Is metformin (biguanide oral hypoglycemic agent) safe during pregnancy?

From the Guidelines

Metformin should not be used as a first-line agent for treating hyperglycemia in gestational diabetes mellitus, as it crosses the placenta to the fetus and lacks long-term safety data, according to the most recent guidelines 1. When considering the use of metformin during pregnancy, it's essential to weigh the potential benefits and risks.

• Metformin has been associated with a lower risk of neonatal hypoglycemia and less maternal weight gain than insulin in some studies 1.
• However, treatment monotherapy failure occurred in 14–46% of individuals, and metformin treatment in pregnancy does not reduce the risk of GDM in high-risk individuals with obesity, polycystic ovary syndrome, or preexisting insulin resistance 1.
• Additionally, metformin readily crosses the placenta, resulting in umbilical cord blood levels of metformin as high or higher than simultaneous maternal levels, which may have long-term effects on the offspring 1.
• Follow-up studies have shown that offspring exposed to metformin in utero may have higher BMI, waist-to-height ratio, and waist circumference, as well as increased obesity, compared to those exposed to insulin 1. Given the potential risks and lack of long-term safety data, insulin is the preferred medication for treating hyperglycemia in gestational diabetes mellitus, and metformin should be discontinued by the end of the first trimester in women with polycystic ovary syndrome who conceive while on metformin 1.
• Treatment decisions should always be individualized based on the specific clinical situation and made in consultation with healthcare providers.
• Lifestyle behavior change, including diet and exercise, is an essential component of management of gestational diabetes mellitus and may suffice as treatment for many individuals, and telehealth visits can improve outcomes compared with standard in-person care 1.

From the FDA Drug Label

Limited data with metformin hydrochloride tablets in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy

The use of metformin during pregnancy is not sufficiently studied to determine its associated risks. However, poorly controlled diabetes poses risks to both the mother and the fetus. Given the limited data, a conservative clinical decision would be to carefully weigh the benefits and risks of using metformin during pregnancy, considering the potential risks of uncontrolled diabetes 2.

• Key considerations include the potential for major birth defects and miscarriage, as well as the risks associated with poorly controlled diabetes.
• The decision to use metformin during pregnancy should be made on a case-by-case basis, taking into account the individual patient's circumstances and the potential benefits and risks of treatment.

From the Research

Metformin Use in Pregnancy

• Metformin is considered a safe and effective option for managing gestational diabetes, with studies showing similar outcomes to insulin therapy 3, 4, 5.
• Compared to glyburide, metformin has been shown to have a higher failure rate in achieving adequate glycemic control, with 34.7% of patients requiring insulin therapy 6.
• The use of metformin during pregnancy has been associated with reduced risk of hypertensive disorders, hypoglycemia, and macrosomia, as well as lower gestational weight gain 7.
• However, there are concerns about the long-term effects of metformin exposure on offspring, including increased risk of obesity and altered fat distribution 5, 7.
• Some studies have reported lower birthweight but accelerated postnatal growth and higher body mass index in metformin-exposed children, as well as an increased prevalence of central adiposity and obesity among children 5-10 years old 7.

Safety and Efficacy

• Metformin has been shown to be safe and effective in managing blood glucose levels in patients with gestational diabetes who prefer not to use insulin or cannot afford insulin therapy 3.
• The drug has been used in pregnancy since the 1970s and is widely available and acceptable to women 5.
• However, controversy remains surrounding its benefits and risks, and further research is needed to examine the mechanisms linking metformin to obesity reported during childhood in some follow-up studies 5.

Comparison to Other Treatments

• Metformin has been compared to glyburide in several studies, with mixed results 3, 6.
• While glyburide may have a lower failure rate than metformin, it has been associated with higher rates of neonatal intensive care unit admissions and longer lengths of stay for hypoglycemia and respiratory distress 3.
• Insulin therapy remains the preferred treatment for gestational diabetes, but metformin may be a viable alternative for women who cannot or prefer not to use insulin 3, 4, 5.