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

Introduction

Patent ductus arteriosus (PDA) is one of the most common cardiovascular conditions in extremely preterm infants. A hemodynamically significant PDA (hsPDA) can lead to pulmonary overcirculation and systemic hypoperfusion and has been associated with an increased risk of prematurity-related morbidities and mortality (1-3). The optimal management of PDA in preterm infants—particularly whether early pharmacological treatment should be initiated—has challenged neonatologists for more than five decades and remains one of the most controversial issues in neonatology (4,5).

Numerous randomized controlled trials (RCTs) have evaluated pharmacological treatment for PDA but have failed to demonstrate that ductal closure improves clinical outcomes in preterm infants (6-13). Although recent RCTs have adopted increasingly rigorous designs, marked and strongly held differences in clinical opinion regarding PDA treatment persist, resulting in a lack of sufficient clinical equipoise and substantial challenges in patient recruitment. Consequently, a considerable proportion of eligible infants—particularly those at higher risk—have not been enrolled in randomization (6,8,14). As a result, infants enrolled in prior RCTs may have disproportionately represented those for whom PDA had a relatively limited impact on clinical outcomes, such that ductal closure was unlikely to confer a measurable benefit (14).

Clinically, extremely preterm infants exhibit interindividual variability in their tolerance to PDA-related hemodynamic changes. While most infants are able to tolerate the hemodynamic effects of PDA, a subset develop cardiopulmonary instability due to inadequate compensation and require higher levels of respiratory or hemodynamic support. These clinically intolerant, high-risk infants may have been underrepresented in prior RCTs, and whether they benefit from pharmacological treatment remains unclear.

Accordingly, we used prospective cohort data from the Chinese Multicenter Collaboration Platform for PDA in Extremely Preterm Infants (CMCP-PDA) to emulate a target trial evaluating the association between early ibuprofen treatment for hsPDA and clinical outcomes in extremely preterm infants. We further conducted subgroup analyses based on infants’ clinical tolerance to PDA-related hemodynamic changes, with the aim of identifying subpopulations that may derive benefit from pharmacological treatment and of informing targeted therapeutic strategies and the design of future randomized trials. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0017/rc).

Methods

Data source

This study employed a target trial emulation design based on a multicenter prospective cohort. Data were derived from the CMCP-PDA cohort, which has been registered with the Chinese Clinical Trial Registry (ChiCTR2400091371). The CMCP-PDA cohort was established to investigate the epidemiology and management of PDA in extremely preterm infants in China, to address ongoing clinical controversies regarding the identification of infants who may benefit from PDA treatment, and to promote collaborative quality improvement and multicenter clinical research. The CMCP-PDA cohort was initiated on November 1, 2024, and prospectively enrolled all preterm infants with a gestational age ≤29⁺⁶ weeks who were admitted to participating centers within 3 days after birth. Clinical data were prospectively collected using the REDCap electronic data capture system. The database comprehensively captured neonatal demographic characteristics, maternal perinatal factors, laboratory findings, therapeutic interventions, and major neonatal morbidities. Echocardiographic assessments were systematically performed on postnatal days 3–5 to evaluate PDA-related hemodynamic characteristics, with concurrent recording of the level of respiratory and hemodynamic support at the time of assessment. A total of 13 tertiary neonatal intensive care units participated in CMCP-PDA, including 3 pediatric specialty hospitals and 10 maternal and child health hospitals, all of which are large tertiary centers with established capacity for the care of extremely preterm infants in China. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Institutional Ethics Committee of the Children’s Hospital of Nanjing Medical University (No. 202406018-1), and informed consent was obtained from all individual participants’ legal guardians.

