Cardiac Problems in Pregnancy [4th Edition] 9781119409823

Table of contents :
About the Editor ix

List of Contributors x

Preface xiii

Acknowledgments xiv

Part I Physiologic Changes During Normal Pregnancy and the Puerperium 1

1 Hemodynamic and Cardiac Function 3
Ofer Havakuk and Uri Elkayam

Part II Cardiac Evaluation of the Pregnant Woman 17

2 Cardiovascular Evaluation During Pregnancy 19
Uri Elkayam

3 Cardiovascular Imaging in the Pregnant Patient 32
Patrick Colletti and Uri Elkayam

Part III Cardiac Disorders and Pregnancy 41

4 Risk Assessment Prior and During Pregnancy 43
Samuel C. Siu and Candice K. Silversides

5 Congenital Heart Disease and Pregnancy 60
Candice K. Silversides, Jack M. Colman, and Samuel C. Siu

6 Native Valvular Heart Disease and Pregnancy 75
Uri Elkayam

7 Pregnancy in the Patient with Prosthetic Heart Valves 90
Uri Elkayam

8 Myocarditis and Pregnancy 107
Avraham Shotan and Andrei Keren

9 Pericardial Disorders and Pregnancy 116
Marla A. Mendelson

10 Peripartum Cardiomyopathy 128
Sorel Goland and Uri Elkayam

11 Dilated Cardiomyopathy and Pregnancy 155
Kathleen Stergiopoulos and Fabio V. Lima

12 Hypertrophic Cardiomyopathy and Pregnancy 167
Iris M. van Hagen, Uri Elkayam, Sorel Goland, and Jolien W. Roos-Hesselink

13 Left Ventricular Noncompaction 181
Radha J. Sarma

14 Acute Myocardial Infarction and Pregnancy 201
Uri Elkayam and Ofer Havakuk

15 Cardiac Arrhythmias and Pregnancy 220
Danna Spears and Uri Elkayam

16 Pulmonary Arterial Hypertension and Pregnancy 252
Dianne Zwicke, Sara Paulus, and Vinay Thohan

17 Infective Endocarditis 261
Ramin Ebrahimi, Michael Shenoda, Sheila Sahni, and David Fisk

Part IV Vascular Disease in Pregnancy 275

18 Vascular Dissections and Aneurysms During Pregnancy 277
Afshan B. Hameed

19 Marfan Syndrome and Pregnancy 285
Sorel Goland and Uri Elkayam

20 Non-Marfan Aortopathies and the Pregnant Patient 305
John Bois and Heidi Connolly

21 Takayasu’s Arteritis and Pregnancy 319
Abha Khandelwal

22 Thromboembolic Disease in Pregnancy 326
Courtney C. Bilodeau and Karen Rosene-Montella

23 Amniotic Fluid Embolism and Pregnancy 334
Irene A. Stafford, Steven L. Clark, and Gary A. Dildy

24 Hypertension During Pregnancy 339
Chonyang L. Albert and Leslie Cho

25 Syncope in Pregnancy 349
Paul S. Gibson

Part V Cardiac Surgery and Catheter Based Interventions During Pregnancy 359

26 Cardiac Surgery During Pregnancy 361
Anita Nguyen and Hartzell V. Schaff

27 Catheter-Based Interventions in Women with Heart Disease During Pregnancy 370
Anil Mehra, Gassan Muadi, Pavan Reddy, and Uri Elkayam

28 Analgesia and Anesthesia During Pregnancy, Labor, and Delivery 389
Katherine W. Arendt

29 Cardiopulmonary Resuscitation of Pregnant Women 397
Joan Briller

30 Pregnancy After Cardiac Transplantation 419
Serban Constantinescu, Dawn P. Armenti, Lisa A. Coscia, Lynn R. Punnoose, John M. Davison, and Michael J. Moritz

Part VI Cardiovascular Drug Therapy During Pregnancy 433

31 Pharmacokinetics of Drugs in Pregnancy and Lactation 435
Irving Steinberg

32 Cardiovascular Drugs in Pregnancy and Lactation 456
Petronella G. Pieper, Uri Elkayam, Joy Eskandar, and Titia P.E. Ruys

33 Tocolytic Therapy in the Cardiac Patient 491
Joseph G. Ouzounian

34 Fertility Control in the Cardiac Patient 497
Joan Briller, Mark R. Johnson, and Jolien W. Roos-Hesselink

Part VII Labor and Delivery 513

35 Management of Labor and Delivery in a Cardiac Patient 515
Rohan D’Souza and Mathew Sermer

36 Cardiac Effects of Drugs Used for Induction of Labor and Prevention and Treatment of Postpartum Hemorrhage 530
Mark R. Johnson

Index 537

Citation preview

Cardiac Problems in Pregnancy

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Cardiac Problems in Pregnancy Fourth Edition Edited by

Uri Elkayam MD Department of Medicine, Division of Cardiovascular Medicine and the department of Obstetrics and Gynecology University of Southern California Keck School of Medicine, Los Angeles, California

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This edition first published 2020 © 2020 by John Wiley & Sons [Edition History 3e,1998] All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions. The right of Uri Elkayam to be identified as the author of editorial in this work has been asserted in accordance with law. Registered Office(s) John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial Office 9600 Garsington Road, Oxford, OX4 2DQ, UK For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com. Wiley also publishes its books in a variety of electronic formats and by print-on-demand. Some content that appears in standard print versions of this book may not be available in other formats. Limit of Liability/Disclaimer of Warranty The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting scientific method, diagnosis, or treatment by physicians for any particular patient. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. Library of Congress Cataloging-in-Publication Data Names: Elkayam, Uri, editor. Title: Cardiac problems in pregnancy / edited by Uri Elkayam. Description: Fourth edition. | Hoboken, NJ : Wiley-Blackwell, 2020. | Includes bibliographical references and index. | Identifiers: LCCN 2019015645 (print) | LCCN 2019016617 (ebook) | ISBN 9781119409830 (Adobe PDF) | ISBN 9781119409823 (ePub) | ISBN 9781119409793 (hardback) Subjects: | MESH: Pregnancy Complications, Cardiovascular–diagnosis | Pregnancy Complications, Cardiovascular–therapy | Fetal Diseases | Heart Diseases | Pregnancy Classification: LCC RG580.H4 (ebook) | LCC RG580.H4 (print) | NLM WQ 244 | DDC 618.3–dc23 LC record available at https://lccn.loc.gov/2019015645 Cover image: © KonstantinChristian/Shutterstock Cover design by Wiley Set in 9/11pt MinionPro by Aptara Inc., New Delhi, India 10 9 8 7 6 5 4 3 2 1

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This book is dedicated to my late parents Dvora and Mordechai Elkayam, who made it all possible. To my wife Batia for her unending love and support. To my children Ifat, Yonatan, and Danielle; my son-in-law Tamir; and my grandchildren Noam, Lior, and Geffen for being in my life.

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Contents

About the Editor ix List of Contributors x Preface xiii Acknowledgments xiv

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15

Part I Physiologic Changes During Normal Pregnancy and the Puerperium 1 1

Hemodynamic and Cardiac Function 3 Ofer Havakuk and Uri Elkayam

Part II Cardiac Evaluation of the Pregnant Woman 17 2

3

4

5

6

7

8

9

16

Pulmonary Arterial Hypertension and Pregnancy 252 Dianne Zwicke, Sara Paulus, and Vinay Thohan

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Infective Endocarditis 261 Ramin Ebrahimi, Michael Shenoda, Sheila Sahni, and David Fisk

Part IV Vascular Disease in Pregnancy

Cardiovascular Evaluation During Pregnancy 19 Uri Elkayam Cardiovascular Imaging in the Pregnant Patient 32 Patrick Colletti and Uri Elkayam

Part III Cardiac Disorders and Pregnancy

Left Ventricular Noncompaction 181 Radha J. Sarma Acute Myocardial Infarction and Pregnancy 201 Uri Elkayam and Ofer Havakuk Cardiac Arrhythmias and Pregnancy 220 Danna Spears and Uri Elkayam

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Risk Assessment Prior and During Pregnancy 43 Samuel C. Siu and Candice K. Silversides Congenital Heart Disease and Pregnancy 60 Candice K. Silversides, Jack M. Colman, and Samuel C. Siu Native Valvular Heart Disease and Pregnancy 75 Uri Elkayam Pregnancy in the Patient with Prosthetic Heart Valves 90 Uri Elkayam Myocarditis and Pregnancy 107 Avraham Shotan and Andrei Keren Pericardial Disorders and Pregnancy 116 Marla A. Mendelson

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Peripartum Cardiomyopathy 128 Sorel Goland and Uri Elkayam

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Dilated Cardiomyopathy and Pregnancy 155 Kathleen Stergiopoulos and Fabio V. Lima

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Hypertrophic Cardiomyopathy and Pregnancy 167 Iris M. van Hagen, Uri Elkayam, Sorel Goland, and Jolien W. Roos-Hesselink

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20

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275

Vascular Dissections and Aneurysms During Pregnancy 277 Afshan B. Hameed Marfan Syndrome and Pregnancy 285 Sorel Goland and Uri Elkayam Non-Marfan Aortopathies and the Pregnant Patient 305 John Bois and Heidi Connolly Takayasu’s Arteritis and Pregnancy 319 Abha Khandelwal Thromboembolic Disease in Pregnancy 326 Courtney C. Bilodeau and Karen Rosene-Montella Amniotic Fluid Embolism and Pregnancy 334 Irene A. Stafford, Steven L. Clark, and Gary A. Dildy Hypertension During Pregnancy 339 Chonyang L. Albert and Leslie Cho Syncope in Pregnancy 349 Paul S. Gibson

Part V Cardiac Surgery and Catheter Based Interventions During Pregnancy 26

Cardiac Surgery During Pregnancy 361 Anita Nguyen and Hartzell V. Schaff

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Catheter-Based Interventions in Women with Heart Disease During Pregnancy 370 Anil Mehra, Gassan Muadi, Pavan Reddy, and Uri Elkayam

359

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28

29

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Contents

Analgesia and Anesthesia During Pregnancy, Labor, and Delivery 389 Katherine W. Arendt Cardiopulmonary Resuscitation of Pregnant Women 397 Joan Briller Pregnancy After Cardiac Transplantation 419 Serban Constantinescu, Dawn P. Armenti, Lisa A. Coscia, Lynn R. Punnoose, John M. Davison, and Michael J. Moritz

Part VI Cardiovascular Drug Therapy During Pregnancy 433 31

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Pharmacokinetics of Drugs in Pregnancy and Lactation 435 Irving Steinberg Cardiovascular Drugs in Pregnancy and Lactation 456 Petronella G. Pieper, Uri Elkayam, Joy Eskandar, and Titia P.E. Ruys

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Tocolytic Therapy in the Cardiac Patient 491 Joseph G. Ouzounian

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Fertility Control in the Cardiac Patient 497 Joan Briller, Mark R. Johnson, and Jolien W. Roos-Hesselink

Part VII Labor and Delivery 35

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513

Management of Labor and Delivery in a Cardiac Patient 515 Rohan D’Souza and Mathew Sermer Cardiac Effects of Drugs Used for Induction of Labor and Prevention and Treatment of Postpartum Hemorrhage 530 Mark R. Johnson

Index

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About the Editor

Uri Elkayam, MD is currently a Professor of Medicine (Cardiology) and a Professor of Obstetrics and Gynecology and director of maternal cardiology at the University of Southern California (USC) in Los Angeles, California. He has served in the past as both the Chief of the Cardiovascular Division and Director of the Heart Failure Program. Soon after his arrival at USC in 1981 professor Elkayam inherited a busy clinic of pregnant women with heart disease at the Women and Children Hospital from Dr. Frank Lau the former chief of cardiology at the Los Angeles County/USC hospital. At the same time, he pioneered one of the first academic, multidisciplinary program of Maternal Cardiology at the United States, which he continues to direct to these days. Professor Elkayam publications have included over 230 peer review articles and over 80 book chapters, the major-

ity of them in the areas of heart failure and heart disease in pregnancy. His original publications and many state-ofthe-art reviews have included a broad spectrum of topics related to the approach to pregnancy in women with a wide range of cardiac conditions. He co-edited three editions of the books “Principle and Practice of Medical Therapy in Pregnancy” and the first three editions of this book with Professor Norbert Gleicher. In addition, almost four decades, he has been extensively involved in educating health-care professionals on management of pregnancyrelated cardiac disease both nationally and internationally. In 2009, Professor Elkayam founded in collaboration with Professor Avraham Shoran, the biennial International Congress on Cardiac Problems in Pregnancy (PCC), which he has directed since.

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List of Contributors

Chonyang L. Albert

Jack M. Colman

Robert and Suzanne Tomsich Department of Cardiovascular Medicine, Sydell and Arnold Miller Heart & Vascular Institute, Cleveland Clinic, Cleveland, OH, USA

Division of Cardiology, University of Toronto Pregnancy and Heart Disease Research Program, Mount Sinai Hospital/Sinai Health System, and Toronto General Hospital/University Health Network, Toronto, Ontario, Canada

Katherine W. Arendt Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA

Dawn P. Armenti Transplant Pregnancy Registry International (TPR), Gift of Life Institute, Philadelphia, PA, USA

Courtney C. Bilodeau Department of Obstetric Medicine, Women’s Medicine Collaborative, Miriam Hospital, Providence, RI, USA Department of Medicine, Brown University, Warren Alpert Medical School, Providence, RI, USA

John Bois Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA

Joan Briller Division of Cardiology, University of Illinois at Chicago, Chicago, IL, USA

Leslie Cho Preventative Cardiology and Rehabilitation, Robert and Suzanne Tomsich Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, USA

Steven L. Clark Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Baylor College of Medicine, Houston, TX, USA

Patrick Colletti Department of Radiology, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA

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Heidi Connolly Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA

Serban Constantinescu Transplant Pregnancy Registry International (TPR), Gift of Life Institute, Philadelphia, PA, USA Department of Medicine, Temple University, Lewis Kate School of Medicine, Philadelphia PA, USA

Lisa A. Coscia Transplant Pregnancy Registry International (TPR), Gift of Life Institute, Philadelphia, PA, USA

John M. Davison Department of Obstetric Medicine and Consultant Obstetrician, Institute of Cellular Medicine, Newcastle University Medical School, Newcastle upon Tyne, UK

Gary A. Dildy Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Baylor College of Medicine, Houston, TX, USA

Rohan D’Souza Department of Obstetrics & Gynaecology, Division of Maternal and Fetal Medicine, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada

Ramin Ebrahimi Department of Medicine, University of California, Los Angeles, CA, USA Department of Cardiology, Veteran Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA

List of Contributors

Uri Elkayam

Abha Khandelwal

Department of Medicine, Division of Cardiovascular Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA Department of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA

Cardiovascular Medicine, Stanford University, Stanford, CA, USA

Joy Eskandar Department of Medicine, Division of Cardiovascular Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA Department of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA

David Fisk Department of Infectious Diseases, Sansum Clinic, Santa Barbara, CA, USA

Paul S. Gibson Medicine and Obstetrics & Gynecology, University of Calgary, Calgary, Alberta, Canada

Sorel Goland The Heart Institute, Kaplan Medical Center, Rehovot, Israel Hebrew University and Hadassah Medical School, Jerusalem, Israel

Afshan B. Hameed Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of California, Irvine, CA, USA Department of Medicine, Division of Cardiology, University of California, Irvine, CA, USA

Ofer Havakuk Department of Medicine, Division of Cardiovascular Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA Department of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA Department of Cardiology, Tel Aviv Medical Center, Tel Aviv University, Sackler School of Medicine, Tel Aviv, Israel

Mark R. Johnson Institute of Reproduction and Developmental Biology, Surgery and Cancer, Imperial College London, Chelsea and Westminster Hospital, London, UK Academic Department of Obstetrics and Gynecology, Imperial College London, Chelsea and Westminster Hospital, London, UK

Andrei Keren Hadassah-Hebrew University Hospital, Jerusalem, Israel

Fabio V. Lima Cardiovascular Institute, Warren Alpert Medical School of Brown University, Providence, RI, USA

Anil Mehra Department of Medicine, Division of Cardiovascular Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA

Marla A. Mendelson Department of Medicine, Division of Cardiology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA

Michael J. Moritz Transplant Pregnancy Registry International (TPR), Gift of Life Institute, Philadelphia, PA, USA Department of Surgery, Lehigh Valley Health Network, Allentown, PA, USA University of South Florida Morsani College of Medicine, Tampa, FL, USA

Gassan Muadi Department of Medicine, Division of Cardiovascular Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA

Anita Nguyen Department of Cardiovascular Surgery, Mayo Clinic, Rochester, MN, USA

Joseph G. Ouzounian Department of Obstetrics & Gynecology, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA

Sara Paulus Department of Cardiovascular Diseases: Pulmonary Hypertension/Heart Failure Circulatory Supports Aurora St. Luke’s Medical Center, University of Wisconsin School of Medicine and Public Health, Milwaukee, Wisconsin, USA

Petronella G. Pieper Department of Cardiology, University hospital Groningen, Groningen, The Netherlands

Lynn R. Punnoose Department of Medicine, Temple University, Lewis Kate School of Medicine, Philadelphia, PA, USA

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List of Contributors

Pavan Reddy

Candice K. Silversides

Department of Medicine, Division of Cardiovascular Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA

Division of Cardiology, University of Toronto Pregnancy and Heart Disease Research Program, Mount Sinai Hospital/Sinai Health System, and Toronto General Hospital/University Health Network, Toronto, Ontario, Canada Department of Obstetrics & Gynaecology, Division of Maternal-Fetal Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

Jolien W. Roos-Hesselink Department of Cardiology, Erasmus University Medical Center, Rotterdam, The Netherlands

Samuel C. Siu Karen Rosene-Montella Department of Medicine, Brown University, Warren Alpert Medical School, Providence, RI, USA

Department of Medicine, Divisions of Cardiology, University of Western Ontario, Schulich School of Medicine & Dentistry, London, Canada

Danna Spears Titia P.E. Ruys Department of Cardiology, Erasmus medical center, Rotterdam, The Netherlands

Sheila Sahni Department of Medicine, University of California, Los Angeles, CA, USA Department of Cardiology, Veteran Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA

Department of Medicine, Division of Cardiology, University of Toronto, University Health Network, Toronto General Hospital, Toronto, Canada Department of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA

Irene A. Stafford department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Baylor College of Medicine, Houston, TX, USA

Radha J. Sarma

Irving Steinberg

Department of Internal Medicine, Western University of Health Sciences, Pomona, CA, USA

Department of Pediatrics, Division of Pediatric Pharmacotherapy, University of Southern California, School of Pharmacy and Keck School of Medicine, Los Angeles County + USC Medical Center, Clinical Pharmacy and Pediatrics, Los Angeles, CA, USA

Hartzell V. Schaff Department of Cardiovascular Surgery, Mayo Clinic, Rochester, MN, USA

Mathew Sermer Department of Obstetrics & Gynaecology, Division of Maternal and Fetal Medicine, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada

Michael Shenoda Department of Cardiology, Sansum Clinic, Santa Barbara, CA, USA

Avraham Shotan Hillel Yaffe Medical Center, Hadera, Israel Rappaport Medical School, Technion, Haifa, Israel

Kathleen Stergiopoulos Department of Medicine, Division of Cardiovascular Medicine, State University of New York, Stony Brook University Medical Center, Stony Brook, NY, USA

Vinay Thohan Department of Cardiovascular Diseases: Pulmonary Hypertension/Heart Failure Circulatory Supports Aurora St. Luke’s Medical Center, University of Wisconsin School of Medicine and Public Health, Milwaukee, Wisconsin, USA

Iris M. van Hagen Department of Cardiology, Erasmus University Medical Center, Rotterdam, The Netherlands

Dianne Zwicke Department of Cardiovascular Diseases: Pulmonary Hypertension/Heart Failure Circulatory Supports Aurora St. Luke’s Medical Center, University of Wisconsin School of Medicine and Public Health, Milwaukee, Wisconsin, USA

Preface

It has been estimated that approximately 2% of pregnant women have heart disease. This number is rising due to an increased number of women with congenital heart conditions who survive to child bearing age, as well as an increased prevalence of pregnancy at older maternal age associated with higher rate of comorbidities including obesity, hypertension, preeclampsia and diabetes. Maternal mortality has been improving worldwide, though it is still unacceptably high in some developing and developed countries alike. In the United States, for example, mortality has been persistently rising, and cardiovascular disease remains the leading cause of both maternal morbidity and mortality, having a significant effect on fetal outcomes as well. In many cases, these adverse outcomes are potentially preventable. The management of heart disease in pregnancy is challenging, and successful outcomes require interdisciplinary expertise in multiple areas including, but not limited to, cardiology, maternal fetal medicine, anesthesia, cardiac surgery, and neonatology. This is the fourth edition of a book dedicated to the field of heart disease in pregnancy, a feat that started almost 40 years ago with the publication of the first edition in 1982. As with the previous editions of this reference book, this edition attempts to provide a comprehensive summary of available information as well as provide practical recommendations based on the ever-expanding literature and growing personal experience of international experts in the diagnosis

and management of cardiac disease in pregnancy. The book includes 36 chapters that cover a wide spectrum of cardiovascular conditions. Chapters included in the previous edition were updated and expanded to include additional information published during the last two decades. New chapters in this edition include risk assessment prior and during pregnancy, dilated cardiomyopathy, left ventricular noncompaction, non-Marfan aortopathies, syncope, catheter-based interventions during pregnancy, management of labor and delivery in the cardiac patient, and cardiac effects of drugs used for induction of labor and management of postpartum hemorrhage. The chapters in the book have been prepared by cardiologists, obstetricians, internists, surgeons, anesthesiologists, nuclear medicine specialists, and pharmacists, all led by clinician-academicians with long-standing interest, remarkable clinical experience, and significant contribution to the contemporary literature related to cardiac problems in pregnancy. It is my hope that this new edition will contribute to the management of pregnant women with heart disease and their fetuses all over the world and ultimately improve the narrative of care for this challenging patient’s population. Uri Elkayam, MD Los Angeles, California 2019

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Acknowledgments

I would like to pay special thankfulness to all 55 authors and coauthors who contributed their time and expertise to create this extensive book for the benefit of pregnant women with heart disease and their babies around the globe. A very special thanks to my friends and colleagues who have been part of my journey over the last four decades in the attempt to advance the knowledge in the area of heart disease in pregnancy. Professor Norbert Gleicher, my classmate in medical school and my close friend for over five decades who was the coeditor of the first three editions of this book. Professor Frank Lau, the former chief of cardiology at the Los Angeles County Hospital from whom I inherited in 1981 the busiest clinic of pregnant women with heart disease in the United States. Professor Thomas M. Goodwin, the former director of the Maternal Fetal Medicine (MFM) division at the University of Southern California (USC), who

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partnered with me in establishing an excellent clinical and academic multidisciplinary cardio obstetric program at USC. The many MFM faculty, and fellows who have helped me take care of thousands of patients over the years. A special thank goes also to professor Avraham (Avi) Shotan, a friend, research collaborator and a my co-director of the International Congress on Cardiac Problems in Pregnancy (CPP), my friends and colleagues Professor Enrique Ostrzega and Professor Anil Mehra for their clinical wisdom, the late professor Arie Roth, Professor Afshan Hameed, Professor Sorel Goland, Dr. Sawan Jalnapurkar, and Dr. Ofer Havakuk for their invaluable help and contribution to our research program and Professor Dennis McNamara for his ongoing leadership of our investigations of pregnancy-associated cardiomyopathy (IPAC) program.

PART I

Physiologic Changes During Normal Pregnancy and the Puerperium

1

2

CHAP T E R 1

Hemodynamics and Cardiac Function Ofer Havakuk1,2,3 and Uri Elkayam1,2 1 Department

of Medicine, Division of Cardiovascular Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA

2 Department

of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA

3 Department

of Cardiology, Tel Aviv Medical Center, Tel Aviv University, Sackler School of Medicine, Tel Aviv, Israel

Introduction Pregnancy is associated with marked physiologic changes that require adaptation of the cardiovascular (CV) system. These changes result in a substantial increase in circulatory burden that can unmask previously unrecognized cardiac disorders, lead to a rapid deterioration of heart disease and result in a significant maternal morbidity or even mortality along with important effects on fetal outcome. A comprehensive understanding of cardiocirculatory adaptation during pregnancy and the early postpartum (PP) period is critically important for the management of pregnant patients with CV disease.

Cardiovascular effects of pregnancy-related hormonal changes To better understand the complex hemodynamic changes associated with pregnancy, the cardiac effect of pregnancyrelated hormonal changes needs to be described. Estrogen and progesterone Early pregnancy is characterized by an increase in the levels of estrogen and progesterone. The CV effect of estrogen is complex; laboratory models have demonstrated that estrogen induces nephron sodium resorption [1] and increases the levels of angiotensin (ANG) II [2]. At the same time, however, estrogen was also shown to activate type 2 ANG II receptors [3] and can increase the levels of nitric oxide (NO) through the stimulation of NO synthase [4] with consequent vasodilation. Progesterone was reported to block the sodiumretaining effect of aldosterone [5] and was found to induce a direct natriuretic effect on the kidneys [6]. In a laboratory rat model [7], progesterone ameliorated the hypertensive effect of norepinephrine in the intact animals and blunted the vasoconstrictive effect of vasopressin and calcium channel current in isolated vascular smooth muscle cells, suggesting that its vasodilatory effect might be through a decrease in intracellular calcium content [7]. Altogether, estrogen probably has

a neutral effect on blood pressure (BP), while progesterone induces significant vasodilation. Relaxin A peptide hormone mainly secreted by the female reproductive system [8]. Although originally named after its ability to induce pelvis, uterine, and cervix relaxation prior to delivery [9], relaxin was found to induce significant CV changes. Compared with levels of 10 pg/ml found in men and postmenopausal women, relaxin levels peak to 900 pg/ml in early pregnancy [10]. Relaxin exerts its CV effects mostly through the relaxin-family peptide receptor type 1, an abundant receptor found not only in the reproductive system but also in the heart, lungs, kidneys, and the brain [11]. Studies in nonpregnant animals have shown that intravenous administration of relaxin reduced BP and systemic vascular resistance (SVR) and also increased cardiac output (CO) [12,13]. Similarly, pregnancy-related CO increase was blunted in animals exposed to relaxin-neutralizing antibodies [14]. A laboratory model of resected human arteries showed a significant endothelium-dependent vasodilating effect of relaxin [15]. Other studies demonstrated that relaxin-induced vasodilation was NO-dependent [16], and also, that relaxin stimulated the expression of endothelial (but not vascular smooth muscle) endothelin type B receptors, with consequent increase in endothelin clearance and endothelial release of NO, leading to increased vasodilation [17]. Additionally, the administration of relaxin has been shown to induce an increase in renal blood flow and glomerular filtration rate in nonpregnant rats [18], whereas relaxin-neutralizing antibodies prevented renal vasodilation and pregnancy-related glomerular filtration rate increase in pregnant rats [19]. Natriuretic peptides These peptides are known to induce vasodilation and natriuresis, blunt the effect of catecholamines, and prevent cardiac remodeling [20]. Levels of B-type natriuretic peptide (BNP)

Cardiac Problems in Pregnancy, Fourth Edition. Edited by Uri Elkayam. © 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.

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PART I Physiologic Changes During Normal Pregnancy and the Puerperium

and NT-proBNP have been shown to be significantly elevated during normal pregnancy, although their levels remained within normal range throughout gestation [21–23]. In a longitudinal study, BNP levels were measured in each trimester and four to six weeks postpartum in 29 women and in 25 healthy matched controls [24]. Overall, median BNP levels were 10 pg/ml in the control group and 19 pg/ml in the pregnancy group (p = 0.003). However, no statistically significant difference was found between median BNP levels in the first (20 pg/ml), second (18 pg/ml), and third (26 pg/ml) trimesters or four to six weeks postpartum (18 pg/ml). Notably, BNP levels as high as 143 pg/ml were measured in some women during the third trimester of normal pregnancy [24]. Similar mild but significant increase in NT-proBNP levels were found by Franz et al. during the first two trimesters in 94 normal pregnant women [22]. Lev-Sagie et al. [23] measured N-terminal proBNP in 88 healthy pregnant women and showed doubling of the levels within 28 hours postpartum compared with predelivery levels (165 ± 102 pg/ml vs. 81 ± 32 pg/ml, p < 0.001). This increased level of natriuretic peptides in the early postpartum period is probably related to the increased venous return to the heart and results in increased diuresis after the delivery.

However, in 2001, Greenwood et al. compared normotensive, nonpregnant women with age and race matched women at 35-week gestation with either normal pregnancies or pregnancy-induced hypertension (PIH) [34]. The study showed a statistically significant elevation of sympathetic activity and impaired baroreflex sensitivity in normal pregnancy compared with nonpregnant state, (albeit to a lesser degree compared with PIH), which returned to nonpregnancy values after the delivery. Similar results were reported by Jarvis et al. [35] who found an increased sympathetic tone as early as six-week gestation compared with prepregnancy state, despite reduced diastolic BP and vascular resistance. This change in sympathetic activity was accompanied by elevated levels of noradrenaline and renin [35]. The mechanism for increased sympathetic tone in early pregnancy is not completely clear and is probably multifactorial. Studies have suggested that elevated levels of estrogen [36], ANG II [37], and aldosterone [38] might stimulate the sympathetic system. Another explanation for the elevated sympathetic tone during pregnancy is probably related to a compensatory mechanism to the pregnancy-related peripheral vasodilation [35].

Renin–angiotensin–aldosterone system Compared with nonpregnancy state, higher levels of angiotensinogen (AT), ANG II, renin, and plasma renin substrate have been demonstrated in normal pregnancy [25]. Both AT and ANG II levels were reported to rise progressively throughout pregnancy. Plasma prorenin levels peak during the first trimester whereas active renin levels increase during the second trimester, and angiotensin converting enzyme levels remain stable throughout pregnancy [26,27]. Notably, aldosterone levels are increased beyond those expected by renin and ANG II levels, resulting in an increased aldosterone: renin ratio in pregnancy [28,29]. A possible cause for this finding could be the effect of placenta-originated elevated levels of vascular endothelial growth factor (VEGF) on aldosterone production. In a laboratory model, Gennari-Moser et al. demonstrated that VEGF directly increased the production of aldosterone from adrenocortical cells and, in addition, synergistically increased the effect of ANG II-mediated aldosterone synthesis [30]. The vasoactive effect of angiotensin II is not straightforward; it can bind to both ANG II type 1 receptors (with consequent vasoconstriction) and to ANG II type 2 receptors (with consequent vasodilation). In pregnancy, the density and the response of ANG II receptors change, with a propensity toward higher activity of the vasodilating angiotensin II type 2 receptors [31,32]. High levels of ANG II play a role in maintaining blood volume, BP, and uroplacental blood flow by the interaction with the ANG type I and II receptors [27].

Hemodynamic changes during pregnancy

The sympathetic system Sympathetic hyperreactivity was originally thought to occur only in pregnancy-related hypertensive disorders [33].

Blood volume An increase in blood volume of 34–70% (50% average) compared with nonpregnancy levels is seen by the third trimester of normal pregnancy, and plasma volume ranging from 3200 to 4280 ml/m2 (depending on parity) is found in a normal singleton pregnancy [39,40]. The rise in volume starts as early as in the fourth gestational week, it is increased 10– 15% by the 6–12 weeks with continuous rises until parturition (Figure 1.1). The mechanism leading to hypervolemia in pregnancy seems to be multifactorial (Table 1.1). Both estradiol and progesterone have been found to have important effects on body water primarily by increasing renal sodium and water retention [42]. Increase of aldosterone production mediated by progesterone, ANG II, and plasma originated VEGF results in increased sodium reabsorption [27]. The threshold for vasopressin secretion decreases in pregnancy due to a reset of osmoregulation. In addition, the threshold of thirst was also found to be reset at a lower plasma osmolality level facilitating water retention [43]. The peripheral arterial dilatation with relative under filling of the arterial circulation has been suggested to lead to stimulation of the renin–ANG–aldosterone axis and contribute to the sodium and water retention [44]. Ohara et al. have also shown an up-regulation of the collecting duct aquaporin 2 channels in pregnant rats, which play a pivotal role in renal water regulation and may contribute to water retention in pregnancy [45]. Red blood cell mass increases by 33% during normal pregnancy and constitutes a significant proportion of blood volume expansion [46,47]. The mechanism for red blood cell mass increase is complex; erythropoietin concentration

CHAPTER 1 Hemodynamics and Cardiac Function

+50

5

Plasma volume

Percent change from pre pregnant value

+40

+30

Erythrocyte volume (iron supplements)

+20

Erythrocyte volume (no iron supplements)

+10

0 Hematocrit (iron supplements)

–10

Hematocrit (no iron supplements) –20

4

8

12

16

20

24

28

32

36

40

Duration of pregnancy (weeks) Figure 1.1 Changes in plasma volume, erythrocyte volume, and hematocrit during pregnancy. Increase in plasma volume is more rapid than the increase in erythrocyte volume, causing the “physiological anemia of pregnancy.” Source: Pitkin 1976 [41]. Reproduced with permission of Wolters Kluwer Health, Inc.

in the plasma and urine of pregnant women increases only slightly during early pregnancy, and it peaks around mid-pregnancy and decreases thereafter [48]. This pattern contrasts the continued increase in red blood cell mass throughout pregnancy. Jepson reported that higher degree of erythropoietin activity was measured in blood vessels draining the gravid uterus compared with peripheral blood, indicating that a certain factor (now recognized as human placental lactogen) increases erythropoietin activity during

Table 1.1 Potential mechanisms of pregnancy-induced increased blood volume Increased sodium and water retention due to: Increased levels of estrogen and progesterone Increased aldosterone production stimulated by progesterone, angiotensin II, and plasma originated VEGF Decreased threshold for vasopressin secretion due to reset of osmoregulation Reset of threshold for thirst at lower plasma osmolality level Stimulation of renin–angiotensin–aldosterone axis due to peripheral vasodilation Up-regulation of collecting duct aquaporin 2 water channels Increased red blood cell mass due to: A mild increase in plasma erythropoietin levels Augmentation of erythropoietin activity by increased levels of human placental lactogen and prolactin Counteraction of the negative effect of estrogen on erythropoietin production and activity by increased levels of progesterone Increased iron absorption and utilization

q q q q q

pregnancy [49]. A second potential explanation may be related to the elevated levels of progesterone during pregnancy and the peripartum period, which neutralizes the negative effect of estrogen on production and activity of erythropoietin [49]. It should be also noted that prolactin, a hormone biologically similar to human placenta lactogen, also enhances, synergistically, the effect of endogenous erythropoietin during lactation. The larger increase in plasma volume during pregnancy compared to that of red blood cell mass results in the “physiologic pregnancy-related anemia” found in most pregnant women. Meta-analysis of collected data showed a decrease in hematocrit from prepregnancy value of 39 ± 2.5% to 37 ± 3% at 17 weeks, 36 ± 6% at 27 weeks, and 34 ± 3% at 39 weeks’ gestation [40]. Importantly and paradoxically, the physiologic anemia of pregnancy occurs concomitantly with an increasing need of the developing fetus for oxygen. As a compensatory mechanism, increased levels of erythrocyte 2,3-diphosphoglycerate are found in pregnant women and contribute to an increased dissociation of oxygen from the mother’s hemoglobin and elevated levels of oxygen delivered to the fetus [50].

q q q q q

Cardiac output Bader et al. in 1955 used right heart catheterization with Fick method to show an increase in CO reaching its peak by the end of the second trimester and decreasing thereafter toward prepregnancy values by the end of the third trimester (Table 1.2, Figure 1.2) [52]. This study, however, was not longitudinal and was done in five different groups of women at different phases of pregnancy (none prior to

6

PART I Physiologic Changes During Normal Pregnancy and the Puerperium

Table 1.2 Circulatory changes during normal pregnancy Changes at various times (wk) Parameters

5

12

20

24

32

38

Heart rate

↑

↑↑↑

↑↑↑

↑↑↑↑

↑↑↑↑

↑↑↑↑

Systolic blood pressure

↔

↓

↓

↔

↑

↑↑

Diastolic blood pressure

↔

↓

↓↓

↓

↔

↓↓

Stroke volume

↑

↑↑↑↑↑

↑↑↑↑↑↑

↑↑↑↑↑↑

↑↑↑↑↑

↑↑↑↑↑

Cardiac output

↑↑

↑↑↑↑↑↑

↑↑↑↑↑↑↑

↑↑↑↑↑↑↑

↑↑↑↑↑↑↑

↑↑↑↑↑↑↑

Systemic vascular resistance

↓↓

↓↓↓↓↓

↓↓↓↓↓↓

↓↓↓↓↓↓

↓↓↓↓↓↓

↓↓↓↓↓

Left ventricular ejection fraction

↑

↑↑

↑↑

↑↑

↑

↑

↑ – ≤5%; ↑↑ – 6–10%; ↑↑↑ – 11–15%; ↑↑↑↑ – 16–20%; ↑↑↑↑↑ – 21–30%; ↑↑↑↑↑↑ – >30%; ↑↑↑↑↑↑↑ – >40%. Source: Based on data by Robson et al. 1989 [51].

14th week gestation due to the concern of fetus exposure to radiation). In 1966, Walters et al. [53] confirmed these findings with serial evaluations of CO using a dye dilution technique in 30 women throughout pregnancy. The introduction of echocardiography, which safely allowed the serial evaluations of pregnant women throughout pregnancy [51,54–58], showed that the start of CO rise in pregnancy was early and occurred by week 5. From the systematic review on CO in pregnancy conducted by van Oppen et al. [59], five studies of genuine longitudinal design could be identified; all reported a rise in CO which occurred early in the first trimester, with further increase in the second trimester. Reported change in CO between the second and third trimester were diverse; one study showed further increase [57], two showed no change [51,60], and the last two demonstrated a decrease [61,62].

Conclusions regarding the total increase in CO during pregnancy can be best derived from the echocardiographic study by Robson et al. [51], who uniquely measured baseline CO before conception and showed 11% increase by fifth gestational weeks, 34–39% at 12 weeks and 50% rise (from 4.88 to 7.34 l/min) at 34 weeks (Figure 1.2). Atkins et al. [62] used impedance cardiography for the serial measurements of CO in a group of eight women from preconception along pregnancy and up to 4–16 months postpartum. The authors did not provide specific CO values; however, a graph showed an initial increase, reaching its peak by 20 weeks and declining thereafter to levels lower than prepregnancy at term. It is possible that these unique results were derived from water and salt accumulation in late stages of pregnancy, which might have affected CO readings with the use of impedance

% change in hemodynamics throughout pregnancy

44

46

48

50

50

48

29

27

27

47

38

25

10 5 5 5

26

30

32

32

29

11

11

11

12

13

17

17

17

12

16

20

24

28

32

36

38

17 7 8

Gestational week Heart rate

Stroke volume

Cardiac output

Figure 1.2 Percent changes of heart rate, stroke volume, and cardiac output measured in the lateral position throughout pregnancy compared to prepregnancy values. Source: Based on data by Robson et al. 1989 [51].

CHAPTER 1 Hemodynamics and Cardiac Function

Fetus

7

Placenta

Inferior vena cava

Aorta

Supine

Lateral decubitus Figure 1.3 After about 20 weeks of gestation, vasocaval compression of the inferior vena cava can lead to reduced venous return and thus to decreased cardiac output and blood pressure.

cardiography in this study. A contemporary serial echocardiographic examination of 51 women in each pregnancy trimester and three to six months postpartum showed a 19% higher CO during the first trimester compared to 10 nonpregnant age-matched women, which further increase to 29% and 37% during the second and third trimesters, respectively [63]. The overall increase in CO observed in normal pregnancy is achieved initially through an increase in both heart rate and stroke volume (SV) and a continued increase in heart rate starting at midterm until the end of pregnancy [56,60,63] (Figure 1.2). Recent utilization of magnetic resonance imaging (MRI) for the serial measurements (12–16 weeks, 26–30 weeks, 32– 36 weeks, and 12 weeks postpartum) of CO during pregnancy in a cohort of 23 women [64] confirmed a significant early increase in CO, which reached its peak at 26–30 weeks and remained stable at 32–36 weeks [64]. A study comparing MRI with echocardiography in women in the third trimester and 12 weeks PP showed a similar >50% increase in CO between nonpregnant state and third trimester pregnancy with the use of both modalities [65]. MRI measurements, however, tended to be 10–15% higher for both pregnant and nonpregnant states. Twin pregnancy Robson et al. reported a significantly larger increase in CO during twin compared to singleton pregnancy, mainly because of a larger increase in heart rate [66]. These findings were confirmed by Kametas et al. [67], who performed an echocardiographic study in 119 pregnant women with twin pregnancies at 10–40 weeks gestation and compared the measurements with those obtained from 128 women with singleton pregnancies. Maternal CO was greater in twin pregnancies by 20%. In addition, women with twin pregnancies

had greater left ventricular (LV) dimensions, systolic function, and mass. Effect of maternal posture After about 20-week gestation, maternal posture has a significant effect on CO [68], and changing from a supine to lateral position results in a marked increase in CO due to reduced caval compression (Figure 1.3). A recent MRI study by Rossi et al. [69] demonstrated 35% and 24% positionrelated increase in SV and CO, respectively, in a group of healthy women in their late pregnancy. In spite of this change in CO in the supine position, BP is maintained in most women due to a compensatory rise in SVR. Supine hypotensive syndrome of pregnancy This can be found in up to 15% of term pregnancies and is defined as a decrease in systolic BP of at least 15–30 mmHg in the supine position. Symptoms develop within 3–10 minutes after lying down and usually include weakness, dizziness, nausea, diaphoresis, and even syncope [70] as a result of a 30–40% decrease in CO and BP due to compression of the inferior vena cava (IVC) by the gravid uterus with resultant decrease in venous return to the heart. Maternal and fetal death has been reported in extreme cases [71]. A limited form of the syndrome may be more prevalent and includes asymptomatic CO and BP decrease in supine position, which can deteriorate to the full clinical picture in case of sympathetic blockade (e.g. spinal anesthesia) [72]. Nevertheless, considering the significant compressive effect of the gravid uterus on the IVC, it is surprising that only a relatively small proportion of women demonstrate this syndrome. A possible protective mechanism is the development of collateral venous drainage through the vertebral vessels as was described by Scott and Kerr [73]. Another proposed protective mechanism of an increased baroreflex response and a compensatory increase

8

PART I Physiologic Changes During Normal Pregnancy and the Puerperium

in heart rate was refuted by Lanni et al., who showed that compared with nonaffected third trimester women, those with the syndrome had a higher degree of tachycardia [74]. Systemic vascular resistance A significant decrease in SVR in pregnancy compared with nonpregnant state has been demonstrated in numerous studies using different methodologies. The early invasive study by Bader et al. [52] showed the lowest SVR in the second trimester. Another invasive hemodynamic study reported a significant decrease in SVR in late pregnancy compared to 12-week postpartum [75]. In this study, however, no measurements were made in the first or second trimesters of pregnancy. With the use of echocardiography, Robson et al. showed a gradual fall in SVR starting as early as 5-week gestation (9%) with a maximum decrease of 34% at 20 weeks followed by a plateau between the 20th and 32nd week, and a slight increase from week 32 to term [51]. Despite this late increase, SVR was still lower by 27% compared to the preconception levels. Savu et al. [63] showed close to 20% reduction in SVR during pregnancy compared to both age-matched control and postpartum values, with further decrease of about 30% during the second and third trimesters. There are multiple mechanisms, which contribute to the fall in SVR during pregnancy (Table 1.3). These include the vasodilatory effect of pregnancy hormones as well as relaxin and natriuretic peptides and an increased resistance to the pressor effect of angiotensin and noradrenalin [76,77]. A number of investigators have also reported enhanced endothelium-dependent flow-mediated vasodilation during gestation [78,79] and an increase in NO production throughout normal pregnancy, which returned to nonpregnant levels by 9–12 weeks PP [80,81]. In addition, increased levels of prostacyclin may lead to direct vasodilation [82]. Poppas et al. [83] showed an increase in arterial compliance and distensibility, beginning in the first trimester of pregnancy. Similarly, Macedo et al. [84] showed a reduction in aortic wave reflection (a measure of aortic stiffness), which reached

Table 1.3 Potential mechanisms for pregnancy-induced systemic vascular resistance reduction

q q q q q q q q

Vasodilatory effect of increasing levels of estrogen, relaxin, natriuretic peptides, and prostacyclin Increased prevalence of estrogen receptors in blood vessels Increased vessel wall relaxation and distensibility through flow mediated, endothelium dependent, vasodilation Increased nitric oxide production throughout pregnancy Increased resistance to the vasoconstrictive effect of angiotensin and noradrenaline Increased arterial compliance The development of a low resistance, high flow uteroplacental circulation Increased mammary vascularity

its nadir in the second trimester. This increased compliance might be due to elevated levels of estrogen and increased prevalence of estrogen receptors in the endothelium and vascular smooth muscle [85]. This assumption is supported by similar vascular changes found both in animal models and in transsexual men exposed to estrogen [86,87]. Additionally, vessel wall histologic changes, including alteration in collagen/elastin ratio, have been reported in pregnancy and might affect arterial compliance and vascular resistance [88,89]. Finally, pregnancy is a proangiogenic state, the growth of the low-resistance, high-flow uteroplacental circulation increases blood supply to the growing uterus and affect SVR. Jaffe and Warsof [90] and Jurkovic et al. [91] have demonstrated that shunting of blood from the systemic circulation to the uteroplacental circulation increased during the first and second trimesters of pregnancy and that diastolic blood flow to the uteroplacental circulation was shown as early as the first few weeks after conception. Coppens et al. [92] further showed that resistance dropped to a higher degree at earlier stages of pregnancy in the blood vessels surrounding the trophoblast, indicating the probable effect of trophoblast implantation on local vascular resistance. The marked increase in vascularity to the mammary vascular bed may also play a role in the overall reduction in SVR. Blood pressure Despite different methods and devices used for BP measurement in different studies which could have produced dissimilarities in the data collected, pregnancy-induced BP drop was reported in most studies and is probably the consequence of a higher degree of SVR reduction compared with the degree of CO increase in pregnancy [93–96]. The decrease in BP is most significant in the initial few weeks after conception [93,97], and accordingly, might be missed if the patients are first evaluated at a later stage of pregnancy. This decrease in BP is mostly driven by a drop in diastolic BP and, to a lesser degree, by a reduction in systolic BP, leading to an increase in pulse pressure [98]. The continued BP decrease between the first and second trimesters is less significant compared to the one seen between prepregnancy and first trimester. However, most studies reported on a nadir in BP drop around midpregnancy [93–96]. A mild increase in BP is usually found during the third trimester and continues toward delivery and the PP period. Nevertheless, 2–3 mmHg lower BP levels compared to prepregnancy values can be found up to 16 weeks PP [93]. Although within normal range, higher body weight and older age were shown to be associated with higher BPs during pregnancy [99,100] and might predispose these women to PIH and preeclampsia. Heart rate Heart rate rises gradually during pregnancy (Figure 1.2) with a mean maximum increase of about 10–20 beats per minute [51,57,63]. Occasionally, women present with inappropriate sinus tachycardia with rates >100 bpm and even >120 bpm,

CHAPTER 1 Hemodynamics and Cardiac Function

which are usually well tolerated [101] and do not have an effect on LV function (personal observation). Pulmonary artery pressure and pulmonary vascular resistance (PVR) In the early study by Bader et al. [52], who performed cardiac catheterization in 46 normal pregnant women at different stages of pregnancy, normal pulmonary pressures were recorded both at rest and during exercise throughout pregnancy. Although pulmonary artery wedge pressure was not measured, the significant increase in CO indicated a substantial reduction in total pulmonary vascular resistance (PVR) [52]. Similar findings were reported by Clark et al. who described no significant changes in invasively measured pulmonary pressures at 36–38 weeks compared with 12-week postpartum. No hemodynamic measurements were performed, however, during the first or second trimesters [75]. A later study by Robson et al. [102] reported serial pulmonary hemodynamic assessments using Doppler and cross-sectional echocardiography in 13 women prior to conception, at monthly intervals throughout pregnancy, and six months after delivery. Baseline mean pulmonary artery pressure was 14 mmHg with no significant change during pregnancy. Pulmonary resistance decreased by 24% at eight weeks without a further significant change later on. Values returned to prepregnancy levels by six months PP [102]. A recent echocardiographic study assessed serial hemodynamic changes during the course of pregnancy in 60 pregnant women compared to 15 nonpregnant control women matched by age and body size [103]. This study confirmed previous reports and demonstrated normal pulmonary artery pressures during the first trimester without a significant change later in pregnancy. In the second trimester, pulmonary blood flow was increased by 29% and PVR decreased by 15% compared to the first trimester. A further 13% increase in pulmonary blood flow and 17% decrease in PVR were seen during the third trimester [103]. Cardiocirculatory changes during labor and delivery Labor, delivery, and the early PP period are associated with marked and sudden changes in hemodynamics [104]. During labor, the combination of increased blood volume and venous return to the heart from the contracting uterus and increased heart rate and myocardial contractility mediated by catecholamine surge results in significant hemodynamic changes. Seminal early report by Ueland and Hansen [105] who studied 23 supine laboring women during the first stage of labor and before sedation showed an average increase of 33% in SV with each uterine contraction accompanied by a reflex 15% decrease in heart rate resulting in a 24% rise in CO and 26% rise in pulse pressure. It should be noted that during each contraction, there is a complete occlusion of the distal aorta and/or common iliac arteries resulting in

9

an increase in BP measured in the upper extremities but a decrease in BP measured in the femoral arteries [106]. Compared with supine position, the hemodynamic changes during labor were significantly different in the lateral position. Because venous return was maintained at all times and there was less obstruction of the distal aorta during contractions, higher CO and SV were measured. Changes during contractions in the lateral position were much smaller with only 8% increase in SV and CO, no change in heart rate and only a small change in BP. A later assessment of CO during labor in the semilateral position using Doppler and cross-sectional echocardiography of the pulmonic valve showed a progressive increase in the rise in CO during uterine contraction [107]. At ≥8 cm cervical dilatation, CO increased >30% as a result of a rise of both SV and heart rate and was accompanied by a 10% increase in mean BP. It should be noted that all women were given pethidine and nitrous oxide for analgesia and did not have epidural labor analgesia [107]. This fact is of great importance because the form of anesthesia plays a substantial role in modifying the CV response to labor and delivery. Under local anesthesia, CO showed progressive increase throughout labor. The changes were less striking during caudal anesthesia [108], partially because of better control of pain. Similar changes were recorded in both groups of patients during the Valsalva maneuver, which was associated with a marked increase in systemic BP and central venous pressure [108]. The effect of cesarean section (CS) on maternal hemodynamics Performing cesarean section (CS) prior to onset of labor can prevent the hemodynamic changes observed during contractions but can result in cardiocirculatory responses related to the use of anesthetics and to surgery. The hemodynamic effect of CS is greatly influenced by the mode of anesthesia used and the type of drugs utilized during the operation. A series of studies by Ueland et al. [109–111] evaluated the hemodynamic effects of CS delivery at term under various forms of anesthesia. In women receiving local anesthesia during labor in the supine position, there was a progressive increase in CO measured by the dye dilution technique which reached 25% above prelabor values at the late first stage, 49% at the second stage, and 80% immediately after delivery [108]. In women receiving caudal analgesia, the corresponding figures were 21%, 24%, and 59% respectively. Although caudal anesthesia attenuated CO increase during labor and after the delivery, both techniques were associated with a similar 15–20% increase in CO during uterine contractions regardless of the stage of labor [108]. The effect of general anesthesia using thiopental, nitrous oxide, and succinylcholine was investigated in 17 normal pregnant women undergoing repeat CS at term [111]. Baseline CO before anesthesia increase 29% and heart rate decreased 16% in the lateral compared to supine position. During anesthesia, CO increased only slightly, and intubation was associated

10

PART I Physiologic Changes During Normal Pregnancy and the Puerperium

with additional 16% increase in CO, 18% in heart rate, and 14% in BP. Peak CO increase (41% over control) was seen 10 minutes after the delivery. Notably, the reflex tachycardia and hypertension associated with endotracheal intubation has been shown to be associated with profound decrease in LV ejection fraction and an increase in LV filling pressure in nonpregnant patients with mild LV dysfunction [112]. Spinal anesthesia was reported by Ueland and coworker to be associated with a significant decrease in BP prior to the onset of surgery [104]. These findings were later confirmed by Langesaeter et al. [113], who performed a double-blinded study in 80 healthy women scheduled to undergo an elective CS who were randomized to spinal aesthesia with low vs. high dose bupivacaine with or without a concomitant infusion of lowdose phenylephrine. The study showed a marked decrease in mean BP in both the low- and the high-dose groups mediated by a fall in SVR, despite a substantial increase in CO. This decrease in BP was significantly attenuated by phenylephrine in the low dose group, suggesting that this approach combined with moderate rehydration gives the best hemodynamic stability during spinal anesthesia for CS. Similar to spinal anesthesia, the use of epidural anesthesia with epinephrine was associated with preoperative hypotension in all patients and often required treatment including uterine displacement, and/or intravenous fluid and/or compression bandaging of the lower extremities in addition to intravenous vasopressors [104]. In contrast, epidural anesthesia without epinephrine was reported to be associated with better hemodynamic stability during surgery and at delivery [109]. There were, however, minor changes in CO and heart rate following the administration of anesthesia with a transient decline in BP that could be corrected by uterine displacement without the need for vasopressor drugs. Milsom et al. [114] compared hemodynamic changes during CS in 20 women treated with either epidural or general anesthesia. In women receiving epidural anesthesia, CO increased significantly before delivery, largely as a result of a significant increase in heart rate, with further increase after the delivery. There was also a significant decrease in systolic and diastolic BP as a result of a fall in SVR. General anesthesia was associated with a significant decrease in SV during the delivery, while CO did not change (because of a marked increase in heart rate), but increased after delivery probably due to increased venous return. In contrast to epidural anesthesia, general anesthesia was associated with a significant increase in both systolic and diastolic BP due to increased SVR [114]. Milsom et al. also investigated the effect of change in body position before and after the delivery on maternal circulation in patients undergoing epidural anesthesia. Assumption of the supine position before delivery was associated with a significant reduction in CO and SV and a significant increase in heart rate, SVR, and BP. In contrast, the supine position postpartum was associated with only minor and insignificant hemodynamic changes [114]. In summary, hemodynamic changes during CS are influenced considerably by the patient’s position and the form

of anesthesia or analgesia used. Marked variations have been demonstrated among various anesthetic techniques and anesthetic agents that need to be taken into account in the delivery plan of the cardiac patient.

Hemodynamic changes during the puerperium Major hemodynamic changes occur immediately after the delivery (Figure 1.4) [116]. CO and SV have been reported to increase >50% [105] probably as a result of an “auto transfusion” from the contracting uterus and an increase in venous return to the heart due to relief of IVC compression by the gravid uterus [117]. At 1 hour following delivery, heart rate and CO returned to prelabor values, whereas BP and SV remained elevated and returned to prelabor values at 24 hours PP [107,118]. Evaluation of hemodynamic at 38 weeks gestation, 48 hours and two weeks PP in 10 healthy women in the semilateral position showed that CO remained elevated for at least 48 hours after the delivery due to increased SV and despite a substantial fall in heart rate. At two weeks PP, CO decreased significantly owing to decline in SV and further decrease in heart rate [117]. The same group reported on hemodynamic evaluation of 15 healthy women at 38-week gestation and at 2, 6, 12, and 24 weeks postpartum. Both CO and heart rate fell progressively and returned to predelivery values at two weeks after the delivery, whereas SV was reduced only partially at two weeks and showed a further decline by 6 months [115] (Figure 1.4). A unique study by Capeless and Clapp [119] compared hemodynamic parameters in 13 women before conception and at 6 and 12 weeks postpartum. Hemodynamic parameters as well as LV dimensions were studied with M mode echocardiography in the left lateral position. While heart rate returned to preconception values, SV, CO, and LV end diastolic volume remained significantly elevated both at 6 and 12 weeks postpartum, and SVR remained decreased. Robson et al. evaluated the effect of postpartum hemorrhage in 10 women with estimated blood loss of >500 ml (550–1900 ml) in comparison with a control group of 30 women who had uncomplicated labor (estimated blood loss 50–400 ml), during which they received an average of 280 ml of intravenous fluid. All women received syntometrine at the time of delivery. Compared to the control group, SV decreased and heart rate increased in the patients with PP hemorrhage. Nevertheless, CO and BP were the same due to higher heart rate and SVR [120]. In summary, significant hemodynamic changes are seen in the immediate PP period. These changes may be affected by the amount of blood loss. In women with uncomplicated delivery, there is a marked increase in CO despite a rapid decline in heart rate, which remains higher than the prelabor value for at least 48 hours. Postdelivery hemodynamics return fairly rapidly toward prelabor values, but complete return to preconception values occurs only after several weeks to months.

CHAPTER 1 Hemodynamics and Cardiac Function

11

40% 30% 20% 10% 00% –10% –20% –30% –40% 1

2 6 Postpartal day

10

2

Heart rate

Cardiac output

Diastolic BP

Stroke volume

6 12 Postpartal week

24

Systolic BP Systemic vascular resistance

Figure 1.4 Percent postpartum changes in hemodynamic parameters compared to 38 weeks gestation. Source: Based on data by Robson et al. 1987 [115].

Structural and functional cardiac changes Dimensions Pregnancy is a state of volume overload, and the woman’s heart usually responds to this new state with a small increase in dimensions and mass. Echocardiography has been the most widely used tool for the evaluation of pregnancyassociated structural changes. While few studies showed no significant increase in cardiac chambers dimensions during pregnancy [58,121], most studies have demonstrated a small yet significant increase in the size of the LV (i.e. LV end systolic diameter, LV end diastolic diameter, LV volume) and the left atrium [63,65,122–124] which remain, however, within normal limits. A recent study by Savu et al. have shown a maximum increase of most measures in the second and third trimesters, including an 8% increase of LV end diastolic dimension, 15% of LV end systolic dimension, 33% of LV end diastolic volume, 31% of LV end systolic volume, and 20% increase in left atrial area [63]. The same investigators also reported a reduction in sphericity index (indicating that the LV becomes more globular) as pregnancy progressed [63]. Left ventricular mass was shown to increase by more than 30% in the third trimester compared with baseline measures. The study of Cardiac Hemodynamic Imaging and Remodeling in Pregnancy (CHIRP) examined the change in cardiac chamber size during the third trimester compared to four months PP with both echocardiography and MRI and showed a 50% increase in LV mass [65]. A good

correlation was found in changes of LV end diastolic volume and LV mass between the two imaging modalities, but the values were somewhat underestimated by echocardiography. Though the data on the right heart are more scares, studies have also shown an increase in right ventricular (RV) and right atrial dimensions throughout pregnancy [125]. In the CHIRP study, compared with four months PP, MRI measurements at the third trimester showed an increase in RV end diastolic dimension from 33 ± 4 to 39 ± 3 mm, RV volume from 93 ± 4 to 115 ± 4 ml, and RV mass from 51 ± 5 to 71 ± 6 gr (all p < 0.05) [65]. LV outflow tract diameter was shown to either increase [58] or remain constant [121] during pregnancy. The return to prepregnancy values of various echocardiographic parameters can be delayed; women evaluated six to eight weeks PP still showed residual enlargement of their cardiac chambers [121,122]. Complete resolution, however, was shown by four months postpartum [65]. Contractility Using right heart catheterization and arterial line in a study limited to 36–38 weeks gestation, Clark et al. [75] reported no change in LV stroke work (the product of SV and systolic BP) compared with 12 week PP. They, however, did not report on myocardial performance in the first or second trimesters. Most recent data on systolic function in pregnancy, drawn from echocardiographic studies, have shown small and inconsistent changes. Using ejection fraction as a measure of systolic function, some of these trials reported

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PART I Physiologic Changes During Normal Pregnancy and the Puerperium

no change [58,83,121,126], while others reported either a decrease [127] or an increase [51,56,115]. The use of MRI in the CHIRP study showed no significant change in ejection fraction during the third trimester compared to four months PP [65]. A number of recent studies, which used speckletracking echocardiography to assess LV functional changes during normal pregnancy, also reported inconsistent results. Naqvi et al. reported an increase in cardiac contractility demonstrated by increased LV radial and longitudinal rate of deformation, especially during the first and second trimester [128]. Savu et al. [63] evaluated 51 women in each trimester and three to six months postpartum. Despite an increase in stroke work (which reflects global cardiac performance) throughout pregnancy, no significant change in ejection fraction and circumferential or radial strain was demonstrated, though a decrease in longitudinal strain during the third trimester was shown [63]. The authors concluded that the reduction in longitudinal strain did not necessarily represent systolic dysfunction but could be related to the increased heart rate and loading conditions in the third trimester [63]. Ando et al. [129] reported on a retrospective speckle tracking echocardiographic study in 74 normal pregnant women and 21 healthy age-matched female controls. These investigators found no change in myocardial mechanical function measured by global longitudinal strain, radial strain, circumferential strain, systolic and diastolic global longitudinal strain rate, global radial strain rate, and global circumferential strain rate, and concluded that despite heart remodeling, LV function remains unchanged. Cong et al. [130] used sequential two-dimensional echocardiography and 3D speckle tracking echocardiography in 68 pregnant women during each trimester of pregnancy and six to nine months PP, and 30 age-matched healthy controls. These investigators reported a significant decrease in global longitudinal strain, global circumferential strain, global area strain, and global radial strain in late pregnancy along with a small (5%) decrease in ejection fraction. Information on RV function in pregnancy is limited. In the CHIRP study [65], no change in RV ejection fraction (62 ± 3 to 61 ± 3) was demonstrated. Savu et al. evaluated RV function using tissue Doppler strain rate imaging of the RV free wall and reported an increase in longitudinal strain rate in the first and second trimesters and a decrease in the third trimester [63]. Diastolic function There have been a number of reports of changes in LV diastolic function during normal pregnancy with somewhat different results [121,122,131]. In an early study, Mesa et al. [121] conducted an echocardiographic evaluation at the end of each trimester in 37 healthy pregnant women (8 women were also followed 4–10 weeks). This study showed complex changes including an increase in early mitral inflow velocity (E wave) with a significantly increased E/A ratio in early pregnancy, and in contrast, a significant increase in late mitral inflow velocity (A wave) in the second and third trimesters.

Additionally, an increase in pulmonary vein reverse (PVr) flow was demonstrated throughout pregnancy. While these changes might represent an impaired diastolic function, the ratio of A wave to PVr was preserved or even increased [121], implying that the observed changes were more likely due to an increase in plasma volume rather than a marker of diastolic dysfunction. Nevertheless, the increase in both A wave and PVr may represent a need for a more powerful atrial contraction to overcome a possible decrease in ventricular compliance in pregnancy secondary to increased LV mass. Moran et al. [131] also showed an early increase in E velocity, peaking at 18 weeks and returning to normal level during late pregnancy and an increase in A velocity and fall of the E/A ratio at 18 weeks remaining high throughout the rest of the pregnancy. Fok et al. [122] performed a prospective, longitudinal, observational study of tissue Doppler imaging in 35 healthy pregnant women These investigators showed that early diastolic myocardial velocities (E′ ) peaked in the beginning of the second trimester and were subsequently decreased during the third trimester and PP, while late diastolic myocardial velocities (A′ ) were found to be increased in the second trimester, but decreased again in third trimester and in the PP period. As a result, the often used marker of diastolic function, E/E′ ratio, was shown to be decreased as pregnancy progressed, though it was maintained within a normal range [122].These investigators concluded that LV diastolic function was preserved during pregnancy and is augmented at late diastole to accommodate the increased preload. In the CHIRP study [65], the authors did not report on diastolic function with the use of MRI. However, echo findings showed an increase in late mitral inflow velocities (A wave) and a decrease in E/A ratio in the third trimester of pregnancy compared with postpartum [65]. Valvular regurgitation A-single center echocardiographic study examined the prevalence of valvular regurgitation in 107 pregnant women, 55 of whom prior to 28 weeks gestation, compared to 51 age-matched non-pregnant controls [132]. Rates of tricuspid regurgitation (TR) was 42% in the control group and 67% in the pregnant group with a median peak regurgitant velocity of 1.7 ms. Pulmonic regurgitation (PR) increased from 50% in the control group to 96% at ≥28 weeks gestation with a median peak regurgitant velocity of 1.1 ms. Incidence of mitral and aortic regurgitation was 27% and 2% in the control group, respectively, and was not increased in the pregnancy group [132]. Similar findings were reported by Campos et al. in a study published one year later. These investigators evaluated 18 healthy pregnant women and 18 agematched controls and demonstrated early and progressive dilatation of pulmonary, tricuspid, and mitral annuli during pregnancy [125], which was associated with progressive increase in valvular regurgitation. Forty-four percent of the control patients had TR and 39% had PR, but none had left-sided regurgitation. The prevalence of TR and PR increased as pregnancy progressed, and both reached 94%

CHAPTER 1 Hemodynamics and Cardiac Function

by 36–40 week gestation. Mitral regurgitation was demonstrated in 27% of participants in late pregnancy and none showed aortic regurgitation. By three to six weeks postpartum, mitral regurgitation resolved completely, while TR and PR were still more prevalent compared to the beginning of pregnancy [125]. Pericardial effusion Haiat and Halphen [133] examined 123 women at various stages of pregnancy and reported pericardial effusion in 19/48 (40%) at ≥32-week gestation. All of them were asymptomatic, despite moderate-large effusion shown in 6/19 cases. Within four weeks postpartum, all effusions resolved [133]. Abduljabbar et al. [134] followed 52 women throughout pregnancy, and 11 of them were also examined at six-weeks postpartum. Pericardial effusion was found in 15%, 19%, and 44% of women in the first, second, and third trimester, respectively, and was more prevalent in first pregnancies and in women who gained more than 12 kg weight during their pregnancy. The effusions were resolved by six-weeks postpartum in all 11 patients who were reexamined PP [134].

Ventilation and gas exchange Both oxygen consumption (VO2 ) and carbon dioxide production (VCO2 ) are increased in pregnancy [135,136], probably as a result of an increased metabolic rate in the pregnant woman and the increased metabolic demands of the growing fetus, and are 20–30% higher at term compared with baseline levels while the ratio of VCO2 /VO2 is maintained [136,137]. Minute ventilation is increased from the beginning of pregnancy to a greater degree than VO2 or VCO2 [138,139], probably as a result of the effect of progesterone (and to a lesser degree, estradiol) on the brain-breathing center [140,141]. The increased awareness of many pregnant women to this elevated ventilatory drive contributes to the commonly reported “physiologic dyspnea of pregnancy.”

Summary Pregnancy is associated with a mark adaptation of the CV system with important changes in blood volume and hemodynamics during gestation, labor, delivery and the puerperium. These changes can represent a significant burden and a “stress test” to the patient with heart disease and limited cardiac reserve. With increased number of pregnant women with heart disease due to pregnancy at older age and increasing number of women with congenital heart disease surviving to childbearing age, more physicians are involved in the care of such women. A good understanding of the physiologic changes of pregnancy and their potential impact on both maternal and fetal outcome is critical.

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90 Jaffe, R. and Warsof, S.L. (1991). Transvaginal color Doppler imaging in the assessment of uteroplacental blood flow in the normal firsttrimester pregnancy. Am J Obstet Gynecol 164: 781–785. 91 Jurkovic, D., Jauniaux, E., Kurjak, A. et al. (1991). Transvaginal color Doppler assessment of the uteroplacental circulation in early pregnancy. Obstet Gynecol 77: 365–369. 92 Coppens, M., Loquet, P., Kollen, M. et al. (1996). Longitudinal evaluation of uteroplacental and umbilical blood flow changes in normal early pregnancy. Ultrasound Obstet Gynecol 7: 114–121. 93 Mahendru, A.A., Everett, T.R., Wilkinson, I.B. et al. (2014). A longitudinal study of maternal cardiovascular function from preconception to the postpartum period. J Hypertens 32: 849–856. 94 Grindheim, G., Estensen, M.E., Langesaeter, E. et al. (2012). Changes in blood pressure during healthy pregnancy: a longitudinal cohort study. J Hypertens 30: 342–350. 95 Ochsenbein-Kolble, N., Roos, M., Gasser, T. et al. (2004). Cross sectional study of automated blood pressure measurements throughout pregnancy. Br J Obstet Gynaecol 111: 319–325. 96 Strevens, H., Wide-Swensson, D., and Ingemarsson, I. (2001). Blood pressure during pregnancy in a Swedish population; impact of parity. Acta Obstet Gynecol Scand 80: 824–829. 97 Mahendru, A.A., Everett, T.R., Wilkinson, I.B. et al. (2012). Maternal cardiovascular changes from pre-pregnancy to very early pregnancy. J Hypertens 30: 2168–2172. 98 Kristiansson, P. and Wang, J.X. (2001). Reproductive hormones and blood pressure during pregnancy. Hum Reprod 16: 13–17. 99 Gaillard, R., Bakker, R., Willemsen, S.P. et al. (2011). Blood pressure tracking during pregnancy and the risk of gestational hypertensive disorders: the Generation R Study. Eur Heart J 32: 3088–3097. 100 Gaillard, R., Bakker, R., Steegers, E.A. et al. (2011). Maternal age during pregnancy is associated with third trimester blood pressure level: the Generation R Study. Am J Hypertens 24: 1046–1053. 101 Belham, M., Patient, C., and Pickett, J. (2017). Inappropriate sinus tachycardia in pregnancy: a benign phenomena? BMJ Case Rep 2017. 102 Robson, S.C., Hunter, S., Boys, R.J., and Dunlop, W. (1991). Serial changes in pulmonary haemodynamics during human pregnancy: a non-invasive study using Doppler echocardiography. Clin Sci (London) 80: 113–117. 103 Sharma, R., Kumar, A., and Aneja, G.K. (2016). Serial changes in pulmonary hemodynamics during pregnancy: a non-invasive study using Doppler echocardiography. Cardiol Res 7: 25–31. 104 Metcalfe, J. and Ueland, K. (1974). Maternal cardiovascular adjustments to pregnancy. Prog Cardiovasc Dis 16: 363–374. 105 Ueland, K. and Hansen, J.M. (1969). Maternal cardiovascular dynamics. II. Posture and uterine contractions. Am J Obstet Gynecol 103: 1–7. 106 Bieniarz, J., Yoshida, T., Romero-Salinas, G. et al. (1969). Aortocaval compression by the uterus in late human pregnancy. IV. Circulatory homeostasis by preferential perfusion of the placenta. Am J Obstet Gynecol 103: 19–31. 107 Robson, S.C., Dunlop, W., Boys, R.J., and Hunter, S. (1987). Cardiac output during labour. BMJ 295: 1169–1172. 108 Ueland, K. and Hansen, J.M. (1969). Maternal cardiovascular dynamics. 3. Labor and delivery under local and caudal analgesia. Am J Obstet Gynecol 103: 8–18. 109 Ueland, K., Akamatsu, T.J., Eng, M. et al. (1972). Maternal cardiovascular dynamics. VI. Cesarean section under epidural anesthesia without epinephrine. Am J Obstet Gynecol 114: 775–780. 110 Ueland, K., Gills, R.E., and Hansen, J.M. (1968). Maternal cardiovascular dynamics. I. Cesarean section under subarachnoid block anesthesia. Am J Obstet Gynecol 100: 42–54. 111 Ueland, K., Hansen, J., Eng, M. et al. (1970). Maternal cardiovascular dynamics. V. Cesarean section under thiopental, nitrous oxide, and succinylcholine anesthesia. Am J Obstet Gynecol 108: 615–622. 112 Giles, R.W., Berger, H.J., Barash, P.G. et al. (1982). Continuous monitoring of left ventricular performance with the computerized nuclear probe during laryngoscopy and intubation before coronary artery bypass surgery. Am J Cardiol 50: 735–741.

