Water-Soluble Vitamins in Human Milk Factors Affecting Their Concentration and Their Physiological Significance.

Most B vitamins and vitamin C are among the nutrients in milk most strongly affected by maternal status and/or dietary intake. Recent analytical methods are more efficient and valid, revealing major differences in water-soluble vitamins across population groups. An inadequate supply in milk can be detrimental to the breastfed infant's health and development although cutoff points below which risk is increased are often uncertain, and little attention has been paid to adverse effects of low milk water-soluble vitamins on infant health and function. Concentrations change during lactation: thiamine, niacin, and pantothenic acid increase; B6, B12, and ascorbic acid gradually decrease; while riboflavin concentrations are stable, as is choline after an initial increase. Folate fluctuates until stabilizing in late lactation. Water-soluble vitamin concentrations in milk are also influenced by maternal supplementation, and, for some, by parity, preterm delivery, smoking, and maternal illness. However, there is relatively little change in concentrations during a feed nor is diurnal variation a major influence. Reported concentrations are used to set adequate intakes for infants and incremental requirements for lactation. However, the status of available data is poor due to the small number of participants in most studies, uncertainties about maternal nutritional status, and variable times of milk collection postpartum.

Global Birth Prevalence of Spina Bifida by Folic Acid Fortification Status: A Systematic Review and Meta-Analysis.

BACKGROUND: Birth defects remain a significant source of worldwide morbidity and mortality. Strong scientific evidence shows that folic acid fortification of a region's food supply leads to a decrease in spina bifida (a birth defect of the spine). Still, many countries around the world have yet to approve mandatory fortification through government legislation. OBJECTIVES: We sought to perform a systematic review and meta-analysis of period prevalence of spina bifida by folic acid fortification status, geographic region, and study population. SEARCH METHODS: An expert research librarian used terms related to neural tube defects and epidemiology from primary research from 1985 to 2010 to search in EMBASE and MEDLINE. We searched the reference lists of included articles and key review articles identified by experts. SELECTION CRITERIA: Inclusion criteria included studies in English or French reporting on prevalence published between January 1985 and December 2010 that (1) were primary research, (2) were population-based, and (3) reported a point or period prevalence estimate of spina bifida (i.e., prevalence estimate with confidence intervals or case numerator and population denominator). Two independent reviewers screened titles and abstracts for eligible articles, then 2 authors screened full texts in duplicate for final inclusion. Disagreements were resolved through consensus or a third party. DATA COLLECTION AND ANALYSIS: We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses, or PRISMA, abstracting data related to case ascertainment, study population, folic acid fortification status, geographic region, and prevalence estimate independently and in duplicate. We extracted overall data and any subgroups reported by age, gender, time period, or type of spina bifida. We classified each period prevalence estimate as "mandatory" or "voluntary" folic acid fortification according to each country's folic acid fortification status at the time data were collected (as determined by a well-recognized fortification monitoring body, Food Fortification Initiative). We determined study quality on the basis of sample representativeness, standardization of data collection and birth defect assessment, and statistical analyses. We analyzed study-level period prevalence estimates by using a random effects model (α level of < 0.05) for all meta-analyses. We stratified pooled period prevalence estimates by birth population, fortification status, and continent. RESULTS: Of 4078 studies identified, we included 179 studies in the systematic review and 123 in a meta-analysis. In studies of live births (LBs) alone, period prevalences of spina bifida were (1) lower in geographical regions with mandatory (33.86 per 100,000 LBs) versus voluntary (48.35 per 100,000 LBs) folic acid fortification, and (2) lower in studies of LBs, stillbirths, and terminations of pregnancy in regions with mandatory (35.22 per 100,000 LBs) versus voluntary (52.29 per 100,000 LBs) fortification. In LBs, stillbirths, and terminations of pregnancy studies, the lowest pooled prevalence estimate was in North America (38.70 per 100,000). Case ascertainment, surveillance methods, and reporting varied across these population-based studies. CONCLUSIONS: Mandatory legislation enforcing folic acid fortification of the food supply lags behind the evidence, particularly in Asian and European countries. This extensive literature review shows that spina bifida is significantly more common in world regions without government legislation regulating full-coverage folic acid fortification of the food supply (i.e., Asia, Europe) and that mandatory folic acid fortification resulted in a lower prevalence of spina bifida regardless of the type of birth cohort. African data were scarce, but needed, as many African nations are beginning to adopt folic acid legislation.

