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The EBCOG Postgraduate Textbook
of Obstetrics & Gynaecology
Volume 1: Obstetrics & Maternal-Fetal Medicine
The EBCOG Postgraduate
Textbook of Obstetrics &
Gynaecology
Volume 1: Obstetrics & Maternal-Fetal Medicine

Edited by
Tahir Mahmood
Victoria Hospital, Kirkcaldy, Scotland

Charles Savona-Ventura
University of Malta, Msida, Malta

Ioannis Messinis
University of Thessaly, Greece

Sambit Mukhopadhyay
Norfolk & Norwich University Hospital, Norwich, United Kingdom
University Printing House, Cambridge CB2 8BS, United Kingdom
One Liberty Plaza, 20th Floor, New York, NY 10006, USA
477 Williamstown Road, Port Melbourne, VIC 3207, Australia
314–321, 3rd Floor, Plot 3, Splendor Forum, Jasola District Centre,
New Delhi – 110025, India
103 Penang Road, #05–06/07, Visioncrest Commercial, Singapore 238467

Cambridge University Press is part of the University of Cambridge.

It furthers the University’s mission by disseminating knowledge in the
pursuit of education, learning, and research at the highest international
levels of excellence.

www.cambridge.org
Information on this title: www.cambridge.org/mahmoodvol1
DOI: 10.1017/9781108863049
© Cambridge University Press 2022
This publication is in copyright. Subject to statutory exception
and to the provisions of relevant collective licensing agreements,
no reproduction of any part may take place without the written
permission of Cambridge University Press.
First published 2022
Printed in the United Kingdom by TJ Books Limited, Padstow Cornwall
A catalogue record for this publication is available from the British Library.
Library of Congress Cataloging-in-Publication Data
Names: Mahmood, Tahir (Tahir Ahmed), editor. | Savona-Ventura, Charles,
editor. | Messinis, Ioannis, 1947– editor. | Mukhopadhyay, Sambit, editor.
Title: The EBCOG postgraduate textbook of obstetrics & gynaecology /
edited by Tahir Mahmood, Forth Park Hospital, Kirkcaldy, Charles
Savona Ventura, Msida Medical School, Malta, Ioannis Messinis,
Sambit Mukhopadhyay.
Other titles: EBCOG postgraduate textbook of obstetrics and gynaecology
Description: Cambridge, United Kingdom ; New York, NY : Cambridge
University Press, [2021] | Includes bibliographical references and index.
Identifiers: LCCN 2021024740 (print) | LCCN 2021024741 (ebook) |
ISBN 9781108495783 (hardback) | ISBN 9781108863049 (ebook)
Subjects: LCSH: Obstetrics – Examinations – Study guides. | Gynecology –
Examinations – Study guides. | BISAC: MEDICAL / Gynecology &
Obstetrics | MEDICAL / Gynecology & Obstetrics
Classification: LCC RG106 .E23 2021 (print) | LCC RG106 (ebook) | DDC
618.10076–dc23
LC record available at https://lccn.loc.gov/2021024740
LC ebook record available at https://lccn.loc.gov/2021024741
ISBN - 2 Volume Set 9781108955591 Hardback
ISBN - Volume 1 9781108495783 Hardback
ISBN - Volume 2 9781108499392 Hardback
Cambridge University Press has no responsibility for the persistence or
accuracy of URLs for external or third-party internet websites referred to
in this publication and does not guarantee that any content on such
websites is, or will remain, accurate or appropriate.
...........................................................................................................

Every effort has been made in preparing this book to provide accurate and
up-to-date information that is in accord with accepted standards and
practice at the time of publication. Although case histories are drawn
from actual cases, every effort has been made to disguise the identities of
the individuals involved. Nevertheless, the authors, editors, and
publishers can make no warranties that the information contained herein
is totally free from error, not least because clinical standards are
constantly changing through research and regulation. The authors,
editors, and publishers therefore disclaim all liability for direct or
consequential damages resulting from the use of material contained in
this book. Readers are strongly advised to pay careful attention to
information provided by the manufacturer of any drugs or equipment
that they plan to use.
To
Aasia, Marylene, Nikoletta and Samita
For their support, tolerance, patience and love during the arduous
editing process in bringing together the two volumes of this book.
Tahir, Charles, Ioannis and Sambit
Contents
List of contributors x
Preface xv

Section 1 Basic Sciences in Obstetrics 13 Invasive Fetal Therapies 109

Catherine E. Aiken & Jeremy Brockelsby
1 Surgical Anatomy of the Female Pelvis 1
Jean Calleja-Agius 14 Normal Fetal Growth and Fetal Macrosomia 117
Juriy W. Wladimiroff
2 Maternal Physiology during Pregnancy, Including
Immunology of Pregnancy 8 15 Fetal Haemolysis 122
Ksenija Gersak Manjiri Khare & Ganga Verma

3 Developmental Abnormalities of the Reproductive 16 Antenatal Care of a Normal Pregnancy 130

System and Their Relevance to Obstetric Practice 19 Irene Hösli, Gwendolin Manegold-Brauer &
Parivakkam S. Arunakumari, Vennila Palaniappan & Olav Lapaire
Richard Haines 17 Screening for High-Risk Pregnancy 139
4 Pharmacology and Pharmacokinetics in Obstetric Mirosław Wielgoś & Przemyslaw Kosinski
Practice 30 18 Multiple Pregnancy 147
Charles Savona-Ventura & Yvonne Savona-Ventura Andrii V. Tkachenko, Asma Khalil & Iryna Tepla
5 Genetics in Fetomaternal Medicine 38 19 Intrauterine Growth Restriction 158
Jennifer Allison George J. Daskalakis, Panos Antsaklis, Maria
Papamichail & Aris J. Antsaklis
Section 2 Early Pregnancy Problems 20 Fetal Origin of Adult Disease 167
Johann Craus
6 Bleeding in Early Pregnancy 45
Kahyee Hor & Tahir A. Mahmood 21 Antepartum Haemorrhage 174
Neela Mukhopadhaya
7 Acute Abdomen in Early Pregnancy 55
David K. Gatongi, Shittu Akinola Saheed & 22 Obstetric Care of Migrant Populations 183
Tahir A. Mahmood Apostolos M. Mamopoulos, Ioannis Tsakiridis &
Apostolos P. Athanasiadis
8 Gestational Trophoblastic Disease 64
Patrick Chien, Lesley McMahon, Anne Chien & 23 Care of Women with Previous Adverse Pregnancy
Leigh Jenkins Outcome 190
Manjiri Khare & Gauri Karandikar
9 Hyperemesis Gravidarum 73
Jone Trovik, Hedvig Nordeng & Åse Vikanes 24 Preterm Prelabour Rupture of Membranes 197
Kamaleswari Camille Aiyaroo Thyne & Tahir
A. Mahmood
Section 3 Fetal Medicine
10 Pre-Conception Care 83
Chu Chin Lim & Tahir A. Mahmood
Section 4 Maternal Medicine
25 Hypertensive Disorders in Pregnancy and
11 Ultrasound Scanning in the First Trimester of Eclampsia 201
Pregnancy 92
Anne Cathrine Staff & Ralf Dechend
Juriy W. Wladimiroff
26 Obesity and Metabolic Syndrome in Pregnancy 213
12 Prenatal Diagnostic Techniques 102
Aoife M. Egan & Fidelma P. Dunne
Guttorm Haugen & Vasilis Sitras

vii
 Contents

27 Screening for Gestational Diabetes Mellitus and Care 44 Issues during Labour for Migrant Populations 367
of Diabetes Mellitus in Pregnancy 221 Apostolos M. Mamopoulos, Ioannis Tsakiridis &
Peter Hornnes & Jeannet Lauenborg Apostolos P. Athanasiadis
28 Cardiac Disease in Pregnancy 225 45 Prolonged Pregnancy 373
Sarah Vause, Anna Roberts & Bernard Clarke Christina I. Messini & Alexandros Daponte
29 Respiratory Disease in Pregnancy 236 46 Induction of Labour 381
Katharine Rankin & Tahir A. Mahmood Yves Muscat Baron & Martina Schembri
30 Thromboembolism in Pregnancy 244 47 Intrapartum Fetal Monitoring 389
Vrinda Arora & Sambit Mukhopadhyay Branka M. Yli, Jørg Kessler & Diogo Ayres-
de-Campos
31 Haemoglobinopathies in Pregnancy 252
Panos Antsaklis, Maria Papamichail, George 48 Augmentation of Labour 398
J. Daskalakis & Aris J. Antsaklis Rumana Rahman & Neela Mukhopadhaya
32 Kidney Diseases in Pregnancy 260 49 Analgesia and Anaesthesia during Labour 403
Giorgina Barbara Piccoli, Rossella Attini & Britt Ingjerd Nesheim
Gianfranca Cabiddu
50 Preterm Labour 409
33 Gastrointestinal Disorders in Pregnancy 277 William C. Maina
Laura Kitto & Hasnain M. Jafferbhoy
51 Management of Multiple Pregnancy during
34 Systemic Lupus Erythematosus and Pregnancy 287 Labour 414
Sarah McRobbie & Katrina Shearer Nikolaos Vrachnis, Dimitrios Zygouris & Asma
Khalil
35 Autoimmune Rheumatic Disorders in
Pregnancy 295 52 Abnormal Obstetric Presentation 421
Laura Andreoli, Maria Chiara Gerardi & Angela Frank Louwen
Tincani
53 Intrapartum Emergencies 427
36 Thyroid Disease in Pregnancy 304 Nikolaos Vrachnis, Vasilios Pergialiotis & Austin
Anastasios Malakasis & Francoise H. Harlow Ugwumadu
37 Infections in Pregnancy 311 54 Caesarean Section 434
Sarah McRobbie Charles Bircher & Edward Prosser-Snelling
38 HIV Infection in Pregnancy 324 55 Instrumental Operative Obstetrics 440
Christine M. Bates Jørg Kessler & Anke Reitter
39 Acute Management of Sepsis in Pregnancy 329 56 Maternal Collapse in Labour 448
Lucy Maudlin & Francoise H. Harlow William C. Maina
40 Psychological Disorders in Pregnancy 337 57 Management of Postpartum Haemorrhage 452
Sibil Tschudin Emma Leighton & Edwin Chandraharan
41 Pregnancy after Solid Organ Transplantation 343 58 Birth Injuries and Perineal Trauma 462
Giuseppe Benagiano, Patrick Puttemans & Ivo Katariina Laine & Sari Räisänen
Brosens
59 Management of Stillbirth 469
42 Oral Health and Periodontal Diseases in Martin Cameron
Pregnancy 354
Hans Ulrich Brauer, Irene Hösli & Gwendolin
Manegold-Brauer Section 6 Neonatal Problems
60 Intrapartum Asphyxia and Its Sequelae 477
Section 5 Intrapartum Care Simon Attard Montalto

43 Normal Labour 359 61 Short- and Long-Term Challenges of Neonatal

Care 486
Silvia Serrano & Diogo Ayres-de-Campos
Omobolanle Kazeem & Rahul Roy

viii
 Contents

Section 7 Placenta 70 Legal Considerations in Obstetric Practice 569

George Gregory Buttigieg
62 The Placenta and Its Association with Fetal
Growth 505 71 Research and Audit in Obstetric Practice 576
Gwendolin Manegold-Brauer, Olav Lapaire & Irene Paul Simpson & Martin Cameron
Hösli
63 Placental Pathology 513 Section 9 Co-Morbidities during Pregnancy
Olav Lapare, Irene Hösli & Gwendolin Manegold-
Brauer 72 Management of Malignant and Premalignant
Disease of the Cervix during Pregnancy 587
64 Placenta Accreta Spectrum Disorders 518 Antonios Athanasiou, Panagiotis Cherouveim,
Edwin Chandraharan, Sabaratnam Arulkumaran & Maria Kyrgiou & Evangelos Paraskevaidis
Amarnath Bhide
73 Breast Cancer and Pregnancy: Diagnostics, Therapy
and Influence on Fertility and Further
Section 8 Public Health Issues in Obstetrics Pregnancies 595
Martin Weiss, Sara Y. Brucker, Diethelm Wallwiener
65 Social and Cultural Aspects Affecting Pregnancy & Eva-Maria Grischke
Outcomes in Migrant Populations 525
Pauline L. M. de Vries & Thomas van den Akker 74 Gynaecological Cancers and Pregnancy 602
Charlotte Maggen, Christianne A. R. Lok & Frédéric
66 Immunization in Pregnancy 532 Amant
Babill Stray-Pedersen, Kirsten Maertens, Elke
Leuridan & Gilbert G. G. Donders 75 Non-Gynaecological Cancers and Pregnancy 612
Chiara Benedetto, Emilie Marion Canuto &
67 Saving Lives, Improving Mothers’ Care: UK and Francesca Salvagno
Ireland Confidential Enquiries into Maternal Deaths
and Morbidity 541 76 Simulation for Obstetric Emergencies 623
Rohan Chodankar, Ruth Howie, Chu Chin Lim & Cécile Monod & Irene Hösli
Tahir A. Mahmood
68 Clinical Governance in Obstetric Practice 557
William C. Maina
Index 628
69 Ethical Issues and Conflict in Maternal-Fetal Medicine
and Obstetrics 562 Colour plates can be found between pages 336 and 337
Pierre Mallia

ix
 Contributors

Antonios Athanasiou MD
Catherine E. Aiken MB/BChir MA PhD MRCOG MRCP
Department of Surgery & Cancer, Imperial College London,
University Department of Obstetrics & Gynaecology,
London, UK
The Rosie Hospital, Cambridge, UK
Simon Attard Montalto MBChB MD FRCP FRCPCH DCH
Jennifer Allison BSc MBChB MRCOG Department of Paediatrics, University of Malta Medical
NHS Fife, UK School, Msida, Malta
Frédéric Amant MD PhD Rossella Attini PhD
Department of Obstetrics & Gynaecology, University Department of Obstetrics and Gynecology, Città della Salute
Hospitals Leuven, Leuven, Belgium e della Scienza- Sant’Anna Hospital, Torino, Italy
Laura Andreoli MD PhD Diogo Ayres-de-Campos MD PhD
Unit of Rheumatology and Clinical Immunology, Department of Obstetrics & Gynaecology, University of Porto,
ASST Spedali Civili, Brescia, Italy. Department of Porto, Portugal
Clinical & Experimental Sciences, University of Brescia,
Brescia, Italy Yves Muscat Baron MD FRCOG FRCPI PhD
Department of Obstetrics & Gynaecology, Mater Dei Hospital,
Aris J. Antsaklis MD PhD Malta
First Department of Obstetrics and Gynaecology,
Division of Maternal-Fetal Medicine, Alexandra Hospital, Christine M. Bates MBBS FRCP DRCOG DipVen DFSRH
National and Kapodistrian University of Athens, Athens, Royal Liverpool University Hospital, Liverpool, UK
Greece
Giuseppe Benagiano MD PhD FRCOG
Panos Antsaklis MD, PhD Department of Maternal and Child Health and Urology,
First Department of Obstetrics and Gynecology, National and Sapienza, University of Rome, Rome, Italy
Kapodistrian University of Athens, Alexandra Maternity
Hospital, Greece Chiara Benedetto MD PhD FRCOG
Department of Obstetrics & Gynaecology, University of Turin
Vrinda Arora MBBS DNB MRCOG S. Anna Hospital, Turin, Italy
Norfolk and Norwich University Hospital and Foundation
Trust, Norwich, UK Amarnath Bhide MD PhD FRCOG
Fetal Medicine Unit, St George’s Hospital Medical School,
Sabaratnam Arulkumaran MD PhD FRCOG London, UK
Academic Department of Obstetrics & Gynaecology,
St George’s University of London, London, UK Charles Bircher MBBS MRCOG
Department of Obstetrics & Gynaecology, Norfolk & Norwich
Parivakkam S. Arunakumari MD FRCOG MFFP University Hospital, Norwich, UK
Department of Obstetrics & Gynaecology, Norfolk & Norwich
University Hospital, Norwich, UK Hans Ulrich Brauer DMD DPhil MA MSc
Dental Academy for Continuing Professional Development,
Apostolos P. Athanasiadis MD PhD Karlsruhe, Germany
First Department of Obstetrics and Gynecology, National and
Kapodistrian University of Athens, Alexandra Maternity Jeremy Brockelsby MB/BSc PhD MRCOG
Hospital, Greece University Department of Obstetrics & Gynaecology, The
Rosie Hospital, Cambridge, UK

x
 List of contributors

Ivo Brosens MD PhD Alexandros Daponte MD DrMed FCOG

Faculty of Medicine, Catholic University of Leuven, Leuven, Department of Obstetrics & Gynaecology, University of
Belgium Thessaly, Larissa, Greece
Sara Y. Brucker MD George J. Daskalakis MD, PhD
Department of Obstetrics and Gynaecology, Department of First Department of Obstetrics and Gynecology, National and
Women’s Health, University of Tuebingen, Germany Kapodistrian University of Athens, Alexandra Maternity
Hospital, Greece
George Gregory Buttigieg KM MD LRCP MRCS Dip.FP MA
FRCOG FRCPI FRCPEd Ralf Dechend MD
Department of Obstetrics and Gynaecology, University of Helios Clinic, Berlin, Germany
Malta. Department of Obstetrics and Gynaecology, Plovdiv
Medical University and Hospital St George, Bulgaria Pauline L. M. de Vries MD
Department of Obstetrics & Gynaecology, Leiden University
Gianfranca Cabiddu Medical Centre, Leiden, Netherlands
Department of Medical Sciences and Public Health, University
of Cagliari, Cagliari, Italy Gilbert G. G. Donders MD PhD
Department of Obstetrics & Gynaecology, University Hospital
Jean Calleja-Agius MD MSc FRCOG FRCPI PhD Antwerp, Antwerp, Belgium
Department of Anatomy, Faculty of Medicine & Surgery, Fidelma P. Dunne MBBCh BAO MD PhD
University of Malta, Malta
Galway Diabetes Research Centre, School of Medicine,
Martin Cameron BMSc MD MRCOG National University of Ireland Galway, Galway, Ireland
Maternal-Fetal Medicine Unit, Norfolk & Norwich University
Aoife M. Egan MBBCh BAO PhD
Hospital, Norwich, UK
Division of Endocrinology and Metabolism, Mayo Clinic,
Emilie Marion Canuto MD Rochester, MN, USA
Department of Obstetrics & Gynaecology, University of Turin
S. Anna Hospital, Turin, Italy David K. Gatongi MSc MRCOG
Victoria Hospital, Kirkcaldy, Fife, UK
Edwin Chandraharan MBBS MS DFSRH DCRM FSLCOG
FRCOG Maria Chiara Gerardi MD
Global Academy of Medical Education & Training, London / Unit of Rheumatology and Clinical Immunology, ASST
Basildon & Thurrock University Hospital, Essex, UK Spedali Civili, Brescia, Italy. Department of Clinical &
Experimental Sciences, University of Brescia, Brescia, Italy
Panagiotis Cherouveim MD
Department of Obstetrics & Gynaecology, University Hospital Ksenija Gersak MD PhD
of Ioannina, Ioannina, Greece Department of Obstetrics and Gynecology, Ljubljana
University Medical Centre, and Faculty of Medicine,
Anne Chien MSc University of Ljubljana, Ljubljana, Slovenia
Scottish Hydatidiform Mole Follow-Up Service, Ninewells
Hospital, Dundee, UK Eva-Maria Grischke MD
Department of Obstetrics and Gynaecology, Department
Patrick Chien MD MbChB FRCOG of Women’s Health, University of Tuebingen,
Scottish Hydatidiform Mole Follow-Up Service, Ninewells Germany
Hospital, Dundee, UK
Richard Haines BSc MBBS MRCOG
Rohan Chodankar MBBS MD MRCOG Department of Obstetrics & Gynaecology, Norfolk & Norwich
Department of Obstetrics & Gynaecology, Edinburgh Royal University Hospital, Norwich, UK
Infirmary, Edinburgh, UK
Francoise H. Harlow BSc (Hons) MBBS MRCOG
Bernard Clarke BSc MD FRCP FESC FACC FRCOG(Hon) Department of Obstetrics & Gynaecology, Norfolk & Norwich
Department of Cardiology, Manchester Royal Infirmary, University Hospital, Norwich, UK
Manchester, UK
Guttorm Haugen MD PhD
Johann Craus MD DFSHRH MRCOG PhD Division of Obstetrics & Gynaecology, Oslo University
Department of Obstetrics & Gynaecology, Mater Dei Hospital, Hospital, Oslo, Norway
Birkirkara, Malta

xi
 List of contributors

Kahyee Hor MB ChB MRCOG Jeanet Lauenborg MD PhD

University of Edinburgh, Edinburgh, UK Department of Obstetrics, Gynecology & Pediatrics,
Nykoebing Falster Hospital, Region Zealand, Denmark
Peter Hornnes MD DSc FRCOG
Department of Obstetrics & Gynaecology, North Zealand Emma Leighton MBBS
University Hospital, Hillerød, Denmark St. George’s University Hospitals NHS Foundation Trust,
London, UK
Irene Hösli MD
Professor of Gynaecology & Obstetrics, University Hospital Elke Leuridan MD PhD
Basel, Basel, Switzerland Centre for the Evaluation of Vaccination, Vaccine & Infectious
Diseases Institute, University of Antwerp, Antwerp, Belgium
Ruth Howie MRCOG
Department of Obstetrics & Gynaecology, Edinburgh Royal Chu Chin Lim FRCOG
Infirmary, Edinburgh, UK Victoria Hospital, Kirkcaldy, UK
Dr Hasnain M. Jafferbhoy FRCPE Christianne A. R. Lok MD PhD
Consultant Physician, Division of Gastero-enterology, Department of Gynaecological Oncology, Netherlands Cancer
Department of Medicine, Victoria Hospital,Kirkcaldy, Institute, Amsterdam, Netherlands
Scotland
Frank Louwen MD
Leigh Jenkins Department of Gynecology & Obstetrics, Goethe University
Scottish Hydatidiform Mole Follow-Up Service, Ninewells Hospital, Frankfurt, Germany
Hospital, Dundee, UK
Kirsten Maertens PhD
Gauri Karandikar MD DGO FCPS FICOG
Centre for the Evaluation of Vaccination, Vaccine & Infectious
Department of Obstetrics & Gynaecology, Karandikar
Diseases Institute, University of Antwerp, Antwerp, Belgium
Hospital & Research Centre, Nasik, India
Charlotte Maggen MD
Omobolanle Kazeem MBChB, MPH, MRCPCH
Department of Obstetrics & Gynaecology, University
Norfolk & Norwich University Hospital, Norwich, UK
Hospitals of Leuven, Leuven, Belgium
Jørg Kessler MD PhD Tahir A. Mahmood CBE MD FRCPI MBA FACOG FRCPE
Department of Obstetrics & Gynaecology, Haukeland FEBCOG FRCOG
University Hospital, Bergen, Norway Department of Obstetrics & Gynaecology, Victoria Hospital,
Asma Khalil MD MRCOG MSc Kirkcaldy, Fife, UK
Fetal Medicine Unit, St George’s Hospital, London, UK William C. Maina MBChB MRCOG
Royal Bolton Hospital NHS Trust, Bolton, UK
Manjiri Khare FRCOG
Women’s & Perinatal Services, University Hospitals of Anastasios Malakasis BSc MBBS MSc
Leicester NHS Trust, UK Department of Obstetrics & Gynaecology, Norfolk & Norwich
University Hospital, Norwich, UK
Laura Kitto
Gastroenterology Department, Royal Infirmary, Edinburgh, Pierre Mallia MA MD MPhil PhD MRCP FRCGP CBiol
UK DipICGP
Bioethics Research Programme, University of Malta Mater Dei
Przemyslaw Kosinski MD PhD
Hospital, Msida, Malta
First Department of Obstetrics & Gynecology, Medical
University of Warsaw, Warsaw, Poland Apostolos M. Mamopoulos MD PhD
Third Department of Obstetrics & Gynaecology, School of
Maria Kyrgiou MSc PhD MRCOG
Medicine, Faculty of Health Sciences, Aristotle University of
Department of Surgery & Cancer, Imperial College London,
Thessaloniki, Greece
London, UK
Gwendolin Manegold-Brauer, MD PD
Katariina Laine MD PhD
Department of Obstetrics & Gynaecology, Division of
Department of Obstetrics, Oslo University Hospital, Oslo,
Gynecologic Ultrasound and Prenatal Diagnostics, University
Norway
Hospital of Basel, Basel, Switzerland
Olav Lapaire
Lucy Maudlin MRCOG MSc
Department of Obstetrics & Antenatal Care, University
West Suffolk NHS Trust, UK
Hospital of Basel, Basel, Switzerland
xii
 List of contributors

