The relationship between MSAFP and NTDs has been known for more than 3 decades. Routine prenatal screening has been conducted in the United States since the mid-1980s. About 2–10% of the patients with an elevated MSAFP will have a fetus with an NTD or another significant congenital anomaly. The positive predictive value of an MSAFP level between 2.5 and 2.9 MoM for NTDs is about 1.45%, with the predictive value as high as 13.4% if the MSAFP level is above 7 MoM; overall, the risk of having an affected fetus is about 4.5% for an MSAFP value above 2.5 MoM.15 In a low-risk population, MSAFP screening for NTDs can detect 71–75% of all defects.16 Birth prevalence of NTDs in the United States has fallen steadily since the epidemic of the 1930s. During the 1990s, before supplementation, there were no significant changes in incidence nor were there any dramatic changes in prenatal diagnosis. Techniques that could give an alternative explanation, such as ultrasonography, did not change significantly between 1997 and 2000.
In this study, we used high MSAFP values as a surrogate for the likelihood of NTDs. The rationale for the surrogate is that birth-registry data do not include data from prenatal diagnosis and terminations. Our thesis is that the incidence of NTDs and subsequent terminations have decreased because of folic acid fortification, perhaps by more than the 20% decrement reflected in the birth-certificate data.
These data, obtained from Quest Diagnostic's database, reflect results from both urban and suburban populations and are generally reflective of the general population of the United States. The laboratories in the system are distributed all over the United States and resemble the population distribution. However, we did not have access to a state-by-state or county-by-county analysis. Such microanalyses have been done for the Atlanta area by the Centers for Disease Control and Prevention and confirm birth prevalence decreases.9
U.S. birth certificate data have shown a 19% decline in NTD incidence in 2001 compared with 1996, before mandatory fortification was instituted.9 Although these results are positive and statistically significant, the decrease in NTDs was less than the decline predicted on the basis of observational studies.12,13 It had been estimated that if 100 μg/d of folic acid were added to the average daily diet of reproductive-aged women, this fortification would result in a 23% decrease in NTDs. However, recent data14 suggest that fortification of cereal-grain food products in the United States has increased typical folic acid consumption by more than 200 μg/d, approximately twice the 70–130-μg/d increment predicted by the Food and Drug Administration.15,16 The prediction for this level should lead to a 41% reduction in NTDs.12 Another predictive study showed 18% and 35% reductions at 100 μg/d and 200 μg/d, respectively.13 These predictions are close to the decrease in the MSAFP levels found in our study.
Even still, our results and all the U.S. data show less improvement than the Hungarian Center randomized trials. There are many possible reasons for these differences. One of the possible explanations for the discrepancy in findings is that many of these studies collected data from birth certificates. An evaluation of birth-certificate data on birth defects showed that birth data had only a 67–86% sensitivity to detect anencephaly and 40% for spina bifida.17,18 Moreover, about 71% of women carrying a fetus with these defects decide to terminate their pregnancy,19 and therefore these would be lost in birth-certificate studies. Another limitation is that national birth certificates do not include fetal deaths or stillbirths, which are common occurrences in fetuses with NTDs.20 Therefore, completed data regarding number of fetuses affected with NTDs are difficult to obtain and probably underestimate the overall incidence. This would decrease the apparent impact of folic acid fortification. If all these limitations are taken into account, it is possible that the decrease would be near that initially predicted. A recent study conducted in Canada after the fortification of grain products in 1998 showed a more than 50% reduction in NTDs when data from live births, stillbirths, and terminations of pregnancies were studied.21
However, during the last 10 years, there has been an overall decrease in the incidence of NTDs. This decline began before fortification was mandatory and may be due to several reasons.22 Since the 1980s, there has been an expansion of second-trimester screening programs for Down syndrome and NTDs, together with an overall improvement in ultrasound detection of fetal anomalies.23,24 The increase in prenatal diagnoses results in an increase in terminations, which decreases birth rates of infants with these anomalies. In addition, it can be assumed that some NTDs were primarily prevented in those women who followed the 1992 recommendation for folic acid supplementation by women who are planning to become pregnant.6 All these efforts in prevention and in prenatal diagnosis had already decreased the incidence of NTDs at birth.25 Therefore, the decrease of these defects at birth after fortification has not been as spectacular as was originally predicted.
Before mandatory fortification, less than 30% of women were using folic acid supplements with 400 μg/d in the preconceptional period,7 although 70% of them were aware of the preventive role of folic acid.7,27 This low compliance is partially explained by the fact that more that 50% of pregnancies in United States are unplanned. A study conducted in Germany in 1995 concluded that important factors affecting awareness and use of folic acid were socioeconomic status and level of education.28 Mandatory fortification makes uniform primary prevention possible and is not social-class dependent.29 This expands primary prevention to all women of childbearing age.
More studies are required to determine the optimal level of fortification for the U.S. population.30 The daily upper limit of intake set by the Food and Drug Administration is 1 mg.15 However, it has been suggested that between 0.5% and 5% of adults consume more than 1 mg/d of folic acid.31 With high doses of folic acid, there is a risk of masking the diagnosis of pernicious anemia by delaying the recognition of an underlying vitamin B12 or cobalamin deficiency, even beyond the point of irreversible neurologic damage.32
As first-trimester screening with nuchal translucency and serum biochemical markers becomes more common,33 the incidence of anomalies diagnosed in the second trimester will further decrease. The move toward first-trimester screening will accelerate the phenomenon of diminishing incidence of elevated MSAFPs. Therefore, as the incidence decreases, the cost-effectiveness of screening will decrease, and the positive predictive value of second-trimester MSAFP levels will also decrease. We should then consider higher cutoff values of abnormal MSAFPs to decrease the false-positive rate. This will improve cost-effectiveness and alleviate maternal anxiety arising from false-positive results and the subsequent evaluation with possibly unnecessary invasive procedures.
Overall, the introduction of folic acid fortification of breads and grains in the United States has proven to be a profoundly successful public health experiment, achieving a diminution of the rate of screening positive for MSAFP by approximately 32%. Our results are consistent with observational studies of NTDs at birth in our population and help to validate the decision to fortify food with folic acid. This represents the biggest single step in the reduction of birth defects to date.
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