Quality control

CMCP-PDA employed a standardized data entry manual, and all data abstractors at participating centers received standardized training. The electronic data capture system incorporated automated input validation and error-checking functions to ensure standardized and consistent data collection across sites. The CMCP-PDA coordinating center (Children’s Hospital of Nanjing Medical University) performed regular audits of data accuracy and completeness across participating centers and provided timely feedback to maintain data quality. Additionally, standardized echocardiography protocols were developed based on the 2024 American Society of Echocardiography guidelines for targeted neonatal echocardiography in the neonatal intensive care unit (15) and Practical Neonatal Echocardiography, edited by Siassi (16). These protocols included detailed echocardiographic operating procedures and standardized forms for PDA assessment and measurement (Table S1). Echocardiographic examinations were performed as targeted neonatal echocardiography, primarily by physicians specialized in neonatal cardiac ultrasonography and, in some centers, by trained neonatologists. In all cases, image acquisition and interpretation were performed by the same physician at each center. All participating sonographers underwent dedicated training to ensure consistency and adherence to standardized echocardiographic techniques across centers.

Patients

All preterm infants with a gestational age ≤29⁺⁶ weeks admitted to CMCP-PDA-participating centers within 3 days after birth between November 1, 2024, and September 30, 2025 were assessed for eligibility. Infants were eligible for inclusion if they underwent echocardiographic assessment on postnatal days 3–5 and were diagnosed with hsPDA. Infants were excluded if they were transferred to non-CMCP-PDA hospitals, received pharmacological treatment for PDA prior to echocardiographic assessment, died on the day of echocardiography, or had contraindications to pharmacological PDA therapy. Contraindications included a platelet count <50×10⁹/L on admission, intraventricular hemorrhage (IVH) grade ≥3, necrotizing enterocolitis (NEC) stage ≥ II, or spontaneous intestinal perforation occurring before or on the day of echocardiography. hsPDA was defined according to Clyman’s echocardiographic criteria as a ductal diameter ≥1.5 mm with left-to-right shunting in combination with one or more of the following: ductal flow velocity ≤2.5 m/s; a left atrial-to-aortic root diameter ratio ≥1.5; or absent or reversed diastolic flow in the descending aorta (17). The study sample size was determined by accrual within the CMCP-PDA cohort.

Target trial emulation

Time zero

Time zero was defined as the day of echocardiographic assessment on postnatal days 3–5. To emulate the eligibility and exclusion process of a RCT, infants were required to meet all inclusion criteria at time zero. Infants who had received pharmacological treatment for PDA prior to time zero, died at time zero, or had contraindications to pharmacological treatment were excluded.

Grace period

Given that pharmacological treatment for PDA is not routinely initiated immediately after echocardiographic assessment in clinical practice, a 2-day grace period was specified.

Treatment strategies and assignment

Across all participating CMCP-PDA centers, initial pharmacological treatment for PDA consisted of oral ibuprofen, administered at a dose of 10 mg/kg on the first day, followed by 5 mg/kg on each of the subsequent two days. Other pharmacologic agents for PDA, including acetaminophen/paracetamol or indomethacin, were not used as initial treatment during the study period. Infants were classified into the treatment group or the non-treatment group according to whether ibuprofen was initiated within the grace period. Treatment assignment was defined based on the grace period and was not altered by any subsequent pharmacologic treatments. Inverse probability of treatment weighting (IPTW) was applied to balance baseline characteristics between groups and emulate random treatment assignment.

Follow-up and outcomes

All infants were followed until death or discharge from the neonatal intensive care unit. Outcomes included mortality, IVH grade ≥3, NEC stage ≥ II, bronchopulmonary dysplasia (BPD) grade ≥2, death or BPD grade ≥2, and a composite outcome of death, IVH grade ≥3, NEC stage ≥II, or BPD grade ≥2.

Target trial emulation design and participant assignment

A schematic illustration of the target trial design and participant assignment pathways is presented in Figure 1.

Figure 1 Target trial emulation design and participant assignment. IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis; PDA, patent ductus arteriosus; SIP, spontaneous intestinal perforation.

