The Protective Effect of Maternal Folic Acid Supplementation on Childhood Cancer: A Systematic Review and Meta-analysis of Case-control Studies.

OBJECTIVES: Maternal folic acid supplementation is considered mandatory in almost every country in the world to prevent congenital malformations. However, little is known about the association of maternal folic acid intake with the occurrence of childhood cancer. Hence, this study aimed to determine the effects of maternal folic acid consumption on the risk of childhood cancer. METHODS: A total of 158 related articles were obtained from PubMed, Google Scholar, Scopus, and ProQuest using standardized keywords, of which 17 were included in the final review. RESULTS: Eleven of the 17 articles showed a significant protective association between maternal folic acid supplementation and childhood cancer. Using a random-effects model, pooled odds ratios (ORs) showed a protective association between maternal folic acid supplementation and childhood acute lymphoblastic leukaemia (OR, 0.75; 95% confidence interval [CI], 0.66 to 0.86). However, there was no significant association between maternal folic acid supplementation and acute myeloid leukaemia (OR, 0.70; 95% CI, 0.46 to 1.06) or childhood brain tumours (OR, 1.02; 95% CI, 0.88 to 1.19). CONCLUSIONS: Maternal folic acid supplementation was found to have a protective effect against childhood acute lymphoblastic leukaemia. Thus, healthcare professionals are recommended to provide regular health education and health promotion to the community on the benefits of folic acid supplementation during pregnancy.

Comparison of Nutrient Reference Values for Food Labeling in Japan with CODEX Recommendations, Based on DRIs and Nutrient Intake in Japan.

To clarify the degree of consistency between the international recommendations and the national Japanese system, the nutrient reference values (NRVs) adopted by the CODEX were compared with current Japanese NRVs 2015, the dietary reference intakes for Japanese (DRIs-J) 2015, and actual nutrient intake levels by the Japanese population. The Japanese NRV for protein was high relative to CODEX NRV-R (i.e., NRV-Requirement). The Japanese NRVs for folate and calcium were low, and vitamin K was high, relative to each CODEX NRV-R. However, it was similar to the DRI-J values, and current intake levels for the Japanese population. For iron, calculation methods were different between the CODEX and Japan. Japanese iron NRV was calculated based on the RDA without menstruatating women, whereas CODEX NRV-R was calculated based on the INL98 of all adult men and women. Actual intake levels of iron for the Japanese population were similarly low. The Japanese NRV for sodium was high and potassium was low based on DRI-J values, relative to the CODEX NRV-NCD. For nutrients that show large discrepancies between the CODEX and Japanese NRVs, the values should be discussed further.

Applying inappropriate cutoffs leads to misinterpretation of folate status in the US population.

BACKGROUND: Folate cutoffs for risk of deficiency compared with possible deficiency were originally derived differently (experimental compared with epidemiologic data), and their interpretations are different. The matching of cutoffs derived from one assay with population-based data derived from another assay requires caution. OBJECTIVE: We assessed the extent of folate-status misinterpretation with the use of inappropriate cutoffs. DESIGN: In the cross-sectional NHANES, serum and red blood cell (RBC) folate were first measured with the use of a radioprotein-binding assay (RPBA) (1988-2006) and, afterwards, with the use of a microbiologic assay (2007-2010). We compared prevalence estimates for assay-matched cutoffs (e.g., with the use of an RPBA cutoff with RPBA data) and assay-mismatched cutoffs (e.g., with the use of microbiologic assay cutoff with RPBA data) for risk of deficiency on the basis of megaloblastic anemia as a hematologic indicator in persons ≥4 y of age (e.g., serum folate concentration <7 nmol/L and RBC folate concentration <305 nmol/L derived with the use of a microbiologic assay), possible deficiency on the basis of rising homocysteine as a metabolic indicator in persons ≥4 y of age (e.g., serum folate concentration <10 nmol/L and RBC folate concentration <340 nmol/L derived with the use of an RPBA), and insufficiency on the basis of elevated risk of neural tube defects in women 12-49 y old (e.g., RBC folate concentration <906 nmol/L derived with the use of a microbiologic assay). RESULTS: Pre-folic acid fortification (1988-1994), risks of deficiency for assay-matched compared with assay-mismatched cutoffs were 5.6% compared with 16% (serum folate), respectively, and 7.4% compared with 28% (RBC folate), respectively; risks declined postfortification (1999-2006) to <1% compared with <1% (serum folate), respectively, and to <1% compared with 2.5% (RBC folate), respectively. Prefortification (1988-1994), risks of possible deficiency for assay-matched compared with assay-mismatched cutoffs were 35% compared with 56% (serum folate), respectively, and 37% compared with 84% (RBC folate), respectively; risks declined postfortification (1999-2006) to 1.9% compared with 7.0% (serum folate), respectively, and to 4.8% compared with 53% (RBC folate), respectively. Postfortification (2007-2010), risks of insufficiency were 3% (assay matched) compared with 39% (assay mismatched), respectively. CONCLUSIONS: The application of assay-mismatched cutoffs leads to a misinterpretation of folate status. This confusion likely applies to clinical assays because no comparability data are available, to our knowledge.

