Published online September 1, 2006
PEDIATRICS Vol. 118 No. 3 September 2006, pp. 906-915 (doi:10.1542/peds.2005-2784)
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ARTICLE

Hospitalizations of Newborns With Folate-Sensitive Birth Defects Before and After Fortification of Foods With Folic Acid

James M. Robbins, PhD, John M. Tilford, PhD, T.M. Bird, MS, Mario A. Cleves, PhD, J. Alex Reading, MS and Charlotte A. Hobbs, MD, PhD

Arkansas Center for Birth Defects Research and Prevention, College of Medicine, Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital Research Institute, Little Rock, Arkansas


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
CONTEXT. The prevalence of neural tube defects is reduced in populations of women who receive folic acid supplementation. Since 1998, grain products in the United States have been fortified with folic acid. Fortification may have additional benefits by reducing the national prevalence of newborn hospitalizations for other folate-sensitive birth defects.

OBJECTIVE. Our purpose with this work was to compare rates of hospitalizations of newborns with folate-sensitive birth defects before and after implementation of fortification of grains.

METHOD. National hospital discharge data from the Healthcare Cost and Utilization Project were used to compute rates of newborn hospitalizations for selected birth defects per 10000 live births in the United States. Newborn hospitalization rates involving congenital anomalies recognizable at birth were analyzed for 5 years before fortification of grains and 5 years after fortification. Additional analyses compared changes in newborn hospitalization rates for birth defects by race/ethnicity, income, insurance status, and region of the country.

RESULTS. Newborn hospitalization rates for spina bifida decreased 21% from 1993–1997 to 1998–2002. Newborn hospitalization rates also decreased for anencephaly (20%) and limb-reduction defects (4%). Decline in hospitalizations for spina bifida occurred more often among Hispanic newborns (33%) than among white (13%) or black (21%) newborns. Decline in limb-reduction defects was seen primarily among blacks (11%). Findings using hospitalization data were similar to recent reports using birth defect surveillance systems with the exception of findings for orofacial clefts and conotruncal heart defects. No reductions were noted in newborn hospitalizations for these anomalies.

CONCLUSIONS. Results from this ecological study fail to demonstrate substantial declines in newborn hospitalizations beyond those anticipated from a reduction in neural tube defects. The society-wide impact of the fortification program on birth defects and other health conditions should continue to be monitored.

Key Words: hospitalization rates • neural tube defects • folic acid • newborn • congenital abnormalities/anomalies

Abbreviations: NTD—neural tube defect • AHRQ—Agency for Healthcare Quality and Research • HCUP—Healthcare Cost and Utilization Project • NIS—Nationwide Inpatient Sample • KID—Kids' Inpatient Database • ICD-9-CM—International Classification of Diseases, Ninth Revision, Clinical Modification • PR—prevalence ratio • CI—confidence interval

In response to firm evidence that the prevalence of neural tube defects (NTDs) is reduced in populations of women who received folic acid supplementation,1,2 the US Food and Drug Administration mandated that fortification of grain products with folic acid should begin in 1998.3 It was anticipated that fortification would result in reduced rates of NTDs and corresponding economic benefits from reductions in direct medical expenditures, as well as improvements in the quality-adjusted life years of children born free of defects.4–6 Concerns about masking the effects of pernicious anemia, unknown effects on children and adults of a long-term increased exposure to folic acid, and incomplete knowledge of the impact of current levels of fortification have led to calls to monitor the impact of fortification on the population.7–13 Greater-than-expected increases in folic acid blood levels after fortification14,15 have also prompted interest in the true population effects of fortification.

Honein et al16 used national birth certificate data from 45 states for 10 years to demonstrate a reduction in rates of live births with NTDs corresponding with the period of mandatory fortification. Similarly, Williams et al,17,18 and the Centers for Disease Control and Prevention19 confirmed this finding using data from select state birth defects surveillance systems participating in the Neural Tube Defect Surveillance Committee of the National Birth Defects Prevention Network. These studies have demonstrated reductions for NTDs in the range of 18% to 30%, an effect greater than that assumed in 3 economic evaluations conducted before fortification.4–6

Because folic acid may have a protective effect for birth defects other than NTDs, it is possible that fortification has had a more extensive impact on the population than initially assumed. Epidemiological studies have generally demonstrated a decreased risk of cardiac defects, specifically conotruncal20,21 and septal defects,20–22 among women taking folic acid or multivitamins before pregnancy. Similar evidence suggests that folic acid and multivitamins may also reduce the risk of orofacial clefts23–28 and limb defects29,30 although some studies show no effect on these anomalies.22,28,31,32 Some but not all studies have found that Down syndrome children and their mothers have a greater prevalence of genes encoding for polymorphisms that downregulate critical enzymes in the folic acid pathway.33,34 This evidence suggests a possible effect of folic acid on the risk of Down syndrome.

