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Margaret A. Honein, PhD,MPH; Leonard J. Paulozzi, MD; T. J. Mathews, MS; J. David Erickson, DDS,PhD; Lee-Yang C. Wong, MS

JAMA. 2001;285:2981-2986.

ABSTRACT
Context  Daily consumption of 400 µg of folic acid before conception and during early pregnancy dramatically reduces the occurrence of neural tube defects (NTDs). Before food fortification, however, only an estimated 29% of US reproductive-aged women were taking a supplement containing 400 µg of folic acid daily. The US Food and Drug Administration authorized addition of folic acid to enriched grain products in March 1996, with compliance mandatory by January 1998.

Objective  To evaluate the impact of food fortification with folic acid on NTD birth prevalence.

Design, Setting, and Population  National study of birth certificate data for live births to women in 45 US states and Washington, DC, between January 1990 and December 1999.

Main Outcome Measure  Birth certificate reports of spina bifida and anencephaly before fortification (October 1995 through December 1996) compared with after mandatory fortification (October 1998 through December 1999).

Results  The birth prevalence of NTDs reported on birth certificates decreased from 37.8 per 100 000 live births before fortification to 30.5 per 100 000 live births conceived after mandatory folic acid fortification, representing a 19% decline (prevalence ratio [PR], 0.81; 95% confidence interval [CI], 0.75-0.87). During the same period, NTD birth prevalence declined from 53.4 per 100 000 to 46.5 per 100 000 (PR, 0.87; 95% CI, 0.64-1.18) for women who received only third-trimester or no prenatal care.

Conclusions  A 19% reduction in NTD birth prevalence occurred following folic acid fortification of the US food supply. However, factors other than fortification may have contributed to this decline.

INTRODUCTION

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Spina bifida and anencephaly, the most common neural tube defects (NTDs), together affect approximately 4000 pregnancies resulting in 2500 to 3000 US births annually.^1-2 In randomized controlled trials, folic acid supplementation before conception and during the first trimester has been shown to reduce the recurrence of NTDs by 72% (relative risk, 0.28; 95% CI, 0.12-0.71) in women with a previous NTD-affected pregnancy,³ and in another randomized study, supplementation reduced the occurrence of NTDs by 100% (95% CI, 0.0-0.63).⁴

In 1992, the US Public Health Service issued a recommendation that all US reproductive-aged women who are capable of becoming pregnant should consume 400 µg of folic acid daily^{2, 5}; however, a recent survey indicated that only 29% of US women were following this recommendation in 1998.⁶ In a further effort to reduce the occurrence of folate-preventable NTDs, the US Food and Drug Administration (FDA) authorized the addition of folic acid to enriched grain products in March 1996 and made compliance mandatory by January 1998. The current level of fortification was expected to add approximately 100 µg of folic acid to the daily diet of the average person and to result in approximately 50% of all reproductive-aged women receiving 400 µg of folate from all sources.^7-9 In addition, other countries recently fortified their grain supplies on either a voluntary or mandatory basis,^10-12 and several more countries are considering folic acid fortification.^13-16

Birth certificates are an important data source for monitoring national NTD trends. They are completed for all US live births, and since 1989, they include check boxes for selected congenital anomalies, including anencephaly and spina bifida.^17-19 The quality of data on birth defects from birth certificates is limited, ^20-22 in particular, sensitivity is low. Nonetheless, birth certificates represent a stable source of data that can be used for monitoring approximately 4 million births per year. The impact of universal folic acid fortification as a public health intervention was assessed by evaluating birth certificate data on NTDs to determine its effect on the US NTD birth prevalence.

METHODS

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Data Source

Birth certificate information is routinely collected by state vital statistics offices and compiled by the Centers for Disease Control and Prevention's (CDC's) National Center for Health Statistics (NCHS). We evaluated the prevalence of NTDs in births to US residents, specifically spina bifida and anencephaly, reported on birth certificates from 45 states and Washington, DC, from January 1990 through December 1999. Residents of Connecticut, Maryland, New Mexico, New York, and Oklahoma were excluded for the following reasons: New Mexico, New York, and Oklahoma birth certificates did not report congenital anomalies for 1 or more years during this period, and in Connecticut and Maryland, congenital anomaly status was "not stated" for more than 25% of births during several years between 1990 and 1999. To determine whether the overall sensitivity of birth certificates to birth defects varied during this period, the percentage of certificates noting 1 or more defects by year for 1990 through 1999 was calculated. Any birth certificate that did not indicate an NTD but did indicate at least 1 of 19 other congenital anomalies was included.¹⁸ Birth certificates with only "other" checked in the congenital anomaly list were excluded. This analysis was conducted because a decline in the sensitivity of birth certificates to other birth defects during this time period would suggest that any observed decline in NTDs would need to be viewed more cautiously.

Folic acid fortification was first authorized in March 1996 and was mandatory by January 1998.⁷ Information on the estimated time from grain production to consumption or on the proportion of the grain supply that was fortified before the mandatory deadline was not obtainable. In at least some US regions, evidence of substantial folic acid fortification was shown by increasing serum folate levels beginning in 1997^23-24 and continuing to increase through 1998.²⁴ From this evidence, we assumed that nearly all births from October 1998 through December 1999 (conceptions from approximately January 24, 1998, to April 23, 1999) were exposed to folic acid fortification periconceptionally. (The dates of conception are estimated assuming a 38-week gestation because this is the mean gestation for NTD-affected pregnancies reported on birth certificates.) The birth prevalence of NTDs from October 1995 through December 1996 (5 quarters of births before folic acid fortification) was compared with the birth prevalence of NTDs from October 1998 through December 1999 (5 quarters of births conceived after mandatory folic acid fortification). In addition, the postfortification NTD prevalence (October 1998 to December 1999 births) was compared with the mean prevalence from 1990 to 1996 as the reference group to assess if any reduction in NTDs observed was dependent on our choice of comparison group. Differences between these periods were expressed as prevalence ratios (PRs) and 95% confidence intervals (CIs), which were calculated using Epi Info (version 6; CDC, Atlanta, Ga). Furthermore, these estimates were calculated for spina bifida and anencephaly birth prevalences (defined as the number of infants whose birth certificates indicated that they had either spina bifida or anencephaly, with the denominator as the total number of live births during the same period).

