2. To Veena, Abir, Anita and Niki for their love and
patience
3. Newborn Surgery Second Edition Edited by Prem Puri MS FRCS
FRCS (Ed) FACS Newman Clinical Research Professor, University
College Dublin Consultant Paediatric Surgeon, Our Ladys Hospital
for Sick Children and National Childrens Hospital, Dublin, Ireland
Director of Research, Childrens Research Centre, Our Ladys Hospital
for Sick Children, Dublin, Ireland A member of the Hodder Headline
Group LONDON
4. First published in Great Britain in 1996 by
Butterworth-Heinemann Ltd This edition published in 2003 by Arnold,
a member of the Hodder Headline Group, 338 Euston Road, London NW1
3BH http://www.arnoldpublishers.com Distributed in the United
States of America by Oxford University Press Inc. 198 Madison
Avenue, New York, NY 10016 Oxford is a registered trademark of
Oxford University Press 2003 Arnold All rights reserved. No part of
this publication may be reproduced or transmitted in any form or by
any means, electronically or mechanically, including photocopying,
recording or any information storage or retrieval system, without
either prior permission in writing from the publisher or a licence
permitting restricted copying. In the United Kingdom such licences
are issued by the Copyright Licensing Agency: 90 Tottenham Court
Road, London W1T 4LP Whilst the advice and information in this book
are believed to be true and accurate at the date of going to press,
neither the author[s] nor the publisher can accept any legal
responsibility or liability for any errors or omissions that may be
made. In particular (but without limiting the generality of the
preceding disclaimer) every effort has been made to check drug
dosages; however it is still possible that errors have been missed.
Furthermore, dosage schedules are constantly being revised and new
side effects recognized. For these reasons the reader is strongly
urged to consult the drug companies printed instructions before
administering any of the drugs recommended in this book. British
Library Cataloguing-in-Publication Data A catalogue record for this
book is available from the British Library Library of Congress
Cataloging-in-Publication Data A catalog record for this book is
available from the Library of Congress ISBN 0 340 76144 X (hb) 2 3
4 5 6 7 8 9 10 Publisher: Joanna Koster Development Editor: Michael
Lax Production Editor: James Rabson Production Controller: Bryan
Eccleshall Cover Design: Stewart Larking Typeset in Great Britain
by Phoenix Photosetting, Chatham, Kent Printed and bound in Great
Britain by CPI Bath
5. Contents Preface xi Contributors xiii PART 1 GENERAL 1 1
Embryology of malformations 3 Dietrich Kluth, Wolfgang Lambrecht
and Christoph Bhrer 2 Prenatal diagnosis of surgical diseases 15
Tippi C. MacKenzie and N. Scott Adzick 3 Fetal and birth trauma 27
Prem Puri 4 Transport of the surgical neonate 39 Prem Puri and
Diane De Caluw 5 Preoperative assessment 45 Prem Puri and Diane De
Caluw 6 Anesthesia 59 Declan Warde 7 Postoperative management 71
Desmond Bohn 8 Fluid and electrolyte balance in the newborn 89
Winifred A. Gorman 9 Nutrition 103 Agostino Pierro 10 Vascular
access in the newborn 121 Juda Z. Jona 11 Radiology in the newborn
131 Noel S. Blake 12 Immune system of the newborn 139 Denis J. Reen
13 Hematological problems in the neonate 147 Owen P. Smith 14
Genetics in neonatal surgical practice 157 Andrew Green 15 Ethical
considerations in newborn surgery 173 Jacqueline J. Glover and
Donna A. Caniano 16 Minimally invasive neonatal surgery 183 Ashley
Vernon, Timothy Kane and Keith E. Georgeson
6. 17 Fetal surgery 189 Jyoji Yoshizawa, Loureno Sbragia and
Michael R. Harrison PART 2 HEAD AND NECK 199 18 Choanal atresia in
the newborn 201 Francesco Cozzi and Denis A. Cozzi 19 Pierre Robin
sequence 207 Evelyn H. Dykes 20 Macroglossia 215 George G. Youngson
21 Tracheostomy in infants 219 Thom E. Lobe 22 Miscellaneous
conditions of the neck and oral cavity 227 Anies Mahomed PART 3
CHEST 237 23 Congenital thoracic deformities 239 Robert C.
Shamberger 24 Mediastinal masses in the newborn 247 Steven J.
Shochat 25 Subglottic stenosis 253 Felix Schier 26 Tracheomalacia
259 I. Vinograd and R. M. Filler 27 Vascular rings 267 Ehud Deviri
and Morris J. Levy 28 Pulmonary air leaks 277 Prem Puri 29
Chylothorax and other pleural effusions in neonates 283 Richard G.
Azizkhan 30 Congenital malformations of the lung 295 Horace P. Lo
and Keith T. Oldham 31 Congenital diaphragmatic hernia 309 Tina
Granholm, Craig T. Albanese and Michael R. Harrison 32
Extracorporeal membrane oxygenation for neonatal respiratory
failure 317 Eugene S. Kim and Charles J. H. Stolar 33 Bronchoscopy
in the newborn 329 John D. Russell PART 4 ESOPHAGUS 335 34
Esophageal atresia and tracheo-esophageal stula 337 Paul D. Losty
and Colin T. Baillie 35 Congenital esophageal stenosis 353 Shintaro
Amae, Masaki Nio, Yutaka Hayashi and Ryoji Ohi vi Contents
7. 36 Esophageal duplication cysts 359 Leela Kapila, H. W.
Holliday 37 Esophageal perforation in the newborn 365 Hirikati S.
Nagaraj 38 Gastro-esophageal reux 369 Victor E. Boston PART 5
GASTROINTESTINAL 381 39 Pyloric atresia and prepyloric antral
diaphragm 383 Vincenzo Jasonni 40 Hypertrophic pyloric stenosis 389
Prem Puri and Ganapathy Lakshmanadass 41 Gastric volvulus 399 Mark
D. Stringer 42 Gastric perforation 405 Robert K. Minkes 43
Gastrostomy 411 Michael W. L. Gauderer 44 Duodenal obstruction 423
Yechiel Sweed 45 Malrotation 435 Lewis Spitz 46 Persistent
hyperinsulinemic hypoglycemia of infancy 441 Lewis Spitz 47
Jejuno-ileal atresia and stenosis 445 Heinz Rode and A. J. W.
Millar 48 Colonic and rectal atresias 457 Tomas Wester 49 Meconium
ileus 465 Edward Kiely 50 Meconium peritonitis 471 Jose Boix-Ochoa
and J. Lloret 51 Duplications of the alimentary tract 479 Prem Puri
52 Mesenteric and omental cysts 489 Daniel L. Mollitt 53 Neonatal
ascites 497 Prem Puri 54 Necrotizing enterocolitis 501 Ann M.
Kosloske 55 Hirschsprungs disease 513 Prem Puri 56 Anorectal
anomalies 535 Alberto Pea 57 Congenital segmental dilatation of the
intestine 553 Hiroo Takehara and Hiroki Ishibashi Contents vii
8. 58 Intussusception 557 Spencer W. Beasley 59 Inguinal hernia
561 Juan A. Tovar 60 Short bowel syndrome and surgical techniques
for the baby with short intestines 569 Michael E. Hllwarth PART 6
LIVER AND BILIARY TRACT 577 61 Biliary atresia 579 Ken Kimura 62
Congenital biliary dilatation (choledochal cyst) 589 Takeshi Miyano
and Atsuyuki Yamataka 63 Hepatic cysts and abscesses 597 David A.
Partrick and Frederick M. Karrer PART 7 ANTERIOR ABDOMINAL WALL
DEFECTS 603 64 Omphalocele and gastroschisis 605 Steven W. Bruch
and Jacob C. Langer 65 Omphalomesenteric duct remnants 615 David A.
Lloyd 66 Bladder exstrophy: considerations and management of the
newborn patient 619 Fernando A. Ferrer and John P. Gearhart 67
Cloacal exstrophy 629 Jonathan I. Groner and Moritz M. Ziegler 68
Prune belly syndrome 637 Prem Puri and Hideshi Miyakita 69
Conjoined twins 643 Harry Applebaum PART 8 TUMORS 649 70
Epidemiology and genetic associations of neonatal tumors 651 Sam W.
Moore and Jack Plaschkes 71 Hemangiomas and vascular malformations
663 Prem Puri and Laszlo Nemeth 72 Congenital nevi 675 Bruce S.
Bauer and Julia Corcoran 73 Lymphatic malformations (cystic
hygroma) 687 Jacob C. Langer and Vito Forte 74 Cervical teratomas
697 Michael W. L. Gauderer 75 Sacrococcygeal teratoma 703 Kevin C.
Pringle 76 Nasal tumors 715 Alfred Lamesch and Peter Lamesch viii
Contents
9. 77 Neuroblastoma 721 Raymond J. Fitzgerald 78 Soft-tissue
sarcoma 733 David A. Lloyd 79 Hepatic tumors 739 Yoshiaki Tsuchida
and Norio Suzuki 80 Congenital mesoblastic nephroma and Wilms tumor
747 Robert Carachi 81 Neonatal ovarian tumors 751 Jean Gaudin PART
9 SPINA BIFIDA AND HYDROCHEPHALUS 759 82 Spina bida and
encephalocele 761 Prem Puri and Rajendra Surana 83 Hydrocephalus
775 Raymond J. Fitzgerald PART 10 GENITOURINARY 785 84 Imaging of
the renal tract in the neonate 787 Isky Gordon 85 Management of
antenatally detected hydronephrosis 793 Jack S. Elder 86
Multicystic dysplastic kidney 809 David F. M. Thomas and Azad S.
