Red Blood Cell Folate Concentrations Research Articles

RBC Folate and Serum Folate, Vitamin B-12, and Homocysteine in Chinese Couples Prepregnancy in the Shanghai Preconception Cohort

BackgroundThe protective effects of maternal folate on neural tube defects are well-established. Emerging evidence has shown paternal folate also is related to pregnancy outcome and offspring health. ObjectivesThis study aimed to assess the status of red blood cell (RBC) folate and serum folate, vitamin B-12, and homocysteine (Hcy) and their associated factors in a cohort of pregnancy-preparing couples. MethodsThis was a cross-sectional study involving 14,178 participants from the extension of the Shanghai Preconception Cohort conducted in 2018–2021. Circulating biomarker concentrations were measured, and the prevalence of abnormal status was reported. Linear and logistic regression analyses were conducted to examine associations of demographic factors (age, education, and income), lifestyle factors (smoking, drinking, and folic acid supplement use), and BMI with concentrations of the folate-related biomarkers, abnormal status of folate (deficiency and insufficiency) and vitamin B-12 (deficiency and marginal deficiency), and hyperhomocysteinemia. ResultsThe geometric mean (95% CI) concentrations of RBC folate, serum folate, vitamin B-12, and Hcy were 490 nmol/L (485, 496 nmol/L), 20.1 nmol/L (19.8, 20.3 nmol/L), 353 pmol/L (350, 357 pmol/L), and 7.54 μmol/L (7.48, 7.60 μmol/L) in females, respectively, and 405 nmol/L (401, 409 nmol/L), 13.5 nmol/L (13.4, 13.7 nmol/L), 277 pmol/L (274, 279 pmol/L), and 12.0 μmol/L (11.9, 12.2 μmol/L) in males, respectively. Prevalence of abnormal status was higher in males than females for the 4 folate-related biomarkers: RBC folate deficiency (<340 nmol/L, 32.2% compared with 18.9%), serum folate deficiency (<10.0 nmol/L, 26.5% compared with 7.3%), RBC folate insufficiency (<906 nmol/L, 96.6% compared with 90.1%), serum folate insufficiency (<15.9 nmol/L, 65.5% compared with 31.4%), vitamin B-12 marginal deficiency (148–221 pmol/L, 21.4% compared with 8.8%), and hyperhomocysteinemia (>15.0 μmol/L, 22.1% compared with 2.5%). ConclusionsMost pregnancy-preparing couples failed to achieve the optimal RBC folate status (>906 nmol/L) as recommended by the WHO. These findings call for attention to the insufficiency status of folate and promising strategies to improve the folate status of the pregnancy-preparing population not exposed to folic acid fortification.

Reduced Kidney Function Is Associated with Increasing Red Blood Cell Folate Concentration and Changes in Folate Form Distributions (NHANES 2011-2018).

Background: Current studies examining the effects of high concentrations of red blood cell (RBC) or serum folates assume that high folate concentrations are an indicator of high folic acid intakes, often ignoring the contributions of other homeostatic and biological processes, such as kidney function. Objective: The current study examined the relative contributions of declining kidney function, as measured by the risk of chronic kidney disease (CKD), and usual total folic acid intake on the concentrations of RBC folate and serum folate (total as well as individual folate forms). Design: Cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) collected in 2-year cycles were combined from 2011 to 2018. A total of 18,127 participants aged ≥16 years with available folate measures, kidney biomarker data (operationalized as a categorical CKD risk variable describing the risk of progression), and reliable dietary recall data were analyzed. Results: RBC folate concentrations increased as CKD risk increased: low risk, 1089 (95% CI: 1069, 1110) nmol/L; moderate risk, 1189 (95% CI: 1158, 1220) nmol/L; high risk, 1488 (95% CI: 1419, 1561) nmol/L; and highest risk, 1443 (95% CI: 1302, 1598) nmol/L (p < 0.0001). Similarly, serum total folate concentrations increased as CKD risk increased: low risk: 37.1 (95% CI: 26.3, 38.0) nmol/L; moderate risk: 40.2 (95% CI: 38.8, 41.7) nmol/L; high risk: 48.0 (95% CI: 44.3, 52.1) nmol/L; the highest Risk: 42.8 (95% CI: 37.8, 48.4) nmol/L (p < 0.0001). The modeled usual intake of folic acid showed no difference among CKD risk groups, with a population median of 225 (interquartile range: 108–390) µg/day. Conclusion: Both RBC and serum folate concentrations increased with declining kidney function without increased folic acid intake. When analyzing associations between folate concentrations and disease outcomes, researchers may want to consider the confounding role of kidney function.

