Prenatal exposure to high-dose folic acid raised the risk of cancer in children of mothers with epilepsy, Scandinavian registry data showed.
Over 7 years of follow-up, the absolute risk of pediatric cancer was 1.5% (95% CI 0.5-3.5) in children of mothers with epilepsy who filled prescriptions for high-dose folic acid -- defined as 1 mg daily or more -- compared with an absolute risk of 0.6% (95% CI 0.3-1.1) for children of mothers with epilepsy unexposed to high-dose folic acid, reported Håkon Magne Vegrim, MD, of Haukeland University Hospital in Bergen, Norway, and co-authors.
The adjusted hazard ratio for cancer was 2.7 (95% CI 1.2-6.3), the researchers reported in JAMA Neurology. Prenatal exposure to high-dose folic acid was not associated with increased cancer risk in children born to mothers without epilepsy.
"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," Vegrim and colleagues wrote.
"Because of the combined use of antiseizure medications and folic acid in high doses in mothers with epilepsy, future studies should investigate possible etiologic mechanisms between folic acid and antiseizure medication exposure in pregnancy and the risk of cancer," they added.
Women with epilepsy are recommended to take folic acid before and during pregnancy due to risks of congenital anomalies associated with antiseizure medications. Recommendations vary from 0.4 to 4-5 mg/day, according to the International League Against Epilepsy Task Force on Women and Pregnancy.
In general, folic acid supplementation during pregnancy has been shown to reduce the risk of neural tube defects in children. But whether there's a link between folic acid supplementation and childhood cancer is unclear, Vegrim and co-authors noted.
"Data on the association between prenatal exposure to folic acid and childhood cancer derive from studies of folic acid dose levels commonly used by mothers in the general population, but little is known regarding prenatal exposure to higher doses," they wrote. "Because antiseizure medication use can be an indication for high-dose folic acid supplementation in pregnancy, it is essential to consider their role in the potential association between childhood cancer and high-dose folic acid."
The researchers culled data from nationwide registries in Denmark, Norway, and Sweden from 1997 to 2017, evaluating maternal prescriptions for high-dose folic acid between 90 days before the start of pregnancy and birth.
Median age of children at the end of follow-up was 7.3 years. Of 27,784 children born to mothers with epilepsy, 5,934 (21.4%) were exposed to high-dose folic acid at a mean daily dose of 4.3 mg.
Among children of mothers without epilepsy, 46,646 (1.4%) were exposed to high-dose folic acid at a mean daily dose of 2.9 mg. In this group, the adjusted hazard ratio for pediatric cancer was 1.1 (95% CI 0.9-1.4) and the absolute risk was 0.4% (95% CI 0.3-0.5).
The incidence rate of cancer in children of mothers with epilepsy who filled prescriptions for high-dose folic acid was 42.5 (95% CI 26.8-67.5) per 100,000 person-years, compared with 18.4 (95% CI 12.8-26.5) per 100,000 person-years in children of mothers with epilepsy who did not fill folic acid prescriptions.
No association emerged between any specific antiseizure drug and childhood cancer. "Removing mothers with any prescription fills for carbamazepine and valproate was not associated with the point estimate," the researchers wrote. "Hence, these two antiseizure medications were not important effect modifiers for the cancer association."
"The most frequent childhood cancer types in children among mothers with epilepsy who filled prescriptions for high-dose folic acid did not differ from the distribution in the general population," they added.
The study had several limitations, Vegrim and co-authors acknowledged. Exposure information was based on filled prescription data. Serum folic acid levels were not assessed and other folic acid intake, including over-the-counter supplements, may have influenced results.
Disclosures
The study was supported by the NordForsk Nordic Program on Health and Welfare.
Vegrim had no disclosures. Co-authors reported relationships with UCB, Ra Pharma, Roche, Alexion, Argenx, Merck, Immunovant, Innovative Medicines Initiative, Sanofi, Novartis, NordForsk, AbbVie, Jazz, Angelini Pharma, Eisai, GSK, Bial, Teva, Sun Pharma, Arvelle, GW Pharma, and Lundbeck.
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