(BSPOT16) Paternal metformin use before pregnancy and risk of congenital malformations: a cross-national cohort study in Norway and Taiwan

Background: A previous study has suggested an association between paternal preconception use of metformin, a widely used first-line glucose-lowering agent for the management of type 2 diabetes mellitus (T2DM), and an increased risk of congenital malformations in offspring. However, this finding has not been replicated and causality remains unclear due to limited control for confounding factors.

Objectives: To assess the association between paternal metformin use and risk of congenital malformations.

Methods: We conducted a population-based, cross-national cohort study in Norway and Taiwan. The study identified 619,389 offspring with paternal data in the Norwegian cohort from 2010 to 2021 and 2,563,812 in the Taiwanese cohort from 2004 to 2018. We compared the risk of any major congenital malformation among infants born to fathers who were exposed to metformin during the period of sperm development (3 months before pregnancy) with those who were unexposed. Relative risks were estimated in unadjusted analysis, analyses that restricted the cohort to men with T2DM, and using overlap propensity-score (PS) weighting to control for diabetes severity and other potential confounders. Sibling-matched comparisons were conducted to account for shared genetic and lifestyle factors. Relative risk estimates for Norwegian and Taiwanese data were pooled using a random-effects meta-analytic approach.

Results: In Norway, fathers of 2,075 (0.34%) offspring and in Taiwan, fathers of 15,276 (0.60%) offspring were exposed to metformin before pregnancy. Increased risks of any congenital malformation associated with paternal metformin use were observed in the unadjusted analysis and attenuated with increasing levels confounding control. The relative risks of any malformations with paternal metformin use were 1.29 (95% CI, 1.07-1.55) in Norway and 1.08 (95% CI, 0.99-1.17) in Taiwan in the unadjusted analysis, and 1.20 (95% CI, 0.94-1.53) in Norway and 0.93 (95% CI, 0.80-1.07) in Taiwan in the analysis restricted to men with T2DM. In the overlap PS weighting analysis restricted to men with T2DM, the relative risks were 0.98 (95% CI, 0.72-1.33) in Norway and 0.87 (95% CI, 0.74-1.02) in Taiwan, resulting in a pooled estimate of 0.89 (95% CI, 0.77-1.03). No associations were observed between paternal metformin use and any organ-specific malformations. These findings were consistent in sibling-matched comparisons and sensitivity analyses.

Conclusions: Our findings suggest that paternal use of metformin before pregnancy is not associated with any congenital malformations in offspring. Metformin, therefore, can continue to be considered a suitable first-line oral agent for managing glucose levels in young men with T2DM who aspire to fatherhood.