In this study, spanning two consecutive time periods, we found no significant differences in the rates of BPD, sepsis, ROP, neurologic injury or mortality between infants treated with early PDA surgery compared with those treated more conservatively (with surgical ligation only if the PDA became hemodynamically significant following indomethacin treatment failure). We observed a decrease in risk for NEC in the conservatively treated infants. Although a more conservative approach still resulted in eventual surgical ligation in the majority of infants, a significant number of infants did not receive surgery prior to hospital discharge, and several had spontaneous closure of their PDA despite initial indomethacin failure.
Our study was not a randomized controlled trial because we were unable to find any neonatal units where the medical and nursing staffs felt that they could successfully randomize and implement the two different surgical approaches concurrently without introducing significant bias into their treatment decisions. Therefore, we evaluated the effects of a change in practice between two consecutive time periods. Even though our study cannot provide definitive evidence for the benefits of one treatment over the other, there are several features of our study that enable us to have some confidence in the associations that we observed: (a) during the years bracketed by our study there appeared to be no significant changes in our study population in the incidence of perinatal and neonatal risk factors (except for clinical chorioamnionitis) or in the incidence of neonatal morbidities (compare Periods 1 and 2 - ); nor were there changes in our protocols for prophylactic indomethacin, feeding advances or ventilator management during these Periods; (b) a treatment approach was uniformly applied to all infants during a study Period (i.e., none of the infants during Period 2 were treated with an Aggressive treatment approach, and vice versa during Period 1); and (c) multivariate statistical models were used to adjust for potential differences between the two treatment approaches that might be due to differences in the period of birth or in other perinatal or neonatal risk factors.
For our study, we chose a “conservative” treatment approach that contained an option for ligation if symptoms of cardiopulmonary compromise developed. Although some authors have argued that any benefits derived from PDA ligation are outweighed by the risks of ligation (10
), we did not feel that there was enough evidence to completely abandon the use of ligation: Numerous studies have demonstrated that infants with clinical and radiographic signs of pulmonary edema have improvement in their lung compliance following surgical ligation (32
). In addition, the only RCTs that have examined the issue of PDA ligation versus no intervention at all
to close a persistent PDA, found that significant pulmonary morbidity occurred in the group that was not allowed to have their PDA ligated when signs of congestive failure developed (8
Currently, there are no RCTs that address the pros or cons of continuing enteral feeding in the presence of a PDA. Hemodynamic studies have shown that a PDA decreases mesenteric blood flow during both fasting and fed states (36
) and population-based, retrospective, observational studies have found an association between the presence of a PDA and NEC (11
). Currently, 70% of neonatologists in the United States believe that enteral feedings need to be stopped in the presence of a symptomatic PDA (22
). In our study, infants treated with the “conservative” approach received enteral feedings despite the presence of a PDA. It is interesting to note that the rate of NEC among infants treated with the “conservative” approach was decreased compared with the infants treated with early surgery. This finding appears to support the feeding approach used by neonatologists outside of the United States (70% of whom believe that enteral feedings should continue in the presence of a symptomatic PDA) (22
Despite our desire to avoid ligation in infants treated with the “conservative” approach, 72% of the infants ultimately met ligation criteria and were ligated during the neonatal period. The likelihood that infants would meet ligation criteria during the neonatal period was inversely related to their gestational age. Infants born at 24-25 weeks gestation were much more likely to meet ligation criteria (81%) than those born at 26-27 weeks (56%). The ligation rate continued to drop among more mature infants: only 14% of infants born at 28-29 weeks gestation, who were managed with the same conservative treatment approach (after failing to close their PDA with indomethacin), ultimately met ligation criteria (data not shown).
Although most of the conservatively treated immature infants ultimately met ligation criteria, there was a significantly longer delay (13±8 days) before the ligation was performed (compared with infants ligated during the early surgery period (2.4±2.3 days)). The delay in ligation may be beneficial because accumulating evidence suggests that several of the morbidities associated with ligation (hypotension and need for inotropic support (17
), vocal cord paralysis (15
), and bronchopulmonary dysplasia (18
)) are significantly reduced when ligation is delayed.
In conclusion, we examined the effects of a conservative approach to PDAs that fail to close after indomethacin treatment. We found that a conservative approach (that tolerates the presence of a PDA as long as signs of cardiopulmonary compromise do not develop) is associated with a 28% decrease in the rate of ductus ligation and lower rates of NEC. These findings support the need for new controlled, randomized trials to reexamine the benefits and risks of different approaches to PDA treatment in the modern era.