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Folic Acid Supplementation & Autism

Folic Acid May Ward Off Autism

By Todd Neale, Senior Staff Writer, MedPage Today, Published: February 12, 2013, Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

Taking folic acid supplements around the time of conception may lower the risk of autistic disorder in the offspring, an observational study showed.

Compared with women not using the supplements, those taking a folic acid supplement from 4 weeks before to 8 weeks after conception were less likely to have a child later diagnosed with autistic disorder (0.1% versus 0.21%; OR 0.61, 95% CI 0.41 to 0.90), according to Pål Surén, MD, MPH, of the Norwegian Institute of Public Health in Oslo, and colleagues.

Similar associations were not observed for Asperger syndrome or pervasive developmental disorder-not otherwise specified (PDD-NOS), the researchers reported in the Feb. 13 issue of the Journal of the American Medical Association.

The study "does not establish a causal relation between folic acid use and autistic disorder but provides a rationale for replicating the analyses in other study samples and further investigating genetic factors and other biological mechanisms that may explain the inverse association," Surén and colleagues wrote.

"The finding that periconceptional supplement use might reduce the risk of autism is encouraging; however, it is important to confirm this finding in other population-based birth cohorts," Robert Berry, MD, MPHTM, of the CDC's Division of Birth Defects and Developmental Disorders in Atlanta, and colleagues wrote in an accompanying editorial.

The fact that folic acid supplementation was not associated with an increased risk of autism spectrum disorders is reassuring, they said, and "this should ensure that folic acid intake can continue to serve as a tool for the prevention of neural tube birth defects."

The effects of maternal folic acid supplementation on outcomes other than neural tube birth defects remain uncertain, although prior studies have identified relationships with lower risks ofsevere language delays and autism spectrum disorders (ASDs).

Surén and colleagues further explored the issue using data from the prospective Norwegian Mother and Child Cohort Study and a substudy called the Autism Birth Cohort study. The analysis included 85,176 singleton children born between 2002 and 2008, with a gestational age of at least 32 weeks and a weight of at least 2,500 grams (5.5 pounds).

The age of the children at follow-up for ASD diagnoses ranged from 3.3 to 10.2 years (mean 6.4 years).

ASD cases were identified based on questionnaires completed by the mothers, professional and parental referrals of children suspected of having an ASD, and information from the Norwegian Patient Registry, which collects diagnoses made in all hospitals and outpatient clinics in the country. The cases were then invited for a clinical assessment.

In Norway, the recommendation is for all women attempting to become pregnant to take a supplement containing 400 µg of folic acid daily from 1 month before conception through the first trimester. At the time of the study, no foods in Norway were fortified with folic acid.

In the current study, 71.7% of women used folic acid around the time of conception, defined as the period 4 weeks before to 8 weeks after the first day of the last menstrual cycle before becoming pregnant.

By the end of follow-up, 270 children (0.32%) had been diagnosed with an ASD -- 114 with autistic disorder, 56 with Asperger syndrome, and 100 with PDD-NOS.

After adjustment for year of birth, parity, and maternal education level, only the risk of autistic disorder was significantly associated with maternal folic acid supplementation. Additional adjustment for maternal illness and medication use did not affect the findings.

"Use of folic acid supplements was associated with higher socioeconomic status and more health-conscious maternal behavior patterns in the study sample," which highlights the possible influence of residual, unmeasured confounding, according to the authors.

"However, if residual confounding was substantial, we would have expected to find a lowering of risk associated with fish oil supplement use as well, because the use of fish oil was associated with the same parental characteristics in the study sample," they wrote. "No such lowering of risk was observed."

The researchers also replicated the findings using an additional nationwide dataset that included 473,095 children (0.17% received a diagnosis of autistic disorder). Despite the underreporting of folic acid use in one of the registries supplying data, there was an inverse association between supplementation and autistic disorder (OR 0.83, 95% CI 0.71 to 0.97).

The study “really reemphasizes the need for good nutrition in women who are of reproductive age and can become pregnant,” Laura Borgelt, PharmD, of the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences in Denver, commented in an interview.

Surén and colleagues acknowledged some limitations of the study, including the incomplete ascertainment of ASD cases, possible ascertainment bias stemming from lower response rates among parents with children with more severe autistic disorder, and the reliance on subtype diagnoses of ASDs.

The Norwegian Mother and Child Cohort is supported by the Norwegian Ministry of Health and Care Services, the Norwegian Ministry of Education and Research, the Research Council of Norway/FUGE, the National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute of Environmental Health Sciences. The Autism Birth Cohort study is funded by NINDS. Surén's salary is funded by the Research Council of Norway.

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