Folic Fortification Research Articles

Folate induces stemness and increases oxygen consumption under glucose deprivation by notch-1 pathway activation in colorectal cancer cell.

Evidence for folate's protective effects on neural tube defects led the USA and Chile to start mandatory folic acid (FA) fortification programs, decreasing up to 50%. However, ∼30% of the population consuming fortified foods reach supraphysiologic serum levels. Although controversial, several epidemiological and clinical observations suggest that folate increases cancer risk, giving concern about the risks of FA supplementation. The Cancer stem cells (CSCs) model has been used to explain survival to anticancer therapies. The Notch-1 pathway plays a role in several cancers and is associated with the stemness process. Different studies show that modulation of metabolic pathways regulates stemness capacity in cancer. Supraphysiologic concentrations of FA increase the proliferation of HT-29 cells by Notch-1 activation. However, whether folate can induce a stemness-like phenotype in cancer is not known. We hypothesized that FA protects from glucose deprivation-induced cell death through Notch-1 activation. HT-29 cells were challenged with glucose deprivation at basal (20 nM) and supraphysiological (400 nM) FA and 5-MTHF concentrations. We analyzed changes in stemness-like gene expression, cell death and different energetic metabolic functions. Supraphysiological concentrations of FA increased stemness-like genes, and improved survival and oxygen consumption, inducing AMPK phosphorylation and HSP-70 protein expression. We evaluated the Notch-1 pathway using the DAPT and siRNA as inhibitors, decreasing the stemness-like gene expression and preventing the FA protection against glucose deprivation-induced cell death. Moreover, they decreased oxygen consumption and AMPK phosphorylation. These results suggest that FA protects against glucose deprivation. These effects were associated with AMPK activation, a critical metabolic mediator in nutrient consumption and availability that activates the Notch-1 pathway.

Pediatric reference intervals for serum folate and cobalamin based on a European population without exposure to folic acid fortification

The aim of the present study was to define pediatric reference intervals for serum cobalamin and folate utilizing data generated from a population not exposed to food fortified with folic acid. Folate and cobalamin results analyzed by electrochemiluminescence immunoassay (Roche Cobas) were obtained from 2375 children (2 months to 17.99 years of age). The serum samples were collected between 2011 and 2015 as part of the LIFE (Leipzig Research Centre for Civilization Diseases) Child cohort study in Germany, where folic acid fortification of food is not mandated. These results were used to generate age- and gender-specific reference intervals presented as non-parametric 2.5 and 97.5 percentiles. Because of a subsequent restandardisation of the Roche folate assay in 2016, folate values were recalculated accordingly for adaptation to results obtained using the present calibration. In both genders, folate concentrations decreased continuously with age, whereas cobalamin concentrations peaked at five years of age and then declined. Teenage females had higher concentrations of cobalamin in the age group 12–17.99 years.

Fetal In-Utero Microneurosurgical Repair of Myelomeningocele and Myeloschisis: Neursurgical Outcome Updated

Conference presented at the Brazilian Academy of Neurosurgery Pediatric Symposium on December 9th, 2024. Myelomeningocele (MMC) is recognized as the most prevalent neural tube defect (NTD) and the most complex congenital anomaly that is still consistent with life. In the era of folic acid fortification, its incidence has been observed at 3.4 per 10,000 live births. The observed decrease in incidence is attributed to a synergy of enhanced folate supplementation, along with advancements in prenatal diagnostics, and, in certain cases, the option of selective termination. Recently, innovative technology and growing expertise have sparked considerable excitement within the scientific community regarding fetal MMC repair. In this lecture, Dr. Elbabaa shares his surgical outcomes and provides an updated overview of the current state of the art in this surgical field.

Update on the impact of voluntary folic acid fortification of corn masa flour on red blood cell folate concentrations-National Health and Nutrition Examination Survey, 2011-March 2020.

