[Folate, Choline, and Vitamin B12 Supplementation for Pre-Conceptional and Pregnant Women]. / Folat-, Cholin-, und Vitamin-B12-Supplementierung für präkonzeptionelle und schwangere Frauen.

Folate, Choline, and Vitamin B12 Supplementation for Pre-Conceptional and Pregnant Women Abstract. Inadequate maternal folate status is associated with higher risk of neural tube defects. The threshold for a good supply of folate (e.g., folate concentration in erythrocytes) is > 906nmol/L for all women who may become pregnant. This quite high folate concentration should already be reached before the onset of pregnancy, which can hardly be achieved with food. Supplementation with folate or folic acid is therefore strongly recommended for all women planning pregnancy (four to eight weeks before the start of pregnancy until the end of the first trimester). Folate supplementation can significantly reduce the risk of neural tube defects at the population level (approximately 50%), but it cannot prevent all cases. Recent studies show that low maternal choline and vitamin B12 intake during pregnancy is also associated with higher risk of neural tube defects. The role of choline in fetal brain development is biologically plausible based on its function as a source of methyl groups, acetylcholine, and cell membrane phospholipids and is not completely interchangeable with folate. Data on the association between maternal choline intake during preconception and the first trimester and fetal brain development suggest a causal relationship. The intake recommendation for choline is 480mg/day for pregnant women and 550mg/day for lactating women. Choline intake (mainly from animal-based diets) averages about 300mg/day and is thus insufficient for optimal supply during pregnancy. To date, no specific recommendations exist for choline supplementation before and during pregnancy. In Europe, prevention approaches at the population level are generally poorly followed. Therefore, individual counseling of young women planning pregnancy is more relevant than ever.

Dietary and lifestyle predictors of folate insufficiency in non-supplemented German women.

Low folate status is a risk factor for birth defects. We studied concentrations of red blood cell (RBC)- and serum folate in 198 German women in relation to information on dietary folate intake, demographic and lifestyle factors. Median serum- and RBC-folate levels were; (14.7 and 589 nmol/L, respectively. Serum < 7.0 nmol/L or RBC-folate < 405 nmol/L were observed in 3.5% and 18.7% of the women, respectively. Three per cent of the women had both lowered serum and RBC-folate. Whereas RBC-folate > 952 nmol/L (optimal levels around conception) were observed in 9.6%. Serum- and RBC-folate were positively associated; they showed the expected correlations with homocysteine, but only weak correlations with folate intake. Younger age, lower fibre and higher carbohydrate intakes were associated with lower blood folate. Thus, folate intake of approximately 278 µg/d was not sufficient to achieve optimal folate status in young women. In conclusion, in the absence of fortification with folic acid, the majority of the women did not achieve folate status that is optimal for prevention of birth defects.

The effectiveness of daily supplementation with 400 or 800 µg/day folate in reaching protective red blood folate concentrations in non-pregnant women: a randomized trial.

PURPOSE: Folate required to achieve desirable red blood cell (RBC) folate concentrations within 4-8 weeks pre-pregnancy is not known. We studied the effect of supplementation with 400 or 800 µg/day folate in achieving RBC-folate ≥906 nmol/L. METHODS: Non-pregnant women were randomized to receive multinutrient supplements containing 400 µg/day (n = 100) or 800 µg/day (n = 101) folate [folic acid and (6S)-5-CH3-H4folate-Ca (1:1)]. The changes of folate biomarkers were studied after 4 and 8 weeks in the 198 women who returned at least for visit 2. RESULTS: At baseline, 12 of the 198 participants (6.1%) had RBC-folate <340 nmol/L, but 88% had levels <906 nmol/L. The RBC-folate concentrations increased significantly in the 800 µg/day (mean ± SD = 652 ± 295 at baseline; 928 ± 330 at 4 weeks; and 1218 ± 435 nmol/L at 8 weeks) compared with the 400 µg/day [632 ± 285 at baseline (p = 0.578); 805 ± 363 at 4 weeks (p < 0.001); 1021 ± 414 nmol/L at 8 weeks (p < 0.001)]. The changes of RBC-folate were greater in the 800 µg/day than in the 400 µg/day at any time (changes after 8 weeks: 566 ± 260 vs. 389 ± 229 nmol/L; p < 0.001). Significantly more women in the 800 µg group achieved desirable RBC-folate concentrations at 4 weeks (45.5 vs. 31.3%; p = 0.041) or 8 weeks (83.8 vs. 54.5%; p < 0.001) compared with the 400 µg group. RBC-folate levels below the population median (590 nmol/L) were associated with a reduced response to supplements. CONCLUSIONS: 88% of the women had insufficient RBC-folate to prevent birth defects, while 6.1% had deficiency. Women with low RBC-folate were unlikely to achieve desirable levels within 4-8 weeks, unless they receive 800 µg/day. The current supplementation recommendations are not sufficient in countries not applying fortification. TRIALS REGISTER: The trial was registered at The German Clinical Trials Register: DRKS-ID: DRKS00009770.

