Recurrent Pregnancy Loss: Causes, Controversies and Treatment [3 ed.] 1138325651, 9781138325654

Table of contents :
Cover
Half Title
Series Page
Title Page
Copyright Page
Contents
Preface
Contributors
Part I: Basic Principles
1. The Epidemiology of Recurrent Pregnancy Loss
2. The Signaling between Embryo and Mother as a Basis for the Development of Tolerance
3. Recurrent Pregnancy Loss from Evidence-Based to Personalized Medicine
Part II: Etiology
4. The Genetics of Spontaneous Abortions
5. The Endometrial Factor in Recurrent Pregnancy Loss
6. Fetal Structural Malformations and Recurrent Pregnancy Loss
7. The Endocrinology of Recurrent Pregnancy Loss
8. The Etiology of the Antiphospholipid Syndrome
9. Defects in Coagulation Factors Leading to Recurrent Pregnancy Loss
10. The Immunobiology of Recurrent Miscarriage
11. Immune Testing in Recurrent Pregnancy Loss
12. Uterine Anomalies and Recurrent Pregnancy Loss
13. The Male Factor in Recurrent Pregnancy Loss
Part III: The Developing Pregnancy
14. Ultrasound Follow-Up in Early Pregnancy
15. Threatened Miscarriage and Recurrent Pregnancy Loss
16. The Role of Cerclage and Pessaries
17. What Genetic Screening Is Appropriate in Recurrent Pregnancy Loss?
18. Obstetric Outcomes after Recurrent Pregnancy Loss
Part IV: Management
19. Investigation Protocol for Recurrent Pregnancy Loss
20. Debate: Should Progestogens Be Used in Recurrent Pregnancy Loss? Yes
21. Debate: Should Progestogens Be Used in Recurrent Pregnancy Loss? No
22. Human Chorionic Gonadotropin Supplementation in Recurrent Pregnancy Loss
23. Antiphospholipid Syndrome: Management of the Obstetric Patient
24. Can Recurrent Pregnancy Loss Be Prevented by Antithrombotic Agents?
25. Empirical In Vitro Fertilization for Recurrent Pregnancy Loss: Is It a Valid Concept?
26. Debate: Should PGT-A Still Be Performed in Recurrent Pregnancy Loss? Yes
27. Debate: Should PGT-A Still Be Performed in Recurrent Pregnancy Loss? No
28. Third Party Reproduction in Recurrent Pregnancy Loss
Part V: Immunotherapy
29. Leucocyte Immunotherapy for Recurrent Miscarriage
30. IVIg Treatment for Recurrent Pregnancy Loss
31. The Role of Filgrastim
32. Opinion: Immunotherapy Has No Place in the Treatment of Recurrent Pregnancy Loss
Index

Citation preview

Recurrent Pregnancy Loss Causes, Controversies, and Treatment

Series in Maternal-Fetal Medicine About the Series Published in association with the Journal of Maternal Fetal and Neonatal Medicine, the series in Maternal Fetal Medicine keeps readers up to date with the latest clinical therapies to improve the health of pregnant patients and ensure a successful birth. Each volume in the series is prepared separately and typically focuses on a topical theme. Volumes are published on an occasional basis, depending on the emergence of new developments. Obstetric Evidence Based Guidelines, Third Edition Vincenzo Berghella Maternal-Fetal Evidence Based Guidelines, Third Edition Vincenzo Berghella Maternal-Fetal and Obstetric Evidence Based Guidelines, Two Volume Set, Third Edition Vincenzo Berghella The Long-Term Impact of Medical Complications in Pregnancy: A Window into Maternal and Fetal Future Health Eyal Sheiner Operative Obstetrics, Fourth Edition Joseph J. Apuzzio, Anthony M. Vintzileos, Vincenzo Berghella, Jesus R. Alvarez-Perez Placenta Accreta Syndrome Robert M. Silver Neurology and Pregnancy: Clinical Management Michael S. Marsh, Lina Nashef, Peter Brex Fetal Cardiology: Embryology, Genetics, Physiology, Echocardiographic Evaluation, Diagnosis, and Perinatal Management of Cardiac Diseases, Third Edition Simcha Yagel, Norman H. Silverman, Ulrich Gembruch New Technologies and Perinatal Medicine: Prediction and Prevention of Pregnancy Complications Moshe Hod, Vincenzo Berghella, Mary D’Alton, Gian Carlo Di Renzo, Eduard Gratacos, Vassilios Fanos Problem-Based Obstetric Ultrasound, Second Edition Amar Bhide, Asma Khalil, Aris T. Papageorghiou, Susana Pereira, Shanthi Sairam, Basky Thilaganathan Recurrent Pregnancy Loss: Causes, Controversies, and Treatment, Third Edition Howard J.A. Carp For more information about this series please visit: https://www.crcpress.com/Series-in​ -Maternal-Fetal-Medicine/book-series/CRCSERMATFET

