Can folic acid mitigate autism risk for kids with epileptic mothers?

A new study suggests that mothers who take medications to control their seizures without folic acid supplementation during their pregnancy may be placing their unborn children at risk of later displaying autistic traits.

The large-scale Norwegian study was published in JAMA Neurology in December 2017. Researchers used the Norwegian Mother and Child Cohort Study to assess the effects of both antiepileptic drugs (AEDs) and folic acid supplementation between June 1999 and December 2008. The women’s children were studied at age 18 to 36 months. In the folic acid group, supplementation was given from 4 weeks before to 12 weeks after conception, with plasma folate levels tested at between 17 and 19 weeks’ gestation, according to the report. As for the outcomes in children, autistic traits were assessed using the Modified Checklist for Autism in Toddlers and Social Communication Questionnaire.

The research team found that of the 335 children exposed to AEDs in utero, the risk for autistic traits was significantly higher at 18 and 36 months of age when folic acid supplementation was not used in comparison with the mothers who took AEDs and folic acid supplements. In women with untreated epilepsy, 389 children displayed insignificant risks of autistic traits, the report notes. The study suggests that the degree of autistic traits was inversely associated with the plasma folate concentration of the mother during pregnancy, but that the concentration of AEDs was not specifically associated with any degree of autistic traits.

The results suggest that women who take AEDs to treat epilepsy during pregnancy need to mitigate the dangers of these medications with folic acid supplementation even before conception.

Marte Bjørk, MD, of Haukeland University Hospital, Bergen, Norway, led the study and says considering that there are a high number of unplanned pregnancies in women with epilepsy, clinicians should consider advocating for low-dose daily folic acid supplementation in women of childbearing age who take AEDs.

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Bjørk says overall prevalence of children exposed to AEDs in utero that later displayed autistic traits was between 26% and 32% when folic acid supplementation was not used. That prevalence dropped to 6% to 9% when folic acid supplementation was used.

“It is important to notice that all children with autistic traits not necessarily fulfill the criteria for an autism disorder diagnosis,” Bjørk adds. “However, most of the children without an autism diagnosis will have autistic traits in the frame of a developmental disorder.”

An accompanying commentary by Kimford J. Meador, MD, of Stanford University School of Medicine, Palo Alto, California, agrees with the research team’s assessment of their data, noting that the study had “novel findings with important healthcare implications.” Folic acid supplementation is recommended for all women of childbearing years, she notes, but optimal doses in this particular population have yet to be determined.

Bjørk says the study did examine dosage to a certain extent but was not conclusive.

“We investigated doses from 0.4 mg to 5 mg and found that higher doses were associated with less autistic traits. However, our data was observational. There are no large studies that systematically have investigated the exact folic dose to use in women that use antiepileptic drugs, and clinical guidelines are not consistent,” she says.

At least 0.4 mg daily is generally recommended, with some guidelines going as high as 5 mg for pregnancy. However, Bjørk notes that higher doses of folic acid-5 mg and above-have been associated with other adverse conditions in children.

“I give my female patients on antiepileptic drugs 0.4 mg if there is any chance that they may get pregnant. When they plan pregnancy, I increase the dose to 4 mg and they stay on this dose throughout the first trimester,” Bjørk says. “I then lower the dose to 0.4 mg. I also check their blood levels of folate, methylmalonic acid, and B12 regularly.”

Bjørk says she hopes the study will emphasize the importance of examining folate levels in women with epilepsy.

“It is very sad if children of women on antiepileptic drugs have to live their life with the many challenges of having autistic traits if it could have been prevented with something as harmless and easily accessible as folic acid supplements,” she adds.