Sex-based analysis of treatment responses in animal models of sepsis: a preclinical systematic review and meta-analysis

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Abstract Objectives To examine the effect of biological sex on mortality, inflammation, organ dysfunction, and bacterial burden in preclinical sepsis models. Data sources MEDLINE and Embase from January 1, 2011, to May 13, 2025. Study selection We included in vivo animal models of experimentally- induced sepsis with or without intervention that reported sex-stratified data. We excluded non-infectious models and interventions hypothesized to worsen sepsis outcomes. Data extraction We performed full-text screening and data extraction on mortality (primary outcome), inflammation, organ dysfunction, and bacterial burden. We applied a novel three-level analytic framework to determine: (1) baseline sepsis effect (female versus male differences), (2) unadjusted treatment effect (post-treatment risk differences), and (3) adjusted treatment effect (post-treatment risk differences accounting for baseline sepsis differences). Using random-effects models, we pooled outcomes as risk differences (RDs) or difference of standardized mean differences with differences > 0 indicating worse outcomes in males. Data synthesis We screened 7,896 citations; 94 studies met eligibility criteria, and 83 studies were analyzed quantitatively. Cecal ligation and puncture (CLP) was the most common model (46%), followed by bacteremia (37%). Across the three-level framework (baseline sepsis effect, unadjusted and adjusted treatment effects), effect estimates were generally imprecise. Direction of effect analysis more often suggested worse outcomes in males (69/99 pooled comparisons). For mortality, the pooled RDs were 0.04 [95% CI, -0.02 to 0.10] for baseline sepsis effect, 0.05 [95% CI, 0.00 to 0.09] for unadjusted treatment effect, and 0.07 [95% CI, 0.00 to 0.14] for adjusted treatment effect. We observed similar direction of effects for inflammation (22/27 pooled comparisons) and organ dysfunction (9/12 pooled comparisons). The direction of effect for bacterial burden suggested worse outcomes in females (12/22 pooled comparisons). Most studies had “unclear” risk of bias. Conclusions Sex-stratified reporting in preclinical sepsis studies remains rare. The available evidence was uncertain but showed a recurring direction toward worse outcomes and less favourable treatment responses in males. Future studies should systematically incorporate sex as a biological variable in their design and analysis to reduce this uncertainty and better define sex-based differences in sepsis and treatment response.