Subgroup analysis

Clinical tolerance to hsPDA was prespecified as a potential effect modifier, based on the physiological concept that the clinical consequences of ductal shunting depend not only on echocardiographic characteristics, but also on the infant’s ability to tolerate the resulting cardiopulmonary load. Infants requiring escalation of respiratory or hemodynamic support are more likely to experience clinically significant PDA-related compromise. Therefore, subgroup analyses were performed according to tolerance status (intolerant vs tolerant) to evaluate whether treatment effects differed by clinical tolerance. The intolerant subgroup was defined as infants unable to tolerate the hemodynamic effects of hsPDA at the time of echocardiography, operationalized by a requirement for higher levels of respiratory or hemodynamic support. Specifically, infants were classified as intolerant if they required conventional mechanical ventilation with a fraction of inspired oxygen (FiO₂) >30%, high-frequency ventilation regardless of FiO₂, or one or more vasoactive-inotropic agents to maintain blood pressure. The tolerant subgroup comprised infants who tolerated the hemodynamic effects of hsPDA and required only noninvasive respiratory support, or conventional mechanical ventilation with FiO₂ ≤30%, without the need for vasoactive-inotropic support. Vasoactive-inotropic agents included dopamine, dobutamine, epinephrine, norepinephrine, and vasopressin.

Definitions

IVH was defined and graded according to Papile criteria (18). NEC was defined and staged according to Bell criteria (19). BPD was defined and graded according to Jensen criteria (20). BPD grade ≥2 was defined as a requirement for supplemental oxygen via nasal cannula (>2 L/min), noninvasive positive pressure ventilation, or invasive mechanical ventilation at 36 weeks’ postmenstrual age or at discharge to home, whichever occurred first. Small for gestational age was defined as a birth weight below the 10th percentile for gestational age and sex. Clinical risk index for babies II (CRIB-II) score was calculated using sex, gestational age, birth weight, temperature, and base excess on admission (21). Antenatal corticosteroids were defined as receipt of a partial or complete course of antenatal corticosteroids prior to delivery. Chorioamnionitis was diagnosed based on clinical findings and/or histopathological examination.

Statistical analysis

Categorical variables were presented as frequencies and percentages, and continuous variables were summarized as medians with interquartile ranges (IQRs) because they were not normally distributed. In the unweighted observational cohort, between-group comparisons for categorical variables were performed using the chi-squared test, and comparisons for continuous variables were conducted using the Mann-Whitney U test. In the weighted target trial emulation cohort, descriptive statistics were calculated using survey-weighted analytical methods to account for the weighting structure. Between-group comparisons for categorical variables were performed using the Rao-Scott adjusted Chi-squared test, with P values reported based on the Rao-Scott F statistic. Comparisons of continuous variables were conducted using weighted linear regression models to obtain weight-adjusted P values. In addition, balance in baseline characteristics between groups was assessed using standardized mean differences (SMDs), with an SMD <0.10 considered indicative of adequate covariate balance.

Because treatment allocation in this study was not randomized, estimates of the effect of pharmacological treatment may be subject to confounding. Based on prior literature and clinical expertise, potential confounders were prespecified before study initiation (22,23). These included multiple births, cesarean delivery, premature rupture of membranes >24 hours, chorioamnionitis, antenatal corticosteroids, sex, gestational age, birth weight, small for gestational age, 5-minute Apgar score, CRIB-II score, the number of surfactant administrations within 3 days of life, and the level of respiratory and hemodynamic support on the day of echocardiographic assessment. Echocardiographic variables used to define cohort eligibility were not included in the propensity score model, as they were conditioned on at the design stage.

