Revisiting modifiable determinants of bronchopulmonary dysplasia in very preterm infants

Abstract

In infants who are born with a gestational age of 32 weeks or less, bronchopulmonary dysplasia (BPD) is persistently a significant cause of morbidity. Early gestational age, low birth weight, prolonged mechanical ventilation, prolonged oxygen exposure, and neonatal sepsis were found to be important predictors of BPD in Palestinian private hospitals by Algharabeh et al in a retrospective cohort study published in World Journal of Clinical Pediatrics. These results underline the ongoing significance of modifiable postnatal exposures and support the complex character of BPD. The study additionally shows several significant maternal-newborn relationships, including preeclampsia and patent ductus arteriosus, eclampsia and neonatal sepsis, preterm rupture of membranes and retinopathy of prematurity (ROP), and multiple gestations with late-onset sepsis and ROP. Impaired alveolarization and aberrant pulmonary vascular development due to oxidative stress, inflammation, and ventilator-associated lung injury are the main features of BPD. These findings necessitates the need for lung-protective ventilation strategies, judicious use of oxygen, infection prevention and control, and improvement in maternal health. The study by Algharabeh et al has limitations like a retrospective design and a single-center setting. But still, it provides useful insights and highlights the need for further prospective research design to refine prevention strategies and improve adverse respiratory outcomes.

Key Words: Preterm infants; Low birth weight baby; Bronchopulmonary dysplasia; Oxidative stress; Mechanical ventilation; Neonatal sepsis; Inflammation

Core Tip: The study by Algharabeh et al suggests that bronchopulmonary dysplasia in preterm infants remains strongly associated with modifiable exposures, including prolonged mechanical ventilation, oxygen toxicity, and sepsis. Significant maternal interactions are also found in the present study, which includes associations between preeclampsia and patent ductus arteriosus, and between multiple gestation and late-onset sepsis. These findings highlight the importance of respiratory care, infection control, and appropriate prenatal care to reduce lung injury and improve long-term respiratory outcomes.

This editorial refers to "Risk factors for bronchopulmonary dysplasia among preterm infants born before thirty-two weeks of gestation in Palestinian private hospitals" by Algharabeh et al, 2026; https://dx.doi.org/10.5409/wjcp.v15.i2.117297.

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INTRODUCTION

One of the most serious complications of preterm is bronchopulmonary dysplasia (BPD). The syndrome was first identified by Northway et al[1] in 1967. Since then, it has changed from being a fibrotic lung disease of the pre-surfactant period to a disorder of halted alveolar and vascular development in extremely preterm newborns[2]. BPD still affects a significant percentage of babies delivered before 32 weeks of gestation, despite advancements in non-invasive ventilation, surfactant replacement, and prenatal corticosteroids[3].

Algharabeh et al[4] assessed BPD factors in private hospitals in Palestine by a retrospective cohort study. Given the paucity of data from the Middle Eastern environment and the potential for focused quality improvement activities to be informed by knowledge of risk variables within particular healthcare systems, especially private hospital settings, this regional addition is especially relevant. Low birth weight, shorter gestational age, longer mechanical ventilation, prolonged oxygen exposure, and sepsis are all significant predictors, according to the authors. These results demonstrate the continued relevance of modifiable exposures in disease development and are consistent with current epidemiologic data. Crucially, the study also reveals important correlations between maternal conditions and neonatal outcomes, such as multiple gestation with both late-onset sepsis and retinopathy of prematurity (ROP), preeclampsia with patent ductus arteriosus (PDA), eclampsia with sepsis, and premature rupture of membranes (PROM) with ROP.

Notably, maternal-neonatal correlations found in this cohort—such as preeclampsia with PDA and eclampsia with neonatal sepsis—are more likely to reflect shared underlying mechanisms, such as prematurity, systemic inflammation, and hemodynamic instability, which together increase pulmonary vulnerability, than to be direct causal pathways to BPD.

The purpose of this editorial is to evaluate the results of Algharabeh et al[4] in World Journal of Clinical Pediatrics critically, place them in the context of current pathophysiology frameworks of BPD, and identify modifiable factors that are pertinent to very preterm infant prevention measures. Figure 1 summarizes the multifaceted pathophysiology of BPD in very preterm newborns, incorporating postnatal exposures, developmental immaturity, and maternal-fetal interactions.

Figure 1 Multifactorial pathogenesis of bronchopulmonary dysplasia in very preterm infants. Developmental immaturity interacts with postnatal exposures such as mechanical ventilation, oxygen toxicity, and infection-driven inflammation, along with maternal-fetal factors, leading to impaired alveolar and vascular development. PROM: Premature rupture of membranes.