Using folic acid-fortified flour should be mandatory policy.

Research published last month states that pregnancy multivitamins do not contribute anything towards boosting the health of mothers and babies.

What is the safe upper intake level of folic acid for the nervous system? Implications for folic acid fortification policies.

Between 1945 and 1959 it was convincingly documented that folic acid can precipitate or aggravate the neurological and haematological consequences of vitamin B12 deficiency by increasing the demand for vitamin B12. Since then there has been much misunderstanding of the issues, mainly by advocates of folic acid fortification who have been inclined to minimise or even dismiss the risks by misinterpreting the evidence as only a 'masking' of the anaemia of pernicious anaemia. Recent studies in the era of fortification are rediscovering the risks to the nervous system, especially cognitive function, of excess folate in the presence of vitamin B12 deficiency. I have reviewed the Reports of four Expert Advisory Committees in Europe and the USA, which suggest that the safe upper tolerable limit (UL) for folic acid is 1 mg in adults. These reports are unsound and there is already evidence of neurological harm from long-term exposure to doses of folic acid between 0.5 and 1 mg in the presence of vitamin B12 deficiency. There is an urgent need to review the safe UL for folic acid and to consider the addition of vitamin B12 to folic acid fortification policies.

A review of European guidelines on periconceptional folic acid supplementation.

Strong evidence that folic acid (FA) prevents the majority of cases of neural tube defects (NTDs) has led to national organisations developing guidelines for women concerning periconceptional supplementation. In Europe, there is evidence of national variations in the incidence of NTDs, with a recent Irish study reporting an increase in the rate. This review compares the periconceptional FA supplementation guidelines between the different countries in Europe. An online search of country-specific guidelines produced before 2015 concerning periconceptional FA supplementation was conducted. If an English version was not available directly, the EUROCAT register was searched for the English version of the recommendations. We identified national guidelines from 20 European countries. Over half recommended that FA supplements be taken by women planning a pregnancy, but three recommended that they should be taken by all women of child-bearing age. Four guidelines recommended starting FA at least 4 weeks preconceptionally, but no country recommended starting FA at least 12 weeks preconceptionally as suggested by recently published studies. There is a need for further consideration of the duration of preconceptional FA supplementation specifically. The latest scientific evidence in this area should inform the development of European guidelines on FA, as there is wide variation in current recommendations. Overall, the wide variation in national guidelines concerning periconceptional FA supplementation may in part explain the differences in national rates of NTDs reported by EUROCAT. National guidelines on FA supplementation should be standardised across European countries.

Critical evaluation of folate data in European and international databases: recommendations for standardization in international nutritional studies.