Folic acid is a micronutrient that is effective at preventing neural tube defects (NTDs). In 2016, the FDA authorized the voluntary fortification of corn masa flour (CMF) with folic acid to reduce disparities in NTDs among infants of women who do not regularly consume other fortified cereal grains, in particular Hispanic women of reproductive age (WRA). We analyzed data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to March 2020 assessing the impact of voluntary fortification of CMF on the folate status of Hispanic WRA. We analyzed folic acid usual intake and red blood cell (RBC) folate concentrations among non-pregnant, non-lactating Hispanic WRA, comparing pre-fortification (2011-2016) to post-fortification (2017-March 2020) data. RBC folate concentrations were used to create model-based estimation of NTD rates. The proportion of Hispanic WRA with folic acid usual intakes <400 μg/d did not change (2011-2016: 86.1% [95% Confidence Interval, CI: 83.7-88.5]; 2017-March 2020: 87.8% [95% CI: 84.8-90.7]; p = .38) nor did the proportion of Hispanic WRA with RBC folate below optimal concentrations (<748 nmol/L, 2011-2016: 16.0% [95% CI: 13.7-18.2]; 2017-March 2020: 18.1% [95% CI: 12.1-24.0]; p = 0.49). Model-based estimates of NTD rates suggest further improvements in the folate status of Hispanic WRA might prevent an additional 157 (95% Uncertainty Interval: 0, 288) NTDs/year. Voluntary fortification of CMF with folic acid has yet to have a significant impact on the folate status of WRA. Continued monitoring and further research into factors such as fortified product availability, community knowledge, and awareness of folic acid benefits would inform and improve future public health interventions.

Dosage exploration of combined B-vitamin supplementation in stroke prevention: a meta-analysis and systematic review

BackgroundThe optimal dosage range for B-vitamin supplementation for stroke prevention has not received sufficient attention. ObjectiveOur aim was to determine the optimal dosage range of a combination of folic acid, vitamin B12, and vitamin B6 supplementation in stroke prevention. MethodsWe searched PubMed, the Cochrane Central Register of Controlled Trials, and Embase database for randomized controlled trials published between January 1966 and April 2023, whose participants received B-vitamin supplementation and that reported the number of stroke cases. Relative risk (RR) was used to measure the effect of combined supplementation on risk of stroke using a fixed-effects model. Risk of bias was assessed with the Cochrane risk-of-bias algorithm. ResultsThe search identified 14 randomized controlled trials of folic acid combined with vitamin B12 and vitamin B6 supplementation for stroke prevention that included 76,664 participants with 2720 stroke cases. In areas without and with partial folic acid fortification, combined B-vitamin supplementation significantly reduced the risk of stroke by 34% [RR: 0.66; 95% confidence interval (CI): 0.50, 0.86] and 11% (RR: 0.89; 95% CI: 0.79, 1.00), respectively. Further analysis showed that a dosage of folic acid ≤0.8 mg/d and vitamin B12 ≤0.4 mg/d was best for stroke prevention (RR: 0.65; 95% CI: 0.48, 0.86) in these areas. In contrast, no benefit of combined supplementation was found in fortified areas (RR: 1.04; 95% CI: 0.94, 1.16). ConclusionsOur meta-analysis found that the folic acid combined with vitamin B12 and vitamin B6 supplementation strategy significantly reduced the risk of stroke in areas without and with partial folic acid fortification. Combined dosages not exceeding 0.8 mg/d for folic acid and 0.4 mg/d for vitamin B12 supplementation may be more effective for populations within these areas.This trial was registered at PROSPERO asCRD42022355077.

Spina Bifida Prevention: A Narrative Review of Folic Acid Supplements for Childbearing Age Women.

Neural tube defects (NTDs) are malformations that occur during embryonic development, and they account for most central nervous system birth anomalies. Genetic and environmental factors have been shown to play a role in the etiology of NTDs. The different types of NTDs are classified according to anatomic location and severity of the defect, with most of the neural axis anomalies occurring in the caudal spinal or cranial areas. Spina bifida is a type of NTD that is characterized by an opening in the vertebral arch, and the level of severity is determined by the extent to which the neural tissue protrudes through the opened arch(es). Prevention of NTDs by administration of folic acid has been studied and described in the literature, yet there are approximately 300,000 cases of NTDs that occur annually, with 88,000 deaths occurring per year worldwide. A daily intake of at least 400 μg of folic acid is recommended especially for women of childbearing age. To provide the benefits of folic acid, prenatal vitamins are recommended in pregnancy, and many countries have been fortifying foods such as cereal grain products with folic acid; however, not all countries have instituted folic acid fortification programs. The present investigation includes a description of the pharmacology of folic acid, neural tube formation, defects such as spina bifida, and the relevance of folic acid to developing spina bifida. Women's knowledge and awareness of folic acid regarding its importance in the prevention of spina bifida is a major factor in reducing incidence worldwide.

