Children whose mothers took folic acid or multivitamin supplements before or during pregnancy may be at lower risk for autism spectrum disorder (ASD), a new study suggests.
The results have important public health implications regarding use of these supplements during pregnancy, the authors, led by Stephen Z. Levine, PhD, professor, Department of Community Mental Health, University of Haifa, Israel, conclude.
But such policies are not the entire solution for preventing autism, and Dr Levine stressed that mothers are not to blame if their child develops this condition.
“Autism is a highly heterogeneous disorder with complex genetic and environmental etiologies,” he told Medscape Medical News. “Plenty of mothers who use adequate vitamins before and during pregnancy will have a child who develops autism, so clearly, we still need much more research.”
The study was published online January 3 in JAMA Psychiatry.
Dr Levine and his fellow researchers established a case-cohort study by linking healthcare registries from the Meuhedet healthcare organization, which covers 35% of Israelis younger than 15 years.
They analyzed all live births between January 1, 2003, and December 31, 2007. Case patients included those with ASD; control participants included one third of the children and were randomly selected. The cohort was followed from birth to January 26, 2015.
The Meuhedet Prescription Register holds information on drugs dispensed by most pharmacies across Israel. The researchers extracted information on dispensed folic acid (vitamin B9) and multivitamin supplements (vitamins A, B, C, and D).
In Israel, food is not fortified with folic acid, but supplementation with folic acid is recommended before and during pregnancy. Dr Levine noted that the rates of vitamin supplementation in the current study were largely similar to those found in previous registry-based research.
The researchers analyzed data for two time intervals: before pregnancy (540 to 271 days before childbirth), and during pregnancy (270 days before childbirth to the date of the birth).
Of 45,300 children born to 26,702 mothers, 1.3% received a diagnosis of ASD.
Maternal exposure to folic acid and/or multivitamin supplements before pregnancy was associated with a lower likelihood of ASD in the offspring compared with no exposure before pregnancy (relative risk [RR], 0.39; 95% confidence interval [CI], 0.30 – 0.50; P < .001).
Maternal exposure to folic acid and/or multivitamin supplements during pregnancy was also associated with a lower likelihood of ASD in offspring compared with no exposure during pregnancy (RR, 0.27; 95% CI, 0.22 – 0.33; P < .001).
Separate analyses of folic acid use before and during pregnancy and multivitamin supplement use before and during pregnancy showed that such use was associated with a lower likelihood of ASD in children.
It is difficult to distinguish the effect of folic acid on ASD risk from that of multivitamin supplements because multivitamin supplements contain folic acid, said Dr Levine.
He also pointed out that the reasons mothers took multivitamins “might reflect an intentionally healthier lifestyle,” moreso than for folic acid.
Supplement Timing
The researchers carried out a number of sensitivity analyses to determine whether the timing of vitamin supplementation is important to the risk for ASD.
“This is a topic we looked at in detail,” commented Dr Levine. “There are critical periods during pregnancy that are associated with fetal brain development.”
For example, they analyzed use of maternal vitamin supplementation before but not during pregnancy, during but not before pregnancy, and before and during pregnancy. They also examined exposure during the period from 4 weeks before pregnancy to 8 weeks into pregnancy, and maternal vitamin supplementation 2 years before pregnancy, during pregnancy, and 2 years before and during pregnancy.
The results of these sensitivity analyses generally remained statistically significant, but Dr Levine stressed that this issue requires further research to pinpoint critical periods of fetal development that relate to risk. “Certainly pregnant mothers should follow existing medical advice regarding the timing of vitamin use.”
The researchers also carried out analyses that controlled for different sources of confounding. For example, they analyzed male and female offspring separately, as well as ASD patients who had an intellectual disability and such patients who did not have an intellectual disability. Here, too, the results essentially were unchanged.
But another analysis found that folic acid supplementation before pregnancy did not significantly reduce the risk for ASD among offspring of parents with a psychiatric condition. This, say the authors, may reflect noncompliance, higher rates of vitamin deficiency, or poor diet among these parents.
The reduced ASD risk in offspring whose mothers were exposed to supplements remained after adjusting for maternal vitamin deficiency, but the risk was not reduced in offspring of women with a vitamin deficiency who were already receiving supplements before pregnancy. This “rules out the possibility that the association is solely due to confounding,” the authors write.
The study had a number of limitations. For example, residual confounding cannot be ruled out, the sample size was limited, there was a lack of information on gestational age, and the underlying indication for the supplement was unknown.
“We cannot rule out the possibility that the observed risk reduction is due to other causes associated with the dispensation,” write the authors. “However, most dispensations appeared to occur around pregnancy.”
The authors also note that some mothers may have used nonprescribed, over-the-counter supplements. This could be a form of misclassification that is “in the direction of false negatives,” they write.
“This suggests that if women classified as false negative were accurately identified, the results would be more pronounced than they are.”
Difficult Comparison
Reached for a comment, Nada Stotland, MD, professor of psychiatry, Rush Medical College, Chicago, Illinois, who is former president of the American Psychiatric Association, said it is difficult to compare populations who did take prenatal vitamins with those who did not.
Although the authors tried to correct for confounding factors, that is all but impossible to do, even in a large study such as this one, she said.
Dr Stotland agreed that “people shouldn’t panic” if, for whatever reason, they decide not to take prenatal vitamins. Autism is not very common, and “we really don’t know what causes it,” she said.
She noted that one reason for not taking supplements could be the cost.
Results of this new study might provide “another clue” to a condition that is “probably multifactorial,” said Dr Stotland, and there is not enough evidence to advise women to take vitamins just to prevent autism, she said.
“This is an observational study, and maybe the people who didn’t take prenatal vitamins smoked, drank, or didn’t eat well. Maybe these people in Israel were very disadvantaged; maybe they were not well treated and suffered from a lot of anxiety or displacement.”
However, there are other reasons for pregnant women, or those wishing to become pregnant, to take vitamin supplements, said Dr Stotland.
The study was supported by the National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Environmental Health Sciences, the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health, the Beatrice and Samuel A. Seaver Foundation, the Fredrik and Ingrid Thuring Foundation, and the Swedish Society of Medicine. In unrelated work, Dr Levine has receiving research support from Shire Pharmaceuticals. Dr Stotland has disclosed no relevant financial relationships.
JAMA Psychiatry. Published online January 3, 2018. Full text
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