Lesley McMahon PhD DipRCPath Sari Räisänen RN MSc PhD

Scottish Hydatidiform Mole Follow-Up Service, Ninewells School of Health Care & Social Service, Tampere
Hospital, Dundee, UK University of Applied Sciences, Tampere, Finland
Sarah McRobbie MRCOG DFSRH PGcert MBChB BSc Katharine Rankin BMSc MBChB MRCOG PGDipClinEd
Aberdeen Maternity Hospital, Aberdeen, UK FHEA
Specialist Registrar in Obstetrics & Gynaecology, South East
Christina I. Messini MD Scotland Deanery, UK
Department of Obstetrics & Gynaecology, University of
Thessaly, Larissa, Greece Anke Reitter MD FRCOG
Department of Obstetrics & Gynaecology, Krankenhaus
Cécile Monod MD Sachsenhausen, Frankfurt, Germany
Department of Gynaecology & Obstetrics, University Hospital
Basel, Basel, Switzerland Anna Roberts MRCOG
St Mary’s Hospital, Manchester, UK
Neela Mukhopadhaya MRCOG
Department of Obstetrics & Gynaecology, Luton & Dunstable Rahul Roy MRCPCH, DCH
Hospital, Luton, UK Consultant Neonatologist Paediatrician with expertise in
Cardiology, Norfolk and Norwich University Hospital,
Sambit Mukhopadhyay MD DNB MMedSci FRCOG Norwich, UK
Department of Obstetrics & Gynaecology, Norfolk & Norwich
University Hospital, Norwich, UK Shittu Akinola Saheed MRCOG FMCOG DFSRH
Hamand Medical Centre Al Rayyan, Qatar
Britt Ingjerd Nesheim MD PhD
Faculty of Medicine, University of Oslo, Oslo, Norway Francesca Salvagno MD
Department of Obstetrics & Gynaecology, University of Turin
Hedvig Nordeng MSc PhD S. Anna Hospital, Turin, Italy
Department of Pharmacy, University of Oslo, Norway
Charles Savona-Ventura MD DScMed FRCOG FRCPI
Vennila Palaniappan FRCPE
Department of Obstetrics & Gynaecology, Norfolk & Norwich Department of Obstetrics & Gynaecology, Faculty of Medicine
University Hospital, Norwich, UK & Surgery, University of Malta, Msida, Malta
Maria Papamichail MD Yvonne Savona-Ventura B.Pharm M.Pharm
Alexandra Maternity Hospital, Athens, Greece Department of Pharmacy, Faculty of Medicine & Surgery,
Evangelos Paraskevaidis MD PhD University of Malta, Msida, Malta
Department of Obstetrics & Gynaecology, University Hospital Martina Schembri MD EFOG-EBCOG MRCPI
of Ioannina, Ioannina, Greece Department of Obstetrics & Gynaecology, Mater Dei Hospital,
Vasilios Pergialiotis MD MSc PhD Malta
First Department of Obstetrics and Gynaecology, Alexandra Silvia Serrano MD
Hospital, National and Kapodistrian University of Athens, Department of Obstetrics & Gynaecology, Santa Maria
Athens, Greece Hospital, Lisbon, Portugal
Giorgina Barbara Piccoli MD Katrina Shearer MbChB MRCOG
Department of Clinical and Biological Science, University of Aberdeen Maternity Hospital, Aberdeen, UK
Turin, Turin, Italy
Paul Simpson MA (Cantab) BMBS MRCOG MD
Edward Prosser-Snelling BA(Hons) MBBS MRCOG Department of Obstetrics & Gynaecology, Norfolk & Norwich
Department of Obstetrics & Gynaecology, Norfolk & Norwich University Hospital, Norwich, UK
University Hospital, Norwich, UK
Vasilis Sitras MD PhD
Patrick Puttemans MD Division of Obstetrics & Gynaecology, Oslo University
Unit of Reproductive Medicine, Heilig Hart Hospital, Leuven, Hospital, Oslo, Norway
Belgium
Anne Cathrine Staff MD PhD
Rumana Rahman Division of Obstetrics & Gynaecology, Oslo University
Luton & Dunstable University Hospital, UK Hospital, Oslo, Norway

xiii
 List of contributors

Babill Stray-Pedersen MD PhD Thomas van den Akker MD PhD

Department of Obstetrics & Gynaecology, University of Oslo Department of Obstetrics & Gynaecology, Leiden University
National Hospital, Oslo, Norway Medical Centre, Leiden, Netherlands
Iryna Tepla MD Sarah Vause MD FRCOG
Department of Obstetrics & Gynaecology, Shupyk National St Mary’s Hospital, Manchester, UK
Medical Academy of Postgraduate Education, Kyiv,
Ukraine Ganga Verma
Women’s & Perinatal Services, University Hospitals of
Kamaleswari Camille Aiyaroo Thyne MBBS MRCOG Leicester NHS Trust, UK
Royal Infirmary of Edinburgh, Edinburgh, UK
Åse Vikanes MD PhD
Angela Tincani MD Intervention Centre, Oslo University Hospital, Oslo, Norway
Unit of Rheumatology and Clinical Immunology, ASST
Spedali Civili, Brescia, Italy. Department of Clinical & Nikolaos Vrachnis
Experimental Sciences, University of Brescia, Brescia, Third Department of Obstetrics & Gynaecology, University of
Italy Athens, Athens, Greece

Andrii V. Tkachenko MD PhD Diethelm Wallwiener MD

Department of Obstetrics & Gynaecology, Shupyk National Department of Obstetrics and Gynaecology, Department of
Medical Academy of Postgraduate Education, Kyiv, Women’s Health, University of Tuebingen, Germany
Ukraine Martin Weiss MD
Jone Trovik MD PhD Department of Obstetrics and Gynaecology, Department of
Department of Obstetrics & Gynecology, Haukeland Women’s Health, University of Tuebingen, Germany
University Hospital, Bergen, Norway Mirosław Wielgoś MD PhD
Ioannis Tsakiridis MD MSc First Department of Obstetrics & Gynecology, Medical
Third Department of Obstetrics & Gynaecology, School of University of Warsaw, Warsaw, Poland
Medicine, Faculty of Health Sciences, Aristotle University of Juriy W. Wladimiroff MD
Thessaloniki, Greece
Rosie Maternity, Addenbrooke’s University Hospital,
Sibil Tschudin MD Cambridge, UK
Department of Obstetrics and Gynaecology, University Branka M. Yli MD PhD
Hospital Basel, Basel, Switzerland
Labour Ward, Oslo University Hospital, Oslo, Norway
Austin Ugwumadu PhD FRCOG
Dimitrios Zygouris MD PhD MSc
Department of Obstetrics & Gynaecology, St. George’s
Third Department of Obstetrics & Gynaecology, University of
Hospital NHS Trust, London, UK
Athens, Athens, Greece

xiv
Preface

The art of practising modern medicine is influenced by its specialists and subspecialist care. The EBCOG curriculum is
complexity and changing socio-economic factors. Money, supported by the promotion of a standard format training
power and resources influence health outcomes globally, portfolio. On the other hand, the introduction of the EBCOG
nationally and locally. Europe with its wide geographic varia- Fellowship examination (EFOG) has gone a long way towards
tion has different healthcare, training and education systems. promoting a wide-based standardization of healthcare provision
Clinical guidelines are aimed to reduce variation and increase in the speciality within a wide-ranging spectrum of healthcare
cost-effectiveness of healthcare delivery. However, economic service provision and ensuring the training of specialists com-
and policy differences amongst various states influence the petent to respond to the ever-changing frontiers of medical
uptake of guidelines and the standards of care specialists are services.
expected to provide for their patients. The practice of obstetrics The present project provides an up-to-date reference text-
and gynaecology within the various European countries also book written by authors familiar with a European perspective
varies extensively from one country to another and sometimes of care in general obstetrics and gynaecology. It aims to address
even from one hospital to another within the same country. the competencies defined by EBCOG curriculum and builds
The European Board and College of Obstetrics and the clinical practice related to these competencies upon the
Gynaecology (EBCOG) has long recognized that, within the basic sciences foundations. It thus is an ideal reference book for
wide diversity of healthcare service systems, basic postgraduate postgraduate trainees not only in Europe but also globally who
training standards in the speciality are necessary to ensure safety are targeting to sit the EFOG or any other postgraduate exam-
and quality of healthcare for women and their babies in the inations. This book will also serve as a postgraduate reference
European Region. To help define competencies towards achiev- book for specialists currently practising the speciality any-
ing standardization of training and delivering high-quality where in the world and who need to update their knowledge
equitable care, EBCOG has published documents describing and competencies with the ever-evolving clinical practice of
‘Standards of Care in Obstetrics, Neonatal and Gynaecology’ today’s modern world.
and a ‘European Training Requirement’ through the publication We are very grateful to all the contributors who studiously
of The Project for Achieving Consensus in Training (PACT). In prepared and revised the chapters. Without their sterling con-
addition, EBCOG publishes state-of-the-art position statements tributions, the work would not have seen the light of day.
that are based on evidence.
European Training Curriculum of EBCOG defines the core Tahir Mahmood, Charles Savona-Ventura, Ioannis Messinis,
competencies required by all specialist obstetricians- Sambit Mukhopadhyay
gynaecologists wherever they may be practising, and the elective
optional competencies that support the delivery of advanced

xv
 Section 1 Basic Sciences in Obstetrics
Chapter
Surgical Anatomy of the Female Pelvis

1 Jean Calleja-Agius

1.1 Development of the Female Pelvis Time frame for ovarian development

and Its Contents 6 weeks: enter gonad Primordial Germ

Cells
The female genitourinary system is mainly derived from the
intermediate cell mass, which in turn is derived from the 6 to16 weeks Oogonia
Mitosis
4 million oogonia
mesoderm following gastrulation. The pelvic girdle, however,
2 million oocytes at birth
is derived from the caudal mesoderm, which, as the name
16 weeks fetal
implies, is the mesoderm found caudal to the cloacal mem- Meiosis I
brane. Upon folding, the caudal mesoderm folds ventrally at 1° oocytes
Meiotic Arrest
the point of the cloacal membrane, distal to the paraxial meso-
puberty Oocyte degeneration
derm and notochord, in such a way that the pelvic girdle wraps
around the distal end of the trunk to fuse with the sacral Postpubertal
1° oocyte
somites and encase the developing female genitourinary sys- cyclic Release from meiotic arrest
tem, and leads to the formation of the rump. Blastogenic development 2° oocyte
Meiosis II
defects involving the cloaca and caudal folding may also be mature ovum
associated with urogenital and possibly ano-rectal malforma-
tions, which can lead to reproductive problems [1]. Figure 1.1 Time frame for ovarian development
Soon after gastrulation and folding at the end of the fourth
week after fertilization, the gonadal ridge starts appearing as
a thickened ridge at the border between the developing meso- neonate starts off with around 2 million oogonia, which by
nephros within the substance of the intermediate cell mass and the time of puberty (average 11.5 years) continue degenerat-
the intra-coelomic cavity within the lateral plate mesoderm. ing, with only around 500 oogonia ever managing to be
This gonadal ridge will start developing into an indifferent released from meiotic arrest and develop into secondary
gonad. The proliferation of the coelomic epithelium over the oocytes, start meiosis II and be ovulated as a mature ovum.
genital ridge gives rise to primitive sex cords. At the same time, Completion of meiosis II happens only physiologically upon
primordial germ cells start arising from the region of the fertilization by a sperm (Figure 1.1).
allantois and start migrating towards the developing gonadal The paramesonephric (or Mullerian) ducts develop as
ridge. By the sixth week the primordial germ cells invade the invaginations from the epithelium lining the urogenital
primitive sex cords. If the sex chromosomes in the primordial ridges, growing laterally to the mesonephric (Wolffian)
germ cells are XX, this will lead to the formation of the ovary, ducts, but then crossing ventrally towards the caudal end of
in contrast to a testis if the sex chromosomes are XY. Failure of the mesonephric duct. These paramesonephric ducts fuse
migration of these germ cells can occur in certain congenital caudally in the midline, with the fused caudal tip projecting
conditions such as Turner syndrome, leading to ovarian on the posterior wall of the urogenital sinus. The fallopian
dysgenesis. tubes and their fimbriae develop from the cranial part of the
By the seventh week, primordial follicles appear from paramesonephric ducts, while the fused paramesonephric
the second generation of cords from the coelomic epithe- ducts lead to the formation of the uterus and cervix. The
lium, and start proliferating rapidly by mitosis between medial border of each of the two paramesonephric tubes will
the second and fourth month. By the end of the 16th week, atrophy, in order to form one uterine cavity (Figure 1.2).
there are around 4 million oogonia, which then enter the Incomplete atrophy may lead to different degrees of uterine
first phase of meiosis. These oogonia remain arrested until septation, causing bifid, unicornuate and other types of uter-
puberty, when, periodically, batches of primary oocytes ine anomalies. These may present with fertility problems and
resume the meiotic cycle, forming at least one dominant recurrent miscarriages [2]. Treatment of such septa is still
secondary oocyte which ovulates. There is a degree of oocyte debatable, with further trials under way [3]. Due to the close
degeneration throughout all of the duration of the meiotic association with the development of the urinary system, such
arrest, with only around half of the original amount of uterine congenital anomalies may have concomitant urinary
oogonia making it until the time of birth. A healthy female anomalies.

1
 Section 1 Basic Sciences in Obstetrics
Chapter
Surgical Anatomy of the Female Pelvis

1 Jean Calleja-Agius

1.1 Development of the Female Pelvis Time frame for ovarian development

and Its Contents 6 weeks: enter gonad Primordial Germ

Cells
The female genitourinary system is mainly derived from the
intermediate cell mass, which in turn is derived from the 6 to16 weeks Oogonia
Mitosis
4 million oogonia
mesoderm following gastrulation. The pelvic girdle, however,
2 million oocytes at birth
is derived from the caudal mesoderm, which, as the name
16 weeks fetal
implies, is the mesoderm found caudal to the cloacal mem- Meiosis I
brane. Upon folding, the caudal mesoderm folds ventrally at 1° oocytes
Meiotic Arrest
the point of the cloacal membrane, distal to the paraxial meso-
puberty Oocyte degeneration
derm and notochord, in such a way that the pelvic girdle wraps
around the distal end of the trunk to fuse with the sacral Postpubertal
1° oocyte
somites and encase the developing female genitourinary sys- cyclic Release from meiotic arrest
tem, and leads to the formation of the rump. Blastogenic development 2° oocyte
Meiosis II
defects involving the cloaca and caudal folding may also be mature ovum
associated with urogenital and possibly ano-rectal malforma-
tions, which can lead to reproductive problems [1]. Figure 1.1 Time frame for ovarian development
Soon after gastrulation and folding at the end of the fourth
week after fertilization, the gonadal ridge starts appearing as
a thickened ridge at the border between the developing meso- neonate starts off with around 2 million oogonia, which by
nephros within the substance of the intermediate cell mass and the time of puberty (average 11.5 years) continue degenerat-
the intra-coelomic cavity within the lateral plate mesoderm. ing, with only around 500 oogonia ever managing to be
This gonadal ridge will start developing into an indifferent released from meiotic arrest and develop into secondary
gonad. The proliferation of the coelomic epithelium over the oocytes, start meiosis II and be ovulated as a mature ovum.
genital ridge gives rise to primitive sex cords. At the same time, Completion of meiosis II happens only physiologically upon
primordial germ cells start arising from the region of the fertilization by a sperm (Figure 1.1).
allantois and start migrating towards the developing gonadal The paramesonephric (or Mullerian) ducts develop as
ridge. By the sixth week the primordial germ cells invade the invaginations from the epithelium lining the urogenital
primitive sex cords. If the sex chromosomes in the primordial ridges, growing laterally to the mesonephric (Wolffian)
germ cells are XX, this will lead to the formation of the ovary, ducts, but then crossing ventrally towards the caudal end of
in contrast to a testis if the sex chromosomes are XY. Failure of the mesonephric duct. These paramesonephric ducts fuse
migration of these germ cells can occur in certain congenital caudally in the midline, with the fused caudal tip projecting
conditions such as Turner syndrome, leading to ovarian on the posterior wall of the urogenital sinus. The fallopian
dysgenesis. tubes and their fimbriae develop from the cranial part of the
By the seventh week, primordial follicles appear from paramesonephric ducts, while the fused paramesonephric
the second generation of cords from the coelomic epithe- ducts lead to the formation of the uterus and cervix. The
lium, and start proliferating rapidly by mitosis between medial border of each of the two paramesonephric tubes will
the second and fourth month. By the end of the 16th week, atrophy, in order to form one uterine cavity (Figure 1.2).
there are around 4 million oogonia, which then enter the Incomplete atrophy may lead to different degrees of uterine
first phase of meiosis. These oogonia remain arrested until septation, causing bifid, unicornuate and other types of uter-
puberty, when, periodically, batches of primary oocytes ine anomalies. These may present with fertility problems and
resume the meiotic cycle, forming at least one dominant recurrent miscarriages [2]. Treatment of such septa is still
secondary oocyte which ovulates. There is a degree of oocyte debatable, with further trials under way [3]. Due to the close
degeneration throughout all of the duration of the meiotic association with the development of the urinary system, such
arrest, with only around half of the original amount of uterine congenital anomalies may have concomitant urinary
oogonia making it until the time of birth. A healthy female anomalies.

1
 Basic Sciences in Obstetrics

The female genital duct system derived from at the pubic symphysis, and posteriorly, they articulate with the
the paramesonephric duct sacrum at the sacroiliac joints [6]. The pelvic inlet is circular in
shape in women, as opposed to being heart shaped in males, due
to the less prominent sacral promontory and broader iliac alae.
Also, the subpubic arch is around 20 degrees wider in women,
Fimbriated end of and the ischial spines project less into the pelvic cavity.
uterine tube The measurements of the pelvis include: the sagittal inlet,
between the promontory and the top of the symphysis pubis,
11 cm; the transverse diameter, 11.5 cm; the bispinous outlet,
Uterine tube 9 cm; and the sagittal outlet, between the tip of the coccyx and
the inferior margin of the pubic symphysis, 10 cm [6]. During
labour, these diameters increase in a clinically significant
Broad ligament with manner with squatting [7]. The ligaments of the pelvic wall
ovary in posterior wall are the sacrospinous and the sacrotuberous. They convert the
greater and the lesser sciatic notches into foramina, and also
help stabilize the sacrum on the pelvic bones.

