DIABETES IN PREGNANCY

1. DIABETES IN PREGNANCY Josephine Carlos-Raboca, MD Chief, Section of Endocrinology,Diabetes and Metabolism Makati Medical Center

2. M.E 39 year old female She is a G3P1 (1011) who was referred to Endocrinology service on her 28th week of gestation due to findings of elevated blood sugar values in her 75g OGTT. (fasting 107 mg/dL, 1hr 191 mg/dL 2-h 158 mg/dL)

3. Past Medical History Non diabetic, non hypertensive, non asthmatic FMHx (+) Diabetes and Hypertension – Mother PSHx Non smoker, non alcoholic beverage drinker No regular form of exercise

4. Physical Examination • BP = 120/70 mmHg, HR = 76 bpm, RR 16 Wt 85 kg, Ht = 5’3” BMI = 33.2 Anicteric, pink palpebral conjunctivae, (-) cervical adenopathy, (-) carotid bruits, Thyroid not enlarged, no pharyngeal congestion • Equal chest expansion with clear breath sounds both lungs, (-) crackles • Adynamic precordium, Normal rate, regular rhythm with distinct S1, S2, (-) murmur

5. Physical Examination • Gravid abdomen, normal bowel sounds, (+) fetal heart tones • Full and equal pulses, pink nail beds with good turgor, (-) edema, (-) cyanosis, (-) hyperpigmentation

6. She was initially started on a diet plan and 4x/day blood sugar monitoring for 1 week

7. She was started on 2x/day insulin with a dose of aspartame insulin 6 units (novorapid) pre breakfast and pre dinner

8. repeat LSCS 2, breech presentation cord coil Live baby boy BW 2,863 gm AS 8/9

9. Outline • Gestational Diabetes • Definition/Prevalence • Pathogenesis • Complications • Screening and Diagnosis • Management • Pregestational Diabetes

10. Gestational Diabetes Mellitus (GDM) • Any degree of glucose in tolerance with onset or first recognition during pregnancy. • 4th International Workshop-Conference on GDM, 1998.

11. Prevalenceof GDM • 1 – 14% • USA--- 3-5% • MMC (Asian Population) – Raboca et al 13.4%

12. Pathogenesis

13. Pregnancy is a diabetogenic state characterized by insulin resistance and hyperinsulinemia

14. Metabolic Adaptations during Pregnancy placental hormones affect both glucose and lipid metabolism to ensure ample fetal fuel supply and nutrients always. There is a switch from carbohydrate to fat utilization that is facilitated by both insulin resistance and increased plasma concentration of lipolytic hormones Butte, NF. Carbohydrate and lipid metabolism in pregnancy: normal compared with gestational diabetes mellitus. Am J Clin Nutr 2000; 71:1256S.

15. Metabolic Adaptations during Pregnancy The fasted state is one of “accelerated starvation”. Alternative fuels are made available for the mother and glucose is reserved for the fetus Maternal Fuels: Free fatty acids, ketones, glycerol There is hyperplasia of Beta cells, increased insulin secretion and early increase in insulin sensitivity followed by progressive insulin resistance. Butte, NF. Carbohydrate and lipid metabolism in pregnancy: normal compared with gestational diabetes mellitus. Am J Clin Nutr 2000; 71:1256S.

16. Maternal insulin resistance results from increased release of diabetogenic hormones such as • Corticotropin Releasing Hormone • Chorionic Somatomammotropin • Progesterone • Tumor necrosis factor-a • A post receptor defect in the skeletal muscle B-subunit and at Insulin receptor substrate-1 may also contribute to the decline in insulin action. Yamashita, H, Shao, J, Friedman, JE. Physiologic and molecular alterations in carbohydrate metabolism during pregnancy and gestational diabetes mellitus. Clin Obstet Gynecol 2000; 43:87.

