Newborn Surgery 3rd Ed

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Newborn Surgery


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First published in Great Britain in 1996 by Butterworth-Heinemann Ltd

Second edition published in 2003 by Hodder ArnoldThis third edition published in 2011 byHodder Arnold, an imprint of Hodder Education, a division of Hachette UK

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http://www.hodderarnold.com

2011 Hodder & Stoughton Ltd

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To Veena, Abir, Anita and Niki for their love and patience


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Contents

Contributors xiii

Prefaces xix

PART I GENERAL 1

1 Embryology of malformations 3

Dietrich Kluth, Wolfgang Lambrecht, Christoph Buhrer, and Holger Till

2 Perinatal physiology 15

Carlos E Blanco, Eduardo Villamor, and Luc JI Zimmermann

3 Clinical anatomy of the newborn 29

Mark D Stringer

4 The epidemiology of birth defects 39

Edwin C Jesudason

5 Perinatal diagnosis of surgical disease 46

Tippi C MacKenzie and N Scott Adzick

6 Fetal counseling for surgical malformations 60Kokila Lakhoo

7 Fetal and birth trauma 71

Prem Puri and Piotr Hajduk

8 Transport of the surgical neonate 83

Prem Puri and Reshma Doodnath

9 Preoperative assessment 91

Prem Puri and John Gillick

10 Anesthesia 104

Declan Warde and Nicholas Eustace

11 Postoperative management 115Desmond Bohn

12 Fluid and electrolyte balance in the newborn 133

Joseph Chukwu, Winifred A Gorman, and Eleanor J Molloy

13 Nutrition 145

Agostino Pierro and Simon Eaton

14 Vascular access in the newborn 159

Sean J Barnett and Frederick C Ryckman

15 Radiology in the newborn 167

J Kelleher and Ian HW Robinson

16 Immune system of the newborn 178

Fiona OHare, Denis J Reen, and Eleanor J Molloy


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17 Neonatal sepsis 191

James Pierce, Tracy Grikscheit, and Henri Ford

18 Hematological problems in the neonate 205

Owen P Smith

19 Genetics in neonatal surgical practice 214

Andrew Green20 Ethical considerations in newborn surgery 228

Jacqueline J Glover and Donna A Caniano

21 Minimal invasive neonatal surgery 237

Richard Keijzer, Oliver J Muensterer, and Keith E Georgeson

22 Fetal surgery 246

Shinjiro Hirose and Michael R Harrison

23 Liver transplantation 254

Alastair Millar

PART II HEAD AND NECK 265

24 Choanal atresia 267

Stephen M Kieran and John D Russell

25 Pierre Robin Sequence 271

Udo Rolle and Robert Sader

26 Macroglossia 277

George G Youngson

27 Tracheostomy in infants 281

Thom E Lobe

28 Congenital cysts and sinuses of the neck 288

Yousef El-Gohary and George K Gittes

PART III CHEST 295

29 Congenital thoracic deformities 297

Konstantinos Papadakis and Robert C Shamberger

30 Mediastinal masses in the newborn 305

Stephen J Shochat

31 Congenital airway malformations 310

Richard G Azizkhan

32 Vascular rings 321Benjamin O Bierbach and J Mark Redmond

33 Pulmonary air leaks 333

Prem Puri and Jens Dingemann

34 Chylothorax and other pleural effusions in neonates 339

Richard G Azizkhan

35 Congenital malformations of the lung 348

Li Ern Chen and Keith T Oldham

36 Congenital diaphragmatic hernia 361

Prem Puri and Takashi Doi

37 Extracorporeal membrane oxygenation for neonatal respiratory failure 369

Jeffrey W Gander and Charles JH Stolar

38 Bronchoscopy in the newborn 380

Stephen M Kieran and John D Russell

viii Contents


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PART IV ESOPHAGUS 385

39 Esophageal atresia and tracheoesophageal fistula 387

Paul D Losty, Wajid B Jawaid, and Basem A Khalil

40 Congenital esophageal stenosis 401

Shintaro Amae and Masaki Nio

41 Esophageal duplication cysts 406

Dakshesh Parikh and Michael Singh

42 Esophageal perforation in the newborn 412

David S Foley and Hirikati S Nagaraj

43 Gastro-esophageal reflux in the neonate and small infant 416

Michael E Hollwarth

PART V GASTROINTESTINAL 425

44 Pyloric atresia and prepyloric antral diaphragm 427

Vincenzo Jasonni, Alessio Pini Prato, Giovanni Rapuzzi, and Girolamo Mattioli

45 Hypertrophic pyloric stenosis 433

Prem Puri, Balazs Kutasy, and Ganapathy Lakshmanadass

46 Gastric volvulus 444

Alan E Mortell

47 Gastric perforation 450

Robert K Minkes

48 Gastrostomy 455

Michael WL Gauderer

49 Duodenal obstruction 467

Yechiel Sweed

50 Malrotation 482Agostino Pierro and Shireen Anne Nah

51 Persistent hyperinsulinemic hyperglycemia of infancy 488

Paul RV Johnson

52 Jejuno-ileal atresia and stenosis 494

Alastair Millar, Alp Numanoglu, and Heinz Rode

53 Colonic and rectal atresias 505

Tomas Wester

54 Meconium ileus 512

Guido Ciprandi and Massimo Rivosecchi

55 Meconium peritonitis 518Jose Boix-Ochoa and Jose L Peiro

56 Duplications of the alimentary tract 525

Alan Mortell and Prem Puri

57 Mesenteric and omental cysts 535

Benno Ure

58 Neonatal ascites 541

Prem Puri and Elke Ruttenstock

59 Necrotizing enterocolitis 546

Shannon Castle, Tracy Grikscheit, and Henri R Ford

60 Hirschsprungs disease 554

Prem Puri

61 Anorectal anomalies 566

Marc A Levitt and Alberto Pena

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62 Congenital pouch colon 582

Amulya K Saxena and Praveen Mathur

63 Congenital segmental dilatation of the intestine 590

Hiroo Takehara and Hisako Kuyama

64 Intussusception 594

Spencer W Beasley65 Inguinal hernia 599

Thambipillai Sri Paran and Prem Puri

66 Short bowel syndrome and surgical techniques

for the baby with short intestines 606

Michael E Hollwarth

67 Megacystis microcolon intestinal hypoperistalsis syndrome 617

Prem Puri and Jan-H Gosemann

PART VI LIVER AND BILIARY TRACT 621

68 Biliary atresia 623

Mark Davenport

69 Congenital biliary dilatation 634

Hiroyuki Koga and Atsuyuki Yamataka

70 Hepatic cysts and abscesses 643

Stephanie A Jones, Frederick M Karrer, and David A Partrick

PART VII ANTERIOR ABDOMINAL WALL DEFECTS 649

71 Omphalocele and gastroschisis 651Steven W Bruch and Jacob C Langer

72 Omphalomesenteric duct remnants 661

Kenneth KY Wong and Paul KH Tam

73 Bladder exstrophy: considerations and management of the newborn patient 665

Andrew A Stec and John P Gearhart

74 Cloacal exstrophy 674

Duncan Wilcox and Moritz M Ziegler

75 Prune belly syndrome 681

Prem Puri and Hideshi Miyakita

76 Conjoined twins 686

Juan A Tovar

PART VIII TUMORS 695

77 Epidemiology and genetic associations of neonatal tumors 697

Sam W Moore and Jack Plaschkes

78 Hemangiomas and vascular malformations 711

Arin K Greene and Steven J Fishman

79 Congenital nevi 726

Christina M Plikaitis and Bruce S Bauer

80 Lymphatic malformations (cystic hygroma) 739Emily Christison-Lagay, Vito Forte, and Jacob C Langer

x Contents


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81 Cervical teratomas 749

Michael WL Gauderer

82 Sacrococcygeal teratoma 754

Kevin C Pringle

83 Nasal tumors 764

Peter Lamesch84 Neuroblastoma 770

Andrew M Davidoff

85 Soft-tissue sarcoma 781

Martin T Corbally

86 Hepatic tumors 784

Jai Prasad and Michael P La Quaglia

87 Congenital mesoblastic nephroma and Wilms tumor 800

Robert Carachi

88 Neonatal ovarian tumors 804

Chad Wiesenauer and Mary E Fallat

PART IX SPINA BIFIDA AND HYDROCEPHALUS 809

89 Spina bifida and encephalocele 811

Michael D Jenkinson, Maggie K Lee, and Conor L Mallucci

90 Hydrocephalus 824

Jothy Kandasamy, Maggie K Lee, and Conor L Mallucci

PART X GENITOURINARY 835

91 Urinary tract infections 837

Martin A Koyle

92 Imaging of the renal tract in the neonate 845

Lorenzo Biassoni and Melanie Hiorns

93 Management of antenatal hydronephrosis 856

Jack S Elder

94 Multicystic dysplastic kidney 872

David FM Thomas and Azad S Najmaldin

95 Upper urinary tract obstructions 880

Prem Puri and Boris Chertin

96 Ureteral duplication anomalies 894

Prem Puri and Hideshi Miyakita

97 Vesico-ureteral reflux 900

Prem Puri

98 Ureteroceles in the newborn 907

Jonathan F Kalisvaart and Andrew J kirsch

99 Posterior urethral valves 916

Paolo Caione and Valentina de Pasquale

100 Neurogenic bladder in the neonate 934

Yves Aigrain and Alaa el Ghoneimi

101 Hydrometrocolpos 940

Devendra K Gupta and Shilpa Sharma

102 Intersex disorders 952Maria Marcela Bailez and Estela Cuenca

Contents xi


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103 Male genital anomalies 966

