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Original Investigation
January 3, 2017

Comparative Effectiveness of Nonsteroidal Anti-inflammatory Drug Treatment vs No Treatment for Patent Ductus Arteriosus in Preterm Infants

Author Affiliations
  • 1Department of Pediatrics, The Ohio State University College of Medicine and Nationwide Children’s Hospital, Columbus
  • 2Center for Perinatal Research, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio
  • 3Department of Economics, The Ohio State University, Columbus
  • 4Center for Human Resource Research, The Ohio State University, Columbus
  • 5Department of Epidemiology and Biostatistics, University of California–San Francisco
  • 6Department of Pediatrics, University of California–San Francisco
JAMA Pediatr. Published online January 3, 2017. doi:10.1001/jamapediatrics.2016.4354
Key Points

Question  Is nonsteroidal anti-inflammatory drug treatment of all preterm infants born at 28 weeks or younger with patent ductus arteriosus effective at reducing mortality and chronic lung disease?

Findings  This cohort study that incorporated naturally occurring practice variation to reduce unmeasured confounding and included 12 018 preterm infants born at 28 weeks or younger found no significant association between nonsteroidal anti-inflammatory drug treatment and mortality or moderate to severe bronchopulmonary dysplasia.

Meaning  For preterm infants born 28 weeks or younger with patent ductus arteriosus, our findings agree with the available randomized trial evidence and support a conservative approach to patent ductus arteriosus management.


Importance  Patent ductus arteriosus (PDA) is associated with increased mortality and worsened respiratory outcomes, including bronchopulmonary dysplasia (BPD), in preterm infants. Nonsteroidal anti-inflammatory drugs (NSAIDs) are efficacious in closing PDA, but the effectiveness of NSAID-mediated PDA closure in improving mortality and preventing BPD is unclear.

Objective  To determine the effectiveness of NSAID treatment for PDA in reducing mortality and moderate/severe BPD at 36 weeks postmenstrual age.

Design, Setting, and Participants  This cohort study included 12 018 infants born at 28 gestational weeks or younger discharged between January 2006 and December 2013 from neonatal intensive care units in 25 US children’s hospitals included in the Pediatric Health Information System. We performed an instrumental variable analysis that incorporated clinician preference–based, institutional variation in NSAID treatment frequency to determine the effect of NSAID treatment for PDA on mortality and BPD.

Exposures  Proportion of NSAID-treated infants born at each infant’s institution within ±6 months of that infant’s birth.

Main Outcomes and Measures  The primary composite outcome was death, moderate, or severe BPD at 36 weeks postmenstrual age.

Results  Of the 6370 male and 5648 female infants in this study, 4995 (42%) were white, 3176 (26%) were African American, 1823 (15%) were Hispanic, and 1555 (13%) were other races/ethnicities. The proportion of NSAID-treated infants at each infant's hospital within ±6 months of that infant's birth was associated with NSAID treatment and not associated with gestation, race/ethnicity, or sex. An infant’s chances of receiving NSAID treatment increased by 0.84% (95% CI, 0.8-0.9; P < .001) for every 1% increase in the annual NSAID treatment percentage at a given hospital. An instrumental variable analysis demonstrated no association between NSAID treatment and the odds of mortality or BPD (odds ratio, 0.94; 95% CI, 0.70-1.25; P = .69), mortality (odds ratio, 0.73; 95% CI, 0.43-1.13; P = .18), or BPD (odds ratio, 1.01; 95% CI, 0.73-1.45; P = .94) in survivors.

Conclusions and Relevance  When we incorporated clinician preference–based practice variation as an instrument to minimize the effect of unmeasured confounding, we detected no changes in the odds of mortality or moderate/severe BPD among similar preterm infants born at 28 weeks or younger following NSAID treatment for PDA initiated 2 to 28 days postnatally. Our findings agree with available randomized clinical trial evidence and support a conservative approach to PDA management.