Association Between Sex and Mortality After Traumatic Brain Injury: A Systematic Review and Meta-Analysis

Traumatic brain injury (TBI) is a major cause of trauma-related mortality. While male individuals are disproportionately affected, the influence of sex on mortality remains controversial, with conflicting evidence suggesting female advantage, disadvantage, or no difference. Clarifying this relationship is crucial for prognosis and sex-specific treatment. A systematic search was conducted on 4 June 2025 in PubMed, Embase, Web of Science, and the Cochrane Library without date restrictions. Observational studies reporting sex-stratified TBI patient mortality with sufficient data to derive effect sizes were included. Screening, full-text assessment, and data extraction were performed independently by multiple reviewers. Random-effects meta-analysis was conducted to calculate odds ratios (OR) for mortality in female versus male individuals, with subgroup and leave-one-out sensitivity analyses as well as meta-regression. Heterogeneity was quantified using I² and prediction intervals. Quality was assessed using an adapted Newcastle-Ottawa Scale. The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines. A total of 40 studies, encompassing over 1 million patients (383,914 female individuals; 662,748 male individuals), were included. Overall, sex was not significantly associated with TBI mortality [OR 0.99; 95% confidence interval (CI) 0.90-1.09], though substantial between-study heterogeneity and prediction intervals indicated that female mortality could be higher in some contexts and lower in others. Subgroup analyses showed no significant differences by TBI type, age, or severity. Although initial analyses suggested lower female mortality in good-quality studies and higher female mortality in patients with severe TBI and in studies conducted before the 2000s, the findings were not robust in leave-one-out analyses. Meta-regression indicated that mean age differences did not explain heterogeneity between sex and mortality estimates. Concluding, there is no universal biological association between sex and TBI mortality. Instead, the relationship appears context-dependent, varying by study characteristics and patient populations. Future research should move beyond assessing sex as a simplistic risk factor and focus on identifying specific biological and clinical contexts where sex influences outcomes to inform personalized care.