Najmaldin 87 Upper urinary tract obstructions 817 Prem Puri and
Boris Chertin 88 Duplication anomalies 831 Prem Puri and Hideshi
Miyakita 89 Vesico-ureteric reux 837 Prem Puri 90 Ureteroceles in
the newborn 845 Peter Frey, Mario Mendoza-Sagaon and Blaise J.
Meyrat 91 Congenital posterior urethral obstruction 855 Reisuke
Imaji, Daniel Moon and Paddy A. Dewan 92 Neuropathic bladder 867
Paddy A. Dewan, Paul D. Anderson and Gunnar Aksnes 93
Hydrometrocolpos 875 Devendra Gupta 94 Intersex 883 Ronald J. Sharp
95 Male genital anomalies 903 John M. Hutson 96 Neonatal testicular
torsion 909 David M. Burge Contents ix
10. PART 11 LONG-TERM OUTCOMES IN NEWBORN SURGERY 913 97
Long-term outcomes in newborn surgery 915 Mark D. Stringer Index
925 x Contents
11. The 2nd edition of Newborn Surgery has been extensively
revised. Many new chapters have been added to take account of the
recent developments in the care of the newborn with congenital
malformations. This edition which comprises 97 chapters by 121
contributors from all ve continents of the world, provides an
authoritative, comprehensive and complete account of the various
surgical conditions in the newborn. Each chapter is written by the
current leading expert(s) in their respective elds. Newborn Surgery
in the 21st century demands of its practitioners detailed knowledge
and understanding of the complexities of congenital anomalies as
well as the highest standards of operative techniques. In this
text- book great emphasis continues to be placed on provid- ing a
comprehensive description of operative techniques of each
individual congenital condition in the newborn. The book is
intended for trainees in paediatric surgery, established paediatric
surgeons, general surgeons with an interest in paediatric surgery
as well as neonatologists and paediatricians seeking more detailed
information on newborn surgical conditions. I wish to thank most
sincerely all the contributors for the outstanding work they have
done for the production of this innovative textbook. I also wish to
express my gratitude to Mrs Karen Alfred and Ms Ann Brennan for
their secretarial help and to the staff of Arnold for their help
during the preparation and publication of this book. I am thankful
to the Childrens Medical & Research Foundation, Our Ladys
Hospital for Sick Children, Dublin for their support. Prem Puri
2003 Preface to the Second Edition
12. During the last three decades, newborn surgery has
developed from an obscure subspeciality to an essential component
of every major academic paediatric surgical department throughout
both the developed and the developing world. Major advances in
perinatal diagnosis, imaging, neonatal resuscitation, intensive
care and operative techniques have radically altered the manage-
ment of newborns with congenital malformations. Embryological
studies have provided new valuable insights into the development of
malformations, while improvements in prenatal diagnosis are having
a signi- cant impact on approaches to management. Monitoring
techniques for the sick neonate pre- and postoperatively have
become more sophisticated and there is now greater emphasis on
physiological aspects of the surgical newborn as well as their
nutritional and immune status. This book provides a comprehensive
compendium of all these aspects as a prelude to an extensive
description of surgical conditions in the newborn. Modern-day new-
born surgery demands detailed knowledge of the complexities of
newborn problems. Research develop- ments, laboratory diagnosis,
imaging and innovative surgical techniques are all part of the
challenge facing surgeons dealing with congenital conditions in the
newborn. In this book, a comprehensive description of operative
techniques of each individual condition is presented. Each
contributor was selected to provide an authoritative, comprehensive
and complete account of their respective topics. The book,
comprising 90 chapters, is intended primarily for trainees in
paediatric surgery, established paediatric surgeons, general
surgeons with an interest in paediatric surgery and neonatologists.
I am most grateful to all contributors for their willing- ness to
contribute chapters at considerable cost of time and effort. I am
indebted to Mr Maurice De Cogan for artwork, Mr Dave Cullen for
photography and Ms Ann Brennan and Ms Deirdre ODriscoll for skilful
secretarial help. I am thankful to the Childrens Research Centre,
Our Ladys Hospital for Sick Children, for their support. Finally, I
wish to thank the editorial staff, particularly Ms Susan Devlin, of
Butterworth-Heinemann for their help during the preparation and
publication of this book. Prem Puri Preface to the First
Edition
13. N. Scott Adzick MD Professor of Surgery Surgeon-in-Chief
Department of Surgery The Center for Fetal Diagnosis and Treatment
Childrens Hospital of Philadelphia Philadelphia, USA Gunnar Aksnes
MD PhD Consultant Paediatric Surgeon Department of Paediatric
Surgery Ulleval University Hospital Oslo, Norway Craig T. Albanese
MD Professor of Surgery Chief, Division of Pediatric Surgery
Stanford University Medical Center Palo Alto California, USA
Shintaro Amae MD Lecturer Division of Pediatric Surgery Tohoku
University School of Medicine Sendai, Japan Paul D. Anderson MBBS
Urology Research Fellow Urology Unit Royal Childrens Hospital
Melbourne, Australia Harry Applebaum MD Head, Division of Pediatric
Surgery Department of Surgery Kaiser Permanente Medical Center Los
Angeles California, USA Richard G. Azizkhan MD Surgeon-in-Chief
Lester Martin Chair of Pediatric Surgery Cincinnati Childrens
Hospital Professor of Surgery and Pediatrics University of
Cincinnati School of Medicine Cincinnati Ohio, USA Colin T. Baillie
MBChB DCH ChM FRCS(Paeds) Consultant Paediatric Surgeon Royal
Liverpool Childrens Hospital (Alder Hey) Liverpool, UK Bruce S.
Bauer MD FACS FAAP Professor & Head Division of Pediatric
Plastic Surgery Childrens Memorial Hospital Division of Plastic
Surgery McGraw Medical School of Northwestern University Chicago
Illinois, USA Spencer W. Beasley MBChB (Otago) MS (Melb) FRACS
Professor of Paediatric Surgery Paediatric Surgeon and Urologist
Department of Paediatric Surgery Christchurch Hospital
Christchurch, New Zealand Noel S. Blake FRCR FFRRCSI Consultant
Radiologist Our Ladys Hospital for Sick Children Dublin, Ireland
Desmond Bohn MB FRCPC MRCP(UK) FFARCS Associate Chief Department of
Critical Care Medicine The Hospital for Sick Children Toronto,
Canada Jose Boix-Ochoa MD Chairman of Pediatric Surgery Professor
of Pediatric Surgery Autonomous University of Barcelona Hospital
Materno-Infantil Vall dHebron Barcelona, Spain Victor E. Boston MD
FRCS(Ed) FRCSI FRCS (Eng) Consultant Paediatric Surgeon Royal
Belfast Hospital for Sick Children Honorary Senior Lecturer
Department of Surgery Queens University Belfast, UK
Contributors
14. LCDR Steven W. Bruch MC USNR Staff Pediatric Surgeon Naval
Medical Center Portsmouth, USA Christoph Bhrer MD Consultant
Paediatrician Department of Neonatology Campus-Virchow-Klinikum
Medical Faculty Charite Humboldt University Berlin, Germany David
Burge FRCS FRCPCH Consultant Paediatric Surgeon Wessex Regional
Centre for Paediatric Surgery Southampton, UK Diane De Caluw MD
Consultant Paediatric Surgeon Department of Paediatric Surgery
Chelsea and Westminster Hospital London, UK Donna A. Caniano MD
Surgeon-in-Chief Department of Pediatric Surgery Childrens Hospital
Ohio, USA Robert Carachi MD FRCS Head of Department Department of
Surgical Paediatrics Royal Hospital for Sick Children Glasgow, UK
Boris Chertin MD Consultant Pediatric Urologist Department of
Urology Shane Zedek Medical Center Jerusalem, Israel Julia Corcoran
MD FACS FAAP Attending Surgeon Division of Pediatric Plastic
Surgery Childrens Memorial Hospital Division of Plastic Surgery
McGraw Medical School of Northwestern University Chicago Illinois,
USA Denis A. Cozzi MD Consultant Pediatric Surgeon Department of
Pediatric Surgery University of Rome Rome, Italy Francesco Cozzi MD
Associate Professor and Head of Pediatric Surgery Department of
Pediatric Surgery University of Rome Rome, Italy Ehud Deviri MD
MSurg Consultant Cardiothoracic Surgeon Department of
Cardiothoracic Surgery Hadassah University Hospital Hebrew
University Jerusalem, Israel Paddy A. Dewan PhD MD MS MmedSc FRCS
FRACS Paediatric Urologist Royal Childrens Hospital Melbourne,
Australia Evelyn H. Dykes MBChB FRCS (Paeds) Senior Lecturer in
Paediatric Surgery Kings College London, UK Jack S. Elder MD
Director Division of Pediatric Urology Rainbow Babies &
Childrens Hospital Professor of Urology & Pediatrics Case
Western Reserve University School of Medicine Cleveland Ohio, USA
Fernando A. Ferrer MD Assistant Professor of Pediatric Urology
Connecticut Childrens Hospital Hartford Connecticut, USA R. M.