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.

Red blood cell folate level and associated factors of folate insufficiency among pregnant women attending antenatal care during their first trimester of pregnancy in Addis Ababa, Ethiopia.

Objective:Folate is an essential vitamin for de novo DNA synthesis and cell proliferation. Folate insufficiency at the time of conception and during the first trimester of pregnancy is associated with unintended pregnancy and birth outcomes, particularly neural tube defects. Hence, this study aimed to assess folate status and associated factors of folate insufficiency among pregnant women attending antenatal care during their first trimester of pregnancy in Addis Ababa, Ethiopia.Materials and methods:A cross-sectional study was conducted from 8 August 2017 to 3 January 2018 in Addis Ababa. In this study, 160 participants were enrolled via the convenience sampling method. Red blood cell folate was measured by the electrochemiluminescence binding assay method. Data were entered into Epi-Data version 3.1 and analyzed by SPSS version 22.0. Descriptive statistics were used to describe demographic characteristics and to determine the magnitude of folate deficiency. Logistic regression was used to identify the risk factors for folate deficiency. A p-value of less than 0.05 was considered statistically significant.Results:In this study, 44/160 (27%) participants had red blood cell folate level <400 ng/mL, insufficient to prevent neural tube defect. Multivariate regression showed that regular vegetable consumption was an independent determinant factor for red blood cell folate level (adjusted odds ratio: 0.41, confidence interval: 0.18–0.93).Conclusion:This study shows that a large magnitude of the first-trimester pregnant women had red blood cell folate concentrations below levels that are maximally protective against neural tube defects. Folic acid supplementation and supplemental nutrition containing green leafy vegetables should be promoted during the periconceptional period. In addition, the policymakers should set rules for mandatory folic acid fortification.

Association between cooking fuel and folate insufficiency among pregnant women in Northern China

ABSTRACT This study explored whether using a coal or biomass stove for cooking was associated with a greater risk of red blood cell (RBC) folate insufficiency among pregnant women compared to using clean energy. A researcher-designed questionnaire was used to collect information on exposure-related factors and confounding factors. RBC folate concentrations were examined by microbiological assay. Binary logistic regression analysis was used to identify factors related to RBC folate insufficiency. The use of coal or firewood for cooking was associated with an increased risk of RBC folate insufficiency (<906 nmol/L) compared to gas. In subgroup analyses, associations between the use of polluting cooking fuels and folate insufficiency were positive for both urban and rural residents and statistically significant for rural women. Efforts to promote the use of clean energy and proper ventilation, especially in rural areas, are recommended to improve the health of pregnant women and their offspring.

Prevalence and Disparities in Folate and Vitamin B12 Deficiency Among Preschool Children in Guatemala.

Folate and vitamin B12 deficiencies can impair proper growth and brain development in children. Data on the folate and vitamin B12 status of children aged 6-59months in Guatemala are scarce. Identification of factors associated with higher prevalence of these micronutrient deficiencies within the population is needed for national and regional policymakers. To describe national and regional post-fortification folate and vitamin B12 status of children aged 6-59months in Guatemala. A multistage, cluster probability study was carried out with national and regional representation of children aged 6-59months. Demographic and health information was collected for 1246 preschool children, but blood samples for red blood cell (RBC) folate and vitamin B12 were collected and analyzed for 1,245 and 1143 preschool children, respectively. We used the following deficiency criteria as cutoff points for the analyses: < 305nmol/L for RBC folate, < 148pmol/L for vitamin B12 deficiency, and 148-221pmol/L for marginal vitamin B12 deficiency. Prevalence of RBC folate deficiency and vitamin B12 deficiency and marginal deficiency were estimated. Prevalence risk ratios of RBC folate and vitamin B12 deficiency were estimated comparing subpopulations of interest. The national prevalence estimates of RBC folate deficiency among children was 33.5% [95% CI 29.1, 38.3]. The prevalence of RBC folate deficiency showed wide variation by age (20.3-46.6%) and was significantly higher among children 6-11months and 12-23months (46.6 and 37.0%, respectively), compared to older children aged 48-59months (20.3%). RBC folate deficiency also varied widely by household wealth index (22.6-42.0%) and geographic region (27.2-46.7%) though the differences were not statistically significant. The national geometric mean for RBC folate concentrations was 354.2nmol/L. The national prevalences of vitamin B12 deficiency and marginal deficiency among children were 22.5% [95% CI 18.2, 27.5] and 27.5% [95% CI 23.7, 31.7], respectively. The prevalence of vitamin B12 deficiency was significantly higher among indigenous children than among non-indigenous children (34.5% vs. 13.1%, aPRR 2.1 95% CI 1.4, 3.0). The prevalence of vitamin B12 deficiency also significantly varied between the highest and lowest household wealth index (34.3 and 6.0%, respectively). The national geometric mean for vitamin B12 concentrations was 235.1pmol/L. The geometric means of folate and B12 concentrations were significantly lower among children who were younger, had a lower household wealth index, and were indigenous (for vitamin B12 only). Folate and vitamin B12 concentrations showed wide variation by region (not statistically significant), and the Petén and Norte regions showed the lowest RBC folate and vitamin B12 concentrations, respectively. In this study, a third of all children had RBC folate deficiency and half were vitamin B12 deficient. Folate deficiency was more common in younger children and vitamin B12 deficiency was more common in indigenous children and those from the poorest families. These findings suggest gaps in the coverage of fortification and the need for additional implementation strategies to address these gaps in coverage to help safeguard the health of Guatemalan children.

