Folic Fortification Research Articles

BackgroundCongenital anomalies affect approximately 6% of global births annually and contribute significantly to infant mortality and long-term disability. Low folate status has been linked to malformations such as neural tube defects (NTDs) and orofacial clefts (OFCs). This work aimed to estimate the national prevalence of these two groups of malformations in Chile, a country subjected to mandatory folic acid fortification of flour. We also analyzed the sex dimorphism of the NTD and OFC and described the main associated comorbidities.MethodsIn this cross-sectional descriptive study, we used data from the Chilean National Registry of Congenital Anomalies (2016–2017) to analyze NTD and OFC prevalence and sex bias.ResultsThe study included 3,376 records, revealing a total of 7.63/10,000 births for NTD patients and 12.01/10,000 for OFC patients. Anencephaly and cleft lip/palate were the most prevalent subtypes in the NTD and OFC. Sex-related differences were noted, with a significantly greater prevalence of cleft lip/palate and cleft lip in males and a tendency toward a greater prevalence of anencephaly in females. Approximately 70% of NTD cases were isolated; associated malformations primarily involved the nervous, musculoskeletal, and facial systems. Isolated OFC accounted for 77% of cases, with musculoskeletal and neurological malformations being the most frequently associated.ConclusionsNTD and OFC prevalence and sex-specific variations are consistent with estimates in countries that apply mandatory folic acid fortification policies. This study provides valuable insights into the epidemiology of NTDs and OFCs in Chile and emphasizes the importance of ongoing surveillance through standardized data collection.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12887-025-05999-6.

Neural tube defects (NTDs) are critical birth deformities affecting the central nervous system, causing high morbidity and mortality in sub-Saharan Africa (SSA). This systematic review assesses their prevalence and contributing factors in SSA. Following PRISMA guidelines, databases such as PubMed, Google Scholar, Cochrane Library, AJOL, EMBASE, and Science Direct were searched on January 7, 2025 with additional reference articles and gray literature. Studies published in English from 2010 to 2024 were included. Out of 763 articles, 22 met inclusion criteria. The overall prevalence of NTDs in SSA was 69.8 per 10,000 births (95% CI (confidence interval), 52.8-94.3). Spina bifida had the highest prevalence at 19.43 per 10,000 births (95% CI, 13.76-21.55), anencephaly at 5.77 per 10,000 births (95% CI, 3.22-9.44), and encephalocele at 1.27 per 10,000 births (95% CI, 1.03-3.11). Significant factors associated with NTDs included lack of folic acid supplementation (AOR: 0.42; 95% CI, 0.13-0.98), maternal age > 30 (AOR-Adjusted odds ratio, 2.11; 95% CI, 1.31-7.78), newborn sex (AOR, 3.42; 95% CI, 2.53-8.77), consanguineous marriage (AOR, 2.42; 95% CI, 1.22-8.68), pesticide exposure (AOR, 3.12; 95% CI, 2.33-8.41), maternal alcohol consumption (AOR, 2.42; 95% CI, 1.13-4.98), previous NTD history, radiation exposure (AOR, 2.21; 95% CI, 1.13-3.91), maternal fever (AOR, 3.22; 95% CI, 2.16-5.32), and previous stillbirth history (AOR, 2.55; 95% CI, 2.16-4.11). NTDs remain prevalent in SSA, with many avoidable factors. Folic acid fortification and supplementation for reproductive-age women could significantly reduce the burden of NTDs.

Dietary enhancement of coffee with folic acid: A nutritional approach.

