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1.  Folate Status of Reproductive Age Women and Neural Tube Defect Risk: The Effect of Long-Term Folic Acid Supplementation at Doses of 140 µg and 400 µg per Day 
Nutrients  2011;3(1):49-62.
Primary prevention of most folate-responsive neural tube defects (NTDs) may not require 400 μg folic acid/day but may be achieved by attaining a high maternal folate status. Using RBC folate ≥906 nmol/L as a marker for NTD risk reduction, the study aimed to determine the change in blood folate concentrations in reproductive age women in response to long-term folic acid supplementation at 400 µg/day and 140 µg/day (dose designed to mimic the average daily folic acid intake received from New Zealand’s proposed mandatory bread fortification program). Participants were randomly assigned to a daily folic acid supplement of 140 µg (n = 49), 400 µg (n = 48) or placebo (n = 47) for 40 weeks. RBC folate concentrations were measured at baseline, and after 6, 12, 29 and 40 weeks. At 40 weeks, the overall prevalence of having a RBC folate <906 nmol/L decreased to 18% and 35% in the 400 µg and 140 µg groups, respectively, while remaining relatively unchanged at 58% in the placebo group. After 40 weeks, there was no evidence of a difference in RBC folate between the two treatment groups (P = 0.340), nor was there evidence of a difference in the odds of a RBC folate <906 nmol/L (P = 0.078). In conclusion, the average daily intake of folic acid received from the proposed fortification program would increase RBC folate concentrations in reproductive age women to levels associated with a low risk of NTDs.
PMCID: PMC3257734  PMID: 22254076
neural tube defects; blood folate status; folic acid fortification; supplementation
2.  Folate during reproduction: the Canadian experience with folic acid fortification 
Nutrition Research and Practice  2007;1(3):163-174.
Folate has received international attention regarding its role in the risk-reduction of birth defects, specifically neural tube defects (NTDs). In 1998, health officials in Canada, like the United States, mandated the addition of folic acid to white flour and select grain products to increase the folate intake of reproductive-aged women. Subsequent to this initiative there has been an increase in blood folate concentrations in Canada and a 50% reduction in NTDs. Many countries, including Korea, have not mandated folic acid fortification of their food supply. Reasons vary but often include concern over the masking of vitamin B12 deficiency, a belief that folate intakes among womenare adequate, low priority relative to other domestic issues, and the philosophy that individuals have the right not to consume supplemental folic acid if they so choose. Prior to folic acid fortification of the food supply in Canada, the folate intakes of women were low, and their blood folate concentrations while not sufficiently low to produce overt signs of folate deficiency (eg. anemia) were inconsistent with a level known to reduce the risk of an NTD-affected pregnancy. The purpose of this article is to describe the role of folate during the periconceptional period, pregnancy, and during lactation. The rationale for, and history of recommending folic acid-containing supplements during the periconceptional period and pregnancy is described as is folic acid fortification of the food supply. The impact of folic acid fortification in Canada is discussed, and unresolved issues associated with this policy described. While the incidence of NTDs in Canada pre-folic acid fortification were seemingly higherthan that of Korea today, blood folate levels of Korean women are strikingly similar. We will briefly explore these parallels in an attempt to understand whether folic acid fortification of the food supply in Korea might be worth consideration
PMCID: PMC2849017  PMID: 20368933
Folic acid; fortification; periconceptional period; pregnancy; lactation
3.  Determinants of neural tube defect (NTD)-protective circulating concentrations of folate in women of child-bearing age in the US post-folic acid fortification era 
Nutrition Research and Practice  2013;7(4):315-325.
We evaluated folate status of child-bearing age women diagnosed with abnormal pap smear in the US post-folic acid (FA) fortification era and assessed the determinants of NTD-protective and supra-physiologic (SP) concentrations of folate. The distribution of 843 women according to NTD-protective concentrations of RBC folate, plasma folate and SP concentrations of plasma folate were tested in relation to demographic and life-style factors. Logistic regression models specified NTD-protective concentrations of RBC and plasma folate or SP concentrations of plasma folate as dependent variables and demographic and life-style factors as independent predictors of interest. More than 82% reached NTD-protective concentrations of RBC and plasma folate and ~30% reached SP concentrations of plasma folate. FA supplement use was associated with having SP concentrations of plasma folate rather than NTD-protective concentrations of folate. African American (AA) women and smokers were significantly less likely to achieve NTD-protective concentrations of RBC and plasma folate. A large majority of women reached NTD-protective concentrations of folate with the current level of FA fortification without using supplementary FA. Therefore, the remaining disparities in AA women and in smokers should be addressed by targeted individual improvements in folate intake.
