Expectant Management or Early Ibuprofen for Patent Ductus Arteriosus

Hundscheid, Tim; Onland, Wes; Kooi, Elisabeth M. W.; Vijlbrief, Daniel C.; Vries, Willem B. de; Dijkman, Koen P.; Kaam, Anton H. van; Villamor, Eduardo; Kroon, Abraham A.; Visser, Remco; Tollenaer, Susanne M Mulder-de; Bisschop, Barbara De; Dijk, Peter H.; Avino, Daniela; Hocq, Catheline; Zecic, Alexandra; Meeus, M.T.H.; Baat, Tessa de; Derriks, Frank; Henriksen, Tine Brink; Kyng, Kasper Jacobsen; Donders, Rogier; Nuytemans, Debbie H. G. M.; Overmeire, Bart Van; Mulder, Antonius; Boode, Willem P. de

doi:10.1056/nejmoa2207418

Cited by 107 publications

(63 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although this adverse effect on vascular growth might be absent when ibuprofen is given at a later stage, it may compromise its positive effect on PDA closure. This is in line with a recent clinical trial showing that ibuprofen significantly increased the risk of BPD in infants with a PDA [60] in the absence of its anti-inflammatory and presence of its anti-angiogenic effect. In the experimental BPD pups both the anti-angiogenic and anti-inflammatory effects were present and this might explain the different findings between our and clinical studies.…”

Section: Discussionsupporting

confidence: 91%

Vascular and pulmonary effects of ibuprofen on neonatal lung development

et al. 2023

View full text Add to dashboard Cite

Background Ibuprofen is a nonsteroidal anti-inflammatory drug that is commonly used to stimulate closure of a patent ductus arteriosus (PDA) in very premature infants and may lead to aberrant neonatal lung development and bronchopulmonary dysplasia (BPD). Methods We investigated the effect of ibuprofen on angiogenesis in human umbilical cord vein endothelial cells (HUVECs) and the therapeutic potential of daily treatment with 50 mg/kg of ibuprofen injected subcutaneously in neonatal Wistar rat pups with severe hyperoxia-induced experimental BPD. Parameters investigated included growth, survival, lung histopathology and mRNA expression. Results Ibuprofen inhibited angiogenesis in HUVECs, as shown by reduced tube formation, migration and cell proliferation via inhibition of the cell cycle S-phase and promotion of apoptosis. Treatment of newborn rat pups with ibuprofen reduced pulmonary vessel density in the developing lung, but also attenuated experimental BPD by reducing lung inflammation, alveolar enlargement, alveolar septum thickness and small arteriolar wall thickening. Conclusions In conclusion, ibuprofen has dual effects on lung development: adverse effects on angiogenesis and beneficial effects on alveolarization and inflammation. Therefore, extrapolation of the beneficial effects of ibuprofen to premature infants with BPD should be done with extreme caution.

show abstract

Section: Discussionsupporting

confidence: 91%

Vascular and pulmonary effects of ibuprofen on neonatal lung development

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Personalized medicine requires an adequate characterization of endotypes and clinical phenotypes so that each infant can receive the therapeutic approach best suited to his or her individual characteristics. Finally, very recent evidence from a randomized controlled trial suggests that expectant management of PDA in extremely preterm infants was non-inferior to ibuprofen treatment with respect to moderate-to severe bronchopulmonary dysplasia, necrotizing enterocolitis, or mortality (92). Further research is warranted to elucidate whether the etiology or endotype of prematurity affects the outcome differently when PDA is managed with a non-pharmacological approach.…”

Section: Discussionmentioning

confidence: 99%

Association between endotypes of prematurity and pharmacological closure of patent ductus arteriosus: A systematic review and meta-analysis

2023

Self Cite

View full text Add to dashboard Cite

IntroductionEndotypes leading to very and extremely preterm birth are clustered into two groups: infection/inflammation and dysfunctional placentation. We conducted a systematic review of observational studies exploring the association between these two endotypes and the pharmacological closure of patent ductus arteriosus (PDA) induced by cyclooxygenase (COX) inhibitors. Chorioamnionitis represented the infectious-inflammatory endotype, while dysfunctional placentation proxies were hypertensive disorders of pregnancy (HDP) and small for gestational age (SGA) or intrauterine growth restriction.MethodsPubMed/Medline and Embase databases were searched. The random-effects odds ratio (OR) and 95% confidence interval (CI) were calculated for each association. We included 30 studies (12,639 infants).ResultsMeta-analysis showed a significant association between exposure to HDP and increased rate of pharmacological closure of PDA (17 studies, OR 1.41, 95% CI 1.10–1.81, p = 0.006). In contrast, neither chorioamnionitis (13 studies, OR 0.75, 95% CI 0.47–1.18, p = 0.211) nor SGA (17 studies, OR 1.20, 95% CI 0.96–1.50, p = 0.115) were significantly associated with the response to therapy. Subgroup analyses showed that the higher response to COX inhibitors in the HDP group was significant for indomethacin (OR 1.568, 95% CI 1.147–2.141, p = 0.005) but not for ibuprofen (OR 1.107, 95% CI 0.248–4.392, p = 0.894) or for the studies using both drugs (OR 1.280, 95% CI 0.935–1.751, p = 0.124). However, meta-regression showed that this difference between the drugs was not statistically significant (p = 0.404).Discussion/ConclusionOur data suggest that the pathologic condition that triggers prematurity may alter the response to pharmacological treatment of PDA. The DA of infants exposed to HDP appears to be more responsive to COX inhibitors.

show abstract

“…However, despite the great work and effort undertaken in the past decades to better define hemodynamic ductal significance, there is still no evidence that PDA treatment may improve the overall outcome [ 12 , 13 ]. The recent BeNeDuctus trial showed that the expectant management for PDA in extremely premature infants is non-inferior to ibuprofen therapy administered according to pre-specified echocardiographic criteria of hemodynamic significance [ 13 ].…”

Section: Targeted Neonatal Echocardiographymentioning

confidence: 99%

“…As previously mentioned TnECHO alone does not seem effective in guiding PDA treatment [ 13 ]. LUS can evaluate lung content in neonates with PDA and predict hemodynamic changes in persistent PDA [ 85 ].…”

Section: Cardiopulmonary Ultrasoundmentioning

confidence: 99%