Anesthesia and the Fetus E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 1025

Veröffentlichungsjahr: 2012

Beschreibung

Anesthesia and the Fetus integrates into one volume the multidisciplinary components of:

• fetal development
• fetal pharmacology
• assessments of fetal and neonatal outcome
• anesthesia and analgesia during pregnancy
• anesthesia and analgesia during labor
• ethics and law

Written by an internationally renowned group of clinicians and scientists, Anesthesia and the Fetus provides a contemporary guide and reference to the role of anesthesia, and the anesthesiologist, in protecting the mother and her unborn child during pregnancy.

Leseprobe

Table of Contents

Cover

Dedication

Title page

Copyright page

Contributors

Preface

Acknowledgments

SECTION 1: Basic Principles

1 Intrauterine growth and development

Introduction

Early development and placentation

Organogenesis

Congenital abnormalities amendable to fetal intervention

Fetal growth and development

Fetal growth restriction

Determinants of fetal growth

Macrosomia

Long-term programming effects of altered fetal growth

2 Maternal physiological adaptations to pregnancy

Cardiovascular changes in the mother

The kidneys and the uterus: examples of regional gestational vascular adaptation

Maternal respiratory changes and their effect on oxygen delivery to the fetus

3 Placental respiratory gas exchange

Introduction

The affinity of fetal and maternal blood for respiratory gases

Placental blood flow

Fetal oxygen uptake

Effect of changes in uterine blood flow upon fetal oxygenation

Effect of umbilical blood flow restriction on fetal oxygenation

Effects of blood pressure on uterine and umbilical blood flow

Effect of supplemental maternal oxygen on fetal oxygenation

Summary

4 The fetal circulation

Introduction

Mechanisms of fetal shunt closure

Blood flow regulation of fetal organs

Doppler ultrasound evaluation of the fetal circulation

5 Fetal responses to hypoxia

Introduction

Normal physiology

Milestones in fetal behavioral development

Amniotic fluid dynamics

Abnormalities of the maternal–fetal–placental unit affecting fetal oxygenation

Fetal responses to abnormal oxygenation

Acute fetal hypoxemia

Fetal Doppler

Fetal biophysical profile

Chronic fetal hypoxia

Clinical monitoring

6 Pharmacokinetics in pregnancy

Introduction

Physiological changes during pregnancy and maternal pharmacokinetics

Placental transfer of drugs

Fetal drug distribution, metabolism, and elimination

Considerations in studying placental drug transfer and fetal drug exposure

Summary

Acknowledgments

7 The first few breaths: normal transition from intra- to extra-uterine life

Introduction

Respiratory system

Establishing functional residual capacity

What triggers the initiation of breathing?

Characteristics of postpartum breathing

Neonatal respiratory reflexes

Laryngeal reflex

Carotid body reflex

Respiratory reflexes arising from pulmonary stretch receptors

Cardiovascular adaptation after birth

Immediate neonatal cardio-respiratory assessment

Summary

SECTION 2: Endpoint Variables: Assessments of Fetal Wellbeing and Neonatal Outcome

8 Validity of endpoint measurement

Introduction

Approaches to measurement

Reliability and validity

Surrogate endpoints

Prognostic markers, surrogate endpoints, and the fetus

Summary

SECTION 2.1 Antenatal and Intrapartum Assessment of the Fetus

9 Imaging of the fetus and the uteroplacental blood supply: ultrasound

Introduction

Early screening for aneuploidy

Early diagnosis of fetal abnormalities

Early screening for impaired placentation

Conclusions

10 Imaging of the fetus and the uteroplacental blood supply: MRI

Introduction

Fetal anomalies

Fetal organ volumetry

Alternative fetal MRI techniques

Placental MRI

Safety of MRI in pregnancy

Conclusions

11 Fetal heart rate monitoring

Introduction

How the fetal heart rate is monitored

Fetal heart rate monitoring characteristics and definitions

Fetal heart rate classification

Uterine activity monitoring (tocodynamometry)

Pathophysiology of fetal heart rate characteristics and patterns

Clinical management based on FHR interpretation

Interventions

Fetal testing

Limitations of continuous fetal monitoring

12 Fetal acid-base monitoring

Physiology of fetal acid-base balance and respiratory gas exchange

Fetal respiratory and metabolic acidemia

Base deficit and the strong ion difference

Acid-base balance during normal labor

Fetal surveillance during labor

Fetal scalp blood sampling

Causes of fetal hypoxia/acidemia

Prediction of abnormal fetal outcome

Intrapartum prevention

Postnatal prediction

Clinical interpretation of umbilical blood acid-base and lactate values

Routine analysis of cord blood acid-base balance and lactate at delivery

13 Fetal pulse oximetry

Introduction

Physiological considerations

SpO2 instrumentation

FSpO2 instrumentation

Accuracy and critical threshold

Factors affecting fetal oxygen saturation measurements

Clinical trials

Conclusion

Note

14 Neonatal assessment and prediction of neonatal outcome

Introduction

Adverse neurological outcomes

Neonatal assessments and prediction of outcome

Illness severity scores

Neurological and neurobehavioral assessments

Assessment of specific problems

SECTION 3: Interventions: Anesthesia, Analgesia, and Their Effects on the Fetus

15 Environmental exposure to anesthetic agents

Introduction

Occupational exposure to inhalation anesthetics: general considerations

Occupational exposure to inhalational anesthetics during pregnancy

Nitrous oxide

Developmental outcome

Sterilizing agents

Animal studies

Conclusions

16 Anesthesia and analgesia for assisted reproduction techniques and other procedures during the first trimester

Introduction

Assisted reproduction techniques and early pregnancy interventions

Surgery in early pregnancy

Anesthetic and analgesic drug exposure

Summary

17 The effect of anesthetic drugs on the developing fetus: considerations in non-obstetric surgery

Introduction

Teratogenisis

Risk classification for drugs during pregnancy

Apoptosis in the newborn brain and anesthetic agents

Effects on the baby of individual anesthetic drugs

Volatile anesthetic agents

Intravenous anesthetic agents and adjuncts

Sedatives/hypnotics

Opioids

Neuromuscular blocking agents

Local anesthetics

Summary

18 Substance abuse and pregnancy

Introduction

Opioids

Amphetamines

Marijuana (cannabis)

Tobacco

Solvents

Ethanol

Cocaine

Anesthetic management of the substance-abusing parturient

19 Intrauterine fetal procedures for congenital anomalies

Introduction

Anesthesia for fetal surgery

Fetal pain

Congenital diaphragmatic hernia

Urinary tract obstruction

Disorders of monochorionic twins

Myelomeningocele

Congenital cystic adenomatoid malformations

Sacrococcygeal teratoma

Congenital disorders of the heart

The future of fetal surgery

20 The EXIT procedure

Introduction

Physiology of the EXIT procedure

Preoperative evaluation

Preoperative preparation

Maternal anesthesia

Surgical incision

Fetal monitoring and management

Postpartum maternal management

Complications

Future directions

21 Mechanisms and consequences of anesthetic-induced neuroapoptosis in the developing brain

Introduction

Neurodevelopment: synaptogenesis and apoptosis

Anesthetic-induced neuronal cell death

The mechanism of activation of apoptosis

Prevention of neuronal apoptosis

Animal behavioral studies

Extrapolation of animal findings to humans

The future

22 Relevance to clinical anesthesia of anesthetic-induced neurotoxicity in developing animals

Introduction

Evidence from animal studies that anesthetic drugs can damage the developing brain and cause long-term neurobehavioral disturbances

The window of vulnerability

Fundamentals of drug-induced developmental neuroapoptosis

How does drug-induced neuroapoptosis relate to natural programmed cell death?

How does anesthesia-induced neuroapoptosis relate to other forms of drug-induced neuroapoptosis?

Augmentation by drug combinations

Evidence for anesthesia-induced neuroapoptosis in non-human primates

Can we extrapolate animal data to humans?

