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Background: Periconceptional folic acid (FA) supplementation is recommended to prevent neural tube defects; however, the extent to which recommendations are met through dietary sources and supplements is not clear., Objectives: Our objective was to evaluate the dietary and supplemental intakes of FA in a Canadian pregnancy cohort and to determine the proportions of pregnant women exceeding the Estimated Average Requirement (EAR) and Tolerable Upper Intake Level (UL)., Methods: FACT (the Folic Acid Clinical Trial) was an international multicenter, randomized, double-blinded, placebo-controlled, phase III trial investigating FA for the prevention of pre-eclampsia in high-risk pregnancies. Participants were enrolled from Canadian sites at 8-16 weeks of gestation. Dietary and supplemental FA intake data were collected through participant interviews and FFQs at the time of FACT enrollment. Categorical data were summarized as n (%) and continuous data as median (IQR)., Results: This study included 1198 participants. Participants consumed 485 μg dietary folate equivalents (DFE)/d (IQR: 370-630 μg DFE/d) from dietary sources of folate and FA. Through diet alone, 43.4% of participants consumed ≥520 μg DFE/d, the EAR for pregnant individuals. Of the 91.9% of participants who consumed daily FA supplements, 0.4% consumed <400 μg FA/d and 96.0% consumed ≥1000 μg/d, the UL for FA. Median (IQR) total folate intake was 2167 μg DFE/d (2032-2325 μg DFE/d); 95.3% of participants met or exceeded the EAR from all sources, but 1069 (89.2%) participants exceeded the UL., Conclusions: The majority of participants in this Canadian pregnancy cohort did not consume the recommended amount of folate from dietary sources. However, most prenatal supplements contained 1000 μg FA, resulting in the majority of women exceeding the UL. With no additional benefit associated with FA intakes beyond the UL for most women, modification of prenatal supplement formulations may be warranted to ensure women meet but do not exceed recommended FA intakes.FACT was registered at clinicaltrials.gov as NCT01355159 and at isrctn.com as ISRCTN23781770., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Periconceptional folic acid (FA) supplementation is recommended to prevent the occurrence of neural tube defects. Currently, most over-the-counter FA supplements in Canada and the United States contain 1 mg FA and some women are prescribed 5 mg FA/d. High-dose FA is hypothesized to impair 1-carbon metabolism. We aimed to determine folate and 1-carbon metabolism biomarkers in pregnant women exposed to 1 mg or 5 mg FA., Objectives: This was an ancillary study within the Folic Acid Clinical Trial (FACT), a randomized, double-blinded, placebo-controlled, phase III trial designed to assess the efficacy of high-dose FA to prevent preeclampsia., Methods: For FACT, women were randomized at 8-16 gestational weeks to receive daily 4.0 mg FA (high dose) or placebo (low dose) plus their usual supplementation (≤1.1 mg). Women were recruited from 3 Canadian FACT centers and provided nonfasting blood samples at 24-26 gestational weeks for measurement of RBC and serum total folate, serum unmetabolized FA (UMFA), tetrahydrofolate (THF), 5-methylTHF, 5-formylTHF, 5,10-methenylTHF, and MeFox (pyrazino-s-triazine derivative of 4α-hydroxy-5-methylTHF, a 5-methylTHF oxidation product); total vitamins B-12 and B-6; and plasma total homocysteine. Group differences were determined using χ2, Fisher exact, and Wilcoxon rank-sum tests., Results: Nineteen (38%) women received high-dose FA and 31 (62%) received low-dose FA. The median RBC folate concentration was 2701 (IQR: 2243-3032) nmol/L and did not differ between groups. The high-dose group had higher serum total folate (median: 148.4 nmol/L, IQR: 110.4-181.2; P = 0.007), UMFA (median: 4.6 nmol/L, IQR: 2.5-33.8; P = 0.008), and 5-methylTHF (median: 126.6 nmol/L, IQR: 98.8-158.6; P = 0.03) compared with the low-dose group (median: 122.8 nmol/L, IQR: 99.5-136.0; median: 1.9 nmol/L, IQR: 0.9-4.1; median: 108.6 nmol/L, IQR: 96.4-123.2, respectively). Other biomarkers of 1-carbon metabolism did not differ., Conclusions: High-dose FA supplementation in early pregnancy increases maternal serum folate but not RBC folate concentrations, suggesting tissue saturation. Higher UMFA concentrations in women receiving high-dose FA supplements suggest that these doses are supraphysiologic but with no evidence of altered 1-carbon metabolism., (© Crown copyright 2021.)

