Abstract
Objective:
Despite the institution of mandatory folic acid fortification in the US, folate deficiencies still occur and are associated with an increased risk of several conditions. Since little is known regarding the relationship between folate status and other clinical, demographic, and healthcare-related characteristics, the objective of the study was to compare healthcare-related characteristics among US child-bearing age women with low vs normal red blood cell (RBC) folate levels.
Research design and methods:
Data from the 2003–2006 National Health and Nutrition Examination Survey (NHANES) were used to conduct a retrospective cohort study. Women (aged 18–45 when surveyed) were categorized in two cohorts for comparison: normal RBC folate level (≥140 ng/ml, NFL) and low RBC folate level (<140 ng/ml, LFL).
Results:
Of the 2816 subjects, 5.9% were assigned to the LFL cohort and were significantly younger (28 vs 30 years, p = 0.01); a greater proportion were 18–25 years old (55.7% vs 39.9%, p < 0.001) or African-American (55.1% vs 22.3%, p < 0.01). A lower proportion of LFL women were insured (67.3% vs 75.5%, p = 0.01) with low rates of private insurance (39.5% vs 53.1%, p < 0.01), while Medicaid/SCHIP coverage was similar (16.8% vs 15.1%, p = 0.56). Predictors of low folate levels included aged 36–45 years (OR: 2.14 [95% CI: 1.04, 4.39]) and never being married (2.65 [1.34, 5.24]), while a household income ≥ $75,000 reduced the likelihood of having low folate levels (0.20 [0.06, 0.73]).
Limitations:
The proportion of women with low folate levels was small, with the sample size limiting the ability to adjust for other factors during analysis. Medical histories were based on patient interviews and are subject to recall bias.
Conclusion:
LFL women are younger and have low rates of private insurance coverage compared to women with normal folate levels. Differences in age, marital status, and household income are associated with folate status.
Keywords::
Introduction
Folate, a water-soluble B vitamin, is the naturally occurring form of folic acid. It is necessary for DNA and RNA synthesis, DNA repair, and the metabolism of homocysteineCitation1–5. As a result, it is especially important during periods of rapid cell division and growthCitation6,Citation7. In 1998, the US Food and Drug Administration (FDA) mandated the fortification of enriched grain products with 140 μg of folic acid per 100 g of grain to increase daily folic acid consumption by ∼100 μgCitation8. Despite the institution of this folic acid fortification program, folate deficiencies still occur, either through insufficient dietary intake or folate loss as the result of medical conditions or medication.
One of the most recognized consequences of folate deficiency is the increased incidence of neural tube defects (NTDs) in developing embryos leading to birth defects such as spina bifida and anencephaly, representing the second most common group of serious congenital anomalies after cardiac defectsCitation9. Over the past three decades, numerous studies have provided evidence of a strong association between maternal folic acid intake and a reduction in the risk of having a child with an NTDCitation10–17. In 1992, the US Public Health Service recommended that reproductive-aged women capable of becoming pregnant should consume a minimum of 400 μg of folic acid daily, a recommendation reinforced by the Food and Nutrition Board of the National Academy of Sciences Institute of Medicine (IOM) in 19981Citation8,Citation19. Various studies have also associated low dietary folate intake with an increased risk of several conditions including pancreatic cancer, stroke, Alzheimer’s disease, and vascular dementiaCitation20–22. In addition, treatment with a methylated form of folic acid enhanced the recovery of depressed and schizophrenic patientsCitation23.
Despite the body of scientific evidence to support recommendations for folate supplementation, few women report routine ingestion of a folate supplement due to lack of awareness and/or compliance. A national survey conducted in 2007 by the Gallup Organization for the March of Dimes (MOD) Foundation found that only 30–40% of women (18–45 years of age) reported taking a daily supplement containing folic acidCitation24. The latest National Health and Nutrition Examination Survey (NHANES) results revealed that the lowest red blood cell (RBC) folate levels are among adolescent women, 12–19 years of ageCitation25. Similarly, a recent study assessed women’s self-reported awareness, knowledge, and use of folic acid in Kansas. Eighty-eight per cent of childbearing age women had a general awareness of folic acid, 20% had knowledge that it reduces birth defects, but only 25% reported taking it daily. The study found that women less likely to take folic acid on a daily basis were young, non-Caucasians who reported less education, less income, and no health insuranceCitation26. Similarly, a study of women who had given birth reported that women less than 25 years of age, unmarried, with less than 12 years of education, or with no health insurance were significantly less likely to have taken a folic-acid containing multivitamin prior to their pregnancyCitation27.
