Folic Fortification Research Articles

Prenatal folic acid use associated with decreased risk of myelomeningocele: A case-control study offers further support for folic acid fortification in Bangladesh.

Neural tube defects contribute to severe morbidity and mortality in children and adults; however, they are largely preventable through maternal intake of folic acid before and during early pregnancy. We examined the association between maternal prenatal folic acid supplement intake and risk of myelomeningocele (a severe and common type of neural tube defect) in the offspring. We performed secondary analysis using data from a case-control study conducted at Dhaka Community Hospital, Bangladesh between April and November of 2013. Cases and controls included children with and without myelomeningocele, respectively, and their mothers. Cases were identified from local hospitals and rural health clinics served by Dhaka Community Hospital. Controls were selected from pregnancy registries located in the same region as the cases, and matched (1:1) to cases by age and sex.Myelomeningocele in the offspring was confirmed by a pediatrician with expertise in classifying neural tube defects. Maternal prenatal folic acid supplement intake was the main exposure of interest. We estimated crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) using conditional logistic regression analysis. There were 53 pairs of matched cases and controls in our study. Overall, 51% of case mothers reported using folic acid supplements during pregnancy compared to 72% of control mothers (p = 0.03). Median plasma folate concentrations at the time of study visit were 2.79 ng/mL and 2.86 ng/mL among case and control mothers, respectively (p = 0.85). Maternal prenatal folic acid use significantly decreased the odds of myelomeningocele in the offspring (unadjusted OR = 0.42, 95% CI = 0.18–0.96). The association was slightly attenuated after adjusting for maternal age at the time of pregnancy (adjusted OR = 0.43, 95% CI = 0.18–1.02). Our study confirms the protective association between maternal prenatal folic acid supplement use and myelomeningocele among children born in Bangladesh. Our findings point to an overall low folic acid supplement use and low plasma folate concentrations among women of reproductive age in Bangladesh. Mandatory fortification of staple foods with folic acid can address low folate status among women of child-bearing age, and prevent child morbidity and mortality associated with myelomeningocele in Bangladesh.

Safety of folic acid.

There is a large body of literature demonstrating the efficacy of maternal folic acid intake in preventing birth defects, as well as investigations into potential adverse consequences of consuming folic acid above the upper intake level (UL). Recently, two authoritative bodies convened expert panels to assess risks from high intakes of folic acid: the U.S. National Toxicology Program and the UK Scientific Advisory Committee on Nutrition. Overall, the totality of the evidence examined by these panels, as well as studies published since the release of their reports, have not established risks for adverse consequences resulting from existing mandatory folic acid fortification programs that have been implemented in many countries. Current folic acid fortification programs have been shown to support public health in populations, and the exposure levels are informed by and adherent to the precautionary principle. Additional research is needed to assess the health effects of folic acid supplement use when the current upper limit for folic acid is exceeded.

Polyamines, folic acid supplementation and cancerogenesis

AbstractClinical practice and experimental studies have shown the necessity of sufficient quantities of folic acid intake for normal embryogenesis and fetal development in the prevention of neural tube defects (NTDs) and neurological malformations. So, women of childbearing age must be sure to have an adequate folate intake periconceptionally, prior to and during pregnancy. Folic acid fortification of all enriched cereal grain product flour has been implemented in many countries. Thus, hundreds of thousands of people have been exposed to an increased intake of folic acid. Folate plays an essential role in the biosynthesis of methionine. Methionine is the principal aminopropyl donor required for polyamine biosynthesis, which is up-regulated in actively growing cells, including cancer cells. Folates are important in RNA and DNA synthesis, DNA stability and integrity. Clinical and epidemiological evidence links folate deficiency to DNA damage and cancer. On the other hand, long-term folate oversupplementation leads to adverse toxic effects, resulting in the appearance of malignancy. Considering the relationship of polyamines and rapidly proliferating tissues (especially cancers), there is a need for better investigation of the relationship between the ingestion of high amounts of folic acid in food supplementation and polyamine metabolism, related to malignant processes in the human body.

