Stanford, CA—A higher risk of genital defects in boys appears to be linked to the use of metformin by their fathers during the period of sperm development, according to recent research.

The large cohort study published in Annals of Internal Medicine also cautions, however, that uncontrolled diabetes affects sperm quality, and discontinuing metformin could affect birth outcomes.

Lead authors from Stanford University School of Medicine in California and the University of Southern Denmark in Odense recommend that men prescribed metformin for diabetes should talk with their physicians to determine whether they should switch to another treatment when trying to conceive a child.

Researchers embarked on the study to analyze whether the risk for birth defects in offspring varies with preconceptional pharmacologic treatment of fathers with diabetes. The nationwide prospective registry–based cohort study used data from Denmark from 1997 to 2016. Included in the cohort were all liveborn singletons from mothers without histories of diabetes or essential hypertension.

The authors explained that babies were considered exposed if their father filled one or more prescriptions for a diabetes drug during the development of fertilizing sperm. Researchers compared sex and frequencies of major birth defects across drugs, times of exposure, and siblings.

Of the approximately 1.1 million offspring included, 3.3% had one or more major birth defects. The 5,298 insulin-exposed offspring had the reference birth defect frequency (adjusted odds ratio [aOR], 0.98 [95% CI, 0.85-1.14]).

The study team determined that the 1,451 metformin-exposed offspring had an elevated birth defect frequency (aOR, 1.40 [CI, 1.08-1.82]), as did the 647 sulfonylurea-exposed offspring to a lesser extent (aOR was 1.34 (CI, 0.94-1.92).

"Offspring whose fathers filled a metformin prescription in the year before (n = 1751) or after (n = 2484) sperm development had reference birth defect frequencies (aORs, 0.88 [CI, 0.59 to 1.31] and 0.92 [CI, 0.68 to 1.26], respectively), as did unexposed siblings of exposed offspring (3.2%; exposed vs. unexposed OR, 1.54 [CI, 0.94 to 2.53])," the authors pointed out. "Among metformin-exposed offspring, genital birth defects, all in boys, were more common (aOR, 3.39 [CI, 1.82 to 6.30]), while the proportion of male offspring was lower (49.4% vs. 51.4%, P = 0.073)."

While information on underlying disease status was limited, researchers suggested that preconception paternal metformin treatment is associated with major birth defects, particularly genital birth defects in boys. They called for further research to replicate these findings and provide more information about causation.

"Babies whose fathers took insulin had no increased risk for a birth defect compared with the general group," the authors advised. "Babies whose fathers took metformin had an increased risk for birth defects. There were too few babies whose fathers took sulfonylureas to determine risks for birth defects with any certainty. Taking metformin before or after sperm development did not increase the risk for birth defects. Unexposed siblings were also not at increased risk."

Background information in the article notes that the findings are especially important because diabetes "increasingly occurs in people of reproductive age, compromises sperm quality, and is associated with impaired male fertility. Some diabetes drugs may also affect male reproductive health."

An accompanying editorial from Germaine M. Buck Louis, PhD, MS, of George Mason University writes that it is critical to corroborate the findings because of the extensive use of metformin, which is used as first-line therapy for type 2 diabetes. She also recommends that clinicians help to guide couples planning pregnancy about the risks and benefits of paternal metformin use compared with other medications.

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