SAFES (JULY2015 OCTOBER2015)

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1 SAFES (JULY2015 OCTOBER2015)

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3 Module I: Introduction to Diabetes in Pregnancy SAFES Disclaimer Public Health Foundation of India (PHFI) and Dr. Mohan s Diabetes Education Academy (DMDEA) do not recommend or provide individualized medical diagnosis, treatment or advice, nor do they recommend specific therapies or prescribe medication for anyone using or consulting this publication. The information contained in this publication is intended for general educational and informational purposes only. Medical information changes rapidly. Therefore, PHFI and DMDEA assume no responsibility for how readers use the information contained in this publication and hence assume no legal liability or responsibility arising out of use of this information. Contents included in this module are solely provided by designated experts and represents their viewpoints entirely. Copyright 2015 Public Health Foundation of India, New Delhi & Dr. Mohan s Diabetes Education Academy, Chennai. All rights reserved. This training material (including print material, CDs, Modules and presentations) is the exclusive intellectual property right of PHFI and DMDEA. No part of this training material may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of PHFI and DMDEA. Layout, designed & printed by Fluorescence Communications Pvt. Ltd. UG 31-32, Suneja Tower-I, District Center, Janakpuri, New Delhi

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5 Contents Introduction to Certificate Course in Gestational Diabetes Mellitus-Cycle III 4 Learning Objectives 6 Introduction to Diabetes in Pregnancy 7 Appendix 12 Presentations 15 Primer to Module II 36

6 Introduction Introduction to Certificate Course in Gestational Diabetes Mellitus (CCGDM) Cycle III On behalf of Public Health Foundation of India and Dr. Mohan s Diabetes Education Academy, we wish you a warm welcome to the Certificate Course in Gestational Diabetes Mellitus (CCGDM)-Cycle III. We congratulate you on having been selected to undergo this course and thank you for agreeing to spare your valuable time to ensure the success of this course. The CCGDM is designed to equip general practitioners, physicians and obstetricians / gynecologists with the information and tools needed to manage Gestational Diabetes Mellitus (GDM) and pre-existing diabetes in pregnancy in a clinical setting. The Course will be delivered on a Modular basis. There are four Modules, each of which will be delivered on a fixed Sunday every month. The Modules consist of: Pre-test Learning objectives Teaching slides Case studies Case exercise Group work activity Video Take home messages Post test Primer to Next Module The day s discussions start with listing of the learning objectives. You can help in making the session more interactive by presenting interesting cases you have seen in your practice. This is then followed by the pre-test. This consists of ten multiple choice questions (MCQs) based on the topic to be covered during the particular session. This is designed to assess the trainees baseline knowledge. The same set of MCQs will be administered as the post-test at the end of the session, following which your facilitator will discuss the answers with you. 4

7 Module I: Introduction to Diabetes in Pregnancy The teaching slides have been designed to be as interactive as possible. A number of case studies have also been interspersed among the slides. Please remember that there may not be any right or wrong answer for many of these; they are only meant to provoke thought and discussion. In addition to the pre-test and post-test, you are also expected to submit a case exercise at the beginning of module III and to make the course as interactive a possible, one group work activity have been scheduled in module IV. Please distribute the handouts among the participants, get the activity done and facilitate the discussion at the end of the activity. There will also be an Exit Exam in the form of MCQs at the completion of Module IV, a minimum of 50 % marks is required to pass, which will be one of the criteria for award of the certificate. Further details will be communicated to you closer to the date of the Exam. The Curriculum for the CCGDM has been designed with inputs from eminent Endocrinologists, Diabetologists and Obstetricians / Gynecologists who have agreed to act as the National Expert Panel for this Course. We are thankful to them for sharing their valuable time and invaluable expertise in designing this course. Even though all efforts have been made to ensure that the information provided is accurate and up to date, you may occasionally come across instances where this is not so. We request you to point these errors and omissions to us so that we can rectify them in time for the Cycle IV. Further Reading 1. Seshiah V, Das AK, Balaji V, Joshi SR, Parikh MN, Gupta S for the Diabetes in Pregnancy Study Group (DIPSI). Gestational diabetes mellitus- Guidelines. J Assoc Physicians India 2006;54: Banerjee S, Seshiah V, Zargar AH. Diabetes in Pregnancy- ECAB. New Delhi, Elsevier India, Hod M, Jovanovic L, Di Renzo GC, De Leiva A, Langer O (Eds.). Textbook of Diabetes and Pregnancy, 2 nd Edition. London, Informa Healthcare, Metzger BE, Buchanan TA, Coustan DR, De Leiva A, Bunger DB, Hadden DR et al. Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care 2007;30 (Suppl.2):s251-s International Association of Diabetes and Pregnancy Study Groups Consensus Panel. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010;33: We are sure that you will find this Course Interesting, Enjoyable & Informative! 5

8 Certificate Course in Gestational Diabetes Mellitus Learning Objectives Learn about the evolution of the concept of diabetes in pregnancy Review the metabolic alterations occurring in pregnancy and how these can lead to diabetes Define GDM and discuss its epidemiology Learn about the consequences of GDM to the mother and fetus Understand the great public health importance of GDM 6

