Circulating Angiopoietin-2 Concentrations in Neonates and Children With Sepsis Compared With Non-Septic Controls: A Systematic Review and Meta-Analysis

Abstract Purpose: Angiopoietin-2 (Ang-2) is implicated in endothelial dysfunction during sepsis, but its association with neonatal and pediatric sepsis remains insufficiently characterized. This systematic review and meta-analysis compared circulating Ang-2 concentrations in patients with sepsis and non-septic controls. Methods: PubMed/MEDLINE, Embase, Scopus, the Cochrane Central Register of Controlled Trials, and Google Scholar were searched through September 5, 2026. Eleven studies were included in the systematic review. Random-effects meta-analysis pooled standardized mean differences (SMDs). Risk of bias was assessed using the Newcastle–Ottawa Scale, and certainty of evidence using GRADE. Results: Five studies involving 545 participants (460 with sepsis and 85 controls) contributed to the primary meta-analysis. Ang-2 concentrations were higher in patients with sepsis (SMD, 1.54; 95% CI, 0.91–2.18; p < 0.00001), with substantial heterogeneity (I² = 75%). Excluding one study yielded a similar estimate (four studies; SMD, 1.41; 95% CI, 0.74–2.09; I² = 78%). An expanded seven-study sensitivity analysis incorporating graph-derived estimates produced an SMD of 3.86 (95% CI, 2.01–5.70; I² = 97%). Certainty of evidence was very low. Conclusion: Circulating Ang-2 concentrations were elevated in pediatric sepsis compared with non-septic controls. However, substantial heterogeneity and very low-certainty evidence limit clinical interpretation. Further prospective studies are needed to establish its diagnostic and prognostic utility.