Perfluoroalkyl Substances (PFAS) and Red Blood Cell Folate Levels in the U.S. Adult Population, NHANES

BACKGROUND AND AIM: Adequate folate is essential for many physiological processes, and low folate levels have been associated with cardiovascular disease, anemia, and various health outcomes, including developmental outcomes in relation to low folate status during pregnancy. On the other hand, perfluoroalkyl substance (PFAS) have been associated with multiple health outcomes, with scarce data on the mechanistic pathways by which these substances exert their effects. Our objective is to investigate the individual and joint associations of a mixture of PFAS with red blood cell (RBC) folate concentrations in the adult U.S. population. METHODS: We assessed associations of five chemical biomarkers of 8961 participants ages 18-80 from the U.S. National Health and Nutrition Examination Survey (2007-2016). RBC folate were quantified using a micro bioassay and mass spectrometry. We estimated covariate-adjusted independent and joint associations between PFAS and RBC folate concentrations and triangulated evidence from three approaches developed to examine chemical mixtures: Exposome Wide Association (ExWAS), Bayesian Kernel Regression (BKMR), and Quantile G-Computation (QgComp). We additionally evaluated potential effect modification by sex. RESULTS:The geometric mean RBC folate was 468 µg/L (geometric standard deviation: 1.5 µg/L). In ExWAS analyses, all PFAS were associated with lower RBC folate concentrations. For instance, a twofold increase in Perfluorononanoic acid was associated with a 10% (95% CI: 9%, 11%) decrease in RBC folate concentrations. BKMR and QgComp showed convergent results with a one quartile increase in the PFAS mixture associated with comparable decreases in RBC folate concentrations. Associations did not differ between males and females. CONCLUSIONS:This study is the first to examine the associations between PFAS and RBC folate concentrations in a nationally representative sample. These results may deepen our understanding of the mechanistic pathways by which PFAS impact health outcomes. KEYWORDS: PFAS,Folate,Methods,BKMR,ExWAS,G-Computation

Impact of Voluntary Folic Acid Fortification of Corn Masa Flour on RBC Folate Concentrations in the U.S. (NHANES 2011–2018)

