Effect Of Folic Acid Supplementation Research Articles

A maternal high-fat, high-sucrose diet alters insulin sensitivity and expression of insulin signalling and lipid metabolism genes and proteins in male rat offspring: effect of folic acid supplementation.

A maternal high-fat, high-sucrose (HFS) diet alters offspring glucose and lipid homoeostasis through unknown mechanisms and may be modulated by folic acid. We investigated the effect of a maternal HFS diet on glucose homoeostasis, expression of genes and proteins associated with insulin signalling and lipid metabolism and the effect of prenatal folic acid supplementation (HFS/F) in male rat offspring. Pregnant Sprague-Dawley rats were randomly fed control (CON), HFS or HFS/F diets. Offspring were weaned on CON; at postnatal day 70, fasting plasma insulin and glucose and liver and skeletal muscle gene and protein expression were measured. Treatment effects were assessed by one-way ANOVA. Maternal HFS diet induced higher fasting glucose in offspring v. HFS/F (P=0·027) and down-regulation (P<0·05) of genes coding for v-Akt murine thymoma viral oncogene homolog 2, resistin and v-Raf-1 murine leukaemia viral oncogene homolog 1 (Raf1) in offspring skeletal muscle and acetyl-CoA carboxylase (Acaca), fatty acid synthase and phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit β in offspring liver. Skeletal muscle neuropeptide Y and hepatic Kruppel-like factor 10 were up-regulated in HFS v. CON offspring (P<0·05). Compared with CON, Acaca and Raf1 protein expression levels were significantly lower in HFS offspring. Maternal HFS induced higher homoeostasis model of assessment index of insulin resistance v. CON (P=0·030) and HFS/F was associated with higher insulin (P=0·016) and lower glucose (P=0·025). Maternal HFS diet alters offspring insulin sensitivity and de novo hepatic lipogenesis via altered gene and protein expression, which appears to be potentiated by folate supplementation.

Folic Acid Supplementation for Stroke Prevention in Patients With Cardiovascular Disease

BackgroundControversy remains regarding the efficacy of folic acid supplementation in reducing the risk of stroke. This study aimed to evaluate the effect of folic acid supplementation on stroke prevention in patients with cardiovascular disease (CVD). Materials and MethodsWe searched the PubMed, EMBASE and Cochrane Library databases through October 2016 to identify randomized clinical trials of folic acid supplementation to prevent stroke in patients with CVD. Relative risks (RRs) with 95% CIs were used to examine the association between folic acid supplementation and the risk of stroke with a fixed-effect model. Stratified analyses were performed according to modifiers that may affect the efficacy of folic acid supplementation. ResultsEleven studies with a total of 65,790 participants were included. Folic acid supplementation was associated with a significant benefit in reducing the risk of stroke in patients with CVD (RR = 0.90; 95% CI: 0.84-0.97; P = 0.005). In the stratified analysis, greater beneficial effects were observed in participants with a decrease in homocysteine concentrations of 25% or greater (RR = 0.85; 95% CI: 0.74-0.97; P = 0.03), those with a daily folate dose of less than 2mg (RR = 0.78; 95% CI: 0.68-0.89; P = 0.01), and populations in regions with no or partly fortified grain (RR = 0.87; 95% CI: 0.81-0.94; P = 0.04). ConclusionsOur meta-analysis demonstrated that folic acid supplementation is effective in stroke prevention in patients with CVD.

Abstract 247: Nutrient stress via folic acid modulation causes systemic and cancer-specific metabolic reprogramming and differential effects on primary and metastatic mammary tumor growth in lean and obese mice

Abstract Many foods are currently fortified with folic acid (FA), a synthetic folate (Vitamin B9). Folate deficiency causes many human health defects, most notably anemia and neural tube defects. The effects of excess supplementation on human health have to date been understudied. The rise in obesity in the last three decades further complicates this issue, with the combined effects of excess or insufficient folic acid intake and an obese phenotype being unknown. Obesity is associated with a number of cancers, including triple negative breast cancer (TNBC). TNBC comprises 16% of all breast cancers, is highly aggressive and more likely to recur and metastasize than other breast cancers. Unlike other subtypes, TNBC does not respond to hormone-targeted therapies and treatment options are limited to cytotoxic chemotherapy. Here, we examined the effects of FA supplementation and deficiency on tumor growth, metastasis and metabolism in obesity-responsive models of primary (M-Wnt) and metastatic (metM-Wnt; MDA-MB-231) TNBC. FA supplementation and deficiency significantly enhanced primary tumor growth and invasiveness in lean mice, while no difference in tumor size was detected in obese groups. FA supplementation reduced while deficiency increased survival and reduced lung tumor metastasis incidence in lean, but not obese mice. Liver and tumor metabolomic profiling revealed that modulation of dietary FA caused systemic and tumor-specific metabolic reprogramming, altering pathways involved in fatty acid, purine, amino acid, glutathione and energy metabolism. Short term in vitro FA withdrawal resulted in reduced proliferation, migration and invasion and energy production in all cell lines, as well as significant changes in gene expression profile, particularly of many metabolic pathways. In contrast, chronic in vitro FA depletion resulted in heightened oxidative stress, autophagy and apoptosis in metastatic TNBC cells, with nonmetastatic TNBC cells being able to adapt to and withstand the nutrient stress via the pentose phosphate pathway and glutathione redox signaling. Taken together, these results suggest that modulation of dietary folic acid in lean (but not obese) individuals causes systemic and tumor-specific metabolic reprogramming, which may confer a growth advantage in nonmetastatic cells and from which metastatic TNBC cells cannot recover. Moreover, obesity and FA excess cause similar metabolic and procancer effects and in combination, are not synergistic. Citation Format: Ciara H. O'Flanagan, Xuewen Chen, Zahra Ashkavand, Sergey A. Krupenko, Stephen D. Hursting. Nutrient stress via folic acid modulation causes systemic and cancer-specific metabolic reprogramming and differential effects on primary and metastatic mammary tumor growth in lean and obese mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 247. doi:10.1158/1538-7445.AM2017-247

