Low Red Blood Cell Folate Research Articles

Docosahexaenoic acid, eicosapentaenoic acid, arachidonic acid, and neural tube defects in Tunisian population.

To determine the effect of maternal status in (plasma and red blood cell) folate, vitamin B12, homocysteine, and vitamin D, as well as their interaction with MTHFR (C677T and A1298C) and MTRR A66G polymorphisms, on maternal plasma docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (ARA) levels and the risk of neural tube defects (NTDs). ARA, EPA, and DHA composition was assessed using capillary gas chromatography. ARA and DHA levels were higher in controls than in case mothers for low plasma folate status. For low red blood cell folate status, DHA levels were higher in controls than in case mothers. For high homocysteine levels, ARA and DHA levels were higher in controls than in case mothers. NTD mothers had lower EPA and DHA levels for low vitamin B12 levels. NTD mothers had lower DHA levels for low vitamin D levels. For low plasma folate status, DHA levels in the MTHFR C677T gene and ARA and EPA levels in MTHFR A1298C gene were different among the three genotypes in case mothers. DHA levels in the MTHFR C677T gene were different among the three genotypes in case mothers for both low and high homocysteine levels. For low vitamin B12 levels, ARA and DHA levels were different among the three genotypes of the MTHFR C677T gene in case mothers. In the MTHFR C677T gene, ARA and DHA levels were different among the three genotypes in case mothers for low vitamin D levels. More advanced research is required to verify a suitable biochemical parameter status in relation to the genotypes in pregnant women.

High red blood cell folate is associated with an increased risk of diabetes death among a hypertensive cohort

The relationship between folate and diabetes remains inconclusive, possibly because of folate measured differentially between studies. Interference from mandatory folic acid fortification (FAF) has also been blamed. With both folate intake and circulating concentration measured, we assessed the relationship between folate and the risk of diabetes death in a hypertensive cohort established before FAF. We hypothesized that the association between folate and diabetes death is measurement dependent. We analyzed the data of 3133 hypertensive adults aged ≥19 years who participated in the Third National Health and Nutrition Examination Survey (1991–1994) and were followed up through December 31, 2010. Hazard ratios of diabetes death were estimated for participants with high (4th quarter) folate compared with those with moderate (2nd and 3rd quarters) or low (1st quarter) concentrations of folate. Dietary folate intake, total folate intake (including folate from supplements), serum, and red blood cell (RBC) folate were measured. After 42,025 person-years of follow-up, 165 diabetes deaths were recorded, and a dose-response positive association was observed between diabetes death and RBC folate. The adjusted hazard ratios of diabetes death were 1.00 (reference), 1.42 (95% CI. 1.20–1.68), and 2.21 (1.73–2.82), respectively, for hypertensive adults with low, moderate, and high RBC folate. No association was detected between diabetes death and serum folate concentration, folate intake, or either dietary intake or total intake. With minimized interference from FAF, neither dietary nor serum folate was associated with diabetes death, but elevated RBC folate was associated with a high risk of diabetes deaths among hypertensive patients.

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.

Low folate status, and MTHFR 677C > T and MTR 2756A > G polymorphisms associated with colorectal cancer risk in Thais: a case-control study

Folate plays essential roles in DNA synthesis, repair, and methylation; thus, folate status may affect carcinogenesis. Genetics polymorphisms involved in folate metabolisms have been linked with colorectal cancer (CRC) development. Therefore, we hypothesized that low folate status and related genetic polymorphisms are associated with higher risk of CRC. This case-control study enrolled 105 new cases of CRC, 101 of colorectal adenoma (CRA), and 182 controls from hospitals in Bangkok, Thailand, to examine the association between folate status and methylenetetrahydrofolate reductase (MTHFR) 677C > T, methionine synthase (MTR) 2756A > G, and methionine synthase reductase (MTRR) 66A > G with the risk of CRC and CRA. Regarding CRC risk, the lowest quartile group of serum folate and folate intake had higher risk of CRC than the highest quartile group (odds ratio [OR] = 11.45, 95% confidence interval [CI] = 4.43-29.59) and (OR = 10.29, 95% CI = 4.17-25.41). The lowest quartile group of folate intake also had a higher risk of CRA (OR = 5.22, 95% CI = 2.19-6.09). Low red blood cell folate combined with MTHFR 677C > T polymorphism statistically increased CRC risk (OR = 10.00, 95% CI = 1.36-73.42). Low folate status combined with MTR 2756A > G significantly increased CRA risk (OR = 6.43, 95% CI = 1.38-29.94). Moreover, the risk of CRC was elevated with alcohol consumption and low exercise activity when combined with low folate status (P < .05). This study supported the hypothesis that, in Thais, low folate status is associated with a higher risk of CRC, particularly among those with polymorphisms of the MTHFR 677C > T and MTR 2756 A > G genes.

