Fetal Therapy: Scientific Basis and Critical Appraisal of Clinical Benefits [2nd Edition] 9781108597647

Table of contents :
Cover......Page 1
Fetal Therapy:

Scientific Basis and Critical Appraisal of Clinical Benefits......Page 5
Copyright
......Page 6
Dedication
......Page 7
Contents
......Page 9
Contributors......Page 12
Foreword......Page 19
1 The Rationale for Fetal Therapy......Page 21
2 A Fetal Origin of Adult Disease......Page 28
3 Human Embryology: Molecular Mechanisms of
Embryonic Disease......Page 40
4 Human Genetics and Fetal Disease: Assessment
of the Fetal Genome......Page 56
5 Interventions in Pregnancy to Reduce Risk of Stillbirth......Page 68
6 Fetal Therapy Choices: Uncertain and Emotional
Decisions and the Doctor’s Role in Parental
Decision-Making
......Page 81
7 The Ethics of Consent for Fetal Therapy
......Page 89
8 Open Fetal Surgery: Is There Still a Role?......Page 97
9 The Artificial Womb......Page 103
10 Management of Red Cell Alloimmunization......Page 111
11 Fetal and Neonatal Alloimmune Thrombocytopenia:
Clinical Disease and Management......Page 119
12 Structural Heart Disease: Embryology......Page 130
13 Structural Heart Disease: Genetic Influences......Page 143
14 Deciphering the Mechanisms of Developmental Heart
Disease: Research from Embryonic Knockout Mice......Page 153
15 In Utero Intervention for Cardiac Disease......Page 166
16 Fetal Cerebral Consequences of Structural Heart
Disease: Can These Be Ameliorated?......Page 177
17 Fetal Supraventricular Tachyarrhythmias:
Pharmacokinetics, Modes of Action, and Results
of Anti-Arrhythmic Drug Therapy......Page 186
18 Fetal Dysrhythmias: Diagnosis and Clinical
Management......Page 196
19 Manipulation of Amniotic Fluid Volume: Homeostasis
of Fluid Volumes in the Amniotic Cavity......Page 211
20 Oligohydramnios and Polyhydramnios: Therapeutic
Manipulation of Amniotic Fluid Volume......Page 220
21 Fetal Infections: Immune Response to Infections
during Fetal Life......Page 235
22 Fetal Infections: Clinical Management......Page 244
23 Fetal Growth Restriction: Placental Basis and
Implications for Clinical Practice......Page 268
24 Fetal Growth Restriction: Diagnosis and Management......Page 284
25 Screening and Intervention for Fetal
Growth Restriction......Page 299
26 Maternal and Fetal Therapy: Can We Optimize
Fetal Growth?......Page 307
27 The Pathogenesis of Preterm Birth: A Guide to
Potential Therapeutic Targets......Page 322
28 Clinical Interventions for the Prevention and
Management of Spontaneous Preterm Birth in
the Singleton Fetus......Page 331
29 Clinical Interventions to Prevent Preterm Birth
in Multiple Pregnancies......Page 345
30 Reducing Neurologic Morbidity from Preterm Birth
through Administering Therapy Prior to Delivery......Page 353
31 Twin-to-Twin Transfusion Syndrome: Placental
and Fetal Pathogenesis......Page 364
32 Twin-to-Twin Transfusion Syndrome: Treatment by
Fetoscopic Laser Coagulation of the Placental Vascular
Anastomoses on the Chorionic Plate......Page 373
33 Interventions for Early and Late Twin-Twin
Transfusion Syndrome......Page 383
34 Diagnosis and Treatment in Twin Anemia
Polycythemia Sequence......Page 387
35 Neurological and Long-Term Neurodevelopmental
Outcome after Fetal Therapy in Complicated
Monochorionic Twins......Page 393
36 The Diagnosis and Detection of Fetal Growth
Restriction in Monochorionic Twin Pregnancies......Page 404
37 Clinical Outcome and Management of Selective
Fetal Growth Restriction in Monochorionic Twins......Page 412
38 Twin Reversed Arterial Perfusion Sequence:
Pathophysiology and In Utero Treatment......Page 418
39 Fetal Reduction and Selective Termination......Page 424
40 Selective Termination of One Fetus in
Monochorionic Twin Pregnancies......Page 438
41 Lower Urinary Tract Obstruction: Pathophysiology,
Prenatal Assessment, and In Utero Intervention......Page 446
42 Fetal Pleural Effusions and Pulmonary Pathology:
Pathophysiology and Clinical Management......Page 458
43 Neural Tube Anomalies: An Update on the
Pathophysiology and Prevention......Page 469
44 Neural Tube Anomalies: Clinical Management
by Open Fetal Surgery......Page 476
45 Open Neural Tube Defect Repair: Development and
Refinement of a Fetoscopic Technique......Page 487
46 Fetal Tumors: Clinical Management......Page 500
47 Congenital Diaphragmatic Hernia: Pathophysiology
and Antenatal Assessment......Page 514
48 Congenital Diaphragmatic Hernia: In Utero
Treatment Today and Tomorrow......Page 523
49 Stem Cell Transplantation: Clinical Potential in
Treating Fetal Genetic Disease......Page 532
50 Strategies to Repair Defects in the Fetal Membrane......Page 540
51 Tissue Engineering and the Fetus......Page 552
52 Gene Therapy: Principles and Clinical Potential......Page 560
53 Fetal Therapy and Translational Studies: Global
Alignment, Coordination, and Collaboration in
Perinatal Research – the Global Obstetrics
Network (GONet) Initiative......Page 581
54 Congenital Anomaly Registers: The
European Experience......Page 590
55 A Challenge for Prenatal Diagnosis in Developing
Countries: Zika Virus as an Exemplar......Page 600
Index......Page 608

Citation preview

Fetal Therapy Second Edition

Fetal Therapy Scientific Basis and Critical Appraisal of Clinical Benefits Second Edition Edited by Mark D. Kilby University of Birmingham

Anthony Johnson University of Texas Health Science Center, Houston

Dick Oepkes Leiden University Medical Center

University Printing House, Cambridge CB2 8BS, United Kingdom One Liberty Plaza, 20th Floor, New York, NY 10006, USA 477 Williamstown Road, Port Melbourne, VIC 3207, Australia 314–321, 3rd Floor, Plot 3, Splendor Forum, Jasola District Centre, New Delhi – 110025, India 79 Anson Road, #06–04/06, Singapore 079906 Cambridge University Press is part of the University of Cambridge. It furthers the University’s mission by disseminating knowledge in the pursuit of education, learning, and research at the highest international levels of excellence. www.cambridge.org Information on this title: www.cambridge.org/9781108474061 DOI: 10.1017/9781108564434 © Mark D. Kilby, Anthony Johnson, and Dick Oepkes 2020 This publication is in copyright. Subject to statutory exception and to the provisions of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press. First published 2020 Printed in Singapore by Markono Print Media Pte Ltd A catalogue record for this publication is available from the British Library. Library of Congress Cataloging-in-Publication Data Names: Kilby, Mark, editor. | Johnson, Anthony, 1954– editor. | Oepkes, Dick, editor. Title: Fetal therapy : scientific basis and critical appraisal of clinical benefits / edited by Mark D. Kilby, Anthony Johnson, Dick Oepkes. Other titles: Fetal therapy (Kilby) Description: Second edition. | Cambridge, United Kingdom ; New York, NY : Cambridge University Press, 2020. | Includes bibliographical references and index. Identifiers: LCCN 2019008058 | ISBN 9781108474061 (hardback : alk. paper) Subjects: | MESH: Fetal Diseases–therapy | Fetal Therapies–methods Classification: LCC RG626 | NLM WQ 211 | DDC 618.3/2–dc23 LC record available at https://lccn.loc.gov/2019008058 ISBN 978-1-108-47406-1 Hardback Additional resources for this publication at www.cambridge.org/9781108474061. Cambridge University Press has no responsibility for the persistence or accuracy of URLs for external or third-party internet websites referred to in this publication and does not guarantee that any content on such websites is, or will remain, accurate or appropriate.

.............................................................................................................................. Every effort has been made in preparing this book to provide accurate and upto-date information that is in accord with accepted standards and practice at the time of publication. Although case histories are drawn from actual cases, every effort has been made to disguise the identities of the individuals involved. Nevertheless, the authors, editors, and publishers can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors, and publishers therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this book. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use.

To the patients and families who entrust us with their most precious possession, their developing child, and those who have been our teachers and mentors over the years. A special thank you to each of our families for their support, tolerance, and understanding.

Contents List of Contributors Foreword xvii

x

Section 1. General Principles

11 Fetal and Neonatal Alloimmune Thrombocytopenia: Clinical Disease and Management 99 Dian Winkelhorst and Dick Oepkes

1

The Rationale for Fetal Therapy Ahmet Baschat

1

2

A Fetal Origin of Adult Disease Mark Hanson and Lucy Green

8

3

Human Embryology: Molecular Mechanisms of Embryonic Disease 20 Philippa Francis-West, Jonna Petzold, Guillermo Villagomez Olea, and Isabelle Miletich

4

5

6

7

Structural Heart Disease in the Fetus

Human Genetics and Fetal Disease: Assessment of the Fetal Genome 36 Hsu Chong, Fionnuala Mone, Dominic McMullan, Eamonn Maher, and Mark D. Kilby Interventions in Pregnancy to Reduce Risk of Stillbirth 48 Alexander Heazell and Vicki Flenady Fetal Therapy Choices: Uncertain and Emotional Decisions and the Doctor’s Role in Parental Decision-Making 61 Danielle R. M. Timmermans The Ethics of Consent for Fetal Therapy 69 Sanne van der Hout, Wybo J. Dondorp, and Guido de Wert

8

Open Fetal Surgery: Is There Still a Role? Oluyinka O. Olutoye

9

The Artificial Womb 83 Emily A. Partridge and Alan W. Flake

77

Section 2. Fetal Disease: Pathogenesis and Treatment Blood Cell Alloimmunization 10 Management of Red Cell Alloimmunization 91 Carolien Zwiers, Inge L. van Kamp, and Dick Oepkes

12 Structural Heart Disease: Embryology 110 Adriana C. Gittenberger-de Groot, Monique R. M. Jongbloed, Robert E. Poelmann, and Margot M. Bartelings 13 Structural Heart Disease: Genetic Influences Catherine L. Mercer and David I. Wilson

123

14 Deciphering the Mechanisms of Developmental Heart Disease: Research from Embryonic Knockout Mice 133 Dorota Szumska, Robert Wilson, Wolfgang Weninger, and Tim Mohun 15 In Utero Intervention for Cardiac Disease 146 Helena M. Gardiner 16 Fetal Cerebral Consequences of Structural Heart Disease: Can These Be Ameliorated? 157 Mike Seed

Fetal Dysrhythmias 17 Fetal Supraventricular Tachyarrhythmias: Pharmacokinetics, Modes of Action, and Results of Anti-Arrhythmic Drug Therapy 166 Edgar Jaeggi and Nico A. Blom 18 Fetal Dysrhythmias: Diagnosis and Clinical Management 176 Julene S. Carvalho

Manipulation of Fetal Amniotic Fluid Volume 19 Manipulation of Amniotic Fluid Volume: Homeostasis of Fluid Volumes in the Amniotic Cavity 191 Marie H. Beall and Michael G. Ross

vii

Contents

20 Oligohydramnios and Polyhydramnios: Therapeutic Manipulation of Amniotic Fluid Volume 200 Janice Gibson and Janet Brennand

Fetal Infections 21 Fetal Infections: Immune Response to Infections during Fetal Life 215 Nicolas Dauby and Arnaud Marchant 22 Fetal Infections: Clinical Management 224 Marianne Leruez-Ville, Guillaume Benoist, and Yves Ville

Fetal Growth and Well-being 23 Fetal Growth Restriction: Placental Basis and Implications for Clinical Practice 248 John Kingdom, Melissa Walker, Sascha Drewlo, and Sarah Keating 24 Fetal Growth Restriction: Diagnosis and Management 264 Clare L. Whitehead, Fergus P. McCarthy, and John Kingdom 25 Screening and Intervention for Fetal Growth Restriction 279 Alice E. Hughes and Gordon C. S. Smith 26 Maternal and Fetal Therapy: Can We Optimize Fetal Growth? 287 Katarzyna M. Maksym and Anna L. David

Preterm Birth of the Singleton and Multiple Pregnancy 27 The Pathogenesis of Preterm Birth: A Guide to Potential Therapeutic Targets 302 Phillip Bennett 28 Clinical Interventions for the Prevention and Management of Spontaneous Preterm Birth in the Singleton Fetus 311 Eleanor Whitaker, Sarah Murray, and Jane E. Norman 29 Clinical Interventions to Prevent Preterm Birth in Multiple Pregnancies 325 Maud D. van Zijl, Brenda M. Kazemier, and Ben W. Mol 30 Reducing Neurologic Morbidity from Preterm Birth through Administering Therapy Prior to Delivery 333 Clare L. Whitehead and Jodie M. Dodd

viii

Complications of Monochorionic Multiple Pregnancy: Twin-to-Twin Transfusion Syndrome 31 Twin-to-Twin Transfusion Syndrome: Placental and Fetal Pathogenesis 344 Fiona L. Mackie, Enrico Lopriore, and Mark D. Kilby 32 Twin-to-Twin Transfusion Syndrome: Treatment by Fetoscopic Laser Coagulation of the Placental Vascular Anastomoses on the Chorionic Plate 353 Gihad E. Chalouhi, Julien Stirnemann, Claire Colmant, and Yves Ville 33 Interventions for Early and Late Twin-Twin Transfusion Syndrome 363 Tim Van Mieghem, David Baud, and Greg Ryan 34 Diagnosis and Treatment in Twin Anemia Polycythemia Sequence 367 Lisanne S. A. Tollenaar and Femke Slaghekke 35 Neurological and Long-Term Neurodevelopmental Outcome after Fetal Therapy in Complicated Monochorionic Twins 373 Jeanine van Klink, Marjolijn S. Spruijt, and Enrico Lopriore

Complications of Monochorionic Multiple Pregnancy: Fetal Growth Restriction in Monochorionic Twins 36 The Diagnosis and Detection of Fetal Growth Restriction in Monochorionic Twin Pregnancies Rosemary Townsend and Asma Khalil

384

37 Clinical Outcome and Management of Selective Fetal Growth Restriction in Monochorionic Twins 392 Mar Bennasar, Elisenda Eixarch, Josep Maria Martinez, and Eduard Gratacós

Complications of Monochorionic Multiple Pregnancy: Twin Reversed Arterial Perfusion Sequence 38 Twin Reversed Arterial Perfusion Sequence: Pathophysiology and In Utero Treatment 398 Liesbeth Lewi and Isabel Couck

Complications of Monochorionic Multiple Pregnancy: Multifetal Reduction in Multiple Pregnancy 39 Fetal Reduction and Selective Termination 404 Mark I. Evans, Shara M. Evans, Jenifer Curtis, and David W. Britt 40 Selective Termination of One Fetus in Monochorionic Twin Pregnancies 418 Min Chen and Tak Yeung Leung

Contents

Fetal Urinary Tract Obstruction 41 Lower Urinary Tract Obstruction: Pathophysiology, Prenatal Assessment, and In Utero Intervention 426 K. W. Cheung, R. Katie Morris, and Mark D. Kilby

Pleural Effusion and Pulmonary Pathology 42 Fetal Pleural Effusions and Pulmonary Pathology: Pathophysiology and Clinical Management 438 Nimrah Abbasi and Greg Ryan

Surgical Correction of Neural Tube Anomalies 43 Neural Tube Anomalies: An Update on the Pathophysiology and Prevention 449 Alex J. Eggink and Regine P. M. Steegers-Theunissen 44 Neural Tube Anomalies: Clinical Management by Open Fetal Surgery 456 N. Scott Adzick, Julie S. Moldenhauer, and Gregory G. Heuer 45 Open Neural Tube Defect Repair: Development and Refinement of a Fetoscopic Technique 467 Michael A. Belfort, Alireza A. Shamshirsaz, and William E. Whitehead

Fetal Tumors 46 Fetal Tumors: Clinical Management 480 Sundeep G. Keswani and Timothy M. Crombleholme

Fetal Stem Cell Transplantation 49 Stem Cell Transplantation: Clinical Potential in Treating Fetal Genetic Disease 512 Åsa Ekblad and Cecilia Götherström 50 Strategies to Repair Defects in the Fetal Membrane 520 Tina T. Chowdhury, David W. Barrett, and Anna L. David 51 Tissue Engineering and the Fetus 532 Joseph Davidson and Paolo De Coppi

Gene Therapy 52 Gene Therapy: Principles and Clinical Potential Suzanne M. K. Buckley and Anna L. David

540

Section 3. The Future 53 Fetal Therapy and Translational Studies: Global Alignment, Coordination, and Collaboration in Perinatal Research – the Global Obstetrics Network (GONet) Initiative 561 Janneke van ‘t Hooft, Ben W. Mol (on behalf of the GONet collaborators), and Mark D. Kilby 54 Congenital Anomaly Registers: The European Experience 570 Judith Rankin 55 A Challenge for Prenatal Diagnosis in Developing Countries: Zika Virus as an Exemplar 580 Léo Pomar, David Lissauer, and David Baud

Congenital Diaphragmatic Hernia 47 Congenital Diaphragmatic Hernia: Pathophysiology and Antenatal Assessment 494 Jan Deprest, Francesca Russo, David Basurto, Koen Devriendt, and Roland Devlieger

Index

588

48 Congenital Diaphragmatic Hernia: In Utero Treatment Today and Tomorrow 503 Jan Deprest, Anne Debeer, Lennart Van der Veeken, Karel Allegaert, Liesbeth Lewi, and Luc De Catte

ix

Contributors

Nimrah Abbasi MD Fetal Medicine Unit, Ontario Fetal Centre, Mount Sinai Hospital, and Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Canada N. Scott Adzick MD The Center for Fetal Diagnosis and Treatment, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Karel Allegaert MD, PhD Unit Woman and Child, Department of Development and Regeneration, Group Biomedical Sciences, Katholieke Universiteit Leuven, Leuven, Belgium David W. Barrett PhD Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London, UK Margot M. Bartelings MD, PhD Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, the Netherlands Ahmet A. Baschat MD Johns Hopkins Center for Fetal Therapy, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA David Basurto MD Department of Development and Regeneration, Cluster Woman and Child, and University Hospitals Leuven, KU Leuven, Leuven, Belgium David Baud MD, PhD Materno-Fetal and Obstetrics Research Unit, Department Woman – Mother – Child, Lausanne University Hospital, Lausanne, Switzerland

x

Marie H. Beall MD Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Michael A. Belfort MBBCH, MD, PhD Department of Obstetrics and Gynecology (courtesy appointments in the Departments of Neurosurgery and Surgery) Baylor College of Medicine and Texas Children’s Hospital Fetal Center Houston, Texas Mar Bennasar PhD Fetal Medicine Reseach Center, BCNatal, Hospital Clinic and Hospital Sant Joan de Déu, University of Barcelona, and Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain Phillip Bennett BSc, PhD, MD, FRCOG, FMedSci Institute for Reproductive and Developmental Biology and Department of Obstetrics and Gynaecology, Imperial College London and Imperial College Healthcare NHS Trust, London, UK Guillaume Benoist MD Department of Obstetrics and Fetal Medicine, Paris Descartes University, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants-Malades, Paris, France Nico A. Blom MD, PhD Department of Pediatric Cardiology, Amsterdam University Medical Center, Amsterdam, and Leiden University Medical Center, Leiden, the Netherlands Janet E. Brennand MD, FRCOG The Ian Donald Fetal Medicine Centre, The Queen Elizabeth University Hospital, Glasgow, UK David W. Britt PhD Fetal Medicine Foundation of America, New York, NY, USA

Contributors

Suzanne M. K. Buckley BSc (Hons), PhD Elizabeth Garrett Anderson Institute for Women’s Health, University College London, London, UK Julene S. Carvalho MD, PhD, FRCPCH Brompton Centre for Fetal Cardiology, Royal Brompton Hospital; Fetal Medicine Unit, St. George’s University Hospital and Molecular and Clinical Sciences Research Institute, St. George’s, University of London, London, UK Gihad E. Chalouhi MD National Reference Centre for the Management of Complicated Monochorionic Pregnancies, and Department of Obstetrics and Fetal Medicine, Paris Descartes University, Assistance Publique-Hôpitaux de Paris, Hôpital NeckerEnfants-Malades, Paris, France Min Chen PhD Department of Fetal Medicine and Prenatal Diagnosis, The Third Affiliated Hospital of Guangzhou Medical University, Obstetrics and Gynecology Institute of Guangzhou, The Medical Centre for Critical Pregnant Women in Guangzhou, Key Laboratory for Major Obstetric Diseases of Guangdong Province, and Key Laboratory for Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China K. W. Cheung MBBS, MRCOG Birmingham Women’s and Children’s Hospital, Birmingham, UK; and Department of Obstetrics and Gynaecology, Queen Mary Hospital, University of Hong Kong, Hong Kong SAR, China

Regeneration, Biomedical Sciences, Katholieke Universiteit Leuven, Leuven, Belgium Timothy M. Crombleholme MD Fetal Care Center Dallas, Medical City Children’s Hospital, Dallas, TX, USA Jenifer Curtis ARDMS Fetal Medicine Foundation of America, New York, NY, USA Nicolas Dauby MD, PhD Department of Infectious Diseases, CHU Saint-Pierre, and Institute for Medical Immunology, Université Libre de Bruxelles, Brussels, Belgium Anna L. David MBChB, PhD, FRCOG Elizabeth Garrett Anderson Institute for Women’s Health, University College London, and National Institute for Health Research University College London Hospitals Biomedical Research Centre, London, UK Joseph Davidson MBBS, MRCS Stem Cell and Regenerative Medicine Section, Great Ormond Street Institute of Child Health, University College London, London, UK Luc De Catte MD, PhD Fetal Diagnosis and Therapy Unit, Division of Woman and Child, Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium

Hsu Phern Chong PhD Fetal Medicine Centre, Birmingham Women’s & Children’s NHS Foundation Trust, Birmingham, UK

Paolo De Coppi MD, PhD Stem Cell and Regenerative Medicine Section, Great Ormond Street Institute of Child Health, University College London, London, UK

Tina T. Chowdhury PhD, SFHEA Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London, UK

Guido de Wert MD Department of Health, Ethics and Society, Faculty of Health, Medicine and Life Sciences, Research Schools of CAPHRI and GROW, Maastricht University, Maastricht, the Netherlands

Claire L. Colmant MD National Reference Centre for the Management of Complicated Monochorionic Pregnancies, and Department of Obstetrics and Fetal Medicine, Paris Descartes University, Assistance Publique-Hôpitaux de Paris, Hôpital NeckerEnfants-Malades, Paris, France

Anne Debeer MD, PhD Division of Woman and Child, Department of Neonatology, University Hospitals Leuven, Leuven, Belgium

Isabel Couck MD Department of Obstetrics and Gynecology, University Hospitals Leuven, and Department of Development and

