Is Prenatal Exposure to High-Dose Folic Acid Associated with Risk of Cancer in Children Born to Mothers with Epilepsy?
Women with epilepsy are recommended high doses of folic acid before and during pregnancy owing to risk of congenital anomalies associated with antiseizure medications. Folate is an important vitamin for synthesis and repair of nucleic acids, and supplementation during pregnancy to women in general (0.4-0.8 mg of folic acid daily) has been shown to reduce the risk of neural tube defects in the child. However, concern has been raised about a possible cancer risk with folic acid supplementation, possibly through altered DNA methylation. Recent research suggests that high levels of folate may promote progression of neoplastic lesions and induce oxidative stress. Folate deficiency could impair synthesis and repair of DNA and hence increase the risk of cancer. 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.
Anti-seizure medication (ASMs) use by mothers with epilepsy can be an indication for high-dose folic acid supplementation in pregnancy. It is essential to consider the role of ASMs and the potential association between childhood cancer and high-dose folic acid.
Researchers from Norway, Denmark and Sweden conducted an observational cohort study of more than 3 million pregnancies using nationwide register data from the 3 Nordic countries to examine maternal prescription fill for high-dose folic acid (≥1 mg daily) during pregnancy and risk of cancer in the child, considering the potential role of maternal ASM use.
They identified a 2.7-fold increased risk of cancer in children of mothers with epilepsy who immediately before or during pregnancy filled a prescription for high-dose folic acid (≥1 mg daily) compared with children of mothers with epilepsy who did not fill such a prescription. Maternal epilepsy was not associated with an increased risk of cancer among the study children. 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 did not find any increased risk of cancer in exposed children of mothers without epilepsy. In mothers who filled prescriptions for high-dose folic acid, the mean calculated daily dose after pregnancy start and until birth was higher among those with epilepsy (4.3 mg) than without it (2.9 mg). The mean calculated ASM doses were higher among mothers with epilepsy with a filled prescription for high-dose folic acid compared with those with epilepsy with no prescription, which may imply that an increasing dose of ASM plays a role in carcinogenesis among children born to mothers with epilepsy, possibly through an interaction between ASM and folic acid in high doses.
The authors suggest that 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. Because of the combined use of ASM and folic acid in high doses in mothers with epilepsy, future studies should investigate possible etiologic mechanisms between folic acid and ASM exposure in pregnancy and the risk of cancer.
Reference:
Håkon Magne Vegrim; Julie Werenberg Dreier, Silje Alvestad, et al JAMA Neurol. 2022;79(11):1-10.doi:10.1001/jamaneurol.2022.2977
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