1.3 Overview of the Blood and Lymphatic

Uterus - body & cervix
from fused Supply
paramesonephric ducts The abdominal aorta bifurcates into two common iliac arteries,
Figure 1.2 The female genital duct system derived from the which in turn divide at the pelvic inlet in front of the sacroiliac
paramesonephric duct joint into the internal and external iliac arteries. The external
iliac becomes the femoral artery, while the internal iliac reaches
At the point of contact, a sino-vaginal bulb arises by cell the upper margin of the greater sciatic foramen, dividing into an
proliferation from the paramesonephric ducts and the urogenital anterior and a posterior division. The anterior division gives rise
sinus. This leads to the vaginal plate, which canalizes in the fourth to the umbilical artery, the proximal part of which gives rise to
month, and the fornices develop. The hymen remains as a thin the superior vesical artery; the inferior vesical artery the uterine
plate between the vagina and the urogenital sinus. Abnormal artery, vaginal artery, internal pudendal artery, inferior gluteal
development at this point can lead to imperforate hymen or artery, middle rectal artery and obturator artery. The posterior
Robert’s uterus, among others [4]. In the meantime, the meso- division of the internal iliac artery gives rise to the iliolumbar,
nephric ducts will disappear during female urogenital develop- lateral sacral and superior gluteal arteries. Apart from the inter-
ment; however, some remnants may persist as epi-oophoron or nal iliac artery, the other arteries which enter the pelvic artery
para-oophoron in the broad ligament, which are vestigial struc- are the superior rectal artery, ovarian artery and the median
tures which can lead to Gartner’s cysts, which are usually benign. sacral artery. The lymphatic supply is named after the blood
In the meantime, mesodermal thickenings form around the vessels that are associated with it, namely, the external iliac
cloacal membrane, with a genital tubercle forming cranially, nodes, internal iliac nodes and the common iliac nodes.
leading to the formation of the clitoris and paired cloacal folds
laterally. After separation of the urogenital sinus by the uro- 1.4 Overview of the Innervation
rectal septum, the perineal body forms, and the cloacal folds
are transformed into anterior urethral folds, leading to the in the Female Pelvis
labia and posterior anal folds. The nerves of the pelvis are derived from the sacral plexus,
lumbosacral trunk and autonomic nervous system. The
1.2 The Pelvic Girdle: Bone and Ligaments – sacral plexus is formed from the anterior rami of the fourth
and fifth lumbar nerves and the anterior rami of the
Implications in Obstetrics first, second, third and fourth sacral nerves. The sacral
The pelvis is an anatomically complex set of bones, which plexus lies in front of the piriformis muscles on the posterior
function as one, that contributes directly to human obstetrics, pelvic wall. The lumbosacral trunk is made up of the fourth
as well as locomotion. The unique shape of the human pelvis, and fifth lumbar nerves. Branches to the lower limb leave the
superoinferiorly short and mediolaterally wide, is adapted for pelvis through the greater sciatic foramen, the largest of
habitual bipedalism [5]. which is the sciatic nerve. The pudendal nerves, the nerves
The pelvis consists of the right and left pelvic bones, the to the piriformis muscle and the pelvic splanchnic nerves are
sacrum and the coccyx. Each pelvic bone consists of the ilium, branches of the sacral plexus, which between them supply
ischium and pubis, which at birth are connected by cartilage at the pelvic muscles, pelvic viscera and perineum. The puden-
the acetabulum, which fully ossifies at the end of puberty. dal nerve (S2-4) leaves the pelvis through the greater sciatic
Superiorly, the sacrum articulates with the fifth lumbar vertebra foramen and enters the perineum through the lesser sciatic
at the lumbosacral joint. Anteriorly, the pelvic bones articulate foramen.

2
 Surgical Anatomy of the Female Pelvis

The obturator nerve (L2-4), which lies on the lateral wall of research in women undergoing instrumental delivery may
the pelvis and supplies the parietal peritoneum, is responsible help clarify if routine episiotomy is useful in this particular
for referred pain, for example, from an inflamed ovary or group [10].
appendicitis to be felt on the inner side of the thigh. The Pelvic organ prolapse is a possible consequence of weak-
autonomic nerves consist of the pelvic part of the sympathetic ening of the pelvic floor muscles, which can start as early as
trunk, the pelvic splanchnic nerves form the parasympathetic in adolescence, and is aggravated particularly with child-
part, and the superior and inferior hypogastric plexuses, which bearing and menopause. It may present with urinary incon-
both contain sympathetic and parasympathetic nerve fibres tinence symptoms, particularly urge urinary incontinence
and visceral afferent nerve fibres. The superior and inferior [11]. Women suffering from incontinence tend to have
hypogastric nerves arise from the superior hypogastric plexus. a greater anterior slope of the pelvis, which is directly
proportional to the electrical activity of the pelvic floor
1.5 The Pelvic Floor muscles during rest and in orthostasis [12]. Early education
regarding pelvic floor symptoms may lead to prevention
The pelvic diaphragm, and, in the anterior midline, the peri-
using lifestyle modification and Kegel’s exercises or empow-
neal membrane and the muscles of the deep perineal pouch,
erment to seek treatment.
make up the pelvic floor. This separates the pelvic cavity above
A thorough knowledge of the pelvic anatomy is essential
from the perineum below. The attachment of the pelvic dia-
during pelvic floor surgery, especially in abdominal laparo-
phragm to the inside of the cylindrical pelvic walls separates
scopic sacrocolpopexy, which is the gold standard of pelvic
the greater sciatic foramen from the lesser sciatic foramen, in
organ prolapse repair. This is because it presents a significant
such a way that the latter becomes a route of communication
challenge to surgeons because the technique requires meticu-
between the pelvic cavity and the gluteal region, while the
lous negotiation through abdominopelvic vascular structures
former allows communication between the gluteal region and
and nerves supplying the pelvis and its contents, particularly
the perineum.
the rectum, and ureters [13].
The levator ani and the coccygeus muscles from both sides
of the pelvis form the pelvic diaphragm, which is shaped like
a funnel and, particularly the levator ani, helps to support the 1.6 The Perineum
pelvic viscera and maintain closure of the vagina and rectum. When viewed from below with the thighs abducted, the peri-
Each of levator ani muscles is subdivided into at least three neum is diamond shaped, bound anteriorly by the symphysis
parts, based on the site of origin and the relationship to the pubis, laterally by the ischial tuberosities and posteriorly by the
viscera found in the midline. These are the pubococcygeus, tip of the coccyx. The perineum is anatomically divided into an
puborectalis and iliococcygeus. The levator ani consists of anterior urogenital triangle and a posterior anal triangle, which
a medial part containing smooth muscle cells under autonomic contains the anal canal and the ischiorectal fossa. The latter is
nerve influence and a lateral part containing striated muscle filled with dense fat and has the pudendal nerve and internal
cells under somatic nerve control [8]. In fact, the levator ani pudendal artery and vein passing on its lateral wall through the
muscles are innervated directly by branches from the anterior pudendal canal. The anal canal has an involuntary anal sphinc-
ramus of S4, and by branches of the pudendal nerve (S2-4). The ter and a voluntary external sphincter, which in turn is made
coccygeus muscles overlie the sacrospinous ligaments, span- up of subcutaneous, superficial and deep parts, that then blend
ning from the tips of the ischial spines to the lateral margins of in with the puborectalis fibres of the two levatores muscles
the coccyx and adjacent sacral margins, thus completing the [14].
posterior part of the pelvic diaphragm. The coccygeus muscles Anorectal vaginal fistulas may be obstetric, inflammatory
are innervated by the anterior branches of S4 and S5 [9]. (e.g. Crohn disease and diverticulitis), neoplastic, iatrogenic
Within the deep perineal pouch, anteriorly there is and/or radiation induced. Surgical management is heavily
a group of skeletal muscle fibres forming the external ure- dependent on the cause and complexity of the fistulizing dis-
thral sphincter, the sphincter urethrovaginalis and the com- ease, which are related to the correct identification of location
pressor urethrae, which together facilitate the closure of the of the fistula in the vagina, the type and extent of fistula
urethra. The deep transverse perineal muscles join in the branching, the number of fistulas and any concomitant sphinc-
midline along the posterior edge of the perineal membrane ter tears, inflammation and abscesses [15].
and stabilize the position of the perineal body. The perineal The female urogenital triangle contains the vulva, which is
body is a connective tissue structure into which the muscles the collective term for the external genitalia (the clitoris, mons
of the pelvic floor, the perineum, the posterior end of the pubis, labia minora and majora, vestibule of the vagina, the
urogenital hiatus, the deep and superficial transverse perineal vestibular bulb and the greater vestibular glands) and the
muscles, the sphincter urethrovaginalis, the external anal urethral and vaginal openings [16].
sphincter and the bulbospongiosus muscles attach .The peri- Branches of the internal and external pudendal arteries
neal body is the site which may be stretched or torn during supply both sides of the vulva, and the skin is drained into
childbirth. A posterolateral episiotomy is meant to bypass the the medial group of the superficial inguinal nodes, with the
perineal body and avoid complications like third- and fourth- Cloquet node being considered the sentinel node. The ilioin-
degree tears. However, current evidence does not show that guinal nerves and the genital branch of the genitofemoral
routine episiotomy reduces perineal/vaginal trauma. Further nerves supply the anterior part of the vulva, while the posterior
3
 Basic Sciences in Obstetrics

part is supplied by branches of the perineal nerves and the mesoderm and the developing vaginal dimple from the ecto-
posterior cutaneous nerves of the thigh. derm. This clearly has implications in cases of the spread of
The clitoris is situated at the apex of the vestibule ante- malignancy, especially vaginal and metastatic cervical cancer,
riorly, and its root is made up of the bulb of the vestibule, and its treatment [17,18].
which is attached to the undersurface of the urogenital dia- The paracolpium (paravaginal tissue) is surrounded by the
phragm and is covered by the bulbospongiosus muscles and vaginal wall, the pubocervical fascia and the rectovaginal sep-
the right and left crura, which become the corpora cavernosa tum (Denonvilliers’ fascia). The paracolpium contains the dis-
and are covered by an ischiocavernosus muscle. The glans, tal part of the pelvic autonomic nerve plexus and its branches:
together with its prepuce, caps the body of the clitoris and the nerves to the urethra, the cavernous nerve and the nerves to
has numerous sensory nerve endings, mainly through the the internal anal sphincter (NIAS). There is evidence that with
dorsal nerves of the clitoris. Appropriate sexual stimulation vaginal delivery and with aging, the pelvic plexus is likely to
of the clitoris and the region of the vaginal orifice and labia change from a sheet-like configuration to several bundles [19].
minora, reinforced by afferent nervous impulses from the
breasts and other regions, results in sensory impulses reaching
the central nervous system, which then pass down the spinal
1.8 Overview of the Gross Structures
cord to the sympathetic outflow (T1 to L2), to synapse between in the Female Pelvis
the preganglionic and postganglionic first and second lumbar In the anterior aspect of the female pelvis, there is the bladder
ganglia, which innervate the smooth muscle of the vagina, and and ureters, the uterus, fallopian tubes and broad ligament and
via the pudendal nerve to reach the bulbospongiosus and the ovaries. The rectum, sigmoid colon and the terminal coils
ischiocavernosus muscles. of the ileum occupy the posterior part of the pelvic cavity
The greater vestibular glands, also known as Bartholin’s (Table 1.1).
glands, lie underneath the posterior parts of the bulb of the
vestibule and the labia majora. Each drains its lubricating
mucous secretion via a small duct into a groove between the
1.8.1 The Urinary Bladder and Ureters
posterior part of the labia minora and the hymen. Blockage of The apex of the urinary bladder lies immediately posterior to
this gland can lead to a Bartholin’s cyst or an abscess. the symphysis pubis, with the neck resting on the upper surface
The urethra is just under 4 cm long, extending from the of the urogenital diaphragm. The posterior aspect, or base, of
neck of the bladder to the external meatus. It opens into the the bladder lies immediately in front of the anterior vaginal
vestibule at a point about 2.5 cm below the clitoris, immedi- wall, which in turn separates it from the rectum. The body of
ately in front of the vagina. The relatively short distance the uterus rests superiorly on the bladder, separated by the
between the urethra and the bladder makes it easier for cathe- uterovesical pouch. The inferolateral surfaces lie in front of the
terization; however, it does make women more prone to cysti- retropubic pad of fat and pubic bones, and posteriorly, rest on
tis compared to men. The paraurethral glands open into the the levator ani muscles.
vestibule on either side of the urethral orifice. Each of the two ureters crosses over the pelvic inlet in front
of the bifurcation of the common iliac artery, running down-
wards and backwards in front of the internal iliac artery and
1.7 The Vagina behind the ovary down till the ischial spine. Here, it turns
The vagina is a muscular tube that is approximately 8 cm long forward and medially beneath the base of the broad ligament,
and extends upwards and backwards between the vulva and the where it is crossed by the uterine artery. This point is known as
uterus. The upper half of the vagina lies above the pelvic floor ‘water under the bridge’, because the ureter lies immediately
within the pelvis, posterior to the bladder and in front of the below the uterine artery at 1.5 cm lateral to the cervix. It then
rectum, and with its anterior wall pierced by the cervix. The runs forward, lateral to the lateral vaginal fornix, to enter the
upper third of the vagina is supported by the levator ani base of the bladder, just above the trigone. There is indeed
muscles and the transverse cervical, pubocervical and sacro- a risk of iatrogenic ureteric injury during pelvic surgery, both
cervical ligaments, while the urogenital diaphragm supports for benign and malignant gynaecological pathologies [20].
the middle third. The lower half of the vagina lies between the
urethra anteriorly and the anal canal posteriorly, within the
perineum, and the perineal body supports the lower third of 1.8.2 The Uterus and Tubes
the vagina. The main blood supply is via the vaginal artery, The uterus is a muscular organ which has the shape of an
which is a branch of the internal iliac artery and by the vaginal upside-down pear, measuring about 8 cm in length, 5 cm in
branch of the uterine artery, and then drained by the vaginal width and 2.5 cm in thickness in nulliparous adults of repro-
veins into the internal iliac veins. The internal and external ductive age. It is divided into a fundus (lying above the uterine
iliac nodes drain the upper third of the vagina, the internal iliac tubes), body and a narrow lower part, the cervix.
nodes drain the middle third while the superficial inguinal In most women, the uterus is anteverted and anteflexed, by
nodes drain the lower third of the vagina. This difference is means of the round ligament; however, in some women, the
due to the embryological development of the vagina, as fundus and the body of the uterus are bent backwards on the
described in Section 1.1, with the hymen demarcating the vagina, to lie in the rectouterine pouch, making the uterus
point of fusion between the sinovaginal bulb from the retroverted and retroflexed. The body of the uterus is related
4
 Surgical Anatomy of the Female Pelvis

Table 1.1 Overview of the gross structures in the female pelvis

Pelvic organ Blood supply Lymphatic drainage Nerve supply

Sigmoid colon Arterial: sigmoid branches of inferior Along sigmoid arteries to inferior Sympathetic and parasympathetic
mesenteric artery mesenteric nodes nerves from inferior hypogastric
Venous: tributaries of inferior mesenteric vein, plexus
which joins portal system
Rectum Arterial: superior rectal artery, middle rectal Pararectal nodes to inferior Sympathetic and parasympathetic
artery, inferior rectal artery mesenteric nodes; vessels from the nerves from inferior hypogastric
Venous: veins correspond to the arteries lower part of the rectum follow plexus
middle rectal artery to internal iliac
nodes
Urinary bladder Arterial: superior and inferior vesical arteries, Internal and external iliac lymph Inferior hypogastric plexuses
branches of internal iliac artery nodes
Venous: form vesical venous plexus, drained
into internal iliac vein
Uterus Arterial: uterine artery from the internal iliac, Lymph vessels from the fundus Sympathetic and parasympathetic
ovarian artery from abdominal aorta accompany ovarian artery to drain nerves from inferior hypogastric
Venous: correspond to the arteries in para-aortic nodes; vessels from plexuses
body and cervix drain into internal
and external iliac lymph nodes; few
lymph vessels drain into superficial
inguinal lymph nodes
Uterine tubes Arterial: uterine artery from the internal iliac, Lymph vessels flow corresponding Sympathetic and parasympathetic
ovarian artery from abdominal aorta arteries and drain into internal iliac nerves from inferior hypogastric
Venous: correspond to the arteries and para-aortic nodes plexuses
Ovary Arterial: ovarian artery – branch of abdominal Lymph vessels follow the ovarian Sympathetic fibres: from aortic
aorta at the level of first lumbar vertebra artery and drain into para-aortic plexus (accompanies ovarian
Venous: ovarian vein – drains into inferior vena nodes at the level of first lumbar artery); some parasympathetic
cava on right side, into left renal vein on left vertebra fibres: from inferior hypogastric
side plexus (via uterine artery)
Vagina Arterial: vaginal artery, branch of internal iliac Lymph vessels from the upper third of Inferior hypogastric plexus
artery and the vaginal branch of uterine artery vagina drain to external and
Venous: form a plexus around vagina that internal iliac nodes, from middle
drains into internal iliac vein third to internal iliac nodes and
from lower third to superficial
inguinal nodes

anteriorly to the uterovesical pouch and the superior surface of plexuses provide sympathetic and parasympathetic nerve sup-
the bladder, posteriorly is related to the pouch of Douglas, and ply. Knowledge of this lymphatic drainage is important in cases
laterally to the broad ligament and uterine vessels. The uterine of endometrial cancer [21].
artery, which is a branch of the internal iliac artery, supplies the The thick myometrium is made up of smooth muscle
uterus after running medially in the base of the broad ligament, supported by connective tissue. Leiomyomata, or fibroids,
reaching the cervix at the internal os and then ascending along may occur in this layer, and when treatment is necessary, this
the lateral margin of the uterus within the broad ligament, can happen through myomectomy, total hysterectomy or uter-
anastomosing with the ovarian artery, which also supplies the ine artery embolization [22].
uterus. A small descending branch is given off by the uterine The endometrium lines the body of the uterus and is con-
artery to supply the cervix and the vagina. Blood drains into the tinuous above with the mucous membrane lining the uterine
uterine vein and internal iliac vein. tubes and below with the mucous membrane of the cervix.
The lymph from the fundus drains into the para-aortic Deposits of ectopic endometrium can lead to endometriosis
nodes at the level of the first lumbar vertebra, while the body [23].
and the cervix drain into the internal and external iliac lymph Peritoneum covers all of the uterus except anteriorly below
nodes. Some lymph vessels pass through the inguinal canal, the level of the internal os, where the peritoneum passes for-
following the round ligament, and drain into the superficial ward onto the bladder and laterally between the attachment of
inguinal nodes. Branches from the inferior hypogastric the layers of the broad ligament. Apart from the tone of the
5
 Basic Sciences in Obstetrics

Figure 1.3 Dissection of the female pelvis (carried out on a Thiel embalmed
cadaver at the Department of Anatomy, University of Malta). A black and white
version of this figure will appear in some formats. For the colour version, please
refer to the plate section.

levator ani muscles, the uterus is supported by three ligaments,

namely, the transverse cervical (cardinal), pubocervical and
sacrocervical ligaments, which result from the condensations Figure 1.4 Dissection of the uterus, tubes and ovaries (carried out on a Thiel
of pelvic fascia (Figures 1.3 and 1.4). embalmed cadaver at the Department of Anatomy, University of Malta). A black
The cervical canal communicates with the cavity of the and white version of this figure will appear in some formats. For the colour
version, please refer to the plate section.
uterine body through an internal os and with the vagina
through the external os. There is a transformation zone, also
known as the squamocolumnar junction or the transitional
zone, where there is a high affinity for viruses like human of the pelvis. They are each attached to the back of the broad
papillomavirus due to the increased rate of cell replication at ligament by the mesovarium, while the suspensory ligament
this point. The cervix is related anteriorly to the anterior fornix (infundibulopelvic ligament) attaches the mesovarium to the
of the vagina, posteriorly to the rectouterine pouch with coils lateral wall of the pelvis. The blood and nerve supply, together
of ileum and sigmoid colon, and laterally related to the ureters with the lymph drainage, pass over the pelvic inlet, through the
as they pass forward to enter the bladder. Blood is supplied to lateral end of the broad ligament via the suspensory ligament
the cervix by the descending branch of the uterine artery, and finally enter the hilum of the ovary via the mesovarium.
which in turn drains into the uterine vein. The blood supply is via the ovarian artery, which is a direct
The anterior and lateral cervix drains to the lymph nodes branch of the aorta, arising at the level of the first lumbar
along the uterine arteries, travelling along the cardinal ligaments vertebra. On the right side, blood drains into the inferior
at the base of the broad ligament to the external iliac lymph vena cava, and into the left renal vein on the left side.
nodes and ultimately the para-aortic lymph nodes. The posterior Because ovarian cancer might spread via the lymphatics via
and lateral cervix drains along the uterine arteries to the internal the suspensory ligament and mesovarium, as well as through
iliac lymph nodes and ultimately also the para-aortic lymph the round ligament of the uterus, the sentinel node can be
nodes. The posterior section of the cervix drains to the obturator detected in the para-aortic and paracaval regions, obturator
and presacral lymph nodes. However, there are individual var- fossa and surrounding internal iliac arteries, and inguinal
iations of lymphatic drainage from the cervix [24]. regions. These findings support the strategy of injecting tracers
In cases of cervical malignancy, advances in magnetic reso- in both ovarian ligaments to identify sentinel nodes [27, 28].
nance imaging (MRI) and positron emission tomography/com-
puterized tomography (PET/CT) have made it possible to examine 1.9 The Peritoneum
many of the prognostic factors noninvasively. In radiology. com- From the anterior abdominal wall, the peritoneum passes
bining deep learning and anatomic prior information may down onto the upper surface of the urinary bladder, then
improve segmentation accuracy for cervical tumours [25, 26]. onto the anterior surface of the uterus at the level of the
internal os, upwards onto the anterior surface of the body
1.8.3 The Ovary and fundus of the uterus, and then downwards over the
The ovaries are responsible for the production of ova and the posterior surface of the uterus, covering the upper part of
hormones oestrogen and progesterone. They are covered the posterior surface of the vagina, forming the rectouterine
externally by the germinal epithelium, which is a modified wall (pouch of Douglas). This is the lowest part of the abdo-
area of peritoneum. Both ovaries are often found hanging minopelvic peritoneal cavity in the erect position. The broad
down in the rectouterine pouch, lying against the lateral wall ligaments are two layered folds of peritoneum extending from
6
 Surgical Anatomy of the Female Pelvis

the lateral margins of the uterus to the lateral pelvic walls. 1.10 Conclusion
Peritoneal spread of infection or malignancy is particular to
Accurate knowledge of the anatomy of the female pelvis and its
the pelvic organs, particularly in the case of ovarian cancer
contents is essential for safe management of patients present-
spread [29, 30].
ing with obstetric and/or gynaecological conditions.

