Major Birth Defects Linked With Fathers’ Use of Diabetes Drug Metformin

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A large study found that babies born to men who took metformin during sperm development had a higher risk of birth defects, particularly genital defects in boys.

A large cohort study found that babies born to men who took metformin during the period of sperm development were at increased risk for birth defects, specifically genital defects in boys. These finding suggest that men with diabetes who are taking metformin should talk to their doctors about whether they should switch to another treatment when trying to conceive a child. However, because diabetes control also affects sperm quality, discontinuing metformin treatment could also affect birth outcomes. The findings are published in Annals of Internal Medicine.

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.

Researchers from the University of Southern Denmark and Stanford University studied data from nationwide national registries of births, patients, and prescriptions to evaluate whether the risk for birth defects varied among offspring born to men treated with insulin, metformin, or sulfonylureas prior to conception. Babies were considered exposed to a diabetes drug if their father filled at least 1 prescription during the 3 months when the fertilizing sperm were developing.

The researchers compared birth defects in the babies across diabetes drugs, different times of taking the drug relative to development of fertilizing sperm, and with unexposed siblings of the babies. Babies whose fathers took insulin had no increased risk for a birth defect compared with the general group.

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.

According to the authors, the 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 from Germaine M. Buck Louis, PhD, MS at George Mason University emphasizes the importance of corroborating the findings, given the prevalence of metformin use as first-line therapy for type 2 diabetes. The author also calls for guidance from clinicians to help couples planning pregnancy weigh the risks and benefits of paternal metformin use relative to other medications.


“Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring: A Nationwide Cohort Study” by Maarten J. Wensink, MD, PhD, Ying Lu, PhD, Lu Tian, PhD, Gary M. Shaw, DrPH, Silvia Rizzi, PhD, Tina Kold Jensen, PhD, Elisabeth R. Mathiesen, MD, Niels E. Skakkebæk, MD, DMSc, Rune Lindahl-Jacobsen, PhD and Michael L. Eisenberg, MD, 29 March 2022, Annals of Internal Medicine.
DOI: 10.7326/M21-4389

“Paternal Preconception Diabetes Drugs and Birth Defects in Offspring: A Call for More Conclusive Study” by Germaine M. Buck Louis, PhD, MS, 29 March 2022, Annals of Internal Medicine.
DOI: 10.7326/M22-0770

2 Comments on "Major Birth Defects Linked With Fathers’ Use of Diabetes Drug Metformin"

  1. J. A. Gardner | March 29, 2022 at 9:02 am | Reply

    Sad news, yet good in the fact men have a choice of not taking that medicine/chemical prior to starting a family. Thank you for your research. I wish this work would continue for the Soldiers who were coated with Agent Orange/chemical prior to starting their families. Why, when so many 1st and 2nd generation children born to these soldiers suffer so much, yet research seems to stop prior to getting a full answer. That is also sad news

  2. With so many more choices like Jardiance, Ozempic & the like we should all have the choice to choose which is best for us but’s. insist & require Metformin be the 1st drug taken after diagnosis and continued even after other diabetes drugs are added. I hope this research showing the damage for offspring can start companies and doctors talking about using alternative methods first instead of always going to metformin.

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