Recurrent Pregnancy Loss Causes, Controversies, and Treatment Third Edition

Edited by

Howard J.A. Carp, MB BS, FRCOG Clinical Professor Obstetrics and Gynecology Sheba Medical Center, Tel Hashomer and Sackler School of Medicine Tel Aviv University Tel Aviv, Israel

Front cover: Disorganized embryo as seen on embryoscopy. Picture courtesy of Thomas Philipp, MD, Vienna, Austria.

CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2020 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Printed on acid-free paper International Standard Book Number-13: 978-1-138-32565-4 (Hardback) This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to publish reliable data and information, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. The publishers wish to make clear that any views or opinions expressed in this book by individual editors, authors or contributors are personal to them and do not necessarily reflect the views/opinions of the publishers. The information or guidance contained in this book is intended for use by medical, scientific or health-care professionals and is provided strictly as a supplement to the medical or other professional’s own judgement, their knowledge of the patient’s medical history, relevant manufacturer’s instructions and the appropriate best practice guidelines. Because of the rapid advances in medical science, any information or advice on dosages, procedures or diagnoses should be independently verified. The reader is strongly urged to consult the relevant national drug formulary and the drug companies’ and device or material manufacturers’ printed instructions, and their websites, before administering or utilizing any of the drugs, devices or materials mentioned in this book. This book does not indicate whether a particular treatment is appropriate or suitable for a particular individual. Ultimately it is the sole responsibility of the medical professional to make his or her own professional judgements, so as to advise and treat patients appropriately. The authors and publishers have also attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http:// www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Control Number: 2020930159 Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com

Contents Preface.....................................................................................................................................................viii Contributors............................................................................................................................................... ix

Part I  Basic Principles 1. The Epidemiology of Recurrent Pregnancy Loss.......................................................................... 1 Ole B. Christiansen 2. The Signaling between Embryo and Mother as a Basis for the Development of Tolerance.... 13 Eytan R. Barnea 3. Recurrent Pregnancy Loss­from Evidence-Based to Personalized Medicine........................... 22 Howard J.A. Carp

Part II  Etiology 4. The Genetics of Spontaneous Abortions....................................................................................... 30 Joe Leigh Simpson 5. The Endometrial Factor in Recurrent Pregnancy Loss.............................................................. 43 Luiza Borges Manna and Ying Cheong 6. Fetal Structural Malformations and Recurrent Pregnancy Loss.............................................. 48 Howard J.A. Carp, Thomas Philipp, Micha Baum, and Michal Berkenstadt 7. The Endocrinology of Recurrent Pregnancy Loss....................................................................... 59 Nicola Pluchino, Serena Bellaminutti, Panagiotis Drakapoulos, Antonis Makrigiannakis, and Andrea R. Genazzani 8. The Etiology of the Antiphospholipid Syndrome......................................................................... 70 Sara De Carolis, Giuseppina Monteleone, Cristina Garufi, Rotem Inbar, Miri Blank, and Yehuda Shoenfeld 9. Defects in Coagulation Factors Leading to Recurrent Pregnancy Loss................................... 79 Aida Inbal and Howard J.A. Carp 10. The Immunobiology of Recurrent Miscarriage........................................................................... 89 Marighoula Varla-Leftherioti, Theodora Keramitsoglou, and Christina Tsekoura 11. Immune Testing in Recurrent Pregnancy Loss..........................................................................101 Jeffrey Braverman, Darren Ritsick, and Nadera Mansouri-Attia 12. Uterine Anomalies and Recurrent Pregnancy Loss...................................................................110 Daniel S. Seidman and Mordechai Goldenberg v

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Contents

13. The Male Factor in Recurrent Pregnancy Loss......................................................................... 126 Catherine F. Ingram, Nannan Thirumavalavan, Marc Goldstein, and Dolores J. Lamb