Effect of folic acid supplementation on cancer risk among adults with hypertension in China: A randomized clinical trial.

The relationship of folic acid supplementation with the risk of cancer remains inconclusive. We aimed to evaluate the effects of folic acid supplementation on cancer incidence among adults with hypertension without history of stroke or myocardial infarction (MI) in the China Stroke Primary Prevention Trial (CSPPT). A total of 20,702 hypertensive adults without history of stroke or MI, stratified by MTHFR C677T genotypes(CC, CT and TT), were randomly assigned to receive double-blind daily treatment with a single pill containing 10 mg enalapril and 0.8 mg folic acid(n = 10,348) or a pill containing 10 mg enalapril alone(n = 10,354). During a median treatment duration of 4.5 years, cancer occurred in 116 participants(1.12%) in the enalapril-folic acid group versus 116 participants(1.12%) in the enalapril group (HR, 1.00; 95%CI, 0.77-1.29). There was also no significant difference in the HRs for specific types of cancer(esophageal, gastric, breast, lung, colorectal, head and neck, liver and gynecologic cancer or lymphoma) or cancer mortality(HR, 1.05; 95%CI, 0.69-1.58). For participants not receiving folic acid treatment (enalapril only group), MTHFR 677 TT genotype was an independent predictor of total cancer risk compared to CC genotype (HR, 1.86; 95%CI, 1.07-3.22). Consistently, a beneficial effect was observed in participants with MTHFR TT genotype and low folate levels (<9.0 ng/mL; HR, 0.47; 95%CI, 0.24-0.94). There is no evidence that 0.8 mg daily folic acid supplementation can increase the risk of cancer incidence among adults with hypertension without history of stroke or MI in China. Our data suggest a protective effect in participants with MTHFR TT genotype and low folate levels.

Folic acid therapy reduces the risk of mortality associated with heavy proteinuria among hypertensive patients

We aimed to evaluate whether proteinuria and estimated glomerular filtration rate (eGFR) levels can modify the efficacy of folic acid therapy on the risk of all-cause mortality among hypertensive patients in the China Stroke Primary Prevention Trial, a randomized, double-blind, and controlled trial. A total of 20 702 hypertensive patients without a history of major cardiovascular diseases were randomly assigned to a double-blind daily treatment of a single tablet containing 10-mg enalapril and 0.8-mg folic acid (n = 10 348), or 10-mg enalapril alone (n = 10 354). All-cause mortality, a prespecified endpoint of the China Stroke Primary Prevention Trial, was the main outcome in this analysis. Over a median treatment duration of 4.5 years, in the enalapril alone group, both heavy proteinuria [vs. absent, 10.8 vs. 2.7%; hazard ratio = 3.30; 95% confidence interval (CI): 2.10-5.18] and lower eGFR levels (<60 vs. ≥90 ml/min per 1.73 m, 13.0 vs. 2.2%; hazard ratio = 1.93; 95% CI: 1.19-3.12) were significantly associated with increased risk of all-cause mortality. Folic acid supplementation significantly reduced the risk of all-cause mortality in patients with heavy proteinuria (6.4% in the enalapril-folic acid vs. 10.8% in the enalapril alone group, hazard ratio = 0.49; 95% CI: 0.26-0.94), but not in those with absent or mild proteinuria (2.8 vs. 2.9%, hazard ratio = 0.99; 95% CI: 0.84-1.17; P for interaction = 0.040). However, eGFR levels did not significantly modify the effect of folic acid supplementation in reducing the risk of all-cause mortality (P for interaction = 0.228). Among hypertensive patients without a history of major cardiovascular diseases, folic acid therapy could reduce the mortality risk associated with heavy proteinuria.

Meta-analysis of folic acid efficacy trials in stroke prevention: Insight into effect modifiers.

