Obesity and Pregnancy [1 ed.] 9781614704676, 9781608761111

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Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved. Briese, Volker, et al. Obesity and Pregnancy, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved. Briese, Volker, et al. Obesity and Pregnancy, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

PREGNANCY AND INFANTS: MEDICAL, PSYCHOLOGICAL AND SOCIAL ISSUES SERIES

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

OBESITY AND PREGNANCY

No part of this digital document may be reproduced, stored in a retrieval system or transmitted in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services.

Briese, Volker, et al. Obesity and Pregnancy, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

PREGNANCY AND INFANTS: MEDICAL, PSYCHOLOGICAL AND SOCIAL ISSUES SERIES Focus on Milk and Infants Viroj Wiwanitkit 2009. ISBN: 978-1-60741-106-2 Infectious Pregnancy Complications Richard N. Canfield (Editor) 2009. ISBN: 978-1-60471-038-6 Drugs During Pregnancy Bengt Källén 2009. ISBN: 978-1-60876-154-8 Breastfeeding: Methods, Benefits to the Infant and Mother, and Difficulties Wilma G. Nueland (Editor) 2010. ISBN: 978-1-60741-933-4

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Nonmarital Childbearing: Trends, Reasons and Policy Gilberto de la Rayes (Editor) 2010. ISBN: 978-1-60741-756-9 Human Placenta: Structure and Development, Circulation and Functions Eirik Berven and Andras Freberg (Editors) 2010. ISBN: 978-1-60876-457-0 Handbook of Prenatal Diagnosis: Methods, Issues and Health Impacts Elian Pereira and Juliano Soria (Editors) 2010. ISBN: 978-1-60741-254-0 Meconium Aspiration Syndrome: From Pathomechanisms to Treatment Daniela Mokra and Juraj Mokry 2010. ISBN: 978-1-60876-944-5 Obesity and Pregnancy Volker Briese, Manfred Voigt and Sebastian Straube 2010. ISBN: 978-1-60876-111-1

Briese, Volker, et al. Obesity and Pregnancy, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

PREGNANCY AND INFANTS: MEDICAL, PSYCHOLOGICAL AND SOCIAL ISSUES SERIES

OBESITY AND PREGNANCY

VOLKER BRIESE MANFRED VOIGT AND Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

SEBASTIAN STRAUBE

Nova Biomedical Books New York Briese, Volker, et al. Obesity and Pregnancy, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers‘ use of, or reliance upon, this material.

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Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Library of Congress Cataloging-in-Publication Data Briese, Volker, 1966Obesity and pregnancy / Volker Briese, Manfred Voigt, Sebastian Straube. p. ; cm. Includes bibliographical references and index. ISBN: (eBook) 1. Pregnancy--Complications. 2. Obesity. I. Voigt, Manfred, 1964- II. Straube, Sebastian. III. Title. [DNLM: 1. Pregnancy Complications. 2. Maternal Health Services. 3. Obesity. 4. Risk Factors. WQ 240 B853o 2009] RG571.B65 2009 618.2--dc22 2009028864

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Contents Preface

vii

Section 1: Background

1

Chapter I

Introducing the Problem of Obesity and Pregnancy

3

Chapter II

Definitions

7

Chapter III

Prevalence of Obesity

9

Chapter IV

Fetal Programming: Pregnancy as an Opportunity for the Primary Prevention of Obesity

11

Pathophysiology

15

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Chapter V

Section 2: Obstetric Care for Obese Women

19

Chapter VI

Contraception

21

Chapter VII

Infertility

25

Chapter VIII

Pre-Conceptional Counseling

31

Chapter IX

Pre-Conceptional Weight Reduction

35

Chapter X

Care During Pregnancy

37

Chapter XI

Nutrition in Pregnancy: Some Pointers

41

Chapter XII

Polycystic Ovary Syndrome

45

Chapter XIII

Abdominal Obesity and Metabolic Syndrome

47

Chapter XIV

Dyslipidemia

51

Chapter XV

Smoking

53

Chapter XVI

Weight Gain in Pregnancy

59

Section 3: Complications of Pregnancy

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63

Contents

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vi

Chapter XVII Pregnancy and Birth in Obese Women An Overview of Common Complications

65

Chapter XVIII Miscarriage

73

Chapter XIX

Stillbirth

77

Chapter XX

Uterine Rupture

81

Chapter XXI

Preterm Birth

83

Chapter XXII Pre-Eclampsia and Eclampsia

93

Chapter XXIII Venous Thromboembolism

101

Chapter XXIV Gestational Diabetes

107

Chapter XXV Diabetic Ketoacidosis (DKA) and Hyperosmolar Hyperglycemic Nonketotic Diabetic Coma (HONK) in Pregnancy

111

Chapter XXVI Myocardial Infarction

117

Chapter XXVII Stroke

121

Chapter XXVIII Compression Neuropathies and Carpal Tunnel Syndrome

125

Chapter XXIX Obstructive Sleep Apnea

127

Chapter XXX Acute Pancreatitis

129

Chapter XXXI Restless Legs Syndrome

133

Section 4: Delivery

135

Chapter XXXII Delivery and the Postpartum Period in Obese Women

137

Chapter XXXIII Prevention of Postpartum Hemorrhage

147

Chapter XXXIV Anesthetic Management Issues in Morbidly Obese Women

151

Section 5: Summaries and Appendix

155

Chapter XXXV Summary and Outlook (for Health Care Professionals)

157

Chapter XXXVI A Patient Guide

161

Chapter XXXVII Appendix: Percentiles for the Weight Gain During Pregnancy

165

Index

173

Briese, Volker, et al. Obesity and Pregnancy, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Preface Obesity is now the most common risk factor in pregnancy. Of all pregnant women 10 – 20 % are obese and 1 % are morbidly obese. Both primiparous and multiparous women are increasingly affected by obesity: primiparae because of the rising prevalence of juvenile obesity, multiparae because of inadequate postnatal weight reduction. Pre-conception advice and interventions to minimize maternal and fetal complications of obesity in pregnancy are of vital importance but until now are often sadly inadequate. Obesity associated complications of pregnancy, particularly gestational diabetes, hypertension, preeclampsia, and thromboembolism put mother and child at risk. Furthermore, maternal obesity can lead to neonatal macrosomia. Therefore the Cesarean section rate is high in obese women and vaginal delivery is more often associated with complications of delivery such as shoulder dystocia. Fetal programming during pregnancy is implicated in the development of obesity and the metabolic syndrome in the offspring. This way obesity is passed on from one generation to the next. In order to stop this vicious cycle of obesity, the primary prevention of the obesity epidemic that has taken hold of the Western world has to start in pregnancy. A range of topical issues is discussed in this book including the scientific background behind obesity and pregnancy, complications of pregnancy in the obese, and obstetric care for obese women. What you read in this book is based on clinical experience, a literature review and an analysis of German perinatal statistics based on data from more than 2 million pregnancies. We hope that this book will assist doctors and other health care professionals in their work and that it will also appeal to patients and interested lay people. Obesity is without a doubt a topic of great and increasing importance. The complications arsing from obesity in pregnancy already have a clear impact on obstetric practice; and as the prevalence of obesity increases they are likely to have an even greater impact in the future. This book addresses this topical issue and discusses strategies of prevention and management of such complications. Section 1 introduces the scientific background. Section 2 presents an approach to the care for obese women before and during pregnancy. Section 3 discusses complications of pregnancy in the obese and their management. Section 4 addresses delivery in obese women. Section 5 provides summaries for health care professionals and patients and also contains an appendix with standard values for the weight gain during pregnancy.

Briese, Volker, et al. Obesity and Pregnancy, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved. Briese, Volker, et al. Obesity and Pregnancy, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Section 1: Background

Briese, Volker, et al. Obesity and Pregnancy, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved. Briese, Volker, et al. Obesity and Pregnancy, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

In: Obesity and Pregnancy V. Briese, M. Voigt and S. Straube, pp. 3-5

ISBN: 978-1-60876-111-1 © 2010 Nova Science Publishers, Inc.

Chapter I

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Introducing the Problem of Obesity and Pregnancy For some time now obesity has been a topic of concern both for the general public and the medical community. Obesity is a problem of increasing proportions - more people become obese and people become more obese. Energy rich foodstuff and lack of exercise conspire to generate an obesogenic environment, especially in the Western world, but also in some parts of the developing world. Adipose tissue – if present in excess - can form a ‗risk organ‘ secreting pro-inflammatory and atherogenic cytokines. Abdominal and visceral adipose tissue is especially dangerous. Although the principles of a healthy diet and lifestyle are widely known, also to obese people, such individuals often do not manage to consistently lose weight, especially when left to their own devices. Health care authorities and policy makers across the world have now realized the magnitude of the problem and started to develop and implement a variety of measures to tackle the problem of obesity on a society level - but so far the problem persists and increases in proportions. A multidisciplinary and integrated approach is needed for us to come to terms with the obesity epidemic. This ought to include health education, adequate provision of healthy foods, and opportunities to be physically active, both at home and also in the work place. While the approach has to be multidisciplinary it also has to be individualized - not all obese people are alike; some are ill, some are surprisingly healthy. Stigmatizing and attributing blame won‘t get us anywhere: we know that obesity - once it is established - is difficult to reverse. Obesity is a complex multidimensional phenomenon with a number of known contributory factors - genetic, environmental, and socio-economic in nature - and perhaps also some factors that are as of yet unknown. The list of disorders associated with obesity is long and thanks to considerable research funds (rightly) spent in this area it is still getting longer. The benefits of obesity are few (having reserves in times of starvation being among them) and largely irrelevant in modern day life, at least for most of us. Increased insulin resistance and diabetes, cardiovascular disease, dyslipidemia, and increased incidences of some cancers are amongst the most important health problems that are more common in the obese.

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Volker Briese, Manfred Voigt and Sebastian Straube

Obesity is commonly defined as a body mass index (BMI) of greater than 30. There are alternatives of quantifying the burden of dangerous adipose tissue. Waist circumference (WC) is a good predictor of morbidity and mortality. It takes into account the dangers of abdominal obesity; something BMI as such does not do. WC is well-correlated with cardiovascular risk and insulin resistance. Obesity and pregnancy is a complex topic with implications for maternal morbidity and mortality as well as morbidity of the offspring - from the neonatal period well into adult life. Obesity can make becoming pregnant more difficult. Abdominal obesity especially is associated with infertility. Reduction of obesity, particularly abdominal obesity, can lead to improvements in reproductive function (Zain and Norman 2008). Obesity associated complications of pregnancy and delivery, particularly gestational diabetes, hypertension, preeclampsia, amnion infection syndrome and postpartum hemorrhage put mother and child at risk. Thromboembolism, myocardial infarction, and stroke are life-threatening emergencies in the obese pregnant woman. Thromboprophylaxis is therefore crucial. Unidentified gestational diabetes can be complicated by ketoacidosis. Neurological complications of pregnancy such as compression neuropathies (e.g. carpal tunnel syndrome) are also more common with obesity and may significantly impact on quality of life. Maternal obesity can lead to neonatal macrosomia. It is not surprising, therefore, that the Cesarean section rate is higher in obese women and that vaginal delivery is more often associated with perinatal asphyxia and complications of delivery such as shoulder dystocia. Obstetric operations and anesthetic techniques are more challenging from a physician's perspective and may be more traumatic from a patient‘s perspective in the obese. The risk for difficult or failed intubation is high and early placement of an epidural or intrathecal catheter may be preferable with the aim of not needing general anesthesia. However, there is a high failure rate (Soens et al. 2008). The fetal and maternal complications of obesity in pregnancy tend to become more prominent with increasing BMI and so it is no surprise that morbid obesity (BMI > 40) is associated with especially high risks (Voigt et al. 2008a and b). It is also no surprise that obesity in pregnancy is associated with additional costs. A retrospective study found that the cost of prenatal care in overweight and obese women exceeded that in normal-weight women 5.4- to 16.2-fold (Galtier-Dereure et al. 1995). A later prospective case-control study confirmed these findings; the average cost of hospital prenatal care was found to be five times higher in overweight women (Galtier-Dereure et al. 2000). Obesity is now the most common ‗risk factor‘ in pregnancy. Both primiparous and multiparous women are increasingly affected by obesity: primiparae because of the rising incidence of juvenile obesity, multiparae because of inadequate postnatal weight reduction. Pre-conceptional advice and interventions to minimize maternal and fetal complications of obesity in pregnancy are of vital importance but until now are often sadly inadequate.

References Galtier-Dereure F, Montpeyroux F, Boulot P, Bringer J, Jaffiol C. Weight excess before pregnancy: complications and cost. Int. J. Obes. Relat. Metab. Disord. 1995; 19: 443–8.

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Introducing the Problem of Obesity and Pregnancy

5

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Galtier-Dereure F, Boegner C, Bringer J. Obesity and pregnancy: complications and cost. Am. J. Clin. Nutr. 2000; 71 (5 Suppl): 1242S-8S. Soens MA, Birnbach DJ, Ranasinghe JS, van Zundert A. Obstetric anesthesia for the obese and morbidly obese patient: an ounce of prevention is worth more than a pound of treatment. Acta Anaesthesiol. Scand. 2008; 52: 6-19. Voigt M, Straube S, Zygmunt M, Krafczyk B, Schneider KT, Briese V. Obesity and pregnancy - a risk profile. Z. Geburtshilfe Neonatol. 2008a; 212: 201-5. Voigt M, Zygmunt M, Henrich W, Straube S, Carstensen M, Briese V. Analysis of subgroup of pregnant women in Germany. 16th communication: morbid obesity: pregnancy risks, birth risks and status of the newborn. Geburtsh Frauenheilk. 2008b; 68: 794-800. Zain MM, Norman RJ. Impact of obesity on female fertility and fertility treatment. Womens Health (Lond Engl). 2008; 4: 183-94.

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In: Obesity and Pregnancy V. Briese, M. Voigt and S. Straube, pp. 7

ISBN: 978-1-60876-111-1 © 2010 Nova Science Publishers, Inc.

Chapter II

Definitions The body mass index (BMI) is commonly used to define overweight status and obesity. BMI is calculated by dividing body weight in kilogram by the square of body height in meters (kg/m2). The World Health Organization (WHO) classifies overweight status and obesity as detailed in Table 2-1.

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Table 2.1. Classification of overweight status and obesity according to the WHO BMI in kg/m2

102 cm (> 40 in.) for men and > 88 cm (> 35 in.) for women.

References Leddy MA, Power ML, Schulkin J. The impact of maternal obesity on maternal and fetal health. Rev. Obstet. Gynecol. 2008; 1: 170-8. World Health Organization (WHO) Website: http://www.who.int/bmi/index.jsp? introPage= intro_3.html, accessed 08-04-2009. National Heart, Lung and Blood Institute Website: http://www.nhlbi.nih.gov/guidelines/ obesity/e_txtbk/txgd/4142.htm, accessed 08-04-2009.

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In: Obesity and Pregnancy V. Briese, M. Voigt and S. Straube, pp. 9-10

ISBN: 978-1-60876-111-1 © 2010 Nova Science Publishers, Inc.

Chapter III

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Prevalence of Obesity A large multinational study showed that more than 24 % of men and 27 % of women aged between 18 and 30 years had a BMI of 30 or greater, making them obese (Balkau et al. 2007). Of the women aged 22 to 44 in the US, 23 % were found to be obese in a recent survey (Vahratian 2008). In Germany, a study of more than 35,000 adults found a prevalence of obesity of 24.7 % for men and 23.3 % for women (Hauner et al. 2008). In the same study 36.4 % of men and 41.5 % of women had a high WC (greater than the cut-off levels defined in the last chapter). A population study of nearly 500,000 singleton pregnancies and births from the German perinatal statistics of 1998-2000 found that 10.3 % of all pregnant women were obese at the beginning of pregnancy (Voigt et al. 2008). The prevalence and degree of obesity is increasing, especially in those already obese. An illustrative study compared National Health and Nutrition Examination Survey (NHANES) data of 1988-1994 with those of 1999-2004 (Beydoun and Wang 2009). BMI and WC distributions increased faster at the upper end of the population distribution, i.e. in those with high BMI and WC. Those already obese had become more so. There were ethnic disparities, too. Black women had the largest distribution shifts over time and were projected to have an obesity prevalence of 70.7 % by 2020 - a truly alarming figure. This problem is by no means exclusive to the US. The trend of increasing obesity prevalence can be observed in Europe, also. Blissing et al. (2007) presented an illustrative analysis of women who delivered at the Department of Obstetrics at Würzburg (Germany) in 1980 (n = 1359) and 2005 (n = 1351). Overall the proportion of women in the overweight and obese categories increased from 10.9 % to 29.8 %. The percentage of those with overweight status increased from 8.8 % to 18.5 %; obesity class I increased from 1.4 % to 6.4 %; obesity class II from 0.7 % to 3.5 % and obesity class III from 0.08 % to 1.4 %. Overall the prevalence of overweight status and obesity tripled within 25 years. The proportion of obese class III individuals increased 18-fold.

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Volker Briese, Manfred Voigt and Sebastian Straube

References

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Balkau B, Deanfield JE, Després JP, Bassand JP, Fox KA, Smith SC Jr, Barter P, Tan CE, Van Gaal L, Wittchen HU, Massien C, Haffner SM. International Day for the Evaluation of Abdominal Obesity (IDEA): a study of waist circumference, cardiovascular disease, and diabetes mellitus in 168,000 primary care patients in 63 countries. Circulation. 2007; 116: 1942-51. Beydoun MA, Wang Y. Gender-ethnic Disparity in BMI and Waist Circumference Distribution Shifts in US Adults. Obesity (Silver Spring). 2009; 17: 169-76. Blissing S, Roloff R, Rehn M, Frambach T, Dietl J. Prävalenz von Übergewicht und Adipositas bei Schwangeren an der Universitäts-Frauenklinik Würzburg und resultierende perinatale Ergebnisse – ein Vergleich zwischen 1980 und 2005. Geburtsh Frauenheilk. 2008; 68: 159-164 Hauner H, Bramlage P, Lösch C, Steinhagen-Thiessen E, Schunkert H, Wasem J, Jöckel KH, Moebus S. Prevalence of obesity in primary care using different anthropometric measures--results of the German Metabolic and Cardiovascular Risk Project (GEMCAS). BMC Public Health. 2008; 8: 282. Vahratian A. Prevalence of Overweight and Obesity Among Women of Childbearing Age: Results from the 2002 National Survey of Family Growth. Matern. Child Health J. 2009; 13: 268-73. Voigt M, Straube S, Zygmunt M, Krafczyk B, Schneider KT, Briese V. Obesity and pregnancy - a risk profile. Z. Geburtshilfe Neonatol. 2008; 212: 201-5.

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ISBN: 978-1-60876-111-1 © 2010 Nova Science Publishers, Inc.

Chapter IV

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Fetal Programming: Pregnancy as an Opportunity for the Primary Prevention of Obesity The primary prevention of obesity is aimed at avoiding adult obesity and the associated adverse health effects. The opportunities for the primary prevention of obesity throughout life are limited, but the very beginning of life may hold the key to a successful prevention strategy. Three periods of time prior to adulthood are important in the development of adult obesity and associated diseases: the prenatal period, the period of ‗adiposity rebound‘ (between ages 4 and 6 years in which BMI - after a rise in infancy and subsequent decline begins to increase again), and adolescence (Dietz 1997). These periods of time therefore present opportunities for the prevention of obesity. Obesity in pregnancy can affect later health in the offspring. Such children have an elevated risk of future obesity, diabetes, and heart disease (Leddy et al. 2008). During critical periods of development (including prenatally) the future functioning of organs and organ systems is ‗programmed‘ by ‗external‘ factors such as nutrition and maternal hormones. Barker presented evidence of a link between birth weight and the risk of disease later in life and pointed to a role of ―programming by the environment in fetal and infant life‖ (Barker 1990). Although Barker initially concentrated on low birth weight subsequent evidence showed that high birth weight also was associated with later disease. Prenatal development is influenced by maternal nutrition. High levels of glucose, free fatty acids and amino acids result in fetal overnutrition. This is hypothesized to cause an adaptation of the fetus to overnutrition. Such fetal programming is though to be the basis of obesity in adult age. Maternal obesity with its associated insulin resistance and glucose intolerance is implicated in ‗passing on‘ overweight status and obesity to the next generation. High birth weight, and also low birth weight, are associated with the subsequent development of adult obesity (Simmonds 2008). Lawlor and colleagues found a greater maternal-offspring BMI association than paternal-offspring BMI association, providing support for the hypothesis that an intrauterine effect, rather than a pure genetic effect is involved (Lawlor et al. 2007). Fetal programming through maternal nutrition has implications not only for obesity and associated

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Volker Briese, Manfred Voigt and Sebastian Straube

12

diseases but also for at first glance unrelated outcomes, such as brain development (Walker et al. 2008). In addition to maternal weight at the beginning of pregnancy, maternal weight gain during pregnancy is another risk factor for high infant BMI (Oken et al. 2007). The weight gain during pregnancy is about 10-15 kg on average across populations, but with a large inter-individual variability that can be at least partly explained by differences in maternal height and weight at the beginning of the pregnancy (Straube et al. 2008). A number of epidemiological and experimental studies have investigated possible pathological mechanisms underlying fetal programming of chronic diseases in later life. A summary of some factors and mechanisms proposed to be involved is shown below. A variety of influences and pathways has been suggested. Some factors and mechanisms hypothesized to be involved in fetal programming:

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• • • • • • • •

Hyperglycemia Proinflammatory environment Shifts in the growth hormone/insulin-like growth factor-1 (IGF-1) axis Effects on beta-cell development Effects on fetal appetite centers (hypothalamic) Effects of fetal glucocorticoid exposure Downregulation of fetal myogenesis Peroxisomal promoter gene DNA methylation

The evidence for the underlying mechanisms is controversial, however. For example, fetal exposure to glucocorticoids has been linked to later development of central obesity and insulin resistance. However, Fasting et al. (2009) showed in a prospective pre-birth cohort study from eastern Massachusetts that higher maternal blood levels of corticotropin-releasing hormone were associated with higher - not lower - levels of adiponectin, an adipokine inversely associated with insulin resistance, at age 3 years. This led Fasting and colleagues to speculate about a compensatory mechanism to increase insulin sensitivity. With the underlying mechanisms unclear, some of the proposed hypotheses are rather radical. A recent article implicats cow's milk protein (Melnik 2009), a key constituent of the Western diet. It argues that milk protein consumption induces postprandial hyperinsulinemia and shifts the growth hormone/insulin-like growth factor-1 (IGF-1) axis to permanently elevated IGF-1 levels. Insulin/IGF-1 signalling is involved in the pathogenesis of conditions such as obesity, atherosclerosis, and diabetes mellitus. A concern was raised about the possibility that milk consumption in pregnancy adversely affects fetal programming of the IGF-1 axis. Despite uncertainty about the underlying mechanisms, there is good evidence that fetal programming can lay the foundation of obesity in later life, and that high maternal BMI has an adverse effect. There is an opportunity for the primary prevention of obesity during the prenatal period, beginning with pre-conceptional counseling with the aim of reducing or stabilizing maternal pre-pregnancy weight. Weight gain during pregnancy should be monitored. Monitoring weight gain by maternal BMI is problematic (Straube et al. 2008). Monitoring by maternal

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Fetal Programming

13

phenotype (height and weight) provides an alternative; one way of doing so is included in the appendix to this book.

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References Barker DJ. The fetal and infant origins of adult disease. BMJ. 1990; 301: 1111. Dietz WH. Periods of risk in childhood for the development of adult obesity – what do we need to learn? J. Nutr. 1997; 127: 1884S – 1886S. Fasting MH, Oken E, Mantzoros CS, Rich-Edwards JW, Majzoub JA, Kleinman K, RifasShiman SL, Vik T, Gillman MW. Maternal levels of corticotrophin-releasing hormone during pregnancy in relation to adiponectin and leptin in early childhood. J. Clin. Endocrinol. Metab. 2009; 94: 1409-15. Lawlor DA, Smith GD, O'Callaghan M, Alati R, Mamun AA, Williams GM, Najman JM. Epidemiologic evidence for the fetal overnutrition hypothesis: findings from the materuniversity study of pregnancy and its outcomes. Am. J. Epidemiol. 2007; 165: 418 – 424. Leddy MA, Power ML, Schulkin J. The impact of maternal obesity on maternal and fetal health. Rev. Obstet. Gynecol. 2008; 1: 170 – 178. Melnik BC: Milk – The promoter of chronic Western diseases. Med. Hypotheses. 2009; 72: 631-9. Oken E, Taveras EM, Kleinman KP, Rich-Edwards JW, Gillman MW. Gestational weight gain and child adiposity at age 3 years. Am. J. Obstet. Gynecol. 2007; 196: 322.e1-8. Simmons R. Perinatal programming of obesity. Semin. Perinatol. 2008; 32: 371-4. Straube S, Voigt M, Briese V, Schneider KT, Voigt M. Weight gain in pregnancy according to maternal height and weight. J. Perinat. Med. 2008; 36: 405-12. Walker CD, Naef L, d'Asti E, Long H, Xu Z, Moreau A, Azeddine B. Perinatal maternal fat intake affects metabolism and hippocampal function in the offspring: a potential role for leptin. Ann. N.Y. Acad. Sci. 2008; 1144: 189-202.

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Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved. Briese, Volker, et al. Obesity and Pregnancy, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

In: Obesity and Pregnancy V. Briese, M. Voigt and S. Straube, pp. 15-18

ISBN: 978-1-60876-111-1 © 2010 Nova Science Publishers, Inc.

Chapter V

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Pathophysiology Fat is stored inside adipocytes in small lipid droplets, to be mobilized in times of need. If the regulation of fat storage and mobilization is disturbed, overweight status and obesity can result. On a cellular level this means hypertrophy of the adipocytes, as well as hyperplasia of the adipocytes: new fat cells are generated from precursor cells. The origin of obesity is multifactorial. Genetic predisposition, deranged regulation of hunger and satiety, caloric excess, lack of exercise, as well as psycho-social factors, and, infrequently, certain endocrine diseases can individually or in combination cause obesity. Specific single gene mutations can also cause obesity, but this is rare. It has recently become clear that adipose tissue is not only a means of fat storage but also an endocrine ‗organ‘ and part of the innate immune system (Rasouli and Kern 2008). The endocrine function of adipocytes and how dysregulation of adipocyte signaling is implicated in the generation of obesity are topics of considerable current research interest. At the moment, however, our understanding is far from complete. Especially the relative importance of the recently discovered signaling pathways is at present unclear. Not all adipose tissue is alike - visceral and subcutaneous fat differs in its structure and function. Visceral adipose tissue has smaller adipocytes, is better perfused and innervated, and contains more hormone receptors, for catecholamines and androgens, than subcutaneous adipose tissue. Visceral fat has a higher metabolic activity. However, subcutaneous fat secretes more of the hormone leptin (Van Harmelen 1998). The discovery of the fat hormone leptin resulted in considerable interest and sparked hope that a solution of the obesity problem might be at hand. While this hope could not yet be fulfilled, leptin was found to play an essential role in the endocrine regulation of the body, influencing metabolism, the immune system, reproduction and sexual development. At the hypothalamus leptin acts to release alpha-melanocyte stimulating hormone (alpha-MSH) and inhibit the release of neuropeptide Y (NPY). In the absence of leptin action, the appetite stimulating effect of NPY causes increased caloric intake and can lead to obesity. A defect or deficiency in alpha-MSH, its precursor proopiomelanocortin (POMC), or its receptor can likewise cause obesity. Leptin is the product of the ob (‗obese‘) gene. If this gene is defective, not enough leptin is synthesized in adipose tissue. A mutation in the ob gene can therefore cause a kind of obesity that responds to substitution with recombinant leptin. Sadly,

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it turned out that leptin deficiency is an infrequent cause of obesity, and so the vast majority of obese people do not respond to leptin stimulation. In fact, obese people commonly have high leptin levels. This has given rise to the idea that leptin resistance may play a role in the generation of obesity. Adipocytes have recently been found to also secrete a number of other so-called adipokines in addition to leptin, including adiponectin, resistin and visfatin, as well as cytokines and chemokines such as tumor necrosis factor-alpha, interleukin-6, and monocyte chemoattractant protein-1 (Antuna-Puente et al. 2008). Many of these adipokines have been implicated in the pathophysiology of obesity. Obese people have larger fat cells. Large adipocytes release more glycerol and free fatty acids, more pro-inflammatory factors, and less adiponectin. These changes have been linked to insulin resistance and subsequent cardiometabolic complications (Cannon 2008). Skurk and colleagues found a differential expression of pro-inflammatory and anti-inflammatory adipokines depending on adipocyte size. There is a predominance of proinflammatory adipokines secreted by large adipocytes (Skurk 2007). Cytokines secreted by adipose tissueresident macrophages may also contribute. Obesity seems to be associated with a chronic sub-inflammatory state. This forms the basis for obesity-associated complications such as diabetes/insulin resistance and cardiovascular disease (Antuna-Puente 2008). Furthermore, adipocyte functionality is lost in obesity and dysfunctional fat cells are implicated in abnormal utilization of fatty acids leading to lipotoxicity in other organs including liver, pancreas and heart (Vázquez-Vela et al. 2008). Chemokine secretion by adipocytes could be the cause of leukocyte infiltration into the adipose tissue of the obese and be implicated in the generation of the phenomenon of chronic inflammation. The chemokine RANTES is chemotactic for different types of leukocytes and recruits them into inflammatory sites. Most human adipocytes seem to secrete RANTES depending on cell size and source. Adipocytes from obese people secrete more RANTES (Skurk et al. 2009a). Further work by Skurk and co-workers showed the factors secreted from adipocytes reduced insulin-stimulated Akt/PKB phosphorylation in a manner depending on BMI and fat cell volume. This mechanism may contribute to the pathogenesis of insulin resistance in obesity (Skurk et al. 2009b). Details are not fully elucidated but it is interesting that the adipokine lipocalin 2 has been shown to be increased in obesity and promotes insulin resistance (Yan et al. 2007). Adipose tissue also produces interleukin-18 (IL-18), a proatherogenic cytokine (Skurk et al. 2005). Other adipokines may have anti-obesogenic effects and deficiencies in those signaling pathways can potentially also contribute to obesity. A low serum level of adiponectin was found to be associated with obesity in a study of severely obese young adult patients from Southern Italy and variants in the adiponectin gene promoter region seem to be implicated (Daniele et al. 2008). A number of other signaling pathways may play a role in the pathophysiology of obesity. Catecholamines, for example, normally stimulate lipolysis in adipocytes. There is evidence that this is reduced in obesity and may contribute to the development of increased fat stores (Jocken and Blaak 2008). The molecular pathophysiology of how obesity may cause complications of pregnancy is still largely unclear. There is increasing evidence, however, that some of the adipokines

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Pathophysiology

17

mentioned above are implicated in the development of complications of pregnancy. Preeclampsia and gestational diabetes are more common in obese pregnant women than in those with normal weight. Visfatin is an adipokine that is up-regulated when weight is gained. Maternal visfatin levels were found to be increased in pre-eclampsia patients (Fasshauer et al. 2008a). The maternal plasma concentration of visfatin was also found to be higher in patients with gestational diabetes (Mazaki-Tovi et al. 2008). Leptin levels - commonly high in obese people - were also found to be increased in women with pre-eclampsia (Mumtaz et al. 2008), as were levels of the recently discovered adipokine adipocyte fatty acid-binding protein (Fasshauer et al. 2008b). More research is needed in this area to work out the molecular mechanisms involved. In conclusion, current evidence indicates that the key to the pathophysiology of obesity lies in adipocyte dysfunction. Multiple signaling pathways seem to be involved, and we are beginning to understand how derangements in these signaling pathways are linked to the generation of obesity and also to the consequences of obesity in pregnancy.

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References Antuna-Puente B, Feve B, Fellahi S, Bastard JP. Adipokines: the missing link between insulin resistance and obesity. Diabetes Metab. 2008; 34: 2-11. Cannon CP. Obesity-related cardiometabolic complications. Clin. Cornerstone. 2008; 9: 1122. Daniele A, Cammarata R, Pasanisi F, Finelli C, Salvatori G, Calcagno G, Bracale R, Labruna G, Nardelli C, Buono P, Sacchetti L, Contaldo F, Oriani G. Molecular Analysis of the Adiponectin Gene in Severely Obese Patients from Southern Italy. Ann. Nutr. Metab. 2008; 53: 155-161. Jocken JW, Blaak EE: Catecholamine-induced lipolysis in adipose tissue and skeletal muscle in obesity. Physiol. Behav. 2008; 94: 219-30. Fasshauer M, Waldeyer T, Seeger J, Schrey S, Ebert T, Kratzsch J, Lossner U, Bluher M, Stumvoll M, Faber R, Stepan H. Serum levels of the adipokine visfatin are increased in pre-eclampsia. Clin. Endocrinol. (Oxf). 2008a; 69: 69-73. Fasshauer M, Seeger J, Waldeyer T, Schrey S, Ebert T, Kratzsch J, Lössner U, Blüher M, Stumvoll M, Faber R, Stepan H. Serum levels of the adipokine adipocyte fatty acidbinding protein are increased in preeclampsia. Am. J. Hypertens. 2008b; 21: 582-6. Mazaki-Tovi S, Romero R, Kusanovic JP, Vaisbuch E, Erez O, Than NG, Chaiworapongsa T, Nhan-Chang CL, Pacora P, Gotsch F, Yeo L, Kim SK, Edwin SS, Hassan SS, Mittal P. Visfatin in human pregnancy: maternal gestational diabetes vis-à-vis neonatal birthweight. J. Perinat. Med. 2009; 37: 218-31. Mumtaz F, Memon AR, Yousfani S, Tahir SM, Khushk I, Memon M, Memon A. Role of serum leptin level as a marker of severity of pre-eclampsia. J. Ayub. Med. Coll. Abbottabad. 2008; 20: 13-5. Rasouli N, Kern PA. Adipocytokines and the metabolic complications of obesity. J. Clin. Endocrinol. Metab. 2008; 93(11 Suppl 1): S64-73.

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Skurk T, Kolb H, Müller-Scholze S, Röhrig K, Hauner H, Herder C. The proatherogenic cytokine interleukin-18 is secreted by human adipocytes. Eur. J. Endocrinol. 2005; 152: 863-868. Skurk T, Alberti-Huber C, Herder C, Hauner H. Relationship between adipocyte size and adipokine expression and secretion. J. Clin. Endocrinol. Metab. 2007; 92: 1023-1033. Skurk T, Mack I, Kempf K, Kolb H, Hauner H, Herder C. Expression and Secretion of RANTES (CCL5) in Human Adipocytes in Response to Immunological Stimuli and Hypoxia. Horm. Metab. Res. 2009a; 41: 183-9. Skurk T, Alberti-Huber C, Hauner H. Effect of Conditioned Media from Mature Human Adipocytes on Insulin-stimulated Akt/PKB Phosphorylation in Human Skeletal Muscle Cells: Role of BMI and Fat Cell Size. Horm. Metab. Res. 2009b; 41: 190-6. Van Harmelen V, Reynisdottir S, Eriksson P, Thörne A, Hoffstedt J, Lönnqvist F, Arner P. Leptin secretion from subcutaneous and visceral adipose tissue in women. Diabetes. 1998; 47: 913-7. Vázquez-Vela ME, Torres N, Tovar AR. White adipose tissue as endocrine organ and its role in obesity. Arch. Med. Res. 2008; 39: 715-728. Yan QW, Yang Q, Mody N, Graham TE, Hsu CH, Xu Z, Houstis NE, Kahn BB, Rosen ED. The adipokine lipocalin 2 is regulated by obesity and promotes insulin resistance. Diabetes. 2007; 56: 2533-2540.

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Section 2: Obstetric Care for Obese Women

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In: Obesity and Pregnancy V. Briese, M. Voigt and S. Straube, pp. 21-23

ISBN: 978-1-60876-111-1 © 2010 Nova Science Publishers, Inc.

Chapter VI

Contraception

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At first glance it might be surprising to find a chapter on contraception in a book on pregnancy but some of the therapeutic measures aimed at weight loss or the treatment of obesity-associated conditions necessitate concurrent contraception, as will be detailed below. Some recent studies show that obese women are more reluctant to use contraception compared to normal weight women. Yahratian et al. (2009) analyzed contraceptive measures taken by sexually active women aged 20 - 44 years based of responses to the 2002 National Survey for Family Growth. Women with a BMI > 35 were more likely to lack contraception than women with a BMI under 25. Chuang et al. (2005) found a rate of contraceptive non-use of 23.4 % in obese women. This means that there is an appreciable risk of unintended pregnancies in the obese.

Some Points of Note on Oral Hormonal Contraception • • •

•

Relatively contraindicated in women with a BMI > 35 Should be critically evaluated in women with a BMI > 25 Additional risk factors to consider are: hypertension, cardiovascular and cerebrovascular disease, hypercholesterolemia, hypertriglyceridemia, thrombophilia, a history of venous thromboembolism, migraine headaches (in migraines with aura, the combined oral contraceptive pill is contraindicated, Allais et al. 2009), raised transaminases, and smoking. Exclude factor V and prothrombin mutations before commencing hormonal contraception; perform a 75 g oral glucose tolerance test, measure serum triglycerides, HDL cholesterol, and LDL cholesterol.

Transdermal contraceptive patches are contra-indicated in obesity. Depot medroxyprogesterone acetate (Depo-Provera) can be used in overweight women, but only after a critical assessment of risk factors. This is a hormonal injection that has to be repeated every three months. Use of condoms as a secondary contraceptive measure should be

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22

encouraged, particularly in adolescents (Pitts and Emans 2008). Caution is needed with regard to any hormonal contraception, including Depo injections, in the obese and anyone prescribing hormonal contraception in overweight and obese women should consult local guidelines. At present, a final verdict on the associated risks cannot yet be reached. Clark et al. (2005) found unhealthy patterns of fat distribution (central redistribution of fat) after longer term use of Depo contraceptive. Alternative methods of contraception that should be considered are: • • •

Barrier methods Hormonal or copper IUD Vaginal contraceptive ring

Complications

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Steroid hormones are fat soluble and are stored predominantly in visceral and mesenteric fat, where they could accumulate. Possible interactions with the recently discovered adiposetissue derived factors leptin, adiponectin and resistin have not been sufficiently investigated. Oral contraceptive failure has been suggested to be increased in obese women, though this is still controversial and more work is needed to clarify the relationship between body weight and contraceptive failure (Brunner Huber et al. 2006, Brunner Huber and Toth 2007). The risk of venous thrombosis in women using oral contraceptives with a BMI > 25 increases ten-fold (Abdollahi et al. 2003), in obese women on oral contraceptives even 24fold compared to normal weight women not on oral contraceptives (Pomp et al. 2007). Inherited thrombophilias increase the risk further. Factor V Leiden increased the hormoneassociated risk of thrombosis about seven-fold (Cushman et al. 2004).

Indications for Using Contraception in Overweight and Obese Women • • • •

Management of polycystic ovary syndrome (PCOS) before pregnancy (Bhathena 2007) Therapy with antiandrogens (hyperandrogenemia, hirsutism) (Rosenfield 2008) Weight loss surgery less than two years ago (Patel et al. 2007) Use of pharmacologial agents in weight reduction (Nelson and Fleming 2007)

References Abdollahi M, Cushman M, Rosendaal FR. Obesity: risk of venous thrombosis and the interaction with coagulation factor levels and oral contraceptive use. Thromb. Haemost. 2003; 89: 493 – 498.