Is High Folic Acid Intake a Risk Factor for Autism?—A Review

Folate is required for metabolic processes and neural development. Insuring its adequate levels for pregnant women through supplementation of grain-based foods with synthetic folic acid (FA) in order to prevent neural tube defects has been an ongoing public health initiative. However, because women are advised to take multivitamins containing FA before and throughout pregnancy, the supplementation together with natural dietary folates has led to a demographic with high and rising serum levels of unmetabolized FA. This raises concerns about the detrimental effects of high serum synthetic FA, including a rise in risk for autism spectrum disorder (ASD). Some recent studies have reported a protective effect of FA fortification against ASD, but others have concluded there is an increased risk for ASD and other negative neurocognitive development outcomes. These issues are accompanied by further health questions concerning high, unmetabolized FA levels in serum. In this review, we outline the reasons excess FA supplementation is a concern and review the history and effects of supplementation. We then examine the effects of FA on neuronal development from tissue culture experiments, review recent advances in understanding of metabolic functional blocks in causing ASD and treatment for these with alternative forms such as folinic acid, and finally summarize the conflicting epidemiological findings regarding ASD. Based on the evidence evaluated, we conclude that caution regarding over supplementing is warranted.

Cautionary Note About Magnitude of Decline in Neural Tube Birth Defects Following Folic Acid Fortification in the United States.

Cautionary Note About Magnitude of Decline in Neural Tube Birth Defects Following Folic Acid Fortification in the United States.

Finding the genetic mechanisms of folate deficiency and neural tube defects-Leaving no stone unturned.

Neural tube defects (NTDs) occur secondary to failed closure of the neural tube between the third and fourth weeks of gestation. The worldwide incidence ranges from 0.3 to 200 per 10,000 births with the United States of American NTD incidence at around 3-6.3 per 10,000 dependent on race and socioeconomic background. Human NTD incidence has fallen by 35-50% in North America due to mandatory folic acid fortification of enriched cereal grain products since 1998. The US Food and Drug Administration has approved the folic acid fortification of corn masa flour with the goal to further reduce the incidence of NTDs, especially among individuals who are Hispanic. However, the genetic mechanisms determining who will benefit most from folate enrichment of the diet remains unclear despite volumes of literature published on studies of association of genes with functions related to folate metabolism and risk of human NTDs. The advances in omics technologies provides hypothesis-free tools to interrogate every single gene within the genome of NTD affected individuals to discover pathogenic variants and methylation targets throughout the affected genome. By identifying genes with expression regulated by presence of folate through transcriptome profiling studies, the genetic mechanisms leading to human NTDs due to folate deficiency may begin to be more efficiently revealed.

A Cross-Sectional Study of Dietary and Genetic Predictors of Blood Folate Levels in Healthy Young Adults.

Since 1998, the U.S. has mandated folic acid (FA) fortification of certain grain products to reduce the risk of neural tube defects. Folate intake and red blood cell (RBC) folate concentrations increased substantially post-intervention, although recent studies raise concerns about the level of ongoing benefit. This study investigated blood folate level determinants in healthy young adults, including intake of naturally occurring food folate, synthetic FA, and the interaction of naturally occurring food folate with a common missense variant in the FOLH1 gene thought to affect absorption. Participants (n = 265) completed the Diet History Questionnaire II, RBC folate testing, and were genotyped for the 484T>C FOLH1 variant. Men reported significantly greater intake of all folate sources except for supplemental FA, but RBC folate levels did not significantly differ by sex. Synthetic FA was a stronger predictor of RBC folate than naturally occurring food folate. In the largest racial group, synthetic FA and the interaction of FOLH1 genotype with naturally occurring food folate significantly predicted RBC folate, with the overall model accounting for 13.8% of the variance in RBC folate levels. Blood folate levels rely on a complex interaction of natural and synthetic folate intake as well as FOLH1 genotype.

Folic Acid in Pregnancy and Childhood Asthma: A US Cohort.

