Publication: A SYSTEMATIC REVIEW AND META-ANALYSIS OF THE IMPACT OF 5-METHYLTETRAHYDROFOLATE SUPPLEMENTATION ON FOLATE LEVELS IN WOMEN OF CHILDBEARING AGE
Date
2025
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Publisher
IMU University
Abstract
Background: Neural tube defects (NTDs) are congenital malformations of the brain, spine, or spinal cord resulting from genetics or nutritional deficiencies in folates and other micronutrients during early embryonic development. Inadequate folate increases homocysteine, which increases the risk of NTDs. Numerous discussions and studies on the efficacy of supplementation with activated 5-Methylhydrofolate (5-MTHF) versus synthetic folic acid in improving blood folate levels in women of childbearing age. This systematic review and meta-analysis aim to evaluate the available evidence and synthesise data on the comparative impact of these two forms of folate supplementation.
Methods: A systematic review and meta-analysis were conducted by PRISMA guidelines. Relevant studies were identified through electronic searches of PubMed, Scopus, and ScienceDirect, covering randomised controlled trials published up to March 2024. Inclusion criteria focus on trials comparing 5-MTHF and folic acid supplementation across various populations, including pre-pregnancy, pregnancy, postpartum, lactation, and women with MTHFR gene polymorphisms. Risk of bias was assessed using the Cochrane Risk of Bias tool, which evaluated factors such as randomisation, blinding, and completeness of outcome data. Meta-analysis was performed using Comprehensive Meta-Analysis (CMA) and RevMan software to synthesize data on plasma folate, and red blood cell folate levels.
Results: The study aims to review existing evidence from a total of ten studies involving 1,351 women across various stages of pre-pregnancy, pregnancy, post-partum, and lactation, as well as women with MTHFR gene polymorphism. The methodologies included randomised, controlled trials with different dosages of folic acid, 5-MTHF, or placebos. Key biomarkers measured included plasma folate, red blood cell (RBC) folate, homocysteine, and unmetabolised folic acid levels. Results indicate variability among studies where four studies showed higher blood or plasma folate levels with 5-MTHF compared to folic acid/placebo, while three others showed similar increases in folate levels but with potential additional benefits such as reduced unmetabolised folic acid or lower homocysteine levels in the 5-MTHF groups. The remaining three studies found comparable efficacy between the two forms of folate, one of which suggested a relationship between the MTHFR (methylenetetrahydrofolate reductase) genotype and high levels of plasma homocysteine, which can contribute to various health risks. There were ten studies assessed for risk of bias. Two studies were of some concerns due to lack of clarity in the reported outcome data and the remaining eight studies have a low risk of bias. Of the eight studies included in the analysis, two studies, short-term duration of 12 weeks or less weeks, reported significant positive differences in favour of 5-MTHF while six studies, long-term duration of more than 12 weeks, favoured folic acid over 5-MTHF.
Discussion: Optimal blood folate levels are important in preventing NTDs. Many variations exist in these studies that warrant further standardised research to clarify optimal dosages and durations of supplementation with 5-MTHF versus folic acid. The benefits of reduced homocysteine and unmetabolised folic acid through 5-MTHF supplementation may bring additional benefits to high-risk groups.
Conclusion: This review highlights the substantial heterogeneity among studies comparing 5-MTHF and folic acid supplementation. While short-term studies favour 5-MTHF, long-term studies generally favour folic acid. These findings highlight the need for further research to standardize methodologies and clarify supplementation guidelines.
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Keywords
Systematic Review, Meta-Analysis, 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase, Folic Acid, Women, Neural Tube Defects