Trial Of Folic Acid Supplementation Research Articles

Unveiling the Therapeutic Potential of Folate-Dependent One-Carbon Metabolism in Cancer and Neurodegeneration.

Cellular metabolism is crucial for various physiological processes, with folate-dependent one-carbon (1C) metabolism playing a pivotal role. Folate, a B vitamin, is a key cofactor in this pathway, supporting DNA synthesis, methylation processes, and antioxidant defenses. In dividing cells, folate facilitates nucleotide biosynthesis, ensuring genomic stability and preventing carcinogenesis. Additionally, in neurodevelopment, folate is essential for neural tube closure and central nervous system formation. Thus, dysregulation of folate metabolism can contribute to pathologies such as cancer, severe birth defects, and neurodegenerative diseases. Epidemiological evidence highlights folate's impact on disease risk and its potential as a therapeutic target. In cancer, antifolate drugs that inhibit key enzymes of folate-dependent 1C metabolism and strategies targeting folate receptors are current therapeutic options. However, folate's impact on cancer risk is complex, varying among cancer types and dietary contexts. In neurodegenerative conditions, including Alzheimer's and Parkinson's diseases, folate deficiency exacerbates cognitive decline through elevated homocysteine levels, contributing to neuronal damage. Clinical trials of folic acid supplementation show mixed outcomes, underscoring the complexities of its neuroprotective effects. This review integrates current knowledge on folate metabolism in cancer and neurodegeneration, exploring molecular mechanisms, clinical implications, and therapeutic strategies, which can provide crucial information for advancing treatments.

The Association of Female and Male Preconception Dyslipidemia with Live Birth in Couples Seeking Fertility Treatment.

Dyslipidemia is common, and resultant endothelial dysfunction may impact reproductive outcomes. No prospective study has examined the effect of preconception lipid parameters in both female and male partners or their interaction on live birth. To determine whether live birth is associated with preconception lipids in both partners by planned fertility treatment. Secondary analysis of the Folic Acid and Zinc Supplementation Trial, conducted between June 2013-December 2017. Couples were followed for nine months after randomization and until delivery. Multicenter study. Couples seeking fertility treatment (n = 2370; females 18-45 years, males ≥18 years). Female, male, and couple abnormal versus normal preconception lipid concentrations (total cholesterol [TC], low-density lipoprotein [LDL], high-density lipoprotein [HDL], triglycerides [TG]). Live birth. Among 2370 couples, most males (84%) and females (76%) had at least one abnormal lipid parameter. Males planning in vitro fertilization (IVF, n = 373) with elevated LDL had lower probability of live birth than those with normal levels (47.4% vs. 59.7%, aRR 0.79, 95% CI 0.65-0.98). In couples planning IVF where both partners had elevated TC or LDL, live birth was lower than those with normal levels (TC: 32.4% vs. 58.0%, aRR 0.53, 95% CI 0.36-0.79; and LDL: 41.9% vs. 63.8%, aRR 0.69, 95% CI 0.55-0.85). Lipid parameters were not associated with live birth for couples planning non-IVF treatments. Couples planning IVF where both partners had elevated TC or LDL and males planning IVF with elevated LDL had decreased probability of live birth. These findings may support lipid screening in patients seeking fertility treatment for prognostic information for reproductive outcomes.

Daily Folic Acid and/or Vitamin B12 Supplementation Between 6 and 30 Months of Age and Cardiometabolic Risk Markers After 6–7 Years: A Follow-Up of a Randomized Controlled Trial

BackgroundDeficiencies of vitamin B12 and folate are associated with elevated concentrations of metabolic markers related to CVDs. ObjectivesWe investigated the effect of supplementation of vitamin B12 with or without folic acid for 6 mo in early childhood on cardiometabolic risk markers after 6–7 y. MethodsThis is a follow-up study of a 2 × 2 factorial, double-blind, randomized controlled trial of vitamin B12 and/or folic acid supplementation in 6–30-mo-old children. The supplement contained 1.8 μg of vitamin B12, 150 μg of folic acid, or both, constituting >1 AI or recommended daily allowances for a period of 6 mo. Enrolled children were contacted again after 6 y (September 2016–November 2017), and plasma concentrations of tHcy, leptin, high molecular weight adiponectin, and total adiponectin were measured (N = 791). ResultsAt baseline, 32% of children had a deficiency of either vitamin B12 (<200 pmol/L) or folate (<7.5 nmol/L). Combined supplementation of vitamin B12 and folic acid resulted in 1.19 μmol/L (95% CI: 0.09; 2.30 μmol/L) lower tHcy concentration 6 y later compared to placebo. We also found that vitamin B12 supplementation was associated with a lower leptin–adiponectin ratio in subgroups based on their nutritional status. ConclusionsSupplementation with vitamin B12 and folic acid in early childhood was associated with a decrease in plasma tHcy concentrations after 6 y. The results of our study provide some evidence of persistent beneficial metabolic effects of vitamin B12 and folic acid supplementation in impoverished populations.The original trial was registered at www.clinicaltrials.gov as NCT00717730, and the follow-up study at www.ctri.nic.in as CTRI/2016/11/007494.