A recent study based on data from state birth defects surveillance programs found a decrease in certain defects in addition to NTDs after mandatory fortification.35 This study pooled data from 9 to 23 state surveillance programs and covered 30% to 40% of US births. It is not clear how findings from birth defect surveillance systems translate into economic benefits from reduced newborn hospitalizations and reduced use of other health care resources.

In this study, we used national hospitalization data to evaluate the impact of increased folic acid consumption on changes in hospitalization rates for NTDs and other birth defects thought to be possibly affected by folic acid (conotruncal heart defects, orofacial clefts, limb defects, and Down syndrome) over the period 1993–2002. For comparison, we also determined changes in national newborn hospitalization rates for birth defects not known to be influenced by folic acid (hypospadias/epispadias, diaphragmatic hernia, abdominal wall defects, esophageal atresia, rectal atresia, and obstructive genitourinary defects). The study interval corresponds with a period of no fortification of grains with folic acid (1993–1996), gradual but not full implementation of the fortification policy by grain producers (1997), and a period of full implementation (1998–2002). Differences in rates between periods were compared across racial and ethnic groups, income category, insurance coverage, and region of the country.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Databases
Data for this study come from 2 large national hospital discharge databases of the Agency for Healthcare Quality and Research (AHRQ) Healthcare Cost and Utilization Project (HCUP): the Nationwide Inpatient Sample (NIS) and the Kids' Inpatient Database (KID). The NIS is designed to approximate a 20% stratified random sample of all US community hospitals from states that contribute their state inpatient databases to the HCUP. The NIS includes discharges for all age groups and all of the payers from each sampled hospital. Discharges of newborn infants from 1993 through 2002 are included in this study. In 1993, 17 states contributed their data to NIS, representing ~52% of all US births. In 2002, 35 states contributed data representing ~86% of all US births.

To allow for more precise study of rare pediatric conditions, in 1997 and 2000 AHRQ drew a larger sample of infants and children from state inpatient databases. The resulting KID is an 80% sample of hospital discharges of patients 0 to 20 years of age with the exception of normal newborns, which were sampled at a rate of 10%. Because of the possibility that the NIS might miss large pediatric hospitals that are not in its sampling frame, data from the larger sample of the KID are used to replace the smaller NIS sample once in the prefortification period (1997) and once in the postfortification period (2000). The KID samples hospital discharges, not hospitals, assuring that large pediatric hospitals are represented in both periods. Analyses were repeated using only NIS samples for all years. Results that differed between analyses are reported.

The HCUP allows monitoring of newborn hospitalization rates over a 10-year period. AHRQ has developed discharge weights to generate national estimates of hospitalizations from the NIS and the KID databases. With these weights, national estimates of hospitalizations and hospitalization rates are comparable across years despite the varying number of states participating in each year of the HCUP.36–38 In this report, the HCUP is used to monitor yearly trends in newborn hospitalizations for birth defects for 10 years from 1993 through 2002. This study was reviewed and approved by the Institutional Review Board of the University of Arkansas for Medical Sciences. Because the study relies exclusively on existing publicly available data with no personal identifiers, it was classified as exempt from further institutional review board review.

Unlike some state birth defect surveillance programs,39 the HCUP includes no data on elective terminations or stillbirths. State registries vary greatly in their case definitions and case ascertainment methodologies. In 2001, 18 state registries reported prevalence figures that included live births, stillbirths and elective terminations.39 An additional 15 states reported figures that included live births and stillbirths only, and 17 states reported no birth defect prevalence figures. Only 29 states reported registry data earlier than 1997. Because of variations in case definitions, case ascertainment, and limited state reporting, national rates of birth defects are not typically reported from registry data. The HCUP offers a standardized data reporting mechanism, longitudinal coverage, and weights appropriate for longitudinal assessment of national prevalence.

