The pathogenesis of bronchopulmonary dysplasia: “It is never the heart, it is always the lung” – myth or maxim?

Abstract

“This is not the heart; this is the lung.” Who among paediatric pulmonologists has never faced this situation with a cardiologist? Joking aside, discussions for some cases may be tricky and our common ultimate goal is always to provide the best care to the patients and their families. In this review, we will focus on the links between the heart, or more widely the cardiovascular system, and bronchopulmonary dysplasia, in order to determine if this quote is a myth or a maxim.

Shareable abstract

This review explores the interactions between preterm birth, lung vascular development, heart disease, pulmonary hypertension and bronchopulmonary dysplasia https://bit.ly/4j0jXlY

Introduction

Bronchopulmonary dysplasia (BPD) is a lung developmental disease characterised by an interruption of alveolarisation following premature birth (figure 1). This interruption of the alveolar stage leads to the formation of fewer and larger alveoli with a lower gas exchange surface area (figure 2a and b) [1, 2]. BPD is clinically defined as a chronic respiratory failure following premature birth [3]. These pathological and clinical features are characteristic of a respiratory disease and suggest at first sight that the heart and the cardiovascular system are not involved. With these considerations in mind, the subject of this review appears to be rather a maxim than a myth.

FIGURE 1.

The five stages of lung development in humans. The embryonic stage (Emb) corresponds to the formation of the respiratory bud that originates from a ventral evagination of the primitive gut. The bronchial tree is formed during the pseudoglandular stage. The first signs of alveolar epithelial differentiation occur during the canalicular stage; canaliculi correspond to the extension of the terminal bronchioles with the appearance of alveolar epithelial cells. Saccules are primitive alveolar sacs and issue from canaliculi. Surfactant secretion starts during the saccular stage. Alveolar formation, corresponding to the appearance of numerous thin septa inside the saccules, occurs very late during pregnancy and starts just before birth. Premature birth occurs mainly at the saccular and sometimes at the late canalicular stage of lung development. Premature birth leads to a disruption of lung development.

FIGURE 2.

Disruption of secondary septation is the hallmark of bronchopulmonary dysplasia (BPD). a, b) Pathological slides of lungs from a) a term-born infant and b) an infant with BPD (both haematoxylin–eosin stained, 20×). Normal lungs have numerous and small alveoli with thin septa. The lung from the BPD patient has fewer and larger alveoli with thicker septa. c) Schematic representation of secondary septation. During the alveolar stage of lung development, secondary septa are emerging from the primary septa of the saccules to form the definitive alveoli. The formation of secondary septa involves cellular migration, especially myofibroblasts that secrete elastin. Elastin accumulates in the thickness of the primary septa between the two capillary networks and “drags” the wall to form the secondary septa perpendicularly, with the elastin at the apex of the septa (black arrows). In parallel, the double capillary network present in the primary septa fuses to form only one capillary network. This stage considerably increases the surface area for gas exchange and optimises gas diffusion on both sides of the air/blood barrier.

However, this conventional view that BPD primarily involves the lungs and not the heart may oversimplify the complex interplay between the lungs and cardiovascular system during lung development and in BPD. Alveolarisation and microvascular development are interdependent. Indeed, the formation of definitive alveolar septa is accompanied by the fusion of the double capillary network to form the definitive alveolar–capillary barrier, leading to an optimal gas exchange surface area. Emerging evidence indicates that pulmonary microvascular development is also altered in BPD. Therefore, it finally appears that the cardiovascular system also plays a significant role, directly challenging the long-held assumption that BPD primarily involves the lungs without significant cardiovascular involvement.

In this review, we will explore the interactions between preterm birth, lung vascular development, heart disease and BPD. We will first focus on the vascular hypothesis of BPD pathophysiology, then detail the aspects of pulmonary hypertension (PH) in BPD, then explore the potential role of left-to-right intra-cardiac shunts, and finally look at particular cases of pulmonary vein stenosis (PVS) in infants with BPD. In the last section, we will link these elements to the essential practical implications for clinicians.

