Supplementation with Folic Acid or 5-Methyltetrahydrofolate and Prevention of Neural Tube Defects: An Evidence-Based Narrative Review

Abstract

Background: Folic acid (FA), which in its chemical form is pteroylglutamic acid, is the fully oxidised, water-soluble, monoglutamic form of vitamin B9. This compound is part of the folate group but with higher bioavailability, and it is found in vitamin supplements and fortified foods and drugs. Folate metabolism is complex and associated with various metabolic pathways, all of which confer protection on the cell and allow its survival. Methods: We conducted a non-systematic search of articles published in English and Spanish including controlled trials, cohort studies, systematic re-views, and meta-analyses were included, as well as key studies in animal models related to pharmacokinetic studies. Search terms encompassed: "folic acid", "folates", "5-metyltetrahydrofolate", "5-MTHF", "neural tube defects", "supplementation", "fortification", AND "homocysteine" Results: A crucial role demonstrated for FA is to help prevent neural tube defects (NTDs). However, more studies are definitely still needed to establish 5-MTHF as a safe and effective therapeutic approach comparable with FA. Moreover, there is a lack of clinical studies that evaluate the efficacy of 5-MTHF supplementation in the prevention of NTDs. The present evidence-based narrative review discusses differences between FA and 5-MTHF in terms of structure, metabolism, bioavailability, clinical efficacy, and safety. Conclusions: Despite the potential value of 5-MTHF as an alternative to FA, clinical studies would be urgently needed to support the efficacy, dosage, timing, and/or safety of its use as a supplement.

Keywords: 5-methyltetrahydrofolate; NTD; folates; folic acid; fortification; homocysteine; neural tube defects; pregnancy; supplementation.

Figure 1

Methionine and folate cycles and connecting pathways. Created with BioRender.com.

Figure 2

Folic acid and 5-MTHF chemical structures. Created with BioRender.com.

Figure 3

Hierarchy of evidence for FA and 5-MTHF regarding neural tube defects (NTDs). A literature search was conducted in PubMed using the following search terms: ‘folic acid[title] AND neural tube defects[title] AND supplementation’; or ‘(5-MTHF[title] OR methyltetrahydrofolate[title]) AND neural tube defects[title] AND supplementation’. Created with BioRender.com.