Red Blood Cell Folate Concentrations Research Articles

The unique presentation of the relationship between red blood cell folate and appendicular skeletal muscle mass: a cross-sectional study

The overconsumption of folic acid has been associated with deleterious health effects; however, the extant body of research on this matter remains controversial. The principal objective of our investigation was to scrutinize the correlation between red blood cell (RBC) folate levels and appendicular skeletal muscle mass (ASM) among adult individuals. A total of 4117 adults aged over 20 years were included. The weighted prevalence of low muscle mass status (LMMS) was 14.50%. The correlation between RBC folate and ASM showed an inverted U-shaped curve. When the RBC folate concentration is below 500 nmol/L, ASM increases with increasing RBC folate concentration. However, when the RBC folate level exceeds 500 nmol/L, ASM decreases with increased RBC folate level. After correcting multiple confounding factors, a positive correlation was found between RBC folate and LMMS (p < 0.001). Compared with the RBC folate first quartile, the multivariable-adjusted ORs and 95% CIs of the second quartile, third quartile, and highest quartile were 1.08(0.81–1.44), 1.06(0.79–1.43), and 1.96(1.47–2.61), respectively. Our research suggested that excessive levels of RBC folate may be associated with an increased risk of LMMS in adults. Thus, being more cautious when considering folic acid supplementation is recommended.

Dietary folic acid intake, 13 genetic variants and other factors with red blood cell folate concentration in pregnancy-preparing population

PurposeThis study aims to evaluate a combined effect of dietary folic acid intake, multiple genetic polymorphisms in folate metabolism, and other environmental factors on red blood cell (RBC) folate concentration in pregnancy-preparing population.Methods519 pregnancy-preparing subjects (260 couples) were investigated. Dietary intake was measured by 3-day dietary recalls. 13 Single Nucleotide polymorphisms (SNPs) reported in association with one-carbon metabolism including the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C were genotyped. RBC folate concentration was measured using chemiluminescence assay. Hierarchical regression was applied for covariate selection. Factors showed significance(p < 0.0125) on RBC folate level was included for prediction model construction and R2 estimation. Validation cohort analysis was performed as post-hoc analysis if applicable.ResultsThe median RBC folate was 212.8 ng/ml. Only 10% took folic acid supplementation within three months. Based on hierarchical selection, folic acid supplementation, genetic polymorphism (especially TT genotype of MTHFR C677T), serum folate level were determinants of the variance of RBC folate concentrations, with adjusted R2 of 0.178–0.242. MTHFR A1298C polymorphism, sex difference with other socio-demographic and lifestyle factors (age, BMI, alcohol drinking, smoking, education, occupation) explained little to change in RBC folate level. Validation in another sub-cohort(n = 8105) had adjusted R2 of 0.273.ConclusionIn pregnancy-preparing subjects, folic acid supplementation, serum folate level and TT allele of MTHFR C677T polymorphism were determinants of the total variance of RBC folate level, which explained 19.8% variance in our subjects and 27.3% in the validation cohort. Food folate intake, sex and other environmental factors explained little to RBC folate level.

Dolutegravir- Versus Efavirenz-Based Treatment in Pregnancy: Impact on Red Blood Cell Folate Concentrations in Pregnant Women and Their Infants.

In IMPAACT 2010/VESTED, pregnant women were randomized to initiate dolutegravir (DTG)+emtricitabine (FTC)/tenofovir alafenamide (TAF), DTG+FTC/tenofovir disoproxil fumarate (TDF), or efavirenz (EFV)/FTC/TDF. We assessed red blood cell folate concentrations (RBC-folate) at maternal study entry and delivery, and infant birth. RBC-folate outcomes were: 1) maternal change entry to delivery (trajectory), 2) infant, 3) ratio of infant-to-maternal delivery. Generalized estimating equation models for each log(folate) outcome were fit to estimate adjusted geometric mean ratio (Adj-GMR)/GMR trajectories (Adj-GMRT) of each arm comparison in 340 mothers and 310 infants. Overall, 90% of mothers received folic acid supplements and 78% lived in Africa. At entry, median maternal age was 25 years, gestational age was 22 weeks, CD4 count was 482 cells/mm3 and log10HIV RNA was 3 copies/mL. Entry RBC-folate was similar across arms. Adj-GMRT of maternal folate was 3% higher in the DTG+FTC/TAF versus EFV/FTC/TDF arm (1.03, 95%CI 1.00, 1.06). The DTG+FTC/TAF arm had an 8% lower infant-maternal folate ratio (0.92, 95%CI 0.78, 1.09) versus EFV/FTC/TDF. Results are consistent with no clinically meaningful differences between arms for all RBC-folate outcomes and they suggest that cellular uptake of folate and folate transport to the infant do not differ in pregnant women starting DTG- vs. EFV-based ART.