Part III  The Developing Pregnancy 14. Ultrasound Follow-Up in Early Pregnancy................................................................................ 134 Akhila Vasudeva and Pratap Kumar 15. Threatened Miscarriage and Recurrent Pregnancy Loss.........................................................145 Howard J.A. Carp 16. The Role of Cerclage and Pessaries..............................................................................................153 Israel Hendler and Howard J.A. Carp 17. What Genetic Screening Is Appropriate in Recurrent Pregnancy Loss?............................... 164 Howard Cuckle 18. Obstetric Outcomes after Recurrent Pregnancy Loss...............................................................172 Rakefet Yoeli-Ullman, Howard J.A. Carp, and Shali Mazaki-Tovi

Part IV  Management 19. Investigation Protocol for Recurrent Pregnancy Loss.............................................................. 184 Howard J.A. Carp 20. Debate: Should Progestogens Be Used in Recurrent Pregnancy Loss? Yes............................ 197 Ashok Kumar and Simar Kaur 21. Debate: Should Progestogens Be Used in Recurrent Pregnancy Loss? No............................. 202 Roy Mashiach 22. Human Chorionic Gonadotropin Supplementation in Recurrent Pregnancy Loss............... 206 Carlo Ticconi, Adalgisa Pietropolli, and C.V. Rao 23. Antiphospholipid Syndrome: Management of the Obstetric Patient........................................215 Ashley E. Benson and D. Ware Branch 24. Can Recurrent Pregnancy Loss Be Prevented by Antithrombotic Agents?........................... 223 Audrey A. Merriam and Michael J. Paidas 25. Empirical In Vitro Fertilization for Recurrent Pregnancy Loss: Is It a Valid Concept?.......231 Michal Kirshenbaum and Raoul Orvieto 26. Debate: Should PGT-A Still Be Performed in Recurrent Pregnancy Loss? Yes.................... 239 Carmen M. García-Pascual, Pilar López, Nasser Al-Asmar, Pere Mir, Lorena Rodrigo, Carlos Simon, and Carmen Rubio 27. Debate: Should PGT-A Still Be Performed in Recurrent Pregnancy Loss? No..................... 243 Raoul Orvieto and Norbert Gleicher

Contents

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28. Third Party Reproduction in Recurrent Pregnancy Loss........................................................ 249 Gautam Nand Allahbadia, Rubina Merchant, Akanksha Allahbadia Gupta, and A.H. Maham

Part V  Immunotherapy 29. Leucocyte Immunotherapy for Recurrent Miscarriage............................................................ 257 Salim Daya 30. IVIg Treatment for Recurrent Pregnancy Loss........................................................................ 268 Carolyn B. Coulam 31. The Role of Filgrastim.................................................................................................................. 275 Fabio Scarpellini and Marco Sbracia 32. Opinion: Immunotherapy Has No Place in the Treatment of Recurrent Pregnancy Loss.............................................................................................................................. 280 Micha Baum Index....................................................................................................................................................... 287

Preface Six years have passed since the second edition of this book, and thirteen since the first edition. Major advances have necessitated a new edition. Genetics, in particular, has evolved out of all recognition with the introduction of higher and higher-resolution analyses which are being employed to make more accurate diagnoses. These changes are summarized in Chapters 4 and 6. However, the prevention of genetic aberrations by PGT-A is a hotly debated issue; the two sides are summarized in Chapters 26 and 27. The first two editions contained numerous debates on controversial subjects in recurrent pregnancy loss (RPL). Many of these contentious issues have now reached a consensus and can be summarized in chapters rather than debates. The guidelines of the various professional organizations have narrowed their differences somewhat. However, none relates to the resistant patient who continues to miscarry despite the various treatment modalities recommended in the guidelines. The resistant patient is addressed in Chapters 19 and 28. New chapters have been added regarding structural anomalies, empirical in vitro fertilization, and personalized medicine as opposed to evidence-based medicine and which immune assessment should be used. RPL remains a distressing problem. Patients understandably expect answers and solutions. The physician often does not have these answers. Recommendations vary from inactivity and follow-up to intensive investigation and treatment. Recommendations are confounded by the lack of a universal definition of RPL and often failure to distinguish between good and poor prognosis patients. This edition, like the previous editions of this book, tries to summarize the controversies and discuss the scientific basis for various causes of RPL in depth and to clarify the various treatment modalities. It is hoped that we have succeeded in this endeavor. The book is planned for general gynecologists, and specialists working in the field. Each contributing author is an authority on a specific area of recurrent pregnancy loss. All chapters have undergone major revision to include the changes that have occurred since the second edition. I would like to thank each author for the time and effort taken in preparing the manuscripts to make the publication of this book possible. I would also like to thank those responsible in a more indirect way for the publication of this book: my teachers over the years, and my collaborators. However, special recognition goes to the greatest teachers and collaborators of all, the patients. Howard J.A. Carp, MB BS, FRCOG

