Nutrition throughout life: folate.

Scientific evidence supports a number of roles for folate in maintaining health from early life to old age. Folate is required for one-carbon metabolism, including the remethylation of homocysteine to methionine; thus elevated plasma homocysteine reflects functional folate deficiency. Optimal folate status has an established role in preventing NTD and there is strong evidence indicating that it also has a role in the primary prevention of stroke. The most important genetic determinant of homocysteine in the general population is the common 677C → T variant in the gene encoding the folate-metabolising enzyme, MTHFR; homozygous individuals (TT genotype) have reduced enzyme activity and elevated plasma homocysteine concentrations. Meta-analyses indicate that the TT genotype carries a 14 to 21 % increased risk of CVD, but there is considerable geographic variation in the extent of excess CVD risk. A novel interaction between this folate polymorphism and riboflavin (a co-factor for MTHFR) has recently been identified. Intervention with supplemental riboflavin targeted specifically at individuals with the MTHFR 677TT genotype was shown to result in significant lowering of blood pressure in hypertensive people and in patients with CVD. This review considers the established and emerging roles for folate throughout the lifecycle, and some public health issues related to optimising folate status.

Maternal obesity and baseline vitamin D insufficiency alter the response to vitamin D supplementation: a double-blind, randomized trial in pregnant women.

BACKGROUND: The achievement of target 25-hydroxyvitamin D [25(OH)D] concentrations in pregnancy may be altered by maternal obesity. OBJECTIVE: The authors examined the effects of maternal supplementation of 10 µg compared with 20 µg vitamin D3/d on maternal and umbilical cord 25(OH)D. The secondary aim was to investigate the influence of maternal BMI (in kg/m2) on the response of the primary outcomes. METHODS: The authors performed a 2-arm parallel double-blind randomized trial with 240 pregnant women recruited throughout the year in Northern Ireland. Women were stratified by BMI to receive 10 or 20 µg vitamin D3/d from 12 gestational wk (GW) until delivery. Maternal blood samples collected at 12, 28, and 36 GW and from the umbilical cord were analyzed for total serum 25(OH)D. A total of 166 women completed the study. RESULTS: Mean ± SD 25(OH)D at 36 GW was 80.8 ± 28.2 compared with 94.4 ± 33.2 nmol/L (P < 0.001) (10 compared with 20 µg vitamin D3/d, respectively). In those classified with 25(OH)D <50 nmol/L at baseline and assigned 10 µg vitamin D3/d, mean 25(OH)D concentrations remained <50 nmol/L at 36 GW, whereas those <50 nmol/L at baseline and assigned 20 µg vitamin D3/d, had mean 25(OH)D concentrations ≥50 nmol/L at 28 and 36 GW. In women with obesity and 25(OH)D <50 nmol/L at baseline, the related mean umbilical cord 25(OH)D was deficient (<25 nmol/L) in both treatment groups, whereas those with obesity and 25(OH)D ≥50 nmol/L at baseline had an average umbilical cord 25(OH)D between 25 and 50 nmol/L in both treatment groups. CONCLUSIONS: Supplementation of 20 µg vitamin D3/d is needed to attain maternal and umbilical cord 25(OH)D concentrations ≥50 nmol/L on average, in those who start pregnancy with low 25(OH)D concentrations (<50 nmol/L). Under current recommendations, women with obesity and low 25(OH)D in early pregnancy are particularly vulnerable to maintaining a low 25(OH)D concentration throughout pregnancy and having an infant born with deficient 25(OH)D concentrations. This trial was registered at ClinicalTrials.gov as NCT02713009.

Associations of atrophic gastritis and proton-pump inhibitor drug use with vitamin B-12 status, and the impact of fortified foods, in older adults.

BACKGROUND: Atrophic gastritis (AG) and use of proton pump inhibitors (PPIs) result in gastric acid suppression that can impair the absorption of vitamin B-12 from foods. The crystalline vitamin B-12 form, found in fortified foods, does not require gastric acid for its absorption and could thus be beneficial for older adults with hypochlorhydria, but evidence is lacking. OBJECTIVES: To investigate associations of AG and PPI use with vitamin B-12 status, and the potential protective role of fortified foods, in older adults. METHODS: Eligible participants (n = 3299) not using vitamin B-12 supplements were drawn from the Trinity-Ulster and Department of Agriculture cohort, a study of noninstitutionalized adults aged ≥60 y and recruited in 2008-2012. Vitamin B-12 status was measured using 4 biomarkers, and vitamin B-12 deficiency was defined as a combined indicator value < -0.5. A pepsinogen I:II ratio <3 was considered indicative of AG. RESULTS: AG was identified in 15% of participants and associated with significantly lower serum total vitamin B-12 (P < 0.001) and plasma holotranscobalamin (holoTC; P < 0.001), and higher prevalence of vitamin B-12 deficiency (38%), compared with PPI users (21%) and controls (without AG and nonusers of PPIs; 15%; P < 0.001). PPI drugs were used (≥6 mo) by 37% of participants and were associated with lower holoTC concentrations, but only in participants taking higher doses (≥30 mg/d). Regular, compared with nonregular, consumption of fortified foods (i.e., ≥5 and 0-4 portions/wk, respectively) was associated with higher vitamin B-12 biomarkers in all participants, but inadequate to restore normal vitamin B-12 status in those with AG. CONCLUSIONS: Older adults who have AG and/or use higher doses of PPIs are more likely to have indicators of vitamin B-12 deficiency. Fortified foods, if consumed regularly, were associated with enhanced vitamin B-12 status, but higher levels of added vitamin B-12 than currently provided could be warranted to optimize status in people with AG.

