Nirsevimab Prophylaxis and Respiratory Syncytial Virus Hospitalizations Among Infants.

Importance: Respiratory syncytial virus (RSV) is the leading cause of infant hospitalizations, and preterm infants and those with older siblings are at increased risk. Despite recommendations for nirsevimab prophylaxis, data on outcomes in high-risk infants are lacking. Objective: To assess the association of nirsevimab prophylaxis with RSV-related lower respiratory tract infection (LRTI) hospitalization risk and in-hospital severity among infants, overall and by high-risk groups. Design, Setting, and Participants: This retrospective multicenter cohort study comparing RSV seasons before (April 1, 2023, to March 31, 2024) and after (April 1, 2024, to March 31, 2025) universal nirsevimab prophylaxis implementation included all live births from 5 neonatal hospitals serving the Italian provinces of Ravenna, Faenza, Forlì, Cesena, and Rimini with no exclusions based on gestational age or comorbidities. Participants were followed up from hospital discharge until first RSV hospitalization, first birthday, or season end, with time-to-event analysis. Data from centralized electronic medical records included demographics, nirsevimab administration, and polymerase chain reaction-confirmed RSV. Exposure: Nirsevimab prophylaxis vs no prophylaxis. Main Outcomes and Measures: The primary outcome was RSV-associated hospitalization in the first year of life. The secondary outcome was LRTI severity measures-hospital length of stay, high-flow nasal cannula (HFNC) use, and intensive care unit (ICU) admission. Hierarchical Cox proportional hazards regression models (with health care center as a random effect) were used to adjust for seasonality and relevant covariates, with sensitivity analyses using multiple models and non-RSV LRTI comparisons. Results: Among 13 624 newborns (mean [SD] gestational age of 39.4 [1.8] weeks; 51.4% male, 4.8% preterm, and 49.5% with older siblings), nirsevimab prophylaxis achieved 79.2% coverage of the study population. Among 292 infants hospitalized with RSV LRTI (2.1%), fewer were in the postnirsevimab than prenirsevimab season group (72 [24.7%] vs 220 [75.3%]; P < .001), with a population-level reduction in hospitalization hazard (hazard ratio [HR], 0.32; 95% CI, 0.25-0.44; P < .001). In a separate within-month analysis comparing infants born in the same calendar month and therefore at similar baseline RSV risk, nirsevimab prophylaxis was associated with a lower hazard of RSV hospitalization (HR, 0.11; 95% CI, 0.06-0.21; P < .001). Prematurity (HR, 2.93; 95% CI, 2.11-4.07; P < .001) and living with older siblings (HR, 4.57; 95% CI, 4.15-5.03; P < .001) remained associated with higher hospitalization risk among infants who received prophylaxis. Among hospitalized infants, nirsevimab was associated with reduced HFNC use (OR, 0.33; 95% CI, 0.11-0.97; P = .04) but not with shorter stays (incidence rate ratio, 0.81; 95% CI, 0.63-1.03; P = .09). Conclusions and Relevance: In this multicenter cohort study, nirsevimab prophylaxis was associated with substantially lower RSV hospitalization risk and reduced in-hospital RSV severity, supporting its implementation as a public health strategy. However, the persistent risk associated with prematurity and household RSV exposure suggests a need for supplemental approaches to optimize RSV prevention in high-risk infants.