Dose Folic Acid Supplementation Research Articles

The effect of folate deficiency and different doses of folic acid supplementation on liver diseases.

Liver has multiple functions such as detoxification, metabolism, synthesis and storage. Folate is a water-soluble vitamin B9, which participates in one-carbon transfer reactions, maintains methylation capacity, and improves oxidative stress. Folic acid is a synthetic form commonly used as a dietary supplement. The liver is the main organ for storing and metabolizing folate/folic acid, and the role of folate/folic acid in liver diseases has been widely studied. Deficiency of folate results in methylation capacity dysfunction and can induce liver disorders. However, adverse effects of excessive use of folic acid on the liver have also been reported. This review aims to explore the mechanism of folate/folic acid in different liver diseases, promote further research on folate/folic acid, and contribute to its rational clinical application.

The effect of folic acid supplementation and folate deficiency on embryo implantation

Implantation is a critical stage of pregnancy, which occurs in a short period of interaction between the receptive endometrium and the embryo. Folic acid (FA) is a synthetic derivative of folate and is recommended as a pre-conceptional supplement. However, the impact of different doses of FA supplementation and folate deficiency during the early stages of pregnancy requires further investigation. The aim of this study was to investigate the possible effects of FA supplementation and folate deficiency on expression of Estrogen Receptor Alpha (ER-α), Vascular Endothelial Growth Factor-A (VEGFA), and Integrin alpha V and beta3 (Integrin αVβ3). A total of 32, 6–8-week old Wistar albino rats were divided into four groups of control, folate-deficiency, low-dose, and high-dose FA supplement groups. After five weeks of FA supplementation and folate deficiency model formation, mated rats were sacrificed on the 5th gestational day (GD), and implantation sites were collected. The expression of ER- α, VEGFA, and Integrin αVβ3 in the implantation sites were examined with immunohistochemistry and real-time PCR. The results revealed that the mRNA levels of ESR1, VEGFA, and Integrin αV and β3 were significantly increased in the high-dose FA group and significantly decreased in the folate deficiency group compared to the control group (p < 0.05). Based on these results, it can be concluded that FA supplementation before pregnancy has positive effects on the maintenance of pregnancy, and folate deficiency may lead to implantation disorders.

Prescribing patterns for higher dose folic acid in pregnant women with epilepsy treated with antiseizure medication.

This study was undertaken to characterize the use of higher doses of folic acid (≥1 mg daily) in relation to pregnancy in Denmark, Norway, and Sweden in women with epilepsy treated with antiseizure medication (ASM). In this observational study, we used data from national medical birth, patient, and prescription registers in Denmark, Norway, and Sweden to retrospectively identify pregnancies in women with epilepsy treated with ASM from 2006 to 2017. The proportion of higher dose folic acid supplementation in pregnancies among women receiving ASM for epilepsy was calculated according to country of origin, time period, and type of ASM. Logistic regression with restricted cubic splines was used to model country-specific time trends. Among a total of 2 748 882 pregnancies, we identified 8695 (.3%) pregnancies after restricting the population to women with ASM-treated epilepsy. A prescription for higher dose folic acid was filled in 4719 (54.3%) of these pregnancies. The proportion supplemented with higher dose folic acid was highest in Sweden (74.3%) and lower in Norway (41.4%) and Denmark (34.3%). Furthermore, we observed a decreasing trend of higher dose folic acid use in Denmark and Norway from year 2012 to 2017. Among those who used higher dose folic acid, 42% did not start preconception supplementation with higher dose folic acid. Supplementation with higher dose folic acid occurred in approximately half of pregnancies in women with ASM-treated epilepsy, with many not starting supplementation until after becoming pregnant. Considerable variability was observed in the use of higher dose folic acid across the countries, despite similar population characteristics and health care systems. Future guidelines should be simplified with clear recommendations developed in a collaborative manner by relevant specialists including neurologists, obstetricians, pediatricians, and public health specialists to enhance real-world applicability.

Sperm DNA methylation defects in a new mouse model of the 5,10-methylenetetrahydrofolate reductase 677C>T variant and correction with moderate dose folic acid supplementation.