Folate status and health: challenges and opportunities.

Each year approximately 2400 pregnancies develop folic acid-preventable spina bifida and anencephaly in Europe. Currently, 70% of all affected pregnancies are terminated after prenatal diagnosis. The prevalence of neural tube defects (NTDs) has been significantly lowered in more than 70 countries worldwide by applying fortification with folic acid. Periconceptional supplementation of folic acid also reduces the risk of congenital heart diseases, preterm birth, low birth weight, and health problems associated with child mortality and morbidity. All European governments failed to issue folic acid fortification of centrally processed and widely eaten foods in order to prevent NTDs and other unwanted birth outcomes. The estimated average dietary intake of folate in Germany is 200 µg dietary folate equivalents (DFE)/day. More than half of German women of reproductive age do not consume sufficient dietary folate to achieve optimal serum or red blood cell folate concentrations (>18 or 1000 nmol/L, respectively) necessary to prevent spina bifida and anencephaly. To date, targeted supplementation is recommended in Europe, but this approach failed to reduce the rate of NTDs during the last 10 years. Public health centers for prenatal care and fortification with folic acid in Europe are urgently needed. Only such an action will sufficiently improve folate status, prevent at least 50% of the NTD cases, reduce child mortality and morbidity, and alleviate other health problems associated with low folate such as anemia.

Preventable spina bifida and anencephaly in Europe.

BACKGROUND: Promotion of voluntary folic acid supplement use among women of reproductive age has been proven to be ineffective in lowering the risk of neural tube defects in Europe. METHODS: Using surveillance data from all births covered by the full member countries of the European Surveillance of Congenital Anomalies (EUROCAT), we estimated the total prevalence of spina bifida and anencephaly per 10,000 births between 2000 and 2010. We also estimated additional lifetime direct medical costs among individuals with spina bifida, compared with those without, in Germany for the year 2009. RESULTS: During the study period, there were 7478 documented cases of spina bifida and anencephaly among the 9,161,189 births, with an estimated average combined prevalence of 8.16 per 10,000 births (95% confidence interval, 7.98 - 8.35). For the 241 spina bifida-affected live births in 2009 in Germany, the estimated additional lifetime direct medical costs compared with non-spina bifida affected births were €65.5 million. Assuming a 50% reduction in the prevalence if folic acid has been provided to all women before pregnancy, 293 spina bifida cases could have been prevented in Germany in 2009. The estimated lifetime direct medical cost saving for the live births in 2009 was €32.9 million assuming a 50% reduction, or €26.1 million assuming a 40% risk reduction. CONCLUSION: Europe has an epidemic of spina bifida and anencephaly compared with countries with mandatory folic acid fortification policy. Primary prevention through mandatory folic acid fortification would considerably reduce the number of affected pregnancies, and associated additional costs.

Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?

