Meta-analysis provides safety reassurance for metformin use during pregnancy

Antenatal exposure to metformin does not appear to harm neurodevelopmental outcomes in children, according to the results of a meta-analysis.

Pooled data from seven studies that involved a cohort of 14,042 children followed for up to 14 years of age showed that compared with nonexposure, antenatal exposure to metformin was not associated with global neurodevelopmental delay in infancy (relative risk [RR], 1.09, 95 percent confidence interval [CI], 0.54–2.17; 3 studies; 9,668 children) or in early childhood (age 3–5 years: RR, 0.90, 95 percent CI, 0.56–1.45; 2 studies; 6,118 children). [Am J Obstet Gyn 2024;231:308-314.e6]

Moreover, children who were born to mothers who used metformin during pregnancy had similar motor and cognitive outcomes as those born to mothers who had no antenatal exposure to the drug. The mean difference in motor scores was 0.30 (95 percent CI, −1.15 to 1.74; 3 studies; 714 children), while the mean difference in cognitive scores was −0.45 (95 percent CI, −1.45 to 0.55; 4 studies; 734 children).

The studies included in the meta-analysis were of high quality and deemed to be at low risk of bias.

“Our findings suggest that metformin use during pregnancy does not seem to be associated with altered neurodevelopmental outcomes for children or adolescents,” the investigators said. “With rising rates of metformin use in pregnancy, these findings may offer reassurance to clinicians and patients who are considering metformin.”

Of the seven studies included, five were follow-up studies of randomized controlled trials and two were observational cohort studies. Four studies involved women with gestational diabetes, one included women with polycystic ovary syndrome, one was conducted in the context of a high BMI, and one evaluated metformin use in pregnancy for any indication with the exception of type 1 diabetes.

A total of 7,641 children had in-utero exposure to metformin.

While the studies included in the meta-analysis had extensive follow-up periods, which extended into adolescence, many of these studies involved younger children, potentially limiting the generalizability of findings to older age groups, according to the investigators. Additionally, the use of developmental measures that may not accurately predict later childhood function and the varying indications and control groups across studies present challenges in drawing definitive conclusions, they said.

“Diabetes in pregnancy may increase the risk for autism spectrum disorder, attention-deficit/hyperactivity disorder, and other psychiatric diagnoses in the offspring; however, we did not identify any papers that examined the impact of metformin on the development of these conditions. This remains an avenue for future research,” the investigators noted.

“Knowledge of potential lasting effects [of metformin use during pregnancy] is crucial for shared decision-making between women and their care providers,” they added.