Folic acid intervention during pregnancy alters DNA methylation, affecting neural target genes through two distinct mechanisms

BackgroundWe previously showed that continued folic acid (FA) supplementation beyond the first trimester of pregnancy appears to have beneficial effects on neurocognitive performance in children followed for up to 11 years, but the biological mechanism for this effect has remained unclear. Using samples from our randomized controlled trial of folic acid supplementation in second and third trimester (FASSTT), where significant improvements in cognitive and psychosocial performance were demonstrated in children from mothers supplemented in pregnancy with 400 µg/day FA compared with placebo, we examined methylation patterns from cord blood (CB) using the EPIC array which covers approximately 850,000 cytosine–guanine (CG) sites across the genome. Genes showing significant differences were verified using pyrosequencing and mechanistic approaches used in vitro to determine effects on transcription.ResultsFA supplementation resulted in significant differences in methylation, particularly at brain-related genes. Further analysis showed these genes split into two groups. In one group, which included the CES1 gene, methylation changes at the promoters were important for regulating transcription. We also identified a second group which had a characteristic bimodal profile, with low promoter and high gene body (GB) methylation. In the latter, loss of methylation in the GB is linked to decreases in transcription: this group included the PRKAR1B/HEATR2 genes and the dopamine receptor regulator PDE4C. Overall, methylation in CB also showed good correlation with methylation profiles seen in a published data set of late gestation foetal brain samples.ConclusionWe show here clear alterations in DNA methylation at specific classes of neurodevelopmental genes in the same cohort of children, born to FA-supplemented mothers, who previously showed improved cognitive and psychosocial performance. Our results show measurable differences at neural genes which are important for transcriptional regulation and add to the supporting evidence for continued FA supplementation throughout later gestation. This trial was registered on 15 May 2013 at www.isrctn.com as ISRCTN19917787.

The impact of zinc and folic acid supplementation on sperm DNA methylation: results from the folic acid and zinc supplementation randomized clinical trial (FAZST)

To determine if 6-month folic acid (5 mg) and zinc (30 mg) supplementation impacts sperm DNA methylation patterns. A multicenter, double-blind, block randomized, placebo-controlled trial titled "The Folic Acid and Zinc Supplementation Trial (FAZST)." Infertility care centers. Male partners (18 years and older) from heterosexual couples (female partners aged 18-45 years) seeking fertility treatment were recruited. Men were randomized 1:1 to receive folic acid (5 mg) and elemental zinc (30 mg) (n = 713) or a matching placebo (n=757) daily for 6 months. Sperm DNA methylation was analyzed using the EPIC methylation array (Illumina) at 6 months. Differential sperm DNA methylation was assessed at multiple levels (regional, single cytosine phosphate guanine, etc.). We additionally assessed the impact of supplementation on epigenetic age. No significant differences were identified between the treatment and placebo groups although some trends appeared to be present. To determine if these trends were noteworthy, we implemented various permutations and found that the patterns we identified were no more than would be expected by random chance. The data presented here strongly suggest that this supplementation regimen is not effective at altering sperm DNA methylation. These data comport well with previous findings from the FAZST study that found no impact of supplementation on basic semen analysis parameters or live birth. ClinicalTrials.gov Identifier: NCT01857310.