Women have higher requirements for folate during pregnancy. An optimal folate status must be achieved before conception and in the first trimester when the neural tube closes. Low maternal folate status is causally related to neural tube defects (NTDs). Many NTDs can be prevented by increasing maternal folate intake in the preconceptional period. Dietary folate is protective, but recommending increasing folate intake is ineffective on a population level particularly during periods of high demands. This is because the recommendations are often not followed or because the bioavailability of food folate is variable. Supplemental folate [folic acid (FA) or 5-methyltetrahydrofolate (5-methylTHF)] can effectively increase folate concentrations to the level that is considered to be protective. FA is a synthetic compound that has no biological functions unless it is reduced to dihydrofolate and tetrahydrofolate. Unmetabolized FA appears in the circulation at doses of >200 µg. Individuals show wide variations in their ability to reduce FA. Carriers of certain polymorphisms in genes related to folate metabolism or absorption can better benefit from 5-methylTHF instead of FA. 5-MethylTHF [also known as (6S)-5-methylTHF] is the predominant natural form that is readily available for transport and metabolism. In contrast to FA, 5-methylTHF has no tolerable upper intake level and does not mask vitamin B12 deficiency. Supplementation of the natural form, 5-methylTHF, is a better alternative to supplementation of FA, especially in countries not applying a fortification program. Supplemental 5-methylTHF can effectively improve folate biomarkers in young women in early pregnancy in order to prevent NTDs.

Efficacy of a 28-day oral cyanocobalamin supplementation on vitamin B status in Spanish institutionalized elderly.

BACKGROUND: Cobalamin deficiency is a common problem in the elderly. There is no consensus about adequate doses for supplementation. SUBJECTS/METHODS: We performed an intervention study in order to establish the efficacy of a supplement providing 500 µg cyanocobalamin for four weeks in sixty-four institutionalized elderly residents, over 60 years of age, in Madrid (Spain). Before and after treatment, concentrations of serum cobalamin, serum holotranscobalamin, serum total homocysteine, and serum and red blood cell folate were analyzed. Clusters were built according to the initial cobalamin status and differences in the effect of supplementation were checked using a general linear model for repeated measures. RESULTS: Cobalamin and holotranscobalamin increased highly significantly from 308 to 558 pmol/L and from 54 to 96 pmol/L (p < 0.001) in the whole study group as well as in each subgroup (clustered by initial cobalamin levels, all p < 0.01), with the highest relative change in the subgroup with the lowest initial cobalamin values. Total homocysteine decreased from 15 to 13 µmol/l, p < 0.001). Only the change of cobalamin (F = 4.61, p < 0.01), but not of holotranscobalamin nor total homocysteine, depended on the initial serum cobalamin status. CONCLUSIONS: A supplementation with an oral supplement solution of 500 µg cyanocobalamin daily for only four weeks, a shorter period than that found in former studies, may be considered suitable in institutionalized elderly.

Health Risk, Functional Markers and Cognitive Status in Institutionalized Older Adults: A Longitudinal Study.

A Follow-up of vitamin B12 and lipids status is essential in older people, being closely related to non-communicable diseases. Their relationships with cognitive and physical status are not clear. The aim was to analyze the evolution of vitamin B12 and related parameters, lipid and hematological profiles, and their relationships with cognitive and physical status among institutionalized elderly. Sixty residents, ranged from 62 to 99, were evaluated. Biomarkers (vitamin B12 and related parameters, lipid and hematological profiles), functional capacity (handgrip, arm and leg strength), and cognitive status (Mini-Mental State Examination) were evaluated four times at 4-month intervals. At the beginning of the study, 63% and 70% of the sample showed abnormal homocysteine and folate values, respectively. At the end of the year, abnormal homocysteine increased to 68%, abnormal folate values decreased to 50%. Throughout the year, serum folate showed a significant increase (14.9 vs. 16.3 nmol/L), (p < 0.05). Serum cobalamin (299 vs. 273 pmol/L). HDL-cholesterol (49.9 vs. 47.0 mg/dL) and triglyceride levels (102.4 vs. 123.2 mg/dL) showed a significant decrease and increase respectively in mean values (all p < 0.05). Serum cobalamin and HDL-cholesterol were the most important biomarkers associated with cognitive function (both p < 0.05). The most relevant biomarkers associated with poor physical strength depending on the body part analyzed were low concentrations of HDL-cholesterol, LDL-cholesterol, apolipoprotein A1, and albumin (all p < 0.05). The evolution of lipid biomarkers, their significance with cognitive values, and association with handgrip, point to the importance of the handgrip measurement, a very simple test, as an important health marker. Both serum albumin and physical strength are important health markers in older people.