9 Module I: Introduction to Diabetes in Pregnancy Introduction to Diabetes in Pregnancy History of Diabetes in Pregnancy Until the middle of the 19 th century, diabetes was thought to be incompatible with successful pregnancy. Blott, writing in Paris in 1856, concluded that true diabetes was inconsistent with conception. This statement was probably linked to the short life expectancy of women with type 1 diabetes in the days before insulin was discovered, meaning that their chances of surviving long enough to reach reproductive age were negligible. Even in those women who managed to conceive, death from uncontrolled diabetes during or soon after pregnancy was exceedingly common. The dire outlook for women with pre-existing diabetes did not change until a few years after the discovery of insulin, when the subspeciality of diabetes in pregnancy was created following the efforts of Priscilla White and other pioneers. The concept of Gestational Diabetes that is, diabetes occurring on account of the pregnancy itself, dates back to the middle of the 19 th century. In 1824 a German physician, Bennewitz, described a single case in whom diabetes developed following conception, only to disappear after delivery (her baby weighed 12 pounds at birth and was said to be robust and healthy ). The term Gestational Diabetes was first used by O Sullivan in 1961, following the lead of Hoet from Belgium who used the term Metagestational Diabetes. Definition of Gestational Diabetes Mellitus (GDM) Gestational diabetes is defined as glucose intolerance of varying severity with onset or first recognition during pregnancy. This definition does not discount the possibility that diabetes could have existed prior to the pregnancy. Therefore we can have different categories of women clubbed together under this definition: Normal glucose tolerance prior to pregnancy which becomes abnormal with pregnancy and returns to normal following delivery ( True GDM ) Mild glucose intolerance ( pre-diabetes ) before pregnancy which worsens during pregnancy Previously undiagnosed type 2 diabetes Previously undiagnosed type 1 diabetes (rare) Previously undiagnosed MODY or secondary forms of diabetes (rare) As will be seen from the subsequent discussions, it is important to differentiate gestational diabetes from pre-existing diabetes in pregnancy. The classification of diabetes and the diagnostic criteria in non-pregnant individuals are described in the Appendix. 7

10 Certificate Course in Gestational Diabetes Mellitus Pathogenesis of Diabetes in Pregnancy Metabolic Alterations Occurring During Pregnancy During pregnancy, maternal intermediary metabolism undergoes major changes, most of which are designed to provide a continuous supply of energy and nutrients to the growing fetus while also meeting the nutritional requirements of the mother. From the metabolic standpoint, pregnancy can be divided into two distinct halves: During the first half of pregnancy, there occur changes that promote storage of energy and nutrients. At this point, there is increased appetite combined with normal or increased insulin sensitivity. This promotes storage of energy in the form of fat. These accumulated energy reserves can then be used during the second half of pregnancy to meet the demands of the rapidly growing fetus. In the second half of pregnancy, there develops a state of insulin resistance in the mother, facilitating preferential supply of glucose to the growing fetus. Insulin resistance reduces the uptake of glucose by maternal tissues such as white adipose tissue and skeletal muscle, and diverts glucose to the fetus. The mother s energy requirements are met using alternate fuels such as free fatty acids and ketone bodies. Increased uptake of glucose by the fetus leads to low maternal fasting plasma glucose levels. Human Placental Lactogen (HPL) secreted by the placenta is the main driver of insulin resistance in pregnancy. Other hormones implicated include cortisol, prolactin and progesterone. Intermediary metabolism in late pregnancy has been described as an exaggeration of the normal swings between fed-state anabolism and fasting catabolism that occur in nonpregnant individuals. During feeding, glucose and insulin concentrations increase rapidly as a result of the marked insulin resistance and compensatory hyperinsulinemia. Following a period of no calorie intake, blood glucose levels fall much more rapidly than in nonpregnant individuals and insulin release is suppressed. This leads to accelerated lipolysis and ketone body formation ( accelerated starvation ) Figure 1.1 Fig. 1.1: Schematic representation of maternal metabolic changes during gestation. Anabolism during feeding and catabolism during fasting are exaggerated in a progressive fashion, reflecting the combined effects of placental hormones and nutrient use by the fetus. Ref: Buchanan TA, Coustan DR. Diabetes mellitus. In: Burrows GN, Ferris TF, eds. Medical complications during pregnancy, 4 th ed. Philadelphia: WB Saunders,1994:

11 Module I: Introduction to Diabetes in Pregnancy Pathogenesis of GDM GDM develops when the maternal pancreatic beta cell is unable to compensate for the insulin resistance of late pregnancy by increasing its output of insulin. While the exact nature of the beta cell defect remains unknown, the following factors may play a role. Genetic factors Chronic insulin resistance preceding pregnancy (which would have already worn out the beta cell) Subclinical inflammation Since insulin resistance develops only during the second trimester of pregnancy, GDM is very unlikely to develop before this time. Diabetes diagnosed during the first trimester usually indicates pre-existing type 2 diabetes rather than GDM. Risk Factors for GDM The following have conventionally been considered to be risk factors for GDM: Obesity Metabolic syndrome/ diabetes in first degree relative Previous macrosomic baby Member of high risk ethnic group Age > 25 years Polycystic ovarian syndrome (PCOS) Polyhydramnios in previous pregnancy Previous unexplained perinatal loss / birth of malformed baby From the above list it can be seen that many of the risk factors for GDM are also risk factors for type 2 diabetes. Also, women of Asian Indian origin are at high risk of GDM even if they do not have any of the other risk factors. Implications of GDM GDM is associated with a host of adverse maternal and fetal implications. Maternal Implications Pre-eclampsia Polyhydramnios Operative delivery Perineal trauma Risk of future diabetes Ketosis Fetal Implications Macrosomia Birth trauma Prematurity Respiratory distress syndrome (RDS) even without prematurity Neonatal metabolic complications (Hypoglycemia, hyperbilirubinemia, polycythemia, hypocalcemia) Future risk of diabetes and metabolic syndrome 9