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113 Langesaeter, E., Rosseland, L.A., and Stubhaug, A. (2008). Continuous invasive blood pressure and cardiac output monitoring during cesarean delivery: a randomized, double-blind comparison of low-dose versus high-dose spinal anesthesia with intravenous phenylephrine or placebo infusion. Anesthesiology 109: 856–863. 114 Milsom, I., Forssman, L., Biber, B. et al. (1985). Maternal haemodynamic changes during caesarean section: a comparison of epidural and general anaesthesia. Acta Anaesthesiol Scand 29: 161–167. 115 Robson, S.C., Hunter, S., Moore, M., and Dunlop, W. (1987). Haemodynamic changes during the puerperium: a Doppler and M-mode echocardiographic study. Br J Obstet Gynaecol 94: 1028–1039. 116 Kjeldsen, J. (1979). Hemodynamic investigations during labour and delivery. Acta Obstet Gynecol Scand Suppl 89: 1–252. 117 Robson, S.C., Dunlop, W., and Hunter, S. (1987). Haemodynamic changes during the early puerperium. BMJ 294: 1065. 118 Hunter, S. and Robson, S.C. (1992). Adaptation of the maternal heart in pregnancy. Br Heart J 68: 540–543. 119 Capeless, E.L. and Clapp, J.F. (1991). When do cardiovascular parameters return to their preconception values? Am J Obstet Gynecol 165: 883–886. 120 Robson, S.C., Boys, R.J., Hunter, S., and Dunlop, W. (1989). Maternal hemodynamics after normal delivery and delivery complicated by postpartum hemorrhage. Obstet Gynecol 74: 234–239. 121 Mesa, A., Jessurun, C., Hernandez, A. et al. (1999). Left ventricular diastolic function in normal human pregnancy. Circulation 99: 511–517. 122 Fok, W.Y., Chan, L.Y., Wong, J.T. et al. (2006). Left ventricular diastolic function during normal pregnancy: assessment by spectral tissue Doppler imaging. Ultrasound Obstet Gynecol 28: 789–793. 123 Duvekot, J.J. and Peeters, L.L. (1994). Maternal cardiovascular hemodynamic adaptation to pregnancy. Obstet Gynecol Surv 49: S1–S14. 124 Katz, R., Karliner, J.S., and Resnik, R. (1978). Effects of a natural volume overload state (pregnancy) on left ventricular performance in normal human subjects. Circulation 58: 434–441. 125 Campos, O., Andrade, J.L., Bocanegra, J. et al. (1993). Physiologic multivalvular regurgitation during pregnancy: a longitudinal Doppler echocardiographic study. Int J Cardiol 40: 265–272. 126 Geva, T., Mauer, M.B., Striker, L. et al. (1997). Effects of physiologic load of pregnancy on left ventricular contractility and remodeling. Am Heart J 133: 53–59. 127 Zentner, D., du Plessis, M., Brennecke, S. et al. (2009). Deterioration in cardiac systolic and diastolic function late in normal human pregnancy. Clin Sci (London) 116: 599–606.

128 Naqvi, T.Z., Lee, M.S., Aldridge, M. et al. (2016). Abstract 16377: normal cardiac adaptation during pregnancy – assessment by velocity vector imaging and three-dimensional echocardiography in healthy pregnant women. Circulation 128: A16377. 129 Ando, T., Kaur, R., Holmes, A.A. et al. (2015). Physiological adaptation of the left ventricle during the second and third trimesters of a healthy pregnancy: a speckle tracking echocardiography study. Am J Cardiovasc Dis 5: 119–126. 130 Cong, J., Fan, T., Yang, X. et al. (2015). Structural and functional changes in maternal left ventricle during pregnancy: a threedimensional speckle-tracking echocardiography study. Cardiovasc Ultrasound 13: 6. 131 Moran, A.M., Colan, S.D., Mauer, M.B., and Geva, T. (2002). Adaptive mechanisms of left ventricular diastolic function to the physiologic load of pregnancy. Clin Cardiol 25: 124–131. 132 Robson, S.C., Richley, D., Boys, R.J., and Hunter, S. (1992). Incidence of Doppler regurgitant flow velocities during normal pregnancy. Eur Heart J 13: 84–87. 133 Haiat, R. and Halphen, C. (1984). Silent pericardial effusion in late pregnancy: a new entity. Cardiovasc Interv Radiol 7: 267–269. 134 Abduljabbar, H.S., Marzouki, K.M., Zawawi, T.H., and Khan, A.S. (1991). Pericardial effusion in normal pregnant women. Acta Obstet Gynecol Scand 70: 291–294. 135 Ueland, K., Novy, M.J., and Metcalfe, J. (1973). Cardiorespiratory responses to pregnancy and exercise in normal women and patients with heart disease. Am J Obstet Gynecol 115: 4–10. 136 Pernoll, M.L., Metcalfe, J., Schlenker, T.L. et al. (1975). Oxygen consumption at rest and during exercise in pregnancy. Respir Physiol 25: 285–293. 137 Artal, R., Wiswell, R., Romem, Y., and Dorey, F. (1986). Pulmonary responses to exercise in pregnancy. Am J Obstet Gynecol 154: 378–383. 138 Contreras, G., Gutierrez, M., Beroiza, T. et al. (1991). Ventilatory drive and respiratory muscle function in pregnancy. Am Rev Respir Dis 144: 837–841. 139 Alaily, A.B. and Carrol, K.B. (1978). Pulmonary ventilation in pregnancy. Br J Obstet Gynaecol 85: 518–524. 140 Bayliss, D.A. and Millhorn, D.E. (1992). Central neural mechanisms of progesterone action: application to the respiratory system. J Appl Physiol (1985) 73: 393–404. 141 Jensen, D., Wolfe, L.A., Slatkovska, L. et al. (2005). Effects of human pregnancy on the ventilatory chemoreflex response to carbon dioxide. Am J Physiol Regul Integr Comp Physiol 288: R1369–R1375.

PART II

Cardiac Evaluation of the Pregnant Woman

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CHAP T E R 2

Cardiovascular Evaluation During Pregnancy Uri Elkayam1,2 1 Department

of Medicine, Division of Cardiovascular Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA

2 Department

of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA

Introduction The evaluation of cardiac disease in pregnancy may be complicated by the normal anatomical and functional changes of the cardiovascular system. Such changes may result in signs and symptoms that can either simulate or obscure heart disease. It is therefore imperative in many cases to use additional diagnostic tools to obtain objective and reliable information about cardiac status. The selection of such tools should be influenced by their diagnostic yield as well as by the potential risk to the fetus.

History and physical examination Symptoms Reduction in exercise tolerance and tiredness are the most commonly found symptoms during pregnancy and are most probably related to increased body weight and anemia of pregnancy (Table 2.1). Lightheadedness, or even syncopal episodes, can occur in the later phases of gestation mostly due to orthostatic hypotension and vasovagal mechanisms (Chapter 25). Palpitations are a common complaint during pregnancy; they are probably due to sensation of the hyperdynamic circulation of pregnancy and are usually not associated with cardiac arrhythmias [1,2]. Episodes of palpitations are usually short-lasting but can also last longer time and be associated with additional symptoms such as lightheadedness and shortness of breath. Similarly, common is dyspnea, which occurs in about half of women before the 19th week of gestation and in as many as 76% of women by 31 weeks. Shortness of breath is usually exertional, associated with variable degrees of decreased exercise tolerance but typically does not interfere with daily activity [3,4]. The mechanisms of dyspnea are not entirely clear, it is probably multifactorial including hormonal effect on the drive to breath [5], higher sensitivity to the central chemoreflex response to carbon dioxide [6], reduced total respiratory system compliance due to progressive changes in the shape and configuration of the abdomen,

diaphragm, and chest wall [7], and a change in the perception of normal respiration, hyperventilation in response to a reduced diffusion lung capacity [8,9]. Recent publications by Goland et al. [10] and Kansal et al. [11] demonstrated subclinical changes in left ventricular (LV) structure and subtle systolic and diastolic dysfunction in some women with significant shortness of breath in pregnancy. The clinical relevance of these findings is questionable. Orthopnea is occasionally seen, especially in the later stages of pregnancy and usually more pronounced in the supine compared to the lateral position and is probably due to mechanical pressure of the enlarged uterus on the diaphragm. Physical signs Hyperventilation is a common phenomenon in pregnancy and can be misinterpreted as dyspnea [3]. The mechanism of hyperventilation may be associated with elevated progesterone and its effect on the respiratory center [3,12]. The physiological dyspnea of pregnancy is not associated with cough or findings of basilar rales or wheezing. A left ventricular impulse is usually easily palpated, diffuse brisk, and unstained. It is usually nondisplaced or slightly displaced to the left. A right ventricular impulse at the midto-lower left sternal border can usually be palpated during the second and third trimesters, as can the pulmonary trunk (second left intercostal space), mimicking findings typical for pulmonary hypertension. The systemic arterial pulse is usually full, becomes sharp and jerky between the 12th and 15th weeks of gestation, and maintains this quality until about one week after delivery. The pulse is often collapsing in character and associated with capillary pulsation; it can simulate the finding of aortic regurgitation, but the reduction in diastolic blood pressure is smaller. The jugular veins may appear somewhat distended from about the 20th week of pregnancy. The venous pulsation in the neck may also be seen, with clear definition of prominent A and V peaks and brisk X and Y descents [13].

Cardiac Problems in Pregnancy, Fourth Edition. Edited by Uri Elkayam. © 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.

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PART II Cardiac Evaluation of the Pregnant Woman

Table 2.1 Cardiac symptoms and findings during normal pregnancy Symptoms Decreased exercise capacity Tiredness Dyspnea Orthopnea Palpitations Lightheadedness Syncope Physical findings Inspection Hyperventilation Peripheral edema Capillary pulsation Precordial palpation Brisk diffuse and slightly displaced left ventricular impulse Palpable right ventricular impulse Palpable pulmonary trunk impulse Ausculation Increased first heart sound with exaggerated splitting Exaggerated splitting of second heart sound Midsystolic ejection-type murmurs at the lower left sternal edge and/or over the pulmonary area With radiation to suprasternal notch and more to the left than the right side of the neck Continuous murmurs (cervical venous hum, mammary souffle) Diastolic murmur (rare)

Edema of the ankles and legs is a common finding in late pregnancy although the degree of edema is rarely severe. The formation of edema can be attributed to fall in colloid osmotic pressure of the plasma and the concomitant increase in femoral venous pressure in the legs. An increase in capillary permeability during pregnancy has also been suggested as a contributing factor to the edema formation but was not convincingly proven [14].

Auscultatory findings Heart sounds The first heart sound shows an increased loudness of both components, starting at the 12th–20th weeks of gestation, and remains loud up to about the 32nd week, when the intensity diminishes in some of the cases. The first sound returns to normal two to four weeks postpartum [15,16]. In addition to the increased intensity, the first sound demonstrates an exaggerated splitting, which may be confused with an early click. The amplitude of the second, or tricuspid, element of the first

heart sound increases on inspiration and decreases on expiration. The cause for the changes in the quality of the first heart sound in pregnancy is not entirely clear. Cutforth and MacDonald [15] suggested that the increased plasma volume is a major contributing factor; Perloff [13] proposed an accentuation of the intensity of the first heart sound due to the hyperkinetic left ventricle during pregnancy. There is no change in the character of the second heart sound during the first 30 weeks of pregnancy. At late pregnancy, however, the second sound is often increased, and when the patient is examined in the lateral position, it exhibits wide splitting. Compression of the inferior vena cava by the uterus and the lack of free diaphragmatic movement have been suggested as the mechanism responsible for the normal or even less than normal splitting of the second sound when patients are examined in the supine position [15]. A high incidence of a third heart sound was reported in pregnancy 30 years ago [15,16]. In our experience, however, such a sound is rare in healthy women during gestation. A fourth heart sound was found by phonocardiographic studies

CHAPTER 2 Cardiovascular Evaluation During Pregnancy

in 16% of pregnant women during early pregnancy (15th– 22nd week) but is rarely detected on auscultation. Systolic murmurs As a result of the hyperkinetic circulation during pregnancy, the incidence of innocent systolic murmurs is high and was found by phonocardiography in late pregnancy in 96% of the cases reported by Cutforth and MacDonald [15]. Recent study using a digital stethoscope found a systolic murmur in only 69% of 29 women at the second trimester of normal pregnancy [17]. The characteristic murmur is midsystolic, grade 1–2/6 and is best heard at the lower left sternal edge and over the pulmonary area and radiating to the suprasternal notch and more to the left side than to the right side of the neck. The murmur represents audible vibrations due to the ejection of blood from the right ventricle into the pulmonary trunk and/or from the left ventricle into the brachiocephalic arteries at the point of branching from the aortic arch. The murmur is best heard with the patient in the supine position and the diaphragm firmly applied to the chest wall. Mishra et al. [18] used echocardiography to examine the significance of a heart murmur in 103 pregnant women who were referred for cardiac opinion. The echocardiogram and Doppler results were normal in all 79 women who had a soft or short ejection systolic murmur. Three of 15 women who had loud or long ejection systolic murmur had abnormalities (one patient had mitral valve prolapse with mild mitral regurgitation; the second, nonobstructive hypertrophic cardiomyopathy; and the third, mild aortic stenosis due to bicuspid aortic valve). All seven patients who had diastolic, pan systolic, or late systolic murmurs or abnormal electrocardiograms had abnormalities (three ventricular septal defects, one atrial septal defect with rheumatic mitral regurgitation, one mitral valve prolapse with mild mitral regurgitation, and one nonobstructive hypertrophic cardiomyopathy). This study and others [19] suggested that echocardiography is not needed in patients with a typical flow murmur of pregnancy but is useful in distinguishing between a functional and an organic murmur in cases of murmurs that are louder or longer or associated with other auscultatory or electrocardiographic abnormalities. Diastolic murmurs A soft, medium-to-high–pitched diastolic murmur has been reported in some normal pregnant women. The murmur can be best heard at the lower left sternal edge and over the pulmonary area and may resemble the early diastolic murmurs of pulmonary or aortic insufficiency, or stenosis of the mitral or tricuspid valves. The murmurs are thought to be due to increased flow through the tricuspid or mitral valve or to a physiologic dilatation of the pulmonary artery during pregnancy [20,21]. In our experience, however, the occurrence of a diastolic murmur in a healthy pregnant woman is rare, and therefore, the presence of a diastolic murmur should result in further evaluation to rule out valvular disease.

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Continuous murmurs A cervical venous hum is the most common innocent continuous murmur in children; it is also found frequently in nonpregnant women and was reported to be present in pregnant women [13,21]. The venous hum is heard maximally over the supraclavicular fossa just lateral to the sternocleidomastoid muscle. It is more prominent on the right side and only rarely below the clavicle. The mammary souffle is sometimes heard during late pregnancy and the early postpartum period, especially in lactating women, and is thought to be due to increased flow in the mammary vessels [21]. The mammary souffle can be either systolic or continuous [21,22]. The continuous murmur is louder in systole. The murmur is maximally heard at the second left or right intercostal space; but it can be louder at the third or fourth intercostal space and is occasionally bilateral. It can also be heard over the breast during the later phase of gestation and during the postpartum period in lactating women. The murmur is best heard when the patient is examined in the supine position and can be modified or obliterated in the upright position or when the stethoscope is pressed harder against the skin [21]. It is characterized by a significant day-to-dayor even beat-to-variation and disappears after termination of lactation [13]. In our experience, the mammary souffle is rarely appreciated by auscultation and is of a very limited clinical significance.

Chest X-ray The radiation dose associated with a routine chest X-ray examination is minimal: [23] (chapter 3). In spite of the small amount of radiation, this diagnostic test should not be used casually during pregnancy because of the potential adverse biological effects of any amount of radiation. When chest radiography is performed; the pelvic area should be shielded by protective lead material. Changes seen on chest films in normal pregnancy may simulate cardiac disease and should be interpreted with caution [24,25] (Table 2.2). Straightening of the left upper cardiac border because of prominence of the pulmonary conus is often seen. The heart may seem enlarged because of its horizontal positioning secondary to the elevated diaphragm. In addition, an increase in lung markings may simulate a pattern of flow redistribution typically seen with increased pulmonary venous pressure due to increased left atrial pressure. Pleural effusion is often found early postpartum [25,26]. It is usually small and bilateral, resorbing—one to two weeks after delivery. Table 2.2 Chest X-ray findings during normal pregnancy – – – –

Straitening of the left upper cardiac border Horizontal position of the heart Increased lung marking Small pleural effusion in early postpartum period

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PART II Cardiac Evaluation of the Pregnant Woman

Table 2.3 Electrocardiographic findings during normal pregnancy Left QRS axis deviation Q wave in leads II, III, and AVF T wave abnormalities (flattening or inversion in leads III, V1–V3) ST-segment and T wave changes (ritodrine tocolysis, cesarean section, anesthesia) Sinus tachycardia Atrial and ventricular premature beats Increased R/S ratio in leads V1 and V2

Electrocardiographic changes The change in position of the maternal heart in relation to the chest wall as a result of elevation of the diaphragm as well as changes in cardiac chambers size and wall thickness and possible changes in the electrical properties of the myocardium due to sympathetic and hormonal changes result in various changes in the surface electrocardiogram (Table 2.3). The most recent study by Sunitha et al. [27] reported on changes in the EKG in 50 normal pregnant women in the second and third trimester compared to 50 normal nonpregnant women of the same age group. This study confirmed findings described in a number of earlier studies [28–32] and reported EKG changes, which included deviation of the QRS axis toward left as pregnancy progressed (control 64 ± 7, second TR 53 ± 17, and third TR 46 ± 22), significantly increased

incidence of findings of prominent Q waves in leads II, III, and AVF, and T wave abnormalities (flattening or inversion) in leads III, V1–V3. T wave axis has been shown to rotate superiorly with advanced pregnancy [28]. EKG changes usually return to baseline after the delivery. ST segment depression of up to 1 mm has been described in 8–14% of pregnant women. These changes were transient and did not resemble ischemic changes [32]. Electrocardiographic changes have been described in healthy pregnant women receiving ritodrine tocolysis [33–35]. Sinus tachycardia has been reported in almost all patients; in addition, high incidence of ST-segment depression, T-wave flattening, and prolongation of QT interval were observed. ST-segment depression was found to be related to the degree of maternal tachycardia and the level of hypokalemia and hyperglycemia that occur during early ritodrine tocolysis [35]. Several reports have described electrocardiographic changes during cesarean section (Figure 2.1). In the majority of patients, ST-segment depressions mimicking myocardial ischemia were recorded. The majority of changes were reported to occur between induction of anesthesia and end of surgery [37] or early postsurgery. They were transient and were seen most commonly in leads I, AVL, and V5 [36–42]. A study by Mathew et al. [40] reported a high incidence of ST-segment depression on Holter monitoring in patients undergoing cesarean section but failed to find such changes during vaginal delivery in 22 women. Concomitant use of echocardiographic evaluation failed to detect regional wall motion abnormality during

Patient 3

Patient 5

preanesthetic

preanesthetic

1 min postdelivery

25 min postdelivery

Patient 9

Patient 10

preanesthetic

preanesthetic

4 min postdelivery

5 min postdelivery

Figure 2.1 ST-segment depression associated with cesarean section in healthy women. These changes were not associated with ventricular wall motion abnormalities. Source: McLintic et al. 1992 [36]. Reproduced with permission of Wolters Kluwer Health, Inc.

CHAPTER 2 Cardiovascular Evaluation During Pregnancy

the appearance of electrocardiographic changes [36,40], and in one study, troponin T levels were in the normal range at all time points studied [43]. These findings strongly suggest that ST-segment depression seen during cesarean section is not a result of myocardial ischemia [36,39,41]. Similar electrocardiographic changes have been documented with various anesthetic techniques [40,43]. The incidence however may be somewhat higher with the use of epidural vs. spinal or general anesthesia [40]. Second degree, type 1 AV block (Wenckebach) was reported in pregnancy and the puerperium by Copeland and Stern, the incidence, however, was very small (six cases of 26 000 electrocardiograms studied) [44]. The similar finding of multiple transient episodes of type I, second-degree AV block in 2 of 50 young, nonpregnant women without apparent heart disease [45] suggests that the relationship between pregnancy and the development of the block is doubtful. Increased susceptibility to arrhythmias during pregnancy can be manifested by frequent finding of sinus tachycardia and premature beats both supraventricular and ventricular [1]. Increased incidence of arrhythmias has been documented in normal pregnancies (Chapter 13). An early study (1970) of maternal electrocardiograms recorded during labor and delivery described high incidence of arrhythmias [46], which included atrial and ventricular premature beats, sinus bradycardia and tachycardia, episodes of sinus arrest, paroxysmal supraventricular tachycardia, and aberrant ventricular conduction. Shotan et al. [1] demonstrated a high incidence of atrial and ventricular premature beats in a group of pregnant women, referred for investigation of a heart murmur, in whom organic heart disease was excluded. A significant reduction in the number of ventricular premature beats was seen in nine of the women with a large number of premature beats when Holter monitoring was repeated postpartum [1]. An increased susceptibility to paroxysmal supraventricular tachycardia during normal pregnancies has also been demonstrated [47,48], and paroxysmal ventricular tachycardia has been reported in several cases with apparently normal heart [49].

Doppler echocardiography Transthoracic echocardiography is the preferred diagnostic test for the evaluation of structural, functional, and hemodynamic abnormalities during pregnancy for its general availability and safety. Published information on the safety of transesophageal information is limited [50]. A report of 12 procedures in 10 patients between 5 and 31 weeks of gestation was published by Stoddard et al. [51] and described the use of transesophageal echocardiography in pregnant women. The procedure was performed in the first (n = 2), second (n = 5), and third (n = 5) trimester of pregnancy. Midazolam in a dose ranging from 1.0 to 4.0 mg was used for sedation, and the probe insertion time ranged between 6 and 21 minutes. The procedure was found to be safe and well tolerated, without evidence of adverse effect to the fetus. It

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should be noted however, that pregnancy-induced anatomic changes such as swelling of the oropharyngeal tissues and decreased caliber of the glottis opening can interfere with the procedure. Caution should be used in administering any level of sedation to a pregnant woman because of the increased risk of aspiration and possible difficult airway. Sedation during pregnancy There are no category A drugs used for sedation for patients undergoing a TEE examination during pregnancy. Category B and when necessary, category C drugs may be recommended. Category D drugs may be used when the benefits outweigh the risks [52]. Topical anesthesia with lidocaine (category B) is safe. The patient should however, be instructed to gurgle and spit out the drug, rather than swallow it [53]. Benzodiazepines (diazepam and midazolam) are commonly used in the nonpregnant patient before TEE to reduce anxiety, increase muscle relaxation, and induce brief amnesia. The guidelines for the performance of TEE by the society of echocardiography and cardiovascular anesthesiologists recommend avoiding the use of benzodiazepines in pregnancy in the first trimester [54]. Although the safety of one-time use is not known, a sustained use of diazepam during early part of pregnancy may be associated with cleft palate. The use in the first trimester may also lead to mental retardation, neurological and cardiac defects, and Mobius syndrome (neurological disorder with normal intelligence but sixth and seventh nerve paralysis) [52]. Data on the use of Midazolam (category D) has been limited, it has not been associated with congenital abnormalities, and it is the preferred benzodiazepine when other drugs cannot be used. Meperidine (category B for regular use and D for prolonged use) does not seem to be teratogenic but may cause maternal respiratory depression and seizures as well as loss of fetal beat to beat cardiac variability that can last for up to one hour after drug administration, but not fetal distress [53]. Fentanyl (category C) has a rapid onset of action and shorter patient recovery time compared to meperidine and is not teratogenic. Although this drug appears safe when given in low dose during pregnancy, guidelines for endoscopy during pregnancy prefer meperidine over fentanyl in pregnancy [53]. Sedation during lactation The American academy of pediatrics considers the effect of midazolam on the nursing infant unknown [55]. Based on limited available information, it is recommended to withhold nursing for at least four hours following administration of midazolam. Fentanyl is excreted in breast milk, but the concentration is too low to be pharmacologically significant and is undetectable by 10 hours [56]. The American Academy of pediatrics considers fentanyl compatible with breast-feeding [55]. Meperidine is concentrated in breast milk and may be detectable up to 24 hours after administration. It can be

24

PART II Cardiac Evaluation of the Pregnant Woman

dimension and volume increase slightly but significantly (5–7% in the third trimester), although it remains within normal limits. Left ventricular mass increase gradually (∼20– 25% in the third trimester) as a result of the increased left ventricular size and increased posterior wall and intraventricular septal thickness. Similar to the left ventricle, right ventricle also increases in size over the course of pregnancy. There is inconsistency among studies regarding the change in left ventricular ejection fraction during normal pregnancy [58], but most studies have found no significant change [57,59–61]. Gilson et al. [60] found a decrease in the ratio of the loaddependent wall stress to velocity of circumferential fiber shortening, implying enhanced myocardial contractility. In contrast, other investigators have reported a decline in LVEF or fractional shortening especially in the third trimester [62–66]. Naqvi and coworkers [67] used speckle tracking strain rate and found an increase in cardiac contractility, which was demonstrated by an increase in LV radial and longitudinal rate of deformation, especially during the first and second trimesters. Savu et al. [57] also reported an increase in LV and right ventricular longitudinal strain rate in the first trimester and LV stroke work toward the third trimester in spite no change in EF. There have been a number of reports of changes in LV diastolic function during normal pregnancy. Most studies

Table 2.4 Echocardiographic findings during normal pregnancy – Slightly increased left ventricular diastolic and systolic dimensions – Unchanged left ventricular ejection fraction or fractional shortening – Increased left ventricular radial and longitudinal strain – Moderate increase in left atrium diameter and volume – Moderate increase in right atrial and ventricular size – Progressive dilatation of pulmonary, tricuspid, and mitral valve annuli – Functional pulmonary, tricuspid, and mitral regurgitation – Small pericardial effusion

transferred to the breast-fed infant and may cause neurobehavioral effects. Although it has been classified as compatible with breast-feeding [55], the guidelines recommend the use of an alternative such as fentanyl whenever possible especially when the woman is nursing a newborn or preterm infant [53]. Echocardiographic findings in normal pregnancy The increased blood volume during pregnancy results in a small but significant increase in the size of cardiac chambers (Tables 2.4 and 2.5) [57–59]. Left ventricular end-diastolic

Table 2.5 Two-dimensional echocardiographic parameters and myocardial velocities

Variable

Control

Trimester 1 (13 wk [12–16 wk])

Trimester 2 (23 wk [22–24 wk])

Trimester 3 (32 wk [32–33 wk])

Postpartum (4 mo [3–6 mo])

p Valuea

p Value control vs. postpartum

LVEDD (mm)

43 ± 3

45 ± 3b

47 ± 3b

47 ± 3b

46 ± 2.5c

20 weeks gestation) in women with AVSD, arrhythmias occurred in 19% of pregnancies, and heart failure occurred in 2% of pregnancies [31]. Recurrence of CHD was found in 12% of offspring. Symptomatic women with severe left atrioventricular valve regurgitation or ventricular dysfunction should be considered for valve repair or replacement prior to pregnancy. Patent ductus arteriosus Repaired patent ductus arteriosus (PDA) and small restrictive PDA, without LV volume overload or pulmonary hypertension do not impart any significant pregnancy risk. Larger PDA can be associated with LV volume overload and pulmonary arterial hypertension. PDA with pulmonary hypertension and Eisenmenger syndrome is associated with high pregnancy risk and is discussed later in the chapter. Left ventricular outflow tract lesions Aortic stenosis Aortic stenosis (AS) in women of childbearing age is usually secondary to bicuspid aortic valve (BAV) disease. BAV can be associated with dilation of the proximal ascending aorta and/or coarctation of the aorta. Patients with BAV disease should have complete imaging of the thoracic aorta. Unicuspid aortic valves, subvalvular stenosis, or supravalvular stenosis are less common causes of left ventricular outflow tract obstruction (see also Chapter 6). In pregnant women with mild AS, complications are rare. However, women with moderate and severe LV outflow obstruction are at risk of developing cardiac complications because the increased plasma volume and cardiac output of pregnancy may be poorly tolerated. Maternal mortality is rare in contemporary series [32–35]. Heart failure is the most common complication during pregnancy in women with severe AS with rates varying between 10% and 100%. The risk of developing heart failure is related to the symptom status of the mother prior to pregnancy [34]. Atrial and ventricular arrhythmias are less common [32–35]. Women with severe AS who develop angina should be admitted to hospital for bed rest and observation. Heart failure should be treated with diuretics. Valvuloplasty or valve replacement should be considered, but only in women whose symptoms are refractory to medical therapy. Even in severe AS, vaginal delivery is appropriate, with good pain management and assisted second stage of labor to avoid maternal expulsive effort. Blood pressure monitoring with an arterial line may be helpful. Blood loss leading to loss of preload in women with hypertrophied noncompliant left ventricles is likely to result in poorly tolerated hypotension at the time of delivery, so it is particularly important to maintain intravascular volume. Women with severe AS who are symptomatic or have LV systolic dysfunction should undergo intervention prepregnancy. Asymptomatic women with severe AS who develop

symptoms or demonstrate a decrease in blood pressure during exercise testing should also have an intervention prepregnancy [7]. Prophylactic replacement of the ascending aorta prior to pregnancy is recommended in BAV aortopathy if the aortic diameter exceeds 5.0 cm [7]. Coarctation of the aorta Coarctation of the aorta can be isolated or occur in conjunction with other congenital cardiac lesions, especially BAV. Saccular (berry) aneurysms in the cerebral circulation can be found in patients with coarctation of the aorta. Most women of childbearing age will have had a coarctation repair in childhood, by one of a variety of coarctation repair techniques, including end-to-end anastomosis, subclavian flap repair, interpositional graft, intraluminal stent, and, rarely, bypass graft. Systemic hypertension is common after coarctation repair even in absence of recoarctation. Recoarctation can be identified by arm and leg blood pressure discrepancies, high gradient across the coarctation repair site by echocardiography, or by imaging with computed tomography or cardiac magnetic resonance. Aneurysms at the coarctation repair site are more common after Dacron patch repairs and subclavian flap repairs. Women should have aortic imaging with computed tomography or magnetic resonance imaging as adults prior to pregnancy. MRI early pregnancy may be helpful if not previously done. Most pregnancy outcomes are reported in women with repaired coarctation. The main concern during pregnancy is related to new or preexisting hypertension. Women with preexisting hypertension are at higher risk of developing preeclampsia. Hypertensive complications are reported in more than 25% of pregnancies [19,36,37]. The hypertension risk in pregnancy is related to the coarctation gradient. Poorly controlled hypertension can lead to perinatal and maternal complications. Optimal blood pressure targets for treatment of hypertension in the setting of coarctation or re-coarctation are not established. There is theoretical concern that severe coarctation will result in decreased blood pressure distal to the site of stenosis and consequent placental hypoperfusion. Women with Turner syndrome are at risk for aortic dissection. In Turner syndrome with coarctation, BAV, and/or aortopathy, aortic dissection occurs more frequently. Pregnancy in women with Turner syndrome and a dilated aorta should be avoided. In women with short stature, aortic diameters need to be referenced to body surface area. Women with unrepaired severe coarctation are at higher risk for pregnancy complications and should have repair prior to pregnancy (see also Chapter 20). Right ventricular outflow tract lesions Pulmonary stenosis Pulmonary stenosis is often due to a bicuspid or dysplastic pulmonary valve. Women may have associated dilated pulmonary arteries. Pulmonary valve stenosis (PS), even when severe, is usually well tolerated during pregnancy (Chapter 6).

CHAPTER 5 Congenital Heart Disease and Pregnancy

Tetralogy of Fallot ToF is the most common cyanotic cardiac lesion and consists primarily of a malalignment VSD and right ventricular outflow tract obstruction, with associated overriding aorta and right ventricular hypertrophy. Almost all pregnant women with ToF will have had an intracardiac repair in childhood. After intracardiac repair, residual pulmonary regurgitation (especially following transannular patch repair) or residual pulmonary stenosis (often after valve sparing repair) are common. Patients with significant pulmonary regurgitation may also have right ventricular dilation, right ventricular dysfunction, and tricuspid regurgitation secondary to annular dilation. Arrhythmias occur in patients with ToF secondary to surgical scar and to dilation of the right atrium and ventricle. Pregnancy imposes a hemodynamic load on the right ventricle and predisposes to arrhythmia for that reason as well as because of proarrhythmic hormonal changes. In general, women with ToF who have normal right ventricular function and no history of arrhythmias do well during pregnancy. Reported rates of adverse maternal cardiac events have varied between 0% and17% [38–41]. Both atrial and ventricular arrhythmias are described during pregnancy. The risk of right-sided heart failure is higher in presence of severe pulmonary regurgitation, right ventricular systolic dysfunction, right ventricular hypertrophy, branch pulmonary artery stenosis, or twin pregnancy [39]. Pulmonary valve replacement prior to pregnancy is advised in women with severe pulmonary regurgitation who are symptomatic or in absence of symptoms when there is significant right ventricular systolic dilation or dysfunction [7]. During pregnancy, serial clinical and echocardiographic assessment should be performed during and early postpartum to evaluate the size and function of the right ventricle and the severity of pulmonary and tricuspid regurgitation. Vaginal delivery is recommended. Ebstein anomaly Ebstein anomaly is a congenital malformation of the tricuspid valve with additional involvement of RV myocardium and the RV outflow tract in many cases. The septal and posterior leaflets of the tricuspid valve are displaced apically and malformed leading to atrialization of part of the right ventricle. The anterior tricuspid leaflet is also abnormal. The valve abnormalities are associated with tricuspid regurgitation, or much less commonly, tricuspid stenosis. The functional right ventricle may be hypoplastic, or dilated, if there has been chronic volume overload from tricuspid regurgitation. Right atrial dilation and accessory pathways increase the risk of atrial arrhythmias. A patent foramen ovale or an ASD is common and may allow shunt reversal due to high right atrial pressure with right to left flow causing low oxygen saturation at rest or only with exercise and potential for paradoxical emboli. The volume load of pregnancy can contribute to cardiac complications in women with Ebstein anomaly. Most women do well during pregnancy. Arrhythmias are the most

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common complication [42,43]. Heart failure is rare. Women with interatrial shunt may demonstrate worsening cyanosis during pregnancy because of the inability of the right ventricle to handle the volume load of pregnancy leading to higher right atrial pressure promoting right to left shunting. Women with Ebstein anomaly who have symptoms or cyanosis at rest or with exercise should have repair prior to pregnancy. Complete transposition of the great arteries Complete transposition of the great arteries is a rare cyanotic congenital cardiac condition in which there is ventriculoarterial discordance. Patients would have undergone repair in childhood, having had either an atrial switch operation (Mustard or Senning operation) or an arterial switch operation (Jatene operation). The difference in childhood surgery drives substantial differences in clinical course as adults. Atrial switch operations (Mustard/Senning operation) The older surgical approach was the atrial switch operation (Mustard or Senning operation). This operation diverted blood at the atrial level by constructing intraatrial baffles. While this approach corrected cyanosis and improved longevity, the operation left patients with a subaortic right ventricle supporting the systemic circulation and a tricuspid valve in the subaortic position prone to regurgitation, as well as a propensity to arrhythmias. The most common complications late after an atrial switch operation are atrial and ventricular arrhythmias, tricuspid regurgitation, and subaortic right ventricular systolic dysfunction and failure. Arrhythmias and heart failure are the most common cardiac complications during pregnancy, although the rates of cardiac complications vary among studies [11,13,44–46]. During pregnancy, the hemodynamic load on the subaortic right ventricle contributes to worsening ventricular function, tricuspid valve regurgitation, and clinical heart failure. These hemodynamic changes can also precipitate arrhythmias; atrial arrhythmias, ventricular tachycardia, and cardiac arrest are reported. Some women who develop deterioration in subaortic right ventricular function or worsening of tricuspid regurgitation do not recover after pregnancy [11,13]. There is no way to predict which women will develop permanent deterioration in subaortic ventricular function, and all women should understand this risk before embarking on a pregnancy. Careful clinical and echocardiographic surveillance during pregnancy is important for early detection of heart failure. When clinical identification of heart failure is difficult, BNP may be a helpful surrogate marker. Women with atrial switch operations who have severe subaortic right ventricular dysfunction and/or severe tricuspid regurgitation should be advised against pregnancy. There are significant perinatal risks as well from preterm deliveries and low birth weight babies [11].

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PART III Cardiac Disorders and Pregnancy

Arterial switch operation (Jatene operation) The more contemporary surgical approach, the arterial switch operation (Jatene operation), seems to be associated with less late complications, but dilated aortic root, supravalvular aortic and pulmonic stenosis, and ostial stenosis of a reimplanted coronary artery can be found in adults as late sequelae. Young women following arterial switch operation have recently reached childbearing age. In an early reported cohort of 13 term pregnancies in women with arterial switch operations, one woman with ventricular dysfunction had ventricular tachycardia during pregnancy, and one woman with a mechanical valve had valve thrombosis [47]. In women with preserved ventricular function and no significant great vessel dilation or valve disease, pregnancy will likely be well tolerated. Congenitally corrected transposition of the great arteries Congenitally corrected transposition of the great arteries, or atrioventricular and ventriculoarterial discordance, is rare. With this anatomical arrangement, the morphologic right ventricle serves as the subaortic ventricle supporting the systemic circulation. Congenitally corrected transposition can occur in isolation but is often associated with additional congenital cardiac lesions, especially pulmonary stenosis, VSD, and Ebstein-like malformation of the tricuspid valve. Late complications may be secondary to subaortic right ventricular dysfunction, tricuspid valve regurgitation, conduction disease including complete heart block or other associated congenital cardiac lesions. Although many women do well during pregnancy, deterioration in subaortic right ventricular function and tricuspid valve regurgitation, heart failure, and atrial arrhythmias are reported [48,49]. Women with good functional class and normal subaortic ventricular function are unlikely to develop cardiac complications. Women with severe subaortic right ventricular dysfunction, with or without tricuspid valve regurgitation, are at risk for further deterioration in ventricular function and clinical heart failure during pregnancy. Close surveillance with serial transthoracic echocardiograms is advised, and arrhythmias should be sought and rapidly controlled. Truncus arteriosus Truncus arteriosus is a rare congenital lesion in which a single arterial vessel exits the heart giving rise to the pulmonary and systemic circulation. A nonrestrictive VSD is associated. Truncus repair involves isolating the pulmonary arteries from the truncus and reattaching them to the right ventricle with a conduit. Conduit failure, truncal (“aortic”) root dilation, truncal (“aortic”) valve regurgitation, branch pulmonary artery stenosis, ventricular dysfunction, ischemia, and pulmonary vascular disease have all been described late after repair. Few cases of pregnancy have been reported in women born with truncus arteriosus; however, women

without significant ventricular dysfunction or residual valve lesions will likely do well [50]. Fontan operation The Fontan operation, used to palliate patients with a single ventricle, has had several modifications since it was first introduced. Originally conceived for tricuspid atresia, its use has expanded to palliation of other single ventricle lesions. Caval flow enters directly into the pulmonary arteries without interposition of a subpulmonary ventricle: the superior vena cava is connected directly to the pulmonary arteries (Glenn operation, bidirectional cavopulmonary anastomosis), and the inferior vena cava is connected to the pulmonary arteries using one of right atrial to pulmonary artery connection, intraatrial conduit (lateral tunnel Fontan), or extracardiac conduit (extracardiac Fontan). Complications increase with age in this population. Some women may have cyanosis due to arteriovenous malformations or Fontan fenestration. Interatrial reentrant arrhythmias are common. Failure of the Fontan circulation occurs in patients who, over time, develop diastolic or systolic dysfunction, atrioventricular valve regurgitation, and/or increase in pulmonary vascular resistance (overt pulmonary hypertension does not occur). Clinical heart failure may be difficult to identify in this population. The low-flow circuit also predisposes to thromboembolic complications, which, in the setting of Fontan physiology, can be fatal. Protein-losing enteropathy often identifies endstage disease. Women following Fontan operations who have ventricular dysfunction, moderate to severe atrioventricular valvular regurgitation, cyanosis or protein-losing enteropathy should be advised against pregnancy. The hemodynamic changes that occur during pregnancy can destabilize the Fontan circulation. Women are at risk of developing atrial arrhythmias and heart failure [51–53]. In a systematic review of studies published between 1986 and 2015, supraventricular arrhythmia occurred in 8.4% of pregnancies and heart failure occurred in 3.9% of pregnancies [53]. The prothrombotic state of pregnancy also increases the risk of thromboembolic complications [52,53]. Women with a history of arrhythmias or thromboembolic complications should receive anticoagulation during pregnancy. While some experts advocate anticoagulation therapy in all women with Fontan circulation during pregnancy, the benefit of anticoagulation needs to be weighed against the risk of bleeding, which is also increased in this population, reported in up to 25% of pregnancies [53]. Our group only uses anticoagulation therapy in pregnant women with the Fontan operation, who are at high risk for thromboembolic complications. Although maternal deaths are rare, careful patient selection for pregnancy is crucial. Shortened life span is expected following the Fontan operation and is a critical issue to sensitively explore and clarify during preconception counseling, since it may influence decisions regarding proceeding with pregnancy [17]. In addition to maternal cardiac risks, there are significant fetal and neonatal risks. Miscarriages are common, occurring

CHAPTER 5 Congenital Heart Disease and Pregnancy

71

70% 60% 59% 50% 40%

45%

30% 20% 20% 10% 5%

0% Live births

Premature delivery

Small for gestational age

Neonatal death

Figure 5.3 Perinatal complications in women with the Fontan operation. The y axis represents the percent of pregnancies complicated by perinatal complications. Source: Modified from Garcia Ropero et al. [53].

in up to 45% of pregnancies in women with Fontan. Approximately, half of pregnancies are complicated by adverse perinatal outcomes including prematurity, small for gestational age babies and fetal death (Figure 5.3) [53]. Serial clinical and echocardiographic assessment should be performed during pregnancy and early postpartum to identify changes in ventricular function and atrioventricular valve regurgitation. Delivery must be carefully planned. The Fontan circulation is preload dependent and Valsalva maneuvers, blood loss or arterial or venous vasodilatation from medications during labor and delivery can result in circulatory collapse. Women with hypoplastic left heart syndrome have a more complex Fontan operation. The Norwood procedure is used as initial palliation of children with hypoplastic left heart syndrome. The operation is the first part of a staged procedure and involves the construction of a neoaorta and creation of an aortopulmonary shunt. This is followed by the creation of a bidirectional cavopulmonary shunt (Glenn operation) and eventually a Fontan operation. Potential pregnancy complications in women with repaired hypoplastic left heart syndrome relate to the hemodynamic stress on the morphologic subaortic RV and the reconstructed aorta as well as the other Fontan pregnancy complications already described. Women born with hypoplastic left heart syndrome and managed as described are only now reaching childbearing age, but pregnancy outcomes are not yet well described [54]. Cyanotic heart disease and Eisenmenger syndrome Cyanotic heart disease Cyanotic heart disease not primarily due to pulmonary hypertension is associated with a variety of congenital cardiac lesions including unrepaired TOF, pulmonary atresia with aortopulmonary collaterals, Ebstein anomaly with

shunt reversal, and corrected transposition of the great arteries with VSD and pulmonary stenosis. Cyanosis due to pulmonary hypertension and shunt reversal is discussed in the section on Eisenmenger syndrome that follows. While some women with cyanotic heart disease may experience an uncomplicated pregnancy, maternal death, heart failure, arrhythmias, hemoptysis, thromboembolic complications, cerebrovascular events, and endocarditis are reported [55,56]. Preconception assessment by an expert in CHD and pregnancy is mandatory. In a study of 71 pregnancies in women with cyanotic heart disease, 27% were complicated by cardiac events. Perinatal complications are even more common: in a study of 96 pregnancies, only 43% result in a live birth, lack of erythrocytosis and higher arterial oxygen saturation were important predictors of successful perinatal outcomes (Figure 5.4) [56]. Women with resting oxygen saturation less than 85% should be advised against pregnancy because of maternal risk and expectation of very poor neonatal outcome [7]. Delivery in women with cyanotic heart disease requires careful coordination. Oxygen saturation should be monitored throughout labor and delivery and well into the postpartum period as well. Blood loss or hypotension from medications at the time of delivery or postpartum can lead to worsening right to left shunting. Eisenmenger syndrome Eisenmenger syndrome occurs as a complication of larger left to right shunts. Pulmonary arterial hypertension leads to reversal of the shunt, becoming bi-directional or rightto-left across the septal defect or aortopulmonary communication. Eisenmenger syndrome is a multisystem disease with cyanosis, secondary erythrocytosis, hyper viscosity syndrome, thromboembolic events, hemoptysis, cerebrovascular complications, renal dysfunction, gout, cholelithiasis, and hypertrophic osteoarthropathy. Life span is shortened.

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PART III Cardiac Disorders and Pregnancy

100% 90%

92%

80% 70% 60% 50% 40%

45%

30% 20% 10%

12%

0% Oxygen saturation ≤85%

Oxygen saturation 85–89%

Oxygen saturation ≥90%

Figure 5.4 Live birth rates in women with cyanotic heart disease. The y axis represents the percent of live births in women with cyanotic heart disease. Source: Modified from Presbitero et al. [56].

The increased volume load of pregnancy and pregnancyassociated reduction in systemic vascular resistance predispose to further right-to-left shunting and worsening hypoxia as well as volume overload of the right heart. Hypoxemia can lead to further pulmonary vasoconstriction and pulmonary hypertensive crisis. Thromboembolic complications increase during pregnancy because of the hypercoagulable state. Maternal mortality is high. In a literature review of publications between 1997 and 2007, mortality in women with idiopathic pulmonary arterial hypertension, pulmonary arterial hypertension in association with congenital heart, and pulmonary arterial hypertension from other causes was 17%, 28%, and 33% respectively [25]. Reported causes of death include right heart failure, cardiogenic shock, arrhythmias and sudden death, thromboembolic complications, and pulmonary artery rupture. In addition to maternal mortality, morbidity is high due to right heart failure, arrhythmias, and nonfatal thromboembolic disease. Although a few studies from specialized centers have reported lower maternal mortality than previously reported [57,58], in view of the high maternal morbidity and mortality, women with significant pulmonary hypertension from any cause should be discouraged from pregnancy, and if pregnant offered termination as the safest option [7]. There have been significant advances in the treatment of pulmonary hypertension, and while it is likely that these advanced therapies can improve pregnancy outcomes, this has not been clearly demonstrated (see also Chapter 16). Women taking pulmonary arterial hypertension medications prior to pregnancy should continue the medications during pregnancy when possible. However, bosentan, and probably other endothelin receptor antagonists as well, is teratogenic, so alternative medications should be considered when possible.

Cardiac decompensation can occur at the time of delivery, so careful planning is essential. Blood loss or hypotension from anesthetic agents or other drugs can lead to worsening right to left shunting, hypoxemia, pulmonary vasoconstriction, and a vicious spiral potentially to death. Vaginal deliveries are often possible with close monitoring, good pain management, and careful postpartum surveillance. Aggressive postpartum diuresis is helpful to prevent right heart failure, but caution is advised because over diuresis can be dangerous in women with Eisenmenger syndrome. Reported maternal mortality extends through the first week postpartum, so extended postpartum in-hospital monitoring for seven days or so is justified.

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27 Warnes, C.A., Williams, R.G., Bashore, T.M. et al. (2008). ACC/AHA 2008 Guidelines for the Management of Adults with Congenital Heart Disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to develop guidelines on the management of adults with congenital heart disease). Circulation 118: e714–e833. 28 Zuber, M., Gautschi, N., Oechslin, E. et al. (1999). Outcome of pregnancy in women with congenital shunt lesions. Heart 81: 271–275. 29 Yap, S.C., Drenthen, W., Meijboom, F.J. et al. (2009). Comparison of pregnancy outcomes in women with repaired versus unrepaired atrial septal defect. BJOG 116: 1593–1601. 30 Yap, S.C., Drenthen, W., Pieper, P.G. et al. (2010). Pregnancy outcome in women with repaired versus unrepaired isolated ventricular septal defect. BJOG 117: 683–689. 31 Drenthen, W., Pieper, P.G., van der Tuuk, K. et al. (2005). Cardiac complications relating to pregnancy and recurrence of disease in the offspring of women with atrioventricular septal defects. Eur Heart J 26: 2581–2587. 32 Silversides, C.K., Colman, J.M., Sermer, M. et al. (2003). Early and intermediate-term outcomes of pregnancy with congenital aortic stenosis. Am J Cardiol 91: 1386–1389. 33 Yap, S.C., Drenthen, W., Pieper, P.G. et al. (2008). Risk of complications during pregnancy in women with congenital aortic stenosis. Int J Cardiol 126: 240–246. 34 Orwat, S., Diller, G.P., van Hagen, I.M. et al., and ROPAC Investigators (2016). Risk of pregnancy in moderate and severe aortic stenosis: from the Multinational ROPAC Registry. J Am Coll Cardiol 68: 1727–1737. 35 Hameed, A., Karaalp, I.S., Tummala, P.P. et al. (2001). The effect of valvular heart disease on maternal and fetal outcome of pregnancy. J Am Coll Cardiol 37: 893–899. 36 Beauchesne, L.M., Connolly, H.M., Ammash, N.M., and Warnes, C.A. (2001). Coarctation of the aorta: outcome of pregnancy. J Am Coll Cardiol 38: 1728–1733. 37 Vriend, J.W., Drenthen, W., Pieper, P.G. et al. (2005). Outcome of pregnancy in patients after repair of aortic coarctation. Eur Heart J 26: 2173– 2178. 38 Veldtman, G.R., Connolly, H.M., Grogan, M. et al. (2004). Outcomes of pregnancy in women with tetralogy of Fallot. J Am Coll Cardiol 44: 174– 180. 39 Greutmann, M., Von Klemperer, K., Brooks, R. et al. (2010). Pregnancy outcome in women with congenital heart disease and residual haemodynamic lesions of the right ventricular outflow tract. Eur Heart J 31: 1764–1770. 40 Balci, A., Drenthen, W., Mulder, B.J. et al. (2011). Pregnancy in women with corrected tetralogy of Fallot: occurrence and predictors of adverse events. Am Heart J 161: 307–313. 41 Kamiya, C.A., Iwamiya, T., Neki, R. et al. (2012). Outcome of pregnancy and effects on the right heart in women with repaired tetralogy of Fallot. Circ J 76: 957–963. 42 Connolly, H.M. and Warnes, C.A. (1994). Ebstein’s anomaly: outcome of pregnancy. J Am Coll Cardiol 23: 1194–1198. 43 Kanoh, M., Inai, K., Shinohara, T. et al. (2018). Influence of pregnancy on cardiac function and hemodynamics in women with Ebstein’s anomaly. Acta Obstet Gynecol Scand https://doi.org/10.1111/aogs.13373. 44 Canobbio, M.M., Morris, C.D., Graham, T.P., and Landzberg, M.J. (2006). Pregnancy outcomes after atrial repair for transposition of the great arteries. Am J Cardiol 98: 668–672. 45 Gelson, E., Curry, R., Gatzoulis, M.A. et al. (2011). Pregnancy in women with a systemic right ventricle after surgically and congenitally corrected transposition of the great arteries. Eur J Obstet Gynecol Reprod Biol 155: 146–149. 46 Drenthen, W., Pieper, P.G., Ploeg, M. et al. (2005). Risk of complications during pregnancy after Senning or Mustard (atrial) repair of complete transposition of the great arteries. Eur Heart J 26: 2588– 2595.

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47 Tobler, D., Fernandes, S.M., Wald, R.M. et al. (2010). Pregnancy outcomes in women with transposition of the great arteries and arterial switch operation. Am J Cardiol 106: 417–420. 48 Connolly, H.M., Grogan, M., and Warnes, C.A. (1999). Pregnancy among women with congenitally corrected transposition of great arteries. J Am Coll Cardiol 33: 1692–1695. 49 Kowalik, E., Klisiewicz, A., Biernacka, E.K., and Hoffman, P. (2014). Pregnancy and long-term cardiovascular outcomes in women with congenitally corrected transposition of the great arteries. Int J Gynaecol Obstet 125: 154–157. 50 Steckham, K.E., Bhagra, C.J., Siu, S.C., and Silversides, C.K. (2017). Pregnancy in women with repaired truncus arteriosus: a case series. Can J Cardiol 33: 1737.e1–1737.e3. 51 Canobbio, M.M., Mair, D.D., van der Velde, M., and Koos, B.J. (1996). Pregnancy outcomes after the Fontan repair. J Am Coll Cardiol 28: 763–767. 52 Gouton, M., Nizard, J., Patel, M. et al. (2015). Maternal and fetal outcomes of pregnancy with Fontan circulation: a multicentric observational study. Int J Cardiol 187: 84–89.

53 Garcia Ropero, A., Baskar, S., Roos Hesselink, J.W. et al. (2018). Pregnancy in women with a Fontan circulation: a systematic review of the literature. Circ Cardiovasc Qual Outcomes 11: e004575. 54 Opotowsky, A.R., Shellenberger, D., Dharan, V. et al. (2010). Successful pregnancies in two women with hypoplastic left heart syndrome. Congenit Heart Dis 5: 476–481. 55 Ladouceur, M., Benoit, L., Basquin, A. et al. (2017). How pregnancy impacts adult cyanotic congenital heart disease: a multicenter observational study. Circulation 135: 2444–2447. 56 Presbitero, P., Somerville, J., Stone, S. et al. (1994). Pregnancy in cyanotic congenital heart disease. Outcome of mother and fetus. Circulation 89: 2673–2676. 57 Kiely, D.G., Condliffe, R., Webster, V. et al. (2010). Improved survival in pregnancy and pulmonary hypertension using a multiprofessional approach. BJOG 117: 565–574. 58 Ladouceur, M., Benoit, L., Radojevic, J. et al. (2017). Pregnancy outcomes in patients with pulmonary arterial hypertension associated with congenital heart disease. Heart 103: 287–292.

CHAP T E R 6

Native Valvular Heart Disease and Pregnancy Uri Elkayam1,2 1 Department

of Medicine, Division of Cardiovascular Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA

2 Department

of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA

The presence of valvular heart disease (VHD) due to both congenital and acquired etiologies in pregnant patients continues to pose a challenge to clinicians and their patients [1]. This condition increases the risk of pregnancy to both the mother and the fetus and requires specific care to avoid or at least minimize maternal morbidity and mortality and assure fetal well-being.

General considerations Preconception evaluation The management of women with VHD should ideally begin before conception. A careful cardiac examination and assessment of functional capacity are needed to determine the likelihood of the patient to tolerate the increased hemodynamic burden of pregnancy and the risk of complications during gestation (see also Chapter 4). Preconception evaluation, therefore, should include a careful history and physical examination, a 12-lead electrocardiogram, an echocardiogram, and a Doppler study. Because of the limitations of the various noninvasive as well as invasive methods of assessment of the severity of valvular disease [2], an exercise test, preferably a cardiopulmonary exercise test [3] is mandatory for an objective assessment of functional capacity, especially in the patient who claims to be asymptomatic or have nonspecific symptoms. The anticipated risk of pregnancy on the basis of the evaluation should be discussed with the patient and her family by both the cardiologist and the obstetrician. In anticipation of pregnancy, drugs with potential harm to the fetus should be discontinued (see also Chapter 32) [4]. Antepartal and peripartal care Antepartal care should include a joint obstetric and cardiologic evaluation with a frequency determined by the type and severity of the disease as well as the patient condition. In general, antenatal visits should be scheduled every month in

women with mild disease and every 2 weeks in women with moderate and severe disease until 28–30 weeks and every 1–2 weeks thereafter until delivery. When drug therapy seems necessary, the smallest therapeutic dose of drugs known to be safe for the fetus should be used. In assessing a patient with VHD during pregnancy, it should be noted that the evaluation may be complicated by normal anatomical and functional changes of the cardiovascular system that may result in signs and symptoms that can mimic heart disease (see also Chapter 2). These include fatigue, decreased exercise capacity, shortness of breath, palpitations, light-headedness, and even syncope. Physical examination often reveals increased jugular venous pulsation, leg edema, palpable right ventricular heave, and a systolic murmur. Therefore, in many cases, it is imperative to use additional diagnostic tools including brain natriuretic peptide (BNP) or NT-proBNP levels, hemodynamic assessment using EchoDoppler or invasive studies, to obtain accurate information about cardiac status before therapeutic decisions are made. Labor and delivery Timing and mode of delivery should be discussed and decided upon jointly by the obstetrician, cardiologist, neonatologist, and obstetric anesthesiologist. In general, vaginal delivery with appropriate anesthesia and shortening of the second stage is safe and can be performed in the majority of patients with VHD [1,5,6]. Cesarean section is potentially associated with a higher rate of complications [7] and should usually be performed for obstetric indications and in the patient with cardiac instability. Hemodynamic monitoring during labor and delivery allows hemodynamic assessment and optimization prior to delivery and continuous monitoring during and after the delivery. We recommend and use hemodynamic monitoring in all symptomatic patients with VHD and in patients with severe valvular stenosis, left ventricular dysfunction, elevated BNP levels, and pulmonary hypertension.

Cardiac Problems in Pregnancy, Fourth Edition. Edited by Uri Elkayam. © 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.

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Early puerperium In spite of the blood loss associated with delivery, the early puerperium is associated with increased venous return to the heart caused by blood shift from the emptied uterus into the systemic circulation, decreased caval compression, and mobilization of fluid from the limbs and lower part of the body (Chapter 1). These hemodynamic changes can lead to heart failure [5,6] and require close observation for 12–24 hours after the delivery and often the use of diuretics before and immediately after the delivery.

Antibiotic prophylaxis The use of antibiotic prophylaxis for uncomplicated vaginal delivery in patients with native valvular disease was not recommended by the last American Heart Association/ American College of Cardiology Guidelines [8] or by the European Society of Cardiology guidelines [9] based on a very low incidence of endocarditis in pregnancy [9]. A recent review of all cases of maternal bacteremia between 2009 and 2012 among >37 000 obstetric cases found however, 58 cases of bacteremia with 19 diagnosed prepartum, 20 intrapartum, and 19 postpartum. There was no maternal death [10]. Multiple earlier studies also reported a higher rate of bacteremia after labor and delivery. Boggess et al. [11] detected bacteremia in 14% of 93 women after labor or rupture of membranes, and many of the organisms isolated were capable of causing endocarditis. Petanovi´c and Zagar [12] reported positive blood cultures in 19% of 235 blood culture samples examined in women during delivery, and Furman et al. [13] reported bacteremia in the postpartum in 9.4% of 968 women with and 5% of 4692 women without prelabor rupture of membranes. Cesarean section is associated with significantly higher incidence of infections compared to vaginal delivery. Rate of wound infection and other infections can be as high as 25% [14]. There has been a debate about the benefit of prophylactic antibiotics for a woman who has an elective cesarean section with intact membranes and without labor. A meta-analysis of four studies found that antibiotic prophylaxis resulted in a decrease in postoperative fever (RR: 0.25; 95% CI: 0.14–0.44) and endometritis [15]. Antimicrobial prophylaxis is recommended for all cesarean deliveries unless the patient is already receiving appropriate antibiotics (e.g. for chorioamnionitis) and that prophylaxis should be administered within 60 minutes before the start of the cesarean delivery. For cesarean delivery prophylaxis, a single dose of a targeted antibiotic, such as a first-generation cephalosporin, is the first-line antibiotic of choice, unless significant drug allergies are present. Antibiotic prophylaxis is indicated for patients with preterm premature rupture of membranes (PROMs) to prolong the latency period between membrane rupture and delivery. For women with a history of a significant penicillin or cephalosporin allergy (anaphylaxis, angioedema, respiratory distress, or urticaria), a single-dose combination of clindamycin with an aminoglycoside is a reasonable alternative choice for

cesarean delivery prophylaxis [16]. Infective endocarditis prophylaxis is no longer recommended for vaginal delivery in the absence of infection except possibly for the small subset of patients at highest potential risk of adverse cardiac outcomes. The recommendations for prophylaxis in women with valvular disease are limited to patients with any prosthetic valve, including transcatheter valve, or those in whom any prosthetic material was used for cardiac valve repair [8]. In a review of bacterial endocarditis complicating 68 pregnancies, the calculated maternal and fetal mortality rate was 22% and 15%, respectively [17]. Because of the information indicating a higher risk of bacteremia even after uncomplicated vaginal delivery, the relative low risk and cost of therapy, and the potential devastating effect of endocarditis, prophylactic antibiotic treatment for labor is given routinely in patients with VHD in many institutions, including our own [18,19]. The recommended regimens for antibiotic prophylaxis include ampicillin (2.0 g intramuscular [IM] or intravenous [IV]) plus gentamicin (1.5 mg/kg, not to exceed 120 mg) given at initiation of labor or within 30 minutes of a cesarean section, followed by ampicillin (1 g IM or IV) or amoxicillin (1 g orally) six hours later. For patients allergic to ampicillin and amoxicillin, vancomycin (1.0 g IV over one to two hours) is recommended instead [20].

Specific valvular lesions Mitral stenosis (MS) Mitral stenosis (MS) in women in the childbearing age is almost exclusively due to rheumatic etiology. The incidence of rheumatic heart disease has almost been eliminated in high-income countries during the late twentieth century in part due to improvement in socioeconomic conditions and the wide spread use of penicillin G benzathine to treat streptococcal pharyngitis [21,22]. At the same time, rheumatic heart disease is still a common disease in low- and middle-income countries and among immigrants and special populations in high-income countries [21]. World-wide rheumatic mitral stenosis is still a commonly encountered valvular lesion in pregnancy [23,24]. A recent report by the European Registry of pregnancy and cardiac (ROPAC) disease, which has included many patients from low-income countries described 334 women with VHD, almost a quarter of these patients had mitral stenosis [25]. Rheumatic MS is often accompanied by some degree of mitral regurgitation (MR) [5,25], which may lead to additional hemodynamic worsening and symptomatic deterioration.

Evaluation The severity of mitral stenosis should be assessed by a careful history of exercise tolerance and transthoracic echocardiography. Measurement of valve area by planimetry has been suggested as the reference method for the echocardiographic assessment of mitral stenosis severity [26]. Transvalvular gradient, increased left atrial size and volume, and the presence

CHAPTER 6 Native Valvular Heart Disease and Pregnancy

of pulmonary hypertension provide further indication for the severity of the valvular stenosis. Exercise echocardiography may be used to obtain additional objective information regarding changes in pressure gradient across the mitral valve and relation to symptoms. The size of the left atrium and the presence of spontaneous echocardiographic contrast will help to determine the indication for anticoagulation. Suitability for percutaneous mitral balloon commissurotomy (PMBC) should be determined by the standard echocardiographic scoring systems [27]. Transesophageal echo (TEE) can and should be performed prior to or during pregnancy to exclude left atrial thrombus prior to PMBC. Indications for mitral valvuloplasty in the nonpregnant patient with mitral stenosis include symptoms due to mitral stenosis with favorable characteristics for the procedure. Surgical valve replacement is indicated in the symptomatic patient who is not suitable for PMBC. Other indications for balloon valvuloplasty or mitral valve surgery in the asymptomatic patient include high thromboembolic risk, history of systemic embolism, dense spontaneous contrast in the left atrium, new onset of paroxysmal atrial fibrillation, and/or high risk of hemodynamic decompensation and increased systolic pulmonary pressure (≥50 mmHg at rest). Although the guidelines also include a desire for pregnancy as a relative indication for valvuloplasty in the asymptomatic woman with mitral stenosis, an intervention prior to pregnancy in such patient who has a normal exercise tolerance and no other reasons for the procedure is not necessary. Patients who meet the guidelines criteria for mitral valve intervention should have the procedure prior to becoming pregnant.

Maternal risk Several reports published in the last two decades on pregnancies in women with heart disease have provided outcome information on over 600 patients with MS in different parts of the globe [5,6,18,19,23,28–32]. In early publication, our group [5] reported the only case-control study of 46 pregnancies in 44 patients with MS who were compared with a healthy control group of women carefully matched for age, ethnicity, obstetric and medical history, time of initial prenatal care, and year of delivery. Twenty-eight of these cases were in the New York Heart Association (NYHA) functional class I, and 18 were in class II at the time of their initial clinic visit. Seventy-four percent of all patients demonstrated clinical deterioration during pregnancy (Figure 6.1). Maternal outcome was favorable in patients with mild MS and comparable to their controls; in contrast, there was a significantly higher incidence of maternal morbidity in women with moderate and severe MS, including the development of heart failure, arrhythmias (atrial fibrillation or supraventricular tachycardia), the need to start and/or increase a dose of cardiac medications, and the need for hospitalizations. Similar findings were reported by Silversides et al. [6] from Canada who described the outcome of 80 pregnancies in 74 women with rheumatic MS, which was moderate in 36% and

77

Mitral valve disease

NYHA I

13

3

12

2

3 6 NYHA II

6 6

NYHA III

NYHA IV

First visit

5 1

8 5

1 1

2

3

4

3

2

2

1

2

1

Follow-up

Figure 6.1 Change in New York Heart Association (NYHA) functional class between first visit and follow-up during pregnancy in patients with predominant mitral valve disease. Circles, mild mitral stenosis; squares, moderate mitral stenosis; and diamonds, severe mitral stenosis. Open symbols, NYHA functional class I on presentation and closed symbols, NYHA functional class II on presentation. Source: Hameed et al. 2001 [5]. Reproduced with permission of Elsevier.

severe in 11% of the cases. Of these pregnancies, 35% were associated with maternal cardiac complications, including pulmonary edema in 31% and arrhythmias in 11%. The first episode of pulmonary edema occurred in 60% of the patients in the antepartum period at a mean gestational age of 30 ± 0.4 weeks, and 20% occurred in the setting of atrial tachyarrhythmias. Of the nine women who developed arrhythmias during pregnancy, 70% had atrial fibrillation, and the rest had supraventricular tachycardia. The incidence of maternal complications was related to the severity of MS and was 67% in women with severe, 38% in those with moderate, and 26% in those with mild MS. Barbosa et al. [28] reported prognostic factors in 41 patients followed in Brazil between 1991 and 1999. The risk of maternal events, which included progression of heart failure, need for cardiac surgery or balloon mitral valvuloplasty, death, and thromboembolism, was strongly associated with the severity of MS and NYHA functional class before pregnancy. A strong

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PART III Cardiac Disorders and Pregnancy

association between patient’s NYHA functional class and both maternal and fetal complications was confirmed by Bhatla et al. [19], who reported a retrospective analysis of 207 pregnancies in Indian women with cardiac disease who delivered at ≥28 weeks; 71 of these patients had MS, and by Madazli et al. [31], who reported on 125 Turkish women with rheumatic heart disease. Avila et al reported on 54 patients with moderate or severe mitral stenosis who developed congestive heart failure and pulmonary congestion. In addition, 20 patients developed cardiac arrhythmias, mostly atrial fibrillation, and there were eight episodes of thromboembolism, the majority associated with atrial fibrillation [33]. The early publication from the ROPAC registry included 79 women with mitral stenosis, 31% developed heart failure between weeks 13 and 37 gestation with a media of 25 weeks [34]. A more recent report from the ROPAC registry included 273 women with MS with or without MR. A third of the patients had mild MS and the rest moderate and severe MS (20%) [32]. Rate of admission during pregnancy for the entire group was 23% and was 49% in those with severe MS and 41% in women with moderate MS who were symptomatic prior to their pregnancy. The main reason for hospitalization was heart failure that presented during pregnancy only in 71% of the patients, during pregnancy and early after the delivery in 14%, and only after the delivery in 15%. A cardiac intervention was performed in only 6% of all patients with a higher rate in developed countries (19% vs. 5% in women with isolated MS). The majority had PMBC, which was done in the second trimester in most patients. Forty-three percent of the patients were symptomatic prior to pregnancy including almost 80% who were categorized as having less than severe MS. Compared to prepregnancy asymptomatic patients, symptomatic women had higher incidence of pulmonary hypertension, heart failure, and arrhythmias and had more interventions during pregnancy. Women with an intervention before pregnancy had a significant fewer cardiac events than those without prior intervention. In spite of the fact that most of the patients came from emerging countries, mortality was low. One patient with severe MS died at 35 weeks because of acute heart failure and two others died postpartum. One of these patients who had severe MS died two weeks after spontaneous abortion of sepsis, and the second patient who had moderate MS and atrial fibrillation died after discontinuation of anticoagulation because of hemorrhagic complications after a C-section, most likely due to thromboembolic complication. The low mortality related to pregnancy in women with MS reported in this study supports previous publications. No mortality was reported in 124 pregnancies in women with MS included in two studies from tertiary-care facilities with high-risk obstetric/cardiology clinics in North America and in 71 cases treated in a high-volume center in India [5,6,19]. Avila et al. [33] reported mortality in nine cases with rheumatic heart disease (1.6%) without detailing the cause of death. Isolated cases of maternal death have been described in women with critical MS who were in NYHA functional class III and IV

in other reports [17,29]. The ROPAC registry reported on death in three women with mitral stenosis. One patient died at 35 weeks after developing cardiogenic shock, the second patient died at 6 weeks as a result of a sepsis and the third 1-week postdelivery because of brain stem embolism. In summary, pregnancy in women with MS is associated with a significant risk of complications and hospitalizations mostly due to heart failure and arrhythmias. The risk is higher in women with moderate and severe MS and those who are symptomatic prior to pregnancy. In spite of the high rate of complications, mortality is uncommon, including in women with severe MS. In patients in sinus rhythm, oral anticoagulation is indicated when there has been a history of systemic embolism or a thrombus is present in the LA (recommendation class I, level of evidence C) and should also be considered when TEE shows dense spontaneous echocardiographic contrast or an enlarged LA (M-mode diameter >50 mm or LA volume >60 ml/m2 ) (recommendation class IIa, level of evidence C). Although retrospective evaluations reported a low incidence of thromboembolism in patients with MS during pregnancy [18,19,33], Hameed et al. [35] reported on three patients who presented with clinically significant left atrial thrombus in the absence of atrial fibrillation that resulted in a stroke in one patient and partial occlusion of the mitral valve orifice leading to worsening of heart failure in another patient. The third patient had multiple, large left atrial thrombi that were successfully treated with low-molecularweight heparin throughout the pregnancy. Because of these findings and the hypercoagulable state of pregnancy, these investigators have recommended strong considerations for anticoagulation prophylaxis during gestation in women with severe MS and enlarged left atrium, even in the absence of atrial fibrillation.