SCOPE: The objective was to perform an inventory and critical evaluation of folate data in selected European and international databases. The ultimate aim was to establish guidelines for compiling standardized folate databases for international nutritional studies. METHODS AND RESULTS: An ad hoc questionnaire was prepared to critically compare and evaluate folate data completeness, quantification, terminologies, and documentation of 18 European and international databases, and national fortification regulations. Selected countries participated in the European Prospective Investigation into Nutrition and Cancer project and European Food Information Resource Network (EuroFIR). Folate completeness was generally high. "Total folate" was the most common terminology and microbiological assay was the most frequently reported quantification method. There is a lack of comparability within and between databases due to a lack of value documentation, the use of generic or non-appropriate terminologies, folate value conversions, and/or lack of identification of synthetic folic acid. CONCLUSION: Full value documentation and the use of EuroFIR component identifiers and/or INFOODS tagnames for total folate ("FOL") and synthetic folic acid ("FOLAC"), with the additional use of individual folates, will increase comparability between databases. For now, the standardized microbiological assay for total folate and HPLC for synthetic folic acid are the recommended quantification methods.

[Folic acid supplementation--voluntary enrichment of different foodstuffs or mandatory fortification of a single staple food?]. / Folsäure--Freiwilliger Zusatz bei diversen Lebensmitteln oder obligate Anreicherung eines Grundnahrungsmittels?

Regular, customary nutrition is not sufficient to cover the recommended daily intake of 400 microg of folic acid as it has been defined by several scientific committees. The provision of various foodstuffs enriched with folic acid would therefore seem to be justified. Whether such products would have a prophylactic effect against different homocysteine-associated diseases of the second part of life is not (yet) proven but certainly a well founded hypothesis. It has been shown that for the prevention of neural tube defects and other embryonic malformations, as well as malignancies of early childhood a pharmaceutical supply of 0,4-0,8 mg before and during the first 12 weeks of pregnancy is required. Mandatory general fortification of all grain products would be an attractive alternative to meet this goal. This measure has been successful in many countries, mainly on the North American continent. The controversy surrounding possible mandatory folic acid fortification of flour in our country is discussed.

Preventing birth defects with folic acid.

There a few birth defects known to be preventable, but neural tube defects (NTDs) are one group of congenital anomalies that can potentially be prevented. When 400 micrograms of maternal periconceptional folic acid is taken daily, it can prevent many neural tube-related birth defects and thus reduce morbidity and mortality due to these birth defects. Health care providers should encourage every woman of reproductive age to consume 400 micrograms of synthetic folic acid daily, not just those who are planning a pregnancy. Supplementation needs to be started prior to conception for optimal effectiveness.

Micronutrients and genomic stability: a new paradigm for recommended dietary allowances (RDAs).

Diet as a key factor in determining genomic stability is more important than previously imagined because we now know that it impacts on all relevant pathways, namely exposure to dietary carcinogens, activation/detoxification of carcinogens, DNA repair, DNA synthesis and apoptosis. Current recommended dietary allowances for vitamins and minerals are based largely on the prevention of diseases of deficiency such as scurvy in the case of vitamin C. Because diseases of development, degenerative disease and aging itself are partly caused by damage to DNA it seems logical that we should focus better our attention on defining optimal requirements of key minerals and vitamins for preventing damage to both nuclear and mitochondrial DNA. To date, our knowledge on optimal micronutrient levels for genomic stability is scanty and disorganised. However, there is already sufficient evidence to suggest that marginal deficiencies in folate, vitamin B12, niacin and zinc impact significantly on spontaneous chromosome damage rate. The recent data for folate and vitamin B12 in humans with respect to micronucleus formation in blood and epithelial cells provide compelling evidence of the important role of these micronutrients in maintenance of genome integrity and the need to revise current RDAs for these micronutrients based on minimisation of DNA damage. Appropriately designed in vitro studies and in vivo placebo controlled trials with dose responses using a complementary array of DNA damage biomarkers are required to define recommended dietary allowances for genomic stability. Furthermore these studies would have to be targeted to individuals with common genetic polymorphisms that alter the bioavailability of specific micronutrients and the affinity of specific key enzymes involved in DNA metabolism for their micronutrient co-factor. That there is a need for an international collaborative effort to establish RDAs for genomic stability is self-evident.

Commercially available folic acid supplements and their compliance with the British Pharmacopoeia test for dissolution.