Homocysteine concentration, related B vitamins, and betaine in pregnant women recruited to the Seychelles Child Development Study.

BACKGROUND: Both folate and betaine are important predictors of total homocysteine (tHcy) during pregnancy. However, studies to date have only been undertaken in populations with Western dietary patterns. OBJECTIVE: We investigated the predictors of tHcy in pregnant women recruited in the Seychelles, a population where access to fortified foods is limited and where women habitually consume diets rich in fish, eggs, rice, and fruit. DESIGN: Pregnant women (n = 226) provided blood samples at enrollment, at week 28 of gestation, and at delivery. Cord blood was obtained from a subset of participants (n = 135). RESULTS: As in other studies, maternal tHcy was lower during pregnancy than at delivery, whereas folate and vitamin B-12 status declined significantly to delivery. Despite low maternal folate status at delivery (median: 9.0 nmol/L), with 35% of women in the deficient range (serum folate: <6.8 nmol/L), cord blood folate status (median: 40.2 nmol/L) was similar to concentrations reported in Western populations. Folate was a significant predictor of tHcy at all time points (P < 0.001). In contrast with previous studies, betaine was only a significant predictor of maternal tHcy (P < 0.001) when the essential amino acid methionine was low. CONCLUSIONS: The current study reports 2 important findings. First, fetal requirements for folate are paramount, such that cord blood folate status is maintained, even when maternal status is low. Second, betaine is a significant predictor of tHcy in pregnant women with low serum folate and low serum methionine concentrations.

Effect of a voluntary food fortification policy on folate, related B vitamin status, and homocysteine in healthy adults.

BACKGROUND: Mandatory folic acid fortification of food is effective in reducing neural tube defects and may even reduce stroke-related mortality, but it remains controversial because of concerns about potential adverse effects. Thus, it is virtually nonexistent in Europe, albeit many countries allow food fortification on a voluntary basis. OBJECTIVE: The objective of the study was to examine the effect of a voluntary but liberal food fortification policy on dietary intake and biomarker status of folate and other homocysteine-related B vitamins in a healthy population. DESIGN: The study was a cross-sectional study. From a convenience sample of 662 adults in Northern Ireland, those who provided a fasting blood sample and dietary intake data were examined (n = 441, aged 18-92 y). Intakes of both natural food folate and folic acid from fortified foods were estimated; we used the latter to categorize participants by fortified food intake. RESULTS: Fortified foods were associated with significantly higher dietary intakes and biomarker status of folate, vitamin B-12, vitamin B-6, and riboflavin than were unfortified foods. There was no difference in natural food folate intake (range: 179-197 microg/d) between the fortified food categories. Red blood cell folate concentrations were 387 nmol/L higher and plasma total homocysteine concentrations were 2 micromol/L lower in the group with the highest fortified food intake (median intake: 208 microg/d folic acid) than in the nonconsumers of fortified foods (0 microg/d folic acid). CONCLUSIONS: These results show that voluntary food fortification is associated with a substantial increase in dietary intake and biomarker status of folate and metabolically related B vitamins with potential beneficial effects on health. However, those who do not consume fortified foods regularly may have insufficient B vitamin status to achieve the known and potential health benefits.

Eating fish for two.