Fetal outcome A comparison of fetal outcome between women with MS and a well-matched control group of healthy women in an early study by our group [5] demonstrated an important effect of MS on the incidence of preterm delivery (28% [moderate MS] vs. 6% [control] and 44% [severe MS] vs. 11% [control]) and intrauterine growth retardation (27% [moderate MS] vs. 0% [control] and 33% [severe MS] vs. 0% [control]). Similarly, there was a substantial impact on birth weight, which was reduced from 3427 ± 426 g in the control patients to 2706 ± 1039 g (p = 0.02) in women with moderate MS and from 3332 ± 403 to 2558 ± 947 g (p = 0.05) in cases with severe MS. Birth weight in women with mild MS was comparable to their control subjects (3135 ± 419 vs. 3288 ± 531 g). A substantial increase in rate of premature birth was also reported by Silversides et al. [6]. The rate of prematurity was 14% in patients with mild MS, 28% in patients with moderate MS, and 33% in patients with severe MS. The recently published results of the ROPAC study also showed reduced birth weight in women with MS and

CHAPTER 6 Native Valvular Heart Disease and Pregnancy

increased rate of small for gestational especially in women with severe MS [32].

Management For clinicians treating women with MS, there are two separate groups of patients: the patients with MS who desire to become pregnant and are being evaluated before pregnancy and those who are already pregnant Table 6.1. Asymptomatic patients contemplating pregnancy who are found to have mild MS (mitral valve is ≥1.5 cm2 ) usually have a favorable pregnancy outcome [5,6]; valve repair before pregnancy in order to allow favorable outcome, is therefore, not indicated. In general, indication for percutaneous mitral balloon valvuloplasty (PMBV) prior to pregnancy should Table 6.1 Management of mitral stenosis Pregnancy not advised (indications for intervention prior to pregnancy) Significant (moderate to severe) mitral stenosis (valve area 50 mmHg) Pregnancy management Close follow-up with frequent monitoring of symptoms, BNP or NT-ProBNP levels, and echocardiographic pulmonary pressures Reduction of heart rate by reducing activity and administration of β-blockers (β-1 selective preferred, high dose often required) if symptoms related to increased MV gradient develop Cardioversion to sinus rhythm in a case of a new atrial fibrillation and rapid ventricular response with heart failure Diuretics if symptoms persist in spite of heart rate reduction. Anticoagulation for paroxysmal or permanent atrial fibrillation or sinus rhythm with a history of TE events, left atrial thrombus, spontaneous echocardiographic contrast in the left atrium and large left atrium (M-mode diameter >50 mm or LA volume >60 ml/m2 ). Percutaneous mitral balloon commissurotomy in increasingly symptomatic patients with moderate or severe MS who do not respond to medical therapy Surgical mitral valve replacement in cases not amenable to PMBC Early C-section delivery should be considered before surgery in women who are past 28 weeks of gestation Delivery Vaginal delivery at term preferred C-section in case of fetal or maternal instability Consider hemodynamic monitoring during labor, delivery and early post-delivery period in severe, symptomatic MS Reduce dose of β-blockers after the delivery to prevent bradycardia

79

follow the guidelines recommendation for the nonpregnant patients and should be limited to patients with clinically significant (moderate to severe) mitral stenosis (valve area 30% and in the asymptomatic patients, left ventricular dysfunction with left ventricular end diastolic diameter of ≥45 mm and/or ejection fraction ≤60%, and atrial fibrillation or pulmonary hypertension [27,76]. Women with MR who meet criteria for surgical intervention should have the surgery before becoming pregnant. Maternal risk A recent study demonstrated a greater enlargement of left atrial and left ventricular size during pregnancy, which persisted on the 45th day after the delivery in women with MR compared to controls [77]. Because of the significant fall in systemic vascular resistance during pregnancy and reduced left ventricular afterload (Chapter 1), pregnancy is well tolerated in patients who are asymptomatic prior to pregnancy, with normal exercise tolerance and normal left ventricular systolic function (ejection fraction ≥60%). [78]. The recent report from the ROPAC registry provided outcome information in 108 patients with isolated rheumatic MR, 43 mild and 65 moderate to severe, the majority living in emerging countries and about 20% were symptomatic prior to pregnancy [32]. Mortality was reported in one patient who had normal LV function and developed cardiogenic shock predelivery at 39 weeks. Hospital admission for any cardiac reason was required in 14% of patients, heart failure occurred in 17% of the patients compared to 32% of women with MS.

Table 6.3 Mode of delivery in patients with mitral and aortic stenosis Number (%) of cesarean deliveries for cardiac indications

Number of patients

Number of pregnancies

Number (%) of cesarean deliveries

Mitral stenosis

39

49

16 (33%)

1 (2%)

Aortic stenosis

74

80

21 (26%)

1 (1.25%)

Valvular disease

Source: Based on information published by Silversides et al. [6,69].

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Surgical valve replacement was with a mechanical prosthetic valve and was performed in one patient at 10 weeks gestation. Fetal outcome The rate of preterm birth, birth weight 60%) and LVESD 40–44 mm when a durable repair is highly likely. Procedure may be delayed to after pregnancy in women who prefer a mechanical prosthetic valve in case of failure to achieve a good repair Management Close follow-up with frequent monitoring of symptoms and BNP or NT-ProBNP levels Diuretics for heart failure

Management For the patient with MR who is contemplating pregnancy but is not considered a candidate for surgical mitral valve repair or replacement on the basis of usual clinical indications [27], prophylactic surgery should not be done because pregnancy after valve replacement may be less desirable, especially in the patient with mechanical prosthetic heart valves (see also Chapter 7). Asymptomatic patients do not require therapy during pregnancy, while women with left ventricular dysfunction are likely to show hemodynamic and symptomatic deterioration and need to be closely monitored for change in symptoms, BNP levels, and hemodynamics determined by echocardiography and if needed, by right heart catheterization (Table 6.4). The treatment of patients with left ventricular dysfunction who develop hemodynamic abnormalities and symptoms of heart failure can include the use of diuretics and digoxin. Because angiotensinconverting enzyme (ACE) inhibitors or angiotensin receptor antagonists are contraindicated during pregnancy [4,79], organic nitrates and hydralazine can be used for vasodilation. Because of the high incidence of fetal loss [68], surgery for mitral valve repair or replacement should be avoided if possible during pregnancy and considered only in patients with severe symptoms not controlled by medical therapy.

Mitral valve prolapse Women with mitral valve prolapse in the absence of severe MR and heart failure tolerate pregnancy well [80]. Nevertheless, serious complications including arrhythmias, infective endocarditis, and cerebral ischemic events can occur. Anzalone and Landi [81] reported on a 20-year-old woman with mitral valve prolapse, who presented with pure motor hemiparesis due to a deep hemispheric infarction after delivery of twins followed by marked blood loss and anemia, and Artal et al. [82] described a case of transient ischemic attack in a 32year old pregnant women with mitral valve prolapse. Sugrue et al. [83] and Strasberg [84] each reported a case of group B

β-blockers and oral vasodilators (Hydralazine and isosorbide dinitrate) for patients with reduced LVEF Delivery Vaginal delivery at term preferred in the stable patient C-section in case of fetal or maternal instability Hemodynamic monitoring and early delivery should be considered in patients with clinical and hemodynamic deterioration, LV dysfunction, elevated BNP, and pulmonary hypertension not responding to medical therapy LVEF – left ventricular ejection fraction; LVESD – left ventricular end systolic diameter; BNP – brain natriuretic peptide.

streptococcal endocarditis after uncomplicated vaginal delivery in women with mitral valve prolapse. Fetal outcome in women with mitral valve prolapse was studied by Chen et al. [85], who conducted a large-scale study with the aim of evaluating pregnancy outcome in 3104 women in Taiwan. These investigators showed in a multivariate model a 27% higher rate of preterm birth and 334% increased rate of cesarean section deliveries in women with mitral valve prolapse compared with unaffected mothers. The investigators speculated that the association between mitral valve prolapse and preterm delivery was due to discordant muscle traction or lower muscle tone. No significant difference was observed between women with and without mitral valve prolapse for other outcomes including low birth weight, intrapartum complications, low Apgar score, and congenital malformations.

Aortic stenosis (AS) Aortic stenosis (AS) during pregnancy is mostly due to congenital etiology [69,86]. Rheumatic AS is less common and occurs in conjunction with mitral valve disease in approximately 5% of pregnant women with rheumatic valvular disease [5]. Cases with subvalvular and supravalvular aortic stenosis have also been described in pregnancy [69,87].

CHAPTER 6 Native Valvular Heart Disease and Pregnancy

Evaluation Preconception analysis of the severity of aortic stenosis should take into considerations the limitations of the echocardiographic assessment [88]. In questionable cases, evaluation should include stress echocardiography and cardiopulmonary exercise test and in selected cases, cardiac catheterization. Maternal risk Most patients with mild and moderate aortic stenosis have a favorable outcome of pregnancy [5,69,86]; at the same time, however, the presence of severe aortic stenosis may result in hemodynamic and symptomatic deterioration with the development of heart failure, leading to hospitalizations and in the absence of appropriate management, even to mortality [89]. Silversides et al. [69] reported on 49 pregnancies in 39 women with congenital aortic stenosis, mostly asymptomatic before pregnancy but severe in one-half of them. Early cardiac complications, including pulmonary edema and atrial arrhythmias, occurred in three pregnancies; one of them with severe aortic stenosis (aortic valve area 0.5 cm2 , peak gradient 112 mmHg) required urgent percutaneous aortic valvuloplasty at 12 weeks’ gestation. Rate of cardiac morbidity during pregnancy, as well as cardiac surgery at follow-up after pregnancy, was related to severity of AS, with cardiac complications occurring in 10% of patients with severe, compared with none in mild or moderate AS. Six pregnancies were associated with adverse fetal event, which included prematurity (8%), small for gestational age (2%), and neonatal distress respiratory syndrome (6%). In addition, 31% of the patients underwent surgery during a follow-up period of 2.6 years after the index pregnancy. Hameed et al. [5] reported on 12 pregnancies in 12 women with predominant AS. There was a higher incidence of maternal complications in patients with moderate and severe disease compared with their individually matched normal control subjects, with congestive heart failure reported in 44% of patients, arrhythmias in 25%, need to commence or increase cardiac medications in 33%, and hospitalizations in 33%. In spite of increased incidence of morbidity, mortality was limited to only 1 of 61 pregnancies reported in the aforementioned two studies [5,69]. This patient had severe AS in addition to a coarctation of the aorta and died after aortic valve replacement 10 days following a successful abdominal delivery. Maurya and Dasari reported on maternal mortality in a woman with severe AS at 35 weeks’ gestation, who deteriorated after going into preterm labor [89]. A recent report from the multinational ROPAC registry described the outcome of 96 women who had at least moderate AS [86]. Over 50% of the patients had bicuspid aortic valve, 18 patients had rheumatic aortic valve disease, 12 of the patients had repaired aortic coarctation, 8 patients had previously implanted bio prosthetic valve, 7 in the aortic position and 1 in the mitral position, and 13 patients had a mechanical prosthetic heart valves (10 in the aortic position, 4 in the mitral position, and 1 in both). Mean

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gradient across the aortic valve was 28 ± 5 mmHg in the patients with bio prosthetic aortic valve and 39 ± 20 mmHg in the mechanical prosthetic valves. The mean peak aortic gradient was 39 ± 18, and with the exception of one patient who had a reduced ejection fraction of 39%, the rest of the patients had normal left ventricular systolic function, and 62.5% of the patients were asymptomatic prior to pregnancy, whereas 33.3% were classified as NYHA functional class II and the rest class III. No death was observed during pregnancy and the first week after delivery. However, 21% of the women were hospitalized for cardiac reasons during pregnancy with a higher incidence among women with severe AS (33%) compared to moderate aortic stenosis (13%) and the highest incidence (42%) in women with symptomatic, severe aortic stenosis. The leading cardiac complications were new or worsening heart failure and arrhythmias, there was no cerebrovascular complication, and one patient developed endocarditis during pregnancy. Heart failure could be managed medically in all patients except one patient with severe AS and left ventricular dysfunction that required aortic valvotomy. One patient underwent aortic valve replacement with mechanical valve as a consequence of aortic valve endocarditis at four months into pregnancy. Fetal outcome Hameed et al. [5] showed that fetal outcome was also affected by the presence of moderate and severe AS with higher incidence of preterm birth (44%), intrauterine growth retardation (22%), and lower birth weight (2,650 ± 987, vs. 3,391 ± 412 g, p = 0.002). In the ROPAC registry, median pregnancy duration in patients with AS was almost 39 weeks and was significantly shorter in patients with severe AS [86]. Patients with severe stenosis also had a markedly higher rate of C-section delivery (66%) compared to those with moderate disease (48%). The main reason for cesarean section was cardiac. A low Apgar score was seen in 5% and 16% of women with moderate and severe AS, and newborns to women with severe disease had smaller body weight compared to moderate stenosis (2648 ± 797 g compared to 3198 ± 549 g). In summary, most patients with AS, especially those with valve area ≥1.0 cm2 , tolerate pregnancy well, provided early diagnosis and close follow-up. Severe AS can be associated with important maternal morbidity and unfavorable fetal outcome including preterm delivery, low birth weight, and low Apgar score, but maternal mortality is rare. In addition, a high rate of expected cardiac surgery after the pregnancy in women with severe AS should be considered and explained to the patients at the time of prepregnancy counseling. Management Ideally, women with severe AS should undergo either balloon valvuloplasty, if appropriate, or valve replacement before pregnancy (Table 6.5). The medical treatment in symptomatic patients with AS during gestation is limited to diuretics. Patients who develop severe symptoms during pregnancy but are resistant to medical therapy and cannot

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Table 6.5 Management of aortic stenosis Pregnancy not advised (indications for surgery prior to pregnancy) Symptomatic, severe aortic stenosis Asymptomatic patients with markedly decreased exercise tolerance Impaired LV systolic function Aortic diameter >5 cm Pregnancy management Close follow-up with frequent monitoring of symptoms and BNP or NT-ProBNP levels Percutaneous balloon valvuloplasty (PCBV) in severely symptomatic patients

to the fetus and the mother and an increased risk of aortic rupture or dissection in women with bicuspid aortic valve and aortopathy in pregnancy (Chapter 20). In addition, TAVR in patients with a noncalcified bicuspid aortic stenosis and reduced tissue holding forces has been associated with a lower device success and a higher incidence of moderate and severe aortic regurgitation (AR). In the recent report of an international registry of TAVR in patients with bicuspid aortic stenosis, the incidence of a new pace maker associated with the procedure was 16% even with the new generation devices [93]. It should be noted that only limited information is available regarding hemodynamic valve deterioration after TAVR [95], and long-term durability of these valves especially in women in the child-bearing age is not known.

Surgical valve replacement if PCBV not possible or not successful Early C-section delivery should be considered before surgery in women who are past 28 weeks of gestation Delivery Vaginal delivery at term preferred C-section in case of fetal or maternal instability Consider hemodynamic monitoring during labor and delivery in severe, symptomatic AS, or LV dysfunction

be delivered, may require early termination of pregnancy or valve repair either by percutaneous balloon valvuloplasty [69,90,91] or surgery [92] (Chapters 26 and 27). Because balloon valvuloplasty seems to be associated with a smaller risk of fetal loss compared with surgical replacement [68], it is preferred when possible, as a temporary measure to improve symptoms and prevent premature delivery and as a bridge to surgery after the delivery. Both interventions carry risk to the fetus (radiation with valvuloplasty and fetal loss with surgery), and because complaints related to pregnancy itself can mimic cardiac disease, symptoms should be carefully evaluated before the decision to perform these procedures is made. When intervention seems to be indicated and fetal maturity can be confirmed, the patient should be delivered first, and valve repair or replacement should be performed after delivery if possible. Transcatheter aortic valve replacement (TAVR) is an approved and widely accepted treatment for severe aortic stenosis in high-risk surgical candidates [76]. A recent review of a registry of TAVR in patients with bicuspid aortic stenosis showed favorable results in patients with the use of new generation valves [93]. Hodson et al. recently published a case report of a 22-year-old pregnant female who presented with severe symptomatic aortic stenosis at 15 weeks gestation and was treated with TAVR at 22 weeks [94] The authors concluded that this anecdotal case may suggest that TAVR should be researched as a possible low-risk option for the treatment of aortic stenosis during pregnancy. This suggestion should however take in consideration a number of limitations and potential risks involved, which include radiation exposure

Labor and delivery Most women with AS can be delivered vaginally with assisted second stage of labor, and cesarean section delivery should be done for obstetrical indications or maternal hemodynamic instability. Orwat et al. [86] reported cesarean section in over 50% of the patients with moderate and severe AS included in the ROPAC registry. This high incidence reflects the tendency among clinicians to recommend cesarean section delivery to patients with AS regardless of the clinical condition. Vaginal delivery was performed in 67% of 49 pregnancies in women with AS reported by Silversides et al. [69]. Cesarean delivery was performed in only one case due to maternal cardiac indication (Table 6.3). Regional anesthesia for labor and delivery should be used with caution (chapter 28) in patients with AS to prevent a decrease in systemic vascular resistance that may be poorly tolerated, and general anesthesia remains the preferred technique for cesarean section in patients with AS [71]. Hemodynamic monitoring is strongly recommended for labor and delivery in patients with moderate and severe AS especially those who are symptomatic due to AS during pregnancy or have elevated levels of BNP.

Aortic regurgitation Aortic regurgitation in young women may be due to congenital bicuspid valve, rheumatic disease, endocarditis, or dilated aortic annulus. Evaluation Women who meet indications for surgery should have the procedure prior to becoming pregnant. Indications for surgery in women without aortic aneurysm include symptomatic aortic regurgitation, and left ventricular ejection fraction ≤50% [27]. In asymptomatic women with ejection fraction >50% with severe left ventricular dilatation (left ventricular end diastolic dimension >70 mm or left ventricular end systolic diameter >50 mm or LVESD >25 mm/m2 BSA in patients with small body size) where the guidelines recommend considerations for surgery (class IIa). Decision should be made after discussion of the risk of pregnancy

CHAPTER 6 Native Valvular Heart Disease and Pregnancy

prior to surgery on one hand and the risks associated with pregnancy in the presence of a prosthetic heart valve as well as the lifelong limitations of bio prosthetic valves in young women (Chapter 7). Maternal risk Similar to MR, aortic regurgitation without left ventricular dysfunction is usually well tolerated during pregnancy, probably secondary to a marked fall in systemic vascular resistance and possibly due to the physiological increase in heart rate, which may shorten diastolic time and thus reduce degree of regurgitation [96]. In cases of severe aortic regurgitation and left ventricular dysfunction that are symptomatic, medical therapy during pregnancy can include salt restriction, diuretics, and digoxin (Table 6.6). The vasodilators hydralazine and isosorbide dinitrate can be used as a substitute to ACE inhibitors, which are contraindicated during pregnancy [79] (Chapter 32). Surgery, if indicated, should be delayed if possible until after the delivery to avoid the high risk of fetal loss [68] (Chapter 26). Symptomatic patients and patients with left ventricular dysfunction should benefit from hemodynamic monitoring during labor and delivery. Asymptomatic patients with severe aortic regurgitation but normal left ventricular function who contemplate pregnancy and are not considered candidates for valve replacement on the basis of established indications [27] will do well and should not have prophylactic valve surgery before pregnancy. Table 6.6 Management of aortic regurgitation Pregnancy not advised (indications for surgery prior to pregnancy) Symptomatic aortic regurgitation Asymptomatic severe AR with LVEF 70 mm, or LVESD >50 mm (exception may be made in women who prefer a mechanical prosthetic valve where surgery may be delayed to after the delivery in order to prevent the risk of such a PHV in pregnancy) Pregnancy management

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Pulmonic stenosis Isolated pulmonic stenosis (PS) during pregnancy is most commonly due to a congenital obstruction at the valvular level but can also occur at the subvalvular or supravalvular level and as a consequence of deterioration of a homograft inserted as part of the Ross procedure. In nonpregnant patients with valvular PS, balloon valvotomy is recommended for asymptomatic patients with a domed pulmonary valve and a peak instantaneous Doppler gradient > 60 mmHg or a mean Doppler gradient > 40 mmHg in association with less than moderate pulmonic valve regurgitation. In symptomatic patients, the recommendations are to perform the procedure in patients with a peak or a mean Doppler gradients of >50 or >30 mmHg, respectively. Surgical therapy is recommended for patients with severe PS associated with hypoplastic pulmonary annulus, severe pulmonary regurgitation, subvalvular or supravalvular PS, dysplastic pulmonary valve, associated tricuspid regurgitation, or the need for a surgical Maze procedure. Patients with PS who meet the aforementioned criteria for intervention should ideally have the procedures performed prior to becoming pregnant. Maternal risk Isolated valvular PS, even when severe, is usually well tolerated during pregnancy. An early study by Neilson et al. [97] reported on 26 pregnancies in 11 patients with PS. There were four spontaneous abortions, one in a patient with severe PS who had right heart failure during the first pregnancy but then had three additional uneventful pregnancies after valvotomy. More recently, Hameed et al. [98] reported the outcome of pregnancy in 17 patients with isolated PS from 1995 to 2003 (Table 6.7). Eleven patients were in NYHA functional class I, and six in class II at the time of presentation. All patients remained stable during pregnancy except one who deteriorated from class I to III early during pregnancy but then improved to class II as pregnancy progressed. There was no difference between patients and their matched control subjects in duration of pregnancy (38.4 ± 1.9 weeks vs. 39.3 ± 1.2 weeks, p = 0.17), birth weight (3278 ± 474 vs.

Close follow-up with frequent monitoring of symptoms and BNP or NT-ProBNP levels Salt restriction, diuretics for heart failure Vasodilators and digoxin for LV systolic dysfunction Delivery Vaginal delivery at term preferred in the stable patient C-section in case of fetal or maternal instability Hemodynamic monitoring and early delivery should be considered in a minority of AR patients with clinical and hemodynamic deterioration, elevated BNP, LV dysfunction, and pulmonary hypertension not responding to medical therapy LVEF – left ventricular ejection fraction; LVEDD – left ventricular end diastolic dimension; LVESD – left ventricular end systolic dimension; BNP – brain natriuretic peptide; AR – aortic regurgitation; PHV – Prosthetic heart valve.

Table 6.7 Fetal and neonatal outcomes in patients with PS and their controls Seventeen pregnant women with isolated PS

Patients

Controls

38.4 ± 1.9

39.3 ± 1.2

Apgar score at 1 min

9 (8–9)

9 (8–9)

Apgar score at 5 min

9 (8–9)

9 (8–9)

3278 ± 47.4

3360 ± 432

648 ± 184

693 ± 421

Gestational age

Birth weight Placental weight

Source: Hameed et al. 2007 [98]. Reproduced with permission of Elsevier.

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Table 6.8 Fetal and neonatal outcomes in patients with mild and severe PS 50 mmHg with a mean of 82 ± 28 mmHg) and those with milder stenosis (mean gradient 34 ± 11 mmHg) revealed no difference in any of the studied parameters. In summary, in spite of the limited number of patients with PS reported, the available information and our continued experience indicate that pregnancy in patients with isolated valvular PS is tolerated well and that, in contrast to mitral stenosis and aortic stenosis, the severity of PS does not adversely impact maternal or fetal outcome. Balloon valvuloplasty is rarely indicated during pregnancy even in patients with severe disease who are either asymptomatic or mildly symptomatic before pregnancy. Vaginal delivery is tolerated well and can be permitted in most patients with PS.

Tricuspid regurgitation Isolated tricuspid valve disease in young women is rare [1] and can be caused by congenital cardiac lesions, such as Ebstein’s anomaly, rheumatic heart disease, and endocarditis. Maternal risk Most women with tricuspid regurgitation, including those with Ebstein’s anomaly, tolerate the hemodynamic changes of pregnancy well [99]. However, in the setting of congenitally corrected transposition of the great arteries or the atrial switch operations for complete transposition of the great arteries (Mustard or Senning operation), the tricuspid valve is the systemic atrioventricular valve. In adults, this valve is often regurgitant and is associated with subaortic ventricular dilation and dysfunction. This group of women is at higher risk for pregnancy complications (Chapter 5). In the ZAHARA study, systemic atrioventricular valve

regurgitation was a predictor of complications during pregnancy [100]. There have been a number of reports on the outcome of pregnancy in women with Ebstein’s anomaly. In 1994, Connolly and Warnes [99] reported on 44 women who had 111 pregnancies resulting in 85 live births (76%). There were no serious pregnancy-related maternal complications such as maternal death, stroke, congestive heart failure, arrhythmias, or endocarditis. Fetal outcome In 111 pregnancies in women with Ebsein’s anomaly reported by the Mayo clinic, there were 19 spontaneously unsuccessful pregnancies, 7 therapeutic abortions and 2 early neonatal deaths. Birth weight of the infants born to cyanotic women was significantly lower than birth weight of infants born to acyanotic women (2.53 vs. 3.14 kg, p > 0.001). The incidence of congenital heart disease was 6% [99]. Additional small studies included a report by Chopra et al., who described eight pregnancies in four women with Ebstein’s anomaly. Pregnancy was well tolerated in two patients; while one had right heart failure during early pregnancy, and one had arrhythmia during labor and in the postpartum period. There were two premature deliveries. Of the eight babies, six did not have any cardiac anomalies, one had an unexplained neonatal death, and no information was available for the last patient [101]. Katsuragi et al examined retrospectively 27 pregnancies in 13 patients with Ebstein’s anomaly. Two patients underwent ASD closure prior to pregnancy, and one received tricuspid valve replacement. There were 6 spontaneous abortions and 21 live births. In all patients, the cardiothoracic ratio increased from 55% at conception to 57% during pregnancy and to 58% postpartum. One patient developed ventricular tachycardia and orthopnea preterm and was delivery by Cesarean section and one patient with a mechanical tricuspid valve developed cerebellum hemorrhage at 27 weeks, and the baby died of prematurity. In all other cases, neonatal prognoses were good without congenital heart disease. Recurrent paroxysmal supraventricular tachycardia occurred during pregnancy in two patients and was treated with adenosine or verapamil. In 17 pregnancies, NYHA class remained at I, and all had a full-term vaginal delivery [102]. In summary, although pregnancy is tolerated well in the majority of women with Ebstein’s anomaly, it can be complicated by tachyarrhythmias or cardiac failure.

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45 Nobuyoshi, M., Arita, T., Shirai, S. et al. (2009). Percutaneous balloon mitral valvuloplasty: a review. Circulation 119 (8): e211–e219. 46 Salom´e, N., Dias, C.C., Ribeiro, J. et al. (2002). Balloon mitral valvuloplasty during pregnancy—our experience. Rev Port Cardiol 21 (12): 1437–1444. 47 Mishra, S., Narang, R., Sharma, M. et al. (2001). Percutaneous transseptal mitral commissurotomy in pregnant women with critical mitral stenosis. Indian Heart J 53 (2): 192–196. 48 Abouzied, A.M., Al Abbady, M., Al Gendy, M.F. et al. (2001). Percutaneous balloon mitral commissurotomy during pregnancy. Angiology 52 (3): 205–209. 49 Pershad, A., Byrne, T.J., Morgan, J.M., and Desser, K.B. (2000). Precipitous labor in association with percutaneous mitral valvuloplasty: successful delivery in the catheterization laboratory. Cathet Cardiovasc Interv 49 (4): 459–460. 50 Routray, S.N., Mishra, T.K., Swain, S. et al. (2004). Balloon mitral valvuloplasty during pregnancy. Int J Gynaecol Obstet 85 (1): 18–23. 51 Brent, R.L. (1989). The effect of embryonic and fetal exposure to X-ray, microwaves, and ultrasound: counseling the pregnant and nonpregnant patient about these risks. Semin Oncol 16 (5): 347–368. 52 Fawzy, M.E., Kinsara, A.J., Stefadouros, M. et al. (2001). Long-term outcome of mitral balloon valvotomy in pregnant women. J Heart Valve Dis 10 (2): 153–157. 53 Mangione, J.A., Lourenc¸o, R.M., dos Santos, E.S. et al. (2000). Longterm follow-up of pregnant women after percutaneous mitral valvuloplasty. Cathet Cardiovasc Interv 50 (4): 413–417. 54 Kinsara, A.J., Ismail, O., and Fawzi, M.E. (2002). Effect of balloon mitral valvoplasty during pregnancy on childhood development. Cardiology 97 (3): 155–158. 55 Lee, C.H., Chow, W.H., and Kwok, O.H. (2001). Percutaneous balloon mitral valvuloplasty during pregnancy: long-term follow-up of infant growth and development. Hong Kong Med J 7 (1): 85–88. 56 Gulraze, A., Kurdi, W., Niaz, F.A., and Fawzy, M.E. (2014). Mitral balloon valvuloplasty during pregnancy: the long term up to 17 years obstetric outcome and childhood development. Pak J Med Sci 30 (1): 86–90. 57 de Souza, J.A., Martinez, E.E., Ambrose, J.A. et al. (2001). Percutaneous balloon mitral valvuloplasty in comparison with open mitral valve commissurotomy for mitral stenosis during pregnancy. J Am Coll Cardiol 37 (3): 900–903. 58 Cheng, T.O. (2002). Percutaneous mitral valvuloplasty by the Inoue balloon technique is the ideal procedure for treatment of significant mitral stenosis in pregnant women. Cathet Cardiovasc Interv 57 (3): 323–324. 59 Kramer, M.S., Demissie, K., Yang, H. et al. (2000). The contribution of mild and moderate preterm birth to infant mortality. Fetal and Infant Health Study Group of the Canadian Perinatal Surveillance System. JAMA 284 (7): 843–849. 60 Barker, D.J., Osmond, C., Golding, J. et al. (1989). Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ 298 (6673): 564–567. 61 Jaquet, D., L´eger, J., L´evy-Marchal, C., and Czernichow, P. (2003). Low birth weight: effect on insulin sensitivity and lipid metabolism. Horm Res 59 (1): 1–6. 62 Oren, A., Vos, L.E., Bos, W.J. et al. (2003). Gestational age and birth weight in relation to aortic stiffness in healthy young adults: two separate mechanisms? Am J Hypertens 16 (1): 76–79. 63 Kugelman, A. and Colin, A.A. (2013). Late preterm infants: near term but still in a critical developmental time period. Pediatrics 132 (4): 741– 751. 64 Ben Farhat, M., Gamra, H., Betbout, F. et al. (1997). Percutaneous balloon mitral commissurotomy during pregnancy. Heart 77 (6): 564–567. 65 American Thoracic Society; American College of Chest Physicians (2003). ATS/ACCP statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med 167 (2): 211–277. 66 de Andrade, J., Maldonado, M., Pontes, S. Jr. et al. (2001). The role of mitral valve balloon valvuloplasty in the treatment of rheumatic mitral valve stenosis during pregnancy. Rev Esp Cardiol 54 (5): 573–579.

67 Malhotra, M., Sharma, J.B., Tripathii, R. et al. (2004). Maternal and fetal outcome in valvular heart disease. Int J Gynaecol Obstet 84 (1): 11–16. 68 Weiss, B.M., von Segesser, L.K., Alon, E. et al. (1998). Outcome of cardiovascular surgery and pregnancy: a systematic review of the period 1984–1996. Am J Obstet Gynecol 179 (6 Pt. 1): 1643–1653. 69 Silversides, C.K., Colman, J.M., Sermer, M. et al. (2003). Early and intermediate-term outcomes of pregnancy with congenital aortic stenosis. Am J Cardiol 91 (11): 1386–1389. 70 Essop, M. and Sareli, P. (1998). Rheumatic valvular disease and pregnancy. In: Cardiac Problems in Pregnancy (ed. U. Elkayam and N. Gleicher), 55–60. New York, NY: Wiley-Liss. 71 Ramanathan, J., D’Alessia, J., Geller, E. et al. (1998). Analgesia and anesthesia during pregnancy. In: Cardiac Problems in Pregnancy (ed. U. Elkayam and N. Gleicher), 285–313. New York, NY: Wiley-Liss. 72 Clark, S.L., Cotton, D.B., Lee, W. et al. (1989). Central hemodynamic assessment of normal term pregnancy. Am J Obstet Gynecol 161 (6 Pt. 1): 1439–1442. 73 Hemmings, G.T., Whalley, D.G., O’Connor, P.J. et al. (1987). Invasive monitoring and anaesthetic management of a parturient with mitral stenosis. Can J Anaesth 34 (2): 182–185. 74 Clark, S.L., Phelan, J.P., Greenspoon, J. et al. (1985). Labor and delivery in the presence of mitral stenosis: central hemodynamic observations. Am J Obstet Gynecol 152 (8): 984–988. 75 Goodwin, T. (1998). Tocolytic therapy in the cardiac patient. In: Cardiac Problems in Pregnancy (ed. U. Elkayam and N. Gleicher), 437–499. New York, NY: Wiley-Liss. 76 Nishimura, R.A., Otto, C.M., Bonow, R.O. et al. (2017). AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 70 (2): 252–289. 77 Borges, V.T., Matsubara, B.B., Magalh˜aes, C.G. et al. (2011). Effect of physiological overload on pregnancy in women with mitral regurgitation. Clinics (Sao Paulo) 66 (1): 47–50. 78 Elkayam, U. and Bitar, F. (2005). Valvular heart disease and pregnancy. J Am Coll Cardiol 46 (2): 223–230. 79 Shotan, A., Widerhorn, J., Hurst, A., and Elkayam, U. (1994). Risks of angiotensin-converting enzyme inhibition during pregnancy: experimental and clinical evidence, potential mechanisms, and recommendations for use. Am J Med 96 (5): 451–456. 80 Yuan, S.M. and Yan, S.L. (2016). Mitral valve prolapse in pregnancy. Braz J Cardiovasc Surg 31 (2): 158–162. 81 Anzalone, N. and Landi, G. (1988). Lacunar infarction in a puerpera with mitral valve prolapse. Ital J Neurol Sci 9 (5): 515–517. 82 Artal, R., Greenspoon, J.S., and Rutherford, S. (1988). Transient ischemic attack: a complication of mitral valve prolapse in pregnancy. Obstet Gynecol 71 (6 Pt. 2): 1028–1030. 83 Sugrue, D., Blake, S., Troy, P., and MacDonald, D. (1980). Antibiotic prophylaxis against infective endocarditis after normal delivery—is it necessary? Br Heart J 44 (5): 499–502. 84 Strasberg, G.D. (1987). Postpartum group B streptococcal endocarditis associated with mitral valve prolapse. Obstet Gynecol 70 (3 Pt. 2): 485– 487. 85 Chen, C.H., Huang, M.C., Liu, H.C. et al. (2011). Increased risk of preterm birth among women with mitral valve prolapse: a nationwide, population-based study. Ann Epidemiol 21 (6): 391–398. 86 Orwat, S., Diller, G.P., van Hagen, I.M. et al. (2016). Risk of pregnancy in moderate and severe aortic stenosis: from the multinational ROPAC registry. J Am Coll Cardiol 68 (16): 1727–1737. 87 Hameed, A.B., Tummala, P.P., Goodwin, T.M. et al. (2000). Unstable angina during pregnancy in two patients with premature coronary atherosclerosis and aortic stenosis in association with familial hypercholesterolemia. Am J Obstet Gynecol 182 (5): 1152–1155. 88 Clavel, M.A. (2016). Echocardiographic assessment of aortic stenosis severity: do not rely on a single parameter. J Am Heart Assoc 5 (10). 89 Maurya, D. and Dasari, P. (2009). Maternal mortality in aortic stenosis: case report with review of literature. Internet J Gynecol Obstet 1–5.

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90 Bhargava, B., Agarwal, R., Yadav, R. et al. (1998). Percutaneous balloon aortic valvuloplasty during pregnancy: use of the Inoue balloon and the physiologic antegrade approach. Cathet Cardiovasc Diagn 45 (4): 422– 425. 91 Tumelero, R.T., Duda, N.T., Tognon, A.P. et al. (2004). Percutaneous balloon aortic valvuloplasty in a pregnant adolescent. Arq Bras Cardiol 82 (1): 98–101, 94–7. 92 Ben-Ami, M., Battino, S., Rosenfeld, T. et al. (1990). Aortic valve replacement during pregnancy. A case report and review of the literature. Acta Obstet Gynecol Scand 69 (7–8): 651–653. 93 Yoon, S.H., Bleiziffer, S., De Backer, O. et al. (2017). Outcomes in transcatheter aortic valve replacement for bicuspid versus tricuspid aortic valve stenosis. J Am Coll Cardiol 69 (21): 2579–2589. 94 Hodson, R., Kirker, E., Swanson, J. et al. (2016). Transcatheter aortic valve replacement during pregnancy. Circ Cardiovasc Interv 9 (10): e004006. 95 Del Trigo, M., Munoz-Garcia, A.J., Wijeysundera, H.C. et al. (2016). Incidence, timing, and predictors of valve hemodynamic deterioration after transcatheter aortic valve replacement: multicenter registry. J Am Coll Cardiol 67 (6): 644–655.

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96 Judge, T.P., Kennedy, J.W., Bennett, L.J. et al. (1971). Quantitative hemodynamic effects of heart rate in aortic regurgitation. Circulation 44 (3): 355–367. 97 Neilson, G., Galea, E.G., and Blunt, A. (1970). Congenital heart disease and pregnancy. Med J Aust 1 (22): 1086–1088. 98 Hameed, A.B., Goodwin, T.M., and Elkayam, U. (2007). Effect of pulmonary stenosis on pregnancy outcomes—a case-control study. Am Heart J 154 (5): 852–854. 99 Connolly, H.M. and Warnes, C.A. (1994). Ebstein’s anomaly: outcome of pregnancy. J Am Coll Cardiol 23 (5): 1194–1198. 100 Drenthen, W., Boersma, E., Balci, A. et al. (2010). Predictors of pregnancy complications in women with congenital heart disease. Eur Heart J 31 (17): 2124–2132. 101 Chopra, S., Suri, V., Aggarwal, N. et al. (2010). Ebstein’s anomaly in pregnancy: maternal and neonatal outcomes. J Obstet Gynaecol Res 36 (2): 278–283. 102 Katsuragi, S., Kamiya, C., Yamanaka, K. et al. (2013). Risk factors for maternal and fetal outcome in pregnancy complicated by Ebstein anomaly. Am J Obstet Gynecol 209 (5): 452.e1-6.

CHAPTE R 7

Pregnancy in the Patient with Prosthetic Heart Valves Uri Elkayam1,2 1 Department

of Medicine, Division of Cardiovascular Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA

2 Department

of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA

The first successful replacement of heart valve in human was reported in 1960 [1]. Since then, prosthetic heart valves (PHVs) have developed into remarkably useful devices (Figure 7.1). A large number of PHVs are being implanted every year worldwide including in women of childbearing age [3]. Pregnancy in women with PHVs is associated with a substantial risk of morbidity and even mortality [4]. The choice between a bio prosthetic heart valve (BPHV) and a mechanical prosthetic heart valve (MPHV) in women of childbearing age is difficult because the ideal valve is not available, and both types of valves provide advantages and limitations. Important areas of difference are durability, incidence of thromboembolism and bleeding, and valve hemodynamics and effect on fetal outcome, mostly due to anticoagulation (AC). Decisions on the choice of anticoagulation should be made by both physicians and patients, who need to be fully informed of the potential risks and benefits associated with the various therapeutic options.

Preconception evaluation and consultation The risk of complications during pregnancy in a patient with PHV depends on type, position, and function of the valve as well as cardiac function, patient symptoms, and functional capacity. Pregnancy evaluation should include a careful history and physical examination as well as an echo-Doppler study to evaluate cardiac and valvular function. Exercise testing, including the determination of maximum oxygen consumption, can provide an objective estimation of functional capacity. The patient and her family should be advised on potential complications that might occur during pregnancy, including hemodynamic and symptomatic worsening; higher incidence of thromboembolism; deterioration of bio prosthetic valves; and potential harm to the fetus due to cardiac medications including anticoagulation (increased rate of fetal loss, prematurity, and fetal growth retardation). Because

Cardiac Problems in Pregnancy, Fourth Edition. Edited by Uri Elkayam. © 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.

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clinical deterioration often occurs during pregnancy, patients with marked impairment of left ventricular and/or valvular function that are moderately or severely symptomatic (New York Heart Association [NYHA] Class III and IV) should be advised against pregnancy.

Bio prosthetic valves This group of valves can be separated into three categories such as heterografts, homografts, and autografts. Most of the data regarding pregnancy in women with BPHVs have been obtained in women with porcine heterografts. The use of BPHVs reduces the risk of thromboembolism and anticoagulation-related bleeding complications but is associated with a high risk of structural valve deterioration (SVD) in young women. A recent report of the Registry of Pregnancy and Cardiac Disease (ROPAC) [4] has described pregnancy outcome in 212 patients with MPHVs and compared it to that of 134 women with BPHVs and 2620 other pregnant patients with a variety of cardiac diseases but without prosthetic valves. Maternal mortality occurred in 1.4% of women with MPHVs, 1.5% of women with BPHVs, and 0.2% of women without PHVs. Valve thrombosis occurred in 4.7% of women with MPHVs, and hemorrhagic complications in 23% compared to 5% of those with BPHVs (p = 0.001) and those without PHVs. Rate of pregnancy free of serious adverse events was 58% in women with MPHVs, 79% of those with BPHVs, and 78% of women without PHVs. Rate of fetal loss due to miscarriage and fetal death after 24 weeks were both substantially higher in patients with MPHVs compared to women without PHV (18.4% vs. 2.3%, p < 0.01). The results of this study have confirmed the advantages associated with BPHVs in pregnant women compared to MPHVs, especially in developing countries or when high-level anticoagulation management is not possible. At the same time however, the trade-off of the use of BPHVs is a high risk of SVD which has been reported in 80% of young

CHAPTER 7 Pregnancy in the Patient with Prosthetic Heart Valves

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Figure 7.1 Different types of prosthetic valves. (a) Bileaflet mechanical valve (St. Jude); (b) monoleaflet mechanical valve (Medtronic Hall); (c) caged ball valve (Starr–Edwards); (d) stented porcine bio prosthesis (Medtronic Mosaic); (e) stented pericardial bio prosthesis (Carpentier-Edwards Magna); (f) stentless porcine bio prosthesis (Medtronic Freestyle); (g) percutaneous bio prosthesis expanded over a balloon (Edwards Sapien); and (h) self-expandable percutaneous bio prosthesis (CoreValve). Source: Pibarot and Dumesnil 2009 [2]. Reproduced with permission of Wolters Kluwer Health, Inc.

patients at 10 years and 90% at 15 years [5–7]. A recent report by Chan et al. [8] examined the need for reoperation in 3975 patients who underwent first time bio prosthetic aortic or mitral valve (MV) replacement. The median interval to reoperation in patients 60% male with an average age of 77 years. This report provided important preliminary data showing that new generation TAVR devices might be a reasonable treatment option to overcome some of the challenges of bicuspid anatomy [50]. Because of the risk of surgery to the fetus and the limited duration of effect of balloon valvuloplasty, TAVR may be considered as a bridge to allow favorable outcome of pregnancy in women with severe symptomatic AS who require a mechanical intervention during pregnancy. There are however a number of important limitations to TAVR during pregnancy, which need to be considered and discussed with the patient. These include the immediate risk associated with radiation exposure, the risk of aortic complications in women with a bicuspid aortic valve and aortopathy in pregnancy where the aorta is more likely to dissect. There is also a considerable risk of a need for a pacemaker after the procedure [49] and the risk of failure to achieve good TAVR results in a noncalcified aortic stenosis with reduced tissue holding forces. In addition, the long-term durability of these valves, especially in women in the child bearing age is unknown.

Valve-in-valve (VIV) transcatheter aortic valve replacement This procedure has been increasingly and successfully used for the treatment of deteriorated bio prosthetic aortic valves in older patients [51]. Implantation of a transcatheter valve is now being done in lower-risk patients, and valve-in-valve (VIV) procedure is offered to patients with a failed tissue prosthesis that is large enough. However, no information is available about the safety and durability of such a procedure in young women. The feasibility, value, and safety of this

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strategy should therefore be demonstrated [52] before a young patient is advised to undergo AVR with a surgically implanted BPHV with the hope of performing VIV TAVR if the valve fails [53].

Mechanical prosthetic heart valves Mechanical PHV are classified into three major groups: caged-ball, tilting-disc, and bileaflet valves [1] (Figure 7.1). The most widely employed mechanical valves are currently the bileaflet valves (St. Jude valve). The old generation Bjork– Shiley valve, a tilting-disc prosthesis, and the Starr–Edwards caged-ball valve are no longer in use and have only an historical importance [7,41–44]. Mechanical PHVs, including those in the smaller sizes [11], offer excellent long-term durability [54] and superior hemodynamic profile; however, their thrombogenicity and need for life-long anticoagulation are associated with an increased risk of thromboembolism and bleeding during pregnancy. In addition, available information on fetal outcome suggests an increased risk of fetal loss as well as prematurity, low birth weight, birth defects, and neonatal mortality. A recent report from the ROPAC registry [4] reported on 212 patients with MPHVs. Although mortality was comparable to patients with BPHVs (1.5%), mechanical valve thrombosis was reported in 10 patients (4.7%), hemorrhagic events occurred in 23% of the patients and only 58% were free of serious adverse events. The use of warfarin for anticoagulation was associated with a high incidence of miscarriage and late fetal death. Although these results demonstrate the potential risks associated with MPHVs in pregnancy, it should be noted that 74% of the patients with MPHV included in the ROPAC registry were from emerging countries with lower level of care, and MPHV thrombosis occurred in patients with poor anticoagulation. The findings of this study may therefore not be applicable to patients with MPHVs who receive an appropriate selection of anticoagulation and close monitoring during pregnancy that can significantly reduce the incidence of both maternal and fetal complications [55,56]. The use of MPHVs in young women has been shown to result in lower incidence of reoperation compared to BPHVs and superior lifelong survival benefit that need to be considered in the selection of a PHV. A recent study by Goldstone et al. [10] showed a higher rate of reoperation in a large group of patients with BPHVs with a high surgical mortality and reduced survival compared to MPHVs in both the mitral and aortic position. Superior rate of lifelong survival with MPHVs was also documented by other groups [19,57].

Management of complications Heart failure Physiological hemodynamic changes during pregnancy might result in cardiac decompensation in patients with PHV, especially those with left ventricular dysfunction

and small valve sizes. In addition, increased incidence of arrhythmias during pregnancy might also lead to hemodynamic and symptomatic deterioration. Although most patients with PHVs who are asymptomatic or only mildly symptomatic before conception, tolerate the hemodynamic burden of pregnancy, decreased functional capacity, pulmonary edema, and even death have been reported [4,26]. The treatment of heart failure in patients with PHV depends on its cause. Safe drugs include digoxin, diuretics, nitrates, hydralazine, and β-blockers. In contrast, angiotensinconverting enzyme inhibitors and angiotensin receptor antagonist are contraindicated, and amiodarone as well as sodium nitroprusside should be avoided [58].

Prosthetic valve thrombosis (PVT) A thrombosis of MPHV is a life-threatening complication, and the incidence is higher during pregnancy [4]. Valve thrombosis is more likely to occur in patients with older-generation mechanical prostheses (Bjork–Shiley, Starr–Edwards) and with any mechanical valve in the mitral or tricuspid positions [5]. Recent guidelines recommend thrombolysis as a first-line treatment or heparin in cases of small, nonobstructive thrombi and in those cases where thrombolysis is contraindicated [59–61]. Administration of thrombolytic therapy (TT) in pregnancy is associated with potential hemorrhagic complications that need to be con¨ sidered, especially before or after the delivery. Ozkan et al. [62] from Turkey published the largest series of prosthetic valve thrombosis (PVT) cases in pregnancy. These investigators reported PVT in 25 pregnancies, all of them involving the mitral valve. A total of 50% of the episodes occurred during the first trimester, 14% during the second, and 36% in the third trimester. The clinical presentation was mostly dyspnea or palpitations, and one patient presented with a transient ischemic attack. A total of 15 patients had been using warfarin and 10 used low-molecular-weight heparin (LMWH) during the pregnancy. Poor compliance with warfarin or subtherapeutic anti-factor Xa levels or international normalized ratio (INR) was present in 93% of the cases. All patients were treated with low-dose TT (tissue-type plasminogen activator 25 mg without bolus, given over up to one hour). Dose was repeated once after 24 hours, and up to six times if needed, for a maximum total dose of 150 mg (mean dose 48 ± 29 mg), which resulted in complete thrombolysis in all cases. One patient had placental hemorrhage with preterm live birth at 30 weeks, and another patient had minor bleeding. These results were significantly better than the results of several previous reports on full-dose thrombolysis given to a total of 32 pregnancies with 38 episodes of PVT [62]. These studies reported thrombolytic success in 76% of the cases, but maternal mortality and major complications in 10% and 14%, respectively, and fetal/neonatal mortality in 28%. The recent American Heart Association (AHA)/American College of Cardiology (ACC) guidelines recommend a transesophageal echocardiogram to diagnose PVT, evaluate the thrombus size

CHAPTER 7 Pregnancy in the Patient with Prosthetic Heart Valves

and valve motion, assess the hemodynamic severity, and follow resolution of valve dysfunction [59]. Valve motion can be assessed by fluoroscopy, although, because of radiation risk, echocardiographic assessment may be preferred in pregnancy. TT was defined as reasonable in PVT of recent onset (5 mg/d. Thirty-three gestations in women taking a daily warfarin dose of 5 mg or less were associated with 28 healthy babies (82%) in comparison to 22 fetal complications (fetal loss 76%, warfarin embryopathy 8%) in 25 women treated with >5 mg daily. The same group of investigators [87] later reported poor outcome in 30 of 71 pregnancies (fetal loss in 28 cases, and embryopathy in 2 cases). Multivariable analysis identified warfarin at daily dose >5 mg as a significant predictor (p = 0.001) of poor fetal outcome. This information resulted in a recommendation to consider the use of oral anticoagulation throughout pregnancy when warfarin dose does not exceed 5 mg daily by the European Society of Cardiology (ESC) guidelines [88,89] for the management of women with heart disease in pregnancy and by the guidelines for the management of valvular heart disease by the American Heart

Association/American College of Cardiology [59]. A later study by De Santo et al. [90] reported additional 16 pregnancies in women with native aortic valve disease requiring valve replacement who received therapeutic anticoagulation with a daily warfarin dose 5 mg daily. Shannon et al. [93] reported spontaneous abortion in 8 of 10 women receiving warfarin during the first trimester; 6 of these were treated with 5 mg/d and the other 2 received 6 mg, and an additional case of warfarin embryopathy was associated with a warfarin dose of 5–6 mg/d. McLintock et al. [94] reported two perinatal deaths and two stillbirths as a result of fetal intracerebral hemorrhage in women taking warfarin at daily doses of 4 and 5 mg, respectively, and an infant death due to warfarin embryopathy in a woman taking 6 mg/d until week 34. Mehndiratta et al. [95] reported a case of severe growth retardation and warfarin embryopathy in a patient treated with warfarin 3 mg/d throughout pregnancy. Finkelstein et al. reported warfarin embryopathy following low dose maternal exposure during the first 18 weeks of pregnancy diagnosed by postmortem examination after a therapeutic abortion [80]. In addition De Santo et al. [90] used a relatively low INR goal between 1.5 and 2.5 on the basis of recent studies showing a low incidence of thromboembolic events among nonpregnant patients with newgeneration MPHV [96,97]. Because pregnant patients were not included in these studies, the safety of this approach for pregnancy remains unproven. For this reason, and until more data are available, it seems advisable to follow the ACC/AHA guidelines [59] and use a warfarin dose during pregnancy aiming to achieve an INR level of at least 2.5 even in patients with new-generation MPHV. Another limitation associated with the protocol used by De Santo et al. [90] of LDW administration throughout pregnancy was a mandatory cesarean section delivery in all patients. Although relatively safe, a cesarean delivery is associated with a substantial increase in short- and long-term risks, including surgery-related infections, bleeding, thromboembolism, pain, and damage to pelvic organs, and later, increased risk of miscarriage, ectopic gestation, placenta previa, and placenta accrete [98]. In summary, there is evidence to support a lower rate of fetal complications with LDW compared to high dose. Because of the limitations of the reports and the inconsistency of the data, there is however, a remaining concern regarding fetal effects of warfarin even at a low dose. We agree

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with the conclusion of D’Souza et al. [99] that recent guidelines recommendations to use LDW throughout pregnancy are premature, and the safety of this approach requires further validation. At this point, it is advisable to obtain a consent form from the patients after detailed discussion of the benefit and risk of the use of LDW. Because of the risk of not achieving therapeutic levels of INR during pregnancy even in those patients who were therapeutic prior to pregnancy, patients receiving LDW should be followed closely with frequent measurements of INR levels for early detection of subtherapeutic INR level and adjustment of warfarin dose. Unfractionated heparin (UFH) Unfractionated heparin (UFH) does not cross the placenta and therefore offers no direct risk to the fetus. The prolonged use of UFH, however, is not without problems and may be associated with adverse effects such as pain and bruising and heparin-induced osteopenia in women who receive large daily dose for longer than six months that can lead to symptomatic vertebral fracture in approximately 2% of women and thrombocytopenia in a rare minority [85]. In addition, subcutaneous administration has been associated with a high incidence of thromboembolic complications, possibly due to the lower plasma heparin concentration in pregnancy and inaccurate monitoring [100] and is not recommended for anticoagulation of pregnant women with MPHV [101–103]. UFH should be used intravenously in the last two weeks of pregnancy in preparation for the delivery. Clinically, heparin concentration is estimated by prolongation of the clotting test activated partial thromboplastin time (aPTT). However, prolongation of the aPTT in pregnancy may fail to accurately reflect the heparin concentration. The results of the aPTT are expressed in seconds, and the recommended aPTT in ratio (subject aPTT in seconds per subject baseline aPTT in seconds). The patient’s baseline sample (without heparin) is commonly not available, and the mean value obtained from a population of nonpregnant control subjects is used. Normally, the aPTT becomes short (to a variable degree) during pregnancy as a result of elevation of procoagulant factors. Thus, for this reason alone, the reported aPTT ratio may be misleading. Other conditions limit the value of aPTT for the measurement of heparin intensity, this will include presence of lupus anticoagulant which prolongs aPTT before heparin, and the addition of heparin further prolongs coagulation. For these reasons, measurement of heparin concentration may require a more specific heparin assay such as inhibition of exogenous activated factor X [104]. We recommend monitoring heparin effect if all possible using anti-Xa activity. Low-molecular-weight heparin Similar to UFH, LMWH does not cross the placenta and does not have a direct effect on the fetus. Furthermore, this drug is superior to UFH in a number of ways, including better bioavailability, longer half-life, more predictable and stable

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dose response, less bleeding, and a lower risk of heparininduced thrombocytopenia [67]. Although thromboembolic complications have been reported in pregnant women with MPHVs receiving LMWH, most if not all of these cases have been due to subtherapeutic anticoagulation secondary to inappropriate dosing, insufficient monitoring, or poor patient compliance [4,85,99]. Van Hagen et al. have reported valve thrombosis in 10 patients with MPHVs included in the ROPAC registry. Seven of these patients had a mitral valve prosthesis, one had tricuspid valve, one mitral and aortic valves, and one an aortic valve. Six of these patients were treated with LMWH prior to 14-week gestation. Anti-factor Xa levels were not checked, not reported, or were intermittently subtherapeutic. Quinn et al. [105] reported valve thrombosis in 1 of 12 patients on LMWH who had a Bjork–Shiley valve in the mitral position with a history of prior thromboembolic complication due to thrombophilia. The patient received dalteparin during pregnancy without anti-factor Xa monitoring. Abildgaard et al. [106] reported valve thrombosis in 2 of 12 women on LMWH; both patients were infrequently monitored, and the peak anti-factor Xa levels were subtherapeutic, at 0.67 and 0.71 IU/ml. Previous reports have also demonstrated a close relationship between thromboembolic complications in pregnant women with MPHVs treated with LMWH and subtherapeutic anticoagulation [94,107]. Oran et al. [107] reported valve thrombosis in almost 9% of pregnant women with MPHVs and 12% incidence of overall thromboembolic complications. Nine of 10 women received a fixed dose of LMWH, one of whom had monitoring of anti-factor Xa, but no further

information was provided. McLintock et al. [94] reported on 37 pregnancies treated predominately with enoxaparin. Five developed thromboembolic complications, all of which were due to noncompliance or subtherapeutic anticoagulation. Two patients reported by Yinon et al. [108] and De Santo et al. [90] developed valve thrombosis on LMWH despite guideline-recommended peak anti-factor Xa levels; however, trough levels were not measured in both patients. In summary, LMWH has been associated with valve thrombosis in pregnant women with MPHVs. Most if not all cases however have been associated with poor anticoagulation management. With appropriate patient selection, dose regimen, and careful monitoring, the efficacy and safety of LMWH is comparable to that of warfarin [82,94,99,105,107– 109]. The protocol used by us for the safe use of LMWH in pregnant women with PHVs is shown in Table 7.1. The protocol puts a great emphasis on patients’ education and compliance, switching from warfarin to LMWH and from LMWH done in the hospital, weekly measurement of trough and peak anti-Xa levels, close follow-up of symptoms, brain natriuretic peptide (BNP) levels and echocardiographic assessment for early diagnosis of valve thrombosis, addition of low dose ASA in the second and third trimester, as recommended by the AHA/ACC guidelines (Class 1a) and the American College of Chest Physicians (ACCP) guidelines (Grade 2C) [110], hospitalization at 36–37 weeks for IV heparin treatment to avoid delivery when patients on LMWH and careful restoration of anticoagulation with warfarin after the delivery to prevent postpartal bleeding complications especially in patients undergoing a C section delivery.

Table 7.1 Our recommended approach to AC therapy with LMWH throughout pregnancy for women with MPHVs 1. Counseling risks and benefits of various AC regimens and determining likelihood of the patient and family to follow very strict follow-up and treatment regimens 2. Baseline transthoracic echocardiogram and BNP or NT-proBNP levels 3. Switch from VKA to LMWH in the hospital when INR 6 h prior to regional anesthesia 11. Vaginal delivery unless fetal indications for a cesarean section delivery or maternal instability 12. Resume UFH in 2–12 h, depending on risk of bleeding, and continue for 24–48 h before start of VKA 13. Start VKA in the hospital after a wait of 24–48 h 14. Continue IV UFH in the hospital until INR is therapeutic AC – anti coagulation, VKA – vitamin K antagonist, BNP – brain natriuretic peptide, LMWH – low-molecular-weight heparin, UFH – unfractionated heparin, aPTT – activated partial thromboplastin time, IV – intravenous, INR – international normalized ratio, IU – international units, MPHVs – mechanical prosthetic heart valves, NT-proBNP – N-terminal pro–B-type natriuretic peptide. a Mitral, tricuspid, and pulmonic mechanical valves; previous thromboembolism; atrial fibrillation; ventricular systolic dysfunction; or hypercoagulable condition other than pregnancy. b In the infrequent case of peak anti-factor Xa level >1.5 IU/ml, total daily dose is divided into three parts given every 8 h each.

CHAPTER 7 Pregnancy in the Patient with Prosthetic Heart Valves

Published Guidelines for anticoagulation in pregnant patients with MPHVs: strengths and limitations Guideline recommendations for anticoagulation during pregnancy in women with MPHVs by the ESC [88,89], the AHA/ACC [59], and the ACCP [110] are shown in Tables 7.2–7.4. In the absence of controlled clinical trials, current recommendations are based on small studies and limited observational data [67,99,111]. The recommendations emphasize the importance of careful prepregnancy evaluation, close follow-up during pregnancy, and the need for care of pregnant women with MPHV in tertiary care centers with dedicated, multidisciplinary teams that are experienced in the management of such patients. The European guidelines and the ACCP suggest the option of continuing warfarin after conception for the first 36 weeks of pregnancy even if the dose is high (>5 g/d) because of its efficacy in preventing valve thrombosis [89]. In our experience, this recommendation is not practical because women and their physicians are not likely to select this therapeutic option due to the concern for the increased risk of embryopathy, fetopathy and fetal loss. Both the ESC and AHA/ACC guidelines suggest that continuation of warfarin during the first trimester is reasonable for women with MPHV if the daily dose required to achieve a therapeutic level is not higher than 5 mg. This recommendation is debatable due to the reasons discussed in the previous paragraph. Women need to know that although the fetal risk of warfarin seems to be dose related, low dose does not completely eliminate the risk of embryopathy and fetopathy and increased fetal loss. The recommendations for the optional use of subcutaneous unfractionated heparin (SC UFH) at a dose adjusted to achieve aPTT of at least 2× control is problematic

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because of the failure of such regimen to prevent serious thrombotic complications including fatal valve thrombosis [99]. If UFH is used, it should be administered intravenously at the dose aimed to achieve aPTT levels of at least 2.5× control. The ACCP recommendations to use adjusted dose LMWH aiming at achieving a peak anti-Xa levels of 0.35– 0.7 IU/ml are inappropriate and can lead to under dosing. The recommended peak anti-Xa levels of 0.8–1.2 IU/ml in the ESC and AHA/ACC and the suggestion to aim at a level of 1.0–1.2 U/ml in mitral and right-sided valves in the ESC guidelines are more appropriate. At the same time however, even such peak levels are likely to result in subtherapeutic trough levels in a substantial number of patients. The new ESC guidelines have included an IIb recommendation for the measurement and aiming at a predose anti-Xa levels >0.6 U/ml. Although this is a welcome addition to the guidelines, the level of recommendation should be higher, and in our experience, the dose of LMWH should be guided by the trough anti-Xa level while the peak level should be used to avoid over anticoagulation (Table 7.1). The new recommendations by the ESC guidelines for dose adjustment of both anti-Xa and INR according to the risk of valve thrombosis and the in-hospital change from one anticoagulation regimen to another are important addition that should increase safety and efficacy and prevent complications associated with AC in women with MPHVs during pregnancy. Importance of measuring trough anti-Xa levels A number of studies have demonstrated a high incidence of subtherapeutic trough levels of anti-Xa activity despite what is considered by the guidelines to be adequate peak levels [112–115]. The importance of measuring trough levels was first demonstrated by Barbour et al. [113], who evaluated 138 peaks and 112 troughs anti-Xa levels in 13 pregnancies and found only 9% of trough levels at >0.5 IU/ml. Even

Table 7.2 Guideline-recommended anticoagulation for pregnant patients with mechanical prosthetic heart valve American Heart Association/American College of Cardiology 2014 [59] Class I 1. Therapeutic anticoagulation with frequent monitoring is recommended for all pregnant patients with a mechanical prosthesis (level of evidence: B) 2. Warfarin is recommended in pregnant patients with a mechanical prosthesis to achieve therapeutic INR in the second and third trimesters (level of evidence: B) 3. Discontinuation of warfarin with initiation of intravenous UFH (with an aPTT >2 control) is recommended before planned vaginal delivery in pregnant patients with a mechanical prosthesis (level of evidence 1a) 4. Low-dose aspirin (75–100 mg) once per day is recommended for pregnant patients in the second and third trimesters with either a mechanical prosthesis or bioprosthesis (class 1a) Class IIa 1. Continuation of warfarin during the first trimester is reasonable for pregnant patients with a mechanical prosthesis if the dose of warfarin to achieve a therapeutic INR is 5 mg/d or less, after full discussion with the patient about risks and benefits (level of evidence: B) 2. Dose-adjusted LMWH at least twice per day (with a target anti-Xa level of 0.8–1.2 U/ml, 4–6 h postdose) during the first trimester is reasonable for pregnant patients with a mechanical prosthesis if the dose of warfarin is >5 mg/d to achieve a therapeutic INR (level of evidence: B) 3. Dose-adjusted continuous intravenous UFH (with an aPTT at least two control) during the first trimester is reasonable for pregnant patients with a mechanical prosthesis if the dose of warfarin is >5 mg/d to achieve a therapeutic INR (level of evidence: B) Source: Nishimura et al. 2014 [59]. Reproduced with permission of Wolters Kluwer Health, Inc.

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Table 7.3 Guideline-recommended anticoagulation for pregnant patients with mechanical prosthetic heart valve European Society of Cardiology [89] Class I level C recommendations: Manage pregnancy in women with mechanical heart valve in a center with pregnancy heart team Delivery by Cesarean section if delivery starts while on VKA or less than 2 wk after discontinuation of VKA Weekly anti-Xa level or aPTT monitoring in pregnant women on LMWH or UFH INR monitoring weekly or every 2 wk in pregnant women on VKA Target anti-Xa levels 4–6 h post dose at 0.8–1.2 IU/ml for aortic valve prosthesis or 1.0–1.2 IU/ml for women with mitral and right-sided valve prosthesis Replace LMWH with IV UFH (aPTT at least 2× control) at least 36 h before planned delivery. UFH should be continued until 4–6 h before planned delivery and restarted 4–6 h after delivery in there are no bleeding complications Anticipate time of delivery to ensure safe and effective peripartum anticoagulation Immediately implement changes in anticoagulation regimen in hospital VKA is recommended during the second and third trimester in women needing low dose

q q q q q q q q q

Class IIa level C recommendations: A bioprosthesis should be considered in young women contemplating pregnancy VKA should be considered during the second and third trimester until the 36 wk in women needing a high dose Continuation of VKAs should be considered during the first trimester if the dose required for therapeutic anticoagulation is 2 mg/d

q q q q

Class IIb level C recommendations: LMWH with anti-Xa level monitoring and dose adjustment may be considered after patient information and consent, in women who need a high dose (>5 mg/d) In pregnant women with LMWH monitoring predose levels targeted at 0.6 IU/ml or higher in addition to monitoring peak anti-Xa levels may be considered

q q

Class III level C recommendations LMWH is not recommended when weekly anti-Xa level monitoring and dose adjustment is not available

q

Source: Regitz-Zagrosek 2018 [89]. Reproduced with permission of Oxford University Press.

when peak levels were between 0.75 and 1.0 IU/ml, only 15% of trough levels were >0.5 IU/ml. These findings were later confirmed by Friedrich and Hameed [114], who studied 15 pregnant subjects receiving therapeutic doses of enoxaparin given twice daily. While all peak levels at three to four hours were between 0.5 and 1.0 IU/ml, 20% of levels at eight hours and 73% of the trough levels were

subtherapeutic. A recent study by our group analyzed 187 paired (trough and peak) determinations of anti-Xa levels in 30 pregnant patients receiving subcutaneous enoxaparin twice daily [112]. Trough anti-Xa levels were subtherapeutic in about 70% of cases with peak anti-Xa levels between 0.7 and 1.0 U/ml and in about 40% of those with peak levels of 1.0–1.2 U/ml (Figures 7.4 and 7.5). These data strongly

Table 7.4 Guideline-recommended anticoagulation for pregnant patients with mechanical prosthetic heart valve American College of Chest Physicians [109] For pregnant women with mechanical heart valves, we recommend one of the following anticoagulant regimens in preference to no anticoagulation (all Grade 1A): a. Adjusted-dose bid LMWH throughout pregnancy. We suggest that doses be adjusted to achieve the manufacturer’s peak anti-Xa LMWH 4 h postsubcutaneous injection; or b. Adjusted-dose UFH throughout pregnancy administered subcutaneously every 12 h in doses adjusted to keep the midinterval aPTT at least twice control or attain an anti-Xa heparin level of 0.35–0.70 U/ml; or c. UFH or LMWH (as previously mentioned) until the 13th week with substitution by VKA until close to delivery when UFH or LMWH is resumed In women judged to be at very high risk of thromboembolism in whom concerns exist about the efficacy and safety of UFH or LMWH as previously dosed (e.g. older-generation prosthesis in the mitral position or history of thromboembolism), we suggest VKA throughout pregnancy with replacement by UFH or LMWH (as aforementioned) close to delivery rather than one of the regimens mentioned previously (Grade 2C) For pregnant women with prosthetic valves at high risk of thromboembolism, we suggest the addition of low-dose aspirin 75–100 mg/d (Grade 2C) Source: Vijayan and Rachel 2012 [109]. Reproduced with permission of Med J Malaysia.

Percentage of subtherapeutic trough anti-Xa levels (%)

CHAPTER 7 Pregnancy in the Patient with Prosthetic Heart Valves

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 0.7–0.79

0.8–0.89

0.9–0.99

1.0–1.2

>1.2

Peak anti-Xa level (unit/ml)

Figure 7.4 Percentage of subtherapeutic trough levels according to peak anti-Xa level categories. Source: Goland et al. 2014 [112]. Reproduced with permission of SAGE Publications.

support routine measurement and maintenance of trough levels in the therapeutic range to ensure adequate AC and prevent complications in pregnant women with MPHV.

University of Southern California protocol for anticoagulation in pregnant women with MPHVs Table 7.5 demonstrates the AC protocol used for over two decades in pregnant women with MPHV at the University of Southern California, with excellent results. The protocol favors the use of LMWH during the first 36–37 weeks of gestation in the majority of women who can be monitored closely (once weekly), followed by intravenous, in-hospital administration of UFH until parturition. Table 7.1 describes 2.00 1.80 1.60

Peak (4 h)

1.40 1.20 1.00 0.80 0.60 0.40 0.20 0.00 0.00

0.20

0.40

0.60

0.80

1.00

1.20

1.40

Trough

Figure 7.5 Correlation between peak and trough anti-Xa levels. Therapeutic peak anti-Xa levels associated with subtherapeutic trough anti-Xa levels (constituting 80% of the therapeutic peak anti-Xa measurements) are marked in white circles; therapeutic peak anti-Xa levels associated with therapeutic trough anti-Xa levels are marked in black-filled circles (constituting 20% of the therapeutic peak anti-Xa measurements). In a minority (12%) of the patients, both peak and trough levels were subtherapeutic, and they were marked in gray-filled circles. Source: Goland et al. 2014 [112]. Reproduced with permission of SAGE Publications.

