Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for this review and scientific analysis, which provides a new perspective on current care practices for the management of patent ductus arteriosus in premature newborns.

I have a few minor comments that you will find in the attached file.

Comments for author File: Comments.pdf

Author Response

Reviewer #1: “Thank you for this review and scientific analysis, which provides a new perspective on current care practices for the management of patent ductus arteriosus in premature newborns. I have a few minor comments that you will find in the attached file.”

 

Answers: We would like to thank the reviewers for their helpful comments that helps us improve the manuscript.

 

Reviewer #1: “The literature review is very well structured and documented, however, I am surprised that the TREOCAPA study is not cited. Prophylactic Treatment of Patent Ductus Arteriosus With Acetaminophen: A Randomized Clinical Trial - PubMed This is a recent international randomized phase 2/3 clinical trial in which 778 patients born between 23 and 28 weeks of gestational age were included, and which aimed to evaluate the administration of prophylactic acetaminophen versus placebo on survival without severe neonatal morbidity at 36 weeks postmenstrual age. The results of this study did not support the use of prophylactic acetaminophen and therefore agree with your conclusions. In my opinion, this reference must be cited.”

 

Answer: We thank the reviewers for bringing this important study up. We agree that this large-scale international trial is essential to the current debate. We have now incorporated the TREOCAPA trial throughout the manuscript, including:

• A detailed discussion of its prophylactic acetaminophen results in Section 11.
  • “The TREOCAPA trial, an international phase 2/3 trial involving 43 NICUs across 14 European countries, specifically addressed whether prophylactic acetaminophen increased survival without severe morbidity at 36 weeks’ postmenstrual age. The trial utilized a loading dose (20-25 mg/kg) followed by maintenance doses for 5 days, stratified by gestational age (23-26 weeks and 27-28 weeks). Ultimately, the results did not support the use of prophylactic acetaminophen for improving survival without severe neonatal morbidity, aligning with findings from NSAID-based trials that early active closure does not necessarily translate to improved clinical outcomes.”
• An analysis of its contribution to the evidence base for infants <26 weeks' GA in Section 8.
  • “The TREOCAPA trial included 803 infants born between 23 and 28 weeks’ gestation, with specific dosing regimens tailored for the 23-26 week subgroup to ensure adequate assessment of efficacy and safety in the most immature patients. Despite this optimized pharmacological approach, the trial found that prophylactic acetaminophen did not increase survival without severe morbidity (defined as BPD grade 3, NEC stage II/III, IVH grade III–IV, or cystic leukomalacia) compared to placebo. Notably, the trial results suggest that even if early pharmacological intervention facilitates more frequent ductal closure, such anatomical success is clinically inconsequential as it fails to improve major neonatal outcomes or survival in this population.”

 

Reviewer #1: “Furthermore, there is no mention or comparison of the different strategies for treating PDA: prophylactic, early, or later. Do you have an opinion on this issue?”

 

Answer: We would like to thank the reviewers for their helpful comments that helps us improve the manuscript. We will clarify the distinctions between prophylactic, early targeted, and conservative strategies in Section 5:

• “Management strategies for the PDA are generally categorized by the timing and indication for intervention: prophylactic, early targeted, and conservative (expectant) management. Prophylactic treatment involves the administration of pharmacological agents (typically indomethacin) within the first hours of life, regardless of clinical symptoms or echocardiographic findings, to prevent IVH or facilitate early closure. Early targeted treatment relies on echocardiographic screening within the first 24 to 72 hours of life to identify a 'hemodynamically significant' PDA in asymptomatic or minimally symptomatic infants, with the goal of preventing later complications. Finally, conservative or expectant management prioritizes supportive care and allows for the natural evolution of the ductus, reserving intervention only for infants who demonstrate persistent, severe respiratory failure or hemodynamic instability later in the clinical course. While early active strategies aim to mitigate the perceived risks of prolonged ductal exposure, recent high-quality evidence from trials such as BeNeDuctus and Baby OSCAR increasingly suggests that these approaches may not provide the intended clinical benefits compared to a more conservative paradigm.”

 

Reviewer #1: “You place the principle of “primum non nocere” at the center of your analysis, which is indeed crucial in medicine, and even more so in neonatal intensive care. However, this precautionary principle also applies to the use of corticosteroids, whose long-term effects can be harmful: this is worth pointing out.”

 

Answer: We thank the reviewer for this suggestion. We agree that "primum non nocere" must be applied to all interventions including to corticosteroid use; we have added a cautionary note in Section 15.

