The ductus arteriosus is a vascular structure that connects the aorta and the pulmonary artery. Essential during fetal life, it typically closes spontaneously after birth. Patent ductus arteriosus refers to the failure of ductal closure beyond the neonatal period, which is particularly common in preterm infants. The global incidence of PDA in preterm neonates ranges from 50% to 70%, reaching up to 80% in very-low-birth-weight neonates. Ductal patency in preterm infants results in left-to-right blood flow shunting. This shunt between the systemic and pulmonary circulations leads to pulmonary hyperperfusion with cardiac chamber overload and simultaneous systemic hypoperfusion, a phenomenon commonly referred to as “ductal steal.” Thus, the failure of early ductus arteriosus closure in preterm infants is associated with an increased risk of comorbidities such as intraventricular hemorrhage, necrotizing enterocolitis, pulmonary hemorrhage, and bronchopulmonary dysplasia, among others.
To date, the management of PDA in preterm neonates remains a contentious issue in perinatal and neonatal medicine. Historically, therapeutic approaches for PDA included active interventions such as pharmacological or surgical closure. However, over the past two decades, a conservative management strategy has gained popularity, emphasizing avoidance of potentially harmful drugs or surgical procedures. Recently, a new perspective has emerged: prolonged pulmonary overcirculation caused by hsPDA has detrimental effects on the pulmonary vascular bed, increasing the risk of bronchopulmonary dysplasia and pulmonary hypertension. Hence, is active treatment of hsPDA justified? If so, should surgical closure be performed? And, what is the optimal timing for intervention?
To address these questions, the article under discussion conducted a single-center retrospective observational study involving very-low-birth-weight preterm neonates (<1500 g) with haemodynamically significant PDA who received active treatment between September 2014 and March 2021. Exclusion criteria included the absence of echocardiographic evaluation during hospitalization, major congenital anomalies, death within the first 48 hours of life, and critical intrauterine or perinatal illness. The decision for hsPDA closure was based on clinical and echocardiographic criteria. Pharmacological closure was achieved using intravenous or oral ibuprofen. Surgical closure was considered in cases where pharmacological treatment failed or was contraindicated and was performed via left posterior thoracotomy through the third or fourth intercostal space using a titanium clip.
The study compared hospital outcomes among (i) primary surgical closure versus primary ibuprofen treatment; (ii) early primary surgical closure (before the 14th postnatal day) versus late primary surgical closure (from the 14th postnatal day onward); and (iii) primary surgical closure versus secondary surgical closure following ibuprofen failure, using 1:1 propensity score matching. Additionally, logistic regression analysis was performed to estimate the risk of the combined outcome of post-ligation cardiac syndrome (PLCS) and acute kidney injury (AKI) after surgical closure, stratified by gestational age.
A total of 145 very-low-birth-weight preterm infants with hsPDA requiring active treatment were analyzed. No statistically significant differences were observed in hospital mortality or severe bronchopulmonary dysplasia between the primary surgical closure and primary ibuprofen groups. The rate of severe bronchopulmonary dysplasia was significantly higher in the late primary surgical closure group compared to the early group (72.7% vs. 40.9%; p = .033). Outcomes were similar between the primary surgical closure and secondary surgical closure groups following ibuprofen failure. However, the probability of PLCS/AKI was significantly higher in the secondary surgical closure group compared to both early and late primary surgical closure groups (early 15.2% vs. late 28.1%; p < .001; late 28.1% vs. secondary 38.6%; p < .001) among extremely preterm neonates (gestational age <28 weeks). After 28 weeks, the probability of PLCS/AKI was low, with no statistically significant differences between groups.
The authors concluded that surgical closure is not inferior to pharmacological closure in this patient cohort. Considering the harmful effects of prolonged left-to-right shunting in the presence of hsPDA, appropriate and timely decisions should be made to minimize the risk of severe bronchopulmonary dysplasia and PLCS/AKI following surgical closure.
COMMENTARY:
To date, the medical community has not reached a consensus on the indication for surgical closure of haemodynamically significant patent ductus arteriosus in preterm neonates or the ideal timing for intervention. In general, surgical closure has been reserved for neonates in whom medical treatment is ineffective or contraindicated, given that it is considered an invasive procedure not devoid of major complications, especially in such a fragile population. Previous publications revealed potential adverse effects of surgical closure on respiratory and neurological outcomes. However, Weisz et al. pointed out the presence of selection and confounding biases in those series and reported a lack of association between surgical closure and adverse outcomes, such as neurodevelopmental impairment, bronchopulmonary dysplasia, retinopathy of prematurity, or death, compared to conservative management. In the present study, the comparison between primary surgical closure and primary ibuprofen treatment showed no differences in complication rates.
Regarding primary surgical closure of hsPDA, the authors observed a lower incidence of severe bronchopulmonary dysplasia with early surgical closure compared to late closure. Similarly, Lee et al. previously reported that early surgical closure (before the 10th postnatal day) following refractory medical treatment reduces the risk of necrotizing enterocolitis, severe intraventricular hemorrhage, and culture-proven sepsis, while also facilitating early extubation. Other related studies have also indicated that prolonged exposure to hsPDA is associated with increased suboptimal outcomes, including bronchopulmonary dysplasia. These findings reflect the deleterious effects of pulmonary overcirculation in the presence of hsPDA, which leads to alterations in pulmonary compliance, impaired gas exchange at the alveolar-capillary membrane, and eventual development of pulmonary vascular disease due to pulmonary hypertension.
The authors also highlighted that secondary surgical closure after ibuprofen failure is associated with a higher risk of post-ligation cardiac syndrome and acute kidney injury in neonates under 28 weeks of gestational age. This underscores the role of PDA in the development of the immature heart and kidneys, which depends on organ maturation at birth and throughout the postnatal period. Renal dysfunction in these patients is multifactorial, involving incomplete nephrogenesis, compromised renal perfusion due to “ductal steal,” and ibuprofen-induced nephrotoxicity. Post-ligation cardiac syndrome, which occurs in the context of left ventricular systolic dysfunction in response to a sudden increase in afterload following surgical closure, is influenced by myocardial maturation dependent on gestational age.
While this study is highly rigorous, it presents certain limitations that warrant discussion. First, inherent constraints of the retrospective design may have led to the omission of potential clinical confounders not documented in medical records. Second, although the treatment approach for hsPDA was guided by established clinical and echocardiographic criteria, the ultimate decision depended on the discretion of the attending medical team. As a result, there may be variability in treatment strategies. Furthermore, the single-center nature of the study limits the generalizability of the findings to other institutions. Despite these limitations, the results of this study are encouraging and provide valuable insight into a field characterized by significant uncertainty. Nevertheless, randomized controlled trials are essential to draw definitive conclusions and to develop standardized treatment protocols that could improve clinical practice in neonatal intensive care units.
In summary, based on the evidence presented, the following conclusions can be drawn:
- Primary surgical closure represents a valid treatment alternative within the therapeutic arsenal for haemodynamically significant PDA, even in very-low-birth-weight preterm neonates.
- Early surgical intervention may be associated with potential advantages in terms of reducing neonatal morbidity.
- Efforts should focus on minimizing the risks associated with both severe bronchopulmonary dysplasia and post-ligation cardiac syndrome/acute kidney injury, while ensuring timely decision-making to mitigate the harmful effects of prolonged ductal patency.
REFERENCE:
Lee WY, Yum SK, Seo Y, Kim S, Shin JA, Lee C. Patent ductus arteriosus management in very-low-birth-weight prematurity: a place for an early operation? Eur J Cardiothoracic Surg. 2024. doi:10.1093/ejcts/ezae175.