The vascular hypothesis of BPD

The ultimate stage of lung development is secondary septation (figure 2c). During this step, secondary septa emerge from the saccular walls to form the alveoli. In parallel, the double capillary network fuses to form one thin capillary layer next to the alveolar epithelial layer, leading to the alveolar–capillary barrier. This interdependency of alveolar formation and microvascular maturation raised the hypothesis of the involvement of vascular growth factors and pathways in the pathophysiology of BPD. In 2001, Abman [4] even proposed the “vascular hypothesis” for BPD, i.e. that angiogenesis would drive the alveolarisation process and that impaired vascular growth would be the initial event leading to the arrested alveolarisation seen in BPD. Several observational human and interventional animal studies investigated this hypothesis.

Autopsy findings from infants with severe BPD showed the persistence of a prominently subepithelial capillary network, mostly arranged in a dual parallel pattern, forming thickened septa surrounding large alveolar spaces [5]. Bhatt et al. [6] studied the distribution of capillaries and the angiogenic activity in lungs of infants who died from BPD. The number of endothelial cells and the morphology of the vessels were assessed by mRNA and protein expression studies of platelet endothelial cell adhesion molecule (PECAM)-1. Angiogenesis was assessed by similar measurements of vascular endothelial growth factor (VEGF) and the angiogenic receptors Flt-1 and TIE-2. Compared to controls (infants dying from another cause but at a similar age), lungs from infants dying from BPD had decreased PECAM-1 mRNA and protein expression, consistent with a decreased number of endothelial cells. Both gene and protein expression of VEGF were decreased, as were gene expression of Flt-1 and TIE-2.

Animal models investigated whether vascular alterations were secondary to arrested septation or played an independent role in BPD pathophysiology. Jakkula et al. [7] studied the impact of angiogenesis inhibition on lung development in rat pups using SU-5416, an inhibitor of the receptor VEGFR-2. Animals treated with SU-5416 had decreased alveolarisation and arterial density compared to controls, with lesions resembling BPD. In 2005, Thébaud et al. [8] showed that gene therapy with VEGF prevents hyperoxia-induced alveolar lesions in rat pups. More recently, in a hyperoxic mouse model of BPD, Appuhn et al. [9] showed that endothelial lesions precede epithelial ones, by studying the endothelial and epithelial surface areas sequentially at post-natal days 7, 14 and 21. Compared to lungs of controls in room air, the capillary endothelial area was already reduced at day 7, whereas the epithelial surface area was similar at day 7 and reduced at days 14 and 21. Finally, in 2023, Kolesnichenko et al. [10] performed experimental administration of embryonic stem cell-derived endothelial progenitor cells (c-KIT⁺/FOXF1⁺) at post-natal day 5 in neonatal mice exposed to 85% oxygen from birth to day 5. Lungs were examined at post-natal day 15. A single administration of endothelial progenitor cells corrects hyperoxia-induced alterations of alveolar development.

Together, these data support a pivotal role of the maturation of the microvasculature in the process of alveolarisation. Nevertheless, VEGF, the main endothelial growth factor in play in this setting, is mainly expressed by alveolar epithelial and mesenchymal cells [11]. Therefore, even though altered microvascular development plays a significant role, the initial event might happen in the alveolar epithelial cells, as it has been often assumed.

Whatever the case, the take-home message from all these studies is that it is necessary to protect preterm infants from microvascular damage, at least as much as damage to the alveolar epithelium. This is all the more important as abnormal capillaries probably persist later in life in former preterms, as shown by several studies. Measurements of pulmonary capillary volume in adolescents from the French EPIPAGE cohort showed significantly lower values in adolescents born preterm compared to controls, with even lower values in those with BPD [12]. This may reflect a lower microvascular surface area and contribute to a lower pulmonary vascular reserve in this population.

Pulmonary hypertension

A mean pulmonary artery pressure (mPAP) >20 mmHg defines PH [13]. PH is a cardiovascular complication of BPD and is categorised by the World Symposium on Pulmonary Hypertension classification as group 3 PH (i.e. PH associated with lung disease) [14, 15]. PH can occur at different stages in preterm infants. A meta-analysis of 25 articles showed a global prevalence of PH, whatever the time of assessment, of 20% among infants with BPD and of 12% among all preterm infants [16]. This global prevalence was similar to the prevalence shown in a recent monocentric retrospective study by Gentle et al. [17] in 398 preterm infants. In a prospective study in 277 preterm infants by Mourani et al. [18], early PH (within 7 days of life) was diagnosed in 42% of the patients, and late PH (at 36 weeks post-menstrual age (wPMA)) in 14%. In a large multicentre retrospective study of 1677 infants from the North American Children's Hospital Neonatal Consortium, PH diagnosed at ≥34 wPMA had a median prevalence of 14% in all infants and of 22% in infants with severe BPD [19].

