Association between Use of Prophylactic Indomethacin and the Risk for Bronchopulmonary Dysplasia in Extremely Preterm Infants

Abstract

Objective To assess the association between prophylactic indomethacin and bronchopulmonary dysplasia (BPD) in a recent, large cohort of extremely preterm infants. Study design Retrospective cohort study using prospectively collected data for infants with gestational ages < 29 weeks or birth weights of 401–1000g born between 2008 and 2012 at participating hospitals of the National Institute of Child Health and Human Development Neonatal Research Network. Infants treated with indomethacin in the first 24 hours of life were compared with those who were not. Study outcomes were BPD, defined as use of supplemental oxygen at 36 weeks postmenstrual age among survivors to that time point, death, and the composite of death or BPD. Pre-specified subgroup analyses were performed. Results Prophylactic indomethacin use varied by hospital. Treatment of a patent ductus arteriosus (PDA) after the first day of life was less common among 2,587 infants who received prophylactic indomethacin compared with 5,244 who did not (21.0% vs. 36.1%, p<0.001). After adjustment for potential confounders, use of prophylactic indomethacin was not associated with higher or lower odds of BPD (OR 0.89, 95% CI 0.72–1.10), death (OR 0.80, 95% CI 0.64–1.01), or death or BPD (OR 0.87, 95% CI 0.72–1.05). The only evidence of subgroup effects associated with prophylactic indomethacin were lower odds of death among infants with birth weights above the 10th percentile and those who were not treated for a PDA after the first day of life. Conclusions Prophylactic indomethacin was not associated with either reduced or increased risk for BPD or death.

Diagnosis and Management of Patent Ductus Arteriosus

“…(34) Despite successful reduction in short-term outcomes (IVH, pulmonary hemorrhage, hypotension, symptomatic PDA, need for ligation), long-term benefits are uncertain and infants may needlessly be exposed to a potentially harmful agent. (3)(35)(36)(37)(38)(39) On the other hand, NICUs with consistent, high-level use of a prophylactic strategy (40) or an echocardiography guided selective approach to prophylactic treatment (41) may have improved outcomes or less drug exposure. Well-designed studies are needed to clarify the risks/benefits of this approach.…”

“…Although PDA is associated with CLD, there is limited evidence to suggest that early pharmacologic closure improves incidence of CLD. (40)(45) Pharmacologic closure is associated with decreased pulmonary edema and improved alveolarization (in premature baboons). This may be due at least in part to a direct effect on the lung.…”

Treatment and Nontreatment of the Patent Ductus Arteriosus: Identifying Their Roles in Neonatal Morbidity

“…Although many factors may contribute to the lack of improvement in the incidence of BPD, it is interesting to note that this has occurred during the same time interval that PDA treatment has been in decline (1–3, 52). It is also noteworthy that neonatal centers that regularly use prophylactic indomethacin as part of their admission care have significantly lower rates of BPD and BPD/Death than centers that only consider PDA treatment later in the neonatal hospitalization (53). …”

Prophylactic Indomethacin Revisited

“…In this volume of The Journal , Jensen et al 36 revisit the question of the missing benefits of PDA prophylaxis on BPD. They acknowledge the low likelihood that large placebo-controlled trials of prophylactic indomethacin will be repeated and instead analyzed 5 years of data from 35 hospitals in the Neonatal Research Network’s (NRN) registry of prospectively collected trial data.…”

“…These results are unexpected, given the current perceptions that the use of indomethacin prophylaxis is declining and its use is not supported by the existing literature. 32 For example, approximately 28% of US and 30% of French neonatal intensive care units use prophylactic indomethacin, whereas only 8% of eligible infants in Canadian nurseries receive prophylactic treatment 36–39 ; prophylaxis rates throughout Europe and Asia may be even lower. 40–42 The authors of the present study performed a post-hoc analysis to address the asymmetric rates of prophylaxis use.…”