Food Fortification to Prevent Neural Tube Defects: Title and subTitle BreakIs It Working?

Whether your dinner plans include tacos, spaghetti carbonara, crispy fried rice, or just a bacon-lettuce-tomato on toast, you can bet that you will be having folic acid tonight. Since January 1, 1998, the US Food and Drug Administration (FDA) has required that all enriched cereal grains must be fortified with 140 µg of folic acid per 100 g of grain.¹ This regulation was introduced because folic acid, taken prior to conception, can prevent many neural tube defects (NTDs) and because an alarming number of women of childbearing age were not following the US Public Health Service recommendation to take 400 µg/d of folic acid routinely.

Has the food fortification strategy worked? Until now there was little good evidence one way or the other. In this issue of THE JOURNAL, Honein and colleagues² report that the birth prevalence of NTDs has decreased by 19% since food fortification began. This exciting news clearly validates the US government's decision to intervene on a massive scale to prevent these devastating birth defects.

Prior to publication of this study, most information about the effects of food fortification was not related to NTDs. Blood levels of folate have skyrocketed since fortification,^{3 - 4} making folate deficiency much less common. Because some Americans now have blood folate levels that are literally off the scale, that is, above the range of standard tests, it is safe to assume that blood homocysteine levels are decreasing. This is important because a high blood homocysteine level is an independent risk factor for cardiovascular disease.⁵ It remains uncertain whether the decrease in blood homocysteine levels that occurs with increased folic acid intake will result in a decrease in the rate of cardiovascular disease. Blood homocysteine levels are higher in patients with cardiovascular disease than those without cardiovascular disease, but it is not yet clear whether this is a cause and effect relationship. Numerous clinical trials are under way to determine whether folic acid supplements can reduce the risk of cardiovascular disease. Ironically, the US food fortification campaign has been so successful that it may turn the trials' placebo groups into treated groups, thus making it impossible to tell if a negative result, should one occur, is correct.

The study by Honein et al leaves some important questions unanswered as well, largely because of 2 limitations of using birth certificate data. First, national birth certificate records do not include fetal deaths or stillbirths, both of which are common in NTD-affected pregnancies.⁶ Recording of birth defects on birth certificates is generally poor; it is well known that approximately 3% of newborns have major birth defects,⁷ yet only slightly more than 1% of birth certificates record major birth defects.²

Second, birth prevalence data do not provide a true picture of the NTD problem. Many fetuses with NTD are identified by prenatal screening programs or obstetrical ultrasound examinations. These pregnancies are generally terminated; they are not reported on birth certificates. Stevenson et al⁸ reported that 297 (83%) of the 360 NTD cases in South Carolina between 1992 and 1998 were detected by prenatal screening either by ultrasound (55%) or maternal serum α-fetoprotein screening (28%). Moreover, the proportion of NTD cases that were detected by prenatal screening may be increasing over time, making it more difficult to interpret a declining rate of live births with NTDs. Honein et al attempt to overcome this problem by looking at NTD rates in pregnancies among mothers who received no prenatal care or began prenatal care in the third trimester and, therefore, were not candidates for prenatal testing. As the authors indicate, this approach has limitations, including the changing proportion of women who present late for prenatal care and the small sample size. Moreover, birth certificate data regarding time of registration for prenatal care may not be accurate. For instance, in Tennessee, the month of registration on the birth certificate disagreed with the medical record 68% of the time.⁹ Because of these problems, this study, while important, is not definitive.

In fact, this study raises some intriguing questions. Although there are no data from randomized clinical trials to estimate the proportion of NTDs that can be prevented in the US population, data from case-control studies suggest that approximately half of NTD cases can be prevented by women taking a 400 µg/d folic acid supplement.¹ Honein et al found a decrease of only 19%. Why were more NTD cases not prevented? Although the FDA¹ food intake calculations indicated that the average woman of childbearing age would receive about 100 µg/d of folic acid under the fortification plan, there is good evidence that food is being overfortified.¹⁰ In fact, the exposure levels could be twice what the FDA estimated. The level of exposure is critical because our previous research on the Irish population¹¹ showed that intake of folic acid of 100 µg/d and 200 µg/d could prevent roughly 20% and 40% of NTD cases, respectively.

What explanations may account for the difference between the observed decrease of 19% and the maximum expected benefit of a 50% decline in NTD rates? First, birth certificate NTD rates may be inaccurate for the reasons noted above. Second, the estimate that 50% of NTDs are preventable by folic acid might be too high, because the case-control studies compared women who elected to take folic acid supplements with those who did not, a potentially biased comparison. Third, the US population is at lower risk for NTDs than the Irish population; there may be less benefit for a given level of folic acid in a low-risk than a high-risk population.¹² Fourth, the folic acid dose US women are receiving from fortified foods may actually be closer to 100 µg/d, in which case the 19% decrease in NTD rates is approximately what should be expected based on data from the Irish investigation.¹¹

The last possibility raises the contentious question of whether the fortification level should be increased. Before considering raising the fortification level, much more information is needed. Data are needed on the change in NTD rates for prenatally diagnosed cases, fetal deaths, and stillbirths, not just cases reported on birth certificates. Unfortunately, there are few data sources that have both this kind of complete ascertainment and enough subjects for a good before and after comparison of NTD rates. More data also are needed on the overall risk-benefit ratio. It is estimated that approximately 2000 NTD cases can be prevented per year by optimal folic acid delivery (by supplements or fortified food).¹ This benefit must be weighed against potential effects in the larger population. For example, an estimated 2% of elderly persons have undiagnosed pernicious anemia¹³ ; data are needed on how often masking of vitamin B₁₂ deficiency is occurring in this group because they are exposed to high levels of folic acid. In addition, there are no data on the effect of long-term, high-dose folic acid exposure in children. This lack of data led the Institute of Medicine to recommend an upper limit of 300 µg/d of folic acid in young children.¹³ Increasing food fortification would certainly result in children receiving more than the US Public Health Service recommended limit. On the other hand, if folic acid does prevent cardiovascular disease, the risk-benefit ratio would shift dramatically in favor of higher-dose fortification because of the enormous population at risk.

In conclusion, the study by Honein et al provides important information—food fortification works. Birth certificate data can, however, provide only imprecise estimates of how well it works. Much hard work lies ahead to determine how many cases of NTD are actually being prevented. Meanwhile, women of childbearing age should be advised to take a vitamin supplement containing 400 µg/d of folic acid to obtain the maximum protection against the development of NTDs.