Pathophysiology of PH in BPD is multifactorial and is represented in figure 3. First, disruption of alveolarisation leads to a reduction in gas exchange surface area that is responsible for hypoxic vasoconstriction. As in other group 3 PH, hypoxic vasoconstriction plays an important role, as optimal oxygenation in infants with BPD-PH at 36 wPMA is often sufficient to significantly decrease pulmonary pressures. However, prolonged hypoxaemia may ultimately also lead to structural remodelling of the arterial pulmonary circulation. Secondly, the care of infants with respiratory failure through artificial ventilation and high oxygen exposure during the first weeks of life may also lead to endothelial dysfunction and vascular remodelling [20]. Thirdly, as described in the first part of this review, the abnormal development of the pulmonary capillary bed is associated with dystrophic capillaries. Finally, the increase in pulmonary blood flow in cases of left-to-right shunts has recently been shown to be involved in the pathogenesis of PH in BPD [21] and is detailed in the next part of this review.

FIGURE 3.

Mechanisms of pulmonary hypertension (PH) in bronchopulmonary dysplasia (BPD). Disruption of alveolarisation leads to a reduction in gas exchange surface area that is responsible for hypoxic vasoconstriction. Furthermore, the abnormal development of the pulmonary capillary network is associated with dystrophic capillaries. Prolonged hypoxaemia may ultimately participate in PH in BPD patients by leading to structural remodelling of the arterial pulmonary circulation. The means of care (i.e. use of a ventilator or supplemental oxygen) for respiratory failure may also lead to endothelial dysfunction and vascular remodelling. Finally, the increase in pulmonary blood flow in cases of left-to-right shunts has recently been shown to be involved in the pathogenesis of PH in BPD.

When present, PH is a poor prognostic factor for BPD, with increased mortality and morbidity. In their meta-analysis, Arjaans et al. [16] identified an association between the severity of BPD and the prevalence of PH in extremely preterm infants, with the proportion of infants with PH increasing with the severity of BPD. In the prospective study of Mourani et al. [18], early PH was a risk factor for increased BPD severity and late PH. Infants with late PH had greater duration of oxygen therapy and increased mortality in the first year of life [18]. A prospective national surveillance study of very severe forms of BPD performed via the British Paediatric Surveillance Unit showed that the presence of PH at or beyond 38 wPMA was significantly associated on regression analysis with the following outcomes up to 1 year of age: death, death or major neurodevelopmental impairment, and death or long-term ventilation [22]. Lagatta et al. [19] obtained similar results on outcomes at discharge and at 1 year of age in their multicentric retrospective cohort study of 1677 infants with severe BPD. At discharge, PH at 34 wPMA or beyond was associated with tracheostomy, supplemental oxygen use and enteral nutrition. Through 1 year of corrected age, it was associated with increased frequency of readmission.

As with lung function alterations in children, adolescents and adults born preterm, the possible persistence of PH and increased pulmonary vascular resistance and tone later in life have also been the subject of many studies in the past years. In 10 patients with BPD aged from 6 months to 27 years (median 5 years) who underwent cardiac catheterisation, mPAP was increased (34 mmHg) and was reactive to hypoxia, hyperoxia and inhaled nitric oxide, suggesting that increased pulmonary vascular tone and vasoreactivity persist in older patients with BPD [23]. In 11 adults born preterm, average age 27 years, mPAP measured during cardiac catheterisation was higher than in 10 controls [24]. Total pulmonary vascular resistance was also increased compared to the controls, suggesting a stiffer vascular bed. This was associated with right ventricular dysfunction during exercise, as the preterm-born adults were less able to increase their cardiac index or right ventricular stroke work during exercise [24]. The main limitation of these two studies is the small size of the study samples. Interestingly, several large studies in adults support a significant increase in mortality risk even for mild elevations in mPAP [25–28], suggesting a possible increased risk of cardiovascular disease mortality in adults born preterm. For example, in 547 adults with unexplained dyspnoea and/or at risk of PH, after adjusting for age and comorbidities, borderline PH (mPAP between mean +2 sd and 25 mmHg) was associated with poor survival (hazard ratio 2.37; p=0.0222) [26].

