Introduction

Bronchopulmonary dysplasia (BPD) is a chronic lung disease predominantly affecting premature infants who require mechanical ventilation and oxygen therapy. However, it can also occur in term infants with severe or milder respiratory conditions. Despite improvement in perinatal care, BPD remains a significant challenge, representing the leading cause of late respiratory morbidity in preterm infants [1,2]. The long-term impact of BPD includes persistent respiratory symptoms and airflow obstruction, potentially affecting lung function into adulthood [2,3].

The incidence of BPD varies widely across institutions, reflecting differences in neonatal risk factors, care practices (such as the use of noninvasive ventilation and target oxygen saturation levels), and clinical definitions of BPD. Studies have reported BPD approximately 40% in infants born at ≤ 28 weeks gestational age [4] and up to 77% in those born at <32 weeks’ gestational age and weighing <1,000 g [1]. Infants with a birth weight <1,250 g account for 97% of BPD cases [5].

Infants with BPD face considerable morbidity and mortality, with approximately 40% of those died. Survivors are at high risk for long-term complications, including airway functional impairment as exhibited by abnormal forced expiratory volume in 1 second (FEV₁), vital capacity (VC), and functional residual capacity (FRC) within the first five years [6]. Infants with moderate to severe BPD had lower FEV₁ and forced expiratory flow (FEF_25–75) than those with mild BPD, along with greater developmental delays [7], increased hospital readmission due to lower respiratory infection especially caused by respiratory syncytial virus (RSV) infections [8,9], reactive pulmonary disease, persistent airway obstruction [10], and pulmonary hypertension [11].

Despite the global burden of BPD, data on the incidence and outcomes in Indonesia are limited. Therefore, this study aimed to evaluate the outcome and predictors of mortality in children with BPD in Yogyakarta, providing valuable insights into the management and prognosis of BPD in resourse-limited settings.

Materials and methods

Results

During the study period, among 8,490 newborns hospitalized in the neonatology ward and NICU, only 100 infants (1.2%) were diagnosed with BPD, with complete data available for 85 of these infants. The majority of the infants were born at < 32 weeks of gestational age and had a birth weight of less than 1,500 g (Table 1). The median gestational age was 30 weeks (range: 25−42 weeks), and the median birth weight was 1,190 gram (range: 600−3,684 gram).

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Table 1. Characteristics of BPD patients.

https://doi.org/10.1371/journal.pone.0337083.t001

The incidence of respiratory problems such as cough, wheeze and dyspnea was only 8.2% among infants with BPD. On the other hand, neonatal sepsis was the most common comorbidity, especially among those with severe BPD. Infants with mild and severe BPD who received oxygen supplementation for more than 10 days were more prevalent compared to those with moderate group.

Echocardiography performed before 7 months of age was conducted in 28 infants, with 9 (32%) diagnosed with pulmonary hypertension (PH). Among those with PH, two (22%) died before reaching 7 months, compared to 7 out of 19 (37%) infants without PH (Fig 1). Congenital heart disease was detected in 35 infants (83.3%), with 74.2% diagnosed before 7 months old (26/35) (Fig 1). The incidence of PH and congenital heart disease was similar across the three BPD severity groups (Table 1). Among the 14 surviving children, four (29%) were diagnosed with PH at the last follow-up (Fig 1).

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Fig 1. Patient selection algorithm.

https://doi.org/10.1371/journal.pone.0337083.g001

Almost half (48.2%) of the infants died before the age of 7 months (Fig 2).

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Fig 2. Kaplan-Meier curves showing survival rate by severity of BPD infant.

https://doi.org/10.1371/journal.pone.0337083.g002

Table 2 shows predictors of mortality before the age of 7 months.

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Table 2. Results of echocardiography in patients with BPD.

https://doi.org/10.1371/journal.pone.0337083.t002

Univariate logistic regression revealed that PMA of < 28 weeks significantly increased the risk of mortality (OR 3.67; 95% CI 1.06–12.6; p = 0.04), while mechanical ventilation was associated with a decreased risk of mortality (OR 0.37; CI95% 0.15–0.91; p = 0.03). In multivariate analysis, PMA < 28 weeks remained independently associated with increased risk of mortality (OR 5.27; CI95% 1.36–20.43; p = 0.16), and mechanical ventilation remained associated with a decreased risk of mortality (OR 0.26; CI95% 0.09–0.75; p = 0.013). However, the variable of appropriate gestational age (AGA) and congenital heart disease did not demonstrate significant associations with mortality in infants with BPD (Table 3).

