas, 1 202- 1 203, 1 202t malignant melanoma, 1 203-1 204 miscarriage, 348 miscellaneous tumors, 1 204 pancreatic and hepatocellular cancer, 1 204 placental metastases, 1 1 6, 1 1 92 proportion, by rype, 1 1 90, 1 1 90/ reproductive tract neoplasms, 1 1 92- 1 200 (See also Reproductive tract neoplasms; specic ypes) thyroid cancer, 1 20 1 - 1 202 Nephrectomy, unilateral, pregnancy after, 1 026 Nephritis, lupus, 1 1 4 1 Nephrolithiasis, 1 030 Nephropathy, fetal-growth restriction, 850 Neural-tube defects (NTDs) amniocentesis diagnosis, 278 folic-acid supplement prevention, 1 28- 129 imaging, fetal, 1 92-1 93 amnionic-band sequence, 1 93 anencephaly, 1 92, 1 92/ cephalocele, 1 92- 1 93 , 1 9/ Chiari I I I malformation, 1 93 encephalocele, 1 93 Meckel-Gruber syndrome, 1 93 spina bifida, 1 93, 1 93/(See also Spina biida, fetal sonography) matenal serum AFP elevation, 283, 283t multifactorial inheritance, 270 preconceptual care, 149 screening, prenatal, 1 6 5

Neuraminidase inhibitors, 1 2 1 4 Neuraxial analgesia, obstetric, 490-497. See also Analgesia, neuraxial; Epidural block, continuous lumbar Neurodegenerative diseases, 1 1 65-1 1 66 deinition, 1 1 64 H untington disease, 1 1 65 myasthenia gravis, 1 1 65- 1 1 66 Neuroibromatosis, 1 1 30, 1 1 88 Neurohypophysis, fetal, 1 36 Neurological disorders, 1 1 56-1 1 69, 1 1 60t. See also speciic ypes central nervous system imaging, 1 1 56 cerebrovascular diseases, 1 1 60-1 1 64 demyelinating or degenerative diseases, 1 1 64-1 1 66 headache, 1 1 57-1 1 58, 1 1 57/ idiopathic intracranial hypertension, 1 1 6 8 maternal brain death, 93 1 , 1 1 68-1 1 69 maternal ventricular shunts, 1 1 68 neuropathies, 1 1 66- 1 1 67 seizure disorders, 1 1 58-1 1 59, 1 1 60t spinal cord injury, 1 1 67-1 1 68 Neuronal migration, 1 29, 1 29/ Neuronal proliferation, 1 29, 1 29/ Neuropathies, 1 1 66- 1 1 67 Bell palsy, 1 1 67, 1 1 67/ carpal runnel syndrome, 1 1 67 G uillain-Barre syndrome, 1 1 66 mononeuropathies, 1 1 66 obstetrical, 66 1 polyneuropathies, 1 1 66 Neuropeptide Y, placental, 99t, 1 02 Neurophysin, 4 1 6 Newborn, 606-6 1 6. See also speciic topics air breathing, transition to, 606-607 delivery room care, 607-6 1 0 (See also Delivery room care, newborn) evaluation, newborn condition, 6 1 0-6 1 3 (See also Evaluation, newborn condition) preventive care, 6 1 3-6 1 4 eye infection prophylaxis, 6 1 3-6 1 4 hepatitis B immunization, 6 1 4, 1 065 screening, 6 1 4, 6 1 4t vitamin K, 6 1 4 zika virus, 6 1 4 routine care, 6 1 4-6 1 6 feeding and weight loss, 6 1 5 gestational-age estimation, 6 1 4-6 1 5 hyperbilirubinemia, neonatal, 6 1 5 male circumcision, 1 6 1/ 6 1 5-6 1 6 rooming i n and hospital discharge, 6 1 6 skin and umbilical cord care, 6 1 5 stools and urine, 6 1 5 Newborn, preterm, 3 , 636-642. See also specic disorders brain disorders, 639-640 cerebral palsy, 640-642 complications of prematuriry, 636, 636t necrotizing enterocolitis, 638-639 respiratory distress syndrome, 636-638 retinopathy of prematuriry, 639 Newborn diseases, 6 1 9-627 autism spectrum diseases, 625 cerebral palsy, 622-624 neuroimaging, 624-625 hematological disorders, 625-627 anemia, 625-626

1 307

1 308

I n dex Newborn diseases (Cont: hemorrhagic disease of the newborn, 626-627 hyperbilirubinemia, 626 polycythemia [nd hyperviscosity, 626 thrombocytopenia, 627 intellectual disability, 625 neonatal abstinence syndrome, 625 neonatal encephalopathy, 620-622 neuroimaging, 624-625 respiratory distress, 6 1 9-620 meconium aspiration syndrome, 620 respiratory distress syndrome, 6 1 9-620 seizure disorders, 625 Newborn injuries, 627-63 1 congenital deformiry, 63 1 cranial, 627-629 extracranial hematomas, 628-629, 629/ intracranial hemorrhage, 628, 628t skull fractures, 629, 629/ fractures, 630-63 1 incidence, 627, 627t muscle, 63 1 peripheral nerve brachial plexopathy, 630 facial paralysis, 630, 630/ soft tissue, 63 1 spinal cord, 630 Nexplanon, 685-688 insertion technique, 688-689, 688/ Nifedipine for chronic hypertension, in pregnancy, 980-98 1 for hypertension with preeclampsia-eclampsia, 740 Nipples inverted, 659 stimulation, in contraction stress test, 334 Nitabuch layer, 86-87 Nitinol, transcervical sterilization, 705 Nitric oxide matenal, 63-64 in preeclampsia, 7 1 6 for respiratory distress syndrome, preterm newborn, 637 Nitric oxide donors. See also specic ypes for preinduction cervical ripening, 507 for preterm labor, 827 Nitrofurantoin, teratogenicity, 242 Nitroglycerin, for fetal heart rate problems, 475, 475t Nitrous oxide, for labor, 488 Nodular thyroid disease, 1 1 28 Nomegestrol acetate, 690 Nonalcoholic fatty liver disease (NAFLD) , 938, 939-940, 1 067 Nonalcoholic steatohepatitis (NASH), 938, 1 067 Noncardiogenic permeability edema, 9 1 7-9 1 8, 9 1 7t Noncardiogenic pulmonary edema, 9 1 7 Nondisjunction, 254-255 Nongoitrous hypothyroidism, fetal and neonatal, 1 1 22 Non-Hodgkin lymphomas, 1 202- 1 203, 1 202t Nonmaternal death, 4 Nonpuerperal tubal sterilization, 704 Nonreassuring fetal status, defined, 472

Nonreassuring fetal status, intrapartum assessment, 4 2-4 8 definition and classiication, 472-475 diagnosis, 4 3-474, 473t fetal heart rate patterns and brain injulJ , 476-477, 476/ heart rate monitoring benefits, electronic fetal, 47 management options, 475-476, 4 5 t amnioinfusion, 475-4 6, 4 5 t tocolysis, 4 5 meconium in amnionic luid, 474 recommendations, current, 4 8, 478t Nonsteroidal antiinflammatory drugs (NSAIDs). See also specic ypes oligohydramnios, 23 1 for rheumatoid arthritis, 1 1 47 teratogenicity, 24 1 Nonstress tests, fetal heart rate, 334-337. See also Heart rate tests, fetal Nontreponemal testing, 1 237-1 238 Noonan syndrome, cystic hygroma, 1 97, 1 98/ Normal uterine activity, 480 Norplant-2, 688 Norplant system, 688 No-scalpel vasectomy (NSY) , 706 NovoSeven, for hemorrhage, 790 Nuchal arm, partial breech extraction, 546, 546/ Nuchal cord, 1 1 9- 1 20 Nuchal skinfold, second-trimester aneuploid screening, 286, 287/ Nuchal translucency (NT), 1 86, 1 86t, 28 1-282, 282/ crown-rump length on, 28 1 Nuclear medicine, in pregnancy, 908-909, 909t Nucleated red blood cells, cerebral palsy, 624 Nulligravida, 1 60 Nullipara, 1 60 Nurse/patient ratios, labor, 434, 434t Nursing, 657-658, 657t, 658t Nutrition, fetal on fetal growth, 845 in fetal-growth restriction, 850 Nutrition, maternal, 13 - 1 39 amino acids, 1 39 in fetal-growth restriction, 850 free fatty acids and triglycerides, 1 38 for gastrointestinal disorders, 1 043, 1 043t glucose and fetal growth fetal macrosomia, 1 38 glucose transport, 1 38 heavy metals, placental sequestration, 1 39 ions and trace metals, 1 39 leptin, 1 38 proteins, 1 39 on twinning, 866-867 vitamins, 1 39 Nutritional counseling, prenatal, 1 65- 1 69 calories, 1 67, 1 67/ dietary reference intakes, 1 67, 1 67 t minerals, 1 67t, 1 68 pragmatic nutritional surveillance, 1 69 protein, 1 67-1 68, 1 67t recommended dietary allowances, 1 67, 1 67t undernutrition, severe, 1 66 vitamins, 1 6-t, 1 68- 1 69 weight gain recommendations, 1 65-1 66, 1 66t weight retention after pregnancy, 1 66-1 67 , 1 67/ NuvaRing, 692-693, 69/ NYHA class I & II, 9 5 1 -952 NYHA class III & Y, 952-953

o Obamacare, 6 Obesity, maternal, 936-945 adipose pathophysiology, 936-937 bariatric surgery, 943-945 pregnancy, 944-945 restrictive malabsorptive procedures, 944, 944/ restrictive procedures, 943-944, 944t in cerebrovascular diseases, 1 1 60 classiication, 936 definitions, 936 in girls and women, 936, 937/ laparoscopic surgery in pregnancy, 887-888 on macrosomia, with gestational diabetes, 1 1 1 1 management, 941 -943 antepartum, 94 1 -942 dietary intervention, 94 1-942 prenatal care, 942 weight gain, matenal, 94 1 intrapartum, 942-943, 943/ anesthesia risks, 942 cesarean delivery, 942 labor induction, 942 surgical concerns, 943, 943/ metabolic syndrome, 937, 938t nonalcoholic fatty liver disease, 938 obesiy-associated morbidity, 938, 938/ pregnancy and, 938-943 adverse pregnancy efects, 939, 939t gestational diabetes, 939 maternal morbidity, 938-940, 939t morbidity, long-term ofspring, 94 1 morbidity, perinatal, 940-941 mortality, perinatal, 940 on pregnancy outcomes, 939, 940/ prevalence, 938, 939/ prevalence, 936, 937/ treatment, 938 Obesity gene, 845 Obesity paradox, 938 Ob/Gyn hospitalist, 8 Oblique lie, 422, 452 Obstetrical estimate, 846 Obstetrical neuropathies, 661 Obstructive renal failure, 1 037, 1 037/ Occiput anterior presentation, 423, 427-43 1 cardinal movements of labor, 427, 428/ descent, 42 engagement, 42 , 429/ synclitism and asynclitism, 427, 429/ explusion, 43 1 extension, 429, 430/ external rotation, 428, 429-43 1 flexion, 429, 429/ internal rotation, 429, 430/ left occiput anterior, 423, 427 right occiput anterior, 423f, 427 vaginal delivery, 5 1 7-5 1 9 cord clamping, 5 1 8-5 1 9 delivery of head, 5 1 7-5 1 8, 5 1 7/ delivery of shoulder, 5 1 8, 5 1 8/ modiied Ritgen maneuver, 5 1 7, 5 1 7/ Occiput posterior presentation forceps delivery, 560-56 1 , 560/-56 1/ normal labor mechanisms, 4 3 1 persistent, 43 1 vaginal delivery, 5 1 9-520 delivery, 5 1 9-520 morbidity, 5 1 9

I ndex Occiput presentation, 422 Occiput transverse presentation forceps delivery, 5 6 1 -562, 562/ left occiput transverse, 427, 430/ right occiput transverse, 424] 427 vaginal delivery, 5 1 9 Occupation, on pregnancy, 1 70. See also Teratogens fatigue, prenatal care, 1 70 miscarriage, 348 Octreotide, for acromegaly, 1 1 33 Ocular parameters, fetal, by gestational age, 1 268t Ogilvie syndrome, 1 052 Oligohydramnios, 1 89, 225, 230-232 amnioinfusion for, 476 "borderline," 232 clinical presentation, 230 congenital anomalies, 23 1 deformiry injuries, 63 1 early-onset, 23 1 etiology, 230-23 1 management, 232 medication, 231 after midpregnancy, 23 1 , 23 1 t postterm pregnancy, 23 1 , 837-838, 838] 839, 839/ pregnancy outcomes, 23 1-232 prognosis, 230 pulmonary hypoplasia, 232 sonographic diagnosis, 230 Olsalazine, for ulcerative colitis, 1 050 Omphalocele, fetal sonographic, 205-206, 206/ Onapristone, on parturition, 402 Ondansetron, for hyperemesis gravidarum, 1 045 Online Mendelian Inheritance in Man (OMIM), 254 Onset, labor, normal, 43 1 -432, 432/ Oocytes, 8 1 , 82, 83/ Open fetal surgery, 3 1 9-32 1 fundamentals, 3 1 9 indications, 3 1 9t myelomeningocele, 3 1 9-32 1 , 320] 320t risks, 3 1 9, 320t sacrococcygeal teratoma, 32 1 , 32 1f thoracic masses, 3 2 1 Open spina bifida, sonography, 1 93 Opioids-narcotics, teratogenicity, 248-249 Opioid use disorders, in pregnancy, 9 OPPTIMUM study, 8 1 8 Opt-out approach, 1 247- 1 248 Oral contraceptives, combination (COCs), 689-690 Oral hypoglycemic agents, for gestational diabetes, 1 1 1 2-1 1 1 3 Oral intake, labor, 437 Oromandibular limb hypogenesis, with chorionic villus sampling, 294, 294/ Ortho Evra, 692 Orthopedic injuries, 92 Oseltamivir, 1 2 1 4 Osmotic dilators, 358-359, 358/ Osteitis pubis, 662 Osteochondrodysplasia, 2 1 0 Osteogenesis imperfecta, 2 1 0, 2 1 1 , 2 1 1] 1 1 5 1 Osteoporosis heparin-induced, 1 0 1 5 pregnancy-associated, 1 1 29- 1 1 30, 1 1 29/ Ostomy, pregnancy and, 1 0 5 1 Outlet, contracted, 449

Ovarian abscess, postpartum, 67 1 Ovarian artery, 26, 26/ Ovarian cancer, 1 1 99- 1 200 Ovarian cycle, 8 1-83 follicular phase, 8 1-82, 8 1] 82/ I ureal phase, 8 1] 82-83 ovulation, 8 1] 82-83, 82/ selection window, 82 Ovarian-endometrial cycle, 80-85 duration, 8 1 , 8 1/ endometrial cycle, 83-85 menstruation, 84] 8 5 proliferative phase, 83-84, 83/ secretory phase, 84-85, 84/ endometrial histology changes, cyclical, 80, 8 1/ estrogen and progesterone action, 83 follicle stimulating hormone, 80, 8 1/ luteinizing hormone, 80, 8 1/ ovarian cycle, 8 1-83 follicular phase, 8 1 -82, 8 1] 82/ luteal phase, 8 1] 82-83 ovulation, 8 1] 82-83, 82/ selection window, 82 Ovarian hyperstimulation syndrome, 1 1 99 Ovarian ligament, 24] 28 Ovarian neoplasms, 1 1 97-1 200 adnexal cysts, 1 200 asymptomatic adnexal mass, in pregnancy, 1 1 98-1 1 99 complications, 1 1 98 diagnosis, 1 1 98, 1 1 98/ hyperreactio luteinalis, 1 1 99 incidence, 1 1 97 ovarian cancer, 1 1 99-1 200 ovarian hyperstimulation syndrome, 1 1 99 pregnancy lureoma, 1 1 99 pregnancy-related ovarian tumors, 1 1 99 types, 1 1 97-1 1 98 Ovarian pregnancy, 384 Ovarian vein thrombosis, septic, 673-674, 674/ Ovaries, 24] 28, 5 1-52 decidual reaction, 5 1 -52 relaxin, 52 theca-lutein cysts, 52, 3 9 1/ Overgrowth, fetal, 1 38 , 856-859. See also Macrosomia euglycemic mothers, 845 fetal-growth restriction, 849 lipid transfer, excessive, 845 posrrerm pregnancy, 837] 839 Overlap syndrome, 744 Overweight, 936 Ovotesticular, deined, 39 Ovulation, 1 24/ Ovulation age, 1 24, 1 24/ Oxcarbazepine, teratogenicity, 1 1 60t Oxidant stress, preeclampsia, 725t, 726 Oxygen delivery, maternal, 65 maternal arteriovenous oxygen diference, 65 total hemoglobin mass, 65 Oxyhemoglobin dissociation curve, 920, 920/ Oxytocin for abortion, induced, 362t, 364 for cervical ripening, in trial of labor after cesarean section, 550 after cesarean delivery, 576 fetal, 1 36 for labor, third-stage, 527

Oxytocin (Cont: for labor induction and augmentation, 509-5 1 1 , 509t active-phase arrest, 5 1 0-5 1 1 IV administration, 509-5 1 0, 509t risks vs. benefits, 5 1 0 uterine contraction pressures, 5 1 0 lactation, 65 maternal, 69 amnion epithelial cells, 96 parturition, 4 1 6 for uterine atony, 759 Oxytocin challenge test, 334 Oxytocin-receptor antagonist (ORA), for preterm labor, 827 Oxytocin receptors, on myometrium in parturition, 408 p

Packed red blood cells, for hemorrhage, 789t, 790 Pain relief. See also Analgesia, obstetric hospital care, puerperium, 66 1 maternal, labor, 436 Palmar erythema, 54 Palmer point, 903 Pancreas, fetal, 1 3 5 Pancreatic cancer, 1 204 Pancreatic transplantation, 1 07 1 Pancreatitis, 1 070- 1 07 1 , 1 07 1 t acute fatty liver o f pregnancy, 1 062 PAP test abnormalities, 1 1 93, 1 1 94t Paracentric inversion, 263, 263/ Paracervical block, 490 Paracrine system, maternal, implantation and early trophoblast formation, 87 Paradoxical chest wall movement, fetal, 333, 333/ ParaGard T 380A, 68 1-685. See also Intrauterine devices (IUDs) device, 68 1 , 68 1/ emergency contraception, 696t, 697 insertion, 685, 687/ Parametrial phlegmon, 672-673, 672] 673/ Parametrium, 25 Parasitic rwins, external, 875] 8 6 Parasympathetic nerves, pelvic, 27] 28 Parathyroid disease, 1 1 28-1 1 30 calcitonin, 1 1 28 fetal calcium demands, 1 1 28 hypercalcemic crisis, 1 1 28, 1 1 29 hyperparathyroidism, 1 1 28- 1 1 29 hypoparathyroidism, 1 1 29 parathyroid hormone, 1 1 28 pregnancy-associated osteoporosis, 1 1 29- 1 1 30, 1 1 29/ PTH-related protein, 7 1 , 1 1 28 Parathyroid glands, maternal, 7 1 calcitonin, 7 1 parathyroid hormone, 71 Parathyroid hormone (PTH), 1 1 28 maternal, 71 serum and blood tests, 1 258t Parathyroid hormone-related protein (PTH-rp) fetal, 1 39 placental, 99t, 1 02 serum and blood tests, 1 258t Paraurethral glands, 1 7, 1 7/ Parenteral nutrition for gastrointestinal disorders, 1 043, 1 043t for hyperemesis gravidarum, 1 046