Human epidemiological studies

Summary and conclusions

23 External cephalic version

Introduction

Benefit of ECV for the fetus

Predictors of ECV success

Timing of ECV

Increasing the ECV success rate

Neuraxial analgesia

Safety of ECV (fetal and maternal considerations)

Summary

SECTION 3.1 Anesthesia for Cesarean Delivery

24 Effects on the fetus of general versus regional anesthesia

Introduction

Effects of cesarean delivery on the fetus and neonate

Effects of general anesthesia on fetus and newborn

Direct effects

Indirect effects

Effects of regional anesthesia on fetus and neonate

Direct effects

Indirect effects

Potentially beneficial effects of anesthesia on the fetus and neonate

Comparing effects on the fetus and neonate of general versus regional anesthesia

25 Anesthesia for cesarean delivery: effects on the fetus of maternal blood pressure control

Introduction

Physiologic considerations

Regional anesthesia

General anesthesia

Maternal resuscitation

26 Effects on the fetus of maternal oxygen administration

Introduction

Means of administering oxygen to the mother

Transfer of oxygen to the fetus

Effect of increased fetal PO2 on neonatal condition

Potential adverse fetal effects of high maternal FiO2

Maternal considerations

Conclusions

27 Effects on the fetus of maternal position during cesarean delivery

Introduction

Posture and aortocaval compression

Neuraxial anesthesia and maternal position

Positioning during spinal anesthesia

Positioning during epidural anesthesia

Conclusions

SECTION 3.2 Analgesia for Labor

28 Effects on the fetus of systemic vs. neuraxial analgesia

Introduction

Placental drug transfer

Direct effects on the fetus

Indirect effects on the fetus

Systemic vs. neuraxial analgesia – clinical effects on the fetus

Summary

29 The effects on the fetus of early versus late regional analgesia

Introduction

Initiation of analgesia in early vs. late labor

Fetal effects

Neonatal outcomes

Summary

30 Regional analgesia, maternal fever, and its effect on the fetus and neonate

Introduction

Evidence linking epidural analgesia to maternal hyperthermia

Fetal consequences of maternal hyperthermia

Proposed mechanisms for epidural related fever

Preventing fetal harm due to temperature rise

31 Effects on the fetus of major maternal anesthetic complications

Introduction

Fetal responses to hypoxia

Anesthetic catastrophes

Summary

SECTION 4: Confounding Variables: The Compromised Fetus, the Compromised Mother

32 Multiple pregnancy

Introduction

Incidence of twins

Types of twins

Maternal physiology

Antenatal maternal complications

Maternal complications during parturition

Fetal complications

Complications unique to monochorionic twins

Twin–twin transfusion syndrome

Delivery

Intrapartum management

33 Preeclampsia: the compromised fetus, the compromised mother

Introduction

Hemodynamic changes in preeclampsia

Treatment of hypertension

Gastrointestinal complications

Cardiopulmonary complications and their management

Neurologic complications

Renal complications

Placental abruption and disseminated intravascular coagulopathy

Intrauterine growth restriction (IUGR)

Eclampsia

Maternal and fetal effects of anesthesia

Conclusion

34 Fetal distress

Introduction

Physiological changes in uteroplacental circulation relevant to the anesthetist

Assessment of neonatal outcome

The degree of urgency of cesarean section

Fetal resuscitation

Choice of method of anesthesia: safety and timing

Effects of anesthesia

Animal studies

Clinical studies

SECTION 5: Trauma and Resuscitation

35 Maternal trauma

Introduction

Epidemiology

Maternal and fetal outcome

Mechanism and etiology of injury

Prevention

Basic principles

Clinical practice

Hemodynamics: monitoring, fluids, vasopressors, and tocolytics

Cesarean section in trauma

Diagnostic imaging and radiation exposure in pregnancy

Summary

36 Maternal resuscitation and perimortem cesarean delivery

Introduction

Resuscitation guidelines

Basic life support

Advanced life support

Treatment after return of spontaneous circulation

Perimortem cesarean delivery

Perimortem cesarean delivery for maternal survival

Perimortem cesarean delivery for fetal salvage

Technique

Brief summary and conclusion

37 Intrauterine fetal resuscitation

Introduction

Oxygen delivery to the fetal vital organs

Indications for fetal resuscitation

Factors reducing oxygen delivery

Measures to restore oxygen delivery

Application of fetal resuscitation

38 Neonatal resuscitation and immediate neonatal emergencies

Introduction

Neonatal resuscitation algorithm

Resources and personnel

Initial steps in resuscitation

A: Airway

B: Breathing

C: Circulation

D: Drugs

Resuscitation in special circumstances

Congenital anomalies

Neonatal complications

Discontinuing resuscitation

Use of simulation in preparing for neonatal emergencies

Summary

Acknowledgment

SECTION 6: Medicine, Ethics, and the Law

39 Fetal beneficence and maternal autonomy: ethics and the law

Introduction

Forced intervention: the law

Ethical and legal challenges

Duty of care to the fetus

Competency

Conclusion

40 Maternal-fetal research in pregnancy

Introduction

Key definitions

The ethical concept of the fetus as a patient

Research ethics

Maternal-fetal research ethics

Conclusion

Index

First Breaths

Mother and baby, teacher and pupil, ideas and words

Each breathes life, one into the other,

Back and forth and on forever.

We dedicate this book to our parents (and theirs), our children (and theirs),

Our teachers (and theirs), our students (and theirs),

And to mothers and babies and all those who breathe life into them.

To Nurit, Janice, Aoife and Carol

This edition first published 2013 © 2013 by Blackwell Publishing Ltd.

Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing program has been merged with Wiley’s global Scientific, Technical and Medical business to form Wiley-Blackwell.

Registered office: John Wiley & Sons, Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK

Editorial offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK

The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK

111 River Street, Hoboken, NJ 07030-5774, USA

For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley-blackwell

The right of the author to be identified as the author of this work has been asserted in accordance with the UK Copyright, Designs and Patents Act 1988.

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher.

Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought.

The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by physicians for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom.

Library of Congress Cataloging-in-Publication Data

Anesthesia and the fetus / [edited by] Yehuda Ginosar ... [et al.]. – 1st ed.

p. ; cm.

 Includes bibliographical references and index.

 ISBN 978-1-4443-3707-5 (hardback : alk. paper)

 I. Ginosar, Yehuda.

 [DNLM: 1. Anesthesia, Obstetrical–adverse effects. 2. Fetal Development–drug effects. 3. Anesthetics–adverse effects. 4. Fetal Monitoring. 5. Fetus–drug effects. 6. Pregnancy Outcome. WO 450]

 617.9'64–dc23

2012021654

A catalogue record for this book is available from the British Library.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.

Cover image: iStockphoto.com © Noel Powell

Contributors

Cheryl A. Albuquerque MDDepartment of Obstetrics and GynecologySanta Clara Valley Medical CentreSan Jose, California, USA

Pamela J. Angle MD FRCPC MSc (Health Research Methodology), MSc Evidence based Health Care (Oxford)Associate Professor of AnesthesiaAssistant Professor of ClinicalEpidemiology (Institute for Health Policy Management and Evaluation)Associate Scientist, Sunnybrook Research Institute, Sunnybrook Health Sciences Ctr,University of TorontoToronto, Canada

Philip Baker FRCOG FMedSciDirector, National Research Centre for Growth and DevelopmentConsultant Obstetrician and Senior ScientistProfessor of Maternal and Fetal HealthThe University of AucklandAuckland, New Zealand

Benjamin Bar-Oz MDHead, Department of NeonatologyHadassah and Hebrew University Medical CentreJerusalem, Israel

Jon Barrett MBBCh MD FRCOG FRCS(C)Chief MFM, Sunnybrook Health Science CenterToronto, Canada

Ahmet A. Baschat MB BChHead, Section of Fetal TherapyDivision of Maternal Fetal MedicineDepartment of Obstetrics, Gynecology and Reproductive ScienceUniversity of Maryland School of MedicineBaltimore, Maryland, USA

