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Folic Acid Fortification and Women’s Folate Levels in Selected Communities in Brazil - A First Look
Abstract and Figures
Several countries have implemented mandatory folic acid fortification of wheat flour and selected grain products to increase the folate intake of reproductive-aged women. Brazil implemented a folic acid fortification program in 2004. No previous studies have examined folate differences among Brazilian women following the mandate.
We evaluate differences in serum and red blood cell (RBC) folate concentrations between two samples of women of childbearing age from selective communities in Brazil, one tested before (N = 116) and the other after the mandate (N = 240).
We compared the baseline folate levels of women enrolled in a prevention study shortly before the fortification mandate was implemented, to baseline levels of women from the same communities enrolled in the same study shortly after fortification began. The participants were women enrolled in a folate supplementation clinical trial, at a hospital specializing in treating craniofacial anomalies in the city of Bauru from January 29, 2004 to April 27, 2005. We only compared baseline folate levels before the women received oral cleft prevention program (OCPP) folic acid supplements.
Women enrolled after the fortification mandate had higher means of serum folate (20.3 versus 11.2 nmol/L; p < 0.001) and RBC folate (368.3 versus 177.6 nmol/L; p < 0.001) than women enrolled before the mandate. Differences in folate levels between the two groups remained after adjusting for several co-variables.
The results suggest that serum and RBC folate levels among women of childbearing age increased after implementing the folic acid fortification mandate in Brazil.
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... Plasma folate levels improved remarkably by month six of the study follow up, consistent with the rollout and scale-up of national food fortification program. These findings are consistent with other studies, that assessed the impact of the folic acid fortification programs [30,[43][44][45], where significant increases in folate levels and declines in folate deficiency among women have been reported. A decline in the incidence of neural tube defects in Tanzania can be anticipated based on the decreased prevalence of folate deficiency observed, and in line with a 46% decline in NTD prevalence internationally [25]. ...
... Despite above-mentioned benefits, several countries have not yet mandated fortification due to concerns for potential adverse effects from large-scale population based folic acid fortification [53]. Although the evidence is limited, these concerns include potential masking of vitamin B12 deficiency [54] and presence of unmetabolized folic acid in serum [55], although this has shown to be less likely in countries where increase in folic acid consumption does not exceed 400 μg/d [43]. Supraphysiological, and possibly even physiological, folate status may potentially favour malaria parasite growth and inhibit parasite clearance effect for some antimalarial drugs, hence increasing malaria recrudescence [56].Further risk-benefit analysis for folic acid fortification assessing secondary outcomes of interest such as the masking of B12 deficiency, increased levels of unmetabolized folic acid, and supraphysiologic folate status is warranted and important for future research. ...
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
... Mandatory fortification occurs when a government legally obliges food manufacturers to fortify particular foods or categories of foods with specified micronutrients, e.g. folic acid fortification of wheat flour in order to prevent the occurrence of neural tube defects in newborns was implemented in several countries, including the United States, Canada and Brazil [2,3]. Fortification is voluntary when a food producer freely chooses to fortify particular foods in some nutrients pursuant to the food law [2]. ...
Objective:
To estimate vitamin and mineral intakes from voluntarily fortified foods (VFFs) in relation to the Dietary Reference Intake (DRI) in children aged 6 - 12.
Methods:
The study was conducted among 677 school children from Central-Eastern Poland. Data on VFFs consumption were collected using a semi-quantitative food frequency questionnaire containing 58 food items available on the Polish market; the content of nutrients in VFFs was estimated using the producers labelling declaration. The amounts of nutrients consumed from VFFs were compared to DRI and Tolerable Upper Intake Levels (ULs). The distribution of nutrient intakes according to the percentage of DRI categories (<20%, 20 - 39.9%, 40 - 59.9%, 60 - 79.9%, 80 - 99.9%, 100 - 119%, and >120%) was investigated.
