Why is metformin (biguanide oral hypoglycemic agent) not recommended during pregnancy?

Why Metformin is Not Recommended as First-Line Treatment in Pregnancy

Metformin is not "not allowed" in pregnancy, but insulin is strongly recommended as the first-line agent because metformin crosses the placenta completely and long-term follow-up studies show concerning metabolic effects in offspring, including higher childhood BMI, increased waist circumference, and accelerated postnatal growth. 1

Primary Concerns About Metformin Use

Placental Transfer

• Metformin readily crosses the placenta, resulting in umbilical cord blood levels equal to or higher than simultaneous maternal levels. 1
• Unlike insulin, which does not cross the placenta to any measurable extent, metformin achieves full fetal exposure. 1, 2

Long-Term Offspring Safety Data

The most compelling evidence against first-line metformin use comes from long-term follow-up studies:

• The MiG TOFU study found 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 in children whose mothers had polycystic ovary syndrome showed higher BMI, weight-to-height ratios, waist circumferences, and borderline increased fat mass. 1
• Meta-analyses demonstrate that metformin exposure results in smaller neonates with acceleration of postnatal growth, leading to higher BMI in childhood. 1

These findings raise concerns about long-term metabolic programming and obesity risk in offspring, which directly impacts quality of life. 1

Treatment Failure Rates

• Metformin fails to provide adequate glycemic control in 25-28% of women with gestational diabetes mellitus (GDM), requiring supplemental insulin. 1
• This substantial failure rate means many patients will ultimately need insulin anyway. 1

When Metformin May Be Considered

Metformin can be used as a second-line alternative only in specific circumstances when insulin cannot be used safely or effectively due to cost barriers, language barriers, comprehension issues, or cultural factors that interfere with insulin acceptance. 1

Mandatory Requirements Before Using Metformin:

• Comprehensive counseling about placental transfer and long-term offspring concerns must be provided. 1
• The patient must understand that long-term safety data for offspring remains concerning. 1

Absolute Contraindications for Metformin in Pregnancy:

• Maternal hypertension or preeclampsia 1
• Risk of intrauterine growth restriction 1
• Suspected placental insufficiency (due to potential for growth restriction or acidosis) 1

Why Insulin Remains First-Line

The American Diabetes Association clearly states that insulin is the preferred agent for management of both type 1 and type 2 diabetes in pregnancy. 1

Advantages of Insulin:

• Does not cross the placenta to any measurable extent 1, 2
• Most robust long-term safety data available 1
• Demonstrated to improve perinatal outcomes in large randomized studies 1
• No concerning long-term metabolic effects on offspring 1

Common Clinical Pitfalls to Avoid

• Do not switch from insulin to metformin simply because the patient prefers oral medication - fetal safety must be prioritized over maternal convenience. 1
• Do not continue metformin in women with PCOS once pregnancy is confirmed unless there are specific indications like type 2 diabetes, as trials show no benefit in preventing spontaneous abortion or GDM. 1
• Do not minimize the significance of placental passage - metformin achieves fetal concentrations equal to or higher than maternal levels. 1
• Do not ignore the long-term follow-up data - while immediate neonatal effects may appear favorable (less hypoglycemia, less maternal weight gain), the long-term metabolic consequences for the child are concerning. 1

The Bottom Line

Metformin is not absolutely prohibited in pregnancy, but it is not recommended as first-line therapy because of placental transfer and concerning long-term offspring metabolic outcomes. 1 Insulin remains the gold standard with the most reassuring safety profile for both immediate and long-term outcomes. 1