Dietary Folate and Cofactors Accelerate Age-dependent p16 Epimutation to Promote Intestinal Tumorigenesis.

Our study demonstrates that dietary folate and cofactors modulate tumor-suppressor gene methylation to increase intestinal tumorigenesis. Our findings highlight the need for monitoring the long-term safety of folate fortification in high-risk individuals.

Relationship of dietary natural folate and synthetic folic acid co-exposure patterns with biological aging: findings from NHANES 2003-2018.

Background: The mandatory folic acid fortification program in the United States has inevitably exposed most Americans to both natural folate and synthetic folic acid. We aim to examine the association of dietary folate co-exposure patterns with biological aging indicators. Methods: A total of 18 889 participants were enrolled from 2003 to 2018. Dietary intake of folate from diverse sources was evaluated by 24-hour dietary recall. Biological aging indicators were developed based on age-related clinical indicators, including the phenotypic age (PA), Klemera-Doubal method (KDM), homeostatic dysregulation (HD), and allostatic load (AL). The unsupervised K-means clustering method, logistic regression model, and restricted cubic spline (RCS) regression model were used to explore the relationship of natural folate and synthetic folic acid co-exposure with biological aging indicators. Results: The results indicated that higher intake of total folate, dietary folate, and food natural folate was associated with lower PA [OR = 0.75 (0.64, 0.88); OR = 0.79 (0.70, 0.90); OR = 0.65 (0.57, 0.75)], KDM [OR = 0.63 (0.53, 0.75); OR = 0.80 (0.65, 0.98); OR = 0.62 (0.49, 0.77)], HD [OR = 0.69 (0.56, 0.84); OR = 0.78 (0.67, 0.92); OR = 0.78 (0.68, 0.90)], and AL [OR = 0.69 (0.58, 0.82); OR = 0.73 (0.63, 0.85); OR = 0.74 (0.62, 0.90)], consistently. Four co-exposure patterns were generated based on the intake of folate from diverse sources, as follows: "low folate exposure group" to cluster 1, "dietary folate exposure group" to cluster 2, "mixed source high folate exposure group" to cluster 3, and "mixed source excessive folate exposure group" to cluster 4. Compared with cluster 1, participants in cluster 2 are associated with lower biological age indicators (ORPA = 0.82 [0.72, 0.93]; ORKDM = 0.58 [0.47, 0.70]; ORHD = 0.85 [0.75, 0.97]; ORAL = 0.87 [0.77, 0.98]), while participants in cluster 3 and cluster 4 are not. Conclusion: For individuals subjected to folic acid fortification programs, a higher intake of dietary folate, especially natural folate, coupled with a lower consumption of folic acid supplements, was found to be associated with lower biological age indicators.

Low-dose daily folic acid (400 μg) supplementation does not affect regulation of folate transporters found present throughout the terminal ileum and colon of humans: a randomized clinical trial