A recent report suggested that some folic acid preparations available in the United States failed to meet the specifications for dissolution specified by the US Pharmacopoeia (USP), of 70 per cent drug release in the first hour of testing. The Teratology Society recommends that women of childbearing age should take a daily supplement of 400 microg folic acid when they are trying to conceive, to reduce the risk of foetal neural tube defects. The consequence of this failure to meet the USP requirements may be that an inadequate dose of folate may be absorbed and thus the expected level of protection against neural tube defects not afforded. The purpose of the present study was to examine a number of brands of folic acid (400 microg), available commercially in the United Kingdom, for compliance with the British Pharmacopoeia (BP) test for dissolution. Ten tablets (or capsules) from each of 11 brands were tested using dissolution apparatus compliant with BP requirements, using 0.1 M sodium hydroxide as the dissolution medium. The results indicated that four of the brands failed to release 70 per cent of the nominal drug content in the first hour of test and thus did not comply with the test. Two of the seven brands that passed the test went on to release more than 150 per cent of the nominal 400 microg drug content. These results highlight the problems of dose uniformity and the potential health risks of slow dissolution and under-dosing in commercially available folic acid dosage forms.

Recommended dietary allowances (RDAs) for genomic stability.

Diet as a key factor in determining genomic stability is more important than previously imagined because we now know it impacts on all relevant pathways, i.e. exposure to dietary carcinogens, activation/detoxification of carcinogens, DNA repair, DNA synthesis and apoptosis. Current recommended dietary allowances for vitamins and minerals are based largely on the prevention of diseases of deficiency such as scurvy in the case of Vitamin C. Because diseases of development, degenerative disease and ageing itself are partly caused by damage to DNA, it seems logical that we should focus better our attention on defining optimal requirements of key minerals and vitamins for preventing damage to both nuclear and mitochondrial DNA. To date our knowledge on optimal micronutrient levels for genomic stability is scanty and disorganised. Appropriately designed placebo, controlled trials are required to define recommended dietary allowances for genomic stability. Recently, it has been shown that above RDA intakes of folic acid and Vitamin B12 are required to reduce the micronucleus index in humans by 25%. In the future, clinical trials with a defined wider array of complementary DNA damage end-points would be necessary. That there is a need for an international collaborative group to establish RDAs for genomic stability is self-evident and this paper is a call for such a process to begin.

Non-fasting reference intervals for the Abbott IMx homocysteine and AxSYM plasma folate assays: influence of the methylenetetrahydrofolate reductase 677 C-->T mutation on homocysteine.

Plasma homocysteine comes under both genetic and nutritional control. B vitamins and particularly folate are important factors in homocysteine metabolism. We have obtained reference intervals for total plasma homocysteine and plasma folate. We have also determined the influence of methylenetetrahydrofolate reductase (MTHFR) genotype on plasma homocysteine concentrations in healthy individuals. Reference intervals for Abbott IMx homocysteine and AxSYM plasma folate assays were established using 116 volunteers recruited from hospital staff. Exclusion criteria included cardiac, hepatic or renal disorders, and use of over-the-counter prescription medications. An exception was the inclusion of three women using oral contraceptives and one woman receiving post-menopausal oestrogen supplementation. Methylenetetrahydrofolate reductase 677C-->T genotyping was performed on 101 of the volunteers to determine whether the MTHFR 677T allele influences homocysteine concentrations in healthy individuals. Reference intervals for homocysteine and folate were determined using the mean+/-2 standard deviations of the data. Folate/homocysteine ratios were sorted by MTHFR C677T genotype. Homocysteine correlated negatively with plasma folate. Mean male homocysteine concentrations were significantly higher (9.0 micromol/L; P<0.05) than the mean value (7.1 micromol/L) obtained for females. Mean homocysteine values were significantly higher in subjects who were homozygous for the MTHFR 677T allele when compared with the 677CC genotype (P<0.05). Ratios of folate/homocysteine were 20% and 7.4% lower in the male and female 677TT group than in the 677CC group, respectively. The mean homocysteine value of 43 volunteers who were taking multivitamins was not significantly different from that of 73 who were not vitamin supplemented. Conversely, the mean folate value was slightly greater, and statistically significant, in the group taking vitamin supplements. The mean folate values and reference intervals were not significantly different when grouped by sex or age. MTHFR 677C-->T mutations influenced homocysteine values observed in our study of healthy volunteers, even though we did not observe outright folate-deficient individuals. Our random homocysteine values were similar to the fasting homocysteine values obtained in other studies.