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Table 3. Multivariate analysis of the predictors of mortality in BPD infants before 7 months old.

https://doi.org/10.1371/journal.pone.0337083.t003

Discussion

This study evaluated outcomes and explored predictors of mortality among infants with BPD in Yogyakarta, Indonesia. The results indicated significant mortality, with independent predictors of mortality being a post-menstrual age of <28 weeks and the use of mechanical ventilation.

The incidence of BPD varies globally, with our study revealing a relatively low incidence of 1.2% among all infants and 4.8% among those born at < 32 weeks gestation. Nearly half of the infants diagnosed with BPD in our cohort died, while 32% developed pulmonary hypertension later in life. In contrast, some studies reported much higher proportion of BPD, with 49% among infants < 32 weeks’ gestation in Korea [14], and 34% among < 28 weeks’ gestation in USA [15]. A study involving premature infants (< 37 weeks gestation) in Quebec found a BPD incidence of 36.1% [16], with 20.5% [17] classified as moderate to severe BPD. Another study among extremely low birth weight infant (≤ 1,000 g) in Birmingham documented the proportion of moderate-severe BPD was 37.2%, and in Cincinnati was 29.4% [18]. The different findings among studies may be due to the variations in diagnostic criteria and clinical practices across different settings and time periods.

Historically, defining BPD has been a challenge, with criteria evolving over time. Early definitions primarily relied on the need for supplemental oxygen as a marker of pulmonary damage [19,20], while newer criteria incorporate clinical and radiographic changes alongside continued oxygen dependency during the first 28 days [19]. Understanding the concepts of old and new BPD may provide insights for refining diagnostic approaches and optimizing care strategies for neonates in our hospital.

The lung damage in these infants was primarily attributed to aggressive mechanical ventilation and high inspired oxygen concentrations. Infants with severe respiratory symptoms and characteristic radiographic changes presented little diagnostic difficulty. However, with the widespread use of antenatal corticosteroids, postnatal surfactant therapy, and less aggressive mechanical ventilation, this classic presentation of BPD has become relatively uncommon. At the same time, there has been a striking increase in survival rates among extremely premature infants, for whom underlying lung immaturity plays a predominant role in the pathogenesis and clinical presentation of BPD. This new presentation has created confusions regarding the definitions and diagnostic criteria of BPD. Diagnostic challenges arise particularly with milder forms of BPD, where infants may have only mild initial respiratory failure and require shorter durations of respiratory support. In these cases, the radiographic findings can differ significantly from the classic pattern described by Northway and colleagues [10]. These various clinical and radiographic manifestations reflect the different pathogenic processes that underlines the new presentation of BPD.

Classic BPD was characterized by severe morphologic changes, including emphysema, atelectasis fibrosis, squamous metaplasia, and smooth muscle hypertrophy in the airways and pulmonary vasculature. These changes were associated with severe respiratory failure, airway obstruction, pulmonary hypertension, and cor pulmonale. In contrast, the milder forms of BPD that are more frequently observed today are mainly characterized by increased fluid, a diffuse inflammatory response, and significant decrease in alveolar septation and impaired vascular development [21–25]. These changes are more compatible with an arrest in lung development rather than mechanical injury. It remains unclear to what extent this developmental arrest is a result of premature lung exposure to gas breathing versus the effects of volutrauma and oxygen toxicity. Additional factors including incomplete development, inflammatory processes due to ante- or postnatal infections [26–30], and exposure of the immature pulmonary vasculature to increased flow through a persistent ductus arteriosus [31,32] are also implicated in the pathogenesis of BPD.