This article is based on the British Nutrition Foundation's Annual Lecture, which focused on maternal fish consumption and the effects of methylmercury (MeHg) on fetal development, with respect to current guidance and policy on fish consumption during pregnancy. Fish makes a valuable contribution to nutrient intakes across the globe and is the primary protein source for many individuals, particularly those in the developing world. Populations with a high fish consumption, such as in the Republic of the Seychelles, have a greater exposure to MeHg, which is present in varying amounts in all fish. Methylmercury is a toxic pollutant, which is known to impair neurodevelopment. The dose of MeHg from fish consumption, however, needed to impair neurodevelopment is unknown. Current UK and US guidance on fish consumption during pregnancy tend to focus more on avoiding risks rather than highlighting the benefits which can be obtained from eating fish. Such recommendations have been mainly based on data arising from epidemiological studies in the Faroe Islands, where methylmercury exposure was largely from pilot whale consumption. Although small adverse effects on child development have been reported in data from the Faroe Islands, data from the on-going Seychelles Child Development Studies have shown no adverse effects of prenatal methlymercury exposure from high maternal fish consumption (9-12 meals containing fish per week) on developmental outcomes. Instead these data suggest that nutrients, including long chain polyunsaturated fatty acids (LC-PUFAs), provided by fish may offer a beneficial effect and attenuate or modify any effects of MeHg on developmental outcomes. Recent expert consultations have concluded that the health benefits of fish consumption outweigh the risks posed by MeHg exposure and have argued the need for improved education and guidance to highlight the importance of consuming nutrients, including LC-PUFAs, from fish for optimal child development and to encourage fish consumption during pregnancy.

A dose-finding trial of the effect of long-term folic acid intervention: implications for food fortification policy.

BACKGROUND: The lowest dose of folic acid required to achieve effective reductions in homocysteine is controversial but important for food fortification policy given recent concerns about the potential adverse effects of overexposure to this vitamin. OBJECTIVE: We compared the effectiveness of 0.2 mg folic acid/d with that of 0.4 and 0.8 mg/d at lowering homocysteine concentrations over a 6-mo period. DESIGN: A randomized dose-finding trial with folic acid was conducted. Of 203 participants screened, 101 patients with ischemic heart disease and 71 healthy volunteers completed the study. Participants were randomly assigned to receive placebo or folic acid at doses of 0.2, 0.4, or 0.8 mg/d for 26 wk; subsamples of patients with ischemic heart disease were also examined at 6 or 12 wk. RESULTS: Participants with higher baseline homocysteine concentrations had the greatest reductions in homocysteine in response to folic acid doses of 0.2 mg (-20.6%), 0.4 mg (-20.7%), and 0.8 mg (-27.8%); in those with lower baseline homocysteine concentrations, the responses were -8.2%, -8.9%, and -8.3%, respectively. No significant differences in homocysteine responses to the different doses were observed. In the patient group sampled at intervals during the intervention, the maximal homocysteine response appeared to be achieved by 6 wk in the 0.8-mg/d group and by 12 wk in the 0.4-mg/d group. However, the homocysteine response was suboptimal in the 0.2-mg/d group at both 6 and 12 wk compared with that at 26 wk. CONCLUSIONS: A folic acid dose as low as 0.2 mg/d can, if administered for 6 mo, effectively lower homocysteine concentrations. Higher doses may not be necessary because they result in no further significant lowering, whereas doses even lower than 0.2 mg/d may be effective in the longer term. Previous trials probably overestimated the folic acid dose required because of a treatment duration that was too short. This trial was registered at clinicaltrials.gov as ISRCTN45296887.

Low vitamin D status adversely affects bone health parameters in adolescents.

BACKGROUND: The effects of subclinical vitamin D deficiency on bone mineral density (BMD) and bone turnover in adolescents, especially in boys, are unclear. OBJECTIVE: We aimed to investigate the relations of different stages of vitamin D status and BMD and bone turnover in a representative sample of adolescent boys and girls. DESIGN: BMD was measured by dual-energy X-ray absorptiometry at the nondominant forearm and dominant heel in a random sample of 12- (n = 260) and 15-y-old (n = 239) boys and 12- (n = 266) and 15-y-old (n = 250) girls. Serum 25-hydroxyvitamin D, parathyroid hormone, osteocalcin, and type I collagen cross-linked C-telopeptide were assessed by using enzyme-linked immunoassays. Relations between vitamin D status and bone health indexes were assessed by using regression modeling. RESULTS: Using multivariate regression to adjust for potential physical, lifestyle, and dietary confounding factors, we observed that 12- and 15-y-old girls with high vitamin D status (>/=74.1 nmol/L) had significantly greater forearm (but not heel) BMD (beta = 0.018; SE = 0.008; P < 0.05 for each age group) and lower serum parathyroid hormone concentrations and bone turnover markers than did those with low vitamin D status. These associations were evident in subjects sampled throughout the year and in winter only. There was no significant relation between vitamin D status and BMD in boys. CONCLUSIONS: Maintaining serum 25-hydroxyvitamin D concentrations above approximately 50 nmol/L throughout the year may be a cost-effective means of improving bone health. Increased emphasis on exploring strategies for improving vitamin D status in adolescents is needed.