1. INSULIN THERAPY FOR GDM M.M. Ebrahimi, MD Endocrinology Center Taleghani Hospital 20-7-85

2. 2 INDICATIONS Approximately 15 percent of women with GDM are placed on insulin therapy With diet, 75 - 80 percent of women with GDM will achieve normoglycemia main purpose of drug intervention at these levels is to minimize the incidence of macrosomia

3. 3 INDICATIONS target glucose levels are exceeded despite dietary therapy when FBG is 90 mg/dL or 1h pp BG is 120 mg/dL on two or more occasions within a two-week interval despite dietary therapy

4. 4 INDICATIONS ACOG & ADA recommend: administration of insulin when : FBG > 95 mg/dL (PG >105 ) or 1h pp BG >130 to 140 mg/dL ( PG >155 ) or 2h-pp BG > 120 mg/dL ( PG > 130 )

5. 5 Dose of insulin Varies in different populations but the majority of studies have reported a total insulin dose ranging from 50 to 90 units to achieve glucose control

6. 6 Calculation of dose If insulin is required because the FBS is high, an intermediate-acting insulin, such as NPH insulin, is given qhs initial dose : 0.2 U/kg Eg : 0.2u * 70kg = 14 u

7. 7 Calculation of dose If postprandial BS are high :regular insulin or insulin lispro before meals 1.5 U per 10 gr CHO in the breakfast meal 1 U per 10 gr CHO in the lunch and dinner meals

8. 8 Calculation of dose If both preprandial and postprandial blood glucose are high four injection per day regimen 0.7 U/kg up to week 18 0.8 U/kg for weeks 18 to 26 0.9 U/kg for weeks 26 to 36 1.0 U/kg for weeks 36 to term

9. 9 Calculation of dose In a morbidly obese woman, the initial doses of insulin may need to be increased to 1.5 to 2.0 units/kg to overcome the combined insulin resistance of pregnancy and obesity

10. 10 INSULIN insulin is divided : 45% as NPH insulin (30% before breakfast and 15% hs) 55% as preprandial regular insulin (22% before breakfast, 16.5% before lunch, and 16.5% before dinner)

11. 11 Initial calculation of insulin for 4 injections a day Fraction of total insulin dose Time NPH regular prebreakfast 5/18 2/9 prelunch _ 1/6 Predinner _ 1/6 HS 1/6 _

12. 12 Eg : 0.7u * 51 kg = 36 u Fraction of total insulin dose Time NPH regular prebreakfast 5/18=10 2/9=8 prelunch _ 1/6=6 Predinner _ 1/6=6 HS 1/6=6 _

13. 13 INSULIN A four-times daily regimen improved glycemic control and perinatal outcome compared to a twice-daily regimen

14. 14 Titration of insulin dose Based upon frequent SMBG 4 or more glucose measurements each day are needed to optimize therapy and ensure a smooth increase of insulin as insulin requirements increase with pregnancy progression. Twin gestations have an approximate doubling of the insulin requirement throughout pregnancy

15. 15 Goals FBS / PM BG : 60 – 90 mg/dl 1hr pp : < 120 mg/dl 3AM : 60 – 100 mg/dl

16. 16 Acute hypoglycemia Acute hypoglycemia remote from meal or snack time treated by 10 to 20 g of carbohydrate immediately also use a correction factor of one unit of rapid-acting insulin lowers blood glucose by 25 mg/dL

17. 17 Acute hypoglycemia For glucose <50 mg/dL, subtract two units of regular insulin from the dose of insulin given before the meal for glucose 50 to 75 mg/dL, we subtract one unit from the dose of insulin given before the meal

18. 18 Titration of insulin dose for glucose 75 to 100 mg/dL do not change insulin dose for glucose 100 to 125 mg/dL add one unit regular insulin to the dose of insulin given before the meal for glucose 100 to 150 mg/dL, add two units regular insulin to the dose of insulin given before the meal

19. 19 Not recommended use of insulin pumps insulin pumps are expensive and Do not clearly provide a benefit in the setting of GDM

20. 20 Type of insulin The three rapid acting insulin analogs (lispro, aspart, glulisine) are comparable in immunogenicity to human Regular insulin, but only lispro and aspart have been investigated in pregnancy and shown to have acceptable safety profiles, minimal transfer across the placenta, and no evidence of teratogenesis

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22. 22 Type of insulin lispro and aspart insulin analogs both improve postprandial excursions compared to human Regular insulin and are associated with lower risk of delayed postprandial hypoglycemia

