Potential fathers with type 2 diabetes can be reassured that taking the drug metformin is not associated with birth defects in their offspring, concludes a large study of more than 3 million pregnancies published by The BMJ today.
The researchers say the findings show that metformin can continue to be considered a suitable drug for managing blood sugar levels in men with type 2 diabetes who plan on having children.
Metformin is widely used to treat type 2 diabetes in men of reproductive age, but a recent Danish study reported a link between metformin use by fathers-to-be and an increased risk of congenital malformations, particularly genital, in male infants.
However, questions about the biological plausibility and causality between paternal metformin use and risk of congenital malformations in offspring remain unresolved.
To provide further guidance on this issue, researchers set out to evaluate the association between paternal metformin use and risk of congenital malformations in offspring from Norway and Taiwan.
Using national birth registries and prescription databases, they identified 619,389 offspring with paternal data during the period of sperm development (three months before pregnancy) in Norway during 2010-21 and 2,563,812 in Taiwan during 2004-18.
Among these, fathers of 2,075 (0.3%) offspring in Norway and 15,276 (0.6%) offspring in Taiwan used metformin during the sperm development period.
In Norway, congenital malformations were found in 24,041 (3.9%) offspring of fathers who did not use metformin during the period of sperm development, compared with 104 (5%) offspring of fathers who used metformin.
Similarly, in Taiwan, congenital malformations were found in 79,278 (3.1%) offspring of fathers who did not use metformin, compared with 512 (3.4%) offspring of fathers who used metformin.
But after restricting analyses to fathers with type 2 diabetes, and adjusting for other important factors, such as father's age and related conditions, no increased risk of any congenital malformations among infants born to fathers who used metformin during the sperm development period was found in either Norway or Taiwan.
And no notable increases in risk were found for any specific organ malformations, including genital malformations.
These are observational findings, so can't establish cause, and the authors acknowledge that diagnostic data may not be completely accurate and there may have been misclassification of drug use. Nor can they rule out the possibility that other unmeasured factors may have affected their results.
However, findings were consistent after further analyses accounting for genetic and family factors, suggesting that they withstand scrutiny.
As such, they conclude: "These results provide reassurance and can assist clinicians in making informed treatment decisions when selecting metformin in the treatment of type 2 diabetes mellitus among men who are planning a family."
In a linked editorial, researchers in Australia say differences in the quality of the data available and the analyses conducted may help explain the inconsistent findings of this and the Danish study.
The lack of a known biological mechanism also adds to the case against a link between paternal metformin use and fetal malformations.
"For some, these findings may not completely lay to rest concerns raised by the Danish analyses, and further confirmatory studies are worthwhile," they write. "At the very least, however, these findings provide some reassurance for clinicians, and for fathers-to-be prescribed metformin preconception."
Meng, L.-C., et al. (2024) Paternal metformin use and risk of congenital malformations in offspring in Norway and Taiwan: population based, cross national cohort study. BMJ. doi.org/10.1136/bmj-2024-080127.
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