High-dose Folic Acid Research Articles

Suplementação excessiva com ácido fólico durante a gravidez e desenvolvimento de asma na infância: uma revisão baseada na evidência

Objective: Maternal supplementation with folic acid has a positive effect on the prevention of neural tube defects. The relationship between high-dose supplementation of folic acid (5mg) and the development of asthma in children is controversial. The aim of this review is to appraise the evidence on the association between the supplementation with high doses of folic acid during pregnancy and the risk of developing asthma in childhood. Data sources: National Guideline Clearinghouse, Canadian Medical Association Practice Guidelines, Cochrane Library, DARE, Bandolier, PubMed and Index of Portuguese Medical Journals. Review method: We searched meta-analyses, systematic reviews, original studies and clinical guidelines published between July/2006 and July/2016 in Portuguese, English, Spanish and French languages, using the MeSH terms: ‘Folic Acid’, ‘Asthma’ and ‘Pregnancy’. The Strength of Recommendation Taxonomy (SORT) scale of the American of Family Physicians was used to assign evidence levels and strength of recommendation grades. Results: Five studies were selected from a total of 29 articles found, including two meta-analyses and three original studies. Results from meta-analyses do not support an association between periconceptional folic acid supplementation and increased risk of developing childhood asthma. However, none of the studies included in the meta-analyses stratified the results according to the dose of folic acid used during pregnancy and risk of asthma. On the other hand, original studies suggest that supplementation with high doses of folic acid during pregnancy may increase the risk of developing asthma in childhood. Conclusions: Evidence on the association between folic acid supplementation during pregnancy and the risk of developing asthma during childhood is controversial. Studies showing results stratified according to the dose of folic acid reveal that high doses (>800mg) are associated with an increased risk of developing childhood asthma (SORT B).

Acid folic and pregnancy: A mandatory supplementation

Neural tube defects (NTD) occur in 0.5 to 2 per 1000 pregnancies with various handicaps for the affected child. It is now well established that folic acid deficiency (absolute or relative) is a predisposing factor to this type of malformation. Several randomized controlled trials showed that high-dose folic acid (4mg) is an essential factor for prevention of neural tube defects recurrence and significantly prevents the first occurrence of neural tube defects with a lower dose (0.4mg). Other etiologies can favor the occurrence of NTD such as MTHFR polymorphism, some antiepileptic therapies, obesity and pregestational mellitus diabetes. Necessity of a preconception folic acid supplementation or at least folate nutritional status evaluation should be known for all of us including patients and public.

STUDY OF THE ANTIDEPRESSANT ACTIVITY OF FOLIC ACID AND VITAMIN-D ON RESERPINE INDUCED DEPRESSION IN MICE.

Objective: Low levels of folic acid and deficiency of Vitamin D have been found to be associated with poor mood and depression. This study was designed to investigate whether these vitamins show antidepressant activity in models of depression in mice.Methods: Reserpine was used to induce depression in the study groups. Low and high doses of folic acid and Vitamin D as well as combinations of these vitamins in low and high doses were administered after induction of depression. The test animals were then tested on forced swim test, tail suspension test, and open field test models for evaluation of the antidepressant activity.Results: After 2 weeks of drug treatment, all the treated groups showed a significant reduction in immobility time in both the test models (p<0.05). High dose folic acid showed consistently greater antidepressant property in all the test models throughout the study period. High dose Vitamin D (p<0.05) also showed good antidepressant activity after 2 weeks, the delayed antidepressant effect of which might be attributable to the molecular mechanism of action of Vitamin D.Conclusion: Our study demonstrates that both folic acid and Vitamin D have antidepressant activity. The antidepressant activity of high dose folic acid (50 mg/kg) in reserpine-induced depression in mice at the end of 2 weeks was more pronounced in our study. Studies with longer duration of treatment are warranted to further evaluate their antidepressant effect.

Testicular MTHFR deficiency may explain sperm DNA hypomethylation associated with high dose folic acid supplementation.

