Assisted Reproduction Techniques: Challenges and Management Options [2nd Edition] 1119622107, 9781119622109, 9781119622123, 9781119622215

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Assisted reproduction techniques

Assisted reproduction techniques Challenges and management options

Second Edition

Edited by

Khaldoun Sharif MBBCh (Hons), MD, MFFP, FRCOG, FACOG Consultant Obstetrician and Gynaecologist Subspecialist in Reproductive Medicine and Surgery Clinical Director Fertility Center Jordan Hospital Amman, Jordan

Arri Coomarasamy MBChB, MD, FRCOG, FMedSci

Professor of Gynaecology Director, Tommy’s National Centre for Miscarriage Research Director, WHO Collaborating Centre for Global Women’s Health Institute of Metabolism and Systems Research University of Birmingham; Consultant Gynaecologist and Subspecialist in Reproductive Medicine CARE Fertility Birmingham and Birmingham Women’s Hospital Birmingham, UK

This edition first published 2021 © 2021 John Wiley & Sons Ltd Edition History 1e (2012 by Blackwell Publishing) 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 Khaldoun Sharif and Arri Coomarasamy to be identified as the authors of the editorial material in this work has been asserted in accordance with law. Registered Offices 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 applied for HB ISBN: 9781119622109 Cover Design: Wiley Cover Image: © xia yuan/Getty Images Set in 9.5/12.5pt StixTwoText by Straive, Pondicherry, India 10  9  8  7  6  5  4  3  2  1

To my mother, my father, and Zena (KS) To Amma, Appa, Abdea, Tara, and Leela (AC)

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Contents Contributors  xiii Preface to the second edition  xxviii Preface to the first edition  xxix How to use this book  xxx Abbreviations  xxxi

Section 1: Counseling and preparation 1 1 2 3 4 5 6 7 8 9 10 11 12 13

Risk of cancer from ovarian stimulation  3 Yadava Jeve Risk of early menopause following IVF treatment  9 Sesh Kamal Sunkara The HIV-positive female  12 Mark V. Sauer and Shelley Dolitsky The HIV-positive male  19 Mark V. Sauer and Shelley Dolitsky The hepatitis B or C carrier patient  26 Justin Chu The patient with cystic fibrosis  32 Tarek El‐Toukhy The patient on medication  37 Pedro Melo and Arri Coomarasamy The patient with thrombophilia  48 Yorain Sri Ranjan and Ying C. Cheong The patient with autoimmune disorders  56 Giulia Mariani and José Bellver The patient with malignant disease: fertility preservation  61 Arri Coomarasamy and Manal Elgendy The patient with heart disease  69 Anna S. Herrey and Catherine Nelson-Piercy The patient with diabetes  75 Mohammed A. Khan, Neelam Potdar, and Justin C. Konje The patient with thyroid disease  81 Shiao-yng Chan

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Contents

14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37

The patient with hyperprolactinemia  89 John Ayuk The patient with polycystic ovaries  96 Adam H. Balen The renal transplant patient  103 Justin Chu and Lynne Robinson The patient with previous pelvic irradiation  110 Vishvanath C. Karande Female fertility after chemotherapy  116 Nivedita Reddy The patient with abnormal cervical cytology  123 Martyn Underwood and William Rhys Parry-Smith The patient with previous borderline ovarian tumor  127 Arri Coomarasamy, Kavita Singh, and Jennifer Tamblyn The patient with an endometrioma  132 Spyros Chouliaras and Luciano G. Nardo The patient with cervical stenosis  137 Khaldoun Sharif Vaccination and ART  142 Arri Coomarasamy and Rima Dhillon-Smith The patient with hydrosalpinx  147 Annika Strandell The patient with hydrosalpinx and contraindication to laparoscopy  153 Basim Abu-Rafea The patient with reduced ovarian reserve  159 Scott M. Nelson The patient with congenital uterine anomalies  166 Rima Dhillon-Smith and Pallavi Latthe The patient with congenital cervico-vaginal anomalies  171 Rima Dhillon-Smith and Pallavi Latthe The patient with uterine fibroids  176 Kugajeevan Vigneswaran and Haitham Hamoda The patient with adenomyosis  182 Andreas Athanasakis and Arri Coomarasamy The patient with previous Essure® sterilization  187 T. Justin Clark The patient with previous endometrial ablation  192 T. Justin Clark The couple with recurrent implantation failure  200 Lukasz Polanski and Yakoub Khalaf The patient with previous uterine artery embolization  207 Kugajeevan Vigneswaran and Haitham Hamoda The patient with endometrial polyp  212 Arri Coomarasamy and Laurentiu Craciunas The obese female patient  217 Mostafa Metwally and Bolarinde Ola The patient with Asherman syndrome  223 Alessandro Conforti, Giuseppe Iorio, and Carlo Alviggi

Contents

38 39 40 41 42 43 44

The older patient  228 Giselle Crawford and William Ledger Requests for mild or natural cycle IVF treatment  234 Brad B. Swelstad and Suheil J. Muasher The patient with psychosexual problems  239 Penny Goold and Elizabeth Howland The patient needing third-party reproduction  246 Imad Aboujaoude and Teddy Tadros Social oocyte freezing  252 Valerie L. Peddie and Smriti Ray Chaudhuri Bhatta The male and female patients following bariatric surgery  258 Zaher Merhi and Ali Ahmed Bazzi Endometrial receptivity testing  265 Laurentiu Craciunas and Arri Coomarasamy

Section 2: Pituitary suppression and ovarian stimulation phase 271 45 46

47 48 49 50 51

52

Poor response during ovarian stimulation  273 Pedro Melo, Lynne Robinson, and Arri Coomarasamy Ovarian stimulation for IVF in a patient at high risk of ovarian hyperstimulation syndrome  279 Khaldoun Sharif and Ahmed G. Serour Unable to achieve pituitary down-regulation  284 K. Jayaprakasan and Nicholas Raine-Fenning The patient discovered pregnant during pituitary down-regulation  291 Mohammed Khairy Mahmoud and Arri Coomarasamy Ovarian cysts following pituitary down-regulation  296 Alison Taylor Missed IVF medications  302 Pedro Melo, Lynne Robinson, and Arri Coomarasamy The ART patient with a history of estrogen-receptor positive cancer  309 Murat Sönmezer and Volkan Turan The patient over-responding to controlled ovarian stimulation during IVF  315 Khaldoun Sharif

Section 3: Oocyte retrieval 323 53 54 55 56

General anesthesia or sedation for oocyte retrieval?  325 Claire Scanlon and David Green Delayed oocyte retrieval  331 Khaldoun Sharif Empty follicle syndrome  337 Aboubakr Mohamed Elnashar Bleeding following oocyte retrieval  344 Annika K. Ludwig and Barbara Sonntag

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57 58 59 60 61

To flush or not to flush follicles at oocyte retrieval  351 Anne E. Martini and Micah J. Hill Inaccessible ovaries at oocyte retrieval  358 Aboubakr Mohamed Elnashar Endometriotic cysts at oocyte retrieval  363 Graciela Kohls Ilgner and Juan Antonio García-Velasco Inadvertent injury during oocyte retrieval  369 Khaldoun Sharif Dealing with equipment failure during oocyte retrieval  377 Isla Robertson and Ying C. Cheong

Section 4: Embryo transfer 381 62 63 64 65 66 67

How many embryos to transfer?  383 Ellen Armstrong and Arri Coomarasamy Poor endometrial development in ART  390 Jyotsna Pundir and Arri Coomarasamy Endometrial cavity fluid identified during IVF treatment  400 Arri Coomarasamy and Yealin Chung Difficult embryo transfer  404 Khaldoun Sharif Excess cervical mucus and retained embryos at embryo transfer  413 Hassan N. Sallam, Ahmed F. Galal, and Fady S. Moeity Life after embryo transfer  419 Kelton Tremellen

Section 5: The luteal phase 427 68 69 70 71 72

Vaginal bleeding in the luteal phase after IVF  429 Carol Coughlan and Bolarinde Ola Pelvic infection after IVF  435 Muhammad Faisal Aslam and Ali Ahmad Bazzi The patient presenting with ovarian hyperstimulation syndrome  440 Khaldoun Sharif and Dania Al‐Ramahi Adnexal torsion after IVF  447 Jenna Turocy and Beth W. Rackow Exposure to infection in the luteal phase of IVF  453 Pedro Melo and Arri Coomarasamy

Section 6: The ART laboratory 465 73 74

Total failure of fertilization after conventional IVF – rescue ICSI  467 A. Albert Yuzpe Couples not wishing to create surplus embryos in IVF  473 Hossam Mohamed

Contents

75 76 77 78 79 80 81 82 83 84

Routine preimplantation genetic testing for aneuploidy  478 Lukasz Polanski and Yakoub Khalaf Choosing an embryo for transfer  484 Peter Kovacs and Szabolcs Matyas Globozoospermia  492 Odai A. M. Alqawasmeh and Christopher L. R. Barratt Total failure of fertilization after ICSI  498 Kaoru Yanagida Refreezing of embryos  503 Jerome H. Check and Donna Summers Infection in embryo culture medium  509 Alison Campbell and Louise Best ICSI or IVF for nonmale-factor infertility?  515 Samuel Dobson and Bolarinde Ola Cryostorage failure in ART  522 Christopher P. Moutos, Angela H. Liu, and John Y. Phelps The ART program during a disaster  527 Richard P. Dickey and Carla Ball White Using the wrong sperm or embryos in IVF  533 Khaldoun Sharif and Majd M. Ezal‐Deen

Section 7: The male patient 539 85 86 87 88

89

90 91 92 93 94 95

Unexpected inability to produce a semen sample on the day of oocyte retrieval  541 Khaldoun Sharif, Majd M. Ezal‐Deen, and Gyath Karadsheh The azoospermic patient  545 Khaldoun Sharif   and Ali Al-Rawahneh ART in men with Klinefelter syndrome  553 Medhat Amer and Emad Fakhry ART in men with 100% immotile sperm  559 Jose Vázquez Núñez , Juan José Artazkoz Marques de Oliveira, Patricia Hernández Delgado, Ayrton Artazkoz Marques de Oliveira, and Neuda Marques de Oliveira Request for posthumous fatherhood with perimortem surgical sperm retrieval  565 Mahmoud Mima, Samuel J. Ohlander, Rodrigo L. Pagani, Heather E. Ross, and Lawrence S. Ross Retrograde ejaculation and anejaculation  575 Hussain M. Alnajjar and Asif Muneer Sperm retrieval in cancerous testes  580 Wael Almajed, Saad Aldousari, and Armand Zini Leukocytospermia and ART  584 Giuseppe Ricci The infertile male patient with a genetic cause  589 Marlon P. Martinez and Ashok Agarwal Y chromosome microdeletions and ART  598 Sherman J. Silber and Sierra Goldsmith DNA fragmentation, antioxidants and ART  606 Sarah J. Martins da Silva

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Section 8: The ART pregnancy 613 96 97 98 99 100 101 102 103 104

Unexpected number or sex of babies after IVF  615 Majd M. Ezal-Deen, Mohamad Bani-Domi, and Omar Sharif Suspected ectopic pregnancy after IVF  620 Vishvanath C. Karande, Liselotte Mettler,, and Ibrahim Alkatout Cervical ectopic pregnancy after IVF  626 Usha Verma and Sabrina Pastor-Carvajal Heterotopic pregnancy after IVF  632 Abdel‐Maguid Ramzy Multifetal pregnancy reduction after IVF  638 Omar Taso and Maher Maaita Multiple pregnancy after IVF: how to reduce preterm delivery  644 Shawqi Saleh and Maysa Khadra Hyperreactio luteinalis after IVF  650 Muataz Al-Ramahi and Omar Sharif Lactation by a commissioning mother in surrogacy  654 Pavithra Rao and Frank P. Biervliet Children of ART  658 Defne Saatci and Alastair G. Sutcliffe

Section 9: General and organizational issues 665 105 106 107 108 109 110 111 112 113 114 115 116

Managing physical symptoms during IVF  667 Chiara Achilli and Jyotsna Pundir IVF when the prognosis is very poor or futile  673 Khaldoun Sharif Dealing with the emotional distress following failed IVF  678 Sarah R. Holley, Lauri A. Pasch, and Alice D. Domar Couple splitting while embryos are in storage  684 Masoud Afnan Unexpected drop in the IVF clinic pregnancy rate  690 Bulent Urman and Kayhan Yakin Natural fertility after IVF  696 Frank Nawroth and Annika K. Ludwig Training in ART  699 Ryan J. Heitmann Keeping up to date in ART practice  706 Bassel H. Al-Wattar and Khalid S. Khan Cross-border reproductive care  714 Mahmoud Salama, Lynn M. Westphal, Marcia C. Inhorn, and Pasquale Patrizio Satellite and transport ART treatment  720 M. F. González Echeverría and J. A. Blaquier Social media use in ART  725 Natalie M. Crawford, Roohi Jeelani, Lora K. Shahine, and Kenan Omurtag Managing an ART unit as a profitable business  733 Michael H. Fakih, Ahmad Fakih, and Amanda Fakih Index  739

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Contributors Imad Aboujaoude MD, AIHP (Paris) Director of the Center of Reproductive Medicine and Genetics Chief, Department of Obstetrics and Gynecology Medical Director Aboujaoude Hospital Beirut Lebanon Basim Abu-Rafea MD Division of Reproductive Endocrinology and Infertility Schulich School of Medicine and Dentistry Western University London, Ontario Canada Chiara Achilli MD Consultant in Gynaecology and Reproductive Medicine Hewitt Fertility Centre Liverpool Women’s Hospital Liverpool UK Masoud Afnan MB, BS, FRCOG Chair, Department of Obstetrics and Gynaecology Qingdao United Family Hospital Qingdao People’s Republic of China

Ashok Agarwal PhD, HCLD Professor in Surgery (Urology) Lerner College of Medicine and Case Western Reserve University Director, American Center for Reproductive Medicine Department of Urology Cleveland Clinic Cleveland, Ohio USA Muataz Al-Ramahi MD, MSc Director of Noor Fertility and Assisted Reproduction Unit Eye Specialty Hospital Amman Jordan Dania Al-Ramahi Faculty of Medicine The University of Jordan Amman Jordan Ali Al-Rawahneh MD Urology Resident Department of Urology Royal Medical Services Amman Jordan

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Contributors

Bassel H. Al-Wattar MD, PGD, MRCOG, PhD NIHR Academic Clinical Lecturer in Women’s Health The University of Warwick; Subspecialty Trainee in Reproductive Medicine University College London Hospital London UK Saad Aldousari MBBCh, FRCSC, FACS Assistant Professor of Urology Department of Surgery Kuwait University, Faculty of Medicine Kuwait City Kuwait Ibrahim Alkatout MD, PhD, MA, MaHM Senior Consultant in Gynecology and Obstetrics Kiel School of Gynaecological Endoscopy University Hospitals Schleswig-Holstein Campus Kiel Kiel Germany Wael Almajed MBBS Urology Resident McGill University Montreal Canada Hussain M. Alnajjar BSc (MedSci), MBBS, MRCS, ChM (Urol), FEBU, FRCS (Urol) Consultant Urological Surgeon and Andrologist Institute of Andrology Department of Urology University College London Hospital London UK Odai Alqawasmeh PhD Embryologist Department of Obstetrics and Gynaecology Faculty of Medicine The Chinese University of Hong Kong Hong Kong

Carlo Alviggi MD, PhD Professor Department of Neuroscience, Reproductive Science and Odontostomatology University of Naples Federico II Naples Italy Medhat Amer MD Chairman of Adam International Hospital Professor of Andrology Cairo University Cairo Egypt Ellen Armstrong BSc Laboratory Manager Embryology CARE Fertility Birmingham UK Muhammad Faisal Aslam MD, FACOG, FRCOG Clinical Associate Professor Female Pelvic Medicine and Reconstructive Surgery, Obstetrics and Gynecology Ascension St. John/Michigan State University Detroit, Michigan USA Andreas Athanasakis MD Clinical Fellow Bristol Centre for Reproductive Medicine Bristol UK John Ayuk MD, FRCP Consultant Endocrinologist University Hospitals Birmingham Birmingham UK Adam H. Balen MBBS, MD, DSc, FRCOG Professor of Reproductive Medicine and Surgery Leeds Fertility Leeds UK

Contributors

Mohamad Bani-Domi BSc Senior Embryologist Fertility Center Jordan Hospital Amman Jordan Christopher L.R. Barratt PhD Professor, Reproductive and Developmental Biology, Maternal and Child Health Sciences Laboratories Centre for Oncology and Molecular Medicine University of Dundee, Ninewells Hospital Dundee UK Ali Ahmad Bazzi BS, MD Fellow, Reproductive Endocrinology and Infertility, Obstetrics and Gynecology Detroit Medical Center/Wayne State University Detroit, Michigan USA José Bellver MD, PhD Gynecologist at IVI-RMA; Associate Professor at Department of Pediatrics, Obstetrics and Gynecology Valencia School of Medicine University of Valencia; Researcher at IVI Foundation Health Research Institute La Fe Valencia Spain Louise Best BSc (hons), MSc Group Embryology Support and Improvement Lead CARE Fertility Nottingham UK Smriti Ray Chaudhuri Bhatta MD, MRCOG Senior Clinician Aberdeen Centre for Reproductive Medicine Institute of Applied Health Sciences

School of Medicine University of Aberdeen Aberdeen Maternity Hospital Aberdeen UK Frank P. Biervliet MRCOG Consultant in Obstetrics and Gynaecology Hull University Teaching Hospitals Hull UK Jorge Alberto Blaquier MD Medical Director Centro Médico FERTILAB Buenosa Aires Argentina Alison Campbell PhD, M Med Sci, BSC (hons), Dip. RCPath Group Director of Embryology CARE Fertility Nottingham UK Shiao-yng Chan MBBChir, PhD, FRCOG Associate Professor Department of Obstetrics and Gynaecology Yong Loo Lin School of Medicine National University of Singapore Singapore Jerome H. Check MD, PhD Professor, Obstetrics and Gynecology Division Head of Reproductive Endocrinology and Infertility Cooper Medical School of Rowan University Camden, New Jersey USA Ying C. Cheong MBCHB, BAO, MA, MD, FRCOG Professor of Reproductive Medicine Department of Obstetrics and Gynaecology University of Southampton Southampton UK

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Contributors

Spyros Chouliaras MD, FRCOG Attending Physician Department of Reproductive Medicine Sidra Medicine; Assistant Professor of Clinical Obstetrics and Gynecology Weill Cornell Medicine Doha Qatar Justin Chu PhD, MRCOG Subspecialist Trainee in Reproductive Medicine Honorary Academic Clinical Lecturer University of Birmingham Birmingham Women’s Hospital Birmingham UK Yealin Chung MBBS, BSc, MRCOG Clinical Research Fellow in Reproductive Medicine Tommy’s National Centre for Miscarriage Research University of Birmingham Birmingham UK T. Justin Clark MB ChB, MD (Hons), FRCOG Consultant Gynaecologist and Honorary Professor of Gynaecology Birmingham Women’s Hospital and the University of Birmingham Birmingham UK Alessandro Conforti PhD Assistant Professor Department of Neuroscience, Reproductive Science and Odontostomatology University of Naples Federico II Naples Italy Arri Coomarasamy MBChB, MD, FRCOG, FMedSci Professor of Gynaecology Director, Tommy’s National Centre for Miscarriage Research

Director, WHO Collaborating Centre for Global Women’s Health University of Birmingham; Consultant Gynaecologist and Subspecialist in Reproductive Medicine CARE Fertility Birmingham and Birmingham Women’s Hospital Birmingham UK Carol Coughlan MD, FRCOG, FRCPI Consultant Obstetrician and Gynaecologist Subspecialist in Reproductive Medicine and Surgery IVI Middle East Fertility and Gynaecology Clinic Dubai UAE Laurentiu Craciunas MSc, MRCOG Registrar in Obstetrics and Gynaecology Birmingham Women’s Hospital and University of Birmingham Birmingham UK Giselle Crawford Med (Hons), MRMed, FRANZCOG Fellow in Reproductive Endocrinology and Infertility The Fertility and Research Centre Royal Hospital for Women Sydney Australia Natalie M. Crawford MD, MSCR, FACOG Director of Patient Experience and Education Fora Fertility; Clinical Assistant Professor of Women’s Health University of Texas at Austin Dell Medical School Austin, Texas USA

Contributors

Sarah J. Martins da Silva MRCOG Consultant Gynaecologist and Honorary Senior Lecturer Medical Research Institute Ninewells Hospital and Medical School Dundee UK Neuda Marques de Oliveira MD, MSc Medical Director IRMO S.L. Santa Cruz de Tenerife Spain Patricia Hernández Delgado MSc Embryologist IRMO S.L. Santa Cruz de Tenerife Spain Rima Dhillon-Smith PhD, MRCOG, MBChB Academic Clinical Lecturer in Reproductive Medicine Birmingham Women’s Hospital and University of Birmingham Birmingham UK Richard Palmer Dickey PhD Medical Director Fertility Institute of New Orleans Clinical Professor Emeritus in Obstetrics and Gynecology Louisiana State University School of Medicine New Orleans New Orleans, Louisiana USA Samuel Dobson BM BS, BMedSci (Hons), MRCOG Subspecialty Trainee in Reproductive Medicine and Surgery Jessop Wing, Sheffield Teaching Hospitals Sheffield UK Shelley Dolitsky MD Housestaff Department of Obstetrics, Gynecology and Reproductive Sciences

Robert Wood Johnson Medical School New Brunswick, New Jersey USA Alice D. Domar PhD Executive Director, Domar Centers for Mind/ Body Health; Associate Professor of Obstetrics, Gynecology and Reproductive Biology Boston IVF Harvard Medical School Waltham, Massachusetts USA María Fernanda González Echeverría Assisted Reproduction Laboratory Director Centro Médico FERTILAB Buenos Aires Argentina Tarek El-Toukhy MBBCh, MSc, MD, MRCOG Consultant in Reproductive Medicine Assisted Conception Unit Guy’s and St. Thomas’ Hospital London UK Manal Elgendy MBBCh, MD Specialty Doctor in Assisted Reproduction Birmingham Women’s Fertility Centre Birmingham Women’s Hospital Birmingham UK Aboubakr Mohamed Elnashar MD Professor of Obstetrics and Gynecology Benha University Hospital Benha Egypt Majd M. Ezal-Deen BSc Director of Embryology Laboratory Fertility Center Jordan Hospital Amman Jordan

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Contributors

Emad Fakhry MD IVF Lab Director Adam International Hospital Cairo Egypt Ahmad Fakih MD, MSc Consultant Reproductive Medicine and Infertility Fakih IVF Dubai UAE Amanda Fakih MHSA Interim Chief Administrative Officer Pathology and Laboratory Medicine UCLA Health Los Angeles, California USA Michael H. Fakih MD Consultant Reproductive Endocrinology and Infertility Medical Director Fakih IVF; CEO Emirates Healthcare Group Dubai UAE Ahmed F. Galal MD Assistant Professor Department of Obstetrics and Gynecology University of Alexandria Alexandria Egypt Juan A. García-Velasco MD, PHD Associate Professor of Obstetrics and Gynecology Department of Human Reproduction Rey Juan Carlos University; Director, IVI Madrid Madrid Spain

Sierra Goldsmith BSc Research Scientist Coordinator Infertility Center of St. Louis St. Luke’s Hospital St. Louis, Missouri USA Penny Goold MBBS, FRCP, Membership of Institute of Psychosexual Medicine Consultant Sexual Health and HIV Clinical Lead for Psychosexual Service University Hospitals Birmingham Birmingham UK David Green MB, ChB, FRCA, MBA Consultant Anaesthetist Priory Hospital Birmingham UK Haitham Hamoda MD, FRCOG Consultant Gynaecologist, Subspecialist in Reproductive Medicine and Surgery King’s College Hospital London UK Ryan J. Heitmann DO Director, Obstetrics and Gynecology Residency Program Division of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology Madigan Army Medical Center Tacoma, Washington USA Anna S. Herrey MD, PhD, FRCP Consultant Cardiologist St. Bartholomew’s Hospital London UK Micah J. Hill DO, FACOG Director, REI Fellowship, National Institutes of Health Director, Assisted Reproductive Technologies

Contributors

Walter Reed National Military Medical Center; Professor Uniformed Services University of the Health Sciences Bethesda, Maryland USA Sarah R. Holley PhD Associate Professor Psychology Department San Francisco State University San Francisco, California USA Elizabeth Howland MBBS, FRCOG Deputy Chief Medical Officer Consultant Obstetrician and Gynaecologist University Hospitals Birmingham Birmingham UK Graciela Kohls Ilgner MD Gynecologist IVI Madrid Madrid Spain Marcia C. Inhorn PhD, MPH Professor of Anthropology Yale University New Haven, Connecticut USA Giuseppe Iorio Obstetrics and Gynaecology Trainee Department of Neuroscience, Reproductive Science and Odontostomatology University of Naples Federico II Naples Italy Kannamannadiar Jayaprakasan MBBS MRCOG, PhD Associate Professor and Subspecialist in Reproductive Medicine and Surgery

Division of Obstetrics and Gynaecology School of Clinical Sciences Queen’s Medical Centre University of Nottingham Nottingham UK Roohi Jeelani, MD, FACOG Director of Research and Education Vios Fertility Institute; Assistant Professor of Obstetrics and Gynecology Wayne State University Detroit, Michigan USA Yadava Jeve MSc, MRCOG. MBA, PhD Subspecialist in Reproductive Medicine and Surgery Consultant Obstetrician and Gynaecologist Deputy Clinical Director for Gynaecology and Theatres Birmingham Women’s Hospital Birmingham UK Gyath Karadsheh BSc Embryologist Fertility Center Jordan Hospital Amman Jordan Vishvanath C. Karande MD, FACOG Medical Director IVF Program InVia Fertility Specialists Hoffman Estates, Illinois USA Maysa Khadra MD MMed(RHHG) Associate Professor of Obstetrics and Gynaecology The University of Jordan Amman Jordan

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Contributors

Yakoub Khalaf MD, FRCOG Professor of Reproductive Medicine and Surgery Assisted Conception Unit Guy’s Hospital London UK Mohammad A. Khan FRCOG Senior Attending Physician Sidra Medicine; Assistant Professor of Obstetrics and Gynaecology Weill Cornell Medicine-Qatar Doha Qatar Khalid Saeed Khan MBBS, FCPS, MSc, MRCOG, MMEd, FHEA, FRCOG Professor Distinguished Investigator Beatriz Galindo Programme Department of Preventive Medicine and Public Health University of Granada Granada Spain Justin C Konje MD, MBA, FMCOG (Nig), FWACS, FRCOG Senior Attending Physician Sidra Medicine; Professor of Obstetrics and Gynaecology Weill Cornell Medicine-Qatar Doha Qatar Peter Kovacs MD, PhD Medical Director IVF Center Kaali Institute Budapest Hungary Pallavi Latthe MD, FRCOG Consultant Obstetrician and Gynaecologist Birmingham Women’s Hospital Birmingham UK

William Ledger MA, DPhil (Oxon), MB, ChB, FRCOG, FRANZCOG, CREI Professor and Head of Discipline of Obstetrics and Gynaecology School of Women’s and Children’s Health University of New South Wales Sydney Australia Angela H. Liu Resident Physician Department of Obstetrics and Gynecology University of Nevada Las Vegas Las Vegas, Nevada USA Annika Kristin Ludwig Professor of Obstetrics and Gynecology Praxis für Frauengesundheit and Pränatalmedizin Hamburg Germany Maher Maaita MBBS, FRCOG Subspecialist in Feto-Maternal Medicine Clinical Associate Professor Consultant and Head of Department of Obstetrics and Gynaecology King Hussein Medical Centre Amman Jordan Mohammed Khairy Mahmoud MD, MRCOG Consultant in Reproductive Medicine CARE Fertility Birmingham UK Giulia Mariani MD Gynecologist IVI-RMA Valencia Spain Ayrton Artazkoz Marques de Oliveira Barcelona University Barcelona Spain

Contributors

Juan José Artazkoz Marques de Oliveira Girona University Girona Spain Marlon P. Martinez MD, FPUA, FPCS Consultant Section of Urology Department of Surgery University of Santo Tomas Hospital Manila Philippines Anne E. Martini MD, FACOG Fellow in Reproductive Endocrinology and Infertility Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda, Maryland USA

Liselotte Mettler MD, PhD Emeritus Professor and Deputy Director Department of Obstetrics and Gynecology/ Reproductive Medicine University Clinics of Schleswig Holstein Kiel Germany Mostafa Metwally FRCOG, MD Consultant in Reproductive Medicine and Surgery Jessop Wing Sheffield Teaching Hospitals Sheffield UK Mahmoud Mima MD Assistant Professor of Clinical Urology University of Illinois at Chicago Chicago, Illinois USA

Szabolcs Matyas PhD Chief Embryologist IVF Center Kaali Institute Budapest Hungary

Fady Moeity MD Professor Department of Obstetrics and Gynaecology University of Alexandria Alexandria Egypt

Pedro Melo MD, MRCOG Clinical Research Fellow in Reproductive Medicine Tommy’s National Centre for Miscarriage Research University of Birmingham Birmingham UK

Hossam Mohamed MBBCh, MD, FRCOG Senior Consultant Department of Obstetrics and Gynaecology Women’s Wellness and Research Center Doha Qatar

Zaher Merhi MD, HCLD Associate Professor of Reproductive Endocrinology and Infertility SUNY Downstate University Brooklyn, New York USA

Christopher P. Moutos MD Resident Physician Department of Obstetrics and Gynecology University of Texas Medical Branch at Galveston Galveston, Texas USA

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Contributors

Suheil J. Muasher MD Associate Professor Department of Gynecology and Obstetrics Division of Reproductive Endocrinology and Infertility Johns Hopkins School of Medicine Baltimore, Maryland USA Asif Muneer MD, FRCS (Urol) Consultant Urological Surgeon and Andrologist Associate Professor Division of Surgery Department Urology University College London Hospital London UK Luciano G. Nardo MD, MRCOG Clinical Director Reproductive Health Group Daresbury UK Frank Nawroth MD, PhD Centre for Infertility, Prenatal Medicine, Endocrinology and Osteology Amedes Group Hamburg Germany Scott M. Nelson BSC, MBCHB, PhD, MRCOG Muirhead Chair in Obstetrics and Gynaecology School of Medicine University of Glasgow Glasgow UK Catherine Nelson-Piercy FRCP, FRCOG Professor of Obstetric Medicine King’s College London; Consultant Obstetric Physician

Guy’s and St. Thomas’ NHS Foundation Trust Imperial College Healthcare NHS Trust London UK Jose Vázquez Núñez MSc Director of Embryology and Andrology Laboratory IRMO S.L. Santa Cruz de Tenerife Spain Samuel J. Ohlander MD Assistant Professor of Urology University of Illinois at Chicago Chicago, Illinois USA Bolarinde Ola MBBS, FRCOG, FWACS, MD, MBA Consultant Gynaecologist and Subspecialist in Reproductive Medicine and Surgery Department of Obstetrics and Gynaecology Jessop Wing, Sheffield Teaching Hospitals Sheffield UK Kenan Omurtag MD, FACOG Division of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology Washington University School of Medicine St. Louis, Missouri USA Rodrigo L. Pagani MD Assistant Professor of Urology University of Illinois at Chicago Chicago, Illinois USA William Rhys Parry-Smith BSc, MBBS MD, PGCert MRCOG, FHEA, BSCCP Consultant Obstetrician and Gynaecologist Shrewsbury and Telford NHS Trust Shrewsbury UK

Contributors

Lauri A. Pasch PhD Professor Psychiatry and Behavioral Sciences University of California San Francisco San Francisco, California USA Sabrina Pastor-Carvajal MD Assistant Professor Department of Obstetrics and Gynecology University of Miami/Miller School of Medicine Miami, Florida USA Pasquale Patrizio MD, MBE, HCLD, FACOG Professor of Reproductive Endocrinology and Infertility Yale University New Haven, Connecticut USA Valerie L Peddie RGN, RM, ADM, BA(Hons), MSc Nurse Consultant and Fertility Specialist Aberdeen Centre for Reproductive Medicine Institute of Applied Health Sciences School of Medicine University of Aberdeen Aberdeen Maternity Hospital Aberdeen UK John Y. Phelps MD, JD, LLM, MHA Professor Department of Obstetrics and Gynecology University of Nevada Las Vegas Las Vegas, Nevada USA Lukasz Polanski PhD, MRCOG Subspecialty trainee in Reproductive Medicine and Surgery Assisted Conception Unit Guy’s Hospital London UK

Neelam Potdar MRCOG Consultant in Reproductive Medicine Women’s Clinical Management Group University Hospitals of Leicester NHS Trust Leicester UK Jyotsna Pundir MRCOG Consultant Gynaecologist Subspecialist in Reproductive Medicine and Surgery Centre for Reproductive Medicine St. Bartholomew’s Hospital; Honorary Senior Lecturer Queen Mary University London UK Beth W. Rackow MD Associate Professor of Obstetrics, Gynecology and Pediatrics Department of Obstetrics and Gynecology Columbia University Irving Medical Center New York, New York USA Nicholas Raine-Fenning MBChB, MRCOG, PhD Associate Professor and Reader of Reproductive Medicine and Surgery Director of Research Nottingham University Research and Treatment Unit in Reproduction Division of Human Development School of Clinical Sciences Nottingham University Hospitals NHS Trust Nottingham UK Abdel-Maguid Ramzy MD Professor Department of Obstetrics and Gynaecology Cairo University Cairo Egypt

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Contributors

Yorain Sri Ranjan BSc, MPhil, MRCOG Clinical Research Fellow in Reproductive Medicine; Specialist Registrar in Obstetrics and Gynaecology Department of Human Development and Health Faculty of Medicine University of Southampton Southampton UK Pavithra Rao MBBS, MRCOG Specialist Registrar in Obstetrics and Gynaecology Hull University Teaching Hospitals Hull UK Nivedita Reddy MBBS, MRCOG Associate Specialist Assisted Conception Unit Guy’s Hospital London UK Giuseppe Ricci MD Associate Professor of Obstetrics and Gynecology Department of Medical Sciences University of Trieste; Director Assisted Reproduction Unit, Institute for Maternal and Child Health IRCCS Burlo Garofolo Trieste Italy Isla Robertson BMBCh, BA (Medical Sciences), MRCOG Clinical Research Fellow in Reproductive Medicine Department of Obstetrics and Gynaecology University of Southampton Southampton UK

Lynne Robinson MBCHB, MD, MRCOG Consultant Obstetrician and Gynaecologist Fertility and Menopause Clinical Lead Birmingham Women’s Hospital Birmingham UK Lawrence S. Ross MD Past President American Urological Association Clarence C. Saelhof Professor Emeritus of Urology University of Illinois at Chicago Chicago, Illinois USA Heather E. Ross JD Partner Founding Partner, Ross and Zuckerman, LLP Chicago, Illinois USA Defne Saatci BA, MBBChir, MRes Research Fellow Great Ormond Street Institute of Child Health London UK Mahmoud Salama MD, PhD Adjunct Assistant Professor of Obstetrics and Gynecology Northwestern University Chicago, Illinois USA Shawqi Saleh MD, FRCOG Professor of Obstetrics and Gynaecology The University of Jordan Amman Jordan Hassan N. Sallam MD, FRCOG, PhD Professor of Obstetrics and Gynecology University of Alexandria Alexandria Egypt

Contributors

Mark V. Sauer, MD, MS Professor and Chairman Department of Obstetrics, Gynecology and Reproductive Sciences; Senior Associate Dean for Women’s Health Rutgers Robert Wood Johnson Medical School New Brunswick, New Jersey USA

Amman Jordan

Claire Scanlon MB, ChB Specialist Trainee in Anaesthesia Birmingham Children’s Hospital Birmingham UK

Kavita Singh MD, MRCOG Consultant Gynaecologist Pan-Birmingham Women’s Gynaecological Cancer Centre City Hospital Birmingham UK

Ahmed G. Serour MD Assistant Professor of Obstetrics and Gynaecology Al Azhar University Cairo Egypt Lora K. Shahine, MD, FACOG Director of the Center for Recurrent Pregnancy Loss Pacific NW Fertility; Clinical Assistant Professor Department of Obstetrics and Gynecology University of Washington Washington USA Khaldoun Sharif MBBCh (Hons), MFFP, MD, FACOG, FRCOG Consultant Obstetrician and Gynaecologist Subspecialist in Reproductive Medicine and Surgery Clinical Director Fertility Center Jordan Hospital Amman Jordan Omar Sharif Faculty of Medicine The University of Jordan

Sherman J. Silber MD Director Infertility Center of St. Louis St. Luke’s Hospital St. Louis, Missouri USA

Murat Sönmezer MD Professor of Obstetrics and Gynecology Ankara University School of Medicine Ankara Turkey Barbara Sonntag MD, PhD Professor of Obstetrics and Gynecology Facharztzentrum für Kinderwunsch, pränatale Medizin, Endokrinologie und Osteologie Amedes Experts Hamburg Hamburg Germany Annika Strandell MD, PhD Senior lecturer, Associate Professor Department of Obstetrics and Gynecology Institute of Clinical Sciences Sahlgrenska Academy University of Gothenburg Gothenburg Sweden Donna Summers MS, ELD (ABB) Embryology /Laboratory Director Cooper Institute for Reproductive Hormonal Disorders Mt. Laurel, New Jersey USA

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Contributors

Sesh Kamal Sunkara MBBS, MD, FRCOG Senior Clinical Lecturer in Reproductive Medicine Department of Women’s Health King’s College London; Consultant Gynaecologist and Subspecialist in Reproductive Medicine King’s Fertility London UK Alastair G. Sutcliffe MB, ChB, MD, PhD Professor of General Paediatrics The UCL and Great Ormond Street Institute of Child Health London UK Brad B. Swelstad MD Clinical and Research Fellow Department of Gynecology and Obstetrics Division of Reproductive Endocrinology and Infertility Johns Hopkins School of Medicine Baltimore, Maryland USA Teddy Tadros MD IVF Specialist Center of Reproductive Medicine and Genetics Aboujaoude Hospital Beirut Lebanon Jennifer Tamblyn MBChB, BMedSci (Hons), PhD Clinical Lecturer in Obstetrics and Gynaecology Institute of Metabolism and Systems Research University of Birmingham Birmingham UK Omar Taso MD, JBOG Senior Specialist in Obstetrics and Gynecology Fellow in Feto-Maternal Medicine

King Hussein Medical Centre Amman Jordan Alison Taylor MBBS, MD, MRCOG Consultant Gynaecologist and Subspecialist in Reproductive Medicine Lister Fertility Clinic Lister Hospital London UK Kelton Tremellen MBBS(Hons), PhD, FRANZCOG, CREI Professor of Reproductive Medicine Department of Obstetrics Gynaecology and Reproductive Medicine Flinders University Bedford Park Australia Volkan Turan MD Associate Professor İstanbul Üsküdar University School of Medicine Istanbul Turkey Jenna Turocy MD Fellow in Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology Columbia University Irving Medical Center New York, New York USA Martyn Underwood MBChB, MRCOG, BSCCP Consultant Gynaecologist and Care Group Medical Director for Women and Children Shrewsbury and Telford NHS Trust Shrewsbury UK Bulent Urman MD Professor Department of Obstetrics and Gynecology

Contributors

Koc University School of Medicine Istanbul Turkey Usha Verma MD Professor and Director Division of Gynecology Department of Obstetrics and Gynecology University of Miami/Miller School of Medicine Miami, Florida USA Kugajeevan Vigneswaran MRCOG Subspecialty Trainee in Reproductive Medicine Department of Obstetrics and Gynaecology King’s College Hospital London UK Lynn M. Westphal MD, FACOG Professor Emerita​of Reproductive Endocrinology and Infertility Stanford University Stanford, California USA Carla Ball White Administrator Fertility Institute of New Orleans New Orleans, Louisiana USA

Kayhan Yakin MD, PhD Professor Department of Obstetrics and Gynecology Koc University School of Medicine Istanbul Turkey Kaoru Yanagida MD, PhD Professor and Director Center for Infertility and IVF International University of Health and Welfare Hospital Otawara Tochigi Japan A. Albert Yuzpe MD, MSc, FRCS(C) Emeritus Professor of Obstetrics and Gynecology University of Western Ontario, London, Ontario, Canada; Co-Director, Genesis Fertility Centre Vancouver, British Columbia Canada Armand Zini MD Professor Department of Surgery McGill University Montreal Canada

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Preface to the second edition Since the first edition of this book 9 years ago, the number of in  vitro fertilization babies in the world has doubled to over 8 million. New challenges have emerged, and new approaches to many old challenges have been proposed. A new edition is now due. We were heartened to see the first edition being used as study material in numerous assisted reproduction techniques (ART) training programs and workshops all over the world. Moreover, we were humbled by many of our established colleagues telling us that they frequently refer to the book during their clinical work. In fact, this is exactly why we had written the book: to help ART practitioners successfully

navigate the various day‐to‐day challenges in looking after their patients, based on the best available evidence. More evidence has accumulated since the first edition, and all chapters have been updated, with the addition of new ones. As well as covering the counseling, medical, surgical and laboratory steps of ART, this edition also addresses training issues, organizational and business skills, and social media use. Khaldoun Sharif, Amman, Jordan Arri Coomarasamy, Birmingham, UK 2021

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Preface to the first edition Louise Brown, the world’s first baby conceived through in  vitro fertilization (IVF), was  born on July 25, 1978, in Oldham, England. Since then, in a relatively short time in terms of scientific evolution, over 4 million babies have been born worldwide from IVF treatment. IVF and other assisted reproduction techniques (ART) involve counseling, medical, surgical and laboratory steps, all contributing to the eventual potential success of the process. As sure as night follows day, at each step various challenges could be encountered.

The aim of this book is to stimulate resourceful thinking in the ART practitioner when dealing with those challenges, by outlining various management options, the reasoning behind them, and the evidence on which they are based. The practitioner would then be ­better equipped to choose the most suitable solution that best fits the needs of each particular patient. Khaldoun Sharif, Amman, Jordan Arri Coomarasamy, Birmingham, UK 2012

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How to use this book This is intended to be a highly practical manual, providing viable solutions to real‐life ART problems. To this end, the major sections of the book have been written mirroring the patient’s journey in the ART process. In addition, each chapter has been written concisely, starting with one or more case histories outlining the problem, followed by a discussion on how the problem occurred, how it could have been prevented, what management options are available, and the reasoning and evidence behind them. Also, high‐quality medical care involves not only doing the right thing but also explaining it

clearly to patients and answering their questions. Accordingly, we have included in each chapter a list of patients’ questions and their suggested answers. How will you get the most out of this book? We suggest you read the case history and work out some management solutions yourself before reading the rest of the chapter. Compare and contrast your solutions with the options provided in the book. Discuss with your colleagues – seniors and juniors; nurses, counselors, embryologists, and clinicians.

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Abbreviations ABOG

American Board of Obstetrics and Gynecology

CFTR

cystic fibrosis transmembrane regulator

ACOG

American College of Obstetricians and Gynecologists

CGH

comparative genomic hybridization

ACS

acute coronary syndrome

CI

confidence interval

ADHD

attention‐deficit hyperactivity disorder

CMV

cytomegalovirus

COCP

AFC

antral follicle count

combined oral contraceptive pill

AHR

adjusted hazard ratio

COS

controlled ovarian stimulation

AMH

anti‐Müllerian hormone

CT

computerized tomography

anti‐HBc

hepatitis B core antibody

CVS

chorionic villus sampling

APA

antiphospholipid antibodies

DCM

dilating cardiomyopathy

ART

assisted reproduction techniques

DHEA

dehydroepiandrosterone

AS

Asherman syndrome

DI

donor insemination

ASD

autism spectrum disorder

DVT

deep venous thrombosis

ASRM

American Society for Reproductive Medicine

ECF

endometrial cavity fluid

ED

erectile dysfunction

BMI

body mass index

EFS

empty follicle syndrome

BNF

British National Formulary

EMT

endometrial thickness

BOT

borderline ovarian tumor

EP

ectopic pregnancy

c‐TESE

conventional‐testicular sperm extraction

ER

estrogen receptor

ERA

endometrial receptivity array

CBAVD

congenital bilateral absence of the vas deferens

ESG

European Society of Gynecology

CBRC

cross border reproductive care

ESGE

CCS

childhood cancer survivors

European Society for Gynaecological Endoscopy

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Abbreviations

ESHRE

European Society of Human Reproduction and Embryology

ICSI

intra‐cytoplasmic sperm injection

ET

embryo transfer

IUI

intrauterine insemination

FDA

Food and Drug Administration

IUP

intrauterine pregnancy

IVF

in vitro fertilization

FET

frozen embryo transfer

IVM

in vitro maturation

FGR

fetal growth restriction

KS

Klinefelter syndrome

FISH

fluorescence in situ hybridization

LDA

low dose aspirin

LH

luteinizing hormone

FSH

follicle stimulating hormone

LLETZ

GA

general anesthesia

large loop excision of transformation zone

GEA

global endometrial ablation

LMWH

low molecular weight heparin

GH

growth hormone

LPS

luteal phase support

GnRH

gonadotropin releasing hormone

MBMS

multiple birth minimization strategy

HARRT

highly active antiretroviral therapy

MFPR

multifetal pregnancy reduction

HBsAg

hepatitis B surface antigen

micro‐TESE

HBV

hepatitis B virus

micro‐dissection testicular sperm extraction

hCG

human chorionic gonadotropin

MNC‐IVF

modified natural cycle IVF

MRI

magnetic resonance imaging

HCM

hypertrophic cardiomyopathy

MTHFR

HCV

hepatitis C virus

methylene tetrahydro‐folate reductase

HFEA

Human Fertilisation and Embryology Authority

NC‐IVF

natural cycle IVF

NGS

next generation sequencing

HIV

human immunodeficiency virus

NHS

National Health Service

NICE

HL

hyperreactio luteinalis

National Institute for Health and Care Excellence

HMG

human menopausal gonadotropin

NNT

number needed to treat

NTPR

HPO

hypothalamic‐pituitary‐ ovarian

National Transplant Pregnancy Registry

OHSS

HPV

human papilloma virus

ovarian hyperstimulation syndrome

HSG

hysterosalpingogram

OR

odds ratio

HTA

Human Tissue Authority

ORT

ovarian reserve test

HyCoSy

hystero‐contrast sonography

OTC

ovarian tissue cryopreservation

Abbreviations

PCA

patient controlled analgesia

RCT

randomized controlled trial

PCC

preconception care and counseling

RIF

recurrent implantation failure

PCOS

polycystic ovary syndrome

ROS

reactive oxygen species

PESA

percutaneous epidydimal sperm aspiration

RR

relative risk

PGH

preimplantation genetic haplotyping

SART

Society for Assisted Reproductive Technologies

PGS

preimplantation genetic screening

SHBG

sex hormone binding globulin

SLE

systemic lupus erythematosus

PGT

preimplantation genetic testing

SMI

social media influencer

SSR

surgical sperm retrieval

PGT‐A

preimplantation genetic testing for aneuploidy

TESA

testicular sperm aspiration

TESE

testicular sperm extraction

PGT‐M

preimplantation genetic testing for monogenic disorders

TFF

total fertilization failure

PGT‐SR

preimplantation genetic testing for structural chromosomal rearrangements

TFNA

testicular fine needle aspiration

TIVA

total intravenous anesthesia

TMET

transmyometrial embryo transfer

TPO

thyroid peroxidase

TSH

thyroid stimulating hormone

TVOR

transvaginal oocyte retrieval

UAE

uterine artery embolization

VEGF

vascular endothelial growth factor

PID

pelvic inflammatory disease

POR

poor ovarian response

POSEIDON

patient‐oriented strategies encompassing individualized oocyte number

PrEP

pre‐exposure prophylaxis

PRL

prolactin

PSR

posthumous sperm retrieval

VTE

venous thromboembolism

PUL

pregnancy of unknown location

VZV

varicella zoster virus

WGA

whole genome amplification

r‐FSH

recombinant follicle stimulating hormone

WHO

World Health Organization

RCOG

Royal College of Obstetricians and Gynaecologists

YCMD

Y chromosome microdeletion

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1

SECTION ONE

Counseling and preparation

3

1 Risk of cancer from ovarian stimulation Yadava Jeve Birmingham Women’s Hospital, Birmingham, UK

Case History: A 36-year-old woman had controlled ovarian stimulation as part of IVF treatment, resulting in a term pregnancy 2 years previously. Following that, her mother developed breast cancer at the age of 61 years. Now the patient desires another pregnancy, but she is concerned about the risk of cancer due to ovarian stimulation. How should she be counseled?

Background Women suffering from subfertility are often concerned about the safety of the drugs and the risk of cancer. A belief that using hormones could increase the risk of cancer is one of the most significant fears. In recent years, there have been many debates about the relationship between infertility, fertility drugs and cancer. Early studies raised substantial concern with ovulation‐stimulating drugs being linked with large increases in ovarian cancer [1,2]. However, it is difficult to separate cancer risk after fertility treatment from the underlying condition of infertility. Comorbidities such as obesity, excessive smoking, anovulation, endometriosis and nulliparity are frequently related to subfertility, but they are also independently related to an increased risk of cancer [3]. The delay or the inability to achieve a pregnancy is an important risk factor for breast, endometrial and ovarian cancer. However, the relationship between infertility

treatment and cancer incidence remains an open question [2,4].

Management options Breast cancer Breast cancer is the most common malignancy in women, affecting one in eight women. Breast cancer is a multifactorial disease; however, most breast cancers are hormone‐dependent [5]. Compared with a normal menstrual cycle, estradiol concentration increases up to tenfold in ovulation stimulation cycle [6]. Therefore, the effect of subfertility and its treatment on breast cancer is widely investigated in the literature. The association between polycystic ovary syndrome (PCOS) and breast cancer has been examined in several studies. Meta‐analysis showed that PCOS does not increase the risk of breast cancer [7, 8]. As for fertility drugs and breast cancer risk, some studies showed no association while

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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Risk of cancer from ovarian stimulation

­ thers demonstrated a possible increase in risk o [9–12]. An Australian study (n = 21,025) showed commencing IVF treatment at a young age (less than 24 years of age) is associated with an increased rate of breast cancer [13]. It is expected that, if ovulation induction per se causes breast cancer, such tumors may have distinct characteristics such as strong estrogen receptor expression, but a study showed that breast cancer diagnosed within the first 2 years following infertility treatment is similar in tumor characteristics such as tumor size and histological types, estrogen receptor, progesterone receptor and Her2/Neu expression status compared to those occurring in patients without prior infertility treatment [14]. Women with BRCA1 or BRCA2 mutation have an increased risk of breast cancer. A study of 1,550 BRCA1 and 964 BRCA2 mutation carriers did not show any evidence that ovarian stimulation for IVF increases the breast cancer risk in BRCA1/2 mutation carriers [15]. A large UK‐based data linkage cohort study of 255,786 women did not find an increase in the overall risk of breast cancer but a small increase in the risk of in situ breast cancer was reported [16]. A meta‐analysis of eight cohort studies showed IVF treatment does not increase the breast cancer risk [17]. A total of seven systematic reviews or meta‐analyses evaluated the relationship between fertility drugs and breast cancer [17-23]. They have either shown no increase in the risk of breast cancer or a decrease in risk following infertility treatment. Therefore, as per the American Society of Reproductive Medicine guideline, women could be reassured that fertility drugs are not associated with an increased risk of breast cancer [24].

Ovarian cancer Ovulation is considered to be a potential biologic promoter of ovarian cancer, which is called the “incessant ovulation” hypothesis. A second hypothesis is that gonadotropin stimulation increases the risk of malignant changes directly, or by acting in combination with a

raised concentration of estrogen. Yet another hypothesis frequently suggested by epidemiological data is that undiagnosed early ovarian cancer causes, in some manner, infertility [25]. Data from 12 case‐control studies conducted in the period 1956–1986 showed pregnancy, breastfeeding and oral contraceptive use induce biological changes that protect against ovarian malignancy. A small fraction of the excess ovarian cancer risk among nulliparous women was due to infertility [26]. Only 3 of the 12 studies examined the association between the use of fertility drugs and invasive ovarian cancer. One study showed an increased risk of ovarian cancer in infertile women who had used fertility drugs. This study had several limitations. Subsequently, a large cohort study [27] suggested an increased risk of invasive and borderline ovarian tumors, a finding that was supported by other studies [28,29]. A pooled analysis of case‐control studies showed fertility drug use in nulligravid women was associated with borderline serous tumors but not with any invasive histologic subtypes [30]. Several other epidemiological studies showed no convincing association between the use of fertility drugs and risk of ovarian cancer [18,31–34]. An important group of women who are at increased risk of developing ovarian cancer are those with BRCA1 and BRCA2 gene mutations. Recent studies suggested that BRCA mutation carriers may have decreased ovarian reserve compared with women without BRCA mutations [35,36]. The studies suggested that treatment for infertility does not significantly increase the risk of ovarian cancer among women with a BRCA mutation [37,38]. A meta‐ analysis of nine cohort studies showed that IVF is not associated with ovarian cancer when the confounding effect of infertility was adjusted for in such studies [39]. A recent Cochrane review consisting of 24 cohort studies and 13 case‐control studies concluded that there is no convincing evidence of an increase in the risk of invasive ovarian tumors with fertility drug treatment, and even women with a BRCA genetic mutation are not at increased risk due

Management options 

to fertility treatment [25]. Risk of borderline ovarian tumors may be increased in infertile women treated with in vitro fertilization, but the evidence is classed as low grade [25]. To summarize, current evidence is sufficient to reassure women that there is no clear increase in the risk of invasive ovarian cancer following the use of fertility drugs. A few studies have shown a small increase in the absolute risk of borderline ovarian tumors after fertility treatments, but this risk is small, and the evidence is insufficient to recommend against the use of fertility medications to avoid borderline ovarian tumors [24].

Endometrial cancer Endometrial cancer is the most common malignancy of the lower female genital tract in developed countries [40]. It is a hormone‐ dependent malignancy in the majority of cases. PCOS and unexplained infertility have also been linked directly to endometrial cancer [9,41]. The suggested mechanism is that fertility drugs result in prolonged exposure of the endometrium to high levels of estrogen, which raises the risk of endometrial cancer by increasing mitotic activity and DNA replication errors [42]. However, fertility drugs induce ovulatory cycles and pregnancies, which results in progesterone production, exerting potentially protective effects and a reduction in endometrial cancer risk. A meta‐analysis of nine cohort studies concluded that IVF does not seem to be associated with increased risk of cervical cancer or endometrial cancer when the confounding effect of infertility was neutralized [39]. A 2017 Cochrane review of 19 studies (1,937,880 participants) concluded that women who need treatment with clomiphene citrate should be aware that they are at increased risk of endometrial cancer. The risk is largely due to underlying conditions causing subfertility, and it is not possible to assess the additional effect of clomiphene citrate, based on available data  [43]. The review found the quality of evidence was very low.

Overall, there is no evidence to support that fertility drugs are associated with an increased risk of endometrial cancer.

Cervical cancer The literature investigating the risk of cervical cancer following fertility medication use has consistently shown no increased risk compared to both the general population and infertile patients as controls [44]. On the other hand, a few studies showed a reduced incidence of cervical cancer in women undergoing IVF which could be related to better access to healthcare and ensuring cervical cytology screening are up to date [18,45].

Key points Challenge: Counseling women about the risks of cancer from ovarian stimulation. Background: ●● Nulliparity is a risk factor for breast, ovarian and endometrial cancers. ●● Infertility and associated comorbidities may act as a risk factor for many gynecological cancers. ●● PCOS, a condition associated with infertility, is linked to endometrial cancer but not with breast cancer. ●● It is difficult to separate the cancer risks attributable to infertility from that of fertility drugs. ●● Most epidemiologic studies that have examined the association between fertility drugs and cancer risks have used the general population as the comparator. A more appropriate comparator is the untreated infertile population as this would allow better assessment of the cancer risk attributable to fertility drugs. ●● Some studies have shown a small increase in the risk of borderline ovarian tumors following the use of fertility drugs, but the evidence is insufficient to recommend against their use. Management options: ●● Women should be counseled about the uncertainty in the available evidence. ●● Women may be counseled that there is no clear evidence that the use of fertility drugs for IVF increases the risk of cancers.

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6

Risk of cancer from ovarian stimulation

Answers to questions patients ask Q1 Does IVF treatment increase the risk of cancer? A1.  No it doesn’t. There were initial worries about this issue because we use hormones to stimulate the ovaries in IVF, but subsequently many studies looked at the effect of having IVF on cancers of the breast, ovary and womb, and their conclusions were that there is no increased risk. Q2 My aunt had IVF in the past and now she developed cancer. Do you think it was the IVF that caused it? A2.  Unfortunately, cancer is not uncommon, and it is estimated

that about one in three people will develop cancer in their lifetime. The good news is that many of these cancers are diagnosed early enough to treat them, but the point is that cancer could happen whether the woman had IVF or not. Many studies looked at the effect of having IVF on cancers of the breast, ovary and womb, and their conclusions were that there is no increased risk. Sometimes, having conditions that make the woman more likely to need IVF (such as PCOS) in itself increases the risk of cancer.

References 1 Brinton L. Long‐term effects of ovulation‐ stimulating drugs on cancer risk. Reproductive Biomedicine Online. 2007;15(1):38–44. 2 Venn A, Jones P, Quinn M, Healy D. Characteristics of ovarian and uterine cancers in a cohort of in vitro fertilization patients. Gynecol Oncol. 2001;82(1):64–8. 3 Katzke VA, Kaaks R, Kuhn T. Lifestyle and cancer risk. Cancer Journal. 2015;21(2):104–10. 4 Momenimovahed Z, Taheri S, Tiznobaik A, Salehiniya H. Do the fertility drugs increase the risk of cancer? A review study. Front Endocrinol (Lausanne). 2019;10:313. 5 Santen R, Cavalieri E, Rogan E, Russo J, Guttenplan J, Ingle J, et al. Estrogen mediation of breast tumor formation involves estrogen receptor‐dependent, as well as independent, genotoxic effects. Annals of the New York Academy of Sciences. 2009;1155:132–40. 6 Sonmezer M, Oktay K. Fertility preservation in female patients. Human Reproduction Update. 2004;10(3):251–66. 7 Chittenden BG, Fullerton G, Maheshwari A, Bhattacharya S. Polycystic ovary syndrome and the risk of gynaecological cancer: a

systematic review. Reproductive Biomedicine Online. 2009;19(3):398–405. 8 Barry JA, Azizia MM, Hardiman PJ. Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta‐analysis. Human Reproduction Update. 2014;20(5):748–58. 9 Venn A, Watson L, Bruinsma F, Giles G, Healy D. Risk of cancer after use of fertility drugs with in‐vitro fertilisation. Lancet. 1999;354(9190):1586–90. 10 Reigstad MM, Larsen IK, Myklebust TA, Robsahm TE, Oldereid NB, Omland AK, et al. Risk of breast cancer following fertility treatment—a registry based cohort study of parous women in Norway. International Journal of Cancer. 2015;136(5):1140–8. 11 Reigstad MM, Storeng R, Myklebust TA, Oldereid NB, Omland AK, Robsahm TE, et al. Cancer risk in women treated with fertility drugs according to parity status‐a registry‐ based cohort study. Cancer Epidemiology, Biomarkers & Prevention. 2017;26(6):953–62. 12 Burkman RT, Tang MT, Malone KE, Marchbanks PA, McDonald JA, Folger SG, et al.

References 

Infertility drugs and the risk of breast cancer: findings from the National Institute of Child Health and Human Development Women’s Contraceptive and Reproductive Experiences Study. Fertility and Sterility. 2003;79(4):844–51. 13 Stewart LM, Holman CD, Hart R, Bulsara MK, Preen DB, Finn JC. In vitro fertilization and breast cancer: is there cause for concern? Fertility and Sterility. 2012;98(2):334–40. 14 Sönmezer M, Cil AP, Oktem O, Oktay K. Breast cancer diagnosis following ovarian stimulation: Are the tumours different? Reproductive Biomedicine Online. 2010;21(2):266–71. 15 Derks‐Smeets IAP, Schrijver LH, de Die‐ Smulders CEM, Tjan‐Heijnen VCG, van Golde RJT, Smits LJ, et al. Ovarian stimulation for IVF and risk of primary breast cancer in BRCA1/2 mutation carriers. British Journal of Cancer. 2018;119(3):357–63. 16 Williams CL, Jones ME, Swerdlow AJ, Botting BJ, Davies MC, Jacobs I, et al. Risks of ovarian, breast, and corpus uteri cancer in women treated with assisted reproductive technology in Great Britain, 1991–2010: data linkage study including 2.2 million person years of observation. BMJ. 2018;362:k2644. 17 Sergentanis TN, Diamantaras AA, Perlepe C, Kanavidis P, Skalkidou A, Petridou ET. IVF and breast cancer: a systematic review and meta‐analysis. Human Reproduction Update. 2014;20(1):106–23. 18 Brinton LA, Trabert B, Shalev V, Lunenfeld E, Sella T, Chodick G. In vitro fertilization and risk of breast and gynecologic cancers: a retrospective cohort study within the Israeli Maccabi Healthcare Services. Fertility and Sterility. 2013;99(5):1189–96. 19 Li LL, Zhou J, Qian XJ, Chen YD. Meta‐ analysis on the possible association between in vitro fertilization and cancer risk. International Journal of Gynecological Cancer. 2013;23(1):16–24. 20 Salhab M, Al Sarakbi W, Mokbel K. In vitro fertilization and breast cancer risk: a review. International Journal of Fertility and Women’s Medicine. 2005;50(6):259–66.

