Folate fortification for spina bifida: preventing neural tube defects.

Neural tube defects (NTDs), such as spina bifida and anencephaly, are severe congenital anomalies affecting the development of the brain and spine. These conditions are often linked to folic acid deficiency during early pregnancy, a modifiable risk factor. While high-income countries have implemented mandatory folic acid fortification in staple foods, resulting in significant reductions in NTD prevalence, low- and middle-income countries (LMICs) continue to experience disproportionately high rates of these birth defects. Folic acid supplementation and fortification are proven interventions for preventing NTDs, but many LMICs face political, financial, and logistical barriers to implementing these programs. This paper highlights the importance of mandatory folic acid fortification as a cost-effective public health intervention and advocates for its expansion in LMICs. It reviews the successes of fortification programs in high-income countries, explores alternative food vehicles like rice for regions with different dietary staples, and discusses the potential of multi-nutrient fortification strategies. Additionally, this paper emphasizes the need for global collaboration, enhanced monitoring and evaluation, and public health education campaigns to ensure that women of reproductive age, especially in LMICs, receive adequate folic acid. By addressing these challenges, the global health community can significantly reduce the incidence of NTDs, improve maternal and child health, and promote health equity worldwide. The time to act is now, as the benefits of folic acid fortification far outweigh the costs of inaction.

Improvement of serum folate status in the US women of reproductive age with fortified iodised salt with folic acid (FISFA study).

OBJECTIVE: Mandatory folic acid fortification of enriched grains has reduced neural tube defect prevalence in several countries. We examined salt as an additional vehicle for folic acid fortification. The primary objective was to examine the change in serum folate concentration after 1 month of consumption of fortified iodised salt with folic acid (FISFA) among women of reproductive age. The secondary objectives were to examine (1) the feasibility of implementing FISFA intervention and (2) the acceptability of FISFA. DESIGN: We conducted a pre­post intervention study (January­April 2023). Participants received a FISFA saltshaker with the study salt (1 g of sodium chloride salt fortified with 100 mcg of folic acid) to use instead of regular table salt for 1 month. Serum folate was measured using the Elecsys Folate-III immunoassay method at baseline and 1-month endpoint. Change in serum folate was assessed using a two-tailed Wilcoxon signed rank test for paired samples. SETTING: Metropolitan city, Southern USA. PARTICIPANTS: Non-pregnant, 18­40-year-old women who lived alone/with a partner. RESULTS: Thirty-two eligible women consented to participate, including eleven non-Hispanic-White, eleven non-Hispanic-Black and ten Hispanic. Post-intervention, there was a significant increase in median serum folate concentration of 1·40 nmol/l (IQR 0·74­2·05; P < 0·001) from 24·08 nmol/l to 25·96 nmol/l in an analytical sample of n 29. An increase was seen in 28/29 (93 %) participants. Feasibility: 100 % study consent and compliance. FISFA acceptability: 25 d average use; 1·28 g average daily intake; 96·7 % and 90 % reported taste and colour of FISFA as highly acceptable, respectively. CONCLUSIONS: FISFA is an effective approach to increasing serum folate concentrations among women of reproductive age. Findings should be replicated in a larger study.

Folic acid supplementation during fattening period affects growth and nutritional metabolism in Japanese Black beef cattle.

The folate requirements for beef cattle have not been established. Therefore, we investigated whether rumen-unprotected folic acid supplementation during the fattening period affects carcass traits and nutritional metabolism in Japanese Black beef cattle. Eighteen Beef cattle aged 16 months were divided into three groups: control, low folic acid supplementation (0.43 g DM/day), and high folic acid supplementation (0.86 g DM/day). Treatment was administered for 12 months. Folic acid supplementation dose-dependently increased serum folate levels, suggesting that supplemental folic acid can be absorbed into the body. Folic acid supplementation dose-dependently decreased serum vitamin B12 levels, while plasma total homocysteine and methylmalonic acid levels-markers for deficiency of folate and/or vitamin B12-were unaffected. Thus, the treatment did not clearly affect the nutritional status of these vitamins. Supplementation increased body weight, with no negative effects on other carcass traits. The levels of insulin-like growth factor 1, retinol, albumin, and some amino acids in serum or plasma were affected by supplementation. These results suggest that rumen-unprotected folic acid supplementation during the fattening period could increase the body weight of Japanese Black beef cattle and the mechanism of action may be related to growth-related hormones and/or the metabolism of some nutrients, including folate.