Serum Folate, Red Blood Cell Folate, and Zinc Serum Levels Are Related with Gestational Weight Gain and Offspring's Birth-Weight of Adolescent Mothers.

Gestational weight gain below or above the Institute of Medicine recommendations has been associated with adverse perinatal and neonatal outcomes. Very few studies have evaluated the association between serum and red blood cell folate concentrations and gestational weight gain in adolescents. Additionally, zinc deficiency during pregnancy has been associated with impaired immunity, prolonged labor, preterm and post-term birth, intrauterine growth restriction, low birth weight, and pregnancy-induced hypertension. The purpose of our study is to evaluate the association between serum concentrations of zinc, serum folate, and red blood cell folate, with the increase in gestational weight and the weight and length of the newborn in a group of adolescent mothers from Mexico City. In our study, 406 adolescent-neonate dyads participated. The adolescents' median age was 15.8 years old. The predominant socioeconomic level was middle-low (57.8%), single (57%), 89.9% were engaged in home activities, and 41.3% completed secondary education. Excessive gestational weight gain was observed in 36.7% of cases, while insufficient gestational weight gain was noted in 38.4%. Small for gestational age infants were observed in 20.9% of the sample. Low serum folate (OR 2.1, 95% CI 1.3-3.3), decreased red blood cell folate (OR 1.6, 95% CI 1.0-2.6), and reduced serum zinc concentrations (OR 3.3, 95% CI 2.1-5.2) were associated with insufficient gestational weight gain. Decreased serum zinc levels (OR 1.2, 95% CI 1.2-3.4) were linked to an increased probability of delivering a baby who is small for their gestational age. Low serum folate, red blood cell folate, and serum zinc concentrations were associated with gestational weight gain and having a small gestational age baby. Both excessive and insufficient gestational weight gain, as well as having a small gestational age baby, are frequent among adolescent mothers.

Maternal serum unmetabolized folic acid concentration following multivitamin and mineral supplementation with or without folic acid after 12 weeks gestation: A randomized controlled trial.

Pregnant women are advised to take folic acid (FA) supplements before conception and during the first trimester of pregnancy. Many women continue FA supplementation throughout pregnancy, and concerns have been raised about associations between excessive FA intake and adverse maternal and child health outcomes. Unmetabolized folic acid (UMFA) is found in serum after high FA intakes and is proposed as a biomarker for excessive FA intake. We aimed to determine if removing FA from prenatal micronutrient supplements after 12 weeks of pregnancy reduces serum UMFA concentrations at 36 weeks gestation. In this double-blind, randomized controlled trial conducted in South Australia, 103 women with a singleton pregnancy were randomly assigned at 12-16 weeks gestation to take a micronutrient supplement containing noFA or 800 µg/day FA from enrollment until 36 weeks gestation. Ninety women (0 µg/day FA n = 46; 800 µg/day FA n = 44) completed the study. Mean, UMFA concentration was lower in the women randomized to the 0 µg/day group compared to the 800 µg/day FA group, 0.6 ± 0.7 and 1.4 ± 2.7 nmol/L, respectively. The adjusted mean difference (95% CI) in UMFA between the groups was [-0.85 (-1.62, -0.08) nmol/L, p = 0.03]. Maternal serum and red blood cell folate concentrations were lower in the 0 µg/day FA group than in the 800 µg/day group (median 23.2 vs. 49.3 and1335 vs. 1914 nmol/L, respectively; p < 0.001). Removing FA at 12-16 weeks gestation from prenatal micronutrient supplements reduced the concentration of UMFA at 36 weeks gestation.

