Paternal use of metformin during sperm production not associated with major birth defects, States study

A study of almost 400,000 live births found that paternal use of metformin monotherapy was not associated with major congenital malformations (MCMs) in newborns. Associations between metformin in polytherapy and birth defects could potentially be explained by worse underlying parental cardiometabolic risk profile of those taking multiple diabetes medications. The study is published in Annals of Internal Medicine.

Researchers from Harvard T.H. Chan School of Public Health, Kahn-Sagol-Maccabi (KSM) Research and Innovation Institute, and Brigham and Women's Hospital studied data from a large Israeli health fund from 1999 to 2020 to assess the potential adverse intergenerational effect of metformin use during the sperm production period preceding conception. MCMs and parental cardiometabolic conditions were ascertained using clinical diagnoses, medication dispensing information, and laboratory test results.

Although crude findings suggested that metformin was associated with increased risk of MCM (6.2% versus 4.7% when father used no diabetic medication), this association did not persist with adjustment for paternal cardiovascular and metabolic co-morbid conditions and exclusion of children born to mothers with diabetes or hyperglycemia (to eliminate possible effects mediated through the mother). Fathers prescribed metformin and other diabetic medication were more likely to be older, with co-existent cardiovascular and metabolic conditions, to be smokers and to have fertility problems. Similarly, mothers were more likely to have cardiovascular co-morbidity and to have experienced fertility problems when the father used metformin.

The author of an accompanying editorial from the University of Dundee suggests that these findings underscore the importance of considering paternal health in the context of reproductive planning and prenatal care. The author notes that metformin is a safe and effective treatment option for type 2 diabetes for men and women trying to conceive as well as for managing hyperglycemia in pregnant women in the first trimester. As such, it may be time to reconsider current prenatal care guidelines that advocate switching to insulin therapy for those trying to conceive. 

Reference:

Ran S. Rotem, Marc G. Weisskopf, Krista F. Huybrechts, and Sonia Hernández-Díaz, Paternal Use of Metformin During the Sperm Development Period Preceding Conception and Risk for Major Congenital Malformations in Newborns, Annals of Internal Medicine, https://doi.org/10.7326/M23-1405.