PMCID: PMC3746167  PMID: 23964320
Folate; neural tube defect; child-bearing age
4.  Gene–environment interactions in the causation of neural tube defects: folate deficiency increases susceptibility conferred by loss of Pax3 function 
Human Molecular Genetics  2008;17(23):3675-3685.
Risk of neural tube defects (NTDs) is determined by genetic and environmental factors, among which folate status appears to play a key role. However, the precise nature of the link between low folate status and NTDs is poorly understood, and it remains unclear how folic acid prevents NTDs. We investigated the effect of folate level on risk of NTDs in splotch (Sp2H) mice, which carry a mutation in Pax3. Dietary folate restriction results in reduced maternal blood folate, elevated plasma homocysteine and reduced embryonic folate content. Folate deficiency does not cause NTDs in wild-type mice, but causes a significant increase in cranial NTDs among Sp2H embryos, demonstrating a gene–environment interaction. Control treatments, in which intermediate levels of folate are supplied, suggest that NTD risk is related to embryonic folate concentration, not maternal blood folate concentration. Notably, the effect of folate deficiency appears more deleterious in female embryos than males, since defects are not prevented by exogenous folic acid. Folate-deficient embryos exhibit developmental delay and growth retardation. However, folate content normalized to protein content is appropriate for developmental stage, suggesting that folate availability places a tight limit on growth and development. Folate-deficient embryos also exhibit a reduced ratio of s-adenosylmethionine (SAM) to s-adenosylhomocysteine (SAH). This could indicate inhibition of the methylation cycle, but we did not detect any diminution in global DNA methylation, in contrast to embryos in which the methylation cycle was specifically inhibited. Hence, folate deficiency increases the risk of NTDs in genetically predisposed splotch embryos, probably via embryonic growth retardation.
PMCID: PMC2581426  PMID: 18753144
5.  Clinical utility of folate-containing oral contraceptives 
Folate is a generic term for a water-soluble B-complex vitamin which plays an important role in protein synthesis and metabolism and other processes related to cell multiplication and tissue growth. Pregnant and lactating women are at increased risk of folic acid deficiency because generally their dietary folate is insufficient to meet their physiological requirements and the metabolic demands of the growing fetus. The evidence pertaining to the reduction of the risk of neural tube defects (NTDs) due to folate is so compelling that supplementation with 400 μg of folic acid to all women trying to conceive until 12 weeks of pregnancy has been recommended by every relevant authority. A recent Cochrane review has also found protective effects of folate supplementation in occurrence and reoccurrence of NTDs. Despite food fortification and targeted public health campaigns promoting folic acid supplementation, 4,300,000 new cases occur each year worldwide resulting in an estimated 41,000 deaths and 2.3 million disability-adjusted life years (DALYS). This article will review the burden and risk factors of NTDS, and the role of folate in preventing NTDs. It will also describe different modes of supplementing folate and the newer evidence of the effectiveness of adding folate in oral contraceptives for raising serum and red blood cell folate levels.
PMCID: PMC3346209  PMID: 22570577
folate; folate-containing oral contraceptives; oral contraceptives; contraceptives
6.  Estimates of Total Dietary Folic Acid Intake in the Australian Population Following Mandatory Folic Acid Fortification of Bread 
Mandatory folic acid fortification of wheat flour for making bread was implemented in Australia in September 2009, to improve the dietary folate status of women of child-bearing age, and help reduce the incidence of neural tube defects in the population. This paper presents estimates of folic acid intake in the target population and other subgroups of the Australian population following implementation of the mandatory folic acid fortification standard. In June/July 2010 one hundred samples from seven bread categories were purchased from around the country and individually analysed for the amount of folic acid they contained. A modification to the triple enzyme microbiological method was used to measure folic acid in the individual bread samples. The folic acid analytical values together with national food consumption data were used to generate estimates of the population's folic acid intake from fortified foods. Food Standards Australia New Zealand's (FSANZ) custom-built dietary modelling program (DIAMOND) was used for the estimates. The mean amount of folic acid found in white bread was 200 μg/100 g which demonstrated that folic-acid-fortified wheat flour was used to bake the bread. The intake estimates indicated an increase in mean folic acid intake of 159 μg per day for the target group. Other sub-groups of the population also showed increases in estimated mean daily intake of folic acid.