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our protocol for the use of LMWH throughout pregnancy in women with MPHVs. The risk and benefits of various anticoagulation regimens is discussed with the patients and the family either prior to pregnancy or as early as possible after conception. Patients are told about the close follow-up and treatment regimen they need to agree to and be able to follow very carefully. In the absence of recent echocardiographic study, a baseline trance thoracic echocardiogram is performed and baseline levels of Nterminal pro–B-type natriuretic peptide (NT-proBNP) are obtained. The switch from warfarin to LMWH is done as early as possible. Although most guideline recommended substituting heparin for warfarin between 6 and 12 weeks, this recommendation does not consider that with half-life of 60 hours, circulating drug will be detected for an additional 300 hours, or almost two weeks after discontinuation of the drug. For this reason, substitution starting at six weeks gestation may be too late to prevent embryopathy [116]. The switch from warfarin to LMWH should be done in the hospital starting with enoxaparin at the dose of 1 mg/kg with a first dose given in the evening of day one replacing the warfarin evening dose. Trough and peak anti-Xa levels are obtained in the morning 12 hours after the administration of the first dose and just before the administration of the second dose, with measurements of peak anti-Xa level four to five hours after the injection. Dose titration is performed with measurements of trough and peak anti-Xa levels before and after each consecutive dose to achieve a trough level of ≥0.6 IU/ml in low risk patients (bileaflet prosthetic valves in the aortic position without additional risk factors), and ≥0.7 IU/ml in high risk patients (prosthetic valve in the mitral and tricuspid positions, atrial fibrillation, history of thromboembolism on anticoagulation, and additional hypercoagulable conditions). The rational for the higher level of anticoagulation in high-risk patients is supported by the AHA/ACC guidelines which recommend a higher level of INR in high risk, nonpregnant patients with MPHVs [59]. The rational to use a higher level of AC in women with mitral prosthesis is supported by recent reports including a study by ¨ Ozkan et al. [62], who described 28 cases with valve thrombosis in pregnancy all of them involved the mitral valve. In addition, the results from the ROPAC registry reported 10 cases of mechanical PVT, eight of them with mitral, and one with tricuspid valves and only one with aortic valve prosthesis. ASA at a dose of 75–100 is used in the second and third trimesters in addition to the anticoagulation in all patients. Patients are discharged home after achieving the desired level of anticoagulation to be followed weekly for symptoms and determination of trough and peak anti-Xa levels and assure patient’s compliance with the treatment. In case of a need for dose adjustment, anti-Xa levels are repeated in two to three days. In a case that peak anti-Xa levels >1.5 IU/ml, the daily dose is divided into three doses given every eight hours. Echocardiogram and NT-proBNP levels are repeated in case of worsening symptoms for early detection of valve thrombosis. Because of the increased incidence of premature labor and delivery in patients with MPHVs [4], patients

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Table 7.5 Recommended approach to USC anticoagulation in women with MPHV, during pregnancy Higher risk

Lower risk

Definition

MPHV in the mitral, tricuspid, or pulmonic position. Atrial fibrillation, history of TE on anticoagulation. Hypercoagulable state other than pregnancy

MPHV in the aortic position, no risk factors

Treatment

LMWH (trough anti-Xa level ≥0.7 IU/ml, peak ≤1.5 IU/ml) + ASA 81–100 mg daily. Switch to IV UFH at 36–37 wk (anti-Xa level 0.8–1.0 IU/ml or aPTT ≥2.5× control to parturition)

LMWH (trough anti-Xa level ≥0.6 IU/ml, peak ≤1.5 IU/ml) + ASA 81–100 mg daily. Switch to IV UFH at 36 wk (anti-Xa level 0.8–1.0 IU/ml aPTT ≥2.0× control)

Or

Or

LMWH (trough anti-Xa level ≥0.7, peak ≤1.5 IU/ml for 12 wk) + ASA 81–100 mg daily, followed by warfarin (INR 3.0–4.0) to 36 wk + ASA 81–100 mg daily), then IV UFH (anti-Xa 0.8 = 1.0 IU/ml or aPTT ≥2.5× control to parturition)

LMWH (trough anti-Xa level ≥0.6 IU/ml, peak ≤1.5 IV/ml for 12 wk) + ASA 81–100 mg daily followed by warfarin (INR 2.5–3.5) to 36 wk + ASA 81–100 mg daily), then IV UFH (anti-Xa level 0.8–1.0 IU/ml or aPTT ≥2.0× control to parturition)

are hospitalized at 36–37 weeks for substituting LMWH for intravenous UFH. For reasons discussed previously, we prefer monitoring the effect of intravenous UFH by measuring anti-Xa levels rather than aPTT. In addition, monitoring IV UFH infusion with anti-Xa achieves therapeutic anticoagulation more rapidly compared to aPTT and maintains therapeutic goal for a longer time, with less fluctuations and fewer dose adjustments and needs for repeated testing [117]. In a study by Guervil et al. [117], an odd of reaching therapeutic anticoagulation at 24 hours were 3.5 higher for anti-Xa–monitored patients compared to aPTT and 10 times higher at 48 hours. In addition, an aPTT-based protocol led to greater fluctuations compared to anti-Xa-based protocol. The importance of achieving rapid therapeutic anticoagulation is well established in clinical trials [118]. In case of the use of aPTT, we recommend a level of 2.5× control rather than the 2.0× control recommended by the guidelines, because of the hypercoagulable state of pregnancy. Induction of labor is usually aimed at 38 weeks, and UFH is stopped on the onset of labor or greater than six hours prior to regional anesthesia. Vaginal delivery is preferred over cesarean section in order to prevent bleeding complications during and after delivery. UFH is resumed 2–12 hours after the delivery (depending on the risk of bleeding) and continues for 24–48 hours before starting warfarin. Patients remain in the hospital until therapeutic INR level is achieved.

and identified 800 pregnancies from 18 publications up to June 2016, reported a rate of composite fetal outcome which included spontaneous abortion, fetal death, and the presence of any congenital defect in 34% with the regimen of UFH and VKA and 16% for LMWH and VKA. These data demonstrate not only the superiority of the use of LMWH compared to UFH but also the continued effect of VKA on fetal loss even beyond the first trimester. D’Souza et al. [99] in a recent metaanalysis which included 46 publications before 2016 reported higher maternal mortality and thromboembolic events with the sequential regimen compared to VKA and lower than LMWH. This regimen was associated with lower live birth rate compared to LMWH and higher than VKA. At the same time, sequential regimen was associated with the lowest number of small for gestational age babies, miscarriages, and preterm birth. Because of the superiority of sequential treatment compared to VKA, this regimen should be used when the use of LMWH throughout pregnancy is not possible due to financial constraints or inability to provide the appropriate monitoring. It should be noted that sequential anticoagulation regimen is associated with multiple switches of anticoagulation regimens that require a close monitoring of anticoagulation level in order to avoid over- or under-anticoagulation and increase the risk of thromboembolic events as well as bleeding complications. Switch of anticoagulation should therefore be done in the hospital with close monitoring.

Sequential treatment with LMWH and vitamin K antagonists (VKA) The use of heparin during the first trimester and vitamin K antagonists (VKA) during the second and third trimester (sequential treatment) reduces the fetal side effects associated with VKA but is associated with a higher incidence of fetal loss mainly due to miscarriage compared to LMWH throughout and a higher incidence of thromboembolic complications compared to VKA throughout [99,111]. In a review of 317 cases included in seven reports published between 2000 and 2011 with the use of sequential treatment, the incidence of fetal wastage was 27% and spontaneous abortion was 10% [104]. Steinberg et al. [111], who performed a Medline search

Direct oral anticoagulants (DOACs) A recent communication by Godin and Tanguay [119] has suggested a consideration for the use of direct oral anticoagulants (DOACs) for the management for pregnant women with MPHVs. Only limited information, however, is available regarding the use of these drugs during pregnancy. Beyer-Westendorf et al. [120] reported on 137 cases exposed to DOACs during pregnancy in whom information on the outcome of pregnancy was available. Only 49% of the cases had live birth, 23% had miscarriages, and 28% therapeutic abortion. Seven newborns showed abnormalities of which three could potentially be interpreted as embryopathy (live birth with facial dysmorphism; miscarriage in week 10 with

CHAPTER 7 Pregnancy in the Patient with Prosthetic Heart Valves

limb abnormality; and elective pregnancy termination due to a fetal cardiac defect in a woman who had to terminate a previous pregnancy due to Fallot tetralogy). The experience with the use of DOAC in nonpregnant patients with MPHVs is limited to a study of dabigatran vs. warfarin in 252 patients [121]. The study was prematurely terminated because of an excess of thromboembolic and bleeding events among patients in the dabigatran group. In summary therefore, because of maternal and fetal safety, the use of DOAC in pregnant women with MPHVs is not recommended.

Use of anticoagulation in breast-feeding women Warfarin Warfarin is polar, nonlipophilic, and highly protein bound and is not detected in breast milk and does not induce an anticoagulant effect in the breast-fed infant [122,123]. Therefore, the use of warfarin in breast-feeding women who require postpartum anticoagulant therapy is safe [110]. Both warfarin and dicumarol were classified by the American academy of pediatrics as compatible with breast-feeding [124]. UFH and LMWH Because of its high molecular weight and strong negative charge, UFH does not pass into breast milk and can be safely given to nursing mothers [125]. In a case series of 15 women receiving 2500 International Units of LMWH after cesarean section, there was evidence of excretion of small amounts of LMWH into the breast milk in 11 patients [126]. However, given the very low bioavailability of oral heparin, there is unlikely to be any clinically relevant effect on the nursing infant [110]. Aspirin Maternal ASA ingestion is associated with excretion of salicylates into breast milk. For this reason, the use of high-dose ASA may be associated with complications in the breast-fed infant including platelet dysfunction, gastrointestinal (GI) bleeding, Reye syndrome [127,128], and metabolic acidosis [129]. The use of low-dose ASA that is recommended in women with MPHVs in addition to anticoagulation is safe [130–132]. Heparin-induced Thrombocytopenia Heparin induced thrombocytopenia (HIT) rarely appears in pregnant patients receiving heparin [133]. The general recommendations for alternative AC have been recently reviewed [134]. Alternative AC treatment is recommended after confirmation of the diagnosis by laboratory results or based on high clinical suspicion. Alternative AC should not include either warfarin or LMWH, both can worsen the risk of thrombosis. Only limited information has been published regarding the management and outcome of pregnant women with MPHV who developed HIT. Chaudhary et al [135] published a systemic review of 12 patients with the median age of 28 years who were diagnosed with HIT at a median gestational age of 20 weeks, only 2 of these cases were

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receiving AC because of a MPHV. Both were treated with UFH prior to the development of HIT. One of the patients was treated with Danaparoid 3000 anti Xa units sc BID followed by warfarin, pregnancy was complicated by a preeclampsia and the patient was delivered by C section. The 2nd patient was treated with IV argatroban 0.7 mcg/Kg/min. The patient developed valve thrombosis and required surgery for mitral valve replacement. No information was provided on the level of AC. All 12 patients were initially managed with lepirudin (33%), argatroban (25%), danaparoid (25%) or fondaparinux (17%) and later were bridged to VKA or maintained on lapirudin. Gerhardt and coworkers [136] reported on a successful use of danaparoid in 2 pregnant women with MPHV and HIT. The 1st patient had a tricuspid valve prothesis and the 2nd a St Jude mitral valve. Anti Xa levels were between 0.6-1.2 IU/mL during pregnancy. Cesarean section was performed at anti-Xa levels of 0.3 and 0.7 IU/mL. One patient developed placental hematoma at 32 weeks which remained stable in size. Both patients delivered healthy boys. Management of HIT in a pregnant patient with a MPHV should follow the recent guidelines of the American society of hematology [137]. Because of the great risk of valve thrombosis in pregnant women with MPHV the diagnosis of HIT should be made based on guidelines recommended 4Ts score. The recommended options for AC include the use of argatroban, bivalirudin, and fondaparinux. The choice of agent for the management of pregnant women with MPHV may be influenced by drug factors (availability, cost, ability to monitor the anticoagulant effect, route of administration, half-life), patient’s factors (kidney function, liver function, bleeding risk, clinical stability), experience of the clinician and fetal safety. There are limited safety human data for all 3 drugs [138]. Both bivalirudin and argatroban are FDA category B and described as compatible by Briggs and Freeman et al. [138]. Fondaparinux has not received FDA category but is defined by Briggs and Freeman as probably compatible. No information is available on the safety of all 3 drugs during lactation.

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8 Chan, V., Malas, T., Lapierre, H. et al. (2011). Reoperation of left heart valve bioprostheses according to age at implantation. Circulation 124 (11 Suppl.): S75–S80. 9 Jamieson, W.R., Munro, A.I., Miyagishima, R.T. et al. (1995). Carpentier-Edwards standard porcine bioprosthesis: clinical performance to seventeen years. Ann Thorac Surg 60 (4): 999–1006; discussion 7. 10 Goldstone, A.B., Chiu, P., Baiocchi, M. et al. (2017). Mechanical or Biologic Prostheses for Aortic-Valve and Mitral-Valve Replacement. N Engl J Med 377 (19): 1847–1857. 11 Vongpatanasin, W., Hillis, L.D., and Lange, R.A. (1996). Prosthetic heart valves. N Engl J Med 335 (6): 407–416. 12 Hellmeier, F., Nordmeyer, S., Yevtushenko, P. et al. (2018). Hemodynamic evaluation of a biological and mechanical aortic valve prosthesis using patient-specific MRI-based CFD. Artif Organs 42 (1): 49–57. 13 Yadlapati, A., Diep, J., Barnes, M. et al. (2014). Comprehensive hemodynamic comparison and frequency of patient-prosthesis mismatch between the St. Jude Medical Trifecta and Epic Bioprosthetic aortic valves. J Am Soc Echocardiogr 27 (6): 581–589. 14 Chambers, J.B., Rajani, R., Parkin, D. et al. (2008). Bovine pericardial versus porcine stented replacement aortic valves: early results of a randomized comparison of the Perimount and the Mosaic valves. J Thorac Cardiovasc Surg 136 (5): 1142–1148. 15 Christ, T., Holinski, S., Zhigalov, K. et al. (2017). Hemodynamics of pericardial aortic valves: contemporary stented versus stentless valves in a matched comparison. Ann Thorac Cardiovasc Surg 23 (6): 298–303. 16 Zayat, R., Arias-Pinilla, J., Aljalloud, A. et al. (2017). Performance of the Labcor Dokimos Plus pericardial aortic prosthesis: a single-centre experience. Interact Cardiovasc Thorac Surg 24 (3): 355–362. 17 Said, S.M., Ashikhmina, E., Greason, K.L. et al. (2012). Do pericardial bioprostheses improve outcome of elderly patients undergoing aortic valve replacement? Ann Thorac Surg 93 (6): 1868–1874; discussion 74–75. 18 Thalji, N.M., Suri, R.M., Michelena, H.I. et al. (2015). Do differences in early hemodynamic performance of current generation biologic aortic valves predict outcomes 1 year following surgery? J Thorac Cardiovasc Surg 149 (1): 163-73.e2. 19 Suri, R.M. and Schaff, H.V. (2013). Selection of aortic valve prostheses: contemporary reappraisal of mechanical versus biologic valve substitutes. Circulation 128 (12): 1372–1380. 20 Anastasiadis, K., Kambouroglou, D., and Spanos, P. (2004). The use of valve homografts and autografts in adult cardiac surgery. Hell J Cardiol 36–41. 21 Kim, J.Y., Kim, J.B., Jung, S.H. et al. (2016). Long-term outcomes of homografts in the aortic valve and root position: a 20-year experience. Korean J Thorac Cardiovasc Surg 49 (4): 258–263. 22 Solari, S., Mastrobuoni, S., De Kerchove, L. et al. (2016). Over 20 years experience with aortic homograft in aortic valve replacement during acute infective endocarditis. Eur J Cardiothorac Surg 50 (6): 1158–1164. 23 Lund, O., Chandrasekaran, V., Grocott-Mason, R. et al. (1999). Primary aortic valve replacement with allografts over twenty-five years: valverelated and procedure-related determinants of outcome. J Thorac Cardiovasc Surg 117 (1): 77–90; discussion 1. 24 Kumar, A.S., Choudhary, S.K., Mathur, A. et al. (2000). Homograft mitral valve replacement: five years’ results. J Thorac Cardiovasc Surg 120 (3): 450–458. 25 Denbow, C.E., Matadial, L., Sivapragasam, S., and Spencer, H. (1983). Pregnancy in patients after homograft cardiac valve replacement. Chest 83 (3): 540–542. 26 Sadler, L., McCowan, L., White, H. et al. (2000). Pregnancy outcomes and cardiac complications in women with mechanical, bioprosthetic and homograft valves. BJOG 107 (2): 245–253. 27 Gopal, K., Hudson, I.M., Ludmir, J. et al. (2002). Homograft aortic root replacement during pregnancy. Ann Thorac Surg 74 (1): 243–245. 28 Hasnat, K., Birks, E.J., Liddicoat, J. et al. (1999). Patient outcome and valve performance following a second aortic valve homograft replacement. Circulation 100 (19 Suppl.): II42–II47. 29 Gulbins, H., Kreuzer, E., and Reichart, B. (2003). Homografts: a review. Expert Rev Cardiovasc Ther 1 (4): 533–539.

30 Skillington, P.D., Mokhles, M.M., Takkenberg, J.J. et al. (2015). The Ross procedure using autologous support of the pulmonary autograft: techniques and late results. J Thorac Cardiovasc Surg 149 (2 Suppl.): S46– S52. 31 Al-Halees, Z., Pieters, F., Qadoura, F. et al. (2002). The Ross procedure is the procedure of choice for congenital aortic valve disease. J Thorac Cardiovasc Surg 123 (3): 437–441; discussion 41–42. 32 Dore, A. and Somerville, J. (1997). Pregnancy in patients with pulmonary autograft valve replacement. Eur Heart J 18 (10): 1659–1662. 33 Martin, T.C., Idahosa, V., Ogunbiyi, A. et al. (2003). Successful pregnancy and delivery after pulmonary autograft operation (Ross procedure) for rheumatic aortic valve insufficiency. West Indian Med J 52 (1): 62–64. 34 Martin, E., Mohammadi, S., Jacques, F. et al. (2017). Clinical outcomes following the Ross procedure in adults: a 25-year longitudinal study. J Am Coll Cardiol 70 (15): 1890–1899. 35 Mazine, A., David, T.E., Rao, V. et al. (2016). Long-term outcomes of the Ross procedure versus mechanical aortic valve replacement: propensity-matched cohort study. Circulation 134 (8): 576–585. 36 Buratto, E., Shi, W.Y., Wynne, R. et al. (2018). Improved survival after the Ross procedure compared with mechanical aortic valve replacement. J Am Coll Cardiol 71 (12): 1337–1344. 37 Pettersson, G.B. and Blackstone, E.H. (2018). Is it time to reconsider use of the Ross procedure for adults? J Am Coll Cardiol 71 (12): 1345–1346. 38 Sievers, H.H., Stierle, U., Charitos, E.I. et al. (2016). A multicentre evaluation of the autograft procedure for young patients undergoing aortic valve replacement: update on the German Ross Registry. Eur J Cardiothorac Surg 49 (1): 212–218. 39 Sharabiani, M.T., Dorobantu, D.M., Mahani, A.S. et al. (2016). Aortic valve replacement and the Ross operation in children and young adults. J Am Coll Cardiol 67 (24): 2858–2870. 40 Schaff, H.V. (2016). Ross procedure for aortic valve replacement in young adults: preferred procedure or “double, double toil and trouble”? Circulation 134 (8): 586–588. 41 Hanania, G., Thomas, D., Michel, P.L. et al. (1994). Pregnancy in patients with heart valve prosthesis. A French retrospective cooperative study (155 cases). Arch Mal Coeur Vaiss 87 (4): 429–437. 42 Sbarouni, E. and Oakley, C.M. (1994). Outcome of pregnancy in women with valve prostheses. Br Heart J 71 (2): 196–201. 43 Born, D., Martinez, E.E., Almeida, P.A. et al. (1992). Pregnancy in patients with prosthetic heart valves: the effects of anticoagulation on mother, fetus, and neonate. Am Heart J 124 (2): 413–417. 44 Lee, C.N., Wu, C.C., Lin, P.Y. et al. (1994). Pregnancy following cardiac prosthetic valve replacement. Obstet Gynecol 83 (3): 353–356. 45 Badduke, B.R., Jamieson, W.R., Miyagishima, R.T. et al. (1991). Pregnancy and childbearing in a population with biologic valvular prostheses. J Thorac Cardiovasc Surg 102 (2): 179–186. 46 Avila, W.S., Rossi, E.G., Grinberg, M., and Ramires, J.A. (2002). Influence of pregnancy after bioprosthetic valve replacement in young women: a prospective five-year study. J Heart Valve Dis 11 (6): 864–869. 47 Jamieson, W.R., Miller, D.C., Akins, C.W. et al. (1995). Pregnancy and bioprostheses: influence on structural valve deterioration. Ann Thorac Surg 60 (2 Suppl.): S282-S286; discussion S7. 48 Salazar, E., Espinola, N., Rom´an, L., and Casanova, J.M. (1999). Effect of pregnancy on the duration of bovine pericardial bioprostheses. Am Heart J 137 (4 Pt. 1): 714–720. 49 Yoon, S.H., Bleiziffer, S., De Backer, O. et al. (2017). Outcomes in transcatheter aortic valve replacement for bicuspid versus tricuspid aortic valve stenosis. J Am Coll Cardiol 69 (21): 2579–2589. 50 Ben-Dor, I. and Stewart, A. (2017). A cautionary tale of 2 leaflets: TAVR in bicuspid aortic valve stenosis. J Am Coll Cardiol 69 (21): 2590–2591. 51 Webb, J.G., Mack, M.J., White, J.M. et al. (2017). Transcatheter aortic valve implantation within degenerated aortic surgical bioprostheses: PARTNER 2 Valve-in-Valve Registry. J Am Coll Cardiol 69 (18): 2253– 2262. 52 Webb, J.G. and Dvir, D. (2013). Transcatheter aortic valve replacement for bioprosthetic aortic valve failure: the valve-in-valve procedure. Circulation 127 (25): 2542–2550.

CHAPTER 7 Pregnancy in the Patient with Prosthetic Heart Valves

53 Carabello, B.A. (2017). Valve-in-Valve TAVR: insights into the pathophysiology of aortic stenosis. J Am Coll Cardiol 69 (18): 2263–2265. 54 Remadi, J.P., Baron, O., Roussel, C. et al. (2001). Isolated mitral valve replacement with St. Jude medical prosthesis: long-term results: a follow-up of 19 years. Circulation 103 (11): 1542–1545. 55 Elkayam, U., Goland, S., Pieper, P.G., and Silverside, C.K. (2016). Highrisk cardiac disease in pregnancy: Part I. J Am Coll Cardiol 68 (4): 396– 410. 56 Elkayam, U. (2017). Anticoagulation therapy for pregnant women with mechanical prosthetic heart valves: how to improve safety? J Am Coll Cardiol 69 (22): 2692–2695. 57 Badhwar, V., Ofenloch, J.C., Rovin, J.D. et al. (2012). Noninferiority of closely monitored mechanical valves to bioprostheses overshadowed by early mortality benefit in younger patients. Ann Thorac Surg 93 (3): 748–753. 58 Qasqas, S.A., McPherson, C., Frishman, W.H., and Elkayam, U. (2004). Cardiovascular pharmacotherapeutic considerations during pregnancy and lactation. Cardiol Rev 12 (4): 201–221. 59 Nishimura, R.A., Otto, C.M., Bonow, R.O. et al. (2014). AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 63 (22): e57–e185. 60 Whitlock, R.P., Sun, J.C., Fremes, S.E. et al. (2012). Antithrombotic and thrombolytic therapy for valvular disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141 (2 Suppl.): e576S–e600S. 61 Vahanian, A., Alfieri, O., Andreotti, F. et al. (2012). Guidelines on the management of valvular heart disease (version 2012): the Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur J Cardiothorac Surg 42 (4): S1–S44. ¨ 62 Ozkan, M., C ¸ akal, B., Karakoyun, S. et al. (2013). Thrombolytic therapy for the treatment of prosthetic heart valve thrombosis in pregnancy with low-dose, slow infusion of tissue-type plasminogen activator. Circulation 128 (5): 532–540. 63 John, A.S., Gurley, F., Schaff, H.V. et al. (2011). Cardiopulmonary bypass during pregnancy. Ann Thorac Surg 91 (4): 1191–1196. 64 Sepehripour, A.H., Lo, T.T., Shipolini, A.R., and McCormack, D.J. (2012). Can pregnant women be safely placed on cardiopulmonary bypass? Interact Cardiovasc Thorac Surg 15 (6): 1063–1070. 65 Arnoni, R.T., Arnoni, A.S., Bonini, R.C. et al. (2003). Risk factors associated with cardiac surgery during pregnancy. Ann Thorac Surg 76 (5): 1605–1608. 66 Hosseini, S., Kashfi, F., Samiei, N. et al. (2015). Feto-maternal outcomes of urgent open-heart surgery during pregnancy. J Heart Valve Dis 24 (2): 253–259. 67 Goland, S. and Elkayam, U. (2012). Anticoagulation in pregnancy. Cardiol Clin 30 (3): 395–405. 68 Bremme, K.A. (2003). Haemostatic changes in pregnancy. Best Pract Res Clin Haematol 16 (2): 153–168. 69 Franchini, M. (2006). Haemostasis and pregnancy. Thromb Haemost 95 (3): 401–413. 70 Rosenkranz, A., Hiden, M., Leschnik, B. et al. (2008). Calibrated automated thrombin generation in normal uncomplicated pregnancy. Thromb Haemost 99 (2): 331–337. 71 Kjellberg, U., Andersson, N.E., Ros´en, S. et al. (1999). APC resistance and other haemostatic variables during pregnancy and puerperium. Thromb Haemost 81 (4): 527–531. 72 James, A.H. (2009). Pregnancy-associated thrombosis. Hematol Am Soc Hematol Educ Program 277–285. 73 Heit, J.A., Kobbervig, C.E., James, A.H. et al. (2005). Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 143 (10): 697–706. 74 James, A.H., Bushnell, C.D., Jamison, M.G., and Myers, E.R. (2005). Incidence and risk factors for stroke in pregnancy and the puerperium. Obstet Gynecol 106 (3): 509–516.

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CHAP T E R 8

Myocarditis and Pregnancy Avraham Shotan1,2 and Andrei Keren3 1 Hillel

Yaffe Medical Center, Hadera, Israel

2 Rappaport

Medical School, Technion, Haifa, Israel

3 Hadassah-Hebrew

University Hospital, Jerusalem, Israel

Definition and incidence of myocarditis The 1995 World Health Organization/International Society and Federation of Cardiology task force defined Myocarditis: “Inflammatory disease of the myocardium diagnosed by established histological, immunological, and immunohistochemical criteria” [1]. Myocarditis is a nonfamilial form of heart muscle disease based on the current European Society of Cardiology (ESC) classification of cardiomyopathies [2]. Myocarditis can be acute, subacute, or chronic, and there may be either focal or diffuse involvement of the myocardium [3]. However, diagnosis of myocarditis is very challenging due to the heterogeneity of the clinical presentations of the disease. Clinical manifestations of myocarditis are not specific and may vary from asymptomatic electrocardiographic abnormalities, observed during viral Coxsackie B or influenza outbreaks in the community, to severe dilated cardiomyopathy (DCM) with fulminant heart failure (HF), leading to transplantation or death [4]. Myocarditis can affect individuals of all ages, although it is most frequent in the young. The true incidence of the disease is also unknown as the gold-standard of diagnosis by endomyocardial biopsy (EMB) is not performed in the majority of cases, and the diagnosis is assumed to be underestimated [3–6]. Autopsy reports have revealed varying estimates of the incidence of myocarditis according to the population studied, with estimates of around 0.5% in the general population [7–9]. Based on pathologic series examining young adults that died from sudden death, the incidence of myocarditis was 8.6%, while 6% of autopsies of sudden death athletes had evidence of myocarditis [10,11]. In addition, myocarditis was demonstrated in more than 40% of cases of idiopathic DCM [12,13]. Based on recent reports of the Global Burden of Diseases Study 2010 [14,15], the estimated global prevalence of myocarditis was 22 of 100 000 patients/year, and the age-standardized death rate due to myocarditis and cardiomyopathies was 6.1 per 100 000 in 2010. These studies suggest that the incidence of

myocarditis is not negligible, however with a wide variation in the clinical presentation and sequel, from complete clinical resolution to extensive myocardial damage and death.

Etiology Although the etiology of myocarditis often remains undetermined, a large variety of infectious agents, systemic diseases, drugs, and toxins can cause the disease [3,6,16] (Table 8.1). Molecular techniques mainly reverse transcriptase (RT)– polymerase chain reaction (PCR) amplification [5,17] suggest that viral infections are the most important and frequent cause of myocarditis. The earliest evidence of virus infection and its association with myocarditis and pericarditis was acquired during outbreaks of influenza, poliomyelitis, measles, mumps, and pleurodynia associated with enterovirus infection [6]. By detection of persistence of viral genomes with adequate, sensitive molecular biological techniques, such as in situ hybridization and nested PCR, further viruses have been detected in addition to the classic cardiotropic viruses (enteroviruses and adenoviruses), and currently parvovirus (PV) B19 and human herpes virus type 6 (HHV-6) are the most frequent viruses, while enteroviruses such as coxsackie B were in the past [3,18–20]. By damaging mainly endothelial cells of the blood vessels, PV B19 often causes an acute myocarditis, which mimics acute coronary syndrome, with severe chest pain, ST-T changes and significant elevation of blood troponin I and T [16]. The viruses commonly tested for in the setting of suspected myocarditis are PV B19, adenovirus, cytomegalovirus, enterovirus, Epstein–Barr, hepatitis C, herpes simplex 1, 2, and 6, and influenza viruses A and B [3,6]. In Latin America, Trypanosoma cruzi infection and activation of the immune system lead to the clinical manifestations of Chagas disease [6]. Lymphocytic and giant cell myocarditis are presumed idiopathic or autoimmune if no viruses are identified in EMB, and other known causes are excluded. Autoimmune myocarditis may occur with exclusive cardiac involvement

Cardiac Problems in Pregnancy, Fourth Edition. Edited by Uri Elkayam. © 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.

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Table 8.1 Causes of myocarditis

CAUSES OF MYOCARDITIS

INFECTIOUS • Viral • • • • • •

Bacterial Spirochaetal Fungal Protozoal Parasitic Rickettsial

IMMUNE-MEDIATED • Allergens:

Tetanus toxoid, vaccines, serum sickness, Drugs

• Alloantigens: Heart transplant rejection • Autoantigens: Infection-negative lymphocytic, infection-negative giant cell, associated with autoimmune or immune-oriented disorder

or in the context of autoimmune disorders with extracardiac manifestations, most frequently in sarcoidosis, hypereosinophilic syndrome, scleroderma, and systemic lupus erythematosus [3,21,22].

Pathogenesis The causative organism, usually viral, or the noninfectious insulting process evokes immune responses. Myocardial damage is due not only to direct injury but also a result of postinfectious, autoimmune-mediated, myocardial inflammatory damage. The typical viral pathogens enter the body through the gastrointestinal or the upper respiratory tracts. They produce a systemic viremia, invade the myocardium, and replicate in the myocyte, causing myocytolysis. By day 5–10, a generalized macrophage and IgM antibody response occurs, with myocardial inflammatory infiltrate. Antigenspecific IgG antibodies peak by day 14, with myofibers dropout and interstitial fibrosis [23]. This inflammatory process aims at viral elimination and is not primarily detrimental to the heart [24]. Concomitantly with the humoral and cellular immune response, patients may increase production of pro-inflammatory cytokines, resulting in viral clearance and resolving of the inflammation. However, the immune response may continue unabated despite viral elimination. Two major pathways are responsible for the pathogenesis of virus-induced myocardial damage: direct cytopathic effects of the cardiotropic viruses and the virus-induced anticardiac immune response. Myocytolysis liberates cryptic cardiac antigens, thereby evoking anticardiac autoimmunity, which may ultimately persist even after complete viral elimination [25]. Viral persistence perpetuates the anti-cardiac immune response. Genetic predisposition might be an important contributing factor for the ultimate cardiac pathogenicity of these viruses [26,27].

TOXIC • Drugs • Heavy Metals • Hormones, e.g. catecholamines (Pheochromocytoma) • Physical agents

Activated B-lymphocytes produce a multitude of antibodies, primed against viral and cross-reactive myocardial antigens, which can impair cardiac contractility [28,29]. Concomitantly produced pro-inflammatory cytokines may exert cardiodepressive, arrhythmogenic effects [30]. Cytokines induce cell adhesion molecules (CAMs), which mediate the transendothelial migration of immunocompetent infiltrates, including the intramyocardial infiltration of cytotoxic T-lymphocytes, that mediate myocytolysis [25,30]. Some of the patients with acute myocarditis respond with reduced production of pro-inflammatory cytokines, which may result in virus persistence and, sometimes, lesser myocardial inflammation. Histologically, there is an active inflammatory cellular infiltrate within the myocardium, associated with myocyte necrosis (Dallas Criteria) [20,31]. The inflammatory infiltrate is predominantly lymphocytic in more than 90% of cases. However, eosinophilic infiltration or giant cell formation may occasionally be seen [3]. In a majority of cases, the inflammatory process resolves with minimal or no damage or remodeling [25]. In humans, ongoing myocardial inflammation may result in DCM or restrictive cardiomyopathy. If the host immune response is overwhelming or inappropriate, the inflammation may destroy the heart tissue acutely leading to left ventricular (LV) failure frequently even without dilatation (fulminant myocarditis) and death [6]. Myocardial inflammation is, therefore, no longer restricted to the very acute phase of myocarditis. Progression of myocarditis to DCM has been documented and is pathogenically frequently linked to chronic autoimmune virus negative inflammation or to viral persistence, which induce the chronic inflammatory process defined as “inflammatory cardiomyopathy” [3,16]. Thus, persistence of cardiotropic viruses constitutes one of the predominant etiological factors in etiology of DCM. Additionally, circulating autoantibodies to distinct cardiac autoantigens have been described

CHAPTER 8 Myocarditis and Pregnancy

in patients with DCM, providing evidence for autoimmune involvement [3,6,25].

Myocarditis in pregnancy Only a few cases of myocarditis have been reported in pregnancy [32–43]. In an early review, published in 1968, 4 of 22 patients with viral myocarditis were in the postpartum period [32]. Grimes and Cates reported four cases with fatal outcome following an abortion, with autopsy evidence of myocardial inflammation [34]. Gehrke et al. reported a case of a 28year-old asthmatic female who developed postpartum acute heart failure accompanied by diarrhea, fever, and hypereosinophilia. During steroid treatment, cytomegalovirusassociated myocarditis developed [35]. Chen et al. described a patient with a history of repeated episodes of acute myocarditis who developed heart failure in the 36th week of gestation, with rapid deterioration and death [36]. Ciccone et al. reported a 40-year-old woman who developed, after childbirth, hyperthermia associated with neck and left arm pain, who died suddenly few days later. Autopsy disclosed normal sized heart with fulminant myocarditis, congested organs, and negative microbiological tests [37]. Massengill et al. described a pregnant woman who developed infectious myocarditis presenting as acute respiratory distress [38]. Malhotra et al. described a 38-year-old postpartum female who had a cesarean section a week before presentation for preeclampsia who developed acute pericarditis and myocarditis related to systemic lupus erythematosus, complicated by acute respiratory failure and cardiogenic shock with dramatic improvement within days under steroid therapy [39]. Several reports have demonstrated a relatively high incidence histologically proven myocarditis in patients with peripartum cardiomyopathy (PPCM). These findings have led to the suggestion that myocarditis may be an important etiologic factor in patients with PPCM [40,41]. The incidence of active myocardial inflammation in this patient population, however, varied significantly in different reports. Rizeq et al. reported a low incidence (9%) of myocarditis in 34 patients with PPCM, which was comparable to that found in an ageand sex-matched control population with idiopathic-DCM [42]. B¨ultmann et al. studied 26 patients with PPCM in whom EMB specimens revealed viral genomes: PV B19, HHV-6, Epstein–Barr virus, and human cytomegalovirus in eight patients (30.7%) [43]. These inconsistent results, therefore, cannot be considered as strong evidence for an etiologic role of myocarditis in PPCM/pregnancy associated cardiomyopathy (PAC).

Clinical features The clinical presentation may correlate with the extent and location of the myocardial inflammatory process and the associated systemic illness. The disease often presents as a recent systemic illness with viral symptomatology, such as fever, sore throat, cough,

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arthralgia, myalgia, abdominal pain, nausea, vomiting, diarrhea, and skin rash. Cardiac involvement usually becomes apparent only a few days to a few weeks later and is usually manifested as fatigue, decreased exercise tolerance, dyspnea, palpitations, and precordial discomfort. Pleuropericardial chest pain is not infrequent, especially when there is associated pericarditis. However, chest pain may occur without inflammatory involvement of the pericardium as was proven by MRI. The development of new physical findings depends on the severity of the disease. They include persistent fever, excessive tachycardia, hypotension, and narrow pulse pressure. Clinical findings of heart failure with mitral and tricuspid regurgitation may occur in more severe cases. Neck veins may be distended in patients with HF, pericardial effusion, or both. In the acute phase, there is no dilatation of cardiac chambers, but within a few days to weeks it may occur, and is associated with a diffuse and displaced point of maximal impulse and right ventricular heave. Auscultatory sounds may include a muffled first heart sound, a third heart sound, a friction rub, and murmurs due to mitral and tricuspid regurgitation. Myocarditis may also cause ventricular arrhythmias and heart block or mimic acute myocardial infarction, especially when presented with localized electrocardiographic changes and wall motion abnormalities [3,6,44]. Hemodynamic instability, and even circulatory collapse, may develop in cases with severe left and/or right ventricular dysfunction, a high degree atrioventricular block, ventricular arrhythmias, or associated cardiac tamponade. Myocarditis may be the cause of approximately 20% of cases of sudden, unexpected death in young adults, less than 40 years of age and in young athletes, secondary to tachyarrhythmias or complete atrioventricular block. In autopsy studies of young adults, myocarditis is responsible for 4–12% of sudden deaths, ranking as the third cause after hypertrophic cardiomyopathy and congenital and atherosclerotic coronary artery disease [6]. In addition, systemic and pulmonary emboli have been reported in myocarditis and may be the presenting feature [19]. Myocarditis resolves spontaneously in approximately 80% of patients, but in those who did not recover, prospective studies revealed a 10-year survival rate of only 45%, mostly due to manifestation of DCM and sudden cardiac death [25,45].

Electrocardiogram In the acute stage, the electrocardiogram is usually abnormal, demonstrating ST segment elevation with inversion or flattening of the T wave and possible prolongation of the QT interval. ST-T segment elevation in myocarditis is typically concave (rather than convex as seen in myocardial infarction) and diffuse without reciprocal changes or limitation to a specific coronary territory. The ST segment changes usually return to baseline within a few days, whereas T-wave changes may persist for several weeks or months. Abnormal Q waves may sometimes develop and mimic acute

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myocardial infarction. Ventricular premature beats are common, and atrial and ventricular tachyarrhythmias are present in many patients. QRS prolongation may be an independent negative predictor for survival. Atrioventricular conduction disturbances of varying degrees associated with ventricular tachyarrhythmias should raise the suspicion of giant cell myocarditis, considered the most malignant form of myocarditis, which requires histopathologic confirmation and aggressive immunosuppressive therapy. A–V block in the presence of mild left ventricular dilatation may be also suggestive of Lyme disease or cardiac sarcoidosis [3,6,23].

Chest X-ray A chest roentgenogram is frequently within normal limits, but it may show cardiac enlargement due to chamber dilatation, pericardial effusion, or both. Additional findings may include pulmonary venous congestion, interstitial and even alveolar edema, mild atrial enlargement, a prominent superior vena cava or azygos vein, patchy pulmonary infiltrates, and pleural effusion [23].

Laboratory data Erythrocyte sedimentation rate and C reactive protein (CRP) levels are often raised in myocarditis, but they do not confirm the diagnosis [3]. The white blood cell count may be slightly to moderately elevated, with a neutrophil response in about one-half the patients [6]. Eosinophilia may indicate an underlying parasitic etiology. Cardiac biomarkers are usually elevated, especially high sensitive troponins I or T, which are more sensitive than creatine kinase (CK), including CK-MB levels. However, they are nonspecific and when normal do not exclude myocarditis. We have recently found [46] that in comparison to acute myocardial infarction CRP values are relatively much more elevated than high sensitive troponin values. This also applies to other biomarkers such as brain natriuretic peptides, circulating cytokines, markers related to extracellular matrix degradation, and new biomarkers such as pentraxin 3, galectin 3, and growth differentiation factor 15 that are frequently elevated in myocarditis [47–49]. Antibodies are usually not found until about one week after the onset of the illness. The immunoglobulin class may help in determining the duration of the disease process because IgM antibody levels peak in two to three weeks and are later undetectable, whereas IgG antibody levels peak later and may remain elevated for months or years [23]. Positive viral serology does not imply myocardial infection, but rather indicates the interaction of the peripheral immune system with an infectious agent. Viral serology is, therefore, of limited utility in the diagnosis of viral myocarditis, as the prevalence of circulatory IgG antibodies to cardiotropic viruses in the general population is high in the absence of viral heart disease. While elevated IgM antibodies, which are usually transient, represent a current viremia/infection, elevated IgG antibodies merely reflects immune response to the virus in the past. Viral serology (elevated IgG) has, therefore, a low clinical

value and is currently not routinely recommended, as it did not correlate with EMB viral findings [3,49].

Echocardiography Depending on the severity of cardiac involvement, echocardiographic findings may vary from normal size and function of cardiac chambers to a substantial enlargement with focal or diffuse left ventricular hypokinesia, wall thickening due to edema in the inflamed myocardium, and various degrees of severity of mitral and tricuspid valves regurgitation. Additionally, pericardial effusion and endocavity thrombi may be found.

Nuclear imaging Radionuclide ventriculography may reveal biventricular global dysfunction and enlargement or regional hypokinesis. Myocardial imaging with technetium-99 pyrophosphate [50], gallium-67 [51], or indium-111-labeled leukocytes [52] may show uptake as evidence of diffuse or focal myocardial inflammation or necrosis. Antimyosin scintigraphy often reveals myocyte injury in patients with clinically suspected myocarditis [53]. Rubidium-FDG PET imaging is useful to diagnose cardiac sarcoidosis [54]. The use of nuclear imaging during pregnancy is limited due to potential teratogenic effects of its irradiation.

Cardiovascular magnetic resonance (CMR) imaging Cardiovascular magnetic resonance imaging provides noninvasive tissue characterization of the myocardium, mainly edema and/or late gadolinium enhancement (LGE) that can support the diagnosis of myocarditis. The diagnostic cardiac magnetic resonance criteria for myocarditis in the setting of clinically suspected myocarditis CMR findings (Lake Louise criteria) [55] are as follows: 1 Regional or global myocardial signal intensity increase in T2-weighted edema images. 2 Increased global myocardial early gadolinium enhancement ratio between myocardium and skeletal muscle in gadolinium-enhanced T1-weighted images. 3 There is at least one focal lesion with nonischemic regional distribution in inversion recovery-prepared gadoliniumenhanced T1-weighted images (LGE). A CMR study is consistent with myocardial inflammation, if at least two of the criteria are present and consistent with myocyte injury and/or scar caused by myocardial inflammation if criterion 3 is present [3,55]. Currently, the technology of native or contrast-enhanced T1 imaging promises to improve the diagnostic accuracy of CMR both in acute and chronic inflammatory phases of the disease [56,57]. It seems also to provide an important prognostic information [58]. CMR does not replace EMB in the diagnosis of myocarditis. It is unable to differentiate between infectious and immune-mediated forms and does not provide information on the type of inflammation including special types of myocarditis, which may require special therapies (such as

CHAPTER 8 Myocarditis and Pregnancy

giant cell, eosinophilic myocarditis, or sarcoidosis). In addition, it does not provide information on the type of virus and can be nondiagnostic in milder cases. CMR is a valuable tool to support the clinical suspicion of myocarditis and for noninvasive follow-up. This might be particularly important in patients with minor symptoms, e.g. young patients with unexplained arrhythmia, or troponin positive patients with normal coronary arteries [6,55,58–60].

Endomyocardial biopsy Since the mid-1980s, EMB has become the “gold standard” for the diagnosis of myocarditis. The Dallas criteria for the histologic diagnosis of myocarditis include findings of inflammatory infiltrates associated with adjacent myocyte necrosis or degeneration [31]. The efficacy of immunosuppressive therapy in giant cell myocarditis had confirmed its necessity [61]. EMB confirms the diagnosis of myocarditis and identifies the underlying etiology, especially specific type of inflammation (giant cell, eosinophilic myocarditis, sarcoidosis), which imply different treatments and prognosis [3]. However, the negative results of the multicenter Myocarditis Treatment Trial that used the Dallas criteria to recruit myocarditis patients to six months immunosuppression had a substantial negative effect in the next decade on the use of EMB to detect and treat myocarditis [62]. Alternative evolutions rely upon cell-specific immunohistological staining for surface antigens, such as anti-CD3 (T-cells), anti-CD4 (T-helper cells), anti-CD20 (B-cells), anti-CD68 (macrophages), and anti-human leukocyte antigen (HLA). This technique is associated with less sampling error, therefore is more sensitive than histopathology and has better prognostic value [27]. The diagnostic contribution of EMB is enhanced by molecular analysis with DNA–RNA extraction and RT–PCR amplification of viral genome. In order to exclude systemic infection, peripheral blood should be investigated in parallel with EMB. Quantification of virus load and determination of virus replication may add a diagnostic value [3,27]. Viral isolation from the culture of biopsy specimens are complementary to histopathology and are mandatory for the identification and characterization of the inflammatory infiltrate. The ability to perform EMB is somewhat limited during pregnancy because the use of fluoroscopy is undesirable. The procedure should, therefore, be performed under echocardiographic guidance, if possible [63]. Viral persistence in the myocardium has been associated with ventricular dysfunction, and viral genome clearance with improvement of ventricular function and a better 10year prognosis [64,65]. In contrast, immunohistological evidence of inflammation, but not the presence of viral genome alone, was an independent predictor of survival [27].

Treatment Acute myocarditis resolves within two to four weeks in 50% of cases, but about 25% will develop persistent cardiac dysfunction, and 12–25% may acutely deteriorate and either die or progress to end-stage DCM [45,48,64].

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The treatment of many milder forms of myocarditis is symptomatic, mainly optimal care of arrhythmia and of heart failure and, where supported by evidence, etiology-targeted therapy [3,66]. All pregnant women with suspected myocarditis should be hospitalized for clinical monitoring, until a definite diagnosis is established, since cardiopulmonary emergency, such as severe heart block or life-threatening arrhythmia, may occur even if systolic function is initially preserved [4,66]. Patients with hemodynamic instability, heart failure, significant pericardial effusion, at risk of tamponade, and serious arrhythmias should be adequately monitored in an intensive cardiac care unit. Exercise testing is contraindicated in the acute stage as it can precipitate arrhythmia [3]. Heart failure should be treated with diuretics and βblockers [3,4,6,66]. The use of angiotensin-converting enzyme inhibitors is contraindicated during pregnancy [67]. Similarly, the use of angiotensin receptor blockers, aldosterone antagonists, and Sacubitril/Valsartan (angiotensin receptor neprilysin inhibitor) during pregnancy is currently contraindicated, due to their teratogenicity and/or lack of evidence. Digoxin has been commonly used. However, digoxin increases proinflammatory cytokines and mortality in a murine model of viral myocarditis [53]. As therapeutic levels of digoxin may be associated with toxicity in myocarditis and serum digoxin levels cannot be accurately measured during pregnancy, it should be used with caution and only at low doses. In acute/fulminant cases with cardiogenic shock and severe ventricular dysfunction, besides intravenous inotropic agents and intraaortic counterpulsation, ventricular assist devices (VADs) or extracorporeal membrane oxygenation (ECMO) may be needed early (sometimes within 12–24 hours) to provide a bridge to cardiac transplantation or to recovery [68]. Important arrhythmias should be treated with β-blockers, lidocaine, quinidine, or procainamide, which are relatively safe in gestation, and if persistent, the implantation of a defibrillator should be considered. However, whenever clinically feasible, ICD implantation should be deferred until resolution of the acute episode [3]. Temporary pacing should be inserted for high degree AV block. As conduction disturbances are transient in the majority of patients with myocarditis, a permanent pacemaker is usually not indicated. Cardiac electronic implantable device either pacemaker or defibrillator (ICD/CRTD) can be implanted during pregnancy using echocardiography with relatively minimal X-ray irradiation. In the last years, there is an increased use of a wearable defibrillator (LifeVest) during pregnancy, awaiting cardiac recovery or internal ICD/CRTD implantation after delivery [69]. Nonsteroidal anti-inflammatory drugs, in particular acetylsalicylic acid, are a cornerstone of treatment for acute pericarditis but have been associated with increased mortality in experimental models of myocarditis [24]. Clinical data for their administration in myocarditis are inconclusive and controlled trials are needed.

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Anticoagulation may be added, especially if patients have severe left ventricular dysfunction, with or without evidence of a left ventricular thrombus, to reduce the risk of emboli. Anti-viral therapies – Interferon β-treatment can eliminate enteroviral and adenoviral genomes in patients with left ventricular dysfunction, is associated with improvement in NYHA functional class, and in enteroviral infection, it is associated with a better 10-year prognosis [65]. However, Interferon β was not effective against parvoviral B19 infection in the recently published BICC trial [70]. High dose intravenous immunoglobulin (IVIG) has been associated with improved left ventricular ejection fraction in chronic symptomatic heart failure of various causes [61]. However, IVIG was ineffective in the Intervention in Myocarditis and Acute Cardiomyopathy (IMAC) controlled trial of recentonset DCM [62]. As IVIG has no major side effects, it may be used in myocarditis refractory to conventional heart failure therapy, both viral and autoimmune forms, particularly if autoantibody-mediated [54]. Immunosuppression should be started only after ruling out active infection on EMB by PCR. Most data have been obtained using steroids alone, azathioprine and steroids, or cyclosporine A [3,27]. Current recommendation of immunosuppression is in proven autoimmune forms of myocarditis, with no contraindications to immunosuppression, including giant cell myocarditis, cardiac sarcoidosis, eosinophilic myocarditis, and myocarditis associated with known

extracardiac autoimmune disease [49,63]. Steroid therapy is indicated in cardiac sarcoidosis in the presence of ventricular dysfunction and/or arrhythmia, and in some forms of infection-negative eosinophilic or toxic myocarditis with heart failure and/or arrhythmia. Immunosuppression may be considered by a recent position statement [3] in infectionnegative lymphocytic myocarditis refractory to standard therapy in patients with no contraindications to immunosuppression. This approach is based on the positive results of the TIMIC randomized trial [71] and a recently published observational retrospective study [72]. These studies included patients with inflammatory cardiomyopathy of at least six months duration. The use of immunosuppression in infection negative acute myocarditis unresponsive to supportive treatment had been documented only in sporadic cases [73,74]. Strenuous activity may be deleterious and should be prohibited during the acute phase of myocarditis for at least six months both in athletes and nonathletes [3].

Comparison between myocarditis and PPCM/PAC The incidence of myocarditis during pregnancy is currently unknown, probably low. The incidence of PPCM/PAC in developed countries is estimated 1 : 3000. Frequently, the differential diagnosis is difficult, as some evidence of an

Table 8.2 Comparison of myocarditis during pregnancy to peripartum cardiomyopathy (PPCM)/pregnancy-associated cardiomyopathy (PAC) Myocarditis

PPCM/PAC

Age (yr)

All

All, more frequent >30

Number of pregnancies

Unknown

More frequent in multipara

Etiology

Mostly viral (see Table 8.1)

Unknown

Genetic background

Unknown

>16%

Twin pregnancy

Unknown

16%

Preeclampsia/HTN/tocolytic therapy

Unknown

Yes

Symptom onset

Entire pregnancy and postpartum Suspected when occur at first and second trimesters

Toward the end of pregnancy and several months afterward

Flu-like preceding symptoms

Frequently

Sometimes

Diagnosis

Delayed (usually within few days unless severe)

Delayed (on average 2 wk unless severe)

Fever

Very frequently

Sometimes

Pericardial pain

Quite frequently

Rarely

Inflammatory markers

Always

Sometimes

Endomyocardial biopsy

In clinical severe cases

Currently not recommended

Treatment HFrEF Guidelines recommended

Yes

Yes

Interferon β

When viral persistence (not effective in parvovirus [19])

No

Immunosuppression

Yes – mostly biopsy guided

No

Bromocriptine

No

Yes (still debatable)

Subsequent pregnancy

Recurrence rate not reported. Probably low. When full recovery it may be safe

20–40% recurrence

CHAPTER 8 Myocarditis and Pregnancy

inflammation has been detected in a significant percentage of endomyocardial biopsies taken from PPCM patients. In addition, viral etiology may sometimes occur in clinically diagnosed PPCM/PAC patients. Table 8.2 compares several clinical parameters that may help to distinguish between the two diagnoses. Myocarditis is clinically suspected when it occurs at first or second gestational trimesters, and when it presents with preceding symptoms of flu-like symptoms, fever, typical pleurapericardial pain, and high-inflammation markers such as CRP. Although there are similarities in treatment, such as using guidelines recommended therapies for HFrEF, there are some important differences. Currently, the modern treatment of myocarditis, especially in severe cases, is EMB guided, including antiviral therapies when viral persistence is detected, and immunosuppression and sometimes immunoglobulins when viral persistence is excluded, and inflammation is diagnosed. On the other hand, there is a rare usage of EMB in PPCM/PAC. In addition, the role of immunosuppression and immunoglobulins has not been confirmed in PPCM, while bromocriptine, although still debatable, is frequently used.

4

5

6

7 8

9

10 11

12

13

Summary Myocarditis during pregnancy is rare. Its clinical presentation varies from asymptomatic, mild nonspecific symptoms to cardiogenic shock and/or life-threatening arrhythmias. Its diagnosis is based on combination of clinical features, electrocardiographic, laboratory, echocardiographic, and CMR findings. EMB confirms the diagnosis of myocarditis, identifies the underlying etiology, and may reveal particular types of inflammation. (e.g. giant cell, eosinophilic myocarditis, and sarcoidosis), which require specific immunosuppressive treatment. In addition, a panel of experts of the ESC recommended to consider the use of immunosuppressive therapy in selected patients unresponsive to standard therapy, in whom inflammation was demonstrated, and viral persistence was excluded by EMB [27]. Myocarditis resolves within few weeks. However, patients may develop persistent cardiac dysfunction, and 12–25% of them may deteriorate to end-stage cardiomyopathy and even death.

14

15

16

17

18 19

20 21

References 1 Richardson, P., McKenna, W., Bristow, M. et al. (1996). Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation 93: 841–842. 2 Elliott, P., Andersson, B., Arbustini, E. et al. (2008). Classification of the cardiomyopathies: a position statement from the European Society of Cardiology working group on myocardial and pericardial diseases. Eur Heart J 29: 270–276. 3 Caforio, A.L., Pankuweit, S., Arbustini, E. et al., and European Society of Cardiology Working Group on Myocardial and Pericardial Diseases (2013). Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society

22 23

24 25

26

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27 Kindermann, I., Kindermann, M., Kandolf, R. et al. (2008). Predictors of outcome in patients with suspected myocarditis. Circulation 118: 639– 648. 28 Maisch, B., Ristic, A.D., Hufnagel, G., and Pankuweit, S. (2002). Pathophysiology of viral myocarditis: the role of humoral immune response. Cardiovasc Pathol 11: 112–122. 29 Warraich, R.S., Noutsias, M., Kazak, I. et al. (2002). Immunoglobulin G3 cardiac myosin autoantibodies correlate with left ventricular dysfunction in patients with dilated cardiomyopathy: immunoglobulin G3 and clinical correlates. Am Heart J 143: 1076–1084. 30 Furukawa, Y., Kobuke, K., and Matsumori, A. (2001). Role of cytokines in autoimmune myocarditis and cardiomyopathy. Autoimmunity 34: 165– 168. 31 Aretz, H.T., Billingham, M.E., Edwards, W.D. et al. (1985). Myocarditis: a histopathologic definition and classification. Am J Cardiol Pathol 1: 1– 10. 32 Ergaz, Z. and Ornoy, A. (2006). Review: parvovirus B19 in pregnancy. Reprod Toxicol 21: 421–435. 33 Sainani, G., Krompotic, E., and Slodki, S. (1968). Adult heart disease due to coxsackie virus B infection. Medicine (Baltimore) 47: 133–147. 34 Grimes, D.A. and Cates, W. Jr. (1980). Fatal myocarditis associated with abortion in early pregnancy. South Med J 73: 236–238. 35 Gehrke, D., Herzum, M., Sch¨onian, U. et al. (1994). Eosinophilic endomyocarditis postpartum or pregnancy related cardiornyopathy. Herz 19: 176–181. 36 Chen, H.F., Lee, C.N., Huang, G.D. et al. (1994). Delayed maternal death after perimortem cesarean section. Acta Obstet Gynecol Scand 73: 839– 841. 37 Ciccone, M.M., Dentamaro, I., Carbonara, S. et al. (2016). Fulminant peripartum myocarditis associated with sudden cardiac death: a case report. Cardiovasc Pathol 25: 87–89. 38 Massengill, A., Rodriguez, J., Cotter, T., and Cotter, J.G. (2016). Infectious myocarditis in pregnancy: an unlikely cause of respiratory distress. Am J Obstet Gynecol 215: S846. 39 Malhotra, G., Chua, S., Kodumuri, V. et al. (2016). Rare presentation of lupus myocarditis with acute heart failure-a case report. Am J Ther 6: e1952–e1955. 40 Melvin, K.R., Richardson, P.J., Olsen, E.G. et al. (1982). Peripartum cardiomyopathy due to myocarditis. N Engl J Med 307: 731. 41 O’Connell, J.B., Constanzo-Nordin, M.R., Subramanian, R. et al. (1986). Peripartum cardiomyopathy: clinical, hemodynamic, histologic and prognostic characteristics. J Am Coll Cardiol 8: 52–56. 42 Rizeq, M.N., Rickenbacher, P.R., Fowler, M.B., and Billingham, M.E. (1994). Incidence of myocarditis in peripartum cardiomyopathy. Am J Cardiol 74: 474–474. 43 B¨ultmann, B.D., Klingel, K., N¨abauer, M. et al. (2005). High prevalence of viral genomes and inflammation in peripartum cardiomyopathy. Am J Obstet Gynecol 193: 363–365. 44 Dec, G.W. Jr., Waldman, H., Southern, J. et al. (1992). Viral myocarditis mimicking acute myocardial infarction. J Am Coll Cardiol 20: 85–89. 45 McCarthy, R.E. III, Boehmer, J.P., Hruban, R.H. et al. (2000). Long-term outcome of fulminant myocarditis as compared with acute (nonfulminant) myocarditis. N Engl J Med 342: 690. 46 Meisel, S.R., Kleiner-Shochat, M., Abu Fanne, R. et al. (2019). The diagnostic value of C-reactive protein to troponin ratio for differentiation of perimyocarditis from acute myocardial infarction. J Am Coll Cardiology 73 (1 Suppl.): 263. 47 Emdin, M., Vittorini, S., Passino, C., and Clerico, A. (2009). Old and new biomarkers of heart failure. Eur J Heart Fail 11: 331–335. 48 Dennert, R., Crijns, H.J., and Heymans, S. (2008). Acute viral myocarditis. Eur Heart J 29: 2073–2082. 49 Mahfoud, F., G¨artner, B., Kindermann, M. et al. (2011). Virus serology in patients with suspected myocarditis: utility or futility? Eur Heart J 32: 897–903. 50 Mitsutake, A., Nakamura, M., Inou, T. et al. (1981). Intense persistent myocardial avid technetium 99M pyrophosphate scintigraphy in acute myocarditis. Am Heart J 101: 683–684.

51 O’Connell, J.B., Henkin, R.E., Robinson, J.A. et al. (1984). Gallium-67 imaging in patients with dilated cardiomyopathy and biopsy-proven myocarditis. Circulation 70: 58–62. 52 Yasuda, T., Palacios, I.F., Dec, G.W. et al. (1987). Indium Ill-monoclonal antimyosin antibody imaging in the diagnosis of acute myocarditis. Circulation 76: 306–311. 53 K¨uhl, U., Lauer, B., Souvatzoglu, M. et al. (1998). Antimyosin scintigraphy and immunohistologic analysis of endomyocardial biopsy in patients with clinically suspected myocarditis – evidence of myocardial cell damage and inflammation in the absence of histologic signs of myocarditis. J Am Coll Cardiol 32: 1371–1376. 54 Kim, J.S., Judson, M.A., Donnino, R. et al. (2009). Cardiac sarcoidosis. Am Heart J 157: 9–21. 55 Friedrich, M.G., Sechtem, U., Schulz-Menger, J. et al., and International Consensus Group on Cardiovascular Magnetic Resonance in Myocarditis (2009). Cardiovascular magnetic resonance in myocarditis: a JACC White Paper. J Am Coll Cardiol 53: 1475–1487. 56 Bohnen, S., Radunski, U.K., Lund, G.K. et al. (2015). Performance of T1 and T2 mapping cardiovascular magnetic resonance to detect active myocarditis in patients with recent-onset heart failure. Circ Cardiovasc Imaging 8: 1–7. 57 Hinojar, R., Foote, L., Arroyo Ucar, E. et al. (2015). Native T1 in discrimination of acute and convalescent stages in patients with clinical diagnosis of myocarditis: a proposed diagnostic algorithm using CMR. JACC Cardiovasc Imaging 8: 37–46. 58 Gr¨un, S., Schumm, J., Greulich, S. et al. (2012). Long-term follow-up of biopsy-proven viral myocarditis: predictors of mortality and incomplete recovery. J Am Coll Cardiol 59: 1604–1615. 59 Thavendiranathan, P., Walls, M., Giri, S. et al. (2012). Improved detection of myocardial involvement in acute inflammatory cardiomyopathies using T2 mapping. Circ Cardiovasc Imaging 5: 102–110. 60 van Heeswijk, R.B., De Blois, J., Kania, G. et al. (2013). Selective in vivo visualization of immune-cell infiltration in a mouse model of autoimmune myocarditis by fluorine-19 cardiac magnetic resonance. Circ Cardiovasc Imaging 6: 277–284. 61 Cooper, L.T., Berry, G.J., and Shabetai, R. (1997). Idiopathic giantcell myocarditis-natural history and treatment. Multicenter giant cell myocarditis study group investigators. N Engl J Med 336: 1860–1866. 62 Mason, J.W., O’Connell, J.B., Herskowitz, A. et al. (1995). The myocarditis treatment trial investigators: a clinical trial of immunosuppressive therapy for myocarditis. N Engl J Med 333: 269–275. 63 Caforio, A.L.P. (2013). Foreword to special issue on “Myocarditis”. Heart Fail Rev 18: 669–671. 64 Miller, L.W., Labovitz, A.J., McBride, L.A. et al. (1988). Echocardiographic-guided endomyocardial biopsy: a 5-year experience. Circulation 78 (Suppl.): III99–III102. 65 K¨uhl, U., Pauschinger, M., Seeberg, B. et al. (2005). Viral persistence in the myocardium is associated with progressive cardiac dysfunction. Circulation 112: 1965–1970. 66 K¨uhl, U., Lassner, D., von Schlippenbach, J. et al. (2012). Interferon-beta improves survival in Enterovirus-associated cardiomyopathy. J Am Coll Cardiol 60: 1295–1296. 67 Japanese Circulation Society (JCS) Joint Working Group (2011). Guidelines for diagnosis and treatment of myocarditis (JCS 2009). Circ J 75: 734–743. 68 Shotan, A., Widerhorn, J., Hurst, A., and Elkayam, U. (1994). Risks of converting enzyme inhibition during pregnancy: experimental and clinical evidence, potential mechanisms, and recommendations for use. Am J Med 96: 451–456. 69 Montero, S., Aissaoui, N., Tadi´e, J.M. et al. (2018). Fulminant giantcell myocarditis on mechanical circulatory support: management and outcomes of a French multicentre cohort. Int J Cardiol 253: 105– 112. 70 Duncker, D., Haghikia, A., K¨onig, T. et al. (2014). Risk for ventricular fibrillation in peripartum cardiomyopathy with severely reduced left ventricular function-value of the wearable cardioverter/defibrillator. Eur J Heart Fail 16 (12): 1331–1336.

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71 Schultheiss, H.P., Piper, C., Sowade, O. et al. (2016). Betaferon in chronic viral cardiomyopathy (BICC) trial: effects of interferon-β treatment in patients with chronic viral cardiomyopathy. Clin Res Cardiol 105: 763– 773. 72 Frustaci, A., Russo, M.A., and Chimenti, C. (2009). Randomized study on the efficacy of immunosuppressive therapy in patients with virusnegative inflammatory cardiomyopathy: the TIMIC study. Eur Heart J 30: 1995–2002.

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CHAPTE R 9

Pericardial Disorders and Pregnancy Marla A. Mendelson Department of Medicine, Division of Cardiology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA

Introduction The pericardium, comprised of a serous visceral or epicardial layer and a fibrous, parietal layer, encases and protects the heart and the origin of the great vessels. It serves to stabilize the heart and reduce friction with movement. It may also serve as a barrier to infection. Pericardial fluid within this sac is an ultrafiltrate of plasma, and normally, there may be 15–50 ml in the pericardial space [1,2]. The pericardium may become involved in numerous primary and secondary disease processes: the inflammatory response of infectious or idiopathic pericarditis, systemic infection, neoplasia, autoimmune diseases, connective tissue disease, renal failure, prior cardiac or thoracic surgery, myocardial infarction, trauma, aortic dissection, therapeutic radiation, or affected by drug therapy [1]. Pericardial effusion may result in subsequent development tamponade, long-term fibrosis or pericardial constriction. Pericardial inflammation has been found in 2–6% of autopsy studies (but is clinically recognized only in 0.1% of hospital admissions) [3–5]. A woman may be as susceptible to pericardial disease during pregnancy. As the pericardium may exert a restraining effect on cardiac dilatation, the woman with subclinical pericardial disease may first become symptomatic during pregnancy as the heart dilates to accommodate the expected and progressive increase in cardiac output. An altered immune response during pregnancy may make a woman of childbearing age more susceptible to pericarditis due to infection or inflammation, which is the most common form of pericardial disease in the woman of childbearing age. She may also have systemic illness or a medical/surgical history that predisposes her to pericardial disease. It is important to consider these historical factors, as the diagnosis of pericardial disease during pregnancy may be difficult and requires a higher index of suspicion if a “risk factor” is present.

Acute pericarditis As stated by Osler in 1912 [6] “Probably, no serious disease is so frequently overlooked by the practitioner”. Cardiac Problems in Pregnancy, Fourth Edition. Edited by Uri Elkayam. © 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.

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Pericarditis is most often a self-limited, mild condition that is idiopathic in origin. The severity of disease and hemodynamic consequences vary with the etiology, which may be due to a viral or bacterial infection or generalized inflammatory process. Pericarditis may occur with myocarditis affecting cardiac function [2,7]. In conjunction with the already increased blood volume of pregnancy, heart failure may develop. Pericarditis can be detected during pregnancy by the usual diagnostic modalities. Depending on the severity of the presentation, hemodynamic assessment and intervention may be required during pregnancy, but even the most complicated case may be brought safely to term [8–11]. The incidence is probably similar to the nonpregnant state, and the condition can be treated similarly though there are rare reported cases. The woman with a history of pericarditis may experience a recurrence during pregnancy.

Etiology The potential etiologies of acute pericarditis in a woman of childbearing age are summarized in Table 9.1 [1,12–15]. The pericardium may be involved as a primary process or secondary to another medical illness. Idiopathic pericarditis is probably the most common form of acute pericarditis. The second important category to be considered is trauma, accidental or surgical. Prior chest trauma could include hemopericardium following thoracic surgery, pacemaker insertion, valve replacement, or coronary artery bypass grafting. Infectious pericarditis may be caused by a variety of viral or bacterial agents. The reported incidence of infectious pericarditis during pregnancy is low. The causative agents discussed would be those most likely to affect a specific population. Viral pericarditis is the most common and may be due to Coxsackie A or B viruses, echovirus, endovirus, herpesviruses (Epstein–Barr), adenoviruses, mumps, infectious mononucleosis, varicella, hepatitis B, and human immunovirus-1 [2,16,17]. A case of rubella

CHAPTER 9 Pericardial Disorders and Pregnancy

Table 9.1 The etiology of acute pericarditis Etiology

Estimated incidence in literaturea

Idiopathic

85–90%

Infectious Viral

1–2%

Bacterial

1–2%

Tuberculosis

4%

Fungal

Rare

Parasitic

Rare

Neoplasm

7%

Systemic autoimmune disease

3–5%

After cardiothoracic surgery

Rare

Aortic dissection

Rare

Chest wall trauma

Rare

Adverse drug reaction

Rare

Chest wall irradiation

Rare

Acute myocardial infarction

—

Myocarditis

—

Uremia – before dialysis

5%

After dialysis started

13%

a Adapted

from Refs. [12–15].

Source: Adapted from Khandaker et al. 2010 [1].

myopericarditis has been documented during pregnancy [18]. Often, there is a nonspecific viral prodrome with chest pain, lymphadenopathy, or myocarditis. Viral syndromes usually result in fatigue and malaise that may persist for weeks after the chest pain, and acute symptoms have abated. Bacterial pericarditis is often a complication of a systemic bacterial infection. The bacterial agents classically involved include pneumococci, staphylococci, streptococci, Gram-negative septicemia, Neisseria, Listeria, and Legionella [1,2,19–21]. Often, there is a concomitant pneumonia or empyema. The immune-compromised host is susceptible to Gram-negative organisms and fungal infections such as histoplasmosis, coccidioidomycosis, Candida, and blastomycosis [2]. Other causes of infection are toxoplasmosis or amebiasis [16]. Tuberculosis should be considered when the patient who has a positive skin test or quantiFERON-TB assay presents with classic signs of weight loss, night sweats, anorexia, arthralgias, and fever. There often are associated large, sanguineous effusions [16,22]. Women of childbearing age who have survived childhood malignancy such as lymphoma or Hodgkin’s disease may have undergone prior chest or mediastinal irradiation that could result in the late development of pericarditis, pericardial effusion, and even constrictive pericarditis exacerbated by the expected hemodynamic changes of pregnancy.

