INTRODUCTION — Bronchopulmonary dysplasia (BPD), also known as neonatal chronic lung disease (CLD), is an important cause of respiratory illness in preterm newborns that results in significant morbidity and mortality.
The pathogenesis and clinical features of BPD are reviewed here. Management, prognosis, and potential strategies to prevent BPD are discussed separately. (See "Bronchopulmonary dysplasia: Management" and "Outcome of infants with bronchopulmonary dysplasia" and "Bronchopulmonary dysplasia: Prevention".)
TERMINOLOGY — Different degrees of prematurity are defined by gestational age (GA), which is calculated from the first day of the mother's last period, or birth weight (BW). Data on BPD are often based upon the following classification of preterm infants who are categorized by their BW or GA (table 1):
●Birth weight:
•Low birth weight (LBW) − BW less than 2500 g
•Very low birth weight (VLBW) − BW less than 1500 g
•Extremely low birth weight (ELBW) − BW less than 1000 g
●Gestational age:
•Late preterm infants – GA between 34 weeks and <37 weeks
•Moderate preterm – GA between 32 weeks and <34 weeks
•Very preterm (VPT) infants – GA at or below 32 weeks
•Extremely preterm (EPT) – GA less than 28 weeks
DEFINITIONS
Overview — BPD is a condition of chronic lung disease due to disruption of pulmonary development and injury in preterm infants (see 'Pathology' below). By contrast, the term chronic lung disease has been used to describe full-term infants with a variety of chronic conditions (eg, pulmonary hypoplasia, congenital diaphragmatic hernia) who require respiratory support, including oxygen supplementation.
Clinically, BPD is defined by a requirement of oxygen supplementation either at 28 days postnatal age or 36 weeks postmenstrual age. Several definitions have been used since the first description of BPD by Northway in 1967 (table 2). The authors believe that the best diagnostic definition to define severity of BPD utilizing data from a prospective study from National Institute of Child Health and Human Development (NICHD) is the 2019 revision based on the mode of respiratory support and not the degree of oxygen supplementation.
However, when evaluating the literature, it is important to identify the definitions used in each study, especially when comparing data across different studies, and to ensure that results are applicable to the clinical setting at hand [1,2]. Although BPD is one of the primary outcome measures of clinical trials for preterm infants, it has been challenging to reach a consensus definition as there are changes in the population at risk (ie, greater number of patients at earlier gestational ages [GA]) and advances in neonatal management (ie, surfactant and antenatal glucocorticoid therapy and less aggressive mechanical ventilation) that have impacted the initial description by Northway in 1967. These factors have altered the pathology and clinical course of BPD and led to revisions in its definition. BPD definitions that have been used include (table 2):
●BPD defined as a single entity of oxygen requirement either at 28 postnatal days or 36 weeks postmenstrual age (PMA) [3-5]. This definition does not account for extreme prematurity (ie, birth weight [BW] <1000 g or GA <28 weeks) and the severity of respiratory disease [5,6]. However, it is frequently used as the outcome measure for BPD in clinical trials because of its simplicity [1,7,8]. (See 'Oxygen supplementation alone' below.)
●2001 NICHD workshop categorized BPD based on severity, GA, and PMA (table 3). (See 'NICHD definition' below.)
However, the challenge of using different definitions was illustrated by a multicenter study that compared these definitions in diagnosing BPD in a cohort of 765 preterm infants (GA between 230/7 and 286/7 weeks) [1]. BPD was diagnosed in 41, 59, and 32 percent of patients using oxygen requirement alone, 2001 NICHD criteria, and physiologic testing, respectively. The number of unclassified patients was lowest (2 percent) using the 2001 NICHD criteria and highest (12 percent) using physiologic testing. The physiologic testing was the most difficult to apply, resulting in the largest number of patients who were not classified. Similar discrepancy in determining the incidence of BPD based on the definition was observed in a subsequent report from a single quaternary center [9].
In addition, these definitions do not incorporate interventions introduced since the 2001 NICHD workshop, and thus, not all infants with chronic lung injury are identified [10]. For example, in the above study, the definitions used provided no guidance on how to categorize infants who were supported by high-flow nasal cannulae or the use of positive pressure without oxygen supplementation [1]. These definitions are also limited by their inconsistency in predicting long-term pulmonary morbidity [10,11]. They also miss infants with the most severe lung damage who do not survive to 36 weeks PMA referred to as “early lethal BPD” [10]. As a result, additional consensus changes were made in 2016 to reflect ongoing changes in management and the at-risk population (table 2).
