Contemporary Topics in Gestational Diabetes Mellitus [1 ed.] 9789386107725, 9789351523727

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Contemporary Topics in

Gestational Diabetes Mellitus

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Contemporary Topics in

Gestational Diabetes Mellitus

Editor

Veeraswamy Seshiah MD FRCP DSc Chairman Dr V Seshiah Diabetes Research Institute Dr Balaji Diabetes Care Centre Chennai, Tamil Nadu, India

The Health Sciences Publishers New Delhi | London | Philadelphia | Panama

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Jaypee Brothers Medical Publishers (P) Ltd Headquarters Jaypee Brothers Medical Publishers (P) Ltd 4838/24, Ansari Road, Daryaganj New Delhi 110 002, India Phone: +91-11-43574357 Fax: +91-11-43574314 Email: [email protected] Overseas Offices J.P. Medical Ltd 83 Victoria Street, London SW1H 0HW (UK) Phone: +44 20 3170 8910 Fax: +44 (0)20 3008 6180 Email: [email protected]

Jaypee-Highlights Medical Publishers Inc City of Knowledge, Bld. 237, Clayton Panama City, Panama Phone: +1 507-301-0496 Fax: +1 507-301-0499 Email: [email protected]

Jaypee Medical Inc The Bourse 111 South Independence Mall East Suite 835, Philadelphia, PA 19106, USA Phone: +1 267-519-9789 Email: [email protected]

Jaypee Brothers Medical Publishers (P) Ltd 17/1-B Babar Road, Block-B, Shaymali Mohammadpur, Dhaka-1207 Bangladesh Mobile: +08801912003485 Email: [email protected]

Jaypee Brothers Medical Publishers (P) Ltd Bhotahity, Kathmandu, Nepal Phone: +977-9741283608 Email: [email protected] Website: www.jaypeebrothers.com Website: www.jaypeedigital.com © 2015, Jaypee Brothers Medical Publishers The views and opinions expressed in this book are solely those of the original contributor(s)/ author(s) and do not necessarily represent those of editor(s) of the book. All rights reserved. No part of this publication may be reproduced, stored or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission in writing of the publishers. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. Medical knowledge and practice change constantly. This book is designed to provide accurate, authoritative information about the subject matter in question. However, readers are advised to check the most current information available on procedures included and check information from the manufacturer of each product to be administered, to verify the recommended dose, formula, method and duration of administration, adverse effects and contraindications. It is the responsibility of the practitioner to take all appropriate safety precautions. Neither the publisher nor the author(s)/ editor(s) assume any liability for any injury and/or damage to persons or property arising from or related to use of material in this book. This book is sold on the understanding that the publisher is not engaged in providing professional medical services. If such advice or services are required, the services of a competent medical professional should be sought. Every effort has been made where necessary to contact holders of copyright to obtain permission to reproduce copyright material. If any have been inadvertently overlooked, the publisher will be pleased to make the necessary arrangements at the first opportunity. Inquiries for bulk sales may be solicited at: [email protected] Contemporary Topics in Gestational Diabetes Mellitus First Edition:  2015 ISBN: 978-93-5152-372-7 Printed at

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Dedicated to I dedicate this book to my wife Mrs Jano Seshiah, Dr Vijayam Balaji, Dr Madhuri Balaji, Dr Puvi Seshiah, and Radhika Radhakrishnan for their constant encouragement in my academic pursuits and also my mentor Professor Sam G Moses

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Contents Contributors xi Preface xv 1. Hyperglycemia during Pregnancy: Epidemiology and Public Health Relevance

1

Anil Kapur

2. Hormono-metabolic Adaptations in Pregnancy

11

Subhash K Wangnoo

3. Pathogenesis of Gestational Diabetes Mellitus

18

Sudip Chatterjee

4. Overweight, Obesity, and Gestational Diabetes Mellitus

25

David A Sacks

5. Current Status in Diagnosing Gestational Diabetes Mellitus

32

Veeraswamy Seshiah, Hema Divaker

6. Gestational Diabetes Mellitus: Rationale for Screening Glucose Tolerance in Early Weeks of Pregnancy

42

Vijayam Balaji, Madhuri Balaji

7. Glycemic Targets and Assessing Glycemic Control in Pregnant Diabetic

49

Hemraj B Chandalia

8. Medical Nutrition Therapy in Gestational Diabetes Mellitus

56

Navneet Magon, Savitha Padmanabhan, Veeraswamy Seshiah

9. Oral Hypoglycemic Agents in Gestational Diabetes Mellitus: Current Status

67

Denice S Feig

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10. Insulin in Pregnancy Diabetes

77

Sunil S Gupta

11. Continuous Glucose Monitoring in Diabetic Pregnancy: Is it Necessary or Optional?

93

Banshi D Saboo, Praful A Talaviya

12. Bariatric Surgery in Women of Childbearing Age

110

Shyam S Kalavalapalli, Akheel A Syed

13. Psychosocial Aspects of Diabetes in Pregnancy

117

Bharti Kalra

14. Long-term Implications for Offsprings of Mothers with Gestational Diabetes Mellitus

124

Tine D Clausen, Liv Borch-Johnsen, Elisabeth R Mathiesen, Peter Damm

15. Neonatal Aspects of Gestational Diabetes Mellitus

135

Ranjan K Pejaver, Maneesha Halkar

16. Immunology and Inflammation in Gestational Diabetes Mellitus

156

Chengjun Sun, Sanjeevi B Carani

17. Maternal Obesity: Short and Long-term Consequences and Intervention in Pregnancy

164

Per Ovesen, Matte Tanvig, Ditte D Iversen, Christina A Vinter

18. Gestational Diabetes Mellitus: Can The Obstetrician Make A Difference?

176

Susheela Rani

19. Gestational Diabetes Mellitus: Risks and Treatment

194

Per Ovesen, Charlotte Wolff, Gitte O Skajaa, Dorte M Jensen

20. Thyroid Disorders in Pregnancy

201

Rakesh K Sahay, Sri Nagesh V

21. Gestational Diabetes Mellitus and Metabolic Syndrome

211

Sidhartha Das, Manoranjan Behera

22. Metabolic Syndrome: Perils for Pregnancy and Precursor for Childhood Obesity

222

Shailini Singh

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ix

Contents

23. Lifestyle Interventions during Pregnancy, Why They have Limited Success: Too Little Too Late

235

Patrick M Catalano, Sylvie Hauguel-deMouzon

24. Factors Predicting the Development of Type 2 Diabetes Mellitus in Women with Prior Gestational Diabetes Mellitus and Action Plan for Prevention

245

Yashdeep Gupta, Sanjay Kalra

25. Postpartum Care and Breastfeeding in Gestational Diabetes Mellitus, Benefits for Mother and Baby

263

Smiti Nanda, Sanjiv Nanda

Appendix A: North Indian Diet Charts for Women with Gestational Diabetes Mellitus 269 Appendix B: South Indian Diet Charts for Women with Gestational Diabetes Mellitus 273 Appendix C: Glycemic Index of Common Indian Foods 276 Appendix D: Food Exchange List 278 Appendix E: Calorie Reckoner of Common Indian Food Items 283 Index

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Contributors EDITOR Veeraswamy Seshiah MD FRCP DSc Chairman Dr V Seshiah Diabetes Research Institute Dr Balaji Diabetes Care Centre Chennai 600 029, Tamil Nadu, India

CONTRIBUTORS Madhuri Balaji MB Fellow in Diabetology Consultant Diabetologist Dr Balaji Diabetes Care Centre and Dr V Seshiah Diabetes Research Institute Chennai 600 029, Tamil Nadu, India Vijayam Balaji MD FRCP (Glas) FRCP (Edin) FRCP (Lon)

Director and Senior Consultant Diabetologist Dr Balaji Diabetes Care Centre and Dr V Seshiah Diabetes Research Institute Chennai 600 029, Tamil Nadu, India Manoranjan Behera MD Assistant Professor P.G. Department of Medicine S.C.B. Medical College and Hospital Cuttack 753007, Odisha, India Liv Borch-Johnsen Bsc Medical Student Faculty of Health and Medical Sciences University of Copenhagen Copenhagen, Denmark

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Sanjeevi B Carani MD PhD Associate Professor Department of Medicine Karolinska Hospital, Karolinska Institute Solna, SE-17176 Stockholm, Sweden Patrick M Catalano MD Professor of Reproductive Biology Case Western Reserve University Metrohealth Medical Center Cleveland, Ohio 44109, USA Hemraj B Chandalia MD FACP Director, Diabetes Endocrine Nutrition Management and Research Center Director, Endocrinology, Diabetes and Metabolism Jaslok Hospital and Research Center Mumbai 400 021, Maharashtra, India Sudip Chatterjee MD MNAMS FRCP FACP Professor Department of Endocrinology Vivekananda Institute of Medical Sciences Honorary Secretary of Park Clinic Kolkata, West Bengal, India

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Tine D Clausen MD PhD Department of Gynecology and Obstetrics Nordsjællands Hospital – Hillerød Faculty of Health and Medical Sciences University of Copenhagen Dyrehavevej 29, 3400 Hilleroed, Denmark Peter Damm DMSc MD Professor, Department of Obstetrics Center for Pregnant Women with Diabetes Rigshospitalet, University of Copenhagen Copenhagen, Denmark Sidhartha Das MD FRCP (Glas) FRCP (Edin) Senior Most Professor P.G. Department of Medicine S.C.B.Medical College and Hospital Cuttack 753 007, Odisha, India Hema Divaker DGO MD FICPS PGDMLE FRCOG Chairman and CEO – Obstetrics and Gynecology Divakars Speciality Hospital Bangalore, Karnataka 560 078, India Denice S Feig MD MSc FRCPC Associate Professor University of Toronto Head Diabetes and Pregnancy Program, Mount Sinai Hospital Toronto, Ontario, Canada Sunil S Gupta MD FICP FIAMS FIAM Director Sunil’s Diabetes Care and Research Center Pvt. Ltd Nagpur 440 010, Maharashtra, India Yashdeep Gupta MD DM Assistant Professor Department of Endocrinology Government Medical College and Hospital Sector 32, Chandigarh 160 030, India

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Maneesha Halkar DNB Fellowship in Neonatology

Consultant Neonatologist Meenakshi Hospitals Bengaluru, Karnataka, India Sylvie Hauguel-deMouzon PhD Professor of Reproductive Biology Case Western Reserve University Metrohealth Medical Center Cleveland, Ohio 44109, USA Ditte D Iversen Medical Student Department of Gynecology and Obstetrics Aarhus University Hospital Skejby, 8200 Aarhus N, Denmark Dorte M Jensen MD PhD Consultant, Assistant Professor Department of Endocrinology Odense University Hospital DK-5000 Odense C, Denmark Shyam S Kalavalapalli MRCP FRCP CCT MRCP

Head of Department Department of Endocrinology KIMS Hospital Bengaluru, Karnataka 560 004, India Bharti Kalra MD Cert Diab Consultant Department of Obstetrics Bharti Hospital & BRIDE Karnal 132 001, Haryana, India Sanjay Kalra MD DM Consultant Department of Endocrinology Bharti Hospital Karnal 132 001, Haryana, India Anil Kapur MD Director World Diabetes Foundation Bangalore 560 066, Karnataka, India

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Contributors

Navneet Magon MS Head of Department Department of Obstetrics and Gynecology Air Force Hospital Jorhat 785 005, Assam, India Elisabeth R Mathiesen DMSc MD Department of Endocrinology Center for Pregnant Women with Diabetes Rigshospitalet, University of Copenhagen Copenhagen, Denmark Sri Nagesh V MD DM Consultant Endocrinologist CARE Hospitals Hyderabad, Telangana, India Sanjiv Nanda MD Professor Department of Pediatrics Pandit Bhagwat Dayal Sharma Postgraduate Institute of Medical Sciences Rohtak 124 001, Haryana, India Smiti Nanda MD Professor and Head Department of Obstetrics and Gynecology Pandit Bhagwat Dayal Sharma Postgraduate Institute of Medical Sciences Rohtak 124 001, Haryana, India Per Ovesen MD DMSc Consultant, Assistant Professor Department of Obstetrics and Gynecology Aarhus University Hospital Skejby, 8200 Aarhus N, Denmark Savitha Padmanabhan MSc MPhil (PhD) Consultant Nutritionist Dr V Seshiah Diabetes Research Institute Dr Balaji Diabetes Care Centre Chennai 600 029, Tamil Nadu, India

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Ranjan K Pejaver FRCPI FRCPCH Professor of Neonatology Kempegowda Institute of Medical Sciences Bengaluru, Karnataka 560 004, India Senior Consultant Neonatologist, Meenakshi Hospitals Bengaluru, Karnataka, India Susheela Rani MD PGDMLE FICOG Consultant and Director Manjushree Speciality Hospital Bangalore 560 042, Karnataka, India Banshi D Saboo MD FICP FICN MNAMS Diabetologist and Metabolic Physician DiaCare: Diabetes Care & Hormone Clinic Ahmedabad 380 015, Gujarat, India David A Sacks MD Associate Investigator Department of Research and Evaluation Kaiser Permanente Southern California Pasadena, California, USA Rakesh K Sahay MD DNB DM Professor Department of Endocrinology Osmania Medical College Hyderabad 500 095, Telangana, India Shailini Singh MBBS FRCS FACOG Professor of Gynecology and Obstetrics University at Buffalo, The State University of New York Buffalo 14221, New York, USA Gitte O Skajaa MD PhD Student Department of Obstetrics and Gynecology Aarhus University Hospital Skejby, 8200 Aarhus N, Denmark Chengjun Sun md PhD Student, Department of Medicine Karolinska Hospital, Karolinska Institute Solna, SE-17176 Stockholm, Sweden

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Akheel A Syed MBBS MRCP CCT PhD FRCP Consultant Endocrinologist Department of Diabetes and Endocrinology Salford Royal NHS Foundation Trust & University Teaching Hospital Salford M6 8HD, United Kingdom Praful A Talaviya MPH PhD Pharmacologist DiaCare: Diabetes Care & Hormone Clinic Ahmedabad 380 015, Gujarat, India Mette Tanvig MD Medical Doctor Department of Gynecology and Obstetrics Odense University Hospital 5000 Odense C, Denmark

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Christina A Vinter MD PhD Post-doctoral Fellow Department of Gynecology and Obstetrics Odense University Hospital 5000 Odense C, Denmark Subhash K Wangnoo MD DM FRCP Senior Consultant Apollo Hospitals New Delhi, India Charlotte Wolff RD Department of Obstetrics and Gynecology Aarhus University Hospital Skejby, 8200 Aarhus N, Denmark

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Preface The uniqueness of diabetes and pregnancy is that it involves many specialties like obstetrics, diabetology, neonatology, epidemiology, etc. Diabetes and pregnancy includes known diabetics conceiving, pregestational diabetes and carbohydrate intolerance detected first time in pregnancy, gestational diabetes mellitus. The global prevalence of hyperglycemia in pregnant women (20–49 years) is 16.9% or 21.4 million live births in 2013. The highest prevalence was found in the South-East Asia region at 25.0% compared with 10.4% in the North America and Caribbean region. More than 90% cases of hyperglycemia in pregnancy are estimated to occur in low- and middle-income countries. Indian women have 11-fold increased risk of developing glucose intolerance during pregnancy compared to Caucasian women. Among ethnic groups in South Asian countries, Indian women have the highest frequency of gestational diabetes mellitus. The concern is, gestational diabetes mellitus represents detection of chronic beta cell dysfunction and is a stage in the evolution of type 2 diabetes mellitus. The implication is, women with a history of gestational diabetes mellitus are at increased risk of future diabetes; predominantly type 2 diabetes, as are their children, intrageneration transmission occurs. Now gestational diabetes mellitus has become a public health priority issue as gestational diabetes mellitus may play a crucial role in increasing the prevalence of diabetes and obesity. Preventive measures against type 2 diabetes mellitus should start during intra uterine period and continued throughout life from early childhood. Gestational diabetes mellitus offers an important opportunity for the development of methods for diagnosing gestational diabetes mellitus and implementation of clinical strategies for diabetes prevention. Hence we need to “focus on the fetus for the future” in our endeavor to contain the epidemic of diabetes. It is understandable that timely action taken now in screening all pregnant women for glucose intolerance, achieving euglycemia in them and ensuring adequate nutrition may prevent in all probability the vicious cycle of transmitting glucose intolerance from one generation to another. The chapters in this book Contemporary Topics in Gestational Diabetes Mellitus are like pearls threaded together. Each topic has important bearing in care of women diagnosed to have gestational diabetes mellitus. The topics deal from basics to bedside practice and are of extreme clinical importance. I sincerely thank every author and acknowledge their support for willingly contributing their best and sharing their rich experiences. I  must admit in all humility, but for the timely contribution of these experts, this book would not have taken this shape.

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I appreciate the encouragement given by Jaypee Brothers Medical Publishers (P) Ltd. to edit this book. I would feel happy and served the purpose if this book is accepted by my professional colleagues. I acknowledge the valuable input given by Professor Vijayam Balaji, Medical Director and Senior Consultant, Dr V Seshiah and Dr Balaji Diabetes Care Centre and Research Institute. Mention has to made about secretarial support by Mr. Mohammed Jaffar.

Veeraswamy Seshiah

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Hyperglycemia during Pregnancy: Epidemiology and Public Health Relevance

1 Anil Kapur

INTRODUCTION Cardiovascular diseases (CVDs), diabetes, cancers, and chronic respiratory diseases are the most common noncommunicable diseases (NCDs), accounting for 63% of global deaths (36 million) in 2008 and projected to claim 52 million lives by 2030. Almost 80% of these deaths occur prematurely in low- or middle-income countries.1 NCDs become burdensome, costly, and debilitating over time, negatively impacting productivity and family income. In addition, these diseases create a poverty trap as well as reduce chances of preventing escape from it. The World Economic Forum has for 2 years in a row rated chronic diseases amongst the five top threats to the Global Economy including in the low- and middle-income countries.2 The global community is beginning to understand the enormity of the humanitarian, societal, and economic challenge of NCDs as evidenced by the political declaration from the high-level meeting (HLM) of the United Nations (UN) General Assembly on the Prevention and Control of NCDs, New York, 2011.3 When faced with a challenge of this magnitude, we need to carefully consider where we can make the greatest immediate and long-term impact to eventually break the curve of the NCD epidemic. Up to 80% of the NCD burden can be prevented by addressing the common risk factors of tobacco use, unhealthy diet including excessive use of alcohol and physical inactivity—interventions targeting adults at high risk—a strategy fraught with implementation difficulties.4 LINKS BETWEEN MATERNAL HEALTH AND NONCOMMUNICABLE DISEASES Mounting body of evidence from high-quality research shows that prenatal and early-life development through epigenetic programming influences the risks of NCD in later life5-9 and this might be, especially relevant to low-resource countries.9-12 Parent’s health particularly the mother’s diet, body composition, and metabolic status during pregnancy determine fetal environment and affect risk for later NCDs.13,14 Early intervention to ensure healthy pregnancy, safe delivery, and disease-free early childhood may, therefore, be the most effective means of attaining best future health and preventing NCDs. Fetal environment determines whether one starts life with a “health head start” or a “health handicap” because it is on this foundation that risk factors play out in later life. People starting life with a “health handicap” may be less able to withstand lifestyle risks and prone to develop

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disease early compared to those starting with a “health advantage”. Similarly, lifestyle interventions in adult life to prevent diseases may have variable effects based on early-life programming.15 The impact of life conditions on health—the social determinants of health is high on the global development agenda, and it is relevant to consider that these determinants get hard wired into the genome of the next generation through epigenetic changes during fetal life. The recognition of early-life influences on chronic diseases, however, does not imply deterministic processes that cannot be overcome by later-life intervention; only that the task becomes more difficult. In the last one and half decades, a lot of attention and resources have been provided to Maternal and Child Health Programs, especially in the developing world. In order to optimize these resources, Maternal and Child Health Programs have taken the straight and narrow path of focusing on factors that directly lead to maternal, neonatal and infant mortality. These laudable efforts have led to improvements in access to maternity services in many low- and middle-income countries and to improved survival for even the “at risk” small for gestational age (SGA) babies born to undernourished mothers in rural settings and to substantial improvements in both measures with more infants and mothers surviving. Unfortunately this narrow biomedical focus has failed to address the social determinants, or the root causes of mortality; moreover, the very individuals saved—the low-birth-weight babies or babies surviving obstructed and difficult deliveries are the ones that have the highest risk of future ill health both from communicable and noncommunicable diseases at an early stage of life. Focusing on early survival might not capture outcomes that have long-term implications for adult health, life expectancy, quality of life, and accumulation of human capital.15 Further, recommendations for nutritional interventions are frequently based on raising birth weight, focusing on gains in stature, or micronutrient status in the short-term.16 Long-term follow-up data confirm the existence of a narrow window of opportunity for intervention up to 24 months of age, and only limited benefit, or even harm, of feeding strategies thereafter.17,18 These small babies continuing to be malnourished and stunted during childhood and early adult life, will remain at relatively low risk for NCDs as long as they have subsistence living. With changes in living conditions as a consequence of economic development or urban migration, these individuals manifest diabetes and other NCDs at much lower body mass index (BMI) and central adiposity threshold.19,20 Studies on survivors of the Dutch21,22 and Chinese23 famine show that individuals exposed to intrauterine under nutrition had significantly higher rates of diabetes in adult life and the risk was highest in the subgroup that were relatively well off in adult life. Developmental effects operate through a gamut of subtle influences which provide the fetus the cues (via the intrauterine environment) to predict the external environment it will be born into; as well as the flexibility to adjust its growth trajectory to match that environment. Termed as developmental plasticity, these influences operate through epigenetic changes24,25 across the entire range of environment, from under nutrition to excessive nutritional environments associated with gestational diabetes mellitus (GDM) or maternal obesity,26,27 or other maternal health insults like malaria, human immunodeficiency virus (HIV)/ acquired immunodeficiency syndrome (AIDS), etc. leading to multigenerational cycles of disease.28 The mismatch between the predicted environment for survival

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programming and the actual environment in adult life may be a critical factor driving the type 2 diabetes and obesity epidemic. In young women, themselves born small, the effects of pregnancy-induced weight gain, insulin resistance, and increased insulin requirements are exaggerated by the preexisting insulin resistance and the lower ability to produce insulin as a consequence of early-life programming, resulting in higher rates of GDM and/or pregnancy-induced hypertension. Seshiah et al.29 reported prevalence rates of 8–10% for GDM among women of low socioeconomic status who had a prepregnancy BMI of less than 19. Undiagnosed or poorly managed GDM sets off a cycle of future obesity and type 2 diabetes in the offsprings and the cycle may repeat in subsequent generations with ever growing risk accumulation. Compared to a decade ago, in nearly all parts of the world, the number of women of reproductive age who are overweight now exceeds the number of women who are underweight.30 The rising level of overweight and obesity amongst women of reproductive age makes them even more vulnerable to GDM than their mothers. Between 1999 and 2005, age, race, and ethnicity adjusted prevalence of pre-GDM amongst pregnant women in southern California doubled.31 Over the last 20 years, the age of onset of diabetes has been declining; at the same time the age of marriage and child bearing is increasing; as a consequence in the future we may see more women entering pregnancy with preexisting diabetes.1,32 Offsprings of mothers with uncontrolled diabetes, either preexisting or originating, during pregnancy are 4–8 times more likely to develop diabetes themselves in later life33,34 compared to their siblings born to the same parents in a non-GDM pregnancy. This shows that the uterine environment contributes significantly to the higher risk for diabetes than can be explained by genetic inheritance alone. A recent study suggests that a significant proportion (47.2%) of diabetes and obesity in the youth can be attributed to maternal GDM and obesity.35 Another study suggests that GDM may be responsible for 19–30% of all type 2 diabetes seen among Saskatchewan First Nations people in Canada.36 GDM thus creates a vicious cycle in which diabetes begets more diabetes. According to the International Diabetes Federation (IDF), Diabetes Atlas, 6th edition,37 there are now an estimated 382 million people (184 million women) with diabetes. In addition, there are about 316 million with prediabetes. The number is likely to grow to over 592 million people with diabetes and almost 471 million with prediabetes by 2035. Asia-pacific region is at the center of this rising trend for diabetes and accounts for about half the global burden with China, India, Indonesia, Pakistan, and Bangladesh figuring amongst the top ten countries with the highest number of people with diabetes.37 HYPERGLYCEMIA DURING PREGNANCY AND ITS CONSEQUENCES Worldwide, one in six pregnancies may be associated with hyperglycemia, 84% of which involve GDM.37 The IDF estimates that 21.4 million out of the 127 million live births, i.e., 16.8% of live births in 2013 were associated with hyperglycemia in pregnancy. An estimated 16% of those cases were due to diabetes in pregnancy. This does not take into account the number of pregnancies ending in spontaneous abortions, still births, or intrauterine deaths that may have been associated with

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hyperglycemia proven or otherwise. In South-East Asia, one in four live births may occur in the setting of maternal hyperglycemia during pregnancy.37 In high-risk groups, up to 30% of pregnancies may involve diabetes.38,39 The age-adjusted prevalence of GDM in women in United States shows that the rates are higher for women with Asian or Pacific Island origin, but more so (almost threefold compared to non-Hispanic whites) for migrant women born in the country of their origin.36 A staggering 91.6% of cases of hyperglycemia in pregnancy are in low- and middleincome countries, where access to maternal care is often limited.37 The prevalence of hyperglycemia in pregnancy increases rapidly with age and is the highest in women over the age of 45 years (47.7%), although there are fewer pregnancies in that age group. This explains why just 23% of global cases of hyperglycemia in pregnancy occurred in women over the age of 35 years, even though the risk of developing the condition is higher in these women.37 In 2010, there were an estimated 22 million women with diabetes in the reproductive age-group of 20–39 years; an additional 54 million in this age-group had impaired glucose tolerance (IGT) or prediabetes with potential to develop GDM if they become pregnant.40 Thus, over 76 million women are at risk of their pregnancy being complicated with pregestational (existing) diabetes or GDM. Hemorrhage, hypertensive disorders, obstructed labor, and infection/sepsis are among the leading global causes of maternal mortality.41 High blood pressure and gestational hyperglycemia are linked directly or indirectly to all of them. According to WHO’s report on women and health, high blood pressure and high blood glucose are two leading risk factors for death from chronic conditions in women above 20 years of age,42 yet women are not routinely screened for hyperglycemia during pregnancy and the diagnosis of GDM is often missed; maternal mortality and morbidity attributable to diabetes in women may, therefore, be actually higher than current estimates. Diabetes in pregnancy is associated with serious complications for both the mother and child. It has been shown that the negative consequences on the fetus and the mother increase linearly with increasing maternal blood glucose. 43 It is now recognized that a proportion of women diagnosed during pregnancy may have had diabetes before pregnancy (type 1 or type 2), also called pre-GDM. Infants of mothers with pre-GDM have higher rates of malformation.44-46 Good bloodglucose control before conception and throughout pregnancy reduces these risks substantially.47,48 Major problems related to hyperglycemia during pregnancy are shown in table 1. Several markers, such as age, race/ethnicity, BMI, history of type 2 diabetes in first-degree relatives, history of GDM, macrosomia, unexplained stillbirth, spontaneous abortion in previous pregnancies, excessive weight gain, presence of polycystic ovary syndrome, metabolic syndrome, polyhydramnios, and suspected macrosomia during current pregnancy, have been described to clinically identify women with high risk of GDM;49 in practice, they fail to correctly identify more than half the women with GDM;50-53 thus universal screening for hyperglycemia during pregnancy must be the standard practice. Women diagnosed with GDM—are at high risk of developing type 2 diabetes within a few years of the pregnancy compared to women without previous history of GDM. A meta-analysis shows that women with GDM had an increased risk of developing type 2 diabetes [relative risk (RR) = 7.43; 95% confidence interval