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Contributors Nasser Al-Asmar Igenomix Valencia Valencia, Spain

D. Ware Branch University of Utah Health Salt Lake City, Utah

Gautam Nand Allahbadia Reproductive Endocrinology and IVF, MMC IVF and Bourn Hall IVF Jumeirah, Dubai, United Arab Emirates and Orchid Fertility and Andrology Services, DHCC and Dr. Amal Elias Fertility Center and Millennium Medical Center MMC IVF Dubai, United Arab Emirates

Jeffrey Braverman Reproductive Immunology New York City, New York

Eytan R. Barnea Society for the Investigation of Early Pregnancy New York City, New York Micha Baum Sheba Medical Center Tel Hashomer, Israel Serena Bellaminutti Division of Obstetrics and Gynaecology University of Geneva Geneva, Switzerland Ashley E. Benson University of Utah Health Salt Lake City, Utah Michal Berkenstadt Danek Gertner Institute of Human Genetics Sheba Medical Center Tel Hashomer, Israel Miri Blank Zabludowicz Center for Autoimmune Diseases Sheba Medical Center Sackler Faculty of Medicine Tel Aviv University Tel Aviv, Israel

Sara De Carolis Department of Obstetrics, Gynaecology and Pediatrics F. Policlinico Gemelli IRCCS Università Cattolica del Sacro Cuore Rome, Italy Howard J.A. Carp Department of Obstetrics and Gynecology Sheba Medical Center Tel Hashomer, Israel and Sackler School of Medicine Tel Aviv University Tel Aviv, Israel Ying Cheong University of Southampton and Complete Fertility Southampton Southampton, United Kingdom Ole B. Christiansen Department of Obstetrics and Gynaecology Center for Recurrent Pregnancy Loss of Western Denmark Aalborg University Hospital Aalborg, Denmark Carolyn B. Coulam Clinical Immunology Laboratory Rosalind Franklin University of Medicine and Science North Chicago, Illinois Howard Cuckle Department of Obstetrics and Gynecology Columbia University Medical Center New York City, New York ix

x Salim Daya McMaster University Hamilton, Ontario, Canada and Newlife Fertility Centre Mississauga, Ontario, Canada Panagiotis Drakapoulos Center for Reproductive Medicine Universitair Ziekenhuis Brussel Brussels, Belgium Carmen M. García-Pascual Igenomix Valencia Valencia, Spain Cristina Garufi Lupus Clinic, Rheumatology, Dipartimento di Medicina Interna e Specialità Mediche Sapienza Università di Roma Rome, Italy Andrea R. Genazzani Division of Obstetrics and Gynaecology University of Pisa Pisa, Italy Norbert Gleicher The Center for Human Reproduction and Foundation for Reproductive Medicine and Stem Cell Biology and Molecular Embryology Laboratory The Rockefeller University New York City, New York and Department of Obstetrics and Gynecology Vienna University of Medicine Vienna, Austria Mordechai Goldenberg Department of Obstetrics and Gynecology Chaim Sheba Medical Center Tel Hashomer, Israel and Sackler School of Medicine Tel Aviv University Tel Aviv, Israel Marc Goldstein Department of Urology Weill Cornell School of Medicine New York City, New York