21 Gennari A, Costa M, Puntoni M, Paleari L, De Censi A, Sormani MP, et al. Breast cancer incidence after hormonal treatments for infertility: systematic review and meta‐analysis of population‐based studies. Breast Cancer Research and Treatment. 2015;150(2):405–13. 22 Zreik TG, Mazloom A, Chen Y, Vannucci M, Pinnix CC, Fulton S, et al. Fertility drugs and the risk of breast cancer: a meta‐analysis and review. Breast Cancer Research and Treatment. 2010;124(1):13–26. 23 Lo Russo G, Tomao F, Spinelli GP, Prete AA, Stati V, Panici PB, et al. Fertility drugs and breast cancer risk. European Journal of Gynaecological Oncology. 2015;36(2):107–13. 24 Pfeifer S, Butts S, Dumesic D, Fossum G, Gracia C, La Barbera A, et al. Fertility drugs and cancer: a guideline. Fertility and Sterility. 2016;106(7):1617–26. 25 Rizzuto I, Behrens RF, Smith LA. Risk of ovarian cancer in women treated with ovarian stimulating drugs for infertility. Cochrane Database of Systematic Reviews. 2019(6). 26 Whittemore AS, Harris R, Itnyre J. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case‐ control studies. II. Invasive epithelial ovarian cancers in white women. Collaborative Ovarian Cancer Group. American Journal of Epidemiology. 1992;136(10):1184–203. 27 Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumors in a cohort of infertile women. New England Journal of Medicine. 1994;331(12):771–6. 28 Shushan A, Paltiel O, Iscovich J, Elchalal U, Peretz T, Schenker JG. Human menopausal gonadotropin and the risk of epithelial ovarian cancer. Fertility and Sterility. 1996;65(1):13–8. 29 Nugent D, Salha O, Balen AH, Rutherford AJ. Ovarian neoplasia and subfertility treatments. British Journal of Obstetrics and Gynaecology. 1998;105(6):584–91. 30 Ness RB, Cramer DW, Goodman MT, Kjaer SK, Mallin K, Mosgaard BJ, et al. Infertility, fertility drugs, and ovarian cancer: a pooled analysis of case‐control studies. American Journal of Epidemiology. 2002;155(3):217–24.

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Risk of cancer from ovarian stimulation

31 Dor J, Lerner‐Geva L, Rabinovici J, Chetrit A, Levran D, Lunenfeld B, et al. Cancer incidence in a cohort of infertile women who underwent in vitro fertilization. Fertility and Sterility. 2002;77(2):324–7. 32 Doyle P, Maconochie N, Beral V, Swerdlow AJ, Tan SL. Cancer incidence following treatment for infertility at a clinic in the UK. Human Reproduction (Oxford, England). 2002;17(8):2209–13. 33 Franceschi S, La Vecchia C, Negri E, Guarneri S, Montella M, Conti E, et al. Fertility drugs and risk of epithelial ovarian cancer in Italy. Human Reproduction(Oxford, England). 1994;9(9):1673–5. 34 Jensen A, Sharif H, Frederiksen K, Kjær SK. Use of fertility drugs and risk of ovarian cancer: Danish population based cohort study. BMJ. 2009;338:b249. 35 Finch A, Valentini A, Greenblatt E, Lynch HT, Ghadirian P, Armel S, et al. Frequency of premature menopause in women who carry a BRCA1 or BRCA2 mutation. Fertility and Sterility. 2013;99(6):1724–8. 36 Wang ET, Pisarska MD, Bresee C, Chen YD, Lester J, Afshar Y, et al. BRCA1 germline mutations may be associated with reduced ovarian reserve. Fertility and Sterility. 2014;102(6):1723–8. 37 Gronwald J, Glass K, Rosen B, Karlan B, Tung N, Neuhausen SL, et al. Treatment of infertility does not increase the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation. Fertility and Sterility. 2016;105(3):781–5. 38 Perri T, Lifshitz D, Sadetzki S, Oberman B, Meirow D, Ben‐Baruch G, et al. Fertility treatments and invasive epithelial ovarian

cancer risk in Jewish Israeli BRCA1 or BRCA2 mutation carriers. Fertility and Sterility. 2015;103(5):1305–12. 39 Siristatidis C, Sergentanis TN, Kanavidis P, Trivella M, Sotiraki M, Mavromatis I, et al. Controlled ovarian hyperstimulation for IVF: impact on ovarian, endometrial and cervical cancer‐‐a systematic review and meta‐analysis. Human Reproduction Update. 2013;19(2):105–23. 40 Bamberger A, Bamberger C, Schulte H. Molecular mechanisms of proliferation in endometrial tumour cells. Human Reproduction Update. 1998;4(5):526–31. 41 Navaratnarajah R, Pillay OC, Hardiman P. Polycystic ovary syndrome and endometrial cancer. Seminars in Reproductive Medicine. 2008;26(1):62–71. 42 Akhmedkhanov A, Zeleniuch‐Jacquotte A, Toniolo P. Role of exogenous and endogenous hormones in endometrial cancer: review of the evidence and research perspectives. Annals of the New York Academy of Sciences. 2001;943:296–315. 43 Skalkidou A, Sergentanis TN, Gialamas SP, Georgakis MK, Psaltopoulou T, Trivella M, et al. Risk of endometrial cancer in women treated with ovary‐stimulating drugs for subfertility. The Cochrane Database of Systematic Reviews. 2017;3(3):CD010931‐CD. 44 Kroener L, Dumesic D, Al‐Safi Z. Use of fertility medications and cancer risk: a review and update. Current Opinion in Obstetrics & Gynecology. 2017;29(4):195–201. 45 Yli‐Kuha AN, Gissler M, Klemetti R, Luoto R, Hemminki E. Cancer morbidity in a cohort of 9175 Finnish women treated for infertility. Human Reproduction (Oxford, England). 2012;27(4):1149–55.

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2 Risk of early menopause following IVF treatment Sesh Kamal Sunkara Department of Women’s Health, Faculty of Life Sciences and Medicine, King’s College London, London, UK

Case History 1: A 34-year-old woman due to commence ICSI treatment for male factor infertility is concerned about the risk of premature menopause from ovarian stimulation. She has regular menstrual cycles and normal FSH, LH and estradiol levels. A pelvic ultrasound scan showed a normal sized uterus, and both ovaries were of normal morphology and volume with a total antral follicle count of 16. She is fit and well with no significant medical history. Case History 2: A woman who is now 43 years of age had IVF treatment 5 years ago which was unsuccessful. She had only three oocytes retrieved following ovarian stimulation with gonadotropins. Her periods had become irregular 2 years following the IVF treatment cycle, and they stopped a year ago.

Background In women, the ovaries age with time and finally lose their function, with menopause marking the definite end of female reproductive life. The ovarian concept of reproductive aging assumes that the age‐related loss in female fertility is dictated by the decline of both the quantity and quality of the follicles [1]. Women with regular menstrual cycles (premenopausal) have ovarian follicle counts 10 times greater than in perimenopausal women of similar age, while follicles are virtually absent in postmenopausal women [2]. Both fertility and the age at menopause vary substantially between women [3]. Results from a large cohort study, the population of which was selected from the Prospect‐EPIC (European Prospective Investigation into Cancer and

Nutrition) project that involved a questionnaire survey of women aged 50–69 years from the city of Utrecht in the Netherlands, showed that fertility problems are frequently followed by early menopause  [4], supporting the view that both are an expression of accelerated ovarian aging. Questions have been raised on whether gonadotropin stimulation used in assisted reproductive technology (ART) treatments has an impact on ovarian aging and menopause. A retrospective cohort study investigating whether menopausal age is inversely related to the number of ART cycles found no such correlation [5], supporting the view that gonadotropin stimulation in women does not accelerate follicular depletion, an observation consistent with experimental studies that showed primordial follicle recruitment to be independent of gonadotropin stimulation.

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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Risk of early menopause following IVF treatment

In this context it is also important to address the association between poor ovarian response to gonadotropin stimulation and early menopause. A large questionnaire survey of women selected from participants of a nationwide cohort study (the OMEGA Project) of 19,840 women who underwent IVF treatment in the Netherlands from 1983 to 1995 indicated that a low number of retrieved oocytes at the first IVF treatment was an important predictor of early menopausal transition [6]. The results of this study were in line with an earlier finding that anticipated poor responders are at a greater risk of becoming postmenopausal at the age of 46 years or before than normal responders [7].

Management options A question not infrequently asked by women embarking on ovarian hyperstimulation for IVF treatment is whether this would lead to a depletion of the primordial follicles in the ovaries and thereby an increased risk of early menopause. It is important to counsel women,

Key points

explaining the various steps involved in IVF treatment and implications they are likely to have for the woman in the short and long term. Women should be reassured that there is substantial evidence to suggest that gonadotropin stimulation to induce multifollicular recruitment and optimize the outcome of IVF treatment does not result in a depletion of the ovarian primordial follicles. Women should be informed that those encountering fertility problems may have an increased background risk of reaching early menopause than fertile women, but gonadotropin stimulation during IVF treatment does not increase their risk of attaining early menopause. Women who have responded poorly to controlled ovarian hyperstimulation during IVF treatment indicated by a low number of retrieved oocytes have a compromised ovarian reserve and are at risk of becoming menopausal earlier (Case History 2) than women who have had a normal response. Women should be informed that all procedures involved in the IVF treatment process are generally safe and do not put the woman at risk of premature ovarian failure.

Challenge: IVF treatment and the risk of early menopause.

Women with a compromised ovarian reserve (indicating ovarian aging) are at risk of becoming menopausal earlier than women with a good ovarian reserve.

Background: The question is frequently raised by women undergoing IVF treatment. ●● Women with fertility problems have a higher background risk of reaching menopause earlier than fertile women. ●● Gonadotropin stimulation does not cause depletion of primordial follicles.

Management options: ●● Reassure women that the procedures involved in the IVF treatment cycle do not put them at a risk of reaching earlier menopause. ●● There is no association between the number of attempts at IVF treatment and the age at menopause.

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References 

Answers to questions patients ask Q1 Will having ovarian stimulation for IVF make me get early menopause? A1. No, it wouldn’t. Ovarian stimulation is a routine part of IVF, aiming to increase the number of eggs available for treatment, compared with what happens in a spontaneous menstrual cycle. During a menstrual cycle, several follicles start to grow initially, but only one follicle and sometimes two follicles become dominant and release an egg following ovulation. The remaining follicles die out, as they require a higher level of follicle stimulating hormone for their continued growth. During ovarian stimulation, this hormone is given

in the form of injections to recruit and mature these follicles so that they do not die out. Therefore, ovarian stimulation is only salvaging follicles that would have ­otherwise perished in a natural menstrual cycle. Hence, ovarian stimulation for IVF does not lead to early menopause. Q2 I have had seven IVF cycles, and each time they collected about 10 eggs. Does that mean that I will run out of eggs in my ovaries earlier? A2. No, it doesn’t. Studies have shown that the number of IVF cycles and the number of eggs collected do not affect the age of menopause.

References 1 Te Velde ER, Pearson PL. The variability of female reproductive ageing. Hum Reprod Update. 2002;8:141–54. 2 Richardson SJ, Senikas V, Nelson JF. Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion. J Clin Endocrinol Metab. 1987;65:1231–7. 3 Te Velde ER, Dorland M, Broekmans FJ. Age at menopause as a marker of reproductive ageing. Maturitas. 1998:30:119–25. 4 Kok HS, Van Asselt KM, van der Schouw YT, Grobbee DE, te Velde ER, Pearson PL, et al. Subfertility reflects accelerated ovarian ageing. Hum Reprod. 2003;18:644–8. 5 Elder K, Mathews T, Kutner E, Kim E, Espenberg E, Faddy M, et al. Impact of

gonadotrophin stimulation for assisted reproductive technology on ovarian ageing and menopause. Reprod Biomed Online. 2008;16:611–16. 6 de Boer EJ, Den Tonkelaar I, Te Velde ER, Burger CW, van Leeuwen FE; OMEGA Project Group. Increased risk of early menopausal transition and natural menopause after poor response at first IVF treatment. Hum Reprod. 2003;18:1544–52. 7 de Boer EJ, Den Tonkelaar I, Te Velde ER, Burger CW, Klip H, van Leeuwen FE. Low number of retrieved oocytes at IVF treatment is predictive of early menopause. Fertil Steril. 2002;77:978–85.

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3 The HIV-positive female Mark V. Sauer and Shelley Dolitsky Department of Obstetrics, Gynecology & Reproductive Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA

Case History 1: A 37-year-old woman presents for reproductive counseling. The patient has a history of substance abuse and contracted HIV from a contaminated hypodermic needle at age 27. She states that for over 8 years she has not used illicit drugs and now wishes to conceive with her husband. She has no significant medical or surgical history. She has never been pregnant, and her gynecologic history is notable for irregular periods, with her menstrual cycles occurring from 30 –58 days. The patient’s husband is also HIV-seropositive. He acquired HIV from a sexual relationship with a male partner when he was aged 23. He has one child from a previous partner and no other significant medical or surgical history. Both the patient and her husband are under the care of an infectious disease specialist, and they are compliant with their highly active antiretroviral therapy. They have both achieved an undetectable viral load with CD4 counts of 800 and 600 cells/ mm3, respectively. Case History 2: A 27-year-old woman presents for reproductive counseling. The patient acquired HIV from a sexual relationship when she was 18 years. Since diagnosis, she has been cared for by an infectious disease specialist, and as a result of compliance with medical treatment, she has achieved an undetectable plasma viral load; CD4 has always been >400 cells/mm3. Her boyfriend is HIVseronegative, and they have always practiced safe sex with condoms. She has no significant medical or surgical history, but she was hospitalized for pelvic inflammatory disease twice in her early 20s which resolved with antibiotic therapy.

Background According to 2017 data from the USA, approximately 1.1  million people are infected with HIV, of whom 23% (258,000) are females  [1]. Nearly 20% (7,401) of newly diagnosed HIV in the USA and nearly half of people living with

HIV worldwide are females  [2]. The majority of the female HIV burden is borne by reproductive‐aged women (15–44 years old). Prior to the widespread availability of effective HIV therapy (specifically, highly active antiretroviral therapy: HAART), the impact of HIV disease on maternal health, as well as the

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

Management options 

alarming rates of vertical transmission (7–71%  [3]), generally rendered childbearing an unreasonable and unsafe consideration in HIV‐seropositive women. The risk of horizontal transmission to serodiscordant partners was simply addressed by advocating universal condom use in these couples. The introduction of HAART has transformed both patients’ and providers’ perspective on HIV disease. Maternal morbidity and mortality now resemble rates seen in many other chronic diseases and if appropriate steps are taken (medical treatment for mother and newborn, cesarean delivery and avoidance of breastfeeding), vertical transmission can be reduced to 2% or less [4]. The CDC developed a framework to guide organizations to reduce the risk of vertical transmission [5], and studies show that the vertical transmission rate can be less than 1% if HAART is started in the first trimester  [7]. According to 2019 UN AIDS global statistics, 82% of pregnant women had access to antiretroviral medications, compared with 47% in 2010 [2]. These developments have created the need for recommending various safe approaches to childbearing in HIV‐serodiscordant couples. While genital HIV shedding generally correlates with plasma HIV RNA concentration, a significant proportion of women will harbor HIV in the genital tract even at low levels of plasma HIV RNA [7]. Therefore, even in HIV‐ seropositive women on HAART and/or with undetectable plasma viral load, the risk of horizontal transmission during unprotected intercourse is difficult to quantify, and natural efforts at conception via unprotected intercourse are not endorsed. Much progress was made in the application of sperm washing techniques and assisted reproductive technology (ART) for HIV‐seropositive males seeking fertility care in the 1990s. Yet, lingering concerns regarding possible vertical transmission and/or ART laboratory specimen, equipment and personnel contamination and cross‐contamination delayed significant attention to the needs of HIV‐seropositive females seeking care until the 2000s [8].

Management options Similar to the approach for HIV‐seropositive males, management of seropositive females requires careful multidisciplinary healthcare coordination [9]. First and foremost, the medical fitness of the woman should be verified in consultation with internal medicine and infectious disease specialists. Special attention to recent history of CD4 counts, viral load and general treatment compliance (including consistent condom use) is required. Psychosocial assessment is performed to screen for issues of substance abuse, mental health, domestic violence or other issues that are more prevalent in the HIV‐seropositive population and might affect reproductive fitness or compliance with care. Finally, consultation with maternal‐fetal medicine specialists or obstetricians specifically trained to manage HIV‐infected patients is indicated to discuss issues related to the antiretroviral therapy used during pregnancy, prenatal screening and diagnostic testing (specifically invasive diagnostic maneuvers, e.g. amniocentesis, that carry a risk of transmission), and the plan for delivery. Once the patient’s medical and psychosocial fitness for pregnancy has been established, an HIV‐seropositive female with an HIV‐seronegative partner may be instructed in self‐insemination techniques synchronized with ovulation. For patients who object to self‐ insemination, well timed intercourse that decreases the need for repetitive exposure is a reasonable alternative  [10]. Recent studies have investigated the efficacy of pre‐exposure prophylaxis (PrEP) for the uninfected partner during the time conception is attempted to further safeguard the uninfected partner [11]. If unsuccessful after several attempts or if the patient is 35 years old or has a history suggestive of reproductive dysfunction (e.g. menstrual irregularity, poor antral follicle count), clinicians should initiate a basic infertility workup, including day 2–3 follicle stimulating hormone (FSH), semen analysis and

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The HIV-positive female

hysterosalpingogram (aggressive antibiotic prophylaxis, e.g. doxycycline for 5–7  days or Azithromycin should be prescribed). HIV‐seropositive females may be vulnerable to two major categories of infertility. First, HIV is known to coexist with a high prevalence of other sexually transmitted diseases, which may lead to pelvic inflammatory disease (PID) [12]. Tubal disease is therefore a common cause of infertility among HIV‐ seropositive women  [13,14]. Second, studies suggest that HIV may have a direct deleterious effect on the ovaries [15]. Various investigators have shown a higher rate of ovarian dysfunction  [16,17], diminished ovarian reserve  [18], premature ovarian insufficiency  [19] and amenorrhea  [20–22] in this population. In population studies, HIV disease progression has been observed to be associated with a decline in fertility, even after controlling for nutritional status and weight loss  [23], and with oligomenorrhea and amenorrhea  [20]. However, it has been suggested that confounding variables, such as substance abuse and smoking, may have contributed to these disorders and more recent data from North America has not confirmed these findings  [24]. One study evaluated ovarian reserve as reflected in anti‐Müllerian hormone (AMH) levels and found no association with HIV‐seropositivity [25]. If the couple demonstrates infertility, ART should be recommended. In the absence of significant male factor or tubal disease, intrauterine insemination (IUI) with or without controlled ovarian stimulation (COS) may also be recommended. IUI has been performed in HIV patients with good results  [26], although it should be noted that because multiple pregnancy increases obstetric complications associated with higher rates of vertical transmission (e.g. preterm birth), aggressive COS is best avoided. In the case of significant male factor, intra‐ cytoplasmic sperm injection (ICSI) is the clear treatment of choice. Tubal disease can

be addressed with IVF with or without ICSI; most practitioners nevertheless advocate using ICSI in order to minimize the amount of infected material in the laboratory by denuding the oocyte and performing repeated washings prior to fertilization  [27]. In this regard, it should be noted that the American Society for Reproductive Medicine (ASRM) “highly recommends” that material from viral carriers be processed in a separate laboratory or designated space within the main laboratory using dedicated equipment  [28]. Unfortunately, the heavy financial burden of fulfilling these recommendations has contributed to the scarcity of American centers offering treatment to HIV‐seropositive patients [10,29]. To date, there are no published cases of children born to HIV‐seropositive women after ART who were subsequently found to be HIV‐ seropositive. Self‐insemination and IUI data in this setting are largely absent from the literature. However, many studies demonstrate overall poorer IVF outcomes in women with HIV compared with uninfected patients  [26– 27,30–32]. In two studies, an increased amount of gonadotropin and prolonged duration of stimulation were required in comparison to matched controls; however, this pattern was not consistently observed  [27,33]. Overall, reported pregnancy rates are in the range of approximately 10–25%, slightly lower than those reported for age‐matched controls [27,31,34]. While it is possible these data may lend support to the negative effects of HIV on the ovaries, two factors should be considered: 1. In an effort to limit multiple pregnancy, fewer embryos were transferred in HIV‐ seropositive patients; this may account for lower pregnancy rates. Indeed, implantation rates per embryo are generally more comparable to those of controls. 2. Other factors potentially associated with decreased ART success, including African race, leiomyomata and smoking are likely

Answers to questions patients ask  15

more prevalent in the HIV‐seropositive groups studied and these variables were not adequately controlled. Ultimately, there is little doubt that for HIV‐ seropositive women, who previously had few safe options for building a family, reproductive medicine and ART has had an enormously positive impact on their quality of life and disease prevention. Efforts need to continue to focus on making care more accessible and affordable in hope of expanding services universally.

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An untreated and unattended HIV-­ seropositive woman may transmit the virus to her partner and child.

Challenge: Managing the fertility needs of HIV-seropositive women.

Management options: ●● Consult specialists in infectious disease, maternal-fetal medicine and social services. ●● If tubes are patent, attempt self-­ insemination, ovulation induction IUI or natural cycle IUI. ●● If tubes are blocked or there is male factor infertility present, consider ICSI. ●● Material from viral carriers should be ­processed in a separate laboratory or ­designated space within the main laboratory using dedicated equipment. ●● Maintain viral load as near to undetectable as possible. ●● Avoid medications known to be ­contraindicated in pregnancy (e.g. efavirenz).

Background: Over 17 million women worldwide live with HIV. ●● Most newly diagnosed cases of HIV occur in women between the ages of 15–44 years. ●● One-third of HIV-infected individuals wish to have children despite their diagnosis. ●● Tubal disease is common among HIV-infected patients.

Prevention: ●● Antiretroviral therapy improves survival and enhances quality of life of HIV-infected patients. ●● Antiretroviral therapy reduces the risk of vertical transmission to fetus and child. ●● Safe sex with condoms should be ­practiced to reduce risk of infection to the male partner.

Key points

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Answers to questions patients ask Q1 Can a woman with HIV receive fertility care? A1.  Women who are HIV‐seropositive can achieve pregnancy in a variety of ways including through natural conception. However, depending upon their health status, the risk to themselves, their partner and their child may be significant if the condition is not well managed. Goals of therapy relate to minimizing the viral load of the female using HAART prior to conception and throughout the pregnancy in order to reduce the risk of transmission.

Timed intercourse, IUI and IVF are all reasonable choices depending upon the circumstances of the patient and her partner once the HIV is well controlled. Q2 Will my HIV medications interfere with my attempts to conceive? A2.  In most cases women prescribed HAART should remain on their current medications while attempting to conceive, throughout the pregnancy and following delivery, in order to control the virus from replicating. The medications do

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The HIV-positive female

not interfere with attempts to conceive. However, efavirenz, also known as EFV and Sustiva, is not considered safe during the first trimester (pregnancy category D in US) due to potential teratogenicity but may be used in later trimesters. However, in developing countries EFV is widely prescribed throughout pregnancy due to its low cost, ease of administration and relatively low risk profile. Collaborative management efforts involving the obstetrician and infectious disease doctor are important in order to select medications best suited to the patient’s needs throughout the course of her pregnancy. Q3 Why do many programs exclude women with HIV from participating in fertility care? A3.  American women with HIV are protected by the Americans with Disability Act (ADA) and therefore should not be discriminated against under federal law. This protection extends to employment, transportation, public accommodations, communications and access to state and local government services. Although the American Medical Association and the American Society for Reproductive Medicine have published opinions stating that physicians should not refuse treatment to HIV‐positive patients, it is conditional on the clinician’s competence and ability to treat such patients. Many fertility providers lack expertise within the field of infectious disease medicine or lack laboratory facilities to safely manage reproductive fluids and tissues and therefore will not offer the range of treatment options available to noninfected patients. In such cases, healthcare

providers should refer care to centers staffed and equipped to manage the reproductive needs of virally infected patients. Q4 Does HIV affect my reproductive organs? A4.  Women with HIV commonly complain of menstrual irregularities. This is likely a result of ­hormonal aberrations created by the effect of the virus on the ovary or the medications used to control viral replication. Fertility rates appear to be lower in HIV‐­ seropositive women, and spontaneous miscarriage rates are higher. HIV affects the body’s immune system which may partly explain the lower implantation rate of embryos, although the exact mechanism underlying subfertility is unknown. Women with HIV also more commonly experience pelvic inflammatory disease which may damage the fallopian tubes and uterus, key components to normal reproductive function. Q5 What is the chance my baby will have HIV as a result of my infection? A5.  HIV may be passed from mother to child either through the bloodstream during pregnancy or later when breastfeeding. The risk to the fetus is greatest and may be as high as 25% if the mother is not prescribed HAART and has active viral replication. However, this risk is dramatically reduced to less than 1% if antiviral medication is provided. The goal of therapy is to attain undetectable viral load during pregnancy and delivery. Cesarean section delivery is recommended to further reduce transmission risk and breastfeeding avoided.

References 

References 1 Centers for Disease Control and Prevention. Estimated HIV incidence and prevalence in the United States, 2010–2016. HIV Surveillance Supplemental Report. 2019;24(No. 1). http://www.cdc.gov/ hiv/ library/reports/hiv‐surveillance.html. Published February 2019. 2 Joint United Nations Programme on HIV/ AIDS. Global HIV & AIDS Statistics ‐ 2019 Fact Sheet. 2019. https://www.unaids.org/ en/resources/fact‐sheet. 3 St Louis ME, Kamenga M, Brown C, Nelson AM, Manzila T, Batter V, et al. Risk for perinatal HIV‐1 transmission according to maternal immunologic, virologic, and placental factors. JAMA. 1993; 69:2853–9. 4 International Perinatal HIV Group. The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1: a meta‐analysis of 15 prospective cohort studies. N Engl J Med. 1999; 340:977–87. 5 Centers for Disease Control and Prevention. HIV and Pregnant Women, Infants, and Children. https://www.cdc.gov/hiv/group/ gender/pregnantwomen/index.html Published Match 2019. 6 Selph SS, Bougatsos C, Dana T, Grusing S, Chou R. Screening for HIV infection in pregnant women: updated evidence report and systematic review for the US preventive services task force. JAMA. 2019; 321(23):2349–2360. 7 Kovacs A, Wasserman SS, Burns D, Wright DJ, Cohn J, Landay A, et al. Determinants of HIV‐1 shedding in the genital tract of women. Lancet. 2001; 358:1593–601. 8 Sauer, MV. Providing fertility care to those with HIV: time to re‐examine healthcare policy. Am J Bioethics. 2003; 3:33–40. 9 Douglas NC, Wang JG, Yu B, Gaddipati S, Guarnaccia MM, Sauer, MV. A systematic, multidisciplinary approach to address the reproductive needs of HIV‐seropositive women. Reprod BioMed Online. 2009; 19:257–63. 10 Ethics Committee of the American Society for Reproductive Medicine. Human

immunodeficiency virus (HIV) and infertility treatment: a committee opinion. Fertil Steril. 2015; 104(1):e1–8. 11 Vernazza PL, Graf I, Sonnenberg‐Schwan U, Geit M, Meurer A. Preexposure prophylaxis and timed intercourse for HIV‐discordant couples willing to conceive a child. AIDS. 2011; 25:2005–8. 12 Sobel JD. Gynecologic infection in human immunodeficiency virus‐infected women. Clin Infect Dis. 2000; 31:1225–33. 13 Santulli P, Gayet V, Fauque P, Chopin N, Dulioust E, Wolf JP, et al. HIV‐positive patients undertaking ART have longer infertility histories than age‐matched control subjects. Fertil Steril. 2011; 95(2):507–12. 14 Nurudeen SK, Grossman LC, Bourne L, Guarnaccia MM, Sauer MV, Douglas NC. Reproductive outcomes of HIV seropositive women treated by assisted reproduction. J Women’s Health. 2013; 22(3):243–9. 15 Savasi V, Mandia L, Laoreti A, Cetin I. Reproductive assistance in HIV serodisordant couples. Human Reproductive Update. 2013; 19:136–150. 16 Clark RA, Mulligan K, Stamenovic E, Chang B, Watts H, Andersen J, Squires K, Benson C. Frequency of anovulation and early menopause among women enrolled in selected adult AIDS clinical trials group studies. J Infect Dis. 2001; 184:1325–1327. 17 Englert Y, Lesage B, Van Vooren JP, Liesnard C, Place I, Vannin AS, Emiliani S, Delbaere A. Medically assisted reproduction in the presence of chronic viral diseases. Hum Reprod Update. 2004; 10:149–162. 18 Seifer DB, Golub ET, Lambert‐Messerlian G, Springer G, Holman S, Moxley M, Cejtin H, Nathwani N, Anastos K, Minkoff H et al. Biologic markers of ovarian reserve and reproductive aging: application in a cohort study of HIV infection in women. Fertil Steril. 2007; 88:1645–1652. 19 Ohl J, Partisani M, Demangeat C, Binder‐ Foucard F, Nisand I, Lang JM. Alterations of

17

18

The HIV-positive female

ovarian reserve tests in human immunodeficiency virus (HIV)‐infected women. Gynecol Obstet Fertil. 2010; 38:313–317. 20 Chirgwin KD, Feldman J, Muneyyirci‐Delale O, Landesman S, Minkoff H. Menstrual function in human immunodeficiency virus‐infected women without acquired immunodeficiency syndrome. J Acquir Immune Defic Syndr Hum Retrovirol. 1996; 12:489–494. 21 Cejtin HE, Kalinowski A, Bacchetti P, Taylor RN, Watts DH, Kim S, Massad LS, Preston‐ Martin S, Anastos K, Moxley M et al. Effects of human immunodeficiency virus on protracted amenorrhea and ovarian dysfunction. Obstet Gynecol. 2006; 108:1423 –1431. 22 Schoenbaum EE, Hartel D, Lo Y, Howard AA, Floris‐Moore M, Arnsten JH, Santoro N. HIV infection, drug use, and onset of natural menopause. Clin Infect Dis. Nov 2005; 41:1517–1524. 23 Sedgh G, Larsen U, Spiegelman D, Msamanga G, Fawzi WW. HIV‐1 disease progression and fertility in Dar es Salaam, Tanzania. J Acquir Immune Defic Syndr. 2005; 39:439–45. 24 Harlow SD, Schuman P, Cohen M, Ohmit SE, Cu‐Uvin S, Lin X, et al. Effect of HIV infection on menstrual cycle length. J Acquir Immune Defic Syndr. 2000; 24:68–75. 25 Seifer DB, Golub ET, Lambert‐Messerlian GL, Springer G, Holman S, Moxley M, et al. Biologic markers of ovarian reserve and reproductive aging: application in a cohort study of HIV infection in women. Fertil Steril. 2007; 88:1645–52. 26 Ninive C, X Ferraretto, S Gricourt, M A Llabador, J Lepage, C Gauché‐Cazalis, S Epelboin, M Peigné. Assisted reproductive technologies in HIV patients: Which results and which strategy in France in 2019?

Gynecologie, Obstetrique, Fertilite & Senologie. 2019; 47(4): 362–369. 27 Terriou P, Auquier P, Chabert‐Orsini V, Chinchole JM, Cravello L, Giorgetti C, et al. Outcome of ICSI in HIV‐1‐infected women. Hum Reprod. 2005; 20:2838–43. 28 Practice Committee of American Society for Reproductive Medicine. Guidelines for reducing the risk of viral transmission during fertility treatment. Fertil Steril. 2008; 90(Suppl. 5):156–62. 29 Sauer, MV. American physicians remain slow to embrace the reproductive needs of human immunodeficiency virus‐infected patients. Fertil Steril. 2006; 85:295–7. 30 Ohl J, Partisani M, Wittemer C, Schmitt MP, Cranz C, Stoll‐Keller F, Rongieres C, Bettahar‐Lebugle K, Lang JM, Nisand I. Assisted reproduction techniques for HIV serodiscordant couples: 18 months of experience. Hum Reprod. 2003; 18:1244–1249. 31 Coll O, Suy A, Figueras F, Vernaeve V, Martı´nez E, Mataro´ D, Durban M, Lonca M, Vidal R, Gatell JM. Decreased pregnancy rate after in‐vitro fertilization in HIV‐infected women receiving HAART. AIDS. 2006; 20:121–123. 32 Marques C, Guerreiro C, Soares SR. Lights and shadows about the effectiveness of IVF in HIV infected women: a systematic review. Infect Dis Obstet Gynecol. 2015; 2015:517208. 33 Martinet V, Manigart Y, Rozenberg S, Becker B, Gerard M, Delvigne A. Ovarian response to stimulation of HIV‐positive patients during IVF treatment: a matched, controlled study. Hum Reprod. 2006; 21(5):1212–17. 34 Ohl J, Partisani M, Wittemer C, Lang JM, Viville S, Favre R. Encouraging results despite complexity of multidisciplinary care of HIV‐infected women using assisted reproduction techniques. Hum Reprod. 2005; 20:3136–40.

19

4 The HIV-positive male Mark V. Sauer and Shelley Dolitsky Department of Obstetrics, Gynecology and Reproductive Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA

Case History 1: An HIV-serodiscordant couple wished to have a child. The man had a history of intravenous drug use as a teenager and contracted HIV from an infected needle. He claims to have discontinued all illicit drug use 15 years ago and is compliant with his highly active antiretroviral therapy (HAART). His viral load was undetectable, and his CD4 count was 800 cells/mm3 at a recent visit to his primary care physician. The couple’s infertility evaluation was entirely unremarkable. Intrauterine insemination (IUI) of washed/swim up prepared sperm was performed on his partner during her natural spontaneous ovulatory cycles using a previously frozen semen specimen. Prior to the sample being frozen and used for treatment, an aliquot of semen was tested for the presence of detectable HIV RNA using a nucleic acid sequence-based amplification (NASBA) method and found to be negative. The patient conceived on her third attempt with IUI. Both mother and child were HIV-seronegative at delivery and three months postpartum. Case History 2: An HIV-seropositive male wished to have a child. He was medically stable and taking antiretroviral therapy resulting in undetectable viral loads and a CD4 count above 400 cells/mm3. His wife takes pre-exposure prophylaxis (PrEP) daily. They chose to have timed unprotected sexual intercourse using ovulation kits but had no success after 6 months attempting pregnancy. At the time of his infertility evaluation, he was noted to have low testosterone levels and oligoastheno-teratospermia. He was prescribed clomiphene citrate, 25  mg daily for 25 days, followed by a break of 5 days, for 6 months. He was advised to repeat the semen analysis in six months, with some improvement in all parameters noted on repeat testing. However, the specimen overall remained below normal counts and morphology. A decision was made to proceed with intra-cytoplasmic sperm injection (ICSI), which was performed several weeks later following density gradient sperm washing with swim up on the semen sample. The patient conceived following the transfer of one blastocyst. Both mother and child were HIVseronegative at delivery.

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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The HIV-positive male

Background It is estimated that globally nearly 40 million people are infected and living with HIV with 1.7  million new infections reported annually  [1]. The majority of cases occur in men who are young, and many will later desire to have children. The advent of effective antiretroviral therapies allows infected individuals the opportunity to live relatively normal lives and has dramatically improved life expectancy. However, the known risk of sexual transmission of HIV endangers their partners and offspring unless measures to safeguard against infection, such as condom only sex, are practiced. Past reports of estimated male‐to‐female transmission risk ranged from 1  in 100 to 1  in 200 acts of intercourse [2], but the risk can be decreased substantially if the unaffected partner is prescribed pre‐exposure prophylaxis (PrEP) therapy [3–5]. Since 1992 a relatively simple method for processing the semen of HIV‐seropositive men has been used to separate the seminal plasma and nonmotile cellular components (e.g. lymphocytes and other CD4 receptor positive cell lines) from the motile spermatozoa [6]. HIV is a retrovirus that primarily infects T lymphocytes and other immune cells and is also present as free virus in semen and other body fluids. Spermatozoa do not express CD4, CCR5 and CXCR4 receptors and therefore are unlikely to be a significant vector of HIV infection [7]. “Sperm washing” of HIV‐seropositive men is best performed by laboratories specially equipped to handle virally infected patients. Samples are prepared in class II biologic hoods located in a separate area outside of the embryology laboratory. Fresh samples used for IUI or ICSI are first processed by centrifugation in a discontinuous density gradient. Then, two different methods have been utilized to separate the sperm from the seminal plasma. In the originally described method, the sperm pellet is resuspended and centrifuged again before

preparation with a final swim up stip. Thus, the specimen is “double washed with swim up” prior to use  [8]. A different method has also been proposed using a polypropylene tube insert during the centrifugation step, thus eliminating the need for the “double washed swim up” step. The latter method led to a 98.1% and 100% effectiveness in eliminating HIV‐ DNA and HIV RNA from semen samples, respectively [9,10].

Management options Based upon surveys of HIV‐seropositive individuals attending medical clinics, approximately 15–30% of HIV‐infected patients demonstrate an interest in reproductive care  [11,12]. A multidisciplinary team approach to the management of HIV‐seropositive patients is advocated. Consultation with the infectious disease specialist treating the infected patient is vitally important to understand the general health status of the prospective patient. Individuals should be medically stable and compliant with medications prescribed by their primary care provider. A review of prescribed drugs should be undertaken in order to recognize any medications that may interfere with or impact upon the success of fertility treatments. This includes the use of androgens which are known to ­dramatically lower sperm counts and impair fertilization. Social workers, psychologists and psychiatrists may also be called upon to address issues related to anxiety, depression and substance abuse, conditions known to be more prevalent in HIV‐seropositive populations. Prescribing PrEP for the unaffected partners of sexually active HIV‐seropositive males has been associated with negligible transmission rates when males have undetectable viral loads  [13,14]. This has led to renewed debate about whether unprotected timed sexual intercourse is a reasonable option for HIV‐serodiscordant patients to

Prevention 

consider. In the United Kingdom, the National Institute for Health and Care Excellence (NICE) has supported unprotected well‐timed intercourse for couples in which the HIV‐positive male has undetectable viral loads. With respect to timed intercourse, patients are encouraged to use ovulation kits or basal body temperature in order to decrease the need for repetitive sexual exposure. However, it has been reported that patients who choose this option are more likely to use condoms inconsistently and therefore may actually increase their risk of transmission over time [13]. In one study, the seroconversion rate was 4.3% in patients trying to establish pregnancies through timed intercourse. Therefore, the American Society for Reproductive Medicine (ASRM) does not endorse this plan for conception [15]. Whether IUI or IVF best addresses the needs of patients with HIV seeking fertility care remains contentiously debated. There are advantages and disadvantages inherent to both methods, and neither has proven to be safer than the other. More attempts have been published using the less invasive IUI approach which is technically simpler and less expensive than IVF [16,17]. However, efficacy per treatment cycle is lower with IUI and therefore multiple attempts, entailing multiple exposures, are often required. Testing specimens used for insemination for HIV is commonly recommended as a necessary precaution against infection but also represents a significant additional expense and is not an evidence‐ based requirement. IUI preparations contain millions of recovered cells, including leukocytes if not properly prepared. It has been reported that up to 5% of sperm samples are contaminated with HIV [12]. As a precaution, specimens are often frozen and tested prior to their use, ensuring only HIV‐negative fluids are inseminated. However, freezing may decrease fertilization potential in men who exhibit borderline or abnormal semen profiles  [18]. Under optimal circumstance, pregnancies following IUI typically occur in 5–15%

of treatment cycles, and couples should ­anticipate the need for multiple attempts at IUI over an extended period of time. ICSI has been widely practiced for the treatment of male factor infertility for nearly 30 years. ICSI requires the selection of only a single sperm per retrieved egg although the gametes chosen for injection cannot be HIV tested. Only the highly motile fraction of prepared sperm is chosen for ICSI and typically fewer than 30 sperm are needed per patient. It is believed that mature motile spermatozoa from the fraction of prepped semen do not harbor HIV, and therefore specimens do not need to be virally tested before use, reducing the complexity and cost of implementation. However, ICSI is inherently invasive and expensive and has been associated with a higher risk of multiple births than IUI unless single embryo transfer is practiced. Pregnancies from ICSI typically occur in 35–60% of treatment cycles depending upon the age of the patient, the circumstances of the treatment cycle and the number of embryos transferred. ICSI also commonly produces supernumerary embryos that may be cryopreserved for future use, a feature that cannot be accomplished through any other methodology.

Prevention Clinical outcomes of patients undergoing sperm washing techniques to prevent HIV infection have been good both in terms of disease prevention and pregnancy results. Throughout treatment couples should be encouraged to continue practicing safe sex with condoms. A seroconversion occurred in one woman preparing to undergo ICSI that was secondary to noncompliance with safe sex practices [19]. Since the Centers for Disease Control (CDC) reported in 1990 an alleged HIV infection of a patient following the insemination of processed semen  [20], practitioners in the USA and elsewhere

21

22

The HIV-positive male

have been reluctant to provide assisted ­reproduc­tive care to HIV‐seropositive patients  [21]. However, the increasingly favorable results of clinical studies from both IUI and IVF ­methods used to prevent infection in HIV‐serodiscordant couples has led to greater acceptance of their clinical utility and safety. The cumulative tally of over 4,000 published cases without a single infection is compelling evidence. Reversal of prohibitions that limited the availability of such services in states such as California are a testament to the willingness of physicians and patient advocacy groups to work together to adopt new guidelines for patient evaluation and treatment [22]. The American College of Obstetricians and Gynecologists (ACOG) and the ASRM have published recommendations for the treatment of virally infected patients embracing a broad policy of nondiscrimination  [15,23]. Included are the use of sperm washing techniques for both IUI and IVF. The underlying purpose common to all clinical programs, whether offering IUI or IVF, relates to access to care. Congruent with the basic principles of bioethics, HIV‐seropositive patients should have the opportunity to have a biologic child without causing harm to uninfected partners and their children. As preventive health care measures, IUI and IVF both appear very promising in accomplishing this goal. Although it remains uncertain as to whether one method is superior to the other in this regard, both do appear to be safe and efficacious choices. Albeit small, all patients undergoing fertility treatments are at theoretical risk of disease transmission. Therefore, it is important to engage them in a frank discussion related to the biology of HIV and inform them that other options, including artificial insemination with donor sperm and adoption also present safe traditional choices. Not all patients will choose sperm washing techniques once they are aware of the infectious risk inherent to all procedures. However, respecting a patient’s right to

exercise autonomy and choose to be treated or not is justified since the risk of infection is quite low and the benefit of childbearing so great [24].

Key points Challenge: Caring for the fertility needs of HIVseropositive males Background: ●● 40 million people are living with HIV. ●● Most HIV-infected individuals are males of reproductive age. ●● At least one-third of infected individuals wish to have a family. ●● Patients require a multidisciplinary ­approach. ●● Safe sex practice with condoms is ­recommended to prevent infection in the partner, and partners should talk to their doctors about pre-exposure prophylaxis (PrEP). ●● Co-infection with hepatitis is a common comorbidity. Management options: ●● IUI in men with normal semen analysis and partners without fertility problems. ●● ICSI which has highest efficacy per ­treatment cycle. ●● Well-timed intercourse or self-­insemination if viral load undetectable, males are ­compliant with HAART and women are prescribed PrEP. ●● Partners should be tested following ­treatment and throughout pregnancy. ●● Baby should be tested for HIV at delivery and 3 months postpartum. ●● No prophylaxis is required in women ­receiving processed specimens. Prevention: ●● Sperm washing techniques separate sperm from infected seminal plasma. ●● Sperm lack viral receptors and co-receptors and are unlikely to be viral vectors. ●● HIV has not been detected in aliquots obtained from properly prepared sperm specimens.

Answers to questions patients ask  23

Answers to questions patients ask Q1 Do sperm cells carry HIV? A1.  HIV infection can be transmitted through semen since the virus is found in HIV‐infected white blood cells and may also be free‐floating in the seminal fluid. Sperm cells lack the receptors to bind the virus and allow infection to occur. Isolating the sperm cells from the seminal fluid through “sperm washing” essentially eliminates the risk of transmitting the infection which is the basis for all the various reproductive therapies offered. Q2 Does HIV infection affect male fertility? A2.  Men who are HIV‐seropositive have been shown to have higher risk for abnormalities in their semen analysis including lower sperm counts, reduced sperm motility, reduced fertilization potential and lower ejaculatory volumes, all of which may impair natural fertility. Many men with HIV also demonstrate lower serum testosterone levels which may impact both the semen analysis and their libido. Drug treatment for HIV may also adversely affect spermatogenesis and further lower natural fertility. Q3 Is it safe for my HIV‐seronegative female partner to have a baby with me if I am HIV‐seropositive? A3.  The risk of transmission is believed to be negligible when men are fully compliant with HAART, demonstrate undetectable viral loads (VL) in their blood tests, have no other associated sexually transmitted diseases and limit unprotected intercourse to the

time of ovulation. Sperm washing techniques are necessary when the VL is detectable or in cases where males are noncompliant with medications. Sperm washing prior to IUI or IVF is routinely offered to serodiscordant couples as a further safeguard. Q4 Can you guarantee my partner will not become infected while trying to become pregnant using washed sperm techniques? A4.  Although well‐performed sperm washing techniques appear to greatly reduce the risk of infection, there are no 100% risk free methods for assisting HIV‐seronegative women to conceive with HIV‐seropositive males. Partners should obtain maximal viral suppression before attempting pregnancy regardless of the method chosen for treatment to minimize risk to the uninfected partner. Use of donor sperm from an uninfected male is commonly recommended in order to eliminate the risk of HIV transmission entirely but precludes the male partner from genetic parentage. Q5 Do I need to have my semen frozen and tested for HIV in order undergo fertility treatment? A5.  Viral testing of semen has been commonly performed in men interested in fertility treatment and has often been used in the past to triage fertility care. However, individual sperm cells cannot be assessed and are unlikely to harbor the virus. Most HIV‐positive results in semen are associated with detectable VL in the blood

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The HIV-positive male

and are likely a result of free virus and leukocytes associated with virus found in their semen. Performing viral testing of an aliquot of semen prior to it being frozen and later processed for clinical use adds expense and is of questionable necessity. However, patients wishing to have viral test-

ing of their semen may be accommodated by labs licensed to provide this service. Men compliant with HAART demonstrating undetectable VL in their blood have negligible risk of transmitting infection and therefore do not need to undergo testing of their semen.

References 1 Joint United Nations Programme on HIV/ AIDS. Global HIV & AIDS Statistics ‐ 2019 Fact Sheet. 2019. https://www.unaids.org/en/ resources/fact‐sheet. 2 Boily MC, Baggaley RF, Wang L, Masse B, White RG, Haynes RJ, et al. Heterosexual risk of HIV‐1 infection per sexual act: systematic review and meta‐analysis of observational studies. Lancet Infect Dis. 2009; 9:118–29. 3 Center for Disease Control and Prevention. Pre‐Exposure Prophylaxis (PrEP). https:// www.cdc.gov/hiv/risk/prep/index.html. Published August 2019. 4 U.S. Department of Health and Human Services: AIDS info. FEM‐PrEP (Truvada): Study to assess the role of Truvada in preventing HIV acquisition in women. https:// aidsinfo.nih.gov/clinical‐trials/details/ NCT00625404. Published June 2018. 5 Nicol MR, Adams, JL, Kashuba, AD. HIV PrEP Trials: The road to success. Clinical Investigation. 2013; 3(3):10.4155/cli.12.155. doi:10.4155/cli.12.155 6 Semprini AE, Levi‐Setti P, Bozzo M, Ravizza M, Taglioretti A, Sulpizio P, et al. Insemination of HIV‐negative women with processed semen of HIV positive partners. Lancet. 1992; 340:1317–19. 7 Quayle AJ, Xu C, Tucker L, Anderson DJ. The case against an association between HIV‐1 and sperm: molecular evidence. J Reprod Immunol. 1998; 41:127–36. 8 Sauer MV. Sperm washing techniques address the fertility needs of HIV‐seropositive men: a

clinical review. Reprod Biomed Online. 2005; 10:135–40. 9 Murphy DA. Processing, selecting, and ritualizing: ambivalent relationships to semen. Reproductive Biomedicine Online. 2015; 30(5):443–446. 10 Fourie, JM, Loskutoff N, Huyser C. Semen decontamination for the elimination of seminal HIV‐1. Reprod Biomed Online. 2015 Mar; 30(3):296–302 11 Chen JL, Philips KA, Kanouse DE, Collins RL, Mui A. Fertility desires and intentions of HIV‐positive men and women. Fam Plann Perspect. 2001; 33:144–52. 12 Gilling‐Smith C, Nicopoullos JDM, Semprini AE, Frodsham LCG. HIV and reproductive care: review of current practice 2006. Br J Obstet Gynecol. 2006; 113: 869–78. 13 Pralat, R. Repro‐sexual intersections: sperm donation, HIV prevention and the public interest in semen. Reprod Biomed Online. 2015; 30(3): 211–219. 14 National Institute for Health and Clinical Excellence (NICE), National Collaborating Centre for Women’s and Children’s Health. Fertility: assessment and treatment for people with fertility problems. Royal College of Obstetricians and Gynaecologists, 2nd Edition, London, UK. February 2013; p. 16. 15 Ethics Committee of the American Society for Reproductive Medicine. Human immunodeficiency virus (HIV) and infertility treatment: a committee opinion.

References 

Fertil Steril. 2015. doi: 10.1016/j. fertnstert.2015.04.004. 16 van Leeuwen E, Repping S, Prins JM, Reiss P, van der Veen F. Assisted reproductive technologies to establish pregnancies in couples with an HIV‐1‐infected man. Neth J Med. 2009; 67:322–327. 17 Vitorino RL, Grinsztejn BG, de Andrade CA, et al. Systematic review of the effectiveness and safety of assisted reproduction techniques in couples serodiscordant for human immunodeficiency virus where the man is positive. Fertil Steril. 2011; 95:1684. 18 Pena JE, Thornton MH, Sauer MV. Reversible azoospermia: anabolic steroids may profoundly affect HIV seropositive men undergoing assisted reproduction. Obstet Gynecol. 2003; 101:1073–5. 19 Sauer MV, Choi J. HIV seroconversion in a woman preparing for assisted reproduction: an inherent risk in caring for HIV infected couples. Reprod Biomed Online. 2006; 12: 375–7.

20 Centers for Disease Control. Epidemiologic notes and reports: HIV‐1 infection and artificial insemination with processed semen. MMWR. 1990; 249:255–6. 21 Sauer MV. American physicians remain slow to embrace the reproductive needs of human immunodeficiency virus‐infected patients. Fertil Steril. 2006; 85:295–7. 22 Barnhart N, Shannon M, Weber S, Cohan D. Assisted reproduction for couples affected by human immunodeficiency virus in California. Fertil Steril. 2009; 91:1540–43. 23 Practice Committee of the American Society for Reproductive Medicine. Guidelines for reducing the risk of viral transmission during fertility treatment. Fertil Steril. 2008; 90 (Suppl 3): S156–62. 24 Sauer MV. Providing assisted reproductive care to HIV‐serodiscordant couples: time to re‐examine healthcare policy. Am J Bioethics. 2003; 3:33–40.

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5 The hepatitis B or C carrier patient Justin Chu Birmingham Women’s Hospital, Birmingham, UK

Case History 1: A couple with unexplained infertility are referred for IVF. During their workup the 31-year-old female is found to be positive for both hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc). Case History 2: A couple with male factor infertility of 3 years duration are referred for ICSI. The female partner is found to be positive for hepatitis C infection.

Background Hepatitis B Hepatitis B virus (HBV), a DNA virus, is the most common chronic viral infection in the world, having infected approximately 2 billion people [1]. It is estimated that there are more than 350 million people who are chronic carriers of HBV and that the virus causes approximately 786,000 deaths per year. HBV‐related death is caused by chronic hepatic inflammation leading to chronic liver failure, cirrhosis and hepatocellular cancer. HBV vaccination programs are safe and effective. However, global prevalence of HBV is highly variable due to differences in the uptake of universal HBV vaccination programs [2]. HBV is transmitted through contact with infected blood or semen. Where HBV prevalence is high, the most common route of transmission is vertical, from infected mother to neonates. Where HBV prevalence is low, the commonest mode of transmission is through

sexual contact. HBV can also be transmitted by blood transfusion, renal dialysis or unsafe use of needles for drug injection [3]. The risk of developing chronic infection is age dependent. In neonatal transmission, the risk of chronic liver disease is 95%. If transmitted in childhood, the chance of chronic liver disease is 80%. If infected in adulthood, the chance of chronic liver disease is 5% [4]. The diagnosis of HBV infection is made by serological testing. HBV surface antigen (HBsAg) is diagnostic of acute and chronic infection. Positive HBsAg indicates that the patient is infective. Two weeks after acute infection, hepatitis B core antibody (anti‐HBc) IgG becomes positive by serological testing, and the infected patient will have raised liver transaminase activity and also become symptomatic (flu‐ like symptoms, loss of appetite, diarrhea, vomiting and jaundice). During recovery from acute infection or after successful vaccination, hepatitis B surface antibodies (anti‐HBs) appear. Clinical interpretation of the serological mark-

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

Background 

ers of HBV infection should be made with all available serological test results (table 5.1) [1].

Hepatitis C Hepatitis C virus (HCV) is an RNA virus thought to affect approximately 143  million people worldwide. Although the incidence is not well understood, as most infected people are asymptomatic, it is estimated that 1.75 million people are infected each year. Prevalence is highest in Central and East Asia, North Africa and the Middle East. Of those infected, 70–85% develop chronic liver disease, of which 20% develop cirrhosis and 5–7% die of HCV sequelae [5]. HCV is transmitted primarily by blood to blood contact, from blood transfusions and unsafe drug injections. Less frequently, HCV can be transmitted perinatally or through sexual transmission. Acute HCV symptoms develop in 20–30% of those infected, 4–12  weeks after

transmission. Symptoms include flu like illness, nausea, vomiting and jaundice. Diagnosis of HCV infection is made by serological testing for anti‐HCV antibody, which becomes positive 6–8 weeks after transmission or by HCV RNA PCR testing [6]. There is no vaccine against HCV; prevention is focused around harm reduction by encouraging safe needle use and screening blood products. Antiviral medications have been developed to cure chronic liver disease resulting from HCV. However, left untreated, chronic HCV infection can also lead to cirrhosis and liver cancer [5]. The European Society of Human Reproduction and Embryology (ESHRE) recommends that HBV and HCV screening should be undertaken in both partners before performing assisted reproductive techniques (ART). This is to reduce the risk of transmission to the partner and neonate whilst also ensuring that the gametes and embryos can be handled with precaution.

Table 5.1  Clinical interpretation of serological markers of hepatitis B virus infection [1]. HBV serological test

Results

Clinical interpretation

HBsAg Anti‐HBc Anti‐HBs

Negative Negative Negative

Susceptible

HBsAg Anti‐HBc Anti‐HBs

Negative Positive Positive

Immune due to previous HBV infection

HBsAg Anti‐HBc Anti‐HBs

Negative Negative Positive

Immune due to HBV vaccination

HBsAg Anti‐HBc Anti‐HBs IgM anti‐HBc

Positive Positive Negative Positive

Acutely infected

HBsAg Anti‐HBc Anti‐HBs IgM anti‐HBc

Positive Positive Negative Negative

Chronically infected/ carrier

HBsAg Anti‐HBc Anti‐HBs

Negative Positive Negative

Unclear interpretation. Possibly: 1)  Resolved HBV infection (most common) 2)  Low‐level chronic infection 3)  Resolving acute infection

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28

The hepatitis B or C carrier patient

Management of patients Hepatitis B Infertility patients known to have chronic carrier status of HBV should be managed in a fertility unit with appropriate expertise. In cases where partners have discordant HBV serological status, it is recommended that the unaffected partner receives HBV vaccination. In women who are HBV chronic carriers, there has been conflicting evidence regarding the effect of HBV on pregnancy. Overall, pregnancy does not seem to affect the disease course of chronic HBV infection. If pregnancy is achieved naturally, the risk of neonatal infection from a chronically infected mother is 2–15% [7]. If the mother is acutely infected with positive HBsAg and anti‐HBc then the risk of vertical transmission rises to 80–90%. In either case, the neonate should be vaccinated at birth. Hepatitis B vaccination and a dose of HBV immunoglobulin administered to the neonate within the first 24 hours of life reduces the risk of HBV infection and carrier status by up to 90% [8]. In ART, previously published studies assessing the fertility treatment outcomes in couples with at least one partner who is HBV seropositive have yielded conflicting results [9]. Some observational studies have shown lower pregnancy rates in couples undergoing ART with HBV whilst others have not shown this [10,11]. It has been suggested that the lower pregnancy rates amongst couples with HBV undergoing ART may be due to extra precautions in handling gametes and embryos  [9]. Overall, it appears that in couples where one or both of the partners have HBV, the pregnancy outcomes are similar to unaffected couples. Male partners with HBV have been shown to have poorer sperm results and lower oocyte fertilization rates; however, this does not seem to impact on ART outcomes [12]. In male HBV carriers, the female partner should have HBV vaccination to reduce the risk of sexual transmission. Sperm washing during ART is a common practice in this situation but is now not

thought to be of clear benefit. Previously, it was considered unsafe to perform intra‐cytoplasmic sperm injection (ICSI) treatment for male HBV carriers due to the risk of HBV integration into the fetal genome. However, newer evidence has proven that this is not a risk. In ART treatments involving HBV‐positive female partners, there has been evidence to show that HBV can affect the follicular fluid, oocytes and ovaries. However, women with HBV infected follicular fluid or oocytes do not appear to have worse ART outcomes [13]. Overall, ART is considered safe in both male and female carriers, and the risk of vertical transmission is similar to pregnancies conceived naturally. Therefore, the couple in Case History 1 should be reassured. They can commence their IVF treatment after appropriate pre‐pregnancy counseling and involvement of a hepatologist to ensure that the female partner does not have any signs of chronic liver disease.

Hepatitis C Previous HCV infection is not known to directly affect fertility [14]. Therefore, natural pregnancy may occur in HCV positive couples. When pregnancy is naturally conceived, HCV increases the risk of preterm birth, which is thought to be due to the effects of HCV on trophoblasts [15]. The risk of vertical transmission in pregnancy is estimated to be approximately 95%) of men with only one cystic fibrosis mutation (true carriers) don’t exhibit CBAVD and are generally fertile as in the case of the male partner of the couple described in Case History 2.

Screening of the female partner of men with CBAVD is crucial to fully understand the future reproductive risks for the couples such as in Case History 1. After accurate genetic diagnosis is made, appropriate genetic counseling is an integral part of the two couples’ management to explain the genetic test results and emphasize the reproductive risks and wider family implications.

Management options

Case history 1

Management of the two couples in Case Histories 1 and 2 require the collaborative expertise of fertility specialists and a genetics center with advanced molecular diagnostic facilities.

Diagnosis and counseling Clinical diagnosis of CBAVD is easily made via palpation. Secondary sexual characteristics are normally developed. Testicular size is usually normal, and the epididymis may be engorged and distended on palpation depending on whether it is involved in the process of atresia or not. Typically, the vas deferens on either side is absent, although occasionally testicular ultrasound is required for confirmation of diagnosis. Renal ultrasound is indicated to rule out associated renal tract anomalies. In addition to azoospermia, the semen analysis exhibits normal or reduced volume, increased acidity and low concentration of fructose. Serum hormone levels show normal FSH, LH, testosterone and prolactin levels. Molecular genetic confirmation is obtained via extended mutation analysis typically involving over 100 different cystic fibrosis mutations to identify not only the 32  most common mutations, but also to detect the less common mutations responsible for the CBAVD condition. This detailed mutation testing is particularly indicated if only one mutation was detected in either partner on routine cystic fibrosis screening in the presence of a history of recurrent respiratory or digestive disease, as could be in Case History 2, for example.

If the female partner was found to be a carrier of a cystic fibrosis mutation after extended mutation screening, this couple will have a 50% risk of conceiving a child affected with cystic fibrosis, although the range of phenotypic expression could be wide and vary from very mild to severe clinical manifestations. In addition, 50% of this couple’s children will be carriers of a cystic fibrosis mutation. If the female partner is tested negative for cystic fibrosis mutation, the risk of conceiving a child affected with cystic fibrosis drops to approximately 1 in 1,000. Case history 2

If extended cystic fibrosis testing in this couple fails to reveal a second mutation in either partner, their risk of conceiving a second child affected with cystic fibrosis is 25%, and 50% of their children will be carriers of the delta‐ F508  mutation. Statistically, a quarter of this couple’s children are likely to be healthy noncarriers.

Treatment options The treatment options available for the couple in Case History 1 differ considerably from those available for the couple in Case History 2.