Ruth Bedson MBBS FRCADepartment of AnaesthesiaQueen Charlotte’s & Chelsea HospitalLondon, UK

Yaakov Beilin MDProfessor of Anesthesiology and Obstetrics/Gynecology/Reproductive SciencesMount Sinai School of MedicineNew York, New York, USA

Frank A. Chervenak MDGiven Foundation Professor and ChairmanDepartment of Obstetrics and GynecologyNew York Presbyterian HospitalWeill Medical College of Cornell UniversityNew York, New York, USA

Ritu Chitkara MDAttending NeonatologistDivision of NeonatologyDepartment of PediatricsCedars-Sinai Medical CenterClinical InstructorDepartment of PediatricsDavid Geffen School of MedicineUniversity of CaliforniaLos Angeles, USA

Paul B. Colditz MB BS FRACP M Biomed Eng D PhilFoundation Professor of Perinatal MedicineUniversity of QueenslandDirector, Perinatal Research CentreRoyal Brisbane and Women’s HospitalBrisbane, Australia

Melissa Covington MDAnesthesiologist, Department of AnesthesiaUniversity of Vermon College of Medicine andFletcher Allen Health CareBurlington, Vermont, USA

Catherine E. Creeley PhDResearch InstructorDepartment of Psychiatry,Washington UniversitySt Louis, USA

Lowell Davis MDProfessor Maternal-Fetal MedicineOregon Health and Science UniversityPortland, Oregon, USA

M. Joanne Douglas MD FRCPCClinical ProfessorDepartment of Anesthesiology, Pharmacology and TherapeuticsUniversity of British ColumbiaVancouver, Canada

Robert A. Dyer FCA (SA) PhDProfessor, Second ChairDepartment of AnesthesiaUniversity of Cape Town and Groote Schuur HospitalCape Town, South Africa

Christine East PhDSenior Lecturer, University of Melbourne Department of Obstetrics and Gynaecology and Department of Perinatal Medicine Pregnancy Research CentreRoyal Women’s HospitalVictoria, Australia

Sharon Einav MDSenior Lecturer in Anesthesiology and Critical Care MedicineDirector of Surgical Intensive Care and Chair of Resuscitation Committee Shaare Zedek Medical CenterHebrew UniversityJerusalem, Israel

Uriel Elchalal MDAssociate Professor of Obstetrics and GynecologyHead of High Risk Pregnancy ClinicDepartment of Obstetrics and GynecologyHadassah Hebrew University Medical CenterJerusalem, Israel

Smadar Eventov-Friedman MD PhDSenior Lecturer in PediatricsDirector of NeonatologyDepartment of NeonatologyHadassah and Hebrew University Medical CentreEin Kerem, Jerusalem, Israel

Yossef Ezra MDAssociate Professor of Obstetrics and GynecologyHead of Delivery UnitDepartment of Obstetrics and GynecologyHadassah-Hebrew University Medical CenterEin Kerem, Jerusalem, Israel

Henry L. Galan MDProfessor of Obstetrics & GynecologyChief of Maternal-Fetal MedicineDepartment of Obstetrics and GynecologyUniversity of Colorado DenverAurora, Colorado, USA

Richard S. Gist MD CDR MC USNDivision Head Obstetric AnesthesiaNaval Medical Center PortsmouthPortsmouth, Virginia, USA

Anne Greenough MD FRCPCHDivision of Asthma, Allergy and Lung BiologyMRC and Asthma UK Centre in AllergicMechanisms of AsthmaHead of SchoolKings College School of Medicine and DentistryProfessor of Neonatology and Clinical Respiratory PhysiologyKing’s CollegeLondon, UK

Sorina Grisaru-Granovsky MD PhDProfessor in Obstetrics GynecologyHead of High Risk Pregnancy UnitDivision of Maternal MedicineShaare Zedek Medical Center Hebrew UniversityJerusalem, Israel

Yehuda Habaz MD FRCSSpecialist in Obstetrics & GynecologyThe Maternal-Fetal UnitSunnybrook Health Sciences CentreToronto, Ontario, Canada

Louis P. Halamek MDProfessorDirector, Fellowship Training Program in Neonatal-Perinatal MedicineDirector, Center for Advanced Pediatric and Perinatal EducationDivision of Neonatal and Developmental MedicineDepartment of PediatricsStanford University School of MedicinePalo Alto, California, USA

Stephen H. Halpern MD MSc FRCPCProfessor of Anesthesia, Obstetrics and GynecologyUniversity of TorontoDivision Head, Obstetrical AnesthesiaSunnybroook Health Sciences CentreToronto, Ontario, Canada

Richard Harding PhD DScProfessorial FellowSchool of Biomedical SciencesMonash UniversityMelbourne, Australia

Kazumasa Hashimoto MDFellow in Maternal Fetal MedicineDepartment of Obstetrics, Gynecology and Reproductive SciencesUniversity of Maryland, BaltimoreBaltimore, Maryland, USA

Janine R. Hutson MScThe Division of Clinical Pharmacology & ToxicologyThe Motherisk ProgramThe Hospital for Sick ChildrenToronto, Ontario, Canada

Adam P. Januszewski MBBS BsCDepartment of AnaestheticsPain Medicine & Intensive CareChelsea & Westminster HospitalImperial CollegeLondon, UK

Tania L. Kasdaglis MDDepartment of Obstetrics, Gynecology and Reproductive ScienceUniversity of Maryland School of MedicineBaltimore, Maryland, USA

Sarah J. Kilpatrick MD PhDTheresa S. Falcon-Cullinan Professor and HeadDepartment of Obstetrics and Gynecology; andVice Dean, College of MedicineUniversity of IllinoisChicago, Illinois, USA

Stephen Michael Kinsella FRCAConsultant AnaesthetistSt Michael’s HospitalBristol, UK

Alexander J. Kiss PhDAssistant ProfessorInstitute of Health PolicyManagement and EvaluationUniversity of TorontoToronto, Ontario, Canada

Chagit Klieger MD PharmBScObstetric GynecologistTel Aviv Sourasky Medical CenterTel Aviv, Israel

Gideon Koren MD FRCPC FABMTThe Division of Clinical Pharmacology and ToxicologyThe Motherisk ProgramThe Hospital for Sick ChildrenToronto, Ontario, Canada

Hanmin Lee MDProfessor, Surgery, Ob-Gyn and Reproductive Health ServicesChief, Division of Pediatric SurgeryDirector, Fetal Treatment CenterUCSF School of MedicineSan Francisco, USA

Allison J. Lee MDUniversity of Miami Miller School of MedicineJackson Memorial HospitalMiami, Florida, USA

Todd R. Lovgren MDMaternal Fetal Medicine FellowDepartment of Obstetrics and GynecologyUniversity of ColoradoHealth Sciences CenterAurora, Colorado, USA

Daqing Ma MD PhDReader in Anaesthetics, Imperial College LondonDepartment of AnaestheticsChelsea & Westminster HospitalLondon, UK

Mervyn Maze MB ChB FRCP FRCA FMedSciWilliam K. Hamilton Distinguished Professor of AnesthesiaProfessor and Chair,Department of Anesthesia and Perioperative CareUniversity of CaliforniaSan Francisco, USA

Laurence B. McCullough PhDDalton Tomlin Chair in Medical Ethics and Health PolicyBaylor College of MedicineHouston, Texas, USA

Yuval Meroz MDDepartment of Anesthesiology and Critical Care MedicineHadassah-Hebrew University Medical Center,Ein Karem, Jerusalem, Israel

Timothy J.M. Moss PhDThe Ritchie CentreMonash Institute of Medical ResearchDepartment of Obstetrics and GynecologyMonash UniversityClayton, Victoria, Australia

Vadivelam Murthy MBBS DCH MRCPHDivision of Asthma, Allergy and Lung BiologyMRC and Asthma UK Centre in Allergic Mechanisms of AsthmaKing’s College, CollegeLondon, UK

