Published online March 1, 2006
PEDIATRICS Vol. 117 No. 3 March 2006, pp. 803-813 (doi:10.1542/10.1542/peds.2005-1364)
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Survival of Infants With Neural Tube Defects in the Presence of Folic Acid Fortification

Kirk A. Bol, MSPHa, Julianne S. Collins, PhDb, Russell S. Kirby, PhD, MSc for the National Birth Defects Prevention Network

a Colorado Responds to Children With Special Needs, Colorado Department of Public Health and Environment, Denver, Colorado
b JC Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina
c Department of Maternal and Child Health, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE. Neural tube defects (NTDs) are preventable through preconceptional and periconceptional folic acid intake. Although decreases in the prevalence of NTDs have been reported since folic acid fortification of United States grain products began, it is not known whether folic acid plays a role in reducing the severity of occurring NTDs. Our aim was to determine whether survival among infants born with spina bifida and encephalocele has improved since folic acid fortification and to measure the effects of selected maternal, pregnancy, and birth characteristics on first-year (infant) survival rates.

METHODS. A retrospective cohort study was conducted and included 2841 infants with spina bifida and 638 infants with encephalocele who were born between 1995 and 2001 and were registered in any of 16 participating birth defects monitoring programs in the United States. First-year survival rates for both spina bifida and encephalocele cohorts were measured with Kaplan-Meier estimation; factors associated with improved chances of first-year survival, including birth before or during folic acid fortification, were measured with Cox proportional-hazards regression analysis.

RESULTS. Infants with spina bifida experienced a significantly improved first-year survival rate of 92.1% (adjusted hazard ratio: 0.68; 95% confidence interval: 0.50–0.91) during the period of mandatory folic acid fortification, compared with a 90.3% survival rate for those born before fortification. Infants with encephalocele had a statistically nonsignificant increase in survival rates, ie, 79.1% (adjusted hazard ratio: 0.76; 95% confidence interval: 0.51–1.13) with folic acid fortification, compared with 75.7% for earlier births.

CONCLUSIONS. Folic acid may play a role in reducing the severity of NTDs in addition to preventing the occurrence of NTDs. This phenomenon contributes to our understanding of the efficacy of folic acid. Additionally, as survival of NTD-affected infants improves, health care, education, and family support must expand to meet their needs.

Key Words: birth defects • folic acid • neural tube defects • spina bifida • encephalocele • infant mortality • first-year survival

Abbreviations: NTD—neural tube defect • HR—hazard ratio • CI—confidence interval • ICD-9-CM—International Classification of Diseases, Ninth Revision, Clinical Modification

Neural tube defects (NTDs) are characterized as congenital defects of the central nervous system resulting from incomplete or incorrect closure of the neural tube during early embryologic development.1,2 NTDs are thought to be caused primarily by chromosomal abnormalities, single-gene disorders, and environmental agents.3 Two randomized, controlled, clinical trials demonstrated the success of the B vitamin folic acid in preventing a substantial proportion of NTDs.4,5 A number of observational studies reported that periconceptional use of folic acid may prevent NTDs.4,6–10 Folic acid also reduces the risk of recurrent NTD-affected births among mothers at higher risk because of a previous NTD-affected birth.1,2,9,11–15 The US Public Health Service and the Institute of Medicine recommended that women of childbearing age who are capable of becoming pregnant consume 400 µg of folic acid daily, to reduce the risk of a NTD-affected pregnancy.16,17 Meanwhile, the US Food and Drug Administration established regulations authorizing optional fortification of the US flour and enriched grain supply with 140 µg of folic acid per 100 g of grain in March 1996 and requiring such fortification by January 1, 1998.18,19

Several studies demonstrated decreases in the prevalence of NTDs19–23 and the rates of infant deaths attributable to NTDs,24,25 coinciding with both early and widespread introduction of folic acid into the US food supply. Despite these reported successes, children continue to be born with and die as a result of NTDs. Although the prevalence of births affected by NTDs is decreasing, infants affected by congenital anomalies remain at increased risk of neonatal morbidity and perinatal death.26 This raises the question of whether changes in the severity of NTDs have occurred with folic acid fortification. This interest is twofold. (1) If severity is decreasing in the presence of folic acid fortification, as measured by increased survival rates for infants with NTDs, then steps must be taken by parents and care providers to plan for the needs of a longer-lived population of children with NTDs. (2) Such improvements would suggest another beneficial effect of folic acid consumption.