Case history 1 Historically, men with CBAVD were considered sterile and their female partners were offered treatment with cystic fibrosis–negative sperm donation. Since the introduction of ­surgical

34

The patient with cystic fibrosis

sperm retrieval and intra-cytoplasmic sperm injection (ICSI), assisted ­conception treatment has become a realistic treatment option to enable these men to conceive their own genetic child. Percutaneous epididymal sperm aspiration (PESA) under local anesthesia with or without sedation is usually performed on the same day as oocyte retrieval. Typically, a large number of motile sperm is retrieved, which is used for ICSI and could possibly allow for sperm cryopreservation for future use. If the female partner was found to be a carrier of a cystic fibrosis mutation, in conjunction with ICSI and where expertise and facilities allow, the couple would ideally be offered preimplantation genetic testing (PGT) to ensure only embryos unaffected by cystic fibrosis are transferred in utero. PGT has the ability to reduce the couple’s reproductive risk of conceiving an affected child from 50% to =3 Smoker Ovarian hyperstimulation syndrome Dehydration Immobility Prolonged bed rest Prolonged travel Medical conditions (such as infections, malignancies, cardiac conditions, active systemic lupus erythematosus, inflammatory bowel disease, sickle cell disease, type 1 diabetes with nephropathy, nephrotic syndrome etc.) (Continued)

49

50

The patient with thrombophilia

Table 8.1  Continued

Inherited thrombophilia

Odds ratio for VTE (95% confidence interval)

Factor V Leiden heterozygous

9.2 (5.44–12.70)

Factor V Leiden homozygous

34.40 (9.86–120.05)

Antithrombin deficiency

4.69 (1.30–16.96)

Protein C deficiency

4.76 (2.15–10.57)

Prothrombin G20210A heterozygous

6.80 (2.46–19.77)

Prothrombin G20210A homozygous

26.36 (1.24–559.29)

Family history of VTE in one or more first degree relatives

2.7 (1.8–3.8)

Acquired thrombophilia

Lupus anticoagulant Anticardiolipin antibodies

Acquired thrombophilia

Antiphospholipid syndrome is the most common acquired thrombophilia associated with an increased risk of recurrent miscarriage and pregnancy morbidity. Antiphospholipid syndrome is present if at least one of the clinical criteria and one of the laboratory criteria shown in Box 8.1 are present [9].

thrombophilia in women with severe OHSS undergoing ovulation induction. Therefore, the clinical and cost effectiveness for screening in this context could not be demonstrated [12]. Screening for thrombophilias should include the following: ●● ●●

Management options

●●

There is currently little evidence to support universal screening for thrombophilia in pregnancy or prior to IVF for the prevention of VTE  [10]. However, screening for thrombophilia should be considered in women with a history of recurrent miscarriage, or personal or family history of VTE. The association between thrombophilia and OHSS is conflicting. According to one study thrombophilia is thought to be associated with a high risk of developing OHSS [11], and this has been proposed as an additional reason for screening for thrombophilia in women with a family or personal history of thrombosis prior to undergoing ovarian stimulation and in women who have developed OHSS. However, another study failed to show an increased prevalence of

●●

●●

plasma antithrombin proteins S and C antiphospholipid antibodies factor V Leiden mutation MTHFR C677T

The management of the woman with a single previous VTE has been controversial, but data from studies of pregnancy may guide therapy in the context of IVF. In a woman with a previous VTE that was not related to pregnancy or oral contraceptive use, and in whom no thrombophilia or other additional risk factor is present, thromboprophylaxis probably need not be prescribed [13]. However, in women with a previous VTE and underlying thrombophilia, or where the VTE was related to pregnancy or the oral contraceptive pill, or where additional risk factors are present, pharmacologic prophylaxis should be considered. This is illustrated in the Case History.

Management options 

Box 8.1  Clinical and laboratory criteria for the diagnosis of antiphospholipid syndrome.

Clinical criteria ●●

●●

Vascular thrombosis: one or more clinical episodes of arterial, venous or small vessel thrombosis, in any tissue or organ. Thrombosis must be confirmed by objective validated criteria (i.e. unequivocal findings of appropriate imaging studies or histopathology). For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall. Pregnancy morbidity: ●● one or more unexplained deaths of a morphologically normal fetus at or beyond 10  weeks’ gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus; or ●● one or more premature births of a morphologically normal neonate before 34  weeks’ gestation because of: (i) eclampsia or severe preeclampsia defined according to standard definitions; or (ii) recognized features of placental insufficiency; or ●● three or more unexplained consecutive spontaneous abortions before 10 weeks’

Prophylactic therapy is probably not necessary during controlled ovarian stimulation, when the risk of thrombosis is minimal  [14]. Given the rarity of occurrence of VTE prior to hCG, and the potential for increased risk of significant intra‐abdominal bleeding, which may occur following oocyte retrieval, medical thromboprophylaxis should be delayed until after oocyte retrieval. A suggested approach is provided in Figure 8.1. If thromboprophylaxis is commenced with ovarian stimulation, a good approach would be to withhold LMWH for 24 hours prior to oocyte retrieval and recommence it 12 hours after the procedure [15]. All patients diagnosed with moderate to severe OHSS, even those being managed on an

gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded.

Laboratory criteria ●●

●●

●●

Lupus anticoagulant present in plasma, on two or more occasions at least 12  weeks apart, detected according to the guidelines of the International Society on Thrombosis and Haemostasis (scientific subcommittee on lupus anticoagulants/phospholipiddependent antibodies). Anticardiolipin antibody of immunoglobulin G (IgG) and/or IgM isotype in serum or plasma, present in medium or high titer (i.e. >40 GPL units or MPL units, or >99th centile), on two or more occasions, at least 12  weeks apart, measured by a standardized enzyme-linked immunosorbent assay (ELISA). Anti-β2 glycoprotein-I antibody of IgG and/or IgM isotype in serum or plasma (in titer >99th centile), present on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA, according to recommended procedures.

outpatient basis, should receive thromboprophylaxis. The duration of treatment should be individualized, taking into account risk factors and whether or not conception occurs [8].

Post IVF follow-up Clinical reports of DVT occurring following IVF treatment indicate that it most frequently presents in early pregnancy [16] between 5 and 10 weeks after hCG administration [17]. This has implications for both the duration for which prophylaxis should be administered in high risk patients, and for the duration for which clinical surveillance should be maintained in order ensure early detection and

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52

The patient with thrombophilia

Multidisciplinary approach

Check platelet count 1 week before LMWH commencement

If LMWH was commenced prior to oocyte retrieval:

If LMWH is to be commenced after oocyte retrieval:

Withhold LMWH for 24 hours prior to procedure and recommence 12 hours after

Start LMWH 24 hours after oocyte retrieval+ compression stockings

Check platelet count (1 week later)

Continue treatment for 3 weeks, or longer if OHSS or pregnant Figure 8.1  A suggested approach to thromboprophylaxis in a patient undergoing IVF.

treatment. It is apparent from literature that thrombophilic tendencies associated with OHSS persist and VTE can present weeks after resolution of the clinical syndrome. Therefore, a prolonged duration of prophylaxis and extended vigilance might be necessary [18]. A 2009 review suggests “thromboprophylaxis should be considered for patients who develop moderate‐to‐severe OHSS for an extended period of 1–2 months beyond the resolution of clinical OHSS”  [19]. This approach was not only deemed safe but also shown to be cost effective [20]. In patients who conceive, it may be necessary to continue thromboprophylaxis throughout the antenatal period. Additionally, focus should also be placed on the judicious use of methods for preventing ovarian hyperstimulation as it is a major risk factor in developing IVF related VTE, ­especially in high risk patients. Techniques that can be employed include use of an antagonist cycle  [21], milder stimulation protocols and

use of gonadotropin releasing hormone (GnRH) agonist trigger instead of hCG. Additionally, cryopreservation of all embryos and natural cycle (if possible) frozen embryo transfer avoids the use of exogenous hCG completely [22]. Many reported cases of DVT following IVF are in sites other than the lower limb, but this may simply reflect publication bias  [23]. The jugular vein appears to be a relatively frequent site, with the majority of thromboses occurring here being associated with hormonal ovarian stimulation [16]. It should be emphasized that clinical diagnosis for DVT is highly unreliable [24]. Early recourse to objective diagnosis of DVT is advised, particularly in the at‐risk patient. Compression and duplex Doppler ultrasound techniques have been demonstrated to be reliable noninvasive means of diagnosing or excluding DVT, including those affecting upper extremities and neck veins, and are readily available [25].

Answers to questions patients ask  53

Key points

●●

Challenge: The patient with thrombosis risk or thrombophilia. Background: DVT occurring after IVF is a rare but ­potentially life-threatening complication of IVF. ●● Considerable changes in the coagulation and fibrinolytic systems are observed following hCG administration. ●● OHSS is a major risk factor in developing VTE in all patients undergoing ART.

●●

Management: ●● All patients beginning IVF should be subject to an individual risk assessment prior to commencing treatment. ●● Screening for thrombophilias should be ­considered in women who have had a ­previous thrombotic event or a family ­history of thrombosis, and maybe in women who have developed OHSS.

●●

●●

Thromboprophylaxis should be considered in women with a previous DVT, women who develop moderate to severe OHSS and in women with a thrombophilia. In addition, women who develop serious infections or immobilization should receive thromboprophylaxis. Compression stockings and low-molecular weight heparin constitute first line ­thromboprophylaxis. Thromboprophylaxis should normally ­commence 24 hours after oocyte retrieval to reduce the risk of hemorrhagic complications. This should be extended throughout the first trimester. In cases where thrombophilia has been detected, consideration should be given to extending prophylaxis throughout pregnancy.

Prevention: Judicious employment of methods to prevent OHSS, especially in high-risk patients.

Answers to questions patients ask Q1 If I am at “high risk” of venous thromboembolism (VTE) during IVF, what is the treatment that will be recommended to me? A1.  Low‐molecular weight heparin administered subcutaneously is the treatment of choice for VTE prophylaxis. The dose is calculated according to body weight and is taken daily. An example of a dos-

Table 8.2  Enoxaparin dosing regimen for VTE prophylaxis [8]. Weight

Enoxaparin

170kg

0.6 mg/ kg/ day*

* can be given in 2 divided doses

ing regimen using a commonly used LMWH is shown in Table 8.2. Q2 When will I be expected to commence this treatment? A2.  This will depend on the local protocol of your fertility unit. Treatment can commence soon after egg collection or even earlier during the stimulation process. If it is commenced prior to egg collection, it should be withheld for 24 hours before the procedure. Q3 If I develop deep vein thrombosis during my IVF cycle, how will it be treated? A3.  It will be treated with low‐molecular weight heparin administered subcutaneously, but at a higher dose than for prophylaxis. Again, it will be calculated according to body weight.

54

The patient with thrombophilia

Q4 What are the risks of this treatment? A4.  Administration of low‐molecular weight heparin is largely safe. It carries a small risk of heparin induced thrombocytopenia (low

platelets) or heparin induced osteoporosis (bone thinning). Patients can also develop allergic skin reactions, but again this risk is very small [8].

References 1 Grandone E, Colaizzo D, Vergura P, Cappucci F, Vecchione G, Lo BA, et al. Age and homocysteine plasma levels are risk factors for thrombotic complications after ovarian stimulation. Hum Reprod. 2004;19(8):1796–9. 2 Stewart JA, Hamilton PJ, Murdoch AP. (1997) Thromboembolic disease associated with ovarian stimulation and assisted conception techniques. Hum Reprod. 1997;12(10):2167–73. 3 Sennstrom M, Rova K, Hellgren M, Hjertberg R, Nord E, Thurn L, et al. Thromboembolism and in vitro fertilization—a systematic review. Acta Obstet Gynecol Scand. 2017;96:1045–52. 4 Rova K, Passmark H, Lindqvist PG. Venous thromboembolism in relation to in vitro fertilization: an approach to determining the incidence and increase in risk in successful cycles. Fertil Steril. 2012;97(1):95–100. 5 Lox C, Canez M, DeLeon F, Dorsett J, Prien S. Hyperestrogenism induced by menotropins alone or in conjunction with luprolide acetate in in vitro fertilization cycles: the impact on hemostasis. Fertil Steril. 1995;63(3):566–70. 6 Lox C, Canez M, Prien S. The influence of hyperestrogenism during in vitro fertilization on the fibrinolytic mechanism. Int J Fertil Womens Med. 1998;43(1): 34–9. 7 Kodama H, Fukuda J, Karube H, Matsui T, Shimizu Y, Tanaka T. Status of the coagulation and fibrinolytic systems in ovarian hyperstimulation syndrome. Fertil Steril. 1996;66(3):417–24. 8 Royal College of Obstetricians and Gynaecologists. Reducing the risk of venous thromboembolism during pregnancy and the puerperium. Green‐top Guideline No. 37a. London;2015.

 9 Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2): 295–306. 10 Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet. 1999;353(9160):1258–65. 11 Dulitzky M, Cohen SB, Inbal A, Seidman DS, Soriano D, Lidor A, et al. Increased prevalence of thrombophilia among women with severe ovarian hyperstimulation syndrome. Fertil Steril. 2002;77(3):463–7. 12 Fábregues F, Tàssies D, Reverter JC, Carmona F, Ordinas A, Balasch J. Prevalence of thrombophilia in women with severe ovarian hyperstimulation syndrome and cost‐effectiveness of screening. Fertil Steril. 2004;81:989–95. 13 Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet. 1999;353(9160):1258–65. 14 Ludwig M, Felberbaum RE, Diedrich K. Deep vein thrombosis during administration of HMG for ovarian stimulation. Arch Gynecol Obstet. 2000;263(3): 139–41. 15 Yinon Y, Pauzner R, Dulitzky M, Elizur SE, Dor J, Shulman A. Safety of IVF under anticoagulant therapy in patients at risk for thrombo‐embolic events. Reprod Biomed Online. 2006;12: 354–8. 16 Arya R, Shehata HA, Patel RK, Sahu S, Rajasingam D, Harrington KF, et al. Internal jugular vein thrombosis after assisted conception therapy. Br J Haematol. 2001;115(1):153–5.

References 

17 Stewart JA, Hamilton PJ, Murdoch AP. Thromboembolic disease associated with ovarian stimulation and assisted conception techniques. Hum Reprod. 1997;12(10):2167–73. 18 Rao AK, Chitkara U, Milki AA. A subclavian vein thrombosis following IVF and ovarian hyperstimulation syndrome: a case report. Hum Reprod. 2005;20:3307–12. 19 Chan WS. The “ART” of thrombosis: a review of arterial and venous thrombosis in assisted reproductive technology. Curr opin Obstet Gynecol. 2009;21:207–18. 20 Wormer KC, Jangda AA, El Sayed FA, Stewart KI, Mumford SL, Segars JH. Is thromboprophylaxis cost effective in ovarian hyperstimulation syndrome: A systematic review and cost analysis. Eur J Obstet Gynecol Reprod Biol. 2018;224:117–24. 21 Al‐Inany HG, Youssef MA, Aboulghar M, Broekmans F, Sterrenburg M, Smit J, et al.

GnRH antagonists are safer than agonists: an update of a Cochrane review. Hum Reprod Update. 2011;17:435. 22 Nelson SM. Venous thrombosis during assisted reproduction: Novel risk reduction strategies. Thromb Res. 2013;131 Suppl 1:S1–3. 23 Grandone E, Di Micco PP, Villani M, Colaizzo D, Fernández‐Capitán C, Del Toro J, et al. Venous thromboembolism in women undergoing assisted reproductive technologies: data from the RIETE registry. Thromb Haemost. 2018;118(11):1962–8. 24 Macklon NS. Diagnosis of deep venous thrombosis and pulmonary embolism. Baillieres Clin Obstet Gynaecol. 1997;11(3):463–77. 25 Jesudason WV, Small M. Internal jugular vein thrombosis following ovarian hyperstimulation. J Laryngol Otol. 2003;117(3):222–3.

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56

9 The patient with autoimmune disorders Giulia Mariani1 and José Bellver 1,2 1

IVI-RMA, Valencia, Spain Department of Pediatrics, Obstetrics and Gynecology. Faculty of Medicine. University of Valencia, Spain

2

Case History: A 35-year-old woman with a 3-year history of systemic lupus erythematosus (SLE) was referred to a fertility unit to undergo ICSI treatment after 2 years of infertility due to a severe male factor. She had a normal ovarian reserve. The last lupus flare occurred 12  months before and was managed with corticosteroids. At the time of attending the fertility unit, she was not receiving any treatment. At the age of 28, with a different partner, the woman reported a preterm birth at 32 weeks for severe preeclampsia and fetal growth restriction, delivered by cesarean section. In the postpartum period, the patient developed a deep venous thrombosis that was treated with heparin. She was then tested for thrombotic markers and was diagnosed with positive anti-cardiolipin antibodies.

Background SLE is a chronic multisystem autoimmune disease with a highly variable course of flares and remissions[1]. It is characterized by the generation of autoantibodies and the deposition of immune complexes in various organs, causing inflammatory responses and tissue damage [2]. SLE is more prevalent in women, with a female to male ratio of 9:1 and mainly affects young women during their childbearing years [3]. Although the etiology of the disease is not yet fully known, the high prevalence of women suffering from SLE suggests that estrogen hormones play a role in its pathogenesis. Some women with SLE experience menstrual irregularities [4]. Anticoagulant drugs or, more rarely, thrombocytopenia, can contribute to menorrhagia. A hypothalamic‐pituitary‐­ovarian

(HPO) axis dysfunction or lupus nephritis‐ related hyperprolactinemia can lead to amenorrhea. Permanent amenorrhea can also be due to premature ovarian failure, autoimmune or drug induced. Despite these issues, reproductive function in women with mild SLE is comparable to the general healthy population  [5]. The patient in the Case History presented with a normal ovarian reserve. Treatment, which includes nonsteroidal anti‐inflammatory drugs, glucocorticoids and immunosuppressive drugs, aims to minimize or stop disease progression and organ damage. Cyclophosphamide (CTX), the agent of choice used to treat severe disease flares, may induce ovarian failure by depletion of oocytes  [6]. Gonadotoxic effects of CTX are permanent and related to cumulative dose, age of exposure and treatment duration. SLE can occur in

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

Management options 

a­ ssociation with other autoimmune diseases, such as antiphospholipid syndrome (APS). APS is a systemic acquired thrombophilic disorder, with a prevalence of 40–50 cases per 100,000 persons [7]. It is characterized by vascular thrombosis and/or obstetric complications in the presence of antiphospholipid (aPL) antibodies (lupus anticoagulant, anticardiolipin antibodies (aCL) or antibeta2 glycoprotein I antibodies) [7]. Diagnosis consists of at least one clinical and one laboratory criteria. The presence of aPL antibodies is not a cause of reduced fertility, hence routine screening is not required in the infertile population  [8]. Around 40% of SLE patients carry aPL, and aPL have been shown to be one of the strongest predictors of adverse events, vascular or obstetric. In the Case History, the patient, suffering from SLE with positive aCL antibodies, had a premature delivery 10 Gy causes >75% increase [2]. The exposure required to induce ovarian failure and infertility decreases with increasing age. Radiation as low as 1 Gy was found to be associated with increased risk of premature menopause [3]. There are two key aspects to fertility preservation: 1. Minimization of the effect of cancer treatment on fertility; and 2. Provision of effective options for storage of gametes, embryos or germinal (e.g. ovarian) tissues.

Management options Management of cancer patients requiring fertility preservation is often complex; ­navigation

through the complexities and uncertainties will require a multidisciplinary team ap­proach and thorough counseling of the patient, and often the partner too. The following issues will need to be assessed by the fertility specialist: 1. History: including age, menstrual history, pregnancies and fertility wishes. 2. Cancer: type, location, stage, prognosis and proposed treatment. 3. Time available for fertility preservation. 4. Patient’s general condition and medical history. 5. Baseline ovarian reserve (anti‐Müllerian hormone and antral follicle count). 6. Fertility preservation funding. The available fertility preservation options are given in Table 10.1.

Table 10.1  Fertility preservation options according to gender and age at cancer presentation. Group

Fertility preservation options

Comments

Prepubertal girls

Laparoscopic removal and cryopreservation of ovarian tissue for transplantation when fertility is required

Transplantation carries a theoretical risk of reintroduction of cancer cells IVM may become a viable option in the future Consenting issues in minors

Postpubertal girls

COS, and preservation of oocytes Ovarian tissue cryopreservation for transplantation when fertility is required. GnRH agonist co‐treatment during chemotherapy

COS introduces delay in cancer treatment

Women

COS, and preservation of oocytes or embryos. Ovarian tissue cryopreservation for transplantation when fertility is required. GnRH agonist co‐treatment during chemotherapy

Sperm required for the creation of embryos If the male withdraws consent in the future, the woman is unlikely to be able to use the embryos (see Chapter 108)

Prepubertal boys

No established procedures

Experimental: stem cell extraction and later repopulation of the testis

Postpubertal boys

Electro‐ejaculation or masturbatory ejaculation and sperm banking SSR and sperm banking

Consenting issues in minors

Men

Ejaculatory sperm banking SSR and sperm banking (see Chapter 91)

COS, controlled ovarian stimulation; GnRH, gonadotropin releasing hormone; IVM, in vitro maturation; SSR, surgical sperm retrieval.

Management options 

Ovarian tissue cryopreservation (OTC) Cryopreservation of ovarian cortex may be the only fertility preservation option in prepubertal girls or in women who need cancer treatment within the minimum of 2  weeks required for controlled ovarian stimulation. OTC has been used to enable multiple ovulations and pregnancies in the future as well as for restoration of endocrine function  [4]. With more than 130 babies born after ovarian tissue transplantation reported till 2017  [5], OTC has moved from being experimental to a more established method of fertility preservation in various countries  [6,7,8]. However, it should only be offered by specialized centers with relevant clinical and laboratory expertise, facilities and appropriate accreditation, such as Human Tissue Authority (HTA) licensing in the UK. Generally, no more than 50% of one of the ovaries is removed in a day‐case laparoscopic procedure (Figure 10.1), and the cortical tissue is prepared to a thickness of approximately 1mm, cut into small pieces and then cryopreserved [4]. If the woman becomes menopausal following her cancer treatment, she may have the ovarian cortical tissue transplanted as and when she decides to try to conceive a pregnancy. There is a theoretical risk of transplantation resulting in the reintroduction of cancer (a)

(b)

cells. This risk can be mitigated by the use of in vitro maturation (IVM). The first live birth achieved using IVM in a woman with cancer has been reported in 2020 [9], and this could become an important option for fertility management. Nevertheless, a recent systematic review of all peer‐reviewed published reports of women receiving ovarian tissue transplantation has found no evidence of reseeding malignant cells present in the frozen ovarian tissue in ­sufficient numbers to cause recurrence of cancer [8].

Controlled ovarian stimulation and cryopreservation of oocytes or embryos This is the most established female fertility preservation method. However, it requires approximately 2  weeks to complete the treatment to the oocyte retrieval stage. Ovarian stimulation can be started at any stage of the menstrual cycle, which is called random start protocol (Figure 10.2); however, if it is started in the late follicular phase or luteal phase, it is essential that: ●●

A follicle stimulating hormone (FSH) only preparation is used, rather than human menopausal gonadotropin (hMG), which contains human chorionic gonadotropin (hCG) driven luteinizing hormone (LH) activity that can induce luteinization); and, (c)

Figure 10.1  Laparoscopic removal of part of an ovary. Stay suture to stabilize the ovary (a). Removal of 1/3-1/2 of the cortex without the use of energy (b,c). Images courtesy of Mr. Yousri Afifi, Birmingham Women’s Hospital, Birmingham, UK.

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64

The patient with malignant disease: fertility preservation

GnRH antagonist FSH or HMG Early follicular phase start

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

Late follicular start

Luteal phase start

FSH (do not use HMG) GnRH antagonist (start at the same time as FSH) Figure 10.2  Controlled ovarian stimulation at various stages in menstrual cycle. FSH, follicle stimulating hormone; GnRH, gonadotropin releasing hormone; HMG, human menopausal gonadotropin.

●●

●●

A gonadotropin releasing hormone (GnRH) antagonist is started at the same time as the FSH injections (to prevent luteinization if a late follicular phase start, or to induce luteolysis if a luteal phase start). GnRH agonist should be used, unless contraindicated, to induce final follicular maturation as it significantly reduces the risk of ovarian hyperstimulation syndrome  [10]. GnRH agonist trigger also has an additional value in hormone dependent breast cancer patients as it reduces the estrogen levels in the luteal phase following the trigger with no negative impact on the number of mature oocytes available for storage (see Chapter 51) [11].

For the patients in Case Histories 1 and 2, controlled ovarian stimulation and oocyte retrieval should be offered, as long as approximately 2  weeks delay in cancer therapy is acceptable. For the woman in Case History 1, cryopreservation of oocytes and/or embryos should be offered. However, with embryos there could always be a risk that she would not be able to use them if her partner withdraws consent to the use of embryos (see Chapter 108). One way of addressing this risk

is to divide the lot of oocytes in half, and store half as embryos and the other half as oocytes; alternatively, the woman may decide to cryopreserve oocytes, rather than create any embryos with her partner’s sperm. Two additional issues are worth considering for the woman in Case History 1: 1. As she has an estrogen receptor positive breast cancer, the co‐administration of 5 mg of letrozole daily, commencing on Day 2 and continued throughout COS, is recommended as it reduces peak estradiol concentrations without significantly decreasing oocyte yield (see Chapter 51) [12]. 2. As a pregnancy will be associated with very high levels of estrogen, gestational surrogacy may need to be considered [13]. For the girl in Case History 2, oocyte c­ ryopreservation should be offered. The success rate of oocyte cryopreservation has risen, and the increasing use of vitrification has improved outcomes, with IVF pregnancy rates now similar to those achieved with fresh oocytes [14]. There is no evidence that babies born from cryopreserved eggs have an increased risk of congenital abnormalities [15].

Management options 

GnRH agonist co-treatment during chemotherapy Administration of GnRH analog (GnRHa) during chemotherapy has been proposed to protect ovarian reserve and fertility. One hypothesis is that GnRHa may protect the ovary by shutting down the hypothalamic–pituitary–ovarian axis, thus mimicking a prepubertal state when ovaries may be less vulnerable to the effects of chemotherapy  [16]. Another hypothesis is that GnRHa may provide protection via reduced ovarian blood flow, resulting in reduced amounts of chemotherapeutic agents reaching the follicles  [16]. Research evidence on the effects of GnRHa co‐treatment during chemotherapy has yielded conflicting results  [16–19]. However, a 2019 Cochrane review concluded that GnRH agonist appears to be effective in protecting the ovaries during chemotherapy, in terms of maintenance and resumption of menstruation, treatment‐related premature ovarian failure and ovulation. However, evidence for protection of fertility was insufficient and needs further investigation [20]. Until more evidence is available, it would be reasonable to offer women GnRHa treatment during chemotherapy.

Sperm banking The most common cancers in men during their reproductive years are leukemia, Hodgkin lymphomas and testicular germ cell tumors  [21]. Semen analysis may be abnormal in men with germ cell tumors. Furthermore, there is evidence that the integrity of sperm DNA is affected even before initiation of cancer therapy in men with Hodgkin lymphomas and testicular cancers [13]. Chemotherapeutic agents, particularly alkylating agents such as cyclophosphamide, can have profound gonadotoxic effects. Radiotherapy, even at low doses, is toxic to sperm  [13]. Thus, the man in Case History 3 should be offered the opportunity of sperm banking. Men with testicular cancer who cannot produce a sample or are azoospermic can undergo surgical sperm retrieval (see Chapter 91).

Key points Challenge: Fertility preservation in patients with cancer. Background: Young patients with many cancers have excellent survival prognosis and should be promptly referred to explore their fertility preservation options. ●● The effect of chemotherapy on ovarian function and fertility will depend on drug(s) used, dosage, duration of treatment, age of the patient and baseline ovarian reserve. ●● Radiotherapy, particularly if directed to the pelvis, can affect fertility. ●●

Management options: ●● Multidisciplinary team approach. ●● Fertility preservation options will be ­determined by the pubertal stage of the patient, baseline ovarian reserve, time ­available for fertility preservation and whether the patient is in a stable ­relationship with a partner who can offer sperm for the creation of embryos. ●● Fertility preservation options are: ⚪⚪ prepubertal girls: ovarian tissue ­cryopreservation; ⚪⚪ postpubertal girls: controlled ovarian stimulation (COS) and oocyte storage; ovarian tissue cryopreservation; GnRHa co‐treatment during chemotherapy; ⚪⚪ women: COS and embryo and/or oocyte storage; ovarian tissue c­ ryopreservation; GnRHa co‐treatment during ­chemotherapy; ⚪⚪ prepubertal boys: no established options; ⚪⚪ postpubertal boys: sperm banking (sperm obtained from masturbation, ­electro‐­ejaculation or SSR); ⚪⚪ men: sperm banking. ●● Ovarian tissue cryopreservation and ­transplantation: generally, no more than 50% of one ovary is removed for storage; storage and transplantation should be c­ arried out in specialized centralized facilities. ●● COS: requires approximately 2 weeks to complete treatment to the oocyte retrieval stage. COS can start at any stage in the menstrual cycle. However, if starting in late follicular or luteal phase, use an FSH only preparation (and not HMG) and start GnRH

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●●

antagonist at the same time as starting the FSH injections. In women with estrogen receptor positive cancers, consider using antiestrogens (Letrozole or Tamoxifen) during ovarian stimulation. Consideration should also be given to gestational surrogacy to avoid high levels of circulating estrogens that can result from a pregnancy.

●●

GnRH agonist appears to be effective in providing some protection to the ovaries during chemotherapy. Therefore, it would be reasonable to offer a woman GnRHa treatment during chemotherapy. However, the evidence for protection of fertility is insufficient and needs further investigation.

Answers to questions patients ask Q1 How can I find out the effect cancer treatment had on my fertility and what would be my options if I don’t go for fertility preservation? A1.  We can do fertility tests, at least 6  months after cancer treatment is completed to assess your ovarian store of eggs. It should be remembered that it can often take longer than 6 months for the ovaries to recover their function. The ovarian function will depend on age, ovarian reserve before cancer treatment and the cancer treatment received. Based on your fertility potential, options could be natural conception, ovulation induction, IVF, treatment with donor egg or embryo, or surrogacy. Q2 How often does oocyte cryopreservation result in a pregnancy? A2.  Based on the available evidence, an overall 4% live‐birth rate can be expected per oocyte thawed following vitrification. So, multiple eggs will need to be stored to give a patient a reasonable chance of pregnancy. However, older women will require more frozen oocytes to achieve a live birth compared to younger women [22,23,24].

Q3 How long can my embryos be stored for and does the storage duration affect success rate? A3.  In the UK, the standard storage period for embryos is 10 years; however, this could be extended for up to 55 years in certain circumstances. Available data showed that duration of storage has no negative effects on success rate [25]. Q4 I’m having pelvic radiation; what can I do to reduce its effect on my fertility? A4.  The ovaries can be protected from radiation injury by moving them out of the radiation field through key hold surgery (ovarian transposition/oophoropexy)  [26]. Natural pregnancies as well as pregnancies following IVF treatment have been reported following oophoropexy [27,28]. However, due to the potential effects of radiation on the uterus, surrogacy might be needed for some women. Q5 Does OTC affect the well‐being of children conceived from this procedure? A5.  It does not seem likely from the available evidence that OTC affects the well‐being of children born from this procedure [8].

References 

References 1 Logan S, Perz J, Ussher JM, Peate M, Anazodo A. Systematic review of fertility‐related psychological distress in cancer patients: Informing on an improved model of care. Psychooncology. 2019;28(1):22–30. 2 Poorvu PD, Frazier AL, Feraco AM, Manley PE, Ginsburg ES, Laufer MR, LaCasce, AS, Diller LR, Partridge AH. Cancer treatment‐ related infertility: a critical review of evidence. JNCI Cancer Spectrum. 2019;3(1). 3 Chemaitilly W, Mertens AC, Mitby P, Whitton J, Stovall M, Yasui Y, Robison L, Sklar CA. Acute ovarian failure in the childhood cancer survivor study. J Clin Endocrinol Metab. 2006;91(5):1723–28. 4 Andersen CY, Mamsen LS, Kristensen SG. Fertility preservation, freezing of ovarian tissue and clinical opportunities. Reproduction. 2019;158:27–34. 5 Donnez J, Dolmans MM. Fertility preservation in women. N Engl J Med. 2017;377(17): 1657–65. 6 Beckmann MW et al. Concept paper on the technique of cryopreservation, removal and transplantation of ovarian tissue for fertility preservation. Geburtshilfe Frauenheilkd. 2019;79(1):53–62. 7 Lotz L, Dittrich R, Hoffmann I, Beckmann MW. Ovarian tissue transplantation: experience from Germany and worldwide efficacy. Clin Med Insights: Reprod Health. 2019;(13):1–8. 8 Gellert SE, Pors SE, Kristensen SG. Transplantation of frozen‐thawed ovarian tissue: an update on worldwide activity published in peer‐reviewed papers and on the Danish cohort. J Assist Reprod Genet. 2018;35(4):561–70. 9 Grynberg M, Mayeur L, Hesters L, Gallot V, Frydman N. First birth achieved after fertility preservation using vitrification of in vitro matured oocytes in a woman with breast cancer. Annals of Oncology. 2020;31 (4):541–2.

10 Youssef M, Van Der Veen F, Al‐Inany Mochtar M, Griesinger G, Mohesen M, Aboulfoutouh I, van Wely M. Gonadotropin‐ releasing hormone agonist versus hcg for oocyte triggering in antagonist‐assisted reproductive technology. Cochrane Database Syst Rev. 2014;31(10). 11 Oktay K, Turkcuoglu I, Rodriguez‐Wallberg KA. GnRH agonist trigger for women with breast cancer undergoing fertility preservation by aromatase inhibitor/FSH stimulation. Reprod Biomed. 2010;20(6):783–8. 12 Rodgers RJ, Reid GD, Koch J, Deans R, Ledger WL, Friedlander M, Gilchrist RB, Walters KA, Abbott JA. The safety and efficacy of controlled ovarian hyperstimulation for fertility preservation in women with early breast cancer: a systematic review. Hum Reprod. 2017;32(5):1033–45. 13 Jeruss JS, Woodruff TK. Preservation of fertility in patients with cancer. N Engl J Med. 2009;360(9):902–11. 14 Argyle CE, Harper JC, Davies MC. Oocyte cryopreservation: where are we now? Hum Reprod Update. 2016;22(4):440–9. 15 Noyes N, Porcu E, Borini A. Over 900 oocyte cryopreservation babies born with no apparent increase in congenital anomalies. Reprod Biomed Online. 2009;18(6):769–76. 16 Clowse ME, Behera MA, Anders CK, Copland S, Coffman CJ, Leppert PC, et al. Ovarian preservation by GnRH agonists during chemotherapy: a meta analysis. J Womens Health (Larchmt). 2009;18 (3):311–9. 17 Ben‐Aharon I, Gafter‐Gvili A, Leibovici L, Stemmer SM. Pharmacological interventions for fertility preservation during chemotherapy: a systematic review and meta‐analysis. Breast Cancer Res Treat. 2010;122(3):803–11.

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18 Blumenfeld Z, von Wolff M. GnRH‐ analogues and oral contraceptives for fertility preservation in women during chemotherapy. Hum Reprod Update. 2008;14(6):543–52. 19 Beck‐Fruchter R, Weiss A, Shalev E. GnRH agonist therapy as ovarian protectants in female patients undergoing chemotherapy: a review of the clinical data. Hum Reprod Update. 2008;14(6):553–61. 20 Chen H, Xiao L, Li J, Cui L, Huang W. Adjuvant gonadotropin‐releasing hormone analogues for the prevention of chemotherapy‐induced premature ovarian failure in premenopausal women. Cochrane Database of Syst Rev. March 2019. 21 Dohle GR. Male infertility in cancer patients: review of the literature. Int J Urol. 2010;17(4):327–31. 22 Oktay K, Cil AP, Bang H. Efficiency of oocyte cryopreservation: a meta‐analysis. Fertil Steril. 2006;86:70–80. 23 The Practice Committee of the Society for Assisted Reproductive Technology and the Practice Committee of the American Society for Reproductive Medicine. Essential elements of informed consent for elective oocyte cryopresevation: a Practice Committee opinion. Fertil Steril. 2008;90:134–5.

24 Goldman RH, Racowsky C, Farland LV, Munné S, Ribustello L, Fox JH. Predicting the likelihood of live birth for elective oocyte cryo‐ preservation: a counseling tool for physicians and patients. Hum Reprod. 2017;32:853–9. 25 Aflatoonian N, Pourmasumi S, Aflatoonian A, Eftekhar M. Duration of storage does not influence pregnancy outcome in cryopreserved human embryos. Iran J Reprod Med. 2013;11(10):843–6. 26 Turkgeldi L, Cutner A, Turkgeldi E, Al Chami A, Cassoni A, Macdonald N, Mould T, Nichol A, Olaitan A, Saridogan E. Laparoscopic ovarian transposition and ovariopexy for fertility preservation in patients treated with pelvic radiotherapy with or without chemotherapy. Facts Views Vis Obgyn. 2019;11(3):235–42. 27 Terenziani M, Piva L, Meazza C, Gandola L, Cefalo G, Merola M. Oophoropexy: a relevant role in preservation of ovarian function after pelvic irradiation. Fertil Steril. 2009;91(3):15–6. 28 Morice P, Thiam‐Ba R, Castaigne D, Haie‐Meder C, Gerbaulet A, Pautier P, Duvillard P, Michel G. Fertility results after ovarian transposition for pelvic malignancies treated by external irradiation or brachytherapy. Hum Reprod. 1998; 13(3):660–3.

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11 The patient with heart disease Anna S. Herrey1 and Catherine Nelson-Piercy 2 1

Department of Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, UK Department of Women’s Health, Guy’s and St Thomas’ Foundation Trust, London, UK

2

Case History 1: A 42-year-old woman is being assessed for IVF treatment. She smokes 20 cigarettes per day and has chronic hypertension and diet-controlled type 2 diabetes mellitus. Her body mass index (BMI) is 33 kg/m2. She takes ramipril 10 mg once a day and simvastatin 20 mg once a day. Because of her increased risk of ischemic heart disease, she is advised to undergo ischemia testing before receiving infertility treatment. Case History 2: A 27-year-old patient is attending with her partner to discuss IVF. She has had a mechanical mitral valve replacement 2 years previously for rheumatic mitral valve stenosis and is currently taking 7  mg/day warfarin. She reports normal exercise tolerance. Appropriate preconception counseling is provided, including a discussion about the choice of anticoagulant (vitamin K antagonist or low-molecular weight heparin with anti X-a monitoring) as well as the high risk of thromboembolic and bleeding complications she is taking (direct oral anticoagulants are ineffective in mechanical heart valves and contraindicated in pregnancy). Case History 3: A 53-year-old woman with a previous medical history of breast cancer treated with chemotherapy and severe left ventricular (LV) impairment presents to the obstetric service at 14 weeks gestation. She had received IVF with oocyte donation in another country and had no preconception counseling or cardiac risk assessment prior to pregnancy. She had been advised to discontinue all her cardiac medications including ramipril and bisoprolol. The woman undergoes preconception counseling alerting her to the risk of LV function deterioration, arrhythmia and increased risk of cardiac events and possible poor fetal outcome. She is restarted on betablocker, with the plan of keeping her on this drug throughout the pregnancy (ACE-inhibitors are contraindicated in pregnancy but not while breastfeeding).

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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Background Cardiovascular disease complicates approximately 1–4% of all pregnancies and remains the leading cause of maternal death in the Western World [1,2]. The Registry of Pregnancy and Cardiac Disease (ROPAC) recognizes that structural heart disease significantly increases maternal morbidity and mortality  [3]. Preexisting cardiovascular disease may deteriorate as a result of increased cardiac workload during pregnancy, and previously undiagnosed cardiac disease may be unmasked. In addition, there is an increasing cohort of older women with multiple cardiac risk factors wishing to receive fertility treatment. These women should be counseled prior to conception by a cardiologist, an obstetric physician or a highrisk obstetrician [1].

Management options Any cardiovascular condition which could impact on the mother’s ability to increase cardiac output and tolerate intravascular volume expansion can lead to problems in pregnancy. Data from the ROPAC registry suggest that structural heart disease significantly increases maternal risk  [4]. Therefore, all women with cardiovascular disease wishing to embark on pregnancy should receive preconception counseling  [5]. Assisted reproduction techniques (ART) may add to risk in this patient population: superovulation increases the pro-thrombotic state of pregnancy, which is particularly relevant to patients at risk of thrombotic complications, e.g. those with mechanical heart valves, certain types of congenital and inherited cardiac conditions etc. Ovarian hyperstimulation syndrome (OHSS) can lead to significant fluid shifts, which may not be tolerated by women with brittle cardiovascular disease, and single embryo transfer is preferable in any woman with cardiovascular disease undergoing fertility treatment.

According to the 2018 European Society of Gynecology (ESG) guidelines on management of cardiovascular disease in pregnancy, IVF is contraindicated in any women considered to be in WHO class IV, and those in class III and/ or on anticoagulation are at high risk from superovulation so that alternative methods such as natural cycle IVF should be considered [6].

Ischemic heart disease A meta‐analysis of myocardial infarction in pregnancy, including 66,470,100 pregnancies from high income countries, found the pooled incidence of myocardial infarction in pregnancy was 3.34 per 100,000 (95% CI 2.09–4.58) with a maternal fatality rate of around 5% [7]. Currently in the UK, approximately a quarter of all cardiovascular deaths in pregnancy are due to myocardial ischemia. With increasing prevalence of obesity, type 2 diabetes and advanced female age, the incidence of acute coronary syndromes in pregnancy is likely to rise, and with every year of increasing maternal age, the risk of myocardial infarction rises by 20%  [8]. Therefore, women with multiple risk factors for coronary disease such as hypertension, diabetes, smoking, dyslipidemia and older reproductive age should have a cardiac assessment prior to undergoing ART. A high index of suspicion is needed to diagnose acute coronary syndrome (ACS) in a young pregnant or postpartum patient. As in the nonpregnant patient, there is often a history of chest pain, palpitations and breathlessness. However, presentation may be atypical with dizziness, nausea or epigastric pain without chest pain. Interpretation of the ECG may be challenging with T‐wave inversion and ST shift frequently seen in the pregnant population in the absence of coronary ischemia. ST elevation, however, is always abnormal, and elevated troponin levels, even in the presence of preeclampsia, should

Management options 

t­ rigger investigations for ACS. The treatment is the same as in the nonpregnant patient. Complications include arrhythmia, heart failure, cardiogenic shock and death of both mother and baby. Due to improved outcomes for patients with congenital heart disease (CHD), there is an increasing number of women with congenital heart disease who reach childbearing age  [9,10]. In most cases, the woman is well known to adult congenital heart disease services where individualized prepregnancy counseling should take place. Individual risk is dictated by the nature and complexity of the defect, but in general those with more complex disease have a higher risk of obstetric complications. Maternal risk is strongly influenced by cardiac output and functional class prior to pregnancy, and during pregnancy women with CHD are at risk of arrhythmia. The presence of cyanosis is also relevant to offspring outcome: if maternal oxygen saturation is 10 cm3) [2]. The response of the polycystic ovary to ovulation induction aimed at the development of unifollicular ovulation is well documented and differs significantly from that of normal ovaries. The response tends to be slow initially, with a significant risk of ovarian hyperstimulation once recruitment has started and so there are significant challenges in achieving safe ovulation induction  [3]. The response of the polycystic ovary in the context of an IVF program also differs from the normal, whether the patient has the full syndrome or not. Indeed, a number of studies have shown that significantly more oocytes are recovered per cycle in women with polycystic ovaries compared with normal ovaries. Despite the fact that they often require a lower total dose of gonadotropin during stimulation compared with women with normal ovaries, women with PCOS are at a greater risk of developing moderate to severe OHSS. It is difficult to know the true rate of OHSS, as studies vary considerably with an estimated prevalence of 20% to 33% in its mild form and 3% to 8% in its moderate or severe form, and possibly even higher for women with polycystic ovaries [4]. A 2019 meta‐analysis [5] aimed to study whether pregnancy‐related outcomes and complications differed between patients with PCOS and those with other causes of infertility who had undergone IVF. Women with PCOS had higher risks of miscarriage (OR 1.41, 95% CI 1.04–1.91), OHSS (OR 4.96, 95% CI 3.73–6.60), gestational diabetes mellitus (OR 2.67, 95% CI 1.43–4.98), pregnancy‐ induced hypertension (OR 2.06, 95% CI 1.45–2.91), preterm birth (OR 1.60, 95% CI 1.25–2.04) and large‐for‐gestational‐age babies (OR 2.10, 95% CI 1.01–4.37). On the other

hand, they had similar rates of clinical pregnancy, multiple pregnancy, small for gestational age and congenital malformations, and a higher live birth rate. So when preparing women with PCOS for IVF treatments, it is important to remember that they are at increased risk of adverse pregnancy‐related outcomes, which may be related to higher rates of obesity and metabolic disturbance; and so enhancing preconception health is essential before commencing treatment. Another consequence of obesity among women with PCOS is an increased requirement for FSH stimulation. Therefore, they may not respond to a low dose stimulation regimen. However, once the dose of FSH is increased and the threshold reached, the subsequent response can be explosive, with an increasing risk of OHSS. There are several possible explanations for the excessive response to ovarian stimulation. Women with PCOS have an increased cohort of antral follicles due to an increase in recruitment of primordial follicles from the resting pool, which are sensitive to exogenous gonadotropins. The increased number of antral follicles is also reflected by elevation of anti‐Müllerian hormone (AMH) levels in women with PCOS compared with those with normal ovaries.

Management options All patients undergoing ovarian stimulation, whether to correct anovulation or for assisted reproduction techniques (ART), should of course have a pretreatment ultrasound scan and if polycystic ovaries are detected the dose of gonadotropin lowered (to a starting dose of no more than 50–150 IU depending upon age and other factors). OHSS is usually associated with the presence of a large number of small to moderate sized follicles (< 14 mm diameter) rather than larger, more mature follicles. When serum estradiol concentrations are 10,000–15,000 pmol/L with 20–30 follicles, the patient is at

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risk of OHSS. A decision then has to be taken as to whether or not to proceed with oocyte retrieval and then potentially electively cryopreserve any embryos created or decide if it is safe to perform a fresh embryo transfer, with the inherent increased risk of late‐onset and prolonged OHSS. If the serum estradiol concentration becomes greater than 15,000 pmol/L (5,000 pg/ml) with more than 30–40 follicles, the treatment cycle should be canceled.

The long GnRH agonist protocol Historically a “long” protocol with pituitary desensitization using a GnRH agonist was used although this has now largely been replaced by the GnRH antagonist protocols in women with PCOS. If a long protocol of GnRH agonist treatment is followed by treatment with one of the “pure” or recombinant FSH preparations, one must also be aware that the lack of LH changes the usual relationship of follicle number to circulating estradiol levels. In this situation measurement of serum estradiol concentrations underestimates follicle development. It is therefore essential that endocrine monitoring is supported by high quality ultrasound, otherwise low circulating estradiol concentrations may encourage further and inappropriate gonadotropic stimulation despite adequate follicular development. Indeed, these days, most use ultrasound as the keyway of monitoring follicular growth. Meta‐analyses of the different gonadotropin preparations have indicated no significant differences in the risk of developing OHSS [6]. For the patient with overstimulated ovaries who is approaching the time of human chorionic gonadotropin (hCG) administration several strategies to make treatment safer may be considered. The first is to administer a low dose of hCG to initiate oocyte maturation (i.e. not more than a single injection of 5,000  IU, rather than the dose of 10,000 IU which many clinics use in routine practice) and, in patients

receiving GnRH agonist treatment and who therefore require luteal support, to give ­progesterone rather than hCG (which is virtually obsolete now as a form of luteal support). Insulin resistance and compensatory hyperinsulinemia contribute to the pathogenesis of PCOS. A number of studies have investigated the effects of using the insulin sensitizing agents, mainly metformin, on women with PCOS undergoing IVF treatment. The use of metformin as an adjunct for IVF is associated with no significant difference in live birth rates (OR 1.39, 95% CI 0.81 to 2.40, five RCTs, 551  women, low‐quality evidence), but a significant lowering of the incidence of OHSS (OR 0.29; 95% CI 0.18 to 0.49, eight RCTs, 798  women, moderate‐quality evidence), but with a higher incidence of gastrointestinal side effects [7]. However, as stated, the GnRH agonist regimens have been superseded by the use of GnRH antagonist regimens for women with PCOS undergoing IVF.

The GnRH antagonist protocol The GnRH antagonist cycle is now widely recognized as superior to the agonist cycle in reducing the risk of OHSS in women with polycystic ovaries [8]. With equivalent pregnancy rates, the adoption of this strategy appears unquestionable. It is also prudent to consider the option of using a GnRH agonist trigger instead of hCG to further reduce OHSS rates in those at risk. In a meta‐analysis of studies looking at agonist versus antagonist protocols for pituitary suppression during IVF, the GnRH antagonist protocols were associated with a reduced risk of OHSS (OR 0.61, 95% CI 0.51 to 0.72; 36 RCTs; n = 7944; moderate quality evidence) whilst not compromising the live birth rate (OR 1.02, 95% CI 0.85 to 1.23; 12 RCTs; n = 2303; moderate quality evidence) [8]. The GnRH antagonist cycle also allows the use of GnRH agonist rather than hCG as the

Management options 

pre‐ovulatory trigger further reducing the risk of OHSS (OR 0.15, 95% CI 0.05 to 0.47; eight RCTs, 989  women; moderate‐quality evidence)  [9]. However, the use of a GnRH ­agonist in this way may be associated a lower live birth rate due to a deficient luteal phase (OR 0.47, 95% CI 0.31 to 0.70; five RCTs, 532  women, moderate‐quality evidence)  [9]. Two approaches have been suggested to overcome the luteal phase deficiency – supplementation with exogenous estrogen and progesterone in the luteal phase or rescuing the corpus luteum using low dose hCG given either alongside the GnRH agonist trigger or on the day of the oocyte retrieval. Use of modified luteal phase support appears to lead to similar live birth rates with a GnRH agonist trigger as with hCG (OR 0.84, 95% CI 0.62 to 1.14; five RCTs; n = 857) [10]. An alternative approach has been elective cryopreservation of embryos following oocyte retrieval, followed by transfer in a frozen embryo transfer cycle – the “segmentation”

Key points Challenge: Polycystic ovaries and PCOS in IVF treatment. Background: ●● Polycystic ovarian morphology is present in 20–30% of IVF patients. ●● Not all women with polycystic ovaries have polycystic ovary syndrome (PCOS). ●● The presence of polycystic ovaries is associated with sensitive response to stimulation and an increased risk of OHSS. Assessment: ●● Baseline pelvic USS provides morphological appearance of polycystic ovaries. ●● Baseline endocrine profile enables appropriate regimen choice. ●● Assessment of glucose tolerance is important if overweight.

approach  [11]. A recent multicenter trial including 1508 women found that the segmentation approach led to a higher live birth rate (49.3% vs. 42.0%; RR 1.17, 95% CI 1.05 to 1.31) with a lower risk of OHSS (1.3% vs. 7.1%, RR 0.19, 95% CI, 0.10 to 0.37), but a higher risk of pre‐eclampsia (4.4% vs. 1.4%, RR 3.12, 95% CI, 1.26 to 7.73) [12]. New concepts include the possibility of using Kisspepetin as the pre‐ovulatory trigger [13], which has generated much interest. It is also possible to use dopamine agonists, such as cabergoline, to inhibit phosphorylation of the receptor for VEGF, which has also been shown to reduce the incidence of OHSS [14]. There is the possibility to consider in vitro maturation (IVM) of oocytes collected from unstimulated or minimally stimulated ovaries, although this requires particular expertise in the clinic and laboratory, and despite some clinics demonstrating success with this approach it has not gained widespread popularity [15].

●●

Counsel for increased obstetric risk (gestational diabetes, preeclampsia and fetal morbidity) if overweight.

Management options: ●● Treatment plan aimed to minimize risk of OHSS which is a life-threatening condition ●● Use low dose stimulation in a short GnRHantagonist protocol. ●● Metformin therapy may reduce the risk of OHSS in a long GnRH-agonist protocol ●● Use progestogens and not hCG for luteal support ●● Consider a GnRH-agonist trigger in GnRHantagonist protocols if there is a significant risk of OHSS ●● Consider segmentation, that is elective ­cryopreservation of all embryos for use in subsequent frozen embryo replacement cycles

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Answers to questions patients ask Q1 What are polycystic ovaries? A1. Polycystic ovaries are ovaries in which there are more than the usual number of small cystic structures that contain eggs, otherwise commonly known as follicles. It is normal for there to be several follicles that are developing each month in a woman’s ovaries. In women with polycystic ovaries there are more than the usual number, and usually more than 20 in each ovary. Polycystic ovaries are detected by ultrasound which can be performed either with a probe in the vagina or a probe on the lower part of the abdomen. Q2 What is polycystic ovary syndrome? A2. Polycystic ovary syndrome (PCOS) is a common condition in which women with polycystic ovaries also have other symptoms usually of irregular or absent menstrual cycles and also signs of excess androgen hormones leading to unwanted hair growth on the face and body, sometimes acne and occasionally thinning of the hair on the head. Women with polycystic ovaries often have an imbalance of the natural hormones that are produced by the ovaries with an excess of the androgen hormone testosterone, which is a naturally occurring hormone in all ovaries. Some women with PCOS have a tendency to gain weight in which case there is a concurrent elevation of insulin levels which has additional metabolic effects. Women with polycystic ovaries

also have high levels of anti‐ Müllerian hormone (AMH) as this correlates with the number of small follicles. Q3 Can I have polycystic ovaries without polycystic ovary syndrome? A3. Approximately 20–25% of women have polycystic ovaries as detected by ultrasound scan; of these, three quarters have symptoms consistent with polycystic ovary syndrome. Therefore, it is possible to have polycystic ovaries without any symptoms of the syndrome. Symptoms can sometimes develop over time particularly in those who gain weight. Q4 What are the implications of having polycystic ovaries if I am due to have IVF treatment? A4. Women with polycystic ovaries have a tendency to respond excessively to the drugs that are used to stimulate the ovaries and therefore there is an increased risk of ovarian hyperstimulation syndrome (OHSS). For this reason, a low dose of the stimulation drugs is used in a protocol that is designed to minimize the risk. However, if ovarian hyperstimulation does occur the treatment cycle is either discontinued or alternatively the eggs can be collected and fertilized and then the resultant embryos frozen for future use but not transferred in a fresh cycle. This enables the ovaries to settle down, minimizes the risks and also increases the chance of having a pregnancy.

References 

Q5 Is IVF the only treatment for PCOS? A5. If you are wishing to get pregnant and have polycystic ovary ­syndrome it is important first to optimize your heath, body weight and nutritional status. If you are having irregular periods and therefore not ovulating regularly, we usually advocate the use of medication to stimulate ovulation,

which has to be monitored carefully by ultrasound. It is only if this treatment doesn’t work that IVF might be considered as an option. IVF is sometimes required for women with PCOS or polycystic ovaries alone, if there are other fertility problems such as damaged or blocked fallopian tubes.

References 1 The Rotterdam ESHRE/ASRM‐sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long‐term health risks related to polycystic ovary syndrome (PCOS). Authors: Fauser B, Tarlatzis B, Chang J, Azziz R, Legro R, Dewailly D, Franks S, Balen AH, Bouchard P, Dahlgren E, Devoto, Diamanti E, Dunaif A, Filicori M, Homburg R, Ibanez L, Laven J, Magoffin D, Nestler J, Norman R, Pasquali R, Pugeat M, Strauss J, Tan SL, Taylor A, Wild R, Wild S. Human Reproduction 2004; 19: 41–47. 2 Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Misso ML, Moran L, Piltonen T, Norman RJ on behalf of the International PCOS Network. Recommendations from the international evidence‐based guideline for the assessment and management of polycystic ovary syndrome. Simultaneous publication: Fertility and Sterility, 2018; 110:364–379; Clinical Endocrinology, 2018; 89: 251–268; Human Reproduction, 2018; 33:1602–1618. 3 Balen AH, Morley LC, Misso M, Franks S, Legro RS, Wijeyaratne CN, Stener‐Victorin E, Norman RJ, Fauser BJCM, Teede H. WHO recommendations for The Management of Anovulatory Infertility in Women with Polycystic Ovary Syndrome (PCOS), Human Reproduction Update 2016; 22: 687–708 doi: 10.1093/humupd/dmw 025. 4 Mourad S, Brown J, Farquhar C. Interventions for the prevention of OHSS in ART cycles: an

overview of Cochrane reviews. Cochrane Database Syst Rev. 2017 Jan 23;1:CD012103. doi: 10.1002/14651858.CD012103.pub2. 5 Sha T, Wang X, Cheng W, Yan Y.A meta‐ analysis of pregnancy‐related outcomes and complications in women with polycystic ovary syndrome undergoing IVF. Reprod Biomed Online. 2019 Aug;39(2):281–293. doi: 10.1016/j. rbmo.2019.03.203. Epub 2019 Mar 29. 6 van Wely, M., et al., Recombinant versus urinary gonadotrophin for ovarian stimulation in assisted reproductive technology cycles. Cochrane Database Syst Rev. 2011;(2): CD005354. 7 Tso LO, Costello MF, Albuquerque LET, Andriolo RB, Macedo CR. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2014;CD006105. 8 Al‐Inany HG, Youssef MA, Ayeleke R, Brown J, Lam W, Broekmans FJ. Gonadotrophin‐ releasing hormone antagonists for assisted reproductive technology. Cochrane Database of Syst Rev. 2016, Issue 4. Art. No.: CD001750. DOI:10.1002/14651858.CD001750.pub4 9 Youssef MAFM, Van der Veen F, Al‐Inany HG, Mochtar MH, Griesinger G, Nagi Mohesen M, et al. Gonadotropin‐releasing hormone agonist versus HCG for oocyte triggering in antagonist‐assisted reproductive technology. Cochrane Database Syst Rev. 2014;CD008046.

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The patient with polycystic ovaries

10 Haahr T, Roque M, Esteves SC, Humaidan P. GnRH Agonist Trigger and LH Activity Luteal Phase Support versus hCG Trigger and Conventional Luteal Phase Support in Fresh Embryo Transfer IVF/ICSI Cycles‐A Systematic PRISMA Review and Meta‐ analysis. Front Endocrinol (Lausanne). 2017;8:116. 11 Devroey P, Polyzos NP, Blockeel C. An OHSS‐Free Clinic by segmentation of IVF treatment. Hum Reprod. 2011;26:2593–7. 12 Chen Z‐J, Shi Y, Sun Y, Zhang B, Liang X, Cao Y, et al. Fresh versus Frozen Embryos for Infertility in the Polycystic Ovary Syndrome. N Engl J Med. 2016;375:523–33. 13 Abbara A, Jayasena CN, Christopoulos G, Narayanaswamy S, Izzi‐Engbeaya C, Nijher GMK, et al. Efficacy of Kisspeptin‐54 to

Trigger Oocyte Maturation in Women at High Risk of Ovarian Hyperstimulation Syndrome (OHSS) During in vitro Fertilization (IVF) Therapy. J Clin Endocrinol Metab. 2015;100:3322–31. 14 Siristatidis CS, Maheshwari A, Vaidakis D, Bhattacharya S. in vitro maturation in subfertile women with polycystic ovarian syndrome undergoing assisted reproduction. Cochrane Database Syst Rev. 2018 Nov 15;11:CD006606. doi: 10.1002/14651858. CD006606.pub4. 15 Mourad S, Brown J, Farquhar C. Interventions for the prevention of OHSS in ART cycles: an overview of Cochrane reviews. Cochrane Database Syst Rev. 2017 Jan 23;1:CD012103. doi: 10.1002/14651858. CD012103.pub2.

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16 The renal transplant patient Justin Chu and Lynne Robinson Birmingham Women’s Hospital, Birmingham, UK

Case History 1: A 30-year-old woman with unexplained infertility is scheduled to undergo IVF treatment. She has a background history of renal transplant for IgA nephropathy. She takes mycophenolate mofetil, prednisolone, enalapril and cephalexin. Case history 2: A 24-year-old woman plans to undergo a second cycle of ICSI treatment for male factor infertility. She is a kidney transplant recipient who developed OHSS in her previous ICSI cycle.

Background Women with chronic kidney disease have disrupted hypothalamus‐pituitary‐ovarian axis function leading to deranged menstrual cycles, anovulation and therefore reduced fertility [1]. When chronic kidney disease reaches end‐ stage, prolactin is raised (due to reduced renal clearance) and there are often low LH and FSH levels due to lack of pulsatile gonadotropin releasing hormone release  [2]. Estradiol and progesterone levels are characteristically low, and women tend to reach menopause 4.5 years earlier compared with women in general population [3]. Therefore, pregnancy is rare in women on hemodialysis with an incidence of conception as low as 0.3% [4]. With the development of more intense hemodialysis regimes, the live birth rates seen in women on dialysis are improving [5]. In women who have undergone peritoneal dialysis, there is an increased

incidence of tubal infertility due to the risk of generalized peritonitis [6]. The incidence of renal transplantation is increasing. After successful renal transplantation, the hypogonadotropic hypogonadism seen in women with end‐stage renal disease can normalize within six months [7]. Normal ovulatory cycles can be restored with regular menstrual cycles [8,9]. There is still much debate surrounding the optimal time women should be advised to wait to conceive after renal transplant. However, both the American Society of Transplantation and European Transplantation Society suggest that the optimal time is after one year post transplantation [1]. If conception is achieved, the allografted kidney is able to adapt to the physiological changes of pregnancy and the elevated glomerular filtration rates. It is able to cope with the intrarenal vasodilatation allowing for greater

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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creatinine clearance required for pregnancy  [10]. Recent data demonstrated a live birth rate of around 75% in women who conceived a pregnancy after renal transplantation  [6,11]. Reassuringly, the miscarriage and ectopic pregnancy rates do not differ from that of the general population [12]. Encouragingly, recent data have also shown that live birth in renal transplant recipients does not adversely affect the functioning of the graft and the long‐term survival of the woman [11]. The same study reported survival rates after a live birth in women with a renal graft as 92% at 10 years and 75% at 20 years [11]. When considering IVF treatment in renal transplant recipients, there are specific risks that clinicians should be aware of and patients should be well counseled before embarking on fertility treatment. It is important to consider that both renal transplantation and IVF are independently associated with greater risks of preterm birth, small for gestational age and perinatal mortality  [13]. There are only a few case reports and series published on live births following IVF treatment in women who have been renal transplant recipients [13,14,15].

Risks of IVF and the graft recipient Women who are renal transplant recipients are at higher risk than the general population of having their IVF treatment complicated by ovarian hyperstimulation (OHSS)  [13]. Approximately 10% of gonadotropins are excreted renally  [1]. Therefore, if renal clearance is not at optimal levels, gonadotropins may have an enhanced effect on renal transplant recipients, leading to OHSS. This can lead to intravascular dehydration, oliguria and deterioration of renal function and so ovarian stimulation must be well monitored and be carried out cautiously using lower gonadotropin doses  [13]. Additionally, enlarged ovaries due to OHSS can lead to ureteric obstruction causing further deterioration of renal function [16].