Prenatal folic acid exposure has been linked to higher risk of childhood asthma in countries that do not fortify the food supply with folic acid. This study seeks to examine this association in the United States, where the food supply is generally fortified with folic acid. Participants were 1279 mother-child pairs from Project Viva, an ongoing prospective birth cohort, with folic acid intake in pregnancy assessed through validated food frequency questionnaires. The primary outcome was physician-diagnosed asthma at mid-childhood. In an unadjusted logistic regression model, higher folic acid intake was associated with lower odds of asthma in mid-childhood (odds ratio [OR] 0.48; 95% CI 0.31-0.76). However, in the adjusted analysis this association was attenuated (adjusted OR [aOR] 0.80; 95% CI 0.49-1.33). Our results suggest that in the United States, where there is generalized folic acid fortification of food, maternal folic acid intake during pregnancy is not associated with asthma development in offspring.

Neural tube defects and folic acid in Japan: Prologue introduction ‐ Understanding of the current status of Japan and the proposal from Japanese Teratology Society

Neural tube defects and folic acid in Japan: Prologue introduction ‐ Understanding of the current status of Japan and the proposal from Japanese Teratology Society

A Meta-Analysis of Folic Acid in Combination with Anti-Hypertension Drugs in Patients with Hypertension and Hyperhomocysteinemia.

Folic acid is generally used to lower homocysteine concentrations and prevent stroke and cardiovascular disease (CVD) at present. However, the efficacy of therapies that lower homocysteine concentrations in reducing the risk of CVD and stroke remains controversial. Our objective was to do a meta-analysis of relevant randomized controlled trials (RCTs) to evaluate the efficacy of folic acid supplementation among patients with hypertension and Hyperhomocysteinemia (HT/HHcy). We included RCTs examining the effects of folic acid plus antihypertensive therapy compared to antihypertensive alone. Weighted Mean Difference (WMD) and Relative risk (RR) were used as a measure of the effect of folic acid on the outcome measures with a random effect model. Sixty-five studies including 7887 patients met all inclusion criteria. Among them, 49 trials reported significant effect of combination therapy for reducing SBP (systolic Blood Pressure) and DBP (Diastolic Blood Pressure) levels compared with antihypertensive alone (WMD = −7.85, WMD = −6.77, respectively). Meanwhile, folic acid supplementation apparently reduced the level of total homocysteine (WMD = 5.5). In addition, folic acid supplementation obviously reduced the risk of cardiovascular and cerebrovascular events (CVCE) by 12.9% compared with control groups. In terms of the stratified analyses, a bigger beneficial effect was seen in those RCTs with treatment duration of more than 12 weeks, a decrease in the concentration of total homocysteine of more than 25%, with folic acid fortification. Our findings indicated that folic acid supplementation was effective in the primary prevention of CVCE among HT/HHcy patients, as well as reducing the blood pressure and total homocysteine levels.

Folate Stability in Folic Acid Enriched Corn Masa Flour, Tortillas, and Tortilla Chips over the Expected Shelf Life

Neural tube defects occur at higher rates in Hispanic populations in the United States. Such populations would benefit from folic acid fortification of corn masa flour (CMF). This study evaluated folate stability in fortified CMFs and tortillas and tortilla chips made therefrom. There was no significant loss of folate during the six‐month shelf life of fortified tortilla CMF and tortilla chip CMF. There was a 13% loss (P < 0.05) of folate during tortilla baking and no loss during tortilla chip frying. Both tortillas and tortilla chips showed significant folate losses over the two‐month shelf life for these products, with a 17% loss in fortified tortillas and a 9% loss in tortilla chips. Folate in fortified CMFs, tortillas, and tortilla chips is relatively stable and comparable to the stability of folate in wheat flour and breads.

Large -scale wheat flour folic acid fortification program increases plasma folate levels among women of reproductive age in urban Tanzania.