5,10-Methylenetetrahydrofolate reductase (MTHFR) is an enzyme that plays a key role in providing methyl groups for DNA methylation, including during spermatogenesis. A common genetic variant in humans (MTHFR 677C>T) results in reduced enzyme activity and has been linked to various disorders, including male infertility. A new animal model has been created by reproducing the human equivalent of the polymorphism in mice using CRISPR/Cas9. Biochemical parameters in the Mthfr 677TT mice recapitulate alterations found in MTHFR 677TT men. Our aims were to characterize the sperm DNA methylome of the Mthfr 677CC and TT mice on a control diet (2 mg folic acid/kg diet) and assess the effects of folic acid supplementation (10 mg/kg diet) on the sperm DNA methylome. Body and reproductive organ weights, testicular sperm counts, and histology were examined. DNA methylation in sperm was assessed using bisulfite pyrosequencing and whole-genome bisulfite sequencing (WGBS). Reproductive parameters and locus-specific imprinted gene methylation were unaffected by genotype or diet. Using WGBS, sperm from 677TT mice had 360 differentially methylated tiles as compared to 677CC mice, predominantly hypomethylation (60% of tiles). Folic acid supplementation mostly caused hypermethylation in sperm of males of both genotypes and was found to partially correct the DNA methylation alterations in sperm associated with the TT genotype. The new mouse model will be useful in understanding the role of MTHFR deficiency in male fertility and in designing folate supplementation regimens for the clinic.

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.

High-dose folic acid and cancer risk; unjustified concerns by von Wrede and colleagues regarding our paper.

Women using antiseizure medication in pregnancy are often advised to use high doses of folic acid supplements (1mg to 5 mg) to reduce the risk of teratogenicity. Recently, we published a report showing an association between maternal prescription fill of high dose folic acid in relation to pregnancy and childhood cancer in the offspring. The report has sparked a debate about which dose of folic acid that should be recommended in pregnancy in women in need of antiseizure medication. In this Commentary, we explain our findings and the method used in our report, and answer recent questions that have emerged.

Effects of folic acid supplementation in pregnant mice on glucose metabolism disorders in male offspring induced by lipopolysaccharide exposure during pregnancy

The DOHaD theory suggests that adverse environmental factors in early life may lead to the development of metabolic diseases including diabetes and hypertension in adult offspring through epigenetic mechanisms such as DNA methylation. Folic acid (FA) is an important methyl donor in vivo and participates in DNA replication and methylation. The preliminary experimental results of our group demonstrated that lipopolysaccharide (LPS, 50 µg/kg/d) exposure during pregnancy could lead to glucose metabolism disorders in male offspring, but not female offspring; however, the effect of folic acid supplementation on glucose metabolism disorders in male offspring induced by LPS exposure remains unclear. Therefore, in this study, pregnant mice were exposed to LPS on gestational day (GD) 15–17 and were given three doses of FA supplementation (2 mg/kg, 5 mg/kg, or 40 mg/kg) from mating to lactation to explore its effect on glucose metabolism in male offspring and the potential mechanism. This study confirmed that FA supplementation of 5 mg/kg in pregnant mice improved glucose metabolism in LPS-exposed offspring during pregnancy by regulating gene expression.

Just supplement Thiamine! A simple yet dramatic solution! (P9-4.004)