A propensity score-based approach was applied, and a weighted target trial emulation cohort was constructed using IPTW. Propensity scores were estimated using a logistic regression model, with receipt of pharmacological treatment as the dependent variable and the prespecified confounders as independent variables. IPTW weights were calculated based on the estimated propensity scores, with weights defined as 1/propensity score for treated infants and 1/(1 − propensity score) for untreated infants, to balance baseline characteristics between groups and emulate random treatment assignment. All subsequent effect estimates were derived from the IPTW-weighted cohort. Weighted log-binomial regression was used to estimate risk ratios (RRs) and corresponding 95% confidence intervals (CIs). When log-binomial models failed to converge, weighted Poisson regression was used as an alternative. All regression analyses incorporated robust standard errors clustered by study center to account for inter-facility variation in clinical practices. In analyses of the overall cohort, no additional covariate adjustment was performed beyond weighting to estimate marginal treatment effects. In subgroup analyses, regression models were forced to adjust for four key covariates (sex, gestational age, birth weight, and CRIB-II score), with further adjustment for any additional baseline covariates that remained imbalanced after weighting.

To assess the robustness of the findings, three sensitivity analyses were performed. First, analyses were repeated in the unweighted observational cohort using generalized linear mixed models, specifying a binomial distribution with a logit link function, with study center included as a random intercept to account for clustering. Second, in the non-treatment group, a small number of infants died within 2 days after echocardiographic assessment and therefore did not reach the prespecified grace period (patient 1 in Figure 1). Classifying these infants as untreated could potentially introduce immortal time bias. Accordingly, these infants were excluded, and the analyses were repeated. Third, the length of the grace period was shortened from 2 days to 1 day after echocardiographic assessment to evaluate whether the estimated effect of pharmacological treatment remained consistent across different grace periods.

There was one missing value for chorioamnionitis in this cohort. Because this missing observation was considered likely to represent the absence of the event, the value was imputed as “no”. All statistical analyses were performed using SAS version 9.4. All tests were two-sided, and a P value <0.05 was considered statistically significant.

Results

Study population

During the study period, a total of 641 preterm infants with a gestational age ≤29⁺⁶ weeks who were admitted within 3 days after birth were enrolled across CMCP-PDA participating centers. Among these infants, 492 underwent echocardiographic assessment on postnatal days 3–5, of whom 271 (55.1%) were diagnosed with hsPDA. After excluding infants who did not meet the eligibility criteria of the target trial emulation, 239 infants were ultimately included in the analysis (Figure 2).

Figure 2 Study population. CMCP-PDA, Chinese Multicenter Collaboration Platform for PDA in Extremely Preterm Infants; GA, gestational age; IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit; PDA, patent ductus arteriosus; SIP, spontaneous intestinal perforation.

In the final analytic cohort, the median gestational age was 27.9 weeks (IQR, 26.9–29.0 weeks), and the median birth weight was 1,040 g (IQR, 890–1,235 g). Echocardiographic assessment was performed at a median postnatal age of 4 days (IQR, 3–5 days): 114 infants (47.7%) were assessed on postnatal day 3, 65 (27.2%) on day 4, and 60 (25.1%) on day 5. Within 2 days after echocardiographic assessment, 65 infants received ibuprofen treatment, whereas 174 infants did not. Among 65 treated infants, ibuprofen was initiated at a median postnatal age of 5 days (IQR, 4–5 days): 4 infants (6.2%) initiated treatment on postnatal day 3, 21 (32.3%) on day 4, 24 (36.9%) on day 5, 12 (18.5%) on day 6, and 4 (6.2%) on day 7. After construction of the weighted target trial emulation cohort using IPTW, the effective weighted sample size was 239 infants in both the treatment and non-treatment groups.

Baseline characteristics

The distribution of IPTW weights for the treatment and non-treatment groups is shown in Figure S1. The weights for both groups were distributed within the region of common support, with no evidence of extreme weights.

Maternal and neonatal baseline characteristics of the treatment and non-treatment groups in the unweighted observational cohort and the IPTW-weighted target trial emulation cohort are presented in Table 1. Baseline characteristics between the treatment and non-treatment groups in the target trial emulation cohort were well balanced, with all SMDs <0.10.