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Contraception

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Allais G, Gabellari IC, De Lorenzo C, Mana O, Benedetto C. Oral contraceptives in migraine. Expert Rev Neurother. 2009; 9: 391 – 393. Bhathena RK. Therapeutic options in the polycystic ovary syndrome. J. Obstet. Gynaecol. 2007; 27: 123 – 129. Brunner Huber LR, Hogue CJ, Stein AD, Drews C, Zieman M. Body mass index and risk for oral contraceptive failure: a case-cohort study in South Carolina. Ann. Epidemiol. 2006; 16: 637 – 643. Brunner Huber LR, Toth JL. Obesity and contraceptive failure: findings from the 2002 National Survey of Family Growth. Am. J. Epidemiol. 2007; 166: 1306 – 1311. Chuang CH, Chase GA, Bensyl DM, Welsman CS. Contraceptive use by diabetic and obese women. Womens Health Issues. 2005; 15: 167 – 173. Clark MK, Dillon JS, Sowers M, Nichols S. Weight, fat mass, and central distribution of fat increases when women use depot-medroxyprogesteron acetate for contraception. Int. J. Obes. (Lond). 2005; 29: 1252 – 1258. Cushman M, Kuller LH, Prentice R, Rodabough RJ, Psaty BM, Stafford RS, Sidney S, Rosendaal FR. Estrogen and progestin and risk of venous thrombosis. JAMA. 2004; 292: 1573 – 1580. Nelson SM, Fleming RF. The preconceptual contraception paradigm: obesity and infertility. Hum. Reprod. 2007; 22: 912 – 915. Patel JA, Colella JJ, Esaka E, Patel NA, Thomas RL. Improvement in infertility and pregnancy after weight loss surgery. Med. Clin. North Am. 2007; 91: 515 – 528. Pitts SA, Emans SJ. Controversies in contraception. Curr. Opin. Pediatr. 2008; 20: 383 – 389. Pomp ER, le Cessie S, Rosendaal FR, Doggen CJ. Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations. Br. J. Haematol. 2007; 139: 289 – 296. Rosenfield RL. What every physician should know about polycystic ovary syndrome. Dermatol. Ther. 2008; 21: 354 – 36. Yahratian A, Barber JS, Lawrence JM, Kim C. Family Planning Practices among Women with Diabetes and Overweight and Obese Women in the 2002 National Survey for Family Growth. Diabetes Care. 2009; 32: 1026-31.

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In: Obesity and Pregnancy V. Briese, M. Voigt and S. Straube, pp. 25-30

ISBN: 978-1-60876-111-1 © 2010 Nova Science Publishers, Inc.

Chapter VII

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Infertility About 10 – 15 % of couples planning pregnancy cannot become pregnant, in 50 % of these cases the reasons are predominantly to do with the women, in 30 % of cases predominantly to do with the man, and in about 20 % to do with both parties. We recommend that concerned couples seek help after about one year of unsuccessfully trying to become pregnant and present to an infertility clinic. This may seem early but a thorough diagnostic work-up takes time and such a thorough work-up is needed. Especially juvenile and abdominal obesity predispose to infertility. A main component of treatment of infertility in the obese is pre-conceptional weight reduction. Both undernutrition and overnutrition decrease the likelihood of pregnancy (ESHRE Capri Workshop Group 2006). Obesity is often associated with anovulatory cycles. These are due to altered steroid metabolism caused by changes in leptin, adiponectin, insulin, androgens and sex hormone binding globulin. There is evidence that hyperinsulinemia can cause androgen excess, which, in turn, leads to altered ovarian physiology and ovulatory disturbances (Pasquali et al. 2006, 2007). Hyperandrogenization together with further metabolic abnormalities caused by obesity and hyperinsulinemia are characteristic of polycystic ovarian syndrome (PCOS). Obesity also impacts on gonadotropin release from the pituitary. Jain et al. (2007) investigated the effect of obesity on pulsastile luteinizing hormone (LH) release. Comparing obese and normal weight women (both groups with normal menstrual cycles) they found that, while the pulse frequency was maintained, there was a significant reduction in LH amplitude in obese women. Furthermore, with increased adipose tissue more leptin and resistin is synthesized and less adiponectin. These changes impact on energy homeostasis and can have a direct or indirect adverse effect on the reproductive system (Mitchell et al. 2005). Obesity reduces the chances of spontaneous pregnancy. Van Steeg et al. (2008) investigated the effect of obesity on the likelihood of a spontaneous pregnancy in a prospective cohort study of 3029 subfertile couples. They found that the probability of spontaneous pregnancy decreased with increasing BMI. For every BMI unit above 29, the probability of pregnancy was reduced by about 5 %. Of note, women in this study had to be ovulatory to be included. Therefore the decreased likelihood of pregnancy in obesity cannot solely be explained by anovulation.

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To confirm that fertility rates in obesity are lower and that this impacts on couples‘ lives we investigated whether obese women more often undergo fertility treatment than normal weight women. Based on the perinatal statistics of the German federal state of MecklenburgWestern Pomerania we investigated whether overweight and obese women had more commonly undergone fertility treatment than normal weight women. Perinatal statistics in Germany provides information about previous fertility treatment for every pregnancy. We analyzed 68,362 singleton pregnancies from the perinatal statistics of Mecklenburg-Western Pomerania of 1994 – 2000 (Table 7-1). Overall 1209 pregnant women (1.77 %) had previously undergone fertility treatment. The preterm birth rate overall was 11.25 %. Of the 1209 women with previous infertility treatment 36.2 % were overweight or obese. Table 7-1 and Figure 7-1 illustrate the proportion of women with previous infertility treatment according to BMI. Previous infertility treatment was more common for women with a higher BMI compared to normal weight women. When overweight status and obesity are analyzed together, we derived figures of 1.66 % (normal weight) vs. 2.08 % (overweight or obese) for the proportion of women with previous infertility treatment (Figure 7-2). We also calculated preterm birth rates (neonates born at < 36 weeks‘ gestation) according to BMI in those women who had undergone infertility treatment. Women with a BMI 30.00 – 34.99 who had undergone fertility treatment had the highest rates, 12.5 %, but the differences between groups was rather small and there was no convincing trend (Table 7-1, Figure 7-3).

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Table 7-1. Women (primiparae and multiparae) with singleton pregnancies according to BMI and percentage of these women with previous infertility treatment. (Data from the perinatal statistics of Mecklenburg-Western Pomerania, 1994 – 2000, n = 68,362). Preterm birth rates for women with previous infertility treatment are also given. BMI

40

total

2,953 1.15

18.5024.99 44,418 1.66

All women (n) Women with previous infertility treatment (% of total) Preterm births (< 36 weeks) in women with previous infertility treatment (n) Preterm birth rate in women with previous infertility treatment (%)

478 2.09

68,362 1.77

4

85

29

13

5

0

136

11.74

11.52

10.86

12.5

8.93

0

11.25

To confirm the above findings and also to account for the influence of maternal age we conducted another analysis of rates of previous infertility treatment according to BMI, on a different data-set and adjusted for age. We used data from German perinatal statistics of 1998 – 2000 (Table 7-2, Figure 7-4). With increasing age the percentage of women who have had fertility treatment increased, as expected. In all age groups there was an obvious trend towards higher rates of previous infertility treatment in obese women. For example, in the age

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Infertility

27

group of 25 – 29 year-olds 2.3 % of women in the normal weight category have had previous infertility treatment vs. 12.5 % in obese women with a BMI > 35.

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Figure 7-1. Rate (in %) of women with previous infertility treatment according to BMI.

Figure 7-2. Rate of previous infertility treatment (in %) in normal weight and overweight/obese women.

Figure 7-3. Preterm birth rate according to BMI in women with previous infertility treatment.

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28

Table 7-2. Previous infertility treatment according to maternal age and BMI. We show numbers of women who have had previous infertility treatment (first number in each field), total number of women in each age and BMI group (second number), and the percentage with previous infertility treatment (German perinatal statistics 1998 – 2000; after age adjustment n = 248,608). Included were primiparous and multiparous women.

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Maternal age (years) < 20 20 - 24 25 - 29 30 - 34 35 - 39 > 39

BMI 18.50 - 24.99

BMI 30.00 – 34.99

BMI > 35

17 / 10,902 0.2 % 280 / 40,163 0.7 % 1,412 / 60,455 2.3 % 2,231 / 39,568 5.6 % 849 / 9,226 9.2 % 131 / 1,090 12.0 %

2 / 611 0.3% 62 / 3,872 1.6 % 221 / 5,074 4.4 % 216 / 2,986 7.2 % 90 / 757 11.9 % 25 / 123 20.3 %

1 / 175 0.6% 47 / 1,391 3.4 % 256 / 2,044 12.5 % 129 / 1,218 10.6 % 49 / 344 14.2 % 11 / 51 21.6 %

Figure 7-4. Rate of previous infertility treatment (in %) according to BMI in women aged 25 – 29 years (German perinatal statisitics, 1998 – 2000).

In conclusion, the effect of obesity on fertility – though it has long been underestimated – is considerable. Increased adipose tissue mass affects metabolic and hormonal homeostasis. As a consequence, irregular cycles, anovulation, reduced conception and implantation rates, and increased rates of pregnancy loss can result (Zain and Norman 2008; Ku et al. 2006). Hyperleptinemia can directly affect ovarian function causing impairment in follicular maturation. Also, obesity goes along with decreased chances for live birth after assisted reproduction (IVF and ICSI) and with an impaired response to ovarian stimulation

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Infertility

29

(Fedorcsák et al. 2004). When eggs are harvested for in vitro fertilization in obese women they are more often immature. Defects of implantation implicate malfunction of the endometrium, though details are at present unclear (Levens and Skarulis 2008). Even small amounts of weight loss can have a positive impact on the disordered menstrual cycles and hormonal imbalances. Weight reduction should precede in vitro fertilization in obese women. An adequate nutritional plan should take account of peripheral insulin resistance and dyslipidemias. We recommend foods with low glycemic index and avoiding excess animal fats.

Some Hints for Clinical Practice • • •

• • •

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• •

Weight reduction (5 % - 10 %) improves ovulation and fertility (Balen et al. 2007, Nelson et al. 2007). Hyperinsulinemia/impairedglucose tolerance/type 2 diabetes and hyperandrogenemia should be excluded. In PCOS patients, consider using metformin (in the presence of hyperinsulinemia as demonstrated by elevated insulin levels on a 75 g oral glucose tolerance test) (see Mathur et al. 2008). Consider a combination of metformin with clomiphene citrate or FSH (follicle stimulating hormone) for ovarian stimulation. Address insulin resistance before infertility treatment. Insulin resistance is an independent risk factor for spontaneous abortion (Tian et al. 2007). Don‘t forget the partner. Disturbed spermatogenesis and erectile dysfunction can occur in obese men (Pasquali et al. 2006). Previous infertility treatment is associated with higher preterm birth rates, also in obese women. Finally, a piece of ‗good news‘: Increased BMI decreased the risk of endometriosis (Parazzini et al. 2008).

References Balen AH, Anderson RA. Impact of obesity on female reproductive health: British fertility society, Policy and Practice Guidelines. Hum. Fertil. (Camb). 2007; 10: 195 – 206. ESHRE Capri Workshop Group. Nutrition and reproduction in women. Hum. Reprod. Update. 2006; 12: 193-207. Fedorcsák P, Dale PO, Storeng R, Ertzeid G, Bjercke S, Oldereid N, Omland AK, Abyholm T, Tanbo T. Impact of overweight and underweight on assisted reproduction treatment. Hum. Reprod. 2004; 19: 2523-2528. Jain A, Polotsky AJ, Rochester D, Berga SL, Loucks T, Zeitlian G, Gibbs K, Polotsky HN, Feng S, Isaac B, Santoro N. Pulsatile luteinizing hormone amplitude and progesterone metabolite excretion are reduced in obese women. J. Clin. Endocrinol. Metab. 2007; 92: 2468-2473.

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Ku SY, Kim SD, Jee BC, Suh CS, Choi YM, Kim JG, Moon SY, Kim SH. Clinical efficacy of body mass index as predictor of in vitro fertilisation and embryo transfer outcomes. J. Korean Med. Sci. 2006; 2: 300-303. Levens ED, Skarulis MC. Assessing the role of endometrial alteration among obese patients undergoing assisted reproduction. Fertil Steril. 2008; 89: 1606 – 1608. Mathur R, Alexander CJ, Yano J, Trivax B, Azziz R. Use of metformin in polycystic ovary syndrome. Am. J. Obstet. Gynecol. 2008; 199: 596 – 609. Mitchell M, Armstrong DT, Robker RL, Norman RJ. Adipokines: implications for female fertility and obesity. Reproduction. 2005; 130: 583-597. Nelson SM, Fleming RF. The preconceptual contraception paradigm: obesity and infertility. Hum. Reprod. 2007; 22: 912-915. Parazzini F, Cipriani S, Bianchi S, Gotsch F, Zanconato G, Fedele L. Risk factors for deep endometriosis: a comparison with pelvic and ovarian endometriosis. Fertil Steril. 2008; 90: 174 – 179. Pasquali R. Obesity, fat distribution and infertility. Maturitas. 2006; 54:363-71. Pasquali R, Patton L, Gambineri A. Obesity and infertility. Curr. Opin. Endocrinol. Diabetes Obes. 2007; 14: 482-7. Tian L, Shen H, Lu Q, Norman RJ, Wang J. Insulin resistance increases the risk of spontaneous abortion after assisted reproduction technology treatment. J. Clin. Endocrinol. Metab. 2007;92:1430-3. Van der Steeg JW, Steures P, Eijkemans MJ, Habbema JD, Hompes PG, Burggraaff JM, Oosterhuis GJ, Bossuyt PM, van der Veen F, Mol BW. Obesity affects spontaneous pregnancy chances in subfertile, ovulatory women. Hum. Reprod. 2008; 23: 324-328. Zain MM, Norman RJ. Impact of obesity on female fertility and fertility treatment. Womens Health. (London Engl). 2008; 4: 183 – 194.

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In: Obesity and Pregnancy V. Briese, M. Voigt and S. Straube, pp. 31-34

ISBN: 978-1-60876-111-1 © 2010 Nova Science Publishers, Inc.

Chapter VIII

Pre-Conceptional Counseling

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The aim of pre-conceptional counseling is to optimize the state of health in women before pregnancy and to minimize risk factors for complications of pregnancy. The task of the obstetrician in this context is to explain to his obese patient, firstly, the consequences of being pregnant on the chronic disease of obesity, and, secondly, the consequences of obesity on pregnancy and the well-being of the child. Few women planning pregnancy follow the recommendations for nutrition and lifestyle (Inskip et al. 2009) and often women only change their lifestyle for the better after a positive pregnancy test. At this time, the critical time for organogenesis (about 17-56 days after conception) will have often passed. A recent paper nicely summarized the approach to pre-conceptional counseling. An adapted version is shown in Table 8-1. Table 8-1. An approach to preconceptional counseling (adapted from Kind and Surbek 2008) 1. Recognizing risk

2. Health counseling

3. Interventions

• • •

Medical history (single most important parameter in risk assessment)

• • •

Test for toxoplasmosis

• •

Vaccinations/boosters

Physical exam Screening: cervical cytology, infections screen/serology, urine test, blood pressure, body weight Genetic screening (if applicable) General health and nutritional counseling including folate supplementation, smoking and drinking cessation, vaccinations, weight reduction, physical activity, attention to psychosocial well-being Adjust medications

Body weight and BMI should not be considered alone; the fat distribution matters also. Abdominal obesity with comparatively little fat in the gluteal and thigh regions signifies greater health risk. Subcutaneous fat - in contrast to visceral fat - is not of so great importance in determining risk.

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Some laboratory tests can be informative in assessing overall risk, and should be considered - depending on local practice and availability: • • • • • • • • • •

Lipid profile Liver function tests Fetuin CRP Thyroid function tests Thrombophilia screen Uric acid Adiponectin (sometimes recommended, not yet standard) Fasting insulin Oral glucose tolerance test

There is an increased risk for developing cardiovascular disease and type 2 diabetes, if at least three of the following five parameters are met:

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• • • • •

Blood pressure above 130/85 mmHg. Fasting blood sugar above 110 mg/dl (6.1 mmol/l). Triglycerides above 150 mg/dl (1.7 mmol/l). HDL cholesterol below 40 mg/dl (1.0 mmol/l). Waist circumferences greater than 88 cm

Pre-conceptional smoking cessation and abstinence from alcohol are of paramount importance. Smoking during pregnancy causes fetal growth restriction and leads to low birth weight. As far as alcohol is concerned, no amount of drinking can be considered entirely safe in pregnancy. Alcoholic embryopathy can already occur at a consumption of 20 - 25 g of ethanol per day. Fetal alcohol syndrome is characterized by craniofacial dysmorphism, learning disability, behavioral abnormalities and multiple malformations. Recreational drug use should also be a topic of discussion during pre-conceptional counseling. ‗Ecstacy‘ for example increases the rate of congenital anomalies several-fold (15.4 % rather than the expected incidence of 2 - 3 %) (McElhatton et al. 1999). Medical conditions that adversely impact on fertility or are associated with complications of pregnancy ought to be treated. In case of insulin resistance or frank diabetes treatment with metformin or rosiglitazone can improve ovulation rates and increase fertility.

Preventing Malformations A number of studies indicate that children of obese pregnant women are at greater risk of neural tube defects. A recent meta-analysis on the subject (Rasmussen et al. 2008) examined 12 studies and found odds ratios for a neural tube defect-affected pregnancy of 1.22 (95 % confidence interval (CI), 0.99-1.49), 1.70 (95 % CI, 1.34-2.15), and 3.11 (95 % CI, 1.755.46) among overweight, obese, and severely obese women, respectively - compared with

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Pre-Conceptional Counseling

33

normal-weight women. Neural tube defect is caused by a failure of neural tube closure three to four weeks post conception. At this point, pregnancy is often not even diagnosed, underlining the importance of pre-conceptional folate supplementation with 800 μg/day. In a case-control study, Ray et al. (2007) implicated the metabolic syndrome in the generation of neural tube defects. They defined maternal features of the metabolic syndrome as the presence of pre-pregnancy diabetes mellitus, body weight > 90th centile, non-white ethnicity and/or serum highly sensitive C-reactive protein > 75th centile, and found a two-fold higher risk for neural tube defects if one of the above features was present. In the presence of two or more features there was a six-fold higher risk for neural tube defects.

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Dietary Supplements Taking a folate-containing multivitamin is a very effective pre-conceptional preventive measure to lower the rate of fetal malformations. To obtain the full beneficial effect the supplement needs to be taken before conception occurs. This measure alone would already justify pre-conceptional counseling. Supplementation with folate-containing multivitamins does not only prevent neural tube defects but also lowers the rates of cardiac malformations, cleft lip and palate, and other anomalies (Czeizel and Dudás 1992, Shaw et al. 1995, Botto et al. 2004). In addition to benefits for the fetus, folate supplementation may also reduce the risk of gestational hypertension (Hernandez-Diaz et al. 2002). If there is a history of fetal malformatons in a women secondary prevention with high dose folic acid (5 mg per day) is indicated for at least 4 to 8 weeks after conception. Omega-3 fatty acids (docosahexaenoic acid, DHA) are likewise important for intrauterine fetal development. During pregnancy and breast feeding a daily substitution with 200 mg DHA can be recommended. A case can also be made for vitamin D and iodine supplementation. Furthermore, zinc deficiency has been linked with neural tube defects (Cengiz et al. 2004). The use of nutritional supplements is an active field of research and we recommend looking out for latest developments. Further pointers about nutrition in pregnancy are given in a separate chapter.

References Botto LD, Olney RS, Erickson JD. Vitamin supplements and the risk for congenital anomalies other than neural tube defects. Am. J. Med. Genet. C Semin. Med. Genet. 2004; 125C: 12-21. Cengiz B, Söylemez F, Oztürk E, Cavdar AO. Serum zinc, selenium, copper, and lead levels in women with second-trimester induced abortion resulting from neural tube defects: a preliminary study. Biol. Trace Elem. Res. 2004; 97: 225 – 235. Czeizel AE, Dudás I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N. Engl. J. Med. 1992; 327: 1832-5.

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Hernandez-Diaz S, Werler MM, Louik C, Mitchell AA. Risk of gestational hypertension in relation to folic acid supplementation during pregnancy. Am. J. Epidemiol. 2002; 156: 806 – 812. Inskip HM, Crozier SR, Godfrey KM, Borland SE, Cooper C, Robinson SM; Southampton Women's Survey Study Group. Women's compliance with nutrition and lifestyle recommendations before pregnancy: general population cohort study. BMJ. 2009; 338:b481. Kind A, Surbek D. Präkonzeptionelle Beratung und Prävention. Gynäkologie. 2008; 3: 6-11. McElhatton PR, Bateman DN, Evans C, Pughe KR, Thomas SH. Congenital anomalies after prenatal ecstasy exposure. Lancet. 1999; 354: 1441 – 1442. Rasmussen SA, Chu SY, Kim SY, Schmid CH, Lau J. Maternal obesity and the risk of neural tube defects: a metaanalysis. Am. J. Obstet. Gynecol. 2008; 198: 611-619. Ray JG, Thompson MD, Vermeulen MJ, Meier C, Wyatt PR, Wong PY, Summers AM, Farrell SA, Cole DE. Metabolic syndrome features and risk for neural tube defects. BMC Pregnancy Childbirth. 2007; 19: 21. Shaw GM, Lammer EJ, Wasserman CR, O'Malley CD, Tolarova MM. Risks of orofacial clefts in children born to women using multivitamins containing folic acid periconceptionally. Lancet. 1995; 346: 393-6.

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Chapter IX

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Pre-Conceptional Weight Reduction Pre-conceptional weight reduction aims to reduce the risks associated with obesity in pregnancy. We advocate an integrated approach including nutritional counseling, excercise, and – if indicated - psychological counseling. The principles of successful weight reduction, pre-conceptionally and otherwise, are simple: eating in moderation and reducing the intake of foods high in refined carbohydrates and fats. Sugery drinks, chocolate, fried foods etc. should be substituted. We furthermore recommend 30 minutes of excercise a day. None of this is new but the reason it might work pre-conceptionally when it has not worked before is that the motivation is different. In this context it is important to point out the risks associated with obesity in pregnancy and the advantages of losing weight. A good strategy is to take ‗one step at a time‘, for example, to gradually increase the amount of excercise. This avoids frustration when too ambitious goals are not reached. Because of the dependence of obesityassociated risks on the extent of obesity, even a small weight reduction is associated with a risk decrease. While this is so, the amount of weight reduction per se is not the only determinant of success, though it is the most easily measured one. With the loss of adipose tissue, muscle tissue has to be built up and nutrition adjusted in the long term. A number of weight loss diets have been tried in premenopausal women and there is no consensus about the composition of the ideal weight loss diet. A recent study compared the Atkins, Zone, LEARN, and Ornish diets in a randomized trial involving 311 overweigt or obese premenopausal women (Gardner et al. 2007). The women who were assigned to the Atkins (low carbohydrate) diet lost most weight at 12 months. Furthermore, secondary outcomes for the Atkins group were at least as good as – if not better than – those for the groups following the other diets. However, the long term safety of a low carbohydrate, highprotein, and high-fat diet has not been established. We believe the choice of which weight loss diet to follow can to some extent reflect personal preferance. Importantly, the principle of a healthy nutrition should not be compromized and the caloric intake should be less than caloric expenditure; then weight loss will occur. Eating less – especially less of high calorie foods – together with exercise is more important than calculating fats contents of foods or counting calories. Without a change in lifestyle, away from obesogenic influences and towards healthy nutrition and physical exercise, no long term weight loss is possible (Figure 9-1)

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Figure 9-1. Three approaches to weight loss (conservative therapy).

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Pharmacotherapy may be considered when conservative measures have failed. Orlistat (an inhibitor of pancreatic lipase, reducing fat absorption) and sibutramine (a serotoninnorepinephrine reuptake inhibitor) have been shown to have higher efficacy in weight loss than placebo (Rubio et al. 2007). Weight loss surgery is only indicated in morbid obesity (Colquitt et al. 2005), or - if other therapy has failed and there are complications of the metabolic syndrome - perhaps also for a BMI > 35. Associated risks, including wound infection and thromboembolism, need to be considered. Successful pregnancy after weight loss surgery has been reported, but such patients are a high risk group from an obstetric perspective and need close supervision (Guelinckx et al. 2009). There is some evidence that surgery may not only reduce excess weight in severely obese patients but also improve their metabolic risk profile within a short time-frame (Wolf and Beisiegel 2007). This area needs further study. A French study agrued that adjustable gastric banding is generally well tolerated during pregnancy and should not be deflated unless there were symptoms (such as total dysphagia, severe epigastric pain, or vomiting after the first trimester of pregnancy) or intrauterine growth restriction. (Jasaitis et al. 2007)

References Colquitt J, Clegg A, Loveman E, Royle P, Sidhu M, Colquitt J. Surgery for morbid obesity. Cochrane Database Syst. Rev. 2005; 4: CD003641. Gardner CD, Kiazand A, Alhassan S, Kim S, Stafford RS, Balise RR, Kraemer HC, King AC. Comparison of the Atkins, Zone, Ornish, and LEARN Diets for Change in Weight and Related Risk Factors Among Overweight Premenopausal Women. JAMA. 2007; 297: 969 – 977. Guelinckx I, Devlieger R, Vansant G. Reproductive outcome after bariatric surgery: a critical review. Hum. Reprod. Update. 2009; 15: 189-201. Jasaitis Y, Sergent F, Bridoux V, Paquet M, Marpeau L, Ténière P. [Management of pregnancies after adjustable gastric banding] J. Gynecol. Obstet. Biol. Reprod. (Paris). 2007; 36: 764-9. Rubio MA, Gargallo M, Isabel Millán A, Moreno B. Drugs in the treatment of obesity: sibutramine, orlistat and rimonabant. Public Health Nutr. 2007; 10(10A):1200-5. Wolf AM, Beisiegel U.The effect of loss of excess weight on the metabolic risk factors after bariatric surgery in morbidly and super-obese patients. Obes. Surg. 2007; 17: 910-9.

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Chapter X

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Care During Pregnancy Counseling obese women during pregnancy with regard to nutrition, lifestyle, obstetric examinations and investigations, and resources of social support is an important part of their care. The main aim is to spot high risk pregnancies early. Routine examinations (see below) during the first half of pregnancy will help to find such high risk pregnancies that will then need enhanced care (weekly or fortnightly visits). Clinically important changes can occur quickly and therefore close surveillance is needed for high risk cases. During history taking particular attention needs to be paid to additional cardiovascular risk factors: smoking, hypertension (night time dip in blood pressure less than 10 %), sleep apnea, a history of thromboembolic and cardiovascular disease (deep vein thrombosis, pulmonary embolism, angina and myocardial infarction, stroke, lipid disorders, diabetes). Young women need special attention: the rate of smokers is high among young women, and only a minority of them present for pregnancy counseling before 12 weeks‘ gestation (Tiller et al. 2008). Treating hypertension in pregnancy decreases the risk of developing severe hypertension. In addition to monitoring absolute blood pressure, an eye needs to be kept on blood pressure increases (30 mmHg systolic and 15 mmHg diastolic). In terms of antihypertensive therapy, beta-blockers seem superior to methyldopa. There is so far no way to significantly reduce the risk of pre-eclampsia or to reliably predict its occurrence. Imbalance between angiogenesis-related factors is implicated in the development of pre-eclampsia, and may potentially be used in determining pre-eclampsia risk. Lim et al. (2008) investigated 40 women who subsequently developed pre-eclampsia and 100 normotensive women. They found that levels of sFlt-1 (soluble FMS-like tyrosine kinase) and soluble endoglin - collected at 14 to 21 weeks‘ gestation - were significantly higher in women with pre-eclampsia, and that levels of PlGF (placental growth factor) and TGF-beta1 (transforming growth factor beta1) were lower. By forming ratios, they were able to predict pre-eclampsia: in women affected by pre-eclampsia, the ratios sFlt-1/PlGF and soluble endoglin/TGF-beta1, and the combined ratio of (sFlt-1+soluble endoglin) / (PlGF+TGF-beta1) were significantly higher than in normotensive women. This way of predicting pre-eclapmsia is promising but needs to be validated by larger studies before routine use.

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Ultrasound can be used for the diagnosis of fetal macrosomia. The parameters to be assessed include biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), and femur length (FL). Macrosomia most often manifests in the third trimester. The risk of developing macrosomia is < 1 % for an AC < 35 cm, but is 37 % for an AC > 37 cm (Woodward et al. 2005). Further features to watch out for are increased subcutaneous adipose tissue and a large amount of echogenic subcutaneous fat. One third of fetuses with idiopathic hydramnios exhibit macrosomia. Growth graphs are useful visual tools. The occurrence of fetal macrosomia should be taken as an indication to investigate possible gestational diabetes in the mother.

Recommendations for the Care of Obese Pregnant Women

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At 12 weeks‘ gestation

Every 2-4 weeks Every 6 weeks At 20 weeks‘ gestation At 24 weeks‘ gestation At 28 weeks‘ gestation At 36 weeks‘ gestation At 40 weeks‘ gestation Screening tests

General history Obstetric history Basic gynecological examination General medical examination (including blood pressure, consider 24 hour blood pressure monitoring) Dermatological exam (intertrigo during pregnancy can make life uncomfortable) Laboratory tests: - Hemoglobin - Creatinine - Lipid profile (triglycerides, LDL cholesterol, HDL cholesterol) - Liver function tests ECG (if indicated: excercise ECG) Echocardiography 75 g oral glucose tolerance test (75g OGTT) Prophylaxis against venous thromboembolism Discuss nutrition and physical exercise: Folate 800 μg/day Iodine 100 μg/day Vitamin D 800 IU/day Consider iron and zinc supplementation (Wisser 2008). Check for hypertension, proteinuria and edema 75 g OGTT Ultrasound for malformations, macrosomia, incompetent cervix, amniotic fluid (hydramnios), uterine artery Doppler Uterine artery Doppler; In future it may become feasible to determine proangiogenic and antiangiogenic factors (see below). Assess respiratory function of the placenta: weekly fetal heart rate monitoring, measure fetal blood flow every 2 weeks Plan delivery, make arrangements Macrosomia is an important issue (risk of shoulder dystocia), consider Cesarean section Hepatitis B (3rd trimester), Chlamydia, group B streptococci, vaginal candidosis (obesity - along with psychosocial factors – is a risk factor for recurrent vaginal candidosis).

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Care During Pregnancy

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References

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Lim JH, Kim SY, Park SY, Yang JH, Kim MY, Ryu HM. Effective prediction of preeclampsia by a combined ratio of angiogenesis-related factors. Obstet. Gynecol. 2008; 111: 1403 – 1409. Tiller R, Friedrich A, Tiller G. Teenagerschwangerschaften – Morbidität und Mortalität von Neugeborenen jugendlicher Mütter der Geburtsjahrgänge 1998 – 2005. Gyn. 2008; 421 – 425. Wisser J. Evidenzbasiertes Wissen in der Geburtshilfe. Entscheidungen nach Cochrane und Co. Gynäkologie und Geburtshilfe. 2008; 8:33–36. Woodward PJ, Kennedy A, Sohaey R, Byrne JLB, Oh KY, Puchalski MD. Diagnostic Imaging Obstetrics. Amyrsis Inc, Salt Lake city, Utah, 2005.

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ISBN: 978-1-60876-111-1 © 2010 Nova Science Publishers, Inc.

Chapter XI

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Nutrition in Pregnancy: Some Pointers The authors of this book are not nutritionists. We do not want to discuss nutrition during pregnancy at length. This would be beyond the scope of this book. Rather we would like to provide some pointers that we feel are important to the care of obese pregnant women. The causation of obesity is of course multifactorial but unhealthy nutrition often plays a role. Nutritional counseling will commonly fall on fertile ground during pregnancy as pregnant women often have an increased health awareness and will be susceptible to advice, when perhaps otherwise they would not have been. Pregnancy may therefore represent an opportunity for nutritional counseling with the aim of adopting healthy eating habits long term. Pregnancy is no time for radical dieting with the aim of weight loss. Dieting may compromise fetal well-being. Calorie reduction may be called for but always under strict and frequent medical supervision. Standard advice for a healthy diet holds true during pregnancy: About 20% of calories should be obtained through protein, 30% to 35% through fat, and about half through carbohydrates. There is no need to ―eat for two‖. Even for normal weight women, standard advice is that the usual amount of calories should be maintained for the first three months. Between months four to seven a weight gain of 4-6 kg on average is normal, and thereafter another 4-6 kg. Weight gain is very dependent on maternal height and weight, but not per se on BMI (Straube et al. 2008). The percentile tables for weight gain during pregnancy according to maternal height and weight that we include as an appendix to this book may be of help. Obtaining the necessary amounts of protein and fat is important during pregnancy and breastfeeding. Some fat intake is necessary, even for obese women, not least to ensure adequate supply of fat soluble vitamins. Attention should be paid to the kind of fats used, however. The use of saturated fats should be restricted. This means that fats of animal origin ought to be used sparingly. Furthermore attention should be paid to include a sufficient amount of omega-3 fatty acids and to avoid hydrogenated fats (trans fats) where possible. Food consumed during pregnancy should be rich in vitamins and minerals. For some vitamins and minerals it is not easy to meet the increased need during pregnancy and breastfeeding, among them calcium, iron, iodine, and vitamins B1, B6, B12, folic acid and vitamin D. For folic acid, for example, the recommended amount cannot be obtained only

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through food. Folic acid therefore needs to be supplemented. Such supplementation is especially important in the obese because lack of sufficient folic acid intake has been linked with neural tube abnormalities (such as spina bifida) and the incidence of such neural tube abnormalities increases with increasing maternal BMI (Voigt et al. 2008). Vitamin D deficiency is already very common in the general population (Holick 2007). Obesity is an additional risk factor for vitamin D deficiency and is associated with poor vitamin D status in mothers and neonates (Bodnar et al. 2007, Wortsman et al. 2000). A large proportion of pregnant women receive only half (sometimes even less) of their recommended daily doses of some vitamins and minerals (Briese et al. 2001). An analysis of 852 nutritional diaries showed that 20 % of women had an excessive energy intake; 24 % were overweight (Briese et al. 2001, Figure 11-1).

Figure 11-1. Nutritional energy intake in pregnant women (from Briese et al. 2001).

We recommend the following supplements per day: • • •

Folic acid 800 μg Iodine 100 μg Vitamin D 800 IU

There is good evidence that a Mediterranean diet (Willet et al. 1995) is beneficial for a number of health outcomes. We recommend following such a diet during pregnancy; the components of a Mediterranean diet are in good agreement with the nutritional needs during pregnancy. Pulses, vegetables, fruits and cereals should be consumed daily. Fish and seafood can be consumed several times per week; consumption of red meat should be restricted.

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References

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Bodnar LM, Catov JM, Roberts JM, Simhan HN. Prepregnancy obesity predicts poor vitamin D status in mothers and their neonates. J. Nutr. 2007; 137: 2437 – 2442. Briese V, Kirschner W, Friese K. Ernährungsberatung: Ernährungsdefizite in der Schwangerschaft. Frauenarzt. 2001; 42: 1220 – 1228. Holick MF.Vitamin D deficiency. N. Engl. J. Med. 2007; 357: 266-81. Straube S, Voigt M, Briese V, Schneider KT, Voigt M. Weight gain in pregnancy according to maternal height and weight. J. Perinat. Med. 2008; 36: 405-12. Voigt M, Straube S, Zygmunt M, Krafczyk B, Schneider KT, Briese V. Obesity and pregnancy - a risk profile. Z. Geburtshilfe Neonatol. 2008; 212: 201-5. Willet WC, Sacks F, Trichopoulou A. Mediterranean diet pyramid: a cultural model for healthy eating. Am. J. Clin. Nutr. 1995; 61(6 Suppl): 1402S-1406S. Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity. Am. J. Clin. Nutr. 2000; 72: 690 – 693.

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In: Obesity and Pregnancy V. Briese, M. Voigt and S. Straube, pp. 45-46

ISBN: 978-1-60876-111-1 © 2010 Nova Science Publishers, Inc.

Chapter XII

Polycystic Ovary Syndrome Polycystic ovary syndrome (PCOS) includes a number of overlapping and difficult to delineate dysfunctions of ovary and adrenal cortex. PCOS is common (prevalence about 5-10 %), perhaps the most common endocrine disorder in women of reproductive age, and is characterized by the following features:

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1 2 3

Oligomenorrhea and/or anovulation Hyperandrogenemia (androgenization) Polycystic ovaries. (On ultrasound 12 or more peripherally oriented follicles of 2 - 9 mm should be seen in an ovary or the ovary should be > 10 ml in volume.)

Of these three features, two have to be present for a diagnosis of PCOS. Features of the metabolic syndrome can also develop in PCOS patients. Obesity is strongly correlated with PCOS as are insulin resistance and diabetes. The risk of cardiovascular disease is increased. While details of the etiology and pathogenesis of PCOS remain elusive, there is good evidence for a genetic basis. For example, the plasminogen activator inhibitor 14G/5G polymorphism is associated with PCOS as shown by a recent meta-analysis (Bagos 2009). PCOS typically manifests during adolescence but it has been hypothesized to originate during fetal life (Franks et al. 2006). These is evidence that altered endothelial function occurs is PCOS. A study of 50 women with PCOS and 50 matched controls found that adverse endothelial parameters (increased intima-media thickness, decreased brachial artery flowmediated dilation) were correlated with insulin resistance and lower levels of the adipokine adiponectin (Carmina et al. 2006). For patients with PCOS, as for all obese women planning pregnancy, pre-conceptional weight reduction should be aimed for. In PCOS long term treatments with anti-androgens (‗micro-pill‘) is indicated, independent of the extent of apparent androgenization. The cyclical use of the oral contraceptive pill cannot be recommended, as it does not appreciably affect ovarian volume or the number of follicles (Mulders et al. 2005). Fertility is reduced in PCOS and a number of fertility treatments can be used in obese women with PCOS, including in vitro fertilization (IVF). Not surprisingly, chances of success with IVF can be enhanced by weight reduction. A recent study found that morbidly

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obese women with PCOS had lower pregnancy rates after IVF than patients with who were not morbidly obese (Jungheim et al. 2008). Fertility treatment in PCOS is a complex topic in its own right extending from life-style interventions (addressing obesity, smoking, and alcohol) to ovulation induction with the anti-estrogen clomiphene citrate, gonadotrophins or laparoscopic ovarian surgery (Tarlatzis et al. 2008). PCOS is associated with recurrent miscarriage. It has been suggested that weight loss, along with ovarian drilling and metformin could help to reduce the rate of miscarriage (Cocksedge et al. 2008).

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References Bagos PG. Plasminogen activator inhibitor-1 4G/5G and 5,10-methylene-tetrahydrofolate reductase C677T polymorphisms in polycystic ovary syndrome. Mol. Hum. Reprod. 2009; 15: 19 – 26. Carmina E, Orio F, Palomba S, Longo RA, Cascella T, Colao A, Lombardi G, Rini GB, Lobo RA. Endothelial dysfunction in PCOS: role of obesity and adipose hormones. Am. J. Med. 2006; 119: 356.e1-6. Cocksedge KA, Li TC, Saravelos SH, Metwally M. A reappraisal of the role of polycystic ovary syndrome in recurrent miscarriage. Reprod. Biomed. Online. 2008; 17: 151-60. Franks S, McCarthy MI, Harsy K. Development of polycystic ovary syndrome: involvement of genetic and environmental factors. Int. J. Androl. 2006; 29: 278-285. Jungheim ES, Lanzendorf SE, Odem RR, Moley KH, Chang AS, Ratts VS. Morbid obesity is associated with lower clinical pregnancy rates after in vitro fertilization in women with polycystic ovary syndrome. Fertil Steril. 2009; 92: 256-61. Mulders AG, ten Kate-Booij M, Pal R, De Kruif M, Nekrui L, Oostra BA, Fauser BC, Laven IS. Influence of oral contraceptive pills an phenotype expression in women with polycystic ovary syndrome. Reprod. Biomed. Online. 2005; 11: 690-696. Tarlatzis BC, Fauser BC, Legro RS, Norman RJ, Hoeger K, Pasquali R, Franks S, Messinis IE, Casper RF, Homburg JN, Lobo R, Rebar RW, Fleming R, Carr BR, Bouchard P, Chang J, Hugues JN, Azziz R, Kolibianakis EM, Griesinger G, Diedrich K, Balen A, Farquhar C, Devroey P, Ho PC, Collins J, Goulis DG, Eijkemans R, Crosignani PG, DeCherney A, Van Steirteghem A. Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Hum. Reprod. 2008; 23: 462-77.