12 Certificate Course in Gestational Diabetes Mellitus Pre-eclampsia Women with diabetes during pregnancy are at an increased risk of developing pre-eclampsia. This may be due to insulin resistance or may be associated with a combination of genetic factors, advanced age and high BMI. The rate of pre-eclampsia has been shown to be related to the severity of diabetes. Risk of Future Diabetes in the Mother GDM can be regarded as an unmasking of future type 2 diabetes. Following delivery, diabetes usually resolves in most women with GDM but it may persist in 5% to 10%. Another 35% to 60% of these women will develop type 2 diabetes within the next decade. Conversion to diabetes occurs more rapidly and more frequently in high risk ethnic groups such as Asian Indians. Macrosomia A macrosomic baby (or large for gestational age ) is defined as one whose weight is above the 90 th percentile for the gestational age. While the western guidelines use a cut-off birth weight of 4.5 kg to define macrosomia, 3.5 kg seems reasonable in the Indian setting. There are two types of macrosomia- symmetrical and asymmetrical. Infants of mothers with GDM have asymmetrical macrosomia with abnormal thoracic and abdominal circumference, which is larger than the head circumference. Organomegaly is also present. A macrosomic baby has a high risk of sustaining birth injury such as Erb s palsy, facial palsy, clavicle fracture and humerus fracture. The risk of shoulder dystocia is also high. Women whose babies are large for gestational age are also more likely to go in for cesarean section. In the long run, individuals who were LGA at birth have a high risk of developing type 2 diabetes in later life. The pathogenesis of macrosomia is best explained by the Pedersen- Freinkel hypothesis. The maternal blood flowing through the placenta is the sole source of glucose and energy for the fetus. Glucose freely passess across the placental barrier down its concentration gradient. This means that higher the maternal blood glucose, more the glucose received by the fetus. The fetal pancreas responds to this excess supply of glucose and other nutrients ( mixed nutrients ) by secreting more insulin. Hyperinsulinemia, in association with plentiful supply of nutrients, leads to excess growth of fetal tissues and consequently, macrosomia. It therefore follows that maintaining good control of blood glucose in the mother can limit nutrient transfer to the fetus and minimize the risk of macrosomia. Figure 1.2 Fig. 1.2: The Pedersen hypothesis (modified by Freinkel) suggests that macrosomia develops from excess supply of glucose and other nutrients ( mixed nutrients ) to the fetus, and consequent hypersecretion of insulin by the fetal pancreas. 10

13 Module I: Introduction to Diabetes in Pregnancy Hypoglycemia Neonatal hypoglycemia is a major metabolic problem faced by infants of women with poorly controlled diabetes (GDM or pre-existing diabetes). As mentioned above, high levels of maternal blood glucose promote hyperinsulinemia in the fetus, which persist for some time even after the umbilical cord has been clamped and the supply of glucose terminated. This mismatch between glucose supply and insulin levels can lead to hypoglycemia in the neonatal period, which is usually transient. Other Metabolic Problems in the Neonate Polycythemia occurs due to chronic intrauterine hypoxemia and placental insufficiency secondary to poor glycemic control As these excess RBCs break down, hyperbilirubinemia occurs days to weeks after birth The exact mechanism of hypocalcemia is unknown but may be related to functional hypoparathyroidism Respiratory Distress Syndrome Infants of women with poorly controlled diabetes have delayed maturation of their lungs. Pulmonary surfactant production is found to be decreased due to a combination of hyperglycemia and hyperinsulinemia. Management of RDS in these babies is complicated by the fact that use of antepartum steroids for accelerating lung maturity may worsen diabetes control in the mother. Still Births The rates of stillbirth are higher in GDM than in the non-diabetic population. The risk of stillbirth depends on the severity of diabetes and adequacy of glycemic control. If the mean blood glucose levels are kept between mg/dl, the rate of stillbirth approximates that of the non-diabetic population. The main causes for stillbirth in GDM are: Excess fetal growth secondary to hyperglycemia and hyperinsulinemia Fetal growth restriction Congenital anomalies are a rare cause of stillbirth in GDM Congenital anomalies are rare in GDM, since organogenesis is complete by the time at which GDM usually develops. Risk of Future Diabetes in the Offspring Studies in Pima Indians and other ethnic groups have shown that infants exposed to maternal hyperglycemia during gestation have a high risk of developing type 2 diabetes in later life. Their risk of developing other components of the metabolic syndrome, such as hypertension, central obesity and low high density lipoprotein (HDL) cholesterol was also found to be high. 11