<h3>Objective:</h3> We present a case showing how while the diagnostic process in neuropathy may be long and cumbersome, the solution is usually simple, dramatic and life changing. <h3>Background:</h3> 55-year-old female with acute-on-chronic, rapidly progressive numbness and weakness. She first noted numbness and tingling in her feet over 8 years ago, but with rapid progression over the past year up to her trunk and hands. She presented to the ER after falling in the house, laying on the floor for hours, unable to be lifted by her husband. Examination revealed several bruises, symmetric wasting of upper and lower extremity muscles, proximal greater than distal weakness, loss of pinprick, vibration and temperature sensation from toes up to the thighs. She was areflexic with bowel and bladder incontinence and urine retention of 1L on arrival. She gave a history of excessive alcohol intake since her teenage years, with a heavy increase in intake over the COVID pandemic due to loss of employment and depression. Low folic acid, ESR 72, CT abdomen notable for steatohepatitis, fecal loading and urine retention. CSF analysis showed no albumino-cytological dissociation. Autoimmune workup, RPR, B12, serum copper, CSF paraneoplastic panel, CT chest, MRI brain and complete spine were unremarkable. EMG/NCV showed moderate, length dependent, sensory-motor axonal polyneuropathy. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> She was started on high dose thiamine and folic acid supplementation in hospital. Initially, she was unable to feed herself, turn in bed or sit without support. She slowly recovered, regained continence and can ambulate independently with a walker now. She can play the piano. <h3>Conclusions:</h3> Thiamine associated neuropathy or Dry Beri-Beri can present with axonal predominant sensorimotor polyneuropathy that can mimic Guillain Barre Syndrome. While workup for other etiologies of neuropathy should be simultaneously pursued in alcoholics, thiamine supplementation is a simple treatment that can lead to satisfying and dramatic results. <b>Disclosure:</b> Dr. Bhende has nothing to disclose. Dr. Zafar has nothing to disclose. Dr. Prabhu has nothing to disclose. Dr. Undavia has nothing to disclose.

Joint effect of maternal pre-pregnancy body mass index and folic acid supplements on gestational diabetes mellitus risk: a prospective cohort study

BackgroundThe joint effect of folic acid (FA) supplements and maternal pre-pregnancy body mass index (BMI) on gestational diabetes mellitus (GDM) has not been fully addressed. This study aimed to examine the joint effect of FA supplements and pre-pregnancy BMI on GDM.MethodsPregnant women at 4 to 14 weeks of gestation (n = 3186) were recruited during their first prenatal visit in Qingdao from May 1, 2019, to June 27, 2021. The main outcome was GDM at 24–28 weeks’ gestation. Screening was based on 75 g 2-hour oral glucose tolerance (OGTT), a fasting glucose ≥ 5.1 mmol/L, or a 1-hour result ≥ 10.0 mmol/L, or a 2-hour result ≥ 8.5 mmol/L. The interactive effect of FA supplements and pre-pregnancy BMI on GDM was examined using logistic regression analysis and ratio of odds ratios (ROR) was used to compare subgroup differences.ResultsOverall, 2,095 pregnant women were included in the analysis, and GDM incidence was 17.76%. Compared with women with pre-pregnancy BMI lower than 25.0 kg/m2 and FA-Sufficient supplements ≥ 400 µg/day (FA-S) population, the adjusted odds ratios (aORs) of FA-S and FA-Deficiency supplements < 400 µg/d (FA-D) were 3.57 (95% confidence interval [CI]: 2.02–6.34) and 10.82 (95% CI: 1.69–69.45) for the obese women (BMI ≥ 30.0 kg/m2), and the aORs of FA-S and FA-D were 2.17 (95% CI: 1.60–2.95) and 3.27 (95% CI: 1.55–6.92) for overweight women (25.0 kg/m2 ≤ BMI < 30.0 kg/m2). However, the risk of GDM did not differ significantly between the FA-D and the FA-S group in pre-pregnancy obese women (ROR = 2.70, 95%CI: 0.47–2.30), or overweight women (ROR = 0.66, 95%CI: 0.30–1.49). After further stratification of FA supplementation time, F-D and FA-S in obese women showed an interaction when FA supplement intake time < 3 months. However, there was no significant difference between subgroups (ROR = 1.63, 95% CI: 0.37–7.04).ConclusionMaternal pre-pregnancy BMI was associated with the incidence of GDM, the dose of FA supplementation from pre-pregnancy to early pregnancy was not found to be related to the incidence of GDM. The dosage of FA supplement was not associated with GDM irrespective of maternal pre-pregnancy BMI.

Association of Folic Acid Supplementation, Dietary Folate Intake and Serum Folate Levels with Risk of Gestational Diabetes Mellitus: A Matched Case-Control Study.