Supplementation with high doses of folic acid, an important mediator of one-carbon transfers for DNA methylation, is used clinically to improve sperm parameters in infertile men. We recently detected an unexpected loss of DNA methylation in the sperm of idiopathic infertile men after 6 months of daily supplementation with 5 mg folic acid (>10× the daily recommended intake-DRI), exacerbated in men homozygous for a common variant in the gene encoding an important enzyme in folate metabolism, methylenetetrahydrofolate reductase (MTHFR 677C>T). To investigate the epigenomic impact and mechanism underlying effects of folic acid on male germ cells, wild-type and heterozygote mice for a targeted inactivation of the Mthfr gene were fed high-dose folic acid (10× the DRI) or control diets (CDs) for 6 months. No changes were detected in general health, sperm counts or methylation of imprinted genes. Reduced representation bisulfite sequencing revealed sperm DNA hypomethylation in Mthfr+/- mice on the 10× diets. Wild-type mice demonstrated sperm hypomethylation only with a very high dose (20×) of folic acid for 12 months. Testicular MTHFR protein levels decreased significantly in wild-type mice on the 20× diet but not in those on the 10× diet, suggesting a possible role for MTHFR deficiency in sperm DNA hypomethylation. In-depth analysis of the folic acid-exposed sperm DNA methylome suggested mouse/human susceptibility of sequences with potential importance to germ cell and embryo development. Our data provide evidence for a similar cross-species response to high dose folic acid supplementation, of sperm DNA hypomethylation, and implicate MTHFR downregulation as a possible mechanism.

High doses of folic acid in the periconceptional period and risk of low weight for gestational age at birth in a population based cohort study.

We investigated the association between maternal use of folic acid (FA) during pregnancy and child anthropometric measures at birth. We included 2302 mother-child pairs from a population-based birth cohort in Spain (INMA Project). FA dosages at first and third trimester of pregnancy were assessed using a specific battery questionnaire and were categorized in non-user, < 1000, 1000-4999, and ≥ 5000µg/day. Anthropometric measures at birth (weight in grams, length and head circumference in centimetres) were obtained from medical records. Small for gestational age according to weight (SGA-w), length (SGA-l) and head circumference (SGA-hc) were defined using the 10th percentile based on Spanish standardized growth reference charts. Multiple linear and logistic regression analyses were used to explore the association between FA dosages in different stages of pregnancy and child anthropometric measures at birth. In the multiple linear regression analysis, we found a tendency for a negative association between the use of high dosages of FA (≥ 5000µg/day) in the periconceptional period of pregnancy and weight at birth compared to mothers who were non-users of FA (β = -73.83; 95% CI -151.71, 4.06). In the multiple logistic regression, a greater risk of SGA-w was also evident among children whose mothers took FA dosages of 1000-4999 (OR = 2.21; 95% CI 1.17, 4.19) and of ≥ 5000µg/day (OR = 2.32; 95% CI 1.06, 5.08) compared to mothers non-users of FA in the periconceptional period of pregnancy. Our findings suggest that a high dosage of FA (≥ 1000µg/day) may be associated with an increased risk of SGA-w at birth.

The preventive effects of edible folic acid on cardiomyocyte apoptosis and survival in early onset triple-transgenic Alzheimer's disease model mice.

In recent years, neuropathological and epidemiological studies have indicated an association between Alzheimer's disease (AD) and several cardiovascular risk factors. In this study, the cardio-protective effects of folic acid (FA) in early stage AD was elucidated using a triple-transgenic (3xTg) Alzheimer's mouse model. Eleven-month-old C57BL/6 mice and 3xTg mice were assigned to five groups. During the four-month treatment period, the low-FA treatment group received FA through their diet, and the high-FA treatment groups received 3 mg/dl folate in drinking water and were also gastric-fed 1.2 mg/kg folate every day. In the C57B1/6J mice, treatment with high doses of FA (HFA) did not show any considerable effect compared to the control group or the low-dose dietary FA treatment group. However, Alzheimer's mice treated with HFA showed enhanced cardio-protection. Western blot analysis revealed that FA treatment restored SIRT1 expression, which was suppressed in 3xTg mice, through enhanced AMPK expression. FA significantly enhanced the IGF1 receptor survival mechanism in the hearts of the 3xTg mice and suppressed the expression-intrinsic and extrinsic apoptosis-associated proteins. The results suggest that FA intake may significantly alleviate cellular pathological events in the heart associated with AD.