Pharmacokinetics of Sodium and Calcium Salts of (6S)-5-Methyltetrahydrofolic Acid Compared to Folic Acid and Indirect Comparison of the Two Salts.

(6S)-5-Methyltetrahydrofolic acid ((6S)-5-Methyl-THF) salts and folic acid may differ in their abilities to raise plasma (6S)-5-Methyl-THF levels. We compared the area under the curve (AUC), Cmax, and Tmax of plasma (6S)-5-Methyl-THF after intakes of (6S)-5-Methyl-THF-Na salt (Arcofolin®) and folic acid. Moreover, we compared the AUCs after intakes of (6S)-5-Methyl-THF-Na and the calcium salt, (6S)-5-Methyl-THF-Ca, that were tested against folic acid in two independent studies. The study was randomized, double blind, and cross over. Twenty-four adults (12 men and 12 women) received a single oral dose of 436 µg (6S)-5-Methyl-THF-Na and an equimolar dose of folic acid (400 µg) on two kinetic days with two weeks washout period in between. The plasma concentrations of (6S)-5-Methyl-THF were measured at 9 time points between 0 and 8 h. We found that the AUC0-8 h of plasma (6S)-5-Methyl-THF (mean (SD) = 126.0 (33.6) vs. 56.0 (25.3) nmol/L*h) and Cmax (36.8 (10.8) vs. 11.1 (4.1) nmol/L) were higher after administration of (6S)-5-Methyl-THF-Na than after the administration of folic acid (p < 0.001 for both). These differences were present in men and women. Only administration of folic acid resulted in a transient increase in plasma unmetabolized folic acid (2.5 (2.0) nmol/L after 0.5 h and 4.7 (2.9) nmol/L after 1 h). Intake of (6S)-5-Methyl-THF-Na was safe. The ratios of the AUC0-8 h for (6S)-5-Methyl-THF-Na and (6S)-5-Methyl-THF-Ca to the corresponding folic acid reference group and the delta of these AUC0-8 h did not differ between the studies. In conclusion, a single oral dose of (6S)-5-Methyl-THF-Na caused higher AUC0-8 h and Cmax of plasma (6S)-5-Methyl-THF compared to folic acid. The Na- and Ca- salts of (6S)-5-Methyl-THF are not likely to differ in their pharmacokinetics. Further studies may investigate whether supplementation of the compounds for a longer time will lead to differences in circulating or intracellular/tissue folate concentrations.

Supplementation with a multivitamin containing 800 microg of folic acid shortens the time to reach the preventive red blood cell folate concentration in healthy women.

BACKGROUND: The lowest risk of having a child with a neural tube defect (NTD) was related to red blood cell (RBC) folate concentrations of >906 nmol/L. For NTD prevention, it is recommended that women use periconceptional supplementation of 400 microg/day folic acid. Using this dose previous studies indicate that RBC folate >906 nmol/L was not reached within four weeks of supplementation. OBJECTIVE: The effectiveness of a multivitamin/multimineral supplement containing 800 microg folic acid (verum) was evaluated using RBC folate concentration exceeding 906 nmol/L as primary endpoint. In addition, the time frame of achieving the threshold level was established as well as the effect of supplementation of other B vitamins on folate metabolism. SUBJECTS AND METHODS: 46 healthy females received 800 microg/day of folic acid or placebo for 16 weeks. Blood samples were collected in four-week intervals. Plasma and RBC folate were measured with the microbiological method. RESULTS: Mean (+/-SED) RBC folate increased over time to 1430+/-53 nmol/L, but did not reach a steady state after 16 weeks of intervention. Mean time to reach the target level was 4.2 +/- 3.5 weeks in the verum group. Intake of verum also led to an increase over time of plasma folate. CONCLUSIONS: Preventive RBC folate concentration of more than 906 nmol/L can be reached within four weeks of supplementation with daily intake of 800 microg folic acid. With respect to NTD prevention, we suggest the re-evaluation of the current recommendation of folic acid supplementation.