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Table 1: Risks associated with hyperglycemia in pregnancy Fetal risks

Maternal risks

• Spontaneous abortion, intrauterine death, and still birth • Lethal or handicapping congenital malformation • Shoulder dystocia and birth injury • Neonatal hypoglycemia • Infant respiratory distress syndrome

• Polyhydramnios • Pregnancy-induced hypertension and preeclampsia • Prolonged/obstructed labor-assisted delivery and Caesarean section • Uterine atonia and postpartum hemorrhage • Infections • Progression of retinopathy

(CI) = 4.79–11.51]. Women within 5 years of a pregnancy complicated by GDM had a RR of 4.69, which is more than doubled to 9.34 in those who were examined more than 5 years postpartum.54 The risk can be considerably reduced or the onset of diabetes considerably delayed by taking appropriate preventive steps in terms of postpartum weight loss and a healthy lifestyle.55 Evidence is now emerging that women with past history of GDM also have a higher prevalence of the metabolic syndrome and an increased risk of CVD. In the years following a GDM pregnancy, women exhibit an enhanced cardiovascular risk profile and ultimately an increased incidence of CVD.56 Over a median follow-up of 12.3 years women with GDM had a higher risk of CVD [adjusted hazard ratio (HR)  = 1.66; 95% CI = 1.30–2.13, p < 0.001].57 In another study over a 10-year follow-up period, after adjusting for age, ethnicity and comorbidities, such as preeclampsia and obesity, women with history of GDM had higher rates of cardiovascular morbidity including noninvasive cardiac diagnostic procedures [odds ratio (OR) = 1.8; 95% CI = 1.4–2.2], simple cardiovascular events (OR = 2.7; 95% CI = 2.4–3.1), and total cardiovascular hospitalizations (OR = 2.3; 95% CI = 2.0–2.5).58 Without screening and diagnosis in pregnancy, the possibility of reducing risk in these women will be missed and in view of the dramatic increase in obesity and diabetes, we should accept that diagnosing and treating GDM is worthwhile.59 Sceptics, however, continue to question whether screening women for GDM is costeffective. Most cost effectiveness analysis in the past have only assessed benefits related to immediate pregnancy outcomes and not included long-term benefits.60 A few recent studies show that GDM screening associated with postpartum lifestyle interventions for type 2 diabetes prevention is cost-effective in both high-income countries (United States, Israel) and low-income countries (India).61-63 The concept of fetal programming and its consequences is paradigm changing. It highlights that pregnancy offers a window of opportunity to provide maternal care services, not only to reduce the traditionally known maternal and perinatal morbidity and mortality indicators, but also for intergenerational prevention of several chronic diseases, such as diabetes, arterial hypertension, CVD, and stroke. Thus, with one high-quality intervention related to maternal and child health services, it is now possible to achieve several objectives with far reaching health and economic benefits.39 There are several barriers in achieving these objectives. These have been recently studied through a systematic review.64 Knowledge of and adherence to existing

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GDM guidelines and procedure for screening and diagnosis seem suboptimal at best and arbitrary at worst, with no clear or consistent correlation to health provider, health system or client characteristics. Most women express commitment and motivation for behavior change to protect the health of their unborn baby, but knowledge about how to change is missing. Compliance to recommended treatment and advice is seen challenging and precious little is known about health system or societal factors that hinder compliance and what can be done to improve it. Immediately following a GDM pregnancy, many women when properly informed desire and intend to maintain healthy lifestyles to prevent future diabetes but find the effort challenging. Adherence to recommended postpartum screening and continued lifestyle modifications seems even lower. Here, some healthcare provider, health system and client related determinants and barriers have been identified. Studies reveal that sense of self-efficacy and social support is important. Noncompliance to screening or nonacceptance of diagnosis of GDM may be due to poor understanding of the consequences or fear of stigmatization and one needs to be careful not to create another platform for women to be blamed for adverse effects on their children’s future health. POLICY RECOMMENDATIONS What can be recommended as a public health approach for GDM? The recommendations made at the symposium “Diabetes – A Missing Link to Achieve Sexual and Reproductive Health in Asia-Pacific Region” at the 6th Asia-Pacific Conference on Sexual and Reproductive Health and Rights held in Yogyakarta, Indonesia65 aptly sum up the issue. • Building awareness: Considering the magnitude of the problem, the seriousness of the consequences and the opportunity for improving health that it offers, raising awareness of the risks and consequences of diabetes in women including GDM must be given top priority. Awareness needs to be heightened amongst future mothers, general public, health professionals, and policy makers not only about the specific issue, but also about the importance of good health of women in general and during pregnancy, in particular • Advocacy: Ensure due attention is accorded to diabetes among women including GDM and program interventions are put in place. There are several platforms that provide the opportunity for advocacy. These include: – The International Conference on Population and Development (ICPD, 1994) recommendations, one of which was “all countries should strive to make accessible through the primary healthcare (PHC) system, reproductive health to all individuals of appropriate age, as soon as possible and no later than 2015.” – Millennium Development Goals (MDGs): Although diabetes is not a specific goal in the MDGs, countries are encouraged to implement programs for achieving MDGs according to their own needs and situations, and indeed the issue can clearly be taken up under MDG 5, “improve maternal health”. Besides MDG 5, the management of GDM and diabetes in women, in general, will also contribute to MDG 4 (child survival) and MDG 3 (gender equality).

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Hyperglycemia during Pregnancy: Epidemiology and Public Health Relevance

•

•

•

– The Global Reproductive Health Strategy endorsed by the World Health Assembly in 2004, calls for strengthening and ensuring access to reproductive health and for reducing maternal morbidity and mortality. Again although specific mention of diabetes is not made, the strategies to improve reproductive health will have to take into account all matters that affect sexual and reproductive health, such as diabetes and GDM. – The Political Declaration at the UN HLM in September 2011 and the report of the UN Secretary General to the General Assembly before the UN HLM on NCDs. This report clearly states the need to create linkages between NCDs and Maternal and Child Health Programs. The report also raises concern that the rising prevalence of high blood pressure and GDM is increasing adverse outcomes of pregnancy and maternal health.3 Mainstreaming or integrating diabetes into Sexual and Reproductive Health and Rights Agenda: This is crucial in building and sustaining action—managers and providers of reproductive health services are in an advantageous position to integrate diabetes into their programs. There is need to systematically deliberate on appropriate interventions. A fitting beginning would be making policies for all pregnant women, with priority to high-risk women, to be tested for diabetes and to take the appropriate follow-up actions. In many developing countries where the problem of GDM is significant and requires intervention and health systems are weak, it may call for concerted efforts among international development partners to provide support. To get it right will require strengthening of health systems to further reinforce maternal and child care services at primary care level and integrating elements of NCD prevention and health promotion.66 Using information technology: Having saved a mother with GDM with preeclampsia from dying of obstructed labor or postpartum hemorrhage and her large-for-gestational age baby; or a mother with severe malnutrition and anemia and her low-birth-weight baby, what can be done to ensure their future good health and prevent or significantly delay the onset of hypertension or type 2 diabetes? This will require integration of services and cost effective investments in information technology to identify and track highrisk individuals to enlighten, empower, and encourage them to adopt healthy living throughout life as well as empowering local community health workers to support and follow their progress. Enrolling, monitoring, and tracking GDM mothers during and after the pregnancy and their offsprings using information technology may be the most appropriate place to begin this health system transformation.68 Operational research: Evidence generation through pilot programs is urgently needed to provide answers to several questions regarding policy formulation, program planning, and implementation.

REFERENCES 1. World Health Organization. (2011). Global status report on noncommunicable diseases 2010: Description of the global burden of NCDs, their risk factors and determinants. [online] Available from: www.who.int/nmh/publications/ncd_report2010/en/. [Accessed AprilJanuary, 2014].

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Contemporary Topics in Gestational Diabetes Mellitus 2. Bloom DE, Cafierio ET, Jane-Llopis E, et al. (2012). The Global Economic Burden of Noncommunicable Diseases (Geneva, World Economic Forum 2011). [online]. Available from: www.hsph.harvard.edu/pgda/WorkingPapers/2012/PGDA_WP_87.pdf. [Accessed January, 2014]. 3. United Nations General Assembly. (2011). Prevention and control of non-communicable diseases: Report of the Secretary-General. [online] Available from: www.un.org/ga/search/ view_doc.asp?symbol=A/66/83&referer=/english/&Lang=E. [Accessed January, 2014]. 4. Hanson MA, Gluckman PD. Developmental origins of noncommunicable disease: population and public health implications. Am J Clin Nutr. 2011;94(6 Suppl):1754S-8S. 5. Gluckman PD, Hanson MA, Beedle AS. Non-genomic transgenerational inheritance of disease risk. Bioassays. 2007;29(2):145-54. 6. Gluckman PD, Hanson MA, Spencer HG, et al. Environmental influences during development and their later consequences for health and disease: implications for the interpretation of empirical studies. Proc Biol Sci. 2005;272(1564):671-7. 7. Godfrey KM. Maternal regulation of fetal development and health in adult life. Eur J Obstet Gynecol Reprod Biol. 1998;78(2):141-50. 8. McCance DR, Pettitt DJ, Hanson RL, et al. Birth weight and non-insulin dependent diabetes: thrifty genotype, thrifty phenotype, or surviving small baby genotype? BMJ. 1994;308(6934):942-5. 9. Gluckman PD, Hanson MA, Cooper C, et al. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med. 2008;359(1):61-73.. 10. Yajnik CS, Deshmukh US. Maternal nutrition, intrauterine programming and consequential risks in the offspring. Rev Endocr Metab Disord. 2008;9(3):203-11. 11. Ma RC, Chan JC. Pregnancy and diabetes scenario around the world: China. Int J Gynaecol Obstet. 2009 Mar;104( Suppl 1):S42-5. 12. Tam WH, Ma RC, Yang X, et al. Glucose intolerance and cardio-metabolic risk in children exposed to maternal gestational diabetes mellitus in utero. Pediatrics. 2008;122(6):1229-34. 13. Bateson P. Fetal experience and good adult design. Int J Epidemiol. 2001;30(5):928-34. 14. Kuzawa CW. Fetal origins of developmental plasticity: are fetal cues reliable predictors of future nutritional environments? Am J Hum Biol. 2005;17(1):5-21. 15. Gluckman PD, Hanson MA, Bateson P, et al. Towards a new developmental synthesis: adaptive developmental plasticity and human disease. Lancet. 2009;373(9675):1654-7. 16. Rivera JA, Sotres-Alvarez D, Habicht JP, et al. Impact of the Mexican program for education, health, and nutrition (Progresa) on rates of growth and anemia in infants and young children: a randomized effectiveness study. JAMA. 2004;291(21):2563-70. 17. Victora CG, Adair L, Fall C, et al. Maternal and child under nutrition: consequences for adult health and human capital. Lancet. 2008;371(9609):340-57. 18. Stein AD, Wang M, Ramirez-Zea M, et al. Exposure to a nutrition supplementation intervention in early childhood and risk factors for cardiovascular disease in adulthood: evidence from Guatemala. Am J Epidemiol. 2006;164(12):1160-70. 19. Ramachandran A, Snehalatha C, Baskar AD, et al. Temporal changes in prevalence of diabetes and impaired glucose tolerance associated with lifestyle transition occurring in the rural population in India. Diabetologia. 2004;47(5):860-5. 20. Snehalatha C, Ramachandran A. Cardiovascular risk factors in the normoglycaemic AsianIndian population—influence of urbanisation. Diabetologia. 2009;52(4):596-9. 21. Ravelli AC, van der Meulen JH, Michels RP, et al. Glucose tolerance in adults after prenatal exposure to famine. Lancet. 1998;351(9097):173-7. 22. de Rooij SR, Painter RC, Roseboom TJ, et al. Glucose tolerance at age 58 and the decline of glucose tolerance in comparison with age 50 in people prenatally exposed to the Dutch famine. Diabetologia. 2006;49(4):637-43. 23. Li Y, He Y, Qi L, et al. Exposure to the Chinese famine in early life and the risk of hyperglycemia and type 2 diabetes in adulthood. Diabetes. 2010;59(10):2400-6. 24. Goldberg AD, Allis CD, Bernstein E. Epigenetics: a landscape takes shape. Cell. 2007;128(4): 635-8.Cell 128:

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Hyperglycemia during Pregnancy: Epidemiology and Public Health Relevance 25. Burdge GC, Hanson MA, Slater-Jeffries JL, et al. Epigenetic regulation of transcription: a mechanism for inducing variations in phenotype (fetal programming) by differences in nutrition during early life? Br J Nutr. 2007;97(6):1036-46. 26. Armitage JA, Poston L, Taylor PD. Developmental origins of obesity and the metabolic syndrome: the role of maternal obesity. Front Horm Res. 2008;36:73-84. 27. Gluckman PD, Hanson MA, Beedle AS, et al. Fetal and neonatal pathways to obesity. Front Horm Res. 2008;36:61-72. 28. Fall CH. Non-industrialised countries and affluence. Br Med Bull. 2001;60:33-50. 29. Seshiah V, Balaji V, Balaji MS, et al. Pregnancy and diabetes scenario around the world: India. Int J Gynaecol Obstet. 2009;104( Suppl 1):S35-8. 30. Mendez MA, Monteiro CA, Popkin BM. Overweight exceeds underweight among women in most developing countries. Am J Clin Nutr. 2005;81(3):714-21. 31. Lawrence JM, Chen W, Contreras R, et al. Trends in the prevalence of pre-existing diabetes and gestational diabetes mellitus among a racially/ethnically diverse population of pregnant women, 1999-2005. Diabetes Care. 2008;31(5):899-904. 32. Matyka KA. Type 2 diabetes in childhood: epidemiological and clinical aspects. Br Med Bull. 2008;86:59-75. 33. Damm P. Future risk of diabetes in mother and child after gestational diabetes mellitus. Int J Gynaecol Obstet. 2009;104( Suppl 1):S25-6. 34. Clausen TD, Mathiesen ER, Hansen T, et al. High prevalence of type 2 diabetes and pre-diabetes in adult offspring of women with gestational diabetes mellitus or type 1 diabetes: the role of intrauterine hyperglycemia. Diabetes Care. 2008;31(2):340-6. 35. Dabelea D, Mayer-Davis EJ, Lamichhane AP, et al. Association of intrauterine exposure to maternal diabetes and obesity with type 2 diabetes in youth. The SEARCH Case-Control Study. Diabetes Care. 2008;31(7):1422-6. 36. Osgood ND, Dyck RF, Grassmann WK. The inter- and intragenerational impact of gestational diabetes on the epidemic of type 2 diabetes. Am J Public Health. 2011;101(1):173-9. 37. International Diabetes Federation. (2013). International Diabetes Federation IDF Atlas, 6th ed. [online] Available from: www.idf.org/diabetesatlas. [Accessed January, 2014]. 38. Jiwani A, Marseille E, Lohse N, et al. Gestational diabetes mellitus: Results from a survey of country prevalence and practices. J Matern Fetal Neonatal Med. 2012;25(6):600-10. 39. World Diabetes Foundation, Global Alliance for Women’s Health. Diabetes, women, and development. Meeting, expert recommendations for policy action, conclusions, and follow-up actions. Int J Gynaecol Obstet. 2009;104( Suppl 1):S46-50. 40. Hedderson MM Darbinian JA, Ferrara A. Disparities in the risk of gestational diabetes by raceethnicity and country of birth. Paediatr Perinat Epidemiol. 2010;24(5):441-8. 41. Khan KS, Wojdlya D, Say L, et al. WHO analysis of causes of maternal death: a systematic review. Lancet. 2006;367(9516):1066-74. 42. World Health Organization. (2009). Women and health: Today’s evidence, tomorrow’s agenda 2009. [online] Available from: www.who.int/gender/women_health_report/en/. [Accessed January, 2014]. 43. Metzger BE, Lowe LP, Dyer AR, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008;358(19):1991-2002. 44. Cundy T. Pregnancy loss and neonatal death in women with type 1 or type 2 diabetes mellitus. Insulin. 2008;3(27);167-75. 45. International Diabetes Federation. (2009). Women and Diabetes. [online] Available from: www.idf.org/women-and-diabetes. [Accessed January, 2014]. 46. Fetita LS, Sobngwi E, Serradas P, et al. Consequences of fetal exposure to maternal diabetes in offspring. J Clin Endocrinol Metab. 2006;91(10):3718-24. 47. Crowther CA, Hiller JE, Moss JR, et al. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005;352(24):2477-86. 48. Landon MB, Spong CY, Thom E, et al. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med. 2009;361(14):1339-48. 49. Berger H, Crane J, Farine D, et al. Screening for gestational diabetes mellitus. J Obstet Gynaecol Can. 2002;24(11):894-912. 50. Lavin JP. Screening of high-risk and general populations for gestational diabetes: clinical application and cost analysis. Diabetes. 1985;34( Suppl 2):24-7.

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Contemporary Topics in Gestational Diabetes Mellitus 51. Coustan DR, Nelson C, Carpenter MW, et al. Maternal age and screening for gestational diabetes: a population-based study. Obstet Gynecol. 1989;73(4):557-61. 52. Moses RG, Moses J, Davis WS. Gestational diabetes: do lean young Caucasian women need to be tested? Diabetes Care. 1998;21(11):1803-6. 53. Neilsen KK, de Courten M, Kapur A. The urgent need for universally applicable simple screening procedures and diagnostic criteria for gestational diabetes mellitus--lessons from projects funded by the World Diabetes Foundation. Glob Health Action. 2012;5. 54. Bellamy L, Casas JP, Hingorani AD, et al.. Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis. Lancet. 2009;373(9677):1773-9. 55. Ratner RE, Christophi CA, Metzger BE, et al. Prevention of diabetes in women with a history of gestational diabetes: effects of metformin and lifestyle interventions. J Clin Endocrinol Metab. 2008;93(12):4774-9. 56. Retnakaran R. Glucose tolerance status in pregnancy: a window to the future risk of diabetes and cardiovascular disease in young women. Curr Diabetes Rev. 2009;5(4):239-44. 57. Retnakaran R, Shah BR. Mild glucose intolerance in pregnancy and risk of cardiovascular disease: a population-based cohort study. CMAJ. 2009;181(6-7):371-6. 58. Kessous R, Shoham-Vardi I, Pariente G, et al. An association between gestational diabetes mellitus and long-term maternal cardiovascular morbidity. Heart. 2013;99(15):1118-21. 59. Meltzer SJ. Treatment of gestational diabetes. BMJ. 2010;340:1708. 60. Poncet B, Touzet S, Rocher L, et al. Cost-effectiveness analysis of gestational diabetes mellitus screening in France. Eur J Obstet Gynecol Reprod Biol. 2002;103(2):122-9. 61. Marseille E, Lohse N, Jiwani A, et al. The cost-effectiveness of gestational diabetes screening including prevention of type 2 diabetes: application of a new model in India and Israel. J Matern Fetal Neonatal Med. 2013;26(8):802-10. 62. Li R, Zhang P, Barker LE, et al. Cost-effectiveness of interventions to prevent and control diabetes mellitus: a systematic review. Diabetes Care. 2010;33(8):1872-94. 63. Werner EF, Pettker CM, Zuckerwise L, et al. Screening for gestational diabetes mellitus: are the criteria proposed by the International Association of the Diabetes and Pregnancy Study Groups cost-effective? Diabetes Care. 2012;35(3):529-35. 64. Nielsen KK, Kapur A, Damm P, et al. From screening to postpartum follow-up - the determinants and barriers for gestational diabetes mellitus (GDM) services, a systematic review. BMC Pregnancy and Childbirth. 2014;14(1):41. 65. Asian-Pacific Resource and Research Centre for Women (ARROW) and the World Diabetes Foundation (WDF). (2012). Diabetes: A Missing Link to Achieving Sexual and Reproductive Health in Asia-Pacific Region. [online] Available from: www.arrow.org.my/publications/ Diabetes_A_Missing_Link.pdf. [Accessed January, 2014]. 66. Kapur A. Pregnancy a window of opportunity for improving current and future health. Int J Gynaecol Obstet. 2011;115( Suppl 1):S50-1.

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Hormono-metabolic Adaptations in Pregnancy

2 Subhash K Wangnoo

INTRODUCTION Maternal metabolism changes substantially during pregnancy. Amongst the functioning systems regulating the metabolism in pregnancy, endocrine system is the earliest to develop and start functioning. The endocrinology of pregnancy involves endocrine and metabolic changes as a consequence of physiological alterations at the fetoplacental boundary between mother and fetus. During the early pregnancy, most of the physiologic changes are hormone-mediated; while in the second and third trimesters, the uteroplacental vascular system and mechanical factors associated with the enlarging gravid uterus combine with the hormonal environment to have an effect on each and every system. The vast physiological variations in maternal hormones during the course of pregnancy complicate the assessment of the normal level of most hormones. GENERAL ADAPTATIONS The average weight gain during normal pregnancy is approximately 12.5 kg, with the fetus accounting for 3.4 kg, placenta 0.65 kg, amniotic fluid 0.8 kg, uterus 1  kg, breasts 0.4 kg, blood 1.5 kg, extravascular fluid 1.5 kg, and maternal fat stores approximately 3.3 kg. The volume of uterine cavity increases to about 5 L at term from about 10 mL and blood flow through the uteroplacental circulation reaches 450–650 mL/min. The blood volume increases by 40–45% at term compared to nonpregnant state to maintain appropriate perfusion of maternal-fetal unit. The plasma volume also increases by 40–50% due to the action of aldosterone leading to sodium and water retention. The red cell mass increases approximately 20% as a response to enhanced erythropoietin secretion. As a result, hematocrit declines to about 15% at term.1 The renal blood flow and the glomerular filtration rate increase rapidly reaching a peak during second trimester. There is a 50% reduction in creatinine clearance resulting in reduction in serum creatinine.2 Heart rate increases by 10–15 beats/ minute, cardiac output by 30–50%, reduction in diastolic pressure with no effect on systolic pressure, and a reduction in peripheral vascular resistance by about 20%. The pulmonary vascular resistance is reduced by about one-third. There are no changes in respiratory rate, maximum breathing capacity, or forced or timed vital capacity. Gastric emptying time is reduced by 50% at term; tone of lower

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esophageal sphincter is reduced leading to a marked symptom of reflux. Intestinal motility is reduced leading to constipation and gall bladder emptying is delayed leading to a more lithogenic bile and increased incidence of cholelithiasis.1 THE ROLE OF PLACENTA IN DEFINING ENDOCRINE METABOLISM Pregnancy-related proteins can be found in the maternal circulation shortly after conception, and human chorionic gonadotropin (hCG) is detectable in maternal serum after initiation of implantation, as early as from the 8th day after ovulation. hCG functions to prolong the hormonal activity of the corpus luteum to continue production of progesterone and maintain the early pregnancy endometrium. The decidua is the site of maternal steroid and protein biosynthesis in order to maintain and protect the pregnancy from immunologic rejection which acts in conjunction with hCG and progesterone secreted by the conceptus to suppress the maternal immune response conferring the immunologic privilege required by the implanting conceptus.3 The decidua furthermore produces prolactin, insulin-like growth factor binding protein-1 and other protein hormones (Table 1). The placenta plays an important role in balancing fetal growth and development with maternal homeostasis. It functions partly as a hypothalamic-pituitary-end organ-like entity with stimulatory and inhibitory feedback mechanisms, to

Table 1: Placental hormones and their functions

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Placental hormones

Functions

Human chorionic gonadotropin

•  Maintains corpus luteum of pregnancy •  Stimulates the secretion of testosterone by the developing testes of XY embryo

Estrogen (also secreted by the corpus luteum of pregnancy)

•  Stimulates growth of the myometrium, increasing uterine strength for parturition •  Helps prepare mammary glands for lactation

Progesterone (also secreted by the corpus luteum of pregnancy)

•  Suppresses uterine contractions to provide a quite environment for the fetus •  Promotes formation of a cervical mucus plug to prevent uterine contamination •  Helps prepare mammary glands for lactation

Human chorionic somatomammotropin (also called placental lactogen; has a structure similar to both prolactin and growth hormone)

•  Helps prepare mammary glands for lactation •  Believed to reduce maternal utilization of glucose and to promote the breakdown of stored fat so that greater quantities of glucose and free fatty acids may be shunted to the fetus

Relaxin (also secreted by the corpus luteum of pregnancy)

•  Softens the cervix in preparation for cervical dilatation at parturition •  Loosens the connective tissue between the pelvic bones in preparation for partuition

Placental parathyroid hormonerelated protein

•  Increases maternal plasma calcium levels for use in calcifying fetal bones; if necessary, promotes localized dissolution of maternal bone, mobilizing her calcium stores for use by the developing fetus

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Hormono-metabolic Adaptations in Pregnancy

regulate dynamic factors affecting fetal growth and development under a variety of conditions. However, in the placenta there are no direct neural inputs as in the fully developed hypothalamo-pituitary-end organ and the exact mechanism(s) responsible for regulation of the secretion of hypothalamic-like placental peptides is unknown. The placenta as a site of active steroidogenesis depends on interactions with both mother and fetus, and is characterized by significant aromatase, sulfatase, and 11β-hydroxysteroid dehydrogenase type 2 activities in conjunction with lack of 17α-hydroxylase and 17/20 lyase activities. The principal precursor for decidual and placental steroid production is maternal low-density lipoproteins (LDL)-cholesterol.4 HYPOTHALAMUS AND PITUITARY The maternal pituitary enlarges two- to threefolds during pregnancy and may become hyperintense on scan5,6 primarily caused by estrogen-stimulated hypertrophy and hyperplasia of the lactotrophs.7 Thus, maternal plasma prolactin levels parallel the increase in pituitary size throughout gestation. Gonadotrophs decline in number, and corticotrophs and thyrotrophs remain constant.8 Somatotrophs are generally suppressed due to negative feedback suppression9,10 by the placental production of growth hormone (GH), and may function as lactotrophs.11 The placental GH differs from pituitary GH by 13 amino acids and is synthesized by the syncytiotrophoblast. The regulation of placental GH secretion remains unknown, and it has similar carbohydrate, lipid, and somatogenic properties as pituitary GH, with less lactogenic activity. Corticotropin-releasing hormone (CRH) levels rise several 100-folds by term.12 It stimulates both syncytotrophoblastic placental and pituitary adrenocorticotropic hormone (ACTH) production.13,14 ACTH levels consequently increase throughout gestation, with a further increase in labor mirroring an increase in corresponding cortisol levels. Cortisol binding globulin levels rise secondary to estrogenstimulated production, leading to an increase in total cortisol of two- to threefolds by term.15 The posterior pituitary gland diminishes in size during pregnancy. The levels of maternal plasma arginine vasopressin levels are not believed to play a pivotal role in human pregnancy. Maternal oxytocin levels are also low throughout pregnancy, until they increase during labor.16 THYROID GLAND Maintaining maternal euthyroidism during pregnancy is of absolute importance for growth and development, in particular neurodevelopment of the fetus. Maternal thyroid gland enlarges by approximately 18% during gestation. This enlargement is due to an increase in the size of follicles with increased colloid and enhanced blood volume.17 The maternal thyroid status is subject to substantial pregnancy-related physiological changes. hCG has a thyroid-stimulating hormone (TSH)-like activity and the steep increase in hCG levels during the first trimester may result