1 309

1 31 0

I n dex Parity, increased, multifetal pregnancies, 866, 866/ Paroxysmal nocturnal hemoglinuria, 1 079 Partial birth abortion, 363 Partial breech extraction, 544-548. See also under Delivery, breech Partial thromboplastin time (PTT) coagulopathies, 784-785 lupus anticoagulant, 1 1 44 Partograph abnormal labor, 443 normal labor, 439 Parturition. See Labor Parvovirus infection, 1 2 1 6- 1 2 1 7, 1 2 1 8/ Patau syndrome. See Trisomy 1 3 (Patau syndrome) Patch, transdermal contraceptive, 692 Paternal age advanced autosomal dominant inheritance, 265 ET proto-oncogene, 265 on trisomy 2 1 , 265 on preconceptual care, 1 52 Pathological retraction ring, 4 1 3 Peak expiratory flow rates, 64 Peak systolic velocity, fetal anemia, 2 1 4-2 1 5 Pedigree construction, 1 49, 1 50/ Pegfilgrastim, for cancer, 1 1 9 1 Pegvisomant, for acromegaly, 1 1 33 Pelvic capacity, fetopelvic disproportion, 448-449 contracted inlet, 448-449 contracted mid pelvis, 449 contracted oudet, 449 estimation, 449-450 Pelvic diaphragm, 2 1 Pelvic division, labor, 432 Pelvic floor disorders, after operative vaginal delivety, 5 5 5 fetal descent, 2 1 , 4 1 4-4 1 5 injury, dystocia with, 455 labor, changes, 42 1 Pelvic fractures, fetopelvic disproportion, 449 Pelvic infections, puerperal, 666-675 abdominal incisional infections, 670-67 1 , 6 0/ vacuum-assisted wound closure, 670-67 1 wound dehiscence, 67 1 adnexal abscesses and peritonitis, 67 1 -672 complications, 670 necrotizing fasciitis, 67 1 , 67 1/ parametrial phlegmon, 672-673, 672/ 6 3/ perineal (episiotomy) infections, 674-675 , 675t psoas abscess, 673 puerperal fever, 666-667 septic pelvic thrombophlebitis, 673-674, 673/ 674/ toxic shock syndrome, 675 uterine infection, 667-6 0 (See also Uterine infection, postpartum) Pelvic inlammatolY disease (PID) , from IUD, 684 Pelvic inlet, 30, 30/ Pelvic organ prolapse, 52-53 Pelvic outlet, 30, 30/ Pelvic packing, for hemorrhage, 794 Pelvic plexus, 2 f 28 Pelvic reconstructive surgery, prior, vaginal delivery, 525 Pelvic thrombophlebitis, septic, 673-674, 673/ 674/

Pelvis blood supply, 24/ 25-27, 26/ internal iliac artery branches, 26/ 27 ovarian artery, 26, 26/ Sampson artery, 26, 26/ uterine artery, 25-26, 26/ veins, 26 Caldwell-Molloy classiication, 3 1 , 3 1/ innervation, 2 -28 , 27/ hypogastric nerves, 27/ 28 inferior hypogastric plexus, 27/ 28 parasympathetic, 27/ 28 splanchnic nerves, 27/ 28 superior hypogastric plexus, 27/ 28 sympathetic, 2 , 2 f uterovaginal plexus, 27/ 28 vesical plexus, 27/ 28 renal pelvis dilatation, 208, 208/ 208t, 287, 287/ shapes, 3 1 , 3 1/ Pemphigoid gestationis, 1 1 84-1 1 86, 1 1 8 5/ 1 1 8 5 t Penetrance, autosomal dominant inheritance, 2 6 5 Penetrating trauma, 929 Penicillin for group B Streptococcus, 1 22 1 - 1 222 reactions to, 1 239, 1 239t Penicillin G for Lyme disease, 1 225 for syphilis, 1 238, 1 238t reactions to, 1 239, 1 239t Pentalogy of Cantrell, 206 Peptic ulcer disease (PUD) , 1 047 Peramivir, 1 2 1 4 Percutaneous endoscopic gastrostomy (PEG) , 1 042 Percutaneous fetal surgety, 3 1 9t, 324-327 Percutaneous umbilical blood sampling (PUBS), 294-29 5 , 295/ Pericentric inversion, 263, 263/ Perinatal injury, infant, after operative vaginal delivery, 5 5 5-556 Perinatal mortality rate, 3, 4, 4/ Perinatal period, 3 Perineal body, 1 9, 1 9/ Perineal care, puerperium, 660 Perineal infections, postpartum, 674-675, 675t Perineal membrane, 1 9, 1 9/ 20, 20/ Perineal nerve, 22-23, 22/ Perineum, anatomy, 1 8/ 1 9-23 anterior triangle, deep space, 20, 20/ bulbospongiosus muscle, 20, 20/ clitoris, 20, 20/ compressor urethrae muscle, 20, 20/ hymeneal ring, 20, 20/ ischiocavernous muscles, 20, 20/ ischiopubis ramus, 20, 20/ labium minus, 20, 20/ levator ani muscles, 20, 20/ perineal membrane, 20, 20/ sphincter urethrae, 20, 20/ striated urogenital sphincter complex, 20, 20/ supericial transverse perineal muscles, 20, 20/ urethra, 20-2 1 , 20/ urethrovaginal sphincter muscle, 20, 20/ anterior triangle, supericial space, 1 9-20, 1 9/ 765/ Bartholin glands, 1 9-20, 1 9/ bulbospongiosus muscle, 1 9-20, 1 9/ clitoris, 1 9, 1 9/ Colles fascia, 1 9, 1 9/ ischiocavernous muscles, 1 9/ 20 ischiopubic ramus, 1 9, 1 9/

Perineum, anatomy (Cont.: perineal body, 1 9, 1 9/ perineal membrane, 1 9, 1 9/ Scarpa fascia, 1 9, 1 9/ superficial transverse perineal muscles, 1 9/ 20 vestibular bulb, 1 9, 1 9/ 20 pelvic diaphragm, 2 1 posterior triangle, 2 1 -22, 2 1/ anal canal, 2 1 -22, 2 1/ anal sphincter complex, 2 1/ 22 ischioanal (ischiorectal) fossae, 2 1 , 2 1/ pudendal nerve and vessels, 22-23, 22/ Perineum, congenital abnormalities, 4 1 clitoral anomalies, 4 1 cloacal exstrophy, 4 1 epispadias, 4 1 hymenal anomalies, 4 1 Perineum, maternal, 5 2-53 acidic pH and Lactobacilus acidophilus, 52 Chadwick sign, 52 pelvic organ prolapse, 5 2-53 Periodontal disease, preterm birth, 8 1 2-8 1 3 Peripartum cardiomyopathy, 963-964, 963/ Peripartum hysterectomy, 5 67, 580-586. See also Hysterectomy, peripartum Peripherally inserted central catheter (PICC), for gastrointestinal disorders, 1 043 Peripheral nerve injuries, newborn brachial plexopathy, 630 facial paralysis, 630, 630/ Peritonitis, postpartum, 67 1 -672 Periventricular-intraventricular hemorrhage, 639-640 Periventricular leukomalacia, 640 Periviable fetuses, preterm breech presentation, 54 1 Perivillous fibrin deposition, maternal, 1 1 4, 1 1 4/ Persistent (patent) ductus arteriosus, 959 Persistent gestational trophoblastic disease, 388, 393-396. See also Gestational trophoblastic neoplasia (GTN) Persistent miillerian duct syndrome (PMDS), 40 Persistent occiput posterior position, 43 1 vaginal delivery, 5 1 9-520 delivery, 5 1 9-520 morbidity, 5 1 9 Persistent pulmonary hypertension o f the newborn (PPHN) fetal overgrowth and risk factors, 849 SSRI medications, 245, 1 1 78 Persistent severe postpartum hypertension, 743 furosemide for, 743-744 Personality disorders, 1 1 8 1 Personality traits, 1 1 8 1 Petit mal seizures, 1 1 5 9 Pfannenstiel incision for cesarean delivery, 57 1 -5 2 nerve severing, 1 6 Pfannenstiel-Kerr cesarean delivery, 5 2/-577/ 573-578 adhesions, 578 fetus delivery, 575-576, 5 75/-5 6/ placenta delivery, 576-57 , 5 7/ uterine, 574-575, 574/ uterine repair, 577, 577/ pH, serum eclamptic convulsion on, 1 9-720 in preeclampsia, 7 1 9 serum and blood tests, 1 260t Phase of maximum slope, 432, 432/ Phencyclidine (PCP) , teratogenicity, 249

I nd ex Phenobarbital, teratogenicity, 240 Phenotype-genotype relationship, 264-265 heterogeneity, 264-265 Phenotypic expression, preeclampsia syndtome, 7 1 3-7 1 4 Phenotypic gender, 3 8 Phenotypic heterogeneity, 265 Phenoxybenzamine, for pheochromocytoma in pregnancy, 1 1 3 1 Phenylalanine hydroxylase deiciency, autosomal recessive inheritance, 265-266 Phenylketonuria autosomal recessive inheritance, 265-266 preconceptual care, 1 49- 1 50, 1 49t Phenytoin, teratogenicity, 240, 1 1 60t Pheochromocytoma, 1 1 30-1 1 3 1 , 1 1 30] 1 1 30t Phlebotomy, preoperative patient, 79 1 Phlegmon, parametrial, 672-673, 672] 673/ Phocomelia, 2 1 2 from thalidomide and lenalidomide, 246 Phosphate, maternal, 57 Phosphatidylglycerol (PG) amniocentesis assessment, 638, 638/ surfactant, 1 34 Phosphatidylinositol (PI) , surfactant, 1 34 Physical abuse, 925-926, 926t Physiological retractiun ring, 4 1 3 Physiology fetal, 1 28-1 37 (See aLso Fetal development and physiology) labor, 400-4 1 7 (See aLso Labor, physiology) Physiology, maternal, 49-73. See aLso specic organs and systems breasts, 52] 53 cardiovascular system, 60-64 central nervous system, 72-73 coagulation and ibrinolysis, 59-60, 60t, 784] 1 005/ complications, medical and surgical, 900-90 1 endocrine system, 68-72 fat metabolism, 56-57 gastrointestinal tract, 68 hematological changes, 57-58, 58/ immunological functions, 58-59, 1 005] 1 259t metabolic changes, 54-57, 54t, 55] 5 5 t multifetal pregnancy, 870-871 musculoskeletal system, 72 pituitary gland, 68-69 reproductive tract, 49-53 , 5 1/ respiratoty tract, 64-65, 64] 65] 987-988, 1 266t skin, 53-54 urinaty system, 65-68, 65] 66t, 67/ Pica deinition, 1 52 preconceptual care, 1 52 prenatal care, 1 4 Piriformis muscle hematoma, 66 1 , 66 1/ Pituitaty disorders, 1 1 32-1 1 33 acromegaly, 1 1 33 diabetes insipidus, 1 1 33 lymphocytic hypophysitis, 1 1 33 prolactinomas, 1 1 32, 1 1 33/ Sheehan syndrome, 1 1 33 Pituitary gland fetal, 1 36 maternal, 68-69 antidiuretic hormone, 69 growth hormone, 69 oxytocin, 69 prolactin, 69

Placenta, 90-95 bilobate, 1 1 2 breaks, placental "barrier," 94-95 erythrocyte D-antigen alloimmunization, 9 5 microchimerism, 95 chorionicity, multifetal pregnancies, 865] 869, 869/ circulation, 94-95 , 94/ amnion, 94, 94/ anatomy, 94, 94/ fetal, 94 maternal, 94, 94/ circummarginate, 1 1 3, 1 1 3/ circumvallate, 1 1 3, 1 1 3/ debris, in preeclampsia, 7 1 4 delivery, 4 1 5-4 1 6, 4 1 5] 4 1 6] 525-526, 526/ development, 80- 1 06 (See aso Implantation and placental development) in embryofetal development, 1 39-1 4 1 intervillous space, 1 39- 1 40 placental transfer, 1 40-1 4 1 , 140t mechanisms, 1 40 oxygen and carbon dioxide transfer, 1 40- 1 4 1 , 1 40/ selective transfer and facilitated difusion, 141 endometrial invasion, 9 1 fetal-maternal interface decidual immune cells, 95 decidual macrophages, 9 5 decidua natural killer cells, 9 5 dendritic cells, 9 5 human leukocyte antigens, 9 5 immunogenicity, trophoblasts, 95 natural killer cells, 9 5 T cells, maternal, 95 growth and maturation, 93 fetal vessels, 90] 93 Hofbauer cells, 93 hormones, 98- 1 04, 99t (See aLso Hormones, placental; specic hormones) lesions, 1 1 1- 1 1 2 low-lying, 774 (See aLso Placenta previa) magnetic resonance imaging, 220 manual removal, 58-759, 759/ metastases, 1 1 6, 1 1 92 migration, placenta previa, 73-7 4 morbidly adherent, 777-782 (See aLso Morbidly adherent placenta) multilobate, 1 1 2 normal, 1 1 1- 1 1 2 perfusion, preeclampsia, 725- 26, 725t postterm pregnancy, dysfunction, 83 , 837/ in pregnancy, 40 1 , 40 1/ prostaglandin synthesis, 40 1 , 401/ ring-shaped, 1 1 2-1 1 3 after second-trimester abortion, evaluation, 364 spiral artery invasion, 89] 9 1 -92 succenturiate lobes, 1 1 2, 1 1 2/ tears, traumatic, 927-929, 928/ trophoblast invasion regulators, 90-9 1 villus branching, 92-93, 92/ Placenta, abnormalities, 1 1 1 - 1 20 calciication, 1 1 5 circulatory disturbances, 1 1 3-1 1 5 fetal blood flow disruption fetal thrombotic vasculopathy, 1 1 4] 1 1 5 subamnionic hematoma, 1 1 5 villous vascular lesions, 1 1 5 maternal blood Row disruption, 1 1 4-1 1 5

Placenta, abnormalities (Cont): hematoma, 1 1 4-1 1 5, 1 1 4/ infarction, 1 1 4 intervillous thtombosis, 1 1 4 maternal floor infarction, 1 1 4 perivillous ibrin deposition, 1 1 4, 1 1 4/ extrachorial placentation, 1 1 3, 1 1 3/ fetal-growth restriction, 848, 8 5 1 lesions, 1 1 1 -1 1 2 pathological examination, indications, 1 1 2t shape and size variants, 1 1 2- 1 1 3, 1 1 2/ tumors, 1 1 5-1 1 6 chorioangioma, 1 1 5- 1 1 6, 1 1 6/ metastatic, 1 1 6 umbilical cord, 1 1 7- 1 20 coiling, 1 1 7 cysts, 1 1 8 funic presentation, 1 20 insertion, 1 1 8, 1 1 8/ knots, 1 1 9 length, 1 1 7 loops, 1 1 9-120 remnants, 1 1 8 strictures, 1 1 9 vasa previa, 1 1 8- 1 1 9, 1 1 9/ vascular cord hematomas, 1 20 umbilical artery aneurysm, 1 20 umbilical cord vessel thromboses, 1 20 umbilical vein varix, 1 20 vessel number, 1 1 7-1 1 8, 1 1 7/ Placenta accreta, 778] 779 cesarean-scar pregnancy, 778 hysterectomy for, 363 Placenta adherens, 527 Placenta increta, 778] 779 Placental abruption, 767-773 classiication, 767 clinical indings and diagnosis, 7 1 -772 acute kidney injury, 772 consumptive coagulopathy, 77 1 Couvelaire uterus, 7 1 , 7 2/ diferential diagnosis, 77 1 hypovolemic shock, 77 1 Sheehan syndrome and pituitary failure, 772 coagulopathies, 785 coagulopathies with, 785 etiopathogenesis, 767-768, 768/ chtonic abruption, 68 clot age, 768, 768/ traumatic abruption, 768 frequency, 768-769, 769/ with hypertension, chtonic, 979 management, 772-773 cesarean delivery, 772 expectant, with preterm fetus, 773 with fetal compromise, 772, 772/ vaginal delivery, 772-773 morbidity and mortality, perinatal, 69, 769t predisposing factors cigarette smoking, 770 cocaine abuse, 770 demographic, 769-770 pregnancy-related hypertension, 770 preterm prematurely ruptured membranes, 770 prior abruption, 770 umbilical artery, isolated single, 70 uterine leiomyomas, 770 traumatic, 927-929, 928/

1 31 1

1312

I ndex Placental growth factor, decidual natural killer cells, 9 1 Placental mesenchymal dysplasia, 1 1 3 Placental separation and expulsion stage, 4 1 1 Placental site involution, puerperium, 654 subinvolution, 654 Placenta membranacea, 1 1 2-1 1 3 Placenta percreta, 778, 779 morbidly adherent placenta, -79, 780/ Placenta previa, 773-777 classiication low-lying placenta, 774 placenta previa, 774, 774/ clinical features, 775 delivery, 777 D & E with, 363 diagnosis, 776, 776/ hysterectomy, 777 incidence and associated factors clinical factors, 775 demographic, T4-775 management, 776outcomes, matenal and perinatal, 777 persistence, likelihood, 773-774, 774/ placental migration, 773-774 Placenta-uterine interface, implantation and early trophoblast formation, 87 Placenta vascularity index, 725 Placentomegaly, 1 1 3 Plasma exchange, for preeclampsia-eclampsia and HELLP syndrome, 744 Plasma proteins, fetal, 1 33 Plasma thrombin antecedent deficiency, 1 09 1 Plasma volume expansion, for preeclampsia, 740, 74 1 t maternal, 63 Plasminogen activator inhibitor type 1 (PAl- I ) thrombophilia, 1 008 Plasmodiumolciparum, 1 226- 1 227, 1 227/ Plasmodium knowlesi, 1 226-1 227, 1 227/ Plasmodium malariae, 1 226- 1 227, 1 227/ Plasmodium ovale, 1 226- 1 227, 1 227/ Platelet-activating factor (PAF), fetal, parturition, 41 1 Platelet disorders, 1 086- 1 089 thrombocytopenia, 1 086- 1 087, 1 086t thrombocytosis, 1087-1 088 thrombotic microangiopathies, 1 088-1 089, 1 089t Platelet neutralization procedure, 1 1 44 Platelets fetal, 1 3 1 , 1 32/ hemopoiesis, 1 3 1 , 1 32/ maternal, 60 in coagulation and ibrinolysis, 60 for hemorrhage, obstetrical, 789t, 790 immunological system, 60 preeclampsia, dysfunction, 726 Pneumococcal vaccines, 993-994 Pneumocystis jiroveci pneumonia, 994-995 Pneumonia, 992-995 bacterial, 992-994, 992, 993t classiication, 992 community-acquired, 992 fungal and parasitic fungal, 995 Pneumocystis, 994-995 health-care-associated, 992 incidence, 992

Pneumonia (Cont: influenza, 994 severe acute respiratory syndrome, 995 varicella, 994 Pneumonitis, mycotic, 1 228 Podalic pole, 422 Polar body analysis, 295 Poliovirus infection, 1 2 1 6 Polyarteritis nodosa, 1 1 49 Polycystic kidney disease (PKD) , 2 1 0, 1 03 1 -1 032 Polycystic ovarian syndrome, recurrent pregnancy loss, 353 Polycythemias maternal polycythemia vera, 1 08 1 secondary polycythemia, 1 08 1 newborn, 626 with maternal pregestational diabetes, 1 1 02 Polycythem ia vera, 1 08 1 Polydactyly, 2 1 0 Polygalactia, 659 Polyglandular autoimmune syndromes, 1 1 32 Polyhydramnios, 1 89, 225 Polymastia, 659 Polymorphic eruption of pregnancy, 1 1 85t, 1 1 86, 1 1 86/ Polymyositis, 1 1 50- 1 1 5 1 Polyp, endocervical, 1 1 92-1 1 93 Polyploidy, 259 deinition, 254 diandric triploidy, 259 digynic triploidy, 259 tetraploid pregnancies, 259 Polythelia, 659 Population reference, 846 Porencephaly, sonography, 1 96 Portal hypertension, 1 068 Portio supravaginalis, 23, 24/ Position (presentation), fetal. See Delivery; Fetal position (presentation) ; speciic positions Positive-predictive value, aneuploidy screening, 280, 280t, 28 1 t Postconception age, 1 24, 1 24/ Postdates, 835. See also Postterm pregnancy Posterior axilla sling traction, 522-523 Posterior reversible encephalopathy syndrome (PRES), 723, 724 Posterior urethral valves magnetic resonance imaging, 2 1 8, 2 1 9/ sonography, 2 1 0 Postmature, 835 . See also Postterm pregnancy Postmaturity syndrome, postterm pregnancy, 836-837, 837/ Postnecrotic cirrhosis, 1 067 Postpartum analgesia, 500 Postpartum angiopathy, 1 1 6 1 Postpartum blues, 66 1 , 1 1 74 Postpartum care, vaginal delivery, immediate, 527-533 birth canal lacerations, 5 27-529, 528/ episiotomy, 5 29-53 1 , 529/ fundamentals, 527 laceration and episiotomy repairs, 530f-533, 53 1 -532 Postpartum depression, 1 1 76- 1 1 7 Postpartum diuresis, 656 Postpartum psychosis, 1 1 79 Postpartum thyroiditis, 1 1 27 Postpuncture headache, from spinal block, 49 1 -492

