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Assessment of tailor-made prevention of atherosclerosis with folic acid supplementation: randomized, double-blind, placebo-controlled trials in each MTHFR C677T genotype.

This study aimed at assessing the effect of folic acid supplementation quantitatively in each MTHFR C677T genotype and considered the efficiency of tailor-made prevention of atherosclerosis. Study design was genotype-stratified, randomized, double-blind, placebo-controlled trials. The setting was a Japanese company in the chemical industry. Subjects were 203 healthy men after exclusion of those who took folic acid or drugs known to effect folic acid metabolism. Intervention was folic acid 1 mg/day p.o. for 3 months. The primary endpoint was plasma total homocysteine level (tHcy). In all three genotypes, there were significant tHcy decreases. The greatest decrease was in the TT homozygote [6.61 (3.47-9.76) micromol/l] compared with other genotypes [CC: 2.59 (1.81-3.36), CT: 2.64 (2.16-3.13)], and there was a significant trend between the mutated allele number and the decrease. The tHcy were significantly lowered in all the genotypes, but the amount of the decrease differed significantly in each genotype, which was observed at both 1 and 3 months. Using these time-series data, the largest benefit obtained by the TT homozygote was appraised as 2.4 times compared with the CC homozygote. Taking into account the high allele frequency of this SNP, this quantitative assessment should be useful when considering tailor-made prevention of atherosclerosis with folic acid.

Alleles↗

[Effects of public initiatives aimed at reducing neural tube defects with folic acid supplementation].

BACKGROUND: In order to prevent neural tube defects, a daily supplement of 400 microg (microgram) folic acid has been recommended in Norway since 1998, during the last month before conception and the first two or three months of pregnancy. Compliance with and effects of this recommendation has recently been evaluated in Norway in a report to the Directorate of Health and Social Welfare. MATERIAL AND METHODS: Reports published on periconceptional folic acid intake in Norway and some other countries from 1998 to autumn 2003 have been evaluated. RESULTS: In spite of several information activities, few Norwegian women start folic acid supplementation before verified pregnancy. The supplementation is started too late for the prevention of neural tube defects. A reduction is not observed in Norway. Internationally, information has not proven effective either, whereas compulsory fortification of foods with folic acid has been associated with reduced incidence. Information about periconceptional folic acid intake should be intensified. Compulsory fortification of foods with folic acid will affect the whole population, not only the target group of fertile women. If ongoing large intervention studies show improved clinical prognosis for patients with cardiovascular disease, this will be an additional argument for fortification of foods.

Female↗

Folic acid inhibits homocysteine-induced superoxide anion production and nuclear factor kappa B activation in macrophages.

Folic acid supplementation is a promising approach for patients with cardiovascular diseases associated with hyperhomocysteinemia. We have demonstrated that homocysteine (Hcy) activates nuclear factor-kappaB (NF-kappaB), a transcription factor that plays an important role in inflammatory responses. The aim of the present study was to investigate the effect of folic acid on Hcy-induced NF-kappaB activation in macrophages. Hcy treatment (100 micromol/L) resulted in NF-kappaB activation and increased monocyte chemoattractant protein-1 (MCP-1) expression in THP-1 derived macrophages. Hcy-induced NF-kappaB activation was associated with a significant increase in the intracellular superoxide anion levels. There was a significant increase in phosphorylation and membrane translocation of NADPH oxidase p47phox subunit in Hcy-treated cells. Addition of folic acid (200 ng/mL) to the culture medium abolished NADPH oxidase-dependent superoxide anion generation in macrophages by preventing phosphorylation of p47phox subunit. Consequently, Hcy-induced NF-kappaB activation and MCP-1 expression was inhibited. Such an inhibitory effect of folic acid was independent of its Hcy-lowering ability. Taken together, these results suggest that folic acid treatment can effectively inhibit Hcy-induced oxidative stress and inflammatory responses in macrophages. This may represent one of the mechanisms by which folic acid supplementation exerts a protective effect in cardiovascular disorders.

Cell Line↗

Use of vitamins containing folic acid among women of childbearing age--United States, 2004.