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in an increased production of thyroid hormones and thus decreased TSH levels. Pregnancy-related hyperestrogenism induces an increased production of thyroxine-binding globulin (TBG) and thus an approximately 50% physiological increase of total thyroxine (T4). In the second and third trimesters, the hCG-induced stimulation of the thyroid gland decreases, while the maternal level of total T4 continues to be in the high end or above the nonpregnant reference values, and levels of TSH in the low end of the range.18,19 The renal iodine clearance and the maternal blood volume are increased, and in addition, maternal thyroid hormone is metabolized by or crosses the placenta to reach the fetus.20,21 As a result of the increased need for thyroid hormone production, vascularity of the thyroid gland increase and glandular hyperplasia occurs, leading to slightly increased size of the thyroid gland during pregnancy. During gestation, the mother remains in a euthyroid state, if sufficient iodine is available. Total triiodothyronine (T3) and T4 levels increase, but do not result in hyperthyroidism because of the parallel increase in TBG. Transthyretin transports thyroid hormones across the blood-placenta barriers. However, the placental exchange of maternal thyroid hormones is strictly regulated by placental deiodinases, securing a minimal, but highly significant supply of thyroid hormone to the fetus.22 Since iodine is an essential component in the synthesis of thyroid hormones, maternal iodine status becomes vital to fetal development, also in the light of increased renal clearance of iodine. In the first trimester, the fetus relies solely on thyroid hormones and iodine from the mother. The placenta is relatively impermeable to TSH and T4, so the fetal hypothalamo-pituitary-thyroid axis develops and functions independently of that of the mother. The levels of TSH and T4 are low in fetal blood until mid-gestation. At 24–28 weeks of gestation, serum T4 as well as the biologically inactive reverse T3 begins to rise progressively, while the TSH concentration peaks. PARATHYROID GLANDS AND CALCIUM HOMEOSTASIS The amount of calcium to the fetus is regulated by transfer of calcium across the placenta from the mother. Approximately 30 g of calcium is transferred from the maternal compartment to the fetal compartment, with the major chunk of transport occurring in the last trimester. Maternal compartment changes permit calcium accumulation by increase in maternal dietary intake and doubling of intestinal calcium absorption by end of first trimester and increases in maternal 1,25-dihydroxyvitamin D3 levels due to increase in estrogen-induced rise in vitamin D binding globulin.23 Parathyroid hormone (PTH) levels generally remain constant, but the circulating levels of PTH-related protein (PTHrp) keep on rising during pregnancy which is probably responsible for placental calcium transport. The higher calcitonin levels during pregnancy may be partly responsible for the elevated 24-hour calcium excretion, and an increased risk of kidney stones during pregnancy may be clinically relevant. By approximately 10–12 weeks’ gestation, the fetal parathyroid glands secrete PTH. Maternal PTH is not transferred across the placenta, and therefore, the changes in fetal calcium levels are probably related to the fetal changes in PTH and calcitonin, and consistent with an adaptation to conserve and stimulate fetal bone growth.24

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Hormono-metabolic Adaptations in Pregnancy

ADRENAL GLANDS The maternal adrenal gland does not change morphologically during pregnancy. Plasma adrenal steroid levels increase with advancing gestation. However, the increase in total plasma cortisol concentration is mostly due to a concomitant increase in cortisol-binding globulin due to hyperestrogenemia of pregnancy. Plasma and urinary free cortisol increase 2–3 times, but pregnant women normally do not exhibit any overt clinical features of hypercortisolism probably due to antiglucocorticoid effects of elevated progesterone. The diurnal rhythm of cortisol secretion is maintained; the enhanced cortisol production is due to an increase in maternal plasma ACTH concentrations and hyperesponsiveness of adrenal cortex during pregnancy.25 Levels of renin and angiotensin rise during pregnancy, leading to elevated angiotensin II levels and markedly elevated levels of aldosterone, up to eight- to tenfolds. The aldosterone levels peak in midgestation and are maintained until delivery. Despite baseline elevations, the various components of rennin-angiotensinaldosterone system demonstrate a normal response to positional changes, sodium restriction and sodium loading. Another mineralocorticoid, 11-deoxycorticosterone shows a six- to tenfold elevation in concentration at term. Levels of androstenedione and testosterone are elevated because of estrogen-induced increase in hepatic synthesis of sex hormone-binding globulin. Free androgen levels remain normal or low. The production rates of dehydroepiandrosterone and dehydroepiandrosterone sulfate are increased twofold.26 Adrenal medullary function remains normal during pregnancy. The measure­ ments of 24-hour catecholamines and plasma epinephrine and norepinephrine are same as that of nonpregnant state.27 INSULIN AND METABOLIC HOMEOSTASIS Hyperplasia and hypertrophy of the beta cells are probably due to results of stimulation by estrogen and progesterone.28 In early pregnancy, glucose tolerance is generally normal and peripheral sensitivity to insulin and glucose similar to pregravid levels.29 Although basal insulin levels are normal, there is hypersecretion of insulin in response to meals. Over the course of gestation, the insulin response to nutrients further increases, while glucose tolerance changes only slightly. The balance is maintained by a progressive increase in basal and postprandial insulin concentrations to counteract with the increase in insulin resistance.30 Towards the end of pregnancy, the basal and 24-hour mean insulin concentration may be twofold greater than nonpregnancy, with first and second phases of insulin secretion threefold greater31 due to elevated levels of human placental lactogen (hPL) and glucocorticoids. With increases in peripheral insulin resistance slightly higher levels of postparandial concentrations of metabolic fuels—including glucose, lipids, and amino acids—are available for the fetus. Lipid metabolism is also altered with normal pregnancy. Overall, there is an increase in triglycerides, fatty acids, cholesterol, and lipoproteins throughout pregnancy.32 Whereas, accumulation of fat depots occurs during the first two-thirds of gestation, increased adipose tissue lipolysis and hyperlipidemia develops in the last trimester. Insulin resistance and increased estrogens in late pregnancy

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contribute to these changes. Lipoprotein receptors and fatty acid binding proteins in the placenta allow the transfer of long-chain polyunsaturated fatty acids to the fetus. Enhanced oxidative stress in pregnancy may be related to maternal hyperlipidemia. Maternal plasma nonesterified fatty acids and cholesterol correlate with those in the fetus, and maternal adipocytokines have been associated with fetal growth. At the molecular level, cytokines are important links between lipid metabolism and insulin resistance. POINTS TO REMEMBER • • • •

Pregnancy is a dynamic state and evaluation for metabolic dysfunction needs astute observation and planned investigations rather than a blanket of investigations Estimation and interpretation of hormonal status during pregnancy is to be correlated to the understanding of normal physiology A suppressed TSH level during pregnancy in a previously healthy female does not always point to thyroid dysfunction Estimation for hypercortisolism and hypercortisol states is fraught with confounders. Urinary and free cortisol are better markers but maybe spuriously elevated.

REFERENCES 1. Cunningham EG, Leveno KJ, Bloom SL, et al. Maternal Physiology. In: Williams Obstetrics. 2nd  ed. New York, USA: McGraw-Hill Medical Publishing; 2005. p. 121. 2. Lindheimer MD, Davison JM. Osmoregulation, the secretion of arginine vasopressin and its metabolism during pregnancy. Eur J Endocrinol. 1995;132(2):133-43. 3. Murphy BE. Cortisol and cortisone in human fetal development. J Steroid Biochem. 1979;11(1B):509-13. 4. Carr BR, MacDonald PC, Simpson ER. The role of lipoproteins in the regulation of progesterone secretion by the human corpus luteum. Fertil Steril. 1982;38(3):303-11. 5. Gonzalez JG, Elizondo G, Saldivar D, et al. Pituitary gland growth during normal pregnancy: an in vivo study using magnetic resonance imaging. Am J Med. 1988;85(2):217-20. 6. Miki Y, Asato R, Okumura R, et al. Anterior pituitary gland in pregnancy: hyperintensity at MR. Radiology. 1993;187(1):229-31. 7. Goluboff LG, Ezrin C. Effect of pregnancy on the somatotroph and the prolactin cell of the human adenohypophysis. J Clin Endocrinol Metab. 1969;29(12):1533-8. 8. Scheithauer BW, Sano T, Kovacs KT, et al. The pituitary gland in pregnancy: a clinicopathologic and immunohistochemical study of 69 cases. Mayo Clin Proc. 1990;65(4):461-74. 9. Frankenne F, Closset J, Gomez F, et al. The physiology of growth hormones (GHs) in pregnant women and partial characterization of the placental GH variant. J Clin Endocrinol Metab. 1988;66(6):1171-80. 10. Eriksson L, Frankenne F, Eden S, et al. Growth hormone 24-h serum profiles during pregnancydlack of pulsatility for the secretion of the placental variant. Br J Obstet Gynaecol. 1989;96(8):949-53. 11. Stefaneanu L, Powell-Braxton L, Won W, et al. Somatotroph and lactotroph changes in the adenohypophyses of mice with disrupted insulin-like growth factor I gene. Endocrinology. 1999;140(9):3881-9. 12. Stalla GK, Bost H, Stalla J, et al. Human corticotrophin releasing hormone during pregnancy. Gynecol Endocrinol. 1989;3(1):1-10. 13. Rees LH, BurkeCW, Chard T, et al. Possible placental origin of ACTH in normal human pregnancy. Nature. 1975;254(5501):620-2.

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Hormono-metabolic Adaptations in Pregnancy 14. Sasaki A, Shinkawa O, Yoshinaga K. Placental corticotrophin-releasing hormone may be a stimulator of maternal pituitary adrenocorticotropic hormone secretion in humans. J Clin Invest. 1989;84(6):1997-2001. 15. Nolten WE, Lindheimer MD, Rueckert PA, et al. Diurnal patterns and regulation of cortisol secretion in pregnancy. J Clin Endocrinol Metab. 1980;51(3):466-72. 16. Davison JM, Sheills EA, Philips PR, et al. Serial evaluation of vasopressin release and thirst in human pregnancy. Role of human chorionic gonadotrophin in the osmoregulatory changes of gestation. J Clin Invest. 1988;81(3):798-806. 17. Glioner D. The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocr Rev. 1997;18(3):404-33. 18. Boas M, Forman JL, Juul A, et al. Narrow intra-individual variation of maternal thyroid function in pregnancy based on a longitudinal study on 132 women. Eur J Endocrinol. 2009;161(6):903-10 19. Haddow JE, Knight GJ, Palomaki GE, et al. The reference range and within-person variability of thyroid stimulating hormone during the first and second trimesters of pregnancy. J Med Screen. 2004;11(4):170-4. 20. Burrow GN, Fisher DA, Larsen PR. Maternal and fetal thyroid function. N Engl J Med. 1994;331(16):1072-8. 21. Chan SY, Vasilopoulou E, Kilby MD. The role of the placenta in thyroid hormone delivery to the fetus. Nat Clin Pract Endocrinol Metab. 2009;5(1):45-54. 22. Koopdonk-Kool JM, de Vijlder JJ, Veenboer GJ, et al. Type II and type III deiodinase activity in human placenta as a function of gestational age. J Clin Endocrinol Metab. 1996;81(6):2154-8. 23. Kovacs CS. Calcium and bone metabolism in pregnancy and lactation. J Clin Endocrinol Metab. 2001;86(6):2344-8. 24. Strewler GJ. The physiology of parathyroid related protein. N Engl J Med. 2000;342(3):177-85. 25. Carr BR, Parker CR, Madden JD, et al. Maternal plasma adrenocorticotropin and cortisol relationships throughout human pregnancy. Am J Obstet Gynecol. 1981;139(4):416-22. 26. Linsday JR, Nieman LK. The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment. Endocr Rev. 2005;26(6):775-99. 27. Turnbridge RD, Donnai P. Plasma noradrenaline in normal pregnancy and in hypertension of late pregnancy. Br J Obstet Gynaecol. 1981;88(2):105-8. 28. Costrini NV, Kalkhoff RK. Relative effects of pregnancy, estradiol and progesterone on plasma insulin and pancreatic islet insulin secretion. J Clin Invest. 1971;50(5):992-9. 29. Lain KY, Catalano PM. Factors that affects maternal insulin resistance and modify fetal growth and body composition. Metab Syndr Relat Disord. 2006;4(2):91-100. 30. Catalano PM, Huston L, Amini SB, et al. Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus. Am J Obstet Gynecol. 1999;180(4):903-16. 31. Barbour LA, Shao J, Qiao L, et al. Human placenta growth hormone causes insulin severe resistance in transgenic mice. Am J Obstet Gynecol. 2002;186(3):512-7. 32. Schaefer-Graf UM, Graf K, Kulbacka I, et al. Maternal lipids as strong determinants of fetal environment and growth in pregnancies with gestational diabetes mellitus. Diabetes Care. 2008;31(9):1858-63.

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Pathogenesis of Gestational Diabetes Mellitus

Sudip Chatterjee

INTRODUCTION Blood glucose rises when there is a mismatch between insulin supply by the beta cell and the insulin demand of the body. Insulin resistance (IR) plays a major role in determining insulin demand in that higher the IR, the greater is the amount of insulin secretion necessary to achieve set metabolic targets. Deficiency of insulin in gestational diabetes mellitus (GDM) can be due to autoimmune factors as in type 1 diabetes or due to monogenic disease, as in maturity onset diabetes of the young (MODY), or multifactorial as in type 2 diabetes.1 As the first two are relatively uncommon entities, this presentation will deal with the common type of GDM that is comparable to type 2 diabetes. In normal late pregnancy, the growing fetus has to be supplied with nutrients to enable its growth. The mother’s post-meal glucose levels go up enabling transplacental glucose transfer. In the fasting state, there is more hepatic glucose output so that the fasting levels are kept up presumably for the same purpose. Increased lipolysis occurs in the mother leading to increased levels of free fatty acids (FFA). The normal inhibition of lipolysis by insulin is reduced and FFA is used as fuel by the mother. This allows glucose to be preferentially transferred to the fetus. These processes are mediated by placental products because there is sudden reversal of these changes on delivery. Possible products implicated are placental progesterone, human chorionic somatomammotrophin, and human placental lactogen (HPL).2 INSULIN RESISTANCE IN GESTATIONAL DIABETES MELLITUS Insulin resistance rises in pregnancy. Increase in maternal weight plays a role, but the major source of IR resides in the placenta because, as noted above, IR quickly falls after delivery. There are varying data on the extent of IR rise in GDM, in comparison to non-GDM pregnancies. Ryan found that in GDM subjects, IR rose by about twofold compared to non-GDM pregnancies.3 Other studies have found that IR rose comparably in GDM and non-GDM pregnancies with a slightly higher rise in the former. One study compared GDM women between 26 weeks and 29 weeks of pregnancy with non-GDM, body mass index (BMI) matched pregnant controls.4 The authors found significantly higher glycosylated hemoglobin (HbA1c), fasting glucose, insulin, and C-peptide levels in GDM subjects. This suggested that IR was

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higher in GDM women. They also found evidence of a higher glucose threshold for insulin release and reduced hepatic glucose uptake. These processes operate in normal pregnancy as well, though their magnitude is greater in GDM. After delivery, GDM women continue to have high IR whereas the non-GDM women exhibit a marked fall in IR.5 Thus women with GDM have chronically elevated IR which does not resolve upon delivery. Higher levels of FFA that are present in pregnancy can contribute to elevation of IR.6 BETA CELL FUNCTION IN GESTATIONAL DIABETES MELLITUS Stimulated insulin response rises steadily in pregnancy and can reach around 300% of prepregnancy values at term.2 Using fixed hyperglycemia, Homko and co-workers5 found that at comparable levels of insulin sensitivity, the insulin secretion rate was lower in GDM pregnant women compared to non-GDM pregnancies. After delivery, both groups showed the same insulin secretion rate but GDM women continued to have elevated IR. It, therefore, appears that there is a temporary beta cell secretory defect in GDM. GDM patients generally revert to normoglycemia after delivery. The rapid reversal after delivery suggests that the placenta contributes in some way to the beta cell secretory defect in GDM pregnancies. Further, an element of beta cell damage persists after delivery in GDM women, as by 5 years up to 50% of them go on to develop type 2 diabetes.7 THE PLACENTA IN GESTATATIONAL DIABETES MELLITUS It has long been known that placental products primarily HPL contribute to IR in pregnancy. Placentas of GDM women are generally large and have been found to have hypervascularization and vascular dysfunction. As metalloproteinases play a role in angiogenesis, some workers looked at production of membrane type matrix metalloproteinase 1 (MT1-MMP) in GDM and control placenta. It was found that the active compound was increased by 54% in GDM placenta. In vitro the MT1-MMP producing placental cells stimulated angiogenesis which could be reduced by 25% by addition of blocking antibodies. Both insulin and insulin-like growth factor 2 (IGF-2) stimulate the process. As these proteins had to be of fetal origin to stimulate the placenta in vivo, the authors concluded that the fetus plays a role in the process of placental vascular dysfunction.8 Cytokines and the Placenta The placenta is known to secrete virtually all known cytokines.9 It is assumed that a set point is reached between maternal IR and placental cytokines in early pregnancy. When beta cell dysfunction appears in late pregnancy, the set point is disturbed leading to higher cytokine production which further enhances IR.10 Leptin Levels Leptin is an anti-obesity hormone found in adipocytes and placenta. Leptin concentrations in pregnancy have been variously reported to be high, normal, or low. A large study looked at 1,988 women with GDM and 477 normal controls

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and found no difference in leptin levels. However, prepregnancy BMI was strongly correlated to leptin levels in both groups.11 Adiponectin is a protein secreted by adipocytes which increases insulin sensitivity. It is not secreted by placenta.12 In a study on pregnant women, Worda13 found significantly lower levels of adiponectin in GDM subjects when compared with non-GDM controls. Another study found lower adiponectin and higher tumor necrosis factor-alpha (TNF-α) levels in GDM women compared to normoglycemic pregnant controls.14 It is known that TNF-α levels suppress adiponectin. In this study, adiponectin emerged as an independent risk factor for GDM, while TNF-α was dependent on prepregnancy BMI. There is a profusion of recent literature on TNF-α and GDM. Certain TNF-α gene promoter polymorphisms are more common in GDM.15 High levels of TNF-α have been identified in many studies on GDM. Also adipose tissue and placenta from women with GDM release more TNF-α in vitro in a high glucose environment compared to control tissue.16 One year after a GDM pregnancy, skeletal muscle messenger ribonucleic acid (mRNA) for TNF-α was 5–6 times higher than in controls and was positively correlated to IR.17 The authors felt that chronically increased IR in GDM women could be mediated by cytokines. It has been postulated that TNF-α in skeletal muscle plays a paracrine role in mediating IR.18 Efforts to form a comprehensive model accounting for the role of cytokines in development of GDM have been hampered by the lack of placental perfusion data. It is possible that in early pregnancy, cytokines from the placenta and IR of the mother are maintained in a stable feedback loop. High glucose levels in later pregnancy can cause increase of cytokines, thereby disrupting this loop. The rise of cytokine levels increase IR and can contribute to beta cell dysfunction. Other studies have found that in early pregnancy, the presence of markers of inflammation was linked to subsequent GDM. A similar association has been long established in type 2 diabetes, although the cause and effect relationship remains unclear.19 Nutritional Factors In India, a significant proportion of the population is vegetarian and thereby possibly deficient in vitamin B12. At the same time, supraphysiological folate supplementation is often given in pregnancy. A study from Mysore20 found that amongst the vitamin B12 deficient women, the incidence of GDM increased with increasing serum folate concentration. B12 deficiency during pregnancy was associated with IR [by homeostatic model assessment (HOMA) 2 model] and increased prevalence of type 2 diabetes at 5 years. However, the authors did not postulate on the biochemical mechanisms involved in the process. Nutritional studies in GDM are generally retrospective or cross-sectional and have relatively small numbers of subjects. There are data to suggest that a low fat intake is protective; of the fats, polyunsaturated fats are protective. There are studies that show that vitamins C and D are protective.21 Vitamin D levels appear to have an inverse relationship with plasma glucose levels in pregnancy. Poel22 performed a meta-analysis of studies looking at vitamin  D and GDM published up to 2011. In seven observational studies, looking at 2,146 subjects, 433 women with GDM were found. Vitamin D levels below 50

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nmol/L were significantly associated with GDM with an odds ratio (OR) of 1.61 [95% confidence interval (CI) = 1.19–2.17]. The authors found significantly lower levels of vitamin D in GDM subjects compared to their normoglycemic counterparts (p = 0.018). As with most vitamin D studies, no mechanism has been elucidated, the cause and effect relationship is unknown, and randomized controlled trials (RCTs) on the subject are yet to be published. Data from the Nurses’ Health Study identified two types of diets in the participants. A “western” diet was identified containing a significant portion of red meat, processed meat, sweets, fries, pizza, and refined carbohydrates. Another diet pattern emerged, called the “prudent” pattern, where there was a high intake of fruits, green-leafy vegetables, poultry, and fish. The prudent diet if consumed prepregnancy was associated with a significant decrease of risk of GDM.23 It is possible that saturated fat and cholesterol in red meat adversely affected beta cell sensitivity and IR. Nitrosamines present in processed meat could have a beta cell toxicity. Also red meat contains advanced glycation end products (AGE) which have an adverse effect on IR. Many similar postulates are present in the literature, for example, the effect of heme (in red meat) on glucotoxicity.24 None of the theories to account for the benefits of the prudent diet can withstand strict scientific scrutiny. Fiber in diet was found to be protective. It has been calculated that for each 10 g/day increase in total dietary fiber there was a 26% decrease in risk of GDM. Conversely, a low cereal fiber diet with a high carbohydrate load, i.e., containing refined carbohydrates was associated with a 2.15 increased risk of GDM.25 OTHER FACTORS IN THE PATHOGENESIS OF Gestational Diabetes Mellitus In the Nurses’ Study, women in the highest quintile of physical activity had about 20% decreased risk for GDM.26 Obstructive sleep apnea (OSA) was found to be more common in GDM. After adjusting for prepregnancy body weight, the OR for the association of OSA with GDM was 6.6 (95% CI = 1.15–37.96). Again the cause and effect relationship was not established.27 Ethnicity plays a role in pathogenesis of GDM. In one study, the prevalence of GDM in Asians was 2.5 times higher in comparison to Caucasians.28 Another study using the same but updated database found a 9.9% prevalence of GDM in Asian and 8.5% in Filipino women. Low BMI did not protect against GDM in these highrisk groups. In some other groups like Hispanic, non-Hispanic white and AfricanAmericans, the prevalence of GDM rose to 8% only if the BMI was 30 or more.29 Gestational Diabetes Mellitus and Polycystic Ovary Syndrome Insulin resistance is a well-recognized feature of polycystic ovary syndrome (PCOS).30 When PCOS subjects become pregnant, they are more likely to develop GDM. Lo and colleagues31 studying a mainly white population, examined 92,933 pregnancies between 2004 and 2006. Of these 1,542 pregnancies (1.7%) had earlier been diagnosed with PCOS. After adjusting for age, ethnicity, and multiple

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versus single gestation status, it was found that PCOS subjects had an OR of 2.44 of developing GDM (95% CI = 2.1–2.83) as compared to non-PCOS subjects. Toulis32 performed a meta-analysis of observational studies of PCOS and GDM. In PCOS subjects, the authors found an OR of 2.89 (95% CI = 1.68–4.98) for developing GDM. These findings are in keeping with the observation that PCOS subjects have a higher lifetime risk of developing type 2 diabetes. The risk is more pronounced in women of South Asian origin. A study from Sri Lanka found that women with a history of GDM and a much higher risk of PCOS and the metabolic syndrome when studied 5 years after delivery.33 The Incretin Axis and Gestational Diabetes Mellitus There is no difference in glucagon levels between GDM and non-GDM pregnancies.3 Pregnancy causes suppression of the incretin axis as a whole, an effect that is more pronounced in GDM pregnancies. Again, the cause and effect relationship is unclear. However, the incretin axis reverts to normal after delivery.34 SUMMARY There are several features in common to the pathogenesis of type 2 diabetes and GDM. In both conditions, diminished beta cell secretory capacity and IR play a role. In studies specific to GDM, obesity and ethnicity have been associated with GDM. Several dietary factors have been associated with GDM, like vitamin B12 and vitamin  D deficiency, fiber deficiency, and a tendency to consume a western style meat enriched diet. Low exercise levels have also been associated with GDM. IR rises during pregnancy, and the rise of IR in GDM is more than in non-GDM pregnancies. There is varying data on the extent of the IR rise in GDM when compared to non-GDM women. It has been consistently shown that in non-GDM pregnancies, IR reverts to normal after delivery. In GDM subjects postpregnancy, the IR remains chronically high as do markers of TNF-α production. Normally, insulin demand rises about fourfold by term compared to prepregnancy requirements. In GDM, there is an insulin secretory defect which translates into hyperglycemia. The metabolic perturbations in GDM cease abruptly on delivery and, therefore, must be primarily due to the placenta. The placenta is an organ of fetal origin. It secretes several hormones and cytokines which increase IR and raise the glucose threshold for insulin secretion. Fetal hyperglycemia and hyperinsulinemia are known to occur in GDM. Fetal factors have a complex relationship with the placenta and its secretory products. Placental dynamics change throughout pregnancy and are difficult to study. Placental perfusion studies are at present underway in several centers which hopefully will shed more light on this complex issue. PCOS is strongly associated with GDM as indeed it is with type 2 diabetes. Several studies have shown increased prevalence of PCOS both before and after GDM pregnancies. What are the lessons to be drawn from these studies? If GDM is to be prevented, avoidance of obesity and a healthy lifestyle are important. Lifestyle factors include exercise, habitual use of a balanced fiber rich diet with adequate micronutrients, and avoidance of meats and processed foods. Risk factors for GDM like ethnicity, PCOS can be identified early and such women can be kept under increased surveillance.