To examine the efficacy and effect modifiers of folic acid supplementation in the prevention of stroke in regions without folic acid fortification based on relevant, up-to-date published randomized trials. Relative risk (RR) was used to measure the effect of folic acid supplementation on risk of stroke using a fixed effects model. Overall, folic acid supplementation significantly reduced the stroke risk by 11% (22 trials, n = 82,723; RR 0.89, 95% confidence interval [CI] 0.84-0.96). The effect was greater in low folate regions (2 trials, n = 24,020; Asia, 0.78, 0.67-0.90) compared to high folate regions (7 trials, n = 14,655; America, 1.05, 0.90-1.23), and among patients without folic acid fortification (11 trials, n = 49,957; 0.85; 0.77-0.94) compared with those with folic acid fortification (7 trials, n = 14,655; 1.05, 0.90-1.23). In further stratified analyses among trials without folic acid fortification, a larger beneficial effect was found in those trials that used a low dosage of folic acid (≤0.8 mg: 0.78, 0.69-0.88) or low baseline vitamin B12 levels (<384 pg/mL: 0.78, 0.68-0.89). In the corresponding comparison groups, the effect sizes were attenuated and insignificant (p for interaction <0.05 for both). Although the interaction tests were not significant, there might be a higher benefit in trials with a low dosage of vitamin B12, a low prevalence of statin use, but a high prevalence of hypertension. Folic acid supplementation could reduce the stroke risk in regions without folic acid fortification, particularly in trials using a relatively low dosage of folic acid and with low vitamin B12 levels.

Folic acid therapy reduces serum uric acid in hypertensive patients: a substudy of the China Stroke Primary Prevention Trial (CSPPT)1–3

Background: The effect of folic acid supplementation on uric acid (UA) concentrations is still inconclusive.Objective: We aimed to test the efficacy of folic acid therapy in reducing serum UA in hypertensive patients.Design: A total of 15,364 hypertensive patients were randomly assigned to a double-blind daily treatment with a single tablet that contained 10 mg enalapril and 0.8 mg folic acid (n = 7685) or 10 mg enalapril alone (n = 7679). The main outcome was the change in serum UA, which was defined as UA at the exit visit minus that at baseline. Secondary outcomes were as follows: 1) controlled hyperuricemia (UA concentration <357 µmol/L after treatment) and 2) new-onset hyperuricemia in participants with normal UA concentrations (<357 µmol/L).Results: After a median of 4.4 y of treatment, the mean ± SD UA concentration increased by 34.7 ± 72.5 µmol/L in the enalapril-alone group and by 30.7 ± 71.8 µmol/L in the enalapril–folic acid group, which resulted in a mean group difference of −4.0 µmol/L (95% CI: −6.5, −1.6 µmol/L; P = 0.001). Furthermore, compared with enalapril alone, enalapril–folic acid treatment showed an increase in controlled hyperuricemia (30.3% compared with 25.6%; OR: 1.31; 95% CI: 1.01, 1.70) and a decrease in new-onset hyperuricemia (15.0% compared with 16.3%; OR: 0.89; 95% CI: 0.79, 0.99). A greater beneficial effect was observed in subjects with hyperuricemia (P-interaction = 0.07) or higher concentrations of total homocysteine (tHcy) (P-interaction = 0.02) at baseline. Furthermore, there was a significant inverse relation (P < 0.001) between the reduction of tHcy and the change in UA concentrations.Conclusions: Enalapril–folic acid therapy, compared with enalapril alone, can significantly reduce the magnitude of the increase of UA concentrations in hypertensive adults. This trial was registered at clinicaltrials.gov as NCT00794885.

Regulation of Hepatic Inflammation by Folic Acid in Non‐alcoholic Fatty Liver Disease (NAFLD)

Non‐alcoholic fatty liver disease (NAFLD) is a multifaceted liver disorder that often exists with the comorbidities of obesity and type 2 diabetes. The histopathology of NAFLD is characterized by steatosis, inflammation, fibrosis, and liver injury. Chronic hepatic inflammation is an important pathogenic mediator of NAFLD that contributes to disease severity. The progression of NAFLD may be associated with development of cardiovascular disease which is the primary cause of death in patients. Dietary supplementation of vitamins is important for health maintenance, and has been suggested to be a beneficial strategy for NAFLD management. Folic acid is a water soluble B vitamin that has been demonstrated to have lipid‐lowering and anti‐oxidant effects. The objective of our study was to investigate the effects of folic acid supplementation on hepatic inflammation and to identify the underlying mechanisms. Male C57Bl/6J mice were fed a control diet (10% kcal fat), a high‐fat diet (60% kcal fat), or a high‐fat diet supplemented with folic acid (26mg/kg diet) for a 5 week period. High‐fat diet feeding induced a significant body weight gain and increased aggregation of inflammatory foci in the liver. Folic acid supplementation did not alter the body weight of mice fed a high‐fat diet. However, folic acid supplementation reduced the number of inflammatory foci as well as lipid vacuoles in the liver of high‐fat diet fed mice. This correlated with reduced expression of pro‐inflammatory cytokines mediated through attenuation of NF‐κB transcription activity, an inflammatory transcriptional regulator. Our results suggest that folic acid supplementation can alleviate the hepatic inflammatory response induced by chronic consumption of high‐fat diets, which may contribute to the hepatoprotective effect by folic acid.Support or Funding InformationThis study was supported, in part, by NSERC and CIHR.

Proposal for supplemental intake of folic acid to reduce the risk of neural tube defects.