BackgroundFolic acid supplementation during the periconceptional period reduces the risk of neural tube defects in infants, but concern over chronic folic acid exposure remains. An improved understanding of folate absorption may clarify potential risks. Folate transporters have been characterized in the small intestine, but less so in the colon of healthy, free-living humans. The impact of folic acid fortification or supplementation on regulation of these transporters along the intestinal tract is unknown. ObjectiveThe objective was to characterize expression of folate transporters/receptor (FT/R) and folate hydrolase, glutamate carboxypeptidase II (GCPII), from the terminal ileum and throughout the colon of adults and assess the impact of supplemental folic acid. MethodsIn this 16-wk open-labeled randomized clinical trial, adults consumed a low folic acid-containing diet, a folate-free multivitamin, and either a 400 μg folic acid supplement or no folic acid supplement. Dietary intakes and blood were assessed at baseline, 8 wk, and 16 wk (time of colonoscopy). Messenger RNA (mRNA) expression and protein expression of FT/R and GCPII were assessed in the terminal ileum, cecum, and ascending and descending colon. ResultsAmong 24 randomly assigned subjects, no differences in dietary folate intake or blood folate were observed at baseline. Mean ± SD red blood cell folate at 16 wk was 1765 ± 426 and 911 ± 242 nmol/L in the 400 and 0 μg folic acid group, respectively (P < 0.0001). Reduced folate carrier, proton-coupled folate transporter, and folate-receptor alpha expression were detected in the terminal ileum and colon, as were efflux transporters of breast cancer resistance protein and multidrug resistance protein-3. Other than a higher mRNA expression of FR-alpha and GCPII in the 400 μg supplement group in the ascending colon, no treatment differences were observed (P < 0.02). ConclusionsFolate transporters are present throughout the terminal ileum and colon; there is little evidence that a low dose of folic acid supplementation affects colonic absorption.This trial was registered at clinicaltrials.gov as NCT03421483.

Folic acid supplementation use during the peri-conceptional period among professionals of a hospital in France

Folic acid insufficiency is an important risk factor for congenital neural tube defects. Despite recommendations and national campaigns, the proportion of women taking folic acid in the peri-conceptional period remains insufficient worldwide. We describe in this study the proportion of peri-conceptional folic acid supplementation use and its determinants among a population of hospital workers during the course of a prevention campaign. We performed a single-center cross sectional study in a university hospital in France. Data were collected during 2 months in 2019 by an online questionnaire sent to all professionals. We collected information about folic acid supplementation use, its modalities (form, period, frequency and dosage) and reason for initiating or not supplementation. Response rate was 11.4 % (n = 1,075/9,447). Among the 748 women who reported at least one pregnancy, 72.7 % (95 % CI: 69.4–76.0 %) reported taking folic acid during their last pregnancy. Main reason for initiating supplementation was information given by a health professional (87.8 %), especially by gynaecologists-obstetricians. Principal factors associated with folic acid supplementation use were age between 25 and 35 years, high level of education and recent pregnancy. Folic acid supplementation use is still not systematic before and during pregnancy, even among health professionals. There is a case for mandatory folic acid fortification for the French general population.

Global heterogeneity in folic acid fortification policies and implications for prevention of neural tube defects and stroke: a systematic review

Folic acid (pteroylmonoglutamic acid) supplements are highly effective for prevention of neural tube defects (NTD) prompting implementation of mandatory or voluntary folic acid fortification for prevention of NTDs. We used plasma folate levels in population studies by country and year to compare effects of folic acid fortification types (mandatory or voluntary folic acid fortification policies) on plasma folate levels, NTD prevalence and stroke mortality rates. We conducted systematic reviews of (i) implementation of folic acid fortification in 193 countries that were member states of the World Health Organization by country and year, and (ii) estimated population mean plasma folate levels by year and type of folic acid fortification. We identified relevant English language reports published between Jan 1, 1990 and July 31, 2023 using Google Scholar, Medline, Embase and Global Health. Eligibility criteria were observational or interventional studies with >1000 participants. Studies of pregnant women or children <15 years were excluded. Using an ecological study design, we examined the associations of folic acid fortification types with NTD prevalence (n=108 studies) and stroke mortality rates (n=3 countries). Among 193 countries examined up to 31 July 2023, 69 implemented mandatory folic acid fortification, 47 had voluntary fortification, but 77 had no fortification (accounting for 32%, 53% and 15% of worldwide population, respectively). Mean plasma folate levels were 36, 21 and 17nmol/L in populations with mandatory, voluntary and no fortification, respectively (and proportions with mean folate levels >25nmol/L were 100%, 15% and 7%, respectively). Among 75 countries with NTD prevalence, mean (95% CI) prevalence per 10,000 population were 4.19 (4.11-4.28), 7.61 (7.47-7.75) and 9.66 (9.52-9.81) with mandatory, voluntary and no folic acid fortification, respectively. However, age-standardised trends in stroke mortality rates were unaltered by the introduction of folic acid fortification. There is substantial heterogeneity in folic acid fortification policies worldwide where folic acid fortification are associated with 50-100% higher population mean plasma folate levels and 25-50% lower NTD prevalence compared with no fortification. Many thousand NTD pregnancies could be prevented yearly if all countries implemented mandatory folic acid fortification. Further trials of folic acid for stroke prevention are required in countries without effective folic acid fortification policies. Medical Research Council (UK) and British Heart Foundation.