Periconceptional folate supplementation is prevalent, raising concerns about possible side effects. The aim of this study was to investigate the associations of folic acid supplementation, dietary folate, serum folate with gestational diabetes mellitus (GDM) risk. In this matched case-control study, 81 pregnant women with GDM (cases) and 81 pregnant women with non-GDM (controls) were identified through age difference (≤3 y) and parity (Both primipara or multipara women) matching, and serum folate levels were measured during the GDM screening (24-28 gestational wk). Folic acid supplementation and dietary folate intake from three months prepregnancy through midpregnancy were assessed using a self-reported questionnaire and food frequency questionnaire. Multivariate binary logistic regression models were used to evaluate the association between folate and GDM. After adjusting for confounding factors, we observed that compared with folic acid supplementation dose ≤400 μg/d, pregnancies without folic acid supplementation and supplemental dose >800 μg/d were associated with GDM risk (adjusted odds ratio=7.25, 95% confidence interval: 1.34-39.36; adjusted odds ratio=4.20, 95% confidence interval: 1.03-17.22), while no significant association with a 400-800 μg/d dose of folic acid supplementation and GDM. Compared with folic acid supplementation dose ≤24 wk, pregnancies without folic acid supplementation were associated with GDM risk (adjusted odds ratio=6.70, 95% confidence interval: 1.22-36.77), while no significant association with folic acid supplementation dose >24 wk and GDM. No significant association of dietary folate and serum folate with GDM was found. No or a higher dose of folic acid supplementation would increase GDM risk and a dose of <800 μg/d is the safe dose.

Protective and sex-specific effects of moderate dose folic acid supplementation on the placenta following assisted reproduction in mice.

Epigenetic defects induced by assisted reproductive technologies (ART) have been suggested as a potential mechanism contributing to suboptimal placentation. Here, we hypothesize that ART perturbs DNA methylation (DNAme) and gene expression during early placenta development, leading to abnormal placental phenotypes observed at term. Since folic acid (FA) plays a crucial role in epigenetic regulation, we propose that FA supplementation can rescue ART-induced placental defects. Female mice were placed on a control diet (CD), a moderate 4-fold (FAS4) or high dose 10-fold (FAS10) FA-supplemented diet prior to ART and compared to a natural mating group. ART resulted in 41 and 28 differentially expressed genes (DEGs) in E10.5 female and male placentas, respectively. Many DEGs were implicated in early placenta development and associated with DNAme changes; a number clustered at known imprinting control regions (ICR). In females, FAS4 partially corrected alterations in gene expression while FAS10 showed evidence of male-biased adverse effects. DNAme and gene expression for five genes involved in early placentation (Phlda2, EphB2, Igf2, Peg3, L3mbtl1) were followed up in placentas from normal as well as delayed and abnormal embryos. Phlda2 and Igf2 expression levels were lowest after ART in placentas of female delayed embryos. Moreover, ART concomitantly reduced DNAme at the Kcnq1ot1 ICR which regulates Phlda2 expression; FAS4 partially improved DNAme in a sex-specific manner. In conclusion, ART-associated placental DNAme and transcriptome alterations observed at mid-gestation are sex-specific; they may help explain adverse placental phenotypes detected at term and are partially corrected by maternal moderate dose FA supplementation.

Relationship between maternal folic acid supplementation during pregnancy and risk of childhood asthma: Systematic review and dose-response meta-analysis.