Our assessment of newborn hospitalization rates generated by the NIS and KID when compared with published rates of birth defects from individual state birth defect surveillance programs39 shows that hospitalization records consistently underestimate defects known to lead to elective terminations (eg, anencephaly and trisomy 13) and defects often not identified until ≥2 weeks of life (eg, biliary atresia, including duct obstruction, hypoplasia, or stricture).40 Rates of other defects, those identified at birth but often ruled out after subsequent confirmatory assessment (eg, congenital hip dislocation and patent ductus arteriosis), are overestimated by HCUP hospitalization records. Rates for most other defects, including most cardiovascular, orofacial clefts, limb reduction, and genitourinary defects, are closely approximated by HCUP data.

Preventive Effects of Folic Acid
Evidence supporting the benefit of folic acid or multivitamins containing folic acid in reducing the risk of birth defects was reviewed to guide the analyses. Results from randomized trials and case-control studies consistently support the effect of folic acid or multivitamins containing folic acid in preventing NTDs.1,2,32,41–43 Reports have also suggested a protective effect of folic acid against orofacial clefts,23–28 conotruncal heart defects,20–22 and limb-reduction defects,29,30 although some studies have failed to confirm protection against these defects.22,28,31,32 See Botto et al44 for a recent review of the evidence. Other studies have demonstrated alternations in genes, enzymes, and/or metabolites of the folic acid pathway that are associated with Down syndrome,33,34 orofacial clefts,45 and heart defects.46,47 Analyses compared rates of newborn hospitalizations for these potentially folate-sensitive birth defects for 5 years before fortification and 5 years after fortification. Defects addressed in this report and International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes used to define them are listed in the Appendix.


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  		APPENDIX ICD-9-CM Codes for Birth Defects

 
Other congenital anomalies that have not been shown to be influenced by folic acid were included as comparison birth defects. These conditions include hypospadias/epispadias, diaphragmatic hernia, surgically repaired gastroschisis, esophageal atresia, rectal atresia/stenosis (including atresia/stenosis of the anus and large intestine), and obstructive genitourinary defects. Following Williams et al,48 procedure codes for surgical repair were used to separate gastroschisis from omphalocele. These abdominal wall defects share the same ICD-9-CM diagnosis code but can be distinguished by surgical procedure codes.

Selected Defects
All of the infants with a primary or secondary ICD-9-CM diagnosis code indicative of a selected birth defect admitted to a hospital within the first 10 days of life were included in the study sample. Infants with multiple selected anomalies were included in analyses of prevalence rates for each anomaly. Infants with any ICD-9-CM code for a chromosomal anomaly (758.0–758.9) were not included in the calculation of rates for structural anomalies. Co-occurring structural anomalies, if present, were included in calculation of rates of newborn hospitalizations for trisomies 13, 18, and 21. ICD-9-CM coding changes were monitored across the years of the NIS to assure comparable grouping of defects over time.49

Septal heart defects, although often recognizable at or soon after birth, were excluded from our study. Recent improvements in high-resolution echocardiography and greater precision in imaging has likely resulted in identification of many more small defects in later years compared with earlier years.50–52 Advances in defect ascertainment would likely artificially inflate the number of newborn hospitalizations diagnosed with septal heart defects over time.

Infants born with a birth defect are often transferred from the birthing hospital to another acute care inpatient facility for management of the defect. To avoid double-counting of these newborn cases, those whose hospital disposition was listed as transferred to another short-term, acute care hospital were excluded from computation of rates.53 These patients would likely be captured in our databases a single time.

Statistical Analysis
Newborn hospitalization rates were calculated per 10000 newborns. Numbers of observed birth defects were first computed from the NIS and the KID. Weights were then applied to the observed defects to derive national estimates. Similarly, numbers of all newborns were computed from the NIS and the KID, then weighted up to represent all hospital births in the country. This value forms the denominator in the calculation of defect rates per 10000 newborns.