Although the value of folate supplementation to neonatal health and preconception is well established, and other studies have associated low folate intake with the increased risk of several conditions, to our knowledge there is limited research evaluating the complex relationship between existence and type of healthcare coverage along with demographic and clinical characteristics of child-bearing women and folate status. The objective of this study was to compare healthcare-related characteristics among US child-bearing age women with low vs normal RBC folate levels.
Patients and methods
Data source
National Health and Nutrition Examination Survey (NHANES) data were used for this evaluation. NHANES is a program of surveys designed to assess the health and nutritional status of adults and children in the US. A major program of the National Center for Health Statistics (NCHS) division of the Centers for Disease Control and Prevention (CDC), the NHANES survey examines a nationally representative sample of ∼5000 persons located in counties across the country, 15 of which are visited each yearCitation28. The survey is unique in that it combines interviews and physical examinations. The NHANES interview includes demographic, socioeconomic, dietary, and health-related questions. The examination component consists of medical, dental, and physiological measurements, as well as laboratory tests administered by highly trained medical personnel. Findings from this survey have been used to determine the prevalence of major diseases and risk factors for diseases as well as to assess nutritional status and its association with health promotion and disease prevention. NHANES findings are also the basis for national standards for such measurements as height, weight, and blood pressure. Data from this survey have been used in epidemiological studies and health sciences research, which help develop sound public health policy, direct and design health programs and services, and expand the health knowledge for US. The current study utilized data from the NHANES 2003–2004 and 2005–2006 surveys and included information collected from interviews conducted from January 2003 to December 2006. The data provided included red blood cell folate levels, co-morbid conditions, an overall assessment of the hospitalization rate based on survey responses, and medication usage.
Study criteria and variables
The study sample was comprised of female survey respondents that were of child-bearing age, defined as being between the ages of 18–45 at the time of the survey interview. All available demographic characteristics were extracted for each respondent and included age, ethnicity, marital status, household income, and health insurance when available. Clinical characteristics were determined from the medical history provided by each subject during the survey interview and included self-reported medical conditions and birth control use in addition to blood folate levels from the physical examination component of the survey. Folate status was determined by RBC serum folate levels which are based on total intake, both supplemental folic acid intake and dietary folate intake. Survey respondents were assigned to one of two study cohorts based on the RBC folate level reported in the NHANES laboratory results: (a) Normal Folate (NFL): women with RBC folate levels ≥140 ng/ml; and (b) Low Folate (LFL): women with RBC folate levels <140 ng/ml.
Statistical analyses
Subject demographic information such as age, ethnicity, etc. was reported for survey participants included in the normal and low folate level cohorts. Since demographic data in NHANES was derived from subject interviews that were conducted during the survey, the availability of data was dependent upon whether the respondent provided the information; for each variable evaluated, the proportion of subjects was determined as the percentage of the total number of respondents with data, which was not necessarily the total number of women in the cohort. Descriptive statistics were used to measure and compare the subject demographic information and clinical characteristics of both cohorts with p-values provided by Chi-square test or t-test where appropriate. Logistic regression models were used to identify demographic characteristics that were associated with low folate levels. Odds ratio estimates with Wald 95% confidence limits were reported for each regression parameter, with p-values derived from the analysis of maximum likelihood estimates. The demographic characteristics analyzed included age, marital status, household income, and health insurance status. A p-value of 0.05 was used to determine the level of statistical significance. All statistical analysis was carried out using SAS® 9.2.
Results
illustrates the selection criteria applied to determine the final study population used to conduct the study. The NHANES surveys from 2003–2006 contained interviews for 20,470 individuals. Eighty-five per cent of these individuals were male, less than 18 years old or greater than 45 years of age, and were subsequently excluded from the study. Among the remaining 3012 female respondents between the ages of 18–45, 196 (6.5%) were excluded due to incomplete laboratory results lacking a folate measurement. After all exclusion criteria were applied, the remaining 2816 qualified respondents were then assigned to one of two study cohorts based on their RBC folate level. The majority of the qualified respondents (94.1%) were assigned to the normal folate level cohort, while the remaining 5.9% had folate levels less than 140 ng/ml and were assigned to the low folate level cohort.
Figure 1. Subject flow. The number (n) of respondents at each exclusion level and the final number respondents within each cohort. RBC, red blood cell.