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REFERENCES 1. Kuhl C. Etiology and pathogenesis of gestational diabetes. Diabetes Care. 1998;21(Suppl  2): B19-26. 2. Freinkel N. Banting Lecture 1980. Of pregnancy and progeny. Diabetes. 1980;29(12):1023-35. 3. Ryan EA, O’Sullivan MJ, Skyler JS. Insulin action during pregnancy. Studies with the euglycemic clamp technique. Diabetes. 1985;34(4):380-9. 4. Kautzky-Willer A, Prager R, Waldhausl W, et al. Pronounced insulin resistance and inadequate beta-cell secretion characterize lean gestational diabetes during and after pregnancy. Diabetes Care. 1997;20(11):1717-23. 5. Homko C, Sivan E, Chen X, et al. Insulin secretion during and after pregnancy in patients with gestational diabetes mellitus. J Clin Endocrinol Metab. 2001;86(2):568-73. 6. Sivan E, Homko CJ, Whittaker PG, et al. Free fatty acids and insulin resistance during pregnancy. J Clin Endocrinol Metab. 1998;83(7):2338-42. 7. Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care. 2002;25(10):1862-8. 8. Hiden U, Lassance L, Tabrizi NG, et al. Fetal insulin and IGF-II contribute to gestational diabetes mellitus (GDM)-associated up-regulation of membrane-type matrix metalloproteinase 1 (MT1-MMP) in the human feto-placental endothelium. J Clin Endocrinol Metab. 2012; 97(10):3613-21. 9. Bowen JM, Chamley L, Keelan JA, et al. Cytokines of the placenta and extra-placental membranes: roles and regulation during human pregnancy and parturition. Placenta. 2002;23(4):257-73. 10. Desoye G, Hauguel-de Mouzon S. The human placenta in gestational diabetes mellitus. The insulin and cytokine network. Diabetes Care. 2007;30(Suppl 2):S120-6. 11. Maple-Brown L, Ye C, Hanley AJ, et al. Maternal pregravid weight is the primary determinant of serum leptin and its metabolic associations in pregnancy, irrespective of gestational glucose tolerance status. J Clin Endocrinol Metab. 2012;97(11):4148-55. 12. Caminos JE, Nogueiras R, Gallego R, et al. Expression and regulation of adiponectin and receptor in human and rat placenta. J Clin Endocrinol Metab. 2005;90(7):4276-86. 13. Worda C, Leipold H, Gruber C, et al. Decreased plasma adiponectin concentrations in women with gestational diabetes mellitus. Am J Obstet Gynecol. 2004;191(6):2120-4. 14. Altinova AE, Toruner F, Bozkurt N, et al. Circulating concentrations of adiponectin and tumor necrosis factor-alpha in gestational diabetes mellitus. Gynecol Endocrinol. 2007;23(3):161-5. 15. Guzmán-Flores JM, Escalante M, Sánchez-Corona J, et al. Association analysis between -308G/A and -238G/A TNF-alpha gene promoter polymorphisms and insulin resistance in Mexican women with gestational diabetes mellitus. J Investig Med. 2013;61(2):265-9. 16. Coughlan MT, Oliva K, Georgiou HM, et al. Glucose-induced release of tumour necrosis factor-alpha from human placental and adipose tissues in gestational diabetes mellitus. Diabet Med. 2001;18(11):921-7. 17. Friedman JE, Kirwan JP, Jing M, et al. Increased skeletal muscle tumor necrosis factor-alpha and impaired insulin signaling persist in obese women with gestational diabetes mellitus 1  year postpartum. Diabetes. 2008;57(3):606-13. 18. Ofei F, Hurel S, Newkirk J, et al. Effects of an engineered human anti-TNF-alpha antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes. 1996;45(7):881-5. 19. Megia A, Gallart L, Fernández-Real JM, et al. Mannose-binding lectin gene polymorphisms are associated with gestational diabetes mellitus. J Clin Endocrinol Metab. 2004;89(10):5081-7. 20. Krishnaveni GV, Hill JC, Veena SR, et al. Low plasma vitamin B12 in pregnancy is associated with gestational 'diabesity' and later diabetes. Diabetologia. 2009;52(11):2350-8. 21. Ley SH, Hanley AJ, Retnakaran R, et al. Effect of macronutrient intake during the second trimester on glucose metabolism later in pregnancy. Am J Clin Nutr. 2011;94(5):1232-40. 22. Poel YH, Hummel P, Lips P, et al. Vitamin D and gestational diabetes: a systematic review and meta-analysis. Eur J Intern Med. 2012;23(5):465-9. 23. Bao W, Bowers K, Tobias DK, et al. Prepregnancy dietary protein intake, major dietary protein sources, and the risk of gestational diabetes mellitus: a prospective cohort study. Diabetes Care. 2013;36(7):2001-8.

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Contemporary Topics in Gestational Diabetes Mellitus 24. Tobias DK, Zhang C, Chavarro J, et al. Prepregnancy adherence to dietary patterns and lower risk of gestational diabetes mellitus. Am J Clin Nutr. 2012;96(2):289-95. 25. Zhang C, Liu S, Solomon CG, et al. Dietary fiber intake, dietary glycemic load, and the risk for gestational diabetes mellitus. Diabetes Care. 2006;29(10):2223-30. 26. Zhang C, Solomon CG, Manson JE, et al. A prospective study of pregravid physical activity and sedentary behaviors in relation to the risk for gestational diabetes mellitus. Arch Intern Med. 2006;166(5):543-8. 27. Reutrakul S, Zaidi N, Wroblewski K, et al. Interactions between pregnancy, obstructive sleep apnea, and gestational diabetes mellitus. J Clin Endocrinol Metab. 2013;98(10):4195-202. 28. Lawrence JM, Contreras R, Chen W, et al. Trends in the prevalence of preexisting diabetes and gestational diabetes mellitus among a racially/ethnically diverse population of pregnant women, 1999-2005. 29. Diabetes Care. 2008;31(5):899-904. Hedderson M, Ehrlich S, Sridhar S, et al. Racial/ethnic disparities in the prevalence of gestational diabetes mellitus by BMI. Diabetes Care. 2012;35(7):1492-8. 30. Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev. 2012;33(6):981-1030. 31. Lo JC, Feigenbaum SL, Escobar GJ, et al. Increased prevalence of gestational diabetes mellitus among women with diagnosed polycystic ovary syndrome: a population-based study. Diabetes Care. 2006;29(8):1915-7. 32. Toulis KA, Goulis DG, Kolibianakis EM, et al. Risk of gestational diabetes mellitus in women with polycystic ovary syndrome: a systematic review and a meta-analysis. Fertil Steril. 2009;92(2):667-77. 33. Wijeyaratne CN, Waduge R, Arandara D, et al. Metabolic and polycystic ovary syndromes in indigenous South Asian women with previous gestational diabetes mellitus. BJOG. 2006;113(10):1182-7. 34. Kosinski M, Knop FK, Vedtofte L, et al. Postpartum reversibility of impaired incretin effect in gestational diabetes mellitus. Regul Pept. 2013;186:104-7.

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Overweight, Obesity, and Gestational Diabetes Mellitus

David A Sacks

Defined by the World Health Organization as “abnormal or excessive fat accumulation that may impair health”, overweight (OW) and obesity (OB) affect an estimated 300 million women worldwide. In 65% of the world’s countries, OB and OW were associated with more deaths than were being underweight.1 In the United States, 59.5% of reproductive age women were reported as being OW or obese.2 With the possible exception of the Far East, OW and obese women are at increased risk of gestational diabetes mellitus (GDM) in comparison with their normal and underweight sisters.3 The definitions of the four major weight categories and their subgroups to be used in this chapter are those of the United States Institute of Medicine (IOM)3 and are listed in table 1. Overweight and OB have potentially serious consequences prior to, during, and following pregnancy. An increased prevalence of subfecundity, spontaneous abortion, and fetal congenital malformations has been reported in OW/OB women independent of GDM.4 A litany of pregnancy complications, including pre­eclampsia, gestational hypertension, GDM, excessive fetal growth, Caesarean delivery, urinary tract infections, postoperative and postpartum infections, postoperative and postpartum hemorrhage, thromboembolism, and maternal mortality are also associated with maternal OW/OB5 (Table 2). In the period immediately following delivery, failure of initiation of breast-feeding6 as well as maternal weight retention7 occur more often in OW women. Absolute per-pregnancy weight gain as well as postpartum weight retention, decrease with increasing maternal prepregnancy weight body mass index (BMI).8 However, in at least one study, although absolute weight gain was less with increasing IOM categories of BMI, the proportion of women who gained in excess of IOM— suggested weight gain increased with increasing BMI.9 Excessive weight gain may Table 1: Institute of Medicine (IOM) weight categories3 Category

Body mass index* (kg/m2)

Underweight

30: •  30–34.9 •  35–39.9 •  >40 or >35 with comorbidities

*Body mass index is calculated as weight (kg) divided by height (m)2.

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Table 2: Adverse outcomes of pregnancy associated with overweight and obesity and gestational diabetes Overweight and obesity

Gestational diabetes

• Preeclampsia, gestational hypertension • Gestational diabetes • Excessive fetal growth (macrosomia, large for gestational age) • Congenital malformations • Spontaneous abortions • Induction of labor • Caesarean delivery • Urinary tract infections • Intrapartum/postpartum/postoperative infection • Intrapartum/postpartum/postoperative hemorrhage • Thromboembolism • Maternal mortality • Perinatal morbidity and mortality

• Preeclampsia, gestational hypertension • Overweight and obesity • Excessive fetal growth (macrosomia, large for gestational age) • Congenital malformations • Spontaneous abortions • Induction of labor • Caesarean delivery • Urinary tract infections • Intrapartum/postpartum/postoperative infection • Intrapartum/postpartum/postoperative hemorrhage • Thromboembolism • Maternal mortality • Perinatal morbidity and mortality

Table 3: Institute of Medicine suggested weight gain for each category of pre­ pregnancy body mass index3 Prepregnancy body mass index

Underweight (0.85 in women • TG >150 mg/dL • BP >140/90 mmHg • Urinary albumin excretion rate >20 µg/min or • Albumin to creatinine ratrat ratio >30 mg/g

Any three of the following: • Waist circumference >102 in men, >88 in women • TG >150 mg/dL • BP >130/85 mmHg • HDLC 150 mg/dL • SBP >130 mmHg or DBP >85 mmHg • HDLC 30 kg/m2

56

11.8

9

28.1

2.65

1.23–5.70

0.013

Triglycerides ≥150 mg/dL

82

17.2

10

31.3

2.01

0.96–4.21

0.064

HDL cholesterol 30 (kg/m2) 20–39 years

31.9 (28.6–35.5)

Body mass index >25 (kg/m2) 20–39 years

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Fig. 1:  Gestational weight gain recommendation issued by the Institute of Medicine.12 Source: Institute of Medicine. (2013). Toolkit: Pregnancy weight gain guidelines dissemination webinar. [online] Available from: www.iom.edu/whattogaintoolkit. [Accessed February, 2014].

obligatory physiologic changes of pregnancy.12 Despite these recommendations, approximately 60% of overweight and obese women gain in excess of the IOM recommendations (Fig. 1). Hence, one of the primary goals of lifestyle interventions during pregnancy have been to avoid excessive GWG in overweight and obese women and decrease the risk of perinatal morbidities, such as metabolic dysfunction in the mother (GDM and preeclampsia) and fetal overgrowth [large for gestational age (LGA) and macrosomia]. This chapter will assess the success of these lifestyle interventions and rationale for their success or failure. LIFESTYLE INTERVENTIONS DURING PREGNANCY There have been numerous prospective trials examining lifestyle interventions for overweight and obese women during pregnancy. These studies examined outcomes that included avoiding excessive GWG and decreasing adverse perinatal outcomes, specifically macrosomia, GDM, and hypertensive disorders. The low glycemic index diet (LGID) in pregnancy study to prevent macrosomia evaluated more than 800 women with a history of delivering a greater than 4,000 g or macrosomic infant.13 Women were randomized to LGID or no intervention at 13 weeks. The primary objective was to reduce the incidence of macrosomia. Despite a decrease in GWG (12.2 kg vs. 13.7 kg), in the intervention group, there was no difference in birth weight, birthweight centile, ponderal index, or macrosomia between the groups. In 2011, a Danish group reported a randomized control lifestyle intervention trial.14 The intervention consisted of dietary guidance, free membership in a fitness center, and personal coaching initiated between 10–14 weeks’ gestation. Although there was a decrease in GWG in the intervention group (7.0 kg vs. 8.6 kg, p = 0.01), paradoxically the infants in the intervention group had significantly higher birth weight (3,742 g vs. 3,593 g, p = 0.04) compared to controls. The fit for delivery study examined whether behavioral intervention during pregnancy could decrease the proportion of women exceeding IOM recommendations for GWG and return to pregravid weight by 6 months postpartum.15 The investigators were able to show that the intervention during pregnancy reduced excessive GWG in normal weight women, but not in overweight or obese women. However, the behavioral

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intervention prevented postpartum weight retention in both normal weight and overweight/obese groups. Finally, there have been at least five meta-analyses published in the past 2 years of randomized control trials (RCTs) examining lifestyle interventions during pregnancy. The majority concluded that lifestyle interventions initiated during pregnancy have limited success in reducing excessive GWG, but not necessarily to within IOM guidelines. Furthermore, the literature contains scant evidence to support further benefits for infant or maternal health (fetal overgrowth, GDM, or hypertensive disorders including preeclampsia).16-20 A Cochrane review concluded that results from three RCTs suggested no significant difference in GDM incidence between women receiving exercise intervention versus routine care.21 PHYSIOLOGICAL ADAPTATIONS DURING PREGNANCY Why have these lifestyle intervention studies not had greater success? Early pregnancy can be considered an anabolic condition, where at least, for normal weight women there is an accrural of adipose tissue in early pregnancy in order to meet the energy demands in later gestation. In contrast, obese women are more likely to be insulin-resistant and gain less adipose tissue in early gestation.22 As a result from a population perspective overweight and obese women gain less weight during pregnancy as compared with normal weight women.23 There is a 50–60% decrease in insulin sensitivity with advancing gestation in all pregnant women, regardless of pregravid BMI. The decreased insulin sensitivity observed in obese, in contrast to normal weight women in pregnancy, is but a reflection of the maternal pregravid condition.24 The decreased insulin sensitivity in late gestation results in increased nutrient availability, such as glucose and lipids, to the fetus, resulting in fetal overgrowth and adiposity (Figs 2 and 3). Because the

BMI, body mass index.

Fig. 2:  The longitudinal changes in insulin sensitivity, pregravid, early pregnancy (12–14 weeks), and late pregnancy (34–36 weeks) as estimated using the hyperinsulinemic euglycemic clamp in normal weight, overweight, and obese women.24

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BMI, body mass index.

Fig. 3:  The longitudinal changes in basal plasma triglyceride concentrations, pregravid, early pregnancy (12–14 weeks), and late pregnancy (34–36 weeks) in normal weight, overweight, and obese women.

increased adiposity and decrease in insulin sensitivity in overweight and obese women exists before and during early pregnancy, lifestyle interventions initiated usually in the second trimester are less likely to have any effect on maternal metabolism or metabolic conditions during pregnancy, such as GDM. Hence, in obese women, maternal pregravid measures of obesity are more strongly correlated with maternal outcome measures, such as GDM, preeclampsia, and fetal macrosomia, as compared with other clinical parameters, such as GWG.25 These maternal metabolic alterations during pregnancy are less amenable to lifestyle changes because of the physiological adaptations during pregnancy, the relatively short time between initiation of dietary changes and delivery, and last the decreased ability to perform increased physical activity with advancing gestation. ADIPOSE TISSUE STORAGE AND ENDOCRINE FUNCTION The changes in body composition during pregnancy are primarily driven by adap­­tations of maternal metabolic homeostasis. The ultimate goal of pregnancyinduced metabolic changes is to meet the high energy demands of fetal development. Glucose, the primary energy fuel used by fetal tissues, needs to be readily available for transplacental transfer, whereas maternal tissues can rely on other energy substrates, such as lipids.26 The adaptations of lipid metabolism follow a well described biphasic pattern. The first half of pregnancy is centered on storing maternal energy as adipose tissue triglycerides, whereas in late pregnancy the stored lipids are mobilized to be used by peripheral tissues and in preparation for lactation.27 These sequential adaptations are facilitated by modifications of insulin secretion and action occurring over the course of pregnancy. The higher insulin

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sensitivity of early pregnancy facilitates cellular anabolism through activation of lipogenesis. In contrast, the insulin resistance, which culminates in third trimester, allows adipose tissue to mobilize the lipids stored earlier and skeletal muscle to utilize less glucose.28 These changes in maternal metabolic homeostasis combined to result in increased circulating levels of insulin and triglycerides in late pregnancy.29 In addition to alterations in its capacity for energy storage, the endocrine function of adipose tissue also evolves during pregnancy. The synthesis and plasma concentration of leptin and adiponectin, two major adipokines, exhibit longitudinal changes parallel to those of insulin sensitivity. Whereas leptin concentrations increase early, there is a significant decrease in plasma adiponectin during the third trimester.30,31 The longitudinal modifications of adipokines in healthy pregnancy are further enhanced in the context of pregnancy with diabetes and obesity.32,33 White adipose tissue displays a remarkable flexibility with an important and reversible capacity for expansion throughout adult life. Remodeling of the adipose tissue mass requires the integration of cellular mechanisms to support an increase in size and/or number of adipocytes. The turnover of fat cells is highly sensitive to variations in the metabolic and hormonal milieu, i.e., development, aging, diet or metabolic disorders, occurring throughout the lifespan.34-36 Adaptations of adipose tissue to healthy pregnancy develop in a temporal manner with an array of molecular changes preceding the anthropometric expansion of adipose mass. Adipose tissue enlargement is a complex process relying on molecular cross-talk between distinct cell types of the stromal-vascular fraction surrounding the adipocytes.37,38 In agreement with this concept, our research suggests that pregnancy-induced adipose tissue expansion involves a combination of cellular mechanisms shared by preadipocytes, adipocytes, macrophages, and endothelial cells (Fig. 4). Different types of cells which located within the adipose tissue itself cooperate to its remodeling during pregnancy. Components of the extracellular matrix (ECM), which connect the adipocytes and angiogenic factors, are needed for the vascular growth and differentiation of small preadipocytes into mature adipocytes able to store lipids. Lipogenic genes and transcription factors need to be activated to help differentiation and maturation of the small preadipocytes into functional adipocytes. The macrophages which have infiltrated the stromal cells produce proinflammatory cytokines, interleukin-6 (IL-6), IL-8, and tumor necrosis factor-alpha (TNF-α) that may facilitate the development of insulin resistance. The microenvironment surrounding the adipocytes may also be shaped by the production of adipokines, which exert both paracrine effects and endocrine function. TNF-α and IL-6 exhibit increased expression in both early and late stages of pregnancy, and may, therefore, regulate the expression of other genes which contribute to the negative action of insulin.37 The increase in leptin receptor expression is in agreement a stimulatory role of leptin on angiogenesis. And, the rise in plasma leptin levels in pregnancy is mainly contributed by the placenta.39 Low-grade inflammation can be detected in adipose tissue from early stages throughout the end of pregnancy with an activation of the toll-like receptor  4 (TLR4). TLR4 belongs to a family of transmembrane receptors first recruited in innate sensing through binding of the lipid A moiety of lipopolysaccharide (LPS) released from Gram-negative bacteria.40 The environmental factors which trigger the recruitment of innate immune pathways in early pregnancy are not known.

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LPS, lipopolysaccharide; TLR, toll-like receptor; IL, interleukin; TNF, tumor necrosis factor; MCP-1, monocyte chemoattractant protein 1; HCP, homocyte chemoattrqotant protein; ECM, extracellular matrix; MMP, matrix metalloproteinase; IGF, insulin-like growth factor; COL 1A 2, collagen type 1 alpha 2; VCAM, vascular cell adhesion molecule; VEGF, vascular endothelial growth factor; PPARG, peroxisome proliferator-activated receptor gamma; LPL, lipoprotein lipase; C/EBP, CCAAT, enhancer-binding protein; SREBP1, sterol regulatory element-binding protein.

Fig. 4:  Models of cellular networks which contribute to remodeling of the adipose tissue in human pregnancy. Multiple factors produced by several adjacent cell types cooperate to remodeling of the adipose tissue during pregnancy. ECM components and angiogenic factors are needed for vascular and adipocyte growth. Lipogenic genes are required for cell differentiation and lipid storage. Macrophages located outside the adipocytes produce proinflammatory cytokines, such as IL-6, IL-8, and TNF-α that may enhance neovascularization and facilitate the development of insulin resistance.

However, the activation of TLR4 signal transduction has been proposed as a molecular link between diet-induced obesity and increased insulin resistance.41 Nutritional changes, through either maternal hyperphagia or dysphagia, are potential candidates to impact adipose tissue receptors and function.42 Along this line, changes in microbiota have also been documented in relation to GWG and may impact TLR4 signaling in pregnancy.43 THE MATERNAL-FETAL INTERFACE: ROLE OF THE PLACENTA The insulin resistance of pregnancy and particularly the mechanisms of insulin action are not well understood at the maternal-fetal interface. The circulating hormone adiponectin, which has potent insulin sensitizing properties, has some interest in this regard. Hence, mechanisms leading to decrease the expression or secretion of adiponectin, during pregnancy may be particularly relevant to regulate insulin action.44 The negative correlation of adiponectin with maternal BMI in late pregnancy (Fig. 5) supports that the pregnancy–related regulation of plasma adiponectin has some similarity with adiponectin induced regulation in obesity.45

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A

B

Fig. 5:  Associations between plasma adiponectin, BMI and gestational weight gain variables were examined in the cohort of 133 women at term pregnancy using univariate regression analysis.

There is a large overlap in the cytokine expression of adipose tissue and the placenta. Maternal adipose tissue and the placenta represent the two primary sources of systemic cytokines during pregnancy.46 Leptin, one of the best studied adipokines, is secreted by adipose tissue and the placenta;33 in contrast, adiponectin is not produced by the placenta.47 These data suggest that if the placenta is not a source of adiponectin secreting cells, it may act as a functional target of maternal plasma adiponectin because there is a large amount of maternal adiponectin which reaches the placental circulation. Just like leptin, maternal adiponectin does cross the placenta to be delivered to the fetal circulation. However, maternal adiponectin may exert endocrine action in the placenta. The metabolic actions of adiponectin are mediated via binding to specific adpN receptors.48 Both R1 and R2 adiponectin receptors are expressed in the human placenta.49 Furthermore, adiponectin regulates placental amino acid transporters via R2 receptor binding.50,51 Adiponectin also decreases human chorionic gonadotropin (hCG) and progesterone production.52 Hence, modification of adiponectin availability at the maternal-fetal interface is likely to impact placental function. These findings suggest that implementing lifestyle intervention strategies before and early in pregnancy (i.e., before the changes in insulin action take place) to decrease maternal adiponectin may impact placental transport of nutrients to the fetus. Conclusion Lifestyle interventions initiated during pregnancy may, to some degree, reduce excessive GWG; however, they have not been successful in reducing fetal overgrowth, GDM or preeclampsia in obese women. Based on our research, we conclude that interventions need to be initiated prior to conception. Just as women with preexisting diabetes need to normalize glucose levels before pregnancy to decrease the risk of congenital anomalies, overweight and obese women should improve metabolic conditioning before pregnancy to decrease complications of fetal overgrowth and GDM during pregnancy.53 Concepts, such as “Metabolic Rehabilitation” by Ethan Sims54 and “Fuel Mediated Teratogenesis” by Norbert Freinkel55 were used to describe the importance of preconceptual metabolic control to avoid later metabolic dysfunction in the offspring. We report in this

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chapter that because there is increased expression of lipogenic and inflammatory genes in maternal adipose tissue and placenta of obese women in the early first trimester; before any phenotypic change becomes apparent, these women are less amenable to lifestyle changes improving metabolic function and clinical outcomes. These and other preliminary data provide evidence that lifestyle interventions should be initiated prior to conception to achieve short- and possibly long-term benefit for mother and fetus. REFERENCES 1. ACOG Committee Obstetric Practice. ACOG Committee opinion. Number 267, January 2002: exercise during pregnancy and the postpartum period. Obstet Gynecol. 2002;99(1):171-3. 2. Flegal KM, Carroll MD, Kit BK, et al. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010. JAMA. 2012;307(5):491-7. 3. Ananth CV, Wen SW. Trends in fetal growth among singleton gestations in the United States and Canada, 1985 through1998. Semin Perinatol. 2002;26(4):260-7. 4. Surkan PJ, Hsieh CC, Johansson AL, et al. Reasons for increasing trends in large for gestational age births. Obstet Gynecol. 2004;104(4):720-6. 5. Catalano PM. Management of obesity in pregnancy. Obstet Gynecol. 2007;109(2 Pt 1):419-33. 6. Donahue SM, Kleinman KP, Gillman MW, et al. Trends in birth weight and gestational length among singleton term births in the United States: 1990-2005. Obstet Gynecol. 2010;115(2 Pt 1): 357-64. 7. Stothard KJ, Tennant PW, Bell R, et al. Maternal overweight and obesity and the risk of congenital anomalies: a systemic review and meta-analysis. JAMA. 2009;301(6):636-50. 8. Weiss JL, Malone FD, Emig D, et al. Obesity, obstetric complications and cesarean delivery rate – A population-based screening study. Am J Obstet Gynecol. 2004;190(4):1091-7. 9. American College of Obstetricians and Gynecologists, Practice Bulletin. Clinical management Guidelines for Obstetricians-Gynecologists. Thromboembolism in Pregnancy. Obstet Gynecol. 2011;118:718-29. 10. Sewell MF, Huston-Presley L, Super DM, et al. Increased neonatal fat mass, not lean body mass, is associated with maternal obesity. Am J Obstet Gynecol. 2006;195(4):1100-3. 11. Catalano PM, Farrell K, Thomas A, et al. Perinatal risk factors for childhood obesity and metabolic dysregulation. Am J Clin Nutr. 2009;90(5):1303-13. 12. Rasmussen KM, Yaktine AL. Institute of Medicine. Weight gain during pregnancy: reexamining the guidelines. Washington, DC: National Academy Press; 2009. 13. Walsh JM, McGowan CA, Mahony R, et al. Low glycaemic index diet in pregnancy to prevent macrosomia (ROLO study): randomized control trial. BMJ. 2012;345:e5605. 14. Vinter CA, Jensen DM, Ovesen P, et al. The LiP (Lifestyle in Pregnancy) Study. A randomized controlled trial of lifestyle intervention in 360 obese pregnant women. Diabetes Care. 2011;34(12):2502-7. 15. Phelan S, Phipps MG, Abrams B, et al. Randomized trial of a behavioral intervention to prevent excessive gestational weight gain: the Fit for Delivery Study. Am J Clin Nutr. 2011;93(4):772-9. 16. Dodd JM, Grivell RM, Crowther CA, et al. Antenatal interventions for overweight or obese pregnant women: a systematic review of randomized trials. BJOG. 2010;117(11):1316-26. 17. Tanentsapf I, Heitmann BL, Adegboye AR. Systematic review of clinical trials on dietary interventions to prevent excessive weight gain during pregnancy among normal weight, overweight and obese women. BMC Pregnancy Childbirth. 2011;11:81. 18. Quinlivan JA, Julania S, Lam L. Antenatal dietary interventions in obese pregnant women to restrict gestational weight gain to Institute of Medicine recommendations: a meta-analysis. Obstet Gynecol. 2011;118(6):1395-401. 19. Thangaratinam S, Rogozińska E, Jolly K, et al. Effects of interventions in pregnancy on maternal weight and obstetric outcomes: meta-analysis of randomized evidence. BMJ. 2012;344:e2088. 20. Thangaratinam S, Jolly K. Obesity in pregnancy: a review of reviews on the effectiveness of interventions. BJOG. 2010;117(11):1309-12.