The position of the transplanted kidney should be known prior to embarking IVF treatment. Access to the ovaries for oocyte retrieval may also be difficult if the allografted kidney is situated in the pelvis. Resultant elevated estradiol levels from ovarian stimulation may lead to higher risks of thrombo‐embolic disease in renal transplant recipients  [13]. This is especially the case in some renal patients who may have pro‐ thrombotic conditions such as systemic lupus erythematosus (SLE) with antiphospholipid autoantibodies.

Risks to the fetus Renal transplant recipients are at more risk of miscarriage, preterm delivery, fetal growth restriction (FGR) and stillbirth  [1]. A study of 1418 pregnancies showed a mean gestational age of 36 weeks, but 20% of babies had FGR and 10% were very low birthweight ( 4 cm). Laparoscopy is the preferred surgical approach as this is associated with less postoperative pain, shorter hospital stay, less risk of adhesions and quicker recovery compared with laparotomy [14]. Excision of endometrioma has been demonstrated to be superior to drainage or ablation of the cystic capsule in terms of recurrence and spontaneous pregnancy rate [15]. A scoring system to aid the clinician in the decision‐making process has been suggested by Muzii and colleagues (16). It would make sense that any potential surgery is planned and undertaken by a gynecologist with special interest and expertise in the management of endometriosis and infertility, as they may be more considerate towards preserving the normal ovarian tissue. Medical management can reduce the size of the endometrioma by up to 57% [17,18]. Older studies suggested that administration of gonadotropin releasing hormone (GnRH) agonist for a period of 3–6 months prior to IVF significantly improves clinical pregnancy rate [19], although a 2020 randomized placebo‐controlled trial showed no difference [20]. Segmentation of the cycle especially for older patients is an approach which may also be beneficial and with the optimization of freezing techniques is gaining in popularity. Transferring the cryopreserved blastocysts in a subsequent scheduled cycle could eliminate the compromise to endometrial performance associated with controlled ovarian stimulation [21,22].

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The patient with an endometrioma

Currently, there are only a few well‐ conducted trials that have evaluated the management of endometriomas in infertile women undergoing IVF [23]. Due to the lack of robust evidence on the benefits of the available options for the treatment of endometriomas, as well as the potential risks of compromising the ovarian reserve after surgical intervention, management should be highly tailored. Furthermore, women should be made aware of the advantages and disadvantages of each approach to help them make a well‐informed decision. Practical considerations for the treating clinician include: ●●

●●

●●

Careful monitoring of the cycle, as ultrasound imaging may be suboptimal. Access at the time of transvaginal oocyte retrieval, as this can be challenging. Risk of infection during oocyte retrieval.

At the time of oocyte retrieval, it is important to avoid draining or puncturing the endometrioma as the cyst fluid has toxic effect on gametes and embryos and may also cause pelvic infection. In the event of inadvertently entering the endometriotic cyst during oocyte recovery, the needle must be washed with culture media before continuing to aspirate other follicles. To reduce the risk of pelvic infection and abscess following oocyte retrieval, intraoperative prophylactic antibiotics are recommended to all women with an endometrioma.

Key points Challenge: The patient with an endometrioma. Background: ●● Occurs in around 5% of IVF patients. ●● Reduces ovarian response to stimulation. ●● IVF is commonly recommended, particularly if other infertility factors coexist. ●● Surgical treatment before IVF does not increase pregnancy rate. Management options: ●● Diagnose endometriomas by transvaginal ultrasound scan. ●● Establish outcomes of previous surgical and/or medical treatments. ●● Check ovarian reserve (AMH, AFC). ●● Evaluate access for oocyte retrieval. ●● Recommend treatment with IVF and ­consider segmentation of the cycle. ●● Consider laparoscopic excision for ­symptomatic patients with large (common ­thresholds for “large” is > 4 cm) endometriomas, no previous surgery, adequate ovarian reserve and difficult vaginal access to the ovaries for oocyte retrieval ●● Avoid surgery in patients with previous history of surgeries and reduced ovarian reserve. ●● If the cyst is large and surgical treatment is not planned, GnRH agonists pretreatment for at least 3 consecutive months before the IVF cycle may be considered. ●● Avoid puncturing or draining the ­endometrioma during oocyte retrieval. ●● Give intravenous antibiotics at oocyte retrieval.

Answers to questions patients ask Q1 Can IVF flare up my endometriosis? A1.  As stimulation only lasts for a short period of time this is unlikely. However, using a less aggressive stimulation protocol may be preferable. Q2 Can you drain my endometrioma during the egg collection? A2.  This is something that we actually try to avoid as it can cause infection which can occasionally be serious. Still this may inadvertently happen

and is one of the recognized complications of the procedure. You will be receiving prophylactic antibiotics during your egg collection to decrease the risk of an infection. Q3 Do I need surgery to remove the endometriomas before IVF? A3.  This is controversial and answered on a case by case basis. Removing the endometriomas per se will not increase your chances of success.

References 

Q4 Are my chances of conceiving good? A4.  Women with endometriosis appear to have similar chances of live

birth after IVF compared with women who don’t suffer with endometriosis.

References 1 Brosens IA, Puttemans PJ, Deprest J. The endoscopic localization of endometrial implants in the ovarian chocolate cyst. Fertil Steril. 1994;61:1034–6. 2 Nisolle M, Donnez J. Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil Steril. 1997;68:585–96. 3 Jenkins S, Olive DL, Haney AF. Endometriosis: pathogenetic implications of the anatomic distribution. Obstetr Gynecol. 1986;67:335–8. 4 Redwine DB. Ovarian endometriosis: a marker for more extensive pelvic and intestinal disease. Fertil Steril. 1999;72:310–15. 5 Al‐Azemi M, Bernal AL, Steele J, Gramsbergen I, Barlow D, Kennedy S. Ovarian response to repeated controlled stimulation in in‐vitro fertilization cycles in patients with ovarian endometriosis. Hum Reprod. 2000;15:72–5. 6 Somigliana E, Infantino M, Benedetti F, Arnoldi M, Calanna G, Ragni G. The presence of ovarian endometriomas is associated with a reduced responsiveness to gonadotrophins. Fertil Steril. 2006;86:192–6. 7 Dunselman GA, Vermeulen N, Becker C, Calhaz‐Jorge C, D’Hooghe T, De Bie B, Heikinheimo O, Horne AW, Kiesel L, Nap A et al. ESHRE guideline: management of women with endometriosis. Human Reprod. 2014;29:400–12. 8 Hirsch M, Begum MR, Paniz E, Barker C, Davis CJ, Duffy JMN. Diagnosis and management of endometriosis: a systematic review of international and national guidelines. BJOG. 2018;25:556–64. 9 Kunz G, Kallat‐Sabri S. Treatment of women with endometriosis and subfertility: results from a meta‐analysis. Geburtsh Frauenheilk. 2008;68(3):236–43.

10 Hamdan M, Dunselman G, Li TC, and Cheong Y. The impact of endometrioma on IVF/ICSI outcomes: a systematic review and meta‐analysis, Human Reproduction Update. 2015;21:809–25. 11 Tsoumpou I, Kyrgiou M, Gelbaya TA, Nardo LG. The effect of surgical treatment for endometrioma on in vitro fertilization outcomes: a systematic review and meta‐ analysis. Fertil Steril. 2009;92:75–87. 12 Maouris P, Brett L. Endometriotic ovarian cysts: the case for excisional laparoscopic surgery. Gynaecol Endosc. 2002;11:231–4. 13 Mais V, Ajossa S, Guerriero S, Piras B, Floris M, Palomba M, et al. Laparoscopic management of endometriomas versus laparotomy: a randomized trial. J Gynecol Surg. 1996;12:41–6. 14 Hachisuga T, Kawarabayashi T. Histopathological analysis of laparoscopically treated ovarian endometriotic cysts with special reference to loss of follicles. Hum Reprod. 2002;17:432–5. 15 Hart RJ, Hickey M, Maouris P, Buckett W, Garry R. Excisional surgery versus ablative surgery for ovarian endometriomata. Cochrane Database Syst Rev 3. 2005;CD004992. Update in: Cochrane Database Syst Rev 2008;2, CD004992. 16 Muzii L, Di Tucci C, Di Feliciantonio M, Galati G, Verrelli L, Di Donato V, Marchetti C, Benedetti Panici P. Management of endometriomas. Semin Reprod Med. 2017;35:025–030. 17 Farquhar C, Sutton C. The evidence for the management of endometriosis. Curr Opin Obstetr Gynecol. 1998;10:321–32. 18 Rana N, Thomas S, Rotman C, Dmowski WP. Decrease in the size of ovarian endometriomas during ovarian suppression

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in stage IV endometriosis: role of preoperative medical treatment. J Reprod Med. 1996;41:384–92. 19 Sallam HN, Garcia‐Velasco JA, Dias S, Arici A. Long‐term pituitary down‐regulation before in vitro fertilization (IVF) for women with endometriosis. Cochrane Database Syst Rev 1, 2006;CD004635. 20 Rodríguez‐Tárrega E, Monzo AM, Quiroga R, Polo‐Sánchez P, Fernández‐Colom P, Monterde‐Estrada M, et al. Effect of GnRH agonist before IVF on outcomes in infertile endometriosis patients: a randomized controlled trial. Reprod Biomed Online. 2020;41(4):653–62.

21 Ozgur K, Bulut H, Berkkanoglu M, Coetzee K. Reproductive Outcomes of Segmented In Vitro Fertilization in Patients Diagnosed with Endometriomas. J Minim Invasive Gynecol. 2018;25:105–10. 22 Mohamed AM, Chouliaras S, Jones CJ, Nardo LG. Live birth rate in fresh and frozen embryo transfer cycles in women with endometriosis. Eur J Obstet Gynecol Reprod Biol. 2011;156:177–80. 23 Somigliana E, Viganò P, Benaglia L, Busnelli A, Paffoni A, Vercellini P. Ovarian stimulation and endometriosis progression or recurrence: a systematic review. Reprod Biomed Online. 2019;38:185–194.

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22 The patient with cervical stenosis Khaldoun Sharif Fertility Center, Jordan Hospital, Amman, Jordan

Case History 1: A couple was referred for IVF with a 5-year history of tubal infertility. Previously, an attempt at hysterosalpingography was unsuccessful, as the catheter could not be passed through the cervix. Following that, she had laparoscopy and hysteroscopy. Hysteroscopy was not possible as the scope could not be passed through the cervix, even after attempts at cervical dilatation. Also, no catheter could be inserted to inject dye. Laparoscopy showed moderate to server pelvic adhesions. There was no history of previous cervical surgery. Case History 2: A 38-year-old patient, who underwent radical vaginal trachelectomy at the age of 33 years for early stage (IA2) cervical adenocarcinoma, presented with a 3-year history of primary infertility due to low sperm count. The couple was referred for ICSI. Case History 3: A couple was referred for IVF with a 4-year history of unexplained infertility. Ten oocytes were collected, six fertilized and one good blastocyst was planned for transfer on day 5. However, on attempting the transfer, the catheter could not be passed more than 0.5cm through the cervical canal.

Background Cervical stenosis is a rare problem, occurring in about 1% of women presenting for embryo transfer (ET) [1]. It has been defined as an external cervical opening of less than 2.5 mm [2], but clinically it manifests as the inability to pass instruments such as dilators and hysterosalpingography (HSG) or ET catheters easily through the cervical canal [3]. Some women with cervical stenosis may have associated dysmenorrhea or even amenorrhea, but most are asymptomatic, so presumably the cervical canal is

a­ dequate for the passage of menstrual blood but not instruments  [4–7]. Also, it is not just the diameter of the cervical opening but also the tortuosity of the canal as well as the degree of uterine flexion or version that determine the difficulty in inserting instruments [3]. Cervical stenosis could be congenital or acquired. Congenital cases could result from diethylstilbestrol (DES) exposure in utero, while acquired cases could be caused by previous cervical surgery such as cone biopsy, loop excision or trachelectomy  [3]. However, many women with cervical stenosis have no such history.

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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The patient with cervical stenosis

Cervical stenosis is associated with difficult ET [4–7], which in turn is associated with a significantly lower pregnancy rate when compared with easy transfers [8,9].

Management options Take a precise history Many women presenting for IVF have had attempts at cervical instrumentation in the past. This includes HSG, hysteroscopy, intrauterine insemination (IUI) or even previous ET. It is important to ask specifically about any history of difficulty in instrumenting the cervix. The woman may have been told about this by her clinician or may recall difficult, painful or prolonged attempts. All these are indicators that there might be cervical stenosis. History of previous cervical surgery is also significant. However, history of dysmenorrhea is very common, rendering it an inaccurate indicator of cervical stenosis.

Mock embryo transfer In cases referred for IVF (or IUI) where there is suggestion from the history or examination of cervical stenosis (as in Case Histories 1 and 2), a “mock” ET (also called “dummy” or “trial” ET) should be performed  [10]. This is when an empty ET catheter is passed through the cervix, thus mimicking what would happen at the actual ET. This should be carried out as an interval procedure before the start of the IVF process, so as to identify women who have cervical stenosis and allow time to plan remedial action. Because most cases of cervical stenosis have no indicative history (as in Case History 3), some IVF units perform mock ET as a routine in all cases [10].

Cervical dilatation In cases of confirmed cervical stenosis, mechanical dilatation of the cervix under

g­ eneral anesthesia has been tried to make subsequent ET easier. This has been tried either as an interval procedure (at the start of the IVF cycle)  [6,11], or at the time of the oocyte retrieval  [4,12]. Both have been associated with easier subsequent ET, but only interval dilatation has led to improvement in pregnancy rate, perhaps because it allows sufficient time for the endometrium to recover from any trauma, inflammation or bacterial contamination resulting from the dilatation at the time of oocyte retrieval [13]. Other reported methods involve the use of osmotic cervical dilatation. These include the use of hygroscopic cervical rods (Dilapan) inserted in the cervix for 4 hours early (day 4) in the stimulation phase  [14], and the use of intracervical laminaria tents for 24 hours – either at oocyte retrieval  [5] or early in the stimulation phase  [13]. All have been associated with easier ET and pregnancies, but the reported numbers are too small to allow for a meaningful comparison amongst different methods. These methods allow cervical dilatation on an outpatient basis without the need for general anesthesia.

Transmyometrial embryo transfer An alternative method to transferring embryos through the cervix is transmyometrial embryo transfer (TMET), also known as the Towako method  [15–18]. The technique is performed under transvaginal ultrasound guidance (see Chapter 65) and is not too dissimilar to oocyte retrieval. A special needle (Towako Needle Set, Cook IVF, Queensland, Australia) with its stylet attached to the vaginal probe needle holder is inserted transmyometrially and guided into the endometrial cavity. The stylet is removed, and a transfer catheter loaded with embryos is passed through the needle [18]. Despite concern about possible trauma to the endometrium, the pregnancy rate following TMET is similar to that with easy transcervical transfer  [15–17]. The advantages of TMET include the ability to transfer embryos

Answers to questions patients ask  139

regardless of the severity of cervical stenosis, such as cases of post radical trachelectomy (Case History 2)  [19,20]. It could also be performed with minimal or no sedation and provides an immediate solution to cases of cervical stenosis discovered for the first time at ET [18]. However, it requires special expertise and catheters that may not be available in every center.

Tubal embryo transfer In cases with normal tubes, the embryos could be transferred through the fimbrial end of the fallopian tubes  [21]. However, this requires laparoscopy and general anesthesia.

Hysteroscopic canalization of the cervix In refractory cases, it has been reported that operative hysteroscopic shaving of the cervix to create a new canal could be used  [7]. However, this method risks altering the structure of the cervix and may predispose to cervical weakness in a subsequent pregnancy. Therefore, it should be reserved for cases associated with amenorrhea or significant dysmenorrhea due to cervical stenosis.

Postponing ET If cervical stenosis is discovered at ET, and facilities or expertise were not available for immediate remedial action (such as TMET), then it is far better to postpone the transfer than persist with a difficult procedure. If the attempted transfer was performed on day 2 or 3 post–oocyte retrieval, then it could be postponed till day 5 or 6  [22]. This gives time to implement suitable steps to facilitate ET.

Alternatively, the embryos could be cryopreserved for later transfer, allowing plenty of time to prepare. The aim should be an easy transfer, now or later.

Key points Challenge: Patient with cervical stenosis presenting for IVF. Background: Cervical stenosis occurs in about 1% of cases presenting for IVF. ●● Some are associated with severe dysmenorrhea or even amenorrhea, but most are asymptomatic. ●● Could be caused by DES exposure in utero or previous cervical surgery but most are of unknown etiology. ●●

Management options: ●● Take history of previous cervical surgery or difficult or painful cervical instrumentation. ●● Perform mock ET to identify cases and plan action. ●● Cervical dilatation at the start of the IVF cycles will make ET easier and increase the pregnancy rate. ●● Cervical dilatation at the time of oocyte retrieval makes ET easier but does not seem to increase the pregnancy rate. ●● Transmyometrial ET could overcome the most difficult or impossible cases as it bypasses the cervix and leads to a pregnancy rate similar to easy transcervical transfer. ●● Tubal ET is an alternative in cases with normal fallopian tubes but requires laparoscopy and general anesthesia. ●● Hysteroscopic canalization of the cervix has been reported but should only be reserved for cases associated with amenorrhea or significant dysmenorrhea due to cervical stenosis.

Answers to questions patients ask Q1 Why is my embryo transfer difficult? A1. The canal that leads into the cavity of your womb (called the cervix or

the neck of the womb) is very tight. This is rare and occurs in 1 out of every 100  women and

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doesn’t harm your health in anyway. It just can lead to difficulty in embryo transfer, but there are steps we can take to overcome that difficulty. It may result from previous surgery but in most case no cause is known. Q2 I had surgery on the cervix for abnormal smears and was told that it may make my embryo transfer difficult. Will this affect my success rate and what are you going to do about it? A2. In some case surgery on the cervix can lead to narrowing, which can make embryo transfer difficult. A  difficult embryo transfer can reduce the chance of pregnancy, and that is why we need to be prepared. Before you start your IVF treatment, we will do a “trial” embryo transfer, when we will try to pass the embryo transfer catheter (a small plastic tube) through the cervix, just like the real thing but without embryos. If that goes well, then your embryo transfer will be

easy. If we encounter any difficulty, then we will plan how to overcome it, either by dilating the cervix or using a special transfer catheter. That way, when we get to the real embryo transfer, we will be ready, and your transfer will be easy. Q3 What will happen if my embryo transfer turns out to be difficult on the day of the treatment? A3. We will try using different catheters or techniques to make it easy, but if we couldn’t, we will freeze the embryos and then work out a plan to overcome the tight cervix (which may involve dilating it or using special catheters) and then do the embryo transfer on a later date. Studies have shown that the pregnancy rate from frozen embryos is as good as fresh embryos. Our aim is to give you the highest pregnancy rate through an easy transfer, and if that could not be done on the planned date, then it is better to freeze the embryos.

References 1 Wood C, McMaster R, Rennie G, Trounson A, Leeton J. Factors influencing pregnancy rates following in vitro; fertilization and embryo transfer. Fertil Steril. 1985;43:245–50. 2 Valle RF, Sankpal R, Marlow JL, Cohen L. Cervical stenosis: a challenging clinical entity. J Gynecol Surg. 2002 Dec 1;18(4):129–43. 3 Wood MA, Kerrigan KL, Burns MK, Glenn TL, Ludwin A, Christianson MS, et al. Overcoming the challenging cervix: identification and techniques to access the uterine cavity. Obstet Gynecol Surv. 2018;73(11):641–9. 4 Groutz A, Lessing JB, Wolf Y, Yovel I, Azem F, Amit A. Cervical dilatation during ovum

pick‐up in patients with cervical stenosis: effect on pregnancy outcome in an in vitro; fertilization‐embryo transfer program. Fertil Steril. 1997;67(5):909–11. 5 Glatstein IZ, Pang SC, McShane PM. Successful pregnancies with the use of laminaria tents before embryo transfer for refractory cervical stenosis. Fertil Steril. 1997;67:1172–4. 6 Abusheikha N, Lass A, Akagbosu F, Brinsden P. How useful is cervical dilatation in patients with cervical stenosis who are participating in an in vitro; fertilization‐embryo transfer program? The Bourn Hall experience. Fertil Steril. 1999;72:610–2.

References 

7 Pabuccu R, Ceyhan ST, Onalan G, Goktolga U, Ercan CM, Selam B. Successful treatment of cervical stenosis with hysteroscopic canalization before embryo transfer in patients undergoing IVF: A case series. J Minim Invasive Gynecol. 2005;12:436–8. 8 Tomás C, Tikkinen K, Tuomivaara L, Tapanainen JS, Martikainen H. The degree of difficulty of embryo transfer is an independent factor for predicting pregnancy. Hum Reprod. 2002 Oct 1;17(10):2632–5. 9 Agameya A‐F, Sallam HN. Does a difficult embryo transfer affect the results of IVF and ICSI? A meta‐analysis of controlled studies. Fertil Steril. 2014;101(2):e8. 10 Sharif K, Serour GI. Dummy Embryo Transfer. In: Kovacs G, Salamonsen L, editors. How to Prepare the Endometrium to Maximize Implantation Rates and IVF Success. Cambridge: Cambridge University Press; 2019. p. 104–8. 11 Prapas N, Prapas Y, Panagiotidis Y, Prapa S, Vanderzwalmen P, Makedos G. Cervical dilatation has a positive impact on the outcome of IVF in randomly assigned cases having two previous difficult embryo transfers. Hum Reprod. 2004;19:1791–5. 12 Visser DS, Fourie F, Kruger HF. Multiple attempts at embryo transfer: effect on pregnancy outcome in an in vitro; fertilization and embryo transfer program. J Assist Reprod Genet. 1993;10:37–43. 13 Mains L, Van Voorhis BJ. Optimizing the technique of embryo transfer. Fertil Steril. 2010;94(3):785–90. 14 Serhal P, Ranieri DM, Khadum I, Wakim RA. Cervical dilatation with hygroscopic rods prior to ovarian stimulation facilitates embryo transfer. Hum Reprod. 2003;18(12):2618–20.

15 Kato O, Takatsuka R, Asch RH. Transvaginal‐transmyometrial embryo transfer: the Towako method; experience of 104 cases. Fertil Steril. 1993;59:51–3. 16 Kato O. Four years’ experience of transmyometrial embryo transfer. IXth World Congress on In vitro Fertilisation and Alternate Assisted Reproduction, Vienna. J Assist Reprod Genet. 1995;12 (Supple:11S). 17 Sharif K, Afnan M, Lenton W, Bilalis D, Hunjan M, Khalaf Y. Transmyometrial embryo transfer after difficult immediate mock transcervical transfer. Fertil Steril. 1996;65(5):1071–4. 18 Sharif K, Kato O. Technique of transmyometrial embryo transfer. Middle East Fertil Soc J. 1998;3(2):124–9. 19 Jamal W, Phillips SJ, Hemmings R, Lapensée L, Couturier B, Bissonnette F, et al. Successful pregnancy following novel IVF protocol and transmyometrial embryo transfer after radical vaginal trachelectomy. Reprod Biomed Online. 2009;18(5):700–3. 20 Wong I, Justin W, Gangooly S, Sabatini L, Al‐Shawaf T, Davis C, et al. Assisted conception following radical trachelectomy. Hum Reprod. 2008 Dec 18;24(4):876–9. 21 Yang YS, Melinda S, Ho HN, Hwang JL, Chen SU, Lin HR, et al. Effect of the number and depth of embryos transferred and unilateral or bilateral transfer in tubal embryo transfer (TET). J Assist Reprod Genet. 1992;9:534–8. 22 Maxwell SM, Melzer‐Ross K, McCulloh DH, Grifo JA. A comparison of pregnancy outcomes between day 3 and day 5/6 embryo transfers: does day of embryo transfer really make a difference? J Assist Reprod Genet. 2015;32:249–54.

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23 Vaccination and ART Arri Coomarasamy and Rima Dhillon-Smith University of Birmingham and Birmingham Women’s Hospital, Birmingham, UK

Case History 1: A woman who had a blastocyst transfer a week previously finds herself in a situation of needing to travel to Pakistan to be with her ill grandmother. The area she is traveling to is known to be endemic for malaria infection. Case History 2: A woman who is 7  weeks pregnant following an IVF cycle is advised by her primary care physician to have H1N1 (swine flu) vaccination. She is unsure if this is a reasonable course of action to take.

Background A pregnant, or potentially pregnant (Case History 1) woman may need vaccinations, malaria prophylaxis or antidiarrheal treatment if she is embarking on international travel. No vaccine can be regarded as entirely safe in pregnancy, nor would any vaccine provide complete protection against a target condition [1]. Thus, the safest option for a pregnant woman is to avoid areas of endemic infections. If traveling cannot be avoided, then a careful risk‐benefit assessment should be made for vaccines that she may need. Active or passive immunity can be employed to fend off infections. Active immunity refers to protection acquired from natural disease or by vaccination. Passive immunity is achieved from immunoglobulin injections (e.g. injections of preparations made from plasma of immune individuals who contain adequate levels of antibodies

against the target condition). The effects of passive immunity are immediate, but may last only for a few weeks, although passive immunization can be repeated [2]. Vaccines can be: 1) Live attenuated viruses (e.g. measles, mumps and rubella) or bacteria (e.g. Bacillus Calmette–Guérin [BCG]). Live vaccines generally provide long‐lasting protection with a single dose. 2) Killed or inactivated microbes (e.g. influenza vaccine). Inactivated vaccines may require multiple doses and periodic boosters to provide continued immunity. 3) Detoxified exotoxins (e.g. tetanus toxoid). 4) Particles produced from recombinant DNA technology (e.g. hepatitis B vaccine). Live attenuated vaccines should not be administered to pregnant women, because of the risk of fetal infection, unless the benefits of vaccination outweigh the risks (as may be the

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

Management options 

case with yellow fever for example)  [2]. In determining the benefits and risks of vaccines, it should be remembered that most target diseases will be more harmful to a pregnancy than the vaccines. Nonlive vaccines and immunoglobulins can generally be used in pregnancy without much concern, but, as with any drug, there should be a clear indication for their use.

Management options Vaccinations If the woman in Case History 1 cannot avoid traveling to Pakistan, her travel vaccination requirements for that destination can be checked at the National Travel Health Network and Centre (NaTHNaC; www.nathnac.org). The NaTHNaC is funded by the Health Protection

Agency in the UK, and provides country‐specific comprehensive travel health information for health professionals and the public. Another source of information is the guidance from the Centers for Disease Control and Prevention (CDC), which can be accessed at www.cdc.gov/ vaccines/pubs/pregguide.htm. NaTHNaC identifies the following diseases to be a risk in all or part of Pakistan: cholera, diphtheria, hepatitis A, hepatitis B, Japanese encephalitis, polio, rabies, tetanus, tuberculosis and typhoid. There is no absolute contraindication to any of the above vaccines, except for the BCG vaccine for tuberculosis. It is likely that she would have been immunized to tuberculosis in childhood. The vaccination history of the woman in Case History 1 should be checked; necessary vaccines can then be administered before she travels. Advice on commonly used vaccinations are given in Table 23.1.

Table 23.1  Vaccines and pregnancy. Condition

Method of immunity

Comments

Cholera

Inactivated; can be used in pregnant women. Immunization should be completed at least 1 week before travel.

Strict food, water and personal hygiene needed. Vaccination indicated only if the woman is traveling to a known endemic or epidemic area for cholera.

Diphtheria

A toxoid; considered safe in pregnancy.

It should be recommended to women who have not had the immunization or a booster in the preceding 10 years.

Hepatitis A

Hepatitis A vaccine given as three doses Although hepatitis A vaccine is inactivated, its use is not preferred over 6 months confers 10‐year protection. in pregnancy due to the febrile response it causes in many women. Passive immunization with human normal immunoglobulin is preferred in pregnancy.

Passive immunization with immunoglobulins offers 4 months’ protection.

Hepatitis B

If a pregnant woman is negative by Hepatitis B vaccine is inactivated serology, vaccination is recommended. hepatitis B surface antigen manufactured through recombinant DNA technology.

Influenza A (H1N1) (swine flu)

Inactivated vaccine; considered safe A woman traveling to a pandemic area of in pregnancy. swine flu should be recommended to have swine flu vaccine. The preferred vaccine is Pandemrix®. In the USA, all pregnant women are recommended to have both seasonal influenza and H1N1 vaccines. (Continued)

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Table 23.1  (Continued) Condition

Method of immunity

Japanese encephalitis

Inactivated virus, but manufacturer Mosquito bite avoidance measures needed. Indicated for travelers to Asia and suggests avoidance in pregnancy. the Far East. Despite this, pregnant women traveling to high risk areas should be considered for this vaccine.

Measles, mumps and rubella (MMR)

Live attenuated; should be avoided in pregnancy.

Most women would have had MMR vaccination in childhood.

Meningococcal meningitis

No effective vaccine for B serotype (most common in the UK). Vaccine for serotypes A, C, W135 and Y are based on purified bacterial capsule.

Travelers to sub‐Saharan Africa, Asia and Saudi Arabia would benefit from ACWY vaccination.

Poliomyelitis

Live attenuated (oral) vaccine (Sabin) should not be used in pregnancy.

For travelers, injectable polio vaccine is often given in combination with diphtheria and tetanus.

Injectable killed vaccine (Salk) can be used in pregnancy. Vaccine is made of inactivated rabies virus, and can be used for prophylaxis as well as immediate postexposure treatment. An immunoglobulin is also available to provide passive immediate immunity. A toxoid; safe in pregnancy. Live attenuated vaccine; contraindicated in pregnancy. The oral live vaccine is contraindicated in pregnancy. Vi capsular polysaccharide vaccine or heat‐killed monovalent whole cell vaccine may be used in pregnancy. Live attenuated vaccine; contraindicated in pregnancy. Live attenuated vaccine; actual risks to the fetus unknown.

Injectable polio vaccine gives up to 10 years’ protection. Immunization is recommended to pregnant women only if there is a significant risk of exposure and there is no rapid access to medical facility that can provide post‐exposure prophylaxis.

Rabies

Tetanus Tuberculosis Typhoid

Varicella zoster Yellow fever

Malaria prophylaxis Effects of malaria can be devastating in pregnancy; risks include transplacental infection, miscarriage, preterm birth, growth restriction, severe maternal anemia and maternal cerebral

Comments

A booster is recommended every 10 years. Most women in Western countries would have had childhood immunization. Strict food hygiene necessary. Vaccination provides protection for 3 years.

If traveling to a high‐risk area (especially tropical Africa and South America) cannot be avoided, immunization is likely to result in greater benefit compared with the potential risks it would pose. Mosquito bite avoidance measures needed.

malaria. Pregnant women are particularly susceptible to malaria. Malaria is prevalent in Africa, South and Central America, Asia and the Middle East. No prophylactic regimen provides complete protection against malaria, and thus

Management options 

the recommendation to pregnant women is to avoid traveling to countries of high malaria prevalence. However, if traveling cannot be avoided, the following steps need to be taken [2–4]: 1) Wearing long‐sleeved top, full length trousers and socks. 2) Use of a mosquito repellent that is safe in pregnancy. 3) Sleeping inside a mosquito net. 4) Chemoprophylaxis: chloroquine and proguanil can be given during pregnancy. Proguanil users will require folate supplementation. If the woman is traveling to chloroquine‐resistant area, mefloquine can be considered in pregnancy. Doxycycline is contraindicated in pregnancy, and Malarone should be avoided unless no suitable alternative can be found.

H1N1 vaccination and pregnancy Pregnant women with swine flu are at increased risk of developing severe complications  [5–7].

Key points Challenge: Vaccination use in ART and pregnancy. Background: Women who cannot avoid traveling to high risk areas for infection may need vaccinations, malaria prophylaxis and other treatments. ●● Live vaccines are contraindicated in pregnancy. These include BCG, MMR, oral polio vaccine, varicella zoster and oral typhoid vaccine. One exception is yellow fever vaccine which should be given to women who cannot avoid traveling to a high-risk area. ●● Inactivated (killed) vaccines or toxoids are generally safe in pregnancy: cholera, diphtheria, hepatitis B, influenza H1N1, meningococcal meningitis, injectable polio vaccine, rabies and tetanus. ●● Immunoglobulins are generally safe in pregnancy (e.g. hepatitis A immunoglobulin). ●●

The H1N1 vaccine provides significant protection for the pregnant woman against catching swine flu. Furthermore, if the mother is immunized, the antibodies that she develops will also provide passive immunity to the neonate. Various agencies, including the Chief Medical Officer (England), the Royal College of Obstetricians and Gynaecologists (UK), the American College of Obstetricians and Gynecologists, the European Medicines Agency (EMEA), the Joint Committee on Vaccines and Immunisation (JCVI) and the World Health Organization (WHO) recommend H1N1 vaccination in pregnancy. Ongoing surveillance attests to the high level of safety of H1N1 vaccination [8]. The woman in Case History 2 should therefore be advised that her primary care physician’s advice is in keeping with national and international recommendations. If the woman has any comorbidities (e.g. diabetes, asthma or obesity) then it is particularly important that she is vaccinated against H1N1 and seasonal influenza virus strains.

Management options: ●● Vaccination and malaria prophylaxis needs depend on the country and often the area the pregnant woman is traveling to. Countryspecific recommendations on vaccination can be ­obtained from the National Travel Heath Network and Centre (www.nathnac. org). ●● If malaria prophylaxis is needed, recommend: ○○ Long-sleeved top, full-length trousers and socks. ○○ Mosquito repellent that is safe in pregnancy. ○○ Sleeping inside a mosquito net. ○○ Chemoprophylaxis: chloroquine and proguanil. In chloroquine-resistant areas, mefloquine. ●● H1N1 swine flu vaccine is recommended to all pregnant women, but particularly to those with comorbidities such as diabetes, asthma and obesity.

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Answers to questions patients ask Q1 Can I travel abroad after IVF treatment while waiting for my pregnancy test? A1. You will need to obtain the latest guidance for vaccination and malaria prophylaxis, which will depend on the country you plan to travel to. Country‐specific recommendations on vaccination can be obtained from the National Travel Heath Network and Centre (www. nathnac.org). Where possible, you should avoid countries where there is high risk of infectious diseases and in particular Zika virus. Information about Zika virus can be found the on the World Health Organization (WHO) website. Q2 Will a vaccination harm my baby? A2. This depends on the type of vaccination. The commonly recommended vaccines in pregnancy, for

seasonal influenza and Influenza A (swine flu), are safe in pregnancy and should be given, especially if you have other risk factors. Your doctor will know which vaccines are safe and those which are to be avoided in pregnancy. Q3 Does the Covid-19 vaccine affect fertility? A3. There is no evidence that any of the existing COVID-19 vaccines affect the fertility of women or men. There is also no evidence that the vaccine increases the risk of miscarriage. According to the British Fertility Society, it is safe to have fertility treatment immediately after taking the Covid-19 ­vaccine. It is also safe to have the vaccine during your fertility treatment.

References 1 Centers for Disease Control and Prevention. Guidelines for vaccinating pregnant women. http://www.cdc.gov/vaccines/pubs/preg‐ guide.htm. Published 2010. 2 British National Formulary. London: BMJ Publishing Group;2010. 3 UK malaria treatment guidelines. J Infect. 2007;54(2):111–21. 4 Sevene E, Gonzalez R, Menendez C. Current knowledge and challenges of antimalarial drugs for treatment and prevention in pregnancy. Expert Opin Pharmacother. 2010;11(8):1277–93. 5 ANZIC Influenza Investigators and Australasian Maternity Outcomes Surveillance System. Critical illness due to 2009 A/H1N1 influenza in pregnant and

postpartum women: population based cohort study. BMJ. 2010;340:c1279. 6 Hewagama S, Walker SP, Stuart RL, Gordon C, Johnson PD, Friedman ND, et al. H1N1 influenza A and pregnancy outcomes in Victoria, Australia. Clin Infect Dis. 2009;50(5):686–90. 7 Siston AM, Rasmussen SA, Honein MA, Fry AM, Seib K, Callaghan WM, et al. Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States. JAMA. 2010;303(15):1517–25. 8 Tamma PD, Ault KA, del Rio C, Steinhoff MC, Halsey NA, Omer SB. Safety of influenza vaccination during pregnancy. Am J Obstet Gynecol. 2009;201(6):547–52.

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24 The patient with hydrosalpinx Annika Strandell Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

Case History: A couple, both 32 years of age, presented with 2 years of infertility. The diagnostic workup found normal hormone analyses but an elevated titer of chlamydial antibodies. A transvaginal ultrasound scan showed a cystic elongated structure measuring 4  ×  5 cm, adjacent to the right ovary, and a diagnosis of hydrosalpinx was made. A discussion on how best to proceed was initiated.

Background Hydrosalpinx describes a spectrum of pathol­ ogy of distal tubal occlusion. A strict definition is a collection of watery fluid in the fallopian tube, occurring as the end‐stage of tubal infec­ tion. Chlamydia trachomatis is the most com­ mon pathogen to cause tubal infection. Numerous studies have reported on the poor outcome in IVF in patients with hydrosal­ pinx  [1]. Live birth, pregnancy and implanta­ tion rates are reduced by half and miscarriage rate is doubled in patients with hydrosalpinx, compared with patients with other types of tubal infertility. Different theoretical mecha­ nisms have been proposed but it is not com­ pletely understood how hydrosalpinx exerts its negative effects [2]. The presence of fluid seems to be an important factor, because patients with visible fluid on ultrasound form a subgroup with particularly poor outcome. Thus, the ­initial

theories focused on the hydrosalpinx fluid, its potentially embryotoxic components and growth inhibiting factors. Another theory is the possibility of wash‐out of embryos through leakage of fluid through the endometrial cavity. The hydrosalpinx fluid may also cause endome­ trial alterations, making the endometrium hos­ tile to embryo implantation and development.

Management options Despite the lack of precise knowledge of the mechanism, several treatments with the aim of eliminating the hydrosalpingeal fluid before commencing IVF have been suggested.

Salpingectomy Laparoscopic salpingectomy has shown its effi­ cacy in a large randomized trial, in which

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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The patient with hydrosalpinx

patients with ultrasound‐visible ­hydrosalpinges undergoing salpingectomy doubled their live birth rate compared with those who did not have any surgery before IVF [3]. The pooling of results from randomized trials have shown a doubling of the clinical and ongoing preg­ nancy rate after salpingectomy compared with no surgical intervention among all hydrosal­ pinx patients  [4,5]. However, the recommen­ dation of salpingectomy is particularly for those with ultrasound‐visible hydrosalpinges. Noteworthy is the positive effect on natural pregnancy after unilateral salpingectomy when the contralateral tube is healthy, as described by a few case series. Salpingectomy carries a potential risk of damaging the vascu­ lar and nervous supply to the ovary. Numerous studies have explored the ovarian response to controlled ovarian stimulation after salpingec­ tomy. A systematic review including 48 publi­ cations concluded that salpingectomy did not appear to significantly affect ovarian stimula­ tion response  [6]. However, the impact on ovarian reserve was dependent on the indica­ tion for salpingectomy, with salpingectomy for ectopic pregnancy demonstrating a slight impairment. If surgical skill to reconstruct the tube is available, the tubal mucosa can be eval­ uated. A salpingotomy can be considered if the mucosa is healthy and the patient is young enough to await natural pregnancy [7].

Tubal occlusion Tubal occlusion is an option when severe adhesions make salpingectomy technically dif­ ficult or if there is a risk of damaging the ovary. A Cochrane review included two small randomized trials of laparoscopic tubal occlusion and their pooled result showed a benefit in clinical pregnancy rate compared with no intervention  [4], although based on low quality evidence. The dilated tube can be left in place after occlusion of the proximal part. Sclerotherapy of the remaining dilated tube has been suggested, but not tested in ran­ domized trials.

Tubal occlusion through the hysteroscopic route may be a solution for patients in whom laparoscopy is risky or contraindicated  [8]. However, the only randomized trial utilizing the Essure device has demonstrated inferior pregnancy outcomes compared with salpin­ gectomy  [9]. Other micro inserts have been developed and diathermy through the hystero­ scopic route has also been tested, but none of the methods has not yet been evaluated in a randomized trial. It may be very difficult for a patient to give her consent to salpingectomy or tubal occlusion, because a bilateral procedure will definitely ren­ der her sterile with a possible psychological bur­ den. Nevertheless, if she agrees to the surgical interventions, her chances of pregnancy with IVF will increase considerably.

Transvaginal aspiration To increase the chance of pregnancy without undergoing any sterilizing surgery, one potential option is to perform a transvaginal aspiration of the hydrosalpingeal fluid at the time of oocyte retrieval. A meta‐analysis of three randomized trial has demonstrated an increased clinical pregnancy rates compared with no intervention  [4]. However, one trial comparing aspiration with salpingectomy suggested that aspiration may be inferior [10]. One major drawback was the recurrence of fluid, affecting the pregnancy rate negatively. Transvaginal aspiration may be considered in cases where fluid develops during stimulation and the hydrosalpinx becomes visible on the ultrasound scan. The alternative option in this situation is to freeze the embryos, cancel the fresh transfer and perform salpingectomy or tubal occlusion before a freeze‐thaw transfer. To summarize the management options, an updated Cochrane review concluded that sur­ gical treatment should be considered for all women with hydrosalpinges prior to IVF treat­ ment  [4]. Also, a network meta‐analysis including direct and indirect comparisons of the various methods recognized the benefit of

Prevention 

Hydrosalpinx visible by ultrasound before start

Laparoscopy

Accessible hydrosalpinx

Extensive adhesions

Evaluate mucosa if reconstructive surgery is indicated

Tubal occlusion

Laparoscopy contraindicated

Patient wishes no surgery

Transvaginal aspiration at Oocyte retrieval + antibiotics

Transvaginal aspiration at Oocyte retrieval + antibiotics

Hydrosalpinx becomes visible during stimulation

Failed cycle Salpingostomy

Discuss surgery before next cycle

Transvaginal aspiration at Oocyte retrieval + antibiotics

Embryo Transfer

Failed cycle

Laparoscopy

Salpingectomy Figure 24.1  Treatment protocol for patients with hydrosalpinx undergoing IVF.

the three suggested surgical procedures  [11]. Laparoscopic salpingectomy is still the best evidence‐based intervention to improve preg­ nancy rates, but tubal occlusion and aspiration of hydrosalpingeal fluid also have their places among therapeutic options, as described in a treatment protocol in Figure 24.1.

Prevention The ideal is the prevention of hydrosalpinx on a population level by preventing sexually trans­ mitted diseases. National programs directed at  young people, including campaigns for ­condom use, complete treatment of sexually transmitted diseases and effective partner noti­ fication may reduce the future incidence of hydrosalpinx. Hydrosalpinx has already become a rare condition in some countries. An accurate infertility workup is important. The patient’s history may reveal previous pelvic inflammatory disease. Chlamydia antibody ­testing can be used to detect a previous

s­ ubclinical infection. The presence of chla­ mydia antibodies is positively correlated to the risk of tubal pathology. A high serum titer may thus strengthen the decision to perform a lapa­ roscopy [12]. Hydrosalpinx is an adnexal pathol­ ogy which can be easily recognized and confidently confirmed using grayscale and Doppler ultrasound  [13]. The most consistent sonographic feature is a tubular structure with a well‐defined echogenic wall and fold configura­ tions protruding into the watery content (Figure 24.2). If a hydrosalpinx is detected or even if a sus­ picion of hydrosalpinx is raised, it is important to discuss prognosis and treatment options with the patient. The patient may not be pre­ pared to undergo salpingectomy or tubal occlu­ sion prior to her first IVF cycle, but the discussion can be renewed after a failed cycle if appropriate. Prior to a laparoscopy it is impor­ tant to discuss potential findings and associ­ ated surgical procedures thoroughly with the patient, in order to avoid a repeat procedure caused by lack of consent prior to surgery.

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The patient with hydrosalpinx

Figure 24.2  Typical appearance of a hydrosalpinx on transvaginal gray-scale ultrasound. (Picture provided by Associate Professor Seth Granberg, Oslo University, Norway).

Key points

●●

Challenge: The patient with hydrosalpinx before IVF.

During ovarian stimulation:

Background: ●● Hydrosalpinx is the end result of a tubal infection with the closure of the fimbriae, resulting in a watery collection inside the tube. ●● Chlamydia trachomatis is a common cause. ●● The presence of a hydrosalpinx during IVF treatment is associated with a poor outcome. Live birth, pregnancy and implantation rates are lower and miscarriage rate is higher than in patients with other types of tubal infertility. Management options:

Prior to starting IVF:

●●

Salpingectomy through laparoscopy

●●

●●

Tubal occlusion through laparoscopy if adnexal adhesions are present Transvaginal aspiration of hydrosalpingeal fluid at the time of oocyte retrieval. Freeze all embryos, abandon fresh cycle, surgery for hydrosalpinx and then freezethaw cycle.

Prevention: ●● Accurate infertility workup to detect a hydrosalpinx. History, chlamydia antibody testing and transvaginal ultrasound are important. ●● Information to the patient about poor prognosis without surgical intervention and a careful discussion of options.

Answers to questions patients ask Q1 Why did I get a hydrosalpinx? A1. A hydrosalpinx is the end result of a tubal infection, often caused by chlamydia. A hydrosalpinx can also develop after inflammation and surgery in the pelvis, e.g. after a severe appendicitis.

Q2 What are my chances of getting pregnant with IVF with a hydrosalpinx still in place? A2. The chances are low but not zero. In a large study, the group of women who did not have any sur­ gery before IVF, approximately

References 

16% had a live birth after their first embryo transfer [3]. Q3 Can I get pregnant without IVF if my tube with hydrosalpinx is removed? A3. Yes. If only one of the tubes is affected, your chance of getting pregnant naturally increases after the diseased tube is removed. Q4 Why was my hydrosalpinx not picked up before I started treatment? A4. Sometimes the tube is not filled with fluid. In that case it is not vis­ ible on ultrasound. Only a hystero­ salpingography or a laparoscopy

would pick up the diagnosis, but these tests are not routinely done as the tests themselves are associ­ ated with risks. During ovarian stimulation for IVF, the fluid may increase and become visible also with ultrasound. Q5 Should I have salpingectomy if my tubes are blocked near the uterus (proximal tubal blockage)? A5. It has not been shown that the chance of pregnancy after IVF would increase, if tubes without hydrosalpinx were removed, so it is not recommended.

References 1 Zeyneloglu HB, Arici A, Olive DL. Adverse effects of hydrosalpinx on pregnancy rates after in vitro fertilization‐embryo transfer. Fertil Steril. 1998;70:492–9. 2 Savaris RF, Giudice LC. The influence of hydrosalpinx on markers of endometrial receptivity. Semin Reprod Med. 2007;25:476–82. 3 Strandell A, Lindhard A, Waldenström U, Thorburn J, Janson PO, Hamberger L. Hydrosalpinx and IVF outcome: a prospective, randomized multicentre trial in Scandinavia on salpingectomy prior to IVF. Hum Reprod. 1999;14:2762–9. 4 Melo P, Georgiou EX, Johnson N, van Voorst S, Sowter MC, Strandell A, Mol BWJ, Becker C, Granne IE. Surgical treatment for tubal disease in women due to undergo in vitro fertilisation. Cochrane Database of Systematic Reviews 2019, Issue 12. Art. No.: CD002125. DOI: 10.1002/14651858.CD002125.pub4. 5 Xu B, Zhang q, Zhao J, Wáng, Xu D, Li Y. Pregnancy outcome of in vitro; fertilization after Essure and laparoscopic management of hydrosalpinx: a systematic review and meta‐analysis. Fertil Steril. 2017;108:84–95.

6 Kotlyar A, Gingold J, Shue S, Falcone T. The effect of salpingectomy on ovarian function. J Minim Invas Gynecol. 2017;24:563–78. 7 Yu X, Cai H, Zheng X, Feng J, Guan J. Tubal restorative surgery for hydrosalpinges in women due to in vitro fertilization. Arch Gynecol Obstet. 2018;297:1169–73. 8 Mijatovic V, Veersema S, Emanuel MH, Schats R, Hompes PGA. Essure hysteroscopic tubal occlusion device for the treatment of hydrosalpinx prior to in vitro fertilization‐embryo transfer in patients with a contraindication for laparoscopy. Fertil Steril. 2010;93:1338–42. 9 Dreyer K, Lier MC, Emanuel MH, Twisk LW, Mol BW, Schats R, Hompes PG, Mijatovic V. Hysteroscopic proximal tubal occlusion versus laparoscopic salpingectomy as a treatment for hydrosalpinges prior to IVF or ICSI: an RCT. Hum Reprod. 2016;31:2005–16. 10 Fouda UM, Sayed AM, Abdelmoty HI, Elsetohy KA. Ultrasound guided aspiration of hydrosalpinx fluid versus salpingectomy in the management of patients with ultrasound visible hydrosalpinx undergoing IVF‐ET: a randomized controlled trial. BMC

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Women’s Health [Internet]. 2015;15(1):21. Available from: https://doi.org/10.1186/ s12905‐015‐0177‐2 11 Tsiami A, Chaimani A, Mavridis D, Siskou M, Assimakopoulos E, Sotiriadis A. Surgical management for hydrosalpinx prior to in‐ vitro fertilization embryo transfer: a network meta‐analysis. Ultrasound Obstet Gynecol. 2016;48:434–45.

12 Land JA, Evers JL, Goossens VJ. How to use Chlamydia antibody testing in subfertility patients. Hum Reprod. 1999;14:268–70. 13 Sokalska A, Timmerman D, Testa AC, Van Holsbeke C, Lissoni AA, Leone FP, et al. Diagnostic accuracy of transvaginal ultrasound examination for assigning a specific diagnosis to adnexal masses. Ultrasound Obstet Gynecol. 2009;34:462–70.

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25 The patient with hydrosalpinx and contraindication to laparoscopy Basim Abu-Rafea Division of Reproductive Endocrinology and Infertility, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada

Case History: A 35-year-old woman has a 3-year history of primary infertility. Her past medical history is significant for Crohn’s disease, obesity and hypothyroidism. Her past surgical history includes a subtotal colectomy with a J-pouch and three midline laparotomies for bowel related complications and extensive peritoneal adhesions. Her investigations revealed bilateral tubal occlusion and a right hydrosalpinx measuring 10.6 x 3.8 x 1.6 cm. She requires IVF.

Background Tubal factor infertility is one of the major indications for IVF  [1,2]. Up to 30% of infertile  patients with tubal factor infertility undergoing IVF have hydrosalpinges diagnosed by hysterosalpingography (HSG) or laparoscopy [3,4,5]. The presence of a hydrosalpinx during an IVF cycle is associated with a significant reduction in pregnancy and implantation rates [1,6,7]. The proposed pathophysiology in the context of a hydrosalpinx is attributed to tubal‐uterine reflux of the hydrosalpinx fluid, possibly causing embryo toxicity and altered endometrial receptivity, among other proposed mechanisms [8]. As such, studies have focused on interventions to disrupt continuity between the uterine cavity and the affected fallopian tube such as to eliminate the negative effects of the hydrosalpinx fluid on IVF outcomes (see Chapter 24).

Several studies have demonstrated that laparoscopic salpingectomy or tubal occlusion prior to IVF significantly improves implantation, ongoing pregnancy and live birth rates  [9,10]. However, it is not uncommon to encounter IVF patients with hydrosalpinges and contraindications to laparoscopy for various reasons such as extensive pelvic‐abdominal adhesions, multiple prior laparotomies or morbid obesity. This is definitely a challenging situation and requires considerations of less invasive treatment options.

Management options Hysteroscopic options Hysteroscopic tubal occlusion using Essure microinsert

This device was approved for use in the USA for female sterilization as it induced fallopian tube  fibrosis and eventually blockage (see

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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Chapter 31). In 2005, the first IVF live birth following Essure microinsert placement was reported in an obese woman with hydrosalpinx and extensive pelvic adhesions [11]. It is important to note that the use of Essure microinsert as a pretreatment for IVF in the context of hydrosalpinx is off label. A randomized clinical trial comparing hysteroscopic proximal tubal occlusion using Essure with laparoscopic salpingectomy as a treatment of hydrosalpinges prior to IVF concluded that hysteroscopic proximal tubal occlusion with the Essure microinsert is inferior to laparoscopic salpingectomy with respect to ongoing pregnancy rates [12]. A systematic review and meta‐analysis comparing pregnancy outcome of IVF after Essure and laparoscopic management of hydrosalpinx concluded that the hysteroscopic approach produced inferior pregnancy outcomes compared with those following the laparoscopic approach  [13]. It is important to note that in 2018, the distributors of the Essure device withdrew the product voluntarily from North America and several European countries, and as such it is currently unavailable for clinical use [14]. Hysteroscopic tubal electrocoagulation

This approach was first investigated in the past as a method of sterilization. However, the success rate for bilateral tubal occlusion was reported at approximately 87% [15,16]. In 2008, a pilot study was reported on the use of hysteroscopic electrocoagulation of the tubal ostia for potential tubal occlusion in 10 patients with hydrosalpinx prior to IVF [17]. Four cases underwent electrocoagulation of the tubal ostia using a roller ball electrode while six patients underwent electrocoagulation using a needle electrode placed within the tubal ostium. In the rollerball group, the average power was set at 40–55W, activated for 3 to 4 seconds, while in the needle electrode group the power was set at 40–50W, activated for 4 to 6 seconds. HSG, performed eight weeks postoperatively, indicated tubal occlusion in 17% versus 90%, respectively. This was in

contrast to a 2015 retrospective review of 10 patients who could not undergo laparoscopic tubal occlusion due to severe pelvic adhesions and as such underwent hysteroscopic tubal ostia electrocoagulation using a 3 mm rollerball with power setting of 40 to 60W for 5 to 10 seconds [18]. Postoperative HSG demonstrated complete tubal occlusion of the affected tube in all cases and following IVF treatment, the clinical pregnancy rate was 50% [18]. One prospective study compared hysteroscopic tubal electrocoagulation to laparoscopic tubal ligation in patients with hydrosalpinges undergoing IVF  [19]. In this study, 63 patients underwent laparoscopic tubal occlusion and were compared to 22 patients who underwent hysteroscopic tubal electrocoagulation due to contraindications to laparoscopy. The authors reported a tubal occlusion rate of 93% versus 96%, respectively and concluded that hysteroscopic tubal electrocoagulation was a successful treatment for hydrosalpinges before IVF when laparoscopy is contraindicated. Unfortunately, there was no mention of IVF or pregnancy outcomes in the two groups. Therefore, due to absence of robust evidence, the hysteroscopic electrocoagulation technique should only be considered when a laparoscopic approach is not suitable.

Ultrasound guided tubal occlusion Ultrasound guided aspiration of the hydrosalpinx

A study reported on 32 women who had their hydrosalpinges aspirated a month before beginning an IVF stimulation cycle compared with 32  women who did not have an aspiration of the hydrosalpinx  [20]. Aspiration of the hydrosalpinx led to a greater ovarian response and an improved pregnancy rate. Two retrospective studies on ultrasound guided aspiration of a hydrosalpinx during oocyte retrieval showed conflicting results  [21,22]. Two randomized clinical trials evaluated outcomes of IVF in patients who had hydrosalpinx ­aspiration compared with those who did not

Management options 

have hydrosalpinx aspiration. The first study showed a higher clinical pregnancy rate with aspiration, but without statistical significance; however, the study was terminated before achieving the required sample size due to recruitment issues and as such was underpowered  [23]. The second study demonstrated higher clinical pregnancy rate in the aspiration group [24]. A randomized comparison of 160 patients having ultrasound guided aspiration of hydrosalpinx versus salpingectomy in patients undergoing IVF failed to detect significant differences in implantation and pregnancy rates among the groups [25]. The authors attributed this to the small sample size. A 2019  meta‐ analysis comparing ultrasound guided aspiration of the hydrosalpinx with laparoscopic salpingectomy demonstrated similar numbers of retrieved oocytes and total dose of FSH utilized; however, the clinical pregnancy rate and live birth rate were significantly higher in the salpingectomy group [26].

Ultrasound guided aspiration followed by sclerotherapy This treatment was advocated to reduce the entry of hydrosalpinx fluid into the uterine cavity prior to IVF. The purpose of the procedure is to decrease the recurrence of the hydrosalpinx following its aspiration and as such increase pregnancy rates in IVF cycles. The procedure involves aspiration of the hydrosalpinx followed by injection of 98% ethanol in a volume that is approximately half the volume of the aspirated fluid; the ethanol is left in the tube for 5–10 minutes and then reaspirated. Antibiotics are ­recommended prior to and following the procedure. It is also recommended to use a separate aspiration needle for each tube. Follow‐up is usually done two weeks post procedure to assess whether the hydrosalpinx has recurred. The procedure is considered successful if there is less than 10% of the original volume visible on ultrasonography [27,28]. The recurrence rate of the hydrosalpinx is approximately 30% [28,29].

Potential complications of ultrasound‐guided sclerotherapy include ethanol leakage into the abdominal cavity, abdominal pain, pelvic adhesions and infection [29,30]. A systematic review evaluated 10 studies and reported similar clinical pregnancy rates between the sclerotherapy and the salpingectomy groups and concluded that this method can be used as an alternative to salpingectomy [31].

Embolization of the hydrosalpinx Using a radiologically guided transcervical catheter, tubal occlusion with embolization of the proximal part of the hydrosalpinx was recently compared to laparoscopic salpingectomy prior to IVF in patients with hydrosalpinx [32]. The investigators compared 42 cases that underwent radiologically guided tubal occlusion with 113 cases that underwent laparoscopic salpingectomy. They found no difference in implantation or clinical pregnancy rate among the groups and concluded that this procedure may represent an alternative to salpingectomy for patients with a hydrosalpinx prior to IVF.

Key points Challenge: IVF patient with hydrosalpinx and contraindication to laparoscopy. Background: The presence of a hydrosalpinx during an IVF cycle is associated with a significant reduction in pregnancy and implantation rates. ●● Laparoscopic salpingectomy or tubal occlusion prior to IVF significantly improves implantation, ongoing pregnancy and live birth rates. ●● It is not uncommon to encounter IVF ­patients with hydrosalpinges and contraindications to laparoscopy. ●●

Management options: ●● Hysteroscopic options: ⚪⚪ Hysteroscopic tubal occlusion using Essure microinsert. ⚪⚪ Hysteroscopic tubal electrocoagulation.

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●●

Ultrasound-guided option: Ultrasound-guided aspiration of the hydrosalpinx. ⚪⚪ Ultrasound-guided aspiration followed by sclerotherapy. Embolization of the hydrosalpinx. ⚪⚪

●●

●●

The evidence for all these methods is ­limited, and therefore they should be ­considered only if the “gold standard” of laparoscopic removal/ proximal occlusion of the hydrosalpinx is not safely possible.

Answers to questions patients ask Q1 Can the fluid collected in my fallopian tube affect my IVF success rate? A1. A hydrosalpinx can cause up to a 50% reduction in pregnancy rates after IVF, and if you get pregnant with it, it can double the chances of having a miscarriage. Q2 What are my options to improve my IVF success rate knowing that I am not suitable to have laparoscopic surgery to remove my affected tube? A2.  There are several options available, such as closing the opening of the tube using a hysteroscope

inserted through the cervix or aspirating the fluid from the tube under ultrasound guidance. These methods would not usually be our first choice because they are not as good as laparoscopic surgery in improving your chances. But in your case, balancing the benefits and risks, we would use them.

References 1 Camus E, Poncelet C, Goffinet F, Wainer B, Merlet F, Nisand I, et al. Pregnancy rates after in‐vitro fertilization in cases of tubal infertility with and without hydrosalpinx: a meta‐ analysis of published comparative studies. Hum Reprod. 1999;14(5):1243–9. 2 Honoré GM, Holden AE, Schenken RS. Pathophysiology and management of proximal tubal blockage. Fertil Steril. 1999;71(5): 785–795. doi:10.1016/s0015‐0282(99)00014‐x 3 Strandell A, Waldenström U, Nilsson L, Hamberger L. Hydrosalpinx reduces in‐vitro fertilization/embryo transfer pregnancy rates. Hum Reprod. 1994;9(5):861–863. doi:10.1093/ oxfordjournals.humrep.a138606

4 Blazar AS, Hogan JW, Seifer DB, Frishman GN, Wheeler CA, Haning RV. The impact of hydrosalpinx on successful pregnancy in tubal factor infertility treated by in vitro; fertilization. Fertil Steril. 1997;67(3):517–520. doi:10.1016/s0015‐0282(97)80079‐9 5 Ajonuma LC, Ng EH, Chan HC. New insights into the mechanisms underlying hydrosalpinx fluid formation and its adverse effect on IVF outcome. Hum Reprod Update. 2002;8(3): 255–264. doi:10.1093/humupd/8.3.255 6 Strandell A, Lindhard A, Waldenström U, Thorburn J. Hydrosalpinx and IVF outcome: cumulative results after salpingectomy in a randomized controlled trial. Hum Reprod.