Demographic characteristics for the respondents in each folate level cohort were determined and consisted of age, ethnicity, marital status, household income, and health insurance when available. The demographic characteristics were then compared between the two cohorts (). Compared to NFL respondents, LFL women were significantly younger (28 years vs 30 years, p = 0.010), with a greater proportion between the ages of 18–25 (55.7% vs 39.9%, p < 0.001). In addition, a significantly higher percentage of the low folate women were of non-Hispanic black racial background in comparison to the women with normal folate levels (55.1% vs 22.3%), while a greater proportion of the women with normal folate levels were of non-Hispanic white racial background (42.7% vs 22.8%). With regard to marital status, higher proportions of NFL women were either married (44.8%) or living with a partner (11.3%) compared to LFL (24.5% and 8.4%, respectively). Conversely, greater proportions of LFL women (58.7%) were never married compared to NFL women (34.5%). The overall differences in marital status among NFL and LFL women were statistically significant (p < 0.001). Health insurance coverage status and coverage type were also determined and compared between NFL and LFL women (). A higher proportion of NFL women had health insurance coverage when compared to LFL women (75.5% vs 67.3%; p = 0.010, ). Of those that had health insurance, a significantly higher proportion of NFL women had private insurance coverage (53.1% vs 39.5%; p = 0.0007, ).
Figure 2. Health insurance coverage for child-bearing US women by folate status. The percentage of women with low and normal folate levels that reported having (Yes) or not having (No) health insurance coverage in the 12-month period prior to the survey interview. The p-value for the comparison between the low and normal folate level cohorts was 0.01.
Figure 3. Type of health insurance coverage for child-bearing US women by folate status. The percentage of women within the low or normal folate level cohorts that had one of the following types of insurance: private insurance, Medicare, Medicaid/State Children’s Health Insurance Program (SCHIP), other government insurance or single plan service. The p-value for the comparison between the low and normal folate level cohorts was 0.0007.
Table 1. Demographic characteristics among the normal and low folate cohorts.
The medical histories of the survey respondents were determined using the NHANES survey interview data which contained self-reported medical conditions that were present during the 12-month period prior to the interview. The proportions of subjects with these co-morbid conditions were determined and compared between the two cohorts (). Examination of their medical histories revealed that a significantly greater proportion of the women in the low folate cohort reported having emphysema (4.9-fold) and arthritis (1.8-fold). In addition, a greater proportion of women with low folate levels reported coronary events such as a heart attack or stroke. In contrast, the only condition present in a greater percentage of the normal folate women was asthma (15.7% vs 9.6%; p = 0.033).
Table 2. Clinical characteristics among the normal and low folate cohorts.
Multivariable logistic regression modeling was used to identify patient characteristics that were associated with an increased likelihood of having low folate levels (). In comparison to women between the ages of 18–25, women that were 36–45 years of age were over twice as likely to have low folate levels (p = 0.04). In addition, women who were never married had 2.65-fold increased risk of having low folate levels compared to married women (p = 0.005). However, women with household incomes over $75,000 had a 5-fold greater likelihood of having normal folate levels than women with household incomes between $20,000–$45,000 (p = 0.01).
Table 3. Patient characteristics associated with low folate status.
Discussion
This study demonstrated that women of child-bearing age with low folate levels are younger, non-Hispanic black women, are less likely to be married or living with a partner, have low rates of private insurance coverage, and tend to have a higher rate of chronic health conditions compared to women with normal folate levels. In addition, differences in age, marital status, and household income were predictors of folate status. In particular, the respondent’s age was closely associated with folate status. Logistic regression modeling found that women between the ages of 36–45 were over twice as likely to have low folate levels as women of 18–25 years of age. Similar outcomes have been reported by other studies. A survey assessing the awareness, knowledge, and use of folic acid in women of child-bearing age in Kansas reported that women of 35 years of age or older were over 4-times less likely to be aware of the benefits of folic acid and, as a result, are less likely to supplement their folic acid intakeCitation26. Furthermore, a smaller proportion of women over the age of 35 have their folic acid intake increased by their healthcare provider than women between the ages of 25–34Citation29. Correspondingly, women of 25–45 years of age that had a previous pregnancy were less likely to use folic acid supplementation, a reduction that was hypothesized to be the consequence of older women who have ended childbearingCitation30.
In the current study, marital status was also found to be associated with folate status. Women that were never married were more than twice as likely to have low folate levels as women that were married. Women that are married or living with their partner are more likely to consider or plan a future pregnancy, becoming aware of the benefits of folic acid in the process. Correspondingly, other studies have also found that being married or living with a partner increased the odds of folic acid supplementation and, consequently, folic acid levelsCitation30–32.