To examine trends unaffected by changes in the use of prenatal diagnosis or termination of affected pregnancies, the prevalence of NTDs among women who began prenatal care in the third trimester or had no prenatal care at all was evaluated. Although some states are increasing restrictions on and decreasing access to pregnancy termination services,²⁵ second-trimester elective terminations are legal in the United States. However, in the practice of obstetrics in the United States today, third-trimester terminations are rare, even with a prenatal diagnosis of an NTD.²⁶ Therefore, affected pregnancies without obstetric oversight in the first 2 trimesters are unlikely to be terminated. As a result, the birth prevalence of NTDs in women receiving only third-trimester or no prenatal care should be relatively unaffected by changes or trends in the use of prenatal diagnosis and termination. This group of women also may be less likely to be affected by any changes in patterns of vitamin supplement use. The birth certificate has a field to indicate what month prenatal care began. The trimester that prenatal care began was dichotomized to "first or second trimester prenatal care," meaning that the mother began prenatal care in the first 6 months of pregnancy, and "third trimester/no prenatal care," meaning that the mother either received no prenatal care or began prenatal care in the seventh month of pregnancy or later. The percentage of women who received third-trimester or no prenatal care decreased from 6.4% in 1989 to 3.9% in 1998,²⁷ limiting the number of births for subgroup analysis to approximately 150 000 births in 1998.

Data Analyses

The exponential weighted moving average (EWMA) method (using SAS; SAS Institute, Cary, NC) was used to determine the timing of statistically significant changes from a baseline mean, that is, the timing and occurrence of any statistically significant changes during the entire 10-year period. This method sets a boundary that is analogous to upper and lower confidence limits using the baseline SD. The baseline mean and SD were based on the 1990 through 1996 data. Observed values above and below the baseline mean increase the value of the EWMA statistic. When the EWMA statistic is large enough to cross the boundary (an out-of-control point), it means an increase or decrease beyond the limits of the model has occurred. The EWMA statistic was reset to the 1990 to 1996 baseline mean after each out-of-control point. The level was set at .01, and the weight was set at 0.075 to yield an average run length of 25 years, meaning that only 1 false out-of-control signal should occur in every 25 years of data analyzed.²⁸ The EWMA method was used to detect the timing of statistically significant shifts from the overall mean quarterly spina bifida and anencephaly prevalence. Among women receiving third-trimester only or no prenatal care, the total NTD birth prevalence was analyzed for 6-month intervals instead of quarters because of the limited numbers in this subgroup. Also examined for ease of comparability was the total NTD prevalence among all births by 6-month intervals.

RESULTS

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The percentage of infants whose birth certificate indicated the presence of at least 1 congenital anomaly other than an NTD was highest in 1990 and was relatively stable from 1991 through 1999, with slight increases noted in 1998 and 1999 (Table 1). Approximately 1% of all birth certificates indicated at least 1 congenital anomaly other than an NTD.

View this table: [in this window] [in a new window] Table 1. Prevalence of at Least 1 Congenital Anomaly Reported on the Birth Certificate in 45 US States and Washington, DC, January 1990 to December 1999

A total of 1123 infants with spina bifida (26.2 per 100 000 births) and 497 infants with anencephaly (11.6 per 100 000 births) were reported on birth certificates from October 1995 through December 1996 (Table 2). The birth prevalence of spina bifida decreased to 20.2 per 100 000 births during October 1998 through December 1999, representing a 23% decline (PR, 0.77; 95% CI, 0.70-0.84). The birth prevalence of anencephaly declined 11% (PR, 0.89; 95% CI, 0.78-1.01), reaching a birth prevalence of 10.3 per 100 000 live births during October 1998 through December 1999. The decline in total NTDs during October 1998 through December 1999 compared with October 1995 through December 1996 was 19% (PR, 0.81; 95% CI, 0.75-0.87), from 37.8 to 30.5 per 100 000 live births. The decline in spina bifida and total NTDs was similar when the entire 7-year period from 1990 to 1996 was used as the referent group; however, the decline in the prevalence of anencephaly was greater when this alternative comparison group was used.

View this table: [in this window] [in a new window] Table 2. Effect Estimates for the Observed Decline in NTDs Following US Folic Acid Fortification of the Grain Supply, January 1990 to December 1999*

The NTD birth prevalence for women who received third-trimester only or no prenatal care was 53.4 per 100 000 from October 1995 through December 1996 and declined to 46.5 per 100 000 for October 1998 through December 1999 (PR, 0.87; 95% CI, 0.64-1.18). Comparing data from October 1998 through December 1999 with the entire period from 1990 through 1996 yielded a similar result (PR, 0.79; 95% CI, 0.62-1.00) (Table 2).

Among all women, data are presented by quarter of birth for spina bifida and anencephaly separately (Figure 1). Spina bifida prevalence has been declining since early 1997. The EWMA statistical analysis demonstrated a statistically significant increase in spina bifida prevalence in the fourth quarter of 1996, and statistically significant decreases in spina bifida prevalence in the second quarter of 1992, the fourth quarter of 1998, and the second and third quarters of 1999. Anencephaly prevalence was higher in 1990 to 1991, declined from late 1991 through 1994, remained relatively stable from 1995 to 1997, and showed a further slight decline in 1998 to 1999. For anencephaly, the EWMA analysis indicated 5 statistically significant increases in 1990 to 1991 and 3 statistically significant decreases from 1994 through 1997. There were also statistically significant decreases in anencephaly in the first and fourth quarters of 1998 and the second and fourth quarters of 1999.

