Metformin and valproate safe for dads during conception

3 minute read

No significant risk increase to offspring has been observed in two large studies of paternal medication use.

Some medications often avoided by fathers when trying to conceive may not increase risk to offspring, two long-term studies have found.

Valproate has known teratogenic effects when used by pregnant women, but the effects of paternal use have been uncertain, and advice may be to avoid taking this medication when trying to conceive.

One study included over 1.2 million kids in Denmark, Sweden and Norway between 1999 and 2017, 1300 of whom had fathers who filled prescriptions for valproate in the three months prior to conception.

Results indicated no statistically significant difference in the risk of major congenital malformations (MCMs) (AHR 0.89, 95% CI 0.67-1.18), neurodevelopmental disorders (AHR 1.10, 95% CI 0.88-1.37), and autism spectrum disorder (AHR 0.92, 95% CI 0.65-1.30) in children whose fathers were exposed to valproate preconceptionally.

In the cohort, 3.6% of children (43,903) were diagnosed with MCMs in their first year, 4.2% (51,633) were diagnosed with neurodevelopmental disorders, and 2% (24,540) were diagnosed with autism spectrum disorder.

The results were consistent across different analyses, including dose-response analyses, comparisons with siblings and comparisons with children of fathers who used other antiseizure medications (e.g lamotrigine). The researchers also accounted for time trends and used negative exposure controls. Adjustments were made for child’s sex, birth year, and parental characteristics such as psychiatric disease, epilepsy diagnosis, age, and education level.

Another study showed paternal use of metformin as a monotherapy during spermatogenesis was also not associated with a higher risk of MCMs in offspring.

However, the use of metformin in combination with other antidiabetic medications was associated with a greater prevalence of MCMs. The study indicated that this may be due to the severity of the father’s diabetes, other comorbidities, and worse underlying cardiometabolic conditions rather than the medications themselves.

The study involved nearly 400,000 live births in Israel spanning from 1999 to 2020. Among children born to mothers without diabetes or antidiabetic medication use, 6% (94 out of 1567) whose fathers used metformin developed MCMs, compared to 4.7% (1736 out of 37,047) of children whose fathers were not exposed to metformin preconceptionally.

As a monotherapy, metformin was associated with a nearly 30% increased odds of MCMs in children, but after adjusting for demographic covariates, parental infertility indications and exposure to infertility treatments, the research concluded that paternal metformin use during spermatogenesis does not increase the risk for MCMs in offspring.

The study found that fathers who used diabetes medications were more likely to have fertility problems and a history of smoking. Compared to unexposed offspring, exposed children were more likely to live in lower socioeconomic areas and to have been conceived through assisted reproductive treatments.

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