Comparison of Prenate Advance with other prescription prenatal vitamins: a folic acid dissolution study.

Folic acid is important in the prevention of neural tube defects. This study assessed the folic acid dissolution performance of Prenate Advance and six other commonly prescribed prenatal vitamins and compared the results with the United States Pharmacopeia (USP) standards. Of the seven products tested, only three met the USP standard for folic acid dissolution. At 110% of the labeled amount, the Prenate Advance product had the highest folic acid dissolution level. Average dissolution for the four products failing to meet the USP standard ranged from 0% to 38% of labeled amount. These results corroborate findings from other studies suggesting marked differences in dissolution of prescription prenatal vitamins. These findings raise concerns of whether some women could fail to achieve the recommended folate levels needed in early pregnancy to prevent neural tube defects. Prenate Advance met the USP requirement for folic acid dissolution.

Will an increased dietary folate intake reduce the incidence of cardiovascular disease?

Based on a meta-analysis of published studies, it has been estimated that approximately 10% of coronary artery disease cases are attributable to hyperhomocyst(e)inemia. It has also been calculated that food fortification with folate might reduce the number of cases of coronary artery disease in the United States by 50,000 per year. However, the use of statistical concepts to estimate the expected benefits of this intervention strategy may be misleading.

Folic acid fortification.

The relationship of folic acid to neural tube defects has provided us with one of the richest case studies in nutrition science policy of this half century. The concepts of nutritional adequacy in the periconceptual period, the power of well-designed and controlled intervention trials, the challenges of altering the intake of a critical nutrient, the risks and benefits of food fortification, proper targeting with supplementation, and the effectiveness of achieving dietary change are all elements of this case study that we will continue to explore throughout the pages of this journal in the months ahead.

Periconceptional vitamin supplementation to prevent neural tube defects: how can we do it?

The discovery that folic acid can reduce neural tube defect rates offers a great opportunity for primary prevention. Unfortunately, women must receive the folic acid before or immediately after conception, before many know that they are pregnant. Thus, we are faced with a difficult choice: (1) ask all women at risk of getting pregnant to take supplements, or (2) fortify the food supply to ensure that all women at risk receive additional folic acid. Neither approach is ideal. Many women will not take vitamin supplements. Fortification at sufficiently high levels to provide all women with 400 micrograms of folic acid will expose other segments of the population to unacceptably high levels. Because many women of child-bearing age are unaware of the benefits of folic acid, a vigorous education campaign should begin immediately to encourage women at risk to take supplements. Adding 70 micrograms of folic acid per 100 g of grain could be justified easily because this amount is removed from grain in processing. If it is technically feasible, adding up to 140 micrograms is likely to be safe, and could prevent more NTDs. A major educational campaign and modest fortification of grain with folic acid may be the best practical solution.

Current regulatory status of foods for special dietary uses.

The Food and Drug Administration has redefined foods for "special dietary use". Such foods must now: (1) Supply a special dietary need that exists by reason of a physical or physiological condition, such as convalescence, a pregnancy, lactation, or by reason of a specific disease or disorder; (2) Supply a vitamin, mineral, or other dietary property to supplement diet by increasing total dietary intake; (3) Meet a special nutritional need as the sole item of the diet. The stricter definition of this category of food means that the conventional foods with added nutrients or food for which nutritional claims are made or nutritional information provided will no longer be considered as foods for special dietary uses, although they must conform to standard nutritional labeling requirements. The new regulation establishes a clearly delineated position within which the consumer, industry, and FDA can deal with special dietary foods without the past confusion as to what belonged in this category.