In accordance with other studies, a significantly greater proportion of women with low folate levels were of non-Hispanic black ethnicity. Previous analysis of NHANES data revealed that, although the 1998 institution of folic acid fortification increased folate levels overall, racial inequality persistedCitation33. When sub-divided into racial-ethnic groups, the prevalence of low folate levels from 2003–2004 was over 3-times higher among the non-Hispanic black women relative to non-Hispanic white and Mexican-American women. A separate NHANES study found that the prevalence of folic acid-containing dietary supplement use among non-Hispanic whites was twice that of both non-Hispanic blacks and Mexican-AmericansCitation34. The Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study examined African-American and white individuals between 30–64 years of age living in Baltimore, Maryland to determine the impact of various demographic variables on dietary micronutrient levelsCitation16. The study revealed that, based on a micronutrient composite index, diet quality was lower among African-Americans; mean folate levels were significantly lower and 25% of individuals had low folate intake. In addition, gender, poverty income ratio (the ratio of a family’s income to the poverty threshold defined by the US Census Bureau), level of education, and income level were significant predictors of diet qualityCitation16. Similarly, a study assessing the impact of the 1998 folic acid fortification policy found that, although folate levels improved overall, there was an almost 4-fold greater prevalence of low folate levels among African-Americans in comparison to Caucasians or Mexican-Americans. Furthermore, low folate levels were twice as prevalent in the lower third and fourth income quartiles in comparison to the top income quartileCitation35. In the current study, logistic regression modeling found that women with household incomes greater than $75,000 were 5-times more likely to have normal folate levels in comparison to women with household incomes between $20,000–$45,000. Correspondingly, other studies have also found that women in higher household income brackets were significantly more likely to be both aware of and use folic acid supplementsCitation26,Citation32,Citation36. Women with higher household incomes are more likely to be more educated and have greater access to healthcare than women in the lowest income brackets; a greater proportion of women with normal folate levels had private insurance coverage in comparison to women with low folate levels. Similarly, other studies have found that women with health insurance had a greater awareness of folic acid and an increased likelihood of using a folic acid supplementCitation26,Citation27,Citation30.
When comparing the medical histories of the women within the normal and low folate level cohorts in the current analysis, it was found that a greater proportion of the women in the low folate cohort had experienced coronary events such as a heart attack or stroke, but did not have significantly higher proportions of chronic cardiovascular conditions including congestive heart failure, coronary heart disease, or anemia. A population study that compared stroke mortality prior to and after folic acid fortification in the US and Canada to the UK, which did not implement food fortification, determined that elevated folate levels resulted in a decreased incidence of strokeCitation37. Similarly, a meta-analysis of studies concerning the use of folic acid supplementation in the prevention of stroke found a significant reduction in the risk of stroke, particularly when there was no prior history of strokeCitation22. Elevated homocysteine levels have been associated with a 2.2–2.5-fold increased risk of myocardial infarctionCitation38,Citation39. Folate is an important co-factor in the metabolism of homocysteine such that folate deficiency is associated with a detrimental increase in homocysteine levelsCitation40. Increasing folate intake can result in a corresponding reduction in homocysteine. However, meta-analyses of studies testing the ability of folic acid supplements to decrease the risk of cardiovascular disease have not found an association between increases in folate intake and the reduction of the risk of myocardial infarctionCitation41,Citation42.
The effect of folate levels upon chronic cardiovascular conditions are less defined. Many studies focus upon the use of folic acid as a treatment or determine folate levels through dietary intake. One study where folate levels were measured found that there was no association between folate levels and congestive heart failureCitation43. While epidemiological studies have associated low folate levels with an increased risk of coronary artery disease, clinical trials involving folic acid supplementation have not demonstrated any benefit from the treatmentCitation44,Citation45. Finally, folate deficiency is associated with the development of megaloblastic anemia, a condition where the development of erthyrocytes is disturbed. While folic acid supplementation prevents megaloblasty, it does not improve hemoglobin levelsCitation46. Another study found that elevated folate levels increased the risk of developing anemia in elderly patients by over 5-foldCitation47.
In the current analysis, a 4.9-fold greater percentage of the low folate cohort had emphysema and 1.8-fold more had arthritis. The relationship between an increased incidence of emphysema and low folate levels may be indirect. It is well accepted that the leading cause of emphysema is smoking. Several studies have found an association between smoking and decreased folate levelsCitation48–50. For example, a recently published study on the lifestyle and genetic determinants of folate level among the Danish population found that low serum folate levels were associated with smoking, low alcohol intake, high coffee intake, and an unhealthy dietCitation51. The increased proportion of emphysema among women with low folate levels may be more a reflection of the symptom rather than the cause in that the act of smoking cigarettes resulted in both the development of emphysema as well as a decrease in folate levels. Very little is known about the effect of folate levels on arthritis. Previous studies found no significant connection between folate levels and the incidence of hip or knee osteoarthritisCitation52,Citation53.
