Biomarker responses to folic acid intervention in healthy adults: a meta-analysis of randomized controlled trials

Maresa E Duffy, Leane Hoey, Catherine F Hughes, J J Strain, Audrey Rankin, Olga W Souverein, Carla Dullemeijer, Rachel Collings, Lee Hooper, Helene McNulty

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)


BACKGROUND: The task of revising dietary folate recommendations for optimal health is complicated by a lack of data quantifying the biomarker response that reliably reflects a given folate intake.

OBJECTIVE: We conducted a dose-response meta-analysis in healthy adults to quantify the typical response of recognized folate biomarkers to a change in folic acid intake.

DESIGN: Electronic and bibliographic searches identified 19 randomized controlled trials that supplemented with folic acid and measured folate biomarkers before and after the intervention in apparently healthy adults aged ≥18 y. For each biomarker response, the regression coefficient (β) for individual studies and the overall pooled β were calculated by using random-effects meta-analysis.

RESULTS: Folate biomarkers (serum/plasma and red blood cell folate) increased in response to folic acid in a dose-response manner only up to an intake of 400 μg/d. Calculation of the overall pooled β for studies in the range of 50 to 400 μg/d indicated that a doubling of folic acid intake resulted in an increase in serum/plasma folate by 63% (71% for microbiological assay; 61% for nonmicrobiological assay) and red blood cell folate by 31% (irrespective of whether microbiological or other assay was used). Studies that used the microbiological assay indicated lower heterogeneity compared with studies using nonmicrobiological assays for determining serum/plasma (I(2) = 13.5% compared with I(2) = 77.2%) and red blood cell (I(2) = 45.9% compared with I(2) = 70.2%) folate.

CONCLUSIONS: Studies administering >400 μg folic acid/d show no dose-response relation and thus will not yield meaningful results for consideration when generating dietary folate recommendations. The calculated folate biomarker response to a given folic acid intake may be more robust with the use of a microbiological assay rather than alternative methods for blood folate measurement.

Original languageEnglish
Pages (from-to)96-106
Number of pages11
JournalThe American journal of clinical nutrition
Issue number1
Early online date13 Nov 2013
Publication statusPublished - Jan 2014


  • Biomarkers
  • Diet
  • Dietary Supplements
  • Dose-Response Relationship, Drug
  • Erythrocytes
  • Folic Acid
  • Homocysteine
  • Humans
  • Randomized Controlled Trials as Topic
  • Reproducibility of Results
  • Sensitivity and Specificity

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