PMCID: PMC3432557  PMID: 22957218
7.  Folate Intake and Markers of Folate Status in Women of Reproductive Age, Pregnant and Lactating Women: A Meta-Analysis 
Background. Pregnant and breastfeeding women are at risk for folate deficiency. Folate supplementation has been shown to be associated with enhanced markers of folate status. However, dose-response analyses for adult women are still lacking. Objective. To assess the dose-response relationship between total folate intake (folic acid plus dietary folate) and markers of folate status (plasma/serum folate, red blood cell folate, and plasma homocysteine); to evaluate potential differences between women in childbearing age, pregnant and lactating women. Methods. Electronic literature searches were carried out on three databases until February 2010. The overall pooled regression coefficient (β) and SE(β) were calculated using meta-analysis on a double-log scale. Results. The majority of data was based on nonpregnant, nonlactating women in childbearingage. The pooled estimate of the relationship between folate intake and serum/plasma folate was 0.56 (95% CI = 0.40–0.72, P < 0.00001); that is, the doubling of folate intake increases the folate level in serum/plasma by 47%. For red blood cell folate, the pooled-effect estimate was 0.30 (95% CI = 0.22–0.38, P < 0.00001), that is, +23% for doubling intake. For plasma-homocysteine it was –0.10 (95% = –0.17 to –0.04, P = 0.001), that is, –7% for doubling the intake. Associations tended to be weaker in pregnant and lactating women. Conclusion. Significant relationships between folate intake and serum/plasma folate, red blood cell folate, and plasma homocysteine were quantified. This dose-response methodology may be applied for setting requirements for women in childbearing age, as well as for pregnant and lactating women.
PMCID: PMC3449134  PMID: 23024859
8.  Serum homocysteine is related to food intake in adolescents: the Child and Adolescent Trial for Cardiovascular Health2 
An understanding of the relation in adolescents between serum homocysteine and foods rich in vitamin B-6, vitamin B-12, and folate is important because high homocysteine concentrations in childhood and adolescence may be a risk factor for later cardiovascular disease. However, little is known about the relation between food intake and homocysteine in adolescents.
Five years after national folic acid fortification of enriched grain products, cross-sectional relations between food intake and serum homocysteine concentrations were examined in 2695 adolescents [x̄ age: 18.3 (range: 15−20) y] enrolled in the Child and Adolescent Trial for Cardiovascular Health.
A nonfasting blood specimen was analyzed for serum homocysteine, folate, and vitamins B-6 and B-12. Dietary intake was assessed by using a food-frequency questionnaire. Multiple regression analyses were used to evaluate the relation of intakes of whole grains, refined grains, fruit, vegetables, dairy products, red and processed meats, and poultry with serum homocysteine concentrations after adjustment for demographic characteristics, lifestyle factors, and food intake.
Serum homocysteine concentrations were lower with greater intakes of whole grains (P for trend = 0.002), refined grains (P for trend = 0.02), and dairy foods (P for trend <0.001); were higher with greater intake of poultry (P for trend = 0.004); and were not related to intakes of fruit, vegetables, or red or processed meat. After additional adjustment for serum B vitamins, the relations of serum homocysteine with most food groups were attenuated.
These observational findings suggest a beneficial effect of whole-grain, refined-grain, and dairy products on serum homocysteine concentrations in an adolescent population.
PMCID: PMC2430626  PMID: 16762950
Homocysteine; serum folate; cardiovascular disease; adolescents; food groups; whole grain
9.  Folate and colorectal cancer prevention 
British Journal of Cancer  2008;100(2):233-239.
Anti-folate chemotherapy agents such as methotrexate and fluorouracil reduce proliferation of neoplastic cells by inhibiting DNA synthesis. Paradoxically epidemiological data suggests an inverse relationship between dietary folate intake and incidence of colorectal cancer (CRC). On the basis of this and other putative health benefits around 35% of the North American population take folic acid supplements, in addition to natural food folates and fortified flour and cereal grains. Recently, randomised controlled trials investigating folic acid as a secondary preventative agent in colorectal neoplasia have shed further light on the relationship between folate and colorectal carcinogenesis, corroborating data from animal models indicating opposing effects dependent on the timing of exposure in relation to the development of neoplastic foci. A ‘dual-modulator' role for folate in colorectal carcinogenesis has been proposed in which moderate dietary increases initiated before the establishment of neoplastic foci have a protective influence, whereas excessive intake or increased intake once early lesions are established increases tumorigenesis. Functional polymorphic variants in genes encoding key enzymes in the folate metabolic pathway add a further layer of complexity to the relationship between folate and CRC risk. Here, we review the evidence concerning the efficacy and safety of folate as a potential CRC chemopreventive agent.
