The Epidemiology and Causes of Global and Regional Sepsis Mortality in Children Under Five, 1990-2021: A Systematic Analysis

University of Washington Abstract The Epidemiology and Causes of Global and Regional Sepsis Mortality in Children Under Five, 1990–2021: A Systematic Analysis Erin Chung Chair of the Supervisory Committee:Jeffrey Stanaway Health Metrics Sciences Introduction: Despite the significant burden of sepsis in children under five years of age, estimating the global burden of sepsis in this group as well as further characterization of its epidemiology is challenging due to heterogeneity in defining and measuring sepsis in children and data sparsity from low- and middle-income countries, where the mortality is highest. Methods: Using multiple cause of death data from multinational individual level records, we applied the Sepsis-3 definition to identify explicitly and implicitly coded sepsis deaths (e.g., a non-infectious underlying cause with an infectious intermediate cause of death). We applied sepsis fractions from binomial logistic regression models to cause-specific mortality estimates from the 2021 Global Burden of Disease (GBD) study to estimate annual pediatric (defined as children under five years of age) sepsis-related mortality by sex, GBD super-region, and underlying cause of death from 1990 to 2021. Results: We estimated 2.66 million deaths (95% uncertainty interval: 2.18–3.14) related to pediatric sepsis worldwide in 2021, the lowest sepsis mortality since 1990. Neonates had the greatest burden with 949,000 deaths (751,000–1,150,000) in 2021. The Sub-Saharan Africa super-region showed the greatest decline in pediatric sepsis-related mortality but continued to disproportionately lead other super-regions with 1.71 million deaths (1.39–2.04) in 2021. The sepsis burden associated with infectious underlying causes decreased: lower respiratory infections and diarrheal diseases, the leading two causes of sepsis in 1990, have been supplanted by neonatal disorders. Neonatal encephalopathy due to birth asphyxia and trauma, a non-infectious underlying cause of sepsis, remained the leading sub-cause of the sepsis-related mortality burden associated with the neonatal disorders cause group. Conclusions: From 1990 to 2021, global pediatric sepsis-related mortality decreased, primarily from progress addressing sepsis with infectious underlying causes. The burden of sepsis-related mortality concentrated among neonates, especially in Sub-Saharan Africa and South Asia, and neonatal disorders led as underlying causes of both neonatal and pediatric sepsis deaths. Further attention is needed to define neonatal sepsis and address sepsis as a complication of non-infectious neonatal conditions.