Jan Deprest MD, PhD, FRCOG Fetal Diagnosis and Therapy Unit, Division of Woman and Child, Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium; and Department of Maternal Fetal Medicine, Institute for Women’s Health, University College London, London, UK

xi

Contributors

Roland Devlieger MD, PhD Department of Development and Regeneration, Cluster Woman and Child, and University Hospitals Leuven, KU Leuven, Leuven, Belgium Koen Devriendt MD, PhD Department of Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium Jodie Dodd MB BS, PhD, FRANZCOG, CMFM Discipline of Obstetrics and Gynaecology, Women’s and Children’s Hospital, North Adelaide, SA, Australia Wybo J. Dondorp MD Department of Health, Ethics and Society, Faculty of Health, Medicine and Life Sciences, Research Schools of CAPHRI and GROW, Maastricht University, Maastricht, the Netherlands Sascha Drewlo PhD Department of Obstetrics and Gynecology, Michigan State University, Grand Rapids, MI, USA Alex J. Eggink MD, PhD Department of Obstetrics and Gynecology, Division of Obstetrics and Fetal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands Elisenda Eixarch PhD Fetal Medicine Reseach Center, BCNatal, Hospital Clinic and Hospital Sant Joan de Déu, University of Barcelona and Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona; and Centre for Biomedical Research on Rare Diseases (CIBER-ER), Madrid, Spain Åsa Ekblad PhD Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden Mark I. Evans MD Fetal Medicine Foundation of America; and Comprehensive Genetics, Mount Sinai School of Medicine, New York, NY, USA Shara M. Evans MSc, MPH Department of Maternal and Child Health, Gillings School of Public Health, University of North Carolina, Chapel Hill, NC, USA Alan W. Flake MD Division of General, Thoracic and Fetal Surgery, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

xii

Vicki Flenady RM, PhD Centre of Research Excellence in Stillbirth, Mater Research Institute, University of Queensland, Brisbane, Australia Philippa Francis-West BA, PhD Cell and Developmental Biology, Centre for Craniofacial and Regenerative Biology, King’s College London, London, UK Helena M. Gardiner MD, PhD, FRCP, FRCPCH, DCH (retired) Department of Obstetrics and Gynecology, McGovern Medical School, University of Texas Health Sciences Center, Houston, TX, USA Janice L. Gibson MD, MRCOG The Ian Donald Fetal Medicine Centre, The Queen Elizabeth University Hospital, Glasgow, UK Adriana C. Gittenberger-de Groot PhD Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands Cecilia Götherström PhD Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden Eduard Gratacós PhD Fetal Medicine Reseach Center, BCNatal, Hospital Clinic and Hospital Sant Joan de Déu, University of Barcelona and Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona; Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat and Centre for Biomedical Research on Rare Diseases (CIBER-ER), Madrid, Spain Lucy R. Green BSc, PhD Assistant Director, Institute of Developmental Sciences, University of Southampton, University Hospital Southampton, Southampton, UK Mark A. Hanson MA, DPhil, CertEd, FRCOG British Heart Foundation Professor, Director, Institute of Developmental Sciences, University of Southampton, University Hospital Southampton, Southampton, UK Alexander Heazell PhD, MRCOG Maternal and Fetal Health Research Centre, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, and St. Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK

Contributors

Gregory G. Heuer MD The Center for Fetal Diagnosis and Treatment, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

Tak Yeung Leung MD FRCOG Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong

Alice E. Hughes BSc (Hons), BMBS, MSc Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, UK

Liesbeth Lewi MD, PhD Fetal Diagnosis and Therapy Unit, Division of Woman and Child, Department of Obstetrics and Gynecology, University Hospitals Leuven, and Department of Development and Regeneration, Biomedical Sciences, Katholieke Universiteit Leuven, Leuven, Belgium

Edgar Jaeggi MD, FRCP(C) Fetal Cardiac Program, Labatt Family Heart Center, Hospital for Sick Children, University of Toronto, Toronto, Canada Monique R.M. Jongbloed MD, PhD Departments of Anatomy and Embryology and Cardiology, Leiden University Medical Center, Leiden, the Netherlands Brenda M. Kazemier MD, PhD Department of Obstetrics and Gynecology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands Sarah Keating MD Department of Laboratory Medicine and Pathobiology, University of Toronto, and Mount Sinai Hospital, Toronto, Canada Sundeep G. Keswani MD Fetal Center, Division of Pediatric General, Thoracic and Fetal Surgery, Texas Children’s Hospital and Baylor University School of Medicine, Houston, TX, USA Asma Khalil MBBCh, MD, MRCOG, MSc (Epi), DFSRH, Dip (GUM) Fetal Medicine Unit, St George’s Hospital NHS Foundation Trust, London, UK Mark D. Kilby DSc, MD, FRCOG, FRCPI Institute of Metabolism and Systems Research, University of Birmingham, and Birmingham Women’s Hospital NHS Foundation Trust, Birmingham, UK

David Lissauer PhD, MBChB Malawi-Liverpool-Wellcome Research Institute, Blantyre, Malawi; and Institute of Translational Medicine, University of Liverpool, Liverpool, UK Enrico Lopriore MD, PhD Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, Leiden, the Netherlands Fiona L. Mackie MBChB, MRes, PhD Obstetrics and Gynaecology Academic Department, Birmingham Women’s Hospital NHS Foundation Trust, Birmingham, UK Eamonn R. Maher MD Academic Department of Medical Genetics, Addenbrooke’s Treatment Centre, Addenbrooke’s Hospital, Cambridge, UK Katarzyna M. Maksym MD, MRCOG Institute for Women’s Health, University College London, London, UK Arnaud Marchant MD, PhD Institute for Medical Immunology, Université Libre de Bruxelles, Brussels, Belgium Josep Maria Martinez PhD Fetal Medicine Reseach Center, BCNatal, Hospital Clinic and Hospital Sant Joan de Déu, University of Barcelona and Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona; and Centre for Biomedical Research on Rare Diseases (CIBER-ER), Madrid, Spain

John Kingdom MD Maternal-Fetal Medicine Division, Mount Sinai Hospital, and Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Canada

Fergus P. McCarthy MB ChB, PhD, MRCOG Anu Research Centre, Department of Obstetrics and Gynaecology, University College Cork, Cork, Ireland

Marianne Leruez-Ville MD Department of Obstetrics and Fetal Medicine, Paris Descartes University, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants-Malades, Paris, France

Dominic McMullan PhD West Midlands Regional Genetics Laboratory, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UK

xiii

Contributors

Catherine L. Mercer BA, BM, PhD, MRCPCH Centre for Human Development, Stem Cells and Regeneration, Faculty of Medicine, University of Southampton, Southampton, UK Isabelle Miletich DDS, BSc, MSc, PhD Centre for Craniofacial and Regenerative Biology, King’s College London, London, UK Tim J. Mohun PhD The Francis Crick Institute, London, UK Ben W. Mol MD, PhD Department of Obstetrics and Gynaecology, School of Medicine, Monash University, Clayton, Australia Julie S. Moldenhauer MD The Center for Fetal Diagnosis and Treatment, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

Robert E. Poelmann PhD Department of Animal Science and Health, Leiden University, Leiden, the Netherlands Léo Pomar MSc Materno-foetal and Obstetrics Research Unit, Obstetric Service, Department “Femme-Mère-Enfant,” University Hospital, Lausanne, Switzerland; and Department of Obstetrics and Gynecology, Centre Hospitalier de l’Ouest Guyanais Franck Joly, Saint-Laurent-du-Maroni, France Judith Rankin BSc (Hons), PhD, FFPH Maternal and Child Health, Institute of Health and Society, Newcastle University, Newcastle-upon-Tyne, UK

Fionnuala Mone PhD Fetal Medicine Centre, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UK

Michael G. Ross MD, MPH Obstetrics and Gynecology and Public Health, David Geffen School of Medicine at UCLA, Los Angeles, and Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, Torrance, CA, USA

Rachel Katie Morris MBChB, PhD, MRCOG Birmingham Women’s and Children’s Hospital, and The Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK

Francesca Russo MD, PhD Department of Development and Regeneration, Cluster Woman and Child, University Hospitals Leuven, KU Leuven, Leuven, Belgium

Sarah Murray MBChB, MSc, PhD, MRCOG University of Edinburgh MRC Centre for Reproductive Health, Edinburgh, UK

Greg Ryan MD Fetal Medicine Unit, Ontario Fetal Centre, Mount Sinai Hospital, and Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Canada

Jane E. Norman MD, MBChB, FRCOG, FRCPE, FMedSci, FRSE Faculty of Health Sciences, University of Bristol, Bristol, UK Dick Oepkes MD, PhD, FRCOG Division of Fetal Medicine, Department of Obstetrics, Leiden University Medical Center, Leiden, the Netherlands

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Jonna Petzold PhD Centre for Craniofacial and Regenerative Biology, King’s College London, London, UK

Mike Seed MBBS Department of Pediatrics, University of Toronto, and Division of Cardiology, The Hospital for Sick Children, Toronto, Canada

Oluyinka O. Olutoye MD, PhD Department of Surgery, Nationwide Children’s Hospital, Ohio State University, Columbus, OH, USA

Alireza A. Shamshirsaz MD Department of Obstetrics and Gynecology (courtesy appointment in the Department of Surgery) Baylor College of Medicine and Texas Children's Hospital Fetal Center Houston, Texas

Emily A. Partridge MD, PhD Division of General, Thoracic and Fetal Surgery, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

Femke Slaghekke MD, PhD Department of Obstetrics, Division of Fetal Medicine, Leiden University Medical Center, Leiden, the Netherlands

Contributors

Gordon C. S. Smith MD, PhD, DSc, FRCOG, FMedSci Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, UK Marjolijn S. Spruijt MD Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, Leiden, the Netherlands Regine P. M. Steegers-Theunissen MD, PhD Department of Obstetrics and Gynecology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands Julien Stirnemann MD National Reference Centre for the Management of Complicated Monochorionic Pregnancies, and Department of Obstetrics and Fetal Medicine, Paris Descartes University, Assistance Publique-Hôpitaux de Paris, Hôpital NeckerEnfants-Malades, Paris, France Dorota Szumska PhD Department of Cardiovascular Medicine, BHF Centre of Research Excellence, and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK Danielle R. M. Timmermans PhD Department of Public and Occupational Health, Amsterdam Public Health Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands Lisanne S. A. Tollenaar BSc Division of Fetal Medicine, Department of Obstetrics, Leiden University Medical Center, Leiden, the Netherlands Rosemary Townsend MBChB, MRCOG Fetal Medicine Unit, St George’s University of London, London, UK Sanne van der Hout PhD Department of Health, Ethics and Society, Faculty of Health, Medicine and Life Sciences, Research Schools of CAPHRI and GROW, Maastricht University, Maastricht, the Netherlands Lennart Van der Veeken MD Fetal Diagnosis and Therapy Unit, Department of Obstetrics and Gynecology, Division of Woman and Child, University Hospitals Leuven, Leuven, Belgium Inge L. van Kamp MD, PhD Division of Fetal Medicine, Department of Obstetrics, Leiden University Medical Center, Leiden, the Netherlands

Jeanine M. M. van Klink PhD Division of Child and Adolescent Psychology, Department of Pediatrics, Leiden University Medical Center, Leiden, the Netherlands Tim Van Mieghem MD, PhD Fetal Medicine Unit, Department of Obstetrics and Gynaecology, Mount Sinai Hospital and University of Toronto, Toronto, Canada Janneke van ‘t Hooft MD, PhD Department of Obstetrics and Gynecology, Amsterdam UMC (Academic Medical Center), Amsterdam, the Netherlands Maud D. van Zijl MD Department of Obstetrics and Gynecology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands Guillermo Villagomez Olea PhD Centre for Craniofacial and Regenerative Biology, King’s College London, London, UK Yves Ville MD National Reference Centre for the Management of Complicated Monochorionic Pregnancies, and Department of Obstetrics and Fetal Medicine, Paris Descartes University, Assistance Publique-Hôpitaux de Paris, Hôpital NeckerEnfants-Malades, Paris, France Melissa Walker MD, MSc Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Canada Wolfgang Weninger, PhD Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria Eleanor Whitaker BA, BM BCh University of Edinburgh MRC Centre for Reproductive Health, Edinburgh, UK Clare L. Whitehead MB ChB, PhD, FRANZCOG Department of Obstetrics and Gynaecology, University of Adelaide, Adelaide, Australia David I. Wilson BA, MBBS, PhD, FRCP Centre for Human Development, Stem Cells and Regeneration, Faculty of Medicine, University of Southampton, UK

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Contributors

William E. Whitehead MD Department of Neurosurgery (courtesy appointment in the Department of Obstetrics and Gynecology) Baylor College of Medicine and Texas Children's Hospital Fetal Center Houston, Texas Robert Wilson PhD The Francis Crick Institute, London, UK

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Dian Winkelhorst MD Department of Obstetrics, Leiden University Medical Center, Leiden, the Netherlands Carolien Zwiers MD, PhD Division of Fetal Medicine, Department of Obstetrics, Leiden University Medical Center, Leiden, the Netherlands

Foreword

The dawn of fetal therapy occurred over five decades ago. Sir William Liley pioneered the first successful fetal therapy when he transfused donor red blood cells into the peritoneal cavity of an anemic fetus in a pregnant woman with Rh(D) alloimmunization. What is most remarkable is that this procedure was accomplished before the introduction of obstetrical ultrasound. Liley used radiopaque dye injected into the amniotic cavity to outline the fetus as an amniogram in order to target the fetal peritoneal cavity. Since these early days, remarkable progress has been achieved in the areas of fetal diagnosis and therapy. With ultrasound, using increasingly sophisticated technology, becoming part of routine obstetrical practice most fetal structural anomalies are easily diagnosed. Rapid acquisition, high resolution magnetic resonance imaging has further refined these diagnoses. Chromosomal microarray and whole exome sequencing have led to new diagnostic capabilities. Invasive procedures to acquire chorionic villi or amniotic fluid are rapidly being replaced by analyzing free fetal DNA in the maternal circulation. These tools have led to a rapid evolution in fetal therapy. Early attempts to correct major congenital anomalies such as lower urinary tract obstruction, diaphragm hernia and sacrococcygeal teratoma were attempted by the pediatric surgical community through open hysterotomy. Premature delivery or fetal demise was often the result, leading many to question the future of fetal therapy for structural anomalies. A renewed interest in fetoscopy, once used primarily as a diagnostic tool, occurred when laser photocoagulation of placental anastomoses proved successful in the treatment of severe twin-twin transfusion syndrome (TTTS). Open hysterotomy returned to the spotlight with interest in correcting fetal myelomeningocele (MMC) – the first non-lethal congenital condition where fetal therapy attempted to improve lifelong morbidity instead of perinatal mortality. A notable shift in the mindset of fetal therapy has occurred in the last decade. New therapies are no longer accepted as

the standard of care after a period of simple innovation. Randomized clinical trials for laser therapy for TTTS and fetal MMC repair have proven these therapies to be scientifically sound. Tracheal occlusion for the treatment of fetal diaphragm hernia is currently being evaluated in such a trial. Multicenter alliances such as the EUROFOETUS group and the North American Fetal Treatment Network have been established to further research collaboration. This second edition of Fetal Therapy: Scientific Basis and Critical Appraisal of Clinical Benefits builds on this new paradigm of an evidence-based approach to therapeutic maneuvers to aid the unborn patient. The editors have assembled a renowned group of international experts in their respective fields. Many aspects of fetal therapy that have evolved since the publication of the first edition are now addressed in this updated version. Notably a new section on the pathophysiology and prevention of preterm birth has been added. Ongoing research and potential therapies to ameliorate neurologic sequelae in cases of severe growth restriction, congenital heart disease, TTTS and the premature infant in general are included in new chapters. Evolving therapies such as the artificial womb, fetoscopic repair of fetal MMC, and the use of stem cells to address the issue of premature rupture of the membranes after fetoscopy are included in this edition. This text deserves a prominent place in the library of any provider of fetal medicine. Its owner will be well served with a contemporary and authoritative reference on the care of the unborn patient with complex issues. Kenneth J. Moise, Jr., MD Professor of Obstetrics, Gynecology and Reproductive Sciences and Pediatric Surgery McGovern School of Medicine – UTHealth Co-Director, The Fetal Center Children’s Memorial Hermann Hospital Houston, TX, USA

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Section 1

General Principles

Chapter

The Rationale for Fetal Therapy

1

Ahmet Baschat

Introduction In 1982, a group of subspecialists in fetal medicine, pediatric surgery, pediatrics, radiology, genetics, and bioethics reported on a meeting that discussed the emerging field of ‘fetal therapy’ [1]. Their summary statement laid down the foundation and principles for the treatment of prenatally diagnosed congenital anomalies where the natural history of the disease can potentially be influenced by intervention before birth (Table 1.1). In principle, this document defines the criteria of candidate conditions for fetal therapy, the goals of fetal treatment, and the appropriate setting for where fetal therapy should be performed. Since this original publication there have been significant advances in prenatal diagnostic and prognostic assessments of the fetus, the scope of treatments, and the care settings where fetal therapy is offered that require consideration [2].

Prenatal Diagnosis and Prognostic Assessment – Defining Candidate Conditions for Fetal Treatment Fetal therapy targets specific conditions that carry significant risk for the fetus where prenatal intervention can be anticipated to significantly improve outcome. In order to be certain that a disease meets these fundamental criteria, a precise prenatal diagnosis and prognostic assessment is required. The principle diagnostic tools include a combination of ultrasound modalities, magnetic resonance imaging (MRI), or specialized computerized tomography (CT) imaging [3]. Following the formulation of a primary and differential diagnosis a major determining factor for eligibility for fetal treatment is the presence of any underlying untreatable conditions that affect outcome. Major advances have been made in genetic testing since the inception of fetal therapy. The range of prenatal genetic studies now ranges from traditional karyotyping to microarray analysis, targeted single gene testing, and exome sequencing [4, 5]. Another significant advance since the inception of fetal therapy is the transition of infection testing to polymerase chain reaction (PCR) for viral particles or viral culture from amniotic fluid [6, 7]. This contemporary approach to prenatal genetic testing and infection testing increases the diagnostic yield for significant underlying genetic or other abnormalities, and can now more deliberately identify fetuses that may benefit from prenatal

Table 1.1 Criteria for the advancement of fetal therapy: 1982

Topic

Viewpoint

Nature of the disorder

The disorder must be of a significant nature and should be a simple structural defect that interferes with organ development, whose alleviation might allow fetal development to proceed normally

Appropriateness criteria

The fetus should be a singleton without concomitant anomalies according to advanced ultrasonographic examination and amniocentesis for karyotype, α-feto protein, and cultures

Candidate diseases

Selection for treatment must be based on careful clinical evaluation and sound knowledge of the natural history of the fetal disease; intervention can be ethically justified only if there is reasonable probability of benefit

Goals of treatment

The family should be fully counseled about risks and benefits and should agree to treatment, including long-term follow-up to determine efficacy

Maternal safety and autonomy

Implied but not stated: maternal risks should be minor and acceptable to mother and family

Center infrastructure

There should be access to a level III high-risk obstetric unit and bioethical and psychosocial counseling

Checks and balances

A multidisciplinary team, including a perinatal obstetrician experienced in fetal diagnosis and intrauterine transfusion, an ultrasonographer experienced in the diagnosis of fetal anomalies, and a pediatric surgeon and neonatologist who will manage the infant after birth, should concur on the plan for innovative treatment and obtain approval of an institutional review board

Reporting requirements

All case material should be reported, regardless of outcome, to a fetal treatment registry or in the medical literature (or both)

1

Section 1: General Principles

interventions and exclude those who do not. The importance of this approach is illustrated by the outcomes of shunting for fetal hydrocephaly, which was abandoned in an era where the exclusion of diseases with no anticipated benefit was not uniformly applied. Now that a group of fetuses with isolated aqueductal stenosis is more likely to be identified, fetal therapy for this specific subset of patients may need to be re-explored [8]. Concurrently with rendering a precise diagnosis of the fetal condition, assessing the severity of the fetal condition is part of identifying suitable candidates for fetal therapy. It is important to recognize that despite the prominent role of ultrasound in evaluating physical abnormalities of the fetus, MRI is complementary in many conditions, including spina bifida and congenital diaphragmatic hernia, in delineating the abnormality as well as its prognosis [9, 10]. Since most fetal conditions that are currently offered fetal therapy are considered severe, most prognostic assessments measure the mortality or irreversible damage that is associated with a particular condition rather than morbidity. To render a prognosis, several specific parameters have been described that offer disease-specific quantification of severity. These include the traditional [11] and observed to expected lung-to-head ratio [12] for congenital diaphragmatic hernia and the cyst-volume ratio [13] for cystic adenomatoid malformations of the lung. In addition to individual measurements, combinations of several parameters in scoring or staging systems have been described to grade the severity of fetal cardiovascular disease [14, 15], hydrops [16], or twin-twin transfusion syndrome (TTTS) [17, 18, 19]. The utilization of standardized prenatal prognostic markers is of critical importance from several perspectives. The relationship with outcome forms the basis of the risk-benefit assessment and the selection of appropriate candidates for fetal therapy. Uniform assessment of conditions allows the study of natural disease evolution and a more consistent case selection facilitates a more robust evaluation of the impact of fetal therapies. The ability to re-evaluate defining key prognostic indicators also allows appropriately targeted monitoring for resolution following fetal treatment. The evaluation of any prenatal abnormality should ideally reach the highest level of certainty about the condition, any underlying contributors to lifelong health impacts, and the severity of the condition in terms of its anticipated prenatal and postnatal outcome if left untreated. Only when this level of information is available can the risks of the natural disease be weighed against the risks of the therapy and parents be provided with the opportunity to select the appropriate scope of treatment. At any point in these decisions it is the obligation of the fetal medicine provider to put safeguards in place to protect the pregnant women from undue risk. For conditions not meeting intervention criteria longitudinal observations at the appropriate surveillance intervals are often required in order to ensure that deterioration to a degree that meets treatment criteria is detected. This is often required for complicated monochorionic multiple gestation [20], or fetal anemia due to red cell alloimmunization [21].