Survival analyses applied to a large cohort of infants with NTDs provide the opportunity to measure both the survival experiences of selected subpopulations and factors contributing to increased or decreased survival rates among these infants. Examples of such survival analyses include 2 studies based on data from the Metropolitan Atlanta Congenital Defects Program, which analyzed survival rates among infants with spina bifida and encephalocele.27,28

Building on these earlier studies, we assembled a large birth cohort from 16 population-based state or regional birth defects surveillance programs in the United States. We examined patterns of survival among infants born with spina bifida or encephalocele, to determine whether survival rates during the period of mandatory folic acid fortification were greater than survival rates for births that occurred before such fortification and to measure the effects of selected maternal, pregnancy, and birth characteristics on the survival rates for infants with NTDs.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Design and Description of Variables
Information on infants with NTDs was provided by population-based birth defects monitoring programs from the following states or regions: Alabama, California, Colorado, Hawaii, Illinois, Iowa, Kentucky, metropolitan Atlanta, Michigan, New York, North Carolina, Oklahoma, Rhode Island, South Carolina, Texas, and West Virginia. This cooperative effort was facilitated by the sponsorship and guidance of the National Birth Defects Prevention Network and its NTD Surveillance and Folic Acid Education Committee. The Colorado birth defects monitoring program, Colorado Responds to Children With Special Needs, served as the data collection and analysis center for this study.

Specific birth defect records requested were anencephalus (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 740.0, 740.1, and 740.2), spina bifida (ICD-9-CM codes 741.0 and 741.9), and encephalocele (ICD-9-CM code 742.0) occurrences among live-born infants born between 1995 and 2001; cases were neither reviewed nor verified for accuracy of diagnosis on receipt by Colorado Responds to Children With Special Needs. Fetal deaths, including elective terminations and unintended fetal deaths, were excluded from the cohort. Merging of the NTD-affected live birth data with individual state linked birth/infant death files and/or vital status follow-up activities were conducted by each participating monitoring program individually, to ascertain survival status for the first 1 year of life and the duration of life in days.

Among the states represented by participating programs, between 95% and 100% of all infant deaths were linked to a birth certificate in 2001 (with similar percentages in previous years).29 Also, as part of agreements between states and the National Center for Health Statistics, the state of infant death is responsible for obtaining birth certificate information from the state of birth when the 2 states are different.29 Therefore, few if any infant deaths among the reported cases of NTDs are thought to have been missed.

Participating programs were asked to provide survival time, reported as age in days at the time of death, for each case record linked to a corresponding death certificate. Records were classified according to date of birth into 3 time periods, corresponding to the status of folic acid fortification in the United States, ie, "prefortification" for births between January 1995 and December 1996, "optional fortification" for births between January 1997 and September 1998, and "mandatory fortification" for births between October 1998 and December 2001.19

Individual cohorts of infants with spina bifida and encephalocele were constructed, and cases with concurrent anencephaly were excluded. Plural births were also excluded from this analysis. Cases with concurrent spina bifida and encephalocele, without anencephaly, were included in both spina bifida and encephalocele cohorts, so as not to exclude these rare cases from either group and to account for the special needs resulting from each diagnosis. Survival data for births with anencephaly were not analyzed because of the incompatibility of this condition with life and previously reported infant fatality rates of 100%.30,31 Multiple anomalies were accounted for by grouping additional concurrent anomalies into 1 of 12 organ systems, and the number of diagnosis groups, including the NTD, was tallied for each case.32,33 These organ systems corresponded to 3-digit ICD-9-CM categories for congenital anomalies, including central nervous system (ICD-9-CM codes 740, 741, and 742), eye (ICD-9-CM code 743), ear (ICD-9-CM code 744), cardiovascular (ICD-9-CM codes 745, 746, and 747), respiratory (ICD-9-CM code 748), oral clefts and alimentary (ICD-9-CM codes 749 and 750), digestive (ICD-9-CM code 751), genitourinary (ICD-9-CM codes 752 and 753), musculoskeletal (ICD-9-CM codes 754, 755, and 756), integument (ICD-9-CM code 757), chromosomal (ICD-9-CM code 758), and other specified/unspecified anomalies (ICD-9-CM code 759). Cases from registries using a diagnosis coding scheme other than ICD-9-CM (for example, the British Pediatric Association birth defect codes or modifications thereof) were converted after receipt by the analysis center, on the basis of the concordance at the 3-digit level of these coding schemes with ICD-9-CM.