Growing evidence suggests that maternal folic acid supplementation during pregnancy may be associated with the risk of childhood asthma, but these findings remain controversial. Therefore, the purpose of this systematic review and meta-analysis was to assess the association between maternal folic acid supplementation during pregnancy and the risk of childhood asthma, and to determine the safe dose of folic acid supplementation during pregnancy based on a dose-response analysis to lower the risk of childhood asthma. The PubMed, Embase, Cochrane Library, and Web of Science databases were searched for relevant studies published before April 2022. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of eligible studies, and a fixed-effect model was employed to calculate the odds ratio (OR) of asthma with 95% confidence intervals (CI). In addition, the generalized least-squares trend (GLST) was used to explore a nonlinear dose-response relationship. Stata 15.0 was used for the statistical analysis mentioned above. This systematic review included 18 studies (13 cohort studies, 5 case-control studies) with a total of 252,770 participants, 50,248 of whom were children with asthma. The meta-analysis showed that maternal folic acid supplementation during pregnancy was significantly associated with the risk of childhood asthma (OR = 1.07; 95% CI = 1.04-1.11). The subgroup analysis revealed a significant correlation between the risk of childhood asthma and the folic acid supplementation in the first Trimester (OR = 1.09; 95% CI = 1.05-1.12), the third Trimester (OR = 1.15; 95% CI = 1.04-1.26) and the whole pregnancy (OR = 1.13; 95% CI = 1.10-1.16). At the same time, the dose-response analysis showed a nonlinear relationship between maternal folic acid intake during pregnancy and the risk of childhood asthma. The risk of asthma in children significantly increased when maternal folic acid intake reached 581 μg/day. This meta-analysis showed that maternal folic acid supplementation during pregnancy increased the risk of asthma in children. Based on the results of the dose-response analysis, less than 580 μg folic acid per day is advised in order to effectively prevent birth defects without increasing the risk of childhood asthma. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?, identifier: CRD42022332140.

Folic acid supplementation and malaria susceptibility and severity among people taking antifolate antimalarial drugs in endemic areas.

Folic acid supplementation and malaria susceptibility and severity among people taking antifolate antimalarial drugs in endemic areas.

Effect of folic acid supplementation on the change of plasma S-adenosylhomocysteine level in Chinese hypertensive patients: a randomized, double-blind, controlled clinical trial.

The relationship between folic acid and S-adenosylhomocysteine (SAH) is controversial. This study aims to explore the effect of different doses of folic acid supplementation on SAH levels in hypertensive patients and the modification of methylene-tetrahydrofolate reductase (MTHFR) C677T gene polymorphism. A randomized, double-blind, controlled clinical trial was conducted. Hypertensive patients aged 45-75 years without a history of stroke and cardiovascular disease were selected, who were randomly assigned to one of 8 dose groups. This trial has been registered with Trial Number: ChiCTR1800016135. In the total population, folic acid supplementation of 0.4-2.0 mg/day had no effect on SAH level (β = 0.47, 95% CI: -0.86-1.79, p = 0.491), while folic acid supplementation of 2.4 mg/day significantly increased SAH level (β = 1.93, 95% CI: 0.22-3.64, p = 0.027). Stratified analysis found that MTHFR C677T genotype CC supplemented with 2.4 mg/day folic acid had no effect on SAH level (β = 0.30, 95% CI: -2.74-3.34, p = 0.847), while CT and TT genotype supplemented with 2.4 mg/day folic acid showed a significant increase in SAH level (CT: β = 2.98, 95% CI: 0.34-5.62, p = 0.027; TT: β = 3.00, 95% CI: -0.51-6.51, p = 0.095; CT combined with TT: β = 2.99, 95% CI: 0.90-5.09, p = 0.005). In conclusion, supplementation of 2.4 mg/day folic acid can lead to increased SAH levels, especially in MTHFR C677T genotype CT and TT.

Precise Dose of Folic Acid Supplementation Is Essential for Embryonic Heart Development in Zebrafish

Simple SummaryFolic acid is an essential vitamin for human beings. It has become a consensus to supplement folic acid during pregnancy. It is reported that 15~20% of people in the world supplement folic acid excessively. We found that excessive folic acid supplementation or insufficient folic acid intake could lead to abnormal heart development in zebrafish embryos. We elucidated the mechanism of folic acid on early cardiac development for the first time. These results provide a scientific basis for the important reasonable supplement dose of folic acid. At the same time, we constructed zebrafish mutants with abnormal folate metabolism, which provide a novel biological model for the study of folate acid metabolism.Folic acid, one of the 13 essential vitamins, plays an important role in cardiovascular development. Mutations in folic acid synthesis gene 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with the occurrence of congenital heart disease. However, the mechanisms underlying the regulation of cardiac development by mthfr gene are poorly understood. Here, we exposed zebrafish embryos to excessive folate or folate metabolism inhibitors. Moreover, we established a knock-out mutant of mthfr gene in zebrafish by using CRISPR/Cas9. The zebrafish embryos of insufficient or excessive folic acid and mthfr−/− mutant all gave rise to early pericardial edema and cardiac defect at 3 days post fertilization (dpf). Furthermore, the folic acid treated embryos showed abnormal movement at 5 dpf. The expression levels of cardiac marker genes hand2, gata4, and nppa changed in the abnormality of folate metabolism embryos and mthfr−/− mutant, and there is evidence that they are related to the change of methylation level caused by the change of folate metabolism. In conclusion, our study provides a novel model for the in-depth study of MTHFR gene and folate metabolism. Furthermore, our results reveal that folic acid has a dose-dependent effect on early cardiac development. Precise dosage of folic acid supplementation is crucial for the embryonic development of organisms.

