Red Blood Cell Folate Research Articles

Homocysteine pathway and in vitro fertilization outcome

A prospective study investigating whether levels of the homocysteine pathway are associated with pregnancy rate in in vitro fertilization (IVF). Prior to initiate treatments, women gave a blood sample to test serum and red blood cell (RBC) folates, homocysteine and vitamin B12. The main outcome was cumulative clinical pregnancy rate according to basal levels of serum and RBC folates, homocysteine and vitamin B12. Two-hundred-nine women were selected, of whom 56 achieved a clinical pregnancy (27%). Median [interquartile range] levels of RBC and serum folate in women who did and did not become pregnant were 328 and 263 ng/ml (p = 0.018) and 13.6 and 9.4 ng/ml (p = 0.001), respectively. The adjusted ORs (95%CI) of pregnancy in women with RBC and serum folate concentrations in the upper tertile of the distributions were 2.6 (1.4–5.1) and 1.9 (1.0–3.7), respectively. Women undergoing IVF treatments with higher levels of folate have a higher chance of clinical pregnancy

Folate status in women of reproductive age as basis of neural tube defect risk assessment.

Reliable folate status data for women of reproductive age (WRA) to assess global risk for neural tube defects (NTDs) are needed. We focus on a recent recommendation by the World Health Organization that a specific "optimal" red blood cell (RBC) folate concentration be used as the sole indicator of NTD risk within a population and discuss how to best apply this guidance to reach the goal of assessing NTD risk globally. We also emphasize the importance of using the microbiologic assay (MBA) as the most reliable assay for obtaining comparable results for RBC folate concentration across time and countries, the need for harmonization of the MBA through use of consistent key reagents and procedures within laboratories, and the requirement to apply assay-matched cutoffs for folate deficiency and insufficiency. To estimate NTD risk globally, the ideal scenario would be to have country-specific population-based surveys of RBC folate in WRA determined utilizing a harmonized MBA, as was done in recent studies in Guatemala and Belize. We conclude with guidance on next steps to best navigate the road map toward the goal of generating reliable folate status data on which to assess NTD risk in WRA in low- and middle-income countries.

Folic acid intake and folate status and colorectal cancer risk: A systematic review and meta-analysis

To evaluate the controversies among the studies assessing the association between folic acid intake or folate status and colorectal cancer risk. PubMed, Cochrane library and references of related articles were searched from January 2000 to September 2016. Studies on folic acid intake or folate status and colorectal cancer or adenoma risk were included. Full text review was conducted for potentially eligible studies. Quality assessment was performed. Random-effects meta-analysis was used to estimate risk ratio and 95% Confidence Intervals. Analysis was conducted by Comprehensive Meta-Analysis software. Folic acid supplement intake showed no significant effect on colorectal cancer risk in meta-analysis of randomized controlled trials, RR: 1.07(95% CI: 0.86-1.43). The effect on risk was not significant in cohort studies either; RR=0.96(95% CI: 0.76-1.21). However, there was significant reduced colorectal cancer risk in total folate intake in cohort studies; 0.71 (95% CI: 0.59-0.86). Odds Ratio was also significantly reduced in case control studies; 0.77 (95% CI: 0.62-0.95). Nevertheless once folate status was measured as Red Blood Cell folate content, no significant effect on colorectal cancer risk was observed; 1.05 (95% CI: 0.85-1.30). The differences in bioavailability and metabolism of synthetic folic acid and natural dietary folate as well as variation in the baseline characteristics of subjects and various methods of folate status assessment might be the main reasons for these controversies. Findings of present study highlightthe importance of individualized folic acid supplement intake given the fact that the beneficiary effects of long term folic acid supplementation is not confirmed.

Optimization of folic acid supplementation in the prevention of neural tube defects.

We examined the relationship between timing and duration of folic acid (FA) supplementation in achieving red blood cell (RBC) folate levels in early pregnancy which are optimal (>906 nmol/l) for the prevention of neural tube defects (NTDs). Clinical, FA supplementation and dietary folate details were computerized at the first antenatal visit. Maternal blood samples were analysed for RBC and serum folate. Of the 502 women, 98.2% (n = 493) reported taking FA. There was a positive correlation between duration of supplementation and both RBC folate (r = 0.43, P < 0.001) and serum folate (rho = 0.29, P < 0.001). The optimal RBC folate level was achieved in 80.4% (n = 46) of women who started FA 400 μg 4-8 weeks before their LMP compared with only 53.6% (n = 153) in women who started 4-8 weeks after their LMP (P < 0.001). This study provides, for the first time, information on both the timing and duration of FA that will achieve the optimum RBC folate levels associated with the prevention of NTDs. Women who are taking FA (400 μg) need to start before they conceive.