View larger version (42K): [in this window] [in a new window] Figure 1. Trends in Spina Bifida and Anencephaly Among All Births, National Center for Health Statistics Vital Statistics Data, 1990-1999, for 45 US States and Washington, DC Arrows indicate statistically significant increases and decreases by the exponential weighted moving average analyses with parameters of = .01 and weight = 0.075.

Among women receiving third-trimester only or no prenatal care, data are presented in 6-month intervals (Figure 2). While the data are unstable, the point estimates for the last half of 1998 and all of 1999 are the 3 lowest points on the figure. A statistically significant decline in total NTDs was detected by the EWMA analysis in the second half of 1999 among women who received only third-trimester or no prenatal care. For comparability purposes, total NTDs among all births also are presented by 6-month intervals. The EWMA analysis for NTDs among all births showed 1 statistically significant increase (January to June 1991) and 3 statistically significant decreases in the last 3 time periods (July to December 1998, January to June 1999, and July to December 1999).

View larger version (40K): [in this window] [in a new window] Figure 2. Trends in Total NTDs (Anencephaly and Spina Bifida) Among All Births and All Births to Women Receiving Third-Trimester Only or No Prenatal Care, National Center for Health Statistics Vital Statistics Data, 1990-1999, for 45 US States and Washington, DC Arrows indicate statistically significant increases and decreases by the exponential weighted moving average analyses with parameters of = .01 and weight = 0.075. NTD indicates neural tube defects.

COMMENT

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Data from US birth certificates indicate a 19% decline in the birth prevalence of NTDs and a 23% decline in spina bifida prevalence among births conceived after mandatory folic acid fortification (October 1998 through December 1999) compared with the NTD prevalence before folic acid fortification (October 1995 through December 1996). This decline was temporally associated with the fortification of the grain supply with folic acid: the EWMA analysis indicated that a statistically significant decline in spina bifida prevalence occurred in the fourth quarter of 1998 and the second and third quarters of 1999. These declines were observed despite no apparent decline in sensitivity of the birth certificate during this time. Due to the public health importance of the NTD declines observed in our study, a brief announcement was published on the CDC's NCHS Web site in December 2000.²⁹

The long-term downward trend in anencephaly prevalence that preceded folic acid fortification makes it difficult to interpret the 11% decline following fortification. In particular, the mean anencephaly prevalence from 1990 through 1996 was heavily influenced by the high prevalence observed in 1990 to 1991 and may have resulted from reporting differences in those years. The check box format for reporting birth defects was introduced on the birth certificate in 1989, and anencephaly was the first check box on the congenital anomaly list. It is unclear why the EWMA analysis showed 5 statistically significant increases and 2 statistically significant decreases in anencephaly prevalence from 1990 to 1996, complicating the interpretation of the 4 significant decreases observed in 1998 and 1999.

Among infants whose mothers received third-trimester or no prenatal care, the magnitude of the decline in NTDs was similar when the entire period from 1990 through 1996 was used as the reference group, but the decline was not statistically significant when the 5 quarters just before fortification were used as the reference group. There was a statistically significant decline in this group during the last half of 1999 by the EWMA analysis. We expected that the birth prevalence of NTDs in this subgroup would be unaffected by changes in prenatal diagnosis or termination. While the NTD prevalence was higher among women receiving third-trimester only or no prenatal care, the trend was very similar to that for all births.

The 1999 National Health and Nutrition Examination Survey data documented dramatic increases in serum and red blood cell (RBC) folate levels among reproductive-aged women in the US population following folic acid fortification of enriched grain products.³⁰ This increase confirms the findings of 2 earlier studies of selected US populations that noted increases in serum folate levels beginning in 1997 that also may have been due to folic acid food fortification.^23-24 It is not known whether the increase in serum folate levels observed is sufficient to maximize NTD prevention, ³¹ but measurements of RBC folate levels taken early in pregnancy have shown a dose-response relation to the risk for having an infant with an NTD, with the lowest risk among those women with the highest RBC folate levels.³²

The authors of a study conducted in Ireland predicted a decline in NTD prevalence of a magnitude similar to that observed in our study if fortification added 100 µg of folic acid to the average daily diet of reproductive-aged women.^33-34 Daly et al³⁴ estimated that folic acid levels equivalent to the current level of fortification in the United States would result in a 22% reduction in the NTD risk. They also estimated that 200 µg would lead to a 41% reduction, and 400 µg would lead to a 47% reduction in NTD risk. Wald et al³³ extended these analyses and predicted 18%, 35%, and 53% reductions from 100, 200, and 400 µg, respectively. These estimates of 22% and 18% bracket the 19% decline observed in our study. However, recent data suggest that women may be getting more folic acid from fortification than was originally projected.³⁵ Despite these possibly higher levels of folic acid in fortified foods, we may have observed only a 19% decline due to differences between the US population and the Irish population on which these predictions were originally made or due to differences in lab techniques for measuring RBC folate levels in the Irish vs US studies.

A major concern is the validity of birth defect data from birth certificates. The sensitivity of birth certificates is low for total birth defects, but it is higher for defects that are usually diagnosed at birth. An evaluation of 1989 birth certificate data on birth defects in Tennessee found that the birth certificate had a 67% sensitivity to detect anencephaly and an 89% positive predictive value.²¹ One study found that of all 1989 and 1990 births in metropolitan Atlanta the sensitivity of the birth certificates was 86% for anencephaly and 40% for spina bifida and the positive predictive value was 100% for both defects.²⁰ A recent unpublished evaluation that indicated a sensitivity for anencephaly is closer to the Tennessee study than to the Atlanta study (written communication, L. Miller, MD, September 16, 1999). However, despite their limited sensitivity, the positive predictive value of NTDs reported on birth certificates is high. The high positive predictive value indicates that trends in true NTD cases are being observed rather than false positives.