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In: Obesity and Pregnancy V. Briese, M. Voigt and S. Straube, pp. 47-49

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Chapter XIII

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Abdominal Obesity and Metabolic Syndrome BMI alone is not a sufficient indicator of risk in obesity. The distribution of fat matters, too: peripheral obesity is different from abdominal obesity. Abdominal obesity, also known as visceral, central or ‗apple-type‘ obesity goes along with intra-abdominal fat deposition. Intra-abdominal fat is considered the main adverse factor because it is metabolically very active and may also constrict intra-abdominal organs and vessels. Abdominal obesity can be described by waist circumference (> 88 cm is considered dangerous for women) or waist to hip ratio (indicative of abdominal obesity in women if greater than 0.85). Peripheral obesity (‗pear-type‘) is characterized by a fat distribution largely around hips, buttocks and thighs and is not associated with the risks of abdominal obesity. Traditionally, abdominal obesity was thought to predominate in man, whereas peripheral obesity was believed to more commonly occur in women. However, a significant number of women are affected by abdominal obesity, too. There is no doubt that abdominal obesity is the worst of the two forms. Abdominal obesity is more strongly associated with the metabolic syndrome (see below), cardiovascular disease and diabetes (Balkau et al 2007), and possibly stroke (according to a recent study for men but not women (Hu et al. 2007). Furthermore, reducing abdominal obesity has been shown to improve fertility (Zain and Norman 2008). The risks associated with abdominal obesity seem to increase with increasing waist circumference, even in non-obese people. There are strong genetic factors in the development of abdominal obesity. Wade and colleagues studied 5092 twin pairs and concluded that while most of the genetic effect on abdominal adiposity was common to BMI, 40% was attributable to independent genetic influences. Environmental effects were small. Interestingly, depressive symptoms have been found to result in an increase in abdominal obesity independent of overall obesity (Vogelzangs et al. 2008), leading to a speculation that there could be specific pathophysiological mechanisms that link depression with visceral fat accumulation. Social status and occupation also impact on the prevalence of abdominal obesity. Shift workers are especially at risk. Copertaro and others studied 262 healthcare providers: 130 rotating shift nurses and 132 day nurses. In comparison with day workers, rotating shift nurses had a significantly greater waist circumference.

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The metabolic syndrome is associated with abdominal obesity and comprises the following conditions: • • • •

(Abdominal) obesity, Hypertension, Type 2 diabetes, and dyslipidemia.

There are different definitions of the metabolic syndrome about; which does not help in assessing its prevalence (Moebus et al. 2007). WHO criteria for diagnosis of the metabolic syndrome in women (quoted from Grundy at al. 2004) require the presence of: • • • •

Type 2 diabetes, Impaired fasting glucose, Impaired glucose tolerance or insulin resistance

and two of the following:

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• • • • •

Blood pressure ≥ 140/90 mmHg Plasma triglycerides ≥ 150 mg/dl (1.7 mmol/l) HDL cholesterol < 39 mg/dl (1.0 mmol/l) BMI >30 and/or waist to hip ratio > 0.85 Urinary albumin excretion rate ≥ 20 µg/min or albumin to creatinine ratio ≥ 30 mg/g

Obesity and - in particular - abdominal obesity can be seen as the primary cause of the metabolic syndrome (Lawler et al. 2006). Overweight status, obesity and the metabolic syndrome - through an association with hypertension - are linked with left ventricular hypertrophy and dilatation. Affected women are a high-risk population when pregnant. Of note in this context is the ―obesity paradox‖ that in heart failure BMI is inversely associated with mortality; so that patients with high BMI may have a better prognosis (Artham et al. 2006). Still, overall, obesity is clearly an adverse influence on cardiovascular and general health. The abnormalities of the metabolic syndrome or a tendency to develop them can already be seen in young patients and even in children. McCarthy warns that a ―global epidemic of obesity in children‖ would result in a rise in the number of patients with the metabolic syndrome. Not overall obesity per se (as assessed by BMI), but rather excess abdominal obesity (measured by waist circumference) would be the better measure of risk for the metabolic abnormalities associated with the metabolic syndrome in children (McCarthy 2006).

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References Artham SM, Lavie CJ, Milani RV, Ventura HO. The obesity paradox: impact of obesity on the prevalence and prognosis of cardiovascular diseases. Postgrad. Med. 2008; 120: 3441. Balkau B, Deanfield JE, Després JP, Bassand JP, Fox KA, Smith SC Jr, Barter P, Tan CE, Van Gaal L, Wittchen HU, Massien C, Haffner SM. International Day for the Evaluation of Abdominal Obesity (IDEA): a study of waist circumference, cardiovascular disease, and diabetes mellitus in 168,000 primary care patients in 63 countries. Circulation. 2007; 116: 1942-51. Copertaro A, Bracci M, Barbaresi M, Santarelli L. Role of waist cirumference in the diagnosis of metabolic syndrome and assessment of cardiovascular risk in shift workers. Med. Lav. 2008; 99: 444-53. Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C; American Heart Association; National Heart, Lung, and Blood Institute. Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004; 109: 433-8. Hu G, Tuomilehto J, Silventoinen K, Sarti C, Männistö S, Jousilahti P. Body mass index, waist circumference, and waist-hip ratio on the risk of total and type-specific stroke. Arch. Intern. Med. 2007; 167: 1420-7. Lawlor DA, Lean M, Sattar N. ABC of obesity: obesity and vascular disease. BMJ. 2006; 333: 1060 – 1063. McCarthy HD. Body fat measurements in children as predictors for the metabolic syndrome: focus on waist circumference. Proc. Nutr. Soc. 2006; 65: 385-92. Moebus S, Hanisch JU, Aidelsburger P, Bramlage P, Wasem J, Jöckel KH: Impact of 4 different definitions used for the assessment of the prevalence of the Metabolic Syndrome in primary healthcare: The German Metabolic and Cardiovascular Risk Project (GEMCAS). Cardiovasc. Diabetol. 2007; 6: 22. Wardle J, Carnell S, Haworth CMA, Plomin R: Evidence for a strong genetic influence on childhood adiposity despite the force oft the obesogenic environment. Am. J. Clin. Nutr. 2008; 87: 398–404. Zain MM, Norman RJ. Impact of obesity on female fertility and fertility treatment. Womens Health. (Lond Engl). 2008; 4: 183-94.

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Chapter XIV

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Dyslipidemia Dyslipidemia is characterized by a disproportion of the concentrations of plasma lipids: hypertriglyceridemia, decreased HDL cholesterol and increased LDL cholesterol. Dyslipidemia during pregnancy is not only detrimental to maternal health but also enhances susceptibility to atherosclerosis in the offspring through fetal programming. In addition to maternal cholesterol, the CRP level during pregnancy is also a predictor of increased atherogenesis in children of hypercholesterolemic mothers (Liquori et al. 2008). Dyslipidemias can be primary or secondary. Primary dyslipidemias are genetically determined. Primary dyslipidemia can lead to a hypertriglyceridemia-induced pancreatitis during pregnancy, a condition with a high maternal mortality. A therapeutic option to avoid pancreatitis is plasma exchange (Sivakumaran et al. 2009). Secondary dyslipidemias occur with a number of conditions including obesity, diabetes, the metabolic syndrome, hypothyroidism, nephritic syndrome, chronic renal insufficiency, cholestatic liver disease, and also as drug side effects (with corticosteroids, thiazide diuretics, and contraceptives) or with alcohol abuse (Chait and Brunzell 1990, Mooradian 2009, Tsimihoimos et al. 2008). Secondary dyslipidemia is also physiologic during pregnancy. A study on the National Health and Nutrition Examination Survey found a prevalence of dyslipidemia in the morbidly obese of 19 % (Nguyen et al. 2004). An analysis of 1008 consecutive young (15 – 49 year-old) ischemic stroke patients from Helsinki University Central Hospital found that dyslipidemia was the most frequent risk factor for ischemic stroke in young people, affecting 60 % of them (Putaala et al. 2009). Dyslipidemia is a major risk factor for cardiovascular and cerebrovascular complications of maternal obesity, so that pre-conceptional diagnosis and treatment of dyslipidemia are of the utmost importance. An analysis of the Framingham Heart Study found that over a 10-year period there was a decrease in dyslipidemia (increase in HDL cholesterol, decrease in triglyceride levels) despite an overall increase in BMI. However, people with the least increase in BMI were found to have had the most favorable changes in their lipid profile. Controlling BMI makes sense from the point of view of preventing dyslipidemia. The target values for LDL cholesterol are determined by cardiac risk. For low cardiac risk patients LDL cholesterol should be < 160 mg/dl (4.13 mmol/l), for those with medium risk < 130 mg/dl (3.36 mmol/l), and for those with high risk (metabolic syndrome) < 100

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mg/dl (2.58 mmol/l). For triglycerides the target value is < 150 mg/dl (1.69 mmol/l); though for younger women (< 30 years) levels of > 128 mg/dl (1.45 mmol/l) already merit treatment. HDL cholesterol in women should be at least 50 mg/dl (1.3 mmol/l). For a correction of dyslipidemia - after lifestyle and nutritional measures have been exhausted - statins are often used. Statins are contraindicated in pregnancy. Pre-conceptional statin therapy therefore necessitates concurrent contraception. Hormonal contraception, however, is contra-indicated in older women with obesity and dyslipidemia because of increased cardiovascular risk.

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References Chait A, Brunzell JD. Acquired hyperlipidemia (secondary dyslipoproteinemias). Endocrinol. Metab. Clin. North Am. 1990; 19: 259-78. Dörner K. Clinical Chemistry and Hematology. Georg Thieme Verlag, Stuttgart 2006; 158 165. Ingelsson E, Massaro JM, Sutherland P, Jacques PF, Levy D, D‘Agostino RB, Vasan RS, Robins SJ. Contemporary trends in dyslipidemia in the Framingham Heart Study. Arch. Intern. Med. 2009; 169: 279 – 286. Liquori A, D‘Armiento FP, Palagiano A, Palinski W, Napoli C. Maternal C-reactive protein and developmental programming of atherosclerosis. Am. J. Obstet. Gynecol. 2008; 198: 281.e1 – 5. Mooradian AD. Dyslipidemia in type 2 diabetes mellitus. Nat. Clin. Pract. Endocrinol. Metab. 2009; 5: 150 – 159. Nguyen NT, Magno CP, Lane KT, Hinojosa MW, Lane JS. Association of hypertension, diabetes, dyslipidemia, and metabolic syndrome with obesity: findings from the National Health and Nutrition Examination Survey, 1999 to 2004. J. Am. Coll. Surg. 2008; 207: 928-934. Putaala J, Metso AJ, Metso TM, Konkola N, Kraemer Y, Haapaniemi E, Kaste M, Tatlisumak T. Analysis of 1008 Consecutive Patients Aged 15 to 49 With First-Ever Ischemic Stroke. The Helsinki Young Stroke Registry. Stroke. 2009; 40: 1195-203 Sivakumaran P, Tabak SW, Gregory K, Pepkowitz SH, Klapper EB. Management of familial hypertriglyceridemia during pregnancy with plasma exchange. J. Clin. Apher. 2009; 24: 42 – 46. Tsimihoimos V, Dounousi E, Siamopoulos KC. Dyslipidemia in chronic kidney disease: an approach to pathogenesis and treatment. Am. J. Nephrol. 2008; 28: 958 – 973.

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Chapter XV

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Smoking Smoking is the most important avoidable cause of death. Smoking and (morbid) obesity in isolation are about equally dangerous, leading to a shortening of life expectancy of about 10 years (Whitlock et al. 2009). Together they are an extremely harmful combination. Like obesity smoking also favors the development of diseases associated with the metabolic syndrome. Smoking, obesity, and diabetes are a ‗deadly triad‘, especially with regard to causing cardiovascular disease. Smoking has a variety of adverse effects. It has been associated with vascular, pulmonary, and neoplastic diseases for a while but also has a diabetogenic effect. Both smoking and obesity increase insulin resistance and therefore favor the pathogenesis of type 2 diabetes (Chelland et al. 2008, Berlin 2009). Smoking decreases glucose tolerance, increases insulin levels, and worsens glycemic control. About 20 - 30 % of women smoke during pregnancy, despite medical advice to the contrary (Santos et al. 2008, Somm et al. 2008). Pre-conceptional smoking cessation along with weight reduction is an effective intervention in terms of risk reduction, though the best strategy how this can be done is unclear; more studies are needed here. Objective measures of tobacco smoking, expiratory CO and cotinine, can confirm smoking or abstinence, and can also inform about passive smoking (cotinine). In smokers, CO should be measured at least yearly. To plan smoking cessation the Fagerström test for nicotine dependence can be helpful (Heatherton et al. 1991). Importantly, abstinence from smoking achieved during pregnancy should be maintained after delivery. Weight gain following smoking cessation commonly concerns patients (Berg et al. 2008). This concern must be addressed during the consultation and placed into the context of the overall health benefits of smoking cessation. We wondered how smoking and obesity interacted and analyzed data from German perinatal statistics. Figure 15-1 shows the proportion of smoking mothers (percentages on top of the columns) according to BMI groups and also a subdivision of the smoking women according to the number of cigarettes smoked per day (percentage figures on the y-axis). The proportion of smokers among all women and the proportion of smokers consuming > 10 cigarettes per day among the smokers both increased with increasing BMI. Smoking was more common in the obese and the obese were heavier smokers.

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Figure 15-1. Smoking rates and daily cigarette consumption in pregnant women (German perinatal statistics, 1998 – 2000, singleton pregnancies).

One of the main adverse effects of smoking in pregnancy is the increased rate of smallfor-gestational-age (SGA) infants in smokers (Magee et al. 2004). The interactions between smoking and obesity on the one hand and fetal growth and pre-eclampsia on the other hand are still unclear and need further attention (Conde-Agudelo et al. 1999, Newman et al. 2001, Ness et al. 2006, 2008). There is some evidence that smoking has an anti-inflammatory effect and may be ‗protective‘ from pre-eclampsia. Ness et al. (2008) investigated 7,757 singleton pregnancies regarding the interaction of BMI and smoking with SGA and pre-eclampsia rates. For both underweight and overweight women, smoking increased SGA risk. Among underweight and normal weight women, smoking decreased pre-eclampsia risk; but this was not true for overweight and obese women. In obese women, a ‗protective‘ effect of smoking regarding pre-eclampsia risk could not be demonstrated. Obesity is a risk factor for neonatal macrosomia and smoking is a risk factor for fetal growth restriction. This leads to a ‗smoking paradox‘. Smoking among obese women lowers the rate of neonatal macrosomia, as shown in our analysis of German perinatal statistics (Tables 15-1 and 15-2). The LGA rate for women with a BMI > 40 was 25.2 % in nonsmokers vs. 16.2 % in smoker (-9.0 %). The SGA rates were 5.6 % vs. 8.7 % (+ 3.1 %). Smoking clearly restricts fetal growth. Table 15-3 illustrates the ‗paradoxical‘ influence of maternal smoking on gestational hypertension and associated disorders, likewise based on an analysis of German perinatal statistics. We analysed data for the following pregnancy risks: hypertension (blood pressure greater than 140/90 mmHg), proteinuria > 1 g/l, moderate to severe edema, and preeclampsia/eclampsia in smokers and non-smokers and according to BMI. For all four risk factors the rates decreased in smokers compared to nonsmokers. This is true for all three BMI groups. For instance, nonsmokers with a BMI > 35 have a rate of hypertension in pregnancy of 15.2 % vs. 11.1 % in smokers. The causality and implications of these findings need to be elucidated by future work.

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Table 15-1. Somatic classification of the neonates in nonsmokers according to maternal BMI. SGA = small for gestational age, AGA = appropriate for gestational age, and LGA = large for gestational age. We also analyzed our data by length of gestation (preterm, term, and post term births). (German perinatal statistics of 1998 – 2000, singleton pregnancies, n = 235,923 nonsmoking women, significant differences between BMI groups were established with the chi2 test)

Table 15-2. Somatic classification of the neonates in smokers according to maternal BMI. Numbers in brackets illustrate the comparison to nonsmokers. (German perinatal statistics, 1998 – 2000, singleton pregnancies, n = 41,492 smoking women, significant differences between BMI groups were established with the chi2 test)

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Table 15-3. Complications of pregnancy according to maternal smoking status and BMI (German perinatal statistics of 1998 – 2000, singleton pregnancies, nonsmokers n = 235,931; smokers n = 41,494). BMI groups, primiparous and multiparous women

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Complication of pregnancy

18.50 – 24.99

n % Hypertension 3,153 1.3 Proteinuria 1,069 0.5 Edema 2,725 1.2 Pre3,904 eclampsia/eclampsia 1.7 Hypertension 346 0.8 Proteinuria 121 0.3 Edema 432 1.0 Pre460 eclampsia/eclampsia 1.1

30.00 – 34.99 n % 1,998 7.8 413 1.6 1,350 5.3 1,947 7.6 281 4.8 63 1.1 203 3.5 294 5.0

> 35

Nonsmokers or

n %

Smokers

1,644 15.2 263 2.4 875 8.1 1,562 14.4 300 11.1 52 1.9 180 6.6 300 11.1

Nonsmokers Nonsmokers Nonsmokers Nonsmokers Smokers Smokers Smokers Smokers

Points of Note for Pre-Conceptional Counseling • • • • • • • • •

Obesity and smoking: increased risk of diabetes as well as cardiovascular disease Exhaled CO and cotinine are objective measures of smoking Consider interventions to aid smoking cessation before weight reduction Changing attitude towards smoking in patients is a first step Agree with patients on a program of smoking cessation and on intermediate targets (reduced number of cigarettes per day) Consider nicotine replacement therapy and varenicline (but note that varenicline is contra-indicated in pregnancy) Inquire about passive smoking Offer support (smoking cessation is difficult, as is weight reduction) General counseling about healthy life style

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In conclusion, smoking and obesity are a dangerous combination with regard to cardiovascular endpoints and glucose homeostasis. Smoking cessation is of paramount importance when addressing glycemic control, blood pressure and dyslipidemia. Treating obesity without smoking cessation cannot be recommended, both need to be addressed. Smoking restricts fetal growth. The lower LGA rate in obese smokers (compared to obese nonsmokers) is evidence for smoking-related fetal growth restriction and should not be misinterpreted as an excuse to smoke.

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References Berg CJ, Park ER, Chang Y, Rigotti NA. Is concern about post-cessation weight gain a barrier to smoking cessation among pregnant women? Nicotine Tob. Res. 2008; 10: 1159 – 1163. Berlin I. Endocrine and metabolic effects of smoking cessation. Curr. Med. Res. Opin. 2009; 25: 527 – 534. Chelland Campbell S, Moffatt RJ, Stamford BA. Smoking and smoking cessation -- the relationship between cardiovascular disease and lipoprotein metabolism: a review. Atherosclerosis. 2008; 201: 225-35. Conde–Agudelo A, Althabe F, Belizan J, Kafury-Goeta AC. Cigarette smoking during pregnancy and risk of preeclampsia: a systematic review. Am. J. Obstet. Gynecol. 1999; 181: 1026 – 1035. Heatherton TF, Koziowski LT, Frecker RC, Fagerström KO. The Fagerström Test for Nicotine Dependence: A revision of the Fagerström Tolerance Questionnaire. Brit. J. Addict. 1991; 86: 1119-27. Magee BD, Hattis D, Kivel NM. Role of smoking in low birth weight. J. Reprod. Med. 2004; 49: 23 – 27. Ness RB, Sibai BM. Shared and disparate components of the pathophysiologies of fetal growth restriction and preeclampsia. Am. J. Obstet. Gynecol. 2006; 195: 40 -49. Ness RB, Zhang J, Bass D, Klebanoff MA. Interactions between Smoking and Weight in Pregnancies Complicated by Preeclampsia and Small-for-Gestational Age. Am. J. Epidemiol. 2008; 168: 427 – 433. Newman MG, Lindsay MK, Graves W. Cigarette smoking and pre-eclampsia: their association and effects on clinical outcome. J. Matern. Fetal. Med. 2001; 10: 166 – 170. Santos IS, Barros AJ, Matijasevich A, Tomasi E, Medeiros RS, Domingues MR, Bertoldi AD, Barros FC, Victora CG. Mothers and their pregnancies: a comparison of three population-based cohorts in Southern Brazil. Cad. Saude Publica. 2008; 24 Suppl 3: S381 – S389. Somm E, Schwitzgebel VM, Vauthay DM, Camm EJ, Chen CY, Giacobino JP, Sizonenko SV, Aubert ML, Hüppi PS. Prenatal nicotine exposure alters early pancreatic islet and adipose tissue development with consequences on the control of body weight and glucose metabolism later in life. Endocrinology. 2008; 149: 6289 – 6299. Prospective Studies Collaboration, Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J, Halsey J, Qizilbash N, Collins R, Peto R. Collaborators (157) Body-mass

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index and cause-specific mortality in 900,000 adults: collaborative analyses of 57 prospective studies. Lancet. 2009; 373: 1083-96. Van der Vaart H, Postma DS, Timens W, ten Hacken NH. Acute effects of cigarette smoke on inflammation and oxidative stress: a review. Thorax. 2004; 59: 713 – 721.

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Chapter XVI

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Weight Gain in Pregnancy Weight gain during pregnancy is discussed here because it is an important parameter of pregnancy – in general and especially in obese women - and because it can differ considerably between obese and normal weight women. As discussed below there is one important difference between weight gain in pregnancy as a parameter and the other perinatal outcomes discussed in other chapters of this book. Weight gain in pregnancy depends on maternal height and weight, but in contrast to some of the other perinatal outcomes is not well described by maternal BMI. The optimal weight gain during pregnancy is a controversial topic. Searching the literature we found that while average weight gain differed little over time and between study populations (Abrams et al. 2000, Becker et al. 2004, Grabow und Straube 1987, OchsenbeinKölble et al. 2007, Voigt et al. 2004, Voigt et al. 2007), inter-individual differences can be quite pronounced, often without apparent consequences for mother and child. Nonetheless, maternal weight gain during pregnancy is an important determinant of perinatal outcome, especially in obese women. On the one hand, small weight gain is associated with preterm delivery and SGA infants (Hediger et al. 1989). On the other hand, obese women with low gestational weight gain have a decreased risk for pre-eclampsia, Cesarean section, instrumental delivery, and LGA infants (Cedergren 2006). Large weight gain has been linked with some adverse maternal outcomes such as diabetes and hypertension that obese pregnant women are already at risk for and also with fetal macrosomia, again a problem more common in obese women (Johnson and Yancey 1996). Pre-gestational obesity and high weight gain during pregnancy were found to independently increase the risk of Cesarean delivery (Seligman et al. 2006). The combination of obesity and high weight gain further increases the risk. The effects of high maternal weight gain extend beyond infancy. Greater weight gain is associated with higher rates of overweight status and obesity at age 3. This effect of excessive weight gain was greater among obese women compared to normal weight women (Okens et al. 2007, Olson et al. 2008). What factors determine the weight gain in pregnancy? Pre-pregnancy weight and height of the mother are important. Roughly speaking, height is proportional to the weight gain while pre-pregnancy weight is inversely proportional to the weight gain (Voigt et al. 2007). Height and weight can be expressed as BMI and, indeed, the Institute of Medicine

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recommendations regarding desirable weight gain during pregnancy are specified according to maternal BMI (Rasmussen and Yaktine 2009). This approach has been adopted by professional societies around the world. There is a caveat, however. Even though both BMI and the weight gain during pregnancy depend on maternal height and weight they do so in different ways. An analysis of German perinatal statistics reveals that groups of women with the same BMI but different body heights and weights can differ significantly with regard to their weight gain (Voigt et al. 2007). This is true for normal weight women and also for obese women (Figure 16-1).

Figure 16-1. Obese women with the same BMI but different body heights and weights differ significantly in their weight gain during pregnancy. (adapted from Voigt et al. 2007).

If BMI is not suitable for an assessment of the weight gain during pregnancy, maternal height and weight can perhaps be combined in another manner. We have previously shown how this can be done (Straube et al. 2008), and present percentile tables describing the weight gain during pregnancy according maternal height and weight in an appendix to this book. The assessment of the weight gain during pregnancy with the suggested percentiles has not been validated in clinical practice. It is therefore to be used with caution. However, as the other ways of assessing weight gain in pregnancy (by BMI or using an overall population averages) have obvious shortcomings (BMI is not useful as shown in Figure 16-1, overall averages do not reflect individual variability), we still feel that the percentiles presented in the appendix may be of use in pointing out what is expected and what is likely abnormal. For morbidly obese women we found the lowest rate of fetal macrosomia (15.3 %) in the group of women with a weight gain of less than 4 kg (unpublished data from German perinatal statistics). On the one hand, having such a small weight gain would keep the rate of fetal macrosomia low; on the other hand there could be fetal growth restriction due to undernutrition during pregnancy. A balanced approach is needed.

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References Abrams B, Altman S, Pickett K. Pregnancy weight gain: still controversial. Am. J. Clin. Nutr. 2000; 71 (Suppl.): 1233 – 1241. Becker S, Fedtke M, Felun T, Wallwiener D, Aydeniz B. Entwicklung des Körpergewichts vor, während und ein Jahr nach der Schwangerschaft. Geburtsh Frauenheilk. 2004; 64: 706 – 710. Cedergren M. Effects of gestational weight gain and body mass index on obstetric outcome in Sweden. Int. J. Gynaecol. Obstet. 2006; 93: 269 – 274. Grabow D, Straube W. Über den Einfluss mütterlicher konstitutioneller Faktoren und der Gewichtszunahme während der Schwangerschaft auf die Neugeborenenmaße Gewicht und Länge. Zbl. Gynakol. 1987; 109: 681 – 692. Hediger ML, Scholl TO, Belsky DH, Ances IG, Salmon RW. Patterns of weight gain in adolescent pregnancy: effects on birth weight and preterm delivery. Obstet. Gynecol. 1989; 74: 6 – 12. Johnson WC, Yancey MK. A critique of the new recommendation for weight gain in pregnancy. Am. J. Obstet. Gynecol. 1996; 174: 254 – 258. Ochsenbein-Kölble N, Roos M, Gasser T, Zimmermann R. Cross-sectional study of weight gain and increase in BMI throughout pregnancy. Europ. J. Obstet. Gynecol. 2007, 130: 180 – 186. Oken E, Taveras EM, Kleinman KP, Rich-Edwards JW, Gillman MW. Gestational weight gain and child adiposity at age 3 years. Am. J. Obstet. Gynecol. 2007; 196: 322.e1-8. Olson CM, Strawderman MS, Dennison BA. Maternal Weight Gain During Pregnancy and Child Weight at Age 3 Years. Matern. Child Health J. 2009; 13: 839-46. Rasmussen KM, Yaktine AL (Eds); Committee to Reexamine IOM Pregnancy Weight Guidelines; Institute of Medicine; National Research Council. Weight Gain During Pregnancy: Reexamining the Guidelines. Washington, DC: National Academies Press; 2009. Seligman LC, Duncan BB, Branchtein L, Gaio DS, Mengue SS, Schmidt MI: Obesity and gestational weight gain: cesarean delivery and labor complications. Rev. Saude Publica. 2006; 40: 457 – 465. Straube S, Voigt M, Briese V, Schneider KT, Voigt M. Weight gain in pregnancy according to maternal height and weight. J. Perinat. Med. 2008; 36: 405-12. Voigt M, Schneider KTM, Fusch Ch, Hesse V, Röhl S, Helmers C, Schücking B: Normwerte der Gewichtszunahme in der Schwangerschaft. Geburtsh Frauenheilk. 2004; 64: 53 – 58. Voigt M, Straube S, Olbertz D, Häuser B, Schneider KT. Beziehungen zwischen Körpergewicht, Körperhöhe, Body-Mass-Index und der Gewichtszunahme von Frauen in der Schwangerschaft. Z. Geburtshilfe Neonatol. 2007; 211: 147-52.

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Section 3: Complications of Pregnancy

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In: Obesity and Pregnancy V. Briese, M. Voigt and S. Straube, pp. 65-72

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Chapter XVII

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Pregnancy and Birth in Obese Women - An Overview of Common Complications We are going to discuss some important complications of pregnancy associated with obesity - both common complications and less common but serious complications - in the following chapters. Before doing so, we want to provide an overview of the common complications of pregnancy and birth in the obese. It has been known for a while that overweight and obese pregnant women are at increased risk of suffering some complications of pregnancy (Odell 1945). The problem is hardly new, therefore, but its importance in increasing because the prevalence of obesity is increasing. We have recently conducted an analysis of the risks to mother and child associated with obesity in pregnancy, with a special focus on morbid obesity (where women are most at risk), based on data of about five hundred thousand singleton pregnancies taken from the German perinatal statistics of 1998-2000 (Voigt et al. 2008a and b). We will summarize some of the results of our analysis here and put the main findings into the context of other work in this field. An overview of common complications of pregnancy and birth from German perinatal statistics (data of 1998 - 2000) and their relationship to maternal BMI is shown in Table 17-1. Our analysis shows that rates of hypertension, proteinuria, edema, pre-eclampsia, gestational diabetes, placental insufficiency, amnion infection syndrome, pathological CTG, and cephalopelvic disproportion all increased with increasing BMI. Comparing morbidly obese women with those of normal weight we also found higher rates of coagulopathies (1.1 % for BMI 18.5 - 24.99, 2.5 % for BMI 40 - 40.99 and 3.4 % for BMI 45 or above) (Voigt et al. 2008a). There is more evidence that obesity increases the likelihood of common complications of pregnancy and birth. Robinson and colleagues conducted an analysis of more then 140,000 singleton pregnancies from Nova Scotia. They show that moderately obese women (there defined as those weighing 90-120 kg) had an increased risk of pregnancy-induced hypertension (adjusted odds ratio [OR] 2.38), antepartum venous thromboembolism (OR 2.17), and wound infection (OR 1.67). Severely obese women (defined as those > 120 kg) had even higher risks of pregnancy-induced hypertension (OR 3.00), antepartum venous

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thromboembolism (OR 4.13), and wound infection (OR 4.79) (Robinson et al. 2005). An analysis of more than 24,000 women from Aberdeen (UK) found that increasing BMI was associated with increased incidences of pre-eclampsia and gestational hypertension. Morbidly obese women (there defined as BMI > 35) faced the highest risk of pre-eclampsia (28.2 %) and gestational hypertension (42.2 %) (Bhattacharya et al. 2007). Table 17-1. Complications of pregnancy and birth and the influence of maternal BMI. Redrawn from Voigt et al. 2008b

Complication

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Hypertension Proteinuria > 1 g/l Edema Pre-eclampsia Gestational diabetes Placental insufficiency Amnion infection syndrome Pathological CTG Cephalopelvic disproportion total

% 1.2 0.4 1.1 1.6

BMI-groups 30.00 – 34.99 35.00 – 39.99 n % n % 2551 7.1 1434 12.5 527 1.5 238 2.1 1683 4.7 819 7.2 2570 7.1 1395 12.2

≥ 40.00 n 728 111 325 708

% 18.3 2.8 8.2 17.8

1295

0.4

531

1.5

280

2.4

150

3.8

8515

2.7

1033

2.9

402

3.5

137

3.4

2211

0.7

412

1.1

138

1.2

52

1.3

45,063

14.1

5970

16.5

2090

18.3

761

19.1

9031

2.8

1929

5.3

767

6.7

269

6.8

18.50 – 24.99 n 3920 1316 3491 5071

320,148

36,087

11,144

3975

Sebire and co-workers examined a total of 287,213 singleton pregnancies from London, England. They found that compared to women with a normal BMI, a number of adverse pregnancy outcomes were significantly more common in the obese: gestational diabetes (OR 3.6); proteinuric pre-eclampsia (OR 2.14); induction of labor (OR 1.70); delivery by emergency Cesarean section (OR 1.83); postpartum hemorrhage (OR 1.39); genital tract infection (OR 1.30); urinary tract infection (OR 1.39); wound infection (OR 2.24); birth weight above the 90th centile (OR 2.36), and intrauterine death (OR 1.40). Psychosocial factors are affected by obesity, too, though they are perhaps somewhat harder to quantify. Laraia and colleagues discovered a significant trend between increasing pregravid weight categories and increasing scores for perceived stress, anxiety and depressive symptoms based on an analysis of 2006 pregnant women (Laraia et al. 2009). The influence of obesity on preterm birth is shown in Figure 17-1. The rates of both moderately early (32 - 36 weeks‘ gestation) and very early preterm birth (before 32 weeks‘ gestation) increase with increasing degree of obesity.

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Figure 17-1. Preterm birth and maternal BMI. Redrawn from Voigt et al. 2008b.

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Neonates born to obese women have higher birth weights. The rates of neonates with a birth weight of 4500 g and more were several-fold higher in the morbidly obese (Figure 172).

Figure 17-2. Birth weight and maternal BMI. Redrawn from Voigt et al. 2008a.

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Table 17-2. Somatic classification and BMI. Redrawn from Voigt et al. 2008b

Newborns LGA AGA SGA total

18.50 – 24.99 n % 25,388 7.9 262,050 81.8 32,809 10.3 320,247

BMI groups 30.00 – 34.99 35.00 – 39.99 n % n % 5927 16.5 2263 19.8 27,583 76.4 8386 73.2 2576 7.1 793 7.0 36,086 11,442

≥ 40.00 n 913 2809 252 3974

% 23.0 70.7 6.3

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Table 17-2 illustrates the ‗somatic classification‘ of the newborns according to pregnancy duration and maternal BMI. For the somatic classification of the newborn we used the 10 th and 90th birth weight percentiles. Those newborns below the 10th percentile were defined as small for gestational age (SGA), those above the 90th percentile as large for gestational age (LGA), and all those in-between as appropriate for gestational age (AGA). Overall, the LGA rate was significantly higher for women with a BMI of 40 or above (23.0 %) compared to women with normal weight (7.9 %). The highest LGA rate (32.4 %) occurred in women with a BMI of 40 or above and an increased weight gain during pregnancy (Voigt et al. 2008b). Fetal macrosomia goes hand in hand with an increased rate of Cesarean section. This is illustrated in Figure 17-3. Both primary and secondary Cesarean section occurred more frequently in obese women.

Figure 17-3. Mode of delivery in normal weight and morbidly obese women. Redrawn from Voigt et al. 2008a.

Not surprisingly, there also was a higher rate of neonatal ‗injuries, fractures and pareses‘ recorded in obese women: 0.25 % for women with normal weight and 0.5 % for morbidly obese women (Voigt et al. 2008b). Neonatal well-being, as described by the 5-minute Apgar score was likewise somewhat worse for the newborns of obese women. The rates of neonates with the most alarming Apgar

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scores of 0-3 were about three times higher in morbidly obese compared with normal weight women (Figure 17-4).

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Figure 17-4. Five-minute Apgar score in normal weight and morbidly obese women. Redrawn from Voigt et al. 2008a.

Other studies have also reported higher rates of fetal macrosomia and Cesarean section in obese women. The above-mentioned study from Aberdeen found that increasing BMI was associated with fetal macrosomia (25 % of newborns had a birth weight > 4000 g for women with a BMI > 35), induction of labour (49 %), and Cesarean section (42.7 %) (Bhattacharya et al. 2007). A cohort study of 916 women from Italy also found significantly increased rates of fetal macrosomia (defined as birth weight of at least 4000 g; 13.7 %), preterm delivery (31.4 %) and Cesarean section (56.9 %) in women with a BMI of 30 or greater (Driul et al. 2007). There are reasons for the greater prevalence of Cesarean sections in the obese other than the higher rate of fetal macrosomia. Obese women are more likely to experience arrest-oflabor disorders and a protracted course of labor. Furthermore, Hibbard et al. (2006) found that increasing BMI was associated with failed trial of labor after previous Cesarean delivery: rates were 15.2 % in normal weight women compared to 39.3 % in morbidly obese women. Comparing trial of labor and elective repeat Cesarean delivery they discovered that among morbidly obese women with previous Cesarean section, trial of labor was associated with a five-fold increase in the risk of uterine rupture or dehiscence (2.1 % vs. 0.4 %) and similarly a five-fold increase in the risk of neonatal injury - fractures, brachial plexus injuries, and lacerations - (1.1 % versus 0.2 %). Furthermore, morbidly obese women failing a trial of labor had six-fold greater composite maternal morbidity than those undergoing a successful trial of labor (14.2 % versus 2.6 %). These increased risks should be considered before undertaking a trial of labor after previous Cesarean delivery in obese women. We found that the frequency of structural anomalies in the neonates increased with increasing BMI: 1.9 % (BMI 30.00–34.99), 2.0 % (BMI 35.00–39.99) and 2.4 % (BMI 40 or above) versus 1.8 % in those with normal weight. Neural tube defects were detected in 0.1 %

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of women with a BMI of 40 or above but only in versus 0.02 % of women with a normal body weight (Voigt et al. 2008b). A role for obesity in the generation of fetal neural tube defects is confirmed by an analysis of Ray and colleagues who found a higher risk of neural tube defects in the presence one or more features of the metabolic syndrome, including high body weight (Ray et al. 2007). A recent systematic review confirms that obesity is associated with an increased risk of a number of structural anomalies, though the absolute risk increases are small (Stothard et al. 2009). Having introduced some common complications of pregnancy that are more prevalent in the obese, it is necessary not to lose sight of the fact that the many general (not per se pregnancy-related) complications of obesity can also manifest during pregnancy and can make management of the pregnancy more difficult. We will not at this point re-iterate lists well familiar to the reader of complications associated with adult obesity but perhaps it is of use to briefly summarize the complications of obesity in young women, as pregnancy in obese teenagers is a phenomenon of increasing importance.

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Complications of obesity in young women (modified from Ebbeling et al. 2002) Psychosocial

Poor self esteem, depression, eating disorders

Neurological

Pseudotumor cerebri (see also Worrel and Lane 2007)

Pulmonary

Sleep apnoea, asthma, exercise intolerance

Cardiovascular

Dyslipidemia, hypertension, coagulopathy, chronic inflammation

Gastrointestinal

Gallstones, steatohepatitis

Renal Gynecological

Glomerulosclerosis Infertility, colpitis, period irregularities, oligo-anovulation (Pasquali and Gambineri 2006)

Endocrine

Polycystic ovary syndrome, type 2 diabetes

Dermatological

Vulvocandidiasis, intertriginous inflammation, acanthosis nigricans

Musculoskeletal

Slipped capital femoral epiphysis, Blount‘s disease, forearm fracture, flat feet

In summary, a number of common complications of pregnancy and birth occur more frequently in the obese. Approximate figures for such risks generated by epidemiological studies may assist practicing clinicians in counseling patients. Complications of obesity per se unrelated to pregnancy can still occur during pregnancy and may complicate its course. Figure 17-5 below summarizes the important risks at various times during pregnancy.

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Figure 17-5. Risks of pregnancy and birth according to duration of pregnancy (in weeks).

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References Bhattacharya S, Campbell DM, Liston WA, Bhattacharya S. Effect of Body Mass Index on pregnancy outcomes in nulliparous women delivering singleton babies. BMC Public Health. 2007; 7: 168. Driul L, Cacciaguerra G, Citossi A, Martina MD, Peressini L, Marchesoni D. Prepregnancy body mass index and adverse pregnancy outcomes. Arch. Gynecol. Obstet. 2008; 278: 23-6. Ebbeling CB, Pawlak DB, Ludwig DS. Childhood obesity: public-health crisis, common sense cure. Lancet. 2002; 360: 473 – 482. Hibbard JU, Gilbert S, Landon MB, Hauth JC, Leveno KJ, Spong CY, Varner MW, Caritis SN, Harper M, Wapner RJ, Sorokin Y, Miodovnik M, Carpenter M, Peaceman AM, O'Sullivan MJ, Sibai BM, Langer O, Thorp JM, Ramin SM, Mercer BM, Gabbe SG; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Trial of labor or repeat cesarean delivery in women with morbid obesity and previous cesarean delivery. Obstet. Gynecol. 2006; 108: 125-33. Laraia BA, Siega-Riz AM, Dole N, London E. Pregravid weight is associated with prior dietary restraint and psychosocial factors during pregnancy. Obesity. (Silver Spring). 2009; 17: 550-8. Pasquali R, Gambineri A. Metabolic effects of obesity on reproduction. Reprod. Biomed. Online. 2006; 12: 542 – 551. Ray JG, Thompson MD, Vermeulen MJ, Meier C, Wyatt PR, Wong PY, Summers AM, Farrell SA, Cole DE. Metabolic syndrome features and risk of neural tube defects. BMC Pregnancy Childbirth. 2007; 7: 21. Robinson HE, O'Connell CM, Joseph KS, McLeod NL. Maternal outcomes in pregnancies complicated by obesity. Obstet. Gynecol. 2005; 106: 1357-64.