2

The Scope and Goals of Fetal Therapy Fetal therapy may involve medical and surgical treatments that are performed before separation of the fetus from the placenta during birth. Within this scope, fetal therapy can be divided into medical or surgical approaches that aim to achieve either a complete prenatal resolution, alleviate severe pediatric developmental or functional deficiencies, or optimize the fetal transition to extrauterine life. In the latter two instances, treatment requires completion after birth and therefore relies on an appropriate pediatric subspecialty setting (Figure 1.1). Fetal interventions carry different levels of complexity both in terms of required operator training and experience and the systems requirement to safely administer the treatment. At the most basic level, ultrasound-guided needle procedures have been adapted from the sampling of amniotic fluid or chorion villus tissue. Fetal therapy techniques based on this approach include fetal blood sampling, intrauterine transfusions [22], shunt placements for renal or thoracic abnormalities [23], balloon valvuloplasty for cardiac lesions [24], and interstitial coagulation techniques utilizing laser, radiofrequency ablation or microwave technology [25, 26]. A greater level of complexity exists for diagnostic or operative fetoscopic procedures. While the insertion of the instrumentation relies on ultrasound guidance, the instrumentation required is more complex and most optimally used in an operative room setting. Fetoscopic techniques now encompass laser ablation of communicating vessels in TTTS [27], umbilical cord occlusion [28], tracheal balloon occlusion and reversal [29], amniotic band release [30], laser ablation for lower urinary tract obstruction [31], and more complex surgical procedures such as myelomeningocele (MMC) repair [32]. The highest level of complexity involves open fetal surgery that is performed through a hysterotomy through the muscular portion of the myometrium or the ex utero intrapartum treatment (EXIT), which is a specialized delivery technique that enables securing of the fetal airway on a placental bypass. These types of procedures require a specific approach guided by the anatomy of the fetus and have high system requirements for monitoring of maternal and fetal well-being at the time of the procedure and afterwards, as well as the ability to immediately respond to complications such as obstetric hemorrhage or maternal cardiopulmonary collapse [33]. Open fetal surgeries are most frequently performed for MMC repair [34] and less often for resection of lung masses or teratomas [35]. The EXIT delivery technique is specifically intended for the management of anomalies that compromise the newborn’s airway at birth [36, 37, 38]. These treatment techniques evolved following the consideration of the fetal, neonatal and lifelong risks of the untreated condition as well as the potential fetal benefits of treatment and the risks to the mother and the fetus. With regards to the fetal benefits, treatments may achieve prenatal cure or alleviation of damage. Examples for approaches that aim to achieve a prenatal cure include fetal blood transfusions for anemia [22] and

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Chapter 1: The Rationale for Fetal Therapy

Prenatal Treatment Goal Prenatal Correction

Alleviate damage before birth

Optimize condition at birth

Fetal blood transfusion - Fetal anemia Fetoscopic laser surgery - TTTS - TAPS Cord coagulation - TRAP - sIUGR Open fetal surgery - MMC repair - Tumor resection

Vesicoamniotic shunting - LUTO Fetal cystoscopy - LUTO Thoracoamniotic shunting - hydropic CPAM - hydrothorax Fetoscopic tracheal occlusion - CDH

Disease-specific surveillance - Cardiac defects - sIUGR - non-immune hydrops - SVT Ex utero intrapartum treatment - obstructive airway lesions

Post-delivery care requirement •

•

Specific pediatric treatment prior to discharge only required for residual disease Long-term care as appropriate

•

•

Pediatric condition-specific treatment is invariably required prior to discharge Follow-up care with long-term follow-up is required

Figure 1.1 Treatment goals in fetal therapy. The schematic represents the prenatal treatment goals for various fetal interventions and their associated postnatal care needs. TTTS, twin-twin transfusion syndrome; TAPS, twin anemia polycythemia sequence; TRAP, twin reversed arterial perfusion; sIUGR, selective intrauterine growth restriction; MMC, myelomeningocele; LUTO, lower urinary tract obstruction; CPAM, cystic pulmonary airway malformation; CDH, congenital diaphragmatic hernia; SVT, supraventricular tachycardia.

fetoscopic laser dichorionization of the placenta in TTTS [39]. In addition to the appropriate care setting, the ability to achieve the intended outcome with these low- to medium-complexity therapies relies on operator experience and ongoing caseload [40–44]. Because the mortality of the underlying conditions in the absence of treatment is high, thresholds for the establishment of treatment centers are lower than for more complex treatments. A treatment that is also aimed at prenatal correction is fetal MMC repair. However, irrespective of whether an open or fetoscopic approach is chosen the multidisciplinary nature of the treatment team requires an appropriate resource setting to achieve the desired outcomee [45]. Since fetal MMC is not a lethal condition and treatment is also complex because of the maternal care requirements, prenatal repair can only be offered in an appropriately resourced setting. In fact it is the significant maternal risk with open fetal MMC repair that is one of the driving forces to transition to a viable fetoscopic technique that maintains the fetal benefits [46]. An example for a treatment that does not achieve prenatal cure, but rather alleviates prenatal damage until definitive postnatal repair can occur, is fetoscopic tracheal occlusion (FETO) for severe congenital diaphragmatic hernia (CDH) [12]. After successful FETO, delivery of the neonate at a center with expertise in the management of CDH is required to complete the treatment. It is important to recognize that caseload and operator experience improve outcomes in both the

prenatal and postnatal components of FETO followed by postdelivery surgical CDH management [47, 48]. The ideal setting for a FETO program with an experienced fetal team would therefore be at a facility with a coexisting high-volume experienced pediatric CDH program [49]. The importance of the appropriate pediatric care setting at delivery is particularly evident for anomalies such as cardiac defects, where the primary contribution of the fetal medicine specialist is to optimize delivery circumstances to facilitate post-delivery surgical repair [50]. Accordingly, as the management goal of fetal therapies shifts from prenatal cure to alleviation of damage the emphasis on delivery in an appropriate pediatric care setting increases. With the exception of fetal therapies carried out prior to viability the need for a high-level neonatal intensive care unit (NICU) is universal for all fetal therapy centers [1, 2, 45].

Risk-Benefit Assessment for Fetal Therapy Fundamental to the endeavor of fetal treatment is the construction of a risk-benefit assessment that considers potential benefits to the fetus, newborn and mother balanced against the risks to these parties. Since all fetal therapy, medical and surgical, must pass through the mother it cannot be performed without her informed consent, given with the necessary safeguards in place and full consideration of maternal and fetal risks. Assuming an accurate prenatal diagnosis, this assessment

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Section 1: General Principles

rests on a reasonable degree of certainty about the natural history of the condition, the likelihood of treatment success, and the preparedness for the potential of unintended consequences. Fetal therapy is unique in that the potential complications for a given procedure may include the mother or fetus. For surgical interventions the potential for unintended consequences depends on the complexity of the procedures as well as operator experience and caseload. The correct risk-benefit estimate therefore relies on all of these factors. The neonatal risks relate to the likelihood of premature delivery and the additional outcome impact of the underlying condition, and are partly mitigated when delivery occurs at a facility with the appropriate level of neonatal care [1]. For conditions that require surgical correction after birth risks may arise from the combination of residual morbidity after fetal therapy and superimposed neonatal complications. As prematurity is a risk factor associated with many fetal treatments, accurate representation of institution-specific, disease-specific outcomes of centers that perform fetal therapy is most pertinent to gauge the overall impact on outcome [1, 2, 45]. Over time advances in any of the subspecialties involved in the care of the fetal patient potentially alter outcome, and therefore ongoing reappraisal of the risk-benefit ratio is required whenever such developments occur. Examples include the transition from open fetal surgery to maternal steroid use as a primary treatment of congenital pulmonary airway malformations [51], or reappraisal of the relative safety of CO2 insufflation for operative fetoscopy [52]. Once a riskbenefit assessment for a fetal treatment has been completed administration in the appropriate care setting is essential to mitigate some of the adverse effects.

Care Settings for Fetal Therapy Since all fetal therapies pass through the mother the need to establish the most appropriate maternal care setting is universal for all fetal therapies. The resources required to ensure maternal safety may range from obstetric care facilities, including obstetric anesthesia, all the way to medical and intensive care facilities [38]. These requirements depend on the complexity of the fetal treatments performed. Ultrasound-guided procedures such as amniocentesis and chorion villous sampling have a negligible miscarriage rate and overall procedurerelated risks ranging from 0.4% to 1% in high-risk populations [53, 54]. Fetal blood sampling and transfusion require a higher level of operator skill and carry a 5–10% risk of fetal bradycardia and a pregnancy loss rate of up to 25% in complex fetal conditions [55, 56, 57]. Fetal shunt procedures and fetoscopic laser ablation for TTTS involve larger diameter uterine instrumentation and accordingly can carry an up to 40% risk of obstetric complications, including preterm premature rupture of membranes (PPROM), preterm labor, and preterm birth [58, 59]. If intervention for fetal status is appropriate as part of the management plan or significant obstetric risks are recognized complications such fetal treatments should be performed

4

in the vicinity of a Labor and Delivery unit to ensure that obstetric management, including delivery if appropriate, can be achieved in a timely fashion. Procedures that are performed at viability, carry significant obstetric risks, or require multidisciplinary effort may benefit from a dedicated intervention suite near Labor and Delivery. Fetal cardiac interventions have fetal mortality rates of 10–30% and may require additional treatment of complications such as bradycardia and hemopericardium in 27–52% of procedures [60, 61]. FETO with subsequent balloon removal is associated with a 47% rate of PPROM and the need for emergency balloon removal in over 50% of cases. Inability to remove the balloon prior to birth in the latter setting may lead to neonatal death in almost 5% of patients [29]. Hybrid or open fetal surgeries, including fetoscopic spina bifida repair [62] and EXIT, naturally require an appropriately staffed operation room setting [6, 63]. The significant risk for healing complications of the uterotomy with partial or complete dehiscence in 2.3% of patients, and the need for blood transfusion at delivery in 8%, emphasize the importance of follow-up dedicated obstetric care [34]. As integration of subspecialties is one of the core achievements that drives a fetal treatment center, the complete integration of the required level of maternal care is necessary. For the highest risk procedures this requires the in-house availability of an appropriate level of maternal care services, including intensive care and adult medical specialty availability. As all neonates that are delivered after fetal therapy require post-delivery assessment, stabilization and potentially further management, a high-level NICU is recommended for all fetal therapy centers offering treatment after viability [1, 2, 45]. This level of care is recommended since most conditions targeted by fetal therapy have neonatal care requirements that reach beyond prematurity-related complications, and management of anomalies and associated problems is required [64, 65]. Specifically for neonates with congenital abnormalities such as CDH, MMC or cardiac defects, the in-house presence of the appropriate pediatric surgical specialties is highly desirable. In the US the ‘Task Force for Children’s Surgical Care’ defines the highest level of center by its ability to manage congenital anomalies in an in- and outpatient setting [66]. The improved outcome for neonates cared for in such centers has been documented for several conditions, including CDH and MMC, and is in part attributable to infrastructure, higher surgical volumes and an enhanced ability to triage, recognize and manage complications compared with lower volume centers [67–69].

Requirements for a Fetal Therapy Center A Fetal Therapy Center is ethically obliged to consider both maternal and fetal well-being and complications of any fetal intervention that may be offered. In order to provide safe care the appropriate infrastructure, dedicated institutional support and oversight are required. The level of infrastructure and support are dictated by the level of the maternal, fetal and neonatal care needs that arise as a consequence of the fetal

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Chapter 1: The Rationale for Fetal Therapy

intervention. Once the appropriate multidisciplinary care context has been established the monitoring and reporting of outcomes allows for effective oversight monitoring at the institutional level. It has been considered essential for centers that perform invasive fetal procedures to report their maternal, fetal, and newborn outcomes as transparently as possible to allow for ongoing scientific scrutiny [1, 2, 45]. This can be in the form of institutional, national, regional, or international registries or trials. Examples include treatment registries for FETO for severe CDH [29] or fetal cardiac interventions [24] as well as randomized trials for laser therapy for TTTS [27, 70] and open fetal MMC repair [34]. Particularly for procedures that are still considered as innovative or under research a multidisciplinary institutional oversight committee is important, and ideally includes individuals not directly involved in the clinical care of patients. Such committees may sometimes also serve as reviewing bodies for the purposes of institutional or ethical review board submissions. An important obligation of a Fetal Therapy Center is also to provide education for physicians and other healthcare

References [1] Harrison MR, Filly RA, Golbus MS, Berkowitz RL, Callen PW, Canty TG, et al. Fetal treatment 1982. N Engl J Med. 1982; 307: 1651–2. [2] Moon-Grady A, Baschat A, Cass D, et al. Fetal treatment 2017: the evolution of fetal therapy centers – a joint opinion from the International Fetal Medicine and Surgical Society (IFMSS) and the North American Fetal Therapy Network (NAFTNet). Fetal Diagn Ther. 2017; 42: 241–8. [3] Snyder E, Baschat A, Huisman TAGM, Tekes A. Value of fetal MRI in the era of fetal therapy for management of abnormalities involving the chest, abdomen, or pelvis. Am J Roentgenol. 2018; 210: 998–1009. [4] Wapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, Zachary JM, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012; 367: 2175–84. [5] Drury S, Williams H, Trump N, Boustred C, GOSGene, Lench N, Scott RH, Chitty LS. Exome sequencing for prenatal diagnosis of fetuses with sonographic abnormalities. Prenat Diagn. 2015; 35: 1010–7. [6] Reddy UM, Baschat AA, Zlatnik MG, Towbin JA, Harman CR, Weiner CP. Detection of viral deoxyribonucleic acid in amniotic fluid: association with fetal

personnel to train the next generation of fetal therapists. While there are currently no formal training programs for fetal therapy it is only a matter of time before a curriculum will be formalized and an appropriate training model developed in which junior faculty are gradually allowed to develop the necessary skill set to operate independently.

Conclusion As both diagnostic and surgical techniques continue to evolve so does the role of fetal therapy in conditions that can be prenatally diagnosed. With advances in fetal treatment techniques and the management of maternal risks the focus is likely to shift from just enabling survival to improving quality of life (e.g. fetal MMC repair). The formalization of appropriate care settings and potentially levels of care is likely to not only ensure the safety of the mother and fetus but also expand the rationale for fetal therapy in the future.

malformation and pregnancy abnormalities. Fetal Diagn Ther. 2005; 20: 203–7. [7] Adams LL, Gungor S, Turan S, Kopelman JN, Harman CR, Baschat AA. When are amniotic fluid viral PCR studies indicated in prenatal diagnosis? Prenat Diagn. 2012; 32: 88–93. [8] Emery SP, Greene S, Hogge WA. Fetal Therapy for Isolated Aqueductal Stenosis. Fetal Diagn Ther. 2015; 38: 81–5. [9] Micu R, Chicea AL, Bratu DG, Nita P, Nemeti G, Chicea R. Ultrasound and magnetic resonance imaging in the prenatal diagnosis of open spina bifida. Med Ultrason. 2018; 20: 221–7. [10] Madenci AL, Sjogren AR, Treadwell MC, Ladino-Torres MF, Drongowski RA, Kreutzman J, Bruch SW, Mychaliska GB. Another dimension to survival: predicting outcomes with fetal MRI versus prenatal ultrasound in patients with congenital diaphragmatic hernia. J Pediatr Surg. 2013; 48: 1190–7. [11] Metkus AP, Filly RA, Stringer MD, Harrison MR, Adzick NS. Sonographic predictors of survival in fetal diaphragmatic hernia. J Pediatr Surg. 1996; 31: 148–51. [12] Jani J, Nicolaides KH, Keller RL, Benachi A, Peralta CF, Favre R, et al. Observed to expected lung area to head circumference ratio in the prediction of

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syndrome: spectrum of cardiovascular abnormality and development of a cardiovascular score to assess severity of disease. Am J Obstet Gynecol. 2007; 197: 392. e1–8. [19] Shah AD, Border WL, Crombleholme TM, Michelfelder EC. Initial fetal cardiovascular profile score predicts recipient twin outcome in twin-twin transfusion syndrome. J Am Soc Echocardiogr. 2008; 21: 1105–8. [20] O’Donoghue K, Cartwright E, Galea P, Fisk NM. Stage I twin-twin transfusion syndrome: rates of progression and regression in relation to outcome. Ultrasound Obstet Gynecol. 2007; 30: 958–64. [21] Oepkes D, Seaward PG, Vandenbussche FP, Windrim R, Kingdom J, Beyene J, Kanhai HH, Ohlsson A, Ryan G, DIAMOND Study Group. Doppler ultrasonography versus amniocentesis to predict fetal anemia. N Engl J Med. 2006; 355: 156–64.

[28] Quintero RA, Reich H, Puder KS, Bardicef M, Evans MI, Cotton DB, Romero R: Brief re- port: umbilicalcord ligation of an acardiac twin by fetoscopy at 19 weeks of gestation. N Engl J Med 1994; 330: 469–471. [29] Jani JC, Nicolaides KH, Gratacós E, Valencia CM, Doné E, Martinez JM, Gucciardo L, Cruz R, Deprest JA. Severe diaphragmatic hernia treated by fetal endoscopic tracheal occlusion. Ultrasound Obstet Gynecol. 2009; 34: 304–10. [30] Richter J, Wergeland H, DeKoninck P, De Catte L, Deprest JA. Fetoscopic release of an amniotic band with risk of amputation: case report and review of the literature. Fetal Diagn Ther. 2012; 31: 134–7.

treatment) procedure. Am J Obstet Gynecol. 1997; 177: 870–4. [37] Mychaliska GB, Bealer JF, Graf JL, Rosen MA, Adzick NS, Harrison MR. Operating on placental support: the ex utero intrapartum treatment procedure. J Pediatr Surg. 1997; 32: 227–30. [38] Norris MC, Joseph J, Leighton BL. Anaesthesia for perinatal surgery. Am J Perinatol. 1989; 6: 39–40. [39] Slaghekke F, Lopriore E, Lewi L, Middeldorp JM, van Zwet EW, Weingertner AS, et al. Fetoscopic laser coagulation of the vascular equator versus selective coagulation for twin-totwin transfusion syndrome: an openlabel randomised controlled trial. Lancet. 2014; 383: 2144–51. [40] Peeters SH, Van Zwet EW, Oepkes D, Lopriore E, Klumper FJ, Middeldorp JM. Learning curve for fetoscopic laser surgery using cumulative sum analysis. Acta Obstet Gynecol Scand. 2014; 93: 705–11.

[22] Zwiers C, Lindenburg ITM, Klumper FJ, de Haas M, Oepkes D, Van Kamp IL. Complications of intrauterine intravascular blood transfusion: lessons learned after 1678 procedures. Ultrasound Obstet Gynecol. 2017; 50: 180–6.

[31] Sananes N, Cruz-Martinez R, Favre R, Ordorica-Flores R, Moog R, Zaloszy A, Giron AM, Ruano R. Two-year outcomes after diagnostic and therapeutic fetal cystoscopy for lower urinary tract obstruction. Prenat Diagn. 2016; 36: 297–303.

[41] Inglis SR, Lysikiewicz A, Sonnenblick AL, Streltzoff JL, Bussel JB, Chervenak FA. Advantages of larger volume, less frequent intrauterine red blood cell transfusions for maternal red cell alloimmunization. Am J Perinatol. 1996; 13: 27–33.

[23] Manning FA, Harrison MR, Rodeck C. Catheter shunts for fetal hydronephrosis and hydrocephalus. Report of the International Fetal Surgery Registry. N Engl J Med. 1986; 315: 336–40.

[32] Kohl T, Hering R, Heep A, Schaller C, Meyer B, Greive C, et al. Percutaneous fetoscopic patch coverage of spina bifida aperta in the human – early clinical experience and potential. Fetal Diagn Ther. 2006; 21: 185–93.

[24] Moon-Grady AJ, Morris SA, Belfort M, Chmait R, Dangel J, Devlieger R, et al. International Fetal Cardiac Intervention Registry: a worldwide collaborative description and preliminary outcomes. J Am Coll Cardiol. 2015; 66: 388–99.

[33] Abraham RJ, Sau A, Maxwell D. A review of the EXIT (Ex utero Intrapartum Treatment) procedure. J Obstet Gynaecol. 2010; 30: 1–5.

[42] Edwards AG, Teoh M, Hodges RJ, Palma-Dias R, Cole SA, Fung AM, Walker SP. Balancing Patient Access to fetoscopic laser photocoagulation for twin-to-twin transfusion syndrome with maintaining procedural competence: are collaborative services part of the solution? Twin Res Hum Genet. 2016; 19: 276–84.

[25] Bebbington MW, Danzer E, Moldenhauer J, Khalek N, Johnson MP. Radiofrequency ablation vs bipolar umbilical cord coagulation in the management of complicated monochorionic pregnancies. Ultrasound Obstet Gynecol. 2012; 40: 319–24. [26] Stephenson CD, Temming LA, Pollack R, Iannitti DA. Microwave ablation for twin-reversed arterial perfusion sequence: a novel application of technology. Fetal Diagn Ther. 2015; 38: 35–40.

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[27] Senat MV, Deprest J, Boulvain M, Paupe A, Winer N, Ville Y. Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome. N Engl J Med. 2004; 351: 136–44.

[34] Adzick NS, Thom EA, Spong CY, Brock JW 3rd, Burrows PK, Johnson MP, et al. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med. 2011; 364: 993–1004. [35] Cass DL, Olutoye OO, Ayres NA, Moise KJ Jr., Altman CA, Johnson A, Cassady CI, Lazar DA, Lee TC, Lantin MR. Defining hydrops and indications for open fetal surgery for fetuses with lung masses and vascular tumors. J Pediatr Surg. 2012; 47: 40–5. [36] Liechty KW, Crombleholme TM, Flake AW, Morgan MA, Kurth CD, Hubbard AM, Adzick NS. Intrapartum airway management for giant fetal neck masses: the EXIT (ex utero intrapartum

[43] Perry KG Jr., Hess LW, Roberts WE, Allbert JR, Floyd RC, McCaul JF, Martin RW, Martin JN Jr., Morrison JC. Cordocentesis (funipuncture) by maternal-fetal fellows: the learning curve. Fetal Diagn Ther. 1991; 6: 87–92. [44] Chang YL, Chao AS, Chang SD, Hsieh PC, Wang CN. Short-term outcomes of fetoscopic laser surgery for severe twintwin transfusion syndrome from Taiwan single center experience: demonstration of learning curve effect on the fetal outcomes. Taiwan J Obstet Gynecol. 2012; 51: 350–3. [45] Cohen AR, Couto J, Cummings JJ, Johnson A, Joseph G, Kaufman BA, et al. Position statement on fetal

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Chapter 1: The Rationale for Fetal Therapy

myelomeningocele repair. Am J Obstet Gynecol. 2014; 210: 107–11. [46] Belfort MA, Whitehead WE, Shamshirsaz AA, Ruano R, Cass DL, Olutoye OO. Fetoscopic repair of meningomyelocele. Obstet Gynecol. 2015; 126: 881–4. [47] Araujo Júnior E, Tonni G, Martins WP, Ruano R. Procedure-related complications and survival following Fetoscopic Endotracheal Occlusion (FETO) for severe congenital diaphragmatic hernia: systematic review and meta-analysis in the FETO Era. Eur J Pediatr Surg. 2016; 27: 297–305. [48] Grushka JR, Laberge JM, Puligandla P, Skarsgard ED, Canadian Pediatric Surgery Network: effect of hospital case volume on outcome in congenital diaphragmatic hernia: the experience of the Canadian Pediatric Surgery Network. J Pediatr Surg. 2009; 44: 873–6. [49] Snoek KG, Greenough A, van Rosmalen J, Capolupo I, Schaible T, Ali K, Wijnen RM, Tibboel D. Congenital diaphragmatic hernia: 10-Year evaluation of survival, extracorporeal membrane oxygenation, and foetoscopic endotracheal occlusion in four high-volume centres. Neonatology. 2018; 113: 63–8. [50] Sanapo L, Moon-Grady AJ, Donofrio MT. Perinatal and delivery management of infants with congenital heart disease. Clin Perinatol. 2016; 43: 55–71. [51] Loh KC, Jelin E, Hirose S, Feldstein V, Goldstein R, Lee H. Microcystic congenital pulmonary airway malformation with hydrops fetalis: steroids vs open fetal resection. J Pediatr Surg. 2012; 47: 36–9. [52] Baschat AA, Ahn ES, Murphy J, Miller JL. Fetal blood gas values during fetoscopic myelomeningocele repair performed under carbon dioxide insufflation. Ultrasound Obstet Gynecol. 2018; 52: 400–402. [53] Wulff CB, Gerds TA, Rode L, Ekelund CK, Petersen OB, Tabor A, Danish Fetal Medicine Study Group: risk of fetal loss associated with invasive testing following combined first-trimester screening for Down syndrome: a national cohort of 147,987 singleton pregnancies. Ultrasound Obstet Gynecol. 2016; 47: 38–44.

