Surgical ligation of the ductus arteriosus has been identified as an independent risk factor for the development of BPD in earlier observational studies (13
), even when other risk factors for BPD (like immature gestation, male sex, and necrotizing enterocolitis) have been included in the statistical model (14
). Because infants in these studies were usually ligated after exposure to a PDA, and after failing indomethacin treatment, it is difficult to know if the increased incidence of BPD is due to the ligation itself, or to other factors that may coexist in infants that require ductus ligation.
We examined the data from the controlled trial by Cassady et al because the ligated infants in the study treatment group were randomized to ligation and were not exposed to indomethacin or to a persistent PDA (12
). We hypothesized that infants in the prophylactic ligation group would have a higher incidence of BPD because they had more surgical ligations than infants in the control group. The original report of this trial concluded that prophylactic ductus ligation reduced the incidence of necrotizing enterocolitis, but had no effect on the incidence of BPD (12
). We re-examined the original data set, using as our definition of BPD a supplemental oxygen requirement at 36 weeks postmenstrual age (which includes both moderate and severe forms of BPD) (13
). We found that BPD was more common among infants in the prophylactic ligation group. We also found that the most severe form of BPD (infants that still required mechanical ventilation at 36 weeks postmenstrual age) was significantly higher in the prophylactic ligation group. These findings are even more striking when one considers that the incidence of necrotizing enterocolitis (a known risk factor for BPD) was significantly higher in the control group, and that more than half of the infants in the control group also underwent PDA ligation (although, at a later time than in the prophylactic ligation group (). Infants who were eligible for this study were the sickest of the ELBW infants (12
). Fifty percent did not survive to 36 weeks postmenstrual age. There was no difference between the groups in the rate of survival to 36 weeks, although mortality was high in both study groups. The incidence of BPD was higher in the prophylactic ligation group even when we examined the subpopulations that survived to 36 weeks postmenstrual age.
The present study may be criticized for comparing prophylactic surgery with later surgery. If so, we may be understating the potential deleterious effects of surgical ligation on the lungs. It is also possible that later surgery may not have the same deleterious effects as early surgery. It should be noted, however, that all four of the infants in the Control group that required supplemental oxygen at 36 weeks postmenstrual age had undergone ductus ligation. Therefore, although PDA ligation decreased the incidence of necrotizing enterocolitis in this trial, it also significantly increased the risk of moderate/severe BPD.
An important caveat needs to be mentioned if one tries to extrapolate our results to present day clinical care. The study patients in the original trial differed in many ways from today’s neonatal population. They were not exposed to prenatal steroids and did not receive surfactant or indomethacin. A large proportion were also small-for-gestational age. In addition, changes in perinatal management, fluid management, ventilation strategies, and advances in early nutrition, etc, may limit the applicability of our findings to the present day.
On the other hand, ductus ligation is associated with several known morbidities: thoracotomy, post-operative myocardial dysfunction (24
), hypotension (25
), pneumothorax (16
), chylothorax, and infection. In addition, the incidence of unilateral vocal cord paralysis (which increases the requirements for tube feedings, respiratory support and hospital stay) has been recognized recently in a significant proportion of infants following PDA ligation (26
). Neonatal transport to another facility may also be necessary if skilled surgeons are not readily available. Ductus ligation, while eliminating one potential cause for neonatal morbidity, may thus introduce another set of problems.
Our results should not be used as justification for abandoning surgical ligation as a treatment for PDA. Ligation can improve pulmonary function and lessen the burden of BPD when the alternative is prolonged exposure to a moderate/large PDA shunt (1
). Our findings suggest that although prophylactic ductus ligation eliminates the PDA, it may contribute to the very problem it is trying to prevent - BPD.