Congenital AnomaliesVolume 57, Issue 2 p. 44-44 Message from the JTSFree Access Proposal for supplemental intake of folic acid to reduce the risk of neural tube defects First published: 07 March 2017 https://doi.org/10.1111/cga.12210Citations: 5AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL The Japanese Teratology Society releases the following message for reducing the birth of babies with neural tube defects (congenital defects in the brain and/or spinal cord). Women who are planning to get pregnant or those who may be pregnant are advised to reduce the risk of having a baby with such defects by taking 400 μg (0.4 mg) of supplementary folic acid per day from 4 weeks before impregnation through gestation week 12. We also suggest that women who are at a high risk, such as those having a neural tube defect patient within their family and those having delivered a baby with such defects previously, should take hospital consultation on folic acid intake because the risk of their next baby suffering from neural tube defects is relatively higher than usual. Neural tube defects (spina bifida, anencephaly and encephalocele) arise at around gestation week 6 (4 weeks after fertilization) to obstruct the normal development of the brain and spinal cord. Most patients with spina bifida need to receive medical treatment including a surgical treatment soon after birth and treatments for hydrocephaly, walking difficulties and/or excretion disturbances, which may be followed by continuous rehabilitation through their whole life. Babies with anencephaly hardly survive after birth and those having encephalocele may suffer from neurological disorders even if the mass on the brain is removed surgically. Epidemiological studies have shown that maternal intake of folic acid, a kind of water soluble vitamins, decreases the risk of neural tube defects. According to a British epidemiological study (MRC Vitamin Research Group 1991), treatment of women of the high risk group, who have had a baby with neural tube defects previously, with 4 mg/day of folic acid successfully reduced the incidence of these anomalies in the next pregnancy: the preventive efficiency was estimated to be 72%. Another study in China (Berry et al. 1999) also demonstrated similar preventive effects of folic acid supplementation in primiparas (women bearing their first child) at daily doses of 0.4 mg. The Japanese Ministry of Health and Welfare (MHW), the present Ministry of Health, Labor and Welfare (MHLW), announced in 2000 that women who are planning to get pregnant should take 0.4 mg/day of supplementary folic acid, in addition to well-balanced food containing 0.4 mg/day of folic acid (MHW 2000). Daily intake of folic acid at approximately 1 mg/day does not cause excess symptoms (MHLW 2014). However, the percentage of Japanese women who take folic acid supplement is only 10–20% (Kondo et al. 2013; Obara et al. 2016) and the incidence of neural tube defects in Japan has remained unreduced (International Clearinghouse for Birth Defects Serveilance and Research 2014, MHW 2000). The Japanese Teratology Society aims to contribute to the health and welfare of Japanese people by making efforts to prevent the birth of babies with congenital anomalies. References MRC Vitamin Study Research Group. 1991. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 338: 131– 137. Berry RJ, Li Z, Erickson JD. 1999. Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention. N Engl J Med 341: 1485– 1490. International Clearinghouse for Birth Defects Serveilance and Research (ICBDSR) (2014) ICBDSR Annual Report 2014 with data for 2012. http://www.icbdsr.org/filebank/documents/ar2005/Report2014.pdf Kondo A, Morota N, Ihara S. 2013. Risk factors for the occurrence of spina bifida (a case–control study) and the prevalence rate of spina bifida in Japan. Birth Defects Res A Clin Mol Teratol 97: 610– 615. Ministry of Health and Welfare (MHW) in Japan (2000) 12-Jibo no. 72 (in Japanese). http://www1.mhlw.go.jp/houdou/1212/h1228-1_18.html Ministry of Health, Labor and Welfare (MHLW) in Japan (2014) Dietary refference intakes for Japanese (in Japanese). https://www.icbdsr.org/filebank/documents/ar2005/Report2014.pdf Obara T, Nishigori H, Nishigori T. 2016. Prevalence and determinants of inadequate use of folic acid supplementation in Japanese pregnant women: the Japan Environment and Children's Study (JECS). J Matern Fetal Neonatal Med 26: 1– 6. Citing Literature Volume57, Issue2March 2017Pages 44-44 ReferencesRelatedInformation

Sex-Specific Associations between One-Carbon Metabolism Indices and Posttranslational Histone Modifications in Arsenic-Exposed Bangladeshi Adults.

Posttranslational histone modifications (PTHMs) are altered by arsenic, an environmental carcinogen. PTHMs are also influenced by nutritional methyl donors involved in one-carbon metabolism (OCM), which may protect against epigenetic dysregulation. We measured global levels of three PTHMs, which are dysregulated in cancers (H3K36me2, H3K36me3, H3K79me2), in peripheral blood mononuclear cells (PBMC) from 324 participants enrolled in the Folic Acid and Creatine Trial, a randomized trial in arsenic-exposed Bangladeshi adults. Sex-specific associations between several blood OCM indices (folate, vitamin B12, choline, betaine, homocysteine) and PTHMs were examined at baseline using regression models, adjusted for multiple tests by controlling for the false discovery rate (PFDR). We also evaluated the effects of folic acid supplementation (400 μg/d for 12 weeks), compared with placebo, on PTHMs. Associations between choline and H3K36me2 and between vitamin B12 and H3K79me2 differed significantly by sex (Pdiff < 0.01 and <0.05, respectively). Among men, plasma choline was positively associated with H3K36me2 (PFDR < 0.05), and among women, plasma vitamin B12 was positively associated with H3K79me2 (PFDR < 0.01). Folic acid supplementation did not alter any of the PTHMs examined (PFDR = 0.80). OCM indices may influence PTHMs in a sex-dependent manner, and folic acid supplementation, at this dose and duration, does not alter PTHMs in PBMCs. This is the first study to examine the influences of OCM indices on PTHMs in a population that may have increased susceptibility to cancer development due to widespread exposure to arsenic-contaminated drinking water and a high prevalence of hyperhomocysteinemia. Cancer Epidemiol Biomarkers Prev; 26(2); 261-9. ©2016 AACR.