There is widespread vitamin and mineral deficiency problem in Tanzania with known deficiencies of at least vitamin A, iron, folate and zinc, resulting in lasting negative consequences especially on maternal health, cognitive development and thus the nation’s economic potential. Folate deficiency is associated with significant adverse health effects among women of reproductive age, including a higher risk of neural tube defects. Several countries, including Tanzania, have implemented mandatory fortification of wheat and maize flour but evidence on the effectiveness of these programs in developing countries remains limited. We evaluated the effectiveness of Tanzania’s food fortification program by examining folate levels for women of reproductive age, 18–49 years. A prospective cohort study with 600 non-pregnant women enrolled concurrent with the initiation of food fortification and followed up for 1 year thereafter. Blood samples, dietary intake and fortified foods consumption data were collected at baseline, and at 6 and 12 months. Plasma folate levels were determined using a competitive assay with folate binding protein. Using univariate and multivariate linear regression, we compared the change in plasma folate levels at six and twelve months of the program from baseline. We also assessed the relative risk of folate deficiency during follow-up using log-binomial regression. The mean (±SE) pre–fortification plasma folate level for the women was 5.44-ng/ml (±2.30) at baseline. These levels improved significantly at six months [difference: 4.57ng/ml (±2.89)] and 12 months [difference: 4.27ng/ml (±4.18)]. Based on plasma folate cut-off level of 4 ng/ml, the prevalence of folate deficiency was 26.9% at baseline, and 5% at twelve months. One ng/ml increase in plasma folate from baseline was associated with a 25% decreased risk of folate deficiency at 12 months [(RR = 0.75; 95% CI = 0.67–0.85, P<0.001]. In a setting where folate deficiency is high, food fortification program with folic acid resulted in significant improvements in folate status among women of reproductive age.

The US Food and Drug Administration’s role in improving nutrition: Labeling and other authorities

The US Food and Drug Administration’s Center for Food Safety and Applied Nutrition establishes regulations and guidance to enable consumers to make nutritious, healthy food choices and to protect the public from contaminated or otherwise unhealthy foods. The Center is known for its robust portfolio in the area of food safety, including prevention of foodborne illness, but also in nutrition, which is the emphasis of this overview. The breadth of the agency’s efforts and accomplishments in this and related areas is demonstrated by recent regulations and policies issued on food labeling, trans fat, sodium, folic acid fortification, and inorganic arsenic in foods, each of which is briefly discussed. As this work was presented at the annual meeting of the National Nutrient Databank Conference held in 2016, implications of FDA’s actions for nutrient databases are included as appropriate.

Abstract 5314: Long-term folate intake and prostate cancer risk in the health professionals follow-up study

Abstract Background: Randomized trials of supplemental folate and observational studies of circulating folate support a positive association with prostate cancer risk. However, epidemiological studies of dietary and synthetic folate intake are conflicting. Given mandatory folic acid fortification of grains in the US beginning in 1998, evaluation of long-term folate intake from natural and synthetic sources in relation to prostate cancer risk is warranted. Methods: We examined the association between folate intake and prostate cancer risk among 47,884 men in the Health Professionals Follow-up Study who were free from diagnosed cancer at baseline in 1986. Total, natural (from food sources), and synthetic (from supplements/fortification) folate intake was assessed every 4 years using a validated food frequency questionnaire, and categorized as the cumulative average and lagged (0-4, 4-8, 8-12, and 12-16 years in the past) intakes. Cox proportional hazards regression was used to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (CI). Results: We identified 6,186 incident prostate cancer cases from 1986-2012, including 1,078 with lethal disease (distant metastasis or death). Mean total folate intake was 481 µg/day in 1986 and increased to 671 µg/day by 2010. The proportion of men meeting the recommended intake of 400 µg/day increased from 47% in 1986 to 74% after fortification began in 1998. Folate intake was positively correlated with physical activity, multivitamin use, and PSA testing, and inversely correlated with smoking. Total folate intake averaged over time was not significantly associated with total prostate cancer risk: HR≥800 vs. 400-599=1.03 (95% CI: 0.95-1.13, p-trend=0.76). Neither natural nor synthetic folate intake was associated with risk of total prostate cancer. No associations were observed between total, natural, or synthetic folate intake and risk of lethal, advanced stage, or high-grade disease. Conclusions: Our findings do not support strong associations between intakes of total, natural, or synthetic folate and prostate cancer risk. We found no indication that folate intake of ≥800 µg/day (twice the recommended level) increases prostate cancer risk. Citation Format: Nadine M. Hamieh, Julie L. Batista, Sarah C. Markt, Mary K. Downer, Lorelei A. Mucci, Meir J. Stampfer, Edward L. Giovannucci, Kathryn M. Wilson. Long-term folate intake and prostate cancer risk in the health professionals follow-up study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5314. doi:10.1158/1538-7445.AM2017-5314