A Cross-Sectional Study of Dietary and Genetic Predictors of Blood Folate Levels in Healthy Young Adults.

Since 1998, the U.S. has mandated folic acid (FA) fortification of certain grain products to reduce the risk of neural tube defects. Folate intake and red blood cell (RBC) folate concentrations increased substantially post-intervention, although recent studies raise concerns about the level of ongoing benefit. This study investigated blood folate level determinants in healthy young adults, including intake of naturally occurring food folate, synthetic FA, and the interaction of naturally occurring food folate with a common missense variant in the FOLH1 gene thought to affect absorption. Participants (n = 265) completed the Diet History Questionnaire II, RBC folate testing, and were genotyped for the 484T>C FOLH1 variant. Men reported significantly greater intake of all folate sources except for supplemental FA, but RBC folate levels did not significantly differ by sex. Synthetic FA was a stronger predictor of RBC folate than naturally occurring food folate. In the largest racial group, synthetic FA and the interaction of FOLH1 genotype with naturally occurring food folate significantly predicted RBC folate, with the overall model accounting for 13.8% of the variance in RBC folate levels. Blood folate levels rely on a complex interaction of natural and synthetic folate intake as well as FOLH1 genotype.

Discontinuation of Folic Acid Supplementation in Young Patients With Sickle Cell Anemia.

Folic acid (FA) is commonly prescribed for patients with sickle cell anemia, but evidence for the efficacy of this practice is lacking. We stopped FA supplementation and measured red blood cell folate levels after discontinuation of FA in 72 patients with clinically severe forms of sickle cell disease. We compared hemoglobin and reticulocyte counts before and after FA discontinuation in 51 of those patients, the majority of whom were on hydroxyurea. No patients had red blood cell folate levels below normal and no significant difference in hemoglobin levels (P=0.18) or reticulocyte counts (P=0.37) was found before and after FA discontinuation.

Red blood cell folate concentrations and coronary heart disease prevalence: A cross-sectional study based on 1999–2012 National Health and Nutrition Examination Survey

Background and aimFolate is involved in a number of metabolic pathways. Red blood cell (RBC) folate is a well-established indicator of folate intake. However, studies focused on the association between RBC folate and coronary heart disease (CHD) are limited. The aim of the current study was to investigate the effect of RBC folate concentrations on the presence of CHD in a nationally representative sample of American adults. Methods and resultsIn the 1999–2012 National Health and Nutrition Examination Survey (NHANES), 22,499 subjects aged 30–74 years with RBC folate concentrations, CHD status and responses to co-variates questions were included; 822 (3.65%) participants were identified as having CHD. Bio-Rad Quanta Phase II radioassay and microbiological assay were used to measure RBC folate concentrations. Firstly, we treated RBC folate as a categorical variable, based on RBC folate tertiles, and used logistic regression analysis to display the RBC folate and CHD relationship. Secondly, we explored associations using a combination of restricted cubic spline and logistic regression models, stratified by sex. After adjusting for several well-established traditional CHD risk factors, RBC folate was positively related to CHD presence in the total population and the association was more pronounced among males than females. A J-shaped pattern was observed in RBC folate concentrations for females. ConclusionElevated RBC folate concentrations were associated with higher CHD risk. Further investigation is needed to test the association in large-scale follow-up studies.

Folate and vitamin B12 status is associated with insulin resistance and metabolic syndrome in morbid obesity