DEVELOPMENTAL IMMATURITY, LUNG INJURY, AND RESPIRATORY SUPPORT

Disruption of late canalicular and saccular lung development is reflected in the pathophysiology of contemporary BPD[5]. Alveolar septation and microvascular development are disrupted by premature birth, making the lung structurally susceptible. BPD is a sign of developmental halt rather than classical fibrosis, according to Jobe and Bancalari[2]. By producing reactive oxygen species that overpower developing antioxidant mechanisms, hyperoxia directly causes lung damage[6]. Oxidative stress interferes with proper alveolarization and damages angiogenic signaling pathways[7]. Through volutrauma and barotrauma, mechanical breathing exacerbates injuries and increases inflammatory cascades[8].

Ventilator-induced lung damage in extremely preterm newborns is still relevant, as demonstrated by the link between extended ventilation and BPD revealed by Algharabeh et al[4]. A high burden of invasive respiratory support is reflected in their finding that all infants needed mechanical ventilation, with 75.6% requiring immediate intubation at birth and 16.0% requiring prolonged ventilation beyond four weeks. This finding highlights the role of ventilator-induced lung injury in the pathophysiology of BPD.

INFLAMMATION AND SEPSIS AS CENTRAL MEDIATORS

One important factor in the pathophysiology of BPD is inflammation. Tumor necrosis factor-α and interleukin-6 are examples of pro-inflammatory cytokines that impede lung growth and encourage fibrosis[9]. Late-onset sepsis dramatically raises the risk of BPD, according to several clinical investigations[10]. According to Algharabeh et al[4], 60.5% of newborns had sepsis, and 26.1% had late-onset sepsis, indicating a significant infection load. Also, there was a substantial relationship between maternal eclampsia and both late-onset sepsis (36.8% vs 16.1%; P = 0.009) and newborn sepsis (68.4% vs 53.2%; P = 0.046). Alveolar development may be affected by the combination of ventilator-associated damage and infection-induced systemic inflammatory responses. Inflammatory exposures during pregnancy and after delivery are becoming widely recognized as cumulative causes of chronic lung disease[11].

MATERNAL-FETAL INTERACTIONS: NOVEL INSIGHTS FROM THE PALESTINIAN COHORT

The work by Algharabeh et al[4] makes a significant addition by examining maternal illnesses and their correlation with newborn morbidities that may indirectly affect the risk of BPD. The authors highlight the intrauterine environment as a crucial factor of early pulmonary susceptibility and expand the debate beyond postnatal respiratory exposures by looking at maternal–neonatal associations[12].

Maternal hypertensive disorders demonstrated notable associations. Preeclampsia was linked with a higher incidence of PDA. This relationship may reflect shared vascular and endothelial mechanisms, as both preeclampsia and persistent ductal patency involve dysregulated angiogenic signaling and altered vascular reactivity[13]. Hemodynamically significant PDA may indirectly increase the risk of chronic lung damage in preterm children because it increases pulmonary blood flow, interstitial edema, and impairs respiratory mechanics[14].

Similarly, greater incidences of newborn sepsis, particularly late-onset sepsis, were linked to eclampsia. Systemic inflammation, placental insufficiency, and fetal hypoxia are characteristics of severe maternal hypertensive illness, which may put newborns at risk for immunological dysregulation and increased susceptibility to infection[15]. Alveolar and vascular development in BPD is known to be disturbed by infection-related inflammatory cascades.

PROM showed an association with ROP, a finding consistent with the concept of a fetal inflammatory response affecting multiple developing organ systems. Intra-amniotic inflammation may influence both pulmonary and retinal vascular maturation through shared angiogenic pathways[16]. Multiple gestation was also linked with increased late-onset sepsis and ROP. Infants from multifetal pregnancies are more likely to be born at earlier gestational ages, have lower birth weights, require prolonged hospitalization, and undergo more invasive procedures—all factors associated with nosocomial infection and microvascular injury[17,18].

All of these findings support the idea that antenatal and perinatal factors, in addition to postnatal respiratory exposures, influence the risk of BPD. Optimizing maternal health may indirectly reduce pulmonary morbidity in extremely preterm newborns. This includes managing hypertensive diseases, preventing intrauterine infections, and closely monitoring multifetal pregnancies. Key determinants identified in the study and their corresponding mechanisms and clinical implications are summarized in Table 1

Table 1 Key determinants of bronchopulmonary dysplasia and their clinical implications.

Determinant	Findings from Algharabeh et al[4]	Mechanism	Clinical implication
Low birth weight	Higher incidence in BPD group	Immature lung structure	Risk stratification
Prolonged ventilation	16% required ventilation > 4 weeks	Ventilator-induced lung injury	Early extubation strategies
Oxygen exposure	Prolonged exposure	Oxidative stress	Oxygen targeting protocols
Sepsis	60.5% prevalence	Inflammatory injury	Infection prevention
Preeclampsia - PDA	73.7% vs 48.4%	Endothelial dysfunction	Hemodynamic monitoring
Eclampsia - sepsis	Increased risk	Systemic inflammation	Early infection screening
PROM - ROP	39.0% vs 19.0%; P = 0.020	Intrauterine inflammation affecting vascular development	Screening and prevention strategies
Multiple gestation	Increased sepsis and ROP rates	Prematurity, prolonged hospitalization, invasive procedures	Intensive monitoring and supportive care

BPD: Bronchopulmonary dysplasia; PROM: Premature rupture of membranes; PDA: Patent ductus arteriosus; ROP: Retinopathy of prematurity.