Effects of maternal folic acid supplementation during the second and third trimesters of pregnancy on neurocognitive development in the child: an 11-year follow-up from a randomised controlled trial

BackgroundMaternal folic acid (FA) supplementation before and in early pregnancy prevents neural tube defects (NTD), but it is uncertain whether continuing FA after the first trimester has benefits on offspring health. We aimed to evaluate the effect of FA supplementation throughout pregnancy on cognitive performance and brain function in the child.MethodsFollow-up investigation of 11-year-old children, residing in Northern Ireland, whose mothers had participated in a randomised trial of Folic Acid Supplementation in the Second and Third Trimesters (FASSTT) in pregnancy and received 400 μg/day FA or placebo from the 14th gestational week. Cognitive performance (Full Scale Intelligence Quotient, Verbal Comprehension, Working Memory, Perceptual Reasoning, and Processing Speed) was assessed using the Wechsler Intelligence Scale for Children. Neuronal function was assessed using magnetoencephalographic (MEG) brain imaging.ResultsOf 119 mother-child pairs in the FASSTT trial, 68 children were assessed for neurocognitive performance at 11-year follow-up (Dec 2017 to Nov 2018). Children of mothers randomised to FA compared with placebo scored significantly higher in two Processing Speed tests, i.e. symbol search (mean difference 2.9 points, 95% CI 0.3 to 5.5, p = 0.03) and cancellation (11.3 points, 2.5 to 20.1, p = 0.04), whereas the positive effect on Verbal Comprehension was significant in girls only (6.5 points, 1.2 to 11.8, p = 0.03). MEG assessment of neuronal responses to a language task showed increased power at the Beta (13–30 Hz, p = 0.01) and High Gamma (49–70 Hz, p = 0.04) bands in children from FA-supplemented mothers, suggesting more efficient semantic processing of language.ConclusionsContinued FA supplementation in pregnancy beyond the early period currently recommended to prevent NTD can benefit neurocognitive development of the child. MEG provides a non-invasive tool in paediatric research to objectively assess functional brain activity in response to nutrition and other interventions.Trial registrationISRCTN ISRCTN19917787. Registered on 15 May 2013.

The determinants of maternal homocysteine in pregnancy: findings from the Ottawa and Kingston Birth Cohort.

Observational studies have linked elevated homocysteine to vascular conditions. Folate intake has been associated with lower homocysteine concentration, although randomised controlled trials of folic acid supplementation to decrease the incidence of vascular conditions have been inconclusive. We investigated determinants of maternal homocysteine during pregnancy, particularly in a folic acid-fortified population. Data were from the Ottawa and Kingston Birth Cohort of 8085 participants. We used multivariable regression analyses to identify factors associated with maternal homocysteine, adjusted for gestational age at bloodwork. Continuous factors were modelled using restricted cubic splines. A subgroup analysis examined the modifying effect of MTHFR 677C>T genotype on folate, in determining homocysteine concentration. Participants were recruited in Ottawa and Kingston, Canada, from 2002 to 2009. Women were recruited when presenting for prenatal care in the early second trimester. In 7587 participants, factors significantly associated with higher homocysteine concentration were nulliparous, smoking and chronic hypertension, while factors significantly associated with lower homocysteine concentration were non-Caucasian race, history of a placenta-mediated complication and folic acid supplementation. Maternal age and BMI demonstrated U-shaped associations. Folic acid supplementation of >1 mg/d during pregnancy did not substantially increase folate concentration. In the subgroup analysis, MTHFR 677C>T modified the effect of folate status on homocysteine concentration. We identified determinants of maternal homocysteine relevant to the lowering of homocysteine in the post-folic acid fortification era, characterised by folate-replete populations. A focus on periconceptional folic acid supplementation and improving health status may form an effective approach to lower homocysteine.

Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment

Importance Dietary supplements marketed for male fertility commonly contain folic acid and zinc based on limited prior evidence for improving semen quality. However, no large-scale trial has examined the efficacy of this therapy for improving semen quality or live birth. Objective To determine the effect of daily folic acid and zinc supplementation on semen quality and live birth. Design, Setting, and Participants The Folic Acid and Zinc Supplementation Trial was a multicenter randomized clinical trial. Couples (n = 2370; men aged ≥18 years and women aged 18-45 years) planning infertility treatment were enrolled at 4 US reproductive endocrinology and infertility care study centers between June 2013 and December 2017. The last 6-month study visit for semen collection occurred during August 2018, with chart abstraction of live birth and pregnancy information completed during April 2019. Interventions Men were block randomized by study center and planned infertility treatment (in vitro fertilization, other treatment at a study site, and other treatment at an outside clinic) to receive either 5 mg of folic acid and 30 mg of elemental zinc (n = 1185) or placebo (n = 1185) daily for 6 months. Main Outcomes and Measures The co–primary outcomes were live birth (resulting from pregnancies occurring within 9 months of randomization) and semen quality parameters (sperm concentration, motility, morphology, volume, DNA fragmentation, and total motile sperm count) at 6 months after randomization. Results Among 2370 men who were randomized (mean age, 33 years), 1773 (75%) attended the final 6-month study visit. Live birth outcomes were available for all couples, and 1629 men (69%) had semen available for analysis at 6 months after randomization. Live birth was not significantly different between treatment groups (404 [34%] in the folic acid and zinc group and 416 [35%] in the placebo group; risk difference, −0.9% [95% CI, −4.7% to 2.8%]). Most of the semen quality parameters (sperm concentration, motility, morphology, volume, and total motile sperm count) were not significantly different between treatment groups at 6 months after randomization. A statistically significant increase in DNA fragmentation was observed with folic acid and zinc supplementation (mean of 29.7% for percentage of DNA fragmentation in the folic acid and zinc group and 27.2% in the placebo group; mean difference, 2.4% [95% CI, 0.5% to 4.4%]). Gastrointestinal symptoms were more common with folic acid and zinc supplementation compared with placebo (abdominal discomfort or pain: 66 [6%] vs 40 [3%], respectively; nausea: 50 [4%] vs 24 [2%]; and vomiting: 32 [3%] vs 17 [1%]). Conclusions and Relevance Among a general population of couples seeking infertility treatment, the use of folic acid and zinc supplementation by male partners, compared with placebo, did not significantly improve semen quality or couples’ live birth rates. These findings do not support the use of folic acid and zinc supplementation by male partners in the treatment of infertility. Trial Registration ClinicalTrials.gov Identifier:NCT01857310

Effect of folic acid supplementation during pregnancy on brain health of the child at 11 years: the FASSTT Offspring trial

AbstractPericonceptional folic acid (FA) has an established role in the prevention of neural tube defects (NTDs), leading to global recommendations for FA supplementation before and in early pregnancy. However, it is unclear whether there are any benefits for offspring brain health arising from continued maternal FA supplementation beyond the first trimester. The aim of this study was to investigate the role of maternal folate nutrition during pregnancy in relation to cognitive performance and brain function in the offspring at 11 years. The children of mothers who had participated in a randomised trial of Folic Acid Supplementation in the Second and Third Trimesters (FASSTT) were investigated, providing a unique opportunity to examine offspring brain health in relation to maternal folate (the FASSTT Offspring trial; n = 68). Cognitive performance was assessed using the Wechsler Intelligence Scale for Children, Fourth UK Edition (WISC-IV). The WISC-IV measures Full Scale IQ and specific domains of cognitive performance: Verbal Comprehension, Perceptual Reasoning, Working Memory and Processing Speed. Brain function was measured using magnetoencephalography (MEG) in a subset of the child participants (n = 33). The results showed no significant difference in Full Scale IQ between the children of mothers who had received folic acid versus placebo during pregnancy (P = 0.993). Processing Speed subtest scores were however significantly higher in the folic acid group compared with placebo (Symbol Search: P = 0.046 and Cancellation: P = 0.011). The application of MEG analysis showed that at rest, there were differences in brain functioning with significantly lower overall power at Broad band [1–48Hz] (P = 0.041) and a trend (not significant) towards lower power in all other frequency bands (Theta, Mu, Beta, Low Gamma and High Gamma) in children from the FA group compared with placebo. Results for the responses to the language task (congruent and incongruent sentences) in children from the FA group showed significantly lower power within the Theta band [4–8Hz] and significantly higher power within high frequency bands i.e. Beta [13–30 Hz] and High Gamma [49–70 Hz]. This suggested more efficient language processing abilities in these children compared to children of mothers in the placebo group. The findings provide scientific evidence that continuing FA supplementation beyond the periconceptional period that is protective against NTDs, may be beneficial for brain health in the offspring. Furthermore, this study demonstrates that MEG is a useful tool for objective assessment of functional brain activity in healthy children in response to nutrition intervention.

