Children exposed to metformin in utero had similar physical, social, emotional, language, or cognitive developmental outcomes at school entry after accounting for measured confounders. Metformin crosses the placenta, and although short-term perinatal safety data are reassuring, longer-term outcomes among exposed children remain less well characterized.
Researchers conducted a population-based cohort study of singleton births in Victoria, Australia, from 2009 to 2020, linking pregnancy and birth records with developmental data collected during the first year of full-time school. Among 177,409 children with linked developmental outcomes, 1,095 had been exposed to metformin in utero. Exposure was defined as at least 1 metformin prescription dispensed between the first day of the last menstrual period and birth. Of the exposed pregnancies, 703 (64%) involved first-trimester exposure and 467 (43%) involved more than 1 prescription.
Development was assessed at ages 4 to 6 years using the Australian Early Development Census (AEDC), a standardized teacher-completed assessment. The primary outcome was developmental vulnerability, defined as scoring below the 10th percentile in at least 2 of 5 domains: physical health and well-being, social competence, emotional maturity, school-based language and cognitive skills, and communication skills and general knowledge. Vulnerability within each individual domain was also assessed.
Developmental vulnerability occurred in 199 of 1,095 children (18%) exposed to metformin compared with 24,379 of 176,314 children (14%) without exposure. Although the unadjusted analysis showed a higher risk among exposed children, this association was no longer statistically significant after adjustment for measured confounders (adjusted relative risk, 0.97).
Metformin exposure was also not associated with developmental vulnerability in any of the 5 individual domains after adjustment. Adjusted relative risks ranged from 0.84 for emotional maturity to 1.09 for school-based language and cognitive skills.
Findings remained similar in sensitivity analyses. Among 16,121 children born to women with gestational diabetes or type 2 diabetes, developmental vulnerability occurred in 21% of metformin-exposed children compared with 16% of unexposed children, but the association was not statistically significant after adjustment (adjusted relative risk, 1.08).
Results were also consistent in analyses restricted to children with complete developmental outcomes and no special educational needs, as well as analyses of first-trimester exposure and alternative statistical approaches.
Residual confounding remained possible, including by race and ethnicity, which were unavailable in the data. The indication for metformin was also not directly available, although maternal comorbidities were incorporated into the analyses. Medication adherence could not be established, although exposure required pharmacy dispensing rather than prescription alone, and metformin dose was unavailable. Some women who received metformin immediately prior to conception and continued treatment during early pregnancy may have been misclassified as unexposed. Analyses examining multiple prescriptions and metformin initiation during the second and third trimesters were also underpowered for fully adjusted analyses.
The researchers noted that the findings may provide reassurance regarding developmental outcomes at early school age following metformin exposure in utero. “Further research is still needed to examine the association of antenatal metformin use with offspring growth and cardiometabolic health,” wrote first author Hannah Gordon, MD, of the University of Melbourne, and colleagues.
Tong reported receiving grants from the National Health and Medical Research Council of Australia, personal fees from multiple pharmaceutical companies, and involvement in trials evaluating metformin and preeclampsia. Hastie reported receiving research grants during the study. No other disclosures were reported. The study received funding from the Norman Beischer Medical Research Foundation and Australasian Diabetes in Pregnancy Society, with additional scholarship and fellowship support.
Source: JAMA Network Open