BackgroundNeural tube defects are serious congenital abnormalities caused by abnormal neural tube closure that occur between third and fourth weeks of pregnancy. Globally, neural tube defect is one of the top causes of morbidity and mortality among children under the age of five years. Ethiopia bears the highest adjusted mortality rate attributable to neural tube defects among sub-Saharan African countries. Despite this burden, neural tube defects remain understudied in Tigray, a region recently devastated by conflict.ObjectiveTo assess the prevalence and factors associated with neural tube defect among newborns in public hospitals of Tigray, northern Ethiopia, 2024MethodsA facility based cross sectional study design was conducted among 1155 newborns in randomly selected public hospitals in the Tigray region from April 1 to May 30, 2024. Study participants were selected using a systematic random sampling technique. Data were collected through interviewer-administered, pretested, and structured questionnaires. Variables with a p-value of less than 0.25 in the bivariate logistic regression were included in the multivariable analysis to assess their independent effects. Associations between dependent and independent variables were considered statistically significant at a p-value < 0.05.ResultsThe overall prevalence of neural tube defects in this study was 3%. Residence (AOR=3.37, 95% CI: 1.46-7.77), folic acid supplementation before and during pregnancy (AOR=0.14, 95% CI: 0.06-0.33), having no medical illness during pregnancy (AOR=0.10, 95% CI: 0.04-0.21), food consumption score (AOR=2.90, 95% CI: 1.10-7.82), and alcohol consumption during pregnancy (AOR=2.90, 95% CI: 1.30-6.45) were the determinants for neural tube defects.ConclusionsThe prevalence of neural tube defects is comparatively high among newborns born in Tigray’s public hospitals as compared to previous studies. Residing in rural areas, folic acid supplementation before and during pregnancy, having no medical illnesses during pregnancy, poor food consumption scores, and alcohol consumption during pregnancy were the determinants for neural tube defects. Preventive strategies, such as periconceptional folic acid supplementation, folate fortification, promoting healthy dietary practices, avoiding alcohol consumption, early maternal screening, and treatment of medical illnesses, are essential at both regional and national levels.

Background/Objectives: Gestational diabetes mellitus (GDM) prevalence in Australia has increased from 5.6% (2010) to 19.3% (2022), coinciding with the introduction of mandatory folic acid (FA) food fortification and increased supplementation. Animal studies show that high FA intake in pregnancy impairs maternal glucose regulation, but the underlying mechanisms are unknown. We investigated whether fortification has altered maternal folate status to increase GDM risk, and whether key hormones that regulate maternal glucose homeostasis are affected following FA fortification. Methods: Serum folate, red cell folate (RCF), prolactin (PRL), human placental lactogen (hPL) and placental growth hormone (GH2) were measured in early pregnancy samples from women enrolled in prospective cohorts: SCOPE (N = 1164; pre-fortification) and STOP (N = 1300; post-fortification). Associations with GDM were assessed. Results: Compared to pre-fortification, women post-fortification had a higher GDM incidence (5.0% vs. 15.2%), serum folate (↑ 18%), RCF (↑ 259%), hPL (↑ 29%), and GH2 (↑ 13%) concentrations. RCF concentrations above the clinical reference range were found in 57.6% of women post-fortification. Causal mediation analysis suggests that higher RCF contributed to increased GDM risk. Women with RCF excess had 48% more GDM cases, and higher PRL (↑ 24.2%) and hPL (↑ 12.7%) levels compared to those within the reference range. Conclusions: Maternal folate excess is likely contributing to the rising prevalence of GDM in Australia. These findings highlight the need to evaluate excess FA/folate safety in pregnancy, particularly in countries with mandatory fortification. Placental hormones may represent a mechanistic link between excess folate and GDM, warranting further investigation.

Folate, vitamin B12, one carbon metabolism and the nervous system: Excess folic acid is potentially harmful.