In contrast, the only condition present in a greater percentage of the normal folate women was asthma (15.7% vs 9.6%; p = 0.0329). While prior studies have associated the use of folic acid supplements during pregnancy to an increased risk of later childhood asthma, little is known about the effect of folate levels on adult asthmaCitation54,Citation55. Contrary to the result of this study, a recent population-based prospective study associated low serum folate levels with an increased prevalence of self-reported doctor-diagnosed asthmaCitation56. A possible explanation for this difference is the use of serum folate levels in the previous study. While both serum and RBC folate levels can be used to determine folate status, serum folate levels are an indicator of recent folate intake. In contrast, RBC folate levels are a measure of long-term folate stores and a better indicator of long-term folate status. The use of RBC folate levels in the current study identified women with prolonged folate deficiency. In addition, the study population in the previous study was not stratified by gender and measures the prevalence of asthma for the entire study cohort. Furthermore, the increased prevalence of asthma in relation to serum folate level was somewhat bi-modal. Serum folate levels were divided into four groups consisting of low (<6.2 nmol/l), low-middle (6.2 to <8.6 nmol/l), middle-high (8.6 to <12.3 nmol/l), and high (>12.3 nmol/l) folate levels. The highest prevalence of asthma was among the lowest folate levels (10%; adjusted odds ratio [OR] of 1.37), with a second, slightly lower peak at the ‘high-middle’ folate level (8.5%; adjusted OR of 1.13). As a result, it is possible that this second peak, with serum folate levels that are closer to normal, represents the increased proportion of normal folate women with asthma seen in our study. Finally, the development of asthma can be influenced by many confounding factors which were not evaluated in the current study. Any correlation between asthma and folate status requires further validation from additional clinical investigation.
The current study investigated women of child-bearing age, a relatively young population. Consequently, the increased incidence of myocardial infarction, stroke, and emphysema, which are primarily age-related diseases, was unexpected. One explanation may be the method of data collection. The incidence of the diseases and conditions examined in the current study were based on medical histories reported in subject surveys with no clinical verification. As a result, the reporting of the medical conditions is subject to recall bias. However, the NHANES program maintains high standards to minimize non-sampling and measurement errors; NHANES data is widely used and is well accepted in clinical literature. In addition, due to the limited number of low folate subjects, the study cohorts were not adjusted for potential confounders such as the presence of smokers. The absolute number of respondents with the conditions was low and presents the possibility that women in each category are the same. As a result, drawing robust conclusions about the association between folate levels and coronary events or emphysema will likely require further research.
While increasing folate intake may not be a protective measure, pre-existing folate deficiencies may play a role in the development of disease. For example, studies have demonstrated the importance of periconceptional folate supplementation at least 1 month before pregnancy and through the first trimester in order to reach sufficient serum folate levels that may be protective against NTDsCitation57. However, supplementation that began after conception had no beneficial effect on birthweight, placental weight, or gestational ageCitation58. Similarly, in colorectal, breast, and prostate cancer, some studies have found that increased dietary folate was associated with a decreased risk of developing the diseaseCitation59–63. However, subsequent clinical trials using folic acid supplements to increase folate levels suggested that elevated folate levels were associated with an increased risk of these types of cancerCitation64–68. This dual effect of folate on cancer may be explained by animal studies where the timing and folate dosage was critical in that folate decreased the development of tumors, but enhanced the growth of established neoplasmsCitation45,Citation69. Accordingly, normal folate levels may be most effective in preventing the development of disease and not in the treatment or prevention of subsequent episodes.
Previous NHANES data for all women aged 15–44 years has shown that folate levels have consistently increased from 1988–1999Citation70. However, more recent evidence from NHANES seems to suggest a plateau or a slight decline in the folate levels of US women of childbearing age from 1999–2000 through 2003–2004Citation33,Citation71. One study found that only 7.2% of non-pregnant women of child-bearing age were prescribed folic acid or folic acid-containing multivitamins by their healthcare providerCitation29. Even with mandated food fortification programs in the US and strong evidence linking folate deficiency to various health problems, this study highlights the fact that there continue to be low levels of folate among child-bearing women, especially in younger, ethnic minorities, and those with lower levels of healthcare coverage. This is disconcerting, as these groups also tend to have higher rates of intended and unintended pregnancies compared to older, Caucasian, and privately insured women, increasing the potential for birth defectsCitation72–75. Educational public health awareness programs need to be targeted to at-risk populations as identified in this study, confirming previous research, to raise folate benefit awareness and ultimately blood folate levels.
