Association of folic acid supplementation during pregnancy with the risk of autistic traits in children exposed to antiepileptic drugs In utero

Bjørk M, Riedel B, Spigset O, Veiby G, Kolstad E, Daltveit AK, Gilhus NE. Association of Folic Acid Supplementation During Pregnancy With the Risk of Autistic Traits in Children Exposed to Antiepileptic Drugs In Utero. JAMA Neurol. 2017 Dec 26. doi: 10.1001/jamaneurol.2017.3897. [Epub ahead of print]

Abstract

IMPORTANCE:

Strategies to prevent autism in children exposed to antiepileptic drugs (AEDs) during pregnancy are important.

OBJECTIVE:

To explore whether folic acid supplementation and folate status in pregnancy are associated with reduced risk of autistic traits owing to in utero AED exposure.

DESIGN, SETTING, AND PARTICIPANTS:

The population-based, prospective Norwegian Mother and Child Cohort Study approached Norwegian-speaking women attending routine ultrasonographic examinations from June 1999 through December 31, 2008 (163 844 of 277 702 women refused). No exclusion criteria were applied beyond language. Questionnaires during and after pregnancy, analysis of blood samples, and linkage to the Medical Birth Registry of Norway were performed. Children aged 18 to 36 months of women with available information on use of AEDs and of folic acid supplementation (n = 104 946) were included in the analysis from March 1, 2016, through June 13, 2017.

EXPOSURES:

Maternal folic acid supplementation 4 weeks before to 12 weeks after conception. Plasma folate concentration was analyzed at gestational weeks 17 to 19.

MAIN OUTCOMES AND MEASURES:

Autistic traits were evaluated using the Modified Checklist for Autism in Toddlers and Social Communication Questionnaire. Odds ratios (ORs) for autistic traits in children by maternal use vs nonuse of folic acid supplements were adjusted for maternal health and socioeconomic factors. Folate concentrations and folic acid doses were associated with the degree of autistic traits.

RESULTS:

The overall mean (SD) age of the 104 946 mothers of participating children was 29.8 (4.6) years, with complete information available for analysis in 103 868. Mean (SD) age of women with epilepsy who received AED treatment was 29.4 (4.9); women with epilepsy who did not receive AED treatment, 29.1 (4.9); and without epilepsy, 29.8 (4.6) years. In the 335 children exposed to AEDs, the risk for autistic traits was significantly higher at 18 months of age (adjusted OR [AOR], 5.9; 95% CI, 2.2-15.8) and 36 months of age (AOR, 7.9; 95% CI, 2.5-24.9) when their mothers had not used folic acid supplements compared with children of mothers who had used supplements. Among women without epilepsy, the corresponding risks were lower at 18 months of age (AOR, 1.3; 95% CI, 1.2-1.4) and 36 months of age (AOR, 1.7; 95% CI, 1.5-1.9); among the 389 children of women with untreated epilepsy, the corresponding risks were not significant at 18 months of age (AOR, 1.0; 95% CI, 0.4-3.0) and 36 months of age (AOR, 2.5; 95% CI, 0.4-16.6). Degree of autistic traits was inversely associated with maternal plasma folate concentrations (β = -0.3; P = .03) and folic acid doses (β = -0.5; P < .001). Concentrations of AEDs were not associated with the degree of autistic traits.

CONCLUSIONS AND RELEVANCE:

Risk of autistic traits in children exposed to AEDs in utero may be mitigated by periconceptional folic acid supplementation and folate status. Fertile women using AEDs should take folic acid supplements continuously.

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Women on antiepileptic drugs (AEDs) who take folic acid while pregnant may reduce their risk of having a child with autistic traits, according to a new study from Norway.

The study found that among children exposed to AEDs in utero, the risk of having autistic traits was significantly higher at 18 months and 36 months of age for those whose mothers did not take folic acid before and during early pregnancy compared to children whose mothers took the supplement.

“We saw that women with low levels of plasma folate had children with more autistic traits than those who had high levels of plasma folate during pregnancy,” said study coauthor Marte Bjørk, MD, PhD, a consulting neurologist at Haukeland University Hospital in Norway and a post-doctoral fellow at University of Bergen, who led the study.

The study, published online first on December 26 in JAMA Neurology, recommended that all women of childbearing age on AEDs take folic acid.

“Unplanned pregnancies are common in the epilepsy cohort, and folic acid supplements should be taken continuously by all women taking AEDs if they could become pregnant,” the study concluded.

But whether women act on that advice is another matter, something Dr. Bjørk said she knows well from her experiences with her own patients.

“I usually explain how epileptic drugs could affect folate levels and why it is important to avoid low blood folate,” Dr. Bjørk said. “I also measure folate in all my patients that use antiepileptic drugs...and show them the results to increase compliance.”

She said there are many reasons why patients don't follow through. “Personal economy may be important,” Dr. Bjørk said. “In our data, we saw that women with low household income less often used folic acid supplements. It is also difficult for patients to take several types of medication daily.”

Why children exposed to AEDs have an increased risk of autism during pregnancy is not totally clear, the study authors said. It is known that AEDs, such as lamotrigine, carbamazepine, and phenytoin “interfere with folate absorption and metabolism,” they noted. “Thus, the risk of folate deficiency is higher among women with epilepsy than among healthy women.”

Women in general are advised to take folic acid supplements when contemplating pregnancy to reduce the risk of neural tube defects, and the supplements are also thought to modestly reduce the risk of autism spectrum disorders.

The AAN guidelines, published in 2009 in Neurology, recommend folic acid supplementation for women with epilepsy who are considering pregnancy, both due to the possible influence of AEDs and for the same reasons women in general are advised to do so….

Alison Pack, MD, associate professor of neurology at Columbia University Medical Center, said the new study from Norway builds on other research that suggests a folic acid benefit for women on AEDs.

“This adds to the story as to why these women should be getting folic acid,” she said, “though the optimal dose is still a question and may vary depending on what medication a woman takes.” She believes that at the minimum a dose of 1 mg a day is wise.

She said the study findings also support the need for planning pregnancy, noting that “a high percentage of pregnancies among women with epilepsy are unplanned.” One study published in Neurology in 2017 put the number at 65 percent, she said.

“You clearly want to begin folic acid supplementation before the baby is conceived,” she said, noting that epilepsy specialists and obstetricians and gynecologists should reinforce that approach with their patients beginning well before they think of pregnancy…

Jacqueline A. French, MD, FAAN, professor of neurology at NYU Langone Medical Center and chief scientific officer for the Epilepsy Foundation, said she too puts a strong emphasis on cognitive outcomes when recommending and prescribing folic acid for her epilepsy patients.

“I say ‘This is a vitamin that protects the brains of babies and the babies are smarter,’” she said. But even then, she said patients often don't see the urgency in filling the prescription, and it is typical for two or three office visits to pass until a patient follows through.

Dr. French said “compliance is very linked to a belief that a drug is going to help you.” The benefit of taking an AED (reducing or eliminating seizures) is apparent, but not so with a vitamin, especially if pregnancy is not in a patient's immediate game plan.

“It doesn't seem that important because they think they're the one who isn't going to get pregnant,” she said.

Dr. French said neurologists need to stay on top of whether their patients of child-bearing age take folic acid and not treat the issue as an after-thought.

“You have to make them believe this is going to help them and their baby,” she said.

https://journals.lww.com/neurotodayonline/Fulltext/2018/02080/In_the_Clinic_Prenatal_Epilepsy__Folic_Acid_During.10.aspx