Can metformin extended-release (ER) be used during pregnancy?

Metformin Extended-Release in Pregnancy: Not Recommended as First-Line

Insulin is the preferred medication for treating hyperglycemia in pregnancy, and metformin (including extended-release formulations) should not be used as a first-line agent because it crosses the placenta to the fetus. 1

Key Clinical Guidance

For Gestational Diabetes Mellitus (GDM)

• First-line treatment: Lifestyle modification (medical nutrition therapy and exercise)
• If lifestyle fails: Insulin is preferred 1, 2
• Metformin as alternative: Only consider if the patient refuses or cannot safely use insulin, and NOT in the first trimester 3
• Additional restrictions: Do not use metformin if:
  • Fasting glucose ≥110 mg/dL (6.1 mmol/L) 3
  • GDM diagnosed before 25 weeks gestation 3
  • Hypertension, preeclampsia, or risk for intrauterine growth restriction present 2

For Type 2 Diabetes in Pregnancy

• Insulin remains the mainstay of treatment 4, 5
• Against routine addition of metformin: The 2025 Endocrine Society/European Society of Endocrinology guideline specifically recommends against routinely adding metformin to insulin in pregnant individuals with type 2 diabetes already on insulin 5

For Polycystic Ovary Syndrome (PCOS)

• Discontinue metformin by the end of the first trimester if it was used for ovulation induction 1, 2
• No evidence supports continuing metformin throughout pregnancy for PCOS 2, 6

Critical Safety Concerns

Placental Transfer and Fetal Exposure

Metformin (all formulations, including extended-release) crosses the placenta freely, achieving fetal blood levels equal to or higher than maternal levels 2, 4. This occurs because:

• High expression of OCT3 cation transporters in the placenta during second and third trimesters 5
• Metformin concentrates in fetal and placental mitochondria 1000-fold 5

Long-Term Offspring Concerns

Multiple follow-up studies raise concerns about childhood outcomes:

• 9-year-old children exposed to metformin in the MiG TOFU study (Auckland cohort) had higher weight, waist-to-height ratio, and waist circumference compared to insulin-exposed children 2, 4
• 4-10 year follow-up of children whose mothers used metformin for PCOS showed higher BMI, increased obesity, higher weight-to-height ratios, and borderline increased fat mass 2, 4
• Meta-analysis demonstrated metformin exposure resulted in smaller neonates with acceleration of postnatal growth leading to higher BMI in childhood 2, 4

Short-Term Risks

• Increased preterm birth rates in some studies 3
• Small-for-gestational-age (SGA) births: Risk may be doubled in some populations, particularly with maternal hypertension or kidney disease 5
• Treatment failure: 14-46% of women with GDM on metformin monotherapy require conversion to insulin 4

FDA Labeling Position

The FDA label states that limited data are insufficient to determine drug-associated risk for major birth defects or miscarriage 7. Published studies have not reported a clear association with major birth defects, but these studies cannot definitively establish absence of risk due to methodological limitations, including small sample size and inconsistent comparator groups 7.

Extended-Release vs. Immediate-Release: No Distinction in Guidelines

No guideline differentiates between metformin formulations (immediate-release vs. extended-release) regarding safety or efficacy in pregnancy. The recommendations apply to metformin regardless of formulation 1, 2, 4. While extended-release may offer better gastrointestinal tolerability and once-daily dosing in non-pregnant populations, this does not change the fundamental concerns about placental transfer and fetal exposure.

When Metformin Might Be Considered (Second-Line Only)

Metformin may be an alternative only when:

1. Patient refuses insulin or cannot use it safely (cost, language barriers, comprehension, cultural factors) 2
2. NOT in first trimester 3
3. GDM diagnosed ≥25 weeks AND fasting glucose <110 mg/dL 3
4. No hypertension, preeclampsia, or intrauterine growth restriction risk 2
5. After full discussion of known risks and lack of long-term offspring safety data 3

Common Pitfalls to Avoid

1. Do not assume extended-release is safer: All metformin formulations cross the placenta equally
2. Do not continue PCOS-related metformin: Discontinue by end of first trimester 1, 2
3. Do not use in early pregnancy: Avoid first trimester use when possible 3
4. Do not ignore growth restriction risk: Contraindicated with placental insufficiency concerns 2
5. Do not forget counseling: Patients must understand the uncertainty regarding long-term offspring effects

Breastfeeding Exception

Metformin is safe during breastfeeding for women who successfully used it during pregnancy 3. Infant exposure is only 0.11-1% of the maternal weight-adjusted dose 7.