If the sensitivity and specificity of birth certificates have remained stable over time, then observed declines in NTDs reported on birth certificates should represent actual declines in the birth prevalence of these defects. The percentage of all birth certificates with 1 or more defects other than NTDs remained relatively stable from 1991 through 1999 and even increased slightly in 1998 and 1999. Therefore, a variation in reporting of all defects on the birth certificate over time does not explain the decline observed in NTDs after folic acid fortification. However, we cannot rule out the possibility that subtle changes in the sensitivity of NTD reporting on birth certificates have contributed to the observed trends.

Birth certificates are completed for live births only; any NTD-affected pregnancies ending in induced or spontaneous abortions are not recorded. Any observed changes in the birth prevalence of NTDs may actually be due to changing patterns in the percentage of affected fetuses being born alive. There has been some debate on the possible role of folic acid in increasing or decreasing the likelihood of a spontaneous abortion of an NTD-affected pregnancy^36-38; however, in the absence of evidence to the contrary, we have assumed that the proportion of NTD-affected pregnancies that are spontaneously aborted has not changed over time.

The proportion of NTD-affected pregnancies that are electively terminated may be influenced by many factors, including the proportion of pregnant women receiving prenatal care, insurance reimbursement for prenatal diagnostic tests, availability of termination services, and improvements in the prognosis of the affected fetus. Termination is more likely to occur among pregnancies affected by anencephaly than among pregnancies affected by spina bifida.^39-40 Techniques, such as -fetoprotein screening and ultrasound, now are often used during the second trimester of pregnancy to detect fetal defects. In concert with pregnancy termination, these techniques have had a substantial impact on the prevalence of NTDs in live births as measured by surveillance systems. Several recent studies show that the percentage of NTD-affected pregnancies that were prenatally diagnosed and terminated ranged from 39% to 48%.^41-44 However, the Hawaii study,⁴⁴ which included cases from 1987 through 1996, suggested that the proportion of fetuses prenatally diagnosed with NTDs and terminated has remained relatively stable during that time, and no other evidence indicates that the percentage of affected pregnancies that are terminated has changed since 1990 in the United States. Indeed, spina bifida prevalence for 1990 to 1996 was relatively stable. It seems unlikely that a substantial increase in use of prenatal diagnosis and termination of pregnancies affected by an NTD occurred between 1996 and 1999.

The decline in NTDs observed among infants born to women who received only third-trimester or no prenatal care was similar to that observed for all women, but this was only statistically significant when the entire period from 1990 to 1996 was used as the reference group. This may be due to the limited number of women obtaining only third-trimester or no prenatal care. Our analysis comparing postfortification with prefortification births only had 40% power to detect a 20% decline in NTDs among women in this subgroup, but the analysis did have more than 90% power to detect a 40% decline in NTDs for these women. This difference in power means that is it unlikely that a large decline occurred that was not detected in our analysis. It seems implausible that increased use of prenatal diagnosis and termination caused the reduction in NTDs among total live births because the declines in women receiving third-trimester or no prenatal care were of similar magnitude to those observed among all births. We will continue to monitor the birth prevalence of NTDs to further evaluate the impact of folic acid fortification on the occurrence of NTDs.

AUTHOR INFORMATION

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Author Contributions: Study concept and design:Honein, Paulozzi, Mathews, Erickson.

Acquisition of data: Mathews.

Analysis and interpretation of data: Honein, Paulozzi, Mathews, Erickson, Wong.

Drafting of the manuscript: Honein.

Statistical expertise: Mathews, Wong.

Supervision: Paulozzi, Erickson.

Corresponding Author and Reprints: Margaret A. Honein, PhD, MPH, National Center on Birth Defects and Developmental Disabilities, Mailstop F-45, Centers for Disease Control and Prevention, 4770 Buford Hwy NE, Atlanta, GA 30341-3724 (e-mail: MHonein{at}cdc.gov).

Author Affiliations: National Center on Birth Defects and Developmental Disabilities (Drs Honein, Paulozzi, and Erickson, and Ms Wong) and Division of Vital Statistics, National Center for Health Statistics (Mr Mathews), Centers for Disease Control and Prevention, Atlanta, Ga.

