researchers have found.
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 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 (Calif.) University, who is a coauthor of the study, said in an interview. “However, if it is confirmed in other populations, then it may begin to enter counseling discussions.”
Dr. 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, Dr. Eisenberg and 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 7,029 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 = 1,451), 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 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 reported.
In an editorial accompanying the journal article, Germaine Buck Louis, PhD, a reproductive and perinatal epidemiologist, wrote: “Given the prevalence of metformin use as first-line therapy for type 2 diabetes, corroboration of these findings is urgently needed.”
Dr. Louis, dean of the College of Health and Human Services at George Mason University, Washington, 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, “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.
A version of this article first appeared on Medscape.com.