What is the safety and recommended dosage of Diabex (metformin) in pregnant women with diabetes?

Diabex (Metformin) in Pregnancy

Insulin is the first-line and preferred pharmacologic agent for treating diabetes in pregnancy, not metformin (Diabex), because metformin crosses the placenta and long-term offspring safety data raises concerns about increased childhood obesity and metabolic effects. 1, 2

Primary Recommendation

The American Diabetes Association and American College of Obstetricians and Gynecologists explicitly state that insulin should be the first-line treatment for both gestational diabetes mellitus (GDM) and type 2 diabetes in pregnancy. 1, 2 Metformin is not recommended as first-line therapy because:

• Metformin readily crosses the placenta, with umbilical cord blood levels equal to or higher than maternal levels 1
• Long-term offspring safety data is concerning, showing increased childhood obesity, higher BMI, increased waist-to-height ratios, and greater waist circumferences at ages 4-10 years 1
• Metformin fails to provide adequate glycemic control in 25-28% of women with GDM, requiring insulin supplementation anyway 1

When Metformin May Be Considered (Second-Line Only)

Metformin may be used as a second-line alternative only in specific circumstances after discussing risks with the patient: 1

• Cost barriers to insulin access 1
• Language barriers or comprehension issues preventing safe insulin use 1
• Cultural influences making insulin unacceptable 1

Critical Contraindications for Metformin in Pregnancy

Metformin should NOT be used in pregnant women with: 1

• Hypertension or preeclampsia (risk of fetal acidosis) 1
• Risk factors for intrauterine growth restriction 1
• Placental insufficiency concerns 1

Short-Term Outcomes: Mixed Evidence

While metformin shows some maternal benefits compared to insulin, these do not outweigh long-term offspring concerns:

Potential maternal benefits: 1

• Lower risk of neonatal hypoglycemia 1
• Less maternal weight gain during pregnancy 1
• Reduced need for cesarean births 1

Concerning neonatal outcomes: 1

• Possible increased risk of prematurity 1
• Doubling of small-for-gestational-age neonates when added to insulin for type 2 diabetes 1

Long-Term Offspring Safety Concerns (Critical)

The most recent evidence (2020-2023 guidelines) emphasizes growing concerns about long-term metabolic effects on offspring: 1

• At age 9 years: Children exposed to metformin in the Auckland MiG TOFU cohort were heavier with higher waist-to-height ratios and waist circumferences 1
• At ages 4-10 years: Studies in polycystic ovary syndrome showed higher BMI, increased obesity, higher weight-to-height ratios, and borderline increased fat mass 1
• Meta-analysis conclusion: Metformin exposure resulted in smaller neonates with acceleration of postnatal growth leading to higher childhood BMI 1

FDA Labeling Position

The FDA label for metformin states that limited data in pregnant women are insufficient to determine drug-associated risk for major birth defects or miscarriage. 3 The label acknowledges that:

• Published studies have not reported a clear association with major birth defects or miscarriage, but methodological limitations prevent definitive conclusions 3
• Animal studies showed partial placental barrier to metformin 3
• There is insufficient information about effects on breastfed infants 3

Clinical Algorithm for Diabetes Management in Pregnancy

Step 1: Lifestyle modifications first 1, 2

• Medical nutrition therapy with registered dietitian 1, 2
• Minimum 175g carbohydrate, 71g protein, 28g fiber daily 1, 2
• Target fasting glucose <95 mg/dL, 1-hour postprandial <140 mg/dL, or 2-hour postprandial <120 mg/dL 1, 2

Step 2: If targets not met within 1-2 weeks 2

• Initiate insulin as first-line pharmacologic therapy 1, 2
• Multiple daily injections or insulin pump are both acceptable 1

Step 3: Consider metformin only if 1

• Insulin is not safely accessible or usable due to cost, language, comprehension, or cultural barriers
• AND patient does not have hypertension, preeclampsia, or risk of intrauterine growth restriction
• AND patient is fully informed about placental transfer and long-term offspring metabolic concerns

Common Pitfalls to Avoid

• Do not continue metformin from pre-pregnancy without reassessing: Women with polycystic ovary syndrome taking metformin for ovulation induction do not need to continue it once pregnancy is confirmed 1
• Do not use metformin as equivalent to insulin: The failure rate of 25-28% means many women will ultimately require insulin anyway 1
• Do not ignore contraindications: Using metformin in women with hypertension or at risk for growth restriction can cause fetal harm 1
• Do not dismiss long-term offspring concerns: The most recent 2020-2023 guidelines increasingly emphasize childhood metabolic effects that were not apparent in earlier studies 1