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Neoplastic disease in the adult patient also may secondarily involve the pericardium, as seen in lung pathologies including lung cancer, as well as breast cancer, leukemia, Hodgkin’s disease, and lymphoma [1,23]. Acute pericarditis may be secondary to another medical illness such as amyloidosis or sarcoidosis [1]. It can be seen in metabolic diseases such as uremia or myxedema [24]. Autoimmune disease often involves the pericardium, specifically in systemic lupus erythematosus, rheumatoid arthritis, and scleroderma [10,25,26]. Systemic lupus erythematosus may involve the pericardium in 17–50% of patients, although clinical evidence may only occur in 5% (Table 9.1) [1,10,27,28]. There may be exacerbation of lupus during the last trimester of pregnancy and several months postpartum. Treatment with steroids may prevent constriction and tamponade. Pericardial effusion is more common than pericarditis in rheumatoid arthritis, and steroid therapy may not be as effective [25]. Other collagen vascular diseases to consider include acute rheumatic fever, scleroderma, Wegener’s granulomatosis, Sjogren’s, and dermatomyositis [1,10,29]. Anticoagulation resulting in hemopericardium is a rare cause of pericarditis. The woman of childbearing age at risk would be chronically anticoagulated for atrial fibrillation, pulmonary embolus, or a mechanical prosthetic valve. Either anticoagulation in the setting of subclinical pericarditis or superimposed trauma with therapeutic anticoagulation could result in a hemopericardium. This patient would have had thoracic surgery or some other disease process present [1,12,13]. As the population of women of childbearing age becomes older, obstetrical patients with a history of coronary artery disease or myocardial infarction may be encountered [1,2,12, 13]. Pericarditis has been described after myocardial infarction and as a result of a pericardiotomy and may be the cause, though this is less likely in the woman of childbearing age. Pericardial inflammation may occur after cardiac surgery. As women with medical illnesses become pregnant, they may be taking medications known to cause pericardial inflammation (e.g. hydralazine, procainamide, diphenylhydantoin, isoniazid, penicillin, minoxidil, bromocriptine, antitumor necrosis factor agents, antineoplastic drugs, and methotrexate) [1,2,12,30]. Though dissecting aneurysm, vascular rupture, a chylopericardium [31], endocarditis, and thymic cyst are rare clinical events, these conditions have the potential to cause pericardial inflammation and/or effusion [1,2,12].

Clinical presentation Symptoms Chest pain is the most common complaint in the patient with pericarditis. It is usually sudden, sharp, and stabbing and may radiate to the back, neck, left shoulder, or upper arm. It may vary in quality and location. Classically, the pain is relieved by leaning forward and is exacerbated by lying supine, swallowing, breathing deeply, or coughing [1].

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The differential diagnosis may include an acute abdominal process, myocardial infarction, esophageal spasm, or pulmonary embolus. Dyspnea is also a common presentation, especially when a moderately large pericardial effusion is present. This occurs with impaired filling of the ventricle due to an effusion and/or mechanical compression of the lung parenchyma (Ewart’s sign) and bronchi [1,2]. Mechanical compression may also cause hoarseness, coughing, and dysphasia. Dyspnea during the latter half of pregnancy may be misconstrued as hyperventilation of pregnancy. Generalized symptoms, especially in viral pericarditis, may include upper respiratory symptoms preceding the onset of chest pain, a low-grade fever, lymphadenopathy, myalgias, or a rash. In a viral illness, symptoms of fatigue and malaise may persist for weeks after the chest pain has subsided. Pericarditis secondary to systemic illnesses may have clinical features to suggest the underlying etiology such as fever, cough, cachexia, edema, arthralgias, myalgias, or ascites.

Signs A pericardial friction rub is a pathognomonic finding in pericarditis described as a “leathery,” squeaky or grating sound best heard over the second and fourth left intercostal space in the midclavicular line or at the left sternal border [1]. It is present in approximately 85% of cases [13]. It is best heard with diaphragm on the stethoscope while the patient is leaning forward and deeply inspiring. The rub may be evanescent. It is often of three components corresponding to atrial systole, ventricular systole, and rapid early diastolic filling. It may have only one or two components [1]. A third heart sound may also be present. The pericardial friction rub remains constant throughout the respiratory cycle, does not radiate as would a heart murmur, often is loudest in the left sternal border rather than in a specific valve area, and may change in quality at different times of examination and clinical course. Tachycardia has been noted frequently. On examination of the chest, lungs are often clear to auscultation. Ewart’s sign is dullness below the left scapula if there is lung compression caused by a large pericardial effusion. Neck veins are distended in the presence of large effusion or pericardial constriction due to elevated right ventricular diastolic pressure, causing an elevation in right atrial pressure. Although usually idiopathic or viral, pericarditis runs a limited course and responds to therapy. There are risk factors, however, which portend poor prognosis [1,32]. This would include younger age, arrhythmias, fever greater than 38 °C; subacute onset; large pericardial effusion; cardiac tamponade: fever with gastrointestinal symptoms: myalgias; elevated cardiac enzymes; and myocardial dysfunction imaging or lack for response to one week of standard therapy. Other risk factors could include myopericarditis, chronic immunosuppression, trauma, or concomitant oral anticoagulation. Hospitalization should be considered for these high-risk patients [1,2].

Diagnostic evaluation Laboratory blood tests may suggest the underlying cause of pericarditis: for example, leukocytosis, lymphocytosis, elevated C-reactive protein (CRP), elevated erythrocyte sedimentation rate (ESR), an elevated level of antinuclear antibodies and/or rheumatoid factor, a positive tuberculin test, positive blood cultures, elevated cardiac enzymes or infections, or specific antibody titers [1,2]. Diagnostic testing serology may be nonspecific but aid in assessing the severity, etiology, and potential sequelae of pericarditis. Electrocardiogram: Electrocardiographic changes have been reported in up to 80% of patients with acute pericarditis [1,2,33]. Initially, there is ST-segment elevation in multiple leads and/or PR segment depression. The ST segment elevation often has a characteristic upward concavity with upright T waves. These changes may occur within the first hour after chest pain or fever. Most commonly, the elevations are seen in leads I, II, V5 , and V6 and persist for hours to days. The second phase consists of a return of the ST segment to the isoelectric baseline. The T waves remain upright, and the PR segment may be isoelectric or depressed. Late in this phase, T waves begin to flatten and invert. Phase III is characterized by isoelectric ST segments with diffuse T-wave inversion. The PR segment is isoelectric at this time [1]. The fourth phase is characterized by isoelectric ST segments and the return of upright T waves within weeks to months. Sinus tachycardia is probably the most common cardiac rhythm, though there may be transient atrial fibrillation or atrial flutter. Rarely, sinus bradycardia is seen [1,2]. Chest radiography: In the pregnant woman, a chest X-ray is indicated only when pneumonia is suspected. If a chest X-ray is obtained for another reason, pericarditis or pericardial effusion may be the explanation for an enlarged cardiac silhouette. A chest X-ray may be helpful for any underlying lung process, such as neoplasm or tuberculosis. In idiopathic pericarditis, pulmonary infiltrates and pleural effusion are not uncommon. The cardiac shadow will not be enlarged until 250–300 ml of pericardial fluid has accumulated [1,2]. Cardiac imaging: echocardiography is recommended for the diagnosis of pericarditis [1,2,34]. It may reveal thickening of the pericardium, a pericardial effusion, and most importantly, evidence of cardiac tamponade. Echocardiography also provides information about the valvular and myocardial function, which may help to determine the etiology of the pericardial process. In patients with concomitant myocarditis, there may be left ventricular systolic dysfunction. If an effusion has impaired diastolic filling, the diastolic dimension of the left ventricle will be normal or small, with good systolic contraction of left ventricle. Echocardiography assessment during the course of pericarditis can determine whether a pericardial effusion is increasing and if there is impending cardiac tamponade. Ultrafast computed tomography can best assess the thickness of the pericardium as well as the location and size of the effusion, but of course carries the risk of radiation during pregnancy. This technique may establish the diagnosis

CHAPTER 9 Pericardial Disorders and Pregnancy

of constriction. Magnetic resonance imaging has also been used in pregnancy and may aid in determining the etiology and extent of the pericardial effusion and the thickness of the pericardium [1,2]. Therefore, the clinical diagnosis of pericarditis is established when at least two of the following four criteria are present: pericardial chest pain, pericardial friction rub, characteristic electrocardiographic changes, or pericardial effusion. Additional diagnostic testing may aid in determining the etiology of the pericarditis.

Management Initially, bed rest and hospitalization for observation may be indicated in the pregnant patent with acute pericarditis, while evaluation ensues to rule out any of the other causes of pericarditis that may be present. In the nonpregnant state, pericarditis is usually self-limited, with the inflammation lasting two to six weeks [1,2,10]. It is not uncommon for pericarditis to recur in 20–28% of patients [35,36]. In idiopathic pericarditis associated with a pericardial effusion, 9% may develop mild pericardial constriction [1,2,37]. Tamponade has been reported in up to 15% of patients with pericarditis [14]. Complications of pericarditis may include arrhythmias, which are usually treated as in the nonpregnant state. Sinus tachycardia does not need to be treated but may be an indication of progression to tamponade or constriction. Atrial fibrillation may occur, possibly resulting in heart failure especially in the pregnant woman who has significantly increased blood volume. With hemodynamic compromise and the loss of an atrial “kick,” congestive heart failure may ensue. In

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the setting of atrial fibrillation, the rate can be slowed by a variety of agents, including digoxin and cardioselective βadrenergic blocking agents. Diltiazem can be used for rate control although this is rarely necessary because the arrhythmias are transient. Direct current cardioversion should be reserved for situations of hemodynamic compromise [38]. Safety of medications during pregnancy should be considered. Treating the chest pain of pericarditis often responds to nonsteroidal anti-inflammatory agents such as high-dose aspirin (2015 ESC guidelines recommend 500–1000 mg q 6– 8 h) [1,2,9,11]. Although low dose aspirin is commonly used for the prevention of preeclampsia and seems to be safe, highdose aspirin (Category C) may be associated with risk of hemorrhage, IUGR, teratogenic effects, and perinatal mortality [39]. Most nonsteroidal anti-inflammatory agents, including ibuprofen 600 mg q 8 h (Category B) and indomethacin 25–50 mg q 8 h (Category B), also can be effective. After gestational week 20, all nonsteroidal anti-inflammatory drugs (NSAIDs; except aspirin ≤100 mg/d) can cause constriction of the ductus arteriosus and impair fetal renal function, and they should be withdrawn in any case at gestational week 32 [2,9,11,39]. For severe persistent pain, over 48 hours, corticosteroids could be used. Prednisone may be given at the lowest effective dose [2,9,11] in amounts of 60–80 mg/d in divided doses. When the patient is asymptomatic, the steroids may be tapered. Steroids should not be used if tuberculosis is suspected. Exacerbation of symptoms may occur once steroids have been withdrawn. Antibiotics should be used only in cases of documented bacterial or tuberculous pericarditis. The agents and doses used are as in the nonpregnant state with caveats as noted in Table 9.2 [10,11]. Long-term effects

Table 9.2 Treatment of pericarditis during pregnancy Drug (FDA class)

Crosses placenta

Aspirin (C/D) NSAIDs

Breastfeeding

Adverse effects

Dose

Yes

Premature ductal closure Reduced renal blood flow

500–1000 mg every 8 h before 20 wk

With caution

Yes

Premature ductal closure

Before 30 wk

Yes

Ibuprofen

600 mg every 8 h

Yes

Indomethacin (C)

25–50 mg every 8 h

Yes

500–1000 mg every 12 h

Yes

10–25 mg daily

Yes

Naproxen Prednisone (B)

Limited

Cleft palate, still birth, adrenal insufficiency

Azathioprine (D)

Yes

Congenital abnormalities

No

Intravenous immunoglobulin (C)

Yes

None known

Unknown

Cyclosporine (C)

No

Methotrexate (X)

Yes

Fetal death or congenital anomalies

Colchicine (C)

Yes

Fetal: None reported Maternal: gastrointestinal symptoms

Immunosuppressive agents

Source: Adapted from Refs. [1,2,9,11].

No No 0.5–0.6 mg twice daily

With caution

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PART III Cardiac Disorders and Pregnancy

on the offspring from medical treatment are either not studied or there are limited reports [9–11]. Colchicine is not advised to be used during pregnancy due to possible teratogenic effect in animals (Category D), there is rare data reported. CRP levels and ESR may be useful to help follow the patient’s clinical response to therapy [10,11]. The American Academy of Pediatrics classified ibuprofen, indomethacin, colchicines, and prednisone as compatible with breastfeeding and recommended that aspirin will be used cautiously because of potential effects on the neonate [39]. Myopericarditis may occur as a result of a viral or bacterial infection [7,40]. The presenting symptom is often chest pain and dyspnea with signs of left ventricular failure. In laboratory testing, ESR, CRP, and troponin may be elevated. Cardiac imaging may detect left ventricular dysfunction. These patients should be hospitalized to initiate treatment for pericarditis and congestive heart failure. Recurrent pericarditis is defined as recurrent clinical evidence of pericarditis at least four to six weeks after treatment and symptom resolution after the initial acute event [35,36]. This may occur in 20–50% of patients (Imazio, Lazaros). Etiology is most commonly idiopathic and viral infection. Systemic inflammatory disease, autoimmune disease, neoplasm, or insufficient initial treatment may also cause recurrence. In the woman with a prior history of pericarditis, pregnancy should be planned during remission if possible [9,11]. Chronic pericarditis is defined as lasting for more than three months [35]. In the event of cardiac tamponade, pericardiocentesis with possible biopsy may be performed in the pregnant person by the subxiphoid approach. This also may be required for purposes of diagnosis, especially in the case of bacterial pericarditis. Pericardiectomy may be indicated for relapsing pericarditis that is refractory to medical management and can increase the yield of diagnosing tuberculosis during pregnancy [41]. Specific diagnosis of inflammatory or neoplastic pericardial disease can be made by epicardial and pericardial biopsy and by cytologic analysis of the pericardial fluid [42].

Acute pericarditis during pregnancy Few cases of acute, idiopathic pericarditis during pregnancy responding to conventional therapy and associated with uncomplicated term delivery have been reported [9,11,39, 43–46]. The incidence may be the same as in the general population, given the rarity of reports in the literature. Chest pain was the most common initial presentation [8,39,43]. Hagley, Simpson, et al. described a case of acute idiopathic pericarditis resulting in pulmonary edema complicated by cardiac tamponade [44,45]. Pajuelo-Gallego et al. described a case of pericarditis with involvement of the myocardium (myopericarditis) in the third trimester of an uncomplicated pregnancy [46]. Treatment was most often aspirin and/or steroids [8,9].

There have been reports of infectious pericarditis during pregnancy caused by staphylococci [20], meningococci [21], Haemophilus influenzae [17], rubella [18], Listeria [19], mycobacterium tuberculosis [22], and secondary to a pleural empyema [47]. The course of pregnancy in these women was complicated by fetal death [18,21], maternal heart failure [18], and pericardiectomy [17,20]. Pericarditis associated with systemic lupus erythematosus has also been reported occurring during pregnancy [28,48]. Both patients developed cardiac tamponade in the postpartum period. It has been suggested that exacerbation of systemic lupus erythematosus may occur during pregnancy [49,50]. Pericarditis responding to standard therapy has been reported in a woman with scleroderma and primary Sjogren’s during pregnancy [26,29]. Duclos et al. reported on a woman with Takayasu’s disease who initially presented with acute pericarditis and tamponade in the fifth month of pregnancy [51]. In addition, there is one reported case of chylopericardium, a rare disorder associated with mechanical obstruction of the thoracic duct or impedance of drainage occurring as a postoperative or posttraumatic complication or due to neoplasm or tuberculosis [31]. The patient had an uneventful delivery but required pericardiocentesis during the postpartum period. Viral or idiopathic pericarditis usually has a benign course during pregnancy and should not alter the course of the pregnancy [8]. The incidence in pregnancy is most likely similar to the nonpregnant patient. Purulent pericarditis is rare and often related to pneumonia or empyema. Urgent pericardiocentesis is recommended for both diagnosis of bacterial agent and treatment. Purulent pericarditis with tamponade in a hemodialysis patient secondary to Staphylococcus aureus was treated at 27-week gestation resulting in premature delivery [24]. Exudative pericarditis was reported as a presentation of cardiac lymphoma [23]. Myopericarditis has been reported in a patient with lupus presenting with hypertensive urgency and pulmonary edema. She had a marked decrease in ejection fraction and a pericardial effusion [50]. Severe sepsis due to group A streptococcal toxic shock syndrome may result in myopericarditis and cause fetal distress [7]. Pericarditis of neoplastic origin is rare, but in this population, it is most often due to breast cancer. The clinical findings of pericarditis should be evident during pregnancy as in the nonpregnant patient with at least two of the four criteria mentioned previously. These criteria include characteristic chest pain, a pericardial friction rub, electrocardiographic changes, or a new or expanding pericardial effusion [1,9,11]. Women present with pleuritic chest pain that is exacerbated in the supine position. Dyspnea may also be reported. The pathognomonic sign of acute pericarditis is the pericardial friction rub. This may be diminished if there is a significant pericardial effusion.

CHAPTER 9 Pericardial Disorders and Pregnancy

Diagnostic evaluation during pregnancy Laboratory investigation should look for markers of inflammation as well as help determine etiology, such as collagen vascular disease, infection, autoimmune disease or neoplasm. The electrocardiographic and echocardiographic diagnostic criteria should be present as in the nonpregnant state. The differential diagnosis in the pregnant woman presenting with chest pain would include pulmonary embolism, myocardial infarction, or aortic dissection. Pulmonary embolism may manifest as pleuritic chest pain and be associated with dyspnea, tachycardia, and hemoptysis. Myocardial infarction is less likely, and the pain is rarely pleuritic or positional in nature. The quality of pain is different and is often described as a constant, retrosternal chest pressure. It may also have an exertional component, is usually relieved by nitroglycerin, and does not change with position. Even during pregnancy, angina in the nondiabetic female should be readily identifiable. Pericarditis may develop 24–72 hours after the onset of pain. Aortic dissection is described as a sharp, tearing pain, radiating to the back. It is often associated with decreasing loss of distal pulses, aortic insufficiency, hypotension, and possibly hemodynamic compromise.

Management The chest pain of pericarditis usually responds to aspirin therapy, but steroids may be required. Treatment regimens during pregnancy are illustrated in Table 9.2 [1,2,9,11]. High-dose aspirin use and NSAIDs are not recommended in the third trimester as they may cause premature closure of the ductus arteriosus in the fetus. It is recommended that aspirin and NSAIDs be stopped after 20-week gestation [10,11]. Prednisone is often effective at low or medium doses [9,11]. It has low placental transference but may cause maternal fluid retention and vertebral fractures from osteoporosis. Calcium and vitamin D supplementation should be considered [9,11]. Colchicine, often used for treatment of acute or recurrent pericarditis in the nonpregnant patient, is contraindicated during pregnancy and lactation because it interferes with microtubular function and mitosis, which may impact fertility, pregnancy, and fetal teratogenicity. Complications have been reported in women on long-term use for familial Mediterranean fever. In women with chronic pericarditis, colchicine should be withdrawn prior to conception. However, limited reports are available regarding maternal and fetal effects [2,9,11]. Physical activity should be limited especially in the setting of myopericarditis [2]. Pericardiocentesis may aid in diagnosis of purulent bacterial effusion and tuberculosis of a neoplasm [2]. Recurrent pericarditis is defined as recurrence of symptoms four to six weeks after acute pericarditis with a symptoms-free interval [35,36]. Chronic pericarditis is clinical signs and symptoms lasting more than three months [2,11,36]. This may be due to inappropriate treatment with

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insufficient dosage of medications, duration of therapy, or failure to restrict physical activity. Risk factors for recurrence include underlying systemic illness such as inflammatory disease or cancer. This could also be due to a new viral infection. There are physical (friction rub), electrocardiographic or echocardiographic signs of pericarditis. The leukocyte count, ESR, or CRP may be elevated [2,11]. Corticosteroids should be considered, specifically during pregnancy. Although immunosuppressive agents such as azathioprine or immunoglobulins are used for recurrent pericarditis, they are not safe to use during pregnancy [2].

Pericardial effusion, cardiac tamponade, and pericardial constriction A small pericardial effusion may be seen during pregnancy, but cardiac tamponade and pericardial constriction are extremely rare and may occur as sequelae of pericarditis or a systemic illness as previously described. The etiology of a pericardial effusion is similar to that of pericarditis (Table 9.3). It may be more common with systemic connective tissue or autoimmune disease such as systemic lupus erythematosus, rheumatoid arthritis, or scleroderma. Small pericardial effusions have been documented by echocardiography in the course of normal pregnancy, regardless of trimester or associated pericarditis [34,52]. A study of 123 pregnant women without heart disease were examined by echocardiography during pregnancy. During the third trimester, 41% had a pericardial effusion. The patients were asymptomatic of mild, moderate, or even large pericardial effusions. There was no sign of infection (leukocytosis) or serum CRP elevation [53]. In abnormal conditions, the size of the effusion and the rapidity of accumulation of the fluid will determine the effect on diastolic filling and the development of cardiac tamponade. Pericardial effusion may be generalized or regional

Table 9.3 Etiology of pericardial effusion during pregnancy Idiopathic Acute pericarditis Collagen vascular disease Autoimmune disorder Neoplastic Postirradiation Post-traumatic Postpericardiectomy HIV Pharmacologic Chronic myxedema

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PART III Cardiac Disorders and Pregnancy

and can ultimately lead to right atrial and right ventricular collapse with hemodynamic compromise [1,2]. Initially, this occurs during early diastole but later extends throughout the diastole so that ventricular filling becomes impaired. The inability of the right ventricle to expand during diastole causes a rapid rise of right ventricular end diastolic pressure. As a consequence of the restricted right ventricular diastolic filling, a decrease in stroke volume and blood pressure occurs with compensatory tachycardia. The increase in right atrial pressure results in retrograde elevation of the venous pressure clinically manifested by distention of the neck veins. A paradoxical pulse in which the systolic blood pressure decrease is greater than 15–20 mmHg on quiet inspiration is caused by increased venous return and filling of the right ventricle. The normal value used for this disparity should be less than 10 mmHg. The right ventricle then encroaches on the left ventricle, causing a decrease in stroke volume and a decrease in cardiac output and systolic blood pressure [1]. Pericardial constriction occurs when there is fibrosis of the pericardium, often due to a prior process, thus limiting the diastolic filling of one or both ventricles [1,2,51]. During pregnancy, both ventricles distend to accommodate the increased blood volume. Therefore, it is possible that with the normal hemodynamic changes of pregnancy, the woman with subclinical constriction may become symptomatic during the latter half of pregnancy [1].

Etiology The etiologies of the pericardial effusion in a woman of childbearing age are summarized in Table 9.3. The most common cause in pregnancy is idiopathic or viral pericarditis [44–46]. Other reported cases of pericardial effusion in pregnancy include Takayasu’s disease [51]. The potential acute and subacute etiologies of cardiac tamponade during pregnancy are summarized in Table 9.4. Reported cases have described tamponade secondary to hemopericardium due to rupture of a dissecting aneurysm of the pulmonary artery in a 27-year-old pregnant woman who had uncorrected patent ductus arteriosus and severe pulmonary hypertension [54]. Subacute tamponade has been reported in the setting of idiopathic or viral pericarditis [44,45]. Pericardial constriction during pregnancy is rare, but potential etiologies in the woman of childbearing age are summarized in Table 9.5. Reported cases during pregnancy described constrictive pericarditis secondary to irradiation [55–57] (which in one case, resulted in maternal death [55]), recurrent pericarditis secondary to juvenile rheumatoid arthritis [58], and unknown causes [56,58,59].

Table 9.4 Etiology of cardiac tamponade during pregnancy Acute Trauma Aortic dissection Cardiovascular rupture Subacute Iatrogenic Pericarditis Tuberculosis Trauma Neoplasm Prior irradiation Collagen vascular disease (lupus erythematosus) Postmyocardial infarction Anticoagulation Uremia Bacterial infection

orthopnea, and, at times, a dull chest pain or pressure. There may be a cough, dysphagia, or hiccups due to mechanical compression of the lungs, esophagus, or phrenic nerve. Compression of the laryngeal nerve may cause hoarseness. The absence of paroxysmal nocturnal dyspnea will help distinguish cardiac tamponade from heart failure. Edema may be present, and hepatomegaly may result in right upper quadrant discomfort and tenderness. Cardiac tamponade is associated with tachycardia, dyspnea, agitation, shock or stupor. Pericardial constriction is associated with dyspnea, cough, orthopnea, ascites, and edema. Distinguishing pericardial constriction from cardiac tamponade may be clinically difficult. General clinical, hemodynamic, and echocardiographic differences are summarized in Table 9.6 [2,57].

Signs Jugular venous distention with clear lungs is found in both constriction and tamponade. Differentiation between these two diagnoses may be difficult, Table 9.6 comparing the Table 9.5 Etiology of constrictive pericarditis in a woman of childbearing age Idiopathic Pericarditis Prior cardiothoracic surgery Neoplasm

Clinical findings

Postmediastinal irradiation

The presenting symptoms may help distinguish between the clinical entities under discussion. Patients with pericardial effusions may complain of weakness, malaise, dyspnea, or

Tuberculosis Collagen vascular disease

CHAPTER 9 Pericardial Disorders and Pregnancy

123

Table 9.6 Features of pericardial constriction vs. cardiac tamponade Clinical features

Pericardial constriction

Cardiac tamponade

Timing of symptoms

Weeks–years

Hours–days

Chest pain

Remote history

Common presentation

Pulsus paradoxus

Often present

Marked

Kussmaul’s sign

Present

Absent

Neck veins

Prominent “X” descent

Absent “Y” descent

Arial fibrillation

Often present

Absent

Pericardial calcification

Present

Absent

Pericardial effusion

Variable

Present

Intracardiac filling pressure

Equalization

Equalization

Echocardiogram

Abnormal septal motion, IVC and hepatic vein dilation

Cardiac chamber collapse, IVC dilated

clinical presentation of pericardial constriction and cardiac tamponade. In both entities, tachycardia, hypotension, and narrow pulse pressure (50% of patients [7,21,56,57]. Recently published data from the worldwide registry on PPCM by Sliwa et al. [1] showed that despite marked differences in the sociodemographic parameters and ethnic background of patients from around the world, the baseline characteristics of subjects with PPCM were similar including mean gravidity of 3.6 ± 1.9.

Diabetes mellitus A large population-based study from Alberta, Canada reported 194 PPCM cases (1/2418 birth events) in addition to previously described associated conditions such as older age, multiple gestations, and higher pregnancy-associated hypertensive disorders (29.9% in PPCM and 5.9% in non-PPCM groups; p < 0.01), identified for the first time preexisting DM (3.6% in PPCM and 0.9% in non-PPCM groups; p < 0.01) as a potential risk factor for PPCM [54]. The association between PPCM and DM needs however further investigation.

Genetics of peripartum cardiomyopathy PPCM has been classified as a nongenetic form of DCM [77]. However, a number of studies have reported familial clustering [78–82]. Moreover, 15% of patients in a German cohort included in a registry had a family history of cardiomyopathy [10]. Two groups recently evaluated rare pedigrees of patients affected by both PPCM and DCM and identified variants in genes encoding myofibrillar proteins, including TTN, the gene encoding the sarcomere protein titin [8,77]. Morales et al. [8] recently performed a systematic search of a large DCM database for cases associated with pregnancy and the PP period. Of 4110 women from 520 families of patients with nonischemic DCM, they identified 45 patients with PPCM/PACM. Nineteen of the patients had been sequenced for genes known to be associated with DCM and six carried mutations. This observation was further supported by a study from van Spaendonck-Zwarts et al. [77] that found PPCM in 6% of 90 families with DCM in Europe. Screening of firstdegree relatives of three patients with PPCM with persistent LV dysfunction revealed undiagnosed DCM in all three families. Furthermore, genetic analyses showed a mutation in the gene encoding cardiac troponin C (TNNC1) in a single DCM family with members with PPCM. More recently, the same group collected 18 families with PPCM and DCM cases from various countries and applied a targeted nextgeneration sequencing (NGS) approach to detect mutations in 48 genes known to be involved in inherited cardiomyopathies. They identified four pathogenic mutations in four of 18 families (22%) and six variants of unknown clinical significance that may be pathogenic in six other families (33%). The investigators concluded that mutations which are potentially causal in cardiomyopathy-related genes are common in families with both PPCM and DCM supporting the notion that PPCM can be part of familial DCM [83]. Most recently, a genetic study was undertaken with 172 patients with PPCM who were not preselected for family history or other indexes of genetic origin and identified the TTN-truncating variants as the most prevalent genetic predisposition in both PPCM and DCM [84]. Twenty-six rare truncating variants in eight genes among women with PPCM were identified. The prevalence of truncating variants (15% vs. 4.7%) was significantly higher than that in a reference population but

CHAPTER 10 Peripartum Cardiomyopathy

was similar to that in a cohort of patients with DCM (15% vs. 17%, p = 0.81). Two-thirds of identified truncating variants were in TTN, and almost all TTN variants were located in the titin A-band. Moreover, in a subgroup of clinically well-characterized cohort of 83 women with PPCM, the presence of TTN-truncating variants was significantly correlated with a lower EF at one-year follow-up (p = 0.005). These results support the notion that PPCM often has a genetic cause and that PPCM shares a genetic origin with familial and sporadic DCM.

Clinical presentation As previously mentioned, PPCM is diagnosed in the vast majority women during the first weeks of the postpartum period. A subset of patients, however, presented in the second and third trimester of pregnancy, or later than one month postpartum [3,7,31]. Many of the signs and symptoms associated with normal pregnancy are similar to those of HF; for this reason, and because of the low incidence and awareness of this condition, the diagnosis of PPCM is often missed or delayed, allowing for the development of catastrophic complications, which otherwise are preventable [85, 86]. Most patients present with typical signs and symptoms of HF, including dyspnea and orthopnea [21,87]. In addition, cough, chest pain, and abdominal pain are frequently encountered and tend to confuse the initial clinical evaluation [87]. Physical examination often reveals tachycardia and tachypnea, blood pressure may be elevated or reduced, and patients are often not able to lie down flat because of shortness of breath. There is usually an increased jugular venous pressure, displaced apical impulse, right ventricular heave, murmurs of mitral and tricuspid regurgitation, third heart sound, pulmonary rales, and peripheral edema. Recent report of 12 lead electrocardiogram (ECG) in 78 consecutive African women with PPCM (90%) black described sinus tachycardia in 90% (mean heart rate 100 ± 21 beats/min). Major ECG abnormalities were detected in 49% of the cases; the most common being T-wave changes (59%), P wave abnormalities (29%), and QRS axis deviation (25%). Bundle brunch block (BBB) was seen in 12% of patients (mostly left BBB). Repeat ECG in six months was obtained in 44 women and showed reduction of heart rate (average of 27 beats/min) and normalization of initial changes in 25% of cases and 75% of those with normalization of LV function [88]. Analysis of ECG findings at the time of diagnosis of 88 women in the IPAC study showed sinus tachycardia in 44% of patients, sinus bradycardia in 6%, normal QRS axis in 84%, left atrial enlargement in 17%, left ventricular hypertrophy in 9%, ST segment depression or elevation in 24%, T wave flattening in 70%, and T wave inversion in 64% of patients. Conduction abnormalities included incomplete right BBB in 5% and complete right and left BBB in 1% each [89]. Chest radiography usually shows cardiomegaly and pulmonary venous congestion or pulmonary edema, with or without pleural effusion [20,90]. Echocardiography shows variable degrees

133

of LV dilatation, with moderate to severe depression of systolic function, and LV apical thrombi can be seen in those with severely depressed LV function. It should be noted that PPCM can occur either with or without LV enlargement. Right ventricular and bi-atrial dilatation as well as moderate to severe mitral and tricuspid regurgitation are commonly seen, with increased pulmonary pressures and mild pulmonary regurgitation [5,7,20,21,90]. Cardiac MRI has been used in a limited number of patients for the assessment of cardiac function and the detection of mural thrombi or myocardial fibrosis [80,91–94]. Although MRI is probably safe during pregnancy [95,96], intravenous gadolinium crosses the placenta, and the 2007 American College of Radiology document on safe MRI practices recommended to avoid during pregnancy and used only if absolutely essential [96]. In a group of eight women with PPCM who were studied with MRI, none exhibited abnormal myocardial late enhancement, and no difference was found in the MRI patterns in four patients who recovered normal LV function compared with those who did not [97]. Recently, a number of studies looked at LGE in women with PPCM [36–38]. In the prospective IPAC study, of 40 patients detectable by LGE was not prevalent and was observed in only two women at baseline and three women at six months. Brain natriuretic peptide Levels of BNP do not change significantly during pregnancy or the postpartum period in healthy women and may show a mild increase in preeclampsia [71,73,98,99]. An early measurement of BNP could help in diagnosing PPCM, in which levels of BNP have been shown to be markedly elevated [100].

Prognosis Recovery of LV function Rate of LV function recovery has varied in recent reports (Table 10.1). Recent publications combining approximately 300 US patients have reported recovery of LV function (LVEF to ≥50%) at six months in 45–78% of patients, with a mean of 54% [31,56,57,86]. Data from Elkayam et al. [7] on 40 patients with longitudinal follow-up of 30 ± 29 months showed that improvement usually occurred within the first six months after the diagnosis. Amos et al. [56] demonstrated LV recovery in 45% of 55 women, mostly occurring within the first two months, with continued improvement over one year. Most recently, a preliminary report from a Utah PPCM registry described LV recovery in 62% of 58 patients, with an average time of nine months [110]. In a recent large retrospective study including 187 patients from South California, Louisiana, and web-based registry, the recovery of LV function (LVEF ≥50%) at six months after diagnosis was found in 115 patients (61%) [76]. In contrast, Modi et al. [102] reported recovery of LV function in only 35% of 40 indigent patients, with a median time to recovery of 54 months. Because 87.5% of the patients in this group were AAs, the investigators suggested that race and ethnicity

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PART III Cardiac Disorders and Pregnancy

Table 10.1 Rate of recovery of left ventricular function in patients with PPCM Rate of recovery (%)

Mean follow-up (mo)

Study design

55

45

41

Retrospective single center

106

52

6

Prospective, multi-center

USA

44

35

24

Retrospective

2011

USA

187

61

6

Retrospective, nationwide

Kamiya et al. [9]

2011

Japan

102

63

9.6 ± 6.5

Retrospective, nationwide survey

Safirstein et al. [57]

2012

USA

55

78

NA

Internet survey

Biteker et al. [103]

2012

Turkey

42

30

19.3

Prospective study

Haghikia et al. [10]

2013

Germany

96

47

6±3

Prospective registry

Blauwet et al. [104]

2013

South Africa

141

21

6

Prospective

Laghari et al. [105]

2013

Pakistan

45

71

6

Retrospective

Pillarisetti et al. [106]

2014

USA

100

23

33

Retrospective

McNamara et al. [55]

2015

USA

96

72

12

Prospective

Cuenza et al. [107]

2016

Philippines

38

39

6

Retrospective

Ersboll et al. [108]

2017

Denmark

61

67

3–12

Retrospective

Hilfiker-Kleiner et al. [109]

2017

Germany

63

60

6

Prospective

References

Year

Country

Amos et al. [56]

2006

USA

Hu et al. [101]

2007

China

Modi et al. [102]

2009

Goland et al. [70]

Number of patients

might be responsible for poorer outcomes. This assumption has been supported by a recent analysis by Goland et al. demonstrating a significantly lower rate of LV recovery in 52 AA patients compared with 104 Caucasians (40% vs. 61%, p = 0.02) [70]. The most recent prospective IPAC enrolled 100 women from multiple centers throughout the United States and followed their clinical course for 12 months with careful clinical evaluations, including repeated echocardiography interpreted in a central laboratory. This study which included 30% AA women has supported the results of previous retrospective investigations and found that 71% of the women recovered LVEF to ≥50% and only 13% had major events or persistent cardiomyopathy with LVEF 50% of women with PPCM, mostly occurring within two to six months after diagnosis; later recovery, however, is possible and occurs in some patients. The rate of LV recovery is significantly lower in AA patients compared with whites. Reports of rate of recovery from other countries have been variable. Haghikia et al. [10] in the prospective PPCM national registry in Germany of 115 patients, described full recovery in 47% at six months. A recently published retrospective study from China by Li et al. [111] of 71 PPCM subjects, reported a full recovery in 56% of subjects at 12 months. In

a single-center study of 45 patients with PPCM in Pakistan, 71% recovered LV function within six months. In contrast, in a larger study of 176 patients in South Africa only 21% of the survivors had fully recovered LVEF (recovery defined as LVEF ≥55%) [104]. Similarly, low rates of LVEF recovery (35% at six months was reported in Turkey [103] and in Haiti (28%) [112]. Predictors of LV recovery A number of factors have been shown to be associated with a higher likelihood of recovery, including LV diastolic dimension (6.0 cm) recovered (Figure 10.5) compared with recovery in nearly 90% of the 65 women who presented with LVEF >30% [55]. Similarly, in the German cohort, mean presenting LVEF in women who recovered was significantly higher compared to those who did not (28% vs. 17%, p < 0.0001) [10]. Recent multivariate analysis by Goland et al. [70] in 187 patients with PPCM found LVEF >30% and LV enddiastolic dimension 2 in the parasternal short axis view, at end systole; absence of other coexisting cardiac structural abnormalities plus numerous excessively prominent trabeculations and deep intertrabecular spaces; recesses perfused by intraventricular blood as seen on the color Doppler imaging. Stollberger et al. [6]: More than three trabeculations protruding from the left ventricular free wall apically to the papillary muscles seen on one imaging plane; intertrabecular spaces perfused from the left ventricular cavity shown by the color Doppler. These were later revised to include the trabeculations move synchronously with the compacted myocardium, and these trabeculations were the noncompacted part of a two-layered myocardial structure best visible at end systole. The two most commonly used CMR criteria are as follows: Petersen criteria [38]: Two-layered structure with compacted (C) epicardial and noncompacted (NC) endocardial layer; end diastolic NC/C > 2.3 was considered diagnostic of LVNC. Jacquier criteria [39]: LV trabeculated mass >20% of myocardial mass at end diastole was considered diagnostic of LVNC. As stated earlier, these criteria when applied to different populations appeared to over diagnose noncompaction [10,11], and 8% of healthy black patients were also reported to have satisfied one or more of the echocardiographic criteria. In addition, Gati et al. [12] reported reversible de novo development of increased trabeculations in 25% of 102 first time healthy pregnant females, and eight of these women satisfied the Chin and Jenni criteria for LVNC, which needs further research. The authors suggested that in the absence of clinical symptoms and any cardiac complications, the presence of trabeculations alone should not be the criteria for the diagnosis of LVNC in otherwise healthy pregnant women. Based on their prior investigations in 1146 highly trained athletes, 415 controls and 75 LVNC patients Gati’s group proposed an algorithm for separating LVNC from normal variants. (Figure 13.3a). Recently, Aung et al. [41] also suggested a clinical algorithm to guide the management of patients with increased trabeculations diagnosed by imaging studies

(Figure 13.3b). Both recommendations seem to have common clinical variables and propose the need for screening family members. Neither of these are validated by other independent investigators.

Advanced imaging techniques helpful to further refine the diagnosis of LVNC In addition to the left ventricular morphology, the role of advanced multimodality imaging techniques in the diagnosis and assessment of LVNC was summarized by Chebrolu et al. [42]. They also suggested a diagnostic algorithm to help performing the various diagnostic imaging procedures, Figure 13.4. Using tissue Doppler imaging, Williams et al. [43] reported unique appearances of paradoxical alternating bands of compression and expansion throughout the cardiac cycle in a pregnant woman with LVNC. Cortes et al. [44] studied 28 patients with LVNC, using speckle tracking echocardiography and found it very useful to separate patients with LVNC and left ventricular ejection fraction (LVEF)< 50% from 13 patients with DCM and 28 healthy controls. Transesophageal imaging also might be very useful to obtain clear images of the left ventricle, diagnose any thrombi, and exclude other cardiac pathology. Transesophageal imaging was used for intraoperative monitoring during cesarean section in patients with LVNC and cardiac complications [45–48]. Live real-time 3D imaging [49] was shown to help confirm left ventricular thrombi, in two cases with LVNC. When the echocardiographic images are suboptimal, using echo contrast agents [50] may be helpful to opacify the left ventricle, if there are no contraindications. There are no systematic studies in pregnant women about the use of these agents. According to the current prescribing guidelines, Definity belongs to Pregnancy Category B; if the benefits outweigh the risk and the patient is agreeable, this contrast may be used for diagnostic purposes.

Cardiovascular radiological procedures and their safety in pregnant patients with LVNC In 2016, The American College of Obstetricians and Gynecologists [51] published the guidelines for diagnostic imaging during pregnancy and lactation. That recommendation states ultrasonography and magnetic resonance imaging (MRI) are not associated with risk and are the imaging techniques of choice for the pregnant patient. Ray et al. [52] reported no increased risk of harm to the fetus or in early childhood when the mother was exposed to MRI alone; however, Gadolinium MRI at any time during pregnancy was associated with high risk. Bural et al. [53] reported the current status of nuclear imaging in pregnant patients. A summary of all cardiovascular imaging procedures and the safety concerns for the pregnant patient and fetus is published by Ntusi et al. [54] from South Africa in 2016. It is reassuring

CHAPTER 13 Left Ventricular Noncompaction

185

(a)

Normal variant

– – – – – – – – – – –

LVNC

+ + + + + + + + + + +

Symptoms Family history T wave inversion LBBB E’ lateral < 9 cm/s Peak VO2 < 85% LVEF on exercise echo Exercise induced VT/AF Abnormal myocardial strain Late gadolinium enhancement on CMR Family member with similar features

(b)

Increased LV trabeculation (any criteria, any imaging modality)

Normal

Increased Pre-test probability? • Arrhythmia • Syncope • Thromboembolic event • Family history of cadiomyopathy • Neuromuscular disorder

LV function?

Yes

No

Impaired

Patient management according to clinical needs and guidelines

Screening of relatives

Reassure, no follow-up

Figure 13.3 (a) Algorithm proposed by Gati et al. Differentiating physiological increased LV trabeculations from pathological LVNC. Clinical assessment and electrocardiographic and multi-imaging modalities are required for cases in the gray zone of physiology and pathological noncompaction. AF – atrial fibrillation; CMR – cardiac magnetic resonance imaging; EF – ejection fraction; LBBB – left bundle branch block; LV – left ventricle/ventricular; LVED – left ventricular end-diastolic diameter; LVH – left ventricular hypertrophy; VT – ventricular tachycardia. Source: Gati et al. 2014 [10]. Reproduced with permission of Elsevier. (b) Clinical algorithm guiding management of patients with increased LV trabeculations. Aung’s proposed algorithm for management of patients with increased trabeculations. Source: Aung et al. 2017 [41]. Reproduced with permission from Elsevier.

to find that majority of the cardiac diagnostic procedures are relatively safe especially when the tests are used appropriately.

Pregnancy in women with isolated LVNC Although the condition has been described for over 25 years, there are very few publications on the management of pregnancy and child birth in women with LVNC. However, as early as 1997, there are genetic studies in many families where affected women as well as carriers with LVNC gave birth to several children [29]. From Bleyl’s series [29]

(Figure 13.5), five pregnancies were reported as uncomplicated and one with premature delivery. Table 13.2 shows few family pedigree studies of patients diagnosed with LVNC [29,30,33–36]. A total of 121 pregnancies were presented in these reports. In many cases, the details of pregnancy and delivery are not available. This table also shows that multiple pregnancies were common in carriers as well as affected females, and many children inherited the disease and had serious complications including heart transplantation and death. In these families, the symptoms of heart failure, palpitations, arrhythmias, sepsis, and syncope are mostly same as in any other cases of cardiomyopathy. LVNC is listed

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PART III Cardiac Disorders and Pregnancy

Diagnostic algorithm of suspected noncompaction Clinical evaluation (findings suggestive of NCCM¥) ± Family history

ECG, CXR, pertinent laboratory findings

CCT • Confirmation of number and structure of trabeculations • Calculate NC/C area and ratio • Identify coronaries/coronary anomalies and other supporting abnormalities

Inadequate/unclear 2D image

2DE

Contrast echo

CMR Assess LVEF/segm ental function

Rule out thrombus (mural/ped unculated)

Assess LV function/Region al wall motion£

Identification and numbering of trabeculations

If trabeculations + are there > 3 Adequate 2D image

Advanced Strain analysis (strain and torsion)

Identify hypertrabeculation‡

• Conventional CMR • Trabecular mass • Late Gadolinium enhancement • Fractal analysis

Advanced research

? NC vs C ratio-is the ratio meeting standard echo criteria

?LV thrombus

• 3D model printing • Gene mapping

RT3DE Assess EF, segmental function identify and delineatetrabeculations±RV Supportive diagnosis of NCCM

• ≥4 trabeculations but unclear diagnosis • Strong clinical suspicion with inadequate or inconclusive echo images • Definitive confirmation if clinically indicated • Patient affordability • Research purposes

¥? Neuromuscular disease/other genetic syndromes £ Dilated Cardiomyopathy-rule out prominent trabeculations secondary to dilated LV and LVHT * Rule out other cardiac conditions causing prominent trabeculations-Anatomical variants (see Table 1) Physiological LVHT/Essential HTN related LVH/HCM/CKD etc.

Figure 13.4 Proposed clinical and diagnostic algorithm for evaluation of suspected noncompaction cardiomyopathy. 2DE – 2-dimensional echocardiogram; RT3DE – real time 3-dimensional echocardiogram; CCT – cardiac computed tomography; CMR – cardiac magnetic resonance. Source: Chebrolu et al. 2017 [42]. Requested permission of John Wiley & Sons.

under etiology of DCM [55]; hence, it is not surprising to find the similarity in the presentation of these two familial cardiomyopathies. Table 13.3 is compiled from 33 published case reports of pregnancy with LVNC/LVHT [24,43,45–48,56–82]. Eight of the reports [45,58,63,71,72,75,77,81] described patients with

features of both LVNC and peripartum cardiomyopathy (PPCM), indicating some overlap between these two conditions. Prior to pregnancy, patients were known to have LVHT in 5 cases and LVNC in 10 cases (from two months to five years). Diagnosis of LVNC was made using Jenni’s criteria in eight cases; Stollberger’s criteria in five cases; others used

(I) I-1

(II) II-5

II-0

(III) III-2

III-6

III-16

III-19

III-21

(IV) IV-3

IV-5

Figure 13.5 Pedigree of one family with isolated noncompaction of myocardium (INVM). Four generation pedigree of one family with isolated noncompaction of ventricular myocardium. Solid circles and squares indicate affected females and males, respectively; open circles and squares, unaffected; circles with central dots, female carriers; and slashes, death. Proband is indicated by arrow. Line with triangle tip, aborted. Source: Bleyl et al. 1997 [29]. Reproduced with permission from John Wiley & Sons.

CHAPTER 13 Left Ventricular Noncompaction

187

Table 13.2 Multiple generations in which women with LVNC gave birth to offspring with or without LVNC Authors Bleyl et al. [29]

Pregnancies in carrier/affected women One female carrier had nine pregnancies from two husbands; five girls, two boys, and two abortions. Two girls were carriers and were asymptomatic. Cases III-2, III-5, III-19, III-21, and IV-5 were born after uncomplicated term pregnancy and delivery; IV-3 was born at 36 wk

Ichida et al. [35]

Family NLVNC-09: Three generations of affected mothers; last female III-2 had three pregnancies; all three were boys

Pregnancies in their daughters

Comments

One of the carrier daughter had seven pregnancies; five boys, one girl and one abortion; two boys were affected; one died of heart failure other had heart transplant

Boy who had heart transplantation at age 9 mo was alive at 34 mo

The second carrier daughter had 11 pregnancies and 12 children (one set of twins). Her carrier daughter had three pregnancies; two affected boys and one unaffected girl

—

Family 10: Two of the three females had LVNC; no deaths

Family LVNC-10: one female with LVNC; three pregnancies all three were females Ichida et al. [35]

Family BSD: One female carrier had five pregnancies, and all five girls were carriers.

Family 09: All three boys had LVNC and one died

Family BSD: three girls had one pregnancy each; all three were boys; all were with LVNC. Two girls had two pregnancies each. Four boys

BSD: Six of the seven boys had LVNC and one died

Family BSG; one carrier female one pregnancy; one boy

Lorsheyd et al. [34]

Family BSL; one carrier female -one pregnancy one boy

Family BSL: One boy with LVNC died

Family BSH: one female carrier: four pregnancies; three boys and one girl. All three boys had LVNC; girl was carrier

Family BSH: Two of the three boys with LVNC died The affected daughter had syncope and atrial fibrillation; had two pregnancies; both were females; one with LVNC had severe heart failure

Girl from third generation had severe heart failure; got heart transplant at 14 yr of age

One partially affected female; seven pregnancies; five boys and two girls;

One affected daughter had three pregnancies; one boy with LVNC

Two girls and one boy were affected with LVNC; one boy partially affected and died

Second affected daughter had two pregnancies and two daughters; one with LVNC

Mother had atrioventricular (AV) block and had pacemaker and died of infection

Family A:one female with LVNC had seven pregnancies; five girls and two boys. One of five girls had LVNC Family B: No affected females

Her mother got an ICD

Cases were initially misdiagnosed as DCM or HCM Budde et al. [30]

Both affected daughters were on heart transplant list

Used Jenni’s criteria for echo diagnosis Klaassen et al. [33]

Family: 107: One female with LVNC; five pregnancies (four boys and one girl)

Two of the four boys had LVNC

One had shock, systemic and pulmonary emboli and heart transplant at age 26 yr

Klaassen et al. [33]

LVNC Family 101: First-generation mother and father with clinical status unknown

Family LVNC 101: four females from the third generation had LVNC; one female had one pregnancy, and the girl was also affected. Two other females had two pregnancies each; three girls and one boy; none were affected

Second generation two boys with LVNC. One of them had stroke and peripheral emboli other had heart failure and pulmonary emboli

In the second generation, the two women with LVNC + HCM had five pregnancies; in the third generation one woman with LVNC + HCM had two pregnancies

This fourth-generation family has members with echo features of LVNC and HCM in the same hearts

First and second generations there were no affected women Yuan et al. [36]

First-generation parents were unaffected with HCM or LVNC

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PART III Cardiac Disorders and Pregnancy

Table 13.3 Pregnancy in women with left ventricular noncompaction Age (yr)

Echo criteria used /LVEF%

No. of pregnancies

Delivery type

Complications

Medical Rx (any time of pregnancy)

Surgical/ device RX

Williams et al. [43]/2003/UK

28

Apical views; trabeculations and deep sinusoids.EF: N/A

3

First two pregnancies are uncomplicated. Third was C-section at 36 wk

HF; severe MR from 22nd week

Standard; at 6-mo f/u NYHA class II

ICD for VT 10th day postpartum

Kitao et al. [56]/2004/Japan

N/I

Excessive trabeculations and deep intertrabecular recesses. EF: Low

1

Emergency C-section at 24 wks

HF; infant died second day LVNC at autopsy

N/I

—

Uesugi et al. [57]/2005/Japan

N/I

Not specified EF N/A

2

First C-section at 24 wk Second C-section at 34 wk Both uneventful

HF at first pregnancy; No HF at second pregnancy

N/I

—

♥Bahl et al. [58]/2006/India

23

NC/C 2 : 1. Cardiac phase not specified; EF 19%

1

Normal vaginal delivery at 40 wk

Dyspnea 36 wk. PPCM with LVNC by echo

Dig, diuretics, ACEI ASA, carvedilol; 2-yr f/u EF 20%; MR

—

Fernandez Sanchez et al. [59]/2006/Spain

N/I

Not specified; EF N/A

1

Elective C-section under GA

Ischemic cerebral infarct

Anticoagulation

—

Finsterer et al. [60]/2006/Austria

39

Stollberger’s criteria; LVHT and NC/C > 2; EF N/A

1?

Normal delivery with significant blood loss and hypotension

Syncope 1 hr after delivery. Fall with fracture left occipital bone; subdural hematoma

N/I

—

Salemi et al. [61]/2006/Brazil

28

Missed diagnosis for 24 yr after extensive work-up; CMR confirmed LVNC Moderate systolic dysfunction

1

No details

Heart failure since age 4. Son had LVNC on screening echo

Vasodilators and warfarin

None

Munehisa et al. [62]/2007/Japan

24

Two-layered LV; NC/C = 2.3; EF 45%

2

First pregnancy aborted at 5 wk. Second C-section at 32 wk under GA

WPW on EKG; baby and grandmother had LVNC by echo

Warfarin, Enalapril, Carvedilol

—

Author/year/country

CHAPTER 13 Left Ventricular Noncompaction

189

♥Patel et al. [63]/2007/USA

26

LV trabeculations at the apex and apical lateral walls; EF < 20%

2

First induced at 35 wk for preeclampsia. Second induced at 37 wk

Dyspnea, dizziness, and anemia

Metoprolol, digoxin, hydralazine, nitrates and iron

RF ablation of Aflutter and VT 2 mo later

♥Patel et al. [63]/2007/USA

14

LV trabeculations at the apex and apical lateral walls; EF 17%

1

C-section at 36 wks

Anemia and infection. HF treated with IV nesiritide, milrinone, and dobutamine

Standard meds; at 17-mo f/u EF 30%

—

♥Rehfeldt et al. [45]/2008/USA

25

Two-layer appearance with trabeculations and deep recesses; EF 5%; 6-mo f/u EF 47%

2

Two normal deliveries

Cardiac arrest 8 wk postpartum; myocarditis on biopsy; LVNC and PPCM features

N/I

IABP on admission; LVAD for 3 mo

Kobza et al. [64]/2008/Switzerland

N/I

Known case of LVNC using Jenni’s criteria; EF N/A

1

C-section; healthy baby

ICD 33 mo prior to pregnancy. No arrhythmias during pregnancy

N/I

ICD for LVNC before pregnancy

Stangl et al. [65]/2008/Germany

N/I

N/I; EF 2.5; echo two layered, NC/C at end systole >2; EF: Preserved

1

Vaginal delivery

None

None

—

Panduranga et al. [70]/2012/Oman

30

NC/C > 2; spongy appearance and deep recesses in RV and LV; EF 35%. Known case of biventricular noncompaction

3

N/I

Seen once at 31 wk. LBBB on EKG. Had LV diverticulum on echo. No f/u

Carvedilol and Lisinopril stopped by patient. Advised anticoagulants

—

♥de Souza et al. [71]/2012/Brazil

37

Echo c/w Noncompaction; EF 42% dilated LA, LV; severe MR CMR excluded noncompaction

Multiparous

Normal delivery at term

HF 15 d postdelivery; criteria for LVNC and PPCM

Carvedilol; enalapril, spironolactone and warfarin

—

♥Lea et al. [72]/2012/USA

23

Prominent trabeculations and deep recesses on echo; CMR confirmed the diagnosis of LVNC. Dilated LV; EF 15–20%

1

Vaginal delivery at 40 wk and 5 d; no past medical history; normal prenatal course

Severe HF during labor. PPCM + LVNC Explanted heart confirmed LVNC. Baby has LVNC

Medical RX failed and readmitted in 2 wk for HF

Heart transplant done; 12-mo f/u normal

Kilic et al. [73]/2013/Turkey

19

Prominent trabeculations and blood flow into sinusoidal recesses. EF 20%

1

N/I

Cough before delivery. EF 20% severe MR TR PAP 57 mmHg

β-Blocker ACEI diuretic and ASA

—

Sawant et al. [74]/2013/UK

37

Known to have LVNC for 3 yr prior to pregnancy. Trabeculations and recesses by 2D echo and MRI; EF 28%

1

C-section at 34 wks using low dose spinal with incremental epidural top up

Severe HF at 32 wk At 6-mo f/u doing well

Bisoprolol, LMWH, furosemide, and amiloride; ACEI and ASA spironolactone

ICD for VT

CHAPTER 13 Left Ventricular Noncompaction

191

30

LVNC by Jenni’s criteria and confirmed by CMR; EF 20%

4

Prior three pregnancies were uneventful

LVNC + PPCM; severe HF no improvement

IV Milrinone ASA

29

LVNC by CMR criteria; EF 16%

1

Normal delivery

LVNC + PPCM 12-mo f/u EF 20%

ASA

41

LVNC by echo and CMR criteria; EF 21%

3

Normal delivery

LVNC + PPCM; EF improved to 40%

ASA

—

21

LVNC by Jenni’s criteria: EF 15%

1

Uneventful delivery

LVNC + PPCM. At 6-mo f/u; EF improved to 45%

ASA

—

Dogan and Karabulut [76]/2013/Turkey

32

Known LVNC; EF 25%

1

C-section at 35th week

Dyspnea at 27 wk; EF 5% CVA 3 wk after delivery

HF meds and warfarin

—

♥Peters et al. [77]/2013/USA

30

LVNC by Jenni’s criteria; EF 32% PPCM clinical picture

3

All normal deliveries

Biventricular failure 1 mo after delivery. At 6-mo follow-up improved EF 48%

Furosemide, ACEI carvedilol, spironolactone

—

Koster et al. [78]/2013/Germany

39

Known to have IVNC 1 yr prior to pregnancy for TIA workup; Jenni’s criteria; EF 25%

2

C-section under GA; 35 wk of pregnancy

Ventricular arrhythmias; EF 20%; PAP 80 mmHg; baby was healthy

Dobutamine and milrinone IV infusion

ECMO standby

Stollberger et al. [79]/2014/Austria

Mean age 30 ± 7

Known to have LV hypertrabeculation; EF normal in all 4 patients

1

C-section

1

Normal delivery

C-section for breach presentation

1

Normal delivery

1

Normal delivery

2

First pregnancy normal delivery 10 yr prior. Baby died at 11 wk. Second C-section at 33 wk under GA with TEE monitoring

♥Rajagopalan et al. [75]/2013/USA

Ashford et al. [47]/2014/USA

27

Known LVNC – multiple deep recesses and thick myocardium; EF 15–30%

LVAD as bridge to transplant. ICD for syncope

—

Asymptomatic on no medicines Presumed preeclampsia at 32 wk.RVSP 97 mmHg. EKG PVCs and T wave changes, Long QT. LA thrombus on TEE. HF 4 mo later

Furosemide; Heparin IV and 6 wk of warfarin. β-Blocker and ACEI

HF 4 mo’ f/u requiring admission

(continued)

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PART III Cardiac Disorders and Pregnancy

Table 13.3 (Continued) Age (yr)

Echo criteria used /LVEF%

No. of pregnancies

Spitzer et al. [48]/2015/USA

31

Known LVNC and pulmonary HTN after first delivery; EF 38% later 23%; PA systolic pressure 73 mmHg

Gandasegui et al. [80]/2015/Spain

37

Known LVNC from at age 32 yrs after first delivery; EF 44%; At 30th week EF 38%; mother had DCM

Reuschel et al. [24]/2016/Germany

27

Known LVHT since 2 yr; EF 49% later 45% then to 38% sister with HCM had ICD but died with HF and sepsis

♥Antlanger et al. [81]2016/Austria

34

Echo criteria for LVNC and PPCM; 2 mo after C-section EF was 21%; Mod severe MR; CMR showed LVNC

Kochmareva et al. [82]/2016/Russia

26

Personal communication CK/USA Personal communication JB/USA

Author/year/country

Delivery type

Complications

Medical Rx (any time of pregnancy)

Surgical/ device RX

4

C-section; healthy boy was delivered

Heart failure; presented for C-section at 34 wk under GA and TEE monitoring

Dobutamine in OR; ergonovine carvedilol, furosemide, and enoxaparin

Refused ICD

2

First pregnancy normal delivery at 40 wk;second vaginal delivery at 40 wk; normal baby

Every 3 wk clinic visit; echo every 4 wk from 20 wk on

ASA till 32 wk enoxaparin from 12 wk; carvedilol

—

C-section under peridural anesthesia at 37 wk. Healthy baby girl

Presented at 16 wk. Holter 2 NSVT

Bisoprolol 5 mg/d

Refused ICD. Wearable CD while pregnant

1

C-section at 27 wk and baby died 3 d later

Hemodialysis; PPCM LVNC; preeclampsia; Near complete LVNC regression and EF 56% by CMR at 4 mo

α-methyldopa and labetalol; on dialysis

Received kidney transplant at 6 mo and doing well

EF 26% NSVT Inf MI + RV MI normal coronaries; family Hx of sudden death

3

Two abortions at 6–8 wk C-section at 31 wk; baby alive and normal

Thrombophilia; admitted at 18–19 wk; EF 36% then down to 20%; normal PA pressure

ACEI β-blocker, diuretics, digoxin warfarin before pregnancy; during pregnancy fraxiparin

ICD placed for VT; 8 mo f/u EF 32%

35

EF normal EF 50–55%

2

First C-section Second C-section

PVCs; NSVT; dizziness Migraine head ache

36

MRI noncompaction EF normal

2

1 C-section Two C-section

HF – recovered well Second delivery doing well

ICD for VT

ASA; NYHA 1

—

♥ – The authors report patients met criteria for PPCM as well as noncompaction. C-section – cesarean section; HF – heart failure; LVEF – left ventricular ejection fraction; NSVT – nonsustained ventricular tachycardia; ICD – implantable cardioverter defibrillator; N/I – no information; N/A – not available; ASA – aspirin; f/u – follow-up; wk – weeks; DCM – dilated cardiomyopathy; PPCM – peripartum cardiomyopathy; TR – tricuspid regurgitation; PAP – pulmonary artery pressure; OR – odds ratio; MR – mitral regurgitation; GA – gestational age; CVA – cerebro-vascular accident; RVSP – right ventricular systolic pressure; Others are same as in text.

CHAPTER 13 Left Ventricular Noncompaction

excessive apical trabeculations or the ratio NC/C >2, to diagnose LVNC. There were 42 women in this summary. Average age was 29 ± 6 years; range 14–41 years. The total number of pregnancies in this group is about 64 (one multiparous woman had no details on the number); two women had four pregnancies each; four women had three pregnancies each, and 10 women had two pregnancies each while the rest of the women presented during the first pregnancy. Four women gave birth to babies with LVNC [56,61,62,72]; one neonate had LVNC confirmed at autopsy [56]. There was only one maternal death due to cerebral infarction in a patient with LVNC after a cesarean section, reported from China [68]. There were three interesting cases reported as having clinical PPCM and LVNC criteria, who were in severe heart failure. Rehfeldt et al. [45] reported one 25-year-old woman with no significant prior history, who had cardiac arrest eight weeks after an uncomplicated pregnancy and delivery. She was resuscitated and an emergency coronary angiogram showed normal coronaries, but her echocardiogram showed LVEF 5%; intra-aortic balloon pump (IABP) was inserted, and she was transferred to another hospital where a left ventricular assist device (LVAD) was placed; intraoperative transesophageal echocardiography (TEE) showed EF 5–10% and LVHT. During the removal of the LVAD three months later, intraoperative TEE showed LVHT and EF improved to 47%. This case was diagnosed as PPCM with LVHT/NC [45]. Rajagopalan et al. [75] described another case which was diagnosed as PPCM with LVNC confirmed by CMR criteria; this is a 30-year-old woman with three normal pregnancies before the fourth pregnancy, which was complicated by heart failure, 10 weeks after delivery. Her LVEF was 20%, and despite intensive medical therapy, she was in low output heart failure and received LVAD as bridge to transplantation [75]. Lea reported one other case with diagnosis of PPCM and LVNC who developed severe shortness of breath during labor and delivery; heart failure became refractory, and heart transplantation was done seven weeks postpartum [72]. The fourth case who was reported by Antlanger et al. [81] is a woman with chronic renal failure on hemodialysis; patient presented with diagnosis of PPCM two months after an induced labor and delivery at 27 weeks; echocardiogram showed severe reduction in systolic function, and CMR showed LVNC criteria. She improved significantly on medical therapy over six months, and CMR showed near complete regression of noncompaction. She got a kidney transplant and was in excellent condition. Twenty-one women delivered by cesarean section; indications were obstetrical in two cases, one for breach presentation and the other was high fetal heart rate; rest all appear to be cardiac indications, mostly heart failure and few for ventricular arrhythmias along with heart failure. Heart failure was the most common complication in this group; LVEF% was available in 27 cases; average EF% was 28 ± 12; LVEF was reported as normal in six cases; moderately depressed in one case; low in one case; preserved in one case; and not available in the rest.

193

Abnormal EKGs and arrhythmias Fourteen reports included some information on the electrocardiogram, arrhythmias, ablation of arrhythmia, or implantation of devices Table 13.4. One patient had preexcitation with sinus rhythm, but no arrhythmias were reported [62]. One patient had left bundle branch block (LBBB) [70]. Some type of ventricular tachycardia was found in six cases [24,43,63,67,75,82]; six patients got implantable cardioverter defibrillator (ICD), and one case was treated with radio frequency (RF) ablation [63]; this patient also had RF ablation of her atrial flutter at the same time. One patient with severe LV dysfunction got an ICD after a syncopal episode. One patient with several episodes of nonsustained ventricular tachycardia agreed for a wearable cardioverter defibrillator and wore it throughout the pregnancy; no shocks were delivered [24]. One patient was reported to have multiple polytopic ventricular extra systoles during her delivery, but no information was available on the treatment. Another patient with severe systolic dysfunction, severe pulmonary hypertension (HTN), long QT interval, and premature ventricular contractions (PVCs) refused ICD [47]. One other patient (who is not in this table) with known LVNC had an ICD implanted 33 months prior to pregnancy, delivered a healthy baby by cesarean section; no tachyarrhythmias were detected by the device during pregnancy [64]. According to the 2008 ACC/AHA/HRS Guidelines for Device-Based Therapy [83], ICD therapy may be considered in patients with LV noncompaction, for prevention of sudden cardiac death. (Class IIb recommendation with level of evidence C.)

Anticoagulation in pregnant patients with LVNC Fifteen reports mentioned the use of aspirin, warfarin, heparin, or low-molecular-weight heparins (LMWHs); three reports did not specify the anticoagulant used (Table 13.5). In 15 cases, the LVEF% was depressed and ranged from 15% to 46%. Aspirin alone was given in the postpartum period in seven cases; warfarin was given to eight patients in the postpartum period; one of them had a 1 cm left atrial appendage (LAA) thrombus seen on TEE while monitoring the case during cesarean section [47]. One patient with multiple transient ischemic attacks (TIAs) was on warfarin for one year before pregnancy, was changed to LMWH during pregnancy [78]; the case report did not list the discharge medicines. One patient suffered a cerebrovascular accident, three weeks after a cesarean delivery; etiology for this was considered cardioembolic, and warfarin therapy was initiated [76]. Another pregnant woman was presented to the emergency department with ischemic cerebral infarction due to cardiac embolism due to noncompaction and few days later delivered by cesarean section [59]. One patient with thrombophilia and history of inferior wall myocardial infarction with right ventricular thrombus was treated with warfarin for four years prior to her pregnancy; fraxiparin

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Table 13.4 Abnormal EKGs and arrhythmias Author/year

EKG

Rhythm problem

Med RX

Surgical RX

Williams et al. [43]/2003

Low voltage inferior leads; poor r wave progression

Sustained VT, 10 d after delivery

β-Blocker

ICD for VT

Bahl et al. [58]/2006

LAE; T flat in inferolateral leads

None

None

None

Munehisa et al. [62]/2007

Sinus rhythm with WPW pattern

None on Holter monitor

None

None

Patel et al. [63]/2007

Sinus tachycardia; nonspecific ST–T changes

PACs PVCs and atrial flutter on Holter; reentry VT at EP study

β-Blocker

RF ablation of atrial flutter and VT, 2 mo after delivery

Fischer et al. [46]/2009

No information

No information

β-Blocker

ICD eighth postop day for primary prevention EF 15%

Moeschler et al. [67]/2009

Wide complex tachycardia

Wide complex tachycardia; intraop runs of VT x 3; defibrillated successfully

Procainamide; amiodarone; β-blocker

ICD for VT on seventh day after delivery

Panduranga et al. [70]/2012

LBBB

None

None

None

Kilic et al. [73]/2013

Nonspecific T wave changes

None

β-Blocker, ACEI, diuretics

None

Sawant et al. [74]/2013

No information

Runs of NSVT on readmission at 10 d postpartum

β-Blocker

ICD for VT 3 wk postpartum

Rajagopalan et al. [75]/2013

No information

No information

Standard therapy + Milrinone

ICD for syncope; has LVAD also

Koster et al. [78]/2013

Multiple polytopic ventricular extra systoles

Severe ventricular arrhythmias

No information

Refused ICD

Dogan and Karabulut [76]/2013

Nonspecific intraventricular conduction delay

None

No information

None

Ashford et al. [47]/2014

Sinus rhythm; PVCs; long QT interval; T wave abnormalities

None

Furosemide; β-blocker; ACEI; heparin; warfarin

Denied ICD

Reuschel et al. [24]/2016

No information

NSVT x2 on Holter at 24 wk; no other

Bisoprolol 5 mg/d

Wearable CD only during pregnancy

Kochmareva et al. [82]/2016

Inferior MI and RV infarction

NSVT in 2009 and 2014

Digoxin β-blocker

ICD-implanted post cesarean section

ICD – implantable cardioverter defibrillator; LAE – left atrial enlargement; LVAD – left ventricular assist device; MI – myocardial infarction; NSVT – nonsustained ventricular tachycardia; PVC – premature ventricular contractions; RV – right ventricle; WPW – Wolf Parkinson White syndrome; PAC – pregnancy associated cardiomyopathy; EP – electrophysiology.

was administered during pregnancy, and warfarin was reinstituted in the postpartum period [82]. Patients with left ventricular systolic dysfunction (LVEF 65 times the human dose [90], and no excretion of metabolites was detected in milk of rats. It is not known whether these drugs are excreted in human milk, and breast-feeding is therefore not recommended in women taking clopidogrel [67]. At least one week is needed for the elimination of clopidogrel for a safe application of regional anesthesia. Reproduction studies in rats and rabbits in oral doses of prasugrel 30 times the recommended therapeutic dose in human revealed no evidence of fetal harm. Based on these data, prasugrel is listed as category B by the food and drug administration. Havakuk et al. [8] reported the use of prasugrel in 4 of 120 patients with pregnancy associated MI due to SCAD without complications. No report on the use of prasugrel during human lactation is available. Similarly,

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no report on the use of ticagrelor has been found. Animal studies have shown risk, but with the absence of human data, embryo–fetal risk cannot be assessed. The drugs have received FDA category C. No report is available on the use of these drugs during lactation. Pharmacotherapy for PASCAD The ideal drug therapy for patients with AMI due to SCAD has not been established due to lack of randomized studies. The use of dual antiplatelet therapy (aspirin + P2Y12 receptor inhibitors) has been suggested for the theoretical possibility of reducing false lumen thrombosis with resulting true lumen compression [54]. Saw et al. suggested the use of long-term aspirin and clopidogrel for 1–12 months in nonpregnant patients with SCAD. At the same time, antiplatelet therapy in women with MI due to SCAD rather than atherosclerotic coronary artery disease does not seem to be supported by good rationale. In addition, the use of these drugs as well as thrombolytic therapy may lead to unfavorable effect because of possible extension of the dissection. Given the lack of safety and efficacy information with clopidogrel to both mother and fetus in pregnancy, the administration of the drug should be given after a detailed discussion with the patient. β-Blockers reduce arterial shear stress and may be useful for prevention of recurrence. In a recent report by Saw et al. of 327 troponin-positive nonpregnant patients with acute coronary syndrome with nonatherosclerotic SCAD treated between 2012 and 2016, those with hypertension were more than twice as likely to have a recurrence over three years of follow-up, whereas β-blocker use was associated with greatly reduced risk of recurrent SCAD [16]. β-blockers in women with SCAD during pregnancy should be given in an effective dose aiming at a reduction of heart rate by ≥20%. Because of the high incidence of symptoms due to persistent or new SCAD shown by Havakuk et al. in women with PASCAD [8], β-blockers should be continued for at least one year. The use of anticoagulation in women with SCAD is also debatable because of the risk of extending the dissection, which is balanced by the potential benefit of resolving overlying thrombus and improving true lumen patency. In a recent review, Saw et al. [14] suggested discontinuation of heparin once the SCAD diagnosis is made. Although this recommendation makes clinical sense, it lacks supportive data. HMG CoA-reductase inhibitors are routinely used in patients with AMI due to atherosclerotic CAD. There is no proven benefit of these drugs in patients with SCAD, and they should not be given to women with PASCAD. Angiotensin-converting enzyme inhibitors are recommended after the delivery in patients with reduced EF. Labor The mode of delivery in a patient with pregnancy-associated MI should be determined by obstetric considerations and the clinical status of the mother. An elective cesarean section avoids a long or stressful labor and allows a better control of the time of delivery and the presence of an appropriate

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medical team including an experienced obstetrician, obstetric anesthesiologist, cardiologist, and pediatrician. Vaginal delivery, on the other hand, eliminates the potential risks associated with general anesthesia and a major surgical procedure which includes hemodynamic fluctuations, larger blood loss, pain, infection, respiratory complications, damage to pelvic organs, and potential unfavorable effects on future reproductive health (risks of miscarriage, ectopic gestation, placenta previa, and placenta accreta) [102]. Only 10 of the 68 patients reported by Roth and Elkayam who developed PAMI antepartum or peripartum, delivered by cesarean section, a rate lower than the contemporary, >30% rate in the general pregnant population [103]. These data therefore suggest that vaginal delivery can be accomplished relatively safely in the stable patient with a non-SCAD pregnancy-associated AMI when measures aimed to reduce cardiac workload and oxygen demands are taken. Instrumental vaginal delivery is recommended to avoid excessive maternal efforts and prolonged labor. Positioning the patient in the left lateral position can help to improve cardiac output during labor and delivery. In addition, the patient’s pain, fear, and apprehension, which may lead to tachycardia and hypertension and thus to increase in myocardial oxygen demand, should be prevented and treated. Vital signs as well as oxygen saturation, electrocardiogram, and fetal heart rate should be monitored continuously. For prevention or treatment of myocardial ischemia during labor, intravenous nitroglycerin, β-blockers, and calcium antagonists can be used. It should be noted that nitroglycerin and calcium antagonists have some tocolytic effects and may prolong labor. The majority of women with PAMI due to SCAD present after the delivery. Of 28 patients reported by Havakuk et al. who presented antepartum, 21 (75%) were delivered by cesarean section, which seems to be indicated in such patients because of the high rate of new dissection shown in these patients [8].

