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Original Investigation
July 2, 2018

Association of Early Inhaled Nitric Oxide With the Survival of Preterm Neonates With Pulmonary Hypoplasia

Author Affiliations
  • 1Division of Neonatal Medicine, Mayo Clinic, Rochester, Minnesota
  • 2Department of Child Health, University of Arizona, Phoenix
  • 3Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
  • 4Center for Research, Education and Quality, Pediatrix Medical Group, Sunrise, Florida
JAMA Pediatr. 2018;172(7):e180761. doi:10.1001/jamapediatrics.2018.0761
Key Points

Question  Does early treatment with inhaled nitric oxide improve survival in extremely preterm neonates diagnosed with pulmonary hypoplasia?

Findings  This cohort study compared outcomes within a propensity score–matched cohort of neonates born at less than 29 weeks’ gestation with respiratory failure and a clinical diagnosis of pulmonary hypoplasia who were or were not treated with inhaled nitric oxide. Treatment during the first week of life was not significantly associated with improved in-hospital survival, even among neonates with a concomitant diagnosis of pulmonary hypertension.

Meaning  There may not be a benefit to prescribing inhaled nitric oxide to extremely preterm neonates with pulmonary hypoplasia, whether or not pulmonary hypertension is also suspected.


Importance  Pulmonary hypoplasia affects a very small percentage of preterm neonates, but its presence is associated with high rates of mortality.

Objective  To determine whether treatment with inhaled nitric oxide during the first week of life was associated with improved in-hospital survival in a cohort of extremely preterm neonates with pulmonary hypoplasia.

Design, Setting, and Participants  This cohort study used data from the Pediatrix Medical Group’s Clinical Data Warehouse, a data set containing information from more than 350 neonatal intensive care units in 35 US states and Puerto Rico. Since inhaled nitric oxide was not randomly prescribed, we used 1-to-1 propensity score matching to reduce the imbalance of measured covariates between the 2 treatment groups. The initial, unmatched cohort included singleton neonates who were born between 22 and 29 weeks’ gestation, had a birth weight of 400 g or more, were diagnosed with pulmonary hypoplasia as a cause of their respiratory distress, remained free of major anomalies, and were discharged between January 1, 2000, and December 31, 2014. We defined exposure as the initiation of inhaled nitric oxide on day t in days 0 to 7 of the life of a neonate. Each exposed neonate was matched 1-to-1 to a neonate who had not initiated inhaled nitric oxide on a given day.

Main Outcomes and Measures  The primary outcome was mortality defined as death prior to transfer or discharge home. Secondary outcomes were any-stage necrotizing enterocolitis, retinopathy of prematurity requiring treatment, chronic lung disease, and periventricular leukomalacia.

Results  Among 92 635 neonates in our study sample, we identified 767 (0.8%) with pulmonary hypoplasia who met all study inclusion criteria, of whom 185 (0.2%) were exposed to inhaled nitric oxide. Among 151 matched pairs of exposed and unexposed neonates, we did not identify a significant association between inhaled nitric oxide use and mortality (hazard ratio [HR], 0.79; 95% CI, 0.57-1.11). Subgroup analyses of neonates with and without persistent pulmonary hypertension (PPHN) likewise revealed no significant association between inhaled nitric oxide use and mortality (pulmonary hypoplasia with PPHN: HR, 0.67; 95% CI, 0.45-1.01; pulmonary hypoplasia without PPHN: HR, 1.11; 95% CI, 0.61-2.02), but these findings may have been influenced by ascertainment bias.

Conclusions and Relevance  Early treatment with inhaled nitric oxide is not associated with improved survival among extremely preterm neonates with pulmonary hypoplasia. Clinical trials are warranted to clarify the matter.