High-Dose Folic Acid During Pregnancy May Increase Cancer Risk for Children, When Mother Also Takes Epilepsy Drugs

High doses of folic acid are often used to prevent birth defects for women taking epilepsy drugs like Depakote and Topamax

While most doctors recommend that women take folic acid supplements during pregnancy to reduce the risk of congenital birth defects, the findings of a new study suggests the practice may be increasing the risk of cancer for children born to women who have epilepsy.

In a report published last week in the medical journal JAMA Neurology, Norwegian researchers warn that children born to women who use epilepsy drugs like Topamax and Depakote are more likely to develop cancer if high doses of folic acid were also taken during pregnancy.

Folic Acid and Anti-seizure Medications Cancer Risks

The cohort study involved data on more than 3.3 million children from national registries in Denmark, Norway, and Sweden from 1997 to 2017. The researchers used birth, patient, prescription, and cancer registries, as well as the Nordic Register-Based Study of Antiepileptic Drugs in Pregnancy collaboration project, to compare outcomes for children born from mothers both with and without epilepsy, differentiating those not taking folic acid and those receiving taking high-doses.

The use of folic acid among those with epilepsy was linked with an increased risk of cancer in their children. The findings indicate children faced triple the risk of cancer if they were born to women who had epilepsy and took a high-dose folate supplement of 4.3 mg. There was no link to cancer seen among women who didn’t have epilepsy, or who had epilepsy but didn’t take folic acid. Across 7 years of follow-up, the absolute risk was 1.5%.

Doctors often recommend that women diagnosed with epilepsy take high doses of folic acid prior to, and during, pregnancy to prevent the risk of congenital anomalies because of the known effects associated with use of anti-seizure medications (ASMs), like Depakote and Topamax. Recommendations vary from 0.4 to 5 mg per day, according to the International League Against Epilepsy Task Force on Women and Pregnancy.

The rate of cancer in children of mothers with epilepsy who took folic acid was 42 per 100,000 person-years, compared to 18 per 100,000 person years in children of mothers with epilepsy who did not take folic acid.

Researchers found no link between specific anti-seizure medications and cancer, just an overall increased risk among women with epilepsy. The possible pathway may be through DNA methylation, oxidative stress, and impairment of the repair of DNA, but more research is needed to determine the exact mechanism of action, the researchers noted.

Folic Acid Risks and Benefits

There has been conflicting prior research about the benefits and risks of folic acid supplements. While most doctors call for folic acid use during pregnancy, some studies have indicated high-doses of folic acid may not be protective against preeclampsia or pregnancy-induced high blood pressure. However, other studies have called for women with epilepsy to take folic acid during pregnancy to reduce the risk of autism associated with anti-epileptic medications.

Researchers in this latest study emphasize the importance of folic acid supplements and early neurodevelopment in pregnant women. Folate helps with normal growth and brain development. They recommend pregnant women continue to take folic acid, but at a lower dose, especially if they have epilepsy.

There was no correlation between low-dose supplementation and cancer risk. Taking the recommended 0.4 mg dose can provide protective benefits while reducing the risk of  cancer in the child, researchers noted. However, pregnant women should have a conversation with their health care provider regarding the risks and benefits of folic acid supplementation and their specific medical history.

“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 researchers concluded. “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.”