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Objective: To estimate the national and regional population attributable fraction (PAF) and potential number of preventable anemia cases for three nutritional risk factors (iron, red blood cell folate [RBCF], and vitamin B12 deficiencies) among women of childbearing age in Belize., Methods: A national probability-based household and micronutrient survey capturing sociodemographic and health information was conducted among 937 nonpregnant Belizean women aged 15-49 years. Blood samples were collected to determine hemoglobin, ferritin, alpha-1-glycoprotein (AGP), RBCF, and vitamin B12 status. All analyses used sample weights and design variables to reflect a complex sample survey. Logistic regression was used to determine adjusted prevalence risk (aPR) ratios, which were then used to estimate national and regional PAF for anemia., Results: The overall prevalence of anemia (hemoglobin <12 g/dL) was 21.2% (95% CI [18.7, 25.3]). The prevalence of anemia was significantly greater among women with iron deficiency (59.5%, 95% CI [48.7, 69.5]) compared to women without iron deficiency (15.2%, 95% CI [12.2, 18.3]; aPR 3.9, 95% CI [2.9, 5.1]). The three nutritional deficiencies examined contributed to 34.6% (95% CI [22.1, 47.1]) of the anemia cases. If all these nutritional deficiencies could be eliminated, then an estimated 5 953 (95% CI [3 807, 8 114]) anemia cases could be prevented., Conclusions: This study suggests that among women of child-bearing age in Belize, anemia cases might be reduced by a third if three modifiable nutritional risk factors (iron, RBCF, and vitamin B12 deficiencies) could be eliminated. Fortification is one potential strategy to improve nutritional status and reduce the burden of anemia in this population., Competing Interests: Conflict of interest. None declared.

Background: Folate deficiency, vitamin B-12 deficiency, and anemia can have adverse effects on birth outcomes. Also, low vitamin B-12 reduces the formation of metabolically active folate. Objectives: We sought to establish the baseline prevalence of and factors associated with folate deficiency and insufficiency, vitamin B-12 deficiency, and anemia among women of childbearing age (WCBA) in Belize. Methods: In 2011, a national probability-based survey was completed among Belizean nonpregnant WCBA aged 15-49 y. Blood samples for determination of hemoglobin, folate (RBC and serum), and vitamin B-12 (plasma) and sociodemographic and health information were collected from 937 women. RBC and serum folate concentrations were measured by microbiologic assay (MBA). Folate status was defined based on both the WHO-recommended radioproteinbinding assay and the assay adjusted for the MBA. Results: The national prevalence estimates for folate deficiency in WCBA, based on serum and RBC folate concentrations by using the assay-matched cutoffs, were 11.0% (95% CI: 8.6%, 14.0%) and 35.1% (95% CI: 31.3%, 39.2%), respectively. By using the assay-matched compared with the WHO-recommended cutoffs, a substantially higher prevalence of folate deficiency was observed based on serum (6.9% absolute difference) and RBC folate (28.9% absolute difference) concentrations. The prevalence for RBC folate insufficiency was 48.9% (95% CI: 44.8%, 53.1%). Prevalence estimates for vitamin B-12 deficiency and marginal deficiency and anemia were 17.2% (95% CI: 14.2%, 20.6%), 33.2% (95% CI: 29.6%, 37.1%), and 22.7% (95% CI: 19.5%, 26.2%), respectively. The adjusted geometric means of the RBC folate concentration increased significantly ( P -trend < 0.001) in WCBA who had normal vitamin B-12 status relative to WCBA who were vitamin B-12 deficient. Conclusions: In Belize, the prevalence of folate and vitamin B-12 deficiencies continues to be a public health concern among WCBA. Furthermore, low folate status co-occurred with low vitamin B-12 status, underlining the importance of providing adequate vitamin B-12 and folic acid intake through approaches such as mandatory food fortification., Competing Interests: 2: Author disclosures: J Rosenthal, N Largaespada, LB Bailey, M Cannon, CJ Alverson, D Ortiz, GPA Kauwell, J Sniezek, R Figueroa, R Daly, and P Allen, no conflicts of interest., (© 2017 American Society for Nutrition.)

