[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.

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.

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.

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.

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.

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.

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.

Critical evaluation of lowering the recommended dietary intake of folate.

We evaluated the recommendation of the Austrian, German, and Swiss Societies for Nutrition of lowering dietary folate intake from 400 to 300 µg dietary folate equivalents/d. A dose-response relation exists between folate intake or plasma level and disease risk within the normal range. Improving folate status can prevent between 30% and 75% of neural tube defects. A prepregnancy plasma folate of >18.0 nmol/L (mean 26.1 nmol/L) is associated with low total homocysteine (tHcy) (<10.0 µmol/L) and optimal prevention of birth defects. Because the closure of the neural tube occurs in the first 8 weeks after conception, women with low prepregnancy folate intake cannot achieve maximal risk reduction. The Austrian, German, and Swiss Societies for Nutrition recommend that young women should additionally supplement with 400 µg folic acid at least 4 weeks before conception. This short time window is not sufficient to achieve optimal plasma folate and tHcy levels in the majority of women. Factors affecting the relation between folate intake and blood biomarkers are total folate intake, baseline plasma folate, time available for supplement use, dose and form (folic acid or methyl folate), genetic polymorphisms, physiological and lifestyle factors. Lowering the recommended dietary folate intake may have important public health consequences. Elderly people and young women are at risk for diseases related to folate shortage. Reducing birth defects through supplementation of folic acid remains a poor option, as <20% of young women (i.e., in Germany) supplement with the vitamin. Recommending adequate food folate intake is crucial for reaching the target protective plasma folate levels in the population.

Algorithm for the early diagnosis of vitamin B12 deficiency in elderly people.

BACKGROUND: The elderly population is particularly at risk for developing vitamin B12-deficiency. Serum cobalamin does not necessarily reflect a normal B12 status. The determination of methylmalonic acid is not available in all laboratories. Issues of sensitivity for holotranscobalamin and the low specificity of total homocysteine limit their utility. The aim of the present study is to establish a diagnostic algorithm by using a combination of these markers in place of a single measurement. METHODS: We compared the diagnostic efficiency of these markers for detection of vitamin B12 deficiency in a population (n = 218) of institutionalized elderly (median age 80 years). Biochemical, haematological and morphological data were used to categorize people with or without vitamin B12 deficiency. RESULTS: In receiver operating curves characteristics for detection on vitamin B12 deficiency using single measurements, serum folate has the greatest area under the curve (0.87) and homocysteine the lowest (0.67). The best specificity was observed for erythrocyte folate and methylmalonic acid (100% for both) but their sensitivity was very low (17% and 53%, respectively). The highest sensitivity was observed for homocysteine (81%) and serum folate (74%). When we combined these markers, starting with serum and erythrocyte folate, followed by holotranscobalamin and ending by methylmalonic acid measurements, the overall sensitivity and specificity of the algorithm were 100% and 90%, respectively. CONCLUSION: The proposed algorithm, which combines erythrocyte folate, serum folate, holotranscobalamin and methylmalonic acid, but eliminate B12 and tHcy measurements, is a useful alternative for vitamin B12 deficiency screening in an elderly institutionalized cohort.

Introducción: Los mayores son una población que presenta un riesgo importante de desarrollar una deficiencia de vitamina B12, pero las concentraciones de cobalamina en suero no reflejan necesariamente un estado abnormal en el estado de B12 . Existen biomarcadores asociados a la vitamina B12: el ácido metilmalónico no está disponible en todos los laboratorios, la holotranscobalamina es poco sensible y la homocisteína presenta una baja especificidad. El objetivo del presente estudio es establecer un algoritmo de diagnóstico mediante el uso de una combinación de estos biomarcadores en lugar de la medición de uno sólo de ellos. Métodos: Se comparó la eficacia diagnóstica de estos marcadores para la detección de deficiencia de vitamina B12 en una población (n = 218) de ancianos institucionalizados (edad media 80 años). Los parámetros bioquímicos, hematológicos y morfológicos fueron utilizados para clasificar a los sujetos con o sin deficiencia de vitamina B12. Resultados: Se establecieron las curvas ROC (Receiver Operating Curves) para determinar la eficacia diagnóstica de cada parámetro, tomado individualmente. El folato sérico tenía la mayor área bajo la curva (0,87) y la homocisteína la más baja (0,67). Se observó que la mejor especificidad la presentaba el folato eritrocitario y el ácido metilmalónico (100% para ambos), pero sus sensibilidades eran muy bajas (17% y 53%, respectivamente). Y se observó que la sensibilidad más alta la presentaba la homocisteína (81%) y el folato sérico (74%), pero en contrapartida una especificidad baja. Cuando se combinaron estos marcadores, iniciando las determinaciones con el folato sérco y eritrocitario, seguido por holotranscobalamina y terminando por las mediciones de ácido metilmalónico, la sensibilidad y especificidad global del algoritmo fueron 100% y 90%, respectivamente. Conclusión: El algoritmo propuesto, que combina la determinación de folato sérico y eritrocitario, holotranscobalamina y ácido metilmalónico, sin necesidad de evaluar la vitamina B12 y la homocisteína, es una alternativa útil para la detección de un estado abnormal del estado de vitamina B12 en una población de ancianos institucionalizados.

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.

Gender and age influence blood folate, vitamin B12, vitamin B6, and homocysteine levels in European adolescents: the Helena Study.