The relationship between maternal folic acid supplementation in pregnancy and infant birthweight has not been well described in low- and middle-income countries. We conducted a systematic review and meta-analysis of the current evidence of the association between folic acid supplementation in pregnancy on three primary outcomes: the incidence of low birthweight, small for gestational age, and mean birthweight. Seventeen studies were identified, which satisfied the inclusion criteria, covering a total of 275,421 women from 13 cohort studies and four randomized controlled trials. For the primary outcome of mean birthweight (n = 9), the pooled mean difference between folic acid and control groups was 0.37 kg (95% confidence interval [CI]: 0.24 to 0.50), and this effect was larger in the randomized controlled trials (0.56, 95% CI: 0.15 to 0.97, n = 3). The pooled odds ratio was 0.59 for low birthweight (95% CI: 0.47 to 0.74, n = 10) among folic acid supplementation versus control. The pooled odds ratio for the association with small for gestational age was 0.63 (95% CI: 0.39 to 1.01, n = 5). Maternal folic acid supplementation in low- and middle-income countries was associated with an increased mean birthweight of infants and decreases in the incidence of low birthweight and small for gestational age., (© 2019 The Authors. Maternal & Child Nutrition published by John Wiley & Sons, Ltd.)

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., Competing Interests: The authors have declared that no competing interests exist.

Objective: To evaluate the effect of folic acid supplementation during pregnancy on the risk of gestational hypertension/preeclampsia., Methods: A systematic review and meta-analysis were conducted. Medline, Embase, Scopus, and the Web of Science were searched from inception to December 2014., Results: Out of 1224 potentially relevant studies, 13 studies met our inclusion criteria (2 randomized controlled trials (RCTs), 10 cohort studies, and 1 case-control study). The pooled relative risk (RR) and 95% confidence interval (CI) of the two RCTs were 0.62 (0.45-0.87) in the trial arm as compared with the placebo arm. The pooled RR was 0.92 (95% CI: 0.79-1.08) for nine cohort studies with available data on folic acid supplementation in pregnancy and gestational hypertension/preeclampsia. Pooled RR was 0.88 (95% CI: 0.76-1.02) for eight cohort studies with available data on folic acid supplementation and preeclampsia., Conclusion: Whether folic acid supplementation in pregnancy can prevent the occurrence of gestational hypertension/preeclampsia remains uncertain.

Objective: To examine the association between BMI and folate concentrations in serum and red blood cells (RBC) in pregnant women., Design: A cross-sectional comparison of folate concentrations in serum and RBC sampled simultaneously from the same individual., Setting: The Ottawa Hospital and Kingston General Hospital, Ontario, Canada., Subjects: Pregnant women recruited between 12 and 20 weeks of gestation., Results: A total of 869 pregnant women recruited from April 2008 to April 2009 were included in the final analysis. Serum folate was inversely associated and RBC folate positively associated with BMI, after adjusting for folic acid supplementation, age, gestational age at blood sample collection, race, maternal education, annual income, smoking and MTHFR 677C→T genotype. In stratified analyses, this differential association was significant in women with the MTHFR CC variant. In women with the CT and TT variants, the differential associations were in the same direction but not significant. Folic acid supplementation during pregnancy did not alter the differential association of BMI with serum and RBC folate concentration. This indicates that the current RBC folate cut-off approach for assessing risk of neural tube defects in obese women may be limited., Conclusions: BMI is inversely associated with serum folate and positively associated with RBC folate in pregnant women, especially for those with the MTHFR CC variant.