ObjectivesSurveillance data have highlighted continued disparities in neural tube defects (NTDs) among infants of Hispanic women of reproductive age (HWRA) in the United States. Starting in 2017, the US Food and Drug Administration implemented voluntary folic acid fortification of corn masa flour to reduce the risk of NTDs. We assessed folate status, using red blood cell (RBC) folate concentrations, in HWRA (aged 12–49 y) before (2011–2016) and after (2017–2018) voluntary fortification of corn masa, stratified by acculturation factors (i.e., primary language spoken at home, length of time residing in the US). MethodsCross-sectional data from the National Health and Nutrition Examination Survey (NHANES) 2011–2018 with available RBC folate concentrations for HWRA were analyzed. Additional analyses were conducted among HWRA whose only folic acid source was fortified foods (enriched cereal grain products (ECGP) only), including usual intake and NTD prevalence estimations based on previously published models. ResultsOverall, RBC folate concentrations (adjusted geometric means) among HWRA remained similar from 2011–2016 to 2017–2018, though RBC folate significantly increased in 2017–2018 among lesser acculturated HWRA consuming ECGP only. Concentrations for those who were born outside the US and resided in the US < 15 y increased from 894 nmol/L (95% CI: 844–946) in 2011–2016 to 1018 nmol/L (95% CI: 982–1162; p < 0.001) in 2017–2018. Primarily Spanish speaking HWRA who consumed ECGP only increased from 941 nmol/L (95% CI: 895–990) in 2011–2016 to 1034 nmol/L (95% CI: 966–1107; p = 0.03) in 2017–2018. We observed no significant changes in the proportion at risk of NTD (<748 nmol/L) and no changes in Bayesian model-based estimated NTD rates. ConclusionsThis early analysis following voluntary corn masa fortification found an increase in RBC folate concentrations in lesser acculturated groups relying on fortified foods as their primary folic acid source, though HWRA overall had no significant increase in folate concentrations. These early data suggests that there is remaining risk among Hispanics for folate sensitive NTDs; continued monitoring of folate status with NHANES will help assess the long-term efficacy of voluntary fortification. Funding SourcesNo funding sources outside of salaries.

Red blood cell folate, high-risk human papillomavirus risk and cervical intraepithelial neoplasia development: A large Chinese community-based cohort study of cervical screening.

10547 Background: Although low folate status has been implicated in cervical carcinogenesis, large-scale population-based prospective cohort studies controlling for high-risk types of human papillomavirus (hrHPV) infection are lacking. The aim of this study is to evaluate the associations of red blood cell (RBC) folate, hrHPV infection risk and cervical intraepithelial neoplasia (CIN) development. Methods: In this prospective, population-based cohort study, we analyzed the cross-sectional data of 2304 women from a large cervical cancer screening program of 40,000 women aged 19-65 years in the Chinese rural area from 2014-2015. We conducted a nested case-control study including 35 CIN1 progression cases and 105 CIN1 regression controls. A logistic regression model was used to evaluate the associations of RBC folate and hrHPV infection risk and CIN1 development. Results: The median RBC folate concentration decreased gradually with cervical lesion severity. The risks of CIN 1 and CIN2 or worse (CIN 2+) in the 1st quartile of RBC folate concentration were significantly higher than those in the 4th quartile (Odds Ratio [OR], 2.27; 95% confidence interval [CI], 1.71-3.01 and OR, 2.33; 95% CI,1.52-3.56; respectively). We did not observe a significant relationship between hrHPV infection and CIN1 risk in the unadjusted and adjusted models, however, a statistically significant association was observed for CIN2+. Interestingly, RBC folate concentration was not associated with hrHPV infection among women with CIN1 or CIN2+. After full adjustment for potential confounders, a highly significant inverse linear relation between RBC folate concentration and CIN2+ was observed ( P-overall＜0.001, P-nonlinearity = 0.969). We further observed a positive additive interaction between RBC folate concentration and hrHPV infection on the risk of CIN2+ ( P-interaction＜0.01). Moreover, during the 21-month follow-up, CIN1 progression risk was significantly higher in the lowest RBC folate quartile (1st quartile compared with 4th quartile: OR, 3.86; 95% CI,1.01-14.76). Conclusions: Our findings indicates that RBC folate is inversely associated with the risk of higher-grade CIN and CIN1 progression in the Chinese rural population, either with or without hrHPV infection. Therefore, improving folate status has the potential to prevent higher-grade CIN and cervical cancer among women in the areas without mandatory folic acid food fortification. Clinical trial information: ChiCTR-ROC-15006479 .

Impact of the increasing concentrations of selected perfluoroalkyl acids on the observed concentrations of red blood cell folate among US adults aged ≥20 years.