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Lifestyle Interventions During Pregnancy, Whey they have Limited Success: ... 21. Han S, Middleton P, Crowther CA. Exercise for pregnant women for preventing gestational diabetes mellitus. Cochrane Database Syst Rev. 2012;7:CD009021. 22. Okereke NC, Huston-Presley L, Amini SB, et al. Longitudinal changes in energy expenditure and body composition in obese women with normal and impaired glucose tolerance. Am J Physiol Endocrinol Metab. 2004;287(3):E472-9. 23. Nohr EA, Vaeth M, Baker JL, et al. Combined associations of prepregnancy body mass index and gestational weight gain with the outcome of pregnancy. Am J Clin Nutr. 2008;87(6):1750-9. 24. Catalano PM, Ehrenberg HM. The short- and long-term implications of maternal and obesity on the mother and her offspring. BJOG. 2006;113(10):1126-33. 25. Catalano PM, Drago NM, Amini SB. Factors affecting fetal growth and body composition. Am J Obstet Gynecol. 1995;172(5):1459-63. 26. Battaglia FC, Meschia G. Principal substrates of fetal metabolism. Physiol Rev. 1978;58(2): 499-527. 27. Herrera E. Metabolic adaptations in pregnancy and their implications forthe availability of substrates to the fetus. Eur J Clin Nutr. 2000;54(Suppl 1):S47-51. 28. Ryan EA, O’Sullivan MJ, Skyler JS. Insulin action during pregnancy. Studies with the euglycemic clamp technique. Diabetes. 1985;34(4):380-9. 29. Knopp RH, Warth MR, Carrol CJ. Lipid metabolism in pregnancy. I. Changes in lipoprotein triglyceride and cholesterol in normal pregnancy and the effects of diabetes mellitus. J Reprod Med. 1973;10(3):95-101. 30. Catalano PM, Hoegh M, Minium J, et al. Adiponectin in human pregnancy: implications for regulation of glucose and lipid metabolism. Diabetologia. 2006;49(7):1677-85. 31. Highman TJ, Friedman JE, Huston LP, et al. Longitudinal changes in maternal serum leptin concentrations, body composition, and resting metabolic rate in pregnancy. Am J Obstet Gynecol. 1998;178(5):1010-5. 32. Catalano PM, Presley L, Minium J, et al. Fetuses of obese mothers develop insulin resistance in utero. Diabetes Care. 2009;32(6):1076-80. 33. Hauguel-de Mouzon S, Lepercq J, Catalano P. The known and unknown of leptin in pregnancy. Am J Obstet Gynecol. 2006;194(6):1537-45. 34. Doyle SL, Donohoe CL, Lysaght J, et al. Visceral obesity, metabolic syndrome, insulin resistance and cancer. Proc Nutr Soc. 2012;71(1):181-9. 35. Lee MJ, Wu Y, Fried SK. Adipose tissue remodeling in pathophysiology of obesity. Curr Opin Clin Nutr Metab Care. 2010;13(4):371-6. 36. Van Harmelen V, Skurk T, Röhrig K, et al. Effect of BMI and age on adipose tissue cellularity and differentiation capacity in women. Int J Obes Relat Metab Disord. 2003;27(8):889-95. 37. Kirwan JP, Hauguel-De Mouzon S, Lepercq J, et al. TNF-alpha is a predictor of insulin resistance in human pregnancy. Diabetes. 2002;51(7):2207-13. 38. Zhang L, Sugiyama T, Murabayashi N, et al. The inflammatory changes of adipose tissue in late pregnant mice. J Mol Endocrinol. 2011;47(2):157-65. 39. Lepercq J, Cauzac M, Lahlou N, et al. Overexpression of placental leptin in diabetic pregnancy: a critical role for insulin. Diabetes. 1998;47(5):847-50. 40. Shi H, Kokoeva MV, Inouye K, et al. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. 2006;116(11):3015-25. 41. Baranova IN, Bocharov AV, Vishnyakova TG, et al. CD36 is a novel serum amyloid A (SAA) receptor mediating SAA binding and SAA-induced signaling in human and rodent cells. J Biol Chem. 2010;285(11):8492-506. 42. Björntorp P. Growth hormone, insulin-like growth factor-I and lipid metabolism: interactions with sex steroids. Horm Res. 1996;46(4-5):188-91. 43. Collado MC, Isolauri E, Laitinen K, et al. Distinct composition of gut microbiota during pregnancy in overweight and normal-weight women. Am J Clin Nutr. 2008;88(4):894-9. 44. Wong GW, Wang J, Hug C, et al. A family ofAcrp30/adiponectin structural and functional paralogs. Proc Natl Acad Sci USA. 2004;101(28):10302-7. 45. Lihn AS, Bruun JM, He G, et al. Lower expression of adiponectin mRNA in visceral adipose tissue in lean and obese subjects. Mol Cell Endocrinol. 2004;219(1-2):9-15. 46. Hauguel-de Mouzon S, Guerre-Millo M. The placenta cytokine network and inflammatory signals. Placenta. 2006;27(8):794-8.

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Contemporary Topics in Gestational Diabetes Mellitus 47. Haghiac M, Presley L, Hauguel de-Mouzon S, et al. ω-3 poly-unsaturated fatty acids decrease inflammation in obese pregnant women. Presented at the American Diabetes Association Scientific Meeting, June 21-25, 2013, Chicago IL. 48. Yamauchi T, Nio Y, Maki T, et al. Targeted disruption of adipoR1 and adipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med. 2007;13(3):332-9. 49. Corbetta S, Bulfamante G, Cortelazzi D, et al. Adiponectin expression in human fetal tissues during mid- and late gestation. J Clin Endocrinol Metab. 2005;90(4):2397-402. 50. Rosario FJ, Schumacher MA, Jiang J, et al. Chronic maternal infusion of full-length adiponectin in pregnant mice down-regulates placental amino acid transporter activity and expression and decreases fetal growth. J Physiol. 2012;590(Pt 6):1495-509. 51. Jones HN, Jansson T, Powell TL. Full length adiponectin attenuates insulin signaling and inhibits insulin-stimulated amino acid transport in human primary trophoblast cells. Diabetes. 2010;59(5):1161-70. 52. McDonald EA, Wolfe MW. Adiponectin attenuation of endocrine function within human term trophoblast cells. Endocrinology. 2009;150(9):4358-65. 53. Villamore E, Cnattingius S. Interpregnancy weight change and risk of adverse pregnancy outcomes: a population-based study. Lancet. 2006;368(9542):1164-70. 54. Sims EA, Horton ES. Endocrine and metabolic adaptation to obesity and starvation. Am J Clin Nutr. 1968;21(12):1455-70. 55. Freinkel M, Cockroft DL, Lewis NJ, et al. The 1986 McCollum award lecture. Fuel-mediated teratogenesis during early organogenesis: the effects of increased concentrations of glucose, ketones, or somatomedin inhibitor during rat embryo culture. Am J Clin Nutr. 1986;44(6):986-95.

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Factors Predicting the Development of Type 2 Diabetes Mellitus in Women with Prior Gestational Diabetes Mellitus and Action Plan for Prevention

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Yashdeep Gupta, Sanjay Kalra

INTRODUCTION Gestational diabetes has classically been defined as any glucose intolerance identified during pregnancy.1 Recent recommendations for gestational diabetes screening strategies attempt to distinguish between overt diabetes and gestational diabetes during pregnancy, i.e., glucose elevations that precede pregnancy and glucose elevations that occur during pregnancy.2 With these recommendations, gestational diabetes mellitus (GDM) is now defined as diabetes diagnosed during pregnancy that is not clearly overt diabetes.3 Women with history of GDM are at increased risk for glucose intolerance following delivery, including gestational diabetes in future pregnancies, and type 2 diabetes mellitus (T2DM). Compared with women with healthy pregnancies, women with history of gestational diabetes have elevated cardiovascular risk factors including blood pressure, unhealthy high-density lipoprotein cholesterol (HDLC) and high triglyceride levels.4 Also, women with history of gestational diabetes are more likely to experience cardiovascular events, at earlier ages, than women without such history.5 In this chapter, we discuss the risk factors associated with increased conversion to T2DM or impaired glucose tolerance (IGT) state, and suggest a feasible action plan to reduce this risk. As per the 2013 International Diabetes Federation (IDF) Diabetes Atlas, the estimated age-standardized prevalence (20–49 years) of hyperglycemia in pregnancy for South-East Asia is 25%.6 The prevalence rate for India is 27.5%, with 90% of women affected by GDM. The figures imply that there are nearly 5.4 million women in India annually, whose pregnancy is complicated by GDM.6 This represents a huge number at risk for future diabetes. It should also be borne in mind that diabetes develops at a younger age in Asian populations than in Caucasians.7 Hence, morbidity and mortality associated with diabetes and its complications are greater in young Asian people.7 The high rates of cardiovascular risk factors seen in relatively young Asian people substantially increase the lifetime risk of cardiovascular disease.

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RISK OF TYPE 2 DIABETES MELLITUS IN WOMEN WITH PRIOR GESTATIONAL DIABETES MELLITUS A recent meta-analysis found sevenfold increased risk of developing T2DM in women with gestational diabetes compared to women with normoglycemic pregnancy.8 There have been limited data in this context from India. Krishnaveni et al. found conversion rates of 37% to T2DM in 35 women with GDM at 5 years, as compared to 2% in controls.9 Kale et al. found conversion rates of 52% for T2DM at mean follow-up period of 4.5 years in 126 women with history of GDM.10 Tandon et al. reported conversion rates of 34.5% to diabetes and 40% to prediabetes within 5 years of delivery among women with history of GDM.11 It should be noted that modern recommendations of screening for GDM were not in place when these studies were planned, and some patients with GDM actually could be cases of overt diabetes or preexisting diabetes. However, the data clearly shows increased risk of development of diabetes as compared to other studies, and that too at an early age. These studies imply that the window of action is narrow for Asians, especially Indians, if we need to work to reduce the risk of diabetes. This chapter reviews the relationship between GDM and future risk of T2DM. While searching for ways to best utilize this narrow window, we pose, and try to answer three important questions: 1. What are the potential risk factors for T2DM in women with history of GDM? 2. How does one identify these women at risk? 3. How does one reduce this risk? POTENTIAL RISK FACTORS FOR TYPE 2 DIABETES MELLITUS IN WOMEN WITH HISTORY OF GESTATIONAL DIABETES MELLITUS The risk factors for development of T2DM can be divided into prepregnancy, pregnancy related factors, and postpartum factors (Table 1).

Table 1: Risk factors for type 2 diabetes mellitus in women with gestational diabetes mellitus Prepregnancy/general

Pregnancy

Postpartum

• Weight and body mass index

• Weight gain during pregnancy

• Anthropometric measures

• Family history of diabetes

• Gestational age at diagnosis of gestational diabetes mellitus

• Suboptimal breastfeeding

• More than one pregnancy complicated by gestational diabetes mellitus • Multiparity • Age • Ethnicity

• Method of glucose control

• Duration of follow-up • Progestin-only pills as contraception

• Basis of diagnosis of gestational diabetes mellitus

• Genetic risk

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Prepregnancy Prepregnancy Body Mass Index and Prepregnancy Weight A significant positive association between prepregnancy body mass index (BMI), prepregnancy weight, and the development of T2DM has been noticed. Pallardo et  al. found that, as compared with women with a prepregnancy BMI less than or equal to 27 kg/m2, women with a BMI greater than 27 kg/m2 had an eightfold increased risk of developing T2DM.12 Jang et al. reported that for every 1 kg increase in prepregnancy weight, there was a 40% increase in the odds of developing T2DM.13 Family History In a systematic review, for risk factors for T2DM among women with GDM, family history of T2DM was reported as risk factor in five studies. Only one study reported measure of association with relative risk of 1.7 with family history of T2DM.13 Parity In a systematic review, the relative hazard has been reported as 1.2 for women with parity 1–2, and relative hazard ratio as 2.5 with parity greater than 2 as compared to women with zero parity.14 Previous Pregnancy Complicated by Gestational Diabetes Mellitus In a systematic review, the odds ratio was 1.63 for future diabetes in women whose previous pregnancy was complicated by GDM as compared to those without such history.14 Pregnancy Weight Gain during Pregnancy In a meta-analysis of nine studies, women who had gestational weight gain that was below Institute of Medicine recommendations retained 3 kg less than women who had gestational weight gain within recommendations, at 6 months after pregnancy. Women who exceeded gestational weight gain recommendations retained 3 kg more than women with recommended weight gain, at 3 years after pregnancy as well as at 15 years postpartum.15 The risk of developing diabetes later on, correlates with the weight of the patient as discussed below. Gestational Age at Diagnosis of Gestational Diabetes Mellitus The studies reported a reduction in the likelihood of developing T2DM associated with a gestational age at gestational diabetes diagnosis in the fourth quartile as compared with the first quartile.16,17 Jang et al. assessed gestational age at gestational diabetes diagnosis as a continuous variable and found that for each week of increase in gestational age at gestational diabetes diagnosis, there was a 0.99 decrease in the odds of developing T2DM.13

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Method of Glucose Control Cheung and Helmink reported that compared with women who did not use insulin, those that used insulin during pregnancy had a threefold higher risk of developing T2DM.18 Löbner et al. reported that compared with women who were dietcontrolled, women who received insulin during pregnancy had an almost fivefold increased risk of developing T2DM after adjusting for confounding factors.19 It must be noted, however, that insulin requirement is an indicator of abnormal glucose metabolism. Patients who are well controlled on medical nutrition therapy have lesser degree of hyperglycemia. Basis of Diagnosis of Gestational Diabetes Mellitus The women who are diagnosed with more stringent Carpenter and Coustan criteria are more likely to progress to T2DM in future than those diagnosed with modern International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. Postpartum Anthropometric Measures Cho et al. assessed seven anthropometric parameters (weight, body fat weight, subscapular skin-fold thickness, suprailiac skin-fold thickness, triceps skinfold thickness, waist circumference, waist to hip ratio), comparing women in the highest quartile to those in the lowest quartile. Each of the seven measures was positively associated with the development of T2DM after adjustment of confounding factors.20 Increased waist circumference was the key risk factor for conversion of GDM women to T2DM in their study.20 Dacus et al. reported a fourfold increased risk in the development of T2DM among women with a postpartum BMI of 27 kg/m2 or greater compared with women with a postpartum BMI less than 27 kg/m2.21 Peters et al. assessed the association of the change in weight between delivery and follow-up and the development of T2DM.22 They reported that for every 10-pound change in weight, there was a twofold increase in the risk of developing T2DM.22 Postpartum weight not only increases the risk of T2DM, but is also associated with recurrence of GDM in subsequent pregnancy. In one recent examination of 22,351 women, women had a significant increase in their odds of gestational diabetes in their subsequent pregnancy with each unit of BMI gained between pregnancies.23 Specifically, women who gained 1–1.9 kg/m2 had 1.7 increased odds of future gestational diabetes; women who gained 2.0–2.9 kg/m2 had 2.5 increased odds, and women who gained over 3 kg/m2 had 3.4 increased odds.23 While less than 10% of women lost weight between pregnancies, women who were overweight or obese at their index pregnancy, but who then lost weight (approximately 2.0 kg/m2) significantly lowered their risk of future gestational diabetes by almost 80% [odds ratio 0.26, 95% confidence interval (CI) 0.14–0.47]. Of note, women who were not overweight at their index gestational diabetes pregnancy, but lost weight after their index pregnancy, did not significantly reduce their odds of future gestational diabetes.

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Duration of Follow-up A systematic review of studies investigating the incidence of postpartum T2DM in women with a history of GDM reported that 50% develop T2DM in the 5 years following delivery.24 After controlling for variable testing rates and lengths of follow-up between and within studies, progression to T2DM increased steeply in the first 5 years postpartum and then appeared to plateau.24 Bellamy et al. reported relative risk of 4.7 where follow-up duration was less than 5 years, whereas it was 9.3 in studies where follow-up was greater than 5 years as compared to normoglycemic women.8 Suboptimal Breastfeeding Suboptimal breastfeeding is considered as one of the risk factors for dysglycemia. Although the beneficial effects of lactation on maternal metabolism are known, it is uncertain if they influence the progression to glucose intolerance and overt diabetes in mid to late life, particularly among women with previous GDM.25 Lactation is characterized by increased glucose utilization and lipolysis through non-insulinmediated processes for milk production by the mammary gland, as well as higher maternal basal metabolic rates and mobilization of fat stores. Lactating women manifest lower blood glucose and insulin concentrations and higher glucose production rates resulting from increased glycogenolysis (not gluconeogenesis or increased use of free fatty acids).25 Emerging evidence indicates that lactation may have enhanced pancreatic β-cell mass and function, as well as decreased insulin resistance. In a study of women from the Atlantic Diabetes and Pregnancy Study, women who were classified as lactating versus non-lactating at the time of the 2-hour oral glucose tolerance test (OGTT) had a 60% lower odds of persistent dysglycemia.26 The Study of Women, Infant Feeding, and Type 2 Diabetes after GDM pregnancy (SWIFT), evaluated the relationship between lactation duration and intensity and postpartum glucose tolerance among women with a previous GDM pregnancy.27 SWIFT reported that higher lactation intensity at 6–9 weeks postpartum was inversely associated with lower fasting plasma glucose and insulin concentrations.27 Higher lactation intensity was also linked to lower prevalence of prediabetes among obese women as well as non-obese women with exclusive or mostly breastfeeding groups had lower prevalence of diabetes or prediabetes (p = 0.02).27 Contraceptive Methods There is no consistent evidence that combined oral contraceptives significantly influence the risk of developing diabetes, even in women with a history of gestational diabetes. The use of low-dose estroprogestive pills is now recognized as a safe and effective option in cases of use of contraception.28 Non-hormonal methods like intrauterine devices and tubal ligation are metabolically neutral and should not impact diabetes risk.29 Progestin-only preparations have been associated with increased diabetes risk from nonrandomized observational studies, so a cause-and-effect relationship has not been established clearly.29

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General Race or Ethnicity Aside from body mass, the most consistent risk factor for future glucose intolerance after a gestational diabetes delivery is non-White race/ethnicity.4 The cumulative incidence of diagnosed diabetes at the median follow-up time of 7.6 years was 16.5% and 1.8% for Chinese women with and without GDM, 25.7% and 1.8% for White women with and without GDM, and 31.8% and 3.6% for South-Asian women with and without GDM in a study by Mukerji et al.30 Genetic Risk After adjustment for age and ethnicity, the TCF7L2 rs7903146 and the FTO rs8050136 variants significantly predicted postpartum diabetes in one study.31 Variants in CDKN2A/2B and HHEX were associated with early conversion (2 months), whereas variants in CDKAL1 were associated with late conversion (1 year) to T2DM in another study.32 Weighted genetic risk score (wGRS) was significantly associated with the future development of diabetes in a study by Kwak et al.33 Age Age has also been reported as a risk factor after adjustment of covariates.14 However, meta-analysis did not find it as a major factor.8 Summary In a systematic review of risk factors for T2DM among women with GDM, substantial and consistent evidence was found with anthropometric measures of obesity, gestational age at gestational diabetes diagnosis, and method of glucose control.14 IDENTIFICATION OF WOMEN AT RISK Pregnancy provides an opportunity to screen women at high risk of developing diabetes in the future. In order to make full use of this opportunity, women with GDM are advised to have their glucose tolerance assessed 6 weeks after delivery and periodically.34 Postpartum screening helps identify women with early diabetes mellitus or prediabetes. Timely evidence-based interventions can be put in place to prevent further progression of disease. However, most studies show that less than 50% of women receive any glucose screening in the postpartum period and are thus denied this opportunity.35 REDUCTION OF RISK The majority of women with GDM have clinical characteristics indicating a risk for T2DM. Table 2 summarizes the important factors (modifiable and nonmodifiable) associated with increased risk of conversion to T2DM. We now discuss an action plan for the modifiable factors.

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Table 2: Modifiable and nonmodifiable risk factors for type 2 diabetes mellitus in women with gestational diabetes mellitus Modifiable risk factors

Nonmodifiable risk factors

• Major – Increase weight gain or retention from preconception to postpartum – Duration of follow-up at postpartum screening • Minor – Parity

• Major – Insulin use during pregnancy – Asian ethnicity – Gestational age at diagnosis • Minor – Family history of type 2 diabetes mellitus – Previous pregnancy complicated by gestational diabetes mellitus – Genetic risk – Age

– Breastfeeding – Contraceptive method – Basis of diagnosis of gestational diabetes mellitus

Interventions, such as lifestyle modification to promote weight loss, and pharmacotherapy to improve insulin sensitivity, have been shown to be effective in preventing or delaying the onset of T2DM in high-risk populations.36 Evidence supports lifestyle modification for women with GDM during pregnancy, and through the postpartum period.36 Clinical management should include assessment of glucose tolerance in the postpartum period to detect diabetes or assess diabetes risk. Studies also show that young women with GDM may not be aware of their diabetes risk. There also may be certain psychosocial barriers in increasing physical activity and adopting a healthy diet.35 Therefore, to reduce the risk for future diabetes in women with GDM, more effort is required than mere clinical consultations. We propose an action plan, which also takes the family and large community in its ambit. Lifestyle Modification Physical Activity and Diet The most successful intervention was among women who were overweight and glucose intolerant and enrolled in the Diabetes Prevention Program (DPP), a multicenter randomized trial that concluded in 2001.37 Among the 350 women with histories of gestational diabetes, intensive lifestyle change targeting 7% reduction in enrolment weight and increased physical activity led to significant reductions in diabetes incidence compared with placebo.37 The incidence of diabetes in women with gestational diabetes randomized to lifestyle was 7.4 per 100 person-years, compared with an incidence of diabetes in the placebo group of 15.2 per 100 person-years, with 53% reduction in incidence.37 Women with histories of gestational diabetes in the DPP were approximately 43 (±7.6) years of age and the date of their prior gestational diabetes pregnancy specifically was not known, although they were approximately 12 years from their last pregnancy. Moreover, women with a history of GDM in DPP were less successful in adhering to intensive lifestyle modification in the long term; they also lost less weight as compared to women without history of GDM. In addition, women who

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were at extremely high risk for diabetes, and perhaps with the greatest barriers to lifestyle change, would have already converted to diabetes in their first decade postpartum in DPP study.37 The feasibility or adoption of lifestyle modification may be limited among women with recent history of GDM, as these women may have to meet caregiving demands imposed by young children. A recent study highlighted the difficulties in recruitment of subjects in randomized controlled trial (RCT) study aimed at evaluation of the effectiveness of an established lifestyle intervention compared to standard care for delaying diabetes onset in European women with recent GDM. Only 22% women agreed to participate in the study.38 An observational study from O’Sullivan found that after 23 years of follow-up of women with a history of GDM, T2DM was present in 61% of the women who were obese prior to pregnancy, in 42% of the women who had gained weight since pregnancy, and in only 28% of the women who were not obese or had lost weight since pregnancy.39 An intervention for women with GDM that aims to avoid excessive gestational weight gain and help women to return to their prepregnancy weight in the postpartum period, or lose additional weight if overweight prior to pregnancy, has the potential to prevent T2DM in both the short- and long-term. Behavioral interventions are preferred to pharmacological interventions, which have the potential to harm developing fetus or breast-fed infant.36 There has been only one (early in first postpartum year) RCT published till date in 450 Chinese women who had GDM and IGT postpartum, and followed them for 36 months.40 Advice on diet and exercise was given to the intervention group. Fewer women in the intervention group developed DM (15% vs. 19%) but this was not statistically significant, and there was a lower incidence of DM among women over 40 years old.40 Healthier diets may be associated with decreased risk of diabetes among women with histories of gestational diabetes, although studies are few on this aspect.4 Among women with histories of gestational diabetes in the Nurses’ Health Study II cohort,41 women’s dietary patterns were scored by several scales examining degree of adherence to the Mediterranean diet, Dietary Approaches to Stop Hypertension (DASH) diet, and the Healthy Eating Index. Women who were the most adherent to or in the highest quartile of the Mediterranean diet scale had a 40% lower risk of T2DM compared with women in the lowest quartile. Similar reductions in risk were observed in women who were in the highest quartile of the DASH diet and the Healthy Eating Index compared with the lowest quartile. Among Korean women, greater animal fat intake was associated with the presence of prediabetes and diabetes in the early postpartum period.42 Ongoing Trials The Mothers after Gestational Diabetes in Australia Diabetes Prevention Program (MAGDA-DPP) aims to assess the effectiveness of a structured diabetes prevention intervention for post-GDM women. This trial will have an intervention group that will participate in a DPP, and a control group that will receive usual care from their general practitioners during the study period (12 months).43 Another 2-year, RCT in North Carolina tests the effects of intervention (breastfeeding, diabetes, nutrition and exercise education, coping skills training, exercise, a home-based exercise

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program, and weekly educational and motivational text messages) on maternal outcomes from baseline (22–36 weeks pregnant) to 10 months postpartum. Primary maternal outcomes will include fasting blood glucose and weight (BMI) from baseline to 10 months postpartum. This study will also quantify the effects of the intervention on infant feeding and growth.44 Tianjin Gestational Diabetes Mellitus Prevention Program being carried out in nearly 1,200 subjects will assess whether lifestyle intervention can reduce T2DM risk in women with prior GDM. The 1-year interim results support the efficacy and feasibility of the lifestyle intervention program.45 Pharmacotherapy The Troglitazone in Prevention of Diabetes (TRIPOD) was the first RCT to examine the effectiveness of a pharmacotherapy intervention in delaying or preventing the development of T2DM among women with a history of GDM. Women at high risk for developing T2DM, based on 75 g OGTT postpartum, were recruited. After 28–30 months of follow-up, the authors found a significantly lower cumulative incidence of diabetes among women receiving troglitazone as compared with women who received placebo (5.4% vs 12.1%).46 The TRIPOD trial was discontinued in between, as drug was withdrawn from the market due to reports of hepatotoxicity. In DPP study, metformin also resulted in significant reduction of about 50% in incidence of T2DM as compared to placebo among women with GDM.37 Postpartum Screening Clinical trials provide evidence that lifestyle modification as well as pharmacological intervention can prevent progression to T2DM in women with a history of GDM. There is also robust evidence that these interventions are as effective in GDM women as in people with prediabetes. Effective interventions, however, are possible only if high-risk individuals are identified. This, in turn, needs rigorous postpartum follow-up. There is a dire need to improve postpartum screening rates in women with history of GDM. In most studies, screening rates have been below 50%. Even in an RCT where postal reminders were sent to both doctors and patients, follow-up rates were a dismal 60%.47 Three important steps are necessary if we are to improve postpartum screening rates. These are: 1. Understanding barriers which results in poor postpartum screening 2. Channels or means to increase postpartum screening 3. Utilizing optimal screening tests, and in optimal frequency. Understanding the Barriers Patient-related: The change in attitude toward healthy lifestyle measures, among women with GDM after delivery, creates a challenge for any postpartum screening program. As highlighted by a recent European study, pregnancy motivated behavior changes to benefit the unborn child, but these changes were often not maintained after delivery. Women were aware of their risk of developing diabetes, but did not always act on such knowledge.48