Oxygen supplementation alone — This definition based upon oxygen requirement either at 28 postnatal days or 36 weeks PMA is commonly used as an outcome measure for clinical trials due to its simple dichotomous manner (oxygen supplementation: yes or no?) [3,4,7]. However, it does not account for the effects of extreme prematurity (ie, BW <1000 g or GA <28 weeks) and the severity of respiratory disease leading to concerns that this definition is inadequate as an outcome measure and predictor of long-term pulmonary morbidity [5,6]. In particular, it becomes less accurate in predicting outcome with the increasing survival rate of extremely preterm (EPT) infants (GA <28 weeks) and the increased prevalence of milder forms of BPD due to improved treatment of respiratory distress syndrome.
NICHD definition — The NICHD definition has evolved from the original proposed definition in 2001 based on accumulating prospective data that have refined the definition with a goal of improving predictive outcome. This has resulted in the 2019 revised NICHD definition that the authors believe is the best diagnostic definition to define BPD and its severity (table 2).
●2001 definition – In 2001, a consensus workshop conference of the United States NICHD modified the preexisting definitions of oxygen requirement by adding criteria that included GA and severity of disease (table 3) [12]. The timing of assessment is based upon GA:
•Patients who are <32 weeks GA are assessed at 36 weeks PMA or when discharged home, whichever comes first.
•Patients who are ≥32 weeks GA are assessed between 29 to 55 days of age or when discharged home, whichever comes first.
Infants who require supplemental oxygen for at least 28 postnatal days are classified as having mild, moderate, or severe BPD, depending upon the extent of oxygen supplementation and other respiratory support. A study from the NICHD Neonatal Research Network reported that the NICHD criteria more accurately predicted pulmonary and neurodevelopmental outcomes at 18 to 22 months corrected age in preterm infants <32 weeks GA with BPD than the previous definition of oxygen supplementation alone [13]. In particular, the definition of supplemental oxygen at 36 weeks PMA would have missed a substantial number of patients with mild BPD who may be at risk for pulmonary and neurodevelopmental complications.
However, the 2001 NICHD criteria are still limited by their inability to identify infants using respiratory interventions developed after the convening of the workshop and the inability to accurately predict long-term pulmonary morbidity.
●2016 NICHD revisions — The initial 2001 definition for BPD was limited, as it did not account for interventions developed after 2001 (ie, respiratory support without supplemental oxygen), poorly predict long-term respiratory outcomes, and did not account for early lethal BPD [14]. In 2016, an NICHD workshop was held to revise the definition of BPD and to identify areas of research opportunity to address knowledge gaps [10].
Suggested refinements to the 2001 NICHD definition include (table 2):
•Addition of newer modes of noninvasive ventilation (eg, nasal cannula flow) not included in the previous 2001 NICHD definition.
•Reclassification of severity based on grades (I, II, III, IIIA) rather than the use of the more subjective terms of mild, moderate, and severe. The revision adds a new category (IIIA) for early lethal BPD for infants who die with lung disease between 14 days and 36 weeks postnatally.
•Adding radiographic evidence of pulmonary parenchymal disease to the definition.
●2019 NICHD revision — A prospective study from the NICHD network of 2677 very preterm (VPT) infants (GA <32 weeks, 90 percent of the cohort were extremely preterm (EPT) with GA <27 weeks) born between 2011 and 2015 reported that the best BPD definition out of 18 prespecified evaluated definitions to predict death or serious respiratory morbidity through 18 to 26 months of corrected age was based on the mode of respiratory support administered at 36 weeks PMA, regardless of whether supplemental oxygen was used [15]. In this study, the best diagnostic definition was a simplified version of the proposed 2016 revisions dependent only on the mode of respiratory support and not the degree of oxygen supplementation (table 2).