REFERENCES

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1. Mulinare J, Erickson D. Prevention of neural tube defects. Teratology. 1997;56:17-18. FULL TEXT | ISI | PUBMED 2. CDC. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Morb Mortal Wkly Rep. 1992;41(RR-14):1-7. 3. MRC Vitamin Study Research Group. Prevention of neural tube defects. Lancet. 1991;338:131-137. FULL TEXT | ISI | PUBMED 4. Czeizel AE, Dudas I. Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation. N Engl J Med. 1992;327:1832-1835. ABSTRACT 5. Cornel MC, Erickson JD. Comparison of national policies on periconceptional use of folic acid to prevent spina bifida and anencephaly (SBA). Teratology. 1997;55:134-137. FULL TEXT | ISI | PUBMED 6. CDC. Knowledge and use of folic acid by women of childbearing age. MMWR Morb Mortal Wkly Rep. 1999;48:325-327. PUBMED 7. Food and Drug Administration. Food Standards. Federal Register. 1996;61:8781-8797. 8. Gregory III JF. Bioavailability of folate. Eur J Clin Nutr. 1997;51(suppl 1):554-559. 9. Romano PS, Waitzman NJ, Scheffler RM, Pi RD. Folic acid fortification of grain. Am J Public Health. 1995;85:667-676. FREE FULL TEXT 10. Freire WB, Hertrampf E, Cortes F. Effect of folic acid fortification in Chile: prelimary results. Eur J Pediatr Surs. 2000;10 Suppl 1:42-43. 11. Adams T, Jeffreson S. Australia implements voluntary folate fortification. Am J Public Health. 1996;86:593-594. FREE FULL TEXT 12. Turner LA, McCourt C. Folic acid fortification. CMAJ. 1998;158:773-774. PUBMED 13. Skeaff M, Mann J. Should folate be added to flour to prevent neural tube defects? N Z Med J. 1998;111:417-418. ISI | PUBMED 14. Daly S, Scott JM. The prevention of neural tube defects. Curr Opin Obstet Gynecol. 1998;10:85-89. FULL TEXT | ISI | PUBMED 15. Wynn M, Wynn A. Fortification of grain products with folate. Nutr Health. 1998;12:147-161. PUBMED 16. Committee on Medical Aspects of Food and Nutrition Policy (COMA). Folic acid and the prevention of disease. London, England: Department of Health; 2000. 17. Tolson GC, Barnes JM, Gay GA, Kowaleski JL. The 1989 revision of the US standard certificates and reports. Vital Health Stat. June 1991;No.28:1-34. DHHS publication PHS 91-1465. 18. Freedman MA, Gay GA, Brockert JE, Potrzebowski PW, Rothwell CJ. The 1989 revisions of the US standard certificates of live birth and death and the US standard report of fetal death. Am J Public Health. 1988;78:168-172. FREE FULL TEXT 19. Taffel SM, Ventura SJ, Gay GA. Revised US certificate of birth. Birth. 1989;16:188-193. ISI | PUBMED 20. Watkins ML, Edmonds L, McClearn A, Mullins L, Mulinare J, Khoury M. The surveillance of birth defects. Am J Public Health. 1996;86:731-734. FREE FULL TEXT 21. 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. 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Average run lengths of exponentially weighted moving average charts. J Qual Technol. 1987;19:161-164. 29. CDC. Trends in spina bifida and anencephalus in the United States, 1991-1999. Available at: http://www.cdc.gov/nchs/products/pubs/pubd/hestats/folic/folic.htm. Accessed December 12, 2000. 30. CDC. Folate status in women of childbearing age-United States, 1999. MMWR Morb Mortal Wkly Rep. 2000;49:962-965. PUBMED 31. Watkins ML, Erickson JD, Mulinare JRE. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med. 1999;341:923-924. PUBMED 32. Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM. Folate levels and neural tube defects. JAMA. 1995;274:1698-1702. FREE FULL TEXT 33. Wald NJ, Law M, Jordan R. Folic acid food fortification to prevent neural-tube defects. Lancet. 1998;351:834. ISI | PUBMED 34. Daly S, Mills JL, Molloy AM, et al. Minimum effective dose of folic acid for food fortification to prevent neural-tube defects. Lancet. 1997;350:1666-1669. FULL TEXT | ISI | PUBMED 35. Rader JI, Weaver CM, Angyal G. Total folate in enriched cereal-grain products in the United States following fortification. Food Chem. 2000;70:275-289. FULL TEXT 36. Hook EB, Czeizel AE. Can terathanasia explain the protective effect of folic-acid supplementation on birth defects? Lancet. 1997;350:513-515. FULL TEXT | ISI | PUBMED 37. Nelen W, Blom H, Steegers E, Den Heijer M, Thomas C, Eskes T. Homocysteine and folate levels as risk factors for recurrent early pregnancy loss. Obstet Gynecol. 2000;95:519-524. FULL TEXT | ISI | PUBMED 38. Wald NJ, Hackshaw AK. Folic acid and miscarriage. Am J Med Genet. 2001;98:204. FULL TEXT | ISI | PUBMED 39. Grevengood C, Shulman LP, Dungan JS, et al. Severity of abnormality influences decision to terminate pregnancies affected with fetal neural tube defects. Fetal Diagn Ther. 1994;9:273-277. ISI | PUBMED 40. Pryde PG, Isada NB, Hallak M, Johnson MP, Odgers AE, Evans MI. Determinants of parental decision to abort or continue after non-aneuploid ultrasound-detected fetal abnormalities. Obstet Gynecol. 1992;80:52-56. ISI | PUBMED 41. Roberts HE, Moore CA, Cragan JD, Fernhoff PM, Khoury MJ. Impact of prenatal diagnosis on the birth prevalence of neural tube defects, Atlanta, 1990-1991. Pediatrics. 1995;96:880-882. FREE FULL TEXT 42. Velie EM, Shaw GM. Impact of prenatal diagnosis and elective termination on prevalence and risk estimates of neural tube defects in California, 1989-1991. Am J Epidemiol. 1996;144:473-479. FREE FULL TEXT 43. Allen WP, Stevenson RE, Thompson SJ, Dean JH. The impact of prenatal diagnosis on surveillance. Prenat Diagn. 1996;16:531-535. FULL TEXT | ISI | PUBMED 44. Forrester MB, Merz RD, Yoon PW. Impact of prenatal diagnosis and elective termination on the prevalence of selected birth defects in Hawaii. Am J Epidemiol. 1998;148:1206-1211. FREE FULL TEXT

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Serum Folate and Cancer Mortality Among U.S. Adults: Findings from the Third National Health and Nutritional Examination Survey Linked Mortality File
Yang et al.
Cancer Epidemiol. Biomarkers Prev. 2009;18:1439-1447.
ABSTRACT | FULL TEXT  

Maternal Vitamin B12 Status and Risk of Neural Tube Defects in a Population With High Neural Tube Defect Prevalence and No Folic Acid Fortification
Molloy et al.
Pediatrics 2009;123:917-923.
ABSTRACT | FULL TEXT  

Is it time for vitamin B-12 fortification? What are the questions?
Green
Am. J. Clin. Nutr. 2009;89:712S-716S.
ABSTRACT | FULL TEXT  

Folate, Related B Vitamins, and Homocysteine in Childhood and Adolescence: Potential Implications for Disease Risk in Later Life
Kerr et al.
Pediatrics 2009;123:627-635.
ABSTRACT | FULL TEXT  

Demographic, Lifestyle, and Health Characteristics and Serum B Vitamin Status Are Determinants of Plasma Total Homocysteine Concentration in the Post-Folic Acid Fortification Period, 1999-2004
Ganji and Kafai
J. Nutr. 2009;139:345-352.
ABSTRACT | FULL TEXT  