Low vitamin B12 and high folate during pregnancy are associated with visceral obesity and insulin resistance in offspring. In the general population, high folate exacerbates the increase of methylmalonic acid, a marker of vitamin B12 deficiency. However, the influence of vitamin B12 and folate and their related markers on insulin resistance and metabolic syndrome remains unknown in severe obesity. To evaluate the influence of vitamin B12 and folate on HOMA-IR and components of metabolic syndrome in severe obesity. 278 consecutive obese patients were assessed prospectively for HOMA-IR, red blood cell (RBC) folates, homocysteine and methylmalonic acid. We compared the associations with the components of metabolic syndrome during the preoperative multidisciplinary evaluation (period-1) and before bariatric surgery (period-2). The HOMA-IR was higher in patients with highest tertile of RBC and either lowest tertile of plasma B12 or highest tertile of MMA (p<0.034 and 0.011, respectively). Lg HOMA-IR was negatively correlated with Lg homocysteine (p<0.0001) and positively correlated with Lg serum folate (p<0.001). The independent predictors for HOMA-IR at period 2 were either BMI and homocysteine (model 1 without serum folate, p=0.010 and p=0.002, respectively)or BMI and MMA (model 2 without homocysteine, p=0.030 and p=0.004, respectively). Age and RBC folate remained independently associated with the number of metabolic syndrome components (p=0.006 and 0.020, respectively). RBC folate, homocysteine, and MMA predict HOMA-IR in severe obesity. Our findings challenge the benefit of folate fortified food in severe obesity, in particular in patients with a deficit of vitamin B12. The cohort study was registered at clinicaltrials.gov as NCT02663388.

Predictors of Hand-Foot Syndrome and Pyridoxine for Prevention of Capecitabine–Induced Hand-Foot Syndrome

ImportanceHand-foot syndrome (HFS) is a common adverse effect of capecitabine treatment.ObjectiveTo compare the incidence and time to onset of grade 2 or greater HFS in patients receiving pyridoxine vs placebo and to identify biomarkers predictive of HFS.Design, Setting, and ParticipantsThis single-center, randomized double-blind, placebo-controlled phase 3 trial conducted at National Cancer Centre Singapore assessed whether oral pyridoxine could prevent the onset of grade 2 or higher HFS in 210 patients scheduled to receive single-agent capecitabine chemotherapy for breast, colorectal, and other cancers.InterventionsPatients were randomized to receive concurrent pyridoxine (200 mg) or placebo daily for a maximum of 8 cycles of capecitabine, with stratification by sex and use in adjuvant or neoadjuvant vs palliative setting. Patients were withdrawn from the study on development of grade 2 or higher HFS or cessation of capecitabine.Main Outcomes and MeasuresPrimary end point was the incidence of grade 2 or higher HFS in patients receiving pyridoxine. Secondary end points included the time to onset (days) of grade 2 or higher HFS and identification of biomarkers predictive of HFS, including baseline folate and vitamin B12 levels, as well as genetic polymorphisms with genome-wide arrays.ResultsIn this cohort of 210 patients (median [range] age, 58 [26-82] years; 162 women) grade 2 or higher HFS occurred in 33 patients (31.4%) in the pyridoxine arm vs 39 patients (37.1%) in the placebo arm (P = .38). The median time to onset of grade 2 or higher HFS was not reached in both arms. In univariate analysis, the starting dose of capecitabine (odds ratio [OR], 1.99; 95% CI, 1.32-3.00; P = .001), serum folate levels (OR, 1.27; 95% CI, 1.10-1.47; P = .001), and red blood cell folate levels (OR, 1.25; 95% CI, 1.08-1.44; P = .003) were associated with increased risk of grade 2 or higher HFS. In multivariate analyses, serum folate (OR, 1.30; 95% CI, 1.12-1.52; P < .001) and red blood cell folate (OR, 1.28; 95% CI, 1.10-1.49; P = .001) were the only significant predictors of grade 2 or higher HFS. Grade 2 or higher HFS was associated with 300 DNA variants at genome-wide significance (P < 5 × 10−8), including a novel DPYD variant (rs75267292; P = 1.57 × 10−10), and variants in the MACF1 (rs183324967, P = 4.80 × 10−11; rs148221738, P = 5.73 × 10−10) and SPRY2 (rs117876855, P < 1.01 × 10−8; rs139544515, P = 1.30 × 10−8) genes involved in wound healing.Conclusions and RelevancePyridoxine did not significantly prevent or delay the onset of grade 2 or higher HFS. Serum and red blood cell folate levels are independent predictors of HFS.Trial Registrationclinicaltrials.gov Identifier: NCT00486213

Short interpregnancy intervals, maternal folate levels, and infants born small for gestational age: a preliminary study in a Canadian supplement-using population.