Prevention of neural tube defects in Lrp2 mutant mouse embryos by folic acid supplementation.

Neural tube defects (NTDs) are among the most common structural birth defects in humans and are caused by the complex interaction of genetic and environmental factors. Periconceptional supplementation with folic acid can prevent NTDs in both mouse models and human populations. A better understanding of how genes and environmental factors interact is critical toward development of rational strategies to prevent NTDs. Low density lipoprotein-related protein 2 (Lrp2) is involved in endocytosis of the folic acid receptor among numerous other nutrients and ligands. We determined the effect of iron and/or folic acid supplementation on the penetrance of NTDs in the Lrp2null mouse model. The effects of supplementation on folate and iron status were measured in embryos and dams. Periconceptional dietary supplementation with folic acid did not prevent NTDs in Lrp2 mutant embryos, whereas high levels of folic acid supplementation by intraperitoneal injection reduced incidence of NTDs. Importantly, Lrp2null/+ dams had reduced blood folate levels that improved with daily intraperitoneal injections of folate but not dietary supplementation. On the contrary, iron supplementation had no effect on the penetrance of NTDs in Lrp2 mutant embryos and negated the preventative effect of folic acid supplementation in Lrp2null/null mutants. Lrp2 is required for folate homeostasis in heterozygous dams and high levels of supplementation prevents NTDs. Furthermore, high levels of dietary iron supplementation interfered with folic acid supplementation negating the positive effects of supplementation in this model. Birth Defects Research 109:16-26, 2017. © 2016 The Authors Birth Defects Published by Wiley Periodicals, Inc.

Preconceptional use of folic acid and knowledge about folic acid among low-income pregnant women in Korea.

BACKGROUND/OBJECTIVESFolic acid supplementation before pregnancy is known to significantly reduce the risk of having a baby with neural tube defects (NTDs). Therefore, it is important for women to be aware of the effects of folic acid supplementation before pregnancy. The purpose of this study was to investigate the awareness and preconceptional use of folic acid and to assess the current knowledge about folic acid among low-income pregnant women in Korea.SUBJECTS/METHODSA questionnaire survey was conducted in 2012. Five hundred pregnant women were selected from the waiting list for the Nutriplus program implemented in public health centers using a multistage clustered probability sampling design. Data from 439 women were analyzed after excluding ones with incomplete answers.RESULTSAmong women who responded to the questionnaire, 65.6% had heard of folic acid before pregnancy, and 26.4% reported on the preconceptional use of folic acid. Women with a university degree or higher education were more likely to be aware of folic acid and to take folic acid in the preconception period. In a multivariate logistic regression, when age, education level, household income, employment status, gravidity, parity, and folic acid awareness were included in the model, folic acid awareness was a strong predictor of preconceptional folic acid use. As of interview, 85.4% and 77.7% of women were aware of the NTD-preventive role of folic acid and the appropriate time to take folic acid, respectively. The main sources of information on folic acid were healthcare professionals (41.2%), friends and family members (31.2%), and the media (26.5%).CONCLUSIONSOur results suggest that public health strategies are needed to increase the preconceptional use of folic acid among Korean women.

Effects of folic acid supplementation on serum homocysteine levels, lipid profiles, and vascular parameters in post-menopausal Korean women with type 2 diabetes mellitus.

BACKGROUND/OBJECTIVESComplications of diabetes, such as cardiovascular disease, are associated with increased mortality among type 2 diabetes mellitus patients. Homocysteine has been recently identified as a predictor of cardiovascular disease-related complications in diabetes. We investigated whether or not supplementation with folic acid tablets can lower homocysteine levels and improve parameters related with vascular complications.SUBJECTS/METHODSWe conducted a non-randomized 8-week trial involving postmenopausal diabetic women (n = 25) supplemented with 800 µg of folic acid (400 µg twice a day) daily. Subjects' serum levels of folate, homocysteine, and vitamin B12 were measured, along with vascular function and brachial-ankle pulse wave velocity.RESULTSFolic acid supplementation significantly increased serum folate levels (P < 0.0001), reduced homocysteine levels (P < 0.0001), and increased vitamin B12 levels (P = 0.0063). There were significant decreases in low-density lipoprotein cholesterol levels as well as the ratios of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol and total cholesterol to high-density lipoprotein cholesterol. Brachial-ankle pulse wave velocities were not altered by supplementation. Changes in serum vitamin B12 after folic acid supplementation were negatively correlated with changes in brachial-ankle pulse wave velocity.CONCLUSIONSIn this study on postmenopausal Korean women with type 2 diabetes mellitus, folic acid supplementation reduced serum homocysteine levels, increased serum folate and vitamin B12 levels, and lowered lipid parameters.

