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Fol8.0
Folic Acid Research
Too few graded studies
22 peer-reviewed studies
What the evidence says
Too few graded studies
Folic Acid doesn't have enough studies with structured effect-size data yet to pool a verdict. Browse the studies below for individual findings.
Most evidence is from high-quality meta-analyses and randomised trials published 1991–2026.
Based on 22 studies · 7 meta-analyses · 6 RCTs
Confidence
High confidence
By outcome
Women's healthSubstantially lower risk of a neural tube defect when started before conception · Best started at least 1 month before conception and continued through the first 2-3 months of pregnancy (USPSTF, NCBI Bookshelf NBK593617); if pregnancy has already begun, start promptly
Too few graded studies6 studies
Therapeutic & clinical
Too few graded studies3 studies
Heart & blood pressure
Too few graded studies2 studies
Anemia & hematology
Too few graded studies2 studies
Lean body mass & muscle growth
Too few graded studies1 study
Energy & fatigue
Too few graded studies1 study
Glucose & metabolic
Too few graded studies1 study
Fertility & reproductive
Too few graded studies1 study
5 more outcomes with fewer studies not shown.
Active research area
18 studies in the last 5 years · Latest meta-analysis: 2026
199120082026
1Meta-Analysis2026
In plain English: Malaria prevention: None of the included trials reported primary outcomes.
Qi YP, Crider KS, Gutman J, Centeno-Tablante E, Fothergill A, Daniels K, Yeung LF, Mai CT, Mehta S, Williams JL, Finkelstein JL. · The Cochrane database of systematic reviews (2026)
Authors' conclusions Malaria prevention: None of the included trials reported primary outcomes.
Malaria treatment: People who received folic acid supplementation (alone or with iron) and antifolate antimalarial treatment were less likely to clear malaria parasitaemia (day 3), and had increased treatment failure (days 7, 14, 28).
Most of the included trials provided folic acid with doses above the tolerable UL (> 1.0 mg).
In plain English: The Cochrane synthesis for this indication (CD007950, third edition), covering both the effects and the safety of periconceptional oral folate supplementation for preventing birth defects.
In plain English: This study synthesized the best available evidence regarding folic acid supplementation for preventing NTDs in women of childbearing age, providing an evidence-based foundation to inform clinical practice, particularly for healthcare systems and populations in regions without mandatory folic acid food fortification.
Li J, Chen B, Liu N, Dong W, Lv D, Li S, Zhu X. · Nutrients (2026)
Results The review included 17 publications: 10 guidelines, 4 expert consensuses, 2 recommended practices, and 1 best practice.
In plain English: The pivotal recurrence-prevention trial: a randomised, multicentre study of periconceptional folic acid in women who had already had a neural-tube-defect-affected pregnancy.
MRC Vitamin Study Research Group · Lancet (1991)
Randomised, multicentre trial of periconceptional folic acid for prevention of RECURRENT neural tube defects (PubMed publication types: Randomized Controlled Trial, Multicenter Study, Comparative Study)
Cited here as the pivotal recurrence-prevention trial and the origin of the high-dose regimen
The USPSTF evidence review states that 4 mg folic acid reduces the risk of recurrent neural tube defects by more than 70 percent (NCBI Bookshelf NBK593617); that review does not name the trial, so the figure is NOT attributed to this paper and has not been verified against it
5RCTCited 2,351×1992
In plain English: The USPSTF evidence review identifies this Hungarian trial as the only eligible randomised trial of FIRST-occurrence prevention and reports an odds ratio for neural tube defects of 0.131 (95% CI 0.026 to 0.648, p=0.013).
Czeizel AE, Dudás I · N Engl J Med (1992)
Randomised trial of periconceptional vitamin supplementation for prevention of a FIRST neural tube defect (PubMed publication types: Randomized Controlled Trial, Clinical Trial)
Odds ratio for neural tube defects 0.131 (95% CI 0.026 to 0.648), p=0.013, as reported by the USPSTF evidence review 'Folic Acid Supplementation to Prevent Neural Tube Defects' (NCBI Bookshelf NBK593617)
The intervention was a multivitamin containing folic acid, not folic acid alone, so it supports periconceptional supplementation containing folic acid rather than the isolated compound
In plain English: High-dose folic acid supplementation (4 mg/day) may reduce the risk of miscarriage and increase pregnancy rates in women trying to conceive.
Vinti D, Fiore A, Fornelli G, Reschini M, Viganò P, Somigliana E, Salmeri N. · American journal of obstetrics & gynecology MFM (2026)
Data were pooled using random-effects meta-analysis models and reported as risk ratios (RRs) with 95% confidence intervals (CIs).
In this population, high-dose folic acid supplementation was associated with a statistically significant reduction in miscarriage risk (RR 0.73; 95% CI: 0.56-0.94; I 2 =0%).
An additional intention-to-treat (ITT) analysis, which included all randomized participants regardless of pregnancy status, showed a nonsignificant reduction in miscarriage risk (RR 0.79; 95% CI: 0.61-1.04).