11. Arbuckle JL, Parden AM, Hoover K, a systematic review and meta-analysis.
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1. Vilanova-Sanchez A, McCracken K, awareness of pelvic floor disorders in (5):459–76.e10.
Halleran DR, et al. Obstetrical outcomes adolescent females seeking gynecologic
in adult patients born with complex 22. Anton K, Rosenblum NG, Teefey P,
care. J Pediatr Adolesc Gynecol. 2019;32 Dayaratna S, Gonsalves CF. The
anorectal malformations and cloacal (3):288–92.
anomalies: a literature review. J Pediatr enlarged fibroid uterus: aberrant
Adolesc Gynecol. 2019 Feb;32(1):7–14. 12. Lemos AQ, Brasil CA, Alvares CM, arterial supply via the omental artery.
et al. The relation of the pelvis and the Cardiovasc Intervent Radiol. 2019
2. Bailey AP, Jaslow CR, Kutteh WH. perineal function in incontinent Apr;42(4):615–19.
Minimally invasive surgical options for women: a neglected subject. Neurourol
congenital and acquired uterine factors 23. Alimi Y, Iwanaga J, Loukas M,
Urodyn. 2018 Nov;37(8):2799–2809. Tubbs RS. The clinical anatomy of
associated with recurrent pregnancy
loss. Womens Health (Lond). 2015 13. Muavha DA, Ras L, Jeffery S. endometriosis: a review. Cureus. 2018
Mar;11(2):161–7. Laparoscopic surgical anatomy for Sep 25;10(9):e3361.
pelvic floor surgery. Best Pract Res Clin 24. Ercoli A, Delmas V, Iannone V, et al.
3. Rikken JFW, Kowalik CR, Obstet Gynaecol. 2019 Jan;54:89–102.
Emanuel MH, et al. The randomised The lymphatic drainage of the
uterine septum transsection trial 14. Snell RS. The perineum. In Clinical uterine cervix in adult fresh cadavers:
(TRUST): design and protocol. BMC Anatomy by Regions, 9th ed. Philadelphia: anatomy and surgical implications.
Womens Health. 2018 Oct 5; 18(1):163. Wolters Kluwer Health, Lippincott Eur J Surg Oncol. 2010 Mar;36
Williams and Wilkins, 2012, pp. 302–33. (3):298–303.
4. Ludwin A, Ludwin I, Bhagavath B,
Lindheim SR. Pre-, intra-, and 15. VanBuren WM, Lightner AL, Kim ST, 25. Narayan K, Lin MY. Staging for cervix
postoperative management of Robert’s et al. Imaging and surgical management cancer: role of radiology, surgery and
uterus. Fertil Steril. 2018 Sep;110 of anorectal vaginal fistulas. clinical assessment. Best Pract Res Clin
(4):778–9. Radiographics. 2018 Sep-Oct;38 Obstet Gynaecol. 2015 Aug;29
(5):1385–1401. (6):833–44.
5. DeSilva JM, Rosenberg KR. Anatomy,
development, and function of the 16. Wu Y, Dabhoiwala NF, Hagoort J, et al. 26. Chen L, Shen C, Zhou Z, et al.
human pelvis. Anat Rec (Hoboken). Architecture of structures in the Automatic PET cervical tumor
2017 Apr;300(4):628–32. urogenital triangle of young adult segmentation by combining
males; comparison with females. J Anat. deep learning and anatomic prior.
6. Drake RL, Vogl W, Mitchell AWM. Pelvis 2018 Oct;233(4):447–459. Phys Med Biol. 2019 Feb 12;65
and perineum. In Gray’s Anatomy for (8):085019.
Students, 3rd ed. London: Churchill 17. Rajaram S, Maheshwari A,
Srivastava A. Staging for vaginal cancer. 27. Kimmig R, Buderath P, Mach P,
Livingstone Elsevier, 2015, pp. 406–504.
Best Pract Res Clin Obstet Gynaecol. Rusch P, Aktas B. Surgical treatment of
7. Hemmerich A, Bandrowska T, 2015 Aug;29(6):822–32. early ovarian cancer with
Dumas GA. The effects of squatting compartmental resection of regional
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understand childbirth. J Biomech. 2019 resection: surgical treatment of locally compartmental lymphadenectomy
Apr 18;87:64-74. pii: S0021- advanced and recurrent cancer of the (TCL, paraaortic part). J Gynecol Oncol.
9290(19)30147–2. uterine cervix and vagina based on 2017 May;28(3):e41.
ontogenetic anatomy. Gynecol Oncol.
8. NyangohTimoh K, Moszkowicz D, 2012 Nov;127(2):297–302. 28. Kleppe M, Kraima AC,
Zaitouna M, et al. Detailed muscular Kruitwagen RF, et al. Understanding
structure and neural control anatomy of 19. Hinata N, Hieda K, Sasaki H, et al. lymphatic drainage pathways
the levator ani muscle: a study based on Nerves and fasciae in and around the of the ovaries to predict sites for
female human fetuses. Am J Obstet. paracolpium or paravaginal tissue: an sentinel nodes in ovarian cancer.
Gynecol. 2018 Jan;218(1):121.e1-121.e12. immunohistochemical study using Int J Gynecol Cancer. 2015 Oct;25
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Selective versus routine use of 30. Le O. Patterns of peritoneal spread of
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Database Syst Rev. 2017 Feb 8;2: Tanner EJ. Sentinel lymph node World J Radiol. 2013 Mar 28;5
CD000081. assessment in endometrial cancer: (3):106–12.

7
 Chapter
Maternal Physiology during Pregnancy, Including

2 Immunology of Pregnancy
Ksenija Gersak

Pregnancy is a specific relationship between two or more Table 2.1 Hormone production in corpus luteum and fetoplacental unit
organisms inside their unique ecosystem. Although they
belong to the same species, the relationship can be qualified Hormone Production site
as a symbiotic and parasitic form of biological interaction [1].
Progesterone Corpus luteum
The question might be rooted more in the psychology rather Placenta
than physiology of pregnancy. On the other hand, however,
a fetus does control maternal adaptation to pregnancy, and for Oestradiol Corpus luteum
its successful development and growth it needs an effective Placenta
exchange of nutritive and metabolic products with the mother, Human chorionic Decidualized endometrium
combined with a reliable life-support system composed of the gonadotropin Placenta
placenta, umbilical cord and amniotic sac. Fetal cortisol, Fetal adrenal gland
This chapter reviews the biochemical, physiological and corticosterone,
immunological adaptations of a woman’s body to pregnancy. aldosterone
Hypothalamic-like Placenta
2.1 Endocrine Changes during Pregnancy releasing hormones

2.1.1 Steroid and Protein Hormones Human placental

lactogen
Placenta
Hormones associated with pregnancy are steroid hormones,
protein hormones and prostaglandins. Their production takes Human chorionic Placenta
place in the corpus luteum, placenta and fetus. Separately, fetal thyrotropin
and placental tissues do not possess the necessary enzymatic Human chorionic Placenta
capabilities for an adequate synthesis of these hormones. adrenocorticotropin
Together, however, they are complementary and form
Placental growth Placenta
a complete unit that utilizes the maternal compartment as
hormone
both a source of basic building materials and a resource for
the clearance of hormones [2]. Hormone production in the Alpha-fetoprotein Fetal liver and yolk sac
corpus luteum and fetoplacental unit are presented in Table Relaxin Corpus luteum
2.1.
Progesterone is a steroid hormone with a number of phy- Prolactin Fetal pituitary
siological effects that are mainly amplified in the presence of Maternal pituitary
oestrogens. It is produced by the corpus luteum until about 7 Decidualized endometrium
weeks’ gestation. During a transition period of 3 weeks, its Myometrium
production is shared between the corpus luteum and placenta, Insulin-like growth Placenta
and after 10 weeks’ gestation, placenta becomes the key source hormones
of its synthesis [3]. Epidermal growth Placenta
The majority of placental progesterone is derived from factor
maternal cholesterol and is relatively independent of uteropla-
cental perfusion, fetal well-being or even the presence of a live Inhibin A Placenta
fetus. Unlike steroidogenesis elsewhere, it is not clear whether Activin A Placenta
the production of placental progesterone requires the control
Follistatin Decidualized endometrium
of tropic hormones. Some evidence exists indicating that
Placenta
a small amount of human chorionic gonadotropin (hCG)
must be present [4]. Atrial natriuretic Placenta
The main biological function of progesterone is the pre- peptide Myometrium
vention of myometrial contractility during pregnancy, mani- Source: Adapted from [2].
festing as an increased membrane electrical resting potential
8
 Maternal Physiology during Pregnancy, Including Immunology of Pregnancy

and prevention of electrical coupling between myometrial the time of blastocyst implantation, and its plasma levels
cells. Progesterone also decreases the uptake of extracellular increase rapidly, doubling every 2 days during the first trime-
calcium, which is needed for myometrial contraction, by ster. Between 10 and 12 weeks’ gestation, plasma levels begin to
downregulating the expression of genes that encode subunits decline, settling during 16 weeks’ gestation and maintaining
of voltage-dependent calcium channels. Its concentration in stable values until the end of pregnancy.
the myometrium is about three times higher than maternal hCG plays an important role in male sexual differentiation
plasma levels in early pregnancy. Throughout pregnancy it by stimulating testosterone secretion from fetal testes, and is
remains high, and is about equal to the maternal plasma level also presumed to regulate placental development by influen-
at term. cing differentiation of cytotrophoblast cells.
During pregnancy, the plasma concentration of two active Production and secretion of hCG are the result of complex
metabolites of progesterone increases: 5α-dihydroprogesterone interactions between sex steroids, cytokines, placental GnRH,
and 5β-dihydroprogesterone. The kidneys excrete both of them growth factors and other locally produced peptides. About
into the urine. 5α-dihydroprogesterone contributes to the resis- 20–30 isoforms have so far been discovered in maternal
tance to vasopressor action of angiotensin II during the course blood. A major route of clearance for hCG is maternal renal
of pregnancy. metabolism, during which a final reduced fragment of the beta
Progesterone also serves as the substrate for fetal adrenal subunit is produced, known as the beta-core fragment. hCG
gland production of glucocorticoids and mineralocorticoids. fetal plasma levels follow the same pattern as those in maternal
In the amniotic fluid, progesterone level is highest between 10 circulation, with the peak at the end of the first trimester of
and 20 weeks’ gestation and then decreases gradually [2]. gestation.
Oestrogens are steroid hormones produced primarily by Human placental lactogen is a non-glycosylated polypep-
the ovaries, and during pregnancy by the placenta. They influ- tide with a similar structure to the human growth hormone,
ence progesterone production, mammary gland development, and mimics the action of prolactin. It is primarily secreted into
uterine angiogenesis and fetal adrenal gland function [5]. maternal circulation and stimulates the secretion of insulin
Together and with progesterone, they induce uterine and sys- and insulin-like growth factor 1. Placental production appears
temic artery vasodilation [6]. 5–10 days after conception [7, 8].
Like progesterone, initial oestrogen production depends on Human placental lactogen influences maternal metabolic
precursors from outside the placenta: maternal cholesterol and processes, especially lipolysis. Through its action, maternal
androgen compounds. The major oestrogens during preg- blood free fatty acid levels increase, becoming a more promi-
nancy are oestradiol, oestrone, oestriol and oestetrol. Oestriol nent source of energy for maternal metabolism, enabling the
and oestetrol are almost solely produced from fetal steroid fetus to utilize relatively more glucose. With its diabetogenic
precursors. action, it stimulates protein production and, as an angiogenic
In maternal circulation, a rise in oestradiol begins during 6 hormone, plays an important role in the formation of the fetal
to 8 weeks’ gestation, when placental function becomes appar- vascular network. Human placental lactogen also exhibits weak
ent, followed by a rise of oestriol and oestrone during 7 to 10 actions similar to those of the growth hormone, thus stimulat-
weeks’ gestation. By the end of 20 weeks’ gestation, approxi- ing the formation of protein tissues.
mately 90% of oestrogen production can be attributed to
synthesis in the fetal adrenal gland from the precursor dehy-
droepiandrosterone sulphate (DHEAS). At term, an equal
2.1.2 Thyroid Gland
amount of oestrogen arises from maternal DHEAS and fetal During a normal pregnancy, changes in maternal thyroid func-
DHEAS, and their production is increased about 100 times tion can be viewed as a balance between hormone require-
over non-pregnant levels. ments and the availability of iodine [9].
Prior to excretion into maternal urine, maternal liver Due to the structural analogy with thyroid-stimulating
rapidly metabolizes the oestrogens into a variety of more hormone (TSH), hCG causes thyroid stimulation as early as
than 20 metabolites. during the first trimester, with a resulting slight decrease in
Human chorionic gonadotropin (hCG) is a glycoprotein serum TSH levels. At the same time circulating levels of
with an alpha subunit identical to that of the luteinizing hor- thyroid-binding globulin (TBG) are increased by oestrogen-
mone (LH), follicle-stimulating hormone (FSH) and thyroid- stimulated hepatic synthesis and by oestrogen-mediated pro-
stimulating hormone (TSH). While it could be produced in longation of TBG half-life.
different tissues, only the placenta has the ability to glycosylate Thyroid volume and intrathyroidal blood flow increase
the protein, and it is the process of glycosylation that is respon- gradually towards the third trimester and decrease after deliv-
sible for the longer circulating half-life of hCG. Since the beta ery [10]. The changes in volume are associated with changes in
subunit promoter does not contain steroid hormone response TSH levels and alterations in maternal body mass index.
elements, it allows hCG secretion to escape feedback regulation The apparent increased functional iodine uptake by the
mechanisms controlled by sex steroids, in contrast to FSH and thyroid gland is relative rather than absolute, and reflects
LH [2]. the decrease in the total systemic iodine pool. A decline in the
The main biological function of hCG is the maintenance of availability of iodide is induced by the onset of fetal intake and
corpus luteum function. It first enters maternal circulation at increased renal clearance. Nevertheless, circulating unbound

9
 Basic Sciences in Obstetrics

levels of triiodothyronine (T3) and thyroxine (T4) are minimally the external muscle layer, and by accumulation of elastic tissue.
altered. Free serum T4 level rises slightly during the first trime- The increase in uterine size is related predominantly to the
ster, its concentration peaking concurrently with peak hCG pressure exerted on it by the expanding conceptual mass [12].
levels, and then returning to normal values at 11–13 weeks’ After 20 weeks’ gestation, the uterus begins to elongate and
gestation. assumes a cylindroid shape. Myofibril density is the highest in
During normal pregnancy, basal metabolic rate increases the corpus and the lowest in the isthmus. The uterus comes in
by a total of 25% in a progressive manner. Relative to the contact with the anterior abdominal wall, displaces the intes-
increased body surface areas of the mother and fetus, however, tines laterally and superiorly and extends upwards almost to
it remains unchanged. the liver. Also, it usually rotates to the right. By term, the
myometrium is only 1 to 2 cm thick, and the architectural
2.1.3 Pituitary Gland and Prolactin arrangement reflects the salient features of uterine behaviour
during normal labour.
The pituitary gland enlarges during pregnancy. The enlarge-
The uterine wall is arranged in three layers. The outer layer
ment is primarily caused by oestrogen-stimulated hypertrophy
arches over the fundus and extends into various ligaments.
and hyperplasia of the lactotrophic cells in the anterior pitui-
Most of the wall is formed by the middle layer, which is
tary. Production of gonadotropins declines, while synthesis in
composed of a dense network of muscle fibres arranged in
corticotropic and thyrotropic cells remains constant.
the same direction as blood vessels. The inner layer contains
Somatotropic cells are generally suppressed due to the negative
sphincter-like fibres around fallopian tube orifices and the
feedback by placental synthesis of growth hormone.
internal cervical long axis.
Prolactin is a single-chain polypeptide. It has a similar
The uterus undergoes irregular contractions early in preg-
structure to growth hormone and human placental lactogen.
nancy. During the second trimester, the contractions can be
Maternal serum prolactin levels begin increasing gradually at 8
detected by manual examination, first described by Dr John
weeks’ gestation with the increasing size of the gland, reaching
Braxton Hicks in 1871 [13]. The Braxton Hicks contractions are
their peak at term [11]. Only the myometrium, endometrium
unpredictable, sporadic and usually non-rhythmic. Their fre-
and the maternal and fetal pituitary are responsible for its
quency increases during the last two weeks of pregnancy.
secretion. Endometrium requires the presence of progesterone
Similarly, studies of uterine electrical activity have shown low
to initiate prolactin production, whereas in the myometrium,
and uncoordinated patterns during early gestation, which
progesterone suppresses prolactin production [2].
become progressively more intense and synchronized by term
The major physiological roles of prolactin are priming of
[14 , 15].
the breasts for lactation, maintenance of lactation during the
The isthmic segment elongates at the end of the first
puerperium, modulation of prostaglandin-mediated uterine
trimester of pregnancy, before the conceptual mass has filled
muscle contractility and contribution to surfactant synthesis
the available place in the uterine corpus. The elongation is
in the fetal lung. It also has an impact on maternal metabolism,
accompanied by thickening of the wall of the lower uterine
reducing the permeability of the amnion in the fetus-to-
segment and corpus. During the second trimester, the isthmus
mother direction, and influencing regulation of fetal water
undergoes incorporation into the lower uterine segment,
and electrolyte balance by acting as an antidiuretic hormone.
which is accompanied by thinning of its musculature. This
process stops at the border between isthmus and cervix. Later
2.2 Physiological Adaptation to Pregnancy on, the junction is seamless, and no distinct margin can be
ascertained [16].
2.2.1 Uterus The cervix becomes softer during pregnancy due to loosen-
The uterus grows in order to accommodate the growing ing of the connective tissue by the means of collagen fibril
conceptual mass (the fetus, placenta and amniotic fluid) with- dissociation. Increased vascularity and oedema additionally
out increasing intrauterine pressure. The non-pregnant contribute to its softening and cyanosis, together with hyper-
uterus of a nulliparous woman weighs about 40 g and that trophy and hyperplasia of the cervical glands [12]. Soon after
of a multiparous woman about 70 g. At term, its weight is conception, endocervical mucosal cells produce dense mucus
about 1 200 g. that obstructs the cervical canal. All the changes intensify as the
During the first trimester, the uterus grows more rapidly pregnancy progresses. At term, cervical glands occupy up to
than the conceptual mass. Mitotic proliferation of myocytes is one half of the total cervical mass, and with the onset of labour
responsible for a major proportion of total uterine growth due or slightly before it, the mucus plug is expelled.
to oestrogen stimulation. The conceptual mass fills the entire Sufficient uteroplacental blood flow is essential for
uterine cavity approximately at the end of 12 weeks’ gestation, a normal pregnancy outcome [17]. Blood is transported to
when decidua capsularis fuses with decidua parietalis, which the uterus bidirectionally via a dual arterial anastomotic loop,
obliterates the uterine cavity. the ovarian loop originating from the aorta and the uterine
Production of new myocytes is limited. After the first tri- loop from the internal iliac arteries.
mester, further uterine growth is due to hypertrophy of myo- Perpendicular vessels branch out from the main utero-
cytes rather than due to replication. Myocytes increase in size, ovarian arteries and pass into the uterine corpus to form the
accompanied by accumulation of fibrous tissue, particularly in actuate arteries. They encircle the uterus by coursing within the
10
 Maternal Physiology during Pregnancy, Including Immunology of Pregnancy