Postterm neonate, 3 Postterm pregnancy, 835-842 complications macrosomia, 837f, 839 oligohydramnios, 23 1 , 839, 839/ gestational age, estimated, 835 incidence, 836 management, antepartum, 839-84 1 induction factors, 840 induction vs. fetal testing, 840-84 1 , 84 1 t strategies, 84 1 , 84 1/ management, intrapartum, 84 1 -842 mortality and morbidity, perinatal, 836, 836f 836t pathophysiology, 836-839 fetal distress and oligohydramnios, 837-838, 838/ fetal-growth restriction, 838-839 meconium aspiration syndrome, 836t, 838, 840, 84 1 -842 placental dysfunction, 837, 837/ postmaturity syndrome, 836-837, 837/ Posttraumatic stress syndrome, after hyperemesis gravidarum, 1 046 Potassium maternal, 57 pregnancy and lactation, 1 67t, 1 68 Potter sequence, 209 Potter syndrome, 209 Prader-Willi syndrome imprinting, 268, 268t micro deletions, 26 1 t Prague maneuver, modiied, 547-548, 548/ Prasugrel, for sickle-cell hemoglobinopathies, 1 0 8 1 Pratt dilator, 359 Precipitous labor and delivery, 448 Preconceptual care, 1 46-1 54 deinition, 1 46 genetic diseases, 1 49- 1 5 1 Eastern European and Jewish descent, 1 5 1 family history, 1 49, 1 50/ neural-tube defects, 1 49 phenylketonuria, 1 49-1 50, 1 49t thalassemias, 1 50-1 5 1 importance, 1 46 medical history, 1 47-1 49 diabetes mellitus, 1 47-1 48, 148/ epilepsy, 1 48-1 49, 1 48t immunizations, 1 49 parental age assisted reproductive technologies, 1 5 1- 1 52 maternal age, 1 5 1 , 1 5 1/ paternal age, 1 52 pregestational diabetes, 1 1 04-1 1 05 reproductive history, 1 5 1 screening tests, 1 53, 1 53t- 1 54t social history diet, 1 52 environmental exposures, 1 52 exercise, 1 52 intimate partner violence, 1 52-1 53 recreational drugs and smoking, 1 52 Preconceptual counseling, 1 47 on cardiovascular disorders, 95 1 on cystic ibrosis, 998 on hypertension, chronic, 976-977, 977t on pregnancy outcomes, 1 46-1 47 for seizures, 1 1 59 session, 1 47

I n dex Prednisone for Crohn disease, 1 050 for lupus, 1 1 42 for pemphigoid gestationis, 1 1 86 for rheumatoid arthritis, 1 1 4 Preeclampsia, 7 1 1 , 7 1 2t, 728-734. See aLso Hypertensive disorders of pregnancy acute kidney injury, 720, 1 036 coagulopathies, 785 continuous lumbar epidural block and, 496-49 deinition, 728 depression, 1 1 74 diagnosis, 728 early-onset, expectant management, 983 evaluation, 28-729 fetal-growth restriction, 85 1 heart failure, 964 hepatocellular damage, 1 05 8 ischemic stroke, 1 1 6 1 management, 729- 33 antihypertensive therapy, 730 corticosteroids, 733, 734/ delivery, consideration, 729 delivery, delayed, 730- 33 expectant, midtrimester severe preeclampsia, 732-733 expectant, preterm severe preeclampsia, 73 1- 32, 732t expectant, recommendations, 732/ 733, 33t glucocorticoids, for lung maturation, 733, 733t experimental therapies, 733-734 hospitalization vs. outpatient, 729-730, 30t pregnancy termination, 729 multifetal pregnancy, 872-873 pregestational diabetes, 1 1 03, 1 1 03/ prevention, 726-728, 979 with superimposed chronic hypertension, 9 9 severity indicators, 7 1 1-7 1 2, 1 2t stroke risk, 1 1 60 superimposed, on chronic hypertension, 7 1 2-7 1 3 , 978-979, 979/ management, in pregnancy, 983 vs. systemic lupus erythematosus, 1 1 4 1 , 1 1 4 1 t thrombocytopenia, newbon, 62 Pregestational diabetes, 1 098-1 1 07 diagnosis, 1 098- 1 099, 1 099t fetal-growth restriction, 850 management, 11 04- 1 1 07 irst trimester, 1 1 05 diet, 1 1 06 hypoglycemia, 1 1 06 insulin monitoring, 1 1 06, 1 1 06t insulin treatment, 1 1 05-1 1 06, 1 1 05t preconceptual care, 1 1 04-1 1 05 puerperium, 1 1 07 second trimester, 1 1 06 third trimester and delivery, 1 1 06-1 1 07, 1 1 07t on pregnancy, 1 099-1 1 04, 1 099t fetal efects, 1 099- 1 1 02 fetal demise, unexplained, 1 1 0 1 - 1 1 02 fetal growth, altered, 1 1 00- 1 1 0 1 , 1 1 0 1/ hydramnios, 1 1 02 malformations, 1 1 00, 1 1 00t, 1 1 0 1/ preterm delivery, 1 1 00 spontaneous abortion, 1 099 maternal efects, 1 1 03- 1 1 04 diabetic ketoacidosis, 1 1 04, 1 1 05 t

Pregestational diabetes (Cont.: diabetic nephropathy, 1 1 03 diabetic neuropathy, 1 1 04 diabetic retinopathy, 1 1 03- 1 1 04 infections, 1 1 04 preeclampsia, 1 1 03, 1 1 03/ neonatal efects, 1 1 02-1 1 03 cardiomyopathy, 1 1 02 cognitive development, long-term, 1 1 02 hyperbilirubinemia, 1 1 02 hypocalcemia, 1 1 02 hypoglycemia, 1 1 02 inheritance of diabetes, 1 1 02- 1 1 03 polycythemia, 1 1 02 respiratory distress syndrome, 1 1 02 prevalence, 1 098 Pregnancy. See aLso speciic topics achieving, basic biological steps, 80 (See aso Implantation and placental development) after breast cancer, 1 20 1 after cancer therapy, 1 1 92 ectopic, 349 failed, transvaginal ultrasound, 346 heterotopic (See aLso Tubal pregnancy) incidence, 3 7 1 with I U D , 684-685 multifetal (See Multifetal pregnancy) opioid abuse in, 9 postterm, 835-842 (See aLso Postterm pregnancy) after pregnancy-related hypertension, 744 rates, U.S., 4, 4t risk assessment, 1 63-1 64, 1 64t after stillbirth, prior, 648-649, 649t teratogen registries, 237 after trachelectomy, radical, 1 1 95 travel precautions, 1 228 unintended, rates, 680, 680t Pregnancy, diagnosis, 1 58-1 59 pregnancy tests, 1 58-1 59, 1 58/ hCG measurement, 1 58- 1 59, 1 58/ home, 1 59 symptoms and signs, 1 58 Pregnancy, ectopic. See Ectopic pregnancy Pregnancy, interval between cesarean delivery, prior, and trial of labor, 596 preterm birth, 8 1 3 Pregnancy-associated arglycoprotein, 1 1 48 Pregnancy-associated death, 4 Pregnancy-associated hemolysis, 1 079 Pregnancy-associated osteoporosis, 1 1 29-1 1 30, 1 1 29/ Pregnancy complications, multi fetal pregnancy, 871-873 congenital malformations, 8 1-872 on development, long-term infant, 873 hypertension, 872-873 low birthweight, 872, 872/ 873/ spontaneous abortion, 87 1 Pregnancy-induced hemolysis, 1 079 Pregnancy-induced hypervolemia, 655-656, 655/ 1 034, 1 034/ Pregnancy-induced hypoplastic anemia, 1 080 Pregnancy loss early, 346-347, 349-35 1 crow-rump length, 350 guidelines, 350t yolk sac, 350, 350/ recurrent, 34 , 352-353, 352t, 353t

Pregnancy luteoma, 1 1 99 Pregnancy of unknown location (PUL), 1 59, 347, 349. See aLso Ectopic pregnancy beta-human chorionic gonadotropin, 373 Pregnancy-related death, 4 Pregnancy-related hypertension, 7 1 0-745. See aLso Hypertensive disorders of pregnancy Pregnancy-related ovarian tumors, 1 1 99 Pregnancy Risk Assessment Surveillance System (PRAMS), 652, 653t Pregnancy-speciic antimalarial immunity, 1 226 Pregnancy termination hydatidiform mole, 392-393, 392t preeclampsia, 729 Pregnancy tests, 1 5 8-1 59, 1 58/ hCG measurement, 1 58-1 59, 1 58/ home, 1 59 Prehypertension, 977 Preimplantation genetic diagnosis (PGD) , 1 50, 295-296, 295/ Preimplantation genetic screening (PGS), 295-296, 295/ Preimplantation period, teratogenicity, 235, 236/ Premature atrial contractions (PACs) echocardiography, 204-205, 205/ fetal, therapy for, 3 1 5-3 1 6 Premature Birth Report Card, 7 Prematurely ruptured membranes at term, 44 -448 Premenstrual dysphoric disorder (PM DD) , oral contraceptives on, 692 Prenatal care, 1 57-1 75 common concerns, 1 70-1 75 automobile and air travel, 1 7 1 cafeine, 174 coitus, 1 7 1 cord blood banking, 1 75 dental care, 1 1 employment, 1 70 exercise, 1 70, 1 70t headache or backache, 1 74- 1 75 immunization, 1 7 1 - 1 74, 1 72t- 1 73t lead screening, 1 70- 1 7 1 nausea and heartburn, 1 74 pica and ptyalism, 1 74 seafood consumption, 1 70 sleeping and fatigue, 1 75 varicosities and hemorrhoids, 1 75 initial evaluation, 1 59-1 64 clinical evaluation, 1 63 laboratory tests, 1 60t, 1 63 prenatal record, 1 59- 1 63 (See aLso Prenatal record) risk assessment, 1 63- 1 64 multifetal pregnancy, 884-885 diet, 884 fetal surveillance, antepartum, 884-8 8 5 sonography, 884 nutritional counseling, 1 65-1 69 calories, 1 67, 1 6 1 dietary reference intakes, 1 67, 1 67/ pragmatic nutritional surveillance, 1 69 protein, 1 67-1 68, 1 67t recommended allowances, 1 67, 1 67t undernutrition, severe, 1 66 vitamins, 1 67t, 1 68-1 69 weight gain recommendations, 1 65-1 66, 1 66t weight retention after pregnancy, 1 66- 1 6 , 1 67/

1313

1 314

I ndex Prenatal care (Cont.): for obese, pregnant, 942 pregnancy diagnosis, 1 58-1 59 pregnancy tests, 1 58-1 59, 1 58/ hCG measurement, 1 58-1 59, 1 58/ home, 1 59 symptoms and signs, 1 58 sonographic recognition, 1 59, 1 59/ subsequent visits, 1 64-1 65 laboratory tests gestational diabetes, 1 65 group B streptococcal infection, 1 65 neural-tube defect and genetic screening, 1 65 prenatal surveillance fetal heart sounds, 1 65 fundal height, 1 64-1 65 fundamentals, 1 60t, 1 64 sonography, 1 6 5 scheduling, 1 64 in U.S. efectiveness, 1 57-1 58 use, 1 57, 1 57/ Prenatal diagnosis, 277-296. See also speciic topics aneuploidy screening, 278-288 carrier screening, for genetic disorders, 288-2 9 1 historical perspective and maternal serum alphafetoprotein, 277-278 procedures, 2 9 1 -295 amniocentesis, 2 9 1 -293 complications, 293 early, 293 indications, 2 9 1 -292 multifetal pregnancy, 292-293 technique, 292, 292/ 292t time to complete, 292 chorionic villus sampling, 293-294, 293/ 294/ fetal blood sampling, 294-295, 295/ Prenatal record, 1 59-1 63 deinitions, 1 60- 1 6 1 health status, previous and current, 1 6 1- 1 63 alcohol, 1 62 cigarette smoking, 1 6 1- 1 62, 1 62t illicit drugs, 1 62 intimate-partner violence, 1 62-1 63 menstrual and conceptive histories, 1 6 1 psychosocial screening, 1 6 1 pregnancy duration, normal, 1 6 1 standardized, 1 59-1 60, 1 60t trimesters, 1 6 1 Prenatal surveillance fetal heart sounds, 1 65 fundal height, 1 64-1 65 fundamentals, 1 60t, 1 64 sonography, 1 65 Preoperative patient phlebotomy, 79 1 Preparatory division, labor, 432, 432/ Presentation, fetal. See Delivery; Fetal position (presentation) ; speciic positions Presenting part, 422 Pressor responses, increased, hypertensive disorders, 716 Preterm birth, 802-828 39-week rule, 648-649, 804 17-alpha hydroxyprogesterone caproate, inefectiveness, 7 birthweight extremely low, 803

Preterm birth (Cont.): low, 803 very low, 803 causes, 809-8 1 2 multifetal pregnancy, 8 1 2 preterm premature rupture o f membranes, 8 1 1 -8 1 2 spontaneous preterm labor, 809-8 1 1 cervical dysfunction, 8 1 0 cytokines, origin, 8 1 1 infection, 8 1 0-8 1 1 inflammatory responses, 8 1 0-8 1 1 maternal-fetal stress, 809-8 1 0 uterine distention, 809 vaginal microbiota, 8 1 1 contributing factors genetic, 8 1 2 infection antibiotic prophylaxis, 8 1 3 bacterial vaginosis, 8 1 3 interval between pregnancies, 8 1 3 lifestyle, 8 1 2 periodontal disease, 8 1 2-8 1 3 prior preterm birth, 8 1 3 deinition, 803-804 diagnosis ambulatory uterine monitoring, 8 1 4 cervical change, 8 1 4 cervical length management, 8 1 5 fetal ibronectin, 8 1 4 symptoms, 8 1 4 early preterm, 804 incidence, U.S., 804, 804/ late preterm, 804 management, 8 1 9-828 preterm labor with intact membranes, 822-828 (See aso Preterm labor with intact membranes, management) preterm premature rupture of membranes, 8 1 9-822 (See also Preterm premature rupture of membranes (PPROM)) morbidity, newborn, 805-809, 805t late-preterm birth, 807-809 distribution, 807-808, 807/ neonatal morbidity rates, 808-809, 808t neonatal mortality rates, 808-809, 808/ obstetrical complications, 808, 808/ threshold of viability, 805-807 clinical management, 806-807, 807 t deinition, 805 periviable neonatal survival, 806, 806/ 806t periviable period, 805 mortality, infant, 804, 804t multi fetal pregnancy, 8 1 2, 873, 885-887 delayed delivery of second twin, 887 prediction, 885 preterm labor, treatment, 886 preterm premature rupture of membranes, 8 1 9-822, 886-887 prevention bed rest, 885 cervical cerclage, 886 pessary, 886 progesterone therapy, 1M, 885 progesterone therapy, vaginal, 885-886 tocolysis, prophylactic, 885 pregestational diabetes, 1 1 00

Preterm birth (Cont): preterm premature rupture of membranes, 8 1 9-822, 886-887 prevention, 8 1 5-8 1 9 cervical cerclage, 8 1 5-8 1 6, 8 1 6/ OPPT1MUM study, 8 1 8 progesterone, without prior preterm birth, 8 1 7-8 1 8, 8 1 7t, 8 1 8t progestogen compounds, prior preterm birth, 8 1 6-8 1 7, 8 1 t progestogen compounds, prophylaxis, 8 1 6 public health programs, geographic-based, 8 1 9, 8 1 9/ rates, U.S., 4, 4t rate trends, 804-805 factors, 805 methodology, 804, 804/ size appropriate for gestational age, 803 fetal-growth restriction, 803 (See also Fetal­ growth restriction) large for gestational age, 803 small for gestational age, 803 Preterm labor with intact membranes, management, 822-828 amniocentesis, infection detection, 822 antimicrobials, 825 bed rest, 825 cerclage, emergency or rescue, 825 cervical pessaries, 825 corticosteroids, for fetal lung maturation, 823-824 delivery, 827 intracranial hemorrhage prevention, 827-828 labor, 827 magnesium sulfate, for neuroprotection, 824-825, 824t tocolysis, for preterm labor, 825-827 atosiban, 827 3-adrenergic receptor agonists, 826 calcium-channel blockers, 827 fundamentals, 825-826 magnesium sulfate, 826 nitric oxide donors, 827 prostaglandin inhibitors, 826-827 Preterm newborn, 3, 636-642. See also specic disorders brain disorders, 639-640 cerebral palsy, 640-642 complications of prematurity, 636, 636t necrotizing enterocolitis, 638-639 respiratory distress syndrome, 636-638 retinopathy of prematurity, 639 Preterm premature rupture of membranes (PPROM), 3 5 1 , 8 1 1 -8 1 2 management, 8 1 9-822 antimicrobial therapy, 822 chorioamnionitis, clinical, 821-822 corticosteroids, for fetal lung maturity, 822 expectant management, consideration, 821 hospitalization, 8 1 9 intentional delivery, 8 1 9-82 1 membrane repair, 3 5 1 , 822 natural history, 8 1 9, 820/ overview, 8 1 9, 820t preterm premature rupture of membranes, 8 1 9-822 multifetal pregnancy, 886-887 placental abruption, 770

I ndex Preventive care, newborn, 6 1 3-6 1 4 eye infection prophylaxis, 6 1 3-6 1 4 hepatitis B immunization, 6 1 4, 1 065 screening, 6 1 4, 6 1 4t vitamin K, 6 1 4 zika virus, 6 1 4 Primary subarachnoid hemorrhage, preterm newborn, 639 Primary villous stalks, 90 Primipara, 1 60- 1 6 1 PRlMS study, 1 1 64 Proatrial natriuretic peptide, in preeclampsia, 1 9 Procalcironin, 59 Procoagulants. See also specic ypes maternal, 59-60, 60t PROCR 6936G allele thrombophilia, 1 008 Progesterone biosynthesis, placental, 1 02- 1 03 , 1 03/ endometrial cycle, 83-84 labor, 40 1-402 menstruation, 85 ovarian-endometrial cycle, 83 parturition, withdrawal, 408 for preterm birth prevention, without prior preterm birth, 8 1 7-8 1 8, 8 1 7t, 8 1 8t serum and blood, 1 259t withdrawal, before parturition, 40 1 Progesterone-receptor type A (PR-A), ovarianendometrial cycle, 83 Progesterone-receptor type B (PR-B), ovarian­ endometrial cycle, 83 Progestin injectable, 693 progestin-only pills, 682t-683t, 693 Progestin implants, 68 5-689 etonogestrel, 685-688 insertion Nexplanon technique, 688-689, 688/ timing, 688 levonorgestrel, 688 method-specific adverse events, 688 Progestin-only contraceptives, 689 actions and side efects, 689 contraindications, 682t-683t, 689 Progestin-only pills, 682t-683t, 693 Progestogen compounds, for preterm birth prevention, 8 1 6 prior preterm birth, 8 1 6-8 1 7, 8 1 7t Progressive familial intrahepatic cholestasis, 1 059 Progressive-relapsing multiple sclerosis, 1 1 64 Prolactin (PRL) breast milk, 657 fetal, 1 36 maternal, 69 decidual, 87 serum and blood, 1 259t Prolactin-inhibiting factor (PIF), lactation, 657 Prolactinomas, 1 1 32, 1 1 33/ Prolonged pregnancy, 835. See aLso Postterm pregnancy Prolonged QT interval, 967 Promethazine, for labor, 488 Propranolol for chronic hypertension, in pregnancy, 980 for migraine, 1 1 58 Propylthiouracil (PTU) , for thyrotoxicosis in pregnancy, 1 1 20 Prostacyclin (PGr2) , 63 in preeclampsia, 7 1 6