Unmetabolized folic acid and total folate concentrations in breast milk are unaffected by low-dose folate supplements
Houghton et al.
Am. J. Clin. Nutr. 2009;89:216-220.
ABSTRACT | FULL TEXT  

Hemoglobin and hematocrit values are higher and prevalence of anemia is lower in the post-folic acid fortification period than in the pre-folic acid fortification period in US adults
Ganji and Kafai
Am. J. Clin. Nutr. 2009;89:363-371.
ABSTRACT | FULL TEXT  

Neural Tube Defects and Maternal Folate Intake Among Pregnancies Conceived After Folic Acid Fortification in the United States
Mosley et al.
Am J Epidemiol 2009;169:9-17.
ABSTRACT | FULL TEXT  

Invited Commentary: Preventing Neural Tube Defects and More via Food Fortification?
Mills and Carter
Am J Epidemiol 2009;169:18-21.
ABSTRACT | FULL TEXT  

Unexplained decline in the prevalence of anemia among US children and women between 1988-1994 and 1999-2002
Cusick et al.
Am. J. Clin. Nutr. 2008;88:1611-1617.
ABSTRACT | FULL TEXT  

Circulating folic acid in plasma: relation to folic acid fortification
Kalmbach et al.
Am. J. Clin. Nutr. 2008;88:763-768.
ABSTRACT | FULL TEXT  

Folic Acid Supplementation and Cancer Risk: Point
Kim
Cancer Epidemiol. Biomarkers Prev. 2008;17:2220-2225.
FULL TEXT  

Folate status and homocysteine response to folic acid doses and withdrawal among young Chinese women in a large-scale randomized double-blind trial
Hao et al.
Am. J. Clin. Nutr. 2008;88:448-457.
ABSTRACT | FULL TEXT  

Improper Supplementation Habits of Folic Acid Intake by Hungarian Pregnant Women: Improper Recommendations
Bognar et al.
J. Am. Coll. Nutr. 2008;27:499-504.
ABSTRACT | FULL TEXT  

Prevalence and effects of gene-gene and gene-nutrient interactions on serum folate and serum total homocysteine concentrations in the United States: findings from the third National Health and Nutrition Examination Survey DNA Bank
Yang et al.
Am. J. Clin. Nutr. 2008;88:232-246.
ABSTRACT | FULL TEXT  

Does Folic Acid Supplementation Prevent or Promote Colorectal Cancer? Results from Model-Based Predictions
Luebeck et al.
Cancer Epidemiol. Biomarkers Prev. 2008;17:1360-1367.
ABSTRACT | FULL TEXT  

One-carbon metabolism-related gene polymorphisms and risk of breast cancer
Suzuki et al.
Carcinogenesis 2008;29:356-362.
ABSTRACT | FULL TEXT  

Moderately High Folic Acid Supplementation Exacerbates Experimentally Induced Liver Fibrosis in Rats
Marsillach et al.
Exp. Biol. Med. 2008;233:38-47.
ABSTRACT | FULL TEXT  

Reassessing folic acid consumption patterns in the United States (1999 2004): potential effect on neural tube defects and overexposure to folate
Quinlivan and Gregory
Am. J. Clin. Nutr. 2007;86:1773-1779.
ABSTRACT | FULL TEXT  

Effect of a voluntary food fortification policy on folate, related B vitamin status, and homocysteine in healthy adults
Hoey et al.
Am. J. Clin. Nutr. 2007;86:1405-1413.
ABSTRACT | FULL TEXT  

Calculation of red blood cell folate steady state conditions and elimination kinetics after daily supplementation with various folate forms and doses in women of childbearing age
Pietrzik et al.
Am. J. Clin. Nutr. 2007;86:1414-1419.
ABSTRACT | FULL TEXT  

Proportion of individuals with low serum vitamin B-12 concentrations without macrocytosis is higher in the post folic acid fortification period than in the pre folic acid fortification period
Wyckoff and Ganji
Am. J. Clin. Nutr. 2007;86:1187-1192.
ABSTRACT | FULL TEXT  

Trends in blood folate and vitamin B-12 concentrations in the United States, 1988 2004
Pfeiffer et al.
Am. J. Clin. Nutr. 2007;86:718-727.
ABSTRACT | FULL TEXT  

Utility of Family History Reports of Major Birth Defects as a Public Health Strategy
Romitti
Pediatrics 2007;120:S71-S77.
ABSTRACT | FULL TEXT  

A Temporal Association between Folic Acid Fortification and an Increase in Colorectal Cancer Rates May Be Illuminating Important Biological Principles: A Hypothesis
Mason et al.
Cancer Epidemiol. Biomarkers Prev. 2007;16:1325-1329.
ABSTRACT | FULL TEXT  

Should folic acid fortification be mandatory? Yes
Wald and Oakley
BMJ 2007;334:1252-1252.
FULL TEXT  

Wheat Flour Fortification Is Unlikely to Benefit the Neediest in Guatemala
Imhoff-Kunsch et al.
J. Nutr. 2007;137:1017-1022.
ABSTRACT | FULL TEXT  

Assistive Technology Use Among Adolescents and Young Adults With Spina Bifida
Johnson et al.
AJPH 2007;97:330-336.
ABSTRACT | FULL TEXT  

Very Low Oral Doses of Vitamin B-12 Increase Serum Concentrations in Elderly Subjects with Food-Bound Vitamin B-12 Malabsorption
Blacher et al.
J. Nutr. 2007;137:373-378.
ABSTRACT | FULL TEXT  

Meta-analyses of Observational and Genetic Association Studies of Folate Intakes or Levels and Breast Cancer Risk.
Lewis et al.
JNCI J Natl Cancer Inst 2006;98:1607-1622.
ABSTRACT | FULL TEXT  