New options for replenishing the iron stores in patients with abnormal uterine bleeding

Introduction. The high incidence of abnormal uterine bleeding (AUB) (over 30%) among patients of reproductive age is accompanied by the development of iron deficiency anaemia (IDA), which, in turn, is a social problem among global burden diseases throughout the world.Aim. To evaluate the clinical efficacy and compliance with the Vojea complex regimen to prevent IDA in women with abnormal uterine bleeding.Materials and methods. A multicentre clinical observational study was conducted in 6 health care facilities and women’s health clinics in Yekaterinburg and Moscow. The study included 52 patients with latent iron deficiency (serum ferritin level &lt; 15 ng/ml) who were diagnosed with abnormal uterine bleeding (AUB) due to ovulatory dysfunction. All patients received Vojea complex at a dose of 1 tablet QD for 3 months while taking pharmaceutical therapy for AUB. The clinical and laboratory efficacy and medication compliance were assessed at 30, 60 and 90 days after initiation of treatment.Results. Starting from the 1st month of treatment with the study complex, positive trends in clinical and laboratory findings were observed in both groups. After the three-month therapy with Vojea, ferritin levels increased 5.4 times (a clinically significant growth was reported after the two-month intake), plasma folate levels increased 4.9 times and red blood cell folate concentrations increased by 45%. The complex therapy helped reach and maintain the average red blood cell folate concentration &gt;400 ng/ml (906 nmol/l). Side effects included isolated events of gastrointestinal dyspepsia and individual intolerance. All patients reported good and excellent tolerance of the complex, which ensured high compliance with the drug regimen (92%).Conclusion. The three-month therapy with Vojea complex as part of the combination approach to the treatment of AUB in women with latent iron deficiency showed high clinical and laboratory efficacy, as well as good compliance with the drug regimen.

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.

Development and validation of a cognitive dysfunction risk prediction model for the abdominal obesity population.

This study was aimed to develop a nomogram that can accurately predict the likelihood of cognitive dysfunction in individuals with abdominal obesity by utilizing various predictor factors. A total of 1490 cases of abdominal obesity were randomly selected from the National Health and Nutrition Examination Survey (NHANES) database for the years 2011-2014. The diagnostic criteria for abdominal obesity were as follows: waist size ≥ 102 cm for men and waist size ≥ 88 cm for women, and cognitive function was assessed by Consortium to Establish a Registry for Alzheimer's Disease (CERAD), Word Learning subtest, Delayed Word Recall Test, Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST). The cases were divided into two sets: a training set consisting of 1043 cases (70%) and a validation set consisting of 447 cases (30%). To create the model nomogram, multifactor logistic regression models were constructed based on the selected predictors identified through LASSO regression analysis. The model's performance was assessed using several metrics, including the consistency index (C-index), the area under the receiver operating characteristic (ROC) curve (AUC), calibration curves, and decision curve analysis (DCA) to assess the clinical benefit of the model. The multivariate logistic regression analysis revealed that age, sex, education level, 24-hour total fat intake, red blood cell folate concentration, depression, and moderate work activity were significant predictors of cognitive dysfunction in individuals with abdominal obesity (p < 0.05). These predictors were incorporated into the nomogram. The C-indices for the training and validation sets were 0.814 (95% CI: 0.875-0.842) and 0.805 (95% CI: 0.758-0.851), respectively. The corresponding AUC values were 0.814 (95% CI: 0.875-0.842) and 0.795 (95% CI: 0.753-0.847). The calibration curves demonstrated a satisfactory level of agreement between the nomogram model and the observed data. The DCA indicated that early intervention for at-risk populations would provide a net benefit, as indicated by the line graph. Age, sex, education level, 24-hour total fat intake, red blood cell folate concentration, depression, and moderate work activity were identified as predictive factors for cognitive dysfunction in individuals with abdominal obesity. In conclusion, the nomogram model developed in this study can effectively predict the clinical risk of cognitive dysfunction in individuals with abdominal obesity.