Maternal folic acid supplementation does not impact skeletal muscle function and metabolism in male and female CD-1 mouse offspring.

Folic acid fortification of all white flour, enriched pasta, and cornmeal products became mandatory in Canada to reduce risk of neural tube defects at birth. Furthermore, Health Canada and the Society of Obstetricians and Gynaecologists of Canada recommend women take daily prenatal folic acid supplements in addition to folic acid fortified foods during pregnancy. However, the influence of maternal folic acid supplementation on offspring development, specifically the highly abundant and metabolically active skeletal muscle, is currently unknown. Thus, the purpose of this study was to determine the effect of supplemental folic acid (four times higher than normal dietary consumption), in utero and throughout suckling on muscle size, function, and metabolism in male and female CD-1 mouse offspring. The major findings were that maternal exposure to supplemental folic acid (i) had no impact on postpartum growth rates or muscle mass in female and male offspring, (ii) had no impact on skeletal muscle contractile kinetics in females and male offspring, and (iii) increased maximal phosphofructokinase activity in extensor digitorum longus of female and male offspring. These findings suggest that exposure to folic acid supplementation in utero and throughout suckling at levels four times higher than recommended had minimal effect on skeletal muscle size, function, and metabolism regardless of sex. Future research is needed explore the underlying biological pathways and mechanisms affected by folic acid supplementation during pregnancy and lactation on offspring skeletal muscle tissue, specifically in humans.

MTHFR and risk of stroke and heart disease in a low-folate population: a prospective study of 156 000 Chinese adults.

The relevance of folic acid for stroke prevention in low-folate populations such as in China is uncertain. Genetic studies of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, which increases plasma homocysteine (tHcy) levels, could clarify the causal relevance of elevated tHcy levels for stroke, ischaemic heart disease (IHD) and other diseases in populations without folic acid fortification. In the prospective China Kadoorie Biobank, 156 253 participants were genotyped for MTHFR and 12 240 developed a stroke during the 12-year follow-up. Logistic regression was used to estimate region-specific odds ratios (ORs) for total stroke and stroke types, IHD and other diseases comparing TT genotype for MTHFR C677T (two thymine alleles at position 677 of MTHFR C677T polymorphism) vs CC (two cytosine alleles) after adjustment for age and sex, and these were combined using inverse-variance weighting. Overall, 21% of participants had TT genotypes, but this varied from 5% to 41% across the 10 study regions. Individuals with TT genotypes had 13% (adjusted OR 1.13, 95% CI 1.09-1.17) higher risks of any stroke [with a 2-fold stronger association with intracerebral haemorrhage (1.24, 1.17-1.32) than for ischaemic stroke (1.11, 1.07-1.15)] than the reference CC genotype. In contrast, MTHFR C677T was unrelated to risk of IHD or any other non-vascular diseases, including cancer, diabetes and chronic obstructive lung disease. In Chinese adults, the MTHFR C677T polymorphism was associated with higher risks of stroke. The findings warrant corroboration by further trials of folic acid and implementation of mandatory folic acid fortification programmes for stroke prevention in low-folate populations.

