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Am J Clin Nutr 89: 363-371, 2009. First published December 3, 2008; doi:10.3945/ajcn.2008.26287
 American Journal of Clinical Nutrition, doi:10.3945/ajcn.2008.26287
Vol. 89, No. 1, 363-371, January 2009
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© 2009 American Society for Clinical Nutrition

ORIGINAL RESEARCH COMMUNICATION

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 adults1,2

Vijay Ganji and Mohammad R Kafai

1 From the Division of Nutrition, School of Health Professions, College of Health and Human Sciences, Georgia State University, Atlanta, GA (VG), and the Department of Mathematics, San Francisco State University, San Francisco, CA (MRK).

2 Reprints not available. Address correspondence to V Ganji, Division of Nutrition, 140 Decatur Street, Suite 862, Georgia State University, Atlanta, GA 30302. E-mail: vganji{at}gsu.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: It is not known whether the improved folate status from mandatory folic acid fortification had any impact on indexes and prevalence of anemias in the United States.

Objective: We investigated trends in indexes and prevalence of anemia and macrocytosis with a focus on comparison of prefortification data with postfortification data.

Design: Hemoglobin, hematocrit, mean corpuscular volume (MCV) and prevalences and likelihood of anemia and macrocytosis were determined for 26,596 adults examined in the National Health and Nutrition Examination Surveys, 1988–2004.

Results: From 1988–1994 to 1999–2004, hemoglobin modestly but significantly improved from 15.1 to 15.4 g/dL ({approx}2.0%; P < 0.0001) and from 13.3 to 13.6 g/dL ({approx}2.3%; P < 0.0001) in men and women, respectively. There was a significant increase in MCV from 1988–1994 to 1999–2004 in men (from 90.2 to 90.7; P = 0.0123) and older (>60 y) men (from 91.6 to 92.4; P = 0.0105) and in women (from 90.7 to 91.4; P = 0.0141). Only in women was the prevalence of anemia significantly lower in 1999–2004 than in 1988–1994 (27.9% reduction; P = 0.0005). The odds of having anemia in the postfortification period relative to the prefortification period was 0.64 (95% CI: 0.54, 0.75; P < 0.0001) in women and 0.79 (95% CI: 0.62, 0.99; P < 0.0433) in men. In general, the prevalence of macrocytosis and the odds of having macrocytosis did not change significantly from 1988–1994 to 1999–2004.

Conclusion: The improvement in hemoglobin and the decreased prevalence of anemia from 1988–1994 to 1999–2004, especially in women, may be attributable to improved folate status, increased vitamin/mineral supplements use, and other unknown causes after the initiation of folic acid fortification. The cause of increased MCV in men, and in older persons of both sexes, warrants further investigation.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The Food and Drug Administration mandated that all processed cereal and cereal products be fortified with folic acid at the level of 140 g/100 g of cereal product in the United States by 1 January 1998 (1). This legislation was in response to the Public Health Service's recommendation that all women who are capable of getting pregnant should consume 400 µg folic acid/d to reduce the risk of having a child with a neural tube defect (NTD) (2). The predicted increase in intake of folic acid was 100 g/d by the target population (1). However, the actual intake of folic acid after folic acid fortification has exceeded the projected intake (3, 4) because several fortified foods contain higher amounts of folic acid than the amount required by the Food and Drug Administration regulation (5). Since folic acid fortification began, the prevalence of NTDs has decreased by 19% in the United States (6). Additionally, folic acid fortification has significantly improved circulating folate and red blood cell folate concentrations (7–11) and has lowered circulating total homocysteine concentrations (7, 8, 12, 13).

Because folic acid supplementation cures folate deficiency–induced macrocytic or megaloblastic anemia (macrocytosis), we hypothesized that folic acid fortification would have a positive impact on indexes of anemia and the prevalence of anemia, especially macrocytosis, in the United States. No data on the possible impact of folic acid fortification on indicators of anemia or the prevalence of overall anemia and macrocytosis have been published. From a public health perspective, it is important to monitor the impact of nationwide folic acid fortification efforts on the overall health and well being of US residents on a continuous basis because the actual consumption of folic acid from food fortification has exceeded the predicted intake (3, 4).