Population-Level Changes in Folate Intake by Age, Gender, and Race/Ethnicity after Folic Acid Fortification
Bentley et al.
AJPH 2006;96:2040-2047.
ABSTRACT | FULL TEXT  

Hospitalizations of Newborns With Folate-Sensitive Birth Defects Before and After Fortification of Foods With Folic Acid
Robbins et al.
Pediatrics 2006;118:906-915.
ABSTRACT | FULL TEXT  

Are Encephaloceles Neural Tube Defects?
Rowland et al.
Pediatrics 2006;118:916-923.
ABSTRACT | FULL TEXT  

Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age
Lamers et al.
Am. J. Clin. Nutr. 2006;84:156-161.
ABSTRACT | FULL TEXT  

Folate and human reproduction
Tamura and Picciano
Am. J. Clin. Nutr. 2006;83:993-1016.
ABSTRACT | FULL TEXT  

Improvement in Stroke Mortality in Canada and the United States, 1990 to 2002
Yang et al.
Circulation 2006;113:1335-1343.
ABSTRACT | FULL TEXT  

Survival of Infants With Neural Tube Defects in the Presence of Folic Acid Fortification
Bol et al.
Pediatrics 2006;117:803-813.
ABSTRACT | FULL TEXT  

Folate supplementation: too much of a good thing?
Ulrich and Potter
Cancer Epidemiol. Biomarkers Prev. 2006;15:189-193.
FULL TEXT  

Trends in Serum Folate, RBC Folate, and Circulating Total Homocysteine Concentrations in the United States: Analysis of Data from National Health and Nutrition Examination Surveys, 1988-1994, 1999-2000, and 2001-2002
Ganji and Kafai
J. Nutr. 2006;136:153-158.
ABSTRACT | FULL TEXT  

Low folate status is associated with impaired cognitive function and dementia in the Sacramento Area Latino Study on Aging
Ramos et al.
Am. J. Clin. Nutr. 2005;82:1346-1352.
ABSTRACT | FULL TEXT  

Decline in the Prevalence of Spina Bifida and Anencephaly by Race/Ethnicity: 1995-2002
Williams et al.
Pediatrics 2005;116:580-586.
ABSTRACT | FULL TEXT  

Preventing neural tube defects in Europe: population based study
Busby et al.
BMJ 2005;330:574-575.
FULL TEXT  

International retrospective cohort study of neural tube defects in relation to folic acid recommendations: are the recommendations working?
Botto et al.
BMJ 2005;330:571.
ABSTRACT | FULL TEXT  

Common dihydrofolate reductase 19-base pair deletion allele: a novel risk factor for preterm delivery
Johnson et al.
Am. J. Clin. Nutr. 2005;81:664-668.
ABSTRACT | FULL TEXT  

Status of plasma folate after folic acid fortification of the food supply in pregnant African American women and the influences of diet, smoking, and alcohol consumption
Stark et al.
Am. J. Clin. Nutr. 2005;81:669-677.
ABSTRACT | FULL TEXT  

Folic Acid Supplementation Diminishes Diabetes- and Glucose-Induced Dysmorphogenesis in Rat Embryos In Vivo and In Vitro
Wentzel et al.
Diabetes 2005;54:546-553.
ABSTRACT | FULL TEXT  

Will mandatory folic acid fortification prevent or promote cancer?
Kim
Am. J. Clin. Nutr. 2004;80:1123-1128.
ABSTRACT | FULL TEXT  

Determining bioavailability of food folates in a controlled intervention study
Hannon-Fletcher et al.
Am. J. Clin. Nutr. 2004;80:911-918.
ABSTRACT | FULL TEXT  

Plasma folate concentrations are associated with depressive symptoms in elderly Latina women despite folic acid fortification
Ramos et al.
Am. J. Clin. Nutr. 2004;80:1024-1028.
ABSTRACT | FULL TEXT  

Risk of congenital anomalies detected during antenatal serum screening in women with pregestational diabetes
Ray et al.
QJM 2004;97:651-653.
ABSTRACT | FULL TEXT  

Changes in knowledge and attitudes of folate, and use of dietary supplements among women of reproductive age in Norway 1998 - 2000
Daltveit et al.
Scand J Public Health 2004;32:264-271.
ABSTRACT  

Balancing benefits and harms in public health prevention programmes mandated by governments
Oakley and Johnston
BMJ 2004;329:41-43.
FULL TEXT  

Treatment of coronary heart disease with folic acid: is there a future?
Moat et al.
Am. J. Physiol. Heart Circ. Physiol. 2004;287:H1-H7.
FULL TEXT  

Folic Acid Supplementation Does Not Prevent Lipomyelomeningocele
Piatt
AAP Grand Rounds 2004;11:43-44.
FULL TEXT  

Supplementation with [6S]-5-methyltetrahydrofolate or folic acid equally reduces plasma total homocysteine concentrations in healthy women
Lamers et al.
Am. J. Clin. Nutr. 2004;79:473-478.
ABSTRACT | FULL TEXT  

The Short-Term Bioavailabilities of [6S]-5-Methyltetrahydrofolate and Folic Acid Are Equivalent in Men
Pentieva et al.
J. Nutr. 2004;134:580-585.
ABSTRACT | FULL TEXT  

Determination of Folate Vitamers in Human Serum by Stable-Isotope-Dilution Tandem Mass Spectrometry and Comparison with Radioassay and Microbiologic Assay
Pfeiffer et al.
Clin. Chem. 2004;50:423-432.
ABSTRACT | FULL TEXT  

Facts and Recommendations about Total Homocysteine Determinations: An Expert Opinion
Refsum et al.
Clin. Chem. 2004;50:3-32.
ABSTRACT | FULL TEXT  

Long-latency deficiency disease: insights from calcium and vitamin D
Heaney
Am. J. Clin. Nutr. 2003;78:912-919.
ABSTRACT | FULL TEXT  

