Paternal metformin use associated with major birth defects
A prospective registry-based study in Denmark found that offspring of men who filled one or more prescriptions for metformin during the three months of developing fertilizing sperm were more likely to have a birth defect, while insulin and sulfonylureas were not associated with increased risk.
Preconception paternal metformin treatment was associated with major birth defects, particularly genital birth defects in boys, but more research is needed to replicate findings and clarify causation, a study found.
To evaluate whether the risk for birth defects in offspring varies with preconception metformin use by fathers with diabetes, researchers conducted a nationwide prospective registry-based cohort study in Denmark from 1997 to 2016 among all liveborn singletons from mothers without histories of diabetes or essential hypertension. Researchers assessed men who filled one or more prescriptions for a diabetes drug during the three months of developing fertilizing sperm. Sex and frequencies of major birth defects were compared across drugs, times of exposure, and siblings. Results were published March 28 by Annals of Internal Medicine.
Of 1,116,779 offspring, 3.3% had one or more major birth defects. Insulin-exposed offspring (n=5,298) had a birth defect frequency similar to the reference level (adjusted odds ratio [OR], 0.98; 95% CI, 0.85 to 1.14). Metformin-exposed offspring (n=1,451) had higher birth defect frequency compared to those with no metformin exposure (adjusted OR, 1.40; 95% CI, 1.08 to 1.82). For sulfonylurea-exposed offspring (n=647), the adjusted OR was 1.34 (95% CI, 0.94 to 1.92).
Offspring whose fathers filled a metformin prescription in the year before (n=1,751) or after (n=2,484) sperm development had reference birth defect frequencies (adjusted ORs, 0.88 [95% CI, 0.59 to 1.31] and 0.92 [95% CI, 0.68 to 1.26], respectively), as did unexposed siblings of exposed offspring (exposed vs. unexposed OR, 1.54; 95% CI, 0.94 to 2.53). Among metformin-exposed offspring, genital birth defects, all in boys, were more common compared with the cohort (adjusted OR, 3.39; 95% CI, 1.82 to 6.30), while the proportion of male offspring was lower (49.4% vs. 51.4%; P=0.073).
“The observed effect size is similar to that of maternal age greater than 45 years, a recognized risk factor, with 4.8% birth defects among liveborn singletons in our data,” the study authors wrote. “The sheer size of the diabetes pandemic suggests that treatment of prospective fathers with diabetes, including pharmacologic management and counseling on diet, physical exercise, and weight loss, should be subject to further study.”
An editorial noted the difficulties of studying human teratogens and called for more research to identify underlying mechanisms and to differentiate drug effects from changes in metabolic state or other confounders. A key limitation includes the lack of data on men's adherence to prescribed medications and glycemic control. “If corroborated, metformin would not be the first medication to pose iatrogenic risk or be recognized as a human teratogen,” the editorial stated. “However, its attributable risk could be large given its prevalent use.”