Nutrition, One-Carbon Metabolism and Neural Tube Defects: A Review.

Neural tube defects (NTDs) are a group of severe congenital malformations, induced by the combined effects of genes and the environment. The most valuable finding so far has been the protective effect of folic acid supplementation against NTDs. However, many women do not take folic acid supplements until they are pregnant, which is too late to prevent NTDs effectively. Long-term intake of folic acid–fortified food is a good choice to solve this problem, and mandatory folic acid fortification should be further promoted, especially in Europe, Asia and Africa. Vitamin B2, vitamin B-6, vitamin B-12, choline, betaine and n-3 polyunsaturated fatty acids (PUFAs) can also reduce the NTD risk by interacting with the one-carbon metabolism pathway. This suggest that multivitamin B combined with choline, betaine and n-3 PUFAs supplementation may have a better protective effect against NTDs than folic acid alone. Genetic polymorphisms involved in one-carbon metabolism are associated with NTD risk, and gene screening for women of childbearing age prior to pregnancy may help prevent NTDs induced by the risk allele. In addition, the consumption of alcohol, tea and coffee, and low intakes of fruit and vegetable are also associated with the increased risk of NTDs, and should be avoided by women of childbearing age.

New Perspective on Impact of Folic Acid Supplementation during Pregnancy on Neurodevelopment/Autism in the Offspring Children - A Systematic Review.

It has been conclusively established that folic acid supplementation prior to and during early pregnancy (up to 12 weeks of gestation) can prevent neural tube defects (NTDs). We hypothesized that folate effects may extend from neuro-structural defects to alterations in neuro-behavioural and emotional skills including autism spectrum disorders (ASDs) and other developmental disorders. The objective of this review was to comprehensively evaluate evidence on the impact of folic acid on neurodevelopment other than NTDs. We conducted an online search of relevant literature compiled by the National Library of Medicine from Medline and EMBASE (searched on Dec 31, 2014: http://www.ncbi.nlm.nih.gov/entrez/query/fcgi and http://www.elsevier.com/online-tools/embase). We first created 3 files (search restricted to English literature) using the following key words: 1) folate or folic acid (171322 papers identified by this search); 2) maternal or pregnancy or pregnant or gestation or gestational or prenatal or antenatal or periconception or periconceptional (1349219 papers identified by this search); and 3) autism or autism spectrum disorders or developmental delay or development or neurodevelopment or mental or cognitive or language or personal-social or gross motor or fine motor or behaviour or intellectual or intelligence or Bayley Scale (8268145 papers identified by this search). We then merged the 3 files and reviewed the papers that addressed these three issues simultaneously. A total of 22 original papers that examined the association between folic acid supplementation in human pregnancy and neurodevelopment/autism were identified after the screening, with 15 studies showing a beneficial effect of folic acid supplementation on neurodevelopment/autism, 6 studies showed no statistically significant difference, while one study showed a harmful effect in > 5 mg folic acid supplementation/day during pregnancy. Folic acid supplementation in pregnancy may have beneficial effects on the neurodevelopment of children beyond its proven effect on NTDs.

Effect of folic acid supplementation on preterm delivery and small for gestational age births: A systematic review and meta-analysis

ObjectiveTo investigate the effect of folic acid (FA) supplementation on the risks of preterm delivery (PTD) and small for gestational age births (SGA). Data sourcesCohort studies were identified from MEDLINE, EMBASE, the Cochrane Library, CINAHL, and CBM from inception to January 2015. Participants and included studiesHealthy women who want to get pregnancy or being pregnant. Main outcome measuresPTD and SGA. ResultsThe association of FA and PTD was significant when supplement initiated after pregnancy (RR=0.68, 95%CI, 0.52–0.90), whereas no effect was founded if the initiation time was before conception (RR=0.89, 95%CI, 0.80–1.01). The results for the association between FA supplementation and SGA showed significant protective effect: initiated before conception (RR=0.70, 95%CI, 0.57–0.85) and initiated after conception (RR=0.84, 95%CI, 0.81–0.89). ConclusionFolic acid supplementation is associated with a significant reduction on the risk of PTD when initiated after conception. It can also protect fetus from SGA.

Hyperhomocysteinaemia in children receiving phenytoin and carbamazepine monotherapy: a cross-sectional observational study

ObjectiveLong-term therapy with phenytoin and carbamazepine is known to cause hyperhomocysteinaemia. We evaluated the prevalence of hyperhomocysteinaemia in North Indian children receiving phenytoin or carbamazepine monotherapy for >6 months duration...