A Daily Dose of 5 mg Folic Acid for 90 Days Is Associated with Increased Serum Unmetabolized Folic Acid and Reduced Natural Killer Cell Cytotoxicity in Healthy Brazilian Adults

The effects of high-dose folic acid (FA) supplementation in healthy individuals on blood folate concentrations and immune response are unknown. Objective: The aim of the study was to evaluate the effects of daily consumption of a tablet containing 5 mg FA on serum folate; number and cytotoxicity of natural killer (NK) cells; mRNA expression of dihydrofolate reductase (DHFR), methylenetetrahydrofolate reductase (MTHFR), interferon γ (IFNG), tumor necrosis factor α (TNFA), and interleukin 8 (IL8) genes; and concentrations of serum inflammatory markers. Methods: This prospective clinical trial was conducted in 30 healthy Brazilian adults (15 women), aged 27.7 y (95% CI: 26.4, 29.1 y), with a body mass index (in kg/m2) of 23.1 (95% CI: 22.0, 24.3). Blood was collected at baseline and after 45 and 90 d of the intervention. Serum folate concentrations were measured by microbiological assay and HPLC-tandem mass spectrometry [folate forms, including unmetabolized folic acid (UMFA)]. We used real-time polymerase chain reaction to assess mononuclear leukocyte mRNA expression and flow cytometry to measure the number and cytotoxicity of NK cells. Results: Serum folate concentrations increased by ∼5-fold after the intervention (P < 0.001), and UMFA concentrations increased by 11.9- and 5.9-fold at 45 and 90 d, respectively, when compared with baseline (P < 0.001). UMFA concentrations increased (>1.12 nmol/L) in 29 (96.6%) participants at day 45 and in 26 (86.7%) participants at day 90. We observed significant reductions in the number (P < 0.001) and cytotoxicity (P = 0.003) of NK cells after 45 and 90 d. Compared with baseline, DHFR mRNA expression was higher at 90 d (P = 0.006) and IL8 and TNFA mRNA expressions were higher at 45 and 90 d (P = 0.001 for both). Conclusion: This noncontrolled intervention showed that healthy adults responded to a high-dose FA supplement with increased UMFA concentrations, changes in cytokine mRNA expression, and reduced number and cytotoxicity of NK cells. This trial was registered at www.ensaiosclinicos.gov.br as RBR-2pr7zp.

High-dose maternal folic acid supplementation before conception impairs reversal learning in offspring mice

Maternal folic acid (FA) supplementation prior to and during gestation is recommended for the prevention of neural tube closure defects in the developing embryo. Prior studies, however, suggested that excessive FA supplementation during gestation can be associated with toxic effects on the developing organism. Here, we address whether maternal dietary folic acid supplementation at 40 mg/kg chow (FD), restricted to a period prior to conception, affects neurobehavioural development in the offspring generation. Detailed behavioural analyses showed reversal learning impairments in the Morris water maze in offspring derived from dams exposed to FD prior to conceiving. Furthermore, offspring of FD dams showed minor and transient gene expression differences relative to controls. Our data suggest that temporary exposure of female germ cells to FD is sufficient to cause impaired cognitive flexibility in the subsequent generation.

Preconception care for women with type 2 diabetes mellitus: A mixed-methods study of provider knowledge and practice.