Sonographic Signs of Fetal Neural Tube and Central Nervous System Defects
Stephenson
Journal of Diagnostic Medical Sonography 2003;19:347-357.
ABSTRACT  

Antagonism of Hypervitaminosis A-Induced Anterior Neural Tube Closure Defects with a Methyl-Donor Deficiency in Murine Whole-Embryo Culture
Santos-Guzman et al.
J. Nutr. 2003;133:3561-3570.
ABSTRACT | FULL TEXT  

Bioaccessibility of Folic Acid and (6S)-5-Methyltetrahydrofolate Decreases after the Addition of Folate-Binding Protein to Yogurt as Studied in a Dynamic In Vitro Gastrointestinal Model,2
Arkbage et al.
J. Nutr. 2003;133:3678-3683.
ABSTRACT | FULL TEXT  

Role of Folate in Colon Cancer Development and Progression
Kim
J. Nutr. 2003;133:3731S-3739.
ABSTRACT | FULL TEXT  

Consumption of Folic Acid-Fortified Bread Improves Folate Status in Women of Reproductive Age in Chile
Hertrampf et al.
J. Nutr. 2003;133:3166-3169.
ABSTRACT | FULL TEXT  

Management issues for women with epilepsy: Neural tube defects and folic acid supplementation
Yerby
Neurology 2003;61:S23-26.
ABSTRACT | FULL TEXT  

Complete sequencing shows a role for MSX1 in non-syndromic cleft lip and palate
Jezewski et al.
J. Med. Genet. 2003;40:399-407.
ABSTRACT | FULL TEXT  

Folic Acid Supplements and Fortification Affect the Risk for Neural Tube Defects, Vascular Disease and Cancer: Evolving Science,
Bailey et al.
J. Nutr. 2003;133:1961S-1968.
ABSTRACT | FULL TEXT  

Folic acid and reduction of plasma homocysteine concentrations in older adults: a dose-response study
van Oort et al.
Am. J. Clin. Nutr. 2003;77:1318-1323.
ABSTRACT | FULL TEXT  

Vitamin B12 insufficiency and the risk of fetal neural tube defects
Ray and Blom
QJM 2003;96:289-295.
ABSTRACT | FULL TEXT  

Genetic and nutritional factors contributing to hyperhomocysteinemia in young adults
Kluijtmans et al.
Blood 2003;101:2483-2488.
ABSTRACT | FULL TEXT  

Comparison of the effect of low-dose supplementation with L-5-methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebo-controlled study
Venn et al.
Am. J. Clin. Nutr. 2003;77:658-662.
ABSTRACT | FULL TEXT  

Folate fortification: enough already?
Shane
Am. J. Clin. Nutr. 2003;77:8-9.
FULL TEXT  

Influence of reporting error on the relation between blood folate concentrations and reported folic acid-containing dietary supplement use among reproductive-aged women in the United States
Yang and Erickson
Am. J. Clin. Nutr. 2003;77:196-203.
ABSTRACT | FULL TEXT  

Plasma Folate Levels and Risk of Spontaneous Abortion
George et al.
JAMA 2002;288:1867-1873.
ABSTRACT | FULL TEXT  

Use of folic acid supplements in the first trimester of pregnancy
Langley-Evans and Langley-Evans
The Journal of the Royal Society for the Promotion of Health 2002;122:181-186.
ABSTRACT  

D-chiro-inositol is more effective than myo-inositol in preventing folate-resistant mouse neural tube defects
Cogram et al.
Hum Reprod 2002;17:2451-2458.
ABSTRACT | FULL TEXT  

Folic Acid Intake from Fortification in United States Exceeds Predictions
Choumenkovitch et al.
J. Nutr. 2002;132:2792-2798.
ABSTRACT | FULL TEXT  

Incidence of open neural tube defects in Nova Scotia after folic acid fortification
Persad et al.
CMAJ 2002;167:241-245.
ABSTRACT | FULL TEXT  

Neural tube defects and periconceptional folic acid
Kadir and Economides
CMAJ 2002;167:255-256.
FULL TEXT  

The Importance of Promoting a Whole Grain Foods Message
Jones et al.
J. Am. Coll. Nutr. 2002;21:293-297.
ABSTRACT | FULL TEXT  

Folic Acid Fortification, Folate Status and Plasma Homocysteine
Rader
J. Nutr. 2002;132:2466S-2470.
ABSTRACT | FULL TEXT  

What Vitamins Should I Be Taking?
Blackman et al.
NEJM 2002;346:1914-1916.
FULL TEXT  

Changes in frequencies of heterozygous thermolabile 5,10-methylenetetrahydrofolate reductase gene in fetuses with neural tube defects
Johanning et al.
J. Med. Genet. 2002;39:366-367.
FULL TEXT  

American Cancer Society Guidelines on Nutrition and Physical Activity for Cancer Prevention: Reducing the Risk of Cancer with Healthy Food Choices and Physical Activity
Byers et al.
CA Cancer J Clin 2002;52:92-119.
ABSTRACT | FULL TEXT  

The Evolution of Research in Family and Consumer Sciences: Food, Nutrition, and Health
Schlenker
Family and Consumer Sciences Research Journal 2001;30:140-196.
ABSTRACT  

Folic Acid Fortification Increases Red Blood Cell Folate Concentrations in the Framingham Study
Choumenkovitch et al.
J. Nutr. 2001;131:3277-3280.
ABSTRACT | FULL TEXT  

Fortification of flour with folic acid
Wharton and Booth
BMJ 2001;323:1198-1199.
FULL TEXT  

Public Health 101 for Informaticians
Koo et al.
J. Am. Med. Inform. Assoc. 2001;8:585-597.
ABSTRACT | FULL TEXT  

Food Fortification to Prevent Neural Tube Defects: Is It Working?
Mills and England
JAMA 2001;285:3022-3023.
FULL TEXT