Warwick D. Ngan Kee BHB MBChB MD FANZCA FHKAMProfessorDepartment of Anaesthesia and Intensive CareThe Chinese University of Hong KongShatin, Hong Kong, China

Kypros Nicolaides MD FRCOGDirector, Harris Birthright Research Centre for Fetal MedicineKing’s College HospitalDenmark HillLondon, UK

Amar Nijagal MDPostdoctoral FellowDivision of Pediatric SurgeryFetal Treatment CenterUniversity of CaliforniaSan Francisco, USA

Lennart Nordström MD PhDAssociate Professor, ConsultantDepartment of Obstetrics & GynecologyKarolinska University HospitalKarolinska InstituteStockholm, Sweden

John W. Olney MDJohn P. Feighner Professor of PsychiatryProfessor of Pathology and ImmunologyDepartment of PsychiatryWashington University, St Louis, USA

Sharon Orbach-Zinger MDDepartment of AnesthesiologyRabin Medical Center-Beilinson HospitalPetach Tikva, Israel

Asher Ornoy MDProfessor of Anatomy, Embryology & TeratologyDepartment of Medical NeurosciencesHadassah-Hebrew University Medical CenterEin Kerem, Jerusalem, Israel

George Osol PhDProfessor, Department of Obstetrics, Gynecology and Reproductive SciencesUniversity of Vermont College of MedicineBurlington, Vermont, USA

Arvind Palanisamy MD FRCAAssistant Professor of Anaesthesia Harvard Medical SchoolBrigham and Women’s HospitalBoston, Massachusetts, USA

Donald H. Penning MD MS FRCPDirector of Anesthesia, Denver HealthMedical Director Perioperative ServicesProfessor, University of ColoradoDenver, Colorado, USA

Julie Phillips MDFellow, Maternal Fetal MedicineDepartment of ObstetricsGynecology and Reproductive SciencesUniversity of Vermont College of MedicineBurlington, Vermont, USA

Felicity Plaat BA MBBS FRCAConsultant AnaesthetistQueen Charlotte’s & Chelsea HospitalImperial CollegeLondon, UK

Alison M. Premo MDAnesthesiologistDirector of Obstetric AnesthesiaOakwood AnesthesiaDearborn, Michigan, USA

Anand K. Rajani MDAttending Neonatologist Community Regional Medical Center Perinatal Medical Group IncFresno, California, USA

Avraham I. Rivkind MD FACSProfessor of SurgeryDirector of Shock Trauma UnitHadassah Hebrew University Medical CenterJerusalem, Israel

Mark Rosen MDFetal Treatment CenterDepartment of AnesthesiaUniversity of CaliforniaSan Francisco, USA

Robin Russell MB BS MD FRCAConsultant Anaesthetist & Honorary Senior Clinical LecturerNuffield Department of AnaestheticsJohn Radcliffe HospitalOxford, UK

Neeti Sadana MDAssistant Professor, Department of AnesthesiologyThe University of Oklahoma Health Sciences CenterCollege of MedicineOklahoma CityOklahoma, USA

Leann K. Schoeman MBChB FCOG MMedSenior SpecialistDepartment of Obstetrics and GynecologyUniversity of Cape Town and Groote Schuur HospitalCape Town, South Africa

Scott Segal MD MHCMProfessor of AnesthesiologyTufts University School of MedicineChair, Department of AnesthesiologyTufts Medical CenterBoston, Massachusetts, USA

Andrew Shennan MBBS MD FRCOProfessor of ObstetricsMaternal and Fetal Research UnitSt Thomas′ HospitalLondon, UK

Eric S. Shinwell MDDirector of NeonatologyKaplan Medical Center, ReehovotHebrew UniversityJerusalem, Israel

Marcos Silva Restrepo MDAnesthesia ResidentUniversity of TorontoToronto, Ontario, Canada

Philip J. Steer BS MD FRCOG FCOGSA (hon)Emeritus ProfessorAcademic Department of Obstetrics and GynaecologyImperial College LondonChelsea and Westminster HospitalLondon, UK

Sheldon M. Stohl MDAttending AnesthesiologistDepartment of Anesthesiology & Critical Care MedicineThe Children’s Hospital of Philadelphia andDepartment of Anesthesiology & Critical Care MedicineHadassah-Hebrew University Medical CenterJerusalem, Israel

Hindi E. Stohl MDFellow, Division of Maternal Fetal MedicineDepartment of Obstetrics and GynecologyUniversity of Southern CaliforniaLos Angeles, California, USA

William J. Sullivan QC LLB MCLPartner, Guild Yule LLPAdjunct ProfessorFaculty of MedicineUniversity of British ColumbiaVancouver, Canada

Tabitha A. Tanqueray MBChB FRCAResearch FellowAnaesthetic DepartmentChelsea and Westminster HospitalLondon, UK

Loren P. Thompson PhDAssociate Professor, Department of ObstetricsGynecology and Reproductive SciencesUniversity of MarylandBaltimore, Maryland, USA

Kha M. Tran MDAssistant Professor of Anesthesiology & Critical CarePerelman School of Medicine at the University of PennsylvaniaDirector, Fetal Anesthesia TeamDepartment of Anesthesiology & Critical Care MedicineThe Children’s Hospital of PhiladelphiaPhiladelphia, USA

Lawrence C. Tsen MDVice Chair, Faculty Development and EducationDirector of AnesthesiaCenter for Reproductive MedicineDepartment of Anesthesiology, Perioperative and Pain MedicineBrigham and Women’s HospitalAssociate Professor of AnaesthesiaHarvard Medical School BostonMassachusetts, USA

Joseph Varon MD FACP FCCP FCCMChief of Critical Care ServicesUniversity General HospitalClinical Professor of Medicine and Professor of Acute and Continuing CareThe University of Texas Health Science Center – HoustonProfessor of Clinical MedicineThe University of Texas Medical Branch at Galveston Texas, USA

Carolyn F. Weiniger MB ChBSenior Lecturer of Anesthesiology and Critical Care MedicineHadassah-Hebrew University Medical CenterEin Kerem, Jerusalem, Israel

Ari Y. Weintraub MDAssistant Professor of Anesthesiology & Critical CarePerelman School of Medicine at the University of Pennsylvania; andDepartment of Anesthesiology & Critical Care MedicineThe Children’s Hospital of PhiladelphiaPhiladelphia, USA

Cynthia A. Wong MDProfessor and Vice ChairDepartment of AnesthersiologyNorthwestern University Feinberg School of MedicineChicago, IIllinois, USA

Caroline WrightMaternal and Fetal Health Research CentreSt. Mary’s Hospital, University of ManchesterManchester, UK

Steve M. Yentis BSc MBBS FRCA MD MAConsultant AnaesthetistChelsea and Westminster HospitalHonorary ReaderImperial College LondonLondon, UK

Zhaowei Zhou BSc BMDepartment of AnaestheticsPain Medicine & Intensive CareChelsea & Westminster HospitalImperial CollegeLondon, UK

Preface

It may well be argued that the textbook is an outmoded vehicle for the transfer of modern medical knowledge. Recent years have seen an exponential increase in published original manuscripts in basic science and clinical medicine, not to mention reviews, editorials, guidelines, and consensus statements (see Figure 1). When the duration of gestational development of a textbook is considered against the backdrop of this unparalleled explosion of information, it may be thought that all textbooks are doomed to obsolescence even before they hit the bookshops (or the Internet retailer). Why read a textbook when you can find all you want (and more) at the touch of a button? We believe that there is a difference between information and knowledge. Although knowledge is grounded on the acquisition of information, it also requires the active filtration and integration of relevant information from this data bombardment, its synthesis into understanding, which must be further refined by its application to new situations. The modern textbook aims to filter and integrate this information “tsunami” into a concise resource of current knowledge, refined by clinical insights. This is particularly important in multidisciplinary fields of medicine.