References 

2001;16(11):2403–2410. doi:10.1093/ humrep/16.11.2403 7 Zeyneloglu HB, Arici A, Olive DL. Adverse effects of hydrosalpinx on pregnancy rates after in vitro; fertilization‐embryo transfer. Fertil Steril. 1998;70(3):492–499. doi:10.1016/ s0015‐0282(98)00200‐3 8 Strandell A, Lindhard A. Why does hydrosalpinx reduce fertility? The importance of hydrosalpinx fluid. Hum Reprod. 2002;17(5):1141–1145. doi:10.1093/ humrep/17.5.1141 9 Strandell A, Lindhard A, Waldenström U, Thorburn J, Janson PO, Hamberger L. Hydrosalpinx and IVF outcome: a prospective, randomized multicentre trial in Scandinavia on salpingectomy prior to IVF. Hum Reprod. 1999;14(11):2762–2769. doi:10.1093/humrep/14.11.2762 10 Johnson N, van Voorst S, Sowter MC, Strandell A, Mol BW. Surgical treatment for tubal disease in women due to undergo in vitro; fertilisation. Cochrane Database Syst Rev. 2010;2010(1):CD002125. Published 2010 Jan 20. doi:10.1002/14651858. CD002125.pub3 11 Rosenfield RB, Stones RE, Coates A, Matteri RK, Hesla JS. Proximal occlusion of hydrosalpinx by hysteroscopic placement of microinsert before in vitro; fertilization‐ embryo transfer. Fertil Steril. 2005;83(5): 1547–1550. doi:10.1016/j.fertnstert.2004.10.056 12 Dreyer K, Lier MC, Emanuel MH, et al. Hysteroscopic proximal tubal occlusion versus laparoscopic salpingectomy as a treatment for hydrosalpinges prior to IVF or ICSI: an RCT. Hum Reprod. 2016;31(9): 2005–2016. doi:10.1093/humrep/dew050 13 Xu B, Zhang Q, Zhao J, Wang Y, Xu D, Li Y. Pregnancy outcome of in vitro; fertilization after Essure and laparoscopic management of hydrosalpinx: a systematic review and meta‐analysis. Fertil Steril. 2017;108(1): 84–95.e5. doi:10.1016/j.fertnstert.2017.05.005 14 www.essure.com 15 Quiñones GR, Alvarado AD, Ley EC. Tubal electrocoagulation under hysteroscopic

control (three hundred and fifty cases). Am J Obstet Gynecol. 1975;121(8):1111–1113. doi:10.1016/s0002‐9378(16)33599‐2 16 Richart RM, Neuwirth RS, Israngkun C, Phaosavasdi S. Female sterilization by electrocoagulation of tubal ostia using hysteroscopy. Am J Obstet Gynecol. 1973;117(6):801–804. doi:10.1016/ 0002‐9378(73)90495‐x 17 Abulghar, M., A. Nada, O. Azmy, and O. Shawky, Hysteroscopic tubal electrocoagulation in cases with communicating hydrosalpinx and planning for IVF—a pilot study, The International Medical Journal, 2008. 18 Bao HC, Wang MM, Wang XR, Wang WJ, Hao CF. Clinical application of operative hysteroscopy in treatment of complex hydrosalpinx prior to IVF. Iran J Reprod Med. 2015 May;13(5):311–6. PMID: 26221131; PMCID: PMC4515239. 19 El‐Mazny A, Abou‐Salem N, Hammam M, Saber W. Hysteroscopic tubal electrocoagulation versus laparoscopic tubal ligation for patients with hydrosalpinges undergoing in vitro; fertilization. Int J Gynaecol Obstet. 2015;130(3):250–252. doi:10.1016/j.ijgo.2015.04.039 20 Aboulghar MA, Mansour RT, Serour GI, Sattar MA, Awad MM, Amin Y. Transvaginal ultrasonic needle guided aspiration of pelvic inflammatory cystic masses before ovulation induction for in vitro; fertilization. Fertil Steril. 1990;53(2):311–314. doi:10.1016/ s0015‐0282(16)53287‐7 21 Sowter MC, Akande VA, Williams JA, Hull MG. Is the outcome of in‐vitro fertilization and embryo transfer treatment improved by spontaneous or surgical drainage of a hydrosalpinx?. Hum Reprod. 1997;12(10):2147–2150. doi:10.1093/ humrep/12.10.2147 22 Van Voorhis BJ, Sparks AE, Syrop CH, Stovall DW. Ultrasound‐guided aspiration of hydrosalpinges is associated with improved pregnancy and implantation rates after in‐vitro fertilization cycles. Hum Reprod.

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1998;13(3):736–739. doi:10.1093/ humrep/13.3.736 23 Hammadieh N, Coomarasamy A, Ola B, Papaioannou S, Afnan M, Sharif K. Ultrasound‐guided hydrosalpinx aspiration during oocyte collection improves pregnancy outcome in IVF: a randomized controlled trial. Hum Reprod. 2008;23(5):1113–1117. doi:10.1093/humrep/den071 24 Fouda UM, Sayed AM. Effect of ultrasound‐ guided aspiration of hydrosalpingeal fluid during oocyte retrieval on the outcomes of in vitro fertilisation‐embryo transfer: a randomised controlled trial (NCT01040351). Gynecol Endocrinol. 2011;27(8):562–567. doi: 10.3109/09513590.2010.507290 25 Fouda UM, Sayed AM, Abdelmoty HI, Elsetohy KA. Ultrasound guided aspiration of hydrosalpinx fluid versus salpingectomy in the management of patients with ultrasound visible hydrosalpinx undergoing IVF‐ET: a randomized controlled trial. BMC Womens Health. 2015;15:21. doi:10.1186/ s12905‐015‐0177‐2 26 Volodarsky‐Perel A, Buckett W, Tulandi T. Treatment of hydrosalpinx in relation to IVF outcome: a systematic review and meta‐ analysis. Reprod Biomed Online. 2019;39(3): 413–432. doi:10.1016/j.rbmo.2019.04.012 27 Jiang H, Pei H, Zhang WX, Wang XM. A prospective clinical study of interventional ultrasound sclerotherapy on women with hydrosalpinx before in vitro fertilization and embryo transfer. Fertil Steril.

2010;94(7):2854–2856. doi:10.1016/j. fertnstert.2010.06.065 28 Song XM, Jiang H, Zhang WX, Zhou Y, Ni F, Wang XM. Ultrasound sclerotherapy pretreatment could obtain a similar effect to surgical intervention on improving the outcomes of in vitro fertilization for patients with hydrosalpinx. J Obstet Gynaecol Res. 2017;43(1):122–127. doi:10.1111/jog.13152 29 Na ED, Cha DH, Cho JH, Kim MK. Comparison of IVF‐ET outcomes in patients with hydrosalpinx pretreated with either sclerotherapy or laparoscopic salpingectomy. Clin Exp Reprod Med. 2012;39(4):182–186. doi:10.5653/cerm.2012.39.4.182 30 Shokeir T. Letter to the Editor: Re: Comparison of IVF‐ET outcomes in patients with hydrosalpinx pretreated with either sclerotherapy or laparoscopic salpingectomy. Clin Exp Reprod Med. 2014;41(1):37–38. doi:10.5653/cerm.2014.41.1.37 31 Cohen A, Almog B, Tulandi T. Hydrosalpinx Sclerotherapy Before in vitro Fertilization: Systematic Review and Meta‐analysis. J Minim Invasive Gynecol. 2018;25(4): 600–607. doi:10.1016/j.jmig.2017.12.004 32 Yang X, Zhu L, Le F, et al. Proximal Fallopian Tubal Embolization by Interventional Radiology prior to Embryo Transfer in Infertile Patients with Hydrosalpinx: A Prospective Study of an Off‐label Treatment. J Minim Invasive Gynecol. 2020;27(1):107–115. doi:10.1016/j. jmig.2019.02.026

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26 The patient with reduced ovarian reserve Scott M. Nelson School of Medicine, University of Glasgow, Glasgow, UK

Case History 1: A 30-year-old woman is scheduled to have IVF for unexplained infertility. Her anti-Müllerian hormone level was 2.3 pmol/L. She wants to know what this means for her chances of pregnancy. Case History 2: A 32-year-old patient with tubal infertility had a cycle of IVF using a long gonadotropin releasing hormone (GnRH) agonist protocol and 225 IU/day gonadotropins. After 14 days of stimulation only two follicles were evident, and one oocyte was collected at retrieval. A poor-quality embryo was transferred on day 2 and she did not become pregnant. She wishes a further IVF cycle and is asking whether the stimulation strategy will be altered in the next cycle.

Background

are destined to be removed through atresia at earlier stages of follicular development.

Ovarian reserve The human ovary establishes its complete complement of primordial follicles during fetal life. Recruitment and thereby depletion of this dormant primordial follicle pool leads to reproductive senescence. Primordial follicles are recruited continuously (initial recruitment). In addition, after puberty, at every new cycle a limited number of follicles are recruited from the cohort of small growing follicles (cyclic recruitment). Following this, a final subset of follicles are selected for dominance and ovulation  [1]. Thus, at any specific time, the majority of primordial follicles are held in a dormant state. When eventually recruited most will not reach the preovulatory stage and

Management options Anti-Müllerian hormone as a marker of ovarian reserve Anti‐Müllerian hormone (AMH) is now recognized as the principal mechanism regulating early follicular recruitment from the primordial pool  [2]. AMH null mice demonstrate accelerated depletion of primordial follicle number and an almost threefold increase in smaller growing follicles [3]. Furthermore, this increase in number of growing follicles occurs despite a lower serum follicle stimulating hormone (FSH) level  [4], suggesting that

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

The patient with reduced ovarian reserve

in the absence of AMH, follicles are more sensitive to FSH and progression through the early stages of follicular development. In  adult life, despite AMH not being produced by primordial follicles but rather the later stages of follicular development  [5–7], AMH concentrations correlate with primordial follicle number  [8]. Consequently, across the female adult lifespan, paralleling the decline in the primordial follicle pool [9–13], circulating AMH exhibits a nonlinear decline and becomes undetectable several years in advance of the menopause [14]. A validated AMH normogram has been established based on 9601  infertility patients (Figure 26.1) [15], with similar estimates previously shown in smaller studies of women with proven fertility [16]. This normogram highlights that the woman in Case History 1 has a very low AMH for her age. AMH has been shown to be one of the best predictors of ovarian response to

25

50th

75th

90th

controlled ovarian stimulation  [17], with an almost linear relationship with oocyte yield [18]. Furthermore, AMH can also be a useful predictor of the chance of live birth in assisted conception [18–20]. Consequently, the woman in Case History 1 should be counseled that it is highly likely that she will have a poor response to ovarian stimulation with only two to three oocytes produced  [18]. A low AMH will also alert the clinician to ensure that an optimal stimulation strategy is used in the first cycle [21,22]. Although the chance of a live birth is reduced, withholding treating based solely on an AMH result is fraught with difficulty as the performance of the test in the prediction of live birth is limited. Although alternatives such as oocyte donation may have higher success rates, this may not be acceptable for all patients. Preassessment of AMH allows identification of women at risk of a poor response, thereby allowing patients to

95th

20

15 (pmol/l)

160

25th 10

5

10th 5th

0 25

30

35 (years)

40

45

Figure 26.1  Anti-Müllerian hormone (AMH) nomogram for the DSL AMH assay, based on a quadratic model of log(AMH) on age using DSL assay. The figure shows predicted AMH value vs. age, with reference lines for the 5th, 10th, 25th, 75th, 90th and 95th percentiles of the distribution. Reproduced with permission from Nelson SM et al. (2011) [15].

Management options 

adjust their expectations with respect to oocyte yield and chance of live birth. Other markers of ovarian reserve include basal FSH levels and antral follicle count. Antral follicle count has a similar accuracy to AMH.

Strategies to improve ovarian response Gonadotropin dose, type and timing

In Case History 2, ovarian stimulation resulted in a suboptimal response to exogenous gonadotropins. A poor ovarian response (POR) has variable definitions, although many units have defined it as recruitment of three or fewer ­follicles and serum estradiol levels lower than 300 pg/mL at the time of human chorionic gonadotropin administration. In an attempt to standardize the definition of POR in a simple and reproducible manner, the “Bologna” criteria have been suggested [23]: in order to define the poor response in IVF, at least two of the following three features must be present: (i) advanced maternal age or any other risk factor for POR; (ii) a previous POR; and (iii) an abnormal ovarian reserve test (ORT). Additionally, two episodes of POR after maximal stimulation are sufficient to define a patient as poor responder in the absence of advanced maternal age or abnormal ORT [23]. Numerous strategies have been proposed in order to improve ovarian stimulation in poor responders. However, the lack of adequately designed randomized controlled trials and the inconsistency in inclusion criteria have made it difficult to demonstrate an advantage of a single protocol. A Cochrane analysis of studies in poor responders concluded that there was insufficient evidence to support the routine use of any particular intervention for pituitary down‐regulation, ovarian stimulation or adjuvant therapy in the management of poor responders to IVF [24]. Given the necessity to ensure that the FSH threshold has been met, many clinicians will

increase the daily dose of gonadotropins to at least 300  IU/day. Although it is tempting to increase this further, and many clinicians and patients may consider more to be better, there is no evidence that increasing above 300 IU is any more effective. The lack of effect of massive doses of gonadotropins reflects that all follicles available for recruitment will be selected using 300  IU. However, it may be feasible to accelerate the time to steady state FSH concentrations and thereby the recruitment of the leading follicle cohort by injecting every 12 hours on days 1 and 2. There is some evidence that luteinizing hormone (LH) activity during the early stages of folliculogenesis (i.e. early in the stimulation protocol) may have a beneficial effect on the quality of oocytes and number of embryos available for transfer. Although there have been several very small studies examining commencement of FSH during the luteal phase to try to widen the window of follicular recruitment, the overall effect on IVF outcomes was negligible [25–27]. A 2017 randomized study, which included 394 patients with low ovarian reserve, showed equivalent ongoing pregnancy rates in both mild (GnRH antagonist + daily 150  IU gonadotropins) and conventional (long protocol GnRH agonist + daily 450 IU gonadotropins) stimulation groups, but with much shorter duration and lower cost in the mild group  [28]. This low‐burden treatment approach ought to be considered in poor responders [28].

Gonadotropin releasing hormone agonists and antagonists

Gonadotropin releasing hormone (GnRH) agonists have been the mainstay of controlled ovarian stimulation because of their ability to prevent premature LH surges, inadequate follicular development and improve pregnancy rates. A variety of approaches can be used employing GnRH agonists including luteal

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phase GnRHa, GnRHa flare, minidose GnRHa, microdose GnRHa flare and inevitably further modifications will be proposed. Although none of these have been shown to consistently improve outcomes, the flare approach does have the significant advantage of reducing the amount of gonadotropin required to be injected and consequently cost and patient acceptability may be higher. GnRH antagonists have substantial theoretical benefits for the potential poor responder. These include shorter duration of stimulation, fewer doses of gonadotropins, reduced risk of ovarian cyst formation, lack of menopausal symptoms, reduced patient costs, shorter time between cycles and increased acceptability. However, at present no trials have shown an improvement in overall live birth rate compared with the standard long course agonist or flare protocols [24]. Whether improved patient acceptability will ensure that they will pursue further attempts and thereby have a higher cumulative live birth rate is unclear. Alternative approaches and adjuvant therapy

IVF following a natural cycle has received renewed attention with particular acceptance in women with poor response. Although good pregnancy rate was reported [29], this has not been replicated by others [21]. Although many adjuvant therapies including aspirin, nitric oxide, nitroglycerine, ­sildenafil citrate, heparin and estradiol supplementation have been studied, none has been shown to have consistent effects and consequently are not recommended for routine use [30]. However, there is great interest in the role of growth hormone (GH) and dehydroepiandrosterone (DHEA) supplementation in women with a poor ovarian response. The rationale for adding GH for the improvement of pregnancy rates in poor responders has been based on both animal and human data,

which suggest that GH has an important role in ovarian steroidogenesis and follicular development. In mice lacking GH receptor and GH‐binding protein, follicular development is significantly reduced in response to gonadotropin stimulation. Moreover, GH may increase the intraovarian production of insulin‐like growth factor 1, which is considered to have an important role in ovarian function, stimulating follicular development, estrogen production and oocyte maturation. Meta‐analysis of randomized controlled trials has demonstrated a benefit for the use of the adjuvant GH, with reduction in the duration of ovarian stimulation required prior to oocyte retrieval, with a greater number of oocytes collected and improvements in many of the early clinical parameters with the use of GH. However, no benefit of an increased chance of a live birth with the use of GH for the “poor responding” patient has been determined [31]. Since the initial description of a positive effect in 2,000  [32], several cohort studies of DHEA have demonstrated an improvement in AMH, oocyte quality, embryo quality, live birth rates and a lower miscarriage rate with DHEA at a dose of 25 mg three times a day for several months in advance of the treatment cycle  [33–36]. A similar positive effect has been reported in a small placebo controlled randomized trial  [37]. Consequently, adequately powered randomized controlled trials are urgently required to confirm the reported positive effects of GH and DHEA. In summary, there are several potential strategies to improve ovarian response in women with a history of a poor response. However, none of these have consistently been shown to be of benefit. In due course GH and DHEA may provide an exciting advance, although at present the focus should be on using established markers of ovarian reserve including AMH and AFC to alter couples’ expectations in advance of treatment.

References 

Key points Challenge: reserve.

●●

Patient

with

reduced

ovarian

Background: Oocyte yield is directly related to live birth success rates. ●● Women with a poor response to IVF show a reduced live birth rate. ●●

Management options: ●● Assessment of the ovarian reserve: ⚪⚪ Ultrasound: antral follicle count (AFC). ⚪⚪ AMH: low intracycle and intercycle variability, relatively stable across the menstrual cycle. ⚪⚪ AMH and AFC can be used to predict oocyte yield and individualize patients’ expectations and treatment strategy.

●●

Treatments for a low ovarian reserve: ⚪⚪ Various treatments have been proposed but at present there is no evidence that any single stimulation strategy is more effective than the standard long course agonist protocol with 300 IU gonadotropins. ⚪⚪ Low burden treatments such as mild stimulation with GnRH antagonist may facilitate repeated cycles and an overall higher cumulative live birth rate. The evidence to support the use of adjuvant therapy (such as GH or DHEA) for a low ovarian reserve is scant.

Prevention: ●● Stopping smoking, as smoking accelerates decline in ovarian reserve.

Answers to questions patients ask Q1 I am young (23 years old), but the AMH test for my ovarian reserve is low. Does that mean I will not get pregnant with IVF? A1. No, it doesn’t. The AMH test predicts that the number of eggs you will produce will be less than the average number, but you will still produce eggs and you have a chance of pregnancy.

Q2 I produced only three eggs. Could that be because you just gave me 2 amps (150 IU) daily dose of stimulation? We knew in advance that my AMH was low, so shouldn’t you have given me a much higher dose to produce more eggs? A2. I can see why you think so, but studies have shown that in cases like yours the number of eggs produced and the chances of pregnancy are the same whether you take this dose or a much higher dose.

References 1 McGee EA, Hsueh AJW. Initial and cyclic recruitment of ovarian follicles. Endocr Rev. 2000;21(2):200–14. 2 Durlinger ALL, Gruijters MJG, Kramer P, Karels B, Ingraham HA, Nachtigal MW, et al. Anti‐Müllerian hormone inhibits initiation of primordial follicle growth in the mouse ovary. Endocrinology. 2002;143(3):1076–84.

3 Durlinger ALL, Kramer P, Karels B, de Jong FH, Uilenbroek JT, Grootegoed JA, et al. Control of primordial follicle recruitment by anti‐Müllerian hormone in the mouse ovary. Endocrinology. 1999;140(12):5789–96. 4 Durlinger ALL, Gruijters MJG, Kramer P, Karels B, Kumar TR, Matzuk MM, et al. Anti‐müllerian hormone attenuates the effects

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of FSH on follicle development in the mouse ovary. Endocrinology. 2001;142(11):4891–9. 5 Weenen C, Laven JSE, von Bergh ARM, Cranfield M, Groome NP, Visser JA, et al. Anti‐Müllerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment. Mol Hum Reprod. 2004;10(2):77–83. 6 Bezard J, Vigier B, Tran D, Mauleon P, Josso N. Immunocytochemical study of anti‐ Müllerian hormone in sheep ovarian follicles during fetal and postnatal development. J Reprod Fertil. 1987;80(2):509–16. 7 Baarends WM, Uilenbroek JT, Kramer P, Hoogerbrugge JW, van Leeuwen EC, Themmen AP, et al. Anti‐Müllerian hormone and anti‐Müllerian hormone type II receptor messenger ribonucleic acid expression in rat ovaries during postnatal development, the estrous cycle, and gonadotropin‐induced follicle growth. Endocrinology. 1995;136(11):4951–62. 8 Hansen KR, Hodnett GM, Knowlton N, Craig LB. Correlation of ovarian reserve tests with histologically determined primordial follicle number. Fertil Steril. 2010;95:170–5. 9 Faddy MJ, Gosden RG, Gougeon A, Richardson SJ, Nelson JF. Accelerated disappearance of ovarian follicles in mid‐life: implications for forecasting menopause. Hum Reprod. 1992;7(10):1342–6. 10 Faddy MJ, Gosden RG. Ovary and ovulation: a model conforming the decline in follicle numbers to the age of menopause in women. Hum Reprod. 1996;11(7):1484–6. 11 Faddy MJ. Follicle dynamics during ovarian ageing. Mol Cell Endocrinol. 2000;163(1–2):43–8. 12 Hansen KR, Knowlton NS, Thyer AC, Charleston JS, Soules MR, Klein NA. A new model of reproductive aging: the decline in ovarian non‐growing follicle number from birth to menopause. Hum Reprod. 2008;23(3):699–708. 13 Wallace WH, Kelsey TW. Human ovarian reserve from conception to the menopause. PLoS One. 2010;5(1):e8772.

14 Sowers MR, Eyvazzadeh AD, McConnell D, et al. Anti‐Müllerian hormone and inhibin B in the definition of ovarian aging and the menopause transition. J Clin Endocrinol Metab. 2008;93(9):3478–83. 15 Nelson SM, Messow MC, Wallace AM, Fleming R, McConnachie A. Nomogram for the decline in serum anti‐Müllerian hormone: a population study of 9,601 infertility patients. Fertil Steril. 2011;95(2):736–41.e1–3. 16 La Marca A, Sighinolfi G, Giulini S, Traglia NM, Argento C, Sala C, et al. Normal serum concentrations of anti‐Müllerian hormone in women with regular menstrual cycles. Reprod Biomed Online. 2010;21:463–9. 17 La Marca A, Sighinolfi G, Radi D, Argento C, Baraldi E, Artenisio AC, et al. Anti‐ Müllerian hormone (AMH) as a predictive marker in assisted reproductive technology (ART). Hum Reprod Update. 2010;16:113–30. 18 Nelson SM, Yates RW, Fleming R. Serum anti‐Müllerian hormone and FSH: prediction of live birth and extremes of response in stimulated cycles implications for individualization of therapy. Hum Reprod. 2007;22(9):2414–21. 19 Li HW, Biu Yeung WS, Lan Lau EY, Ho PC, Ng EH. Evaluating the performance of serum anti‐Müllerian hormone concentration in predicting the live birth rate of controlled ovarian stimulation and intrauterine insemination. Fertil Steril. 2010;94:2177–81. 20 Majumder K, Gelbaya TA, Laing I, Nardo LG. The use of anti‐Müllerian hormone and antral follicle count to predict the potential of oocytes and embryos. Eur J Obstet Gynecol Reprod Biol. 2010;150(2):166–70. 21 Nelson SM, Yates RW, Lyall H, Jamieson M, Traynor I, Gaudoin M, et al. Anti‐Müllerian hormone‐based approach to controlled ovarian stimulation for assisted conception. Hum Reprod. 2009;24:867–75. 22 Nelson SM, Fleming R. Low AMH and GnRH antagonist strategies. Fertil Steril. 2009;92(2):e40; author reply e41.

References 

23 Ferraretti AP, La Marca A, Fauser BCJM, Tarlatzis B, Nargund G, Gianaroli L. ESHRE consensus on the definition of “poor response” to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod. 2011;26(7):1616–24. 24 Pandian Z, McTavish AR, Aucott L, Hamilton MP, Bhattacharya S. Interventions for “poor responders” to controlled ovarian hyper stimulation (COH) in in‐vitro fertilisation (IVF). Cochrane Database Syst Rev. 2010;1:CD004379. 25 Kansal Kalra S, Ratcliffe S, Gracia CR, Martino L, Coutifaris C, Barnhart KT. Randomized controlled pilot trial of luteal phase recombinant FSH stimulation in poor responders. Reprod Biomed Online. 2008;17(6):745–50. 26 Rombauts L, Suikkari AM, MacLachlan V, Trounson AO, Healy DL. Recruitment of follicles by recombinant human follicle‐ stimulating hormone commencing in the luteal phase of the ovarian cycle. Fertil Steril. 1998;69(4):665–9. 27 Kucuk T, Sozen E. Luteal start of exogenous FSH in poor responder women. J Assist Reprod Genet. 2007;24(12):635–8. 28 Youssef MA, van Wely M, Al‐Inany H, Madani T, Jahangiri N, Khodabakhshi S, et al. A mild ovarian stimulation strategy in women with poor ovarian reserve undergoing IVF: a multicenter randomized non‐inferiority trial. Hum Reprod. 2017;32:112–8. 29 Schimberni M, Morgia F, Colabianchi J, Giallonardo A, Piscitelli C, Giannini P, et al. Natural‐cycle in vitro fertilization in poor responder patients: a survey of 500 consecutive cycles. Fertil Steril. 2009;92(4):1297–301.

30 Nardo LG, Granne I, Stewart J. Medical adjuncts in IVF: evidence for clinical practice. Hum Fertil (Camb). 2009;12(1):1–13. 31 Hart RJ. Use of growth hormone in the IVF treatment of women with poor ovarian reserve. Front Endocrinol (Lausanne). 2019;10:500. 32 Casson PR, Lindsay MS, Pisarska MD, Carson SA, Buster JE. Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders: a case series. Hum Reprod. 2000;15(10):2129–32. 33 Barad DH, Gleicher N. Increased oocyte production after treatment with dehydroepiandrosterone. Fertil Steril. 2005;84(3):756. 34 Barad D, Gleicher N. Effect of dehydroepiandrosterone on oocyte and embryo yields, embryo grade and cell number in IVF. Hum Reprod. 2006;21(11):2845–9. 35 Barad D, Brill H, Gleicher N. Update on the use of dehydroepiandrosterone supplementation among women with diminished ovarian function. J Assist Reprod Genet. 2007;24(12):629–34. 36 Gleicher N, Weghofer A, Barad DH. Improvement in diminished ovarian reserve after dehydroepiandrosterone supplementation. Reprod Biomed Online. 2010;21(3):360–5. 37 Wiser A, Gonen O, Ghetler Y, Shavit T, Berkovitz A, Shulman A. Addition of dehydroepiandrosterone (DHEA) for poor‐ responder patients before and during IVF treatment improves the pregnancy rate: a randomized prospective study. Hum Reprod. 2010;25(10):2496–500.

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27 The patient with congenital uterine anomalies Rima Dhillon-Smith and Pallavi Latthe Birmingham Women’s Hospital, Birmingham, UK

Case History: A 25-year-old woman was referred for ICSI with primary male factor infertility and a long-standing history of worsening dysmenorrhea and dyspareunia. The pain would start a couple of days before her periods and last for a day or two after completion of her menses. Ultrasound scan of her pelvis showed a mixed content mass, measuring approximately 5 cm, that appeared separate from her left ovary. MRI of pelvis and abdomen demonstrated a right hemi-uterus and a left rudimentary uterine horn with functioning endometrium. Both ovaries and kidneys were normal.

Background Congenital uterine anomalies occur as a result of incomplete development of one or both Müllerian ducts (uterine agenesis, unicornuate uterus), incomplete fusion of the ducts (uterus didelphys, bicornuate uterus) or failure of regression of the midline septum that forms during the unification of the two ducts (septate uterus). The previously used classification by the American Society of Reproductive Medicine (ASRM) has been replaced by the European Society of Human Reproduction and Embryology (ESHRE) and the European Society for Gynaecological Endoscopy (ESGE) joint consensus which has seven categories (U0 to U6), as shown in Figure 27.1 [1]. Class U0 incorporates all cases with normal uterus. Class U1 or dysmorphic uterus incorporates all cases with normal uterine outline but with an abnormal shape of the uterine

cavity excluding septa. Class U2 or septate uterus incorporates all cases with normal fusion and abnormal absorption of the midline septum. Class U3 or bicorporeal uterus incorporates all cases of fusion defects. Class U4 or hemi‐uterus incorporates all cases of unilaterally formed uterus. Class U5 or aplastic uterus incorporates all cases of uterine aplasia. It is a formation defect characterized by the absence of any fully or unilaterally developed uterine cavity. Class U6 is for unclassified cases. Uterine anomalies often remain asymptomatic, unless they lead to amenorrhea or pain resulting from menstrual obstruction. Certain anomalies can be detected at a routine gynecologic examination, or they are more commonly diagnosed during investigations for infertility or recurrent miscarriage, or during assessment for obstetric complications. Their exact ­incidence is therefore unknown and varies according to the studied population.

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

Management options 

Class U0/normal Uterus

Class U1/Dysmorphic Uterus

b. Infantilis

a. T-shaped

Class U2/septate Uterus

c. Others

Class U3/Bicorporeal Uterus > 50%

> 150%

a. Partial

b. Complete

a. With rudimentary cavity

b. Complete

a. Partial

c. Bicorporeal septate

Class U5/Aplastic Uterus

Class U4/Hemi Uterus

b. Without rudimentary cavity

a. With rudimentary cavity

b. Without rudimentary cavity

Class U6/Unclassified cases Figure 27.1  ESHRE/ESGE classification of uterine anomalies: schematic representation (Class U2: internal indentation >50% of the uterine wall thickness and external contour straight or with indentation 50% of the uterine wall thickness, Class U3b: width of the fundal indentation at the midline >150% of the uterine wall thickness). Reproduced from reference 1.

Management options Aplastic uterus Uterine agenesis, also known as Mayer– Rokitansky–Kuster–Hauser syndrome (MRKH) has an incidence of 1  in 5000  women  [2]. Women with MRKH usually have a short blind‐ ending vagina. Current management strategies consist of specialist psychological support and vaginal dilatation therapy in order to allow sexual intercourse. When appropriately counseled and emotionally prepared, almost all patients (90–96%) will be able to achieve functional success by primary vaginal dilation [3–5]. Uterine transplantation (UTx) was first suggested over 50 years ago, and in 2014 the first live birth following UTx was reported, suggesting that UTx may be a feasible fertility‐restoring intervention for women [6]. More than 60 UTx operations have now been performed across the

world, with 18  live births reported  [7]. While still in the early stages, it does appear that UTx is a viable option for women with absent uterus. Teams undertaking UTx are now established worldwide, with the numbers of uterine transplant procedures performed expected to increase exponentially in the future. However, the procedure is associated with significant risks to both live donors and recipients, and there is a considerable risk of graft failure [7]. Aside from UTx, the ability to produce one’s own offspring is still possible through surrogacy, as the ovaries are expected to be normal both in terms of oocytes and hormone production.

Hemi-uterus (formerly unicornuate uterus) A hemi‐uterus often remains asymptomatic, unless there is a rudimentary horn with functional endometrium in the contralateral side,

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as in the Case History presented. The incidence of hemi‐uterus is thought to be approximately 1 in 4,000 women [8]. The presence of a functional cavity in the contralateral part is a clinically important factor for complications, such as hemato‐cavity or ectopic pregnancy in the rudimentary horn, and the ESHRE/ESGE guideline recommends treatment by laparoscopic removal, even if the horn is communicating  [1], as was done for the case discussed above. It is important to counsel the woman about her reduced fertility potential. A hemi‐uterus is associated with a 35% risk of first or second trimester miscarriage and has a 20% risk of preterm labor. Thus, the overall live birth rate is approximately 50% [8]. Cervical incompetence is a common concern and serial assessment of cervical length is recommended during pregnancy. Insertion of a cervical cerclage is sometimes necessary. A hemi‐uterus also has smaller dimensions than a normal uterus and this might affect success rates if the woman was to proceed to IVF [9].

Partial bicorporeal uterus (formerly bicornuate uterus) Women with a partial bicorporal uterus have been found to have a live birth rate of 55% [10]. Fertility impairment is dependent on the degree of separation between the two cavities [11]. In the past, it was suggested that performing a metroplasty in cases of a complete or partial bicorporeal uterus would improve fertility outcomes. However, this is no longer considered to be the case and surgical reconstruction is not recommended. If a metroplasty has been performed a cesarean section delivery is indicated due to high risk of uterine rupture. A single embryo transfer is recommended for women with a partial bicorporeal uterus undergoing IVF treatment. This is to avoid an increased risk of pregnancy loss and preterm birth with a multiple pregnancy, given these risks are already heightened in women with a

partial bicorporeal uterus. Furthermore, the embryo should be transferred into the larger of the two horns under ultrasound guidance.

Complete bicorporeal uterus with double cervix (formerly uterus didelphys) This fusion abnormality is rare and usually asymptomatic. Nevertheless, it may be associated with vaginal anomalies, such as an obstructed hemivagina with ipsilateral renal agenesis (OHVIRA) or a longitudinal vaginal septum. In these cases, the presentation is usually in adolescence or early adulthood due to the pain caused from obstructed menstruation or difficulties during intercourse. Reproductive outcomes are impaired; however, a didelphys uterus appears to have the best prognosis among uterine anomalies, with a with live birth rate of 75% [12]. No surgical intervention is recommended unless there are adverse symptoms.

Septate uterus A septate uterus is considered the most common uterine anomaly and may affect as many as 1% of the female population. It is caused by a failure of resorption of the midline septum and can be partial or complete with defects ranging from small indentations of the uterine cavity at the level of the fundus, to a complete septum reaching or affecting the cervical canal. Distinction of septate uterus from other uterine anomalies is possible through three‐ dimensional ultrasound  [13], which is less costly than magnetic resonance imaging (MRI) and less invasive than the combination of hysteroscopy and laparoscopy. Women with a uterine septum have the worst reproductive performance of all uterine anomalies, with a term live birth rate of 30%  [11], mostly because of the high rate of first and second trimester miscarriages. This is thought to occur as the septum provides a poor implantation milieu for a pregnancy [14]. The results of a multicenter randomized

Answers to questions patients ask  169

controlled trial comparing hysteroscopic septum resection versus expectant management in women with recurrent miscarriage or subfertility are eagerly awaited  [15]. In the meantime, septum resection for improving fertility outcomes should be decided on case‐ by‐case basis, taking into account previous reproductive performance.

Key points Challenge: The patient with congenital uterine anomalies. Background: ●● Uterine anomalies are caused by agenesis or hypoplasia of one or both of Müllerian ducts (MRKH syndrome, hemi-uterus), incomplete fusion between the two Mullerian ducts (complete or partial bicorporeal uterus) or failure of resorption of the joining septum (septate uterus). ●● Anomalies occur in approximately 2–3% of the population, although incidence varies depending on the studied population. ●● Presentation and complications: –– Pain through obstructed menstruation in cases of a rudimentary uterine horn or obstructed hemivagina. –– Increased first and second trimester miscarriage rate.

––

––

Higher risk of preterm delivery and malpresentation. Live birth rate of 50–55%, with the worst prognosis among women with a septate uterus.

Management options: ●● Surgery is indicated in the case of a functioning rudimentary horn. ●● Metroplasty is not recommended for partial or complete bicorporeal uterus. ●● It remains unknown whether hysteroscopic resection of a uterine septum improves fertility and pregnancy outcomes. The results of the TRUST trial will inform practice. ●● For women with severe uncorrectable uterine anomalies or absent uterus, surrogacy should be considered. ●● Uterine transplants are becoming more commonly performed but are associated with significant risks. ●● For a woman with a partial bicorporeal uterus having IVF treatment, the aim should be for single embryo transfer (to reduce the risks of pregnancy loss and preterm births) into the larger of the two horns under ultrasound guidance. ●● Cervical length assessment and serial growth scans are usually recommended during pregnancy in view of the higher risk of preterm birth and fetal growth restriction.

Answers to questions patients ask Q1 Can I still get pregnant? A1. Yes, you are still able to get pregnant, but complications are more common, so there is a need to keep a closer eye on you during pregnancy. Studies have shown that the risk of miscarriage, preterm delivery and lower birthweight are increased with abnormalities of the womb. There is also a higher

chance that your baby will not be lying in the correct position which may mean you need a cesarean section delivery. Q2 How will my pregnancy be managed differently to avoid complications? A2. You may be offered extra scans in your pregnancy. In the earlier part of your pregnancy these may be to

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measure the length of your cervix, and you may be offered a procedure to put a stitch into your cervix to prevent it from opening up. You

may also be offered regular scans to check that the baby is growing well through the pregnancy.

References 1 Grimbizis GF, Gordts S, Di Spiezio Sardo A, Brucker S, De Angelis C, Gergolet M, et al. The ESHRE/ESGE consensus on the classification of female genital tract congenital anomalies. Hum Reprod Oxf Engl. 2013;28(8):2032–44. 2 Aittomäki K, Eroila H, Kajanoja P. A population‐based study of the incidence of Müllerian aplasia in Finland. Fertil Steril. 2001;76(3):624–5. 3 Roberts CP, Haber MJ, Rock JA. Vaginal creation for Müllerian agenesis. Am J Obstet Gynecol. 2001;185(6):1349–52; discussion 1352–1353. 4 Edmonds DK, Rose GL, Lipton MG, Quek J. Mayer‐Rokitansky‐Küster‐Hauser syndrome: a review of 245 consecutive cases managed by a multidisciplinary approach with vaginal dilators. Fertil Steril. 2012;97(3):686–90. 5 Committee on Adolescent Health Care. ACOG Committee Opinion No. 728: Müllerian agenesis: diagnosis, management, and treatment. Obstet Gynecol. 2018;131(1):e35–42. 6 Brännström M, Johannesson L, Bokström H, Kvarnström N, Mölne J, Dahm‐Kähler P, et al. Livebirth after uterus transplantation. Lancet Lond Engl. 2015;385(9968): 607–16. 7 Jones BP, Saso S, Bracewell‐Milnes T, Thum M‐Y, Nicopoullos J, Diaz‐Garcia C, et al. Human uterine transplantation: a review of outcomes from the first 45 cases. BJOG Int J Obstet Gynaecol. 2019;126(11):1310–9.

8 Reichman D, Laufer MR, Robinson BK. Pregnancy outcomes in unicornuate uteri: a review. Fertil Steril. 2009;91(5):1886–94. 9 Chun SS, Chung MJ, Chong GO, Park KS, Lee TH. Relationship between the length of the uterine cavity and clinical pregnancy rates after in vitro fertilization or intracytoplasmic sperm injection. Fertil Steril. 2010;93(2):663–5. 10 Grimbizis GF, Camus M, Tarlatzis BC, Bontis JN, Devroey P. Clinical implications of uterine malformations and hysteroscopic treatment results. Hum Reprod Update. 2001;7(2):161–74. 11 Rackow BW, Arici A. Reproductive performance of women with Müllerian anomalies. Curr Opin Obstet Gynecol. 2007;19(3):229–37. 12 Kachhawa G, Kriplani A. Management of reproductive tract anomalies. J Obstet Gynaecol India. 2017;67(3):162–7. 13 Salim R, Jurkovic D. Assessing congenital uterine anomalies: the role of three‐ dimensional ultrasonography. Best Pract Res Clin Obstet Gynaecol. 2004;18(1):29–36. 14 Homer HA, Li TC, Cooke ID. The septate uterus: a review of management and reproductive outcome. Fertil Steril. 2000;73(1):1–14. 15 Rikken JFW, Kowalik CR, Emanuel MH, Bongers MY, Spinder T, de Kruif JH, et al. The randomised uterine septum transsection trial (TRUST): design and protocol. BMC Womens Health. 2018 05;18(1):163.

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28 The patient with congenital cervico-vaginal anomalies Rima Dhillon-Smith and Pallavi Latthe Birmingham Women’s Hospital, Birmingham, UK

Case History 1: A 30-year-old woman presents with primary infertility and a history of dysmenorrhea and pelvic pain. She underwent surgery for imperforate hymen at the age of 15 years. Case History 2: A 32-year-old woman reported a history of having to use two tampons during menstruation and dysmenorrhea as an adolescent. She underwent corrective surgery aged 14 years and was informed she has only one kidney. She now presents with primary infertility and significant superficial dyspareunia.

Background The paramesonephric (or Müllerian) ducts are paired ducts that run down the lateral sides of the urogenital ridge and terminate at the sinus tubercle in the primitive urogenital sinus of an embryo. In the female, they will develop to form the fallopian tubes, uterus, cervix, and the upper one‐ third of the vagina. The lower third of the vagina is a derivative of the urogenital sinus. Where the two portions of the vagina meet, a solid plate initially forms which then canalizes to form the vaginal lumen [1]. A variety of congenital anomalies can occur. The clinical presentation and the treatment of female genital tract anomalies are directly related to the anatomical status of the defect. In 2013, the European Society of Human Reproduction and Embryology (ESHRE) and

European Society for Gynaecological Endoscopy (ESGE) produced a new classification system for female genital anomalies [2]. A clear definition of all types of anomaly is provided, and the anomalies are categorized in well‐described classes and subclasses [2]. Figure 28.1 shows the overall classification system, including cervico‐ vaginal anomalies. Cervico‐vaginal anomalies can either be isolated or accompanied by other developmental defects of the Müllerian system. As the urinary system develops alongside the genital system, it is also common for the kidneys to be abnormally placed or formed [3]. Patients presenting for assisted ­reproduction techniques (ART) treatment may have ­­cervico‐ vaginal anomalies, either previously ­diagnosed or discovered at the time of presentation.

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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The patient with congenital cervico-vaginal anomalies

Uterine anomaly Sub-class

U0

Main class Normal uterus

U1

Dysmorphic uterus

U2

Septate uterus

U3

Bicorporeal uterus

U4

Hemi-uterus

U5

U6

Aplastic

Cervical/vaginal anomaly Co-existent class

a. T-shaped b. lnfantilis c. Others a. Partial b. Complete a. Partial b. Complete c. Bicorporeal septate a. With rudimentary cavity (communicating or not horn) b. Without rudimentary cavity (horn without cavity/no horn) a. With rudimentary cavity (bi- or unilateral horn) b. Without rudimentary cavity (bi- or unilateral uterine remnants/ aplasia)

C0

Normal cervix

C1

Septate cervix

C2

Double 'normal' cervix

C3

Unilateral cervical aplasia

C4

Cervical aplasia

V0

Normal vagina

V1 V2 V3 V4

Longitudinal non-obstructing vaginal septum Longitudinal obstructing vaginal septum Transverse vaginal septum and/or imperforate hymen Vaginal aplasia

Unclassified malformations

U Figure 28.1 

C

V

ESHRE/ESGE classification of female genital tract anomalies. Reproduced from reference 2.

Management options Imperforate hymen An imperforate hymen is the complete failure of the inferior plate of the vagina to canalize and is prevalent in approximately 1  in 2,000 females. Typically, adolescents present after menarche when menstrual blood trapped in the vagina causes cyclical pain from cryptomenorrhea (hidden menses). After few months, the vagina distends and leads to the formation of hematocolpos. In cases of delayed diagnosis, hematometra and hematosalpinx may also be encountered. Retrograde menstruation may lead to the development of endometriosis or rarely tubo‐ovarian masses. Definitive surgery should take place after appropriate evaluation. Clinical evaluation may be sufficient. Ultrasound or MRI is required only to confirm obstruction at a higher level. Simple vertical, T‐shaped, cruciform, X‐shaped, or Mercedes logo shaped incisions may be used, but an X‐shaped incision

has the advantage of a reduced risk of injury to the urethra. Although an imperforate hymen presents much earlier than the time of presentation to the infertility specialist, its potential consequences (such as endometriosis) could impact fertility.

Vaginal septum Transverse vaginal septum

Transverse vaginal septum has an incidence of around 1 in 80,000 females and causes obstructive symptoms of cryptomenorrhea. It can occur at various levels in the vagina but appears to be more common in the upper part (46%) followed by middle (35%) and lower part (19%) of the vagina [4]. The thickness of the septum varies, usually between 1–5cm. If it is present at a higher level near the cervix, it is more commonly associated with cervical anomalies. The diagnosis of transverse septum is suspected if there is a foreshortened vagina with the inability to visualize cervix, or if a ­hematometra

Management options 

is encountered. An MRI is useful in identifying whether a cervix is present, thereby differentiating a high transverse vaginal septum from cervical agenesis or aplasia. If the septum is thin and positioned in the lower third of the vagina, it is reasonable to attempt reconstruction of the vagina from the perineum. The procedure is similar to treating an imperforate hymen. Resection of a thick septum is technically more difficult and requires the necessary surgical expertise. In such cases, care has to be taken to join the vaginal mucosa on either side of the defect and a combined abdominal‐perineal approach will be necessary. A possible risk of the operation is re‐stenosis at the site of the junction and so postoperative dilatation therapy may be required [5]. In other cases, when the vaginal defect is extensive and the gap to be joined is long, it might be necessary to use a section of bowel to line the area of defect. Long‐term data on fertility prognosis and outcomes are scarce and based on only a few case series and case reports [6,7]. Longitudinal vaginal septum

Longitudinal vaginal septum is often associated with complete uterine septum, uterine didelphys or rarely bicornuate uteri. Presentation of a longitudinal septum is commonly with normal menarche and the need for two tampons, as well as dyspareunia. Vaginal examination with a speculum is usually adequate for visualization of a longitudinal septum, with patent vagina and cervix. A unilateral vaginal and pelvic mass may be felt due to obstructed hemivagina. The most common obstructed lateral fusion defect is a unilateral obstruction and is seen in females with complete duplication of the reproductive tract and ipsilateral renal agenesis (obstructed hemivagina and ipsilateral renal agenesis [OHVIRA]) [8]. A longitudinal vaginal septum is fairly straightforward to correct surgically, although one needs to be aware that the septum becomes thicker proximally, near the cervix or cervices. Vaginal

dilatation, or early recourse to sexual intercourse after surgery, is recommended in order to avoid adhesions and stenosis.

Vaginal agenesis Varying degrees of Müllerian hypoplasia or agenesis affects one in every 5,000  women. Vaginal atresia, distal or segmental vaginal agenesis with normally developed uterus, cervix and upper vagina are managed similarly to transverse vaginal septum.

Cervical agenesis Congenital agenesis of the uterine cervix is a rare Müllerian anomaly, which is associated with both partial or complete vaginal aplasia in 52% of cases and renal anomalies in 17.8%. Treatment methods have included creation of a neovagina and reconstruction of the cervix around various stents; this approach is both challenging and controversial [9,10]. Potential complications after uterovaginal anastomosis are significant and include endometritis, pelvic inflammatory disease, persistent pelvic pain, bowel and bladder injury, reobstruction and stenosis requiring reoperation [11].

Management for case histories Women with history of obstructive anomalies often develop endometriosis because of retrograde menstruation. Although endometriosis is thought to resolve after resolution of the obstruction [12], damage to fallopian tubes can be irreversible. The patient in Case History 1 should be offered early diagnostic laparoscopy and tubal dye test to assess tubal patency and assess for evidence of endometriosis. This will then inform the decision for further surgery or recourse to IVF. In Case History 2 the likely diagnosis is OHVIRA. She is likely to have vaginal stenosis from adhesion formation following her corrective surgery, resulting in superficial dyspareunia,

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potentially affecting the frequency of sexual activity as well as the ability to have full penetrative intercourse. The vaginal adhesions should be excised, and the vagina kept patent using vaginal dilators postsurgery. A decision can then be made whether to proceed with IVF or aim for natural conception. In patients with congenital cervico‐vaginal anomalies, embryo transfer may be a problem, mainly because of cervical stenosis and the lack of easy access to the uterine cavity through the cervical canal. In the more difficult cases, transmyometrial embryo transfer under ultrasound guidance (see Chapter 65) has been successfully reported [13–15].

Nonobstructive lesions present later because of superficial dyspareunia or during routine gynecologic examination. What is the relationship with infertility? –– In obstructive lesions, retrograde menstruation occurs and can lead to endometriosis and tubal damage. –– Cervico-vaginal anomalies are often associated with uterine anomalies, including septum. There can be abnormal uterine size or function contributing to infertility. –– Postoperative stenosis following previous corrective surgery is common and can cause sexual dysfunction and difficult embryo transfer. ––

●●

Management options: Use of ultrasound or MRI to fully assess the gynecological and renal anatomy, especially for preoperative planning. ●● The case should ideally be discussed in a disorder of sex development multidisciplinary team (radiologist, minimal access surgeon, psychologist and others). ●● Use of vaginal dilators to improve access to the cervix and maintain vaginal patency. ●● Earlier recourse to laparoscopy to diagnose tubal disease. ●● IVF treatment may be appropriate and ultrasound-guided transmyometrial embryo transfer may be necessary. ●●

Key points Challenge: The patient with congenital ­cervicovaginal anomalies. Background: ●● Cervico-vaginal anomalies result from defects in resorption of midline septum or canalization of the vaginal plate. ●● Transverse vaginal septa and cervical agenesis are rare anomalies, occurring in approximately 1 in 80,000 women. ●● Presentation: –– Obstructive lesions present in early adolescence because of pain.

Answers to questions patients ask Q1 Can I conceive naturally? A1. This depends on the exact abnormality of the reproductive system. If only the vagina is affected, and this is corrected with surgery then there should be no problem conceiving naturally. If there are issues with the cervix and rest of the womb, then more complicated surgery may be needed, with fertility treatment thereafter.

Q2 Will I be at a higher risk of having a miscarriage or preterm birth? A2. There is an increased risk of miscarriage and preterm birth for women who have abnormalities with their cervix and womb. This does not mean you cannot have a successful pregnancy. You would be under the care of a specialist in pregnancy.

References 

References 1 Acién P. Embryological observations on the female genital tract. Hum Reprod Oxf Engl. 1992;7(4):437–45. 2 Grimbizis GF, Gordts S, Di Spiezio Sardo A, Brucker S, De Angelis C, Gergolet M, et al. The ESHRE/ESGE consensus on the classification of female genital tract congenital anomalies. Hum Reprod Oxf Engl. 2013;28(8):2032–44. 3 Acién P, Ruiz JA, Hernandez JF, Susarte F, Martin del Moral A. Renal agenesis in association with malformation of the female genital tract. Am J Obstet Gynecol. 1991;165(5 Pt 1):1368–70. 4 Kachhawa G, Kriplani A. Management of reproductive tract anomalies. J Obstet Gynaecol India. 2017;67(3):162–7. 5 Lacy J, Correll GR, Walmer DK, Price TM. Simple vaginal mold for use in the postoperative care of patients with a transverse vaginal septum. Fertil Steril. 2007;87(5):1225–6. 6 Acién P, Acién MI, Quereda F, Santoyo T. Cervicovaginal agenesis: spontaneous gestation at term after previous reimplantation of the uterine corpus in a neovagina: Case report. Hum Reprod. 2008;23(3):548–53. 7 Aimen FM, Atef Y, Majed G, Radhouane A, Manel M, Monia M, et al. Spontaneous pregnancy after vaginoplasty in a patient presenting a congenital vaginal aplasia. Asian Pac J Reprod. 2016;5(4):351–3. 8 Smith NA, Laufer MR. Obstructed hemivagina and ipsilateral renal anomaly (OHVIRA) syndrome: management and follow‐up. Fertil Steril. 2007;87(4): 918–22.

9 Nguyen DH, Lee C‐L, Wu K‐Y, Cheng M‐H. A novel approach to cervical reconstruction using vaginal mucosa‐lined polytetrafluoroethylene graft in congenital agenesis of the cervix. Fertil Steril. 2011;95(7):2433.e5–8. 10 Kriplani A, Kachhawa G, Awasthi D, Kulshrestha V. Laparoscopic‐assisted uterovaginal anastomosis in congenital atresia of uterine cervix: follow‐up study. J Minim Invasive Gynecol. 2012;19(4):477–84. 11 Rock JA, Roberts CP, Jones HW. Congenital anomalies of the uterine cervix: lessons from 30 cases managed clinically by a common protocol. Fertil Steril. 2010;94(5):1858–63. 12 Sanfilippo JS, Wakim NG, Schikler KN, Yussman MA. Endometriosis in association with uterine anomaly. Am J Obstet Gynecol. 1986;154(1):39–43. 13 Lai TH, Wu MH, Hung KH, Cheng YC, Chang FM. Successful pregnancy by transmyometrial and transtubal embryo transfer after IVF in a patient with congenital cervical atresia who underwent uterovaginal canalization during caesarean section: case report. Hum Reprod Oxf Engl. 2001;16(2):268–71. 14 Anttila L, Penttilä TA, Suikkari AM. Successful pregnancy after in‐vitro fertilization and transmyometrial embryo transfer in a patient with congenital atresia of cervix: case report. Hum Reprod Oxf Engl. 1999;14(6):1647–9. 15 Khairy M, Shah H, Rajkhowa M. Transmyometrial versus very difficult transcervical embryo transfer: efficacy and safety. Reprod Biomed Online. 2016;32(5):513–7.

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29 The patient with uterine fibroids Kugajeevan Vigneswaran and Haitham Hamoda The Assisted Conception Unit, King’s College Hospital, London, UK

Case History 1: A 36-year-old woman who is about to start IVF treatment is found to have an anterior intramural fibroid measuring 8  ×  6 ×  5  cm and a further posterior intramural fibroid measuring 9 × 7 × 6 cm. Both are noted to be distorting the endometrial cavity. Case History 2: A 32-year-old woman gives a 5-year history of infertility and is due to commence IVF treatment. She has a contrast cavity sonogram which shows a 2-cm submucous fibroid with more than 50% protrusion into the endometrial cavity.

Background Uterine fibroids (myomas) are the most common benign tumours found in women of reproductive age. They are whirling bundles of smooth muscle cells arising from the myometrium and are thought to arise from the mutation of a single myometrial cell. It is estimated that approximately 20–40% of all women of reproductive age have a symptomatic uterine fibroid  [1]. Although fibroids can be asymptomatic, common presenting symptoms include abnormal uterine bleeding, pain (with fibroid degeneration or torsion of pedunculated fibroids), pressure symptoms (pelvic mass, urinary symptoms or bowel symptoms) and infertility. Approximately 5–10% of women with infertility have fibroids; however, it is only in 2–3%

women that fibroids are thought to be the sole cause of infertility [2]. The main risk factors for fibroids are advancing age and ethnicity. There is a gradual increase in incidence from puberty to menopause. The incidence of fibroids is two to three times greater in Afro‐Caribbean women compared with Caucasian women. Afro‐Caribbean women are also more likely to develop fibroids earlier in their reproductive life as well as being more symptomatic, as the fibroids are more prone to being both larger as well as more numerous in this population. In an ultrasonography study conducted in the USA, Afro‐Caribbean women developed fibroids approximately 10 years earlier than Caucasian women; the incidence of fibroids rising sharply around 25 years of age for Afro‐ Caribbean women and 35 years of age for

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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Caucasian women, and by the time menopause is reached, fibroids could be identified by ultrasound in approximately 80% of Afro‐ Caribbean women and in almost 70% of Caucasian women [3,4]. Early menarche and prenatal exposure to diethylstilbestrol (DES) also appear to increase the risk of fibroid development, with parity and exposure to long‐acting progestogens conferring a protective influence. This would imply that fibroids appear to develop under the influence of cyclical menstrual activity. The genetic basis of fibroids may be related to genetic variations in estrogen and progesterone regulation and its impact on local growth factors. Fibroids are categorized according to their anatomic location into submucous, intramural or subserous. The International Federation of Gynaecology and Obstetrics (FIGO) has outlined a numerical classification system for fibroids based on their proximity to the endometrium. The system uses an 8‐point numerical classification to describe fibroid location in relation to the submucosal surface of the endometrium and the serosal surface, with lower numbers indicating proximity to the uterine cavity [5]. Submucosal fibroids (Figure  29.1), through the nature of their location, distort the endometrial cavity, and are classified as type 0 (pedunculated), type 1 (less than 50% myometrial extension) and type 2 (more than 50% myometrial extension). Intramural fibroids lie within the myometrial layer, while subserosal fibroids are those where 50% or more of the fibroid is protruding from the serosal surface.

Diagnosis of fibroids Pelvic examination may demonstrate a firm, multilobular mass extending from the uterus. Diagnosis can usually be reliably confirmed by transvaginal ultrasound or abdominal ultrasound for a large fibroid uterus. Studies have shown ultrasound to have high sensitivity

0 2 1

Figure 29.1  Types of submucosal fibroid: type 0 (pedunculated), type 1 (less than 50% myometrial extension) and type 2 (more than 50% myometrial extension).

(>90%) and specificity (>85%) in detecting fibroids [6]. Magnetic resonance imaging (MRI) has a sensitivity and specificity approaching 100% in the diagnosis of fibroids; however, it is significantly more expensive than ultrasound scanning. MRI performs better at assessment of volume and calculation of total fibroid number than ultrasound and can be of particular use in patients with a high body mass index, those with large uteri extending beyond the pelvis or in women who are unable to tolerate transvaginal imaging. Instillation of saline into the uterine cavity (sonohysterography) can be useful to differentiate small submucous fibroids from the surrounding endometrium [7]. The drawbacks for this test, however, is discomfort associated with injection of saline as well as the small risk of infection (1%). The gold standard investigation for the diagnosis of submucosal fibroids is hysteroscopy, reaching a sensitivity and specificity of 100%  [8]. It is also possible to combine this diagnostic test with therapeutic resection of

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fibroids; however, it carries the risks associated with an invasive procedure such as infection and perforation as well as the need for anesthesia. Furthermore, hysteroscopy does not enable assessment of any myometrial component of type 1 and 2 fibroids as well as being less accurate at estimating fibroid size. For this reason, hysteroscopy should be preceded by preoperative imaging studies. The information required from imaging includes determination of the number of fibroids, size, location and relation to the endometrial cavity. This will help determine the possible association between the fibroids and the patient’s presenting symptoms, and will aid the clinician to individualize each patient’s management.

Fibroids and infertility Studies have suggested an association between fibroids and infertility, although the underlying mechanism for the association is poorly understood. Several hypotheses have been proposed to explain the impact of fibroids on fertility, including impairment in sperm transport, implantation, uterine contractility as well as alteration of endometrial receptivity. The junctional zone or endomyometrial junction (EMJ) appears to have an important role on implantation. The EMJ, which consists of the inner third of the myometrium and the endometrium, plays an important role in uterine wave peristalsis. Uterine peristalsis originating in the EMJ has been shown to facilitate sperm and embryo transport. During the mid‐secretory phase of the menstrual cycle, there is a significant reduction in uterine wave frequency to facilitate implantation. It has been shown that women with fibroids have a marked increase in uterine peristalsis frequency, thus potentially impairing implantation. Histologically, there is a reduction in endometrial gland concentration in the endometrium overlying fibroids, and this may contribute to the late maturation of the

endometrium and impair implantation. Other possible mechanisms include inflammation and alteration of endometrial blood supply resulting in a hostile endometrial environment affecting sperm motility and embryo implantation [9,10].

Management options Submucosal fibroids Submucous fibroids are associated with decreased pregnancy rates, and the outcome of IVF treatment is believed to be improved following surgical removal of such fibroids. A systematic review addressing all fibroids with an element of cavity distortion, including FIGO groups 0–2, showed that for women with submucous fibroids there was significantly lower implantation (RR 0.28), clinical pregnancy (RR 0.36) and live birth rates (RR 0.32) as well as significantly higher miscarriage rates (RR 1.68)  [11]. Clinical pregnancy rates were significantly higher in women with submucosal fibroids who underwent myomectomy when compared with women where fibroids were left untreated. There was no significant difference, however, in implantation, live birth or miscarriage rates. Furthermore, a 2018 Cochrane review questioned the role of hysteroscopy in managing infertility associated with submucous fibroids, concluding that there was insufficient evidence of benefit in clinical pregnancy rates for hysteroscopic myomectomy [12]. Despite the limited evidence, many clinicians would recommend a hysteroscopic myomectomy in women with submucous fibroids.

Intramural fibroids Studies have also suggested that the presence of intramural fibroids is associated with reduced fertility even in the absence of any

Answers to questions patients ask  179

cavity distortion. However, the evidence on the effect of treatment of intramural fibroids that do not distort the endometrial cavity is limited. Two systematic reviews have assessed the association between the presence of intramural fibroids and infertility. Both acknowledge the clinical heterogeneity of the studies included limited the ability to reach a meaningful conclusion. One review meta‐analyzed the effect of intramural fibroids without uterine cavity involvement on IVF outcomes and found a significant decrease in clinical pregnancy and live birth rates when compared with those who had no fibroids  [13]. Another systematic review reported on pregnancy outcomes in relation to the location of the fibroids and the effect of surgical treatment on outcomes [11]. The evidence on surgical treatment was limited but suggested no significant benefit from surgical treatment.

Case discussion The woman in Case History 1 should be counseled about the limitations of the evidence. She should be informed that her fibroids could potentially compromise her chances of success with IVF treatment. The option of surgical removal of her fibroids (myomectomy) prior to starting IVF needs to be discussed with her, highlighting all the risks alongside potential benefits. The woman in Case History 2 should be informed that the evidence suggests that her

fibroid is likely to reduce her chances of success with IVF, and the option of having her fibroid removed (hysteroscopic resection) should be discussed.

Key points Challenge: The patient with uterine fibroids undergoing ART. Background: 20–40% of women are reported to have fibroids. ●● There is a higher prevalence in AfroCaribbean women who are also more likely to develop larger, multiple fibroids, earlier in their lives compared with Caucasian women. ●● The evidence suggests an association between fibroids and infertility. ●● This association is more likely in women with submucous fibroids or intramural fibroids distorting the endometrial cavity. ●●

Management options: ●● Surgical removal of submucous fibroids is likely to improve pregnancy rates in ART patients. ●● The evidence on surgical treatment for intramural fibroids is limited. In practice, clinicians commonly offer surgical treatment to infertile women with intramural fibroids that distort the endometrial cavity or those that are greater than 5 cm in diameter. ●● The evidence suggests a less favorable reproductive outcome with uterine artery embolization than myomectomy in women with fibroids, and infertility remains a relative contraindication for uterine artery embolization.

Answers to questions patients ask Q1 Why did I get a fibroid? A1. The exact reason is not known; however, it is known that they are sensitive to the hormones of the  menstrual cycle. Factors that

increase the risk of fibroids being present include increasing age and ethnicity, with Afro‐Caribbean women more likely to have fibroids compared with Caucasian women.