Beyond PH and right ventricular dysfunction, other studies have addressed the risk of heart failure in adults born preterm. A very large register-based cohort study performed in Sweden demonstrated a strong association between preterm birth before 32 weeks of gestation and heart failure in young adulthood [29]. In this study including 2 665 542 individuals born in Sweden and registered in the Medical Birth Register between 1987 and 2012, compared with individuals born at term, the adjusted incidence relative risk for heart failure was 17.0 (95% CI 7.96–36.3) after extremely preterm birth. This increased risk could be explained by a reduced myocardial functional reserve, as suggested by a study showing an impaired left ventricular response to physiological stress in adults born preterm [30]. All these results are in favour of an increased risk of cardiovascular disease mortality in preterm-born adults.

In conclusion, PH, abnormal vasculature and persistent vascular reactivity are deleterious morbidities in BPD throughout life. Pathogenesis of these alterations involves pulmonary and cardiovascular factors. The weight of each category is difficult to determine. Nevertheless, more and more immature babies are resuscitated and survive with less and less aggressive ventilator strategies. Therefore, the consequences of primitive developmental abnormalities of the pulmonary vasculature and the role of increased pulmonary blood flow could progressively exceed or at least equal those of hypoalveolarisation and iatrogenically induced lesions. In the future, identification of the more at risk children could help to develop systematic follow-up strategies and treatments when necessary.

Left-to-right intra-cardiac shunts

As mentioned, the role of the increase of pulmonary blood flow in BPD and BPD-PH has gained progressive interest in the past years. One cause of this blood flow increase is left-to-right intra-cardiac shunts, such as patent ductus arteriosus (PDA).

PDA has been recognised for a long time as a risk factor for BPD [31, 32]. Nevertheless, the pathophysiology of this association is not clear, and several retrospective and prospective studies have failed to demonstrate that early closure of the ductus arteriosus protects against BPD. One explanation could be the selection of the patients relative to the duration of the exposure to a haemodynamically significant shunt. Clyman et al. [33] found, in a prospective study in 423 extremely preterm infants, that an exposure to a moderate-to-large PDA for ≥7 days was necessary before a significant increase in the incidence of BPD/death appeared. Additional interesting results came from the TRIOCAPI trial, initially designed to study the effect of early treatment of PDA with ibuprofen on survival without cerebral palsy at 2 years in preterm infants [34]. A secondary analysis showed that infants with prolonged (≥14 days) exposure to a moderate-to-large PDA had an increased incidence of BPD only when they required intubation for >10 days [35]. The PDA-TOLERATE trial obtained similar results [36]. Thus, early treatment to close the ductus arteriosus may have an impact on subsequent cardiopulmonary evolution if the shunt is haemodynamically significant and in infants with severe respiratory disease.

Further studies have investigated the role of PDA on BPD-PH. The pathophysiological hypothesis was recently reviewed by McNamara and Lakshminrusimha [21]. Prolonged PDA exposure may induce endothelial injury via the pulsatile increased pulmonary blood flow, with an exacerbated myogenic response and hypertensive-like remodelling. This was demonstrated in an animal model in lambs that consisted of placing a tube between the aorta and the main pulmonary artery in utero, thus reproducing a persistent and haemodynamically significant ductus arteriosus [37]. This shunt induced an increase in pulmonary blood flow and pulmonary pressures. On structural studies, lungs of 1-month-old lambs displayed increased medial thickness and muscularisation of small arteries relative to controls, suggesting early pulmonary vascular remodelling. In humans, pulmonary vascular resistances were measured during transcatheter PDA closure in 100 extremely preterm infants and compared according to the timing of the closure. Compared to infants who underwent early closure (≤4 weeks of post-natal age), infants with closure beyond 8 weeks of post-natal age had significantly higher pulmonary vascular resistance [38]. Regarding the association between PDA and BPD-PH, Gentle et al. [17] retrospectively compared 138 extremely preterm infants with BPD to 82 infants with BPD-PH. After adjustment for covariates, PDA and moderate-to-large PDA were significantly associated with BPD-PH, with a continuous and almost linear relationship between the duration of exposure to PDA and the probability of BPD-PH or death. These associations remained significant when dividing patients into PH groups, i.e. PH during hospitalisation, either early (≤28 days) or late (>28 days), and PH at discharge. A recent meta-analysis of 32 studies including 8513 infants showed similar results. Prolonged PDA and PDA requiring surgery increased the risk of BPD-PH [39]. Finally, Bjorkman et al. [40], in their monocentric retrospective study of 133 very preterm infants, showed that an exposure of >60 days to a haemodynamically significant PDA was associated with PH at 36 wPMA.