Filler MD FRCS(C) Professor and Surgeon-in-Chief Hospital of Sick
Children Professor of Pediatrics University of Toronto Ontario,
Canada Raymond J. Fitzgerald MA MB FRCSI FRCS FRACS (Paed Surg)
FRCS (Ed) Ad. hom Associate Professor in Paediatric Surgery Trinity
College Consultant Paediatric Surgeon Childrens Hospital and Our
Ladys Hospital for Sick Children Dublin, Ireland Vito Forte MD
FRCSC Paediatric Otolaryngologist Hospital for Sick Children
Associate Professor of Otolaryngology University of Toronto
Toronto, Canada Peter Frey MD BSc PD FMH Consultant Pediatric
Surgeon Department of Pediatric Surgery Centre Hospitalier
Universitaire Vaudois (CHUV) Lausanne, Switzerland xiv
Contributors
15. Michael W. L. Gauderer MD FACS, FAAP Professor of Surgery
University of South Carolina School of Medicine Chief, Department
of Pediatric Surgery Childrens Hospital Greenville Hospital System
Greenville South Carolina, USA Jean Gaudin MD Paediatric Surgeon
Department of Paediatric Surgery Hpital St Louis La Rochelle,
France John P. Gearhart MD Professor & Director Division of
Pediatric Urology James Buchanan Brady Urological Institute Johns
Hopkins Hospital Baltimore Maryland, USA Keith E. Georgeson MD
Professor and Director Division of Pediatric Surgery Childrens
Hospital of Alabama Birmingham Alabama, USA Jacqueline J. Glover
PhD Associate Professor Center for Health Ethics and Law West
Virginia University College of Medicine and Childrens Hospital
Morgantown West Virginia, USA Isky Gordon FRCR Consultant
Radiologist Great Ormond Street Hospital for Children Honorary
Senior Lecturer Institute for Child Health London, UK Winifred A.
Gorman BSc FRCPI FAAP Consultant Paediatrician Department of
Neonatology National Maternity Hospital Dublin, Ireland Tina
Granholm MD PhD Associate Professor Department of Pediatric Surgery
Astrid Lindgren Childrens Hospital Director of Postgraduate Studies
Department of Woman and Child Health Karolinska Hospital Karolinska
Institute Stockholm, Sweden Andrew Green MB, PhD, FRCPI,
FFPath(RCPI) Director National Centre for Medical Genetics Our
Ladys Hospital for Sick Children Dublin, Ireland Jonathan I. Groner
MD Assistant Professor Department of Surgery Childrens Hospital
Columbus Ohio State University Columbus Ohio, USA Devendra Gupta MS
MCH Professor of Paediatric Surgery All India Institute of Medical
Sciences New Delhi, India Michael R. Harrison MD Professor of
Surgery Pediatrics and Obstetrics Gynecology and Reproductive
Sciences Director, Fetal Treatment Center Chief, Division of
Pediatric Surgery University of California` San Francisco
California, USA Yutaka Hayashi MD Professor Division of Pediatric
Oncology Tohoku University School of Medicine Sendai, Japan Howard
W. Holliday FRCS Consultant Paediatric Surgeon Derbyshire Childrens
Hospital Derbyshire, UK Michael E. Hllwarth MD Professor & Head
Department of Paediatric Surgery University of Graz Medical School
Graz, Austria John M. Hutson BS MD(Monash), MD(Melb) FRACS
Professor & Director Russell Howard Department of General
Surgery Royal Childrens Hospital F Douglas Stephens Surgical
Research Laboratory Murdoch Childrens Research Institute Melbourne,
Australia Reisuke Imaji MD PhD Clinical Research Fellow Urology
Unit Royal Childrens Hospital Department of Paediatrics University
of Melbourne Murdoch Childrens Research Institute Melbourne,
Australia Contributors xv
16. Hiroki Ishibashi MD Pediatric Surgeon Department of
Digestive and Pediatric Surgery University of Tokushima Tokushima,
Japan Vincenzo Jasonni MD Professor and Director School of
Pediatric Surgery Istituto Scientico G Gaslini University of Genoa
Genoa, Italy Juda Z. Jona MD FACS FAAP(S) Chief Division of
Pediatric Surgery Evanston Northwestern Healthcare Evanston
Illinois, USA Timothy Kane MD Chief Clinical Fellow Division of
Pediatric Surgery Childrens Hospital of Alabama Birmingham Alabama,
USA Leela Kapila OBE FRCS Consultant Paediatric Surgeon Department
of Paediatric Surgery Queens Medical Centre Nottingham, UK
Frederick M. Karrer MD Associate Professor of Surgery &
Pediatrics & Head Division of Pediatric Surgery University of
Colorado Health Sciences Center Surgical Director Pediatric Liver
Transplantation Department of Pediatric Surgery The Childrens
Hospital Denver Colorado, USA Edward Kiely FRCSI FRCS FRCPCH
Consultant Paediatric Surgeon Hospital for Sick Children Great
Ormond Street London, UK Eugene S. Kim MD Chief Resident Division
of Pediatric Surgery College of Physicians and Surgeons Columbia
University Childrens Hospital of New York New York Presbyterian
Hospital New York, USA Ken Kimura MD Professor of Surgery and
Pediatrics Department of Surgery University of Iowa Hospitals &
Clinics Iowa City Iowa, USA Dietrich Kluth MD PhD Paediatric
Surgeon Department of Paediatric Surgery University Hospital
Hamburg Hamburg, Germany Ann M. Kosloske MD MPH Professor of
Surgery and Pediatrics Texas Technical University Health Science
Center Lubbock Texas, USA Ganapathy Lakshmanadass MS MChFRCS Senior
Registrar in Paediatric Surgery Department of Paediatric Surgery
National Childrens Hospital Dublin, Ireland Wolfgang Lambrecht MD
Surgeon-in-Chief Department of Paediatric Surgery Eppendorf
University Hospital Hamburg, Germany Alfred Lamesch MD FACS
Emeritus Professor Universit Libre de Bruxelles Surgeon-in-Chief
Emeritus Department of Paediatric Surgery Luxembourg Hospital
Center Honorary Member of the Acadmie Royale de Mdecine Belgium
Peter Lamesch MD FACS Professor of Surgery Department of Abdominal,
Transplant & Vascular Surgery University of Leipzig Leipzig,
Germany Jacob C. Langer MD FRCSC Chief, Paediatric General Surgery
Hospital for Sick Children Toronto, Canada Morris J. Levy MD
Professor of Surgery Department of Thoracic and Cardiovascular
Surgery Sackler School of Medicine Tel Aviv University Tel Aviv,
Israel David A. Lloyd MChir FRCS FCS(SA) Professor of Paediatric
Surgery Institute of Child Health Royal Liverpool Childrens
Hospital (Alder Hey) Liverpool, UK xvi Contributors
17. J. Lloret MD Pediatric Surgeon Neonatal and Oncological
Unit Hospital Materno-Infantil Vall dHebron Barcelona, Spain Horace
P. Lo MD Senior Resident Department of Surgery Medical College of
Wisconsin Milwaukee Wisconsin, USA Thom E. Lobe MD Chairman,
Section of Pediatric Surgery University of Tennessee Memphis
Tennessee, USA Paul D. Losty MD FRCSI FRCS(Eng) FRCS(Ed) FRCS(Paed)
Reader & Honorary Consultant Paediatric Surgeon Department of
Paediatric Surgery Royal Liverpool Childrens Hospital (Alder Hey)
and The University of Liverpool Liverpool, UK Tippi C. MacKenzie MD
Fetal Surgery Research Fellow The Center for Fetal Diagnosis and
Treatment Childrens Hospital of Philadelphia Philadelphia, USA
Anies Mahomed MBBCH FCS(SA) FRCS(Glas.Ed) FRCS(Paeds) Consultant
Paediatric Surgeon Department of Paediatric Surgery Royal Aberdeen
Childrens Hospital Aberdeen, UK Mario Mendoza-Sagaon MD Senior
Registrar Department of Pediatric Surgery CHUV Lausanne,
Switzerland Blaise J. Meyrat MD Consultant Paediatric Urologist and
Surgeon Department of Pediatric Surgery CHUV Lausanne, Switzerland
A. J. W. Millar FRCS (Eng) (Edin) FRACS DCH Associate Professor
Department of Paediatric Surgery University of Cape Town Senior
Surgeon Red Cross War Memorial Childrens Hospital Cape Town, South
Africa Robert K. Minkes MD PhD Associate Professor of Surgery
Chief, Section of Pediatric Surgery Louisiana State University
Heath Sciences Center Childrens Hospital of New Orleans Louisiana,
USA Hideshi Miyakita MD Consultant Paediatric Urologist Tokai
University School of Medicine Kanagawa, Japan Takeshi Miyano MD,
PhD, FAAP(Hon), FACS, FAPSA(Hon) Director of Juntendo University
Hospital Professor and Head Department of Pediatric Surgery
Juntendo University Scholl of Medicine Tokyo, Japan Daniel L.
Mollitt MD Professor and Chief Division of Pediatric Surgery
University of Florida Health Scince Center Jacksonville Florida,
USA Daniel Moon MB, BS Urology Research Fellow Kids Urology
Research Unit Royal Childrens Hospital Melbourne, Australia Sam W.
Moore MBChB FRCS MD Professor & Head Department of Paediatric
Surgery Faculty of Medicine University of Stellenbosch Tygerberg,
South Africa Hirikati S. Nagaraj MD Associate Professor of Surgery
Kosair Childrens Hospital University of Louisville Chief, General
and Thoracic Surgery Kentucky, USA Azad S. Najmaldin MB ChB MS
FRCSEd FRCS Consultant Paediatric Surgeon & Urologist St Jamess
University Hospital Leeds, UK Laszlo Nemeth MD Consultant
Paediatric Surgeon University of Szeged Szeged, Hungary Masaki Nio
MD Associate Professor of Pediatric Surgery Senior Lecturer
Division of Pediatric Surgery Tohoku University School of Medicine
Sendai, Japan Contributors xvii
18. Ryoji Ohi MD Professor and Chief Division of Pediatric
Surgery Tohoku University School of Medicine Sendai, Japan Keith T.