Folate supplementation for prevention of congenital heart defects and low birth weight: an update.

Women planning a pregnancy and pregnant women in the first trimester are recommended to use folate-containing supplements in order to prevent neural tube defects. The prevention of many cases of neural tube defects with folic acid is evident from meta-analysis, randomized controlled trials (RCTs), observational studies in humans and experimental evidence in animals. However, folate supplementation in pregnant women or a higher maternal folate status has been shown to be protective against other adverse birth outcomes such as congenital heart defects, low birth weight, and preterm birth. Additionally, infants and children with congenital heart defects often show disorders in folate metabolism (low folate, higher homocysteine, or low vitamin B12). Maternal genotype for several folate metabolizing genes has shown associations with the risk of having a child with congenital heart defect. There is some evidence that folate supplementation could have differential effects on sub-types of congenital heart defects, but it is not clear whether the prevention time window is the same as for neural tube defects. Some studies proposed a high dose of folic acid (in mg/d) to prevent congenital heart defects in women with a high global risk (such as those with diabetes or obesity). There are currently no RCTs to support that doses of folic acid in mg range are more effective than the currently recommended 400-800 µg/d taken at least 2-3 months before conception until the end of the first trimester.

Methylenetetrahydrofolate reductase 677CT polymorphism and cobalamin, folate, and homocysteine status in Spanish adolescents.

BACKGROUND: Folate and cobalamin are responsible for healthy growth. However, the B-vitamin and homocysteine status of adolescents is not well known. The aim was to assess the status of folate, cobalamin, and homocysteine in healthy Spanish adolescents. METHODS: Serum cobalamin, serum folate, homocysteine, methylenetetrahydrofolate reductase 677C>T variant, BMI, smoking habits, and Tanner stage were determined according to gender in 165 adolescents (84 females, 81 males; 13-18.5 years) using the Student's t test, Mann-Whitney U test and chi(2) test, respectively. Interactions between socioeconomic status, age group, methylenetetrahydrofolate reductase polymorphism, BMI, smoking habits, Tanner stage, and vitamin status, respectively, were examined by ANOVA or Kruskal-Wallis H test (p < 0.05). RESULTS: Boys had markedly higher homocysteine (males 8.92 (5.51-22.94) micromol/l; females 7.91 (5.09-13.86) micromol/l), whereas girls showed higher serum cobalamin concentrations (males 540.00 (268.00-946.47) pmol/l; females 594.82 (280.63-1,559.64) pmol/l). Data are shown as medians and the 2.5th to 97.5th percentiles in parentheses. Adolescents with the homozygous variant of methylenetetrahydrofolate reductase displayed significantly higher homocysteine and lower serum folate: normal 5.73 (3.09-10.73) ng/ml serum folate, 7.57 (4.94-12.94) micromol/l homocysteine; homozygous 4.10 (2.75-7.88) ng/ml serum folate, 10.83 (7.00-22.82) micromol/l homocysteine. CONCLUSION: The present study provides data on the folate, cobalamin, and homocysteine status of Spanish adolescents. To assure a better assessment, revision of references for adolescents is still needed.

Response of Red Blood Cell Folate to Supplementation in Nonpregnant Women is Predictable: A Proposal for Personalized Supplementation.

SCOPE: We modeled red blood cell (RBC)-folate response to supplementation and developed personalized folate supplementation concepts. METHODS AND RESULTS: The changes of RBC-folate were modeled in a time- (4 or 8 weeks) and dose- (400 or 800 µg d-1 folate) dependent manner. Post-supplementation RBC-folate levels were predicted from folate-loading capacities (= measured RBC-folate - [baseline RBC-folate × RBC-survival]). The prediction equations were validated in 119 participants. The median increase of RBC-folate was higher in the 800 µg d-1 than in the 400 µg d-1 group (275 vs 169 nmol L-1 after 4 weeks, and 551 vs 346 nmol L-1 after 8 weeks). Medians (interquartile range) of RBC-folate loading were (4 weeks: 299 (160) vs 409 (237) nmol L-1 ) and (8 weeks: 630 (134) versus 795 (187) nmol L-1 ) in the 400 and 800 µg d-1 group, respectively. The individual measured and predicted RBC-folate values (after 4 weeks/400 µg d-1 = 25 + 1.27 × baseline RBC-folate) and (after 4 weeks/800 µg d-1 = 65 + 1.41 × baseline RBC-folate) did not differ significantly. The measured and predicted concentrations showed high agreement in the validation cohort. CONCLUSIONS: The models can guide nutritional recommendations in women when baseline RBC-folate concentrations are measured and the time to pregnancy between 4 and 8 weeks.

