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.
Funding Information
  • Canadian Institutes of Health Research