Defining the plasma folate concentration associated with the red blood cell folate concentration threshold for optimal neural tube defects prevention: a population-based, randomized trial of folic acid supplementation

For women of reproductive age, a population-level red blood cell (RBC) folate concentration below the threshold 906nmol/L or 400 ng/mL indicates folate insufficiency and suboptimal neural tube defect (NTD) prevention. A corresponding population plasma/serum folate concentration threshold for optimal NTD prevention has not been established. The aim of this study was to examine the association between plasma and RBC folate concentrations and estimated a population plasma folate insufficiency threshold (pf-IT) corresponding to the RBC folate insufficiency threshold (RBCf-IT) of 906 nmol/L. We analyzed data on women of reproductive age (n=1673) who participated in a population-based, randomized folic acid supplementation trial in northern China. Of these women, 565 women with anemia and/or vitamin B-12 deficiency were ineligible for folic acid intervention (nonintervention group); the other 1108 received folic acid supplementation for 6 mo (intervention group). We developed a Bayesian linear model to estimate the pf-IT corresponding to RBCf-IT by time from supplementation initiation, folic acid dosage, methyltetrahydrofolate reductase (MTHFR) genotype, body mass index (BMI), vitamin B-12 status, or anemia status. Using plasma and RBC folate concentrations of the intervention group, the estimated median pf-IT was 25.5 nmol/L (95% credible interval: 24.6, 26.4). The median pf-ITs were similar between the baseline and postsupplementation samples (25.7 compared with 25.2 nmol/L) but differed moderately (±3-4 nmol/L) by MTHFR genotype and BMI. Using the full population-based baseline sample (intervention and nonintervention), the median pf-IT was higher for women with vitamin B-12 deficiency (34.6 nmol/L) and marginal deficiency (29.8 nmol/L) compared with the sufficient group (25.6 nmol/L). The relation between RBC and plasma folate concentrations was modified by BMI and genotype and substantially by low plasma vitamin B-12. This suggests that the threshold of 25.5 nmol/L for optimal NTD prevention may be appropriate in populations with similar characteristics, but it should not be used in vitamin B-12 insufficient populations. This trial was registered at clinicaltrials.gov as NCT00207558.

Abstract MP13: Plasma Homocysteine is Causally Associated With Ischemic Stroke in a Han Chinese Population: A Mendelian Randomization Study

Introduction: Observational studies identified plasma homocysteine as a risk factor for ischemic stroke, but randomized controlled trials of folate supplementation reported inconsistent findings. The methylenetetrahydrofolate reductase ( MTHFR) gene encodes an enzyme critical for homocysteine metabolism and can serve as an unconfounded proxy for plasma homocysteine levels. Hypothesis: We assessed the hypothesis that there was a causal association between plasma homocysteine and risk of ischemic stroke by Mendelian randomization method. Methods: We examined the association between the MTHFR gene and ischemic stroke among 11,753 Chinese participants. The discovery stage included 999 ischemic stroke cases and 1,001 controls with no history of atherosclerotic disease. The MTHFR gene was sequenced using the SOLiD 4hq platform. Variants with minor allele count &gt;10 were each tested for association with stroke using logistic regression models. Interactions between significant variants and alcohol drinking on stroke were also tested. Aggregate analysis of rare variants (minor allele count &lt;20) used the sequence kernel association test. Variants achieving P&lt;1х10 -4 were tested for replication among 4,724 ischemic stroke cases and 5,029 controls from the China Stroke Project. Results: An association between MTHFR rs1801133, a missense variant known to reduce enzyme activity and increase plasma homocysteine level, and ischemic stroke was identified in discovery, replication and joint analyses (P=2.10х10 -8 , 2.65х10 -11 , and 6.93х10 -17 , respectively). Each copy of the rs1801133 risk allele conferred respective odds ratios (95% confidence interval) of 1.44 (1.27, 1.64), 1.21 (1.15, 1.28), and 1.25 (1.18, 1.31). This variant also interacted with alcohol intake on stroke risk (P for interaction=7.82х10 -9 , 1.86х10 -10 , and 1.46х10 -18 , respectively). Odds ratios (95% confidence interval) of stroke associated with the risk allele were 1.66 (1.40, 1.96), 1.26 (1.18, 1.36), and 1.32 (1.23, 1.40) in non-drinkers and 1.17 (0.92, 1.49), 1.12 (1.01, 1.23), and 1.12 (1.03, 1.23) among alcohol drinkers in discovery, replication and joint analyses, respectively. No additional variants were identified. Conclusions: In conclusion, this is the first large scale genomic study to implicate the etiologic relevance of plasma homocysteine in ischemic stroke. An attenuating effect of alcohol intake on this relation was also observed.