14 Certificate Course in Gestational Diabetes Mellitus Epidemiology of GDM It is difficult to give a single accurate figure for the worldwide prevalence of GDM, since data is lacking from many parts of the world, and different authors have used different tests and varying criteria for the diagnosis of the condition. Nevertheless, it is clear that the prevalence of GDM varies in direct proportion to the prevalence of type 2 diabetes and impaired glucose tolerance (IGT) in a population. From the available literature, the prevalence rates of GDM in different countries vary from <1% to more than 15%. Data on the prevalence of GDM in India is scanty, but the available literature shows a clear increasing trend in prevalence. The prevalence rates increased from 2% in 1982 to 7.6% in 1991 and 16.5% in In a multicentric study from India, the highest prevalence of GDM was found in Tamil Nadu and the lowest in Kashmir. With the increasing prevalence of type 2 diabetes and IGT in India, the numbers of women with GDM (and pre-existing diabetes complicating pregnancy) can also be expected to go up further. APPENDIX The criteria for diagnosing diabetes and states of impaired glucose homeostasis in non-pregnant adults are given in Tables 1 and 2, while the currently accepted classification of diabetes is shown in Table 3. Table 1: Diagnostic criteria for diabetes in nonpregnant individuals Symptoms of diabetes + casual plasma glucose concentration > 200mg/dl (casual - any time of the day without regard to time since last meal) Fasting plasma glucose > 126mg/dl* (Fasting - no caloric intake for at least 8 hours) 2 Hour plasma glucose during OGTT > 200mg/dl* (OGTT according to WHO criteria) HbA1c > 6.5%* * in the absence of unequivocal hyperglycemia, should be confirmed by retesting on a different day Table 2: Criteria for diagnosis of states of impaired glucose homeostasis Impaired Fasting Glucose (IFG): Fasting Plasma Glucose > 110 and < 126 mg per dl Impaired Glucose Tolerance (IGT): 2hr Post Glucose load Plasma Glucose < 199 mg per dl > 140 and 12 Table 3: Etiologic classification of diabetes mellitus I. Type 1 diabetes (beta cell destruction, usually leading to absolute insulin deficiency) A. Immune-mediated B. Idiopathic II. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance) III. Other specific types A. Genetic defects of beta-cell function 1. Chromosome 12, HNF-1α (MODY 1) 2. Chromosome 7, glucokinase (MODY 2) 3. Chromosome 20, HNF- 4α (MODY 3) Contd...

15 Module I: Introduction to Diabetes in Pregnancy Table 3: Etiologic classification of diabetes mellitus 4. Chromosome 13, IPF-1 (MODY 4) 5. Chromosome 17, HNF-1β (MODY 5) 6. Chromosome 2, NeuroD1 (MODY 6) 7. Mitochondrial DNA 8. Others B. Genetic defects in insulin action 1. Type A insulin resistance 2. Leprechaunism 3. Rabson- Mendenhall syndrome 4. Lipoatrophic diabetes 5. Others C. Diseases of exocrine pancreas Pancreatitis Trauma/pancreatectomy Neoplasia Cystic fibrosis Hemochromatosis Fibrocalculous pancreatopathy Others D. Endocrinopathies Acromegaly Cushing s syndrome Glucagonoma Pheochromocytoma Hyperthyroidism Somatostatinoma Aldosteronoma Others E. Drug- or chemical-induced Vacor Pentamidine Nicotinic acid F. Infections G. Uncommon forms of immune-mediated diabetes H. Other genetic syndromes sometimes associated with diabetes IV. Gestational diabetes Take Home Messages Pregnancy is a diabetogenic state GDM results when the beta cell is unable to adapt to the diabetogenic milieu of pregnancy The prevalence of GDM is high in India Diabetes in pregnancy is associated with serious consequences to the baby as well as the mother, if early detection and appropriate treatment are not offered 13

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17 Powerpoint Presentations SAFES INTRODUCTION TO DIABETES IN PREGNANCY Slide 1 LEARNING OBJECTIVES Learn about the evolution of the concept of diabetes in pregnancy Review the metabolic alterations occurring in pregnancy and how these can lead to diabetes Define GDM and discuss its epidemiology Learn about the consequences of GDM to the mother and fetus Understand the great public health significance of GDM Slide 2 SAFES HISTORICAL PERSPECTIVE OF GDM Slide 3 15

18 Certificate Course in Gestational Diabetes Mellitus DIABETES IN PREGNANCY The Early Days Pre-insulin era Pregnancy in untreated diabetes was almost unknown True diabetes was inconsistent with conception (Blott, Paris, 1856)- a statement probably prompted by the short lifespan of women with type 1 diabetes (the major cause of pre-gestational diabetes in women of reproductive age in that era) Abortion and IUD were quite frequent Major risk was the death of the mother during, or soon after, pregnancy due to uncontrolled diabetes Overall maternal mortality was also high in that era Slide 4 PRISCILLA WHITE ( ) The Doyenne of Diabetic Pregnancy Identified the link between diabetes duration, vascular complications and outcomes in pre-existing diabetes complicating pregnancy Introduced the world-famous White classification of diabetes in pregnancy in 1949 However, this classification did not include GDM as a separate entity until 1980 Slide 5 DIABETES AND PREGNANCY The Concept of Gestational Diabetes While the first case of GDM was reported by Bennewitz in Germany in 1853 (he considered diabetes a symptom of pregnancy and noted that glycosuria resolved after delivery), the concept itself is relatively recent Contd Slide 6 16