Does the father matter? The association between the periconceptional paternal folate status and embryonic growth

To study the association between periconceptional paternal folate status and embryonic growth trajectories in early pregnancy. Prospective periconceptional cohort study. Single tertiary hospital. A total of 511 singleton pregnancies, with 303 conceived spontaneously and 208 after invitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment. None. Crown-rump length (CRL) and embryonic volume (EV) at 7, 9, and 11weeks of gestation measured offline using three-dimensional ultrasound data and a virtual reality system. Using the third quartile of paternal red blood cell (RBC) folate levels as reference values, we found statistically significantly negative associations between RBC folate and longitudinal CRL measurements in the second quartile (beta: -0.14 √mm [95% confidence interval (CI), -0.28 to -0.006]) and fourth quartile (beta: -0.19 √mm [95% CI, -0.33 to -0.04]) in spontaneously conceived pregnancies. Comparable results were found for longitudinal EV measurements in the fourth quartile (beta: -0.12 ∛cm3 [95% CI, -0.20 to -0.05]). No statistically significant associations were observed between RBC folate levels and embryonic growth trajectories in IVF-ICSI pregnancies. These data demonstrate for the first time that low and high periconceptional paternal RBC folate levels are associated with reduced embryonic growth trajectories in spontaneously conceived pregnancies. These data underline the importance of paternal folate status during the periconception period.

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.

The Dihydrofolate Reductase 19 bp Polymorphism Is Not Associated with Biomarkers of Folate Status in Healthy Young Adults, Irrespective of Folic Acid Intake1–3

Background: Dihydrofolate reductase (DHFR) is essential for the conversion of folic acid to active folate needed for one-carbon metabolism. Common genetic variation within DHFR is restricted to the noncoding regions, and previous studies have focused on a 19 bp deletion/insertion polymorphism (rs70991108) within intron 1. Reports of an association between this polymorphism and blood folate biomarker concentrations are conflicting.Objective: In this study, we evaluated whether the DHFR 19 bp deletion/insertion polymorphism affects circulating folate biomarkers in, to our knowledge, the largest cohort to address this question to date.Methods: Healthy young Irish individuals (n = 2507) between 19 and 36 y of age were recruited between February 2003 and February 2004. Folic acid intake from supplements and fortified foods was assessed with the use of a customized food intake questionnaire. Concentrations of serum folate and vitamin B-12, red blood cell (RBC) folate, and plasma total homocysteine (tHcy) were measured. Data were analyzed with the use of linear regression models.Results: Folic acid intake was positively associated with serum (P < 0.0001) and RBC (P = 0.0005) folate concentration and was inversely associated with plasma tHcy (P = 0.001) as expected. The DHFR 19 bp polymorphism was not significantly associated with either serum (P = 0.82) or RBC (P = 0.21) folate, or plasma tHcy (P = 0.20), even in those within the highest quintile of folic acid intake (>326 μg folic acid/d; P = 0.96). A nonsignificant trend toward lower RBC folate by genotype (P = 0.09) was observed in the lowest folic acid intake quintile (0–51 μg/d).Conclusion: In this cohort of healthy young individuals, the DHFR 19 bp deletion allele did not significantly affect circulating folate status, irrespective of folic acid intake. Our data rule out a strong functional effect from this polymorphism on blood folate concentrations.

Maternal predictors of RBC folate levels in an urban Canadian population.

To assess factors associated with low Red Blood Cell folate (RBCf) levels in an obstetric population in a tertiary centre. Cross-sectional study. Three hundred and fifty women completed a questionnaire detailing use of folic acid supplementation, and had their RBCf levels measured. Values ≥ 906 nmol/L were considered optimal. Factors associated with optimal RBCf were assessed, individually and in a logistic regression model. Median RBCf was 1282 nmol/L. Thirty-five women (10%) had suboptimal levels. Predictors of suboptimal RBCf were non-Caucasian ethnicity, non-consumption of folic acid supplementations, and inadequate health care provider information regarding the benefits of folic acid consumption. Although, in our population, a high proportion of women achieved optimal levels of RBCf, some women remain at risk due to inadequate folate consumption. Patient and health care provider education regarding folate can still be improved, particularly in the groups identified to be at greater risk.