Folic acid supplementation is recommended by WHO for all pregnancies to reduce the risk of neural tube defects and improve neurodevelopmental outcomes. No study to date directly compares the effects on children's outcomes for different folic acid dosages taken by pregnant people with epilepsy. Thus, the optimal folic acid dosing remains unclear, with current guidelines recommending a wide range of doses (.4-5 mg/day). The optimal folic acid dosage is influenced by multiple factors, including dietary intake, food fortification, genetic background, interactions with antiseizure medications, and comorbidities such as anemia or obesity. This study aimed to survey experts on their current clinical practices and recommendations regarding folic acid supplementation dosage for pregnant people with epilepsy. A survey was distributed to expert providers in the international Epilepsy in Childbearing Age through Menopause consortium. The survey collected open-ended responses regarding recommendations and practices for folic acid supplementation in pregnant people with epilepsy, categorizing responses by dosage ranges and clinical scenarios. Fifty-two experts responded to the survey: 42 adult epileptologists, 3 pediatric neurologists, 2 obstetrician/maternal-fetal medicine specialists, 1 epilepsy pharmacist, and 4 unspecified. Geographically, respondents were primarily from North America, a region with mandatory folate fortification, as well as from Northern Europe and Asia, where such practices vary. The majority of the respondents (73.1%, n = 38) recommended folic acid supplementation doses of 1-2 mg/day, with a recommendation of either 1 mg folic acid alone (24/52) or 1 mg folic acid plus prenatal vitamins (12/52). Lower doses (.4-.8 mg/day) were recommended by 15.4% (n = 8). Additionally, 42.3% (n = 22) of respondents recommended individualized dosing strategies, particularly higher doses for patients on valproate (36.5%, n = 19) or enzyme-inducing ASMs (17.3%, n = 9). A small proportion (1.9%, n = 1) recommended routine folate serum level testing to guide supplementation. This international expert survey revealed that folate supplementation was favored at doses of 1-2 mg/day for pregnant people with epilepsy, reflecting a shift away from previously higher-dose practices. Many experts advocated individualized dosing strategies.

Concerns have been raised about potential hazards associated with folic acid fortification. This study aimed to explore associations between diverse folic acid fortification policies (mandatory vs. no mandatory fortification) and global late-onset colorectal cancer (LOCRC) incidence rates. The study systematically assessed (i) folic acid fortification policies in 193 member states of the World Health Organization, and (ii) age-standardized LOCRC incidence rates by country. We examined the associations between folic acid fortification types and LOCRC incidence using an ecological study design. Incidence trends before and after fortification were analyzed using a log-linear joinpoint regression model, and the annual percent change and average annual percent change with 95% confidence interval were determined for representative countries with mandatory fortification (the United States [U.S.] and Canada). By September 2024, 69 countries enacted mandatory folic acid fortification legislation, while 124 had no fortification. The overall LOCRC incidence rates per 100,000 were 70.8 and 84.0 with mandatory and no mandatory fortification, respectively. The decreasing trends after implementing folic acid fortification were more rapid than in the pre-fortification period in the U.S. and Canada. These findings suggested an association between mandatory folic acid fortification policies and reduced LOCRC incidence. These global data provide a scientific basis for transitioning fortification policies and inform strategies for cancer prevention through the fortification with folic acid.

The benefits of folic acid fortification are well known but less understood or acknowledged is the growing evidence of potential harms to the nervous system from excess folate, primarily because of a combination of fortification and/or high and sustained intake of folic acid supplements. We have summarised the historical, clinical, epidemiological and experimental evidence accumulated over the last 60 years in the pre and postfortification eras, which consistently and substantially suggests that excess folate, in particular in folic acid users, can have direct harms to the nervous system, especially in the presence of vitamin B12 deficiency. The harms are related both to the dose and duration of exposure to excess folic acid. Recent experimental evidence suggests that impaired cortical neurogenesis with excess folic acid is similar to that of folate or vitamin B12 deficiency and greatest when folate excess is present with vitamin B12 deficiency. Excess folate leads to a fall in vitamin B12 levels and aggravation of the block in folate metabolism resulting from vitamin B12 deficiency. The balance between folate and vitamin B12 is crucial to the functioning of one carbon metabolic pathways, the methylation cycle and ultimately to DNA and RNA structure and function, genetic and epigenetic stability. Vitamin B12 deficiency is an independent risk factor for NTDs and accounts for the increased risk of NTDs in some countries where B12 deficiency is more common than folate deficiency. A more prudent and balanced approach to fortification with folic acid, or preferably a natural reduced folate, combined with vitamin B12 would potentially improve the benefits and reduce the harms, including epigenetic and transgenerational risks, associated with current public health policies.

