Ibuprofen for hemodynamically significant patent ductus arteriosus in extremely preterm infants: a target trial emulation.

BACKGROUND

The optimal management of patent ductus arteriosus (PDA), particularly hemodynamically significant PDA (hsPDA), in extremely preterm infants remains highly controversial. This study aimed to evaluate whether early ibuprofen for hsPDA was associated with clinically meaningful outcomes in extremely preterm infants and whether this association was modified by clinical tolerance to PDA-related hemodynamic changes.

METHODS

This prospective cohort study used data from the Chinese Multicenter Collaboration Platform for PDA in Extremely Preterm Infants and included infants with a gestational age ≤29+6 weeks who were admitted between November 2024 and September 2025 and diagnosed with hsPDA by echocardiography on postnatal days 3-5. A target trial emulation framework was applied, with the day of echocardiography as time zero and a 2-day grace period. Ibuprofen initiation within the grace period defined treatment. Inverse probability of treatment weighting was used to balance baseline characteristics and emulate random treatment assignment. Infants were stratified as clinically tolerant and intolerant based on respiratory and hemodynamic support at the time of echocardiography. Outcomes included mortality and major prematurity-related morbidities.

RESULTS

A total of 239 infants were included, of whom 65 received ibuprofen within the grace period and 174 did not. In the overall cohort, ibuprofen was associated with a lower, but not statistically significant, risk of mortality [risk ratio (RR), 0.51; 95% confidence interval (CI): 0.25-1.02]. In analyses stratified by clinical tolerance, ibuprofen was associated with a reduced risk of mortality only in the intolerant subgroup (RR, 0.18; 95% CI: 0.06-0.51), but not in the tolerant subgroup (RR, 0.96; 95% CI: 0.23-4.00).

CONCLUSIONS

The effect of ibuprofen for hsPDA in extremely preterm infants appears heterogeneous, with differences in mortality associations observed across clinical tolerance subgroups. These findings are exploratory and warrant confirmation in future adequately powered randomized trials.