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Ibuprofen for hemodynamically significant patent ductus arteriosus in extremely preterm infants: a target trial
Ai-Min Qian1,2, Ai-Ling Su3, Lei Du4
1Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China.
Insights
Early ibuprofen for hemodynamically significant patent ductus arteriosus (hsPDA) in extremely preterm infants showed reduced mortality in intolerant infants, but not in tolerant ones. Further trials are needed to confirm these findings.
Area of Science:
- Neonatal Medicine
- Pediatric Cardiology
- Pharmacology
Background:
- Management of hemodynamically significant patent ductus arteriosus (hsPDA) in extremely preterm infants is controversial.
- Early intervention strategies require evaluation for clinical impact.
Purpose of the Study:
- To assess the association of early ibuprofen treatment for hsPDA with clinical outcomes in extremely preterm infants.
- To investigate if clinical tolerance to PDA modifies the effect of ibuprofen.
Main Methods:
- Prospective cohort study of infants with gestational age ≤29+6 weeks and hsPDA.
- Target trial emulation with inverse probability of treatment weighting.
- Stratification based on clinical tolerance to PDA-related hemodynamic changes.
Main Results:
- Overall, ibuprofen showed a non-significant trend towards lower mortality (RR 0.51).
- In intolerant infants, ibuprofen was associated with significantly reduced mortality (RR 0.18).
- In tolerant infants, ibuprofen was not associated with a significant change in mortality (RR 0.96).
Conclusions:
- The effect of early ibuprofen for hsPDA in extremely preterm infants is heterogeneous.
- Clinical tolerance appears to be a modifying factor in the association between ibuprofen and mortality.
- Findings are exploratory and require validation in larger randomized controlled trials.
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.
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