A randomized controlled trial of folic acid intervention in pregnancy highlights a putative methylation-regulated control element at ZFP57

BackgroundMaternal blood folate concentrations during pregnancy have been previously linked with DNA methylation patterns, but this has been done predominantly through observational studies. We showed recently in an epigenetic analysis of the first randomized controlled trial (RCT) of folic acid supplementation specifically in the second and third trimesters (the EpiFASSTT trial) that methylation at some imprinted genes was altered in cord blood samples in response to treatment. Here, we report on epigenome-wide screening using the Illumina EPIC array (~ 850,000 sites) in these same samples (n = 86).ResultsThe top-ranked differentially methylated promoter region (DMR) showed a gain in methylation with folic acid (FA) and was located upstream of the imprint regulator ZFP57. Differences in methylation in cord blood between placebo and folic acid treatment groups at this DMR were verified using pyrosequencing. The DMR also gains methylation in maternal blood in response to FA supplementation. We also found evidence of differential methylation at this region in an independent RCT cohort, the AFAST trial. By altering methylation at this region in two model systems in vitro, we further demonstrated that it was associated with ZFP57 transcription levels.ConclusionsThese results strengthen the link between folic acid supplementation during later pregnancy and epigenetic changes and identify a novel mechanism for regulation of ZFP57. This trial was registered 15 May 2013 at www.isrctn.com as ISRCTN19917787.

Abstract WP252: A Mendelian Randomization Study of Plasma Homocysteine and Ischemic Stroke in a Han Chinese Population

Introduction: Observational studies identified plasma homocysteine as a risk factor for ischemic stroke, but randomized controlled trials of folate supplementation reported inconsistent findings. The MTHFR gene encodes an enzyme critical for homocysteine metabolism and can serve as an unconfounded proxy for plasma homocysteine levels. We examined the association between the MTHFR gene and ischemic stroke among 11,753 Chinese participants. Methods: The discovery stage included 999 ischemic stroke cases and 1,001 controls with no history of atherosclerotic disease. The MTHFR gene was sequenced using the SOLiD 4hq platform. Variants with minor allele count (MAC) &gt;10 were each tested for association with stroke using logistic regression models. Interactions between significant variants and alcohol drinking on stroke were also tested. Aggregate analysis of rare variants (MAC &lt;20) used the sequence kernel association test. Variants achieving P&lt;1х10 -4 were tested for replication among 4,724 ischemic stroke cases and 5,029 controls from the China Stroke Project. Results: An association between MTHFR rs1801133, a missense variant known to reduce enzyme activity and increase plasma homocysteine level, and ischemic stroke was identified in discovery, replication and joint analyses (P=2.10х10 -8 , 2.65х10 -11 , and 6.93х10 -17 , respectively). Each copy of the rs1801133 risk allele conferred respective odds ratios (95% CI) of 1.44 (1.27, 1.64), 1.21 (1.15, 1.28), and 1.25 (1.18, 1.31). This variant also interacted with alcohol intake on stroke risk (P for interaction=7.82х10 -9 , 1.86х10 -10 , and 1.46х10 -18 , respectively). Odds ratios (95% CI) of stroke associated with the risk allele were 1.66 (1.40, 1.96), 1.26 (1.18, 1.36), and 1.32 (1.23, 1.40) in non-drinkers and 1.17 (0.92, 1.49), 1.12 (1.01, 1.23), and 1.12 (1.03, 1.23) among alcohol drinkers in discovery, replication and joint analyses, respectively. No additional variants were identified. Conclusions: This is the first large scale genomic study to implicate the etiologic relevance of plasma homocysteine in ischemic stroke. An attenuating effect of alcohol intake on this relation was also observed.

Assessment of candidate folate sensitive-differentially methylated regions in a randomised controlled trial of continued folic acid supplementation during the second and third trimesters of pregnancy.

The aim of this study was to identify if specific regions of the human genome were sensitive to folate status by displaying changes in their DNA methylation patterns in response to continued folic acid supplementation during pregnancy. Samples (n=119) from a previous randomised controlled trial in pregnancy were used to compare the DNA methylation profiles of the same woman pre- versus post-folic acid intervention. Candidate genes were identified from the literature and a pilot genome wide screen of six women (three from each of the folic acid and placebo arms of the trial). We did not observe consistent DNA methylation changes in response to folic acid intervention at any of our candidate genes (RASA4, DHFR, DHFR2, RASSF1A, EIF2C3, ATPF1). We did identify a 40% decrease in DNA methylation at the RASA4 promoter correlating with a 3.5-fold increase in its mRNA abundance in an in vitro cell culture model. Continued folic acid intervention over a 22-week period did not appear to significantly influence the DNA methylation status of six candidate genes in blood samples of women compared to placebo. However, DNA methylation may play a role in the gene expression control of the RASA4 gene.

