Our data reaffirms the potential relationship of duration of exposure to PDA, MV, and risk of BPD. More importantly, in the absence of comprehensive echocardiography adjudication of PDA shunt volume, a larger PDA >2.5 mm is an important threshold within Chinese NICUs to aid discrimination of patients at higher risk of death or BPD and triage suitability for medical intervention. Failure of normal postnatal closure of DA occurs in 40– 55% preterm infants born less than 29 weeks’ gestation [18,19]. Evidence from animal and human observational studies demonstrates that prolonged exposure to a hsPDA may result in pulmonary edema, worsening lung compliance, impaired pulmonary function and arrested alveolar development which contribute to the development of BPD [20,21]. Increased distance between the alveolar surface and the surrounding capillary bed limits the ease of gaseous molecular diffusion which clinically manifests as hypoxemia. These effects are mitigated by either increasing inspired oxygen and/or alveolar distending pressure. Preclinical data demonstrates, however, that exposure of the immature lung to hyperoxia leads to arrested alveolarization and the development of a heterogeneous, simplified pulmonary architecture . In addition, prolonged MV exposure induces apoptosis of alveolar cells and inflammatory cascade in the neonatal lungs contributing to the development of BPD [23, 24].
In alignment with animal experimental evidence, data from the current study demonstrates that infants who developed BPD or died had a longer duration of MV, higher incidence of inotrope use and prolonged exposure to PDA compared with infants in low-risk group. After adjustment for other risk factors, use of inotropes, duration of MV and persistent exposure to a large PDA remained positively associated with BPD or death. Our results are consistent with findings from previous studies. El-Khuffash et al. demonstrated that a composite score of PDA severity based on the echocardiography criteria of hemodynamic significance measured at the time of PDA treatment predict the later occurrence of BPD/death . More recently, Schena et al found that infants exposed to a more severe PDA, based on the McNamara and Sehgal PDA staging system, for a longer period are at increased risk of developing BPD. They found that with each additional week of exposure to an hsPDA the risk of BPD is increased by 70% . Finally, Clyman et al. also demonstrated that infants with prolonged exposure to a large PDA and more than 10 days of MV are at increased risk of moderate/severe BPD . Our study provides additional evidence that longer duration of exposure to PDA diameter > 2.5 mm is an important determinant of mortality and risk of BPD. In addition, subgroup analysis showed that prolonged PDA exposure was also associated with severity of BPD.
Despite evidence of a strong associative relationship between the PDA and BPD, numerous randomized controlled trials of PDA treatment failed to demonstrate any consistent reduction in the rates of neonatal morbidities, including BPD[1–3, 5]. The side effects of medical treatment or surgical ligation have led to the trend toward conservative approach regarding PDA management. Lokku et al. demonstrated that, in Canadian centers, conservative PDA management increased while pharmacotherapy and/or surgical ligation decreased between 2006 and 2012 . Bixler et al showed a significant decrease in diagnosis and medical/surgical treatment of PDA, with no evidence of increased morbidities, in a large cohort of premature infants from 280 NICUs across US . The discrepancy between the findings from epidemiologic studies and the results of randomized clinical trials may relate to the use of non-standardized definitions of hsPDA, variance in diagnostic criteria for BPD, and heterogeneity in clinical trial design. In addition, it is important to recognize that treatment was not uniformly effective in patients randomized to medical treatments, whereas patients in the control arm were not uniformly exposed to hsPDA due to higher-than-expected rates of spontaneous closure. It has been proposed that future trials on PDA treatment need to focus on high-risk premature infants with objective evidence of hemodynamic significance which will help to draw inference on the effect of PDA on clinical outcomes. In addition, it is crucial to perform a standardized assessment of the PDA in order to define the physiological variability or the magnitude of ductal shunt when selecting target population [29,30].
The application of conservative therapy in both routine clinical practice and randomized clinical trials has been applied in a non-consistent manner. Although originally proposed as the use of shunt modulation strategies (based on the Hagen-Poiseulle principle) and/or fluid restriction or diuretics, its application includes an approach based on non-evaluation or non-consideration of the PDA. The safety of conservative treatment has not been formally evaluated until recently. First, Altit et al reported that policy change to a strict non-intervention approach to PDA resulted in a 31% increase in the incidence of death/BPD among infants less than 26 weeks GA, whereas there was no change in outcomes among infants born between 26 to 29 weeks . Second, Relangi et al evaluated the impact of a less aggressive approach to PDA management on the development of BPD in premature infants. Fewer infants received PDA treatment (54% vs 90%, P <.001), which was administered at a later age (9.8 vs 5.6 days, P < .001) in epoch 2 (2011-2015), compared with a prior epoch (2005-2007). With a more conservative approach, infants in Epoch 2 had greater odds of BPD, composite of BPD or death, and were more likely to receive treatment with postnatal steroids than those in epoch1.
The question of whether early targeted intervention of hsPDA positively mitigates neonatal morbidity has been the subject of recent consideration. Reliable determination of the modulator effect of PDA closure requires the conductance of well-designed clinical trials in which enrollment is restricted to patients at greatest risk of abnormal outcome, and where spontaneous closure is less likely thereby ensuring exposure of sufficient magnitude and duration, and treatment efficacy is guaranteed in the comparator group. The hemodynamic effects of the transductal shunt are influenced by factors including transductal diameter, balance between pulmonary and systemic vascular resistance, and the compensatory ability of the immature myocardium. Our imaging protocol was based on a limited appraisal of shunt volume, which may influence the reliability of our findings. Comprehensive echocardiography protocols, based on multimodal echocardiography parameters related to cardiac volume overload, systemic and/or end organ perfusion and myocardial performance in infants with PDA may offer value in distinguishing a subpopulation of patients at increased risk of PDA-attributable morbidity. Several PDA scoring systems have been associated with BPD [31,10,29]. Increased access to neonatologists with the skill of echocardiography increases the feasibility of conducting clinical trials based on populations at risk.
The present study has several limitations, most importantly the retrospective nature of the data collection. In addition, the enrolled population was drawn from a single tertiary center which may have introduced selection bias. It is therefore uncertain whether our findings are broadly generalizable. Some infants were excluded because parents didn’t wish to pursue ICU care, which is a unique bias of the Chinese context. This is an important consideration and provides a putative explanation for the lower mortality rate in our cohort. In addition, it is possible that the unavailable or missing data in our study (status of chorioamnionitis diagnosed by placental pathology, the use of prenatal dexamethasone, the grading of severity of RDS and neonatal critical illness score), may lead to hidden bias due to unmeasured variables. In addition, we were unable to acquire details of the age at onset, number of episodes or status of blood culture of patients with sepsis. The competing effects of infection and inflammation in the setting of a PDA are important determinants of the risk of BPD. On the contrary, the strength of our study, which covered a wide time span, lies in the uniform and standard protocol of structural echocardiography with accurate measurement of ductal size and close monitoring based on patient’s medical conditions.
In conclusion, prolonged exposure to a large PDA is an important contributor to both mortality and BPD. Comprehensive appraisal of hemodynamic significance is an important consideration in determining the relative contribution of shunt volume to abnormal parenchymal versus vascular maldevelopment.