Results:
In our study, 78.3% (n = 530) of children were classified as VFF-consumers. The most often consumed groups of VFFs were cereal products and juices/non-alcoholic beverages (92.5% and 76.6% of children, respectively). The amounts of vitamin D intake were negligible (92.5% of children did not exceed 20% of DRI from VFFs); vitamins A, E, B12 and calcium were small (>60% did not exceed 40% of DRI); vitamins B1, B2, niacin, folic acid, pantothenic acid and iron were moderate (>25% consumed 80% of DRI or above); while vitamins C, B6 and biotin were high (>40% consumed 100% of DRI or above). Intake above ULs was observed for niacin and folic acid (2.6% and 1.1% of children, respectively).
Conclusions:
Substantial differences between the VFFs contribution of various micronutrients to the DRIs were observed. Consumption of VFFs may prevent inadequate intakes for the majority of nutrients.
... 11 In addition, a significant reduction in the prevalence of neural tube defects and related mortality has been shown. 13,14 In the same population, the prevalence of inadequate serum folate levels was low. 15 The purpose of this work was to determine the frequency of folic acid deficiency in consecutive serum folate measurements performed at the Hospital Privado, Universitario de Córdoba in Argentina from 2001 to 2008 (pre-supplementation) and from July 2009 to June 2014 (post-supplementation). ...
Objectives
To determine the frequency of folic acid deficiency in consecutive serum folate determinations and to determine whether there was a significant decrease in serum folate deficiency after folate was added to wheat flour.
Methods
A retrospective descriptive observational study was performed of consecutive folate measurements at the Hospital Privado Universitario, Cordoba, Argentina.
Results
Two cohorts were analyzed: 1197 folate measurements between 2001 and 2008 (before supplementation) and 3335 folate measurements from 2009 to 2014 (after supplementation). Folate deficiency was found in 84/1197 (7%) subjects in the pre-supplementation group and in 58/3335 (1.73%) after supplementation. The prevalence of folate deficiency was 12% between 2001 and 2003 when folate was not added to flour compared to 4% in 2004–2007 (p-value < 0.0001) when folate was added to the flour but no widespread use was documented.
Conclusions
In the studied population, the prevalence of serum folic acid deficiency after folate supplementation was low at 1.73%. There was a significant decrease in folate deficiency after folate was added to wheat flour. Given the low prevalence of folic acid deficiency observed in this and similar studies, and the observed change with supplementation, we conclude that routine measurement of serum folate is of limited clinical use.
... Following this, a 30% reduction in neural tube defects was reported in Western Australia; likely reflecting the combined influence of a folate promotion project and voluntary fortification measures [52]. Similar reductions in neural tube defects were reported in other countries, following mandatory folic acid fortification of staple foods, including Chile (43% reduction after 2000) [53], Brazil (35% reduction after 2004) [54], and South Africa (30% reduction) [55]. ...
Since the early 1990s, maternal folic acid supplementation has been recommended prior to and during the first trimester of pregnancy, to reduce the risk of infant neural tube defects. In addition, many countries have also implemented the folic acid fortification of staple foods, in order to promote sufficient intakes amongst women of a childbearing age, based on concerns surrounding variable dietary and supplementation practices. As many women continue to take folic acid supplements beyond the recommended first trimester, there has been an overall increase in folate intakes, particularly in countries with mandatory fortification. This has raised questions on the consequences for the developing fetus, given that folic acid, a methyl donor, has the potential to epigenetically modify gene expression. In animal studies, folic acid has been shown to promote an allergic phenotype in the offspring, through changes in DNA methylation. Human population studies have also described associations between folate status in pregnancy and the risk of subsequent childhood allergic disease. In this review, we address the question of whether ongoing maternal folic acid supplementation after neural tube closure, could be contributing to the rise in early life allergic diseases.
Background
Childhood acute lymphoblastic leukaemia (ALL) is a heterogeneous disease associated with multiple risk factors including genetic susceptibility. Polymorphisms in folate genes have been associated with a protective effect against ALL, although some studies contradict these findings. We aimed to test whether there is an association between the MTHFR rs1801133 variant and the occurrence of B-cell precursor ALL (BCP-ALL) taking in account molecularly distinct subtypes of fetal origin.