It is important to be able to evaluate vitamin status correctly at any age, but this is especially vital during adolescence since there are higher requirements for healthy growth and development. However, there are no currently available B-vitamin reference values for healthy adolescents. The aim of the present study is to assess the vitamin B status in European adolescents in order to contribute to the development of reference values for selected B-vitamins and total homocysteine (tHcy). Within the HELENA (Healthy Lifestyle in Europe by Nutrition in Adolescence) cross-sectional study, a sub sample of 1051 (499 males, 552 females) adolescents from ten European cities aged 12.5 to 17.49 were analyzed for fasting plasma folate (PF), red blood cell (RBC) folate, serum cobalamin (Cbl), holo-transcobalamin (Holo-TC), Vitamin B(6) (PLP), and tHcy. The level of significance was set at P < .05. Following the current cut-off for adults, 2% had low Cbl and 5% had low holo-TC concentrations. Low concentrations of both PF and RBC folate were identified in 10%. Five percent had PLP concentrations <20 nmol/L and 20% <30 nmol/L. Moreover, 5% had high tHcy; median values for the whole sample were: PF 16.0 nmol/L, RBC folate 721.9 nmol/L, Cbl 319 pmol/L, Holo-TC 57.8 pmol/L, and tHcy 6.7 µmol/L. Females had significantly higher median Cbl but lower PLP and tHcy concentrations (P < .01). THcy increased (P < .001) and PF (P < .001) concentrations decreased across age categories. Subjects showed significantly higher tHcy values at the fifth percentile of PF, corresponding with 7.5 nmol/L. Sex and age had an influence on most of the studied biomarkers and should be taken into account. The HELENA percentile distribution is consistent with data from smaller studies and could be used as reference value to characterize B-vitamin status of European adolescents.

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.

Adding folate to the contraceptive pill: a new concept for the prevention of neural tube defects.

Although it is proven for a long time that folic acid supplementation in the periconceptional period can prevent neural tube defects (NTDs) effectively, all measures taken so far including food fortification and awareness campaigns so far had only limited success. Since more than 50% of the pregnant women in Europe get pregnant after they have used oral contraceptives (OCs) before, OCs are an ideal vehicle to increase not only the awareness for periconceptional folate application, but they can also help to bridge the gap between the recognition of a pregnancy and closure of the neural tube which is before day 26. In order to reach a truly protective folate level at the critical time period during pregnancy, now OCs are available which contain metafolin. The availability of this innovative type of OC will significantly reduce the number of NTDs.

Micronutrients and women of reproductive potential: required dietary intake and consequences of dietary deficiency or excess. Part II--vitamin D, vitamin A, iron, zinc, iodine, essential fatty acids.

Part II of this review considers additional micronutrients. Vitamin D is a fat soluble vitamin found in foods of animal origins (fatty fish, liver oil) or fortified products (milk, cheese). Vitamin D deficiency is common in African-American women living in northern latitudes. Vitamin D supplementation may be needed to reach desired 25-(OH)D3 concentrations of >50 nmol/L. In foods of animal origin, preformed Vitamin A is present; in plants (fruits and vegetables) vitamin A precursors (ß-carotenoids) are present. Vitamin A supplementation is usually not warranted, and in developing countries should not exceed 3000 µg (10,000 IU)/day. Iron in the form of haem-iron is found in meat, fish and poultry; non-haem (inorganic) iron is found in vegetables, fruits and grains. Iron supplementation may be necessary in the third trimester, earlier in pregnancy or in non-pregnant states if serum ferritin is <20 µg/L or haemoglobin <10.9 g/dL. Zinc is available in red meat, seafood including oysters and unpolished grains; supplementation is not necessary. To assure adequate iodine, food is fortified worldwide with iodated salt. If urinary iodine levels are low, supplementation is needed. Essential fatty acids requirements can be met by one to two portions of fish per week.

Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics.

There is a large body of evidence to suggest that improving periconceptional folate status reduces the risk of neonatal neural tube defects. Thus increased folate intake is now recommended before and during the early stages of pregnancy, through folic acid supplements or fortified foods. Furthermore, there is growing evidence that folic acid may have a role in the prevention of other diseases, including dementia and certain types of cancer. Folic acid is a synthetic form of the vitamin, which is only found in fortified foods, supplements and pharmaceuticals. It lacks coenzyme activity and must be reduced to the metabolically active tetrahydrofolate form within the cell. L-5-methyl-tetrahydrofolate (L-5-methyl-THF) is the predominant form of dietary folate and the only species normally found in the circulation, and hence it is the folate that is normally transported into peripheral tissues to be used for cellular metabolism. L-5-methyl-THF is also available commercially as a crystalline form of the calcium salt (Metafolin(R)), which has the stability required for use as a supplement. Studies comparing L-5-methyl-THF and folic acid have found that the two compounds have comparable physiological activity, bioavailability and absorption at equimolar doses. Bioavailability studies have provided strong evidence that L-5-methyl-THF is at least as effective as folic acid in improving folate status, as measured by blood concentrations of folate and by functional indicators of folate status, such as plasma homocysteine. Intake of L-5-methyl-THF may have advantages over intake of folic acid. First, the potential for masking the haematological symptoms of vitamin B(12) deficiency may be reduced with L-5-methyl-THF. Second, L-5-methyl-THF may be associated with a reduced interaction with drugs that inhibit dihydrofolate reductase.