Is metformin safe for use during pregnancy in women with type 2 diabetes mellitus, polycystic ovary syndrome (PCOS), or gestational diabetes mellitus (GDM)?

Is Metformin Safe During Pregnancy?

Insulin, not metformin, is the first-line and preferred pharmacologic treatment for gestational diabetes mellitus (GDM), type 2 diabetes, and type 1 diabetes in pregnancy. 1, 2

Primary Safety Concerns

Metformin crosses the placenta completely, achieving umbilical cord blood concentrations equal to or higher than maternal levels, which raises significant concerns about long-term offspring safety. 2, 3 While limited published data have not established a clear association between metformin and major birth defects or miscarriage, the available evidence is insufficient to definitively rule out drug-associated risks. 4

Long-Term Offspring Effects

Meta-analyses demonstrate that metformin exposure results in smaller neonates with accelerated postnatal growth, leading to higher BMI, increased weight-to-height ratios, waist circumferences, and borderline increases in fat mass during childhood. 1, 2, 3 These concerning metabolic trends in children exposed to metformin in utero represent the primary reason guidelines recommend against first-line use. 2

When Metformin May Be Considered as Second-Line

Metformin may serve as an alternative only for women who cannot use insulin safely or effectively due to cost barriers, language barriers, comprehension issues, or cultural factors—but only after thorough counseling about known risks and incomplete long-term safety data. 1, 2

Efficacy Limitations

Treatment failure rates with metformin are substantial: 25-28% of women with GDM fail to achieve adequate glycemic control and require supplemental insulin. 1, 2 This high failure rate necessitates close monitoring and readiness to add insulin therapy. 2

Absolute Contraindications in Pregnancy

Metformin must not be used in pregnant women with:

• Hypertension 1, 2, 5
• Preeclampsia 1, 2, 5
• Risk factors for intrauterine growth restriction 1, 2, 3

The rationale is potential for growth restriction or acidosis in the setting of placental insufficiency. 1, 2

Condition-Specific Guidance

Type 2 Diabetes in Pregnancy

Insulin is the preferred agent. 1 One randomized trial found that adding metformin to insulin resulted in less maternal weight gain and fewer cesarean births, but also doubled the rate of small-for-gestational-age neonates. 1 This risk-benefit profile does not support routine metformin use.

Gestational Diabetes Mellitus

Insulin remains the gold standard first-line treatment. 1, 2 While individual randomized trials show metformin can reduce glucose levels, the agents are not recommended as first-line because they cross the placenta and long-term offspring safety data are concerning. 1

Polycystic Ovary Syndrome (PCOS)

For women using metformin for ovulation induction in PCOS, there is no evidence-based need to continue metformin once pregnancy is achieved. 2 Randomized trials comparing metformin with other therapies have not demonstrated benefit in preventing spontaneous abortion or GDM. 2 Metformin should be discontinued at the end of the first trimester if used solely for ovulation induction. 5

Short-Term Maternal and Neonatal Outcomes

Metformin offers some short-term advantages compared to insulin:

• Lower risk of neonatal hypoglycemia 2
• Less maternal weight gain during pregnancy 2
• Lower risk of macrosomia 3
• Greater patient acceptability 2

However, these short-term benefits must be weighed against the concerning long-term metabolic consequences for offspring. 1, 2, 3

Clinical Algorithm for Decision-Making

Step 1: Initiate lifestyle modifications for all women with GDM or type 2 diabetes in pregnancy. 2

Step 2: When pharmacologic therapy is needed, start insulin as first-line treatment. 1, 2

Step 3: Consider metformin as second-line only if:

• Patient cannot use insulin safely or effectively due to specific barriers (cost, language, comprehension, cultural factors) 1, 2
• AND patient does not have hypertension, preeclampsia, or risk for intrauterine growth restriction 1, 2
• AND thorough counseling about risks and incomplete long-term safety data has been provided 2

Step 4: Monitor closely for treatment failure, anticipating that approximately one-quarter to one-third of patients will require insulin supplementation. 2

Critical Pitfalls to Avoid

Do not minimize placental passage: Metformin achieves fetal concentrations equal to or exceeding maternal levels, not partial exposure. 3

Do not ignore long-term follow-up data: While immediate neonatal effects may appear favorable, the long-term metabolic consequences for children are concerning and represent the primary safety issue. 3

Do not continue metformin throughout pregnancy in PCOS patients: If metformin was used solely for ovulation induction, discontinue it once pregnancy is achieved, as preconception benefits do not translate to pregnancy benefits for PCOS patients without diabetes. 5