[54] Enzensberger C, Pulvermacher C, Degenhardt J, Kawacki A, Germer U, Gembruch U, Krapp M, Weichert J, Axt-Fliedner R. Fetal loss rate and associated risk factors after amniocentesis, chorionic villus sampling and fetal blood sampling. Ultraschall Med. 2012; 33: E75–9. [55] Society for Maternal-Fetal Medicine, Berry SM, Stone J, Norton ME, Johnson D, Berghella V. Fetal blood sampling. Am J Obstet Gynecol. 2013; 209: 170–80. [56] Bigelow CA, Cinelli CM, Little SE, Benson CB, Frates MC, Wilkins-Haug LE. Percutaneous umbilical blood sampling: current trends and outcomes. Eur J Obstet Gynecol Reprod Biol. 2016; 200: 98–101. [57] Wilson RD, Gagnon A, Audibert F, Campagnolo C, Carroll J, Genetics committee: prenatal diagnosis procedures and techniques to obtain a diagnostic fetal specimen or tissue: maternal and fetal risks and benefits. J Obstet Gynaecol Can. 2015; 37: 656–68. [58] Papanna R, Block-Abraham D, Mann LK, Buhimschi IA, Bebbington M, Garcia E, Kahlek N, Harman C, Johnson A, Baschat A, Moise KJ Jr. Risk factors associated with preterm delivery after fetoscopic laser surgery for twin-twin transfusion syndrome. Ultrasound Obstet Gynecol. 2014; 43: 48–53. [59] Ruano R, Sananes N, Sangi-Haghpeykar H, Hernandez-Ruano S, Moog R, Becmeur F, Zaloszyc A, Giron A, Morin B, Favre R. Fetal intervention for severe lower urinary tract obstruction: a multicenter case-control study comparing fetal cystoscopy with vesicoamniotic shunting. Ultrasound Obstet Gynecol. 2015; 45: 452–8. [60] Moon-Grady AJ, Morris SA, Belfort M, Chmait R, Dangel J, Devlieger R, et al. International fetal cardiac intervention registry: a worldwide collaborative description and preliminary outcomes. J Am Coll Cardiol. 2015; 66: 388–99. [61] Araujo Júnior E, Tonni G, Chung M, Ruano R, Martins WP. Perinatal outcomes and intrauterine complications following fetal intervention for congenital heart disease: systematic review and metaanalysis of observational studies.

Ultrasound Obstet Gynecol. 2016; 48: 426–33. [62] Belfort MA, Whitehead WE, Shamshirsaz AA, Ruano R, Cass DL, Olutoye OO. Fetoscopic repair of meningomyelocele. Obstet Gynecol. 2015; 126: 881–4. [63] Johnson MP, Bennett KA, Rand L, Burrows PK, Thom EA, Howell LJ, et al. The Management of Myelomeningocele Study: obstetrical outcomes and risk factors for obstetrical complications following prenatal surgery. Am J Obstet Gynecol. 2016; 215: 778. e1–778. e9. [64] Crenshaw C Jr., Payne P, Blackmon L, Bowen C, Gutberlet R. Prematurity and the obstetrician. A regional neonatal intensive care nursery is not enough. Am J Obstet Gynecol. 1983; 147: 125–32. [65] American Academy of Pediatrics Committee on Fetus and Newborn. Policy statement: Levels of Neonatal Care. Pediatrics. 2012; 130: 587–97. [66] Task Force for Children’s Surgical Care. Optimal resources for children’s surgical care in the United States. J Am Coll Surg. 2014; 218: 479–87. [67] Birkmeyer JD, Stukel TA, Siewers AE, Goodney PP, Wennberg DE, Lucas FL. Surgeon volume and operative mortality in the United States. New Engl J Med. 2003; 349: 2117–27. [68] Grayson AD, Moore RK, Jackson M, Rathore S, Sastry S, Gray TP, Schofield I, Chauhan A, Ordoubadi FF, Prendergast B, Stables RH. north west quality improvement programme in cardiac interventions: multivariate prediction of major adverse cardiac events after 9914 percutaneous coronary interventions in the north west of England. Heart. 2006; 92: 658–63. [69] Wright JD, Herzog TJ, Siddiq Z, Arend R, Neugut AI, Burke WM, Lewin SN, Ananth CV, Hershman DL. Failure to rescue as a source of variation in hospital mortality for ovarian cancer. J Clin Oncol. 2012; 30: 3976–82. [70] Slaghekke F, Lopriore E, Lewi L, Middledorp JM, van Zwet EW, Weingertner AS, et al. Fetoscopic laser coagulation of the vascular equator versus selective coagulation for twin-totwin transfusion syndrome: an openlabel randomised controlled trial. Lancet. 2014; 383: 2144–51.

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Section 1 Chapter

2

General Principles

A Fetal Origin of Adult Disease Mark Hanson and Lucy Green

Introduction There is a worldwide epidemic of non-communicable diseases (NCDs), including cardiovascular disease (CVD), type 2 diabetes, chronic lung disease, and some forms of cancer; predisposition to these is linked to obesity. This is despite efforts by individuals to modify their diet and lifestyle, and government and global programs aimed at promoting healthy eating or increased physical activity. Some initiatives have begun to target childhood eating and activity. But a strong and international body of scientific and epidemiological data suggests that health interventions should be focused on a much earlier period of development: pregnancy. Expectant couples are often focused on the immediate result of their pregnancy – a viable baby. It may come as a surprise to many of them to hear that the finer details of building a baby are in fact the foundation of lifelong health. A number of potentially serious clinical conditions originate during fetal life, and these include neurological handicap, premature birth, fetal growth restriction (FGR), and pulmonary hypoplasia. These are often viewed as ‘pathophysiological’ conditions where normal development (or physiology) has been disrupted by a challenge in utero that has had immediate and longer-term damaging effects. But, current concepts suggest that the developing organism may respond to cues (e.g. nutrient supply, maternal stress) from the environment and that its development is ‘channelled’ (rather than disrupted) to give a phenotype optimized for the subsequent postnatal environment. However there may be limits to the responses that the developing organism (e.g. fetus) can make or the postnatal environment may not turn out to be what was expected. Either or both of these circumstances may lead to an increased disease risk in adulthood [1]. In this chapter we will explore human and animal studies that investigate how cues from the environment (e.g. nutrient supply) before and during gestation invoke one or several fetal adaptive strategies involving the timing of birth, fetal growth, metabolism, and cardiovascular control. These strategies are not simply linked to immediate survival but may put the offspring at a disadvantage in terms of health in later life.

An Early Origin for the Epidemic of Adult Non-communicable Disease The Problem CVD affects more than 40% of adults in the UK. Despite the fall in death from coronary heart disease (CHD) in the

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second half of the twentieth century, the combination of unhealthy lifestyle in the young and an ageing population is expected to increase the number of people suffering CVD such as heart failure. Globally, it is estimated that 17.9 million people died from CVD in 2016 and, without intervention, this number is projected to rise [2]. The number of people with diabetes rose from 108 million in 1980 to 422 million in 2014 [3]. Obesity is a component of metabolic syndrome and is considered to be an intermediate risk factor for CVD, even in the young. The speed with which the incidence of these diseases has escalated has been attributed to changing lifestyles, especially the consumption of high glycemic index foods with a high fat and salt content and a sedentary lifestyle. However, not all individuals have the same risk of developing pathological conditions, even in the same environment. In the last 30 years it has emerged that the developmental environment (periconceptionally through early postnatal life) influences an individual’s response to their adult environment and lifestyle, hence determining in part their risk of disease.

The DOHaD Concept Epidemiological studies show that small size at birth and during infancy is associated with a greater risk of CHD, hypertension and stroke in later life [4]. Importantly, the degree of these changes, and hence disease risk, is graded across the normal range of size at birth, i.e. it is not just a consequence of FGR. The Developmental Origins of Health and Disease (DOHaD) concept suggested that the low birth weight-disease risk association may underestimate the true influence of the early environment effect. Birth size is one measure of fetal environment and DOHaD might be better viewed as a later consequence of a normal developmental response to environmental cues. The risk of adult CHD is particularly increased if small size at birth and during infancy is followed by rapid childhood weight gain [5]. Recent proposals suggest that the developing organism responds to its environment to develop a phenotype optimal for survival to reproduce in the postnatal environment in which it predicts that it will live, and that a mismatch between the in utero and childhood nutritional environments increases risk of CVD [1, 6]. The degree of mismatch will be increased by an unhealthy lifestyle (unbalanced diet, reduced physical activity, smoking, and excessive alcohol consumption) and this is of particular concern in light

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Chapter 2: A Fetal Origin of Adult Disease

of the rising incidence of childhood obesity and the links between obesity and CVD.

Human and Animal Evidence There is potential for the embryo and fetus to be exposed to a range of such cues, including environmental toxins, ‘maternal constraint’ (from e.g. body composition, stature, nutrition, age, and parity), maternal stress, umbilical-placental complications (including resultant hypoxia/asphyxia), and maternal diseases. Environmental factors such as maternal nutrition can channel development (i.e. influence developmental plasticity). The adaptations that are made might be of immediate adaptive value and help survival, or could confer little or no immediate benefit but nonetheless be predictive of the postnatal environment. If the postnatal environment is not as predicted this may increase the risk of disease [1]. But studies attempting to investigate DOHaD should distinguish these sort of adaptive responses from pathophysiological effects of the environment (disrupting development, e.g. toxins or umbilical-placental complications) with no obvious adaptive value at any point in the life course. This is important since these simply disrupt the normal pattern of development and do not necessarily lead to an increased risk of disease. There are a few key human cohorts in which the DOHaD concept has been investigated [7]. In addition a number of experimental animal models have been developed in a range of species. Ascertaining the risk of disease is usually not possible in animal models, but making sure that the challenges are of physiological rather than pathophysiological magnitude and of a type relevant to DOHaD remains crucial to progress in this field. In this chapter, we focus primarily on maternal constraint-type cues for which a cohesive and persuasive body of evidence exists. Many women in the UK consume unbalanced or ‘imprudent’ diets, including during pregnancy. The influence of a poor intrauterine environment on later CVD was highlighted in the Dutch winter famine cohort [8]. Maternal body composition and metabolism provide the backdrop against which more acute changes in diet act and influence the compartmentalization of nutrients between the mother, placenta, and fetus. In England 15.6% of women are obese (body mass index (BMI) 30 kg/m2) at the start of pregnancy and a smaller proportion (2.88%) are underweight (BMI < 18.5 kg/m2) [9]. In the Southampton Women’s Survey by the Institute of Medicine Standards (2009), excessive (49%) and inadequate (21%) weight gain in pregnancy are prevalent [10]. Both extremes of maternal weight profile are thought to pose a significant threat to maternal and fetal/neonatal well-being and may have substantial ramifications for cardiovascular health in later life. Excessive weight gain is linked to offspring obesity [10, 11] and to higher systolic blood pressure into early adulthood (21 years [12]). Human data suggest that whilst gestational weight gain is associated with adverse cardiovascular risk factors at 9 years, pre-pregnancy weight has a greater overall impact [11]. Slimness in mothers is linked to CHD and raised blood pressure, while high maternal weight/adiposity is linked to CHD

[13, 14]. In this regard, new guidelines on pregnancy weight management were issued in 2010 [9] and their implementation may serve to break the cycle of obesity and reduce the incidence of CVD. Numerous studies in animal models (rodents, guinea pigs, sheep, and non-human primates) corroborate the idea that maternal diet during gestation and breastfeeding are very important in determining adult propensity to obesity, cardiovascular and renal dysfunction [15–23], and left ventricular hypertrophy [23, 24], in ways that mimic predisposition to CVD with increasing age. The phenotypic effects of an altered early environment include altered adult growth, glucose intolerance and insulin resistance [15, 25, 26] and changes in sympathoadrenal function and hypothalamic-pituitary-adrenal (HPA) axis responses [20, 24, 27, 28], and these may constitute part of the mechanism by which cardiovascular control is affected. There is emerging evidence that the nature of the response is sex dependent [15, 23]. It is striking that, without further dietary challenges in the F1 pregnancy, features of the cardiovascular dysfunction in adult guinea pig offspring following F0 maternal diet challenge can persist into the F2 generation [24, 29]. In sheep, maternal obesity abolishes the normal leptin spike in their neonatal offspring (important for development of hypothalamic appetite circuitry) and this effect is also observed in their granddaughters [30]. Importantly, maternal dietary restriction even before conception can induce effects on vascular function in adult offspring [31], which emphasizes the importance of life-long good nutrition. Maternal body composition can be reliably manipulated through diet in sheep and it can induce long-term adverse metabolic effects and skeletal muscle structural alterations, along with cardiovascular and renal effects, in offspring [32, 33]. This underlines the concept that these effects are part of a coordinated strategy affecting development of a range of tissues, as opposed to a pathological effect. A comparatively small number of animal studies have tested directly the concept that a mismatch between the in utero and childhood nutritional environments increases risk of CVD. In sheep, cardiovascular dysfunction in offspring exposed to either prenatal or postnatal undernutrition alone was not seen when pre- and post-weaning environments were similar (Figure 2.1) [23]. Also, undernutrition in early-mid gestation was associated with more renal lipid deposition in young adult obese sheep [34]. Late gestation undernutrition in sheep increased the neonatal appetite for fat, changed the pattern of fat deposition [35], and predisposed adult sheep offspring to hypercholesterolemia in an obesogenic environment [36]. In rats, dietary manipulation to minimize the mismatch between pre- and post-weaning nutrition minimizes endothelial dysfunction and the disruption of mechanisms regulating appetite and energy expenditure in offspring [17, 37]. In rats, a greater pre- and postnatal dietary mismatch worsened liver function [38] and decreased life span [39]. In pigs, the coronary atherosclerotic effects of a high-fat diet were prevented by prior feeding of a similar diet to the pregnant mother [40].

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Section 1: General Principles

(A)

(B) CC RV

LVW

CU UC

Wall thickness (mm)

LV

*

15

IVS

UU 10

5

0

(C)

(D)

* 1.5 1.0 0.5

6.75

*

6.50 pEC50 (−log M)

MLCK mRNA/18s rRNA

2.0

6.25 6.00 5.75 5.50 5.25

0.0

5.00

The Fetus Responds to Its Environment Adaptive or Disruptive? Early detection of individuals who are at risk of disease is a cornerstone of predictive and personalized medicine. Children can show early signs of CVD, including atherosclerosis, and lower birth weight is associated with impaired endothelial function [41] and altered cardiac structure [42] in 8–9 year olds. In sheep, elevated blood pressure and HPA axis responsiveness were observed in 3-month-old offspring of ewes fed 85% total requirements for the first half of gestation [20]. However the fetus offers the potential for detection of an individual’s risk of disease even earlier in life, and may provide future early routes for intervention. But, rather than being viewed as the start of a pathological process, current thinking suggests that some of these fetal changes might be of immediate adaptive value (prioritize and conserve energy use) and optimize a phenotype for better chance of survival over the life course [1]. Such prenatal physiological adaptive responses may operate over a broader range of normal development (Figure 2.2). The cardiovascular system is a key part of a coordinated adaptive response, designed to get nutrients where they are really needed. Any redistribution of the cardiovascular resources might preserve the growth of some organs at the expense of others. There are also likely to be limits to the extent that the fetus can cope through cardiovascular or growth adaptations (stretched to the limit by duration or severity of challenge), at which point the cue from the maternal environment becomes ‘disruptive’ [1], or if the adaptations that it has made do not suit the postnatal environment this may lead to impaired function after birth and longer-term health problems. An alternative strategy would be for the fetus to be born early,

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Figure 2.1 Altered cardiac morphology and coronary function in male adult sheep are absent when the mismatch of pre- and postnatal nutrition is minimized. Sheep were fed a control diet throughout pre- and postnatal life (CC), or they were exposed to moderate undernutrition either during early gestation (1–31 days’ gestation, where term is 147 days; UC), during early postnatal life (12–25 weeks; CU), or both (UU). (A) An echocardiograph showing the right ventricle (RV), interventricular septum (IVS), left ventricle (LV), and left ventricular wall (LVW) of the ovine heart. (B) Thickness of the intraventricular septum; CC (n = 14), CU (n = 10), UC (n = 14), and UU (n = 14). Also shown are myosin light chain kinase (MLCK) relative mRNA expression in the coronary artery of male sheep as measured by real-time PCR [CC (n = 7), UC (n = 7), and UU (n = 4)] (C) and vascular response to acetylcholine in the coronary artery [CC (n = 10), UC (n = 9), and UU (n = 7)] (D). *, P 84 mm) the second trimester quadruple serum test may be offered. This combines (i) maternal age, (ii) β-HCG,

2010

Present

Chromosome microarray analysis

First trimester screening

G-banded Karyotype

Quantitative fluorescence polymerase chain reaction

Next-generation whole genome and exome sequencing

Non-invasive prenatal testing and screening (cell-free fetal DNA)

(nuchal translucency, age and biomarkers)

Figure 4.1 The evolution of screening and diagnostics for prenatal testing for chromosomal and gene anomalies. Description of developments in prenatal screening since its inception in the 1960s to present day.

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Chapter 4: Human Genetics and Fetal Disease: Assessment of the Fetal Genome

(iii) alfa-fetoprotein (AFP), (iv) inhibin-A, and (v) estriol to formulate a risk value. Although this combination of biomarkers has a lower sensitivity (80% detection rate for an FPR of 3.5%) than the combined test, it is the nationally recommended UK screening strategy after 14+2 weeks’ gestation [4]. In modern obstetric practice, couples can now decide to undergo non-invasive prenatal testing (NIPT), which detects cell-free fetal DNA in the maternal circulation. This highly sensitive test is performed after 9 weeks’ gestation and can screen for common autosomal aneuploidies [7–10]. Metaanalyses of results from contemporaneous cohort studies (with post-test definitive karyotyping) indicate that detection rates for trisomies 21, 18 and 13 are 99.7% (95% CI [confidence interval], 99.1–99.9%), 97.9% (95% CI, 94.9–99.1%) and 99.0% (95% CI, 65.8–100%) respectively, with an overall FPR of 0.04% (95%

CI, 0.02–0.07%) [11, 12]. Due to this high degree of sensitivity and specificity, it is very probable that such technology, when applied to screening for chromosomal anomalies, will lead to a significant reduction in prenatal invasive testing [13]. Thus, the debate is whether NIPT should be offered as a first-line screening test or in a contingent fashion after an FCT (with modification of the 1:150 cutoff ). Using NIPT as a first-line screening tool would reduce the number of invasive tests performed, but might increase the financial costs of screening if NIPT remains more expensive than the FCT. Moreover, obviating the use of FCT altogether could impact on other care pathways such as detection of pregnancies at risk of preeclampsia, growth restriction, or first trimester structural fetal anomalies., Figure 4.2 shows a suggested pathway of an approach to screening and diagnosis of chromosomal anomalies.

FIRST TRIMESTER ULTRASOUND SCAN MID-TRIMESTER ULTRASOUND SCAN

Suspected structural anomaly

Invasive test

No further testing

High-risk first trimester screening (NT + PAPP-A + βHCG) (11-13+6 weeks)

Results normal

Non-invasive prenatal test (>9weeks)

Figure 4.2 Suggested pathway for screening and prenatal diagnosis of a chromosomal anomaly. Patients may be offered further testing in the event of a high-risk screening result from the first trimester combined test or if an anomaly is identified at the mid-trimester ultrasound scan. The flow diagram demonstrates the pathway if an abnormal result is identified to illustrate sequential testing with microarray and exome sequencing.

Result abnormal

QF-PCR fetal DNA

Results normal

CMA fetal +/- parental DNA

Result abnormal

Results normal

Targeted fetal exome capture

Result abnormal

Counseling with a clinical genecist

Key Indicates potenal alternave test Indicates recommended follow-on test in the event of a normal result

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Section 1: General Principles

The main focus of this chapter is the genomic investigation of the fetus with structural anomalies. Between 3 and 5% of pregnancies will have a sonographically detected fetal structural abnormality noted at the first trimester (11+0 – 13+6 weeks) or the 18+0 – 21+6 week detailed anomaly screening scan. In addition, structural anomalies may be incidentally identified after this time when ‘fetal growth scans’ or scans for other reasons are performed. These may range from a single, relatively minor anomaly (e.g. cleft lip) to severe multisystem abnormalities associated with increased perinatal mortality [14]. The risk of associated structural chromosomal anomalies and single gene abnormalities will alter depending upon: a) the type of structural anomaly and anatomical system affected; and b) the number of identified anomalies on an ultrasound scan. However, even apparently ‘isolated’ anomalies (such as cleft lip and club foot) may be associated with a genetic disease, as subtle phenotypic anomalies of the fetus may not always be detectable using prenatal ultrasound. In such cases, patients are usually offered prenatal invasive testing first line as subsequent genomic analysis may play an important part in evaluation and prognostication [15]. Traditionally, conventional karyotyping would have been undertaken as the chromosome analysis of choice. Since the early 1990s, with the introduction of the molecular techniques of interphase fluorescence in situ hybridization (FISH) and quantitative fluorescent polymerase chain reaction (QF-PCR), it has been possible to reduce the turnaround time for results of chromosomal analysis from 2 weeks to 48 hours for detection of the common aneuploidies, with almost equal accuracy to karyotyping, thus avoiding the more challenging scenario of a later termination of pregnancy, should this be the parental wish [16]. The field of genetics in fetal medicine is rapidly accelerating, and the use of chromosomal microarray analysis (CMA) is replacing karyotyping to become the standard practice in many situations [17]. CMA facilitates sub-microscopic chromosomal analysis at a resolution much higher than the 5 Mb provided by conventional karyotyping, increasing the diagnostic yield of micro-deletions and duplications. Looking into the future, the next step in genomic testing and the application of NGS in pediatric and adult medicine is enabling resolution to the level of a single base pair and thus facilitating detection of monogenic disorders only previously diagnosable via targeted genetic mutation analysis of a genetic syndrome with a recognized phenotype [18]. International review documentation, however, does not currently recommend the routine use of NGS in the context of prenatal diagnosis beyond a research setting [19]. One must bear in mind that all screening and diagnostic tests have their own strengths and pitfalls, and appropriate selection of investigations in the context of clinical circumstances is an important issue in prenatal genetics.

Chromosomal Analysis Chromosomal analysis using conventional cytogenetic techniques has been an integral component of fetal medicine since

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the 1960s. Combined, trisomies 13, 18 and 21 account for 95% of aneuploidies [20]. Nadler and Gerbie in 1970 described the utility of amniocentesis in the second trimester in their management of ‘high-risk’ pregnancies, demonstrating that amniotic fluid contained amniocytes that could be grown in laboratory conditions [21]. Henceforth, prenatal identification of genetic disorders became more prevalent and eventually formed part of standard antenatal care [4].

Conventional Karyotyping In relation to the conventional karyotype, chromosomal assessment begins with microscopic chromosome counting at metaphase (Figure 4.3). This process was refined through G-banding, which produced light and dark bands of the chromosomes representing gene poor/rich areas, visible using light microscopy. Such analysis is useful for identifying triploidy, chromosome inversions, deletions, duplications, and translocations of 5–10 Mb. Examples of syndromes that may be identified include cri-duchat (5p deletion), Miller–Dieker (17p13.3 deletion), and Wolf–Hirschhorn (4p16.3 deletion) [20]. Conventional full karyotyping is a well established and useful method used in prenatal diagnosis, but is limited by its relatively low resolution and turnaround time of up to 21 days, caused by the need to harvest live cultured cells during metaphase in order to visualize chromosomes.

