Preconception Paternal Metformin Use Associated With Birth Defects in Offspring

Paternal metformin use before conception was found to be associated with major birth defects in offspring, especially genital birth defects in boys, according to the results of a study published in the Annals of Internal Medicine.¹

The findings are based on analysis of newborns and parents identified in the Medical Birth Registry from 1997 to 2016, which contains all registered pregnancies from 20 weeks of gestation occurring during that time period in Denmark.

All live-born singletons were eligible for inclusion in the study; however, the researchers excluded births from mothers who used diabetes medication or were diagnosed with diabetes mellitus or gestational diabetes at any time before giving birth, mothers who were diagnosed with essential hypertension at any time before giving birth, and mothers who were prescribed cardiovascular drugs in the 6 months before conception.

The primary outcome was diagnosis of at least 1 major birth defect in the first year of life among offspring of study participants.

A total of 1,116,779 offspring (51.4% male) were included, of whom 3.3% had at least 1 major birth defect (reference). The median ages of the mothers and fathers were 30 and 33 years, respectively. A total of 7029 offspring were exposed to paternal diabetes medications, including insulin (n=5298), metformin (n=1451), and sulfonylureas (n=647).

The adjusted odds ratio (aOR) for having at least 1 major birth defect was 0.98 (95% CI, 0.85-1.14) for insulin, 1.40 (95% CI, 1.08-1.82) for metformin, and 1.34 (95% CI, 0.94-1.92) for sulfonylureas, according to the main regression analysis.

Offspring of fathers who filled a metformin prescription in the year before (n=1751) or after (n=2484) sperm development had reference birth defect frequencies (aOR, 0.88 [95% CI, 0.59-1.31] and 0.92 [95% CI, 0.68-1.26], respectively).

Odds ratios for paternal metformin use during sperm development were 1.54 (95% CI, 0.94-2.53) in a comparison of exposed vs unexposed offspring of the same father and 1.66 (95% CI, 1.00-2.75) in a comparison of exposed vs unexposed offspring of the same mother, according to conditional logistic regression analysis.

Genital birth defects were found to be increased among metformin-exposed offspring vs the overall cohort (0.90% vs 0.24%; aOR, 3.39 [95% CI, 1.82-6.30]), with all of these genital birth defects occurring in boys. Metformin-exposed offspring were 49.4% male compared with 51.4% in the reference group (P =.073).

Genital birth defects were not found to be increased among offspring exposed to sulfonylureas (aOR, 0.96).

The researchers noted that information on participants’ underlying disease status was limited.

“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,” stated the investigators. “Further research should replicate the findings while accounting for glycemic control and other metabolic features, and expose the underlying pathway.”

In an accompanying editorial, the author comments that “these data suggest that altered testosterone levels may be an underlying mechanism raising concern about the antiandrogenic activity of oral diabetes pharmacologic agents, including metformin.”²

Disclosure: One of the study authors declared an affiliation with a biotech company. Please see the original reference for a full list of authors’ disclosures.

References

1. Wensink MJ, Lu Y, Tian L, et al. Preconception antidiabetic drugs in men and birth defects in offspring: a nationwide cohort study. Ann Intern Med. Published online March 29, 2022. doi:10.7326/M21-4389 

2. Buck Louis GM. Paternal preconception diabetes drugs and birth defects inoffspring: a call for more conclusive study. Published online March 29, 2022.  doi:10.7326/M22-0770