Indomethacin Prophylaxis for Preterm Infants: The Impact of 2 Multicentered Randomized Controlled Trials on Clinical Practice

Abstract

Objectives-Two multicentered RCTs in premature infants TIPP, 2001) found beneficial effects of indomethacin prophylaxis on the incidences of patent ductus arteriosus (PDA), PDA ligation, and severe intracranial hemorrhage (ICH). The Ment-trial recommended its use. The TIPP-trial failed to find a benefit in its primary outcome (improved survival/ neurodevelopmental outcome). This negative result may have discouraged prophylactic indomethacin use.Study Design-We used the NICHD Neonatal Network Registry to determine the association between the two trials and the use of prophylactic indomethacin. We also statistically assessed the assumptions that led to the TIPP trial's negative results.Results-Use of prophylactic indomethacin among Network clinicians increased after publication of the Ment-trial and decreased after the TIPP-trial. Analysis of the TIPP-trial showed that the primary outcome's anticipated effect size (≥20%) was too large; a smaller effect size (<3%) would have been more appropriate based on the incidence of ICH in their population, and its association with neurodevelopmental outcome.. Conclusions-Two multicenteredRCTs were associated with changes in indomethacin prophylaxis. Following the Ment-trial, its use increased. Following the TIPP-trial, which reported negative results based on too large an anticipated effect size, its use decreased.

Impact of Sepsis on Neurodevelopmental Outcome in a Swiss National Cohort of Extremely Premature Infants

“…16,29 In contrast, sepsis represents a partially preventable disease. Studies in adults, children, and neonates have shown that institutional protocols, such as care bundles, if applied correctly, can significantly reduce nosocomial infections.…”

Reflections of the changes in patent ductus arteriosus management during the last 10 years

“…However a consistent lack of demonstrable improvement in neonatal and neurodevelopmental outcomes has sparked an existential debate regarding the role of ductal closure therapies in the neonatal intensive care unit 3 23. Trials of pharmacological agents have demonstrated improved PDA closure rates and a decrease in symptomatic PDA and surgical ligation, though they were conducted within a clinical practice paradigm of early diagnosis and treatment.…”

Patent ductus arteriosus in the preterm infant: to treat or not to treat?

“…The reason for the lack of long-term beneficial effects despite a decrease in the incidence of severe IVH is not clear, but has, among others, been attributed to an excessively large anticipated effect size. 34 The third reason for the controversy is that the medications most commonly used to close the PDA are not without significant side effects. Fortunately, the adverse renal side effects and inhibition of platelet aggregation are, in the vast majority of the cases, transient.…”