Impact on mortality of inhaled nitric oxide in newborns ≤34 weeks with early hypoxemic respiratory failure: systematic review and meta-analysis

Introduction: Inhaled nitric oxide (iNO) is approved for hypoxemic respiratory failure (HRF) associated with pulmonary hypertension (PH) in term and near-term neonates; however, its use in preterm infants ≤34 weeks’ gestation remains controversial, with limited and inconsistent evidence of survival benefit. Objective: To evaluate the association between iNO use and mortality in preterm neonates ≤34 weeks’ gestation. Methods: A systematic review and meta-analysis were conducted following PRISMA 2020 guidelines. Major databases were searched up to October 11, 2025. Observational studies and clinical trials reporting mortality in preterm infants with early HRF treated with iNO were included. A random-effects meta-analysis was performed. Results: Nineteen studies were included in the qualitative synthesis, and six (n = 556 infants) in the meta-analysis. Study quality ranged from poor to good, with limitations related to confounding and heterogeneity. No significant reduction in mortality was observed with iNO compared with standard care (RR 0.65; 95% CI 0.29–1.48; I² = 55.7%). Infants receiving iNO were more severely ill at baseline. A positive oxygenation response was associated with improved outcomes and varied by gestational age (GA), timing of PH onset, echocardiographic confirmation, and hypoxemia severity. Conclusions: Current evidence regarding the survival benefit of iNO in preterm infants ≤34 weeks remains inconclusive. Impact: This systematic review and meta-analysis show that inhaled nitric oxide (iNO) is not associated with a consistent reduction in mortality in preterm infants ≤34 weeks at the population level. It adds evidence that outcomes are strongly influenced by clinical context, particularly, illness severity, gestational age, timing of pulmonary hypertension onset, echocardiographic confirmation, and response to therapy. These findings support a selective, phenotype-driven approach rather than routine iNO use in all preterm infants with hypoxemic respiratory failure. The results may inform clinical decision-making and highlight the need for well-designed randomized trials in this high-risk population.