Opposing roles of folate in prostate cancer.

The US diet has been fortified with folic acid to prevent neural tube defects since 1998. The Physician Data Queries from the National Cancer Institute describe folate as protective against prostate cancer, whereas its synthetic analog, folic acid, is considered to increase prostate cancer risk when taken at levels easily achievable by eating fortified food or taking over-the-counter supplements. We review the present literature to examine the effects of folate and folic acid on prostate cancer, help interpret previous epidemiologic data, and provide clarification regarding the apparently opposing roles of folate for patients with prostate cancer. A literature search was conducted in Medline to identify studies investigating the effect of nutrition and specifically folate and folic acid on prostate carcinogenesis and progression. In addition, the National Health and Nutrition Examination Survey database was analyzed for trends in serum folate levels before and after mandatory fortification. Folate likely plays a dual role in prostate carcinogenesis. There remains conflicting epidemiologic evidence regarding folate and prostate cancer risk; however, there is growing experimental evidence that higher circulating folate levels can contribute to prostate cancer progression. Further research is needed to clarify these complex relationships.

The role of B vitamins in the management of heart failure.

Heart failure (HF) is the leading cause of morbidity and mortality in industrialized countries, creating a significant burden on both the healthcare system and quality of life. Research efforts continue to explore new pharmaceutical or surgically based approaches to HF management, but the role of nutrition as an adjunct therapy has been largely ignored. Elderly age, anorexia, malabsorption, premature satiety, and disease severity are among the factors identified as contributing to reduced nutrient intakes in patients with HF. These factors suggest that patients with HF are at increased risk of multiple-nutrient deficiencies, including B vitamins. B vitamins may be of particular therapeutic interest because of their key roles as cofactors in energy-producing pathways. Recently, impaired stores of high-energy compounds have been linked with myocardial dysfunction and prognosis in patients with HF. Therefore, deficiencies of B vitamins might contribute to reduced energy stores and disease progression. This review summarizes the existing literature both with respect to the prevalence of B vitamin deficiency as well as evidence from supplementation trials in patients with HF. The findings suggest that most of the literature in this area has focused on thiamin deficiency in patients with HF, whereas other B vitamins remain largely unstudied. Although few sporadic trials suggest a role for B vitamins in the management of HF, none are conclusive. Therefore, there is a need for larger, more robust trials to assist in defining the B vitamin requirements as well as the impact of supplementation on both morbidity and mortality in patients with HF.

Homocysteine and vascular disease: review of published results of the homocysteine-lowering trials.

Moderately elevated homocysteine levels have been associated with a higher risk of cardiovascular disease in observational studies, but whether these associations are causal is uncertain. Randomized trials of dietary supplementation with B vitamins were set up to assess whether lowering homocysteine levels could reduce the risk of vascular disease. This review is based on a meta-analysis of published results of eight homocysteine-lowering trials for preventing vascular disease. The eight trials comprised a total of 37,485 individuals and provided comparisons of the effects of B vitamins on 5,074 coronary heart disease (CHD) events, 1,483 stroke events, 2,692 incident cancer events, and 5,128 deaths. Our meta-analysis assessed the effects of lowering homocysteine levels by about 25% for about 5 years. Allocation to B vitamins had no beneficial effects on any cardiovascular events, with hazard ratios (95% confidence intervals) of 1.01 (0.96-1.07) for CHD and 0.96 (0.87-1.07) for stroke. Moreover, allocation to B vitamins had no significant adverse effects on cancer [1.08 (0.99-1.17)], or for death from any cause [1.02 (0.97-1.07)]. Thus, supplementation with B vitamins had no statistically significant effects on the risks of cardiovascular events, total mortality rates, or cancer. A meta-analysis based on individual participant data from all available trials will assess the effects of lowering homocysteine levels on a broader range of outcomes, overall and in all relevant subgroups. However, available evidence does not support the routine use of B vitamins to prevent cardiovascular disease.

Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control.

In addition to its essential role in permitting mitochondrial import and oxidation of long chain fatty acids, carnitine also functions as an acyl group acceptor that facilitates mitochondrial export of excess carbons in the form of acylcarnitines. Recent evidence suggests carnitine requirements increase under conditions of sustained metabolic stress. Accordingly, we hypothesized that carnitine insufficiency might contribute to mitochondrial dysfunction and obesity-related impairments in glucose tolerance. Consistent with this prediction whole body carnitine diminution was identified as a common feature of insulin-resistant states such as advanced age, genetic diabetes, and diet-induced obesity. In rodents fed a lifelong (12 month) high fat diet, compromised carnitine status corresponded with increased skeletal muscle accumulation of acylcarnitine esters and diminished hepatic expression of carnitine biosynthetic genes. Diminished carnitine reserves in muscle of obese rats was accompanied by marked perturbations in mitochondrial fuel metabolism, including low rates of complete fatty acid oxidation, elevated incomplete beta-oxidation, and impaired substrate switching from fatty acid to pyruvate. These mitochondrial abnormalities were reversed by 8 weeks of oral carnitine supplementation, in concert with increased tissue efflux and urinary excretion of acetylcarnitine and improvement of whole body glucose tolerance. Acetylcarnitine is produced by the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT). A role for this enzyme in combating glucose intolerance was further supported by the finding that CrAT overexpression in primary human skeletal myocytes increased glucose uptake and attenuated lipid-induced suppression of glucose oxidation. These results implicate carnitine insufficiency and reduced CrAT activity as reversible components of the metabolic syndrome.

B-vitamins and prevention of dementia.

Elevated plasma homocysteine (Hcy) concentrations have been implicated with risk of cognitive impairment and dementia, but it is unclear whether low vitamin B12 or folate status is responsible for cognitive decline. Most studies reporting associations between cognitive function and Hcy or B-vitamins have used a cross-sectional or case-control design and have been unable to exclude the possibility that such associations are a result of the disease rather than being causal. The Hcy hypothesis of dementia has attracted considerable interest, as Hcy can be easily lowered by folic acid and vitamin B12, raising the prospect that B-vitamin supplementation could lower the risk of dementia. While some trials assessing effects on cognitive function have used folic acid alone, vitamin B12 alone or a combination, few trials have included a sufficient number of participants to provide reliable evidence. An individual-patient-data meta-analysis of all randomised trials of the effects on cognitive function and vascular risk of lowering Hcy with B-vitamins will maximise the power to assess the epidemiologically-predicted differences in risk. Among the twelve large randomised Hcy-lowering trials for prevention of vascular disease, data should be available on about 30 000 participants with cognitive function. The principal investigators of such trials have agreed to combine individual-participant data from their trials after their separate publication.

Reduced folate status is common and increases disease risk. It can be corrected by daily ingestion of supplements or fortification.