myometrium just beneath its outer serosal surface. Vessels being required for the synthesis of progesterone receptors.
from each side form anastomoses along the uterine midline. Similar changes occur during each normal menstrual cycle,
Smaller radial arteries originate from the actuate arteries and especially in the late luteal phase, when mitotic activity, fluid
penetrate the myometrium centripetally before branching into secretion and DNA production in glandular and non-
either straight basal or spiral arteries at the myoendometrial glandular tissue reach their peak [2].
border. Basal vessels spread to form a network along the Final differentiation of the alveolar epithelial tissue into
myoendometrial border, while the spiral arteries penetrate mature milk cells is accomplished by gestational increase in
further into the endometrium and terminate close to the uter- oestrogen and progesterone levels, combined with the presence
ine lumen in capillaries that are drained by venules into larger of prolactin after prior exposure to cortisol and insulin. As
veins that enter the inferior vena cava. pregnancy progresses, the nipples become significantly larger
The underlying reason responsible for the unique structure and more pigmented. All in all, in most normal pregnancies,
of spiral arteries is trophoblast invasion. Fetal trophoblast cells pre-pregnancy breast size and post-pregnancy amount of milk
migrate into the arterial lumen, ablate the endothelium and production do not correlate [18].
smooth muscle of the arterial wall and reorganize the matrix
elements. 2.2.3 Osmoregulation and Water Metabolism
Due to endovascular invasion, vessels lose their ability to Pregnant women experience a decrease in tonicity of body
contract, resulting in decreased vascular resistance, facilitating fluids. Early in pregnancy, plasma osmolality decreases to its
an increased blood flow. The combined effect of increasing lowest level of approximately 10 mOsmol/kg below non-
both the length and the diameter of the vessels by a factor of 2 pregnant levels [19]. This puts it below the pre-pregnancy
theoretically reduces vascular resistance by a factor of 8. And osmotic thirst threshold, and a new steady state needs to be
according to Poiseuille’s law, together with additional factors, established. Lowering the threshold stimulates increased
such as reduced blood viscosity and the growth of new vessels, water intake and dilution of body fluids. The exact mechan-
it contributes to a significant reduction in blood flow ism responsible for altered osmoregulation in pregnancy is
resistance. unclear, chorionic gonatotropin and relaxin possibly being
The flow increases from a baseline value of 20–50 mL/min responsible for the changes. As far as we know, relaxin
to 450–800 mL/min in singleton pregnancies, with values in stimulates increased vasopressin secretion, resulting in
excess of 1 L/min measured in twin pregnancies [17]. Since increased drinking and water retention.
blood pressure normally decreases during pregnancy, uterine Water content of lean tissue increases from approximately
haemodynamic changes can principally be attributed to 72% at 10 weeks’ gestation to about 75% at the end of preg-
a profound decrease in uterine vascular resistance. The nancy, with total amount of extracellular extravascular fluid
increase of uteroplacental blood flow is gradual and fairly reaching about 1.6 to 2.6 litres [20]. Most of this fluid is stored
linear. Absolute blood flow to the myometrium increases pro- in the connective tissue under the influence of oestrogen.
portionally to uterine mass, whereas relative uterine blood flow There is also an approximately 1.2 litre increase in water
(millilitre/minute/100 g) may fluctuate or remain fairly con- content in the intravascular compartment, and about 0.8
stant during the entire pregnancy. litres of fluid in the amniotic cavity itself, also contributing
to the total body water content increase (Table 2.2).
2.2.2 Breast Additional extracellular water can be found also in the cere-
Breast growth and milk production depend on numerous brospinal fluid, lymph system, various body secretions and
hormonal factors that occur in two periods: at puberty and intestinal fluid.
during pregnancy. About 30% of pregnant women exhibit physiological leg
At puberty, the major influence on breast growth is oedema, due to the effect of gravity and increased venou
oestrogen, which potentiates prolactin release stimulation by pressure below the level of the uterus as a consequence of
gonadotropin-releasing hormone (GnRH). The first main partial vena cava occlusion.
response to the increasing level of oestrogen is an increase in
size and pigmentation of the areola and the formation of 2.2.4 Weight Gain
a mass of breast tissue underneath the areola. Breast tissue The physiological average of total weight gain in healthy
expresses oestrogen receptors ER-alpha and ER-beta, but primigravida eating without restriction is 12.5 kg [20].
only in the presence of prolactin. Besides prolactin, complete Components of weight gain can be divided into two groups:
differentiation of the gland requires insulin, cortisol, the conceptual mass (fetus, placenta, amniotic fluid) and the
thyroxine, growth hormone and the presence of local growth maternal part (enlarged uterus, breast tissue, maternal fat
factors. deposition, extracellular extravascular and intravascular
The breast enlarges rapidly during the first two months of fluid) (Table 2.2).
pregnancy. Later on, progressive enlargement continues at On average, the fetus represents approximately 25% of the
a slower rate. The enlargement is due to an increase in gland- total gain, the placenta about 5% and the amniotic fluid about
ular tissue volume. 6%. Fetal growth follows a sigmoid curve, with growth slowing
The key hormone for breast differentiation and growth in the final week of gestation. The rate of placental growth also
during this period is progesterone, with oestrogen additionally declines towards the end of pregnancy.
11
 Basic Sciences in Obstetrics

Table 2.2 Changes in body water, blood and weight gain Iodide is produced from dietary iodine in the intestine,
from which it is absorbed into the circulation. Together with
Compartment Increase during
peripheral catabolism and deiodination of thyroid hormones
pregnancy
and iodothyronines, dietary iodine constitutes the extrathyr-
Extracellular extravascular fluid 1600 to 2600 mL oidal inorganic iodine pool [9]. The pool is in a dynamic
Intravascular fluid (plasma and red cell 1200 mL equilibrium with two main organs, the thyroid gland and the
volume) kidneys. In pregnancy, renal clearance of iodide increases sig-
nificantly due to increased glomerular filtration rate.
Water content of uterus and breast 2000 mL A second mechanism of iodine deprivation occurs later in
Amniotic fluid, water content of the fetus 3500 mL gestation, by the passage of a proportion of available iodine
and placenta from the maternal circulation into the fetus and the placenta.
In non-pregnant women, adequate iodine intake is estimated
Red cell volume 250 mL
to be 100–150 mg/day. Based on several studies, the consensus
Plasma volume 1000 mL recommendation of the World Health Organization is that
Total body water gain 8000 to 9000 mL iodine supply should be increased in pregnant and lactating
women to at least 200 mg/day.
Fetus, placenta and amniotic fluid 5.0 kg
Uterus 1.0 kg 2.2.6 Haematological Changes and Iron
Breast 0.4 kg Metabolism
Maternal fat deposition 3.5 kg Haematological changes during pregnancy affect plasma
volume, red cell volume, haematocrit, haemoglobin and serum
Average weight gain 12.5 kg
iron concentrations, as well as coagulation and fibrinolysis.
Source: Adapted from [16, 21]. Plasma volume increases progressively by 40–50%
throughout normal pregnancy, equating to about a 1 200 mL
total increase (Table 2.2). Changes in red cell volume are less
well defined, rising approximately by 200–400 mL (Figure 2.1).
During the first trimester, plasma volume expands by
2.2.5 Serum Electrolytes 15–20% compared to non-pregnant volumes. The most rapid
Concentrations of most serum electrolytes decrease during increase can be observed during the second trimester. This
pregnancy. The decrease is not substantial, and the mean values increase keeps up with the increased metabolic demands of
are within normal ranges established for non-pregnant women. the enlarged uterus with its hypertrophied vascular system, and
The total amount of sodium and potassium increases dur- provides sufficient nutrients and electrolytes to support the
ing pregnancy, but their serum concentrations decrease slightly growing fetus and placenta.
because of the expanded plasma volume. In the second and third Total plasma volume increases from 2 600 mL to 3 800 mL
trimesters, there is a net gain of approximately 1000 mEq of at 34 weeks’ gestation [12]. This increase is mediated by a direct
sodium and 300 mEq of potassium. On the other hand, proges- action of progesterone and oestrogen on the kidneys, causing
terone, being a potent aldosterone antagonist that acts on the the release of renin and subsequent activation of the renin-
mineralocorticoid receptor, prevents sodium retention and pro- angiotensin-aldosterone mechanism. This leads to renal
tects against hypokalaemia. Despite an increased glomerular sodium retention and an increase in total body water.
filtration of sodium and potassium, urine excretion thus During the last few weeks of pregnancy, plasma volume
remains unchanged due to enhanced tubular reabsorption. may decline by about 200 mL or remain constant.
Serum calcium levels, both ionized and non-ionized, Plasma volume changes disproportionately with the
decline during pregnancy. The reduction follows a lowered increase in red blood cell mass, resulting in physiological
plasma albumin concentration, more specifically a decrease haemodilution (Figure 2.1). There is a fall in haemoglobin
in the amount of circulating protein-bound non-ionized cal- concentration and haematocrit. Haemodilution has
cium. The fetal skeleton accumulates approximately 30 g of a protective function by decreasing blood viscosity in order
calcium at term, 80% of which is deposited during the third to counter the concurrent predisposition to thromboembolic
trimester. For this reason, maternal intestinal absorption is events, and can be beneficial for intervillous perfusion [22].
doubled during the same period, in part by 1,25-OH vitamin Red blood cell (RBC) mass starts to increase at 8–10 weeks’
D. Dietary intake is necessary and especially important for gestation aligned with erythropoietin production, and con-
pregnant adolescents, in whom bones are still developing [12]. tinues to increase until delivery by 15–20% in women who
Furthermore, total and ionized serum magnesium concentra- are not taking iron supplements and by 20–30% in women
tions are also lower during pregnancy due to extracellular deple- who have been taking iron supplements.
tion. Serum phosphate concentration, however, remains within RBC life span is gradually decreased. Reticulocyte count,
non-pregnant ranges due to increased calcitonin levels and ele- however, is slightly elevated due to a moderate rise of erythro-
vated renal threshold for non-organic phosphate excretion. poiesis in the bone marrow. Maternal erythropoietin does not

12
 Maternal Physiology during Pregnancy, Including Immunology of Pregnancy

120 Figure 2.1 Changes in plasma volume, RBC

volume, serum ferritin level, cardiac output and
heart rate during pregnancy (adapted from [2, 24]).
100

80
Changes (%)

60

40

20

–20
0 4 8 12 16 20 24 28 32 36 40
Pregnancy duration (weeks)

serum ferritin cardiac output plasma volume RBC volume

cross the placenta [23]. Despite haemodilution, mean corpus- markedly increased levels of plasminogen activator inhibitor-
cular volume (MCV) and mean corpuscular haemoglobin con- 1 (PAI-1) produced by endothelial cells can be seen, along with
centration (MCHC) remain on the same level. high levels of plasminogen activator inhibitor-2 (PAI-2), which
Most women begin their pregnancy with a total body iron is very seldom found in non-pregnant circulation but is pro-
amount of 2.5 g, requiring an additional net intake of at least duced in large quantities by the placenta. Thrombin-activated
1000 mg over the course of 40 weeks [16]. The amount of fibrinolysis inhibitor (TAFI) is reported to be unaffected by
400–500 mg is required to compensate for the increased red normal pregnancy [25].
cell volume, 350 mg for the transfer to the fetus and placenta, Platelet function remains normal during normal preg-
and 200 mg for the baseline maternal body iron loss. nancy. Although there is an increase in their production,
Serum ferritin level is proportional to body iron stores. the platelet count falls due to haemodilution, as well as due
During pregnancy, its level gradually decreases, reaching its to their increased activity and consumption particularly dur-
lowest level in the third trimester (Figure 2.1). ing the last trimester [26]. Production of thromboxane
The placenta retains about 90 mg of iron for its own func- A progressively increases during the second trimester and
tion, and transports 270 mg of iron on average to the fetus. can induce aggregation. Increased platelet consumption and
Maternal transferrin production steadily increases during their production also lead to a greater proportion of younger
pregnancy, with most of the transfer to the fetus occurring and larger platelets.
during the last trimester.
After being transported from syncytiotrophoblast by ferro- 2.2.7 Cardiovascular System
portin, iron is probably oxidized to the ferric form before being Multiple factors contribute to the overall alterations in mater-
loaded onto fetal transferrin. nal haemodynamic functions during pregnancy.
Pregnancy induces a hypercoagulable state. Plasma concen- Pregnancy is associated with vasodilation of the systemic
trations of fibrinogen; coagulation factors XII, X, VIII and VII; circulation as an effect of progesterone, prostaglandins and
and von Willebrand factor gradually increase, with an exception low-resistance uteroplacental circulation. Systemic vasodila-
being factors XI and XIII, the levels of which decrease. The most tion occurs as early as at 5 weeks’ gestation and precedes full
pronounced changes can be observed in the third trimester and placentation and complete development of the uteroplacental
are currently attributed to hormonal changes, especially circulation. Corpus luteum produces a peptide hormone
increased oestrogen levels, as the pregnancy progresses [25]. relaxin, which has an endothelium-dependent vasodilatory
Blood levels of coagulation inhibitors such as antithrom- role in pregnancy, and influences small arterial resistance
bin are unchanged, those of protein C are slightly increased or vessels.
unchanged, while protein C inhibitor as well as free and total A substantial decrease in peripheral vascular resistance
protein S levels are decreased. Low levels of protein S can be during the first trimester is continued to a nadir in
observed until at least 8 weeks postpartum. the second trimester, followed by a plateau or slight increase
Increase in fibrinolysis also occurs, and is reflected in in the last trimester [22].
increased concentrations of antithrombin III, plasminogen Due to vasodilation and subsequent decrease in peripheral
and fibrin degradation products. Inactive pro-enzyme plasmi- vascular resistance, blood pressure, including systolic, dia-
nogen levels increase during normal pregnancy due to its stolic, mean arterial and central systolic blood pressure, is
reduced utilization and increased production. Furthermore, decreased [27].
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 Basic Sciences in Obstetrics

Diastolic blood pressure and mean arterial pressure Increase in stroke volume is responsible for the early
decrease more than systolic blood pressure. Compared with increase in cardiac output. During pregnancy, stroke volume
pre-conception baseline values, arterial pressure drops increases gradually until the end of the second trimester and
5–10 mm Hg between 24 to 26 weeks’ gestation. Later on, then remains constant until shortly after delivery, or decreases
during the third trimester, it begins to increase and during slightly late in pregnancy. In the late third trimester, cardiac
postpartum period returns close to its pre-conception levels. output is primarily maintained by maternal tachycardia.
In the supine position, femoral venous pressure rises stea-
dily: from 8 mm Hg early in pregnancy to 24 mm Hg at term 2.2.8 Respiratory System
[12]. The elevated venous pressure can return to normal by the
Changes in the respiratory system may be categorized as ana-
woman lying on her left side.
tomical and physiological.
Blood stagnation in the legs during the last trimester results
Anatomical changes include mucosal oedema, hyperaemia
from occlusion of the pelvic veins and inferior vena cava by the
and capillary congestion from the upper airway to the pharynx,
enlarged uterus. Vena cava compression can also diminish
false cords, glottis and arytenoids. Decreased pharyngeal lumen
venous return and decrease stroke volume and cardiac output.
diameter and fragility of the upper airway commence in the first
Although most women do not become hypotensive, up to 8%
trimester and persist to the end of pregnancy. Symptoms of
of them do demonstrate occurrences of the supine hypotensive
rhinitis and nosebleeds commonly occur due to the effect of
syndrome, manifested by a sudden drop in blood pressure,
oestrogen.
bradycardia and syncope [22].
Thoracic subcostal angle increases by about 50% and is
The growing uterus displaces the heart to the left and
mediated by relaxin. As a result, chest diameter increases by
upwards and rotated on its long axis. Left atrium diameter
up to 2 cm and the thoracic circumference by about 6 cm.
and left ventricular end-diastolic diameter increase due to the
Increased progesterone levels mediate many of the physio-
increased preload. Although multiple cardiovascular para-
logical changes that occur in the respiratory system.
meters are altered during pregnancy, myocardial contractility
Progesterone relaxes bronchial and tracheal smooth muscle,
as well as left and right ventricular ejection fractions do not
and directly stimulates the respiratory centre of the medulla to
change.
increase respiratory drive (Figure 2.2).
Heart rate increases progressively throughout the course of
Minute ventilation increases by 30–50%, with the increase
pregnancy by 10–20 beats per minute (bpm), reaching
primarily due to an approximately 40% increase in tidal
a maximum in the third trimester. The overall change in
volume (Figure 2.2) [28].
heart rate represents a 20–25% increase above baseline.
Functional residual capacity decreases on average by 20%
Cardiac output increases during pregnancy (Figure
(300–500 mL) due to the elevated diaphragm and decreased
2.1). The sharpest rise in cardiac output occurs in the
chest wall compliance, which is not completely balanced by the
beginning of the first trimester, with further increase in
increase in the chest wall diameter.
the second trimester. By 24 weeks’ gestation, increase in
At the same time, a number of respiratory parameters do
cardiac output can be up by to 45% in a normal, singleton
not change during pregnancy. Total lung capacity, vital capa-
pregnancy [27]. In a twin pregnancy, cardiac output is
city, lung compliance and diffusion capacity remain unaffected.
higher still, with values approximately 15% higher than in
As a result of increased minute ventilation, maternal arter-
singleton pregnancies.
ial partial pressure of carbon dioxide (PaCO2) decreases to

80 Figure 2.2 Changes in respiratory rate, and

alveolar, tidal and minute ventilation during
70 pregnancy (adapted from [28]).

60
Changes (%)

50

40

30

20

10

0
0 4 8 12 16 20 24 28 32 36 40
Pregnancy duration (weeks)

alveolar ventilation minute ventilation tidal ventilation respiratory rate

14
 Maternal Physiology during Pregnancy, Including Immunology of Pregnancy

60 Figure 2.3 Changes in renal plasma flow (RPF)

and glomerular filtration rate (GFR) during
pregnancy (adapted from [30, 31]).
50

40
Changes (%)

30

20

10

0
0 4 8 12 16 20 24 28 32 36 40
Pregnancy duration (weeks)

RPF GFR

a level of 26–32 mm Hg. Alveolar oxygen tension increases, of the ureters. Hydronephrosis occurs in 43–100% of pregnant
with partial pressures of oxygen (PaO2) in arterial blood rising women, and is more prevalent during the last trimester [29].
as high as 106 mm Hg. Oxygen-carrying capacity also increases Progesterone can reduce ureteral tone, peristalsis and con-
as total haemoglobin amount increases, while the actual arterial traction pressure. The dilated system can hold approximately
oxygen content gets decreased by the expanded plasma volume. 200–300 mL of urine, leading to a possible urinary stasis and an
Therefore, oxygen delivery is maintained at normal levels in asymptomatic bacteriuria. The right ureter is more commonly
spite of cardiac output increase, and as such, a pregnant woman affected as a result of the angle at which it crosses the iliac and
is much more dependent on cardiac output for the maintenance ovarian vessels at its entry into the pelvic space. The elongated
of sufficient oxygen delivery than a non-pregnant woman [28]. ureters often form curves of various radii, with smaller curves
Hyperventilation facilitates the transfer of carbon dioxide possibly sharply angulated.
from the fetus to the mother and is partially compensated for Maternal hormones cause renal haemodynamic changes in
by an increased renal secretion of hydrogen ions. A mild pregnancy [30]. Renal plasma flow increases by up to 80% during
chronic respiratory alkalosis is therefore normal in pregnancy, the first trimester, followed by a plateau, and again decreases later
with an arterial pH of 7.44, compared to 7.40 in the non- during the last trimester of pregnancy (Figure 2.3) [31]. In the
pregnant state [22]. renal circulation itself, relaxin influences endothelin and nitric
At the same time, bicarbonate excretion by the kidneys oxide production. This leads to vasodilation and decreased renal
increases to compensate for the elevated pH. Thus, the meta- afferent and efferent arteriolar resistance.
bolic state of respiratory alkalosis is accompanied with Normal pregnancy is marked by an upregulation of the
a compensatory metabolic acidosis. renin-angiotensin-aldosterone system. Renin is released from
Dyspnoea affects up to 75% of pregnant women. This extra-renal sources, specifically the ovaries and decidua. The
physiological dyspnoea does not interfere with normal daily placenta produces oestrogen, which increases angiotensinogen
activities, and is not associated with exercise, cough, wheezing synthesis by the liver, leading to an increased angiotensin II
or other pulmonary symptoms. It typically begins in the first synthesis. Despite this upregulation, systolic blood pressure
or second trimester and often improves as the pregnancy decreases during pregnancy due to the presence of progester-
progresses. Respiratory rate (RR) increases slightly during one and its influence on vascular muscle relaxation [31].
pregnancy, raising the bar of what is to be considered abnormal Glomerular filtration rate (GFR) increases by 50% by the
tachypnoea to above 20 breaths per minute (Figure 2.2). beginning of the second trimester and persists until term, even
though renal plasma flow decreases during the last trimester
2.2.9 Urinary System (Figure 2.3). Increased kidney blood flow, decreased oncotic
Pregnancy affects the anatomy and physiology of the urinary pressure, and changes in glomerular ultrafiltration coefficient
system. (the product of surface area available for filtration and perme-
Anatomical changes involve kidneys with their pelvis and ability of the filtration membrane) are suggested to be respon-
calyceal systems, ureters and the bladder. Length of the kidneys sible for the increased GFR [29, 32].
increases by 1–1.5 cm during pregnancy, and decreases to its Changes in urinary excretion of different substances also
previous value over a period of 6 months postpartum. This occur. Urea and creatinine are excreted only by the means of
growth occurs primarily on account of increased vascular and glomerular filtration and as such, their serum levels are sig-
interstitial space, and secondarily due to mechanical obstruction nificantly reduced during pregnancy. Uric acid clearance can