Methods
We performed a case-control genotyping study with 2067 samples, 1309 ALL and 758 controls, from children aged ≤ 15 years for MTHFR rs1801133 polymorphism. Risk associations were calculated by odds ratios estimated with unconditional logistic regression, adjusted for frequency-matched ethnic groups.
Results
Overall, MTHFR rs1801133 does not impact ALL risk in children with more than 6 years of age. A significant positive association for MTHFR rs1801133 variant was found for ALL with KMT2A-r in the dominant model (adj. OR, 1.48, 95 % CI, 1.01–2.17), while ETV6-RUNX1 and Hyperdiploid subgroups have shown a borderline effect (adj. OR, 1.33, 95 % CI, 0.99–1.78).
Conclusions
The polymorphism MTHFR rs1801133 increased the risk of infant ALL in Brazilian population.
Background
Folic acid fortification program has been established to prevent tube defects. However, concern has been raised among patients using anti-folate drug, i.e. psoriatic patients, a common, chronic, autoimmune inflammatory skin disease associated with obesity and smoking.
Objective
To investigate dietary and circulating folate, vitamin B12 (B12) and homocysteine (hcy) in psoriatic subjects exposed to the national mandatory folic acid fortification program.
Methods
Cross-sectional study using the Food Frequency Questionnaire, plasma folate, B12, hcy and psoriasis severity using the Psoriasis Area and Severity Index score. Median, interquartile ranges (IQRs) and linear regression models were conducted to investigate factors associated with plasma folate, B12 and hcy.
Results
82 (73%) mild psoriasis, 18 (16%) moderate and 12 (11%) severe psoriasis. 58% female, 61% non-white, 31% former smokers, and 20% current smokers. Median (IQRs) were 51 (40, 60) years. Only 32% reached the Estimated Average Requirement of folate intake. Folate and B12 deficiencies were observed in 9% and 6% of the blood sample respectively, but hyperhomocysteinaemia in 21%. Severity of psoriasis was negatively correlated with folate and B12 concentrations. In a multiple linear regression model, folate intake contributed positively to 14% of serum folate, and negative predictors were psoriasis severity, smoking habits and saturated fatty acid explaining 29% of circulating folate.
Conclusion
Only one third reached dietary intake of folate, but deficiencies of folate and B12 were low. Psoriasis severity was negatively correlated with circulating folate and B12. Stopping smoking and a folate rich diet may be important targets for managing psoriasis.
Fortification of food products of mass consumption with vitamins is a modern, most cost-effective, efficient and physiological way to improve the vitamin status of the population. Free or voluntary enrichment on the initiative of producers is used in the industrialized countries at low risk for inadequate population intake of micronutrients. Enrichment of products of mass consumption is almost always mandatory, legislative consolidated, while target enrichment of foods intended for different groups can be both mandatory and voluntary. The criteria for the effectiveness of mandatory food fortification are an increase of certain vitamin consumption, reduce of the relative number of people with inadequate intake of certain micronutrients, improvement of micronutrient sufficiency (blood level), enhancement of biomarkers of some alimentary diseases, reduction of the frequency of congenital defects (neural tube defect). Assessment of risk/benefit ratio indicates safety of mandatory fortification of flour with B vitamins. In Russia, the regulatory framework for food fortification (enrichment levels, forms of vitamins) has been yet laborated. But initiative enrichment, held in Russia, does not give the desired result. An urgent need for legislative mandatory fortification of products consumed by the majority of the population (bread, milk) with B vitamins (the lack of which is the most frequently detected in the population of Russia) arose in a lack of knowledge of the population about the benefits of fortified foods and lack of preference in the selection of such products.