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Q2 Do I need to have my fibroid removed before I start fertility treatment? A2. Studies have shown that if a fibroid is found within the cavity of the womb, and as a result is distorting the area of the womb where implantation of a pregnancy is likely to occur, then undergoing surgery to remove the fibroid may increase the chances of a successful pregnancy. If the fibroid is seen within the muscle of the womb and is less than 5  cm, or on the outside of the womb, then generally it is okay to proceed with fertility treatment without surgery beforehand. Q3 What are the risks of having the fibroid removed? A3. Fibroids can be removed using a hysteroscope, a keyhole camera instrument, to look inside the womb. This procedure is performed under general anesthesia, and although complications are uncommon with this procedure, they may include perforation of the womb, bleeding, infection, damage to the urinary or digestive tract, absorption of excessive

fluid during the procedure as well medical complications resulting from reactions to drugs or anesthetic medicines. Large fibroids seen within the muscle of the womb will require removal through the abdomen, with either an open operation or with key‐ hole surgery. Q4 Could the fibroid come back again after removal? A4. The risk of fibroid coming back after surgery is high. Studies have shown that within 5 years after surgery there is between a 50–60% chance that the fibroids will have come back. The chances of reoccurrence are lower if only one fibroid needed to be removed or the fibroids removed were small. Becoming pregnant after surgery is also likely to reduce the chance of the fibroids coming back. Q5 Could the fibroid be cancerous? A5. Fibroids are almost always benign. A type of cancerous fibroid can occur, but this is very rare (less than 1 in 1,000). This is known as a leiomyosarcoma.

References 1 Cramer SF, Patel A. The frequency of uterine leiomyomas. Am J Clin Pathol. 1990;94: 435–8. 2 Practice Committee of American Society for Reproductive Medicine in collaboration with Society of Reproductive S. Myomas and reproductive function. Fertil Steril. 2008;90 (5 Suppl):S125–30. 3 Day Baird D, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol 2003;188:100–7.

4 Stewart EA, Laughlin‐Tommaso SK, Catherino WH et al. Uterine fibroids. Nature Reviews Disease Primers. 2016;2:16043. 5 Laughlin‐Tommaso SK, Hesley GK, Hopkins MR, Brandt KR, Zhu Y, Stewart EA. Clinical limitations of the International Federation of Gynecology and Obstetrics (FIGO) classification of uterine fibroids. International Journal of Gynecology & Obstetrics. 2017 Nov;139(2):143–8. 6 Somigliana E, Vercellini P, Daguati R, Pasin R, De Giorgi O, Crosignani PG. Fibroids and

References 

female reproduction: a critical analysis of the evidence. Hum Reprod Update. 2007;13(5): 465–76. 7 Dueholm M, Forman A, Jensen ML, Laursen H, Kracht P. Transvaginal sonography combined with saline contrast sonohysterography in evaluating the uterine cavity in premenopausal patients with abnormal uterine bleeding. Ultrasound Obstet Gynecol 2001;18:54–61. 8 Cicinelli E, Romano F, Anastasio PS et al. Transabdominal sonohysterography, transvaginal sonography, and hysteroscopy in the evaluation of submucous myomas. Obstetrics and Gynecology. 1995;85(1):42–7. 9 Ng EH, Chan CC, Tang OS, Yeung WS, Ho PC. Endometrial and subendometrial blood flow measured by three‐dimensional power Doppler ultrasound in patients with small intramural uterine fibroids during IVF treatment. Hum Reprod. 2005;20:501–6.

10 Richards PA, Richards PD, Tiltman AJ. The ultrastructure of fibromyomatous myometrium and its relationship to infertility. Hum Reprod Update. 1998;4(5):520–5. 11 Pritts EA, Parker WH, Olive DL. Fibroids and infertility: an updated systematic review of the evidence. Fertil Steril. 2009;91(4):1215–23. 12 Bosteels J, van Wessel S, Weyers S, Broekmans FJ, D’Hooghe TM, Bongers MY, Mol BW. Hysteroscopy for treating subfertility associated with suspected major uterine cavity abnormalities. Cochrane Database of Systematic Reviews. 2018(12). 13 Sunkara SK, Khairy M, El‐Toukhy T, Khalaf Y, Coomarasamy A. The effect of intramural fibroids without uterine cavity involvement on the outcome of IVF treatment: a systematic review and meta‐analysis. Hum Reprod. 2018; 25(2):418–29.

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30 The patient with adenomyosis Andreas Athanasakis1 and Arri Coomarasamy2 1

 Bristol Centre for Reproductive Medicine, Bristol, UK  University of Birmingham and Birmingham Women’s Hospital, Birmingham, UK

2

Case History 1: A 27-year-old single woman wishes to have intrauterine insemination with donor sperm. At her baseline scan, anterior-posterior asymmetrical myometrial thickening is observed. The echotexture of the myometrium is heterogeneous with hypoechoic striations, consistent with adenomyosis. Case History 2: Four years ago, a 37-year-old woman with adenomyosis had an ICSI cycle with one fresh ET and two months later one FET. She became pregnant with the FET but miscarried at 6 weeks of gestation. She has two blastocysts in storage and wishes to attempt another cycle of treatment.

Background Adenomyosis is a benign uterine disorder that was first described in 1860. Its etiology is unclear. It can be asymptomatic in up to one third of cases. When it is symptomatic, the most frequent symptoms are pelvic pain and abnormal uterine bleeding  [1]. Adenomyosis can coexist with fibroids, making the symptoms worse [2]. With advances in imaging, adenomyosis is being diagnosed more often and at a younger age than in the past. Interpreting results from studies on IVF outcomes in women with adenomyosis can be tricky, as most studies are retrospective, often include a small number of patients, and there is significant heterogeneity on the diagnostic criteria for inclusion into the adenomyosis group and on the reported outcomes. Hopefully, the situation will change as

v­ alidated classification systems for reporting results are being developed [3]. Adenomyosis may be difficult to diagnose. Various ultrasound features have been suggested to be associated with adenomyosis (Figure 30.1), but at present it is not clear which of the ultrasound criteria are most important for diagnosis. According to the Morphological Uterus Sonographic Assessment (MUSA) group consensus opinion  [4], some features may carry a greater diagnostic weight than others, and the presence of more than one ultrasound feature might increase the likelihood of the diagnosis. A review of 14 studies with 1895 participants found that the sensitivity and specificity of 2D TVS for the diagnosis of adenomyosis were 83% and 85% respectively, when compared with the reference standard diagnosis of adenomyosis using a hysterectomy specimen [5].

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

Management options 

(a)

(b)

(c)

(d)

(e)

(f)

(g)

(h)

Figure 30.1  Schematic drawings illustrating the ultrasound features currently considered to be typical of adenomyosis: asymmetrical thickening (a), cysts (b), hyperechoic islands (c), fan-shaped shadowing (d), echogenic subendometrial lines and buds (e), translesional vascularity (f), irregular junctional zone (g) and interrupted junctional zone (h).

There seems to be a strong association between adenomyosis and endometriosis. It has even been suggested that endometriosis and adenomyosis are variants of the same disease process, which involves the dislocation of basal endometrium. In one study, adenomyosis had a prevalence of 90% in women with endometriosis below the age of 36 [6]. Special care should therefore be taken during the baseline ultrasound assessment of women with endometriosis to ensure adenomyosis is ruled out. When the baseline ultrasound scan is inconclusive, a 3D TVS or an MRI of the pelvis might reveal an abnormal junctional zone. Normal junctional zone is considered to be 1.5cm and ­submucous fibroids. ●● If there is evidence of hydrosalpinx, ­recommend laparoscopy and tubal clipping or removal. ●● If the patient has thin endometrium on ultrasound scan, consider a hysteroscopy. ●● If there is adenomyosis, consider ­prolonged pituitary downregulation with GnRH ­agonists for 6–8 weeks before ovarian stimulation. ●● There is little or no evidence to support the following treatments in RIF patients: IMSI, AH, PGT-A, endometrial biopsy (scratch), IVIg administration, oral steroids, sildenafil, intralipid, platelet rich plasma, DHEA, and granulocyte colony stimulating factor. ●● Approach to management of each case should be individualized. ●●

Answers to questions patients ask Q1 What is the cause of me not getting ­pregnant after three IVFs? A1.  Recurrent implantation failure can have many causes, and in some cases, we will not be able to find out the reason why you are not getting pregnant. Q2 Can you test the embryos to check if they are “normal”? A2.  Yes, this is called preimplantation genetic testing and we can check for a wide range of genetic conditions. Selecting a normal embryo does not mean that you will definitely get pregnant, as other factors may also contribute. Although genetic testing may provide an

explanation for implantation failure, the technology is not perfect and can lead to the embryos being damaged or erroneously discarded. Q3 What can I do to help to get pregnant in the next cycle? A3.  Healthy lifestyle is essential when trying to get pregnant. Limiting caffeine intake, stopping smoking and regular exercise in order to maintain a healthy weight are very important. You should also strictly adhere to the treatment protocol provided and discuss any issues with your clinician. Psychological support and various relaxation techniques can be beneficial to you.

References 

Q4 How many cycles do I need to go through in order to get pregnant? A4.  There is no single or simple answer to this question. It is expected that in any good clinic half of the patients would leave the clinic with a baby if they committed to trying three times.

Q5 Can I have four or five embryos transferred? A5.  No. Transferring more embryos may increase the chance of pregnancy slightly, but it also significantly increas­es the risk of high‐order ­(triplets, quadruplets or higher) ­multiple pregnancies, which are very high risk to you and your unborn children.

References 1 Polanski, LT, MN Baumgarten, S Quenby, J Brosens, BK Campbell, and NJ Raine‐ Fenning, What exactly do we mean by “recurrent implantation failure”? A systematic review and opinion. Reprod Biomed Online, 2014;28(4):409–23. 2 Malizia, BA, MR Hacker, and AS Penzias, Cumulative live‐birth rates after in vitro fertilization. N Engl J Med. 2009;360(3):236–43. 3 Ferraretti, AP, A La Marca, BC Fauser, B Tarlatzis, G Nargund, L Gianaroli, et al., ESHRE consensus on the definition of “poor response” to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod. 2011;26(7):1616–24. 4 Rubio, C, J Bellver, L Rodrigo, G Castillon, A Guillen, C Vidal, et al., In vitro fertilization with preimplantation genetic diagnosis for aneuploidies in advanced maternal age: a randomized, controlled study. Fertil Steril. 2017;107(5):1122–1129. 5 Friden, B, P Sjoblom, and J Menezes, Using anti‐Mullerian hormone to identify a good prognosis group in women of advanced reproductive age. Aust N Z J Obstet Gynaecol. 2011;51(5):411–5. 6 Spandorfer, SD, J Goldstein, J Navarro, L Veeck, OK Davis, and Z Rosenwaks, Difficult embryo transfer has a negative impact on the outcome of in vitro fertilization. Fertil Steril. 2003;79(3):654–5. 7 Tremellen, K and P Russell, Adenomyosis is a potential cause of recurrent implantation failure during IVF treatment. Aust N Z J Obstet Gynaecol. 2011;51(3):280–3.

8 Johnson, N, S van Voorst, M Sowter, A Strandell, and B Mol, Surgical treatment for tubal disease in women due to undergo in vitro fertilisation. Cochrane Database Syst Rev. 2010(1):CD002125. 9 Grimbizis, GF, A Di Spiezio Sardo, SH Saravelos, S Gordts, C Exacoustos, D Van Schoubroeck, et al., The Thessaloniki ESHRE/ESGE consensus on diagnosis of female genital anomalies. Hum Reprod. 2016;31(1):2–7. 10 Maheux‐Lacroix, S, A Boutin, L Moore, ME Bergeron, E Bujold, P Laberge, et al., Hysterosalpingosonography for diagnosing tubal occlusion in subfertile women: a systematic review with meta‐analysis. Hum Reprod. 2014;29(5):953–63. 11 Vasan, SS, Semen analysis and sperm function tests: How much to test? Indian J Urol. 2011;27(1):41–8. 12 Avendano, C, A Franchi, S Taylor, M Morshedi, S Bocca, and S Oehninger, Fragmentation of DNA in morphologically normal human spermatozoa. Fertil Steril. 2009;91(4):1077–84. 13 Tomlinson, M, S Lewis, D Morroll, and S British Fertility, Sperm quality and its relationship to natural and assisted conception: British Fertility Society guidelines for practice. Hum Fertil (Camb). 2013;16(3):175–93. 14 De Sutter, P, R Stadhouders, M Dutre, J Gerris, and M Dhont, Prevalence of chromosomal abnormalities and timing of karyotype analysis in patients with recurrent

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implantation failure (RIF) following assisted reproduction. Facts Views Vis Obgyn. 2012;4(1):59–65. 15 Greco, E, S Bono, A Ruberti, AM Lobascio, P Greco, A Biricik, et al., Comparative genomic hybridization selection of blastocysts for repeated implantation failure treatment: a pilot study. Biomed Res Int. 2014;2014:457913. 16 Blockeel, C, V Schutyser, A De Vos, W Verpoest, M De Vos, C Staessen, et al., Prospectively randomized controlled trial of PGS in IVF/ICSI patients with poor implantation. Reprod Biomed Online. 2008;17(6):848–54. 17 Ledee, N, M Petitbarat, L Chevrier, D Vitoux, K Vezmar, M Rahmati, et al., The Uterine immune profile may help women with repeated unexplained embryo implantation failure after in vitro fertilization. Am J Reprod Immunol. 2016;75(3):388–401. 18 Tang, AW, Z Alfirevic, and S Quenby, Natural killer cells and pregnancy outcomes in women with recurrent miscarriage and infertility: a systematic review. Hum Reprod. 2011;26(8):1971–80. 19 Ata, B and B Urman, Thrombophilia and assisted reproduction technology‐any detrimental impact or unnecessary overuse? J Assist Reprod Genet. 2016;33(10):1305–1310. 20 Tong, M, CA Viall, and LW Chamley, Antiphospholipid antibodies and the placenta: a systematic review of their in vitro effects and modulation by treatment. Hum Reprod Update. 2015;21(1): 97–118. 21 Sauer, R, R Roussev, RS Jeyendran, and CB Coulam, Prevalence of antiphospholipid antibodies among women experiencing unexplained infertility and recurrent implantation failure. Fertil Steril. 2010;93(7):2441–3. 22 Hornstein, MD, OK Davis, JB Massey, RJ Paulson, and JA Collins, Antiphospholipid

antibodies and in vitro fertilization success: a meta‐analysis. Fertil Steril. 2000;73(2):330–3. 23 Carty, DM, F Doogan, P Welsh, AF Dominiczak, and C Delles, Thyroid stimulating hormone (TSH) >/=2.5mU/l in early pregnancy: Prevalence and subsequent outcomes. Eur J Obstet Gynecol Reprod Biol. 2017;210:366–369. 24 Bellver, J, SR Soares, C Alvarez, E Munoz, A Ramirez, C Rubio, et al., The role of thrombophilia and thyroid autoimmunity in unexplained infertility, implantation failure and recurrent spontaneous abortion. Hum Reprod. 2008;23:278–284. 25 Kim, CH, RM You, HY Nah, HJ Kang, S Kim, HD Chae, et al., Effect of granulocyte colony‐stimulating factor on pregnancy outcome following IVF/ICSI in patients with repeated implantation failure. Hum Reprod. 2011;26:i244. 26 Sunkara, SK, V Rittenberg, N Raine‐Fenning, S Bhattacharya, J Zamora, and A Coomarasamy, Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles. Hum Reprod. 2011;26(7):1768–74. 27 Guerif, F, R Bidault, O Gasnier, ML Couet, O Gervereau, J Lansac, et al., Efficacy of blastocyst transfer after implantation failure. Reprod Biomed Online. 2004;9(6):630–6. 28 Potdar, N, TA Gelbaya, JC Konje, and LG Nardo, Adjunct low‐molecular‐weight heparin to improve live birth rate after recurrent implantation failure: a systematic review and meta‐analysis. Hum Reprod Update. 2013;19(6):674–84. 29 NICE. Hysteroscopic metroplasty of a uterine septum for recurrent miscarriage. 2015 06.09.2019]; Available from: https:// www.nice.org.uk/guidance/ipg510. 30 Lensen, S, D Osavlyuk, S Armstrong, C Stadelmann, A Hennes, E Napier, et al., A randomized trial of endometrial scratching before in vitro fertilization. N Engl J Med. 2019;380(4):325–334.

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34 The patient with previous uterine artery embolization Kugajeevan Vigneswaran and Haitham Hamoda The Assisted Conception Unit, King’s College Hospital, London, UK

Case History 1: A 39-year-old woman gives a 5-year history of secondary infertility and frequency of micturition. She is planning to have IVF treatment. Her recent ultrasound scan showed a solitary intramural fibroid (anterior 9  x  7  x 6  cm) distorting the endometrial cavity. She had uterine artery fibroid embolization 5 years ago, and wishes to know if she should undergo another attempt of fibroid embolization before starting IVF treatment. Case History 2: A 35-year-old patient with a 4-year history of infertility is about to start IVF treatment. She has a 3-cm intramural fibroid that is clear of the endometrial cavity. She has read about fibroid embolization on the Internet and wishes to have this before she starts IVF treatment.

Background Hysterectomy and myomectomy are the main forms of treatment for symptomatic uterine fibroids, with myomectomy having the potential to preserve reproductive potential. In 1995, Ravina et  al. reported the first case series of uterine artery embolization (UAE) indicated solely as a treatment for fibroids, which was followed up by several other reports showing high effectiveness with low complication rates [1]. Uterine artery embolization has now become a widely accepted alternative to myomectomy, as an equally efficacious uterus‐sparing procedure, with approximately 25,000 procedures performed annually worldwide [2].

Menstrual symptoms following UAE UAE is recognized as an effective treatment for fibroids‐associated symptoms including heavy uterine bleeding as well as pressure effects resulting in pain, bladder and bowel symptoms. A summary of the published literature showed that an improvement in menorrhagia was noted in 80–90% of women following UAE, while the mean reduction in fibroid volume was reported to be 50–60% at one year. A total of 1% of women subsequently required a hysterectomy, and 1% developed an infection following the procedure. Early ovarian failure can occur in 1–2% of patients undergoing UAE, although this is largely confined to women over the age of 45 years [3].

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The patient with previous uterine artery embolization

An updated Cochrane review in 2014, encompassing seven randomized controlled trials, found that pooled data showed no difference between UAE and alternative surgery in terms of women’s satisfaction with treatment at 2 or 5 years. Compared with hysterectomy and myomectomy, UAE provided the benefits of shorter procedure time (procedure reduced by about 16 to 50  minutes), shorter hospital stays (by about 1 to 4 days) and quicker resumption of normal activities (by about 10 to 23 days). The potential disadvantages included a greater risk of minor postprocedural complications within 6 weeks with UAE (368 vs. 226 per 1,000  women), an increase in unscheduled admissions within 6  weeks (279 vs. 144 per 1,000 women) and an increase in need for further surgical procedures within 2 years (166 vs. 51 per 1,000 women) [4]. Owing to this higher rate of reintervention, the initial cost effectiveness of UAE as an alternative to hysterectomy is lost by follow‐up at 5 years [5]. The higher reintervention rates seen with UAE may be as a consequence of the establishment of a collateral blood supply that is able to compensate for the occluded uterine vessels or recanalization of the embolized vessels.

Reproductive outcomes following UAE As with any new intervention, early consensus was to exercise caution and therefore avoid UAE in women who wished to become pregnant. This guidance was not based on any substantial evidence and it was apparent from the very outset of UAE use for fibroids, that women could still become pregnant and carry pregnancies to term following UAE. After several years of experience, reports of possible negative effects on future fertility emerged. It was postulated that the ischemia that resulted from UAE induced a degree of endometrial damage, leading to a high rate of miscarriage. A successful UAE can be defined by complete occlusion of the uterine arteries resulting

in regression of fibroid symptoms. It is understood that a healthy collateral circulation prevents total uterine infarction and necrosis. Whether this collateral supply is able to maintain function when challenged during pregnancy has led to the question of whether UAE affects future gestational uterine function. A study of hysteroscopic and histological examination of the endometrial cavity performed 6 months after UAE found a functional endometrium in 90% of cases histologically but an abnormal appearance of the endometrium in 63% cases at hysteroscopy. These findings included intrauterine protrusion of the existing fibroids, discoloration of the endometrium, intrauterine or cervical adhesions and communications between the fibroid and endometrial cavity interface [6]. The implications of such findings on fertility potential is yet to be elucidated. Fertility outcomes following UAE can be impaired by the inherent impact of residual fibroids or the consequences of the UAE procedure itself. Although a myomectomy can result in complete absence of remaining fibroids, a UAE deemed successful from a symptom‐perspective may still retain up to 40% of fibroid mass. Animal studies have demonstrated that induced restriction of uterine artery blood flow resulted in reduced spiral artery infiltration into the intervillous space [7]. In a rat model, where the uterine artery supplying one horn of the uterus was ligated, there was resulting intrauterine growth restriction as well as intrauterine death [8]. However, to date, there has been only one study published on the impact of UAE versus myomectomy on pregnancy and live birth rates. The pregnancy rate was calculated from the limited cohort of participants who attempted to conceive (26  women after UAE and 40  women after myomectomy)  [9]. The study found a nonsignificant difference in pregnancy rate of 50% after UAE and 78% after myomectomy. The miscarriage rate was found to be 60% after UAE and 20% after myomectomy (p 1.5 cm), or if there is a history of implantation failure or recurrent miscarriage, then the option of freeze all embryos, polypectomy, followed by FET 2–3 months later should be considered. Polypoid endometrium does not require treatment from the fertility point of view (although a biopsy may be needed from the

●●

point of view of ruling out hyperplasia or cancer in older women and in women with menstrual disorders). Polypectomy is best performed under direct hysteroscopic visualization, or if the polyp has a broad base, with a resectoscope.

Prevention: To avoid the situation of finding a polyp during controlled ovarian stimulation, a baseline ultrasound scan in the follicular phase is recommended.

Answers to questions patients ask Q1 Why did I get a polyp? A1. The exact cause of endometrial polyps is not known; however, it is known that endometrial polyps are sensitive to estrogen, a hormone that promotes thickening of the lining of the womb. Factors that increase the risk of developing endometrial polyps include obesity, perimenopause or treatment with the drug Tamoxifen. Q2 Why wasn’t the polyp picked up before I started treatment? A2. Endometrial polyps may be as small as a sesame seed or as large as golf balls. The ease of diagnosis increases proportional to the size of the polyp. If the polyp was very small, it may not have been visible during the ultrasound scan. Furthermore, endometrial polyps may start developing anytime, even after the initial pretreatment scan, which may lead to their diagnosis only during the subsequent scans. Q3 What are the risks of having the polyp removed? A3. Endometrial polyps are usually removed using a hysteroscope, an instrument with a camera to look inside the womb. This procedure

may be performed using local or general anesthesia. Complications are very rare with this procedure, but may include perforation of the womb, bleeding, infection, damage to the urinary or digestive tract and medical complications resulting from reactions to drugs or anaesthetic agents. Q4 Could the polyp come back again after removal? A4. The risk of developing recurrent endometrial polyps increases with the number of previous polyps excised and the duration of follow up–the longer you look for them, the more likely you are to diagnose them again in the future. Previous studies have reported recurrence rates ranging between 13–43% following hysteroscopic removal of endometrial polyps [13,14]. Q5 Could the polyp be cancerous? A5. There is a very small risk. The risk of cancer is about 1% in premenopausal women [15], but higher in menopausal women (5%). This is why persistent polyps should be removed so that they can be examined under the microscope to ensure there is no evidence of any serious pathology.

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The patient with endometrial polyp

References 1 Afifi K, Anand S, Nallapeta S, Gelbaya TA. Management of endometrial polyps in subfertile women: a systematic review. Eur J Obstet Gynecol Reprod Biol 2010; 151: 117–21. 2 Fatemi HM, Kasius JC, Timmermans A, van DJ, Fauser BC, Devroey P, et al. Prevalence of unsuspected uterine cavity abnormalities diagnosed by office hysteroscopy prior to in vitro fertilization. Hum Reprod 2010; 25: 1959–65. 3 Karayalcin R, Ozcan S, Moraloglu O, Ozyer S, Mollamahmutoglu L, Batioglu S. Results of 2500 office‐based diagnostic hysteroscopies before IVF. Reprod Biomed Online 2010; 20: 689–93. 4 Yanaihara A, Yorimitsu T, Motoyama H, Iwasaki S, Kawamura T. Location of endometrial polyp and pregnancy rate in infertility patients. Fertil Steril 2008; 90: 180–2. 5 Lass A, Williams G, Abusheikha N, Brinsden P. The effect of endometrial polyps on outcomes of in vitro fertilization (IVF) cycles. J Assist Reprod Genet 1999; 16: 410–5. 6 Isikoglu M, Berkkanoglu M, Senturk Z, Coetzee K, Ozgur K. Endometrial polyps smaller than 1.5 cm do not affect ICSI outcome. Reprod Biomed Online 2006; 12: 199–204. 7 Ayida G, Chamberlain P, Barlow D, Kennedy S. Uterine cavity assessment prior to in vitro fertilization: comparison of transvaginal scanning, saline contrast hysterosonography and hysteroscopy. Ultrasound Obstet Gynecol 1997; 10: 59–62. 8 Perez‐Medina T, Bajo‐Arenas J, Salazar F, Redondo T, Sanfrutos L, Alvarez P, et al.

Endometrial polyps and their implication in the pregnancy rates of patients undergoing intrauterine insemination: a prospective, randomized study. Hum Reprod 2005; 20:1632–5. 9 Bosteels J, Weyers S, Puttemans P, Panayotidis C, Van HB, Gomel V, et al. The effectiveness of hysteroscopy in improving pregnancy rates in subfertile women without other gynaecological symptoms: a systematic review. Hum Reprod Update 2010; 16:1–11. 10 El‐Toukhy T, Sunkara SK, Coomarasamy A, Grace J, Khalaf Y. Outpatient hysteroscopy and subsequent IVF cycle outcome: a systematic review and meta‐analysis. Reprod Biomed Online 2008; 16: 712–9. 11 Batioglu S, Kaymak O. Does hysteroscopic polypectomy without cycle cancellation affect IVF? Reprod Biomed Online 2005; 10: 767–9. 12 Madani T, Ghaffari F, Kiani K, Hosseini F. Hysteroscopic polypectomy without cycle cancellation in IVF cycles. Reprod Biomed Online 2009; 18: 412–5. 13 Paradisi R, Rossi S, Scifo MC, Dall’O’ F, Battaglia C, Venturoli S. Recurrence of endometrial polyps. Gynecol Obstet Invest 2014; 78: 26–32. 14 Yang JH, Chen CD, Chen SU, Yang YS, Chen MJ. Factors Influencing the Recurrence Potential of Benign Endometrial Polyps after Hysteroscopic Polypectomy. PLoS One 2015; 10: e0144857. 15 Uglietti A, Buggio L, Farella M, et al. The risk of malignancy in uterine polyps: A systematic review and meta‐analysis. Eur J Obstet Gynecol Reprod Biol 2019; 237: 48–56.

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36 The obese female patient Mostafa Metwally and Bolarinde Ola Department of Obstetrics and Gynaecology, Jessop Wing, Sheffield Teaching Hospitals, Sheffield, UK

Case History: A 28‐year‐old woman with anovulatory infertility and body mass index (BMI) of 38 kg/m2 had three cycles of failed clomiphene therapy. Contrary to medical advice, she insisted on progressing to IVF. Basal follicle stimulating hormone (FSH), luteinizing hormone (LH) and antral follicle counts (AFC) were all within normal ranges, suggesting good ovarian reserve. Nevertheless, she responded suboptimally to 150 IU of follicle stimulating hormone (FSH) with only five follicles, two oocytes, with none fertilized. She returned with a BMI of 33. The dose of FSH was increased to 250  IU and eight follicles developed. A clinical pregnancy was achieved but ended in a miscarriage at 10 weeks.

Background This case demonstrates common problems encountered in obese female patients undergoing assisted conception. Despite her young age and normal ovarian reserve, the patient responded poorly to ovarian stimulation and when pregnancy did occur, it ended in a miscarriage. There is substantial evidence from the literature that obesity in both women and men has an adverse effect on the outcomes of assisted conception  [1–13]. A meta‐analysis of observational studies found that female patients with a BMI of 25 kg/m2 or more had a lower pregnancy rate than women with a normal BMI (OR 0.71; 95% CI 0.62–0.81) [12]. Overweight and obese women are also 1.5 to 3 times more likely to suffer from obstetric complications like pregnancy hypertension,

cesarean section and SGA  [14]. Another meta‐analysis looking at the effect of raised male patients BMI (> 30 kg/m2) found it to be associated with a significant reduction in both clinical pregnancy (OR 0.78, 95% CI 0.63 to 0.98, P = 0.03) and live birth rates (OR 0.88, 95% CI 0.82 to 0.95, P = 0.001) per IVF‐ICSI treatment cycle  [13]. However, most of the published literature relates to the effect of female obesity, and this will be discussed further in this chapter. Obese patients may need a higher dose of gonadotropins to achieve adequate ovarian stimulation  [15]. It has been postulated that metabolic alterations such as insulin resistance, increased insulin concentrations or increased leptin concentrations, may directly or indirectly interfere with gonadotropin action. Furthermore, drug sequestration in inflammatory cells of obese women may

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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regulate gonadotropin availability and hence gonadotropin action. This may also be the result of poor drug absorption because of the increased subcutaneous fat compartment  [3,16]. This raises a question on the optimal route for drug administration in these patients, although there is no clear evidence to suggest the use of the intramuscular over the subcutaneous route. One study compared the intramuscular with the subcutaneous routes for administration of recombinant FSH (rFSH) in obese women and found no evidence for a significant difference in the maximum concentrations (Cmax), time to maximum concentration (Tmax) and extent of absorption (area under curve [AUC]) whether the intramuscular or subcutaneous route was used [17]. The lower clinical pregnancy rates in obese women undergoing IVF may be related to poor oocyte or embryo quality, an associated endometrial defect or both [15]. Some studies found that in young women, obesity had a significant adverse effect on the mean embryo grade, the embryo utilization rate, number of embryos discarded and cryopreserved; but another suggested no significant impact on outcomes when a single embryo was transferred  [18]. The total number of studies that have addressed the issue of oocyte and embryo quality in obese patients remains small and the current methods used to assess oocyte and embryo quality remain subjective; therefore, the evidence that obesity adversely affects the oocyte or embryo remains suggestive but not conclusive. There is evidence that obese women may suffer from an endometrial defect; studies that have used the oocyte donation model have demonstrated that when good quality embryos from women of normal BMI are transferred to obese women there is still a reduction in pregnancy rates, suggesting that the defect lies at least partly in the endometrium [19]. An embryo or endometrial defect may also explain the higher risk of miscarriage in obese women, as shown by two meta‐analyses [12,20].

There is also evidence, albeit from only two studies, that obese women are at higher risk of recurrent miscarriage [21,22,23]. The aim of assisted conception is not merely the achievement of a clinical pregnancy, but rather the achievement of a healthy live birth. Obese patients who do become pregnant after successful assisted conception are at risk for several other pregnancy complications that may affect both the mother and the fetus. Apart from early pregnancy losses, there are increased risks of gestational diabetes and hypertensive disorders (both these conditions have been shown to be directly proportional to the BMI) [16,24] and fetal complications such as a higher risk cardiac septal and neural tube defects [25,26].

Management options The key to improving reproductive outcomes in an obese patient is weight loss. Even as little as 10% loss in body weight can lead to a rapid improvement in the hormonal profile and improve the chances of conception [27]. Weight loss should be achieved primarily through lifestyle changes and physical activity. There is currently insufficient evidence to recommend one specific diet over another. Similarly, there is no evidence to support the recommendation of a precise daily physical activity program, although one study demonstrated that the risk of anovulatory infertility dropped by 5% with each hour per week of vigorous physical activity [28]. Pharmacologic agents for weight loss can also be considered when patients fail to lose at least 10% of body weight despite lifestyle changes and diet control [29]. The most promising drug in this group of patients is orlistat, a lipase inhibitor. This drug has the potential advantage of minimal risk to the fetus should a pregnancy occur, because of its low systemic absorption. Furthermore, its effectiveness in  restoring ovulation and normalizing the

Answers to questions patients ask  219

hormonal profile has been demonstrated in a randomized controlled trial [30]. Bariatric surgery also offers an option in morbidly obese women who fail to lose weight by other means. The guidelines of the UK National Institute for Health and Clinical Excellence (NICE) state that “Surgery is recommended as a treatment option for people with morbid obesity (body mass index equal to or greater than 40  kg/m2) or with a BMI equal to or greater than 35 kg/m2 in the presence of significant comorbid conditions that could be improved by weight loss.” The most suitable technique for women aiming to achieve conception is laparoscopic adjustable gastric banding (LAGB) where the tightness of the band can be adjusted to accommodate for the increased demands of pregnancy. Despite reassuring evidence regarding pregnancy outcomes after this technique [31,32], more studies are needed before a definite conclusion can be reached regarding the safety of this procedure for women with fertility problems. To improve response to ovarian stimulation in obese women, a higher dose of gonadotropins may be needed. However, these patients have a particular tendency to overrespond to

ovarian stimulation and therefore any increased dosage should be administered with caution, particularly in obese women with polycystic ovary syndrome (PCOS). Key points Challenge: ART and the obese woman. Background: ●● Obesity has an adverse effect on the ­outcomes of assisted conception. ●● Higher doses of gonadotropins are required for ovulation induction or superovulation. ●● There is increased risk of early pregnancy loss, gestational diabetes and hypertensive disorders. ●● Fetal complications such as cardiac septal and neural tube defects are also more likely. Management options: ●● Dietary and lifestyle changes. ●● Pharmacologic agents for weight loss (orlistat). ●● Bariatric surgery: laparoscopic adjustable gastric band. ●● Increasing doses of gonadotropins for ovulation induction and superovulation; however, note that obese patients with PCOS may suffer from ovarian hyper stimulation syndrome.

Answers to questions patients ask Q1 How do I know if my weight is not right for IVF? A1.  Doctors will recommend that your body mass index (BMI) should be between 18.5 and 30 by the time you start IVF. When your BMI is less than 18.5 you are underweight. When it is 25–29.9, you are considered overweight. Above BMI of 30 you are medically classified as obese. Q2 How do I calculate BMI? A2.  First, you need to find out your weight in kilograms and your height

in meters. Then use one of the many apps and websites to calculate your BMI. Most of these apps and website tools will also help you convert your weight and height in imperial units to kilograms and meters. Q3 How does my weight affect my fertility? A3.  Obese women are more likely to have hormone imbalance and associated medical conditions which may prevent them from releasing eggs every month or not at all. Therefore, obese women usually take longer to get pregnant.

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Q4 Why does excessive weight reduce IVF success rate? A4.  Investigations and treatments of obese women are more difficult and may be costlier. During IVF, obese women require more fertility drugs, yet may not respond as expected. When they do eventually get pregnant, miscarriages are more common. Obese women are also more likely to suffer from medical conditions like hypertension, diabetes mellitus and increased chances of delivery by cesarean section. Q5 How can excessive weight affect my unborn child? A5. Early pregnancies are more likely to be miscarried in obese women. Of babies not miscarried, there are slightly increased risks of birth

defects affecting the heart, brain, spine or spinal cord. Q6 What is the best way to approach reducing my weight before IVF? A6. Adopt a positive attitude: doctors recommend weight loss because it will improve your fertility and increase your chances of successful treatment. In most cases, losing weight is all about self‐led adjustments to diet and physical activities, such that you are regularly burning more calories than you consume in food, snacks and drinks. In some cases, however, you need professional help. In a very small minority, your excessive weight is linked to a medical condition: if you are in this category, your doctor should refer you to the appropriate specialist.

References 1 Spandorfer SD, Kump L, Goldschlag D, Brodkin T, Davis OK, Rosenwaks Z. Obesity and in‐vitro fertilization: negative influences on outcome. J Reprod Med. 2004;49:973–7. 2 Wittemer C, Ohl J, Bailly M, Bettahar‐Lebugle K, Nisand I. Does body mass index of infertile women have an impact on IVF procedure and outcome? J Assist Reprod Genet. 2000;17:547–52. 3 Fedorcsak P, Dale PO, Storeng R, Ertzeid G, Bjercke S, Oldereid N, et al. Impact of overweight and underweight on assisted reproduction treatment. Hum Reprod. 2004;19:2523–8. 4 Lintsen AM, Pasker‐de Jong PC, de Boer EJ, Burger CW, Jansen CA, Braat DD, et al. Effects of subfertility cause, smoking and body weight on the success rate of IVF. Hum Reprod. 2005;20:1867–75.

5 Loveland JB, McClamrock HD, Malinow AM, Sharara FI. Increased body mass index has a deleterious effect on in vitro fertilization outcome. J Assist Reprod Genet. 2001;18:382–6. 6 Fedorcsak P, Dale PO, Storeng R, Tanbo T, Abyholm T. The impact of obesity and insulin resistance on the outcome of IVF or ICSI in women with polycystic ovarian syndrome. Hum Reprod. 2001;16:1086–91. 7 van Swieten EC, van der Leeuw‐Harmsen L, Badings EA, van der Linden PJ. Obesity and Clomiphene Challenge Test as predictors of outcome of in vitro fertilization and intracytoplasmic sperm injection. Gynecol Obstet Invest. 2005;59:220–4. 8 Fedorcsak P, Storeng R, Dale PO, Tanbo T, Abyholm T. Obesity is a risk factor for early Pregnancy loss after IVF or ICSI. Acta Obstet Gynecol Scand. 2000;79:43–8.

References 

9 Dokras A, Baredziak L, Blaine J, Syrop C, VanVoorhis BJ, Sparks A. Obstetric outcomes after in vitro fertilization in obese and morbidly obese women. Obstet Gynecol. 2006;108:61–9. 10 Leeners B, Rath W, Kuse S, Irawan C, Imthurn B, Neumaier‐Wagner P. BMI: new aspects of a classical risk factor for hypertensive disorders in pregnancy. Clin Sci (Lond). 2006;111:81–6. 11 Ku SY, Kim SD, Jee BC, Suh CS, Choi YM, Kim JG, et al. Clinical efficacy of body mass index as predictor of in vitro fertilization and embryo transfer outcomes. J Korean Med Sci. 2006;21:300–3. 12 Maheshwari A, Stofberg L, Bhattacharya S. Effect of overweight and obesity on assisted reproductive technology: a systematic review. Hum Reprod Update. 2007;13:433–44. 13 Mushtaq R, Pundir J, Achilli C, Naji O, Khalaf Y, El‐Toukhy T. Effect of male body mass index on assisted reproduction treatment outcome: an updated systematic review and meta‐analysis. Reprod Biomed Online. 2018;36(4):459–71. 14 Frankenthal D, Hirsh‐Yechezkel G, Boyko V, Orvieto R, Ron‐El R, Lerner‐Geva L, Farhi A. The effect of body mass index (BMI) and gestational weight gain on adverse obstetrical outcomes in pregnancies following assisted reproductive technology as compared to spontaneously conceived pregnancies. Obes Res Clin Pract. 2019;13(2):150–155. 15 Zhang JJ, Feret M, Chang L, Yang, M, Merhi Z. Obesity adversely impacts the number and maturity of oocytes in conventional IVF not in minimal stimulation IVF. Gynecol Endocrinol. 2015;31(5):409–413. 16 Dechaud H, Anahory T, Reyftmann L, Loup V, Hamamah S, Hedon B. Obesity does not adversely affect results in patients who are undergoing in vitro fertilization and embryo transfer. Eur J Obstet Gynecol Reprod Biol. 2006;127(1):88–93. 17 Steinkampf MP, Hammond KR, Nichols JE, Slay‐den SH. Effect of obesity on

recombinant follicle‐stimulating hormone absorption: subcutaneous versus intramuscular administration. Fertil Steril. 2003;80:99–102. 18 Ben‐Haroush A, Sirota I, Salman L, Son WY, Tulandi T, Holzer H, Oron G. The influence of body mass index on pregnancy outcome following single‐embryo transfer. J Assist Reprod Genet. 2018;35(7): 1295–1300. 19 Bellver J, Melo MA, Bosch E, Serra V, Remohi J, Pellicer A. Obesity and poor reproductive outcome: the potential role of the endometrium. Fertil Steril. 2007;88:446–51. 20 Metwally M, Ong KJ, Ledger WL, Li TC. Does high body mass index increase the risk of miscarriage after spontaneous and assisted conception? A meta‐analysis of the evidence. Fertil Steril. 2008;90:714–26. 21 Cavalcante MB, Sarno M, Peixoto AB, Araujo Junior E, Barini R. Obesity and recurrent miscarriage: A systematic review and meta‐analysis. J Obstet Gynaecol Res. 2019;45(1):30–8. 22 Metwally M, Saravelos SH, Ledger WL, Li TC. Body mass index and risk of miscarriage in women with recurrent miscarriage. Fertil Steril. 2010;94:290–5. 23 Lashen H, Fear K, Sturdee DW. Obesity is associated with increased risk of first trimester and recurrent miscarriage: matched case–control study. Hum Reprod. 2004;19:1644–6. 24 Fiala JE, Egan JF, Lashgari M. The influence of body mass index on pregnancy outcomes. Conn Med. 2006;70:21–3. 25 Cedergren MI, Kallen BA. Maternal obesity and infant heart defects. Obes Res. 2003;11:1065–71. 26 Shaw GM, Todoroff K, Schaffer DM, Selvin S. Maternal height and prepregnancy body mass index as risk factors for selected congenital anomalies. Paediatr Perinat Epidemiol. 2000;14:2349. 27 Farquhar CM, Gillett WR. Prioritising for fertility treatments: should a high BMI

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exclude treatment? Br J Obstet Gynaecol. 2006)113:1107–9. 28 Rich‐Edwards JW, Spiegelman D, Garland M, Hertzmark E, Hunter DJ, Colditz GA, et al. Physical activity, body mass index, and ovulatory disorder infertility. Epidemiology. 2002;13:184–90. 29 Mathys M. Pharmacologic agents for the treatment of obesity. Clin Geriatr Med. 2005;21:735–46, vii. 30 Metwally M, Amer S, Li TC, Ledger WL. An RCT of metformin versus orlistat for the

management of obese anovulatory women. Hum Reprod. 2009;24:966–75. 31 Skull AJ, Slater GH, Duncombe JE, Fielding GA. Laparoscopic adjustable banding in pregnancy: safety, patient tolerance and effect on obesity‐related pregnancy outcomes. Obes Surg. 2004;14:230–5. 32 Maggard MA, Yermilov I, Li Z, Maglione M, Newberry S, Suttorp M, et al. Pregnancy and fertility following bariatric surgery: a systematic review. JAMA 2008; 300:2286–96.

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37 The patient with Asherman syndrome Alessandro Conforti, Giuseppe Iorio, and Carlo Alviggi University Department of Obstetrics, Gynaecology, Urology and Reproductive Medicine, University of Naples Federico II, Naples, Italy

Case History 1: A 36-year-old women with a 4-year history of secondary tubal infertility is scheduled for IVF. She reports very light menstrual periods over the past 2 years, and previously she has had three dilatation and curettage procedures. Hysteroscopic assessment showed intrauterine adhesions. Case History 2: A 37-year-old women with a history of intrauterine adhesions, previously treated with hysteroscopic adhesiolysis. Despite surgery and reported complete removal of adhesions, this patient shows a thin endometrium and amenorrhea, resistant to estrogen therapy. Case History 3: A 31-year-old women presented with a history of heavy menstrual bleeding and infertility of 4 years duration. Her partner’s seminal fluid analysis showed reduced count and motility, and ICSI was recommended. Transvaginal scan showed a 3.5  cm submucosal fibroid, and she was advised to undergo hysteroscopic myomectomy prior to ICSI. The patient says she has read that this operation could be complicated by adhesions inside the uterus, which would severely reduce her chances of pregnancy, even with ICSI. She asks what is going to be done to reduce the chance of that happening.

Background Although the first case of intrauterine adhesions was published in 1894 by Heinrich Fritsch, it was only after 54 years that a full description of Asherman syndrome (AS) was carried out by Joseph Asherman [1]. This syndrome is characterized by the formation of adhesions in the uterine cavity or cervical canal, often associated with fibrosis in the endometrium [2]. The impact of AS on fertility is widely reported, with a high rate of infertility and miscarriage in women affected  [3]. Approximately, 40% of women with AS present

with infertility [4]. Furthermore, AS could also exert a detrimental effect during pregnancy causing abnormal placentation [5]. AS is being diagnosed with increased frequency, and it is now accepted that it could adversely affect embryo implantation during natural or assisted conception. Normal endometrial development is vital to the success of assisted conception treatment [6,7]. The common risk factors involved in AS development are miscarriage and postpartum dilatation and curettage (D&C)  [4]. However, any kind of intrauterine surgery could potentially cause AS [8].

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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The patient with Asherman syndrome

Hysterosalpingogram or hystero‐contrast‐ sonography (HyCoSy) can be useful for screening for this condition. Transvaginal scan is commonly used to assess the normality of the endometrium prior to or during assisted conception. In severe cases of AS, transvaginal scan may show characteristic features of a disrupted endometrial echo, with fibrotic ridges and areas of fluid trapped between the fibrotic lesions. However, hysteroscopy is the most accurate method for the diagnosis of AS because it can detect even a small amount of adhesions. Furthermore, immediate treatment can be performed in the same setting. Having said that, it is important to realize that surgery for AS is often technically challenging, requires special equipment and has a higher complication rate than diagnostic hysteroscopy. Therefore, if suitable expertise or equipment are not available at the time of hysteroscopic diagnosis of AS, or the patient was not appropriately counseled preoperatively, it is better to defer the treatment.

Management options Removal of adhesions The aims of treatment of AS are the removal of adhesions within the uterine cavity, to promote the repair and regeneration of the destroyed endometrium and the prevention of recurrence of the adhesions. Sometimes, several repeat procedures are required to successfully eliminate intrauterine adhesions [9–11]. Before the introduction of hysteroscopic approach, D&C was the most widely adopted treatment strategy for intrauterine adhesiolysis. Given the high risk of uterine perforation and the poor diagnostic value, this technique is considered obsolete nowadays. Hysteroscopic adhesiolysis is the gold standard approach. In favorable cases, hysteroscopic adhesiolysis could be performed in out‐patients setting without anesthesia. In these circumstances, given the potential damage to residual endometrium, cold‐knife approach should be considered as the preferred method. Several

techniques are available to remove the intrauterine adhesions. Adhesions that are situated in the midline may be removed by the use of hysteroscopic scissors. However, adhesions that are situated over the side wall of the uterus, called marginal adhesions, are best dealt with by use of the resectoscope with a pointed knife. The minimum amount of electrical energy should be used with a view to minimize further damage to the endometrium. In cases of severe and dense adhesions, it is highly recommended that the surgery is performed under ultrasound or laparoscopic guidance to minimize the risk of perforation. Cases of severe intrauterine adhesions with complete obliteration of the uterine cavity present a particularly challenging situation, and several innovative hysteroscopic strategies have been suggested. Among them is the technique in which a curved Pratt cervical dilator (gauge 13F) is inserted from the cervix towards one uterine cornu, under laparoscopic control, to create a “passage,” and then repeated on the other side. Then a 5‐mm hysteroscopy is passed through each passage to identify the tubal ostium. Thus, the obliterated uterine cavity is converted into a configuration of uterine “septum” between the two created passages. Following that, the created “septum” is resected hysteroscopically in the usual manner until the fundus is reached and the cavity is “liberated” [9]. Another innovative method is the “myometrial scoring” technique, also performed under laparoscopic or abdominal ultrasound control [10]. It consists of hysteroscopically cutting 6–8 4‐mm‐deep incisions from the fundus of the uterus to the isthmus using a knife electrode, aiming to uncover deep functioning endometrium. Both techniques were reported in six and seven patients, respectively, and were associated with restoration of menstruation and fertility in the majority of those patients [9,10].

Endometrial restoration and prevention of recurrence After division of adhesions, consideration must be given to preventing recurrence and promot-

Prevention 

ing endometrial growth. In the past, it was common to insert an intrauterine contraceptive device but the efficacy of such a method has been challenged. The placement of an intrauterine balloon (e.g. inflated pediatric Foley’s catheter) has instead been advocated. The intrauterine balloon should be left in situ for at least 5 days, or longer if there were extensive adhesions. Antibiotics should be used for as long as the uterine balloon is in place to reduce the risk of infection. Another alternative is to introduce an anti‐adhesion barrier such as hyalobarrier to the uterine cavity following the procedure. It is unclear if the combined use of hyalobarrier and intrauterine balloon produces better results than the use of balloon or anti‐adhesion gel alone. It is standard practice to start estrogen therapy after the surgery to promote regeneration of the endometrium [2,12]. One possible regimen is the use of 6 mg/day of estradiol valerate for a total of 6 weeks, and in the fifth and sixth weeks of the estrogen therapy a progestogen such as medroxyprogesterone acetate at a dose of 10  mg thrice daily could be added to complete the process of shedding of the endometrium. Thereafter, serial ultrasonography may be used to assess endometrial development at different stages of the cycle [13]. However, it is usual to offer second‐ look hysteroscopy to assess the normality of the cavity. It would also provide an opportunity to remove any residual adhesions and to provide a prognostic indicator for any future assisted conception treatment. Complete elimination of intrauterine adhesions may not imply normal endometrial function. Endometrium damaged by fibrosis may not regenerate. Other treatments (apart from estrogen) that have been advocated include the use of low‐dose aspirin [14], vaginal sildenafil [15,16] and pentoxifylline and high‐dose vitamin E [17], but the studies are either too small or not in the context of AS. However, perhaps they could be tried as a rescue strategy when estrogen‐­ progestin therapy fails, as in Case History 2.

Prevention There is an argument for the use of expectant or medical treatment for delayed miscarriage, and to offer surgery (evacuation of uterus) only in selected cases. If curettage is required it must be performed gently without undue trauma to the gravid uterine cavity. Intrauterine adhesions may also follow after intrauterine surgery such as removal of submucous fibroid (Case History 3). The lowest amount of electrical energy must be used to minimize damage to the endometrium. The routine use of intrauterine contraceptive device, intrauterine balloon or anti‐adhesion gel following intrauterine surgery needs further evaluation [18,19]. An early second look hysteroscopy after surgery could be of use to remove any possible adhesions and check the integrity of uterine cavity.

Key points Challenge: The ART patient with intrauterine adhesions (Asherman syndrome). Background: ●● 40% of women with Asherman syndrome present with infertility. ●● Intrauterine adhesions adversely affect success of IVF and may be a cause of recurrent IVF failure. ●● Hysterosalpingogram, ultrasound and hysteroscopy are useful investigations. Management options: ●● Hysteroscopic surgery is the gold standard for both diagnosis and treatment. ●● Cases of severe and dense adhesions are best performed under ultrasound or laparoscopic guidance to minimize the risk of perforation. ●● Reformation of intrauterine adhesions is common; it may be reduced by the use of estrogen therapy, intrauterine balloon or hyaluronic acid gel.

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The patient with Asherman syndrome

Answers to questions patients ask Q1 I am getting regular light periods, but your tests say that I have adhesions inside my womb. Shouldn’t I be getting no periods at all if that was correct? A1. Not necessarily. You get periods because the lining of the womb sheds. If the adhesions involve part, but not all of the lining, you would still get periods, but they will be lighter than normal, just like in your case. Q2 If you say that part of my womb lining is still working, can’t you do IVF, which I need anyway, and just put the embryos in that part? A2. Unfortunately, it doesn’t work that way. It is well known that after we put the embryos in the womb they do move around a bit before implanting. That is why, for example, we can put the embryo in the womb, and it ends up in the tube, leading to an ectopic pregnancy. So, the best way forward is to do an operation to cut all the adhesions, and then do your IVF. Q3 My previous doctor told me I had a very bad case of intrauterine adhesions,

where it is totally blocking the cavity of my womb, and he said that was why I was not having periods or getting pregnant. He tried cutting it, but with no success and I am not better. What can you do for me? A3. Cases such as yours have been reported to get better with treatment, but a few things are needed. You need to be treated by a team with special expertise in these advanced cases. We use special techniques that have been devised especially for similar cases. The operation is done using two scopes, one in the uterus (hysteroscopy) and one in the abdomen (laparoscopy) to provide maximum safety and effectiveness. Also, we need to give you medications after the operation to help the lining of the womb grow and stop the adhesions coming back. And sometimes we need to do more than one operation to achieve our goal of giving you a normal uterine cavity. But as I said, this has been done with similar cases before, and hopefully we can do it with yours.

References 1 Yu D, Wong Y‐M, Cheong Y, Xia E, Li T‐C. Asherman syndrome—one century later. Fertil Steril. 2008;89(4):759–79. 2 Conforti A, Alviggi C, Mollo A, De Placido G, Magos A. The management of Asherman syndrome: a review of literature. Reprod Biol Endocrinol. 2013;11:118. 3 Dreisler E, Kjer JJ. Asherman’s syndrome: current perspectives on diagnosis and management. Int J Womens Health. 2019;11:191–8.

4 Schenker JG, Margalioth EJ. Intrauterine adhesions: an updated appraisal. Fertil Steril. 1982;37(5):593–610. 5 Chen L, Zhang H, Wang Q, Xie F, Gao S, Song Y, et al. Reproductive outcomes in patients with intrauterine adhesions following hysteroscopic adhesiolysis: experience from the largest women’s hospital in China. J Minim Invasive Gynecol. 2017;24(2):299–304. 6 Bakas P, Hassiakos D, Grigoriadis C, Vlahos N, Liapis A, Gregoriou O. Role of hysteroscopy

References 

prior to assisted reproduction techniques. J Minim Invasive Gynecol. 2014;21(2):233–7. 7 Richter KS, Bugge K, Bromer J, Levy M. Relationship between endometrial thickness and embryo implantation, based on 1,294 cycles of in vitro; fertilization with transfer of two blastocyst‐stage embryos. Fertil Steril. 2007;87(1):53–9. 8 Taskin O, Sadik S, Onoglu A, Gokdeniz R, Erturan E, Burak F, et al. Role of endometrial suppression on the frequency of intrauterine adhesions after resectoscopic surgery. J Am Assoc Gynecol Laparosc. 2000;7(3):351–4. 9 McComb PF, Wagner BL. Simplified therapy for Asherman’s syndrome. Fertil Steril. 1997;68(6):1047–50. 10 Protopapas A, Shushan A, Magos A. Myometrial scoring: a new technique for the management of severe Asherman’s syndrome. Fertil Steril. 1998;69(5):860–4. 11 Capella‐Allouc S, Morsad F, Rongières‐ Bertrand C, Taylor S, Fernandez H. Hysteroscopic treatment of severe Asherman’s syndrome and subsequent fertility. Hum Reprod. 1999 1;14(5):1230–3. 12 Sugimoto O. Diagnostic and therapeutic hysteroscopy for traumatic intrauterine adhesions. Am J Obstet Gynecol. 1978;131(5):539–47. 13 Bromer JG, Aldad TS, Taylor HS. Defining the proliferative phase endometrial defect. Fertil Steril. 2009;91(3):698–704. 14 Weckstein LN, Jacobson A, Galen D, Hampton K, Hammel J. Low‐dose aspirin for

oocyte donation recipients with a thin endometrium: prospective, randomized study. Fertil Steril. 1997;68(5): 927–30. 15 Zinger M, Liu JH, Thomas MA. Successful use of vaginal sildenafil citrate in two infertility patients with Asherman’s syndrome. J Womens Health (Larchmt). 2006;15(4):442–4. 16 Sher G, Fisch JD. Vaginal sildenafil (Viagra): a preliminary report of a novel method to improve uterine artery blood flow and endometrial development in patients undergoing IVF. Hum Reprod. 2000;15(4):806–9. 17 Lédée‐Bataille N, Olivennes F, Lefaix J‐L, Chaouat G, Frydman R, Delanian S. Combined treatment by pentoxifylline and tocopherol for recipient women with a thin endometrium enrolled in an oocyte donation programme. Hum Reprod. 2002;17(5):1249–53. 18 Guida M, Acunzo G, Di Spiezio Sardo A, Bifulco G, Piccoli R, Pellicano M, et al. Effectiveness of auto‐crosslinked hyaluronic acid gel in the prevention of intrauterine adhesions after hysteroscopic surgery: a prospective, randomized, controlled study. Hum Reprod. 2004;19(6):1461–4. 19 Healy MW, Schexnayder B, Connell MT, Terry N, DeCherney AH, Csokmay JM, et al. Intrauterine adhesion prevention after hysteroscopy: a systematic review and meta‐analysis. Am J Obstet Gynecol. 2016;215(3):267–275.e7.

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38 The older patient Giselle Crawford and William Ledger Fertility and Research Centre, Royal Hospital for Women and School of Women’s and Children’s Health, University of New South Wales, Sydney, Australia

Case History 1: A couple have a one-year history of infertility. The female partner is 43 years old and the male partner is 37 years old. The female partner has a regular menstrual cycle, normal pelvic ultrasound and hysterosalpingogram. Baseline endocrine assessment on day 2 of the menstrual cycle showed follicle stimulating hormone (FSH) of 10.4  IU/L, luteinizing hormone (LH) of 7.3  IU/L, estradiol of 115 pmol/L and anti-Müllerian hormone (AMH) of 1.2 pmol/L. Transvaginal scan showed a total antral follicle count of 2. They now seek your second opinion, following two prior unsuccessful IVF cycles. On both occasions an antagonist protocol was used with 300 IU of highly purified human menopausal gonadotropin. The first cycle resulted in one oocyte that failed to fertilize with IVF. The second cycle resulted in two oocytes. Fertilization was attempted by intracytoplasmic sperm injection (ICSI); one oocyte failed to fertilize and the other failed to reach cleavage stage. Case History 2: A recently married couple were referred for fertility treatment. The male partner is 57 years of age with two teenage children from a previous relationship. The female partner is 34 years of age and nulliparous. Basic investigations included normal day 2 FSH, estradiol and AMH, normal pelvic ultrasound and hysterosalpingogram. A semen analysis showed a total sperm count of 13 million/mL with 22% progressive motility, Tygerberg strict morphology of 3% and DNA fragmentation index of 33% on sperm chromatin structure assay.

Background There continues to be an increasing demand for fertility treatments from couples affected by infertility due to advanced reproductive age. Many of these couples will be categorized as having “unexplained” infertility. The decline in fecundity with advancing female age is well documented and directly relates to the decline in the number of ­primordial

follicles. Tests of ovarian reserve, such as AMH and antral follicle count are useful for assessing the prognosis of assisted reproductive technologies (ART) and ensuring adequate pretreatment counseling. Similar to the trend seen in women, advancing paternal age (APA) is also on the increase. The definition of APA remains arbitrary, with no universally accepted criteria. Aging has a small but significant negative effect on sperm

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

Management options  229

parameters, including on semen volume, motility and morphology  [1]. APA has been associated with increased time to conception, decreased pregnancy rates, increased miscarriage and decreased live birth rates, although such data may be confounded by female partner age and decreasing coital frequency with age.

Management options Advanced maternal age (case history 1) Advanced maternal age (AMA) is associated with an increased risk of poor response to ovarian stimulation, increased chance of cycle cancelation increase in the rate of miscarriage, chromosomal defects in the offspring and obstetric risks such as preeclampsia and fetal growth restriction. The patient in Case History 1  had borderline elevation of FSH and a significantly low concentration of AMH, consistent with her chronologic age. The chance of pregnancy from IVF would be less than 10% per cycle [2]. Pretreatment counseling should include discussion of the options available to the couple including IVF with own oocytes while accepting low chance of success, use of donor oocytes, adoption and acceptance of infertility. Many couples will opt for the first option, but pretreatment ovarian reserve testing allows more directed “preparation for failure” and may allow couples to move more quickly away from repeated IVF cycles and into donor egg treatment  [3,4]. Successful treatment with donor oocyte depends almost entirely on the age of the donor and live birth rates of over 30% per cycle are not uncommon even in older recipients [2,5]. For the couple proceeding with IVF with the use of the female partner’s own oocytes, there are various proposed strategies for improving the response to superovulation; however, none has been rigorously evaluated. Ovarian stimulation with the use of very high doses of FSH has largely been abandoned as unsuccessful in favor of more moderate or mild stimulation

regimens, with no apparent difference in cumulative live birth rate [6,7]. The addition of luteinizing hormone to the controlled ovarian stimulation regimen has long been debated with conflicting evidence for its use in AMA patients [8]. The protocol could use either gonadotropin releasing hormone (GnRH) antagonist or a microdose flare regimen; the disadvantage of long protocol in this circumstance is the possibility that long suppression will prove to be irreversible and the ovarian response will be too poor to allow for oocyte retrieval to be undertaken. A delayed start GnRH antagonist regimen may prove beneficial for improved pregnancy rates, but data remain lacking for any improvement in live birth rate [9]. The protocol should be individualized to the patient and may include the decision to administer the hCG trigger for final oocyte maturation and proceed to oocyte retrieval even when a suboptimal number of follicles have reached the necessary criteria. A multitude of adjuvant therapies have been considered for the older patient with the aim of improving outcomes. Of those proposed, androgens such as DHEA and testosterone, and growth hormone show the most promise, but their use continues to be hindered by lack of data on live birth rate from randomized ­trials, safety data, as well as cost considerations [10,11]. The use of ICSI to fertilize oocytes in cases of nonmale factor infertility has not been shown to be associated with improved fertilization or pregnancy rates  [12]. However, in cases where the oocyte yield is extremely low and the possibility of improvement in subsequent cycles is virtually nonexistent, it seems prudent to minimize the chance of failed fertilization by using ICSI rather than IVF. Given the increasing rates of aneuploidy with advancing female age, use of preimplantation genetic testing for aneuploidy (PGT‐A) via blastocyst trophectoderm biopsy offered the possibility of improvement in the chance of livebirth per embryo transfer. However, although recent studies suggest an increase in

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per cycle pregnancy rate and ­reduction in miscarriage rate, the cumulative live birth rate remains unchanged [13]. The outcome in Case History 1 is all too familiar, and it is unsurprising that pregnancy did not result after two controlled ovarian stimulation cycles. Despite the many advances in ART, most datasets continue to show modest pregnancy rates of less than 10% per cycle for this age group, and several studies have now shown a clear association between low AMH and low pregnancy rate. The aim of counseling is to ensure the couple are fully informed about the prognosis of treatment and to discourage the couple from undergoing repeated failed treatment cycles which can incur a profound psychosocial and cost burden. If donor oocyte treatment is an acceptable option, this would provide the couple in Case History 1 with the best chance of success.