A major strength of this study is its large, nationally representative sample of US child-bearing women who are ethnically diverse. Limitations include the use of cross-sectional data to examine possible relationships between folate levels determined by only one laboratory test, and healthcare characteristics that were self-reported, introducing the potential for inter-subject variation and recall bias.
Conclusions
Women with low folate levels are younger and have low rates of private insurance coverage. In addition, differences in age, marital status, and household income are associated with folate status. Analysis of the NHANES data reveals that, despite supplementation programs, folate deficiencies still occur and are associated with an increased risk of several chronic conditions. The at-risk populations identified in the study can be targeted to increase folate awareness.
Transparency
Declaration of funding
The study was sponsored by Bayer HealthCare Pharmaceuticals Inc.
Declaration of financial/other relationships
V.J. and R.L. are employees of Bayer HealthCare Pharmaceuticals. G.L. is an employee of Novosys Health which received research funding for conducting the study from Bayer Healthcare Pharmaceuticals. The authors are fully responsible for all content and editorial decisions.
The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.
References
- Selhub J. Folate, vitamin B12 and vitamin B6 and one carbon metabolism. J Nutr Health Aging 2002;6:39-42
- Selhub J. Homocysteine metabolism. Annu Rev Nutr 1999;19:217-46
- Kamen B. Folate and antifolate pharmacology. Semin Oncol 1997;24:S18-39
- Duthie SJ. Folate and cancer: how DNA damage, repair and methylation impact on colon carcinogenesis. J Inherit Metab Dis 2011;34:101-9
- Stanger O. Physiology of folic acid in health and disease. Curr Drug Metab 2002;3:211-23
- Scholl TO, Johnson WG. Folic acid: influence on the outcome of pregnancy. Am J Clin Nutr 2000;71:1295S-303S
- Bohnsack BL, Hirschi KK. Nutrient regulation of cell cycle progression. Annu Rev Nutr 2004;24:433-53
- FDA. USFaDA. Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid. Fed Regist 1996;61:8781-97
- Petrini JR, Hamner HC, Flores AL, et al. Use of supplements containing folic acid among women of childbearing age–United States, 2007. MMWR Morb Mortal Wkly Rep 2008;57:5–8
- Meijer WM, de Walle HE. [Differences in folic-acid policy and the prevalence of neural-tube defects in Europe; recommendations for food fortification in a EUROCAT report]. Ned Tijdschr Geneeskd 2005;149:2561-4
- Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992;327:1832-5
- Wald N and Sneddon J. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet 1991;338:131-7
- Berry RJ, Li Z, Erickson JD, et al. Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention. N Engl J Med 1999;341:1485-90
- Blencowe H, Cousens S, Modell B, et al. Folic acid to reduce neonatal mortality from neural tube disorders. Int J Epidemiol 2010;39(1 Suppl):i110-21
- De-Regil LM, Fernandez-Gaxiola AC, Dowswell T, et al. Effects and safety of periconceptional folate supplementation for preventing birth defects. Cochrane Database Syst Rev 2010;10:1-134:CD007950
- Raffensperger S, Kuczmarski MF, Hotchkiss L, et al. Effect of race and predictors of socioeconomic status on diet quality in the HANDLS Study sample. J Natl Med Assoc 2010;102:923-30
- Tinker S, Cogswell M, Devine O, et al. Folic acid intake among U.S. women aged 15-44 Years, National Health and Nutrition Examination Survey, 2003–2006. Am J Prev Med 2010;38:534-42
- Centers for Disease Control and Prevention. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Recomm Rep 1992;41:1-7
- National Research Council. (IOM) IoM. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, DC: National Academy Press, 1998. p 196-305
- Larsson SC, Hakansson N, Giovannucci E, et al. Folate intake and pancreatic cancer incidence: a prospective study of Swedish women and men. J Natl Cancer Inst 2006;98:407-13
- Quadri P, Fragiacomo C, Pezzati R, et al. Homocysteine, folate, and vitamin B-12 in mild cognitive impairment, Alzheimer disease, and vascular dementia. Am J Clin Nutr 2004;80:114-22
- Wang X, Qin X, Demirtas H, et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet 2007;369:1876-82
