Gestational diabetes mellitus

1. Gestational diabetes mellitus Dr. Kanakamani Madhivanan, M.D., D.M. (Endocrinology), Assistant Professor Department of Endocrinology, Diabetes, Metabolism Christian Medical College, Vellore

2. Plan of presentation • Introduction • Physiology of fuel metabolism in normal pregnancy • Pathophysiology of GDM • Epidemiology of GDM • Screening and diagnosis • Maternal and fetal risks • Management of GDM • Obstetric management

3. Introduction

4. Introduction • Global increase in prevalence of DM • Individual importance - Hyperglycemia in pregnancy has adverse effects on both mother and fetus • Public health importance – rising epidemic of DM in part attributed to the diabetic pregnancies • Prevention of type 2 DM should start intrauterine and continue throughout life

5. Introduction • Gestational diabetes (GDM) is defined as any degree of impaired glucose tolerance of with onset or first recognition during pregnancy . • Many are denovo pregnancy induced • Some are type 2 ( 35-40%) • 10% have antibodies

6. Introduction • Difficult to distinguish pregestational Type 2 DM and denovo GDM • Fasting hyperglycemia • blood glucose greater than 180 mg/dL on OGT • acanthosis nicgrans • HbA1C > 5.3% • a systolic BP > 110 mm Hg • BMI > 30 kg/m2 • Fetal anomalies • Clues for Type 1 • Lean • DKA during pregnancy • Severe hyperglycemia with large doses of insulin

7. Fuel metabolism in pregnancy

8. Fuel metabolism in pregnancy • Goal is uninterrupted nutrient supply to fetus • The metabolic goals of pregnancy are • 1) in early pregnancy to develop anabolic stores to meet metabolic demands in late pregnancy • 2) in late pregnancy to provide fuels for fetal growth and energy needs.

9. Glucose metabolism in pregnancy • Early pregnancy • E2/PRL stimulates b cells –Insulin sensitivity same and peripheral glucose utilisation – 10% fall in BG levels • Late pregnancy • Fetoplacental unit extracts glucose and aminoacids, fat is used mainly for fuel metabolism • Insulin sensitivity decreases progressively upto 50-80% during the third trimester • variety of hormones secreted by the placenta, especially hPL and placental growth hormone variant, cortisol, PRL,E2 and Prog

10. Glucose metabolism in pregnancy FASTING accelerated starvation and esxaggerated ketosis (maternal hypoglycemia, hypoinsulinemia, hyperlipidemia, and hyperketonemia) FED hyperglycemia, hyperinsulinemia, hyperlipidemia, and reduced tissue sensitivity to insulin Fat Hyperinsulinemia Insulin resistance Glucose Aminoacids Fetus

11. 24-hour insulin requirement before conception is approximately 0.8 units / kg. • In the first trimester, the insulin requirement rises to 0.7units / kg of the pregnant weight – more unstable glycemia with a tendency to low fasting plasma glucose and high postprandial excursions and the occurrence of nocturnal hypoglycemia • By the second trimester, the insulin requirement is 0.8 units per kilogram. From 24th month onwards steady increase in insulin requirement and glycemia stabilises • By third trimester the insulin requirement is 0.9 - 1.0 unit /kg pregnant weight per day • Last month – may be a decrease in insulin and hypoglycemias esp. nocturnal

12. EPIdemiology AND Risk factors

13. Magnitude of problem: Global • Prevalence of GDM varies worldwide and among different racial and ethnic groups within a country • America – white women (3.9%) and Asian (8.7%) • Europe – 0.6% to 3.6% • Australia – 3.6% to 4.7% (Indian women – 17.7%) • China – 2.3%; Japan – 2.9% • Variability is partly because of the different criteria and screening regimens

14. Magnitude of the problem - India • Chennai, hospital based, universal screening – 18.9% had FPG ≥ 126 and PPPG ≥ 140. • Trivandrum – 15% • Bangalore – 12% • Erode – 18.8% • Chennai, community based, universal screning, 17.8% in urban, 13.8% in semi urban and 9.9% in rural areas. • Chennai : 0.56% • Mysore Parthenon Study: 6% • Maharashtra, hospital based, selective screening – 7.7% had GDM; 13.9% had IGGT.

15. Risk factors • A family history of diabetes, especially in first degree relatives • Prepregnancy weight ≥110% of ideal body weight or body mass index over 30 kg/m2 or significant weight gain in early adulthood, between pregnancies, or in early pregnancy • Age greater than 25 years • Previous delivery of a baby greater than 4.1 kg • Personal history of abnormal glucose tolerance • Member of an ethnic group with higher than the background rate of type 2 diabetes (in most populations, the background rate is approximately 2 percent) • Previous unexplained perinatal loss or birth of a malformed child • Maternal birthweight greater than 4.1 kg or less than 6 pounds 2.7 kg • Glycosuria at the first prenatal visit • Polycystic ovary syndrome • Current use of glucocorticoids • Essential hypertension or pregnancy-related hypertension