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Tiredness, maternal attachment, and childcare demands were prominent barriers in the early postnatal months. Later, work, family, and child development became more significant barriers.48 In addition to these, distance from hospital, poor socioeconomic condition of the patient, pressure for household work, coming alone for testing, lack of adequate family support for child care, and inability of working women to come for glucose screening on working day, are seen as factors which negatively impact the postpartum screening response in developing countries like India.49 Doctor-related: There are marked differences amongst health care providers with relation to advising postpartum investigations. Shah et al. found that internists/ endocrinologists in Ontario, Canada ordered the majority of postpartum diabetes screening tests, and obstetricians the fewest.50 Stuebe and colleagues found primary care providers more likely than obstetricians in Massachusetts, United States, to order a postpartum screening test for women with a known history of GDM.51 Kim et al. investigated different scenarios to predict postpartum glucose testing in a University Hospital in Michigan, United States. After adjusting for confounders the only scenario that significantly predicted testing was a visit to an endocrinologist after delivery.52 We share similar sort of experience in our settings. Eight out of ten women with GDM are controlled by medical nutrition therapy alone,53 and most of them are not referred to physicians. This adversely affects postpartum screening, as most patients do not know what investigations have to be done, at what time, why and with whom to follow later on. There is low awareness regarding long-term implications of GDM. This is especially important as one-third of women with diabetes pass through the stage of GDM.18 Therefore, interdepartmental coordination along with communication amongst medical professionals is extremely important. Healthcare-related: Lack of universal insurance, easy access to centers, and inconsistent guidelines are major healthcare-related issues which results in poor postpartum screening.35 Health insurance schemes in India do not pay for postpartum screening tests. Utilizing the Best Screening Test There has been debate on which test needs to be implemented for increasing postpartum screening rates. It should be kept in mind that the 75 g OGTT remains the gold standard. Fasting glucose estimation may miss 30–40% of cases of T2DM, and will not detect isolated IGT. Glycosylated hemoglobin (HbA1c) as a screening test has not been adequately studied.4 In Asian populations, fasting plasma glucose (FPG) and HbA1c concentrations have much lower sensitivity than postprandial glucose concentration for detection of diabetes. In the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Asia (DECODA) study (a study of 11 Asian cohorts), more than half of patients with diabetes had isolated postprandial hyperglycemia.54 We feel that postpartum women with a history of GDM should be informed that OGTT is the most sensitive screening test. In cases of lack of acceptance or practical infeasibility of OGTT, FPG, or HbA1c can be used for postpartum screening.55

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Increasing Postpartum Screening The other problem in identifying postpartum diabetes after GDM, which may be of greater concern than the choice of test itself, is poor postpartum screening rate. In an RCT by Clark and colleagues, response rate was 60.5% in the group in which both patient as well as doctor received reminders for screening, but only 14.3% if no postal reminders were given.47 We feel that in view of the dramatic response to reminders, they should be introduced into regular practice.54 For example, in patients with normal glucose tolerance or HbA1c, reminders can be sent every 3 years. If results fall in the prediabetic range, reminders could be sent annually (as per American Diabetes Association guidelines on frequency of testing). If there is lack of response to periodic reminders (perhaps two or three), an effort should be made to contact the patient, i.e., a home visit by a health care worker. Collecting a sample at home would help to diagnose additional women with diabetes or at risk of diabetes. HbA1c may be best for this scenario as it is a single investigation and does not require fasting. Furthermore, home sampling could overcome barriers that prevent women from coming to healthcare facilities for investigation but which do not reflect their unwillingness for testing or further acceptance of healthcare advice.55 Recently, an Indian study found text messaging as cost-effective means of curtailing the risk of future diabetes in men. Utility of same if proven in women, especially postpartum women, would increase the postpartum screening rates, and reduce the progression to diabetes that too at low cost.56 An RCT on this aspect has been planned. Women in the intervention group will receive a text reminder to attend for an OGTT at 6 weeks postpartum, with further reminders at 3 months and 6 months if they do not respond to indicate test completion. Women in the control group will receive a single text message reminder at 6 months postpartum. This trial aims to assess whether a text message reminder system for women who have experienced gestational diabetes in their index pregnancy will increase attendance for OGTT within 6 months after birth.57 It should be remembered that screening is not an aim or an end-point; rather, it is a means or a strategy of limiting disease and its negative impact on the concerned individual, as well as society. While treatment of disease may belong to the corridors of hospitals, screening has to go beyond the ivory towers of modern medicine. We must remember that we have achieved success in smallpox and polio eradication, because health care reached the community’s doorsteps, not because the community came to us. INTEGRATING POSTPARTUM SCREENING INTO PRACTICE: AN INDIAN PERSPECTIVE India has a strong health care system. We discuss possible ways where we can improve postpartum screening for diabetes, by integrating this activity with preexisting health care. Clinic-based Interventions The clinic is a suitable ground for prevention of GDM. Personalized messages for women with history of GDM including leaflets and stickers, which can be attached

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to discharge cards, help in improving postpartum follow-up rates. The American Congress of Obstetricians and Gynecologists (ACOGs) provide a tear pad58 in English and Spanish to give to persons with GDM, during the late antenatal period, or after childbirth. Other clinic-based interventions include the use of posters, telephone calls, letters, and telemessages [short message services (SMS)] to remind women with GDM to return for postpartum follow-up. The use of SMS-based reminders has recently been demonstrated to help reduce the rate of progression of prediabetes to diabetes in Indian.56 The interventions listed above can be used to target not only women, but their immediate family members as well. The Indian mother-in-law plays an important role in deciding health care seeking and health care utilization patterns. Involving the mother-in-law in shared decision making during the antepartum and immediate postpartum period gives her a feeling empowerment, and facilitates the daughter-in-law’s visit to the health center for postpartum screening. Similarly, active involvement of the husband in obstetric care encourages him to bring the wife for postpartum checkup. Community-based Interventions Gestational DM is a condition which involves women, and is linked with nutrition. Woman-to-woman (WtW) strategy is the name given to sharing of knowledge, skill and confidence amongst women, on a 1:1 basis. This individualized strategy encourages sharing of information and skills, by practical methods, using indigenous solutions, among women. It promotes self-reliance and selfmanagement, and does not include didactic teaching or instruction. The WtW strategy has been put to good use in spreading nutrition awareness and health education. Establishing a successful WtW strategy in GDM will involve identification of local key women (women active in social, political, religious, or cultural organizations, who may be relatives of women with GDM, or women with a past history of GDM), and “target” women (women with GDM). Key messages which should be disseminated: the importance of early detection and management of diabetes; the need for postpartum screening and follow-up; who transfer the information to needy women, through informal conversation or dialogue, on a continuous basis. Such a strategy can be implemented by identifying and training key women amongst patients attending antenatal or gynecology clinics, or their relatives. Messages specific to GDM can be integrated into general health education, and combined with other facts-related maternal and reproductive health. Health Care System-based Strategies Postpartum follow-up of women with GDM should be integrated into existing health care system. This creates concordance with other reproductive/maternal and medical health care activities, maximizes efficiency of delivery, and improves acceptance of diagnostic and therapeutic interventions. India has a strong and extensive public health network, which works through a “bottom-up” approach. The vast system of primary, secondary and tertiary health centers is guided by well-drafted Indian Public Health Standards (IPHS), 2012 which

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lay down minimum requirements for provision of care at each level. Care and follow-up of GDM can easily be integrated into the IPHS. Postpartum Screening at Subcenters The health subcenter is acknowledged to be the first point of contact between the health care system and the community, providing interface with the community at the grass root level.59 Subcenters are expected to focus on all aspects of preventive care, including noncommunicable diseases, and maternal health. Postnatal care that must be provided (essential services) includes postnatal home visits on days 0, 3, 7, and 42 for home and subcenter delivers; days 3, 7, and 42 visits for institutional delivers; and additional visits on days 14, 21, and 28 to mothers with low-birth-weight babies.59 These visits are expected to include counseling on diet, and are a perfect opportunity to remind women with GDM to follow-up for postpartum screening. Subcenters are expected to provide minimum laboratory investigations including urine test for sugar, while linking up with primary health centers for other required tests. Activities to promote healthy lifestyle, sensitize the community about prevention of diabetes, and early detection of diabetes through enhanced awareness and referral are already a part of the subcenter’s duties.59 Hence, promoting postpartum screening glucose tolerance in women with GDM can become part of the health care providers’ work. Postpartum Screening at Primary Centers Recommendations for postnatal care at primary health care level state that the auxiliary nurse midwife (ANM) is expected to perform a home visit at 7th and 42nd day postpartum60 counseling for diabetes screening can easily be included in these visits. Three additional visits for mothers of low-birth-weight babies, on days 14, 21, and 28 provide additional opportunities for motivation.60 The mandate for primary health care centers also includes as essential activities, the “early detection, management and referral for DM, through simple measures like blood, urine sugar”. Both “urine test” and “blood sugar” are included in the list of essential laboratory services at this level.60 The Janani Suraksha Yojana (JSY) is laudable scheme, launched under the National Rural Health Mission, which links cash assistance with delivery and postdelivery care. Counseling for prevention, detection, management, and follow-up of GDM should be included in the JSY packages to help improve quality of care to the women enrolled in this scheme. This can easily be done at minimal cost. The National Immunization Programme makes it mandatory to administer oral polio vaccine, DPT (diphtheria, pertussis, tetanus) vaccine, and hepatitis B vaccines to infants at 6 weeks of age. The need for maternal postpartum screening at the same time should be explained along with advice for vaccination. If this is done successfully, India should easily be able to achieve near-universal postpartum screening for diabetes, just as it has done in the field of immunization. Vaccination dose to be administered at 10 weeks and 14 weeks provides further opportunities for glucose monitoring in women who bring the infants to the health center for these.

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Uristix for urine albumin and sugar analysis are included in essential laboratory reagents, while glucometer is listed under essential glassware and other equipments, though it is qualified by a “desirable” description. Thus, already available manpower and facilities can easily be leveraged to provide screening to women with GDM. Combining this screening with home visit or with immunization-related visits obviates the need for extra travel to the health center. Integration of this activity with preexisting maternal and child health service, instead of creating a new “vertical” system, will enhance its acceptability among both health workers and patients. Postpartum Screening at Community Health Centers The community health center is expected to provide essential services, including health promotion, to “healthy population” treatment, timely referral, and certain assured investigations including urine sugar, blood sugar to persons with DM.61 Early detection of diabetes, by clinical and laboratory methods, and risk stratification, is considered a desirable (as opposed to partum screening of diabetes in women with GDM as an essential activity at the community health center level). As these centers are staffed by a physician and obstetrician, apart from by other doctors, this activity should be easy to perform. Postpartum Screening at District Hospitals Indian Public Health Standards for District Hospitals specify a “recommended service mix” or suggested action for different illnesses in all specialties, including obstetrics.62 This exhaustive list, which includes various obstetric and medical complications of pregnancy, should be expanded to include GDM and postpartum case of GDM. This will help formalize the existence of GDM as a significant source of morbidity, and add impetus to its management and prevention. The action required at an individual level is summarized in figure 1 and that required beyond an individual is summarized in table 3.

Fig. 1:  Levels of risk modification in gestational diabetes mellitus.

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Table 3: Actions required to improve postpartum follow-up Family

Community

Health care system

• Involving family members, especially husband and mother-in-law

• V  olunteer women with gestational diabetes mellitus (GDM) can themselves become role models for others • Involving influential women of the region in this cause

• I ntegrating postpartum screening and lifestyle modification advice with existing health care services like Universal Immunization Programme, Janani Suraksha Yojana

Conclusion Women with history of GDM are at increased risk for glucose intolerance following delivery, including gestational diabetes in future pregnancies, and T2DM. Diabetes develops at a younger age in Asian populations than in Caucasians. There are nearly 5.4 million women in India annually, whose pregnancy is complicated by GDM. The conversion rates to T2DM are high in India, giving us narrow window of opportunity for action. There are certain barriers which results in poor postpartum screening rates. Even, after detection of women at high risk of future T2DM, implementation of healthy lifestyle itself comes as a challenge. There is need to increase postpartum screening rates, as well as to develop strategies to overcome the challenges. Involvement of family members of women and volunteers from community, and integration of postpartum screening with existing health care programs will help us in reducing the risk of future T2DM in women with history of gestational diabetes. REFERENCES 1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2006;29(Suppl 1):S43-8. 2. Blumer I, Hadar E, Hadden DR, et al. Diabetes and pregnancy: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2013;98(11):4227-49. 3. Coustan DR. Gestational diabetes mellitus. Clin Chem. 2013;59(9):1310-21. 4. Kim C. Maternal outcomes and follow-up after gestational diabetes mellitus. Diabet Med. 2014;31(3):292-301. 5. Carr DB, Utzschneider KM, Hull RL, et al. Gestational diabetes mellitus increases the risk of cardiovascular disease in women with a family history of type 2 diabetes. Diabetes Care. 2006;29(9):2078-83. 6. Guariguata L, Linnenkamp U, Beagley J, et al. Global estimates of the prevalence of hyperglycaemia in pregnancy. Diabetes Res Clin Pract. 2014;103(2):176-85. 7. Ramachandran A, Ma RC, Snehalatha C. Diabetes in Asia. Lancet. 2010;375(9712):408-18. 8. Bellamy L, Casas JP, Hingorani AD, et al. Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis. Lancet. 2009;373(9677):1773-9. 9. Krishnaveni GV, Hill JC, Veena SR, et al. Gestational diabetes and the incidence of diabetes in the 5 years following the index pregnancy in South Indian women. Diabetes Res Clin Pract. 2007;78(3):398-404. 10. Kale SD, Yajnik CS, Kulkarni SR, et al. High risk of diabetes and metabolic syndrome in Indian women with gestational diabetes mellitus. Diabet Med. 2004;21(11):1257-8. 11. Tandon N, Gupta Y, Kapoor D, Doddamaneni S, Rozati R, Bhatla N, et al.  Distribution of glucose tolerance among women with previous history of gestational diabetes mellitus in

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12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36.

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urban India. Abstract: OP-0579. Presented at IDF 2013. Available from: http://conference2.idf. org/MEL2013/World%20Diabetes%20Congress%202013/data/HtmlApp/main.html#. Pallardo F, Herranz L, Garcia-Ingelmo T, et al. Early postpartum metabolic assessment in women with prior gestational diabetes. Diabetes Care. 1999;22(7):1053-8. Jang HC, Yim CH, Han KO, et al. Gestational diabetes mellitus in Korea: prevalence and prediction of glucose intolerance at early postpartum. Diabetes Res Clin Pract. 2003;61(2):117-24. Baptiste-Roberts K, Barone BB, Gary TL, et al. Risk factors for type 2 diabetes among women with gestational diabetes: a systematic review. Am J Med. 2009;122(3):207-214.e4. Nehring I, Schmoll S, Beyerlein A, et al. Gestational weight gain and long-term postpartum weight retention: a meta-analysis. Am J Clin Nutr. 2011;94(5):1225-31. Kjos SL, Peters RK, Xiang A, et al. Predicting future diabetes in Latino women with gestational diabetes. Utility of early postpartum glucose tolerance testing. Diabetes. 1995;44(5):586-91. Schaefer-Graf UM, Buchanan TA, Xiang AH, et al. Clinical predictors for a high risk for the development of diabetes mellitus in the early puerperium in women with recent gestational diabetes mellitus. Am J Obstet Gynecol. 2002;186(4):751-6. Cheung NW, Helmink D. Gestational diabetes: the significance of persistent fasting hyperglycemia for the subsequent development of diabetes mellitus. J Diabetes Complications. 2006;20(1):21-5. Löbner K, Knopff A, Baumgarten A, et al. Predictors of postpartum diabetes in women with gestational diabetes mellitus. Diabetes. 2006;55(3):792-7. Cho NH, Jang HC, Park HK, et al. Waist circumference is the key risk factor for diabetes in Korean women with history of gestational diabetes. Diabetes Res Clin Pract. 2006;71(2):177-83. Dacus JV, Meyer NL, Muram D, et al. Gestational diabetes: postpartum glucose tolerance testing. Am J Obstet Gynecol. 1994;171(4):927-31. Peters RK, Kjos SL, Xiang A, et al. Long-term diabetogenic effect of single pregnancy in women with previous gestational diabetes mellitus. Lancet. 1996;347(8996):227-30. Ehrlich SF, Hedderson MM, Feng J, et al. Change in body mass index between pregnancies and the risk of gestational diabetes in a second pregnancy. Obstet Gynecol. 2011;117(6):1323-30. Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care. 2002;25(10):1862-8. Gunderson EP. The role of lactation in GDM women. Clin Obstet Gynecol. 2013;56(4):844-52. O’Reilly MW, Avalos G, Dennedy MC, et al. Atlantic DIP: high prevalence of abnormal glucose tolerance postpartum is reduced by breast-feeding in women with prior gestational diabetes mellitus. Eur J Endocrinol. 2011;165(6):953-9. Gunderson EP, Hedderson MM, Chiang V, et al. Lactation intensity and postpartum maternal glucose tolerance and insulin resistance in women with recent GDM: the SWIFT cohort. Diabetes Care. 2012;35(1):50-6. Gourdy P. Diabetes and oral contraception. Best Pract Res Clin Endocrinol Metab. 2013;27(1):67-76. Buchanan TA, Page KA. Approach to the patient with gestational diabetes after delivery. J Clin Endocrinol Metab. 2011;96(12):3592-8. Mukerji G, Chiu M, Shah BR. Impact of gestational diabetes on the risk of diabetes following pregnancy among Chinese and South Asian women. Diabetologia. 2012;55(8):2148-53. Ekelund M, Shaat N, Almgren P, et al. Genetic prediction of postpartum diabetes in women with gestational diabetes mellitus. Diabetes Res Clin Pract. 2012;97(3):394-8. Kwak SH, Choi SH, Jung HS, et al. Clinical and genetic risk factors for type 2 diabetes at early or late postpartum after gestational diabetes mellitus. J Clin Endocrinol Metab. 2013;98(4):E744-52. Kwak SH, Choi SH, Kim K, et al. Prediction of type 2 diabetes in women with a history of gestational diabetes using a genetic risk score. Diabetologia. 2013;56(12):2556-63. American Diabetes Association. Standards of medical care in diabetes--2014. Diabetes Care. 2014;37(Suppl 1):S14-80. Keely E. An opportunity not to be missed--how do we improve postpartum screening rates for women with gestational diabetes? Diabetes Metab Res Rev. 2012;28(4):312-6. Ferrara A, Ehrlich SF. Strategies for diabetes prevention before and after pregnancy in women with GDM. Curr Diabetes Rev. 2011;7(2):75-83.

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Factors Predicting the Development of Type 2 Diabetes Mellitus in Women with Prior ... 37. Ratner RE, Christophi CA, Metzger BE, et al. Prevention of diabetes in women with a history of gestational diabetes: effects of metformin and lifestyle interventions. J Clin Endocrinol Metab. 2008;93(12):4774-9. 38. Infanti JJ, O’Dea A, Gibson I, et al. Reasons for participation and non-participation in a diabetes prevention trial among women with prior gestational diabetes mellitus (GDM). BMC Med Res Methodol. 2014;14:13. 39. O’Sullivan JB. Gestational diabetes: factors influencing the rates of subsequent diabetes. In: Sutherland HW, Stowers JM, editors. Carbohydrate Metabolism in Pregnancy and the Newborn 1978. Berlin, Germany: Springer-Verlag; 1979. p. 425-35. 40. Shek NW, Ngai CS, Lee CP, et al. Lifestyle modifications in the development of diabetes mellitus and metabolic syndrome in Chinese women who had gestational diabetes mellitus: a randomized interventional trial. Arch Gynecol Obstet. 2014;289(2):319-27. 41. Tobias DK, Hu FB, Chavarro J, et al. Healthful dietary patterns and type 2 diabetes mellitus risk among women with a history of gestational diabetes mellitus. Arch Intern Med. 2012;172(20):1566-72. 42. Kim SH, Kim MY, Yang JH, et al. Nutritional risk factors of early development of postpartum prediabetes and diabetes in women with gestational diabetes mellitus. Nutrition. 2011;27(7-8):782-8. 43. Shih ST, Davis-Lameloise N, Janus ED, et al. Mothers After Gestational Diabetes in Australia Diabetes Prevention Program (MAGDA-DPP) post-natal intervention: study protocol for a randomized controlled trial. Trials. 2013;14:339. 44. Berry DC, Neal M, Hall EG, et al. Rationale, design, and methodology for the optimizing outcomes in women with gestational diabetes mellitus and their infants study. BMC Pregnancy Childbirth. 2013;13:184. 45. Hu G, Tian H, Zhang F, et al. Tianjin Gestational Diabetes Mellitus Prevention Program: study design, methods, and 1-year interim report on the feasibility of lifestyle intervention program. Diabetes Res Clin Pract. 2012;98(3):508-17. 46. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes. 2002;51(9):2796-803. 47. Clark HD, Graham ID, Karovitch A, et al. Do postal reminders increase postpartum screening of diabetes mellitus in women with gestational diabetes mellitus? A randomized controlled trial. Am J Obstet Gynecol. 2009;200(6):634.e1-7. 48. Lie ML, Hayes L, Lewis-Barned NJ, et al. Preventing type 2 diabetes after gestational diabetes: women’s experiences and implications for diabetes prevention interventions. Diabet Med. 2013;30(8):986-93. 49. Gupta Y, Gupta A. Response to Lie et al. Preventing type 2 diabetes after gestational diabetes: women’s experiences and implications for diabetes prevention interventions. Diabet Med. 2013;30(12):1509-10. 50. Shah BR, Lipscombe LL, Feig DS, et al. Missed opportunities for type 2 diabetes testing following gestational diabetes: a population-based cohort study. BJOG. 2011;118(12):1484-90. 51. Stuebe A, Ecker J, Bates DW, et al. Barriers to follow-up for women with a history of gestational diabetes. Am J Perinatol. 2010;27(9):705-10. 52. Kim C, Tabaei BP, Burke R, et al. Missed opportunities for type 2 diabetes mellitus screening among women with a history of gestational diabetes mellitus. Am J Public Health. 2006;96(9):1643-8. 53. Crowther CA, Hiller JE, Moss JR, et al. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005;352(24):2477-86. 54. Qiao Q, Hu G, Tuomilehto J, et al. Age- and sex-specific prevalence of diabetes and impaired glucose regulation in 11 Asian cohorts. Diabetes Care. 2003;26(6):1770-80. 55. Gupta Y, Gupta A. Post-partum screening after gestational diabetes. Lancet Diabet Endocrinol. 2013;1(2):90-1. 56. Ramachandran A, Snehalatha C, Ram J, et al. Effectiveness of mobile phone messaging in prevention of type 2 diabetes by lifestyle modification in men in India: a prospective, parallelgroup, randomised controlled trial. Lancet Diabet Endocrinol. 2013;1(3):191-8.

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Contemporary Topics in Gestational Diabetes Mellitus 57. Heatley E, Middleton P, Hague W, et al. The DIAMIND study: postpartum SMS reminders to women who have had gestational diabetes mellitus to test for type 2 diabetes: a randomised controlled trial - study protocol. BMC Pregnancy Childbirth. 2013;13:92. 58. American Congress of Obstetricians and Gynecologists (ACOG). (2009). Tool for postpartum GDM follow-up. [online] Available from: www.acog.org/~/media/Departments/Public%20 Health%20and%20Social%20Issues/Diabetes%20Tear%20Pad.pdf?dmc=1&ts=20140 112T0918016104. [Accessed March, 2014]. 59. Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India. (2012). Indian Public Health Standards (IPHS) Guidelines for Sub-Centres. [online] Available from: health.bih.nic.in/Docs/Guidelines/Guidelines-Sub-Centers-%28Revised%29-2012.pdf. [Accessed March, 2014]. 60. Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India. (2012). Indian Public Health Standards (IPHS) Guidelines for Primary Health Centres. [online] Available from: health.bih.nic.in/Docs/Guidelines/Guidelines-PHC-2012.pdf. [Accessed March, 2014]. 61. Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India. (2012). Indian Public Health Standards (IPHS) Guidelines for community Health Centres. [online] Available from: health.bih.nic.in/Docs/Guidelines/Guidelines-CommunityHealth-Centres.pdf. [Accessed March, 2014]. 62. Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India. (2012). Indian Public Health Standards (IPHS) Guidelines for District Hospitals (101 to 500 Bedded). [online] Available from: health.bih.nic.in/Docs/Guidelines/Guidelines-DistrictHospitals-2012.pdf. [Accessed March, 2014].

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Postpartum Care and Breastfeeding in Gestational Diabetes Mellitus, Benefits for Mother and Baby

25

Smiti Nanda, Sanjiv Nanda

INTRODUCTION In the postnatal period, glucose metabolism in women who have been diagnosed with gestational diabetes mellitus (GDM) may return to normal, or there may be ongoing impaired glucose regulation or impaired fasting glycemia (IGT) or frank diabetes (including preexisting type 1 or type 2 diabetes that was unrecognized before pregnancy). Women who have been diagnosed with GDM are likely to develop type 2 diabetes postnatally and should be informed of the symptoms of hyperglycemia and its associated metabolic abnormalities, including hypertension, dyslipidemia, and atherosclerotic cardiovascular disease (Box 1).1,2 Less than 10% of women with GDM remain hyperglycemic after delivery. The management of these women requires ongoing care. Approximately 35–65% of women go on to develop type 2 diabetes within 10 years. There is evidence that prevention information and lifestyle/education interventions are effective for people with IGT to prevent progression to type 2 diabetes and, therefore, women who have been diagnosed with GDM should be offered lifestyle advice and follow-up to have their blood glucose tested at the 6 week postnatal check, and annually thereafter.3 Regular physical activity, healthy eating, and weight control are important preventive measures. It is proven that regular physical activity improves blood glucose control, reduces cardiovascular risk factors, contributes to weight loss, and improves overall well-being. However, a 2-hour 75 g oral glucose tolerance test (OGTT) is recommended at the 6- to 12-week postpartum check, then at 1 year followed by at least every 3 years thereafter.4 Table 1 summarizes the postpartum recommendations for women with GDM.5 Thus prior to discharge, all women with GDM should be offered information about: •• Healthy eating patterns (small frequent low fat meals and snacks) •• Regular physical activity (30 min/day—moderate intensity) •• Weight control •• Contraception Box 1:  Postnatal risks of uncontrolled gestational diabetes to the mother • •

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Development of gestational diabetes mellitus in subsequent pregnancies Development of metabolic disorders later in life (hypertension, dyslipidemia, arterio­ sclerotic cardiovascular disease, and type 2 diabetes

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Table 1: Postpartum recommendations for women with gestational diabetes mellitus Periodically evaluate glucose tolerance

Women with GDM should be screened for diabetes with a 75 g. 2-hour OGTT at 6–12 weeks (before 3 months) postpartum or after 3 months postpartum, an HbA1c test should be done to determine her diabetic status • If the screen is normal, repeat at 1 year after delivery and every 3 years thereafter as long as values remain within normal limits • Encourage women to obtain a glucose screen before conceiving again • Subsequent pregnancy should include early prenatal care, risk-assessment, and testing for GDM with a 2-hour 75 g OGTT • If prediabetes, IGT/IFG is diagnosed, refer for aggressive lifestyle change. This include: –  Seeing a dietician for medical nutrition therapy –  Receiving instruction regarding activity, and/or – Evaluation for the need for insulin sensitizer medication, such as metformin • If diabetes is diagnosed postpartum, refer the woman to a specialist

Evaluate for other metabolic risk factors

• 1 year after delivery and yearly thereafter • Follow recommendations for testing and evaluations, such as lipids, waist-hip ratio, etc.

HbA1c, glycosylated hemoglobin; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; OGTT, oral glucose tolerance test.

