Smoking Has Dose-Dependent Association With Subarachnoid Hemorrhage Risk

In an adjusted model that included interaction terms between sex and cigarettes per day or pack-years, female sex was no longer an independent risk factor for subarachnoid hemorrhage.

Subarachnoid hemorrhage risk is typically higher in women vs men; however, a recent study suggests that smoking has a dose-dependent and cumulative association, and that this risk is highest in women who are heavy smokers.

Joni Valdemar Lindbohm, MD, of the Department of Public Health at the University of Helsinki in Finland, and colleagues sought to determine why the difference in subarachnoid hemorrhage incidence exists between the sexes. Their findings were recently published in Stroke.

They utilized data from the population-based FINRISK study cohort (n=65 521), which was followed up for 1.38 million person-years, and identified 492 cases of subarachnoid hemorrhage (266 in women; mean age: 45.3; median age: 45.0 years). Follow-up began at enrollment and ended at first-ever subarachnoid hemorrhage or on December 31, 2011.

Current smokers made up 19% of the female patient population and 38% of the male patient population. Overall, men had smoked longer, smoked more cigarettes daily, and their total exposure in pack-years was greater than women.

Dr Lindbohm and colleagues found that current smokers had a hazard ratio (HR) of 2.77 (95% confidence interval [CI]: 2.22-3.46) compared with never-smokers. For male smokers, the HR was 2.20 (95% CI: 1.56-3.10) and 3.43 (95% CI: 2.58-4.55) for female smokers. Recent quitters were at higher risk for subarachnoid hemorrhage than former smokers (HR: 1.93; 95% CI: 0.98-3.79 and HR; 1.34; 95% CI: 0.98-1.82, respectively). Light smokers, who smoked1 to 10 cigarettes per day were at an elevated risk, and this risk increased gradually up to an HR of 3.91 (95% CI: 1.97-7.75) in heavy smokers.

Women who smoked more than 20 cigarettes per day had an HR of 8.35 (95% CI: 3.86-18.06) compared with an HR of 2.76 (95% CI: 1.68-4.52) in men. HRs also differed by sex when comparing all cigarettes per day and pack-year categories, and the association was stronger in women across the board (P=.01).

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Current smokers with fewer than 5 pack-years had an elevated risk compared with never-smokers and an HR of 2.13 (95% CI: 1.44-3.16). The risk gradually increased and reached an HR of 5.62 (95% CI: 2.88-10.97) among those smokers with more than 50 pack-years. “When we compared pack-year categories of current smokers and nonsmokers (by combining both quitter groups with never-smokers), we found even stronger evidence supporting the sex difference (likelihood ratio test P=.02),” researchers wrote.

However, they noted, “When an adjusted model included interaction terms between sex and cigarettes per day or pack-years, female sex was no longer an independent SAH [subarachnoid hemorrhage] risk factor.” In the cigarette per day model, the HR was 1.18 (95% CI: 0.86-1.62) and in the pack-years model, the HR was 1.05 (95% CI: 0.82-1.34).

“Our results suggest that female sex may not be an independent risk factor for SAH, challenging the current understanding of SAH epidemiology,” Dr Lindbohm and colleagues wrote. “We found that multiplicative and additive effect modification between sex and CPD [cigarettes per day] may explain why previous prospective studies find female sex to be an independent risk factor for SAH.”

They explained that if cumulative doses of smoking are not considered by sex, then categorical analyses may indicate that female sex is a strong risk factor for subarachnoid hemorrhage.

Disclosures: Dr Kaprio consulted for Pfizer on nicotine dependence from 2012 to 2014.


Lindbohm JV, Kaprio J, Jousilahti P, Salomaa V, Korja M. Sex, smoking, and risk for subarachnoid hemorrhage. Stroke. 2016;47:1975-1981. doi: 10.1161/STROKEAHA.116.012957.