John M Hutson

104 Neonatal testicular torsion 972

David M Burge

PART XI LONG-TERM OUTCOMES IN NEWBORN SURGERY 975

105 Long-term outcomes in newborn surgery 977

Casey M Calkins and Keith T Oldham

Index 995

xii Contents


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Contributors

N Scott Adzick MD

Surgeon-in-Chief, Department of Surgery, Childrens Hospital of

Philadelphia, C Everett Koop Professor of Pediatric Surgery,

University of Pennsylvania, School of Medicine, Philadelphia, USA

Yves Aigrain MD FEBPS FEAPU

Professor, UniversiteParis Descartes Department of Pediatric

Surgery and Urology, Hopital Necker Enfants Malades, Paris,

France

Shintaro Amae MD

Department of Surgery, Miyagi Childrens Hospital, Sendai, Japan

Richard G Azizkhan MD PhD

Surgeon-in-Chief, Lester Martin Chair of Pediatric Surgery,

Cincinnati Childrens Hospital, Cincinnati, OH, USA

Maria Marcela Bailez MD

Head of the Surgical Center at the Garrahans Childrens Hospital,

University of Buenos, Aires, ArgentinaSean J Barnett MD MS

Assistant Professor of Surgery, Cincinnati Childrens Hospital

Medical Center, Cincinnati, OH, USA

Bruce S Bauer MD FACS FAAP

Clinical Professor of Surgery, Pritzker School of Medicine at

University of Chicago, Chief Division of Plastic Surgery,

NorthShore, University Health System, Northbrook, IL, USA

Spencer W Beasley MB ChB MS FRACS

Department of Paediatric Surgery, Christchurch Hospital,

Christchurch, New Zealand

Lorenzo Biassoni MSc FEBNM FRCP

Consultant in Nuclear Medicine, Great Ormond Street Hospital for

Children NHS Trust, Honorary Senior Lecturer, University College

London, London, UK

Benjamin O Bierbach MD

Cardiothoracic Surgeon, University Hospital Kiel, Department of

Cardiovascular Surgery, Kiel, Germany

Carlos E Blanco MD PhD FRCPI

Professor of Pediatrics, Director of Research, National Childrens

Research Centre, Consultant Neonatologist, National Maternity

Hospital, Dublin, Ireland

Desmond Bohn MB FRCPC MRCP

Professor of Anaesthesia and Paediatrics, University of Toronto,

Toronto, Ontario, Canada

Jose Biox-Ochoa MD

Professor Emeritus, Autonomous University of Barcelona, Spain

Steven W Bruch MD MSc

Clinical Associate Professor, Mott Childrens Hospital, University of

Michigan, Ann Arbor, MI, USA

David M Burge FRCP FRCS FRACS

Consultant Paediatric Surgeon, Southampton General Hospital,

Southampton, UK

Christoph Buhrer MD PhD

Professor of Pediatrics, Department of Neonatology, Medical

Faculty Charite, Humboldt University, Berlin, Germany

Paolo Caione MD FEAPLI

Professor, Chief Division Paediatric Urology, Director Department

Nephrology and Urology, Bambino Gesu Childrens Hospital,

Rome, Italy

Casey M Calkins MDAssociate Professor of Surgery, Medical College of Wisconsin,

Childrens Hospital of Wisconsin, Milwaukee, WI, USA

Donna A Caniano MD

Professor Emeritus, Department of Surgery, The Ohio State

University College of Medicine, Columbus, OH, USA

Robert Carachi FRCS PhD FRCS(ENG) (ad eundem) FEBPS

Professor, Division of Developmental Medicine, Section of Surgical

Paediatrics, University of Glasgow, The Royal Hospital for Sick

Children, Glasgow, UK

Shannon L Castle MD

Research Fellow, Department of Pediatric Surgery, ChildrensHospital Los Angeles, Los Angeles, CA, USA

Li Ern Chen MD

Assistant Professor of Surgery, University of Texas Southwestern

Dallas, TX, USA

Boris Chertin MD

Chairman, The Department of Paediatric Urology, Shaare Zedek

Medical Center, Clinical Professor in Surgery/Urology, Faculty of

Medicine, Hebrew University, Jerusalem, Israel

Emily Christison-Lagay MD

Fellow in Pediatric General and Thoracic Surgery, Hospital for Sick

Children, Toronto, Ontario, Canada

Joseph Chukwu MRCPI, DCH, Dip(HSM), MBBS

Pediatric Registrar, National Maternity Hospital, Dublin, Ireland


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Guido Ciprandi MD

Consultant Pediatric Surgeon, Bambino GesuChildrens Hospital,

IRCCS Palidoro and Rome, Italy

Martin T Corbally MD FRCSI

Associate Professor Paediatric Surgery RCSI, Consultant Paediatric

Surgeon, Our Ladys Childrens Hospital, Crumlin, Dublin, Ireland

Estela Cuenca MD

Pediatric Surgeon, Research Fellow, Colorectal Unit, JP Garrahan

Childrens Hospital, Buenos, Aires, Argentina

Andrew M Davidoff MD

Chairman, Department of Surgery, St Jude Childrens Research

Hospital, Memphis, TN, USA

Mark Davenport ChM FRCS (Eng) FRCS (Paeds)

Professor of Paediatric Surgery, Kings College Hospital,

London, UK

Jens Dingemann MD

Centre of Pediatric Surgery, Hannover Medical School and BultChildrens Hospital, Hannover, Germany

Takashi Doi MD PhD

Department of Paediatric General and Urogenital Surgery,

Juntendo University School of Medicine, Tokyo, Japan

Reshma Doodnath MB BCh BaO IMRCS

Clinical Research Fellow, National Childrens Research Centre,

Our Ladys Childrens Hospital, Crumlin, Dublin 12, Ireland

Simon Eaton PhD

Department of Paediatric Surgery, UCL Institute of Child Health,

London, UK

Jack S Elder MDVattikuti Urology Institute, Henry Ford Hospital, Detroit, MI USA

Yousef El-Gohary MD MRCS (Glas)

Pediatric Surgery Research Fellow, Childrens Hospital of

Pittsburgh, Pittsburgh, PA, USA

Nicholas Eustace MB MMedSci FCARCSI FJFICMI

Anaesthesia, Intensive Care and Pain Medicine, Childrens

University Hospital, Dublin, Ireland

Mary E Fallat MD

Professor and Division Chief, Chief of Surgery, Kosair Childrens

Hospital, Department of Pediatric Surgery, University of Louisville,

Louisville, KY, USA

Steven J Fishman MD

Stuart and Jane Weitzman Family Chair in Surgery,

Co-Director, Vascular Anomalies Center, Childrens Hospital

Boston, Boston, MA, USA

David S Foley MD FACS

Associate Professor of Surgery, Division of Pediatric Surgery,

University of Louisville School of Medicine, Louisville, KY, USA

Henri R Ford MD MHA

Vice President and Surgeon-in-Chief, Childrens Hospital

Los Angeles, Professor of Surgery and Vice Dean for Medical

Education, University of Southern California, Keck School ofMedicine, Los Angeles, CA, USA

Vito Forte MD FRCSC

Chief, Hospital for Sick Children, Toronto, Ontario, Canada

Jeffrey W Gander MD

Morgan Stanley Childrens Hospital of New York,

New York City, NY, USA

Michael WL Gauderer MD

Professor of Surgery and Pediatrics, University of South

Carolina School of Medicine (Greenville), Childrens Hospital,Greenville Hospital System University Medical Center,

Greenville, SC, USA

John P Gearhart MD FAAP FACS FRCSEd(HON)

Professor and Chief of Pediatric Urology, The Johns Hopkins

Hospital, Baltimore, MD, USA

Keith E Georgeson MD

The Childrens Hospital of Alabama, Birmingham, AL, Sacred Heart

Childrens Hospital, Spokane, WA, USA

Alaa el Ghoneimi MD PhD FEBPS FEAPU

Professor, UniversiteParis Diderot, Head of Department of

Paediatric Surgery and Urology, Hospital Robert Debre,Paris, France

John Gillick MD FRCSI (Paed Surg)

Consultant Paediatric Surgeon, The Childrens University Hospital

and Our Ladys Childrens Hospital, Dublin, Ireland

George K Gittes MD

Surgeon-in-Chief and Professor of Surgery, Childrens Hospital of

Pittsburgh and University of Pittsburgh School of Medicine,

Pittsburgh, PA, USA

Jacqueline J Glover MD PhD

Professor, Department of Pediatrics, Center for Bioethics and

Humanities, University of Colorado, Anschutz Medical Campus,Aurora, USA

Winifred A Gorman BSc FRCPI FAAP

Consultant Neonatologist, National Maternity Hospital and Our

Ladys Hospital for Sick Children, Dublin, Ireland

Jan-H Gosemann MD

Senior Research Fellow, National Childrens Research Centre,

Our Ladys Childrens Hospital, Dublin, Ireland

Andrew Green PhD FRCPI FFPath(RCPI)

Director, National Centre for Medical Genetics, Professor of

Medical Genetics, UCD School of Medicine and Medical Science,

Consultant in Clinical Genetics, Our Ladys Childrens Hospital,Dublin, Ireland

Arin K Greene MD MMSc

Department of Plastic Surgery Childrens Hospital Boston, Boston,

MA, USA

Tracy C Grikscheit MD FACS FAAP

Assistant Professor of Surgery, Department of Surgery,

Keck School of Medicine, University of Southern California,

Los Angeles, CA, USA

Devendra K Gupta MS MCh FAMS Hon. FRCS (Edin. & Glas.) Hon. FAMS (Rom)

Hon. DSc (H.C.)