Short interpregnancy intervals (SIPI) have been associated with increased risks for adverse neonatal outcomes including preterm delivery and infants small for gestational age (SGA). It has been suggested that mechanistically, adverse neonatal outcomes after SIPI arise due to insufficient recovery of depleted maternal folate levels prior to the second pregnancy. However, empirical data are lacking regarding physiological folate levels in pregnant women with SIPI and relationships between quantified physiological folate levels and outcomes like SGA. Therefore, we sought to test 2 hypotheses, specifically that compared with controls women with SIPI would: (i) have lower red blood cell folate (RBCF) levels and (ii) be more likely to have SGA infants (defined as <10th percentile). Using data collected in British Columbia, Canada, for a larger study on perinatal psychopathology, we documented supplementation use and compared prenatal RBCF levels and proportion of SGA infants between women with SIPI (second child conceived ≤24 months after previous birth, n = 26) and matched controls (no previous pregnancies, or >24 months between pregnancies, n = 52). There were no significant differences in either mean RBCF levels (Welch's t test, p = 0.7) or proportion of SGA infants (Fisher's exact test, p = 0.7) between women with SIPI and matched controls. We report the first data about RBCF levels in the context of SIPI. If confirmed, our finding of no relationship between these variables in this population suggests that continued folic acid supplementation following an initial pregnancy mitigates folate depletion. We found no relationship between SIPI and SGA.

One-Carbon Metabolism Biomarkers and Cognitive Decline in the Very Old: The Newcastle 85+ Study

ObjectivesAlthough the biological rationale for the association between folate, vitamin B12, and homocysteine with cognitive function seems plausible, conflicting results have been reported. This study aimed to determine the associations between 1-carbon (1-C) metabolism biomarkers (folate, vitamin B12, and homocysteine), and cognitive impairment at baseline and the rate of cognitive decline over 5 years in the very old. DesignThe Newcastle 85+ Study was a prospective longitudinal study of people 85 years old and followed over 5 years in Northeast England. SettingCommunity-dwelling and institutionalized. ParticipantsThe analytical sample included 765 very old participants with 1-C metabolism biomarkers and cognitive measures. MeasurementsGlobal cognition was measured by the Standardized Mini-Mental State Examination (SMMSE) at baseline, and at 3 and 5 years of follow-up and, attention-specific cognition with the Cognitive Drug Research (CDR) System at baseline, and at 1.5 and 3.0 years of follow-up. Baseline red blood cell folate (RBC folate), plasma vitamin B12, and total homocysteine (tHcy) concentrations were determined by immunoassay. Linear mixed models were used to estimate the associations between quartiles of 1-C metabolism biomarkers and cognition over 3 (CDR) and 5 years (SMMSE). ResultsCompared with participants in the lowest quartile of RBC folate concentrations (<612 nmol/L), those in the highest quartile of RBC folate concentrations (>1280 nmol/L) had 1 more point on the SMMSE at baseline (β = +1.02, SE = 0.43, P = .02). Those in quartile 4 of tHcy (>21.4 μmol/L) had 1 point less in the SMMSE at baseline than those in the lowest quartile (<13.5 μmol/L) (β = −1.05, SE = 0.46, P = .02). Plasma vitamin B12 was not predictive of global or attention-specific cognition at baseline and at follow-up. None of the 1-C metabolism biomarkers except tHcy was associated with the rate of decline in attention scores over 3 years. ConclusionRBC folate and tHcy, but not plasma vitamin B12, were associated with better global cognition in the very old at baseline but were not predictive of rate of decline over 5 years.

A Black Cohosh Extract Causes Hematologic and Biochemical Changes Consistent with a Functional Cobalamin Deficiency in Female B6C3F1/N Mice.

Black cohosh rhizome, available as a dietary supplement, is most commonly marketed as a remedy for dysmenorrhea and menopausal symptoms. A previous subchronic toxicity study of black cohosh dried ethanolic extract (BCE) in female mice revealed a dose-dependent ineffective erythropoiesis with a macrocytosis consistent with the condition known as megaloblastic anemia. The purpose of this study was to investigate potential mechanisms by which BCE induces these particular hematological changes. B6C3F1/N female mice (32/group) were exposed by gavage to vehicle or 1,000 mg/kg BCE for 92 days. Blood samples were analyzed for hematology, renal and hepatic clinical chemistry, serum folate and cobalamin, red blood cell (RBC) folate, and plasma homocysteine and methylmalonic acid (MMA). Folate levels were measured in liver and kidney. Hematological changes included decreased RBC count; increased mean corpuscular volume; and decreased reticulocyte, white blood cell, neutrophil, and lymphocyte counts. Blood smear evaluation revealed increased Howell-Jolly bodies and occasional basophilic stippling in treated animals. Plasma homocysteine and MMA concentrations were increased in treated animals. Under the conditions of our study, BCE administration caused hematological and clinical chemistry changes consistent with a functional cobalamin, and possibly folate, deficiency. Further studies are needed to elucidate the mechanism by which BCE causes increases in homocysteine and MMA.

