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.


METHODS
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.
Northern Ireland Centre for Food and Health, University of Ulster, Coleraine, Northern Ireland (MED, L Hoey, CFH, JJS, AR, and HM); the Division of Human Nutrition, Wageningen University and Research Centre, Wageningen, Netherlands (OWS and CD); and Norwich Medical School, University of East Anglia, Norfolk, United Kingdom (RC and L Hooper).
Maresa E
ME
Duffy
Leane
L
Hoey
Catherine F
CF
Hughes
J J
JJ
Strain
Audrey
A
Rankin
Olga W
OW
Souverein
Carla
C
Dullemeijer
Rachel
R
Collings
Lee
L
Hooper
Helene
H
McNulty
D015415:Biomarkers / Q000097:blood*; D004032:Diet; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000737:chemistry; D005492:Folic Acid / Q000008:administration & dosage* / Q000097:blood*; D006710:Homocysteine / Q000097:blood; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
D015415:Biomarkers; D006710:Homocysteine; D005492:Folic Acid