Oldham MD Professor and Chief Division of Pediatric Surgery Vice
Chairman Department of Surgery Medical College of Wisconsin
Milwaukee Wisconsin, USA David A. Partrick MD Assistant Professor
in Surgery and Pediatrics University of Colorado Health Sciences
Center Director of Surgical Endoscopy The Childrens Hospital Denver
Colorado, USA Alberto Pea MD FACS FAAP Professor & Chief
Division of Pediatric Surgery Albert Einstein College of Medicine
Schneider Childrens Hospital New Hyde Park New York, USA Agostino
Pierro MD FRCS FAAP Professor of Paediatric Surgery Institute of
Child Health and Great Ormond Street Hospital London, UK Jack
Plaschkes MD FRCS Department of Paediatric Surgery Faculty of
Medicine University of Stellenbosch Tygerberg, South Africa Kevin
C. Pringle MB ChB FRACS Professor of Paediatric Surgery & Head
Department of Obstetrics & Gynaecology Wellington School of
Medicine and Health Sciences University of Otago Wellington, New
Zealand Prem Puri MS FRCS FRCS(Ed) FACS Newman Clinical Research
Professor University College, Dublin Consultant Paediatric Surgeon,
Our Ladys Hospital for Sick Children and National Childrens
Hospital, Dublin Director of Research, Childrens Research Centre,
Dublin, Ireland Denis Reen MSc PhD Adjunct Professor in Medicine,
University College, Dublin Professor, The Childrens Research Centre
Our Ladys Hospital for Sick Children Dublin, Ireland Heinz Rode
Mmed(Chir) FCS(SA) FRCSEd Charles F M Saint Professor of Paediatric
Surgery Department of Paediatric Surgery Red Cross Childrens
Hospital Rondebosch, South Africa John D. Russell FRCSI, FRCS(ORL)
Consultant Paediatric Otolaryngologist Our Ladys Hospital for Sick
Children Dublin, Ireland Loureno Sbragia MD PhD Postdoctoral
Research Scholar Fetal Treatment Center Division of Pediatric
Surgery University of California San Francisco, USA Robert C.
Shamberger MD Professor of Surgery Harvard Medical School Chief of
Surgery (Interim) Department of Paediatric Surgery Childrens
Hospital Boston Massachusetts, USA Ronald J. Sharp MD Director of
Surgery Childrens Mercy Hospital Kansas City Missouri, USA Felix
Schier MD Head of Department Department of Paediatric Surgery
University Medical Centre Jena, Germany Steven J. Shochat MD
Surgeon-in-Chief & Chairman Department of Surgery St Jude
Childrens Research Hospital Memphis Tennessee, USA Owen P. Smith MA
MB BA Mod (Biochem), FRCPCH FRCPI, FRCPLon, FRCPEdin, FRCPGlasg,
FRCPath Consultant Paediatric Haematologist Our Ladys Hospital for
Sick Children, and St Jamess Hospital, Dublin Senior Lecturer in
Haematology, Trinity College Dublin, Ireland xviii
Contributors
19. Lewis Spitz MB ChB PhD MD(Hon), FRCS(Edin), FRCS(Eng),
FAAP(Hon), FRCPCH Nufeld Professor of Paediatric Surgery Institute
of Child Health University College London and Great Ormond Street
Hospital London, UK Charles J. H. Stolar MD Professor of Surgery
and Pediatrics Division of Pediatric Surgery College of Physicians
and Surgeons Columbia University Director of Pediatric Surgery
Childrens Hospital of New York New York Presbyterian Hospital New
York, USA Mark D. Stringer BSc MS FRCS FRCS(Paed) FRCP FRCPCH
Consultant Paediatric Surgeon Childrens Liver & GI Unit St
Jamess University Hospital Leeds, UK Rajendra Surana MS FRCS(Paed)
Consultant Paediatric Surgeon Welsh Centre for Paediatric Surgery
University Hospital of Wales Cardiff, UK Norio Suzuki MD Chief of
Surgery Department of Surgery Gunma Childrens Medical Center Gunma,
Japan Yechiel Sweed MD Senior Lecturer in Surgery Rappaport School
of Medicine The Technion Haifa Head Pediatric Surgery Western
Galilee Hospital Nahariya, Israel Hiroo Takehara MD Associate
Professor and Chief of Pediatric Surgeons Department of Digestive
and Pediatric Surgery University of Tokushima Tokushima, Japan
David F.M. Thomas FRCP FRCS Consultant Paediatric Urologist Reader
in Paediatric Surgery Leeds Teaching Hospitals University of Leeds
Leeds, UK Juan A. Tovar MD Professor of Surgery Department of
Surgery Hospital Infantil La Paz Madrid, Spain Yoshiaki Tsuchida MD
PhD FACS Director Department of Surgery Gunma Childrens Medical
Center Gunma, Japan Ashley Vernon MD Research Fellow Division of
Pediatric Surgery Childrens Hospital of Alabama Birmingham Alabama,
USA I. Vinograd MD Head Department of Pediatric Surgery DANA
Childrens Hospital Tel-Aviv, Israel Declan Warde MB BCH FFARCSI
Consultant Anaesthetist Department of Anesthesia The Childrens
Hospital Dublin, Ireland Tomas Wester MD PhD Consultant Paediatric
Surgeon Department of Paediatric Surgery University Childrens
Hospital Uppsala, Sweden Atsuyuki Yamataka MD Associate Professor
of Pediatric Surgery Department of Pediatric Surgery Juntendo
University School of Medicine Tokyo, Japan Jyoji Yoshizawa MD PhD
Assistant Professor of Surgery Fetal Treatment Center University of
California San Francisco, USA George G. Youngson PhD FRCS Honorary
Professor of Paediatric Surgery Department of Paediatric Surgery
Royal Aberdeen Childrens Hospital Aberdeen, UK Moritz M. Ziegler MD
Robert E Gross Professor of Surgery Harvard Medical School
Surgeon-in-Chief Childrens Hospital Boston Maryland, USA
Contributors xix
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21. 1 General
22. This page intentionally left blank
23. 1 Embryology of malformations DIETRICH KLUTH, WOLFGANG
LAMBRECHT AND CHRISTOPH BHRER INTRODUCTION Approximately 3% of
human newborns present with congenital malformations.1 Without
surgical inter- vention, one-third of these infants would die since
their malformations are not compatible with sustained life outside
the uterus.1,2 In gures, this means that in a country such as
Germany, nearly 6000 children are born every year with a
life-threatening malformation. Due to the development of prenatal
diagnostic procedures, advanced surgical techniques, and intensive
postoperative care, most infants with otherwise fatal malformations
can be rescued by an operation in the neonatal period. However,
morbidity remains high in some of these children2 with the
necessity of repeated operations and hospitalizations despite a
successful primary operation. This may also be the fate of many
children with non-life-threatening malformations such as
hypospadias or cleft palate. Mortality is still high in newborns
with certain mal- formations such as congenital diaphragmatic
hernias or severe combined defects. As a consequence, congenital
malformations today are the main cause of death in the neonatal
period. In the USA, 21% of neonatal mortality can be related to
congenital malformations.3 These gures probably do not reect a real
increase of the actual incidence of congenital malformation. The
observed mortality shift might rather be due to improved intensive
care medicine in todays western world countries where neonates
(even those with birth defects) have a better chance of survival.
On the other hand, this statistical shift indicates that knowledge
about congenital malformations lags behind the progress clinical
research has made in the surrounding elds. Efforts are needed to
close the gap and learn more about baby killer No. 1. Identication
of teratogens will help to reduce the incidence of malformations
when exposure can be avoided, and pathogenetic studies might aid in
designing therapeutic measures. Both treatment and prevention
critically depend on basic embryological research. DEFINITION OF
THE TERM MALFORMATION After birth neonates can present with a broad
spectrum of deviations from normal morphology. This extends from
minor variations of normal morphology without any clinical
signicance to maximal organ defects with extreme functional decits
of the malformed organs or of the whole organism. The degree of
functional disorder is decisive when dealing with the question of
whether a variation of normal morphology has to be viewed as a
dangerous malformation requiring surgical correction. This means
that functional disturbance is essential when using the term
malformation. Inborn deviations can be detri- mental, neutral, or
even benecial, otherwise evolution- ary progress could not take
place. An example of a benecial deviation is the longevity syndrome
of people with abnormally low serum cholesterol levels. Abnor-
malities with little or no functional disturbance might still
require surgical correction when patients are in danger of social
stigmatization. Coronal or glandular hypospadias might serve as an
example for this condition. ETIOLOGY OF CONGENITAL MALFORMATIONS In
most cases, the etiology of congenital malformations remains
unclear. Possible etiological factors are listed in Table 1.1. In
about 20% of cases genetic factors (gene mutation and chromosomal
disorders) can be identied.1,2,4 In 10% an environmental origin can
be demonstrated.1,2 In 70% the factors responsible remain obscure.
Table 1.1 Etiology of congenital malformations Genetic disorders
20% Environmental factors 10% Unknown etiology 70%
24. Environmental factors A large number of agents are known
which might interfere with the normal development of organ systems
during embryogenesis.1,4 The underlying mechanisms of this
interference is poorly understood in most cases.