17. Metabolic Adaptations during Pregnancy • Insulin levels are higher in both the fasting and the postprandial states during pregnancy • The fasting glucose is 10-20% lower in pregnancy due to: • Increased storage of tissue glycogen • Increased peripheral glucose utilization • Decreased hepatic glucose production • Glucose consumption by the fetus

18. Metabolic Adaptations during Pregnancy • The placenta readily transfers glucose, amino acids, and ketone bodies to the fetus but is impermeable to large lipids. • Serum triglyceride and cholesterol levels increase during pregnancy by approximately 300 and 50% respectively. • The large rise in TG is largely due to • Increased hepatic lipase activity • Reduced lipoprotein lipase activity Herrera, E. Metabolic adaptations in pregnancy and their implications for the availability of substrates to the fetus. Eur J Clin Nutr 2000; 54 Suppl 1:S47.

19. Why Screen for GDM?

20. Perinatal Complications: • Macrosomia • Hypoglycemia • Respiratory Distress Syndrome (RDS) • Hypocalcemia • Hyperbilirubinemia • Polycythemia

21. Congenital Malformations • Skeletal • Cardiac (septal and outflow tract lesions) • CNS and neural tube defects • Gastrointestinal Defects • Genitourinary Tract lesions

22. Other complications • Pre-ecclampsia • Operative delivery • Obesity and diabetes later in life

23. Who do we screen? • Pregnant women with any of the following: • A family history of diabetes, especially in first degree relatives • Prepregnancy weight 110 percent of ideal body weight or significant weight gain in early adulthood • Age greater than 25 years • Previous delivery of a baby greater than 9 pounds [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)

24. Who do we screen? • Previous unexplained perinatal loss or birth of a malformed child • Maternal birth weight greater than 9 pounds [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 Solomon, CG, Willett, WC, Carey, VJ, et al. A prospective study of pregravid determinants of gestational diabetes mellitus. JAMA 1997; 278:1078.

25. When to screen? Screening is optimally performed at 24-28 weeks of gestation. Jovanovic, L, Peterson, CM. Screening for gestational diabetes. Optimum timing and criteria for retesting. Diabetes 1985; 34 Suppl 2:21. It should be done during the first prenatal visit if there is high degree of suspicion that the patient has undiagnosed type 2 diabetes Gestational diabetes mellitus. Diabetes Care 2004; 27 Suppl 1:S88. Women with a history of GDM have a 33-50% risk of recurrence, and some of these recurrences may represent type 2 DM ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists. Number 30, September 2001 (replaces Technical Bulletin Number 200, December 1994). Gestational diabetes. Obstet Gynecol 2001; 98:525.

26. How to screen for GDM • A fasting plasma glucose level of >126 mg/dL (7.0 mmol/l) or a casual plasma glucose >200mg/dL (11.1 mmol/l)meets the threshold for the diagnosis of diabetes, if confirmed on a subsequent day • Precludes the need for any glucose challenge Diabetes care vol 26, jan 2003

27. Screening and Recommendations5th International Workshop Conference on GDM • Diabetes Care Vol 30 Sup 2 July 2007 • GDM should be ascertained at first prenatal visit

28. Low Risk: screening is not routine if all conditions are met • Belongs to an ethnic group with low prevalence of GDM • Negative history of diabetes mellitus type 2 in first degree relative • Less than 25 years old • Normal weight before pregnancy • Normal weight at birth • No history of abnormal glucose metabolism • No history of poor obstetric outcome

29. Average risk: screen at 24-28 weeks of gestation • Two step method • 50gm GCT if positive go to diagnostic test • One step method • proceed to diagnostic test

30. High Risk • Severe obesity • Strong family history of diabetes mellitus type 2 • Previous history of GDM, impaired glucose metabolism or glucosuria. • If initially negative for GDM, repeat at 24-28 weeks of gestation or anytime with signs and symptoms suggestive of hyperglycemia

31. Screening • Glucose Challenge Test • Give 50 g oral glucose load without regard to time of day. • Measure plasma or serum glucose after 1 hour. • A glucose level >130 mg/dL (7.8 mmol/l) is abnormal. • Proceed with Oral Glucose Tolerance Test (OGTT)

32. Diagnosis 100 gram oral glucose load is given to patient who is fasting. Data from: Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diab Care 2000; 23(suppl 1):S4.