Professor of Pediatric Surgery, Department of Pediatric

Surgery, All India Institute of Medical Sciences, New Delhi, India

Piotr Hajduk MD

Senior Research Fellow, National Childrens Research Centre,


xiv Contributors


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Michael R Harrison MD

Professor of Surgery, Pediatrics, Obstetrics, Gynecology and

Reproductive Sciences, Emeritus, University of California

San Francisco, San Francisco, USA

Melanie Hiorns MBBS MRCP FRCR

Consultant Paediatric Radiologist, Clinical Unit Chair for Medicine

and Diagnostic and Therapeutic Services, Great Ormond Street

Hospital for Children NHS Trust, Honorary Senior Lecturer,

Institute of Health (University College London), London, UK

Shinjiro Hirose MD

Assistant Professor, Pediatric Surgery, University of California San

Francisco, San Francisco, USA

John M Hutson AO MB MD FRACS FAAP (Hon)

Chair of Paediatric Surgery, University of Melbourne, Urology

Surgery Department, Royal Childrens Hospital, Parkville, Victoria,

Australia

Michael E Hollwarth MD

Professor in Paediatric Surgery, Department of Paediatricand Adolescent Surgery, Medical University of Graz,

Graz, Austria

Vincenzo Jasonni MD

Department of Pediatric Surgery, Istituto Scientifico G Gaslini,

University of Genoa, Genoa, Italy

Wajid B Jawaid MRCS(Ed) MRCS(Eng)

NIHR Academic Clinical Fellow in Paediatric Surgery, Division of

Child Health, Alder Hey Childrens NHS Foundation Trust,

University of Liverpool, UK

Michael D Jenkinson PhD FRCS

Consultant Neurosurgeon and Honorary Clinical Lecturer,The Walton Centre for Neurology and Neurosurgery Foundation

Trust, Liverpool and University of Liverpool, Liverpool, UK

Edwin C Jesudason MA FRCS(Paed) MD

MRC New Investigator, Reader and Consultant Paediatric Surgeon,

Alder Hey Childrens Hospital, The Division of Child Health,

University of Liverpool, UK; Clinical Associate Professor of Surgery,

Childrens Hospital of Los Angeles, Keck School of Medicine,

University of Southern California, Los Angeles, USA

Paul RV Johnson MBCh MA MD FRCS(Eng) FRCS(Edin) FRCS(Paed Surg) FAAP

Professor of Pediatric Surgery, Nuffield Department of Surgery,

John Radcliffe Hospital, Oxford, UK

Stephanie A Jones DO

The University of Colorado Health Sciences Center, Pediatric

Surgery Fellow, The Childrens Hospital Denver, CO, USA

Jonathan F Kalisvaart MD

Department of Pediatric, Urology Emory University, Atlanta, GA,

USA

Jothy Kandasamy MRCS

Neurosurgical Registrar/Resident, The Walton Centre, Liverpool

and Alder Hey Royal Liverpool Childrens Hospital, Liverpool,

Honorary Clinical Lecturer, School of Clinical Sciences, Faculty of

Medicine, University of Liverpool, Liverpool, UK

Frederick M Karrer MDProfessor of Surgery and Pediatrics, Head, Division of Pediatric

Surgery, The University of Colorado Health Sciences Center,

Surgical Director, Pediatric Liver Transplantation, The Childrens

Hospital, Denver, CO, USA

Richard Keijzer MD PhD MSc

Assistant Professor, Department of Surgery, Division of Pediatric

Surgery, University of Manitoba, Winnipeg, Manitoba, Canada

J Kelleher FFR RCSI

Director of Radiology, Radiology Department, Our Ladys Childrens

Hospital, Dublin, Ireland

Basem A Khalil PhD FRCS(Paed)

Specialist Registrar in Paediatric Surgery, Alder Hey Childrens NHS

Foundation Trust Liverpool, UK

Stephen M Kieran MCh FRCS (ORL-HNS)

Senior Registrar, Department of Otolaryngology, St. Vincents


Andrew J Kirsch MD FAAP FACS

Professor of Urology, Department of Pediatric, Urology Childrens

Healthcare of Atlanta Emory, University School of Medicine,

Atlanta, GA, USA

Dietrich Kluth MD PhD

Paediatric Surgeon, Klinik und Poliklinik fur Kinderchirurgie,

Universitatsklinikum Leipzig, Leipzig, Germany

Hiroyuki Koga MD PhD

Assistant Professor, Pediatric General and Urogenital Surgery,


Martin A Koyle MD

Division of Paediatric Urology, The Hospital for Sick Children,

Toronto, ON, Canada

Balazs Kutasy MD

National Childrens Research Centre, Our Ladys Hospital, Dublin,Ireland

Hisako Kuyama MD

Department of Pediatric Surgery and Pediatric Endosurgery,

Tokushima University Hospital, Tokushima, Japan

Kokila Lakhoo PhD FRCS(ENGEDIN) FCS(SA) MRCPCH MBCHB

Consultant Paediatric Surgeon, Childrens Hospital Oxford, John

Radcliffe Hospital, University of Oxford, Oxford, UK

Ganapathy Lakshmanadass MD

Associate Paediatric Surgeon, Department of Paediatric Surgery,

National Childrens Hospital, Dublin, IrelandWolfgang Lambrecht MD PhD

Professor of Paediatric Surgery (Emeritus), Department of

Paediatric Surgery, Eppendorf University Hospital, Hamburg,

Germany

Peter Lamesch FACS

Klinik fur Allgemein- und Visceralchirurgie, Leipzig, Germany

Jacob C Langer MD

Professor of Surgery, University of Toronto and Chief, Division of

General and Thoracic Surgery, Hospital for Sick Children, Toronto,

Ontario, Canada

Maggie K Lee MRCS

Department of Neurosurgery, The Walton Centre for Neurology

and Neurosurgery Foundation Trust, Liverpool and Alder Hey Royal

Childrens Hospital, Liverpool, UK

Contributors xv


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Marc A Levitt MD

Director, Colorectal Center for Children, Cincinnati Childrens

Hospital Medical Center, Associate Professor of Surgery, Division

of Pediatric Surgery, Department of Surgery, University of

Cincinnati, Cincinnati, OH, USA

Thom E Lobe MD

Beneveda Medical Group, Beverly Hills, California, USA

Paul D Losty MD FRCSI FRCS FRCS(Eng) FRCS(Ed) FRCS(Paed)

Professor of Paediatric Surgery, Division of Child Health, University

of Liverpool, Liverpool, UK

Tippi C MacKenzie MD

Assistant Professor of Surgery, University of California,

San Francisco School of Medicine, San Francisco, CA, USA

Conor L Mallucci FRCS

Department of Neurosurgery, Royal Liverpool Childrens Hospital,

Liverpool, UK

Praveen Mathur MS MCh FMAS

Professor, Department of Pediatric Surgery, SMS Medical College,

Jaipur, India

Girolamo Mattioli MD

School of Pediatric Surgery, Istituto Scientifico G Gaslini,


Alastair JW Millar FRCS FRACS (Paed Surg) FCS (SA) DCH

Charles FM Saint Professor of Paediatric Surgery, University of

Cape Town and Red Cross War Memorial Childrens Hospital,

Cape Town, South Africa

Robert K Minkes MD PhD

Professor of Surgery, University of Texas, Southwestern Medical

Center at Dallas, Childrens Medical Center at Legacy, Plano,TX, USA

Hideshi Miyakita MD PhD

Professor of Urology, Department of Urology, Tokai University

School of Medicine, Oiso Hospital, Oiso, Japan

Eleanor J Molloy MB PhD FRCPCH FRCPI

Associate Professor of Paediatrics, Royal College of Surgeons of

Ireland, Consultant Neonatologist, National Maternity Hospital

and Our Ladys Hospital for Sick Children, University College

Dublin, Dublin, Ireland

Sam W Moore MD MBChB FRCS

Head of Pediatric Surgery, Division of Pediatric Surgery,Tygerberg Hospital, University of Stellenbosch, Tygerberg,

South Africa

Alan Mortell MD FRCSI FRCS (Paed Surg)

Consultant Paediatric Surgeon, Our Ladys Childrens Hospital and

The Childrens University Hospital, Dublin, Ireland

Oliver J Muensterer MD PhD

Associate Professor, Weill Cornell Medical College, Division of

Pediatric Surgery, New York, NY, USA

Hirikati S Nagaraj MD

Associate Professor of Surgery, Department of Surgery, University

of Louisville, Louisville, KY, USA

Shireen Anne Nah MBBS MRCS MS

Clinical Research Associate, Surgery Unit, UCL Institute of Child

Health and Great Ormond Street Hospital for Sick Children,

London, UK

Azad S Najmaldin MB CHB MS FRCS(Edin) FRCS(Eng)

