2. Diabetes Mellitus And Pregnancy BY Mohammed shereif MD of Internal Medicine Endocrine unit Faculty of Medicine-Mansoura University

3. ☻ AGENDA: Review On Diabetes Mellitus. Endocrinology Of Pregnancy. Diabetes Mellitus And Pregnancy. Complications of Diabetes on pregnancy. Management.

4. Review On Diabetes Mellitus

5.  DIABETES MELLITUS: DEFINED Diabetes is a group of metabolic diseases characterized by hyperglycemia. Hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels

6.  DIABETES CLASSIFICATION : ♣ Type 1 (IDDM). ♣ Type 2 (NIDDM). ♣ Gestational diabetes. ♣ Other specific types.

7.  Criteria for the diagnosis of diabetes mellitus: Symptoms of diabetes and rondam plasma glucose ≥ 200 mg/dl (11.1 mmol/l). OR FPG ≥ 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 hours. OR 2-h plasma glucose ≥ 200mg/dl (11.1 mmol/l) during an OGTT. OR A1C ≥ 7%.

8. Endocrinology Of Pregnancy

9. The placenta produces larger quantities of more hormones than any other human organ. Placental Diabetogenic Hormones are:  Progesterone, Cortisol, GH  Human Placental Lactogen (HPL), Prolactin Placental hormones affect glucose and lipid metabolism to ensure that fetus has ample supply of nutrients.

10.  Changes in maternal metabolism during normal pregnancy: ♣ Decreased fasting plasma glucose level. ♣ Increased post prandial plasma glucose. ♣ Increased plasma insulin level and IR. ♣ ß- cell hypertrophy and hyperplasia. ♣ Increased fat metabolism. ♣ Increased ketone production. ♣ Decreased circulating amino acids. ♣ Decreased glucose production in the liver. ♣  renal threshold for glucose  glycosuria.

11.  Pregnancy Pathophysiology:  Insulin resistance occurs because the hormonal changes associated with pregnancy partially block the effects of insulin.  Maternal pancreatic beta cells increase insulin secretion almost three fold to compensate for increased insulin resistance.  If the mother’s pancreas is unable to produce sufficient insulin to overcome insulin resistance, maternal glucose levels increase and GDM occurs.  GDM may disappears after pregnancy because the hormonal changes that caused insulin resistance are no longer present.

12. Diabetes Mellitus And Pregnancy

13.  Diabetes in Pregnancy: Types Gestational Diabetes Mellitus (GDM) ♣ Type A1: abnormal (OGTT) but normal blood glucose levels during fasting and 1-2 hours after meals. ♣ Type A2: abnormal (OGTT) with abnormal glucose levels during fasting and/or after meals. Pregestational Diabetes Mellitus ♣ Type 1: autoimmune process that destroys pancreatic B cells. ♣ Type 2 (“lifestyle diabetes”): acquired insulin resistance related to obesity.

14. CriterionWhite Classification Gestational diabetes, insulin not requiredA1 Gestational diabetes, insulin requiredA2 Onset at age 20 years or older and duration of less than 10 yearsB Onset at age 10-19 years or duration of 10-19 years C Age of onset < 10 years of ageD1D1 Duration >= 20 yearsD2D2 Calcification of vessels of the leg (macrovascular disease), formerly called Class E D3D3 Benign retinopathy (microvascular disease) or Hypertension (not preeclampsia) D4D4 Proliferating retinopathyR NephropathyF Criteria for both classes R and FRF Many pregnancy failuresG Evidence of arteriosclerotic heart diseaseH Renal transplantT  Diabetes in Pregnancy: Classification

15. Pregestational Diabetes: Types 1 and 2

16.  Gestational Diabetes Mellitus: “Any degree of glucose intolerance with onset or first recognition during pregnancy.” ♣ The definition applied whether insulin or only diet modification is used for treatment of GDM. ♣ It does not exclude the possibility that unrecognized glucose intolerance may have antedated or begun concomitantly with the pregnancy.

17. Risk Assessment

18.  Risk factors for developing GDM:  A family history.  Gestation diabetes in a previous pregnancy.  Obesity and BMI > 30 kg/m2  Older maternal age > 30 y.  Previous still birth or spontaneous miscarriage.  A previous delivery of a large baby ( > 9 bounds).  Women of hispanic, or African American.