Maternal folate status and body mass index (BMI) are independent risk factors for neural tube defects (NTD). Population-based studies have identified an inverse association between serum folate and BMI, after adjusting for intake. The objective of this intervention study was to compare the relationship between BMI and the short-term pharmacokinetic response to an oral dose of folic acid. Healthy obese (BMI 30.0 kg m(-2); n=16) and normal-weight (BMI 18.5-24.9 kg m(-2); n=16) women of childbearing age (18-35 years) were administered a single oral dose of folic acid (400 μg). Blood samples were collected over a 10-h period to evaluate the serum folate response. Fasting baseline serum folate was lower in the obese group (P=0.005); in contrast, red blood cell folate was higher (P=0.05). Area-under-the-curve for the absorption phase (0-3 h) and peak serum folate concentrations were lower in obese versus normal-weight women (P<0.005). Overall serum folate response (0-10 h) was lower in obese versus normal-weight women (repeated-measures ANOVA, P=0.001). Data suggest body distribution of folate is significantly affected by obesity, and, should pregnancy occur, may reduce the amount of folate available to the developing embryo. These findings provide additional support for a BMI-adjusted folic acid intake recommendation for NTD risk reduction.

Background: Studies have questioned whether the current Recommended Dietary Allowance (RDA) of 2.4 microg vitamin B-12/d is adequate., Objective: We examined the association between dietary vitamin B-12 intake and biomarkers of vitamin B-12 status., Design: Dietary vitamin B-12 intake was estimated, and biomarkers of vitamin B-12 status were measured, in healthy men and women (n = 299; age range: 18-50 y) who were recruited from a Florida community. The National Cancer Institute Diet History Questionnaire was used. Plasma cobalamin, total transcobalamin, holo-transcobalamin, methylmalonic acid (MMA), total homocysteine (tHcy), and autoantibodies against intrinsic factor (IF) and Helicobacter pylori were analyzed in blood samples., Results: Antibodies to H. pylori were detected in 12% of subjects (35/299), and negative results for IF antibodies were obtained for all subjects. The intake of vitamin B-12 correlated significantly with cobalamin, holo-transcobalamin, MMA, and tHcy. Subjects were divided into quintiles on the basis of their dietary vitamin B-12 intake (range: 0.42-22.7 microg/d), and biomarkers of vitamin B-12 status were plotted against estimated dietary vitamin B-12 intake. All biomarkers appeared to level off at a daily dietary vitamin B-12 intake between 4.2 and 7.0 microg., Conclusion: In persons with normal absorption, our data indicate that an intake of 4-7 microg vitamin B-12/d is associated with an adequate vitamin B-12 status, which suggests that the current RDA of 2.4 microg vitamin B-12/d might be inadequate for optimal biomarker status even in a healthy population between 18 and 50 y of age.

Background: It has been hypothesized that the response of holo-transcobalamin (holo-TC) to oral vitamin B-12 may be used to assess absorption. To develop a reliable clinical absorption test that uses holo-TC, it is necessary to determine the optimal timeline for vitamin B-12 administration and postdose assessment., Objective: The objective of this study was to assess the magnitude and patterns of change in the postabsorption response of holo-TC to oral vitamin B-12., Design: Adult (18-49 y) male and female participants (n = 21) with normal vitamin B-12 status were given three 9-mug doses of vitamin B-12 at 6-h intervals beginning early morning (baseline) on day 1. Blood was drawn at 17 timed intervals over the course of 3 d for the analysis of holo-TC and other indicators of vitamin B-12 status., Results: Mean holo-TC increased significantly (P < 0.001) from baseline at 6 h (11%) and 24 h (50%). TC saturation increased significantly (P < 0.001) from baseline at 12.5 h (33%) and 24 h (50%). The mean cobalamin concentration changed significantly (P < 0.001) from baseline at 24 h (15%) and 48 h (14%). The ratio of holo-TC to cobalamin increased significantly (P < 0.001) at 24 h (32%)., Conclusions: The greatest increase in holo-TC was observed 24 h after ingestion of three 9-mug doses of vitamin B-12. Our results indicate that a vitamin B-12 absorption test based on measurement of holo-TC after administration of three 9-mug doses of vitamin B-12 should run for 24 h.