8.A. Round table: An exploration of the EAT Lancet Commission on healthy diets for sustainable food systems

Abstract Sustainable food systems are those that are healthy, sustainable, and equitable, while also addressing environmental challenges. The 2019 EAT-Lancet Commission on Healthy Diets for Sustainable Food Systems provides comprehensive recommendations for transforming the global food system to address malnutrition, reduce the use of antibiotics in animal agriculture, environmental degradation and climate change. However, the implementation of the EAT-Lancet recommendations has been slow and uneven across different regions and sectors. Holistic approaches to achieve food system sustainability are needed, emphasising the interconnectedness of different systems and the need for multidisciplinary approaches. One Health, Health Impact Assessment (HIA), and mandatory food fortification are all approaches that can contribute to the implementation of EAT-Lancet recommendations. The One Health approach recognizes that human health, animal health, and environmental sustainability are interconnected and that collaboration across sectors is necessary to address complex health challenges. By considering the health of animals and the environment in addition to human health, the One Health approach can inform the development of sustainable food systems that promote health for all. Health Impact Assessment (HIA) is a structured process that evaluates the potential health impacts of policies, programs, and projects. HIAs can be used to identify and address potential health risks associated with food systems and help to promote policies and interventions that support healthy and sustainable food systems. Mandatory food fortification is a strategy that involves adding essential vitamins and minerals to food products to address nutrient deficiencies. Mandatory fortification can be used to ensure that essential nutrients are present in the food supply, which can have significant impacts on public health, when consumed passively. The objective of this round table session is to show how multisectoral approaches can be used to achieve better human and planetary health and promote more sustainable and healthy food systems. This session will bring together experts from different disciplines to explore how holistic approaches can promote healthy and sustainable food systems. There will be three short presentations followed by a round table discussion in which the audience is invited to interact with the discussants. First, the One Health approach of AMR will be discussed outlining the need for a binding international legal framework. Second, a presentation on Health Impact Assessment, planning and public health in relation to the food environment in the UK will be conducted. Finally, the case for a mandatory approach of folic acid supplementation in Ireland with strict regulation, monitoring and oversight with penalties for non-compliance by the food industry is presented. Panellists will share lessons learnt from the Netherlands, the UK, Ireland and Bulgaria and the case for EU-wide approaches will be made. Key messages • Holistic approaches to achieve food system sustainability are needed, emphasising the interconnectedness of different systems and the need for multidisciplinary approaches from local to transnational. • There is a clear role for binding international legal frameworks to tackle challenges related to the food system, such as AMR, fast food outlet density and folic acid fortification. Speakers/Panelists Thom Geertsema Groningen Center Health Law, Faculty of Law, University of Groningen, Groningen, Netherlands Ben Cave Ben Cave Associates Ltd, Leeds, UK Mary Rose Sweeney Faculty of Nursing and Midwifery, Royal College of Surgeons in Ireland, Dublin, Ireland Desislava Vankova Medical University of Varna, Varna, Bulgaria Nikhil Gokani University of Essex, Colchester, UK

Prevalence of neural tube defects in England prior to the mandatory fortification of non-wholemeal wheat flour with folic acid: a population-based cohort study

ObjectivesTo determine the baseline trends in the total birth prevalence of neural tube defects (NTDs) in England (2000–2019) to enable the impact of folic acid fortification of non-wholemeal wheat flour...

National Diet and Nutrition Survey data reveal a decline in folate status in the United Kingdom population between 2008 and 2019

BackgroundFolate is essential for healthy growth and development. Fortification of foods with folic acid can improve folate status and reduce risk of neural tube defects (NTD). Following concern around folate status in the United Kingdom, the United Kingdom government announced in 2021 the intention to introduce mandatory folic acid fortification. ObjectiveThis study aimed to describe folate status in the United Kingdom population prior to the implementation of mandatory folic acid fortification of non-whole wheat (non-wholemeal) flour and to assess trends in folate status, including in females of reproductive age (FRA). MethodsData were from the United Kingdom National Diet and Nutrition Survey Rolling Program (2008–2019), a cross-sectional, nationally representative survey of children and adults aged 1.5+ (n = 5792 with folate result). Serum folate concentration was measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) and red blood cell (RBC) folate concentration by microbiological assay. Concentration data were compared against method-specific cut-offs and thresholds, and relationships were explored against demographic and lifestyle characteristics. ResultsRBC and serum folate concentration significantly decreased by ∼3 percentage points per year between 2008 and 2019 in all age/sex groups. Prevalence of deficiency (RBC folate < 305 nmol/L) was highest in children aged 11 to 18 y (17% in 2016–2019). The proportion of FRA below the cut-off for increased risk of NTD (RBC folate < 748 nmol/L) increased from 69% to 89% between 2008 and 2019. Ethnicity, smoking status, and income were significant determinants of RBC and serum folate concentrations. ConclusionsThese data reveal a decline in population folate status in the United Kingdom between 2008 and 2019 and a high prevalence of folate deficiency. A high proportion of FRA had RBC folate concentrations below the cut-off for increased risk of NTD. These data provide information on folate status in a population not currently exposed to mandatory folic acid fortification and are essential to model and assess its impact.