Adequacy of prenatal care was measured with the Kotelchuck Adequacy of Prenatal Care Utilization index, which takes into account number of prenatal care visits, month of the first prenatal care visit, gender of the infant, estimated gestational age at the time of birth, and birth weight.34 An index accounting for birth weight and gestational age was used to model these factors and their likely interaction.35 The clinical estimates of gestation were grouped as term (≥37 weeks) or preterm (<37 weeks), birth weights were categorized as normal (≥2500 g), low (1500–2499 g), or very low (<1500 g), and the 6 resultant combinations were used in analyses. Groupings for additional prognostic factors considered for this study, including other maternal, pregnancy, and birth characteristics, are presented in Table 1.


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  		TABLE 1 Descriptive Data, Univariate Rank Results, and Multivariate HRs for Spina Bifida

 
Statistical Analyses
Kaplan-Meier estimates of the infant survival rates of both spina bifida and encephalocele cohorts were generated by using reported age (in days) at death as the measure of survival time; patients who had survival times of >365 days or were reported to have survived beyond infancy were censored.36,37 Because cause of death could not be obtained from all participating registries, an outcome of death attributable to any cause was used for this study, so that all deaths among patients with spina bifida or encephalocele contributed to the survival estimates.

We also calculated unadjusted hazard ratios (HRs) for each prognostic factor, by using the Cox method for proportional-hazards regression.36–38 Finally, multivariate proportional-hazards modeling with interactive modeling techniques was performed for both spina bifida and encephalocele cohorts, with published modeling strategies.37 The strategy used here includes the manual inclusion and exclusion of variables of interest on the basis of significant univariate analysis results, plausibility of effect, and considerations of statistical significance based on changes in log-likelihood estimates as variables were introduced and removed from the increasingly refined models. The product of proportional-hazards regression, the HR, is the ratio of the hazard of death at any time (from birth to 1 year of age) in a group with a given exposure to that of a reference group. The significance of factors was determined with log-likelihood testing (2-tailed testing with {alpha} = .05). Kaplan-Meier survival estimates were computed with PROC LIFETEST, and Cox proportional-hazards estimates were computed with PROC PHREG, both in SAS version 9.1 (SAS Institute, Cary NC).39


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Group Characteristics
A total of 4402 cases of congenital anomalies of the central nervous system involving infants born between 1995 and 2001 were submitted from 16 participating birth defects monitoring programs. Of these, 4052 cases met the case selection criteria of singleton birth with anencephaly, spina bifida, or encephalocele. For this analysis, 614 cases of anencephaly (either isolated or concurrent with another anomaly) were excluded, yielding study cohorts of 2841 cases of spina bifida and 638 cases of encephalocele. Included in both cohorts were 41 cases with concurrent spina bifida and encephalocele (Fig 1).


Figure 1
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  		FIGURE 1 Flowchart for case identification and selection.

 
Some of the participating programs were unable to submit cases for all birth years between 1995 and 2001. These final spina bifida and encephalocele cohorts arose from a combined population of 7 281 479 births, the total coverage of the monitoring programs, accounting for the unequal time periods submitted. This coverage represents ~41% of all live births in the states represented by the 16 participating monitoring programs during the prefortification period, 52% of live births during the optional fortification period, and 56% of live births during the mandatory fortification period.40 Coverage of the participating programs was obtained through reports submitted to a National Birth Defects Prevention Network-sponsored NTD-reporting system, which was described previously.19

Univariate and Multivariate Survival Measures and Predictors
For both the spina bifida and encephalocele cohorts, survival rates were estimated with Kaplan-Meier estimation across the 3 folic acid fortification periods, ie, prefortification, optional fortification, and mandatory fortification. The estimated first-year survival rates for infants with spina bifida were 90.3%, 90.5%, and 92.1%, respectively, whereas the survival rates for infants with encephalocele were 75.7%, 79.5%, and 79.1%, respectively. Figure 2 presents the Kaplan-Meier survival curves for each of these birth cohorts. Initial analyses of differences across the 3 fortification periods for both cohorts with log-rank tests showed nonsignificant (at the P = .05 level) associations between fortification period and survival rates. Univariate, Cox proportional-hazards, regression analysis of fortification period for NTD cohorts also produced nonsignificant HRs (results not shown). Survival rates for both spina bifida and encephalocele cohorts with respect to other selected maternal, pregnancy, and birth characteristics, as well as case counts and numbers of infant deaths, are presented in Tables 1 and 2. Results from complete, multivariate, Cox proportional-hazards, regression models, controlling for all prognostic factors, are also presented in Tables 1 and 2. These factors include period of birth, maternal age, gestation/birth weight, number of diagnosis groups, maternal race/ethnicity, maternal education, induction of labor, maternal smoking, infant gender, maternal marital status, occurrence of previous live birth, method of delivery, and Kotelchuck prenatal care index value.