The National Center for Health Statistics of the Centers for Disease Control and Prevention conducts cross-sectional National Health and Nutrition Examination Surveys (NHANES) on civilian, noninstitutionalized residents of the United States. NHANES 1988–1994 was conducted before mandatory folic acid fortification commenced and NHANES 1999–2000, 2001–2002, and 2003–2004 were conducted after folic acid fortification began. Data collected in these 4 NHANES cycles allowed us to evaluate changes in health indexes of the US population from the time of initiation of folic acid fortification (1988–1994) to a period of time after folic acid fortification began (1999–2004).

In this report, we present trends in indexes of anemia and prevalence estimates of overall anemia and macrocytosis in various demographic categories of the US population using data from nationally representative sample surveys (NHANESs) conducted before folic acid fortification (1988-1994) and after folic acid fortification (1999-2004). Additionally, the impact of folic acid fortification on indexes of anemia and prevalence of overall anemia and macrocytosis was evaluated by comparing data from before with data after folic acid fortification began in US adults.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Survey description and design
The data used in this report were derived from publicly available databases released by the National Technical Information Service, Springfield, VA. NHANES is based on a complex, stratified, multistage probability sample survey design. Demographic, socioeconomic, dietary, and health-related data were collected in the participants' home as part of a household interview. Health examination was administered by a physician on all persons in the household interviewed in Mobile Examination Centers (MECs). Some received health examinations in their homes because they were unable to come to the MECs. Certain individuals, such as young children, older persons, and non-Hispanic black (NHB) and Mexican American/Hispanic (MA/H) participants were oversampled to yield reliable estimates for these groups.

In this study, we used data from 4 surveys: NHANES 1988–1994 (14–16), NHANES 1999–2000 (17), NHANES 2001–2002 (18), and NHANES 2003–2004 (19). The detailed description of the survey methodologies and analytic guidelines was reported previously (20, 21). Briefly, of 36,995 persons surveyed in NHANES III, 33,994 were interviewed in their homes; 30,818 were examined in MECs; and 493 were examined in the home. NHANES 1999–2000, 2001–2002, and 2003–2004 were conducted as continuous, annual surveys rather than as periodic surveys. NHANES 1999–2000 was conducted between March 1999 and December 2000 in 9965 individuals (all were home-interviewed; 9282 were examined in MECs); NHANES 2001–2002 was conducted between January 2001 and December 2002 in 11,039 individuals (all were home-interviewed; 10,477 were examined in MECs); and NHANES 2003–2004 was conducted between January 2003 and December 2004 in 12,761 individuals (10,122 were home-interviewed; 9643 were examined in MECs). The survey response rates for NHANES 1988–1994 were 84% for the household-interview component and 78% for the examination component; whereas, the survey response rates for NHANES 1999–2000, NHANES 2001–2002, and NHANES 2003–2004 were 76%, 80%, and 76%, respectively.

Study sample
From the analysis, missing values for sex, race-ethnicity, age, poverty:income ratio, vitamin/mineral supplement use, hemoglobin, hematocrit, and mean corpuscular volume (MCV) were excluded. Additionally, individuals who reported their race-ethnicity as "unknown" or other than non-Hispanic white (NHW), NHB, or MA/H were excluded because of a small sample size. After the above criteria were applied, the final study sample consisted of 26,596 individuals (men = 12,671; women = 13,926).

For the purpose of data analysis, age was classified into 3 categories, ie, 19–40, 41–60, and >60. Poverty:income ratio was used to define the socioeconomic status. Poverty:income ratio is the ratio of the family's income to the family's appropriate threshold income. A poverty:income ratio of <1.0 was considered an income below poverty level (22). The poverty:income ratio was divided into low (<1.0), medium (1.0 to <3.5), and high (≥3.5) categories. Individuals who took vitamin/mineral supplements 1 mo before the survey were categorized as supplement users.

Dietary intake assessment
In NHANES, nutrient intakes were calculated from 24-h dietary recalls, which were collected by using an automated, microcomputer-based dietary interview and coding system known as Dietary Data Collection. Participants reported all foods and beverages consumed, except plain water, for the previous 24-h time period (2400–2400). The nutrient composition of foods reported in food recalls was based on the US Department of Agriculture Survey Nutrient Databases (23). A number of quality-control measures were used to ensure the accuracy of food recalls. A detailed description of dietary intake methodology was published elsewhere (20). For this study, the intakes of folate, iron, vitamin B-6, and vitamin B-12 for NHANES 1988–1994 and NHANES 1999–2004 were determined because these nutrients are known to cure anemia.