19.  Low risk for GDM: ♣ Age less than 25 years. ♣ Normal weight before pregnancy (BMI less than 25 kg/m2). ♣ Member of an ethnic group with a low prevalence of GDM ♣ No first degree relative with diabetes mellitus. ♣ No history of abnormal glucose tolerance. ♣ No history of poor obstetric outcome.

20. Screening For GDM

21. Selective Universal Obesity Age  25 years Familial diabetes Poor obstetric outcome Abnormal glucose metabolism based on Clinics in laboratory medicine, 21.1 March 2001, 173-192 Diabetes Care 23.1, ADA clinical practice recommendation 2000 High GDM prevalence ethnic groups Performing GCT in all pregnant women Screening Strategy

22.  Whom to Screen for GDM ? Low Risk Group ♣ No screening required for GDM Intermediate Risk Group ♣ Screen around 24–28 weeks of gestation High Risk Group ♣ As soon as possible after conception ♣ Must - before 24–28 weeks of gestation ♣ Better do a full 3 hr OGTT for GDM ♣ If negative  screening in 2 nd & 3 rd trimester

23. Screening strategies for GDM ☻ The approach One-step approach Two-step approach

24. ☻ One step approach: ♣ Perform a diagnostic oral glucose tolerance test (OGTT) without prior plasma or serum glucose testing. ♣ Cost effective in high risk patients or population.

25. ☻ Two step approach: Initial screening plasma or serum glucose 1h after 50gm oral glucose load. Exceeding the Glucose threshold value or the GCT Diagnostic OGTT

26. ♣ Two step approach  glucose threshold > 140 mg  80% of women with GDM and the yield is further increased to 90% by using a cutoff of > 130 mg/dl. POSITIVE SCREEN DOES NOT ESTABLISH THE DIAGNOSIS OF GESTATIONAL DIABETES!!!

27. 50-g oral glucose challenge The screening test for GDM, may be performed in the fasting or fed state. Sensitivity is improved if the test is performed in the fasting state. A plasma value above 130 - 140 mg/dl one hour after is commonly used as a threshold for performing a 3-hour OGTT. If initial screening is negative, repeat testing is performed at 24 to 28 weeks.

28. Diagnosis Of GDM

29. 3 hour Oral glucose tolerance test Prerequisites: ♣ Normal diet for 3 days before the test. ♣ At least 10 hours fast. ♣ Test is done in the morning at rest. Giving 75 gm (100 gm by other authors) glucose in 250 ml water orally.  2 or more values greater than or equal to the following cutoffs is diagnostic of GDM.  single abnormal value indicates CHO intolerance.

30. ♣ For ADA criteria 2 or more values from either 100 or 75 g OGTT must be met or exceeded to make the diagnosis of GDM ♣ For WHO criteria, one of the 2 values must be met or exceeded to make the diagnosis of GDM OGTTGTT 100grGTT 75gr Criteria ADA Sample Plasma (mg/dl) Plasma (mg/dl) Fasting 95 1 h 180 2 h 155 3 h 140 ---  Diagnostic Criteria for GDM

31. Complications of Diabetes on pregnancy

32.  NEONATAL COMPLICATIONS: Congenital anomalies. Premature delivery. Perinatal asphyxia. Macrosomia and Shoulder Dystocia. Respiratory distress syndrome. Hyperbilirubinemia.

33. Cardiomyopathy. Polycythemia and hyperviscosity syndrome. Metabolic complications. Late effects on the offspring:  Increased risk of IGT.  Future risk of T2DM.  Risk of Obesity.

34. Macrosomic Newborn (4.2kg)

35. Shoulder Dystocia Erb’s palsy

36.  Maternal COMPLICATIONS: ♣ Difficult diabetic control (Ketoacidosis). ♣ Repeated infections during pregnancy and puerperium. ♣ PET and eclampsia: 15-20%. ♣ Operative and difficult deliveries: increased CS rate. ♣ Postpartum hemorrhage. ♣ Increase incidence of diabetic complications: nephropathy, neuropathy and retinopathy.