High folate levels in Aboriginal children after subsidised fruit and vegetables and mandatory folic acid fortification.

To evaluate the impact of a fruit and vegetable (F&V) subsidy program for disadvantaged Aboriginal children in Australia, implemented alongside the introduction of mandatory folic acid fortification of bread-making flour. A before-and-after evaluation was undertaken of a F&V subsidy program at three Aboriginal community-controlled health services in New South Wales. The program provided a weekly box of subsidised F&V linked to preventive health services and nutrition promotion for families. In this analysis, red blood cell (RBC) folate was assessed together with self-reported dietary intake at baseline and 12 months later in a cohort of 125 children (aged 0-17 years). No children had low RBC folate at baseline or at follow-up; however, 33 children (26%) exceeded the reference range of RBC folate at baseline and 38 children (30%) exceeded the reference range at follow-up. Mean RBC folate levels increased substantially in children at follow-up (mean RBC folate z-score increased +0.55 (95%CI 0.36-0.74). Change in F&V intake (p=0.196) and mean bread intake (p=0.676) were not statistically significant predictors for change in RBC folate levels. RBC folate levels increased among these disadvantaged Aboriginal children following mandatory folic acid fortification and participation in a subsidised F&V program. Even before mandatory folic acid fortification, none of these children had low RBC folate. The effect on health of mandatory fortification of foods with folate is not clear, hence, ongoing population-based monitoring of folate levels to assess the impact of mandatory folic acid fortification is important.

Maternal Phenylketonuria International Collaborative Study revisited: evaluation of maternal nutritional risk factors besides phenylalanine for fetal congenital heart defects

Maternal phenylketonuria (MPKU) is known to affect fetal outcome, often being associated with microcephaly and congenital heart defects (CHD) if the maternal diet is not appropriately managed. We hypothesized that other nutrients aside from phenylalanine (Phe) may have significant effects on fetal outcome in MPKU pregnancies. The 416 pregnancies that resulted in live births reported in the Maternal PKU Collaborative Study (MPKUCS) were grouped according to whether or not the offspring were diagnosed with CHD. The groups were compared on first-trimester values of maternal data, including weight gain, plasma amino acids, protein and Phe intake, and red blood cell (RBC) folate. Patients were also grouped by first-trimester average blood Phe (≤910 μmol/L and >910 μmol/L) and then divided by total natural protein and medical food intake. The CHD group of 28 offspring had significantly higher blood Phe and lower proline, valine, methionine, isoleucine, leucine, lysine, arginine, and RBC folate. A significantly higher risk for CHD was found in the groups with lower natural protein and medical food intake, regardless of blood Phe levels. Insufficient natural protein and medical food product intake appears to be a risk factor for CHD independent of first-trimester plasma Phe levels. Low RBC folate and plasma methionine levels in the CHD group may suggest involvement of global DNA hypomethylation.

Maternal Mthfd1 disruption impairs fetal growth but does not cause neural tube defects in mice

MTHFD1 encodes C1-tetrahydrofolate synthase, which is a folate-dependent enzyme that catalyzes the formation and interconversion of folate-activated one-carbon groups for nucleotide biosynthesis and cellular methylation. A polymorphism in MTHFD1 (1958G→A) impairs enzymatic activity and is associated with increased risk of adverse pregnancy outcomes, but the mechanisms are unknown. The objective of this study was to determine whether disruption of the embryonic or maternal Mthfd1 gene or both interacts with impaired folate and choline status to affect neural tube closure, fetal growth, and fertility in mice and to investigate the underlying metabolic disruptions. Dams with a gene-trapped (gt) allele in Mthfd1 and wild-type dams were fed a control or folate- and choline-deficient AIN93G diet (Dyets Inc). Litters were examined for gross morphologic defects, crown-rump length, and resorptions. Folate status and amounts of folate-related metabolites were determined in pregnant dams. Reduced folate and choline status resulted in severe fetal growth restriction (FGR) and impaired fertility in litters harvested from Mthfd1(gt/+) dams, but embryonic Mthfd1(gt/+) genotype did not affect fetal growth. Gestational supplementation of Mthfd1(gt/+) dams with hypoxanthine increased FGR frequency and caused occasional neural tube defects (NTDs) in Mthfd1(gt/+) embryos. Mthfd1(gt/+) dams exhibited lower red blood cell folate and plasma methionine concentrations than did wild-type dams. Maternal Mthfd1(gt/+) genotype impairs fetal growth but does not cause NTDs when dams are maintained on a folate- and choline-deficient diet. Mthfd1(gt/+) mice exhibit a spectrum of adverse reproductive outcomes previously attributed to the human MTHFD1 1958G→A polymorphism. Mthfd1 heterozygosity impairs folate status in pregnant mice but does not significantly affect homocysteine metabolism.