For the first time (N = 6291), a study was undertaken to estimate associations between the concentratio ns of red blood cell folate (RBCF) and concentration of six perfluoroalkyl acids (PFAAs), namely, perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), perfluorodecanoic acid (PFDA), perfluorononanoic acid (PFNA), and perfluoroundecanoic acid (PFUnDA) for US adults aged ≥20 years by fitting regression models for the data from National Health and Nutrition Examination Survey for 2007-2014. In almost consistent fashion, increasing concentrations of PFAAs were associated with decreasing concentrations of RBCF. For the total population, for a 10% increase in the concentrations of PFOA, PFOS, PFDA, PFHxS, PFNA, and PFUnDA, percent decreases in RBCF concentrations were found to be 0.33%, 0.66%, 0.83%, 0.16%, 0.89%, and 0.43%, respectively. RBCF concentrations of PFAAs were found to be 1104, 1042, 100, and 936 nmol/L across the four quartiles of PFOS; 112, 1068, 1009, and 948 nmol/L across the four quartiles of PFDA; 1125, 1054, 1005, and 967 nmol/L across the four quartiles of PFNA; and 1099, 1094, 989, and 952 nmol/L across the four quartiles of PFUnDA. Perfluorinated carboxylic acids with carbon chain length > 8 decreased concentrations of RBCF to a greater degree than those carbon chain length ≤ 8. Perfluorinated chemicals with a sulfonic group with carbon chain length > 6 decreased concentrations of RBCF to a greater degree than those carbon chain length ≤ 6. The degree to which concentrations of RBCF decrease varied by age, gender, and race/ethnicity. Non-Hispanic blacks as compared to non-Hispanic whites and Hispanics had the lowest decreases in RBCF concentrations. Mechanisms responsible for negative associations between RBCF and PFAA concentrations are not known and will need to be researched further.

Impact of Voluntary Folic Acid Fortification of Corn Masa Flour on RBC Folate Concentrations in the U.S. (NHANES 2011-2018).

Surveillance data have highlighted continued disparities in neural tube defects (NTDs) by race-ethnicity in the United States. Starting in 2016, the Food and Drug Administration (FDA) authorized voluntary folic acid fortification of corn masa flour to reduce the risk of neural tube defects (NTDs) among infants of Hispanic women of reproductive age. To assess the impact of voluntary corn masa fortification, cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) 2011–2018 for Hispanic women of reproductive age with available red blood cell (RBC) folate concentrations were analyzed, with additional analyses conducted among Hispanic women whose sole source of folic acid intake was fortified foods (enriched cereal grain products (ECGP) only), excluding ready-to-eat cereals and supplements. RBC folate concentration (adjusted geometric mean) among Hispanic women of reproductive age did not differ between 2011–2016 and 2017–2018, though RBC folate concentration increased significantly among lesser acculturated Hispanic women consuming ECGP only. Concentrations of RBC folate for those born outside the U.S and residing in the U.S <15 years increased from 894 nmol/L (95% CI: 844–946) in 2011–2016 to 1018 nmol/L (95% CI: 982–1162; p < 0.001) in 2017–2018. Primarily Spanish-speaking Hispanic women of reproductive age who only consumed ECGP saw an increase from 941 nmol/L (95% CI: 895–990) in 2011–2016 to 1034 nmol/L (95% CI: 966–1107; p = 0.03) in 2017–2018. By subpopulation, we observed no significant changes in the proportion at risk of NTDs (<748 nmol/L) and no changes in the model-based estimated NTD rates following voluntary corn masa fortification. This analysis suggests that there is a remaining risk among Hispanics for folate sensitive NTDs, though continued monitoring of folate status in future NHANES data cycles will help inform the long-term efficacy of voluntary fortification of corn masa flour.

Inadequate Status and Low Awareness of Folate in Switzerland-A Call to Strengthen Public Health Measures to Ensure Sufficient Intakes.

Background: Folate plays an essential role in the prevention of neural tube defects, yet little is known about the folate status of women of reproductive age or to what degree the general population is aware of the importance of folate in early-life development. We aimed to determine folate status in women of reproductive age and pregnant women in Switzerland, and to assess folate awareness in the Swiss population. Methods: In a convenience sample of 171 women of reproductive age and 177 pregnant women throughout Switzerland, we measured red blood cell (RBC) folate concentration. In a second convenience sample (n = 784, men and women) we assessed folate knowledge with an online survey. Results: RBC folate concentration (median interquartile range) was 442 (366, 564) nmol/L in women of reproductive age and 873 (677, 1177) nmol/L in pregnant women. Folate deficiency (RBC folate <340 nmol/L) was found in 19.9% of women of reproductive age and 2.8% of pregnant women, while 91.8% of women of reproductive age and 52.0% of pregnant women showed folate concentrations indicating an elevated risk of neural tube defects (RBC folate <906 nmol/L). The online survey showed that a high proportion (≥88%) of participants were aware of folate’s role in neural tube defect (NTD) prevention and fetal development, yet knowledge about dietary sources and national recommendations of folate supplementation when planning pregnancy were limited. Conclusion: The high prevalence of folate inadequacy in Swiss women suggests an elevated risk of neural tube defects and calls for urgent measures to increase folate intakes.