Fig. 1 The number of English language medical publications per year since 1966, taken from MEDLINE © 1966–2010.

The care of the fetus as a patient is an emerging specialty that has evolved on the borders of many traditional disciplines: obstetrics and perinatology, neonatology, genetics, pediatrics, pediatric surgery, and midwifery. The anesthesiologist is an increasingly important member of this team. There is an increasing appreciation of the potential for anesthetic drugs to affect the fetus, from the period of embryonic development and fetal growth through to early neonatal life. There is also an emerging literature concerning the long-term effects of anesthetic drugs on the developing mamalian brain and the possible implications for the exposure of children and fetuses to anesthetic drugs. Additionally, with advanced technologies for antenatal diagnosis and minimally-invasive surgery, there is a growing range of fetal disorders that are amenable to surgical intervention; many of these procedures require anesthetic care for both the mother and the fetus. Finally, there is an enticing possibility that in the future, anesthetic drugs or procedures may have a role as antenatal interventions to improve fetal wellbeing.

The stated aim of this textbook is to integrate into one volume different aspects of fetal development, fetal pharmacology, assessments of fetal outcome, and the impact on the fetus and newborn of anesthetic interventions. We hope that this book will fill a significant gap in this expanding area of multidisciplinary care. We are fortunate to have assembled an international roll of leading clinicians and scientists from the fields of anesthesiology (and not just obstetric anesthesia), obstetrics, neonatology, human development, and ethics. In many cases, chapters are written by two or more authors from different disciplines in order to provide the balance and integration that we are looking for. We hope that this book will be of value not only for anesthesiologists but also for obstetricians and perinatologists, neonatologists, pediatricians, midwives, and others concerned with the care of the unborn child.

Yehuda GinosarFelicity ReynoldsStephen HalpernCarl P. Weiner

Acknowledgments

We are deeply indebted to the authors who contributed to this book; a considerable effort that is not rewarded either academically or financially. Unusually for a textbook, we would also like to acknowledge those authors who submitted chapters that did not meet our editorial requirements and whose work could not be accommodated.

We are extremely grateful to Dr Martin Sudgen, Medical Publisher at Wiley-Blackwell, for supporting this project from its conception and to a series of dedicated development editors for nurturing it throughout its gestation: Lewis O’Sullivan, Michael Bevan, Annette Abel, Lucinda Yeates, and Simone Dudziak and project manager Aileen Castell; we thank you all for your patience and professionalism. Special thanks and love to our families who are used to our work routines but who rarely get the acknowledgment they deserve. Finally, special thanks to Felicity from Yehuda, Steve, and Carl for having been the most dependable, tireless and efficient co-editor imaginable.

SECTION 1Basic Principles

1

Intrauterine Growth and Development

Timothy J.M. Moss1, Cheryl A. Albuquerque2 & Richard Harding3

1Ritchie Centre, Monash Institute of Medical Research, and Department of Obstetrics and Gynaecology, Monash University, Clayton, Australia

2Department of Obstetrics and Gynecology, Santa Clara Valley Medical Centre, San Jose, USA

3Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia

Introduction

The birth of a healthy, full-term infant is the result of the successful orchestration of a multitude of individual developmental events. These processes are affected by genetic and environmental influences starting before conception and extending throughout gestation. Congenital abnormalities, which are present in up to 5% of human births, usually result from abnormalities in very early development. For example, many organ systems form between four and eight weeks after fertilization (Table 1.1), making them particularly vulnerable to teratogenic exposure during this period. The majority of congenital abnormalities can be detected in utero by routine ultrasound imaging [1]. For those that may be fatal to the fetus or neonate or result in severe life-long disability, the option of fetal surgical intervention is becoming increasingly possible [2]. However, the widespread adoption of fetal interventions for prenatal correction of congenital abnormalities has not yet been established and most techniques are currently experimental [2, 3]. By far the greatest obstacle to successful outcomes after fetal interventions is preterm birth and its associated complications [3].

Table 1.1 Timing of structural and functional development of major organs.

Organ

Anatomical origin

Onset of function

Adrenals

The adrenal cortex arises from mesenchymal cells (mesoderm), superior to the developing gonads, at 6 weeks. The adrenal medulla is formed from an adjacent sympathetic ganglion (ectoderm) during the eighth week.

Dihydroepiandosterone sulfate is synthesized at 6–8 weeks. Cortisol is produced from progesterone at 8–12 weeks.

Heart

The angioblastic cords, which arise from splanchnic mesenchyme (mesoderm) fuse to form the primitive endothelial heart tube at ∼22 days. Folding of the heart tube and septation to form left and right atria and ventricles are complete by 8 weeks.

Myogenic contractions first begin on day 21–22. Coordinated contractions resulting in forward flow occur by 4 weeks. The conducting system of the heart originates with the formation of the sinoatrial node during the fifth week.

Lungs

The lower respiratory tract begins as the laryngotracheal tube by budding of endoderm, into the surrounding splanchnic mesenchyme, from the ventral primitive foregut during weeks 4–5. Bronchial buds form and progressively branch to form the conducting and respiratory regions of the lungs. Lung structural development (airway branching and alveolarization) continues until after birth.

The fetal lungs actively secrete fluid that expands the lungs, which is critical for normal lung growth. Clearance of lung liquid at birth allows the initiation of gas exchange. Production of pulmonary surfactant, which is critical for lung function after birth, is initiated at ∼24 weeks.

Kidneys

After the pronephroi and mesonephroi, the metanephroi develop during the 5th week as the ureteric bud penetrates metanephric mesoderm. Ureteric bud branching forms the renal tubules, which are invaginated by glomeruli to form nephrons (the functional unit of the kidney). Nephrogenesis is complete before full term.

Glomerular filtration begins at approximately the 9th week. The fetal kidneys produce copious dilute urine, which provides the majority of amniotic fluid volume.

Gonads

Sexual differentiation of the gonads does not occur until the seventh week after fertilization. The undifferentiated gonads arise from mesodermal epithelium and underlying mesenchyme, medial to the mesonephros, during the 5th week to form the gonadal ridges. Primary sex chords (of epithelial origin) then penetrate the underlying mesenchyme. The undifferentiated gonads consist of an epithelial cortex and mesenchymal medulla by 6 weeks. Primordial germ cells, present in the yolk sac endoderm early in the 4th week, migrate to the primary sex chords during the 6th week.

 Testis

Under the influence of the SRY gene, the primary sex chords develop into extended and anastomosed seminiferous tubules at approximately 7 weeks. The epithelial cells of the tubules give rise to the sertoli cells; spermatogonia arise from the primordial germ cells.

Testosterone production by the developing testis begins at ∼8 weeks. Spermatogenesis does not occur until puberty.

 Ovaries

The ovaries are first apparent at ∼10 weeks. The primary sex cords degenerate and secondary sex chords develop from the cortical epithelium to form primordial follicles at ∼12 weeks, which contain oogonia, differentiated from primordial germ cells, surrounded by follicular cells derived from the secondary sex chords.

Ovarian steroidogenesis begins after the 28th week of gestation. Ovulation does not occur until puberty.

Brain

The nervous system arises from the neural folds (ectoderm) on the dorsal surface of the embryonic disc at ∼3 weeks. During week 4 the prosencephalon, mesencephalon (which gives rise to the midbrain and superior and inferior colliculi), and rhombencephalon (demarcated from the spinal cord by the cervical flexure) form. During the 5th week the prosencephalon gives rise to the telencephalon (which gives rise to the cerebral cortex and basal nuclei) and diencephalon (which forms the retina, thalamus, and hypothalamus); the metencephalon (which forms the pons and cerebellum) and myelencephalon (which becomes the medulla) form from the rhombencephalon.

Disorganized neural activity is likely to be present from 5–6 weeks. Synapses do not form substantially until 17 weeks and peak later in gestation, continuing postnatally (in combination with synaptic pruning). Fetal responsiveness indicative of higher brain function does not occur until the second half of gestation. Fetal behavioural (sleep) states are indirectly identifiable (based on the presence of rapid eye movements) at 28–31 weeks.