Calculation of red blood cell folate steady state conditions and elimination kinetics after daily supplementation with various folate forms and doses in women of childbearing age.

BACKGROUND: A maternal red blood cell (RBC) folate concentration > 906 nmol/L is thought to be optimal for lowering the risk of neural tube defects (NTDs) in pregnancy. Whereas the appearance of folate in RBCs has been followed during folic acid supplementation, data on elimination kinetics are not yet available. OBJECTIVE: The aim of our investigation was to estimate the steady state conditions and elimination kinetics of folate in RBCs. DESIGN: Data from 2 randomized, placebo-controlled, double-blind intervention trials were used for kinetic modeling. These studies were performed to investigate the appearance of folate in RBCs in healthy women of childbearing age after different supplementation strategies (study 1: n = 69; 400 microg folic acid/d and 416 microg [6S]-5-methyltetrahydrofolate/d for 24 wk; study 2: n = 21; 800 microg folic acid/d for 16 wk). RESULTS: For RBC folate concentrations, steady state conditions were not reached after 24 (study 1) and 16 (study 2) wk of folate supplementation. However, with the use of these data, we calculated the biological half-life (t(1/2)) of RBC folate to be approximately 8 wk. With the application of pharmacokinetic principles, steady state conditions for RBC folate should be reached after 40 wk (t(1/2) x 5). CONCLUSION: With the use of pharmacokinetic principles, the appearance and elimination kinetics of RBC folate can be calculated on the basis of this t(1/2) value.

Cardiovascular fitness is negatively associated with homocysteine levels in female adolescents.

OBJECTIVE: To examine the association between cardiovascular fitness and homocysteine levels in adolescents. DESIGN: Cross-sectional study. SETTING: Madrid, Murcia, Granada, Santander, and Zaragoza, Spain. PARTICIPANTS: One hundred fifty-six Spanish adolescents (76 boys and 80 girls) aged (mean +/- SD) 14.8 +/- 1.4 years. MAIN EXPOSURES: Cardiovascular fitness was measured by the 20-m shuttle run test. Pubertal stage, birth weight, smoking status, and socioeconomic status were determined, and the sum of 6 skinfold thickness measurements, and serum folic acid and vitamin B(12) levels were measured. Methylenetetrahydrofolate reductase (MTHFR; 677C>T genotype) polymorphism was done by DNA sequencing. MAIN OUTCOME MEASURE: Fasting homocysteine levels. RESULTS: Mean values of homocysteine were significantly higher in the MTHFR 677CT and TT genotype subgroups compared with the CC genotype subgroup in adolescent boys, whereas in adolescent girls, mean values of homocysteine were significantly higher in the MTHFR 677CT and TT genotype subgroup compared with the CC and CT genotype subgroups. Multiple regression analyses showed that cardiovascular fitness was significantly associated with homocysteine levels in female adolescents after controlling for potential confounders including the MTHFR 677C>T genotype (beta = -0.40; semipartial correlation = -0.35; P = .007). No associations were found between cardiovascular fitness and homocysteine levels in male adolescents (beta = 0.12; semipartial correlation = 0.08; P = .51). CONCLUSION: The results suggest that cardiovascular fitness is negatively associated with homocysteine levels in female adolescents after controlling for potential cofounders including MTHFR 677C>T genotype.

B-vitamins and homocysteine in Spanish institutionalized elderly.