Folic Acid Supplementation throughout pregnancy: psychological developmental benefits for children.

To test the effect of folic acid supplements taken throughout pregnancy on children's psychosocial development. A randomised controlled trial of folic acid supplementation in pregnancy, with parental rating using the Resiliency Attitudes and Skills Profile (RASP), the Strengths and Difficulties Questionnaire (SDQ) and the Trait Emotional Intelligence Questionnaire Child Short Form (TEIQue-CSF). Children aged 6-7 whose mothers received folic acid throughout pregnancy (n = 22) were compared to those whose mothers only received it during the first trimester (n = 17). Children whose mothers received the full-term supplement scored significantly higher on emotional intelligence and resilience. Hierarchical multiple regression analysis identified folate level at 36th gestational week as an important predictor of emotional intelligence (EI) and resilience. Although conclusions must be drawn with caution, this research presents a number of potential implications, the main one being a proposed policy recommendation for women to take folic acid for the duration of pregnancy rather than stopping at the end of the first trimester. The second is the potential for future research to explore the possible psychological and social development benefits and in line with this to try and identify the explanatory mechanism involved.

The long-term impact of folic acid in pregnancy on offspring DNA methylation: follow-up of the Aberdeen Folic Acid Supplementation Trial (AFAST).

BackgroundIt has been proposed that maternal folic-acid supplement use may alter the DNA-methylation patterns of the offspring during the in-utero period, which could influence development and later-life health outcomes. Evidence from human studies suggests a role for prenatal folate levels in influencing DNA methylation in early life, but this has not been extended to consider persistent effects into adulthood.MethodsTo better elucidate the long-term impact of maternal folic acid in pregnancy on DNA methylation in offspring, we carried out an epigenome-wide association study (EWAS) nested within the Aberdeen Folic Acid Supplementation Trial (AFAST—a trial of two different doses: 0.2 and 5 mg, folic acid vs placebo). Offspring of the AFAST participants were recruited at a mean age of 47 years and saliva samples were profiled on the Illumina Infinium Human Methylation450 array. Both single-site and differentially methylated region analyses were performed.ResultsWe found an association at cg09112514 (p = 4.03×10–9), a CpG located in the 5’ untranslated region of PDGFRA, in the main analysis comparing the intervention arms [low- (0.2 mg) and high-dose (5 mg) folic acid combined (N = 43)] vs placebo (N = 43). Furthermore, a dose–response reduction in methylation at this site was identified in relation to the intervention. In the regional approach, we identified 46 regions of the genome that were differentially methylated in response to the intervention (Sidak p-value <0.05), including HLA-DPB2, HLA-DPB1, PAX8 and VTRNA2–1. Whereas cg09112514 did not replicate in an independent EWAS of maternal plasma folate, there was suggested replication of differential methylation in PAX8.ConclusionsThe results of this study suggest that maternal folic-acid supplement use is associated with changes in the DNA methylation of the offspring that persist for many years after exposure in utero. These methylation changes are located in genes implicated in embryonic development, immune response and cellular proliferation. Further work to investigate whether these epigenetic changes translate into detectable phenotypic differences is required.

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.

Unmetabolized Folic Acid, Tetrahydrofolate, and Colorectal Adenoma Risk.

In a randomized trial of folic acid supplementation for the prevention of colorectal adenomas, we previously found indications of increased risk during later treatment and follow-up. This could have been due to the unmetabolized folic acid (UFA) or natural reduced and methylated folates (mF) to which it is metabolized. In post hoc analyses, we measured mF (the sum of 5-methyl-tetrahydrofolate and 4-alfa-hydroxy-5-methyl-THF) and UFA concentrations in the serum of 924 participants. Using binomial regression models with a log link, we assessed the associations between plasma mF or UFA and adenoma occurrence. We found no association between plasma mF or UFA and overall adenoma risk. However, during later follow-up, the prespecified, composite endpoint of high-risk findings (advanced or multiple adenomas) was positively associated with plasma mF (Plinear trend = 0.009), with a 58% increased risk for participants in the upper versus lowest quartile. An irregular association was seen with plasma UFA, with suggestions of an inverse trend (Plinear trend=0.049). A modest, significant inverse association was also seen between mF and risk of serrated lesions, with a 39% lower risk for upper versus lower quartile participants (Plinear trend = 0.03). In conclusion, during the later follow-up period in which folic acid supplementation was previously seen to increase the risk of advanced and multiple adenomas, higher serum mF was associated with a higher risk of multiple and/or advanced adenomas, but no clear indication that UFA played a direct role. There were indications that higher mF was associated with reduced risk of serrated polyps. Cancer Prev Res; 10(8); 451-8. ©2017 AACR.

