Folate (the naturally occurring form) and folic acid are forms of a water-soluble B vitamin (B9) that were first synthesized in 1945. Folate functions as an important cofactor in the transfer and use of 1-carbon moieties, primarily methyl groups. An important advance in understanding subclinical folate deficiency came in 1991 with the demonstration that folic acid supplementation before and during pregnancy dramatically reduced the risk of neural-tube defects in newborns. Folate supplementation of women before and during the first trimester of pregnancy has a dose-response effect in preventing neural-tube defects, ranging from a 23% reduction with 200 μg to an 85% reduction with 5000 μg of folic acid per day. The strong evidence demonstrating reduced risks of neural-tube defects led to mandatory folic acid fortification of cereal grain products in the United States by January 1, 1998. Fortification of foods with folic acid in the United States costs about $1,000 per neural-tube defect prevented. Even with all the information on the benefits of folate, many studies show inadequate folate intake among young women. Adequate folate levels have also been associated with reduced risks of coronary artery disease, colorectal cancer, and dementia.
In contrast to these well-documented beneficial effects, there are now 2 studies, 1 in mice and 1 in human subjects, suggesting that folic acid supplementation during early pregnancy increases the risk of asthma, wheezing, and respiratory disease.
Although the mouse studies of Hollingsworth et al were very well done, they were performed in a single inbred strain of mice. It is possible that the particular mouse strain chosen by these investigators is uniquely susceptible to the effects of methyl donors, that the dose of folate and other methyl donors was pharmacologic and not physiologic for the mice, or that DNA methylation responses in mice are different from those in human subjects. The study by Håberg et al has the strength of a very large population, but it does not answer the question of whether the increased wheezing during the first 18 months associated with folate supplementation will result in more asthma later in childhood.
Currently, there is abundant scientific evidence showing that folate supplementation of women during the first trimester of pregnancy prevents neural-tube defects and limited evidence suggesting an increased risk of respiratory disease. However, it is always important to consider the possibility of unintended consequences. Studies are now needed to examine whether folic acid supplementation of pregnant women is associated with patterns of DNA methylation in their children similar to those found in the mice pups and whether these DNA changes are also associated with increased childhood asthma.
Ownby DR. Has mandatory folic acid supplementation of foods increased the risk of asthma and allergic disease? J Allergy Clin Immunol. 2009 Jun;123(6):1260-1. Epub 2009 May 17. View Abstract