Background: It has been reported that higher folate intake from food and supplementation is associated with decreased blood pressure (BP). The association between serum folate concentration and BP has been examined in few studies. We aim to examine the association between serum folate and BP levels in a cohort of young Chinese women., Methods: We used the baseline data from a pre-conception cohort of women of childbearing age in Liuyang, China, for this study. Demographic data were collected by structured interview. Serum folate concentration was measured by immunoassay, and homocysteine, blood glucose, triglyceride and total cholesterol were measured through standardized clinical procedures. Multiple linear regression and principal component regression model were applied in the analysis., Results: A total of 1,532 healthy normotensive non-pregnant women were included in the final analysis. The mean concentration of serum folate was 7.5 ± 5.4 nmol/L and 55% of the women presented with folate deficiency (< 6.8 nmol/L). Multiple linear regression and principal component regression showed that serum folate levels were inversely associated with systolic and diastolic BP, after adjusting for demographic, anthropometric, and biochemical factors., Conclusions: Serum folate is inversely associated with BP in non-pregnant women of childbearing age with high prevalence of folate deficiency.

This prospective cohort study designed to assess the effect of folic acid supplementation in pregnancy on the risk of preeclampsia (PE) took place in Ottawa, ON and Kingston, ON, Canada, from September 1, 2002 to August 31, 2008. Pregnant women, less than 20 weeks gestational age were recruited and delivered in the Ottawa region and the Kingston General Hospital. Demographic characteristics of the study participants and the patterns of supplementation of folic acid were described and occurrence of PE between women with folic acid supplementation during pregnancy and women without were compared. Multiple logistic regression was used in the estimation of the independent effect of supplementation of folic acid. Additional analyses assessing the effect of low RBC and serum folate and dose-response relationship were performed. Analyses were performed in all study participants, and then in high risk and low risk sub-groups, respectively. A total of 7,669 participants were included in the final analysis. Ninety five percent of the study participants were taking folic acid supplementation in early second trimester. The rate of PE was lower in the supplementation group than in the no supplementation group, and the difference was statistically significant in high risk women. Similar patterns of associations were observed in analysis by RBC and serum folate levels and in dose-response analysis. Folic acid supplementation in pregnancy may reduce PE risk in pregnant women, especially in those women with increased risk of developing PE.

Preeclampsia (PE) is hypertension with proteinuria that develops during pregnancy and affects at least 5% of pregnancies. The Effect of Folic Acid Supplementation in Pregnancy on Preeclampsia: the Folic Acid Clinical Trial (FACT) aims to recruit 3,656 high risk women to evaluate a new prevention strategy for PE: supplementation of folic acid throughout pregnancy. Pregnant women with increased risk of developing PE presenting to a trial participating center between 8(0/7) and 16(6/7) weeks of gestation are randomized in a 1 : 1 ratio to folic acid 4.0 mg or placebo after written consent is obtained. Intent-to-treat population will be analyzed. The FACT study was funded by the Canadian Institutes of Health Research in 2009, and regulatory approval from Health Canada was obtained in 2010. A web-based randomization system and electronic data collection system provide the platform for participating centers to randomize their eligible participants and enter data in real time. To date we have twenty participating Canadian centers, of which eighteen are actively recruiting, and seven participating Australian centers, of which two are actively recruiting. Recruitment in Argentina, UK, Netherlands, Brazil, West Indies, and United States is expected to begin by the second or third quarter of 2013. This trial is registered with NCT01355159.

