Prevention and 18-month outcomes of serious pulmonary hemorrhage in extremely low birth weight infants

Patent ductus arteriosus (PDA) is a risk factor for the development of pulmonary hemorrhage in preterm infants. Infants with pulmonary hemorrhage may often have worse short- and long-term outcomes than infants without pulmonary hemorrhage. The administration of indomethacine as a prophylactic agent may reduce the incidence of PDA by 50%, but did not reduce the rate of pulmonary hemorrhage in a large sample of 1202 extremely low birth weight (ELBW) infants included in the Trial of Indomethacin Prophylaxis in Preterms (TIPP). However, it has been hypothesized that the inclusion of mild cases of pulmonary hemorrhage into this trial may have masked a beneficial effect of prophylactic indomethacin. Mild hemorrhages were characterized prospectively as blood-tinged tracheal aspirates that did not require any change in therapy. Therefore, traumatic airway management rather than high pulmonary blood flow as a result of a PDA may have been responsible for mild cases of pulmonary hemorrhage in the TIPP study.
Based on such considerations, the TIPP investigators have conducted a post-hoc analysis of the previous results, excluding all mild cases of pulmonary hemorrhage, in order to determine the effect of prophylactic indomethacin on the cumulative risk for serious pulmonary hemorrhage (i.e. requiring increased ventilator and/or oxygen support or transfusion of blood products). A second objective was to compare the outcomes at a corrected age (CA) of 18 months in infants with and without a serious pulmonary hemorrhage. A poor outcome was defined as death or survival with neurosensory impairment (≥1 among the following: cerebral palsy, cognitive delay, blindness, deafness).
A total of 123 (10.2%) of 1202 ELBW infants developed a serious pulmonary hemorrhage. During week 1, prophylactic indomethacin reduced the risk for serious pulmonary hemorrhage by 35%; however, when considering the entire stay in the neonatal intensive care unit (NICU), the risk for such hemorrhages was decreased by only 23%. A reduced risk for patent ductus arteriosus explained 80% of the beneficial effect of prophylactic indomethacin on serious pulmonary bleeds. The analysis of outcomes at a CA of 18 months indicated that the risks for death or for survival with neurosensory impairment were doubled after a serious pulmonary hemorrhage.
In this analysis, a reduced risk for PDA explained most of the favorable effect of prophylactic indomethacin on the prevention of serious pulmonary hemorrhage, thus confirming the important role of PDA in the pathogenesis of pulmonary hemorrhage. Moreover, these data suggest that ductal closure is the most likely mechanism for the observed risk reduction of serious pulmonary bleeds after indomethacin prophylaxis.
In conclusion, ELBW infants with serious pulmonary hemorrhage may have an increased risk for poor long-term outcome. Prophylactic indomethacin reduces the rate of early serious pulmonary hemorrhage, mainly through its action on patent ductus arteriosus. However, indomethacin prophylaxis may be less effective in preventing serious pulmonary hemorrhages that occur after the first week of life.

Top