Preconception care may decrease adverse pregnancy outcomes associated with pre-existing diabetes mellitus. Aboriginal Australians are at high risk of type 2 diabetes mellitus (T2DM), with earlier onset. We explored practitioner views on preconception care delivery for women with T2DM in the Northern Territory, where 31% of births are to Aboriginal women. Mixed-methods study including cross-sectional survey of 156 health practitioners and 11 semi-structured interviews. Practitioners reported low attendance for preconception care however, 51% provided counselling on an opportunistic basis. Rural/remote practitioners were most likely to find counselling feasible. The majority (69%) utilised appropriate guidelines and addressed lifestyle modifications including smoking (81%), weight management (79%), and change medications appropriately such as ceasing ACE inhibitors (69%). Fewer (40%) prescribed the recommended dose of folate (5mg) or felt comfortable recommending delaying pregnancy to achieve optimal preconception glucose control (42%). Themes identified as barriers to care included the complexity of care setting and infrequent preconception consultations. There was a focus on motivation of women to make informed choices about conception, including birth spacing, timing and contraception. Preconception care enablers included cross-cultural communication, a multi-disciplinary care team and strong client-based relationships. Health practitioners are keen to provide preconception counselling and reported knowledge of evidence-based guidelines. Improvements are needed in recommending high dose folate and optimising glucose control. Cross-cultural communication and team-based care were reported as fundamental to successful preconception care in women with T2DM. Continued education and policy changes are required to support practitioners in opportunities to enhance pregnancy planning.

Supplementation with Phycocyanobilin, Citrulline, Taurine, and Supranutritional Doses of Folic Acid and Biotin-Potential for Preventing or Slowing the Progression of Diabetic Complications.

Oxidative stress, the resulting uncoupling of endothelial nitric oxide synthase (eNOS), and loss of nitric oxide (NO) bioactivity, are key mediators of the vascular and microvascular complications of diabetes. Much of this oxidative stress arises from up-regulated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. Phycocyanobilin (PhyCB), the light-harvesting chromophore in edible cyanobacteria such as spirulina, is a biliverdin derivative that shares the ability of free bilirubin to inhibit certain isoforms of NADPH oxidase. Epidemiological studies reveal that diabetics with relatively elevated serum bilirubin are less likely to develop coronary disease or microvascular complications; this may reflect the ability of bilirubin to ward off these complications via inhibition of NADPH oxidase. Oral PhyCB may likewise have potential in this regard, and has been shown to protect diabetic mice from glomerulosclerosis. With respect to oxidant-mediated uncoupling of eNOS, high-dose folate can help to reverse this by modulating the oxidation status of the eNOS cofactor tetrahydrobiopterin (BH4). Oxidation of BH4 yields dihydrobiopterin (BH2), which competes with BH4 for binding to eNOS and promotes its uncoupling. The reduced intracellular metabolites of folate have versatile oxidant-scavenging activity that can prevent oxidation of BH4; concurrently, these metabolites promote induction of dihydrofolate reductase, which functions to reconvert BH2 to BH4, and hence alleviate the uncoupling of eNOS. The arginine metabolite asymmetric dimethylarginine (ADMA), typically elevated in diabetics, also uncouples eNOS by competitively inhibiting binding of arginine to eNOS; this effect is exacerbated by the increased expression of arginase that accompanies diabetes. These effects can be countered via supplementation with citrulline, which efficiently enhances tissue levels of arginine. With respect to the loss of NO bioactivity that contributes to diabetic complications, high dose biotin has the potential to “pinch hit” for diminished NO by direct activation of soluble guanylate cyclase (sGC). High-dose biotin also may aid glycemic control via modulatory effects on enzyme induction in hepatocytes and pancreatic beta cells. Taurine, which suppresses diabetic complications in rodents, has the potential to reverse the inactivating impact of oxidative stress on sGC by boosting synthesis of hydrogen sulfide. Hence, it is proposed that concurrent administration of PhyCB, citrulline, taurine, and supranutritional doses of folate and biotin may have considerable potential for prevention and control of diabetic complications. Such a regimen could also be complemented with antioxidants such as lipoic acid, N-acetylcysteine, and melatonin—that boost cellular expression of antioxidant enzymes and glutathione—as well as astaxanthin, zinc, and glycine. The development of appropriate functional foods might make it feasible for patients to use complex nutraceutical regimens of the sort suggested here.

The Methylene Tetrahydrofolate Reductase (MTHFR) isoform challenge. High doses of folic acid are not a suitable option compared to 5 Methyltetrahydrofolate treatment

The Methylene Tetrahydrofolate Reductase (MTHFR) isoform challenge. High doses of folic acid are not a suitable option compared to 5 Methyltetrahydrofolate treatment

Stability of the human sperm DNA methylome to folic acid fortification and short-term supplementation.

