Efficacy and safety of high versus standard dose ibuprofen for patent ductus arteriosus treatment in preterm infants: A systematic review and meta-analysis

BACKGROUND: Several small randomized controlled trials (RCTs) and observational studies have compared high (15-20/7.5-10/7.5-10 mg/kg/dose) versus standard dose (10/5/5 mg/kg/dose) ibuprofen for patent ductus arteriosus (PDA) closure, with limited evidence on efficacy and safety. OBJECTIVE: To systematically review and meta-analyze studies of high versus standard dose ibuprofen for the closure of PDA in preterm infants. METHODS: Databases were searched for RCTs and observational studies assessing high compared to standard dose of ibuprofen for PDA closure for preterm infants until August 2021. The primary outcome was failure of PDA closure after the first course of ibuprofen. The secondary outcomes were the failure of PDA closure after a second course of ibuprofen, rates of PDA ligation, all-cause mortality prior to hospital discharge, bronchopulmonary dysplasia, necrotizing enterocolitis, bleeding disorders, oliguria, and serum creatinine after treatment. RESULTS: There were 6 studies with 369 patients (3 RCT, N= 190; 3 observational studies, N= 179). Compared to standard dose, high dose ibuprofen did not significantly decrease the failure rate of PDA closure in preterm infants after the first course (Relative risk (RR) 0.74, 95% confidence interval (CI) 0.53 - 1.03, 6 studies, N= 369). High dose ibuprofen significantly decreased the rates of PDA ligation compared to standard dose (RR 0.33, 95% CI 0.16 - 0.70, 5 studies, N= 309). INTERPRETATION: Based on low-grade evidence, high dose ibuprofen may more effectively reduce rates of PDA ligation compared to standard dose with no increase in adverse effects, neonatal morbidities and mortality.