Contributors Akanksha Allahbadia Gupta Indira IVF New Delhi, India Israel Hendler Obstetrics and Gynecology Sackler Medical School Tel Aviv University Tel Aviv, Israel and Department of Obstetrics and Gynecology Sheba Medical Center Tel Hashomer, Israel Aida Inbal Thrombosis and Hemostasis Unit Beilinson Hospital Rabin Medical Center Petah Tikva, Israel and Sackler Faculty of Medicine Tel Aviv University Tel Aviv, Israel Rotem Inbar Zabludowicz Center for Autoimmune Diseases and Department of Obstetrics and Gynecology Sheba Medical Center Tel Hashomer, Israel Catherine F. Ingram Baylor College of Medicine Houston, Texas Simar Kaur Department of Obstetrics and Gynaecology Maulana Azad Medical College and Associated Lok Nayak Hospital New Delhi, India Theodora Keramitsoglou Department of Immunology and Histocompatibility Helena Venizelou Maternity Hospital Athens, Greece Michal Kirshenbaum Department of Obstetrics and Gynecology Chaim Sheba Medical Center Tel Hashomer, Israel and Sackler Faculty of Medicine Tel Aviv University Tel Aviv, Israel

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Contributors Ashok Kumar Department of Obstetrics and Gynaecology Maulana Azad Medical College and Associated Lok Nayak Hospital New Delhi, India Pratap Kumar Department of Obstetrics and Gynecology Kasturba Medical College Manipal Academy of Higher Education Manipal, Karnataka, India Dolores J. Lamb Department of Urology and Center for Reproductive Genomics Weill Cornell School of Medicine New York City, New York Pilar López Igenomix Argentina Caba, Argentina A.H. Maham MMC IVF Dubai, United Arab Emirates Antonis Makrigiannakis Department of Obstetrics and Gynecology University of Crete Heraklion, Greece Luiza Borges Manna North Middlesex Hospital London, United Kingdom and Obstetrics and Gynaecology Wessex Deanery, United Kingdom Nadera Mansouri-Attia Braverman Reproductive Immunology New York City, New York Roy Mashiach Department of Obstetrics and Gynecology Sheba Medical Center Tel Hashomer, Israel Shali Mazaki-Tovi Department of Obstetrics and Gynecology Sheba Medical Center Tel Hashomer, Israel and Sackler School of Medicine Tel Aviv University Tel Aviv, Israel

Rubina Merchant Rotunda—The Center for Human Reproduction Mumbai, India Audrey A. Merriam Division of Maternal-Fetal Medicine Department of Obstetrics, Gynecology and Reproductive Sciences Yale University New Haven, Connecticut Pere Mir Igenomix Valencia Valencia, Spain Giuseppina Monteleone Department of Obstetrics, Gynaecology and Pediatrics F. Policlinico Gemelli IRCCS Università Cattolica del Sacro Cuore Rome, Italy Raoul Orvieto Department of Obstetrics and Gynecology Chaim Sheba Medical Center Tel Hashomer, Israel and Family Planning and Fertility Regulation Sackler Faculty of Medicine Tel Aviv University Tel Aviv, Israel Michael J. Paidas Department of Obstetrics, Gynecology and Reproductive Sciences Miller School of Medicine University of Miami Miami, Florida Thomas Philipp Gynecology and Obstetrics Danube Hospital Vienna, Austria Adalgisa Pietropolli Academic Department of Systems Medicine Tor Vergata University Rome, Italy Nicola Pluchino Division of Obstetrics and Gynaecology University of Geneva Geneva, Switzerland

xii C.V. Rao Department of Cellular Biology and Pharmacology Herbert Wertheim College of Medicine Florida International University Miami, Florida Darren Ritsick Braverman Reproductive Immunology New York City, New York Lorena Rodrigo Igenomix Valencia and Ronda Narciso Monturiol Valencia, Spain Carmen Rubio Igenomix Valencia Valencia, Spain Marco Sbracia Hungaria Center for Endocrinology and Reproductive Medicine (CERM) Rome, Italy Fabio Scarpellini Hungaria Center for Endocrinology and Reproductive Medicine (CERM) Rome, Italy Daniel S. Seidman Department of Obstetrics and Gynecology Chaim Sheba Medical Center Tel Hashomer, Israel and Sackler School of Medicine Tel Aviv University Tel Aviv, Israel Yehuda Shoenfeld Internal Medicine Zabludowicz Center for Autoimmune Diseases Sheba Medical Center Tel Hashomer, Israel and Research of Autoimmune Diseases Sackler Faculty of Medicine Tel Aviv University Tel Aviv, Israel