Do short-term and long-term exposures to low-dose folic acid supplementation alter DNA methylation in sperm? No alterations in sperm DNA methylation patterns were found following the administration of low-dose folic acid supplements of 400 μg/day for 90 days (short-term exposure) or when pre-fortification of food with folic acid and post-fortification sperm samples (long-term exposure) were compared. Excess dietary folate may be detrimental to health and DNA methylation profiles due to folate's role in one-carbon metabolism and the formation of S-adenosyl methionine, the universal methyl donor. DNA methylation patterns are established in developing male germ cells and have been suggested to be affected by high-dose (5 mg/day) folic acid supplementation. This is a control versus treatment study where genome-wide sperm DNA methylation patterns were examined prior to fortification of food (1996-1997) in men with no history of infertility at baseline and following 90-day exposure to placebo (n = 9) or supplement containing 400 μg folic acid/day (n = 10). Additionally, pre-fortification sperm DNA methylation profiles (n = 19) were compared with those of a group of post-fortification (post-2004) men (n = 8) who had been exposed for several years to dietary folic acid fortification. Blood and seminal plasma folate levels were measured in participants before and following the 90-day treatment with placebo or supplement. Sperm DNA methylation was assessed using the whole-genome and genome-wide techniques, MassArray epityper, restriction landmark genomic scanning, methyl-CpG immunoprecipitation and Illumina HumanMethylation450 Bead Array. Following treatment, supplemented individuals had significantly higher levels of blood and seminal plasma folates compared to placebo. Initial first-generation genome-wide analyses of sperm DNA methylation showed little evidence of changes when comparing pre- and post-treatment samples. With Illumina HumanMethylation450 BeadChip arrays, no significant changes were observed in individual probes following low-level supplementation; when compared with those of the post-fortification cohort, there were also few differences in methylation despite exposure to years of fortified foods. Illumina HumanMethylation450 BeadChip data from this study have been submitted to the NCBI Gene Expression Omnibus under the accession number GSE89781. This study was limited to the number of participants available in each cohort, in particular those who were not exposed to early (pre-1998) fortification of food with folic acid. While genome-wide DNA methylation was assessed with several techniques that targeted genic and CpG-rich regions, intergenic regions were less well interrogated. Overall, our findings provide evidence that short-term exposure to low-dose folic acid supplements of 400 μg/day, over a period of 3 months, a duration of time that might occur during infertility treatments, has no major impact on the sperm DNA methylome. This work was supported by a grant to J.M.T. from the Canadian Institutes of Health Research (CIHR: MOP-89944). The authors have no conflicts of interest to declare.

Responses of bovine early embryos to S-adenosyl methionine supplementation in culture.

There is a growing concern about the potential adverse effects of high dose folic acid (FA) supplementation before and during pregnancy. FA metabolism generates S-adenosyl methionine (SAM) which is an important cofactor of epigenetic programming. We sought to assess the impact of a large dose of SAM on early embryo development. In vitro cultured bovine embryos were treated with SAM from the eight-cell stage to the blastocyst stage. In addition to the phenotype, the genome-wide epigenetic and transcription profiles were analyzed. Treatment significantly improved embryo hatching and caused a shift in sex ratio in favor of males. SAM caused genome-wide hypermethylation mainly in exonic regions and in CpG islands. Although differentially expressed genes were associated with response to nutrients and developmental processes, no correspondence was found with the differentially methylated regions, suggesting that cellular responses to SAM treatment during early embryo development may not require DNA methylation-driven changes. Since bovine embryos were not indifferent to SAM, effects of large-dose FA supplements on early embryonic development in humans cannot be ruled out.

