ObjectivesTo describe the typical clinical course of reversible PPHN from perinatal etiologies and compare that with the clinical course of PPHN due to underlying fetal developmental etiologies. Study designThis was a single-center, retrospective cohort study of liveborn newborns either born or transferred to our facility for higher level of care between 2015 through 2020 with gestational age ≥35 weeks and a clinical diagnosis of PPHN in the electronic health record (EHR). Newborns with complex congenital heart disease and congenital diaphragmatic hernia were excluded. Using all data available at time of collection, newborns were stratified into 2 groups by PPHN etiology – perinatal and fetal developmental causes. Primary outcomes were age at initiation, discontinuation, and total duration of extracorporeal life support (ECLS), mechanical ventilation, supplemental oxygen, iNO, inotropic support, and PGE. Our secondary outcome was age at echocardiographic resolution of pulmonary hypertension. Groups were compared by t-test. Time-to-event Kaplan Meier curves described and compared (log-rank test) discontinuation of each therapy. ResultsSixty-four (72%) newborns had perinatal etiologies whereas 24 (28%) had fetal developmental etiologies. The resolution of perinatal PPHN was more rapid compared with fetal developmental PPHN. By 10 days of age, more neonates were off inotropes (98% vs 29%, p<0.01), decannulated from ECLS (100% vs 0%, p<0.01), extubated (75% vs 37%, p<0.01), and had echocardiographic resolution of PH (35% vs 7%, p=0.02). ConclusionsAn atypical PPHN course, characterized by persistent targeted therapies in the second week of life, warrants further work-up for fetal developmental causes.