This cross-sectional study analyzed the prevalence and spatial distribution of neural tube defects before and after folic acid flour fortification. The study used the Information System on Live Births (SINASC) and presented prevalence rates according to maternal characteristics with odds ratios (OR) and 95% confidence intervals (95%CI). Polynomial regression was used in time trend analysis and empirical Bayesian smoothed maps for spatial analysis. Total prevalence of neural tube defects decreased by 35%, from 0.57/1,000 to 0.37/1,000 live births after fortification (OR = 0.65; 95%CI: 0.59-0.72). There was a reduction among newborns of mothers with the following characteristics: all age groups (except
Scientific evidence supports a number of roles for folate in maintaining health from early life to old age. Folate is required for one-carbon metabolism, including the remethylation of homocysteine to methionine; thus elevated plasma homocysteine reflects functional folate deficiency. Optimal folate status has an established role in preventing NTD and there is strong evidence indicating that it also has a role in the primary prevention of stroke. The most important genetic determinant of homocysteine in the general population is the common 677C → T variant in the gene encoding the folate-metabolising enzyme, MTHFR; homozygous individuals (TT genotype) have reduced enzyme activity and elevated plasma homocysteine concentrations. Meta-analyses indicate that the TT genotype carries a 14 to 21 % increased risk of CVD, but there is considerable geographic variation in the extent of excess CVD risk. A novel interaction between this folate polymorphism and riboflavin (a co-factor for MTHFR) has recently been identified. Intervention with supplemental riboflavin targeted specifically at individuals with the MTHFR 677TT genotype was shown to result in significant lowering of blood pressure in hypertensive people and in patients with CVD. This review considers the established and emerging roles for folate throughout the lifecycle, and some public health issues related to optimising folate status.
Objectives:
To evaluate the effects of folic acid supplementation on isolated oral cleft recurrence and fetal growth.
Patients and methods:
The study included 2,508 women who were at-risk for oral cleft recurrence and randomized into two folic acid supplementation groups: 0.4 and 4 mg per day before pregnancy and throughout the first trimester. The infant outcome data were based on 234 live births. In addition to oral cleft recurrence, several secondary outcomes were compared between the two folic acid groups. Cleft recurrence rates were also compared to historic recurrence rates.
Results:
The oral cleft recurrence rates were 2.9% and 2.5% in the 0.4 and 4 mg groups, respectively. The recurrence rates in the two folic acid groups both separately and combined were significantly different from the 6.3% historic recurrence rate post the folic acid fortification program for this population (p = 0.0009 when combining the two folic acid groups). The rate of cleft lip with palate recurrence was 2.9% in the 0.4 mg group and 0.8% in the 4 mg group. There were no elevated fetal growth complications in the 4 mg group compared to the 0.4 mg group.
Conclusions:
The study is the first double-blinded randomized clinical trial (RCT) to study the effect of high dosage folic acid supplementation on isolated oral cleft recurrence. The recurrence rates were similar between the two folic acid groups. However, the results are suggestive of a decrease in oral cleft recurrence compared to the historic recurrence rate. A RCT is still needed to identify the effect of folic acid on oral cleft recurrence given these suggestive results and the supportive results from previous interventional and observational studies, and the study offers suggestions for such future studies. The results also suggest that high dosage folic acid does not compromise fetal growth.
This cross-sectional study analyzed the prevalence and spatial distribution of neural tube defects before and after folic acid flour fortification. The study used the Information System on Live Births (SINASC) and presented prevalence rates according to maternal characteristics with odds ratios (OR) and 95% confidence intervals (95%CI). Polynomial regression was used in time trend analysis and empirical Bayesian smoothed maps for spatial analysis. Total prevalence of neural tube defects decreased by 35%, from 0.57/1,000 to 0.37/1,000 live births after fortification (OR = 0.65; 95%CI: 0.59-0.72). There was a reduction among newborns of mothers with the following characteristics: all age groups (except < 15 years), more than three years of schooling, and seven or more prenatal visits. There was a reduction over time and in most of São Paulo State, except in a few municipalities (counties) located in the western region of the State. Other factors may have contributed to the observed decline, but the results corroborate flour fortification as an important measure to prevent neural tube defects. Further research is needed to elucidate the lack of a decline in neural tube defects in the western part of São Paulo State.