23. 23 Type of insulin Long-acting insulin analogs (insulin glargine, insulin detemir) have not been studied extensively in pregnancy use human NPH insulin as part of a multiple injection regimen in pregnant women Lente insulins are not recommended due to variability of effect

24. 24 INTRAPARTUM MANAGEMENT Spontaneous labor Insulin is required during the latent phase of labor SQ or IV insulin infusion with a goal : blood glucose 70 - 90 mg/dL One method :1-3 U/h N/S may be sufficient to maintain euglycemia when labor is anticipated

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26. 26 Spontaneous labor active labor : insulin resistance rapidly decreases and insulin requirements fall rapidly Thus, continuing insulin therapy is likely to lead to hypoglycemia To prevent this, glucose should be infused at a rate of 2.55 mg/kg per min Capillary blood glucose : q1h glucose infusion should be doubled for the next hour if the blood glucose value is < 60 mg/dL

27. 27 Spontaneous labor BG 120 mg/dL or greater require the administration of rapid-acting insulin analogues SQ or regular insulin intravenously until the blood glucose value falls to 70 to 90 mg/dL At this time, the insulin dose is titrated to maintain normoglycemia while glucose is infused at a rate of 2.55 mg/kg per min Bolus doses of glucose should not be given because they can raise maternal blood glucose concentrations and increase the risk of neonatal hypoglycemia, fetal hypoxia, and fetal or neonatal acidosis

28. 28 Cesarean delivery bedtime NPH insulin dose may be given on the morning of surgery and q8h thereafter if surgery is delayed D10W if PG < 60 mg / dl

29. 29 Induction If induction procedure is judged likely to be lengthy, 25 – 30 % of morning insulin as NPH may be administered especially if the mother will be allowed meals during early labor If BG >110 mg / dl :use insulin drip

30. 30 postpartum BG should be measured on the day after delivery to ensure that the mother no longer has hyperglycemia, using criteria established for nonpregnant individuals

31. 31 POSTPARTUM MANAGEMENT Insulin requirements drop sharply after delivery since expulsion of the fetoplacental unit leads to cessation of production of placental growth hormone and placental lactogen, which have short half-lives

32. 32 Oral anti-hyperglycemic agents The ADA and ACOG do not approve the use of oral anti-hyperglycemic agents during pregnancy Not been approved by the Unites States FDA

33. 33 Tolbutamide and chlorpropamide No tolbutamide or chlorpropamide (older sulfonylureas) as therapy of GDM because these drugs cross the placenta and can cause fetal hyperinsulinemia, which can lead to macrosomia and prolonged neonatal hypoglycemia

34. 34 Glyburide In contrast to older sulfonylureas, transplacental passage of glyburide appears to be minimal and is not associated with an excess of neonatal hypoglycemia. Several reports have suggested that glyburide is a safe and effective treatment of GDM, and its use is becoming more prevalent The fifth International Workshop cautioned its use until there is more research

35. 35 Glyburide The only large, randomized study of glyburide therapy in pregnancy included 404 women with mild GDM who were randomly assigned to receive glyburide or insulin The mean blood glucose concentration during treatment was 105 mg/dL in both groups, and there were no differences in the frequency of macrosomia, neonatal hypoglycemia, and other neonatal morbidity or cord serum insulin concentrations

36. 36 Glyburide Insulin Achieved N BG82%88% LGA infants12%13% Macrosomia74 C Section2324 Hypoglycemia96 Preeclampsia66 Anomalies 22 Oral Hypoglycemic agents Langer NEJM 2000

37. 37 Glyburide Glyburide is not recommended as Rx of women with GDM until its safety and efficacy have been more firmly established

38. 38 Metformin no randomized trials evaluating the use of metformin in women with GDM Several observational series have reported generally good outcomes with use of metformin in pregestational diabetics Currently, there is a large trial in Australia that will be completed in 2007 Until then, metformin should not be used

39. 39 Acarbose an alpha glucosidase inhibitor, is poorly absorbed from the gastrointestinal tract. studies have suggested efficacy in reducing postprandial glucose excursions in GDM, but with the expected frequency of abdominal cramping Since a small proportion of this drug may be absorbed systemically, further study should evaluate potential transplacental passage

40. 40 Thiazolidinediones, glinides, and GLP-1 Use of thiazolidinediones, glinides, and GLP-1 during pregnancy is considered experimental There are no controlled data available in pregnancy One study reported that rosiglitazone crossed the human placenta at 10 to 12 weeks gestation, fetal tissue levels were about half of maternal serum levels Ex vivo human placental perfusion studies of GLP-1 agonists detected minimal levels on the fetal side (fetal:maternal ratio 0.017)