Neural tube defects (NTDs) are severe congenital malformations with complex and multifactorial etiologies involving genetic, environmental, and metabolic factors. Despite folic acid fortification efforts, a considerable proportion of cases remains unexplained at the molecular level. This study aimed to identify rare pathogenic variants in patients with NTDs using whole exome sequencing (WES) and to evaluate their functional significance through systems biology approaches. WES was performed on nine unrelated patients with clinically diagnosed NTDs. Variants were filtered using ACMG-AMP criteria and curated via the Franklin by Genoox platform. Genes carrying pathogenic or likely pathogenic variants were analyzed using STRING for protein-protein interactions and Metascape for functional enrichment. Seven genes (PAH, ADGRG6, MPDZ, NARS1, ITGB2, PIGV, and STIL) harbored rare, clinically significant variants. Mutation types included missense, stop-gain, and frameshift, with both heterozygous and homozygous inheritance patterns. STRING analysis revealed a subnetwork involving MPDZ and ITGB2, related to tight junction integrity. Metascape analysis identified enrichment in biological processes such as catecholamine metabolism, floor plate development, and immune regulation. This study supports a polygenic and mechanistically diverse model of NTD pathogenesis, wherein rare variants affect developmental pathways including metabolism, cell adhesion, and neurogenesis. Integrating high-throughput sequencing with systems biology enhances variant interpretation and may inform future diagnostics and prevention strategies.

The relationship between folate and the risk of colorectal cancer (CRC) remains inconclusive. To control for the interference from folic acid fortification, we assessed the relationship between folate intake, serum folate, and red blood cell (RBC) folate levels and the risk of CRC death in a cohort established before fortification. We analyzed the data of 14,528 adults aged 19 years or older who participated in the National Health and Nutrition Examination Survey (1988-1994) as the baseline examination and were followed through December 31, 2006. Hazard ratios (HR) of CRC deaths were estimated for individuals with different folate intake and biomarker levels. Covariates included age, sex, family income, race/ethnicity, cigarette smoking, alcohol drinking, serum cotinine, vitamin supplements, and dietary energy intake. After 192,973 person-years (pys) of follow-up with a mean of 14 years, 78 CRC deaths were recorded. The CRC death rate was 0.75/1000 pys, 0.39/1000 pys, and 0.29/1000 pys for adults with low (lower quarter), moderate, and high (upper quarter) total dietary folate equivalent (tDFE, including both dietary and supplemental intake of folate); the adjusted HR was 0.12 (95% CI = 0.03, 0.45) for adults with high, and 0.51 (0.24, 1.11) for moderate tDFE compared to adults with low tDFE (p for trend = 0.09). Similar trends appeared with statistical significance for serum folate but not for dietary folate intake and RBC folate. With minimum interference from folic acid fortification, high folate intake was found to be associated with a reduced risk of CRC death.

Maternal intake of folic acid prevents most cases of neural tube defects (NTDs), and arsenic exposure may increase NTD risk. In Bangladesh, where arsenic exposures are high, understanding the potential impacts of arsenic reduction and folic acid-based interventions can guide decision-making. We conducted a systematic review and meta-analysis to estimate the prevalence of NTDs in Bangladesh. We searched PubMed, Embase, Web of Science, Global Health, and Bangladesh Journals Online and extracted data using standardized forms. We used forest plots and random effects models to estimate the prevalence of all NTDs and spina bifida. Decision analysis used assumptions from the literature to compare expected NTD prevalence under strategies incorporating combinations of folic acid supplementation, fortification, and arsenic filters. Sensitivity analyses aimed to quantify the influence of adherence to supplements on estimates. Eleven studies were included. Prevalences of NTD and spina bifida were 27.4 and 11.2 per 10,000 births, respectively; however, when estimated from population red blood cell folate concentrations, NTD prevalence was higher in both high arsenic exposure (drinking water ≥ 50 μg/L) and lower arsenic exposure groups (34.3 and 25.3 per 10,000 births, respectively). Folic acid fortification reduced the prevalence of NTDs to 11.1 and 9.1 per 10,000 births among high exposure and low exposure groups, respectively. Arsenic filters provided little marginal benefit. Benefits of supplements equaled those of fortification when adherence to supplements exceeded 90%. Bangladesh has high rates of NTDs and high arsenic exposures. Folic acid fortification is projected to be the most effective strategy for NTD prevention.

Global evaluation of the impact of food fortification with folic acid on rates of schizophrenia.

