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, 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 (Norway) told this news organization.
The study was published online 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, 5,934 (21.4%) were exposed to high-dose folic acid (mean dose, 4.3 mg), with a cancer incidence rate of 42.5 per 100,000 person-years in 18 exposed cancer cases compared with 18.4 per 100,000 person-years in 29 unexposed cancer cases – yielding an adjusted hazard ratio of 2.7 (95% confidence interval, 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). There were 69 exposed and 4,927 unexposed cancer cases and an aHR for cancer of 1.1 (95% CI, 0.9-1.4) and absolute risk for cancer of 0.4% (95% CI, 0.3%-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 Dr. Vegrim.