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 ≤27^6/7 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) (risk ratio = 0.68, CI: 0.46-0.89) and BPD or death (risk ratio= 0.78, CI: 0.62-0.95) than conservative infants. There were no differences between the epochs in death, intraventricular hemorrhage grades 3 and 4, necrotizing enterocolitis, or retinopathy of prematurity 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.

Conclusions: PINDO decreases BPD and BPD or death compared with delayed conservative PDA management. These effects are mediated by closure of the PDA.

Keywords: bronchopulmonary dysplasia; necrotizing enterocolitis; newborn; premature birth; retinopathy of prematurity.

Figure 1. Weekly incidence of Moderate-to-Large PDA shunts in the Prophylactic and Conservative Epochs

Infants were considered to have had a moderate-to-large shunt during the first week if the PDA was moderate-to-large on day 7. Infants were considered to have had a moderate-to-large shunt during each of the subsequent weeks (weeks 2–8) if the PDA was moderate-to-large for at least 4 days of the indicated week.

Figure 2. Incidence of BPD or BPD/Death when the PDA is still persistently moderate-to-large on day 7, day 15 and during the 4^th postnatal week

The likelihood of developing BPD or BPD/Death is examined in infants whose ductus is constricted by 7 days after birth and compared with those whose PDA is still moderate-to-large at 7 days (see Echo at 7d). Similarly, the likelihood of developing BPD or BPD/Death is examined in infants whose ductus was moderate-to-large at 7 days and was still moderate-to-large at 15 days (see Echo at 5d) or during the 4^th postnatal week (see Echo during 4^th week).