Diabetes, Not Metformin, Increases Risk of Poor Pregnancy Outcomes

Alice Panchaud, PhD

Metformin, although often associated with a higher risk for adverse events (AEs), does not negatively impact pregnancy outcomes—instead, the presence of pre-gestational diabetes influences higher risk for poor outcomes.

New data has revealed that the risk of major birth defects, as classified as major or minor by 2 independent specialists, was 6% higher due to a diagnosis of pre-gestational diabetes (n = 17; 8%) than without the presence of the condition (n = 3; 2%) with both groups exposed to metformin.

The study, led by Alice Panchaud, PharmD, PhD, of the School of Pharmaceutical Sciences at the University of Geneva and Lausanne, in Switzerland, divided patients into 2 groups, a metformin exposed group (n = 471) and a reference group (n = 479).

“Our findings provide first reassuring evidence that metformin might offer a cheaper and simpler alternative to insulin for the management of pre-gestational diabetes in pregnancy when effective,” Panchaud told MD Magazine.

Within the metformin group, patients were divided between those with pre-gestational diabetes (n = 219) and those without (n = 173). Of the total groups members, 97% were exposed to the drug prior to pregnancy (n = 458), with a median dose of 1325 mg (Inter Quartile Range (IQR), 850-1700 mg).

In total, 63% of patients given metformin were indicated for pre-gestational diabetes (median dose, 1325 mg; IQR, 850-1850 mg), 12% for polycystic ovary syndrome (median dose, 1325 mg; IQR, 1000-1500 mg), and 23% for another condition such as obesity, ovary stimulation, insulin resistance, glucose intolerance, or hyperglycemia (median dose, 1000 mg; IQR, 450-1500 mg).

The cumulative risk of pregnancy loss, defined as spontaneous abortion or stillbirth, for the metformin group was 21%, while the reference group’s risk was 10.8% (adjusted hazard ratio [HR], 1.57; 95% CI, 0.90-2.74). Within the metformin using subgroups, those with pre-gestational diabetes had a pregnancy loss risk of 24% (crude HR, 2.51; 95% CI, 1.44-4.36) compared to 17% among those using the therapy for other indications (crude HR, 1.38; 95% CI, 0.74-2.59).

Recent data has shown that adherence to metformin is low among patients with diabetes, often due to worries about adverse events related to the therapy. In pregnancy, though, it may be the opposite for patients due to the drug being an oral therapy, as opposed to injections.

“Regarding adherence, the treatment considered safe in pregnancy so far and thus recommended for pre-gestational diabetes is insulin. This treatment requires injections,” Panchaud said. “In this regard, using metformin could be considered more comfortable by a lot of patients.”

The study’s main limitation, as described by Panchaud and her colleagues, was the “absence of a reference group composed of women treated for similar conditions” as such a group was unavailable in the cohort.

Additionally, although the study is the largest of its kind to date, the sample size was, according to the authors, admittedly too small to reach a final determination on the safety and risks of metformin on pregnancy outcomes. They noted that more studies that include women exposed to alternative therapies will need to conducted in order to ascertain that information.

“Pregnant women with pre-gestational diabetes on metformin are at an increased risk for multiple adverse pregnancy outcomes. However, this risk appears to be due to underlying diabetes, with no indication of a teratogenic or abortifacient effect of metformin itself,” the investigators concluded.