Paediatric Surgeon, St Jamess University Hospital, Leeds, UK

Masaki Nio MD

Department of Pediatric Surgery, Tohoku University School of

Medicine, Sendai, Japan

A. Numanoglu MBChB Turkey FCS SA

Associate Professor, University of Cape Town and Red Cross War

Memorial Childrens Hospital, Cape Town, South Africa

Keith T Oldham MD

Professor and Chief, Division of Pediatric Surgery, Medical College

of Wisconsin, Marie Z Uihlein Chair and Surgeon-in-Chief,

Childrens Hospital of Wisconsin, Milwaukee, WI, USA

Fiona OHare MD

National Maternity Hospital, Dublin, Ireland

Konstantinos Papadakis MD

Instructor in Surgery, Childrens Hospital Boston,

Boston, MA, USA

Thambipillai Sri Paran MD

Our Ladys Hospital for Sick Children, Dublin, Ireland

Dakshesh Parikh MBBS MS FRCS (Paed)

Consultant Paediatric Surgeon, Department of Paediatric Surgery,

Birmingham Childrens Hospital, Birmingham, UK

David A Partrick MD

Department of Pediatric Surgery, The Childrens Hospital, Aurora,

CO, USA

Valentina De Pasquale MD

Director, Department Nephrology and Urology, Bambino GesuChildrens Hospital, Rome, Italy

Jose L Peiro

Department of Pediatric Surgery, Fetal Surgery Unit, Hospital

Universitari Vall Hebron, Universitat Autonoma de Barcelona,

Area Materno infantil, Barcelona, Spain

Alberto Pena MD

Founding Director, Colorectal Center for Children, Cincinnati

Childrens Hospital Medical Center, Professor of Surgery,

Department of Surgery, Division of Pediatric Surgery,

University of Cincinnati, Cincinnati, OH, USA

James Pierce MD

Research Fellow, Childrens Hospital Los Angeles, Los Angeles,

CA, USA

Agostino Pierro MD FRCS (Eng) FRCS (Ed) FAAP

Nuffield Professor of Paediatric Surgery and Head of Surgery Unit,

Surgery Unit, UCL Institute of Child Health, London, UK

Jack Plaschkes MD

Department of Pediatric Surgery, Kinderklinik, Bern,

Switzerland

Christina M Plikaitis MD

Clinical Instructor of Surgery, St. Louis University, St. Louis,

MO, USA

Jai Prasad MBBS MRCS

Clinical Fellow, Pediatric Surgery Oncology,

Memorial Sloan-Kettering Cancer Center, New York, NY, USA

xvi Contributors


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Alessio Pini Prato MD

School of Pediatric Surgery, Istituto Scientifico G Gaslini,


Kevin C Pringle MB ChB FRACS

Professor of Paediatric Surgery and Head of Department of

Obstetrics and Gynaecology, School of Medicine and HealthSciences, University of Otago, Wellington, New Zealand

Prem Puri MS FRCS FRCS(Ed) FACS FAAP (Hon)

Newman Clinical Research Professor, University College Dublin,

National Childrens Hospital, Consultant Paediatric Surgeon

Beacon Hospital; Professor, Director of Research, Childrens

Research Centre, Our Ladys Childrens Hospital,

Dublin, Ireland

Michael P La Quaglia MD

Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Giovanni Rapuzzi MD

School of Pediatric Surgery, Istituto Scientifico G Gaslini,University of Genoa, Genoa, Italy

Professor John Mark Redmond MD FRCSI

Cardiothoracic surgeon, Our Ladys Childrens Hospital, Dublin,

Ireland and Master Misericordiae University Hospital, Dublin,

Ireland

Denis J Reen MSc PhD

Adjunct Professor in Medicine, University College, Dublin;

Proffesor, The Childrens Research Centre, Our Ladys Hospital

for Sick Children, Dublin, Ireland

Massimo Rivosecchi MDHead of Pediatric Surgery Unit, Bambino GesuChildrens Hospital,

IRCCS Palidoro and Rome, Italy

Ian HW Robinson MBChB FRANZCR

Radiology Department, Our Ladys Childrens Hospital, Dublin,

Ireland

H Rode MMed (Surg) FRCS Edin FCS (SA)

Emeritus Professor, Univesity of Cape Town and Red Cross War

Memorial Childrens Hospital, Cape Town, South Africa

Udo Rolle MD PhD

Professor, Department of Pediatric Surgery, Johann Wolfgang

Goethe-University, Frankfurt, Germany

John D Russell MB BCH BAO MCH FRCS (ORL)

Consultant Otolaryngologist, Department of Otolaryngology,


Elke Ruttenstock

Assistenzaerztin, Universitaetsklinik fuer Kinder- und

Jugend-chirurgie, Graz Medizinische Universitaet, Graz, Austria

Frederick C Ryckman MD

Professor of Surgery and Transplantation, Senior Vice President of

Medical Operations, Cincinnati Childrens Hospital, Medical Center

Cincinnati, OH, USA

Robert Sader MD PhD

Professor, Department of Oral, Maxillofacial and Plastic Facial

Surgery, Johann Wolfgang Goethe-University, Frankfurt, Germany

Amulya K Saxena MD

Associate Professor, Department of Pediatric and Adolescent

Surgery, Medical University of Graz, Graz, Austria

Robert C Shamberger MD

Chief, Department of Surgery, Childrens Hospital Boston, Boston,

MA, USAShilpa Sharma MS MCh Dip Nat Board PhD

Assistant Professor, Department of Pediatric Surgery, Postgraduate

Institute of Medical Sciences and Dr RML Hospital, New Delhi,

India

Stephen J Shochat MD

Former Surgeon-in-Chief and Chairman, Department of Surgery,

St Jude Childrens Research Hospital, Memphis, TN, USA

Michael Singh MBBS FRCSEd (Paed Surg)

Consultant Paediatric Surgeon, Birmingham Childrens Hospital,

Birmingham, UK

Owen P Smith MA MB BA Mod (Biochem) FRCPCH FRCPI FRCPLon FRCPEdinFRCPGlasg FRCPath

Professor of Haematology, Department of Haematology and

Oncology, Our Ladys Childrens Hospital, Dublin, Ireland

Andrew A Stec MD

Assistant Professor of Urology and Pediatrics, Department of

Urology, Medical University of South Carolina, Charleston,

SC, USA

Charles JH Stolar MD

Surgeon-in-Chief and Director of Pediatric Surgery, Morgan

Stanley Childrens Hospital of New York, New York City, NY, USA

Mark D Stringer MS FRCP FRCS FRCSEd

Professor of Anatomy, Department of Anatomy, Otago School of

Medical Sciences, University of Otago, Dunedin, New Zealand

Yechiel Sweed MD

Head, Department of Pediatric Surgery, Bar-Ilan University of

Medicine, Western Galilee Hospital, Nahariya, Israel

Hiroo Takehara MD PhD

Department of Pediatric Surgery and Pediatric Endosurgery,

Tokushima University Hospital, Tokushima, Japan

Paul KH Tam MD

Department of Surgery, The University of Hong Kong, Queen Mary

Hospital, Hong Kong

David FM Thomas FRCP FCRPCH FRCS

Emeritus Professor of Paediatric Surgery, University of

Leeds and Consultant Paediatric Urologist, Leeds Teaching

Hospitals, Leeds, UK

Holger Till MD PhD

Surgeon-in-Chief, Professor of Pediatric Surgery, Klinik und

Poliklinik fur Kinderchirurgie, University of Leipzig, Leipzig,

Germany

Juan A Tovar MD PhD EBPS FAAP(HON)

Professor and Chairman, Department of Pediatric Surgery, Hospital

Universitario La Paz, Madrid, Spain

Marie Z Uihlein

Surgeon-in-Chief, Childrens Hospital of Wisconsin, Milwaukee,

Wisconsin, USA

Contributors xvii


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Benno Ure MD

Professor, Director and Chairman, Centre of Pediatric Surgery,

Hannover Medical School and Bult Childrens Hospital, Hannover,

Germany

Eduardo Villamor MD PhD

Associate Professor of Pediatrics, Maastricht University MedicalCenter, Maastricht, The Netherlands

Declan Warde MB FJFICMI FFARCSI

Anaesthesia, Intensive Care and Pain Management, Childrens


Tomas Wester MD PhD

Department of Pediatric Surgery, Astrid Lindgren Childrens

Hospital, Karolinska University Hospital, Stockholm, Sweden

Chad Wiesenauer MD

Assistant Professor of Surgery, Department of Surgery, University

of Louisville, Louisville, KY, USA

Duncan Wilcox MD

Chair of Pediatric Urology, The Ponzio Family Chair in Pediatric

Urology, Childrens Hospital Colorado, Aurora, CO, USA

Kenneth KY Wong MB ChB PhD FRCSEd(Paeds) FHKAM FAAN

Clinical Assistant Professor, Department of Surgery, The University

of Hong Kong, Queen Mary Hospital, Hong Kong

Atsuyuki Yamataka MD PhD

Professor and Head, Pediatric General and Urogenital Surgery,


George G Youngson PhD FRCS

Emeritus Professor of Paediatric Surgery, Department of Paediatric

Surgery, Royal Aberdeen Childrens Hospital, Aberdeen, UK

Moritz M Ziegler MD

Retired, Surgeon-in-Chief and the Ponzio Family Chair,

The Childrens Hospital, Professor of Surgery, Aurora, CO, USA

Luc JI Zimmermann MD PhD

Professor of Pediatrics, Maastricht University Medical Center,

Maastricht, The Netherlands

Yousef EI-Gohary MD MRCS (Glas)

Pediatric Surgical Research Fellow, Childrens Hospital of

Pittsburgh, Pittsburgh, PA, USA

xviii Contributors


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Preface to the third edition

It has been eight years since the second edition of the bookwas published in 2003. Over the last decade, major advances

have occurred in the understanding and treatment of neonatalsurgical conditions. Advances in prenatal diagnosis, imaging,intensive care, and minimally invasive surgery have trans-

formed the practice of surgery in the newborn. The thirdedition of Newborn Surgery has been extensively revisedand contains 105 chapters by 160 contributors from all five

continents of the world. This edition contains many newchapters taking account of the recent advances in neonatalsurgery. The new chapters include: Perinatal physiology;Clinical anatomy of the newborn; Epidemiology of birth

defects; Fetal counselling for surgical malformations; Neona-tal sepsis; Liver transplantation; Congenital pouch colon;Megacystis microcolon intestinal hypoperistalsis syndrome;and Urinary tract infections. Each chapter has been written by

world class experts in their respective fields, along with their

co-authors.This textbook provides an authoritative, comprehensive

and complete account of the pathophysiology and treatment

of various surgical conditions in the newborn. This bookshould be of interest to all those who have a clinical

responsibility for newborn babies. It is particularly intendedfor trainees in pediatric surgery, established pediatric sur-geons, general surgeons with an interest in pediatric surgery

as well as neonatologists and pediatricians seeking moredetailed information on newborn surgical conditions.