Background: Spina bifida (SB) is a congenital defect surrounding the development of the spine and spinal cord leading to neurological impairments, influenced by insufficient folic acid (FA) during gestation. Despite the U.S.'s implementation of a ​F​A fortification program in 1998 to reduce the incidence of SB, there continues to be a discrepancy in SB rates between. Hispanic communities and non-Hispanic communities in the nation​, highlighting a need for further exploration​. Objective: This paper explores the factors that contribute to the disproportionately high prevalence of SB in Hispanic communities as compared to the general population in the U.S. after the 1998 fortification program. Methods: A literature review was conducted to assess the disparity in SB prevalence among ethnic groups in the U.S. post-1998, focusing on genetic, socioeconomic, and dietary factors. Results: Analysis of the retrieved literature revealed that the combined effects of genetic, socioeconomic, and dietary factors correlated with a higher prevalence of spina bifida in Hispanic communities as opposed to non-Hispanic communities. Genetic studies highlighted elevated frequencies of the Methylenetetrahydrofolate reductase (MTHFR) gene variants in Hispanic populations. Additionally, socioeconomic disparities and dietary habits underscored challenges in the intake of folic acid and accessibility to fortified foods. Conclusion: The findings in this paper support the following recommendations to help reduce the disproportionately high prevalence of spina bifida in Hispanic communities​ by​; a) expanding the mandatory FA fortification program to include more products that are consumed by the Hispanic community and b) increasing community education about FA fortification.

Abstract Background Baseline folate status is an under–recognized measure of individual health. Folate metabolism is thought to be a metabolic cornerstone in eucaryotic cells and it is committed to ensure proper functioning across a wide spectrum of task encompassing myelinization, endothelial function via 1–carbon–unit metabolism, embryogenesis. It is commonly accepted that folates–deficiency leads to an higher risk of stroke and death this supporting folate fortification. On the other side there is no knowledge of higher folate–status as a risk factor for death. Objective We investigated association between high folate status and mortality risk, by conducting a meta–analysis of studies expressing quartiles of folates. We explored the relationship between folate levels and mortality, focusing on the highest quartile of folate with respect to the sum of second and third quartiles concentrations. Due to significant heterogeneity of involved studies, a meta–regression analysis was performed to evaluate age as a covariate. Methods We included 9 studies in our meta–analysis, encompassing 439,052 person–year, with 7,195 –years events reported. Using a random–effects models, risk ratios (RR) were calculated. Heterogeneity was quantified using tau², I², and Q statistics, while meta–regression was applied to determine whether age influenced the relationship between folate and mortality. Results The random–effect model indicated a statistically significant reduction in mortality risk for intermediate folate status levels with respect to the higher quartile (RR = 0.7575, 95% CI: 0.6167–0.9305, p = 0.0081 – Graph 1.). Nonetheless, a significant heterogeneity across studies (I² = 93.9%, tau² = 0.0797) was found. A meta–regression with age was assessed. Notably, in the meta–regression, age did not emerge as a significant moderator (estimate = 0.0100, p = 0.5875 – Graph.2 ). Conclusions Our findings highlight a relationship between high folate levels and mortality risk. While moderate folate concentrations appear protective. The lack of moderation by age underscores the need to explore subgroup, to explain such heterogeneity. These results have significant public health implications, warranting a reevaluation of folic acid fortification policies and reconsidering baseline higher folate–status as a risk factor for death from any cause. Future research should prioritize identifying subgroups at risk and clarifying the biological mechanisms underlaid.Graph 1 Graph 2

Folate is crucial for various biological processes, with deficiencies during pregnancy being linked to increased risk for neural tube defects and neurodevelopmental disorders. As a proactive measure, folic acid fortification in foods has been mandated in many countries, in addition to dietary supplementation recommendations during pregnancy. However, the risks of excess prenatal folic acid supply have yet to be fully understood. To better appreciate in utero molecular changes in mouse brain exposed to 5-fold folic acid excess over normal supplementation, we investigated the transcriptome and methylome for alterations in gene networks. RNA-seq analysis of cerebral cortex collected at birth, revealed significant expression differences in 646 genes with major roles in protein translation. Whole genome bisulfite sequencing revealed 910 significantly differentially methylated regions with functions enriched in glutamatergic synapse and glutathione pathways. To explore the physiological consequences of excess prenatal folic acid exposure, we applied high-density microelectrode arrays to record network-level firing patterns of dissociated cortical neurons. Folic acid excess-derived cortical neurons exhibited significantly altered network activity, characterized by reduced burst amplitude and increased burst frequency, indicating compromised network synchronization. These functional deficits align with the observed molecular alterations in glutamatergic synapse pathways, underscoring the potential for excess prenatal folic acid exposure to disrupt developing metabolic and neurological pathways.

