Food fortification to prevent neural tube defects: is it working?

Abstract

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. 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 colleagues 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, 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. 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. Recording of birth defects on birth certificates is generally poor; it is well known that approximately 3% of newborns have major birth defects, yet only slightly more than 1% of birth certificates record major birth defects. 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 al 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 a-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. 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