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Sebire NJ, Jolly M, Harris JP, Wadsworth J, Joffe M, Beard RW, Regan L, Robinson S. Maternal obesity and pregnancy outcome: a study of 287,213 pregnancies in London. Int. J. Obes. Relat. Metab. Disord. 2001; 25: 1175-82. Stothard KJ, Tennant PW, Bell R, Rankin J. Maternal overweight and obesity and the risk of congenital anomalies: a systematic review and meta-analysis. JAMA. 2009; 301: 636-50. Voigt M, Zygmunt M, Henrich W, Straube S, Carstensen M, Briese V. Analysis of Subgroup of Pregnant Women in Germany 16th Communication: Morbid Obesity: Pregnancy Risks, Birth Risks and Status of the Newborn. Geburtsh Frauenheilk. 2008a; 68: 794800. Voigt M, Straube S, Zygmunt M, Krafczyk B, Schneider KT, Briese V. Obesity and pregnancy - a risk profile. Z. Geburtshilfe Neonatol. 2008b; 212: 201-5. Worrel J, Lane S. Impact of pseudotumor cerebri (idiopathic intracranial hypertension) in pregnancy: a case report. AANA J. 2007; 75: 199 – 204.

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Chapter XVIII

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Miscarriage Miscarriage is considered the most common adverse outcome of pregnancy and for many women it is a traumatic experience. Most evidence agrees that about one in five pregnancies will end in miscarriage (fetal death before 24 weeks‘ gestation) (Garcia-Enguidanos et al. 2002, Savitz et al. 2002). Well established risk factors for miscarriage include advanced maternal age, previous miscarriage, previous termination of pregnancy, a history of infertility, assisted conception, alcohol consumption, feeling stressed, high paternal age and changing partner (Maconochie et al. 2006). There is some controversy in the literature about whether obesity increases miscarriage risk. On balance the evidence suggests an adverse effect of obesity on the risk of miscarriage (Metwally et al. 2008). For example, Yu et al. (2006) describe a three-fold increased risk of miscarriage in obesity. Some women will experience recurrent miscarriages. Autoantibodies such as antiphospholipid antibodies are sometimes implicated in the pathogenesis of such recurrent pregnancy loss (Zammiti et al. 2006). It is also necessary, however, to consider polycystic ovary syndrome (PCOS), a disease associated with obesity, as early pregnancy loss is a typical complication of PCOS (Homburg 2006). Maternal obesity is a risk factor for miscarriages both following spontaneous conceptions and after assisted conception. Obese (and also underweight) women were found to have an increased risk of miscarriage after assisted conception, and hormonally substituted frozenthawed embryo transfer was associated with an even higher rate of miscarriages (Veleva et al. 2008). Because there is some disagreement in the literature about the relationship between obesity and risk of miscarriage, we have examined the rate of previous miscarriages in pregnant women based on data from German perinatal statistics in a retrospective population study. Table 18-1 illustrates the prevalence of miscarriages in the medical history for primiparous and multiparous women. Increasing BMI was associated with higher rates of miscarriages. Table 18-2 shows equivalent data for primiparous women only, to eliminate parity as a confounder. The results show a similar dependence on BMI. These data have to be interpreted with caution as they arise from a retrospective study and confounders other than parity likely play a role. Nonetheless they confirm that there is an association between high BMI and increased risk of miscarriages.

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Table 18-1. Previous miscarriages according to BMI. Data from German perinatal statistics, 1998 – 2000 Previous Miscarriages (n) 0 1 ≥2 Total

< 18.50 17,139 86.5 % 2158 10.9 % 527 2.7 % 19,824

18.50 – 24.99 270,009 84.3 % 40,142 12.5 % 9997 3.1 % 320,148

BMI / Primiparous and multiparous women 25.00 – 29.99 30.00 – 34.99 35.00 – 39.99 88,468 82.1 % 15,039 14.0 % 4282 4.0 % 107,789

29,308 81.2 % 5227 14.5 % 1552 4.3 % 36,087

9315 81.4 % 1653 14.4 % 476 4.2 % 11,444

≥ 40.00 3196 80.4 % 577 14.5 % 202 5.1 % 3975

Table 18-2. Previous miscarriages depending on BMI in primiparous women. Data from German perinatal statistics, as above Previous Miscarriages (n) 0 1 ≥2

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Total

< 18.50

18.50 – 24.99

BMI / Primiparous women 25.00 – 29.99 30.00 – 34.99

35.00 – 39.99

≥ 40.00

10,399 90.7 % 906 7.9 % 162 1.47% 11,467

148,794 89.3 % 15,171 9.1 % 2,710 1.6 % 166,675

40,751 88.0 % 4,590 9.9 % 958 2.1 % 46,299

3,498 86.8 % 443 11.0 % 90 2.2 % 4,031

1,132 87.7 % 128 9.9 % 31 2.4 % 1,291

12,170 88.1 % 1,354 9.8 % 284 2.1 % 13,808

References Garcia-Enguidanos A, Calle ME, Valero J, Luna S, Dominguez-Rojas V. Risk factors in miscarriage: a review. Eur. J. Obstet. Gynecol. Reprod. Biol. 2002; 102: 111 – 119. Homburg R. Pregnancy complications in PCOS. Best Pract. Res. Clin. Endocrinol. Metab. 2006; 20: 281 – 292. Maconochie N, Doyle P, Prior S, Simmons R. Risk factors for first trimester miscarriage-results from a UK-population-based case-control study. BJOG. 2007; 114: 170 – 186. Metwally M, Ong KJ, Ledger WL, Li TC. Does high body mass index increase the risk of miscarriage after spontaneous and assisted conception? A meta-analysis of the evidence. Fertil Steril. 2008; 90: 714-26. Savitz DA, Hertz-Pichiotto I, Poole C, Olshan AF. Epidemiologic measures of the course and outcome of pregnancy. Epidemiol. Rev. 2002; 24: 91 – 101. Veleva Z, Tiitinen A, Vilska S, Hyden-Granskog C, Tomas C, Martikainen H, Tapanainen JS. High and low BMI increase the risk of miscarriage after IVF/ICSI and FET. Hum. Reprod. 2008; 23: 878-84.

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Zammiti W, Miraoui N, Kallel C, Mercier E, Almawi WY, Mahjoub T. A case – control study on the association of idiopathic recurrent pregnancy loss with autoantibodies against beta2-glycoprotein I and annexin V. Reproduction. 2006; 131: 817 – 822.

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In: Obesity and Pregnancy V. Briese, M. Voigt and S. Straube, pp. 77-79

ISBN: 978-1-60876-111-1 © 2010 Nova Science Publishers, Inc.

Chapter XIX

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Stillbirth Intrauterine fetal death remains a common occurrence and an under-investigated problem. About one in 200 infants is stillborn and rates of stillbirth have recently increased (Smith and Fretts 2007). This recent rise could be due to the increasing prevalence of some risk factor(s) for stillbirth. A systematic review concluded that the most prevalent risk factors for stillbirth were pre-pregnancy obesity, socioeconomic factors, and advanced maternal age. Nulliparity is another maternal risk factor (Smith and Fretts 2007, Fretts 2005). Potentially, therefore, the increased prevalence of obesity could be implicated in the increased incidence of stillbirths. But caution is warranted because other risk factors, including advanced maternal age, have also recently increased in prevalence. Maternal obesity more than doubled the risk of stillbirth and neonatal death in a cohort study of more than 24,000 pregnancies from Denmark (Kristensen et al. 2005). Maternal overweight status also increases the risk of stillbirth (Stephansson et al. 2001). Chu et al. (2007) conducted a meta-analysis of studies addressing the relationship between maternal overweight and obesity and the risk of stillbirth. They found that compared to normal-weight pregnant women the (unadjusted) odds ratios of a stillbirth were 1.47 (95% CI 1.08-1.94) and 2.07 (95% CI 1.59-2.74) among overweight and obese pregnant women, respectively. These results are confirmed by our analysis of German perinatal statistics (Table 19-1). We found an association between increasing BMI and increasing rates of stillbirth. This dependence on the extent of obesity has also been shown by others (Salihu et al. 2007). Work from Danish National Birth Cohort demonstrated that the excess risks of fetal death among obese women compared to normal weight women increased with increasing duration of pregnancy (Nohr et al. 2005). Compared with normal weight women, the risk of stillbirth in obese women is especially high late in pregnancy. It is thought that most stillbirths are related to placental dysfunction. In maternal obesity subclinical inflammatory processes could impair early placentation (King 2006). In addition, obesity is associated with maternal hypertension and hence with endothelial dysfunction. This could also be implicated in the pathogenesis of stillbirth. Further potentially important mechanisms are illustrated below. Details of how obesity increases the risk of stillbirth need further elucidation. Factors potentially implicated in the increased stillbirth rate in maternal obesity:

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78 • • • • • • • • • •

Impaired implantation/placentation Fetal hyperglycemia Maternal hyperosmolar hyperglycemic state Uterine rupture after previous Cesarean delivery Fetal cardiomegaly Fetal diabetic cardiomyopathy Fetal growth restriction Placentomegaly Placental dysfunction, placental infarcts Pre-eclampsia

Table 19-1. History of stillbirth in previous pregnancies according to maternal BMI (German perinatal statistics of 1998-2000, singleton pregnancies) Previous Stillbirths (n) 0 ≥1 Total

< 18.50 19,742 99.6 % 82 0.4 % 19,824

18.50 – 24.99 318,411 99.5 % 1137 0.5 % 320,148

BMI / Primiparous and multiparous women 25.00 – 29.99 30.00 – 34.99 106,899 35,717 99.2 % 99.0 % 890 370 0.8 % 1.0 % 107,789 36,087

35.00 – 39.99 11,307 98.8 % 137 1.2 % 11,444

≥ 40.00 3921 98.6 % 54 1.4 % 3975

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The following approaches may be considered for the prevention of stillbirth in obese women: • • • • • • • •

Weight reduction before pregnancy Intensive maternal and fetal surveillance Diagnose and treat disorders associated with the metabolic syndrome Screen for gestational diabetes beginning in the 2nd trimester Monitor fetal heart rate pattern twice weekly in the 3rd trimester Avoid durations of pregnancy beyond 40 weeks Increased level of medical care in late pregnancy and delivery in a tertiary perinatal center Cesarean delivery in case of fetal macrosomia

Illustrative Case A 34-year-old woman with morbid obesity (weight 140 kg, height 158 cm, BMI 56) was admitted because of intra-uterine fetal demise at 35 weeks‘ gestation. Ultrasound revealed polyhydramnios. Her obstetric history included two terminations of pregnancy, two miscarriages, and two live births (a Cesarean section followed by a vaginal delivery). The patient also had chronic hypertension, hypothyroidism, and impaired glucose tolerance (controlled by diet). She gave birth to a stillborn infant of 2,470 g. Placental histology was

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indicative of chronic malperfusion. Placental mass was below the 10th percentile for gestational age. This patient combined a number of risk factors: in her obstetric history (terminations of pregnancy, miscarriages, previous Cesarean section), regarding her constitution (morbid obesity, impaired glucose tolerance), and regarding her current pregnancy (polyhydramnios). This case is not atypical. Patients with obesity often have other adverse predictors of pregnancy outcome as well. Women with multiple co-morbidities need special attention and close surveillance.

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References Chu SY, Kim SY, Lau J, Schmid CH, Dietz PM, Callaghan WM, Curtis KM. Maternal obesity and risk of stillbirth: a metaanalysis. Am. J. Obstet. Gynecol. 2007; 197: 223 – 228. Fretts RC. Etiology and prevention of stillbirth. Am J Obstet Gynecol. 2005; 193: 1923-35. King JC. Maternal obesity, metabolism, and pregnancy outcomes. Annu. Rev. Nutr. 2006; 26: 271 – 291. Kristensen J, Vestergaard M, Wisborg K, Kesmodel U, Secher NJ. Pre-pregnancy weight and the risk of stillbirth and neonatal death. BJOG. 2005; 112: 403 – 408. Nohr EA, Bech BH, Davies MJ, Frydenberg M, Henriksen TB, Olsen J. Prepregnancy obesity and fetal death: a study within the Danish National Birth Cohort. Obstet. Gynecol. 2005; 106: 250 – 259. Salihu HM, Dunlop AL, Hedayatzadeh M, Alio AP, Kirby RS, Alexander GR. Extreme obesity and risk of stillbirth among black and white gravidas. Obstet. Gynecol. 2007; 110: 552 – 557. Smith GC, Fretts RC. Stillbirth. Lancet. 2007; 370: 1715 – 1725. Stephansson O, Dickman PW, Johansson A, Cnattingius S. Maternal weight, pregnancy weight gain, and the risk of antepartum stillbirth. Am. J. Obstet. Gynecol. 2001; 184: 464 – 469.

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Chapter XX

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Uterine Rupture The risk of uterine rupture is increased in obese pregnant women, especially after previous Cesarean delivery. Hibbard and colleagues (Hibbard et al. 2006) showed that among morbidly obese women with previous Cesarean section, trial of labor was associated with a five-fold increase in the risk of uterine rupture or dehiscence when compared to elective repeat Cesarean section (2.1% vs. 0.4%). Our own results confirm these findings. In a retrospective cohort study of singleton pregnancies (n=75,060) of 1994–2000 from the German federal state of Mecklenburg–Western Pomerania we determined uterine rupture rates in pregnancies of obese women. Six thousand seven hundred and eleven pregnant women had a BMI > 30. Of these, 13 women (0.18 %) experienced a uterine rupture. Five hundred and fifty obese pregnant women had previously been delivered by Cesarean section. Of these 550 women 9 (1.6%) experienced a uterine rupture in a subsequent pregnancy. This means that there was a nine-fold increase in the risk of uterine rupture after a previous Cesarean section. We found a similar increase in risk of uterine rupture after Cesarean section in women with a BMI < 30. In these non-obese women (n=61,666) there were 83 cases of uterine rupture (0.13 %). Two thousand eight hundred and fourty five women with a BMI < 30 had prevously been delivered by Cesarean section. Of these, 56 experienced uterine rupture in a subsequent pregnancy (1.9 %). Both obese and non-obese women had a higher risk of uterine rupture after previous Cesarean section. The baseline risk of uterine rupture was somewhat higher for obese compared with non-obese women. The increased risk of uterine rupture and dehiscence needs to be considered before a trial of labor in obese women who have had a previous Cesarean delivery. It is useful to remember that with obesity there is also an increased risk of emergency (secondary) Cesarean section following a trial of labor, in itself associated with complications. The mechanism why uterine rupture is more common in the obese may involve changes in the myometrium. Uterine myomas develop more frequently in obese women. Leptin may also be implicated (Markowska et al. 2005).

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Obstetric Management to Avoid Uterine Rupture in Obese Women With regard to the timing of delivery, we think there are good reasons to avoid post term delivery, as detailed previously. Often there will be a maternal indication for preterm delivery. As far as mode of delivery is concerned, we suggest that vaginal delivery is only tried in case of spontaneous commencement of labor or a ripe cervix. Induction of labor is commonly associated with prolonged labor. Uterine rupture can also present ‗silently‘ during delivery and later present as abdominal pain. In addition to obesity, further risk factors for uterine rupture occurring during a trial of labor in women with previous Cesarean sections should also be considered. These include: more than one previous scar, a short inter-delivery interval, and a history of postpartum fever during a previous Cesarean delivery (Lieberman 2001). Delivery by Cesarean section will often be preferable.

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References Hibbard JU, Gilbert S, Landon MB, Hauth JC, Leveno KJ, Spong CY, Varner MW, Caritis SN, Harper M, Wapner RJ, Sorokin Y, Miodovnik M, Carpenter M, Peaceman AM, O´Sullivan MJ, Sibai BM, Langer O, Thorp JM, Ramin SM, Mercer BM, Gabbe SG. Trial of labor or repeat cesarean delivery in women with morbid obesity and previous cesarean delivery. Obstet. Gynecol. 2006; 108: 125-133. Lieberman E. Risk factors for uterine rupture during a trial of labor after cesarean. Clin. Obstet. Gynecol. 2001; 44: 609-21. Markowska A, Belloni AS, Rucinski M, Parenti AR, Nardelli GB, Drews K, Nussdorfer GG, Malendowicz LK. Leprin and leptin receptor expression in the myometrium and uterine myomas: Is leptin involved in tumor development? Int. J. Oncol. 2005; 27: 1505 – 1509.

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Chapter XXI

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Preterm Birth Preterm birth is defined as a birth taking place after less than 37 but at least 20 completed weeks of gestation (Zegers-Hochschild et al. 2006). The rate of preterm births < 36 weeks‘ gestation has remained roughly unchanged for the past three decades at about 5 % - 7 %, despite significant advances in obstetric care. There is even evidence for a recent increase: Willemsen et al. (2009) recently reported a prevalence of preterm births of 12.7 %. The proportion of very early preterm births (< 30 weeks) has also remained more or less constant at about 1 %. Very early preterm infants are a high risk group and often in need of intensive care and infant rehabilitation. Therefore the prevention of preterm birth – especially very early preterm birth - is of paramount importance. We have shown how preterm birth rates increase in obesity in Figure 17-1. Interestingly, though, the highest preterm birth rates are associated with underweight status, not obesity, and the lowest preterm birth rates were found in overweight (BMI 25.00 - 29.99) women (Table 21-1). Table 21-1. Preterm birth rates according to maternal BMI (German perinatal statistics of 1998-2000, singleton pregnancies of primiparous and multiparous women; n = 499,267) BMI n (total)

< 18.50 19,824

18.50-24.99 320,148

25.00-29.99 107,789

30.00-34.99 36,087

35.00-39.99 11,444

> 40 3,975

Preterm births < 36 weeks‘ gestation in % (and n)

9.0 (n=1,791)

6.2 (n = 19,812)

5.8 (n = 6,265)

6.4 (n = 2,317)

7.4 (n = 842)

7.9 (n=314)

Table 21-2 shows the relationship between BMI and preterm birth rate after the exclusion of anamnestic and current risk factors. These excluded risk factors were (among others) previous miscarriages, previous terminations of pregnancy, hypertension, chronic diseases, regular medications, previous stillbirths, previous infertility treatment, diabetes, and hypotension.

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Table 21-2. Preterm birth rates (< 36 weeks’ gestation) in women without anamnestic and current risk factors. (German perinatal statistics of 1998-2000, singleton pregnancies of primiparous and multiparous women; n = 151,831) BMI Singleton pregnancies without risks (n) Prematurity (%)

< 18.50 6,114

18.50–24.55 104,730

25.00–29.99 31,193

30.00 – 34.99 8,049

> 35 1,745

4.3

2.8

2.8

2.9

4.2

After exclusion of risk factors preterm birth rates were lower and also the dependence on BMI was less pronounced. This suggests that such risk factors play an important role in the pathogenesis of preterm birth in the obese. The risk of preterm birth is especially high where there is more than one risk factor. Therefore causes of preterm birth other than obesity need to be born in mind when assessing the risk of preterm birth in obese women. Important causes of preterm birth other than obesity are summarized in Table 21-3.

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Table 21-3. Some causes of preterm birth other than obesity Maternal causes

Fetal and placental causes

• Age under 16 or above 35 years • Grand multiparity (para 5 or more) • Primigravida with hypoplastic uterus • Uterine anomalies (myoma, uterine septa, bicornic uterus) • Cervical insufficiency • Infections (general / vaginal) • Pre-eclampsia • Previous preterm births and miscarriages • Stress • Smoking • Diabetes • Physical labor (occupation) • Low social status

• Multiple births • Premature rupture of membranes • Bleeding in early pregnancy • Placenta praevia and placental abruption • Placental insufficiency • Disorder of placentation • Fetal macrosomia with maternal diabetes • Hydramnios • Latent infection of placenta or fetal membranes • Fetal adrenocortical overactivity

Newton (1993) suspected that obese pregnant women had a decreased local immune response and therefore suggested that obesity, especially together with smoking was a risk factor for chorioamnionitis and intraamniotic infections. This could favour spontaneous preterm delivery. Simhan and Krohn (2009) report - based on an analysis of the cervical concentrations of cytokines in early pregnancy - that women with a relatively hyporesponsive cervical inflammatory milieu are at higher risk of spontaneous preterm birth. The situation is far from clear, however. Some factor in obese pregnant women seems to protect against preterm births, rather than cause it. A recent study found that obese and overweight women who were at risk of spontaneous preterm birth (prior spontaneous preterm birth, vaginal bleeding) exhibit less uterine activity and less frequent spontaneous preterm birth before 35 weeks of gestation than normal or underweight women (Ehrenberg et al. 2009). Likewise our analysis of German perinatal statistics revealed that premature labor was less frequent, not more frequent, with increasing BMI (Table 21-4). First trimester cytokines interact with BMI

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in the causation of spontaneous preterm delivery. Elevated cytokines are associated with increased risk of spontaneous preterm delivery in underweight women but with a reduced risk of preterm delivery in obese women (Curry et al. 2009). Table 21-4. Premature labor according to maternal BMI (German perinatal statistics of 1998-2000, singleton pregnancies of primiparous and multiparous women) BMI

< 18.50

n (total) Premature labor (< 36 weeks)

19,824 11.9%

18.5024.99 320,148 6.8%

25.0029.99 107,789 4.3%

30.0034.99 36,087 3.5%

35.0039.99 11,444 3.2%

> 40 3,975 2.9%

Because very early preterm infants are a group in need of special attention, the question arises if the relationship between rates of preterm delivery and BMI holds true for very early (< 31 weeks‘ gestation) as well as for moderately early (< 36 weeks‘ gestation) preterm deliveries and to what extent these preterm deliveries are caused by premature labor. We examined this based on the perinatal statistics of the German state of Mecklenburg-Western Pomerania. Table 21-5 shows the results of an analysis of the proportion of very early (< 31 weeks‘ gestation) and moderately early preterm deliveries (< 36 weeks) caused by spontaneous premature labor.

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Table 21-5. Preterm delivery and premature labor according to BMI. (Perinatal statistic of Mecklenburg-Western Pomerania of 1994 – 2000, singleton pregnancies of primiparous and multiparous women, n = 68,362) BMI

< 18.50

Preterms < 36 weeks (n) % of total Preterms < 31 weeks (n) % of total Premature labor (total n) % of total Premature labor in preterms < 36 weeks (n and %) Premature labor in preterms < 31 weeks (n and %)

311 10.5 38 1.3 484 16.3 130 41.8 17 44.7

18.5024.99 2919 6.5 422 0.95 4317 9.7 974 33.4 163 38.6

25.0029.99 845 5.9 134 0.94 904 6.3 200 23.7 45 33.6

30.0034.99 315 6.5 60 1.25 248 5.2 64 20.3 17 28.3

35.0039.99 106 7.4 17 1.2 50 3.5 13 12.3 3 17.6

> 40 32 6.7 4 0.84 16 3.3 2 6.25 0

For both very early preterm deliveries and moderately early preterm deliveries the rate of preterm delivery tended to be higher in obese compared to normal weight women, though this was not the case for very early preterm deliveries in morbidly obese women. The rate of spontaneous preterm labor decreases with increasing BMI for both groups of deliveries, very early preterm and moderately early preterm births. The highest rates of premature labor occurred in underweight women.

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There is good evidence from the literature that while spontaneous labor is less common in the obese, obesity - by way of maternal complications such as gestational hypertension – is linked with more frequent induced preterm births (Hacini Afroukh et al. 2008). In case of morbid obesity, the risk of medically indicated preterm and very preterm births was found to be almost twice that for non-obese women (Salihu et al. 2008). The same study also confirmed that obese mothers had a lower risk for spontaneous preterm delivery. We have analysed the frequency of medical indications for induced preterm birth based on German perinatal statistics. We found increased rates of the common medical indications for induced preterm birth (pre-eclampsia, diabetes, previous Cesarean section) with increasing BMI (Table 21-6). Table 21-6. Indications for iatrogenic preterm delivery according to maternal BMI. Data are from the German perinatal statistics of 1998-2000 (primiparous and multiparous women). We show the number of cases where the below-mentioned indications for iatrogenic preterm delivery have been recorded and the percentage relative to all preterm births. BMI Pre-eclampsia Diabetes Previous Cesarean section Maternal disease

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Uterine rupture Number of neonates born preterm Number of neonates born after 37 weeks Total (n = 499,267)

< 18.50 59 3.3 % 4 0.2 % 140 7.8 % 52 2.9 % 8 0.4 %

18.50-24.99 1191 6.0 % 160 0.8 % 2025 10.2 % 596 3.0 % 88 0.4 %

25.00-29.99 685 10.9 % 116 1.9 % 802 12.8 % 195 3.1 % 26 0.4 %

30.00-34.99 395 17.0 % 83 3.6 % 367 15.8 % 79 4.4 % 8 0.3 %

35.00-39.99 191 22.7 % 40 4.8 % 161 19.1 % 36 4.3 % 4 0.5 %

> 40 90 28.7 % 30 9.5 % 59 18.8 % 20 6.4 % 2 0.6 %

1791

19,812

6265

2317

842

314

18,033

300,336

101,524

33,770

10,602

3661

19,824

320,148

107,789

36,087

11,444

3975

Figure 21-1 summarizes the results discussed above. While the rates of preterm birth tend to be increased in obese compared to normal weight women, the rate of spontaneous premature labor decreases with rising BMI. Both rates of premature labor and preterm delivery are high in underweight women. Not only the rate of preterm births but also the consequences of preterm birth are influenced by maternal BMI. For example, Nohr et al. (2007) reported that neonatal mortality in infants born after preterm premature rupture of membranes was significantly increased if they were born to an overweight or obese mother.

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Figure 21-1. Preterm delivery (in %) at < 36 weeks‘ and < 31 weeks‘ gestation and premature labor (in %, ‗Prem lab‘) according to maternal BMI. (Perinatal statistics of Mecklenburg–Western Pomerania, 1994 – 2000, singleton pregnancies, n = 68,362)

In summary, obesity is associated with increased rates of preterm delivery. This is not due to spontaneous preterm labor, as spontaneous preterm labor is less common in obesity. Rather, a higher rate of induced preterm births because of medical indications explains the increase in preterm delivery rate in obesity. Interestingly, materal overweight status was associated with the lowest preterm birth rates. This stands in contrast to other studies (Driul et al. 2008) and is not explained by pregnancy risks (Table 21-6); the causation is unclear. Underweight mothers had the highest risk of preterm delivery and the highest rates of premature labor. Because maternal complications of pregnancy and not spontaneous preterm labor explain increased preterm birth rates in the obese, an important part of the effort to decrease preterm birth rates in the obese must be to prevent and/or adequately treat the complications of pregnancy that can result in preterm delivery.

Bacterial Vaginosis Bacterial vaginosis is discussed in this context because it is an important risk factor for preterm birth. It is also associated with other complications such as postnatal infections (endometritis, sepsis, and wound infections). Even though the higher rates of preterm birth in obesity are due to induced preterm delivery for medical indications (while spontaneous preterm birth is less frequent in obesity), it still makes sense to discuss how spontaneous preterm birth risk can be lowered – both in terms of overall risk reduction for preterm birth and because spontaneous preterm birth may be associated with more severe consequences in the obese (Nohr et al. 2007). Furthermore, obese women may be at increased risk of infection and vaginal infection is associated with a number of adverse outcomes, not only preterm delivery.

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While intravaginal clindamycin cream is an effective method of treating bacterial vaginosis, its effectiveness is preventing preterm births is controversial (Joesoef et al. 1995; Kurkinen-Räty et al. 2001; Kekki et al. 2001; Lamont et al. 2003). Lamont et al. (2003) showed a statistically significant reduction in the incidence of preterm birth in a clindamycin group (4 %) compared to placebo (10 %). Kekki et al. (2001), however, found no significant effect of clindamycin in term of preterm birth rates (5 % in a clindamycin group, 4 % with placebo). Perhaps the discrepancies in studies of clindamycin can be explained, at least in part, by the timing of intervention. Early treatment seems to work best (Lamont et al. 2003). Therefore, timely diagnosis and treatment of vaginal dysbiosis and asymptomatic or symptomatic bacterial vaginosis has the potential to reduce the risks of preterm birth and infection. Current systematic reviews of the use of antibiotics in bacterial vaginosis are not encouraging from the point of prevention of preterm birth. Orkun and colleagues found that for women with bacterial vaginosis, antibiotics reduced the risk of persistent infection but not of preterm birth. For women with Trichomonas vaginalis, metronidazole reduced the risk of persistent infection but was found even to increase the incidence of preterm births (Okun et al. 2005). A recent Cochrane review addressed the question of whether identifying and treating pregnant women with asymptomatic bacterial vaginosis may reduce the risk of preterm birth. It showed there was little evidence such screening will prevent preterm birth and its consequences. However, it did point out that treatment before 20 weeks' gestation may reduce the risk of preterm birth, although more evidence was needed to be sure (McDonald et al. 2007). Because early detection and treatment of bacterial vaginosis seems to be essential, a case can be made for self-monitoring of pregnant women with the aim of detecting vaginal dysbiosis early. In Germany, a program for self-detection of vaginal dysbiosis has proven successful in lowering the rate of preterm birth. Pregnant women were instructed to measure vaginal pH twice weekly. Those with a raised pH (pH > 4.7) were asked to see a doctor to start lactobacillus acidophilus therapy or, in case of frank bacterial vaginosis, to treat with intravaginal clindamycin cream. A study of 2341 such women found that the preterm birth rate was 8.1 % in the self-measurement/intervention group and 12.3 % in the control group (Hoyme et al. 2002). There are three parts to an integrated approach for the prevention of preterm birth: • • •

Screening for risk factors Detecting vaginal dysbiosis as early as possible Restoring vaginal flora following anti-infective therapy

Compared with local antibiotics such as clindymycin and metronidazole, there are some advantages to using antiseptic agents in the treatment of vaginal dysbiosis and bacterial vaginosis: • •

The unspecific nature of the antiseptic effect guards against a selective enrichment with potentially dangerous bacteria. Resistance, commonly seen with antibiotics (clindamycin), does not occur with antiseptic agents.

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There are no systemic effects of antiseptic treatment. Local antibiotic treatment can after absorption of antibiotics - lead to systemic effects.

The use of antiseptics for bacterial vaginosis, in combination with surveillance and early initiation of therapy, seems a good option. Obesity is thought to favor intra-amniotic infections (Newton 1993), and so it would appear sensible to be especially vigilant with regard to the possibility of developing intraamniotic infections in the obese. Independent of any causal consideration, as both obesity and bacterial vaginosis are associated with an increased risk of preterm birth, it makes sense to be especially watchful for bacterial vaginosis in the obese. If obesity indeed affects local immune response one might also expect to find an effect of obesity on the outcome of bacterial vaginosis treatment. Current evidence on this is not supportive, however. Searching the literature we found only one study that addressed this point. Mastrobattista et al. (2008) determined the effect of BMI on response to bacterial vaginosis treatment. They found that the persistence of bacterial vaginosis after treatment was not related to BMI. Further work on the interaction of bacterial vaginosis and obesity is needed. In summary, both obesity and bacterial vaginosis are associated with preterm birth. Furthermore there is evidence that obesity favors intra-amniotic infection. Therefore a convincing case can be made for a heightened alertness and willingness to treat bacterial vaginosis in the obese.

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Illustrative Case A 26-year-old women (weight 121 kg, height 181 cm, BMI 37) presented in labor at 27 weeks‘ and 3 days‘ gestation. Her obstetric history included a spontaneous delivery at term six years ago, as well as two terminations of pregnancy. When the patient was admitted at 27 weeks‘ and 3 days‘ gestation, her cervix was dilated (8 cm) and transverse lie of the fetus was diagnosed. An emergency Cesarean section was performed under spinal anesthesia. A single dose of betamethasone (8 mg) was given to induce pulmonary maturation. The neonatal outcome was poor: birth weight was 1200 g; Apgar scores were 5, 7, and 7 at 1, 5 and 10 minutes, respectively. Infant respiratory distress syndrome was diagnosed. Postnatal development was furthermore complicated by infection, cerebral bleeds, progressive posthemorrhagic hydrocephalus, and bronchopulmonary dysplasia.

References Curry AE, Thorsen P, Drews C, Schendel D, Skogstrand K, Flanders WD, Hougaard D, Olsen J, Vogel I. First-trimester maternal plasma cytokine levels, pre-pregnancy body mass index, and spontaneous preterm delivery. Acta Obstet. Gynecol. Scand. 2009, 88: 332 – 342.

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Driul L, Cacciaguerra G, Citossi A, Martina MD, Peressini L, Mrchesoni D. Prepregnancy body mass index and adverse pregnancy outcomes. Arch. Gynecol. Obstet. 2008; 278: 23 – 26. Ehrenberg HM, Iams JD, Goldenberg RL, Newman RB, Weiner SI, Sibai BM, Caritis SN, Miodovnik M, Dombrowski MP. Maternal obesity, uterine activity, and the risk of spontaneous preterm birth. Obstet. Gynecol. 2009; 113: 48 – 52. Hacini Afroukh N, Burguet a, Thiriez G, Muliu B, Bouthet MF, Abraham L, Boisselier P, villemonteix P, Bauer V, Lathelize J, Pierre F. Very preterm birth: should be interested in maternal pre-pregnancy body mass index? Arch. Pediatr. 2008; 15: 1068 – 1075. Hoyme UB, Möller U, Saling E. Ergebnisse und mögliche Konsequenzen der Thüringer Frühgeburtenvermeidungsaktion 2000. Geburtsh Frauenheilk. 2002; 62: 257-63. Joesoef MR, Hillier SL, Wiknjosastro G, Sumampouw H, Linnan M, Norojono W, Idajadi A, Utomo B. Intravaginal clindamycin treatment for bacterial vaginosis: effects on preterm delivery and low birth weight. Am. J. Obstet. Gynecol. 1995; 173: 1527-31. Kekki M, Kurki T, Pelkonen J, Kurkinen-Räty M, Cacciatore B, Paavonen J. Vaginal Clindamycin in preventing preterm birth and peripartal infections in asymptomatic women with bacterial vaginosis: a randomized, controlled trial. Obstet. Gynecol. 2001; 97: 643-48. Kurkinen-Räty M, Vuopala S, Koskela M, Kekki M, Kurki T, Paavonen J, Jouppila P. A randomised controlled trial of vaginal clindamycin for early pregancy bacterial vaginosis. BJOG. 2000; 107: 1427-32. Lamont RF, Duncan SLB, Mandal D, Bassett P. Intravaginal Clindamycin to reduce preterm birth in women with abnormal genital tract flora. Obstet. Gynecol. 2003; 101: 516-22. McDonald HM, Brocklehurst P, Gordon A. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst. Rev. 2007; (1): CD000262. Mastrobattista JM, Klebanoff MA, Carey JC, Hauth JC, Macpherson CA, Ernest J, Cotroneo M, Leveno KJ, Wapner R, Varner M, Iams JD, Moawad A, Sibai BM, Miodovnik M, Dombrowski M, O'Sullivan MJ, Vandorsten JP, Langer O; National Institute of Child Health and Human Development Maternal-Fetal Medicine Unit Networks. The effect of body mass index on therapeutic response to bacterial vaginosis in pregnancy. Am. J. Perinatol. 2008; 25: 233 – 237. Newton ER. Chorioamnionitis and intraamniotic infection. Clin. Obstet. Gynecol. 1993; 36: 795 – 808. Nohr EA, Yaeth M, Beck BH, Henriksen TB, Cnattingius S, Olsen J. Maternal obesity and neonatal mortality according to subtypes of preterm birth. Obstet Gynecol. 2007; 110: 1083 – 1090. Okun N, Gronau KA, Hannah ME. Antibiotics for bacterial vaginosis or Trichomonas vaginalis in pregnancy: a systematic review. Obstet Gynecol. 2005; 105: 857 – 868. Salihu HM, Lynch O, Alio AP, Liu J. Obesity subtypes and risk of spontaneous versus medically indicated preterm births in singleton and twins. Am. J. Epidemiol. 2008; 168: 13 – 20. Simhan HN, Krohn MA: First-trimester cervical inflammatory milieu and subsequent early preterm birth. Am. J. Obstet. Gynecol. 2009; 200: 377.e1-4.

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Voigt M, Straube S, Zygmunt M, Krafczyk B, Schneider KT, Briese V. Obesity and pregnancy - a risk profile. Z. Geburtshilfe Neonatol. 2008; 212: 201-5. Willemsen RH, Leunissen RW, Stijnen T, Hokken-Koelega AC. Prematurity is not associated with reduced insulin sensitivity in adulthood. J. Clin. Endocrinol. Metab. 2009; 94: 1695-700. Zegers-Hochschild F, Nygren KG, Adamson GD, de Mouzon J, Lancaster P, Mansour R, Sullivan E. International Committee Monitoring Assisted Reproductive Technologies. The ICMART glossary on ART terminology. Hum. Reprod. 2006; 21:1968-70.

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ISBN: 978-1-60876-111-1 © 2010 Nova Science Publishers, Inc.

Chapter XXII

Pre-Eclampsia and Eclampsia

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Hypertension and proteinuria after 20 weeks of gestation are the most important diagnostic criteria of pre-eclampsia (Brown et al. 2001), a materno–placental syndrome characterized by disordered trophoblast invasion, endothelial dysfunction, and glomerular endotheliosis. The activation of anti-angiogenic factors such as fms-like tyrosine kinase 1 (sFlt1) and endoglin are causally implicated. Figure 22-1 illustrates placental infarctions and fat depositions typical of pre-ecalampsia.

Figure 22-1. Placental infarcts and fatty depositions in pre-eclampsia. Photograph by V. Briese.

Obesity and pre-eclampsia are linked in a number of ways. High BMI is a risk factor for pre-eclampsia. Obesity as well as hypertension and pre-eclampsia are also risk factors for cardiovascular and cerebrovascular disease (Ness and Huber 2005). Furthermore, obesity and

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hypertension have a number of other common co-morbidities: dyslipidemia, insulin resistance, hyperuricemia (reduced uric acid clearance because of glomerular endotheliosis in pre-eclampsia), hyperhomocysteinemia and systemic (low grade) inflammation.

Risk Factors and Prevalence

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In addition to an increased BMI, risk factors for the development of pre-eclampsia include nulliparity, a family history of pre-eclampsia, overweight or underweight status during childhood, insulin-dependent diabetes, multiple pregnancy, maternal age > 30 years, renal disease, and autoimmune disease (Leeners et al. 2006a,b; Duckitt and Harrington 2005). A recent study found that pre-existing hypertension, diabetes, obesity and multiple gestation were associated with 22.3 % of pre-eclampsia cases among nulliparous women (Catov et al. 2007). Figures 22-2 and 22-3 summarize an analysis of 508,629 singleton pregnancies from German perinatal statistics. The figures nicely illustrate the association between obesity and hypertensive disease in pregnancy and pre-eclampsia. There is plenty of other evidence that obesity during pregnancy is linked to higher rates of hypertension (Flegal et al. 2002, Harskamp and Zeeman 2007, Robinson et al. 2005). Pre-eclampsia and hypertension are common problems. Pre-eclampsia affects 3 - 5 % of pregnancies (Baumwell and Karumanchi 2008), gestational hypertension occurs in 7 % (Villar et al. 2006). Obesity increases the risk substantially. Compared with a BMI of 20, the odds ratio for severe pre-eclampsia at a BMI of 30 in white women has been estimated at 3.4 (Bodnar et al. 2007). A systematic review concluded that the risk of pre-eclampsia typically doubled with each 5 - 7 point increase in pre-pregnancy BMI (O‘Brien et al. 2003).

