INSULIN THERAPY FOR GDM

M.M. Ebrahimi , MD Endocrinology CenterTaleghani Hospital20-7-85

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

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

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

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

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

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

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

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

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

Initial calculation of insulin for 4 injections a day

Fraction of total insulin doseTime NPH regularprebreakfast 5/18 2/9prelunch _ 1/6Predinner _ 1/6HS 1/6 _

12

Eg : 0.7u * 51 kg = 36 u

Fraction of total insulin doseTime NPH regularprebreakfast 5/18=10 2/9=8prelunch _ 1/6=6Predinner _ 1/6=6HS 1/6=6 _

13

INSULIN

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

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

Goals

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

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

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

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

Not recommended use of insulin pumps

insulin pumps are expensive and

Do not clearly provide a benefit in the setting of GDM

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

21

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

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

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

25

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

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

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

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

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

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

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

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

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

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

Glyburide Insulin

Achieved N BG 82% 88%LGA infants 12% 13%Macrosomia 7 4C Section 23 24Hypoglycemia 9 6Preeclampsia 6 6Anomalies 2 2

Oral Hypoglycemic agents

Langer NEJM 2000

37

Glyburide

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

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

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

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)