Prostaglandin amnion synthesis, 40 1 , 40 1/ maternal, 63 (See also specic ypes) labor, 402, 402/ menstruation, 8 5 parturition, 4 1 6-4 1 7, 4 1 f preeclampsia, 7 1 6 Prostaglandin E I (PGEI), 507. See also Misoprostol antiphospholipid antibodies on, 1 1 44 for cervical ripening, 507 for labor induction and augmentation, 508-509 for uterine atony, 760 Prostaglandin E2 (PGE2) , 63 for abortion, induced, 363 amnion epithelial cells, 96 for cervical ripening postterm pregnancy, 840 preinduction, 506-507, 506/ for trial of labor after cesarean section, 5 5 1 parturition, 407, 4 1 64 1 7, 4 1 7/ for uterine atony, 760 Prostaglandin F2: (PF2:) menstruation, 8 5 parturition, 4 1 64 1 7, 4 1 7/ Prostaglandin H synthase (PGHS) , 402 parturition, 4 1 6 Prostaglandin inhibitors, for preterm labor, 826-82 Protein fetal, 1 39 intake, pregnancy and lactation, 1 67-1 68, 1 67t metabolism, maternal, 55 urinary, maternal measuring, 67 proteinuria, 66-67, 67/ Protein C, antiphospholipid antibodies on, 1 1 44 Protein C deiciency thrombophilia, 1 005] 1 006-1 007, 1 006t Protein 5, antiphospholipid antibodies on, 1 1 44 Protein 5 deficiency thrombophilia, 1 005] 1 006t, 1 007 Proteinuria, 66-67, 67] 720 preeclampsia, 726 pregnancy-related hypertension, 720 Protein Z thrombophilia, 1 008 Proteoglycans, cervical ripening, 409, 409/ Prothrombin G202 1 0A mutation thrombophilia, 1 005] 1 006t, 1 007- 1 008 Prothrombin time (PT), coagulopathies, 784-785 Proton-pump inhibitors, for peptic ulcer disease, 1 047 Protozoal infections, 1 225- 1 228 amebiasis, 1 227-1 228 malaria, 1 226- 1 227, 1 227/ toxoplasmosis, 1 225-1 226 Protraction disorder, 434, 442, 443, 443t, 444 Prune belly syndrome, 325 Prurigo gestationis, 1 1 85t, 1 1 86 Prurigo of pregnancy, 1 1 85t, 1 1 86 Pruritic folliculitis of pregnancy, 1 1 85t, 1 1 86 Pruritic urticarial papules and plaques of pregnancy (PUPPP), 1 1 85t, 1 1 86, 1 1 86/ Pruritus gravidarum, 1 1 84 Pseudocysts, umbilical cord, 1 1 8 Pseudogestational sac, 1 59, 3 5/ Pseudohypoparathyroidism, imprinting, 268, 268t Pseudosac, 1 59, 349, 375/ Pseudo tumor cerebri, 1 1 68 Psoas abscess, 673

Psoriasis, 1 1 87, 1 1 87/ Psychiatric disorders, 1 1 73-1 1 8 1 . See also specic ypes depression screening, 1 1 74, 1 1 75t eating disorders, 1 1 80-1 1 8 1 mood disorders, 1 1 75- 1 1 80 personality disorders, 1 1 8 1 postpartum blues, 1 1 74 psychological adjustments ro pregnancy, 1 1 73-1 1 75 perinatal evaluation and screening, 1 1 74-1 1 75 pregnancy outcomes, 1 1 75 puerperium, 1 1 74 treatment, 1 1 75 schizophrenia spectrum disorders, 1 1 80 stressors of pregnancy, 1 1 74 suicide, 1 1 73 Psychiatric medications, teratogenicity antipsychotics, 245 lithium, 244-245 selective norepinephrine-reuptake inhibitors, 245 selective serotonin-reuptake inhibitors, 245 Psychological adjustments, to pregnancy, 1 1 73-1 1 75 perinatal evaluation and screening, 1 1 74- 1 1 75 pregnancy outcomes, 1 1 75 puerperium, 1 1 74 treatment, 1 1 75 Psychosis, postpartum, 1 1 79 Psychosocial screening, prenatal, 1 6 1 PTH-related protein, 7 1 , 1 1 28 Ptyalism, in pregnancy, 1 74 Pubic symphysis, separation, 66 1 , 662/ Public health ptograms, geographic-based, for preterm birth prevention, 8 1 9, 8 1 9/ Pudenda, 1 6- 1 7, 1 7/ Pudendal arteries, 1 4- 1 5 , 1 5/ Pudendal block, 489490, 489t, 490/ Pudendal canal, 22, 22/ Pudendal nerve, 22-23, 22/ Pudendal nerve block, 22 Pudendal vessels, 22-23, 22/ Puerperal fever, 666-667 Puerperal hematomas, 764- 6 5 classiication and risks, 764, 765/ clinical course and management, 764-765 diagnosis, 64, 765/ Puerperal infections, 666 sepsis syndrome, 923-925, 925] 925t Streptococcus pyogenes, 1 220 Puerperal tubal sterilization, 702-704, 703-704/ Puerperium, 652-663 blood and blood volume, 65 5-656 hematology and coagulation, 655, 655/ postpartum diuresis, 656 pregnancy-induced hypervolemia, 65 5-656, 655/ cardiovascular disorders, 9 1 7, 962-963 deinition, 652 home care, 663 coitus, 663 follow-up care, 663 maternal morbidity, late, 663, 663t hospital care, 659-663 bladder function, 660-66 1 contraception, 662-663, 662] 682t-683t, 69 general, 659-660 hospital discharge, 662 immunizations, 662

1315

1 316

I nd ex Puerperium (Cont.): musculoskeletal injuries, 66 1 -662, 66 1, 662/ obstetrical neuropathies, 66 1 pain, mood, and cognition, 66 1 perineal, 660 lactation and breastfeeding, 656-659 (See aso Lactation and breastfeeding) peritoneum and abdominal wall, 655 pregestational diabetes, 1 1 07 psychiatric disorders, 1 174 reproductive tract involution, 652-654 birth canal, 652 placental site involution, 654 placental site subinvolution, 654 postpartum hemorrhage, late, 392t, 654 uterus, 652-654 afterpains, 654 cervix, 653, 653/ decidua and endometrial regeneration,

653-654 fundamentals, 652-653 lochia, 654 sonographic indings, 653, 653/ urinary tract, 654-6 5 5 Puerperium, complications, 666-676 breast abscess, 676 breast infections, 675-676, 676/ puerperal infection, 666, 923-925, 925, 925t,

1 220 pelvic, 666-675 (See also Pelvic infections, puerperal) Pull method, cesarean delivery, 575 Pulmonary. See also Lung entries Pulmonary angiography, for pulmonary embolism,

1018 Pulmonary artery catheter, 9 1 6-9 1 7 Pulmonary disorders, 987- 1 000. See also speciic

disorders asthma, 988-99 1 bronchitis, acute, 99 1 -992 carbon monoxide poisoning, 999-1 000 cystic ibrosis, 997-999 pneumonia, 992-995 pregnancy pulmonary physiology, 64-65, 65f,

987-988 sarcoidosis, 997 tuberculosis, 995-997 Pulmonary edema, acute, 9 1 7-9 1 8 cardiogenic hydrostatic edema, 9 1 8 cardiogenic vs. noncardiogenic, 9 1 7 management, 9 1 8 noncardiogenic permeability edema, 9 1 7-9 1 8,

9 1 7t preeclampsia, luid therapy for, 740 Pulmonary embolism, 1 0 1 6- 1 0 1 9 clinical presentation, 1 0 1 6 diagnosis, 1 0 1 6-1 0 1 8 algorithm, 1 0 1 7, 1 0 1 7/ intravascular pulmonary angiography, 1 0 1 8 multidetector CT pulmonary angiography,

907, 1 0 1 6- 1 0 1 8, 1 0 1 8/ ventilation-perfusion scintigraphy, lung scan,

1018 management, 1 0 1 8- 1 0 1 9 embolectomy, 1 0 1 9 thrombolysis, 1 0 1 8- 1 0 1 9 vena caval ilters, 1 0 1 8 massive, 1 0 1 6, 1 0 1 7/ oral contraceptives, 69 1

Pulmonary function, maternal, 64-65, 65/ closing volume, 64 expiratory reserve volume, 64 forced vital capacity, 64 functional residual capacity, 64, 65/ inspiratory capacity, 64 lung compliance, 64 maximum breathing capacity, 64 nasal physiology, 64-65 peak expiratory flow rates, 64 residual volume, 64 resting minute ventilation, 64 tidal volume, 64 total lung capacity, 64 total pulmonary resistance, 64 Pulmonary hypertension, 960-962 definition and classification, 960-96 1 , 96 1 t diagnosis, 96 1 management, 962 pregnancy, 962 prognosis, 96 1 -962 Pulmonary hypoplasia, oligohydramnios, 232 Pulmonary physiology, pregnancy, 64-65, 65f,

987-988 Pulmonary scintigraphy. in pregnancy, 908 Pulmonary sequestration fetal, sonography, 1 99, 200/ percutaneous fetal surgery, 324-325, 324/ Pulmonary surfactant ktal, 1 33-1 34, 1 34/ prophylaxis, for respiratory distress syndrome in preterm newborn, 637-638 Pulmonary valvuloplasty, fetal, intracardiac catheter procedures, 326 Pulmonic stenosis, 956t, 958 Pulsed-wave Doppler, 2 1 3 Pulseless disease, 1 1 50 Pulse oximetry, fetal, 47 1 , 471/ Purple coneflower root, teratogenicity, 248t Purpura fulminans, 1 33 coagulopathies, 787 Purtscher retinopathy, 724, 724/ Pushing (labor), 4 1 3 maternal eforts, expulsion disorder, 447 Push method, cesarean delivery, 575 Pustular psoriasis, 1 1 87, 1 1 87/ Pyelography, intravenous, 1 026 Pyelonephritis chronic, reflux nephropathy, 1 029-1 030 postpartum, 667 xanthogranulomatous, 1 029 Pyloric stenosis, inherited genetic factors, 269 Pyoderma faciale, 1 1 88 Pyogenic granuloma, 1 1 87-1 1 88, 1 1 87/ Pyridostigmine, for myasthenia gravis, 1 1 65- 1 1 66 Pyrimethamine-sulfadiazine, for toxoplasmosis,

1 226 Pyrimethamine-sulfonamide, for toxoplasmosis,

1 226 Pyrosis, 68, 1 046 Pyruvate kinase deficiency, 1 080

Q

Quadriphasic pills, 690 Quadruple-marker screening, aneuploidy, 282-283 Quad screening test, 282-283 Quetelet index, 936 Quick birth. See Oxytocin Quinacrine pellets, 06

Quinine, for malaria, 1 227 Quintero staging, 879, 879/ R

Race, on maternal mortality, 6, 6/ Radiation, ionizing, pregnancy and, 904-905,

904t Radiation therapy, in pregnancy, 906 for cancer, 1 1 9 1 for invasive cervical cancer, 1 1 94-1 1 95, 1 1 95/ Radical hysterectomy, 567 Radiofrequency ablation (RFA), fetoscopic, 326 Radiographic contrast agents, in pregnancy, 908 Radiography, in pregnancy, 904-909 abdominal, multifetal pregnancy, 870 cardiac imaging, 95 1 deterministic efects, 905 diagnostic radiation, 906-909 CT, 907-908, 907f, 907t, 908/ fluoroscopy and angiography, 906-907, 907t nuclear medicine studies, 908-909, 909t radiographic contrast agents, 908 radiographs, 906 imaging modalities, 904 ionizing radiation, 904-905, 904t labor diagnosis, 426-427 magnetic resonance imaging, 909-9 1 1 contrast agents, 9 1 0-9 1 1 fetal indications, 9 1 0f, 9 1 1 maternal indications, 9 1 Of, 9 1 1 safety, 9 1 0 sonography, 909 stochastic efects, 905-906 therapeutic radiation, 906 X-ray dosimetry, 906, 906t Radioidine- 1 3 1 , teratogenicity, 244, 1 20 1- 1 202 Radiopharmaceuticals, in pregnancy, 908-909,

909t Rapid influenza diagnostic tests (RIDTs), 1 2 1 4 Rapidly progressive glomerulonephritis, 1 032 Rathke pouch, 1 36-1 37 �LIZE, 944-945, 944t Recall bias, 237 Reciprocal translocations, 2 6 1 -262, 262/ Recombinant activated factor II, for hemorrhage,

790 Recombinant erythropoeitin, 1 077 Recombinant tissue plasminogen activator (rt-PA) for cerebral artery thrombosis, 1 1 62 for pulmonary embolism, 1 0 1 9 Recommended dietary allowances, pregnancy and lactation, 1 67, 1 67 t Recreational drugs. See Drugs, recreational (illicit);

specic drugs Recurrent pregnancy loss (RPL) , 347, 352-353,

352t, 353t Red cell alloimmunization, 300, 30 1 -306 alloimmunization detection, 30 1 , 30 1 t alloimmunization pregnancy management,

303-305 amnionic luid spectral analysis, 304 fetal blood transfusion, 304-305 fetal risk, determining, 303 middle cerebral artery Doppler velocimetry,

303-304, 304/ alloimmunization to minor antigens, 302-303 ABO blood group incompatibility, 302, 303 Kell autoimmunization, 302-303 anti-D alloimmunization prevention, 305-306

I ndex Red cell alloimmunization (Cant.): D phenotypes, serological weak, 306 fetomaternal hemorrhage with, 302, 302t incidence, 301 pathophysiology, 30 1 Red cell transfusion, prophylactic, for sickle-cell syndromes, 1 083 Red degeneration, 1 1 96 Reduction, selective, multifetal pregnancy, 891 Reflux nephropathy, 1 029- 1 030 Refractory crisis, myasthenia gravis, 1 1 65 Regional analgesia, obstetric, 488-490 anesthetic agents, 488, 489t cardiovascular toxicity, 489 central nervous system toxicity, 489 paracervical block, 490 pudendal block, 489-490, 489t, 490/ systemic toxicity, management, 489 Regulatory proteins, maternal, 60, 1 005/ See also speciic ypes activated protein C, 60, 60t immune, 60, 1 005/ Relapsing-remitting multiple sclerosis, 1 1 64 Relaxin, 52 placental, 1 00 Relaxin family peptide receptor 1 (RSFP 1 ) , parturition, 407 Remifentanil, for labor, 488 Remnants, umbilical cord, 1 1 8 Renal. See also Kidney entries Renal agenesis, 208-209, 209/ Renal biopsy, 1 026 Renal disorders, 1 030-1 037. See also Urinary tract disorders; speciic ypes acute kidney injury, 1 036- 1 037 acute nephritic syndromes, 1 032t chronic kidney disease, 1 034- 1 036 glomerular diseases, 1 032-1 034, 1 032t nephrolithiasis, 1 030 nephrotic syndromes, 1 032t, 1 033-1 034, 1 033/ polycystic kidney disease, 1 0 3 1 - 1 032 pregnancy-induced urinary tract changes, 1 025-1 026 reflux nephropathy, 1 029- 1 030 renal hypertrophy, 1 026 renal transplantation, pregnancy after, 1 030- 1 0 3 1 scleroderma renal crisis, 1 1 49 urinary tract changes, pregnancy-induced, 1 025-1 026, 1 02 5/ nephrectomy, unilateral, pregnancy after, 1 026 renal function assessment, 1 026 Renal failure. See also specic ypes obstructive, 1 037, 1 037/ Renal function tests, 1 026, 1 260t maternal, 66 preeclampsia, 725t, 726 serum and blood tests, 1 260t Renal hypertrophy, 1 026 Renal insuiciency, chronic, 1 035, 1 035f 1 035t fetal-growth restriction, 850 Renal pelvis dilatation, 208, 208f 208t second-trimester aneuploid screening, 287, 28 f Renal plasma flow, maternal, 65-66, 65/ Renal transplantation, pregnancy after, 1 030- 1 03 1 Renin, 63 serum and blood tests, 1 258t

Renin-angiotensin-aldosterone axis, 63 Reproductive history, preconceptual care, 1 5 1 Reproductive system, male anatomy, 706, 706/ Reproductive tract, maternal, 49-53 cervix, 5 1 , 5 1/ fallopian tubes, 52 ovaries, 5 1 -52 decidual reaction, 5 1-52 relaxin, 52 theca-lutein cysts, 52, 39 1/ uterine contractility, 50 uteroplacental blood flow, 50-5 1 uterus, 49-50 vagina and perineum, 52-53 acidic pH and Lactobacillus acidophilus, 5 2 Chadwick sign, 52 pelvic organ prolapse, 52-53 Reproductive tract involution, puerperium, 652-654 birth canal, 652 placental site involution, 654 placental site subinvolution, 654 postpartum hemorrhage, late, 392t, 654 uterus, 652-654 afterpains, 654 cervix, 653, 653/ decidua and endometrial regeneration, 653-654 fundamentals, 652-653 lochia, 654 sonographic findings, 653, 653/ Reproductive tract neoplasms, 1 1 92- 1 200 cervix, 1 1 92-1 1 95 endocervical polyp, 1 1 92- 1 1 93 epithelial neoplasia, 1 1 93- 1 1 94, 1 1 94t invasive cervical cancer, 1 1 94-1 1 95 , 1 1 95/ incidence, 1 1 92, 1 1 92/ ovary, 1 1 97-1 200 adnexal cysts, 1 200 asymptomatic adnexal mass, 1 1 98- 1 1 99 complications, 1 1 98 diagnosis, 1 1 98, 1 1 98/ hyperreactio luteinalis, 1 1 99 incidence, 1 1 97 ovarian cancer, 1 1 99- 1 200 ovarian hyperstimulation syndrome, 1 1 99 pregnancy luteoma, 1 1 99 pregnancy-related ovarian tumors, 1 1 99 types, 1 1 9 -1 1 98 PAP test abnormalities, 1 1 93, 1 1 94t uterus, 1 1 95- 1 1 9 endometrial lesions, 1 1 97 leiomyomas, 1 1 95-1 1 97, 1 1 96f 1 1 97/ vulva and vagina, 1 200 Rescue cerclage cervical insuiciency, midtrimester abortion, 355 preterm birth prevention, multifetal pregnancy, 886 Residual volume, 64 in pregnancy, 64, 65f 987 Resistin, 5 1 Respiratory acidemia clinical significance, 6 1 2-6 1 3, 6 1 2/ fetal, 6 1 1 Respiratory distress, newborn, 6 1 9-620

Respiratory distress syndrome (RDS) fetal, 1 33 neonatal, 6 1 9-620 with maternal pregestational diabetes, 1 1 02 preterm newborn, 636-638 clinical coutse, 63 etiopathogenesis, 636-637 prevention, 638, 638/ treatment, 637-638 pyelonephritis, 1 028, 1 028/ Respiratory efort, 65 Respiratory failure, 99 1 Respiratory system, fetal, 1 33-1 34 anatomical maturation, 1 33 breathing, 1 34 corticosteroids and lung maturation, 1 34 pulmonary surfactant, 1 33-1 34, 1 34/ respiratory distress syndrome, 1 33 Respiratory system, maternal, 64-65 acid-base equilibrium, 6 5 Bohr efect, 6 5 physiological dyspnea, 65 respiratory efort, 65 diaphragm, 64, 64/ oxygen delivery, 65 matenal arteriovenous oxygen diference, 65 total hemoglobin mass, 65 pulmonary function, 64-65, 6 5f 987-988 closing volume, 64 expiratory reserve volume, 64 forced vital capacity, 64 functional residual capacity, 64, 65/ inspiratory capacity, 64 lung compliance, 64 maximum breathing capacity, 64 nasal physiology, 64-65 peak expiratory flow rates, 64 residual volume, 64 resting minute ventilation, 64 tidal volume, 64 total lung capacity, 64 total pulmonary resistance, 64 subcostal angle, 64, 64/ thoracic circumference, 64, 64f 1 266t Respiratory virus infection, 1 2 1 6 Resting minute ventilation, 64 Restitution, 428f 429-43 1 Restrictive cardiomyopathy, 964 Restrictive malabsorptive procedures, 944, 944/ Resuscitation, newborn, 607-608, 608/ after cesarean birth, 575 ptotocol, 608-6 1 0, 608/ alternative airway, 608-609 chest compressions, 609 discontinuation of resuscitation, 6 1 0 epinephrine, 6 1 0 initial assessment, 608, 609/ mask ventilation, 608, 6 1 O t Retinal detachment, in preeclampsia, 24 Retinoblastoma, microdeletion, 26 1 t Retinoic acid embryopathy, 245, 246/ Retinoids, teratogenicity acitretin, 245-246 isotretinoin, 245 retinoic acid embryopathy, 245, 246/ topical, 246 vitamin A, 246 Retinol. See Vitamin A Retinopathy of prematurity, 639