Ongoing research continues to evaluate the ability of this revised definition to predict outcome based on BPD severity. This was illustrated by a retrospective cohort study from the Vermont Oxford Network that applied the 2019 revised definition to a cohort of preterm infants (gestational age from 22 to 29 weeks) born in 2018 at 715 centers in the United States [16]. Among the 24,896 infants included in the study, approximately one-half (n = 12,198, 49 percent) did not develop BPD, 9192 (37 percent) developed grade 1 or 2 BPD, 932 (3.7 percent) developed grade 3 BPD, and 2574 (10.3 percent) died before reaching 36 weeks PMA. Grade 3 BPD compared with infants without BPD or with grade 1 or 2 BPD were more likely to have major comorbidities, die during birth hospitalization, or require supplemental oxygen support at discharge.
EPIDEMIOLOGY — The rate of BPD varies among institutions, which reflect different neonatal risk factors, care practices (eg, use of noninvasive ventilation, target levels for acceptable oxygen saturation), and differences in the clinical definitions of BPD [1,17-19]. Infants with birth weight (BW) <1250 g account for 97 percent of the cases of BPD [20]. For extremely preterm (EPT) infants (gestational age [GA] <28 weeks), the incidence of BPD is approximately 40 percent, and the risk increases with decreasing GA. (See 'Definitions' above.)
This was illustrated in a multicenter study from the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network of 9575 infants born between 2003 and 2007 with Gas of 22 to 28 weeks and BWs of 401 to 1500 g [21]. The overall incidence of BPD defined as requiring supplemental oxygen at 36 weeks postmenstrual age was 42 percent (range among centers 20 to 89 percent); the incidence using the physiologic definition was 40 percent (range 15 to 82 percent) (see 'Definitions' above). In this cohort, incidences for each gestational week with ranges among centers using the traditional definition of oxygen supplementation were as follows:
●22 weeks – 85 (0 to 100) percent
●23 weeks – 73 (35 to 100) percent
●24 weeks – 69 (31 to 100) percent
●25 weeks – 55 (20 to100) percent
●26 weeks – 44 (19 to 100) percent
●27 weeks – 34 (13 to 76) percent
●28 weeks – 23 (9 to 88) percent
In the study from the Vermont Oxford Network of 24,896 preterm infants (GA from 22 to 29 weeks) born in 2018, the risk of grade 3 BPD (2019 NICHD criteria) increased tenfold from 0.8 percent for infants born at 29 weeks GA to 9.9 percent for those born at 22 weeks GA [16]. Grade 3 BPD was associated with death and other nonrespiratory serious comorbid conditions. (See 'Nonrespiratory comorbidities' below.)
It is unclear whether or not the incidence of BPD is changing.
●In a report from the NICHD Neonatal Research Network, the incidence of BPD had not changed over a 20-year period from 1993 and 2012 except for an increased rate for infants born at 26 to 27 weeks gestation between 2009 and 2012 [22].
●A study using a United States national database (Nationwide Inpatient Sample) reported a decrease in the rate of BPD of 4.3 percent per year for the study period between 1993 and 2006 [23].
●However, a study in Japan of 19,370 EPT infants reported an increase in the incidence of BPD for the 17,126 survivors between 2003 and 2016 (46 versus 52 percent) [24]. During the same period of time, there was an increase in survival rate (81 to 92 percent).
Black infants appear to have a lower risk of BPD compared to White infants. In a prospective cohort study, Black American infants had a lower risk of BPD compared with White American infants even after adjusting for confounding risk factors (GA, antenatal steroid use, and intubation and surfactant administration at birth) [25].
Higher altitudes — Arterial partial pressure of oxygen (PaO2) and oxygen saturation are lower at high altitudes due to lower barometric pressure, which makes it more difficult to compare rates of BPD used between centers at high altitude and those at sea level [26,27]. The incidence of BPD incidence is greater in hospitals at higher altitudes when it was not corrected for barometric pressure.
PATHOLOGY — In extremely preterm (EPT) infants (gestational age [GA] <28 weeks) who were treated with surfactant, the characteristic pathologic finding of BPD is disruption of the late canalicular or saccular phases of lung development, referred to as the “new” BPD [12,28,29]. In these patients, the following pathologic findings occur:
●Decreased septation and alveolar hypoplasia lead to fewer and larger alveoli with a reduction in the surface area available for gas exchange.
●Dysregulation of pulmonary vasculature development with abnormal distribution of alveolar capillaries and thickening of the muscle layer of the pulmonary arterioles, which results in an increase in pulmonary resistance. Early disruption of vasculogenesis leading to pulmonary vascular disease results in pulmonary hypertension and contributes to morbidity and mortality [30].