Advanced paternal age (case history 2) The impact of APA on reproductive outcomes has received less attention than AMA. There is conflicting evidence on the effect of paternal age on IVF outcomes, with some studies showing no difference, while others show an association between increasing male age and declining semen parameters, increased time to pregnancy and reduced conception rates [14–16]. There appears to be a modest increase in the risk of miscarriage with APA, although this risk is smaller than that associated with AMA  [17,18]. Furthermore, there is evidence that there is a small but significant increase in abnormalities in the offspring of men with advancing age, including autosomal conditions, aneuploidy, autism and schizophrenia [19–22]. However, the overall magnitude of these risks is negligible to small. For the couple in Case History 2, it is unlikely that they will conceive through intrauterine insemination. The young age and normal AMH of the female partner suggest a relatively high chance of pregnancy; however, efforts may be hampered by the high sperm DNA

fragmentation. Given the young age of the female partner, and her normal AMH, IVF/ ICSI treatment should involve single embryo transfer at blastocyst stage with vitrification of any further blastocysts. This maximizes chance of pregnancy while reducing the risk of multiple pregnancy considerably when compared with double embryo transfer. If attempts are hampered by poor fertilization or poor blastocyst development, the use of testicular sperm might be considered to help overcome the high DNA fragmentation  [23]. Other proposed treatments for high DNA fragmentation include antioxidant therapy, lifestyle changes, frequent ejaculation and, if present, varicocele repair [24].

Prevention Reproductive medicine specialists should do their best to educate the public that the image of prolongation of female fertility well into the fourth decade of life as portrayed by various celebrities and media stars is biologically implausible. Women and men who feel that having family is an important part of their life should endeavor to complete their family before the woman reaches her thirty‐sixth birthday in order to maximize the chances of uncomplicated conception and pregnancy. The likelihood of natural conception falls rapidly beyond this point and, contrary to expectation of many patients, IVF treatment is unlikely to be successful in women over 40 years of age. Hence, the strategy for prevention is to encourage couples to try to conceive before the woman’s age becomes a problem. Equally, men should be informed that their fertility also declines with age and that it is prudent to complete their family before their mid‐40s. Elective cryostorage of sperm before vasectomy is an increasingly common practice. Sperm cryopreservation should be discussed with men before vasectomy is undertaken although the man should also be advised of the irreversibility of vasectomy

Answers to questions patients ask  231

and the need for certainty in his decision. The use of long‐acting reversible forms of female contraception have reduced the demand for vasectomy, and in future, reliable and side‐effect‐free male contraception may become available. Cryopreservation of oocytes to allow possibility of conception for older women is also increasingly popular, particularly with the use of vitrification. However, oocyte cryopreservation should not allow women to be “lulled into a false sense of security” as this can lead to great disappointment later in life if the oocytes fail to produce a healthy child.

Key points Challenge: Older female or male patient undergoing ART. Background: Mean age of women and men attending IVF clinics is increasing. ●● Female aging adversely affects oocyte quality and oocyte yield after superovulation, reduces pregnancy rates and increases miscarriage rates. ●● Chromosomal defects are increased with increasing female age. ●● Obstetric risks such as preeclampsia and preterm birth are higher in older women. ●● There is conflicting evidence on the effect of male age on IVF outcomes, with some studies showing no difference, while others show a reduction in pregnancy rates with increasing male age. ●● Miscarriage rate appears to be increased with advancing male age. ●●

●●

There is a small but significant increase in abnormalities in children with older fathers; these include certain forms of autism, schizophrenia and, rarely, retinoblastoma.

Management options: ●● The older female patient should be counseled about the high probability of failure. ●● Very high doses of FSH do not improve the chance of live birth. ●● Superovulation protocol should use antagonist or microdose flare regimen. ●● Oocyte retrieval is unlikely to yield more than two or three eggs. ●● There is limited evidence for the added benefit of any adjuvant treatments. ●● Fertilization may best involve ICSI if the oocyte yield is low. ●● PGT-A may decrease the miscarriage rate, but with no effect on the cumulative live birth rate. ●● Men of advanced paternal age should be counseled about the risks of conception. ●● Welfare of child should be considered paramount, including consideration of the life expectancy of the intended parents. Prevention: ●● The basis of prevention is public health education about the relationship between the female age, male age and fertility. ●● Sex education in schools should include education about reproductive health in a wider context. ●● Social policy supporting both men and women in their parenting endeavors, such as improved parental leave policies and early childhood education, may also aid prevention.

Answers to questions patients ask Q1 What is my chance of pregnancy and live birth with fertility treatment? A1. Success rates require individualization; however, the pregnancy and live birth rate is less than 10% per cycle for female patients

40 years and older. There is an increased chance of poor ovarian response and cycle cancelation as well as failed fertilization resulting in no embryo for transfer.

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Q2 Will my child have an abnormality related to my age? A2. For older mothers there are increased risks of a pregnancy affected by chromosome problems, such as Down syndrome. There are also increased risks of pregnancy complications such as preeclampsia, gestational diabetes and fetal growth restriction, which

can pose subsequent concerns for the infant’s health. Q3 If fertility treatment does not work, what are my other options for parent­­­hood? A3. Options include use of donor oocytes or other nontraditional means to parenthood including adoption.

References 1 Cardona MW, Berdugo J, Cadavid JA. The effects of male age on semen parameters: analysis of 1364 men attending an andrology center. Aging Male. 2009;12(4):100–3. 2 HFEA. Fertility treatment 2017: trends and figures. Human Fertilisation and Embryology Authority, UK. www.hfea.gov.uk. Published 2017. Accessed November 2019. 3 Dewailly D, Andersen CY, Balen A, Broekmans F, Dilaver N, Fanchin R, Griesinger G, Kelsey TW, La Marca A, Lambalk C, et al. The physiology and clinical utility of anti‐Müllerian hormone in women. Hum Reprod Update. 2014;20(3):370–85. 4 Broer SL, Broekmans FJ, Laven JS, Fauser BC. Anti‐Müllerian hormone: ovarian reserve testing and its potential clinical implications. Hum Reprod Update. 2014;20(5):688–701. 5 Martin JR, Bromer JG, Sakkas D, Patrizio P. Live babies born per oocyte retrieved in a subpopulation of oocyte donors with repetitive reproductive success. Fertil Steril. 2010;94(6):2064–8. 6 van Tilborg TC, Torrance HL, Oudshoorn SC, Eijkemans MJC, Koks CAM, Verhoeve HR, Nap AW, Scheffer GJ, Manger AP, Schoot BC, et al. Individualized versus standard FSH dosing in women starting IVF/ICSI: an RCT. Part 1: The predicted poor responder. Hum Reprod. 2017;32(12):2496–2505. 7 Lensen SF, Wilkinson J, Leijdekkers JA, La Marca A, Mol BWJ, Marjoribanks J, Torrance H, Broekmans FJ. Individualised

gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI). Cochrane Database Syst Rev. 2. 2018;CD012693. 8 Mochtar MH, Danhof NA, Ayeleke RO, Van der Veen F, van Wely M. Recombinant luteinizing hormone (rLH) and recombinant follicle stimulating hormone (rFSH) for ovarian stimulation in IVF/ICSI cycles. Cochrane Database Syst Rev 5. 2017;CD005070. 9 Cozzolino M, Franasiak J, Andrisani A, Ambrosini G, Vitagliano A. “Delayed start” gonadotropin‐releasing hormone antagonist protocol in Bologna poor‐responders: a systematic review and meta‐analysis of randomized controlled trials. Eur J Obstet Gynecol Reprod Biol. 2019;23; 244:154–62. 10 Nagels HE, Rishworth JR, Siristatidis CS, Kroon B. Androgens (dehydroepiandrosterone or testosterone) for women undergoing assisted reproduction. Cochrane Database of Systematic Reviews. 2015;Issue 11. Art. No.: CD009749. DOI: 10.1002/14651858.CD009749.pub2. 11 Norman RJ, Alvino H, Hull LM, Mol BW, Hart RJ, Kelly TL, Rombauts L. Human growth hormone for poor responders: a randomized placebo‐controlled trial provides no evidence for improved live birth rate. Reprod Biomed Online. 2019;38(6):908–15.

References 

12 Bhattacharya S, Hamilton MP, Shaaban M, Khalaf Y, Seddler M, Ghobara T, et al. Conventional in‐vitro fertilisation versus intracytoplasmic sperm injection for the treatment of non‐male‐factor infertility: a randomised controlled trial. Lancet. 2001;357(9274):2075–9. 13 Rubio C, Bellver J, Rodrigo L, Castillón G, Guillén A, Vidal C, Giles J, Ferrando M, Cabanillas S, Remohí J. In vitro fertilization with preimplantation genetic diagnosis for aneuploidies in advanced maternal age: a randomized, controlled study. Fertil Steril. 2017;107(5):1122–9. 14 Hassan MA, Killick SR. Effect of male age on fertility: evidence for the decline in male fertility with increasing age. Fertil Steril. 2003;79 Suppl 3:1520. 15 Beguería R, García D, Obradors A, Poisot F, Vassena R, Vernaeve V. Paternal age and assisted reproductive outcomes in ICSI donor oocytes: is there an effect of older fathers? Hum Reprod. 2014;29(10): 2114–22. 16 Johnson SL, Dunleavy J, Gemmell NJ, Nakagawa S. Consistent age‐dependent declines in human semen quality: a systematic review and meta‐analysis. Ageing Res Rev. 2015;19:22. 17 Belloc S, Cohen‐Bacrie P, Benkhalifa M, Cohen‐Bacrie M, De MJ, Hazout A, et al. Effect of maternal and paternal age on pregnancy and miscarriage rates after

intrauterine insemination. Reprod Biomed Online. 2008;17(3), 392–7. 18 de la Rochebrochard E, Thonneau P. Paternal age and maternal age are risk factors for miscarriage; results of a multicentre European study. Hum Reprod. 2002;17(6):1649–56. 19 Sharma R, Agarwal A, Rohra VK, et al. Effects of increased paternal age on sperm quality, reproductive outcome and associated epigenetic risks to offspring. Reprod Biol Endocrinol. 2015;13:35. 20 Yang Q, Wen SW, Leader A, et al. Paternal age and birth defects: how strong is the association? Hum Reprod. 2007;22:696. 21 Sipos A, Rasmussen F, Harrison G, et al. Paternal age and schizophrenia: a population based cohort study. BMJ. 2004; 329:1070. 22 Wu S, Wu F, Ding Y, et al. Advanced parental age and autism risk in children: a systematic review and meta‐analysis. Acta Psychiatr Scand. 2017;135:29. 23 Esteves SC, Roque M, Bradley CK, Garrido N. Reproductive outcomes of testicular versus ejaculated sperm for intracytoplasmic sperm injection among men with high levels of DNA fragmentation in semen: systematic review and meta‐analysis. Fertil Steril. 2017;108(3):456–67.e1. 24 Esteves SC, Santi D, Simoni M. An update on clinical and surgical interventions to reduce sperm DNA fragmentation in infertile men. Andrology. 2019;Nov 6. doi: 10.1111/ andr.12724.

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39 Requests for mild or natural cycle IVF treatment Brad B. Swelstad and Suheil J. Muasher Department of Gynecology and Obstetrics, Division of Reproductive Endocrinology and Infertility, Johns Hopkins School of Medicine, Baltimore, Maryland, USA

Case History 1: A 32-year-old woman presents with a history of primary infertility resulting from tubal disease. Her cycle day 3 bloods are normal including a follicle stimulating hormone (FSH) level of 6 mIU/mL and E2 of 30 pg/mL. The male partner has a normal semen analysis. The couple was counseled for IVF and they expressed concerns over the high costs of medications not covered by insurance. Case History 2: A 35-year-old woman presents with a history of poor ovarian reserve. Her cycle day-3 bloods include an FSH level of 18 mIU/mL and E2 of 50 pg/mL. The male partner has oligospermia. The couple was counseled for IVF with intracytoplasmic sperm injection (ICSI); however, they wanted to explore the “natural cycle IVF” option.

Background IVF is the major treatment strategy of assisted reproductive technologies for dealing with infertility. IVF involves costly and complex ovarian stimulation regimens which are associated with potentially severe complications, high costs and serious discomfort to patients. Ovarian stimulation protocols aim to generate many oocytes to compensate for the inherent inefficiencies of human reproduction and methodologies in the IVF laboratory. Conventional long stimulation protocols include gonadotropin releasing hormone (GnRH) agonists to desensitize the anterior pituitary and prevent a luteinizing hormone

(LH) surge. They are used in combination with relatively high doses of exogenous follicle stimulating hormone (FSH) to override the selection of a single dominant follicle by sustaining the growth of a cohort of recruited follicles. Gonadotropin starting doses vary widely between 150 and 450 IU/day. GnRH antagonists, which are generally considered an integral part of mild IVF, are administered in the mid‐to‐late follicular phase of the menstrual cycle to act as competitive antagonists to the GnRH receptors on the anterior pituitary. GnRH antagonists prevent the LH and FSH rise by competitive blockade of the GnRH receptor and its downstream secondary messengers. GnRH antagonists do not induce

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

Management options 

an initial flare of endogenous gonadotropin release like GnRH agonists, but instead cause an immediate and reversible suppression of gonadotropin secretion. Compared with agonists, GnRH antagonists are associated with a reduced duration and dose of gonadotropin treatment. Mild or minimal ovarian stimulation is associated with less cost and medications and a lower risk of ovarian hyperstimulation syndrome (OHSS). However, a large randomized trial which included 404 couples compared mild IVF with conventional IVF and reported a live birth rate of 16% per cycle started with mild IVF, compared with 24% per cycle started for conventional IVF  [1]. Furthermore, cycle cancelation rates were found to be higher in the mild IVF group (18%) than the conventional IVF group (8.3%). In this study, the mild IVF group had more fresh cycles (2.2 per patient) than the conventional IVF group (1.6 per patient), resulting in a comparable live birth rate over a 1‐year period. In comparison, natural cycle IVF is associated with much higher cancelation rates (between 27% and 71%), reduced chances for

successful oocyte retrieval and a dramatically reduced ongoing pregnancy rate (between 0% and 6.1%) [2].

Management options Mild ovarian stimulation protocols use low dose medications to obtain more than one oocyte, but preferably less than 10  [3]. Mild stimulation protocols use 100–150 IU/day gonadotropins in the early follicular phase with a GnRH antagonist added after 5 days of stimulation (Figure 39.1). Natural cycle IVF consists of monitoring a normal cycle and then retrieving a single oocyte prior to the spontaneous LH surge. In a modified natural cycle, GnRH antagonists are used to prevent premature LH rises and human chorionic gonadotropin (hCG) is used for triggering final oocyte maturation. The risks of multiple pregnancies and OHSS are reduced with both mild stimulation and natural cycle; however, natural cycle IVF consistently results in the lowest pregnancy rates of all ovarian stimulation regimens [2].

hCG 10,000 IU

Cycle day

1 2 3 4 5 6

Transfer

FSH 100–150 IU/day

Retrieval

GnRH-antag. 0.25 mg/day

7 8 9 10 11 12 13 14 15 16 17 18 19 20

Figure 39.1  Mild stimulation protocol with gonadotropins/GnRH antagonist. Low dose gonadotropins in the early follicular phase 100–150 IU/day with a GnRH antagonist added 5 days after stimulation. FSH, follicle stimulating hormone; GnRH, gonadotropin releasing hormone; hCG, human chorionic gonadotropin.

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Requests for mild or natural cycle IVF treatment

Advantages of mild ovarian stimulation include less medications, fewer days of monitoring with blood assays and ultrasounds, simplified protocols for patient compliance, improved endometrial receptivity and minimal rates of OHSS. A meta‐analysis showed a lower number of retrieved oocytes with mild stimulation, but a significantly higher implantation rate [4]. Mild ovarian stimulation using 100  mg/day of clomiphene citrate for 5  days followed by 150 IU/day of gonadotropins with a GnRH antagonist is an effective strategy (Figure  39.2)  [5]. A randomized clinical trial compared conventional protocols to mild stimulation and demonstrated lower rates of aneuploidy in mild stimulation strategies [6]. Mild stimulation protocols for IVF may offer advantages to high responders. In Case History 1, the patient has good ovarian reserve and is a potential high responder to ovarian stimulation. Mild ovarian stimulation with 100 mg/day of clomiphene citrate followed by 100–150  IU/day of gonadotropins with a GnRH antagonist may be an appropriate option for her to reduce both the risk of severe OHSS and the cost of medications [7]. In Case History 2, the couple should be discouraged

from natural cycle IVF given its high cancelation and very low pregnancy rates. Mild IVF may be considered for the woman in Case History 2, as a 2004 randomized study in low responders showed higher pregnancy and implantation rates using a mild stimulation protocol with clomiphene citrate, gonadotropins and a GnRH antagonist when compared with conventional long protocols involving GnRH agonist suppression [8]. A similar 2017 randomized study which included 394 patients with low ovarian reserve showed equivalent ongoing pregnancy rates in both mild and conventional stimulation groups, but with much shorter duration and lower cost in the mild group [9]. Mild ovarian stimulation treatment strategies have a lower incidence and severity of complications compared with more aggressive attempts at controlled ovarian stimulation, but are associated with lower pregnancy rates per cycle started when compared with conventional IVF. Mild stimulation protocols may be suitable for both low responders and high responders, providing a reasonable balance between potential treatment risks and outcomes for some couples.

hCG 10,000 IU

Clomiphene Citrate 100 mg/day Cycle day

Gonadotropins 150 IU/day

1 2 3 4 5 6 7 8

Transfer

GnRH-antag. 0.25 mg/day

Retrieval

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9 10 11 12 13 14 15 16 17 18 19 20

Figure 39.2  Mild stimulation protocol with clomiphene citrate/gonadotropins/GnRH antagonist. Clomiphene citrate 100 mg/day in early follicular phase followed by low dose gonadotropins and a GnRH antagonist [5].

Answers to questions patients ask  237

Key points Challenge: Requests for mild or natural cycle IVF treatment. Background: ●● Mild IVF protocols often employ low dose of gonadotropins (100–150 IU/day) for ovarian stimulation and GnRH antagonist for pituitary suppression. They may also use cotreatment with clomiphene or aromatase inhibitors. ●● Mild or minimal stimulation protocols may optimize the balance between potential treatment risks and outcomes. ●● Mild stimulation may offer a simpler and affordable approach for some couples. ●● There is evidence that mild stimulation may be associated with beneficial effects on oocyte, embryo and endometrium. ●● Natural cycle IVF consists of monitoring a normal cycle and then retrieving a single oocyte prior to the spontaneous LH surge. Management options: ●● Careful counseling of couples wishing to have mild or natural cycle IVF is essential.

A large randomized trial comparing mild IVF with conventional IVF reports a live birth rate of 16% per cycle with mild IVF, compared with 24% per cycle for conventional IVF. Cycle cancellation rates were found to be higher in the mild IVF group (18%) compared with the conventional IVF group (8.3%). –– OHSS risk is more than halved with mild IVF (1.4%) when compared with conventional IVF (3.7%). –– Natural cycle IVF is associated with much higher cancellation rates (between 27% and 71%), reduced chances for successful oocyte retrieval and a dramatically reduced ongoing pregnancy rate (between 0% and 6.1%), and cannot therefore be recommended as an effective treatment. Mild IVF is associated with reduced duration and dose of FSH treatment, and an overall reduction in the duration of treatment. This may allow more IVF cycles to be fitted into a given time period than conventional IVF. ––

●●

Answers to questions patients ask Q1 I read that the first IVF baby in the world resulted from a natural cycle. So, why are you giving me these expensive stimulation medications? A1. You are right, Louise Brown resulted from a natural cycle, but those days the drugs we use today to control the pituitary gland and make IVF more successful were not discovered yet. Now, with these drugs we can significantly increase your chances of success with IVF, and that is why we use them.

Q2 During my last IVF cycle, you gave me high dose stimulation because you said my ovarian reserve was low, but yet I produced only two eggs and it did not work. Surely, next time you are going to give higher dose. A2. Actually, next time we are going to use a protocol called mild stimulation, where we use oral medications for the first 5 days, and then add small doses of the injectable stimulation medications. Studies have shown that in cases similar to yours this mild protocol gives similar or better results compared with the standard high dose protocol.

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Requests for mild or natural cycle IVF treatment

References 1 Heijnen EM, Eijkemans MJ, De Klerk C, Polinder S, Beckers NG, Klinkert ER, et al. A mild treatment strategy for in‐vitro fertilization: a randomized noninferiority trial. Lancet. 2007;369:743–49. 2 Verberg MF, Macklon NS, Nargund G, Frydman R, Devroey P, Broekmans P, et al. Mild ovarian stimulation for IVF. Hum Reprod Update. 2009;15:13–29. 3 Muasher SJ, Garcia JE. Fewer medications for in vitro fertilization can be better: thinking outside the box. Fertil Steril. 2009;92:1187–9. 4 Verberg MF, Eijkemans MJ, Macklon NS, Heijnen EM, Baart EB, Hohmann FP, et al. The clinical significance of the retrieval of a low number of oocytes following mild ovarian stimulation for IVF: a meta‐analysis. Hum Reprod. 2009;15:5–12. 5 Williams SC, Gibbons WE, Muasher SJ, Oehninger S. Minimal ovarian hyperstimulation for in vitro fertilization using sequential clomiphene citrate and gonadotropin with or without the addition of a gonadotropin releasing hormone antagonist. Fertil Steril. 2002;78:1068–72.

6 Baart EB, Martini E, Eijkemans MJ, Van Opstal D, Beckers NG, Verhoeff A, et al. Milder ovarian stimulation for in‐vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial. Hum Reprod. 2007;22:980–8. 7 Hubayter Z, Muasher SJ. Stimulation of the high responders and strategies to prevent ovarian hyperstimulation syndrome. Middle East Fertil Soc J. 2008;3:147–55. 8 D’Amato G, Caroppo E, Pasquadibiscegli A, Carone D, Vitti A, Viziello GM. A novel protocol of ovarian induction with delayed gonadotropin‐releasing hormone antagonist administration combined with high‐dose recombinant follicle stimulating hormone and clomiphene citrate for poor responders and women over 35 years. Fertil Steril. 2004;81:1572–7. 9 Youssef MA, van Wely M, Al‐Inany H, Madani T, Jahangiri N, Khodabakhshi S, et al. A mild ovarian stimulation strategy in women with poor ovarian reserve undergoing IVF: a multicenter randomized non‐inferiority trial. Hum Reprod. 2017;32:112–8.

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40 The patient with psychosexual problems Penny Goold and Elizabeth Howland University Hospitals Birmingham, Birmingham, UK

Case History 1: A couple with a 10-year history of primary unexplained infertility were referred to the fertility clinic. Previously they had one cycle of NHS funded IVF treatment but unfortunately did not conceive and did not have any frozen embryos. On taking the history, the couple reported that they were having intercourse three times a week with no problems. The female patient was examined, and no problems were identified. The consultant pondered with the couple that it was unusual that they hadn’t conceived at all despite all investigations being normal. This was when the female partner volunteered the information that sex was difficult. The male partner also shared the information that he had trouble with his erections and that he was unable to penetrate the vagina. The couple had not been able to consummate their marriage but had been too embarrassed to say. Case History 2: A female patient was referred to fertility clinic with inability to have penetrative sex, after 4 years of marriage.

Background It is important to identify psychosexual problems in couples referred for assisted reproductive techniques (ART) to prevent wasted time and inappropriate investigations, to identify potential challenges for undertaking ART (e.g. oocyte retrieval and embryo transfer) and to offer appropriate support. Addressing sexual difficulties early can help to achieve successful natural conception without the need for ART and may also prevent some women presenting with tokophobia (severe fear of pregnancy and childbirth) once pregnant. Psychosexual problems should also be addressed from a psychological and relationship

perspective. Infertility can cause psychological distress to a couple, with a negative impact on libido and frequency of sexual intercourse [1]. All healthcare professionals involved in ART hold some responsibility to ensure a couple have the best conditions from which to succeed as parents, and a satisfactory sexual relationship can be an important component of this. There is limited understanding of the true prevalence of psychosexual problems leading to infertility amongst couples who have been referred for ART. Sexual difficulties that develop because of infertility or the pressures of treatment are more common. Comparative studies demonstrate increased sexual dysfunction

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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reported in women with infertility with a prevalence ranging from 36–87% in a systematic review  [2]. The reality is that psychosexual problems are not always identified or addressed routinely within the ART setting.

Barriers to disclosure The disclosure of sexual problems prior to referral for ART may not have happened for various reasons including shame, embarrassment, denial, fear, distrust, loyalty and lack of knowledge. Individuals will often have feelings of failure and isolation. These barriers may prevent disclosure on initial visits, or with closed or insensitive questioning. The first indication of a problem may instead occur during intimate examinations or investigation and treatments. Another significant barrier to disclosure is the discomfort of the health care professional in discussing sexual matters with the patient. It is possible a couple can undergo ART without having their sexual difficulties addressed at all. Although ART may still be required, it is important to recognize and manage sexual difficulties appropriately. Sexual difficulties contributing to infertility or psychological distress may be present in either the female or male, or both and so both should be included in the assessment.

Women Psychosexual problems causing nonconsummation in women commonly consist of genito‐pelvic pain/penetration disorders (GPPD). This term encompasses vulvo‐vaginal pain, pelvic floor hypertonicity and vaginismus (an involuntary spasm of muscles that contract the vagina when penetration is attempted), whilst acknowledging the varied and overlapping presentations in clinical practice  [3]. Fear and anxiety of pain or vaginal penetration is often an overwhelming feature of the presentation.

The etiology and natural history of GPPD are individual to each patient and may be complex and multifactorial but include; f­antasies about what might be wrong (e.g. vagina too small or a blockage), negative attitudes towards sex (e.g. religious or culturally driven) or prior traumatic sexual or gynecologic experiences. The sexual difficulty may have been life‐long or acquired because of an event or several events, such as termination of a pregnancy, treatment for cervical dysplasia, fear of infection or an abusive relationship. In some cases, there may be no obvious precipitant, but anxiety or fear of pain or penetration has become the key issue often leading to avoidant behaviors in the couple. A meta‐analysis exploring sexual dysfunctions reported by infertile women found that the most affected areas were lubrication, orgasm and satisfaction, suggesting these elements are also important to explore within an ART assessment [2].

Men Sexual dysfunction in men have not been widely studied and have been complicated by inconsistent definitions but is considered to be a rare cause of male infertility [4]. Erectile dysfunction (ED) has been consistently found to have a higher prevalence (approximately 18%) in infertile men compared with the general population or fertile controls  [5]. Findings from studies of premature ejaculation (PE) in infertile men have been conflicting, partly due to inconsistent definitions and possibly due to geographic and cultural variations [5,6]. Other male sexual dysfunctions reported by infertile couples include hypoactive sexual desire disorder and reduced satisfaction [7]. The reality is sexual dysfunction in men is not routinely assessed in all ART settings. Retrograde ejaculation and anejaculation are discussed in Chapter 90.

Background 

Although ED may be psychogenic, it can be an early indicator of cardiovascular disease, diabetes or a side effect of medication (e.g. antidepressants), and so it is important to screen for these, and appropriate management may lead to better sexual function and ART outcomes. Identifying PE can remove potential barriers to natural conception with self‐ or partner‐led insemination.

History and assessment Informing a couple that sexual problems are common in people presenting with fertility problems and undertaking treatment is a safe and permissive introduction to enable further sensitive questioning about a couple’s sexual activity. Frequency and timing of intercourse

It is important to ask specific questions regarding the frequency and timing of sexual intercourse. Many patients may be timing intercourse around ovulation, or some every day. Some couples may only be having intercourse once a month or less. The pressure on couples to conceive can make intercourse less spontaneous and erotic, and lead to lack of arousal and enjoyment. It is recommended that couples have intercourse every 2–3  days in order to optimize their chances of natural conception [8]. Pain or difficulty with penetration

It is essential to establish the nature of the problem; is it painful sex or inability to achieve penetration or both, is it life‐long or acquired, is it situational (e.g. sex only or difficulty with tampons and/or speculum), were there any precipitating factors or past traumatic events (e.g. sexual abuse, termination of pregnancy), are there any exacerbating factors (e.g. loss of intimacy, distressing gynecologic examinations, abusive relationship), does she have any specific fears or fantasies (e.g. contamination or blockages).

Exclusion of pathology or anatomical anomalies as a cause for GPPD is a crucial component of the initial assessment. Differentiating between deep and superficial dyspareunia is important. Deep dyspareunia may be indicative of endometriosis or other pelvic pathology. Superficial dyspareunia caused by genital skin conditions (e.g. lichen sclerosis) or recurrent candidiasis are important to exclude as they can either be precipitating or exacerbating factors. Other sexual dysfunctions

Asking the couple what they think might be going on can be illuminating. Understanding what is happening for them currently during sex helps to identify if any further assessment may be required. If a psychosexual problem is identified, specifically asking about arousal, lubrication and orgasm is supported by the literature and may help identify the issues  [2]. Finding an opportunity to speak to the woman alone is important to establish any relationship or hidden issues. Psychosexual examination

Performing a genito‐pelvic examination of a woman with a psychosexual problem is an important part of the assessment. The way in which this is undertaken is important in understanding the nature of the problem but also to prevent reinforcement of any fantasies or fears of pain. Exclusion of any physical causes of a GPPD is important. Preceding the examination with a clear explanation of what is intended is important. Liberal use of lubricating gel and starting with a digital examination prior to a speculum examination is recommended. Sometimes the fear of genital penetration or pain is so extreme that any genital examination is difficult; patient may have the knees drawn together and retreat up the bed. It can be useful to ask the patient to use their own finger, this gives them back some control, it may also reveal lack of knowledge of own anatomy or

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disgust with touching genitals. If possible, a careful, slow examination with reassurance regarding normal anatomy, presence or absence of vaginismus and pelvic floor hypertonicity alongside a gentle explanation to the patient can be a therapeutic intervention.

Management options Psychoeducation Enabling the individual to understand what may be contributing to their problem through active listening and reflecting on their response to the examination can be powerful. A clear and simple explanation of what is going on for that individual can serve as a therapeutic intervention. Describing vaginal muscle spasm or presence of a hypertonic pelvic floor musculature, alongside the theory of avoidance cycle with pain, fear, anxiety and musculature tension is useful. Reference to the female sexual response cycle and the impact of pain and fear on sexual arousal and pleasure can contribute to their understanding [9]. Recommendation of digital self‐exploration at home can be beneficial for some patients to reinforce examination findings, discussions and contribute to desensitizing the genital area to touch.

Lubricants The use of lubricants for self‐exploration, massage, vaginal trainers and sexual intercourse is crucial. A study identified that one in four couples trying to conceive use a lubricant  [10]. These should be nonirritant and hypoallergenic and acceptable to the patient. With regard to natural fertility, lubricants have not been shown to reduce the chances of conception  [11]. It is also helpful to recommend general avoidance of skin irritants in the genital area to prevent dryness and inflammation.

Lignocaine/Lidocaine Topical lignocaine (5% ointment or 2% jelly) can be used in the management of GPPD but the evidence is limited and conflicting. The only double‐blind placebo‐controlled trial showed no significant difference in sexual function between lidocaine and placebo in the treatment of vulvodynia, but numbers were small  [12]. Other studies have shown some benefit in sexual function [13,14]. Evidence for use in vaginismus is based on case reports although overlap in definitions complicates interpretation of these studies. Topical anesthetics may cause stinging, sensitization or numbness on the partner’s genitals which sometimes limits their use.

Vaginal trainers Vaginal trainers (also known as dilators) are initiated by a wide range of health care professionals including gynecologists, psychosexual therapists and physiotherapists for the management of GPPD, despite the fact that the evidence for their use is limited [15,16]. One hypothesis is that they work through desensitization, but their success is likely to be multifactorial including helping the patient understand her own genital anatomy, educating her that her fears of pain and penetration are unfounded, increasing confidence and helping her to gain control. They may not work for all patients; a woman who is retreating up the bed on examination is likely to be terrified by a series of vaginal trainers. Used in isolation without the individual understanding her own fears or physical and emotional response to penetration, they are less likely to be effective. Psychoeducation and referral for support from psychosexual therapy or physiotherapy are likely to be more valuable.

Psychosexual therapy Psychosexual therapy is well established for the management of GPPD and other sexual dys-

Management options 

functions. There are different approaches to treatment. Cognitive behavioral therapy (CBT) is the most widely used approach and has been found to be effective in the management of vaginismus [17,18]. The approach is problem‐orientated, includes psychoeducation, and the patient or couple are set homework. Sensate focus is utilized to remove the pressure on sexual performance and focus on awareness of sensations that might start with fully clothed nongenital pleasure with the avoidance of attempts at intercourse. Cognitive restructuring, relaxation techniques and the use of vaginal trainers can all form part of the CBT approach alongside an assessment of the couple’s relationship. Psychodynamic psychotherapy is an alternative approach that explores patients’ emotions and defenses in relation to their sexual problem, utilizing the therapeutic relationship to help solve it. Use of the genital examination can play an important part in this process. Quite often therapists take an integrated approach and blend different methodologies to suit the patient.

or pelvic pain disorders including v­aginismus. Although there are positive outcomes reported in case studies and small case series, clinical trial evidence is required to determine its true efficacy comparative to noninvasive management. Refractory cases that are not responsive to psychoeducation, psychosexual therapy or physiotherapy could be considered.

Management of men with psychosexual problems Management of men presenting with sexual difficulties amongst couples attending for ART may not be the remit of the ART specialist, but identification and initial assessment will help with appropriate onward referrals. Erectile dysfunction

Pelvic floor physiotherapy has been found to help achieve satisfactory sexual intercourse in women with GPPD, particularly in women who have provoked genital pain [19]. This is likely due to a multimodal approach which includes patient education and can encompass techniques such as manual tissue manipulation, stretching and relaxation exercises, use of vaginal trainers, electromyographic biofeedback (EMG) and electrical stimulation. All these methods may contribute by improving pelvic floor function, increasing knowledge and confidence, reducing fear through desensitization and developing effective relaxation techniques.

It is important to establish details of the erectile dysfunction (ED). Is it life‐long or acquired, situational (e.g. does not occur with masturbation) and were there any precipitating factors (e.g. only since trying to conceive)? Sudden onset is more likely to suggest a psychogenic cause. If the man is still experiencing early morning erections and can maintain erections with masturbation, then this is more likely to be psychogenic. Loss of early morning erections is more suggestive of organic pathology. In all cases of ED, the man should be screened for cardiovascular disease, diabetes and testosterone deficiency. A routine medical history should include identification of medications that can precipitate ED, a family history (cardiovascular disease or diabetes) and a psychosocial history including smoking, recreational drug and alcohol use and any background mental health issues.

Botulinum toxin

Premature ejaculation

Physiotherapy

Botulinum toxin injections have been used therapeutically for the management of ge­nital

It is important to establish details of the PE. Is it lifelong or acquired, average time to ejaculation to determine whether this is true PE or

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perceived PE, is vaginal penetration possible, and if not has a second attempt at intercourse been tried. Understanding if it is an issue for the partner and if it is impeding attempts to conceive helps to plan management. Occasionally it may be anxiety from the male about performance, but the female partner does not believe it is a problem.

Undertaking ART in a woman with psychosexual problems In patients who have not been able to have successful vaginal intercourse, intrauterine insemination (IUI) may be an option [8]. IUI cycles require monitoring with transvaginal ultrasound (TVUS), and the insemination would require a speculum examination. Women with psychosexual problems may not be able to tolerate TVUS or speculum examinations and this need be considered prior to commencing this treatment. In  vitro fertilization (IVF) may also be a possibility and carries a higher chance of pregnancy than IUI, although once again there may be difficulties encountered in monitoring with TVUS and embryo transfer. Oocyte retrieval is usually performed under

sedation or general anesthesia, so it is generally less of an issue. Careful explanation of any procedures under sedation or anesthesia is recommended to prevent reinforcement of underlying anxieties.

Key points Challenge: Psychosexual problems in ART patients. Background: The prevalence of psychosexual problems in ART patients is difficult to ascertain. ●● Psychosexual problems can lead to infertility, relationship problems and fear of childbirth. ●●

Management options: ●● Sensitive and comprehensive sexual history ●● Psychosexual examination ●● Psychoeducation ●● Lubricants and consideration for vaginal trainers (dilators) ●● Psychosexual therapy ●● Physiotherapy Prevention: Early sensitive enquiry regarding the couple’s sexual history and relationship is key, in order to identify and address problems early on, and seek appropriate expert care.

Answers to questions patients ask Q1 How often and in what position should we have sex? A1. The recommendation is that ­couples have regular intercourse every 2–3  days. There is no evidence that any particular position during intercourse will improve conception.

Q2 My partner is unable to penetrate as he feels as if there is “a wall blocking entry.” A2. We will examine you to see if there may be any physical problem. However, in most occasions, we find that there is no physical problem, but a perception in the minds of the couple.

References 1 Luk BH, Loke AY. The impact of infertility on the psychological well‐being, marital relationships, sexual relationships, and quality of life of couples: a systematic review. J Sex Marital Ther. 2015;41(6):610–25.

2 Mendoça C, Arruda JT, Noll M, Campoli PMO, Amaral WND. Sexual dysfunction in infertile women: A systematic review and meta‐analysis. Eur J Obstet Gynecol Reprod Biol. 2017;(215):153–63.

References 

3 American Psychiatric Association. Genito‐ pelvic pain/penetration disorder. In: Diagnostic and Statistical Manual of Mental Disorders. 5th ed. (pp. 437–440). Arlington VA: American Psychiatric Association;2013. 4 Krausz, C. Male infertility: pathogenesis and clinical. Best Pract Res Clin Endocrinol Metab. 2011;25, 271–85 5 Gao J, Zhang X, Su P, Liu J, Shi K, Hao Z, Zhou J, Liang C. Relationship between sexual dysfunction and psychological burden in men with infertility: a large observational study in China. J Sex Med. 2013;10:1935–42. 6 Lotti F, Corona G, Rastrelli G, Forti G, Jannini EA, Maggi M. Clinical correlates of erectile dysfunction and premature ejaculation in men with couple infertility. J Sex Med. 2012;9:2698–2707. 7 Lara LA. Effect of infertility on the sexual function of couples: state of the art. Recent Pat Endocr Metab Immune Drug Discov. 2015;9:46–53. 8 NICE. Fertility problems: assessment and treatment. United Kingdom: National Institue for Health and Care Clinical Guidelines [CG156];2013. 9 Basson R, Brotto LA, Laan E, Redmond G, Utian WH. Assessment and management of women’s sexual dysfunctions: problematic desire and arousal. J Sex Med. 2005;2:291–300. 10 Ellington J, Daughty S. Prevalence of vaginal dryness in trying to conceive couples. Fertil Steril. 2003;79 (Suppl 2):21–2. 11 McInnery KA et al. Lubricant use during intercourse and time to pregnancy: a

prospective cohort study. BJOG. 2018;(125)12:1541–8. 12 Foster DC et al. Oral desipramine and topical lidocaine for vulvodynia. Obstet Gynecol. 2010;116:583–93. 13 Danielsson I, Torstensson T, Brodda‐Jansen G, Bohm‐Starke N. EMG biofeedback versus topical lidocaine gel: a randomized study. Acta Obstet Gynecol. 2006;85(11):1360–7. 14 Zolnoun DA, Hartmann KE, Steege JF. Overnight 5% lidocaine ointment for treatment of vulvar vestibulitis. Obstet Gynecol. 2003;102(1):84–7. 15 Macey K, Gregory A, Nunns D, das Nair R. Women’s experiences of using vaginal trainers (dilators) to treat vaginal penetration difficulties diagnosed as vaginismus: a qualitative interview study. BMC Womens Health. 2015;15:49. 16 Idama TO, Pring DW. Vaginal dilator therapy an outpatient gynaecological option in the management of dyspareunia. J Obstet Gynaecol. 2000;20(3):303–5. 17 Bergeron S, Merwin KE, Dubé JP. Couple sex therapy versus group therapy for women with genito‐pelvic pain. Curr Sex Health Rep. 2018;10:79–87. 18 Masheb RM, Kerns RD, Lozano C, Minkin MJ, Richman S. A randomized clinical trial for women with vulvodynia: cognitive‐ behavioural therapy vs. supportive psychotherapy. Pain. 2009;141:31–40. 19 Morin M, Carroll MS, Bergeron S. Systematic review of the effectiveness of physical therapy modalities in women with provoked vestibulodynia. Sex Med Rev. 2017;5:295–322.

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41 The patient needing third-party reproduction Imad Aboujaoude and Teddy Tadros Fertility Center, Aboujaoude Hospital, Beirut, Lebanon

Case History 1: A couple, both 35 years old, were seen in the fertility clinic. They have been trying to conceive for 4 years. The male partner has testicular (nonobstructive) azoospermic and no sperm were retrieved on micro-TESE on two occasions. They wish to consider treatment with donor sperm.

Case History 2: A 23-year-old woman was seen in the fertility clinic. She has been married for one year and was recently diagnosed with premature ovarian failure. She wishes to discuss options for fertility treatment.

Background At a most basic level, sperm, oocytes and a uterus are essential for pregnancy. However, if any of these are not available, pregnancy can still occur through third‐party reproduction. Sperm donation has been available for a very long time and was reported as early as 1884 at the Jefferson Medical College in Philadelphia, USA [1]. Yet, it was not until the 1970s that the sperm bank industry became very popular and commercialized, especially in the USA  [1]. Oocyte donation had to await the successful development of IVF in 1978 in the UK [2], and was reported for the first time in 1983  in Australia  [3]. The first ever report of a baby being born following treatment by gestational surrogacy was from the USA in 1985  [4]. Uterine transplantation was attempted first in humans in Saudi Arabia in 2000  [5], but the first livebirth after a uterine transplant was

reported in 2015 from Sweden [6]. Third‐party reproduction has, thus, been a truly collaborative global effort In 1992, a group in Brussels reported the first pregnancy after intracytoplasmic sperm injection (ICSI) [7], a milestone in the management of male infertility and thereafter followed a reduction in the need for donor insemination  [8]. Nonetheless, for a small number of couples, donor sperm gives them the only chance of having a genetically related child. The common indications for donor sperm treatment include the most severe cases of male factor infertility (e.g. azoospermia with no sperm in the testis), genetic or chromosomal disorders not amenable to preimplantation genetic testing (PGT) in the male partner, single women or those with a nonmale partner. However, some couples who potentially can achieve pregnancy with ICSI will opt for donor insemination (DI) because they find ICSI too

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

Management options 

much for them, either financially, physically or mentally. As for oocyte donation, the indications include premature ovarian failure, advanced maternal age with poor ovarian reserve, poor oocyte quality and genetic or chromosomal disorder not amenable to PGT. Surrogacy is far more complex, both legally and ethically. It is indicated where the uterus is absent, either congenitally or after hysterectomy with ovarian conservation, nonfunctioning due to adhesions or pelvic radiotherapy or in women with unexplained recurrent miscarriage due to uterine factors. Another indication is where pregnancy would be hazardous to the woman’s health because of medical conditions. Uterine transplantation is also indicated where the uterus is absent or nonfunctioning. Third‐party reproduction has specific technical, ethical and legal issues, and it is therefore ideal to have specifically trained and designated staff to deal with it [9].

Management options Third‐party reproduction raises concerns about psychosocial screening and counseling of patients seeking treatment  [10]. It also raises, on one hand, ethical dilemmas about the privacy of gamete donors and the nature of relationships with the children born through use of their gametes and, on the other hand, the implications not only for the couple, but also for the welfare of the child. Therefore, psychological counseling with a health professional has become a central recommendation in guidelines issued in the USA, UK, Australia and New Zealand among other countries. In Europe, gamete donors are screened carefully according to professional guidelines and in accordance with the regulatory requirements of the European Tissue Directive  [11]. Furthermore, a detailed medical and family history with particular details relating to any known inherited disorders, sexual and other infectious disease history is obtained to ensure there are no concerns. The donor undergoes

genetic screening including karyotype, carrier status for common genetic conditions (e.g. cystic fibrosis gene mutation) and an infectious workup in order to detect cytomegalovirus (CMV) and for sexually transmitted infections such as gonorrhea, syphilis, hepatitis B, C and HIV.

Sperm donation When screening potential sperm donors, it is vital to look for assurance of good health status with no hereditary disease, no past history for sexually transmitted disease and absence of genetic abnormalities. In addition, psychological assessment is recommended for all sperm donors in order to detect potential psychological risks and to ascertain whether the donor is well informed about the degree of disclosure and whether any plans exist for future contact. Furthermore, the donor must be of legal age and younger than 40 years old in order to limit to the maximum the potential hazards related to age  [12]. The donor must have a seminal fluid analysis to ensure that it is normal, and a test freeze–thaw should be performed to ensure its freezing durability. Once cleared, semen samples will be collected on several visits and quarantined for 6  months in liquid nitrogen. At the end of this period, the donor will be retested for HIV, hepatitis B and C, and if negative, the samples can be released for use in treatment. For recipient couples, it is important to evaluate the female partner to choose the right treatment (DI or IVF). That includes tubal patency and ovarian reserve. CMV status should be matched between sperm donor and female recipient. If the tubes are patent, DI can be performed with a recommended maximum of 6 cycles. If not, IVF will be required. A 2019 retrospective analysis of 1805 cycles of DI demonstrated that 24.8% resulted in clinical pregnancy and 21.3% resulted in a live birth [13]. Cumulative delivery rates in different recipient age groups after DI have been reported in 6,630 couples  [14]. The live birth

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rate was 14% per cycle, with a cumulative rate of 77% after 12 cycles. Subgroup analysis showed an expected cumulative rate after 12 cycles of 87% for the group aged 20–29 years, 77% for ages 30–34, 76% for ages 35–37, 66% for ages 38–39 and 52% for ages 40–45. Neither indication nor ovarian stimulation protocol had any significant effect on the live birth rate  [14]. Similar to all fertility outcomes (whether natural or assisted), female (recipient) age is the most important predictor of success with DI [15,16]. With regard to the donor sample, there was no improvement in pregnancy rate over 20 million total motile sperm per insemination.

Oocyte donation Oocyte donation accounted for about 10% of ART cycles in the USA in 2015, with a live birth rate around 50% [17]. Because of declining oocyte quality with age, donors must be younger than 36, and they will undergo the same screening process as sperm donors. Taking into consideration the regulations of each country concerning oocyte donation, the single biggest problem that some might face is the lack of adequate number of donors. Attempts to overcome this shortage include cross‐border reproductive care (see Chapter  113) and the use of “egg sharing,” where oocyte donation is offered by women undergoing IVF if they meet the age and screening requirements. It has been shown that the prognosis for oocyte donation is similar with both sharing and altruistic donors [18]. In order to achieve a successful implantation, two elements must be met: a receptive endometrium and the synchronization between the donor and the recipient. Nowadays, with the proven efficiency of embryo vitrification, fresh and vitrified embryos can be used. Moreover, with the use of GnRH antagonist protocol and agonist trigger in the donor, the risk of ovarian hyperstimulation syndrome in the donor is almost eliminated [19].

Surrogacy In surrogacy, the “surrogate” carries a baby for an infertile “commissioning” couple, either as “straight” (the surrogate uses her own eggs; acts as oocyte donor and surrogate) or “host” surrogacy (commissioning couple’s embryos transferred into her uterus). Needless to say, surrogacy is an ethical and legal minefield. Therefore, professional counseling is mandatory. In addition, it is strongly recommended that both parties take proper specialized legal advice before undergoing treatment. They will need to take advice on insurance policies for the surrogate, payment of expenses and the legal cost for the change in the parental order. It must be clear that the surrogacy arrangement is between the commissioning couple and the surrogate, and the clinic does not become involved. The commissioning male and female partners will effectively be sperm and oocyte donors, respectively. Therefore, they need to undergo the same infection screening required from gamete donors.

Uterine transplantation Uterine transplantation has been introduced as a treatment option for women with absolute uterine factor infertility. This includes congenital uterine agenesis (Mayer‐Rokitansky‐ Küster‐Hauser syndrome), major congenital uterine malformations (hypoplastic uterus), a surgically absent uterus or acquired conditions (intrauterine adhesions, leiomyoma) linked to uterine malfunction that causes implantation failure or defective placentation [20]. Although many livebirths have been reported from numerous centers [6,20], the procedure is very complex and requires live or dead donor, major surgeries, immunosuppression, IVF and further surgery to remove the transplanted uterus after the achievement of livebirth, to avoid the continued use of immunosuppressants  [21]. Although the indications are similar to those of surrogacy, many surveys have indicated that

Answers to questions patients ask  249

women prefer uterine transplantation to surrogacy  [20]. Thus, the acceptance of uterine transplantation is high, although the

Key points

procedure remains in its infancy and more progress is required before becoming established practice [20].

●●

Age of female partner is the most important predictor of success with the use of donor sperm insemination. Live birth rates with donor oocytes depend on the age of the donor and can range from 35% to 65%.

Challenge: Request for third-party reproduction.

●●

Background: Indications for donor sperm treatment include the most severe cases of male factor infertility (e.g. azoospermia with no sperm in the testis), genetic or chromosomal disorders not amenable to PGT, single women or those with a nonmale partner. ●● Indications for oocyte donation include premature ovarian failure, advanced maternal age with poor ovarian reserve, poor oocyte quality and genetic or chromosomal disorder not amenable to PGT. ●● Indications for surrogacy include where the uterus is absent, either congenitally or after hysterectomy with ovarian conservation, nonfunctioning due to adhesions or pelvic radiotherapy or in women with unexplained recurrent miscarriage due to uterine factors. Another indication is where pregnancy would be hazardous to the woman’s health because of medical conditions. ●● Indications for uterine transplantation is absolute uterine factor infertility including uterine agenesis, major congenital uterine malformations (hypoplastic uterus), a surgically absent uterus or acquired conditions (intrauterine adhesions, leiomyoma) linked to uterine malfunction that causes implantation failure or defect placentation. ●● Live birth rate with donor insemination varies from 11% to 14% per cycle and an expected cumulative delivery rate of 77% after 12 cycles.

Management options: ●● Arrange for detailed counseling for both the donor and recipient couple. ●● All donors need to have a detailed medical and family history, with particular emphasis on known inherited disorders and sexually transmitted diseases. ●● The donor needs to be screened to ensure a normal karyotype, carrier status for common genetic conditions (e.g. cystic fibrosis gene mutation), CMV and for sexually transmitted infections such as gonorrhea, syphilis, hepatitis B, C and HIV, including HTLV in susceptible populations. ●● The choice of proceeding with donor insemination or IVF with donor sperm will depend on factors including age of female partner and tubal status. ●● Synchronization of donor’s and recipient’s menstrual cycles will be required for oocyte donation treatment. ●● It should be strongly recommended that a commissioning couple and a surrogate take proper legal advice, have agreement on insurance policies for the surrogate, payment of expenses and the legal cost for the change in the parental order. ●● Livebirths have been reported after uterine transplantation, but the technique, although promising and has high acceptance, is still in its infancy.

●●

Answers to questions patients ask Q1 How will you match the sperm donor characteristics to my husband’s? A1. We will definitely match for ethnic group, and try to match for physical

characteristics, such as height, build and hair color, as much as possible. But as you know, children are usually not a copy of their

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parents, so an exact match is not really necessary. Also, our children usually copy our behavior, such as how we talk or walk, through interacting with us, and that is what makes us look similar. Q2 I need egg donation treatment because I have developed premature ovarian failure. My younger sister is willing to donate to me. Do you think it is a good idea? A2. Premature ovarian failure may have a genetic component, so first degree female relatives have a higher risk of developing it and may have lower quality eggs. In fact, studies have shown that women with premature ovarian failure have lower chances of pregnancy with egg donation if the donors were their sisters compared with a nonrelated donor.

Therefore, we do not recommend using your sister as a donor. Q3 I have never had periods, and I am told the reason is I was born with an infantile uterus. What can I do to have a baby? A3. The options available are surrogacy uterus transplantation or adoption. Surrogacy involves taking your eggs, fertilizing them with your husband’s sperm to form embryos, and them putting the embryos in another woman’s womb to have the pregnancy and them give you the baby after birth for adoption. Technically it is easy, but emotionally and legally it is rather complex and is not available in every country. The other option is uterine transplantation, which has been used successfully in a number of cases but is still considered experimental.

References 1 Ombelet W, Van Robays J. Artificial insemination history: hurdles and milestones. Facts, views Vis ObGyn. 2015;7(2):137–43. 2 Steptoe PC, Edwards RG. Birth after the reimplantation of a human embryo (letter). Lancet. 1978;ii:366. 3 Trounson A, Leeton J, Besanko M, Wood C, Conti A. Pregnancy established in an infertile patient after transfer of a donated embryo fertilised in vitro. Br Med J (Clin Res Ed). 1983;286(6368):835–8. 4 Utian WH, Sheean L, Goldfarb JM, Kiwi R. Successful pregnancy after in vitro fertilization and embryo transfer from an infertile woman to a surrogate. N Engl J Med. 1985;313:1351–2. 5 Fageeh W, Raffa H, Jabbad H, Marzouki A. Transplantation of the human uterus. Int J Gynaecol Obstet. 2002;76(3):245–51.

 6 Brännström M, Johannesson L, Bokström H, Kvarnström N, Mölne J, Dahm‐Kähler P, et al. Livebirth after uterus transplantation. Lancet (London, England). 2015;385(9968):607–16.  7 Palermo GD, Joris H, Devroey P, Van Steirteghem AC. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet. 1992;340(8810):17–8.  8 Hamilton M. Sperm donation in the United Kingdom in 2010. Hum Fertil (Camb). 2010 Dec;13(4):257–62.  9 Black JJ. Egg donation: issues & concerns. MCN Am J Matern Child Nurs. 2010;35(3):132–9. 10 Benward J. Mandatory counseling for gamete donation recipients: ethical dilemmas. Fertil Steril. 2015;104(3):507–12.

References 

11 Human Fertilisation and Embryology Authority. Code of Practice. 9th ed. Human Fertilisation and Embryology Authority; 2019. 12 ASRM. 2006 Guidelines for Gamete and Embryo Donation. Fertil Steril. 2006;86(5 Suppl 1):S38–50. 13 Zhang A, Ma X, Zhang L, Zhang X, Wang W. Pregnancy and offspring outcomes after artificial insemination with donor sperm: A retrospective analysis of 1805 treatment cycles performed in Northwest China. Medicine (Baltimore). 2019;98(16):e14975. 14 De Brucker M, Haentjens P, Evenepoel J, Devroey P, Collins J, Tournaye H. Cumulative delivery rates in different age groups after artificial insemination with donor sperm. Hum Reprod. 2009 1;24(8):1891–9. 15 Williams RS, Alderman J. Predictors of success with the use of donor sperm. Am J Obstet Gynecol. 2001;185(2):332–7. 16 Shenfield F, Doyle P, Valentine A, Steele SJ, Tan SL. Effects of age, gravidity and male infertility status on cumulative conception rates following artificial insemination with cryopreserved donor semen: analysis of 2998

cycles of treatment in one centre over 10 years. Hum Reprod. 1993 Jan;8(1):60–4. 17 Centers for Disease Control and Prevention, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology. 2015 Assisted Reproductive Technology Fertility Clinic Success Rates Report. 2017. 18 Oyesanya O, Olufowobi O, Ross W, Sharif K, Afnan M. Prognosis of oocyte donation cycles: a prospective comparison of the in vitro fertilization‐embryo transfer cycles of recipients who used shared oocytes versus those who used altruistic donors. Fertil Steril. 2008;92(3):930–6. 19 Devroey P, Polyzos NP, Blockeel C. An OHSS‐Free Clinic by segmentation of IVF treatment. Hum Reprod. 2011;26(10):2593–7. 20 Brännström M. Uterus transplantation and beyond. J Mater Sci Mater Med. 2017;28(5):70. 21 Jones BP, Saso S, Bracewell‐Milnes T, Thum M‐Y, Nicopoullos J, Diaz‐Garcia C, et al. Human uterine transplantation: a review of outcomes from the first 45 cases. BJOG. 2019;126(11):1310–9.

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42 Social oocyte freezing Valerie L. Peddie and Smriti Ray Chaudhuri Bhatta Aberdeen Centre for Reproductive Medicine, Institute of Applied Health Sciences, School of Medicine, University of Aberdeen, Aberdeen, UK

Case History 1: A 30-year-old woman with previous multiple abdominal surgeries for Crohn’s disease would like to consider social oocyte freezing. Both her sister and close friend experienced fertility problems which has heightened her awareness of, and interest in freezing her oocytes. Case History 2: A 39-year-old professional female self-refers for social oocyte freezing discussion. She has never been in a relationship and unsure whether she will find “Mr. Right.” She is worried about advancing age and its impact on her fertility. On assessment, her ovarian reserve (for age) is satisfactory, however she understands the effect of age on oocyte quality, and that freezing her oocytes offers no guarantee of future live birth.

Background The single most important factor in determining female fertility potential is age; the maximum cohort of oocytes is estimated to be around 6–7  million during embryo development of the female fetus (20  weeks’ gestation), reducing to approximately 2 million at birth; about 450 of these are released during ovulation  [1]. There is a natural decline of female fertility around 30 years, which further decreases around 32 years, diminishing rapidly after 37 years [2]. With advancing female age, both oocyte quantity and quality decline. Oocyte developmental competence, which has been described as the ability of the female gamete to mature sufficiently to facilitate ­fertilization and support embryo development,

is dependent on the oocyte quality  [3,4]. Consequently, there is an age‐related decline in the probability of conception with increased risk of miscarriage and fetal anomaly. Worldwide, there has been a societal shift, with delayed childbearing  [5], and women have become increasingly aware of the advanc­ ing technology and opportunities that exist to supersede age‐related infertility. In recent years, gender equality, greater opportunities for women  [6], together with improving suc­ cess rates associated with social oocyte freez­ ing meant some women took the opportunity to delay pregnancy and childbirth. Oocyte freezing could extend the window of opportu­ nity for single women to find the right partner and offer them hope when their fertility may be in decline [7]. However, it is also perceived

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

Management options 

as a reproductive gamble which offers no guar­ antee of success, and carries financial ­implications, in addition to the side effects associated with the IVF treatment process [8]. Some fear that women of advancing age are considering fertility preservation too late and may enter into expensive contracts instead of making a planned and informed choice in their early to mid‐thirties [9]. Media coverage, together with employer and insurance poli­ cies  [10], further serve to exert pressure on women considering delayed childbearing, whilst being economical with the absolute risks and benefits involved [11]. Despite growing interest throughout Europe, social oocyte freezing is infrequently used [12], with the available evidence suggesting utilization rates between 3.1–9.3%  [10]. However, in the era of procreative liberty, the demand is likely to grow.

Management options The majority of women (90%) requesting social oocyte freezing are single  [13]. It has been speculated that the “lack of a partner” as a reason could be reflective of the international sociodemographic disparities in educational achievement where educated women outnumber the educated men in many societies across the globe  [14]. Other reviews suggest that some women resort to social oocyte freezing for career advancement. Fertility specialists have a duty of care to counsel women fully regarding all aspects of social oocyte freezing and contribute to shared decision making  [10]. Counseling should therefore include the following:

Realistic chances of success Success rate is dependent on the age at which the oocytes are frozen, with higher chance of success in women 35 years. ●● Women resort to social oocyte freezing to delay childbearing because of single status (90%) or career prospects. ●● Whilst oocyte freezing extends the window of opportunity for single women to find the right partner and offers hope when natural fertility may be in decline, the process involves costly and invasive treatment with no guarantee of success. ●● Utilization rate is currently 40 years) and includes misca­ rriage, preterm labor or medical

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c­ omplications (i.e. high blood pres­ sure complications). Q5 What are the costs? A5. This will depend on your fertility center and country. In the UK, the average cost in 2020 was £7000–8000. Q6 What are the success rates? A6. As per UK data, the average live birth rate (for women who have frozen eggs under the age of 35  years) is 19%. The success rate decreases if you are over 35 years at the time of freezing your eggs and chances are extremely low if you are over 40 years.

Q7 How long can I keep the eggs in storage? A7. In the UK, the legal storage period is a maximum of 10 years, but this may vary (up to maximum of 55 years) if you are diagnosed with a condition that has the potential to cause premature infertility. Q8 What other options do I have? A8. You can have a fertility assessment to determine whether your fertility potential is reasonable for your age. You can also attempt a natural pregnancy as soon as you are ready or consider IVF treatment using your own or donor eggs and sperm in the future, depending on per­ sonal circumstances.