Folic acid supplementation, birth defects, and adverse pregnancy outcomes in Chinese women: a population-based mega-cohort study

BackgroundPericonceptional folic acid use has been widely recommended to reduce risk of neural tube defects. However, the effect on other birth defects and adverse pregnancy outcomes, as well as the time window of folic acid use, needs further investigation. Our study aimed to comprehensively assess the effect of periconceptional folic acid use on pregnancy outcomes in a mega-cohort of women of reproductive age. MethodsThe China National Free Preconception Health Examination Project (NFPHEP) was established in 2010 to assess couples who planned to get pregnant within 4–6 months for pre-pregnancy risk factors for birth defects, and was a national project for all couples in 31 provinces. We obtained data on folic acid use before and during pregnancy and pregnancy outcomes from women in the project who became pregnant within 1 year after baseline examinations between 2010 and 2015. Women aged 20–49 years who completed pregnancy outcome follow-up in 220 selected counties were included in the study. Multivariate logistic regression models were used to estimate odds ratios (ORs) and 95% CIs with adjustment for covariates. The current study was approved by the Institutional Research Review Board at the National Health and Family Planning Commission and National Research Institute for Family Planning, and all participants gave written consent. FindingsOur cohort consisted of 1 535 066 women. Compared with the 352 099 (22·9%) women who did not take folic acid supplements before and during early pregnancy, 1 182 967 (77·1%) women who did take folic acid supplements had lower odds of total birth defects (OR 0·88, 95% CI 0·78–0·99), neural tube defect (OR 0·45, 0·33–0·61), preterm birth (OR 0·70, 0·69–0·71), miscarriage (OR 0·59, 0·58–0·61), stillbirth (OR 0·75, 0·69–0·81), and neonatal mortality (OR 0·77, 0·70–0·85). Particularly, those who started folic acid use 3 months before their last menstrual period had a significantly lower risk of total birth defects (OR 0·66, 95% CI 0·58–0·76), neural tube defect (OR 0·42, 0·30–0·60), cleft lip (OR 0·48, 0·28–0·81), face malformation (OR 0·62, 0·41–0·98), preterm birth (OR 0·67, 0·66–0·67), low birthweight (OR 0·74, 0·71–0·78), miscarriage (OR 0·53, 0·52–0·54), stillbirth (OR 0·70, 0·64–0·77), and neonatal mortality (OR 0·70, 0·63–0·78) than did those who did not take folic acid. Subgroup analyses also suggested that the protective effects of folic acid supplementation on preterm birth were significantly stronger among women who resided in the south, were of Han ethnicity, had not been exposed to maternal passive smoking, had a body-mass index of less than 24·0 kg/m2, and were free of pre-pregnancy hypertension or diabetes (all p<0·001). InterpretationThe findings from this mega-cohort of Chinese women of reproductive age demonstrate the protective effect of periconceptional folic acid supplementation on birth defects and adverse pregnancy outcomes, particularly if supplements are taken early before conception. FundingFive-twelfth National Science and Technology Support Program (number 2013BAI12B01), the operation funds for basic scientific research of the central authorities (number 2015GJM09). We are thankful for the support of all the investigators and participants who contributed to the National Free Preconception Health Examination Project.

