The Centers for Disease Control and Prevention’s recent report updating the estimated number of neural tube defects prevented by folic acid fortification of enriched cereal grain products clearly shows the huge impact of fortification: From 1999 through 2011, fortification prevented neural tube defects in about 1,300 births a year in the United States (MMWR 2015;64:1-5).

This is a dramatic example of how a relatively simple public health intervention – in this case, the mandatory addition of an inexpensive B vitamin to a portion of the food supply – is having a dramatic impact on a major birth defect.

Unfortunately, though, people may develop similar expectations that other micronutrients during pregnancy may prevent other birth defects or improve developmental outcomes, without adequate supportive evidence. For example, experimental animal studies have suggested that supplements of polyunsaturated fatty acids (PUFAs) during pregnancy improve brain development in the offspring (J. Perinat. Med. 2008;36;5-14). While there is no evidence that this is true in humans, there are prenatal vitamins that include PUFAs on the market.

Based on a review of nine randomized controlled studies that compared long chain PUFA supplementation to a placebo or no supplement in pregnant women, my colleagues and I concluded that the available research “regarding the maternal supplementation of PUFAs in retinal and neurocognitive development of the infant is not consistent in showing a benefit to supplementation” (Obstet.Gynecol. Int. 2012 [doi:10.1155/2012/591531]).

In a somewhat similar manner, an increasing number of women are taking megavitamins as part of their lifestyle, with the belief that “more is better.”

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Megavitamins may not necessarily be harmless. There is evidence from randomized trials that evaluated vitamin E or vitamin C for preeclampsia that vitamin E supplementation during pregnancy may cause intrauterine growth restriction (IUGR). This was confirmed by a study of 82 women who had been exposed to high doses of vitamin E supplements ranging from 400 IU to 1,200 IU a day during the first trimester. At Motherisk, we found that the mean birth weight among the babies of the women who had been exposed to high doses of vitamin E was significantly lower than the mean birth weight of the babies of the controls. But we did not find a significant difference in the rates of live births, preterm delivery, miscarriages, or stillbirths (Reprod. Toxicol. 2005;20:85-8). These women were on vitamin E as part of their lifestyle and not for any particular medical reason.

The medical community needs to keep in mind that while the folic acid fortification of flour and other products has shown dramatic effects in the overall population, as the CDC report shows, it may not meet the needs of specific populations of women who are at a greater risk of having a baby with a neural tube defect. As pointed out in the Morbidity and Mortality Weekly Report, these groups include Hispanic women, who may not consume as much folic acid or are at a greater risk of having a genetic polymorphism that makes them more susceptible to a folate insufficiency.

Flour fortification provides relatively small amounts of folic acid, possibly 200 mcg more a day, at best. But it has been shown that a woman who has had a previous child with a neural tube defect, a high-risk group, needs 5 mg per day to have an impact on prevention (Lancet 1991;338:131-7).

It is therefore important to keep in mind that there are high-risk groups who may need more than the amount provided by flour fortification. These groups include women on antiepileptic drugs or drugs that have antifolate activity, such as sulfonamide and methotrexate; as well as those with some genetic polymorphisms in the folate cycle.

Courtesy of the National Cancer Institute (NCI)

Women who smoke also tend to have lower folate levels, as do women with diabetes or who are obese. Women with celiac disease may have lower folate levels because they do not eat bread or flour-based products. Low-income women who may not eat sufficient green leafy vegetables, which are expensive and contain high levels of folic acid, may also be at greater risk.

A question that is still not resolved is whether folic acid can prevent other malformations, not just neural tube defects. There is some evidence that folic acid supplementation may also reduce the risk of cardiovascular defects and oral clefts. A randomized trial comparing folic acid to no folic acid to address these questions would be unethical. Instead, observational studies could evaluate the rate of these malformations after the fortification program began. Despite this major public health advance, we should always try to do even better and prevent more cases of neural tube defects and other malformations.

Dr. Koren is professor of pediatrics, pharmacology, pharmacy, and medical genetics at the University of Toronto. He is director of the Motherisk Program. He received grant support to conduct studies on folic acid from Duchesnay Inc., Canada. E-mail him at obnews@frontlinemedcom.com.

Examining the success of folic acid supplementation