Background:
Oral clefts are one of the most common birth defects with significant medical, psychosocial, and economic ramifications. Oral clefts have a complex etiology with genetic and environmental risk factors. There are suggestive results for decreased risks of cleft occurrence and recurrence with folic acid supplements taken at preconception and during pregnancy with a stronger evidence for higher than lower doses in preventing recurrence. Yet previous studies have suffered from considerable design limitations particularly non-randomization into treatment. There is also well-documented effectiveness for folic acid in preventing neural tube defect occurrence at 0.4 mg and recurrence with 4 mg. Given the substantial burden of clefting on the individual and the family and the supportive data for the effectiveness of folic acid supplementation as well as its low cost, a randomized clinical trial of the effectiveness of high versus low dose folic acid for prevention of cleft recurrence is warranted.
Methods/design:
This study will assess the effect of 4 mg and 0.4 mg doses of folic acid, taken on a daily basis during preconception and up to 3 months of pregnancy by women who are at risk of having a child with nonsyndromic cleft lip with/without palate (NSCL/P), on the recurrence of NSCL/P. The total sample will include about 6,000 women (that either have NSCL/P or that have at least one child with NSCL/P) randomly assigned to the 4 mg and the 0.4 mg folic acid study groups. The study will also compare the recurrence rates of NSCL/P in the total sample of subjects, as well as the two study groups (4 mg, 0.4 mg) to that of a historical control group. The study has been approved by IRBs (ethics committees) of all involved sites. Results will be disseminated through publications and presentations at scientific meetings.
Discussion:
The costs related to oral clefts are high, including long term psychological and socio-economic effects. This study provides an opportunity for huge savings in not only money but the overall quality of life. This may help establish more specific clinical guidelines for oral cleft prevention so that the intervention can be better tailored for at-risk women. CLINICALTRIALS.GOV IDENTIFIER: NCT00397917.
The Oral Cleft Prevention Program (OCPP) is a double-blind, randomized, two-arm multi-site clinical trial designed to assess the effect of periconceptional daily folic acid supplementation (4.0 mg vs. 0.4 mg) on the recurrence of cleft lip, with or without cleft palate, among women with elevated risk. Conducted in seven sites in Brazil, the OCPP randomized 2,510 women in the trial (1,257 to the 4.0 mg group, and 1,253 to the 0.4 mg group). A Data Coordinating Center (DCC), located in the United States, is responsible for the trial's statistical design and analysis, data collection system, data management and storage, activity coordination, data quality control, and site training. DCCs of international trials, such as the OCPP, face unique implementation challenges due to de-centralized organization. The objective of this paper is to describe these challenges and to present the innovative solutions developed to address them.
A randomised double-blind prevention trial with a factorial design was conducted at 33 centres in seven countries to determine whether supplementation with folic acid (one of the vitamins in the B group) or a mixture of seven other vitamins (A, D, B1, B2, B-6, C, and nicotinamide) around the time of conception can prevent neural tube defects (anencephaly, spina bifida, encephalocele). A total of 1817 women at high risk of having a pregnancy with a neural tube defect, because of a previous affected pregnancy, were allocated at random to one of four groups - namely, folic acid, other vitamins, both, or neither. 1195 had a completed pregnancy in which the fetus or infant was known to have or not have a neural tube defect; 27 of these had a known neural tube defect, 6 in the folic acid groups and 21 in the two other groups, a 72% protective effect (relative risk 0.28, 95% confidence interval 0.12-0.71). The other vitamins showed no significant protective effect (relative risk 0.80, 95% Cl 0.32-1.72). There was no demonstrable harm from the folic acid supplementation, though the ability of the study to detect rare or slight adverse effects was limited. Folic acid supplementation starting before pregnancy can now be firmly recommended for all women who have had an affected pregnancy, and public health measures should be taken to ensure that the diet of all women who may bear children contains an adequate amount of folic acid.