19 Module I: Introduction to Diabetes in Pregnancy 1940s - First recognition that maternal hyperglycemia influences pregnancy outcomes Jorgen Pedersen puts forward the hyperglycemia - hyperinsulinemia hypothesis to explain fetal macrosomia (later termed the Pedersen Hypothesis) John B. O Sullivan introduced the term Gestational Diabetes Mellitus (GDM) O Sullivan and Mahan criteria for diagnosing GDM introduced; these were later modified by Carpenter and Coustan Early 1970s - Norbert Freinkel introduces the terms facilitated anabolism and accelerated starvation Contd Slide WHO criteria for diagnosis of GDM introduced ACHOIS Study underlined the benefits of treating GDM DIPSI Guidelines published HAPO Study findings published IADPSG revises the diagnostic criteria for GDM ADA endorses IADPSG Criteria NIH states that more evidence is needed before IADPSG criteria are adopted WHO has adopted IADPSG criteria and dropped their own 1999 criteria. Slide 8 DIAGNOSTIC CRITERIA FOR DIABETES (in nonpregnant adults) Symptoms of diabetes + casual plasma glucose concentration > 200mg/dl (casual - any time of the day without regard to time since last meal) Fasting plasma glucose > 126mg/dl* (Fasting - no caloric intake for at least 8 hours) 2 Hour plasma glucose during OGTT > 200mg/dl* (OGTT according to WHO criteria) HbA1c > 6.5%* *In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing Slide 9 17

20 Certificate Course in Gestational Diabetes Mellitus CRITERIA FOR THE DIAGNOSIS OF IMPAIRED GLUCOSE HOMEOSTASIS Impaired glucose homeostasis Impaired Fasting Glucose (IFG): Fasting Plasma Glucose > 110 and < 126 mg per dl Impaired Glucose Tolerance (IGT): 2hr Post Glucose load Plasma Glucose > 140 and < 199 mg per dl World Health Organisation, 2006 Slide 10 CASE STUDY 1 A 28 year old nongravid female has an OGTT performed as part of insurance screening. The following are her results Time 0 hr (Fasting) 2 hour Glucose (mg/dl) What is the diagnosis? Slide 11 CASE STUDY 2 A 35 year old nongravid female with a strong family history of diabetes undergoes an OGTT. The following are her results Time 0 hr (Fasting) 2 hour Glucose (mg/dl) What is the diagnosis? Slide 12 18

21 Module I: Introduction to Diabetes in Pregnancy ETIOLOGIC CLASSIFICATION OF DIABETES MELLITUS (ADA Expert Committee- 1997) Includes four clinical classes Type 1 diabetes ( cell destruction, usually leading to absolute insulin deficiency ) a. Immune mediated b. Idiopathic Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance) Contd Slide 13 ETIOLOGIC CLASSIFICATION OF DIABETES MELLITUS Other specific types Genetic defects of cell function (e.g. MODY) Genetic defects in insulin action Diseases of the exocrine pancreas Endocrinopathies Drug - or chemical induced Infections Uncommon forms of immune-mediated diabetes Other genetic syndromes sometimes associated with diabetes Gestational Diabetes Mellitus (GDM) Slide 14 GESTATIONAL DIABETES MELLITUS Definition Glucose intolerance of any severity with onset or first recognition during pregnancy Metzger BE et al. Diabetes Care, 1998 Contd... Slide 15 19

22 Certificate Course in Gestational Diabetes Mellitus GESTATIONAL DIABETES MELLITUS Definition This definition is applicable irrespective of whether insulin is used or not for treatment It is also applicable irrespective of whether the condition resolves after delivery It does not exclude the possibility that diabetes could have antedated the pregnancy Contd Slide 16 GESTATIONAL DIABETES MELLITUS Definition Women diagnosed with GDM might have: Normal glucose tolerance prior to pregnancy which becomes abnormal with pregnancy and returns to normal following delivery Mild glucose intolerance ( pre-diabetes ) before pregnancy which worsens during pregnancy Previously undiagnosed type 2 diabetes Previously undiagnosed type 1 diabetes (rare) Previously undiagnosed MODY and secondary diabetes (rare) Slide 17 SAFES PATHOGENESIS OF GDM Slide 18 20

23 Module I: Introduction to Diabetes in Pregnancy EFFECT OF PREGNANCY ON BLOOD GLUCOSE Pregnancy is characterised by profound metabolic alterations in the mother The main purpose of these changes is to ensure adequate nutrition (in the form of glucose) to the growing fetus during times of plenty as well as times of scarcity At the same time, the metabolic demands of the mother also need to be met Slide 19 MATERNO - FETAL NUTRIENT TRANSFER The fetus is dependent on the maternal supply of nutrients for all it s requirements Nutrients from the maternal circulation cross the placental barrier and reach the fetus This process is primarily dependent on the materno-fetal concentration gradient of the nutrient in question Slide 20 MATERNO - FETAL NUTRIENT TRANSFER Mother Placenta Fetus Glucose Amino Acids Ketones Triglycerides Insulin Glucagon Glucose Amino Acids Ketones Fatty Acids Note: A schematic representation of maternal-fetal nutrient and hormone exchange across the placenta in pregnancy. Glucose, amino acids, and ketones move freely into the fetal circulation, whereas insulin does not. Glucose travels down its concentration gradient while amino acids are transported against their concentration gradient (their levels are higher in fetal blood than in maternal blood).maternal hyperglycemia and ketosis are thus reflected in the fetal circulation. (Freinkel N, Diabetes, 1980) Glucose and amino acids traverse the placenta while insulin does not Freinkel N. Diabetes, 1980 Slide 21 21