Figure 22-2. Rates of hypertension according to BMI and according to maternal age. Data from German perinatal statistics, 1998 – 2000.

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Figure 22-3. Rates of pre-eclampsia/eclampsia according to BMI and maternal age. Data from German perinatal statistics, 1998 – 2000.

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Pre-Conceptional Counselling and Preventing Pre-Eclampsia During Pregnancy There is currently no way of preventing or reliably predicting pre-eclampsia. Advising patients about the dangers associated with pre-eclampsia and initiating folate prophylaxis (800 g per day) prior to pregnancy are of paramount importance. Sensible physical activity can also be recommended. Women who continue weight-bearing exercise during pregnancy have been shown to maintain their long-term fitness (Clapp 2008). Nutritional advice may help, too. Because of the link of pre-eclampsia and hypertension with insulin resistance a diet with a low glycemic index may be useful during pregnancy. In terms of fat distribution, women with largely visceral obesity and cardiovascular complications are especially in danger. An oral glucose tolerance test is recommended, as pre-eclampsia is associated with insulin resistance (Kaaja 2008). A number of approaches including supplementation with omega-3 fatty acids, calcium, magnesium, vitamins C and E and antihypertensives have been tried but were ineffective, at least in the prevention of recurrent pre-eclampia (Barton and Sibai 2008). Close surveillance during pregnancy is therefore recommended in all cases at risk of pre-eclampsia, including in obese women.

Maternal and Fetal Morbidity and Mortality Pre-eclampsia and obesity both increase the rate of stillbirths and birth asphyxia. Preeclampsia and obesity are also risk factors for postpartum hemorrhage (Jouppila 1995). Early-

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onset pre-eclampsia has been associated with fetal growth restriction (Haram und Gjelland 2007). Some diseases per se unrelated to obesity can increase the risk of pre-eclampsia. Together with obesity the risk then rises substantially. A history of migraines, for example, was shown to lead to a 1.8-fold increased risk of pre-eclampsia. Overweight migrainous women, however, had an impressive 12-fold increase in pre-eclampsia risk when compared with normal weight non-migrainous women (Adeney et al. 2008). Some genetic polymorphisms are potentially of relevance in this context including a hepatic lipase (LIPC) gene promoter polymorphism (-514C/T) and the Trp64Arg polymorphism of the beta3-adrenergic receptor (Zhang et al. 2005, Enquobahrie et al. 2005). Details and clinical implications still have to be elucidated. A dangerous complication of pre-eclampsia is eclampsia, characterized by a focal neurological deficit as a result of cerebral hemorrhage or ischemia, or by encephalopathy that manifests as seizures, headaches or neuropsychiatric symptoms. Any cerebral symptom should ring alarm bells and means the eclampsia must urgently be excluded. A stroke in the weeks following delivery can also be the result of eclampsia, though often the connection is not made. Correct diagnosis is important because the therapy for eclampsia differes from classical stroke therapy. Agents of choice include hydralazine, urapidil, nifedipine and labetolol as antihypertensives, as well as magnesium sulfate as an anticonvulsant and antihypertensive. Symptoms and even imaging changes are often reversible. For ischemic injuries aspirin (75 100 mg) should be given. An important differential diagnosis for eclampsia that manifests with or after delivery is peripartal venous sinus thrombosis, caused by thrombophilia. To diagnose venous sinus thrombosis with confidence, venous MR angiography should be performed. Venous sinus thrombosis is treated by heparinization, or, after delivery, by oral anticoagulation. The HELLP syndrome is a hypertensive complication of pregnancy, a variant of preeclampsia, characterized by hemolysis, elevated liver enzymes, and low platelets - in addition to hypertension, proteinuria and peripheral edema. Upper abdominal pain is a common clinical symptom. There is an appreciable maternal and perinatal mortality. Corticosteroids are often used (Martin et al. 2006), though the definite treatment remains delivery of the patient (Curtin and Weinstein 1999). A recent study found that being overweight or obese did not increase the risk of HELLP syndrome. A raised BMI is correlated with an increased risk of developing pre-eclampsia but not HELLP syndrome (Leeners et al. 2006a).

Deranged Liver Function and Acute Fatty Liver Deranged liver function tests occur in about 3 – 5 % of pregnancies. Apart from preexisting conditions (gallstones and viral hepatitis), there are pregnancy-related causes to be considered: pre-eclampsia, HELLP syndrome, acute fatty liver, hyperemesis gravidarum, and intrahepatic cholestasis of pregnancy (Hay 2008). Acute fatty liver, like HELLP syndrome, is associated with pre-eclampsia. Because pre-eclampsia is more common in the obese the possibility of deranged liver function and acute fatty liver in particular in this group of

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patients needs to be kept in mind. Fatty liver in general is associated with obesity, and we therefore think that the possibility of acute fatty liver in pregnancy has to be watched out for in obese patients, particularly if they also have pre-eclampsia. The pathophysiology of acute fatty liver in pregnancy involves defects in mitochondrial fatty acid beta-oxidation and mutations that may be involved have recently been identified (Lee and Brady 2009). Acute fatty liver of pregnancy manifests in the third trimester and is more common in nulliparous women and with multiple gestation. Overall it is a rare disease, with an estimated incidence of 1 in 7000 to 1 in 20,000 pregnancies (Lee and Brady 2009, Knight et al. 2008, Mjahed et al. 2006) but with appreciable maternal and fetal mortality of 18 % and 23 %, respectively (Lee and Brady 2009). For acute fatty liver in pregnancy, the therapy of choice is early delivery. Postpartum plasma exchange may be used as an adjunct therapy (Martin et al. 2008). Coagulopathy may need to be corrected with fresh frozen plasma, platelets, and vitamin K (Mjahed et al. 2006). Recurrence in the next pregnancy is possible and affected patients should be screened for defects in fatty acid oxidation (Lee and Brady 2009).

Illustrative Cases A couple of typical cases may help to illustrate the consequences of pre-eclampsia and show where improvements in clinical practice are possible.

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Case 1 A 27-year-old primiparous woman has a weight of 93 kg after eight weeks‘ gestation (central obesity was noted). Her height was 163 cm; BMI was therefore 35. At 30 weeks‘ gestation maternal weight had increased to 107 kg. The patient‘s chronic hypertension was now complicated by superimposed pre-eclampsia. Her medication included nifedipine and methyldopa. The patient experienced onset of labor and premature rupture of membranes at 31 weeks‘ gestation. A decision was made to deliver by Cesarean section: birth weight was 2550 g, Apgar scores were 5, 8, and 8 at 1, 5, and 10 minutes. Retrospective analysis of this case revealed that pre-conceptional weight reduction had not been addressed and no glucose tolerance test had been performed during the pregnancy.

Case 2 A morbidly obese woman (height 168 cm, weight 122 kg, BMI 43.2) presented during her second pregnancy. Her history included a previous pregnancy complicated by preeclampsia that had ended in a Cesarean section at 35 weeks‘ gestation. During her second pregnancy the patient developed increasing proteinuria, abdominal pain, and a falling platelet count. A diagnosis of HELLP syndrome was made. She was delivered by Cesarean section at 24 weeks‘ gestation. Maternal platelet count dropped further in the postoperative period.

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Hemoglobin was low (6.1 mmol/l), liver enzymes were raised 10-fold. Maternal hypothyroidism was also diagnosed. The neonatal outcome was poor: Apgar scores were 3 (at one minute) and 5 (at two minutes). Birth weight was only 380 g. At six months the neonate had developed retinopathy and neurological impairment.

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References Adeney KL, Williams MA, Miller RS, Frederick IO, Soensen TK, Luthy DA. Risk of preeclampsia in relation to maternal history of migraine headaches. J. Matern. Fetal Neonatal. Med. 2005; 18: 167-172. Barton JR, Sibai BM. Prediction and prevention of recurrent preeclampsia. Obstet Gynecol. 2008; 112: 359-372. Baumwell S, Karumanchi SA. Pre-eclampsia: clinical manifestations and molecular mechanisms. Nephron. Clin. Pract. 2007; 106: c72-81. Bodnar LM, Catov JM, Klebanoff MA, Ness RB, Roberts JM. Prepregnancy body mass index and the occurrence of severe hypertensive disorders of pregnancy. Epidemiology. 2007; 18: 234-239. Brown MA, Lindheimer MD, de Swiet M, Van Assche A, Moutquin JM. The classification and diagnosis of the hypertensive disorders of pregnancy: statement from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertens Pregnancy. 2001; 20: IX-XIV. Catov JM, Ness RB, Kip KE, Olsen J. Risk of early or severe pre-eclampsia related to preexisting conditions. Int. J. Epidemiol. 2007; 36: 412-419. Clapp JF. Long-Term outcome after exercising throughout pregnancy: fitness and cardiovascular risk. Am. J. Obstet. Gynecol. 2008; 199: e1-489.e6. Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking : systematic review of controlled studies. BMJ. 2005; 330: 565. Enquobahrie DA, Sanchez SE, Muy-Rivera M, Qiu C, Zhang C, Austin MA, Williams MA. Hepatic lipase gene polymorphism, pre-pregnancy overweight status and risk of preeclampsia among Peruvian women. Gynecol. Endocrinol. 2005; 21: 211-217. Flegal KM, Carioo MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among U.S. adults, 1999-2000. JAMA. 2002; 288: 1723-1727. Hay JE. Liver disease in pregnancy. Hepatology. 2008; 47: 1067-76. Haram K, Gjelland K. Foetal growth retardation. Tidsskr. Nor. Laegeforen. 2007; 127: 2665 – 2659. Harskamp RE, Zeemann GG. Preeclampsia at risk for remote cardiovascular disease. Am. J. Med. Sci. 2007; 334: 291-295. Jouppila P. Postpartum haemorrhage. Curr. Opin. Obstet. Gynecol. 1995; 7: 446-450. Kaaja R. Predictors and risk factors of pre-eclampsia. Minerva Ginecol. 2008; 60: 421-9. Knight M, Nelson-Piercy C, Kurinczuk JJ, Spark P, Brocklehurst P, UK Obstretic Surveillance System. A prospective national study of acute fatty liver of pregnancy in the UK. Gut. 2008; 57: 951-956.

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Lee NM, Brady CW. Liver disease in pregnancy. World J. Gastroenterol. 2009 28; 15: 897906. Leeners B, Rath W, Kuse S, Irawan C, Imthurn B, Neumaier-Wagner P. BMI: new aspects of a classical risk factor for hypertensive disorders in pregnancy. Clin. Sci. (Lond). 2006a; 111: 81-86. Leeners B, Rath W, Kuse S, Irawan C, Neumaier-Wagner P. The significance of under- or overweight during childhood as a risk factor for hypertensive diseases in pregnancy. Early Hum. Dev. 2006b; 82: 663-668. Martin JN Jr, Rose CH, Briery CM. Understanding and managing HELLP syndrome: the integral role of aggressive glucocorticoids for mother and child. Am. J. Obstet. Gynecol. 2006; 195: 914-34. Martin JN Jr, Briery CM, Rose CH, Owens MT, Bofill JA, Files JC. Postpartum plasma exchange as adjunctive therapy for severe acute fatty liver of pregnancy. J. Clin. Apher. 2008; 23: 138-143. Mjahed K, Charra B, Hamoudi D, Noun M, Barrou L. Acute fatty liver of pregnancy. Arch. Gynecol. Obstet. 2006; 274: 349-353. Ness RB, Hubel CA. Risk for coronary artery disease and morbid preeclampsia: a commentary. Ann. Epidemiol. 2005; 15: 726-733. O'Brien TE, Ray JG, Chan WS. Maternal body mass index and the risk of preeclampsia: a systematic overview. Epidemiology. 2003; 14: 368-74. Robinson HE, O´Conell CM, Joseph KS, McLeod NL. Maternal outcomes in pregnancies complicated by obesity. Obstet. Gynecol. 2005; 106: 1357-1364. Villar J, Carroli G, Wojdyla D, Abalos E, Giordano D, Ba'aqeel H, Farnot U, Bergsjø P, Bakketeig L, Lumbiganon P, Campodónico L, Al-Mazrou Y, Lindheimer M, Kramer M; World Health Organization Antenatal Care Trial Research Group. Preeclampsia, gestational hypertension and intrauterine growth restriction, related or independent conditions? Am. J. Obstet. Gynecol. 2006; 194: 921-31. Zhang C, Williams MA, Edwards KL, Austin MA. Trp64Arg polymorphism of the beta3adrenergic receptor gene, pre-pregnancy obesity and risk of pre-eclampsia. J. Matern. Fetal. Neonatal Med. 2005; 17: 19-28.

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In: Obesity and Pregnancy V. Briese, M. Voigt and S. Straube, pp. 101-105

ISBN: 978-1-60876-111-1 © 2010 Nova Science Publishers, Inc.

Chapter XXIII

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Venous Thromboembolism Pulmonary embolism (PE) and deep vein thrombosis (DVT) are important causes of maternal morbidity and mortality during pregnancy. A large population based study from Minnesota found that the absolute risk of venous thromboembolism was about 200 per 100,000 woman-years; the relative risk among pregnant or postpartum women compared to non-pregnant women was 4.3 (Heit et al. 1995). Another recent study reported that the rate of venous thromboembolism was 1.72 per 1000 deliveries with 1.1 deaths per 100,000 (James et al. 2006). PEs and DVTs go hand in hand, and it is no surprise that often there are silent PEs in women who present with DVTs and silent DVTs in women who present with PEs (Meignan et al. 2000). The risk for PEs is high during pregnancy and especially after delivery. In fact, the majority of PEs occur postpartum. The risk of thromboembolism increases with BMI. Data from German perinatal statistics illustrate this nicely. Figure 23-1 shows the proportion of women with a history of thromboembolism prior to the current pregnancy according to their BMI. Despite modern treatment there still is a maternal mortality associated with thromboembolism. Older studies demonstrated that without anticoagulation in patients with DVTs there was an appreciable mortality due to associated PEs (Rutherford and Phelan 1986). Pregnancy is a hypercoagulable state. This is partly due to changes in the clotting system (including increased fibrin generation, decreased fibrinolytic activity, increased levels of clotting factors II, VII, VIII, and X). Moreover, anti-coagulant activity is reduced (decreased free protein S levels). In addition to changes in clotting factors there is a reduction in venous flow velocity in the legs from about 25-29 weeks of gestation, extending to about 6 weeks after delivery (Marik and Plante 2008). Stasis of course also predisposes to clotting. To estimate the risk of venous thromboembolism during pregnancy we need to consider all risk factors. Obesity, along with maternal age over 35 years and Cesarean delivery, are perhaps the most important risk factors for thromboembolic disease, because of their high prevalence (Marik and Plante 2008). Inherited thrombophilias, antiphospholipid syndrome, and a past medical history of thromboembolic disease all need to be considered when estimating the risk of venous thromboembolism in pregnancy and the postnatal period. There are a number of

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inherited thrombophilias including activated protein C resistance (mostly factor V Leiden mutation), antithrombin III deficiency, protein C deficiency, protein S deficiency, prothrombin mutation, and some types of dysfibrinogenemia. Further risk factors include immobility, in vitro fertilization, Cesarean section, postpartum hemorrhage, infection, hypertension, pre-eclampsia, diabetes, black race, heart disease, sickle cell disease, diabetes, systemic lupus erythematosus, smoking, and multiple pregnancy (Marik and Plante 2008, Chunihal and Bates 2009). Dehydration, some hematological diseases (e.g. polycythemia), and hyperhomocysteinemia can also contribute to the risk.

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Figure 23-1. Previous thromboembolism according to BMI; data from German perinatal statistics, 1998 – 2000, n = 508,926.

With such a plethora of potential risk factors flow charts such as the one in Figure 23-2 may help practicing clinicians in estimating the risk, albeit crudely.

Figure 23-2. Assessing risk for thromboembolism in pregnancy.

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Clinically, venous congestion of the leg, leg swelling, tachycardia, tachypnoea, and dyspnoea may indicate thromboembolism. Less typical presentations of DVTs also occur, such as abdominal pain (Merhi and Awonuga 2006). Furthermore, as mentioned above, DVTs may be asymptomatic. A high index of suspicion is therefore needed.

Diagnostic Work-up Diagnostic work-up best follows local guideline and diagnostic algorithms, as these differ between centers and countries. We think the following ought to be considered, depending on local availability. Routine tests: Clotting screen and full blood count (for platelets). D-dimer: if negative, it can be very useful in ruling out DVTs, especially in the first two trimesters. Ultrasound: compression ultrasound, Duplex ultrasound Imaging: Ventilation-perfusion (V/Q) scan, CT-pulmonary angiogram (CTPA), MRI

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If the suspicion of thrombophilia is raised, consider testing for the following in addition to the routine tests: plasminogen, antithrombin III, protein C, protein S, lupus anticoagulants, and homocysteine levels. Further tests may include assessing for activated-protein C resistance and prothrombin gene mutation. Thrombophilia screening of pregnant women with a DVT may be useful for postnatal management and perhaps pre-conceptional management if another pregnancy is planned.

Preventing and Treating Venous Thromboembolism in Pregnancy Again we recommend following local guidelines and treatment algorithms. In principle there are the following approaches to drug therapy: antiplatelet agents (aspirin), low molecular weight heparin (LMWH), and unfractionated heparin. Mobilization and thromboembolic deterrent (TED) stockings are of course of paramount importance. Commonly used regimes for treatment and prevention of venous thromboembolism in pregnancy involving heparins are illustrated below (adapted from Chunihal and Bates 2009). Unfractionated Heparin Prophylactic low dose Prophylactic intermediate dose Treatment dose

5,000 IU subcutaneous twice daily Subcutaneous twice daily to target Peak anti-Xa level 0.1-0.3 U/ml Subcutaneous every 12 h to obtain a mid interval (6 h post injection) APTT in the therapeutic range

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Low-Molecular-Weight Heparin (LMWH) Prophylactic low dose

Enoxaparin 40 mg subcutaneous daily Dalteparin 5000 U subcutaneous daily Tinzaparin 4500 U or 75 U/kg subcutaneous daily

Prophylactic intermediate dose

Enoxaparin 40 mg subcutaneous twice daily Dalteparin 5000 U subcutaneous twice daily

Treatment dose

Enoxaparin 1 mg/kg twice daily or 1.5 mg/kg once daily Dalteparin 100 U/kg twice daily or 200 U/kg once daily Tinzaparin 175 U/kg subcutaneous daily

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LMWH does not pose a risk to the fetus because it does not cross the placenta in the last two trimesters (Forestier et al 1984). Mobilization and TED stockings are simple and effective measures, yet often neglected in practice because patients have not been explained why they are important. Patient education is therefore necessary, too. When the rationale of using TED stockings is explained patients are much more likely to use them. For large acute pulmonary emboli more radical measures may be considered such as thrombolysis (using agents such as streptokine or tPA) or cardiothoracic surgery; expert guidance is essential here. Given the importance of obesity, especially morbid obesity, as a risk factor for thromboembolism we recommend routine thromboprophylaxis in morbidly obese women.

Illustrative Case A 28-year old patient with morbid obesity (166 cm, 116 kg, BMI 42) has an obstetric history of two terminations of pregnancy, a missed abortion, a stillbirth after 25 weeks‘ gestation, and a live birth after 30 weeks‘ gestation (delivered by primary Cesarean section, fetal growth restriction was noted). One year after the Cesarean section she expertienced a combined ilio-femoral DVT. Thorough screening for risk factors for thromboembolism was performed. Genetic testing revealed a heterozygous state for the prothrombin gene mutation G2010A, and a homozygous state for the MTHFR variant C677T. In keeping with the latter there was transient hyperhomocysteinemia. For her current pregnancy it was considered necessary to initiate treatment after 16 weeks‘ gestation with LMWH, aspirin and folate (to lower homocysteine levels). LMWH was titrated according to anti-factor Xa activity. The patient was closely monitored with serial ultrasounds. She was hospitalized because of reduced fetal movements and delivered by Cesarean section at 35 weeks‘ gestation. Birth weight was appropriate for gestational age (2270 g), Apgar scores were satisfactory. Because of strict surveillance and appropriate treatment a good pregnancy outcome could be obtained.

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References

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Chunihal SD, Bates SM. Venous thromboembolism in pregnancy: diagnosis, management and prevention. Thromb. Haemost. 2009; 101: 428 – 438. Forestier F, Daffos F, Capella-Pavlovsky M. Low molecular weight Heparin (PK 10169) does not cross the placenta during the second trimester of pregnancy study by direct fetal blood sampling under ultrasound. Thromb. Res. 1984; 34: 557 – 560. Heit JA, Kobbervig CE, James AH. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann. Intern. Med. 2005; 143: 697 – 706. James AH, Jamison MG, Brancazio LR, Myers MR. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am. J. Obstet. Gynec. 2006; 194: 1311 – 5. Marik PE, Plante LA. Thromboembolic Disease and Pregnancy. N. Engl. J. Med. 2008; 359: 2025-33. Meignan M, Rosso J, Gauthier H. Systematic lung scans reveal a high frequency of silent pulmonary embolism in patients with proximal deep venous thrombosis. Arch. Intern. Med. 2000; 160: 159 – 64. Merhi Z, Awonuga A. Acute abdominal pain as the presenting symptom of isolated iliac vein thrombosis in pregnancy. Obstet. Gynec. 2006; 107: 468 – 70. Robertson L, Wu O, Langhorne P. Thrombophilia in pregnancy: a systematic review. Br. J. Haemat. 2006; 132: 171 – 96. Rutherford SE, Phelan JP. Thromboembolic disease in pregnancy. Clin. Perinat. 1986; 13: 719 – 739.

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In: Obesity and Pregnancy V. Briese, M. Voigt and S. Straube, pp. 107-110

ISBN: 978-1-60876-111-1 © 2010 Nova Science Publishers, Inc.

Chapter XXIV

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Gestational Diabetes Gestational diabetes mellitus is common and its prevalence increases with increasing maternal BMI (Voigt 2008). Perhaps 2 - 5 % of all pregnant women in the US are affected (Cheng and Caughey 2008). Certain ethnic groups - Asians, native Americans, and Latin Americans - have a higher risk (Cheng and Caughey 2008), and in some populations the prevalence rates are much higher: 13.9 % in India, for example (Seshiah et al. 2008). Worldwide there is an increase in the prevalence of gestational diabetes. This rise is paralleled by increasing prevalences of obesity, type 2 diabetes, and features of the metabolic syndrome. Gestational diabetes, the most common metabolic disorder in pregnancy, is a genetically heterogeneous disease of varying severity. Apart from the hereditary component, obesity is perhaps the most important risk factor. Increased insulin resistance is though to result from unfavourable proportions of fat and muscle mass in the obese. During pregnancy, placental insulin antagonists such as human placental lactogen and increased maternal cortisol levels contribute to a diabetogenic environment. A recent study of over 25,000 women investigated the relationship between hyperglycemia and adverse pregnancy outcomes (Metzger et al. 2008). A number of adverse pregnancy outcomes are linked with gestational diabetes including fetal macrosomia and associated complications (e.g. need for Cesarean section) but also fetal hyperinsulinemia and hypoglycemia. Interestingly, the above-mentioned study also found an association of maternal glucose levels below those diagnostic of diabetes with increased birth weight. Perhaps gestational impaired glucose tolerance and gestational diabetes should be seen as a continuum. Risk factors for developing gestational diabetes are shown below. Risk factors for gestational diabetes (modified from Berger et al. 2003): • Maternal Obesity • Family history of diabetes in first-degree relative • A history of miscarriages, stillbirths and malformations • Maternal age > 30 years • A history of gestational diabetes-associated adverse pregnancy outcomes • Being a member of an ethnic group with a high prevalence of diabetes (see above) • High maternal birth weight (> 4000 g)

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A general screening program may be needed for gestational diabetes because selective screening in high risk individuals still misses a substantial proportion of diabetic patients. The usefulness of urine dipsticks has been called into question (Ritterrath et al. 2006). The most reliable way to screen for and verify gestational diabetes is a 75 g oral glucose tolerance test. This involves measuring pre-test (fasting) glucose as well as glucose levels one and two hours after glucose intake. Gestational diabetes is present if at least two of the three cut-off levels (Table 24-1) are exceeded. Table 24-1. Diagnosis of gestational diabetes with a 75 mg oral glucose tolerance test

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Time Pre-test (fasting) After one hour After two hours

Capillary blood (mg/dl) > 90 > 180 > 155

(mmol/l) > 5.0 > 10.0 > 8.6

Venous blood (mg/dl) > 95 > 180 > 155

(mmol/l) > 5.3 > 10.0 > 8.6

Impaired glucose tolerance is present when only one cut-off value is exceeded. But given the above-mentioned observation that impaired glucose tolerance may already be associated with some of the adverse outcomes linked with gestational diabetes, we recommend managing gestational impaired glucose tolerance like gestational diabetes. The treatment aim is to reach a pre-meal blood sugar of 90 mg/dl (5.0 mmol/l), and postprandially of 140 mg/dl (6.8 mmol/l). In the blood glucose profile (day and night) a mean value of 100 mg/dl (5.5 mmol/l) should not be exceeded. Hemoglobin A1c should be below 7.0 %. If possible, hyperglycemic intervals should be avoided. Insulin ought to be used with caution. Insulin therapy incurs the risk of hypoglycemia as well as subsequent hyperglycemia and also a risk of weight gain. Oral antidiabetic agents should be considered: metformin (500 mg to 2500 mg daily) (Rowan et al. 2008) or glyburide (2.5 mg to 20 mg daily) (Langer et al. 2005). Continuation of care after delivery is important because glucose intolerance may persist. When a diagnosis of gestational diabetes was made, glucose tolerance should be re-assessed with another 75 g oral glucose tolerance test 6 - 12 weeks after delivery. This will identify women with persistent glucose intolerance (Berger et al. 2002). Undiagnosed type 2 diabetes already present before pregnancy may present during pregnancy and be diagnosed as ‗gestational diabetes‘. Obese women are at risk of such undiagnosed type 2 diabetes. Therefore, in addition to an oral glucose tolerance test, measuring Hemoglobin A1c is recommended (Simmons et al. 2008). The excess risk of later diabetes among patients with gestational diabetes varies between populations and was estimated at 18 % to 31 % in a review by O`Sullivan (O`Sullivan 1991). Obesity and gestational diabetes before 24 weeks‘ gestation are further risk factors for later developing type 2 diabetes.

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Illustrative Cases Case 1 A 30-year-old primiparous woman (weight 120 kg, height 185 cm, BMI 35) presented at 31 weeks‘ gestation because of possible gestational diabetes. There was a family history of diabetes. One fasting blood glucose value of 7.3 mmol/l (132 mg/dl) had been measured. Glycosuria could be demonstrated but was within normal levels (0.78 mmol/l, up to 0.90 mmol/l is normal). There was no ketonuria. An ultrasound examination was not suggestive of fetal macrosomia. A 75 g oral glucose tolerance test was performed. Results are illustrated below. Blood Glucose Time Pre-test (fasting) 1h post-test 2h post test

mmol/l (mg/dl) 3.96 (71.35) 10.7 (192.79) 6.62 (119.28)

Reference values mmol/l (mg/dl) 3.35 – 5.00 (60.36 – 90.09) < 10.0 (< 180.18) < 8.6 (< 154.96)

Insulin Levels

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Time Baseline value (fasting) 1h post-test 2h post test HOMA - Index

mIU/l 23.6 > 304 233 4.2

Reference values 1.9 – 23.6 up to 101 up to 85 1

Homeostatic model assessment (HOMA) can be used to quantify insulin resistance. Interpretation is as follows: HOMA index 1 >2 > 2.5 >5

Interpretation normal points to insulin resistance insulin resistance very likely average value in type II diabetes

This is a case of insulin resistance with - so far – little change in blood glucose levels in the 75 g oral glucose tolerance test. A diagnosis of impaired glucose tolerance could be made.

Case 2 A 33-year-old woman on her second pregnancy (weight 100 kg, height 177 cm, BMI 32) with a family history of diabetes and hypertension was diagnosed with gestational diabetes at 16 weeks‘ gestation. The diagnosis was based on a 75 g oral glucose tolerance test with two elevated glucose levels. She also developed gestational hypertension. Furthermore there was

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a past medical history of Hashimoto‘s thyroiditis. The patient‘s gestational diabetes was managed with insulin (Actrapid three times daily) and her gestational hypertension was managed with methyldopa (500 mg three times daily). Because of possible complications of delivery a decision was made to deliver by Cesarean section at 38 weeks‘ gestation. The patient was delivered of a male infant. Postnatal outcome was good (birth weight 2850 g; Apgar scores satisfactory).

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References Berger H, Crane J, Farine D, Armson A, De La Ronde S, Keenan–Lindsay L, Leduc L, Reid G, Van Aerde J, Maternal-Fetal Medicine Committee; Executive and Council of the Society of Obstetricians and Gynecologists of Canada. Screening for gestational diabetes mellitus. J. Obstet. Gynaecol. Can. 2003; 24: 894 – 912. Cheng YW, Caughey AB. Gestational diabetes: diagnosis and management. J. Perinatol. 2008; 28: 657-64. Langer O, Yogev Y, Xenakis EM, Rosenn B. Insulin and glyburide therapy: dosage, severity level of gestational diabetes, and pregnancy outcome. Am. J. Obstet. Gynecol. 2005; 192: 134 – 139. Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, Coustan DR, Hadden DR, McCance DR, Hod M, McIntyre HD, Oats JJ, Persson B, Rogers MS, Sacks DA. Hyperglycemia and adverse pregnancy outcomes. N. Engl. J. Med. 2008; 358: 19912002. O`Sullivan JH. Diabetes mellitus after GDM. Diabetes. 1991; 40 Suppl 2: 131 – 135. Ritterrath C, Siegmund T, Rad NT, Stein U, Buhling KJ. Accuracy and influence of ascorbic acid on glucose-test with urine dip sticks in prenatal care. J. Perinat. Med. 2006; 34: 285 – 288. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP. Metformin versus insulin for the treatment of gestational diabetes. N. Engl. J. Med. 2008; 358: 2003 – 2015. Seshiah V, Balaji V, Balaji MS, Paneerselvam A, Kapur A. Pregnancy and diabetes scenario around the world: India. Int. J. Gynaecol. Obstet. 2009; 104 Suppl 1: S35-8. Simmons D, Rowan J, Reid R, Campbell N, National GDM Working Party. Screening, diagnosis and services for women with gestational diabetes mellitus (GDM) in New Zealand: a technical report from the National GDM Technical Working Party. N. Z. Med. J. 2008; 121: 74 – 86. Voigt M, Straube S, Zygmunt M, Krafczyk B, Schneider KT, Briese V. Obesity and pregnancy - a risk profile. Z. Geburtshilfe Neonatol. 2008; 212: 201-5.

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Chapter XXV

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Diabetic Ketoacidosis (DKA) and Hyperosmolar Hyperglycemic Nonketotic Diabetic Coma (HONK) in Pregnancy The prevalence of impaired glucose tolerance and gestational diabetes in obese women is about 10 - 20 %; but because there is no general screening program - and even selective screening is often not undertaken - this may escape detection. Gestational diabetes may therefore present as diabetic ketoacidosis in pregnancy. Diabetic ketoacidosis is a severe complication of diabetes in pregnancy, puts the life of mother and fetus at risk (Parker and Conway 2007), and requires careful diagnosis and treatment. Diabetic ketoacidosis is diagnosed by the triad of high blood glucose, acidosis and high levels of ketone bodies. A recent study from China reported that diabetic ketoacidosis had a higher incidence in pregnant women with diabetes than in non-pregnant women with diabetes. Furthermore, in pregnancy diabetic ketoacidosis tended to occur at lower blood sugar levels compared with non-pregnant diabetics (Guo et al. 2008). Even euglycemic diabetic ketoacidosis in pregnancy has been described (Guo et al. 2008, Tarif and Al Badr 2008, Chico et al. 2008). Correct diagnosis therefore requires a high index of suspicion. Every pregnancy is associated with changes in carbohydrate metabolism leading to increased insulin resistance. This transient insulin resistance may allow better transfer of nutrients from mother to fetus. Furthermore lipolysis is enhanced and gluconeogenesis from amino acids is decreased, to meet the fetal demand for alanine and fatty acids. Increased concentrations of cortisol, estradiol, progesterone, and human placental lactogen (insulin antagonists) also predispose to impaired glucose tolerance, diabetes, and ketoacidosis. Elevated concentrations of other insulin antagonists (catecholamines, glucagon, growth hormones) may also play a role in pathogenesis of DKA. The presence of infections and their treatment can increase the likelihood impaired glucose tolerance, diabetes and DKA. Treated HIV infection, for example may be complicated by insulin resistance and diabetes (Aschkenazi et al. 2003, Bader and Kelley 2008). Such patients are at higher risk for developing DKA. The reasons for a metabolic derangement leading to DKA and HONK include:

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Hyperglycemia in the context of known diabetes First presentation of diabetes Therapeutic use of corticosteroids Stress (e.g. operations) Infection Hyperthyroidism and thyrotoxicosis (Moon et al. 2006). Increased concentration of insulin antagonists (pregnancy)

The clinical presentation of the hyperglycemic emergencies may include the following signs and symptoms: • • • • • • • •

Weakness, lethargy, headaches Loss of appetite, nausea, vomiting Signs of dehydration, polyuria, polydipsia Decreased muscle tone, hyporeflexia Visual disturbances Tachycardia, hypotension Abdominal pain (diabetic pseudoperitonitis) In advanced DKA: Kussmaul respiration, foetor (fruity breath)

Some of the complications to look out for include:

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• • • • • • • • • •

Hyperkalemia (lack of insulin effect) Hypokalemia (insulin effect once replaced) Hypernatremia, hyperchloremia (excessive supplementation in the context of reduced renal function) Hypoglycemia (excessive insulin replacement). Thromboembolism (hemoconcentration) Myocardial infarction, stroke, mesenteric infarction Cardiovascular shock Adult respiratory distress syndrome (ARDS) Cerebral edema Infections, sepsis

Table 25-1 compares and contrasts DKA and HONK and may help in making the correct diagnosis.

Diagnostic Work-up • • •

‗Full set‘ of laboratory investigations, including electrolytes, renal function tests, and TSH Urine dipstick Septic screen, blood cultures if signs of infection

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Diabetic Ketoacidosis (DKA)… • • • • •

113

ECG, cardiac monitoring Chest X-ray Consider abdominal ultrasound Frequent blood glucose monitoring / BMs (initially at least hourly) Blood gas analysis, osmolality (every 2-3 hours)

In the differential diagnosis, consider the following: • • • • • • •

Intoxikation Intracerebral bleed ‗Eclampsia sine eclampsia‘ (eclampsia without convulsions) Liver failure Uremia Hypoglycemic coma Premature placental abruption (abdominal pain, a differential diagnosis for diabetic pseudoperitonitis) Table 25-1. Distinguishing DKA and HONK

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DKA

HONK

Mild

Moderate

Severe

Plasma Glucose (mmol/l)

> 14*

> 14

> 14

> 30**

Arterial pH

7.25-7.35

7.0-7.24

< 7.0

> 7.3

Serum bicarbonate (mmol/l)

15-18

10-14

< 10

> 15

Urine ketones

>++

>++

>++

++

>++

>++

340

Anion gap

> 10

> 12

> 12

< 12

Awareness

diminished

diminished/sleepy

stupor/coma

stupor/coma

*202 mg/dl **527 mg/dl.

Management, adapted from Carroll and Yeomans 2005, Kitabchi et al. 2001, Chauhan and Perry 1995, and Ramin 1999: General management in all cases should be as for any emergency (airway, breathing, circulation etc.); specifics of the in-hospital management are given below:

Stage I: Rehydratation, Antithrombotic Therapy, Antibiotic Therapy • •

replace fluid (e.g. normal saline) and electrolytes; for a 10 % dehydration the patient will need 100ml/kg, one third of which should be given in the first 4 hours monitor and replace K+

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initiate insulin therapy (see below); acidosis will normally be corrected by giving insulin antithrombotic therapy (LMWH) consider antibiotics

Stage II: Insulin Therapy • • • •

aim for slow, continuous normalization of blood glucose: 3.3 mmol/l per hour mind the time course of insulin action: short acting insulins start to work after 15-30 minutes and have their maximum effect after about 2 hours do not lower blood glucose too much, 11 – 14 mmol/l is an adequate level administer an intravenous bolus of 0.15 U/kg or 10 U regular insulin initially, followed by either intravenous infusion of insulin at a rate of 0.1 U/kg per hour or subcutaneous or intramuscular injection of 7-10 U per hour. The intravenous route is recommended especially for HONK (Kitabchi et al. 2001).

Stage III: Re-Equilibration; Target Glucose: 10 mmol/l – 16.7 mmol/l

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• •

once the acidosis is corrected decrease the insulin dose, e.g. to 0.05 U/kg per hour when the blood glucose reaches 14 mmol/l (250 mg/dl) add dextrose to intravenous fluids (e.g. 5 % dextrose with 0.45-0.75 % NaCl). Don‘t give glucose orally (danger of vomiting).

There is some evidence that very low dose insulin therapy, slow-motion re-equilibration, and monitored substitution of electrolytes reduce mortality in severe DKA (Wagner et al. 1999). Out of hospital management, if necessary, should include volume replacement with saline and only little (2-5 U) or no insulin. Because hyperglycemic emergencies during pregnancy are so severe, preventive approaches need to be exhausted. These include: • • • • •

Blood glucose monitoring during betamethasone therapy for fetal respiratory distress syndrome (Schumacher et al. 2006) Consider early use of insulin in gestational diabetes Adequate monitoring and treatment of pregnant women with known diabetes Screen for gestational diabetes and impaired glucose tolerance Urine dipstick for diabetic pregnant women

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Illustrative Case A woman at 33 weeks‘ gestation was treated with prednisolone (300 mg) for allergic eczema and dyspnoea. Blood glucose was measured at 29 mmol/l (527 mg/dl). The CTG was silent. Treatment was initiated with 4 - 10 U/h actrapid until a blood glucose of 12 mmol/l (216 mg/dl) was achieved. The CTG remained silent and a decision was made to deliver by Cesarean section. Umbilical artery pH was 6.99 (low); birth weight was 2700 g. A diagnosis of diabetic fetopathy and birth asphyxia was made. Placental histology revealed evidence of chronic infarction with necrosis of the villi.

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References Aschkenazi S, Rochelson B, Bernasko J, Kaplan J. Insulin resistance complicating pregnancy in a human immunodeficiency virus infected patient treated with protease inhibitors and corticosteroids. Obstet. Gynecol. 2003; 102: 1210 – 1212. Bader MS, Kelly DV. Diagnosis and management of common chronic metabolic complications in HIV-infected patients. Postgrad. Med. 2008; 120: 17-27. Carroll MA, Yeomans ER. Diabetic ketoacidosis in pregnancy. Crit. Care Med. 2005; 33: (10 suppl): S347 – 353. Chauhan SP, Perry KG. Management of diabetic ketoacidosis in the obstetric patient. Obstet. Gynecol. Clin. North Am. 1995; 22: 143 – 155. Chico M, Levine SN, Lewis DF. Normoglycemic diabetic ketoacidosis in pregnancy. J. Perinatol. 2008; 28: 310 – 312. Guo RX, Yang LZ, Li LX, Zhao XP. Diabetic ketoacidosis in pregnancy tends to occur at lower blood glucose levels: case-control study and a case report of euglycemic diabetic ketoacidosis in pregnancy. J. Obstet. Gynaecol. Res. 2008; 34: 324 – 330. Kitabchi AE, Umpierrez GE, Murphy MB, Barrett EJ, Kreisberg RA, Malone JI, Wall BM. Management of hyperglycemic crisis in patients with diabetes. Diabetes Care. 2001; 24: 131 – 153. Moon SW, Hahm JR, Lee GW, Kang MY, Jung JH, Jung TS, Lee KW, Jung KA, Ahn YJ, Kim S, Kim MA, Kim DR, Chung SI, Park MH. A case of hyperglycemic hyperosmolar state associated with Graves‘ hyperthyroidism: A case report. J. Korean Med. Sci. 2006; 21: 765 – 767. Parker JA, Conway DL. Diabetic ketoacidosis in pregnancy. Obstet. Gynecol. Clin. North Am. 2007; 34: 533 – 543. Tarif N, Al Badr W. Euglycemic diabetic ketoacidosis in pregnancy. Saudi J. Kidney Dis. Transpl. 2007; 18: 590 – 593. Ramin KD. Diabetic ketoacidosis in pregnancy. Obstet. Gynecol. Clin. North Am. 1999; 26: 481 – 488. Schumacher A, Sidor J, Bühling KJ. Glukosemessung mit dem kontinuierlich messenden Glukosesensor CGMS® bei stoffwechselgesunden Schwangeren während Betamethasontherapie zur fetalen Lungenreifeinduktion. Z. Geburtshilfe Neonatol. 2006; 210: 184 – 190.