1 31 7

1 31 8

I n d ex ETproto-oncogene, advanced paternal age, 265

Sacrum agenesis, causal regression sequence, 1 96

Retraction ring pathological, 4 1 3 physiological, 4 1 3 Retroflexion, uterine, 46 Retrolental fibroplasia, 639 Reversible cerebral vasoconstriction syndrome, 744, 1 1 6 1 Rhabdomyoma, cardiac, 204 Rhabdosphincter, 20, 20/ Rh D genotype evaluation, cell-free DNA, 274 Rheumatoid arthritis, 1 1 46- 1 1 48 classification criteria, 1 1 46, 1 1 47 t etiopathogenesis, 1 1 46 juvenile rheumatoid, 1 1 48 management, 1 1 47 pregnancy and, 1 1 48 prevalence and associations, 1 1 46- 1 1 47 Rheumatoid factor (F) , 1 1 38 Rhinovirus infection, 1 2 1 6 Rhizomelic achondroplasia, 2 1 1 Ribavirin, teratogenicity, 243 Rib fractures, newborn, 63 1 Rickets, vitamin D-resistant, X-linked inheritance, 266 Rifampin, for Hansen disease, 1 224 Right acromiodorsoposterior (RADP), 425/ Right occiput anterior (ROA), 423f, 427 Right occiput posterior (ROP) , 424f, 430f, 43 1 Right occiput transverse (ROT) , 424f, 427 Right ventricular dysplasia, arrhythmogenic, 964 Right ventricular outflow tract, cardiac imaging, 20 1 , 202/ Ring, transvaginal, 692-693, 692/ Ring chromosome, 263 ing of fire, 376 Risk assessment. See also speciic ypes pregnancy, 1 63- 1 64, 1 64t prenatal, 1 63- 1 64 Ritgen maneuver, modified, 5 1 7, 5 1 7/ Rituximab, for lymphomas, 1 203 Rivaroxaban, 1 0 1 5 Robertsonian translocations, 262 Roberts syndrome, limb-reduction defects, 2 1 2 Rohr stria, 87 Roll-over test, 725 Romiplostim, 1 08 Rooming in, newborn, 6 1 6 Rosacea fulminans, 1 1 88 Rotational thromboelastometry (REM) , hemorrhage, 7 8 5 , 79 1 , 79 1/ Round ligament, 24-25 , 24f, 2 5/ Roux-en-Y gastric bypass, pregnancy, 944, 944/ RU-486. See Mifepristone (RU-486) Rubella virus infection, 1 2 1 5- 1 2 1 6 fetal-growth restriction, 8 5 1 Rubenstein-Taybi syndrome, microdeletion, 26 1 t Rubin maneuvers, 522, 523/ Rupture of membranes, labor, 435, 437-438 Russell-Silver syndrome, imprinting, 268, 268t Russell viper venom test, dilute, 1 1 44

Salmonela, 1 224 Salmonella enteritidis, 1 224 Salmonella yphi, 1 224 Salmonela yphimurium, 1 224

5 Saccular aneutysm, ruptured, 1 1 63 Sacculation, uterine, 46, 46/ Sacrococcygeal teratoma (SCT) open fetal surgery, 32 1 , 32 1/ sonographic imaging, 1 96, 1 96/

Salmonellosis, 1 224 Salpingectomy, for tubal pregnancy, 379 Salpingitis isthmic nodosa, 372 Salpingo-oophorectomy, 583 Salpingostomy, for tubal pregnancy, 379 Salt-wasting adrenal crises, 3 1 7 Sampson artery, 26, 26/ "Sandal-gap," 287/ Sarcoidosis, 997 Scalp blood sampling, fetal, 470, 470/ Scalp stimulation, 470 Scarpa fascia, 1 4, 1 9 , 1 9/ Schisis, 1 92 Schizencephaly, sonography, 1 95 , 1 95/ Schizophrenia spectrum disorders, 1 1 80 Schultze mechanism, 4 1 6, 758 Scleroderma, 1 1 48-1 149 Scleroderma renal crisis, 1 1 49 Scoliosis, newborn, 631 Scotomata, in preeclampsia, 723 Screening tests. See also specic ypes newborn, 6 1 4, 6 1 4t preconceptual care, 1 5 3, 1 53t- 1 54t Seafood consumption, in pregnancy, 1 70 Seat-belt position, pregnancy, 927, 927/ Second- and third-trimester sonography, 1 86- 1 9 1 amnionic l uid volume, 1 88-1 89 cervical length assessment, 1 89- 1 9 1 , 1 89/ cervix, transvaginal evaluation, 1 90- 1 9 1 , 1 90f, 1 90t fetal anomal detection, 18 - 1 88 indications, 1 87, 1 87t routine, 1 86- 1 87 standard fetal anatomic survey, 1 87, 1 88t targeted fetal anatomic survey components, 1 87, 1 88t indications, 1 87, 1 89 t Secondaty attack rate, 1 209 Secondary polycythemia, 1 08 1 Secondary villi, 90 Second-trimester screening, aneuploidy, 282-284 sonographic markers, "soft signs," 286-288, 287t clinodactyly, 287/ echogenic fetal bowel, 287-288, 287/ echogenic intracardiac focus, 286-28 7 , 287/ nuchal skinfold, 286, 287/ renal pelvis dilatation, 287, 287/ "sandal-gap," 287/ traditional tests, 282-284 California Prenatal Screening Program, 282-283 detection rates, 282 estriol level, 284 integrated screening, 280t, 284 maternal serum AFP and neural-tube defects, 283, 283t quadruple marker, 282-283 sequential screening, 280t, 284 unexplained abnormalities, 283-284 Sedation. See aso speciic ypes during labor, 487-488, 487t Segment, cardiac tube, 1 29

Seizure disorders, 1 1 5 8-1 1 59 anticonvulsant teratogens, 1 1 59, 1 1 60t definition, 1 1 58 embryofetal malformations, 1 1 59 epidemiology, 1 1 58 newborn, 625 pathophysiology, 1 1 5 8-1 1 5 9 focal seizures, 1 1 5 8 generalized seizures, 1 1 58- 1 1 59 preconceptual care, 1 48- 1 49 , 1 48t preconceptual counseling, 1 1 59 in pregnancy, 1 1 59 Seizures, eclampsia, 723. See also Magnesium sulfate, for eclampsia seizures magnesium sulfate neuroprophylaxis, 74 1 -743 indications, 742 randomized trials, 74 1 -742, 74 1 t selective vs. universal prophylaxis, 742-743, 742t Selection window, ovarian cycle, 82 Selective norepinephrine-reuptake inhibitors (SNRIs), teratogenicity, 245 Selective reduction, multifetal pregnancy, 89 1 Selective serotonin-reuptake inhibitors (SSRIs) for depression, 1 1 77- 1 1 78 fetal and neonatal efects, 1 1 78 persistent pulmonary hypertension of the newbon, 245, 1 1 78 teratogenicity, 245 Semilobar holoprosencephaly, 1 94 Senescent-associated secretory phenotype (SASP), 41 1 Sensitivity, aneuploidy screening, 279 Sentinel bleed, placenta previa, 775 Sentinel lymphoscintigram, 909, 909t Sepsis, neonatal, group B Streptococcus, 1 220 Sepsis syndrome, 92 1 -925 clinical manifestations, 922, 923/ coagulopathies, 787 etiopathogenesis, 92 1 -922, 922/ management, 923-925 algorithm, 923, 924/ surgical, 923-925 adjunctive therapy, 924f, 925 puerperal infections, 923-925, 925f, 925t severity continuum,' 92 1 , 92 1/ Septate uterus, 44f, 45 Septic abortion, 347, 3 5 1-352 from IUD, 684 Septic ovarian vein thrombosis, 673-674, 674/ Septic pelvic thrombophlebitis, 673-674, 673f, 674/ Septo-optic dysplasia, magnetic resonance imaging, 2 1 7, 2 1 8/ Sequential screening, 284 aneuploidy, 280t, 284 contingent, 280t, 284 stepwise, 280t, 284 Serum and blood constituents, 1 25 5 t- 1 260t autoimmune and inflammatory mediators, 1 259t blood gas, 1 260t cardiac, 1 2 59t chemical, 1 257t coagulation, 1 256t hematology, 1 25 5 t lipids, 1 259t metabolic and endocrine tests, 1 258t renal function tests, 1 260t sex hormones, 1 259t vitamins and minerals, 1 258t Serum integrated screening, 284

I n d ex Severe acute respiratory syndrome (SARS), 995, 1 2 1 9 Sex chromosome abnormalities, 2 5 8-259

45,X, 39, 258, 259, 347, 352 47 ,XX, 259 47,Y, 39, 259-260 47,XY, 260 Sex chromosome disorders of sex development, 39, 39t chromosomal ovotesticular, 39 mixed gonadal dysgenesis, 39 Tuner and Klinefelter syndromes, 39, 258,

259-260, 347, 352 Sex determination, fetal, cell-free DNA, 274 Sex-determining region (SRy) gene, 38 Sex development disorders, 38-4 1

46,XX, 39t, 40-4 1 46,X gonadal dysgenesis, 40 46,X ovotesticular, 40 46,X testicular, 40 androgen excess, 40-4 1 ovarian development, 40 46,Y, 39, 39t 46,Y gonadal dysgenesis, 39-40 androgen production or action, 40 mixed gonadal dysgenesis, 40 partial gonadal dysgenesis, 40 pure gonadal dysgenesis, 40 testicular regression, 40 ambiguous genitalia, 38-39 deinitions, 38-39, 39t dysgenetic testis, 38 gender assignment, 4 1 gonadal dysgenesis, 38 ovotesticular, 39 sex chromosome, 39, 39t chromosomal ovotesticular, 39 mixed gonadal dysgenesis, 39 Turner and Klinefelter syndromes, 39, 258,

259-260, 347, 352 streak gonad, 38 Sex hormones. See aso specic ypes serum and blood tests, 1 259t teratogenicity danazol, 243 diethylstilbestrol, 243-244 testosterone and anabolic steroids, 243 Sex ratios, multifetal pregnancies, 867 Sexual assault, 926, 926t Sexual diferentiation, 38, 38t gonadal gender, 38 mullerian-inhibiting substance, 38 phenotypic gender, 38 sex-determining region gene, 38 testis-determining factor, 38 Sexual intercourse pregnancy, 1 7 1 puerperium, 663 Sexually transmitted diseases (STDs) , 1 235-1 250 chancroid, 1 244 chlamydia, 1 240-1 24 1 , 1 24 1 t lymphogranuloma venereum, 1 24 1 condyloma acuminata treatment, 1 244- 1 245 gonorrhea, 1 239- 1 240 disseminated gonococcal infections, 1 240 incidence, 1 239 screening and treatment, 1 239- 1 240 herpes simplex virus, 1 24 1 - 1 244 adult disease, 1 24 1 - 1 242, 1 242/ diagnosis, 1 243 management, 1 243, 1 244t

Sexually transmitted diseases (Cont.): shedding prophylaxis, peripartum, 1 243-1 244 vertical transmission, 1 242-1 243 human immunodeiciency virus, 1 247- 1 250,

1 248, 1 250t antepartum care, 1 248- 1 249 antiretroviral therapy, antepartum, 1 249, 1 250t clinical manifestations, 1 247 delivery planning, 1 249 etiopathogenesis and epidemiology, 1 247 postpartum care, 1 250 prenatal HIV screening, 1 247- 1 248, 1 248/ vertical transmission, 1 248 human papillomavirus, 1 244- 1 245 condyloma acuminata, 1 244, 1 245 incidence, 1 244 neonatal infection, 1 245 prophylaxis, after sexual assault, 926, 926t syphilis, 1 235- 1 239 clinical manifestations congenital syphilis, 1 237, 1 237/ maternal syphilis, 1 236- 1 237, 1 236/ diagnosis, 1 237- 1 238 incidence, 1 235 pathogenesis and transmission, 1 235- 1 236 penicillin reactions, 1 239, 1 239t treatment, 1 238- 1 239, 1 238t vaginitis, 1 245-1 247 bacterial vaginosis, 1 245-1 246, 1 246/ candidiasis, 1 247 trichomoniasis, 1 246- 1 247 Shake test, 638 Sharp dilation and curettage (D & C) , 359, 360/ Sheehan syndrome, 657, 1 1 33 placental abruption, 772 Shigellosis (Shigella), 1 224 Shingles, 1 2 1 2 Shirodkar cerclage, 3 5 5 , 356/ Shock, hypovolemic management, 788 placental abruption, 77 1 Short T l inversion recovery (STIR) MR!, 2 1 Shoulder dystocia, vaginal delivery, 520-524 diagnosis, in labor, 43 1 management, 5 2 1 -523 all-fours maneuver, 522 anterior clavicle fracture, deliberate, 523 cleidotomy, 523 McRoberts maneuver, 52 1 -522, 52 1/-522/ posterior axilla sling traction, 5 22-523 Rubin maneuvers, 522, 523/ suprapubic pressure, 5 2 1 symphysiotomy, 523 Woods corkscrew maneuver, 522, 522/ Zavanelli maneuver, 523 maternal and neonatal consequences, 5 20 prediction and prevention, 520 birthweight, 5 20-5 2 1 prior shoulder dystocia, 5 2 1 shoulder dystocia drill, 523-524 Shoulder presentation, 422, 422t, 425, 453. See also Transverse lie abnormal labor, 452-454, 453/ normal labor, 422, 422t, 425/ Siamese twins. See Conjoined twins Sickle cell anemia, fetal hemoglobin, 1 32 Sickle-cell crisis, 1 08 1 Sickle-cell hemoglobinopathies, 1 08 1 - 1 083 carrier screening, 290

Sickle-cell trait, 1 083 Sighs, fetal , 333, 333/ Sigmoidoscopy, lexible, 1 042 Silent oscillatory pattern, fetal, 336 Simpson forceps, 5 57, 5 5 7/ Sincipus, 422, 422/ Single deepest pocket, 226 Single umbilical artery (SUA), 1 1 7 Sinusoidal heart rate, fetal, 464, 464/ Sinus tachycardia, fetal, therapy for, 3 1 6 Sirenomelia, 1 96 6-cm rule vs. 4-cm, 444 background, 444t-446t, 445-446, 445, 446/ Skeletal abnormalities, fetal sonographic, 2 1 0-2 1 2 clubfoot, 2 1 1 -2 1 2, 2 1 1/ limb-reduction defects, 2 1 2, 2 1 2, 29/ nosology and classiication, 2 1 0 skeletal dysplasias, 2 1 0-2 1 1 , 2 1 1/ Skeletal dysplasias, 2 1 0-2 1 1 , 2 1 1/ Skene glands, 1 7, 1 7/ Skin, maternal, 53-54 abdominal wall, 53 diastasis recti, 53 striae gravidarum, 53 hair changes, 54 hair growth periods, 54 telogen eluvium, 54 hyperpigmentation, 53 chloasma, 53 linea alba, 53 vascular changes, 53-54 palmar erythema, 54 vascular spiders, 53-54 Skin care, newborn, 6 1 5 Skull fractures, newborn, 629, 629/ Skyla intrauterine device, 68 1 . See also I ntrauterine devices (IUDs) Sleep, 73 in pregnancy, 1 75 Small bowel and colon disorders, 1 047- 1 05 3 appendicitis, 1 052- 1 053, 1 053/ Closridium diicile infection, 1 048 colonic pseudo-obstruction, 1 05 2 diarrhea, acute, 1 047-1 048, 1 048t inlammatory bowel disease, 1 048- 1 05 1 ,

1 048t intestinal obstruction, 1 05 1 - 1 052, 1 05f ostomy and pregnancy, 1 05 1 Small-for-gestational age (SGA) , 803. See also Fetal­ growth restriction deinition, 803 fetal growth velocity, 846-847 Small molecular inhibitors, for cancer, 1 1 9 1 - 1 1 92 Small mothers, constitutionally, in fetal-growth restriction, 849 Smallpox bioterrorism, 1 228 Smith-Lemli-Opitz syndrome, estriol, 284 Smith-Magenis syndrome, 26 1 t Smoking cessation, ive A's of, 1 62, 1 63t ectopic pregnancy, 3 2 fetal-growth restriction, 8 5 1 miscarriage, 348 placental abruption, 70 placenta previa, 775 preconceptual care, 1 52 prenatal care, 1 6 1 - 1 62, 1 62t prenatal record, 1 6 1- 1 62, 1 62t

1319

1 320

I nd ex S moking and Nicotine in Pregnancy (SNAP) trial,

1 62 Social deprivation, fetal-growth restriction, 850 Social history, preconceptual care diet, 1 52 environmental exposures, 1 52 exercise, 1 52 intimate partner violence, 1 52-1 53 recreational drugs and smoking, 1 52 Sodium, 57 Sodium escape, 981 Softening, cervical, 407-408 Soft tissue injuries, newborn, 63 1 Solomon technique, 322 Soluble endoglin (sEng), in preeclampsia, 7 1 6,

1 7/ Soluble FMS-like tyrosine kinase (sFLT- l ) , 5 1 i n preeclampsia, 7 1 5 , 7 1 6-7 1 7, 7 1 7/ Sonography cancer, in pregnancy, 1 1 9 1 discordant growth, twin fetuses, 882 m ultifetal pregnancy, 870, 870f 884 in pregnancy, 886-887, 909 Sonography, aneuploidy screening, 286-288 applications and importance, 286, 286t irst-trimester, 282f 288 second-trimester markers, "soft signs," 286-288,

287f 28 t clinodacryly, 287/ echogenic fetal bowel, 287-288, 287/ echogenic intracardiac focus, 286-287,

287/ nuchal skinfold, 286, 287/ renal pelvis dilatation, 287, 287/ "sandal-gap," 287/ Sonography, obstetric, 1 82- 1 9 1 3D and 4 D , 2 1 2-2 1 3 Fetal Intelligent Navigation Echocardiography, 2 1 2-2 1 3 spatiotemporal image correlation, 2 1 2 technology and mechanisms, 2 1 2, 2 1 2/ ALAA principle, 1 83 brachycephaly, 1 84 breech presentation, 542 craniosynostosis, 1 85 dolichocephaly, 1 84 fetal-growth restriction, 852-853, 853/ fetal measurements, 1 83-1 84, 1 262t-1 270t birthweight, smoothed percentiles for twins with dichorionic placentation, 1 265t with monochorionic placentation, 1 265t cerebellar diameter, transverse, by gestational age, 1 269t crown-rump length and menstrual age,

1 83-1 84, 1 84f 1 86f 1 263t gestational sac diameter and, 1 262t gestational sac diameter, mean, 1 262t long bone length, by gestational age, 1 267t ocular parameters, by gestational age, 1 268t thoracic circumference, by gestational age,

1 266t umbilical artery Doppler indices, reference values, 1 270t weight by gestational age, 1 264t irst-trimester, 1 85-1 86 components assessed, 1 8 5- 1 86, 1 85t fetal anomaly detection, 1 86, 1 86t indications, 1 85, 1 85t nuchal translucency, 1 86, 1 86t

Sonography, obstetric (Cont): gestational age assessment, 1 83-1 85 , 1 83t abdominal circumference ratio, 1 85 biparietal diameter, 1 84-1 85 , 1 84/ cephalic index, 1 84 crown-rump length, 1 83-1 84, 1 8f 1 86f 1 262t femur length, 1 85 suboptimally dated, 1 85 labor diagnosis, 426-427 levels I and I I , 277 mechanical index, 1 83 pregnancy diagnosis, 1 59, 1 5 9/ prenatal care, 1 65 prenatal surveillance, 1 65 safety fetal, 1 83 operator, 1 83 second- and third-trimester, 1 86-1 9 1 amnionic luid volume, 1 88- 1 89 cervical length assessment, 1 89-1 9 1 , 1 89/ cervix, transvaginal evaluation, 1 90- 1 9 1 , 1 9 0f 1 90t fetal anomal detection, 1 87- 1 8 8 indications, 1 8 7, 1 87t routine, 1 86-1 87 standard fetal anatomic survey, 1 8 7, 1 88t targeted fetal anatomic survey components, 1 87, 1 88t indications, 1 87, 1 89t technology, 1 82-1 83 thermal index, 1 83 ultrasound, defined, 1 82 yolk sac, 1 59, 1 59/ Spatiotemporal image correlation (STIC), 2 1 2 Spectrin deiciency, 1 079 Spermicides, 695-696 contraceptive sponge, 680t, 695, 695/ diaphragm plus, 694-695, 694/ Spherocytic anemia, 1 079 Sphincter urethrae, 20, 20/ Spina bifida, fetal sonography, 1 93, 1 93/ acrania, 1 92 Anold-Chiari malformation, 1 93 banana sign, 1 93 , 1 93/ lemon sign, 1 93, 1 93/ meningocele, 1 93 myelomeningocele, 1 93, 1 93/ open, 1 93 ventriculomegaly, 1 93 Spinal block, 490-492 cesarean delivery, 49 1 complications, 49 1 -492, 49 1 t contraindications, 492, 492t vaginal delivery, 490-49 1 Spinal cord, fetal, 1 29 Spinal cord injury newborn, 630 in pregnancy, 1 1 67-1 1 68 Spinal muscular atrophy (SMA) , carrier screening,