I wish to thank most sincerely all the contributors for their

outstanding work in producing this innovative text-book. Ialso wish to express my gratitude to Ms Vanessa Woods andMs Lisa Kelly for their skilful secretarial help. I am grateful toDr G.P. Seth for reading each and every word of the galley

proofs of the entire book. I wish to thank the editorial staff ofHodder Arnold, particularly Mr Stephen Clausard, for theirhelp during preparation and publication of this book. I amthankful to the Childrens Medical & Research Foundation,

Our Ladys Childrens Hospital, Dublin for their support.

Prem Puri2011


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Preface to the second edition

The 2nd edition of Newborn Surgery has been extensivelyrevised. Many new chapters have been added to take account

of the recent developments in the care of the newborn withcongenital malformations. This edition, which comprises97 chapters by 121 contributors from all five continents of

the world, provides an authoritative, comprehensive, andcomplete account of the various surgical conditions in thenewborn. Each chapter is written by the current leading

expert(s) in their respective fields.Newborn surgery in the twenty-first century demands of

its practitioners detailed knowledge and understanding of thecomplexities of congenital anomalies, as well as the highest

standards of operative techniques. In this textbook, greatemphasis continues to be placed on providing a com-prehensive description of operative techniques of eachindividual congenital condition in the newborn. The book

is intended for trainees in pediatric surgery, establishedpediatric surgeons, general surgeons with an interest in

pediatric surgery, as well as neonatologists and pediatriciansseeking more detailed information on newborn surgicalconditions.

I wish to thank most sincerely all the contributors for theoutstanding work they have done for the production of thisinnovative textbook. I also wish to express my gratitude to

Mrs Karen Alfred and Ms Ann Brennan for their secretarialhelp and to the staff of Hodder Arnold for their help duringthe preparation and publication of this book. I am grateful tothe Childrens Medical & Research Foundation, Our Ladys

Hospital for Sick Children, Dublin for their support.

Prem Puri2003


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Preface to the first edition

During the last three decades, newborn surgery has developedfrom an obscure subspecialty to an essential component of

every major academic pediatric surgical department through-out both the developed and the developing world. Majoradvances in perinatal diagnosis, imaging, neonatal resuscita-

tion, intensive care, and operative techniques have radicallyaltered the management of newborns with congenital mal-formations. Embryological studies have provided new valuable

insights into the development of malformations, while im-provements in prenatal diagnosis are having a significantimpact on approaches to management. Monitoring techniquesfor the sick neonate pre- and postoperatively have become more

sophisticated and there is now greater emphasis on physiolo-gical aspects of the surgical newborn, as well as their nutritionaland immune status. This book provides a comprehensivecompendium of all these aspects as a prelude to an extensive

description of surgical conditions in the newborn. Modern-day

newborn surgery demands detailed knowledge of the complex-ities of newborn problems. Research developments, laboratorydiagnosis, imaging, and innovative surgical techniques are allpart of the challenge facing surgeons dealing with congenital

conditions in the newborn. In this book, a comprehensivedescription of operative techniques of each individual condi-

tion is presented. Each contributor was selected to provide anauthoritative, comprehensive, and complete account of theirrespective topics. The book, comprising 90 chapters, is intended

primarily for trainees in pediatric surgery, established pediatricsurgeons, general surgeons with an interest in pediatric surgery,and neonatologists.

I am most grateful to all contributors for their willingness tocontribute chapters at considerable cost of time and effort. I amindebted to Mr Maurice De Cogan for artwork, Mr Dave Cullenfor photography, and Ms Ann Brennan and Ms Deirdre

ODriscoll for skilful secretarial help. I am grateful to theChildrens Research Centre, Our Ladys Hospital for SickChildren, for their support. Finally, I wish to thank the editorialstaff, particularly Ms Susan Devlin, of Butterworth-Heinemann

for their help during the preparation and publication of this

book.

Prem Puri1996


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PART I

GENERAL


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1

Embryology of malformations

DIETRICH KLUTH, WOLFGANG LAMBRECHT, CHRISTOPH BUHRER, AND HOLGER TILL

INTRODUCTION

Approximately 3% of human newborns present with con-genital malformations.1 Without surgical intervention, one-third of these infants would die since their malformations are

not compatible with sustained life outside the uterus.1,2 Infigures, this means that in a country such as Germany, nearly6000 children are born every year with a life-threateningmalformation.

Due to the development of prenatal diagnostic proce-dures, advanced surgical techniques, and intensive post-

operative care, most infants with otherwise fatalmalformations can be rescued by an operation in theneonatal period. However, morbidity remains high in someof 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 cleftpalate.

Mortality is still high in newborns with certain malforma-tions such as congenital diaphragmatic hernias or severe

combined defects. As a consequence, congenital malforma-tions today are the main cause of death in the neonatal

period. In the United States, 21% of neonatal mortality canbe related to congenital malformations.3

These figures probably do not reflect a real increase ofthe actual incidence of congenital malformation. Theobserved mortality shift might rather be due to improvedintensive care medicine in todays Western world countries

where neonates (even those with birth defects) have a betterchance of survival. On the other hand, this statistical shiftindicates that knowledge about congenital malformations

lags behind the progress clinical research has made in thesurrounding fields. Efforts are needed to close the gap andlearn more about baby killer No. 1. Identification of

teratogens will help to reduce the incidence of malforma-tions when exposure can be avoided, and pathogeneticstudies might aid in designing therapeutic measures. Bothtreatment and prevention critically depend on basic embry-

ological research.

GENERAL REMARKS ON EMBRYOLOGY ANDTHE EMBRYOLOGY OF MALFORMATIONS

Despite many efforts, the embryology of numerous con-genital anomalies in humans is still a matter of speculation.

This is due to the following reasons:

= a shortage of study material (both normal and abnormal

embryos);= various technical problems (difficulties in the interpreta-

tion of serial sections, shortage of explanatory three-

dimensional reconstructions);= misconceptions and/or outdated theories concerning

normal and abnormal embryology.

Fortunately, a number of animal models are known todaywhich allow advanced embryological studies in variousembryological fields. Especially for the studies of anorectalmalformations, a number of animal models is at hand. In

addition, a Scanning Electron-Microscopic Atlas of humanembryos has been published recently which provides detailed

insights into normal human embryology.4

Appropriate and illustrative findings in various fields of

embryology are still lacking. This explains why today manytypical malformations are still not explained satisfactorily.

Pediatric surgeons are still confused when they are con-fronted with the embryological background of normal andabnormal development.

For the described misconceptions and/or outdated the-

ories, Haeckels biogenetic law5 is one example. Accordingto this theory, a human embryo recapitulates in its individualdevelopment (ontogeny) the morphology observed in all life-

forms (phylogeny). This means that during its developmentan advanced species is seen to pass through stages representedby adult organisms of more primitive species. This theory still

has an impact on the nomenclature of embryonic organs andexplains why human embryos have cloacas like adult birdsand branchial clefts like adult fish.

Another very popular misconception is the theory that

malformations actually represent frozen stages of normal


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embryology (Hemmungsmibildung).6 As a result, ourunderstanding of normal embryology stems more from

pathological-anatomic interpretations of observed malforma-tions than from proper embryological studies. The theory ofthe rotation of the gut as a step in normal development is aperfect example of this misconception.

DEFINITION OF THE TERM MALFORMATION

After birth, neonates can present with a broad spectrum ofdeviations from normal morphology. This extends fromminor variations of normal morphology without any clinical

significance to maximal organ defects with extreme func-tional deficits 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 malformationrequiring surgical correction. This means that functionaldisturbance is essential when using the term malformation.Inborn deviations can be detrimental, neutral, or evenbeneficial, otherwise evolutionary progress could not take

place. An example of a beneficial deviation is the longevitysyndrome of people with abnormally low serum cholesterollevels. Abnormalities with little or no functional disturbance

might still require surgical correction when patients are indanger of social stigmatization. Coronal or glandular hypos-padias might serve as an example for this condition.

ETIOLOGY OF CONGENITAL MALFORMATIONS

In most cases, the etiology of congenital malformationsremains unclear. Possible etiological factors are listed inTable 1.1.

In about 20% of cases genetic factors (gene mutation andchromosomal disorders) can be identified.1,2,7 In 10% anenvironmental origin can be demonstrated.1,2 In 70% thefactors responsible remain obscure.