A study on periconceptional folic acid supplement intake and serum folic acid levels in pregnant mothers

BackgroundSurvey-based studies have examined the timing of receiving periconceptional folic acid supplementation. To assess the impact of the periconceptional folic acid supplementation, a postulate that multigravida mothers are more likely to have received the supplementation and the level of serum folic acid in them assayed during the first trimester is likely to be higher than primigravida mothers was put forth. Serum folic acid levels were measured in primigravida and multigravida mothers during the first trimester. MethodsOne hundred twenty primigravida and multigravida mothers registered at antenatal clinic of a tertiary care referral centre were included. Serum folic acid assay from samples collected during the first trimester was carried out by chemiluminescence immuneassay. The mothers were followed up during subsequent OPD visits, during admission for delivery and through mobile phones for assessing the delivery outcomes. World Health Organization cutoff values for serum folic acid were used to analyse the results. ResultsNone of the mothers received folic acid supplement before conception. Mean interval from last menstrual period to receiving the first dose of folic acid supplementation was 71.2 days in primigravida and 67.6 days in multigravida mothers. Overall, 21/120 (17.5%) of primigravida mothers and 34/120 (28.3%) of multigravida mothers had serum folic acid values less than 6 ng/ml (deficiency and possible deficiency). ConclusionNone of the mothers received folic acid supplements before conception. Significant proportion of mothers, particularly the multigravida having less than normal levels serum folic acid indicates correctable lacunae amenable for preventive intervention.

Folate Transporters Are Found Throughout the Colon of Humans and Their mRNA Expression Appears to Be Unaffected by Low Dose Folic Acid Supplementation

ObjectivesA large depot of folate resides in the colon and can exceed dietary intake. Little is known about the capacity of the colon to absorb folate. We aimed to determine the expression of key folate transporters, reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT), throughout the colon of healthy adults and the impact of low dose folic acid (FA) supplementation. MethodsIn this 16 wk open-labelled randomized control trial, healthy adults (n = 25) from a colonoscopy waiting list were randomized to receive daily a multivitamin plus a 400 μg FA (400FA, n = 12) or no FA supplement (0FA, n = 13). Subjects were provided with low FA bread and pasta and instructions how to follow a low FA containing diet. Six 24-hr diet recalls were administered throughout the study and blood samples were collected at baseline, 8 and 16 wk. At colonoscopy (16 wk), 4 tissue biopsies were collected from the terminal ileum, cecum, ascending and descending colon. Blood folates were determined by microbial assay; mRNA levels of folate transporters were assessed using qPCR. ResultsOne subject was removed from analysis due to missing data (0FA). No group differences in age, sex, BMI, dietary intake, vitamin B12, red blood cell (RBC) and plasma folate levels at baseline were observed. Mean ± SD FA supplement adherence was 92 ± 12% and 96 ± 9% at 8 and 16 wk, respectively. Subjects in the 400FA group had higher total folate intake (P < 0.05) and higher RBC and plasma folate levels (P < 0.01) at 8 and 16 wk compared to 0FA subjects. RBC values at 16 wk were 1764 ± 636 and 865 ± 190 nmol/L in the 400FA and 0FA group, respectively. RFC and PCFT were detected in terminal ileum and colon biopsies (n = 96) and their mRNA levels in each section did not differ between groups. However, expression of RFC was markedly higher than PCFT across all biopsy sections (P < 0.05) and highest in the terminal ileum, compared to the cecum, ascending and descending colon in both groups (P < 0.05). ConclusionsWe demonstrated expression of folate transporters, RFC and PCFT, throughout the human colon suggesting their potential contribution to overall folate absorption. mRNA expressions were not affected by a low dose FA supplement. A deeper understanding of how FA and folate status affect colonic transporter regulation may inform future revisions of folate intake recommendations. Funding SourcesNatural Sciences and Engineering Research Council.

