Risk Factors of Aneurysmal Subarachnoid Hemorrhage Including Analysis by Sex: A Systematic Review and Meta-Analysis

BACKGROUND AND OBJECTIVES: A 2005 review identified smoking, hypertension, and excessive alcohol intake as the most important risk factors of aneurysmal subarachnoid hemorrhage (aSAH), but data on other factors remained inconclusive. While aSAH is more prevalent in female participants, evidence on sex differences and female-specific factors remains limited. Comprehensive identification of all risk factors, including potential sex differences and female-specific factors, is essential for improving prevention and accurately assessing aSAH risk. We aimed to determine whether there is now greater certainty around previously inconclusive risk factors, identify any new emerging factors, and explore sex differences in both established and emerging risk factors.

METHODS: We conducted a systematic review and meta-analysis of cohort and case-control studies on prevalent lifestyle exposures, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. These exposures included smoking, hypertension, alcohol abuse, oral contraception, hormone replacement therapy, hypercholesterolemia, rigorous physical activity, lean body mass index, and diabetes. We calculated pooled sex-specific relative risks (RRs) and odds ratios (ORs) with 95% CIs for overall risk and female-to-male ratios of RRs (RRRs) and ORs (RORs) for sex comparisons.

RESULTS: We included 67 studies (34 cohort [8 with sex-specific data], 33 case-control [6 with sex-specific data]; n = 5,743,262; 57% female). A sex-specific association was found for current smoking (RRR 1.53, 95% CI 1.05-2.23), but not for hypertension (RRR 1.50, 95% CI 0.78-2.89) or excessive alcohol intake (RRR 0.46, 95% CI 0.13-1.63). Regular rigorous exercise (RR 0.74, 95% CI 0.53-1.04; OR 0.69, 95% CI 0.57-0.83) and diabetes (RR 0.75, 95% CI 0.55-1.02; OR 0.52, 95% CI 0.41-0.65) were associated with reduced risk, without sex-specific associations. Data on hypercholesterolemia (RR 1.24, 95% CI 0.97-1.58; OR 0.52, 95% CI 0.37-0.74) and lean BMI (RR 1.31, 95% CI 1.15-1.50; OR 1.39, 95% CI 0.74-2.60) were inconsistent and showed no sex-specific associations. Hormone replacement therapy (RR 1.03, 95% CI 0.72-1.48) and oral contraceptive use (RR 5.40, 95% CI 0.68-42.57) were limited to female patients, with current users compared with never users. Most studies contained potential sources of bias.

DISCUSSION: Current smoking, but not hypertension or excessive alcohol, has a stronger association with aSAH in female patients than in male patients. Regular exercise and diabetes are associated with a reduced risk, with no sex-specific associations. Data on female-specific factors remain inconsistent. Targeted smoking prevention may particularly benefit female patients. Large-scale studies are needed to clarify the role of female-specific factors in explaining the higher incidence of aSAH in female patients.