Contributors Carlos Simon Igenomix Valencia and Department of Obstetrics and Gynaecology Valencia University and INCLIVA Valencia, Spain and Department of Obstetrics and Gynaecology Stanford University Stanford, California Joe Leigh Simpson Department of Human and Medical Genetics Herbert Wertheim College of Medicine Florida International University Miami, Florida and Reproductive Genetic Innovation (RGI) Northbrook, Illinois Nannan Thirumavalavan Scott Department of Urology Baylor College of Medicine Houston, Texas Carlo Ticconi Academic Department of Surgical Sciences Tor Vergata University Rome, Italy Christina Tsekoura Department of Immunology and Histocompatibility Helena Venizelou Maternity Hospital Athens, Greece Marighoula Varla-Leftherioti Department of Immunology and Histocompatibility Helena Venizelou Maternity Hospital Athens, Greece Akhila Vasudeva Department of Obstetrics and Gynecology Kasturba Medical College Manipal Academy of Higher Education Manipal, Karnataka, India Rakefet Yoeli-Ullman Department of Obstetrics and Gynecology Sheba Medical Center Tel Hashomer, Israel

1 The Epidemiology of Recurrent Pregnancy Loss Ole B. Christiansen

Substantial disagreement exists about spontaneous prognosis after recurrent pregnancy loss (RPL), probably due to differences in monitoring intensity between studies. In future studies of prognosis in RPL it is suggested that the live birth rate per time unit is introduced as the main outcome measure.

Introduction The term miscarriage (or abortion) is used to describe a pregnancy that fails to progress, resulting in death and expulsion of the embryo or fetus. The World Health Organization (WHO) definition [1] stipulates that the fetus or embryo should weigh 500 g or less, a stage that corresponds to a gestational age of 20 weeks. The European Society for Human Reproduction and Embryology (ESHRE) defines a miscarriage as an intrauterine pregnancy demise prior to viability confirmed by ultrasound or histology, whereas miscarriages, biochemical pregnancy losses, and pregnancies of unknown location (PULs) are jointly termed pregnancy losses [2]. Recurrent miscarriage (RM) has traditionally been defined as ≥3 consecutive miscarriages, and recurrent pregnancy loss (RPL) as ≥3 pregnancy losses. However, the American Society for Reproductive Medicine (ASRM) RPL defines RPL as ≥2 not necessarily consecutive clinical miscarriages [3], and recently ESHRE’s RPL guideline group also defined RPL as ≥2 not necessarily consecutive pregnancy losses [4]. Including women with two previous pregnancy losses in studies of RPL is epidemiologically very problematic. If the ASRM/ESHRE definition of >2 losses is used, the vast majority of patients will have a good prognosis for live birth. The live birth rate after two consecutive pregnancy losses is 75%–80% in the next pregnancy [5,6] or within 3 years [7]. The ≥2 definition of RM/RPL assumes that the prognosis for pregnancy losses is similar in women with the same number of previous consecutive or nonconsecutive pregnancy losses, e.g., a woman with four pregnancy losses after a birth has the same prognosis in the next pregnancy as a woman with three pregnancy losses followed by a live birth followed by one miscarriage. Only one study [8] has addressed whether pregnancy losses prior to a live birth have similar prognosis as those subsequent to a live birth. In a multivariate analysis of 127 patients with unexplained secondary RPL, each pregnancy loss after the birth, and in particular the presence of a second trimester miscarriage after the birth, increased the risk for subsequent pregnancy loss with incidence rate ratio (IRR) = 1.14 (95% confidence interval [CI] 1.04–1.24, p = 0.002) and IRR = 2.15 (95% CI 1.57–2.94, p 1% indicates that RPL is not a random event but a disorder affecting women who have an increased risk of pregnancy loss. If RPL (according to the old definition) were caused by a random accumulation of “sporadic” miscarriages mainly caused by fetal aneuploidy, the prevalence of RPL would be 0.153 = 0.34% (based on a frequency of sporadic miscarriage of 15% in the population [9]) rather than 1%. The 1% prevalence indicates that most RPL cases are caused by nonrandom factors which increase the risk of pregnancy loss in each pregnancy. Knowledge of changes in the incidence of RPL are important and can inform us about changes in environmental or genetic risk factors of importance for pregnancy loss. Roepke et al. [12] in a nationwide register-based study found that the incidence of women with three or more consecutive pregnancy losses had increased significantly in Sweden from 2003 to 2012. If the denominator was all women in Sweden aged 18–42 years in the period, the incidence increased from 0.042% to 0.069%, relative increase 74% (p