Folic Acid in Pregnant Women on AEDs and Lower Autism Risk

Folic acid supplementation, used before and during pregnancy, may mitigate the risk for autism in offspring of women treated with antiepileptic drugs (AEDs), new research shows.

Norwegian investigators studied the risk for autistic traits in the offspring of close to 105,000 mothers with epilepsy and found those who used an AED during pregnancy had a 5 to 8 times increased risk of having a child with autistic traits if they did not use folic acid during the periconceptional period.

One third of children whose mothers did not use folic acid supplementation during the periconceptional period had autistic traits at 18 and 36 months of age. Higher maternal plasma concentrations of folate during gestational weeks 17 to 19 were associated with fewer autistic traits at 36 months.

"Children of women that used antiepileptic drugs but also took folic acid supplements before pregnancy or in the first trimester had a much reduced risk of autistic traits, compared to children of women that did not use such supplements," lead investigator, Marte Bjørk, MD, PhD, consultant neurologist and postdoctoral fellow, Department of Clinical Medicine, Haukeland University Hospital, Bergen, Norway, told Medscape Medical News.

Women who are taking AEDs and could get pregnant should take low-dose folic acid supplements or, alternatively, blood folate status should be checked regularly, she advised.

The study was published online December 26 in JAMA Neurology.

"Surprising Magnitude"

Children exposed to AEDs during pregnancy have an increased risk for autistic traits, likely due to "embryotoxic mechanisms and gene-environmental interactions," the authors write.

"In utero exposure to AEDs has been associated with autistic traits and autism spectrum disorders and AEDs interfere with folate metabolism, so women with epilepsy run an increased risk of low folate in pregnancy," Dr Bjørk said.

Adequate folic acid intake slightly reduces the risk for autistic spectrum disorders in the general population, but no previous research has investigated whether the reduced risk for autism in women who use periconceptional folic acid supplementation also applies to women using AEDs, she observed.

"We therefore thought to investigate if maternal folate status and folic acid supplement use could mitigate the risk of autistic traits in children exposed to AEDs in pregnancy."

To explore the question, the researchers studied women (n = 104,946; mean age, 29.8 [standard deviation, 4.6] years) participating in the Norwegian Mother and Child Cohort Study.

Questionnaires were sent to the mothers at gestational weeks 17 to 19 (Q1) and week 30 (Q2) and at child ages of 18 and 36 months (Q3 and Q4, respectively).

The study included children of women with epilepsy who used AEDs during pregnancy (n = 335), children of women with epilepsy and no AED use (n = 389), and children of mothers without epilepsy, who served as a reference group (n = 104,222).

AED monotherapy included lamotrigine, carbamazepine, valproate sodium, levetiracetam, topiramate, oxcarbazepine, clonazepam, phenytoin or phenytoin sodium, phenobarbital, gabapentin, primidone, and clobazam. Valproate was included in 19 polytherapy combinations.

"Periconceptional" intake was defined as "use of a folic acid supplement from 4 weeks before to 12 weeks after conception."

Of the 139 mothers with epilepsy taking AEDs, 84 (60.4%) reported taking high-dose folic acid (>0.4 mg/d).

Maternal blood samples were obtained and analyzed during gestational weeks 17 to 19 and from the umbilical cord immediately after delivery in women with epilepsy using AEDs for the biologically active 5-methyltetrahydrofolate (mTHF), degradation products 4-α-hydroxy-mTHF, p-aminobenzoylglutamate, p-acetamidobenzoylglutamate, and unmetabolized folic acid. The samples were also analyzed for AED concentrations.

Autistic traits in the children were measured by using the Modified Checklist for Autism in Toddlers and the Social Communication Questionnaire (SCQ) at 18 and 36 months of age, respectively.

Covariates included in the logistic regression analysis were maternal age, parental socioeconomic status, low household income, parity, smoking, alcohol use, maternal depressive symptoms, and AED polytherapy.

The researchers found that the adjusted odds ratio (AOR) for autistic traits among children aged 18 months whose mothers used AEDs without folic acid supplements was 5.9 (95% confidence interval [CI], 2.2 - 15.8) compared with those whose mothers used supplements. In children aged 36 months, the corresponding AOR was 7.9 (95% CI, 2.5 - 24.9).