16. Maternal and Fetal risks

17. Maternal complications • Worsening retinopathy – 10% new DR, 20% mild NPDR and 55% mod-severe NPDR progresses • Worsening proteinuria. GFR decline depends on preconception creatinine and proteinuria • Hypertension and Cardiovascular disease • Neuropathy – No worsening (gastroparesis, nausea, orthostatic dizziness can be worsened) • Infection

18. Maternofetal complications • Macrosomia: 63 percent • Cesarean delivery: 56 percent • Preterm delivery: 42 percent • Preeclampsia: 18 percent • Respiratory distress syndrome: 17 percent • Congenital malformations: 5 percent • Perinatal mortality: 3 percent • Spontaneous abortion, third trimester fetal deaths, Polyhydramnios, preterm birth, ?adverse neurodevelopmental outcome • Risk for type 2 DM

19. Neonatal complications • Morbidity associated with preterm birth • Macrosomia ± birth injury (shouldeer dystocia, brachial plexus injury) • Polycythemia and hyperviscosity • Hyperbilirubinemia • Cardiomyopathy • Hypoglycemia and other metabolic abnormalities (hypocalcemia, hypomagnesemia) • Respiratory problems • Congenital anomalies

20. Congenital anomalies • 2/3rd CVS or CNS,– 13-20 times common • Cardiac( including great vessel anomalies) : most common • Central nervous system (spina bifida/anencephaly) : 7.2% • Skeletal: cleft lip/palate, caudal regression syndrome • Genitourinary tract: ureteric duplication • Gastrointestinal : anorectal atresia

21. Skeletal and central nervous system • Caudal regression syndrome • Neural tube defects excluding anencephaly • Anencephaly with or without herniation of neural elements • Microcephaly • Cardiac • Transposition of the great vessels with or without ventricular • Ventricular septal defects • Coarctation of the aorta with or without ventricular septal defects or patent ductus arteriosus • Atrial septal defects • Cardiomegaly • Renal anomalies • Hydronephrosis • Renal agenesis • Ureteral duplication • Gastrointestinal • Duodenal atresia • Anorectal atresia • Small left colon syndrome

22. Caudal regression syndrome

23. Caudal regression syndrome

24. SCREENING AND DIAGNOSIS

25. Whom to screen ? • No consensus • recommended screening ranges from selective screening of average- and high-risk individuals to universal diagnostic testing of the entire population dependent on the risk of diabetes in the population. Risk stratification based on certain variables Low risk : no screening Average risk: at 24-28 weeks High risk : as soon as possible

27. Low risk for GDM To satisfy all these criteria • Age <25 years • Not a member of an ethnic group with high prevalence of GDM (not Hispanic, Native American/Alaskan, Asian/Pacific Islander, African American) • Normal prepregnancy body weight (not 20% or more over desired body weight or BMI 27 kg/m2 or more) • No family history of diabetes in first-degree relatives. • No history of abnormal glucose tolerance • No history of poor obstetric outcome

28. High risk • Marked obesity • Prior GDM (30-50% risk for recurrence) • Glycosuria • Strong family history

29. When and how to screen? • 24-28 weeks • High risk • First prenatal visit • 50 g glucose loading test • High risk women – 3 hr GTT with 100 g glucose

31. 50 g GTT • A 50-g oral glucose load is given without regard to the time elapsed since the last meal and plasma or serum glucose is measured one hour later • A value ≥130 mg/dL is considered abnormal ; we use ≥130 mg/dL as the threshold for our patients. • Capillary blood should not be used for screening unless the precision of the glucose meter is known, it has been correlated with simultaneously drawn venous plasma samples, and has met federal standards for laboratory testing.

32. 100 g GTT • Oral glucose tolerance test ( OGTT) with 100 gm glucose • Overnight fast of at least 8 hours • At least 3 days of unrestricted diet and unlimited physical activity • > 2 values must be abnormal

33. 75 g GTT ADA WHO

34. Whom and when to screen? Indian Scenario -The DIPSI Guidelines • 75 gm GCT with single PG at 2 hrs – • ≥ 140 mg/dL is GDM • ≥ 120 mg/dL is DGGT • Universal screening • First trimester, if negative at 24 – 28 weeks and then at 32 – 34 weeks

35. Management of gdm

36. MANAGEMENT ISSUES • Patient education • Medical Nutrition therapy • Pharmacological therapy • Glycemic monitoring: SMBG and targets • Fetal monitoring: ultrasound • Planning on delivery

37. Medical nutrition therapy • Goals • Achieve normoglycemia • Prevent ketosis • Provide adequate weight gain • Contribute to fetal well-being • Nutritional plan • Calorie allotment • Calorie distribution • CH2O intake

38. Calorie allotment • 30 kcal per kg current weight per day in pregnant women who are BMI 22 to 25. • 24 kcal per kg current weight per day in overweight pregnant women (BMI 26 to 29). • 12 to 15 kcal per kg current weight per day for morbidly obese pregnant women (BMI >30). • 40 kcal per kg current weight per day in pregnant women who are less than BMI 22.

