Is metformin (biguanide oral hypoglycemic) safe to use during pregnancy?

Metformin in Pregnancy

Insulin is the preferred first-line agent for treating diabetes in pregnancy, not metformin, though metformin may be considered as a second-line alternative in specific circumstances when insulin cannot be safely or effectively used. 1

Primary Recommendation

• Insulin remains the gold standard and recommended first-line pharmacologic treatment for both gestational diabetes mellitus (GDM) and type 2 diabetes in pregnancy. 1
• Metformin and glyburide are explicitly not recommended as first-line agents because they cross the placenta and long-term offspring safety data raises significant concerns. 1

When Metformin May Be Considered

Metformin can serve as a second-line alternative only in the following specific situations:

• Women who cannot use insulin safely or effectively due to cost barriers, language barriers, comprehension issues, or cultural factors. 1
• These patients must receive thorough counseling about known risks and the lack of complete long-term offspring safety data. 1
• Critical contraindication: Do not use metformin in pregnant women with hypertension, preeclampsia, or those at risk for intrauterine growth restriction due to potential for growth restriction or acidosis in the setting of placental insufficiency. 1

Efficacy Limitations

• Treatment failure rates are substantial: 25-28% of women with GDM fail to achieve adequate glycemic control with metformin monotherapy and require supplemental insulin. 1
• Be prepared to add insulin in approximately one-quarter to one-third of cases when metformin is initiated. 1

Placental Transfer and Offspring Concerns

The most significant concern with metformin use in pregnancy relates to long-term offspring outcomes:

• Metformin readily crosses the placenta, resulting in umbilical cord blood levels equal to or higher than maternal levels. 1, 2
• The MiG TOFU study demonstrated that 9-year-old children exposed to metformin in utero (Auckland cohort) were heavier with higher waist-to-height ratios and waist circumferences compared to insulin-exposed children. 1
• Follow-up studies at 4-10 years showed offspring exposed to metformin had higher BMI, weight-to-height ratios, waist circumferences, and borderline increased fat mass. 1
• Meta-analyses demonstrate metformin exposure results in smaller neonates with acceleration of postnatal growth leading to higher BMI in childhood. 1
• One positive finding: the MiTy Kids trial showed no differences in anthropometrics at 24 months, though longer follow-up is needed. 1

Short-Term Maternal and Neonatal Outcomes

Metformin does offer some short-term advantages compared to insulin:

• Lower risk of neonatal hypoglycemia compared to insulin. 1
• Less maternal weight gain during pregnancy. 1
• Possible reduction in macrosomia (large-for-gestational-age infants). 1
• However, there is concern for increased small-for-gestational-age (SGA) neonates, particularly in women with type 2 diabetes, hypertension, or renal disease. 1, 3

FDA Labeling Perspective

• 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. 2
• Published studies have not reported a clear association with metformin and major birth defects or miscarriage risk, but methodological limitations (small sample sizes, inconsistent comparator groups) prevent definitive conclusions. 2
• The FDA notes that poorly controlled diabetes in pregnancy carries significant risks including diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, stillbirth, and major birth defects. 2

Special Consideration: PCOS and Preconception Use

• For women with PCOS using metformin for ovulation induction, there is no evidence-based need to continue metformin once pregnancy is achieved. 1, 4
• Randomized trials comparing metformin with other therapies for ovulation induction have not demonstrated benefit in preventing spontaneous abortion or GDM. 1, 4
• Discuss discontinuing metformin once pregnancy is confirmed unless there are specific indications such as type 2 diabetes. 4

Clinical Algorithm for Decision-Making

Step 1: Initiate lifestyle modifications (medical nutrition therapy and physical activity) for all women with GDM. 1

Step 2: If pharmacologic therapy is needed, insulin is the first choice. 1

Step 3: Consider metformin only if:

• The patient cannot safely or effectively use insulin due to cost, barriers, or cultural factors, AND 1
• The patient has no contraindications (hypertension, preeclampsia, risk of intrauterine growth restriction), AND 1
• The patient receives comprehensive counseling about placental transfer and long-term offspring concerns. 1

Step 4: Monitor closely and be prepared to add insulin in 25-28% of cases. 1

Common Pitfalls to Avoid

• Do not assume metformin is equivalent to insulin for first-line therapy—it is not recommended as such by current guidelines. 1
• Do not use metformin in women with hypertension, preeclampsia, or suspected placental insufficiency. 1
• Do not continue metformin in women with PCOS once pregnancy is confirmed without specific diabetes indications. 1, 4
• Do not assume metformin monotherapy will be sufficient—anticipate treatment failure in approximately one-quarter of patients. 1
• Do not ignore the long-term offspring data showing concerning trends in childhood BMI and metabolic parameters. 1

Emerging Evidence

Recent research suggests metformin continuation in women with type 2 diabetes already on metformin plus insulin before pregnancy may not increase composite neonatal adverse outcomes, though SGA risk remains a concern. 3 However, this does not change the primary recommendation that insulin remains first-line for initiating therapy in pregnancy. 1