Background: A common genetic polymorphism [transcobalamin (TC) 776C-->G] may affect the function of transcobalamin, the protein required for vitamin B-12 cellular uptake and metabolism. Remethylation of homocysteine is dependent on the production of 5-methyltetrahydrofolate and adequate vitamin B-12 for the methionine synthase reaction., Objectives: The objectives were to assess the influence of the TC 776C--> G polymorphism on concentrations of the transcobalamin-vitamin B-12 complex (holo-TC) and to determine the combined effects of the TC 776C-->G and methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphisms and vitamin B-12 status on homocysteine concentrations., Design: Healthy, nonpregnant women (n = 359; aged 20-30 y) were screened to determine plasma vitamin B-12, serum holo-TC, and plasma homocysteine concentrations and TC 776C-->G and MTHFR 677C-->T genotypes., Results: The serum holo-TC concentration for women with the variant TC 776 GG genotype was significantly different (P = 0.0213) from that for subjects with the CC genotype (74 +/- 37 and 87 +/- 33 pmol/L, respectively). An inverse relation was observed between plasma homocysteine concentrations and both serum holo-TC (P G polymorphism negatively affects the serum holo-TC concentration and provide additional evidence that vitamin B-12 status modulates the homocysteine concentration in this population.

Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) are important for homocysteine remethylation. This study was designed to determine the influence of genetic variants (MTHFR 677C-->T, MTHFR 1298A-->C, and MTRR 66A-->G), folate, and vitamin B-12 status on plasma homocysteine in women (20-30 y; n = 362). Plasma homocysteine was inversely (P < 0.0001) associated with serum folate and plasma vitamin B-12 regardless of genotype. Plasma homocysteine was higher (P < 0.05) for women with the MTHFR 677 TT/1298 AA genotype combination compared with the CC/AA, CC/AC, and CT/AA genotypes. Women with the MTHFR 677 TT/MTRR 66 AG genotype had higher (P < 0.05) plasma homocysteine than all other genotype combinations except the TT/AA and TT/GG genotypes. There were 5.4-, 4.3-, and 3.8-fold increases (P < 0.001) in risk for plasma homocysteine in the top 5, 10, and 20%, respectively, of the homocysteine distribution for subjects with the MTHFR 677 TT compared with the CC and CT genotypes. Predicted plasma homocysteine was inversely associated with serum folate (P = 0.003) and plasma vitamin B-12 (P = 0.002), with the degree of correlation dependent on MTHFR 677C-->T genotype. These data suggest that coexistence of the MTHFR 677 TT genotype with the MTRR 66A-->G polymorphism may exacerbate the effect of the MTHFR variant alone. The potential negative effect of combined polymorphisms of the MTHFR and MTRR genes on plasma homocysteine in at-risk population groups with low folate and/or vitamin B-12 status, such as women of reproductive potential, deserves further investigation.

This study was designed to evaluate the effect of the methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism on folate and homocysteine response in non-Hispanic women consuming a low folate diet followed by a diet providing the Recommended Dietary Allowance (RDA) for folate. Women (aged 20-30 y old) with either the TT (n = 19) or CC (n = 22) MTHFR 677C-->T genotype participated in a folate depletion-repletion study (7 wk, 115 microg dietary folate equivalents (DFE)/d; 7 wk, 400 microg DFE/d). Overall serum folate decreased (P < 0.0001) during depletion and increased (P < 0.0001) during repletion with lower (P = 0.03) postdepletion serum folate in women with the TT versus CC genotype. Folate status was low (serum folate < 13.6 nmol/L) in more women with the TT (59%) compared with the CC genotype (15%) postdepletion. Red blood cell folate for all subjects decreased during depletion (P < 0.0001) and repletion (P = 0.02) with lower (P = 0.04) red blood cell folate in women with the TT compared with the CC genotype postrepletion. Homocysteine increased (P < 0.0001) for both genotype groups postdepletion and decreased (P = 0.02) postrepletion for the CC genotype group only. Homocysteine concentrations tended to be higher (P = 0.09) in the TT versus CC genotype group postdepletion and postrepletion. These data suggest that the MTHFR 677C-->T polymorphism negatively affects the folate and homocysteine response in women consuming low folate diets followed by repletion with the RDA. These results may be important when evaluating the impact of the MTHFR 677C-->T polymorphism in countries in which low folate diets are chronically consumed.