289-290 Spine anomalies. See also speciic ypes fetal, imaging, 1 9 1 - 1 96 (See also Brain and spine imaging) Spine blockage, higher or total from continuous lumbar epidural block, 494 from spinal block, 49 1 Spiral artery invasion, placenta, 89f 9 1 -92 preeclampsia, 25

Spiramycin, for toxoplasmosis, 1 226 Splanchnic nerves, 27f 28 Spleen, 60 Splenomegaly, 60 Spontaneous abortion. See Abortion, spontaneous (miscarriage) Spotting, vaginal, ectopic pregnancy, 372 Stabler sign, 63 1 Standard Certiicate of Live Birth, 2003 revision,

2, 3t, 846 Standard Days Method, 695 Standard fetal anatomic survey, sonography, 1 87,

1 88t STAN system, 4 1 -4 2, 472/

Staphylococcus aureus, 1 222-1 223, 1 223/ breast infections, 675-676, 676/ toxic shock syndrome, postpartum, 675 Stargazing fetus, 540 Starvation, accelerated, 56 Statins, on preeclampsia risk, 727 Station, fetal, 4 1 4, 4 1 5f 436 labor onset, expulsive disorders, 447 Status asthmaticus, 99 1 Status epilepticus, eclampsia, 734, 34/ Stepwise sequential screening, 280t, 284 Sterilization, 02-706 complications, long-term contraceptive failure, 704-705 other, 05 with sickle-cell hemoglobinopathies, 1 083 transcervical, 05- 06, 705/ tubal, 702-705 nonpuerperal, 704 puerperal, 70 2-704 , 703/-704/ reversal, 705 vasectomy, 706, 06/ Steroid sulfatase deficiency, estriol, 284 Stillbirth, 3, 644-649 39-week rule, 649 causes, 645-646, 646t evaluation, stillborn fetus, 646-648, 647/ autopsy, 648 clinical examination, 646, 647/ laboratory evaluation, 646-648 after second-trimester abortion, 364 with hypertension, chronic, 980 incidence, 644-645, 644f 645/ changes, 649 mortality, fetal deinition, 645 rates, 645, 645/ obesity, 940 prior, subsequent pregnancy ater, 648-649, 649t psychological aspects, 648 rate, 3 risk factors, 646, 647t Stochastic efects, 905-906 Stomach emptying, fetal, 1 35 Stones, kidney, 1 030 Stool, newborn, 6 1 5 Strawberry cervix, 1 246 Streak gonad, 38 Streptococcal toxic shock syndrome, postpartum,

675 Streptococcus agalactiae, 1 220- 1 22 1 Streptococcus pneumoniae pneumonia, 992-994, 993t Streptococcus pyogenes, 1 220 septic abortion, 3 5 1

I ndex Stress tests, fetal heart rate, contraction stress testing, 334, 334t Stress urinary incontinence (SUI) , 52-53 Stretch marks, 53 Striae gravidarum, 53, 655 Striated urogenital sphincter complex, 20, 20/ Strictures, umbilical cord, 1 1 9 Stroke hemorrhagic, 1 1 6 1 t, 1 1 62-1 1 64 intracerebral hemorrhage, 1 1 6 1f, 1 1 62- 1 1 63,

1 1 62/ subarachnoid hemorrhage, 1 1 6 1f, 1 1 63 arteriovenous malformations, 1 1 63- 1 1 64 intracranial aneurysm, 1 1 63 incidence, 1 1 60 ischemic, 1 1 6 1- 1 1 62 , 1 1 6 1f, 1 1 6 1 t cerebral artery throm bosis, 1 1 62 cerebral embolism, 1 1 6 1 - 1 1 62, 1 1 6 1/ cerebral venous thrombosis, 1 1 62 preeclampsia syndrome, 1 1 6 1 recurrence risk, 1 1 62 oral contraceptives, 69 1 pregnancy-related hypertension, 44-745 ST-segment changes, fetal, 47 1 -472, 472/ Stuart-Prower factor deficiency, 1 090- 1 09 1 Study of Nicotine Patch in Pregnancy (SNIPP),

1 62 Subacute bacterial endocarditis, 965 Subamnionic hematoma, fetal, 1 1 5 Subarachnoid block, 490-492. See also Spinal block Subarachnoid hemorrhage, 1 1 6 1f, 1 1 63 arteriovenous malformations, 1 1 63- 1 1 64 intracranial aneurysm, 1 1 63 primary, preterm newborn, 639 Subcostal angle, 64, 64/ Subcostal nerves, 1 5- 1 6, 1 5f, 1 6/ Subdural hemorrhage, preterm newborn, 639 Subgaleal hemorrhage, newborn, 628-629, 629/ Suboptimally dated gestational age, 1 85 Succenturiate lobes, placenta, 1 1 2, 1 1 2/ Sucralfate for gastroesophageal relux disease, 1 046 for peptic ulcer disease, 1 047 Suicide, maternal, prenatal, 1 1 73 Sulfasalazine for Crohn disease, 1 0 5 1 for rheumatoid arthritis, 1 1 4 for ulcerative colitis, 1 050 Sulfatase deficiency, fetal-placental, estrogen biosynthesis, 1 0 5 Sulfonamides hypertension, chronic, 9 8 1 teratogeniciry, 242 Sulprostone, for uterine atony, 760 Sumatriptan, for migraine, 1 1 58 Superfecundation, 865, 866/ Superfetation, 864-865 Supericial circumflex iliac artery, 1 4- 1 5, 1 5/ Superficial external pudendal arteries, 1 4- 1 5, 1 5/ Superficial transverse perineal muscles, 1 9f, 20, 20/ Supericial venous thrombophlebitis, 1 0 1 6 Superior hypogastric plexus, 27f, 28 Super-morbid obesity, 936, 939 Supine hypotensive syndrome, 63 Supracervical hysterectomy, 583 Suprapubic pressure, for shoulder dystocia, 52 1 Supraventricular tachycardia (SVT) fetal, therapy for, 3 1 6, 3 1 6/ maternal, 966-967

Surfactant, pulmonary, 1 33-1 34, 1 34/ prophylaxis, for respiratory distress syndrome in preterm newborn, 637-638 Surfactant protein A (SP-A), fetal, parturition, 408 Surgety. See also speciic ypes cancer, in pregnancy, 1 1 9 1 Surgery, fetal, 3 1 8-32 8 ex-utero intrapartum treatment, 327-328, 327f,

Systemic lupus erythematosus (SLE) , 1 1 39-1 1 43 antinuclear autoantibodies, 1 1 39, 1 1 39t classiication criteria, 1 1 40, 1 1 40t clinical manifestations and diagnosis,

1 1 39-1 1 40, 1 1 39t, 1 1 40t conception, 1 1 43 epidemiology, 1 1 39 genetics, 1 1 39 management, in pregnancy general, 1 1 4 1 - 1 1 42 pharmacological, 1 1 42 mortaliry and morbidity, perinatal, 1 1 42- 1 1 43 congenital heart block, 1 1 42- 1 1 43 neonatal lupus syndrome, 1 1 42 pregnancy and, 1 1 40, 1 1 4 1/ lupus nephritis, 1 1 4 1 lupus vs. preeclampsia-eclampsia, 1 1 4 1 ,

327t indications, 3 1 9 t fetoscopic surgery, 3 2 1 -324 (See also Surgery, fetoscopic) guiding principles, 3 1 8-3 1 9, 3 1 8t indications, 3 1 9, 3 1 9t open fetal, 3 1 9-32 1 (See also Open fetal surgery) fundamentals, 3 1 9 indications, 3 1 9 t myelomeningocele, 3 1 9-32 1 , 320f, 320t risks, 3 1 9, 320t sacrococcygeal teratoma, 32 1 , 32 1/ thoracic masses, 3 2 1 percutaneous, 324-327 indications, 3 1 9t Surgery, fetoscopic, 32 1 -324 congenital diaphragmatic hernia, 323-324, 323/ fetal endoscopic tracheal occlusion, 323-324,

323/ indications, 3 1 9 t intracardiac catheter procedures, 326-327 myelomeningocele, endoscopic repair, 324 radiofrequency ablation, 326 thoracic shunts, 324-325, 324/ twin-twin transfusion syndrome, 321-323, 322/ urinary shunts, 325-326, 325f, 326t Surgery, maternal, in p regnancy laparoscopic, 90 1 -904 (See aso Laparoscopic surgery, in pregnancy) perinatal morbidity, 90 1 , 90 1 t pregnancy outcomes, 90 1 Surveillance, antepartum fetal multi fetal pregnancy, 884-885 normal test, stillbirth rates, 34 1 , 34 1 t Surveillance, prenatal discordant growth, twin fetuses, 882 fetal heart sounds, 1 65 fundal height, 1 64- 1 65 fundamentals, 1 60t, 1 64 sonography, 1 65 Survival motor neuron (SMNI) gene, 289-290 Swallowing, fetal, 1 34-1 35 Symmetrical growth restriction, 847 Sympathetic nerves, pelvic, 27, 27/ Symphysiotomy for partial breech extraction, 548 for shoulder dystocia, 523 Symptothermal Method, 695 Synclitism, 427, 429/ Syncytiotrophoblast, 8 8-90, 89/ Syndrome X, 1 067 Syphilis, 1 235-1 239 clinical manifestations congenital syphilis, 1 23 , 1 237/ maternal syphilis, 1 236-1 237, 1 236/ c iagnosis, 1 237- 1 238 fetal-growth restriction, 8 5 1 -852 incidence, 1 23 5 pathogenesis and transmission, 1 235-1 236 penicillin reactions, 1 239, 1 239t treatment, 1 238- 1 239, 1 238t

1 14 1 t prognosis, long-term, 1 1 43 Systemic sclerosis, 1 1 48-1 1 49 Systolic-diastolic (SID) ratio, 2 1 3 Systolic-diastolic (SID) waveform, 2 1 3, 2 1 3/ Systolic flow murmurs, 949, 950/

T T3, free, 1 258t fetal, 1 36 maternal, 70, 70/ T4 , free, 1 2 5 8t fetal, 1 36-1 37 maternal, 0, 0/ Tachyarrhythmias. See also speciic ypes deinition, 3 1 5 fetal, 46 1 electronic monitoring, 46 1 therapy for, 3 1 6, 3 1 6/ supraventricular tachycardias, 966-967 ventricular tachycardia, 96 Tachysystole, uterine contractions, 480 T akayasu arteritis, 1 1 50 Takotsubo cardiomyopathy, 964 Talipes equinovarus, 2 1 1 -2 1 2 , 2 1 If, 63 1 Tamoxifen, teratogenicity, 243 Targeted fetal anatomic survey, sonography aneuploidy screening, 286 components, 1 87, 1 88t indications, 1 8 , 1 89t maternal serum alpha-fetoprotein screening, 278 Targeted regulation of abortion providers (TRAP) laws, 357-35 8 Targeted therapy, cancer, i n pregnancy, 1 1 9 1 - 1 1 92 T ay-Sachs disease carrier screening, 290-291 preconceptual care, 1 5 1 prenatal screening, 1 65 Tazarotenone, 1 1 87 T-cells maternal, fetal-maternal interface, 95 regulatory, trophoblast invasion, 9 1 T-cell tumors, 1 202-1 203 TDx-FLM II, 638 Tei index, 1 085 twin-to-twin transfusion syndrome, 879 Telogen eluvium, 54 Temperature Rhythm Method, 695 1 0-percent tumor, 1 1 30 Tension-type headache, 1 1 57

Ten Steps to Successol Breaseeding, 658, 658t Teratogen Information System (TERIS), 234-235

1 32 1

1 322

I nd ex Teratogens, 234, 234t, 239-249 antipsychotics, 245 fetal-growth restriction, 8 5 1 known and suspected, 239-249 alcohol, 1 62, 239-240, 239t, 240/ angiotensin-converting enzyme inhibitors, 24 1 angiotensin-receptor blocing drugs, 24 1 antiepileptic medications, 240-24 1 , 240/ carbamazepine, 240 hydantoin, 240, 240/ phenobarbital, 240 phenytoin, 240 topiramate, 240 valproic acid, 240 antifungals, 2 4 1 antiinflammatory agents lelunomide, 24 1 NSAIDs, 24 1 antimicrobial drugs, 242 aminoglycosides, 242 nitrofurantoin, 242 sulfonamides, 242 tetracyclines, 242 antineoplastic agents cyclophosphamide, 242 methotrexate, 242-243 tamoxifen, 243 trastuzumab, 243 antiviral agents efavirenz, 243 endothelin-receptor antagonists, 243 ribavirin, 243 drugs, recreational amphetamines, 247 cocaine, 248 marijuana, 249 opioids-narcotics, 248-249 phencyclidine, 249 toluene, 249 immunosuppressants corticosteroid, 244 mycophenolate mofetil, 244 sex hormones danazol, 243 diethylstilbestrol, 243-244 testosterone and anabolic steroids, 243 tobacco, 249 lead, 244 lenalidomide, 247 medication exposure, counseling, 238-239 FDA, letters and labels, 238, 238t risk information, presenting, 238-239 mercury, 244 psychiatric medications antipsychotics, 245 lithium, 244-245 selective norepinephrine-reuptake inhibitors, 245 selective serotonin-reuptake inhibitors, 245 radioidine- 1 3 1 , 244 retinoids acitretin, 245-246 isotretinoin, 245 retinoic acid embryopathy, 245, 246/ topical, 246 vitamin A, 246 studies case-control, 237 case reports and series, 237 cohort, 237

T eratogens (Cont: National Birth Defects Prevention Study, 237 pregnancy registries, 237 pregnant women, 236 teratogenicity criteria, 23 5-236, 235t thalidomide, 246-247 tobacco, 247 toluene, 249 trophogen, 23 5 warfarin, 247, 247/ Teratology, 234-249 medication use, 234-235, 234t studies, 236-237 teratogenicity criteria, 23 5-236, 23 5 t, 236/ Teratogen Information System, 234-235 teratogens, 234, 234t, 238-249 (See also Teratogens) birth defect incidence, 234 Teratoma ovarian mature cystic, 1 1 98 sacrococcygeal, 1 96, 32 1 Terbutaline sulfate, for fetal heart rate problems, 475, 475t Terconazole, for candidiasis, 1 247 Termination, multifetal pregnancy, 89 1 -892 Term neonate, 3 Tertiary villi, 90 Testis, dysgenetic, 38 Testis-determining factor (TDF) , 38 Testosterone maternal, 72 serum and blood test, 1 2 59t supplemental, teratogenicity, 243 Tetracyclines for malaria, 1 227 teratogenicity, 242 Tetralogy of Fallot antifungals, in pregnancy, 24 1 echocardiography, 204, 204/ T etraploidy euploid abortion, 347 pregnancy, 259 h2 bias, 1 209 halassemia intermedia, 1 08 5 Thalassemia syndromes, 1 084- 1 086 a-thalassemias, 1 084- 1 08 5 , 1 08 5 t 3-thalassemias, 1 085-1 086 carrier screening, 290 preconceptual care, 1 50- 1 5 1 Thalidomide, teratogenicity, 246-247 hanatophoric dysplasia, 2 1 1 Theca-lutein cysts, 52, 391/ hyperreactio luteinalis, 52 Therapeutic abortion, 35 . See aso Abortion, induced Therapeutic radiation, in pregnancy, 906 Therapies, fetal, 3 1 5-328 medical, 3 1 5-3 1 8 arrhythmias, 3 1 5-3 1 7 bradyarrhythmia, 3 1 6-3 1 7 definition, 3 1 5 premature atrial contractions, 3 1 5-3 1 6 tachyarrhythmias, 3 1 6, 3 1 6/ congenial adrenal hyperplasia, 3 1 7 congenital cystic adenomatoid malformation, 3 1 7-3 1 8 thyroid disease, 3 1 8 fetal hypothyroidism, 3 1 8 fetal thyrotoxicosis, 3 1 8 surgical, 3 1 8-328 Thermal index, sonography, 1 83

hermal injury, 930-93 1 electrical and lightning injuries, 930-93 1 mortality rates, 930, 930/ Thiazide diuretics, for chronic hypertension, 98 1 Thioamide, for thyrotoxicosis in pregnancy, 1 1 20 Third-trimester sonography, obstetric, 1 86-1 9 1 . See also Sonography, second- and third­ trimester 39-week rule, 648-649, 804 horacic circumference, 64, 64/ fetal, by gestational age, 1 266t Thoracic masses, open fetal surgery, 32 1 horacic shunts, fetoscopic surgery, 324-325 , 324/ Thorax imaging, fetal magnetic resonance imaging, 2 1 8 , 2 1 9/ sonography, 1 98-200 cardiac examination, basic, 20 1 , 20 1/-202/ four-chamber view, 20 1 , 20 1! 202/ left ventricular outflow tract view, 20 1 , 202/ other view, 20 1 , 202/ right ventricular outflow tract view, 20 1 , 202/ congenital cystic adenomatoid malformation, 1 99, 1 99/ congenital diaphragmatic hernia, 1 98, 1 98/ congenital high airway obstruction sequence, 1 99-200, 200/ normal, 1 98 pulmonary sequestration, 1 99, 200/ Threatened abortion, 348-349, 349t Threshold of viability, 805-807 clinical management, 806-807, 807t definition, 805 periviable neonatal survival, 806, 806! 806t periviable period, 805 hreshold trait, multifactorial inheritance, 269, 269/ hrombocythemia, 1 087- 1 08 8 Thrombocytopenia, 1 086- 1 087, 1 086t alloimmune, 307, 1 087 fetal, 307-308, 308t ktal, 307-309, 1 087 immune, 308-309 gestational, 1 086 immune thrombocytopenic purpura, 1 086- 1 087 inherited, 1 086 maternal coagulopathies, 784 management, 789 continuous lumbar epidural block and, 496 deinition, 7 1 9 eclampsia and preeclampsia, 7 1 9 preeclampsia, 726 newborn, 627 hrombocytopenia-absent radius syndrome, limb­ reduction defects, 2 1 2, 258/ hrombocytosis, 1 08 7- 1 088 hromboelastography (TEG) coagulopathies, 7 8 5 , 79 1 -792 preeclampsia, 7 1 9 hromboelastometry, coagulopathies, 785, 79 1 , 9 1/ hromboembolic disorders, 1 004- 1 022. See also

speciic ypes deep-vein thrombosis, 1 0 1 0- 1 0 1 6 incidence, 1 004 oral contraceptives, 69 1 -692 pathophysiology, 1 004-1 005, 1 005t

I nd ex hromboembolic disorders (Cont): pulmonary embolism, 1 0 1 6- 1 0 1 9 risk factors, 1 005-1 006, 1 005t supericial venous thrombophlebitis, 1 0 1 6 thrombophilias, 1 005- 1 0 1 0 thromboprophylaxis, 1 0 1 9- 1 022, 1 020t l1rombolysis. See also speciic agents for pulmonary embolism, 1 0 1 8- 1 0 1 9 hrombophilias, 1 005- 1 0 1 0, 1 068, 1 09 1 acquired anti phospholipid syndrome, 1 008 heparin-induced thrombocytopen ia, 1 008, 101 5 on coagulation cascade, 1 005, 1 005/ dei nition, 1 005 on fetal development, 1 33 inherited, 1 006- 1 008 activated protein C resistance, 1 00 5[ 1 006t,

1 007 antithrombin deiciency, 1 006t, 1 007 factor V Leiden mutation, 1 005[ 1 006t,

1 00 hyperhomocysteinemia, 1 005[ 1 007- 1 008 paternal, PROCR 6936G allele, 1 008 plasminogen activator inhibitor type 1 (PAl- I ) , 1 008 protein C deiciency, 1 005[ 1 006- 1 007,

1 006t protein S deiciency, 1 005[ 1 006t, 1 007 protein Z, 1 008 ptothrombin G202 1 0A mutation, 1 00 5[

