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

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 I² = 77.2%) and red blood cell (I² = 45.9% compared with I² = 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.