Since January 2000 the Chilean Ministry of Health has required the fortification of wheat flour with folic acid (FA) at a concentration of 2.2 mg FA/kg in order to reduce the risk of neural tube defects (NTD) in newborns. This policy was expected to result in a mean additional intake of approximately 400 microg FA/d. We assessed the effectiveness of the FA flour fortification program on bread folate content and on blood folate concentration in women of childbearing age in Santiago, Chile. The prefortification folate status of 751 healthy women of reproductive age was assessed. The folate content of 100 bread samples bought at retail bakeries was measured, average wheat flour consumption was estimated and postfortification FA dietary intake was calculated. The effect of flour fortification on blood folate concentration in this group of women (n = 605) was evaluated in a follow-up study. Blood folate concentrations of the 605 women in the follow-up group increased (P < 0.0001) following fortification. Before fortification the mean serum and red blood cell folate concentrations were 9.7 +/- 4.3 and 290 +/- 102 nmol/L, respectively, compared with 37.2 +/- 9.5 and 707 +/- 179 nmol/L postfortification, respectively. The mean FA content of bread was 2020 +/- 940 micro g/kg. The median FA intake of the group evaluated postfortification was 427 microg/d (95% CI 409-445) based on an estimated intake of 219 g/d (95% CI 201-229) of wheat flour, mainly as bread. Fortification of wheat flour substantially improved folate status in a population of women of reproductive age in Chile. The effect of the FA fortification program on the occurrence of NTD is currently being assessed.

Folic acid supplements reduce the risk of neural tube defects and may be associated with reduced risk for vascular disease and cancer. Research data from both observational and controlled intervention studies provide strong support for the existing public health policies related to folic acid and neural tube defects. However, educational efforts to promote daily intake of folic acid supplements by women of reproductive age have not, in most cases, resulted in increased supplement use. In contrast, food fortification appears to be associated with a reduction in neural tube defects in the United States and Canada but is not practiced universally. The potential for folic acid supplements to reduce the incidence and severity of vascular disease and cancer is the focus of major research efforts including ongoing intervention studies.

Background: The major route of folate turnover is by catabolic cleavage of the C9-N10 bond producing p-aminobenzoylglutamate (pABG) and its primary excretory form, p-acetamidobenzoylglutamate (ApABG). We hypothesize that total pABG (ApABG + pABG) excretion parallels both the mass of body folate pools from which these catabolites originate and the folate-status indicators., Objective: The objective was to determine whether urinary folate catabolite excretion reflects body pool size and parallels the static and functional measures of folate status., Design: Urinary folate catabolite excretion was measured in women (aged 60-85 y) consuming controlled amounts of folate for 14 wk. A low-folate diet (120 microg/d) was consumed (n = 33) for 7 wk, and then subjects were randomly assigned to consume either 200 (n = 14) or 400 (n = 16) microg folate/d. Urinary pABG and ApABG concentrations were measured by HPLC at 0, 7, and 14 wk., Results: Urinary excretion of total pABG was significantly lower (P = 0.001) after depletion (73.9 +/- 4.7 nmol/d) than at baseline (115 +/- 12.7 nmol/d). This rate of decline (approximately 0.7% per day) is consistent with the kinetically measured rate of turnover of total body folate at moderate folate intakes. The average percentage increase in total pABG in response to folate repletion with 400 microg/d (75%) was significant (P = 0.02). Folate catabolite excretion was significantly (P = 0.0001) associated with serum and red blood cell folate, plasma homocysteine, and DNA hypomethylation after depletion and with serum folate (P = 0.001) and plasma homocysteine (P = 0.0002) after repletion with 400 microg folate/d., Conclusions: Total urinary pABG excretion reflects total body folate pool size and is a long-term indicator that parallels functional measures of folate status.