Characteristically, during organogenesis, different organs of the
embryo show distinct periods of greatest sensitivity to the action
of the teratogen. These phases of greatest sensitivity are called
the teratogenetic period of determination.5 The typical patterns of
some syndromes can be explained by an overlap of these phases
during embryological development. In 1983, Shepard2 published a
catalog of suspected teratogenic agents. Over 900 agents are known
to produce congenital anomalies in experimental animals. In 30
evidence for teratogenic action in humans could be demonstrated.
Teratogenic agents can be divided into four groups (Table 1.2). The
teratogenic potential of virus infections,1 especially rubella and
herpes, and that of radiation1 has been clearly established.
Maternal metabolic defects and lack of essential nutritives can be
teratogenic. After a vitamin A-free diet6 and riboavin-free diet7
various congenital malformations were observed in rats and mice.
Among these were diaphragmatic hernias, isolated esophageal
atresias, and isolated tracheo-esophageal stulas. Similarly,
inappropriate administration of hormones can be associated with
intrauterine dysplasias.8 Industrial and pharmaceutical chemicals
such as tetrachlor-diphenyl-dioxin (TCDD) or thalidomide have
inicted tragedies by their teratogenic action. When thalidomide was
prescribed to women in the early 1960s as a safe sleeping
medication, numerous children were born with dysmelic
deformities.4,9,10 In addition, atresias of the esophagus, the
duodenum, and the anus were observed in some children.9 The data
collected suggest that teratogenic agents do not cause new patterns
of malformations but rather mimic sporadic birth defects. This had
posed problems in identifying thalidomide as the responsible agent.
It appears likely that among those 70% congenital malformations
with unclear etiology a considerable percentage might be
precipitated by as yet unidentied environmental factors. In a rat
model, the herbicide nitrofen (2.4-dichloro-phenyl-p-nitrophenyl
ether) has been shown to induce congenital diaphrag- matic hernias,
cardiac abnormalities and hydro- nephrosis.1115 In 1978, Thompson
et al. described the teratogenicity of the anti-cancer drug
adriamycin in rats and rabbits.16 More recently, Diez-Pardo et
al.17 re- described this model with emphasis to its potentials as a
model for foregut anomalies. Today, the adriamycin model is
generally described as a model for the VACTERL-association
(V=vertebral, A=anorectal, C=cardiac, T=tracheal, E=esophageal,
R=renal, L=limb).18,19 Thus, classic malformations such as atresias
of the esophagus and the intestinal tract, intestinal dupli-
cations and others can be mimicked by teratogens in animal models.
Genetic factors Approximately 20% of congenital malformations are
of genetic origin. Most surgically correctable malformations are
associated with chromosomal disorders, e.g. trisomy 21,13, or 18,
or are of multifactorial inheritance20 with a small risk of
recurrence. The assumption of multi- factorial inheritance results
from the fact that with nearly all major anomalies familiar
occurrences had been observed.1 In animals inheritance has also
been found for some malformations.2124 EMBRYOLOGY OF MALFORMATIONS
Disturbances of normal embryological processes will result in
malformations of organs. This was rst shown by Spemann25 in 1901 by
experimentally producing supernumary organs in the triton embryo
after establishing close contact between excised parts of triton
eggs and other parts of the same egg. Spemann and Mangold5 coined
the term induction to describe this observation. They found that
certain parts of the embryo obviously were able to control
embryonic development of other parts. These controlling parts were
called organizers.5 The process of inuence itself was called
induction. It was believed by many scientists in the eld that
induction could serve as the overall principle of hierarchical
control of embryonic development. Ensuing investigations, however,
made modications necessary, which nally resulted in a very complex
model of organizers and inductors. The nature of inductive
substances remained obscure and attempts to isolate inductive
substances, meanwhile called morphogenes, were unsuccessful.26
Interestingly, not only live cells could induce development in
certain experiments but also dead and denaturated material.5 A
process essential for the formation of early embryonic organs is
the invagination of epithelial sheets. This invagination is
preceded by a thickening of the 4 Embryology of malformations Table
1.2 Teratogenic agents in congenital malformations Physical agents
Radiation, heat, mechanical factors Infectious agents Viruses,
treponemes, parasites Chemical, drug, Thalidomide, nitrofen,
environmental agents hormones, vitamin deciencies Maternal, genetic
Chromosomal disorders, factors multifactorial inheritance After
Nadler.1
25. epithelial sheet,27 a process known as placode formation.
The thickening itself is caused by elongation of indi- vidual cells
of the placode. This process can be studied in detail in epithelial
morphogenesis.28 The same sequence of developmental events has been
observed in the formation of the neural plate, in the formation of
the otic and lens placode and in the development of most
epitheliomesenchymal organs including lung, thyroid gland and
pancreas. From these observations it can be concluded that most
epithelial cells behave uniformly in the early phase of embryonic
development. Today it is generally accepted, that early embryonic
organs are especially sensitive for alterations. Therefore
researchers are more and more interested to understand the
formation of early embryonic organs. In 1985 ETTERSOHN.29 stated
that most invagi- nations are the results of mechanical forces that
are local in origin. He focussed on three possible mechanisms which
might lead to placode formation and subsequent invagination: 1
Change of cell shape by cell adhesion 2 Microlament-mediated change
of cell shape 3 Cell growth and division. In the following part, we
will discuss some aspects of these mechanisms. A teratological
method used to determine the function of cell adhesion molecules in
vivo during embryogenesis has been reported recently.30 Mouse
hybridoma cells producing monoclonal antibodies against the avian
integrin complex were grafted into 2- or 3-day-old chick embryos.
Depending on the site of engraftment, local muscle agenesis was
observed. This is an example that the immunologic immaturity of the
embryo can be exploited to study the contribution of cell
attachment molecules to organ development in a functional fashion.
A number of monoclonal antibodies directed against cell attachment
molecules of various species have become available over the last 8
years, and the structure of the binding molecules has been
elucidated biochemically and by cDNA cloning. Functionally,
adhesion molecules may be grouped into three families: Cell
adhesion molecules (CAMs), which mediate specic and mostly
transient cell recognition of other cells, substrate adhesion
molecules (SAMs), necessary for attachment to extracellular matrix
proteins, and cell-junctional molecules (CJMs), found in tight and
gap junctions. Whereas CJMs apparently play an important role for
metabolic signalling within established tissues, CAMs and SAMs are
necessary for the formation of histologically distinct structures
and directed migration of single cells. Among CAMs and SAMs, at
least three families have been identied bio- chemically:
integrins,31 members of the immunoglobulin superfamiliy, and
LEC-CAMS.32 Integrins are hetero- dimeric molecules consisting of a
larger chain, which is associated with a smaller chain in a
calcium-dependent way. Usually, one given chain might be found in
association with various chains but promiscuity of chains has been
described recently. Functionally, members of the integrin family
present as SAMs (adhesion to vitronectin, collagen, bronectin,
comple- ment components, or other intercellular matrix proteins) or
CAMs (direct adhesion to other cells via correspond- ing cell
surface target molecules). For example, cells bearing the integrin
LFA-1 on their cell surface bind to cells expressing ICAM-1 or
ICAM-2, both of which are members of the immunoglobulin
superfamily.33,34 Other members of the immunoglobulin superfamily
which are known to be important during morphogenesis include
L-CAM35 (liver cell adhesion molecule) and N-CAM36,37 (neural cell
adhesion molecule). Both show homophilic aggregation, that is,
N-CAM serves as a target structure for N-CAM, and L-CAM serves as a
target structure for L-CAM, but there is no cross-reactivity. In
developing feather placodes in avian embryos, L-CAM and N-CAM are
mutually exclusive expressed on epidermal or mesodermal cells,
respectively. When the placodes are incubated with antibodies to
L-CAM, primarily only epidermal cell-to-cell contact is
disturbed.38 However, the structure of the surrounding mesoderm is
altered subsequently, suggesting an inductive signal loop between
epidermal and mesodermal cells. A third group of adhesion molecules
has been termed LEC-CAMs to indicate that their extracellular part
consists of a lectin domain, an epidermal growth factor-like
domain, and a complement regulatory protein repeat domain. The
lectin domain is presumed to contain the active center; binding
mediated by the murine homolog to the leuko- cyte adhesion molecule
1 (LAM-1)39 can be blocked by mannose-6-phosphate or its
polymers.40 Lectin- dependent organ formation should be accessible
experimentally by administration of the respective carbo- hydrates
but few if any data have been reported so far. Cell shape is mainly
maintained by microtubules forming the cellular cytoskeleton. In
addition, con- tractile elements exist such as actin, which are
essential for cell movement, the so-called microlaments. These
structures are thought to be essential for the process of placode
formation and invagination.41 Microlament- mediated change of cell
shape is based on the idea that actin laments could alter the shape
of cells by con- traction. Most of these laments are found at the
apex of epithelial cells. Contraction of these laments in each
individual cell of a cell layer would result in an increas- ing
infolding of the whole cell layer,41,42 nally resulting in
invagination. It is a disadvantage of this model, however, that
there is no apparent reason why apical constriction should be
proceeded by cell elongation.29 Cell proliferation is probably an
essential factor in the morphogenesis of epithelio-mesenchymal
organs.22 During morphogenesis of these organs repeated invagi-
nation can be observed, which might be dependent upon cell
proliferation.43 The way in which epithelial cell growth and
proliferation is controlled in the embryo is Embryology of
malformations 5
26. not clear. However, it is believed that the surrounding
mesenchyme might regulate the timing and location of invagination
of the epithelial layer. Goldin and Opperman44 proposed that
epidermal growth factor (EGF) might be excreted by mesenchymal
cells, which would stimulate epithelial cell proliferation and
repeated invagination. When agarose pellets impregnated with EGF
were cultured alongside 5-day embryonic chick tracheal epithelium,
supernumerary buds were induced to form at those sites. EGF and the
related peptide trans- forming growth factor- (TGF) have been shown
to lead to precocious eyelid opening when injected into newborn
mice.45 Thus, complex changes of late-stage organ development can
be induced by physiological stimuli in the laboratory.