Protocol for a community-based, household-randomised, dose-response trial to assess the acceptability, nutritional effects and safety of double-fortified salt containing iodine and folic acid compared with iodised salt among non-pregnant Ethiopian women of reproductive age (DFS-IoFA).

INTRODUCTION: The prevalence of neural tube defects (NTDs) is higher in Ethiopia than most other countries, and ~84% of Ethiopian women of reproductive age (WRA) have folate insufficiency, a major risk factor for NTDs. Salt fortification with folic acid is a potential strategy to improve women's folate status, but data are needed on the acceptability, nutritional impact and safety of folic acid fortification of iodised salt. METHODS AND ANALYSIS: The study is designed as a community-based, household-randomised, dose-response trial. A total of 360 non-pregnant WRA 18-49 years of age will be randomly assigned to one of three intervention arms: (1) iodised salt fortified with 30 ppm folic acid to provide ~200 µg folic acid/day; (2) iodised salt fortified with 90 ppm folic acid to provide ~600 µg folic acid/day; or (3) iodised salt (comparator). The preweighed salts will be delivered to participants' homes biweekly for 26 weeks; unused salt will be collected and weighed. Fasting, venous blood samples will be collected at baseline, end line and a randomly assigned intermediate time point for assessment of folate, iodine, vitamin B12 and other micronutrient status biomarkers. Women's dietary intakes, including discretionary salt consumption, will be measured using weighed food records; 24-hour urine specimens will be analysed for sodium and iodine excretion. Primary outcomes are women's consumption of study salts, change in biomarkers of folate and iodine status and prevalence of adverse events. Results will be analysed using analysis of covariance models to estimate group mean differences for continuous outcomes, controlling for baseline measurements, and log-binomial or modified Poisson regressions for categorical outcomes. Prespecified effect modifications will be explored. ETHICS AND DISSEMINATION: The study has been approved by the Ethiopian Public Health Institute's Institutional Review Board, and the protocol has been registered with ClinicalTrials.gov (registration number NCT06223854). Study results will be published in open access scientific journals and disseminated nationally in Ethiopia. TRIAL REGISTRATION NUMBER: NCT06223854.

Routine uptake of prenatal iron-folic acid supplementation and associated factors among pregnant women in peri-urban areas of Dodoma City, Tanzania: a cross-sectional study.

BACKGROUND: The physiological requirements for iron and folic acid in pregnancy are a significant challenge to achieve through normal dietary intake, especially in low resource settings. The World Health Organization recommends daily oral iron and folic acid supplementation (IFAS) to prevent maternal anaemia and related adverse effects in community settings where the prevalence of anaemia during pregnancy is > 40%. The objective of this study was to assess the routine uptake of prenatal iron-folic acid supplementation and associated factors among pregnant women at peri-urban areas of Dodoma City, Tanzania. METHODS: A cross-sectional study was conducted in peri-urban areas. Data was collected through face-to-face interviews and review of records from maternal clinic card (RCH 4 card). Routine uptake of iron-folic acid supplementation was defined as pregnant woman who reported taking iron-folic acid supplements at least once within the past seven days prior to data collection. Frequency and percentage were used to report respondents' characteristics and uptake of prenatal iron-folic acid supplementation. Chi-square test and logistic regression were conducted to determine the relationship and association of routine uptake of iron-folic acid supplementation with respondents' characteristics. RESULTS: The total respondents were 452. Overall routine uptake of iron-folic acid supplementation was 35.6% (161). The majority of the respondents (66.5%) initiated iron-folic acid supplementation during the second trimester of pregnancy. Most of the respondents (86.3%) obtained IFA supplements at the health centers where they were receiving antenatal care. The prevalence of routine uptake of iron-folic acid supplementation was significantly higher among women in the third trimester of pregnancy (54.9%), those with more than a five-year interval since last pregnancy (40.6%), those with at least four antenatal care (ANC) visits (73.7%) and women who had undergone haemoglobin testing in the current pregnancy (63.0%). Factors associated with routine uptake of iron-folic acid supplementation were; frequency of ANC visits (AOR = 1.69) and haemoglobin testing (AOR = 3.02). CONCLUSION: Approximately one third of the pregnant women took iron-folic acid supplementation at least once a week. The current frequency for intake of iron-folic acid supplementation can be described as intermittent. This practise is unacceptable for prevention of maternal anaemia and associated adverse pregnant outcomes. Frequency of ANC visits and haemoglobin testing during pregnancy were found to be associated with routine uptake of iron-folic acid supplements. Stakeholders are urged to consider novel systems for provision of prenatal IFAS in community settings with limited access to health-care professionals to ensure a timely and continuous supply of supplements.

