Metformin Use Linked to Birth Defects in Boys

Howard Wolinsky

March 28, 2022

The widely used antidiabetic drug metformin may cause genital birth defects such as undescended testicles and urethral problems in the male offspring of men who take the medication, researchers have found.

Dr Michael Eisenberg

The association appears to involve the effects of metformin on the development of sperm during a critical window prior to conception. Female offspring were not affected. Although previous studies have linked diabetes with fertility problems in men, the latest study is the first to show that these problems can result from treatment rather than the disease itself, according to the researchers, whose findings appear in the March 28 issue of Annals of Internal Medicine.

"This is the first data to suggest that paternal metformin [use] may be associated with birth defects in children. As such, it would be early to begin to alter clinical practice," Michael Eisenberg, MD, director of male reproductive medicine and surgery, Department of Urology, Stanford University School of Medicine, Stanford, California, who is a co-author of the study, told Medscape Medical News. "However, if it is confirmed in other populations, then it may begin to enter counseling discussions."

Eisenberg added that eating a nutritious diet, exercising, and maintaining a healthy body weight "can improve a man's health and likely his fertility as well."

For the new study, Eisenberg and his colleagues analyzed records in a registry of all 1.25 million births that occurred in Denmark between 1997 and 2016. The registry included information on birth defects and parental drug prescriptions.

Offspring were considered exposed to a diabetes drug if a father had filled one or more prescriptions for the medications during the 3 months prior to conception, when the fertilizing sperm would have been produced.

The final analysis included 1,116,779 offspring ― all singleton births to women without a history of diabetes or essential hypertension ― of whom 7029 were exposed to diabetes drugs via the father, and 3.3% (n = 36,585) had one or more major birth defects.

Among male offspring whose fathers had taken metformin (n = 1451), there was a 3.4-fold greater incidence of major genitourinary birth defects, according to the researchers. The study failed to find associations between birth defects and the use of insulin. Although a signal did emerge for sulfonylurea-based drugs, it did not reach statistical significance.

The risk associated with metformin did not appear for men who were were prescribed the drug in the year before or after sperm development. Nor was it evident in siblings of the boys with birth defects who were not considered to have been exposed to the medication, the researchers report.

In an editorial accompanying the journal article, Germaine Buck Louis, PhD, a reproductive and perinatal epidemiologist, writes: "Given the prevalence of metformin use as first-line therapy for type 2 diabetes, corroboration of these findings is urgently needed."

Germaine M. Buck Louis, PhD, the dean of the George Mason University College of Health and Human Services, in Washington, DC, said a key limitation of the research is the lack of data on how well men in the study adhered to their diabetes treatment. Nevertheless, she writes, "clinical guidance is needed to help couples planning pregnancy weigh the risks and benefits of paternal metformin use relative to other medications."

The researchers received funding from the National Institutes of Health and the Centers for Disease Control and Prevention.

Ann Intern Med. Published online March 28, 2022. Abstract

Howard Wolinsky is a medical writer in Chicago.

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