Title:Ibubrofen in the Treatment of Patent Ductus Arteriosus in Preterm Infants: What We Know, What We Still Do Not Know
Volume: 18
Issue: 21
Author(s): Isabelle Mercanti, Isabelle Ligi, Farid Boubred, Isabelle Grandvuillemin, Christophe Buffat, Laurance Fayol, Veronique Millet and Umberto Simeoni
Affiliation:
Keywords:
Patent ductus arteriosus, preterm infant, indomethacin, ibuprofen, ligation, randomized controlled trials, low gestational age infants, neurodevelopmental alteration, placebo-controlled design, NSAIDs
Abstract: The patency of the ductus arteriosus has ever been considered as a pathological situation in preterm infants and one likely
cause of mortality and morbidity, including broncho-pulmonary dysplasia, necrotizing enterocolitis, intraventricular haemorrhage, retinopathy
of prematurity. The incidence of patent ductus arteriosus is inversely proportional to gestational age and infants with the lowest
gestational ages are the most exposed to the complications of prematurity. So, associations between patent ductus arteriosus and the other
morbidities may not be causative and patent ductus arteriosus could be more a sign of immaturity and severity of disease than the cause
of these problems. Non-steroidal anti-inflammatory agents, such as indomethacin or ibuprofen, have been shown to be effective in closing
or preventing patent ductus arteriosus, with differences in side effects. However nearly all randomized controlled trials have been designed
with the closure of the ductus arteriosus, not mortality or morbidity, as the main endpoint. Thus, evidence is still lacking on the
eventual benefits for the patient of pharmacological or surgical intervention on PDA. Moreover, both ibuprofen and indomethacin efficacy
seems markedly reduced in extremely low gestational age infants, who are the most likely to benefit from such intervention. The
explanation of the reduced pharmacodymanic effect in such population is unclear; so far, studies using increased dosing of ibuprofen
have failed to show a clear benefit. Prophylaxis with indomethacin or ibuprofen has failed to show sustained benefits on neurodevelopment
at 2 years of age in low gestational age infants. New curative trials may aim at investigating the effects of early curative
administration of ibuprofen, which has reduced side effects compared to indomethacin, on immature kidney function, on mortality and
morbidity in very low gestational age infants, ideally with a combined endpoint such as survival in the absence of severe neurodevelopmental
alteration at 2 years age. Despite an understandable reluctance given the historical background of systematic, therapeutic closure
of ductus arteriosus in preterm infants, there are no definite ethical obstacles to a placebo-controlled design.