Liver

The liver forms from a ventral outgrowth of the foregut in the fourth week.

Hematopoiesis begins in the liver during the 6th week. Bile formation begins during the 12th week.

Spleen

The spleen begins to develop during the 5th week, from mesenchymal cells in the dorsal mesentery. The splenic circulation is established during weeks 6–7.

Lymphoid colonization of the spleen begins during week 18.

Pancreas

The pancreas originates as two buds from the developing duodenum (endoderm) within the ventral mesentery during the 5th week. These buds fuse and their separate ducts anastomose during gut rotation.

Insulin secretion begins in the 10th week.

Pituitary

Ectoderm of oral origin begins to form the adenohypophysis of the pituitary (pars tuberalis, pars distalis, pars intermedia) at the beginning of the 4th week. At this stage the neurohypophysis (median eminence, infundibular stem, pars nervosa) begins to form as an infundibulum of the diencephalon.

Adrenocorticotrophic hormone (ACTH) is released by the pituitary by 8 weeks.

Thyroid

The thyroid develops at ∼24 days from endoderm at the base of the primitive pharynx and attains its adult appearance and anatomical location by 7 weeks.

Thyroid hormone production begins at 10–12 weeks.

Thymus

The thymus develops from epithelial cells (endoderm) of the third pharyngeal pouch, which penetrate the surrounding mesenchyme (which later forms thin septae between thymic lobules). T cell progenitors (hematopoietic stem cells) begin to populate the thymus from 7 weeks.

Mature T cells are evident in the fetal thymus from 8 weeks.

Gastrointestinal tract

During the 4th week, the primitive foregut arises when embryonic folding incorporates the dorsal part of the yolk sac into the embryo. The digestive tract epithelium and glands arise from endoderm and the layers of the wall of the digestive tract are derived from the surrounding splanchnic mesenchyme; ectoderm gives rise to oral and anal epithelia.

Meconium appears in the small bowel during the 14th week and accumulates in the colon from 18 weeks. Some gastrointestinal hormones are secreted from as early as 8 weeks.

In this chapter, we summarize the current understanding of processes involved in implantation and organogenesis, the major developmental abnormalities that are amenable to surgical intervention during gestation and/or delivery, development of the fetus, and factors that affect its growth and development.

Early Development and Placentation

Human development begins with the formation of the zygote soon after fertilization. Initial zygotic cleavage results in two cells (blastomeres), which undergo further divisions (cleavage) within the zona pellucida surrounding the zygote. Cleavage occurs without an increase in cytoplasmic mass, so each division results in successively smaller blastomeres. The blastomeres are compacted to form the morula within four days of fertilization. Fluid spaces within the morula then coalesce to form the blastocyst cavity, marking the formation of the blastocyst. This coincides with differentiation of the inner cell mass (which will ultimately form the embryo), located at the embryonic pole, from the trophoblast (which makes up the wall of the blastocyst) and degradation of the zona pellucida (Figure 1.1).

Fig. 1.1 Schematic illustration of critical periods of development before birth, showing the timing of vulnerability to teratogens. Highly sensitive periods for organs and systems are shown in dark shading; less sensitive periods are shown in light shading.

Reproduced from Moore K, Persaud TVN, editors. The Developing Human: Clinically Oriented Embryology. 8th edn. Philadelphia: Saunders; 2008. P. 473 with permission from Elsevier.

About one week after fertilization, the embryonic pole of the blastocyst attaches to the uterine endometrial epithelium. The trophoblast cells differentiate into an inner cytotrophoblast layer and an outer syncytiotrophoblast, which begins to invade the endometrium and erode maternal capillaries and venules. Lacunae then form, containing maternal blood and endometrial gland secretions. Secretions of the endometrial glands support the growth of the embryo during the first trimester, resulting in uniform autonomous growth despite potentially very different maternal environments between individual preg­nancies [4]. During this period, organogenesis progresses in a low oxygen environment, protected from the potentially mutagenic effects of oxygen free radicals [4].

Normal placentation is dependent on the low oxygen levels present at this time and the privileged immune environment that acts to protect the conceptus from maternal rejection [4, 5]. As the lacunar network increases in volume, maternal arteries in the endometrium begin to contribute to the developing placental circulation and tissue oxygen levels begin to rise. The anatomical relationships between the maternal circulation and invading embryonic tissues, necessary for exchange, are established by the end of the third week after fertilization.

At the end of the second week after fertilization, chorionic villi form from the cytotrophoblast over the entire chorionic surface of the embryo. Eventually, villi adjacent to the uterine lumen regress; those adjacent to the embryo proper branch extensively into the decidua of the endometrium to begin to form the placenta. Failure of normal placentation is considered the root cause for several pregnancy diseases including preeclampsia, a vascular disease of pregnancy that is characterized by maternal hypertension, vascular endothelial cell activation, inflammation and proteinuria [6]. The prevalence of hypertensive diseases in pregnancy (preeclampsia is the most common form) is 6–8% in the USA [7]. It is potentially fatal for mother and fetus, and thus contributes significantly to rates of labor induction and early delivery; it accounts for 10–12% of inductions and 2.5–3% of elective cesarean deliveries in Australia [8].

Organogenesis

One week after fertilization, the inner cell mass of the blastocyst gives rise to the bilaminar embryonic disc, consisting of the embryonic epiblast and hypoblast. Gastrulation, which begins at the start of the third week, is the process whereby the bilaminar embryonic disc becomes trilaminar (consisting of ectoderm, endoderm, and mesoderm) at the initiation of morphogenesis.

The ectoderm eventually differentiates into the tissues of the central and peripheral nervous systems (meninges; brain; spinal cord; sensory epithelia of the visual, auditory, and olfactory systems), the epidermis, hair and nails, mammary glands, adrenal medulla, and pituitary. The mesoderm becomes the connective tissues, dermis, bone, muscles (cardiac, striated and smooth), circulatory system and spleen, kidneys, gonads, and reproductive tracts, adrenal cortex and pericardium, pleural membranes, and peritoneum. The endoderm gives rise to the epithelial linings of the respiratory and gastrointestinal tracts, liver, pancreas, urinary bladder and urethra, thyroid and parathyroid, thymus, tonsils, and parts of the auditory canal and Eustachian tube.

The timing of formation and onset of function of the major organs is shown in Table 1.1.

Congenital Abnormalities Amendable to Fetal Intervention

Congenital Diaphragmatic Hernia (CDH)

The lower respiratory tract, including the trachea, bronchi, and lungs, appears initially as a branch of the foregut on days 26 and 27 after fertilization. The diaphragm forms between weeks 6–14 of gestation. Closure of the diaphragm, usually between weeks 8–10, results from fusion of the septum transversum, pleuroperitoneal membranes, dorsal mesentery of the esophagus, and body wall. Human and mouse studies have identified a number of genes associated with failure of diaphragmatic closure [9, 10]. Failure of normal closure allows herniation of the abdominal contents into the thorax, compromising the space available for the developing lungs. The incidence of CDH is approximately 4.5/10 000 births but may occur in as many as 1 in 1000 pregnancies [11]. CDH occurs in the absence of other congenital anomalies in 60–70% of cases [12]. The greatest morbidity and mortality occur postnatally and result from potentially life-threatening lung hypoplasia (and coincident pulmonary hypertension). Though frequently fatal before the advent of antenatal detection and modern postnatal management [10], survival rates may now be as high as 80% depending on the severity of the thoracic volume compromise [13].