Folate in the United States Population and its Association with Congestive Heart Failure.

To investigate the relationship between red blood cell (RBC) folate and congestive heart failure (CHF). We extracted the concentrations of RBC folate and collated CHF information from the National Health and Nutrition Examination Survey (NHANES) survey (12820 individuals). Weighted univariate logistic regression, weighted multivariate logistic regression, and restrictive cubic spline (RCS) were used to assess the relationship between RBC folate concentrations and CHF. The unadjusted model showed that the highest tertile group of RBC folate concentration was significantly associated with a higher risk of CHF compared to the lowest tertile group of RBC folate levels (odds ratio [OR] = 3.09; 95% confidence interval [CI], 2.14-4.46). Similar trends were seen in the multivariate-adjusted analysis (OR = 1.98; 95% CI: 1.27-3.09). The OR was 1.0 when the predicted RBC folate exceeded 2757 nmol/L in the RCS model, indicating that the risk of CHF was low and relatively stable up to a predicted RBC folate level of 2757 nmol/L, but began to increase rapidly thereafter (p = 0.001). The risk of CHF may be increased either by high RBC folate concentrations (highest tertile of RBC folate or 2637 nmol/L) or by folate deficiency. Considering the two sides of the association between RBC folate and CHF, there is a need for large-scale clinical research to better investigate if the association between RBC folate and CHF is a cause-effect relationship, what are the underlying pathophysiological basis, as well as to identify optimal dietary folate equivalent (DFE) and RBC folate concentration intervals.

Folate, vitamin B12 and vitamin D status in healthy and active home-dwelling people over 70 years

BackgroundAgeing is characterised by physiological changes that can affect the nutrient availability and requirements. In particular, the status of vitamin D, cobalamin and folate has often been found to be critical in older people living in residential care. However, there is a lack of studies investigating the status of these nutrients in healthy and active home-dwelling elderly people.MethodsThe aim of this cross-sectional study was to assess the status of vitamin D based on serum concentrations of 25-hydroxycholecalciferol [25-(OH)D], cobalamin based on serum concentrations of holotranscobalamin (holoTC) and folate based on red blood cell (RBC) folate in unsupplemented, healthy and active German home-dwelling subjects ≥ 70 years of age (n = 134, mean ± SD: 75.8 ± 4.5 years). Dietary intake was assessed by 3-day food recalls. The study was conducted between March and November of 2021 (during the COVID-19 pandemic).ResultsThe mean 25-(OH)D concentration was high at 85.1 ± 26.0 nmol/L, while the majority of women (92%) and men (94%) had 25-(OH)D concentrations ≥ 50 nmol/L. Less than 10% of men and women had 25-(OH)D concentrations < 50 nmol/L. The mean holoTC concentration was 88.9 ± 33.7 pmol/L (94.8 ± 34.6 pmol/L in women and 73.6 ± 25.6 in men). Only 8% of the women were cobalamin deficient (< 50 pmol/L holoTC) compared to 22% of the men. The mean RBC folate concentration was 831 ± 244 nmol/L, while the prevalence of folate deficiency was 10%. Linear regression analysis showed that only folate equivalent intake was associated with the relevant nutrient status marker.ConclusionOur findings suggest that healthy, independently living older people with high levels of education, physical activity, and health awareness are not necessarily at higher risk of vitamin D, folate and cobalamin deficiency. Further studies are needed to verify these findings and to identify lifestyle and dietary patterns that can predict adequate nutrient status for healthy ageing.Trial registrationThis study is officially recorded in the German Clinical Trials Register (DRKS00021302).

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.