Study protocol for a randomised controlled trial evaluating the effect of folic acid supplementation beyond the first trimester on maternal plasma unmetabolised folic acid in late gestation

IntroductionTaking folic acid containing supplements prior to and during early pregnancy reduces the risk of neural tube defects. Neural tube defects occur prior to 28 days postconception, after which, there...

Environmental Chemicals and Red Blood Cell Folate levels in the U.S. Population, NHANES

Background/Aim: Inadequate folate during pregnancy has been associated with congenital birth deficits and adverse neurodevelopmental outcomes, including autism spectrum disorders. Recent studies show that folic acid supplementation may protect against the potential adverse effects of gestational chemical exposures on neurodevelopment. However, it is unclear whether these chemicals impact folate metabolism. Therefore, we investigated the relationship between environmental chemicals and red blood cell (RBC) folate concentrations.Methods: We assessed associations of 41 chemical biomarkers including metals, phthalate metabolites, per- and polyfluroalkyl substances (PFAS), parabens, and polycyclic aromatic hydrocarbons with RBC folate concentrations in 41,433 participants ages 1-80 from the U.S. National Health and Nutrition Examination Survey (2007-2016). We triangulated evidence from three statistical methods developed to examine chemical mixtures: Exposome Wide Association (ExWAS), Bayesian Kernel Regression (BKMR), and SuperLearner with G-computation. We examined the individual and joint associations of these chemicals with RBC folate concentrations, while adjusting for confounders. Results: The geometric mean RBC folate was 463 ng/mL (Interquartile range: 361 - 587.2 ng/mL). Some metals, PFAS, phthalates, and cotinine were consistently associated with lower RBC folate concentrations. Using BKMR, an interquartile range increase in perfluorononanoic acid (PFNA), cotinine, mono-ethyl phthalate, and lead was associated with a -0.15 standard deviation (SD) (95% confidence interval (CI): -0.23, -0.07), -0.11 SD (95% CI: -0.17, -0.03), -0.03 SD (95% CI: -0.07, 0.02), and -0.18 SD (95% CI: -0.25, -0.10) decrease in RBC folate concentrations, respectively. Estimates differed slightly between methods, but these findings remained robust. Conclusion: This study, which is the first to examine an association between a mixture of environmental chemicals and RBC folate concentrations in a nationally representative sample, may help enhance our understanding of the interplay between environmental chemicals, folate, and adverse health outcomes.

Is natural (6S)-5-methyltetrahydrofolic acid as effective as synthetic folic acid in increasing serum and red blood cell folate concentrations during pregnancy? A proof-of-concept pilot study

BackgroundNorth American health authorities recommend 0.4 mg/day folic acid before conception and throughout pregnancy to reduce the risk of neural tube defects. Folic acid is a synthetic form of folate that must be reduced by dihydrofolate reductase and then further metabolized. Recent evidence suggests that the maximal capacity for this process is limited and unmetabolized folic acid has been detected in the circulation. The biological effects of unmetabolized folic acid are unknown. A natural form of folate, (6S)-5-methyltetrahydrofolic acid (Metafolin®), may be a superior alternative because it does not need to be reduced in the small intestine. Metafolin® is currently used in some prenatal multivitamins; however, it has yet to be evaluated during pregnancy.Methods/designThis double-blind, randomized trial will recruit 60 pregnant women aged 19–42 years. The women will receive either 0.6 mg/day folic acid or an equimolar dose (0.625 mg/day) of (6S)-5-methyltetrahydrofolic acid for 16 weeks. The trial will be initiated at 8–21 weeks’ gestation (after neural tube closure) to reduce the risk of harm should (6S)-5-methyltetrahydrofolic acid prove less effective. All women will also receive a prenatal multivitamin (not containing folate) to ensure adequacy of other nutrients. Baseline and endline blood samples will be collected to assess primary outcome measures, including serum folate, red blood cell folate and unmetabolized folic acid. The extent to which the change in primary outcomes from baseline to endline differs between treatment groups, controlling for baseline level, will be estimated using linear regression. Participants will have the option to continue supplementing until 1 week postpartum to provide a breastmilk and blood sample. Exploratory analyses will be completed to evaluate breastmilk and postpartum blood folate concentrations.DiscussionThis proof-of-concept trial is needed to obtain estimates of the effect of (6S)-5-methyltetrahydrofolic acid compared to folic acid on circulating biomarkers of folate status during pregnancy. These estimates will inform the design of a definitive trial which will be powered to assess whether (6S)-5-methyltetrahydrofolic acid is as effective as folic acid in raising blood folate concentrations during pregnancy. Ultimately, these findings will inform folate supplementation policies for pregnant women.Trial registrationClinicalTrials.gov, ID: NCT04022135. Registered on 14 July 2019.

