Should a patient with PCOS, hypercholesterolemia, and hypertriglyceridemia, taking letrozole (Femara) 7.5mg (cd3-7) and metformin (Glucophage) 500mg once daily for fertility, continue metformin through the first trimester of pregnancy or stop at a positive pregnancy test?

Should You Stop or Continue Metformin After a Positive Pregnancy Test?

You should stop metformin at the time of your positive pregnancy test, as current guidelines from the American Diabetes Association and American College of Obstetricians and Gynecologists recommend discontinuing metformin by the end of the first trimester when used for PCOS and ovulation induction, and there is no evidence-based need to continue it once pregnancy is achieved. 1, 2

Why Metformin Should Be Discontinued

Lack of Proven Benefit in Pregnancy

• Randomized controlled trials comparing metformin with other therapies for ovulation induction in women with PCOS have not demonstrated benefit in preventing spontaneous abortion or gestational diabetes once pregnancy is established 1, 2
• A 2023 meta-analysis of 11 randomized controlled trials showed that metformin treatment in pregnancy does not reduce the risk of gestational diabetes in high-risk individuals with obesity, PCOS, or preexisting insulin resistance 2
• A large multicenter randomized controlled trial found that metformin from first trimester to delivery did not reduce pregnancy complications including preeclampsia (7.4% vs 3.7%), gestational diabetes (17.6% vs 16.9%), or preterm delivery (3.7% vs 8.2%) compared to placebo 3

Concerning Long-Term Effects on Offspring

• Metformin readily crosses the placenta, with umbilical cord blood levels equal to or higher than maternal levels 1, 2
• Follow-up studies of children exposed to metformin in utero show concerning metabolic effects at ages 4-10 years, including higher BMI, increased waist circumference, increased waist-to-height ratios, and increased obesity risk 1, 2
• A recent meta-analysis concluded that metformin exposure resulted in smaller neonates with acceleration of postnatal growth resulting in higher BMI in childhood 1

Safety Contraindications During Pregnancy

• The American College of Obstetricians and Gynecologists recommends that metformin should NOT be used in pregnant women with hypertension, preeclampsia, or those at risk for intrauterine growth restriction due to potential for growth restriction or acidosis with placental insufficiency 1, 2
• Given your high cholesterol and triglycerides, you may have additional cardiovascular risk factors that warrant caution 2, 4

Addressing Conflicting Older Evidence

Why Some Older Studies Suggested Continuation

• Two older observational studies from Pakistan (2008,2010) suggested that continuing metformin throughout pregnancy reduced early pregnancy loss rates (8.8% vs 29.4%) and gestational diabetes 5, 6
• However, these were not randomized controlled trials and had significant methodological limitations including selection bias and lack of blinding 5, 6

Why Current Guidelines Override These Studies

• The more recent, higher-quality randomized, placebo-controlled, double-blind, multicenter trial from 2010 with 274 pregnancies found no benefit of continuing metformin throughout pregnancy 3
• Current American Diabetes Association guidelines (2021) and American College of Obstetricians and Gynecologists recommendations (reflected in 2023 Standards of Care) are based on systematic reviews of all available evidence and conclude there is no evidence-based need to continue metformin once pregnancy is achieved 1, 2

What You Should Do Instead

Focus on Proven Pregnancy Support

• Continue your letrozole as prescribed for ovulation induction (it is the first-line agent and should not be continued once pregnant) 2
• Ensure adequate progesterone supplementation for luteal phase support if indicated by your physician 2
• Once pregnant, focus on appropriate prenatal care including monitoring for gestational diabetes through standard screening at 24-28 weeks 1

Manage Your Metabolic Risk Factors

• Your high cholesterol and triglycerides should be managed through diet and lifestyle modifications during pregnancy, as most lipid-lowering medications are contraindicated 7, 4
• Aim for recommended weight gain during pregnancy: 15-25 pounds if overweight, or 10-20 pounds if obese 1
• Monitor blood pressure carefully given your metabolic risk factors 1, 2

Common Pitfalls to Avoid

• Do not continue metformin based on older observational studies when current high-quality randomized trials and guidelines recommend discontinuation 1, 2, 3
• Do not assume metformin will prevent gestational diabetes - it has not been shown to do so in pregnancy 1, 2, 3
• Do not ignore the long-term offspring metabolic concerns - these are increasingly well-documented in follow-up studies 1, 2