Metformin Use in Fathers Linked to Higher Risk for Birth Defects

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Metformin Use in Fathers Linked to Higher Risk for Birth Defects

For men with diabetes who may have children, taking metformin may increase the risk for major birth defects, according to a new study published in the journal Annals of Internal Medicine — although experts emphasize that these results are preliminary and shouldn’t be a cause for alarm.

Metformin is the first-line drug treatment for type 2 diabetes, and its overall safety and effectiveness profile is impressive. In addition to lowering blood glucose levels, metformin is linked to modest weight loss, and taking the drug may help people keep off weight that they previously lost. Taking metformin is also linked to a lower risk for neurodegenerative diseases like Alzheimer’s disease or Parkinson’s disease, as well as less cognitive decline linked to vascular dementia. It may also help improve cardiovascular function in people with chronic kidney disease. But metformin also carries some well-known risks, including raising the risk for more severe neuropathy pain and a higher risk for vitamin B12 deficiency.

For the latest study, researchers were interested in whether metformin had any effect on the rate of birth defects when taking by fathers at the time of fertilization. Since diabetes itself is known to reduce semen quality, this analysis was designed to compare different diabetes treatments, rather than comparing men who take metformin with men who don’t have diabetes. The study participants included men in Denmark who participated in a nationwide prospective study between 1997 and 2016, and who fathered a total of over 1.1 million children during the study period. None of the mothers in this study had diabetes, while some of the fathers did.

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Metformin at time of fertilization linked to increased risk of major birth defects

Out of 1,116,779 children born over the course of the study, 3.3% had one or more major birth defects. Compared with this overall rate of birth defects — and after adjusting for factors known to affect the risk for birth defects, including having diabetes — children born to men who took insulin (but not metformin) were 0.98 times as likely to have a birth defect — essentially no more or less likely. But children born to men who took metformin at the time of fertilization were 1.4 times as likely to have a major birth defect.

The researchers made several comparisons that, taken together, indicate that metformin exposure at the time of fertilization was indeed responsible for this increased risk for birth defects. For example, children of men who filled a prescription for metformin in the year before (but not the year of) fertilization were only 0.88 times as likely to have a birth defect, and children of men who filled a prescription for metformin in the year after (but not the year of) fertilization were 0.92 times as likely to have a birth defect — indicating that taking metformin at any other time isn’t linked to a higher birth defect risk. Similarly, siblings of children born to fathers who took metformin at the time of fertilization — whose fathers had stopped taking metformin or hadn’t started taking it when they were fertilized — had a 3.2% rate of birth defects, almost exactly the same as the general rate seen in the study. Compared with these children from sperm that wasn’t exposed to metformin, their siblings from metformin-exposed sperm were 1.54 times as likely to have a birth defect.

What’s more, the risk for genital birth defects — as opposed to birth defects in general — was even higher in male children whose fathers took metformin at the time of fertilization. These boys were an astonishing 3.39 times as likely to have a genital birth defect — such as hypospadias, in which the urethra exits the penis at a location other than the tip, as noted in an article on the study at Science. Like many other birth defects, hypospadias typically require surgical correction.

The researchers cautioned that while these results are definitely concerning, further research is needed to replicate these findings and to confirm that metformin is, in fact, responsible for the higher rate of birth defects seen in children of men who take the drug. (Do not stop taking any of your medications without first speaking with your health care provider about concerns you may have.)

Want to learn more about metformin? Read “What to Know About Metformin,” “Diabetes Medicine: Metformin,” and “Metformin: The Unauthorized Biography.”

Quinn Phillips

Quinn Phillips

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A freelance health writer and editor based in Wisconsin, Phillips has a degree from Harvard University. He is a former Editorial Assistant for Diabetes Self-Management and has years of experience covering diabetes and related health conditions. Phillips writes on a variety of topics, but is especially interested in the intersection of health and public policy.

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