Examination of Circulating Folate Levels as a Reflection of Folate Intakes among Older Adult Supplement Users and Nonusers in the National Health and Nutrition Examination Survey 2003-2004

High intakes of folic acid and/or elevated blood folate concentrations have been associated with negative health outcomes; thus, it is critical to identify those at greatest risk of such exposures. The goal of this research was to describe folate intakes (folic acid [μg], folate [μg], and total folate [dietary folate equivalent] from food) and identify people 45 years or older in the National Health and Nutrition Examination Survey 2003-2004 at risk of exposure to elevated serum folate concentrations (≥21.8 ng/mL [49.4 nmol/L]) when stratified by race or ethnicity and supplement use within sex. Black men consumed a lower mean food folate and exhibited lower red blood cell folate concentrations when compared to those of white or Mexican-American men (P<0.01 and P<0.01 for both). Black women consumed a lower food folate than Mexican-American women (P<0.01), less total folate (dietary folate equivalent) than white women (P<0.01), and had lower red blood cell folate concentrations than white women (P<0.01). Multivariate odds of elevated serum folate levels increased with age in men (P<0.001) and women (P=0.01). All white subjects and all supplement users (all P<0.001) were more likely to have elevated folate concentrations, while smoking reduced the odds of such exposures in women (P<0.001) and men (P=0.04). These findings highlight the need to understand the impact of chronic exposure to elevated folate intakes, especially among white subjects with increasing age and who use supplements.

Maternal red blood cell folate concentration at 10–12 weeks gestation and pregnancy outcome

Objective: To determine if maternal circulating red blood cell (RBC) folate concentration in early pregnancy is associated with late gestation pregnancy complications including small for gestational age (SGA) infants, preeclampsia and preterm birth (PTB) in a socioeconomically disadvantaged population. Method: This was a retrospective case control study, conducted at Lyell McEwin Health Service, South Australia, including 400 primiparous women. RBC folate and demographic data were collected at 10–12 weeks gestation. Pregnancy outcome data were obtained from patient case notes. Results: Patients who were folate deficient were more likely to develop pregnancy complications, specifically SGA (OR 6.9, 95% CI 2–24.3) and PTB (OR 5.4 95% CI 1.4–21.2). Those who were folate insufficient were also at increased risk of SGA (OR 3.0, 95% CI 1.3–7.7). No association between folate and preeclampsia was found. Women who were supplementing with folic acid delivered infants who were 179 g heavier (5.5% increased birth weight, P = 0.003) and 4.5 days later, compared to those who did not supplement. Furthermore, low RBC folate was associated with cigarette smoking (P < 0.001). Conclusions: Maternal RBC folate concentration in early pregnancy is associated with SGA and PTB, but not with preeclampsia.

The oldest old: red blood cell and plasma folate in African American and white octogenarians and centenarians in Georgia.

