Does paternal use of metformin up risk for congenital malformations?

Use of metformin monotherapy by fathers during the sperm development period prior to conception does not appear to contribute to an increased risk of major congenital malformations (MCMs) in newborns, reveals a study.

This nationally representative cohort study involved a total of 383,851 live births linked to fathers and mothers that occurred between 1999 and 2020.

The researchers confirmed MCMs and parental cardiometabolic conditions using clinical diagnoses, medication dispensing information, and laboratory test results. They estimated the effect of metformin use using general estimating equations, accounting for concurrent use of other antidiabetic medications and parental cardiometabolic morbidity.

Cardiometabolic morbidity was more prevalent among fathers who used metformin during spermatogenesis, and their spouses, than among unexposed fathers. The adjusted odds ratio (OR) was 1.00 (95 percent confidence interval [CI], 0.76‒1.31), while the crude OR for paternal metformin exposure in all formulations and MCMs was 1.28 (95 percent CI, 1.01‒1.64).

On the other hand, the adjusted OR was 0.86 (95 percent CI, 0.60‒1.23) for metformin in monotherapy and 1.36 (95 percent CI, 1.00‒1.85) for metformin in polytherapy. The latter was more common among patients with more poorly controlled diabetes.

The “[a]ssociation for metformin in polytherapy could potentially be explained by worse underlying parental cardiometabolic risk profile,” the researchers said.

The study was limited by laboratory test results for haemoglobin A_1c to assess underlying diabetes severity that were available only for a subset of the cohort.