Recommendations for India-specific multiple micronutrient supplement through expert consultation.

Background & objectives Reducing maternal anaemia and enhancing feto-maternal health to achieve desired birth outcomes is a major health concern in India. Micronutrient deficiencies during pregnancy may impact fetal growth and neonatal outcomes. There is increasing interest in using multiple micronutrient supplement (MMS) during pregnancy. However, the World Health Organization (WHO) recommends use of MMS containing Iron and Folic Acid (IFA) in the context of "rigorous research". Against this backdrop, an Indian Council of Medical Research (ICMR)-led MMS design expert group met over six months to review the evidence and decide on the formulation of an India-specific MMS supplement for pregnant mothers for potential use in a research setting. Methods The India-MMS design expert group conducted a series of meetings to assess the available evidence regarding the prevalence of micronutrient deficiencies in pregnant women in India, the health benefits of supplementing with different micronutrients during pregnancy, as well as nutrient interactions within the MMS formulation. Based on these considerations, the expert group reached a consensus on the composition of the MMS tailored for pregnant women in India. Results The India-specific MMS formulation includes five minerals and 10 vitamins, similar to the United Nations International Multiple Micronutrient Antenatal Preparation (UNIMMAP) composition. However, the quantities of all vitamins and minerals except Zinc, Vitamin E, and Vitamin B6 differ. Interpretation & conclusions This report provides an overview of the process adopted, the evidence evaluated, and the conclusions from the expert working group meetings to finalize an MMS supplement in pregnancy for the Indian context to be used in a research setting.

Effects of high-fat diet on folic acid-induced kidney injury in mice.

Obesity is recognized as a significant contributor to the onset of kidney disease. However, the key processes involved in the development of kidney disease in obese individuals are not well understood. Here, we investigated the effects of high-fat diet (HFD)-induced obesity on folic acid (FA)-induced kidney injury in mice. Mice were fed an HFD for 12 weeks to induce obesity, followed by an additional intraperitoneal injection of FA. The results showed that mice fed HFD developed higher levels of kidney damage than those in the chow group. In contrast, mice exposed to both HFD and FA showed less fibrosis and inflammatory responses compared to the FA only treated group. Furthermore, the HFD with FA group exhibited elevated lipid accumulation in the kidney and reduced expression of mitochondrial proteins compared to the FA-treated group. Under in vitro experimental conditions, we found that lipid accumulation induced by oleic acid treatment reduced inflammatory and fibrotic responses in both renal tubules and fibroblasts. Finally, RNA sequencing analysis revealed that the inflammasome and pyroptosis signaling pathways were significantly increased in the HFD group with FA injection. In summary, these findings suggest that obesity increases renal injury due to a lack of appropriate inflammatory, fibrotic, and metabolic responses and the activation of the inflammasome and pyroptosis signaling pathways.

Efficacy of oral folinic acid supplementation in children with autism spectrum disorder: a randomized double-blind, placebo-controlled trial.

