Is metformin (biguanide oral hypoglycemic agent) safe to use during pregnancy in a woman with a history of diabetes or Polycystic Ovary Syndrome (PCOS)?

Is Metformin Safe in Pregnancy?

Metformin is not recommended as first-line therapy during pregnancy, and insulin should be used instead for both gestational diabetes and type 2 diabetes, due to concerns about placental transfer and potential long-term metabolic effects on offspring. 1, 2

Primary Treatment Recommendation

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

When Metformin May Be Considered as Second-Line

Metformin may be used as an alternative only in specific circumstances after thorough counseling about risks: 1, 2

• Women who cannot use insulin safely or effectively due to:
  • Cost barriers
  • Language barriers
  • Comprehension issues
  • Cultural factors

Critical contraindications where metformin must NOT be used: 1, 2

• Hypertension during pregnancy
• Preeclampsia
• Risk factors for intrauterine growth restriction
• Suspected placental insufficiency (due to potential for growth restriction or acidosis)

Efficacy Limitations

• Treatment failure occurs in 25-28% of women with GDM on metformin monotherapy, requiring supplemental insulin. 1, 2
• Close monitoring is essential to identify the approximately one-quarter to one-third of patients who will need insulin added to their regimen. 2

Placental Transfer and Offspring Safety Concerns

Metformin readily crosses the placenta, resulting in umbilical cord blood levels equal to or higher than maternal levels. 1, 2, 3, 4

Long-term offspring metabolic effects (major concern):

• At 9 years of age, children exposed to metformin for GDM treatment were heavier with higher waist-to-height ratios and waist circumferences compared to insulin-exposed children (Auckland cohort of MiG TOFU study). 1
• At 4-10 years of age, offspring of mothers with PCOS treated with metformin showed higher BMI, weight-to-height ratios, waist circumferences, and borderline increases in fat mass. 1, 3
• 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 benefits (less clinically significant than long-term concerns):

• Lower risk of neonatal hypoglycemia compared to insulin. 1, 2
• Less maternal weight gain during pregnancy. 1, 2

Reassuring findings:

• No clear association with major birth defects or teratogenic effects based on available data. 4, 5, 6
• No increased risk of miscarriage directly attributable to metformin. 4

Special Consideration: PCOS and Preconception Use

For women with PCOS using metformin for ovulation induction: 1, 2, 7, 3

• Metformin can improve ovulation rates when trying to conceive, particularly in women with insulin resistance. 7, 8
• There is no evidence-based need to continue metformin once pregnancy is achieved unless the woman has type 2 diabetes requiring ongoing treatment. 1, 2, 7, 3
• Randomized controlled trials have not demonstrated benefit in preventing spontaneous abortion or GDM when metformin is continued in PCOS pregnancies. 1, 7, 3
• Discontinue metformin at pregnancy confirmation for PCOS patients without diabetes. 7, 3

Clinical Decision Algorithm

Step 1: Determine diabetes type and severity

• GDM or type 2 diabetes diagnosed: Start with lifestyle modifications (minimum 175g carbohydrate daily, 71g protein, 28g fiber; moderate-intensity exercise 20-50 min/day). 1

Step 2: If pharmacologic therapy needed

• First choice: Insulin therapy (multiple daily injections or continuous subcutaneous insulin infusion). 1, 2

Step 3: Assess barriers to insulin use

• If significant barriers exist (cost, language, comprehension, cultural factors), consider metformin as second-line only after:
  • Thorough counseling about placental transfer
  • Discussion of long-term offspring metabolic concerns
  • Explanation of 25-28% treatment failure rate
  • Confirmation that patient does NOT have hypertension, preeclampsia, or risk for intrauterine growth restriction 1, 2

Step 4: Monitor for treatment failure

• Anticipate need for supplemental insulin in approximately one-quarter of patients started on metformin. 2

Common Pitfalls to Avoid

• Do not continue metformin throughout pregnancy simply because it helped with conception in PCOS patients—the preconception benefits do not translate to pregnancy benefits for PCOS without diabetes. 3
• Do not assume metformin prevents GDM—it does not, even in high-risk women. 3
• Do not use metformin in women who develop hypertension or preeclampsia during pregnancy, even if they were tolerating it previously. 1, 2
• Do not overlook the need for close glucose monitoring to identify the substantial proportion of patients who will require insulin supplementation. 2

FDA Labeling Summary

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, though published studies have not reported a clear association with metformin and major birth defects or miscarriage risk. 4 However, metformin is present in human milk at levels resulting in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage. 4