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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, Institute for Genetics and Fetal Medicine, St. Luke’s Roosevelt Hospital Center, Columbia University New York, New York; Hospital Materno-Infantil Vall d’Hebron, Barcelona, Spain; Institute for Human Nutrition, Columbia University, New York, New York; Quest Diagnostics Laboratory, Teterboro, New Jersey; and Department of Pathology, University of Arizona, Tucson, Arizona.
Address reprint requests to: Mark I. Evans, MD, Department of Obstetrics and Gynecology, Institute for Genetics and Fetal Medicine, St. Luke’s Roosevelt Hospital Center, 1000 10th Avenue, Suite 11A, New York, NY 10019; e-mail: mevans{at}chpnet.org.
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ABSTRACT |
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METHODS: Data regarding MSAFP levels in 61,119 patients undergoing maternal serum screening at a large commercial laboratory were categorized by multiples of the median (MoM). The data were compared between 2 groups: before mandatory supplementation in the United States in 1997 and after mandatory supplementation in 2000. High MSAFP values were further categorized as high (2.75–4.00 MoM) or very high (more than 4.00 MoM). Data were analyzed by 
2 analysis.
RESULTS: Comparative data showed a 32% decrease of patients with MoM greater than 2.75 + (2.5% -1.7%). Further categorizations revealed similar decreases.
CONCLUSION: The introduction of folic acid fortification has produced a profound decrease in the number of high MSAFP values, reflective of a decreased incidence of neural tube defects. Our results help to validate the decision to fortify food with folic acid, which represents a highly successful public health policy for primary prevention of birth defects.
LEVEL OF EVIDENCE: II-2
These incidence variations are a function of both genetic background and of nutritional status. Although there was considerable confusion and multiple theories as to the etiology of NTDs including potato blight, infections, and alcohol, a general consensus emerged that NTDs are partially precipitated by functional folic acid deficiencies. These are particularly common in poor diets, especially those lacking in fruits and green leafy vegetables. Beginning in the late 1980s, several European studies were conducted using folic acid supplementation preconceptually and early in pregnancy in an attempt to reduce the recurrence risk of both anencephaly and spina bifida.1 Supplementation was given preconceptually and up to 30 days after conception to women who had previous pregnancies with NTDs. Although supplementation effectively raised serum concentrations through the time that the neural tube closes, there was a reduction in the recurrence risk of such NTDs from about 3% to 1%.1 It became commonplace to suggest folic acid supplementation at 4 mg/d for women who had a previously affected child.
However, the vast majority of NTDs occur in the pregnancies of women with no medical history of such defects. Observational studies, nonrandomized intervention studies, and randomized controlled trials in the past 2 decades were carried out to determine if folic acid taken in the periconceptional period could also effectively reduce the primary incidence of NTDs.2–4 In particular, the Czeizel and Dudas study2 in Hungary showed dramatic reductions in NTD risk with the use of multivitamin supplementation. Pilot studies on primary incidence were more difficult to control and required much larger numbers. The data were always confounded by biases, such as overall health status and likelihood of taking vitamin supplementation. There was always the concern of bias between patients who would pay attention to their health care and who would be willing to take prenatal vitamins versus those who would not. A recent review of the Cochrane database5 of 4 trials involving 6,425 women showed that periconceptional folate supplementation reduced the incidence of NTDs by 72%. There was no increase in miscarriage, ectopic pregnancy, or stillbirth, although there was a nonsignificant trend toward increased incidence of multiple gestation.
While these studies were being conducted, organizations such as the U.S. Public Health Service and the American Public Health Association6 were suggesting that doctors who cared for pregnant patients had an "obligation" to ensure that anyone considering pregnancy be taking folic acid supplements before they actually conceived. By 1998, however, less than 30% of women were following this recommendation.7
In view of the suggestive evidence that folic acid supplementation could reduce the incidence of both recurrences and primary occurrences, in 1996 the U.S. Food and Drug Administration mandated that by January 1998, all breads and grains sold in the United States be fortified with folic acid.8 One study to date has evaluated the efficacy of this program based on the number of children with NTDs at birth and showed a decrease,9 but not the 50–60% decrease predicted by the U.S. Public Health Service in 1992.6 The purpose of this study was to ascertain if the impact of folic acid fortification is more apparent at the time of prenatal diagnosis rather than from birth-certificate data.
