PDA ECHO: INSULIN THERAPY IN PREGNANT WOMEN

Cynthia Halili-Manabat, M.D., PhD

Internal MedicineOctober 2010

abstract

• goal in pregnancy complicated by diabetes is to maintain maternal glucose levels as near normal as possible throughout the pregnancy because near normal glycemia has been shown to decrease the prevalence of neonatal hypoglycaemia, macrosomia, intra-uterine death and caesarean delivery

• steps to achieve normal glucose during pregnancy include medical nutrition therapy and the additional of insulin, if goals are not met

abstract

• only human NPH insulin, regular human insulin and the rapid acting insulin analogs, lispro and aspart, are approved for use during pregnancy

• Lispro or Aspart is preferable to regular human insulin

• fifty percent of the insulin is given as a basal dose using NPH insulin and the other 50% as boluses before meals with lispro or aspart.

abstract

• the total daily insulin dose may be computed based on the current weight of the patient and stage of pregnancy as follows: – prepregnancy, 0.6 U/kg/d– first trimester (wk 1-12), 0.7 U/kg/d– second trimester (wk 13-28), 0.8 U/kg/d– third trimester (wk 29-34), 0.9 U/kg/d– term (wk 35-39), 1.0 U/kg/d

• these doses are only starting doses and need to be adjusted based on results of home glucose monitoring

Fetal Hyperinsulinemia

• LGA or macrosomia are associated with birth trauma (shoulder dystocia)– 0.6-1.4% in fetuses weighing 2500-4000g– 5-9% in fetuses weighing >4000g

• Associated with neonatal hypoglycemia after infant is delivered and no longer exposed to maternal hyperglycemia

Management of Hyperglycemia in Pregnancy

• CGMS– mean fasting glucose 75mg/dL– peak post-prandial glucose 110mg/dL

• Medical Nutrition Therapy– Weight control– Carbohydrate restriction

• Frequent self-monitoring of blood glucose• Insulin

When to Start Insulin

• When MNT fails• Glycemic goals:– Premeals 60-90mg/dL– 1-hour postprandial <140mg/dL– 2-hour postprandial <120-130mg/dL

Insulin and Insulin AnalogsInsulin Onset of action

(minutes)Time to peak concentration(minutes)

Maximum duration of action (hours)

Regular insulin 30-60 90-120 5-12

Insulin lispro(Humalog)

10-15 30-60 3-4

Insulin aspart 10-15 40-50 3-5

Insulin glulisine 10-15 55 3-5

NPH insulin 60-120 240-480 10-20

Insulin glargine 60-120 None 24

Insulin detemir 60-120 None 20

Problem with Regular Insulin

• Slow onset of activity– Inconvenient for patient (administered 30-

60minutes prior to meal)• Long duration of activity– Potential for late postprandial (4-6hours)

hypoglycemia– Lasts up to 12hours

Insulin Lispro in Pregnancy

• More efficacious than human regular insulin to normalize blood glucose levels in gestational and pre-gestational diabetic women

• Rapidly lowered postprandial glucose levels, thereby decreasing A1c levels, with fewer hypoglycemic episodes, and without increasing anti-insulin antibody levels

• Similar neonatal outcomes versus regular insulin• Improved patient satisfaction• Especially helpful in women with hyperemesis or

gastroparesis because they can be dosed after meals

Insulin Aspart in Pregnancy

• The overall safety and effectiveness of insulin aspart is comparable to regular human insulin in pregnant women with GDM/pregestational DM.

• Insulin aspart was more effective than regular insulin in providing postprandial glycemic control.

• Patients showed greater treatment satisfaction with Aspart.

Insulin Glulisine in Pregnancy

• There is inadequate data on glulisine use in pregnancy.

Insulin Glargine in Pregnancy

• Glycemic control, birthweight, and prevalence of macrosomia and neonatal morbidity were similar to human insulin

• Rate of congenital malformations comparable to NPH insulin

• Glargine is not approved for use in pregnancy

NN304-1687: Insulin Detemir in Pregnancy Study

• Randomised, parallel-group, open-labelled, multinational trial comparing the efficacy and safety of insulin detemir versus NPH insulin, used in combination with aspart as bolus insulin, in the treatment of pregnant women with type 1 diabetes

• Expected number of 240 completed pregnancies with 120 subjects in each arm

• To be completed 2010

How to Give Insulin

• 50% of total daily insulin as basal insulin using NPH, 50% as boluses before meals with rapid analog

• Predicted total daily insulin requirement– Prepregnancy 0.6u/kg/d– First trimester 0.7u/kg/d– Second trimester 0.8u/kg/d– Third trimester 0.9u/kg/d– Term (wk 35-39) 1.0u/kg/d

• Rapidly adjust dose based on SMBG

How to Give Insulin

• NPH: 1/6 of total daily insulin dose administered every 8hours

• Lispro or Aspart: 1/6 of total daily insulin dose given before meals

• Monitor BGs before and 1hour after meals• Goals:– 65-90 mg/dL before meals– <120 mg/dL after meals

Continuous Subcutaneous Insulin Infusion Pump

• CSII versus MDI in pregnancy• RCTs show equivalent glycemic control and

maternal and perinatal outcomes• CSII- multiple adjustable basal rates can be

especially useful for patients with daytime or nocturnal hypoglycemia or a prominent dawn phenomenon

• Disadvantages of CSII: cost, potential for marked hyperglycemia and risk of DKA as a consequence of insulin delivery failure

Glycemic Control and Insulin Treatment during Delivery

• Goal: maintain normoglycemia in order to prevent neonatal hypoglycemia

• Target CGBs 80-110 mg/dL during labor• CBG every hour during labor, or every 2-4

hours if stable• CBG >100mg/dL: NS or LR at 100cc/hr• CBG <100mg/dL: supplemental 5% dextrose

infusion at 100cc/hr

Glycemic Control and Insulin Treatment during Delivery

• CBG >120mg/dL: 2-4 units regular insulin IV every hour that CBG >120mg/dL (or RI incorporated into IV)

• After expulsion of placenta, requirement of insulin will fall precipitously

• Postpartum requirements drop to 1/3 to ½ of their previous insulin dosages; no insulin in first 24-48hours

Postpartum

• During lactation: postprandial glucose goals <150mg/dL to minimize high glucose levels in breast milk– Stimulate hyperinsulinemia and accelerate hunger in the

infant– Contribute to excessive weight gain, obesity, and

metabolic syndrome later in life• Human insulin and insulin analogs appear in

breastmilk directly proportional to serum levels in maternal blood, but they are not absorbed in the gut

Summary

• Rapid achievement of normoglycemia with limited weight gain is critical to optimize maternal and fetal outcomes in all women with diabetes during pregnancy.

• Lispro and Aspart have been tested and found to be safe and effective during pregnancy. Their use over regular insulin has been shown to result in improved glycemic control, fewer hypoglycemic episodes, and improved patient satisfaction.

• 2 to 3 doses of NPH insulin may be used to provide basal insulin needs. Neither glargine nor detemir is approved for use in pregnancy.

Thank You!