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Wagner A, Risse A, Brill HL, Wienhausen-Wilke V, Rottmann M, Sondern K, Angelkort B. Therapy of severe diabetic ketoacidosis. Zero-mortality under very-low-dose insulin application. Diabetes Care. 1999; 674 – 677.

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Chapter XXVI

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Myocardial Infarction Obesity and associated features of the metabolic syndrome, especially together with smoking and advanced maternal age can cause a myocardial infarction during pregnancy. This is still a rare event but one to be aware of. Recent incidence estimates for acute myocardial infarction during pregnancy range from 1 in 16,129 deliveries to 1 in 35,700 deliveries (James et al. 2006, Ladner et al. 2005). Ischemic heart disease in pregnancy has been estimated to occur in about 1 in 10,000 deliveries (Hankins et al. 1985). We have at present no data how much obesity increases the risk of acute myocardial infarction during pregnancy but because of the increasing prevalence of obesity and pregnancies late in life thanks in part to assisted reproduction - there is a danger that myocardial infarction during pregnancy could become much more common in the future. Important risk factors - in addition to obesity - include smoking, diabetes, hyperlipidemia, a family history of ischemic heart disease, previous use of oral contraception, hypertension and pre-eclampsia, and collagen vascular disease. Pregnancy and delivery place additional stress on the heart and circulatory system. A review examined coronary artery morphology in 96 patients who had acute myocardial infarction associated with pregnancy (data from 1995-2005) and revealed that atherosclerosis with or without intra-coronary thrombus was found in 41 cases, coronary thrombus without atherosclerotic disease was present in 8, and coronary dissection occurred in 28 women. Coronary dissection is rare in the non-pregnant population but relatively more common during pregnancy. Elevated progesterone levels in pregnancy may play a role in its pathogenesis. Normal coronary arteries were found in 13 cases, and two cases each were ascribed to spasm and embolus (Roth und Elkayam 2008). During the postpartum period, spontaneous coronary artery dissection is often implicated (Ray et al. 2004). Transient coronary artery spasm may explain the cases of myocardial infarction with morphologically normal coronary arteries and perhaps also those cases where there is evidence of thrombus but not of atherosclerosis. A transient coronary spasm could result in acute coronary thrombosis facilitated by the hypercoagulable state of pregnancy (Roth und Elkayam 2008). The consequences of myocardial infarction during pregnancy are commonly severe. Older data indicate that for myocardial infarction within two weeks of labor or delivery,

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mortality may approach 45 % (Hankins et al. 1985). Care has improved in the meantime but a recent review still puts the death rate at 11 % (Roth und Elkayam 2008). Diagnosis of myocardial infarction can be difficult in the context of pregnancy and labor because symptoms of myocardial infarction may be ascribed to pregnancy and labor per se rather than heart disease. Diagnosis relies - as in non-pregnant patients - on ECG abnormalities and changes in cardiac enzyme levels in patients presenting with chest pain. The situation is made even more difficult by the fact that ECG changes that mimic myocardial ischemia occur commonly in women undergoing elective Cesarean section (McLintic et al. 1992). Sweating, dyspnoea, nausea and vomiting are also important symptoms but are more unreliable in the context of pregnancy. Sudden collaps and shock should raise suspicion. Troponin I greater than 0.15 ng/ml is though to be a better indicator of myocardial infarction than creatinine kinase muscle–bone serum concentrations; because the latter increase during normal labor (Ray et al. 2004). Echocardiography, coronary angiography, and - where available - cardiac MRT may also be useful (Zaidi et al 2008). Pulmonary embolus is perhaps the most important differential diagnosis because it is common in pregnancy and can be very similar in its clinical presentation. Furthermore aortic dissection, hemorrhage and, in susceptible populations, sickle crisis should be considered. Therapy is dictated by local guidelines and availability of resources. Treatment would commonly include analgesia, aspirin, clopidogrel and, if indicated, heparin. Coronary angiography with stent placement is the treatment of choice during pregnancy (Pierre-Louis et al. 2008) and, if a catheterization laboratory can be reached quickly, is preferable to thrombolysis. Thrombolysis is also possible during pregnancy, and successful use has been described on an individual case basis. There are and almost certainly will be no large studies of thrombolysis in pregnancy, so that some doubt as to the safety of thrombolysis remains. Therefore the decision has to be made on a case by case basis. If a decision to thrombolyse is made, tissue plasminogen activator (tPA) is preferable (Schuhmacher et al. 1997). Because tPA is a large molecule it should not cross the placenta. Ray and colleagues warn that tPA is contraindicated in the early postpartum period because the risk of hemorrhage outweighs the risk of treatment with angioplasty and stents (Ray et al. 2004). Even bypass surgery has been successfully used in pregnancy (Garry et al. 1996). Further management of the pregnancy will have to depend on individual case characteristics including length of gestation at the time of the cardiac event, size of the infarct, post-infarct cardiac function, state of the fetus, and comorbidities. Under favourable circumstances the pregnancy can be brought to a successful conclusion. Delivery can be vaginal or by Cesarean section. When cardiac function is compromized, as evidenced for instance by recurrent dyspnoea, termination of the pregnancy may be necessary. Complications of myocardial infarction (cardiac failure, valvular dysfunction) can occur during the remainder of pregnancy and following delivery. This possibility needs to be kept in mind and necessitates close surveillance. Interdisciplinary management involving a cardiologist is key.

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Illustrative Case A 30-year-old primiparous woman (weight at the beginning of pregnancy 95 kg, height 167 cm, BMI 34) had experienced an anteroseptal myocardial infarction two years previously. She had at that time undergone angioplasty and stent placement. Furthermore, there was a history of chronic hypertension and smoking. Medications during pregnancy included metoprolol, methyldopa and low dose aspirin. At 38 weeks‘ gestation the aspirin had been stopped and low molecular weight heparin started. At 39 weeks‘ gestation the patient experienced chest tightness. ECG and cardiac enzymes were normal at that time. The patient improved but symptoms recurred after six hours when the CTG became pathological, also. A decision was made to deliver by emergency Cesarean section. A male infant was delivered. The birth weight was 3300 g, umbilical artery pH was 6.96 (low), and the Apgar scores were 1, 6, and 8 after 1, 5, and 10 minutes, respectively. The mother died three hours postpartum. Autopsy revealed acute myocardial infarction: a thrombus had formed at one of her stents. This case illustrates the dramatic consequences of pregnancy-associated myocardial infarction. Aspirin should not have been stopped.

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References Garry D, Leikin E, Fleisher AG, Tejani N. Acute myocardial infarction in pregnancy with subsequent medical and surgical management. Obstet. Gynaecol. 1996; 87: 802-804. Hankins GDV, Wendel GD, Leveno KJ, Stoneham J. Myocardial infarction during pregnancy: a review. Obstet. Gynecol. 1985; 65: 139–46. James AH, Jamison MG, Biswas MS, Brancazio LR, Swamy GK, Myers ER. Acute myocardial infarction in pregnancy: a United States population-based study, Circulation. 2006; 113: 1564–1571. Ladner HE, Danielson B, Gilbert WM. Acute myocardial infarction in pregnancy and the puerperium: a population-based study. Obstet. Gynecol. 2005; 105: 480–484. McLintic AJ, Pringle SD, Lilley S, Houston AB, Thorburn J.Electrocardiographic changes during cesarean section under regional anesthesia. Anesth. Analg. 1992; 74: 51-6. Pierre-Louis B, Singh P, Frishman WH. Acute inferior wall myocardial infarction and percutaneous coronary intervention of the right coronary during active labor: a clinical report and review of the literature. Cardiol. Rev. 2008; 16: 260-268. Ray P, Murphy G, Shurt L. Recognition and management of maternal cardiac disease in pregnancy. Br. J. Anaesth. 2004; 93: 428-439. Roth A, Elkayam U. Acute myocardial infarction associated with pregnancy. J. Am. Coll. Cardiol. 2008; 52: 171-180. Schumacher B, Belfort MA, Card RJ. Successful treatment of acute myocardial infarction during pregnancy with tissue plasminogen activator. Am. J. Obstet. Gynecol. 1997; 176: 716-719. Zaidi AN, Raman SV, Cook SC. Acute myocardial infarction in early pregnancy: definition of myocardium at risk with noncontrast T2-weighted cardiac magnetic resonance. Am. J. Obstet. Gynecol. 2008: e9-e12.

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Chapter XXVII

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Stroke Stroke is another uncommon but serious complication of pregnancy in the obese. For women of child-bearing age, normally the incidence of stroke is low. During pregnancy the incidence of stroke increases somewhat, at least according to most studies.The incidence during pregnancy has been reported to range from 4 to 34 per 100,000 (Bushnell 2008). The rate of stroke was 34 per 100,000 deliveries in an analysis of data from 20002001, higher than previous estimates (James et al. 2005, Bushnell 2008). This increase could have to do with the increasing prevalence of a risk factor for stroke during pregnancy, such as obesity. This increase in stroke risk during pregnancy may be due to the hypercoaguability associated with pregnancy and perhaps because of natural selection to protect against fatal hemorrhage at delivery (Bushnell 2008). Strokes can be ischemic or hemorrhagic. There is good evidence that the risk of ischemic stroke and all stroke in women rises with BMI. Rexrode et al. studied 116,759 women aged 30 to 55 and found a relative risk for ischemic stroke of 1.75 for BMI 27 - 28.9, 1.90 for BMI 29 - 31.9, and 2.37 for BMI > 32, compared with women with a BMI < 21 (Rexrode et al. 1997). In this study, hemorrhagic stroke risk did not increase with BMI. In fact Rexrode et al. found a nonsignificant inverse relation between obesity and hemorrhagic stroke, with the highest risk among women in the leanest BMI category (Rexrode et al. 1997). There is other evidence, however, that suggests that pregnancy may increase the risk of cerebral hemorrhage. A study of 65 public maternities in France (1998-1992) estimated an incidence of nonhemorrhagic strokes of 4.3 per 100,000 deliveries and of intraparenchymal hemorrhage of 4.6 per 100,000 deliveries (Sharshar et al. 1995). This study concluded that (while the incidence of ischemic stroke was not much increased during pregnancy and early puerperium in their study population) the frequency of intracerebral hemorrhage in pregnancy was increased. Based on a database analysis (Nationwide Inpatient Sample) Bateman and colleagues showed that intracerebral hemorrhage accounted for a significant portion of pregnancy-related mortality: there were 6.1 pregnancy-related intracerebral hemorrhages per 100,000 deliveries with an in-hospital mortality of 20.3 % (Bateman et al. 2006). The risk of stroke during pregnancy is increased further if there are additional risk factors other than obesity; these include (according to ESHRE 2006, Gilbert et al 2007, and James et al. 2005):

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• • • • • • • • • • • • • • • • • •

Previous stroke or transient ischemic attack (TIA) Pre-eclampsia and eclampsia (Eclampsia is the main cause of ischemic and hemorrhagic stroke in pregnancy according to Sharshar et al. 1995.) Sepsis Gestational or chronic hypertension Black race Migraines Thrombophilia Thrombocytopenia Sickle-cell disease Systemic lupus erythematosus Diabetes Smoking Dyslipidemia Sepsis Cesarean delivery Choriocarcinoma Valvular heart disease Advanced maternal age Postpartum hemorrhage Postpartum infection

The majority of pregnancy-related strokes – both ischemic and hemorrhagic - occur during the postpartum period. The Baltimore–Washington Cooperative Young Stroke Study examined hospital discharges of patients aged 15 to 44 years with a diagnosis reflecting a possible cerebral infarction or intracerebral hemorrhage in the Baltimore–Washington area between 1988 and 1991. It found that risks of both cerebral infarction and intracerebral hemorrhage were very significantly increased in the six weeks after delivery but not during pregnancy itself. For ischemic stroke, the relative risk was 0.7 (95 % CI 0.3 - 1.6) during pregnancy and 8.7 (95 % CI 4.6 - 16.7) in the postpartum period. For intracerebral hemorrhage, the relative risk was 2.5 (95 % CI 1.0 - 6.4) during pregnancy but 28.3 (95 % CI 13.0 - 61.4) in the postpartum period (Kittner et al. 1996). Clinically, the deficits due to a stroke in pregnancy can be varied, depending on the part of the brain that is affected. Hemiparesis, visual disturbances and speech deficits are the most common symptoms. Imaging (CT) is necessary to differentiate between ischemic and hemorrhagic strokes. Treatment depends on the cause and should ideally be jointly undertaken by obstetricians and stroke physicians. Aspirin (100 mg per day) is indicated for ischemic strokes. Smaller bleeds are often managed conservatively; larger bleeds and cases with cerebral edema need neurosurgical assessment and possibly intervention. Heparin can be used in case of carotid or vertebral artery dissection (Shah and Messé 2007). Thrombolysis should be used with caution in pregnancy; a decision needs to be made on a case by case basis. The use of warfarin for the treatment of ischemic stroke or TIA during pregnancy is controversial. Even though warfarin may be safe during pregnancy after a certain early period

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Stroke

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(6 to 12 weeks), it is not normally recommended because of concerns for fetal health (Sacco et al. 2006). Recent guidelines for the prevention of stroke in patients with stroke or TIA recommend the following for pregnant women (according to Sacco et al. 2006): •

For patients with ischemic stroke or TIA and high-risk thromboembolic conditions (known coagulopathy or mechanical heart valves), the following options may be considered:

a.

adjusted-dose unfractionated heparin throughout pregnancy, for example a subcutaneous dose every 12 hours with activated partial thromboplastin time monitoring b. adjusted-dose LMWH with factor Xa monitoring throughout pregnancy c. unfractionated heparin or LMWH until week 13, then warfarin until the middle of the third trimester, then reinstate unfractionated heparin or LMWH until delivery.

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•

Patients with lower-risk conditions may be considered for treatment with unfractionated heparin or LMWH in the first trimester, then low-dose aspirin for the remainder of the pregnancy.

Depending on local availability platelet function tests can be used to assess platelet inhibition; and if necessary to adjust dose or change therapy. Given the severity of stroke as a condition prevention is of course important. Women with a history of stroke should be treated with aspirin (100 mg per day) during pregnancy and in the postpartum period (Helms et al. 2009). General stroke prevention includes adequate control of blood pressure, blood lipids, diabetes as well as encouraging an active and healthy lifestyle. Pre-conceptional weight reduction should be encouraged. Atrial fibrillation must be excluded. Preventive measures beyond pregnancy and the postpartum period need to be considered in women who have had a stroke and in women with risk factors. Pre-eclampsia, for example, increases the risk for a subsequent stroke after the pregnancy (Bellamy et al. 2007).

References Bateman BT, Schumacher HC, Bushnell CD, Pile-Spellman J, Simpson LL, Sacco RL, Berman MF. Intracerebral hemorrhage in pregnancy: frequency, risk factors, and outcome. Neurology. 2006; 3: 424 – 429. Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ. 2007; 335: 974. Bushnell CD. Stroke in women: risk and prevention throughout the lifespan. Neurol. Clin. 2008; 26: 1161-1176. ESHRE Capri Workshop Group. Hormones and cardiovascular health in women. Hum. Reprod. Update. 2006; 12: 483-97.

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Gilbert WM, Young AL, Danielson B. Pregnancy outcomes in women with chronic hypertension: a population-based study. J. Reprod. Med. 2007; 52: 1046-1051. Helms AK, Drogan O, Kittner SJ. First Trimester Stroke Prophylaxis in Pregnant Women With a History of Stroke. Stroke. 2009; 40: 1158-61. James AH, Bushnell CD, Jamison MG, Myers ER. Incidence and risk factors for stroke in pregnancy and the puerperium. Obstet. Gynecol. 2005; 106: 509-516. Kittner SJ, Stern BJ, Feeser BR, Hebel R, Nagey DA, Buchholz DW, Earley CJ, Johnson CJ, Macko RF, Sloan MA, Wityk RJ, Wozniak MA. Pregnancy and the risk of stroke. N. Engl. J. Med. 1996; 335: 768-774. Rexrode KM, Hennekens CH, Willett WC, Colditz GA, Stampfer MJ, Rich-Edwards JW, Speizer FE, Manson JE. A prospective study of body mass index, weight change, and risk of stroke in women. JAMA. 1997; 277: 1539-45. Sacco RL, Adams R, Albers G, Alberts MJ, Benavente O, Furie K, Goldstein LB, Gorelick P, Halperin J, Harbaugh R, Johnston SC, Katzan I, Kelly-Hayes M, Kenton EJ, Marks M, Schwamm LH, Tomsick T; American Heart Association/American Stroke Association Council on Stroke; Council on Cardiovascular Radiology and Intervention; American Academy of Neurology. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: cosponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Circulation. 2006; 113: e40949. Shah Q, Messé SR. Cervicocranial arterial dissection. Curr. Treat Options Neurol. 2007; 9: 55-62. Sharshar T, Lamy C, Mas JL. Incidence and causes of strokes associated with pregnancy and puerperium. A study in public hospitals of Ile de France. Stroke in Pregnancy Study Group. Stroke. 1995; 26: 930-6.

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Chapter XXVIII

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Compression Neuropathies and Carpal Tunnel Syndrome A number of compressive nerve and root disorders can occur during pregnancy and delivery, including carpal tunnel syndrom (CTS), lumbosacral radiculopathy, meralgia paresthetica, femoral neuropathy, obturator neuropathy, and postpartum foot drop (Sax and Rosenbaum 2006). Of these, CTS – a compression of the median nerve in the carpal tunnel is the most common. Symptoms involve paresthesia and a burning type of pain in the median nerve territory: thumb, index finger, middle finger and the radial aspect of the ring finger. In advanced cases there may be weakness of thumb abduction and waisting of the thenar eminence. Diagnosis is based on history, examination including Phalen‘s test (flexing the wrist and holding it should reproduce symptoms within 60 seconds), Tinel‘s sign (tapping over the median nerve causes paresthesis in the nerve distribution), possibly the tourniquet test (paresthesia and small shocks in the median nerve territory when the tourniquet is inflated above systolic pressure), electrophysiological testing and ultrasound. While carpal tunnel syndrome can occur at any point during pregnancy, it most often does so in the third trimester (Sax and Rosenbaum 2006). An Italian study of 76 women in the 8th and 9th month of pregnancy found that a clinical diagnosis of CTS was made in 62 % or women; neurophysiological testing found that 43% were positive in one hand at least (Padua et al. 2001). Other work estimates the incidence of CTS in the pregnant population to be between 2% and 35% (Sax and Rosenbaum 2006). McCabe and colleagues reported that CTS was associated with increasing age, female sex, increased BMI, diabetes, and pregnancy. They also make a link with sleep disturbances (shared epidemiological risk factors) and sleeping in the lateral position, leading them to hypothesize that sleeping in a lateral position plays a role in the causation of CTS (McCabe et al. 2007). From the above-mentioned risk factors it follows that obese pregnant women are at increased risk of CTS, especially if diabetes and/or advanced maternal age are also present. Local inflammatory, traumatic, or anatomical causes (e.g. thickened transverse carpal ligament, persistent median artery) can lead to CTS. Both osteoarthritis and rheumatoid arthritis can also cause CTS (Aroori and Spence 2008). Systemic causes of CTS other than pregnancy and obesity should be borne in mind. These include (according to Aroori and Spence 2008):

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126 • • • • • • • • • • • •

Diabetes Hypothyroidism Systemic lupus erythematosus Scleroderma Dermatomyositis Renal failure Acromegaly Multiple myeloma Sarcoidosis Leukemia Alcoholism Hemophilia

Furthermore, the risk of CTS is increased by occupational exposure to repetitive work, and vibrating tools (Aroori and Spence 2008). CTS symptoms commonly occur late in pregnancy (third trimester) and are typically worse on one side. With medical management symptoms normally regress after delivery. Such medical management during pregnancy may include systemic steroids, local steroids injection, non-steroidal anti-inflammatory drugs, wrist splints and elevating the wrist at night. If symptoms do not remit after delivery, carpal tunnel decompression surgery can be considered.

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References Aroori S, Spence R AJ. Carpal tunnel syndrome. Ulster Med. J. 2008; 77: 6-17. McCabe SJ, Uebele AL, Pihur V, Rosales RS, Atroshi I. Epidemiologic associations of carpal tunnel syndrome and sleep position: Is there a case for causation? Hand. (N Y). 2007; 2: 127-34. Padua L, Aprile I, Caliandro P, Carboni T, Meloni A, Massi S, Mazza O, Mondelli M, Morini A, Murasecco D, Romano M, Tonali P; Italian Carpal Tunnel Syndrome Study Group. Symptoms and neurophysiological picture of carpal tunnel syndrome in pregnancy. Clin. Neurophysiol. 2001; 112: 1946-51. Sax TW, Rosenbaum RB. Neuromuscular disorders in pregnancy. Muscle Nerve. 2006; 34: 559-71.

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Chapter XXIX

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Obstructive Sleep Apnea Obstructive sleep apnea has been recognized as a considerable problem in the Western world and also in some parts of the developing world where obesity is becoming more prevalent (Sharma et al. 2006). A substantial proportion of the population snore - at least occasionally. Snoring as such is no reason for concern and is not the same as sleep apnea. To qualify as sleep apnea there has to be an interval between breaths of 10 seconds or more. During apneic episodes the upper airway obstructs, oxygen saturation falls, and arousal results. In sleep apnea there is a substantial negative impact on sleep quality at night associated with excessive sleepiness, easy tiring, and poor concentration during the day. The diagnosis is made by a sleep study (polysomnography). Continuous positive airway pressure is quite effective for sleep apnea if it is tolerated. Other options include conservative measures such as oral appliance therapy, or specially shaped pillows. If conservative measures fail, surgery to relieve the intermittent airway obstruction is sometimes used. A suspicion that the pathophysiologic changes of obstructive sleep apnea prolonged over many weeks of pregnancy may have an adverse effect on the feto-placental unit has been there for at least two decades (Schoenfeld et al 1989). Still the details remain to be elucidated. Obesity is among the conditions co-morbid with sleep apnea along with essential hypertension, hypercholesterolemia, type 2 diabetes, smoking, and ischemic heart disease (Huang et al. 2008). It follows that obese pregnant women are at risk of experiencing sleep apnea with potential negative effects on the fetus. The association between obesity in pregnancy and sleep apnea has been confirmed in a small case-control study that compared sleep-related breathing in obese pregnant women with that of pregnant women of normal weight. It found significantly more sleep-related disordered breathing occurring in obese subjects than in those of normal weight (Maasilta et al. 2001). It is intriguing to think that perhaps sleep apnea and some other complications of pregnancy associated with obesity have elements of their pathophysiology is common. This has been investigated but so far convincing evidence from large scale studies is lacking. Obstructive sleep apnoea is associated with gestational hypertension (Champagne et al. 2009). Interestingly, treating sleep apnea with continuous positive airway pressure has been shown to reduce night time blood pressure, although with no consistent effect on day time blood pressure (Dinsdale et al. 2000). Continuous positive airway pressure has also been

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proposed as therapy for pre-eclampsia. A small study on patients with airflow limitations and risk-factors for pre-eclampsia found that while nasal continuous positive airway pressure in pregnant women alleviated sleep-related breathing disturbances it was not sufficient to prevent negative pregnancy outcomes (Guilleminault et al. 2007). More work is needed here.

References

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Champagne K, Schwartzman K, Opatrny L, Barriga P, Morin L, Mallozzi A, Benjamin A, Kimoff RJ. Obstructive sleep apnoea and its association with gestational hypertension. Eur. Respir. J. 2009; 33: 559-65. Dimsdale JE, Loredo JS, Profant J. Effect of continuous positive airway pressure on blood pressure. Hypertension. 2000; 35: 144 – 147. Guilleminault C, Palombini L, Poyares D, Takaoka S, Huynh NT, El-Sayed Y. Pre-eclampsia and nasal CPAP: part 1. Early intervention with nasal CPAP in pregnant women with risk-factors for pre-eclampsia: preliminary findings. Sleep Med. 2007; 9: 9 – 14. Huang QR, Qin Z, Zhang S, Chow CM. Clinical patterns of obstructive sleep apnea and its comorbid conditions: a data mining approach. J. Clin. Sleep Med. 2008; 4: 543-50. Maasilta P, Bachour A, Teramo K, Polo O, Laitinen LA. Sleep-related disordered breathing during pregnancy in obese women. Chest. 2001; 120: 1448-54. Schoenfeld A, Ovadia Y, Neri A, Freedman S. Obstructive sleep apnea (OSA)-implications in maternal-fetal medicine. A hypothesis. Med. Hypotheses. 1989; 30: 51-4. Sharma SK, Kumpaeat S, Banga A, Goel A. Prevalence and risk factors of obstructive sleep apnoea syndrome in a population of Delhi, India. Chest. 2006; 130: 149 – 156.

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Chapter XXX

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Acute Pancreatitis Acute pancreatitis can be difficult to diagnose in pregnancy because pancreatitis may not be on the physician‘s mind when the cause for abdominal pain in pregnant women is sought. Early diagnosis and appropriate treatment are paramount, however, because acute pancreatitis is a severe disease, even more so in pregnancy. Obesity and acute pancreatitis are linked. Gallstones and hypertriglyceridemia are both associated with obesity and are possible causes of acute pancreatitis. Acute pancreatitis is also more severe in the obese (De Waele et al. 2006). The incidence of acute pancreatitis is rising and the rising prevalence of obesity has been implicated in this increase (Lowenfels et al. 2009). Gallstones are one of the common causes of pancreatitis (alcohol being the other). Hypertriglyceridemia is a less frequent cause, but one to be aware of. Patients with hyperlipidemic pancreatitis are often diabetics, and use alcohol (Fortson et al. 1995). The diagnosis of hyperlipidemic pancreatitis can be tricky because pancreatitis can occur with a normal amylase level in hypertriglyceridemia (Sharma et al. 1996, Okerberg et al. 1999). Obesity increases estradiol levels. Pregnancy further increases estrogens. In patients with decreased lipoprotein lipase activity factors such as estrogen, diabetes and alcohol can cause a rise in plasma triglycerides and trigger acute pancreatitis (Bartha et al. 2009, Mahley 1995). Smoking is important as a co-factor in the development of acute pancreatitis (Debenedet et al. 2009, Lowenfels and Maisonneuve 2008). This has to be kept in mind because obesity and smoking often occur together. Obesity and pregnancy are already two risk factors for hypertriglyceridemia; further risk factors for hypertriglyceridemia should also be considered in such patients including the use of beta-blockers and steroids. Infrequent causes of acute pancreatitis during pregnancy need to be thought of in the differential diagnosis. Such causes include choledochal cysts (Beattie et al. 1993, Son et al. 1997) and post-ERCP (endoscopic retrograde cholangiopancreatography) pancreatitis (Tang et al. 2009). Very infreqently there are bizarre causes, e.g. ―Rapunzel syndrome‖: a trichobezoar (hairball) with a long tail - due to swallowed hairs accumulating in the stomach (Salem et al. 2009).

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Diagnosis Plasma lipids should be measured early in pregnancy. The diagnosis of acute pancreatitis relies on raised amylase and/or lipase levels (depending on local availability) in the context of appropriate clinical symptoms: severe upper abdominal pain, with radiation to the back, often also with nausea and vomiting. Imagining (CT, ultrasound) is not normally necessary to make the diagnosis, but can be used as confirmation and may help to elucidate the cause (e.g. gallstones) or inform about severity of the condition (pancreatic necrosis). It is not clear what the threshold in lipid levels is for causing hyperlipidemic pancreatitis, however, a rise in triglycerides above 10 - 20 mmol/l is a considerable risk factor. Reference values for triglycerides differ between laboratories but the numbers given below are a guide (Table 30-1). Table 30-1. Reference values for plasma triglycerides

Triglyceride concentration

Normal 50 – 180 mg/dl (0.57 – 2.07 mmol/l)

Borderline 181 – 200 mg/dl (2.08 – 2.3 mmol/l)

High > 200 mg/dl (> 2.3 mmol/l)

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Therapy Early initiation of treatment is essential. Therapy is largely supportive including adequate management of pain and substituting fluids, electrolytes, protein and calories. Complications of pancreatitis such as shock, and respiratory and renal insufficiency should be actively looked for and treated accordingly. Treatment should include heparin, a glucose and insulin infusion and building up nutrition with a low fat diet and fish oil. This should lower the raised triglycerides, normalize pancreatic enzyme levels, and improve the abdominal pain. Plasma exchange can be considered in the treatment of hypertriglyceridemia when conservative treatment is insufficient (Piolot et al. 1996, Sivakumaran et al. 2009).

Illustrative Case A 31-year-old primiparous women (165 cm, 98 kg, BMI 36) presents at 36 weeks‘ gestation with poorly localized upper and lower abdominal pain. Clinical examination revealed tenderness in the right upper abdominal quadrant and the right renal angle. Proteinuria was noted. The patient was admitted with a suspected right-sided hydronephrosis due to urinary obstruction. Blood taken for testing could not be analyzed because of pronounced lipemia (points to hypertriglyceridemia). The CTG showed sign of hypoxia. The platelet count 12 hours after admission was 149; this goes against a diagnosis of HELLP syndrome.

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Acute Pancreatitis

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The patient gave birth vaginally to a dead infant (stillbirth) and her state remained critical after delivery. The abdomen was exquisitely tender. She developed a fever, along with tachycardia and signs and symptoms of shock. The patient was intubated and transferred to the intensive care unit. The following diagnoses were made: • • •

Necrotizing pancreatitis complicated by septic/toxic multi organ failure; amylase was > 1,000 U/l. Hyperlipidemia Intra-uterine fetal demise at 36 weeks‘ gestation.

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The patient was treated on the intensive care unit for 112 days. There were recurrent episodes of sepsis. Abdominal washouts were performed. A necrotic megacolon developed, necessitating colectomy (with ileostomy formation). Despite further intervention (resection of part of the pancreas, splenectomy, embolization of visceral vessels) the patient eventually died as a result of toxic multi-organ failure. In summary, gallstones are the most common cause of pancreatitis in pregnancy. Triglycerides increase during pregnancy. They do not normally reach levels that trigger acute pancreatitis, but with additional risk factors (familial hypertriglyceridemia, lipoprotein lipase mutations, obesity, alcohol, beta-blockers, and corticosteroids) they can reach dangerous levels. Early diagnosis is essential. The differential diagnosis of HELLP syndrome has to be considered. Some practical hints: • • •

Check triglycerides in obese pregnant women Assess risk factors for pancreatitis (alcohol, gallstones, history of pancreatitis) Have a low threshold for admission in women presenting with abdominal pain in pregnancy.

References Bartha I, Dinva T, Seres I, Paragh G, Ross C, Hayden MR, Biro S, Yaegha G. Acute hypertriglyceridemic pancreatitis during pregnancy due to homozygous lipoprotein lipase gene mutation. Clin. Chim. Acta. 2009; 400: 137 – 138. Beattie GJ, Keay S, Muir BB, Boddy K. Acute pancreatitis with pseudocyst formation complicating pregnancy in a patient with a co-existent choledochal cyst. Br. J. Obstet. Gynaecol. 1993; 100: 957-959. Debenedet AT, Raghunatan TE, Wing JJ, Wamsteker EJ, DiMagno MJ. Alcohol use and cigarette smoking as risk factors for post-endoscopic retrograde cholangiopancreatography pancreatitis. Clin. Gastroenterol. Hepatol. 2009; 7: 353 – 8e4. De Waele B, Vanmierlo B, Van Nieuwenhove Y, Delvaux G. Impact of body overweight and class I, II and III obesity on the outcome of acute biliary pancreatitis. Pancreas. 2006; 32: 343-5.

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Fortson MR, Freedman SN, Webster PD. Clinical assessment of hyperlipidemic pancreatitis. Am. J. Gastroenterol. 1995; 90: 2134 – 2139. Lowenfels AB, Maisonneuve P. Cause(s) of acute pancreatitis: smoke signals from Southern Sweden. Pancreatology. 2008; 8: 61 –62. Lowenfels AB, Maisonneuve P, Sullivan T. The changing character of acute pancreatitis: epidemiology, etiology, and prognosis. Curr. Gastroenterol. Rep. 2009; 11: 97 – 103. Mahley RW. Biochemistry and physiology of lipid and lipoprotein metabolism. In: Becker KL. Principles and Practice of Endocrinology and Metabolism. Philadelphia. JB Lipincott; 1995. p. 1369 – 1378. Okerberg K, Lee M. Spuriously normal amylase levels in a patient with acute pancreatitis secondary to hypertriglyceridemia. J. Am. Board Fam. Pract. 1999; 12: 68 – 70. Pilot A, Nadler E, Cavallero E, Coquard JL, Jacotot B. Prevention of recurrent acute pancreatitis inpatients with severe hypertriglyceridemia: value of regular plasmapheresis. Pancreas. 1996; 13: 96 – 99. Salem M, Fouda R, Fouda U, Maadawy ME, Ammar H: Rapunzel and pregnancy. South Med. J. 2009; 102: 106 – 107. Sharma P, Lim S, James D, Orchard RT, Horne M, Seymour CA. Pancreatitis may occur with a normal amylase concentration in hypertriglyceridemia. BMJ. 1996; 313: 1265. Sivakumaran P, Tabak SW, Gregory K, Pepkowitz SH, Klapper EB. Management of familial hypertriglyceridemia during pregnancy with plasma exchange. J. Clin. Apher. 2009; 24: 42 – 46. Son HJ, Paik SW, Rhee PL, Kim JJ, Koh KC, Rhee JC. Acute pancreatitis complicating pregnancy in a patient with co-existing choledochal cyst. Korean J. Intern. Med. 1997; 12: 105-108. Tang SJ, Mayo MJ, Rodriguez-Frias E, Armstrong L, Tang L, Sreenarasimhaiah J, Lara LF, Rockey DC. Safety and utility of ERCP during pregnancy. Gastrointest. Endosc. 2009; 69: 433 – 461.

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Chapter XXXI

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Restless Legs Syndrome Restless legs syndrome is quite common, with a general prevalence of about 5 %. Restless legs syndrome can be idiopathic but known associations include polyneuropathy, rheumatoid arthritis, and pregnancy. A prevalence of 23 % in the third trimester has been reported, though on a small sample (Lee et al. 2001). Restless legs syndrome is also associated with obesity. An analysis of two US cohorts, the Nurses' Health Study II and the Health Professional Follow-up Study found that both with increased BMI and increased waist circumference restless legs syndrome was more common (Gao et al. 2009). The underlying pathophysiology remains to be worked out. A small study found elevated estradiol plasma levels in women with restless legs syndrome during pregnancy (Dzaja et al. 2009). This may also explain the association with obesity, as adipose tissue produces estrogens. Clinically, restless legs syndrome is characterized by uncomfortable sensations (numbness, paresthesia, and pain) in the legs. Characteristically, these uncomfortable sensations are brought on by rest. Restless legs syndrome is therefore associated with disordered sleep. The diagnosis is made clinically. Associated disorders (e.g. diabetic polyneuropathy) need to be excluded. Regarding management, patient reassurance is essential. Pregnancy associated restless legs syndrome will not normally persist after delivery. In severe cases treatment with folic acid (at most 5 mg per day) can be tried. Treatment with L-DOPA and benserazide is contraindicated during pregnancy.

References Dzaja A, Wehrle R, Lancel M, Pollmächer T. Elevated estradiol plasma levels in women with restless legs during pregnancy. Sleep. 2009; 32: 169-174. Gao X, Schwarzschild MA, Wang H, Ascherio A. Obesity and restless legs syndrome in men and women. Neurology. 2009; 72: 1255-1261. Lee KA, Zaffke ME, Baratte-Beebe K. Restless legs syndrome and sleep disturbance during pregnancy: the role of folate and iron. J. Womens Health Gend. Based Med. 2001; 10: 335-341.

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Section 4: Delivery

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ISBN: 978-1-60876-111-1 © 2010 Nova Science Publishers, Inc.

Chapter XXXII

Delivery and the Postpartum Period in Obese Women

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Obesity has an important impact not only throughout the course of pregnancy but also on delivery. For example, in a recent meta-analysis a link between obesity and increased odds of Cesarean and instrumental deliveries was confirmed (Heslehurst et al. 2008). The following recommendations are based on our experience and guidelines issued by various professional societies. Maternal indications for terminating pregnancy by inducing delivery include • • • • • • • • •

Severe pre-eclampsia/eclampsia Severe therapy-resistant hypertension Therapy-resistant renal insufficiency Disseminated intravascular coagulation Dyspnea, acute pulmonary edema Progressive cholestasis (transaminases increased more than 10-fold) Persistant upper abdominal pain Severe edema (> 1 kg weight gain weekly) New central nervous system symptoms

When an obese pregnant women presents for planning of delivery at 35 weeks‘ gestation the following ought to be included in the risk assessment: • • • • • • •

Blood lipids (cholesterol and triglycerides) Blood glucose Blood pressure Smoking status History of thromboembolism Family history (cardiovascular disease) Maternal age

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Hypertension, pre-eclampsia and threatened eclampsia are common indications for inducing delivery, and thus causing iatrogenic preterm birth. In addition to delivery, acute antihypertensive therapy is necessary as well. Options for acute antihypertensive therapy are: Urapidil Dihydralazine Hydralazine Labetalol

Nifedipine

6.25 – 12.5 mg i.v. initially as a bolus over 2 min, thereafter 3-24 mg/h (infusion) 5 mg i.v. every 20 min or 5 mg i.v. as a bolus and thereafter 2-20 mg (infusion) 5 mg to 10 mg doses i.v. until the desired response is achieved (Schroeder 2002) 20 mg i.v. bolus, followed by 40 mg after 10 minutes if the first bolus was not effective; then 80 mg every 10 minutes (maximum total dose: 220 mg) (Schroeder 2002) 5 mg oral initially, if necessary repeat after 20 min

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In a recent study urapidil was as effective as dihydralazine in lowering blood pressure in patients with pre-eclampsia, but showed a better controllability and tolerability (Wacker et al. 2006). Both maternal and fetal health need to be taken into account when a decision to induce labor is made. Obesity–associated complications of pregnancy such as pre-eclampsia often affect maternal health to a significant degree. Especially severe pre-eclampsia before 24 weeks‘ gestation is associated with increased maternal morbidity and mortality. Risk factors other than obesity will also affect maternal physiology and ought to be considered in an overall risk assessment. Importantly this includes maternal age. For instance, with increasing maternal age the proportion of women with abnormal lung function is increased.