A study of plasma folate under the influence of [6S]-5-MTHF in women with 677C→T polymorphism of mthfr with different types of inheritance

Background and purpose: 5,10-Methylenetetrahydrofolate reductase is responsible for the synthesis of 5-methyltetrahydrofolate (5-MTHF). The 677C→T mutation of 5,10-Methylenetetrahydrofolate reductase reduces the activity of this enzyme. The aim of this study was, first, to compare pharmacokinetic parameters of [6S]-5-MTHF and folic acid in women with the homozygous (TT) and wild-type (CC) 677C→T mutation, and second, to explore genotype differences. The metabolism of [6S]-5-MTHF and folic acid was evaluated by measuring plasma folate derivatives.Experimental approach: Healthy females (TT, n = 16; CC, n = 8) received a single oral dose of folic acid (400 microg) and [6S]-5-MTHF (416 microg) in a randomized crossover design.Plasma folate was measured up to 8 h after supplementation. Concentration-time-profile (area under the curve of the plasma folate concentration vs. time), maximum concentration (Cmax) and time-to-reach-maximum (tmax) were calculated.Key results: Area under the curve of the plasma folate concentration vs. time and Cmax were significantly higher, and tmax significantly shorter for [6S]-5-MTHF compared with folic acid in both genotypes. A significant difference between the genotypes was observed for tmax after folic acid only (p &lt; 0.05). Plasma folate consisted essentially of 5-MTHF irrespective of the folate form given. Unmetabolized folic acid in plasma occurs regularly following folic acid supplementation, but rarely with [6S]-5-MTHF.Conclusions and implications: These data suggest that [6S]-5-MTHF increases plasma folate more effectively than folic acid irrespective of the 677C→T mutation of the 5,10-Methylenetetrahydrofolate reductase. This natural form of folate could be an alternative to folic acid supplementation or fortification.

Prevalence of neural tube defect and hydrocephalus in Northern Ghana

Neural tube defects (NTDs) are congenital anomalies of the central nervous system (CNS) which affects approximately one in every thousand pregnancies. The estimates, however, varies from country to country with countries implementing national programmes on folic acid fortification recording lower estimates. Neural tube defects are a common cause of morbidity and mortality especially in low-middle income countries such as Ghana. The study was conducted to determine the prevalence of neural tube defect and hydrocephalus in the only tertiary hospital in northern Ghana. This was a 4-year retrospective study from January 2010 to December 2014. Data regarding the age, sex, clinical diagnosis, and treatment outcomes were all retrieved from the registry of medical records using a simple data form designed for this study. During the study period, there were 35,426 deliveries at the facility with 57 cases of neural tube defects, thus giving a prevalence of 1.6 per 1000 births. They were more males than females with a male: female ratio of 2.4:1. All cases were diagnosed at birth. All the cases reported in this study were open neural tube defect (NTD). The most common defect was hydrocephalus occurring in 33 patients representing 57.9%, with spinal bifida occurring in 21 patients representing 38.6%. Encephalocele or cranium bifida occurred in only 5.3% (3 patients). Among the spinal bifida cases, myelomeningocele occurred in 13 patients (59.1%), with meningocele occurring in 8 patients (40.9%). Case fatality was about 15% of diagnosed cases. The prevalence of NTDs in this study is relatively high compared to earlier studies but, is consistent with other findings in the subregion. Prenatal screening and diagnosis are highly recommended since most women undergo routine ultrasonography as part of antenatal service.Journal of Medical and Biomedical Sciences (2017) 6(1), 18-23Keywords: neural tube defect, prevalence, spinal bifida, Northern Ghana

A TAS2R38 genotype dependent response to mandatory folic acid fortification: A comparison of two elderly cohorts

A TAS2R38 genotype dependent response to mandatory folic acid fortification: A comparison of two elderly cohorts

Genetic Variants Involved in One-Carbon Metabolism: Polymorphism Frequencies and Differences in Homocysteine Concentrations in the Folic Acid Fortification Era.