Figure 2
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  		FIGURE 2 Spina bifida and encephalocele survival rates according to folic acid fortification periods (Kaplan-Meier survival estimates).

 

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  		TABLE 2 Descriptive Data, Univariate Rank Results, and Multivariate HRs for Encephalocele

 
Application of the interactive modeling procedures to the cohort of infants with spina bifida confirmed that having been born during the period of mandatory folic acid fortification was associated with increased survival rate/reduced hazard (HR: 0.68; 95% confidence interval [CI]: 0.50–0.91), whereas the optional fortification period of birth was not associated with increased survival rate (HR: 0.94; 95% CI: 0.68–1.31) (Table 3). In addition, adjustment for gestation/birth weight interactions and the number of concurrent diagnosis groups demonstrated that induction of labor contributed to increased hazard (HR: 1.96; 95% CI: 1.41–2.71), whereas cesarean delivery reduced hazard (HR: 0.53; 95% CI: 0.40–0.70) (Table 3).


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  		TABLE 3 Results of Interactive, Multivariate, Cox Proportional-Hazards, Modeling Procedure for Spina Bifida

 
Similar interactive modeling performed for the encephalocele cohort revealed that birth in neither the optional nor mandatory folic acid fortification period was associated significantly with increased survival rate (Table 4). However, after adjustment for gestation/birth weight interactions and concurrent diagnosis groups, induction of labor was associated with increased hazard (HR: 1.61; 95% CI: 1.00–2.63), and encephalic infants born to Hispanic mothers were at increased hazard of death during infancy (HR: 1.73; 95% CI: 1.14–2.62).


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  		TABLE 4 Results of Interactive, Multivariate, Cox Proportional-Hazards, Modeling Procedure for Encephalocele

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Survival Results
This report analyzed population-based data on NTDs from 16 birth defects monitoring programs, one of the largest cohorts of live births diagnosed with NTDs assembled to date. These registry data have distinct advantages over the use of birth certificates as a sole source of birth defect reporting, perhaps the greatest of which is more complete reporting of NTDs and other birth defect occurrences.41 This collaborative project provided a rare opportunity to study changes in survival rates in the critical period before, during, and after folic acid fortification of the US flour and grain supply and to assess the contribution of a set of maternal, pregnancy, and birth characteristics to increased risk of death during the first 1 year of life.

The overall first-year survival rate for this cohort of live births from 1995 to 2001 with spina bifida, 91.2%, is in line with, although consistently higher than, other published figures. Wong and Paulozzi28 reported an 87.2% first-year survival rate for such infants born in metropolitan Atlanta between 1979 and 1994, with a rate of 91% for 1989 to 1994. Nembhard et al31 reported an 87.3% first-year survival rate for Texas infants with spina bifida born between 1995 and 1997. We observed a 78.1% overall first-year survival rate for infants born with encephalocele between 1995 and 2001, which compares favorably with the 72.2% survival rate reported by Siffel et al27 for a metropolitan Atlanta cohort born between 1979 and 1998 and the 68.8% rate reported by Nembhard et al31 for encephalic births in Texas between 1995 and 1997.

We found that, although survival rates for infants with spina bifida have improved modestly since the advent of mandatory folic acid fortification of the US grain supply, the increase in survival rates was statistically significant. It is possible that folic acid plays a role not only in preventing NTDs but also in ameliorating the severity of spina bifida among live-born infants. One possible mechanism for reduction of the severity of spina bifida is that folic acid may move the location of the lesion caudally along the developing spine; Wong and Paulozzi28 demonstrated significantly lower survival rates for infants with high lesions (cervical or thoracic), compared with infants with low lesions (lumbar or sacral).