Folate and vitamin B12 (B12) are essential cofactors in folate-mediated one-carbon metabolism (FOCM). FOCM includes a series of methyl transfer reactions for methionine regeneration and de novo synthesis of nucleotides, including thymidylate. Deficiency in either folate or B12 can result in negative health outcomes including megaloblastic anemia, with additional neurocognitive impairments observed as a result of B12 deficiency. While folate deficiency is not common in the United States due to mandatory folic acid fortification, B12 deficiency is observed more frequently, particularly in certain subpopulations such as vegetarians/vegans and older adults. Fortification of the food supply with folic acid has been effective to increase folate status and reduce the incidence of birth defects. However, consumption of fortified foods and use of dietary supplements containing folic acid have led to an increase in the proportion of individuals exceeding the tolerable upper intake level of folic acid. Although the interaction between folate and B12 has been appreciated for decades in relation to megaloblastic anemia, it has been recently proposed that elevated serum folate may worsen neurocognitive effects and other metabolic impairments (altered glucose homeostasis, type2 diabetes in offspring) associated with B12 deficiency. This review highlights molecular mechanisms that may explain the biology underlying these associations with a focus on findings from studies in model systems.

INTRODUCTION: Thirty years after folic acid (FA) was shown to be effective in reducing spina bifida and anencephaly (SBA) prevalence, only 25% of such births are prevented globally. A public health intervention of adding FA to iodized salt can potentially increase blood folate levels in women of reproductive age and prevent SBA. METHODS: All households in four rural Indian villages agreed to consume FA-fortified iodized salt (study salt) in a pre- and post-intervention study. Pre- and post-intervention serum folate levels were analyzed from 83 eligible participants. A pre- and post-intervention study was done after consumption of approximately 300 mcg of FA daily using double fortified salt (FA + Iodine). We assessed the differences in median serum folate concentrations at baseline and 4 months. RESULTS: The median serum folate concentration increased from 14.6 nmol/L at baseline to 54.4 nmol/L at end of study. Two-tailed Wilcoxon Signed Rank Test showed the difference to be highly significant (p-value = 1.8 × 10-14). The villagers found the salt acceptable in color, taste and cooking properties. No untoward effects related to the study salt were noted. CONCLUSIONS: FA-fortified iodized salt rapidly increases serum folate concentrations in women of reproductive age. This intervention can accelerate birth defects prevention in countries using iodized salt where uniform FA fortification of cereal grains is not feasible.

ObjectiveTo describe the total birth prevalence of neural tube defects (NTDs) in Scotland in 2000–2021.DesignNational, population-based study.SettingScotland, UK.ParticipantsBabies with an NTD and pregnancy outcome of live birth, stillbirth (≥20 weeks’...

Curcuma longa powder was prepared by refractance window drying (RWD) and was fortified. Fortification of dried turmeric powder with folic acid and NaFeEDTA, along with its characterization, was achieved. Characterization techniques, such as FTIR, XRD, TGA, DSC, FESEM, and particle size analysis, have been considered to study the morphological, thermal, and crystalline properties of the resulting fortified turmeric. In vitro digestion studies were carried out to determine the retention of nutrients after fortification. The RW-dried and fortified turmeric powder exhibited a stable average particle size and PDI values in the range of 1500–1600 nm, for 0.25–0.29, respectively. The fortified turmeric powder exhibited enhanced crystalline properties with sharp and high intensity peaks for NaFeEDTA-fortified turmeric powder. In vitro digestion studies affirmed the bio-accessibility of the novel fortified turmeric powder at 9.77 mg/100 g and 12.74 mg/100 g for folic acid and NaFeEDTA fortification cases, respectively. Thus, the findings confirmed that there was no significant influence of fortification on the characteristics of folic acid and the NaFeEDTA-fortified RW-dried turmeric powder product.