Shoulder Dystocia Shoulder dystocia occurs when after the delivery of the head, the anterior shoulder of the infant cannot pass below the maternal pubic symphysis. Shoulder dystocia has a prevalence of about 0.2 % - 3 % but is very difficult to predict. The following risk factors are associated with shoulder dystocia (according to Gottlieb and Galan 2007): • • • • • • • • •

Obesity Fetal macrosomia Diabetes Operative vaginal delivery History of macrosomic infant or shoulder dystocia Labor abnormalities Post-term pregnancy Advanced maternal age Fetal anthropometric variations

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Delivery and the Postpartum Period in Obese Women •

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Male fetal gender

The risk is especially high for obesity, diabetes, fetal macrosomia and operative vaginal delivery. Neonatal injury is frequent (brachial plexus injuries, Anderson et al. 2006) and can result in permanent disability. Further complications include fetal asphyxia and skeletal injuries (clavicular fracture). There are significant medico-legal implications. Clinically shoulder dystocia is recognized when after delivery of the head the rest of the baby is not delivered despite moderate traction and maternal pushing. There can be a "turtle sign". (sudden retraction of the fetal head back against the perineum, like a turtle withdrawing into its shell). There is no generally agreed standardized management for shoulder dystocia; the following may be considered: • • • • • • •

Episiotomy (or extending an episiotomy) Acute tocolysis with betamimetics McRoberts maneuver (hyperflexion of the maternal thighs against the abdomen) ‗Relaxation‘ (spasmolytics, betamimetics, intubation) Rotation of the fetal shoulders so that the fetal back passes below the pubic symphysis (rather than the fetal abdomen) Woods‘ corkscrew maneuver (progressively rotating the posterior shoulder (‗like a corkscrew‘) by 180 degrees to release the impacted anterior shoulder). Delivering the posterior shoulder by sweeping the posterior arm of the fetus across the chest, then delivering the arm

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Prevention of shoulder dystocia includes: • • •

Early consideration of secondary Cesarean section in case of a prolonged secondstage of labor Avoiding operative delivery from mid-pelvic level Not starting ‗pushing‘ too early.

We recommend primary Cesarean section if birth weight is estimated (by ultrasound) > 4500 g, or in case of maternal diabetes already for an estimated birth weight > 4000 g. Operative vaginal delivery from mid-pelvic level should be avoided, operative vaginal delivery should be performed only when the fetal head is at the level of the pelvic floor or below.

Delivery after Previous Cesarean Section A previous Cesarean section should always be considered a risk factor in a subsequent delivery. Ultrasound examination in the second and third trimester allows a localization of the placenta relative to the scar and an estimate of the depth of insertion (placenta increta and percreta). Ultrasound estimates of fetal weight, however, are often rather inaccurate. A

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thorough obstetric history – from patient and previous notes - is needed to decide on the appropriate mode of delivery. This should include assessing the indication(s) for the previous Cesarean section, previous complications (e.g. uterine rupture), location of the previous incision (see below). The mode of delivery should be discussed with the patient well ahead of time. In practice an ‗agreement‘ can often be reached with the patient that vaginal delivery is ‗tried‘ first, but that when complications occur Cesarean section is commenced without much delay. For an attempted vaginal delivery inducing labor and epidural anesthesia (risk of silent uterine rupture) are relatively contraindicated. A silent uterine rupture can lead to fetal demise without much pain and may be difficult to diagnose in the obese. An increasing frequency of uterine contractions and, finally, the absence of uterine contractions can be a sign of a beginning uterine rupture. Immediate Cesarean section is needed. Positive predictive factors for a vaginal delivery after previous Cesarean section are: • • • •

A vaginal birth subsequent to the previous Cesarean section Indication for previous Cesarean section was not cephalopelvic disproportion Spontaneous onset of labour Estimated fetal weight < 4000 g

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Indicators of risk are: • • • • • • •

Obesity (with a maternal height < 160 cm) Diabetes Twin pregnancy Post-term birth Induced labor Estimated fetal weight > 4250 g Previous Cesarean section less than 12 months ago

Following a Cesarean section the risk of complications of vaginal delivery is greatly influenced by the interval between pregnancies. A short inter-pregnancy interval increases the risk of uterine rupture. A recent study showed that an interval of less than six months was associated with a more than two-fold increase in risk of uterine rupture and also the likelihood that blood transfusions are needed was increased (Stamilio et al.2007). Absolute contraindications ruling out a vaginal delivery are: • • •

Previous Cesarean section with classical (vertical) incision Previous uterine operations involving opening of the uterine cavity Problems of placental insertion: suspected placenta increta and placenta percreta

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Delivery Following Gastric Bypass Surgery Obstetric and neonatal outcome in pregnant women after gastric bypass surgery does not seem to differ much from that of other women (Wax et al. 2008). General surgical input may be needed for a Cesarean section.

Delivery of the Placenta Obesity is associated with an increased rate of bleeding occurring with delivery of the placenta and also with an increased rate of uterine atony. Timely and carefully dosed application of agents that enhance uterine contraction is important to avoid bleeding and associated complications (coagulopathy). Blood loss of up to 500 ml during delivery can be considered normal. Delivery of the placenta is delayed if it does not occur within 30 minutes after delivery of the neonate. The following complications need to be watched out for: 1. Incarcerated placenta – retention of the placenta after it has separated from the uterus because of a stricture-like contraction of the lower uterine segment Management: Empty urinary bladder, spasmolytics, uterotonic agents

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2. Adherent placenta – prolonged separation of the placenta, occurs more frequently with placental insertion near the tubal opening and following prolonged labor. Management: Atropine and uterotonic agents 3. Placenta accreta, increta, and percreta – the placenta has gown to involve the uterine muscle or even grown beyond it. Management: Uterine extirpation 4. Increased bleeding associated with separation of the placenta. This is caused by failure to contract. Management: Empty urinary bladder, uterotonic agents, manual separation of the placenta Atonic bleeding is more common in the obese and can be caused by failure to contract, prolonged labor, over-stretching of the myometrium (large fetus), or too much abdominal pressure. There is an appreciable risk of consumption coagulopathy and bleeding therefore needs to be controlled quickly. Of note, the bleeding may be small but prolonged and can still reach a significant amount. Furthermore it needs to be kept in mind that an atonic uterus can contain 1-2 liters of blood so that the visible bleeding may only be a small proportion of the total blood loss. Management: Exclude cervical tears, infusion of uterotonic agents. Carefully empty the uterus from the fundus (may be difficult to feel in an obese women) and externally compress

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against the pubic symphysis. Empty the urinary bladder (catheter), and prepare blood products for transfusion (cross match). An atonic uterus in the puerperium is commonly caused by retention of part of the placenta. Management: Empty the uterus with antibiotic cover, give uterotonic agents, transfuse if necessary.

The Postpartum Period A number of complications in the postpartum period are more common in obesity and need to be watched out for. Obesity increases the risk of thromboembolism during the postpartum period as well as during pregnancy (Martinelli 2006, Larsen et al. 2007). Furthermore, endomyometritis, disordered wound healing and wound infection, urinary tract infections, and postpartum bleeding are more common with obesity. (Doherty et al. 2006, Hall and Neubert 2005, Usha Kiran et al. 2005, Myles et al. 2002, Bhattacharya et al. 2007). Andersson et al. (2006) showed that obesity was furthermore significantly associated with new-onset postpartum psychiatric disorders.

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Lactation Obese women have a lower prolactin response to suckling. Moreover, obese women are at risk of prolonged labor, excessive labor stress, and Cesarean section; all of these factors delay lactogenesis II (copious milk production) (Jevitt et al. 2007). A recent systematic review investigated breastfeeding and its relation to obesity (Amir and Donath 2007). The review concluded that obese women are less likely to initiate breastfeeding. Of four studies examining onset of lactation that were included in the review, three reported a significantly delayed lactogenesis in obesity. Furthermore, most large studies in the above-mentioned review found that obese women breastfed for a shorter duration than normal weight women, even after adjusting for possible confounding factors.

Illustrative Cases Case 1 – Secondary Cesarean Section A 32-year-old morbidly obese (weight 135 kg, height 164 cm, BMI 50) primiparous woman was admitted to the delivery suite after 41 weeks‘ and 4 days‘ gestation. Additional risk factors during her pregnancy included chronic hypertension (blood pressure 150/100 mmHg at 10 weeks‘ gestation; treated with methyldopa), proteinuria, and mild generalized edema in the third trimester. During the course of the pregnancy the patient had been admitted because of possible pre-eclampsia, but after admission blood pressure was wellcontrolled and so this diagnosis could not be made. An attempt at vaginal delivery was made but during delivery the CTG showed severe variable decelerations and other adverse features.

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A decision was made to deliver by Cesarean section. Birth weight was 3,170 g (appropriate for gestational age); Apgar scores were satisfactory.

Case 2 – Primary Cesarean Section Because of Breech Presentation A 20-year-old primiparous woman (weight 83 kg, height 165 cm, BMI 30.5) presented at the delivery suite after 37 weeks‘ gestation because of onset of labor. There was a suspicion of intrauterine growth restriction. A breech presentation was diagnosed. A primary Cesarean section was performed under spinal anesthesia at 37 weeks. Birth weight was 2720 g (appropriate for gestational age). Apgar scores were satisfactory.

Case 3 – Shoulder Dystocia

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A 21-year–old primiparous woman (weight 99 kg, height 168 cm, BMI 35) with type I diabetes (HbA1c 7.5 %), had a prolonged second phase of labor after induction of labor at 40 weeks‘ gestation. Both vacuum extraction and forceps delivery were attempted and failed. A diagnosis of shoulder dystocia was made. Tocolysis was performed with a beta-mimetic. McRoberts maneuver and attempted rotation of the shoulders were unsuccessful. A decision was made to administer a general anesthetic. Under general anesthesia delivery of the posterior shoulder was eventually successful, the child was rotated and the anterior shoulder delivered also. Birth weight was 4650 g (large for gestational age). The 1-minute Apgar score was 1, umbilical artery pH was poor (6.99). The neonate needed to be intubated and developed a brachial plexus paresis. In retrospect, a secondary Cesarean section might have been better.

Case 4 - Spontaneous Delivery after Previous Cesarean Section; Vaginal Tear A 36-year-old patient (weight 110 kg, height 170 cm, BMI 38) with multiple sclerosis (on immunoglobulin treatment) presents with her second pregnancy. Her first child was delivered by Cesarean section. The second pregnancy ended after 41weeks‘ and 2 days‘ gestation with a spontaneous vaginal birth. A high vaginal tear developed. Birth weight was 3,700 g. Apgar scores were satisfactory.

Case 5 – Perineal and Labial Tears A 39-year-old woman (weight 113 kg, height 180 cm, BMI 35) giving birth to her fourth child was admitted after rupture of membranes had occurred. Labor started spontaneously within 24 hours after rupture of membranes. The patient gave birth to a male infant (birth weight 4230g; Apgar scores satisfactory) at 41 weeks‘ and 2 days‘ gestation. The child had

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been in the occiput posterior position. The women sustained a perineal tear (first degree) and a labial tear.

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References Amir LH, Donath S. A systematic review of maternal obesity and breastfeeding intention, initiation and duration. BMC Pregnancy Childbirth. 2007; 7: 9. Andersen J, Watt J, Olson J, Van Aerde J. Perinatal brachial plexus palsy. Paediatr. Child Health. 2006; 11: 93-100. Andersson L, Sundström-Poromaa I, Wulff M, Aström M, Bixo M. Depression and anxiety during pregnancy and six months postpartum: a follow-up study. Acta Obstet. Gynecol. Scand. 2006;85:937-944. Bhattacharya S, Campbell DM, Liston WA, Bhattacharya S. Effect of body mass index on pregnancy outcomes in nulliparous women delivering singleton babies. BMC Public Health. 2007;7:168 Doherty DA, Magann EF, Francis J, Morrison JC, Newnham JP. Pre-pregnancy body mass index and pregnancy outcomes. Int. J. Gynaecol. Obstet. 2006; 95: 242-247. Gottlieb AG, Galan HL. Shoulder dystocia: an update. Obstet. Gynecol. Clin. North Am. 2007; 34: 501-531. Hall LF, Neubert AG. Obesity and pregnancy. Obstet. Gynecol. Surv. 2005; 60: 253-360. Heslehurst N, Simpson H, Ells LJ, Rankin J, Wilkinson J, Lang R, Brown TJ, Summerbell CD. The impact of maternal BMI status on pregnancy outcomes with immediate shortterm obstetric resource implications: a meta-analysis. Obes. Rev. 2008; 9: 635-683. Jevitt C, Hernandez I, Groër M. Lactation complicated by overweight and obesity: supporting the mother and newborn. J. Midwifery Womens Health. 2007; 52: 606-613. Larsen TB, Sørensen HT, Gislum M, Johnsen SP. Maternal smoking, obesity, and risk of venous thromboembolism during pregnancy and the puerperium: a population-based nested case-control study. Thromb. Res. 2007; 120: 505-509. Martinelli I. Thromboembolism in women. Semin. Thromb. Hemost. 2006; 32: 709-715. Myles TD, Gooch J, Santolaya J. Obesity as an independent risk factor for infectious morbidity in patients who undergo cesarean delivery. Obstet. Gynecol. 2002; 100: 959964. Schroeder BM; American College of Obstetricians and Gynecologists. ACOG practice bulletin on diagnosing and managing preeclampsia and eclampsia. American College of Obstetricians and Gynecologists. Am. Fam. Physician. 2002; 66: 330-1. Stamilio DM, DeFranco E, Paré E, Odibo AO, Peipert JF, Allsworth JE, Stevens E, Macones GA. Short interpregnancy interval: risk of uterine rupture and complications of vaginal birth after cesarean delivery. Obstet. Gynecol. 2007; 110: 1075-1082. Usha Kiran TS, Hemmadi S, Bethel J, Evans J. Outcome of pregnancy in a woman with an increased body mass index. BJOG. 2005; 112: 768-772. Wacker JR, Wagner BK, Briese V, Schauf B, Heilmann L, Bartz C, Hopp H. Antihypertensive therapy in patients with pre-eclampsia: A prospective randomised

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multicentre study comparing dihydralazine with urapidil. Eur. J. Obstet. Gynecol. Reprod. Biol. 2006; 127: 160-5. Wax JR, Cartin A, Wolff R, Lepich S, Pinette MG, Blackstone J. Pregnancy following gastric bypass surgery for morbid obesity: maternal and neonatal outcomes. Obes. Surg. 2008; 18: 540-544.

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Chapter XXXIII

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Prevention of Postpartum Hemorrhage Prophylactic oxytocin can shorten the third stage of labor. ‗Active management‘ of the third stage includes giving an oxytocic, commonly intravenous injection of 1-3 IU oxytocin, after delivery of the anterior shoulder. Then the umbilical cord is clamped quickly and a ―controlled pull‖ is applied to the cord while at the same time holding back the uterine fundus. Oxcytocin is sometimes given together with ergometrine, an ergot alkaloid. Side effects to watch out for (especially when ergometrine is given) are headaches, nausea and vomiting, and raised blood pressure. Although there is an ongoing debate about expectant versus active management of the third stage of labor, we recommend that especially for high risk births active management is undertaken. However we also feel that morbid obesity should be seen as a contra-indication to oxytocin (see below). Postpartum hemorrhage is significantly reduced by ‗active management‘ (Prendivielle et al. 2000). The challenge is to use optimal (low) doses of oxytocin to minimise adverse effects. While uterotonic agents are undoubtedly of great help in controlling postpartum hemorrhage, care is needed in women with labile blood pressure and a history of cardiovascular disease. Oxytocin can cause hypotension and tachycardia and may also cause myocardial ischemia (Svanström et al. 2008). In the wrong circumstances (hemorrhage, cardiac disease, beta-blockade) this may lead to cardiovascular decompensation. Spinal anesthesia (for a Cesarean section) can be an additional factor causing hypotension and complicating the situation. There have been deaths reported with rapid bolus injection of oxytocin, though recently practice has changed in light of this (Bolton et al. 2003). Contraindications against giving oxytocin postpartum include: • • • •

Pre-eclampsia Maternal cardiac disease Hight strain on the cardiovascular system (e.g. morbid obesity) Pulmonary hypertension

Oxytocin dosage is to some extent empirical, and there are some differences between guidelines. To accelerate delivery of the placenta, 3 IU can be given intravenously. During Briese, Volker, et al. Obesity and Pregnancy, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

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Cesarean section 5 IU of (intramuscular or slow intravenous) oxytocin can be used as prophylaxis, after delivery of the child. 5-10 IU (intramuscular or intravenous) have been recommended in case of atonic bleeding following delivery. We have used an oxytocin bolus of 3-5 IU followed by infusion of 5-10 IU per hour for atonic bleeding with good effect. Blood pressure should be monitored continuously when oxytocin is given. Sartain et al. (2008) compared the effects of two doses of oxytocin in patients undergoing elective Cesarean section. An i.v. bolus of either 2 or 5 IU was given after delivery, followed by an oxytocin infusion of 10 IU per hour. There were no differences with regard to blood loss, uterine tone, or requests for additional uterotonic drugs between the two regimens. However, a 2 IU bolus resulted in less hemodynamic change than 5 IU and also caused less nausea. The bolus dose of oxytocin used at elective Cesarean deliveries in nonlaboring women can be even lower, e.g. 1 IU or less followed by an infusion of 40 mU/min (Carvalho et al. 2004). However, patients requiring Cesarean section for labor arrest after oxytocin augmentation require more, 3 IU by rapid intravenous infusion, to achieve effective uterine contraction following delivery (Balkin et al. 2006). Carbetocin is an oxytocin analogue. A recent study compared the effect of a single dose of carbetocin (100 microgram intravenously) with that of a two-hour 10 IU intravenous infusion of oxytocin for prevention of postpartum hemorrhage after Cesarean section (Borruto et al. 2009). A single i.v. injection of carbatocin was as good in controlling intraoperative blood loss after placental delivery as a continuous two-hour infusion of oxytocin. Tolerance was also found to be comparable. Comparing a single dose of 100 microgram intramuscular carbetocin to a single dose of intramuscular syntometrine (0.5 mg ergometrine and 5 IU oxytocin) for the prevention of post-partum hemorrhage following vaginal delivery a recent study found lower blood loss in the carbetocin group (Nirmala et al. 2009).

References Balki M, Ronayne M, Davies S, Fallah S, Kingdom J, Windrim R, Carvalho JC. Minimum oxytocin dose requirement after cesarean delivery for labor arrest. Obstet. Gynecol. 2006; 107: 45-50. Bolton TJ, Randall K, Yentis SM. Effect of the Confidential Enquiries into Maternal Death on the use of Syntocinon of caesarean section in the UK. Anaesthesia. 2003; 58: 277 – 279. Borruto F, Treisser A, Comparetto C. Utilization of carbetocin for prevention of postpartum hemorrhage after cesarean section: a randomized clinical trial. Arch. Gynecol. Obstet. 2009; 280: 707-12. Carvalho JC, Balki M, Kingdom J, Windrim R. Oxytocin requirements at elective cesarean delivery: a dose-finding study. Obstet. Gynecol. 2004; 104: 1005 - 1010. Nirmala K, Zainuddin AA, Ghani NA, Zulkifli S, Jamil MA. Carbetocin versus syntometrine in prevention of post-partum hemorrhage following vaginal delivery. J. Obstet. Gynaecol. Res. 2009; 35: 48-54.

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Prendivielle WJ, Elbourne D, McDonald S. Active versus expectant management in the third stage of labor. Cochrane Database Syst. Rev. 2000; (3): CD000007. Sartain JB, Barry JJ, Howat PW, McCormack DI, Bryant M. Intravenous oxytocin bolus of 2 units is superior to 5 units during elective Caesarean section. Br. J. Anaesth. 2008; 101: 822-826. Svanström MC, Biber B, Hanes M, Johansson G, Näslund U, Bålfors EM. Signs of myocardial ischaemia after injection of oxytocin: a randomized double-blind comparison of oxytocin and methylergometrine during Caesarean section. Br. J. Anaesth. 2008; 100: 683-9.

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Chapter XXXIV

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Anesthetic Management Issues in Morbidly Obese Women The risks associated with morbid obesity - gestational diabetes, hypertension and preeclampsia, postpartum hemorrhage, infection, thromboembolism, and perioperative pulmonary complications - make morbidly obese patients challenging form an anesthetic perspective (Dixit and Girling 2008, Reber 2005). Because obese patients are a high risk group during delivery necessitating increased medical care, staff has to be trained to recognize and manage complications (Ray et al. 2008). Obese women need an anesthetic consultation before delivery, not least because of an increased risk of emergency Cesarean section. The risk of difficult or failed intubation is increased in morbid obesity. It is sensible to place an epidural or intrathecal catheter – for pain management or regional anesthesia – at an early stage and to confirm its position after transporting the patient because of the risk of migration of the catheter. By having an epidural catheter in place conversion of an attempted vaginal delivery to a Cesarean section is more readily possible. The extent of the block should be checked carefully (Soens et al. 2008, Vallejo 2007). Some obese patients need especially long epidural needles. Nitta et al. (2006) reported successfully managing a Cesarean section in a patient with a BMI of 50.2 by using a custom-made, 120 mm long epidural needle. The depth from the skin to the epidural space was 95 mm. Whitty et al. (2007) reported the case of a morbidly obese patient who presented for elective Cesarean section. Locating the epidural space is technically challenging in such patients and in this case it was located using ultrasound at a distance of over 11 cm from the skin. Cooper et al. (2008) investigated maternal mortality caused by anesthetic complications in the UK between 2003 and 2005. During this period of time six women had died from problems directly related to anaesthesia and obesity was a factor in four of these deaths. Two deaths occurred in women in early pregnancy who received general anaesthesia due to failure to manage the airway and ventilation by inexperienced anaesthetists. Using regional techniques could help to lower the anesthesia–associated maternal mortality in obesity (Saravanakumar et al. 2006). There seems to be considerable inter-patient variability in the sensitivity to spinal anesthesia. Reyes et al. (2004) reported a successful Cesarean section in a morbidly obese

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(BMI 66) pre-eclamptic women who required only a very low total dose of 5 mg hyperbaric spinal bupivacaine without spinal or intravenous supplements. The anesthetic challenge is even greater when morbidly obese parturients have other comorbid conditions. Shnaider et al. (2001) reported the successful use of combined spinalepidural anesthesia for Cesarean section in a morbidly obese patient with a potentially difficult airway and peripartum dilated cardiomyopathy with an ejection fraction of 20 %. Combined spinal epidural anesthesia is now a well-established alternative to epidural analgesia for labor pain and combined spinal epidural anesthesia needle sets specifically designed for morbidly obese patients are available (Kuczkowski et al. 2005). Severe complications of combined spinal epidural labor analgesia in morbidly obese patients such as serious maternal bradycardia and asystole are rare but mandate vigilance, frequent monitoring and, if necessary, resuscitation with ephedrine, atropine, and epinephrine (Pan et al. 2004). Sometimes co-morbid conditions require somewhat unusual measures. Nakanishi et al. (2008) reported the case of a 21-year-old morbidly obese (BMI 45.5) parturient with a history of borderline personality disorder who underwent an emergency Cesarean section for obstructed labor under combined spinal and epidural anesthesia. Because her mental state was unstable it was decided that her psychiatrist was present during anesthesia and surgery to ease her anxiety and mental distress. Analgesia was sufficient throughout surgery and complications did not occur. In some morbidly obese patients, intentional puncture of the dura can be used to confirm the location of the epidural space, as reported by Mychaskiw et al. (2001) for a patient with a BMI of 90. A 27-ga. spinal needle was passed through an epidural needle into the subarachnoid space to confirm placement of the epidural needle. In the postoperative management of obese parturients early mobilization, thromboprophylaxis, chest physiotherapy, and adequate pain control are essential (Saravanakumar et al. 2006). Cooper and McClure (2008) nicely summarized some points of note about anesthesia and obesity, these include: •

• • •

Obstetric units should develop protocols and acquire equipment (e.g. large sphygmomanometer cuffs, hoists, long regional block needles) for the management of morbidly obese women. Morbidly obese women need an anaesthetic assessment before delivery. Because sphygmomanometry can be inadequate, direct arterial pressure measurement may be useful in the morbidly obese patients. Morbidly obese women in childbirth should be given prophylactic low molecular weight heparin. Thromboembolic deterrent stockings (large size) should be available.

References Cooper GM, McClure JH. Anaesthesia chapter from saving mothers‘ lives; reviewing maternal deaths to make pregnancy safer. Br. J. Anaesth. 2008; 100: 17-22. Dixit A, Girling JC. Obesity and pregnancy. J. Obstet. Gynaecol. 2008; 28:14-23.

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Kuczkowski KM. Labor analgesia for the morbidly obese parturient: an old problem—new solution. Arch. Gynecol. Obstet. 2005; 271: 302-303. Mychaskiw G 2nd, Panigrahi T, Ray T, Shah S. Intentional puncture of the dural space as an aid to epidural placement in a morbidly obese parturient. J. Miss. State Med. Assoc. 2001; 42: 303-305. Nakanishi R, Nishimura S, Kimura M, Miyazaki Y, Hamada T, Mori T. Cesarean section in a morbidly obese parturient with borderline personality disorder under combined spinal and epidural anesthesia. Masui. 2008; 57: 628-630. Nitta R, Yabe M, Sato M, Kimura T, Nishikawa T. Successful epidural anesthesia using 120 mm epidural needle for cesarean section in a morbidly obese parturient with body mass index 50.2 kg x m(-2). Masui. 2006; 55: 1409-1411. Pan PH, Moore CH, Ross VH. Severe maternal bradycardia and asystole after combined spinal-epidural labor analgesia in a morbidly obese parturient. J. Clin. Anesth. 2004; 16: 461-464. Ray A, Hildreth A, Esen UI. Morbid obesity and intra-partum care. J. Obstet. Gynaecol. 2008; 28: 301-304. Reber A: [Airways and respiratory function in obese patients. Anaesthetic and intensive care aspects and recommendations]. Anaesthesist. 2005; 54: 715-725. Reyes M, Pan PH. Very low-dose spinal anesthesia for cesarean section in a morbidly obese preeclamptic patient and its potential implications. Int. J. Obstet. Anesth. 2004; 13: 99102. Saravanakumar K, Rao SG, Cooper GM. Obesity and obstetric anaesthesia. Anaesthesia. 2006; 61: 36-48. Shnaider R, Ezri T, Szmuk P, Larson S, Warters RD, Katz J. Combined spinal-epidural anesthesia for Cesarean section in a patient with peripartum dilated cardiomyopathy. Can. J. Anaesth. 2001; 48: 681-683. Soens MA, Birnbach DJ, Ranasinghe JS, van Zundert A. Obstetric anesthesia for the obese and morbidly obese patient: an ounce of prevention is worth more than a pound of treatment. Acta Anaesthesiol. Scand. 2008; 52: 6-19. Vallejo MC. Anesthetic management of the morbidly obese parturient. Curr. Opin. Anaesthesiol. 2007; 20: 175-180. Whitty RJ, Maxwell CV, Carvalho JC. Complications of neuraxial anesthesia in an extreme morbidly obese patient for Cesarean section. Int. J. Obstet. Anesth. 2007; 16: 139-44.

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Section 5: Summaries and Appendix

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Chapter XXXV

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Summary and Outlook (for Health Care Professionals) Obesity and overnutrition are now one of the most important health problems worldwide (Karam et al. 2007). The proportion of overweight and obese women of child-bearing age is steadily increasing. No end to this trend is in sight, even though there is plenty of evidence of the direct and indirect association of obesity and adverse pregnancy outcomes (Dixit and Girling 2008). Amongst the most important complications of pregnancy associated with obesity are gestational diabetes, hypertensive disorders of pregnancy, maternal thromboembolism, preterm birth, and an increased rate of malformations. Delivery in the obese is more commonly associated with complications such as shoulder dystocia, prolonged labor, tears, and with a higher rate of Cesarean delivery. Smoking during pregnancy is correlated with obesity and compounds the obesity-associated complications. Smoking reduces birth weight, in normal weight and obese women. This means that - compared to non-smoking obese women - smoking obese women have lower rates of fetal macrosomia, a smoking-mediated ‗paradox‘. Morbidly obese patients put an additional strain on personnel and equipment of the hospital and necessitate more careful planning of delivery. Overweight status and obesity increase the health care costs associated with pregnancy five-fold; and this does not even take account of long-term effects including higher rates of obesity and diabetes in the offspring. Obstetricians must stress the importance of nutrition and physical exercise. This has the potential to counteract the obesity epidemic and have positive effects on the health of the whole family. Obesity is now also more commonly seen also in infertility clinics; polycystic ovary syndrome is of importance here and can be seen as part of the metabolic syndrome. In clinical practice, complications of pregnancy, especially pre-eclampsia, are the most important adverse effects of maternal morbidity. Avoiding these complications needs preconceptional counseling and counseling during pregnancy. Cohen und Kim (2009) reported that 8.1 % of pregnant women try to lose weight during pregnancy. This finding shows that medical advice does not always reach the target group and/or is not followed. Educating obese women about pregnancy and obesity, therefore, has to be a priority.

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Some known risks of pregnancy occur more commonly in obesity. This includes hypertension in pregnancy and venous thromboembolism. Women with inherited thrombophilias are at even greater risk for the latter.

Hypertensive Disorders of Pregnancy Excessive weight gain during pregnancy is associated with an increased risk of hypertensive disorders of pregnancy (Turzansk Fortner et al. 2009). Avoiding excessive weight gain during pregnancy can potentially limit this. Our analysis of German perinatal statistics suggests that obesity-associated complications of pregnancy - by way of necessitating a medically induced preterm birth – are the reason for the increased preterm birth rates in obese women. Pregnancy–related hypertensive disorders are of importance here. This means that reducing the prevalence of hypertension in pregnancy has the potential to limit the rise in preterm birth rate in obesity.

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Preventing the Obesity Epidemic Pregnancy presents us with an opportunity for the primary prevention of obesity in the offspring. Awareness about pre-conceptional counseling and treatment needs to be raised with patients, nutritionists, midwives, and doctors. This includes avoiding overnutrition during pregnancy but at the same time avoiding malnutrition with a focus on multivitamin and folate supplementation. Nutritional counseling needs to be part of counseling pregnant women. Preconceptional weight loss must be encouraged. Complex carbohydrates with a low glycemic index are indicated. Screening for gestational diabetes should begin in the second trimester. The efforts to prevent obesity in the offspring need to be followed up with appropriate measures throughout childhood (Institute of Medicine 2004). Further research is needed especially with regard to fetal programming and its role in degenerative diseases later in life. Perhaps this will open up further opportunities for prevention.

Open Questions Some important questions about obesity and pregnancy are as of yet unanswered: • • • • • •

What is the precise impact of obesity on fertility? Regarding weight reduction before pregnancy: How much should be aimed for? Regarding nutrition in pregnancy: Which diet is best in obesity? Regarding weight gain in pregnancy: What is appropriate for different phenotypes (different maternal heights and weights, different fat distributions)? Which obese woman are in danger of pre-eclampsia? Why is (moderate) maternal overweight status protective against prematurity?

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Should a concept of ‗congenital obesity‘ be used? What impact would this have on neonatal nutrition?

References

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Cohen JH, Kim H: Sociodemographic and health characteristics associated with attempting weight loss during pregnancy. Prev. Chronic Dis. 2009; 6(1): A07. Dixit A, Girling JC. Obesity and pregnancy. J. Obstet. Gynaecol. 2008; 28: 14 - 23. Institute of Medicine (IOM). Preventing childhood obesity: Health in the balance. Report 2004, http://www.iom.edu/?id=22623 , accessed 17 March 2009 Karam JG, El-Sayegh S, Nessim F, Farag A, McFarlane ST. Medical management of obesity: an update. Minerva Endocrinol. 2007; 32: 185 – 207. Turzansk Fortner R, Pekow P, Solomon CG, CG, Markenson G, Chasan-Taber L: Pregnancy body mass index , gestational weight gain, and risk of hypertensive pregnancy among Latina women. Am. J. Obstet. Gynecol. 2009; 200: 167. e1 – 167. e7.

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Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved. Briese, Volker, et al. Obesity and Pregnancy, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

In: Obesity and Pregnancy V. Briese, M. Voigt and S. Straube, pp. 161-164

ISBN: 978-1-60876-111-1 © 2010 Nova Science Publishers, Inc.

Chapter XXXVI

A Patient Guide The previous chapters of this book have been written largely with an audience of health professionals in mind, although we think that patients and other interested lay people would also have found some of the material interesting. In this chapter we would like to discuss some key points of obesity and pregnancy for a patient audience. We hope that our words of advice are useful and also that this chapter may fill in some of the background needed to understand the other chapters.

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The Importance of Obesity Obesity is a disease that is becoming more and more frequent. Many other diseases are associated with obesity including heart disease, diabetes, and certain cancers. Obesity is also associated with a number of complications during pregnancy. Of special concern, even young people are now commonly affected by obesity. Obesity is defined by the ‖body mass index‖ (BMI, a measure that takes into account height and weight) or by waist circumference. A BMI of 30 or greater implies obesity (this applied to both sexes). There are different classes of obesity as shown in Figure 36-1. Class III is also called ―morbid obesity‖. People between the normal weight category and obesity are ―overweight‖. The cut-off for waist circumference is 88 cm (35 in.) in women.

Figure 36-1. The classification of obesity according to BMI. Briese, Volker, et al. Obesity and Pregnancy, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

162

Volker Briese, Manfred Voigt and Sebastian Straube

Weight Loss

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Weight loss is generally a good idea for obese people and we believe that because of the complications of obesity during pregnancy pre-conceptional weight loss is an especially good idea for obese women who want to become pregnant. However, dieting during pregnancy cannot be recommended because it may deprive the fetus of valuable nutrients. The media are full of advice about how to lose weight. Considering that obesity is the result of a long-term process, however, it is clear that many months and – in some cases – years are necessary to get back to normal weight (BMI 18.55 – 24.99) or even to get back to ―overweight status― (BMI 25.00 – 29.99) from obesity. Obesity is the result of a deranged metabolic equilibrium; a new (and too high) ―set-point― for body weight is established. The common availability of high calorie foods and a decreased need to be physically active as part of our daily routine favor the development of obesity. Life style factors that favor the development of obesity need to be recognized on a case by case basis and a stepwise approach needs to be taken to rectify them. We believe that the key to weight loss involves physical activity, a healthy nutrition, and a change in the habits that favor obesity as summarized in Figure 36-2. Nutritional counseling can be a valuable part of this process.

Figure 36-2. The approach to weight loss in obesity.

To fight obesity it is important to not resign oneself to one‘s condition but to take active steps. Obesity can lead to withdrawal from an active lifestyle for fear of awkwardness or embarrassment. Obese women commonly will feel self-conscious in public and may for that reason avoid using public swimming pools, for example. This sort of behavior can lead to a vicious cycle because physical exercise is a key component of weight reduction. Furthermore, exercise is beneficial in its own right and may help to avoid social isolation that can also contribute to the generation of obesity. Self-help groups may also be a step towards avoiding social isolation and finding encouragement. However, there is no ―one size fits all‖ recipe for weight loss. Moreover, weight loss is no competition and sustainable, slow, long term weight loss is the key to success. At the Department of Obstetrics and Gynecology of the University of Rostock we have some experience with weight reduction in obesity. In clinical practice, we found that obese patients often have an excessive caloric intake, commonly because of high calorie ‗juice‘

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A Patient Guide

163

drinks. Often patients do not know that such sugar-containing juice drinks have a lot of calories. We think that drinking water in combination with eating fruits and vegetables is a better alternative. Even though the diet in obese people often contains caloric excess, it may be deficient in other ways. For example, it may lack sufficient high quality vegetable fats, folic acid, and vitamin D. We aim to change nutrition to increase the proportion of fruits, vegetables and fish and to reduce the consumption of meat products. We also recommend drinking at least 2 l per day. Foods with low glycemic index are preferable to those with a high glycemic index. It is difficult to radically change behaviors that have been followed for years. However, it is not necessary to ban high calorie foods completely from the diet and the aim is to change the diet in a stepwise fashion. As far as physical exercise is concerned, we have had good outcomes with walking, slow running (with breaks for stretching), perhaps for 30 minutes every day.

Obesity and Pregnancy Because of possible complications of obesity in pregnancy it makes sense to plan a pregnancy carefully if you are obese. This is not always possible, of course, but where it is possible, planning ahead is a good idea. Some common questions and answers are presented below.

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Do Overweight and Obese Women More Commonly Have Trouble to Conceive? Because of changes in the hormonal balance and metabolism some obese women do not ovulate. This can occur in polycystic ovary syndrome (PCOS). An ultrasound examination will be needed to make this diagnosis. Sometimes dietary change (foods with a low glycemic index) will lead to weight loss and may be sufficient to enable ovulation to occur. Diabetes needs to be excluded in such women, and further tests may be needed to detect other endocrine (hormone related) disorders.

Is a Medical Check-up before Pregnancy Important? Obesity is associated with a number of common conditions such as heart disease, high blood pressure, diabetes, and occasionally with some other endocrine diseases. Pregnancy places an additional strain on the body and could make such disorders worse. This can affect the health of mother and child. Should obesity-associated disorders be present, detecting them before pregnancy may allow adequate treatment to lower the risk that they get out of control during pregnancy.

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164

What Do I Need to Tell My Doctor About? Your doctor will ask you about diseases you have had in the past. You may be asked about deep vein thromboses and pulmonary emboli (blood clots in the leg veins and in the lungs) in you or your relatives, difficulty in breathing on exertion, water retention (edema), medicines you take, and previous heart attacks and strokes, for example. The answers to these and other questions your doctor may have are important to allow them to provide the best possible care for you during your pregnancy.

What Tests Are Necessary before Pregnancy? Your doctor may perform some routine blood test and some (or all) of the following: • • • • •

ECG (and sometimes an exercise ECG) Measuring blood pressure (and sometimes 24 h blood pressure monitoring) 75 g oral glucose tolerance test (giving you sugar to eat and measuring blood sugar levels), measuring insulin levels Tests to exclude blood clotting disorders In some cases: echocardiography (an ultrasound examination of the heart)

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When Should Weight Loss Occur? Weight loss should occur before pregnancy. As mentioned above, weight loss should not be aimed for during pregnancy because this may cause inadequate supply of the fetus with certain nutrients and can endanger fetal growth.

What About Nutritional Supplements? Many women who plan to become pregnant have a less than optimal intake of folic acid and vitamin D. Folic acid is necessary for a normal development of the organs of the fetus. Some developmental defects of children are more common when the mother is obese. This risk can be reduced if folic acid supplementation is started before pregnancy and continued during pregnancy.

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In: Obesity and Pregnancy V. Briese, M. Voigt and S. Straube, pp. 165-171

ISBN: 978-1-60876-111-1 © 2010 Nova Science Publishers, Inc.