Folate concentrations and serum perfluoroalkyl and polyfluoroalkyl substance concentrations in adolescents and adults in the USA (National Health and Nutrition Examination Study 2003–16): an observational study

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are a family of highly fluorinated aliphatic compounds, which are widely used in commercial applications, including food packaging, textiles, and non-stick cookware. Folate might counteract the effects of environmental chemical exposures. We aimed to explore the relationship between blood folate biomarker concentrations and PFAS concentrations. This observational study pooled cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) 2003 to 2016 cycles. NHANES is a population-based national survey that measures the health and nutritional status of the US general population every 2 years by means of questionnaires, physical examination, and biospecimen collection. Folate concentrations in red blood cells and in serum, and perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS) concentrations in serum were examined. We used multivariable regression models to assess the percentage change in serum PFAS concentrations in relation to changes in folate biomarker concentrations. We additionally used models with restricted cubic splines to investigate the shape of these associations. This study included 2802 adolescents and 9159 adults who had complete data on PFAS concentrations, folate biomarkers, and covariates, were not pregnant, and had never had a cancer diagnosis at the time of the survey. The mean age was 15·4 years (SD 2·3) for adolescents and 45·5 years (17·5) for adults. The proportion of male participants was slightly higher in adolescents (1508 [54%] of 2802 participants) than in adults (3940 [49%] of 9159 participants). We found negative associations between red blood cell folate concentrations and serum concentrations of PFOS (percentage change for a 2·7 fold-increase in folate level -24·36%, 95% CI -33·21 to -14·34) and PFNA (-13·00%, -21·87 to -3·12) in adolescents, and PFOA (-12·45%, -17·28 to -7·35), PFOS (-25·30%, -29·67 to -20·65), PFNA (-21·65%, -26·19 to -16·82), and PFHxS (-11·70%, -17·32 to 5·70) in adults. Associations for serum folate concentrations and PFAS were in line with those found for red blood cell folate levels, although the magnitude of the effects was lower. Restricted cubic spline models suggested linearity of the observed associations, particularly for associations in adults. In this large-scale, nationally representative study, we found consistent inverse associations for most examined serum PFAS compounds in relation to folate concentrations measured in either red blood cells or serum among both adolescents and adults. These findings are supported by mechanistic in-vitro studies that show the potential of PFAS to compete with folate for several transporters implicated in PFAS toxicokinetics. If confirmed in experimental settings, these findings could have important implications for interventions to reduce the accumulated PFAS body burden and mitigate the related adverse health effects. United States National Institute of Environmental Health Sciences.

Folate and vitamin B12 usual intake and biomarker status by intake source in United States adults aged ≥19 y: NHANES 2007–2018

BackgroundFolate and vitamin B12 are important biomarkers of nutritional status of populations. ObjectivesThis study aims to estimate folate and vitamin B12 usual intakes among United States adults and examine folate and vitamin B12 biomarker status by intake source. MethodsWe analyzed data for United States adults aged ≥19 y from National Health and Nutrition Examination Survey 2007–2018 (n = 31,128), during which time voluntary corn masa flour (CMF) fortification was started. Usual intake was estimated using the National Cancer Institute method. Folate intake included folate from natural foods and folic acid from 4 sources: enriched cereal grain products (ECGPs), CMF, ready-to-eat cereals (RTEs), and folic acid–containing supplements (SUP). Vitamin B12 intake was mainly from food and supplements. ResultsThe median natural food folate intake (222 μg dietary folate equivalents (DFE)/d) was below the estimated average requirement (EAR) of 320 μg DFE/d. The proportions of those who consumed folic acid from ECGP/CMF only, ECGP/CMF + RTE, ECGP/CMF + SUP, and ECGP/CMF + RTE + SUP were 50%, 18%, 22%, and 10%, respectively. Median usual folic acid intakes (μg/d) were 236 (IQR: 152, 439) overall and 134, 313, 496, and 695 in the ECGP/CMF only, ECGP/CMF + RTE, ECGP/CMF + SUP, and ECGP/CMF + RTE + SUP folic acid consumption groups, respectively. Overall, 2.0% (95% CI: 1.7%, 2.3%) of adults, all of whom used folic acid supplements, consumed greater than the tolerable upper intake level (UL) of 1000 μg/d folic acid. The median usual vitamin B12 intake (μg/d) was 5.2 for vitamin B12 supplement nonusers and 21.8 for users. Consumption of RTE and/or supplements with folic acid was associated with higher serum and red blood cell folate concentrations. Vitamin B12 supplement users had significantly higher serum vitamin B12 concentrations. ConclusionsFolic acid fortification plays a critical role in helping United States adults meet the folate EAR. At current fortification levels, United States adults who do not consume supplements do not have the usual folic acid intake exceeding the UL.