●Increased elastic tissue formation and thickening of the interstitium. These tissue deformations may, in turn, compromise septation and capillary development. In one autopsy study, the amount of elastic tissue, septal thickness, and alveolar and duct diameters increased with the severity of BPD [31].
These findings are in contrast to “old” BPD seen before the 1980s in usually more mature infants (GA ≥28 weeks) who were cared for prior to the availability of surfactant replacement therapy and widespread use of antenatal steroids. The prominent pathologic findings in “old” BPD were airway injury, inflammation, and parenchymal fibrosis due to mechanical ventilation and oxygen toxicity (figure 1) [12,29]. Similar changes may be seen in certain surfactant-treated infants who develop severe BPD. In these severely affected infants, fibrosis, bronchial smooth muscle hypertrophy, and interstitial edema (“old” BPD) may be superimposed on the characteristic reduced numbers of alveoli and capillaries (“new” BPD). Pulmonary vascular changes, such as abnormal arterial muscularization and obliteration of vessels, may also occur.
PATHOGENESIS AND RISK FACTORS — The etiology of BPD is multifactorial and involves disruption of lung development and injury due to antenatal (intrauterine growth restriction, maternal smoking) and/or postnatal factors (eg, mechanical ventilation, oxygen toxicity, and infection) that cause inflammation and damage to the highly vulnerable premature lung [32] (figure 1). The following section discusses risk factors that contribute to the development of BPD.
Prematurity — The premature lung is susceptible to damage because of its immature, underdeveloped airway-supporting structures, surfactant deficiency, decreased compliance, underdeveloped antioxidant mechanisms, and inadequate fluid clearance [28,33,34]. The premature lung’s structural and functional immaturity increases the risk of injury and disruption of normal pulmonary microvascular and alveolar development from external antenatal and postnatal insults. As discussed above, BPD occurs primarily in extremely preterm (EPT) infants (gestational age [GA] <28 weeks), and the incidence increases with decreasing GA [21,35]. (See 'Epidemiology' above.)
Fetal growth restriction — Fetal (intrauterine) growth restriction in preterm infants is an independent risk factor for BPD [36-38]. Growth restriction may have a significant impact on the vulnerability of lung injury and vasculogenesis. In a case-control study that included 2255 infants with GA less than 33 weeks, infants born small for GA had more than twice the risk of BPD (odds ratio [OR] 2.73, 95% CI 2.11-3.55) [39]. (See "Infants with fetal (intrauterine) growth restriction".)
Maternal smoking — It appears that maternal smoking negatively affects lung development in offspring, resulting in decreased forced expiratory flows and decreased passive respiratory compliance, which increases the risk of BPD [10,40]. In a prospective, longitudinal study of 587 preterm infants (GA <34 weeks and birth weight [BW] between 500 and 1250 g), multivariate analysis found maternal smoking before preterm birth increased the odds of BPD twofold (95% CI 1.09-3.74) [41]. However, this study was limited as only 80 of the 587 mothers had smoked during their pregnancy.
Mechanical ventilation — Injury caused by mechanical ventilation primarily is due to large tidal volumes (volutrauma) that overdistend airways and airspaces, rather than increased airway pressures [42-44]. For EPT infants who received mechanical ventilation at postnatal day 7, the risk of BPD is high [45]. The risk increases with decreasing arterial carbon dioxide tension (partial pressure of carbon dioxide [PaCO2]) as a measure of more aggressive ventilation (eg, large tidal volumes) [3,46].
Because of the strong evidence that aggressive mechanical ventilation plays a major role in the pathogenesis of BPD, management of preterm infants requiring respiratory support has moved towards initial noninvasive measures (eg, nasal continuous airway pressure [nCPAP]) to avoid mechanical ventilation. Differences in the approach for respiratory support including the use of mechanical ventilation may explain some of the variation among hospitals in BPD rates. However, despite the use of noninvasive respiratory support, up to 50 percent of EPT infants will be intubated and mechanically ventilated. If mechanical ventilation is needed, a more conservative approach of volume-targeted ventilation using small tidal volume versus pressure-targeted ventilation is utilized (table 4) [47]. (See "Bronchopulmonary dysplasia: Prevention", section on 'Ventilation strategies to minimize lung injury' and "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Respiratory support devices' and "Approach to mechanical ventilation in very preterm neonates".)