Myocardial infarction and subsequent pregnancy Limited information is available in the medical literature regarding the risk of pregnancy in women with a history of AMI. Vinatier et al. [104] reported on 14 clinical cases published between 1943 and 1991 with overall good results, no detailed information however, was provided. The authors described their own case with a history of anterior wall MI at the age of 18 who became pregnant at the age of 21. The patient was asymptomatic prior to pregnancy, and preconception echocardiogram showed severe LV dilatation and reduced EF. Patient’s stress test did not show any residual ischemia. A cardiopulmonary exercise test showed normal exercise capacity. Pregnancy was complicated by palpitation at 28 weeks that responded initially to β-blockers but reappeared at 35 weeks. Holter monitoring showed 500 ventricular premature beats per 24 hours as well as episodes of nonsustained ventricular tachycardia (VT). Because of an increase in the number of ventricular beats, the patient was

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delivered by a C-section at 37 weeks. Early and late postpartum follow-up was normal. Frenkel et al. [105] reported four cases who conceived between nine months and nine years after myocardial infarction. The first patient had an anterior MI and a stroke at the age of 30. LVEF during the acute phase was 20%. At one month, patient was asymptomatic, and LVEF improved to 28%. The patient became pregnant again at the age of 39 years. Pregnancy was uneventful except for an elevated blood pressure at 38 weeks. Patient delivered a normal female baby weighing 2170 g by assisted vaginal delivery. The second patient had acute extensive anterior wall MI at the age of 33 years, which resulted in a reduced LVEF to 34%. In the following four years, she was hospitalized several times for chest pain. Patient became pregnant eight years after her MI. Pregnancy was uneventful until 36 weeks’ gestation when she was hospitalized for dyspnea and was found to have mild pregnancy-induced hypertension which deteriorated, and the fetus showed intrauterine growth retardation. Hemodynamic evaluation showed pulmonary hypertension that improved significantly after epidural anesthesia. Patient delivered an infant weighing 2120 g by a C-section. Patient did well after the delivery and was well one year later with only occasional complaints of chest pain. The third patient had a non-Q wave lateral MI at the age of 41and had two additional episodes of exertional chest pain during the following year. Patient conceived at the age of 43 and was hospitalized at five months’ gestation because of exertional chest pain and was found to have a blood pressure of 200/90 mmHg and heart failure. Patient was treated with antihypertension therapy and diuretics and was discharged home. She was hospitalized one month later and remained hospitalized until her uncomplicated vaginal delivery. In the following five years, she continued to have hypertension and angina and had two further episodes of recurrent MIs and died of cardiogenic shock at the age of 52. The last case had an extensive lateral and posterior MI resulting with a decreased EF to 40%, which improved to 50% few days later. She remained relatively stable and conceived nine-months postpartum. Patient developed palpitations at 34 weeks’ gestation, which were treated with β-blockers. She was induced at 40 weeks’ gestation because of hypertension and had a normal vaginal delivery to a 3140-g male. Patient remained hypertensive after the delivery and required therapy. Tedoldi and Manfroi [106] described a pregnancy in a 40-year-old woman with two previous MIs, revascularization surgery, and a history of hypertension. Cardiac evaluation including a stress test at 10-week gestation revealed a decreased exercise tolerance, exercise induced angina, and ischemic ECG changes. Echocardiogram showed mild LV enlargement with wall motion abnormalities and a decreased EF to 45%. Patient was admitted at 30 weeks’ gestation because of hypertension and was diagnosed with preeclampsia. She had a C-section delivery at 34 weeks because of fetal distress to a female weighing 1345 g that required hospitalization for three months after delivery for septicemia and to gain weight. Janion-Sadowska et al. [107] described two cases of pregnancy after myocardial

infarction. The first case of a 38-year-old woman who developed MI on the 15th day after delivery complicated by ventricular arrhythmia and treated with CABG surgery. Patient became pregnant again about seven months after her surgery and had an uneventful pregnancy, labor, and delivery. The second case was a 38-year-old woman with familial hypercholesterolemia who had a MI at the age of 32 followed by CABG surgery. Patient was treated with atorvastatin for the first six weeks of pregnancy. The pregnancy, C-section delivery, and post postpartum course were uneventful. A healthy baby without congenital heart disease was born at 38 weeks’ gestation. In summary, several cases of pregnancy after myocardial infarction have been reported. Some of the patients had high risk features including angina and LV dysfunction. Pregnancy was well tolerated in asymptomatic patients with normal ejection fraction but was associated with complications including arrhythmias, heart failure, and chest pain in some of the patients with history of angina, heart failure, and LV dysfunction prior to pregnancy. No mortality however, was reported, and most complications were manageable. Patients with a history of MI should be ideally evaluated prior to subsequent pregnancy. Such an evaluation should include a detailed history and physical examination, an ECG, echocardiogram, and exercise testing. Cardiac drugs which are contraindicated during pregnancy including angiotensinconverting enzyme inhibitors or angiotensin receptor blockers, aldosterone receptor antagonists, statins, Ivabradine, and new oral anticoagulants should be discontinued prior to pregnancy or as soon as pregnancy is diagnosed. Women with an evidence for ongoing myocardial ischemia, heart failure, or severe LV dysfunction prior to pregnancy should be advised against pregnancy, and those who are already pregnant should consider early termination.

Subsequent pregnancy in women with a history of PASCAD Little information is available on the risk of subsequent pregnancy in women with a history of PASCAD [108]. However, because of the high incidence of recurrent SCAD and pregnancy-related vulnerability of the coronary arteries [7,8], a subsequent pregnancy does not seem advisable.

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74 Tanaka, K., Tanaka, H., Kamiya, C. et al. (2016). Beta-blockers and fetal growth restriction in pregnant women with cardiovascular disease. Circ J 80: 2221–2226. 75 Ersboll, A.S., Hedegaard, M., Sondergaard, L. et al. (2014). Treatment with oral beta-blockers during pregnancy complicated by maternal heart disease increases the risk of fetal growth restriction. BJOG 121: 618–626. 76 Page, R.L., Hamdan, M.H., and Joglar, J.A. (2002). Arrhythmias occurring during pregnancy. Card Electrophysiol Rev 6: 136–139. 77 Childress, C.H. and Katz, V.L. (1994). Nifedipine and its indications in obstetrics and gynecology. Obstet Gynecol 83: 616–624. 78 Briggs, G.G., Freeman, R.K., Towers, C.V., and Forinash, A.B. (2017). Drugs in Pregnancy and Lactation, 11e. Philadelphia, PA, Lippincott Williams & Wilkins. 79 Waisman, G.D., Mayorga, L.M., Camera, M.I. et al. (1988). Magnesium plus nifedipine: potentiation of hypotensive effect in preeclampsia? Am J Obstet Gynecol 159: 308–309. 80 Shotan, A., Widerhorn, J., Hurst, A., and Elkayam, U. (1994). Risks of angiotensin-converting enzyme inhibition during pregnancy: experimental and clinical evidence, potential mechanisms, and recommendations for use. Am J Med 96: 451–456. 81 Cooper, W.O., Hernandez-Diaz, S., Arbogast, P.G. et al. (2006). Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 354: 2443–2451. 82 Lambot, M.A., Vermeylen, D., and Noel, J.C. (2001). Angiotensin-IIreceptor inhibitors in pregnancy. Lancet (London, England) 357: 1619– 1620. 83 Quan, A. (2006). Fetopathy associated with exposure to angiotensin converting enzyme inhibitors and angiotensin receptor antagonists. Early Hum Dev 82: 23–28. 84 Gupta, A., Ghimire, G., and Hage, F.G. (2014). Guidelines in review: 2013 ACCF/AHA guideline for the management of heart failure. J Nucl Cardiol 21: 397–399. 85 Manson, J.M., Freyssinges, C., Ducrocq, M.B., and Stephenson, W.P. (1996). Postmarketing surveillance of lovastatin and simvastatin exposure during pregnancy. Reprod. Toxicol. (Elmsford, NY) 10: 439–446. 86 Kazmin, A., Garcia-Bournissen, F., and Koren, G. (2007). Risks of statin use during pregnancy: a systematic review. Journal of obstetrics and gynaecology Canada. J Obstet Gynecol Can: JOGC 29: 906–908. 87 Lecarpentier, E., Morel, O., Fournier, T. et al. (2012). Statins and pregnancy: between supposed risks and theoretical benefits. Drugs 72: 773– 788. 88 Godfrey, L.M., Erramouspe, J., and Cleveland, K.W. (2012). Teratogenic risk of statins in pregnancy. Ann Pharmacother 46: 1419–1424. 89 Karalis, D.G., Hill, A.N., Clifton, S., and Wild, R.A. (2016). The risks of statin use in pregnancy: a systematic review. J Clin Lipidol 10: 1081– 1090. 90 Yarrington, C.D., Valente, A.M., and Economy, K.E. (2015). Cardiovascular management in pregnancy: antithrombotic agents and antiplatelet agents. Circulation 132: 1354–1364. 91 Goland, S. and Elkayam, U. (2012). Anticoagulation in pregnancy. Cardiol Clin 30: 395–405. 92 Sanson, B.J., Lensing, A.W., Prins, M.H. et al. (1999). Safety of lowmolecular-weight heparin in pregnancy: a systematic review. Thromb Haemost 81: 668–672. 93 Imperiale, T.F. and Petrulis, A.S. (1991). A meta-analysis of low-dose aspirin for the prevention of pregnancy-induced hypertensive disease. JAMA 266: 260–264. 94 (1994). CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group. Lancet (London, England) 343: 619–629. 95 Rolnik, D.L., Wright, D., Poon, L.C. et al. (2017). Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med 377: 613–622.

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96 Sullebarger, J.T., Fontanet, H.L., Matar, F.A., and Singh, S.S. (2003). Percutaneous coronary intervention for myocardial infarction during pregnancy: a new trend? J Invasive Cardiol 15: 725–728. 97 Shah, P., Dzavik, V., Cusimano, R.J. et al. (2004). Spontaneous dissection of the left main coronary artery. Can J Cardiol 20: 815–818. 98 Martin, M., Romero, E., and Moris, C. (2003). Acute myocardial infarction during pregnancy. Treatment with clopidogrel. Med Clin 121: 278– 279. 99 Klinzing, P., Markert, U.R., Liesaus, K., and Peiker, G. (2001). Case report: successful pregnancy and delivery after myocardial infarction and essential thrombocythemia treated with clopidrogel. Clin Exp Obstet Gynecol 28: 215–216. 100 Nallamothu, B.K., Saint, M., Saint, S., and Mukherjee, D. (2005). Clinical problem-solving. Double jeopardy. N Engl J Med 353: 75–80. 101 Miller, R.K., Mace, K., Polliotti, B. et al. (2003). Marginal transfer of ReoPro (Abciximab) compared with immunoglobulin G (F105), inulin and water in the perfused human placenta in vitro. Placenta 24: 727– 738.

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102 Ecker, J.L. and Frigoletto, F.D. Jr. (2007). Cesarean delivery and the riskbenefit calculus. N Engl J Med 356: 885–888. 103 Martin, J.A., Hamilton, B.E., Osterman, M.J.K. et al. (2017). Final data for 2015. Natl Vital Stat Rep 66: 1–70. 104 Vinatier, D., Virelizier, S., Depret-Mosser, S. et al. (1994). Pregnancy after myocardial infarction. Eur J Obstet Gynecol Reprod Biol 56: 89–93. 105 Frenkel, Y., Barkai, G., Reisin, L. et al. (1991). Pregnancy after myocardial infarction: are we playing safe? Obstet Gynecol 77: 822–825. 106 Tedoldi, C.L. and Manfroi, W.C. (2000). Myocardial infarction and subsequent pregnancy. Arq Bras Cardiol 74: 347–350. 107 Janion-Sadowska, A., Sadowski, M., Zandecki, L. et al. (2014). Pregnancy after myocardial infarction and coronary artery bypass grafting – is it safe? Postepy w kardiologii interwencyjnej. Adv Interv Cardiol 10: 29–31. 108 Tweet, M.S., Hayes, S.N., Gulati, R. et al. (2015). Pregnancy after spontaneous coronary artery dissection: a case series. Ann Intern Med 162: 598–600.

CHAPTE R 15

Cardiac Arrhythmias and Pregnancy Danna Spears1,3 and Uri Elkayam2,3 1 Department

of Medicine, Division of Cardiology, University of Toronto, University Health Network, Toronto General Hospital, Toronto, Canada

2 Department

of Medicine, Division of Cardiovascular Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA

3 Department

of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA

Pregnancy is associated with an increased incidence of arrhythmias, which are the most common cardiac complication reported in women with and without structural heart disease [1,2]. A recent report in a large administrative data set from the United states has shown an increase in the frequency of arrhythmias in pregnancy from 2000 to 2012 [3], which was related to a 25% increase in pregnant women delivering with heart disease [4,5].

Palpitations Symptoms of palpitations are very common in pregnancy and a frequent reason for cardiac consultation and evaluation. Shotan et al. [1] evaluated 102 patients without evidence of heart disease referred for evaluation of palpitations, dizziness, and syncope and compared them to a control group of 52 patients referred for evaluation of precordial murmurs found to have no structural heart disease. Both groups had a high incidence (>50%) of arrhythmias with mostly atrial premature complexes (APCs) and ventricular premature complexes (VPCs). Rate of arrhythmias was multiple fold higher in symptomatic patient. There was however no correlation between the incidence of both VPCs and APCs and symptoms, and only 10% of the symptomatic episodes were accompanied by the presence of arrhythmias. Because of the extensive differential diagnosis of palpitation, careful clinical evaluation is essential to identify arrhythmia, confirm symptom–rhythm correlation, stratify risk, determine the hemodynamic impact, and exclude underlying precipitants. The first steps in the noninvasive evaluation of the pregnant patient with arrhythmia symptoms (palpitations, syncope, or presyncope) include resting 12-lead electrocardiogram (ECG) and ambulatory ECG monitoring (Holter monitor). When symptoms are sporadic and particularly when the index of suspicion for malignant arrhythmia is high, an implantable loop recorder may be considered [6,7]. If the patient already has an implanted rhythm management device, interrogation of the device may Cardiac Problems in Pregnancy, Fourth Edition. Edited by Uri Elkayam. © 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.

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provide useful diagnostic information [8–10]. Exercise stress testing can be considered in the setting of suspected exerciseinduced arrhythmia, in order to provoke the arrhythmia and to establish symptom–rhythm correlation [11]. Careful history-taking to elicit the details of a syncopal event is critical from a diagnostic perspective. Syncope, particularly in the absence of a prodrome, while supine or seated, or during physical exertion should always raise concern about a potential cardiac etiology. Vasovagal syncope, on the other hand, is more frequently situational, and typically accompanied by a prodrome that may include nausea, malaise, and diaphoresis (Chapter 25). Sinus arrhythmia is the most common disturbances of rhythm during pregnancy, identified in 69% of 49 healthy women [1]. Sinus arrhythmia (>100 bpm) was found in 10%, and sinus bradycardia (50% or dose 17 mg/kg or •100 mg q5 min IV until arrhythmia suppressed

Wide complex tachycardia

*Procainamide should be avoided if there is known underlying QT prolongation

Hemodynamically stable

Regular, monomorphic

Adenosine 6–12 mg IV push

Hemodynamically unstable

Irregular or not monomorphic or Uncertain

*Consider special cases: • Pre-excited AF: IV Procainamide • LQTS: Magnesium IV, β-blockade • Brugada syndrome: IV isoproterenol 2–10 mcg/min

Intravenous procainamide* or amiodarone IV amiodarone

Immediate cardioversion or defibrillation

Consider cardioversion

Long-term management of wide complex rhythms is likely to need specialist support. ICD should be considered for secondary prevention in unstable wide complex arrhythmias Figure 15.3 Management of wide complex arrhythmia in the pregnant patient.

Amiodarone can be used in cases of refractory arrhythmia not responding to first-line therapy [206]. Amiodarone can be used without increasing mortality in individuals with reduced ejection fraction [324]. Despite this, there is no clear mortality reduction associated with amiodarone use in the management of ventricular arrhythmias, and therapy with amiodarone should not preclude ICD implantation when indicated [323]. As discussed previously, amiodarone therapy is associated with extracardiac adverse effects, and in general, up to 10% of patients will require discontinuation of therapy [323]. Sotalol is an effective antiarrhythmic drug, but with no survival advantage [321]. In the setting of refractory ventricular fibrillation or VT storm, catheter ablation can be considered for management in select cases [325–328]. Polymorphic VT Acute management of PMVT should follow advanced cardiac life support (ACLS) guidelines (see cardiac arrest). Pharmacologic management depends on the underlying etiology and the presence or absence of baseline QT prolongation (see LQTS management). In the absence of congenital or acquired LQTS, important causes of PMVT include ischemia and inherited arrhythmia conditions such as catecholaminergic polymorphic ventricular tachycardia (CPVT) and Brugada syndrome (see CPVT, Brugada syndrome).

Ventricular arrhythmias secondary to myocardial ischemia can be temporized with β-blockade, but revascularization should be pursued immediately [303]. Amiodarone may be effective in treatment of PMVT in the absence of baseline QRS prolongation, but magnesium is unlikely to be effective [303]. Arrhythmia induced cardiomyopathy Persistent atrial or ventricular arrhythmias can result in reversible left ventricular dysfunction [230]. Persistent arrhythmia can be the sole cause of systolic dysfunction, or it can exacerbate an existing cardiomyopathy [329]. The incidence of arrhythmia-induced cardiomyopathy ranges from 8.3–10% in adults with focal atrial tachycardia to 9–34% in the setting of frequent PVCs or nonsustained VT [330–332]. Chronic, persistent tachycardia results in adverse left ventricular remodeling, neurohormonal activation, chamber dilatation, and contractile dysfunction in a predictable manner over time [173]. The development of arrhythmia induced cardiomyopathy is more common in persistent arrhythmias, particularly if they are initially well-tolerated, as medical intervention is less likely to be sought [333]. Intermittent tachycardias, particularly those with lower rates during sleep, such as IST and POTS, are not implicated in arrhythmiainduced cardiomyopathy [172,333–335]. There is no clear

CHAPTER 15 Cardiac Arrhythmias and Pregnancy

cutoff for the heart rate at which arrhythmia-induced cardiomyopathy develops, and it is likely that multiple factors contribute to an individual’s vulnerability. A sustained heart rate >100 bpm on Holter monitoring should raise the suspicion for underlying arrhythmia-induced cardiomyopathy. In the setting of frequent PVCs (>10 000/24 hours), the prevalence of arrhythmia-induced cardiomyopathy is as high as 34% [172]. Control of ventricular rate or underlying rhythm with medical therapy, or, in refractory cases, catheter ablation, can result in significant improvement of left ventricular function [333,336,337]. Aggressive arrhythmia management should be undertaken immediately upon recognition of arrhythmia-induced cardiomyopathy to maximize the potential for recovery [329].

Cardiac arrest Cardiac arrest is rare in pregnancy with an incidence of 0.006–0.008% [12,338]. Cardiac symptoms such as chest pain, shortness of breath, syncope, dizziness, or palpitations precede cardiac arrest in a substantial number of cases (37.5%) [339]. It is important to recognize women who are potentially at elevated risk and to have an understanding of the physiologic changes of pregnancy that may impact the efficacy of resuscitation and create potential for complications (Chapter 1). Arrhythmia events causing cardiac arrest are extremely uncommon in pregnancy, and the underlying etiology is typically another catastrophic complication of pregnancy or labor and delivery, underlying comorbidity, or profound vasovagal stimuli [12,338,340,341]. When considering the primary cardiovascular causes of sudden death, leading causes include sudden arrhythmia syndromes (53.8%), cardiomyopathy (13.8%), aortic dissection (8.8%), CHD (2.5%), and valvular disease (3.8%) [339]. Evaluation for these potential underlying etiologies must be undertaken in the survivor of cardiac arrest after stabilization. Coronary anatomy should always be considered in the setting of resuscitated cardiac arrest or life-threatening ventricular arrhythmias, particularly in women over the age of 40 years or those with anatomy associated with a higher risk of coronary ischemia, such as anomalous coronary arteries, coronary AV fistulae, prior coronary surgery, or the presence of vascular conduits or stents that may compress the coronary vasculature [342,343]. Pregnancy-related spontaneous coronary artery dissection (p-SCAD) should always be considered with a severe presentation such as ST segment elevation myocardial infarction, heart failure, or left main/multivessel coronary ischemia. Women with pregnancy-associated SCAD often do not have classic atherosclerotic risk factors or extra coronary vascular abnormalities and may have a history of multiple pregnancies or older age at the time of first childbirth [260,282]. Obstetric units should have a clear plan for management of cardiac arrest during pregnancy, as well as a delivery and neonatal management plan in the event of a maternal cardiac

233

arrest. First responders must recognize the importance of determining hemodynamic stability, presence or absence of a palpable pulse, and to initiate resuscitation measures rapidly. This includes provision of chest compressions, ideally with the placement of a backboard or on another hard surface, airway management, rapid assessment for need of defibrillation, and manual left uterine displacement (LUD) (Chapter 29) [344,345]. The pregnant patient is more vulnerable to hypoxemia [346] and to hemodynamic compromise secondary to aortocaval compression in the supine position [347,348]. Placement in the left lateral position increases ejection fraction and stroke volume, but it is not ideal for resuscitative efforts [349]. Manual LUD has been shown to benefit circulatory hemodynamics in no-arrest situations [350]. Because of potentially compromised venous return from the lower extremities, intravenous access should be obtained above the diaphragm when possible [345]. In situations where immediate delivery is considered to be the most effective way to manage maternal crisis, cesarean delivery, when possible, should be undertaken at the site of cardiac arrest, to avoid delays due to transportation and further maternal deterioration [351]. Defibrillation is the most important intervention to maximize chances of survival in the setting of ventricular fibrillation or pulseless VT, and this should be carried out in a manner similar to that in the nonpregnant state [352]. Defibrillator pad placement is similar to standard ACLS protocols, but care should be taken to apply the lateral pad to the chest wall, under breast tissue [353]. The presence or absence of fetal monitors should not deter rapid defibrillation [344]. Minimal energy from defibrillation is expected to be delivered to the fetus, and defibrillation is advised when indicated in all stages of pregnancy, with no need for deviation from established ACLS guidelines [344]. Airway management and oxygenation are essential components of resuscitation efforts as the pregnant patient is more vulnerable to hypoxemia, and hypoxemia should always be considered as a potential cause of cardiac arrest in pregnancy [346]. ACLS algorithms recommend postmortem cesarean delivery if a spontaneous return of circulation has not occurred four minutes after onset of cardiac arrest, if the uterus extends to or above the umbilicus [344]. For ventricular arrhythmias that are not responsive to defibrillation, medical therapy should be initiated, and amiodarone bolus administered intravenously is considered the first-line agent [206]. This has been shown to have greater efficacy than lidocaine administration [354,355]. No therapy should be withheld out of concern for fetal teratogenicity [345]. Recommendations regarding targeted maintenance of constant temperature between 32 and 36 °C after return of spontaneous circulation should be individualized, given the theoretical risk of inducing coagulopathy [345,356,357]. ICD therapy for secondary prevention is indicated in all survivors of cardiac arrest [206]. Prophylactic therapy with β-blockers or class III antiarrhythmic drugs (amiodarone, ibutilide, sotalol) may reduce arrhythmia episodes but is not adequate preventive therapy without ICD implantation [229].

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ICD therapy Detailed guidelines governing ICD implantation have been published [358,359]. In the presence of structural heart disease, any spontaneous sustained VT, irrespective of hemodynamic stability, or syncope that is felt to be likely arrhythmic in origin, ICD implantation is recommended [358]. Ejection fraction remains an important risk marker for arrhythmic death in the current guidelines, and in the setting of nonischemic cardiomyopathy with ejection fraction ≤35%, ICD implantation is recommended, if recovery of systolic function is not expected [358]. For more preserved LV function, there is a role for diagnostic electrophysiology study to assist with risk stratification in select cases [360–362]. Electrophysiology studies, if indicated, should be postponed until after delivery. In some cases, it is also reasonable to strongly consider ICD implantation in women with sustained VT and normal or near-normal LV function [358,363]. ICD therapy is also indicated in the setting of moderate to severe left ventricular dysfunction that is not expected to recover. ICD implantation is indicated for secondary prevention of sudden cardiac death and ventricular arrhythmia, in patients with documented VF or hemodynamically unstable VT in the absence of reversible causes [206]. Potential reversible causes include electrolyte abnormalities, drug or toxin exposure, and acute ischemia. ICD implantation can also be considered in women with normal LV function who have recurrent sustained VT, without hemodynamic instability [206]. Subcutaneous ICD may be considered as an alternative to transvenous ICD in women who do not need pacing support, cardiac resynchronization therapy (CRT), or antitachycardia pacing as part of their rhythm management strategy [206]. The indications for ICD implantation for primary or secondary arrhythmia management are not altered by pregnancy. With very few exceptions, these recommendations should be followed to identify pregnant women at elevated risk of life-threatening arrhythmias who should be offered an implantable defibrillator. Pregnancy should never preclude ICD implantation when indicated, in the outpatient setting, or when continuous in-hospital rhythm monitoring is not needed or possible [358,364]. However, in the pregnant patient, any uncertainty regarding indication for permanent ICD implantation or potential reversibility of their arrhythmia state should prompt careful review and admission for arrhythmia monitoring. Gestational age may influence timing of ICD implantation. In later stages of pregnancy, it may be more practical for a woman to be monitored with a LifeVest wearable defibrillator or admitted for telemetry monitoring and ICD implantation postpartum. Catheter ablation Catheter ablation may be considered in refractory arrhythmias that are poorly tolerated. Advances in catheter ablation technique have reduced radiation exposure times, and many arrhythmias can be safely ablated with the use of complex mapping systems with no radiation exposure [71,117,

315,365–369]. The potential for radiation exposure must be considered and discussed in all circumstances, however, and if possible, ablation postponed until the second trimester to minimize the risk to the fetus. Lead shielding can reduce the dose of radiation to the fetus, but does not eliminate exposure [370].

Bradyarrhythmias Sinus bradycardia is typically secondary to vagal tone, such as with the Valsalva maneuver during labor and delivery, or the supine hypotensive syndrome of pregnancy caused by uterine compression of the inferior vena cava [125]. This can typically be managed with repositioning to the left lateral decubitus position. Pacemaker implantation is rarely needed, if symptoms are persistent [196]. Bradyarrhythmias are rare in women of child-bearing age, with a prevalence of 1/20 000 [371–373]. First-degree AV block can be seen in the absence of conducting system pathology, without risk of progression to high-grade AV block [125]. Second degree AV block is less common. Second-degree AV block type 1, also known as Mobitz 1 or Wenckebach block, is also seen in conditions associated with higher vagal tone and is benign, without a significant risk of progression to high-grade AV block [125]. The hallmark of this type of AV block is progressive lengthening of the PR interval prior to conduction block. Type 2 second-degree AV block, however is more likely associated with distal conducting system disease and is most often seen in repaired CHD, particularly AV canal defect, Tetralogy of Fallot, or VSD repair [374]. The hallmark of this type of AV block is failure of AV conduction without preceding PR prolongation. Although higher vagal tone or vasovagal episodes can also cause transient high-grade AV block, it is rare in pregnancy, and is typically a manifestation of previously unrecognized congenital AV block [12]. There are many causes of complete AV block, which may present in a woman of child-bearing age. The most common etiology is previously unrecognized congenital heart block. Other potential causes include structural CHD, myocardial ischemia, nonischemic cardiomyopathy, idiopathic degenerative disease, infection, autoimmune disorders, infiltrative processes, and iatrogenic causes [375]. Pregnancy has no clear association with development of conducting system disease [376]. Up to 30% of cases of congenital AV block are diagnosed in adulthood, and the first recognition may be in pregnancy [377,378]. Isolated congenital AV block with a narrow QRS escape rhythm is typically asymptomatic and pacing during pregnancy is not indicated [358]. Permanent pacing is indicated in congenital AV block associated with a wide QRS escape, complex ventricular ectopy, or left ventricular dysfunction. In cases of symptomatic bradyarrhythmia or other strong indications for permanent pacing, pregnancy should not preclude pacemaker implantation [125]. A subset of asymptomatic women with congenital AV block will become symptomatic, or may

CHAPTER 15 Cardiac Arrhythmias and Pregnancy

235

Persistent bradycardia

Hemodynamically stable

Hemodynamically unstable

Sinus bradycardia First degree AV block Second degree AV block, type 1

Second degree AV block, type 2

Elevated vagal tone, or uterine compression of the inferior vena cava

Third degree AV block, other high grade AV block

Associated neuromuscular disease

Temporary transvenous pacing

Narrow QRS escape complexes, asymptomatic

OR Noted during exercise Manage conservatively / reposition to left lateral decubitus position

OR

Periodic Holter monitor, echocardiogram

Associated bifascicular block OR

Symptoms or complex congenital heart disease with persistent heart rate 96% of the patients). Long-term follow-up was not available for seven patients treated during the initial four years of our data collection, although they were known to be alive and well at two years after delivery of their child. There were a total of eight deaths reported during the past 12 years in this population (Table 16.2). Four patients died from progression of their primary autoimmune disease, and three died from congenital heart disease while awaiting a heart-lung transplant. The last patient died from progression of disease and complications of connective tissue disease (lupus). Importantly, no patients died during pregnancy or within 18 months after delivery. Furthermore, none of the patients were known to have died from complications of the pregnancy or PAH during the 16-year period.

Protocol design Our protocol for successful medical management of pregnant women with PAH was a result of the cooperation of all parties involved. A multidisciplinary meeting to develop an individualized “care plan” occurs as early as possible, at a minimum two weeks before the planned delivery, and that plan is revised as necessary. The lead registered nurse in the highrisk obstetrics clinic designs and maintains the care plan. The care plan is placed in the patient record, so all providers can access it at any time, including the emergency department. Meetings are usually held for 30 minutes over a noon hour, start and end on time, and participants can attend in person or by “phone call-in” to the conference room. The call-in option has resulted in much better attendance and information input, as a call to the conference number can be made from anywhere. Care of the mother is the focus throughout the pregnancy. A thorough discussion of whether termination versus continuation of the pregnancy is appropriate and essential. Most of these patients already know what they want to do before they arrive in our office. A termination of pregnancy is contraindicated if the mother is in acute right heart failure. She would need to be stabilized before termination occurs.

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Most of these patients are hemodynamically compromised and have deteriorated prior to the initial evaluation. If the decision is to proceed with pregnancy, then immediate initiation of aggressive PAH therapy is essential. Most often, it is best to initiate these medications as an inpatient. This will also allow the complete medical evaluation/diagnostic testing to be finished efficiently (PHAssociation.org; “clinical evaluation”). If there are any clinical signs of right heart failure or the echocardiographic findings demonstrate reduced RV function, the mother should be started on intravenous prostacyclin immediately. Medications utilized for treatment of PAH in pregnancy have expanded as various pharmacologic agents have come to market. Although none of the PAH medications are “indicated in pregnancy,” only a few are “contraindicated.” Thus far, endothelin receptor antagonist and soluble guanylate cyclase stimulator medications are contraindicated during pregnancy (potential teratogenicity). Furthermore, in pregnant women with PAH and significant right heart dysfunction, calcium channel blocking agents are contraindicated because of their negative inotropic activity. We have now treated five patients who became pregnant while being treated with an Endothelian Receptor Blocker and one patient treated with an SGC medication during the first three months of pregnancy. After thorough counseling, all six patients chose to continue their pregnancies to delivery at 36 weeks of gestation (early delivery secondary to Pulmonary Arterial Hypertension). Follow-up of these six patients demonstrated no birth defects with category X exposure during the first trimester of pregnancy. The medications utilized in our treatment plans have included the drugs listed in Table 16.3. Intravenous prostacyclins were the mainstay for pharmacologic treatment, with aggressive up-titration as tolerated by the patient. Phosphodiesterase 5 inhibitors were used regularly (sildenafil and tadalafil) as supplemental combination pharmacologic therapy for many of the patients. To date, our population has had no reported unexpected late-stage spontaneous abortions, no in-utero deaths, and no birth defects. Breast-feeding is not permitted, as all the PAH medications are believed to enter the breast milk. Throughout the pregnancy, the cardiologist must continually assess the RV function. A complete baseline ECHO, with a bubble study, is performed at the first visit, and a limited right heart ECHO is completed at every clinic visit thereafter. All ECHO studies include the proximal inferior vena cava and part of the first hepatic vein in order to accurately assess the volume status. The right heart catheterization is performed as soon as possible to assist with the pharmacologic management. The normal CO in a pregnant woman is always elevated; in fact, it should reach a norm of 8 l/min by the third trimester. Additionally, it is normal for the RV to appear mildly dilated, but with normal function (for the pregnant state) throughout the pregnancy. The sooner RV function is normalized by PAH medications (to expected level in pregnancy) and maintenance

Table 16.3 Pharmacologic agents used in pregnant patients with PAH at our center Inhaled vasodilators Nitric oxide Epoprostenol (Flolan, Veletri) Treprostinil (Tyvaso) Intravenous prostacyclins IV Epoprostenol Flolan (early years) Veletri (more recently) IV Treprostinil Remodulin Oral prostacyclins Orenitram (Treprostinil Oral) Selexipag (Uptravi) Calcium channel blocker Nifedipine (Procardia) Amlodipine (Norvasc) Diuretics Furosemide (Lasix) Torsemide (Demadex) Bumetanide (Bumex)

Inotropic agents Dobutamine (Dobutrex) Digoxin (Lanoxin) Dopamine Antiarrhythmic (A-Fib) Diltiazem (Cardizem) Amiodarone (Cordarone) Digoxin (Lanoxin)

PDE-5 Sildenafil (Revatio) Tadalafil (Adcirca) Anticoagulants Warfarin (Coumadin) Enoxaparin (Lovenox) Other Potassium chloride Magnesium

Data presented as drug name (common brand name/s). Caution: Not recommended in pregnancy secondary to teratogenicity: r SGC drugs (Adempas) r ERA drugs (Letaris, Macitentan, Tracleer). A-Fib – atrial fibrillation; ERA – endothelin receptor antagonists; PAH – pulmonary arterial hypertension; SGC – soluble guanylate cyclase.

of euvolemia, the lower the risk for the mother and baby will be. If there is a decline in the RV function at any time during pregnancy, the cardiologist must immediately provide the necessary treatment. No delivery plan should be implemented until the RV function is improved prior to the induction of labor or cesarean section unless the infant is in distress, or there is no other option. The usual reason for destabilization as an outpatient is excess sodium and fluid intake. Significant RV failure/dysfunction in the mother may warrant admission to the intensive care unit. The physiologic approach to management of right heart failure is similar to that of the left heart failure: (1) selection of drugs or procedures to lower the preload (diuretics usually by continuous infusion and/or mechanical water removal–gradually and continuously remove the water, allowing it to move from interstitial spaces to the intravascular space); (2) inotrope therapy (low-dose dobutamine is best owing to the high population of fast-twitch muscles in the RV). Titrate the dose so as to not increase the heart beat more than 20 bpm from the mother’s baseline (usually 1–3 mcg/kg/min); and (3) afterload reduction for the RV (inhaled prostacyclin or nitric oxide acutely and intravenous prostacyclin with a

CHAPTER 16 Pulmonary Arterial Hypertension and Pregnancy

slow titration upward as tolerated). The mother should be hemodynamically stable and on a drug regimen before being discharged from the hospital. A follow-up should occur within one to two weeks and usually includes appropriate labs, a record of daily home weights, and a limited right heart ECHO. If the mother is stable, clinic visits then occur monthly until about the 32nd week, after which she is seen every two weeks until delivery. Concerning times during pregnancy for increased water retention are weeks 16–18, 26–28, and 32–34 (when fluid shifts occur). Significant teaching, with an emphasis on dietary changes (2000 mg sodium and 2000 cc fluid restriction) is done by the obstetric and PAH clinics’ registered nurses. These patients need to have ready access to the obstetric and PAH office staffs for questions or issues if they arise between clinic appointment times. The method of preferred delivery is vaginal. An epidural anesthetic is mandated and started as soon as regular contractions are occurring. Delivery is usually completed in the intensive care unit, with the labor and delivery staff and the intensive care unit nursing staff in attendance. The anesthesiologist estimates the volumes in and out during the delivery, and a Foley catheter is placed for accurate intake and output for the next 48–72 hours after delivery. The intensive care unit nurses are asked to maintain a “cumulative 72-hour intake/output” on a clipboard and treat any decrease in 4-hour output intervals with 20–40 mg of intravenous furosemide, as needed to maintain a negative net output of 2 l by 24 hours, negative net 4 l cumulative by 48 hours, and negative net 6–7 l cumulative by 72 hours. This total volume will be 2–3 l less if the patient was hospitalized predelivery for volume management. If a cesarean section is performed, there will be some degree of ileus on postoperative day 1, and there will only be 1-l net negative in the first 24 hours, with it taking an additional day to optimize the intravascular volume. At the time of discharge, most women are placed on a maintenance dose of oral diuretics to maintain an ideal volume status optimized. Outpatient office follow-up after delivery is at one week, three weeks, and seven weeks postdischarge. A limited right heart ECHO is performed one month after hospital discharge (unless indicated sooner). Follow-up thereafter is individualized and based on the severity of the PAH. Long-term pregnancy prevention plans are discussed early and implemented at hospital discharge.

Conclusions While our data are nonrandomized, retrospective over three decades, and subject to referral bias, they do represent the largest single cohort of pregnant PAH patients. Some important observations are worthy of highlighting. First, 94% of patients were diagnosed with PAH after becoming pregnant, and mostly in the late second or early third trimester (mean 17.3 weeks gestation, range 8–29 weeks) when most hemodynamic changes affecting PAH would be expected to

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have occurred. Second, while symptoms of pregnancy may overlap with PAH, the presence of presyncope or syncope and chest discomfort with exercise should raise the index of suspicion and warrant immediate diagnostic evaluation. Third, enrollment in a multidisciplinary program, standard diagnostic evaluation, and clinical follow-up, and the early clinical aggressive use of prostinoid-based medical therapies are the mainstay to assure optimal maternal and fetal outcome. Three decades of experience has broadened our understanding of the pathophysiology of pregnancy, as well as the treatment options for PAH. In 2018, we have 14 approved medications for the treatment of PAH applied to a broad patient demographic base, and our program has 16 years of cumulative experience for pregnant women with PAH. The outcome data were similar in the United States, as well as in foreign locations. In 170 pregnant women who delivered 186 children, we observed no fetal or maternal mortality. Our program incorporated a multidisciplinary approach, structured clinical assessments, early initiation of prostinoid PAH therapies, nurse-driven education through a formal PAH program, and controlled labor and delivery within the confines of a high-risk obstetrics environment to optimize outcome. We believe that women with PAH who become pregnant should not have an automatic recommendation to terminate pregnancy; rather, they should be offered evaluation and care with an experienced program to make an informed decision regarding their plan for pregnancy. Our data should lend credence to the safety of structured care of pregnant women with PAH. Our data have been reproducible at 54 institutions in the United States and foreign countries (Figure 16.3), with assistance from Dr Zwicke and her team via internet and telephone. A total of 79 of the infants (of a total of 186) were born at our center in Milwaukee, Wisconsin, USA. It is hoped that our data will spur new research initiatives. We had 18 additional pregnancies with the mothers having significant PAH diagnosed during their pregnancy. All 18 patients delivered without complications or other issues. Their profile was similar to most other patients. They received treatment similar to other patients, with the mainstay of treatment being continuous intravenous Remodulin, plus another drug (most frequently used oral drug was Tadalafil). This brought the total number of patients we treated and successfully delivered to 193, as of April of 2019. The second piece of “new” information was to report exposure to Endothelin Receptor antagonists during pregnancy (ERA’s during the first trimester of pregnancy). There were eight patients who had unplanned ERA exposure greater than four weeks during the first trimester of pregnancy. All of the mothers were converted to infusion of prostacyclin, as the ERA therapy needed to be rapidly discontinued and the new therapy rapidly put in place, without further shifts in the treatment plan. None of the ERA exposed babies had birth defects, followed for at least two years.

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Acknowledgments The authors thank Obstetrical Anesthesiologist Robert Fish, M.D., Ricardo Mastrolia, M.D. (High-Risk Maternal Fetal Medicine), Sarah Nahn, R.N., (High-Risk Maternal Fetal Medicine), and the entire staff of the Pulmonary Hypertension Clinic at Aurora St. Luke’s for their contributions to the content, Patricia Maglio for secretarial services, Jennifer Pfaff and Susan Nord of Aurora Cardiovascular Services for editorial preparation of the manuscript, and Brian Miller and Brian Schurrer of Aurora Research Institute for assistance with the figures.

References 1 Bassily-Marcus, A.M., Yuan, C., Oropello, J. et al. (2012). Pulmonary hypertension in pregnancy: critical care management. Pulm Med 2012: 709407. 2 Bonnin, M., Mercier, F.J., Sitbon, O. et al. (2005). Severe pulmonary hypertension during pregnancy: mode of delivery and anesthetic management of 15 consecutive cases. Anesthesiology 102: 1133–1137; discussion 1135A–1136A. 3 Easterling, T.R., Ralph, D.D., and Schmucker, B.C. (1999). Pulmonary hypertension in pregnancy: treatment with pulmonary vasodilators. Obstet Gynecol 93: 494–498. 4 Gleicher, N., Midwall, J., Hochberger, D., and Jaffin, H. (1979). Eisenmenger’s syndrome and pregnancy. Obstet Gynecol Surv 34: 721–741. 5 Hsu, C.H., Gomberg-Maitland, M., Glassner, C., and Chen, J.H. (2011). The management of pregnancy and pregnancy-related medical conditions in pulmonary arterial hypertension patients. Int J Clin Pract Suppl 6–14. 6 Olsson, K.M. and Channick, R. (2016). Pregnancy in pulmonary arterial hypertension. Eur Respir Rev 25: 431–437. 7 Weiss, B.M., Zemp, L., Seifert, B., and Hess, O.M. (1998). Outcome of pulmonary vascular disease in pregnancy: a systematic overview from 1978 through 1996. J Am Coll Cardiol 31: 1650–1657. 8 Wong, P.S., Constantinides, S., Kanellopoulos, V. et al. (2001). Primary pulmonary hypertension in pregnancy. J R Soc Med 94: 523–525. 9 Bedard, E., Dimopoulos, K., and Gatzoulis, M.A. (2009). Has there been any progress made on pregnancy outcomes among women with pulmonary arterial hypertension? Eur Heart J 30: 256–265. 10 Benoit, L., Nizard, J., Radojevic, J. et al. (2016). Pregnancy outcomes in Eisenmenger syndrome: a French multicentric cohort study. Eur J Obstet Gynecol Reprod Biol 206: e135–e136.

11 Duarte, A.G., Thomas, S., Safdar, Z. et al. (2013). Management of pulmonary arterial hypertension during pregnancy: a retrospective, multicenter experience. Chest 143: 1330–1336. 12 Jais, X., Olsson, K.M., Barbera, J.A. et al. (2012). Pregnancy outcomes in pulmonary arterial hypertension in the modern management era. Eur Respir J 40: 881–885. 13 Katsuragi, S., Yamanaka, K., Neki, R. et al. (2012). Maternal outcome in pregnancy complicated with pulmonary arterial hypertension. Circ J 76: 2249–2254. 14 Kiely, D.G., Condliffe, R., Webster, V. et al. (2010). Improved survival in pregnancy and pulmonary hypertension using a multiprofessional approach. BJOG 117: 565–574. 15 Meng, M.L., Landau, R., Viktorsdottir, O. et al. (2017). Pulmonary hypertension in pregnancy: a report of 49 cases at four tertiary North American sites. Obstet Gynecol 129: 511–520. 16 Elwing, J.M. and Panos, R.J. (2011). Pregnancy and pulmonary arterial hypertension. In: Pulmonary Hypertension – From Bench Research to Clinical Challenges Rijeka (ed. R. Sulica and I. Preston), 289–304. Croatia: InTech. 17 Madden, B.P. (2009). Pulmonary hypertension and pregnancy. Int J Obstet Anesth 18: 156–164. 18 Zwicke, D.L., Buggy, B.P., and Evans, W. (2003). Successful management of pregnancy in six patients with pulmonary arterial hypertension (PAH) (abstract). Chest 124: 89S. 19 Zwicke, D.L. and Buggy, B.P. (2008). Pregnancy and pulmonary arterial hypertension: successful management of 37 consecutive patients (abstract). Chest 134: S64002. 20 Zwicke, D.L., Paulus, S., and Mastriolia, R. (2016). Successful delivery of elective pregnancies in women with pulmonary arterial hypertension. International Congress on Cardiac Problems in Pregnancy, Las Vegas, Nevada. 21 Zwicke, D.L., Paulus, S., and Mastriolia, R. (2016). Contemporary approach to pulmonary hypertension in pregnancy. International Congress of Cardiac Problems in Pregnancy, Las Vegas, Nevada. 22 Zwicke, D.L. (2011). PAH and pregnancy: physiologic changes, challenges, and outcomes. Adv Pulm Hypertens 10 (3): 181–189. 23 Hemnes, A.R., Kiely, D.G., Cockrill, B.A. et al. (2015). Statement on pregnancy in pulmonary hypertension from the Pulmonary Vascular Research Institute. Pulm Circ 5: 435–465. 24 Roberts, N.V. and Keast, P.J. (1990). Pulmonary hypertension and pregnancy–a lethal combination. Anaesth Intensive Care 18: 366– 374. 25 Parneix, M., Fanou, L., Morau, E., and Colson, P. (2009). Low-dose combined spinal-epidural anaesthesia for caesarean section in a patient with Eisenmenger’s syndrome. Int J Obstet Anesth 18: 81–84.

CHAP T E R 17

Infective Endocarditis Ramin Ebrahimi1,2 , Michael Shenoda3 , Sheila Sahni1,2 , and David Fisk4 1 Department

of Medicine, University of California, Los Angeles, CA, USA

2 Department

of Cardiology, Veteran Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA

3 Department

of Cardiology, Sansum Clinic, Santa Barbara, CA, USA

4 Department

of Infectious Diseases, Sansum Clinic, Santa Barbara, CA, USA

Infective endocarditis (IE) is a rare occurrence during pregnancy [1–7]. The incidence of IE is estimated to be 0.006% of all pregnancies [8] and 0.55–0.9% in those with preexisting cardiac disease [9]. Approximately, 75 cases of peripartum IE have been reported in the literature over the past several decades some of which have had devastating consequences for the mothers and/or fetuses [10,11]. Mortality from IE in pregnant women has been reported to be approximately 22–33% with concomitant fetal death in 14–29% of cases [8]. Early diagnosis is therefore critical. Management of pregnant women with IE is similar to the treatment of IE in nonpregnant patients, with the additional challenge of balancing the risk of treatment with fetal and maternal outcomes.

Predisposing factors Structural heart disease remains the most common substrate for IE predisposition in pregnancy, accounting for approximately three-fourths of IE cases [12,13] and in 74% of cases occurring during pregnancy [14]. Historically, in the 1970s and 1980s, rheumatic heart disease (RHD) was the most common structural cardiac abnormality predisposing to IE and accounted for up to 25% of all cases [15]. The gender predominance of RHD in women is the reason why it was the main predisposing condition for IE during pregnancy [15]. However, this is now less commonly observed given the decline in RHD prevalence over the past few decades. Mitral valve prolapse (MVP) with associated mitral regurgitation has now become a more common risk factor for IE. MVP accounts for 7–30% of native valve endocarditis, which given its 2 : 1 female to male ratio, is an important underlying condition predisposing pregnant women to IE [1,8,10,16–21]. While the incidence of IE has remained unchanged for the general population, an increased incidence in the congenital heart disease (CHD) population has been observed [22]. Congenital heart defects now account for 10–20% of IE in young adults [15]. Recent advancements in surgical and percutaneous correction of congenital heart abnormalities

has led to a greater proportion of women with CHD reaching childbearing age [22]. Bicuspid aortic valves are the most common congenital anomaly found in pregnant women with IE. Dental procedures and periodontal disease are the most common etiologic sources of infection for pregnant women with CHD. Viridans streptococci are the most common causative agents, followed by staphylococci, and more recently, Propionibacterium acnes [22,23]. An emphasis on education and prevention is essential for this group of individuals, in order to promote dental surveillance and hygiene [22]. A prosthetic heart valve is a notable risk factor for the development of IE. As the number of percutaneous and surgical valve replacements increases each year, prosthetic heart valves are being seen more among women of childbearing age, which increases their predisposition for IE during pregnancy. Similarly, as the number of intracardiac device implants grows (i.e. atrial septal occluder device, patent foramen ovale occluder, ventricular septal defect occluders, patent ductus arteriosus occluder, transcatheter aortic valve, percutaneous mitral valve repair with MitraClip™), this will also evolve as a prominent risk factor for IE in pregnancy. Although valvular heart disease is the most common substrate in patients with IE, normal cardiac valves are not immune to infection. Surveys of endocarditis in obstetric and gynecological patients have shown that approximately 21% of IE cases involve normal valves [14]. Intravenous drug abuse is a well-established and prominent risk factor for the development of IE in pregnancy, with a propensity for right-sided heart valves. Intravenous cocaine and heroin appear to confer a higher risk of developing endocarditis over other recreational drugs [8,24–27]. Lastly, a previous history of IE is a strong risk factor for the development of IE during pregnancy [23]. A variety of diagnostic and therapeutic procedures may result in bacteremia that can lead to IE, especially during pregnancy. These include dental, genitourinary, and

Cardiac Problems in Pregnancy, Fourth Edition. Edited by Uri Elkayam. © 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.

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gastrointestinal procedures [28]. Obstetric and gynecologic procedures have been reported to be the cause in approximately 26% of the cases with IE in females [5,29]. Pregnancyrelated bacteremia may occur following abortion, vaginal delivery with manual removal of the placenta, curettage, implantation of infected intrauterine contraception devices, pelvic infection, and caesarian section [29–31]. Although IE following a normal pregnancy has been reported, it is relatively rare. One survey found that IE occurring during pregnancy accounted for 49% of cases seen in the obstetric and gynecologic setting, followed by IE after abortion (25% of cases), IE during the puerperium after vaginal delivery (16%), and IE after cesarean section (2%) [14,32]. In addition, the placement of intravascular devices (central venous lines, tunneled lines, and hemodialysis catheters) also increases the risk of developing IE, although the incidence of the health-care associated IE during pregnancy is unclear.

Microbiology Streptococcal infection remains the most common pathogen responsible for IE during pregnancy [8,25,33–36]. In 1986, one survey found that viridans streptococci accounted for 30% of IE cases found in the obstetrics and gynecology setting, followed by Enterococcus spp. (17%), Staphylococcus aureus (13%), and Streptococcus agalactiae (7%) [14]. However, over the past 30 years, the second most common genus has shifted from Enterococcus to S. aureus [23,37]. A systematic review from 1988 to 2013 included 90 cases of peripartum IE which identified streptococcal infection in 43% of cases and staphylococcal infection in 26% of cases. This finding is consistent with the temporal trend of IE in a community-based population study that found streptococcal species to be the leading cause of IE followed by staphylococcal species [38]. Furthermore, a greater number of leftsided cases were caused by streptococcal species and a greater number of right-sided cases were caused by staphylococcal species. Infection with viridans streptococci, the dominant group of the oral flora, is often subacute with symptoms occurring from weeks to months before diagnosis [39]. This streptococcal group has a high predilection for abnormal valves, which was seen in 89% of the surveyed cases [14]. However, a patient may present with an acute fulminant picture secondary to disease complications, such as valvular rupture or congestive heart failure [40]. S. aureus causes an acute form of IE with a short prodrome of symptoms for days to weeks and has a predilection for normal valves that has been seen in 55% of the cases. Enterococcus spp. has a particularly high occurrence in IE after abortions, accounting for 36% of such cases in one survey [14]. Similar to viridans streptococci, these bacteria typically cause a subacute infection but have a greater ability to infect normal valves, seen in up to 25% of the cases [14].

The β-hemolytic streptococci, especially S. agalactiae [41] also known as group B streptococcus (GBS) is also known to cause an acute IE. In the preantibiotic era, IE caused by GBS was almost exclusively seen in pregnant women and had near universal fatality. Although GBS still classically presents as an acute endocarditis with large, friable vegetations, rapid destruction of heart valves, and early emboli, its mortality has dropped to 36% in more recent surveys [42]. Overall, GBS is a less common cause of endocarditis, with a reported incidence of 1.7% [42], although it accounts for 10% of invasive GBS infections and the majority (68%) of IE caused by the β-hemolytic streptococci [43]. Although GBS is established as an emerging pathogen in adults, limited data available suggests that it is not increasing as a relative cause of endocarditis in pregnancy perhaps due to prenatal screening programs [44]. One survey identified this pathogen in 7% of IE in the obstetric and gynecologic setting [14]. Numerous cases in the literature have reported IE due to GBS infections in both normal and premature vaginal deliveries as well as elective abortions [45]. Similar to S. aureus, this bacterium is also noteworthy in its ability to infect normal valves, as seen in 64–71% of cases [14,46]. Rarely other bacteria have been reported to cause endocarditis during pregnancy, including Pseudomonas aeruginosa [46], Listeria monocytogenes [47], Salmonella enteritidis [48], Haemophilus aphrophilus [49], Chlamydia trachomatis [50], Moraxella catarrhalis [51], Cardiobacterium hominis [52], and Mima polymorpha [53]. Although disseminated infection by Neisseria gonorrhea is most commonly described in women during pregnancy or menses, only a few cases of gonococcal endocarditis have been reported in the literature [39]. In patients with a history of intravenous drug usage, S. aureus with possible methicillin resistance is the predominant organism, although unusual Gram-negative and polymicrobial infections may also occur, as can infection with Candida sp. Many of the organisms reported to cause IE during pregnancy have also been cultured from the normal vaginal flora and the postpartum uterus [54,55]. Studies have shown a 5–10% incidence of positive blood cultures in postpartum women within one hour of delivery. The organisms isolated were mostly Streptococcus spp., including anaerobic, microaerophilic, and hemolytic species, as well as Escherichia coli and Staphylococcus spp. Conditions associated with an increased risk of bacteremia included complications such as endoparametritis, pyelonephritis, and premature amniorrhexis, especially when greater than six hours prior to delivery and greater than six hours of labor [15,30,56,57]. The risk of bacteremia in women undergoing cesarean section after a minimum of four hours of labor or ruptured membranes has been noted to be approximately 14% in one study [31]. Despite these data, IE due to pregnancy-related bacteremia is rare, and antibiotic prophylaxis is not recommended. This will be addressed later in this chapter.

CHAPTER 17 Infective Endocarditis

Clinical features The clinical features of IE during pregnancy are related to the infectious process and its cardiac and noncardiac manifestations [15,58]. Fever is the most common presenting symptom and may be absent in immunosuppressed patients and those treated with antipyretics, steroids, or recent antibiotics. Constitutional symptoms such as headaches, malaise, fatigue, and musculoskeletal pain are common. The acute form of IE may be associated with chills, sweats, nausea, vomiting, chest pain, dyspnea, and signs of peripheral emboli. Although the classic triad of fever, a new murmur, and anemia should raise suspicion for IE, the latter two findings may be present in a routine pregnancy, and therefore require careful interpretation. Heart murmurs are noted in up to 85% of patients but may be inaudible in patients with tricuspid valve endocarditis [15]. A finding of a new cardiac murmur or a change in the character or intensity of a preexisting murmur is an important characteristic feature of IE. However, neither the presence of nor a change in character of a murmur is found consistently. In addition, the development of new murmurs or change in intensity of existing murmurs is common in pregnancy due to the hemodynamic changes seen during this period. This makes the diagnosis of IE on physical exam during pregnancy challenging. Pregnancy may diminish the intensity of aortic and mitral regurgitant murmurs and may amplify the murmurs of aortic and mitral stenosis. Therefore, one cannot solely rely on the presence or absence of murmurs in the evaluation of IE in pregnancy.

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within the glomerular capillary wall, which is similar histologically to membrano-proliferative and poststreptococcal glomerulonephritis [60], and drug-induced renal injury. Differentiation among the different forms of renal disease can be challenging. Acute renal failure is noted to occur in up to one-third of endocarditis patients, usually among older patients [61]. Signs of renal involvement such as red cell casts due to glomerulonephritis, when present, often occur prior to initiation of antibiotic therapy. Acute tubular necrosis, common with aminoglycoside usage, presents with muddy-brown casts several days after initiation of drug therapy. Acute interstitial nephritis may present with eosinophiluria and generally occurs 7–10 days after the initiation of drug therapy. The penicillin and quinolone classes of antibiotics are most commonly associated with acute interstitial nephritis. With acute tubular necrosis and interstitial nephritis, renal function may improve after discontinuation of the offending drug. Renal biopsy may be needed in the diagnosis of glomerulonephritis. Renal emboli may occur months after antibiotic cure. Acute flank pain associated with new renal dysfunction should raise the suspicion for renal embolic phenomenon.

Cutaneous manifestations Four lesions involving the skin have classically been described in patients with IE: petechiae, splinter hemorrhages, Osler nodes, and Janeway lesions. Petechiae, involving conjunctival or oral mucosa, are the most frequent findings and are reported to occur in 26% of patients [58]. Subungual splinter hemorrhages, linear brown lesions under nail beds, are often the result of trauma, especially distal lesions, and therefore have less diagnostic value. Osler nodes, an immunologic phenomenon secondary to a hypersensitivity reaction, are present as tender, erythematous nodules on the pulp of terminal phalanges. Janeway lesions are a vascular phenomenon consisting of small blanching, nontender macular hemorrhagic spots that may present on the palms and soles. Osler nodes and Janeway lesions are not pathognomonic for IE, although they are specific. However, the incidence of cutaneous manifestations in IE during pregnancy is currently unknown.

Neurologic manifestations Neurologic or psychiatric manifestations may occur in approximately one-third of patients with IE. While most are commonly due to embolic ischemic strokes, neurologic symptoms can also be due to hemorrhagic strokes from an embolic source, ruptured mycotic aneurysm, meningitis, encephalopathy, seizures, or a brain abscess [58,62,63]. Aphasia, ataxia, limb weakness, cortico-sensory, or homonymous hemianopsia can be presenting symptoms, and when associated with a fever should heighten the suspicion for IE. Roth spots, although specific for IE, are seen in fewer than 5% of patients. These are oval, retinal hemorrhages with a clear pale center and are rarely noted at the time of the initial physical examination. Embolic cerebral infarction is the most common neurologic complication of IE, occurring in approximately 20% of patients, usually within the first two weeks of therapy [58]. Prompt initiation of anti-microbial therapy has been shown to reduce the risk of early embolism [24,59,64]. Although true meningitis associated with endocarditis is rare, when it occurs, it is most often aseptic suggesting an inflammatory or immunologic phenomenon. However, reports of positive cerebrospinal fluid cultures in acute bacterial endocarditis exist and particularly when S. aureus is the causative agent [65]. A variety of other neurologic manifestations may also occur, including headaches, seizures, or altered mental status.

Renal manifestations Three types of renal abnormalities may occur in IE: Renal infarction due to embolic phenomenon, which have been commonly described in fungal endocarditis [59], glomerulonephritis due to immune-complex deposition

Cardiac and noncardiac complications The most common cause of death in patients with IE is congestive heart failure, with a mortality of 60%. Valvular dysfunction, particularly aortic valve regurgitation, is most common etiology of heart failure in pregnant women with

Peripheral manifestations

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Table 17.1 Cardiovascular complications of infective endocarditis Valve destruction with resultant regurgitation Localized suppuration Perivalvular or myocardial abscesses Creation of left-to-right shunts (sinus of Valsalva rupture, ventricular septal defects, aortopulmonary fistula, and ventriculo-atrial fistula)

be the cause of persistent sepsis, fever, pain, and neurological symptoms. Diagnosis can be difficult, but a combination of imaging and angiography maybe helpful. Since rupture and hemorrhage can occur at any time during or after therapy, surgery is recommended if the aneurysm is located in a surgically accessible site. Nonetheless, the risks and benefits of surgical repair of mycotic aneurysms during pregnancy must be taken into consideration.

Emboli Systemic

Diagnosis

Coronary artery with myocardial infarction

The most useful clinical findings suggestive of IE are fever, a cardiac murmur, and positive blood cultures. A history of preexisting structural heart disease in the setting of the aforementioned findings should also raise suspicion for IE. Physical exam should focus on the peripheral manifestations of IE and the cardiac exam with particular attention to heart failure symptoms. The modified Duke criteria is a classification schema for IE that uses clinical, microbiologic, and echocardiographic data to establish either a definite or possible diagnoses of IE (Tables 17.2 and 17.3). This schema is the preferred method of making a clinical diagnosis of IE. Additionally, criteria for

Mycotic aneurysms Conduction abnormalities; rhythm disturbances Pericarditis

IE [58]. The mechanism of valvular dysfunction from IE include erosion of valve edges, total destruction of the valves by highly invasive organisms, perforation or prolapse of a leaflet, rupture of the chordae tendineae, or valvular stenosis. The valve most frequently involved in IE is the aortic valve (55%) followed by the mitral valve (28%) [66–68]. Cardiovascular complications are listed in Table 17.1. Extension of the infection into the myocardium can lead to sinus of Valsalva aneurysmal rupture and septal perforation with the development of ventricular septal defects, aortopulmonary fistulas, complete heart block, and ventriculo-atrial fistulas [69]. Congestive heart failure due to left-to-right shunting can also result from these defects. Systemic emboli occur in one-third of cases of IE [62,63]. Hemiplegia, aphasia, and sensory loss are the usual clinical manifestations of this complication. Pulmonary emboli are commonly seen with tricuspid valve endocarditis. Other sites of emboli include the coronary arteries (which may result in myocardial infarction), the spleen, and kidneys. Myocardial abscesses have been noted at autopsies in approximately 20% of patients with IE and may be a result of direct extension of the infection or from bacteremia [58]. Abscess-induced intra-cardiac fistula formation may precipitate or worsen congestive heart failure. Myocardial abscesses should be suspected with new-onset conduction abnormalities or arrhythmias during the course of IE. Although pericardial effusions may occur in more than 50% of patients, they are usually reactive and associated with a benign clinical course [70] but less commonly, an intracardiac abscess can extend into the pericardial space, resulting in a suppurative pericarditis. Mycotic aneurysms may develop as a result of direct invasion of bacteria into the arterial wall, embolic occlusion of the vasa vasorum, or deposition of immune complexes. These can be found in the brain, abdominal aorta, superior mesenteric artery, splenic artery, coronary arteries, pulmonary arteries, sinus of Valsalva, and the ligated ductus arteriosus. Mycotic aneurysms that have not ruptured may be associated with few or no symptoms. They can, however,

Table 17.2 Modified Duke classification schema for infective endocarditis Definite infective endocarditis Pathologic criteria Microorganism: Demonstrated by culture or histology in a vegetation, or in a vegetation that has embolized, or in an intracardiac abscess; or Pathologic lesions: Vegetation or intracardiac abscess, confirmed by histology showing active endocarditis Clinical criteria Two major criteria; or One major and three minor criteria; or Five minor criteria Possible infective endocarditis Clinical criteria One major and one minor criteria; or Three minor criteria Rejected infective endocarditis Firm alternate diagnosis for manifestations of endocarditis; or Resolution of manifestations of endocarditis, with antibiotic therapy for four days or less; or No pathologic evidence of infective endocarditis at surgery or autopsy after antibiotic therapy for four days or less Does not meet criteria for possible infective endocarditis, as above Source: [71].

CHAPTER 17 Infective Endocarditis

Table 17.3 Duke major and minor criteria for infective endocarditis Major criteria Positive blood cultures for IE

q

q

q

Typical microorganism for infective endocarditis from two separate blood cultures including Viridans streptococci, Streptococcus gallolyticus, HACEK group, S. aureus, or community-acquired enterococci in the absence of a primary focus; or Persistently positive blood culture, defined as recovery of a microorganism consistent with infective endocarditis from blood cultures drawn more than 12 h apart or three or a majority of four or more separate blood cultures, with first and last drawn at least 1 h apart; or Single positive blood culture for Coxiella burnetii or anti-phase I IgG antibody titer >1 : 800

Evidence of endocardial involvement

q

q q

Positive echocardiogram for infective endocarditis defined as follows: Oscillating intracardiac mass, on valve or supporting structures, or in the path of regurgitant jets, or on implanted material, in the absence of an alternative anatomic explanation; or Abscess; or New partial dehiscence of prosthetic valve

Minor criteria New valvular regurgitation

q q q q q q

Predisposing heart condition or intravenous drug use; or Fever – 38.0 °C (100.4 °F); or Vascular phenomenon: Major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway lesions; or Immunologic phenomenon: Glomerulonephritis, Osler’s nodes, Roth spots, and rheumatoid factor; or Microbiologic evidence: Positive blood culture but not meeting major criterion as noted above or serologic evidence of active infection with organism consistent with infective endocarditis; or Echocardiographic minor criteria eliminated

Source: [72].

rejection of this diagnosis are also outlined [73]. This classification system is both sensitive and specific for IE in the general population and should be used without alteration for diagnosing IE in pregnancy. A definitive diagnosis requires either two major criteria, one major, and three minor criteria, or five minor criteria. One major criterion and one minor criterion or three minor criteria qualify for a diagnosis of possible IE. The bacteremia of IE is continuous, rather than sporadic, and therefore blood cultures are the mainstay for its diagnosis. A minimum of three blood cultures separated by time and location of blood draw should be obtained within a 24-hour period. Blood cultures are positive in more than 95% of cases of streptococci and more than 82% when due to

265

other bacteria [73]. However, blood cultures may be negative in IE in up to 16% of patients [58]. Negative blood cultures usually occur when patients have received antibiotic therapy within a week or two prior to culturing or, less commonly, when the causative agent cannot be easily cultured with standard techniques. In patients with suspected IE who have received antibiotic therapy, the antibiotic should be discontinued, if clinically possible, and cultures redrawn beginning 24–48 hours later. If therapy can be held, blood cultures should be repeated twice during a seven-day interval, and if they remain negative, a diagnosis other than IE (e.g. collagen vascular disease, carcinoid syndrome, thrombotic thrombocytopenic purpura, atrial myxoma, or marantic endocarditis) should be sought. Additional blood cultures may be useful in patients who have been recently treated with antibiotics if discontinuation of therapy is not feasible. Epidemiological data suggest that serologic studies are indicated for suspected organisms that are difficult to culture, such as Bartonella species, Coxiella burnetii, Tropheryma Whipplei, and Chlamydophila psittaci, all of which are relatively rare causes of IE in the general population and even less frequent in pregnancy-related endocarditis. Other laboratory findings suggestive of IE include an elevated erythrocyte sedimentation rate, although nonspecific, is a common finding in this disease. A normochromic, normocytic anemia with low serum iron and low serum iron-binding capacity is seen in up to 90% of patients with endocarditis. However, iron-deficiency anemia, common in pregnancy, may obscure the diagnosis of anemia associated with IE in pregnancy. The white blood cell count is frequently elevated, and a leftward shift is common in patients with acute IE. Thrombocytopenia is most commonly seen in staphylococcal endocarditis but may also be present during routine pregnancies. An abnormal urinalysis lacks specificity for IE but is nonetheless observed in many patients. The presence of active sediment in the urine suggests renal involvement such as glomerulonephritis or renal infarction. A positive urine culture for S. aureus in a noncatheterized patient should always prompt evaluation for possible endocarditis. An elevated rheumatoid factor in patients without a known history of prior rheumatologic disorder should raise the suspicion for IE. An electrocardiogram may reveal new-onset conduction delays or heart block, indicating possible infectious extension into the valve annulus and adjacent septum. A chest radiograph may provide evidence of septic pulmonary emboli, although during pregnancy, the risks to the fetus may outweigh the benefit of a chest radiography given other diagnostic tools. Echocardiography is the most powerful tool for detecting cardiac vegetations, quantifying valvular dysfunction, and evaluating for intracardiac complications. Color Doppler echocardiography is useful in the assessment of valvular stenosis, intracardiac pressure gradients, and valvular regurgitation, whereas contrast echocardiography can be used to detect complications such as intracardiac shunts.

