Should Metformin Be Started During Pregnancy?
Insulin, not metformin, should be the first-line pharmacologic treatment when starting diabetes therapy during pregnancy, whether for gestational diabetes mellitus (GDM) or type 2 diabetes. 1, 2
Primary Recommendation
The American Diabetes Association explicitly states that insulin is the preferred and recommended first-line agent for treating diabetes in pregnancy. 1 Metformin and glyburide are not recommended as first-line treatment because they cross the placenta and raise concerns about long-term offspring safety. 1, 2
Why Insulin Is Preferred Over Metformin
Placental transfer is a critical concern: Metformin readily crosses the placenta, resulting in umbilical cord blood levels equal to or higher than maternal levels. 1, 2, 3
Long-term offspring safety data raises red flags: The MiG TOFU study found that 9-year-old children exposed to metformin in utero were heavier with higher waist-to-height ratios and waist circumferences compared to insulin-exposed children. 1, 4
Childhood metabolic concerns persist: 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, 4
Meta-analyses confirm growth pattern alterations: Metformin exposure results in smaller neonates with acceleration of postnatal growth leading to higher BMI in childhood. 1, 4
When Metformin May Be Considered as Second-Line
Metformin can be used as an alternative only in specific circumstances where insulin cannot be used safely or effectively: 1, 2
- Cost barriers preventing insulin access
- Language barriers affecting insulin education
- Comprehension issues limiting safe insulin administration
- Cultural factors making insulin unacceptable
Critical requirement: Women must receive thorough counseling about known risks and the lack of complete long-term offspring safety data before starting metformin. 1, 2, 4
Absolute Contraindications to Metformin in Pregnancy
Do not use metformin in pregnant women with: 1, 2
- Hypertension
- Preeclampsia
- Risk for intrauterine growth restriction
The rationale: potential for growth restriction or acidosis in the setting of placental insufficiency. 1
Treatment Failure Rates You Must Anticipate
25-28% of women with GDM fail to achieve adequate glycemic control with metformin monotherapy and require supplemental insulin. 1, 4
Be prepared to add insulin in approximately one-quarter to one-third of cases. 2, 4
Special Consideration: PCOS and Preconception Metformin Use
For women with PCOS using metformin for ovulation induction, discontinue metformin once pregnancy is achieved unless there are specific indications like type 2 diabetes. 2, 5
Randomized trials show no benefit in preventing spontaneous abortion or GDM when continuing metformin after conception. 2, 5, 4
Short-Term Outcomes (The Limited Benefits)
While metformin offers some short-term advantages, these do not outweigh the long-term offspring concerns: 2, 4
- Lower risk of neonatal hypoglycemia compared to insulin 1, 2
- Less maternal weight gain during pregnancy 1, 2
- Fewer cesarean births in some studies 1
However, one RCT found a doubling of small-for-gestational-age neonates when metformin was added to insulin for type 2 diabetes treatment. 1
FDA Labeling Position
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. 3 Published studies have not reported a clear association with metformin and major birth defects, but the FDA emphasizes these studies cannot definitively establish the absence of any metformin-associated risk due to methodological limitations. 3
Clinical Algorithm for Starting Diabetes Treatment in Pregnancy
Step 1: Initiate lifestyle modifications (medical nutrition therapy and physical activity) for all women with diabetes in pregnancy. 1, 4
Step 2: If pharmacologic therapy is needed, start insulin as first-line treatment. 1, 2, 4
Step 3: Consider metformin only if:
- Patient cannot safely or effectively use insulin due to specific barriers (cost, language, comprehension, cultural factors) 1, 2
- AND patient has no contraindications (hypertension, preeclampsia, risk for intrauterine growth restriction) 1, 2
- AND comprehensive counseling about placental transfer and long-term offspring concerns has been provided 1, 2, 4
Step 4: Monitor closely for treatment failure and be prepared to add insulin in 25-46% of cases. 2, 4
Common Pitfalls to Avoid
Do not assume metformin is equivalent to insulin simply because some studies show adequate glycemic control—the long-term offspring data favors insulin. 1, 4
Do not use metformin for GDM prevention in high-risk women with obesity or PCOS, as meta-analyses show it does not reduce GDM risk. 4
Do not continue metformin from preconception in women with PCOS once pregnancy is confirmed unless there are other specific indications. 2, 5, 4
Do not overlook the high treatment failure rate—approximately one-quarter of patients will need insulin supplementation. 1, 4