FlSH and QF-PCR FISH harnesses the binding specificity of a nucleotide to its complementary base pair by using large insert ‘clones’ of between 100 and 250kb, mapped to the human genome as part of the human genome sequencing project. Coupling these clones to a ‘tag’ emits fluorescence, enabling the detection of specific DNA sequences (Figure 4.4). The term in situ refers to clone labeling of the chromosome in the interphase state; hence cell cycle arrest is not necessary, thus reducing turnaround time for aneuploidy detection. The main limitation of FISH is that it is a targeted test, and whilst useful for detection of aneuploidy, prior suspicion of a genetic lesion is required. In addition, the region in question must be larger than the clone used, thus limiting resolution. The fluorescent image is analyzed microscopically, which involves counting the number of cells and scoring the proportion of cells with signal patterns consistent with the chromosome complement. Turnaround time is significant shorter than that of karyotyping, with analysis taking as little as 10 minutes. QF-PCR can be performed on DNA extracted from cultured or uncultured cells. Amplification of short polymorphic tandem repeats forms the basis of the test [20]. Multiple polymorphic markers are assessed that are representative of the chromosome copy number being assessed. In samples from a ‘normal’ karyotype, two peaks appear, in a 1:1 ratio, depicting equal proportions of the locus of interest [22]. In trisomy, the three peaks are depicted, two peaks with a 2:1

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Chapter 4: Human Genetics and Fetal Disease: Assessment of the Fetal Genome Figure 4.3 Karyogram depicting Trisomy 21 The karyogram is of a female fetus. Note the appearances of dark and light bands of each chromatid produced by G-band staining and an extra chromosome 21. Courtesy of Susan Hamilton, West Midlands Regional Genetics Laboratory, Birmingham, UK

1

2

3

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7

8

13

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15

19

20

4

9

21

5

10

11

12

16

17

18

X

Y

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the Y chromosome is used in addition to detection of the X chromosome. Figure 4.5 depicts an electrophoretogram in a fetus with trisomy 18. The sensitivity for detection of the common trisomies using QF-PCR is estimated to be 98.6% (86.3–100%, 95% CI 97.8–99.3% for trisomies 21, 18 and 13 respectively). QF-PCR has a number of advantages over FISH; most notably, the ability to analyze multiple samples simultaneously and identify maternal cell contamination [22]. Furthermore, analyses can be automated and results can be returned within a much shorter time period. In the context of possible termination of pregnancy, a shorter turnaround time facilitates timely co-ordination and provision of this service. The nature of QF-PCR dictates that generally only numerical variations in the chromosome number are identified.

Deleted portion of chromosome 4

Chromosomal Microarray Normal chromosome 4 KEY RP11-420A23 4p telomere

(red) (green)

Figure 4.4 FISH depicting deletion in chromosome 4. The green probe highlights the telomeric end of the short arm of chromosome 4. Interphase stage FISH demonstrates a deletion in the long arm of chromosome 4. This is denoted by the absence of the red probe. Courtesy of Susan Hamilton, West Midlands Regional Genetics Laboratory, Birmingham, UK

ratio, and, rarely, a homozygous pattern with a single peak. In monosomy X, only one peak appears. For sex identification, absence of a peak in the region of the amplicon product of

Within the last 10 years, fetal genetics has advanced further with the widespread use of chromosomal microarray (CMA). Using array comparative genomic hybridization (aCGH) oligonucleotide probes are attached to a glass slide (chip), with multiple probes representative of specific regions of the genome with variable resolution depending on clinical application. Following extraction from prenatal samples, target DNA (in this context, fetal) is fluorescently labeled and hybridized to microarray alongside ‘normal’ control DNA. Differences in the nucleotide copy number at different loci in the test sample and control are compared and a software package, such as Agilent®, is used to identify if potential gains and losses in the test sample are significant (Figure 4.6). Specific criteria are used for these analyses (Figure 4.7). Significant copy number

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Section 1: General Principles

D21S11

D13S628

240

D13S634

320

D13S742

400

480

D18S1002

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D13S305 400

CONTROL DNA

480

PATIENT DNA

1

3

Patient and control DNA labeled with fluorescent dyes are applied to the microarray.

The fluorescent signals are measured by the microarray scanner.

2 Patient and control DNA are hybridized to the microarray.

Figure 4.5 QF-PCR electrophoretogram demonstrating trisomy 18. The grey boxes accompanying the top of the electrophoretogram denote the probe set used to interrogate a specific chromosome. The first two numbers denote the chromosome number. D21S11 therefore corresponds to chromosome 21. Red triangles denote the start and end of a gene coding region. Note that 3 spikes are detected by probesets D18S535 and D18S1002, indicating the presence of an extra chromosome 18. All other probesets detect 2 spikes, i.e. normal copy numbers of chromosomes 13 and 21. Courtesy of Susan Hamilton, West Midlands Regional Genetics Laboratory, Birmingham, UK

D18S535

4 HYB R I D IZATION

DNA GAIN

DNA LOSS

The data is then analyzed by computer software which generates a plot.

DNA DOSAGE

NO CHANGE

Figure 4.6 Description of microarray methodology. Courtesy of Susan Hamilton, West Midlands Regional Genetics Laboratory, Birmingham, UK.

variants (CNVs) are interpreted through correlation with online repositories of genomic variants in healthy controls and in individuals with anomalies (e.g. the DECIPHER database: https://decipher.sanger.ac.uk). Identification of a CNV is generally validated using a targeted alternative technique such as FISH, multiplex ligation-dependent probe amplification (MLPA), or repeat CMA. An alternative array method is that of single nucleotide polymorphism (SNP) microarray. SNPs are points within the genome nucleotides that vary within the population and have been found to have associations with common diseases such as diabetes mellitus and autistic spectrum disorder. Following amplification and fragmentation of test DNA into

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oligonucleotides, this is then hybridized on a chip containing hundreds of thousands of allele-specific oligonucleotide probe pairs. By comparing the degree of hybridization one can determine genotype. Compared with aCGH, SNP array has the advantage of being able to detect triploidy and identify areas of loss of heterozygosity that might indicate uniparental disomy or parental consanguinity [17]. Initial CMA platforms identified differences in chromosome copy number at a resolution of 0.5–1 Mb [24] and current CMA platforms are now as optimal as 2 kb, with a significantly greater resolution over standard karyotype [25]. With platforms of variable resolution available, the main dilemma posed with the use of CMA is optimizing the balance

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Figure 4.7 Microarray profile depicting deletion in chromosome 16. Panel (A): Electrophoretogram of array comparative genomic hybridization (aCGH). Dashed arrows correspond to the margin of normal variation in the signal intensity. The bold red arrow demonstrates a reduction in the signal intensity indicating a reduction in hybridization of the test genomic DNA compared with control. This would indicate a deletion in that region. Panel (B): The tested genomic DNA is underlined and marked by the name ‘current.’ The deletion appears to map to the long arm of chromosome 16. The region deleted spans 1.9 Mb. Although this represents a substantial size, the mere presence of a deletion does not indicate its pathogenicity. Further analyses in online repositories of genomics and disease are required. Panel (C): Magnified region of Panel (A). Dashed arrows correspond to the margin of normal variation in the signal. The bold red arrow denotes the deleted region. Note that there is reduced hybridization to 29 probes (circles). Panel (D): Magnified version of Panel B. This demonstrates the exons within the deleted region (small green verticle bars). In this instance, the gene coding for Ankyrin Repeat Domain 11 has been identified (ANKRD11). Thus, the aCGH results indicate a loss of this gene due to a deletion in that region. ANKRD11 deletion results in KBG syndrome. This is an autosomal dominant syndrome that results in dental, neurobehavioral, craniofacial and skeletal anomalies. [23]. Courtesy of Susan Hamilton, West Midlands Regional Genetics Laboratory, Birmingham, UK

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Section 1: General Principles Table 4.1 Advantages and disadvantages of aCGH analyses compared with G-banded karyotype

Advantages of aCGH compared with G-banded karyotype

Disadvantages of aCGH compared with G-banded karyotype

Greater resolution for detection of microduplications and deletions

Cannot detect balanced translocations

Objective evaluation

Tetraploidy and or triploidy may be missed depending on the CMA technique used

Wider range of tissue types can be analyzed

Cannot assess mechanism of CNV, e.g. via unbalanced translocation or marker chromosome

Tissue culture not required

Detection of variants of unknown significance

Platforms can be customized to focus on areas of interest

Greater likelihood of missing low levels of mosaicism

Uniparental disomy and consanguity can be detected (with SNP CMA) Data obtained can be compared with genetic databases to assess phenotypical findings associated with the region Greater throughput of samples using automated devices

between using a CMA platform of greater resolution and the amount of information generated against the risk of increasing the number of variants of uncertain significance (VUS) detected, as these pose challenges for interpretation and counseling [24]. One study by Hillman et al. compared use of a low-resolution CMA platform (1 Mb) with a higher resolution (60 K) array in the presence of congenital fetal anomaly, and found that while the 60 K array offered a non-significant additional pathogenic CNV detection rate (4.8% vs. 4.1%, P=0.31) there was also a significantly greater proportion of VUS (8.0% vs. 0.4%, P < 0.001) [26]. A larger study, which also used a high-resolution platform (75 K), found a pathogenic CNV detection rate of 6.0% and a 1.5% VUS rate, dropping even further to 0.5% following a revision of the VUS in 2015. This study and its author suggest that as CMA testing gains longevity, given the growing deposition of clinical-grade data into public databases, the rate of reported VUS will fall, suggesting that platforms with maximum possible resolution should be used to optimize the chance of detecting a pathogenic CNV [26, 27]. The diagnostic yield of CMA and the prevalence of VUS in prenatal testing have been assessed by several international groups, the findings of which are summarized in Table 4.2. In addition to assessing diagnostic yield, one of the largest prenatal microarray studies, EACH (Evaluation of Array Comparative genomic Hybridization in prenatal diagnosis of fetal anomalies), found that compared with karyotyping, CMA was 5 days faster in terms of turnaround time and cost an additional £113 over karyotype. The number of pathogenic CNVs detected increased with the number of anomalies detected and was also higher in the suspected cardiac anomaly group than with any other system (1.5% vs. 11.2%, P < 0.001) [25]. This has been confirmed through other studies [29, 30]. Findings assessing the incremental yield of CMA

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over karyotype in cases of elevated NT (>3.5 mm) have been variable in different studies, yet after assessment of the literature, EACH concluded that CMA was less beneficial and more costly in cases of isolated NT than in cases of other structural anomalies and hence may only have a limited role in such cases [25]. The advantages and disadvantages of CMA over standard karyotype are shown in Table 4.1 [17]. In Europe and the United States, CMA has replaced conventional karyotyping in prenatal diagnosis, with other international centers moving toward the same position, using karyotyping additionally only when required. Copy number variants detected on CMA can be categorized as benign, likely benign, VUS, likely pathogenic or pathogenic. As mentioned, there are databases of clinical variations, such as DECIPHER and ISCA (http://dbsearch .clinicalgenome.org/search), in addition to clinical guidelines that can aid clinicians and scientists in determining the clinical significance of CNVs [31–35]. Patient counseling and consent must focus on: (i) the variable spectrum of disease with a pathogenic CNV finding; and (ii) the fact that CMA will not detect all genetic anomalies.

Gene Sequencing Strategies It is possible to detect pathogenic nucleotide variations down to the resolution of one base pair using NGS. Such NGS strategies include whole exome sequencing (WES) – whereby coding exons of all known disease-coding genes are interrogated (1–2% of the human genome) – and whole genome sequencing (WGS), where the whole genome, inclusive of non-coding regions, is assessed [36]. A joint consensus statement from the International Society of Prenatal Diagnosis, the Society of Maternal Fetal Medicine, and the Perinatal Quality Foundation recognizes the fast pace at which NGS

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Chapter 4: Human Genetics and Fetal Disease: Assessment of the Fetal Genome Table 4.2 Diagnostic yield and variant of unknown significance rate (VUS)

Population

Study type

Wapner, et al. 2012

4406 women undergoing prenatal diagnosis for (i) maternal age; (ii) high-risk FTS; and (iii) structural anomaly

Hillman, et al. 2013

243 women undergoing prenatal diagnosis for fetal structural anomalies; 18 113 prenatal samples from meta-analysis where women underwent a prenatal test for any reason

Robson, et al. 2017

1123 women undergoing prenatal testing for one or more structural fetal anomalies or elevated NT where QF-PCR testing for major aneuploidies was negative

Primary CMA platform

Additional diagnostic yield

Rate of VUS

Oligonucleotide CGH array Prospective case control study CMA vs. design: 4-plex array in 71% with 44 000 karyotype oligonucleotide probes covering targeted regions of known disease association [coverage 1 probe per 75 kb]

1.7% in cases of maternal age and a high-risk FCT result; 6% in cases of structural fetal anomaly

1.5% of CNVs (revised as 0.9% in 2015)

Prospective case control study CMA vs. karyotype AND meta-analysis of CMA vs. karyotype

Whole genome BAC (Bacterial Artificial Chromosome) microarrays with resolution of >2 Mb in genomic backbone and >200 kb in targeted regions

4.1% for case control study; 5–10% for metaanalysis (fetal structural anomaly)

0.8% for case control study; 1.4% meta-analysis (any indication); 2.1% for structural anomaly

Prospective case control study CMA vs. karyotype And Cost-effectiveness analysis And Qualitative sub-study

Oligonucleotide-CGH array design; 8-plex of 60 000, 60-mer oligonucleotides with a backbone resolution of ≈75 kb

3.7% for any fetal structural anomaly

2.4% for any structural anomaly

Diagnostic yield and VUS rate with different studies assessing use of chromosome microarray over karyotype in a prenatal setting. Note that the diagnostic yield increases when the resolution increases, but so does the VUS rate. The lowest VUS rate was associated with the case control study undertaken by Hillman et al. FCT, first-trimester combined screening test.

Additional 5% yield

· Quantitative fluorescence polymerase chain reaction

Additional 3-6% yield

· G-banding karyotype

Additional 7-8% yield

· Chromosome microarray analysis

71 whole genome sequencing yield

· Whole exome sequencing

Figure 4.8 Diagnostic yield of prenatal tests. This flow diagram depicts how each subsequent test provides additional information over and above the previous one. For instance, chromosomal microarray could provide 7–9% additional information compared with conventional karyotyping with G-banding.

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Section 1: General Principles

technologies are moving and the evidence emerging, which supports its efficacy in prenatal diagnosis. However, caution is suggested, along with the need for widespread education of health professionals and additional research using larger cohorts in this area [19]. Figure 4.8 demonstrates the historic increase in the diagnostic yield of chromosome and genetic disorders up to the current day with the use of NGS.

Whole Exome Sequencing Whole exome sequencing has demonstrated significant clinical utility in the field of pediatric rare Mendelian disorders and has enabled several discoveries, such as Kabuki, Fowler, Schinzel– Giedion, Bohring–Opitz, and Miller syndromes [36–38]. It is foreseen that the transition of such testing into routine clinical practice will aid in bypassing the prolonged ‘diagnostic odyssey’ that the vast majority of children with a rare genetic disease experience [36]. The application of WES in such clinical scenarios can increase the diagnostic yield over standard approaches by up to 25%, a figure which may increase further with time as understanding of the scope of the technology advances. The diagnostic yield has been demonstrated to be greatest for children and fetuses where an underlying neurological phenotype has been attributed, demonstrating the close affinity of the neurological system with genetic anomalies, with an affinity noted for pathogenic de novo mutations in disorders of intellectual disability [37, 38]. Whole exome sequencing can be subcategorized further into a clinical exome, which serves as a targeted panel of a select number of genes (possibly hundreds) already identified and known to be associated with specified syndromes. An example of where such a targeted panel has been used is demonstrated in a study by Chandler et al., where application of a clinical exome using trio (proband and bi-parental) analysis for pregnancies suspected to have an underlying skeletal dysplasia, along with input of the multidisciplinary team to optimize phenotyping, revealed that through using a panel of 240 known skeletal dysplasia gene mutations, a molecular diagnosis was made in 13/16 (81%) cases [39]. In light of studies such as this, guidance has been issued which recommends that prenatal NGS should not be used in routine clinical practice until further studies demonstrating clinical utility and safety are performed. This guidance suggests that it is reasonable to consider such testing on a case-by-case basis following multidisciplinary input when: (i) fetal anomalies suggest a genetic disorder and CMA is negative; (ii) there is no CMA result but anomalies are strongly suggestive of a single gene disorder; (iii) there has been a previously undiagnosed fetus/ child with single or multiple anomalies pointing toward a genetic syndrome that has now recurred in an index pregnancy; and (iv) there is a history of recurrent stillbirth with negative karyotype and/or CMA where the index pregnancy presents with similar anomalies [19]. Whole exome sequencing will identify nucleotide alterations in the protein coding regions of any of the approximately

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>20 000 genes in the human genome [18]. Though WGS provides more genetic information than WES it is currently more expensive, requires larger amounts of DNA, and the large amounts of data generated are difficult to analyze rapidly. Hence, WES is currently more widely used for investigating the genetic basis of fetal structural anomalies, predominantly within clinical research. However, as with CMA, one may predict that more extensive application of sequencing will lead to increased knowledge on the significance of variants, and as suggested by recent guidance it is necessary to determine the clinical utility and cost-effectiveness of this technology before it can be used routinely in prenatal genetics. WES has been used to assess fetuses with a structural anomaly (and their parents, i.e. trio analysis) where post-mortem examination findings were available. This study found pathogenic variants in 37% (n=10/ 27) of cases, illustrating how optimization of phenotypic information can facilitate the interpretation of the significance of genetic variants with increased diagnostic yield [40]. The PAGE study is investigating the application of WES to a prospectively collected series of fetuses with structural anomalies. An interim analysis of a prospective cohort of 610 fetuses and 1206 parental samples (597 case-parental trios and 14 case-parent dyads) noted clinically relevant pathogenic variants were detected in 8.7% of cases (n = 34/392) [3]. Importantly, the diagnostic yield varied between different phenotypic sub-groups, with pathogenic variants more common in fetuses with complex multisystem anomalies, fetal hydrops, and cardiac or skeletal abnormalities (10.5%, 18.4%, and 15.4% respectively) but a low diagnostic yield in those with only an isolated elevated NT (1.1%) [3]. There are some limitations of exome sequencing, most notably the turnaround time and return of results to parents. Additionally, exome sequencing failure can occur [41]. Studies have suggested that an 11–41 day turnaround time is possible, and this should improve as more bioinformatic analysis pipelines are developed [39, 42]. Interpretation of WES-detected variants is more difficult if parental sequences are not available and WES may not reliably identify structural chromosomal variations (hence, CMA is still generally performed to detect CNVs), triplet repeat disorders, or genetic aberrations within introns (non-protein coding genes).

Whole Genome Sequencing Whole genome sequencing has the potential to identify pathogenic variants within the entire genome in addition to detecting CNVs and structural rearrangements. Genetic variations beyond gene coding regions can cause pathology – our understanding of the role of these genes is increasing, but the relevance of such genetic variants outside the exome in fetal structural anomalies is still to be defined [43]. Furthermore, the cost-effectiveness of different molecular genetic strategies (e.g. WES versus WGS) has still to be established in pre- and postnatal genetic practice. Therefore the likelihood is that WES plus CMA will become the most widely used strategy for

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Chapter 4: Human Genetics and Fetal Disease: Assessment of the Fetal Genome

variant detection in the near future, though a decrease in the cost of WGS may change this.

Concerns Regarding Advances in Prenatal Diagnostic Testing More information comes at a cost, and NGS testing is more expensive and has a longer turnaround time compared with standard cytogenetic testing. Patients need to be aware of local failure rates. However, as CMA is more likely to identify a pathogenic CNV than karyotyping when a structural anomaly is found, and with a faster turnaround time, the incremental cost per pathogenic CNV is lower and costings will likely become significantly cheaper over time as more batches are run simultaneously. It is unclear what care providers would be willing to pay for an increase in diagnostic yield. As CMA evaluates variation in chromosome copy number, balanced rearrangements are not detected. Although one might argue that balanced rearrangements are unlikely to be pathogenic, their discovery necessitates a discussion regarding future pregnancies and the increased risk of pathogenic CNVs in the offspring (or siblings if the balanced translocation is inherited). In relation to WES and WGS concerns focus around cost, turnaround time, standardization of bioinformatics pipelines, variant interpretation, and the reporting of incidental findings. Finally, the identification of potentially pathogenic CNVs or gene variants relies on accurate phenotypic characterization, which has limitations when applied to prenatal ultrasound. As with CMA, with time, NGS will evolve and develop to become more efficient and cost-effective.

Ethics Our ever-expanding knowledge base with regards to genetics and fetal disease brings with it far-reaching ethical dilemmas. NGS can not only identify genetic mutations concordant with the phenotypical features under investigation but can be extended to detect ‘incidental’ or ‘secondary’ findings, such as susceptibility genes for adult-onset disorders. One could argue that, for instance in the case of identifying the BRCA gene mutation, parents may choose to terminate or intervene to limit their potential child’s ‘open future.’ There are consensus guidelines to aid the management of such challenging situations [35, 44, 45]. As addressed by Horn and Parker, NGS can open a ‘Pandora’s box.’ Ethical dilemmas center around five primary issues [1]: i. Consent – how clinicians obtain consent and the amount of information they share prior to testing depends very much on the patient and what they wish to know. This is where thorough pre-test counseling is vital, aided by the support of the multidisciplinary team, appropriate literature, and adequate time for decision-making. It is the responsibility of the clinician to ensure that couples provide informed consent, which means that they must understand the potential implications of testing, such as not being able to interpret VUS or additional genetic mutations other than

those the initial test had sought to find. The amount of information that could be given to couples is likely to be somewhat overwhelming, and with the anxiety surrounding co-existence of a fetal anomaly it may prove a challenge to fully appreciate the implications of testing. ii. Feedback of results – As well as thorough pre-test counseling there must be equally informative post-test support available. Information provided from NGS may be challenging to interpret, not answering the original diagnostic query, and can unveil other incidental findings and non-paternity. Just how much of the results must be revealed is an ethical challenge, as in the setting of prenatal testing the information provided may not fully inform a couple in their decision-making on whether to continue with the pregnancy, and the result may have an impact on other family members for which action may be required. Ultimately, one should be guided by the initial consent provided from the couple in relation to what they wish to know, in addition to informing them of the caveat that testing may inform them of non-paternity, which should, ethically, be disclosed. This also raises the issue of who owns/has a rightful claim to the genetic information generated from testing. For example, if findings have significance for other family members, are they ethically entitled to access this information on a ‘right to know’ basis as part of the so-called joint account? iii. Health professionals’ responsibility – in addition to the significant workload that NGS will create for clinical scientists, bio-informatic statisticians, clinical fetal medicine and genetic staff in interpreting a result, one must query if it is also their responsibility to continuously reanalyze results in light of ongoing advances and research with regard to the clinical relevance of VUS. Also, in relation to incidental findings, is it also the responsibility of healthcare staff to counsel the tested child, once they reach an age of appropriate understanding, or the wider family. This poses further ethical challenges in addition to implications for the workload of the relevant health service. iv. Diversity in society – with advances in prenatal genetic testing one could argue that we are witnessing a move toward a designed population where all are perfect and there is limited disability or diversity. This has wider social and theological implications and could mean an alteration of the human race as a whole, so must be considered as technologies advance further in their precision and sophistication.

Conclusions

Over a lifetime, the field of genetic medicine has advanced at a dramatic rate, which was unanticipated when scientists first used light microscopy to assess human chromosomes. Prenatal identification of chromosomal and genetic abnormalities is important for counseling on the prognosis of an index pregnancy and for obtaining information for future pregnancies. With advances in modern technologies, such as NGS, it is now

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Section 1: General Principles

possible to sequence prenatal DNA to a resolution of one base pair and thus make discoveries that will further our understanding of the etiology underlying fetal structural anomalies. Clinicians who request genetic investigations (including CMA and NGS) must be aware of the benefits and pitfalls that might ensue from testing and see that adequate pre- and post-test counseling for parents is provided. As NGS techniques such as

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[2] Genomics England. 2018. 100,000 Genomes Project. https:// www.genomicsengland.co.uk

[10] Mackie FL, Hemming K, Allen S, Morris RK, Kilby MD. The accuracy of cell-free fetal DNA-based non-invasive prenatal testing in singleton pregnancies: a systematic review and bivariate meta-analysis. BJOG. 2017; 124: 32–46.

