The best treatment for the management of hemodynamically significant patent ductus arteriosus in preterm neonates : a network meta-analysis and risk-benefit analysis

Abstract

Various pharmacological treatments are available for preterm infants with patent ductus arteriosus (PDA) but their risks and benefits are controversial. This study aimes to identify the best treatment of PDA using network meta-analysis (NMA) and risk-benefit assessment (RBA). Relevant randomized controlled trials (RCTs) were identified from MEDLINE, Scopus, and Cochrane Library untill March 2019. RCTs were eligible if they studied in preterm (gestational age < 37 weeks) or low-birth-weight infants (weight < 2500 g) with pre-symptomatic PDA and hemodynamically significant PDA (hsPDA) compared to any pair with any dose/route of pharmacological treatments. The final outcomes were PDA-closure for benefit and any serious adverse effects (SAE) e.g., death, bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, or retinopathy of prematurity. An NMA was used to estimate the relative risks of treatment effects. For the RBA, an incremental risk-benefit ratio (IRBR) was calculated by diving the incremental risk by benefit using data from NMA, and they were further jointly simulated using Monte Carlo methods with 1000 replications. A risk-benefit acceptability curve was constructed at varying acceptability thresholds. Sixtyone RCTs with hsPDA were eligible considering 15 different interventions. The NMA indicated that four interventions yielded high PDA closure and low SAE, i.e., a high dose of oral ibuprofen (HOB), standard dose of oral acetaminophen (SOA), oral ibuprofen (SOB), and continuous infusion of ibuprofen (SIBdrip) in comparison with indomethacin. In addition, given an acceptable threshold of 25%, i.e., having one SAE out of four PDA-closure, HOB had 72.40% (69.52, 75.15) being the highest probability of NCB, followed by SOA (68.40 (65.42, 71.27)), SOB (63.10 (60.02, 66.10)), and SIBdrip (59.60 (56.48, 62.66)). There were inadequate studies for pooling data of pre-symptomatic PDA. Trade-off RBA indicated that HOB, SOA, and SOB might be the treatments of choice for hsPDA for short-term clinical outcomes. Optimal high doses and long-term outcomes are needed to study further.