Trial reportThe American journal of clinical nutrition2021
Impact of high-dose folic acid supplementation in pregnancy on biomarkers of folate status and 1-carbon metabolism: An ancillary study of the Folic Acid Clinical Trial (FACT).
Trial report in The American journal of clinical nutrition, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers, 4 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
20 citing papers in PubMed, 4 syntheses or guidelines pooled it, 33 citations in OpenAlex.
- Unmetabolized Folic Acid: Biology, Epidemiology, and Clinical Consequences: A Systematic Review.Nutrients · 2026Pooled it
- Folic Acid Supplementation and Risk of Gestational Diabetes Mellitus: A Systematic Review of the Literature.International journal of molecular sciences · 2025Pooled it
- Effects of maternal folate and vitamin B12 on gestational diabetes mellitus: a dose-response meta-analysis of observational studies.European journal of clinical nutrition · 2022Pooled it
- Pooled it
- Combined use of amlodipine and folic acid are significantly more efficacious than amlodipine alone in lowering plasma homocysteine and blood pressure among hypertensive patients with hyperhomocysteinemia and intolerance to ACEI: A multicenter, randomized, double-blind, parallel-controlled clinical trial.Journal of clinical hypertension (Greenwich, Conn.) · 2023Trial
- Association Between Folic Acid Use and Serum One-Carbon Metabolism-Related Metabolites in Maternal and Cord Blood of Japanese Pregnant Women.Metabolites · 2026Article
- Health professionals require more defined protocols, better funding and patient resources to support couples with recurrent pregnancy loss.Scientific reports · 2025Article
- Biological, dietetic and pharmacological properties of vitamin BNPJ science of food · 2025Review
- Article
- Toxic Effects of Excess Vitamins A, B6, and Folic Acid on the Nervous System.Behavioural neurology · 2025Review
- Article
- Association of serum folate levels during pregnancy and prenatal depression.The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians · 2023Article
- Uncovering the Hidden Dangers and Molecular Mechanisms of Excess Folate: A Narrative Review.Nutrients · 2023Review
- Scientific opinion on the tolerable upper intake level for folate.EFSA journal. European Food Safety Authority · 2023Article
- Associations between folic acid supplement use and folate status biomarkers in the first and third trimesters of pregnancy in the Maternal-Infant Research on Environmental Chemicals (MIREC) Pregnancy Cohort Study.The American journal of clinical nutrition · 2022Article
- Review
- Maternal Folate Status and the Relation between Gestational Arsenic Exposure and Child Health Outcomes.International journal of environmental research and public health · 2022Article
- Maternal folic acid and multivitamin supplementation: International clinical evidence with considerations for the prevention of folate-sensitive birth defects.Preventive medicine reports · 2021Review
- Gestational Folate and Folic Acid Intake among Women in Canada at Higher Risk of Pre-Eclampsia.The Journal of nutrition · 2021Article
- Evaluating the Diagnostic Value of a Combined Indicator of Vitamin BFrontiers in nutrition · 2021Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
13 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundPericonceptional 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.
objectivesThis 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.
methodsFor 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.
resultsNineteen (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.
conclusionsHigh-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.
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