24 Certificate Course in Gestational Diabetes Mellitus Metabolism during pregnancy is best described as a combination of facilitated anabolism and accelerated starvation (catabolism) Note: The figure schematically represents maternal metabolic changes during gestation. Anabolism during feeding and catabolism during fasting are exaggerated in a progressive fashion, reflecting the combined effects of placental hormones and nutrient use by the fetus Buchanan TA, Coustan DR. Diabetes mellitus. In: Medical complications during pregnancy, 4 th ed. Philadelphia: WB Saunders,1994 Slide 22 EARLY PREGNANCY Facilitated Anabolism Main hormones involved are estrogen and progesterone These hormones cause hyperinsulinemia by promoting beta cell hyperplasia and increased insulin release During early pregnancy, the first phase insulin secretion is found to be augmented when compared to pre-gravid state; however, second phase secretion remains unchanged Note: During early pregnancy, insulin resistance is low while beta cell function is normal or increased. This leads to low plasma glucose levels as well as HbA1c till around the 20th week of pregnancy. The placental transfer of glucose to the growing fetus is another important reason for lowering of maternal glucose levels Contd Slide 23 EARLY PREGNANCY Facilitated Anabolism Hyperinsulinism Increased insulin sensitivity Increased glycogenesis Reduced hepatic glucose output Increased peripheral glucose uptake Increased lipid synthesis This leads to a reduction in fasting plasma glucose levels in early pregnancy Contd Slide 24 22

25 Module I: Introduction to Diabetes in Pregnancy EARLY PREGNANCY Facilitated Anabolism Main purpose is to prepare the mother for the increased energy demands expected during later pregnancy During early pregnancy, energy demands from the fetus are relatively low since linear growth is not as rapid as it will be subsequently Slide 25 EARLY PREGNANCY Since insulin sensitivity is normal or raised during early pregnancy and insulin secretion is increased, GDM is rare during this period Women diagnosed to have GDM during early pregnancy may have had hitherto undiagnosed type 2 diabetes Slide 26 LATER PREGNANCY Stage of Insulin Resistance After 20 weeks of gestation, the placental hormones start playing an increasingly important role The main placental hormone contributing to insulin resistance is human placental lactogen (HPL) Other hormones involved are prolactin, cortisol, progesterone and growth hormone All of these hormones antagonise the effect of insulin and bring about a state of physiological insulin resistance Contd... Slide 27 23

26 Certificate Course in Gestational Diabetes Mellitus LATER PREGNANCY Stage of Insulin Resistance Increased levels of placental hormones Insulin resistance Facilitated diffusion following a meal Higher blood glucose levelsenable free diffusion to fetus to meet its increased demands Accelerated starvation in the fasting state High levels of free fatty acids and ketone bodies to provide fuel for the mother, so that glucose is spared for the fetus Slide 28 First-phase insulin response (minutes 1 10 of intravenous glucose tolerance test) in normal women and women who developed GDM Note: Buchanan and Catalano used euglycemic, hyperinsulinemic clamps and intravenous glucose tolerance tests to measure insulin sensitivity and secretion in normal women and in those with GDM before and during early and late pregnancy. Their results demonstrate increasing insulin secretion in both groups, but a much flatter slope in the women with GDM [despite the fact that insulin resistance was somewhat greater in the women with GDM] Buchanan TA et al, Diabetes Rev, 1995 Slide 29 Insulin sensitivity during different stages of pregnancy in women with and without GDM Note: Although insulin secretory defect (failure of compensation) underlies most cases of GDM, it is also noteworthy that women with GDM tend to have lower insulin sensitivity during all stages of pregnancy as well as in the pre-gravid state. Catalano PM et al, Am J Obstetr Gynecol, 1999 Slide 30 24

27 Module I: Introduction to Diabetes in Pregnancy PATHOGENESIS OF GDM In most women, the beta cell can compensate for the increased insulin resistance of pregnancy by hyperplasia and hypertrophy (Van Assche et al, 1978) Third trimester fasting insulin levels are 2 fold higher than pre-pregnant levels in normal pregnant women This results in fasting blood glucose levels that are 10 to 20 mg/dl lower than in the nonpregnant state, even in the last trimester (Kalhan SC, 1979; Metzger BE, 1982; Buchanan TA, 1990; Catalano PM, 1992) GDM develops when the beta cell is unable to compensate for the increased insulin resistance Slide 31 WHY DOES THE BETA CELL FAIL TO ADAPT? Genetic factors Chronic insulin resistance antedating pregnancy (especially in obese women) Subclinical inflammation Slide 32 SAFES RISK FACTORS OF GDM Slide 33 25

28 Certificate Course in Gestational Diabetes Mellitus CASE STUDY 3 Mrs. C is a 22 year old primigravida. She is 156 cm tall and weighs 51 Kg (BMI 20.9 Kg/m 2 ). She has no family history of diabetes. What is her risk of developing GDM? Slide 34 CASE STUDY 4 Mrs. C is 33 years old. She has suffered from two miscarriages in the last three years and has earlier delivered a baby weighing 4.1 Kg. She is 160 cm tall and weighs 81 Kg (BMI 31.6 Kg/m 2 ). Both her parents have diabetes. What is her risk of developing GDM? Slide 35 GDM Risk Factors Note: The risk factors for GDM are listed above. It can be easily appreciated that most pregnant women will have one or more of these risk factors Obesity (BMI >25) and Metabolic syndrome Diabetes in first degree relative Previous GDM or glucose intolerance Previous macrosomic baby Member of high risk ethnic group (all Indians fall in this category) Age >25 Polycystic Ovarian Syndrome (PCOS) Previous polyhydramnios Previous unexplained perinatal loss or birth of a malformed infant Slide 36 26