1 006t, 1 007- 1 008 pregnancy complications, 1 008- 1 009, 1 009 t screening, 1 009- 1 0 1 0, 1 0 l Ot Thrombophlebitis, septic pelvic, 673-674, 673[ 674/ Thromboprophylaxis, 1 0 1 9- 1 022, 1 020t anti phospholipid antibodies, 1 02 1 t cesarean delivery, 1 0 1 9- 1 022, 1 020t prior venous thromboembolism, 1 0 1 9, 1 020t no, 1 0 1 9, 1 020t- 1 02 1 t two, 1 0 1 9, 1 020t recommendations, 1 0 1 9, 1 020t- l 02 1 t hrombosis, maternal intervillous, 1 1 4 prevention, amiphospholipid syndrome, 1 1 45 umbilical cord vessel, 1 20 Ihrombotic microangiopathies, 1 088-1 089, 1 089t,

1 161 Thrombotic thrombocytopenic purpura (TTP),

1 088-1 089, 1 089t Thrombotic vasculopathy, fetal, 1 1 4[ 1 1 5 Thromboxane A2, in preeclampsia, 7 1 6 Thyroid-binding globulin (TBG) fetal, 1 36 maternal, 70, 70/ serum and blood tests, 1 258t Thyroid cancer, 1 20 1- 1 202 Thyroid disease, fetal, therapy for fetal hypothyroidism, 3 1 8 fetal thyrotoxicosis, 3 1 8 Thyroid disorders, 1 1 1 9- 1 1 28 autoimmunity and thyroid disease, 1 1 1 9, 1 1 1 9/ fetal microchimerism, 1 1 1 9 euthyroid autoimmune thyroid disease, 1 1 25-1 1 26 hyperthyroidism, 1 1 20-1 1 22 fetal and neonatal efects, 1 1 2 1- 1 1 22, 1 1 2 1/ fetal diagnosis, 1 1 22 hyperemesis gravidarum and gestational transient thyrotoxicosis, 1 1 22

Thyroid disorders (Cont.): subclinical, 1 1 22-1 1 23 thyroid storm and heart failure, 1 1 22,

1 1 23/ thyrotoxicosis gestational transient thyrotoxicosis, 1 1 22 pregnancy, 1 1 20- 1 1 2 1 , 1 1 2 1 t hypothyroidism, 1 1 23-1 1 24, 1 1 23t, 1 1 24t classiication, 1 1 23-1 1 24 congenital, 1 1 2 postpartum thyroiditis, 1 1 27 subclinical, 1 1 24-1 1 25, 1 1 26t iodine deiciency, 1 1 26- 1 1 27 isolated maternal hypothyroxinemia, 1 1 25 nodular thyroid disease, 1 1 28 thyroid physiology and pregnancy, 69-7 1 ,

1 1 1 8- 1 1 1 9, 1 1 1 9/ Thyroid function tests, 70-7 1 , 70/ hyroid gland fetal, 1 36-1 37 maternal, 69-7 1 , 70/ human chorionic gonadotropin, 69, 0/ iodine status, 7 1 T3, free, 70, 70/ T4, free, 70, 70/ thyroid-binding globulin, 70, 70/ thyroid function tests, 70-7 1 , 70/ thyroid-stimulating hormone, 69, 70/ thyrotropin-releasing hormone, 69 physiology, pregnancy and, 69-7 1 , 1 1 1 8- 1 1 1 9,

1 1 1 9/ hyroid hormone, fetal, 1 36. See also T3, free; T4, free Thyroiditis, postpartum, 1 1 27 hyroid microsomal antibodies, 1 1 1 9, 1 1 1 9/ hyroid peroxidase (TPO), 1 1 1 9 hyroid peroxidase amibodies, 1 1 1 9, 1 1 1 9/ Thyroid-stimulating autoantibodies, 1 1 1 9 Thyroid-stimulating blocking antibodies, 1 1 1 9 hyroid-stimulating hormone (TSH , thyrotopin) ,

1 1 1 8- 1 1 1 9, 1 1 1 9/ fetal, 1 36 maternal, 69, 70/ placental, 99 t, 1 0 1 serum and blood tests, 1 258t hyroid-stimulating immunoglobulin (TS I), 1 1 1 9 fetal, 1 36 Thyroid storm. See also Hyperthyroidism heart failure and, 1 1 22 , 1 1 23/ l1yrotoxicosis. See also Hyperthyroidism destruction-induced, 1 1 27 fetal, 1 1 22 goitrous, 1 1 2 1 , 1 1 2 1/ therapy for, 3 1 8 gestational transiem, 1 1 22 hyperemesis gravidarum and, 1 1 22 neonatal, goitrous, 1 1 2 1 , 1 1 2 1/ pregnancy and, 1 1 20- 1 1 2 1 , 1 1 2 1 t propylthiouracil for, 1 1 20 thioamide for, 1 1 20 Thyrotropin, 1 1 1 9 Thyrotropin-releasing hormone (TRH) , 1 1 1 9 maternal, 69 Tidal volume, 64 in pregnancy, 64, 6 5[ 98 Timed vital capacity, 64 T incision, for cesarean delivery, 5 5 Tinidazole for amebiasis, 1 228 for trichomoniasis, 1 24

Tissue inhibitor of MMP- 1 , amnion epithelial cells, 96 Tissue refractoriness, cortisol, 72 Tobacco. See also Smoking teratogenicity, 247, 249 Tocolysis, for preterm labor, 825-827 atosiban, 827 3-adrenergic receptor agonists, 826 calcium-channel blockers, 827 external cephalic version, 550 fetal heart rate problems, 4 5, 4 5t fundamentals, 825-826 magnesium sulfate, 826 nitric oxide donors, 827 prostaglandin inhibitors, 826-827 Today contraceptive sponge, 680t, 695, 695/ Tolerance, maternal-fetl, 5 8-59 Toluene embryopathy, 249 Topical negative pressure (TNP) , 670-67 1 Topiramate, teratogenicity, 240, 1 1 60t Torsades de pointes, 96 Torticollis, newborn, 63 1 Total hemoglobin mass, 65 Total lung capacity, 64, 64/ Total placenta accreta, 7 8[ 9 Total pulmonary resistance, 64 Toxic shock syndrome (TSS) , postpartum, 675 Toxic shock syndrome toxin- l (TSST- 1 ) , 675 Toxoplasmosis (Toxoplasma gondii), 1 225-1 226 fetal-growth restriction, 852 Trace metals fetal, 1 39 pregnancy and lactation, 1 67t, 1 68 Tracheal intubation, newborn resuscitation,

608-609 Tracheal occlusion, endoscopic, fetoscopic surgery,

323-324, 323/ Trachelectomy, radical, 1 1 95 Tracheoesophageal istula, 206 Tranexamic acid after cesarean delivety, 576 for hemorrhage, 790 Transabdominal cerclage, 356, 357/ Transcervical catheter, for cervical ripening, 508,

508/ Transcervical sterilization, 705-706, 05/ T ranscobalamins, 1 69 T ranscortin, 7 1 Transcutaneous amnionic fluid low, 225 T ransdermal patch, 692 Transforming growth factor . (TGF.), endometrial cycle, 84 Transfusion, 788. See aso Blood component products, for hemorrhage fetal blood, for red cell alloimmunization, 304-305 infections from, 79 1 -792 viral infections from, 792 Transfusion-related acute lung injury (TALI),

79 1 Transient hypertension, 7 1 1 . See also Hypertensive disorders of pregnancy Transient ischemic attack (TlA) , 1 1 6 1 Transient tachypnea of newborn, 607 with cesarean delivery, prior, 594 Transjugular intrahepatic portosystemic stent shunting (TlPSS), 1 068 T ranslocations, chromosomal, 26 1-262 reciprocal, 26 1-262, 262/ Roberrsonian, 262 Transmembranous amnionic luid low, 225, 226t

1 3 23

1 324

I n dex Transmission, infection. See also speciic inections horizontal, 1 209 vertical, 1 209, 1 23 5 H IV, 1 248 Transplantation liver, 1 069, 1 069t lung, for cystic ibrosis, 999 pancreatic, 1 07 1 pregnancy after heart transplat, 9 5 5 renal transplant, 1 030- 1 03 1 for sickle-cell hemoglobinopathies bone marrow, 1 08 1 cord-blood stem-cell, 1 0 8 1 Transposition of the great vessels, correct, 3 1 6 Transvaginal ring, 692-693, 692/ Transvaginal ultrasound. See also Sonography failed pregnancies, 346 for threatened abortion, 349 Transverse arrest, 43 1 Transverse cervical ligament, 25, 25/ Transverse lie abnormal labor, 452-454, 453/ etiology, 453 management, 454 mechanism of labor, 4 53-454, 454/ neglected, 452-453 position and presentation, 452-45 3 fetopelvic disproportion, 452-454, 453/ etiology, 453 management, 454 mechanism of labor, 453-454, 454/ neglected, 453 position and presentation, 452-453 large fetus, cesarean delivery with, 579 normal labor, 422, 422t, 425/ Transverse limb-reduction defect, 2 1 2, 2 1 2/ Transversus abdominis plane, 1 6, 1 6/ T rastuzumab for breast cancer, 1 20 1 for cancer, 1 1 92 teratogenicity, 243 , 1 1 92 Trauma, 925-930. See also Critical care; speciic

ypes automobile accidents, 926-927, 927/ blunt trauma, other, 927 fetal injury and death, 927 fetal-maternal hemorrhage, 930 incidence, 925 management, 929-930 cesarean delivery, 929-930 electronic monitoring, 930 general principles, 929 orthopedic injuries, 927 penetrating, 929 physical abuse, 925-926, 926t placental injuries, 927-929, 928/ sexual assault, 926, 926t uterine rupture, 929 Travel precautions, in pregnancy, 1 228 Treponemal-speciic testing, 1 238 Treponema pallidum, 8 5 1 -852, 1 235-1 239. See aso Syphilis T retinoin, teratogenicity, 1 203 Trial of labor, 443 Trial of labor ater cesarean section (TOAC), 5 9 1 -598. See also Delivery, cesarean, prior Triamcinolone acetonide, 1 1 88

Trichomoniasis (Trichomonas vaginalis), 1 246- 1 247 T riglycerides fetal, 1 38 serum and blood tests, 1 2 59t Trimesters Naegele rule, 1 25 , 1 6 1 prenatal record, 1 6 1 T rimethoprim-sulfamethoxazole, for listeriosis, 1 220 Triphasic pills, 690 Triple edema, 3 1 0 Triplets. See also M ultifetal pregnancy delivery, 890-89 1 infertility therapy, 864 Triploidy, euploid abortion, 347 Triptans, for migraine, 1 1 5 8 Trisomies, autosomal, 254-258. See also speciic ypes etiology, 254-2 5 5 incidence, 2 5 4 , 254/ other, 258 risk maternal age on, 2 5 5 , 2 5 5/ after pregnancy with autosomal trisomy, 256 Trisomy euploid abortion, 34 maternal age on risk of, 278 , 2 9t, 280t maternal age-related risk, 276, 279, 279t Trisomy 13 (Patau syndrome), 1 94, 1 95, 257-25 8 Trisomy 1 8 (Edwards syndrome), 2 5 7 , 258/ fetal-growth restriction, 852 incidence, 254, 254/ Trisomy 2 1 (Down syndrome), 256-257, 256, 257/ age maternal, risk, 276, 279, 279t paternal, advanced, 265 estrogen biosynthesis, placental, 1 0 5 fetal-growth restriction, 8 5 2 incidence, 2 5 4 , 254/ screening (See also Aneuploidy screening) false-positive rate, 279, 280t Trophectoderm, 87, 8 8 Trophectoderm biopsy, 296 Trophoblast, 87, 88 development, 88, 89/ cytotrophoblasts, 88, 89/ endovascular trophoblasts, 88, 89/ extravillous trophoblasts, 88, 89/ interstitial trophoblasts, 88, 89/ syncytiotrophoblast, 88, 89/ villous trophoblasts, 88, 89/ formation, early, 87-90 intermediate, placental site trophoblastic tumor from, 395 invasion, in pregnancy-related hypertension, 7 1 4, 7 1 4/ invasion regulators, 90-9 1 persistent, after tubal pregnancy surgety, 379 Trophoblast formation, early, 87-90 blastocyst, 87, 88 inner cell mass, 87, 88 trophectoderm, 87, 88 trophoblasts, 87, 8 8 chorionic villi, 90, 90, 389/ early invasion, 89-90, 89, 1 26/ chorion, 89, 1 26/ syncytiotrophoblast, 89-90 trophoblastic lacunae, 90 fertilization, 87-88 , 87/

Trophoblast formation, early (Cont: blastocyst, 87, 88 blastomeres, 87-88, 8 / morula, 87, 8 8 zygote, 87-88, 87/ implantation, 88 paracrine system, 87 placenta-uterine interface, 87 trophoblast development, 88, 89/ cytotrophoblasts, 88, 89/ endovascular trophoblasts, 88, 89/ extravillous trophoblasts, 88, 89/ interstitial trophoblasts, 88, 89/ syncytiotrophoblast, 88, 89/ villous trophoblasts, 88, 89/ Trophoblastic lacunae, 90 Trophoblastic mammalian target of rapamycin complex 1 (mTORC 1 ) , fetal, 1 39 Trophogen, 235 Trophotropism, placenta previa, 773 True cysts, umbilical cord, 1 1 8 Truncus arteriosus, 957 T sign, 869, 869/ Tubal abortion, 3 2 Tubal pregnancy, 37 1 -380 classiication, 37 1 clinical manifestations, 372-373, 373/ diagnosis, multimodality, 373-375 algorithm, 373, 374/ beta-human chorionic gonadotropin, 373-375 endometrial sampling, 376 laparoscopy, 376-377 progesterone, serum, 375 transvaginal sonography, 375-377 adnexal findings, 375-376, 376/ endometrial indings, 375 , 375/ hemoperitoneum, 376, 377/ evolution and potential outcomes, 372, 372/ management, 377-380 expectant, 380 medical, 377-378, 377t medical vs. surgical, 379-380 surgical, 378-379 laparotomy vs. laparoscopy, 378-379 persistent trophoblast, 379 salpingectomy, 379 salpingostomy, 379 risks, 37 1 -372 ruptured, 372, 372/ Tubal sterilization, 702-705 non puerperal, 704 puerperal, 702-704, 703/-704/ reversal, 705 Tuberculosis, 99 5-997, 1 225 epidemiology, 995 etiology and pathophysiology, 995 fetal-growth restriction, 8 5 1-852 pregnancy and diagnosis, 996 extrapulmonary TB, 996 incidence, 995-996 treatment, congenital, 997 treatment, latent infection, 996-997 treatment, 995 Tuboovarian abscess, from IUD, 684 Tumors, placental, 1 1 5- 1 1 6 chorioangioma, 1 1 5- 1 1 6, 1 1 6/ metastatic, 1 1 6

I n dex Turner syndrome, 39, 259 cystic hygroma, 1 97 euploid abortion, 347 fetal-growth restriction, 352 monosomy, 258 Twin anemia-polycythemia sequence (TAPS) , 322, 880 Twin peak sign, 868-869, 868/ Twin reversed-arterial-perfusion (TRAP) sequence, 880-88 1 , 880/ 88 1/ fetoscopic radiofrequency ablation for, 326 Twins (twinning) . See also Multifetal pregnancy birthweight, smoothed percentiles with dichorionic placentation, 1 26 5 t with monochorionic placentation, 1 265t chorionicity, determining, 867-869, 868t placental examination, 865/ 869, 869/ sonographic, 867-869, 868/ 869/ conjoined, 8 5-876, 875/-877/ spectrum, 875/ discordant growth, 8 8 1 -882 dizygotic, 864 mechanisms, 864 vs. monozygotic, 864 external parasitic twins, 875/ 876 factors, 86 5-867 demographics, 866, 866/ heredity, 866 infertility therapy, 867 nutrition, 866-867 pituitary gonadotropin, 867 fetus-in-feru, 875/ 876 fraternal, mechanisms, 864 hydatidiform mole, 390 infertility therapy, 864 mirror image, 875 monoamnionic, 873-875, 874/ monochorionic, vascular anastomoses, 876-88 1 artery-to-artery anastomoses, 877-878, 877/ connection number, size, and direction, 8 7, 877/ hydatidiform mole with coexisting normal fetus, 88 1 twin anemia-polycythemia sequence, 880 twin reversed-arterial-perfusion sequence, 880-88 1 , 880/ 8 8 1/ twin-to-twin transfusion syndrome, 8 7/ 878-880 diagnosis, 879, 8 9/ fetal brain damage, 878, 878/ management and prognosis, 879-8 80 Quintero staging, 8 9, 879/ monozygotic, 864 genesis, 864, 865/ mechanisms, 864 sex ratios, 86 superfecundation, 865, 866/ superfetation, 864-865 vascular anastomoses, 8 6-8 8 1 zygosity, determining, 86 Twin-to-twin transfusion syndrome (TTTS), 229, 87/ 8 8-880 diagnosis, 879, 879/ fetal brain damage, 878, 8 8/ fetoscopic surgety, 32 1 -323, 322/ management and prognosis, 8 9-880 Quintero staging, 879, 8 9/

Type 1 diabetes, 1 097, 1 098t Type 2 bias, 7 1 5 Type 2 diabetes, 1 097, 1 098/ 1 098t Typhoid fever, 1 224 Tyrosine kinase, targeted cancer therapy on, 1 1 92 u U incision, for cesarean delivery, 575 UK Obstetric Surveillance System (UKOSS), 6 Ulcerative colitis, 1 049, 1 049/ classiication, 1 048, 1 049t etiopathogenesis, 1 048 fertility and, 1 050 pregnancy and, 1 0 50- 1 0 5 1 Ulipristal, for myoma regression, 1 1 97 Ultraviolet B phototherapy, 1 1 87 Umbilical artery aneurysm, 1 20 Doppler imaging, fetal, 2 1 3-2 1 4 , 854/ Doppler indices, reference values, 1 270t isolated single placental abruption, 770 placental abruption risk, 70 sonographic evaluation, risks from, 1 1 7 velocimetry, fetal Doppler, 339-340 Umbilical coiling index (UC!), 1 1 7 Umbilical cord, 97, 98/ 1 30/ See aso Cord care, newborn, 6 1 5 implantation and placental development, 97, 98/ 1 30/ Umbilical cord, abnormalities, 1 1 7- 1 20 coiling, 1 1 7 cysts, 1 1 8 fetal-growth restriction, 8 5 1 funic presentation, 1 20 fused, with share lumen, 1 1 insertion, 1 1 8 , 1 1 8/ knots, 1 1 9 length, 1 1 7 loops, 1 1 9- 1 20 remnants, 1 1 8 single umbilical artery, 1 1 7 strictures, 1 1 9 �asa previa, 1 1 8-1 1 9, 1 1 9/ vascular cord hemaromas, 1 20 umbilical artery aneurysm, 1 20 umbilical cord vessel thromboses, 1 20 umbilical vein varix, 1 20 vessel number, 1 1 7- 1 1 8 , 1 1 7/ Umbil ical cord blood, acid-base srudies, 6 1 1 , 6 1 2t Umbilical cord blood banking, prenatal, 1 Umbilical cord blood gas studies cerebral palsy, 624 newborn, 6 1 3 Umbilical cord clamping, 607 vaginal delivery, occiput anterior position, 5 1 8-5 1 9 Undergrowth, fetal-growth restriction, 848-849 Undernutrition, maternal fetal-growth restriction, 8 5 0 severe, prenatal, 1 66 Undiferentiated connective tissue disease, 1 1 49 Unfolded-protein response (UPR) , 406 Un fractionated heparin (UFH), 954 for antiphospholipid syndrome, 1 1 4 5- 1 1 46 for deep-vein thrombosis, 1 0 1 2- 1 0 1 3 , 1 0 1 3t