Vitamin-D deficiency predicts infections in young north Indian children: A secondary data analysis.

BackgroundRecent studies have demonstrated a relationship between poor vitamin D status and respiratory infections and diarrhea among young children. Acute lower respiratory infections (ALRI) and diarrhea are among the two most important causes of death in under-5 children. In this paper, we examined the extent to which vitamin-D deficiency (<10 ng/ml) predicts ALRI, clinical pneumonia and diarrhea among 6 to 30 months old children.MethodsWe used data from a randomized controlled trial (RCT) of daily folic acid and/or vitamin B12 supplementation for six months in 6 to 30 months old children conducted in Delhi, India. Generalized estimating equations (GEE) were used to examine the associations between vitamin-D deficiency and episodes of ALRI, clinical pneumonia and diarrhea.ResultsOf the 960 subjects who had vitamin-D concentrations measured, 331(34.5%) were vitamin-D deficient. We found, after controlling for relevant potential confounders (age, sex, breastfeeding status, wasting, stunting, underweight, anemia status and season), that the risk of ALRI was significantly higher among vitamin-D deficient (OR 1.26; 95% CI: 1.03 to 1.55) compared to vitamin-D-replete children in the six months follow-up period. Vitamin-D status was not associated with episodes of diarrhea or clinical pneumonia.ConclusionVitamin-D deficiency is common in young children in New Delhi and is associated with a higher risk of ALRI. The role of vitamin D in Indian children needs to be elucidated in further studies.

Association between maternal nutritional status in pregnancy and offspring cognitive function during childhood and adolescence; a systematic review.

BackgroundThe mother is the only source of nutrition for fetal growth including brain development. Maternal nutritional status (anthropometry, macro- and micro-nutrients) before and/or during pregnancy is therefore a potential predictor of offspring cognitive function. The relationship of maternal nutrition to offspring cognitive function is unclear. This review aims to assess existing evidence linking maternal nutritional status with offspring cognitive function.MethodsExposures considered were maternal BMI, height and weight, micronutrient status (vitamins D, B12, folate and iron) and macronutrient intakes (carbohydrate, protein and fat). The outcome was any measure of cognitive function in children aged <18 years. We considered observational studies and trials with allocation groups that differed by single nutrients. We searched Medline/PubMed and the Cochrane Library databases and reference lists of retrieved literature. Two reviewers independently extracted data from relevant articles. We used methods recommended by the Centre for Reviews and Dissemination, University of York and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.ResultsOf 16,143 articles identified, 38 met inclusion criteria. Most studies were observational, and from high-income settings. There were few randomized controlled trials. There was consistent evidence linking maternal obesity with lower cognitive function in children; low maternal BMI has been inadequately studied. Among three studies of maternal vitamin D status, two showed lower cognitive function in children of deficient mothers. One trial of folic acid supplementation showed no effects on the children’s cognitive function and evidence from 13 observational studies was mixed. Among seven studies of maternal vitamin B12 status, most showed no association, though two studies in highly deficient populations suggested a possible effect. Four out of six observational studies and two trials (including one in an Iron deficient population) found no association of maternal iron status with offspring cognitive function. One trial of maternal carbohydrate/protein supplementation showed no effects on offspring cognitive function.ConclusionsCurrent evidence that maternal nutritional status during pregnancy as defined by BMI, single micronutrient studies, or macronutrient intakes influences offspring cognitive function is inconclusive. There is a need for more trials especially in populations with high rates of maternal undernutrition.Systematic review registrationRegistered in PROSPERO CRD42013005702.Electronic supplementary materialThe online version of this article (doi:10.1186/s12884-016-1011-z) contains supplementary material, which is available to authorized users.