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Two-dimensional transthoracic echocardiography has a low sensitivity for detecting IE (between 29% and 63%), but a relatively high specificity and should be the initial procedure of choice for women with a low to intermediate probability of IE. Transesophageal echocardiography (TEE) has a higher spatial resolution than transthoracic echocardiography, lending to a higher sensitivity (between 85% and 95%) and specificity (as high as 100%). TEE should be the procedure of choice in women with an intermediate-tohigh pretest probability of IE. Other indications for TEE in pregnant women include prosthetic valves (acoustic shadowing severely limits transthoracic views), suspected valve perforations, suspected myocardial abscess formation, and a technically limited transthoracic echocardiography study. During pregnancy, TEE can be safely performed either without conscious sedation or with judicious use of medications accompanied by fetal monitoring. It is important to note that visualization of an echogenic vegetation on either modality does not differentiate between infectious and noninfectious lesions (e.g. healed vegetations, thickened valves, valve calcification, valve nodules, thrombus, or pannus). Thus, the identification of microbiology via blood culture data is imperative to interpret cardiac lesions in the setting of suspected IE.

Management of infective endocarditis in pregnancy Antibiotic therapy of infective endocarditis An infectious disease consultation is strongly recommended in the treatment of IE, particularly in pregnancy given the intricate balance of benefits of eradication and fetal risks involved in the traditional antibiotic regimens for IE in the nonpregnant patient. Such a consultation has been associated with decreased mortality in patients with S. aureus bacteremia, a common organism seen in IE during pregnancy [74]. The choice of antibiotics for IE depends on proper microbiologic identification of isolated organisms from the blood cultures and its susceptibility testing. This has become imperative in the era of increasing antibiotic resistance and recognition of uncommon organisms causing IE. Bactericidal agents, which may involve synergistic combinations of antibiotics, are preferred for the treatment of endocarditis [75]. In pregnancy, the choice of antibiotic must account for any possible adverse affects to the fetus [76]. In general, agents that are used for the treatment of IE that are safe in pregnancy include the β-lactams (penicillins, cephalosporins), and glycopeptides (vancomycin). Pharmacokinetics of antibiotics in pregnancy differ from those in nonpregnant patients, so infectious disease and pharmacy consultation can be beneficial when picking doses for patients. In subacute presentations of IE, antibiotic treatment should be instituted only after obtaining blood cultures. Although the predominant microorganisms seen in pregnancy-associated endocarditis are viridans streptococci,

initial broad-spectrum antibiotic coverage should also include treatment of staphylococci and enterococci, given the microbiologic epidemiology of pregnancy-related IE as previously discussed. An initial regimen of vancomycin and gentamicin to cover streptococci, enterococci, and staphylococci (including MRSA) is reasonable (Table 17.9). While both of these drugs cross the placenta, there is currently no data supporting adverse effects on the fetus. Additionally, their benefit may outweigh the risk in the setting of a life-threatening IE. The doses may need adjustment in pregnancy and a clinical pharmacist should be consulted. Once the organism’s identity and sensitivity have been determined, antibiotic therapy should be tailored to the specific organism and resistance profile. Penicillin-based drugs are preferred, if active in vitro given their known safety profile in pregnancy. In contrast to subacute presentations, acute IE is often caused by highly destructive organisms requiring antibiotic therapy without delay. In such patients, the etiology of IE should be suspected on the basis of the clinical setting and any patient-specific risk factors that may be present. These include infected skin lesions, urinary tract infections, intravenous drug abuse, or recent dental or genitourinary manipulation. Antibiotic therapy should target the most likely causative organism. S. aureus is the leading pathogen in acute IE, and vancomycin has long been used for initial treatment of S. aureus, but newer agents offer enhanced staphylococcal killing compared to vancomycin, so are playing an increasing role in endocarditis management (i.e. daptomycin), but data on safety of these in pregnancy is less robust. Gentamicin, which is needed synergistically to kill enterococci, should be added initially to cover the latter organism as well (Table 17.9). As previously discussed, GBS is associated with rapid valvular destruction, therefore, the addition of gentamicin to high-dose penicillin for at least the first two weeks of therapy is strongly recommended for definitive treatment of these bacteria. The aminoglycosides have a narrow therapeutic index and should be used with careful dosing and monitoring of drug levels. Antibiotic regimens should be adjusted immediately once microbiology sensitivities and specificities have returned. The optimum duration of antibiotic therapy will depend on the organism, valve infected (left vs. right-sided disease), host factor (e.g. prosthetic valve), and clinical response, but generally range from two to six weeks (Table 17.9). The most common etiology of culture negative IE was previously thought to be due to the HACEK organisms (H. aphrophilus, Actinobacillus actinomycetemcomitans, C. hominis, Eikenella corrodens, and Kingella kingae), however, several recent studies have revealed that these organisms are more easily recovered with modern blood culturing systems (usually within five days) than in the past. In patients with true culture-negative IE, either suspected or already established (at least three different negative blood culture samples after seven days of incubation), therapy should be chosen in consultation with an infectious disease specialist. The recommended treatment of culture-negative

CHAPTER 17 Infective Endocarditis

267

endocarditis for the general population is currently ampicillin–sulbactam and gentamicin, with the addition of vancomycin if a prosthetic valve is involved. Prior antibiotic use is the most common etiology of culture-negative IE cases, while fungi and zoonotic organisms are fewer common causes, especially in pregnancy [79,80]. Although the incidence of prosthetic valve endocarditis is rising, its occurrence in pregnancy-associated endocarditis remains rare. Early prosthetic valve endocarditis (i.e. within 60 days of surgery) is usually due to contamination of the implant site, often by coagulase-negative staphylococci, particularly Staphylococcus epidermidis. These infections are more invasive and destructive, commonly extending into the valve annulus and fibrosa, eventually leading to abscess formation and prosthetic dehiscence. A triple antibiotic regimen consisting of vancomycin, gentamicin, and rifampin is recommended (pregnancy category C) until antibiotic susceptibilities are known. However, in certain instances such as coagulase-negative staphylococcal prosthetic valve endocarditis surgical treatment is usually required for complete eradication of infection [15]. Prosthetic valve endocarditis greater than 12 months from implantation is usually caused by the same microorganisms that are found in native valve endocarditis. Once antibiotic therapy is initiated in pregnant women with IE, patients should be assessed for improvement fairly closely given maternal–fetal risks associated with this condition. About half of all the cases treated with antibiotics alone will require surgical treatment for eradication of infection or management of heart failure. Effectiveness of therapy should be monitored with serial blood cultures at 48 hours and frequently throughout the course of therapy, even in cases with defervescence or clinical improvement [81,82]. It is important to note, however, that once the infectious agent has affected a cardiac structure such as a valve, valvular dysfunction may progress despite clearance of the infection.

Table 17.4 Indications for surgery in the treatment of infective endocarditis

Surgical therapy Observational studies have suggested that surgical treatment of IE is generally recommended in cases of complicated IE [83]. Data from a European heart survey, including 159 patients with active IE found that surgical treatment was used in 50% of the cases. Within this cohort, indications for surgery included HF in 60%, persistent sepsis in 40%, vegetation size in 48%, and embolic events in 18% [84]. Patients with moderate-to-severe congestive heart failure secondary to valvular dysfunction have had a dramatic improvement in mortality with surgical valve replacement, especially those with significant valvular destruction or perforation [85]. Those patients with rapidly deteriorating hemodynamics from valve dysfunction have benefited the most from surgical intervention [86]. Additional indications for surgical intervention include uncontrolled infection despite appropriate antibiotic therapy, known ineffectiveness of medical therapy for the offending organism (e.g. infections with fungi, Brucella spp.,

P. aeruginosa, and other enteric Gram-negative bacilli), recurrent embolic events, mycotic aneurysms, and unstable prosthesis (Table 17.4) [59,87]. Furthermore, the development of intracardiac complications such as perivalvular abscess formation, sinus of Valsalva aneurysm with rupture into a cardiac chamber, ventricular septal defects, fistula formation, myocardial abscess, and other structural abnormalities are indications for surgery. Of the three types of aortic valves replacements (bioprosthetic, mechanical, and homograft), the use of homografts in young women in need of aortic valve replacement has been associated with the highest 10-year survival rate [83,88]. In the case of mitral valve IE, mitral valve repair has recently been shown to have better operative results, as well as lower incidence of valve-related complications compared with mitral valve replacement [67,68,77]. Successful cardiac surgery during pregnancy has been reported, and failure of medical therapy should prompt surgical intervention prior to clinical deterioration [26,36,72,89,90]. Fetal

Native valves Class I indications

q q q q

Valve dysfunction leading to signs or symptoms of heart failure; or Persistent bacteremia; or Infection with fungal or highly resistant organisms; or Complications such as heart block, annular or aortic abscess, or destructive penetrating lesions

Class IIa indications

q q

Recurrent emboli and persistent vegetations despite appropriate antibiotic therapy; or Severe valve regurgitation and mobile vegetations >10 mm

Class IIb indications Mobile vegetations larger than 10 mm, particularly when involving the anterior leaflet of the mitral valve Prosthetic valves Class I indications

q q q q

Signs or symptoms of heart failure from valve dehiscence, intracardiac fistulas, or severe prosthetic valve dysfunction; or Persistent bacteremia; or Complications such as heart block, annular or aortic abscess, or destructive penetrating lesions; or Infection with fungal or highly resistant organisms

Class II indications

q q q

Recurrent emboli despite antibiotic treatment; or Relapsing prosthetic valve endocarditis; or Mobile vegetations greater than 10 mm

Source: Baddour et al. 2015 [83]. Adapted with permission of American Heart Association.

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loss associated with open-heart surgery has been reported to be approximately 30%, and therefore elective delivery by cesarean section has been advocated [91–93]. If surgical intervention is deemed necessary during pregnancy, cardiac surgery is best after the 24–28th week, when organogenesis is complete [69,94]. Good perfusion of the placenta must be maintained during cardiopulmonary bypass and therefore invasive hemodynamic monitoring of the mother is indicated. If surgical intervention is pursued, the involvement of a multidisciplinary team with a cardiac surgeon, obstetrician, cardiologist, and infectious disease specialist is strongly recommended. Congestive heart failure management in pregnancy Since congestive heart failure is the most common cause of death in pregnant patients with IE, every effort should be made to achieve early diagnosis and treatment. Treatment of congestive heart failure during pregnancy involves balancing the use of traditional heart failure medications with fetal risks. Drugs such as diuretics, organic nitrates, and hydralazine can be safely used during gestation. Although digoxin crosses the placenta, neonates and children are relatively resistant to their toxicity. Caution should be used with β-blockers, a traditional mainstay of heart failure therapy, as they have been associated with intrauterine growth restriction, bradycardia, and hypoglycemia, especially with use in the second and third trimesters. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are contraindicated because of fetal toxicity. Other drugs used in congestive heart failure such as nitroprusside are not recommended due to potential risk of cyanide toxicity. When concomitant arrhythmia is present, β-blockers, calcium channel blockers, or digoxin can be used for rate control, but amiodarone should be avoided. When the underlying arrhythmia is atrial fibrillation, cardioversion may be required if there is hemodynamic instability. During pregnancy, the formation of atrial thrombi is more likely due to a relatively hypercoagulable state during pregnancy. Unfractionated heparin and low molecular heparins do not cross the placenta, however, low molecular heparin has a lower risk of thrombocytopenia. In contrast, coumadin does cross the placenta, is associated with fetal abnormalities, and should not be used during pregnancy.

history of prosthetic heart valve are at higher risk for developing IE, and therefore, antibiotic prophylaxis has historically been considered for this group. Antibiotic prophylaxis, though, for endocarditis in any patient population has not been shown to improve outcomes, and with the rise in complications associated with antibiotic use (e.g. Clostridioides difficile) and problems associated with antibiotic resistance, prophylaxis should only be prescribed for select patients after detailed risk–benefit analysis is performed and reviewed with the patient. The ACC/AHA guidelines acknowledge that the common practice is to provide antibiotic prophylaxis for this higher risk group even during pregnancy [95]. This remains a controversial topic. In 2008, the National Institute for Health and Clinical Excellence (NICE) in the United Kingdom (UK) published a clinical guideline recommending against antibiotic prophylaxis for women at risk for endocarditis due to lack of evidence of efficacy and cost. Regarding specific procedures, antibiotic prophylaxis for routine dental, genitourinary, or gastrointestinal procedures comes with a Class IIa recommendation (previously a Class Ia recommendation) in patients deemed as high risk (e.g. prosthetic heart valves, previous endocarditis infection, valvular pathology in a transplanted heart, and CHD) (Table 17.5). For patients with nonhigh-risk valvular lesions (aortic stenosis, mitral stenosis, and MVP), antibiotic prophylaxis is no longer recommended. Prophylaxis is also no longer recommended for Table 17.5 Chemoprophylaxis of patients at high risk for infective endocarditis cardiac abnormalities requiring prophylaxis Previous episode of infective endocarditis Cardiac valvulopathy in a transplanted heart Congenital heart disease Unrepaired cyanotic congenital heart disease Completely repaired congenital heart defects with prosthetic material or device Repaired congenital heart disease with residual defects Prosthetic heart valves Prophylaxis not required Congestive heart failure Bicuspid aortic valve Acquired aortic or mitral valve disease

Prevention The most recent recommendations of the American College of Cardiology/American Heart Association (ACC/AHA) for the prevention of IE have undergone significant changes. Currently, antibiotic prophylaxis for women with valvular heart disease during pregnancy is not recommended during routine vaginal delivery or uncomplicated cesarean section [95]. However, pregnant women with a previous history of IE, history of CHD repair, history of heart transplant, and

Hypertrophic cardiomyopathy Previous coronary artery bypass Cardiac pacemakers and implanted defibrillators Cardiac catheterization or coronary stents Physiologic, functional, or innocent heart murmurs Uncomplicated secundum atrial septal defect Source: Adapted from the recommendations of the American Heart Association 2006–2007 [78,96].

CHAPTER 17 Infective Endocarditis

Table 17.6 Procedures associated with possible bacteremia Dental

All dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosaa

Respiratory tractb

Tonsillectomy and/or adenoidectomy Surgical operations that involve the respiratory mucosa Bronchoscopy with biopsy

Gastrointestinal Endoscopic retrograde cholangiopancreatography tractc with biliary obstruction Biliary tract surgery Genitourinary tractd

Prostatic surgery With enterococcal UTI or colonization: cystoscopy or urethral dilation Surgical procedures on infected tissue

Skine

Skin structure Musculoskeletal tissue

a Excluding routine anesthetic injections through noninfected tissue, dental radiographs, placement or adjustment of removable prosthodontic or orthodontic appliances/brackets, shedding of deciduous teeth, and bleeding from trauma to the lips or oral mucosa. b Respiratory tract prophylaxis no longer recommended for endotracheal intubation, bronchoscopy without biopsy, tympanostomy tube insertion. c Gastrointestinal tract prophylaxis no longer recommended for transesophageal echocardiography, endoscopy with or without gastrointestinal biopsy. d Genitourinary tract prophylaxis no longer recommended for vaginal hysterectomy, vaginal delivery, cesarean section, circumcision in uninfected tissue: (urethral catheterization, uterine dilatation and curettage, therapeutic abortion, sterilization procedures, insertion or removal of intrauterine devices). e Skin prophylaxis no longer recommended for incision or biopsy of surgically scrubbed skin, tattoos, or piercings.

Source: Adapted from the recommendations of the American Heart Association 2006–2007 [89,90].

patients with congestive heart disease, bicuspid aortic valve, or hypertrophic cardiomyopathy. Similarly, the American Dental Association now recommends dental prophylaxis for only those with history of CHD, transplant, prior IE, or prosthetic valves, and only for dental procedures that involve manipulation of either gingival tissue or the periapical region of teeth or perforation of the oral mucosa (Tables 17.6–17.9).

Table 17.7 Prophylactic antibiotic regimens for dental procedures Setting

Agent (given as a single dose 30–60 min prior to procedure)

Oral

Amoxicillin 2 g PO

Unable to take oral medication

Ampicillin 2 g IM/IV; or Cefazolin; or Ceftriaxone 1 g IM/IV

Allergic to penicillins or ampicillin

Cephalexina,b 2 g PO; or Clindamycin 600 mg PO; or Azithromycin or clarithromycin 500 mg PO

Allergic to penicillin or ampicillin and unable to take oral medication

Cefazolin or Ceftriaxoneb 1 g IM/IV; or Clindamycin 600 mg IM/IV

IM – intramuscular; IV – intravenous. a Or other first- or second-generation oral cephalosporin in equivalent adult dosing. b Cephalosporins should not be used in an individual with a history of anaphylaxis, angioedema, or urticaria with penicillins or ampicillin. Source: Adapted from the recommendations of the American Heart Association 2006–2007 [89,90].

surgical intervention carries greater risks, and outcomes data are sparse for this population. Antibiotic therapy tailored to the causative pathogen is critical, and treatment decisions for IE during pregnancy should be made in consultation with infections disease specialists. Prenatal counseling should include an assessment of high-risk cardiac lesions so any potential risk for IE can be identified early and prophylactic antibiotic therapy considered. Table 17.8 Prophylactic antibiotic regimens for genitourinary and gastrointestinal procedures Setting

Regimen

High-risk patients

Ampicillin 2 g IV/IM plus gentamicin 1.5 mg/kg within 30 min of procedure, repeat ampicillin 1.0 g IV/IM or give amoxicillin 1 g PO 6 h later

High-risk patients with penicillin allergy

Vancomycin 1 g IV over 1–2 h plus gentamicin 1.5 mg/kg IM/IV infused or injected 30 min before procedure

Moderate-risk patients

Amoxicillin 2 g PO 1 h prior to procedure or ampicillin 2 g IM/IV 30 min prior to procedure

Moderate-risk patients with penicillin allergy

Vancomycin 1 g IV infused over 1–2 h and completed within 30 min of procedure

Conclusion The diagnosis and management of IE in pregnancy is challenging due to physiological changes present in pregnancy as well as the risks to the fetus that must be accounted for during treatment. It is imperative that any significant suspicion for infection be worked-up immediately to avoid progressive and devastating cardiac complications associated with IE of pregnancy. Surgery is an effective option for acute decompensated heart failure associated with IE and surgery reduces mortality in nonpregnant patients with this condition. However, in the setting of pregnancy, the decision to proceed with

269

IM – intramuscular; IV – intravenous; PO – per oral. Source: Adapted from the recommendations of the American Heart Association 2006–2007 [95,97].

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Table 17.9 Organism-specific treatment options and duration of treatment for infectious endocarditis during pregnancy Organism

Suggested antibiotic regimen

Duration

Empiric (acute or subacute)

Vancomycin plus gentamicin 5 mg/kg IV q24 h IV/IM in one dose ± ceftriaxone 2 g IV qDay

Depends on organism

Viridans streptococci and other streptococci highly susceptible to penicillin (MIC ≤ 0.12 μg/ml)

Aqueous crystalline penicillin G sodium 12–18 million U/24 h IV in four or six equally divided doses or Aqueous crystalline penicillin G sodium 12–18 million U/24 h IV in six equally divided doses + gentamicin sulfate 3 mg/kg per 24 h IV/IM in one dose

4 wk

Aqueous crystalline penicillin G sodium 24 million U/24 h IV in four to six equally divided doses or Ceftriaxone 2 g IV qDay or Above regimen + gentamicin sulfate 3 mg/kg per 24 h IV/IM in one dose

4 wk

Aqueous crystalline penicillin G sodium 18–30 million U/24 h IV in six equally divided doses + gentamicin sulfate 3 mg/kg per 24 h IV/IM in one dose or Vancomycin hydrochloride 30 mg/kg per 24 h IV in two equally divided doses + gentamicin sulfate 3 mg/kg per 24 h IV/IM in one dose

4–6 wk

Ampicillin sodium 12 g/24 h IV in six equally divided doses + gentamicin sulfate 3 mg/kg per 24 h IV/IM in three equally divided doses or Vancomycin hydrochloride 30 mg/kg per 24 h IV in two equally divided doses + gentamicin sulfate 3 mg/kg per 24 h IV/IM in three equally divided doses

4–6 wk 6 wk

Nafcillin or oxacillin 12 g/24 h IV in four to six equally divided doses or Cefazolin 6 g/24 h IV in three equally divided doses ± gentamicin sulfate 3 mg/kg per 24 h IV/IM in two or three equally divided doses

4–6 wk

Staphylococcus aureus (methicillin resistant)

Vancomycin 30 mg/kg per 24 h IV in two equally divided doses

6 wk

Streptococcus agalactiae (group B streptococci)

24 million U/24 h IV either continuously or in four to six equally divided doses + gentamicin sulfate 3 mg/kg per 24 h IV/IM

4–6 wk At least initial 2 wk, preferably for duration

HACEK organisms

Ceftriaxone 2 g/24 h IV/IM in one dose

4 wk

Culture-negative (suspected antibiotics given prior to culture)

Ampicillin–sulbactam 12 g/24 h IV in four equally divided doses + gentamicin sulfate 3 mg/kg per 24 h IV/IM in three equally divided

4–6 wk

Culture-negative from zoonotic pathogens (Bartonella spp.)

Ceftriaxone 2 g IV qDay + gentamicin sulfate 3 mg/kg per 24 h IV/IM

6 wk 2 wk

Culture-negative from zoonotic pathogens (Coxiella burnetii)

TMP-SMX (320/1600 mg)

Long term 10–29 wk [77]

Viridans streptococci and other streptococci relatively resistant to penicillin (MIC 0.12–0.5 μg/ml)

Viridans streptococci and other streptococci (Abiotrophia, Gemella, Granulicatella spp.) highly resistant to penicillin (MIC > 0.5 μg/ml)

Enterococcus spp. (susceptible to penicillins and/or vancomycin and synergistic with aminoglycosides)

Staphylococcus aureus (methicillin susceptible)

Source: Adapted from Baddour et al. 2005 [78].

2 wk

2 wk

6 wk

4–6 wk

3–5 d

CHAPTER 17 Infective Endocarditis

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26 Avila, W.S., Grinberg, M., Tarasoutchi, F. et al. (1990). Cerebral malformation of the conceptus associated with maternal bacterial endocarditis and with aortic valve replacement during pregnancy. Arq Bras Cardiol 55 (3): 201–204. 27 Atri, M.L. and Cohen, D.H. (1990). Group B streptococcus endocarditis following second trimester abortion. Arch Int Med 149: 2579–2580. 28 Everett, E.D. and Hirschman, J.V. (1977). Transient bacteremia and endocarditis prophylaxis, a review. Medicine 56: 61–77. 29 Levin, J.N. and Stander, R.W. (1959). Subacute bacterial endocarditis following obstetric and gynecologic procedures; report of eight cases. Obstet Gynecol 13: 568–573. 30 Tiossi, C.L., Rodrigues, F.O., Santos, A.R. et al. (1994). Bacteremia induced by labor. Is prophylaxis for infective endocarditis necessary? Arq Bras Cardiol 62 (2): 91–94. 31 Boggess, K.A., Watts, D.H., Hillier, S.L. et al. (1996). Bacteremia shortly after placental separation during cesarean delivery. Obstet Gynecol 87: 779–784. 32 Shimoni, Z., Ben, D.M., and Niven, M.J. (2006). Postpartum group B streptococcal tricuspid valve endocarditis. Isr Med Assoc J 8 (12): 883– 884. 33 Pimentel, M., Barbas, C.S., de Carvalho, C.R. et al. (1989). Septic pulmonary embolism and endocarditis caused by Staphylococcus aureus in the tricuspid valve after infectious abortion: report of 2 cases. Arq Bras Cardiol 52: 337–340. 34 Zamprogno, R., Neri, G., Alitto, F. et al. (1990). Bacterial endocarditis in pregnancy, description of 2 cases and review of the literature. Minerva Cardioangiol 38: 85–88. 35 Souma, T., Yokosawa, T., Iwamatsu, T. et al. (1990). Successful mitral valve replacement for infective endocarditis in pregnancy. Nippon Kyobu Geka Gakkai Zasshi 38: 1035–1038. 36 Janion, M., Kurzawski, J., Konstantynowicz, H. et al. (1993). Myocardial infarction in pregnancy. Kardiol Pol 38: 351–353. 37 Yuan, S.M. (2014). Right-sided infective endocarditis: recent epidemiologic changes. Int J Clin Exp Med 7: 199–218. 38 Fowler, V.G. Jr., Miro, J.M., Hoen, B. et al., and ICE Investigators (2005). Staphylococcus aureus endocarditis: a consequence of medical progress. JAMA 293: 3012–3021. 39 Bataskov, K.L., Hariharan, S., Horowitz, M.D. et al. (1999). Gonococcal endocarditis complicating pregnancy: a case report and literature review. Obstet Gynecol 78 (3): 494–496. 40 Castillo, R.A., Llado, I., and Adamsons, K. (1987). Ruptured chordae tendineae complicating pregnancy, a case report. J Reprod Med 32: 137– 139. 41 Holt, S., Hicks, D.A., Charles, R.G. et al. (1978). Acute staphylococcal endocarditis in pregnancy. Practitioner 220: 619–622. 42 Sambola, A., Miro, J.M., Tornos, M.P. et al. (2002). Streptococcus agalactiae infective endocarditis: analysis of 30 cases and review of literature 1962–1998. Clin Infect Dis 34: 1576–1584. 43 Baddour, L.M. and The Infectious Diseases Society of America’s Emerging Infections Network (1998). Infective endocarditis caused by betahemolytic streptococci. Clin Infect Dis 26: 66–71. 44 Phares, C.R., Lynfield, R., Farley, M.M. et al., and Active Bacterial Core surveillance/Emerging Infections Program Network (2008). Epidemiology of invasive group B streptococcal disease in the United States, 1999– 2005. JAMA 299: 2056–2065. 45 Crespo, A., Retter, A.S., and Lorber, B. (2003). Group B streptococcal endocarditis in obstetric and gynecologic practice. Infect Dis Obstet Gynecol 11: 109–115. 46 Hodges, R.M. and de Alvarez, R.R. (1960). Puerperal septicemia and endocarditis caused by Pseudomonas aeruginosa. JAMA 173: 1081. 47 Holshouser, C.A., Ansbacher, R., Mcnitt, T. et al. (1978). Bacterial endocarditis due to Listeria monocytogenes in a pregnant diabetic. Obstet Gynecol 51: 9s. 48 Gill, G.V. (1979). Endocarditis caused by Salmonella enteritidis. Br Heart J 42: 353. 49 Anand, C.M., MacKay, A.D., and Evans, J.I. (1976). Haemophilus aphrophilus endocarditis in pregnancy. J Clin Pathol 29: 812.

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50 van der Bel-Kahn, J.M., Watanakunakorn, C., Menefee, M.G. et al. (1978). Chlamydia trachomatis endocarditis. Am Heart J 95: 627. 51 Douer, D., Danziger, Y., and Pinkhas, J. (1977). Neisseria catarrhalis endocarditis. Ann Intern Med 86: 116. 52 Maeland, A., Teien, A.N., Arnesen, H. et al. (1983). Cardiobacterium hominis endocarditis. Eur J Clin Microbiol 2: 216. 53 (1972). Clinicopathologic conference: Rheumatic fever with disseminated intravascular coagulation. J Tenn Med Assoc 65: 1108. 54 Hunter, C.A. Jr. and Long, K.R. (1958). A study of the microbiological flora of the vagina. Am J Obstet Gynecol 75 (4): 865–871. 55 Rabe, L.K., Winterscheid, K.K., and Hillier, S.L. (1988). Association of viridans group streptococci from pregnant women with bacterial vaginosis and upper genital tract infection. J Clin Microbiol 26 (6): 1156– 1160. 56 Blanco, J.D., Gibbs, R.S., and Castaneda, Y.S. (1981). Bacteremia in obstetrics: clinical course. Obstet Gynecol 58: 621–624. 57 McCormack, W.M., Rosner, B., Lee, Y.H. et al. (1975). Isolation of genital mycoplasmas from blood obtained shortly after vaginal delivery. Lancet I: 596–599. 58 Pruitt, A.A., Rubin, R.H., Karchmer, A.W. et al. (1978). Neurologic complications of bacterial endocarditis. Medicine 57 (4): 329–343. 59 Ellis, M.E., Al-Abdely, H., Sandridge, A. et al. (2001). Fungal endocarditis: evidence in the world literature, 1965–1995. Clin Infect Dis 32: 50. 60 Neugarten, J. and Baldwin, D.S. (1984). Glomerulonephritis in bacterial endocarditis. Am J Med 77: 297. 61 Conlon, P.J., Jefferies, F., Krigman, H.R. et al. (1998). Predictors of prognosis and risk of acute renal failure in bacterial endocarditis. Clin Nephrol 49: 96. 62 Jones, H.R. Jr. and Siekert, R.G. (1989). Neurological manifestations of infective endocarditis. Review of clinical and therapeutic challenges. Brain 112 (5): 1295. 63 Ruttmann, E., Willeit, J., Ulmer, H. et al. (2006). Neurological outcome of septic cardioembolic stroke after infective endocarditis. Stroke 37: 2094. 64 Fabri, J. Jr., Issa, V.S., Pomerantzeff, P.M. et al. (2006). Time-related distribution, risk factors and prognostic influence of embolism in patients with left-sided infective endocarditis. Int J Cardiol 110: 334. 65 McComb, J.M., McNamee, P.T., Sinnamon, D.G. et al. (1982). Staphylococcal endocarditis presenting as meningitis in pregnancy. Int J Cardiol 1: 325–327. 66 North, R.A., Sadler, L., Stewart, A.W. et al. (1999). Long-term survival and valve-related complications in young women with cardiac valve replacements. Circulation 99: 2669–2676. 67 Dreyfus, G., Serraf, A., Jebara, V.A. et al. (1990). Valve repair in acute endocarditis. Ann Thorac Surg 49: 706–713. 68 Podesser, B.K., R¨odler, S., Hahn, R. et al. (2000). Mid-term follow up of mitral valve reconstruction due to active infective endocarditis. J Heart Valve Dis 9: 335–340. 69 Mahli, A., Izdes, S., and Coskun, D. (2000). Cardiac operations during pregnancy: review of factors influencing fetal outcome. Ann Thorac Surg 69: 1622–1626. 70 Reid, C.L., Rahimtoola, S.H., and Chandraratna, P.A. (1987). Frequency and significance of pericardial effusion detected by two-dimensional echocardiography in infective endocarditis. Am J Cardiol 60 (4): 394– 395. 71 Li, J.S., Sexton, D.J., Mick, N. et al. (2000). Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 30: 633. 72 Matsumoto, H., Shimokawa, S., Umebayashi, Y. et al. (1993). Simultaneous Cesarean section and mitral valve replacement for infective endocarditis during pregnancy-a case report. Nippon Kyobu Geka Gakkai Zasshi 41: 329–331. 73 Werner, A.S., Cobbs, C.G., Kaye, D. et al. (1967). Studies on the bacteremia of bacterial endocarditis. JAMA 202: 199. 74 Lahey, T., Shah, R., Gittzus, J. et al. (2009). Infectious diseases consultation lowers mortality from Staphylococcus aureus bacteremia. Medicine (Baltimore) 88: 263–267.

75 Wilson, W.R., Giuliani, E.R., Danielson, G.K. et al. (1982). General considerations in the diagnosis and treatment of infective endocarditis. Mayo Clin Proc 57 (2): 81–85. 76 Garland, S.M. and O’Reilly, M.A. (1995). The risks and benefits of antimicrobial therapy in pregnancy. Drug Saf 13 (3): 188–205. 77 Sternik, L., Zehr, K.J., Orszulak, T.A. et al. (2002). The advantage of repair of mitral valve in acute endocarditis. J Heart Valve Dis 11: 91– 98. 78 Baddour, L.M., Wilson, W.R., and Bayer, A.S. (2005). Infective Endocarditis, Diagnosis, Antimicrobial Therapy, and Management of Complication, A Statement for Healthcare Professionals from the Committee on Rheumatic, Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia. Am Heart Assoc Circ 111: 3167–3184. 79 Petti, C.A., Bhally, H.S., Weinstein, M.P. et al. (2006). Utility of extended blood culture incubation for isolation of haemophilus, actinobacillus, cardiobacterium, eikenella, and kingella organisms: a retrospective multicenter evaluation. J Clin Microbiol 44: 257. 80 Baron, E.J., Scott, J.D., and Tompkins, L.S. (2005). Prolonged incubation and extensive subculturing do not increase recovery of clinically significant microorganisms from standard automated blood cultures. Clin Infect Dis 41: 167. 81 Richardson, J.V., Karp, R.B., Kirklin, J.W. et al. (1978). Treatment of infective endocarditis: 10-year comparative analysis. Circulation 58: 589–597. 82 Hubbell, G., Cheitlen, M.D., and Rapaport, E. (1981). Presentation, management and follow-up evaluation of infective endocarditis in drug addicts. Am Heart J 102: 85–94. 83 Baddour, L.M., Wilson, W.R., Bayer, A.S. et al., and American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and Stroke Council (2015). Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation 132: 1435– 1486. 84 Tornos, P., Iung, B., Permanyer-Miralda, G. et al. (2005). Infective endocarditis in Europe: lessons from the Euro heart survey. Heart 91 (5): 571– 575. 85 Sevchenko, I., Guriev, A.V., Shikhverdiev, N.N. et al. (1990). Successful surgical treatment of infectious endocarditis in a pregnant woman. VestinKhirIm II Grek 144: 42–44. 86 North, R.A., Sadler, L., Stewart, A.W. et al. (1999). Long-term survival and valve-related complications in young women with cardiac valve replacements. Circulation 99: 2669–2676. 87 Dyson, C., Barnes, R.A., and Harrison, G.A. (1999). Infective endocarditis: an epidemiological review of 128 episodes. J Infect 38: 87–93. 88 Riberi, A., Caus, T., Mesana, T. et al. (1997). Aortic valve or root replacement with cryopreserved homograft for active infectious endocarditis. Cardiovasc Surg 5: 579–583. 89 Westaby, S., Parry, A.J., and Forfar, J.C. (1992). Reoperation for prosthetic valve endocarditis in the third trimester of pregnancy. Ann Thorac Surg 53: 263–265. 90 Ishibashi, Y., Sasamura, Y., Ohe, K. et al. (1994). A case report of mitral valve replacement for infective endocarditis in pregnancy. Kyobu Geka 47: 474–476. 91 Reid, C.L., Leedom, J.M., and Rahimtoola, S.H. (1983). Infective endocarditis. In: Current Therapy, 28e (ed. H.F. Cohn), 190–197. Philadelphia, PA: WB Saunders. 92 Lapiedra, O.J., Bernal, J.M., Ninot, S. et al. (1986). Open heart surgery for thrombosis of a prosthetic mitral valve during pregnancy: fetal hydrocephalus. J Cardiovasc Surg 27: 217–220. 93 Parry, A.J. and Westaby, S. (1996). Cardiopulmonary bypass during pregnancy. Ann Thorac Surg 61: 1865–1869.

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94 Zitnik, R.S., Brandenburg, R.O., Sheldon, R. et al. (1969). Pregnancy and open-heart surgery. Circulation 39 (Suppl. 1): 257–262. 95 Wilson, W., Taubert, K.A., Gewitz, M., et al., and AHA (2007). Prevention of Infective Endocarditis. Guidelines from the American Heart Association. A Guideline from the American Heart Association, Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 115: 1736–1754.

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96 Carcopino, X., Raoult, D., and Bretelle, F. et al. (2007). Managing Q fever during pregnancy: the benefits of long-term cotrimoxazole therapy. Clin Infect Dis 116: 1736–1754. 97 Bonow, R.O., Carabello, B.A., Chatterjee, K. et al., and AHA (2006). ACC/AHA 2006 guidelines for the management of patients with valvular heart disease. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 guidelines for the management of patients with valvular heart disease). J Am Coll Cardiol 48: e1.

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Vascular Disease in Pregnancy

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CHAP T E R 18

Vascular Dissections and Aneurysms During Pregnancy Afshan B. Hameed1,2 1 Department

of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of California, Irvine, CA, USA

2 Department

of Medicine, Division of Cardiology, University of California, Irvine, CA, USA

Aortic dissection Aortic dissection associated with pregnancy is a rare but catastrophic and potentially fatal condition for both the mother and the fetus [1]. Dissection is typically initiated by a tear in the aortic intimal layer; the blood entering through this tear separates the media by virtue of the high pressure in the aortic lumen in a course parallel to the blood flow that leads to propagation of the dissection to variable distances. Dissection channel usually involves the outer part of the aortic media contained by the thin adventitial layer explaining the high frequency of extravasation of blood outside of the aortic wall [2]. Depending on the location of the dissection, any branch arising from that area may be involved in the dissection process and therefore symptoms vary widely depending on the specific distribution and anatomic structures involved [3]. Epidemiology Aortic dissection in pregnancy comprises about 0.1–0.4% of all cases of aortic dissection reported in a general population [4]. It occurs two to three times more frequently in males compared to their female counterparts at any age [5]. Etiology Predisposing factors among the general population are advancing age, male gender, hypertension, and aortopathies, i.e. Marfan’s syndrome, bicuspid aortic valve, and coarctation of aorta [2,6,7]. Additional high risk conditions include Noonan’s syndrome, Turner syndrome, and cocaine abuse [8]. Hypertension is the single most common denominator noted in adult population with aortic dissection [9]. Interestingly, the prevalence of hypertension is much lower in pregnancies complicated by aortic dissection when compared to their nonpregnant counterparts suggestive of additional mechanisms that play an important role in increasing this risk in pregnancy [4,10]. Furthermore, there is no evidence of increased risk of dissection with preeclampsia/eclampsia.

A significant number of reported cases of aortic dissection in pregnancy or postpartum period do not have additional risk factors [11,12], and therefore, pregnancy by itself is thought to increase the risk for aortic dissection. Early reports indicate that up to 50% of dissections in patients younger than 40 years of age occur in association with pregnancy, either during or shortly after delivery [13,14]. Mandel et al. reported 70 cases of aortic dissection in women of childbearing age, 36 of them occurred in association with pregnancy [5]. Konishi et al. reported characteristics of 52 cases of aortic dissection in pregnancy; women were older (60% >30 years), multiparous (77%), had coarctation of aorta (20%) and a few with Marfanoid features [15]. Pregnancy-related aortic dissection tends to occur most frequently in the late second or the third trimester of pregnancy. Most recently, Zhu et al. described the timing of pregnancy-related aortic dissection in 25 women; 2 out of them occurred in the first trimester, 9 during the second and third trimester, and 5 in the postpartum period. Moreover, type A aortic dissection was more common and occurred in 20 of the patients (80%), while type B was reported in 5 patients (20%). Hypertension was documented in seven (28%) of these patients; three of them carried a diagnosis of Marfan’s syndrome. Nineteen patients (76%) had moderate-to-severe aortic regurgitation, 18 of them were complicated by type A aortic dissection [9]. Chu et al. reported aortic root diameters in 24 cases with aortic dissection in pregnancy that ranged from 2.9–10.0 cm (average 5.6 ± 1.7 cm). Furthermore, Stanford type A dissection was seen in 17 out of 24 (71%) of these reported [16], while type B dissection was less common [17]. Pathophysiology The exact pathophysiology of aortic intimal tear and its propensity for medial dissection remains unknown; however, it is generally believed that intimal disruption represents an aberration in the ongoing process of vascular endothelial injury and repair. Physiologic increases in blood volume,

Cardiac Problems in Pregnancy, Fourth Edition. Edited by Uri Elkayam. © 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.

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stroke volume, and cardiac contractility coupled with the hormone-mediated changes in the vessel wall are implicated as the primary culprits that increase the risk for vascular dissections during pregnancy [18,19]. Hormonal changes seen in the connective tissue of pregnant experimental animals [20] that have also been mirrored in humans may increase propensity to arterial dissection [21]; however, the exact role of hormonal factors is unclear. Estrogens tend to inhibit collagen and elastin deposition in the aortic wall and progesterone accelerates the deposition of aortic noncollagenous proteins in the rat model [20]. Additionally, intimal hyperplasia seen in pregnancy or in hypertensive states has also been demonstrated in women treated with oral contraceptives. Alterations in the structure of the vascular wall during pregnancy are somewhat similar to changes seen in cystic medial necrosis [22,23]. Furthermore, this pattern of vascular fragility continually increases in severity throughout the gestational age peaking in the third trimester, which is the time of presentation of most cases of aortic dissection [9]. On the other hand, normal aortic wall architecture is also frequently demonstrated at autopsy of pregnancy related deaths and even in those complicated by aortic dissection [24]. In most cases of aortic dissection, a continuous intimal tear is identified in addition to disruption of the aortic media. Location of the tear that marks the beginning of the dissection is within 2 cm above the aortic valve cusps in about two-thirds of patients and the rest in the descending thoracic aorta immediately distal to the origin of the left subclavian artery with a very few in the aortic arch or below the diaphragm. The entrance tear is accompanied by a reentry tear in approximately 10% of patients, producing the socalled double-barrel aorta. Although dissection is a longitudinal separation of the media, the percentage of aortic circumference involved by the dissection at any particular level is variable. Typically, half of the aortic circumference is dissected and the other half remains intact. Dissections that begin in the ascending aorta generally involve the right lateral wall and course downstream along the greater curvature of the ascending, transverse, and descending thoracic aortas. Because of their location, involvement of the right coronary, innominate, left common carotid, and the left subclavian arteries is common. Classification of aortic dissections Classification is based on the location and extent of aortic dissection. 1 DeBakey classification: Type I begins at the ascending aorta and extends to the descending aorta, type II begins at the ascending aorta and does not extend beyond, and type III involves the descending thoracic aorta only. Type III dissection is subdivided into type IIIA, in which the dissection is limited to the thoracic aorta, and type IIIB, where the dissection extends below the diaphragm. 2 The Stanford classification: Type A is proximal and distal dissections are with extension into the aortic arch and ascending aorta, and type B is distal dissections.

3 More recently, a simplified descriptive classification has been widely accepted; it differentiates between proximal dissection (DeBakey types I and II or Stanford type A) and distal dissection (DeBakey type III or Stanford type B) [25]. Clinical presentation Most patients with aortic dissection present with severe chest pain that may radiate to the back, shoulders, and/or abdomen. Other symptoms are related to complications of the dissection. The most catastrophic complication is the rupture of the aorta with extravasation of blood into the pericardial space, pleural space, mediastinum, retroperitoneum, the pulmonary artery wall, interatrial septum, interventricular septum with or without involvement of the conduction system, lung, or esophagus. In addition, partial or complete obstruction of any artery arising from the aorta by the medial hematoma can occur. Arteries affected may include the coronaries (sudden death or myocardial infarction), innominate or common carotid (syncope, confusion, stroke, or coma), innominate or subclavian (upper limb ischemia or paralysis), intercostal or lumbar (spinal cord ischemia), celiac, renal, mesenteric, or common iliac arteries. Acute and severe aortic regurgitation can result from dilatation of the aorta or extension of the dissection to the level of the valve that may produce pulmonary edema. Obstruction of the aorta or pulmonary artery may produce circulatory collapse. The physical findings most commonly found in patients with aortic dissection include pulse deficits, murmur of aortic regurgitation, and neurological manifestations such as altered mental status, cerebrovascular accident, or paraplegia due to ischemia of the spinal cord [26]. Aortic dissection may be asymptomatic in 5–15% of cases; it occurs without the typical chest pain but with significant neurologic symptoms that may mask the underlying etiology and make the diagnosis more challenging [3]. Diagnostic testing Chest X-ray The most common finding on chest X-ray is widening of the mediastinum. Pleural effusion may be present (mostly on the left side in patients with distal dissection). It should be noted that chest X-ray findings in aortic dissection are nonspecific, and absence of abnormal finding should not exclude the possibility of a dissection. Aortography Aortography was the gold standard diagnostic modality for the diagnosis of aortic dissection. The limitations of this procedure include its inherent risks related to its invasive nature, use of ionizing radiation, and contrast material, however, aortography outlines the extent of the dissection, including branch vessel involvement. Other diagnostic tests such as contrast-enhanced computed tomography (CT), magnetic

CHAPTER 18 Vascular Dissections and Aneurysms During Pregnancy

resonance imaging (MRI), ultrasound, and transesophageal echocardiography (TEE) provide additional details of the extent and severity of aortic regurgitation and the status of the coronary arteries [27]. Cardiac CT CT scan with contrast offers sensitivity and specificity approaching 95–98% for diagnosis of acute aortic dissection. Unlike aortography, CT is noninvasive but is also associated with the use of radiation and contrast material. Magnetic resonance imaging (MRI) MRI has demonstrated a sensitivity of 95–98% and a specificity of 94–98% for aortic dissections [28]. MRI is especially useful to distinguish aortic dissection from other aortic abnormalities such as thoracic aortic aneurysm or prior aortic graft repair. In addition, this modality is effective in diagnosing the presence of a thrombus, the site of an intimal tear, pericardial effusion, and aortic regurgitation. MRI, however, has a number of limitations including limited view of branch vessels and inability to use it for unstable patients and for patients with pacemakers and old generation heart valves. Echocardiography and abdominal ultrasound Transthoracic echocardiography (TTE) provides only limited diagnostic information in patients with aortic dissection and does not allow visualization of the distal ascending aorta and arch. The yield of Doppler echocardiography is high in the diagnosis of aortic dissection-related complications such as bleeding into the pericardial sac, aortic regurgitation, or wall motion abnormalities. TEE is a relatively noninvasive procedure that overcomes the limitations of TTE and has a sensitivity and specificity of 99% and 89% for aortic dissection [27]. If sub-diaphragmatic dissection is suspected, abdominal ultrasonography may be of considerable value. Abdominal roentgenograms have no role in the pregnant population, where atherosclerosis is rare and radiation exposure should ideally be avoided. Electrocardiogram (EKG) Electrocardiogram (EKG) is of little value in the diagnosis of aortic dissection, but it may be useful in revealing an acute myocardial infarction if there is involvement of the coronary arteries. EKG may demonstrate pericarditis in patients with bleeding into the pericardial sac and left ventricular hypertrophy in patients with long-standing hypertension or aortic coarctation, which are known risk factors for dissection. d-dimer A d-dimer level of 40 mm with or without additional risk factors [105]. Although previous studies reported favorable maternal and fetal outcomes during pregnancy associated with aortic diameter 45 mm and increasing rapidly [81]. Cardiac surgery during pregnancy has been reported to carry a high risk of mortality for the fetus (15–30%) and increased maternal mortality (especially in urgent surgery) compared to the nonpregnant women (2–14%) [112]. Recent publications describing urgent cardiac surgery in 12 pregnant women for severe valvular disease, reported maternal mortality of 8.7% and extremely high intrauterine death (10 out of 12) [113]. Yates et al. [70] reported in 2015 on a series of 11 women who delivered their baby after aortic surgery including aortic root and/or valve replacement without maternal death, but still with high fetal mortality of 27% due to intrauterine demise within 1 week of surgery. Another recent report has suggested similar low maternal mortality (1.5%) to that associated with nonemergent cardiac surgery in nonpregnant women [112]. Since the risk associated with emergency operations for aortic dissection or rupture is high, elective surgery has been

CHAPTER 19 Marfan Syndrome and Pregnancy

recommended in cases of progressive, >5 mm dilation of the aorta during pregnancy either after a therapeutic abortion (up to 20 weeks) or during pregnancy [10,81,83]. Successful surgery during gestation or shortly after delivery has been described in a number of women for a marked dilatation of the aorta [114] and for aortic dissection (Table 19.2) [17,22,25,27,33,40,70,112]. Zeebregts et al. [25] described the outcome of six women presenting with acute aortic dissection in pregnancy; two underwent emergency caesarean section delivery immediately followed by successful aortic repair but only one infant survived. Two other women underwent cardiac surgery with in utero fetuses with successful outcomes for both mothers and babies and two other women with type B aortic dissection survived with medical therapy only, but both fetuses died from asphyxia. As discussed previously cardiac surgery during pregnancy, in general, and aortic surgery, in particular, have been shown to result in a high rate of fetal loss [22,33,70,112,115,116]. For this reason, if fetal maturity can be confirmed, a Csection delivery should be done before or concomitantly with thoracic surgery [21,22,81]. Termination of pregnancy should be considered when aortic dissection occurs early, taking into account the significant risk of fetal complication and loss associated with surgery during pregnancy [70]. In our review of the literature, fetal mortality was reported early (before 20 weeks of gestation) in four out of seven cases due to termination of pregnancy in two (one hysterectomy, one elective abortion) and due to intrauterine fetal death in the last two (Table 19.2). Optimal perioperative management including full maternal and fetal monitoring, attention to cardiopulmonary bypass (CPB), pulsatile perfusion, near-normothermia, maintenance of high flow rate (>2.5 l/min/m2 ), mean blood pressure >70 mmHg, hematocrit >28%, avoidance of maternal hypoglycemia and hypoxia, placing the patient in the lateral position during CPB to avoid inferior vena cava compressing and avoidance of vasoconstrictors, all have been reported to decrease risks of surgery for both the mother and the baby [70,113,116,117]. Recently, the thoracic endovascular aortic repair has been introduced for the management of patients with type B aortic dissection [5]. Data from the International Registry of Acute Aortic Dissection has suggested a lower mortality over a fiveyear period associated with this technique compared with medical therapy [117]. Only limited information from isolated case reports is available on the use of this technique as a bridge to open surgery in pregnant women with MFS [118].

Medical therapy As high blood pressure may increase the risk of aortic complications, strict blood pressure control is recommended for all pregnant women with MFS. Several studies have demonstrated that β-blockers, such as propranolol, atenolol, or metoprolol, increase aortic distensibility and reduce aortic stiffness and pulse wave velocity, especially in young patients and in those with aortic root diameters 26 mm in the proximal descending thoracic aorta, and >24 mm in the distal descending thoracic aorta [6]. Dilation of the aorta is defined as two standard deviations from the expected norm for CT or MRI [6]. Aortic dissection is defined as evidence of an intimal flap with a true or false lumen regardless of which imaging modality was employed [7–9].

The aorta during pregnancy in patients without an underlying aortopathy Approximately half of aortic dissections or ruptures that occur in females under the age of 40 years are associated with pregnancy [10]. More than half of the pregnancy-related aortic dissection/ruptures occur during the third trimester and a third occur during the postpartum period [11,12]. These high event rates are thought to be primarily related to the hemodynamic and hormonal changes unique to pregnancy and the postpartum period, which results in a weakening of the aortic structural integrity as well as an increase in aortic wall tension and intimal shear forces. Specifically, high circulating serologic levels of estrogen and progesterone have been demonstrated to induce reticulin fiber fragmentation as well as elastin fiber disorganization thus weakening the structural integrity of the aorta [11–16]. Furthermore, an increased blood volume by nearly 50% [17,18] coupled with an increased heart rate results in a 60–80% higher cardiac output at the time of birth than pre-pregnancy, thereby resulting in further hemodynamic stress upon the aorta [19].

Cardiac Problems in Pregnancy, Fourth Edition. Edited by Uri Elkayam. © 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.

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While typically systemic vascular resistance drops during pregnancy, aortoiliac compression from the gravid uterus may result in increased vascular resistance [20]. Sequelae of these changes are that the aorta faces greater wall tension and intimal shear forces during pregnancy, specifically during the third trimester and early postpartum period, with studies demonstrating that it may take up to six weeks for cardiac output to return to pre-pregnancy levels [21]. It remains uncertain if these hemodynamic and physiological changes result in permanent dilatation of the aorta after pregnancy. In a cross sectional study of healthy females, Gutin et al. demonstrated that multiparous women had larger aortic diameters than null or uniparous females [22]. Ducas et al., however, assessed aortic root and ascending thoracic aortic dimensions in 34 healthy patients prior to and after pregnancy and did not demonstrate a statistically significant change in the aortic caliber [23]. Regardless of whether or not the aortic caliber does indeed change in the healthy female, the aforementioned physiological and hormonal changes that occur during pregnancy may result in devastating consequences for the pregnant patient with an underlying aortopathy.

General management considerations For each of the aortopathies discussed, including BAV, the recommendations portion will follow the general outline of (i) pre-pregnancy counseling, (ii) imaging assessment, (iii) pharmacological management, and (iv) delivery as well as immediate postdelivery considerations (Table 20.1 and Figure 20.1). Recommendations will often be similar for the different aortopathy groups with some important exceptions, which will be highlighted in the respective sections. All patients with aortopathy contemplating pregnancy should be cared for by a multidisciplinary team. This team consists of a maternal–fetal medicine (MFM) specialist, cardiologist and depending on the nature of the aortopathy a geneticist, and occasionally cardiac or vascular surgical care teams. If a pregnancy is planned and deemed moderate or high risk, then delivery should be coordinated by an experienced MFM specialist, obstetrical anesthesiologist, and cardiologist. Peripartum care and delivery should be performed at a tertiary medical center for moderate and highrisk patients, where prompt cardiac surgical care is available. The highest risk patients may need to be delivered in a cardiac surgical operating room with cardiopulmonary bypass available in case of an aortic emergency.

Bicuspid aortic valve (BAV) Background Considered the most common form of congenital heart disease, the prevalence of BAV ranges from 0.5% to 2% of the population with a roughly 3 : 1 male predominance [24]. BAV is inherited in an autosomal dominant fashion with incomplete penetrance. However, both its male predominance and association with Turner syndrome suggest

a possible X-linked etiology [24]. Given that the aortic valve and the ascending aorta share a common embryologic origin from neural crest cells [25–27], it is not surprising that aortic pathology in this patient group is common with 7% of patients demonstrating aortic coarctation [24] (discussed in the following section) and 50–87% developing aortic dilatation, typically involving the aortic root and ascending thoracic aorta [28–30]. Fibrillin-1, a structural fiber essential for maintaining aortic wall integrity, is deficient in the BAV patient resulting in aortic histopathological changes similar to those demonstrated in the Marfan population [31]. Specifically, similar to the Marfan aorta, the aorta in BAV demonstrates increased matrix metalloproteinase levels, cystic medial necrosis, and, as noted, reduced fibrillin-1 [24,31,32]. The lack of fibrillin1 results in apoptosis of vascular smooth muscle cells, cells that are responsible for the maintenance of the aortic media [31]. With the underlying structure of the aortic wall already compromised, increased tensile and shear stress secondary to a higher volume load experienced by the aorta due to aortic regurgitation from the bicuspid valve can lead to further aortic dilation [33–35]. Even in BAV patients without aortic regurgitation or aortic stenosis, the simple shear stress from turbulent flow through the BAV can place further strain on the already compromised aortic wall [36]. Aortic growth rates in the BAV population vary widely from 0.3 to 2 mm each year with 40% of patients demonstrating stable aortic size over many years [1,11,12]. Studies have suggested that an increased rate of aortic dilatation was associated with (i) a greater baseline diameter [37], (ii) presence of aortic valve regurgitation or stenosis [28,30,37], and (iii) increased aortic stiffness [38]. When compared to an age-matched population, aortic dissection is over eight times more likely in the BAV patient [37]. However, the size at which the aorta dissects is similar to that of patients with degenerative aortic aneurysms [39]. Patients with BAV should undergo initial surveillance of the aortic root, ascending aorta, and arch to determine whether aortic dilatation is present. This can often be achieved by transthoracic echocardiography (TTE), but if images are difficult to acquire, CT or MRI can be implemented. When the aorta is enlarged, cross-sectional imaging is often suggested to confirm the aortic size measured by TTE, and to assess portions of the aorta incompletely visualized by TTE. Serial assessment of the aortic root, ascending aorta and aortic arch should be performed to assess for the development or progression of aortic aneurysm [40]. Surveillance intervals should be at least annually if the aortic caliber is ≥4.5 cm [40]. Clinical trials are ongoing to assess whether β-blockers (specifically atenolol) and angiotensin receptor blockers (ARBs, specifically telmisartan) can effectively slow or prevent aortic dilatation in BAV patients compared to placebo (NCT01202721). Current guidelines for surgical intervention for aortic aneurysm in patients with BAV depend upon the presence or absence of risk factors that

CHAPTER 20 Non-Marfan Aortopathies and the Pregnant Patient

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Table 20.1 The aortopathies in the pregnant patient Aortopathy Bicuspid aortic valve

Aortic coarctation

Pathophysiologic/ clinical background

Surgical indications

Experience in pregnancy

Special pregnancy considerationsa

q q q

q

q

q

q q

Vascular Ehlers–Danlos syndrome

q q q

q

AD, male predominant Fibrillin-1 deficient Associated with Turner syndrome, aortic coarctation, and aortic dilatation

Genetic predisposition and association with Turner syndrome and bicuspid aortic valve Generalized aortopathy with similar histopathology as bicuspid aortic valve

AD (˜50% of cases de novo mutation) COL3A1 gene mutation results in abnormal type III procollagen Predisposed to arterial aneurysms or ruptures, intestinal or uterine rupture, hypermobility of small joints and thin translucent skin 80% have major complication by age 40 with median survival of 50 yr

q

q

q q

Ascending thoracic aortic size ≥5.5 or ≥5.0 cm if risk factors presentb ≥4.5 cm if undergoing aortic valve replacement

Peak–peak gradient ≥20 mmHg or radiologic evidence of significant collateral flow

High perioperative mortality (46% by some studies) Surgical intervention discouraged unless for life threatening condition

q

q

q

q

88 patients with 216 pregnancies with no aortic dissection and no dilatation of the aorta during pregnancy 89 pregnant patients with no aortic dissection and no dilatation of the aorta during pregnancy

50 patients with 118 pregnancies. One patient mortality due to type A dissection, high rate (30%) of hypertension 54 patients with 126 pregnancies with a higher miscarriage (18%) and hypertensive (18%) incidence compared to the national average

565 pregnancies demonstrated a maternal mortality rate of 5.3% causes of death included three aortic ruptures, one iliac artery rupture, and wound dehiscence after delivery. >50% of deliveries were complicated with 14.5% resulting in life-threatening complications

q q q q

q q q

q q

q q

q

q

Pre-pregnancy counseling regarding AD inheritance pattern Consider prophylactic surgery prior to pregnancy if aorta is ≥5.0 cm Surveillance imaging with TTE every 4–8 wk and until 6 mo postpartum No ACEi or ARBs during pregnancy (can restart postpartum). β-blocker use recommendedc Vaginal delivery reasonable if aorta is 4.0 cm Pre-pregnancy counseling regarding risk of aortic coarctation or other CHD in child Consider prophylactic surgery if hemodynamically significant coarctation or aortic dilatation ≥5.0 cm Surveillance imaging with TTE every 4–8 wk and until 6 mo postpartum. If cross-sectional imaging needed then MRI without gadolinium No ACEi or ARBs during pregnancy (can restart postpartum). β-blocker use recommendedc Uncertainty regarding ideal method of delivery. Consider pros and cons of assisted-vaginal delivery vs. cesarean section (see text for details) Given extremely high-risk pregnancy is highly discouraged Pre-pregnancy counseling regarding AD inheritance pattern with prenatal testing available for detection of pathologic variant of the COL3A1 gene Consider surveillance imaging of the entire arterial vasculature before pregnancy, during pregnancy, and in the peripartum period No ACEi or ARBs during pregnancy (can restart postpartum). β-blocker use recommendedc (continued)

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Table 20.1 (Continued) Aortopathy

Pathophysiologic/ clinical background

Surgical indications

Experience in pregnancy

Special pregnancy considerationsa

q

Loeys–Dietz syndrome

q q q q

AD Mutation in TGF-β, TGFBR1 or TGFBR2, or SMAD3 gene Characterized by arterial tortuosity and hypertelorism and a bifid uvula High risk of vascular complications with initial life expectancy to be 26.1 yr (improving recently given enhanced detection and earlier intervention)

q

q

q

Ascending thoracic aorta >4.0 cm (or growth rate >0.5 cm/yr) Descending thoracic aorta >4.5–5.0 cm (or growth rate >1 cm/yr) Abdominal aorta >4.0–4.5 cm (or growth rate >1 cm/yr)

q

85 patients with 217 pregnancies reported 3 (1%) maternal deaths and 15 (7%) severe complications (including aortic and vertebral artery dissection)

q

q

q

q q

Safest mode of delivery unknown (assisted-vaginal delivery vs. cesarean section). Specific surgical care to avoid damage to fragile tissue and arterial walls Pre-pregnancy counseling regarding AD inheritance pattern. Prenatal diagnosis can be made preimplantation or via amniocentesis or chronic villus sampling Consider prophylactic surgery prior to pregnancy if aorta has reached surgical threshold (ascending aorta >4.0 cm, descending aorta >4.5–5.0 cm, abdominal aorta >4.0–4.5 cm) Surveillance imaging of the entire arterial vasculature before pregnancy. TTE at monthly or bimonthly intervals and cross-sectional imaging with MRI if clinically indicated No ACEi or ARBs during pregnancy (can restart postpartum). β-blocker use recommendedc Safest mode of delivery unknown (assisted-vaginal delivery vs. cesarean section)

ACEi – angiotensin converting enzyme inhibitors; ACTA – alpha-actin; AD – autosomal dominant; ARB – angiotensin receptor blocker; COL3A1 – collagen type III alpha 1 chain; MRI – magnetic resonance imaging; MYH – myosin heavy chain; SMAD3 – mothers against decapentaplegic homolog 3 gene; TGF-β – transforming growth factor beta receptor β ligand 2 gene; TGFBR1 – transforming growth factor receptor I; TGFBR2 – transforming growth factor receptor II; TTE – transthoracic echocardiogram. See text for supporting references. a All aortopathy patients considering pregnancy should be evaluated by a team of multidisciplinary specialists and risks of pregnancy should be discussed with the patient (see text for details). b Risk factors include family history of aortic dissection, pregnancy or rapid rate of aneurysm growth (≥0.5 cm/yr). c Avoid hydrophilic β-blockers such as atenolol and carvedilol. In general, metoprolol and labetalol are considered safe.

predispose the patient to aortic dissection/rupture. If risk factors are present such as family history of aortic dissection, planned pregnancy, or rapid growth rate (≥0.5 cm/yr), then surgical intervention should be considered when the aortic size has reached 5.0 cm, and if none of these risk factors are present, then surgical repair is typically performed when the aortic caliber is ≥5.5 cm [40]. If the patient is undergoing aortic valve replacement, or another cardiac surgical procedure, then concomitant repair of the dilated aorta is recommended if the aortic caliber is ≥4.5 cm [40,41].

Experience in pregnancy Several studies report the safety of pregnancy in the BAV population. The community-based study conducted by McKellar et al. analyzed 88 women with BAV, who had a total of 216 pregnancies and 186 deliveries [42]. Five of the women included in this study had an aorta dimension greater than 4.0 cm, and one woman had an aorta dimension greater than 5.0 cm. The study found that pregnancy was not associated with further dilation of the aorta, aortic surgery, or aortic valve replacement. Furthermore, the authors noted that no

CHAPTER 20 Non-Marfan Aortopathies and the Pregnant Patient

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Preconception – Comprehensive clinical, genetic, and imaging assessment – Medication review and adjustment (stop ARB/ACE, start beta-blocker) – Counseling regarding risk of pregnancy and likelihood of fetal inheritance – Prophylactic aortic surgery if guidelines are met*

Acute aortic syndrome – Immediate pharmacologic therapy to reduce the double-product with concomitant fetal heart rate surveillance

Pregnancy

– Disease proximal to left subclavian artery->urgent surgery

– Comprehensive care by a multidisciplinary team at a tertiary referral center

– Disease distal to left subclavian artery->medical therapy and monitoring

– β-blocker therapy*

– Aortic surgery indicated and fetus ≤24 wk then fetus should remain in utero, If fetus ≥30 wk then concomitant cesarean suggested during aortic repair (individualized for 24–30 wk)

– Surveillance imaging of the aorta** – Review delivery plan

Delivery/postpartum – Assisted vaginal delivery vs. cesarean section – Continue close clinical and aortic surveillance for six months postpartum then return to preconception monitoring Figure 20.1 Management overview of the pregnant patient with an aortopathy. ACEi – angiotensin converting enzyme inhibitors; ARB – angiotensin receptor blocker. *See text and Table 20.1 for details. **Type and extent of imaging dependent on underlying aortopathy (see text for details).

aortic dissections occurred in the patient population and ultimately concluded that aortic dissection in pregnant women with BAV is rare. The second study of 89 pregnant patients with BAV demonstrated similar findings with no patients developing aortic dissection during pregnancy or in the postpartum period (with the largest aorta in this study measuring 4.4 cm) [43]. Furthermore, this investigation noted that the aortic diameter did not change in this population during pregnancy. Therefore, the two largest series to date of BAV and pregnancy have demonstrated good outcomes in this patient population with an important caveat that only one of the patients studied had an aortic caliber greater than 5.0 cm. Recommendations for management Prior to conception, the patient with BAV should undergo counseling as to the autosomal dominant heritable nature of the disease [32,44,45]. In conjunction with pre-pregnancy counseling, imaging should be obtained of the entire aorta. We favor MRI given its lack of ionizing radiation. Prophylactic aortic replacement surgery prior to pregnancy should be considered when the patient has reached the threshold (≥5.0 cm in the BAV patient considering pregnancy

as pregnancy is considered a risk factor for dissection) [46]. Surveillance aortic imaging should be individualized depending on the aortic size with some authors suggesting surveillance every four to eight weeks throughout the pregnancy and continued until six months postpartum [45,47]. However, more recent investigations have suggested a relatively low incidence of aortic dissection in the BAV population when compared to other aortopathies such as Marfan syndrome [48] and therefore imaging once a trimester rather than every one to two months would be reasonable. This imaging can generally be performed with TTE, if there is correlation between TTE and cross-sectional imaging aortic measurements, and the dilated aorta segment involves a portion easily imaged by TTE. BAV aortic enlargement typically involves the mid-ascending aorta, aortic sinuses, and less often the aortic arch, which is usually easily assessed by echocardiography. If advanced cross-sectional imaging is required, then MRI without gadolinium (given its ability to cross the placenta and concern for potential fetal harm) should be utilized (note, pregnant patients undergoing MRI should be informed of the theoretical risk of potential auditory damage to the developing fetus).

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Pharmacological management should be reviewed before pregnancy, as critical changes may needed to be made to the patient’s regimen. For instance, β-blockers and ARBs are often administered in the BAV population in hopes to arrest or at least slow the rate of aortic dilation. However, ARBs should not be utilized during pregnancy, given their teratogenic potential [43] and are generally avoided during lactation. The mainstay of pharmacologic treatment for the BAV patient during pregnancy is therefore β-blockers. However, both the physician and the patient should be aware that βblockers can have a negative impact on fetal development particularly with concern for possible intrauterine growth retardation and apnea. Specifically, atenolol and carvedilol should be avoided given their hydrophilic nature and in general metoprolol and labetalol are preferred during pregnancy. β-blockers are also safe to use during lactation. Rigorous blood pressure assessment should be performed throughout the pregnancy and postpartum period with pharmacologic adjustments made as needed. For the BAV patient, vaginal delivery is preferable if the maximal aortic dimension is 4.5 cm [32,44,45]. If there is suspicion of fetal BAV, fetal echocardiography should be performed. Further details regarding the benefits and limitations of different modes of delivery in the aortopathy patient will be discussed in more detail in the Loeys–Dietz section.

