Fifteen randomised controlled trials (55,764 patients, range 315 to 12,064) were included in the review. Nine studies attained quality scores of 5 points, one study was give a quality score of 4 points and the remaining five studies were assigned quality scores of 3 points. All the trials were reported to be randomised, and fourteen trials reported the use of double-blinding.
Folic acid supplementation was associated with statistically significant reductions across all the trials for the risk of stroke (RR 0.92. 95% CI 0.86 to 1.00; Ι²=20.1%). Similar results were observed using a random-effects model.
Statistically significant reductions in stroke risk were also observed in trials in populations with no or partial folic acid fortification (RR 0.89, 95% CI 0.82 to 0.97; 10 trials; Ι²=32.6%,), and trials with no or partial fortification and a lower percentage use (80% or less) of statins (RR 0.77, 95% CI 0.64 to 0.92). The results of the meta-regression analyses were suggestive of a positive dose-response relationship between percentage use of statins and risk for stroke associated with folic acid supplementation. However, the dose of folic acid was not significantly correlated with the effect size.
There were no significant differences in risk of stroke with supplementation compared to no supplementation in the five trials of folic acid fortification. There were no significant effects observed in the subgroup analyses for these populations.
Visual appraisals of funnel plots and results of the Egger's test showed no evidence of publication bias. There was no statistically significant heterogeneity observed across the studies for the results. Sensitivity analyses showed that the results did not substantially change with the removal from the results of any single trial.