Metformin in fathers tied to major birth defects

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The rate was 40% higher in these children, and there was a concerning increase in the risk of genital defects in boys.

Dads who take metformin during sperm development are significantly more likely to have children with major birth defects, according to new research.

The Danish study analysed hospital data from over one million children and found a 40% higher incidence of major birth defects in children whose fathers had taken metformin in the three months prior to the child’s conception.

The analysis of two decades of births found more genital birth defects in male children whose fathers took metformin, at a rate of 0.9% compared with a rate of 0.24% in boys who weren’t exposed.

“Approximately 120 offspring per year have fathers filling a metformin prescription during [the sperm development period [translating] to approximately two defects per year,” the authors wrote in the Annals of Internal Medicine.

“This finding may not translate 1-to-1 to other populations, yet the concern is clearly more general in light of the diabetes pandemic. Some of these defects may be lifelong conditions imposing important emotional, social, and economic costs,” the authors said.

The research suggested that prospective fathers needed to have “excellent” diabetic control, said Monash University’s Professor Beverley Vollenhoven, who was not involved in the study.

“We concentrate a lot on women’s diabetic control when they’re trying to get pregnant, because we know that there is an issue with fetal abnormality, increased risk of miscarriage, big babies, and the list goes on. However, like a lot of things, we forget the men,” said the reproductive endocrinologist and infertility specialist.

“Now we know that their diabetic status is just as important.”

The researchers found that major birth defects occurred at a rate of 3.3% in the total study population.

But among children whose father had filled one or more prescriptions for insulin, sulfonylurea or metformin during the development period of the fertilising sperm, the rate of major birth defects was 5.2%.

There was no apparent increase in birth defects if fathers used insulin or sulfonylureas or took metformin outside of the sperm development period, the authors found.

The figures accounted for the child’s year of birth, the father’s age, income and education, and the mother’s age, smoking status and education.

In Australia, metformin is the ninth most commonly prescribed drug and the most frequently used diabetes medication. Meanwhile, new onset diabetes diagnoses are rapidly increasing for young adults internationally.

Study author Dr Maarten Jan Wensink cautioned that any decisions about changing treatments had to be taken individually by patients in consultation with their doctors.

“In general, metformin is effective, cheap, and safe. Those are important factors to consider,” the epidemiologist and biostatistician told The Medical Republic.

“Observational studies also have their limitations, as treatment was not randomised. In the words of a colleague: this is a first-word study, not a last-word study. I agree.

“What I can say is that the best treatment for type 2 diabetes remains lifestyle intervention, and that this could be an extra reason to put more priority on paternal health,” said Dr Wensink.

Professor Vollenhoven said the findings pointed to a need for greater focus on men’s health, particularly metabolic status.

But important metabolic markers were missing from this study, such as the men’s weight class, cholesterol levels and level of diabetes control, she added.

Annals of Internal Medicine 2022, online 29 March

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