The effect of folate fortification on folic acid-based homocysteine-lowering intervention and stroke risk: a meta-analysis

Abstract

Objective: Folate and vitamin B12 are two vital regulators in the metabolic process of homocysteine, which is a risk factor of atherothrombotic events. Low folate intake or low plasma folate concentration is associated with increased stroke risk. Previous randomized controlled trials presented discordant findings in the effect of folic acid supplementation-based homocysteine lowering on stroke risk. The aim of the present review was to perform a meta-analysis of relevant randomized controlled trials to check the how different folate fortification status might affect the effects of folic acid supplementation in lowering homocysteine and reducing stroke risk.

Design: Relevant randomized controlled trials were identified through formal literature search. Homocysteine reduction was compared in subgroups stratified by folate fortification status. Relative risks with 95 % confidence intervals were used as a measure to assess the association between folic acid supplementation and stroke risk.

Setting: The meta-analysis included fourteen randomized controlled trials,

Subjects: A total of 39 420 patients.

Results: Homocysteine reductions were 26·99 (sd 1·91) %, 18·38 (sd 3·82) % and 21·30 (sd 1·98) %, respectively, in the subgroups without folate fortification, with folate fortification and with partial folate fortification. Significant difference was observed between the subgroups with folate fortification and without folate fortification (P=0·05). The relative risk of stroke was 0·88 (95 % CI 0·77, 1·00, P=0·05) in the subgroup without folate fortification, 0·94 (95 % CI 0·58, 1·54, P=0·82) in the subgroup with folate fortification and 0·91 (95 % CI 0·82, 1·01, P=0·09) in the subgroup with partial folate fortification.

Conclusions: Folic acid supplementation might have a modest benefit on stroke prevention in regions without folate fortification.

Keywords: Folate fortification.

Fig. 1

Flowchart of the search process (RCT, randomized controlled trial)

Fig. 2

The level of homocysteine reduction at the end of follow-up among fourteen randomized controlled trials (RCT), with a total of 39 420 patients, studying the effect of folic acid supplementation on stroke risk, with trials stratified according to the status of folate fortification. The absolute mean homocysteine reduction in the active treatment group in the three different folate fortification subgroups is shown; the floating bars depict minimum to maximum, with a line at the mean. Significant difference: *P≤0·05

Fig. 3

Pooled relative risk (RR) of stroke in the subgroups without folate fortification and with partial folate fortification. The study-specific RR and 95 % CI are represented by the black square and horizontal line, respectively; the area of the black square is proportional to the specific-study weight to the overall meta-analysis. The centre of the black diamond presents the pooled RR risk and its width represents the pooled 95 % CI (NO, Norway; FR, France; GE, Germany; NL, Netherlands; CN, China)

Fig. 4

Pooled relative risk (RR) of stroke in the subgroup with folate fortification. The study-specific RR and 95 % CI are represented by the black square and horizontal line, respectively; the area of the black square is proportional to the specific-study weight to the overall meta-analysis. The centre of the black diamond presents the pooled RR risk and its width represents the pooled 95 % CI (CA, Canada; AU/NZ, Australia/New Zealand)