In plain English: Multiparous women were less likely to take folic acid preconceptional, periconceptional and postconceptionally, despite their previous pregnancy experience.
Ebong U, Wilson JJ, Given J, Casey F, Loane M, Dolk H. · BMJ open (2026)
Three other reviewers independently assessed 10% of the studies as a quality check.
For preconceptional use, the odds were 29% lower among multiparous women (adjusted OR (aOR): 0.71; 95% CI 0.64 to 0.78; n=25 studies; I 2 =88.67%), and 58% lower in multiparous high-risk women (aOR: 0.42, 95% CI 0.27 to 0.64; n=3 studies; I 2 =27.28%).
For periconceptional use, the odds were 32% lower among multiparous women (aOR: 0.68; 95% CI 0.63 to 0.74; n=28 studies; I 2 =85.46%).
In plain English: Continued implementation, alongside supplementation and rigorous monitoring, is crucial to further reduce the global incidence of NTDs.
Moges S, Kotiso KS, Jaldo MM. · BMC nutrition (2026)
RESULTS: The pooled analysis revealed that mandatory folic acid fortification was associated with a 44% reduction in the risk of NTDs (RR = 0.56).
Subgroup analyses demonstrated region-specific benefits: North American studies showed a 54% reduction in NTDs risk (RR = 0.46), while South American studies reported a 38.8% reduction (RR = 0.61).
Therefore, mandatory folic acid fortification significantly reduces the risk of NTDs compared to pre-fortification.
In plain English: This study demonstrated that among hypertensive patients receiving regular antihypertensive treatment, healthy lifestyle profiles were associated with lower risks of stroke and all-cause mortality, partially mediated by improvements in long-term blood pressure and greater time in target range.
Zhou Z et al. · Journal of human hypertension (2026)
The hazard ratios for stroke were 0.70 (95% CI: 0.54-0.92; P = 0.010) in the Favorable group, compared with the Unfavorable group.
Similarly, the hazard ratios for all-cause mortality were 0.72 (95% CI: 0.56-0.93; P = 0.012) in the Favorable group.
The mean treatment systolic blood pressure (SBP), diastolic blood pressure (DBP), 1-year blood pressure time in target range (TTR), SBP-TTR, and DBP-TTR, significantly mediated the association with stroke risk, accounting for 31.1%, 15.9%, 7.1%, 8.3%, and 7.2% of the total effect, respectively.
In plain English: Mandatory grain fortification with folic acid increases blood folate concentrations and decreases the risk of folate insufficiency and folate deficiency.
Parker J, Kisho A, Hou S, Goodman M, Cravens L, Grap ME, Pachón H. · The Journal of nutrition (2026)
All meta-estimates were accompanied by 95% confidence intervals (CIs).
About 19% of studies were conducted in low- or middle-income countries.
Mandatory fortification improved folate status, albeit with considerable heterogeneity across studies (I 2 >73%).
In plain English: Clear definitions of safe upper limits for intake of folic acid and blood folate concentration are needed urgently to prevent potential adverse outcomes.
Ledowsky C et al. · Reproductive biomedicine online (2026)
Excessive intake of folic acid supplements and a high blood folate concentration were associated with gestational diabetes mellitus, and adverse neurodevelopmental issues in offspring, as well as large-for-gestational-age infants and higher birth weight.
Clear definitions of safe upper limits for intake of folic acid and blood folate concentration are needed urgently to prevent potential adverse outcomes.
In plain English: Standardized monitoring protocols and risk stratification are essential to optimize safety, prevent unnecessary treatment discontinuation and improve long-term psoriasis management.
Boehncke WH et al. · Acta dermato-venereologica (2026)
Psoriasis itself may also contribute to liver dysfunction.
There is no consensus on optimal monitoring frequency for liver function tests or the role of noninvasive tools like transient elastography.
While folic acid supplementation may mitigate risk, dosing remains inconsistent.Though MTX carries a potential hepatotoxic risk, this is patient-specific rather than inherent to the drug.
In plain English: A phase III randomised trial that tested high-dose folic acid against a non-pregnancy endpoint — colorectal adenoma prevention — and is the trial most often cited when the safety of long-term supplementation above the upper limit is questioned.
Cole BF et al. · JAMA (2007)
Multicentre phase III randomised clinical trial of folic acid for colorectal adenoma prevention (PubMed publication types: Randomized Controlled Trial, Clinical Trial Phase III, Multicenter Study)
Included as the counterweight to the prenatal evidence: it tests folic acid outside the periconceptional indication, at a dose above the tolerable upper intake level
In plain English: Implications to practice Strengthening antenatal care visits, routine anemia screening, iron-folic acid supplementation and promotion of nutritional education, is essential for reducing newborn anemia.