Folate and other B vitamins are essential co-factors of one-carbon metabolism, and genetic variants, such as polymorphisms, can alter the metabolism. Furthermore, the adoption of food fortification with folic acid showed a decrease of homocysteine concentration. The aim of this study was to investigate the frequencies of the polymorphisms of enzymes and carrier proteins involved in one-carbon metabolism, and to evaluate homocysteine concentrations in the presence of these genetic variants in a population exposed to mandatory food fortification with folic acid. Using data from a population-based cross-sectional study in São Paulo, Brazil, the study population comprised 750 participants above 12 years of age of both genders. A linear regression model was used to evaluate the homocysteine concentrations according to genetic variants and folate level. The results showed that the minor allelic frequencies were 0.33 for MTHFR (rs1801133), 0.24 for MTHFR (rs1801131), 0.19 for MTR (rs1805087), 0.42 for MTRR (rs1801394), 0.46 for RFC1 (rs1051266), and 0.47 for DHFR (19-bp deletion). The genetic variants of MTHFR 677C>T, MTRR 66A>G and RFC-1 80G>A were different according to race. The homocysteine concentrations increased in the CT and TT compared to CC genotypes of polymorphism MTHFR 677C>T in all populations, and differences between the homocysteine concentrations according to the genotypes of MTHFR 677C>T were observed regardless of folate level.

Effects of folic acid fortification on orofacial clefts prevalence: a meta-analysis.

Orofacial clefts (OFC) are the most prevalent craniofacial birth defect. Folic acid (FA) supplementation has been demonstrated as an effective intervention to reduce risk of OFC occurrence. However, the effect of mandatory FA fortification of wheat and/or maize flour on OFC prevalence has shown controversial results among countries adopting this policy. Thus, we performed a meta-analysis to synthesize the available evidence evaluating the global impact of this mandatory policy on OFC occurrence. Literature search in conventional and grey medical/scientific databases showed fifteen studies considering OFC prevalence in pre- and post-fortification periods with FA. The effect of this policy was evaluated by computing relative risk (RR) and separating samples into total OFC, non-syndromic forms, cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO). We found a significant effect of FA fortification only on non-syndromic CL/P (RR=0·88; 95 % CI 0·81, 0·96), whereas neutral effects were detected for total OFC (syndromic plus non-syndromic) and CPO. Our results may reflect the different aetiology of syndromic OFC with respect to non-syndromic forms and the CL/P related to CPO. Although the number of non-syndromic CL/P samples was lower than that for total OFC, the absence of both between-study heterogeneity and publication bias leads us to conclude that FA fortification may have beneficial effects on non-syndromic CL/P.

An overview of folate status in a population-based study from São Paulo, Brazil and the potential impact of 10 years of national folic acid fortification policy.

Food fortification is an important strategy in public health policy for controlling micronutrient malnutrition and a major contributing factor in the eradication of micronutrients' deficiencies. Approximately 50 countries worldwide have adopted food fortification with folic acid (FA). FA fortification of wheat and maize flours has been mandatory in Brazil since 2004. To assess the effect of 10 years of FA food fortification policy on folate status of residents of São Palo, Brazil using a population-based survey. Data were from 750 individuals aged ⩾12 years who participated in a cross-sectional population-based survey in São Paulo city, Brazil. Fasting blood samples were collected, and folate was assayed by affinity-high performance liquid chromatografy method with electrochemical detection. The participants provided information about food intake based on two 24 h dietary recall. Only 1.76% of population had folate deficiency (<6.8 nmol/l). The mean folate concentration was 29.5 (95% confidence interval: 27.3-31.7) nmol/l for all sex-age groups. The mean folate intake for the population was 375.8 (s.e.m.=6.4) μg/day of dietary folate equivalents (DFEs). When comparing folate intake in DFE from food folate and FA from fortified foods, FA contributed 50% or more of the DFE in almost all sex-age groups. The major contributors of folate intake are processed foods made from wheat flour fortified with FA, especially among subjects younger than 20 years old. The deficiency of folate is very low, and food fortification contributed to folate intake and had a notable influence on rankings of food contributors of folate.