15
 Basic Sciences in Obstetrics

decrease during the last trimester as a result of an increase in hyperpigmentation is very common in the area of genitals,
tubular reabsorption. A glomerulotubular imbalance leads to perineum, neck, axillae, inner thighs, periumbilical skin and
mild increases in excretion of vitamins and other nutrients, areolae. The skin above the midline of the abdomen, the linea
with proteinuria and aminoaciduria [12]. alba, becomes darkly pigmented to form the linea nigra, which
Glucose excretion increases 10- to 100-fold over its non- extends from the umbilicus to the symphysis pubis. Chloasma
pregnant values of about 100 mg/day. Glycosuria is present in gravidarum is less common and occurs as irregular brownish
about 40% of pregnant women, and occurs in spite of increased patches of various sizes on the face and neck.
plasma insulin and decreased plasma glucose levels. In non- Although aetiology of hyperpigmentation is not completely
pregnant individuals, approximately 5% of filtered glucose known, increased melanogenesis during pregnancy is thought
normally escapes reabsorption in proximal convoluted tubules, to be the result of increased levels of beta and alpha subunits of
but is later reabsorbed in the collecting tubules and loops of melanocyte-stimulating hormone, oestrogen, progesterone
Henle. In instances of glycosuria, this reabsorption is impaired and beta-endorphin. The added pigmentation often fades post-
[22]. partum; however, it is less likely to completely regress to the
pre-pregnancy state.
2.2.10 Gastrointestinal System Furthermore, striae gravidarum occur in up to 70% of
white women, less frequently in black or Asian women, dur-
Pregnancy brings anatomical and functional changes to the
ing the second and third trimesters of pregnancy. They are
gastrointestinal system.
linear atrophic pink-to-violet-coloured bands, most com-
Nausea, vomiting and dyspepsia affect the upper gastro-
monly appearing in the areas of maximum skin stretch,
intestinal tract during the first trimester. Later, the enlarging
such as the thighs, breasts and abdomen. They typically
uterus displaces the stomach and may anatomically alter the
regress to persistent flesh-coloured atrophic bands postpar-
pressure gradient between the abdomen and thorax. Increased
tum. The increase in corticosteroids, oestrogen and relaxin
pressure within the stomach promotes reflux of gastric con-
decreases adhesiveness between collagen fibres and promotes
tents into the oesophagus, which lies in the intrathoracic cavity
formation of ground substance of the extracellular matrix.
where pressures are negative relative to the abdomen [33].
Collagen and non-sulphated mucopolysaccharide content in
Additionally, lower oesophageal sphincter tone is decreased
the dermis are also increased. From a histological perspective,
due to increased progesterone levels, and symptoms of heart-
there is a rupture and retraction of elastic fibres within the
burn may as such increase nearing term.
reticular dermis [34].
Both progesterone and increased levels of enzyme histami-
nase, produced by the placenta, decrease gastric acid output.
This lowered acid secretion is coupled with increased protec- 2.3 Immunology of Pregnancy
tive gastric mucus secretion.
Motility of the stomach, small intestine and colon is 2.3.1 Allograft Paradigm
decreased. Gastric emptying is slower, and mean small bowel
First observations of the maternal immune system during
transit time significantly increases each trimester, in relation to
pregnancy defined fetus and placenta as semi-allografts (the
elevations in progesterone levels. Together with a concurrent
allograft paradigm). Under normal immunological condi-
decrease in colon motility, the process contributes to an
tions, the fetus should be recognized as foreign to the maternal
increased prevalence of symptoms of constipation in late preg-
immune system and as such rejected. Therefore, it was
nancy [33]. There is also a significant increase in water and
hypothesized that the fetus must somehow escape the maternal
sodium absorption secondary to the increased aldosterone
immune system altogether [35].
levels during pregnancy, leading to reduced stool volume,
In the 1990s, the allograft paradigm was redefined from
which contributes to prolonged colonic transit time.
maternal-fetal tolerance to maternal-placental tolerance,
Pregnancy affects biliary motility and cholesterol secretion.
focusing on the interaction between the maternal immune
Fasting volume and residual volume in the gallbladder are
system and the placenta rather than the fetus [36]. Cells from
increased, promoting bile stasis. Gallbladder emptying is also
external embryonic trophectoderm directly interact with uter-
impaired due to downregulation of contractile G protein
ine cells. Placental cells are thus able to avoid rejection by the
synthesis in gallbladder muscle cells, with stasis progressing
maternal immune system, and the fetus itself has no direct
during the first 20 weeks of pregnancy.
contact with maternal cells [37].
The maternal immune system interacts, at different stages
2.2.11 Skin and under different circumstances, with the invading tropho-
Skin changes represent an important part of physiological blast. This active mechanism prevents a maternal response
changes during pregnancy. They are very common and against paternal antigens, and the trophoblast and the mater-
include hyperpigmentation, hair and nail changes, vascular nal immune system can establish a cooperative status.
changes and shifts in apocrine and eccrine gland activity Moreover, interactions between the placenta and maternal
[34]. immune system create a pregnancy-supportive immunity
Up to 90% of pregnant women develop increased pigmen- environment while still being fully capable of defending the
tation, which is typically generalized and mild. This mother and fetus against pathogens [38].

16
 Maternal Physiology during Pregnancy, Including Immunology of Pregnancy

2.3.2 Mechanisms of Maternal Immune Response HLA-G and HLA-E class I molecules [22]. HLA-G antigen
expression is limited only to cytotrophoblast.
After redefining the allograft paradigm, maternal immune
According to the mechanism of local immune suppres-
response to trophoblast was explained through several
sion hypothesis, and the existence of several plausible potential
mechanisms:
mechanisms for immunological escape of the fetus, immune
– a mechanical barrier effect of the placenta, cells, which specifically recognize paternal alloantigens, are
– systemic suppression of the maternal immune system deleted from the maternal immune system. It is presumed
during pregnancy, that paternal-antigen-recognizing T cells may be deleted by
– a local and systemic cytokine shift from a Th1 to a Th2 profile, the induction of apoptosis by the Fas/Fas ligand system [22].
– the absence of ‘major histocompatibility complex class Most recently, a subpopulation of T regulatory cells was
I molecules’ on trophoblast cells, and described, which are able to suppress the actions of alloreactive
– local immune suppression mediated by the Fas/FasL system T cells to promote fetal-paternal immunotolerance.
[22].
The mechanism of a barrier effect of the placenta was challenged 2.3.3 Immune Cells
by the evidence of bidirectional trafficking across the maternal- Leukocytes act like independent, single-celled organisms and
fetal interface including migration of maternal cells into the fetus are an important part of the innate immune system. During the
and the presence of fetal cells in maternal circulation. first trimester, 70% of decidual leukocytes are natural killer
The idea of systemic suppression of maternal immune cells, 20–25% are macrophages and 1–2% are dendritic cells.
system during pregnancy was the conventional wisdom for All three cell types infiltrate the decidua and accumulate
a long time. This mechanism was widely studied, and from around the invading trophoblast [22].
an evolutionary point of view, early humans with suppressed Natural killer cells are critical for the development of the
immune system would find it very difficult to survive exposed placenta by regulating spiral artery formation and controlling
to numerous microorganisms and unsanitary conditions. the invasion of trophoblast into the endometrium [17]. Despite
Analogically, recent studies clearly demonstrate that maternal their close contact with trophoblast, they do not exert cytolytic
antiviral immunity is not affected by pregnancy [22]. function against trophoblast cells. They are major regulatory
A local and systemic cytokine shift from a Th1 to a Th2 profile cells, and differ from peripheral blood natural killer cells both
is characterized by a unique inflammatory environment. in phenotype and in function. They express activating recep-
The first trimester of pregnancy is a pro-inflammatory tors, but fail to produce the full range of cytokines, and do not
phase. Implantation, placentation and conceptual mass growth excrete vascular endothelial and placental growth factors [22].
in the first and early second trimester resemble an ‘open Macrophages are the predominant population of antigen-
wound’ that requires a strong inflammatory response [37]. presenting cells in the decidua. They are involved in a wide
The blastocyst has to first break through the epithelial lining range of activities including implantation, placental develop-
in order to implant itself, then damage the endometrial tissue ment and cervical ripening. At least two major subtypes of
to invade it and finally replace the endothelium and vascular macrophages have been characterized: M1 and M2. M1 macro-
smooth muscle of maternal blood vessels to secure itself an phages are under the influence of pro-inflammatory cytokines.
adequate placental-fetal blood supply. All these activities create They secrete tumour necrosis factor alpha (TNF-α) and inter-
a ‘battleground’ of invading, dying and reparatory cells [37]. leukin 12 (IL-12), and participate in the process of inflamma-
During the second immunological phase, the placenta, tion in response to microorganisms. M2 macrophages are
fetus and mother are in a symbiotic relationship, the predomi- involved in tissue repair and inhibition of inflammation.
nant immunological feature being induction of an anti- Appropriate removal of dying trophoblast cells prevents the
inflammatory state. release of paternal antigens that could trigger a maternal
The last immunological phase of pregnancy prepares the immune response against the fetus [22].
mother for delivery. Parturition is characterized by an influx of At the same time, trophoblastic factors can induce periph-
immune cells into the myometrium. The pro-inflammatory eral blood monocyte differentiation into macrophages, which
environment is achieved by renewed inflammation, which resemble those found in the decidua.
also promotes contraction of the uterus [37]. A specific subpopulation of T regulatory cells (CD4+/CD25+)
Human leukocyte class I antigens (HLA-A and HLA-B) is responsible for maintaining a normal immunological self-
cannot be detected on the surface of immunologically neutral tolerance by actively suppressing self-reactive lymphocytes.
villous cells, which are in contact with maternal blood at the These cells play a critical role also in preventing a maternal
intervillous interface. Immunologically active extravillous immune system response to fetal cells [22].
cells, however, which invade the decidua, can express HLA-C,

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4. Bhattacharyya S, Chaudhary J, Das C. 15. Trojner Bregar A, Lucovnik M, pregnancy. Circulation.

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Birk SA, McCreary SA. Control of 2010. 31. Cheung KL, Lafayette RA. Renal
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 Chapter
Developmental Abnormalities of the Reproductive

3 System and Their Relevance to Obstetric Practice

Parivakkam S. Arunakumari, Vennila Palaniappan & Richard Haines

3.1 Introduction Several classification systems have been in use, of which three
are popular: American Fertility Society / American Society for
3.1.1 Definition Reproductive Medicine (AFS/ASRM), Vagina Cervix Uterus
Adnex–associated Malformation (VCUAM) and European
Congenital malformations of the female genital tract are
Society of Human Reproduction and Embryology / European
defined as deviations from normal anatomy resulting from
Society for Gynaecological Endoscopy (ESHRE/ESGE).
embryological maldevelopment of the Mullerian (parameso-
nephric) ducts [1].
3.2.1 AFS/ASRM Classification
The AFS/ASRM classification based on Buttram and Gibbons
3.1.2 Background is still in widespread use [6, 7]. This subdivides uterine mal-
Developmental abnormalities of the reproductive tract span formations into seven major classes. This classification system
a wide anatomical spectrum, ranging from the almost imper- groups anomalies with similar clinical manifestations, treat-
ceptible arcuate uterus to the distinctly obvious imperforate ment modalities and prognosis for reproductive performance.
hymen. This diversity also extends to the clinical spectrum,
ranging from abnormalities which are incidentally diagnosed, 3.2.2 VCUAM Classification
as in uterus didelphys, to those associated with classic clinical
The VCUAM classification system is based on the Tumour
presentations, as in Mullerian agenesis.
Node Metastases principle in Oncology [8]. It is intended to
focus on the anomalies (e.g. vaginal) not addressed in the
3.1.3 Prevalence ASRM classification.
True prevalence is often difficult to ascertain due to differences in
diagnostic data acquisition and varied patient populations. Their 3.2.3 ESHRE/ESGE Classification
prevalence in the general female population is thought to be The ESHRE/ESGE classification is a new, updated and more
4–7% and up to 15% in women with recurrent pregnancy loss systematic system now known as CONUTA – CONgenital
[1–3]. UTerine Anomalies [1, 2]. This system provides a comprehen-
sive description and categorization of almost all of the cur-
3.1.4 Causes rently known genital tract anomalies (Figure 3.1).
Several cellular processes are involved in the development of The general characteristics of this classification system
the normal female reproductive system: cellular division, dif- include the following:
ferentiation, duct elongation, fusion, resorption, canalization • Anatomy is the basis for the systematic categorization of
and apoptosis [4]. Disruption of any of these complex and anomalies.
intricately linked processes may result in Mullerian duct • Deviations of uterine anatomy deriving from the same embryo-
anomalies. logical defect are the basis for the design of the main classes.
• The basis for the main subclasses is the anatomical
3.1.5 Genetics variations expressing different degrees of uterine deformity
Mullerian duct anomalies may result from genetic mutation – and sharing similar clinical significance.
often sporadic, but can be inherited, developmental defects or • Cervical and/or vaginal anomalies are classified in
environmental insults that operate at critical stages of embryo- independent supplementary subclasses.
nic development. Most Mullerian anomalies are of multifac- • Absolute numbers are not used, in contrast to the ASRM
torial inheritance rather than single gene disorders [5]. system. For example, uterine deformity is defined as
a proportion of the uterine anatomy to allow for the wide
3.2 Classification interindividual variations in reproductive physiology.
A classification system serves as a framework for description of
anomalies, for categorization of diagnosis, communication 3.3 Uterine Anomalies
between professionals, comparison between treatment modal- As the uterus is the key organ for the design of the ESHRE
ities and effective standardization of conditions. classes, this will be dealt with first.
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 Basic Sciences in Obstetrics

Class U0/Normal uterus Class U1/Dysmorphic Uterus

a. T-shaped b. Infantilis c. Others

Class U2/Septate uterus Class U3/Bicorporeal Uterus

<50% <50%

>50%
>50%

>150%

a. Partial b. Complete a. Partial b. Complete c. Bicorporeal septate

Class U4/Hemi Uterus Class U5/Aplastic Uterus

a. With rudimentary cavity b. Without rudimentary cavity a. With rudimentary cavity a. Without rudimentary cavity

Class U6/Unclassified Cases

Figure 3.1 ESHRE/ESGE classification of uterine anomalies

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 Developmental Abnormalities of the Reproductive System and Their Relevance to Obstetric Practice

3.3.1 Class U0 – Normal Uterus 3.3.5 Class U1c – Arcuate Uterus

Class U0 incorporates all cases with normal uterus. A normal This class includes all minor deformities of the uterine cavity
uterus is defined as a uterus with a straight or curved inter- including those with an inner indentation at the fundal midline
ostial line, but with an internal indentation at the fundal level of <50% of the uterine wall thickness.
midline not exceeding 50% of the uterine wall thickness. ASRM defines arcuate uterus as a uterus where the
The existence of this normal category gives the opportunity depth from interostial line to the apex of the indentation
to independently classify cervical and/or vaginal congenital is less than 1 cm and the angle of the indentation is >90°
malformations [1]. [11]. Developmentally, the arcuate uterus can be consid-
ered to be at the minor end of the spectrum of failure of
3.3.2 Class U1 – Dysmorphic Uterus Mullerian absorption; it is typically considered a normal
variant and therefore functionally not part of the septate
This class incorporates patients with normal uterine external
spectrum [12].
outline but with an abnormal shape of the uterine cavity
The arcuate uterus has an external, normal-appearing fun-
excluding septa.
dus and a small, smooth indentation at the top of the endo-
Class U1 is further subdivided in to three categories: these
metrial cavity.
anomalies were included in class VII of the AFS classifica-
Arcuate uterus is given a separate category in the AFS
tion – mainly related to diethylstilboesterol (DES) exposure
classification as, in contrast to other uterine malformations,
[7].
the arcuate uterus does not cause adverse clinical outcomes.
3.3.3 Class U1a – T-Shaped Uterus The angle of indentation at the fundal midline to the fundal
myometrium is described as obtuse, to differentiate the acute
This class is characterized by a narrow uterine cavity due to angle of indentation seen with a septate uterus.
thickened lateral walls with a correlation of two thirds uterine The CONUTA classification system does not explicitly
corpus and one third cervix. mention this, but includes the arcuate uterus as a new
In a T-shaped uterus, the endometrial cavity is T-shaped subcategory under the general term ‘others’ in Class 1/
rather than triangular. It is more common in women exposed in Dysmorphic Uterus, which includes all minor deformities
utero to DES and is associated with an increased risk of inferti- of the endometrial cavity including midline indentations
lity, recurrent miscarriage and preterm labour and delivery [4]. of less than 50% of uterine wall thickness. This is to
ensure that septate uterus with a midline indentation of
3.3.3.1 Ultrasound Findings more than 50% of uterine wall thickness remains a sepa-
The exact shape of the endometrial cavity is usually not dis- rate category.
cernible on a standard two-dimensional (2D) ultrasound. The ASRM also take the view that ‘the arcuate uterus should be
coronal view of the uterus, usually reconstructed from a three- differentiated from septate uterus for the purposes of prog-
dimensional (3D) volume ultrasound, is necessary to evaluate nosis and surgical management’.
this. A normal uterine cavity is triangular or V-shaped, with Overall, the arcuate uterus represents a variant of a normal
the three apices being the two cornua and the junction of the rather than a Mullerian anomaly [13]. It is often an incidental
lower uterine segment and the cervix (level of internal os). finding with no appreciable impact on fertility and pregnancy
When the uterus is T-shaped, there is a waist in the sides of [14]. Adverse pregnancy outcomes are rare and surgical cor-
the triangle such that the corpus of the endometrial cavity is rection is not warranted.
narrowed and takes on the shape of a T rather than a V. The
outer myometrial surface of the uterus (the serosal surface) is
typically unaffected [9].
3.3.6 Septate Uterus: Class U2
3.3.6.1 Definition
3.3.4 Class U1b – Uterus Infantilis Septate uterus is defined as uterus with normal fundal outline
This class is characterized by a narrow uterine cavity without and an internal indentation at the fundus in the midline
lateral wall thickening and an inverse correlation of one third exceeding 50% of the uterine wall thickness [1].
uterine corpus and two thirds uterine cervix.
By compromising the anatomical integrity of the uterine 3.3.6.2 Classification
cavity, this class of congenital anomalies of the uterus is impli- Class U2 is further subdivided in to two subclasses based on the
cated in infertility and pregnancy loss, as they are known to degree of the uterine cavity deformity:
interfere with normal implantation and placentation. Usually
dysmorphic uteri are smaller in size [1]. Class U2 a – partial septate uterus is characterized by the
Early data from the Hysteroscopic Outpatient Metroplasty existence of a septum dividing the uterine cavity partly above
to Expand Dysmorphic Uteri (HOME-DU) technique, wherein the level of the internal cervical os.
incisions are made on the uterine walls with a 5 Fr bipolar Class U2 b – complete septate uterus is characterized by the
electrode, indicate that this a safe and effective technique to existence of a septum fully dividing the uterine cavity up to
expand uterine volume [10]. the level of the internal cervical os.

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 Basic Sciences in Obstetrics

A complete septate uterus may extend into a duplicated summary statement on diagnosis with imaging modalities con-
cervix (bicervical septate uterus) or may continue thorough the cludes: ‘There is fair evidence that 3D ultrasound, sonohyster-
cervix. The bicervical septate uterus must be distinguished ography and MRI [magnetic resonance imaging] are good
from uterus didelphys, wherein the two uteri are separated diagnostic tests for distinguishing a septate and a bicornuate
externally. Both of these anomalies are typically associated uterus when compared with laparoscopy and hysteroscopy.
with a longitudinal vaginal septum. (Grade B).’
ASRM define a septate uterus as that where the depth from Hysteroscopic assessment is conclusive in establishing the
the interostial line to the apex of the internal fundal indentation diagnosis by visualizing a vertical pillar of tissue extending in
at the midline exceeds >1.5 cm and the angle of indentation is between the anterior and posterior uterine walls dividing the
<90° [11]. uterine cavity into two.
ASRM recommend: ‘Imaging or Imaging with Hysteroscopy
3.3.6.3 Prevalence should be used to diagnose uterine septa rather than Laparoscopy
This is the most common of all the Mullerian anomalies, with Hysteroscopy because this approach is less invasive.’
accounting for over 50% [4]. The true prevalence is difficult Routine evaluation of the renal system is not necessary in
to ascertain as many septa are often asymptomatic, but appear patients with uterine septum, as this is an absorption and not
to range between 1 to 2 per 1000 to 15 per 1000 females [11]. a formation defect.

3.3.6.4 Pathogenesis 3.3.6.7 Obstetric Significance

A septate uterus results from the normal fusion of the two It is important to note that many women with uterine septa do
Mullerian ducts but with abnormal absorption or incomplete not experience any reproductive difficulties.
resorption of the midline septum, prior to 20th embryogenic Septate uterus is generally not thought to increase the rate of
week. preterm labour or caesarean section but is associated with the
The histological structure of the septa ranges from fibrous highest risk of spontaneous miscarriage of all Mullerian anomalies
to fibromuscular tissue. The blood supply to the septum is [14]. However, the ASRM guideline on uterine septum sum-
often markedly reduced compared to that of the normal myo- marizes as follows: ‘There is fair evidence that a uterine septum
metrium. Septal implantation with consequent impaired contributes to miscarriage and preterm birth (Grade B)’ [11, 16].
embryo growth may well explain the pregnancy loss. Early pregnancy loss is significantly more common in sep-
Distortion of the endometrial cavity and associated cervical tate uterus than a bicornuate uterus. The rate of spontaneous
and endometrial abnormalities are also thought to contribute pregnancy loss under 20 weeks is 70% for bicornuate uterus
to their poor reproductive performance. and 88% for septate uterus [6].
Septate uterus can also be associated with intrauterine fetal
3.3.6.5 Clinical Presentation malformation due to its mechanical effect. ASRM summary
ASRM summarize the common clinical presentation in their statement: ‘Some evidence suggests that a uterine septum may
statement: ‘Most women with a septate uterus have efficient increase the risk of other adverse pregnancy outcomes such as
reproductive function.’ malpresentation, intrauterine growth restriction, placental
NICE guidance on hysteroscopic metroplasty of a uterine abruption and perinatal mortality (Grade B).’
septum for recurrent miscarriage states: ‘Uterine septa is more
common in women with infertility and in women with 3.3.6.8 Treatment
repeated miscarriage, and may therefore be one cause of this ASRM recommend: ‘In a patient with infertility, prior preg-
problem.’ nancy loss or poor obstetric outcomes it is reasonable to con-
In a meta-analysis of the effect of congenital uterine sider uterine septum incision’ (Grade C), although ‘there is
anomalies on reproductive outcomes, it was evident that sep- insufficient evidence to recommend a specific method for hys-
tate uterus was the only anomaly that was associated with teroscopic septum incision’. ‘Commonly used techniques to
a significant decrease in the probability of natural conception resect uterine septum include incision or removal of the septum
when compared with controls (Relative Risk 0.86, 95% utilizing cold scissors, unipolar or bipolar cautery or laser.’
Confidence Interval 0.77–0.96) [15]. Abdominal metroplasty (surgical removal of the septum) for
septate uterus is now superseded by hysteroscopic resection [17].
3.3.6.6 Investigation Compared to the abdominal approach, hysteroscopic resection
Hysterosalpingography (HSG) and ultrasound may be sugges- reduces the risk of pelvic adhesions, accelerates postoperative
tive of the diagnosis. Although 2D ultrasound scan can identify convalescence and obviates the mandate for caesarean section.
the two uterine cavities, it is usually not possible to differenti- Hysteroscopic metroplasty is advocated in women with
ate between the septate and bicornuate uterus because the a septate uterus and recurrent second trimester pregnancy loss
outer myometrial contour cannot be visualized in traditional [18]. The septum is excised until the cavity achieves a normal
sonographic planes. internal contour. Live birth rates were found to increase from
In the coronal planes, 3D ultrasound images can be used to 3% to 80% after surgery whilst the miscarriage rates reduce from
measure the intercornual distance, the length of the septum 88% to 14% [19]. The operative hysteroscopy can be supplemented
and the depth of the external fundal indentation. ASRM’s with laparoscopic surveillance or ultrasound guidance.