PMCID: PMC2634716  PMID: 19088716
folate; colorectal cancer; prevention
10.  Human Folate Bioavailability  
Nutrients  2011;3(4):475-490.
The vitamin folate is recognized as beneficial health-wise in the prevention of neural tube defects, anemia, cardiovascular diseases, poor cognitive performance, and some forms of cancer. However, suboptimal dietary folate intake has been reported in a number of countries. Several national health authorities have therefore introduced mandatory food fortification with synthetic folic acid, which is considered a convenient fortificant, being cost-efficient in production, more stable than natural food folate, and superior in terms of bioavailability and bioefficacy. Other countries have decided against fortification due to the ambiguous role of synthetic folic acid regarding promotion of subclinical cancers and other adverse health effects. This paper reviews recent studies on folate bioavailability after intervention with folate from food. Our conclusions were that limited folate bioavailability data are available for vegetables, fruits, cereal products, and fortified foods, and that it is difficult to evaluate the bioavailability of food folate or whether intervention with food folate improves folate status. We recommend revising the classical approach of using folic acid as a reference dose for estimating the plasma kinetics and relative bioavailability of food folate.
PMCID: PMC3257685  PMID: 22254106
folate; folic acid; human bioavailability; intervention trials; post-dose plasma kinetics
11.  Photobiological Implications of Folate Depletion and Repletion in Cultured Human Keratinocytes 
Folate nutrition is critical in humans and a high dietary folate intake is associated with a diminished risk of many types of cancer. Both synthetic folic acid and the most biologically abundant extracellular reduced folate, 5-methyltetrahydrofolate, are degraded under conditions of ultraviolet radiation (UVR) exposure. Skin is a proliferative tissue with increased folate nutrient demands due to a dependence upon continuous epidermal cell proliferation and differentiation to maintain homeostasis. Regions of skin are also chronically exposed to UVR, which penetrates to the actively dividing basal layer of the epidermis, increasing the folate nutrient demands in order to replace folate species degraded by UVR exposure and to supply the folate cofactors required for repair of photo-damaged DNA. Localized folate deficiencies of skin are a likely consequence of UVR exposure. We report here a cultured keratinocyte model of folate deficiency that has been applied to examine possible effects of folate nutritional deficiencies in skin. Utilizing this model, we were able to quantify the concentrations of key intracellular folate species during folate depletion and repletion. We investigated the hypotheses that the genomic instability observed under conditions of folate deficiency in other cell types extends to skin, adversely effecting cellular capacity to handle UVR insult and that optimizing folate levels in skin is beneficial in preventing or repairing the pro-carcinogenic effects of UVR exposure. Folate restriction leads to rapid depletion of intracellular reduced folates resulting in S-phase growth arrest, increased levels of inherent DNA damage, and increased uracil misincorporation into DNA, without a significant losses in overall cellular viability. Folate depleted keratinocytes were sensitized toward UVR induced apoptosis and displayed a diminished capacity to remove DNA breaks resulting from both photo and oxidative DNA damage. Thus, folate deficiency creates a permissive environment for genomic instability, an early event in the process of skin carcinogenesis. The effects of folate restriction, even in severely depleted, growth-arrested keratinocytes, were reversible by repletion with folic acid. Overall, these results indicate that skin health can be positively influenced by optimal folate nutriture.
PMCID: PMC2862485  PMID: 20211567
Folate; Keratinocytes; Skin Biology; Solar Simulated Light; DNA Damage; Cancer
12.  A Practical Approach to Red Blood Cell Folate Analysis 
The measurement of folate in red blood cells (RBCs) is preferred since it reflects long-term folate status in the body compared to plasma/serum folate which may be influenced by recent dietary intake. The commonly accepted technique for RBC folate analysis involves preparation of a hemolysate using a fresh whole blood sample. Hematocrit and plasma folate concentrations are needed to calculate RBC folate values. Because of the need for immediate access to a laboratory where processing can be performed, it may not be practical to assess RBC folate status using this method in field-based epidemiological studies. It is however, feasible to isolate packed RBSs from a blood sample under these conditions. The purpose of this study is to validate RBC folate analysis using packed red cells by comparing the RBC folate values obtained by hemolysate method (routine assay) with those obtained by using packed RBCs (new assay) in the same individuals (n = 50) using the folate microbiological assay. The correlation between plasma folate and the routine RBC folate assay (r = 0.58, p = 0.001) and the correlation between plasma folate and the new RBC folate assay was statistically significant (r = 0.55, p = 0.001). The correlation between RBC folate by the routine assay and new assay was also statistically significant (r = 0.78, p < 0.001). We conclude that measurement of folate in packed RBC is a practical approach in assessing long-term folate status in field-based and or larger scale epidemiological studies where an immediate access to a laboratory is unavailable for necessary sample processing for the routine RBC folate assay.
