Some, but not complete, reassurance on the safety of folic acid fortification

See corresponding article on page 1416. The ability of increased preconception and prenatal intake of folic acid to reduce the incidence of neural tube defects (NTDs) is one of the greatest success stories in the prevention of birth defects and childhood disabilities. It ranks with rubella vaccine and Rho(D) immune globulin treatment (RhoGAM), which is used for prevention of injury from Rh incompatibility, in the preventive pediatrics hall of fame. Yet there is little certainty about the mechanism of action or whether such administration increases or decreases the incidence of any other disorders of infancy, childhood, or early adult life. In the debates about fortification of foods with folic acid, concerns have been raised by some Internet postings that too much folic acid may be detrimental, but there is little if any evidence of harm. However, any harmful effects may require careful epidemiologic studies for detection. There is also the possibility that increased prenatal and postnatal intake of folic acid might decrease the incidence of disorders other than NTDs. The report by Obeid et al (1) in this issue of the Journal provides reassuring information that suggests that unmetabolized folic acid does not accumulate substantially in the cord blood of newborns; this reduces concern regarding the possible toxicity of unmetabolized folic acid. The history of folic acid intake in the United States is well documented but not widely appreciated by younger clinicians. Until the 1970s, the inclusion of folic acid in over-the-counter (OTC) daily vitamins was rare, although a few brands contained 0.1 mg. Restrictions were related to concern that its use would mask the anemia associated with the neurologic effects of vitamin B-12 deficiency. In 1973 the US Food and Drug Administration raised the limit of folic acid in OTC daily vitamins to 0.4 mg, and the intake of folic acid by the US population increased progressively from that time through the implementation of fortification in 1996–1998. The content of folic acid in commonly used daily vitamins went from none to 0.4 mg for the One A Day brand (Bayer HealthCare, Morristown, NJ) in 1976 and for Vidalyn (Abbott Laboratories, Abbott Park, IL) in 1977, based on review of the Physicians’ Desk Reference from that era (2). The National Health and Nutrition Examination Survey I (NHANES I) (1971–1974), NHANES II (1976–1980), and NHANES III (1988–1994) reported that daily vitamin use by the US population was 23%, 35%, and 42%, respectively. The Framingham Offspring Study (3) found that plasma folate concentrations (in ng/mL) were 4.6 from 1991 to 1994 and 4.8 from 1995 to 1998 for nonusers of vitamin B supplements and 11.4 and 14.1, respectively, for users of vitamin B supplements. Thus, it is likely that the intake of folic acid and plasma folate concentrations were bimodal in the US population through the 1980s and 1990s, with the proportion of vitamin users rising progressively. The trend to increased folic acid intake continued when the first reports appeared around 1980 suggesting that increased folic acid intake might reduce the incidence of birth defects; later intake increased further as public health groups mounted awareness campaigns urging preconception and prenatal use of folic acid supplementation. This reached a plateau in the United States possibly with the start of fortification of grain-based foods in 1996–1998. By 2001 there were growing claims that the incidence of autism was increasing dramatically, although there is evidence that much or all of this increase is related to diagnostic substitution of autism for mental retardation for severe disabilities and growing awareness and readiness to apply a diagnosis in milder cases. Although it is clear that ≥3–4-fold more children are given a diagnosis of autism in North America and Europe today than was the case in the 1970s (4), it remains unclear as to whether there is a true change in the incidence of autism phenotypes from 1970 to the present or whether this is completely an artifact of diagnostic practices rather than of any true change in patient phenotypes. Although we are willing to accept that this increase may be entirely an artifact, if there is even a small increase in the true incidence of autism this would be a major public health problem and would present an opportunity for understanding part of the etiology of autism and for attempting prevention. Although the role of vaccines in the etiology of autism has received much attention, despite evidence to the contrary, we would propose that if there is any true increase in the incidence of autism—and we do not claim that this is the case—that factors such as increased intake of folic acid, increased use of prenatal ultrasound (5), and a few other variables may be more deserving of further investigation. The temporal relations of the increases in these factors with the increased diagnosis of autism are relatively compatible. The mechanism of action for the effect of folic acid on prevention of birth defects is unknown. One hypothesis is that its role in the synthesis of DNA precursors is critical for the rapid cell proliferation associated with neural tube closure. More recently, the effects of folic acid on epigenetic variables such as DNA methylation and histone methylation have received increased attention. There is evidence in mice (6) and humans (7) that folic acid intake can affect DNA methylation and gene expression in certain circumstances. Folic acid likely has its beneficial effects through its active metabolites, but harmful effects could also occur via these metabolites or through another mechanism. One hypothesis has been that unmetabolized folic acid might mediate a harmful effect. As explained by Obeid et al (1), the common vitamin form of folic must be reduced by dihydrofolate reductase to be metabolized to various active forms. There is considerable evidence of gene-nutrient interactions between folic acid and the many genes that metabolize it. It is possible that unmetabolized folic acid might accumulate with folate supplementation, particularly in individuals with common genetic variants associated with reduced activity of dihydrofolate reductase (DHFR) (8, 9). Although Obeid et al (1) did not study DHFR genotypes, their results are relatively reassuring in regard to accumulation of unmetabolized folic acid in the fetuses of women talking supplements. They found that unmetabolized folic acid was slightly higher but was “nonsignificantly higher in cord blood from supplemented women than in cord blood from nonsupplemented women (P = 0.154).” In contrast, they concluded that 5-methyltetrahydrofolate and tetrahydrofolate did accumulate in the fetus. It remains possible that folate could have a harmful or beneficial effect through its normal active metabolic forms. For instance, there is evidence that famine increases the incidence of both NTDs and schizophrenia (10). One could speculate that the incidence of schizophrenia might be dropping with a long lag time from prenatal life to diagnosis related to increased maternal intake of folic acid. Could increased intake of folic acid simultaneously increase the risk of autism and decrease the risk of schizophrenia? The likelihood that increased intake of folic acid has harmful effects is low but perhaps not zero. Most important, increased intake of folic acid definitely reduces the incidence of NTDs and therefore has a major, well-documented benefit. Thus, there should be no argument for decreasing intake of folic acid, but perhaps more research is needed regarding the small possibilities of harm or of additional benefits. The work of Obeid et al (1) is relatively reassuring with regard to the possibility of harm through accumulation of unmetabolized folic acid.