Outcomes in the target trial emulation cohort

In the IPTW-weighted target trial emulation cohort, ibuprofen treatment was associated with a lower, but not statistically significant, risk of mortality (RR, 0.51; 95% CI: 0.25–1.02; P=0.055). No statistically significant differences were observed between the treatment and non-treatment groups in the risks of BPD, IVH, NEC, or their related composite outcomes (Table 2).

Outcomes stratified by clinical tolerance subgroups

According to the prespecified clinical tolerance criteria, the study population was stratified into a tolerant subgroup (n=174, 72.8%) and an intolerant subgroup (n=65, 27.2%). Baseline characteristics in the tolerant and intolerant subgroups before and after weighting are presented in Tables S2,S3.

In the target trial emulation analyses, after IPTW with additional adjustment for key clinical covariates and any residual imbalances, ibuprofen treatment was not significantly associated with mortality in the tolerant subgroup (RR, 0.96; 95% CI: 0.23–4.00; P=0.95). In contrast, in the intolerant subgroup, ibuprofen treatment was associated with a significantly reduced risk of mortality (RR, 0.18; 95% CI: 0.06–0.51; P=0.001) (Table 3).

Sensitivity analyses

Across all sensitivity analyses—including analyses using generalized linear mixed models in the unweighted cohort, exclusion of two infants in the non-treatment group who died within 2 days after echocardiographic assessment, and shortening of the grace period from 2 days to 1 day—the direction of the results was consistent with the primary analysis. Specifically, the association between ibuprofen treatment and a reduced risk of mortality remained primarily evident in the intolerant subgroup. Detailed results of the sensitivity analyses are presented in Tables S4-S8.

Discussion

Using prospective cohort data from the CMCP-PDA, we emulated a target trial to evaluate the effects of ibuprofen treatment for hsPDA on clinical outcomes in extremely preterm infants. Our findings suggest that the treatment effect of ibuprofen among infants with hsPDA identified between postnatal days 3 and 5 was strongly modified by clinical tolerance to PDA-related hemodynamic changes. Specifically, ibuprofen treatment was not associated with improved clinical outcomes among infants who were clinically tolerant of hsPDA, whereas it was associated with a reduced risk of mortality among clinically intolerant infants.

In our cohort, the majority of infants (174/239, 72.8%) demonstrated good clinical tolerance to hsPDA-related hemodynamic changes and required only low levels of respiratory or circulatory support. Consistent with the findings of most previous RCTs (6-13) and systematic reviews (24-26), early pharmacological treatment aimed at promoting ductal constriction was not associated with improved clinical outcomes in this population. Although these infants exhibited structurally significant ductal shunting, their apparent compensatory capacity for PDA-related hemodynamic changes prevented functional impairment or clinical instability, thereby limiting the potential benefit of pharmacological treatment. Moreover, while pharmacological treatment facilitates ductal constriction, it may also be accompanied by potential adverse effects, including reduced renal and intestinal perfusion and delayed enteral feeding (1). Ultimately, this pattern mirrors that observed in most studies, with increased rates of ductal closure but without corresponding improvements in clinical outcomes.

In the intolerant subgroup, ibuprofen treatment was associated with a significantly reduced risk of mortality. Nevertheless, this observed association should be interpreted with caution. Mortality is a complex outcome influenced by multiple clinical and contextual factors, and residual confounding cannot be fully excluded in an observational setting, particularly within small subgroups. Although we applied a target trial emulation framework with IPTW to mitigate confounding, unmeasured factors related to illness severity, clinician decision-making, or center-level practices may still have contributed to the observed mortality differences. Therefore, this finding should be regarded as hypothesis-generating rather than definitive evidence of a causal survival benefit.

At first glance, this finding appears inconsistent with the conclusions of most previous studies, which have generally reported overall null effects or even suggested potential harm associated with pharmacological treatment. However, this apparent discrepancy is more likely attributable to differences in effect estimation frameworks and study population selection, rather than to fundamental contradictions in the underlying evidence.