PMCID: PMC2716806  PMID: 19662184
folate; packed RBC; hemolysate
13.  Nutrient Intake Values for Folate during Pregnancy and Lactation Vary Widely around the World 
Nutrients  2013;5(10):3920-3947.
Folate is a B-vitamin with particular importance during reproduction due to its role in the synthesis and maintenance of DNA. Folate is well known for its role in preventing neural tube defects (NTDs) during the periconceptional period. There is also an increased need for folate throughout pregnancy to support optimal growth and development of the fetus and blood volume expansion and tissue growth of the mother. During lactation, women are at risk of folate deficiency due to increased demands to accommodate milk folate levels. Nutrient Intake Values (NIVs) for folate have been calculated to take into account additional needs during pregnancy and lactation. However, these values vary widely between countries. For example, the folate requirement that is set to meet the needs of almost all healthy women during pregnancy varies from 300 µg/day in the United Kingdom to 750 µg/day in Mexico. Currently, there is no accepted standardized terminology or framework for establishing NIVs. This article reviews country-specific NIVs for folate during pregnancy and lactation and the basis for setting these reference values.
PMCID: PMC3820052  PMID: 24084052
folate requirements; Nutrient Intake Values; pregnancy; lactation
14.  EE-drospirenone-levomefolate calcium versus EE-drospirenone + folic acid: folate status during 24 weeks of treatment and over 20 weeks following treatment cessation 
Adequate folate supplementation in the periconceptional phase is recommended to reduce the risk of neural tube defects. Oral contraceptives may provide a reasonable delivery vehicle for folate supplementation before conception in women of childbearing potential. This study aimed to demonstrate that a fixed-dose combination of an oral contraceptive and levomefolate calcium leads to sustainable improvements in folate status compared with an oral contraceptive + folic acid.
This was a double-blind, randomized, parallel-group study in which 172 healthy women aged 18–40 years received ethinylestradiol (EE)-drospirenone-levomefolate calcium or EE-drospirenone + folic acid for 24 weeks (invasion phase), and EE-drospirenone for an additional 20 weeks (folate elimination phase). The main objective of the invasion phase was to examine the area under the folate concentration time-curve for plasma and red blood cell (RBC) folate, while the main objective of the elimination phase was to determine the duration of time for which RBC folate concentration remained ≥ 906 nmol/L after cessation of EE-drospirenone-levomefolate calcium.
Mean concentration-time curves for plasma folate, RBC folate, and homocysteine were comparable between treatment groups during both study phases. During the invasion phase, plasma and RBC folate concentrations increased and approached steady-state after about 8 weeks (plasma) or 24 weeks (RBC). After cessation of treatment with levomefolate calcium, folate concentrations decreased slowly. The median time to RBC folate concentrations falling below 906 nmol/L was 10 weeks (95% confidence interval 8–12 weeks) after cessation of EE-drospirenone-levomefolate calcium treatment. Plasma and RBC folate levels remained above baseline values in 41.3% and 89.3% of women, respectively, at the end of the 20-week elimination phase.
Improvements in folate status were comparable between EE-drospirenone-levomefolate calcium and EE-drospirenone + folic acid. Plasma and RBC folate levels remained elevated for several months following cessation of treatment with EE-drospirenone-levomefolate calcium.
PMCID: PMC3628530  PMID: 23610531
drospirenone; ethinylestradiol; folic acid; levomefolate calcium; neural tube defect; oral contraception
15.  Circulating folic acid in plasma: relation to folic acid fortification 
The implementation of folic acid fortification in the United States has resulted in unprecedented amounts of this synthetic form of folate in the American diet. Folic acid in circulation may be a useful measure of physiologic exposure to synthetic folic acid, and there is a potential for elevated concentrations after fortification and the possibility of adverse effects.
We assessed the effect of folic acid fortification on circulating concentrations of folic acid and 5-methyltetrahydrofolate in the Framingham Offspring Cohort.
This is a cross-sectional study that used plasma samples from fasting subjects before and after fortification. Samples were measured for folate distribution with the use of an affinity-HPLC method with electrochemical detection.