Blood measurements and assessment of anemia
Blood was collected by venipuncture in the MECs according to standard protocols. Whole blood was collected into EDTA-treated tubes for a complete blood count analysis. A quantitative, automated hematology analyzer was used to measure hemoglobin, hematocrit, and MCV (Coulter method). The detailed description on specimen processing and laboratory methods was described elsewhere (24, 25). Anemia was defined as having hemoglobin concentrations <13 g/dL for men and <12 g/dL for women according to the World Health Organization criteria (26), and macrocytosis was defined as having MCV values >98 fL for both men and women.

Statistical analysis
SUDAAN statistical software Windows (version 8.0.2; Research Triangle Institute, Research Triangle Park, NC) was used to account for complex survey design. Sample weights, primary sampling units, and stratification variables were considered in the data analysis so that the differential probabilities of selection and adjustments for noncoverage and nonresponse bias were accounted for. We also used SAS for Windows (version 8.0; SAS Institute Inc, Cary, NC) in conjunction with SUDAAN to manage and analyze the data files.

In the data analysis, final examined sample weights were used per NHANES guidelines (21). For the purpose of comparing data from before to after folic acid fortification, we concatenated NHANES 1999–2000, NHANES 2001–2002, and NHANES 2003–2004 data into one analytic data set, NHANES 1999–2004, according to the NHANES guidelines (20). SEMs and percentages were estimated with the Taylor Series Linearization method. This method incorporates sample weights and accounts for the complex survey design.

For NHANES 1988–1994 and 1999–2004, multivariate-adjusted and univariate values for hemoglobin, hematocrit, and MCV and prevalence rates (%) for overall anemia and macrocytosis were determined according to sex, race-ethnicity (NHW, NHB, and MA/H), age (19–40, 41–60, and >60 y), poverty:income ratio (low, <1.0; medium, 1.0 to <3.5; and high, ≥3.5), and vitamin/mineral supplement use (yes or no). Prevalence of anemia (%) based on low hemoglobin concentrations and prevalence of macrocytosis (%) based on high MCV values were determined for the aforementioned demographic categories. The differences in hemoglobin, hematocrit, MCV, and prevalence of anemia and macrocytosis between NHANES 1988–1994 and NHANES 1999–2004 were determined with a 2-tailed unpaired t test. The multivariate-adjusted dietary intakes of folate, iron, vitamin B-6, and vitamin B-12 between NHANES 1988–1994 and NHANES 1999–2004 were also compared with a 2-tailed unpaired t test. Indexes of anemia and macrocytosis are presented as means ± SEMs, and prevalence rates for anemia and macrocytosis are presented as percentages and SEs of the percentages by sex, race-ethnicity, age, poverty:income ratio, and vitamin/mineral supplement use.

The likelihood of having anemia and macrocytosis in the period after folic acid fortification began relative to that before folic acid fortification began was determined with logistic regression after the adjustment for race-ethnicity, age, poverty:income ratio, and vitamin/supplement use in men and women. Additionally, for both sexes, the likelihood of vitamin/mineral supplement use in the period after folic acid fortification began relative to that before folic acid fortification began was determined with logistic regression after adjustment for sex, race-ethnicity, age, and poverty:income ratio. In all analyses, a P < 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Hemoglobin, hematocrit, and MCV
Sample sizes for indexes of anemia and prevalence of overall anemia and macrocytosis for NHANES 1988–2004 are presented in Table 1. Hemoglobin and MCV values by sex, race-ethnicity, age, poverty:income ratio, and vitamin/mineral supplement use for US adults aged ≥19 y in NHANESs 1988–1994 and 1999–2004 are presented in Table 2. In men, adjusted mean hemoglobin concentrations significantly increased from 15.1 g/dL in 1988–1994 to 15.4 g/dL in 1999–2004 (P < 0.0001), although the increase was modest ({approx}2%). In women, the increase was from 13.3 to 13.6 g/dL ({approx}2.3%) from 1988–1994 to 1999–2004 (P < 0.0001). Similar trends were observed in all demographic categories of the US population. In both sexes, from 1988–1994 to 1999–2004, a significant increase in hemoglobin concentrations was observed in vitamin/mineral supplement users (a {approx}1.3% increase, P < 0.001 for men; a {approx}3.0% increase, P < 0.0001 for women) and nonusers (a {approx}2.6% increase, P < 0.0001 for men; a {approx}2.3% increase, P = 0.0001 for women). Trends observed in hematocrit values by and large were similar to the trends that were observed with hemoglobin (data not shown).


