However, experts have called for the finding to be interpreted with caution.
A high-level overview of systematic reviews has linked prenatal folic acid and multivitamin use to a reduced risk of autism, but not everyone is convinced.
Prenatal folic acid and multivitamin supplementation have been identified as an accessible and cost-effective approach to reduce the risk of autism spectrum disorder in children due to the former’s role in neural tube development.
But despite their widespread use, systematic reviews exploring the association have not always yielded consistently positive results between exposure and outcome.
Now, a new umbrella review of these systematic reviews and meta-analyses has suggested that prenatal folic acid and/or multivitamin supplementation was associated with a 30% reduction in the risk of ASD, prompting its authors to call for healthcare providers to “encourage women to start supplementation during the pre-conception period and continue throughout pregnancy” (emphasis added).
The findings were published in the journal PLoS One.
“This review on the association between periconceptional folate and multivitamins and a reduced risk of childhood autism spectrum disorder (ASD) is timely. It is of considerable interest given that it comes on the back of recent concerns about a possible link between maternal paracetamol ingestion and ASD,” said Professor David Elwood, head of the School of Medicine at Griffith University.
Researchers pooled data from eight previously published systematic reviews and meta-analysis. Five focused on maternal folic acid supplementation, while the remaining three focused on multivitamin supplementation. The eight systematic reviews encompassed 101 different studies and involved data from over three million patients.
Six reviews reported an association between prenatal folic acid and multivitamin use with a reduced risk of ASD, with a random-effects model analysis indicating that taking folic acid and/or multivitamins could reduce ASD risk by as much as 30% compared to women who did not use either supplement.
Subgroup analysis showed similar effects when folic acid (30% reduction) and multivitamins (34% reduction) were considered separately, and sensitivity analysis did not suggest that any one study unfairly influenced the overall results. The other two reviews (one focusing on folic acid, the other multivitamins) did not find an association between prenatal supplementation and ASD risk.
Six of the eight reviews were assessed as high quality (according to the Assessment of Multiple Systematic Reviews-2 tool). Common reasons for not achieving an AMSTAR-2 high quality grade included a failure to prospectively register the systematic review, not evaluating the risk of bias as part of the meta-analysis and an insufficient explanation of potential sources of heterogeneity.
“The findings emphasise the importance of prenatal folic acid and multivitamin supplementation as part of routine maternal care to reduce the risk of ASDs in offspring. Healthcare providers should encourage women to start supplementation during the pre-conception period and continue throughout pregnancy,” the researchers concluded.
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But not everyone agrees with these conclusions.
“This recommendation is entirely premature,” said Professor Michal Davies, a reproductive epidemiologist from the Robinson Research Institute at the University of Adelaide.
“We, and others, have published that supplemental folic acid throughout pregnancy is associated with an increased risk of recurrent asthma in childhood in a time and dose-dependent fashion.”
“It is therefore imperative that we further examine the diverse and complex relationship of folic acid and foetal development before advocating mass prescriptions on the current maternal population and next generation.”
Professor Helen Truby, a professorial research fellow in nutrition and dietetics at the University of Queensland, was similarly apprehensive of the findings and subsequent recommendations.
“The review’s conclusions are constrained by methodological limitations. The quality of the included studies varied, and some datasets may overlap. Because the analysis did not return to primary data for synthesis, there is a risk of confounding, reducing the reliability of the findings. Consequently, the evidence presented is not compelling and should be interpreted as demonstrating a possible association and not a causation,” she told media.
“There is very sound rational for women planning a pregnancy to take additional folic acid. Folic acid is critical for the foetus neural tube development, during the first trimester of pregnancy. This scientific evidence underpins recommendations for folic acid supplementation pre-conception and during the first trimester. However, the role of folic acid in ASD risk remains to be proven.”
The association between prenatal folic acid/multivitamin use and ASD risk isn’t as straightforward as it might sound, according to advanced accredited practising dietitian Melanie McGrice.
“Folate is well established as essential in the earliest weeks of pregnancy for neural tube development, including the formation of the brain and spinal cord. It also supports healthy methylation processes, reduces inflammation, and helps protect against oxidative stress — all biological pathways that have been implicated in ASD risk,” she said.
“[But] as a fertility and prenatal dietitian, I see first-hand that this isn’t simply about whether a woman takes a prenatal [supplement]. Certain groups have higher or more complex folate requirements and may not receive what they need from a standard supplement alone.
“It’s also important to highlight that folate follows a U-shaped curve in relation to ASD risk: too little or too much may be associated with increased risk. This reinforces why personalised assessment matters.”
