Prophylactic Indomethacin Compared with Delayed Conservative Management of the Patent Ductus Arteriosus in Extremely Preterm Infants: Effects on Neonatal Outcomes

Abstract

Objective To determine whether prophylactic indomethacin (PINDO) has more or less morbidity than delayed conservative management of the moderate-to-large patent ductus arteriosus (PDA). Study design We performed a prospective double cohort controlled study of infants delivered at ≤27+6 weeks gestation (n=397). From January 2005 through April 2011, all infants were treated with PINDO (n=247). From May 2011 through August 2016 no infant was treated with indomethacin until at least 8 postnatal days (Conservative epoch, n=150). Echocardiograms were performed on day 7 and at planned intervals until the PDA was small or closed. A single neonatologist prospectively collected all data. Results The incidence of moderate-to-large PDA on day 7 and duration of exposure to moderate-to-large PDA were significantly less in the PINDO epoch (incidence=10%, median=2 days) than the Conservative epoch (incidence=67%, median=14 days). Ligation rates were low in both epochs (PINDO=14%, Conservative=5%). In multivariate analyses PINDO infants had a significantly lower incidence of bronchopulmonary dysplasia (BPD) (RR=0.68, CI:0.46–0.89) and BPD or Death (RR=0.78, CI: 0.62–0.95) than Conservative infants. There were no differences between the epochs in Death, IVH grades 3 & 4, NEC, or ROP receiving treatment. The effects of PINDO on BPD and BPD or death were no longer significant when analyses were adjusted for presence of a moderate-to-large PDA on day 7. The significant effects of PINDO were independent of whether or not a ligation was performed. Conclusion PINDO decreases BPD and BPD or death compared with delayed conservative PDA management. These effects are mediated by closure of the PDA.

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.…”

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

“…Recently there have been several prospective cohort controlled trials specifically designed to examine the effects of exposure to a moderate/large PDA for greater than 8 days (49, 50). In these trials infants were treated with indomethacin to close the PDA either prophylactically or early in the first week and compared with infants in a “no treatment” group.…”

“…As was seen in the earlier RCTs, there were no differences between the “treatment” and “no treatment” groups in the rates of death, NEC, and severe ROP. On the other hand, when PDA “rescue” treatment was delayed beyond 8 days, there was a significant increase in the need for ventilator and inotropic support at the end of the first week (51), as well as an increase in the incidence of BPD and BPD/Death in the “no treatment” group (49, 50). Although “treating” the PDA early in the first week had a significant effect on decreasing the incidence of BPD and BPD/Death, each week that “rescue” treatment was delayed reduced its effectiveness in preventing the occurrence of BPD and BPD/Death (49).…”

“…During the past decade, improvements in clinical care have been associated with a decrease in the incidence of neonatal morbidities that have not been causally linked to the persistence of a PDA (e.g., death, severe IVH, NEC and severe ROP) (1, 52). On the other hand, during the same period the incidence of BPD (which has been causally linked to the presence of a PDA (12, 13, 16, 49, 50)) has remained the same or even increased (1, 3, 52). 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).…”

Hemodynamically significant patent ductus arteriosus and the development of bronchopulmonary dysplasia

“…This was associated with a significant decrease in BPD (RR 0.68, 95% CI 0.46‐0.89) and combined BPD or death (RR 0.78, 95% CI 0.62‐0.95) among infants treated with prophylactic indomethacin. However, among those infants who still had a moderate‐to‐large PDA at 7 days, there was no difference in BPD outcomes between groups . These data suggest that closure of a moderate‐to‐large PDA may reduce the risk of BPD, but only if it is successfully closed within the first week, generally before the onset of clinical signs.…”