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Prenatal exposure to high-dose folic acid is associated with a greater than twofold increased risk for cancer in children of mothers with epilepsy, new data from a Scandinavian registry of more than 3 million pregnancies suggests.

The increased risk for cancer did not change after considering other factors that could explain the risk, pill identifier oxcarbazepine such as use of antiseizure medication (ASM).

There was no increased risk for cancer in children of mothers without epilepsy who used high-dose folic acid.

The results of this study “should be considered when the risks and benefits of folic acid supplements for women with epilepsy are discussed and before decisions about optimal dose recommendations are made,” the authors write.

“Although we believe that the association between prescription fills for high-dose folic acid and cancer in children born to mothers with epilepsy is robust, it is important to underline that these are the findings of one study only,” first author Håkon Magne Vegrim, MD, with University of Bergen in Norway, told Medscape Medical News.

The study was published online September 26 in JAMA Neurology.

Risks and Benefits

Women with epilepsy are advised to take high doses of folic acid before and during pregnancy owing to the risk for congenital malformations associated with ASM. Whether high-dose folic acid is associated with increases in the risk for childhood cancer is unknown.

To investigate, the researchers analyzed registry data from Denmark, Norway, and Sweden for 3.3 million children followed to a median age of 7.3 years.

Among the 27,784 children born to mothers with epilepsy, 5934 (21.4%) were exposed to high-dose folic acid (mean dose, 4.3 mg), with 18 exposed cancer cases compared with 29 unexposed cancer — yielding an adjusted hazard ratio (aHR) of 2.7 (95% CI, 1.2 – 6.3).

The absolute risk with exposure was 1.5% (95% CI, 0.5% – 3.5%) in children of mothers with epilepsy compared with 0.6% (95% CI, 0.3% – 1.1%) in children of mothers with epilepsy who were not exposed high-dose folic acid.

Prenatal exposure to high-dose folic acid was not associated with an increased risk for cancer in children of mothers without epilepsy.

In children of mothers without epilepsy, 46,646 (1.4%) were exposed to high-dose folic acid (mean dose, 2.9 mg), with 69 exposed and 4927 unexposed cancer cases – with an aHR of 1.1 (95% CI, 0.9% to 1.4) and absolute risk for 0.4% (95% CI, 0.3% to 0.5%).

There was no association between any specific ASM and childhood cancer.

“Removing mothers with any prescription fills for carbamazepine and valproate was not associated with the point estimate. Hence, these two ASMs were not important effect modifiers for the cancer association,” the investigators note in their study.

They also note that the most common childhood cancer types in children among mothers with epilepsy who took high-dose folic acid did not differ from the distribution in the general population.

“We need to get more knowledge about the potential mechanisms behind high-dose folic acid and childhood cancer, and it is important to identify the optimal dose to balance risks and benefits — and whether folic acid supplementation should be more individualized, based on factors like the serum level of folate and what type of antiseizure medication that is being used,” said Vegrim.

Practice Changing?

Weighing in on the study for Medscape Medical News, Elizabeth E. Gerard, MD, director of the Women with Epilepsy Program and associate professor of neurology at Northwestern University in Chicago, said, “There are known benefits of folic acid supplementation during pregnancy including a decreased risk of neural tube defects in the general population and improved neurodevelopmental outcomes in children born to mothers with and without epilepsy.”

“However, despite some expert guidelines recommending high-dose folic acid supplementation, there is a lack of certainty surrounding the ‘just right’ dose for patients with epilepsy who may become pregnant,” said Gerard, who wasn’t involved in the study.

Gerard, a member of the American Epilepsy Society, noted that other epidemiologic studies of folic acid supplementation and cancer have had “contradictory results, thus further research on this association will be needed. Additionally, differences in maternal/fetal folate metabolism and blood levels may be an important factor to study in the future.

“That said, this study definitely should cause us to pause and re-evaluate the common practice of high-dose folic acid supplementation for patients with epilepsy who are considering pregnancy,” said Gerard.

The study was supported by the NordForsk Nordic Program on Health and Welfare. Vegrim and Gerard report no relevant financial relationships.

JAMA Neurol. Published online September 26, 2022. Full text

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