Mekonen H, Tsega TD, Ahmed AF, Yeshiwas AG, Mekonnen BA, Alemayehu MA, Aneley Z, Bayeh GM, Tsega SS, Gebeyehu AA, Ejigu AG, Yigzaw ZA, Kassie M, Temesgen A, Enawgaw AS, Yirdaw G, Yenew C, Anteneh RM, Molla G, Asmare ZA, Kebede AM. · Journal of pediatric nursing (2025)
A fixed-effect model was used to estimate the pooled prevalence of anemia among newborns with a 95 % confidence interval.
Result The pooled prevalence of anemia among newborns in Ethiopia was 26.53 % (95 % CI: 24.43, 28.62).
Conclusion The prevalence of anemia among newborns in Ethiopia was significant.
In plain English: Folic acid supplementation combined with resistance training was associated with greater gains in skeletal muscle mass, greater reductions in body fat mass, lower Hcy, and higher HDL-C than either intervention alone.
Yang C, Huang M, Zhou H, Sun H, Wang Q, Yin R, Wu J. · Journal of the International Society of Sports Nutrition (2026)
A significance level of P < 0.05 was used.
Results Regarding body composition, the RF produced the greatest increase in skeletal muscle mass (SMM; + 4.79 ± 2.42 kg), which was significantly larger than the increases observed in the control (+0.96 ± 1.50 kg), FA (+1.03 ± 1.68 kg), and RT (+0.91 ± 1.12 kg) (all P < 0.01).
Body fat mass (BFM) decreased most in the RF (-1.49 ± 1.40 kg), differing significantly from the control (+0.24 ± 1.71 kg; P < 0.01) and FA (+0.04 ± 1.18 kg; P < 0.05).
In plain English: Critically, no included studies reported adjudicated cardiovascular hard endpoints (myocardial infarction, stroke, cardiovascular mortality); target tHcy reduction remains an unvalidated surrogate for clinical cardiovascular disease (CVD) risk reduction, no optimal folic acid dose can be definitively defined from this analysis, and all dose-related considerations are strictly hypothesis-generating.
Long ZP, Wang CW, Sun FF, Xu SB, Yan JZ, Zeng C. · BMC nutrition (2026)
Folic acid supplementation was associated with dose-dependent reductions in tHcy levels (standardised mean difference [SMD] = - 0.99; 95% CI - 1.15 to - 0.83; I²= 90%).
However, these results are statistically significant but highly heterogeneous and at substantial risk of bias, with likely overestimation of effect sizes due to small-study effects and publication bias.
The largest SMDs were observed in the higher dose categories (5-15 mg/day) and after ≥ 6 months of treatment.
In plain English: Increasing folic acid dose to 10 mg/week showed little effect on reducing MTX-related toxicity, although it may improve fatigue in selected patients.
Yoshida Y, Hosokawa Y, Taogoshi T, Oka N, Kobayashi H, Kidoguchi G, Araki K, Ishitoku M, Sugimoto T, Mokuda S, Matsuo H, Hirata S. · Clinical rheumatology (2026)
The presence of liver damage at Day 84 did not differ significantly between the two groups (OR 0.41, 95% CI, 0.01-5.75, p = 0.506).
Adjusted mean differences in aspartate transaminase and alanine transaminase at Day 84 between the groups were - 0.33 U/L (95% CI, - 2.68 to 2.02; p = 0.779) and - 0.44 U/L (95% CI, - 5.39 to 4.51; p = 0.859).
Comparison of outcomes between groups at Day 84 showed no significant differences in any outcomes, except for fatigue severity (adjusted mean difference, - 0.87; 95% CI, - 1.71 to - 0.04; p = 0.041).
In plain English: Compared with .4 mg supplementation, doses above 1 mg/day were associated with a lower risk of LBW (aOR .208, 95% CI .05-.58).
Fu Y, Shi F, Sha L, Ma Y, Lin W, Li X, Yan H, Wang P, Fang J, Huang Q, Chen F, Li Y, Kong Q, Huang H, Hu X, Liu C, Wang J, Xiao X, Zhang Q, Mei R, Han Y, Wu Y, He S, Zhang H, Wang K, Zhu Y, Lin W, Peng Z, Zhu X, Wu X, Yu M, Zou M, Zou X, Wu T, He X, Guo H, Zhong M, Zhang Q, Su Y, Liu Y, Feng Q, Wang H, Chen W, Sun Y, Sun M, Zhou J, Zhao H, Guo C, Gao J, Guo Y, Huang J, Sun H, Luo X, Yang R, Qin H, Tomson T, Chen L. · Epilepsia (2026)
Compared with .4 mg supplementation, doses above 1 mg/day were associated with a lower risk of LBW (aOR .208, 95% CI .05-.58).
In plain English: Folic acid deficiency and malabsorption are significant concerns in cancer therapy involving antifolate drugs.
Tembhurne SV, Kate PM. · Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer (2026)
While folic acid supplementation has shown benefit in reducing toxicity, its dosing must be carefully managed to avoid interference with chemotherapeutic efficacy.
Conclusion Folic acid deficiency and malabsorption are significant concerns in cancer therapy involving antifolate drugs.
Targeted nutritional strategies, including judicious folic acid supplementation, are essential to improving patient outcomes and minimizing treatment-associated complications.