BACKGROUND: Hyperhomocysteinemia is an accepted risk factor for cardiovascular disease, and possibly also for cognitive impairment and dementia. It has also been proposed as a marker for the status of the B vitamins, which participate in the metabolism of homocysteine. Therefore, especially in the elderly, it is important to know the prevalence of high homocysteine (tHcy) levels and the influence that B vitamins have on them. MATERIAL AND METHODS: 218 elderly of both sexes, aged 60-105, living in an elderly home in Granada (Spain), were screened for serum folate, red blood cell (RBC) folate, serum cobalamin (B12) (Abbott, IMx), holotranscobalamin II (Holo-TC II) (HoloTC RIA, Axis-Shield), methylmalonic acid (MMA) (MS-GC), total pyridoxine (B6) (HPLC), and total homocysteine (tHcy) (Abbott, IMx). RESULTS: Hyperhomocysteinemia (tHcy >12 pmol/L) was detected in 80.7%. Serum folate deficiency was severe (< or =4 ng/mL) in 19.3% and moderate (4-7 ng/mL) in 43.1%. In 14.2% of the elderly RBC folate was < or =175 ng/mL, and in 61.0% it was between 175-400 ng/mL. Vitamin B12, measured in serum (< or =200 pg/mL), was deficient in 15.8%, but if measured as Holo-TC II (< or =45 pmol/L), deficiency ranged up to 39.1%. MMA was high (> or =300 nmol/L) in 45.6%. Vitamin B6 (< 20 nmol/L) was low only in one person. In order to identify the factors that could predict tHcy levels, a multiple regression analysis was performed. Best results corresponded to the combination of log serum folate and log Holo-TC II, which gave values of R > 0.5. If analyzed independently, the highest correlation was with log serum folate (r = -0.290), followed by RBC folate (r = -0.263), Holo-TC II (r = -0.228), log B12 (r = -0.175), and log B6 (r = -0.078). CONCLUSION: There is a high prevalence of vitamin B deficiency and hyperhomocysteinemia in the studied population. Our data confirm the influence of these vitamins, especially folate, on tHcy levels, but hyperhomocysteinemia cannot be used as the only diagnostic criterion to detect subclinical vitamin deficiency in elderly people, especially to detect vitamin B12 deficiency.

Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age.

BACKGROUND: For the primary prevention of neural tube defects (NTDs), public health authorities recommend women of childbearing age to take 400 mug folic acid/d 4 wk before conception and during the first trimester. The biologically active derivate [6S]-5-methyltetrahydrofolate ([6S]-5-MTHF) could be an alternative to folic acid. OBJECTIVE: We investigated the effect of supplementation with [6S]-5-MTHF compared with that of folic acid on red blood cell folate concentration, an indicator of folate status. DESIGN: The study was designed as a double-blind, randomized, placebo-controlled intervention trial. Healthy women (n = 144) aged 19-33 y received 400 microg folic acid, the equimolar amount of [6S]-5-MTHF (416 microg), 208 microg [6S]-5-MTHF, or placebo as a daily supplement for 24 wk. Red blood cell and plasma folate concentrations were measured at baseline and at 4-wk intervals. RESULTS: The increase in red blood cell folate over time was significantly higher in the group receiving 416 microg [6S]-5-MTHF/d than in the groups receiving 400 microg folic acid/d or 208 microg [6S]-5-MTHF/d (P < 0.001). No plateau was reached in red blood cell folate concentration in the 3 treatment groups during 24 wk of intervention; however, plasma folate plateaued after 12 wk. CONCLUSIONS: We showed that administration of [6S]-5-MTHF is more effective than is folic acid supplementation at improving folate status. In addition, the study indicates that the recommended period for preconceptional folic acid supplementation should be extended to >4 wk for maximal prevention of NTDs based on folate concentrations. [6S]-5-MTHF might be an efficient and safe alternative to folic acid.

Supplementation with [6S]-5-methyltetrahydrofolate or folic acid equally reduces plasma total homocysteine concentrations in healthy women.

