Use of metformin in the three months prior to conception by men is associated with increased risk of genital birth defects among their male children, according to a recent study published in the journal Annals of Internal Medicine.

To investigate the association between the preconceptional use of antidiabetic drugs like metformin by men and genital birth defects in their sons, live births in Denmark were examined using data from national health registries from 1997 to 2016. All liveborn singletons from mothers without a history of diabetes, essential hypertension or heart disease were included in the study. The preconceptional period considered for the study was during the 3-month window period, the time taken for sperm development and maturation. Babies born to mothers with hypertension or diabetes were not included in the study.

Out of the 1,116,779 births included in the study, 3.3% of the children had at least one major birth defects and 51.4% were boys. Among the 5298 children exposed to insulin, the adjusted odds ratio (aOR) of birth defects in these children was 0.98. No effect on the rate of birth defects or the sex ratio was seen.

Among the 1451 children exposed to metformin, 49.4% were male; the percentage of birth defects in this group of children was 5.2% with aOR of 1.40. In 647 children exposed to sulfonylureas, 5.1% had birth defects and 49.3% were boys with aOR of 1.34.

The researchers found that among children exposed to metformin, boys were 3 times more likely to have genital birth defects with aOR of 3.39. All the genital birth defects were found to occur in boys only, while the proportion of male offspring was lower (49.4% vs 51.4%). “Offspring whose fathers filled a metformin prescription in the year before (n = 1751) or after (n = 2484) sperm development had reference birth defect frequencies (aORs, 0.88 and 0.92, respectively), as did unexposed siblings of exposed offspring (3.2%; exposed vs unexposed OR, 1.54).”

This study has shown a correlation between the preconceptional use of metformin by men and major birth defects in their sons, specifically genital birth defects. A notable finding was that the birth defects occurred only in boys. Taking metformin before or after the 3-month window period was not associated with a higher percentage of birth defects. The findings do not establish a cause-and-effect relationship between the two. “Further research should replicate these findings and clarify the causation”, conclude the authors.

Metformin is the first-choice drug for the treatment of type 2 diabetes. Will these findings affect clinical practice? This remains to be seen. Nevertheless, the findings of this study underscore the significance of preconception health for fathers, which may affect the health of their offspring.

Reference

1. Maarten J Wensink, et al. Preconception antidiabetic drugs in men and birth defects in offspring: a nationwide cohort study. Ann Intern Med. 2022 May;175(5):665-673. doi: 10.7326/M21-4389.