Methylenetetrahydrofolate reductase (MTHFR) polymorphisms may negatively influence one-carbon metabolism and increase health risks in women of reproductive age. The effect of MTHFR single nucleotide polymorphisms at bp 677 and/or 1298 and differences in folate and vitamin B-12 status on plasma homocysteine concentration in women of reproductive age (20-30 y; n = 186) were investigated. From the multivariate regression model, homozygotes (n = 23) for the C677T MTHFR variant had plasma homocysteine concentrations that were higher (P < 0.05) than those observed in the other 5 genotype groups, including those who were heterozygous for both variants (677CT/1298AC; n = 32). Plasma homocysteine was negatively associated with plasma vitamin B-12 concentration (P = 0.015) and serum folate (P = 0.049), with the degree of correlation between plasma vitamin B-12 and homocysteine concentrations dependent on MTHFR genotype. The C677T and A1298C MTHFR polymorphisms were significant predictors (P < 0.05) of plasma homocysteine when regression analysis was used to model plasma homocysteine concentration as a function of genotype, supplement use, serum folate and plasma vitamin B-12 concentration. Plasma homocysteine decreased as vitamin B-12 concentration increased (P = 0.0005) in individuals who were heterozygous for both the C677T and A1298C variants with nonsignificant trends (P = 0.114-0.128) in individuals homozygous for either the C677T or A1298C variants. In contrast, within the group of individuals with the wild-type genotype for both the C677T and A1298C MTHFR variants, homocysteine was not associated with changes in plasma vitamin B-12 concentrations. These data suggest that enhancing vitamin B-12 status may significantly decrease homocysteine in young women with C677T and/or A1298C MTHFR polymorphisms, even when vitamin B-12 concentrations are within the normal range.

Background: Methylation of genomic DNA is dependent on an adequate supply of folate coenzymes. Previous data support the hypothesis that abnormal DNA methylation plays an integral role in carcinogenesis. To date, no studies assessing the effect of inadequate folate status on DNA methylation in older women (aged >63 y) have been reported., Objective: The effect of moderate folate depletion followed by folate repletion on leukocyte genomic DNA methylation was investigated in elderly women (aged 60-85 y) to evaluate whether DNA methylation could be used as a functional indicator of folate status., Design: Healthy, postmenopausal women (n = 33) consumed a moderately folate-depleted diet (118 microg folate/d) for 7 wk, followed by 7 wk of folate repletion with 200 or 415 microg/d, each provided as 2 different dietary treatments for a total of 4 treatment groups (n = 30). Leukocyte DNA methylation was determined on the basis of the ability of DNA to incorporate [(3)H]methyl groups from labeled S:-adenosylmethionine in an in vitro assay., Results: Incorporation of [(3)H]methyl groups increased significantly (P: = 0.0025) in response to folate depletion, suggesting undermethylation of DNA. No significant changes were detected in [(3)H]methyl incorporation in any group over the 7-wk repletion period compared with postdepletion values., Conclusions: DNA methylation status may be used as a functional indicator of moderately depleted folate status. The slow response to the repletion diets observed suggests that normalization of DNA methylation after moderate folate depletion may be delayed in older women.

Background: The risk of neural tube defects (NTDs) is significantly reduced by supplemental folic acid. NTD risk may be associated with impaired absorption of polyglutamyl folate, the primary form of naturally occurring food folate, and of folic acid in supplements or fortified food. Stable-isotope methods provide the specificity needed to test this hypothesis., Objective: We determined whether women who had an NTD-affected pregnancy had a reduced ability compared with control women to absorb polyglutamyl folate relative to folic acid., Design: Healthy, nonpregnant women with a history of an NTD-affected pregnancy (cases; n = 11) and control women (n = 11) were administered an oral dose containing a mixture of [(2)H]pteroylpentaglutamate ([(2)H(2)]PteGlu(5); 233 nmol) and [(13)C]pteroylmonoglutamate ([(13)C(5)]PteGlu(1); 567 nmol) after a 30-d saturation protocol (2 mg unlabeled folic acid/d). Relative extents of absorption were evaluated by urinary excretion of (2)H(2)- and (13)C(5)-labeled folates 48 h postdose., Results: During the first 24 h postdose, cases excreted less (f1.gif" BORDER="0"> +/- SD) [(2)H(2)]PteGlu(5) (21 +/- 12% compared with 37 +/- 19%; P = 0.01) and [(13)C(5)]PteGlu(1) (17 +/- 8% compared with 31 +/- 14%; P = 0.007) than did controls. No significant differences between cases and controls were detected in the percentage of [(2)H(2)]PteGlu(5) or [(13)C(5)]PteGlu(1) excreted during the second 24 h postdose or when the data were averaged over 48 h. However, excretion of the [(2)H(2)]folates tended to be lower in cases than in controls over the 48-h period (33 +/- 13% compared with 45 +/- 26%; P = 0.21). A similar trend (P = 0.29) for lower excretion of [(13)C(5)]folates in cases was also observed (31 +/- 16% compared with 39 +/- 17%). The ratio of urinary [(2)H(2)]folates to [(13)C(5)]folates did not differ significantly between cases and controls., Conclusion: These data suggest the need for a larger-scale study using stable-isotope methods to further investigate this hypothesis.