Neural tube defects (NTDs) are serious birth defects of the spine (spina bifida) and brain (anencephaly), affecting approximately 3,000 pregnancies each year in the United States. Periconceptional consumption of the B vitamin folic acid reduces the occurrence of NTDs by 50%-70%. To prevent these defects, the U.S. Public Health Service (1992) and Institute of Medicine (1998) issued separate recommendations that all women capable of becoming pregnant consume 400 micro g of folic acid daily, and the Food and Drug Administration mandated fortification of cereal grain products with folic acid to increase women's daily intake. Fortification of the U.S. food supply with folic acid has resulted in a 26% reduction in NTDs. However, even with fortification, not all women receive adequate levels of folic acid from their diets. Therefore, increasing the use of vitamins containing folic acid remains an important component of NTD prevention. To monitor the use of vitamins containing folic acid among women of childbearing age, the Gallup Organization has conducted a series of surveys for the March of Dimes Birth Defects Foundation since 1995. This report presents results from the 2004 survey, which indicated that although no substantial increase in the proportion of women who use vitamins containing folic acid daily occurred during 1995-2003, a substantial increase was observed in 2004, with 40% of women aged 18-45 years reporting daily consumption of a vitamin containing folic acid. This report also presents information about women's dieting behaviors. Regardless of dieting status, public health programs should stress the importance of women in their childbearing years consuming 400 micro g of folic acid daily through supplements, fortified foods, and a diet containing folate-rich foods.

Adult↗

Weekly administration of folic acid and epidemiology of neural tube defects.

OBJECTIVE: In 1999, a folic acid campaign for prevention of neural tube defects was started in Nuevo León, México, with the recommendation of taking a 5000 -mcg tablet of folic acid per week. The purpose of this study was to compare the epidemiology of neural tube defects after four years of the campaign. METHODS: Cases of anencephaly, spina bifida, and encephalocele (ICD Q00, Q01, Q05, 10th Ed.) from public and private hospitals were registered by immediate notification, death certificates, and fetal death registries. Comparisons of neural tube defects rates, phenotype distribution of cases, and sex ratios, registered before and after the folic acid campaign, were done using the Student's t Test and Chi square test. RESULTS: There was a 50% reduction in the incidence of anencephaly and spina bifida cases from 93 in 1999 (1.04x1000) to 46 in the year 2003 (0.56x1000) (p<0.001). Spina bifida cases declined up to 70% in 2002 and anencephaly cases up to 50% in 2003. In 1999, overall, the ratio (females: males) was 0.66 with female excess; the sex ratio was similar for anencephaly and spina bifida cases. In the year 2000, female cases showed a significant reduction for both spina bifida and anencephaly (75% and 56% respectively); the sex ratio was 0.57 with a greater male excess for both phenotypes. CONCLUSIONS: Weekly administration of 5000 mcg of folic acid reduces the incidence of neural tube defects 50%, primarily spina bifida, with a higher reduction of female cases.

Anencephaly↗

Four-way calibration applied to the simultaneous determination of folic acid and methotrexate in urine samples.

First-, second- and third-order calibration methods were investigated for the simultaneous determination of folic acid and methotrexate. The interest in the determination of these compounds is related to the fact that methotrexate inhibits the body's absorption of folic acid and prolonged treatment with methotrexate may lead to folic acid deficiency, and to the use of folic acid to cope with toxic side effects of methotrexate. Both analytes were converted into highly fluorescent compounds by oxidation with potassium permanganate, and the kinetics of the reaction was continuously monitored by recording the kinetics curves of fluorescence emission, the evolution with time of the emission spectra and the excitation-emission matrices (EEMs) of the samples at different reaction times. Direct determination of mixtures of both drugs in urine was accomplished on the basis of the evolution of the kinetics of EEMs by fluorescence measurements and four-way parallel-factor analysis (PARAFAC) or multiway partial least squares (N-PLS) chemometric calibration. The core consistency diagnostic (CORCONDIA) was employed to determine the correct number of factors in PARAFAC and the procedure converged to a choice of three factors, attributed to folic acid, methotrexate and to the sum of fluorescent species present in the urine.