Time to Think About Nutrient Needs in Chronic Disease

There is renewed interest in health benefits of folic acid supplementation since the China Stroke Prevention Primary Prevention Trial (CSPPT) showed the potential benefits of folic acid inpreventing stroke in Chinese adults with hypertension.1 It has long been known that folic acid prevents neural tube defects, which are among the most severe anddebilitating congenital birth defectsworldwide. The CSPPTwas terminated earlywhen800μgof folic acid in combination with 10 mg of enalapril significantly reduced primarystroke incidencecomparedwith theenalapril alone treatment arm. This finding was unexpected as other studies had failed to find a preventive effect of folic acid supplementation on cardiovascular events.2 In this issue of JAMA Internal Medicine, Xu et al3 report findings from a prespecified CSPPT substudy that demonstrated that the folic acid–enalapril combination was more effective than enalapril alone in the secondary prevention of renal function decline among Chinese adults with hypertension across a spectrum of mild to moderate chronic kidney disease (CKD). Folic acid is commonly administered to treat hyperhomocysteinemia, but thebenefits ofhomocysteine loweringon the prevention or management of most chronic diseases associatedwith hyperhomocysteinemia remains unproven.2 In the renal substudy of the CSPPT,3 Xu and colleagues report that 42% of participants with CKD exhibited hyperhomocysteinemia (serum homocysteine ≥15 μM) and 24% had diabetes, comparedwithonly26%withhyperhomocysteinemiaand12% with diabetes in those without CKD. Individuals who were homozygous for theMTHFR C677T polymorphism, a genetic variant that expresses anenzymewith reduced5-methyltetrahydrofolate synthesis activity, exhibited the greatest reduction inserumhomocysteine followingfolicacid–enalapril treatmentbecause theirbaseline levelsof circulatinghomocysteine werehigher. This finding is consistentwith other studies suggesting that the current recommended dietary intake for folatemaynotbeadequate for individualshomozygous for the MTHFR 677T variantwhen homocysteine lowering is used as the functional biomarker to assess folate status.4 Importantly, the folicacid–enalapril combinationwasmore effective in reducing rates of renal dysfunction in individuals with CKD (odds ratio [OR], 0.44; 95% CI, 0.26-0.75) compared with enalapril treatment alone, with the primary outcome measure being a prespecified level of decline in the estimated glomerular filtration rate (eGFR).3 The folic acid– enalapril treatment significantly reduced other measures of renal dysfunction in addition to the 21% reduction in risk for theprimaryoutcomecomparedwith theenalapril-onlygroup. These included secondary outcome measures of rapid decline in renal function (OR,0.67;95%CI,0.47-0.96) andacomposite eventmeasure (OR,0.62;95%CI,0.43-0.90); bothwere significantly reduced in the group receiving the folic acid– enalapril combination compared with the enalapril group. Therewasnoevidence forprimarypreventionofCKD ineither arm of the study. Hyperhomocystenemia is a common finding in patients with CKD. However, folic acid–induced reductions in serum homocysteine levels did not affect kidney function in other studies.5,6Xuet al hypothesized that thesedifferencesmaybe owing to the inclusion of other B vitamins, including vitamin B12, in previous vitamin supplementation trials on renal function.Also, the level of folic acid supplementationvariedmarkedly among these trials. The study by Xu et al administered folic acid at levels below 1 mg/d, whereas other studies administered folic acid at much higher levels. Dose may be an importantmodifier of efficacy and toxic effects, especially for specific clinical populations.Forexample, inpatientswithdiabetic nephropathy, subjects receiving 2.5 mg/d folic acid, 25mg/d vitamin B6, and 1mg/d vitamin B12 exhibited greater decreases in serumhomocysteine thandid those receivingplacebo, but kidney function (measured by eGFR) unexpectedly decreased more in the treatment group than in the placebo group.5 In a related study, patients with advanced kidney or end-stage renal diseaseswere treatedwith40mg/d folic acid, 100mg/d vitaminB6, and 2mg/d vitaminB12 daily. Therewas no effect of treatment on all-cause mortality, stroke, or amputation of lower extremities compared with placebo.6 Folic acid is a synthetic, provitamin formof folate that is processed tonatural folate by the enzymedihydrofolate reductase. Very high intakes of folic acid may result in saturation of dihydrofolate reductase activity. Folic acid binds tightly to the folate receptor (FRα), aglycoprotein that is anchored to thecellmembrane of epithelial cells. It is possible that because FRα is expressed in the kidney, the kidneymaybemoreharmedbyunmetabolized folic acid, especially in subjects with kidney disease or impaired kidney function, as observed in a population with diabetic nephropathy.5 Folic acid–induced nephrotoxic effects has been demonstrated in mouse models.7 AnothermajordifferenceamongtheCKDtrialswas theuse of enalapril in the studydesign byXuet al.3 The results of this studydemonstrated that enalapril interactswith folate in human physiology, as enalapril treatment alone in the absence of supplemental folic acid increased serumfolateby5.1 ng/mL (to convert ng/mL to nmol/L,multiply by 2.266), with amodest decrease in serum homocysteine (0.2 μM). While the mechanisms for this interaction are unknown and should be explored, this drug-nutrient interactionmayunderlie the secondary prevention of renal function decline observed in this study. Dietary reference intakes are established to give guidance foradequate intake levelsofessentialnutrients forhealthy individuals, but there is increasing awareness that these recommendations may not apply to populations with chronic Related article page 1443 Effects of Folate on Chronic Kidney Disease Progression Original Investigation Research

Rs6586282 of the CBS Gene: Its Lack of Eff ect on Homocysteine Concentrations, and Interaction Eff ects on Body Weight in Elderly Women.

The aim of the present study is to evaluate the effect of the rs6586282 polymorphism of the cystathionine-β-synthase (CBS) gene, and of the intake of B vitamins on anthropometric parameters, tHcy levels, and lipoprotein levels in women over 60 years of age. 122 volunteers were supplemented with 400 μg/day folic acid for 8 weeks. The intake of B vitamins above the median value was associated with lower levels of blood biomarkers: folate with tHcy post supplementation (6.21 ± 0.24 μM vs 7.11 ± 0.32 μM; p < 0.05), vitamin B6 with baseline triacylglycerol (TAG, 107.3 ± 5.5 mg/dL vs 127.2 ± 6.4 mg/dL; p < 0.05) and glucose (82.3 ± 1.1 mg/dL vs 86.9 ± 1.5 mg/dL; p < 0.05); and vitamin B12 with baseline TAG (106.8 ± 5.5 mg/dL vs 127.7 ± 6.3 mg/dL; p < 0.01). Women with a T allele consuming lower amounts of folate had higher body weight (72.3 ± 2.3 kg vs 64.0 ± 1.7 kg; p < 0.05), body mass index (28.7 ± 0.8 vs 25.2 ± 0.7; p < 0.05), waist (0.90 ± 0.02 m vs 0.82 ± 0.01 m; p < 0.01), and hip circumference (1.08 ± 0.02 vs 1.02 ± 0.01 m; p < 0.01) than the CC homozygotes. Intake of vitamin B6 or B12 may infl uence blood TAG and glucose concentrations in elderly women, but the rs6586282 polymorphism of the CBS gene does not alter either tHcy or the effectiveness of folic acid supplementation. The CBS SNP at rs6586282 may infl uence anthropometric parameters, though only in case of low folate intake.