EFFECT OF FOLIC ACID, PYRIDOXINE AND CYANOCOBALAMIN IN REDUCING THE ELEVATED LEVEL OF HOMOCYSTEINE IN ADVANCE CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE

Homocysteine is an amino acid that is produced by the body and it can be converted into methionine or cysteine with the aid of B-vitamins and tetrahydrofolate. Renal function is a major determinant of plasma homocysteine concentration, and patients with chronic renal failure have severe hyperhomocysteinemia. The aim of study was to determine the effect of high doses of folic acid, vitamin B6 and B12 to reduce the homocysteine levels in chronic kidney disease patients. In present study, 60 renal failure patients fulfilled study criteria. These 60 patients, were divided into two groups of which 30 were selected into control and 30 were recruited in sample. The average of Hcy levels before starting treatment was obtained 31.14 umol/L. After treating patient with folic acid, vitamin B6 and B12 for a period of 3 months the average serum homocysteine level was measured and resulted 27.43 umol/L. Our study showed decrease and/or improve in average level of serum homocysteine among end stage renal failure and chronic kidney disease patients who have been received folic acid and vitamin B6 and B12 supplements, compared with controls. Risks due to increased homocysteine causes heart disease, stroke, peripheral vascular disease, diabetes. Our study concludes that high doses of folic acid, vitamin B6 and B12 treatment has improved or decreased the levels of Hcy in patients with renal failure, which in turn has reduce the risk of cardiovascular complications. This will improve quality of life of patients and decreases the mortality rate due to cardiovascular disorders.

The Effect of High Dose Folic Acid throughout Pregnancy on Homocysteine (Hcy) Concentration and Pre-Eclampsia: A Randomized Clinical Trial.

Pre-eclampsia is a pregnancy-related multi-systemic hypertensive disorder and affects at least 5% of pregnancies. This randomized clinical trial aimed at assessing the effect of low doses and high doses of folic acid on homocysteine (Hcy) levels, blood pressure, urea, creatinine and neonatal outcome. A randomized clinical trial was done at Alzahra Teaching Hospital, Tabriz University of Medical Sciences from April 2008 to March 2013. Four-hundred and sixty nulliparous pregnant women were randomly assigned into two groups. Group 1 (n = 230) received 0.5 mg of folic acid and group 2 (n = 230) received 5 mg of folic acid per daily. They were followed until delivery. Blood pressure and laboratory changes, including plasma Hcy levels, were measured and compared between the groups. Homocysteine concentrations were significantly higher at the time of delivery in group 1 (13.17±3.89 μmol/l) than in group 2 (10.31±3.54, μmol/l) (p<0.001). No statistically significant differences were observed in systolic and diastolic blood pressure (p = 0.84 and 0.15, respectively). Birth weight was significantly higher in group 2 (p = 0.031) and early abortion was significantly higher in group 1 than group 2 (p = 0.001). This study has provided evidence that a high dosage of folic acid supplements throughout pregnancy reduces Hcy concentrations at the time of delivery.Trial Registration: Iranian Registry of Clinical Trials IRCT201402175283N9

Excessive folic acid intake and relation to adverse health outcome.

The recent increase in the intake of folic acid by the general public through fortified foods and supplements, has raised safety concern based on early reports of adverse health outcome in elderly with low B12 status who took high doses of folic acid. These safety concerns are contrary to the 2015 WHO statement that "high folic acid intake has not reliably been shown to be associated with negative healeffects". In the folic acid post-fortification era, we have shown that in elderly participants in NHANES 1999-2002, high plasma folate level is associated with exacerbation of both clinical (anemia and cognitive impairment) and biochemical (high MMA and high Hcy plasma levels) signs of vitamin B12 deficiency. Adverse clinical outcomes in association with high folate intake were also seen among elderly with low plasma B12 levels from the Framingham Original Cohort and in a study from Australia which combined three elderly cohorts. Relation between high folate and adverse biochemical outcomes were also seen in the Sacramento Area Latino Study on Aging (High Hcy, high MMA and lower TC2) and at an outpatient clinic at Yale University where high folate is associated with higher MMA in the elderly but not in the young. Potential detrimental effects of high folic acid intake may not be limited to the elderly nor to those with B12 deficiency. A study from India linked maternal high RBC folate to increased insulin resistance in offspring. Our study suggested that excessive folic acid intake is associated with lower natural killer cells activity in elderly women. In a recent study we found that the risk for unilateral retinoblastoma in offspring is 4 fold higher in women that are homozygotes for the 19bp deletion in the DHFR gene and took folic acid supplement during pregnancy. In the elderly this polymorphism is associated with lower memory and executive scores, both being significantly worse in those with high plasma folate. These and other data strongly imply that excessive intake of folic acid is not always safe in certain populations of different age and ethnical/genetic background.