• “Ultimately, while corticosteroids may indirectly facilitate ductal closure and provide significant respiratory benefits for infants at high risk for BPD, their potential for long-term neurodevelopmental impairment necessitates a cautious approach. They should be reserved for high-risk populations where the potential for reducing severe chronic lung disease clearly outweighs the risks associated with treatment, avoiding indiscriminate use in lower-risk infants where potential harm may exceed benefit.”

 

Reviewer #1: “In paragraph 5 (Reassessing Pharmacological Closure Strategies), you do not mention the effects of PDA treatment on ventilation duration and average length of stay, yet these are important data: have you analyzed them?”

 

Answer: We thank the reviewer for this suggestion. We have updated Section 5 to reflect the lack of effect on ventilation duration and length of stay.

• “Furthermore, pharmacological attempts at closure have largely failed to demonstrate a consistent reduction in the duration of mechanical ventilation or the total length of hospital stay across major randomized controlled trials.”

 

Reviewer #1: “Finally, I believe it is essential for any neonatal treatment or procedure to have long-term follow-up data, but this seems to be lacking in the case of PDA management. You mention the 24-month follow-up of the Baby OSCAR and BeNeDuctus trials concerning neurodevelopment, but it is regrettable that longer-term data are not available, particularly in regard to renal function. Indeed, NSAIDs could have renal consequences in childhood and beyond, and these data should be collected.”

 

Answer: We would like to thank the reviewers for their helpful feedback that helps us improve the manuscript. We have expanded Section 4.6 to acknowledge the critical need for long-term renal follow-up data following NSAID exposure.

• “Furthermore, a critical limitation in the current evidence base for PDA management is the absence of long-term follow-up data regarding renal health beyond the neonatal period. While trials such as Baby OSCAR and BeNeDuctus have provided essential 24-month neurodevelopmental follow-up, similar longitudinal assessments of renal function are significantly lacking. Given that NSAID exposure in extremely preterm infants is associated with acute kidney injury and potential renal and vascular remodeling, these agents may have clinical consequences that persist into childhood and beyond. The collection of long-term data is therefore essential to fully understand the life-course implications of pharmacological PDA closure strategies on renal and cardiovascular health.”

Reviewer 2 Report

Comments and Suggestions for Authors

This is a very comprehensive review of a very much still debated subject and is well written. My comments are as follows:

• while the English is obviously very good, some additional proof reading is required
• the RCT section seems to burdensome and in my opinion could be more concise
• I think it would be best if it would be more clear on which closure strategy the review is about, because I had trouble following the plot line. In our centre, for instance, PDA closure is always individually assessed and is in no way routine, and from my reading of the review, you are discussing early routine closure. I think this needs to be expressed more clearly.

Comments on the Quality of English Language

Some proof reading is required.

Author Response

Reviewer #2: “This is a very comprehensive review of a very much still debated subject and is well written.”

 

Answer: We would like to thank the reviewers for their helpful feedback that helps us improve the manuscript.

 

Reviewer #2: “My comments are as follows: while the English is obviously very good, some additional proof reading is required”

 

Answer: We thank the reviewer for noting that further proofreading would be beneficial. We have carefully re‑examined the manuscript and have implemented minor additional edits to enhance clarity, consistency, and overall readability.

 

Reviewer #2: “the RCT section seems to burdensome and in my opinion could be more concise”

 

Answer: We agree with the reviewer. To address the burden of the RCT section, we have streamlined the narrative in Section 6 and consolidated the results in Table 7.

• “Multiple randomized controlled trials (RCTs), consolidated in Table 7, consistently demonstrate that early active PDA intervention does not significantly improve survival or reduce major morbidities compared to expectant management. Well-designed RCTs are structured to minimize biases and balance known and unknown confounders - factors that observational studies cannot fully control. As illustrated in Figure 4, the evidence from these major trials highlights a consistent lack of benefit for the composite outcomes of death or BPD, further supporting the shift away from routine early pharmacological treatment.”

 

Reviewer #2: “I think it would be best if it would be more clear on which closure strategy the review is about, because I had trouble following the plot line. In our centre, for instance, PDA closure is always individually assessed and is in no way routine, and from my reading of the review, you are discussing early routine closure. I think this needs to be expressed more clearly.”

 

Answer: We thank the reviewer for this suggestion. We have explicitly stated in the Introduction that the review focuses on early routine closure.

• “Specifically, our reassessment centers on the practice of early routine pharmacological closure, defined as systematic attempts to initiate ductal closure in the first days of life, as compared to the growing paradigm of individualized expectant or conservative management.”