Environmental factors

A large number of agents are known which might interfere

with the normal development of organ systems duringembryogenesis.1,7 The underlying mechanisms of this inter-ference 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 theteratogenetic period of determination.8 The typical patterns

of some syndromes can be explained by an overlap of thesephases during embryological development.

In 1983, Shepard2 published a catalog of suspectedteratogenic agents. Over 900 agents are known to produce

congenital anomalies in experimental animals. In 30, evi-dence for teratogenic action in humans could be demon-

strated. Teratogenic agents can be divided into four groups(Table 1.2).

The teratogenic potential of virus infections,1 especiallyrubella and herpes, and that of radiation1 has been clearly

established. Maternal metabolic defects and lack of essentialnutritives can be teratogenic. After a vitamin A-free diet9 andriboflavin-free diet10 various congenital malformations wereobserved in rats and mice. Among these were diaphragmatic

hernias, isolated esophageal atresias, and isolated tracheo-esophageal fistulas. Similarly, inappropriate administration of

hormones can be associated with intrauterine dysplasias.11

Industrial and pharmaceutical chemicals such as tetra-chlor-diphenyl-dioxin (TCDD) or thalidomide have inflictedtragedies by their teratogenic action. When thalidomide was

prescribed to women in the early 1960s as a safe sleepingmedication, numerous children were born with dysmelicdeformities.7,12,13 In addition, atresias of the esophagus, theduodenum, and the anus were observed in some children.12

The data collected suggest that teratogenic agents do notcause new patterns of malformations but rather mimicsporadic birth defects. This had posed problems in identify-ing thalidomide as the responsible agent. It appears likely that

among those 70% congenital malformations with unclearetiology a considerable percentage might be precipitated by as

yet unidentified environmental factors. In a rat model, theherbicide nitrofen (2.4-dichloro-phenyl-p-nitrophenyl ether)has been shown to induce congenital diaphragmatic hernias,cardiac abnormalities and hydronephrosis.1418 In 1978,

Thompson et al.19 described the teratogenicity of the anti-cancer drug adriamycin in rats and rabbits. More recently,Diez-Pardo et al.20 re-described this model with emphasis toits potentials as a model for foregut anomalies. Today, the

adriamycin model is generally described as a model for theVACTERL-association (V vertebral, A anorectal,

C cardiac, T tracheal, E esophageal, R renal,

L limb).21,22 Thus, classic malformations such as atresiasof the esophagus and the intestinal tract, intestinal duplica-tions and others can be mimicked by teratogens in animal

models.

Table 1.1 Etiology of congenital malformations.

Etiology %

Genetic disorders 20

Environmental factors 10

Unknown etiology 70Table 1.2 Teratogenic agents in congenital malformations.

Teratogenic agents

Physical agents Radiation, heat, mechanical factors

Infectious agents Viruses, treponemes, parasites

Chemical, drug,

environmental agents

Thalidomide, nitrofen, hormones,

vitamin deficiencies

Maternal, genetic factors Chromosomal disorders,

multifactorial inheritance

After Nadler.1

4 Embryology of malformations


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Genetic factors

Approximately 20% of congenital malformations are of

genetic origin. Most surgically correctable malformationsare associated with chromosomal disorders, e.g. trisomy

21, 13, or 18, or are of multifactorial inheritance23 with a

small risk of recurrence. The assumption of multifactorialinheritance results from the fact that with nearly all majoranomalies familiar occurrences had been observed.1 In

animals, inheritance has also been found for some mal-formations.2427

EMBRYOLOGY AND ANIMAL MODELS

Over the last two decades a number of animal models weredeveloped with the potential to gain a better understanding

of the morphology of not only malformed but also of normal

embryos. These animal models can be divided into foursubgroups.

Surgical models

In the past, the chicken was an important surgical model tostudy embryological processes. Due to the easy access to theembryo, its broad availability and its cheapness, the chicken isan ideal model for experimental studies. It has been widely

used by embryologists, especially in the field of epithelial/mesenchymal interactions.2830 Pediatric surgeons used

this model to study morphological processes involved inintestinal atresia formation,31,32 gastroschisis,33 and Hirsch-

sprungs disease.34

The Czech embrologist Lemez35 used chicken embryos in

order to induce tracheal agenesis with tracheo-esophagealfistula.

Apart from these purely embryonic models, a largenumber of fetal models exist. However, these models were

mainly used in order to demonstrate the feasibility of fetalinterventions.36

Chemical models

A large number of chemicals can have an impact on the

normal development of humans and animals alike. Mostimportant today are: (1) the adriamycin model,19,20 (2)etretinate,37,38 (3) all-trans retinoic acid (ATRA),3941 (4)ethylenethiourea,4244 and (5) nitrofen.15,16,18

While models (1)(4) are used to study the embryology ofatresias of the esophagus, the gut, and the anorectum, model(5) was developed to study the malformations of thediaphragm, the lungs, and the heart and kidneys (hydrone-

phrosis).

Genetic models

A number of genetic models had been developed which wereused for embryological studies in the past:

= models of spontaneous origin: the SD-mouse model;25,27

= inheritance models: the pig model of anal atresia;24,26

= knock-out models.4547

These animals can be the product of spontaneous mutationsor are the result of genetic manipulations mainly in mice

(transgenic mice).The number of transgenic animal models is growing fast.

For pediatric surgeons those models which result in abnorm-alities of the fore- and hindgut are of major importance.

Here, interference with the sonic hedgehog (Shh) pathwayhas proven to be very effective.4547 There are two ways to

interfere with that pathway: (1) targeted deletion of Shh;45,46

and (2) deletion of one of the three transcription factors,Gli1, Gli2, and Gli3.46,47

In the foregut, targeted deletion of Shh in homozygous

Shh-null mutant mice causes esophageal atresia/stenosis,tracheo-esophageal fistulas, and tracheal/lung anomalies.45

In the hindgut, the deletion of Shh caused the formation ofcloacas46 while Gli2 mutant mice demonstrated the classic

form of anorectal malformations and Gli3 mutants showedminor forms such as anal stenosis.46,47 Interestingly, the

morphology of Gli2 mutant mice embryos resembles that ofheterozygous SD-mice embryos while Shh-null mutant miceembryos had morphological similarities with homozygousSD-mice embryos. Interestingly, after administration of

adriamycin, changes in the normal pattern of Shh distribu-tion in the developing foregut were demonstrated.48

Viral models

Animal models that use virus infections to produce mal-formations important for pediatric surgeons are very rare.

One exception is the murine model of extrahepatic biliaryatresia (EHBA). In this model, newborn Balb/c mice areinfected with rhesus rotavirus group A.49 As a result the fullspectrum of EHBA develops, as is seen in newborns with this

disease. However, this model is not a model to mimic failedembryology, but it highlights the possibility that malforma-

tions are not caused by embryonic disorders but are causedby fetal or even postnatal catastrophes.

This part on embryology and animal models furtherhighlights the importance of the study of normal animal

embryos. Today, much information in current textbooks onhuman embryology stems from studies carried out in animalsof varies species. Many of these are outdated. However, thewide use of transgenic mice in order to mimic congenital

malformations makes morphological studies of the variousorgan systems in normal mice mandatory, otherwise the

interpretation of the effects of the deletion of geneticinformation can be very difficult.50

EMBRYOLOGY OF MALFORMATIONS

Disturbances of normal embryological processes will result inmalformations of organs. This was first shown by Spemann 51

in 1901 by experimentally producing supernumary organs in

Embryology of malformations 5


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the triton embryo after establishing close contact betweenexcised parts of triton eggs and other parts of the same egg.

Spemann and Mangold5 coined the term induction todescribe this observation. They found that certain parts ofthe embryo obviously were able to control embryonicdevelopment of other parts. These controlling parts were

called organizers.5 The process of influence itself was calledinduction.

It was believed by many scientists in the field thatinduction could serve as the overall principle of hierarchicalcontrol of embryonic development. Ensuing investigations,however, made modifications necessary, which finally re-

sulted in a very complex model of organizers and inductors.The nature of inductive substances remained obscure andattempts to isolate inductive substances, meanwhile calledmorphogenes, were unsuccessful.52 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 embryonicorgans is the invagination of epithelial sheets. This invagina-tion is preceded by a thickening of the epithelial sheet,53 aprocess known as placode formation. The thickening itself is

caused by elongation of individual cells of the placode. Thisprocess can be studied in detail in epithelial morphogenesis.54

The same sequence of developmental events has beenobserved in the formation of the neural plate, in the

formation of the otic and lens placode and in the develop-ment of most epitheliomesenchymal organs including lung,thyroid gland, and pancreas. From these observations it canbe 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 researchersare more and more interested to understand the formation ofearly embryonic organs.

In 1985, Ettersohn55 stated that most invaginations are the

result of mechanical forces that are local in origin. He focusedon three possible mechanisms which might lead to placodeformation and subsequent invagination:

1. change of cell shape by cell adhesion;2. microfilament-mediated change of cell shape;3. cell growth and division.

In the following text, we will discuss some aspects of thesemechanisms.