Estimating the serum folate concentration that corresponds to the red blood cell folate concentration threshold associated with optimal neural tube defects prevention: A population-based biomarker survey in Southern India

BackgroundRBC folate concentrations are monitored at the population level, with a recommended threshold for optimal neural tube defect (NTD) prevention. A corresponding threshold for serum folate has not been established. ObjectivesThis study aimed to estimate the serum folate insufficiency threshold corresponding to the RBC folate threshold for NTD prevention and examine how this threshold is modified by vitamin B12 status. MethodsParticipants were women (15–40 y; not pregnant or lactating; n = 977) from a population-based biomarker survey in Southern India. RBC folate and serum folate were measured via microbiologic assay. RBC folate deficiency (<305 nmol/L) and insufficiency (<748 nmol/L), serum vitamin B12 deficiency (<148 pmol/L) and vitamin B12 insufficiency (<221 pmol/L), elevated plasma MMA (>0.26 μmol/L), elevated plasma homocysteine (>10.0 μmol/L), and elevated HbA1c (≥6.5%) were evaluated. Bayesian linear models were used to estimate unadjusted and adjusted thresholds. ResultsCompared with adequate vitamin B12 status, the estimated serum folate threshold was higher in participants with serum vitamin B12 deficiency (72.5 vs. 28.1 nmol/L) or vitamin B12 insufficiency (48.7 vs. 24.3 nmol/L) and elevated MMA (55.6 vs. 25.9 nmol/L). The threshold was lower in participants with elevated HbA1c (HbA1c ≥6.5% vs. <6.5%; 21.0 vs. 40.5 nmol/L). ConclusionsThe estimated serum folate threshold for optimal NTD prevention was similar to previous reports (24.3 vs. 25.6 nmol/L) among participants with sufficient vitamin B12 status. However, this threshold was more than 2-fold higher in participants with vitamin B12 deficiency and substantially higher across all indicators of insufficient vitamin B12 status (<221 pmol/L, elevated MMA, combined B12, impaired vitamin B12 status), and lower in participants with elevated HbA1c. Findings suggest a serum folate threshold for NTD prevention may be possible in some settings; however, it may not be appropriate in populations with high prevalence of vitamin B12 insufficiency. Am J Clin Nutr 2023;xx:xx–xx.This trial was registered at https://clinicaltrials.gov as NCT04048330.

Infant blood concentrations of folate markers and catabolites are modified by 5,10-methylenetetrahydrofolate reductase C677T genotype and dietary folate source

BackgroundFolate intake and polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene may affect folate metabolism in infants. ObjectivesWe investigated the association between infant’s MTHFR C677T genotype, the dietary folate source, and concentrations of folate markers in the blood. MethodsWe studied 110 breastfed infants (reference) and 182 infants who were randomly assigned to receive infant formulas enriched with either 78 μg folic acid or 81 μg (6S)-5-methyltetrahydrofolate (5-MTHF) per 100 g milk powder for 12 wk. The blood samples were available at the ages of <1 mo (baseline) and 16 wk. MTHFR genotype and concentrations of folate markers and catabolites [i.e., para-aminobenzoylglutamate (pABG)] were analyzed. ResultsAt baseline, carriers of the TT genotype (vs. CC) had lower mean (SD) concentrations (all in nmol/L) of red blood cell (RBC) folate [1194 (507) vs. 1440 (521), P = 0.033) and plasma pABG [5.7 (4.9) vs. 12.5 (8.1), P < 0.001] but higher plasma 5-MTHF [33.9 (16.8) vs. 24.0 (12.6), P < 0.001]. Irrespective of the genotype, infant formula with 5-MTHF (vs. folic acid) caused a significant increase in RBC folate concentration [1278 (466) vs. 947 (552), P < 0.001]. In breastfed infants, plasma concentrations of 5-MTHF and pABG increased significantly by 7.7 (20.5) and 6.4 (10.5), respectively, from baseline to 16 wk. Infant formula that complies with the present EU legislation for folate intake increased RBC folate and plasma pABG concentrations at 16 wk (P < 0.001) than formula-fed infants. At 16 wk, plasma pABG concentrations remained ∼50% lower in carriers of the TT (vs. the CC) genotype among all feeding groups. ConclusionsFolate intake from infant formula according to the present EU legislation increased RBC folate and plasma pABG concentrations in infants to a greater extent than breastfeeding, particularly in carriers of the TT genotype. However, this intake did not completely abolish the between-genotype differences in pABG. Whether these differences have any clinical relevance, however, remains unclear. This trial was registered at clinicaltrials.gov as NCT02437721.