Statistical analyses were completed with Stata 8.0 (Stata Corp, College Station, TX) to take into account the complex sampling designs and sample weights of the NIS and the KID. The prevalence ratio (PR) was computed to measure the relative decrease in defect rates from the prefortification period of 1993–1997 to the postfortification period of 1998–2002. The PR is computed as the postfortification rate divided by the prefortification rate. Confidence intervals (CIs) for PRs were constructed using a linearized-robust estimate of variance, a method that takes into account the stratified multistage survey design.54,55 Ten-year trends toward decreasing (or increasing) rates were tested for significance with the Cochran-Armitage trend test.

Changes in rates of newborn hospitalizations for birth defects were assessed across income category, ethnicity, insurance status, and region of birth. Income is defined in the NIS as the median income of households in the census tract of residence of the patient. This proxy measure is coded into large, inclusive categories roughly corresponding with the first, middle, and last third of the income distribution each year.

Three mutually exclusive racial/ethnic codes are available in the NIS with sufficient numbers of cases to allow for meaningful analyses: white, black, and Hispanic. The remaining 10% of cases were identified as Asian or Pacific Islander, Native American, or "other" ethnicity. Race was coded from maternal report. Race-specific birth defects rates were calculated per 10000 newborn hospitalizations. Four regions of the country are coded: Northeast, Midwest, South, and West. Three insurance categories are used in this study: public representing a combination of Medicare and Medicaid, private including health maintenance organizations, and self-pay. Patients coded as "no charge" and "other" insurance were too few to include in analyses by insurance status.

Analyses focus on comparison between the 5-year period before full fortification in 1998 and the 5-year period after full fortification. Because grain producers began adding folic acid in 1997 to prepare for the January 1, 1998, mandate, mothers of infants who were born in early 1998 were likely exposed to folic acid fortification and are correctly classified as exposed. Similarly, most infants born in 1997 were likely conceived before the gradual start up of fortification and are correctly classified as not exposed. The potential misclassification bias of including a small proportion of infants born in 1997 whose mothers were exposed to gradual food fortification in the unexposed group would bias differences between periods toward the null.

All of the analyses were replicated with the implementation years 1997 and 1998 excluded. No substantive or significant differences in results were observed.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Figures 1 through 4 illustrate temporal trends in newborn hospitalization rates from the HCUP for selected birth defects for the years 1993–2002. Whereas the SEs for newborn hospitalization rates from the NIS are relatively large, it is nonetheless apparent that newborn hospitalizations for NTDs have declined substantially since 1993. Newborn hospitalization rates involving NTDs declined from a high of 4.6 per 10000 in 1993, 1994, and 1996 to 3.4 newborns in 2000 and 2.9 in 2002. A similar trend is present but less apparent for limb reductions. Limb reductions declined from ~3.5 newborns per 10000 in 1995 to 3.1 in 2002. Rates of conotruncal heart defects have fluctuated over the 10 years of the NIS. An overall significant increase in rates has occurred. Rates of orofacial clefts have been relatively constant at ~14 per 10000 newborns over the 10-year study period.


Figure 1
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  		FIGURE 1 Estimates of newborn hospitalization rates for NTDs in the United States, 1993–2002. Source: HCUP, NIS, years 1993–1996, 1998–1999, and 2001–2002; KID, years 1997 and 2000. Error bars, 95% CIs. Cochran-Armitage trend test, 2-tailed: z = 15.64; P < .0001 (decrease).

 

Figure 2
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  		FIGURE 2 Estimates of newborn hospitalization rates for limb-reduction defects in the United States, 1993–2002. Source: HCUP, NIS, years 1993–1996, 1998–1999, and 2001–2002; KID, years 1997 and 2000. Error bars, 95% CIs. Cochran-Armitage trend test, 2-tailed: z = 2.11; P = .0349 (decrease).

 

Figure 3
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  		FIGURE 3 Estimates of newborn hospitalization rates for orofacial clefts in the United States, 1993–2002. Source: HCUP, NIS, years 1993–1996, 1998–1999, and 2001–2002; KID, years 1997 and 2000. Error bars, 95% CIs. Cochran-Armitage trend test, 2-tailed: z = 0.20; P = .8408 (no change).

 

Figure 4
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  		FIGURE 4 Estimates of newborn hospitalization rates for conotruncal heart defects in the United States, 1993–2002. Source: HCUP, NIS, years 1993–1996, 1998–1999, and 2001–2002; KID, years 1997 and 2000. Error bars, 95% CIs. Cochran-Armitage trend test, 2-tailed: z = –5.48; P < .0001 (increase).

