Use of diabetes drug by men not associated with major birth defects

New research disputes that paternal metformin use during preconception causes birth defects, contradicting previous research published in the area.

Previous research published in the Annals of Internal Medicine in 2022 associated paternal metformin use during preconception with major birth defects, particularly genital birth defects in boys. Now, researchers based in the USA have analysed health data from Israel and argued that while there is a higher rate of birth defects among the offspring of men who use metformin, this may in fact be due to diabetes and cardiovascular comorbidities rather than a side-effect of the medication.

'Conventionally and traditionally, the mother has been the focus when it comes to pregnancy and when it comes to fetal health and the health of the newborn. What we are increasingly finding is that the father is also important' said Dr Ran Rotem from the Harvard TH Chan School of Public Health in Boston, Massachusetts and lead author of the study. 'We find that paternal use of metformin in the sperm development period is not associated with excess risk of malformation in newborns, proving assurance that fathers planning to start a family can continue using the drug to control their diabetes,' added Dr Rotem.

Published in the Annals of Internal Medicine, researchers accessed Israeli medical records associated with 383,851 births between 1999 and 2020. They studied information on birth defects, parental comorbid conditions and the use of metformin and other diabetes-related medication during the preconception period. Previous research had hypothesised that metformin use while sperm are being formed in the months leading up to conception leads to birth defects, as animal studies have shown it can affect testicle size and sperm characteristics in other species.

Unadjusted findings showed a 28 percent increased risk of birth defects in children of fathers taking metformin during the preconception period (a prevalence of 6.2 percent, compared to 4.7 percent in children of fathers not exposed to diabetes medications in this period). However, this increased risk did not persist after adjustments for paternal cardiometabolic comorbid conditions and exclusion of children born to mothers with laboratory test results indicative of hyperglycaemia, instead of just those with a diagnosis of diabetes or taking antidiabetic medication, two factors that previous research did not account for.

When investigating specific antidiabetic treatment regimens, researchers found that paternal use of metformin in combination with other antidiabetic medications during preconception was associated with a 36 percent increased risk of newborn birth defects, compared to paternal use of metformin on its own, or no use of metformin. This finding persisted after adjustments, but researchers advise it to be interpreted with caution due to the potential for other confounding factors. For example, patients may use more than one antidiabetic medication due to poor control of blood sugar.

'I would not change the way metformin is prescribed for parents trying to conceive' said Dr Meleen Chuang, clinical associate professor at the Department of Obstetrics and Gynaecology at NYU Grossman School of Medicine in New York, who was not involved in the study. 'I would encourage weight loss, diet, exercise as a part of their preconception care for both parents'.