33. Diagnosis Criteria for a positive 2 hour 75 g OGTT for the diagnosis of GDM

34. Management of GDM • Diet/Medical Nutrition therapy • Blood Glucose Monitoring • Exercise • Medication

35. GOALS: • Normal outcome of index pregnancy. • Decrease risk for abnormal glucose and insulin homeostasis. • Mother (before, during, after pregnancy). • Infant subsequent generations.

36. Medical Nutrition Therapy • Goals: • Achieve normoglycemia • Prevent ketosis • Provide adequate weight gain • Contribute to fetal well-being

37. Medical Nutrition Therapy Caloric allotment Nutritional management of obese gestational diabetic woman. J Am Coll Nutr 1992;11:246

38. Medical Nutrition Therapy Gestational Diabetes mellitus 2004

39. ADA 2004 Medical Nutrition Therapy • provide adequate calories to sustain maternal and fetal requirements and • to achieve glycemic control • adequate weight gain • Avoid starvation ketosis • Protein 0 .75 g/kg/d + 10 g • Carbohydrate portion 35-40% • Folic acid 400 ug/day

40. Weight Gain in Pregnancy • BMI weight gain 1st trim 2nd-3rd trim • <20 28-40 lbs 5lb 1.07lb/wk • 21-26 25-35 3.5 .97 • 26-29 15-25 2.0 .67 • >29 15 • Krause’ Food Nutrition and Diet 11th ed L. Kathleen, Mahan and Strump 2004

41. Self Blood Glucose Monitoring Monitor Blood Glucose concentration at least 4 times daily. Timing: Fasting and 1 hour after the first bite of each meal Gestational Diabetes Mellitus. Diabetes care 2004

42. Self Blood Glucose Monitoring • One hour postprandial monitoring was associated with the following benefits as compared to preprandial monitoring • Better glycemic control (HbA1c 6.5 vs 8.1 percent) • Lower incidence of large for gestational age infants (12 vs 42 percent) • A lower rate of cesarian delivery for cephalopelvic disproportion (12 vs 36 percent). Postprandial vs preprandial blood glucose monitoring in women with GDM requiring insulin therapy. N Engl J med 1995; 333:1237

43. Insulin • When to use? • maternal blood glucose levels • fetal abdominal circumference at 29-33 weeks • amniotic fluid insulin at 28 weeks

44. Blood glucose levels • FPG > 95mg/dl (90) • 1 hour PPBG > 140 mg/dl (120) • 2 hppg > 120 mg/dl • ( ) Jovanovic

45. Insulin in pregnancy • Human insulin should be used if prescribed • SBMG should guide the doses and timing of insulin regimen • The rapid Insulin analogs lispro and aspart have been found to be clinically effective with minimal transfer across placenta and no evidence of teratogenesis. Level B • Long acting analogs – no study in pregnancy

46. Insulin Therapy ~15% of women with GDM are placed on insulin therapy The dose of insulin varies in different populations because of varied rates of obesity, ethnic characteristics, and other demographic criteria Generally 0.5 to 1.4 U/kg (present weight) is required to maintain target glucose levels. A “mixed/split” insulin regimen is generally used

47. Oral Anti-hyperglycemic Agents • Currenlty the ADA and ACOG do not endorse the use of oral hyperglygemic agents during pregnancy Gestational diabetes mellitus care 2004 • Tolbutamide or chlorpropamide • Cross the placenta and can cause fetal hyperinsulinemia which can lead to macrosomnia and prolonged neonatal hypoglycemia. Maternal-fetal transport of hyperglycemic drugs. Clin pharmacokinet 2003

48. Oral diabetic drugs • Langer NEJM 343(16):1134-38,2000 use of glyburide after 8 weeks of gestation in 201 women on glyburide vs 203 insulin • Conclusion: No difference in neonatal outcomes such as LGA, hypoglycemia anomaly or stillbirth

49. Metformin in Gestational Diabetes (MIG) Trial • Prospective Randomized controlled trial in women with GDM 20-33 weeks gestation • Randomized to insulin or metformin • Primary outcome – composite of neonatal morbidity • Key trial in assessing potential role of metformin during pregnancy

50. Results • rate of primary outcome • 32% (Met) vs 32.2% (insulin) • Acceptability • 76.6% vs 27.2% • No difference in secondary outcomes