22
 Developmental Abnormalities of the Reproductive System and Their Relevance to Obstetric Practice

NICE recommends: Table 3.1 Clinical presentation

1.1 Current evidence on the safety of hysteroscopic metro- Clinical Bicornuate Uterus
plasty of a uterine septum for recurrent miscarriage includes presentation uterus didelphys
some serious but rare complications. Current evidence on Miscarriage rate 36% 32%
efficacy is adequate to support the use of this procedure pro-
vided that normal arrangements are in place for clinical gov- Preterm labour 23% 16%
ernance, consent and audit. Term deliveries 40% 45%
1.2 Patient selection and treatment should be done by
a multidisciplinary team including specialists in reproductive
medicine, uterine imaging and hysteroscopic surgery. 3.3.7.5 Clinical Presentation
1.3 Clinicians undertaking hysteroscopic metroplasty of See Table 3.1 for a summation of clinical presentations [20].
a uterine septum for recurrent miscarriage should be trained in
hysteroscopic surgery in accordance with the Royal College of 3.3.7.6 Investigation
Obstetricians and Gynaecologists training module. On 3D transvaginal sonography (TVS) and MRI imaging, the
NICE guidance on hysteroscopic metroplasty of uterine fundal contour of the uterus is noted to have a ‘cleft’ of >1 cm
septum for primary infertility states: ‘Current evidence on separating the two divergent but typically equal fundal endo-
efficacy is inadequate in quantity and quality. Therefore, this metrial horns with an endometrial indentation by ASRM cri-
procedure should only be used with special arrangements for teria of >1.5 cm [21].
clinical governance, consent and audit or research.’ Diagnostic differentiation between a septate and a bicor-
nuate uterus cannot be accomplished by hysteroscopy or HSG
3.3.7 Bicornuate Uterus – Class U3 alone. At laparoscopy, the broad (intercornual distance of
wider than 4 cm) and indented fundus with the typical heart-
3.3.7.1 Definition shaped configuration can be observed.
A bicorporeal uterus is defined by ESHRE/ESGE as a uterus
3.3.7.7 Obstetric Significance
with an abnormal fundal outline. It is characterized by the
presence of an external indentation at the fundal midline The reproductive outcomes of a bicornuate uterus are in gen-
exceeding 50% of the uterine wall thickness. eral better than that of a unicornuate uterus but worse than
uterus didelphys [22]. Uterine dysfunction is thought to occur
3.3.7.2 Classification due to reduced cavity size, impaired ability to distend, abnor-
Class U3 is further subdivided into three subclasses based on mal myometrial and cervical functioning, inadequate vascular-
the degree of uterine corpus deformity: ity and abnormal endometrial development.
Bicornuate uterus has been implicated in miscarriage, pre-
Class U3a: Partial bicorporeal uterus characterized by an term labour, malpresentation and low fetal survival rates.
external fundal indentation partly dividing the uterine The high rate of preterm labour in bicornuate uteri (20%
corpus above the level of the cervix. with partial and 66% with complete bicornuate uterus) [23]
Class U3b: Complete bicorporeal uterus characterized by an has led to bicornuate uterus being proposed as an indepen-
external fundal indentation completely dividing the uterine dent risk factor for cervical os insufficiency. As this has not
corpus up to the level of the cervix. been validated, however, cervical cerclage can only be recom-
mended in patients with demonstrable evidence of cervical
Class U3c: Bicorporeal septate uterus characterized by the
incompetence.
presence of an absorption defect in addition to the main
fusion defect. Here the width of the midline fundal 3.3.7.8 Treatment
indentation exceeds by 150% the uterine wall thickness. As The bicornuate uterus may require a unification procedure to
with any other class, these patients could have coexistent enhance the size of the uterine cavity if poor reproductive
cervical and/or vaginal defects. outcomes have been demonstrated [24]. Surgical reconstruc-
tion of the bicornuate uterus has been proposed in women
3.3.7.3 Prevalence with recurrent miscarriage and/or preterm labour.
Bicornuate uterus accounts of 10–20% of all Mullerian anoma- Strassman’s technique involves a wedge-shaped incision
lies [4]. through the body and the fundus of the uterus to include
the myometrium in the midline. The two cavities are then
3.3.7.4 Pathogenesis joined to form a single cavity by layered closure of the uterine
A bicornuate uterus is caused by the incomplete lateral fusion wall in the vertical plane. Although traditionally undertaken
of the two Mullerian ducts. There is normal fusion at the by open laparotomy, this is increasingly being done by the
inferior portion but incomplete fusion at the superior portion laparoscopic method.
of the caudal vertical part of the Mullerian ducts. Typically, Post-surgery reproductive outcomes have been generally
there are two separate but communicating endometrial cavities good with a live birth rate of 85%. Delivery is by caesarean section
and a single uterine cervix. following metroplasty to avoid risk of uterine rupture in labour.
23
 Basic Sciences in Obstetrics

3.3.8 Uterus Didelphys 3.3.9.4 Treatment

Where the hemivagina is obstructed by an oblique or trans-
3.3.8.1 Prevalence verse vaginal septum, surgical resection of the wall of the
Uterus didelphys accounts for approximately 11% of all the obstructed hemivagina is necessary to relieve the obstruction
Mullerian anomalies. and to allow free drainage of menstrual flow.

3.3.8.2 Pathogenesis 3.3.10 Unicornuate Uterus – Class U4

Uterus didelphys results when there is failed fusion of the
paired Mullerian ducts. It is characterized by the presence of 3.3.10.1 Definition
two non-communicating endometrial cavities, each with a Hemi-uterus is defined as unilateral uterine development. The
uterine cervix. There is no obstructive element in this contralateral part could be either incompletely formed or
Mullerian anomaly. absent.
Seventy-five per cent of these patients also have a long-
itudinal vaginal septum. 3.3.10.2 Classification
Class U4 incorporates all cases of unilaterally formed uterus.
3.3.8.3 Diagnosis This is a different class to that of the aplastic uterus due to the
Ultrasonography (USG), 3D and MRI imaging all provide ade- existence of a fully developed functional uterine hemicavity.
quate information on the existence of the two endometrial cav- Class U4 is further subdivided in to two subclasses depend-
ities, two cervices and two fundal contours. Hysterosalpingogram ing on the presence or absence of a functional rudimentary
may exclude the communication between the two endometrial cavity:
cavities.
Class U4a: Hemi-uterus with a rudimentary functional
3.3.8.4 Obstetric Significance cavity characterized by the presence of a communicating or
The specific miscarriage rate for uterus didelphys is not non-communicating functional contralateral horn.
dissimilar to women with normal uterine cavities. Thus, Class U4b: Hemi-uterus without rudimentary functional cavity
surgery is rarely indicated. Of all the major uterine mal- characterized either by the presence of non-functional
formations, uterus didelphys has the best reproductive contralateral uterine horn or by aplasia of the contralateral
prognosis. part.

3.3.9 OHVIRA 3.3.10.3 Prevalence

There is a prevalence of 0.1% in the general population.
3.3.9.1 Definition
OHVIRA (obstructed hemivagina with ipsilateral renal agen- 3.3.10.4 Pathogenesis
esis) is a combination of uterine anomalies (uterus didelphys Arrested or defective development of only one of the Mullerian
or septate uterus) associated with a hemivagina and ipsilateral ducts results in a unicornuate uterus – this is a formation defect.
renal anomalies. Sixty-five per cent of unicornuate uteri have an associated
Herlyn–Werner–Wunderlich syndrome is a constellation uterine horn. Two thirds of rudimentary horns are non-
of uterus didelphys and obstructed hemivagina with ipsilateral communicating.
renal anomalies. Thirty to forty per cent of unicornuate uteri are associated
with renal anomalies.
3.3.9.2 Clinical Features
The classic presentation is progressively worsening severe dys- 3.3.10.5 Clinical Presentation
menorrhoea not responsive to nonsteroidal anti-inflammatory Unicornuate uterus is often asymptomatic and discovered
drugs (NSAIDs) against the background of regular, cyclical during the course of an infertility evaluation.
periods from the non-obstructed tract. On bimanual examina- Women with unicornuate uterus have an increased inci-
tion, a mass is felt bulging from the lateral wall of the vagina dence of infertility, endometriosis and dysmenorrhoea from
towards the midline. retrograde menstruation.
Cyclical abdominal pain / pelvic pain can occur when
3.3.9.3 Diagnosis the hemi-uterus has a non-communicating rudimentary
Ultrasound is invaluable in providing information on the anat- horn due to obstruction to the menstrual outflow.
omy of both the genital and urinary tracts. It is important to be However, there is no pelvic mass, as there is no distension
aware of the potentially confusing picture on ultrasound of the of the upper vagina.
obstructed haematocolpos which will be found below the non- Unicornuate uterus should be suspected in women with
obstructed cervix. The non-obstructed cervix may not be seen poor reproductive performance.
or felt if the vagina is greatly distorted from its contralateral On bimanual examination the uterus is often markedly
obstruction. deviated to one side.

24
 Developmental Abnormalities of the Reproductive System and Their Relevance to Obstetric Practice

3.3.10.6 Investigation Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome,

Unicornuate uterus can be suspected on 2D ultrasound with also known as Mullerian agenesis, is one of the most common
a small uterine volume and presence of a single tubal ostium. disorders of sexual development with an incidence is 1 in 4500
Three-dimensional ultrasound or MRI is invaluable in to 5000 female births [5].
identifying rudimentary horn and in particular determining
3.3.11.3 Types of MRKH Syndrome
the presence / absence of a cavity and/or functional endome-
trial tissue. HSG typically shows a banana-shaped uterine cav- The MRKH syndrome exists as three types:
ity with a single tube. Typical MRKH with no other genital malformation = 55% of
Laparoscopy is not necessary to confirm the diagnosis, but cases
is essential to remove the obstructed non-communicating
rudimentary uterine horn and diagnosis and management of Atypical associated with urinary tract malformation = 26%
associated endometriosis. MURCS (Mullerian aplasia, renal aplasia and
cervicothoracic somite dysplasia) associated with urinary
3.3.10.7 Obstetric Significance and skeletal abnormalities = 13% [5]
There is a significant impairment of the reproductive perfor-
mance of the unicornuate uterus with the fetal survival rate of
3.3.11.4 Pathogenesis
about 29%. Compromised myometrial function and reduced
endometrial capacity do not allow adequate gestational Arrested development of the Mullerian ducts and their failed
growth. Further, congenital alterations in the uterine artery fusion leads to the MRKH syndrome. The ovaries are spared
blood flow are also thought to mediate the uterine and placen- and develop normally in MRKH syndrome due to their sepa-
tal growth disturbances. rate embryological non-Mullerian origin.

3.3.10.8 Treatment 3.3.11.5 Clinical Presentation

Pregnancy in the rudimentary horn is not compatible with term Typical presentation of MRKH syndrome is primary amenor-
gestation. Rupture tends to occur at a later gestation (prior to 20 rhoea, defined as absence of menstruation in normally developed
weeks) than with ectopic pregnancy, and the intraperitoneal hae- 13- to 14-year-old girls. In 2–7% of patients with Mullerian agen-
morrhage tends to be severe. The risk of serious maternal morbid- esis, cyclical recurrent lower abdominal pain develops due to active
ity justifies the need for excision of the cavitary rudimentary horn. endometrium in the rudimentary uterine bulbs.
This is often logically combined with a salpingectomy on the same Physical examination reveals a normal vulva, except that the
side of the rudimentary horn to prevent ectopic pregnancy. area where the vaginal introitus should be shows no opening.
However, if the rudimentary horn is non-cavitary, routine laparo- A small dimple or a short vagina may be seen. A rectal
scopic excision cannot be justified. examination may be helpful to ascertain the presence of mid-
The presence of a functional cavity in the contralateral horn line structures – uterus, cervix and vagina.
is the factor with the greatest clinical relevance, due to com-
plications such as haematocavity and ectopic pregnancy in the 3.3.11.6 Clinical Features
rudimentary horn. In this situation, laparoscopic excision is The classical clinical features are the following:
recommended even if the horn is communicating. 1. Absence of functioning uterus. However, 90% of patients
have rudimentary uterine bulb without endometrial
3.3.11 Class U5 – MRKH activity.
2. Short or absent vagina: shallow vaginal pouch only about
3.3.11.1 Introduction 2 cm deep.
Class U5 or aplastic uterus incorporates all cases of uterine 3. Normal secondary sexual characteristics.
aplasia. 4. Normal appearance of external genitalia except for absent
It is a formation defect characterized by the absence of any vaginal introitus.
fully or unilaterally developed uterine cavity. 5. Normal ovarian function (normal gonatotropins, normal
This group belongs to class I of the AFS classification. serum oestrogen and testosterone levels).
6. Normal female karyotype: 46XX.
3.3.11.2 Classification
Class U5 is further subdivided into two subclasses depending
3.3.11.7 Investigations
on the presence or absence of a functional cavity in an existent
rudimentary horn: A transabdominal or transrectal ultrasound of the abdomen
and pelvis will help to confirm the absence of uterus. It should
Class U5a: Aplastic uterus with a rudimentary cavity in be acknowledged the ultrasound scan may not confidently pick
a unilateral or bilateral functional horn. up the rudimentary horn. The difficulty in identifying a small
Class U5b: Aplastic uterus without rudimentary cavity uterus on ultrasound should not be underestimated.
characterized either by the presence of uterine remnants or Three-dimensional ultrasound or MRI may be helpful to
by complete uterine aplasia. identify functional endometrium in rudimentary uterine
25
 Basic Sciences in Obstetrics

bulbs. Assessment of the renal and urinary tracts should not be absorbable sutures for both skin layers rather than the chromic
overlooked. catgut used in Williams technique. A further layer of sutures is
Laparoscopy is not necessary for the diagnosis of Mullerian used to approximate the subcutaneous fat and perineal mus-
agenesis, but may be indicated for the treatment of associated cles. This is a simple, quick and effective method for the
endometriosis or for the excision of rudimentary uterine horns. treatment of vaginal agenesis with a success rate of about 90%.
Techniques involving the use of human amnion, perito-
3.3.11.8 Treatment neum, ileum, sigmoid, buccal mucosa and artificial dermis as
Management of MRKH involves attention to three aspects: neovaginal linings have been described, but are not in main-
psychological, sexual and reproductive. stream use.
Care is best delivered through a multidisciplinary team (MDT) The Vecchietti procedure involves a flexiglass olive placed
consisting of paediatric and adolescent gynaecologist, nurse spe- in the vaginal dimple, with two sutures placed through the
cialist, psychologist, fertility specialist and radiologist. olive being brought out through the potential neovaginal
space, through the pelvic cavity and out through the abdominal
Psychosexual wall. The sutures are progressively tightened to rapidly create
The diagnosis of MRKH can be devastating to both the patient the neovaginal space over 1 week.
and her parents. It is important that the healthcare team The Davydov method uses the pelvic peritoneum to create
acknowledges this and offers adequate ongoing support. The a functioning vagina laparoscopically.
prospect of not having a vagina and no reproductive ability can Where the presence of rudimentary uterine bulbs become
be profoundly distressing. Psychological support is strongly symptomatic, laparoscopic excision of these is often required.
recommended from the time of diagnosis and should precede
all other treatments. 3.3.11.9 Obstetric Significance
Counselling groups of patients rather than individual Patients with MRKH syndrome have no functioning uterine
counselling may help dispel the feeling of ‘being like a freak’. tissue and therefore traditional conception is impossible.
Option for motherhood is restricted to gestational surrogacy
Neovagina Creation (which involves oocyte retrieval, in vitro fertilization (IVF) and
The timing of treatment is determined by the patient in con- blastocyst implantation in a surrogate mother) or adoption.
junction with her sexual partner, family and the MDT following Uterine transplantation is currently in the research phase
thorough counselling. Strong motivation and a positive attitude but holds potential to become a mainstream operation with
are prerequisites for success. Neovagina creation can be non- five live births being currently reported [26].
surgical through vaginal dilators or through surgical procedures.

Nonsurgical Method
3.4 Cervical Anomalies
Cervical anomalies often occur along with uterine and/or
The ACOG recommends nonsurgical vaginal dilators as first
vaginal anomalies and very rarely in isolation.
choice as it is simple, safe, effective and patient driven with
The ESHRE/ESGE subclasses are as below:
a success rate of about 85% [25].
The technique (Frank method) involves the use of glass, Subclass C0: Normal cervix – incorporates all cases of
Perspex, plastic or silicon vaginal dilators to exert continuous normal cervical development.
pressure against the vaginal dimple towards the sacrum to Subclass C1: Septate cervix – incorporates all cases of cervical
progressively invaginate the vaginal dimple to create a canal absorption defects, characterized by the presence of a normal
of ‘adequate’ size of about 6 cm. This is done for about 20–60 externally rounded cervix with the presence of a septum.
minutes per day. It takes between 2 months and 2 years to
create a functional vagina, depending on patient motivation Subclass C2: Double cervix – incorporates all cases of
and frequency of dilation. The Ingram modification involves cervical fusion defects. It is characterized by the presence of
the use of a bicycle seat mounted on a stool with the dilator on two externally rounded cervices, which could be either fully
the saddle of the bicycle seat, on which the patient sits astride. divided or partially fused.
Subclass C3: Unilateral cervical aplasia – incorporates all
Surgery cases of unilateral cervical formation. It is characterized by
Vaginoplasty can be offered if vaginal dilator therapy fails, but unilateral cervical development: the contralateral part is
only after the patient consents and commits to regular, fre- incompletely formed or absent.
quent and scheduled postoperative dilation, as all the surgical
Subclass C4: Cervical aplasia – incorporates all cases of complete
procedures require ongoing vaginal dilators to avoid vaginal
cervical aplasia and those with severe cervical formation defects.
stricture.
It is characterized by the absolute absence of any cervical tissue
McIndoe’s vaginoplasty uses a split-thickness skin graft
or the presence of severely defective cervical tissue such as
taken from the buttock to line the surgically created space.
cervical cord or cervical fragmentation.
Williams vulvovaginoplasty involves the creation of
a neovagina space between the urethra, bladder and rectum. Of these, only cervical aplasia has significant clinical and
A modification of Williams technique involves the use of obstetric significance – hence it is discussed below.
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 Developmental Abnormalities of the Reproductive System and Their Relevance to Obstetric Practice

3.4.1 Cervical Agenesis 3.5.1 Transverse Vaginal Septum (TVS)

3.4.1.1 Definition 3.5.1.1 Prevalence
Cervical aplasia is a very rare condition in which a functional TVS is a rare congenital anomaly with an incidence of 1 in
uterus exists without a cervix causing outflow obstruction. 20 000 females.