A teratological method used to determine the function ofcell adhesion molecules in vivo during embryogenesis hasbeen reported recently.56 Mouse hybridoma cells producingmonoclonal antibodies against the avian integrin complex

were grafted into 2- or 3-day-old chick embryos. Dependingon the site of engraftment, local muscle agenesis was

observed. This is an example that the immunologic im-maturity of the embryo can be exploited to study thecontribution of cell attachment molecules to organ develop-

ment in a functional fashion. A number of monoclonalantibodies directed against cell attachment molecules ofvarious species have become available over the last 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 specific andmostly transient cell recognition of other cells; substrateadhesion molecules (SAMs), necessary for attachment toextracellular matrix proteins; and cell-junctional molecules

(CJMs), found in tight and gap junctions. Whereas CJMsapparently play an important role for metabolic signaling

within established tissues, CAMs and SAMs are necessary forthe formation of histologically distinct structures anddirected migration of single cells. Among CAMs and SAMs,at least three families have been identified biochemically:

integrins,57 members of the immunoglobulin superfamiliy,and LEC-CAMs.58 Integrins are heterodimeric moleculesconsisting of a larger a chain, which is associated with asmaller b chain in a calcium-dependent way. Usually, one

given a chain might be found in association with variouschains but promiscuity of b chains has been described

recently. Functionally, members of the integrin family presentas SAMs (adhesion to vitronectin, collagen, fibronectin,complement components, or other intercellular matrixproteins) or CAMs (direct adhesion to other cells via

corresponding cell surface target molecules). For example,cells bearing the integrin LFA-1 on their cell surface bind tocells expressing ICAM-1 or ICAM-2, both of which aremembers of the immunoglobulin superfamily.59,60 Other

members of the immunoglobulin superfamily which areknown to be important during morphogenesis includeL-CAM61 (liver cell adhesion molecule) and N-CAM62,63

(neural cell adhesion molecule). Both show homophilic

aggregation, that is, N-CAM serves as a target structure forN-CAM, and L-CAM serves as a target structure for L-CAM,

but there is no crossreactivity. In developing feather placodesin avian embryos, L-CAM and N-CAM are mutuallyexclusive expressed on epidermal or mesodermal cells,respectively. When the placodes are incubated with anti-

bodies to L-CAM, primarily only epidermal cell-to-cellcontact is disturbed.64 However, the structure of the sur-rounding mesoderm is altered subsequently, suggesting aninductive signal loop between epidermal and mesodermal

cells. A third group of adhesion molecules has been termedLEC-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. Thelectin domain is presumed to contain the active center;binding mediated by the murine homolog to the leukocyte

adhesion molecule 1 (LAM-1)65 can be blocked by mannose-6-phosphate or its polymers.66 Lectin-dependent organformation should be accessible experimentally by adminis-tration of the respective carbohydrates, but few if any data

have been reported so far.Cell shape is mainly maintained by microtubules forming

the cellular cytoskeleton. In addition, contractile elementsexist such as actin, which are essential for cell movement, theso-called microfilaments. These structures are thought to be

essential for the process of placode formation and invagina-tion.67 Microfilament-mediated change of cell shape is basedon the idea that actin filaments could alter the shape of cellsby contraction. Most of these filaments are found at the apex



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of epithelial cells. Contraction of these filaments in eachindividual cell of a cell layer would result in an increasing

infolding of the whole cell layer,67,68 finally resulting ininvagination. It is a disadvantage of this model, however, thatthere is no apparent reason why apical constriction should bepreceded by cell elongation.55

Cell proliferation is probably an essential factor in themorphogenesis of epithelio-mesenchymal organs. During

morphogenesis of these organs repeated invagination canbe observed, which might be dependent upon cell prolifera-tion.69 The way in which epithelial cell growth and prolifera-tion is controlled in the embryo is not clear. However, it is

believed that the surrounding mesenchyme might regulatethe timing and location of invagination of the epithelial layer.Goldin and Opperman28 proposed that epidermal growthfactor (EGF) might be excreted by mesenchymal cells, which

would stimulate epithelial cell proliferation and repeatedinvagination. When agarose pellets impregnated with EGF

were cultured alongside 5-day embryonic chick trachealepithelium, supernumerary buds were induced to form atthose sites. EGF and the related peptide transforming growthfactor-b (TGFb) have been shown to lead to precocious

eyelid opening when injected into newborn mice.70 Thus,complex changes of late-stage organ development can beinduced by physiological stimuli in the laboratory. Interest-ingly, EGF is a mitogen for many epithelial cells in vitro

without affecting most mesenchymal cells. A large variety ofcells have been demonstrated to display the receptor for EGF/TGFb on their cell surface, which is encoded by the cellularproto-oncogene c-erbB. Structural alterations of this receptor

are known to result in uncontrolled proliferation andultimately malignant transformation. When secreted locally,

EGF might provide physically associated cells with appro-priate on- and off-signals required for the formation ofcomplex organs. Other polypeptides, such as platelet-derivedgrowth factor (PDGF) or transforming growth factor-a

(TGFa) appear to function in an antagonistic way in thatthey stimulate rather the proliferation of mesenchymalcells.71,72 In defined experimental situations, TGFa has beenshown to be a mitogen for osteoblasts while being a potent

inhibitor of the proliferation of epithelial and endothelialcells at the same time. Embryonic fibroblasts, however, are

also inhibited by TGFa.73 TGFa is a powerful chemotactic

agent for fibroblasts and enhances the production of bothcollagen and fibronectin by these cells. There is, however,little data available concerning the involvement of these

factors during normal and pathologic development ofthe embryo. Future investigations using such powerfulapproaches as in situ hybridization with cloned genes,preparation of transgenic animals, and direct administration

of the recombinant proteins to various parts of the embryomight shed some light on signaling pathways mediated by

soluble cytokines.The surrounding mesenchyme might limit the epithelial

bud to expand,74 forcing the epithelial sheet to fold in

characteristic patterns. If a growing cell layer is restrictedfrom lateral expansion, mitotic pressure by dividing cellswill result in elongation of cells and then invagination of thecrowded cell sheet. This does not necessarily imply that cells

divide more rapidly in the region of invagination than in thesurrounding areas. The main effect is caused by restriction of

lateral expansion.29,30 In the early anlage of the thymus, cellproliferation counts are actually lower in the thymus anlagethan in the surrounding epithelium.75 Steding29 and Jacob30

have shown experimentally that restriction of lateral expan-

sion might be responsible for thickening and subsequentinvagination of epithelial sheets. In their experiments,

restriction of lateral expansion was caused by a tiny silverring placed on the epithelium of chick embryos.

EXAMPLES OF PATHOLOGICAL EMBRYOLOGY

The focus of our research has been the embryology offoregut, anorectal, and diaphragmatic malformations. Westudied the normal development of all embryonic organs

involved by scanning electron microscopy (SEM).7682 In

addition, we employed two rodent animal models to studymalformations of the anorectum and the diaphragm. Patho-genetic concepts concerning these malformations were con-troversial 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 aprocess of septation.83 It is guessed that lateral ridges appearin the lateral walls of the foregut, which fuse in midline in a

caudo-cranial direction thus forming the tracheo-esophagealseptum. This theory of septation has been described in detailby Rosenthal and Smith.84,85 However, others86,87 were notable to verify the importance of the tracheo-esophageal

septum for the differentiation of the foregut. They insteadproposed individually that the respiratory tract developssimply by further growth of the lung bud in a caudaldirection.

Using SEM, we studied the development of the foregut inchick embryos.76,77 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 foregutis 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 inthe primitive foregut. They approach each other but do notfuse (Fig. 1.2).

Based on these observations, the development of themalformation can be explained by disorders either of the

formation of the folds or of their developmental movements:

= Atresia of the esophagus with fistula (Fig. 1.3a): The dorsal fold of the foregut bends too far ventrally. As

a result the descent of the larynx is blocked. Thereforethe tracheo-esophageal space remains partly undividedand lies in a ventral position. Due to this ventralposition it differentiates into trachea.

Embryology of foregut malformations 7


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= premature return of the intestines into the abdominalcavity with the canal still open;89,91

= abnormal persistence of lung in the pleuro-peritonealcanal, preventing proper closure of the canal;93

= abnormal development of the early lung and posthepaticmesenchyme, causing non-closure of pleuro-peritoneal

canals.18

Of these theories, failure of the pleuro-peritoneal membraneto meet the transverse septum is the most popular hypothesis

to explain diaphragmatic herniation. However, using SEMtechniques,78 we could not demonstrate 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 orinhibited closure of the diaphragm will result in a diaphrag-

matic defect that is wide enough to allow herniation of thegut into the fetal thoracic cavity. However, this assumption is

not the result of appropriate embryological observations butrather the result of interpretations of anatomical/pathological

findings. In a series of normal staged embryos we measuredthe width of the pleuro-peritoneal openings and the

transverse diameter of gut loops.82 On the basis of thesemeasurements we estimated that a single embryonic gut looprequires at least an opening of 450 m size to herniate intothe fetal pleural cavity. However, in none of our embryos

were the observed pleuro-peritoneal openings of appropriatedimensions. This means that delayed or inhibited closure ofthe pleuro-peritoneal canal cannot result in a diaphragmaticdefect of sufficient size. Herniation of gut through these

openings is therefore impossible. Thus the proposed theoryabout the pathogenetic mechanisms of congenital diaphrag-

matic hernia (CDH) development lacks any embryological

evidence. Furthermore, the proposed timing of this process ishighly questionable.79,80

Recently, an animal model for diaphragmatic hernia hasbeen developed1418 using nitrofen as noxious substance. Inthese experiments CDHs were produced in a reasonably highpercentage of newborns.15,16 Most diaphragmatic hernias

were associated with lung hypoplasias. Using electronmicroscopy, our group7982 used this model to give a detailed

description of the development of the diaphragmatic defect.Our results are discussed in the following.