References 1 Baker TG. A quantitative and cytological study of germ cells in human ovaries. Philos Trans R Soc Lond. 1963;158:417–33. https://www.ncbi. nlm.nih.gov/pubmed/14070052 2 American College of Obstetricians and Gynaecologists (ACOG). Female age‐related fertility decline; committee opinion. (Replaces committee opinion number 413, August 2008) (Reaffirmed 2018). 2014;589. https://www. acog.org/Clinical‐Guidance‐and‐Publications/ Committee‐Opinions/Committee‐on‐ Gynecologic‐Practice/Female‐Age‐Related‐ Fertility‐Decline?IsMobileSet=false 3 Vollenhoven B, Hunt S. Ovarian ageing and the impact on female fertility. Version 1;7:F1000 Faculty Rev‐1835 https://www.ncbi. nlm.nih.gov/pmc/articles/PMC6259486. Published November 22, 2108. 4 Conti M, Franciosi F. Acquisition of oocyte competence to develop as an embryo: integrated nuclear and cytoplasmic events. Hum Reprod Update. 2018;24(3):245–66. https://doi.org/10.1093/humupd/dmx040 5 Igarashi H, Takahashi T, Nagase S. Oocyte aging underlies female reproductive aging:

biological mechanisms and therapeutic strategies. Reprod Med Biol. 2015;14(4):159– 169. https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC5715832 6 Lemoine ME, Ravitsky V. Sleepwalking into infertility: the need for a public health approach toward advanced maternal age. Am J Bioeth. 2015;15(11): 37–48. https://www. ncbi.nlm.nih.gov/pubmed/26575814 7 Jones BP, Serhal P, Ben‐Nagi J. Social egg freezing should be offered to single women approaching their late thirties: FOR: Women should not suffer involuntary childlessness because they have not yet found a partner. BJOG. 2018;125(12):1579. doi: 10.1111/1471‐0528.15291 8 Royal College of Obstetricians and Gynaecologists. RCOG suggests caution over egg freezing, https://www.rcog.org.uk/en/ news/rcog‐suggests‐caution‐over‐social‐egg‐ freezing. Published August 8, 2018. 9 Bracewell‐Milnes T, Norman‐Taylor J, Nikolaou D. Against: women should be freezing their eggs earlier (debate). BJOG. 2018;125(12):1580. https://obgyn.

References 

onlinelibrary.wiley.com/doi/ epdf/10.1111/1471‐0528.15295 10 Ben‐Rafael Z. The dilemma of social oocyte freezing: usage rate is too low to make it cost‐effective, RBM Online. 2018;37(4):443. https://www.rbmojournal.com/article/ S1472‐6483(18)30353‐5/pdf 11 Petropanagos A, Patacan A, Baylis F, et al. Social egg freezing: risk, benefits and other considerations. Can Med Assoc J. 2015;187(9):666–9. https://www.ncbi.nlm. nih.gov/pmc/articles/PMC4467930 12 ESHRE Working Group on Oocyte Cryopreservation in Europe, Shenfield F, de Mouzon J, et al. Oocyte and ovarian tissue cryopreservation in European countries: statutory background, practice, storage and use. Hum Reprod Open. 2017;2017(1):hox003. Published March 29, 2017. doi:10.1093/ hropen/hox003 13 Pritchard N, Kirkman M, Hammarberg K, et al. Characteristics and circumstances of women in Australia who cryopreserved their oocytes for non‐medical indications. J Reprod Infant Psychol. 2017;35(2):108–18. https:// www.tandfonline.com/doi/abs/10.1080/0264 6838.2016.1275533?journalCode=cjri20 14 Inhorn MC, Birenbaum‐Carmeli DJ, Birger J, Westphal LM, et al. Elective egg freezing and its underlying socio‐demography: a binational analysis with global implications. Reprod Biol Endocrinol. 2018;6:70. 15 Human Fertilisation and Embryology Authority. Egg freezing in fertility treatment: trends and figures (2010–2016). https://www. hfea.gov.uk/media/2656/egg‐freezing‐in‐ fertility‐treatment‐trends‐and‐ figures‐2010‐2016‐final.pdf

16 Stoop D, Maes E, Polyzos NP, et al. Does oocyte banking for anticipated gamete exhaustion influence future relational and reproductive choices? A follow‐up of bankers and non‐bankers. Hum Reprod. 2015;30(2):338–44. https://academic.oup. com/humrep/article/30/2/338/727419 17 Cil AP, Bang H, Oktay K. Age‐specific probability of live birth with oocyte cryopreservation: an individual patient data meta‐analysis. Fertil Steril. 2013;100(2):492– 9. https://www.ncbi.nlm.nih.gov/ pubmed/23706339 18 Cobo A, Garcia‐Velasco JA, Coello A, et al. Oocyte vitrification as an efficient option for elective fertility preservation. Fertil Steril. 2016;105(3):755–64. https://www.ncbi.nlm. nih.gov/pubmed/26688429 19 Human Fertilisation and Embryology Authority. What you need to know about our new egg freezing report. https://www.hfea. gov.uk/about‐us/news‐and‐press‐ releases/2018‐news‐and‐press‐releases/ what‐you‐need‐to‐know‐about‐our‐new‐egg‐ freezing‐report 20 NICE. Fertility problems: assessment and treatment: clinical guideline. http://nice.org. uk/guidance/cg156 21 Alteri A, Pisaturo V, Nogueira D, et al. Elective egg freezing without medical indications: Review. Acta Obstet Gynae Scan. 2019;98(5):647–52. https://obgyn. onlinelibrary.wiley.com/doi/pdf/10.1111/ aogs.13573 22 Hammerberg K, Kirkman M, Pritchard N, et al. Reproductive experiences of women who cryopreserved oocytes for non‐medical reasons. Hum Reprod. 2017;32(3):575–81.

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43 The male and female patients following bariatric surgery Zaher Merhi1 and Ali Ahmed Bazzi2 1

 SUNY Downstate University, Brooklyn, New York, USA  Detroit Medical Center/Wayne State University, Detroit, Michigan, USA

2

Case History 1: A couple presented with a history of infertility for several years. A thorough infertility workup was normal, and they were diagnosed with unexplained infertility. A number of cycles of intrauterine insemination (IUI) with controlled ovarian hyperstimulation were completed but all were unsuccessful. The couple desired to proceed with IVF. Upon obtaining further history, the female partner reported having undergone gastric bypass surgery 6 months prior to presentation. Case History 2: Six couples presented with secondary infertility. All male partners had children from previous partners and had history of Roux-en-Y gastric bypass. After the bypass surgery, all male partners were characterized by nonobstructive azoospermia with complete spermatogenic arrest, despite the healthy appearance and normal sex hormone profiles suggesting a developmental block of spermatogenesis occurred at a point not related to the action of sex hormones on the testis. These data indicated that either the absorption of nutrients required for spermatogenesis was insufficient in these patients, or that the effect on the reproductive system was irreversible. Case History 3: 31-year-old with a 10-year history of infertility due to tubal factor. The patient underwent a Roux-en-Y gastric bypass procedure 5 years before IVF and lost 45 kilograms. Her body mass index at the time of IVF was 23 kg/m2. The patient underwent one IVF cycle. Four out of 10 oocytes were fertilized by conventional insemination and 9 out of 11 oocytes were fertilized by ICSI. She had two blastocysts transferred, resulting in a twin gestation. Her IVF cycle was complicated by ovarian hyperstimulation syndrome with ascites, increased abdominal girth, shortness of breath, and chest pain. She responded well to supportive care, but unfortunately experienced preterm labor and delivered nonviable twins at 24 weeks of gestation.

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

Management options 

Background Obesity has tripled since 1975 worldwide, and in 2014 more than 1.9 billion adults were overweight with 600 million classified as obese [1]. Currently, one of the commonly used treatments for morbidly obese reproductive‐aged patients is bariatric surgery [1]. Medical indications for a patient to have bariatric surgery are a body mass index (BMI) that exceeds 40  kg/m2 or a BMI more than 35  kg/m2 with serious coexisting conditions such as diabetes, cardiovascular disease, severe sleep apnea or joint disease. This surgery is usually performed when the nonsurgical weight reduction programs incorporating diet, exercise and behavioral modifications have failed  [2]. It is not uncommon to have a couple presenting for IVF as an option for infertility treatment with the male or female partner having had bariatric surgery as described above.

Management options Adverse reproductive sequelae like irregular menstrual cycles, alterations in the hypothalamic–pituitary–ovarian (HPO) axis, luteal dysfunction and diminished ovarian reserve have been recognized in obese women when compared with normal weight women [3–8]. These changes contribute to the reproductive compromise commonly seen in obese women. Regarding infertility management, obesity is associated with impaired response to ovulation induction, higher IVF cycle cancelation rates despite administration of more exogenous gonadotropins, lower mature oocyte yield, lower number of cryopreservation cycles, lower embryo implantation and lower live birth rate [9–12]. Obesity impairs ovulation but also exerts its detrimental effects on endometrial development and implantation  [13]. Reduced implantation and pregnancy rates with elevated rates of miscarriage were observed in a case‐ control study of 139  women with a BMI > 25  kg/m2 undergoing 180 cycles of IVF  [14].

However, another study found no relationship between BMI and implantation rates, but this study was smaller and underpowered  [15]. In IVF pregnancies, obesity has been described as an independent risk factor for spontaneous first‐trimester miscarriages [16,17]. The altered reproductive hormone profile associated with morbid obesity seems to revert either partially or completely to normal ranges following weight loss surgery  [18–20]. With surgical weight reduction, there is normalization of menstrual irregularities in more than two‐thirds of women with irregular sporadic menstrual bleeding [21], partial restoration of luteal function [22] and decline in serum estradiol, testosterone and DHEA‐S levels (these hormones are often elevated in obese patients) [18,22]. According to the American College of Obstetricians and Gynecologists (ACOG), all bariatric surgery patients are advised to delay pregnancy for 12–18 months following the procedure because of nutritional deprivation and a potential risk of fetal growth restriction [23]. An improvement in fertility status following massive surgical weight loss has been described [24–27]. There is a greater chance for a woman to conceive naturally following bariatric surgery through her resumption of normal menstrual cyclicity and by correction of the ovulatory dysfunction [25]. There might be a reduction in the risk for spontaneous miscarriage following bariatric surgery [25]. However, there may also be a higher need for fertility treatments following the surgical weight loss  [28]. Furthermore, the type of bariatric procedure (i.e., Roux‐en‐Y gastric bypass versus lap band versus sleeve gastrectomy) that the patient undergoes is of importance, especially if the patient develops adverse symptoms during her IVF cycles  [29]. Although the weight loss from bariatric surgery can be beneficial to a woman’s overall health, reproduction can be impaired as this surgery has been found to have an impact on the formation of follicles and oocytes [30]. With regards to men, bariatric surgery may resolve issues associated

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The male and female patients following bariatric surgery

with obesity such as hypogonadotropic hypogonadism as well as erectile dysfunction  [31]. However, there may be worrisome findings concerning impaired semen quality in the male patients who undergo bariatric surgery [31]. A marked reduction in sperm parameters was observed even up to 18  months following the surgery  [32]. Another study found severe worsening of semen parameters several months after bariatric surgery, which included extreme oligoasthenoteratozoospermia  [33]. Free and total testosterone plasma levels are improved in obese men after bariatric surgery  [34]. Even with improvements in various hormones after bariatric surgery, sperm volume showed a small decrease postsurgery and abnormal sperm concentration persisted in 60% of adults [35]. Therefore, semen freezing prior to surgery is recommended. On the other hand, another study found that bariatric surgery seemed to reduce the IVF treatment costs without affecting oocyte or embryo quality  [36]. Although there are few data regarding IVF success rates in women who underwent bariatric surgery, a pairwise study reviewed five patients who underwent bariatric surgery followed by IVF and three term pregnancies in three patients occurred after the first IVF cycle [37]. Empty follicle syndrome (i.e. failure to recover oocytes despite aspiration and meticulous flushing of follicles) at the time of oocyte retrieval has been reported with the use of subcutaneous recombinant human chorionic gonadotropin (hCG) administration in IVF cycle following bariatric surgery  [25]. However, intramuscular hCG was used in the subsequent cycle in the same patient and resulted in the retrieval of 19 oocytes and a successful pregnancy  [25]. Whether the abdominal skin redundancy affects the absorption of the subcutaneous hCG probably making the intramuscular route a more effective one remains to be determined in large scale studies. Anti‐Müllerian hormone (AMH), a serum marker of ovarian reserve, has been found to

be lower in obese women when compared with normal BMI women  [7]. Although controversial, antral follicle count (AFC) and ovarian volume have not been shown to be affected by obesity  [26]. There seems to be a further drop in AMH levels 3  months after surgical weight loss in women younger than 35 years of age  [27]. One study found the median AMH at 6 and 12 months post bariatric surgery were significantly lower but noted a change in laboratory methods for AMH analysis as a potential limitation  [38]. This raises the possibility of acute oocyte depletion following dramatic surgical weight loss. Opposite results were noted in another study that determined a significant increase in serum AMH in women at their early follow‐up visit from a laparoscopic sleeve gastrectomy  [39]. In studies measuring urinary metabolites  [18], post bariatric surgery estradiol levels dropped significantly, most likely secondary to the loss of adipose tissue; however, follicle‐stimulating hormone (FSH) levels did not change following surgical weight loss. There was a partial increase in the urinary progesterone metabolites following surgical weight loss, probably reflecting a partial recovery of the luteal function. This could mean that morbidly obese women have a better chance of ovulating following the procedure. Studies have supported the use of bariatric surgery in obese infertile women seeking ART treatment showing an increase in pregnancy and live birth rates by 37.5% and 35%, respectively, following bariatric surgery [40]. A repeat assessment of ovarian reserve should be performed and compared with preoperative levels. These women should generally be started on higher doses of stimulation medications and tapered according to the ovarian response. They may need to use IVF drugs intramuscularly rather than subcutaneously for better absorption. In men, semen analysis should be repeated following the surgery and freezing sperm vials should be considered before the operation, for future use for IVF.

Answers to questions patients ask  261

Key points Challenge: Men and women with history of bariatric surgery requesting fertility treatment. Background: Irregular menstrual cycles, alterations in the HPO axis, luteal dysfunction and diminished ovarian reserve are well recognized in obese women. ●● Obesity is associated with impaired response to ovulation induction, higher IVF cycle cancelation rates, lower mature oocyte yield, lower number of cryopreservation cycles, and lower live births. ●● Reduced implantation and pregnancy rates are observed in obese women. ●● The altered reproductive hormone profile reverts to normal range following weight loss surgery. ●● With surgical weight loss, there is normalization of menstrual irregularities, partial restoration of serum steroid levels. ●● Medical indications for a patient to have bariatric surgery are a body mass index (BMI) that exceeds 40 kg/m2, or a BMI more than 35 kg/m2 with serious comorbidities.

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Management options: ●● Bariatric surgery improves the altered reproductive hormone profile in men and women. ●● Bariatric surgery may improve fertility outcome and may reduce the risk of ­miscarriages.

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Bariatric surgery could be associated with a drop in serum AMH levels following the surgery. There may be poor absorption of subcutaneous IVF drugs because of skin redundancy. All bariatric surgery patients are advised to delay pregnancy for 12–18 months. After bariatric surgery, some women conceive naturally and there may be a reduction in miscarriage rates. Reproduction can be impaired through impact on formation of healthy follicles and mature oocytes. Empty follicle syndrome has been reported during IVF in women who had bariatric surgery. IVF medications via intramuscular route seems more effective than the subcutaneous route. Serum AMH and AFC as measurement of ovarian reserve should be interpreted with caution following bariatric surgery. Bariatric surgery improves pregnancy outcomes of women with obesity by reducing the rates of gestational diabetes pregnancyinduced hypertension, and macrosomia. In men, bariatric surgery can improve erectile dysfunction, and semen parameters. In some men bariatric surgery may lead to reduction in sperm parameters, and presurgery semen cryopreservation is advised.

Answers to questions patients ask Q1 Am I advised to have bariatric surgery? A1. Men and women undergo bariatric surgery for multiple reasons. The indications for bariatric surgery include a BMI that exceeds 40  kg/m2, or a BMI more than 35  kg/m2 with serious coexisting conditions such as diabetes, cardiovascular disease, severe sleep apnea, joint disease or others. Bariatric surgery requires a multidisciplinary approach that involves

the primary care doctor, the ­surgeon, the nutritionist and the fertility doctor. Q2 Does bariatric surgery help improve our fertility? A2. It could improve the overall fertility in both men and women. In women, it can help regulate the menstrual cycle and normalize various hormones involved in fertility. However, because of the

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changes that happen in the body after losing a lot of weight, it is advisable to delay pregnancy by 12–18  months after surgery. Also, some alterations to your fertility treatment after the operation would be necessary, such using injections in the muscle rather

than under the skin. In men, it could help in improving erectile dysfunction and alteration in semen parameters, although in some men it may actually reduce sperm quality. Therefore, freezing sperm before the operation is recommended as back‐up.

References 1 Moussa HN, Alrais MA, Leon MG, Abbas EL, Sibai BM. Obesity epidemic: impact from preconception to postpartum. Future Sci OA. 2016;2(3): FSO137. 2 Consensus Development Conference Panel. Gastrointestinal surgery for severe obesity. Ann Intern Med. 1991;115(12):956–61. 3 Santoro N, Lasley B, McConnell D, Allsworth J, Crawford S, Gold EB, et al. Body size and ethnicity are associated with menstrual cycle alterations in women in the early menopausal transition: the Study of Women’s Health across the Nation (SWAN) Daily Hormone Study. J Clin Endocrinol Metab. 2004;89(6):2622–31. 4 Pasquali R, Pelusi C, Genghini S, Cacciari M, Gambineri A. Obesity and reproductive disorders in women. Hum Reprod Update. 2003;9(4):359–72. 5 Jain A, Polotsky AJ, Rochester D, Berga SL, Loucks T, Zeitlian G, et al. Pulsatile luteinizing hormone amplitude and progesterone metabolite excretion are reduced in obese women. J Clin Endocrinol Metab. 2007;92(7):2468–73. 6 Bray GA. Obesity and reproduction. Hum Reprod. 1997;12(Suppl 1):26–32. 7 Freeman EW, Gracia CR, Sammel MD, Lin H, Lim LC, Strauss JF 3rd. Association of anti‐Müllerian hormone levels with obesity in late reproductive‐age women. Fertil Steril. 2007;87(1):101–6. 8 Merhi Z, Bazzi AA, Bonney EA, Buyuk E. Role of adiponectin in ovarian follicular development and ovarian reserve. Biomed Rep. 2019;1(1):1–5.

9 Esinler I, Bozdag G, Yarali H. Impact of isolated obesity on ICSI outcome. Reprod Biomed Online. 2008;17(4):583–7. 10 Lintsen AM, Pasker‐de Jong PC, de Boer EJ, Burger CW, Jansen CA, Braat DD, et al. Effects of subfertility cause, smoking and body weight on the success rate of IVF. Hum Reprod. 2005;20(7):1867–75. 11 Fedorcsak P, Dale PO, Storeng R, Ertzeid G, Bjercke S, Oldereid N, et al. Impact of overweight and underweight on assisted reproduction treatment. Hum Reprod. 2004;19(11):2523–8. 12 Styne‐Gross A, Elkind‐Hirsch K, Scott RT Jr. Obesity does not impact implantation rates or pregnancy outcome in women attempting conception through oocyte donation. Fertil Steril. 2005;83(6):1629–34. 13 Brewer CJ, Balen AH. The adverse effects of obesity on conception and implantation. Reproduction. 2010;140(3):347–64. 14 Loveland JB, McClamrock HD, Malinow AM, Sharara FI. increased body mass index has a deleterious effect on in vitro fertilization outcome. J Assist Reprod Genet. 2001;18:382–386. 15 Wattanakumtornkul S, Damario MA, Stevens SA, Thornhill AR, Tummon IS. Body mass index and uterine receptivity in the oocyte donation model. Fertil Steril. 2003;80:336–340. 16 Bellver J, Rossal LP, Bosch E, Zuniga A, Corona JT, Melendez F, et al. Obesity and the risk of spontaneous abortion after oocyte donation. Fertil Steril. 2003;79(5):1136–40.

References 

17 Fedorcsak P, Storeng R, Dale PO, Tanbo T, Abyholm T. Obesity is a risk factor for early pregnancy loss after IVF or ICSI. Acta Obstet Gynecol Scand. 2000;79(1):43–8. 18 Bastounis EA, Karayiannakis AJ, Syrigos K, Zbar A, Makri GG, Alexiou D. Sex hormone changes in morbidly obese patients after vertical banded gastroplasty. Eur Surg Res. 1998;30(1):43–7. 19 Gerrits EG, Ceulemans R, van Hee R, Hendrickx L, Totte E. Contraceptive treatment after biliopancreatic diversion needs consensus. Obes Surg. 2003;13(3):378–82. 20 Victor A, Odlind V, Kral JG. Oral contraceptive absorption and sex hormone binding globulins in obese women: effects of jejunoileal bypass. Gastroenterol Clin North Am. 1987;16(3):483–91. 21 Teitelman M, Grotegut CA, Williams NN, Lewis JD. The impact of bariatric surgery on menstrual patterns. Obes Surg. 2006;16(11):1457–63. 22 Rochester D, Jain A, Polotsky AJ, Polotsky H, Gibbs K, Isaac B, et al. Partial recovery of luteal function after bariatric surgery in obese women. Fertil Steril. 2009;92(4):1410–15. 23 American College of Obstetricians and Gynecologists. ACOG Committee Opinion number 315. Obesity in pregnancy. Obstet Gynecol. 2005;106(3):671–5. 24 Deitel M, Stone E, Kassam HA, Wilk EJ, Sutherland DJ. Gynecologic–obstetric changes after loss of massive excess weight following bariatric surgery. J Am Coll Nutr. 1988;7(2):147–53. 25 Bilenka B, Ben‐Shlomo I, Cozacov C, Gold CH, Zohar S. Fertility, miscarriage and pregnancy after vertical banded gastroplasty operation for morbid obesity. Acta Obstet Gynecol Scand. 1995;74(1):42–4. 26 Martin LF, Finigan KM, Nolan TE. Pregnancy after adjustable gastric banding. Obstet Gynecol. 2000;95 (6 Pt 1):927–30. 27 Marceau P, Kaufman D, Biron S, Hould FS, Lebel S, Marceau S, et al. Outcome of

pregnancies after biliopancreatic diversion. Obes Surg. 2004;14(3):318–24. 28 Sheiner E, Menes TS, Silverberg D, Abramowicz JS, Levy I, Katz M, et al. Pregnancy outcome of patients with gestational diabetes mellitus following bariatric surgery. Am J Obstet Gynecol. 2006;194(2):431–5. 29 Doblado MA, Lewkowski BM, Odem RR, Jugheim ES. In vitro fertilization after bariatric surgery. Fertil Steril. 2010;94(7):2812–4. 30 Christofolini J, Bianco B, Santos G, Adami F, Christofolini D, Barbosa CP. Bariatric surgery influences the number and quality of oocytes in patients submitted to assisted reproduction techniques. Obesity (Silver Spring). 2014;22(3):939–42. 31 Rosenblatt A, Faintuch J, Cecconello I. Abnormalities of reproductive function in male obesity before and after bariatric surgery–a comprehensive review. Obes Surg. 2015;25 (7):1281–92. 32 Lazaros L, Hatzi E, Markoula S, Takenaka A, Sofikitis N, Zikopoulos K, Georgiou I. Dramatic reduction in sperm parameters following bariatric surgery: report of two cases. Andrologia. 44(6):428–32. 33 Sermondade N, Massin N, Boitrelle F, Pfeffer J, Eustache F, Sifer C, Czernichow S, Levy R. Sperm parameters and make fertility after bariatric surgery: three case series. Reprod Biomed Online. 24(2):206–10. 34 Di Vincenzo A, Busetto L, Vettor R, Rossato M. Obesity, male reproductive function and bariatric surgery. Fron Endocrinol (Lausanne). 2018;9:769. 35 Calderón B, Huerta L, Galindo J, González Casbas JM, Escobar‐Morreale HF, Martín‐ Hidalgo A, Botella‐Carretero JI. Lack of improvement of sperm characteristics in obese males after obesity surgery despite the beneficial changes observed in reproductive hormones. Obes Surg. 2019;29(7):2045–50. 36 Tsur A, Orvieto R, Haas J, Kedem A, Machtinger R. Does bariatric surgery improve ovarian stimulation characteristics,

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oocyte yield, or embryo quality? J Ovarian Res. 2014;7(116). 37 Tan O, Carr B. The impact of bariatric surgery on obesity‐related infertility and in vitro fertilization outcomes. Semin Reprod Med 30(06):517–528. 38 Nilsson‐Condori E, Hedenbro JL, Thurin‐ Kjellberg A, Giwercman A, Friberg B. Impact of diet and bariatric surgery on anti‐ Müllerian hormone levels. Hum Reprod. 2018;33(4):690–3.

39 Pilone V, Tramontano S, Renzulli M, Monda A, Cutolo C, Romano M, Schiavo L. Impact of diet and bariatric surgery on anti‐ Müllerian hormone levels. Gynecol Endocrinol. 2019;35(6):548–51. 40 Milone M, Sosa Fernandez LM, Sosa Fernandez LV, Manigrasso M, Elmore U, De Palma GD, Musella M, Milone F. Does bariatric surgery improve assisted reproductive technology outcomes in obese infertile women? Obes Surg. 2017;27(8):2106–12.

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44 Endometrial receptivity testing Laurentiu Craciunas and Arri Coomarasamy University of Birmingham and Birmingham Women’s Hospital, Birmingham, UK

Case History 1: Following ten days of controlled ovarian stimulation in a fresh IVF cycle a woman is found to have an endometrial thickness of 4 mm on the day of the oocyte retrieval despite good follicular development as part of her first fertility treatment. Case History 2: A 29-year-old nulliparous woman with unexplained infertility goes through her third cycle of IVF. She had a total of five fresh and frozen embryo transfers with good quality embryos and planned to undergo PGT-A to increase her chances of a successful pregnancy. Despite a confirmed euploid embryo and an endometrial thickness of 10  mm on the day of the embryo transfer, the pregnancy test performed two weeks after the transfer was negative. Case History 3: A 33-year-old woman who suffered six recurrent miscarriages within two years of trying for a baby has her first embryo transfer with a moderate quality blastocyst. The pregnancy test is positive two weeks after the procedure, but there is no heartbeat on ultrasound at 8  weeks post embryo transfer. The pregnancy tissues are sent for cytogenetics and the result confirms trisomy 13.

Background It is well accepted that successful embryo implantation depends on the synchronized communication between a good quality blastocyst and a receptive endometrium  [1]. When IVF patients do not get pregnant after the transfer of a morphologically good quality embryo (or embryos), they often assume that the fault is in endometrial receptivity. Clinicians may then tell them that even seemingly morphologically good quality embryos could be aneuploid, and recommend routine preimplantation genetic

testing for aneuploidy (PGT‐A), with no good evidence to back that advice  [2]. When even euploid embryos fail to implant, the assumed fault is back at the foot of endometrial receptivity, for which patients understandably ask what could be done; they demand a test for what is wrong and a treatment to make it right. The straightforward logic of this question is simple, the answer is anything but. Our current understanding of endometrial receptivity is incomplete, our assumptions about it may be wrong, and most of our tests are yet unvalidated [3].

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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Although on the face of it, this issue sounds theoretical, perhaps even bordering on the esoteric, in reality it is actually very practical. In everyday IVF practice patients repeatedly ask questions about endometrial receptivity. They demand explanations, tests and treatments. The fact that we do not have all the answers is all the more reason why we should explain this to them and help them steer the myriad of tests and treatments they often read about on the internet. This chapter attempts to briefly explain our current understanding of endometrial receptivity and assess the currently available tests.

Endometrial receptivity and selectivity Receptivity is an intrinsic function of the endometrium that enables and supports the ­implantation process by providing an optimal environment for embryo development and placenta formation. In a natural cycle, endometrial receptivity is maximal during a narrow time frame called “window of implantation,” surrounded by a refractory endometrial status. In contrast to receptivity, endometrial selectivity is a complementary function aiming to recognize and reject embryos with reduced development potential. These two concepts permit the endometrium to be a biosensor of embryo quality  [4]. Imbalances in endometrial receptivity or selectivity functions may lead to reproductive failure by two distinct mechanisms. On the one hand, increased endometrial receptivity unopposed by selectivity will allow any embryo to implant, irrespective of its quality or development potential. This is relevant for Case History 3  where multiple conceptions occurred naturally in a relatively short period of time, including a positive pregnancy test following IVF despite the transfer of an aneuploid embryo, suggestive of a potential defect in endometrial selectivity. This is a relative ­frequent occurrence in recurrent miscarriage clinics.

On the other hand, increased endometrial selectivity relative to a reduced receptivity will not allow any embryo to implant, despite euploidy and high development potential. This is relevant for Case History 2 where successive transfers of good quality embryos led to negative pregnancy tests in a young woman with otherwise unexplained infertility. Although this concept of endometrial receptivity/ selectivity may sound convincingly simple, the reality is undoubtedly more complex. For example, we do not know if euploid embryos (as tested by PGT‐A) do not actually have genetic defects at a sub‐euploidy level, either detectable by chromosome microarray (CMA) testing (such as microdeletions and microduplications) or undetectable by currently available technology, which are responsible for the lack of implantation. This would explain the frequent occurrence of transferring more than one euploid embryo, for just one of them to implant. Surely endometrial receptivity is the same for all transferred embryos. In many cases we simply do not know if the defect is at an embryo level, an endometrial level, or both.

Management options Testing endometrial selectivity and receptivity Endometrial selectivity is a relatively new concept and no clinically useful test has been developed to quantify it yet; hence, a defect in endometrial selectivity may only be suspected based on the clinical history of a couple. Endometrial receptivity has undergone over eight decades of research since Rock and Bartlett (1937) described the histological changes of the endometrium during the window of implantation  [5]. Nowadays, clinicians have a broad range of options for testing endometrial receptivity using different approaches such as pelvic ultrasound, endometrial biopsy or fluid aspirate and hysteroscopy.

Management options 

Ultrasound

Endometrial thickness measured by ultrasound on various days during the IVF treatment cycle remains the most commonly used test of endometrial receptivity due to its noninvasiveness and accessibility. It is a useful marker to predict the absence of endometrial receptivity when the thickness is below 6 mm on the day of the human chorionic gonadotropin (hCG) injection during fresh cycles or on the day of progesterone start during frozen cycles; however, values above 6  mm do not confirm adequate levels of receptivity with sufficient accuracy [3]. Endometrial volume may be measured using 3D ultrasound, but accuracy of clinical pregnancy prediction is not superior to endometrial thickness. A triple layer pattern suggests receptive endometrium, but its absence does not rule it out accurately. Various Doppler indices have been measured with the hypothesis that uterine and endometrial tissue perfusion is proportional with endometrial receptivity. Some of the Doppler indices such as uterine artery pulsatility and resistance indices, endometrial and subendometrial vascularity and flow indices were associated with endometrial receptivity but had low accuracy in predicting clinical pregnancy. The presence of endometrial wave‐like activity or “contractions” is a marker of reduced receptivity with significantly lower clinical pregnancy rates for women with more than three waves per minute at the time of embryo transfer [6]. In practice, the only method used (and the best validated) is endometrial thickness measured by ultrasound. Endometrial biopsy and fluid aspirate

The histological endometrial dating was first described in 1950 [7]; however, its clinical utility remains limited especially in the context of IVF where endometrial biopsy during the treatment cycle may have a negative influence on the success rates.

Uterine natural killer cells are popular in the context of recurrent implantation failure or recurrent miscarriage, but their poor ability to predict the fate of subsequent pregnancies or embryo transfers means they cannot be recommended in a clinical setting and should be limited to research projects [3,8]. Endometrialomics refer to the application of high‐throughput techniques to inspect changes in different molecular compartments of the endometrium. These include genomics, transcriptomics, proteomics or metabolomics. Data from transcriptomic analyses is promising and form the basis of several commercially available endometrial receptivity tests such as endometrial receptivity array (ERA), ER Map/ ER Grade and ERPeak  [9,10]; however, their scientific validation is not robust enough to recommend their use. Patients (and some clinicians) often perceive the commercial availability of a test as an indication of its scientific and clinical validation. It should be pointed out to them that although this may be true for medications, it is not necessarily so for tests. Hysteroscopy

Inspecting the endometrial cavity using hysteroscopy allows the identification of abnormal changes suggestive of reduced endometrial receptivity such as chronic inflammation, endometrial adhesions or Asherman syndrome, endometrial polyps or fibroids distorting the endometrial cavity. If performed during the window of implantation, hysteroscopy may offer information about the development of the endometrium based on the aspect of endometrial glands and vasculature. The mid‐luteal endometrium was classified as “good” based on the ring type aspect of the glandular openings and presence of well‐developed varicose‐ like vessels [11]. In the context of IVF, however, hysteroscopy during the treatment cycle may have a negative influence on the success rates. Furthermore,

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there is no evidence that routine hysteroscopy before IVF results in better reproductive outcomes, whether before the first cycle  [12] or even after recurrent implantation failure [13]. The current place of hysteroscopy is where there are abnormalities either in the history or ultrasound examination that suggest uterine pathology.

Key points Challenge: Testing endometrial receptivity in ART patients Background: Top quality embryos, even those deemed euploid by PGT-A, can be transferred but not lead to a pregnancy. Patients often ask if this reflects poor endometrial receptivity, what tests could be done to find out what’s wrong and what treatment could be given to make it right. ●● Receptivity is an intrinsic function of the endometrium that enables and supports the implantation process by providing an ­optimal environment for embryo development. ●● Selectivity is a complementary function aiming to recognize and reject embryos with reduced development potential. ●● Current thinking is that endometrial ­receptivity/selectivity are two c­ omplementary functions that enable the endometrium to act as a biosensor of embryo quality. ●● Patients should be informed that our ­current understanding of endometrial receptivity and selectivity is incomplete, our ­assumptions about them may be wrong, and most of our tests are yet unvalidated. ●●

Management options: ●● Currently there are no tests available for endometrial selectivity. ●● The tests available for endometrial ­receptivity testing include ultrasound, endometrial ­biopsy and fluid aspirate, and hysteroscopy. ●● Endometrial thickness by transvaginal ­ultrasound – noninvasive and accessible, ­values below 6 mm predict reproductive failure, while values above 6 mm have low accuracy in predicting clinical pregnancy. ●● Other ultrasound markers such as ­endometrial volume, pattern, and Doppler indices are not more accurate compared to endometrial thickness. ●● Histology and cytology markers have limited clinical usefulness and biopsies should not be performed during IVF cycles. ●● Transcriptomic based tests such as ­endometrial receptivity array (ERA), ER Map/ ER Grade and ERPeak may be useful, but proper scientific validation is awaited before recommending their use. ●● Hysteroscopy may identify causes of reduced endometrial receptivity such as chronic inflammation, Asherman syndrome, ­endometrial polyps or fibroids distorting the uterine cavity. Very often these ­conditions are initially suspected from history or ­ultrasound examination. ●● There is no evidence that routine ­hysteroscopy before IVF results in better reproductive outcomes, whether before the first cycle or even after recurrent implantation failure. ●● Patients should be informed that doing tests that are not validated may be of no benefit or, worse still, could lead to interventions that produce worse outcomes.

Answers to questions patients ask Q1 Why did a thick endometrium and a good embryo not assure a successful pregnancy? A1. There are a number of possible reasons. Endometrial thickness is able to predict reduced receptivity when it is below 6 mm, but values

above 6  mm are not accurate in predicting clinical pregnancies. PGT‐A does not necessarily tell us everything about the embryo, and many euploid embryos do not implant. A good embryo and a receptive endometrium may still

References 

not lead to pregnancy if they are out of sync. There are many things in this field that we do not know, but we know for sure that repeating IVF attempts increases the chances of success. Q2 Should I have a hysteroscopy before the first IVF cycle? A2. Studies have shown that this does not increase the chances of success. Q3 Should I check my uterine natural killer cells counts? A3. Uterine natural killer (uNK) cells have poor accuracy in predicting the fate of subsequent pregnancies, and studies have shown that this testing does not increase the chances of success. Q4 Will having the endometrial receptivity array (ERA) test increase my chance of a successful pregnancy? A4. There are reports of successful pregnancies using ERA test and personalized embryo transfer f­ollowing recurrent implantation failure. However, no comparative data have been published in relation to per-

forming an embryo transfer when the ERA test identifies nonreceptive endometrium which limits our understanding of ERA’s role. We simply do not know for certain if doing ERA will make no difference, increase the chances of pregnancy or, worse still, reduce those chances. To date, the proper studies have not been done yet. Q5 But ERA is commercially available, so surely regulatory bodies around the world would not allow that unless they are certain that it is useful. A5. You would have thought so, but unfortunately it does not work that way. The reason is that tests are not supposed to be used directly by patients, but rather ordered by doctors who presumably understand their pros and cons and their true place in the management of a particular case. If tests get marketed directly to patients (like on the internet) or are ordered by doctors who are not particularly specialized in that area (however well‐intentioned they might be), the wrong test could be done.

References 1 Tabibzadeh S, Babaknia A. The signals and molecular pathways involved in implantation, a symbiotic interaction between blastocyst and endometrium involving adhesion and tissue invasion. Hum Reprod. 1995;10(6):1579–602. 2 Munné S, Kaplan B, Frattarelli JL, Child T, Nakhuda G, Shamma FN, et al. Preimplantation genetic testing for aneuploidy versus morphology as selection criteria for single frozen‐thawed embryo transfer in

good‐prognosis patients: a multicenter randomized clinical trial. Fertil Steril. 2019;112(6):1071–1079.e7. 3 Craciunas L, Gallos I, Chu J, Bourne T, Quenby S, Brosens JJ, et al. Conventional and modern markers of endometrial receptivity: a systematic review and meta‐analysis. Hum Reprod Update. 2019;25(2):202–23. 4 Macklon NS, Brosens JJ. The human endometrium as a sensor of embryo quality. Biol Reprod. 2014 1;91(4):98.

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5 Rock J, Bartlett MK. Biopsy studies of human endometrium: criteria of dating and information about amenorrhea, menorrhagia, and time of ovulation. J Am Med Assoc. 1937;108(24):2022–8. 6 Zhu L, Che HS, Xiao L, Li YP. Uterine peristalsis before embryo transfer affects the chance of clinical pregnancy in fresh and frozen‐thawed embryo transfer cycles. Hum Reprod. 2014;29(6):1238–43. 7 Noyes R, Hertig A, Rock J. Dating the endometrial biopsy. Fertil Steril. 1950;1:3. 8 Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, Middeldorp S, et al. ESHRE guideline: recurrent pregnancy loss. Hum Reprod open. 2018; 2018(2):hoy004. 9 Díaz‐Gimeno P, Horcajadas JA, Martínez‐ Conejero JA, Esteban FJ, Alamá P, Pellicer A, et al. A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature. Fertil Steril. 2011;95(1):50–60.

10 Enciso M, Carrascosa JP, Sarasa J, Martínez‐ Ortiz PA, Munné S, Horcajadas JA, et al. Development of a new comprehensive and reliable endometrial receptivity map (ER Map/ER Grade) based on RT‐qPCR gene expression analysis. Hum Reprod. 2018;33(2):220–8. 11 Inafuku K. [Hysteroscopy in midluteal phase of human endometrium evaluation of functional aspect of the endometrium]. Nihon Sanka Fujinka Gakkai Zasshi. 1992;44(1):79–83. 12 Smit JG, Kasius JC, Eijkemans MJC, Koks CAM, van Golde R, Nap AW, et al. Hysteroscopy before in‐vitro fertilisation (inSIGHT): a multicentre, randomised controlled trial. Lancet (London, England). 2016;387(10038):2622–9. 13 El‐Toukhy T, Campo R, Khalaf Y, Tabanelli C, Gianaroli L, Gordts SS, et al. Hysteroscopy in recurrent in‐vitro fertilisation failure (TROPHY): a multicentre, randomised controlled trial. Lancet (London, England). 2016;387(10038):2614–21.

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Pituitary suppression and ovarian stimulation phase

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45 Poor response during ovarian stimulation Pedro Melo, Lynne Robinson, and Arri Coomarasamy University of Birmingham and Birmingham Women ’s Hospital, Birmingham, UK

Case History 1: A 31-year-old woman with normal basal follicle stimulating hormone (FSH) and anti-Müllerian hormone (AMH) levels started her first cycle of IVF for unexplained infertility. After 12 days of stimulation with 200 IU of human menopausal gonadotropin (hMG), only two follicles were seen on ultrasound scan measuring 18 and 20 mm.

Case History 2: A 32-year-old woman undergoing her first cycle of IVF on 150 IU of hMG attended for her day 9 scan. She was found to have 10 follicles in total, although they all measured less than 10 mm in diameter. She had achieved an adequate endometrial thickness of 9 mm.

Background The principal goal of assisted reproductive technology (ART) is to obtain a healthy singleton live birth with the fewest possible cycles of controlled ovarian stimulation (COS). Yet according to the National Institute for Health and Care Excellence (NICE), most women undergoing IVF will require more than one treatment cycle to conceive [1]. Live birth rates are low (20–35%) following a single cycle of IVF, which stems partly from a lack of robust prognostic markers for poor ovarian response during COS [2]. Research has shown a strong association between the number of oocytes and live birth rate when up to 15–20 eggs are collected. Beyond 20 oocytes, live birth rates in

fresh cycles steadily decline, likely due to endometrial asynchrony [3,4]. Ovarian response varies greatly among individuals and depends on various factors such as  female age and ovarian reserve, usually assessed using anti‐Müllerian hormone (AMH) levels and antral follicle count (AFC). It is estimated that 9–24% of all IVF cycles are complicated by poor response to COS  [2], although there is no standard definition of poor ovarian response (POR). In 2011, the European Society of Human Reproduction and Embryology (ESHRE) introduced the Bologna criteria, whereby at least two of the following three ­features must be present to identify a woman as poor responder: (i) advanced maternal age (   40 years); (ii) previous POR after COS

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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Poor response during ovarian stimulation

(canceled cycles or 3 oocytes with a conventional COS protocol); and (iii) abnormal ovarian reserve tests (AFC 400,000 IVF/ICSI cycles) analysis that evaluated live birth rates by the number of oocytes

Management options 

Table 45.1  Live birth rate (with 95% CI) by oocyte number and age band, based on >400,000 IVF/ICSI cycles [4]. Age band Number of oocytes

18–34 years

35–37 years

38–39 years

≥40 years

1

7% (7, 8)

6% (6, 7)

4% (4, 5)

2% (2, 3)

2

16% (15, 17)

14% (13, 14)

9% (9, 10)

5% (5, 5)

3

22% (21, 22)

19% (18, 19)

13% (13, 14)

7% (7, 8)

retrieved [4]. The live birth rates for one, two and three oocytes for different age bands are provided in Table 45.1. In women over 40 years of age with a poor response, the live birth rate is in the region of 3.5% per oocyte retrieval, which still compares favorably with a live birth rate of 50pg/ml. Patients were randomly allocated to cyst aspiration or conservative management. 122/1,317 (9.3%) patients were found to have functional ovarian cysts, 76 of whom had cyst aspiration and 46  no intervention. The cycle cancelation rate before oocyte retrieval for poor response in the 1,195 patients without cysts was 89/1,195 (7.5%) and for OHSS, it was 33/1,195 (2.8%). The cycle cancelation rate for poor response was 17/76 (22.4%) in the patients with functional cysts who underwent cyst aspiration, and it was 12/46 (26.1%) in those managed conservatively. None of the patients with ovarian cysts were canceled for OHSS. The patients with ­ovarian

cysts had significantly higher day 3 FSH levels, longer stimulation with hMG, larger number of ampoules of hMG, higher cycle cancelation and miscarriage rates, and lower implantation and pregnancy rates. Patients with bilateral cysts had significantly lower number of oocytes than those with unilateral cysts although there was no significant difference in cycle outcome. Patients developing ovarian cysts on a long follicular phase down‐regulation protocol were found to take significantly longer to achieve down-regulation, required more FSH ampoules, developed fewer follicles and had lower embryo quality [15]. However, there was no significant difference in implantation and pregnancy rates between the two groups, although the study was small (51 cycles). Some studies suggest the presence of functional ovarian cysts may be associated with poorer cycle outcomes, but the observation of higher basal day 3 FSH levels in these patients could reflect an association between poor ovarian reserve and propensity for cyst formation during down‐regulation or, alternatively, that the poorer cycle outcome is linked to reduced ovarian reserve rather than the presence of a  cyst per se. Indeed, it has been reported that  cyst formation after luteal phase GnRHa  administration is a marker for poor responders [14]. There are no large randomized controlled studies to definitively address whether functional ovarian cysts are causally associated with poorer outcomes in IVF cycles or simply reflect a group of patients with a poorer prognosis, who are more likely to develop ovarian cysts during treatment.

Management options Management options for cysts have included cycle cancelation, continuing down‐regulation, cyst aspiration or administration of

297

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Ovarian cysts following pituitary down-regulation

hCG [16]. There are a limited number of studies addressing which management option should be used. The presence of nonfunctional cysts is not associated with a reduction in the number of oocytes retrieved and is not an indication for cycle cancelation [17]. An observational study reported no difference in pregnancy rates between patients with cysts and those without cysts during down‐ regulation, having aspirated most of the cysts prior to starting stimulation  [8]. In a small study that looked at 59/936 (5.5%) patients who developed functional ovarian cysts (cyst + estradiol >50pg/ml) after GnRHa administration starting during the luteal phase, 45 patients were allocated to conservative ­management (continuing GnRHa until estradiol 2 hours

1/1,049 (0.1%)

Vaginal bleeding requiring a suture

0

Vaginal bleeding (all cases)

229/2,670 (8.6%)

Vaginal bleeding (>100 mL) (including one case needing a suture)

22/2,670 (0.8%)

Vaginal bleeding requiring local compression

28/2,670 (1.0%)

Vaginal bleeding

35/10,125 (0.5%)

Bennett et al. [3]

Berg & Lunqvist [4]

2,670

10,125

bleeding exceeded 100 mL and in 1.0% application of local pressure was required. In 0.11% of oocyte retrievals severe intra‐abdominal bleeding occurred. The definition of vaginal bleeding as well as the assessment of the amount of blood loss remains unclear in the study by Bennett et al. [3]. Berg and Lunqvist [4] surveyed 12 IVF centers about the complications of a total number of 10,125 oocyte retrievals by use of a questionnaire. They reported that vaginal bleeding occurred in 0.5% of procedures. It is unclear how the reporting centers evaluated their cycles with respect to the complications and how a vaginal bleed was defined [4]. Dessole et al. [5] calculated the blood loss within 24 hours after TVOR by determination of hemoglobin and hematocrit on the days before and after TVOR. The mean blood loss was estimated to be 232  mL (standard deviation ± 131 mL). The number of follicles ­aspirated, the number of oocytes collected, the preovulatory estradiol value and the duration of the TVOR did not correlate with the amount of blood loss in that study of 220 TVOR procedures [5].

Intra-abdominal bleeding Severe intra‐abdominal bleeding is very rare; however, it can be life‐threatening. It can be

caused by direct injury to the ovarian, parametrial or pelvic vessels or by trauma to pelvic organs. Serious cases of injury to the iliac vessels have been described as a result of misidentification of iliac vessels as ovarian follicles  [4]. Severe bleeding from the sacral vein requiring emergency laparotomy has been described  [6]. Hemoperitoneum may also occur after bleeding from small intrafollicular vessels, particularly after follicular flushing with solutions that contain heparin [7]. The literature on intra‐abdominal bleeding is summarized in Table  56.2. In the only two prospective studies on complications of TVOR, intra‐abdominal bleeding was reported in none of 1,059 cases  [2] and in 3 of 2,670 cases (0.11%) [3]. In retrospective studies the incidence of severe intra‐abdominal bleedings after TVOR has been reported as 0.08–0.2% [7–11]. In a registry linkage study on 9,175 IVF cycles in Finland, bleeding necessitating hospital admission was reported in 0.09% of women  [12]. Most instances of bleeding occurred within 2  months of starting therapy. However, the authors did not give information on whether these cases of bleeding were a consequence of oocyte retrieval or whether they were due to other causes. The start of therapy was defined by the day of the purchase of the medications.

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Bleeding following oocyte retrieval

Table 56.2  Incidence of intra-abdominal bleeding after TVOR. Author

N

Diagnosis

Incidence

Therapy

Zhen et al. [10]

10,251 Intra‐peritoneal bleeding

22/10,251 (0.2%)

5 cases managed by laparotomy or laparoscopy, 17 cases by observation

Ludwig et al. [2]

1,059

Berg & Lunqvist [4]

10,125 Intraperitoneal bleeding

2/10,125 (0.02%)

Bennett et al. [3]

2,670

Hematoperitoneum

2/2,670 (0.07%) One case needing laparotomy

Punctured iliac vessel

1/2,670 (0.04%) Spontaneous closure 3/3,656 (0.08%) Laparotomy and blood transfusion

Intra‐abdominal bleeding 0 Laparotomy

Dicker et al. [7]

3,656

Severe intra‐abdominal bleeding

Tureck et al. [8]

674

Intra‐abdominal bleeding 1/674 (0.3%)

Laparoscopy

Govaerts et al. [9]

1,500

Intra‐peritoneal bleeding

3/1,500 (0.2%)

Laparoscopy

54/23,827 (0,23 %)

18 cases managed by laparoscopy, 1 by laparotomy

Levi‐Setti et al. [11] 23,827 Intra‐peritoneal bleeding

Therefore, it was not clear whether this study really assessed the complications caused by oocyte retrieval. Severe bleeding can also occur as a consequence of bleeding disorders and medical problems influencing coagulation. Battaglia et  al.  [13] and El‐Shawarby et  al.  [14] reported on two cases of severe bleeding in patients with a deficit of coagulation factor IX  [13] and in a patient with essential thrombocythemia [14].

Management options Vaginal bleeding There is often mild vaginal bleeding after TVOR. However, in 1–3% of cases there is significant vaginal bleeding that requires attention  [2–4]. A gauze swab is usually used to wipe the vagina at the end of the procedure, and if this is excessively soaked with fresh blood it should alert the clinician to inspect the

vaginal walls with the aid of a speculum. If an active bleeding point is detected, it can be treated in the great majority of cases by application of local pressure or suturing of the bleeding point. However, if this has been missed, and excessive vaginal bleeding is noted in the recovery room, then the vaginal walls should be inspected and appropriate measures (as described above) should be taken. Sometimes this is not possible without reanesthetizing the patient, who is often in discomfort and drowsy, and hence may not be very cooperative. Also, the bed and lighting in the recovery area are often not very conducive to proper inspection of the vagina.

Intra-abdominal bleeding Patients with intra‐abdominal bleeding following TVOR may present with symptoms of abdominal pain and distension and signs of hypovolemia (tachycardia and hypotension). However, as IVF patients are usually young

Prevention 

and healthy, they could compensate well for some time and the presentation may be delayed for a few hours or longer, as in the Case History. Pelvic ultrasound may show fluid collection in the pouch of Douglas. The absence of this finding, however, does not exclude significant internal bleeding, as there is also the possibility of retroperitoneal bleeding. The commoner cause of abdominal pain and distension, with fluid in the pouch of Douglas following TVOR is ovarian hyperstimulation syndrome (OHSS) (see Chapter 70). However, in OHSS hemoglobin and hematocrit are raised due to hemoconcentration secondary to fluid shift to third spaces. Also, OHSS tends to present later. In bleeding, both hemoglobin and hematocrit are low, and the presentation is often a few hours after TVOR. Both cases, however, may coexist and a high index of suspicion is required. On the basis of the clinical presentation, laparoscopy or laparotomy may be necessary. However, in these cases the ovaries are likely to be enlarged with multiple cysts, which may necessitate additional operative measures and precautions. For example, consideration should be given to using the open laparoscopy (Hasson) technique to avoid injury to grossly enlarged ovaries [15]. Also, an extendable incision (such as midline subumbilical) should be used in ­laparotomy, as the exact source of bleeding and  extent of injury are not usually known preoperatively. During the operation, the ovaries may look “abnormal” to the operating gynecologist who is inexperienced in seeing hyperstimulated ovaries (multicystic, enlarged, edematous, with increased vascularization and perhaps free fluid in the pelvis). This situation can arise if the patient is admitted as an emergency to another hospital and operated on by a different team and can lead to unnecessary interventions such as cystectomy or even an oophorectomy. Therefore, patients should be given a 24‐hour telephone number through which

they can keep their ART team informed of any emergency admission to a different hospital. Preoperative liaison between the ART and the operating teams is necessary. Proactively, stand‐alone units (those outside hospital setting) should have service arrangement with local hospitals to facilitate admission of these cases and manage them according to agreed protocols. Intraoperatively, the source of bleeding is identified and secured. This could range from a small bleeding point on the ovary to iliac vessels lacerations  [3]. Therefore, preoperative consent to do what is necessary, including oophorectomy in very rare cases as a life‐­saving measure, should be obtained. In the Case History, a diagnostic laparoscopy was performed and showed a hemoperitoneum resulting from a bleeder on the right ovary, which was coagulated. Postoperatively, she recovered well and was discharged from the hospital 3 days later.

Prevention A comprehensive preoperative evaluation of the patient is crucial before starting ART. Patients with possible risk factors, such as  bleeding tendencies and coagulation defects, should be identified and managed accordingly. During oocyte retrieval the clinician should avoid repeated punctures and movements of the needle in the vaginal wall, because this can cause tearing and bleeding. The aim should be to perform the procedure with as fewer punctures of the vagina as possible. It is also important to avoid repeated penetration of the ovary and follicles in order to reduce the possibility of intraperitoneal bleeding. Overdistension of the aspirated follicles during follicular flushing must be avoided in order to reduce the risk of follicular rupture. Serious injuries to the iliac vessels due to their misidentification as ovarian follicles can be

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Bleeding following oocyte retrieval

Figure 56.1  Transvaginal ultrasound scan in the sagittal plane, showing ovarian follicle (1) and external iliac vessel (2).

Figure 56.2  Transvaginal ultrasound scan of the same patient as in Figure 56.1 in the transverse plane, showing ovarian follicle (1) and external iliac vessel (2), which could be mistaken for a follicle.

avoided if the clinician carefully visualizes all round structures in the sagittal and the transverse planes to distinguish vessels from follicles. The anatomic situation is demonstrated in Figures 56.1 and 56.2. The use of color Doppler can also prevent such complications. Before withdrawing the ultrasound probe the pelvis should always be inspected to ensure that there is no large collection of fluid in the pouch of Douglas. If this is detected, then closer and prolonged postoperative observation is warranted.

Management options: ●● Vaginal bleeding is treatable in the majority of cases by application of local pressure or suturing of the bleeding point. ●● Severe abdominal pain, even in the absence of intra-abdominal fluid, has to be taken seriously and the possibility of bleeding should be considered. ●● On the basis of the clinical presentation, laparoscopy or laparotomy may be necessary to identify and secure the source of bleeding. ●● In cases of grossly enlarged ovaries, the open method is recommended for laparoscopy and an extendable incision for laparotomy. ●● The hyperstimulated ovaries may look abnormal to the inexperienced eye, and preoperative liaison between the ART and operating teams is necessary.

Key points Challenge: Heavy bleeding after TVOR. Background: Vaginal bleeding is the most common complication of TVOR, occurring in 1–3% of cases. ●● Intra-abdominal bleeding occurs in less than 1 in 1000 TVOR. However, it can be lifethreatening. ●●

Prevention: ●● Bleeding tendencies and clotting defects have to be identified before the start of ART therapy by a comprehensive preoperative evaluation. ●● Good surgical technique, avoiding unnecessary repeated punctures of the vagina and ovary and positively identifying the iliac vessels reduce the risk of bleeding.

References 

Answers to questions patients ask Q1 How big is the risk of bleeding due to the egg collection? A1. Smaller vaginal bleeding is quite common and can easily be taken care of right after the procedure by local compression. Heavier vaginal bleeding occurs in about 1% of patients and we may have to put in a suture to stop it. There are very rare cases of intra‐abdominal bleeding in about 0.2 % of patients. Q2 How will I notice if I have bleeding in my abdomen? A2. This is rare. It may be noticed by ultrasound during the procedure when heavy. More often, it may

occur slowly and therefore remain undetected until after you go home. If you notice light headedness, dizziness or nausea and vomiting when you are at home or in case of strong abdominal pain or distension you will have to give us a call or call emergency immediately. Q3 Do I have to be admitted to hospital in case of bleeding complications? A3. In case of suspected bleeding you may be admitted to hospital for observation, or surgery may be required in about 1 per 1,000 cases.

References 1 Wickland M, Lennart M, Hamberger L. Transvesical and transvaginal approaches for the aspiration of follicles by the use of ultrasound. Ann N Y Acad Sci. 1985;442:184. 2 Ludwig AK, Glawatz M, Griesinger G, Diedrich K, Ludwig M. Perioperative and postoperative complications of ultrasound‐ guided oocyte retrieval: prospective study of more than 1000 oocyte retrievals. Hum Reprod. 2006;21:3235–40. 3 Bennett SJ, Waterstone JJ, Cheng WC, Parsons J. Complications of transvaginal ultrasound‐ directed follicle aspiration: a review of 2760 consecutive procedures. J Assist Reprod Genet. 1993;10:772–8. 4 Bergh T, Lundkvist Ö. Clinical complications during in‐vitro fertilization treatment. Hum Reprod. 1992;7:625–6. 5 Dessole S, Rubattu G, Ambrosini G, Miele M, Nardelli GB, Cherchi PL. Blood loss following noncomplicated transvaginal oocyte retrieval for in vitro fertilization. Fertil Steril. 2001;76:205–6.

6 Azem F, Wolf Y, Botchan A, Amit A, Lessing JB, Kluger Y. Massive retroperitoneal bleeding: a complication of transvaginal ultrasound‐guided oocyte retrieval for in vitro fertilization‐embryo transfer. Fertil Steril. 2000;74:405–6. 7 Dicker D, Ashkenazi J, Feldberg D, Levy T, Dekel A, Ben Rafael Z. Severe abdominal complications after transvaginal ultrasonographically guided retrieval of oocytes for in vitro fertilization and embryo transfer. Fertil Steril. 1993;59:1313–15. 8 Tureck RW, Garcia, C, Blaso, L, Mastroianni L. Perioperative complication arising after transvaginal oocyte retrieval. Obstet Gynecol. 1993;81:590–3. 9 Govaerts I, Devreker F, Delbaere A, Revelard P, Englert Y. Short‐term medical complications of 1500 oocyte retrievals for in vitro fertilization and embryo transfer. Eur J Obstet Gynecol Reprod Biol. 1998;77:239–43. 10 Zhen X, Qiao J, Ma X, Fan Y, Liu P. Intraperitoneal bleeding following

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transvaginal oocyte retrieval. Int J Gynaecol Obstet. 2010;108:31–4. 11 Levi‐Setti PE, Cirillo F, Scolaro V, Morenghi E, Heilbron F, Girardello D, Zannoni E, Patrizio P. Appraisal of clinical complications after 23,827 oocyte retrievals in a large assisted reproductive technology program. Fertil Steril. 2018;109:1038–43. 12 Klemetti R, Gissler M, Hemminki E. Comparison of perinatal health of children born from IVF in Finland in the early and late 1990s. Hum Reprod. 2002;17:2192–8.

13 Battaglia C, Regnani G, Giulini S, Madgar L, Genazzani A. Severe intraabdominal bleeding after transvaginal oocyte retrieval for IVF‐ET and coagulation factor XI deficiency: a case report. J Assist Reprod Genet. 2001;18:178–87. 14 El Shawarby SA, Margara RA, Trew GH, Laffan MA, Lavery SA. Thrombocythemia and hemoperitoneum after transvaginal oocyte retrieval for in vitro fertilization. Fertil Steril. 2004;82:735–7. 15 Hasson HM. Open laparoscopy as a method of access in laparoscopic surgery. Gynaecol Endosc. 1999;8:353–62.

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57 To flush or not to flush follicles at oocyte retrieval Anne E. Martini and Micah J. Hill Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Case History: During a regular results-review meeting in an ART clinic it was noted that the average number of oocytes retrieved during the previous 3 months was reduced. The embryologists noted that three out of the five clinicians who worked in the clinic regularly flushed follicles at oocyte retrieval, while the other two did not. Because patients treated by the “nonflushers” had significantly less oocytes collected during the previous 3 months, it was suggested that all clinicians should flush the follicles at oocyte retrieval as a policy. The “nonflushers” argued that in the past they have always had similar average number of oocytes collected from their patients, compared to the “flushers.” More importantly, they argued that their patients’ success rate was consistently above the average for the clinic. Agreement could not be reached, and the director of the clinic was tasked with drawing up an evidence-based policy.

Background Follicle flushing utilizes a double‐lumen retrieval needle with one channel to aspirate follicular fluid and another to instill flushing medium into a follicle for a secondary aspiration  [1,2]. Proponents of follicular flushing maintain that performing additional aspirates increases oocyte yield through recovery of oocytes that would have otherwise been retained [1,3]. However, several studies including a 2018 Cochrane review have refuted these claims, noting that the theoretical benefits of follicle flushing have not translated into improved outcomes in ART  [2,4–6]. Though the current rate of follicle flushing amongst reproductive specialists is unknown, a survey

study from 2001 showed that more than 50% of  ART clinicians surveyed were performing follicle flushing on a routine basis [7].

Management options Follicle flushing in normal responders The purpose of follicle flushing is to increase oocyte yield [1–5,8]. However, only 3 prospective nonrandomized studies have confirmed this notion  [3,8,9]. In those studies, patients initially underwent direct follicular aspiration followed by follicular flushing in situations when an oocyte was not obtained from the initial aspirate. Aspiration alone obtained 40–83%

Assisted Reproduction Techniques: Challenges and Management Options, Second Edition. Edited by Khaldoun Sharif and Arri Coomarasamy. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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To flush or not to flush follicles at oocyte retrieval

Table 57.1  Summary of randomized controlled trials published to date comparing direct aspiration to aspiration with follicle flushing. Patients (n) Direct aspirate

Study

Haines et al. [1]

18

Oocytes retrieved (n)

Flushing

18

Direct aspirate

6.8

Procedure time (minutes)

P value

Direct aspirate

Flushing

P value

5.6

0.22

–

–

–

*

Flushing

Tan et al. [5]

50

50

11.0

9.0

NS

15

30