One study looked at birth genital defects in children of men who take a very common medicine for diabetes

Metformin is one of the first drugs prescribed when a person is diagnosed with type 2 diabetes. It works primarily by decreasing glucose production in the liver and helps the body use insulin more effectively. But a study by researchers from Denmark and the United States prompted a call for attention to the possibility that metformin will impact negatively on the health of the offspring of men who consume it.

The study suggests that this drug (metformin) may increase the risk of birth defects in the offspring of men who take it during sperm development. The children of these men were more than three times more likely to suffer a genital birth defect than unexposed babies, according to the original article, published in the specialized journal Annals of Internal Medicine. He then resumed the research paper and published it in the journal Science.

According to the results of the study, genital defects, such as hypospadias, when the urethra does not leave the tip of the penis, were relatively rare. They occurred in 0.9% of all babies whose biological parents took metformin in the three months prior to conception. But epidemiologists say the results are important because tens of millions of people around the world take metformin.

In the Americas, up to 40% of people with diabetes are undiagnosed, according to the Pan American Health Organization. Among people who have been diagnosed, up to 70% of cases are not well controlled. In Mexico, 14% of the population has type 2 diabetes and 33.5% have prediabetes, according to a study conducted in 2020 by the Mexican Ministry of Health with researchers from the University of California in San Francisco.

In Peru, according to the PERUDIAB study conducted from 2012 to 2015 by the Faculty of Health Sciences, Peruvian University of Applied Sciences with researchers from the United Kingdom, in 1,677 households nationwide, 7% of people had diabetes and 22.4% had prediabetes, and among the complications of this disease were diabetic retinopathy, diabetic nephropathy and diabetic neuropathy.

Consulted by Infobae, Guillermo Dieuzeide, medical specialist and member of the Argentine Diabetes Society and one of the researchers of the CAPTURE study that evaluated patients with diabetes and cardiovascular risk, said of the new work on metformin: “This is a serious study, and it is published in a magazine that is also published. It has long been suggested that mothers exposed to metformin during pregnancy have a higher risk of premature birth. However, it should be borne in mind that metformin is a great drug for the treatment of diabetes. It is also very cheap and accessible in all countries. Therefore, there is a strong commercial interest in banishing it from the first place in the treatment of diabetes.”

According to Dr. Dieuzeide, “we must handle information wisely and wait for further epidemiological studies. Obviously, experimental models will have to be developed to corroborate this finding.”

Germaine Buck Louis, reproductive epidemiologist at George Mason University in the United States, wrote an editorial accompanying the study: “When I saw the article I thought, 'Yes, this is going to go viral. ' [Metformin] is widely used even by young men because of the problem of obesity that we have. So that's potentially a huge source of exposure for the next generation.”

However, scientists warned men with diabetes not to stop taking metformin before trying to conceive. “Metformin is a safe, cheap drug, and does what it has to do” when controlling blood sugar levels, said the article's first author, Maarten Wensink, an epidemiologist and biostatistician at the University of Southern Denmark. Any change in medication “is a complex decision that [the couple] must make together with their doctors,” he acknowledged.

The use of metformin, a synthetic compound that lowers blood sugar by increasing insulin sensitivity, has skyrocketed with the obesity epidemic and the associated diagnoses of type 2 diabetes. In the United States, in 2004, 41 million prescriptions of this drug were prescribed; in 2019, the figure was 86 million, according to the journal Science.

The drug has been used since the 1950s, but this is the first large-scale study to rigorously analyze any father-mediated impact on birth defects in humans. Although the use of metformin is inclined towards older people, the increase in diabetes means that more men of reproductive age are taking the drug. In the United States, prescriptions for people aged 18 to 49 with type 2 diabetes went from less than 2,200 in 2000 to 768,000 in 2015.

Researchers analyzed the records of more than 1.1 million babies born in Denmark between 1997 and 2016, using the country's comprehensive medical records to connect data on births, parental metformin prescriptions and birth defects.

In the 1,451 children of men who filled prescriptions for metformin during the 90 days prior to conception, the period when sperm are manufactured, the team found a rate of 5.2% of birth defects, compared to 3.3% among unexposed babies. This resulted in a 1.4 times greater likelihood of suffering at least one major birth defect, including genitals, digestive, urinary, and cardiac defects, after adjusting parental age and other factors.

Only in the case of genital defects, the increased risk - only observed in male infants - was much greater. Among exposed infants, 0.9% had genital defects, compared with 0.24% of unexposed babies.

The figures were small: 13 children exposed to metformin were born with genital defects. But after researchers adjusted factors such as parents' age and mother's smoking habit, they found a 3.39-fold increase in the chances of suffering a genital defect. “The rate per se was surprisingly high,” Wensink said.

The researchers did not observe any effect on the offspring of men who took the drug before or in the year before or after the 90-day window of sperm production. “It really has to do with taking it in that window when sperm is developing,” said lead author Michael Eisenberg, urologist at Stanford Medicine.

The team also found no additional risk in unexposed siblings of babies exposed to metformin, nor in babies of diabetic parents who were taking insulin or not taking metformin. All these results suggest that it is responsible for the impact of the drug on the formation of sperm, and not diabetes or other intrinsic factor of men.

But researchers acknowledge that men with diabetes who took metformin and those who did not may have differed in attributes such as obesity or how well their disease was controlled, data that researchers did not have access to.

Scientists are also not sure how the drug can affect sperm. Studies in fish and mice suggest that metformin may alter the development of male reproductive organs, and a small study found that metformin reduced serum testosterone levels in men.

The warnings cause scientists to be cautious when drawing conclusions from the document. “This document is the first word, not the last word,” says Russell Kirby, an epidemiologist of birth defects at the University of South Florida. “It's definitely going to require additional research.”

Dr. Sergio Pasqualini, fertility specialist at Halitus Medical Institute, also agreed with this opinion. The expert told Infobae: “This work only reinforces the idea that further research is needed. It's preliminary. Each case of a baby born with the congenital defect could be analyzed. Today more and more young people have diabetes and take metformin. Therefore, the results of the study in Denmark and the United States should not imply that patients are afraid of the drug.”

In Latin America, the use of the drug metformin is not as high as in developed countries. In the study conducted by the Mexican Ministry of Health in 2020, it was noted that high rates of food insecurity and the limited incomes of poor populations make it difficult for many people to consume more healthy food and drinks. In addition, there are barriers to physical activity. The authors noted that “in the absence of significant change in social, economic and environmental policy, strategies to prevent type 2 diabetes that do not depend on lifestyle changes, such as metformin therapy, will be critical to prevention efforts.”

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