Oxygen toxicity — High concentrations of inspired oxygen can damage the lungs, although the exact level or duration of exposure that is unsafe is not known. The risk of BPD for EPT infants rises with increasing accumulation of supplemental oxygen during the first two weeks after delivery [48]. It is thought that cellular damage is caused by the overproduction of cytotoxic reactive oxygen metabolites (ie, superoxide free radical, hydrogen peroxide, hydroxyl free radical, and singlet oxygen), which overwhelm the neonate’s immature antioxidant system, resulting in inflammation and lung injury [49]. Preterm infants are most susceptible to oxygen toxicity compared with term infants due to their more immature antioxidant enzyme systems (superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase) [50,51].
Infection — Both postnatal and antenatal infections have been reported to be associated with BPD:
●Postnatal – Sepsis is associated with an increased risk of BPD. This was illustrated in an observational study from a single Australian tertiary center of 798 preterm infants (mean GA 27.4 weeks) born between 1992 and 2004 that reported neonatal sepsis increased the risk of BPD (OR 2.71, 95% CI 1.64-4.51) [52]. Infants with candidemia had the highest risk of developing BPD (OR 8.68, 95% CI 1.65-45.63).
Infection with Ureaplasma urealyticum has been reported to cause a sustained dysregulated inflammatory response that impairs lung development, resulting in BPD [53,54]. A systematic review of the literature noted that infants with pulmonary colonization with Ureaplasma were more likely to develop BPD than those without colonization at 36 weeks postmenstrual age (OR 2.22, 95% CI 1.42-3.47) or at 28 days of life (OR 3.04, 95% CI 2.41-3.83) [55]. Whether eradication of Ureaplasma respiratory colonization acquired in utero by preterm infants reduces the incidence of BPD requires testing in clinical trials [56,57] In a randomized trial of azithromycin to improve Ureaplasma free-survival in 121 preterm infants (GA <29 weeks), subgroup analysis found that physiological BPD-free survival was 50 percent (95% CI 19 - 81 percent) among azithromycin-assigned infants with lower respiratory tract Ureaplasma colonization versus 18 percent (95% CI 2 - 52 percent) in placebo-treated infants [58].
●Antenatal – Although antenatal infection has been suggested as a risk factor in the development of BPD [59-61], it remains uncertain whether a clinical relationship between chorioamnionitis and BPD exists [49].The hypothesis is based on the finding of increased concentration of proinflammatory cytokines (interleukin [IL]-6, IL-1 beta, and IL-8) in the amniotic fluid of infants who subsequently develop BPD compared with those who did not [62]. Systematic reviews have reported conflicting results regarding an association between BPD and chorioamnionitis [63-65]. There is also substantial heterogeneity among studies due to differences in study design, the GA of patients, therapeutic interventions (eg, antenatal corticosteroid administration), and the definitions used for BPD and chorioamnionitis, as well as potential publication bias. In addition, other factors including gestational age and the risk of respiratory distress syndrome may modulate the effect of chorioamnionitis. (See 'Inflammation' below.)
Inflammation — The development of BPD may begin before birth in some newborns through intrauterine exposure to proinflammatory cytokines, possibly due to chorioamnionitis. However, this relationship remains controversial. Inflammation is a common pathway for many injuries that may disrupt late lung development. Evidence for a role for lung inflammation in the pathogenesis is based on the elevated concentration of proinflammatory and chemotactic factors in the tracheal aspirates of infants who subsequently develop BPD compared with those without BPD [49,66-68]. The presence of these mediators is associated with complement activation, increased vascular permeability, protein leakage, and mobilization of neutrophils into the interstitial and alveolar compartments. Release of reactive oxygen radicals, elastase, and collagenase by activated neutrophils results in lung damage [69]. Interaction between macrophages and other cell types (eg, endothelial and epithelial cells) perpetuates the production of proinflammatory mediators and sustains the cycle of lung injury. Persistence of factors (eg, macrophage inflammatory protein-1 and IL-8) and decreases of counterregulatory cytokines (eg, IL-10, IL-17) may lead to unregulated and persistent inflammation [12].