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MATERIALS AND METHODS |
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Three-month cohorts of 27,020 pregnancies (first quarter) in 1997 and 34,099 pregnancies in 2000 were used for comparison. A competitive radioimmunoassay technique was used for alpha-fetoprotein assays. Reagents were obtained from Sanofi Diagnostics Pasteur Inc. (Marnesla-Coquette, France). Values were assessed for the in-house MoM. Alpha-fetoprotein data were reported in international units per milliliter (coefficient of variation 6.6–7.7% for values from 25–147 IU/mL). Alpha-fetoprotein values were adjusted clinically for maternal weight, age, race, and gestational age. All data were stratified by MoM to eliminate variability from interassay variation, though this was minimized by using the same laboratory. Although the clinical laboratory cutoff value for high alpha-fetoprotein is 2.5 MoM, there was better segregation of the data by using the breakdowns of less than 2.75 MoM, 2.75–4.00 MoM, and more than 4 MoM. Individual outcome data were not available. Differences were analyzed by 2 analysis. (SPSS Inc, Chicago, IL). The study was approved by the St. Luke’s Roosevelt Hospital Center Institutional Review Board.
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RESULTS |
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2 = 50.8, P < .001). The decrease from 2.55% of the population to 1.77% is 32%. Values of more than 4.00 MoM were decreased from 0.75% to 0.52% (2 = 43.3, P < .001) (Table 1
, Figure 1).
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DISCUSSION |
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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.
In a previous study of MSAFP levels from 1991 to 1995,26 we found that 2.66% of women had an alpha-fetoprotein level above 2.5 MoM. In the current study, we found in 1997 that 2.5% of women had a positive screening test result greater than 2.75 MoM. This represents only a 6% decrease in positive screening results between 1991–1995 and 1997, supporting the idea that the decreased incidence in NTD at birth was more likely due to early detection and termination of pregnancies than to supplementation. This study further shows a decreased incidence of elevated MSAFP to 1.7% in 2000, representing a 32% decrease from 1997 and a 36% decrease from 1991 to 1995. This significant decrease in MSAFP likely reflects primary prevention of NTDs through folic acid fortification.
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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Footnotes |
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Received August 25, 2003. Received in revised form November 17, 2003. Accepted December 4, 2003.
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REFERENCES |
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2. Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992;327:1832–5.[Abstract]
3. Werler MM, Shapiro S, Mitchell AA. Periconceptional folic acid exposure and risk of occurrent neural tube defects. JAMA 1993;269:1257–91.[Abstract]
4. Berry RJ, Li Z, Erickson JD, Li S, Moore CA, Wang H, et al. Prevention of neural-tube defects with folic acid in China: China–U. S. collaborative project for neural tube defect prevention. N Engl J Med 1999;341:1485–90.
5. Lumley J, Watson L, Watson M, Bower C. Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects. Cochrane Database Syst Rev 2001;(3):CD001056.
6. Centers for Disease Control and Prevention. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. Morb Mortal Wkly Rep Recomm Rep 1992;41(RR-14):1–7.
7. CDC. Knowledge and use of folic acid by women of childbearing age. Morb Mortal Wkly Rep 1999;48:325–7.[Medline]
8. Food and Drug Administration. Food Standards. Fed Regist 1996;61:8781–97.
9. Honein MA, Paulozzi LJ, Mathews TJ, Erickson JD, Wong LY. Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. JAMA 2001;285:2981–6.
10. Evans MI, Harrison HH, O’Brien JE, Dvorin E, Huang X, Krivchenia EL, et al. Correction for insulin-dependent diabetes in maternal serum alpha fetoprotein testing has outlived its usefulness. Am J Obstet Gynecol 2002;187: 1084–6.[Medline]
11. Evans MI, Harrison HH, O’Brien JE, Huang X, Chervenak FA, Henry GP, et al. Maternal weight correction for alpha-fetoprotein: mathematical truncations revisited. Genet Test 2002;6:221–3.[Medline]
12. Evans MI, O’Brien JE, Dvorin E, Wapner RJ, Harrison HH. Standardization of methods reduces variability: explanation for historical discrepancies in biochemical screening. Genet Test 2003;7:81–3.[Medline]
13. Bryant-Greenwood PK, O’Brien JE, Huang X, Yaron Y, Ayoub M, Johnson MP, et al. Maternal weight differences do not explain ethnic differences in biochemical screening. Fetal Diagn Ther 1998;13:46–8.[Medline]
14. Brooks K, Chik L, O’Brien JE, Critchfield G, Ayoub M, Johnson MP, Evans MI. Variability of adjustments to indices in determining risk in biochemical screening. Fetal Diagn Ther 1999;14:41–6.[Medline]
15. Food and Drug Administration. Food labeling: health claims and label statements; folate and neural tube defects. Fed Regist 1993;58:53254–95.
