Does paternal metformin use raise risk of congenital malformation in offspring?

Fathers who use metformin during the period of sperm development does not seem to contribute to congenital malformations in their children, a study has shown.

“Metformin can therefore continue to be considered a suitable initial oral agent for managing glucose levels in men with type 2 diabetes mellitus (T2DM) who plan on having children,” the researchers said.

This population-based, cross-national cohort study included 619,389 offspring with paternal data during the period of sperm development (3 months before pregnancy) in Norway (2010‒2021) and 2,563,812 offspring in Taiwan (2004‒2018).

Any congenital malformation served as the primary outcome, while organ-specific malformations, classified according to the European surveillance of congenital anomalies guidelines, were secondary.

The researchers estimated relative risks (RRs) through an unadjusted analysis and with analyses restricted to the cohort of men with T2DM and those using overlap propensity score weighting to control for diabetes severity and other confounders.

Sibling-matched comparisons were carried out to account for genetic and lifestyle factors. A random effects meta-analytical approach was used to pool RR estimates for the Norwegian and Taiwanese data.

Paternal data on metformin use during the period of sperm development was available for 2,075 (0.3 percent) and 15,276 (0.6 percent) offsprings in Norway and Taiwan, respectively. Among these children, 104 (5.0 percent) in Norway and 512 (3.4 percent) in Taiwan developed congenital malformations.

Paternal metformin use

The unadjusted analysis revealed a higher risk of any congenital malformation with paternal metformin use, which attenuated with increasing control of confounding. [BMJ 2024;387:e080127]

In unadjusted analysis, the RRs of any malformations with paternal metformin use were 1.29 (95 percent confidence interval [CI], 1.07‒1.55) in Norway and 1.08 (95 percent CI, 0.99‒1.17) in Taiwan. In the analysis restricted to fathers with T2DM, the RRs were 1.20 (95 percent CI, 0.94‒1.53) and 0.93 (95 percent CI, 0.80‒1.07), respectively.

In the overlap propensity score weighting analysis restricted to fathers with T2DM, the RRs were 0.98 (95 percent CI, 0.72‒1.33) in Norway and 0.87 (95 percent CI, 0.74‒1.02) in Taiwan, with a pooled estimate of 0.89 (95 percent CI, 0.77‒1.03).

Additionally, paternal metformin use did not show an association with any organ-specific malformations. These findings persisted in sibling-matched comparisons and sensitivity analyses.

“Our results indicate that paternal use of metformin during the period of sperm development is not associated with an increased risk of any congenital malformations in offspring,” the researchers said. “Additionally, we found no notable increases in risk for any specific organ malformations, including genital malformations.”

T2DM treatment

Concerns were raised regarding the risk of congenital malformations in offspring associated with paternal use of metformin due to its potential to cause epigenetic alterations to the sperm DNA. [Front Endocrinol (Lausanne) 2022;13:1000872; Ann Intern Med 2022;175:665-673]

“The findings of our cross-national study, which includes data from Norway and Taiwan, suggest that metformin keeps its current clinical profile as an initial oral agent for managing glucose levels in men with T2DM who are planning a family,” the researchers said.

“The study also underscores the necessity of considering factors beyond the drug itself, such as the underlying indication, related health conditions, and maternal risk factors, when evaluating the association between paternal drug use and risk of congenital malformations in offspring,” they added.