PDA Closure Rates and Safety after Repeated Courses of Cyclooxygenase Inhibitors in Preterm Infants: A Systematic Review and Meta-Analysis

Background: Cyclooxygenase (COX) inhibitors have been used to treat hemodynamically significant patent ductus arteriosus (PDA) in preterm infants. If the PDA remains hemodynamically significant after an initial course, additional courses of COX inhibitors or surgical intervention are considered. This systematic review evaluates PDA closure rates and safety after repeated courses of COX inhibitors in preterm infants. Methods: Embase, Medline, and two other databases were searched through April 2026 (pre-registered in PROSPERO [CRD42023454003]). Studies reporting PDA closure rates after two or more courses of COX inhibitors were included. Risk of bias was assessed using Joanna Briggs Institute tools. Meta-analyses with random-effects models were performed to calculate the proportions of PDA closure. Multilevel mixed-effects meta-regression was used to compare closure rates across treatment courses while accounting for within-study correlations. Results: A total of 33 studies were included. The PDA closure rates after the first, second, and third courses of COX inhibitors were 62% (95% confidence interval [CI] 57-67%), 46% (95% CI 40-52%; p < 0.001 vs the first course), and 38% (95% CI 27-51%; p = 0.001 vs the first course), respectively. Lower closure rates with repeated courses were also observed across most subgroups (extremely preterm/extremely low birth weight, ibuprofen, indomethacin, and intravenous administration), except for the second course of oral administration. Data on adverse events were limited, preventing meta-analysis. Conclusions: PDA closure rates after the second and third courses of COX inhibitors were lower than those after the first course in preterm infants. Evidence regarding the safety of repeated courses remains limited.