Association between bilirubin levels and risk of stroke: a systematic review and meta-analysis

OBJECTIVE: To evaluate the association between bilirubin levels and stroke risk. DESIGN: Systematic review and meta-analysis, reported in accordance with Meta-analysis Of Observational Studies in Epidemiology guidelines. DATA SOURCES: The PubMed, Embase, Cochrane Central Register of Controlled Trials and China National Knowledge Infrastructure Databases were searched from inception up to 27 February 2022. ELIGIBILITY CRITERIA: Cohort studies assessing the dose–response relationship between bilirubin levels and risk of stroke were eligible for inclusion. There were no language restrictions. DATA EXTRACTION AND SYNTHESIS: All data from eligible studies were collected and assessed by two independent investigators. We generated pooled relative risks (RRs) with 95% CIs. We used a restricted cubic spline model for the dose–response analyses. Subsequent subgroup analyses were conducted according to stroke outcomes, follow-up duration, geographical area and size of the cohort. RESULTS: Nine articles including results from 11 cohort studies with 7835 cases of stroke and 263 596 participants met the inclusion criteria. The summarised RR of stroke comparing the highest and lowest bilirubin level was 0.85 (95% CI 0.72 to 0.99). The dose–response analysis indicated that a 15 µmol/L increment of bilirubin level was associated with an 18% lower risk of stroke (RR=0.82, 95% CI 0.67 to 0.99). For ischaemic stroke, the RR was 0.76 (95% CI 0.58 to 0.99). Significant publication bias was not detected. CONCLUSIONS: Elevated bilirubin levels were associated with a decreased risk of stroke among adults. PROSPERO REGISTRATION NUMBER: CRD42017071497.