Do we need another randomized controlled trial of folic acid alone?

As a public health strategy to help prevent neural tube defect-affected pregnancies, enriched flour and pasta in the United States and Canada are being fortified with folic acid, and women are being advised to take supplementary folic acid around the time of pregnancy to ensure an adequate intake. But in spite of the recently published results of a public health campaign in China, the burden of proof that folic acid alone is responsible for a decreased risk of these birth defects rests on the results of a randomized controlled trial conducted by the Medical Research Council of the United Kingdom. Supporting evidence comes primarily from studies that have shown a protective effect of multivitamins containing folic acid as one of many nutrients. Based on a striking and potentially hazardous type of non-compliance observed in an earlier study in which a participant took multiple vitamin doses simultaneously and a suggestion of similar incidents in the Medical Research Council study, we conclude that a further randomized controlled trial of the protective effect of folic acid alone may be necessary.