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

Abstract

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.

European Consensus Guidelines on the Management of Respiratory Distress Syndrome – 2019 Update

“…There are no indications for routine or rescue use of inhaled nitric oxide (iNO) in preterm babies [190]. However, iNO continues to be used particularly in the setting of PPROM and documented pulmonary hypertension based on the observation that oxygenation can be acutely improved, although evidence for improved longer term outcomes is weak [191], and there is new evidence of an association between iNO therapy and childhood cancer [192]. Until clinical trials are completed, decisions regarding use of this expensive therapy should be taken on a case by case basis and treatment stopped quickly if there is no obvious response.…”

Just Say No to iNO in Preterms—Really?

“…More recently, data from the Pediatrix Clinical Data Warehouse were examined between 2000 and 2014 for iNO use during the first week of life in infants born extremely preterm (22-29 weeks of gestation). 49 Using only diagnostic codes from billing data, diagnoses of pulmonary hypoplasia and PPHN were evaluated based on clinical impressions without any preassigned definition of lung hypoplasia or PPHN. In addition, there were no direct assessments of echocardiography data confirming the presence of PPHN physiology.…”

Birth Size and Gestational Age Specific Outcomes of Inhaled Nitric Oxide Therapy in Preterm Neonates with Clinically Diagnosed Pulmonary Hypertension

“…In this retrospective cohort study, we analyzed data prospectively collected in the Pediatrix Medical Group's (PMG) Clinical Data Warehouse (CDW). 34,[38][39][40][41][42][43][44][45][46] The study was approved by the Western Institutional Review Board (IRB) and considered exempt by the Mayo Clinic IRB (Rochester, MN). The CDW is a multicenter database generated from proprietary software that is used for standardized documentation and billing in more than 350 PMG neonatal intensive care units (NICUs) in 34 states and Puerto Rico.…”

“…Because iNO status was not randomly assigned (i.e., the drug was not prescribed at random) and could be initiated at any time during the first 7 days after birth (t ¼ 0-7), we assembled an analysis cohort that consisted of matched patients using a balanced risk set approach using propensity scores (PS). 34,46,49,50 This enabled us to match a patient receiving iNO on day t with another patient with similar baseline characteristics who had not received iNO on or before day t.…”

“…The limitations of our study include restricted sample sizes in each of the birth size and GA categories, unavailability of echocardiogram reports, and lack of specific criteria required from the providers who diagnosed RDS and PH in the course of their clinical practice. We have encountered these limitations in prior studies, 34,46,75 as they are intrinsic to the source of our data (PMG CDW). However, it is worth noting that among the PH subcohort, the rates of echocardiographic examination were similar between the iNO-exposed group and the referents, as were the rates of PDA.…”