Chapter XXXVII

Appendix: Percentiles for the Weight Gain During Pregnancy

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Based on data of more than 2.2 million pregnancies from the German perinatal statistics of 1995-2000 we have calculated percentiles for the weight gain during pregnancy according to maternal phenotype (height and weight). We have previously published these values (Straube et al. 2008, Voigt et al. 2007) and reproduce them here. We recommend that women are categorized in the appropriate group defined by height and weight (measured at the first obstetric consultation) and that the weight gain is followed over the course of the pregnancy with the tables below. These standard values may help to raise suspicion about complications of pregnancy that are associted with abnormal weight gain, such as pre-eclampsia. This is a new approach to assessing weight gain during pregnancy and it has yet to be validated in clinical practice. Table 37-1. Percentiles for the weight gain during pregnancy for women with a height ≤ 161 cm and a weight ≤ 57 kg; n (total) = 228,307

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Volker Briese, Manfred Voigt and Sebastian Straube Table 37-2. Percentiles for the weight gain during pregnancy for women with a height ≤ 161 cm and a weight of 58 – 73 kg; n (total) = 198,937

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Table 37-3. Percentiles for the weight gain during pregnancy for women with a height ≤ 161 cm and a weight of 74 – 89 kg ; n (total) = 46,903

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Appendix: Percentiles for the Weight Gain During Pregnancy Table 37-4. Percentiles for the weight gain during pregnancy for women with a height ≤ 161 cm and a weight ≥ 90 kg ; n (total) =12,462

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Table 37-5. Percentiles for the weight gain during pregnancy for women with a height of 162 – 171 cm and a weight ≤ 64 kg; n (total) = 674,166

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168

Volker Briese, Manfred Voigt and Sebastian Straube Table 37-6. Percentiles for the weight gain during pregnancy for women with a height of 162 – 171 cm and a weight of 65 – 80 kg; n (total) = 455,711

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Table 37-7. Percentiles for the weight gain during pregnancy for women with a height of 162 – 171 cm and a weight of 81 – 96 kg; n (total) = 111,929

Briese, Volker, et al. Obesity and Pregnancy, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Appendix: Percentiles for the Weight Gain During Pregnancy Table 37-8. Percentiles for the weight gain during pregnancy for women with a height of 162 – 171 cm and a weight ≥ 97 kg; n (total) = 37,751

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Table 37-9. Percentiles for the weight gain during pregnancy for women with a height ≥ 172 cm and a weight ≤ 73 kg; n (total) = 294,538

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169

170

Volker Briese, Manfred Voigt and Sebastian Straube Table 37-10. Percentiles for the weight gain during pregnancy for women with a height ≥ 172 cm and a weight of 74 – 89 kg; n (total) = 129,110

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Table 37-11. Percentiles for the weight gain during pregnancy for women with a height ≥ 172 cm and a weight of 90 – 105 kg; n (total) = 37,033

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Appendix: Percentiles for the Weight Gain During Pregnancy

171

Table 37-12. Percentiles for the weight gain during pregnancy for women with a height ≥ 172 cm and a weight ≥ 106 kg; n (total) = 14,640

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References Straube S, Voigt M, Briese V, Schneider KT, Voigt M. Weight gain in pregnancy according to maternal height and weight. J. Perinat. Med. 2008; 36: 405-12. Voigt M, Straube S, Schmidt P, Pildner von Steinburg S, Schneider KT. [Standard values for the weight gain in pregnancy according to maternal height and weight] Z. Geburtshilfe Neonatol. 2007; 211: 191-203.

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Index

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A ABC, 49 abdomen, 131, 139 abduction, 125 abnormalities, 25, 32, 42, 48, 118, 138 abortion, 29, 30, 33, 104 absorption, 36, 89 abstinence, 32, 53 acetate, 21, 23 acid, 17, 32, 33, 34, 41, 42, 94, 97, 110, 133, 163, 164 acidosis, 111, 114 activity factors, 129 acute, 96, 97, 98, 99, 104, 117, 119, 129, 130, 131, 132, 137, 138 adaptation, 11 adipocyte, 15, 16, 17, 18 adiponectin, 12, 13, 16, 22, 25, 45 adipose, 3, 4, 7, 15, 16, 17, 18, 22, 25, 28, 35, 38, 46, 57, 133 adiposity, 11, 13, 47, 49, 61 adjunctive therapy, 99 adjustment, 28 adolescence, 11, 22, 45 adrenal cortex, 45 adult, 4, 9, 11, 13, 16, 58, 70, 91, 98 age, 11, 12, 13, 26, 28, 45, 54, 55, 59, 61, 68, 73, 77, 79, 94, 95, 101, 104, 107, 117, 121, 122, 125, 137, 138, 143, 157 agents, 22, 88, 103, 104, 108, 141, 142, 147 aid, 56, 153 alanine, 111 albumin, 48 alcohol, 32, 46, 51, 73, 129, 131 alertness, 89 alpha, 15, 16

alternative, 4, 13, 152, 163 alters, 57 American Heart Association, 49, 124 amino acids, 11, 111 amniotic, 4, 38, 65, 89 amplitude, 25, 29 amylase, 129, 130, 131, 132 anaesthesia, 151, 153 analgesia, 118, 152, 153 androgens, 15, 25, 45 angina, 37 angiogenesis, 37, 39 angiography, 96, 118 angioplasty, 118, 119 antagonists, 107, 111, 112 antiangiogenic, 38, 93 antibiotics, 88, 89, 114, 142 anticoagulation, 96, 101, 103 anticonvulsant, 96 antidiabetic, 108 antiphospholipid antibodies, 73 antiphospholipid syndrome, 101 anxiety, 66, 144, 152 apnea, 127 appetite, 12, 15, 112 application, 116, 141 ARDS, 112 arousal, 127 arrest, 69, 148 ART, 91 artery, 38, 45, 99, 115, 117, 119, 122, 125, 143 ascorbic acid, 110 asphyxia, 4, 95, 115, 139 aspirin, 96, 103, 104, 118, 119, 123 assessment, 21, 49, 60, 109, 122, 132, 152 asthma, 70 asymptomatic, 88, 90, 103

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Index

174 asystole, 152, 153 atherogenesis, 51 atherosclerosis, 12, 51, 52, 117 athletes, 7 atonic, 141, 142, 148 atrial fibrillation, 123 atropine, 152 attacks, 164 aura, 21 autoantibodies, 75 autoimmune disease, 94 awareness, 41

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B babies, 71, 144 bacterial, 88, 89, 90 bariatric surgery, 36 barrier, 57 behavior, 162 beneficial effect, 33 benefits, 3, 33, 53 beta-blockers, 37, 129, 131 bicarbonate, 113 binding, 17, 25 bioavailability, 43 birth, 5, 9, 11, 12, 26, 27, 28, 29, 32, 55, 57, 61, 65, 66, 67, 68, 69, 70, 71, 78, 83, 84, 85, 86, 87, 88, 89, 90, 95, 97, 104, 107, 110, 115, 119, 131, 138, 139, 140, 143, 144, 147, 157, 158 birth weight, 11, 17, 32, 57, 61, 66, 67, 68, 69, 89, 90, 97, 107, 110, 115, 119, 139, 143, 157 bladder, 141, 142 bleeding, 84, 141, 142, 148 blood, 12, 31, 32, 37, 38, 54, 57, 103, 105, 108, 109, 111, 112, 113, 114, 115, 123, 127, 128, 138, 140, 141, 142, 147, 148, 163, 164 blood clot, 164 blood cultures, 112 blood flow, 38 blood glucose, 108, 109, 111, 113, 114, 115 blood pressure, 31, 32, 37, 38, 48, 54, 57, 123, 127, 128, 137, 138, 142, 147, 148, 164 blood sampling, 105 blood transfusion, 140 body mass index, 4, 7, 30, 61, 71, 74, 89, 90, 98, 99, 124, 144, 145, 153, 159, 161 body weight, 7, 22, 31, 33, 57, 70, 162 bolus, 114, 138, 147, 148, 149 borderline personality disorder, 152, 153

brachial plexus, 69, 139, 143, 144 bradycardia, 152, 153 brain, 12, 122 breastfeeding, 33, 41, 142, 144 breathing, 113, 127, 128, 164 bronchopulmonary dysplasia, 89 burning, 125 bypass, 118, 141, 145

C calcium, 41, 95 caloric intake, 15, 35, 162 calorie, 35, 162, 163 cancer, 123 carbohydrates, 35, 41, 111, 158 cardiac enzymes, 119 cardiac function, 118 cardiologist, 118 cardiomyopathy, 78 cardiovascular disease, 3, 10, 16, 32, 37, 45, 47, 49, 53, 56, 57, 98, 123, 137, 147 cardiovascular risk, 4, 37, 49, 51, 52, 98 cardiovascular system, 147 carpal tunnel syndrome, 4, 125, 126 catecholamines, 15, 16, 111 category a, 161 catheter, 4, 118, 142, 151 causality, 54 causation, 41, 85, 87, 125, 126 cell, 12, 16, 122 central nervous system, 137 central obesity, 12, 97 cerebral hemorrhage, 96, 121 cerebrovascular, 21, 51, 93 cerebrovascular disease, 21, 93 cervix, 38, 82, 89 cesarean section, 119, 148, 153 chemoattractant, 16 chemokines, 16 childbirth, 152 childhood, 13, 49, 94, 99, 158, 159 children, 11, 32, 34, 48, 49, 51, 164 cholestasis, 96, 137 cholestatic liver disease, 51 cholesterol, 21, 32, 38, 48, 51, 52, 137 chorioamnionitis, 84 chronic disease, 12, 31, 83 cigarette smoking, 58, 131 cigarettes, 53, 56

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Index circulation, 113 classes, 161 classical, 96, 99, 140 classification, 55, 68, 98, 161 cleft lip, 33 clinical diagnosis, 125 clinical presentation, 112, 118 clinical symptoms, 130 clinical trial, 148 clinics, 157 clopidogrel, 118 closure, 33 clotting factors, 101 coagulation, 22, 137 coagulopathy, 70, 123, 141 cohort, 12, 23, 25, 34, 69, 77, 81 colectomy, 131 collaboration, 57 collagen, 117 coma, 113 common symptoms, 122 communication, 5 community, 3 co-morbidities, 79, 94 competition, 162 compliance, 34 complications, vii, 4, 5, 16, 17, 31, 32, 36, 51, 61, 65, 70, 74, 81, 86, 87, 95, 107, 110, 112, 115, 127, 138, 139, 140, 141, 142, 144, 151, 152, 157, 158, 161, 162, 163, 165 components, 42, 57 composition, 35 compounds, 157 concentration, 17, 112, 127, 130, 132 conception, vii, 28, 31, 33, 73, 74 confidence, 32, 96 confounders, 73 congress, iv consensus, 35 consumption, 12, 32, 42, 54, 73, 141, 163 Continuous Positive Airway Pressure (CPAP), 127, 128 contraceptives, 22, 23, 51 contractions, 140 control, 4, 33, 53, 57, 74, 75, 88, 115, 123, 127, 144, 152, 163 controlled studies, 98 conversion, 151 copper, 22, 33 coronary arteries, 117

175

coronary artery disease, 99 coronary artery spasm, 117 coronary thrombosis, 117 cortex, 45 corticosteroids, 51, 112, 115, 131 corticotropin, 12 cortisol, 107, 111 costs, 4, 157 cotinine, 53, 56 counseling, 12, 31, 32, 33, 35, 37, 41, 56, 70, 157, 158, 162 couples, 25, 26 craniofacial, 32 C-reactive protein, 33, 52 creatinine, 48, 118 critical period, 11 CRP, 32, 51 cycles, 25, 28 cyst, 129, 131, 132 cytokine, 3, 16, 18, 84, 89 cytology, 31

D danger, 95, 114, 117, 158 data mining, 128 database, 121 death, 53, 66, 73, 77, 79, 101, 118, 147, 151, 152 death rate, 118 decompression, 126 deep venous thrombosis, 105 defects, 32, 33, 34, 69, 71, 97, 164 deficiency, 15, 33, 42, 43, 102 deficit, 96, 122 definition, 49, 119 degenerative disease, 158 dehiscence, 69, 81 dehydration, 112, 113 delivery, vii, 4, 38, 53, 59, 61, 66, 68, 69, 71, 78, 81, 82, 85, 86, 87, 89, 96, 97, 101, 108, 110, 117, 118, 121, 122, 123, 125, 126, 131, 133, 137, 138, 139, 140, 141, 142, 143, 144, 147, 148, 151, 152, 157 deposition, 47 depression, 47, 66, 70 detection, 88, 111 dextrose, 114 diabetes mellitus, 10, 12, 33, 49, 107, 110 diabetic ketoacidosis, 111, 115, 116 diabetic patients, 108 diagnostic criteria, 93

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Index

176 diet, 3, 12, 35, 41, 42, 43, 71, 78, 95, 158, 162, 163 differential diagnosis, 96, 113, 118, 129, 131 dilated cardiomyopathy, 152, 153 dilation, 45 dimer, 103 disability, 32, 139 discharges, 122 diseases, 12, 15, 53, 96, 99, 102, 161, 164 disorder, 45 distress, 152 distribution, 9, 22, 23, 30, 31, 47, 95, 125 diuretics, 51 DNA, 12 docosahexaenoic acid, 33 doctors, vii, 158 dosage, 110, 147 drinking, 31, 32, 163 drug side effects, 51 drug therapy, 103 drug use, 32 drugs, 148 duration, 68, 71, 77, 142, 144 dyslipidemia, 3, 48, 51, 52, 57, 94 dysphagia, 36 dysplasia, 89 dysregulation, 15

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E eating, 35, 41, 43, 70, 163 eclampsia, 17, 37, 54, 66, 78, 84, 86, 93, 94, 95, 96, 98, 113, 122, 123, 128, 137, 138, 144, 147 ecstasy, 34 eczema, 115 edema, 38, 54, 65, 96, 112, 122, 137, 142, 164 electrolytes, 112, 113, 114, 130 emboli, 101, 104, 131, 164 embolus, 117, 118 embryo, 30, 73 encephalopathy, 96 encouragement, 162 endocrine, 15, 18, 45, 163 endometriosis, 29, 30, 87 endoscopic retrograde cholangiopancreatography, 129, 131 endothelial dysfunction, 77, 93 energy, 25, 42 environment, 3, 11, 12, 49, 107 environmental factors, 46 enzymes, 96, 98, 119

epidemic, vii, 3, 48, 157 epidemiology, 132 epinephrine, 152 epiphysis, 70 episiotomy, 139 equilibrium, 162 erectile dysfunction, 29 estimating, 101, 102 estradiol, 111, 129, 133 estrogen, 23, 46, 129, 133 ethanol, 32 ethnic groups, 107 ethnicity, 33 etiology, 45, 132 examinations, 37 exclusion, 83, 84 excretion, 29, 48 excuse, 57 exercise, 3, 15, 35, 70, 95, 162, 164 exertion, 164 exposure, 12, 34, 57, 126 extraction, 143 eyes, 151

F factor Xa, 104, 123 failure, 4, 22, 23, 33, 113, 118, 126, 131, 141, 151 familial hypertriglyceridemia, 52, 131, 132 family, 94, 109, 117, 157 fasting, 12, 13, 32, 48, 108, 109 fat, 13, 15, 16, 22, 23, 29, 30, 31, 35, 36, 38, 41, 47, 49, 93, 95, 107, 158, 163 fat soluble, 22, 41 fatty acids, 11, 16, 33, 41, 95, 111 fatty liver, 97 fear, 162 feeding, 33 feet, 70 femur, 38 fertility, 5, 26, 28, 29, 30, 32, 45, 46, 47, 49, 102, 158 fetal, vii, 4, 7, 11, 12, 13, 32, 33, 38, 41, 45, 51, 54, 57, 59, 60, 69, 70, 73, 77, 78, 79, 84, 96, 97, 104, 105, 107, 109, 111, 114, 123, 128, 131, 138, 139, 140, 157, 158, 164 fetus, 11, 33, 38, 89, 104, 111, 118, 127, 139, 141, 162, 164 fever, 82, 131 fibrillation, 123 fibrin, 101

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Index fish, 130, 163 fitness, 95, 98 flora, 88, 90 flow, 38, 45, 101, 102 fluid, 38, 113 folate, 31, 33, 38, 95, 104, 133, 158 folic acid, 33, 34, 41, 133, 163, 164 Follicle Stimulating Hormone (FSH), 29 follicles, 28, 45 food, 42 forceps, 143 fractures, 68, 69, 70, 139 fresh frozen plasma, 97 fruits, 42, 163 frustration, 35 funds, 3 fundus, 141, 147

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G gallstones, 96, 130, 131 gas, 113 gastric, 36, 141, 145 gender, 7, 139 gene, 12, 15, 16, 96, 98, 99, 103, 104, 131 gene promoter, 16, 96 general anesthesia, 4, 143 generation, vii, 15, 16, 17, 33, 70, 101, 162 genetic factors, 47 gestation, 26, 37, 38, 55, 66, 73, 78, 83, 84, 85, 87, 88, 89, 93, 94, 97, 101, 104, 108, 109, 115, 118, 119, 130, 131, 137, 138, 142, 143 gestational age, 55, 68, 79, 104, 143 gestational diabetes, vii, 4, 17, 38, 65, 66, 78, 107, 108, 109, 110, 111, 114, 151, 157, 158 globulin, 25 glucagon, 111 glucocorticoids, 12, 99 gluconeogenesis, 111 glucose, 11, 21, 29, 32, 38, 48, 53, 57, 78, 79, 95, 97, 107, 108, 109, 110, 111, 113, 114, 115, 130, 137, 164 glucose metabolism, 57 glucose tolerance, 21, 29, 32, 38, 48, 53, 78, 79, 95, 97, 107, 108, 109, 111, 114, 164 glycemic index, 29, 95, 158, 163 glycerol, 16 glycoprotein, 75 goals, 35 gonadotropin, 25

177

groups, 7, 25, 26, 35, 53, 54, 55, 56, 60, 66, 68, 85, 107, 162 growth, 12, 32, 36, 37, 54, 57, 60, 78, 96, 98, 99, 104, 111, 143, 164 growth factor, 12, 37 growth hormone, 12, 111 guidance, 104 guidelines, 7, 22, 103, 118, 123, 137, 147

H HDL, 21, 32, 38, 48, 51, 52 health, vii, 3, 7, 11, 13, 29, 31, 41, 42, 48, 51, 53, 71, 123, 138, 157, 159, 161, 163 health care professionals, vii health education, 3 health effects, 11 health problems, 3, 157 healthcare, vii, 47, 49, 124, 157 heart, 7, 11, 16, 48, 49, 51, 52, 78, 102, 117, 118, 122, 123, 124, 161, 163, 164 heart attack, 164 heart disease, 11, 102, 117, 118, 122, 127, 161, 163 heart failure, 48 heart rate, 38, 78 heart valves, 123 height, 7, 12, 13, 41, 43, 59, 60, 61, 78, 89, 97, 109, 119, 140, 142, 143, 161, 165, 166, 167, 168, 169, 170, 171 hematological, 102 hemodynamic, 148 hemoglobin, 38, 98, 108 hemorrhage, 4, 66, 95, 102, 118, 121, 122, 123, 147, 148, 151 heparin, 103, 104, 105, 122 hepatitis, 96 hepatitis B, 38 heterogeneous, 107 high blood pressure, 163 high risk, 4, 7, 36, 37, 48, 51, 83, 108, 123, 147, 151 high-fat, 35 hip, 47, 48, 49 hippocampal, 13 hirsutism, 22 histology, 78, 115 HIV, 111, 115 homeostasis, 25, 28, 57 homocysteine, 103, 104 hormone, 11, 12, 13, 15, 22, 25, 29, 46, 111, 163 hospital, 4, 104, 113, 114, 121, 122, 124, 157

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Index

178

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human, 16, 17, 18, 107, 111, 115 human immunodeficiency virus, 115 hydramnios, 38 hydrocephalus, 89 hydronephrosis, 130 hypercholesterolemia, 21, 127 hypercoagulable, 101, 117 hyperemesis gravidarum, 96 hyperglycemia, 78, 107, 108 hyperhomocysteinemia, 94, 102, 104 hyperinsulinemia, 12, 25, 29, 107 hyperlipidemia, 52, 117 hyperplasia, 15 hypertension, vii, 4, 21, 33, 34, 37, 38, 48, 52, 54, 59, 65, 66, 70, 72, 77, 78, 83, 86, 93, 94, 95, 96, 97, 98, 99, 102, 109, 117, 119, 122, 124, 127, 128, 137, 138, 142, 147, 151, 157, 158, 159 hyperthyroidism, 115 hypertriglyceridemia, 21, 51, 129, 130, 132 hypertrophy, 15, 48 hyperuricemia, 94 hypoglycemia, 107, 108 hyporeflexia, 112 hypotension, 83, 112, 147 hypothalamic, 12 hypothalamus, 15 hypothesis, 11, 13, 128 hypothyroidism, 51, 78, 98 hypoxia, 18, 130

I iatrogenic, 86, 138 ICSI, 28, 74 IDEA, 10, 49 idiopathic, 38, 72, 75, 133 IGF, 12 IGF-1, 12 ileostomy, 131 imaging, 96 imbalances, 29 immune response, 84, 89 immune system, 15 immunoglobulin, 143 impaired glucose tolerance, 78, 79, 107, 108, 109, 111, 114 in vitro fertilization (IVF), 28, 29, 30, 45, 46, 74, 102 incidence, 4, 32, 42, 77, 88, 97, 105, 111, 117, 121, 125, 129 indication, 38, 82, 140, 147

individual differences, 59 induction, 46, 66, 69, 143 infants, i, ii, iii, 11, 54, 59, 77, 86 infarction, 112, 115, 117, 118, 119, 122 infection, 4, 31, 36, 65, 66, 84, 87, 88, 89, 90, 102, 111, 112, 122, 142, 144, 151 infertility, 4, 23, 25, 26, 27, 28, 29, 30, 46, 73, 83, 157 inflammatory, 3, 16, 54, 58, 70, 77, 84, 90, 94, 125, 126 inherited, 102, 158 inhibitor, 36, 45, 46, 115, 123 initiation, 89, 130, 144 injection, 21, 22, 103, 114, 126, 147, 148, 149 injury, iv, 68, 69, 96, 139 insertion, 139, 140, 141 insulin, 3, 4, 11, 12, 16, 17, 18, 25, 29, 32, 45, 48, 53, 91, 94, 95, 107, 109, 110, 111, 112, 114, 116, 130, 164 insulin-like growth factor, 12 intensive care unit, 131 interaction, 22, 54, 89 interleukin, 16, 18 intermediate targets, 56 intertrigo, 38 interval, 82, 103, 127, 140, 144 intervention, 53, 88, 119, 122, 128, 131 intima, 45 intracerebral hemorrhage, 121, 122 intracranial, 72 intramuscular, 114, 148 intravascular, 137 intravenous, 114, 147, 148, 152 iodine, 33, 38, 41, 42 iron, 38, 41, 133 ischaemia, 96, 149 ischemic, 51, 96, 117, 121, 122, 123, 124, 127 isolation, 53, 162

K ketoacidosis, 4, 111, 115 ketones, 113 kidney, 52 kinase, 37, 93, 118 Korean, 30, 115, 132

Briese, Volker, et al. Obesity and Pregnancy, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Index

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

L labor, 61, 66, 69, 71, 81, 82, 84, 85, 86, 87, 89, 97, 117, 118, 119, 138, 139, 140, 141, 142, 143, 147, 148, 149, 152, 153, 157 lactation, 142 lactobacillus, 88 laparoscopic, 46 later life, 12, 123 Latin America, 107 LDL, 21, 38, 51 left ventricular, 48 leptin, 13, 15, 16, 17, 22, 25, 82 lethargy, 112 leukocyte, 16 life expectancy, 53 lifespan, 123 lifestyle, 3, 31, 34, 35, 37, 52, 56, 123, 162 life-threatening, 4 ligament, 125 limitations, 128 lipase, 36, 96, 98, 129, 130, 131 lipemia, 130 lipid, 15, 32, 37, 38, 51, 123, 130, 132, 137 lipolysis, 16, 17, 111 lipoprotein, 57, 129, 131, 132 liver, 16, 51, 96, 97, 98, 99 localization, 139 location, 140, 152 low fat diet, 130 low molecular weight, 103, 119, 152 low-dose aspirin, 123 lung, 105, 138, 164 lupus anticoagulant, 103 lupus erythematosus, 102, 122, 126 luteinizing hormone, 25, 29

M macrophages, 16 macrosomia, vii, 4, 38, 54, 59, 60, 68, 69, 78, 84, 107, 109, 138, 139, 157 magnesium, 95, 96 malnutrition, 158 management, vii, 70, 103, 105, 110, 113, 114, 115, 118, 119, 126, 130, 133, 139, 147, 149, 151, 152, 153, 159 maternal age, 26, 28, 73, 77, 94, 95, 101, 117, 122, 125, 138

179

maternal smoking, 54, 56 maturation, 28, 89 measures, 3, 10, 21, 36, 52, 53, 56, 74, 88, 104, 123, 127, 152, 158 meat, 42, 163 media, 45, 125, 162 medical care, 78, 151 medications, 31, 83, 97, 128 melanocyte stimulating hormone, 15 membranes, 84, 86, 97, 143 men, 7, 9, 29, 47, 133 menstrual cycle, 25, 29 mental state, 152 meta-analysis, 32, 45, 72, 74, 77, 123, 137, 144 metabolic, vii, 7, 13, 15, 17, 25, 28, 29, 33, 36, 45, 47, 48, 49, 51, 52, 53, 57, 70, 78, 79, 107, 111, 115, 117, 132, 157, 162, 163 metabolic syndrome, vii, 33, 36, 45, 47, 48, 49, 51, 52, 53, 70, 78, 107, 117, 157 metformin, 29, 30, 32, 46, 108 methylation, 12 methylene, 46 midwives, 158 migraine, 21, 23, 96, 98 migration, 151 milk, 12, 142 minerals, 41, 42 mining, 128 minority, 37 miscarriages, 46, 73, 74, 78, 79, 83, 84, 107 misleading, 7 mitochondrial, 97 molecular mechanisms, 17, 98 molecular weight, 103, 105, 119, 152 monocyte chemoattractant protein, 16 morbidity, 4, 69, 101, 138, 144, 157 morphology, 117 mortality, 4, 48, 51, 58, 86, 90, 96, 97, 101, 105, 114, 116, 118, 121, 138, 151 mothers, 42, 43, 51, 53, 86, 87, 152 motion, 114 motivation, 35 MRI, 103 MTHFR, 104 multidimensional, 3 multidisciplinary, 3 multiple sclerosis, 143 muscle, 7, 17, 35, 107, 112, 118, 141 mutation, 15, 21, 23, 97, 102, 103, 104, 131 myeloma, 126

Briese, Volker, et al. Obesity and Pregnancy, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Index

180 myocardial infarction, 4, 37, 117, 118, 119 myocardial ischemia, 118, 147 myocardium, 119 myogenesis, 12 myometrium, 81, 82, 141

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N National Research Council, 61 natural selection, 121 nausea, 112, 118, 130, 147, 148 necrosis, 16, 115, 130 needles, 151, 152 neonatal, vii, 4, 17, 26, 42, 43, 54, 55, 67, 68, 69, 77, 79, 86, 89, 90, 98, 141, 143, 145, 159 neoplastic diseases, 53 nephritic syndrome, 51 nerve, 125 neurological deficit, 96 Neuropathies, vi, 125 neuropeptide, 15 next generation, 11 nicotine, 53, 56, 57 nifedipine, 96, 97 nonsmokers, 54, 55, 56, 57 non-steroidal anti-inflammatory drugs, 126 norepinephrine, 36 normal, 4, 17, 21, 22, 25, 26, 27, 33, 41, 54, 59, 60, 65, 66, 68, 69, 77, 84, 85, 86, 96, 109, 113, 114, 117, 118, 119, 127, 129, 132, 141, 142, 157, 161, 162, 164 nulliparous, 71, 94, 97, 144 nurses, 47 nutrition, 11, 31, 33, 34, 35, 37, 38, 41, 111, 130, 157, 158, 159, 162, 163, 164

O obese patients, 30, 36, 97, 151, 152, 153, 157, 162 obstetricians, 122 obstruction, 127, 130 Obstructive Sleep Apnea (OSA), vi, 127, 128 occupational, 126 odds ratio, 32, 65, 77, 94 oil, 130 omega-3, 33, 41, 95 oral, 21, 22, 23, 29, 38, 45, 46, 95, 96, 108, 109, 117, 127, 138, 164 organ, 3, 11, 15, 18, 131

osmolality, 113 osteoarthritis, 125 ovary, 45, 70 overnutrition, 11, 13, 25, 157, 158 overweight, 4, 7, 9, 11, 15, 21, 26, 27, 29, 32, 42, 54, 59, 65, 72, 77, 83, 84, 86, 87, 94, 96, 98, 99, 131, 144, 157, 158, 161, 162 ovulation, 29, 32, 46, 163 oxidation, 58, 97 oxygen saturation, 127 oxytocin, 147, 148, 149

P pain, 36, 82, 96, 97, 103, 105, 112, 113, 118, 125, 129, 130, 131, 133, 137, 140, 151, 152 pancreatic, 36, 57, 130 pancreatitis, 16, 51, 129, 130, 131, 132 paradox, 48, 49, 54, 157 parameter, 31, 59 paresis, 143 partial thromboplastin time, 123 passive, 53, 56 paternal, 11, 73 pathogenesis, 12, 16, 45, 52, 53, 73, 77, 84, 111, 117 pathophysiological mechanisms, 47 pathophysiology, 16, 17, 97, 127, 133 pathways, 12, 17 patients, vii, 10, 16, 17, 29, 36, 45, 46, 48, 49, 51, 53, 56, 70, 95, 97, 101, 104, 105, 108, 111, 115, 117, 118, 122, 123, 124, 128, 129, 138, 144, 148, 151, 152, 158, 161, 163 pelvic, 30, 139 percentile, 41, 60, 68, 79 perfusion, 103 perinatal, vii, 4, 9, 26, 28, 53, 54, 55, 56, 59, 60, 65, 73, 74, 77, 78, 83, 84, 85, 86, 94, 95, 96, 101, 102, 158, 165 perineum, 139 peripheral, 47 phenotype, 13, 46, 158, 165 phosphorylation, 16, 18 physical activity, 31, 95, 162 physical exercise, 35, 38, 157, 162, 163 physicians, 122 physiology, 25, 132, 138 physiotherapy, 152 pituitary, 25 placebo, 36, 88

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Index placenta, 38, 84, 104, 105, 118, 139, 140, 141, 142, 147 placental, 37, 65, 77, 78, 84, 93, 107, 111, 113, 127, 140, 141, 148 planning, 25, 31, 45, 137, 157, 163 plasma, 17, 51, 52, 89, 97, 99, 129, 130, 132, 133 plasmapheresis, 132 plasminogen, 45, 103 platelet, 96, 97, 103, 123, 130 play, 15, 16, 73, 84, 111, 117 policy makers, 3 polycystic ovary syndrome, 22, 23, 25, 30, 46, 73, 157, 163 polycythemia, 102 polydipsia, 112 polyhydramnios, 78, 79 polymorphism, 45, 46, 96, 98, 99 polysomnography, 127 polyuria, 112 pools, 162 poor, 42, 43, 89, 98, 127, 143 population, 9, 34, 42, 48, 57, 60, 73, 74, 101, 105, 117, 119, 121, 124, 125, 127, 128, 144 postoperative, 97, 152 postpartum, vi, 4, 66, 82, 95, 97, 98, 99, 101, 102, 105, 117, 118, 119, 122, 123, 125, 137, 142, 144, 147, 148, 151 precursor cells, 15 prediction, 39 predictors, 49, 79 preeclampsia, vii, 4, 17, 37, 39, 54, 57, 59, 65, 66, 86, 93, 94, 95, 96, 97, 98, 99, 102, 117, 128, 137, 138, 142, 144, 151, 157, 158, 165 pre-existing, 94, 96, 98 pregnancy test, 31 pregnant women, vii, 5, 9, 17, 26, 32, 41, 42, 54, 57, 59, 65, 66, 73, 77, 81, 84, 88, 101, 103, 107, 111, 114, 123, 125, 127, 128, 129, 131, 137, 141, 157, 158 premature labor, 84, 85, 86, 87 prematurity, 158 premenopausal women, 35 prenatal care, 4, 110 pressure, 31, 32, 37, 38, 48, 54, 57, 123, 125, 127, 128, 137, 138, 141, 142, 147, 148, 152, 163, 164 preterm delivery, 59, 61, 69, 82, 84, 85, 86, 87, 89, 90 preterm infants, 83, 85 prevention, vii, 5, 11, 12, 33, 78, 79, 83, 88, 95, 98, 103, 105, 114, 123, 124, 148, 153, 158

181

primary care, 10, 49 probability, 25 production, 142 progesterone, 29, 111, 117 prognosis, 48, 49, 132 programming, vii, 11, 12, 13, 51, 52, 56, 88, 108, 111, 158 pro-inflammatory, 3, 16 prolactin, 142 promoter, 12, 13, 16, 96 property, iv prophylactic, 152 prophylaxis, 95, 148 protease inhibitors, 115 protein, 12, 16, 17, 35, 41, 101, 103, 130 proteinuria, 38, 54, 65, 93, 96, 97, 142 prothrombin, 21, 102, 103, 104 protocols, 152 pseudocyst, 131 pseudotumor cerebri, 72 psychiatric disorders, 142 psychiatrist, 152 psychosocial factors, 38, 71 public, 3, 71, 121, 124, 162 puerperium, 119, 121, 124, 142, 144 pulmonary angiogram, 103 pulmonary edema, 137 pulmonary embolism, 37, 105 pulse, 25

Q quality of life, 4

R race, 102, 122 radiation, 130 radiculopathy, 125 range, vii, 103, 117, 121 RANTES, 16, 18 receptors, 15 red meat, 42 redistribution, 22 regional, 119, 151, 152 regular, 83, 114, 132 regulation, 15 rehabilitation, 83 relationship, 22, 57, 65, 73, 77, 83, 85, 107

Briese, Volker, et al. Obesity and Pregnancy, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Index

182 relatives, 164 relevance, 96 renal, 51, 94, 112, 130, 137 reproduction, 15, 28, 29, 30, 71, 117 reproductive age, 45 resection, 131 reserves, 3 resistance, 3, 4, 11, 12, 16, 17, 18, 29, 30, 32, 45, 48, 53, 94, 95, 102, 103, 107, 109, 111, 115 resistin, 16, 22, 25 resources, 37, 118 respiratory, 38, 89, 112, 114, 130, 153 respiratory distress syndrome, 89, 112, 114 restless legs syndrome, 133 resuscitation, 152 retardation, 98 retention, 141, 142, 164 retinopathy, 98 rheumatoid arthritis, 125, 133 risk assessment, 31, 137, 138 risk profile, 5, 10, 36, 43, 72, 91, 110 rosiglitazone, 32

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S safety, 35, 118 saline, 113, 114 sample, 105, 133 saturated fat, 41 saturation, 127 scores, 66, 69, 89, 97, 98, 104, 110, 119, 143 seafood, 42 secretion, 16, 18 seizures, 96 selenium, 33 self esteem, 70 self-monitoring, 88 sensations, 133 sensitivity, 12, 91, 151 separation, 141 sepsis, 87, 112, 131 serology, 31 serotonin, 36 serum, 16, 17, 21, 33, 118 services, iv, 110 severity, 17, 107, 110, 123, 130 sex, 25, 125 sexual development, 15 SGA, 54, 55, 59, 68 shock, 112, 118, 125, 130, 131

short-term, 144 shoulder, vii, 4, 38, 138, 139, 143, 147, 157 sickle cell, 102 side effects, 51 sign, 125, 130, 139, 140 signaling pathways, 15, 16, 17 signs, 12, 112, 131, 132 sine, 113 sinus, 96 sites, 16 skeletal muscle, 17 skin, 151 sleep, 37, 125, 126, 127, 128, 133 sleep apnea, 37, 127, 128 sleep disturbance, 125, 133 smokers, 37, 53, 54, 55, 56, 57 smoking, 21, 31, 32, 37, 46, 53, 54, 55, 56, 57, 84, 102, 117, 119, 127, 129, 131, 132, 144, 157 smoking cessation, 32, 53, 56, 57 social factors, 15 social isolation, 162 social status, 84 social support, 37 socioeconomic, 77 speculation, 47 speech, 122 spermatogenesis, 29 sphygmomanometer, 152 spina bifida, 42 spinal anesthesia, 89, 143, 151, 153 splenectomy, 131 spontaneous abortion, 29, 30 spontaneous pregnancy, 25, 30 starvation, 3 statin, 52 statistics, vii, 9, 26, 28, 53, 54, 55, 56, 60, 65, 73, 74, 77, 78, 83, 84, 85, 86, 87, 94, 95, 101, 102, 158, 165 stent, 118, 119 steroid, 22, 25, 126, 129 stillbirth, 77, 78, 79, 104, 131 stimuli, 18 stock, 103, 104, 152 stomach, 129 storage, 15 strain, 147, 157, 163 strategies, vii streptococci, 38 stress, 58, 66, 117, 142, 157 stretching, 141, 163

Briese, Volker, et al. Obesity and Pregnancy, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Index stroke, 4, 37, 47, 49, 51, 96, 112, 121, 122, 123, 124, 164 stupor, 113 substitution, 15, 33, 114 suffering, 65 sugar, 32, 108, 111, 163, 164 sulfate, 96 supervision, 36, 41 supplements, 33, 42, 152 supply, 41, 164 surgery, 22, 23, 36, 46, 104, 118, 126, 127, 141, 145, 152 surgical, 119, 141 surprise, 4, 101 surveillance, 37, 78, 79, 89, 95, 104, 118 susceptibility, 51 swelling, 103 symptoms, 36, 47, 66, 96, 105, 112, 118, 119, 122, 125, 126, 130, 131, 137 syndrome, 4, 22, 23, 30, 32, 33, 34, 45, 46, 48, 65, 66, 70, 71, 73, 93, 96, 97, 99, 126, 128, 129, 130, 131, 133, 157, 163 systemic lupus erythematosus, 102 systems, 11 systolic pressure, 125

tobacco smoking, 53 tolerance, 21, 29, 32, 38, 48, 53, 95, 97, 108, 109, 111, 164 tourniquet, 125 toxic, 131 toxoplasmosis, 31 TPA, 103 traction, 139 trans, 41 transaminases, 21, 137 transfer, 30, 73, 111 Transforming Growth Factor (TGF), 37 transfusions, 140, 142 transient ischemic attack, 122, 124 trial, 35, 69, 81, 82, 90, 148 triglycerides, 21, 32, 38, 48, 51, 52, 129, 130, 131, 137 trophoblast, 93 TSH, 112 tumor, 16, 82 twins, 90 type 2 diabetes, 29, 32, 52, 53, 70, 107, 108, 109, 127 tyrosine, 37, 93

U

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T tachycardia, 103, 131, 147 targets, 56 technology, 30 teenagers, 70 territory, 125 therapy, 36, 37, 52, 56, 88, 89, 96, 97, 108, 110, 114, 123, 127, 128, 137, 138, 144 thiazide diuretics, 51 threatened, 138 threshold, 130, 131 thromboembolism, vii, 21, 36, 37, 38, 65, 101, 102, 103, 104, 105, 123, 137, 142, 144, 151, 157, 158 thrombosis, 22, 23, 37, 96, 101, 105 thrombus, 117, 119 thyroiditis, 110 thyrotoxicosis, 112 TIA, 122, 123 time, 3, 9, 11, 25, 31, 35, 36, 37, 41, 59, 82, 88, 114, 118, 119, 127, 140, 147, 151, 158 tissue, 3, 4, 7, 15, 16, 17, 18, 22, 25, 28, 35, 38, 57, 118, 119, 133 tissue plasminogen activator, 118, 119

183

ultrasound, 45, 103, 105, 109, 113, 125, 130, 139, 151, 163, 164 umbilical artery, 119, 143 umbilical cord, 147 underlying mechanisms, 12 undernutrition, 25, 60 uric acid, 94 urinary, 66, 130, 141, 142 urinary tract infection, 66, 142 urine, 31, 108, 110 uterus, 84, 141, 142

V vaccinations, 31 values, vii, 7, 51, 109, 130, 165, 171 varenicline, 56 vascular disease, 49, 117 vegetables, 42, 163 vein, 37, 101, 105, 164 velocity, 101 ventilation, 151

Briese, Volker, et al. Obesity and Pregnancy, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Index

184 vertebral artery, 122 vessels, 47, 131 viral hepatitis, 96 virus, 115 visible, 141 vitamin D, 33, 41, 42, 43, 163, 164 vitamin K, 97 vitamin supplementation, 33 vitamins, 41, 42, 95 vomiting, 36, 112, 114, 118, 130, 147

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W walking, 163 warfarin, 122, 123 water, 163, 164 weakness, 125 weight gain, vii, 12, 13, 41, 57, 59, 60, 61, 68, 79, 108, 137, 158, 159, 165, 166, 167, 168, 169, 170, 171 weight loss, 21, 23, 29, 35, 36, 41, 46, 158, 159, 162, 163, 164 weight reduction, vii, 4, 22, 25, 31, 35, 45, 53, 56, 97, 123, 158, 162 well-being, 31, 41, 68 white women, 94 withdrawal, 162 workers, 16, 47, 49, 66 World Health Organization (WHO), 7, 48, 99 wound healing, 142 wound infection, 36, 65, 66, 87, 142

Y young women, 37, 70

Z zinc, 33, 38

Briese, Volker, et al. Obesity and Pregnancy, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,