Objectives: To determine the factors that put Canadian women at risk for not supplementing with folic acid (FA) in the three months before conception, as recommended for the prevention of infant neural tube defects., Methods: This study used data from the Canadian Maternity Experiences Survey. We used Poisson regression analysis with a robust variance to determine which factors were associated with women not supplementing with FA in the three months prior to pregnancy as compared with women who did supplement., Results: Of the 6421 women surveyed, 57.7% were supplementing with FA pre-conceptionally. The risk factors associated with a lack of FA supplementation pre-conceptionally were maternal age <19 (prevalence ratio [PR] = 0.50; 95% CI 0.36 to 0.69) or 20 to 24 (PR = 0.75; 95% CI 0.67 to 0.84); education below high school level (PR = 0.73; 95% CI 0.61 to 0.87), at high school level (PR = 0.77; 95% CI 0.71 to 0.83), or at post-secondary level other than university (PR = 0.93; 95% CI 0.88 to 0.97); being at or below the low-income cut-off (PR = 0.74; 95% CI 0.67 to 0.81); smoking before pregnancy (PR = 0.79; 95% CI 0.73 to 0.86); being non-fluent in the language of the health care provider (PR = 0.66; 95% CI 0.49 to 0.88); being obese (BMI ≥ 30) (PR = 0.91; 95% CI 0.85 to 0.98); being unemployed (PR = 0.94; 95% CI 0.89 to 1.00); and being born outside of Canada (PR = 0.79; 95% CI 0.74 to 0.84)., Conclusion: Young maternal age, low education, low income, smoking, language barriers, obesity, unemployment, and being born outside Canada are risk factors for suboptimal or lack of FA supplementation pre-conceptionally.

Objective: The objective of the study was to evaluate the association between folic acid supplementation in early second trimester and the risk of developing preeclampsia., Study Design: We carried out a prospective cohort study between October 2002-December 2005. We recruited women who had their prenatal care visit (12-20 weeks' gestation) at the Ottawa Hospital and Kingston General Hospital. All charts for participants with a diagnosis of preeclampsia were audited and blindly adjudicated by 4 study investigators to validate the diagnosis., Results: A total of 2951 pregnant women were included in the final analysis. Supplementation of multivitamins containing folic acid was associated with increased serum folate (on average 10.51 micromol/L), decreased plasma homocysteine (on average 0.39 micromol/L), and reduced risk of preeclampsia (adjusted odds ratio, 0.37; 95% confidence interval, 0.18-0.75)., Conclusion: Supplementation of multivitamins containing folic acid in the second trimester is associated with reduced risk of preeclampsia.

Background: Randomized controlled trials have demonstrated that periconceptional folic acid supplementation has a dramatic effect in reducing neural tube defects, one of the most serious congenital anomalies. Unfortunately, supplementation tends to be suboptimal in disadvantaged populations., Objective: The primary objective was to determine patient factors associated with a lack of use of periconceptional folic acid among Canadian women in a multi-ethnic, urban setting. Our secondary objective was to assess patient knowledge about folic acid tablet supplementation and its link to reduced birth defects., Methods: We undertook a cross-sectional study to survey postpartum Toronto women on their use and knowledge of periconceptional folic acid., Results: Of the 383 women surveyed, only 28% took folic acid or a multivitamin containing folic acid during the periconceptional period. Multivariate analysis revealed that the use of periconceptional folic acid was more common among women of Jewish descent (adjusted relative risk [RR] 0.3; 95% confidence interval [CI], 0.04-0.9) and those who had 1 or no children (adjusted RR 0.6; 95% CI, 0.4-0.8). Not taking folic acid was associated with unplanned pregnancy (adjusted RR 1.5; 95% CI, 1.4-1.6) and a lack of knowledge about when folic acid should be taken (adjusted RR 1.8; 95% CI, 1.6-1.8)., Conclusion: Ethnic background is an independent predictor of periconceptional folic acid use.

Objectives: First, to examine the biological basis of why folic acid may have health effects beyond its proven effect of reducing neural tube defects; and second, to explore current controversial policies of folic acid supplementation and food fortification., Methods: We searched MEDLINE for English-language papers published from 1991 to 2003, using the key words "folic acid" and "folate." The literature search was restricted to human studies. Of 8986 publications identified, 65 were relevant to the objectives of this paper., Results: Analysis of the literature revealed that a major mechanism of folic acid in improving infant health may be related to its effect in correcting maternal folate-homocysteine-methylenetetrahydrofolate reductase metabolic defects. Conversely, exposure to high levels of folic acid may have such adverse health effects as increased risk of neurologic disorders in the general population., Conclusions: Randomized trials or well-designed prospective cohort studies are needed to assess the effects of folic acid on various pregnancy outcomes. To enable an examination of the association between folic acid and rare outcomes, such as a specific category of birth defects and fetal and neonatal deaths, it is necessary to recruit a large number of pregnant women to participate in such studies.