To determine the overall folate status of a population-based multi-ethnic sample of octogenarians and centenarians and the specific dietary, demographic and physiological factors associated with observed abnormalities. Population-based multiethnic sample of adults aged 80 to 89 and 98 and above. Northern Georgia, USA. Men and women aged 80 to 89 (octogenarians, n = 77) and 98 and older (centenarians, n = 199). Wilcoxon rank sum tests, and Chi square and logistic regression analyses were used to examine associations of low and high folate status with hematological indicators and other variables of interest. The prevalence of low red blood cell (RBC) folate was low overall, but tended to be higher in centenarians than in octogenarians (6.5% vs. 1.3%, p = 0.058; defined as RBC folate < 317 nmol/L). The risk of having lower RBC folate (< 25th vs. > 25th percentile for RBC folate for 60yr+ in NHANES 1999-2000) was greater in association with vitamin B12 deficiency (OR = 5.36; 95%CI: 2.87-10.01), African American race (OR = 4.29; 95%CI: 2.08-8.83), and residence in a skilled nursing facility (OR = 3.25; 95%CI: 1.56-6.78) but was not influenced by age, gender, B-vitamin supplement use, high/low food score or presence of atrophic gastritis. Combined high plasma folate and low vitamin B12 status was present in some individuals (n=11), but was not associated with increased prevalence of anemia or cognitive impairment in this study. Low RBC folate status (< 317 nmol/L) was rare in this post folic acid fortification sample of octogenarians and centenarians. RBC folate status (< 25th percentile) was strongly associated with 1) vitamin B12 deficiency, which has strong implications for vitamin treatment, and 2) with being African American, suggesting racial disparities exist even in the oldest old.

The impact of mandatory fortification of flour with folic acid on the blood folate levels of an Australian population

To determine the impact that mandatory fortification with folic acid of wheat flour used in breadmaking has had on the blood folate levels of an Australian population since it was introduced in September 2009. A retrospective analysis of serum and red blood cell (RBC) folate levels of 20,592 blood samples collected between April 2007 and April 2010 from a wide variety of inpatients and outpatients and analysed in a large public hospital diagnostic pathology laboratory. Prevalences of low levels of serum and RBC folate and monthly mean levels before and after introduction of mandatory fortification. Between April 2009 and April 2010, there was a 77% reduction in the prevalence of low serum folate levels (from 9.3% to 2.1%) in all samples tested and an 85% reduction in the prevalence of low RBC folate levels (from 3.4% to 0.5%). In April 2010, the prevalence of low RBC folate levels for females of childbearing age was 0.16% for all samples. There was a 31% increase in mean serum folate level (from 17.7 nmol/L to 23.1 nmol/L; t = 9.3, P < 0.01), and a 22% increase in mean RBC folate level (from 881 nmol/L to 1071 nmol/L). The greatest increment in mean serum folate levels occurred in September 2009, the month that mandatory fortification was introduced, although there was evidence of a gradual change during the preceding months. The introduction of mandatory fortification with folic acid has significantly reduced the prevalence of folate deficiency in Australia, including in women of childbearing age.

A Reassessment of the Red Blood Cell Folate Assay

AbstractAbstract 3209 Background:The red blood cell folate (RCF) assay has historically been recommended as a more reliable indicator of tissue folate stores compared to the serum folate (SF) assay, as it is not affected by recent ingestion of food. However, the RCF assay suffers from inherent problems with imprecision and accuracy, which are not encountered with SF measurements. Furthermore, following the advent of required folic acid supplementation of many foods by the Food and Drug Administration (FDA) in 1992, folate deficiency is increasingly rare. Very few studies have looked at the value of the RCF versus the SF. We undertook a 10 year retrospective analysis of RCF and SF results to determine the clinical utility of RCF beyond that of SF. Methods:We retrieved all RCF and SF results from the laboratory information system at Mayo Clinic (Rochester, MN) ordered on inpatients and outpatients between 1999–2009. Data for patients who had concurrent orders for SF and RCF were analyzed and chart reviews were conducted on those patients with normal SF but low RCF. Abnormal values were defined by the National Health and Nutrition Examination Surveys (NHANES)/Center for Disease Control (CDC) criteria for folate deficiency (SF< 3.0 ng/ml, RCF < 140 ng/ml). Results:A total of 152,166 SF and 15,708 RCF were performed over the decade of the study. The prevalence of folate deficiency using only SF values was 0.39% and 0.27% using only RCF values. There were 1082 patients in which SFA and RCFA were ordered concurrently (Table 1).Table 1Analysis of patients with paired SF and RCF using NHANES/CDC definition of folate deficiencySerum FolateAbnormal (<3.0 ng/ml)Normal (>3.0 ng/ml)RECAbnormal (<140 ng/ml)1 (0.09%)4 (0.4%)Normal (>140 ng/ml)8 (0.7%)1069 (98.8%)Only 1 patient (0.09%) had both abnormal SF and RCF. Chart reviews of the 4 patients with a normal SF but low RCF were as follows: 1) a 6 year old (yo). male with known folic acid transporter deficiency treated with Leucovorin. 2) a 58 yo male with history of gout, hypertension, psoriasis, and hyperlipidemia with normal hemoglobin (Hb) and MCV. 3) a 65 yo male with chronic diarrhea and suspected alcohol abuse; slight macrocytosis (MCV=100.3 fL) but normal Hb. 4) a 51 yo male with multifactorial gait disorder and alcohol abuse. There was a previous history of vitamin B12 deficiency but B12 levels were normal at this time. The CBC was notable for macrocytosis (MCV=115.1 fL) without anemia. Only in patient 4 did the RCF value result in the institution of folic acid supplementation. Conclusions:The RCF provides no additional information beyond that provided by the SF in virtually all situations. Thus SF alone is sufficient for assessment of folate stores. However, there is no evidence to support routine ordering of either SF or RCF, as true folate deficiency in the current era of FDA mandated folic acid supplementation is exceedingly rare. Disclosures:No relevant conflicts of interest to declare.