Associations Between Gestational Diabetes Mellitus Risk and Folate Status in Early Pregnancy and MTHFR C677T Polymorphisms in Chinese Women.

PurposeRed blood cell (RBC) folate indicates long-term folate intake, and methylenetetrahydrofolate reductase (MTHFR) gene is the main gene affecting folate status. Increasing evidence suggests an association between gestational diabetes mellitus (GDM) and increased folate levels. Whether RBC folate concentrations in the first trimester of pregnancy or polymorphisms of MTHFR C677T (rs1801133) affect GDM risk in Chinese pregnant women remains unknown. Therefore, we analyzed the associations of RBC folate concentrations and rs1801133 polymorphisms with GDM risk among pregnant women in China.MethodsA total of 366 women with a singleton pregnancy were followed prospectively from their first prenatal visit to delivery. RBC folate concentrations and rs1801133 polymorphisms were assessed during the first trimester of pregnancy. Binary logistic regression analyses were performed to determine the odds ratios (ORs) of GDM and 95% confidence intervals (CIs) by using the RBC folate concentration quartiles and rs1801133 polymorphisms.ResultsParticipants with the TT genotype had the highest RBC folate concentrations. Those with heterozygous or homozygous variants did not have a significantly higher risk of GDM than did women with C alleles. After adjustments for covariates, women in the highest quartile for RBC folate concentration had a higher risk of GDM (adjusted OR = 2.473, 95% CI = 1.013–6.037, P = 0.047) than did those in the lowest quartile, but this association was nonsignificant after adjustment for rs1801133 polymorphisms.ConclusionHigher RBC folate, partly caused by MTHFR 677C→T, may be associated with increased GDM risk, even in early pregnancy. Assessing RBC folate status and appropriately supplementing folate during early pregnancy, particularly for patients with MTHFR 677C→T, may prevent GDM. Further studies with larger populations are warranted.

Red Blood Cell Folate Likely Overestimated in Australian National Survey: Implications for Neural Tube Defect Risk.

In 2009, the Australian government mandated the addition of folic acid to bread flour to reduce the incidence of neural tube defects (NTD)-affected pregnancies. In 2011–2012, the Australian Health Measures Survey (AHMS) reported a mean red blood cell (RBC) folate in women of reproductive age (16–44 y) of 1647 nmol/L. Over 99% of women had an RBC folate ≥ 906 nmol/L, a concentration consistent with a very low risk of NTDs if a woman became pregnant. However, RBC folate was measured using an immunoassay, which is not a recommended method due to questionable accuracy. The microbiological assay is the preferred method for RBC folate measurement. To determine whether the immunoassay method may have led to spurious conclusions about the folate status of Australian women, we collected fasting blood samples from 74 healthy non-pregnant, non-lactating women (18–44 y) and measured RBC folate using both the immunoassay and microbiological methods. Mean RBC folate (95% confidence interval) concentration measured with the immunoassay method was 1735 (1666, 1804) nmol/L compared with 942 (887, 1012) nmol/L using the microbiological method. No woman had an RBC folate < 906 nmol/L using the immunoassay method, whereas 46% of women had an RBC folate < 906 nmol/L using the microbiological method. The NTD risk was estimated to be 0.06% using the immunoassay method and 0.14% using the microbiological method. RBC folate using AHMS survey may have underestimated NTD risk in Australian women.

Maternal folate levels during pregnancy and children's neuropsychological development at 2 years of age.