Development of a Healthy Dietary Habits Index for New Zealand Adults.

Healthful dietary habits are individually associated with better nutrient intake and positive health outcomes; however, this information is rarely examined together to validate an indicator of diet quality. This study developed a 15-item Healthy Dietary Habits Index (HDHI) based on self-reported dietary habits information collected in the 2008/09 New Zealand Adult Nutrition Survey. The validity of HDHI as a diet quality index was examined in relation to sociodemographic factors, 24-diet recall derived nutrient intakes, and nutritional biomarkers in a representative sample of adults aged 19 years and above. Linear regression models were employed to determine associations between HDHI quintiles and energy-adjusted nutrient data and nutritional biomarkers. Significantly higher HDHI scores were found among women, older age groups, Non-Māori or Pacific ethnic groups, and less socioeconomically-deprived groups (all p < 0.001). Increasing quintiles of HDHI were associated with higher intakes of dietary fibre and seven micronutrients including calcium, iron, and vitamin C, and lower intakes of energy, macronutrients, sodium, zinc, vitamins B6 and B12. Associations in the expected directions were also found for urinary sodium, whole blood folate, serum and red blood cell folate, and plasma selenium (all p < 0.001). The present findings suggest that the HDHI is a valid measure of diet quality as it is capable of discerning quality of diets of subgroups and ranking nutrient intakes among NZ adults.

Folic acid intake among U.S. women of childbearing age with suboptimal red blood cell folate concentrations for neural tube defect prevention

BackgroundA recent study reported that 22.8% of U.S. women of childbearing age have folate insufficiency, defined as red blood cell (RBC) folate below optimal concentrations needed for neural tube defect (NTD) prevention per guidelines established by the World Health Organization. Clinical trials have shown that consuming 400 μg of folic acid daily prevents NTDs.ObjectiveWe assessed the daily usual total folic acid intake and RBC folate status of women of childbearing age. We estimated the proportion of women consuming ≥400 μg folic acid/day, the daily amount recommended for NTD prevention for all women capable of becoming pregnant.MethodsWe used 2007–2012 data on non‐pregnant women aged 12–49 years (n = 4783) from the National Health and Nutrition Examination Survey (NHANES) and estimated daily usual total folic acid intake from all fortified foods and dietary supplements. Folate insufficiency was defined as an RBC folate concentration of &lt;748 nmol/L using the NHANES microbiologic assay, which is associated with prevalence of NTDs of ≥9 cases per 10,000 live births.ResultsAmong all women in our study, 21.2% (95% confidence interval [CI]: 18.0, 24.3) had an average total folic acid intake of ≥400 μg /day from fortified foods and supplements. The prevalence of folate insufficiency was 22.5% (95% CI: 20.3, 24.9). Among the subgroup of women with folate insufficiency (n = 1196), only 3.9% (95% CI: 2.0, 5.7) achieved the recommended daily intake of folic acid. Among all women in our study, median usual daily total folic acid intake was highest among non‐Hispanic Whites (264 μg) and lowest among non‐Hispanic Blacks (185 μg). However, among women with folate insufficiency, the median usual daily total folic acid intake did not differ by race/ethnicity. Among women with folate insufficiency, 69.7% (95%CI: 64.8, 74.1) had mandatorily fortified foods (i.e., enriched cereal grain products) as their only source of folic acid; 12.6% (95% CI: 9.7, 16.1) reported taking supplements containing folic acid in the previous 30 days. Among folate‐insufficient women who did not use supplements, less than 1% had usual total folic acid intake ≥400 μg/day.ConclusionsThe majority of U.S. women of childbearing age with RBC folate below the optimal concentration do not consume the amount of folic acid recommended for NTD prevention. Targeted programs and guidance might increase folic acid intake among groups of women at higher risks for folate insufficiency.Support or Funding InformationThis work was supported by the CDC.