37. Management

38. Prepregnancy Evaluation Of Diabetic Women Complete history and physical examination. Multidisciplinary team including obstetricians, endocrinologists, dieticians, & midwives  optimize outcome. To achieve normoglycemia as far as possible: ♣ FBS < 95 mg/dL. ♣ 1h PP < 140 mg/dL. ♣ 2h PP < 120 mg/dL.

39.  Monitoring: ♣ SMBG  intermittent office monitoring. ♣ For women treated by insulin  1h post - prandial monitoring is superior to pre-prandial monitoring. ♣ Urine glucose  not useful in GDM. ♣ Urine ketone  be useful in detecting insufficient caloric or carbohydrate intake in women treated with calorie restriction.

40. Target Blood Glucose Values Our blood glucose goals in pregnant diabetic women are: ♣ ACOG: ♥ Fasting glucose concentrations ≤ 95 mg/dL (5.3 mmol/L). ♥ Preprandial glucose concentrations no higher than 100 mg/dL (5.6 mmol/L). ♥ One-hour postprandial glucose concentrations no higher than 140 mg/dL (7.8 mmol/L).

41. ♥ Two-hour postprandial glucose concentrations no higher than 120 mg/dL (6.7 mmol/L). ♥ Mean capillary glucose 100 mg/dL (5.6 mmol/L) and glycosylated A1C ≤ 6 percent (ACOG, 2005). ♣ ADA: ♥ Preprandial glucose concentrations 80 to 110 mg/dL (4.4 to 6.1 mmol/L). ♥ Two-hour postprandial glucose concentrations no higher than 155 mg/dL (8.6 mmol/L) (ADA, 2004).

42. Nutritional counseling ♣ Registered dietitian. ♣ Individualization of medical nutrition therapy (MNT). ♣ Adequate calories and nutrients to meet the needs of pregnancy. ♣ Non caloric sweeteners.

43. Nutritional Recommendations Distribution of total calories is: ♣ 35-45 % carbohydrates. ♣ 20-25 % protein. ♣ 35-40 % fat. Most programs suggest three meals and three snacks, however, in overweight and obese women the snacks are often eliminated.

44. Exercise ! Moderate regular exercise such as: walking, cycling or swimming are excellent forms of exercise for pregnant women. Keeping well-hydrated and well-nourished is essential

45.  Medical Therapy: If normoglycemia cannot be maintained by medical nutritional therapy, then anti- hyperglycemic agents should be initiated. Insulin. Oral anti-hyperglycemic agents.

46.  Insulin:  Insulin therapy is recommended when MNT fails to maintain self monitored glucose at the following level (ACOG&ADA): ♠ FBG < 95 mg/dl or ♠ 1h PPPG < 130-140mg/dl or ♠ 2h PPPG < 120 mg/dl.  Use of insulin preparations of low antigenicity will minimize the transplacental transport of insulin antibodies: human insulin is the least immunogenic of the commercially available preparations.

47. Regular insulin, which is often used in pregnancy for the treatment of diabetes has some drawbacks:  It starts its action from 30 to 60 min after subcutaneous injection and it peaks too late (2-4 h after injection) to be very effective in postprandial control.  In addition, it lasts too long (duration of 6-8 h), with an increased risk of postprandial hypoglycemia.

48.  Insulin molecules clump in hexamers that must be broken up to dimers and monomers before absorption, so delaying their effectiveness. Therefore, in the last few years insulin analogues started to be used to optimize glucose control during pregnancy.

49. The New Insulin Analogues Insulin Lispro Insulin Aspart Insulin Glulisine Insulin Glargine Insulin Detemir Rapidly Acting Long acting

50.  Insulin Lispro: There are various safety issues to consider: Immunogenicity,Teratogenicity, Embryotoxicity, and Retinopathy. The studies reported to date suggest that insulin lispro may be considered a treatment option in patients with GDM.  Insulin Aspart:  Aspart insulin is now approved for use in pregnancy and offers a valuable treatment option.

51.  Insulin Glulisine: At present no reports on glulisine use in pregnancy are available.  Insulin Detemir: At present there are data on the use of detemir in pregnancy with no difference from NPH

52.  Insulin Glargine: At present the use of insulin glargine in pregnancy is approved: ♣ Concerns have been raised about the high affinity of glargine for the IGF-1 receptor and the potential sequelae of macrosomia.