39. Carb intake • Postprandial blood glucose concentrations can be blunted if the diet is carbohydrate restricted. Complex carbohydrates, such as those in starches and vegetables, are more nutrient dense and raise postprandial blood glucose concentrations less than simple sugars. • Carbohydrate intake is restricted to 33-40% of calories, with the remainder divided between protein (about 20%) and fat (about 40%). • With this calorie distribution, 75 to 80 percent of women with GDM will achieve normoglycemia.

40. Calorie distribution • Variable opinion • Most programs suggest three meals and three snacks; however, in overweight and obese women the snacks are often eliminated • Breakfast — The breakfast meal should be small (approximately 10%of total calories) to help maintain postprandial euglycemia. Carbohydrate intake at breakfast is also limited since insulin resistance is greatest in the morning. • Lunch — 30% of total calories • Dinner — 30% of total calories • Snacks — Leftover calories (approximately 30% of total calories) are distributed, as needed, as snacks.

41. Monitoring BG • Atleast 4 times • Fasting and 3 one hr postprandial • Pre vs postprandial monitoring • Better glycemic control (HbA1c value 6.5 versus 8.1 percent) • A lower incidence of large-for-gestational age infants (12 versus 42 percent) • A lower rate of cesarean delivery for cephalopelvic disproportion (12 versus 36 percent)

42. Monitoring BG • Home monitoring • Maintain log book • Use a memory meter • Calibrate the glucometer frequently • HbA1C • Ancillary test for feedback to the patient • Lower values when compared to nonpregnant state – lower BG and increase in red cell mass and slight decrease in life span – measured every 2-4 weeks • Target < 5.1%

43. Studies report no to moderate correlations between HbA1 and different components of the glucose profile when an HbA1 result of 4% to 5% includes a capillary blood glucose range of 50 to 160 mg/dL. • Levels of HbA1c are related to the rate of congenital anomalies and spontaneous early abortions in pre-existing diabetes, but the use of this measure, which retrospectively reflects glycemic profile in the last 10 weeks, for treatment evaluation in GDM is questionable. In addition, the association between glycosylated hemoglobin and pregnancy outcome in GDM or prediction of macrosomia is poor • Glycosylated protein and fructosamine widely variable and not yet established

44. Glycemic targets (ACOG) • ACOG • Fasting venous plasma ≤ 95 mg/dl • 1 hour postprandial ≤ 140 mg/dl • 2 hour postprandial ≤ 120 mg/dl • Pre-meal ≤ 100 mg/dl • A1C ≤ 6% • ADA • premeal 80-110 • 2 hr postmeal not more than 155 These are venous plasma targets, not glucometer targets

45. PHARMACOLOGICAL INTERVENTION • If the FPG at diagnosis is ≥ 120, can consider immediate therapy. • Otherwise, MNT for 2 weeks • If majority FPG (4/7) > 95 or PP > 120 then to start on insulin.

46. Insulin • ≈ 15% need insulin • Total dose varies. ≈ 0.7 to 2 units per kilogram (present pregnant weight) • FBG high – Night NPH ≈ 0.2 units/kg • PPBG high – bolus ≈ 1.5 units/10 gm CH2O for breakfast and ≈ 1 unit /10 gm CH2O for lunch and dinner • If both pre and postprandial BG high or if the woman's postprandial glucose levels can only be blunted if starvation ketosis occurs - four injection/day regimen. • Total 0.7 unit/kg up to week 18 • 0.8 unit/kg for weeks 18 to 26 • 0.9 unit/kg for weeks 26 to 36 • 1. unit/kg for weeks 36 to term. • In a morbidly obese woman, the initial doses of insulin may need to be increased to 1.5 to 2. units/kg to overcome the combined insulin resistance of pregnancy and obesity.

47. OHA in pregnancy • Systematic review by John Hopkins University • maternal glucose levels did not differ substantially between gravidae treated with insulin versus those treated with oral glucose-lowering agents • there was no consistent evidence of an increase in any adverse maternal or neonatal outcome with use of glyburide, acarbose, or metformin compared with use of insulin • Inconsistent data. ADA, ACOG, USFDA do not endorse.

48. OHA in pregnancy • Tolbutamide and chlorpropamide • Cross placenta. Fetal hperinsulinemia. Prolonged fetal hypoglycemia • Glibenclamide • Minimal transplacental transport • Observational studies – no excess anomalies or hypoglycemia • Only RCT – 404 women. Glib vs insulin. No difference

49. second-generation sulfonylureas especially glyburide, do not significantly cross the diabetic or nondiabetic placenta. Fetal concentrations reached no more than 1% to 2% of maternal concentrations. • tolbutamide diffused across the placenta most freely, followed by chlorpropamide, then glipizide, with glyburide crossing the least. • Metformin crosses placenta – not teratogenic in rat models

50. OHA in pregnancy • Metformin • Category B • No adverse outcome after first trimester • Second, third trimester safe and effective • Vs. insulin – no serious adverse effects • No studies vs. glibenclamide • Acarbose • Two prelim studies • Thiazolidinediones and GLP-1 • Not studied