Patent ductus arteriosus — The role of the patent ductus arteriosus (PDA) in the development of BPD is uncertain. Although clinical trials conducted before 2000 consistently reported that PDA was associated with BPD, the accuracy of these results has been questioned due to study design issues [10]. Subsequent studies of prophylactic indomethacin to prevent PDA resulted in conflicting results on the risk of BPD [70,71]. Ongoing research efforts are focused on comparing early versus no or late treatment of PDA and hope to address whether a persistent PDA contributes to the development of BPD. (See "Patent ductus arteriosus in preterm infants: Pathophysiology, clinical manifestations, and diagnosis", section on 'Consequences of a PDA'.)
Genetics — It remains uncertain whether there is a genetic predisposition that may influence the development of BPD as illustrated in the difference in results between twin cohort studies of preterm infants [72,73].
Similarly, conflicting results were reported in studies trying to identify genetic factors associated with BPD:
●A genome-wide association study (GWAS) that included 899 cases of BPD and 827 controls did not identify any single-nucleotide polymorphisms (SNPs) associated with BPD [74]. These negative findings may have missed a genetic risk due to epigenetic effects, copy number variations, or joint effects of multiple SNPs or interaction among them.
●In a retrospective study of 157 preterm infants who developed respiratory distress syndrome requiring mechanical ventilation, two specific SNPs of a gene encoding for endothelial nitric oxide synthase (eNOS) were independent predictors of an increased risk of developing BPD [75].
●In another study of 751 infants of whom 428 developed BPD or died, pathway analysis of a GWAS identified involvement of several known pathways of lung development and repair that were significant for severe BPD or death and indicated specific molecules that were increased in patients with BPD [76].
Further studies are required to determine whether or not there is a genetic predisposition, and if so, what the underlying genetic factors are.
Late surfactant deficiency — Delayed recovery or late deficiency of postnatal surfactant may play a role in the pathogenesis of BPD. In a study of 68 ventilator-dependent preterm infants (GA between 23 and 30 weeks), 75 percent of tracheal aspirates exhibited abnormally low surface tension [77]. In these samples, surfactant proteins A, B, and C were reduced by 50, 80, and 72 percent, respectively. There also appears to be a temporal association between samples with low surface tension and episodes of infection and respiratory deterioration. These results suggest that preterm infants who require continued respiratory support have transient surfactant dysfunction or deficiency, which may affect their clinical status. However, it appears that late administration of surfactant does not appear to reduce the risk of BPD, as discussed separately. (See "Management of respiratory distress syndrome in preterm infants", section on 'Timing'.)
Impaired angiogenesis — There is increasing evidence that suggests the growth of lung blood vessels actively promotes alveolar growth. Disruption of angiogenesis has been proposed as a mechanism that impairs alveolarization, thereby contributing to the new form of BPD [78]. (See 'Pathology' above.)
Support for the potential role of impaired angiogenesis in the pathogenesis of BPD includes:
●In one study, elevated cord plasma endostatin levels, an antiangiogenic growth factor, was associated with an increased risk of BPD in very low birth weight (VLBW) infants (BW <1500 g) [79].
●In a study of preterm infants less than 35 weeks gestation, cord blood level of placenta growth factor (PlGF), but not vascular endothelial growth factor or soluble fms-like tyrosine kinase-1, was elevated in infants who subsequently developed BPD [80].
●Observational studies have shown that the risk of BPD is twofold greater in infants born to mothers with preeclampsia compared with those born to mothers without preeclampsia [81,82]. These findings suggest factors that trigger maternal endothelial dysfunction (impaired angiogenesis), resulting in preeclampsia, are transferred to infants, which may contribute to the pathogenesis of BPD. (See "Preeclampsia: Pathogenesis", section on 'Role of systemic endothelial dysfunction in clinical findings'.)
CLINICAL FEATURES — BPD is associated with multiple risk factors, including prematurity, mechanical ventilation, oxygen toxicity, and infection. It occurs most frequently in extremely preterm (EPT) infants (gestational age [GA] <28 weeks) [10,20].
Although the need for oxygen supplementation may be present at two weeks of age, the relationship between oxygen need and subsequent development of BPD is not totally predictable. This was illustrated in the previously mentioned Extremely Low Gestational Age Newborns (ELGAN) study that enrolled 1340 EPT infants in a multicenter prospective study between 2002 and 2004 [35]. During the first two weeks of postnatal life, three clinical pulmonary courses emerged with differing rates of BPD (defined as oxygen therapy at 36 weeks’ postmenstrual age [PMA]).