Oral folinic acid has shown potential to improve symptoms in children with autism spectrum disorder (ASD). However, randomized controlled trials (RCTs) are limited. This double-blind, placebo-controlled RCT aimed to compare changes in Childhood Autism Rating Scale (CARS) scores in children with ASD aged 2-10 years, among folinic acid (2 mg/kg/day, maximum of 50 mg/day) and placebo groups at 24 weeks, in comparison with baseline. Both the groups received standard care (ABA and sensory integration therapy). Secondary objectives included changes in behavioral problems measured by the Child Behavior Checklist (CBCL) and serum levels of anti-folate receptor autoantibodies and folic acid, correlated with changes in autism symptom severity. Out of the 40 participants recruited in each group, 39 and 38 participants completed the 24-week follow-up in the folinic acid and placebo groups, respectively. The change in CARS score was higher in the folinic acid group (3.6 ± 0.8) compared to the placebo group (2.4 ± 0.7, p < 0.001). Changes in CBCL total score and CBCL internalizing score were also better in the folinic acid group (19.7 ± 9.5 vs. 12.6 ± 8.4 and 15.4 ± 7.8 vs. 8.5 ± 5.7, p < 0.001 for both). High-titer anti-folate receptor autoantibodies were positive in 32/40 and 33/40 cases in the folinic acid and placebo groups, respectively (p = 0.78). In the placebo group, improvement in CARS score was comparable regardless of autoantibody status (p = 0.11), but in the folinic acid group, improvement was more pronounced in the high-titer autoantibody group (p = 0.03). No adverse reactions were reported in either group. CONCLUSIONS: Oral folinic acid supplementation is effective and safe in improving ASD symptoms, with more pronounced benefits in children with high titers of folate receptor autoantibodies. TRIAL REGISTRATION:  CTRI/2021/07/034901, dated 15-07-2021. WHAT IS KNOWN: • Folate receptor autoantibodies are more prevalent in children with autism spectrum disorder (ASD) compared to typically developing children. • Folate receptor autoantibodies play a significant role in the neuropathogenesis of autism spectrum disorder. WHAT IS NEW: • Add-on oral folinic acid supplementation is safe and effective in reducing the severity of symptoms in children with ASD. • The clinical benefits are more pronounced in children with high titers of folate receptor autoantibodies.

Folate intake and the risk of endometrial cancer: A dose-response meta-analysis.

BACKGROUND: The relationship between folate intake and risk of endometrial cancer (EC) is debatable. The goal of this study was to examine the relationship between folate consumption and EC and then conduct a dose-response analysis in accordance with this. METHODS: Up until February 1, 2024, we conducted a thorough search using PubMed, EMBASE, the Cochrane Library, and Web of Science. Stata 14 software was used to analyze the findings of the article. The study protocol was registered in PROSPERO (CRD42024505943), and the meta-analysis was conducted in accordance with PRISMA guidelines. RESULTS: Nine case-control studies and 6 cohort studies were included, comprising 379,570 participants and 8660 EC cases. The highest level of folate consumption was associated with a 10% reduction in the occurrence of EC (relative risk [RR] = 0.90, 95% confidence intervals [CIs]: 0.78-1.05, I2 = 63.2%) compared to the lowest level of intake. The association exhibited a statistically significant linear trend (P = .231), with a combined RR of 0.974 (95% CI: 0.968-0.981) for each daily intake of 50 µg folate. CONCLUSION: Folate intake may reduce the risk of EC.

Bouillon fortification as a strategy to address inequities in micronutrient adequacy of diets in Nigeria.

Bouillon is a widely consumed condiment in many West African countries, including Nigeria. Although Nigeria has mandatory fortification standards for multiple food vehicles, bouillon fortification could help address remaining gaps in micronutrient intake. Using household food consumption data, we used the nutrient density method to model the additional contribution of bouillon fortified with vitamin A (40-250 µg/g bouillon), folic acid (20-120 µg/g), vitamin B12 (0.2-2 µg/g), iron (0.6-5 mg/g), and zinc (0.6-5 mg/g) for meeting micronutrient requirements of women of reproductive age (WRA) and children aged 6-59 months. Accounting for existing fortification programs, our results showed that, except for iron, the prevalence of inadequacy was substantially higher among WRA and children living in poorer and rural households. Given the ubiquity of bouillon consumption, bouillon fortification has the potential to virtually eliminate vitamin A, folate, and vitamin B12 inadequacy, reduce the prevalence of zinc inadequacy by over 20 percentage points, and improve equity in the micronutrient adequacy of diets across socioeconomic strata and urban and rural residence. Our results also suggested that designing a bouillon fortification program would require careful planning to balance reductions in inadequacy with the risk of high intakes. This evidence provides important input into decisions around bouillon fortification in Nigeria.