Surgical closure of the fetal diaphragm, with repositioning of the herniated abdominal contents to permit improved lung growth, has been tested clinically using open and fetoscopic techniques in a small number of centers, but was abandoned after a small trial showed no improvement in survival [14]. Critically, in fetuses with hepatic herniation (the most severely affected and with the poorest prognosis), repositioning of the liver compromised umbilical venous blood flow and resulted in fetal death [13]. Further, simple closure of the diaphragmatic defect does not provide sufficient stimulus for adequate lung growth postoperatively. A current surgical approach for CDH involves “fetoscopic” occlusion of the trachea to cause accumulation of fetal lung fluid, which stimulates lung growth [14], with postnatal correction of the diaphragmatic defect [13]. The result of a randomized trial is expected shortly. While tracheal occlusion reliably stimulates lung growth, alveolar epithelial cell differentiation is altered [15] and surfactant secretion is inhibited [16], resulting in poor postnatal respiratory function. Careful timing of tracheal occlusion and its relief before birth stimulate growth and maturation of the preterm lungs sufficiently to permit adequate postnatal respiratory function [14].

Fetal Hydronephrosis

The kidneys, ureters, bladder and urethra start to develop in the form of the primitive pronephros early in the 4th week after fertilization. Although the pronephroi and intermediate mesonephroi regress as development progresses, the metanephroi, which develop into the permanent kidneys, form in part from some of these primary structures. The permanent kidneys start development at the beginning of the 5th week post conception and become functional in the 9th week.

Fetal hydronephrosis arises in 2–9 per 1000 fetuses [17], is diagnosed based on dilatation of the urinary tract as measured by obstetric ultrasound, and can be caused by obstruction of the urinary tract at any level. Abnormal development of the urinary collecting system, rather than the kidneys themselves, is the likely cause in the majority of cases. In most of those diagnosed prenatally, especially those showing only minor renal distension, there is spontaneous resolution. However, as fetal urine is the major contributor to amniotic fluid volume, urinary tract obstruction can lead to oligohydramnios, with diverse sequelae. Postnatally, disease results from renal function abnormality or failure, poor bladder function, respiratory insufficiency secondary to pulmonary hypo­plasia due to oligohydramnios, and oligohydramnios-induced musculoskeletal abnormalities.

Posterior urethral valves are the most common cause of lower urinary tract obstruction in males [18], which appears as bilateral hydronephrosis, dilated ureters and bladder, and a thickened bladder wall. If these signs are detectable in fetuses aged less than 24 weeks of gestation, death or chronic postnatal renal failure occur in up to 50% of cases (18). Uteropelvic junction obstruction is the most common cause of prenatally diagnosed hydronephrosis, with a male-to-female ratio of 3 : 1; 20–25% of cases are bilateral. Obstruction of the uterovesicular junction is characterized by ureteric and renal pelvis dilatation on ultrasound; it has a male-to-female ratio of 4 : 1 and is bilateral in 25% of cases. With severe bilateral obstruction, fetal intervention may be indicated [17, 19] and may involve ultrasound-guided percutaneous placement of shunts to establish communication between the dilated urinary tract and the amniotic cavity or open fetal surgery to correct the underlying defect. Such interventions do not improve renal function but restoration of amniotic fluid volume may reduce respiratory morbidity [20].

Placement of vesico-amniotic shunts is reported as successful in 50% of cases; only half of successfully placed shunts remain in position until the end of gestation and complications may be fatal [17, 19]. Experimental animal models of urinary obstruction reveal that the associated renal dysplasia is not reversed by removal of the obstruction, and poor postnatal renal function is not avoided [18].

Sacrococcygeal Teratoma

These teratomas result from a persistence of the primitive node, at the cranial end of the embryonic primitive streak, which forms intra-embryonic mesoderm until the end of the 4th week and thereafter usually regresses. They are the most common tumor observed in newborns, with an incidence of 1 in 20 000–40 000 (female : male incidence 3 : 1) [21]. Most sacrococcygeal teratomas diagnosed neonatally have good outcomes after resection but, when coupled with polyhydramnios, hydrops, placentomegally, and/or rapid growth of the teratoma, are frequently fatal for the fetus [3, 22]. A large teratoma can have substantial metabolic demands, and vascular shunts within the teratoma can result in high-output fetal cardiac failure. Sacrococcygeal teratomas can be graded according to their location, from type I (completely external) to type IV (completely internal): type I is the only type considered amenable to fetal intervention [21], which may be by tumor excision or vascular ablation. Reports of either approach are limited, with varying degrees of success [3].

Neural Tube Defects

Failure of closure of the embryonic neural tube during the 3rd and 4th week after conception brings about the most common forms of CNS abnormality [23]. The majority of neural tube defects involve the lumbo-sacral spine and overlying skin [23]. In spina bifida there is cystic herniation of meninges (meningocele), spinal cord (myelocele), or both (myelomeningocele) through a defect in the vertebral column. Spina bifida is the most common form of neural tube defect and carries significant risk of devastating outcome [24]. Its incidence in the USA was 20/100 000 live births in 2001, after a reduction in incidence of around 24% following the introduction of folic acid supplementation [25]. Anencephaly, in which the neural tube defect occurs cranially and much of the brain tissue is absent, is uniformly fatal. The rate of detection of neural tube defect by routine ultrasound scanning is higher than for thoracic and abdominal abnormalities [1].

Without prenatal intervention, outcome is usually poor because although the gross anatomical defect can be easily repaired surgically, the nerves are dysplastic causing life-long disability [26]. A secondary complication of spina bifida is herniation of the hindbrain, which can lead to brainstem dysfunction, the leading cause of postnatal death in infants [24]. Preliminary animal experimentation and data from a human randomized trial indicate that, by closing the neural tube defect during gestation, the adverse consequences of exposure of the spinal cord are lessened and hindbrain herniation is resolved [26].

Amniotic Bands

Amniotic bands may constrict fetal body parts in 1 in 3000 to 1 in 15 000 live births [27]. The developmental origin of amniotic bands is believed to be either early rupture of the amnion and subsequent entanglement of fetal parts with remnants of the amniotic membrane or an intrinsic developmental anomaly that leads to banding, as suggested by the association of amniotic bands with apparently independent developmental abnormalities such as polydactyly and cleft palate [28]. Amniotic banding can result in a spectrum of abnormalities including digit or limb amputation, craniofacial, visceral, and other bodily defects. Umbilical cord entanglement by amniotic bands can result in fetal death. Fetal structural abnormalities caused by amniotic banding are readily identifiable by routine ultrasound and Doppler assessment of distal blood flow can be used to identify severity of the constriction [27].

There are few reports of prenatal intervention for resection of amniotic bands, with varying degrees of success probably related to the severity of arterial blood flow compromise [27]. As for all other forms of fetal intervention, in utero correction of amniotic banding shows some promise in selected cases but further research is required to identify those patients for whom the risks of surgery are outweighed by improved outcome.

Twin–Twin Transfusion

Division of a single morula or blastocyst before differentiation of embryonic cells yields monozygotic (“identical”) twins, of whom approximately two-thirds will share their placenta. These monochorionic twins are at risk of twin–twin transfusion syndrome due to a deficit and imbalance of the obligatory vascular anastamoses (arterial–arterial, venous–venous or arterial–venous) between their placental circulations. The donor twin becomes hypovolemic, oliguric, and hence oligohydramniotic, hypertensive and growth restricted. The increased blood volume of the recipient twin results in polyuria and hence polyhydramnios, hypertension, and myocardial hypertrophy [29]. Mortality from twin–twin transfusion can be as high as 70% [30].

There are several criteria for diagnosis and assessment of twin–twin transfusion by ultrasound, based on anatomical and cardiovascular characteristics [29]. Adverse outcome of twin–twin transfusion can be predicted during the first and second semesters using ultrasound to assess fetal size, the location of the placen­tal equator and discordant amniotic fluid volumes [31].

A large multicenter randomized controlled trial showed that laser ablation of placental vascular anastomoses improved perinatal survival and short-term neurological outcome compared to amnioreduction (previously the main treatment) [32]. One prospective series of in utero laser ablation reported normal neurological outcome at 3 years of age in 86.8% of survivors [33].