 
Table 1 presents the rates per 10000 newborn hospitalizations for specific defects and groups of defects for the period 1993–1997 and the period 1998–2002. PRs <1 indicate a reduction in the rate from the earlier to the later period. PRs >1 indicate an increase in the rate from the earlier to the later period. Rates declined substantially for NTDs, limb-reduction defects, and trisomy 13. Newborn hospitalizations for NTDs declined 20% from 1993–1997 to 1998–2002. Rates of both anencephaly and spina bifida declined significantly. Rates of conotruncal heart defects as a group increased over the 2 periods, as did each conotruncal defect. Rates of limb-reduction defects as a group declined somewhat.


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  		TABLE 1 Newborn Hospitalizations, Newborn Hospitalization Rates, and PRs for Birth Defects Before and After Mandatory Fortification of Grains With Folic Acid

 
No reductions were observed for rates of orofacial clefts. Rates of Down syndrome and trisomy 18 increased, as did comparison defects not known to be affected by folic acid. Rates of surgically repaired gastroschisis increased 37% over the 2 periods, whereas rates of obstructive genitourinary defects increased 26%.

Analyses reported in Table 1 were replicated using only the National Inpatient Sample (NIS) for all years. Few substantive differences and no differences in levels of statistical significance were observed between these analyses and analyses replacing the NIS with the larger sample KID for years 1997 and 2000. NTDs declined 23% (PR: 0.77) based on analyses using only the NIS compared with 20% in analyses including the KID for years 1997 and 2000.

In Table 2, rates and PRs for NTDs are presented separately for 3 ethnic groups and 3 income categories. As seen from these results, declines in rates of anencephaly and spina bifida occurred among all 3 of the ethnic groups but were greatest for Hispanic infants. Rates of spina bifida decreased 13% for white infants, 21% for black infants, and 33% for Hispanic infants. Declining rates were similar across income categories. With the exception of anencephaly among infants from lower income census tracts, rates of NTDs declined consistently across income categories.


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  		TABLE 2 Newborn Hospitalizations, Newborn Hospitalization Rates, and PRs for NTDs and Limb-Reduction Defects Before and After Mandatory Fortification of Grains With Folic Acid According to Ethnicity and Income

 
Declines in limb-reduction defects were seen only among black infants. Rates for whites and Hispanics were similar between periods.

Few consistent trends were noted in changes in rates of other defects across ethnicity and income. Virtually no changes were noted in rates of orofacial clefts across ethnic or income categories. Trisomy 21 increased among all groups (white PR: 1.12 [CI: 1.1–1.2]; black PR: 1.10 [CI: 1.03–1.17]; Hispanic PR: 1.07 [CI: 1.02–1.13]). Trisomy 13 decreased for all groups but significantly only among white infants (PR: 0.85 [CI: 0.76–0.95]).

Trisomy 21 increased among all of the income groups (low PR: 1.11 [CI: 1.08–1.15]; middle PR: 1.06 [CI: 1.03–1.10]; high PR: 1.09 [CI: 1.06–1.13]). Trisomy 13 decreased among all of the income groups but significantly only among infants from middle (PR: 0.81 [CI: 0.72–0.92]) and higher (PR: 0.83 [CI: 0.74–0.93]) income tracts.

Changes in rates of certain defects were found to vary by region of the country. NTDs declined from 20% to 25% for infants from all regions of the country except the Northeast. No change was noted for this region (PR: 1.03 [CI: 0.94–1.12]). Limb-reduction defects declined primarily among infants from Northeastern states (PR: 0.82 [CI: 0.75–0.90]) and Southern states (PR: 0.89 [CI: 0.83–0.95]) but not among infants from the Midwest (PR: 1.11 [CI: 1.03–1.20]) or West (PR: 1.07 [CI: 0.99–1.16]). Trisomy 13 declined remarkably by 53% among births in the Northeast (PR: 0.47 [CI: 0.39–0.57]), somewhat among infants in the West (PR: 0.86 [CI: 0.75–0.97]), but relatively little among infants in the South (PR: 0.91 [CI: 0.80–1.31]), and not at all among infants from the Midwest (PR: 1.00 [CI: 0.88–1.15]).

