Pregnant women who took metformin for pregestational diabetes had a higher risk for adverse outcomes, but this risk was linked to the diabetes, not the drug, researchers reported.

Pregnant women on metformin for other indications, such as polycystic ovary syndrome (PCOS), had no significantly increased risk for poor outcomes, Alice Panchaud, PhD, of the University of Geneva in Switzerland, and colleagues wrote online in the British Journal of Clinical Pharmacology.

Compared with a matched reference group of pregnant women not taking metformin, metformin users with diabetes were nearly four times more likely to give birth to an infant with major birth defects (odds ratio 3.95; 95% CI 1.77 to 9.41). However, there was no significantly increased risk for pregnant women on metformin for other reasons (OR 0.83; 95% CI 0.18 to 2.81), the study found.

Similarly, women taking metformin for pre-gestational diabetes had more than twice the risk for spontaneous abortion or stillbirth (OR 2.51; 95% CI 1.44 to 4.36), but women taking metformin for other indications had no significant risk increase (OR 1.38; 95% CI 0.74 to 2.59).

The results were similar for other pregnancy outcomes the study examined, including the risk for pre-term birth and assisted delivery.

“Metformin controls glycemia in pregnant women with gestational diabetes, and it has been shown to prevent adverse maternal and neonatal outcomes associated with hyperglycemia,” Panchaud et al said. “However, evidence regarding its safety and effectiveness to achieve glycemic targets in the management of type 2 diabetes in pregnancy is limited. Moreover, since metformin, as do most other drugs, crosses the placental barrier, embryological and fetal risks need to be considered when exposure occurs early in pregnancy.”

The researchers explained that the aim of the observational cohort study was to better characterize the safety of metformin use early in pregnancy, and to evaluate the risk of birth defects and pregnancy losses after first trimester exposure to metformin. “We took advantage of the several potential indications to disentangle the effect of metformin from the known effects of diabetes on pregnancy outcomes,” the team said.

At the time of the study, Panchaud was a research fellow at the Harvard T.H. Chan School of Public Health in Boston. “Our findings provide the first reassuring evidence that metformin might offer a cheaper and simpler alternative to insulin for the management of pregestational diabetes in pregnancy when effective,” she said in a statement.

The multi-center, prospective study included 471 pregnant women who were taking metformin, enrolled from 1993 to 2015. The vast majority (97%) started metformin before pregnancy and took the drug during their first trimester. The median dose was 1,325 mg. A total of 63% of participants were taking metformin for pregestational diabetes; 12% were taking the drug for PCOS; and the remainder, for other indications such as obesity, ovary stimulation, insulin resistance, glucose intolerance, and hyperglycemia.

For a reference group, the study included 497 randomly selected pregnant women matched to the treatment group in terms of study center, maternal age, and week of gestational age at enrollment. These women had not used metformin, insulin, or any other hypoglycemic agent at any time during their pregnancy.

The team used multivariate logistic regression analysis to look for associations between metformin use and pregnancy outcomes, and importantly, distinguished between women who were taking metformin for pregestational diabetes and those taking it for other indications.

“Whether diabetes increases a woman’s risk of having a spontaneous abortion has been under debate for a long time,” the researchers wrote. “Overall, studies suggest that poor metabolic control may be at increased risk of spontaneous abortion. Similarly, in our study the risk of pregnancy losses was higher (21%) in the group exposed to metformin with a diagnostic of pregestational diabetes than in the metformin-exposed group without pregestational diabetes (17%).”

The main limitation of the study, the authors said, was the lack of a reference group of pregnant women being treated for pregestational diabetes with other drugs, especially insulin. In addition, “although this is the largest study published to date, the sample size is still too small and follow-up duration too short to reach a final assessment on the safety and risks associated with the use of metformin in pregnancy. Future studies comparing metformin-exposed pregnancies with women with the same indication and treated with alternative therapies — e.g., on insulin — are warranted.”