Fetal Growth and Development

Organogenesis is completed approximately 8 weeks after conception, by which time all major organs are identifiable. Individual organs continue to grow and increase in complexity to full-term, and indeed most organs continue to grow and mature until body growth ceases. Organs grow as a result of mitosis and/or cellular hypertrophy with cellular differentiation and deposition of extracellular matrix. During embryogenesis, growth is regulated largely by the genome and less so by levels of nutrient and oxygen supply. However, with increasing demands imposed by the greater size and metabolic activity of the fetus, supply of nutrients by the placenta becomes more important, although genetic and epigenetic factors can influence growth. In most cases of restricted fetal growth, reductions in growth below the genetic potential result from limited nutrient or oxygen availability via the placenta, or a reduced ability to utilize these nutrients. Increased fetal growth above normal growth (large for gestational age) is often due to an oversupply of nutrients and growth factors, as in maternal diabetes.

Growth of the fetal body and individual organs can be assessed throughout at least the latter half of gestation by real-time ultrasound. Common measurements used to monitor fetal growth include biparietal diameter, head circumference, femur length, and abdominal circumference. Fetal body weight can be estimated from abdominal circumference and femur length (Figure 1.2). During late gestation, the rate of bone growth declines and may almost cease near term (Figure 1.3). Thus in the final weeks of pregnancy, weight gain is largely due to increases in fat deposition and soft tissue growth; the deposited fat, which is largely brown adipose tissue, is beneficial in supporting survival after birth. Preterm infants are usually deficient in fat deposits, especially brown adipose tissue, which increases the risk of hypothermia and hypoglycemia. After 40 weeks of gestation, there is a marked decline in fetal growth and weight gain with an increasing risk of fetal distress; most fetuses are delivered by 42 weeks.

Fig. 1.2 Fetal body weight during the latter half of human gestation, calculated from ultrasound measurements of abdominal circumference and femur length.

Reproduced from Chitty L, Altmann D. Appendix: Charts of Fetal Measurements. In: Rodeck C, Whittle M, editors. Fetal Medicine: Basic Science and Clinical Practice. 2nd edn. London: Churchill Livingstone; 2009. p. 721–66 with permission from Elsevier.

Fig. 1.3 Fetal skeletal dimensions measured by ultrasound during the latter half of human gestation.

Data are represented for three percentiles; 5th (— —) 50th (——) and 95th (—..). Reproduced from Chitty L, Altmann D. Appendix: Charts of Fetal Measurements. In: Rodeck C, Whittle M, editors, Fetal Medicine: Basic Science and Clinical Practice. 2nd edn. London: Churchill Livingstone; 2009. p. 721–66 with permission from Elsevier.

Fetal Growth Restriction

There is an inverse relationship between birthweight percentile and adverse perinatal outcome, with the greatest neonatal morbidity and mortality seen in infants with birthweights below the third percentile [34]. Furthermore, the adverse effects of restricted fetal growth can be life-long [35]. Intrauterine growth restriction (IUGR) can be defined as the failure of the fetus to achieve its genetic growth potential and by definition affects 3–10% of all pregnancies. IUGR should be distinguished from small for gestational age (SGA), which is defined as a fetal or neonatal body weight less than the 3rd or 10th percentiles. Fetuses that are SGA may be small for genetic reasons and may not be suffering from IUGR. Although IUGR has numerous causes, a common factor is placental dysfunction, which causes a chronic reduction in the delivery of nutrients and/or oxygen to the fetus. The major influence of placental dysfunction on fetal growth is seen during the latter half of gestation, and most commonly during the third trimester when fetal demands are greatest. IUGR is usually diagnosed by comparing ultrasound measurements of head size, abdominal circumference, and long-bone length against growth charts appropriate for the population; values falling below the 10th percentile are suggestive of IUGR.

Symmetric Vs. Asymmetric IUGR

Depending on the stage of gestation in which nutrient restriction occurs, IUGR may differentially affect head and body size. Symmetric IUGR accounts for 20–30% of IUGR fetuses; all organs are decreased proportionally suggesting that nutrient has been restricted throughout much of gestation. Asymmetrical IUGR is thought to result from placental dysfunction later in gestation, and is typified by a greater reduction in abdominal size (i.e. liver volume and abdominal fat) than head size. This “head sparing” is considered to be due to preserved blood flow and nutrient/oxygen delivery to the brain; the fetal heart and adrenal glands may also be relatively spared [36].

Determinants of Fetal Growth

It has been estimated that 30–50% of the variation in fetal body weight is due to genetic factors and around 60% to the intrauterine environment [37]. There is evidence that IUGR is heritable, and that maternal genes affect fetal growth more than paternal genes. In up to 25% of fetuses with early onset IUGR (mostly symmetric IUGR) chromosomal abnormalities can be identified; these may act via effects on placental vascularization. The recent application of DNA arrays to prenatal diagnosis will likely reveal a greater percentage of IUGR reflects chromosome abnormalities.

A wide range of environmental factors are known to affect fetal growth, many of which are associated with nutrient supply or nutrient utilization. The number of fetuses affects fetal growth, especially in the third trimester. Fetuses of a multiple gestation are smaller than singletons of the same sex and age because nutrient supply via the utero-placental circulation has to be shared; this is supported by the difference in size increasing with advancing gestation, as the nutrient demands of the fetus increase (Figure 1.4). Pregnancy complications that can inhibit fetal growth are more common in multiple gestations. Blood samples taken from the umbilical cord show that umbilical vein PO2 and pH progressively decline and PCO2 increases during the latter half of gestation (Figure 1.5); values in SGA fetuses typically lie towards the 95th percentile [38]. In general, female fetuses are smaller than males, which probably results from differences in placental function as well as genetic and/or endocrine factors [39]. Although they tend to be smaller, female preterm infants are known to have better outcomes than males [40].

Fig. 1.4 Umbilical vein PO2, PCO2 and pH measured by cordocentesis during the latter half of human gestation.

Data are presented for three percentiles; 5th (— —) 50th (——) and 95th (—..). Reproduced from Chitty L, Altmann D. Appendix: Charts of Fetal Measurements. In: Rodeck C, Whittle M, editors, Fetal Medicine: Basic Science and Clinical Practice. 2nd edn. London: Churchill Livingstone; 2009. p. 721–66 with permission from Elsevier.

Fig. 1.5 Fetal body weights during the latter half of human gestation in singletons, twins, triplets and quadruplets.

Data taken from McKeown and Record, 1952 [62] with permission.

Maternal Factors Affecting Fetal Growth

Maternal and uterine size, maternal nutrition, uterine blood flow, and oxygen carrying capacity can all influence fetal growth. Major causes of IUGR include disease states that affect maternal vascular function, such as hypertension, diabetes, and preeclampsia; each of these can impair uteroplacental perfusion, which in turn reduces the availability of oxygen and nutrients to the fetus. These maternal disease states account for 25–30% of IUGR in fetuses that are free of anomalies. With maternal hypertension, the incidence of IUGR is directly correlated with disease severity [41].

Maternal weight at the time of conception and weight gain during pregnancy account for about 10% of variation in birthweight. Maternal nutrition is a significant determinant of fetal growth, even in developed countries. Nutrition is an even more important factor in the etiology of IUGR in developing countries, and the incidence of IUGR is greatly increased during times of famine. Reduced maternal protein intake, as well as global caloric intake, can restrict fetal growth. IUGR is more common in teenage pregnancies, and in general the risk of IUGR is increased in a mother who is still growing [42].

Maternal hypoxemia has multiple causes including heart disease, lung disease (e.g. moderate to severe asthma), severe anemia, sickle cell anemia, and high altitude. These conditions can cause IUGR by chronically restricting oxygen delivery to the placenta and hence the fetus. Maternal hyperthermia can also lead to IUGR, as a result of maternal infections or high environmental temperature. Maternal infections such as rubella and cytomegalovirus (CMV) and parasites such as malaria are thought to account for 5–10% of IUGR. Some 20% of neonates have experienced a viral infection in utero. CMV is the most frequent viral cause of IUGR in developed countries.