Hispanic Women's Perceptions of Neural Tube Defects and Folic Acid Supplementation: A Qualitative Study

IntroductionIn the United States, the prevalence of neural tube defects (NTDs) is higher among infants born to Hispanic women compared with those born to non-Hispanic women. The purpose of this study is to investigate perceptions of NTDs and the use of folic acid and folate as a preventive measure among Hispanic women. MethodsPurposive sampling was used to recruit Hispanic women from a prenatal clinic in a Northeastern metropolitan city. In-depth interviews were conducted by native Spanish-speaking researchers using a semistructured interview guide. Thematic analysis was used to develop themes related to a priori domains. FindingsThe study sample consisted of 26 Hispanic women representing nine countries of origin. Four themes were revealed: dietary sources of folic acid, awareness of folic acid supplementation and fortification, preferences for receiving health information, and factors in decision-making concerning an NTD diagnosis. ConclusionsThis study highlights the importance of early and targeted educational interventions sensitive to the cultural needs of this population. Results suggest that current NTD health education efforts may not be sufficient to increase our participants’ knowledge of NTD. Additionally, the disparity may be multimodal, potentially influenced by insufficient understanding of prenatal folic acid use and the role of religiosity in decision-making during pregnancy. If Hispanic women are more likely to continue pregnancies affected by NTDs, this factor could be a part of NTD disparities. Exploring factors beyond supplementation and fortification that might influence rates of NTDs at birth in the U.S. Hispanic population can help to inform prevention efforts.

Prepubertal Continuous Dietary Folate Fortification Enhances the Brain Function of Adult Mice by Modulating Antioxidant Status, Inflammation, and Brain Neurotransmitter Levels.

The benefits of folic acid supplementation have been documented in several studies. However, while evidence exists regarding its benefits for growth and haematologic parameters, its possible effects on the brain have been less examined. The study aimed to examine the benefits of dietary folic acid supplementation (beginning in the prepubertal period) on neurobehaviour, oxidative stress, inflammatory parameters, and neurotransmitter levels in adult mice. Forty-eight prepubertal male mice were assigned into four groups of 12 animals each. Mice were grouped into normal control (fed standard diet) and three groups fed folic acid supplemented diet at 2.5, 5, and 10 mg/kg of feed. Animals were fed a standard diet or folic acid-supplemented diet for eight weeks during which food intake and body weight were assessed. On postnatal day 78, animals were exposed to the open-field, Y-maze, radial arm maze, elevated plus maze, bar test, and models of behavioural despair. 24 hours after the last behavioural test, animals were made to fast overnight and then sacrificed by cervical dislocation. Blood was then taken for the assessment of blood glucose, leptin, and insulin levels. Homogenates of brain tissue were prepared and used for the assessment of biochemical parameters. Results showed a concentration-dependent increase in body weight, and improved antioxidant status, memory scores, and acetylcholine levels. Also, a decrease in food intake, blood glucose, insulin, and leptin levels was observed. A reduction in open-field behaviour, anxiety-related behaviour, and proinflammatory markers, was also observed. The beneficial effect of prepubertal continuous dietary folate fortification on the brain (as the animal ages) has been shown in this study.