Food-sourced guanidinoacetic acid and methylation cycle biomarkers in individuals aged one year and older: a population-based cross-sectional study.

PURPOSE: Several preliminary studies suggest dietary guanidinoacetic acid (GAA) might impact methyl group availability and/or methylation biomarkers, fueling ongoing debates. This study aimed to explore the relationship between dietary GAA intake and plasma indicators of the methylation cycle in individuals aged one year and older, using data from the 2001-2002 National Health and Nutrition Examination Survey (NHANES). METHODS: Dietary information was obtained from individuals who completed a 24-hour Dietary Recall, with total daily intake of GAA calculated by aggregating all relevant food items. Relevant variables related to the methylation cycle, such as red blood cell (RBC) folate and serum folate, vitamin B12, total homocysteine (tHCy), and methylmalonic acid (MMA), were identified from the NHANES 2001-2002 laboratory assessments. RESULTS: A total of 9,115 individuals (51.3% females) were included in the final analysis. Linear regression unveiled a significant association between higher GAA intake and diminished RBC folate (p < 0.001), serum folate (p < 0.001), and MMA levels (p = 0.007). It also revealed an elevation in tHCy levels with increased GAA intake (p < 0.001). These associations remained significant even after adjusting for demographic variables and dietary factors pertinent to the methylation cycle (p < 0.05). CONCLUSION: Our findings suggest that dietary exposure to GAA (resulting in conversion to creatine) could be considered a nutritional factor associated with the consumption of methyl groups in the general population.

Strategies to combat heat stress in Isa Brown layer hens: Unveiling the roles of vitamin A, vitamin E, vitamin K, vitamin C, selenium, folic acid, and in combination.

Background: Due to their efficient insulation, lack of sweat glands, relatively quick metabolic rate, and heightened sensitivity to heat, the poultry industry faces a serious problem with heat stress. Combining vitamins has been demonstrated to be more effective than implementing a single vitamin in reducing the effects of heat stress. Aim: This study aimed to investigate the efficacy of the multivitamin combination in feed on the growth performance, egg quality, and antioxidant enzymes in laying hens exposed to heat stress. Methods: A total of 28 Isa Brown strains aged 18 weeks were randomly designated into seven groups with four replications, i.e., (C-) normal temperature group, (C+) heat stress group, and the others with the administration of vitamin A and E (AE), vitamin K and C (KC), vitamin C and E (CE), vitamin E and selenium (ESE), and vitamin C and folic acid (CAF). Feed intake, feed efficiency, eggshell thickness, shape index, haugh unit (HU), yolk, and albumen index were evaluated at 22, 23, 24, and 25 weeks. Meanwhile, antioxidant enzymes were quantified at 22 and 25 weeks. Results: As a result, feed intake was reported a significant improvement in the AE and CE groups compared to the C+ group. Meanwhile, the feed efficiency was reported to be efficient in the CE and ESE groups. Based on egg quality evaluation, we reported significant shell thickness in the CE, ESE, and CAF groups compared to the C+; yolk index was reported slightly significant results in the AE and CAF groups; albumen index and HU were reported to increase significantly in the CAF group. Meanwhile, superoxide dismutase (SOD), malondialdehyde (MDA), and GPx activity were ameliorated significantly in the ESE and CAF groups. Conclusion: Combinations of multivitamins can thereby enhance feed intake, feed efficiency, egg quality, and antioxidant activity. The CE, ESE, and CAF groups were found to have made equivalent improvements in the eggshell thickness, shape index, HU, yolk, and albumen index.

Supplementation practices among pregnant women and those trying to conceive: a population-representative survey in Vancouver, Canada.