EPIDEMIOLOGIC CONTEXT

Large multicenter studies have documented persistent BPD incidence among extremely preterm infants despite improvements in survival[3,19]. The Neonatal Research Network of the National Institute of Child Health and Human Development has reported stable or modestly declining BPD rates over recent decades[20]. Because care practices differ throughout healthcare systems, regional cohort studies like the one conducted by Algharabeh et al[4] are very useful. Disease burden may be influenced by respiratory practices, infection control strategies, and resource availability[21]. Thus, focused quality improvement programs are informed by local data.

MODIFIABLE DETERMINANTS AND RESPIRATORY CARE

While gestational age and birth weight are inherent risk factors, postnatal exposures remain modifiable. Reduced BPD incidence has been linked to early continuous positive airway pressure, avoiding needless intubation, and prompt extubation[22]. Noninvasive breathing techniques are linked to decreased incidence of BPD when compared to regular intubation and mechanical ventilation, according to a thorough meta-analysis by Isayama et al[23]. Oxygen management is equally critical. Randomized trials evaluating oxygen saturation targets in extremely preterm infants demonstrate the delicate balance between hypoxia and hyperoxia[24]. Excessive oxygen exposure disrupts vascular endothelial growth factor pathways and contributes to pulmonary vascular disease[7]. The findings of Algharabeh et al[4] emphasize that BPD prevention requires meticulous respiratory stewardship. Standardized ventilation protocols, oxygen targeting, and early use of non-invasive support may mitigate cumulative lung injury. These findings reinforce that prevention of BPD is less dependent on identification of novel risk factors and more on consistent implementation of evidence-based respiratory and infection control practices.

LONG-TERM CONSEQUENCES

Beyond the newborn stage, BPD has consequences. Survivors are more likely to experience recurrent wheeze, pulmonary hypertension, decreased pulmonary function, and readmission to the hospital[25]. Long-term follow-up research shows that respiratory restrictions continue throughout adolescence and adulthood[26]. Thus, preventing even mild BPD may have long-term advantages. To change the course of the condition, it is essential to identify modifiable exposures during the newborn period.

METHODOLOGICAL CONSIDERATIONS

Algharabeh et al’s work[4], which is a retrospective cohort study, offers valuable associative data but has limitations in proving causation. Given the interrelationship of gestational age, birth weight, and respiratory support time, the lack of multivariable modeling restricts the interpretation of independent risk attribution. For comparison, standardized definitions are essential. In addition to the National Institutes of Health criteria, contemporary severity-based classification systems—such as the data-driven definition proposed by Jensen et al[27]—incorporate the level of respiratory support at 36 weeks’ postmenstrual age and may better predict long-term outcomes.

Risk stratification may be improved by future studies that use new imaging modalities, genetic susceptibility markers, and inflammatory biomarkers[28-30]. The lack of multivariable modeling restricts the assessment of independent impact sizes and may complicate the interpretation of related factors like gestational age, birth weight, and length of respiratory assistance, even if the study offers useful associative data.

FUTURE DIRECTIONS

A multimodal approach that includes lung-protective ventilation, oxygen stewardship, infection management, optimum nutrition, and early hemodynamic stabilization is necessary to prevent BPD. The gap between evidence and practice may be closed by using implementation science techniques to assess respiratory protocol adherence. Additionally, research into the integration of innovative treatments that target oxidative stress and inflammation is also ongoing. Prospective risk modeling and standardized respiratory regimens should be the main focus of future research in order to convert epidemiologic connections into practical therapeutic treatments.

CONCLUSION

According to Algharabeh et al’s research[4], BPD in extremely preterm neonates is still highly linked to modifiable postnatal exposures such as prolonged mechanical ventilation, oxygen toxicity, and sepsis. Significantly, by showing the link between newborn problems including PDA, sepsis, and ROP, that may indirectly increase the risk of BPD and multiple gestations, preterm rupture of membranes, and maternal hypertensive illnesses, the study also explains the significance of maternal-fetal interactions. These results highlight the significance of all-encompassing approaches for neonatal units in Palestine and comparable surroundings, including improved prenatal care to optimize maternal health, strict infection control to reduce inflammation associated with sepsis, and respiratory stewardship to minimize lung damage from ventilators. To reduce the burden of BPD, particularly in newborn settings with limited resources, respiratory treatment, infection control, and maternal health optimization must be linked. Preventive strategies that are more precise and targeted may result from combining fundamental knowledge with epidemiologic evidence.