•• Long-term follow-up •• Preconception counseling •• Future pregnancy. INFANT RISKS RELATED TO MATERNAL HYPERGLYCEMIA* (BOX 2) Infant risks related to maternal hyperglycemia include (American Diabetes Association, 2012):6 •• Maternal vascular disease affects the uterine blood supply, resulting in fetal growth restriction (FGR) or intrauterine growth restriction (IUGR) •• Hypoglycemia is more common in infants born to mothers on insulin and may require intravenous glucose infusions •• Effects of hyperviscosity or hyperbilirubinemia may be complications in the infant •• Fetal lung maturity may be delayed, resulting in respiratory distress syndrome (RDS) at higher gestational ages, than typically seen •• Hypertrophic cardiomyopathy may be significant enough to require medication •• Neurologically, infants may be immature, have hypotonicity, and a poor suck reflex that delays adequate oral feeding development •• Infants born to mothers with diabetes are at a higher risk for overweight or obesity, as well as glucose intolerance in childhood and thereafter.

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Box 2: Postnatal risks of uncontrolled gestational diabetes to the infant •  Hypoglycemia •  Hypocalcemia •  Respiratory distress syndrome •  Convulsions •  Polycythemia •  Jaundice •  Hypertrophic cardiomyopathy •  Increased risk of developing type 2 diabetes later in life •  Increased risk of obesity later in life

BREAST-FEEDING AND LACTATION Breast milk provides the best nutrition for babies and breast-feeding is recommended for all mothers with either preexisting diabetes or GDM. Research shows that breastfed infants are less likely to become overweight or obese, even if the mother is overweight, obese, or has diabetes. For children at higher risk for type  2 diabetes or obesity because of family history, breast-feeding may play a critical role in helping to lower the risk of obesity throughout the child’s lifetime. Although the exact relationship is not known, it appears that breast-feeding may reduce the risk for developing type 2 diabetes by as much as 39%. Other health benefits of exclusive breast-feeding for the infant include fewer problems with infectious and noninfectious diseases, and milder cases of respiratory infections ear infections and diarrhea.7,8 Recommendations are: •• Early (preferably in the first half hour of life) and often (10–12 times per 24 hours), breastfeeding can reduce the risk of hypoglycemia for the newborn. Recommendations are same for the women who undergo Caesarean birth •• The newborn’s first blood glucose should be obtained after breastfeeding within 30–60 minutes of life or earlier, when indicated by symptoms in the newborn of low blood sugar •• As in pregnancy, the need for certain nutrients increases while breastfeeding. It is important to assure adequate intakes of protein, calcium, magnesium, zinc, vitamin B12, vitamin D, foliate, and vitamin B6. Fluid intake can affect breast milk production, so mothers are encouraged to drink at least eight cups of fluids daily. Consider the risks and benefits during lactation of any medication prior to starting it. The benefits of breastfeeding are an important consideration in determining treatment. There is clear evidence that glibenclamide does not appear in breast milk in more than negligible quantities, and metformin levels in milk are also very low. It is, therefore, reasonable to use these with breastfeeding, if required. However, close monitoring of infant for signs of hypoglycemia is important. Signs of hypoglycemia for the infant include irritability, tremors, jitteriness, lethargy, high pitched or weak cry, apnea or irregular breathing, and convulsions or localized seizures.7-9

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CONTRACEPTIVE CHOICES FOLLOWING A PREGNANCY WITH GESTATIONAL DIABETES MELLITUS (TABLE 2) Women with GDM require effective and safe contraception that suits their lifestyle and does not enhance the risk of developing diabetes, metabolic syndrome, or cardiovascular complications. In the first 5 years after a pregnancy with GDM, a subsequent pregnancy may increase the conversion to overt diabetes. A pregnancy longer than 5 years, after a GDM pregnancy, has a slower rate of conversion to type 2 diabetes and plateaus after 10 years. Studies on contraception in women with prior GDM are limited. Maximizing blood glucose control during the interconception period is a priority. Delaying pregnancy for at least 2 years during this transition period is recommended. As is similar for woman with type 2 diabetes, it is desirable to use the most effective method of birth control with the least adverse effect on carbohydrate metabolism. Efficacy is highest for long-term contraceptive methods, somewhat less high for short-term hormonal therapies (for which daily, weekly, monthly, or quarterly dosing may affect adherence and thus, efficacy) and lowest for barrier or behavioral methods. Women with prior GDM have many contraceptive options and generally can use all forms of contraception, following essentially the same guidelines as other women. The only significant exception is that progestin-only methods during lactation should be avoided or used with caution. Also, cardiovascular risks and baseline health should be considered when prescribing hormonal methods.10 Patients with diabetes mellitus should be counseled about all contraceptive options, including such long-term methods as IUCDs and subdermal implants as first-line recommendations. If the GDM woman does not anticipate conceiving in the few years after the postpartum, IUCDs are highly effective methods that do not appear to adversely affect glucose metabolism. Copper T (CuT 380A) and the levonorgestrel-releasing IUCD are the most commonly used.10,12 For women who have completed childbearing and do not desire pregnancy, surgical sterilization is an excellent option. Vasectomy or bilateral tubal ligation is easy to perform, has little morbidity, and obviously does not adversely affect women’s metabolic profile.11,12 Since GDM is a high risk condition, the following advice may be re-emphasized at every follow-up: Healthy eating habits: A primary focus of GDM education throughout pregnancy and postpartum is to encourage healthy eating. Women with GDM are given

Table 2: World Health Organization medical eligibility criteria for contraceptive use in gestational diabetes mellitus

History of gestational diabetes mellitus

Combined hormonal (pill, patch, ring)

Pregesteroneonly pill

Pregesterone injectable (DMPA)

Implant

IUCD

LNGIUS

1

1

1

1

1

1

DMPA, depot medroxy progesterone acetate; IUCD, intrauterine contraceptive device; LNG-IUS, levonorgestrel intrauterine system.

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information to empower them to make healthy food choices for themselves and their families.5 Regular exercise: Research has demonstrated that a physically active lifestyle plays an important role in the prevention of type 2 diabetes. Physical inactivity postpartum is associated with poor physical function, poor vitality, and depressive symptoms and increased risk of developing type 2 diabetes. Early recognition of features of frank diabetes mellitus: Women who have had GDM should be taught to recognize signs and symptoms that are indicative of diabetes. These include increase thirst and urination, repeat vaginal fungal infections or urinary tract infections, unexplained weight loss, blurring of vision, or extreme tiredness.2,5,6 Next pregnancy: She should space future pregnancies at least 2 years apart and get a 2-hour, 75 g OGTT or HbA1c test before her next pregnancy. A woman who has had GDM should be screened for hyperglycemia at the first prenatal visit. Regular physical check-up: Even women with mild GDM are at increased risk of developing cardiovascular disease. Regular physical check-up, including blood pressure, eye, dental, and foot examinations, is recommended. Without adequate follow-up evaluation and testing, type 2 diabetes may go undetected for several years, during which time cardiovascular damage from elevated blood glucose can be a major problem. At each visit, blood pressure and weight should be measured and a healthy lifestyle should be reinforced.5 References 1. Baptiste-Roberts K, Barone BB, Gary TL, et al. Risk factors for type 2 diabetes among women with gestational diabetes: a systematic review. Am J Med. 2009;122(3):207-14. 2. Bellamy L, Casas JP, Hingorani AD, Williams D. Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis. Lancet. 2009;373(9677):1773-9. 3. McGovern A, Butler L, Jones S, et al. Diabetes screening after gestational diabetes in England: a quantitative retrospective cohort study. Br J Gen Pract. 2014;64:e17-e23. 4. Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care. 2002;25(10):1862-8. 5. American Diabetes Association. Standards of Medical Care in Diabetes—2014. Diabetes Care. 2014;37(Suppl. 1):S14-S80. 6. American Diabetes Association. Standards of Medical Care in Diabetes—2012. Diabetes Care. 2012;35:S11-S63. 7. Barnes-Powell LL. Infants of diabetic mothers: the effects of hyperglycemia on the fetus and neonate. Neonatal Netw. 2007;26(5):283-90. 8. Gunderson EP. Breastfeeding after gestational diabetes pregnancy. Subsequent obesity and type 2 diabetes in women and their offspring. Diabetes Care. 2007;30:S161-S168. 9. Ziegler AG, Wallner M, Kaiser I, et al. Long-term protective effect of lactation on the develop­ ment of type 2 diabetes in women with recent gestational diabetes mellitus. Diabetes. 2012;61(12):3167-71. 10. Understanding and using the U.S. Medical Eligibility Criteria for contraceptive use, 2010. Committee Opinion No. 505. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2011;118:754-60. 11. Beydoun HA, Beydoun MA, Tamim H. How does gestational diabetes affect postpartum contraception in nondiabetic primiparous women? Contraception. 2009;79(4):290-6. 12. Kerlan V. Postpartum and contraception in women after gestational diabetes. Diabetes Metab. 2010;36(6 Pt 2):566-74.

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Appendix A

North Indian Diet Charts for Women with Gestational Diabetes Mellitus North Indian Diet Chart 1: 1,600 kcal Early morning

6.00–6.30 am

Tea/coffee (skimmed milk without sugar)

150 mL

Breakfast: I

8–8.30 am

Brown bread/ Small roti/ Thepla/vegetable wheat paratha (Radius - 6”) Poha/upma Mint/coriander chutney

2 1 1 1 Katorie ½ Cup

Breakfast: II

10–10.30 am

Brown bread/ Small roti/ Thepla/vegetable wheat paratha (Radius - 6”) Poha/upma Mint/coriander chutney

2 1 1 1 Katorie ½ Cup

Midmorning

11.30–12.00 pm

Fruits-small (apple/pear/guava/sweet lime)

1

Lunch

1.00–1.30 pm

Roti/chappati Boiled rice with Dal Curd/rasam Salad

2 1 Katorie 1 Cup 1 Cup 1 Cup

Tea-time

4–4.30 pm

Whole moong/chana Tea/coffee/skimmed milk

1 Cup 150 mL

Dinner

8–8.30 pm

Roti/bhakri Phulka/chappati Curd/dhal

2 2 1 Cup

Bedtime

10–10.30 pm

Skimmed milk Marie biscuits

150 mL 2 nos

1 Cup = 120 mL; 1 Katorie =150 mL.

North Indian Diet Chart 2: 1,800 kcal Early morning

6.00–6.30 am

Tea/coffee (skimmed milk without sugar)

150 mL

Breakfast: I

8–8.30 am

Brown bread/ Small roti/ Thepla/vegetable wheat paratha (Radius - 6”) Poha/upma Mint/coriander chutney

2 1 1 1 Katorie ½ Cup Contd...

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Contemporary Topics in Gestational Diabetes Mellitus Contd... Breakfast: II

10–10.30 am

Brown bread/ Small roti/ Thepla/vegetable wheat paratha (Radius - 6”) Poha/upma Mint/coriander chutney

2 1 1 1 Katorie ½ Cup

Midmorning

11.30–12.00 pm

Fruits-small (apple/pear/guava/sweet lime)

1

Lunch

1.00–1.30 pm

Roti/chappati/phulka Boiled rice with Dal Curd/rasam Salad or Fish/chicken (boiled)

2 1½ Katorie 1 Cup 1 Cup 1 Cup 100 g

Tea-time

4–4.30 pm

Whole moong/chana Tea/coffee/skimmed milk

1 Cup 150 mL

Dinner

8–8.30 pm

Roti/bhakri Phulka/chappati Curd/dal

3 3 1 Cup

Bedtime

10–10.30 pm

Skimmed milk Marie biscuits

150 mL 3 nos

1 Cup = 120 mL; 1 Katorie = 150 mL.

North Indian Diet Chart 3: 2,000 kcal Early morning

6.00–6.30 am

Tea/coffee (skimmed milk without sugar)

150 mL

Breakfast: I

8–8.30 am

Toast with Egg (boiled) Idli/dosa Mint/coriander chutney

3 1 2 ½ Cup

Breakfast: II

10–10.30 am

Toast with Egg (boiled) Idli/dosa Mint/coriander chutney

3 1 2 ½ Cup

Midmorning

11.30–12.00 pm

Small orange Tomato soup

1 1 Cup

Lunch

1.00–1.30 pm

Rice/ Sambar Vegetables Butter milk Cucumber/sprouts salad or Egg or Fish/chicken (boiled)

2 Cup 1 Cup 1 Cup 1 Cup 1 Cup 1 100 g

Tea-time

4–4.30 pm

Rajmah/Bengal gram whole Teal/milk

1C 150 mL

Dinner

8–8.30 pm

Chappati Dal Mixed vegetable curry/ Chicken gravy Fresh salad

3 1 Cup 1 Cup ½ Cup ½ Cup

Bedtime

10–10.30 pm

Milk Walnuts

150 mL 4 nos

1 Cup = 120 mL; 1 Katorie = 150 mL.

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Appendix A: North Indian Diet Charts for Women with Gestational Diabetes Mellitus

North Indian Diet Chart 4: 2,200 kcal Early Morning

6.00–6.30 am

Tea/coffee (skimmed milk without sugar)

150 mL

Breakfast: I

8–8.30 am

Phulka + sabji/ Wheat bread/ Poha/semiya Dhalia

2 2 1 Cup 1 Cup

Breakfast: II

10–10.30 am

Phulka + sabji/ Wheat bread/ Poha/semiya Dhalia

2 2 1 Cup 1 Cup

Midmorning

11.30–12.00 pm

Lemon juice/ Butter milk/ Vegetable soup

150 mL

Lunch

1.00–1.30 pm

Rice/ Greens + dal Vegetables Curd/raita Salad with sprouts Egg

2 Katorie 1 Cup 1 Cup ½ Cup 1 Cup 1

Tea-time

4–4.30 pm

Tea/coffee/milk Boiled grams/sprouts/ Brown bread with salad

150 mL 1 Cup 2

Dinner

8–8.30 pm

Chappati Chicken or fish curry/ Dal/vegetable curry

2 1 Cup 1 Cup

Bedtime

10–10.30 pm

Skimmed milk Threptin biscuits

150 mL 3 nos

1 Cup = 120 mL; 1 Katorie = 150 mL.

North Indian Diet Chart 5: 2,400 kcal Early Morning

6: 00 am

Tea or coffee or milk

150 mL

Breakfast

8:00–8:30 am

Idli or Dosa or chappati and Sambar or chutney or vegetable curry and Egg white or Low fat paneer

3 nos 2 nos 1 cup

Midmorning

10:30–11:00 am

Fruit or Salad or Buttermilk or Vegetable soup and Dry nuts

200 g 1 Cup 150 mL 150 mL 50 g

Lunch

12:30–1:30 pm

Rice or Chappati and Vegetables and Green leafy vegetables and Salad and Nonvegetable (boiled) or Soya bean and Curd

3 Cup 2 nos 1 Cup 1 Cup 1 Cup 75 g 50 g 1 Cup

50 g

Contd...

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272

Contemporary Topics in Gestational Diabetes Mellitus Contd... Tea-time

4:00–6:00 pm

Tea or coffee or milk and Mari biscuits or Sprouts or Bread toast or Vegetable sandwich

150 mL 3 nos 1 Cup 2 slices 1 no

Dinner

8:00–9:00 pm

Chappati and Vegetables and Salad and Curd

2 nos 2 Cup 1 Cup 1 Cup

1 Cup = 120 mL; 1 Katorie = 150 mL.

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Appendix B

South Indian Diet Charts for Women with Gestational Diabetes Mellitus South Indian Diet Chart 1: 1,600 kcal Early morning

6.00–6.30 am

Tea/coffee (skimmed milk without sugar)

150 mL

Breakfast: I

8–8.30 am

Idlies/ Chapatti/ Dosa (Radius - 6”) Tomato/onion/mint/coriander chutney

2 2 2 1 Cup

Breakfast: II

10–10.30 am

Idlies/ Chapathi/ Dosa (Radius - 6”) Tomato/onion/mint/coriander chutney

2 2 2 Cup

Midmorning

11.30–12.00 pm

Buttermilk/lime juice

150 mL

Lunch

1.00–1.30 pm

Rice Sambar/rasam and vegetables skimmed curd or Fish/chicken gravy (twice/week) (Or) Whole grams and Egg white (daily)

3/ 4

Tea-time

4–4.30 pm

Whole grams Tea/coffee/skimmed milk

1 Cup 1 Cup

Dinner

8–8.30 pm

Wheat rava khichdi or chapatti Dal vegetables

1 Cup 2 1 Cup

Bedtime

10–10.30 pm

Skimmed milk Walnuts

1 Cup 5–6 nos

Katorie 1 Cup 1 Cup 50 g 1 Cup 100 g 1 Cup 1

1 Cup = 120 mL; 1 Katorie = 150 mL.

South Indian Diet Chart 2: 1,800 kcal Early morning

6.00–6.30 am

Tea/coffee (skimmed milk without sugar)

150 mL

Breakfast: I

8–8.30 am

Rava pongal/dal pongal (or) Wheat/white rava upma (with) Vegetable sambar

½ Cup ½ Cup 1 Cup

Breakfast: II

10–10.30 am

Rava pongal/dal pongal (or) Wheat/white rava upma (with) Vegetable sambar

½ Cup ½ Cup 1 Cup

Midmorning

11.30–12.00 pm

Vegetable soup/chicken soup/ Butter milk

1 Cup 150 mL Contd...

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274

Contemporary Topics in Gestational Diabetes Mellitus Contd... Lunch

1.00–1.30 pm

Rice-cooked Sambar with vegetables Rasam/buttermilk Greens Mixed vegetables poriyal egg White

1 Katorie ½ Cup 1 Cup 1 Cup 1 Cup 1

Tea-time

4–4.30 pm

Sprouts/boiled grams Skimmed milk

1 Cup 150 mL

Dinner

8–8.30 pm

Whole wheat bread Toast/sandwich/multigrain dosa/ Wheat rava upma

2 2 ½ Cup

Bedtime

10–10.30 pm

Skimmed milk Marie biscuit

150 mL 2 nos

1 Cup = 120 mL; 1 Katorie = 150 mL.

South Indian Diet Chart 3: 2,000 kcal Early morning Breakfast: I

6.00–6.30 am 8–8.30 am

Breakfast: II

10–10.30 am

Midmorning Lunch

11.30–12.00 pm 1.00–1.30 pm

Tea-time

4–4.30 pm

Dinner

8–8.30 pm

Bedtime

10–10.30 pm

Tea/coffee (skimmed milk without sugar) Rava idli/ragi dosa/uthappam/ Wheat dosa Coriander/mint/onion/tomato/ Curry leaves chutney Rava idli/ragi dosa/uthappam/ Wheat dosa Coriander/mint/onion/tomato/ Curry leaves chutney Vegetable soup/chicken soup/butter milk Rice Vegetables with dhal Rasam/buttermilk Vegetable poriyal/green leafy vegetables or Egg white or Fish/chicken boiled Sundal/fresh salad Aval upma Milk (tea/coffee) Multigrain chapatti/ Idli/dosa/ragi adai Onion chutney/tomato chutney Milk Small fruit (pear, guava, apple)

150 mL 2 2 1 Cup 2 1 1 Cup 150 mL 2½ Katorie 1 Cup 1 Cup 1 Cup 1 100 g 1 Cup 1 Cup 150 mL 3 2 1 Cup 150 mL 1

1 Cup = 120 mL; 1 Katorie = 150 mL.

South Indian Diet Chart 4: 2,200 kcal Early morning Breakfast: I

6.00–6.30 am 8–8.30 am

Breakfast: II

10–10.30 am

Tea/coffee (skimmed milk without sugar) Pongal/khichdi/ Idli/dosa/ragi dosa Mint/coriander chutney Pongal/khichdi/ Idli/dosa/ragi dosa Mint/coriander chutney

150 mL 1 Cup 3 1 Cup 1 Cup 3 1 Cup Contd...

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Appendix B: South Indian Diet Charts for Women with Gestational Diabetes Mellitus

275

Contd... Midmorning

11.30–12.00 pm

Vegetable soup/chicken soup/butter milk

150 mL

Lunch

1.00–1.30 pm

Rice with Phulka Greens Dal Vegetables Rasam/buttermilk or Egg white or Fish/chicken (boiled)

3 Katorie 3 1 Cup 1 Cup 1 Cup 1 Cup 1 150 g

Tea-time

4–4.30 pm

Whole wheat bread (with gram/dal/vegetable filling) or Rice flakes upma

2 1 Cup 1 Cup

Dinner

8–8.30 pm

Chapatti with Dal/vegetables Fresh salad

4 1 Cup 1 Cup

Bedtime

10–10.30 pm

Skimmed milk Arrow root biscuits

150 mL 2

1 Cup = 120 mL; 1 Katorie = 150 mL.

South Indian Diet Chart 5: 2,400 kcal Early morning Breakfast: I

6.00–6.30 am 8–8.30 am

Breakfast: II

10–10.30 am

Midmorning Lunch

11.30–12.00 pm 1.00–1.30 pm

Tea-time

4–4.30 pm

Dinner

8–8.30 pm

Bedtime

10–10.30 pm

Tea/coffee (skimmed milk without sugar) Oats idli/oats dosai/ Plain dosa/ragi/wheat/bajra dosai Multigrain chapathi/phulka Onion/tomato chutney or Sambar with vegetable Oats idli/oats dosa/ Plain dosa/ragi/wheat/bajra dosa Multigrain chapatti/phulka Onion/tomato chutney or Sambar with vegetable Vegetable soup/chicken soup/butter milk Rice Sambar with vegetables Rasam/buttermilk Greens Mixed vegetables poriyal or Fish/chicken (boiled) or Egg white and Fresh salad Marie biscuit/oats biscuit/whole Arrow root biscuit/ Sundal/ Aval upma with chutney Milk/tea/coffee Chapatti/ Dal kootu/vegetable curry Fresh fruit (small) apple/pear/guava) Skimmed milk Oats biscuits

150 mL 3 2 2 1 Cup 3 2 2 1 Cup 150 mL 3½ Katorie 1 Cup 1 Cup 1 Cup 1 Cup 150 g 1 1 Cup 3 1 Cup 1 Cup 1 Cup 150 mL 4 1 Cup 1 150 mL 3 nos

1 Cup = 120 mL; 1 Katorie = 150 mL.

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Appendix C

Glycemic Index of Common Indian Foods Cereal Products Item

Glycemic index

Item

Glycemic index

Bread

70

Bajra

58

Millets

71

Barley

25

Rice (white)

72

Jowar

77

Rice (brown)

55

Rye

34

Wheat (paratha)

70

Basmati Rice

58

Item

Glycemic index

Item

Glycemic index

Pongal

55

Chhole

65

Pesarattu

60

Sprouted green gram

60

Upma

75

Sundal

80

Idli

80

Breakfast Snacks

Vegetables Item

Glycemic index

Item

Glycemic index

Brown beans

79

Potato

70

Frozen beans

51

Sweet potato

48

Item

Glycemic index

Item

Glycemic index

Yam

51

Carrot

71

Beetroot

64

Root Vegetables

Dairy Products Item

Glycemic index

Item

Glycemic index

Milk

33

Curds

36

Ice-cream

36

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Appendix C: Glycemic Index of Common Indian Foods

277

Dried Legumes/Grains Item

Glycemic index

Item

Glycemic index

Soyabeans

43

Black gram (urad)

48

Rajmah

29

Ragi

86

Bengal gram

47

Peanuts

14

Green gram

48

Soya boiled

18

Horse gram

51

Whole mung

57

Item

Glycemic index

Item

Glycemic index

Fructose

20

Sucrose

59

Glucose

100

Honey

87

Maltose

105

Sugar

Fruits Item

Glycemic index

Item

Glycemic index

Apple

38

Pear

38

Banana

69

Pineapple

66

Grapes

46

Watermelon

72

Mango

56

Orange

44

Papaya

58

Dried Fruits Item

Glycemic index

Item

Glycemic index

Apricots

31

Dates

103

Raisins

64

Miscellaneous Item

Glycemic index

Item

Glycemic index

Groundnuts

13

Tomato soup

38

Potato chips

51

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Appendix D

Food Exchange List Cereal Exchange 30 g provide 100 calories Carbohydrates—20 g: protein—2 g Bajra

Rice flakes

Barley

Rice puffed

Bread*

Sago**

Jowar

Samal

Corn flakes

Semolina (suji)

Maize, dry

Vermicelli (seviyan)

Oatmeal

Wheat flour

Ragi

Wheat, broken (dalia)

Rice

White flour

Sooji

Cornflakes

Idli

1 medium

Dosa

1 medium

Chapatti

1 medium

*To

meet carbohydrates and calories, add 5 g sugar. supplementation with other high protein foods, when used, within this list, one food item can be exchanged with another item. **Requires

Legume and Pulse Exchange 30 g provide 100 calories Carbohydrates—15 g: protein—6 g Bengal gram

Kabuli chana (white gram)

Bengal gram, roasted

Lentil

Besan (Bengal gram flour)

Moth beans

Black gram

Peas, dried

Cow gram (lobia)

Rajmah

Green gram

Red gram

Horse gram

Dals

Note: Within this list, one food item can be exchanged with another, but not with cereal exchange list.

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279

Appendix D: Food Exchange List

Flesh Food Exchange 10 g provide 70 calories Food

Quantity (g)

Beef

16

Crab

120 nos

Egg (duck)*

2 nos

Egg (hen)

2 nos

Fish (big)

60

Fish (small)

60

Fowl

60

Liver (sheep)

60

Mutton (muscle)*

60

Pigeon

60

Pork

60

Prawn

60

*Provides 100 calories. Note: Some flesh foods contain excess fat, visible fat and skin of poultry should be removed.

Milk Exchange Protein—5 g: 100 calories Buttermilk

750 mL

Cheese

30 g

Curd

210 g

Khoa

30 g

Buffalo milk

90 m

Cow milk

180 mL

Skimmed milk*

260 mL

Skimmed milk powder*

30 g

*Provides 10 g protein.

Fat Exchange Fat—11 g: 100 calories Food

Quantity (g)

Almonds

15

Butter

15

Cashewnuts

20

Coconut

30

Ghee

11 Contd...

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280

Contemporary Topics in Gestational Diabetes Mellitus Contd... Food

Quantity (g)

Groundnuts, roasted

20

Hydrogenated fat (vanaspati)

11

Oil (groundnut, mustard)

11

Pistachio nut

15

Walnuts

15

Margarine

10

Note: Any one food item in the list can be exchanged with another, but it should not be exchanged with any other exchange list.

Vegetable Exchange A* Leafy vegetables

Other vegetables

Amaranth

Ash gourd

Bathua

Bitter gourd

Brussels sprouts

Brinjal

Cabbage

Calabash cucumber

Celery

Cauliflower

Coriander leaves

Ch-cho (marko)

Curry leaves

Cucumber

Fenugreek leaves

Capsicum

Soya leaves

Drumstick

Lettuce

French beans

Mint

Knol-khol

Rape leaves

Lady’s fingers

Spinach

Mango, green Onion stalks Parwal Plantain flower Pumpkin White radish Rhubarb stalks Snake gourd Tinda Tomato, green Turnip

*Carbohydrate and calorie content of these vegetables are negligible and they may be used in any quantity.

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281

Appendix D: Food Exchange List

Vegetable Exchange B Carbohydrates—10 g: 50 calories Items

Quantity (g)

Root vegetables Agathi

100

Beetroot

75

Carrot

105

Colocasia

45

Coriander leaves

100

Onion (big)

90

Onion (small)

75

Potato

45

Sweet potato

30

Tapioca

30

Yam (elephant)

60

Yam

45

Other vegetables Artichoke

60

Broad beans

90

Cluster beans

90

Double beans

50

Jack, tender

105

Jackfruit seeds

30

Peas

45

Plantain, green

75

Pink radish

100

Singhara

45

Fruit Exchange Carbohydrates—10 g: 50 calories Fruit

Quantity (g)

Number of size

Amla

90

20 medium

Apple

75

1 small

Apricot

50

2 fresh

Banana

30

1/ 4

Cape gooseberry (rasbari)

150

40 small

Cashew fruit

90

2 medium

50

1/ 4

Custard apple (sitaphal)

medium

Contd...