To explore the relationship between maternal folate levels during pregnancy and children's neuropsychological development at 2 years of age. In the birth cohort MKFOAD, maternal serum folate concentrations at 12-14, 22-26, and 34-36 weeks of gestation were measured, as well as red blood cell (RBC) folate at 12-14 weeks. Neurodevelopment of 2-year-old children was assessed by Gesell Development Scale (GDS), which contained subscales of gross motor, fine motor, language, adaptive behavior, and social behavior. Linear regression models were applied to investigate the association of maternal folate levels with children's developmental quotients (DQs). One hundred and eighty singleton children participated the GDS assessment, of whom 97 (53.9%) were boys. Median RBC folate concentration was 1002.8 (IQR = 577.6) nmol L-1 in early pregnancy and median serum folate concentrations were, respectively, 33.9 (IQR = 9.2) nmol L-1, 26.3 (IQR = 14.3) nmol L-1, and 26.7 (IQR = 18.9) nmol L-1. Maternal serum folate concentration in late pregnancy was significantly associated with children's language development, where language DQ increases by 3.1 (95% CI 0.6, 5.5) for every 10 nmol L-1 increment of serum folate concentration. And maternal serum folate in early pregnancy was significantly associated with children's fine motor development, with 2.0 (95% CI 0.1, 4.0) DQ decrease for 10 nmol L-1 increase of serum folate. Maternal serum folate in late pregnancy was significantly associated with children's language development at age 2, which supports the importance of remaining folic acid supplementation across the entire gestation. However, maternal serum folate in early pregnancy was also inversely associated with children's fine motor development.

Maternal Cotinine Levels and Red Blood Cell Folate Concentrations in the Periconceptual Period.

Studies have examined the association between tobacco use and folate levels in pregnancy, yet few have assessed this relation using objective and accurate measures of both smoking and folate. In this study, we evaluated the association between maternal cotinine levels and periconceptional red blood cell (RBC) folic acid reserves in a cohort of low-income pregnant mothers. Smoking information, based on salivary cotinine, a highly sensitive and specific tobacco smoke exposure biomarker, was used. Furthermore, folate was assessed using RBC folate, an indicator of long-term folate storage. Participants were early to mid-trimester pregnant women who received antenatal care between 2011 and 2015 at the Genesis Clinic of Tampa (Florida). A total of 496 women were enrolled in the study. Associations between smoking status/maternal salivary cotinine concentrations, sociodemographic factors, and folate concentrations were investigated using Tobit regression analyses. The mean folate level of the participants was 718.3 ± 183.2 ng/mL, and only 2 (0.4%) participants were deficient in folate. We observed no significant difference in folate levels by smoking status. In contrast, salivary cotinine levels were significantly associated with decreased RBC folate concentrations (β -11.43, standard error 5.45, P = 0.032). Prepregnancy maternal body mass index, gestational age, stress, and depression also were associated with folate levels. Low RBC folate is associated with perinatal factors, including high maternal cotinine levels, body mass index, stress, and depression. The effect of low folate levels among smokers cannot be overemphasized, considering that tobacco products not only reduce folate levels but also decrease the bioutilization of folate.

Association between body mass index and folate insufficiency indicative of neural tube defects risk among nonpregnant women of childbearing age in the United States, NHANES, 2007-2010.

Maternal folate status and obesity are known risk factors for neural tube defects (NTD) in the offspring. We examined the association between body mass index (BMI) categories and blood folate concentrations, specifically, red blood cell (RBC) folate concentrations indicative of NTD risk among nonpregnant women of child-bearing age (20-44 years) in the United States. We used data from 2007 to 2010 US National Health and Nutrition Examination Survey (NHANES). Overweight, obesity, and strata within obesity were examined. Serum and RBC folate concentrations were examined as continuous and categorical variables. RBC folate concentrations were grouped indicating high (≤585 nmol/L) and elevated risk (586-747 nmol/L) for NTDs. Unadjusted and adjusted prevalence odds ratios (aPOR) and their 95% confidence intervals (CI) were estimated using logistic regression. Of the 30,878 participants, 25.6% were overweight, 32.7% obese, and 32.3% had RBC folate concentration indicating NTD risk (<748 nmol/L). Overweight was not associated with RBC folate level for NTD risk; however, a marginally significant negative association was noted for overall obesity and RBC folate concentrations indicative of elevated NTD risk (aPOR = 0.76; 95% CI = 0.45, 1.00). A significant protective association was noted between Class 3 obesity (BMI ≥40 kg/m2 ) and folate concentration indicative of high NTD risk (≤585 nmol/L; aPOR = 0.46; 95% CI = 0.24, 0.89). The prevalence of RBC folate concentrations indicating elevated or high NTD risk varied by level of obesity among nonpregnant women of child-bearing age. Further studies are needed to understand the folate pathway in overweight and obese women and subsequent NTD risk in their offspring.