●Approximately 40 percent had persistent lung dysfunction, defined as a consistent requirement of fraction of inspired oxygen (FiO2) above 0.25. Approximately two-thirds of these patients developed BPD.
●Approximately 40 percent had deterioration of lung dysfunction, defined as an increase of FiO2 above 0.25 at 14 days of age. Approximately one-half of these patients developed BPD.
●Approximately 20 percent had no or minimal lung dysfunction, defined as no consistent need of FiO2 above 0.25. Only 17 percent of this group developed BPD.
Physical examination — The physical examination is variable. Infants with BPD usually are tachypneic. Depending upon the extent of pulmonary edema and/or atelectasis, they may have mild to severe retractions, and scattered rales may be audible. Intermittent expiratory wheezing may be present in infants with airway narrowing from scar formation, constriction, mucus retention, collapse, and/or edema.
Chest radiograph — As BPD evolves, the chest radiograph also changes from clear lung fields to findings that include diffuse haziness and a coarse interstitial pattern, which reflect atelectasis, inflammation, and/or pulmonary edema (image 1). Lung volumes are normal or low. With further evolution of the disease, there may be areas of atelectasis that alternate with areas of gas trapping, related to airway obstruction from secretions or bronchiolar injury.
The chest radiograph in infants who develop severe BPD shows hyperinflation. Streaky densities or cystic areas may be prominent, corresponding to fibrotic changes (image 1). During acute exacerbations, pulmonary edema may be apparent.
Cardiopulmonary function — Patients with more severe BPD are hypoxemic and hypercapnic and typically require mechanical ventilation and oxygen supplementation. They have abnormal pulmonary function including decreased tidal volume, increased airway and vascular resistance, and decreased dynamic lung compliance and uneven airway obstruction resulting in gas trapping and hyperinflation with abnormal distribution of ventilation [83]. Bronchomalacia can result in airway collapse during expiration.
In a prospective study, pulmonary function measurements of forced expiratory flows classified infants with severe BPD at a median age of 52 weeks PMA into 1 of 3 distinct phenotypes of obstructive, mixed, or restrictive [84].
In many of these patients, pulmonary vascular resistance is increased because of disruption of pulmonary vascular growth and/or reduced cross-sectional area of pulmonary vessels, resulting in pulmonary hypertension. Alveolar hypoxia in underventilated areas of the lung induces local vasoconstriction. The high microvascular pressure promotes increased fluid filtration into the perivascular interstitium. Elevated right atrial pressure inhibits pulmonary lymphatic drainage, further promoting pulmonary edema.
DIAGNOSIS — The diagnosis of BPD is based on fulfilling criteria based on a standardized definition as discussed above. In our centers, we make the clinical diagnosis based on the need for oxygen supplementation at 36 weeks postmenstrual age as it is the easiest one to apply in practice. A physiologic test (oxygen reduction test) can be performed to define the actual need for oxygen supplementation to confirm the diagnosis. Infants are classified as having BPD if the oxygen saturation falls below 90 percent within 60 minutes of being placed in room air. Corrections for altitude are needed while using the physiologic test at higher altitudes. The National Institute of Child Health and Human Development (NICHD) definition based on the need for oxygen supplementation, the gestational age (GA) and postmenstrual age (PMA) of the patient, and severity of disease are primarily used in the research setting (table 2) [12]. (See 'Definitions' above.)
CLINICAL COURSE — Most infants improve gradually in the two to four months after the diagnosis of BPD is made. As pulmonary function improves with growth, they can be weaned to continuous positive airway pressure (CPAP) or high-flow nasal cannula (HFNC) with supplemental oxygen, then supplemental oxygen alone, until they can maintain adequate oxygenation when breathing room air. (See "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Respiratory support devices'.)
Some infants develop severe BPD that leads to prolonged ventilator dependence [85]. Their clinical course during the first few weeks after birth includes marked instability with swings in oxygen saturation and intermittent episodes of acute deterioration requiring increased ventilator support [86]. The marked instability typically improves slowly after four to six weeks. However, some of these infants require ventilator support or supplemental oxygen beyond six months of age. (See "Bronchopulmonary dysplasia: Management", section on 'Pharmacologic interventions for more advanced BPD'.)
