What is the role of metformin (biguanide) in managing gestational diabetes mellitus (GDM)?

Metformin in Gestational Diabetes Mellitus

Primary Recommendation

Insulin remains the first-line pharmacologic agent for gestational diabetes mellitus (GDM) in the United States, with metformin reserved only as a second-line alternative when insulin cannot be used safely or effectively due to cost, language barriers, comprehension issues, or cultural influences. 1, 2

Treatment Algorithm

Step 1: Initial Management

• Begin with lifestyle modification including medical nutrition therapy (minimum 175g carbohydrate daily) and physical activity (20-50 minutes/day, 2-7 days/week of moderate intensity exercise) 1, 2
• 70-85% of women with GDM achieve glycemic control with lifestyle modification alone 1, 2

Step 2: When Pharmacologic Therapy is Needed

• Insulin is the preferred first-line agent because it does not cross the placenta and has the most robust long-term safety data 1, 2
• Start with basal insulin or multiple daily injections as needed 1

Step 3: When to Consider Metformin

Metformin may be considered only when:

• Patient cannot afford insulin 1, 2
• Language barriers prevent safe insulin administration 1, 2
• Comprehension or cultural factors make insulin use unsafe 1, 2

However, metformin is absolutely contraindicated in women with:

• Hypertension or preeclampsia 1
• Risk for intrauterine growth restriction 1
• Placental insufficiency concerns 1

Critical Safety Concerns with Metformin

Placental Transfer and Offspring Metabolic Effects

• Metformin readily crosses the placenta, with umbilical cord blood levels equal to or higher than maternal levels 1, 2
• The MiG TOFU study (9-year follow-up) demonstrated that children exposed to metformin in utero had significantly higher BMI, increased waist-to-height ratios, and greater waist circumferences compared to insulin-exposed children 1
• Multiple studies of 4-10 year old offspring show higher BMI, increased obesity rates, higher weight-to-height ratios, and borderline increased fat mass 1, 2
• A recent meta-analysis concluded that metformin exposure resulted in smaller neonates with acceleration of postnatal growth resulting in higher BMI in childhood 1

Efficacy Limitations

• Metformin fails to provide adequate glycemic control in 25-28% of women with GDM, requiring supplemental insulin 1
• Women with fasting glucose >4.8 mmol/L (86 mg/dL) at OGTT have 69% sensitivity for metformin failure 3
• Higher fasting glucose levels at diagnosis, higher HbA1c at OGTT, and earlier gestational age at medication initiation predict metformin failure 3

Short-Term Maternal and Neonatal Outcomes

Potential Benefits

• Lower risk of neonatal hypoglycemia compared to insulin 1
• Less maternal weight gain during pregnancy 1, 4
• Lower incidence of pregnancy-induced hypertension 4

Comparable Outcomes

• Similar glycemic control to insulin in women who respond to metformin 5, 6, 4
• Similar cesarean section rates 7, 5, 6
• Similar rates of large for gestational age infants 7

Potential Risks

• Increased incidence of preterm birth (OR 1.74,95% CI 1.13-2.68) 4
• Lower average gestational age at delivery 4

Special Population: PCOS Patients

For women with polycystic ovary syndrome taking metformin for ovulation induction, metformin should be discontinued once pregnancy is confirmed 2

• Randomized trials show no benefit in preventing spontaneous abortion or GDM when continued beyond conception 1, 2
• There is no evidence-based need to continue metformin after the first trimester in PCOS patients 1

Common Pitfalls to Avoid

• Do not use metformin as first-line therapy simply because it is oral and more convenient - the long-term offspring metabolic effects are concerning and still being studied 1, 2
• Do not use metformin in women with hypertension, preeclampsia, or risk factors for intrauterine growth restriction due to potential for growth restriction or acidosis with placental insufficiency 1
• Do not assume metformin will work for all patients - have a low threshold to add or switch to insulin, especially in women with fasting glucose >4.8 mmol/L at diagnosis 3
• Always counsel patients about the lack of long-term safety data and the concerning metabolic effects seen in offspring before choosing metformin over insulin 1, 2

Informed Decision-Making

When metformin must be used due to practical barriers to insulin use, patients must be informed about:

• The known risks of placental transfer 1, 2
• The concerning long-term metabolic effects in offspring 1, 2
• The 25-28% failure rate requiring insulin supplementation 1
• The need for more long-term safety data 1