Active pharmacotherapy versus expectant management of patent ductus arteriosus in extremely preterm infants: a meta-analysis with trial sequential analysis.
OBJECTIVES To assess the effectiveness and safety of active pharmacotherapy for patent ductus arteriosus (PDA) initiated based on echocardiography-criteria versus expectant management in extremely preterm infants <29 w gestation in the first three weeks of life. STUDY DESIGN Systematic review with meta-analysis and trial sequential analysis (TSA). We searched PubMed, Embase, CENTRAL and Emcare for randomised trials published between 2010 and May 2026. We synthesised results using random-effects meta-analysis and conducted a TSA. PATIENTS Extremely preterm infants with PDA considered as significant on echocardiography. INTERVENTIONS Pharmacotherapy versus expectant management. MAIN OUTCOME MEASURES Mortality by 36 weeks postconceptional age or before discharge and chronic lung disease (CLD). RESULTS We included 12 trials involving 2344 extremely preterm infants. Meta-analysis found increased risk of mortality with active pharmacotherapy (RR 1.34, 95% CI 1.08 to 1.67; p=0.008, I2=0%; 12 randomised controlled trials (RCTs)). Number-needed-to-treat for an additional harmful outcome (i.e. mortality) was 25 (95% CI 17 to 100). On TSA conducted with the stringent alpha error 3.3% and beta 10%, the cumulative Z-score touched the O'Brien-Fleming monitoring boundary at the current sample size, supporting the meta-analysis findings under the specified TSA assumptions.For CLD, meta-analysis showed little or no difference (RR 0.99, 95% CI 0.92 to 1.06, p=0.74, I2=14%, 12 RCTs). The certainty of evidence was high for mortality and moderate for CLD. CONCLUSIONS In extremely preterm infants, active pharmacotherapy for PDA based on current echocardiographic criteria in the first three weeks of life was associated with increased mortality with a clinically important number needed to harm. These findings should inform treatment decisions and discussions with parents while ongoing research seeks to identify infants who may benefit from treatment. PROSPERO REGISTRATION NUMBER CRD420261303992.