Calibration↗

High dose folic acid treatment of fragile (X) males.

We conducted an experimental trial of high-dose folic acid given to five males, ages 8 to 26 years, with the fra(X) syndrome. In this double blind study, each subject received 250 mg per day of folic acid for 3 months, followed by placebo for 3 months, and folic acid again for an additional three months. Based on IQ tests, behavior ratings, the Autistic Descriptors Checklist, and parental ratings, there was little evidence to suggest any positive effects seen during the administration of high-dose folic acid. Therefore, this study has provided little support for a hypothesis of benefit of high-dose folic acid in the treatment of the fra(X) syndrome.

Adolescent↗

Methylenetetrahydrofolate reductase polymorphism determines the plasma homocysteine-lowering effect of large-dose folic acid supplementation in patients with cardiovascular disease.

OBJECTIVE: The polymorphism of the gene encoding methylenetetrahydrofolate reductase (MTHFR) and folic acid nutritional status play important roles in atherosclerosis. The present study investigated the total homocysteine-lowering effect of folic acid in response to the MTHFR genotype in patients who have cardiovascular disease. METHODS: Twenty-three patients who had cardiovascular disease (ages 44 to 88 y) were supplemented with 5 mg of folic acid/d for 8 wk. Blood samples were collected before and after supplementation for the measurement of folic acid. The presence of the 677C-->T mutation was assessed by polymerase chain reaction followed by restriction enzyme analysis. RESULTS: After the 8 wk of folic acid supplementation, plasma total homocysteine decreased 40% in patients who had the TT genotype, 23% in those who had the CT genotype, 10% in those who had the CC genotype, and 27% in carriers of the T allele. The plasma total homocysteine-lowering effect of folic acid was significant only in patients who had the CT genotype and in carriers of the T allele. CONCLUSIONS: The MTHFR polymorphism may be involved in the total homocysteine-lowering effect of folic acid in patients who have cardiovascular disease.

Adult↗

Effect of folic acid and glycine supplementation on embryo development and folate metabolism during early pregnancy in pigs.

The present work aimed to determine if different levels of prolificacy either by parity or by genetic origin are linked to folate metabolism. Nulliparous Yorkshire-Landrace (YL) and multiparous YL, and multiparous Meishan-Landrace (ML) sows were randomly assigned to two treatments: 0 ppm or 15 ppm folic acid+0.6% glycine. Supplements were given from the estrus before mating until slaughter on d 25 of gestation. At slaughter, embryo and endometrial tissues were collected to determine concentrations of DNA, protein, and homocysteine. Allantoic fluid samples were also collected to determine concentrations of folates, vitamin B12 and amino acids. Blood samples were taken at first estrus, at mating, and on d 8, 16, and 25 of gestation to determine serum concentrations of folates, vitamin B12, and relative total folate binding capacity (TFBC). Over the entire experiment, multiparous YL sows had higher average serum concentrations of folates than nulliparous YL sows (P < 0.05) but had similar serum concentrations of relative TFBC. Concentrations of folates and relative TFBC averaged higher in ML measured over the entire experiment than in multiparous YL sows (P < 0.05). Concentrations of serum vitamin B12 were higher in multiparous YL than in ML sows or YL nulliparous sows (P < 0.05) over the entire experiment. In allantoic fluid, folates, vitamin B12, and essential amino acids contents were significantly lower in ML than in YL multiparous sows (P < 0.05). The folic acid+glycine supplement increased concentrations of serum folates, but the increase was more marked in nulliparous YL sows (nulliparous x folic acid+glycine, P < 0.05). The folic acid+glycine supplement had no effect on litter size and embryo survival, but it tended to increase embryo DNA in multiparous YL sows (P = 0.06) but not in ML and nulliparous YL sows. Homocysteine was decreased by folic acid+glycine supplement in embryos from all sows, but in endometrium, the folic acid+glycine effect was dependent on parity (nulliparous x folic acid+glycine, P < 0.05). The effects of folic acid+glycine on litter size and embryo development and survival and some aspects of folate metabolism suggest that the basal dietary content of folic acid+glycine was adequate for ML and nulliparous YL sows but not to optimize embryo development in YL multiparous sows.