Treatment-resistant depression: recent developments and future directions

A significant proportion of patients with major depressive disorder (MDD) fail to achieve remission with standard antidepressant therapies, even when optimally delivered. These patients are classified as treatment-resistant depression (TRD), which is distinguished from “difficult-to-treat” depression,[1] defined as depression treated under circumstances that precludes the optimal delivery of a potentially beneficial treatment (e.g., subtherapeutic dosing, intolerable side effects, poor adherence, etc.) TRD is also distinguished from severe depression, as some patients with milder depressive symptoms are markedly treatment resistant, while others with profound, acute depressive symptoms are quite treatment responsive. Defining the boundaries of TRD is critical from a clinical, research, and public health perspective, as drug and device manufacturers seek new regulatory approvals for numerous indications in the TRD spectrum. This article reviews recent developments in TRD, with a focus on classification methods used for regulatory clinical trials; treatments currently approved in the US for TRD; how classification schemes and regulatory rules have limited understanding of their scope of effectiveness; and what changes are needed in research approaches to facilitate novel therapeutic discovery.

Commentary: Health policies in the US: can they increase or decrease the gap between subgroups of the population? The case of folic acid

Effective on January 1, 1998, the Food and Drug Administration (FDA) amended the standards to identify several enriched grain products, bromated flour, vegetable macaroni and vegetable noodle products by requiring folic acid fortication. Specifically, the FDA required that these products be fortified with folic acid levels ranging from 0.43 to 1.4 mg/pound or 95 to 309 mg/100 g of product. Although this requirement affects the entire population, the purpose of this amendment was to ensure that women of childbearing age consume the US Public Health Service recommended daily allowance of at least 0.4 mg (400 mg) of folic acid daily to reduce their risk of having a child with spina bifida or other neural tube defects (NTDs). Spina bifida and anencephaly affect approximately 4000 children in the US prior to the folic acid fortification amendment. However, approximately 1000 of these cases have been prevented with folic acid fortification. As with most conditions in the US, estimates for NTDs vary by race and ethnicity, with Hispanics exhibiting the highest estimates and blacks and Asians the lowest. Moreover, NTDs varies by socioeconomic status defined using income and education with the least educated and those with low income exhibiting the highest estimates. Low folate levels not only affect children in utero, but also evidence suggests that low folate levels are associated with increased prevalence of cancer, cardiovascular disease, physical and mental functioning. Thus, despite the fact that the fortification was targeted to women of childbearing age, the FDA amendment could be a preventive paradox for population health by benefiting everyone. The latter could have implications for health disparities across subgroups of the population if differences exist across the outcomes benefiting from the fortification. Findings from existing studies on folic acid preand post-fortification suggest that there are disparities between groups. For instance, Ford and Bowman showed differences in red blood cell (RBC) folate concentrations between non-Hispanic blacks and nonHispanic whites with the highest differences among those with greater than a high school diploma regardless of gender. Conversely, differences between Mexican Americans and non-Hispanic whites were significant for men with at least 9 years of education and for women at the educational attainment extreme (<9 years of education and more than a high school diploma). Ganji and Kafai showed a decrease in prevalence of low RBC folate between 1988–94 and 1999–2002 across all racial/ ethnic and poverty-income ratio groups. However, nonHispanic blacks continue to exhibit a higher prevalence of low RBC folate through this period. Unlike previous studies examining trends between the preand post-fortification period, Dowd and Aiello focused on investigating the magnitude of the racial/ethnic and socioeconomic status (defined using poverty to income ratio) disparities assessed as absolute and relative differences. Using data from the National Health and Nutrition Examination Surveys (NHANES), Dowd and Aiello examined racial/ethnic and income disparities in folate status in US adults aged 25 years or older before (1991–1994) and after (1999–2002) enactment of the folic acid fortification. They found an increase in relative, but a decrease, in absolute difference before and after the fortification. Non-Hispanic blacks had 1.6 (95% CI: 1.4–1.9) greater odds of having low RBC folate (<362.6 nmol) levels compared with non-Hispanic whites in the pre-fortification period. This estimate was 3.7 (95% CI: 2.8–5.0) in the postfortification period. In the pre-fortification period, individuals in the bottom income quartile had a 1.3 (95% CI: 1.1–1.4) greater odds of having low RBC compared with those in the highest income quartile. Finally, in the post-fortification period, this estimate was 2.1 (95% CI: 1.6–2.7). The corresponding absolute differences were 233 (pre-) and 121 (post-fortification) Department of Health Sciences, Graduate Program in Public Health, Lehman College, CUNY, 250 Bedford Park Boulevard West, Gillet 336, Bronx, NY 10468, USA. E-mail: Luisa.Borrell@lehman.cuny.edu Published by Oxford University Press on behalf of the International Epidemiological Association