[3] Lord J, McMullan DJ, Eberhardt RY, Rinck G, Hamilton SJ, Quinlan-Jones E, et al. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet. 2019; 393: 747–57.

[11] Gil MM, Accurti V, Santacruz B, Plana MN, Nicolaides KH. Analysis of cellfree DNA in maternal blood in screening for aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol. 2017; 50: 302–14.

[4] Fetal Anomaly Screening Programme Handbook. London: Public Health England, 2018.

[12] Hui L, Tabor A, Walker SP, Kilby MD. How to safeguard competency and training in invasive prenatal diagnosis: ‘the elephant in the room’. Ultrasound Obstet Gynecol. 2016; 47: 8–13.

[5] Nicolaides KH. Nuchal translucency and other first-trimester sonographic markers of chromosomal abnormalities. Am J Obstet Gynecol. 2004; 191: 45–67. [22] Wolfson Institute of Preventive Medicine. The Combined Test. https:// www.qmul.ac.uk/wolfson/services/ antenatal-screening/screening-tests/ combined-test [6] Chiu RW, Lo YM. Clinical applications of maternal plasma fetal DNA analysis: translating the fruits of 15 years of research. Clin Chem Lab Med. 2013; 51: 197–204. [7] Gil MM, Brik M, Casanova C, MartinAlonso R, Verdejo M, Ramírez E, Santacruz B. Screening for trisomies 21 and 18 in a Spanish public hospital: from the combined test to the cell-free DNA test. J Matern Fetal Neonatal Med. 2017; 30: 2476–82. [8] Vinante V, Keller B, Huhn EA, Huang D, Lapaire O, ManegoldBrauer G. Impact of nationwide health insurance coverage for non-invasive prenatal testing. Int J Gynaecol Obstet. 2018; 141: 189–93. [9] Lewis C, Hill M, Silcock C, Daley R, Chitty LS. Non-invasive prenatal testing for trisomy 21: a cross-sectional survey

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WES are introduced widely it is essential that other medical specialties are educated in their application and integrate with their local clinical genetics service. Prenatal diagnosis is a unique sub-specialty that requires a rapid turnover of results and testing which is obtainable for all potential patients, thus the emphasis must be on choosing the right test, at the right time, and for the right patient.

[13] Persson M, Cnattingius S, Villamor E, Söderling J, Pasternak B, Stephansson O, Neovius M. Risk of major congenital malformations in relation to maternal overweight and obesity severity: cohort study of 1.2 million singletons. BMJ. 2017; 357: j2563. [14] Chitty LS. Cell-free DNA testing: an aid to prenatal sonographic diagnosis. Best Pract Res Clin Obstet Gynaecol. 2014 ; 28 : 453–66. [15] Ogilvie CM, Lashwood A, Chitty L, Waters JJ, Scriven PN, Flinter F. The future of prenatal diagnosis: rapid testing or full karyotype? An audit of chromosome abnormalities and pregnancy outcomes for women referred for Down’s Syndrome testing. BJOG. 2005; 112: 1369–75. [16] Stosic M, Levy, B, Wapner R. The Use of Chromosomal Microarray Analysis in Prenatal Diagnosis. Obstet Gynecol Clin North Am. 2018; 45: 55–68. [17] Best S, Wou K, Vora N, Van der Veyver IB, Wapner R, Chitty LS. Promises, pitfalls and practicalities of prenatal whole exome sequencing. Prenat Diagn. 2018; 38: 10–19.

[18] International Society for Prenatal Diagnosis, Society for Maternal Fetal Medicine, Perinatal Quality Foundation. Joint Position Statement from the International Society for Prenatal Diagnosis (ISPD), the Society for Maternal Fetal Medicine (SMFM), and the Perinatal Quality Foundation (PQF) on the use of genome-wide sequencing for fetal diagnosis. Prenat Diagn. 2018; 38: 6–9. [19] Luthardt FW, Keitges E. Chromosomal Syndromes and Genetic Disease. In Encyclopedia of Life Sciences. Chichester: John Wiley & Sons, 2001. [20] Nadler HL, Gerbie AB. Role of amniocentesis in the intrauterine detection of genetic disorders. N Engl J Med. 1970; 282: 596–9. [21] Nicolini U, Lalatta F, Natacci F, Curcio C, Bui TH. The introduction of QF-PCR in prenatal diagnosis of fetal aneuploidies: time for reconsideration. Hum Reprod Update. 2004; 10: 541–8. [23] Ockeloen CW, Willemsen MH, de Munnik S, van Bon BW, de Leeuw N, Verrips A, et al. Further delineation of the KBG syndrome phenotype caused by ANKRD11 aberrations. Eur J Hum Genet. 2015; 23: 1176–85. [24] Hillman SC, McMullan DJ, Hall G, Togneri FS, James N, Maher EJ, et al. Use of prenatal chromosomal microarray: prospective cohort study and systematic review and metaanalysis. Ultrasound Obstet Gynecol. 2013; 41: 610–20. [25] Robson SC, Chitty LS, Morris S, Verhoef T, Ambler G, Wellesley DG, et al. Evaluation of array comparative genomic hybridisation in prenatal diagnosis of fetal anomalies: a multicentre cohort study with cost analysis and assessment of patient, health professional and commissioner preferences for array comparative genomic hybridisation. Efficacy Mech Eval. 2017; 4(1).

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Chapter 4: Human Genetics and Fetal Disease: Assessment of the Fetal Genome

[26] Hillman SC, McMullan DJ, Silcock L, Maher ER, Kilby MD. How does altering the resolution of chromosomal microarray analysis in the prenatal setting affect the rates of pathological and uncertain findings? J Matern Fetal Neonatal Med. 2014; 27: 649–57. [27] Wapner RJ, Levy B, Ballif BC, Eng CM, Zachary JM, Savage M, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012; 367: 2175–84. [28] Wapner RJ, Zachary J, Clifton R. Change in classification of prenatal microarray analysis copy number variants over time [abstract]. Prenat Diagn. 2015; 35 (Suppl. S1): 1–26. [29] Xia Y, Yang Y, Huang S, Wu Y, Li P, Zhuang J. Clinical application of chromosomal microarray analysis for the prenatal diagnosis of chromosomal abnormalities and copy number variations in fetuses with congenital heart disease. Prenat Diagn. 2018; 38: 406–413. [30] Egloff M, Hervé B, Quibel T, Jaillard S, Le Bouar G, Uguen K, et al. Diagnostic yield of chromosomal microarray analysis in fetuses with increased nuchal translucency: a French multicenter retrospective study. Ultrasound Obstet Gynecol. 2017; 52: 715–21. [31] Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17: 405–24. [32] Society for Maternal-Fetal Medicine (SMFM). The use of chromosomal

microarray for prenatal diagnosis. Am J Obstet Gynecol. 2016; 215: B2–9. [33] American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 581: the use of chromosomal microarray analysis in prenatal diagnosis. Obstet Gynecol. 2013; 122: 1374–7. [34] Armour CM, Dougan SD, Brock JA, Chari R, Chodirker BN, DeBie I, et al. Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada. J Med Genet. 2018; 55: 215–221. [35] Gardiner C, Wellesley D, Kilby MD, Bronwyn K, on behalf of the Joint Committee on Genomics in Medicine (2015). G144: Recommendations for the use of chromosome microarray in pregnancy. https://www.rcpath.org/ uploads/assets/uploaded/bdde58eb4852-4ce8-95f6325a71c3d550.pdf [36] Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, et al. Clinical whole-exome sequencing for the diagnosis of Mendelian disorders. N Eng J Med. 2013; 369: 1502–12. [37] Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015; 519: 223–8. [38] Ku CS, Naidoo N, Pawitan Y. Revisiting Mendelian disorders through exome sequencing. Hum Genet. 2011; 129: 351–70. [39] Chandler N, Best S, Hayward J, Faravelli F, Mansour S, Kivuva E, et al. Rapid prenatal diagnosis using targeted exome sequencing: a cohort study to assess feasibility and potential impact

on prenatal counseling and pregnancy management. Genet Med. 2018; 20: 1430–7. [40] Quinlan-Jones E, Lord J, Williams D, Hamilton S, Marton T, Eberhardt RY, et al. Molecular autopsy by trio exome sequencing (ES) and postmortem examination in fetuses and neonates with prenatally identified structural anomalies. Genet Med. 2018; 21: 1065–73. [41] Carss KJ, Hillman SC, Parthiban V, McMullan DJ, Maher ER, Kilby MD, Hurles ME. Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasound. Hum Mol Genet. 2014; 23: 3269–77. [42] Talkowski ME, Ordulu Z, Pillalamarri V, Benson CB, Blumenthal I, Connolly S, et al. Clinical diagnosis by wholegenome sequencing of a prenatal sample. N Engl J Med. 2012; 367: 2226–32. [43] Bodian DL, Klein E, Iyer RK, Wong WS, Kothiyal P, Stauffer D, et al. Utility of whole-genome sequencing for detection of newborn screening disorders in a population cohort of 1,696 neonates. Genet Med. 2016; 18: 221–30. [44] American College of Obstetricians & Gynecologists Committee on Genetics. Committee Opinion No. 581: the use of chromosomal microarray analysis in prenatal diagnosis. Obstet Gynecol. 2013; 122: 1374–7 [45] Joint Committee on Medical Genetics (2011). Consent and confidentiality in clinical genetic practice: Guidance on genetic testing and sharing genetic information. https://www.bsgm.org.uk/ media/678746/consent_and_ confidentiality_2011.pdf

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Section 1 Chapter

5

General Principles

Interventions in Pregnancy to Reduce Risk of Stillbirth Alexander Heazell and Vicki Flenady

Stillbirth remains a global health challenge, with more than 2.6 million stillbirths per year [1]. Although only 2% of the global burden of stillbirths is in high-income countries (HICs), with virtually no improvement in rates for over two decades, action in HICs is urgently needed [2]. There is a six-fold difference between the highest and lowest rates (Ukraine 8.8 stillbirths per 1,000 births after 28 weeks vs. Iceland 1.3 stillbirths per 1,000 births). As well as variation between countries it is well established that there is variation within countries, with women from indigenous or minority ethnic groups, migrant populations or socioeconomically deprived groups as well as women at extremes of maternal age being at increased risk of stillbirth [2]. The disparity between and within countries suggests that more could be done in HICs to reduce stillbirth rates: this includes reducing the frequency of substandard care recurrently described in Confidential Enquiries into Stillbirth and implementing strategies to mitigate the increased risk of stillbirth in specific groups of women [3, 4]. Risk factors for stillbirth in HICs have been investigated in various epidemiological studies, some using birth registries, cohort or case-control designs. It has been possible to conduct systematic reviews and meta-analyses of observational studies to better understand these risk factors. In 2011, Flenady et al. conducted a systematic review of risk factors for stillbirth in HICs [5]. This described a series of risk factors for stillbirth including those present prior to pregnancy, including: cigarette smoking (adjusted odds ratio [aOR] 1.36), diabetes (aOR 2.90), hypertension (aOR 2.58), maternal age >35 (aOR 1.65), overweight (aOR 1.23), and obesity (aOR 1.63) [5]. In addition, there are risk factors that develop during pregnancy, e.g. fetal growth restriction (FGR), lethal congenital anomalies, reduced fetal movements (RFM), and obstetric cholestasis (OC). Arguably risk factors that develop during pregnancy have greater relevance as only 19% of women who had a stillbirth had risk factors present at their antenatal booking visit [6]. Critically, the suboptimal screening for and management of conditions which develop in pregnancy (e.g. FGR, RFM and gestational diabetes) has been highlighted in two Confidential Enquiries in the UK carried out approximately 15 years apart [4, 7]. Thus, it is important to assess a mother’s risk status for stillbirth (and other adverse pregnancy outcomes) at her booking visit and to reassess this at subsequent antenatal visits (and for

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women to have antenatal visits at appropriate frequencies). This chapter will address risk factors present in the antenatal period and how these may be managed in order to reduce stillbirth (see Table 5.1).

Obstetric Cholestasis OC describes a condition where there are elevated bile acids in maternal serum; it may present with itching in the absence of a rash (although excoriation marks may be evident). Classically the itching is described as being on the mother’s hands and feet. The risk of stillbirth in OC appears to be related to the level of bile acids in maternal serum. A study of 669 women with severe OC found that women with bile acids over 40 µmol/L were at the highest risk of stillbirth, with a 2.58-fold increased risk (95% confidence interval [CI] 1.03–6.49) [8]. Logistic regression analysis found that doubling of bile acid levels was associated with a 200% increase in stillbirth. Another study of 487 women found that severe OC (bile acids >100 µmol/L) was associated with an increased risk of composite adverse neonatal outcome [adjusted risk ratio (aRR) 5.6; 95% CI 1.3–23.5], while elevations 30

1.6 (1.4–2.0)

>25 Pre-existing diabetes Pre-existing hypertension Pre-eclampsia Eclampsia

-

1.2 (1.1–1.4)β

-

-

1.6 (1.4–2.0)β

-

8–18 2.9 (2.1–4.1) 2.6 (2.1–3.1) 1.6 (1.1–2.2)

2–3 5–10 3.1

10 β

7.6

β

10.4

1.6 (1.1–2.2)

β

2.6

β

2.1

2.9 (2.1–4.1) 2.6 (2.1–3.1)

2.2 (1.5–3.2)

0.1

2.2 (1.5–3.2)

SGA ( 2SD MV Z score > 3

LV long-axis Z score > 0 LV short-axis Z score > 0 MV Z score > 0 2

Monophasic MV inflow Left-to-right FO shunting Bidirectional pulmonary venous waveforms MR gradient > 20 mmHg

LV function capable of generating 10 mmHg AoV 15 mmHg MR

AoV, aortic valve; FO, foramen ovale; LV, left ventricle; LVOT, left ventricular outflow tract; MR, mitral regurgitation; MV, mitral valve.

Table 15.2 Linz criteria for fetal aortic valvuloplasty

Biventricular outcome n=10

Univentricular outcome n=5 0.28 ( 2.86–1.64)

P-value

LV long-axis z-score

0.95 ( 0.99–2.1)

0.014

LV/RV length ratio

1.16 (0.95–1.56)

0.86 (0.64–1.19)

0.008

Normalized MV inflow duration

0.34 (0.23–0.36)

0.23 (0.13–0.44)

0.143

Biphasic MV inflow

8

2

LV, left ventricle; MV, mitral valve; RV, right ventricle. Table adapted from Arzt et al. [39].

compared in a hypothetical situation (where no fetal intervention was performed) with the selection criteria to determine their predictive ability [40]. While the smaller cohort reported the modified criteria to be useful, albeit only 10 had a reported circulatory outcome, the cohort of 80 with circulatory outcomes did not. In the larger study, 40 fetuses showed characteristics of emerging HLHS, with 13 achieving a BV circulation with no fetal intervention. Moreover, 12 of the 40 also satisfied the threshold criteria to be good enough to achieve a BV circulation, and this was achieved in 5 that had a BV outcome without fetal intervention [25].

Interatrial Septostomy and Stenting A degree of interatrial restriction is helpful in the newborn period in cases of borderline-sized left hearts as it preloads the left ventricle and encourages its growth, but a severely restrictive foramen ovale may develop in utero and impact severely on perinatal morbidity and mortality because secondary pulmonary damage occurs [9, 14]. This pathology may be seen in AoS and HLHS. In AoS, more frequently the high left atrial pressure closes the foramen flap, and this may open spontaneously following successful fetal aortic valvuloplasty. However, when the atrial septum is thickened, the main technical difficulty is

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being able to create a sufficient sized atrial defect to prevent pulmonary venous hypertension and optimize the neonate’s condition at delivery [13]. This must be balanced against the risk of tamponade following perforation of the relatively thinwalled atrium and the possibility of septal defect closure (Figure 15.4). Several groups have placed stents across the foramen ovale with varying degrees of short-term success [41]. Unfortunately, experience in animal models has not resulted in improved procedural success in the human fetus to date [41]. In the absence of a safe and successful fetal intervention, clinical decisions include whether a repeat fetal procedure is justified in later pregnancy if the perforation closes or the stent occludes, or whether early delivery with immediate surgical atrial septectomy might be the better option.

Critical Pulmonary Stenosis and Pulmonary Atresia with Intact Ventricular Septum In PAIVS, selection criteria for a fetal valvuloplasty appear at first to be more straightforward. Classically the right ventricle is composed of 3 morphological regions: the inlet – the tricuspid valve; the trabecular portion – the ventricular cavity; and the outlet portion – the infundibular region and pulmonary

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Chapter 15: In Utero Intervention for Cardiac Disease

valve. Using this tripartite method of evaluation, those with a unipartite and most with a bipartite right ventricle will go along a postnatal single ventricle surgical pathway. Fetal Zscores and composite scores for the right heart have been developed and tested [46–48]. The response of fetal hearts with a bipartite anatomy to fetal valvulopasty in the mid-second trimester has been described in two small series [48, 49]. Tulzer and colleagues reported good technical success and improved function that correlated with an increased likelihood of a BV circulation compared with historical natural history reports; however, others have not shown improved post-procedural function, nor a correlation with eventual circulation [48]. No attempts have been reported in hearts with coronary fistulae in these series.

Cardiac Pacing Complete heart block develops in about 2% of fetuses of antiRo positive pregnancies where mothers may have connective tissue disease. It is associated with significant myocardial disease and severe cardiac dysfunction, with development of hydrops and fetal demise in about 9% of affected fetuses [16]. The development of a small fetal pacing system has made cardiac pacing a therapeutic possibility [22]. This may be helpful in the management of a preterm fetus with hydrops before 34 weeks, but after this time it is debatable whether it is better to deliver the fetus prematurely and pace. It is not known whether early elective pacing might improve long-term ventricular function in the human fetus. Fetuses born at term with complete heart block generally do well in the short term, although at least 70% are paced by three months [15], so it is likely that this technique would only be offered for early gestation fetuses with emerging hydrops and for those with heart rates below 55 beats per minute [15, 16].

Maternal Hyperoxygenation Maternal hyperoxygenation (MH) administered for 15 minutes has been used to test the responsiveness of the pulmonary bed in fetuses with a restrictive or closed interatrial septum where a single ventricle surgical pathway is anticipated [2, 3]. However a new role for oxygen therapy is proposed to increase leftsided cardiac structures in cases where they appear borderline in size and may be associated with coarctation of the aorta. Proponents of MH administer oxygen daily for several hours over several weeks from about 30 gestational weeks until term. Small series reports [4, 50] have shown unconvincing incremental cardiac growth and no convincing improvements in outcome when applied to small heterogenous cohorts, without control data. However recently growth and functional outcomes have been reported from a controlled study comprising fetuses enrolled with suspicion of CoA and treated either with MH or maternal air administration along with a second control cohort of normal fetuses [5, 6]. These studies report improved growth of cardiac structures and improved

myocardial deformation indices in treated fetuses compared with those given oxygen, and fewer fetuses required postnatal surgery after MH. Despite these promising preliminary results, it remains unclear how the fetuses were selected to MH or air, and within those receiving MH there was a sub-group that did not increase pulmonary blood flow in response to MH. While they report no adverse events, oxygen is a powerful drug and there are concerns about its safety [24]. Moreover, diagnostic precision of CoA in the fetus is poor and there is concern that fetuses that would not develop CoA might be treated in future studies and good outcomes from MH assumed. Thus its incorporation into clinical practice should be cautious and its future role determined by a large, well-designed RCT.

Which Cases Are Not Suitable for Fetal Cardiac Intervention? Echocardiographic prediction of myocardial mineralization or endocardial fibroelastosis (EFE) is not thought to be reliable, but there are cases where the LV appears to be highly mineralized and stiff. This is an additional risk factor for tamponade, so should such cases be avoided (Figure 15.2)? The rationale behind treatment is to allow improved diastolic function and ventricular filling and to promote normal division of myocardial cells during the remainder of fetal life, thus increasing the proportion of healthy myocardial cells in the myocardium before delivery, which may alter future outcome. Such an improvement would theoretically be advantageous for a child, even if eventual left-sided morphology is too small for a BV management pathway after birth. Right ventricular to coronary artery fistulae are detected in up to a third of fetuses with PAIVS and in about 46% investigated in postnatal series [36]. The majority of fetuses with large fistulous communications have unipartite right ventricles and so are unlikely to achieve a BV circulation. These would not be considered for a fetal intervention, however, some fistulae are small or the right ventricle is a reasonable size and so the impact on the choice of postnatal circulation is uncertain. The importance of fistulae is two-fold. Firstly, the coronary circulation depends in part on maintenance of the high pressure in the hypertrophied right ventricular cavity, and after birth, if the pulmonary valve is opened and the right ventricular pressure falls, there may be coronary steal with compromise of myocardial perfusion and infarction. Secondly, high-pressure retrograde flow in the coronary system leads to stenosis and atresia of the coronary arteries and may result in fatal myocardial infarction in the neonatal period [34]. Although fistulae are readily identified prenatally, the gold standard of diagnosis of a right ventricular-dependent coronary circulation is postnatal angiography, and so a degree of uncertainty exists until this can be performed. However, as these babies are at increased risk of neonatal death, an argument could be made for fetal intervention, the rationale being that early decompression of the high-pressure right ventricle may allow regression of the fistulae and improve survival.

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Section 2: Fetal Disease: Pathogenesis and Treatment

Because fetal ventricular pressures are almost equal, opening the right ventricular outflow tract in utero will not result in coronary steal. After delivery, if a right ventricular-dependent coronary circulation is felt to be present, one option might be to plan for a surgical ligation or coil closure of the fistula in the perinatal period before steal occurs, perhaps at the same time as the placement of a systemic to pulmonary artery shunt.

Recognized Benefits of Fetal Intervention Hemodynamic Improvement Fetal aortic valvuloplasty has been shown to alter hemodynamics [24]. However, it is uncertain whether this can predict normal diastolic function in childhood. Persistent pulmonary hypertension, in part secondary to left ventricular damage, is an important problem leading to significant long-term morbidity and childhood mortality [9]. Pulmonary valvuloplasty has been performed for cases of pulmonary atresia with intact septum or critical PS complicated by fetal hydrops and circulatory difficulties. Decompressing the right ventricle by opening the pulmonary valve has led to a decrease in tricuspid regurgitation, albeit temporary in some cases, sufficient to improve the quality of the fetal circulation and allow increased maturity at delivery, which may improve perinatal survival [11, 48]. Opening a restrictive IAS can help to normalize pulmonary venous waveforms and may encourage more normal development, thus optimizing lung function in the perinatal and perioperative periods (Figure 15.4).

Functional Improvement Tissue Doppler studies made before and immediately after fetal valvuloplasty have been shown to correlate with circulatory outcomes in a cohort of 23 live-born fetuses [51]. In this study, improved left ventricular filling pressure was a good predictor of a future BV circulation, as was a reduction in the Tei index. Significant post-procedural improvements in function were not identified in a smaller series by others, nor could they show correlation with BV or UV circulation. However, the spherical LV was associated with worse diastolic function and more likely to have endocardial fibroelastosis. Therefore despite better Z-scores for inlet ventricular length, the increased sphericity makes these hearts less likely to achieve a BV outcome [49].