Folate deficiency increases the incidence of dolutegravir-associated foetal defects in a mouse pregnancy model

Dolutegravir (DTG) is a recommended first-line regimen for all people with Human Immunodeficiency Virus (HIV) infection. Initial findings from Botswana, a country with no folate fortification program, showed an elevated prevalence of neural tube defects (NTDs) with peri-conceptional exposure to DTG. Here we explore whether a low folate diet influences the risk of DTG-associated foetal anomalies in a mouse model. C57BL/6 mice fed a folate-deficient diet for 2 weeks, were mated and then randomly allocated to control (water), or 1xDTG (2.5mg/kg), or 5xDTG (12.5mg/kg) both administered orally with 50mg/kg tenofovir disoproxil fumarate 33.3mg/kg emtricitabine. Treatment was administered once daily from gestational day (GD) 0.5 to sacrifice (GD15.5). Foetuses were assessed for gross anomalies. Maternal and foetal folate levels were quantified. 313 litters (103 control, 106 1xDTG, 104 5xDTG) were assessed. Viability, placental weight, and foetal weight did not differ between groups. NTDs were only observed in the DTG groups (litter rate: 0% control; 1.0% 1xDTG; 1.3% 5xDTG). Tail, abdominal wall, limb, craniofacial, and bleeding defects all occurred at higher rates in the DTG groups versus control. Compared with our previous findings on DTG usage in folate-replete mouse pregnancies, folate deficiency was associated with higher rates of several defects, including NTDs, but in the DTG groups only. We observed a severe left-right asymmetry phenotype that was more frequent in DTG groups than controls. Maternal folate deficiency may increase the risk for DTG-associated foetal defects. Periconceptional folic acid supplementation could be considered for women with HIV taking DTG during pregnancy, particularly in countries lacking folate fortification programs. This project has been funded by Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN275201800001I and award #R01HD104553. LS is supported by a Tier 1 Canada Research Chair in Maternal-Child Health and HIV. HM is supported by a Junior Investigator award from the Ontario HIV Treatment Network.

Periconceptional intakes of methyl donors and other micronutrients involved in one-carbon metabolism may further reduce the risk of neural tube defects in offspring: a United States population–based case-control study of women meeting the folic acid recommendations

BackgroundNeural tube defects (NTDs) still occur among some women who consume 400 μg of folic acid for prevention. It has been hypothesized that intakes of methyl donors and other micronutrients involved in one-carbon metabolism may further protect against NTDs. ObjectivesTo investigate whether intakes of vitamin B6, vitamin B12, choline, betaine, methionine, thiamine, riboflavin, and zinc, individually or in combination, were associated with NTD risk reduction in offspring of women meeting the folic acid recommendations. MethodsData were from the National Birth Defects Prevention Study (United States population–based, case-control). We restricted deliveries between 1999 and 2011 with daily periconceptional folic acid supplementation or estimated dietary folate equivalents ≥400 μg. NTD cases were live births, stillbirths, or terminations affected by spina bifida, anencephaly, or encephalocele (n = 1227). Controls were live births without a major birth defect (n = 7095). We categorized intake of each micronutrient as higher or lower based on a combination of diet (estimated from a food frequency questionnaire) and periconceptional vitamin supplementation. We estimated NTD associations for higher compared with lower intake of each micronutrient, individually and in combination, expressed as odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for age, race/ethnicity, education, and study center. ResultsNTD associations with each micronutrient were weak to modest. Greater NTD reductions were observed with concurrent higher-amount intakes of multiple micronutrients. For instance, NTD odds were ∼50% lower among participants with ≥4 micronutrients with higher-amount intakes than among participants with ≤1 micronutrient with higher-amount intake (adjusted OR: 0.53; 95% CI: 0.33, 0.86). The strongest reduction occurred with concurrent higher-amount intakes of vitamin B6, vitamin B12, choline, betaine, and methionine (adjusted OR: 0.26; 95% CI: 0.09, 0.77) compared with ≤1 micronutrient with higher-amount intake. ConclusionsOur findings support that NTD prevention, in the context of folic acid fortification, could be augmented with intakes of methyl donors and other micronutrients involved in folate metabolism.