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  		TABLE 1. Sample sizes for indexes of anemia and the prevalence of anemia and macrocytosis by sex, race-ethnicity, age, poverty:income ratio, and vitamin/mineral supplement use in National Health and Nutrition Examination Surveys (NHANESs)1

 

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  		TABLE 2. Indexes of anemia by sex, race-ethnicity, age, poverty:income ratio, and vitamin/mineral supplement use in National Health and Nutrition Examination Surveys (NHANESs) 1988–1994 and 1999–2004: impact of folic acid fortification1

 
In men, adjusted mean MCV values slightly but significantly increased from 1988–1994 (a {approx}1% increase) to 1999–2004 (P < 0.0123). When the data were stratified further, a significant increase in MCV values from 1988–1994 to 1999–2004 was observed in NHW men (P < 0.0021), in NHB men (P < 0.0348), in men aged 19–40 y (P < 0.0174), in men aged >60 y (P < 0.0105), in men in low (P < 0.0036) and medium (P < 0.0014) poverty:income ratio groups, and in supplement users (P < 0.0011). In women, MCV values did not change from 1988–1994 to 1999–2004 in all demographic categories, except those in the age group >60 y ({approx}1.2% increase; P < 0.0141).

Prevalence of anemia and macrocytosis
The prevalence of anemia and macrocytosis (%) by sex, race-ethnicity, age, poverty:income ratio, and vitamin/mineral supplement use for US adults aged ≥19 y in NHANES 1988–1994 and 1999–2004 are presented in Table 3. The prevalence of anemia in men did not change from 1988–1994 to 1999–2004, except in men in the lowest poverty:income ratio group (5.4–2.6%, a {approx}51.9% reduction; P < 0.0038) and in men who took no vitamin/mineral supplements (3.1–2.1%, a {approx}32.3% reduction; P < 0.0177). On the other hand, in women, the prevalence of anemia was significantly lower in 1999–2004 (7.5%) than in 1988–1994 (10.4%) (P < 0.0005). This amounts to an overall decrease of ≥27.9% in the prevalence rate. From 1988–1994 to 1999–2004, the reduction in prevalence of anemia was significant in NHW (7.7–4.6%, a {approx}40.3% reduction; P < 0.0005), in NHB (28.2–23.7%, a {approx}16% reduction; P < 0.0018), in MA/H (13.9–10.1%, a {approx}27.3% reduction; P < 0.0178), and in the 19–40-y-old age group (12.2–8.2%, a {approx}32.8% reduction; P < 0.0002). From 1988–1994 to 1999–2004, in women, the prevalence of anemia decreased significantly in the lowest poverty:income ratio group (a {approx}19.3% reduction; P < 0.041). In those women who took vitamin/mineral supplements and who did not take supplements, the prevalence of anemia was reduced by {approx}27% (P < 0.0122) and by {approx}28.4% (P < 0.0039), respectively, from 1988–1994 to 1999–2004. The prevalence of macrocytosis did not change from the prefortifcation period (1988-1994) to the postfortification period (1999-2004) in both men (4.0–4.3%; P < 0.588) and women (4.0–4.0%; P < 0.9883).


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  		TABLE 3. Prevalence of anemia and macrocytosis by sex, race-ethnicity, age, poverty:income ratio, and vitamin/mineral supplement use in National Health and Nutrition Examination Surveys (NHANESs) 1988–1994 and 1999–2004: impact of folic acid fortification1

 
Likelihood of having anemia and macrocytosis
The likelihood of having anemia and macrocytosis in the postfortification period relative to the prefortification period is presented in Table 4. In men, the odds of having anemia in the postfortification period relative to the prefortification period was marginally significant (P < 0.0433). In women, the odds of having anemia was significantly lower in the postfortification period than in the prefortification period [multivariate-adjusted odds ratio (OR): 0.64; 95% CI: 0.54, 0.75; P < 0.0001]. However, the likelihood of having macrocytosis in the postfortification relative to the prefortification period was not significant in either sex.