Red Blood Cell Folate Modifies the Association between Serum Per- and Polyfluoroalkyl Substances and Antibody Concentrations in U.S. Adolescents.

Per- and polyfluoroalkyl substances (PFAS) exposure has been associated with reduced antibody levels. Higher red blood cell (RBC) folate was previously associated with lower serum PFAS concentrations in adolescents. This study included 819 adolescents aged 12-19 years who had detectable rubella and measles antibody levels in serum from the U.S. National Health and Nutrition Examination Survey 2003-2004 and 2009-2010 cycles. We found inverse associations between serum PFOS and PFHxS and rubella antibodies, between PFOA and mumps antibodies, and between PFAS mixtures and rubella and mumps antibodies, only among adolescents with RBC folate concentrations <66th percentile (lower folate group) while not among adolescents with higher RBC folate levels (upper folate group). Specifically, per quartile increase in serum concentrations of the total PFAS mixture was associated with a 9.84% (95% CI: -15.57%, -3.74%) decrease in rubella antibody and an 8.79% (95% CI: -14.39%, -2.82%) decrease in the mumps antibody concentrations only in the lower folate group, while null associations were found for the upper folate group. If confirmed in mechanistic studies or prospective epidemiologic studies, these findings may have important implications for using folate as a mitigation measure against immune-related PFAS effects.

Association between red blood cell folate and Trichomonas vaginalis infection among women

BackgroundIncreased folic acid has been found to be latently protective against gynecological infection, including several kinds of vaginosis. In this study, we laid emphasis on whether RBC (Red Blood Cell) folate was associated with the infectious ratio of Trichomonas vaginalis, a kind of anaerobic parasitic protozoan.MethodsWe set RBC folate as the exposure variable and Trichomonas vaginalis as the outcome variable. Other subsidiary variables were regarded as covariates that may work as potential effect modifiers. The cross-sectional study was conducted with two merged waves of the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2004, and a sample of 1274 eligible women (1212 negative and 62 positive in Trichomonas vaginalis infection) was integrated for the exploration of the association between RBC folate and Trichomonas vaginalis infection. Multivariate regression analyses, subgroup analyses, and subsequent smooth curve fittings were conducted to estimate the relationship between RBC folate and Trichomonas vaginalis in women.ResultsIn the multivariable logistic regression analyses, a negative association was observed between stratified RBC folate status and Trichomonas vaginalis infection with all confounders adjusted. Referencing the lowest RBC folate concentration quartile, the higher concentration quartiles reported a relatively lower infection ratio, while there was a weak correlation between total RBC folate concentration and T. vaginalis (Trichomonas vaginalis) infection. In subgroup analyses stratified by BMI and age, this association was only found significant in high age and BMI groups.ConclusionsThe cross-sectional study indicated a negative association between RBC folic acid and Trichomonas vaginalis infection, and latent effects of BMI and age on the association were also found.

Periconception Red Blood Cell Folate and Offspring Congenital Heart Disease : Nested Case-Control and Mendelian Randomization Studies.