3.4.1.2 Pathogenesis 3.5.1.2 Pathogenesis

Typically, the upper vagina is also not developed due to com- TVS is a vertical fusion defect that results from the failure of the
mon embryological origin of both the cervix and the upper sinovaginal bulbs (from the urogenital sinus) and uterovaginal
vagina from the Mullerian duct. There is usually a single mid- canal (from the Mullerian ducts) to meet or canalize. TVS can be
line uterus, although hemi-uterus or septate uterus have also located in three levels – low, middle, high – in the vagina.
been described. Rock et al described 46% of the TVS to be in the upper
vagina, 40% in the middle and 14% in the lower third of the
3.4.1.3 Presentation vagina. The thickness of the septum is also variable, ranging
Typical presentation is usually with primary amenorrhoea, from 1 cm to 6 cm. In contrast to other Mullerian anomalies,
cyclical abdominal pain or pelvic pain and/or distended TVS is often not associated with urological anomalies [24].
uterus – typical of an obstructed anomaly. Endometriosis is
3.5.1.3 Clinical Presentation
common due to retrograde menstruation incumbent on the
obstruction. TVS can present as mucocolpos in a neonate or infant.
Adolescent girls can present with gradually worsening
3.4.1.4 Investigation cyclical abdominal pain and primary amenorrhoea with slowly
Diagnosis is by 2D or 3D ultrasound or MRI, which confirms expanding central pelvic mass. The higher the septum is, the
the presence of a uterine corpus and an absence of the uterine shorter the time from menarche to presentation due to reduced
cervix. capacity of the small upper vagina. Endometriosis often devel-
ops, causing chronic pelvic pain.
3.4.1.5 Treatment Examination often reveals a normal vulva and external gen-
Traditionally, hysterectomy with removal of the obstructed uterus italia. The higher the septum is, the more the lower part of the
has been recommended, as attempts at surgical reconstruction of vagina has formed and therefore more likely that the high TVS
the cervix have not been successful. The creation of a uterovaginal will be missed. The low TVS can be often be seen beyond the
fistulous tract has been attempted despite the serious risk of introitus. This differs from an imperforate hymen in that the
ascending infection with sepsis. Successful pregnancies have membrane of the TVS is thicker and does not transilluminate.
been achieved with ZIFT (zygote intrafallopian transfer) following A rectal examination may be helpful to palpate the midline
these surgeries. The most important factor determining the man- structures and thereby differentiate from vaginal agenesis.
agement is the amount of cervical tissue present. If the internal os
3.5.1.4 Diagnosis
is present, then the prognosis is more optimistic.
Current strategy is to manage the adolescent girl with Ultrasound or MRI will help to define the level and the thickness of
cervical agenesis with long-term hormonal suppression with the septum. In addition, imaging will provide information on the
either the combined hormonal contraception or gonatotropin- presence or absence of the cervix, thereby differentiating a high
releasing hormone (Gn-RH) analogue with addback hormone TVS from cervical agenesis with vastly different management
replacement therapy (HRT), until she is ready to embark on strategies.
assisted reproductive techniques (ARTs) and planned caesar-
3.5.1.5 Treatment
ean section for delivery.
Surgical management depends on the distance from the hymen
to the obstruction. In general, the higher the septum the more
3.5 Vaginal Anomalies difficult it is to reconstruct a functioning vagina.
ESHRE/ESGE classifies vaginal abnormalities as TVS in the lower one third can be incised transversely, septum
Subclass V0: Normal vagina – incorporates all cases of normal excised, vagina advanced and end-to-end anastomosis under-
vaginal development. taken. Garcia’s Z plasty technique is useful for a thick TVS to
minimize the tension between the opposing ends of the vagina and
Subclass V1: Longitudinal nonobstructing vaginal septum. minimize circumferential scar formation. Ongoing postoperative
Subclass V2: Longitudinal obstructing vaginal septum. vaginal dilators are essential to avoid vaginal stenosis. Mid- and
Subclass V3: Transverse vaginal septum and/or imperforate upper vagina TVS requires complex surgeries with abdominoper-
hymen. ineal approach with creation of neovagina through split skin grafts
over vaginal moulds [2]. Interdigitating Y-plasty without the need
Subclass V4: Vaginal aplasia – incorporates all cases of for excision of the septal tissues has recently been described with
complete or partial vaginal agenesis. good results.

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 Basic Sciences in Obstetrics

3.5.1.6 Obstetric Significance Although usually sporadic, clustering in family members

Pregnancy outcomes for the lower thin TVS are generally has been reported. It is the most common congenital obstruc-
good. High, thick TVS requiring complex reconstructive sur- tive genital tract abnormality.
gery are often associated with long-term complications and
3.5.3.2 Pathogenesis
poor pregnancy outcomes. Gynaecological problems also arise
from endometriosis from retrograde menstruation and adhe- The hymen is the vestigial remnant of the junction between the
sions impairing fertility. sinovaginal bulb and the urogenital sinus. Patency is usually
established in fetal life. Imperforate hymen is due to the failure
of the inferior end of the vaginal plates to canalize.
3.5.2 Longitudinal Vaginal Septum (LVS)
3.5.2.1 Pathogenesis 3.5.3.3 Clinical Presentation
LVS results from the defective lateral fusion and incomplete As in all forms of obstructive outflow disorders, acute urinary
resorption of paired Mullerian ducts. LVS is often associated retention may be the presenting clinical symptom, caused by
with uterus didelphys. the obstruction of the urethra by the haematocolpos. In the
neonate this could present as hydro- or mucocolpos. In the
3.5.2.2 Clinical Presentation adolescent, typical presentation is with cryptomenorrhoea
Women with LVS often do not encounter any difficulty but (menstrual symptoms without the efflux of menstrual
may complain of blood) – cyclical abdominal / pelvic pain, primary amenor-
rhoea but with normal secondary sexual characteristics.
1. difficulty with tampon insertion
Examination reveals a bulging, bluish, thin membrane
2. failure to contain menstrual efflux despite tampon use which transilluminates with retained menstrual blood.
3. difficulty with sexual intercourse
4. difficulty with vaginal delivery and childbirth 3.5.3.4 Diagnosis
Ultrasound is often sufficient to confirm the diagnosis.
3.5.2.3 Treatment Routine assessment of the renal tract is not necessary, as the
Incidental diagnosis of LVS does not require surgical intervention hymen is not of Mullerian origin.
unless the patient complains of symptoms attributable to HVS.
Excision of LVS can be accompanied by the wedge resec- 3.5.3.5 Management
tion to ensure no ridge remains. Care must be taken to ensure Aspiration should be avoided, as this does not provide ade-
an adequate pedicle and good haemostasis. The septum must quate drainage but only exposes the haematocolpos to asso-
be excised in its entirety to the point where both cervices are ciated infection.
clearly seen entering the vagina. The traditional method of a cruciate incision is no longer
recommended, as it tends to close up. An elliptical or circum-
3.5.3 Imperforate Hymen ferential incision is made close to the hymenal ring to remove
the hymen to allow adequate drainage [27].
3.5.3.1 Prevalence 3.5.3.6 Obstetric Significance
Imperforate hymen occurs in approximately 1 in 2000 females The fertility potential of patients with imperforate hymen is
[22]. probably normal, as these patients present early facilitating
prompt diagnosis and complete curative treatment.

high-risk populations: a systematic 7. The American Fertility Society

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1. Grimbizis GF, Gordts S, Di Spiezio (6):761–71. distal tubal occlusion, tubal
Sardo A, et al. The ESHRE/ESGE occlusion secondary to tubal
consensus on the classification of 4. Kliegman R, Stanton B, St. Geme J,
ligation, tubal pregnancies, Mullerian
female genital tract congenital Schor NF, Nelson WE. Nelson Textbook
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Based Approach. Philadelphia: Elsevier Small uterine septum is an important Mullerian anomalies. Fertil Steril.
Saunders; 2014. pp. 189–91. risk variable for preterm birth. Eur 2006;86(3):S308.
10. Di Spiezio Sardo A, Florio P, J Obstet Gynecol Reprod Biol. 2007;135 22. Venetis CA, Papadopoulos SP,
Nazzaro G, et al. Hysteroscopic (2):154–7. Campo R, et al. Clinical implications of
outpatient metroplasty to expand 17. Khalifa E, Toner JP, Jones HW, Jr. congenital uterine anomalies: a
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Biomed Online. 2015;30(2):166–74. Surg Gynecol Obstet. 1993;176 (6):665–83.
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Uterine septum: a guideline. Fertil 18. Pabuçcu R, Gomel V. Reproductive Gynecology. New York; London:
Steril. 2016;106(3):530–40. outcome after hysteroscopic McGraw-Hill Medical; McGraw-Hill
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et al. Arcuate uterus: is there an impact uterus and otherwise unexplained 24. Rock JA, Thompson JD, Linde RWt. Te
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2018;109(4):638–43. 19. Homer HA, Li TC, Cooke ID, Wilkins; 1997.
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2018;109(4):610. reproductive outcome. Fertil Steril. opinion. Nonsurgical diagnosis and
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Klun I, et al. Septate, subseptate and 20. Grimbizis GF, Camus M, Number 274, July 2002. Committee
arcuate uterus decrease pregnancy and Tarlatzis BC, Bontis JN, on Adolescent Health Care.
live birth rates in IVF/ICSI. Reprod Devroey P. Clinical implications American College of Obstetrics and
Biomed Online. 2010;21(5):700–5. of uterine malformations and Gynecology. Int J Gynaecol Obstet.
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Reproductive outcomes in women with 26. Brannstrom M. Uterus transplantation.
(2):161–74. Curr Opin Organ Transplant. 2015;20
congenital uterine anomalies:
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Gynecol. 2011;38(4):371–82. Stadtmauer L, Abuhamad AZ. P-465: 27. Emans SJH, Laufer MR. Emans, Laufer,
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Pucelj M, Premru-Sršen T, Verdenik I. Gynecology. Philadelphia: Lippincott
ultrasound for the diagnosis of Williams & Wilkins; 2012.

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 Chapter
Pharmacology and Pharmacokinetics in Obstetric

4 Practice
Charles Savona-Ventura & Yvonne Savona-Ventura

4.1 Introduction disorders (e.g. managing pregnancy-induced hypertension),

Pharmaceutical agents have become an essential tool in the or to treat associated acute or chronic medical conditions
medical armamentarium. Pharmaceutical companies over the coincidental to the pregnancy (e.g. managing urinary tract
past century not only have developed more consistently effec- infections, epilepsy or thyroid disease). It is imperative that
tive agents that are used to manage acute-onset conditions, but any woman on medication for any condition should consult
also have improved the quality of life of those suffering from her healthcare professional to review the medication profile
chronic progressive disease. The use of any medication must be before she embarks on a pregnancy. Timely pre-conceptional
tempered by its potential side effects. Thus, the clinician must counselling would allow for a careful review of the medication
assess the benefit-risk ratio between therapeutic efficacy and being taken by the woman and provide the opportunity to alter
safety risks before resorting to any therapeutic intervention in these to safer options. Combined polypharmacy should be
any patient. The benefit-risk assessment (BRA) is made on the avoided. Prescriptions should be targeted specifically to deal
weight of randomized evidence obtained from formal clinical with the medical condition being addressed. Multivitamin
trials and observations collected from pharmacovigilance preparation formulations, especially those directed at general
activities after the drug is put on the market [1]. In obstetric use, may include a significant dose of vitamin A that itself alone
practice, the benefit-risk ratio assessment for a pharmaceutical can act as a teratotoxic agent on the fetus.
agent must further consider the specific benefit-risk ratio Medications may further be administered to the mother
assessment relevant to the developing fetus. The fetal risk with the aim of directly affecting the developing fetus (e.g.
assessment presented by a particular agent may not be imme- folic acid administration to reduce risk of neural tube defects
diately possible since adverse effects may not be specific and or the administration of dexamethasone to promote lung
easily linked to the agent, or may present themselves later on in surfactant production). Pre-conceptional care is also an
life. opportunity to promote the use of folic acid supplementation
The realization that chemical substances could have an at a dose of 0.4–1.0 mg daily which has been proven to
adverse effect on the developing fetus came in the wake of decrease or minimize specific birth defects, particularly
the thalidomide experience in the late 1950s and early 1960s. neural tube defects (NTD). Women known to be at inter-
Thalidomide, administered as an antiemetic to treat morning mediate-high risk for neural tube defects should be pre-
sickness in pregnant women, was found to be causing severe scribed higher folic acid doses of 4.0–5.0 mg daily, provided
birth defects giving rise to what has been termed the thalido- these women have been shown not to suffer from vitamin B12
mide embryopathy or syndrome involving the skeleton and deficiency. Women at high risk of neural tube defects include
soft tissue organs including heart, kidney and gastrointestinal those with a family or personal previous history of an NTD-
tract [2]. The administration time-determined effects of thali- pregnancy or insulin-dependent diabetes, and those women
domide were demonstrated in the original published observa- receiving medication that is a folate antagonist such as anti-
tions by E. Nowack in 1965. The word teratogenesis originates epileptic medication, e.g. valproic acid or carbamazepine [4].
from the Greek word for monster, teratos, thus implying the Pre-conceptional advice should also include advice about
creation of monsters, notably referring to the birth of infants nutrition with an emphasis on partaking of food items with
with structural abnormalities. There has since been increasing a high antioxidant content to decrease the effect of oxidative
realization that the process can result in a whole range of stress known to act as a teratotoxic agent [5].
effects including early pregnancy loss, intrauterine deaths, Medications in the first trimester of pregnancy may be
abnormal growth patterns and effects on mental development partaken to support the pregnancy or to manage a condition
and adult-onset effects such as late-onset carcinogenesis, infer- or distressing symptomatology that crops up during the preg-
tility [3] and metabolic disease. nancy. The increasing use of reproductive technology has
During pregnancy, pharmaceutical agents may be used to introduced an element of medicalization of pregnancy with
manage a number of clinical situations. During the antenatal attempts to support the early pregnancy state, a process that
period, medications may be prescribed prophylactically to has extended to the management of recurrent pregnancy loss.
prevent potential problems from developing with advancing These women are very often managed empirically using a
pregnancy (e.g. haematological supplementation to prevent combination of anticoagulation, progesterone supplementa-
development of anaemia), or to manage pregnancy-related tion and immunomodulatory treatments [6, 7]. Such
30
 Pharmacology and Pharmacokinetics in Obstetric Practice

prescriptions must be tempered with an awareness of the menstruation after implantation may occur. The proportion of
potential teratotoxicity that this polypharmacy may contribute human conceptions that terminate into resorbed or early
to and the knowledge that teratotoxicity may demonstrate expulsion zygotes is not known, but animal studies suggest
itself in later years. One must bear in mind the past experience that about 60% of zygotes fail to implant successfully.
of the antenatal use of diethylstilboestrol (DES) in the manage- Furthermore, during the pre-implantation stage, the zygote
ment of miscarriages and the eventual development of vaginal may react to the biochemical environment, and through the
adenosis-adenocarcinoma and primary infertility in the off- capacity of developmental plasticity and epigenetic mechan-
spring. The thalidomide experience resulting from an attempt isms initiate adaptive processes that can potentially result in
to manage the ‘normal’ nausea and vomiting of pregnancy long-term health consequences [9].
must also temper any attempts at managing non-life-threaten- The second phase of development after implantation is the
ing symptomatology during early pregnancy. Any medications process of embryogenesis, which is characterized by a period of
used during pregnancy should be restricted to those formula- marked structural development and the development of a fetal
tions that experience has shown to be non-teratotoxic. These support system. Any serious error during embryogenesis can
should be used in isolation, for the shortest period of time, and result in early embryonic death, leading to a spontaneous first
in the lowest dose possible. trimester miscarriage. However, if the developmental error is
Medications may also be administered to the mother dur- non-lethal, then morphological malformations may result. The
ing parturition (e.g. oxytocin to augment labour and delivery) developmental process is particularly sensitive at this stage to
and after delivery during lactation (e.g. postoperative antibio- various physical, biological and chemical exogenous teratogens
tics or postoperative anticoagulation prophylaxis). The admin- or to endogenous teratogenic factors. About 15–20% of human
istration of any medication to the pregnant or lactating mother pregnancies are estimated to end in a spontaneous miscarriage.
will have corresponding pharmacological effects on the devel- While a proportion of these miscarriages may be the result of
oping fetus in utero or on the neonate. The pharmacological inherent genetic factors, some will be due to teratotoxic expo-
effects on the child will replicate those experienced by the sure during the embryogenic period. The effects of teratotoxic
mother, but the drug can also have other potentially adverse factors on the developing embryo are dependent on the stage of
inadvertent teratogenic effects depending on the stage of fetal development the embryo has reached at its time of exposure
development at which the drug exposure takes place. and on how long the embryo is exposed to the agent. Exposure
to teratotoxic agents during embryogenesis will thus tend to
4.2 Placental Transfer Mechanisms affect the organs and systems under development during the
period of exposure, resulting in structural and functional
Fetal development can be broadly viewed into three main
abnormalities. The transfer of chemical-based teratotoxic
phases. The first phase, lasting from conception up to day 16
agents is dependent on the physiological mechanisms available
of development, is that referred to as the germinal period when
for the placental transfer of substrates.
blastogenesis is taking place. Implantation of the blastocyst
The placenta is a complex organ that controls the passage of
into the secretory endometrium starts at day 6, the process
substances from the mother to the embryo. It also serves as a
taking a few days to complete. Implantation initiates the devel-
metabolic organ altering the chemical structure of toxic sub-
opment of the placenta, which starts to function from the fifth
stances potentially making these less innocuous or more toxic.
week onwards. During the pre-implantation phase, the energy
The rate of transfer is also dependent on the uterine blood flow,
required for cellular reproduction is provided by the secretions
which is increased during pregnancy and accounts for about
from the fallopian tube cells and endometrial glands. Energy
15% of cardiac output. The passage of substances through the
metabolism is, at this stage, an aerobic form of metabolism
placenta is mainly dependent on the process of simple diffu-
based on oxidizable energy-providing substrates such as non-
sion following the principles of cell membrane transfer.
essential amino acids, pyruvate and glutamine obtained by
However, for some specific substrates, active or facilitated
diffusion following the principles of cell membrane transfer.
transport mechanisms may also play a role. In conformity to
Once implantation takes place, the nutritional demands of the
cell membrane transfer mechanisms, transfer of substances is
zygote are met with by substances obtained from the maternal
therefore dependent on the water or lipid solubility properties
circulation. Energy metabolism now shifts to one primarily
of the substance, the molecular size or whether it is protein- or
based on aerobic glycolysis and oxidative metabolism.
cell-bound, the degree of polarity or ionization and the pH of
Glucose and essential amino acids thus become increasingly
the substance. It also is dependent on the overall concentration
more important [8].
and the degree of metabolization it undergoes within the
In animal studies, alterations in the biochemical milieu
syncytiotrophoblast placental cells (Figure 4.1). Other poten-
interieur of the developing zygote during blastogenesis caused
tial mechanisms of placental transfer include pinocytosis (e.g.
by metabolic disturbances such as diabetes mellitus has shown
immunoglobulins), and transfer through breaks between the
to predispose towards zygote damage and a higher risk of
vascular compartments allowing passage of placental or fetal
resorption of the developing zygotes. Similarly, exposure to
cells to mother (e.g. rhesus isoimmunization) and maternal
any teratotoxic substances may interfere with cellular develop-
cells to the fetus (e.g. melanoma or leukaemic cells).
ment, causing damage to the developing blastocyst. Depending
The principles of placental transfer mechanisms remain in
on the degree of damage, cellular death and resorption of the
play during the third phase of development referred to as the
zygote before implantation or expulsion during the subsequent
31
 Basic Sciences in Obstetrics

MATERNAL
Pethidine pharmacokinetics
SYNCYTIOTROPHOBLAST FETAL
CIRCULATION CIRCULATION Maternal Fetal
pH = 7.4 800
pH = 7.3

Mean pethidine level

Transcellular diffusion 600

μb/l]
400

[μ
Intracellular passive diffusion
Water soluble

Faciliated transfer 200

M/F ratio = 0.85
0
30 90 150 210 270
Active transfer Time after i/m administration
[minutes]
Figure 4.2 Pethidine transplacental pharmacokinetics illustrating quick
equilibration between compartments and eventual drug entrapment in fetal
Highly metabolized
compartment (after Savona-Ventura, Sammut, Sammut 1991) [12].

High molecular weight

or protein/cell-bound Pinocytosis

not yet be fully mature and effective. In spite of the

maternal capacity for eliminating the drug, a tendency
to drug ‘entrapment’ in the fetal compartment may
Figure 4.1 Placental transfer variables
occur, especially if the chemical has a high pH (basic
properties) and has a high ionizing potential (Figure
4.2), a process that further prolongs fetal exposure time
fetal phase. During this last phase of intrauterine life, fetal to the drug.
growth and organ differentiation takes place. After the sixth This process of drug entrapment in the fetus becomes even
month of pregnancy, the loss of the cytotrophoblasts – more significant when medications are used late in pregnancy
Langerhan’s cells – from the placenta will further facilitate and in the peripartum period. Once delivered and separated
the transport of drugs across the placenta. With increasing from its mother’s detoxifying and excretory systems, the fetus
differentiation of the organs, the sensitivity of the developing is obliged to deal with any residual agent using its own
fetus to teratotoxic agents diminishes. The agent will, however, resources that may not yet be fully functional and effective.
continue to exert a pharmacological effect on the fetus similar This effect is exemplified by the association of floppy infant
to that experienced by the mother. The pharmacological effect syndrome and the use of benzodiazepines prescribed during
desired in the mother may be directly or indirectly detrimental the last trimester of pregnancy. Symptoms of floppy infant
to some degree to the fetus. Thus, the inappropriate use of syndrome resulting from benzodiazepine toxicity develop
antithyroid medication administered to the mother to manage directly after birth and can persist for hours to days. The
hyperthyroidism may result in fetal hypothyroidism with mean plasma half-life of benzodiazepine derivatives are two
adverse effects to growth and neurodevelopment [10]. to four times longer for neonates than for adults. Since floppy
Prolonged hypotensive treatment or prolonged nicotine expo- infant syndrome can cause severe morbidity, prescription of
sure of the mother will predispose to reduced placental blood benzodiazepines in the last trimester of pregnancy is thus not
flow, also causing reduced intrauterine fetal growth and neuro- recommended [13].
development [11]. Intrauterine undernutrition from any cause, Fetal development can be extended to a fourth phase to
including the result of pharmacological agents taken by the include the period after the delivery of the child and during
mother, has been linked to epigenetic adaptations in the devel- breastfeeding. During the lactational period, the neonate can
oping fetus predisposing it to adult-onset metabolic disease. also be exposed to pharmacologically active substances that
Prolonged exposure to drugs of addiction such as narcotics will may have an adverse effect on the child. Nearly all drugs
typically result in a withdrawal syndrome in the neonate after transfer into breast milk to some extent by a process of passive
delivery that may necessitate pharmacological intervention. diffusion across the biological membranes. The process is
The mechanisms in play during placental transfer dependent on the maternal serum drug concentration and on
would tend to bring about a maternal-fetal equilibrium the pharmacokinetic properties of the medication such as the
depending on the regression coefficient of the particular protein binding, lipid solubility, molecular weight and ioniza-
agent. Elimination of the drug will mainly depend on the tion properties of the chemical. Transfer is greatest if the drug
efficiency of the maternal detoxification and excretion has low protein binding and high lipid solubility properties,
systems. The fetal contribution towards detoxification is has a small molecular weight composition and is weakly basic.
limited since enzyme maturation affecting acetylation and The infant dose exposure (mg/kg/day) to medications can be
conjugation processes necessary for detoxification may estimated as a product of the maternal plasma concentration
32
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