First, few previous studies were designed to explicitly differentiate infants’ clinical tolerance to PDA shunting. Clinical intolerance was rarely incorporated as a core inclusion criterion or prespecified as an effect modifier, potentially diluting benefits among those most likely to respond (6-9). Consequently, study cohorts often comprised substantial proportions of clinically stable infants with compensated PDA-related hemodynamic changes. If only a small fraction of infants experienced cardiopulmonary instability truly attributable to PDA shunting, any treatment benefit in that subgroup could be masked in marginal (overall) effect estimates, leading to an apparent null effect despite meaningful heterogeneity. In contrast, within the hsPDA population, we further operationalized intolerance using the intensity of respiratory and circulatory support. This approach more closely aligns with bedside assessment of whether PDA is causing functional compromise, and it may therefore better identify a clinically relevant target population most likely to benefit from treatment.

Second, beyond considerations related to effect modification, substantial clinical controversy and strong practice preferences have long existed in the management of PDA. A lack of clinical equipoise among clinicians has been a major barrier to recruitment in RCTs, particularly for high-risk infants (6,14). Multiple randomized trials have shown that a large proportion of otherwise eligible infants were not enrolled in randomization due to a lack of clinical equipoise (6,8,9,13). For example, in the recent NICHD (6) and Baby-OSCAR (8) trials, the proportions of eligible infants who were not enrolled were as high as 77.3% (1,662/2,149) and 48.6% (618/1,271), respectively. Notably, in the NICHD trial, two-thirds of eligible but non-enrolled infants received pharmacological treatment outside the trial (6), suggesting that infants perceived to be at higher risk may have been underrepresented in randomized studies. Furthermore, a post hoc analysis of the PDA-TOLERATE trial revealed that eligible infants who were not enrolled due to clinicians’ lack of equipoise—but who received treatment outside the trial—had lower gestational age, required greater respiratory support, and were more severely ill overall. Despite this higher baseline risk, however, these infants exhibited significantly lower mortality than those who were actually enrolled (27). This finding further highlights the potential impact of a lack of clinical equipoise on the composition and risk profile of trial populations. Taken together, these observations suggest that, to some extent, participants enrolled in prior RCTs may have been preferentially drawn from clinically more stable and PDA-tolerant infants, rather than from those experiencing true cardiopulmonary instability attributable to ductal shunting. In contrast, our study leveraged a real-world, multicenter prospective cohort encompassing the overall population of extremely preterm infants encountered in routine clinical practice. By further conducting targeted analyses among infants who were clinically intolerant of hsPDA, we were able to reveal clinically meaningful heterogeneity in treatment effects.

From a physiological perspective, infants in the intolerant subgroup required high levels of respiratory or hemodynamic support, indicating a state of pulmonary overcirculation, systemic hypoperfusion, or markedly increased myocardial workload. This constellation likely reflects an acute hemodynamic burden imposed by PDA shunting (28). In this context, ibuprofen-induced ductal constriction may reduce left-to-right shunting and pulmonary blood flow, while also improving systemic perfusion and blood pressure stability. Among infants whose hemodynamic compensation is already limited, such changes may be more likely to translate into an early survival benefit.

At present, there is no universally accepted echocardiographic definition or optimal timing for the assessment of PDA, and substantial heterogeneity exists across previous studies (1). The echocardiographic criteria used in this study incorporated ductal characteristics, markers of pulmonary overcirculation, and indicators of systemic hypoperfusion, allowing for a comprehensive assessment of PDA-related hemodynamics. Importantly, these parameters are readily measurable in routine clinical practice and demonstrate good inter-center consistency. This study focused on PDA-related hemodynamics and treatment decisions after the ultra-acute transitional period and did not evaluate pharmacological interventions initiated within the first 72 hours of life. We defined time zero as postnatal days 3–5 for echocardiographic assessment and evaluation of clinical tolerance, based on two key considerations. First, this timing reduced the inclusion of infants undergoing spontaneous ductal constriction or closure. As observed in our cohort, approximately one-third of infants (170/492) had a small or already closed ductus at the time of echocardiographic assessment. Second, by postnatal days 3–5, pulmonary vascular resistance has typically declined in most preterm infants, facilitating the development of left-to-right shunting (29). Consequently, cardiopulmonary instability observed during this period is more likely to be attributable to PDA-related hemodynamic changes. In addition to timing-related considerations, gestational age-related physiological variability may also influence PDA natural history and treatment outcomes. Infants born at the lowest gestational ages, particularly those <25 weeks’ gestation, exhibit markedly lower rates of spontaneous ductal closure and prolonged transitional circulation. Although such infants were included in our cohort, this study was not powered to evaluate gestational age-specific treatment effects, and future studies should further explore PDA management strategies in these extremely immature populations.