Allantois↗

The influence of folic acid supplement on the outcome of pregnancies in the county of Funen in Denmark. Part II. Congenital anomalies. A randomised study.

OBJECTIVE: The effect of folic acid supplement on the prevalence of congenital anomalies was studied in a Danish population. MATERIAL AND METHODS: From 1983 to 1986 all Danish women resident in the county of Funen were offered free folic acid when pregnant or planning a pregnancy. Folic acid dose was randomised to 2.5 or 1.0 mg. A randomised control group was not feasible for ethical reasons. Hospitals, midwives and most general practitioners cooperated to procure information on close to all pregnancies and congenital anomalies were recorded. RESULTS AND CONCLUSIONS: In a total of 14,021 pregnancies resulting in child birth 8184 women (58.4%) had folic acid with randomisation. Supplement was started in the randomised group before the last menstrual period in 1359/8184 (16.6%) and in the first 19 weeks of pregnancy in 6825/8184 (83.4%). The prevalence of congenital anomalies was 224 in 8293 children (27.0/1000). No dose-dependent differences were found in either total anomalies or in those specific malformations which have been reported to occur with reduced prevalence with periconceptional folic acid. The result was probably influenced by a start of supplement too late to affect malformation development in many cases and by the high level of both folic acid doses given compared to usual recommendations. Pregnancies without folic acid supplement showed prevalences similar to the supplemented groups.

Congenital Abnormalities↗

Folic acid supplementation in low birth weight infants.

Low birth weight infants (246) entered a trial to folic acid supplementation from 3 weeks to 12 months of age. The folic acid group had significantly higher mean hemoglobin levels at 6 and 9 months of age but the differences were only about 0.5 gm/dl, there was no significant difference in hematocrit, and in both groups of infants the mean hemoglobin levels were higher than those of normal birth weight infants. The differences in hemoglobin, although statistically significant, are of uncertain clinical significance. Median red cell folate levels remained within the normal adult range in both groups of infants. A minority of infants in the untreated group had low red cell folate levels but this was usually temporary, corrected by dietary folate, and not associated with low hemoglobin. Weight gain was not affected by folic acid supplementation. The infants in this trial were fed with a milk preparation containing 3.5 microgram/100 ml of folic acid which is a similar concentration to that of human milk and we recommend that the folate content of milks fed to low birth weight infants should not fall below this level. We do not have sufficient grounds to recommend routine folic acid supplements for all low birth weight infants throughout the first year of life but there is a possibility that their folate intake may sometimes be suboptimal.

Anemia, Macrocytic↗

[Effect of flour folic acid fortification on the incidence of cranio encephalic congenital defects].

BACKGROUND: In Chile, flour is fortified with folic acid since 2000, and the incidence of neural tube defects has decreased. Cranio-encephalic congenital defects (CECD) have a wider clinical scope, includind classical neural tube defects (NTD) such as anencephalia and acrania, but also incorporating other defects. Therefore, the effects of folic acid fortification on the incidence of CECD could be different. AIM: To study the effect of folic acid fortification on the incidence of CECD. MATERIAL AND METHODS: All prenatal diagnoses of CECD and cases registered locally in the Latin American Collaborative Study of Congenital Malformations (ECLAMC) were reviewed. The obtained data were crossed with all death certificates of newborns or stillborns of more than 500 g in the Sixth Region, in Central Chile. All cases were classified again in four subtypes, according to their phenotype. The incidences of all subtypes prior (1996-2000) and after folic acid supplementation (2001-2004), were compared. RESULTS: Between 1996 and 2004, there were 64 cases of CEDC among 109,176 infants born alive. The global rate was 8.86 per 10,000 born alive in the period prior to fortification and 3.03 per 10,000 born alive after fortification. Comparing both periods, there was a 66% reduction in all CECD and a 77 and 100% reduction in subtypes A and B of CECD, respectively (p <0.05). No significant reductions in type C and D CECD, were observed. CONCLUSIONS: After the start of flour folic acid fortification, there was a global reduction in the incidence of CECD. However, only types A and B CECD, supposedly more responsive to folic acid, were reduced.

