Folic Acid Linked to Less Autism in Kids of Women With Epilepsy

Pauline Anderson

June 09, 2016

COPENHAGEN — Taking folic acid supplements during pregnancy is important to protect the unborn child, but this advice might be even more important for women with epilepsy taking antiepileptic drugs (AEDs), new research suggests.

A new study shows that children of women with epilepsy who were receiving an AED who also took folic acid supplements during early pregnancy had fewer autistic traits at age 3 years compared with offspring of women who didn't take these supplements in early pregnancy.

"I feel very strongly that women who are fertile, who in theory could have children, and who use antiepileptic drugs should take folic acid supplements, every day, regardless of pregnancy planning," said study author Marte H. Bjørk, MD, PhD, Department of Clinical Medicine, University of Bergen Department of Neurology, and Haukeland University Hospital, Bergen, Norway.

She presented the results here at the Congress of the European Academy of Neurology (EAN) 2016.

Previous research showed that exposure in utero to AEDs increases the risk for autism spectrum disorder in offspring, said Dr Bjørk. In 2014, another study showed that folic acid supplements in women without epilepsy slightly reduced the risk for autism in children.

"This inspired our hypothesis that folic acid supplements and folic status in pregnant women with epilepsy could modulate the risk of autistic traits in their children," said Dr Bjørk.

She and her team used the Norwegian Mother and Child cohort study, a large and prospective population-based study of women who were enrolled at week 18 of their pregnancy.

The study included 328 women with epilepsy who took an AED during pregnancy, 389 women with epilepsy who did not use an AED during pregnancy, and 103,151 women who did not have epilepsy.

Supplement Use

The women reported on their use of folic acid supplements from before pregnancy, weeks 0 to 13 of the pregnancy, and weeks 13 to 30 of the pregnancy.

Most women with epilepsy took folic acid supplements at some point during their pregnancy, but those whose pregnancy wasn't planned did not begin taking this regimen until further along in the pregnancy.

In the epilepsy AED group, significantly (P < .05) more women who didn't take folic acid supplements had an unplanned pregnancy than those who took folic acid (34% vs 21%). More of them also used alcohol (9% vs 2%) and were receiving polytherapy (29% vs 17%).

At week 18 and week 30, investigators took blood samples to analyze for folate metabolites and AED concentrations.

The primary outcome of the study was the presence of "autistic traits" when the child was 36 months old, measured by using the 40-item Social Communication Questionnaire (SCQ) with scores reported by the mothers. Autistic traits were defined as a score above 13 on the SCQ.

In all three groups, there were more children with autistic traits if their mothers did not take folic acid supplements, but the difference between those who did and did not take supplements was much greater among women with epilepsy taking an AED.

For this group, about 25% of children whose mother did not take the supplements showed autistic traits compared with just over 5% for those who didn't take the supplement (P < .001).

In all groups, researchers calculated the odds ratio (OR) of having a child with autistic traits if the mother used supplements compared with if she didn't. They adjusted this ratio for polytherapy, socioeconomic factors, depressive symptoms, "and everything you can think of," said Dr Bjørk.

"The risk reduction if you were a woman taking an AED and using folic acid supplements was much larger than in the other groups. And the confidence intervals do not overlap, so it's a significantly different risk reduction in the group that used AEDs."

The ORs were 0.17 for the epilepsy AED group, 0.43 for the epilepsy without AED group, and 0.58 for the group without epilepsy.

Early Is Critical

Dr Bjørk pointed out that AED users whose children did not have autistic traits started their folic acid supplements early in pregnancy.

"The interesting point is that this difference (in autistic traits among children of women with epilepsy taking and not taking supplements) is only there for the first trimester, so later in pregnancy, there is virtually no difference. The critical period is the first trimester."

And it appears that the earlier the supplements are started the better. Analyzing the median start-up time for supplements, the researchers found that women who had children without autistic traits tended to start the supplements before pregnancy, but those whose children had autistic traits did not start using them until late in the first trimester.

The study also showed that maternal plasma folate concentration levels correlated with the degree of autistic traits. "The lower the folate concentration, the higher the score," meaning more autistic traits, said Dr Bjørk.

This linear relationship was significant, after adjustment for AED concentration, general tonic-clonic seizures, socioeconomic factors, maternal age, parity, depressive symptoms, and alcohol and tobacco use.

"Every confounder we could think of does not really do anything to the results," she said.

Asked whether there was a folic acid dose effect, Dr Bjørk said that the researchers didn't have dosage data. "But what dose should be used is an interesting point. What dose is appropriate? Is it okay for women to use 0.4 mg or should they take larger doses?"

She's involved in another project that will look at outcomes of pregnant women using higher doses of folic acid, as reported in the Norwegian prescription registry.

One delegate here commented that lack of folate supplementation could be a marker for low socioeconomic status. Dr Bjørk agreed but said that it was because low socioeconomic status correlates with not taking folate supplements, which she adjusted for in her study.

Dr Bjørk has disclosed no relevant financial relationships.

Congress of the European Academy of Neurology (EAN) 2016. Abstract T201. Presented May 30, 2016.

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