An early PDA is not always a benign entity
We read with interest the article by Rolland et al regarding a retrospective natural history study of the PDA in a cohort of preterm infants in a unit which conservatively managed the presence of a PDA after 24 hours(1). We have concerns about the data analysis and the conclusions drawn. In particular we question the decision to exclude infants who died within the first 72 hrs and the subsequent exclusion of infants who died, due to inability to determine the date of PDA closure. Out of the total cohort (103 infants) 12 died and were excluded in the first 72 hrs and a further 13 subsequently died and were excluded meaning that almost 25% of the cohort died without having their ductal status documented. As the authors themselves acknowledge, a significant number of these infants died from complications that may be related to a PDA, including pulmonary haemorrhage, intraventricular haemorrhage, unresponsive respiratory or multisystem failure and NEC. It is misleading to exclude these from the natural history cohort and this approach by other authors in the past has led to a potential misrepresentation of the harm that may occur as a result of a persisting DA. There are several published natural history series showing significant and strong associations with morbidity and mortality if all-cause mortality is left in the cohort for analysis purposes(2,3). Of the total group of 103 infants in this study only 59 (57%) have certain documentation of ductal closure. The balance of 44 infants either died (26 infants) or did not have spontaneous closure documented using the gold standard of an echocardiogram. 7 infants had a persisting PDA at discharge which is of itself not a benign outcome with potential for increased mortality in the first year(2) and a possible requirement for surgical closure. If it is assumed that all of the unaccounted for patients had a PDA, the spontaneous closure rate is actually only 57% - 16% lower than that reported in the conclusion of this paper of 73%. The premise of Rolland et al is that early ductal shunting is not important, whereas work by our group suggests that the first 24-48 hours may be the most important time for ductal related morbidity. Lack of early assessment of the hemodynamic effects of a PDA in the first 72 hrs of life often results in failure to recognise the association between early PDA and morbidity/mortality. There is clear benefit to early/prophylactic treatment of a significant PDA including reduced pulmonary haemorrhage and intraventricular haemorrhage(4). We have recently published a trial of targeted early treatment vs placebo demonstrating reduction in pulmonary haemorrhage and reduced later treatment of PDA(5). Benefits from later treatment after 3 days are less clear and as identified by many authors should be the subject of well performed RCT's. Performing a cohort study and excluding infants who have uncertain ductal status and suffer an adverse outcome is problematic. An alternative conclusion to the data presented is that a significant number of infants in this cohort died from potential duct related complications such as pulmonary haemorrhage and that earlier identification and treatment may have avoided this. Concluding from the data presented that the exposure to the risk of therapeutic intervention to close a PDA is not warranted based on spontaneous closure rates of a selected surviving sub-group is not justified.
References: 1] Rolland A, Shankar-Aguilera S, Diomand? D et al. Arch Dis Child Fetal Neonatal Ed Published Online First: 28 August 2014 doi:10.1136/archdischild-2014- 306339 2] Noori S. McCoy M. Friedlich P et al. Failure of ductus arteriosus closure is associated with increased mortality in preterm infants. Pediatrics 2009;123(1):e138-44. 3] Sellmer A, Vandborg Bjerre J,T+Rahbek Schmidt M et al. Morbidity and mortality in preterm neonates with patent ductus arteriosus on day 3. Arch Dis Child Fetal Neonatal Ed 2013 Nov;98(6):F505-10. 4] Fowlie PW, Davis PG, McGuire W. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants.[Update of Cochrane Database Syst Rev. 2002;(3):CD000174; PMID: 12137607]. Cochrane Database Syst Rev 2010;CD000174. 5] Kluckow M, Jeffery M, Gill A et al. A randomised placebo-controlled trial of early treatment of the patent ductus arteriosus. Arch Dis Child Fetal Neonatal Ed 2014;99:F99-F104.
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