Association of Added Sugars Intake with Physiologic Parameters in Adults: NHANES 2001–2012

The association of added sugars intake with liver enzymes, cardiovascular risk factors, and markers of red cell counts was determined using NHANES 2001–2012 data from adults (19+ years; n=26,402). Dietary intake was determined using 24‐hour dietary recall interviews using an Automated Multiple‐Pass Method. The usual intake of added sugars as a percent of energy was estimated using the Markov Chain Monte Carlo (MCMC) ratio method as implemented in v1.0 of the SAS programs published by the National Cancer Institute (NCI). Balanced repeated replication (BRR) was used for variance estimation. Subjects were separated into six groups: 0&lt;5, 5 to &lt;10, 10 to&lt;15, 15 to &lt;20, 20 to &lt;25, and ≥25% of energy as added sugars. Group trends and linear trends for were determined using linear regression (p&lt;0.01) for: alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma‐glutamyl transferase, lactate dehydrogenase, blood pressure, high‐ and low‐density lipoprotein cholesterol, triglycerides, glucose, c‐reactive protein, waist circumference, ferritin, serum and red blood cell folate, hemoglobin, and hematocrit. None of the liver enzyme levels showed any significant association with added sugars intake. Mean plasma glucose levels (mg/dL) showed an inverse group (beta = −0.71; p=0.0003) and linear trend (beta = −0.13); p=0.0002) association with increasing percent energy of added sugars. No other cardiovascular risk factors, including metabolic syndrome, showed any association with added sugars intake. Only hemoglobin (g/dL) (beta = −0.03, p=0.0007; beta = 0.005, p=0.0013) and hematocrit (%) (beta = −0.09, p=0.0001; beta = −0.02, p=0.0002) showed a group or linear trend, respectively. No other statistical associations were found. These results suggest that the association of usual added sugars intake, as determined by sophisticated models, up to &gt;25% of energy, had limited effect on physiologic parameters in adults.Support or Funding InformationUSDA Hatch Project LAB 94209 and USDA/ARS through specific cooperative agreement 58‐6250‐6‐003 was received. Partial support was also received from the Corn Refiners Association.

Association of TCN2 rs1801198 c.776G>C polymorphism with markers of one-carbon metabolism and related diseases: a systematic review and meta-analysis of genetic association studies

Background: Vitamin B-12 (cobalamin) deficiency may produce severe neurologic and hematologic manifestations. Approximately 20-25% of circulating cobalamin binds to transcobalamin 2 (TCN2), which is referred to as active vitamin B-12. The G allele of the TCN2 c.776G>C (rs1801198) polymorphism has been associated with a lower plasma concentration of holotranscobalamin. However, genotype association studies on rs1801198 have led to conflicting results regarding its influence on one-carbon metabolism (OCM) markers or its association with pathologic conditions.Objective: We assessed the association of rs1801198 genotypes with OCM marker concentrations and primary risks of congenital abnormalities, cancer, and Alzheimer disease.Design: We conducted a systematic review of the literature that was published from January 1966 to February 2017 and included all studies that assessed the association between rs1801198 and OCM markers or a pathologic condition.Results: Thirty-four studies met the inclusion criteria. Subjects with the rs1801198 GG genotype had significantly lower concentrations of holotranscobalamin [standardized mean difference (SMD): -0.445 (95% CI: -0.673, -0.217; P < 0.001); I2 = 48.16% (95% CI: 0.00%, 78.10%; P = 0.07)] and higher concentrations of homocysteine (European descent only) [SMD: 0.070 (95% CI: 0.020, 0.120; P = 0.01); I2 = 0.00% (95% CI: 0.00%, 49.59%; P = 0.73)] than did subjects with the rs1801198 CC genotype. The meta-analysis on the association between rs1801198 and methylmalonic acid (MMA) lacked statistical power. No significant difference was observed regarding cobalamin, folate, and red blood cell folate. No significant association was observed between rs1801198 and primary risks of congenital abnormalities, cancer, or Alzheimer disease.Conclusions: Meta-analysis results indicate an influence of rs1801198 on holotranscobalamin and homocysteine concentrations in European-descent subjects. In addition, well-designed and -powered studies should be conducted for assessing the association between rs1801198 and MMA and clinical manifestations that are linked to a decreased availability of cobalamin. This review was registered at www.crd.york.ac.uk/prospero as CRD42017058504.

