Is metformin (biguanide oral hypoglycemic agent) safe during pregnancy?

Is Metformin Safe in Pregnancy?

Metformin is not recommended as first-line therapy during pregnancy; insulin is the preferred agent for both gestational diabetes and type 2 diabetes in pregnancy due to concerns about placental transfer and long-term offspring metabolic effects. 1, 2, 3

Primary Treatment Recommendation

• Insulin should be the first-line pharmacologic treatment for gestational diabetes mellitus (GDM) and type 2 diabetes in pregnancy when lifestyle modifications fail to achieve glycemic control 1, 2, 3

• Metformin and glyburide are explicitly not recommended as first-line agents because they cross the placenta, raising significant concerns about long-term offspring safety 2, 3

When Metformin May Be Considered as Second-Line

Metformin can be used as an alternative only in specific circumstances:

• Cost barriers, language barriers, comprehension issues, or cultural factors that prevent safe or effective insulin use 2, 3

• Women must receive thorough counseling about known risks and the lack of complete long-term offspring safety data before initiating metformin 2, 3

Critical Safety Concerns: Placental Transfer

• Metformin readily crosses the placenta, resulting in umbilical cord blood levels equal to or higher than maternal levels 1, 2, 3

• This placental transfer distinguishes metformin from insulin, which does not cross the placenta 1

Long-Term Offspring Metabolic Effects (Most Important Safety Concern)

The most concerning evidence relates to childhood metabolic outcomes:

• At 9 years of age, children exposed to metformin in utero were heavier with higher waist-to-height ratios and waist circumferences compared to insulin-exposed children in the MiG TOFU study 1, 2

• At 4-10 years of age, offspring exposed to metformin for PCOS treatment had higher BMI, weight-to-height ratios, waist circumferences, and borderline increased fat mass 1, 2

• Meta-analyses demonstrate that metformin exposure results in smaller neonates with acceleration of postnatal growth, leading to higher BMI in childhood 1, 2, 3

Short-Term Maternal and Neonatal Outcomes (More Favorable)

While long-term offspring data raise concerns, short-term outcomes show some advantages:

• Lower risk of neonatal hypoglycemia compared to insulin 1, 3

• Less maternal weight gain during pregnancy 1, 3

• No clear association with major birth defects or miscarriage in published studies, though the FDA label notes that data are insufficient to definitively establish absence of risk 4

Treatment Failure Rates (Practical Limitation)

• 25-46% of women with GDM fail to achieve adequate glycemic control with metformin monotherapy and require supplemental insulin 2, 3

• This high failure rate necessitates close monitoring and readiness to add insulin 2, 3

Absolute Contraindications

Do not use metformin in pregnancy when:

• Hypertension or preeclampsia is present due to risks of growth restriction or acidosis in the setting of placental insufficiency 2, 3

• Intrauterine growth restriction is suspected or present 2, 3

Special Population: PCOS

• For women with PCOS using metformin for ovulation induction, there is no evidence-based need to continue metformin once pregnancy is achieved unless there are specific indications like type 2 diabetes 2, 5, 3

• Randomized trials show no benefit in preventing spontaneous abortion or GDM when metformin is continued in PCOS pregnancies 2, 5

Clinical Decision Algorithm

1. First-line approach: Lifestyle modifications for all women with GDM 1, 2, 3

2. If pharmacologic therapy needed: Insulin is the recommended first choice 1, 2, 3

3. Consider metformin only if: Patient cannot safely or effectively use insulin AND has no contraindications (hypertension, preeclampsia, growth restriction) AND receives comprehensive counseling about placental transfer and long-term offspring concerns 2, 3

4. Monitor closely: Be prepared to add insulin in 25-46% of cases 2, 3

Critical Pitfalls to Avoid

• Do not continue metformin in PCOS patients once pregnancy is confirmed unless there are specific indications like type 2 diabetes 2, 5

• Do not use metformin for GDM prevention in high-risk women with obesity or PCOS, as it does not reduce GDM risk 2

• Do not assume metformin monotherapy will be sufficient - anticipate need for insulin supplementation in approximately one-quarter to one-half of patients 2, 3

• Do not use when placental insufficiency is suspected due to risks of growth restriction and acidosis 2, 3

FDA Pregnancy Classification

The FDA label states that limited data with metformin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage, and notes that metformin crosses the placenta with partial placental barrier 4