Dietary supplements including vitamins, minerals, and natural health products are commonly consumed by those aiming to optimize fertility and pregnancy outcomes. The aim of this survey was to describe supplementation practices among individuals who were pregnant or trying to conceive in Vancouver, Canada. An online survey was conducted among 500 individuals who were pregnant (n = 250) or trying to conceive (n = 250). Participants met a substantial proportion of vitamin and mineral recommendations through supplements alone. Exceptions included calcium, magnesium, and choline, with median (interquartile range (IQR)) supplementation doses reported by those who were pregnant and trying to conceive, respectively, of: 250 (200 and 250 mg) and 250 (200 and 250 mg), 50 (50 and 75 mg) and 50 (50 and 90 mg), and 53 (10 and 150 mg) and 55 (10 and 100 mg), as compared to perinatal recommendations of 1000 mg/day (calcium), 350 mg/day (magnesium), and 450 mg/day (choline). Conversely, median (IQR) doses of folate reported by those who were pregnant and trying to conceive, respectively, were: 1000 (780 and 1000 µg) and 1000 (800 and 1000 µg), with ∼70% overall (337/471) reporting doses ≥1000 µg (the tolerable upper intake level). Most participants (451/500; 90%) reported supplementation with a prenatal multivitamin; of these, 83% reported that supplementation occurred daily. Overall, as diet was not considered, we cannot ascertain whether recommendations for calcium, magnesium, and choline were met through the combination of supplements and foods; however, we believe that additional supplementation with choline may be required to meet recommendations in pregnancy. Excessive folate supplementation has been previously identified as a concern throughout North America; here, we provide further evidence for excessively high doses consumed via supplements.

Association between folate intake and radiographic progression, pain function scores in subjects with radiographic knee osteoarthritis: Data from the osteoarthritis initiative.

BACKGROUND: Folate has an important role in the functioning of the musculoskeletal system, including modulation of inflammation, immunity, cartilage regeneration, prevention of osteoporosis, and maintenance of muscle strength, but evidence on the association between folate intake and knee pain, functional scores, and radiographic progression in patients with knee osteoarthritis (OA) is still limited. METHODOLOGY: Our population-based cohort was extracted from the osteoarthritis initiative (OAI), focusing on individuals with prevalent radiographic knee OA (with a Kellgren-Lawrence score ≥2). Folate consumption was determined using the food frequency questionnaire. Data regarding the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores and radiographic readings were collected over 48 months. We analyzed the compiled data using generalized additive mixed models. RESULTS: Our cohort consisted of 1472 OA patients (626 men and 846 women, mean [SD] age 62.35 [8.92]). At the 48-month follow-up, we observed a significant correlation between higher folate intake and a slower progression of knee pain and functional scores, as evidenced by a statistically significant decrease in the WOMAC total score, WOMAC pain subscale score, and WOMAC function/disability subscale score (p < .05). The fully adjusted models estimated a reduction of -0.028 points per 50 µg/1000 kcal of daily folate intake on the WOMAC pain subscale, -0.117 points on the WOMAC function subscale, and -0.160 points on the total WOMAC scale. Furthermore, our nonparametric fit analysis suggested that a higher intake of folate might decelerate the radiographic progression of OA. Stratified analyses indicated that an increase in folate consumption might particularly benefit men, older adults, overweight and obese individuals, and those with a higher dietary fiber intake. CONCLUSION: Higher folate intake is correlated with improved knee function and reduced pain in patients with knee OA and might deter the radiographic progression of OA. The benefits appear to be more pronounced in men, older adults, overweight and obese individuals, and those with a higher dietary fiber intake.

Maternal Folic Acid and Dietary Folate Intake in Relation to Sex Ratio at Birth and Sex-Specific Birth Weight in China.

