Antithrombin III use in pediatric and neonatal ECMO: A systematic review and meta-analysis

Background Antithrombin (AT) supplementation has been increasingly incorporated into pediatric extracorporeal membrane oxygenation (ECMO) anticoagulation protocols to address heparin resistance and optimize anticoagulation. However, considerable variability exists in monitoring practices, replacement strategies, and reported clinical outcomes. We performed a systematic review and meta-analysis to evaluate contemporary evidence regarding AT supplementation in pediatric ECMO. Methods A systematic search of PubMed, Embase, Scopus, and Web of Science identified studies evaluating AT monitoring or supplementation during neonatal or pediatric ECMO through September 2025. Two reviewers independently screened studies and extracted data on monitoring strategies, replacement protocols, anticoagulation parameters, thrombosis, bleeding, and mortality. Comparative studies reporting extractable dichotomous outcomes were included in random-effects meta-analyses. Results Twenty-five studies met inclusion criteria, consisting predominantly of retrospective single-center cohorts. Marked heterogeneity was observed in indications for supplementation, replacement thresholds (50-100%), therapeutic targets (60-120%), formulations, dosing strategies, and anticoagulation monitoring. AT supplementation consistently increased AT activity, improved anti-factor Xa measurements, and in several studies, reduced unfractionated heparin requirement. However, higher anti-Xa levels and increased AT activity did not consistently translate into improved clinical outcomes. Meta-analysis demonstrated no significant association between AT supplementation and thrombosis (OR 1.10, 95% 0.54-2.24), bleeding (OR 1.15, 95% CI 0.85-1.54), or mortality (OR 1.24, 95% CI 0.63-2.43). Pharmacokinetic investigations suggested standard dosing frequently underestimates replacement requirements in pediatric ECMO. Conclusion Current evidence supports the role of AT supplementation in improving laboratory markers of anticoagulation, but does not demonstrate consistent reductions in bleeding, thrombosis, or mortality. Wide variation in monitoring, dosing, and outcome definitions limits comparisons across studies. Future multicenter investigations should prioritize standardized definitions, age-specific therapeutic targets, and prospective evaluation of replacement strategies to better define the role of AT supplementation in pediatric ECMO.