Meta-Analysis to Assess Efficacy and Safety of High-Dose Ibuprofen Compared with Standard Treatment of Patent Ductus Arteriosus in Premature Infants

Background: Patent ductus arteriosus (PDA) is a common congenital heart defect in premature infants. Intravenous injection of ibuprofen is used for PDA treatment, but its optimum dose, efficacy, and safety are unclear.
Objectives: This meta-analysis aimed to access randomized controlled trials that compared high- or low-dose ibuprofen with a standard dose of ibuprofen for closure of PDA in preterm infants.
Methods: The standard search methods of the Cochrane neonatal review group were used to screen ibuprofen versus indomethacin trials. All groups that used ibuprofen in those trials were filtered out. The high-dose group was defined as those using an average dose of ibuprofen greater than or equal to 10 mg/kg in the first three days.
Results: We identified 14 studies of good methodological quality comparing ibuprofen to indomethacin trials among neonates. Results showed that high-dose ibuprofen could remarkably raise the closure rate (relative risk = 0.90, 95% CI = [0.81, 1.00], P = 0.04). No significant differences were found in adverse effects, bleeding disorders, or oliguria. The closure rate in neonates with PDA increased with the ibuprofen dosage (R² = 0.9990). The loading dose produced a significant closure rate compared with the low-dose group (relative risk = 1.91, 95% CI = [1.25, 2.92], P = 0.003), with no increase in toxic side effects.
Conclusions: Loading dose is a necessary strategy for infants with PDA. A high dose of ibuprofen for PDA closure was more effective than a normal dose of ibuprofen. The side effects in both treatment groups were not significantly different. Given the small sample size and risk of bias in all trials, the tolerability and safety of the dose regimen should be assessed in a large population before considering the use of these doses for PDA.