Limited data availability in our medical records constraints our assessment of long-term morbidity. However, neonatal sepsis (64.7%) and congenital heart disease (83.3%) emerged as prevalent comorbidities among infants with BPD, which atrial septal defect (ASD) and patent ductus arteriosus (PDA) being the most common congenital heart diseases. A retrospective study comparing BPD and respiratory distress syndrome (RDS) revealed a higher prevalence of PDA in BPD cases (64.5% vs 15.2%, p < 0.0001) [16], especially among severe BPD cases (95% vs 59%) [14]. Pulmonary hypertension is considered as a cardiovascular complication associated with BPD, although the mechanism responsible for elevated pulmonary vascular resistance and altered reactivity remains incompletely understood. Our study suggested a lower risk of PH in mild BPD cases compared to severe ones, although this association was not statistically significant (RR 0.72; CI95% 0.29–1.76).

The proportion of PH did not significantly differ among infants with mild, moderate and severe BPD. This finding was similar to previous study reported a PH prevalence as high as 25%, with a higher proportion in severe BPD (58%) than in moderate and mild cases [11]. Another study involving 42 preterm infants with BPD complicated by PH (gestational age < 32 weeks) reported that 43% had severe PH, with a mortality rate of 38% [33]. However, due to limitation in data availability, we could not calculate the rate of PH among preterm infants < 32 weeks of gestation with BPD in our study. Our findings revealed an overall mortality rate of 48.2% among infants with BPD, occuring within the first 7 month of age. Among BPD infants with PH, the mortality rate was 15.4%, with detection typically occuring between 2–4 months old. Otherwise, all BPD infants with PH detected before 2 months old survived, raising questions about whether early detection contributed to improved outcomes.

The lack of statistical significance in the incidence of pulmonary hypertension (PH) among patients with BPD may be attributed to incomplete ascertainment, as echo-cardiograms were not universally performed on all newborns with these comorbidities. McKinney et al. implemented a comprehensive screening protocol for PH and structural anomalies using echo-cardiography at 36 weeks PMA, with follow-up echo-cardiograms conducted before discharge or in response to significant clinical deterioration [34]. This systematic screening approach may have contributed to more complete detection of PH. Studies have shown that PH in BPD patients correlates with significantly lower cognitive, language, and motor scores on the Bayley III assessment at 18–24 months of age compared to non-PH infants, as well as lower z-scores for weight and head circumference [17]. These findings underscore the importance of close developmental monitoring and routine screening for cardiac issues in infants with BPD after discharge.

We observed a median length of stay of 57 days, with a trend toward longer hospitalizations associated with increasing severity of BPD. Interestingly, while mechanical ventilation was utilized more frequently in mild BPD cases (71.9%) compared to moderate (48.1%) and severe (61.5%), oxygen supplementation varied among the severity groups. Prolonged hospital stays may be attributed to the complexities of the clinical course, including factors such as sepsis and congenital heart disease, which often require extended stays in the neonatal intensive care unit (NICU). Further analysis is warranted to explore these associations. Identifying factors contributing to prolonged mechanical ventilation dependency may involve various modalities.for instance, bronchoscopy, a proven safe procedure in infants, allows dynamic assessment of airway issues [35], while chest computed tomography (CT) scans offer valuable insights into BPD severity and structural abnormalities detection [36].

The role of mechanical ventilation in bronchopulmonary dysplasia (BPD) is complex, balancing potential harm and necessary support. Initially, aggressive mechanical ventilation was linked to lung injury and severe respiratory symptoms in BPD due to volutrauma and barotrauma, which exacerbate inflammation and hinder lung development. However, our study found that mechanical ventilation was associated with a decreased risk of mortality among BPD infants under 7 months, suggesting its critical role in managing acute respiratory failure. This indicates that while mechanical ventilation can contribute to lung damage, it remains an essential intervention when used appropriately, particularly in severe cases of BPD. Therefore, a nuanced understanding of mechanical ventilation is necessary to optimize care strategies, maximizing its benefits while minimizing risks. Further research is needed to identify the best practices for ventilation that protect lung health in these vulnerable infants.

The higher use of mechanical ventilation in mild BPD patients compared to moderate or severe cases may stem from several factors. Mild BPD often presents with transient respiratory distress, prompting initial ventilation for stabilization. Hospital protocols might advocate for aggressive management of any respiratory issues, and variability in symptom presentation could lead to more cautious approaches. Additionally, surfactant therapy may influence the decision to initiate ventilation. Early intervention strategies and prolonged hospital stays for monitoring could also contribute to the increased use of mechanical ventilation in these infants. Overall, these factors reflect clinical practices aimed at preventing worsening respiratory conditions.