Timing of diaphragmatic defect appearance

Iritani1 was the first to notice that nitrofen-induced dia-phragmatic hernias in mice are not caused by an improperclosure of the pleuro-peritoneal openings but rather theresult of a defective development of the so-called post-hepatic

mesenchymal plate (PHMP). In our study in rats, clearevidence of disturbed development of the diaphragmaticanlage was seen on day 13 (left side) and day 14 (right side,Fig. 1.5).79,82 In all embryos affected, the PHMP was too

short. This age group is equivalent to 45-week-old humanembryos.79

Location of diaphragmatic defect

In our SEM study, the observed defects were localized in thePHMP (Fig. 1.5). We identified two distinct types of defects:

(1) large dorsal defects and (2) small central defects.

79

Large defects extended into the region of the pleuro-peritoneal openings. In these cases, the closure of thepleuro-peritoneal openings was usually impaired by themassive in-growth of liver (Figs. 1.6 and 1.7). If the defects

were small, they were consistently isolated from the pleuro-peritoneal openings closing normally at the 16th or 17th day

Figure 1.4 SEM photograph of right pleural sac in a ratembryo (approximately 16.5 days old). View from cranial. The so-called pleuro-peritoneal canal (PPC) is nearly closed. Small arrowspoint at the margin of PPC. In the depth of the abdomen the rightadrenals (ad) are seen. Large arrows point at margins of the so-called pleuro-peritoneal membrane. Its contribution to the closureof the canal is minimal (es, esophagus).

Figure 1.5 Cranial view of the pleural sacs in a rat embryoafter exposition to nitrofen on day 11 of pregnancy. The embryo isapproximately 15 days old. Note the big defect of the rightdiaphragmatic primordium. Small black arrows point at margins ofthe defect, which leaves parts of the liver (li) uncoated. On the left,the diaphragmatic anlage is normal. Note the low position of thecranial border of the pleuro-peritoneal opening on this side (whitearrows). (ad, adrenals; di, anlage of diaphragm.)

Development of the diaphragm 9


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of gestation. Thus, in our embryos with CDH, the region ofthe diaphragmatic defect was a distinct entity and wasseparated from that part of the diaphragm where thepleuro-peritoneal canals are localized. We conclude there-

fore that the pleuro-peritoneal openings are not the pre-cursors 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 thethoracic cavity (Fig. 1.6). This indicates that from this timeon the available thoracic space is reduced for the lung andfurther lung growth hampered. In the following stages, up totwo-thirds of the thoracic cavity can be occupied by liver

(Fig. 1.7). Herniated gut was found in our embryos andfetuses only in late stages of development (21 days and

newborns). In all of these the lungs were already hypoplasticwhen the bowel entered the thoracic cavity.79

Based on these observations, we conclude that the earlyin-growth of the liver through the diaphragmatic defect is the

crucial step in the pathogenesis of lung hypoplasia in CDH.This indicates that growth impairment is not the result of

lung compression in the fetus but rather the result of growthcompetition in the embryo: the liver that grows faster thanthe lung reduces the available thoracic space. If the remainingspace is too small, pulmonary hypoplasia will result.

DEVELOPMENT OF THE CLOACA

In the literature, several theories have been put forward toexplain the differentiation of the cloaca into the dorsal

anorectum and the ventral sinus urogenitalis. To manyauthors this differentiation is caused by a septum which

develops cranially to caudally and thus divides the cloaca in afrontal plane. Disorders in this process of differentiation arethought to be the cause of cloacal anomalies such aspersistent cloaca and anorectal malformations.

However, there is no agreement on the mechanisms of theseptational process. While some authors94,95 believe that thedescent of a single fold separates the urogenital part fromthe rectal part by in-growth of mesenchyme from cranial,

others96 think that lateral ridges appear in the lumen of thecloaca, which progressively fuse along the midline and thus

form the septum. In a recent paper97

the process of septationhad been questioned altogether.

Using SEM techniques, our group studied cloacal devel-opment in rat and SD-mice embryos. The SD-mouse is a

spontaneous mutation of the house mouse characterized byhaving a short tail (Fig. 1.8). Homozygous or heterozygousoffspring of these mice show skeletal, urogenital, and anorectal

Figure 1.6 Liver (li) protrudes through diaphragmatic defect.Arrows point to the margin of the defect (di, diaphragmaticanlage). Rat embryo (approximately 16 days old), nitrofen exposi-

tion on day 11 of pregnancy.

Figure 1.7 SEM photograph of a right pleural sac in a ratembryo after nitrofen exposure on day 11 of pregnancy. Theembryo is approximately 15.5 days old. Note the big defect of theright dorsal diaphragm (large arrows). The closure of the pleuro-peritoneal canal (PPC) is impaired by the in-growths of liver (smallarrows). Li1 liver growing through PPC. Li1 Li2 liver grow-ing through the defect of the diaphragm.

Figure 1.8 Characteristic short tail (arrow) of SD-mouseembryo (approximately 13 days old) (ll, left lower limb; ge, genitaltuberculum, abnormal).



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Perineal and scrotal hypospadias are different from the typediscussed previously. Pronounced signs of feminization in

these forms suggest that we are dealing with a female-typeurethra. Origin of this malformation complex is an undiffer-entiated stage as maybe seen in the 18.5-day-old rat embryo.104

CONCLUSION

Despite the long history of experimental embryology, we

know very little about etiology and pathogenesis of congenitalmalformations. For decades, hypotheses were abundant whilefew data existed to support them. The tremendous progress of

neighboring biological sciences is now providing powerfultools for researchers in the field, such as recombinant DNA

and hybridoma technology. Future investigations will moni-tor closely how genes are switched on and off duringembryogenesis and determine the relation of spatial andtemporal disturbances to ensuing malformations. Target

structures of chemical or viral teratogens within the embryo-nic cells await identification. Finally, improved understanding

of growth coordination in uterowill extend to related areassuch as wound healing and proliferation of cancer cells.

REFERENCES

1. Nadler HL. Teratology. In: Welch KJ, Randolph JG, Ravitch MM,

ONeill JA, Rowe MJ (eds). Pediatric surgery, 4th edn. Chicago:

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2. Shepard TH. Catalogue of teratogenic agents, 4th edn.

Baltimore: Johns Hopkins Press, 1983.3. United States National Center for Health Statistics. Monthly

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and deaths for May 1982. Hyattsville, MD: Public Health

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4. Steding G. The Anatomy of the human embryo. A scanning

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5. Haeckel E, cited in Starck D: Embryologie, 3rd edn. Stuttgart,

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6. Schwalbe E.Die Morphologie der Missbildungen des Menschen

und der Tiere. 1. Teil Allgemeine Mibildungslehre (Teratologie).

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7. McCredie J, Loewenthal J. Pathogenesis of congenital mal-

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9. Warkany J, Roth CB, Wilson JG. Multiple congenital malforma-

tions: a consideration of etiological factors. Pediatrics1948;1:

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10. Kalter H. Congenital malformations induced by riboflavin

deficiency in strains of inbred mice.Pediatrics1959;23: 22230.

11. Kalter H. The inheritance of susceptibility to the teratogenic

action of cortisone in mice. Genetics1954; 39: 185.

12. Lenz W. Fragen aus der Praxis. Dtsch Med Wochenschr1961;

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13. Ministry of Health Reports on Public Health and Medical

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14. Ambrose AM, Larson PS, Borcelleca JF et al. Toxicological

studies on 2,4-dichlorophenyl-P-nitrophenyl ether.Toxicol Appl

Pharmacol1971; 19: 26375.

15. Tenbrinck R, Tibboel D, Gaillard JLJ et al. Experimentally

induced congenital diaphragmatic hernia in rats. J Pediatr

Surg1990; 25: 4269.

16. Kluth D, Kangha R, Reich P et al. Nitrofen-induced diaphrag-

matic hernia in rats an animal model. J Pediatr Surg1990;

25: 8504.

17. Costlow RD, Manson JM. The heart and diaphragm: target

organs in the neonatal death induced by nitrofen (2,4-dichloro-

phenyl-P-nitrophenyl ether). Toxicology1981; 20: 20927.

18. Iritani L. Experimental study on embryogenesis of congenital

diaphragmatic hernia.Anat Embryol1984; 169: 1339.

Figure 1.12 Genitals of a normal male rat embryo (approxi-mately 20 days old) (gl, glans; pf, preputial fold; sc, scrotum).Arrow points to the raphe up to this stage; disintegration of theurogenital part of the cloacal membrane was not seen. Note

similarity with clinical picture of hypospadia!

Figure 1.11 Genitals of a normal female rat embryo (approxi-mately 18.5 days old) (gl, glans). Arrow points to future opening ofthe female urethra. No signs of disintegration of the cloacalmembrane.



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19. Thompson DJ, Molello JA, Strebing RJ, Dyke IL. Teratogenicy of

adriamycin and daunomycin in the rat and rabbit. Teratology

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20. Diez-Pardo JA, Baoquan Q, Navarro C, Tovar JA. A new rodent

experimental model of esophageal atresia and tracheoesophageal

fistula: preliminary report.J Pediatr Surg1996;31: 498502.

21. Beasley SW, Diez-Pardo J, Qi BQ et al.The contribution of theadriamycin-induced rat model of the VATER association to our

understanding of congenital abnormalities and their embry-

ogenesis.Pediatr Surg Int2000; 16: 46572.

22. Orford JE, Cass DT. Dose response relationship between

adriamycin and birth defects in a rat model of VATER

association.J Pediatr Surg1999; 34: 3928.

23. Rosenbaum KN.

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