NTDs declined among all of the insurance categories but was most pronounced (23%) among infants with public health insurance (PR: 0.77 [CI: 0.74–0.81]). Comparatively NTDs declined by 14% (PR: 0.86 [CI: 0.82–0.90]) among privately insured and by 17% (PR: 0.83 [CI: 0.71–0.96]) among those with no insurance. No consistent insurance differences were noted in changes in rates for limb-reduction defects, orofacial clefts, conotruncal defects, or chromosomal defects.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Studies using birth certificates,16 birth defect registries from select states,17–19 and Canadian registries56 have shown that population rates of NTDs have declined after mandatory fortification of grains with folic acid. In general, these studies have found decreases in the birth prevalence of NTDs in the order of 18% to 30%.16–18 Other folate-sensitive birth defects were not included in these analyses. Using large nationally representative hospitalization data sets from the HCUP, this study found decreases in newborn hospitalization rates for spina bifida (21%) and anencephaly (20%) that are consistent with the known protective effect of folic acid.

Previous case-control studies suggest that hospitalizations for conotruncal heart defects, orofacial clefts, limb reductions, and Down syndrome might also be reduced after fortification of foods with folic acid. In 2 ecological studies using data from single states, no decline was noted in rates of these defects.50,57 A recent study combining surveillance data from select states demonstrated a significant reduction in transposition of the great arteries, cleft palate without cleft lip, upper limb-reduction defects, pyloric stenosis, and omphalocele.35

Because of the similarity in approaches between studies based on surveillance data and this study using hospitalization data, it is instructive to compare findings. Overall, findings for most birth defects in this study were remarkably similar. For example, Canfield et al35 estimated that rates of transposition of the great arteries and tetralogy of Fallot were virtually identical with the number of cases identified in the period before fortification being exactly identical. Our study also found identical prevalence rates for these 2 conditions in the period before fortification with equally identical numbers of cases identified. In contrast to the findings by Canfield et al,35 our analyses indicated a significant decrease in hospitalizations for only limb-reduction defects, and this decrease was minor (4%). Pyloric stenosis and omphalocele were not considered in our analyses. Differences in findings for transposition of the great arteries and cleft palate may be because of more extensive follow-up of cases by surveillance programs, exclusion of the phase-in years of 1997 and 1998 by Canfield et al,35 or less complete coverage of national births by surveillance programs from select states.

The lack of findings with respect to some birth defects may be explained by differences in dose-response relationships. The effective dose to prevent all defects other than NTDs currently is not known. Additional research is required to determine whether a higher dose of folic acid than is currently provided in fortified grains may be required to realize a difference in rates of orofacial clefts or Down syndrome.27 There are considerable efforts currently underway to revisit the decision to fortify grains with only 140 µg of folic acid per 100 g of grain.58,59

One recent study has addressed whether racial or ethnic groups have differential responses to food fortification with folic acid.17 Our research team generated the a priori hypothesis that the reduction in NTDs would be more noticeable among Hispanic populations than other racial or ethnic groups.60 Hispanics are known to be at increased risk for NTDs for at least 2 reasons: they have a higher rate of folate deficiency than other ethnic groups61; and they are much more likely to carry the 677 C>T polymorphism in the methylenetetrahydrofolate reductase gene that is associated with an increased risk of spina bifida.62 Investigation of our a priori hypothesis found that whereas newborn hospitalizations for spina bifida have decreased for all ethnic groups, the decrease among Hispanic infants (33%) was substantially greater than that for whites (13%) or blacks (21%). The greatest benefit of folic acid fortification may be realized among those at greatest risk of an NTD. Efforts are underway to encourage fortification of corn flour sold in the United States.63 Corn flour, comprising a substantial portion of the diet of Hispanics, is not included among grains currently fortified. Such an expanded fortification policy might further decrease rates of NTDs among Hispanics.

We also investigated whether the decrease in hospitalizations for limb-reduction defects varied across racial and ethnic groups. Declines in limb-reduction defects were seen most strongly among black infants. Additional research is needed to clarify racial differences in the changing patterns of these defects.

Trisomy 13 declined by 16% in the postfortification period. This effect was almost exclusively seen in the Northeastern states (53% decline). To our knowledge there have been no major advances in pregnancy counseling, postbirth medical management, or elective termination rates that would account for this large decrease in prevalence. Additional research is required to verify large changes in trisomy 13 in the Northeast.