The role of other left-to-right shunts is less clear. Some studies have focused on atrial septal defects (ASDs) in preterm infants. In a retrospective study including 217 infants born at a mean gestational age of 29 wPMA, the presence of an ASD, whatever its size, was associated with an increase in frequency of PDA requiring surgery and of mild BPD but not with moderate-to-severe BPD [41]. In a large multicentric retrospective North American study including 20 496 patients, very preterm infants with an ASD had an increased risk of developing BPD, either mild, moderate or severe, compared to infants without an ASD [42]. In the cohort of 1677 infants with severe BPD published by Lagatta et al. [19], ASD was significantly more frequent in children with PH. In a multivariable analysis of this same population, ASD was associated with an increased odds of death [19]. The impact of ASD surgical closure in this setting was addressed in a small monocentric retrospective study of 10 infants with moderate-to-severe BPD weighing <10 kg using a pre/post-closure scoring. This scoring included the level of BPD severity, respiratory symptoms, diuretic use, growth, type of respiratory support, inspiratory oxygen fraction needed, and ultrasound-estimated right ventricular pressure 8 weeks before and after the closure [43]. There was a significant improvement of the score after the surgical closure, especially regarding diuretic need and respiratory status.

In conclusion, left-to-right shunts are an aggravating factor in infants with BPD, especially BPD-PH. Regarding PDA, its impact depends on the importance of the shunt and its duration. Data on ASDs are scarcer but favour an increased risk of BPD and a potential interest in an early closure during infancy.

Pulmonary vein stenosis in BPD

PVS is an intraluminal narrowing of the vessels returning blood to the left atrium. It may affect either one, two, three or all four pulmonary veins. It is a rare disorder with a reported incidence of 2–30 cases per 100 000 infants [44]. PVS occurs more frequently in preterm infants and has recently emerged as a cause of PH in infants with BPD. Up to 40% of PVS occurs in former preterm infants [44]. In a retrospective study of 213 patients diagnosed with severe BPD, 5% had PVS [45]. PVS often has poor prognosis and, in this same study, survival rate at the time of discharge was 50% for the patients with PVS, which was notably lower than the 86% survival rate observed in severe BPD patients with PH but without PVS [45]. In another study that retrospectively reviewed 39 former preterm infants with PVS, survival or absence of re-stenosis was 73% at 1 year and 55% from 2 years onwards, with no more deaths after, with a follow-up of at least 10 years. The median survival time was 4 years [46]. PVS is thought to be progressively acquired in the setting of prematurity, as the median age at diagnosis is 6.5–7.5 months and it requires several echocardiograms before being identified [46–48]. The pathophysiological mechanisms are not fully determined and probably involve developmental abnormalities, haemodynamic factors and inflammatory mediators at play in the setting of prematurity [49]. In a recent case–control study comparing infants with severe BPD and PVS to patients with severe BPD but no PVS, being small for gestational age, and having surgical necrotising enterocolitis, ASDs and PH were each independently associated with PVS [50]. Poor prognosis was confirmed in this study, with a 3.6-fold higher odds of in-hospital mortality in patients with PVS relative to controls [50].

In conclusion, PVS needs to be known by neonatologists, paediatric cardiologists and pulmonologists as a severe comorbidity/complication of BPD. This diagnosis should be considered in infants with BPD who have insidious and worsening respiratory symptoms and/or hypoxaemia, new or worsened PH, failure to maintain or gain weight, or require unexplained increases in ventilatory or oxygen support beyond the expected clinical trajectory. In such cases, echocardiograms should be performed to screen for PVS. Contrast chest computed tomography (CT) scanning and right heart catheterisation must also be quickly considered.

Implication for management and future directions

This review shows that, after a premature birth, numerous factors involving the pulmonary microvasculature and the large vessels that communicate between the heart and the lungs are acting in the pathogenesis of BPD, especially as aggravating factors. As with other multifactorial diseases where complex processes unfold over time and across different anatomical sites, developing a uniform and standardised approach to care remains challenging.