Interestingly, EGF is a mitogen for many epithelial cells in vitro
without affecting most mesenchymal cells. A large variety of cells
have been demonstrated to display the receptor for EGF/TGF on their
cell surface, which is encoded by the cellular proto- oncogene
c-erbB. Structural alterations of this receptor are known to result
in uncontrolled proliferation and ultimately malignant
transformation. When secreted locally, EGF might provide physically
associated cells with appropriate on- and off-signals required for
the formation of complex organs. Other polypeptides, such as
platelet-derived growth factor (PDGF) or transform- ing growth
factor- (TGF) appear to function in an antagonistic way in that
they stimulate rather the proliferation of mesenchymal cells.46,47
In dened experi- mental situations, TGF has been shown to be a
mitogen for osteoblasts while being a potent inhibitor of the
proliferation of epithelial and endothelial cells at the same time.
Embryonic broblasts, however, are also inhibited by TGF.48 TGF is a
powerful chemotactic agent for broblasts and enhances the
production of both collagen and bronectin by these cells. There is,
however, little data available concerning the involvement of these
factors during normal and pathologic develop- ment of the embryo.
Future investigations using such powerful approaches as in situ
hybridization with cloned genes, preparation of transgenic animals,
and direct administration of the recombinant proteins to various
parts of the embryo might shed some light on signalling pathways
mediated by soluble cytokines. The surrounding mesenchyme might
limit the epithelial bud to expand49 forcing the epithelial sheet
to fold in characteristic patterns. If a growing cell layer is
restricted from lateral expansion, mitotic pressure by dividing
cells will result in elongation of cells and then invagination of
the crowded cell sheet. This does not necessarily imply that cells
divide more rapidly in the region of invagination than in the
surrounding areas. The main effect is caused by restriction of
lateral expansion.50,51 In the early anlage of the thymus, cell
proliferation counts are actually lower in the thymus anlage than
in the surrounding epithelium.52 Steding50 and Jacob51 have shown
experimentally that restriction of lateral expansion might be
responsible for thickening and subsequent invagination of
epithelial sheets. In their experiments, restriction of lateral
expansion was caused by a tiny silver ring placed on the epithelium
of chick embryos. EXAMPLES OF PATHOLOGICAL EMBRYOLOGY The focus of
our research has been the embryology of foregut, anorectal and
diaphragmatic malformations. We studied the normal development of
all embryonic organs involved by scanning electron microscopy
(SEM).5359 In addition, we employed two rodent animal models to
study malformations of the anorectum and the diaphragm.
Pathogenetic concepts concerning these malformations were
controversial in the past due to lack of detailed data. EMBRYOLOGY
OF FOREGUT MALFORMATIONS The differentiation of the primitive
foregut into the ventral trachea and dorsal esophagus is thought to
be the result of a process of septation.60 It is guessed that
lateral ridges appear in the lateral walls of the foregut, which
fuse in midline in a caudo-cranial direction thus forming the
tracheo-esophageal septum. This theory of septation has been
described in detail by Rosenthal and Smith.6162 However, others6364
were not able to verify the importance of the tracheo-esophageal
septum for the differentiation of the foregut. They instead
proposed individually that the respiratory tract develops simply by
further growth of the lung bud in a caudal direction. Using
scanning electron microscopy (SEM), we studied the development of
the foregut in chick embryos.53,54 In this study, we were unable to
demonstrate the formation of a tracheo-esophageal septum (Fig.
1.1). A sequence of SEM photographs of staged chick embryos
suggests that differentiation of the primitive foregut is best
explained by a process of reduction of size of a foregut region
called tracheo-esophageal space (Fig. 1.2). This reduction is
caused by a system of folds that develops in the primitive foregut.
They approach each other but do not fuse (Fig. 1.2). Based on these
observations, the development of the malformation can be explained
by disorders either of the formation of the folds or of their
developmental move- ments: 1 Atresia of the esophagus with stula
(Fig. 1.3a): The dorsal fold of the foregut bends too far
ventrally.As a result the descent of the larynx is blocked.
Therefore the tracheo-esophageal space remains partly undivided and
lies in a ventral position. Due to this ventral position it
differentiates into trachea. 6 Embryology of malformations
27. 2 Atresia of the trachea with stula (Fig. 1.3b): The
foregut is deformed on its ventral side. The developmental
movements of the folds are disturbed and the tracheo-esophageal
space is dislocated in a dorsal direction. Therefore it
differentiates into esophagus. 3 Laryngo-tracheo-esophageal clefts
(Fig. 1.3c): Faulty growth of the folds results in the persistence
of the primitive tracheo-esophageal space. Recently it has been
shown that esophageal atresias and tracheo-esophageal stulas can be
induced by maternal application of adriamycin into the peritoneal
cavity of pregnant rats.16,17 The dosage may vary between 1.5 mg to
2.0 mg/kg depending on the number of days it will be given. In most
reports the most promising dosage is 1.75 mg/kg given on days 69 of
pregnancy. The adriamycin model has been intensively studied over
the last couple of years, resulting in more than 30 reports between
1997 and 2001.65 It could be demonstrated that in this model not
only foregut malformations but also atypical patterns of
malformation can be observed which are usually summarized under the
term VATER or VACTERL association.18,19 Therefore, this model is
not only promising for the studies of foregut anomalies but also
for anomalies of the hind- and mid-gut. DEVELOPMENT OF THE
DIAPHRAGM In the past, several theories were proposed to explain
the appearance of postero-lateral diaphragmatic defects: 1 Defects
caused by improper development of the pleuro-peritoneal
membrane66,67 Development of the diaphragm 7 Figure 1.1 SEM
photograph of the inner layer of foregut epithelium in a chick
embryo (approx. 3.5 days old). View from cranial. Between trachea
(tr) on bottom and esophagus (es) on top, the tip of the
tracheo-esophageal fold (tef) is recognizable. Lateral ridges or
signs of fusion are not found45,46 Figure 1.2 Summarizing sketch of
foregut development. The tracheo-esophageal space (tes) is reduced
in size by developmental movements of folds (indicated by arrows)
(es, esophagus; la, anlage of larynx; br, bronchus; tr, trachea).
Short arrow marks tip of tracheo-esophageal fold (tef) (compare
Figure 1.1) Figure 1.3 Sketch of formal pathogenesis of typical
foregut malformations (see text for details): (a) atresia of
esophagus with stula; (b) atresia of trachea with stula; (c)
laryngotracheo-esophageal cleft. Arrows indicate sites of possible
deformation of the developing foregut
28. 2 Failure of muscularization of the lumbocostal trigone and
pleuro-peritoneal canal, resulting in a weak part of the
diaphragm66,68 3 Pushing of intestine through postero-lateral part
(foramen of Bochdalek) of the diaphragm69 4 Premature return of the
intestines into the abdominal cavity with the canal still open66,68
5 Abnormal persistence of lung in the pleuro- peritoneal canal,
preventing proper closure of the canal70 6 Abnormal development of
the early lung and posthepatic mesenchyme, causing non-closure of
pleuro-peritoneal canals.15 Of these theories, failure of the
pleuro-peritoneal membrane to meet the transverse septum is the
most popular hypothesis to explain diaphragmatic herniation.
However, using SEM techniques,55 we could not demon- strate the
importance of the pleuro-peritoneal membrane for the closure of the
so-called pleuro-peritoneal canals (Fig. 1.4). As stated earlier,
most authors assume that delayed or inhibited closure of the
diaphragm will result in a diaphragmatic defect that is wide enough
to allow herniation of gut into the fetal thoracic cavity. However,
this assumption is not the result of appropriate embryo- logical
observations but rather the result of interpreta- tions of
anatomical/pathological ndings. In a series of normal staged
embryos we measured the width of the pleuro-peritoneal openings and
the transverse diameter of gut loops.54 On the basis of these
measurements we estimated that a single embryonic gut loop requires
at least an opening of 450 size to herniate into the fetal pleural
cavity. However, in none of our embryos the observed
pleuro-peritoneal openings were of appro- priate dimensions. This
means that delayed or inhibited closure of the pleuro-peritoneal
canal cannot result in a diaphragmatic defect of sufcient size.
Herniation of gut through these openings is therefore impossible.