BACKGROUND: It is well-established that prenatal folic acid supplements can reduce neural tube defects. However, the associations between folic acid supplementation, dietary folate intake, and overall folate intake with sex-specific birth outcomes are not yet fully understood. OBJECTIVES: This study aims to investigate the association of periconceptional folic acid supplement, dietary folate, and total folate intake with the sex ratio at birth and sex-specific birth weight. METHODS: Data were sourced from a cross-sectional survey conducted between August and December 2013 in Northwest China, involving 7318 infants and their mothers, recruited using a stratified multistage random sampling method. Folic acid supplements (400 µg/d) were ascertained via a retrospective in-person interview. Dietary folate was evaluated using a validated food frequency questionnaire. Birth outcomes, including sex and weight at birth, were obtained from the Medical Certificate of Birth. Generalized linear models were employed to calculate relative risks (RRs) or differences with 95% confidence intervals (CIs). RESULTS: No association or dose-response relationship was observed between folic acid supplement, dietary folate, and total folate intake during periconception and the likelihood of male births. However, women who took folic acid supplements during pre- and post-conception were associated with an increased male birth weight by 52.8 (8.1 to 97.5) g. Additionally, the total folate intake during periconception was associated with birth weight for males (upper vs. lower tertile: ß = 38.8, 95%CI: 5.0 to 72.5 g, p-trend = 0.024) and females (upper vs. lower tertile: ß = 42.4, 95%CI: 6.7 to 78.1; p-trend = 0.022). CONCLUSIONS: Our findings indicate that periconceptional total folate intake does not correlate with sex ratio at birth but was positively linked to infant birth weights, regardless of gender. These findings offer novel insights into potential benefits of total folate intake, beyond the prevention of neural tube defects, for policymakers and public health.

Supplementation with Folic Acid or 5-Methyltetrahydrofolate and Prevention of Neural Tube Defects: An Evidence-Based Narrative Review.

Background: Folic acid (FA), which in its chemical form is pteroylglutamic acid, is the fully oxidised, water-soluble, monoglutamic form of vitamin B9. This compound is part of the folate group but with higher bioavailability, and it is found in vitamin supplements and fortified foods and drugs. Folate metabolism is complex and associated with various metabolic pathways, all of which confer protection on the cell and allow its survival. Methods: We conducted a non-systematic search of articles published in English and Spanish including controlled trials, cohort studies, systematic re-views, and meta-analyses were included, as well as key studies in animal models related to pharmacokinetic studies. Search terms encompassed: "folic acid", "folates", "5-metyltetrahydrofolate", "5-MTHF", "neural tube defects", "supplementation", "fortification", AND "homocysteine" Results: A crucial role demonstrated for FA is to help prevent neural tube defects (NTDs). However, more studies are definitely still needed to establish 5-MTHF as a safe and effective therapeutic approach comparable with FA. Moreover, there is a lack of clinical studies that evaluate the efficacy of 5-MTHF supplementation in the prevention of NTDs. The present evidence-based narrative review discusses differences between FA and 5-MTHF in terms of structure, metabolism, bioavailability, clinical efficacy, and safety. Conclusions: Despite the potential value of 5-MTHF as an alternative to FA, clinical studies would be urgently needed to support the efficacy, dosage, timing, and/or safety of its use as a supplement.

Exploring the Impact of Folic Acid Supplementation and Vitamin B12 Deficiency on Maternal and Fetal Outcomes in Pregnant Women with Celiac Disease.

Background: Celiac disease is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten, affecting approximately 1% of the global population and two million Americans. An increasing number of studies have identified a link between celiac disease and adverse maternal and fetal outcomes during pregnancy and after birth. Additionally, both celiac disease and pregnancy are associated with an increased risk for nutrient deficiencies, specifically vitamin B12 and folate. Methods: This review examines the current literature related to the folate trap and vitamin B12 deficiency in patients with celiac disease and pregnant women independently and provides rationale for future research to explore the relationship between the folate-to-12 ratio in pregnant women with celiac disease. Results: Deficiencies in vitamin B12 are linked with several negative maternal and fetal health outcomes including pre-eclampsia, gestational diabetes, spontaneous abortion/miscarriage, preterm birth, neural tube defects, intrauterine growth restriction, and low gestational age and birthweight. Conclusions: Folic acid supplementation is widely recommended during pregnancy, but complementary vitamin B12 supplementation is not standard. Physicians should consider celiac disease screening during pregnancy as well as vitamin B12 supplementation.