338 - Early treatment versus expectant management of hemodynamically significant patent ductus arteriosus (PDA) for preterm infants: update of a Cochrane Systematic Review

Publication Number: 338.4794

Souvik Mitra, University of British Columbia Faculty of Medicine, Vancouver, BC, Canada; Alexandra Scrivens, Oxford university hospitals, Oxford, England, United Kingdom; Michelle Fiander, Cochrane Neonatal Group, Halifax, NS, Canada; Timothy Disher, Dalhousie University Faculty of Computer Science, West Porters Lake, NS, Canada; Dany E. Weisz, University of Toronto, Toronto, ON, Canada

Background: Controversy exists on whether early treatment of a PDA improves clinical outcomes. We published a Cochrane review on this topic in 2020. Several large RCTs on early PDA treatment have been published since then that necessitated an update of this review.

Objective: To assess the effectiveness and safety of early treatment strategies versus expectant management for a hemodynamically significant (hs) PDA in in preterm infants.

Design/Methods: Search methods: We searched 3 databases and 2 trial registries in October 2024.
Selection criteria: We included RCTs in which early pharmacological treatment (initiated within 7 days after birth), was compared to no intervention, placebo or other non-pharmacological expectant management strategies for treatment of an hs-PDA in preterm ( < 37 weeks postmenstrual age) or low birth weight ( < 2500g) infants.
Data collection and analysis: We performed data collection and analyses as per Cochrane Neonatal standards. We used the GRADE approach to assess the certainty of evidence for selected outcomes.

Results: We included 19 RCTs (n=2297) and specified 2 comparisons: 7 RCTs (n=600) compared 'early treatment' (treatment initiated by 7 days) and 12 RCTs (n=1697) compared 'very early treatment' (treatment initiated by 72h) vs expectant management. The latter comparison included 5 new RCTs (n=1413) published after 2020.
Early PDA treatment was not associated with any difference in mortality (6 RCTs; n=500; RR 0.80, 95% CI 0.46 to 1.39; moderate certainty) or any of the important secondary outcomes. The results remain unchanged from our 2020 review (Table 1).
Very early PDA treatment was also not associated with any difference in mortality (12 RCTs; n=1797; RR 1.20, 95% CI 0.96 to 1.51; moderate certainty) overall but led to a significant reduction in interventional PDA closure (10 RCTs, n=1706, RR 0.50, 95% CI 0.32 to 0.79; high certainty) (Table 2). However, pre-specified subgroup analysis based on type of pharmacotherapy, demonstrated a significant increase in mortality with very early ibuprofen (5 RCTs, n=1271, RR 1.36, 95% CI 1.03 to 1.79) (Figure 1).

Conclusion(s): This updated Cochrane review demonstrates that overall, early or very early treatment of an hs-PDA does not improve outcomes in preterm infants. However, there is a concerning signal of increased mortality with very early use of ibuprofen within the first 3 days of birth.

Note: This abstract is based on a pre-peer review version of an update for a Cochrane Review. Upon completion and approval, the final version is expected to be published in the Cochrane Database of Systematic Reviews (www.cochranelibrary.com).

Table 1. Summary of Findings – Early treatment compared to Expectant Management for preterm infants
Explanations
(a) The CI includes appreciable benefit and harm, therefore the quality of evidence was rated down by one level for imprecision;
(b) >50% of meta-analytic weight to studies with high or unclear risk of bias in one of sequence generation, allocation concealment, or blinding. Therefore the quality of evidence was rated by one level for risk of bias;
(c) I-squared value of 59% suggests there is moderate to substantial heterogeneity that cannot be explained by subgroup differences [test for subgroup differences p=0.59]. Therefore the quality of evidence was rated down by one level for inconsistency;
(d) There was high risk of bias for blinding in 1 study and low risk of bias across multiple domains for 1 study;
(e) Does not meet the optimal information size for detecting a 25% difference in benefit or harm (assuming a two-sided alpha of 0.05 with 80% power). Therefore the quality of evidence was rated down by one level for imprecision;
(f) As there were few events from two small-sample RCTs and the CI includes appreciable benefit and harm, the quality of evidence was rated down by two levels for imprecision;
(g) The CI includes appreciable benefit favoring expectant management but crosses the threshold for no difference. Therefore the quality of evidence was rated down by one level for imprecision

Table 2. Summary of Findings – Very early treatment compared to Expectant Management for preterm infants
Explanations
(a) The CI includes appreciable benefit and harm, therefore the quality of evidence was rated down by one level for imprecision;
(b) I-squared value >80% suggesting considerable heterogeneity that cannot be explained by subgroup differences. Therefore the quality of evidence was rated down by 2 levels for inconsistency;
(c) The CI includes appreciable harm with very early treatment but crosses the threshold for no difference. Therefore the quality of evidence was rated down by one level

Figure 1. Forest plot of comparison: Very early treatment vs expectant management, outcome: All-cause mortality during hospital stay