Thus the proposed theory about the pathogenetic mechanisms of
congenital diaphragmatic hernia (CDH) development lacks any
embryological evidence. Furthermore the proposed timing of this
process is highly questionable.57 Recently, an animal model for
diaphragmatic hernia has been developed1115 using nitrofen as
noxious substance. In these experiments CDHs were produced in a
reasonably high percentage of newborns.12,13 Most diaphragmatic
hernias were associated with lung hypoplasias. Using electron
microscopy, our group5659 used this model to give a detailed
description of the development of the diaphragmatic defect. Our
results are as follows: Timing of diaphragmatic defect appearance
Iritani15 was the rst to notice that nitrofen-induced diaphragmatic
hernias in mice are not caused by an improper closure of the
pleuro-peritoneal openings but rather the result of a defective
development of the so- called post-hepatic mesenchymal plate
(PHMP). In our study in rats, clear evidence of disturbed
development of the diaphragmatic anlage was seen on day 13 (left
side) and day 14 (right side, Fig. 1.5).56,59 In all embryos 8
Embryology of malformations Figure 1.4 SEM photograph of right
pleural sac in a rat embryo (approx. 16.5 days old). View from
cranial. The so- called pleuro-peritoneal canal (PPC) is nearly
closed. Small arrows point at the margin of PPC. In the depth of
the abdomen the right adrenals (ad) are seen. Large arrows point at
margins of the so-called pleuro-peritoneal membrane. Its
contribution to the closure of the canal is minimal47 (es,
esophagus) Figure 1.5 Cranial view of the pleural sacs in a rat
embryo after exposition to nitrofen on day 11 of pregnancy. The
embryo is approx. 15 days old. Note the big defect of the right
diaphragmatic primordium. Small black arrows point at margins of
the defect, which leaves parts of the liver (li) uncoated. On the
left, the diaphragmatic anlage is normal. Note the low position of
the cranial border of the pleuro-peritoneal opening on this side
(white arrows). (ad, adrenals; di, anlage of diaphragm)
29. affected, the PHMP was too short. This age group is
equivalent to 45-week-old human embryos.56 Location of
diaphragmatic defect In our SEM study, the observed defects were
localized in the PHMP (Fig. 1.5). We identied two distinct types of
defects: (1) large dorsal defects and (2) small central defects.56
Large defects extended into the region of the pleuro-peritoneal
openings. In these cases, the closure of the pleuro-peritoneal
openings was usually impaired by the massive ingrowth of liver
(Figs 1.6 & 1.7). If the defects were small, they were
consistently isolated from the pleuro-peritoneal openings closing
normally at the 16th or 17th day of gestation. Thus, in our embryos
with CDH, the region of the diaphragmatic defect was a distinct
entity and was separated from that part of the diaphragm where the
pleuro-peritonealcanals are local- ized. We conclude therefore that
the pleuro-peritoneal openings are not the precursors of the
diaphragmatic defect. Why lungs are hypoplastic Soon after the
onset of the defect in the 14-day-old embryo, liver grows through
the diaphragmatic defect into the thoracic cavity (Fig. 1.6). This
indicates that from this time on the available thoracic space is
reduced for the lung and further lung growth hampered. In the
following stages, up to two-thirds of the thoracic cavity can be
occupied by liver (Fig. 1.7). Herniated gut was found in our
embryos and fetuses only in late stages of development (21 days and
newborns). In all of these, the lungs were already hypoplastic,
when the bowel entered the thoracic cavity.53 Based on these
observations, we conclude that the early ingrowth of the liver
through the diaphragmatic defect is the crucial step in the
pathogenesis of lung hypoplasia in CDH. This indicates that growth
impair- ment is not the result of lung compression in the fetus but
rather the result of growth competition in the embryo: the liver
that grows faster than the lung reduces the aviable thoracic space.
If the remaining space is too small, pulmonary hypoplasia will
result. DEVELOPMENT OF THE CLOACA In the literature several
theories have been put forward to explain the differentiation of
the cloaca into the dorsal anorectum and the ventral sinus
urogenitalis. To many authors this differentiation is caused by a
septum which develops cranially then caudally and thus divides the
cloaca in a frontal plane. Disorders in this process of
differentiation are thought to be the cause of cloacal anomalies
such as persistent cloaca and anorectal mal- formations. However,
there is no agreement on the mechanisms of the septational process.
While some authors71,72 believe that the descent of a single fold
separates the urogenital part from the rectal part by ingrowth of
mesenchyme from cranial, others73 think that lateral ridges appear
in the lumen of the cloaca, which progressively fuse along the
midline and thus form the septum. In a recent paper74 the process
of septation had been questioned altogether. Using SEM techniques,
our group studied cloacal development in rat and sd-mice embryos.
The sd-mouse Development of the cloaca 9 Figure 1.6 Liver (li)
protrudes through diaphragmatic defect. Arrows point to the margin
of the defect (di, diaphragmatic anlage). Rat embryo (approx. 16
days old), nitrofen exposition on day 11 of pregnancy Figure 1.7
SEM photograph of a right pleural sac in a rat embryo after
nitrofen exposure on day 11 of pregnancy. The embryo is
approximately 15.5 days old. Note the big defect of the right
dorsal diaphragm (large arrows). The closure of the
pleuro-peritoneal canal (PPC) is impaired by the ingrowths of liver
(small arrows). Li1 = liver growing through PPC. Li1 + Li2 = liver
growing through the defect of the diaphragm
30. is a spontaneous mutation of the house mouse characterized
by having a short tail (Fig. 1.8). Homo- zygous or heterozygous
offspring of these mice show skeletal, urogenital and anorectal
malformations.18 Therefore these animals are ideal in the study of
the development of anorectal malformations. Normal cloacal
embryology (rat) As in the foregut of chick embryos, signs of
median fusion of lateral cloacal parts could not be demonstrated
during normal cloacal development in the rat. However, in
contradiction to vdPUTTE,74 the current authors think that
downgrowth of the urorectal fold takes place, although it is
probably not responsible for the formation of cloacal
malformations. Abnormal cloacal embryology (sd-mouse) Cloacal
malformations are caused by improper develop- ment of the early
anlage of the cloacal membrane as demonstrated in sd-mice
embryos.75,76 Our studies of abnormal cloacal development in sd-
mice had the following results: 1 The basis of the pathogenesis of
anorectal malformations is too short a cloacal membrane 2 The
anlage of the cloacal membrane is too short and results in a
maldeveloped anlage of the cloaca, which is undeveloped in its
dorsal part (Fig. 1.9) 3 The caudal movement of the urorectal fold
is impaired by the malformed cloaca. Thus the hindgut remains in
abnormal contact with the cloaca. This opening is true ectopic and
will develop into the recto-urogenital stula (Fig. 1.10).
HYPOSPADIAS Many investigators7780 believe that the urethra
develops by fusion of the paired urethral folds following the
disintegration of the urogenital membrane. Impairment of this
process is thought to result in the different forms 10 Embryology
of malformations Figure 1.8 Characteristic short tail (arrow) of
sd-mouse embryo (approx. 13 days old) (ll, left lower limb; ge,
genital tuberculum, abnormal) Figure 1.9 Malformed cloaca of
sd-mouse embryo (approx. 11 days old). The surrounding mesenchyme
is removed by microdissection. View on the basal layer of the
cloacal entoderm. The cloaca has lost its contact to the ectoderm
of the genitals (white arrow). The dorsal part of the cloaca is
missing (black arrow). Tailgut (tg) and hindgut (hg) are
hypoplastic. This malformed cloaca developed because the anlage of
the cloacal membrane was too short in early embryogenesis (see text
for details) (cc, rest of cloaca; u, urachus, rudimentary) Figure
1.10 Malformed cloaca of sd-mouse, embryo (approx. 13 days old).
Urachus (u) and rectum (re) nearly normal (cl, ventral part of
cloaca with short cloacal membrane). The dorsal part of the cloaca
is missing (long white arrows). Short white arrow points to the
region of the future stula
31. of hypospadia80 However, in our study of normal cloacal
development,81 we were puzzled by the fact that disinte- gration of
the urogenital part of the cloacal membrane could not be observed
in rat embryos (Fig. 1.11). This nding caused us to call in
question the generally assumed concepts of hypospadia formation.
Instead we found that: 1 The urethra is always present as a hollow
organ during embryogenesis of rats and that it is always in contact
with the tip of the genitals, and that 2 An initially double
urethral anlage exists. The differentiation in female and male
urethra starts in rats of 18.5 days old. On the other hand, we
found no evidence for: The disintegration of the urogenital cloacal
membrane, and A fusion of lateral portions within the perineum. In
our opinion, more than one embryological mech- anism is at play in
the formation of the hypospadias complex. The moderate degrees,
such as the penile and glandular forms, represent a developmental
arrest of the genitalia (Fig. 1.12). They take their origin from a
situation comparable to the 20-day-old embryo. Consequently the
penis, not the urethra is the primary organ of the malformation.
Perineal and scrotal hypospadias are different from the type
discussed previously. Pronounced signs of feminization in these
forms suggest that we are dealing with a female-type urethra.
Origin of this malformation complex is an undifferentiated stage as
may be seen in the 18.5-day-old rat embryo. CONCLUSION Despite the
long history of experimental embryology, we know very little about
etiology and pathogenesis of congenital malformations. For decades,
hypotheses were abundant while few data existed to support them.
The tremendous progress of neighboring biological sciences is now
providing powerful tools for researchers in the eld, such as
recombinant DNA and hybridoma tech- nology. Future investigations
will monitor closely how genes are switched on and off during
embryogenesis and determine the relation of spatial and temporal
disturb- ances to ensuing malformations. Target structures of
chemical or viral teratogens within the embryonic cells await
identication. Finally, improved understanding of growth
coordination in utero will extend to related areas such as wound
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35. 2 Prenatal diagnosis of surgical diseases TIPPI C.