53. Insulin Titration The starting insulin dose can be calculated on the basis of the patient's weight ♣ The average insulin requirement in pregnant women is 0.7 units/kg in the first trimester, often increasing to 0.8 U/kg for weeks 13 to 28, 0.9 U/kg for weeks 29 to 34, and 1.0 U/kg for weeks 35 to term. ♣ In a pregnant diabetic patient the rationale for insulin therapy is based on mimicking the physiology of insulin secretion.

54. ♣ The basal insulin is supplied by the administration of NPH, lente, ultralente insulin at bedtime or both before breakfast and at bedtime. ♣ The meal-related (glucose excursion) insulin includes the use of insulin lispro or aspart before meals (0-15 min) or regular insulin before meals (30-45 min). ♣ This method characterized the intensified therapy (multiple injections daily) versus conventional therapy (one or two injection daily).

55. Oral Anti Diabetic Drugs The use of Acarbose, Thiazolidinediones, Glinides and Glucagon-like peptide 1 agonists is contraindicated during pregnancy

56.  Sulfonylureas are currently the only drugs to be studied in GDM women in randomized controlled trials.  Most data regarding oral antidiabetic drug safety in pregnancy are regarding Glyburide.

57. Metformin Metformin is classified as a category B drug, which implies that there is no evidence of animal or fetal toxicity or teratogenicity. Metformin does not stimulate insulin secretion and does not cause hypoglycemia. The concentration of metformin in breast milk is generally low and mean infant exposure to the drug is clearly below the 10% level. Therefore, use of metformin by breast-feeding mothers is safe.

58. In PCOS, use of Metformin is associated with a tenfold reduction in gestational diabetes (from 31 to 3%) and it is safely associated with spontaneous abortion reduction (from 73 to 10%).

59. Although, most current studies demonstrate that oral hypoglycemic agents, such as Glyburide and Metformin, are safe to use in pregnancy with maternal and perinatal outcomes similar to insulin treatment. But there is a need for a randomized controlled trial with long-term follow up of both mothers and children.

60. Long-term therapeutic considerations ♫At least six weeks after delivery, all women with previous GDM should undergo an oral glucose tolerance test using a two-hour 75 gram oral glucose tolerance test. ♫Reclassification of maternal glycemic status should be performed at least 6 weeks after delivery and according to the guidelines of the “Report of the Expert Comitte on the Diagnosis and Classification of DM”

61. Criteria for the diagnosis of diabetes mellitus NormoglycemiaIFG and IGTDiabetes mellitus FPG <100 mg/dl FPG 100 mg/dl and <126 mg/dl (IFG) FPG > 126 mg/dl 2-h PG <140 mg/dl 2-h PG 140 mg/dl and <200 mg/dl (IGT) 2-h PG > 200 mg/dl —— Symptoms of DM and casual plasma glucose concentration > 200 mg/dl

62. ♣ Women with gestational diabetes rarely require insulin in the postpartum period and approximately 15% of those remain glucose intolerant or demonstrate overt diabetes in the postpartum state. ♣ If glucose level are normal post-partum, reassessment of glycemia should be undertaken at a minimum of 3-years intervals.

63. ♣ Women with IFG or IGT in the postpartum period should be tested for DM annually. These patients should receive intensive MNT and should be placed on an exercise program. ♣ The patients should be educated to seek medical attention if they develops symptoms suggestive of hyperglycemia.

64. Summary

65. Diabetes in pregnancy may be gestational diabetes or pregestational diabetes. pregnancy is diabetogenic as it converts latent to overt diabetes. Adequate blood glucose levels during pregnancy, reduces morbidity of both mother and child Diet represents the mainstay for glycemic control. Insulin aspart and lispro has been approved during pregnancy.

66. Insulin glargine,and detemir do not show any contraindications during pregnancy. Insulin glulisine has no data regarding their use in pregnancy. Glyburide and Metformin, are safe to use in pregnancy with maternal and perinatal outcomes similar to insulin treatment. The routine use of oral antidiabetic drugs during pregnancy is not recommended because of the necessity of randomized clinical trials with long-term follow-up for both mother and child.