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282

Contemporary Topics in Gestational Diabetes Mellitus Contd... Fruit

Quantity (g)

Number of size

Dates

30

3

Figs

135

6 medium

Grapes

105

20

Grape fruit

150

1/ 2

Guava

100

1 medium

Jackfruit

60

3 medium pieces

Jambu fruit

50

10 big

Lemon or lime

90

1 medium

Loquat

105

6 big

Mango

70

1 small

Melon

270

¼ medium

Orange (santra)

90

1 small

Papaya

120

2 medium

Peach

135

1 medium

Pear

90

1 medium

Pineapple

90

1–½ slices (round)

Plum

120

4 medium

Pomegranate

75

1 small

Sapota

50

One

Strawberry

105

40

Sweet lime (mosambi)

150

1 medium

Tomato

240

4 medium

Watermelon

175

¼ small

big

Sources: 1. Gopalan C, Rama Sastri BV, Balasubramanian SC. Nutritive value of Indian foods. National Institute of Nutrition, Indian Council of Medical Research (ICMR). Hyderabad, 2012. 2. Indian Council of Medical Research: Nutrient requirements and recommended dietary allowances for Indians. A report of the Expert Group of Indian Council of Medical Research. 2013. 3. Sheela K, Dharini K. Clinical dietetics manual. Indian Dietetics Association. 2011. 4. Kamala K. Dietary Guidelines for Indians: A manual. National Institute of Nutrition, Indian Council of Medical Research.

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Appendix E

Calorie Reckoner of Common Indian Food Items Calorie Reckoner Food item

Quantity

Calories

Food item

Quantity

Calories

Idli

1

65

Rice flakes

1 Katorie

200

Dosa

1

110

Macaroni (30 g)

1 plate

115

Masala dosa

1

212

Pav bhaji (2) Pav–

Oothappam

1

125

1 Katorie Bhaji

1 plate

235

Wheat dosa

1

110

Pizza (vegetable) cheese

100 gm

325

Pongal

1 Katorie

170

Pizza (meat)

125 g

400

Rice puttu

1 Katorie

150

Popeorn

35 g

140

Upma (sooji)

1 Katorie

140

Samosa

1

210

Upma (dallia)

1 Katorie

145

Sev

1 Katorie

202

Khichdi

1 Katorie

215

Vadai

1

70

Chapatti (25 g flour)

1

65

Potato bonda

1

70

Paratha (50 g flour)

1

180

Masala vada

1

57

Puri

1

80

Bonda

1

85

Idiyappam

1

1

Bajji (4) 1 plate

1 plate

140

Adai

1

145

Dahi vada

1

123

Pesarattu

1

108

Salted biscuit (3 g)

1

20

Aappam (25 g)

1

57

Sweet biscuits (4 g)

Bhel puri

1 plate

185

Cream cracker

Chhole

1 Katorie

170

Nice, marie

1

25

Nan

1

191

Arrowroot biscuit

1

20

Dhokla

1 piece

87

Chocolate cake

1

165

Oats (cooked)

1 Katorie

110

Fruit cake

1

117

Corn flakes

1 Katorie

110

Plain cake

1

146

Bread (25 g)

1 slice

60

Tomato chutney

¼ Katorie

16

Rice (cooked)

1 Katorie

110

Mint chutney

1 tbsp

7

Sambar

1 Katorie

50

Groundnut chutney

1 tbsp

65

Rasam

1 Katorie

15

Coconut chutney

1 tbsp

60

Dal

1 Katorie

80

Coriander chutney

Vegetable pulao

1 Katorie

193

with coconut

1 tbsp

45

Noodles

1 plate

195

Tomato sauce

1 tbsp

16 Contd...

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284

Contemporary Topics in Gestational Diabetes Mellitus Contd... Food item

Quantity

Calories

Food item

Quantity

Calories

Mango pickle

1 piece

45

Papads (fried)

1

25

Chutney power

1 tbsp

33

Pickles without oil

1 piece

20

Green leafy vegetable

100 g

45

Pickles with oil

1 piece

25

Other vegetable

100 g

36

Burfi (25 g)

1

100

Roots and tubers

100 g

170

Gulab jamun

1

100

Mushroom

100 g

42

Rasagulla (30 g)

1

100

Tomato soup

1 Cup

15

Peda (50 g)

1

83

Vegetable soup

1 Cup

15

Mysore pak

100 g

570

Cream of tomato soup

1 Cup

175

Badusha

100 g

469

Mutton soup

1 Cup

28

Badam halwa

100 g

570

Fish

100 g

80

Jalebi

100 g

412

Chicken curry

100 g

95

Milk cake

1 piece

82

Mutton curry

100 g

95

Ice cream

1 Cup

200

Egg whole

1

85

Honey

1 tsp

16

Egg white

1

15

Jaggery

1 tsp

19

Omelette

1

145

Oil/ghee

1 tsp

45

Fish cutlet

1

95

Almond 10–12

10 g

65

Fish fried

1 piece

110

Walnut 8–10

15 g

102

Aavin milk

1 Cup

100

Cashewnut 8–10

10 g

88

Coffee with sugar

1 Cup

50

Groundnut

25 g

140

Coffee without sugar

1 Cup

30

Dates

25 g

80

Butter milk

1 Cup

15

Coconut

30 g

100

Skimmed curd

1 Cup

60

Coconut water

200 mL

50

Kheer (payasam)

100 ml

178

Orange juice

200 mL

95

Cow’s milk

1 Cup

66

Grape fruit juice

200 mL

65

Buffalo’s milk

1 Cup

133

Tomato juice

200 mL

45

Cheese

30 g

100

Cola

200 mL

80

Paneer

30 g

80

Diet pepsi

200 mL

1

Mayonnaise

1 tbsp

45

Alcohol (30 mL)

1 peg

75

Horlicks

1 tbsp

20

Apple juice

200 mL

95

Malted milk drink

1 tbsp

19

Limca

200 mL

50

Papads (roasted)

1

15

1 Cup = 120 mL; 1 Katorie = 150 mL.

Sources: 1. Pasricha S, Rebello LM. Some common Indian recipies and their nutritive value. National Institute of Nutrition. Hyderbad, 2011. 2. Pasricha S. Count what you eat. National Institute of Nutrition, Indian Council of Medical Research. Hyderabad, 2010. 3. Raghuram TC, Pasricha S, Sharma RD. Diet and diabetes, National Institute of Nutrition, Indian Council of Medical Research. Hyderbad, 2012.

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Index Please note page numbers with f, t, and b indicate figure, table, and box, respectively.

A Abortions 3 Abruptio placentae  177 Acarbose  67, 184 Acquired Immunodeficiency syndrome  2 Adipocytes  20, 67, 152, 157 Adipocytokines 214 Adipokines  111, 239 Adiponectin  20, 214, 241 Adipose tissue  27, 68, 111, 158 inflammation in  157 Adrenal glands 15 hemorrhage 149 Adrenocorticotropic hormone (ACTH)  13 Adverse pregnancy outcomes (HAPO)  135, 182 Air bronchograms  141 Albumin  85, 114 Aldosterone  11, 15 Alpha-cells 78 Alpha-glucosidase  72, 75 inhibitors  67, 69, 74 Alternatively activated macrophages (AAM) 158 American College of Obstetricians and Gynecologists (ACOG)  56, 114 American Diabetes Association (ADA)  32, 60, 73, 93, 183 American Thyroid Association  207 Androgen 110 Aneuploidy, biochemical screening  180 Angiotensin 15 Anorectal malformation  149 Anovulation 110 Antenatal care 180 venous thrombosis  165 Anti-TG antibodies  207 Anti-thyroid drugs  207 Anti-TPO antibody  207

INDEX.indd 285

Aortic stenosis  147 Apgar score  198 Arginine vasopressin level  13 Arthrogryposis 149 Asparagine 84 Asphyxia  140, 152, 179t Assisted reproductive treatment (ART)  137 Atherosclerosis, gestational diabetes mellitus 217 Atrial septal defects  147 Australian Carbohydrate Intolerance in Pregnancy (ACHOIS)  194 Australian Carbohydrate Intolerance Study (ACHOIS) 57 Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS)  182 Autoimmune diabetes 160 thyroid disease  203

B Bariatric surgery  110 complications of  113 in women of childbearing age  112 obesity role in gastric band  111 Roux-en-Y gastric bypass  111 sleeve gastrectomy  111 pre- and postoperative evaluation  114 Basal-bolus schedule  84t Beta cell  67, 78, 159, 213, 214 dysfunction 215 insufficiency 211 Betamimetic drugs  185 Birth defects 177 injury 110 trauma 152 Blood glucose, self-monitoring of  57, 77, 94 urea nitrogen  180

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286

Contemporary Topics in Gestational Diabetes Mellitus Body mass index (BMI)  18, 20, 25, 26, 37, 45, 59, 70, 81, 110, 111, 159, 164, 165, 167, 177, 190, 225 classification in united states  229t Brachial plexus injuries  140, 179t trauma 151 Breast cancer resistance protein (BCRP)  68 Breastfeeding 25 and lactation  265

C Caesarean  52, 60, 79, 85 delivery  25, 165 section  35, 68, 71, 78, 141, 169, 186, 196 Calcitonin 14 Calcium 114 channel blockers  87, 185 homeostasis 14 intracellular 67 Carbohydrate metabolism  49 Cardiovascular diseases  1, 152 Caudal regression syndrome  147, 148f Cephalhematoma 140 Cholelithiasis  12, 113 Chorioamnionitis 177 Classically activated macrophages (CAM) 158 Clavicular fracture  140 Coarctation 147 Combined oral contraceptive  188 Complex carbohydrates  68 Conducting delivery  187b Congenital malformations  26t Connecting peptide (C-peptide)  83 Continuous glucose monitoring (CGM)  93 comparison of blood glucose  103 devices  94, 94f impact on glycosylated hemoglobin  98 in normal pregnancy  100 in obese pregnancy  100 interstitial glucose  102 limitations of  105 pregestational diabetes  99 quality of  104 safety of  95 training and education  105 Controlled antenatal thyroid screening study (CATS) 205 Copper T (CuT 380A)  266 Corticosteroids  88, 141 Corticotropin-releasing hormone (CRH) 13 Cortisol  15, 59, 120, 211 binding globulin  15 C-peptide  18, 195, 227, 228, 230 C-reactive protein (CRP)  157, 215

INDEX.indd 286

Cystic kidney  149 Cytokine  16, 211, 214, 215, 241

D Decreased gestational glucose tolerance (DGGT) 81 Dehydroepiandrosterone sulfate  15 Diabetes  1, 3 in pregnancy long-term complications  152 perinatal complications  151 role of counseling  153 mellitus  4, 18, 20, 22, 42, 51, 67, 77, 111, 113, 120, 136, 205, 223 Diabetic cardiomyopathy 95 fetopathy 137 ketoacidosis 87 nephropathy 95 neuropathy 95 retinopathy  51, 95, 176 Diaphragmatic nerve paralysis  140 Dietary reference intakes (DRI)  60 Disodium cromoglycate (DSCG)  158 Distress syndrome  88 Down’s syndrome  181 DPP-IV inhibitors  69, 72, 75 saxagliptin 68 sitagliptin 68 vildagliptin 68 Dual-energy X-ray absorptiometry scans  27 Duodenal atresia  149, 149f Dyslipidemia  30, 211 Dystocia  110, 167

E Eclampsia  177, 195 Ectopic thyroid  202 Endocrine function 238 metabolism, role of placenta  12 Endogenous glucose production  78 Endoscopic dilatation  113 Endothelial dysfunction, gestational diabetes mellitus 217 nitric oxide synthase  225 Epinephrine 15 Erb’s palsy  140 Erythrokinetics 50 E-selectin 217 Estrogen 12t, 15, 201, 203, 211, 213 stimulated hypertrophy  13 Euglycemia 81 Excessive fetal growth  26t Exogenous insulin therapy  49

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Index

F Facial nerve injury  140 Fatty acids  28, 58 Fatty liver  111 Fetal abnormality  43, 110 congenital malformations  25 distress 165 hypothalamo-pituitary-thyroid axis  14 lung maturation  141 malformations 51 Food exchange list  278-282 Free fatty acids (FFA)  18 Fuel-mediated teratogenesis  49

G Gallstones 113 Gastric band 111 erosion 113 bypass surgery  115 Gestational diabetes mellitus (GDM)  2, 33, 33t, 216, 248 assessing glycemic control  53 glycosylated hemoglobin  53 self-monitoring blood glucose  53 autoimmunity 160 beta cell function  19 breastfeeding 263 contraceptive choices  266 diagnosis 194 implementing diagnostic  38 new WHO criteria  38 single test procedure  35 diet charts North Indian  269-272 South Indian  273-275 evidence-based who criterion  34 exercise 197 fetal risks  194 glycemic control assessment  49 control monitoring  53 homeostasis 49 targets  49, 51 high risk for  33t inflammation 157t insulin resistance  18 low risk for  33t maternal health  232 medical nutrition therapy  56-65 neonatal aspects  135-153 nutrition therapy  197t pathogenesis  18-22, 213 pharmacotherapy 198

INDEX.indd 287

287

placenta 19 cytokines 19 leptin levels  19 nutritional factors  20 placental inflammation  159 postpartum care 263 recommendations 264t risk factors for  136 development 213 type 2 diabetes mellitus  243t, 246 treatment of  182, 196 exercise 183 medical nutrition therapy  182 oral antidiabetic agents  184 pharmacotherapy 183 transient thyrotoxicosis  206 weight gain  168, 235 Glibenclamide  73, 198, 199 Gliclazide  73, 74 Glucagon  22, 78 Glucocorticoids  15, 185 Glucose challenge test  32, 70 homeostasis 158 intolerance  35, 38, 211 metabolism 113 oral glucose tolerance test  32 oxidase-peroxidase hexokinase 36 method 43 Glulisine 84 Glutamic acid  84 decarboxylase 160 Glyburide  68, 69, 70, 71, 72, 73, 74, 184, 199 Glycation end products (AGE)  21 Glycemic control  73, 78, 79, 86, 113, 153, 177 intrapartum 88 monitoring 181 excursions 50 index  59, 80, 229 meal 53 of common Indian foods  276, 277 targets  58, 78 Glycolysis 113 Glycosuria 156 Glycosylated hemoglobin  18, 42, 50, 77, 93 GOD-POD method  45 Gonadotrophs 13 Graves’ disease  206, 207 Growth hormone (GH)  13

H HAPO study  194, 195, 196 Hemolytic anemia  50

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288

Contemporary Topics in Gestational Diabetes Mellitus Hemorrhage 110 Heparin 114 Hepatic gluconeogenesis  59, 67 High-density lipoprotein cholesterol (HDLC)  211, 245 Homeostasis maternal 12 model assessment (HOMA)  227 Homeostatic model assessment (HOMA) 2 model 20 Hormone-sensitive lipase (HSL)  28f Hormono-metabolic adaptations, in pregnancy 11-16 Human Chorionic gonadotropin  12, 12t somatomammotrophin 12t, 18 immunodeficiency virus  2 placental growth hormone  211 lactogen  15, 18, 211 Hyaline membrane disease  141 Hydramnios  42, 43, 43t Hydronephrosis 149 Hyperaminoacidemia 78 Hyperbilirubinemia  78, 264 Hypercortisolemia 120 Hypercortisolism 16 Hyperestrogenemia 15 Hyperglycemia  182, 184 during pregnancy  3 fetal  137, 138f in pregnancy, risks associated  5t postprandial  78, 97 Hyperinsulinemia  22, 137, 152, 179, 215 fetal  44, 49 Hyperinsulinism, secondary fetal  137 Hyperlipidemia  15, 78 Hypertension  78, 85, 111, 169, 171, 176, 226 arterial 5 gestational  25, 26t,176, 195, 216 diabetes mellitus  216 management 231 pregnancy-induced  3, 5t, 110 pulmonary 142 severe 177 Hypertensive syndromes  79 Hypertrophic cardiomyopathy  265b Hypoglycemia neonatal 5t, 49, 51, 68, 70, 71, 78, 79, 88, 156 management of  143 nocturnal  87, 89, 97 prolonged hyperinsulinemic  68 Hypoglycemic, nocturnal  85 Hypoplastic femur 149

INDEX.indd 288

left heart syndrome  147 Hypothyroidism  118, 202-206 clinical features  202 congenital 206 diagnosis 203 etiology 202 management of  204f subclinical 203 treatment 203 Hypoxemia 71 Hypoxic ischemic encephalopathy  179t

I Impaired fasting glycemia (IFG)  263 glucose tolerance (IGT)  4, 168, 189, 245 Indomethacin 87 Induction of labor  185 Infant of diabetic mothers cardiovascular anomalies  146 congenital malformations  147 evaluation of  151 hematological problems  145 hyperbilirubinemia 145 hypocalcemia 143 hypoglycemia 142 impaired fetal growth  140 pulmonary disease in  141 thrombocytopenia 145 respiratory distress syndrome  5t Infertility  110, 118 Inflammatory cytokine  29, 29f markers, gestational diabetes mellitus 217 Institute of Medicine (IOM)  25t, 170, 235, 236f nutrition 59 pre­pregnancy body mass index  26t weight categories  25t Insulin  15, 45, 77, 78 antibodies 49 basal  79, 81, 83, 85 bolus  79, 81, 83 breastfeeding 89 choice, in pregnancy  80, 82f delivery 88 detemir 85 dosage adjustment  87 elective caesarean delivery  89 fetal 49 glargine  85, 86 glulisine 84 human  80, 84 infusion, intravenous  88 intermediate-acting  87, 89

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289

Index labor 88 lispro  83, 84 long-acting 87 non-immunogenic 80 NPH  82, 85 postpartum 89 premixed human  84 preterm delivery  87 pump 86 rapid-acting  81, 88 receptor substance  28f, 29f, 214 regimens 81 requirement, factors affecting  79 resistance 29f, 68, 72, 152, 157, 158, 160, 164, 183, 186, 211 abnormal lipid metabolism  214 adipocytokines 214 cellular mechanisms  214 peripheral 79 role of placental hormones  213 secretagogue 199 secretion 183 sensitivity  113, 237f short-acting  82, 87, 88 therapy  67, 79 in pregnancy  78 Intercellular adhesion molecule 1  217 Internal hernias  113 International Association of Diabetes and Pregnancy Study Groups (IADPSG)  27, 194 International Conference on Population and Development (ICPD)  6 International Diabetes Federation  3 Interventricular septal hypertrophy  149 Intranatal care  186 elective caesarean section  187 glucose monitoring in labor  187 insulin 187 Intrapartum asphyxia  151 Intrauterine deaths  3, 5t fetal demise  179, 226 growth restriction  151, 177 retardation  78, 113 Intussusception 113 Islet cell autoantibodies (ICA)  160 Isolated maternal hypothyroxinemia  206

J Jaundice, neonatal  179

K Ketonemia 190 Ketonuria 190

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Ketosis 58 Klumpke’s paralysis  140

L Lactic acidosis  71 Lactotrophs 13 Leptin 214 Levonorgestrel-releasing intrauterine devices (IUDs)  188, 266 Lifestyle interventions, during pregnancy  236 Lipid profile, gestational diabetes mellitus  216 Lipogenic genes  239 Lipolysis  15, 18, 28, 29 Lipoprotein receptors  16 Low density lipoproteins  13 glycemic index diet  236 platelet syndrome  78 Lysine 84

M Macrosomia  4, 44, 51, 58, 70, 78, 79, 80, 98, 103, 106, 110, 137, 156, 165, 166, 178, 179, 182, 185, 186, 196, 198, 226, 236 fetal 49 risk of  140 Magnesium, sulphate  87, 185 Malaria 2 Maternal Diabetes classification of  137 pathophysiology 137 hyperglycemia, infant risks related  264 obesity birth complications  165 fetal 166 management 171 neonatal complications  166 offspring obesity  168 pregnancy complications  164 serum alphafetoprotein  180 vasculopathy 179 Maturity onset diabetes of young (MODY)  18 McRoberts maneuver  186 Medical nutrition therapy (MNT)  45, 56, 59, 183 Caloric allotment 58 distribution 58 intake 60 carbohydrate intake  58 continuation 59 glycemic control 61 index  60, 61

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Contemporary Topics in Gestational Diabetes Mellitus monitoring goals  61 insulin therapy  61 planning and execution  58 practical limitations  57 primary goal  59 Medroxyprogesterone 114 acetate 189 Membrane rupture of  43t type matrix metalloproteinase 1  19 Metabolic syndrome  4, 5, 152, 211, 222, 223 definition of  212 diet therapy  229 dietary precautions  230 effects 222f gestational diabetes mellitus  217 hyperglycemia associated  225 hypoglycemic agents  230 impact on pregnancy  225 in early pregnancy  218t insulin resistance  212 lifestyle changes  228 management of  227 micronutrients 230 pathophysiology of  215, 225 insulin resistance  215 preconception counselling  227 pregnancy care  228 Metagestational diabetes  56 Metformin  69, 70, 72, 73, 74, 184, 198, 253 longer-term outcomes glyburide  71 pharmacokinetics 71 Micronutrient deficiencies  114 Millennium development goals  6 Miscarriage 177 Mothers After Gestational Diabetes in Australia Diabetes Prevention Program (MAGDA‑DPP) 252 Multiple daily injections (MDI)  86

N National Institute for Health and Clinical Excellence (NICE)  73, 141, 185 Neonatal adiposity 195 electrolyte abnormality  156 hypoglycemia 198 jaundice 156 mortality 51 Neural tube defects  147, 178, 225 biochemical screening  180 Neutral protamine hagedorn (NPH)  81 Nitrosamines 21 Nonalcoholic fatty liver disease  168 Noncommunicable diseases (NCDs)  1 Norepinephrine 15

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Normal glucose tolerant (Ngt)  36, 44 Nuchal translucency (NT)  181

O Obesity 25-30 associated diabetes  160 childhood 222 Obesogenic maternal microbiome  58 Obstructed labor  4 Obstructive sleep apnea (OSA)  21, 111 Oral antihyperglycemic agents (OHA)  198 glucose tolerance test (OGTT)  80 hypoglycemic agents  56, 67 alpha-glucosidase inhibitors  67 biguanides 67 congenital anomalies  69 crossing placenta  68 diabetes 73 dipeptidyl peptidase 4 inhibitors  67 during lactation  74 early use of  68 efficacy glyburide  69 gestational diabetes mellitus  73 glucagon-like peptide-1 agonists  67 long term outcomes  72 mechanisms of action  67 miglitol 67 safety glyburide  69 sulfonylureas 67 transfer into breast milk  74 voglibose 68 Organogenesis 83

P Pancreatic beta cells  152 Parathyroid glands 14 hormone 12t, 14 Pedersen hypothesis  137, 138f, 199 Perinatal asphyxia  141 Peroxisome proliferator-activated receptorgamma  68, 215 Phenytoin 202 Phosphoionositol-3 kinase  214 Phosphotidyl inositol 3 kinase  28f Placental hormones, functions  12t Plasma prolactin  13 Plasminogen activator inhibitor 1  215 Pneumonia 142 Polycystic ovary syndrome (PCOS)  4, 21, 110, 118, 191 Polycythemia  152, 265b Polyhydramnios  4, 5t, 150, 176, 177, 185, 226 Polyuria 177

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Index Ponderal index  70 Postnatal care  188 breastfeeding 188 contraception 188 glucose homeostasis  144f management of diabetes  188 Postoperative hemorrhage  26t Postpartum hemorrhage  25, 166, 179t screening 253-259 at community health centers  258 at district hospitals  258 at primary centers  257 at subcenters  257 diabetes 189 thyroiditis 208 screening test  254 Postprandial glucose excursions  82 Preconceptional care 190 counseling 52 Preeclampsia  7, 25, 26t, 52, 78, 85, 150, 165, 169, 171, 176, 185, 186, 195, 216, 225, 226, 236 Pregestational diabetes mellitus  136, 137, 166 Pregnancy complications  43t Premature delivery  78 Preterm births  43, 60 labor  176, 177, 225 management of  185 Previous caesarean section  186 Progesterone 12t, 12, 15, 18, 211, 213 Prolactin  211, 213 Propylthiouracil (PTU)  207 Prostaglandin synthetase inhibitors 185 Psychosocial aspects diabetes in pregnancy  117, 117t antenatal phase  118 glycemic control  122 history taking  121 impact on health  120 management 121 medical nutrition therapy  122 postpartum phase  119 preconception counseling  121 psychosocial concerns  118t Pyelonephritis 150

R Rapid-acting insulin analogs  53, 83 in pregnancy  82 Recurrent laryngeal nerve damage  140 spontaneous abortions  226

INDEX.indd 291

291

Renal agenesis 149 vein thrombosis  149 Renin 15 Respiratory distress syndrome  141, 147, 151, 225, 265 Retinopathy 180 Rifampicin 202 Ritodrine 87 Roux-en-Y gastric bypass  112, 113

S Serum human chorionic gonadotropin  201 low-density lipoprotein  214 total cholesterol  214 triglycerides 214 Sex hormone-binding globulin  15 Shoulder dystocia  140, 151, 186, 196, 225 complications due to  179t maneuvers 187b Sleeve gastrectomy  112 Small bowel obstruction  113 for gestational age  45 left colon syndrome  149, 150 Solitary toxic nodule  206 Spontaneous abortions  4, 5t, 25, 26t preterm labor  185 Still births  3, 4, 5t, 78, 110, 167, 179 Stroke  5, 177 Subdermal implants  266 Subfertility  110, 111, 118 Sulphonylureas 73 Surrogate markers  168

T T cells  159 T helper 1 cells  158 T regulatory cells  158 Terbutaline 87 Thiamine 114 Thiazolidinediones  68, 69, 72, 75 Threonine 85 Threshold plasma glucose (PG)  33 Thromboembolism  25, 26t, 114, 225 Thyroglobulin antibodies  203 Thyroid disorders, in pregnancy  201-209 function tests  203 gland 13 peroxidase (TPO)  203 tumors 202

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Contemporary Topics in Gestational Diabetes Mellitus Thyroiditis destructive 208 subacute 206 Thyroid-stimulating hormone  13, 180, 201 Thyrotoxicosis  206, 209 Thyrotrophs 13 Thyroxine 201 binding globulin  14, 201 Tocolytic therapy  87 Tolbutamide 68 Transdermal contraceptive patches  113 Transient tachypnea of newborn  147 Transthyretin 14 Triiodothyronine  14, 201 Tripod trial  253 TSH-R antibodies  208, 209 stimulating antibodies  207 Tumor necrosis factor  20, 29, 29f, 211, 225

Ureteric duplication  149 Urinary tract infections  25, 26t Uteroplacental perfusion  179

U

Zavanelli maneuver  186

V Vaginal lacerations  179t Very low-density lipoprotein  214 Victoza 232 Vitamin B12  20, 22, 50, 114 D  20, 21, 114 D binding globulin  14

W Wood’s screw maneuver  186

Z

Unconjugated estriol  181

INDEX.indd 292

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