The mortality rate of BPD observed in our study was alarmingly high at 48.2%, with similar proportions observed across mild, moderate, and severe cases. This high mortality is not only attributable to the severity of BPD, but also to perinatal comorbidities such as neonatal sepsis and congenital heart disease. The majority of affected infants were premature (82.9%), with 66% born at less than 32 weeks’ gestation and 92.7% with low birth weight, including 70.7% weighing less than 1500 g. Mortality predominantly occurred within the first 7 months after birth. Risk factors for mortality included a post-menstrual age of less than 28 weeks, while being appropriate for gestational age and the use of mechanical ventilation were identified as protective factors. A study in Korea reported improved survival rates among infants born at 23–26 weeks’ gestation during 2006–2010 (80.3%) compared 2000–2006 (70.0%), especially in infants at 23–24 weeks’ gestation (73.9% vs 47.4%, respectively). Improved survival was significantly associated with larger birth weight, higher Apgar score at 5 minutes, and maternal use of antenatal steroids before delivery [37]. The association between lower gestational age (GA) at delivery and mortality from BPD remains controversial. A gestational age of ≤ 28 weeks results in extreme structural and biochemical lung immaturity, which is the most powerful risk factor for the development of BPD. The increased survival of extremely premature infants might increase the actual number of premature infants at risk for BPD. However, Kim et al., found that increased survival of extremely preterm infants at 23–24 weeks gestation was associated with a reduced incidence of BPD in infants born at 25–26 weeks. Conversely, Botet at al., reported no increase in the survival among extremely low birth weight infants; although survival rate of infants without BPD improved from 58.5% (1997–2000) to 75% (2006–2009) [38]. Ambalavanan et al., employed statistical methods (Classification and Regression Tree/CART) to identify risk factors for death and BPD, finding that increased severity of respiratory failure, lower birth weight, male gender and out-born status were major factors [39]. Intubation and ventilation may induce volutrauma and barotrauma, while less invasive methods such as continuous positive airway pressure (CPAP) could allow continuous alveolar growth and reduce lung damage [40]. Notably, our study found mechanical ventilation to be a protective factor against mortality in infants with BPD, although the specific type of mechanical ventilation used were not detailed in our data. Further exploration and classification of ventilation modalities are necessary to elucidate their impact on patient outcomes.

The study adds to current knowledge by highlighting high mortality rates in infants with BPD in Yogyakarta, Indonesia, underscoring the critical role of low post-menstrual age (<28 weeks) as an independent predictor of mortality. Interestingly, mechanical ventilation was associated with lower mortality, contrasting with earlier findings where it was linked to lung damage in BPD. This suggests that careful, possibly less aggressive, ventilation strategies may improve survival. These results reinforce the importance of early, targeted interventions for high-risk infants in similar healthcare settings.

Our study has several limitations. Firstly, its retrospective nature relied on the accuracy of medical records, which may have led to incomplete data capture. Additionally, the study was conducted at a single hospital with a relatively small sample size, and approximately 15% of medical records were inactive, potentially introducing selection bias. Secondly, varying criteria for defining BPD over time highlight the need for standardized diagnostic criteria to ensure uniformity in diagnosis and data interpretation. Longitudinal studies involving multicenter and employing prospective cohort designs are warranted to provide a more comprehensive understanding of the long-term impact of BPD and chronic lung disease.

Conclusion

In conclusion, our study a 1.2% incidence of BPD among hospitalized newborns, with a mortality rate affecting nearly half. Key predictors included neonatal sepsis, congenital heart disease, and a post-menstrual age of < 28 weeks, while mechanical ventilation appeared to reduce mortality. These findings underscore the importance of early identification and targeted management strategies to mitigate risks and improve outcomes for infants with BPD.

Supporting information

Acknowledgments

We gratefully acknowledge Melita Permata Sari, MD and Mohammad Buston, MD for providing the data collection and statistical support. We also thank to Nadya Arafuri, MD and Hendra Purnasida Bagaswoto, MD for helping data collection.