Dietary Reference Intakes (DRI) for folate for elderly women have been based primarily on data extrapolated from studies in younger women. This study was conducted to provide the first age-specific data in elderly women (60-85 y) from a controlled metabolic study on which to base folate intake recommendations. Subjects (n = 33) consumed a moderately folate-deplete (118 microg/d) diet for 7 wk, followed by repletion diets providing either 200 or 415 microg folate/d as diet plus folic acid (FA) or a combination of FA and orange juice (OJ) for 7 wk (n = 30). Comparisons among and within groups were made for serum folate (SF), RBC folate and plasma total homocysteine (tHcy) concentrations. SF concentrations decreased significantly (P < 0.001) during depletion (65 +/- 15%). Postrepletion, the adjusted SF concentration for subjects consuming 415 microg folate/d was significantly greater (P = 0.003) than for subjects consuming 200 microg folate/d. RBC folate concentrations decreased (P < 0.001) during depletion (21 +/- 10%) and further (P < 0.001) during repletion (5 +/- 14%). During depletion, plasma tHcy concentrations increased significantly (P < 0.001) and an inverse relationship between SF and plasma tHcy concentrations was observed in 94% of subjects (P < 0.001). Reversal of this inverse relationship was significant only for subjects consuming 415 microg folate/d (P < 0.001). Postrepletion, subjects consuming 200 microg folate/d had a significantly higher (P = 0.009) adjusted plasma tHcy concentration than subjects consuming 415 microg folate/d. These data in elderly women indicate that 415 microg/d folate, provided as a combination of diet, FA and OJ, or diet and FA, normalizes folate status more effectively than does 200 microg/d, thus providing age-specific data for future folate intake recommendations.

Continuous assistive-passive exercise (CAPE) is a new exercise modality that has become popular with older females. To evaluate the efficacy of CAPE, 43 sedentary, postmenopausal women (PMW) were randomly divided into three groups: CAPE training (N = 15), cycle ergometer training (N = 14), and control (N = 14). The CAPE training consisted of 10 min bouts on six CAPE tables, twice per week. The cycle ergometer group trained twice per week for 30 min per session, at 70-85% of maximal heart rate. The cycle ergometer and CAPE groups trained for 12 wk, while the control group remained sedentary for the duration of the study. Groups were similar with respect to age, height, weight, girths, skinfolds, and aerobic power (VO2max) upon entering the study (P greater than 0.05). The groups were tested pre- and post-training on the sum of seven body girths (sigma 7G), sum of four skinfolds (sigma 4SF), weight, and VO2max. A 3 d dietary recall was recorded pre and post and analyzed for total caloric intake. Following training, changes in caloric intake, sigma 7G, and sigma 4SF were not significantly different among groups. The cycle group lost 1.1 kg (P less than 0.05) and increased VO2max (l.min-1) by 9.2% (P less than 0.05), while the CAPE group significantly decreased VO2max (P = 0.04). Our results indicate that CAPE does not alter sigma 7G or sigma 4SF in sedentary PMW and that two 30 min sessions of cycle training per week at 70-85% of maximal heart rate can result in moderate but significant increases in VO2max in sedentary PMW.