High-Dose Folic Acid Use Raises Cancer Risk in Children of Mothers With Epilepsy

Among mothers with epilepsy, high-dose folic acid use during pregnancy may increase risk for cancer among their children. These are the findings of an observational cohort study published in JAMA Neurology.

Pregnant women who have epilepsy are often recommended to supplement their diet with high-dose folic acid to reduce the risk for congenital anomalies which can be caused by exposure to antiseizure medications (ASMs). Despite this recommendation, the risks for childhood cancer from high-dose folic acid exposure remain untested.

Researchers of the JAMA Neurology study explained 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.”

The researchers, from the University of Bergen in Norway, sourced data for this study from nationwide registers of babies born in Denmark between 1997 and 2017, Norway between 2005 and 2017, and Sweden between 2006 and 2017. Risk for cancer on the basis of high-dose folic acid use was evaluated among 3,379,171 mother-child pairs, 27,784 of these pairs were mothers with epilepsy. High-dose folic acid was defined as filling a prescription of 1 or 5 mg folic acid between 90 days of the last menstrual period and birth.

A total of 21.4% of children were exposed to high-dose folic acid. The estimated dose was higher among the epileptic cohort than control individuals (mean, 4.3 vs 2.9 mg), respectively.

Among the 27,784 maternal epilepsy pairs, 5934 filled a high-dose folic acid prescription and among the 3,351,387 maternal non-epilepsy pairs, 46,650 filled a high-dose folic acid prescription.

The incidence rate of cancer was as follows:

• 18.4 per 100,000 person-years for babies born to mothers with epilepsy who did not take folic acid
• 18.9 per 100,000 person-years for mothers without epilepsy who did not take folic acid
• 20.0 per 100,000 person-years for mothers without epilepsy who did take folic acid
• 42.5 per 100,000 person-years for mothers with epilepsy who did take folic acid

In the fully adjusted model that accounted for maternal age, education, antiseizure medication exposure, maternal body mass index (BMI), prior births with congenital anomalies, smoking during pregnancy, and the number of hospitalizations, exposure to high-dose folic acid increased risk for childhood cancer among the epileptic cohort (adjusted hazard ratio [aHR], 2.7; 95% CI, 1.2-6.3) but not among the non-epileptic cohort (aHR, 1.1; 95% CI, 0.9-1.4) compared with folic acid non-users.

Stratified by use of ASMs, mothers who used ASMs and high-dose folic acid were associated with increased childhood cancer risk (aHR, 3.0; 95% CI, 1.1-7.9) compared with women who used ASMs but not folic acid.

The major limitation of this study was that filling a prescription was used as a proxy for use which may not be the case.

Overall, the study’s findings showed that among women with epilepsy, use of high-dose folic acid during pregnancy increased risk for cancer in their offspring, especially among women using antiseizure medications.

The researchers concluded that “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.”

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.