Certain defects increased in prevalence over the study period consistent with known increases in these conditions. Rates of Down syndrome increased consistent with increasing maternal age.64 Rates of gastroschisis increased consistent with some studies reporting an increase in this condition,65,66 and rates of obstructive genitourinary defects increased consistent with similar findings from surveillance programs.35,50

There are limitations to these analyses. Hospital discharge data rely on accurate coding of primary and secondary diagnosis codes typically used for reimbursement purposes. Coding of primary and secondary diagnoses, as well as racial and ethnicity data, can vary by hospital, state, and time period.

The ecological nature of this study limits our ability to generate causal inferences. We can assert with confidence that rates of certain birth defects have declined since grains were fortified with folic acid. However, we are unable to state that women delivering fewer infants with birth defects are those who have consumed folic acid-enriched grains. In fact, declines in rates of birth defects we observed could have been because of events that co-occurred with full fortification. For example, the number of women taking folic acid supplements may have increased from 1993 to 2002, although existing data suggest daily use has remained relatively constant at 30% of all women of childbearing age for the past 10 years.67 Similarly, the influence of selective pregnancy terminations is not captured in hospital discharge data. Elective abortion rates are known to vary by racial/ethnic group and may have increased or decreased disproportionately across racial/ethnic groups, although there are no data to support unequal changes in rates.68 Other events may have occurred in the interval between 1993 and 2002, including an increased intake of protective substances other than folic acid.

No information is available in the HCUP databases on fetuses with birth defects who were stillborn or prenatally diagnosed and electively terminated. This limitation likely biases the potential effect of fortification toward the null. Studies approximating full ascertainment of cases including stillbirths and terminations have converged on a 50% reduction in rates of spina bifida after fortification.69 Studies based on live births,16,19 including this one, converge on a 20% reduction. This difference may be because of a decrease in the severity of spina bifida such that some infants are now being born alive who would have been stillborn before fortification. Reducing the severity and increasing the viability of infants with spina bifida would have no effect on changes in rates derived from surveillance systems with full ascertainment. In contrast, increasing the viability of infants with spina bifida would serve to increase the number of live-born infants counted as cases in the postfortification period. If rates of stillbirths with spina bifida have decreased more after fortification than rates of live births with spina bifida, studies based on full ascertainment would produce findings of a greater observed decrease in spina bifida than studies of live births only. Despite the potential shortcomings, the HCUP data provide national estimates of live births with congenital anomalies, as well as consistent findings on the preventive effect of food fortification with folic acid.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Since 1998, intake of folic acid70–73 and serum and red cell folate levels of Americans14,15 have increased to well over twice the levels anticipated before fortification. Because of this substantial change in daily nutrient intake, it is important that the society-wide impact of fortification continue to be monitored for its effects on birth defects.

The folic acid fortification program in the United States was justified largely by the anticipated society-wide reductions in birth prevalence and concomitant reductions in newborn hospitalizations and other health care resource use of infants born with NTDs.4–6 This study provides consistent evidence that newborn hospitalizations for NTDs have declined after fortification of food with folic acid. Despite literature suggesting that folic acid or multivitamins containing folic acid should reduce the risk of cleft palate, cleft lip, and Down syndrome, our results do not support a reduction in rates of newborn hospitalizations for these defects. Overall, the evidence does not suggest additional economic benefits from fortification of grains beyond those anticipated from a reduction in NTDs.74 Analysis of new strategies to prevent NTDs with increased consumption of folic acid should not incorporate expected benefits associated with reduction in birth defects other than NTDs.


   ACKNOWLEDGMENTS
 
This project was supported under cooperative agreements from the Centers for Disease Control and Prevention, Division of Birth Defects and Developmental Disabilities (grant U50/CCU613236-02), and from the Centers for Disease Control and Prevention through the Association of American Medical Colleges (grants U36/CCU319276 and ID MM-0636-04/04).


   FOOTNOTES
 
Accepted Apr 10, 2006.

Address correspondence to James M. Robbins, PhD, Arkansas Center for Birth Defects Research and Prevention, University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Little Rock, AR 72202. E-mail: robbinsjamesm{at}uams.edu

Publication and report contents are solely the responsibility of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention or the Association of American Medical Colleges.

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


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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