To determine the efficacy of high-dose folic acid for the prevention of preeclampsia in twin pregnancies. Secondary analysis of a randomized controlled trial in 70 obstetrical sites in Argentina, Australia, Canada, Jamaica, and the UK between 2011 and 2015. Eligible women pregnant with twins who were aged 18 y or older and between 8 and 16 completed weeks' gestation were randomized between to receive daily high-dose folic acid (4.0–5.1 mg) or placebo. The primary outcome was preeclampsia, presenting as hypertension after 20 weeks' gestation with significant proteinuria. Secondary outcomes included severe preeclampsia, preterm birth, and adverse fetal and neonatal outcomes. Of 2464 participants randomized between 18 April 2011 and 14 December 2015, 462 (18.8%) had a confirmed twin pregnancy. Thirty-four of these participants withdrew consent or did not have primary outcome data available, and 428 women were analyzed. The rate of preeclampsia was significantly higher in the folic acid group compared to the placebo group in crude analyses (17.2 versus 9.9%; relative risk 1.75 [95% CI 1.06–2.88], p =.029). Multivariable analyses attenuated this effect, rendering it not statistically significant (RR 1.58 [95% CI 0.95–2.63], p =.079). High-dose folic acid supplementation was not significantly associated with preeclampsia in a subgroup of twin pregnancies. Although a suggested elevated risk cannot be confirmed, these results may help to gain novel insights in the etiology of preeclampsia, which continues to be poorly understood. ClinicalTrials.gov NCT01355159. [ABSTRACT FROM AUTHOR]

Objective: 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.Design: 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.Setting: Participants were recruited in Ottawa and Kingston, Canada, from 2002 to 2009.Participants: Women were recruited when presenting for prenatal care in the early second trimester.Results: 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.Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background: It remains an enigma whether gestational hypertension (GH) and pre-eclampsia (PE) are distinct entities or different spectrum of the same disease. We aimed to compare the risk factors and outcomes between GH and PE. Method: A total of 7,633 pregnant women recruited between 12 and 20 weeks of gestation in the Ottawa and Kingston Birth Cohort from 2002 to 2009 were included in the analysis. Cox proportional hazards model was used to identify and compare the risk factors for GH and PE by treating gestational age at delivery as the survival time. Logistic regression model was used to compare outcome. Subgroup analysis was performed for early- and late-onset PE. Results: GH and PE shared most risk factors including overweight and obesity, nulliparity, PE history, type 1 and 2 diabetes, and twin birth. Effect size of PE history (RR = 14.1 for GH vs. RR = 6.4 for PE) and twin birth (RR = 4.8 for GH vs. RR = 10.3 for PE) showed substantial difference. Risk factors modified gestational age at delivery in patients with GH and PE in similar pattern. Subgroup analysis showed that early- and late-onset PE shared some risk factors with different effect sizes, whereas folic acid supplementation showed protective effect for early-onset PE only. PE was strongly associated with several adverse outcomes including cesarean section, placental abruption, small for gestational age, preterm birth, and 5 min Apgar score < 7, whereas GH was associated with increased risk of preterm birth only. Conclusions: GH and PE shared common risk factors. Differences in effect sizes of risk factors and outcomes indicate that the conditions may have different pathophysiology and mechanism. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a multisystem disorder of human pregnancy, affecting about 6% of all pregnancies worldwide, and is one of the leading causes of maternal and infant morbidity and mortality. Despite decades of research into the pathogenesis of this complex disease, the underlying mechanisms remain unclear. As a result, the options for prevention and management of PE are limited. In recent years, there has been a growing body of evidence suggesting that folate deficiency is associated with PE, and folic acid supplementation may reduce the risk of developing PE in certain populations. Folate contributes to cell division and growth, and folate metabolism is involved in a large number of physiological and pathophysiological processes in human development. Sufficient supply of folate is therefore particularly important during pregnancy. Nevertheless, the exact mechanisms of folic acid deficiency increasing the risk of developing PE are still unclear. This article reviews what is understood about the aetiology of PE and the relationship between folate metabolism and PE so as to enhance further discussions on the subject. [ABSTRACT FROM AUTHOR]