PDA Treatment Strategy and Pulmonary Hemorrhage Risk in Very Low Birth Weight Infants: A Nationwide Cohort Study

Background/Objectives: Pulmonary hemorrhage (PH) is a life-threatening complication of prematurity associated with patent ductus arteriosus (PDA). Whether PDA treatment timing reduces PH risk remains uncertain because treatment strategies reflect underlying illness severity. We examined PH risk across recorded PDA treatment strategy categories in a national very low birth weight (VLBW) cohort. Methods: We analyzed Korean Neonatal Network (KNN) registry data (2013-2024) using propensity score inverse probability weighting (IPW) to compare recorded PDA treatment strategies among VLBW infants. Sensitivity analyses addressed treatment-opportunity bias, temporal confounding, and positivity violations. Results: Among 23,500 VLBW infants, 1179 (5.0%) developed PH. PH rates were 4.5% (pre-symptomatic), 10.0% (symptomatic treated), 12.3% (symptomatic untreated), 9.9% (prophylactic), and 2.3% (asymptomatic untreated). In IPW analyses, pre-symptomatic treatment consistently showed lower PH risk versus symptomatic treatment (OR 0.57, 95% CI 0.46-0.72) and symptomatic untreated PDA (OR 0.51, 95% CI 0.39-0.66), across sensitivity analyses. Prophylactic treatment showed higher PH risk than pre-symptomatic treatment (OR 1.97, 95% CI 1.31-2.96) and did not differ from symptomatic treatment. Subgroup analyses showed stronger associations in moderately preterm infants, with significant effect modification by gestational age (interaction p = 0.011) and birth weight (interaction p = 0.007). Conclusions: In this national VLBW cohort, infants with a recorded pre-symptomatic PDA treatment strategy had lower observed pulmonary hemorrhage rates compared with those receiving symptomatic treatment, after propensity score adjustment. Prophylactic treatment was not associated with lower PH risk compared with symptomatic treatment but showed higher PH risk than pre-symptomatic treatment. Given the observational design and absence of PH event timing data, causal inferences cannot be drawn. These hypothesis-generating findings support prospective evaluation of risk-based, pre-symptomatic PDA treatment strategies and do not support universal prophylaxis as a pulmonary hemorrhage prevention measure in VLBW infants.