From pulmonary to ocular protection: rethinking inhaled nitric oxide in preterm infants with pulmonary hypertension

Abstract

Persistent pulmonary hypertension of the newborn (PPHN) and retinopathy of prematurity (ROP) are traditionally regarded as distinct morbidities in preterm infants, yet both share common antecedents such as oxygen instability, hyperoxia, and inflammation. Inhaled nitric oxide (iNO) is established as first-line therapy for PPHN, but its broader impact on extra-pulmonary vascular development has remained uncertain. In a nationwide U.S. study, Cho et al. reported that PPHN was independently associated with an increased risk of ROP, and that iNO administration in infants with PPHN was linked to a reduced incidence of severe ROP. Our Japanese cohort studies complement these findings by showing that PPHN independently predicted long-term visual impairment, even after adjusting for severe ROP, and that coexistence with bronchopulmonary dysplasia further amplified ocular risk. In contrast, post-acute iNO use beyond the first week of life, typically in infants with established severe lung disease, was not associated with improved neurodevelopmental or visual outcomes. Together, these observations suggest that PPHN represents a systemic vascular phenotype and that the impact of iNO depends critically on timing and pathology. Integrating pulmonary and ocular outcomes in both clinical management and research may reframe PPHN therapy as multi-organ protection for extremely preterm infants.

Impact

• This Commentary highlights the emerging recognition of persistent pulmonary hypertension of the newborn (PPHN) as a systemic vascular risk phenotype that links pulmonary and ocular outcomes in preterm infants.

• By integrating evidence from U.S. population data and Japanese cohort studies, it emphasizes the phase-specific effects of inhaled nitric oxide (iNO) on both pulmonary and retinal health.

• The article reframes PPHN management as a strategy for multi-organ protection and underscores the importance of future prospective trials that include visual outcomes alongside traditional respiratory and survival endpoints.