The Use of Lower or Higher Than Recommended Doses of Folic Acid Supplements during Pregnancy Is Associated with Child Attentional Dysfunction at 4-5 Years of Age in the INMA Project.

We assessed the association between the use of lower- and higher-than-recommended doses of folic acid supplements (FAs) during pregnancy and attentional function in boys and girls at age of 4–5. We analyzed data from 1329 mother-child pairs from the mother-child cohort INfancia y Medio Ambiente Project (INMA) study. Information on FAs use during pregnancy was collected in personal interviews at weeks 12 and 30, and categorized in <400, 400–999 (recommended dose), and ≥1000 μg/day. Child attentional function was assessed by Conners’ Kiddie Continuous Performance Test. Multivariable regression analyses were used to estimate incidence rate ratios (IRR) and beta coefficients with 95% confidence intervals (CI). Compared to recommended FAs doses, the periconceptional use of <400 and ≥1000 μg/day was associated with higher risk of omission errors—IRR = 1.14 (95% CI: 1.01; 1.29) and IRR = 1.16 (95% CI: 1.02; 1.33), respectively. The use of FAs < 400 μg/day and ≥1000 μg/day was significantly associated with deficits of attentional function only in boys. FAs use < 400 μg/day was associated with higher omission errors with IRR = 1.22 and increased hit reaction time (HRT) β = 34.36, and FAs use ≥ 1000 μg/day was associated with increased HRT β = 33.18 and HRT standard error β = 3.31. The periconceptional use of FAs below or above the recommended doses is associated with deficits of attentional function in children at age of 4–5, particularly in boys.

Epidemiology and (Patho)Physiology of Folic Acid Supplement Use in Obese Women before and during Pregnancy.

Preconception folic acid supplement use is a well-known method of primary prevention of neural tube defects (NTDs). Obese women are at a higher risk for having a child with a NTD. As different international recommendations on folic acid supplement use for obese women before and during pregnancy exist, this narrative review provides an overview of epidemiology of folate deficiency in obese (pre)pregnant women, elaborates on potential mechanisms underlying folate deficiency, and discusses considerations for the usage of higher doses of folic acid supplements. Women with obesity more often suffer from an absolute folate deficiency, as they are less compliant to periconceptional folic acid supplement use recommendations. In addition, their dietary folate intake is limited due to an unbalanced diet (relative malnutrition). The association of obesity and NTDs also seems to be independent of folate intake, with studies suggesting an increased need of folate (relative deficiency) due to derangements involved in other pathways. The relative folate deficiency, as a result of an increased metabolic need for folate in obese women, can be due to: (1) low-grade chronic inflammation (2) insulin resistance, (3) inositol, and (4) dysbiotic gut microbiome, which plays a role in folate production and uptake. In all these pathways, the folate-dependent one-carbon metabolism is involved. In conclusion, scientific evidence of the involvement of several folate-related pathways implies to increase the recommended folic acid supplementation in obese women. However, the physiological uptake of synthetic folic acid is limited and side-effects of unmetabolized folic acid in mothers and offspring, in particular variations in epigenetic (re)programming with long-term health effects, cannot be excluded. Therefore, we emphasize on the urgent need for further research and preconception personalized counseling on folate status, lifestyle, and medical conditions.

Serum folate metabolites, asthma, and lung function in a nationwide US study

In a U.S. nationwide study, a high serum 5-MTHF to UMFA ratio is associated with decreased odds of asthma, increased FEV1 in children and adults, and increased FVC in adults.