16. Choumenkovitch SF, Selhub J, Wilson PWF, Rader JI, Rosenberg IH, Jacques PF. Folic acid intake from fortification in United States exceeds prediction. J Nutr 2002;132: 2792–8.
17. Watkins ML, Edmonds L, McClearn A, Mullins L, Mulinare J, Khoury M. The surveillance of birth defects: the usefulness of the revised US standard birth certificate. Am J Public Health 1996;86:731–4.
18. Piper JM, Mitchel EF, Snowden M, Hall C, Adams M, Taylor P. Validation of the 1989 Tennessee birth certificates using maternal and newborn hospital records. Am J Epidemiol 1993;737:758–68.
19. Cunningham GC, Tompkinson DG. Cost and effectiveness of the California triple marker, prenatal screening program. Genet Med 1999;1:199–206.[Medline]
20. Little J, Elwood M. Fetal loss. In: Elwood JM, Little J, Elwood JH, editors. Epidemiology and control of neural tube defects. New York (NY): Oxford University Press; 1992. p. 324–34.
21. Persad VL, Van den Hof MC, Dubé JM, Zimmer P. Incidence of open neural tube defects in Nova Scotia after folic acid fortification. CMAJ 2002;167:241–5.
22. Olney RS, Mulinare J. Trends in neural tube defect prevalence, folic acid fortification and vitamin supplement use. Semin Perinatol 2002;26:277–85.[Medline]
23. Jorgensen FS, Valentin L, Salvesen KA, Jorgensen C, Jensen FR, Bang J, et al. MULTISCAN: a Scandinavian multicenter second trimester obstetric ultrasound and serum screening study. Acta Obstet Gynecol Scand 1999; 78:501–10.[Medline]
24. Chan A, Robertson E, Haan EA, Ranieri E, Keane RJ. The sensitivity of ultrasound and serum alpha-fetoprotein in population-based antenatal screening for neural tube defects, South Australia 1986–1991. Br J Obstet Gynaecol 1995;102:370–6.[Medline]
25. Erickson JD. Folic acid and prevention of spina bifida and anencephaly 10 years after the U. S. Public Health Service recommendation. Morb Mortal Wkly Rep 2002;51:1–3.[Medline]
26. Yaron Y, Cherry M, Kramer RL, O’Brien JE, Hallak M, Johnson MP, et al. Second-trimester maternal serum marker screening: maternal serum alpha-fetoprotein, beta-human chorionic gonadotropin, estriol, and their various combinations as predictors of pregnancy outcome. Am J Obstet Gynecol 1999;181:968–74.[Medline]
27. Morin P, De Walls P, St-Cyr-Tribble D, Niyonsenga T, Payette H. Pregnancy planning: a determinant of folic acid supplements use for the primary prevention of neural tube defects. Can J Public Health 2002;93:259–63.[Medline]
28. de Walle HE, Cornel MC, de Jong-van de Berg LT. Three years after the Dutch folic campaign: growing socioeconomic differences. Prev Med 2002;35:65–9.[Medline]
29. Brent RL, Oakley GP, Mattison DR. The unnecessary epidemic of folic acid-preventable spina bifida and anencephaly. Pediatrics 2000;106:825–7.
30. Mils JL. Fortification of foods with folic acid: how much is enough? N Engl J Med 2000;342:1442–5.
31. Lewis CJ, Crane NT, Wilson DB, Yetley EA. Estimated folate intakes: data updated to reflect food fortification, increased bioavailability, and dietary supplement use. Am J Clin Nutr 1999;70:198–207.
32. Sauberlilich HE, Dowdy RP, Skala JH. Laboratory test for the assessment of nutritional status. Cleveland (OH): CRC Press; 1974.
33. Evans MI, Krivchenia EL, Yaron Y. Screening. In: Evans MI, Bui TH, editors. The genomic revolution and obstetrics and gynecology: Balliere’s best practice and research in clinical obstetrics and gynecology. London: Harcourt Brace Publishing; 2002. p. 645–57.
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