Among nonsupplement users, the median concentration of folic acid in plasma increased from 0.25 to 0.50 nmol/L (P < 0.001) after fortification, and among supplement users the median increased from 0.54 to 0.68 nmol/L (P = 0.001). Among nonsupplement users, the prevalence of high circulating folic acid (≥85th percentile) increased from 9.4% to 19.1% (P = 0.002) after fortification. Among supplement users, the prevalence of high circulating folic acid increased from 15.9% to 24.3% (P = 0.02). Folic acid intake and total plasma folate were positively and significantly related to high circulating folic acid after adjustment for potential confounding factors (P for trend < 0.001).
Folic acid fortification has resulted in increased exposure to circulating folic acid. The biochemical and physiologic consequences of this are unknown, but these findings highlight the need to understand the effects of chronic exposure to circulating folic acid.
PMCID: PMC3763811  PMID: 18779294
16.  Mandatory fortification of the food supply with cobalamin: an idea whose time has not yet come 
The success of folic acid fortification has generated consideration of similar fortification with cobalamin for its own sake but more so to mitigate possible neurologic risks from increased folate intake by cobalamin-deficient persons. However, the folate model itself, the success of which was predicted by successful clinical trials and the known favorable facts of high folic acid bioavailability and the infrequency of folate malabsorption, may not apply to cobalamin fortification. Cobalamin bioavailability is more restricted than folic acid and is unfortunately poorest in persons deficient in cobalamin. Moreover, clinical trials to demonstrate actual health benefits of relevant oral doses have not yet been done in persons with mild subclinical deficiency, who are the only practical targets of cobalamin fortification because >94% of persons with clinically overt cobalamin deficiency have severe malabsorption and therefore cannot respond to normal fortification doses. However, it is only in the severely malabsorptive disorders, such as pernicious anemia, not subclinical deficiency, that neurologic deterioration following folic acid therapy has been described to date. It is still unknown whether mild deficiency states, which usually arise from normal absorption or only food-bound cobalamin malabsorption, have real health consequences or how often they progress to overt clinical cobalamin deficiency. Reports of cognitive or other risks in the common subclinical deficiency state, although worrisome, have been inconsistent. Moreover, their observational nature proved neither causative connections nor documented health benefits. Extensive work, especially randomized clinical trials, must be done before mandatory dietary intervention on a national scale can be justified.
PMCID: PMC3026896  PMID: 20577903
17.  Marginal folate inadequacy observed in a group of young children in Kwangju, Korea 
Nutrition Research and Practice  2007;1(2):120-125.
Folate is important for multiple metabolic processes such as nucleic acid synthesis and interconversions, and cell division. Folate deficiency may be a risk factor for several pathologies, such as neural tube birth defects, dementia, and cardiovascular diseases. The objectives of this study were to estimate folate intakes and plasma concentrations of young children living in Kwangju, Korea. Three consecutive 24-h food recalls and fasting blood samples were obtained from 24 boys and 30 girls, aged 2-6 y, living in Kwangju, Korea. The daily folate intake (mean ± SD) of the children was 146.7 ± 73.6 µg dietary folate equivalents. No differences in folate intakes were observed by gender (p≥0.05). The mean folate intakes of the 2 and 3 y old groups were significantly lower (p<0.05) than those of 5 and 6 y old groups. Over half of subjects consumed
PMCID: PMC2882586  PMID: 20535397
Folate; plasma folate; children; Korea; fortification
Low folate concentrations are inversely associated with birth defects, including neural tube defects, congenital heart disease and oral clefts. Conversely, high folate concentrations may be associated with adverse outcomes, including increased risk of colorectal cancer among those with pre-existing neoplasms. The purpose of our study was to investigate the folate status of a nationally representative sample of Canadians, including a subset of women of childbearing age.
We examined red blood cell folate concentrations among members of the general population aged 6–79 years (n = 5248) and separately among women of childbearing age (15–45 yr, n = 1162), as recorded by the Canadian Health Measures Survey and measured by immunologic assay. We assessed the data for significant differences by age, sex and socioeconomic status.
Less than 1% of Canadians showed folate deficiency (red blood cell folate < 305 nmol/L) and 40% showed high folate concentrations (> 1360 nmol/L). Among women of childbearing age, 22% showed concentrations below those considered optimal for maximal neural tube defect-risk reduction (< 906 nmol/L). Significant differences by age and socio-economic status, but not sex, were evident in median red blood cell folate concentrations, although concentrations in all groups exceeded recommended levels. No differences by age or income were found among women of child-bearing age.
Folate deficiency is virtually nonexistent in the Canadian population, although high folate concentrations are evident. Additional research is needed to better understand the determinants of red blood cell folate among women of childbearing age who have concentrations below levels that are maximally protective against neural tube defects. Ongoing monitoring of the folate status of Canadians and the relationship between red blood cell folate and health outcomes is warranted.