Comparison of high dose and low dose folic acid supplementation on prevalence, onset and severity of preeclampsia.

Background:Folic acid supplementation had previously mentioned as a protective factor against the onset of preeclampsia (PE). In this study, we aimed to compare the effect of high dose (5 mg daily) and low dose (1 mg daily) of folic acid supplementation on prevalence, onset and severity of PE.Materials and Methods:Pregnant women who were in the first trimester and referred to prenatal care university hospitals of Isfahan, Iran during October 2013–May 2015 were included in this study, then they were randomly divided into two groups of 5 mg and 1 mg (treated with daily 5 mg and 1 mg of folic acid, respectively), both groups received folic acid from the first trimester of pregnancy to 42 days after termination. Blood pressure, body mass index (BMI), and some urine and blood biochemistry parameters were measured. SPSS-22 used for statistical analysis.Results:A total of 943 pregnant women participated in the study (450 women in 1 mg group and 450 women in 5 mg group). Incidence rate of PE was 3.8% in 1 mg group and 2.4% in 5 mg group. In a comparison of preeclamptic patients in 1 mg and 5 mg group, no significant differences were seen regarding age, BMI, laboratory data, the severity of the disease, and onset (early or late) (P > 0.05).Conclusion:Although our findings support that administration of high dose folic acid may decrease the prevalence of PE, there is not enough data to support that higher amount of folic acid administration can reduce the severity of presentation's signs or ameliorate the laboratory data and the onset of PE.

Evaluation of the effect of high-dose folic acid on endothelial dysfunction in pre-eclamptic patients: A randomized clinical trial.

Background:Pre-eclampsia as a hypertensive disorder of pregnancy complicates up to 5–10% of pregnancies worldwide. Endothelial dysfunction plays an important role in the pathogenesis of pre-eclampsia. In this study, we aim to evaluate the effect of high-dose folic acid on endothelial dysfunction in pre-eclamptic patients.Materials and Methods:In this triple-blinded randomized clinical trial, the enrolled patients were divided randomly into two groups. Folic acid 5.0 mg or placebo was taken daily by oral administration from the initiation of diagnosis until 2 months after delivery by the participants. Every patient's flow-mediated dilation (FMD) was evaluated at the beginning of the study and 2 months after delivery with the same experienced operator at the same period of time (3–5 p.m.) by high-resolution B-mode ultrasonography. Potential confounding variables were included in the independent samples t-test. t-test or Mann–Whitney U-test was used in the comparison of means between the intervention and placebo groups. To compare FMD in each group, before and after the intervention, paired t-test was used.Results:Mean value of FMD in intervention (9.64 ± 5.57) and control group (9.30 ± 4.25) has no significant difference before the consumption of drugs (P > 0.05). FMD in intervention group (13.72 ± 7.89) significantly increases after daily consumption of 5 mg folic acid in comparison with control group (10.02 ± 4.81) after daily consumption of placebo (P = 0.002).Conclusion:Increased mean of FMD in intervention group shows that this supplement can improve endothelial function and can be significantly affected by maternal blood pressure during pregnancy and some endothelium-dependent disease such as pre-eclampsia and its associated adverse outcomes.

Early pregnancy B vitamin status, one carbon metabolism, pregnancy outcome and child development.