National Neural Tube Defects Prevention Program in China

Neural tube defects (NTD) are among the most common and devastating birth defects. Annually, in China, between 80,000 and 100,000 pregnancies result in children born with NTD. Northern China has the highest known rate of NTD in the world. Birth defects are becoming the leading cause of infant mortality in the urban and developed areas in China. The results of studies conducted in the early 1990s and early 2000s showed significant geographic and seasonal variations of folate status among Chinese women of childbearing age, with lower serum and red blood cell folate levels in northern China. In the north, 32% to 35% of women had low plasma folate and low red blood cell folate, and folate levels were significantly lower in spring than in fall. Since 1993, Peking University Health Science Center (formerly Beijing Medical University), collaborating with the US Centers for Disease Control and Prevention (CDC), has conducted a large-scale study to evaluate a public health campaign in China among women preparing for marriage in order to determine the effectiveness of daily supplementation of 400 microg of folic acid alone in preventing NTD in both the north and the south of China. The results showed that among the fetuses or infants of the women who took periconceptional folic acid, the reduction in risk of NTD was 85% in the northern region and 40% in the southern region. Daily intake of 400 microg of folic acid may also reduce the risk of nonsyndromic orofacial clefts. We found no evidence that daily consumption of folic acid before and during early pregnancy influenced the risk of miscarriage or twinning. In 2001, the Chinese Ministry of Health and the Chinese Disabled Person Federation released a National Action Plan for Reducing Birth Defects and Disabilities in China for 2002-2010. The Action Plan aims to improve birth outcomes, to reduce infant mortality by reducing the risk of birth defects and disabilities, and to ensure that every baby is born healthy.

Evidence for sex differences in the determinants of homocysteine concentrations

A high homocysteine phenotype, often accompanied by low folate, is associated with several pathologies including cardiovascular disease and birth defects. This phenotype appears to be influenced by both genetic and environmental factors, which may act in a sex-dependent manner. The present analyses were undertaken to identify the determinants of homocysteine concentrations in young men and women, and are based on data from a cohort of young, reproductive age (20–26 years old) individuals in Northern Ireland. Multivariate modeling indicated that homocysteine concentrations are associated with red blood cell (RBC) folate, vitamin B 12, MTHFR 677C>T genotype and smoking status in both males and females. However, the inter-relationships between these variables appear to differ between the sexes. Specifically, homocysteine levels in males were significantly associated with interactions between MTHFR 677C>T genotype and both RBC folate and smoking status. In contrast, homocysteine levels in females were significantly associated with interactions between smoking status and RBC folate. These results suggest that the characteristics of individuals who are at the highest risk for a high homocysteine phenotype differ for males and females. Among males, those with the MTHFR 677TT genotype appear to be at the highest risk and to be the most vulnerable to factors (e.g. smoking, low RBC folate) that are associated with homocysteine raising effects. Among females, smokers (regardless of MTHFR genotype) appear to be at the highest risk, and to be the most vulnerable to a single factor (i.e. RBC folate) that is associated with homocysteine raising effects.