- Godfrey PS, Toone BK, Carney MW, et al. Enhancement of recovery from psychiatric illness by methylfolate. Lancet 1990;336:392-5
- Gallup Organization and March of Dimes Foundation. Foundation. GOaMoD. Improving preconception health: women's knowledge and use of folic acid. White Plains, NY: March of Dimes, 2007
- McDowell MA, Lacher DA, Pfeiffer CM, et al. Blood folate levels: the latest NHANES results. NCHS Data Brief 2008;6:1-8
- Sharp GF, Naylor LA, Cai J, et al. Assessing awareness, knowledge and use of folic acid in Kansas women between the ages of 18 and 44 years. Matern Child Health J 2009;13:814-21
- Lorenz D, Lincoln A, Dooley S, et al. Surveillance of preconception health indicators among women delivering live-born infants–Oklahoma, 2000-2003. MMWR Morb Mortal Wkly Rep 2007;56:631–4
- National Health and Nutrition Examination Survey. CDC, 2005. http://www.cdc.gov/nchs/data/nhanes/nhanes_05_06/general_data_release_doc_05_06.pdf. Accessed May 28, 2011
- Burris HH, Werler MM. U.S. Provider reported folic acid or multivitamin ordering for non-pregnant women of childbearing age: NAMCS and NHAMCS, 2005–2006. Matern Child Health J 2011;15:352-9
- Evans L, Weisman CS. Folic acid supplementation in younger and older nonpregnant women of reproductive age: findings from the Central Pennsylvania Women's Health Study (CePAWHS). Womens Health Issues 2010;20:50-7
- Herrndorf AM, Haydu SC, and Takahashi ER. Trends in folic acid supplement intake among women of reproductive age–California, 2002-2006. MMWR Morb Mortal Wkly Rep 2007;56:1106–9
- Cleves MA, Hobbs CA, Collins HB, et al. Folic acid use by women receiving routine gynecologic care. Obstet Gynecol 2004;103:746-53
- Pfeiffer CM, Johnson CL, Jain RB, et al. Trends in blood folate and vitamin B-12 concentrations in the United States, 1988-2004. Am J Clin Nutr 2007;86:718-27
- Bailey RL, Dodd KW, Gahche JJ, et al. Total folate and folic acid intake from foods and dietary supplements in the United States: 2003-2006. Am J Clin Nutr 2010;91:231-7
- Dowd JB, Aiello AE. Did national folic acid fortification reduce socioeconomic and racial disparities in folate status in the US? Int J Epidemiol 2008;37:1059-66
- de Jong-Van den Berg LT, Hernandez-Diaz S, Werler MM, et al. Trends and predictors of folic acid awareness and periconceptional use in pregnant women. Am J Obstet Gynecol 2005;192:121-8
- Yang Q, Botto LD, Erickson JD, et al. Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation 2006;113:1335-43
- Woodward M, Rumley A, Rumley A, et al. The association between homocysteine and myocardial infarction is independent of age, sex, blood pressure, cholesterol, smoking and markers of inflammation: the Glasgow Myocardial Infarction Study. Blood Coagul Fibrinolysis 2006;17:1-5
- Haim M, Tanne D, Goldbourt U, et al. Serum homocysteine and long-term risk of myocardial infarction and sudden death in patients with coronary heart disease. Cardiology 2007;107:52-6
- Verhoef P, Stampfer MJ, Buring JE, et al. Homocysteine metabolism and risk of myocardial infarction: relation with vitamins B6, B12, and folate. Am J Epidemiol 1996;143:845-59
- Bazzano LA, Reynolds K, Holder KN, et al. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA 2006;296:2720-6
- Marti-Carvajal AJ, Sola I, Lathyris D, et al. Homocysteine lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev 2009;4:1-63:CD006612
- Herrmann M, Muller S, Kindermann I, et al. Plasma B vitamins and their relation to the severity of chronic heart failure. Am J Clin Nutr 2007;85:117-23
- Refsum H. Is folic acid the answer? Am J Clin Nutr 2004;80:241-2
- Smith AD, Kim YI, Refsum H. Is folic acid good for everyone? Am J Clin Nutr 2008;87:517-33
- Fishman SM, Christian P, West KP. The role of vitamins in the prevention and control of anaemia. Public Health Nutr 2000;3:125-50
- Morris MS, Jacques PF, Rosenberg IH, et al. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr 2007;85:193-200
- Cafolla A, Dragoni F, Girelli G, et al. Folate status in Italian blood donors: relation to gender and smoking. Haematologica 2000;85:694-8
- Piyathilake CJ, Macaluso M, Hine RJ, et al. Local and systemic effects of cigarette smoking on folate and vitamin B-12. Am J Clin Nutr 1994;60:559-66
