In the Journals

Maternal folic acid intake reduces risk for autistic traits in some children

Women who took an antiepileptic drug while pregnant had a five to eight times increased risk for having a child with autistic traits if they did not use folic acid prior to conception and during early pregnancy, according to findings recently published in JAMA Neurology.

“In the general population, periconceptional folic acid supplements reduce the risk of autism spectrum disorders,” Marte Bjørk, MD, PhD, of the department of neurology at Haukeland University Hospital in Norway, and colleagues wrote. “However, to our knowledge, no previous studies have investigated whether this reduced risk also applies to children of women using [antiepileptic drugs].”

Researchers administered questionnaires and reviewed blood samples from 104,946 women in Norway during and after their pregnancies. Children aged 18 months to 3 years where data on maternal folic acid and antiepileptic drug use was available were also included. The children’s autistic traits were assessed by utilizing the Modified Checklist for Autism in Toddlers and Social Communication Questionnaire.

Bjørk and colleagues found that in the 335 offspring exposed to antiepileptic drugs in utero, the risk for autistic traits was higher at 18 months of age (adjusted OR = 5.9; 95% CI, 2.2-15.8) and 3 years of age (aOR = 7.9; 95% CI, 2.5-24.9) when their mothers did not take folic acid supplements vs. offspring of mothers who had taken such supplements. In addition, among women who did not have epilepsy, the comparable risks were lower at 18 months of age (aOR = 1.3; 95% CI, 1.2-1.4) and 3 years of age (aOR = 1.7; 95% CI, 1.5-1.9). Among the 389 offspring of women with epilepsy who did not take antiepileptic drugs, the comparable risks were not significant at 18 months of age (aOR = 1; 95% CI, 0.4-3) and 3 years of age (aOR = 2.5; 95% CI, 0.4-16.6). Also, the level of autistic traits was inversely tied to maternal plasma folate concentrations ( = 0.3; P = .03) and folic acid doses ( = 0.5; P < .001).

“Our data demonstrate the critical importance of an early start of folic acid supplement intake,” Bjørk and colleagues wrote. “Supplementation timing represents a clinical challenge, because pregnancies may not be recognized until after the period when folate status is critical. In patients with epilepsy, 24% to 79% of pregnancies are unintended. We therefore recommend that folic acid supplements be used continuously by all women taking [antiepileptic drugs] who could become pregnant.”

In a related editorial, Kimford J. Meador, MD, of the department of neurology and neurological sciences at Stanford University, wrote that though Bjørk and colleagues’ efforts resulted in “novel findings with important health care implications,” several queries remain.

“One remaining question is exactly what dose of folate should be used, because some studies in the general population suggest adverse risk due to high-dose folate,” he wrote. “Furthermore, the most effective and safe doses may differ between women in the general population and women taking [antiepileptic drugs].” – by Janel Miller

Disclosure: Bjørk reports receiving speaker and consultant honoraria from Novartis. Meador reports receiving research support from the NIH and Sonovion 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. No other relevant financial disclosures were reported.

 

Women who took an antiepileptic drug while pregnant had a five to eight times increased risk for having a child with autistic traits if they did not use folic acid prior to conception and during early pregnancy, according to findings recently published in JAMA Neurology.

“In the general population, periconceptional folic acid supplements reduce the risk of autism spectrum disorders,” Marte Bjørk, MD, PhD, of the department of neurology at Haukeland University Hospital in Norway, and colleagues wrote. “However, to our knowledge, no previous studies have investigated whether this reduced risk also applies to children of women using [antiepileptic drugs].”

Researchers administered questionnaires and reviewed blood samples from 104,946 women in Norway during and after their pregnancies. Children aged 18 months to 3 years where data on maternal folic acid and antiepileptic drug use was available were also included. The children’s autistic traits were assessed by utilizing the Modified Checklist for Autism in Toddlers and Social Communication Questionnaire.

Bjørk and colleagues found that in the 335 offspring exposed to antiepileptic drugs in utero, the risk for autistic traits was higher at 18 months of age (adjusted OR = 5.9; 95% CI, 2.2-15.8) and 3 years of age (aOR = 7.9; 95% CI, 2.5-24.9) when their mothers did not take folic acid supplements vs. offspring of mothers who had taken such supplements. In addition, among women who did not have epilepsy, the comparable risks were lower at 18 months of age (aOR = 1.3; 95% CI, 1.2-1.4) and 3 years of age (aOR = 1.7; 95% CI, 1.5-1.9). Among the 389 offspring of women with epilepsy who did not take antiepileptic drugs, the comparable risks were not significant at 18 months of age (aOR = 1; 95% CI, 0.4-3) and 3 years of age (aOR = 2.5; 95% CI, 0.4-16.6). Also, the level of autistic traits was inversely tied to maternal plasma folate concentrations ( = 0.3; P = .03) and folic acid doses ( = 0.5; P < .001).

“Our data demonstrate the critical importance of an early start of folic acid supplement intake,” Bjørk and colleagues wrote. “Supplementation timing represents a clinical challenge, because pregnancies may not be recognized until after the period when folate status is critical. In patients with epilepsy, 24% to 79% of pregnancies are unintended. We therefore recommend that folic acid supplements be used continuously by all women taking [antiepileptic drugs] who could become pregnant.”

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In a related editorial, Kimford J. Meador, MD, of the department of neurology and neurological sciences at Stanford University, wrote that though Bjørk and colleagues’ efforts resulted in “novel findings with important health care implications,” several queries remain.

“One remaining question is exactly what dose of folate should be used, because some studies in the general population suggest adverse risk due to high-dose folate,” he wrote. “Furthermore, the most effective and safe doses may differ between women in the general population and women taking [antiepileptic drugs].” – by Janel Miller

Disclosure: Bjørk reports receiving speaker and consultant honoraria from Novartis. Meador reports receiving research support from the NIH and Sonovion 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. No other relevant financial disclosures were reported.