Anencephaly↗

Folic acid supplementation for 3 wk reduces pulse pressure and large artery stiffness independent of MTHFR genotype.

BACKGROUND: Folic acid reduces plasma homocysteine and may be an important therapy for preventing cardiovascular disease. A key mechanism may be the reduction of arterial stiffness. OBJECTIVE: The effect of folic acid supplementation on blood pressure and large artery stiffness was examined in relation to methylenetetrahydrofolate reductase (MTHFR) genotype. DESIGN: Forty-one asymptomatic men with normal or high-normal ambulatory blood pressure (systolic: >130 to <145 mm Hg; diastolic: >80 to <90 mm Hg) participated. The study had a randomized, placebo-controlled, double-blind, crossover design that incorporated 3-wk treatments with 5 mg folic acid/d or matching placebo; each treatment was separated by a 4-wk washout phase. RESULTS: Folic acid reduced brachial pulse pressure by 4.7 +/- 1.6 mm Hg (P < 0.05) without changing mean arterial pressure. Systemic arterial compliance increased by 0.15 +/- 0.03 mL/mm Hg (P < 0.05) after folic acid treatment but did not change after placebo treatment. These responses did not significantly correlate with either homocysteine or folate plasma concentrations. MTHFR genotype CC homozygotes (without the 677C-->T polymorphism) with normal blood pressure had a larger reduction in homocysteine concentrations in response to folic acid than did T allele carriers. Blood pressure and arterial stiffness responses were independent of MTHFR genotype. CONCLUSION: Folic acid is a safe and effective supplement that targets large artery stiffness and may prevent isolated systolic hypertension.

Adult↗

Behavioural responses of young anaemic Indian children to iron-folic acid supplements.

1. Behavioural responses of young anaemic Indian children to iron-folic acid supplements were assessed in two separate studies using the Indian adaptation of Wechsler's (1967) intelligence scale for children (WISC). 2. The first study was an exploratory study in which the cognitive behaviour of 5-8-year-old children of both sexes was assessed before and after supplementation with 20 mg elemental Fe and 0.1 mg folic acid given daily for a period of 60 d. 3. The supplemented children showed a significant improvement in haemoglobin (Hb) as well as the WISC scores while the control children who did not receive any supplements failed to show an improvement either in Hb or in the WISC scores. However, within the supplemented group when the initially-anaemic children were compared with the initially-non-anaemic ones, only the 7-year-old anaemic children performed significantly poor in the tests than the non-anaemic group of the same age. The study raised the possibility that in addition to increasing the blood Hb levels, Fe-folic acid supplements may have additional benefits in improving the cognitive performance of children. 4. In the second study, cognitive behaviour of fourteen matched pairs of anaemic children in the age-range of 5-6 years was assessed before and after supplementation with 40 mg Fe and 0.2 mg folic acid given daily in two divided doses or sugar placebos for a period of 60 d. The tester did not know the groups to which each child belonged. 5. The supplemented children showed a significant improvement in Hb as well as in the verbal and performance IQ of WISC. The control children showed no improvement in Hb but their verbal IQ improved significantly. However, there was no significant improvement in their performance IQ. 6. The results indicated that Fe-folic acid supplements to anaemic children not only raised Hb levels but also improved intelligence test results, particularly in the performance section.

Anemia, Hypochromic↗

Use of folic acid and delivery outcome: a prospective registry study.

Periconceptional use of folic acid is thought to reduce the risk for both neural tube defects and other congenital malformations. Most published data were obtained retrospectively. We used the Swedish Medical Birth Registry to study congenital malformations in infants born of women who reported the use of folic acid in early pregnancy (of which 70% probably used it also preconceptionally) and compared them with population rates. We divided the material according to two major confounders: subfertility problems and use of antiepileptic drugs. We found no protective effect of folic acid tablet use on the rate of congenital malformations but data on neural tube defects were scarce. Our results support the scepticism recently expressed in the literature on the beneficial effect of folic acid in preventing congenital malformations, especially of a non-neural tube defect type.