Periconception supplementation with folic acid is recommended until 12 gestational weeks to prevent neural tube defects. Doses of folic acid contained in supplements and timing and length of use during pregnancy vary. The effects of status in periconception and pregnancy folate, cobalamin, betaine and their interactions on one carbon metabolism (1C), as well as the global effect of 1C on foetal growth and pregnancy outcome, are reviewed. Results from prospective studies are reviewed. Cessation of folic acid supplement use after the first trimester is associated with a sharp drop in plasma folate status and enhanced conversion of betaine to dimethylglycine. Dimethylglycine production is also higher in mothers with low folate status than in those with normal-high folate status. The effects of high doses of folic acid on one carbon metabolism in mothers with low early pregnancy cobalamin status and on foetal growth are also reviewed. Several studies report that moderately elevated early pregnancy fasting plasma total homocysteine (tHcy) is inversely associated with birth weight and a predictor of intrauterine growth retardation. There is also evidence for increased risk of preterm birth when maternal folate status is low.

High Dose (5mg) Daily Folic Acid Supplement in Healthy Brazilian Volunteers Increases Mononuclear TNF-α Expression and Reduces NK Cell Number and Activity

BackgroundIn Brazil, wheat and corn flour is fortified with 150 µg of folic acid (FA), the synthetic form of folate. Individuals with increased cell duplication, including pregnant women and patients with hemolytic anemia need increased amounts of folate. The effects of amounts of FA higher than the defined tolerable upper intake of 1 mg/day are poorly understood. Some Brazilian patients with hemolytic anemia, such as hereditary spherocytosis (HS), have been receiving 5mg/day supplemental FA, in addition to being exposed to mandated food fortification with FA. Our previous data has shown that patients with HS have higher serum folate levels than healthy controls, as well as higher mRNA expression of DHFR, MTHFR, interferon-γ, TNF-α and interleukin-8 genes (1). However, it was not clear whether the increased mRNA expression resulted from folic acid use or underlying disease.ObjectiveThe aim of this study was to verify the effects of an intervention with 5mg/day FA on folate levels (serum and whole blood), serum inflammatory markers levels, mRNA expression of DHFR, MTHFR, interferon-γ, TNF-α and interleukin-8 genes and cytotoxicity of NK cells in healthy Brazilian volunteers.Material and methodsFifteen male and fifteen female healthy subjects were given 5mg/day FA for 90 days. Blood was collected at baseline, day 45 and day 90 for blood count, including reticulocytes, C-reactive protein and lactate dehydrogenase (LDH). Folate (serum and whole blood) and vitamin B12 were determined by a microbiological method. Serum cytokines levels were measured using a Milliplex Map kit. The mRNA expression of DHFR, MTHFR, interferon-γ, TNF-α and interleukin-8 genes in mononuclear cells were performed using Real Time PCR. Cytotoxicity of lymphocytes and NK cell number were measured by flow cytometry.ResultsAll blood count parameters were unaffected by FA intervention, whereas there was a slight increase in concentrations of LDH (P = 0.001) after 90 days compared with baseline and 45 day measurements. The folate levels (serum and whole blood) were higher at 45 and 90 days of intervention with 5mg/day of FA (P<0.001 for both). There were no differences among the basal and the follow up for serum vitamin B12, total homocysteine, cytokines IL6, IL8, IL10, IFNγ and TNFα levels (P>0.05). The mRNA expression of IL8 was higher at 45 days of intervention (Fig 1), while mRNA expressions of TNF-α were elevated at 45 and 90 days compared with baseline (Fig 1). No difference was found in mRNA of DHFR, MTHFR and IFNγ in this study.The data are median and interquartile intervals. The groups were compared using the Friedman test, when significant was performed for multiple comparisons Dunn`s test. Different letters show significant differences between groupsAfter 5 mg FA daily there was a reduction in the number and cytotoxic capacity of NK cells (Table 1).The data are median and interquartile intervals. The groups were compared using the Friedman test, when significant was performed for multiple comparisons Dunn`s test. Different letters show significant differences between groups.ConclusionsIntervention with 5 mg/day of FA in healthy people was associated with around 4-fold increase in serum and whole blood folate, accompanied by increased mRNA expression of proinflammatory cytokines IL8 and TNF-α and a reduction in NK cell number and cytotoxicity. High dose FA fortification may result in changes in innate immune parameters that could perturb immune surveillance pathways.Financing: FAPESP 2012/12912-1, CNPq 4826412012-6 and CNPq 401586/2014-6