Several studies report socioeconomic inequalities in child health and consequences of early disease. However, not much is known about inequalities in health capital accumulation in the womb in response to fetal health shocks, which is essential for finding the earliest sensitive periods for interventions to reduce inequalities. We identify inequalities in birth weight accumulation as a result of fetal health shocks from the occurrence of one of the most common birth defects, oral clefts, within the first 9 weeks of pregnancy, using quantile regression and two datasets from South America and the USA. Infants born at lower birth weight quantiles are significantly more adversely affected by the health shock compared with those born at higher birth weight quantiles, with overall comparable results between the South American and US samples. These results suggest that fetal health shocks increase child health disparities by widening the spread of the birth weight distribution and that health inequalities begin in the womb, requiring interventions before pregnancy. Copyright © 2013 John Wiley & Sons, Ltd.
In the past, food fortification along with nutritional education and the decrease in food costs relative to income have proven successful in eliminating common nutritional deficiencies. These deficiencies such as goiter, rickets, beriberi, and pellagra have been replaced with an entirely new set of emergent deficiencies that were not previously considered a problem [e.g., folate and neural tube defects (NTDs)]. In addition, the different nutrition surveys in so-called affluent countries have identified shortfalls of nutrients specific to various age groups and/or physiological status. Complex, multiple-etiology diseases, such as atherosclerosis, diabetes, cancer, and obesity have emerged. Food fortification has proven an effective tool for tackling nutritional deficiencies in populations; but today a more reasonable approach is to use food fortification as a means to support but not replace dietary improvement strategies (i. e. nutritional education campaigns). Folic acid (FA) is a potential relevant factor in the prevention of a number of pathologies. The evidence linking FA to NTD prevention led to the introduction of public health strategies to increase folate intakes: pharmacological supplementation, mandatory or voluntary fortification of staple foods with FA, and the advice to increase the intake of folate-rich foods. It is quite contradictory to observe that, regardless of these findings, there is only limited information on food folate and FA content. Data in Food Composition Tables and Databases are scarce or incomplete. Fortification of staple foods with FA has added difficulty to this task. Globally, the decision to fortify products is left up to individual food manufacturers. Voluntary fortification is a common practice in many countries. Therefore, the worldwide map of vitamin fortification may be analyzed. It is important to examine if fortification today really answers to vitamin requirements at different ages and/or physiological states. The real impact of vitamin fortification on some key biomarkers is also discussed. An important question also to be addressed: how much is too much? It is becoming more evident that chronic excessive intakes may be harmful and a wide margin of safety seems to be a mandatory practice in dietary recommendations. Finally, the risk/benefit dilemma is also considered in the new FA-fortified world.
The Australian government recently introduced mandatory folic acid fortification of bread to reduce the incidence of neural tube defects (NTDs). The economic evaluation of this policy contained a number of limitations. This study aimed to address the limitations and to reconsider the findings. Cost-effectiveness analysis was used to assess the cost and benefits of mandatory versus voluntary folic acid fortification. Outcomes measures were quality-adjusted life-years (QALYs), life-years gained (LYG), avoided NTD cases, and additional severe neuropathy cases. Costs considered included industry costs and regulatory costs to the government. It was estimated that mandatory fortification would prevent 31 NTDs, whereas an additional 14 cases of severe neuropathy would be incurred. Overall, 539 LYG and 503 QALYs would be gained per year of mandatory compared with voluntary fortification. Mandatory fortification was cost-effective at A$10,723 per LYG and at A$11,485 per QALY. Probabilistic sensitivity analysis showed that at A$60,000 and A$151,000 per QALY, the probability that mandatory fortification was the most cost-effective strategy was 79% and 85%, respectively. Threshold analysis of loss of consumer choice indicated that with a compensation value above A$1.21 [assuming a willingness to pay (WTP) threshold of A$60,000 per QALY] or A$3.19 (assuming a WTP threshold of A$151,000 per statistical life-year) per capita per year mandatory fortification would not be cost-effective. Mandatory fortification was found to be cost-effective; however, inclusion of the loss of consumer choice can change this result. Even with mandatory fortification, mean folate intake will remain below the recommended NTD preventive level.