The natural folates are chemically unstable and poorly bioavailable in contrast to the chemical form, folic acid. Consequently most people, even those on good diets, have less than optimal nutrition with respect to this vitamin. Increased risks associated with deficiency include neural tube defects (NTDs) (proven), ischaemic heart disease and stroke (probable), certain cancers and decline in cognitive function (possible). Supplements of folic acid at the population reference intake (400 microg/d) completely normalizes all of these risks. Such levels are safe as judged by decades of use in wide sectors of the population. The main drawback of supplements is with respect to their effectiveness in preventing NTDs. They must be taken periconceptionally and before most women realise that they are pregnant. No more than one fifth of women take supplements effectively, largely due to the fact that over half of pregnancies are unplanned. This has led to the alternative of mandatory fortification of flour with folic acid in the USA and Canada. The level for such fortification is suboptimal for NTD prevention, because of fear of overexposure in the elderly. Thus even fortified communities require advice to take supplements for optimum NTD prevention.

Effects of B-vitamins on plasma homocysteine concentrations and on risk of cardiovascular disease and dementia.

PURPOSE OF REVIEW: Dietary supplementation with folic acid and vitamin B12 lowers blood homocysteine concentrations, but it is not known if this reduces the risk of coronary heart disease and stroke. RECENT FINDINGS: Recent evidence suggests that the maximum reduction in plasma homocysteine concentrations is obtained with 0.8 mg of folic acid and doses of 0.2 mg and 0.4 mg of folic acid are associated with about 60 and 90%, respectively, of this maximal effect. Among 12 large trials (involving a total of 52,000 participants) that are currently assessing the effects of B-vitamins on risk of coronary heart disease and stroke, results are available for four trials involving 14 000 participants. A meta-analysis of these four trials demonstrates no beneficial effects of B-vitamins on coronary heart disease (OR 0.99; 95% CI 0.88-1.10) or stroke (OR 89; 95% CI 0.76-1.05) or the combination of coronary heart disease and stroke (OR 0.98; 95% CI 0.90-1.08). The confidence intervals around the odds ratios for these completed trials are compatible with a 10% difference in risk for coronary heart disease and 20% difference for stroke associated with a 25% lower homocysteine predicted by the observational epidemiological studies. SUMMARY: The results of the ongoing homocysteine-lowering trials are required before making recommendations on the use of B-vitamins for prevention of vascular disease.

Thoughts on B-vitamins and dementia.

The B-vitamins, including vitamins B12, B6, B1, B2, niacin (B3) and folate (B9), have been implicated as protective risk factors against cognitive decline and Alzheimer's disease. This commentary reviews the evidence to support protective relations of these vitamins, including consideration of known vitamin deficiency syndromes, theories of underlying biologic mechanisms, and the epidemiologic evidence. We also comment on the potential benefits and harms of vitamin supplementation as well as make recommendations for the direction of future studies.

B-vitamins and exercise: does exercise alter requirements?

The B-vitamins (thiamin, riboflavin, vitamin B-6) are necessary in the energy-producing pathways of the body, while folate and vitamin B-12 are required for the synthesis of new cells, such as the red blood cells, and for the repair of damaged cells. Active individuals with poor or marginal nutritional status for a B-vitamin may have decreased ability to perform exercise at high intensities. This review focuses on the B-vitamins and their role in energy metabolism and cell regeneration. For each vitamin, function related to physical activity, requirement, and status measures are given. Research examining dietary intakes and nutritional status in active individuals is also presented. Current research suggests that exercise may increase the requirements for riboflavin and vitamin B-6, while data for folate and vitamin B-12 are limited. Athletes who have poor diets, especially those restricting energy intakes or eliminating food groups from the diet, should consider supplementing with a multivitamin/mineral supplement.

Vitamins, minerals and supplements: part two.

Vitamins and minerals are organic food substances found only in plants and animals and are essential to the normal functioning of the body. Although only required in small amounts, as previously discussed in the past decade there has been an increased use of vitamin, mineral, herbal and nutritional supplements in the general population. While deficiencies in such nutrients can be harmful to health, conflicting claims have been made about the health benefits of such supplementation. In the second of an occasional series on vitamins, minerals, and supplements, JUNE THOMPSON gives an overview of the role that water-soluble vitamins play in the health of the individual, including their functions, and the potential impact of any deficiency of these.