Pulmonary hypertension — Pulmonary artery hypertension (PAH) is increasingly recognized as an important complication associated with BPD and is discussed in greater detail separately. (See "Complications and long-term pulmonary outcomes of bronchopulmonary dysplasia", section on 'Pulmonary hypertension' and "Pulmonary hypertension associated with bronchopulmonary dysplasia", section on 'Epidemiology and natural history'.)
Other comorbid respiratory conditions — Other comorbid respiratory conditions and complications that are seen in infants with BPD include bronchospasm, acquired tracheobronchomalacia, subglottic stenosis, and aspiration. (See "Complications and long-term pulmonary outcomes of bronchopulmonary dysplasia", section on 'Respiratory disorders associated with bronchopulmonary dysplasia'.)
Nonrespiratory comorbidities — Nonrespiratory comorbid conditions associated with BPD include bacterial sepsis and meningitis, brain injury (intraventricular hemorrhage [IVH] or cystic periventricular leukomalacia), significant patent ductus arteriosus (PDA, surgical or medical closure), necrotizing enterocolitis (NEC), and retinopathy of prematurity [16]. Infants with grade 3 BPD (based on 2019 NICHD definition) are at greater risk for these comorbid conditions.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bronchopulmonary dysplasia".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topics (see "Patient education: Bronchopulmonary dysplasia (The Basics)")
SUMMARY — Bronchopulmonary dysplasia (BPD) remains a major complication of prematurity, resulting in significant mortality and morbidity. (See "Outcome of infants with bronchopulmonary dysplasia".)
●Definition – Several different definitions are used to describe BPD (table 2). When evaluating the literature, it is important to have an appreciation of the definitions used and their limitations, especially if comparing data across different studies and to ensure that results are applicable to the clinical setting at hand. (See 'Definitions' above.)
●Epidemiology – Infants with birth weights (BW) <1250 g account for 97 percent of the cases of BPD. For extremely preterm (EPT) infants (gestational age [GA] <28 weeks), the incidence of BPD is approximately 40 percent, and the risk increases with decreasing GA (See 'Epidemiology' above.)
●Diagnosis – In our centers, the clinical diagnosis of BPD is based on the need for oxygen supplementation at 36 weeks postmenstrual age (PMA) as it is the easiest one to apply in practice. The diagnosis can be confirmed by physiologic testing (oxygen reduction test) if the oxygen saturation falls below 90 percent within 60 minutes of being placed in room air, documenting a need for oxygen supplementation. (See 'Diagnosis' above.)
●Pathogenesis –The etiology of BPD is multifactorial and involves disruption of lung development and injury due to antenatal (intrauterine growth restriction, maternal smoking) and/or postnatal factors (eg, mechanical ventilation, oxygen toxicity, and infection) (figure 1). (See 'Pathogenesis and risk factors' above.)
•Infants who require oxygen supplementation above a fraction of inspired oxygen (FiO2) of 25 percent at two weeks of age are at significant risk for developing BPD. (See 'Clinical features' above.)
●Clinical features
•Physical examination –Although the physical findings of BPD vary, most affected infants are tachypneic. Other findings include retractions, rales, and wheezes. (See 'Physical examination' above.)
•Chest radiograph – The chest radiograph in infants with BPD changes with evolution of the disease from clear lung fields to findings that include diffuse haziness and a coarse interstitial pattern, which reflect atelectasis, inflammation, and/or pulmonary edema (image 1). (See 'Chest radiograph' above.)
•Cardiopulmonary abnormalities - Patients with severe BPD are hypoxemic and hypercapnic because of significant cardiopulmonary abnormalities. These include decreased tidal volume, increased airway resistance, decreased dynamic lung compliance, uneven airway obstruction resulting in trapping and hyperinflation with abnormal distribution of ventilation, and increased vascular resistance. (See 'Cardiopulmonary function' above.)
●Clinical course – Most infants with BPD improve gradually during the first two to four months. Those with severe disease may have a prolonged course of mechanical ventilation and may develop pulmonary hypertension and cor pulmonale. (See 'Clinical course' above and "Complications and long-term pulmonary outcomes of bronchopulmonary dysplasia", section on 'Pulmonary hypertension' and "Pulmonary hypertension associated with bronchopulmonary dysplasia", section on 'Epidemiology and natural history'.)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge James Adams, Jr., MD, who contributed to an earlier version of this topic review.
