This previously described association was not replicated in a new study.

In a provocative Danish study published two years ago, paternal use of metformin just before conception was associated with birth defects among offspring (NEJM JW Gen Med May 15 2022 and Ann Intern Med 2022; 175: 665- 673). The theoretical mechanism is an adverse effect on spermatogenesis, which has been noted in some animal studies.

Now, this issue has been examined in another population. Researchers identified 1730 fathers with diabetes in an Israeli health system database who took metformin during the 90 days before conception. In analyses adjusted for potential demographic, cardiometabolic and maternal confounders, metformin monotherapy was not associated with excess risk for major congenital malformations, compared with no diabetes drug exposure among 380,000 control fathers. For offspring of men taking metformin plus other diabetes medications before conception, a slightly higher incidence of malformations was of borderline statistical significance. 

Comment: The authors conclude that metformin is unlikely to cause major congenital malformations; their analysis controlled for confounders more extensively than did the Danish analysis cited above. The authors also suggest that the borderline outcome in patients taking multiple diabetes medications probably reflects a worse metabolic profile and not the effect of any single drug. At this point, I think we can consider preconception use of metformin to be acceptable in men with type 2 diabetes who have clear indications for it.

Allan S. Brett, MD, Clinical Professor of Medicine, University of Colorado School of Medicine, Aurora, USA.

Rotem RS, et al. Paternal use of metformin during the sperm development period preceding conception and risk for major congenital malformations in newborns. Ann Intern Med 2024 Jun 18; e-pub (https://doi.org/10.7326/M23-1405).

This summary is taken from the following Journal Watch titles: General Medicine, Ambulatory Medicine, Women’s Health.