MACKENZIE AND N. SCOTT ADZICK INTRODUCTION Prenatal diagnosis has
undergone an explosion of growth in the past decade. The primary
impetus for this rapid expansion has come from the widespread use
of prenatal ultrasonography. Most correctable malformations that
can be diagnosed in utero are best managed by appro- priate medical
and surgical therapy after maternal transport and planned delivery
at term. Prenatal diag- nosis may inuence the timing (Box 2.1) or
mode (Box 2.2) of delivery, and in some cases may lead to elective
termination of the pregnancy. In rare cases, various forms of in
utero therapy may be possible (Table 2.1). Prenatal diagnosis has
dened a hidden mortality for some lesions such as congenital
diaphragmatic hernia, bilateral hydronephrosis, sacrococcygeal
teratoma, and cystic hygroma. These lesions, when rst evaluated and
treated postnatally demonstrate a favorable selection bias. The
most severely affected fetuses often die in utero or immediately
after birth, before an accurate diagnosis has been made.
Consequently, such a condition detected prenatally may have a worse
prognosis than the same condition diagnosed after delivery.1 The
perinatal management of the patients involves many different
medical disciplines, including obstetricians, sono- graphers,
neonatologists, geneticists, pediatric surgeons, and pediatricians.
It is essential that the affected family be managed using a team
approach, and that infor- mation and experience be exchanged
freely. In this chapter we will discuss the prenatal diagnosis of
neonatal surgical lesions. First, a brief summary of the diagnostic
methods currently available will be given. Then a review of
prenatal diagnosis by organ system will be presented. DIAGNOSTIC
METHODS Ultrasound Ultrasound testing has become a routine part of
the pre- natal evaluation of almost all pregnancies. It is
especially important to perform ultrasound for pregnancies with
maternal risk factors (e.g. age over 35 years, diabetes, Box 2.1
Defects that may lead to induced preterm delivery Obstructive
hydronephrosis Gastroschisis or ruptured omphalocele Intestinal
ischemia and necrosis secondary to volvulus, meconium ileus, etc.
Sacrococcygeal teratoma with hydrops Box 2.2 Defects that may
require cesarian delivery Myelomeningocele Gastroschisis Large
sacrococcygeal teratoma Giant neck masses (EXIT procedure) Table
2.1 Diseases amenable to fetal surgical intervention in selected
cases Malformation Effect on development In utero treatment
Congenital diaphragmatic hernia Pulmonary hypoplasia, respiratory
failure Tracheal occlusion CCAM or BPS Pulmonary hypoplasia,
hydrops Thoracoamniotic shunting, lobectomy Sacrococcygeal teratoma
Massive arteriovenous shunting, placentomegaly, hydrops Excision
Urethral obstruction Hydronephrosis, lung hypoplasia Vesicoamniotic
shunting Myelomeningocele Damage to spinal cord, paralysis Closure
of defect
36. previous child with anatomic or chromosomal abnor- mality)
and if there is an elevation in maternal serum alphafetoprotein
(MSAFP). Most defects can be reliably diagnosed in the late rst or
early second trimester by a skilled sonographer. More recently,
nuchal translucency measurements have emerged as an independent
marker of chromosomal abnormalities, with a sensitivity of about
60%.2 This abnormality may be detected on trans- vaginal ultrasound
at 1015 weeks gestation, thus providing an early test for high-risk
pregnancies. Nuchal cord thickening may also be a marker for
congenital heart disease3 and may be a valuable initial screen to
detect high-risk fetuses for referral for fetal echocardio- graphy.
It is important to remember that sonography is operator dependent;
the scope and reliability of the information obtained is directly
proportional to the skill and experience of the sonographer.
Magnetic resonance imaging Until recently, the long acquisition
times required for magnetic resonance imaging (MRI) were not
conducive to fetal imaging because fetal movements resulted in poor
quality images. Obtaining adequate images with the traditional
spin-echo techniques required fetal sedation or paralysis.4 With
the development of ultrafast scanning techniques, the artifacts
caused by fetal motion have almost been eliminated.5 This technique
is now an important part of prenatal evaluation of fetuses referred
to our institution and has greatly enhanced our ability to diagnose
and treat fetal malformations. Amniocentesis The rst report of the
culture and karyotyping of fetal cells from amniocentesis was by
Steele and Berg in 1966.6 Since then, it has become the gold
standard for detecting fetal chromosomal abnormalities by
karyotyping. It is usually performed at 1516 weeks gestation and
involves a very low risk of fetal injury or loss. Attempts at early
amniocentesis (at 1112 weeks gestation) have been complicated by a
higher pregnancy loss, increased risk of iatrogenic fetal
deformities and increased postamnio- centesis leakage rate.7 For
this reason, the most reliable method for rst trimester diagnosis
remains chorionic villus sampling. Chorionic villus sampling
Chorionic villus sampling (CVS) may be performed at 1014 weeks
gestation and involves the biopsy of the chorion frondosum, the
precursor for the placenta. Either a transcervical or
transabdominal approach may be used, both under ultrasound
guidance. The cells obtained may be subjected to a variety of tests
including karyotype, genetic probes, or enzyme analysis. Due to the
high mitotic rate of the chorionic villus cells, results for
karyotyping may be obtained in less than 24 hours. Disadvantages
include diagnostic errors due to maternal decidual contamination or
genetic mosaicism of the trophoblastic layer of the placenta. When
preformed by experienced operators, the pregnancy loss rate is
equivalent to that of second trimester amniocentesis.8 BIOCHEMICAL
MARKERS Maternal blood and amniotic uid can be screened for the
presence of various biochemical markers that indi- cate fetal
disease. About two-thirds of women in the USA currently undergo
screening for Down syndrome and other chromosomal abnormalities
with the triple test, which includes measuring serum
alphafetoprotein with human chorionic gonadotropin and unconjugated
estriol.9 This screening is performed in the early second
trimester, and the detection rate for Down syndrome is 69%, with a
5% false-positive test.10 A positive result on the serum screening
test indicates a need for chromo- some analysis by amniocentesis.
Percutaneous umbilical blood sampling Obtaining umbilical venous
blood can also be used to determine the karyotype and diagnose
various metabolic and hematological disorders. The percutaneous
umbilical blood sampling (PUBS) procedure is performed at around 18
weeks gestation under ultra- sound guidance. Karyotype results may
be obtained within 2448 hours. In various large series, the
mortality from the procedure has been reported to be 12%, with
increasing mortality rates with long procedure times and multiple
punctures.1113 Fetal cells in the maternal circulation Since the
advent of uorescence-activated cell sorting (FACS), there has been
growing interest and progress in detecting circulating fetal cells
in maternal blood for diagnostic purposes.14 The cell type most
successfully used in this endeavor is the fetal nucleated red blood
cell, since these are abundant in the rst trimester fetal circu-
lation. These cells may be separated from maternal nucleated red
blood cells by staining for CD71 or fetal and embryonic
hemoglobins.15 Genetic analysis may then be performed using
polymerase chain reaction (PCR) or uorescence in situ hybridization
(FISH) for chromosome-specic probes. Although the test currently
has a low sensitivity (4050%),15 the false- positive rate is
negligible, which is an advantage over the 5% false-positive rate
of the conventional triple screen. 16 Prenatal diagnosis of
surgical diseases
37. PRENATAL DIAGNOSIS OF SPECIFIC SURGICAL LESIONS Neck masses
Fetal airway obstruction could be a result of extrinsic compression
of the airway by lesions such as cervical teratoma or cystic
hygroma, or intrinsic defects in the airway such as congenital high
airway obstruction syndrome. Although large congenital neck masses
caus- ing airway obstruction previously carried an enormous
perinatal mortality16 the advent of the ex utero intra- partum
treatment (EXIT) procedure17,18 has improved their outcome by
providing a means of controlling the airway during delivery and
converting an airway emergency into an elective procedure (Fig.
2.1). Cystic hygroma diagnosed in utero is a severe diffuse
lymphatic abnormality which is frequently associated with hydrops,
polyhydramnios, and other abnormalities.19 Chromosomal
abnormalities are very common (62% overall), the most common being
Turners syndrome.20 There are two groups of prenatally diagnosed
cervical lymphangiomas: those diagnosed in the second trimester
(usually in the posterior triangle of the neck, have a high
incidence of associated abnormalities, and carry a very poor
prognosis),21 and those diagnosed later in gestation (most often
isolated lesions and generally do not lead to hydrops). Hydrops is
an ominous nding in fetuses with cystic hygroma,16 as is the
presence of aneuploidy and septations in the mass.22 However,
fetuses with normal karyotype, non-septated masses, and no evidence
of hydrops may have a good prognosis.23 Therefore, it is important
to monitor the fetus for development of hydrops by serial
evaluations. Teratomas are asymmetrical lesions which are
frequently unilateral, with well-dened margins. They may also be
multiloculated, irregular masses with solid and cystic components.
Most teratomas contain calcica- tions. MRI is a very useful adjunct
to ultrasound in evaluating giant neck masses. We have used it
successfully for showing the relationship of the mass to the airway
in preparation for an EXIT procedure.24 T1-weighted images may help
differentiate teratomas from lymphangiomas.25 The EXIT procedure,
originally designed for removal of tracheal clips,17 has proven to
be life-saving for many fetuses with giant neck masses.18 This
procedure involves performing a maternal hysterotomy and obtaining
control of the fetal airway while the fetus remains on placental
support. In order to prevent uterine con- tractions during the
procedure, the mother is given inhalational anesthetic and
tocolytics, warm saline is infused through a level I device, and
only the head and shoulders of the fetus are delivered. After
attaching a pulse oximeter to the fetal hand to monitor heart rate
and oxygen saturation, direct laryngoscopy and, if possible,
endotracheal intubation is performed. If the airway cannot be
secured in this way, a rigid broncho- scope is inserted to
determine the anatomy. If secure air- way establishm