What is the recommended insulin therapy during pregnancy for women with gestational diabetes or pre-existing diabetes?

Insulin Therapy During Pregnancy

Insulin is the first-line and preferred pharmacologic agent for managing both gestational diabetes mellitus (GDM) and pre-existing diabetes (type 1 and type 2) during pregnancy when lifestyle modifications fail to achieve glycemic targets. 1

Glycemic Targets

Pregnant women with diabetes should aim for the following blood glucose goals:

• Fasting glucose: <95 mg/dL (5.3 mmol/L) 1
• 1-hour postprandial: <140 mg/dL (7.8 mmol/L) 1
• 2-hour postprandial: <120 mg/dL (6.7 mmol/L) 1
• A1C target: <6% if achievable without significant hypoglycemia 1, 2

For women with pre-existing type 1 or type 2 diabetes, more stringent targets include premeal glucose of 60-99 mg/dL and peak postprandial glucose of 100-129 mg/dL. 1

When to Initiate Insulin

For Gestational Diabetes Mellitus

• First-line treatment consists of medical nutrition therapy and physical activity for at least 30 minutes daily. 1
• Insulin should be initiated when lifestyle modifications fail to maintain glycemic targets or when signs of excessive fetal growth appear. 1
• Approximately 15-30% of women with GDM will require insulin therapy beyond lifestyle interventions. 1

For Pre-existing Diabetes

• Insulin is mandatory for all women with type 1 diabetes throughout pregnancy. 1, 2
• Insulin is the preferred agent for type 2 diabetes in pregnancy, though some women may have been using it prior to conception. 1

Insulin Regimens and Delivery Methods

Both multiple daily injections (MDI) and continuous subcutaneous insulin infusion (insulin pump) are acceptable delivery strategies, with neither demonstrating superiority over the other. 1, 2

Multiple Daily Injections

• Typically consists of 3-4 injections per day combining basal and prandial insulin. 1
• Requires matching prandial insulin doses to carbohydrate intake, premeal blood glucose, and anticipated activity. 1, 2

Insulin Pump Therapy

• Provides continuous basal insulin with bolus doses for meals. 1
• Sensor-augmented pumps with predictive low-glucose suspend technology may reduce hypoglycemia risk. 1

Insulin Types and Safety in Pregnancy

FDA-Approved Insulin Analogs

Insulin lispro, insulin aspart, and insulin detemir are approved for use in pregnancy and have been studied in randomized controlled trials. 1, 3, 4, 5

• Insulin detemir (long-acting): Does not cross the placenta in measurable amounts and showed no adverse maternal or fetal outcomes in a randomized trial of 310 pregnant women with type 1 diabetes. 3
• Insulin lispro (rapid-acting): Published studies show no association with major birth defects, miscarriage, or adverse maternal/fetal outcomes. 4, 5
• Insulin aspart (rapid-acting): Considered safe and effective for improving postprandial glucose control in pregnancy. 5, 6

Other Insulin Preparations

• Insulin glargine: Not FDA-approved for pregnancy, but existing studies show no contraindications. 5
• Human insulin (NPH and regular): Remain acceptable alternatives, though analogs may provide more physiologic coverage with less hypoglycemia risk. 1, 5

Insulin Dosing and Titration

Physiologic Changes Requiring Adjustment

Insulin requirements change dramatically throughout pregnancy due to hormonal influences on insulin sensitivity. 2, 7

• First trimester: Enhanced insulin sensitivity; increased hypoglycemia risk. 1, 2
• Second trimester: Progressive insulin resistance begins; requirements start increasing. 2, 7
• Third trimester: Insulin requirements approximately double from baseline due to placental hormones. 2, 7
• After delivery: Insulin needs drop precipitously with placental delivery, requiring immediate dose reduction to prevent hypoglycemia. 1, 2

Titration Strategy

• Frequent adjustments are necessary, typically every 2-3 weeks as pregnancy progresses. 2, 7
• Daily blood glucose monitoring (6-7 times per day) is essential for appropriate insulin titration. 1, 2
• Insulin doses should be adjusted based on blood glucose patterns, carbohydrate intake, physical activity, and gestational age. 2, 8
• A correlation exists between insulin requirements at 24 and 32 weeks (r=0.58) and between 32 and 39 weeks (r=0.99), allowing some predictability. 7

Oral Agents: Why Insulin is Preferred

Metformin

Metformin is NOT recommended as first-line therapy for GDM because it crosses the placenta and long-term offspring safety data raise concerns. 1

• Metformin crosses the placenta, with umbilical cord levels equal to or higher than maternal levels. 1
• Follow-up studies of offspring exposed to metformin show increased BMI, waist circumference, and obesity at ages 4-10 years. 1
• Metformin failed to provide adequate glycemic control in 25-28% of women with GDM. 1
• When added to insulin for type 2 diabetes, metformin doubled the rate of small-for-gestational-age neonates despite reducing macrosomia. 1

Glyburide

Glyburide is NOT recommended as first-line therapy due to increased neonatal complications and failure rates. 1

• Glyburide crosses the placenta (umbilical cord levels 50-70% of maternal levels). 1
• Associated with higher rates of neonatal hypoglycemia and macrosomia compared to insulin. 1
• Failed to achieve adequate glycemic control in 23% of women with GDM. 1
• A large trial found glyburide was not noninferior to insulin for composite neonatal outcomes. 1

Monitoring and Safety Considerations

Hypoglycemia Management

• Education on hypoglycemia prevention, recognition, and treatment is critical for pregnant women and family members before, during, and after pregnancy. 1, 2
• Pregnant women with type 1 diabetes have altered counter-regulatory responses that may decrease hypoglycemia awareness. 1
• Continuous glucose monitoring can improve glycemic control and reduce hypoglycemia risk. 2

Team-Based Care

Referral to a specialized center with multidisciplinary team care is strongly recommended when available, including maternal-fetal medicine specialists, endocrinologists experienced in pregnancy diabetes management, registered dietitians, diabetes educators, and social workers. 1, 2

Additional Pregnancy Management

Aspirin Prophylaxis

Low-dose aspirin 100-150 mg daily should be initiated at 12-16 weeks gestation to reduce preeclampsia risk in women with pre-existing diabetes. 1, 2

• Doses <100 mg are ineffective; doses ≥100 mg are required for preeclampsia prevention. 1
• In the U.S., 81-mg tablets are available, so 162 mg daily (two tablets) may be used. 1

Medications to Avoid

ACE inhibitors, angiotensin receptor blockers, and statins must be discontinued at conception and avoided in sexually active women of childbearing age not using reliable contraception. 1