Adult↗

The effect of folic acid supplementation on plasma homocysteine in an elderly population.

BACKGROUND: Increased plasma homocysteine is associated with coronary artery disease, peripheral vascular disease and venous thrombosis. Folic acid is the most effective therapy for reducing homocysteine levels. The lowest effective supplement of folic acid is not known, particularly for the elderly who have the highest prevalence of these conditions. AIM: To explore the effects of daily supplements of 0, 50, 100, 200, 400 and 600 microg folic acid on plasma homocysteine in an elderly population. DESIGN: Randomized double-blind placebo-controlled trial. METHODS: Participants (n=368) aged 65-75 years were randomly allocated to receive one of the treatments for 6 weeks. Plasma homocysteine was recorded after 3 weeks and 6 weeks of supplementation. RESULTS: Only the 400 microg and 600 microg groups had significantly lower homocysteine levels compared to placebo (p=0.038 and p<0.001, respectively). Using multiple linear regression and each individual's total folic acid intake (diet plus supplement), a total daily folic acid intake of 926 microg per day would be required to ensure that 95% of the elderly population would be without cardiovascular risk from folate deficiency. DISCUSSION: A daily folic acid intake of 926 microg is unlikely to be achieved by diet alone. Individual supplementation or fortification of food with folic acid will be required to reach this target.

Aged↗

Effect of time of initiation and dose of prenatal iron and folic acid supplementation on iron and folate nutriture of Korean women during pregnancy.

BACKGROUND: In Korea, it is customary to prescribe iron and folic acid supplements to pregnant women after the 20th wk of gestation; however, little evidence exists to support this practice. OBJECTIVE: The objective was to determine the effects of time of initiation and dose of prenatal iron and folic acid supplementation on the iron and folate nutriture of Korean women during pregnancy. DESIGN: A total of 131 pregnant women were placed into 1 of 5 experimental groups, either the control group or 1 of 4 supplemented groups. The supplemented groups varied by time of initiation, which was either during the first trimester or at week 20 of gestation, and by dose of iron and folic acid supplements provided, which consisted of either 30 mg Fe plus 175 microg folic acid or 60 mg Fe plus 350 microg folic acid. All supplemented groups continued supplementation until delivery. RESULTS: Improvements in iron and folate nutriture were highly dependent on when the supplement program was initiated, but both supplement doses were equally effective. In contrast, the influence of folic acid supplementation on maternal folate status was not as pronounced as was the influence of iron supplementation on iron status. CONCLUSION: In pregnant Korean women, initiating iron and folic acid supplementation earlier during pregnancy may prevent the deterioration of iron and folate nutriture more than does increasing supplement doses in later stages of pregnancy.

Adult↗

Kinetic modeling of folate metabolism through use of chronic administration of deuterium-labeled folic acid in men.

This study was conducted as an initial investigation of in vivo folate kinetics in healthy men (n = 4) and made use of a chronic-administration protocol with stable-isotope labeling. Subjects were given 0.453 mumol (200 micrograms) total folic acid in aqueous solution daily throughout the 18-wk study while they consumed self-selected folate-adequate diets. After a 2-wk pretrial period with unlabeled folic acid, subjects were given 0.227 mumol (100 micrograms) pteroyl-L-[2H4]glutamic acid/d ([2H4]folic acid) combined with 0.227 mumol nonlabeled folic acid or [2H2]pteroylhexaglutamic acid/d for the next 8 wk; then for the next 8 wk the [2H4]folic acid was withdrawn and the subjects received only nonlabeled folic acid. Little unmetabolized folic acid was excreted in urine. Isotopic enrichment of urinary folate during [2H4]folic acid administration and withdrawal was consistent with a kinetic model having a rapid turnover pool and a slow turnover pool. In contrast with previous two-pool models, provisions were made for folate turnover by urinary folate excretion (as measured here) and by fecal excretion and catabolic processes. The precision of modeling will be improved in future studies by measurement of enrichment of additional pools. However, this study shows clearly the slow turnover of the whole-body folate pool (< or = 1% per day) and the feasibility of further long-term kinetic analysis.

Adult↗