PubMed 42739064

Unmetabolized Folic Acid: Biology, Epidemiology, and Clinical Consequences: A Systematic Review

Frye RE, Rossignol DA · Nutrients · 2026 · PubMed · DOI 10.3390/nu18172887

Summary

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Unmetabolized Folic Acid: Biology, Epidemiology, and Clinical Consequences: A Systematic Review

荟萃分析系统综述Machine-checked 2026年9月21日AI-assisted draft

Frye RE, Rossignol DA Unmetabolized Folic Acid: Biology, Epidemiology, and Clinical Consequences: A Systematic Review. Nutrients, 2026. PubMed 42739064 · DOI

Design
Systematic review and meta-analysis of 65 publications (61 unique studies, 71 analytic contributions: 15 mechanistic, 24 observational, 32 interventional). Random-effects meta-analysis (DerSimonian-Laird, Hartung-Knapp-Sidik-Jonkman CIs) for trials comparing 5-MTHF to folic acid; GRADE-rated certainty; mechanistic and observational data synthesized narratively.
Population
Not stated in the abstract beyond the pooled set of primary studies on folic acid fortification and supplementation.
Intervention
Folic acid (FA) intake, including mandatory fortification exposure, compared with equimolar (6S)-5-MTHF substitution.
Dose as studied
Not stated in the abstract.
Comparator
(6S)-5-MTHF versus folic acid, given as an equimolar substitution in interventional trials.
Duration
Not stated in the abstract; literature search covered January 1995 to May 2026.

Outcomes, as reported

  • Plasma unmetabolized folic acid (UMFA) 5-MTHF substitution reduced UMFA: SMD +0.99 (95% CI +0.20 to +1.79), I2 = 30%, k = 3, GRADE low.
  • Erythrocyte folate Two trials were directionally discordant: Hedges' g +0.40 (95% CI +0.08 to +0.73) and -0.38 (95% CI -0.92 to +0.16), I2 = 83%; not pooled.
  • Total homocysteine (tHcy) No pooled estimate could be derived; reported qualitatively; no between-form difference detected.
  • Observational UMFA-outcome associations Inconsistent, confounded by total folate, and unreplicated across studies.

Limitations stated by the authors · Only two to three trials per outcome, no prespecified equivalence or non-inferiority margins, and no trial designed for that purpose. High heterogeneity for erythrocyte folate (I2 = 83%). GRADE certainty rated low. Observational associations confounded by total folate. Evidence does not establish equivalence, non-inferiority, or that UMFA causes harm.

Funding · Not stated in the abstract.