29 Module I: Introduction to Diabetes in Pregnancy SAFES IMPLICATIONS OF GDM Slide 37 IMPLICATIONS OF GDM Maternal implications Pre-eclampsia Polyhydramnios Operative delivery Perineal trauma Risk of future diabetes Ketosis Fetal and Neonatal implications Fetal macrosomia Birth trauma Prematurity RDS even without prematurity Neonatal metabolic complications (hypoglycemia, hyperbilirubinemia, hypocalcemia, polycythemia) Obesity and diabetes in later life Slide 38 CONGENITAL MALFORMATIONS IN GDM Congenital malformations are extremely uncommon in GDM, since it usually develops in late pregnancy, long after organogenesis is complete Risk of malformation is similar to that in women with pre existing diabetes if GDM is diagnosed in the first trimester Slide 39 27

30 Certificate Course in Gestational Diabetes Mellitus MACROSOMIA A macrosomic baby is one whose weight is above the 90 th percentile for the gestational age Also termed large for gestational age (LGA) The American College of Obstetricians and Gynecologists prefers a cut off of 4.5 kg to define a macrosomic baby No validated cut offs for India kg seems reasonable (3.45 kg corresponds to the 90 th percentile of birth weight for Indians) Contd Slide 40 MACROSOMIA Infants of mothers with GDM have asymmetrical macrosomia with abnormal thoracic and abdominal circumference which is larger than head circumference Organomegaly is also present In untreated GDM, the risk of macrosomia is as high as 40% (Persson and Hanson, Diabetes Care, 1998) Severe maternal diabetes (particularly type 1 DM) with vasculopathy and impaired renal function may be associated with intrauterine growth restriction and microsomia (Van Assche et al, Br Med Bull, 2001) Contd Slide 41 MACROSOMIA High risk of birth trauma (shoulder dystocia, clavicle fracture, humerus fracture, brachial palsy, facial palsy) Increased risk of C-section Increased risk of diabetes in later life Slide 42 28

31 Module I: Introduction to Diabetes in Pregnancy PATHOGENESIS OF MACROSOMIA The Pedersen Hypothesis Maternal hyperglycemia leads to excess exposure of the fetus to maternal glucose, fetal hyperinsulinemia, and excess growth This concept was further refined by Freinkel, who added a potential role of other nutrients ( mixed nutrients ) in fetal overgrowth Slide 43 PATHOGENESIS OF MACROSOMIA The Pedersen - Freinkel Hypothesis Note: The Pedersen hypothesis, later modified by Freinkel, suggests that macrosomia results from excess supply of glucose and other nutrients ( mixed nutrients ) to the fetus, and consequent hypersecretion of insulin by the fetal pancreas. (Freinkel N, Diabetes, 1980) Freinkel N. Diabetes, 1980 Slide 44 OTHER METABOLIC PROBLEMS IN THE NEONATE Hypoglycemia This occurs due to abrupt cessation of delivery of maternal glucose to a neonate whose insulin levels are high following exposure to chronic maternal hyperglycemia during pregnancy Slide 45 29

32 Certificate Course in Gestational Diabetes Mellitus NEONATAL HYPOGLYCEMIA IS INVERSELY RELATED TO MATERNAL HYPERGLYCEMIA AT DELIVERY Note: In any form of diabetes in pregnancy, the higher the maternal plasma glucose levels at delivery, the greater the risk of hypoglycemia in the neonate. (Jovanovic L, Peterson CM. Am J Med, 1983) Therefore good control of maternal diabetes can prevent neonatal hypoglycemia Jovanovic L, Peterson CM. Am J Med, 1983 Slide 46 OTHER METABOLIC PROBLEMS IN THE NEONATE Polycythemia occurs due chronic intrauterine hypoxemia and placental insufficiency secondary to poor glycemic control As these excess RBCs break down, hyperbilirubinemia occurs days to weeks after birth The exact mechanism of hypocalcemia is unknown but may be related to functional hypoparathyroidism (Tsang J et al, J Pediatr, 1975) Slide 47 IMPAIRED FETAL LUNG MATURATION Respiratory Distress Syndrome In a diabetic pregnancy, lung maturation is delayed due to reduced surfactant production secondary to hyperglycemia and hyperinsulinemia Poorly controlled diabetes in pregnancy is an important risk factor for RDS Slide 48 30

33 Module I: Introduction to Diabetes in Pregnancy STILLBIRTHS Stillbirth rate in GDM is greater than that of the general population Majority occur even in the absence of congenital malformations Depends on the severity of diabetes and adequacy of metabolic control Rate of stillbirth is equal to that in the general population if mean blood glucose levels can be kept below mg/dl Mainly related to excess fetal growth, consequent to hyperglycemia and hyperinsulinemia (Pettitt et al, Diabetes Care, 1980) May be due to osmotically induced edema of chorionic villi which decreases O 2 transport and leads to hypoxia and fetal acidemia However, fetal growth restriction can also contribute to stillbirths Slide 49 Good control of glucose levels in the mother can significantly reduce adverse pregnancy outcomes in GDM This is one of the cornerstones of modern GDM management Slide 50 GDM AND RISK OF FUTURE DIABETES IN THE OFFSPRING Infants of mothers who had diabetes during pregnancy have a higher risk of developing obesity, metabolic syndrome and IGT/ type 2 diabetes in the future Dabelea D, Diabetes Care, 2007 Offspring of women with GDM are at 4 to 8 times higher risk of developing type 2 diabetes Clausen TD, Diabetes Care, 2008 Contd Slide 51 31