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  		TABLE 4. Multivariate-adjusted odds ratios (ORs) and 95% CIs of having anemia and macrocytosis before and after folic acid fortification began derived from National Health and Nutrition Examination Surveys (NHANESs) 1988–1994 and 1999–20041

 
Intakes of folate, iron, vitamin B-6, and vitamin B-12 and vitamin/mineral supplement use
For the pre- and postfortification periods, adjusted intakes of folic acid, iron, vitamin B-6, and vitamin B-12 and adjusted ORs and 95% CIs for use of vitamin/mineral supplements for the postfortification period relative to the prefortification period are presented in Table 5 and Table 6, respectively. Adjusted total folate intake was significantly higher in NHANES 1999–2004 than in NHANES 1988–1994 (P < 0.0001). However, there was no significant difference in intakes of iron, vitamin B-6, and vitamin B-12 between NHANESs 1988–1994 and 1999–2004. The likelihood of vitamin/mineral supplement use was significantly higher in NHANES 1999–2004 than in NHANES 1988–1994 (multivariate-adjusted OR: 1.59; 95% CI: 1.43, 1.77; P < 0.0001).


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  		TABLE 5. Adjusted intakes of total folate, iron, vitamin B-6, and vitamin B-12 in National Health and Nutrition Examination Surveys (NHANESs) 1988–1994 and 1999–2004: impact of folic acid fortification1

 

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  		TABLE 6. Association between vitamin/mineral supplement use and folic acid fortification in National Health and Nutrition Examination Surveys (NHANESs) 1988–1994 and 1999–20041

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this report, we present the first data on indicators and prevalence of anemia and macrocytosis using data from NHANES 1988–1994 and 1999–2004 with a focus on comparing data from before with that after folic acid fortification began. We found that hemoglobin and hematocrit values were significantly higher ({approx}2–3%) after folic acid fortification began (1999-2004) than before folic acid fortification began (1988-1994) in all demographic categories of the US population. However, the reduction in prevalence of anemia was observed in women of almost all demographic categories examined. The decrease in the prevalence of anemia from before to after folic acid fortification ranged from 16% to 52%. On the other hand, the prevalence of macrocytosis by and large remained the same in the postfortification period as in the prefortification period.

Folic acid fortification has significantly increased serum folate and red blood cell folate in the United States (7–11). We reported previously that the prevalence of low serum folate decreased from 18.4% in the prefortification period to 0.8% in the postfortification period (7). This decrease is due to increased folic acid intake from fortified cereals (3, 4) and supplements (27) after folic acid fortification. Given the remarkable improvement in folate status after folic acid fortification, one would expect the prevalence of macrocytosis to be lower in the postfortification period than in the prefortification period because folic acid cures folate deficiency–induced macrocytosis. Folate deficiency–induced macrocytosis is not common in the United States. The prevalence of macrocytosis from folate deficiency accounts for 3% of all macrocytosis cases (28). The majority of the macrocytosis cases are related to drug treatment (methotrexate, mercaptopurine, 5-fluouracil, zidovudine, metformin, trimethoprim, sulfamethoxazole, valproic acid, etc), alcoholism, reticulocytosis, alcoholic and nonalcoholic liver disease, hypothyroidism, multiple myeloma, aplastic anemia, acute leukemia, and vitamin B-12 deficiency (29, 30). Thus, mandated folic acid fortification is unlikely to have a significant impact on the prevalence of macrocytosis.

What is remarkable is the 16–52% decrease we observed in the prevalence of overall anemia from the pre- to the postfortification period. The decreased prevalence of anemia was mostly observed in women. Additionally, in women, the odds of having anemia in the postfortification period decreased by 36% relative to the prefortification period (P < 0.0001). Improved indexes of anemia and decreased prevalence of overall anemia in women could partly be attributed to improved folate status due to increased folic acid intake in the postfortification period. Additional analysis on this sample showed that the adjusted folic acid intake increased by {approx}105 µg dietary folate equivalents from 1988–1994 to 1999–2004. Another explanation might be the improvement in nutritional status of several nutrients that cure anemia because of increased consumption of vitamin/mineral supplements in the postfortification period than in the prefortification period. In this study population, we showed that the likelihood of use of vitamin/mineral supplements in the postfortification period increased by 59% (Table 6). Recently, Rock (31) reported that dietary supplement use was 40% in the prefortification period (NHANES 1988–1994) and 52% in the postfortification period (NHANES 1999–2000). This level of supplement use was more frequent in women than in men (32). Hence, a greater decrease in the prevalence of anemia in women than in men was expected. In men, a slight and significant increase in hemoglobin from the pre- to the postfortification period translated into a marginally significant reduction in the prevalence of anemia (OR: 0.79; P < 0.0433), which suggests that most cases of anemia in men are of nonnutritional origin. Men in low socioeconomic strata and men who did not consume supplements experienced a significant reduction in the prevalence of anemia from the pre- to the postfortification period (Table 3). In these specific men, as in women, it is possible that the removal of folate deficiency is likely the explanation for the lower prevalence of anemia in the postfortification period.