A major strength of this study is the use of a multicenter, prospective, real-world cohort combined with a target trial emulation approach to construct a randomized trial-like analytic framework. By explicitly defining time zero, a grace period, and treatment strategies, this design helps mitigate time-related and selection biases that commonly affect traditional observational studies. More importantly, we further incorporated stratification by clinical tolerance, enabling focused analyses of infants who may have been underrepresented in prior studies, particularly those who are clinically intolerant of PDA-related hemodynamic changes. This allowed us to identify a potential subgroup that may derive benefit from pharmacological treatment. Several limitations should also be acknowledged. First, ibuprofen was administered orally in this study. Although no increase in NEC was observed in our cohort, other gastrointestinal adverse outcomes were not systematically assessed. As oral ibuprofen, compared with intravenous ibuprofen, may raise concerns regarding gastrointestinal complications, the absence of an intravenous ibuprofen arm limits the generalizability of our findings to other routes of administration. Second, although a target trial emulation framework was applied, residual confounding and the influence of unmeasured confounders cannot be fully excluded. Third, clinical intolerance was defined based on the intensity of respiratory and hemodynamic support, which reflects real-world clinical decision-making but may still be influenced by subjective judgment and inter-center variability. Fourth, the relatively small sample size of the clinically intolerant subgroup warrants cautious interpretation of mortality and other major morbidities, and these findings should be confirmed in future studies. Finally, mortality was analyzed as an all-cause outcome without adjudication of individual causes.

Conclusions

Our findings suggest that the effects of ibuprofen treatment for hsPDA are heterogeneous, with an association with lower mortality observed among high-risk extremely preterm infants who are clinically intolerant to PDA-related shunting, but not among clinically tolerant infants. Risk stratification based on clinical tolerance may help inform decision-making for PDA management, and future randomized trials may consider specifically targeting this clinically intolerant phenotype to further evaluate these findings.

Acknowledgments

We thank all the data abstractors from the Chinese Multicenter Collaboration Platform for PDA in Extremely Preterm Infants (CMCP-PDA). Group information of the CMCP-PDA: Children’s Hospital of Nanjing Medical University; Changzhou Maternity and Child Health Care Hospital; Nanjing Women and Children’s Healthcare Hospital; General Hospital of Ningxia Medical University; The Affiliated Hospital of Qingdao University; The First Hospital Affiliated with Shandong First Medical University; Beijing Children’s Hospital, Capital Medical University; Affiliated Women’s Hospital of Jiangnan University; Northwest Women’s and Children’s Hospital; The First Affiliated Hospital of Xinjiang Medical University; The Affiliated Hospital of Xuzhou Medical University; Children’s Hospital, Zhejiang University School of Medicine; The First Affiliated Hospital with Nanjing Medical University.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0017/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0017/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0017/prf

Funding: This work was supported by Nanjing Municipal Special Fund for Health Science and Technology Development (No. YKK23167). The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0017/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Institutional Ethics Committee of the Children’s Hospital of Nanjing Medical University (No. 202406018-1) and endorsed by all participating hospitals. Informed consent was obtained from all individual participants’ legal guardians.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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