PMCID: PMC3033951  PMID: 21149516
American Journal of Epidemiology  2008;169(1):18-21.
Many neural tube defects can be prevented if women take folic acid around the time of conception. However, the majority of women do not take folic acid at the critical time, so the US government required that food be fortified with folic acid effective January 1, 1998. Whether the amount being added was sufficient to prevent all folate-related neural tube defects has been hotly debated. Mosley et al. (Am J Epidemiol. 2008;169(1):9–17) found no evidence that folic acid supplement use or dietary folate intake was related to neural tube defects, indicating that fortified food is probably providing sufficient folic acid to prevent folate-related defects. Because data on the effectiveness of fortification in the United States are scarce, this is an important contribution. There is great interest in the other effects of fortification. Folic acid reduces homocysteine levels, and homocysteine has been linked to cardiovascular disease and cancer. On the basis of current evidence, however, it seems unlikely that fortification will reduce cardiovascular disease rates. Its effect on cancer remains unclear. Folic acid may be useful in primary prevention but may also stimulate the growth of existing malignancies or premalignant lesions. Although these issues remain unresolved, Mosley et al. have provided important data to address the primary question: Does fortification prevent folate-related neural tube defects?
PMCID: PMC2720707  PMID: 18953060
anencephaly; folic acid; food, fortified; neural tube defects; spinal dysraphism
Nutrition Research and Practice  2013;7(3):216-223.
The purpose of this study is to assess folate intake, and serum and red blood cell (RBC) folate concentrations, and investigate the association between folate status and health-related behaviors among Korean college students. A total of 169 students, aged between 18 and 27 years, participated in this study. Dietary intake data were collected by trained interviewers using a 24-hour recall method for three non-consecutive days in 2009. Information on health-related behaviors was obtained by a self-administered questionnaire. Serum and RBC folate concentrations were measured by microbiological assay. The average intakes of folate were 456 µgDFE and 347 µgDFE in male and female students, respectively. While the average serum folate concentration was significantly lower in male students (8.9 ng/mL) compared to female students (12.5 ng/mL), RBC concentrations were not significantly different between male (398.6 ng/mL) and female students (405.3 ng/mL). In male students, low serum folate concentrations were associated with total folate intake less than the Estimated Average Requirement, non-use of folic acid supplements, smoking, alcohol drinking at least once a week and low physical activity. In female students, low serum folate concentrations were associated with smoking and alcohol drinking at least two drinks at a time and BMI ≥ 25. Alcohol drinking and low physical activity were also associated with low RBC folate concentrations in both male and female students. In order to improve folate nutritional status of college students, the practice of desirable health-related behaviors, such as non-smoking, moderate alcohol drinking, regular physical activity, and maintenance of healthy BMI should be encouraged along with consumption of folate-rich foods and supplements.
PMCID: PMC3679331  PMID: 23766883
Folate intake; serum folate; RBC folate; health-related behaviors; college students
This study investigated the association of neural tube defects (NTDs) with maternal periconceptional intake of folic acid-containing supplements and dietary nutrients, including folate, among deliveries that occurred after folic acid fortification in selected California counties.
The population-based case-control study included fetuses and live born infants with spina bifida (189) or anencephaly (141) and 625 nonmalformed, live born controls delivered from 1999–2003. Mothers reported supplement use during telephone interviews, which included a 107-item food frequency questionnaire. For dietary nutrients, intakes <25th, 25th–<75th (reference), and ≥75th percentile were compared, based on control distributions.
After adjustment for potential confounders, any versus no supplement intake resulted in ORs of 0.8 (95% CI 0.5, 1.3) for anencephaly and 0.8 (95% CI 0.6, 1.2) for spina bifida. After stratification by maternal intake of vitamin supplements, most factors in the glycemic pathway were not associated with either NTD, with the exception of low levels of fructose and glucose that were significantly associated with anencephaly. Some nutrients that contribute to one-carbon metabolism showed lowered risks (folate, riboflavin, vitamins B6 and B12); others did not (choline, methionine, zinc). Anti-oxidant nutrients tended to be associated with lowered risks (vitamins C, E, A, β-carotene, lutein).
Mother’s intake of vitamin supplements was modestly if at all associated with a lowered risk of NTDs. Dietary intake of several nutrients contributing to one-carbon metabolism and oxidative stress were associated with reduced NTD risk.