A Simplified Red Blood Cell Folate Calculation: Comparison to the Traditional Calculation Using Data from NHANES 2007–2010

Red blood cell folate (RBF) concentrationsare considered an accurate indicator of folate body stores and are usuallymeasured to assess the population baseline status or the impact of folateintervention. The traditional calculation of RBF requires 3 components, wholeblood folate (WBF), serum folate (SFOL), and hematocrit (Hct) and is calculatedas [WBF–SFOL(1–Hct/100)]/(Hct/100). In some cases data for SFOL and/or Hct maynot be available, but the hemoglobin (Hb) concentration is generally availablein health and nutrition surveys. Using data for persons 1 y and olderparticipating in NHANES 2007–2010 (n ~ 17000), we investigated whether asimplified calculation generated accurate RBF results. The available dataincluded SFOL and RBF measured by use of microbiologic assay, Hct, Hb, and meancell Hb content (MCHC); population median values for these indicators were 39.8nmol/L, 1070 nmol/L, 40.8%, 140 g/L, and 344 g/L, respectively. We calculatedthe WBF concentration as (RBF*Hct/100)+SFOL(1–Hct/100). We calculated anestimated Hct as Hb/MCHC, using the population median MCHC; the populationmedian estimated Hct was 40.8%. We investigated 5 simplified calculationscenarios: 1) use simple formula by ignoring SFOL (WBF/Hct); 2) use an imputed SFOLconcentration of 40 nmol/L; 3) use an imputed Hct value of 40%; 4) use an estimated Hct value; 5) use both an imputed SFOL value and an estimated Hct value with WBFand Hb being the only measured parameters. We compared geometric mean RBF results from these 5 scenarios with traditionally calculated RBF results for the entire population and demographic subgroups of age, gender and race‐ethnicity, as well as for women of reproductive age (WRA, 15–44 y). Compared to the traditional formula, the simple formula (ignoring SFOL) produced on average 5.6% (4.5–9.6% in subgroups; 5.9% in WRA) higher RBF results. Using an imputed SFOL concentration had on average 0% bias (−1.2% to 2.8% in subgroups; −1.2% in WRA). Using an imputed Hct value had on average 1.9% bias (−9.2% to 7.6% in subgroups; −3.9% in WRA). Using an estimatedHct had on average 0% bias (−3.5% to 3.5% in subgroups; 0% in WRA). Using both an imputed SFOL and an estimated Hct had on average 0% bias (−1.4% to 1.9%| in subgroups). In summary, ignoring the SFOL concentration in the calculation of RBF or using an imputed Hct value bias the RBF results by as much as 10% incertain demographic subgroups. Conversely, using the population median SFOL as an imputed value, or the estimated Hct, or a combination of the 2 parameters resulted in small average biases. This demonstrates the potential of simplifying the RBF calculation to estimate central tendency in a population by only measuring WBF and Hb in each study participant and by using an estimated population median SFOL value derived from a small subsample. However, this approach will not accurately predict an individual RBF value. These initial findings need to be confirmed in other data sets, particularly in settings with low folate status. Furthermore, the impact of the simplified calculation on prevalence estimates using different folate cutoff value has to be assessed.

Periconceptional maternal one-carbon biomarkers are associated with embryonic development according to the Carnegie stages