BACKGROUND: Increased plasma total homocysteine (tHcy) is a risk factor for vascular disease and adverse pregnancy outcomes. Health authorities recommend periconceptional supplementation with 400 micro g folic acid to prevent neural tube defects. Several countries have implemented food fortification with folic acid. However, excessive intake of folic acid could mask an undiagnosed vitamin B-12 deficiency. The biologically active [6S]-5-methyltetrahydrofolate ([6S]-5-MTHF) may be an alternative to folic acid because it is unlikely to mask vitamin B-12 deficiency symptoms. OBJECTIVE: We compared the tHcy-lowering potential of 2 dosages of [6S]-5-MTHF with that of 400 micro g folic acid during 24 wk of supplementation. DESIGN: In this double-blind, randomized, controlled intervention trial, 144 female participants were supplemented daily with 400 micro g folic acid, 416 micro g [6S]-5-MTHF, 208 micro g [6S]-5-MTHF, or placebo. Concentrations of tHcy and plasma folate were measured at baseline and at 4-wk intervals. RESULTS: After supplementation, there was a significant interaction between time and treatment with respect to changes in tHcy and plasma folate (both P < 0.001 by two-factor repeated-measures analysis of variance). The decrease in tHcy did not differ significantly between the 3 supplemented groups (P > 0.05; Tukey's post hoc test). The increase in plasma folate in the group receiving 208 micro g [6S]-5-MTHF was significantly lower than that in the groups receiving 400 micro g folic acid (P < 0.001) or 416 micro g [6S]-5-MTHF (P < 0.05). CONCLUSIONS: [6S]-5-MTHF was shown to be an adequate alternative to folic acid in reducing tHcy concentrations. Supplementation with 416 micro g [6S]-5-MTHF was no more effective than that with 208 micro g [6S]-5-MTHF.

5,10-Methylenetetrahydrofolate reductase genotype determines the plasma homocysteine-lowering effect of supplementation with 5-methyltetrahydrofolate or folic acid in healthy young women.

BACKGROUND: Elevated plasma total homocysteine (tHcy) is a risk factor for vascular disease and neural tube defects. The polymorphism in the gene encoding 5,10-methylenetetrahydrofolate reductase (FADH(2)) (MTHFR) influences the tHcy concentration and the response to tHcy-lowering therapy. Supplementation with folic acid (FA) decreases plasma tHcy, but limited data are available on the effect of 5-methyltetrahydrofolate (MTHF). OBJECTIVE: We evaluated the tHcy-lowering potential of low-dose FA and of MTHF with respect to the MTHFR genotype. DESIGN: In this randomized, placebo-controlled, double-blind study, 160 women received 400 microg FA, the equimolar amount of MTHF (480 microg, racemic mixture), or a placebo daily during an 8-wk treatment period. Blood samples were collected at baseline and at 4 and 8 wk. RESULTS: Changes in plasma tHcy concentration depended on the supplemented folate derivative and the MTHFR genotype. Supplementation with FA significantly decreased tHcy concentrations by > or = 13% in women of all 3 genotypes after both 4 and 8 wk. The greatest decrease was 20% (P < 0.05) in the women with the TT genotype after 4 wk. MTHF supplementation also decreased tHcy, but only the women with the CT genotype had a significant decrease after 4 wk (7%; P < 0.05). The largest nonsignificant reduction (15%) occurred in the women with the TT genotype after 4 wk of MTHF supplementation. CONCLUSIONS: The response to tHcy-lowering therapy is influenced by MTHFR genotype. Women with the TT genotype seem to benefit the most from supplementation with either FA or MTHF. In women with the CT or CC genotype, FA is more effective than MTHF in lowering plasma tHcy.

Erythrocyte indexes, iron metabolism, and hyperhomocysteinemia in adults with cyanotic congenital cardiac disease.

A high percentage of cyanotic adults (37%) with cyanotic congenital cardiac disease (CCD) presented with depleted iron stores (13 of 52) or latent iron deficiency (6 of 52), even in a CCD center in which cyanotic patient phlebotomy is mostly avoided. In many of these patients, hypochromia and microcytosis was frequent, whereas hyperchromia and macrocytosis were relatively common.Furthermore, 50% of patients presented with hyperhomocysteinemia, possibly related to folate or B vitamin deficiencies, which may increase red blood cell size and color, explaining the lack of microcytosis and hypochromia in many cyanotic patients with iron deficiency.