PMCID: PMC2929981  PMID: 20740594
PLoS ONE  2013;8(2):e56194.
Folate status, as reflected by red blood cell (RCF) and plasma folates (PF), is related to health and disease risk. Folate degradation products para-aminobenzoylglutamate (pABG) and para-acetamidobenzoylglutamate (apABG) in 24 hour urine have recently been shown to correlate with blood folate.
Since blood sampling and collection of 24 hour urine are cumbersome, we investigated whether the determination of urinary folate catabolites in fasted spot urine is a suitable non-invasive biomarker for folate status in subjects before and during folic acid supplementation.
Study Design and Methods
Immediate effects of oral folic acid bolus intake on urinary folate catabolites were assessed in a short-term pre-study. In the main study we included 53 healthy men. Of these, 29 were selected for a 12 week folic acid supplementation (400 µg). Blood, 24 hour and spot urine were collected at baseline and after 6 and 12 weeks and PF, RCF, urinary apABG and pABG were determined.
Intake of a 400 µg folic acid bolus resulted in immediate increase of urinary catabolites. In the main study pABG and apABG concentrations in spot urine correlated well with their excretion in 24 hour urine. In healthy men consuming habitual diet, pABG showed closer correlation with PF (rs = 0.676) and RCF (rs = 0.649) than apABG (rs = 0.264, ns and 0.543). Supplementation led to significantly increased folate in plasma and red cells as well as elevated urinary folate catabolites, while only pABG correlated significantly with PF (rs = 0.574) after 12 weeks.
Quantification of folate catabolites in fasted spot urine seems suitable as a non-invasive alternative to blood or 24 hour urine analysis for evaluation of folate status in populations consuming habitual diet. In non-steady-state conditions (folic acid supplementation) correlations between folate marker (RCF, PF, urinary catabolites) decrease due to differing kinetics.
PMCID: PMC3572985  PMID: 23457526
British Medical Journal  1969;2(5656):543-547.
Malabsorption of folate polyglutamates prepared from yeast has been shown in eight patients with untreated tropical sprue and in three out of six patients receiving therapy for sprue. The absorptive defect for folate polyglutamates among these 14 patients occurred more frequently and in all but one patient more severely than for folic acid.
Folate polyglutamates, the principal dietary form of folate, probably require deconjugation by the jejunal enzyme, folate conjugase, before absorption. The mean concentration of jejunal folate conjugase of 21 patients with untreated sprue and of 13 patients with sprue receiving therapy were both significantly less than the mean concentration in a control group. Nevertheless, all but five of the 34 patients had jejunal folate concentrations within the control range. There was no correlation in the individual patients between the jejunal folate conjugase concentration measured in vitro and the ability to absorb folate polyglutamates—nine patients having normal jejunal folate conjugase levels despite showing malabsorption of folate polyglutamates.
PMCID: PMC1983447  PMID: 5769888
Canadian Family Physician  2008;54(1):36-38.
QUESTION Now that flour and pasta have been fortified with folic acid in Canada, do I still need to recommend folic acid supplements to my patients who are of child-bearing age? If I should recommend supplements, when should I recommend them, and what is an appropriate dose?
ANSWER Non-pregnant women should consume 400 μg of folic acid daily, and pregnant women should consume 600 μg of folic acid daily. Mean intakes of folate in Canada before fortification were around 200 μg/d or less. Fortification increased intake of folic acid by up to 100 μg/d. You should discuss the importance of folic acid with your patients who are planning pregnancy; it is recommended that a folic acid supplement or prenatal multivitamin containing at least 400 μg of folic acid be consumed daily. The upper limit for folic acid is 1 mg/d. Women in intermediate- to high-risk categories for neural tube defects, such as a previous neural tube defect–affected pregnancy, should take 4 to 5 mg of folic acid daily.
PMCID: PMC2329900  PMID: 18208952
The effect of carbamazepine monotherapy on the red cell folate level of 133 patients with trigeminal neuralgia was evaluated. The patient group had a significantly lower mean value of red cell folate levels compared with 110 controls. No significant correlation was found between the red cell folate levels and the mean cell volume or haemoglobin values in either the carbamazepine or control group. In addition no significant correlation was found between the red cell folate levels and drug dosage. Administration of folic acid supplements raised the mean value of red cell folate significantly. Dietary folate intake was assessed in 43 trigeminal neuralgia patients and 33 matched control patients and there was no significant difference between the groups. Patients taking carbamazepine should be advised on a well-balanced diet rich in folate as opposed to being given a routine prescription of folic acid.
PMCID: PMC1293455  PMID: 1548649

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