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

Abstract

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 PARTICIPANTSThis 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 MEASURESThe primary composite outcome was death, moderate, or severe BPD at 36 weeks postmenstrual age. RESULTSOf 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.

Effects of practice change on outcomes of extremely preterm infants with patent ductus arteriosus

“…These data are consistent with emerging evidence in the literature. In a recent report using the Pediatric Health Information System (PHIS), examining patients born at <28 weeks gestation, Slaughter et al found no association between mortality and treatment with non‐steroidal anti‐inflammatory drugs for a PDA. Sung et al examined PDA treatment in two time periods; during the first epoch patients with a PDA were treated with indomethacin and then ligated if not closed, while during the second epoch no patient with a PDA was treated.…”

Bronchopulmonary dysplasia: A review of pathogenesis and pathophysiology

“…The answer to whether hemodynamically significant PDA is a risk factor for BPD continues to be ambiguous. However, it is clear that closure of PDA does not necessarily decrease the incidence of BPD raising doubts that the relationship between PDA and BPD is more of an association rather than causation 95,96 . In fact, some studies indicate that PDA closure by medical or surgical therapies is associated with worsening BPD 97,98 .…”

Paracetamol in Patent Ductus Arteriosus Treatment: Efficacious and Safe?

“…Results in support of conservative PDA treatment have been reported by Slaughter et al [ 132 ] in their cohort study published on January 2017 and by Letshwiti et al [ 133 ]. The first is a large study on n = 12.018 newborns (≤28 weeks' GA) affected by PDA, evaluated and treated in 25 different hospitals.…”