Water-soluble vitamins: research update.

For more than 50 years, the Food and Nutrition Board of the National Academy of Sciences has been reviewing nutrition research and defining nutrient requirements for healthy people, referred to as the recommended dietary allowances (RDA). As new nutrition research is published, the importance of vitamins as vital nutrients is underscored, and new physiologic roles and applications to human health are examined and considered with regard to updating the RDA. Each year a substantial amount of research is published on vitamins. This article examines and summarizes noteworthy research published on individual water-soluble vitamins (excluding vitamin C) in the past 12 months, provides relevant background information on these vitamins, and offers critical reviews as appropriate.

Vitamin and mineral status: effects on physical performance.

Public health recommendations encourage the selection of a balanced diet and increasing physical activity to foster health and well-being. Whereas the adverse effects of restricted intakes of protein, fat, and carbohydrate on physical performance are well known, there is limited information about the impact of low intakes of vitamins and minerals on the exercise capacity and performance of humans. Physically active people generally consume amounts of vitamins and minerals consistent with the recommendations for the general public. However, when intakes are less than recommendations, some noticeable functional impairments occur. Acute or short-term marginal deficiencies, identified by blood biochemical measures of vitamin B status, had no impacts on performance measures. Severe deprivation of folate and vitamin B12 result in anemia and reduce endurance work performance. Evidence of vitamin A and E deficiencies in athletic individuals is lacking apparently because body storage is appreciable. In contrast to vitamins, marginal mineral deficiencies impair performance. Iron deficiency, with or without anemia, impairs muscle function and limits work capacity. Magnesium deprivation increases oxygen requirements to complete submaximal exercise and reduces endurance performance. Use of vitamin and mineral supplements does not improve measures of performance in people consuming adequate diets. Young girls and individuals participating in activities with weight classifications or aesthetic components are prone to nutrient deficiencies because they restrict food intake and specific micronutrient-rich foods. This information will be useful to professionals who counsel physically active people and scientific groups who make dietary recommendations to improve health and optimize genetic potential.

B vitamins, cognition, and aging: a review.

Recent research has highlighted the potential impact of nutritional factors and individual micronutrients on the brain and on cognitive performance, especially in older adults. The B vitamins, folate, B12, and B6, are of particular interest because even subclinical deficiencies in these vitamins are thought to be relatively common in the general population and in older adults in particular. Recent cross-sectional and longitudinal studies have provided evidence for an association between these B vitamins and many aspects of cognitive performance and have raised the possibility that even subclinical differences in nutritional status may have a subtle influence on aspects of cognitive performance, especially in older adults and in clinical populations. Preliminary evidence also indicates the effectiveness of supplementation in enhancing cognitive performance in older adults. Important considerations for future research include the use of placebo-controlled intervention studies, sensitive outcome measures of cognitive performance, and exploration of bioavailability and dose-response relationships.

Vitamin B status in patients with chronic fatigue syndrome.

Some patients with chronic fatigue syndrome say they benefit from taking vitamin supplements. We assessed functional status for the B vitamins pyridoxine, riboflavin and thiamine in 12 vitamin-untreated CFS patients and in 18 healthy controls matched for age and sex. Vitamin-dependent activities--aspartate aminotransferase (AST) for pyridoxine, glutathione reductase (GTR) for riboflavin, transketolase (TK) for thiamine--were measured in erythrocyte haemolysates before and after in-vitro addition of the relevant vitamin. For all three enzymes basal activity (U/g Hb) was lower in CFS patients than in controls: AST 2.84 (SD 0.62) vs 4.61 (1.43), P < 0.001; GTR 6.13 (1.89) vs 7.42 (1.25), P < 0.04; TK 0.50 (0.13) vs 0.60 (0.07), P < 0.04. This was also true of activated values: AST 4.91 (0.54) vs 7.89 (2.11), P < 0.001; GTR 8.29 (1.60) vs 10.0 (1.80), P < 0.001; TK 0.56 (0.19) vs 0.66 (0.08), P < 0.07. The activation ratios, however, did not differ between the groups. These data provide preliminary evidence of reduced functional B vitamin status, particularly of pyridoxine, in CFS patients.