- Vardavas CI, Linardakis MK, Hatzis CM, et al. Smoking status in relation to serum folate and dietary vitamin intake. Tob Induc Dis 2008;4:8
- Thuesen BH, Husemoen LL, Ovesen L, et al. Lifestyle and genetic determinants of folate and vitamin B12 levels in a general adult population. Br J Nutr 2010;103:1195-204
- Holstein JH, Herrmann M, Splett C, et al. Hyperhomocysteinemia is not associated with reduced bone quality in humans with hip osteoarthritis. Clin Chem Lab Med 2010;48:821-7
- McAlindon TE, Jacques P, Zhang Y, et al. Do antioxidant micronutrients protect against the development and progression of knee osteoarthritis? Arthritis Rheum 1996;39:648-56
- Prescott SL, Clifton V. Asthma and pregnancy: emerging evidence of epigenetic interactions in utero. Curr Opin Allergy Clin Immunol 2009;9:417-26
- Whitrow MJ, Moore VM, Rumbold AR, et al. Effect of supplemental folic acid in pregnancy on childhood asthma: a prospective birth cohort study. Am J Epidemiol 2009;170:1486-93
- Thuesen BH, Husemoen LL, Ovesen L, et al. Atopy, asthma, and lung function in relation to folate and vitamin B in adults. Allergy 2010;65:1446-54
- Lumley J, Watson L, Watson M, et al. Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects. Cochrane Database Syst Rev 2001;3:1-27:CD001056
- Charles DH, Ness AR, Campbell D, et al. Folic acid supplements in pregnancy and birth outcome: re-analysis of a large randomised controlled trial and update of Cochrane review. Paediatr Perinat Epidemiol 2005;19:112-24
- Shannon J, Phoutrides E, Palma A, et al. Folate intake and prostate cancer risk: a case-control study. Nutr Cancer 2009;61:617-28
- Kennedy DA, Stern SJ, Moretti M, et al. Folate intake and the risk of colorectal cancer: a systematic review and meta-analysis. Cancer Epidemiol 2011;35:2-10
- Sanjoaquin MA, Allen N, Couto E, et al. Folate intake and colorectal cancer risk: a meta-analytical approach. Int J Cancer 2005;113:825-8
- Maruti SS, Ulrich CM, White E. Folate and one-carbon metabolism nutrients from supplements and diet in relation to breast cancer risk. Am J Clin Nutr 2009;89:624-33
- Larsson SC, Giovannucci E, Wolk A. Folate and risk of breast cancer: a meta-analysis. J Natl Cancer Inst 2007;99:64-76
- Cole BF, Baron JA, Sandler RS, et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 2007;297:2351-9
- Lin J, Lee IM, Cook NR, et al. Plasma folate, vitamin B-6, vitamin B-12, and risk of breast cancer in women. Am J Clin Nutr 2008;87:734-43
- Collin SM, Metcalfe C, Refsum H, et al. Circulating folate, vitamin B12, homocysteine, vitamin B12 transport proteins, and risk of prostate cancer: a case-control study, systematic review, and meta-analysis. Cancer Epidemiol Biomarkers Prev 2010;19:1632-42
- Kim YI. Folic acid fortification and supplementation–good for some but not so good for others. Nutr Rev 2007;65:504-11
- Roswall N, Olsen A, Christensen J, et al. Micronutrient intake and breast cancer characteristics among postmenopausal women. Eur J Cancer Prev 2010;19:360-5
- Lucock M and Yates Z. Folic acid fortification: a double-edged sword. Curr Opin Clin Nutr Metab Care 2009;12:555-64
- Ganji V, Kafai MR. Trends in serum folate, RBC folate, and circulating total homocysteine concentrations in the United States: analysis of data from National Health and Nutrition Examination Surveys, 1988--1994, 1999--2000, and 2001--2002. J Nutr 2006;136:153-8
- Boulet SL, Yang Q, Mai C, et al. Folate status in women of childbearing age, by race/ethnicity–United States, 1999-2000, 2001-2002, and 2003-2004. MMWR Morb Mortal Wkly Rep 2007;55:1377–80
- Finer LB, Henshaw SK. Disparities in rates of unintended pregnancy in the United States, 1994 and 2001. Perspect Sex Reprod Health 2006;38:90-6
- Cubbin C, Braveman PA, Marchi KS, et al. Socioeconomic and racial/ethnic disparities in unintended pregnancy among postpartum women in California. Matern Child Health J 2002;6:237-46
- Kost K, Forrest JD. Intention status of U.S. births in 1988: differences by mothers' socioeconomic and demographic characteristics. Fam Plann Perspect 1995;27:11-7
- Forrest JD. Epidemiology of unintended pregnancy and contraceptive use. Am J Obstet Gynecol 1994;170:1485-9