Prenatal metformin exposure not tied to long-term adverse childhood neurodevelopment

Key takeaways:

• In utero metformin exposure was not tied to neurodevelopmental delay in infancy or early childhood.
• In utero metformin exposure was not tied to altered motor or cognitive scores in children up to age 14 years.

Metformin exposure during pregnancy was not associated with adverse childhood neurodevelopmental outcomes up to age 14 years, according to a systematic review and meta-analysis published in the American Journal of Obstetrics and Gynecology.

Since the 1970s, metformin has been used in pregnancy to treat gestational or preexisting diabetes. Metformin crosses the placenta, exposing the fetus to similar concentrations of the drug as found in the maternal bloodstream, according to Hannah G. Gordon, MD, an obstetrics and gynecology clinical teaching fellow in the department of obstetrics and gynecology at the University of Melbourne and FRANZCOG-accredited registrar at the Mercy Hospital for Women, Victoria, Australia, and colleagues.

“While metformin does not appear to be associated with adverse neonatal outcomes, the long-term effects of exposure remain unclear,” Gordon and colleagues wrote. “In utero metformin exposure has been associated with a higher BMI mid-childhood, though without apparent metabolic sequelae. Less studied are the potential risks of antenatal metformin exposure on childhood neurodevelopment.”

Gordon and colleagues identified five follow-up studies of randomized controlled trials and two observational cohort studies from MEDLINE, Embase and Web of Science published from inception to July 2023. All studies evaluated women treated with metformin at any pregnancy stage for any indication. Studies included neurodevelopmental data for 14,042 children.

Overall, 7,641 children were exposed to metformin during pregnancy.

In utero metformin exposure was not associated with increased risks for neurodevelopmental delay in infancy (RR = 1.09; 95% CI, 0.54-2.17) or at age 3 to 5 years (RR = 0.9; 95% CI, 0.56-1.45) compared with unexposed counterparts. In addition, in utero metformin exposure was not associated with altered motor scores in children aged 2 to 5 years (mean difference, 0.3; 95% CI, –1.15 to 1.74) or cognitive scores in children up to age 14 years (mean difference, –0.45; 95% CI, –1.45 to 0.56) compared with unexposed counterparts.

According to the researchers, the included studies were of high quality and had a generally low risk for bias.

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