Survival rates for infants with encephalocele also have increased since fortification, although not statistically significant. Despite the widely observed protective effect of folic acid on spina bifida and anencephaly, similar declines in the prevalence of encephalocele have not been reported.14,22 However, one study showed that the location of the defect among encephalic infants affected survival rates; infants with anterior lesions experienced greater infant survival rates than did those with posterior lesions.27 If folic acid affects the location of the lesion in cases of spina bifida, then this may also occur among cases of encephalocele. Additional research with more detailed data on the clinical features of NTD cases is necessary to confirm the hypothesis that folic acid fortification affects the level or location of spina bifida or encephalic lesions.

Several other factors may play a role in interpretation of these findings. Advances in prenatal diagnostic techniques might have led to earlier detection of NTD-affected pregnancies and perhaps increased rates of pregnancy terminations. If NTD-affected pregnancies with favorable postnatal prognoses could be differentiated from those with poor prognoses, then disproportionate rates of pregnancy terminations among NTD cases with substantially poorer prognoses might have occurred during the later years of our study. If this were the case, then recent birth cohorts would have more-favorable prognoses, suggesting that greater survival rates are an artifact of prenatal screening and are independent of the role of folic acid.

Survival Predictors
Our measure of the primary exposure of interest, ie, maternal exposure to flour fortification with folic acid, has some limitations, namely, that classification of exposure was made on the basis of the date of birth of each infant rather than the date the infant was conceived. However, the starts of the optional and mandatory fortification periods were adjusted to include only infants whose birth dates indicated conception after the March 1996 (optional fortification) and January 1998 (mandatory fortification) dates.

Also, exposure to folic acid fortification is ecologic in nature and provides only an indirect measure of folic acid intake, with the assumption that each mother represented by this cohort had folic acid intake equal to that of all mothers in their children's respective birth period. A related limitation in measuring maternal exposure to flour fortification is that identifying the periods of prefortification, optional fortification, and mandatory fortification does not necessarily translate into actual folic acid usage among women. The March of Dimes42 reported that, between 1995 and 2001, the proportion of women 18 to 45 years of age taking a daily vitamin containing folic acid increased only from 28% to 29% (with intermediate values of 32%, 32%, and 34% for 1997, 1998, and 2000, respectively). In light of the small sample sizes of the March of Dimes survey (~2000 per year) and differences in results across geographic regions, modest increases in survival rates with modest increases in folic acid intake may suggest little relationship between the two. Alternatively, if the two are related, then perhaps greater increases in folic acid intake could yield corresponding increases in survival rates.

The heterogeneity of NTD classification created a challenge for this analysis; NTDs may arise as isolated defects, in conjunction with defects of other organ systems, as part of developmental syndromes, or as phenotypic manifestations of chromosomal anomalies. Although we did not differentiate between syndromic and nonsyndromic NTDs, the heterogeneity of NTD cases was addressed by examining the number of birth defect diagnosis groups present in each NTD case. The presence of defects from multiple congenital anomaly groups was associated with increased risk for infant death in both the spina bifida and encephalocele cohorts, which is in concordance with other published reports.31,33 What combinations of birth defects or syndromes contribute to greater hazard for infant death among live-born infants with NTDs requires additional exploration.

In the final interactive models for both spinal bifida and encephalocele hazards, induction of labor was shown to increase the risk of infant death. This raises the question of whether induction of labor is present in a causal pathway leading to infant death or is a confounder, a measure of the severity of the defect, or a marker of poor prognosis based on maternal and/or fetal difficulty during pregnancy. A recent review of the quality of reporting of labor induction on US birth certificates raises several issues.43 Although induction is indicated in certain situations related to maternal medical problems and fetal danger, the standard birth certificate used by most participating registries to identify induced labor fails to differentiate fully between indicated induced labor and augmentation of labor or elective induction of labor. This may lead to overestimates of the rates of supposed indicated induction of labor on US birth certificates, limiting the utility of this variable as a meaningful risk or prognostic factor.

Conversely, we found that delivery through cesarean section reduced the risk of death during the first 1 year of life among infants with spina bifida. Among term breech pregnancies, births through cesarean section have been shown to have lower risk of adverse perinatal outcomes attributable to both problems of labor and problems of delivery.44 Breech NTD-affected pregnancies and selected severe NTDs may benefit similarly from cesarean delivery.45 However, it is possible that fetuses undergoing cesarean section may be in better condition than those treated for difficult vaginal delivery. Infants delivered through cesarean section may be those with more-extensive or more-serious defects identified through prenatal diagnosis. Because the use of cesarean section as a measure of NTD severity or as a strong prognostic factor suffers from these conflicting perspectives, the results presented here should not be interpreted as an indication for cesarean delivery for all spina bifida-affected pregnancies.