The corresponding AORs in children of women without epilepsy at 18 and 36 months of age were 1.3 (95% CI, 1.2 - 1.4) and 1.7 (95% CI, 1.5 - 1.9), respectively.

There was no significant risk for autistic traits at 18 and 36 months of age in children of mothers with untreated epilepsy not taking folic acid supplements compared with children of mothers who took supplements.

There was an inverse association in AED-exposed children between mean SCQ score and maternal plasma folate concentration during gestational weeks 17 to 19. The quartile with the lowest folate concentrations had a higher SCQ score than the quartile with the highest folate concentrations, with higher scores signifying more autistic traits.

Ad hoc analyses adjusted for confounding factors likewise showed an inverse linear association between mean SCQ score and folic acid supplement dose at all times during pregnancy, but the association was most pronounced for first trimester folic acid supplementation (β = −0.45; P < .001).

Median time for starting supplementation was gestational week 6.5 for mothers of children with autistic traits at 18 months of age and week 12.5 for those with autistic traits at 36 months.

In contrast, mothers of children without autistic traits more frequently started folic acid supplementation before pregnancy than did mothers of children with autistic traits at 18 and 36 months (median, 6.5 weeks [P = .007] and 12.5 weeks [P = .01], respectively).

The association between periconceptional folic acid supplement use and risk for autistic traits in AED-exposed children appeared to exist across all AEDs.

A post hoc analysis found a "highly significant" interaction of AEDs with folic acid supplement intake and the number of autistic traits (B = −3.1; standard error = 1.1; β = −0.42; P = .004).

Dr Bjørk acknowledged that although the "direction of the findings" was expected, she was "surprised by the magnitude of the effect."

"Our results persisted even after adjustment for relevant confounding factors," she added.

"Unsolved Mystery"

Commenting on the findings for Medscape Medical News, Darrell Wiens, PhD, professor of biology, University of Northern Iowa, Cedar Falls, who was not involved in the study, called it "an important contribution because there has been very little study of the issue of AEDs during pregnancy and whether or not folic acid can offer some protection."

He noted that the large sample size, long-term nature of the study, testing for autism at two different ages, matching maternal age, and controlling for other covariates were "strengths of the study."

However, he said, it was unclear whether the supplementation was folic acid alone or a component of a multivitamin supplement.

"This would make a difference, in that multivitamin supplements would ensure intake of many vitamins, making the correlations actually complete nutrition vs incomplete nutrition."

Additionally, the different AEDs "might probably have different mechanisms of action, yet they were all included in the analysis as one category for most of the analyses."

Although the supplementary data provided a more detailed breakdown, "the authors concluded simply that the association between autism characteristics and AEDs was present for all."

His own research has shown folic acid to be a risk factor for autism spectrum disorder, and "there is a strong reason for caution against high doses of folic acid for pregnant women, especially perinatally and going throughout pregnancy," he warned.

In an accompanying editorial, Kimford J. Meador, MD, professor of neurology and neurosciences, Stanford University, and clinical director, Stanford Comprehensive Epilepsy Center, in California, advised that "women of childbearing potential," especially those taking AEDs, should "take folate supplements continuously."

However, it is unclear what dose should be used "because some studies in the general population suggest adverse risk due to high-dose folate," he noted, adding that the safest and most effective doses "may differ between women in the general population and women taking AEDs."

Dr Bjørk agreed that appropriate dosing requires further investigation. "Although we saw an effect of high-dose folic acid supplements, the correct dose for the various types of AEDs is still an unsolved question that should be targeted in future research."

This study was supported by the Norwegian Epilepsy Association. The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, National Institutes of Health, National Institute of Environmental Health Science, National Institute of Neurological Disorders and Stroke, and the Norwegian Research Council/Functional Genomics. Dr Bj ø rk reports receiving speaker's and consultant's honoraria from Novartis. No other author disclosures were reported. Dr Wiens has disclosed no relevant financial relationships. Dr Meador reports receiving research support from the National Institutes of Health and Sunovion Pharmaceuticals and compensation to Stanford University from the Epilepsy Study Consortium for his research consultant time related to Eisai, GW Pharmaceuticals, Neuro-Pace, Novartis, Supernus, Upsher-Smith Laboratories, UCB Pharma, and Vivus Pharmaceuticals.

JAMA Neurol. Published online December 26, 2017. Abstract, Editorial

For more Medscape Neurology news, join us on Facebook and Twitter

Comments

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.