The role of homocysteine, folate and other B-vitamins in the development of atherosclerosis.

Recently, elevated homocysteine blood concentrations have been identified as an independent risk factor for the development of atherosclerotic lesions. The amino acid homocysteine is metabolized in the human body involving the vitamins folic acid, B12 and B6 as essential cofactors and coenzymes, respectively. There is an inverse relationship between the status of the relevant B-vitamins and the homocysteine blood concentration. Supplementation of these vitamins results in a significant reduction of the homocysteine level. Nutritive amounts seem to be sufficient to obtain this reduction, even in the case of elevated homocysteine levels.

Effect of tobacco extract and N'-nitrosonornicotine on the carcinogen metabolising enzymes under different dietary vitamin B status.

Studies were carried out to evaluate the changes in the phase I and II enzymes of xenobiotic metabolism, on treatment with tobacco extract (TE) and a tobacco specific carcinogen, N'-nitrosonornicotine (NNN) in Sprague-Dawley rats maintained on vitamin B complex sufficient and deficient semi-synthetic diets. Both TE and NNN significantly increased the hepatic and pulmonary phase I enzymes in the vitamin B sufficient (SB+) and deficient (SB-) animals. However, the percent increase in enzyme activities was drastically higher in the SB- treated group as compared to those in the SB(+)-treated group. On the other hand, TE and NNN significantly depressed the liver and lung glutathione (GSH) level and glutathione S-transferase (GST) activity in the SB- animals, while the opposite effect was observed in the SB(+)-treated animals. Furthermore, both the treatments depleted the hepatic pool of vitamin A, with a concurrent increase in that of vitamin C in SB+ and SB- groups.

Vitamins: physiology and deficiency states.

Approximately half of the people in the United States take vitamin supplements, and some use alarmingly high doses. In this article, physiological functions of vitamins and the effects of vitamin deficiencies are summarized. Common food sources of vitamins are listed and a suggested daily eating guide is provided to assist in proper food intake. Adding vitamin supplements to a poor diet may alleviate some symptoms of deficiency, but cannot compensate for the lack of other nutrients. For optimum health, balanced, wholesome meals are recommended.

Vitamin and mineral supplements to athletes: do they help?

Although the general implications of this review would be that vitamin and mineral supplements are ineffective as ergogenic aids when added to the diet of an athlete who is well-nourished, there may be certain instances in which supplementation is warranted. For example, wrestlers on low calorie diets and high levels of energy expenditure may not be receiving a balanced intake of nutrients. Young male athletes and female athletes of all ages should be aware of iron-rich foods and include them in the daily diet. The female athlete who experiences a heavy menstrual flow may consider commercial iron preparations; hemoglobin and other hemotologic variables may be evaluated in order to determine the need for supplementation. More research is needed, particularly with large doses of the vitamin B-complex and vitamin C. Although some of the studies cited herein have used large doses, some athletes have been reported to consume massive dosages, for example, 10,000 mg of vitamin C daily. Unfortunately, there may be some adverse side effects of such massive doses, and it may not be ethical to conduct research with humans at those high intake levels. Do these massive dosages elicit a pharmacodynamic effect on some metabolic reactions that are favorable to physical performance? More research with vitamin E at altitude also appears to be warranted, as does iron supplementation to iron-deficient, but not anemic, athletes. As noted earlier, the current data base suggests that vitamin and mineral supplements are unnecessary for the athlete receiving a balanced diet. However, only with additional controlled research may we expand that data base to help answer some of the questions that still remain relative to nutrition and athletic performance. There are still a large number of athletes who believe that the "racers edge" may be found in a tablet.