Ventricular and Valvar Growth There is no evidence that successful fetal valvuloplasty promotes significant growth of the mitral valve or left ventricle [40]. This supports the principle that fetal AoS is not confined to the valve, but that the disease process potentially involves all left-sided cardiac structures and includes the deposition of endocardial fibroelastosis. This extensive pathology may reduce the likelihood of a successful BV outcome, in spite of a technically successful fetal procedure and extensive postnatal surgery [10, 24, 27].

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In right heart obstructive disease, growth of the tricuspid valve and right ventricle in fetuses may be better when there is tricuspid regurgitation and a high right atrial pressure score [47]. Following successful fetal valvuloplasty, relief of the pulmonary valve obstruction leads to a better appreciation of the anatomy and size of the tricuspid valve and right ventricle, because of reduced afterload and better filling. The preprocedure measurements are likely to be under-estimated and therefore a good initial ‘response’ to fetal valvuloplasty is identified. However despite improved flow through the valves, growth velocities in the right heart are low compared with normal fetuses [48].

Complications and Risks of Fetal Therapy Early fetal valvuloplasties had mixed success, mostly because the catheter equipment available was not suitable for the small fetal heart. Technical improvements have led to renewed interest in fetal therapy and most programs report above 80% technical success using coronary balloons [24, 39–44, 48, 49]. This is usually defined as the passage of a balloon across a valve followed by sonographic evidence of new forward flow and/or new regurgitation [24, 40]. The major theoretical risks are maternal (hemorrhage, respiratory, thrombotic), fetal (demise, hemorrhage, cardiac tamponade, and cerebral ischemia or hemorrhage), and miscarriage [30, 41]. There have been no reports of important maternal morbidity, although volume loading and wound hematomas were reported in early experience and associated with maternal general anesthesia [52]. If the approach is percutaneous, through a 16–18 gauge needle, the risks to the mother and of miscarriage are probably less than when using a fetoscopic approach, although the latter may have the benefits of improved imaging and access to the fetal heart. In most studies, fetal demise occurs in 5–10% of procedures, depending on the expertise of the team; however others have reported rates as high as 32%, which gives cause for concern [43, 44]. Mortality may be attributed to team inexperience, technical difficulties resulting in cardiac tamponade or cerebral hemorrhage, or the fetus being sick secondary to hydrops. The underlying pathology, for example, a heavily mineralized myocardium that fails to seal around the puncture site, is a risk factor for tamponade, which is unlikely to diminish with experience, and this complication may only be resolved by selection only of fetuses with normal echogenicity of the myocardium [30]. Even minimal hemorrhage at the time of intervention may be poorly tolerated by the fetus because of the delicate watershed area in the fetal brain, resulting in cerebral hemorrhage and substantial handicap.

Future Role of Fetal Cardiac Therapies – Designing National Programs? In some countries, national guidelines outline the role of and support for novel treatments. Updated UK guidelines exist

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Chapter 15: In Utero Intervention for Cardiac Disease

for fetal aortic and pulmonary valvuloplasty: www.nice .org.uk/search?q=fetal+valvuloplasty. Others are guided by scientific statements from professional bodies, such as the American Heart Association [53]. Sources of information are updated based on advice by experts in the field who examine current evidence and distill the risks and benefits of treatments.

Size of the Potential Study Population for Fetal Therapy When a new therapy is proposed, investigators usually benchmark it against a gold standard or current practice in the form of an RCT. One important consideration is the rarity of suitable cases of fetal semilunar valve stenosis or atresia, interatrial restriction, or isolated complete heart block. The learning curve has proven steep for some centers [43, 44, 49] and verifiable invasive measures are usually not possible as animal models have not been representative of the complexity of the disease states, and the experimental approaches are more invasive than the percutaneous approaches used successfully in humans [41, 54]. The small sample size and heterogeneity of cases reduces the power to assess fetal cardiac therapies. Some cases of aortic and pulmonary stenosis may be relatively mild at the time of screening and ultrasound signs are subtle [29]. In addition it is likely that those with extracardiac malformations and aneuploidy are more readily detected at screening but are not considered suitable for fetal therapy, while the isolated and relatively milder cases remain undetected until after birth. Poor ascertainment of the milder cases of valvular stenosis at screening has led to a bias in ascertainment, skewed to report outcomes of the more serious cases. These factors make it difficult to plan development of a regional fetal therapy cardiac program. The first challenge is to estimate the size of the population with isolated important valvar stenosis who may be detected by fetal screening programs in the first or second trimester, and determine who may benefit from a fetal intervention. The disease prevalence quoted in live-born series varies depending on the timing and nature of the postnatal investigation (clinical examination versus echocardiography). Additionally, there is a wide range of severity within each category, particularly in PS. Fetal pulmonary and aortic stenosis account for 5.5% and 4.1% respectively of fetal series similar to large populationbased studies [38]. Alternative sources of useful information include verified audits from surgical and interventional catheter procedures reported in national and international databases. The important points to factor into any calculation include that an unknown proportion of HLHS cases may have had only critical AoS at the time of the fetal anomaly screening examination and that less than one-third of suitable cases would be detected at the fetal anomaly scan. This gives a realistic estimate of about 60 cases of semilunar valvar stenosis (AoS and PS) from the 700 000 annual live births in the UK

that might be considered suitable for fetal intervention. This would be further reduced by intrauterine demise (in about 6% of fetuses with a cardiac diagnosis overall) and by families declining fetal intervention following prenatal counseling.

Procedural Modifications and Technical Developments Most fetal cardiac interventional programs successfully use a percutaneous Seldinger approach, directing a needle into the fetal heart and passing an ‘over a wire’ coronary catheter through a flexible introducer under ultrasound guidance. This may be performed under maternal general or local anesthetic. High-pressure small coronary artery catheters are now available for use with low profiles, suitable for small hearts. The earliest gestation fetus reported to undergo fetal cardiac intervention so far has been 20 weeks, and some attribute poor fetal survival to procedures performed at early gestational ages [43]. Small balloon catheters (2 mm) are available to relieve stenosis of the small aortic valve, but a larger balloon to valve ratio may be important to achieve technical success in both aortic and pulmonary stenosis [11, 39, 40, 48]. Newer equipment, suitable for valvuloplasty and fetal pacing, has been developed over the years, but both the approach and hardware needs to be minimally invasive for this to have potential for safe fetal therapy. There are acknowledged dangers of general anesthesia in pregnancy and this is avoided in most centers. However, a general anesthetic might be helpful in fetal cardiac procedures where a good fetal lie is pivotal to the success of the procedure as it relaxes the uterus and allows for a degree of manipulation. Manipulation poses the risk of placental abruption and the duration of the procedure may be longer in the anesthetized woman. Ultrasound imaging may be limited once equipment has been introduced into the uterus, and transesophageal imaging has produced spectacular ultrasound images in animals and in a human fetus undergoing intervention for a closed IAS [55]. However, transesophageal imaging is more invasive and requires a fetoscopic approach, thus increasing the risk of miscarriage and the potential for rupture of the fetal esophagus. Robotics is widely used to train surgeons in many forms of surgery and has been proposed as a more advanced way of planning cardiac procedures and introducing equipment under remote guidance into the fetal heart. It is an intriguing approach that requires further development and evaluation in the clinical setting and may aid procedures in the smaller fetus.

Case Selection and Assessment of Outcomes Although more is known about the natural history of fetal aortic stenosis in the current era, uncertainties about case selection and timing of fetal cardiac intervention remain. There is concern that fetal interventions are currently offered to those who will not benefit from them, whether it is because the ventricle is too healthy or already too damaged [24, 25, 39, 40]. The efficacy

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of a fetal intervention cannot be assessed until at least early childhood, as an initial BV outcome may become UV, and vice versa. A later change in circulation is particularly common in children operated on for right heart obstruction. In addition, institutional bias may result in predominantly BV attempts in hearts that do not justify this approach, or conversely a very conservative approach offering a Norwood to newborns with a well-developed left heart that might have supported the systemic circulation [38]. Survival and circulatory outcomes are relatively easy to document, but a formal assessment of quality of survival and neurodevelopmental outcomes is missing from most studies. We require this to increase our knowledge of the tolerance limits of the human fetal brain and guide future therapeutic endeavors.

Summary and Conclusions Fetal therapy is offered for many disorders diagnosed before birth, but while some are introduced following RCTs, others enter the clinical arena in a more piecemeal fashion. Cardiac malformations are common, with major lesions affecting about 3.5 per 1000 pregnancies; however, only a small proportion of affected fetuses are likely to benefit from an intrauterine intervention. Currently, fetal valvuloplasty is offered for severe aortic and pulmonary stenosis or atresia, perforation

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and stenting of the closed or restrictive IAS, and pacing for complete heart block, all via a percutaneous approach. Technical success is high for fetal valvuloplasty, but is not matched by biventricular outcomes. This may be attributed in part to lack of knowledge of the underlying mechanisms and factors affecting disease progression, which also contributes to the difficulty in patient selection for intrauterine therapy. The place of fetal cardiac intervention remains uncertain. It is unlikely that a borderline two-ventricle repair is better than a good univentricular repair, but there is evidence of a survival advantage in children with a BV circulation, possibly because they are less severely affected fetal cases with less secondary damage. It is certain that these problems will be more difficult to resolve than the treatment of TTTS, in part because cardiac disease is more heterogeneous. There is theoretical potential for important improvement in the rapidly growing heart if fetal therapy is successful, and even if antenatal therapy provides only a temporizing measure, some improvement in the fetal circulation and well-being may permit delivery at a more mature gestation and thus improve postnatal management and eventual outcome. This re-emerging field suffers from too many practitioners with too little experience chasing rare cases. It deserves a more rigorous scientific approach by the leaders in fetal cardiac therapy to ensure its place in future clinical practice.

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Section 2 Chapter

16

Fetal Disease: Pathogenesis and Treatment

Structural Heart Disease in the Fetus

Fetal Cerebral Consequences of Structural Heart Disease: Can These Be Ameliorated? Mike Seed

The heart is the organ most frequently affected by birth defects, and congenital heart disease (CHD) is present in almost 1% of newborns. Over the past 50 years, innovations in cardiac surgery have transformed the outcomes of children born with CHD, such that 85% of these children now survive into adulthood. As a result, our focus is shifting towards the functional outcomes of children with these common birth malformations, not least their neurodevelopmental outcomes. Over recent years, it has become clear that neurodevelopmental problems are common in the survivors of infant CHD surgery. A specific neurodevelopmental phenotype has emerged, characterized by early delays reaching motor and speech milestones, with subsequent mild cognitive impairment, impaired social interaction, and impairments in core communication skills, as well as inattention, impulsive behavior, and impaired executive function [1–3]. Those children with CHD associated with genetic syndromes such as Down syndrome, 22q11.2 deletion syndrome, Noonan syndrome and Williams syndrome, and multiple congenital anomalies such as CHARGE syndrome, are nearly always affected, with about one-third severely impaired [4]. However, in isolated but complex congenital heart lesions – such as transposition, common arterial trunk, interrupted aortic arch, tetralogy of Fallot (TOF) with pulmonary atresia and major aorto-pulmonary collateral arteries, pulmonary atresia with intact ventricular septum, hypoplastic left heart syndrome (HLHS) and tricuspid atresia – only a minority of children are completely normal in all respects. Even simpler lesions such as coarctation of the aorta, complex semilunar valve disease, atrioventricular septal defect, TOF and totally anomalous pulmonary venous connection are associated with developmental delay in more than 25% of subjects, while developmental problems are rare in simpler malformations such as septal defects and isolated semilunar valve disease. The etiology of neurodevelopmental disorders in children with CHD is still not clear. The importance of genetic determinants of brain development cannot be overstated. This is emphasized by the lack of difference in long-term neurodevelopment outcomes between children with and without heart disease associated with genetic syndromes such as Down syndrome and 22q11.2 deletion syndrome [5, 6]. In fetuses with Down syndrome, neurons fail to show normal dendritic development, yielding a ‘tree in winter’ appearance [7]. In

22q.11.2 deletion syndrome a perisylvian polymicrogyria affecting the right hemisphere suggestive of abnormal embryonic vascular development, as well as mild cerebellar hypoplasia or mega cisterna magna, are common [8]. However, the more significant delays in motor development observed in children with Down syndrome undergoing cardiac surgery compared with those with normal hearts also point to additional circulatory or surgical influences on early brain development [9]. The Boston Circulatory Arrest Study (BCAS), which was conducted in newborns with transposition of the great arteries in the 1990s, has provided us with some of our most valuable insights into the neurodevelopmental problems faced by children with CHD [10–12]. Subjects were randomized to circulatory arrest versus low flow cardiopulmonary bypass and have now been followed up with detailed developmental assessments up to 16 years of age. One of the initial observations was that intervals of circulatory arrest lasting beyond 40 minutes were found to confer an increased risk of postoperative seizures and developmental delay. Subsequent efforts to improve intra-operative neuroprotection have focused on maintaining hematocrit and pH within certain ranges during bypass [13]. However, one of the important findings that has emerged with the ongoing follow-up of the BCAS is the similarity between the outcomes of children randomized to the two different surgical approaches. Developmental problems have been common, but usually mild, with most children scoring within normal ranges for a range of neurocognitive domains, but frequently needing remedial education. The conclusion that innate factors may be more important than surgical techniques in the neurodevelopmental outcomes of children with CHD is supported by a recent meta-analysis combining data from more than 1700 children cared for at 22 surgical centers over the past 20 years [14]. This analysis confirms that, despite considerable efforts to improve perioperative brain protection in children undergoing infant surgery for CHD, there has been little improvement in neurodevelopmental outcomes, with average scores of motor development between one and two standard deviations below the mean throughout this period. In 2015, an American Heart Association (AHA) practice guideline was published making recommendations about

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neurodevelopmental surveillance and therapy in children with CHD [15]. This document identified a number of clinical risk factors for adverse neurodevelopmental outcomes, suggesting that neonates or infants with heart disease requiring open heart surgery, cyanotic CHD, prematurity, a suspected genetic abnormality or syndrome associated with developmental delay, history of extracorporeal membrane oxygenation or ventricular assist device, heart transplantation, cardiopulmonary resuscitation at any point, seizures, prolonged hospitalization or significant abnormalities on brain imaging should undergo formal and periodic neurodevelopmental assessments and early therapeutic interventions and education where indicated in order to optimize later academic, behavioral, psychosocial and adaptive functioning. The broad range of risk factors identified by the AHA scientific statement reflects the likely multifactorial etiology of developmental problems in children with CHD. With survival rates into adulthood estimated to be 85% for all CHD patients, neuropathologic material has become more difficult to collect on a systematic basis. However, prior to effective strategies for the palliation of single ventricle lesions, one neuropathologic study found combinations of hypoxicischemic lesions and intracranial hemorrhage [16]. A later study reporting on neuropathologic material obtained from children with a range of congenital cardiac abnormalities after neonatal cardiac surgery emphasized the importance of cerebral white matter injury, including periventricular leukomalacia and diffuse gliosis, although a spectrum of gray matter lesions was also present [17]. Diffuse and focal abnormalities have also been described on neuroimaging studies performed in children with CHD [18–22]. White matter injury and strokes are present on preoperative imaging in about 1 in 5 subjects, with new lesions encountered in around 50% of subjects on postoperative magnetic resonance imaging (MRI) [18, 19]. On follow-up imaging, some of the focal abnormalities are noted to resolve, but may be replaced by a prominence of cerebrospinal fluid (CSF) spaces and reduced brain volumes, sometimes referred to as brain atrophy. The presence of moderate-to-severe white matter injury predicts lower psychomotor development index at 30 months in children with transposition and single ventricle physiology, while stroke has not been associated with outcome in the setting of CHD [20]. The predominance of white matter involvement in the pattern of injury in newborns with CHD is reminiscent of preterm infants and at odds with the predominantly cortical and basal ganglia injuries seen following ischemic injury in term neonates with normal hearts. Miller et al. used diffusion tensor imaging and magnetic resonance spectroscopy to investigate brain maturation in newborns with CHD and found microstructural and metabolic abnormalities that indicate delayed development [19]. Similarly, morphologic features of delayed brain development, including a simplified pattern of cortical folding, presence of the germinal matrix and mitrating bands of glial cells and hypomyelination, reveal the brains of term newborns with CHD are similar in terms of maturation

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to the brains of late preterm infants with normal hearts [21]. Imaging features of delayed brain maturation are in keeping with neurobehavioral and electroencephalographic features of developmental delay that have been described in newborns with CHD [22, 23]. Importantly, brain immaturity at birth appears to predispose children with CHD to white matter injury in the perioperative period, while brain injury has an adverse effect on subsequent brain maturation [24]. Thus, the pathophysiology of neurodevelopmental problems in children with CHD involves a complex interplay of developmental and destructive influences that has much in common with the pathophysiology of brain disease in premature infants and has been referred to as the ‘encephalopathy of congenital heart disease’ [25]. The discovery of brain immaturity in newborns with CHD confirmed that the developmental abnormalities frequently seen later in childhood likely have their origins in the prenatal period. Evidence of impaired fetal brain growth and injury has subsequently been demonstrated by pathological and imaging studies. Hinton et al. showed histopathologic abnormalities in the white matter of second trimester fetuses terminated for HLHS, including chronic inflammation and reactive gliosis [26]. Limperopoulos et al. revealed a tailing off of total brain volume in third trimester fetuses with CHD using MRI, which was more significant in those with more severe forms of heart disease [27]. Abnormal brain growth in fetuses with tetralogy and transposition has since been confirmed by fetal MRI during the second and third trimesters [28, 29]. The demonstration of impaired brain growth and development in fetuses with CHD has raised interesting questions about their etiology. Landmark fetal sheep studies of fetal circulatory physiology performed by Abraham Rudolph and his collaborators in the latter half of the twentieth century using radioactive microspheres and intravascular catheters are still the reference for our modern understanding of the distribution of blood flow and oxygen transport across the normal fetal circulation [30]. Building on prior descriptions of the significantly lower oxygen tensions found in the arteries of fetal sheep, and the demonstration of shunts at the ductus venosus, foramen ovale and ductus arteriosus that result in a parallel fetal circulation, Rudolph and his colleagues defined a fetal circulation that has a dominant right ventricle which supplies the major contribution to the perfusion of the lower body and placenta. The majority of the flow produced by the left ventricle is directed to the head and upper extremities. A remarkable streaming mechanism ensures a reliable source of well-oxygenated blood from the placenta reaches the brain via the umbilical vein and ductus venosus to the inferior vena cava, where two columns of blood ascend towards the right atrium. Within the right atrium, a stream of well-oxygenated blood from the ductus venosus and left hepatic vein passes towards the foramen ovale and into the left heart, while the more deoxygenated blood returning from the lower body and right side of the liver passes across the tricuspid valve and out into the main pulmonary trunk. Thus, just as it is in postnatal life, the oxygen saturations are higher in the left heart than

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Chapter 16: Fetal Cerebral Consequences of Structural Heart Disease: Can These Be Ameliorated?

AAo

HEAD UPPER LIMBS

57

40

80

RV

274

16 PBF

3

MPA

85

AAo

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DA 41

LV

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LV

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75 70 29 SVC 65

146 SVC

FO 27 RA

LA DAo 52

60 IVC 55 50 45 40

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FO 127 RA

UV PLACENTA UA 29

ABDO LOWER LIMBS

Mean flow (% of CVO)

LA DAo 255

IVC UV PLACENTA UA 136

ABDO LOWER LIMBS

Mean flow (mL/min/kg)

Figure 16.1 Distribution of blood flow and oxygen saturations in the normal human late gestation fetal circulation by MRI. AAo, ascending aorta; DA, ductus arteriosus; MPA, main pulmonary artery; PBF, pulmonary blood flow; RV, right ventricle; LV, left ventricle; RA, right atrium; LA, left atrium; SVC, superior vena cava; IVC, inferior vena cava; DAo, descending aorta; UV, umbilical vein; UA, umbilical artery. From: Sun et al. New advances in fetal cardiovascular magnetic resonance imaging for quantifying the distribution of blood flow and oxygen transport: potential applications in fetal cardiovascular disease diagnosis and therapy; Echocardiography 2017 [32]

right. In the fetal sheep, this difference is about 15%, with ascending aortic saturations of about 65% and main pulmonary artery saturations of around 50%. Figure 16.1 shows the results of MRI techniques for measuring vessel flow and oxygen saturation in the normal human fetal circulation, which reveal how human fetal cardiovascular physiology is very similar to that of the sheep [31, 32]. As had been long suspected based on our understanding of fetal circulatory physiology, using this approach it has also been possible to show that the abnormal anatomical connections and obstructions to flow that characterize CHD interrupt the usual streaming of oxygenated blood from the placenta to the fetal brain, resulting in a reduction in the oxygen saturation of the blood supplied to the developing brain [33] (see Figure 16.2). Disruption of fetal streaming is compounded by reductions in total fetal oxygen delivery resulting from reduced umbilical flow and oxygen content. The former is associated with reductions in cardiac output, while the latter may be explained by the structural abnormalities that have been reported in the placentas of fetuses affected by CHD [34]. The detection of cerebral vasodilation in fetuses with CHD is in keeping with known circulatory adaptations to hypoxemia that have been observed in fetal animal models and in human fetuses affected by placental insufficiency [35–37]. In animal models, this socalled brain-sparing physiology is mediated through neuronal release of adenosine, which also down-regulates neuronal

metabolism, presumably in an attempt to protect the brain from energetic collapse [38]. At a cellular level even small reductions in cellular oxygen delivery result in a range of metabolic adaptations that result in decrements in the cell’s requirement for oxygen in a process which has been referred to as oxygen conformance [39]. Many of these adaptations are orchestrated through hypoxic inducible factor (HIF), which influences gene expression. The cell switches from aerobic to anaerobic metabolism, and there is a slowing of flux along the electron transfer chain, with a reduction of mitochondrial respiration and the production of adenosine triphosphate. In fetal mice engineered to over-express HIF, a pathway linking chronic hypoxia to hypomyelination involving Wnt signaling has been demonstrated, whereby downregulation of Wnt signaling results in arrest of premyelinating oligodendrocytes [40]. This could account for the hypomyelination observed in fetal guinea pigs subjected to chronic hypoxia induced with uterine artery ligation [41]. Chronic hypoxia also impacts cortical development, where failure of cortical folding is associated with reduced numbers of neural stem/progenitor cells in juvenile pigs, while similar changes have been observed in the brains of human newborns with CHD [42]. While oxygen is one metabolic substrate that appears to have an important influence on fetal neurodevelopment, the interruption of fetal streaming and the diminished placental perfusion and gas exchange associated with CHD may also impact the availability

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Figure 16.2 Examples of MR oximetry data obtained in late gestation fetuses with congenital heart disease. Aortic desaturation results from interruption of the normal streaming of oxygenated blood from the umbilical vein across the foramen ovale (as in hypoplastic left heart syndrome) or diversion at the ventriculo-arterial level (as in transposition and tetralogy of Fallot). From: Sun et al. Reduced fetal cerebral oxygen consumption is associated with smaller brain size in fetuses with congenital heart disease; Circulation 2015 [33]

Figure 16.3 Magnetic resonance oximetry: T2 map showing higher oxygen saturations in the umbilical vein compared with the descending aorta in a normal late gestation human fetus.

of other important substances to the developing brain. These include glucose, which is the primary substrate for brain metabolism during fetal life. It has been suggested that the absence of lactate in the brains of some fetuses with CHD is out of keeping with significant cerebral hypoxia, and that a lack of glucose may be a more significant determinant of fetal brain growth in CHD [43]. Furthermore, known hormonal influences on

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neuronal and neuroglial development, such as cortisol, which is increased in the setting of fetal growth restriction, and brainderived neurotrophic factor, thyroxine and insulin-like growth factor, which are reduced in chronic placental insufficiency, may also play a role in CHD [44]. While the relative importance of prenatal versus postnatal influences on long-term neurodevelopmental outcomes remains uncertain, abnormal brain development and injury occurring in the perinatal period do appear to have lasting sequelae. Reductions in white matter volume at birth have been linked to delays in speech development, while regional and total brain volumes that correspond to specific developmental deficits are reduced in teenagers who underwent CHD surgery during infancy [45, 46]. Diffusion tensor imaging studies performed in the adolescents from the BCAS have revealed reductions in connectivity that correspond to specific cognitive and development deficits, directly implicating the white matter injury occurring in the perioperative period in their cognitive disorders [47, 48]. However, longitudinal studies of brain development in children undergoing surgical repair of transposition in the neonatal period have revealed the potential for ‘catch-up’ growth [49]. Furthermore, early motor delays observed in children following CHD surgery have not always correlated with subsequent cognitive deficits. The potential importance of innate genetic determinants of cognitive development beyond the known syndromic conditions associated with neurodevelopmental delay (NDD) in children with CHD has been emphasized by the results of large studies using the new deeper genetic analyses such as whole exome or whole genome sequencing [50]. Using exome sequencing of 1213 CHD trios enrolled in the Pediatric Cardiac Genetics Consortium or the Pedatric Heart Network, Homsy

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Chapter 16: Fetal Cerebral Consequences of Structural Heart Disease: Can These Be Ameliorated?