Because folic acid cures folate deficiency–induced macrocytosis, one would expect lower concentrations of MCV in the postfortification period than in the prefortification period. However, we found no such decrease in MCV in women. On the other hand, in men, there was a significant increase in MCV, albeit slight. However, this increase in MCV in men did not result in the increased prevalence of macrocytosis, which suggests that the changes in MCV might have occurred within the normal range in most men (<98 fL).

The observation of increased MCV in the postfortification period, especially in men and in older persons, is at odds with our earlier observation of lower MCVs in the postfortification period than in the prefortification period in patients who received health care in an urban institution (33). Difference in results between this current study and our earlier study can be attributed to the differences in characteristics of subjects. In support of our current study findings, Hirsch et al (34) found an increase in MCV in older Chilean people from the pre- to the postfortification period. They concluded that increased MCV in the postfortification period may be due to continued vitamin B-12 deficiency. Recently, Morris et al (35), using NHANES data, found that a high folate status was directly associated with anemia and cognitive impairment in older subjects with a low vitamin B-12 status. We previously reported that the proportion of individuals with low serum vitamin B-12 without macrocytosis was significantly higher in the postfortification period than in the prefortification period, which suggests a possible masking (delay in diagnosis due to lack of anemia) of vitamin B-12 deficiency (35). However, Mills et al (36) found no masking of vitamin B-12 deficiency in patients who received care in a Veterans Affairs hospital. More recently, Selhub et al (37) provided a possible biochemical explanation for the exacerbation of clinical manifestations of vitamin B-12 deficiency after high folic acid intakes. Oakley (38), in his editorial, called for cofortification of fortified cereals with vitamin B-12 to achieve a daily intake of 6 µg/d to prevent or correct vitamin B-12 insufficiency. However, we cannot ascertain whether the increased MCV in men and in older persons was due to an exacerbation of hematologic symptoms associated with vitamin B-12 insufficiency because of the cross-sectional nature of the study. Nonetheless, the cause of increased MCV in nontarget populations, such as men in general and in older persons specifically, warrants future study.

It is possible that differences in methods used to measure indexes of anemia may account for some of the differences we observed between pre- and postfortification periods. This is unlikely, however, because the methods used to measure indexes of anemia were largely consistent between fortification periods. It is important to note that each fortification period contained different subjects with possibly different dietary behaviors. Dietary intakes collected with the use of 24-h recalls are prone to measurement error because of the participant's inability to recall the foods eaten accurately. Because of the cross-sectional nature of this study, the measurement of cause and effect was not possible.

Because NHANES 1988–1994 was conducted before folic acid fortification was initiated and NHANES 1999–2004 was conducted after folic acid fortification was initiated, the changes we observed in indexes of anemia and in the prevalence of anemia may be attributable to the mandated folic acid fortification and increased use of vitamin/mineral supplements, although other potential unknown confounding factors cannot be ruled out. Folic acid fortification not only reduced the prevalence of NTDs as documented previously (6), but it also indirectly improved indicators of anemia, which led a significant reduction in the prevalence of anemia in target population (an unintended benefit), which suggests much wider public health implications than just NTDs. Because unmetabolized folic acid has been found in the circulation at a dose of 400 µg (39), folic acid status and its effects in both target and nontarget populations should be monitored on a regular basis. Although the prevalence of anemia was found to be significantly lower after the initiation than before the initiation of folic acid fortification, anemia continues to be a public health problem in women, specifically in NHB and MA/H, and in those with incomes below the poverty level.


   ACKNOWLEDGMENTS
 
The authors' responsibilities were as follows—VG: contributed to the study design and writing of the manuscript; MRK: contributed to the data acquisition, data management, and data analysis; and VG and MRK: contributed to the interpretation of results, review, revision, and editing of the manuscript. Neither author had a personal or financial conflict of interest.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication April 15, 2008. Accepted for publication October 20, 2008.





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