Aortic coarctation Background With some exceptions for anatomic variations, aortic coarctation typically manifests as a discrete narrowing of the thoracic aorta distal to the left subclavian artery. This is usually a congenital anomaly; uncommonly, it is acquired related to trauma, atherosclerosis, or scar formation from inflammatory aortitis. Aortic coarctation accounts for 5–8% of all congenital heart disease [47,49], and survival of these patients into adulthood, and therefore childbearing age, is expected [50]. There is a genetic predisposition for the development of aortic coarctation, and it is found in 12% of patients with Turner syndrome [51]. A total of 60% of patients with aortic coarctation also have BAV [32,52]. Therefore, it is not surprising that similar histopathological changes of the aorta are seen in these patients as noted in patients with Marfan syndrome or BAV (described in the BAV section) [32,53]. Given that aortic coarctation results in a generalized aortopathy, rather than simply pathology at the coarctation site, timing of appropriate surgical repair and life-long imaging surveillance are critical. For the region of coarctation, intervention is recommended when the peak-to-peak gradient across the area of narrowing is ≥20 mmHg or if there is radiologic evidence of aortic narrowing and significant collateral arterial flow [47]. Postoperative studies have demonstrated

both recoarctation, and dilatation at the operative site [47,49]. The incidence of aneurysm formation at the repair site has been estimated to be 14% and dissection/rupture at 2.5% [52,54]. Furthermore, even without significant recoarctation, these patients are at an increased risk of aneurysm formation and dissection [50,55]. There is little evidence to guide appropriate timing of intervention on aortic dilatation in patients with aortic coarctation, but given the histopathological similarities to BAV, and its common occurrence in this disorder, it may be reasonable to follow similar guidelines (outlined in the BAV section) [51]. Lastly, these patients should have follow-up with an adult congenital heart disease specialist and regular assessment of the aorta [49]. Experience in pregnancy Two studies assessing outcomes in pregnant patients with aortic coarctation have been informative as to understanding how to manage these patients. The first, conducted by Beauchesne et al., was a tertiary referral center study that assessed 50 patients who had a total of 118 pregnancies [56]. Of these patients, 30 (60%) had coarctation repair prior to pregnancy, 10 (20%) with repair after pregnancy, 6 (12%) with no repair, and 4 (8%) with repair both before and after pregnancy. About 13 (26%) of these women had been advised against pregnancy due to concern for either maternal or fetal health. About 19 (38%) patients had a hemodynamically significant coarctation (defined as a peak–peak gradient of ≥20 mmHg) during their pregnancy. Compared to the US national average of 22% [57], approximately a third of pregnancies in this cohort were delivered by cesarean section. Two critical findings from this patient cohort were a documented miscarriage rate (9%) and a preeclampsia rate (2%) similar to that of the US national average [58,59], but a hypertensive rate during pregnancy (30%) that was markedly higher than the national average (1–5%) [60]. The development of hypertension during pregnancy in these patients was associated with the concomitant presence of a hemodynamically significant coarctation (p = 0.002). There was no difference in maternal or neonatal outcomes between patients who had and had not undergone prior surgical repair of their coarctation. Unfortunately, there was one patient death from an ascending aortic dissection at 36 weeks of pregnancy. This patient had a history of Turner syndrome and BAV who became pregnant by in vitro fertilization. Her maximal aortic size at the time of dissection was 2.9 cm. No pre-pregnancy congenital cardiac assessment was performed in this patient. The second study of note was a national registry of 54 patients with aortic coarctation who had a total of 126 pregnancies [61]. Five (9%) of these patients had a residual gradient across the repaired aortic coarctation site (defined as ≥15 mmHg). Unlike the investigation of Beauchesne et al., all of these patients had previously undergone aortic coarctation repair, and there was less frequent utilization of cesarean section as the method for delivery (7%). Furthermore, the miscarriage rate was higher in this study (18%) than the national average and more comparable to the rate

CHAPTER 20 Non-Marfan Aortopathies and the Pregnant Patient

in women with other forms of congenital heart disease [62]. However, similar to the prior study, Vriend et al. noted a higher rate of hypertension in pregnant patients with aortic coarctation (18%) than what is expected in the general population. No maternal mortality was reported. Recommendations for management A multidisciplinary approach, ideally initiated prior to conception, provides the best opportunity for good outcomes in the pregnant patient with aortopathy related to aortic coarctation. Pre-pregnancy counseling should entail a discussion regarding the risk of recurrence of aortic coarctation or another congenital heart lesion in the child [63] noting that the exact patterns of inheritance for aortic coarctation are complex [64,65]. Given not only the risk of a significant gradient at the aortic coarctation site but also the risk for aneurysm formation (either at the site of repair or elsewhere in the aorta), the patient with aortic coarctation contemplating pregnancy should undergo a thorough imaging evaluation of the thoracic aorta including hemodynamic assessment of the site of aortic coarctation. Any evidence of hemodynamically significant coarctation should be repaired prior to conception to ensure both the health of the mother as well as appropriate placental perfusion. While specific guidelines are lacking, repair of aortic aneurysm related to aortic coarctation should be conducted along similar recommendations for those patients with a BAV (≥5.0 cm). Furthermore, given the risk of intracranial aneurysm formation in this population, appropriate brain imaging should be considered prior to conception. During pregnancy surveillance, imaging with echocardiography can be individualized depending on residual lesions. When the aorta demonstrates residual abnormalities, imaging is considered every four to eight weeks to assess both aortic coarctation as well as aortic dilatation. If cross-sectional imaging is needed, then MRI without gadolinium enhancement would be the modality of choice. Similar to the recommendations for BAV, blood pressure should be well controlled in this population throughout pregnancy with the use of agents such as β-blockers, hydralazine, or methyldopa [66]. As with BAV and other types of maternal congenital heart disease, fetal echocardiography is generally recommended. As reflected in the varied methods of delivery reported in the aortic coarctation population [56,67], there is uncertainty as to whether cesarean section vs. vaginal delivery is ideal for patients with aortopathies. Those in favor of cesarean section note that surgical delivery obviates the need for the Valsalva maneuver during delivery and the consequential increase in blood pressure which could have potentially devastating consequences for the aorta (as well as for intracranial aneurysms) [68]. Alternatively, others have advocated for vaginal delivery with low-dose epidural analgesia and elective instrumental delivery as a means to both avoid the Valsalva maneuver as well as specific risks of surgical delivery including general anesthesia, bleeding, infection, and the potential need for oxytocin [69]. We recommend against the use of oxytocin

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as it has unpredictable cardiovascular effects that may further stress the aorta in the pregnant patient including increasing preload via stimulation of uterine contractions as well as inducing hypotension and accompanying reflex tachycardia [70,71]. Given the lack of current consensus, a thorough discussion of options, cesarean section or assisted vaginal delivery, should be discussed by the multidisciplinary team and with the patient.

A special note Turner syndrome Turner syndrome results from complete or partial loss of the X chromosome with a prevalence of approximately 0.0005%. Cardiovascular abnormalities are common in Turner syndrome patients and include aortic valve abnormalities (primarily BAV) in 15–30%, elongated transverse aortic arch in 40–50%, and aortic coarctation in 12% [72]. Approximately, 6% of these patients will develop aortic dilatation [50]. Given the typical short stature of these patients, aortic caliber should be indexed to BSA with an ascending aorta ≥2.0 cm/m2 considered to be dilated and ≥2.5 cm/m2 a risk for dissection. Turner syndrome is the most common cause of premature ovarian failure; thus, conception and pregnancy can be challenging and may require enhanced reproductive techniques. Consequently, Turner patients often undergo preconception counseling which is an ideal time to assess the potential risk to the aorta during pregnancy. Prior to conception crosssectional imaging with either CT or MRI is recommended to fully evaluate the aorta particularly for the presence of aortic dilatation and/or aortic coarctation. Pregnancy should be avoided if the indexed aortic size measures ≥2.0 cm/m2 with the presence of one more of the following risk factors: BAV, elongation of the transverse aorta, aortic coarctation, or hypertension [73]. Pregnant Turner patients with a normal sized aorta and without any of the aforementioned risk factors should have aortic imaging assessment at least once during pregnancy, generally around 20 weeks gestation [73]. If aortic dilatation or any risk factors for dissection are present, then aortic imaging assessment is recommended every one to two months [73].

Vascular Ehlers–Danlos syndrome (vEDS) Background vEDS is an autosomal dominant disorder with near-complete penetrance (with approximately half of the cases arising from a de novo mutation) [74]. The exact prevalence of the disease is unknown, but it is estimated to afflict roughly 1500 individuals in the United States [74]. In vEDS, a pathologic variant in the collagen type III alpha 1 chain (COL3A1) gene results in abnormalities of type III procollagen production, which is a scleroprotein responsible for structural integrity in connective tissue including the skin and vascular system. Clinically,

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this syndrome should be suspected if a patient presents with arterial aneurysms or ruptures, intestinal or uterine rupture, hypermobility of the small joints, fragile, thin translucent skin particularly on the chest or abdomen, and pneumothorax or a family history of vEDS [74]. Clinical suspicion of the disease is confirmed through either identification of a pathologic variant in the COL3A1 gene or a biochemical analysis that reveals abnormal type III procollagen production. Unfortunately, the sequelae of vEDS can have devastating consequences with a retrospective review of 1200 affected individuals revealing that 80% had a major complication by age 40 and median survival is reported to be 50 years of age [75]. These serious complications are typically a result of an arterial, uterine, or intestinal rupture [74]. While there has been some suggestion that the β-blocker (celiprolol) may be beneficial in preventing complications of vEDS, further assessment is needed to prove its efficacy [76]. Given the extreme fragility of the connective tissue and the vasculature, surgical intervention is discouraged in this patient population unless life-threatening circumstances arise [61,77]. A retrospective review of 31 vEDS patients undergoing surgery reported a 46% procedure-related mortality and 40% graftrelated complications (anastomotic site aneurysms, graft thrombosis, and graft disruption) [61]. Given that surgery is discouraged for all but the most concerning vascular finding [61,77,78], there is debate as to whether or not these patients should undergo routine imaging. Some experts have argued against pursuing imaging since intervention is discouraged and results will only increase patient anxiety [79]. Others have noted the high yield of diagnostic imaging with 50% of vEDS patients having incidental vasculature findings which may aid in shared decision-making regarding when and if intervention may be required [61]. Experience in pregnancy Despite the low prevalence of vEDS coupled with the reduced life expectancy of those afflicted with the disease, there is a relatively large study that aids our understanding of vEDS during pregnancy. A study of 565 pregnancies in patients with vEDS revealed a 5.3% maternal mortality rate [80]. Causes of death included three aortic ruptures (two of which occurred at term delivery and the third one week after an uncomplicated cesarean section), iliac artery rupture following a mechanical fall at 33 weeks gestation and wound dehiscence after a cesarean section at 36 weeks gestation. Over half of the deliveries were complicated with 14.5% of deliveries resulting in life-threatening complications. With the exception of third- and fourth-degree lacerations occurring during vaginal delivery, too few events occurred in this study population to allow for assessment of which mode of delivery resulted in the fewest complications. Recommendations for management Given limited data involving vEDS and pregnancy, no specific guidelines for management of pregnancy in vEDS currently exist. Many experts either discourage pregnancy [81]

or suggest that it is contraindicated [77]. As a result, those who care for female vEDS patients are encouraged to review contraceptive options, pregnancy risks, and management of inadvertent pregnancies with their patients [61]. If pregnancy is desired, it is imperative that the patient be followed closely at a tertiary center with experience in care for vEDS with a multidisciplinary team comprised of MFM specialists, geneticists, cardiologists, anesthesiologists, and cardiac and vascular surgeons. Once pregnant, the patient can be offered prenatal testing for detection of a pathologic variant of the COL3A1 gene in the fetus or if unknown, then chorionic villus sampling can be obtained and biochemical testing performed [74]. Similar to the other aortopathies, teratogenic medications such as ARBs or ACE (angiotensin converting enzyme) inhibitors should be stopped, and hypertension addressed with the use of β-blockers or other agents (Chapter 24). As discussed previously, the routine use of surveillance imaging in the vEDS population has been debated given recommendations only to intervene in life-threatening situations. Despite the lack of imaging guidelines, it would be reasonable to consider a comprehensive imaging assessment of the entire arterial vasculature prior to or in the early stages of pregnancy in an effort to try and foresee any issues that might develop during the pregnancy and formulate potential plans for intervention. Findings from this initial assessment could guide further surveillance throughout the pregnancy and early postpartum period. Given the lack of data, the safest method of delivery in the vEDS is unknown, but some have advocated for cesarean section with or without the concomitant use of desmopressin to prevent hemorrhage [82,83]. During the actual delivery process, caution should be taken with use of retractors so as to avoid damage to adjacent bowel and soft arterial clamps are recommended [61]. Furthermore, care should be utilized to avoid damage to the arterial wall during suture placement [79]. As with the other aortopathies, close follow-up is warranted in the postpartum period.

Loeys–Dietz syndrome (LDS) Background Characterized initially in 2005, LDS is an autosomal dominant connective tissue disorder with an unknown prevalence [84,85]. It results from a mutation in the transforming growth factor beta receptor β ligand 2 gene (TGF-β), transforming growth factor receptor I (TGFBR1) and transforming growth factor receptor II (TGFBR2) genes, or the mothers against decapentaplegic homolog 3 gene (SMAD3) [57,84–88]. Clinically, LDS is characterized by hypertelorism and a bifid or broad uvula as well as generalized arterial tortuosity with a substantial risk of aneurysm formation, rupture, or dissection [84,85]. The diagnosis of LDS is made when a gene mutation is found in correlation with an arterial aneurysm or dissection. Unfortunately, LDS often has an aggressive course in regard to the development of arterial dissections and

CHAPTER 20 Non-Marfan Aortopathies and the Pregnant Patient

ruptures particularly in the patient with marked craniofacial features [84]. Aortic dissection has been documented to occur in patients as young as 3 months [89,90] and mean age of death in the initial series was 26.1 years [84]. Fortunately, with increased recognition of this disease process coupled with enhanced imaging techniques and early medical and surgical interventions, reported life expectancy has increased for the LDS patient. Baseline cranial to pelvic imaging assessment of the vascular tree is recommended in this patient population, and repeat imaging is generally recommended at least every two years [91] as well as annual TTE examinations [92]. Medical management with β-blockers to reduce hemodynamic stress on the vasculature as well as ARBs due to their impact on the TGF-β singling pathway is recommended in the nonpregnant patient [93–95]. Decision to refer for surgical repair of an aortic aneurysm in the LDS patient is dependent upon location of the aneurysm, rapidity of growth, genotype, family history, and desire to carry a pregnancy [91]. General adult guidelines suggest intervening on the aortic root, ascending aorta, and aortic arch if the dimension is >4.0 cm or rapid growth is documented (>0.5 cm/yr), repairing the descending thoracic aorta when the dilatation has reached 4.5–5.0 cm or rapid growth is noted (>1 cm/yr) and intervening on the abdominal aorta between 4.0 and 4.5 cm or again if marked growth is noted (>1 cm/yr) [91]. Postoperatively continuing clinical follow-up and imaging surveillance is warranted given the risk for aortic aneurysm formation both proximal and distal to grafts as well as coronary artery button aneurysm formation that can occasionally progress enough to warrant surgical repair [96]. Experience in pregnancy Given that LDS has been recognized as a clinical entity since 2005, there are limited data regarding outcomes in pregnant patients and not enough information to predict aneurysmal growth rate in pregnancy. However, the information that is available confirms that pregnant patients with LDS are high risk. The available literature has reported 217 pregnancies occurring in 85 patients [97]. Of these pregnancies, there were 3 (1%) maternal deaths and 15 (7%) severe complications including aortic and vertebral artery dissection, uterine rupture, and postpartum hemorrhage. Of the three mortalities, one was attributed to a type A aortic dissection that occurred three weeks postpartum, the second was due to subarachnoid hemorrhage resulting from bilateral vertebral artery dissection occurring in the postpartum period, and the third death occurred suddenly immediately after delivery with an unknown diagnosis. Recommendations for management As with the other aortopathies, management of the patient should begin prior to conception and involve a team of subspecialty experts. The patient should be made aware of the high-risk nature of the pregnancy, and the limited data regarding LDS and pregnancy. The patient should also be made aware that prior surgical repair of an aortic aneurysm

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does not preclude aortic complications from developing during pregnancy or during the postpartum period [98,99]. Genetic counseling should include discussing the 50% risk of fetal inheritance of LDS. Prenatal diagnosis to confirm the presence of a causative mutation can be performed preimplantation or via amniocentesis of chorionic villus sampling [91]. If a child has a presumed de novo gene mutation, parents should be aware that there is an approximate 1% risk of subsequent offspring developing LDS as a result of germline mosaicism [84]. As with the other aortopathies, once conception has occurred ACE inhibitors and ARBs should be discontinued, and β-blockade continued or initiated. Prior to conception, the entire vascular system from head to pelvis should be assessed. Unlike vEDS where surgical intervention is discouraged unless an immediate life-threatening sequela is imminent, the LDS patient should have surgical repair of any aortic aneurysm that meets the aforementioned threshold for repair [100] prior to conception. Aortic assessment via TTE should continue throughout pregnancy at monthly to bimonthly intervals and cross-sectional imaging obtained via MRI if clinically indicated [101]. If there is confirmation or suspicion of fetal LDS, fetal echocardiography should be performed, given the association of LDS with congenital heart disease including BAV and atrial septal defect [100]. As with vEDS, there is no clear consensus regarding best method of delivery in the LDS patient. Some experts have advocated for early delivery via cesarean section so as to avoid increased intra-abdominal pressure [91], whereas others note the risk of increased intra-abdominal pressure could be mitigated with instrumental assistance (forceps or vacuum) during the second stage of labor [97]. Postpartum hemorrhage has been noted in the LDS population. In such an instance, manual techniques to attain hemostasis should be considered instead of the use of ergometrine or prostaglandin analogues due to the risk of developing hypertension and the resultant hemodynamic stress on the vasculature. Close postpartum surveillance should be continued given case reports of mortality occurring during this period in the LDS population [102].

Nonsyndromic familial thoracic aneurysm and dissection (TAAD) Background TAAD accounts for approximately one-fifth of all thoracic aortic aneurysms found in young patients [103]. Given the lack of phenotypic abnormalities in the TAAD population, the diagnosis is often made either serendipitously with incidental discovery of an aortic aneurysm on imaging, aortic dissection, or if there is a family history of aortic aneurysm/dissection that prompts the clinician to screen family members. TAAD is inherited in an autosomal dominant manner, but afflicted individuals often show variable penetrance [104]. Thus far several causative genes have been identified including TGFBR2, myosin heavy chain (MYH)

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11 gene and the most common, accounting for up to 14% of TAAD cases [105], the alpha-actin (ACTA2) gene [44]. Regardless of the type of mutation, the resultant histopathological changes of the aorta are similar including reticulin fragmentation, loss of elastin, and mucopolysaccharide deposition [28,32,46]. In general, TAAD patients dissect at a younger age than patients with degenerative aortic aneurysm, but at an older age when compared with the other inherited aortopathies such as LDS [44]. Aortic repair has been recommended when an aneurysm is ≥5.0 cm [51], but these recommendations should be tailored based on clinical information (such as a family history of dissection at a size smaller than 5.0 cm and rapid aortic growth rate) as well as available genetic information. For instance, by extrapolating from data in the LDS population, if a TGFBR2 mutation is discovered in the TAAD patient, aortic repair is recommended at a size less than 5.0 cm with some guidelines calling for repair at a threshold of 4.2 cm [84]. Experience in pregnancy A retrospective study of pregnant TAAD patients with the ACTA2 mutation revealed that these are high-risk patients. Specifically, this study of 52 women and a total of 137 pregnancies reported eight (6%) aortic dissections with half of these occurring during the third trimester and the other half occurring within the first two weeks after delivery [105]. Six of the eight dissections involved the ascending thoracic aorta, three of these caused maternal mortality. Importantly, half of the patients with ascending thoracic aortic dissections dissected at an aortic caliber less than 5.0 cm with one occurring at a size of 3.8 cm. Of critical note is that none of these women were diagnosed with a TAAD disorder prior to their dissection even though six (75%) of them had a known family history of aortic dissection. Experience during pregnancy is limited for the remaining TAAD gene mutations. There is a case example in the literature of a patient with a MYH 11 mutation and a 6.4 cm ascending thoracic aorta who suffered a type A aortic dissection with extension into the abdominal aorta at 26 weeks gestation [77]. Emergent cesarean section was performed with concomitant ascending thoracic aorta replacement with aortic valve resuspension and aortic arch reconstruction. The descending thoracic and abdominal aortic dissection was managed conservatively. Recommendations for management Given lack of data, it is reasonable to follow similar preconception, gestational, and postpartum guidelines as outlined in the preceding LDS section. However, the findings by Regalado et al. highlight two critical issues involving the pregnant TAAD patient [105]. First, unlike the syndromic aortopathies such as vEDS and LDS discussed previously, TAAD patients are by definition nonsyndromic and thereby appear phenotypically normal. Therefore, as demonstrated by Regalado et al., the diagnosis of TAAD is often missed, as clinical suspicion is low. As a result, pregnant TAAD

patients may not receive the more intensive care they deserve including pharmacologic therapy with β-blockers as well as surveillance imaging. It is therefore imperative that a comprehensive medical history of any patient contemplating pregnancy includes questions regarding a family history of aortic aneurysm/dissections. If such a history is present, then aortic imaging is warranted. The second critical issue that arose from the limited data regarding the pregnant TAAD patient is that these patients may dissect at a small aortic caliber. Therefore, initially normal imaging of the aorta in a patient with TAAD who is considering pregnancy should not preclude continued careful aortic surveillance and management of this patient through the pregnancy.

Acute aortic syndromes during pregnancy The risk of acute aortic syndromes, defined as aortic dissection, intramural hematoma, or symptomatic penetrating atherosclerotic ulcer, during pregnancy is increased in the patient with an underlying aortopathy. Details regarding presentation, diagnosis, and treatment for acute aortic syndromes are beyond the scope of the current discussion, and instead, this section focuses on pearls for management of the pregnant patient. In general, when the pregnant patient with an acute aortic syndrome presents, pharmacologic therapy should be initiated promptly to reduce the double-product and then the patient should be transferred emergently to a tertiary referral center to allow multidisciplinary care and urgent or emergent intervention if needed [44]. Continuous fetal heart rate monitoring is essential in order to detect heart rate decelerations which are suggestive of fetal malperfusion and/or hypoxemia [106]. Stanford type B aortic dissections, those commencing distal to the left subclavian artery, are generally managed medically as long as the patient is stable without organ compromise and fetal perfusion is maintained. A series of four pregnant patients who suffered type B aortic dissection has demonstrated that thoracic endovascular repair (TEVAR) was safe [107] and is an excellent option for the critically ill pregnant patient [108], although generally avoided in genetically triggered aortic diseases. Type A aortic dissection, i.e. any involvement of the aorta proximal to the left subclavian artery, necessitates urgent surgical repair. Unfortunately, the use of cardiopulmonary bypass during pregnancy carries up to a 5% maternal and a 30% fetal mortality rate [109]. Fetal viability is generally accepted to be around 24 weeks, so if a type A dissection occurs prior to this time, the fetus should remain in utero [110]. However, after this period, particularly once 30 weeks gestation has been reached, a cesarean section with concomitant aortic repair is recommended in the pregnant patient with a type A aortic dissection [44]. If cardiac surgery is required during pregnancy, the use of normothermic, high pressure, high flow cardiopulmonary bypass should be used when possible in order to reduce the risk of fetal hypoxia and vasoconstriction [110]. Ultimately, in the pregnant patient with aortopathy the

CHAPTER 20 Non-Marfan Aortopathies and the Pregnant Patient

patient should be advised of the risk of acute aortic syndrome and should be counseled to present immediately if symptoms suggesting such an event should occur. Furthermore, the multidisciplinary team approach to care for these patients is essential as a cardiologist, cardiac, and/or vascular surgeon as well as an MFM specialist and a high-risk anesthesiologist may be needed in an emergent setting.

Summary This chapter discussed physiological changes of the aorta during pregnancy and summarized five specific aortopathies (BAV, aortic coarctation, vEDS, LDS, and TAAD) with a focus on the current available literature and recommendations for the management of the pregnant patient diagnosed with these aortopathies. Our understanding of the various aortopathies continues to evolve, and we expect these advancements to further refine our approach to the pregnant patient with aortopathy. However, we anticipate that the fundamental approach of careful clinical evaluation, multidisciplinary care, and rigorous follow-up will continue to be essential in caring for these complex patients.

3

4

5

6 7

8

9

10

Abbreviation list ACE ARB BAV BSA COL3A1 CT LDS MFM MRI MYH SMAD3 TAAD TEVAR TGF-β TGFBR1 TGFBR2 TTE vEDS

angiotensin converting enzyme angiotensin receptor blocker bicuspid aortic valve body surface area collagen type III alpha 1 chain computed tomography Loeys–Dietz syndrome maternal fetal medicine magnetic resonance imaging myosin heavy chain mothers against decapentaplegic homolog 3 gene thoracic aortic aneurysm and dissection thoracic endovascular repair transforming growth factor beta receptor β ligand 2 gene transforming growth factor beta receptor I transforming growth factor beta receptor II transthoracic echocardiography vascular Ehlers–Danlos syndrome

11 12

13

14 15 16

17 18 19 20 21

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CHAPTER 20 Non-Marfan Aortopathies and the Pregnant Patient

62 Burn, J., Brennan, P., Little, J. et al. (1998). Recurrence risks in offspring of adults with major heart defects: results from first cohort of British collaborative study. Lancet 351: 311–316. 63 Goldmuntz, E. (2001). The epidemiology and genetics of congenital heart disease. Clin Perinatol 28: 1–10. 64 Boon, A.R. and Roberts, D.F. (1976). A family study of coarctation of the aorta. J Med Genet 13: 420–433. 65 Cripe, L., Andelfinger, G., Martin, L.J. et al. (2004). Bicuspid aortic valve is heritable. J Am Coll Cardiol 44: 138–143. 66 Venning, S., Freeman, L.J., and Stanley, K. (2003). Two cases of pregnancy with coarctation of the aorta. J R Soc Med 96: 234–236. 67 Vriend, J.W., Drenthen, W., Pieper, P.G. et al. (2005). Outcome of pregnancy in patients after repair of aortic coarctation. Eur Heart J 26: 2173– 2178. 68 Barno, A. and Freeman, D.W. (1976). Maternal deaths due to spontaneous subarachnoid hemorrhage. Am J Obstet Gynecol 125: 384–392. 69 Yentis, S., Gatzoulis, M.A., and Steer, P. (2003). Pregnancy and coarctation of the aorta. J R Soc Med 96: 471. 70 Uebing, A., Gatzoulis, M.A., von Kaisenberg, C. et al. (2008). Congenital heart disease in pregnancy. Dtsch Arzteb Int 105: 347–354. 71 Lupton, M., Oteng-Ntim, E., Ayida, G., and Steer, P.J. (2002). Cardiac disease in pregnancy. Curr Opin Obstet Gynecol 14: 137–143. 72 Gotzsche, C.O., Krag-Olsen, B., Nielsen, J. et al. (1994). Prevalence of cardiovascular malformations and association with karyotypes in Turner’s syndrome. Arch Dis Child 71: 433–436. 73 Gravholt, C.H., Andersen, N.H., Conway, G.S. et al. (2017). Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol 177: G1–G70. 74 Pepin, M., Schwarze, M.D., Superti-furga, A., and Byers, P.H. (2000). Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med 342: 673–680. 75 Pepin, M.G., Schwarze, U., Rice, K.M. et al. (2014). Survival is affected by mutation type and molecular mechanism in vascular Ehlers–Danlos syndrome (EDS type IV). Genet Med 16: 881–888. 76 Ong, K.T., Perdu, J., De Backer, J. et al. (2010). Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers–Danlos syndrome: a prospective randomised, open, blinded-endpoints trial. Lancet 376: 1476–1484. 77 Strickland, R.A., Oliver, W.C. Jr., Chantigian, R.C. et al. (1991). Anesthesia, cardiopulmonary bypass, and the pregnant patient. Mayo Clin Proc 66: 411–429. 78 Chun, S.G., Pedro, P., Yu, M., and Takanishi, D.M. (2011). Type IV Ehlers–Danlos syndrome: a surgical emergency? A case of massive retroperitoneal hemorrhage. Open Cardiovasc Med J 5: 210–211. 79 Bergqvist, D. (1996). Ehlers–Danlos type IV syndrome. A review from a vascular surgical point of view. Eur J Surg 162: 163–170. 80 Murray, M.L., Pepin, M., Peterson, S., and Byers, P.H. (2014). Pregnancy-related deaths and complications in women with vascular Ehlers–Danlos syndrome. Genet Med 16: 874–880. 81 Lurie, S., Manor, M., and Hagay, Z.J. (1998). The threat of type IV Ehlers–Danlos syndrome on maternal well-being during pregnancy: early delivery may make the difference. J Obstet Gynaecol 18: 245–248. 82 Rochelson, B., Caruso, R., Davenport, D., and Kaelber, A. (1991). The use of prophylactic desmopressin (DDAVP) in labor to prevent hemorrhage in a patient with Ehlers–Danlos syndrome. N Y State J Med 91: 268–269. 83 Weinbaum, P.J., Cassidy, S.B., Campbell, W.A. et al. (1987). Pregnancy management and successful outcome of Ehlers–Danlos syndrome type IV. Am J Perinatol 4: 134–137. 84 Loeys, B.L., Schwarze, U., Holm, T. et al. (2006). Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med 355: 788– 798. 85 Loeys, B.L., Chen, J., Neptune, E.R. et al. (2005). A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 37: 275– 281.

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86 van de Laar, I.M., Oldenburg, R.A., Pals, G. et al. (2011). Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet 43: 121–126. 87 Regalado, E.S., Guo, D.C., Villamizar, C. et al. (2011). Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms. Circ Res 109: 680–686. 88 Lindsay, M.E., Schepers, D., Bolar, N.A. et al. (2012). Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat Genet 44: 922–927. 89 Malhotra, A. and Westesson, P.L. (2009). Loeys–Dietz syndrome. Pediatr Radiol 39: 1015. 90 Williams, J.A., Loeys, B.L., Nwakanma, L.U. et al. (2007). Early surgical experience with Loeys–Dietz: a new syndrome of aggressive thoracic aortic aneurysm disease. Ann Thorac Surg 83: S757–S763; discussion S785–90. 91 MacCarrick, G., Black, J.H. III, Bowdin, S. et al. (2014). Loeys–Dietz syndrome: a primer for diagnosis and management. Genet Med 16: 576–587. 92 Arslan-Kirchner, M., Arbustini, E., Boileau, C. et al. (2016). Clinical utility gene card for: hereditary thoracic aortic aneurysm and dissection including next-generation sequencing-based approaches. Eur J Hum Genet 24: e1–e5. 93 Yetman, A.T., Beroukhim, R.S., Ivy, D.D., and Manchester, D. (2007). Importance of the clinical recognition of Loeys–Dietz syndrome in the neonatal period. Pediatrics 119: e1199–e1202. 94 Everitt, M.D., Pinto, N., Hawkins, J.A. et al. (2009). Cardiovascular surgery in children with Marfan syndrome or Loeys–Dietz syndrome. J Thorac Cardiovasc Surg 137: 1327–1332; discussion 1332–3. 95 Matt, P., Habashi, J., Carrel, T. et al. (2008). Recent advances in understanding Marfan syndrome: should we now treat surgical patients with losartan? J Thorac Cardiovasc Surg 135: 389–394. 96 Tweddell, J.S., Earing, M.G., Bartz, P.J. et al. (2012). Valve-sparing aortic root reconstruction in children, teenagers, and young adults. Ann Thorac Surg 94: 587–590; discussion 590–1. 97 Frise, C.J., Pitcher, A., and Mackillop, L. (2017). Loeys–Dietz syndrome and pregnancy: the first ten years. Int J Cardiol 226: 21–25. 98 Fujita, D., Takeda, N., Morita, H. et al. (2015). A novel mutation of TGFBR2 causing Loeys–Dietz syndrome complicated with pregnancyrelated fatal cervical arterial dissections. Int J Cardiol 201: 288– 290. 99 Braverman, A.C., Moon, M.R., Geraghty, P. et al. (2016). Pregnancy after aortic root replacement in Loeys–Dietz syndrome: high risk of aortic dissection. Am J Med Genet A 170: 2177–2180. 100 Van Hemelrijk, C., Renard, M., and Loeys, B. (2010). The Loeys–Dietz syndrome: an update for the clinician. Curr Opin Cardiol 25: 546– 551. 101 Webb, J.A., Thomsen, H.S., Morcos, S.K., and Members of Contrast Media Safety Committee of European Society of Urogenital Urogenital Radiology (ESUR) (2005). The use of iodinated and gadolinium contrast media during pregnancy and lactation. Eur Radiol 15: 1234– 1240. 102 Tran-Fadulu, V., Pannu, H., Kim, D.H. et al. (2009). Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations. J Med Genet 46: 607– 613. 103 Stewart, F.M. (2013). Marfan’s syndrome and other aortopathies in pregnancy. Obstet Med 6: 112–119. 104 Milewicz, D.M., Chen, H., Park, E.S. et al. (1998). Reduced penetrance and variable expressivity of familial thoracic aortic aneurysms/ dissections. Am J Cardiol 82: 474–479. 105 Regalado, E.S., Guo, D.C., Estrera, A.L. et al. (2014). Acute aortic dissections with pregnancy in women with ACTA2 mutations. Am J Med Genet A 164A: 106–112. 106 Rodney, J.R., Huntley, B.J., and Rodney, W.M. (2012). Electronic fetal monitoring: family medicine obstetrics. Prim Care 39: 115– 133.

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107 Shu, C., Fang, K., Dardik, A. et al. (2014). Pregnancy-associated type B aortic dissection treated with thoracic endovascular aneurysm repair. Ann Thorac Surg 97: 582–587. 108 De Martino, R.R., Johnstone, J., Baldwin, E.A. et al. (2015). Endograft as bridge to open repair for ruptured thoracic aneurysm in a pregnant Marfan patient. Ann Thorac Surg 100: 304–307.

109 Sepehripour, A.H., Lo, T.T., Shipolini, A.R., and McCormack, D.J. (2012). Can pregnant women be safely placed on cardiopulmonary bypass? Interact Cardiovasc Thorac Surg 15: 1063–1070. 110 Immer, F.F., Bansi, A.G., Immer-Bansi, A.S. et al. (2003). Aortic dissection in pregnancy: analysis of risk factors and outcome. Ann Thorac Surg 76: 309–314.

CHAP T E R 21

Takayasu’s Arteritis and Pregnancy Abha Khandelwal Cardiovascular Medicine, Stanford University, Stanford, CA, USA

Introduction Takayasu’s arteritis (TA) is a chronic idiopathic granulomatous arteriopathy involving the large vessels and its first degree branches [1]. TA was first described by Japanese ophthalmologist Mikito Takayasu in 1908 [2,3]. There have been several theories for its etiology including autoimmunity, sex hormones, and genetic predisposition (HLA BW52) [4,5]. The prevalence of TA is reported to be in the range of 2.6–6/million in the general population [6]. The disease is most common in Asian countries, with increasing reports in Europe, Africa, the Middle East, and North America. In Japan, the annual incidence is about 150 cases/yr, whereas in the United States, the overall annual incidence is estimated at 1–3 cases/yr [1]. The disease affects mostly women in their childbearing years with reports ranging ratios from 4–9 : 1 female to male predominance [2,6,7]. The median age of diagnosis has been 26 years old, but varies slightly based on ethnicity [8–10].

Clinical features Clinical presentation has been described as two or three phases [11]. The early stage is an inflammatory period with granulomatous arteritis of the aorta and its branches. The symptoms in this phase can be subtle or overt and include fever, malaise, weight loss, night sweats, polyarthralgia, or arthritis. Subsequent phases include vascular inflammation that results in vessel tenderness or pain. Finally, the late phase can occur months to years after the active phase. Arteritic changes including intimal proliferation, degeneration of medial elastic fibers, and vasa vasorum compromise lead to narrowing that can result in occlusion. These changes can also cause aneurysm formation with possible risk of dissection [1]. There maybe arterial collaterals that form due to chronicity of occlusions, and this can result in insidious onset of symptoms, and often may appear “asymptomatic.” Frequency of clinical features of TA

at presentation and during the course of disease is shown in Figure 21.1. One study described juveniles had a delay in diagnosis four times that of adults [9]. In addition to being aware of these symptoms, it is critical to understand, that asymptomatic disease progression is not uncommon. On physical exam, peripheral pulses maybe weak or absent. Patients often present with new onset hypertension, asymmetric blood pressure readings, or vascular bruits. One should take care to do a thorough vascular exam, as well as palpate the carotids for tenderness. Cardiac exam should assess for presence of aortic regurgitation. Detailed ophthalmologic exam should also be completed. It has been noted that physical exam has great specificity (71–98%), but poor sensitivity (14–50%) for diagnosis [12]. Secondary complications include renovascular hypertension, aortic regurgitation, abdominal or myocardial ischemia, heart failure, cerebrovascular accidents, and pulmonary hypertension. The most common skin manifestations of TA are erythema nodosum and pyoderma gangrenosum. There have been various classification schemes in the past based on angiographic and on clinical features. The angiographic classification includes type I (disease involving aortic arch and its branches) type IIa (lesions confined to ascending aorta, aortic arch, and its branches, type IIb (lesions in the ascending aorta, aortic arch, and its branches and thoracic descending aorta) type III patients with characteristics of both type I and II, type IV (involvement of pulmonary artery), and type V (combined features of IIb and IV) [4]. There is also a clinical classification scheme that demonstrates Group I uncomplicated disease with or without pulmonary involvement Group IIA mild-to-moderate single complication together with uncomplicated disease, Group IIB severe single complication together with uncomplicated disease, Group III two or more complications together with uncomplicated disease [13,14]. Some reports demonstrate that certain subtypes particularly IIb and III have worse prognosis though this has not been thoroughly studied and validated [6,13,15].

Cardiac Problems in Pregnancy, Fourth Edition. Edited by Uri Elkayam. © 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.

319

320

PART IV Vascular Disease in Pregnancy

Percent of patients

100

Onset 100

Vascular (100%)

80

80

60

60

40

40

20

20

0

0 Su Fe D A H Ca Ab Vi Lt Vi St au im. sym BP su su mo ro b d r he o c o ke tid dic tod m a a l or a . a r l l d, B ab los n br ati yn . br v. b al b D e uit on o p P r s u i ru u a i r z it r i lus it . zy t e

Ca

ro

Cl

100

TI A

100 Musculo-skeletal (53%)

Constitutional (43%)

Cardiac (38%)

80

80

60

60

40

40

20

20

0

Total CNS (57%)

Ch

My Jo in alg t w t pa ia in all

es

Ma

lai

0 W Fe Ni t. l g v os ht s se er s we ats

Ao

rtic

re

An gin gu r

g.

a

Pa lpi

tat i

CH F on

Pe ric

ar d

MI itis

Figure 21.1 Clinical symptoms presentation. Abdom – abdominal; Aberr – aberration; Asym – asymmetric; CHF – congestive heart failure; CNS – central nervous system; Dim – diminished; HBP – high blood pressure; Lt – light; MI – myocardial infarction; Regurg – regurgitation; Subclav – subclavian; TIA – transient ischemic attack; Wt – weight. Source: Kerr et al. 1994 [9]. Printed with permission of The American College of Physicians.

Cardiovascular involvement To date a broad range of cardiovascular manifestations have been reported resulting from primary cardiac pathology as well as the result of the vascular disease. There are some conflicting data, however, most support more cardiac involvement in patients with more active disease, and disease onset at an earlier age [12,16]. The manifestations reported include aorto-arteritis, coronary stenosis and aneurysms, hypertension, congestive heart failure, left ventricular (LV) dysfunction due to myocarditis or dilated cardiomyopathy, valvular regurgitation, and pulmonary hypertension. The largest study to date examining cardiovascular manifestations demonstrate that in their cohort the most common type was V, and 69% of their patients had active disease. They noted those with more active disease tended to have more aortic regurgitation and pulmonary hypertension. Their cohort demonstrated a trend toward those having more active disease having more significant LV dysfunction but did not meet statistical significance [17]. The data assessing coronary pathology is largely retrospective, with the largest study looking at 111 patients in Korea who underwent computerized tomographic angiography (CTA) regardless of disease activity or symptoms (71% were asymptomatic). The results demonstrated that over half

had some coronary disease with both ostial and nonostial stenosis and aneurysms. Interestingly, of those with ostial disease, more than half had active TA and increased aortic wall thickness [18]. When looking at right ventricular endomyocardial pathology specimens, mild-to-moderate myofiber hypertrophy has been described. In a small series, features of both myocarditis and dilated cardiomyopathy have been reported [16,19].

Diagnosis Diagnosis for TA can be a complex endeavor. A careful history and physical examination are helpful; however, limitations have been previously noted. Laboratory studies (acute phase reactants erythrocyte sedimentation rate [ESR] and C reactive protein [CRP]) should be drawn. However, they are not the sole determinants in diagnosis. Previous studies have documented that 25% of patients will have normal values despite having active disease. Further, several patients will have elevated acute phase reactants and have unchanged magnetic resonance imaging (MRI) [1]. In addition to ESR and CRP, newer biomarkers are being evaluated: interleukin (IL)-6, serum amyloid A, fibrinogen, complement split fragments, b-cell activating factor (BAFF), IL-2, metalloproteinase 9, and pentraxin 3, though none are definitive.

CHAPTER 21 Takayasu’s Arteritis and Pregnancy

321

Figure 21.2 MRI in a patient with Takayasu’s arteritis demonstrating subclavian disease, and on the right, thickening of aortic wall with enhancement consistent with active inflammation. Source: Courtesy of Guido Davidzon, MD.

Imaging studies can assist in establishing this diagnosis, though no consensus exists as to which is the gold standard. There are pros and cons to each imaging modality and have been published extensively [1,20]. Imaging modalities can include CTA, magnetic resonance angiography (MRA), positron emission tomography (PET) with or without CT, Doppler ultrasound, and catheter directed angiography [1]. Rarely, histopathology of a resected vessel maybe available and assist in diagnosis, though in prior studies only 20% of patients with active histopathology had disease that was thought to be clinically active [1] (Figures 21.2 and 21.3).

At present, there is no reliable tool to assess disease activity. Traditionally, the National Institute Health (NIH) (Kerr) criteria have been used, which define activity as a new development of or worsening of at least two of the following features (constitutional symptoms and signs, elevated acute phase reactants, symptoms and signs of vascular insufficiency, and new vascular lesions of serial imaging studies). There are newer validated instruments being reported like the disease extent index-Takayasu (DEI-TAK) criteria, and the Indian Takayasu Activity Score [1].

Figure 21.3 FDG PET: Maximum intensity projection (MIP) images in a patient with Takayasu’s arteritis showing focal and high diffuse FDG uptake throughout the aortic walls which confirmed an active large vessel vasculitis. Source: Courtesy of Guido Davidzon, MD.

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The course of TA is chronic and recurrent with both active inflammatory and late fibrotic changes. The longterm survival in patients is usually high. Ishikawa and Maetani reported an 83% survival in 120 Japanese patients followed for 15 years [10]. Li et al. retrospectively reviewed 810 patients followed from 1983 to 2014 in a referral center in China, and found only 12 had died (1.2%). When reviewing the literature, mortality ranges from 2% to 21%, and this large variance is partly attributed to variable follow-up periods, advances in therapies, and different methodologies, but it is evident over time that this has improved [21]. Predictors of poor outcome include the presence of aneurysms, hypertension, cardiac involvement, and severe functional disability. Long-term morbidity is related to the disease, its secondary manifestations, and complications of treatment.

carotid (23%), subclavian (35%), and renal arteries (16%). During a mean follow-up of 6 years, the frequency of early complications was similar in both groups (15% vascular vs. 16% endovascular) and by 10-year follow-up the vascular group had 44% and endovascular 66% (p = 0.33) [30]. Restenosis was the most common late complication. The outcome of surgery has been comparatively better than angioplasty and should be performed when the disease is quiescent. There are some studies indicating that when performing endovascular interventions, those with stent placement versus plain angioplasty had worse outcome [20].

Pregnancy recommendations TA has a higher prevalence in young women, which increases the likelihood of pregnancy in patients with this disease. Ideally, preconception evaluation should be performed including disease status and peripartum immunosuppressant management, functional capacity, and presence and severity of hypertension as well as other possible cardiac conditions. Patients should be informed of the potential risks of maternal and fetal morbidity during pregnancy. Primarily, they should be advised regarding exacerbation of hypertension, risk of preeclampsia, and clinical deterioration in case of cardiac involvement. In addition, the increased likelihood of fetal growth retardation and preterm labor should be discussed. Finally, need for vascular intervention should be planned prior to conception so to avoid procedures during pregnancy. In a cross-sectional study evaluating reported mother–childrelated concerns, a large majority had concerns of passing the disease to their offspring [29]. This is surprising as none of the patients had a relative with the same disease, and many studies support that the disease’s genetic susceptibility is low

Treatment The cornerstone to therapy for active disease has traditionally been high-dose glucocorticoids (1 mg/kg for four weeks). Increased reports of frequent relapses have resulted in the addition of a secondary immunosuppressant. This can be either biological or nonbiological. Cyclophosphamide and methotrexate have been utilized with some degree of success. There are newer reports with rituximab and other biologics being utilized with hope for sustained remission as well. Table 21.1 demonstrates the array of new therapeutics being evaluated. Both percutaneous angioplasty and surgery have been applied for correction of vascular complications. A recent report from the Mayo Clinic on 66 patients who had 119 vascular procedures between 1984 and 2009 demonstrated 78% were surgical and 22% endovascular. Surgery was most frequently utilized in the aorta (28%), Table 21.1 Treatment options for TA Medication

Pregnancy

Breast-feeding

Corticosteroids [22,23]

☺

☺

IVIG [24]

☺

☺

☺

☺

Azathioprine

[22]a

Rituximab [25]

?

☺

TNF-α inhibitor Certolizumab [23]

?

☺

Abatacept [1,4]

?

?

Tocilizumab [26]

?

?

Ustekinumab [27] (IL12 Ab)

?

?

Methotrexate [28]

X

X

Mycophenolate mofetil [22]

X

X

Leflunomide [22]

X

X

Cyclophosphamide [29]

X

X

X – contraindicated in pregnancy; ? – needs to be considered on a case-by-case basis; ☺ – safe in pregnancy. a Likely the safest of all immunosuppression during pregnancy, but long onset of therapeutic effect.

CHAPTER 21 Takayasu’s Arteritis and Pregnancy

[29]. In the literature, 12% of the TA pregnancies are electively terminated [31]. Most reports support that pregnancy does not affect course of TA and may even improve it [32]. Matsumura et al. evaluated 20 pregnancies with CRP and digital plethysmography during pregnancy, which demonstrated improvement that persisted at one year postpartum [33]. Earlier reports demonstrated maternal events including elevation of BP, and heart failure being the most frequent, and rarely cerebral vascular accidents, or hemorrhage. Other reported events can include progressive aortic regurgitation, or renal artery disease [5,7,15]. To date, pregnancy outcomes have been published in less than 300 TA patients encompassing around 500 women (see Table 21.2). Most current data reports maternal complications including gestational hypertension, preeclampsia/eclampsia, pregnancy-induced hypertension, cerebrovascular accident, worsening heart function,

323

congestive heart failure aortic regurgitation, and rarely maternal death [34]. Hypertension should be treated to prevent complications such as heart failure and cerebral hemorrhage. The challenging aspect to management, however, is that marked variations in regional blood flow can decrease flow to organs with compromised perfusion. Aggressive BP reduction in patients with abdominal aortic narrowing can potentially compromise placental blood flow and increase risk likelihood of fetal growth retardation [35]. Reported antihypertensive therapy in patients with TA included β-adrenergic blockade, hydralazine, and methyldopa. There have been previously published reports on drug presence in breast milk, which may influence choice of therapy (Chapter 32) [28,36]. Obstetric complications can include spontaneous abortion, intra uterine growth retardation (IUGR), and rarely fetal demise. Table 21.2 details these findings in current case series.

Table 21.2 Maternal and fetal outcomes in previously reported cases Study

Year

Tanaka et al. [7]

2014

Singh et al. [6]

No. of pregnancies

Obstetric

Maternal

27

IUGR 4%, abruption 4%

Preeclampsia 15%

2015

18

IUGR28% (20–40%) Fetal demise 20% Preterm delivery 5.5% SA 28% (10–60%)

Gestational HTN 28% Preeclampsia 11%(10–20%) AR/MR 6% Worsening EF 6%

Comarmond et al. [8]

2015

240

6–40% premature delivery and IUGR

24–40%a gestational HTN, preeclampsia

Sangle et al. [37]

2015

7

Wong et al. [38]

1983

30

SA 13% C-section 13%

HTN 47%

Hidaka et al. [39]

2012

26

IUGR 6.8% SA 23%

AR 23% Pregnancy induced HTN 7%

Mandal et al. [5]

2012

29

IUGR 52%, neonatal ICU admission 59%

Gestational HTN 100% Preeclampsia 93% Post-partum hemorrhage 73% CVA 3%

Hernandez-Pacheco et al. [40]

2011

7

IUGR 29%

Preeclampsia 43%

Suri et al. [41]

2010

37

IUGR 16% Preterm delivery 16% Abruption 3%

Preeclampsia 62% Gestational HTN 27% Maternal death 3%

Sharma et al. [34]

2000

24

IUGR 21% preterm 17% Intrauterine demise 21% SA 8%

Severe HTN 46% CHF 8%

Aso et al. [42]

1992

23

IUGR 26%

HTN 57%

Ishikawa and Matsuura [32]

1982

33

IUGR 15% preterm 6% Abortion 3%

Severe HTN 18% CVA 3%

HTN – hypertension; SA – spontaneous abortion. a Ranges provided when two cohorts were being compared. Source: Singh et al. 2015 [6]. Modified with permission of Elsevier.

14% preeclampsia

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PART IV Vascular Disease in Pregnancy

The French TA network assessed 240 pregnancies and compared the risk of obstetric complications. They noted that those women with diagnosis of TA concomitant with their pregnancy had a 13-fold increased risk of obstetric complications compared to pregnancies before the TA diagnosis. They overall had a maternal complication rate of 39%, but it is notable that 26% were smokers in their cohort. They also described some maternal markers of inflammation being associated with increased risk of preterm birth (IL6 and TNF) [8]. Some preliminary reports indicate tocilizumab (anti IL6 receptor) and infliximab (anti TNF) may help treating TA patients refractory to other therapies [8]. The mode of delivery reported in most patients has been vaginal with an assisted second stage [8]. C-sections have mostly been performed for obstetrical indications and Epidural anesthesia has demonstrated tolerability. Vigilant BP control and consideration of aspirin in patients can be discussed particularly those at high risk for preeclampsia. Prophylactic antibiotics prior to delivery are not recommended. In patients with high risk of heart failure, or with significant valve disease, earlier hemodynamic monitoring during labor and delivery should be considered (see also Chapter 6). Accurate blood pressure monitoring may require arterial line inserted into a nonobstructed artery. Vasoconstrictor drugs should be avoided during labor and delivery and ergot preparation should not be used during delivery or for suppression of lactation. Currently, it is expected that the pregnant TA patient in most instances will have a successful delivery, however, to plan for and manage potential complications, the care team should include rheumatologists, obstetricians, cardiologists, and anesthesiologists aware of the potential threats that may arise while caring for this complex patient population.

References 1 Chatterjee, S., Flamm, S.D., Tan, C.D., and Rodriguez, E.R. (2014). Clinical diagnosis and management of large vessel vasculitis: Takayasu arteritis. Curr Cardiol Rep 16: 499. https://doi.org/10.1007/s11886-0140499-y. 2 Dey, M., Kapur, A., Goyal, M. et al. (2015). Takayasu arteritis in pregnancy. Med J Armed Forces India 71: S227–S229. 3 Takayasu, M. (1908). A case with curious change in the central retinal vessel. J Juzen Med Soc 60: 1–6. 4 Marwah, S., Rajput, M., Mohindra, R. et al. (2017). Case report Takayasu’s arteritis in pregnancy: a rare case report from a Tertiary care infirmary in India. Obstet Gynecol 1–6. https://doi.org/10.1155/2017/ 2403451. 5 Mandal, D., Mandal, S., Dattaray, C. et al. (2012). Takayasu arteritis in pregnancy: an analysis from Eastern India. Arch Gynecol Obstet 285: 567–571. 6 Singh, N., Tyagi, S., Tripathi, R., and Mala, Y.M. (2015). Maternal and fetal outcomes in pregnant women with Takayasu aortoarteritis: does optimally timed intervention in women with renal artery involvement improve pregnancy outcome? Taiwan J Obstet Gynecol 54: 597–602. https://doi.org/10.1016/j.tjog.2015.08.014. 7 Tanaka, H., Tanaka, K., Kamiya, C. et al. (2014). Analysis of pregnancies in women with Takayasu arteritis: complication of Takayasu arteritis involving obstetric or cardiovascular events. J Obstet Gynaecol Res 40 (9): 2031–2036. https://doi.org/10.1111/jog.12443.

8 Comarmond, C., Mirault, T., Biard, L. et al. (2015). Takayasu arteritis and pregnancy. Arthritis Rheumatol 67 (12): 3262–3269. https:// doi.org/10.1002/art.39335. 9 Kerr, G.S., Hallahan, C.W., Giordano, J. et al. (1994). Takayasu arteritis. Am Coll Phys 120: 919–929. 10 Ishikawa, K. and Maetani, S. (1994). Long-term outcome for 120 Japanese patients with Takayasu’s disease clinical and statistical analyses of related prognostic factors. Circulation 90 (4): 1855–1860. 11 Kerr, G.S. (1995). Takayasu’s arteritis. Rheum Dis Clin North Am 21: 1041–1058. 12 Lupi-Herrera, E., Sanchez-Torres, G., Marcushamer, J. et al. (1977). Takayasu’s arteritis: clinical study of 107 cases. Am Heart J 93: 94–103. 13 Ishikawa, K. (1977). Natural history and classification of occlusive thromboaortopathy (Takayasu’s disease). 57: 27–35. 14 Johnston, S.L., Lock, R.J., and Gompels, M.M. (2002). Takayasu arteritis: a review. J Clin Pathol 55: 481–486. 15 Li, L.T., Gilani, R., Tsai, P.I., and Wall, M.J. (2012). Takayasu arteritis complicating pregnancy in adolescence. Ann Vasc Surg https://doi.org/ 10.1016/j.avsg.2011.11.041. 16 Talwar, K., Kumar, K., Chopra, P. et al. (1991). Cardiac involvement in nonspecific (Takayasu’ s arteritis) aortoarteritis. Am Heart J 122: 1666. 17 Lee, G.Y., Jang, S.Y., Ko, S.M. et al. (2012). Cardiovascular manifestations of Takayasu arteritis and their relationship to the disease activity: analysis of 204 Korean patients at a single center. Int J Cardiol 159: 14–20. 18 Kang, E., Kim, S.M., Choe, Y.H. et al. (2014). Takayasu arteritis: assessment of coronary arterial abnormalities with 128-section dual-source CT angiography of the coronary arteries and aorta. Radiology 270: 74– 81. 19 Stojanovi´c, M., Peric-Popadic, A., Raskovic, S. et al. (2015). Late diagnosis of Takayasu arteritis with cardiac involvement: case report. South East Eur J Immunol 2015: 1–4. 20 Seyahi, E. (2016). Takayasu arteritis an update. Curr Opin Rheumatol 29: 51–56. 21 Li, J., Zhu, M., Li, M. et al. (2016). Cause of death in Chinese Takayasu arteritis patients. Medicine (Baltimore) 95: e4069. 22 Mukhtyar, C. and Pathak, H. (2016). Pregnancy and systemic vasculitis. 11: 145–149. https://doi.org/10.4103/0973-3698.194549. 23 Soh, M.C. and Nelson-Piercy, C. (2015). High-risk pregnancy and the rheumatologist. Rheumatol (Oxford, England) 54: 572–587. https://doi. org/10.1093/rheumatology/keu394. 24 Branch, D.W., Porter, T.F., Paidas, M.J. et al. (2001). Obstetric uses of intravenous immunoglobulin: successes, failures, and promises. J Allergy Clin Immunol 108: S133–S138. 25 Sangle, S.R., Lutalo, P.M.K., Davies, R.J. et al. (2013). B-cell depletion therapy and pregnancy outcome in severe, refractory systemic autoimmune diseases. J Autoimmun 43: 55–59. 26 Seyahi, E. (2017). Takayasu arteritis an update. Wolters Kluwer Heal 29: 51–56. 27 Terao, C., Yoshifuji, H., Nakajima, T. et al. (2016). Ustekinumab as a therapeutic option for Takayasu arteritis: from genetic findings to clinical application. Scand J Rheumatol 45: 80–82. 28 American Academy of Pediatrics Committee on Drugs (1994). The transfer of drugs and other chemicals into human milk. Pediatrics 93: S159–S162. 29 Gudbrandsson, B., Molberg, O., Wallenius, M. et al. (2016). Takayasu arteritis and pregnancy: a population based study on outcome and mother/child related concerns. Arthritis Care Res 69 (9): 1384–1390. https://doi.org/10.1002/acr.23146. 30 Labarca, C., Makol, A., Crowson, C. et al. (2016). Retrospective comparison of open versus endovascular procedures for Takayasu’s arteritis. J Rheumatol 43: 427–432. 31 Hauenstein, E., Frank, H., Bauer, J. et al. (2010). Takayasu’s arteritis in pregnancy: review of literature and discussion. J Perinat Med 38: 55–62. 32 Ishikawa, K. and Matsuura, S. (1982). Occlusive thromboaortopathy (Takayasu’s disease) and pregnancy. Clinical course and management of 33 pregnancies and deliveries. Am J Cardiol 50: 1293–1300.

CHAPTER 21 Takayasu’s Arteritis and Pregnancy

33 Matsumura, A., Moriwaki, R., and Numano, F. (1992). Pregnancy in Takayasu arteritis from the view of internal medicine. Heart Vessels 120– 124: https://doi.org/10.1007/BF01744557. 34 Sharma, B.K., Jain, S., and Vasishta, K. (2000). Outcome of pregnancy in Takayasu arteritis. Int J Cardiol 75: S159–S162. 35 Graca, L.M., Cardoso, M.C., and Machado, F.S. (1987). Takayasu’s arteritis and pregnancy: a case of deleterious association. Eur J Obstet Gynecol Reprod Biol 24 (4): 347–351. https://doi.org/10.1016/00282243(87)90161-4. 36 Briggs, G., Freeman, R., and Yaffe, S. (1994). Drugs Pregnancy Lactation, Williams & Wilkins. 37 Sangle, S.R., Vounotrypidis, P., Briley, A. et al. (2015). Pregnancy outcome in patients with systemic vasculitis: a single-centre matched case-control study. Rheumatology (Oxford) 54: 1582–1586. https://doi. org/10.1093/rheumatology/kev018.

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38 Wong, V.C.W., Wang, R.Y.C., and Tse, T.F. (1983). Pregnancy and Takayasu’s arteritis. AM J Med 75: 597–601. 39 Hidaka, N., Yamanaka, Y., Fujita, Y. et al. (2012). Clinical manifestations of pregnancy in patients with Takayasu arteritis: experience from a single tertiary center. Arch Gynecol Obstet 285: 377–385. 40 Hernandez-Pacheco, J.A., Estrada-Altamirano, A., Valenzuela-Jir´on, A. et al. (2011). Takayasu’s arteritis in pregnancy: report seven cases. Ginecol Obstet Mex 79: 143–151. 41 Suri, V., Aggarwal, N., Keepanasseril, A. et al. (2010). Pregnancy and Takayasu arteritis: a single centre experience from North India. J Obstet Gynaecol Res 36: 519–524. 42 Aso, T., Abe, S., and Yaguchi, T. (1992). Clinical gynecologic features of pregnancy in Takayasu arteritis. Heart Vessels 125–132. https://doi. org/10.1007/BF01744558.

CHAPTE R 22

Thromboembolic Disease in Pregnancy Courtney C. Bilodeau1,2 and Karen Rosene-Montella2 1 Department

of Obstetric Medicine, Women’s Medicine Collaborative, Miriam Hospital, Providence, RI, USA

2 Department

of Medicine, Brown University, Warren Alpert Medical School, Providence, RI, USA

Introduction Venous thromboembolism (VTE) during pregnancy remains a leading cause of maternal morbidity and mortality [1–3]. Pregnancy confers a four to fivefold increase in the risk of venous thrombosis [4]. Diagnosis and management of thromboembolism during pregnancy, although critical, are problematic for several reasons. First, anatomical and physiological changes that occur during pregnancy and postpartum not only increase the risk of VTE but also have the potential to cause false-positive tests for deep vein thrombosis (DVT). Second, clinical prediction tools used in the nonpregnant population to objectively determine VTE risk are not validated in pregnancy. Third, there is often an understandable reluctance from both the medical provider and the patient to expose the fetus to the radiation associated with the necessary diagnostic procedures and to agents used in maternal anticoagulant therapy. Fourth, plans must be formulated in anticipation of labor and delivery. Despite these limitations, several key studies have elucidated important information about the epidemiology, diagnosis, and management of pregnant patients with suspected or established VTE. In this chapter, we summarize these studies and provide recommendations for diagnostic and management strategies as well as for future clinical trials.

Epidemiology of VTE in pregnancy Incidence The incidence of VTE in pregnancy is 1.2–2 per 1000 deliveries [4,5]. A 30-year population-based cohort study found the incidence of DVT three times higher than pulmonary embolism (PE) [4]. The subclinical risk may be higher; a 3% incidence of asymptomatic calf DVT postpartum was found in one study using fibrinogen scanning [6]. A personal history of prior thrombosis and/or the presence of an underlying hypercoagulable state may significantly increase the incidence of VTE in given individuals.

Cardiac Problems in Pregnancy, Fourth Edition. Edited by Uri Elkayam. © 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.

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Location There is an overwhelming propensity (70–80%) for DVT during pregnancy to occur in the left leg [3]. In a study of 60 consecutive pregnant women presenting with a first episode of DVT, 58 episodes occurred in the left leg and the remaining two were bilateral; there were no cases of isolated right leg DVT [7]. A plausible explanation for this left-sided predominance is the exaggerated compression by the right iliac artery on the left common iliac vein during pregnancy [8] in addition to compression of the inferior vena cava (IVC) by the gravid uterus later in pregnancy [9]. Pelvic (iliofemoral and isolated iliac vein) DVT are also more common in pregnancy. In a 2013 literature review, greater than 60% of cases of DVT in pregnancy involve pelvic veins compared with less than 5% of DVT in the general population [10]. Timing The day-to-day incidence of VTE in the postpartum period is up to five times greater than in the antepartum, partially because of the shorter duration of the postpartum period [4]. Although venous stasis in the legs is greatest near term, most experts agree the risk for VTE is similar across the three trimesters. Venous stasis begins early in pregnancy due to the progesterone-induced smooth muscle relaxation. However, some conflict remains regarding the distribution of antepartum VTE risk. A large retrospective study of pregnancyassociated VTE found 50% of DVT occurred before 15 weeks gestation and 60.5% of PE occurred postpartum [11]. In a more recent large prospective study of women of childbearing age in the UK, the highest risk for VTE is within the first three weeks of the postpartum, and in the antepartum, the risk is highest in the third trimester [12]. The proportion of women presenting with nonthrombotic causes of leg pain and swelling is highest during the third trimester, probably because of the obstruction of venous outflow due to the enlarging gravid uterus [9].

CHAPTER 22 Thromboembolic Disease in Pregnancy

Table 22.1 Peripartum risk factors for VTE Background Age Race Smoking Comorbid conditions Prior VTE Obesity

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consideration should be given to testing for coagulation abnormalities. Women with a previous VTE have one of the highest increased risks for recurrent VTE during pregnancy and the puerperium [19,20]. In one retrospective study on the VTE recurrence risk of 109 women who had at least one pregnancy following a VTE, the rate was three- to fourfold higher in pregnancy compared to outside of pregnancy (relative risk 3.5; 95% confidence interval, 1.6–7.8) [21]. Finally, the risk for VTE in pregnancy is highest in women with multiple risk factors [19].

Thrombophilia Immobility/hospitalization Superficial venous thrombosis/thrombophlebitis Diabetes Urinary tract infection Irritable bowel disease Pregnancy specific 3+ prior births Assisted reproduction Stillbirth Multiples Hyperemesis gravidarum Gestational hypertension Preeclampsia/eclampsia

Conclusion Based on the results of the cited studies of the epidemiology of VTE during pregnancy, several clinically useful conclusions can be made 1 Pregnancy predisposes patients to venous thromboembolism. 2 Pregnant women presenting with symptoms in the left leg are far more likely to have DVT than women presenting with symptoms in the right leg. Nevertheless, DVT does occur in the right leg; thus, when a woman presents with symptoms in the right leg, investigation with objective tests is necessary. 3 Women presenting with suspected DVT in the postpartum are more likely to have a DVT than women presenting during pregnancy. 4 The incidence of nonthrombotic causes of leg symptoms is highest during the third trimester.

Cesarean section Preterm delivery (35 °C) during CPB when operating on a pregnant woman. Deep

Figure 26.1 Left lateral recumbent position during surgery to avoid aortocaval compression and compromise of uteroplacental blood flow. Source: Camann and Ostheimer 1990 [14]. Copyrighted with permission of Wolters Kluwer Health, Inc.

CHAPTER 26 Cardiac Surgery During Pregnancy

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Fetal heart rate 150 140 130 Meternal temperature 120 110

Fetal heart rate (BPM)

Temperature (°F)

160 104 103 102 101 100 99 98 97 96 95 94 93

100 0100

0300 0700 0900 1100 1300 1500 1700

0100 0300 0500 0700

Time Figure 26.2 Fetal heart rate and relation to maternal temperature demonstrating increase in heart rate as maternal temperature rises. Source: Jadhon and Main 1988 [16]. Copyrighted with permission of Wolters Kluwer Health, Inc.

200 180 160 140 120 100 80 60 40 20 0

increasing CPB flow and pressure, and fetal monitoring is continued during the postoperative period. It is important to note that fetal bradycardia will almost always occur at onset of CPB (Figure 26.3), and fetal tachycardia is common at conclusion of CPB. These are usually short episodes, which are amenable to alteration of CPB parameters. Although transient fetal bradycardia should be expected, prolonged bradycardia can also occur during cardiac surgery. The effects of prolonged bradycardia have not yet been determined, and both successful delivery and severe hypoxic injury with profound disability have been reported following prolonged fetal bradycardia [23,24]. Therefore, it seems prudent to treat unexpected bradycardia aggressively using the aforementioned strategies. CPB may induce sustained uterine contractions, especially during cooling and rewarming if hypothermia is utilized, and uterine contractions should be treated promptly with

Fetal heart rate Maternal systolic blood pressure Maternal diostolic blood pressure Mean perfusion pressure

1 2

3

4

5 6 7 89

1

10

2 Time (h)

200 180 160 140 120 100 80 60 40 20 0

Fetal heart rate (BPM)

Maternal intraarterial blood pressure (mmHg)

hypothermic circulatory arrest is associated with a high rate of fetal loss [18–20], and, therefore, every effort should be made to avoid circulatory arrest in pregnant women. Acid–base balance should be carefully monitored during CPB, and maternal PaCO2 maintained at 30 mmHg by adjusting gas flow rate into the membrane oxygenator. Arterial PO2 around 150 mmHg is also recommended [11]. Fetal monitoring during CPB is routinely performed. Yates and associates monitor Doppler indices in the umbilical and middle cerebral arteries using transabdominal ultrasound [21]. The rationale for fetal monitoring is that CPB can be adjusted and placental perfusion optimized based on these parameters. In our practice, we utilize fetal monitoring in patients who have reached a viable gestational age, typically 25th week of gestation. We use an external Doppler ultrasound transducer attached to the patient’s abdomen. A decrease or loss of fetal heart rate is treated promptly by

3

Figure 26.3 Fetal heart rate and relation to maternal blood pressure perfusion pressure during cardiac surgery. Transient fluctuation of fetal heart rate at start and discontinuation of cardiopulmonary bypass can be seen (start of bypass = 8, discontinuation of bypass = 10). Source: Levy et al. 1980 [22]. Copyrighted with permission of Wolters Kluwer Health, Inc.

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PART V Cardiac Surgery and Catheter Based Interventions During Pregnancy

tocolytics. Placental vasoconstriction mediated by prostaglandin release is also associated with CPB. Some clinicians recommend administration of indomethacin to prevent increased vascular resistance of the placenta [13,25,26]. Another important consideration pertinent to cardiac surgery in pregnant women is anticoagulation. Antithrombin III concentrations decrease during pregnancy and resulting heparin resistance can be expected. However, it has been our practice to maintain heparin bolus dosing at 3 mg/kg in pregnant women and to check activated clotting time (ACT) prior to commencing CPB. If the ACT is considerably lower than expected, we routinely administer recombinant human antithrombin III [11]. Although an in-depth discussion of the pharmacologic drugs utilized in CPB is beyond the scope of this chapter, we consider nitrous oxide and midazolam relatively safe as anesthetic agents. We have also used ephedrine, phenylephrine, isoproterenol, sodium nitroprusside, and nitroglycerin during CPB, but advise careful planning and preoperative review to minimize risks to the fetus [11].

Valvular heart disease Valvular heart disease is the most common indication for heart surgery in pregnant patients, and the most prevalent pathologies affect the left side of the heart. Transvalvular gradients related to mitral and/or aortic stenosis are frequently exacerbated during pregnancy due to increased cardiac output, and this may precipitate symptoms. Furthermore, patients with mechanical valve obstruction due to thrombosis may also require surgical treatment. In contrast, valvular diseases affecting the right side of the heart, and valvular insufficiencies (including mitral/aortic regurgitation) are usually well tolerated during pregnancy, and surgical treatment is rarely necessary (chapter 6). Mitral valve stenosis Mitral stenosis is the most frequently encountered valve disease in pregnant women, and most of these patients have a history of childhood rheumatic fever. Congenital anomalies and infective endocarditis account for the remaining cases (less than 1%) [27]. Maternal death due to mitral stenosis is rare in developed countries, but fetal complications may include preterm delivery, intrauterine growth restriction, and mortality [3]. Due to the high incidence of rheumatic fever in developing countries, mitral stenosis in pregnant women is a particularly prevalent problem in these areas. Pregnancy often exacerbates the symptoms of mitral stenosis, and it is not unusual for the initial diagnosis of valve disease to be made during pregnancy. The physiologic increase in cardiac output leads to a rise in gradient across the mitral valve. Pressure in the left atrium increases, and subsequently, dyspnea or even pulmonary edema may ensue. With severe mitral valve stenosis, pulmonary hypertension and cardiac decompensation can occur. Pregnant women with mitral stenosis frequently present with decline in functional status

and/or atrial arrhythmias. These symptoms often occur in the third trimester of pregnancy, but may also complicate labor and the puerperal period [3]. Guidelines set by the American College of Cardiology (ACC) and American Heart Association (AHA) [28] recommend β-blockers as initial treatment of patients with severe mitral stenosis. Diuretic agents can be utilized in those with congestive heart failure. In patients with severe stenosis (mitral valve area ≤1.5 cm2 ) who remain highly symptomatic (NYHA Classes III–IV) despite medical therapy, percutaneous balloon valvuloplasty should be considered. Surgery is reserved for patients with severe stenosis and NYHA Class IV in whom valve morphology is not favorable for percutaneous intervention [28]. Balloon mitral valvuloplasty can be performed relatively safely in pregnant women and has a reported success rate of 95–97%. Complications of mitral insufficiency, arrhythmia, thromboembolism, and tamponade are relatively rare [29,30]. However, percutaneous therapies may not be suitable in patients with heavily calcified mitral valves, and in these women, open cardiac surgery may be necessary. If possible, the mitral valve should be repaired during surgery, but often, mitral valve replacement is necessary. The choice of mitral valve prosthesis (biologic vs. prosthetic) is individualized depending on the patient’s desire for subsequent pregnancies as well as anticipated risks of reoperation related to underlying cardiac disease. Although accelerated degeneration of bioprostheses during pregnancy has been reported, this appears to be uncommon [31]. Aortic valve stenosis Aortic stenosis is present in approximately 12% of pregnant patients with valvular disease [32] and is usually related to a congenitally bicuspid aortic valve; in these patients, aortic dilation or coarctation of the aorta often coexist. Rheumatic heart disease is rarely associated with isolated aortic stenosis, but should be considered if there is concomitant mitral valve stenosis. Symptoms of aortic stenosis may be exacerbated during pregnancy due to physiologic increase in cardiac output, and obstruction of the left ventricular outflow. Mild aortic stenosis is often well tolerated, but severe stenosis can manifest with angina, arrhythmias, syncope, or pulmonary edema. Maternal mortality is very low for patients with aortic stenosis, but congestive heart failure and need for hospitalization occurs in a third of women [33]. Fetal compromise may occur in patients with aortic stenosis, but risk appears to be low,