Neuroprotective Interventions in Fetal CHD While there is clearly much to be learned about the mechanisms leading to neurodevelopmental problems in children with CHD, the recognition of potential in utero cerebrovascular influences on the development of the fetal brain resulting from abnormal cardiovascular physiology has led to interest in the potential for neuroprotective in utero interventions. However, to date the results of the limited number of clinical studies conducted in this field have been disappointing. The impact of fetal aortic valvuloplasty on in utero brain development in the setting of evolving HLHS has been studied in a cohort of 52 subjects treated at Boston Children’s Hospital [52]. The findings suggest that despite improving antegrade flow through the left ventricle, which might be expected to enhance the normal streaming of substrate and oxygen-rich blood from the placenta to the developing brain, there was no improvement in neurodevelopmental outcomes. Indeed, biventricular outcome was actually associated with worse developmental outcome. However, in patients with borderline left ventricular hypoplasia and valve lesions requiring multiple postnatal surgical interventions, teasing out the relative importance of fetal versus postnatal hemodynamics and brain injury is likely to be extremely challenging. The potential to modify cardiac development using transplacental oxygen has been considered by a number of investigators. Oxygen is a potent pulmonary vasodilator in the fetal circulation, and can be delivered to the fetus by increasing the concentration of maternal inspired oxygen, as shown in Figures 16.4–16.5 [53]. At least 3 studies have reported enhanced growth of underdeveloped left heart structures secondary to intermittent maternal hyperoxygenation during

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Figure 16.4 Increased umbilical vein T2 in fetuses with congenital heart disease during acute maternal hyperoxygenation. From: Porayette et al. MRI reveals hemodynamic changes with acute maternal hyperoxygenation in human fetuses with and without congenital heart disease; Prenat Diag 2016 [53]

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et al. found a significantly higher rate of pathogenic de novo mutations in the genomes of CHD subjects compared with normal controls. This was particularly evident in those children with CHD associated with other congenital malformations or NDD. In children with CHD, NDD and extra-cardiac malformations there was at least a 10-fold increase in the incidence of de novo mutations compared with those children with CHD alone. Importantly, a proportion of the mutations identified are shared by children with NDD without CHD. Thus, there is overlap between the genes controlling heart and brain development and it likely that sporadic mutations are responsible for NDD in children without recognizable syndromes. Just as genetics are likely to be important in CHD outcomes, so is the postoperative environment. For example, in a retrospective analysis of risk factors for poor neurodevelopmental outcomes in 243 children treated at Boston Children’s Hospital, only lower socioeconomic status and a diagnosis of 22q.11.2 deletion syndrome predicted a lower mean full-scale IQ, while variables such as single ventricle diagnosis, longer postoperative intensive care unit stay, and cumulative duration of hypothermic circulatory arrest approached significance as predictors of lower full-scale IQ [51].

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Figure 16.5 Acute maternal hyperoxygenation results in pulmonary vasodilation in fetuses with congenital heart disease. From: Porayette et al. MRI reveals hemodynamic changes with acute maternal hyperoxygenation in human fetuses with and without congenital heart disease; Prenat Diag 2016 [53]

the third trimester [54–56]. In one of these studies, an adverse impact on brain growth was reported, which was thought to be attributable to potential steal of cerebral blood flow from the brain into the lungs or a vasoconstrictor effect on the placental circulation [57]. One consideration in the interpretation of these findings is the observation made in fetal sheep that the vasodilator effect of increased pulmonary artery oxygen tension on the pulmonary circulation is acute, and subsides in a matter of hours [58]. Thus, continuous oxygen therapy might be expected to have a less important impact on cerebral blood flow while still increasing cerebral oxygen delivery. In acute episodes of maternal hyperoxygenation conducted in fetuses with HLHS, a degree of normalization of the middle cerebral artery Doppler pulsatility index was observed in the third trimester, which was more marked in those fetuses with a

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more vasodilated cerebral vasculature at baseline [59]. Thus, chronic maternal hyperoxygenation may provide more normal cerebrovascular physiology and therefore enhance brain growth and maturation in the setting of some forms of CHD. At least one study investigating the potential neuroprotective impact of chronic maternal oxygen therapy in the setting of single ventricle physiology in the fetus is underway in Canada. Other potentially neuroprotective agents are also being investigated in the setting of fetal CHD. Progesterone, which prolongs pregnancy and has a neuroprotective effect in brain trauma, is currently being studied in a randomized controlled trial conducted at the Children’s Hospital of Philadelphia [60, 61]. At the same institution, a radically new approach to supporting normal fetal circulatory physiology has been reported in a group of premature sheep [62]. The system provides oxygen and nutrition to the developing fetus via the umbilical vessels using an extracorporeal membrane oxygenation (ECMO) circuit. The fetus is protected from the harmful effects of oxygen and air ventilation on the immature lungs using liquid incubation. This is achieved using a continuous supply of artificially produced amniotic fluid that is continuously infused and circulated through a sealed and warmed ‘biobag.’ Animals at equivalent gestations to early preterm human infants have been supported for periods of up to 1 month on this system, revealing encouraging features of normal fetal growth and development and no evidence of brain injury. However, a second group reporting success using a similar approach found evidence of white matter injury in some animals [62]. While the sheep brain matures more rapidly than the human, and therefore may not be an ideal model for human perinatal brain development, there is an appealing similarity to normal fetal circulatory physiology intrinsic to this approach, whereby the ECMO circuit, which is entirely powered by the fetal heart, mimics placental function. It is possible that such an approach might have some relevance in the setting of fetal CHD, as the combination of prematurity or low birthweight and CHD has been shown repeatedly to

References [1] Gaynor JW, Nord AS, Wernovsky G, Bernbaum J, Solot CB, Burnham N, Zackai E, Heagerty PJ, Clancy RR, Nicolson SC, Jarvik GP, Gerdes M. Apolipoprotein E genotype modifies the risk of behavior problems after infant cardiac surgery. Pediatrics. 2009; 124: 241–250. [2] Bellinger DC, Newburger JW, Wypij D, Kuban KC, duPlessis AJ, Rappaport LA. Behaviour at eight years in children with surgically corrected transposition: the Boston Circulatory Arrest Trial. Cardiol Young. 2009; 19: 86–97. [3] Bellinger DC, Wypij D, duPlessis AJ, Rappaport LA, Jonas RA, Wernovsky G,

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confer high surgical mortality [63]. Such a system could also potentially allow for interventions to improve fetal cerebrovascular physiology in the setting of CHD by providing a safe way to recover the fetus following cardiac intervention or surgery. The investigation of applications like these would be greatly enhanced by realistic large animal models of CHD, which have hitherto been lacking. Importantly, the accurate detection of CHD in utero has been shown to reduce brain injury in newborns undergoing cardiac surgery [64]. This is attributable to the avoidance of hemodynamic instability resulting from the circulatory changes that occur in the transitional circulation. When the presence of CHD in the fetus is known, particularly in those forms of CHD in which systemic or pulmonary blood flow is likely to be dependent on patency of the ductus arteriosus, adequate preparation can be made for the delivery of neonatal care at a center experienced in providing congenital cardiac treatment. When perinatal brain injury is minimized in this way, subsequent brain development has been shown to benefit.

Conclusion In summary, there is currently no evidence to support the use of fetal interventions to improve neurodevelopmental outcomes in patients with congenital heart disease. The development of neuroprotective therapies is currently hampered by the lack of accurate animal models of fetal CHD. However, new genetic and imaging technologies are improving our understanding of the mechanisms leading to abnormal brain development in CHD and informing trials of potential therapeutic approaches to perinatal brain protection. Meanwhile new technology for recreating the fetal environment ex utero could be revolutionary for perinatal medicine in general. Based on current evidence, fetal medicine can likely benefit the neurodevelopmental outcomes of children with CHD by ensuring accurate detection of CHD by ultrasound screening and making arrangements for term delivery at a center experienced in neonatal critical cardiac care.

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Chapter 16: Fetal Cerebral Consequences of Structural Heart Disease: Can These Be Ameliorated?

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Chapter 16: Fetal Cerebral Consequences of Structural Heart Disease: Can These Be Ameliorated?

cerebrovascular resistance. Ultrasound Obstet Gynecol. 2017; 52: 473–8. [60] da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled doubleblind study. Am J Obstet Gynecol. 2003; 188: 419–24. [60] Stein DG, Wright DW, Kellermann AL. Does progesterone have neuroprotective properties? Ann Emerg Med. 2008; 51: 164–72.

[61] Partridge EA, Davey MG, Hornick MA, McGovern PE, Mejaddam AY, Vrecenak JD, et al. An extra-uterine system to physiologically support the extreme premature lamb. Nat Comm. 2017; 8: 15112.

[63] Jenkins KJ, Gauvreau K, Newburger JW, Spray TL, Moller JH, Iezzoni LI. Consensus-based method for risk adjustment for surgery for congenital heart disease. J Thoracic Cardiovasc Surg. 2002; 123: 110–18.

[62] Usuda H, Watanabe S, Miura Y, Saito M, Musk GC, RittenschoberBöhm J, Ikeda H, Sato S, Hanita T, Matsuda T, Jobe AH. Successful maintenance of key physiological parameters in preterm lambs treated with ex vivo uterine environment therapy for a period of 1 week. Am J Obstet Gynecol. 2017; 217: 457–e1.

[64] Peyvandi S, De Santiago V, Chakkarapani E, Chau V, Campbell A, Poskitt KJ, Xu D, Barkovich AJ, Miller S, McQuillen P. Association of prenatal diagnosis of critical congenital heart disease with postnatal brain development and the risk of brain injury. JAMA Pediatr. 2016; 170: e154450.

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Section 2

Fetal Disease: Pathogenesis and Treatment

Chapter

Fetal Dysrhythmias

17

Fetal Supraventricular Tachyarrhythmias: Pharmacokinetics, Modes of Action, and Results of Anti-Arrhythmic Drug Therapy Edgar Jaeggi and Nico A. Blom

Introduction Supraventricular tachycardia (SVT) belongs to the common cardiac causes of fetal heart failure and perinatal death [1]. With the arrival of ultrasound imaging to non-invasively detect cardiac anomalies before birth, the fetus has increasingly become the target of intended prenatal treatment. This includes the off-label administration of pharmaceutical agents via the maternal circulation or directly into the fetus to treat SVT. As anti-arrhythmic drugs act on one or several ion channels, the autonomous system, or both, we will start with an overview of the normal and abnormal electro-mechanical activation of the heart before discussing indications, modes of action, and effects of anti-arrhythmic therapy for fetal SVT.

Normal Electro-Mechanical Activation of the Fetal Heart The main function of the heart is to pump sufficient blood throughout the body to supply all tissues with adequate amounts of oxygen and nutrients. The cardiac pumping action underlies the control of highly specialized muscle tissue, the electrical conduction system, comprising the sinoatrial (SA) node, the atrioventricular (AV) node, and the His–Purkinje system. The role of the conduction system is to generate the electrical impulse in spontaneously depolarizing SA nodal cells that are located at the upper right atrial wall and to transmit the action potential (AP) across the fibrous ring of the AV junction and throughout the ventricles. Other than via the AV node, the atria and ventricles are electrically isolated from each other. The SA node generates electrical impulses the fastest, between 120 and 160 beats/minute (bpm) in the mid-late gestational fetus, and therefore overdrives the pacemaker potential of any other cardiac tissues that may also exhibit automatic properties. Specialized intercellular connections called ‘gap junctions’ directly link the cytoplasm of neighboring cells and permit electrical impulses and ions to rapidly spread across cardiac tissue. This allows the synchronized electro-mechanical activation of atrial and ventricular myocytes respectively in unison with each heartbeat. Related to structural differences in gap junctions, electrical conduction velocities vary among cardiac tissues and are significantly slower across the AV node

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(0.05 m/s) when compared with the working myocardium (0.5–1 m/s) and His-Purkinje system (2–4 m/s). The delay in impulse propagation across the AV node allows for sufficient time for ventricular filling prior to ventricular contraction. The repetitious cardiac mechanical actions, contraction in systole and relaxation in diastole, are orchestrated by coincident changes in the transmembrane ion currents of myocardial and pacemaker cells with each heartbeat (Figure 17.1). In the resting stage, large electrical potential gradients are upheld between extracellular and intracellular ion concentrations by the plasma membrane Na+–K+-ATPase pump, which continuously transfers Na+ to the outside of the cell in exchange for the influx of K+. The net effect is that the interior of inactive cells exhibits a negative electrical potential with respect to the positive-charged extracellular space. When the membrane potential reaches a less negative threshold of about
40 mV, due to either spontaneous depolarization of pacemaker cells or

+30 mV

1

Time 2

0 mV

3 0 AP

ERP

4

–90 mV K+ Current

Na+ Current Ca2+ Current Figure 17.1 The time course of Na+, Ca2+, and K+ currents (lower panel) during a stylized transmembrane action potential (AP; top panel) of a regular cardiomyocyte. The AP consists of 5 phases (0–4): phase 0, rapid depolarization; phase 1, early rapid repolarization; phase 2, plateau; phase 3, final rapid repolarization; and phase 4, resting membrane potential. Compared with cardiomyocytes, pacemaker cells (not shown) are less depolarized with respect to the positively charged extracellular space, are capable of spontaneous depolarization (automaticity) due to an inherent leakiness to Na+ ions, and have a slower increase in APs that are triggered by slow Ca2+ channel flux rather than by fast Na+ channels. ERP, effective refractory period.

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Chapter 17: Fetal Supraventricular Tachyarrhythmias: Pharmacokinetics, Modes of Action, and Drug Therapy

an advancing wave of electrical current, voltage-gated Na+ channels open with a sudden, rapid cellular influx of positively charged Na+ ions. This depolarizes the cell to potentials close to +20 to +30 mV in phase 0. The rate of rise and amplitude of the AP upstroke are key determinants of the electrical conduction velocity in cardiac tissues: faster conduction results from AP of greater amplitude and steeper rise. The initial upstroke is followed by a brief period of early repolarization (phase 1) due to voltage-dependent activation of transient outward K+ current and, subsequently, by a slow influx of calcium via voltage-gated L-type Ca2+ channels (phase 2). The intracellular calcium triggers the mechanical interaction of actin and myosin filaments, causing cardiac muscle contraction. After a delay, the Ca2+ channels inactivate, and the calcium is removed from the cell, while voltage-gated K+ channels open to allow the outward flow of K+ (phase 3) to repolarize and relax the cell to its pre-action resting state (phase 4). The cell becomes fully excitable again once it reaches its optimal resting membrane potential. If the cell is stimulated before reaching the resting state, it will remain either unresponsive (absolute or effective refractory) or only partly responsive (relative refractory) to an outside stimulus. The period of time during a cardiac cycle that a new AP cannot be initiated by electrical stimulation is termed the effective refractory period (ERP) of the tissue. ERP acts as a protective mechanism against arrhythmias.

Functional Characteristics of the Fetal Heart There are numerous morphological and biochemical differences that limit the functional reserve of the developing heart when compared with mature hearts [2, 3]. Firstly, a normal fetal heart rate is significantly faster than after birth. Secondly, fetal myocardium is less compliant and generates less tensile force, which impacts its ability to tolerate abnormal heart rates [4, 5]. Reasons for this include that fetal myocytes contain larger amounts of non-contractile proteins per gram of muscle fibers and, among others, less sarcoplasmic reticulum and fewer sarcomeres, mitochondria, t-tubules, and β-adrenergic receptors. Unlike the mature heart, contraction of fetal myocytes largely depends on transmembrane influx of extracellular Ca2+ while calcium-induced Ca2+ release from the sparse sarcoplasmic reticulum is negligible. Fetal myocardial energy production depends on glucose as the virtually exclusive substrate, and glycogen storage in the few immature mitochondria is rapidly depleted during a prolonged period of tachycardia [6]. The sympathetic nervous system, which acts to increase cardiac contractility, becomes functional later in fetal development when compared with the slowing actions of parasympathetic stimulation [7]. Due to the above maturational differences, the fetal heart physiologically functions close to its maximal performance to be able to uphold a combined cardiac output of ~450 ml/kg/ minute during gestation. Any significant increase in fetal heart rate will shorten ventricular diastolic filling, reducing cardiac output and causing venous congestion [8, 9]. Yet, even a small

increase in fetal systemic venous pressure by a few mmHg secondary to a protracting tachyarrhythmia results in a significant shift of intravascular venous fluid into the extravascular space, with the build-up of cavity effusions and skin edema [10, 11]. Fetal hydrops secondary to tachycardia-mediated heart failure is an important predictor of an adverse pregnancy outcome and, even with treatment, is associated with a perinatal mortality rate of about 20% [12, 13]. On the other hand, fetal tachyarrhythmias are reversible conditions with efficient anti-arrhythmic medication and fetal hydrops typically resolves within days to weeks once the cardiac rhythm is normalized.

Mechanisms of Fetal SVT SVT is commonly used as term for the subtypes of tachyarrhythmias that either originate from atrial tissue other than the SA node or involve atrial tissue in the arrhythmia mechanism, namely: • Atrial flutter (AF) • Atrial ectopic tachycardia (AET; also known as focal atrial tachycardia) • AV reentrant tachycardia (AVRT) • Permanent junctional reciprocating tachycardia (PJRT) Atrial tachycardias, comprising AF and AET, do not depend on AV conduction tissue for them to be sustained. Atrial flutter results from a circular reentrant pathway within the atrial wall, while the AV node is not part of the circuit. AF typically occurs during the third trimester and does not recur after birth once the arrhythmia is terminated [14]. Atrial rates range between 300 and 500 bpm (average 440 bpm) and this is commonly associated with 2:1 AV conduction with ventricular rates of 150–250 bpm (average 220 bpm). Slower ventricular rates may be observed in AF with slower (3:1 or 4:1) AV conduction. Atrial ectopic tachycardia or focal atrial tachycardia arises when an atrial pacemaker displays enhanced automaticity and surpasses the sinus rate. AET can already manifest during the first trimester and typical presents as persistent atrial tachycardia between 180 and 240 bpm (average 210 bpm) with 1:1 AV conduction. Intermittent changes in tachycardia rate with ‘warming-up and cooling down’ and/or with variable AV conduction may be observed. AV reentrant tachyarrhythmias involve atrial and ventricular myocardium, the AV node, and one or several accessory pathways in the reentrant circuit. Pharmacological alteration of the conduction and refractoriness properties of any of these tissues may terminate AV reentry. The usual (orthodromic) AV reentrant circuit is from the atria down the AV node and from the ventricle up the accessory pathway. If the pathway is rapidly retrograde conducting, which is the case for most affected cases, the atrial contraction closely follows the ventricular contraction. This explains the typical short VA (echocardiography) or short RP (ECG) pattern of AVRT. AVRT may manifest any time after the first trimester as an intermittent or persistent 1:1 tachycardia between 170 and 300 bpm

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(average 250 bpm). If the arrhythmia is intermittent, AVRT is seen terminating with AV block after an atrial event. Permanent junctional reciprocating tachycardia is a rare form of AV reentry. It is mediated by a slowly backwards conducting accessory pathway (long VA/RP pattern). PJRT is often incessant and relatively slow (about 200 bpm) but due to its persistence may induce cardiac dysfunction. AVRT (60%) and AF (30%) account for 90% of referrals with fetal SVT, with AVRT being by far the most prevalent cause of arrhythmia-mediated fetal hydrops [15]. AF is not infrequently accompanied by AVRT and other arrhythmias associated with an accessory pathway [16]. Both arrhythmias are readily discerned from fetal M-Mode and Doppler echocardiographic tracings (see Chapter 18) [14, 17–19]. Unlike, AET and PJRT both present as long VA tachycardia and their echocardiographic differentiation may not be possible before birth.

fetus is near-term, current American Heart Association (AHA) guidelines [20] recommend pharmacological treatment either to terminate or to slow down the tachycardia for a) SVT complicated by cardiac dysfunction or hydrops; b) SVT (other than AF) 200 bpm that is present >50% of observation time; and c) AF present >50% of observation time. These treatment indications are largely based on the odds of arrhythmia-related fetal cardiac decompensation and death. Yet, persistent or intermittent SVT to birth usually requires a delivery by cesarean section as it is not possible to interpret the fetal heart rate during labor as a marker of fetal well-being. By comparison, prenatal conversion to a normal fetal cardiac rhythm allows a normal vaginal delivery without the need of postnatal cardioversion. With this rationale in mind, we have been offering transplacental anti-arrhythmic treatment to most mothers with a fetal SVT unless the tachycardia is brief and/or detected after 37 gestational weeks.

Management of Fetal SVT

Anti-arrhythmic Medication

Due to the functional limitations of the immature heart to tolerate persistently fast heart rates, any detection of a protracted fetal tachycardia >180 beats/minute (bpm) constitutes a medical emergency and should trigger an expedited referral to a fetal medicine specialist. As a general rule, the risk of hemodynamic compromise and death increases if the tachycardia is fast and/or persistent and detected at a younger gestational age. Upon any patient encounter it is therefore relevant to clarify the hemodynamic impact and characteristics of the arrhythmia and to then decide on the most appropriate perinatal management. Available care options include (a) close fetal surveillance without (immediate) treatment; (b) institution of fetal anti-arrhythmic therapy; or (c) delivery for postnatal treatment. The decision on care should be based on a variety of factors, including the gestational age at arrhythmia diagnosis, tachycardia characteristics, presence and severity of fetal compromise, maternal health, and the possible risks and benefits of the fetal therapy versus that of an earlier delivery, usually by cesarean section. Unless the arrhythmia is very fast, close observation without drug therapy may be a safe approach for the fetus with infrequent, brief tachycardia episodes, as heart failure will rarely ensue. Conversely, fetuses with incessant AVRT develop heart failure with hydrops more rapidly and more often when compared with other tachyarrhythmias. In retrospective studies, 40% of fetuses with AVRT presented with hydrops, and this was associated with a perinatal mortality rate between 21% and 27%, while the rate of perinatal mortality was