34 Certificate Course in Gestational Diabetes Mellitus GDM AND RISK OF FUTURE DIABETES IN THE OFFSPRING Prevalence of type 2 diabetes, by mother s diabetes during and after pregnancy in Pima Indians aged 5 34 years., Offspring of nondiabetic mothers;, offspring of pre-diabetic mothers; offspring of diabetic mothers Dabelea D, Pettitt DJ, J Pediatr Endocrinol Metab, 2001 Slide 52 Note: The Figure shows the prevalence of type 2 diabetes by age-group in offspring of diabetic (women who had diabetes before or during pregnancy), pre-diabetic (those who developed diabetes after pregnancy), and nondiabetic mothers. By age 5 9 and years, diabetes was present almost exclusively among the offspring of diabetic women. In all age-groups, there was significantly more diabetes in the offspring of diabetic women than in those of pre-diabetic and nondiabetic women. There were much smaller differences in diabetes prevalence between offspring of pre-diabetic and nondiabetic women. (Dabelea D, Pettitt DJ. Pediatr Endocrinol Metab, 2001) GDM AND RISK OF METABOLIC SYNDROME IN THE OFFSPRING Note: Adult health outcomes and exposure to maternal diabetes. The risk of developing one or other of the components of metabolic syndrome in adulthood is higher in infants exposed to maternal diabetes in utero. Even the presence of risk factor for GDM (without overt hyperglycemia) confers excess risk. (Moore TR. Am J Obstetr Gynecol, 2010) Moore TR. Am J Obstetr Gynecol, 2010 Slide 53 IMPLICATIONS TO THE MOTHER Pre - Eclampsia Diabetic pregnancy is associated with a higher rate of hypertensive complications than normal pregnancy Risk of pre-eclampsia is increased in GDM (15%-20% vs. 5%-7% in non-gdm) This is due to a combination of insulin resistance, genetic factors, age and BMI Sibai BM, Caritis S, Hauth J et al. Am J Obstet Gynecol, 2000 Slide 54 32

35 Module I: Introduction to Diabetes in Pregnancy IMPLICATIONS TO THE MOTHER Pre - Eclampsia Note: The figure shows the rate of preeclampsia in relation to the severity of GDM, as assessed by fasting plasma glucose. Higher the FPG, more the prevalence of PET. (Yogev Y. Am J Obstetr Gynecol, 2004) The rate of pre-eclampsia depends on the severity of GDM Yogev Y, Am J Obstetr Gynecol, 2004 Slide 55 IMPLICATIONS TO THE MOTHER Risk of Future Diabetes Following delivery, diabetes persists in 5% to 10% of women diagnosed to have GDM 35% to 60% of women with GDM will develop type 2 diabetes within 10 years Conversion to diabetes occurs more frequently, and faster, in high risk ethnic groups (such as Asian Indians) Tovar A et al. Prev Chronic Dis, 2011 Slide 56 SAFES EPIDEMIOLOGY OF GDM Slide 57 33

36 Certificate Course in Gestational Diabetes Mellitus EPIDEMIOLOGY OF GDM Global Scenario Prevalence of GDM varies according to the population studied, test used, timing of testing and criteria used Global prevalence rates vary from 1% to >15% The prevalence rate of GDM in a population is proportional to that of diabetes and IGT in that population (King, Diabetes Care, 1998) Slide 58 EPIDEMIOLOGY OF GDM Indian Scenario Prevalence of GDM is steadily rising in India The rates increased from 2% in 1982 (Agarwal and Gupta) to 7.6% in 1991 (Narendra) and 16.55% in 2002 (Seshiah) In a multicentric study in India, the highest prevalence of GDM was found in Tamil Nadu and the lowest in Kashmir (Seshiah et al, 2004) Contd Slide 59 EPIDEMIOLOGY OF GDM Indian Scenario Note: A study conducted in 11,256 pregnant women in Tamil Nadu showed that the urban areas had the highest prevalence rates of GDM compared to semi-urban and rural areas. The prevalence of GDM increased with increasing age and BMI of the mother. (Seshiah et al, J Assoc Physicians India, 2008) GDM is more prevalent in the urban areas and among older and more obese women Seshiah et al, J Assoc Physicians India, 2008 Slide 60 34

37 Module I: Introduction to Diabetes in Pregnancy PUBLIC HEALTH IMPORTANCE OF GDM GDM has public health importance far beyond its immediate effects on the mother and child 35% to 60% of women with GDM will develop type 2 diabetes within 10 years; therefore, GDM is a major driver of the type 2 diabetes epidemic Infants of women with GDM have a higher prevalence of overweight or obesity as young children and adolescents, and a higher risk of developing type 2 diabetes later in life Proper management and follow-up of women with GDM and their offspring has the potential to prevent diabetes in two generations Slide 61 TAKE - HOME MESSAGES Pregnancy is a diabetogenic state GDM results when the beta cell is unable to adapt to the diabetogenic milieu of pregnancy The prevalence of GDM is high in India Diabetes in pregnancy is associated with serious consequences to the baby as well as the mother, if early detection and appropriate treatment are not offered Slide 62 35

38 Certificate Course in Gestational Diabetes Mellitus Primer to Module II SAFES PRIMER TO MODULE II Slide 63 MODULE II Screening and Diagnosis of GDM Screening for GDM Diagnosis of GDM Pre-existing diabetes and pregnancy Slide 64 36

39 Module I: Introduction to Diabetes in Pregnancy

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