Synergistic Association of Prematurity and Preoperative Anemia with Neonatal Postoperative Mortality

BACKGROUND: Prematurity and anemia are common and clinically significant risk factors among neonates undergoing surgery. However, the burden of postoperative mortality associated with their combined effects remains unquantified. We aimed to determine the proportion of neonatal postoperative mortality attributable to their synergistic interaction. METHODS: We conducted a retrospective cohort study using the ACS NSQIP-P database to identify neonates (≤28 days) who underwent noncardiac inpatient surgery between 2012 and 2023. Prematurity was defined as gestational age <37 weeks, and anemia as preoperative hematocrit <40%. Neonates were grouped by prematurity and anemia status. Propensity score weighting was used to adjust for confounding. Robust Poisson regression estimated adjusted relative risks (aRR) for 30-day mortality. Additive interaction was evaluated using the relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (SI). RESULTS: Among 29,281 neonates, 9.7% (n=2853) were both preterm and anemic. Overall, 30-day postoperative mortality was 3.2% (932/29,281), highest among preterm anemic neonates (12.1%; 344/2853). Compared to full-term, nonanemic neonates, the aRR for mortality was 1.66 (95% CI, 1.31–2.10; P < .001) for full-term anemic, 2.94 (95% CI, 2.42–3.58; P < .001) for preterm nonanemic, and 4.63 (95% CI, 3.80–5.64; P < .001) for preterm anemic neonates. RERI was 1.03 (95% CI, 0.29–1.77; P = 0.01), AP was 0.22 (95% CI, 0.08–0.37; P < .01), and SI was 1.40 (95% CI, 1.09–1.79; P = 0.01), indicating significant synergy. CONCLUSIONS: Prematurity and preoperative anemia synergistically increase the risk of postoperative mortality in neonates. These findings support targeted preoperative optimization and improved perioperative risk stratification in this high-risk population.