Periconception folic acid supplementation has been suggested to protect against congenital heart disease (CHD), but the association between maternal red blood cell (RBC) folate, the gold-standard biomarker of folate exposure, and subsequent offspring CHD risk is lacking. To quantify the association between periconception maternal RBC folate and offspring CHD risk. Prospective, nested, case-control study and 1-sample Mendelian randomization. (ClinicalTrials.gov: NCT02737644). 29 maternity institutions in 12 districts of Greater Shanghai, China. All 197 mothers of offspring with CHD and 788 individually matched mothers of unaffected offspring from the SPCC (Shanghai Preconception Cohort). Maternal RBC folate was measured before or at early pregnancy. Odds ratios [ORs] were estimated using conditional logistic regression after adjustment for covariates. Mendelian randomization was done using the methylenetetrahydrofolate reductase (MTHFR) C677T as the genetic instrument. Case patients had lower median maternal RBC folate concentrations than control participants (714 nmol/L [interquartile range, 482 to 1008 nmol/L] vs. 788 nmol/L [557 to 1094 nmol/L]). Maternal RBC folate concentrations were inversely associated with offspring CHD (adjusted OR per 100 nmol/L, 0.93 [95% CI, 0.89 to 0.99]). The adjusted OR for mothers with periconception RBC folate of 906 nmol/L or more (vs. <906 nmol/L) was 0.61 (CI, 0.40 to 0.93). Mendelian randomization showed that each 100-nmol increase in maternal RBC folate concentrations was significantly associated with reduced offspring CHD risk (OR, 0.75 [CI, 0.61 to 0.92]). Potential confounding due to unmeasured covariates in the nested case-control study. Higher maternal RBC folate is associated with reduced offspring CHD risk. For primary CHD prevention, higher target RBC folate levels than currently recommended for neural tube defect prevention may be needed and warrant further study. National Key Research and Development Program of China, National Natural Science Foundation of China, China Postdoctoral Science Foundation, and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences.

Folic Acid and the Prevention of Birth Defects: 30 Years of Opportunity and Controversies.

For three decades, the US Public Health Service has recommended that all persons capable of becoming pregnant consume 400 μg/day of folic acid (FA) to prevent neural tube defects (NTDs). The neural tube forms by 28 days after conception. Fortification can be an effective NTD prevention strategy in populations with limited access to folic acid foods and/or supplements. This review describes the status of mandatory FA fortification among countries that fortify (n = 71) and the research describing the impact of those programs on NTD rates (up to 78% reduction), blood folate concentrations [red blood cell folate concentrations increased ∼1.47-fold (95% CI, 1.27, 1.70) following fortification], and other health outcomes. Across settings, high-quality studies such as those with randomized exposures (e.g., randomized controlled trials, Mendelian randomization studies) are needed to elucidate interactions of FA with vitamin B12 as well as expanded biomarker testing.

Associations of single and multiple perfluoroalkyl substances exposure with folate among adolescents in NHANES 2007–2010

BackgroundThe accumulation of perfluoroalkyl substances (PFAS) in human body has raised concerns about the potential health impacts on children and adolescents. However, no study has evaluated the associations of PFAS exposure with folate concentrations among adolescents. MethodsIn the present study, we mainly used three statistical approaches, namely multiple linear regression, Bayesian Kernel Machine Regression (BKMR), and quantile-based g-computation (Q-gcomp) models, to evaluate associations of individual PFAS and their mixtures with serum and red blood cell (RBC) folate concentrations in a sample of 721 adolescents from the NHANES 2007–2010. ResultsIn multiple linear regression models, for per unit increase in ln-transformed perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) concentrations, RBC folate concentrations decreased by 72.4 (95% confidence interval (CI): −112.7, −32.2), 58.3 (95% CI: −115.0, −1.6), 60.7 (95% CI: −107.5, −13.8), and 76.5 (95% CI: −119.0, −33.9) nmol/L, respectively. A similar significant inverse association was also observed between ln-transformed PFDA and serum folate. BKMR models further confirmed inverse associations of serum PFOS and PFDA with RBC folate, and serum PFDA with serum folate. However, the inverse associations of PFOA and PFNA with RBC folate shown in multiple linear regression model were not observed or less evident in BKMR analyses. We observed interactions of PFOA with PFOS, PFNA, and PFDA on RBC folate in BKMR models, with the negative slopes for PFOS, PFNA, and PFDA increased when PFOA concentration increased from the 10th percentile to the 90th percentile. Both BKMR and Q-gcomp models suggested that the mixtures of five PFAS showed inverse overall associations with RBC folate concentration. ConclusionsThe present study revealed that adolescent exposure to PFAS might affect serum and RBC folate concentrations.