Heterogeneity in treatment response for patent ductus arteriosus: a meta-analysis

While pharmacological interventions promote PDA closure, their impact on overall outcomes remains uncertain due to conflicting results. These inconsistent results indicate that the effectiveness of these treatments may vary considerably among preterm infants, suggesting potential heterogeneity. This meta-analysis and meta-regression aimed to assess the effect of pharmacological interventions on mortality and PDA closure in preterm infants, while critically examining sources of heterogeneity. We searched Ovid MEDLINE and EMBASE for relevant studies. Studies comparing ibuprofen, acetaminophen, indomethacin, or placebo/expectant management in preterm infants with PDA, where the outcome of interest was either mortality or PDA closure. We extracted data on mortality, PDA closure, study design, and patient baseline characteristics following PRISMA guidelines. We used a random-effects model to account for the heterogeneity observed in the studies. Meta-analysis of 72 RCTs revealed that while interventions significantly improved PDA closure rates (OR 5.31, p < 0.00001), they did not consistently reduce mortality (OR 1.03, p = 0.84). Notably, interventions appeared to increase mortality in infants with hemodynamically significant PDA (OR 1.45, p = 0.05). Our analysis revealed substantial heterogeneity (I² = 55%) and significant inconsistencies in outcome reporting across studies. Meta-regression models could not fully explain the observed variability. Potential publication bias, incomplete patient-level data, and inconsistent definitions across studies.

The substantial heterogeneity underscores the complexity of PDA and the limitations of a one-size-fits-all approach. These findings strongly support a shift toward precision medicine in PDA treatment, focusing on identifying factors that predict individual response.

• Pharmacological treatments for PDA increase closure rates but have not consistently improved survival in preterm infants. • Previous studies and meta-analyses have reported conflicting outcomes, likely driven by differences in patient characteristics and trial design.

• This study demonstrates persistent and substantial heterogeneity in both PDA closure and mortality outcomes, even after extensive stratification and meta-regression. • The findings expose the limitations of a one-size-fits all approach and support a shift toward phenotype-driven, precision medicine in PDA management.