Is periconceptional maternal one-carbon (I-C) metabolism associated with embryonic morphological development in non-malformed ongoing pregnancies? Serum vitamin B12, red blood cell (RBC) folate and plasma total homocysteine (tHcy) are associated with embryonic development according to the Carnegie stages. Derangements in maternal I-C metabolism affect reproductive and pregnancy outcomes, as well as future health of the offspring. Between 2010 and 2014, women with singleton ongoing pregnancies were enrolled in a prospective periconceptional cohort study. A total of 234 pregnancies, including 138 spontaneous or IUI pregnancies with strict pregnancy dating and 96 pregnancies derived from IVF, ICSI or cryopreserved embryo transfer (IVF/ICSI pregnancies), underwent longitudinal transvaginal three-dimensional ultrasound (3D US) scans from 6+0 up to 10+2 weeks of gestation. Carnegie stages were defined using internal and external morphologic criteria in a virtual reality system. Maternal venous blood samples were collected at enrollment for serum vitamin B12, RBC folate and plasma tHcy assessment. Associations between biomarker concentrations and longitudinal Carnegie stages were investigated using linear mixed models. We performed a median of three 3D US scans per pregnancy (range 1-5) resulting in 600 good quality data sets for the Carnegie stage annotation (80.5%). Vitamin B12 was positively associated with embryonic development in the total study population (β = 0.001 (95% CI: 0.000; 0.002), P < 0.05) and in the subgroup of strictly dated spontaneous pregnancies (β = 0.002 (95% CI: 0.001; 0.003), P < 0.05). Low vitamin B12 concentrations (-2SD, 73.4 pmol/l) were associated with delayed embryonic development by 1.4 days (95% CI: 1.3-1.4) compared with high concentrations (+2SD, 563.1 pmol/l). RBC folate was positively associated with Carnegie stages only in IVF/ICSI pregnancies (β = 0.001 (95% CI: 0.0005; 0.0015), P < 0.05). In this group, low RBC folate concentrations (-2SD, 875.4 nmol/l) were associated with a 1.8-day delay (95% CI: 1.7-1.8) in development compared with high concentrations (+2SD, 2119.9 nmol/l). tHcy was negatively associated with embryonic development in the total study population (β = -0.08 (95% CI: -0.14; -0.02), P < 0.01), as well as in the IVF/ICSI subgroup (β = -0.08 (95% CI: -0.15; -0.01), P < 0.05). High tHcy concentrations (+2SD, 10.4 µmol/l) were associated with a delay of 1.6 days (95% CI: 1.5-1.7) in embryonic development compared with low concentrations (-2SD, 3.0 µmol/l). The study was performed in a tertiary care center, resulting in high rates of folic acid supplement use and comorbidity that may reduce the external validity of our findings. In periconceptional care, maternal I-C biomarkers should be taken into account as predictors of embryonic morphological development. Combining embryonic size measurements with morphological assessment could better define normal embryonic development. The work was funded by the Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. RPMST is CSO of the startup company Slimmere Zorg and CEO of eHealth Care Solutions. The authors declare no conflicts of interest. Not applicable.

Folate and vitamin B12 concentrations are associated with plasma DHA and EPA fatty acids in European adolescents: the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study.

This study aimed to examine the association between vitamin B6, folate and vitamin B12 biomarkers and plasma fatty acids in European adolescents. A subsample from the Healthy Lifestyle in Europe by Nutrition in Adolescence study with valid data on B-vitamins and fatty acid blood parameters, and all the other covariates used in the analyses such as BMI, Diet Quality Index, education of the mother and physical activity assessed by a questionnaire, was selected resulting in 674 cases (43 % males). B-vitamin biomarkers were measured by chromatography and immunoassay and fatty acids by enzymatic analyses. Linear mixed models elucidated the association between B-vitamins and fatty acid blood parameters (changes in fatty acid profiles according to change in 10 units of vitamin B biomarkers). DHA, EPA) and n-3 fatty acids showed positive associations with B-vitamin biomarkers, mainly with those corresponding to folate and vitamin B12. Contrarily, negative associations were found with n-6:n-3 ratio, trans-fatty acids and oleic:stearic ratio. With total homocysteine (tHcy), all the associations found with these parameters were opposite (for instance, an increase of 10 nmol/l in red blood cell folate or holotranscobalamin in females produces an increase of 15·85 µmol/l of EPA (P value <0·01), whereas an increase of 10 nmol/l of tHcy in males produces a decrease of 2·06 µmol/l of DHA (P value <0·05). Positive associations between B-vitamins and specific fatty acids might suggest underlying mechanisms between B-vitamins and CVD and it is worth the attention of public health policies.

Hydroxytyrosol supplementation increases vitamin C levels in vivo. A human volunteer trial

Hydroxytyrosol (HT) is a main phenolic component of olive oil. In this study, we investigated the safety and effects produced by HT purified (99.5%) from olive mill waste. HT was administered at a daily dosage of 45mg for 8 weeks to volunteers with mild hyperlipidemia (n=14). We measured markers of cardiovascular disease risk, enzyme markers of several clinical conditions, hematology, antioxidant parameters, vitamins and minerals at baseline (T0), 4 weeks (T4) and 8 weeks (T8). The values obtained at T4 and T8 were compared with baseline. We found that the HT dose administered was safe and mostly did not influence markers of cardiovascular disease, blood lipids, inflammatory markers, liver or kidney functions and the electrolyte balance. Serum iron levels remained constant but a significant (P<0.05) decrease in ferritin at T4 and T8 was found. Serum folate and red blood cell folate levels were also reduced at T4 and T8. Finally, vitamin C increased by two-fold at T4 and T8 compared with levels at baseline. These results indicate a physiologically relevant antioxidant function for HT through increasing endogenous vitamin C levels.