Nevertheless, some practical implications for clinicians emerge from this review. First, prevention of prematurity must remain a goal for health systems around the world. Secondly, during the neonatal period, PDA and the importance of the subsequent shunt should be regularly assessed. Medical and/or surgical closure should be considered for a significant shunt, especially in neonates with severe respiratory disease. Thirdly, before discharge, infants with moderate or severe BPD should undergo nocturnal pulse oximetry associated with several awake peripheral oxygen saturation measurements, to ensure optimal oxygenation and to adapt the home oxygen supply if necessary [51–53]. When discharged home on oxygen, or in cases of recent weaning, infants with moderate or severe BPD should undergo cardiac ultrasound, especially to estimate pulmonary pressures and optimise the oxygenation in cases of PH. If PH does not respond to oxygen supply, contrast chest CT and right heart catheterisation must be quickly considered to search for a PVS, to precisely measure pulmonary pressures and pulmonary vascular resistances and to test the effect of vasodilators. In case of an unexplained respiratory worsening before discharge or within the first year after discharge, echocardiograms should be controlled and repeated to rule out PVS, as PVS is a critical complication with a poor prognosis. Finally, long-term follow-up of patients with BPD should include respiratory clinical and functional assessments. In case of important dyspnoea on exercise unexplained by lung function abnormalities, an echocardiogram and exercise test should be considered to evaluate heart function, pulmonary pressures and to precisely determine the cause of limitation during exercise, either respiratory, cardiac or because of peripheral muscular weakness.

Conclusion and take-home message

In this review, we have explored all the possible interactions between cardiovascular disorders (such as shunts, PVS and PH) that may occur in preterm infants during the neonatal period and beyond, and the occurrence and severity of BPD. Several well designed and powerful studies have demonstrated the role and the association of such disorders with BPD, especially in its severest forms. Although for some studies, notably the retrospective ones, it is difficult to determine who is the egg and who the chicken, animal models and convincing pathophysiological hypotheses argue for a role of the cardiovascular system in BPD and other complications of prematurity. Thus, considering the heart as the cardiovascular system, “It's never the heart, it's always the lung involved in the pathogenesis of BPD” should nowadays be considered as a myth.

Key points

• Alveolarisation and microvascular development are interdependent. Disruption of angiogenesis during lung development participates in the pathophysiology of BPD.

• PH is a significant comorbidity of BPD, especially in severe forms of the disease.

• Early and prolonged left-to-right shunts are an aggravating factor in infants with BPD.

• PVS occurs more frequently in preterm infants. It should be suspected in cases of unexplained respiratory worsening, or worsening or delayed onset of PH.

Self-evaluation questions

1. Which of the following statements correctly describe(s) the alveolar stage of human lung development and the associated microvascular development?

   1. The alveolar stage is characterised by the formation of alveolar sacs and an increase in gas exchange surface area, without involvement of angiogenesis.
   2. During the alveolar stage, alveoli continue to multiply and mature, while the microvascular network develops to facilitate efficient gas exchange.
   3. The alveolar stage is marked by a fusion of the double capillary network leading to the formation of the definitive alveolar–capillary barrier.
   4. The alveolar stage marks the end of lung growth and concludes before the onset of microvascular network formation.
2. Which of the following statements is/are correct regarding PH in preterm infants?

   1. PH in preterm infants occurs in 15–20% of cases.
   2. PH in preterm infants is only due to immature alveoli, often associated with abnormal pulmonary vascular development.
   3. PH in preterm infants does not require specific treatment, as it typically resolves on its own within the first few weeks.
   4. PH in preterm infants is solely a consequence of PDA and does not directly affect the lungs.
3. Which of the following statements is/are correct regarding PVS in preterm infants?

   1. PVS in preterm infants is a rare condition that typically resolves without intervention.
   2. PVS in preterm infants is associated with an increased risk of PH and can complicate respiratory outcomes.
   3. PVS in preterm infants only affects one vein and does not have an impact on overall lung function.
   4. PVS in preterm infants is primarily caused by excessive oxygen exposure in the neonatal intensive care unit.
4. Which of the following statements is/are correct regarding PDA in preterm infants?

   1. Early surgical closure of PDA decreases the risk of BPD.
   2. Prolonged exposure to a haemodynamically significant PDA is a risk factor for BPD.
   3. PDA does not increase the risk of PH related to BPD.
   4. The increased pulmonary blood flow in case of PDA may induce endothelial injury.

Suggested answers

1. b and c.

2. a.

3. b.

4. b and d.