Another potential explanation for our results is the use of fetal surgery for elective repair of spina bifida lesions in utero.46,47 At birth, these infants might have lower death and disability risk than would have been the case had the surgery not been performed. However, these surgical techniques, developed during the 1990s, are available at only 4 medical centers, ie, the Children's Hospital of Philadelphia, the University of California, San Francisco, the University of North Carolina at Chapel Hill, and the Vanderbilt University Medical Center. In addition, as of early 2004, only ~270 procedures had been performed at these 4 centers.48 It is unlikely that all of these operations were performed for fetuses whose mothers resided in the catchment areas of the 16 participating surveillance programs. That, coupled with a lack of knowledge about the distribution of the operations over the study time period and uncertainty about the risks to and outcomes among the treated fetuses, leads us to think that our results likely were not affected by this procedure.

Encephalic infants born to Hispanic mothers experienced an increased hazard of death during the first 1 year of life. Infants born to Hispanic mothers have higher rates of NTDs than do infants born to mothers of other race/ethnic backgrounds;49–52 Hispanic infants with NTDs also have higher infant mortality rates than do non-Hispanic white and non-Hispanic black NTD-affected infants.25 A higher prevalence rate of NTDs among Hispanic infants may result in increased mortality rates attributable to NTDs, but poorer survival rates for encephalic infants is more difficult to explain. Canfield et al51 suggested that cultural differences between Hispanic and non-Hispanic groups, including access to and use of folic acid-fortified food products, may contribute to the increased prevalence of NTDs. These factors may in turn affect rates of prenatal diagnosis and elective pregnancy termination, yielding births with more severe NTDs and poorer prognoses.

Future Directions
Future studies of this sort would benefit significantly from thorough accounting of affected pregnancies that end in spontaneous fetal death or elective termination of the pregnancy, complete review of case records for accuracy of diagnosis, improved classification of NTD lesions, and longer study survival period, to assess survival into childhood. In addition, more comprehensive vital status matching to databases such as the National Death Index may better account for interstate movement of case subjects and their families, with potentially more complete birth/infant death linkages.

Studies assessing the survival rates of infants with NTDs contribute to our understanding of the efficacy of flour and grain fortification with folic acid and its role in reducing the occurrence of NTDs. Our results show that folic acid fortification coincided with improved first-year survival rates for infants with spina bifida and encephalocele; however, studies examining survival beyond infancy are needed.53 As the survival rates of NTD-affected infants improve, the national infrastructure for health care, education, and family support must expand to meet their needs.


   ACKNOWLEDGMENTS
 
This project was supported financially through the Centers for Disease Control and Prevention Cooperative Agreement for the Development and Improvement of Population-Based Birth Defects Surveillance Programs and the Integration of Surveillance Data with Public Health Programs, Program Announcement 02011.

We thank the following birth defects monitoring programs for their contribution of data to this project: Alabama Birth Defects Surveillance and Prevention Program, California Birth Defects Monitoring Program, Colorado Responds to Children With Special Needs, Centers for Disease Control and Prevention-Metropolitan Atlanta Congenital Defects Program and the Georgia Division of Public Health, Hawaii Birth Defects Program, Illinois Adverse Pregnancy Outcomes Reporting System, Iowa Birth Defects Registry, Kentucky Birth Surveillance Registry, Michigan Birth Defects Registry, North Carolina Birth Defects Monitoring Program, New York State Congenital Malformations Registry, Oklahoma Birth Defects Registry, Rhode Island Birth Defects Surveillance Program, South Carolina Birth Defects Surveillance and Prevention Program, Texas Birth Defects Monitoring Division, and West Virginia Congenital Anomalies Registry, Education and Surveillance System. We also thank the members of the NTD Surveillance and Folic Acid Education and Data Committees of the National Birth Defects Prevention Network for their assistance and guidance.


   FOOTNOTES
 
Accepted Jul 29, 2005.

Address correspondence to Kirk A. Bol, MSPH, Vital Statistics Unit, Colorado Department of Public Health and Environment, 4300 Cherry Creek Dr South, Denver, CO 80246. E-mail: kirk.bol{at}state.co.us

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
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R. L. Brent and G. P. Oakley Jr
Triumph and/or Tragedy: The Present Food and Drug Administration Program of Enriching Grains With Folic Acid
Pediatrics, March 1, 2006; 117(3): 930 - 932.
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