Unicornuate uterus, 44 Uniparental diosomy, 268, 269/ Unstable (oblique) lie, 422, 452 Upper gastrointestinal endoscopy, 1 042 Ureteropelvic j unction obstruction, 208 Ureteroscopy, 1 026 Ureters, maternal, 29, 65/ 67-68, 67/ inj ury, peripartum hysterectomy, 5 84, 5 8 4/ Urethra, 20-2 1 , 20/ Urethral atresia, fetal, 325 Urethral diverticulum, 1 03 Urethral valves, posterior, 325 magnetic resonance imaging, 2 1 8 , 2 1 9/ sonography, 2 1 0 Urethritis, 1 027t, 1 028 Urethrovaginal sphincter muscle, 20, 20/ Urinalysis, fetal, 326t Urinalysis, maternal, 66-67, 67/ glucosuria, 66 hemaruria, 66, 1 026 proteinuria, 66-67, 67/ 720, 26 urine protein, measuring, 67 Urinary shunts, fetoscopic surgery, 325-326, 325/ 326t Urinary system embryology, 33, 34/ fetal, 1 3 5- 1 36 Urinary system, maternal, 65-68 bladder, 68 kidney, 65-6 , 66t glomerular iltration rate, 65-66, 65/ renal function tests, 66 renal plasma flow, 65-66, 65/ size, 65, 66t urinalysis, 66-67, 67/ urine protein, measuring, 67 ureters, 65/ 6 -68, 6 f Urinary tract fetal sonography, 207-2 1 0 (See also Kidneys and urinary tract, fetal sonography) maternal, lower, 28-29 bladder, 28-29 ureter, 29 pregnancy-induced changes, 1 025-1 026, 1 02 5/ Urinary tract disorders, 1 025-1 030 istulas, urogenital tract, 1 037- 1 038 infections, 1 026- 1 030 (See also Urinary tract infections (UTIs» pregnancy-induced changes, 1 025-1 026, 1 02 5/ urethral diverticulum, 1 037 vesicoureteral reflux, 1 026 Urinary tract infections (UTIs), 1 026-1 030 asymptomatic bacteriuria, 1 027, 1 02 t cystitis and urethritis, 1 02 t, 1 028 etiology, 1 026 postpartum, 667 puerperium, 1 026- 1 02 pyelonephritis, acute, 1 028- 1 029, 1 028/ 1 029t reflux nephropathy, 1 029- 1 030 sequelae, 1 026 Urinary tract inj ury, from peripartum hysterectomy, 583-584, 584/ Urine, newborn, 6 1 5 Urogenital tract istulas, 1 037- 1 038 U.S. health care in crisis, 6-9 assisted reproductive technologies, 9 cesarean delivery rate, 8 family planning services, 9 genomic technology, 8

1 325

1 326

I nd ex u.s. health care in crisis (Cont: home births, 8 inefective, expensive interventions, 7-8 in-vitro fertilization, 9 liability, medical, 8 maternal and infant health care costs, 7-8 Medicaid, 7 Obamacare, 6 Ob/Gyn hospitalist, 8 opioid abuse, in pregnancy, 9 repeal and replace, 7 womb, artificial, 9 Uterine abnormalities, fetal-growth restriction, 8 5 1 Uterine abnormalities, Mullerian, 43-45 arcuate uterus, 44, 45 bicornuate uterus, 44f, 4 5 cerclage treatment, 4 5 discovery, 4 3 imaging, 43-44, 44/ recurrent pregnancy loss, 353 septate uterus, 44f, 45 unicornuate uterus, 44 uterine didelphys, 44-45 Uterine activation, 408 Uterine activity, intrapartum surveillance, 4 8-48 1 contractions, origin and propagation, 450, 450/ external monitoring, 4 8, 478/ internal monitoring, 4 8, 478/ uterine activity pattens, 478-479, 479/ Uterine artery, 25-26, 26/ Doppler imaging, 2 1 4 Doppler velocimetty, 726 fetal, 340 ligation, for hemorrhage, 792, 792/ preeclampsia blood flow velocity, 725-726 notching, 726 Uterine atony, 758-76 1 evaluation and management, 759-76 1 inspection, 759 uterotonic agents, 75 9-760 uterotonic agents, bleeding unresponsive to, 760-76 1 balloon tamponade, 76 1 , 76 1/ bimanual uterine compression, 760, 760/ steps, 760-761 surgical procedures, 76 1 , 792-794 placenta removal, manual, 758- 59, 759/ risk factors, 759 third-stage labor management, 758-759, 759/ Uterine awakening, 408 Uterine cancers, 1 1 95- 1 1 97 endometrial lesions, 1 1 97 leiomyomas, 1 1 95-1 1 97, 1 1 96f, 1 1 97/ Uterine cavity, after delivery, 4 1 5-4 1 6, 4 1 5f, 4 1 6/ Uterine compression, bimanual, 759-760, 760/ Uterine compression sutures, for hemorrhage, 792, 793/ Uterine contractions intrapartum surveillance incoordination, 480 origin and propagation, 480, 480/ patterns of activity, 478-479, 479/ terminology, 480-48 1 labor, 4 1 1 -4 1 2, 4 1 1/ terminology, 480-48 1

Uterine distention, spontaneous preterm labor, 809 Uterine dysfunction, 442, 447 dystocia, 443 fundal dominance, 442 historical, 44 1 hypertonic uterine, 442 hypotonic uterine, 442 incoordinate, 442 risks, labor disorders, 44 Uterine flexion, 46 anteflexion, 46 retroflexion, 46 rotation to maternal right, pregnancy, 46 sacculation, 46, 46/ Uterine infection, postpartum, 667-670 complications, 670 microbiology, 667-668, 66 t pathogenesis and clinical course, 668 perioperative prophylaxis, 669-670 predisposing factors, 667 treatment, 668-669, 669t Uterine inversion, 76 1 -763 causes, 758 degrees of, progressive, 76 1 , 76 1f, 76/ incidence, 76 1 recognition and management, 76 1 -762, 762/ surgical intervention, 762- 63, 763/ Uterine leiomyomas, 1 1 9 5-1 1 97, 1 1 96f, 1 1 97/ Uterine monitoring, ambulatY, preterm birth, 8 14 Uterine ruptute, 765-767 with cesarean delivery, prior, 593, 594t dystocia, 453, 4 54-4 5 5 management a n d outcomes, 767 pathogenesis, 766-767, 767/ predisposing factors, 765-766, 766t traumatic, 929 Uterine scar exploration, after vaginal birth after cesarean, 598 Uterine scar rupture, 598-600, 598/ Uterine segments, labor, 4 1 2-4 1 3, 4 1 2/ Uterine souHe, 1 65 Uterine spiral arteries, 725 Uterine stretch, fetus in, 4 1 0 Uterine tears with hysterectomy, dystocia, 454 U teroovarian ligament, 24f, 28 Uteroplacental apoplexy, 77 1 , 772/ U teroplacental blood flow, 50-5 1 fundamentals, 50 preeclampsia, 724-725 regulation, 50-5 1 Uteroplacental insuiciency, fetal heart rate, 465 Uterosacral ligaments, 24, 24f, 2 5 , 2 5/ Uterotonins. See also speciic ypes chorion, 40 1 , 40 1/ degradation, parturition, 407 for labor, third-stage, 5 26-527 ergonovine and methylergonovine, 527 misoprostol, 52 oxytocin, high-dose, 5 27 parturition, phase 3, 4 1 6-4 1 angiotensin II, 4 1 7 endothelin- l , 4 1 7 oxytocin, 4 1 6 prostaglandins, 4 1 6-4 1 7, 4 1 7/ Uterovaginal plexus, 27f, 28

Uterus, 23-24, 23/ arcuate, 44f, 45 bicornuate, 44f, 45 cervix, 23-24, 2/ endometrium, 24, 24/ fundal height fetal-growth restriction, 852 prenatal , 1 64- 1 65 incision, for cesarean delivery, 574-575, 5 4/ myometrium, 24, 24/ in labor, 400-40 1 physiology, maternal, 49-50 contractility, 50 myocyte arrangement, 50 pregnancy, 400-40 1 shape and position, 50 uterine, 5 0 puerperium, 652-654 afterpains, 654 cervix, 653, 653/ decidua and endometrial regeneration, 653-654 fundamentals, 652-653 lochia, 654 sonographic findings, 653, 653/ repair, after cesarean delivery, 577, 577/ septate, 44, 45 uniconuate, 44

v Vaccines, maternal hepatitis A, 1 063 human papilloma virus, 1 245 inluenza virus, 1 2 1 4 measles, mumps, rubella, 1 2 1 4, 1 2 1 5- 1 2 1 6 pneumococcal, 993-994 preconceprual, 1 49 prenatal, 1 7 1 - 1 4, I 72t- 1 73t puerperium, 662 varicella-zoster, 1 2 1 3 Vaccines, newborn, hepatitis B , 6 1 4 , 1 065 VACTERL, esophageal fistula, 207 Vacuum aspiration, 359-360, 360/ Vacuum-assisted closure (VAC), 670-67 1 Vacuum extraction, 562-564 technique, 563-564, 563, 563t vacuum extractor design, 562-563, 562f, 563t Vacuum extractor, 562-563, 562f, 563t Vagina, 1 8- 1 9 , 1 8/ Vagina, maternal, 5 2-53 acidic p H and LactobacilLus aCidophilus, 52 Chadwick sign, 52 examination, labor diagnosis, 426, 427/ microbiota, 1 24 5 spontaneous preterm labor, 8 1 1 Mullerian abnormalities, 42 Vaginal birth after cesarean (VBAC), 5 9 1 -592, 592t. See also Delivery, cesarean, prior 20 1 8 , 600, 600f, 600t multifetal pregnancy, 890 Vaginal cancer, 1 200 Vaginal cerclage, 3 5 5-3 56, 3 5 5, 356/ Vaginal delivery, 5 1 6-533. See also Delivery, vaginal Vaginal intraepithelial neoplasia (VAlN), 1 200 Vaginal spotting, ectopic pregnancy, 372 Vaginitis, 1 245-1 247 bacterial vaginosis, 1 245- 1 246, 1 246/ candidiasis, 1 247 trichomoniasis, 1 246- 1 247

I nd ex Valacyclovir, for herpes simplex virus, 1 243, 1 244t Valerian, teratogenicity, 248t Valproic acid, teratogenicity, 240, 1 1 60t Valve replacement, before pregnancy, 954, 954t Valvular heart disease, 955-958 aortic insuiciency, 956t, 958 aortic stenosis, 956t, 957-958 mitral insuiciency, 956t, 957 mitral stenosis, 955-957, 956t management, 956-95 , 956/ pathophysiology, 955-957 pregnancy outcomes, 956 mitral valve prolapse, 957 pulmonic stenosis, 956t, 958 Vandal root, teratogenicity, 248t Varicella pneumonia, 994 Varicella-zoster immune globulin (VZIG ) , 1 2 1 3 Varicella-zoster virus infection, 1 2 1 2- 1 2 1 3, 1 2 1 3/ Varicella-zoster virus vaccine, 1 2 1 3 Varicosities, i n pregnancy, 1 75 Varivax, 1 2 1 3 Vasa previa, 1 1 8- 1 1 9, 1 1 9/ Vascular changes, maternal, 53-54 palmar erythema, 54 vascular spiders, 53-54 Vascular endothelial growth factor (VEGF) decidual natural killer cells, 9 1 endometrial cycle, 84 endometrial invasion, 9 1 luteal phase, 83 retinopathy of prematurity, 639 Vascular resistance, maternal m ultifetal pregnancies, 87 1 testing, preeclampsia, 725-726, 725t Vascular spiders, 53-54 Vasculitis syndromes, 1 1 49- 1 1 50 Beh:et disease, 1 1 50 Churg-Strauss vasculitis, 1 1 50 granulomatosis with polyangiitis, 1 1 50 Henoch-Schonlein purpura, 1 1 50 polyarteritis nodosa, 1 1 49 Takayasu arteritis, 1 1 50 Vasectomy, 706, 706/ Vasodilators, for chronic hypertension, 9 8 1 Vasogenic edema, 723 Vasopressin for esophageal varices, 1 068 fetal, 1 36 maternal amnion epithelial cells, 96 preeclampsia, 7 1 9 Vasospasm, hypertensive disorders, 7 1 5-7 1 6 Vedolizumab, for Crohn disease, 1 0 5 1 Vegetarian diet, preconceptual care, 1 52 Veins, pelvic, 26 Velamentous cord insertion, 1 1 8, 1 1 8/ Velocardiofacial syndrome, 26 1 t Vena caval filters, for pulmonary embolism,

1018 Venolymphatic formation, ex-utero intrapartum treatment for, 327, 32 f Venous thromboembolism (VTE). See also hromboembolic disorders; speciic ypes cancer surgery risk, 1 1 9 1 Hodgkin lymphoma, 1 202 incidence, 1 004, 1 005- 1 006 oral contraceptives, 69 1 -692 risk factors, 1 004- 1 005, 1 005t

Ventilation-perfusion scintigraphy, for pulmonaty embolism, 1 0 1 8

Vento use, 562-563, 562, 563t Ventricular function pregnancy, 6 1f, 949 pregnancy-related hypertension, 7 1 8, 7 1 8/ Ventricular performance, 60, 6 1/ v entricular remodeling, in pregnancy, 949 Ventricular septal defects (VS Ds) , 958-959 echocardiography, 202f, 203 Ventricular shunts, maternal, 1 1 68 Ventricular tachycardia, 967 Ventriculofugal system, 64 1 Ventriculomegaly, fetal magnetic resonance imaging, 2 1 7-2 1 8 myelomeningocele, 1 93, 3 1 9 sonography, 1 9 1f, 1 93-1 94, 1 94/ chorioid plexus, 1 93 spina bifida, 1 93 Ventriculopedal system, 64 1 Verapamil, for chronic hypertension in pregnancy,

980-9 8 1 Vermian agenesis, 1 93, 1 94- 1 95, 1 95/ inferior, 1 95 Vertex presentation, 422, 422t. See also Delivery, vaginal; speciic ypes left occiput anterior, 423f, 427 left occiput posterior, 423f, 43 1 left occiput transverse, 427, 430/ right occiput anterior, 423f, 427 right occiput posterior, 424f, 430f, 43 1 right occiput transverse, 424f, 427 Vertical transmission, 1 209, 1 235. See also speciic

inections H IV, 1 248 Vey low birthweight, 3, 803 Vesical plexus, 27f, 28 Vesicoamnionic shunts, 325-326, 325/ Vesicocentesis, fetal, 325 Vesicoureteral relux, 208, 1 026 Vesicouterine fistula, 1 037- 1 038 Vesicovaginal fistula, 1 037 Vessels. See also speciic vessels fetal, placental growth and maturation, 90f, 93 Vestibular bulb, 1 9, 1 9f, 20 Vestibule, 1 7, 1 7/ Vibroacoustic stimulation, fetal, 470-47 1 Videocapsule endoscopy, 1 042 Villi chorionic, 90, 90f, 389/ placental, branching, 92-93, 92/ Villous trophoblasts, 88, 89/ Villous vascular lesions, fetal, 1 1 5 Viral infections, 1 2 1 0- 1 220. See also speciic ypes coronavirus, 1 2 1 9 cytomegalovirus, 1 2 1 0-1 2 1 2, 1 2 1 1/ Ebola virus, 1 2 1 9 enteroviruses, 1 2 1 6 hantaviruses, 1 2 1 6 influenza virus, 1 2 1 3- 1 2 1 4, 1 2 1 4t measles virus, 1 2 1 4-1 2 1 5 mumps virus, 1 2 1 4 parvovirus, 1 2 1 6- 1 2 1 7, 1 2 1 8/ respiratory viruses, 1 2 1 6 rubella virus, 1 2 1 5-1 2 1 6 from transfusions, 92 varicella-zoster virus, 1 2 1 2- 1 2 1 3, 1 2 1 3/ West Nile virus, 1 2 1 7- 1 2 1 9 zika virus, 1 2 1 9- 1 220, 1 2 1 9/

Virgil. See Didephys virginiana Viscoelastic assays, for hemorrhage, 79 1 , 79 1/ Visfatin, 5 1 , 57 Vision, pregnancy-related hypertension on, 724, 724/ Vital capacity, in p regnancy, 64, 987 Vital statistics, 2-3 Vitamin A fetal, 1 3 9 pregnancy and lactation, 1 6 t, 1 69 for respiratory distress syndrome, preterm newborn, 637 serum and blood testing, 1 258t teratogenicity, 246 Vitamin B6, pregnancy and lactation, 1 67t, 1 69 Vitamin B l l pregnancy and lactation, 1 67t, 1 69 serum and blood testing, 1 258t Vitamin B l 2 deficiency anemia, 1 078 Vitamin C fetal, 1 39 on preeclampsia risk, 727 pregnancy and lactation, 1 67t, 1 69 serum and blood testing, 1 258t Vitamin D fetal, 1 3 9 for hypoparathyroidism, 1 1 29 pregnancy and lactation, 1 67t, 1 69 serum and blood testing, 1 258t Vitamin D-resistant rickets, X-linked inheritance,

266 Vitamin E for periventricular-intraventricular hemorrhage prevention, 640 on preeclampsia risk, 727 serum and blood testing, 1 258t Vitamin K deiciency, from hyperemesis gravidarum, 1 044 newborn, 6 1 4 Vitamins. See also specic vitamins fetal, 1 39 pregnancy and lactation, 1 67t, 1 68-1 69 serum and blood tests, 1 25 8 t Voluntary abortion, 35 . See also Abortion, induced Volvulus, 1 0 5 1 - 1 052, 1 052/ von Hippel-Lindau disease, 1 1 30 von Willebrand disease, 1 090 von Willebrand factor (vWF), 1 088, 1 090 VIQ scan, in pregnancy, 908 Vulva (pudenda), 1 6- 1 7, 1 7/ Bartholin glands, 1 , 1 7/ clitoris, 1 , 1 f labia majora, 1 6, 1 7/ labia minora, 1 6- 1 7, 1 7/ mons pubis, 16, 1 f paraurethral glands, 1 7, 1 7/ Skene glands, 1 , 1 7/ vestibule, 1 7, 1 7/ Vulvar cancer, 1 200 Vulvar intraepithelial neoplasia (YIN), 1 200 Vulvovaginal candidiasis, treatment, in pregnancy, 24 1 Vulvovaginal lacerations, 763 W WAGR syndrome, 2 6 1 t Wandering baseline, 4 6 1 Warfarin embryopathy, 247, 247/ postpartum venous thrombosis, 1 0 1 4-1 0 1 5 teratogenicity, 247, 247f, 954, 1 0 1 4

1 3 27

1 328

I n dex Water birth, 5 24 Water intoxication, from oxytocin, 5 1 0 Water metabolism, 54-55, 5 5/ Watershed area, 64 1 Weeks of gestation completed, 1 28, 1 28/ 161 Wegener granulomatosis, 1 1 50 Weigert-Meyer rule, 208, 209/ Weight gain, maternal gestational, nutrition and, in fetal-growth restriction, 849-8 50 with obesity, 94 1 in pregnancy, 54, 54t recommendations, prenatal, 1 65-1 66, 1 66t Weight loss, newborn, 6 1 5 Weight retention after pregnancy, 1 66- 1 67, 1 67/ Wernicke encephalopathy, 1 044 with hyperemesis gravidarum, 1 044 West Nile virus infection, 1 2 1 7- 1 2 1 9 Whey, 657 White classiication, diabetes in pregnancy, 1 098, 1 099t

Whole blood, for hemorrhage, 788- 89, 789t Whole exome sequencing (WES), 272-273 Whole genome sequencing (WGS), 272-273 Williams-Beuren syndrome, 26 1 t Wilson disease, 1 067 Window of implantation, secretory phase of endometrial cycle, 84-85 Wolf-Chaikof efect, 57 Wolf-Parkinson-White (WPW) syndrome, 967 Wolf-Hirschhorn syndrome, 26 1 t Womb, artiicial, 9 Woods corkscrew maneuver, 522, 522/ X Xanthogranulomatous pyelonephritis, 1 029 X-linked ichthyosis estriol level, 284 microdeletions, 26 1 t X-linked inheritance, 264t, 266 y Y-linked inheritance, 266 Yohimbe, teratogenicity, 248t

Yolk sac diameters, 3 5 0 early-pregnancy loss, 3 5 0 sonographic recognition, 1 59, 1 59/ Yuzpe method, 696 Z Zanamivir, 1 2 1 4 Zavanelli maneuver, 523 for partial breech extraction, 548 Zika virus infection, 1 2 1 9- 1 220, 1 2 1 9/ newborn, 6 1 4 Zinc fetal, 1 39 pregnancy and lactation, 1 67t, 1 68 serum and blood testing, 1 258t Zona basalis, decidua, 86 Zona compacta, decidua, 86 Zona functional is, decidua, 86 Zona spongiosa, decidua, 86 Zygosity. See also specic ypes multifetal pregnancies, determining, 867 Zygote, 87-88, 87/ development, 1 25