Bronchopulmonary Dysplasia - Definition, Pathogenesis, and Clinical Features - UpToDate

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Bronchopulmonary dysplasia: Definition, pathogenesis, and clinical features

Authors: Eric C Eichenwald, MD, Ann R Stark, MD
Section Editors: Gregory Redding, MD, Richard Martin, MD
Deputy Editor: Melanie S Kim, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2020. | This topic last updated: Jan 07, 2020.
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

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• 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
DEFINITION
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.
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. When evaluating the literature, it is important to have an appreciation of the definitions used and their limitations, especially when
comparing data across different studies, and to ensure that results are applicable to the clinical setting at hand [1,2].
BPD definitions that have been used include:
● 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 National Institute of Child Health and Human Development (NICHD) workshop categorized BPD based on severity, GA, and PMA (
table 2). (See '2001 NICHD definition' below.)
However, the challenge of using these 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.
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 [9]. 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 [9,10]. They also miss infants with the most severe lung
damage who do not survive to 36 weeks PMA referred to as "early lethal BPD" [9]. As a result, additional consensus changes were made in
2016 to reflect ongoing changes in management and the at-risk population ( table 3). (See '2016 NICHD proposed revisions' below.)
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. As an example, an EPT infant with
mild BPD disease who required oxygen within the first 28 days of age, but not at 36 weeks PMA, would not be diagnosed as having BPD.
2001 NICHD 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 2) [11]. 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 [12]. 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. (See '2016 NICHD proposed revisions'
below.)
To standardize the use of supplemental oxygen, the 2001 NICHD criteria also proposed that the need for oxygen be confirmed by using a
physiologic test, although a specific test was not defined. It was thought that adoption of a BPD definition based upon physiologic testing
would reduce the effect of clinical practice variations when comparing outcome among centers caring for these patients.
Initially, infants were classified as having BPD if their oxygen saturation fell below <88 percent within 60 minutes of a "room air challenge" [13].
Subsequently, the oxygen saturation level was raised to <90 percent [14,15].
2016 NICHD proposed revisions — As noted above, the previous unrevised definitions for BPD were limited as they do not account for
interventions developed after 2001 (ie, respiratory support without supplemental oxygen), poorly predict long-term respiratory outcomes, and
do not account for early lethal BPD [16]. In 2016, an NICHD workshop was held to revise the definition of BPD and to identify areas of research
opportunity to address knowledge gaps [9].
Suggested refinements to the 2001 NICHD definition include ( table 3):
● 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 Assessment — 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 [17]. The predictive accuracy range
amongst the various definitions was narrow but statistically significant from 79 percent (using the definition based on respiratory support
alone) to 74 percent (definition similar to the 2001 NICHD definition) in predicting late death and serious respiratory morbidity. These results
highlight the need to include data regarding the use of newer respiratory care. Further efforts to provide the most clinically pragmatic
definition for BPD will need to validate and incorporate these findings. 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 3).
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 [18,19]. The
incidence of BPD incidence is greater in hospitals at higher altitudes when it was not corrected for barometric pressure.
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 [1,20-22]. Infants with birth weight (BW) <1250 g
account for 97 percent of the cases of BPD [23]. 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 'Definition' 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 [24]. 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 'Definition' 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



● 25 weeks – 55 (20 to100) percent
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 [25]. By contrast, 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 [26].
In addition, a prospective cohort study reported that black infants have a lower risk of BPD compared with white infants even after adjusting
for confounding risk factors (GA, antenatal steroid use, and intubation and surfactant administration at birth) [27].
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 [11,28,29]. 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) [11,29]. 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 [24,35]. (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 [9,40]. 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 [47]. (See "Bronchopulmonary dysplasia: Prevention", section on
'Protective ventilation strategies' and "Prevention and treatment of respiratory distress syndrome in preterm infants", section on 'Failure of
CPAP' and "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Respiratory support and oxygen use
post-delivery devices' and "Mechanical ventilation in neonates", section on 'Comparison between pressure- and volume-controlled
ventilation'.)
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].
● Antenatal – Although antenatal infection has been suggested as a risk factor in the development of BPD [58-60], 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 [61]. Systematic reviews have reported conflicting results regarding an association
between BPD and chorioamnionitis [62-64]. 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 [49,65-67]. 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 [68]. 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 [11].
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 [9]. Subsequent studies of prophylactic indomethacin to prevent PDA resulted in conflicting results on the risk of BPD
[69,70]. 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 'Bronchopulmonary dysplasia'.)
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 [71,72].
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 [73]. 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 [74].
● 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 [75].
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 [76]. 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 reduce the risk of BPD. In addition, a combination of

nitric oxide and surfactant does not prevent BPD. These interventions are discussed separately. (See "Bronchopulmonary dysplasia:
Prevention", section on 'Combination of surfactant and nitric oxide'.)
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 [77].
(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) [78].
● 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 [79].
● 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 [80,81]. 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) [9,23].
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 [82]. 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 [83].
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. We also
perform a physiologic test (oxygen reduction test) 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 3) [11]. (See 'Definition' 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 and oxygen use post-delivery devices'.)
Some infants develop severe BPD that leads to prolonged ventilator dependence [84]. 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 [85]. 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'.)
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".)
● Several different definitions are used to describe BPD ( table 3). 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 'Definition' above.)
● 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.)
● In our centers, we make the clinical diagnosis 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 is 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.)
● 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.)
● Although the physical findings of BPD vary, most affected infants are tachypneic. Other findings include retractions, rales, and wheezes.
(See 'Physical examination' above.)
● 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.)
● 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.)
● 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 would like to acknowledge James Adams, Jr., MD, who contributed to an earlier version of this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
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Topic 4987 Version 34.0

GRAPHICS
Classification of prematurity categorized by birth weight or gestational age
Birth weight
Low birth weight (LBW) <2500 g
Very low birth weight (VLBW) <1500 g
Extremely low birth weight (ELBW) <1000 g
Gestational age
Late preterm 34 weeks to <37 weeks
Moderate preterm 32 weeks to <34 weeks
Very preterm ≤32 weeks
Extremely preterm <28 weeks
In using these definitions, the definition of VLBW infants includes ELBW infants, and the category of very preterm infants also includes those who are extremely preterm. This is an important
consideration when one is reviewing published data of VLBW and very preterm infants.
Graphic 119362 Version 1.0

Definition of bronchopulmonary dysplasia: Diagnostic criteria 2001 NICHD consensus workshop
Gestational age

<32 weeks ≥32 weeks
Time point of 36 weeks PMA or discharge to home, whichever comes first >28 days but <56 days postnatal age or discharge to home, whichever comes first
assessment
Treatment with oxygen >21% for at least 28 days plus
Mild BPD Breathing room air at 36 weeks PMA or discharge, whichever comes first Breathing room air by 56 days postnatal age or discharge, whichever comes first
Moderate BPD Need* for <30% oxygen at 36 weeks PMA or discharge, whichever comes first Need* for <30% oxygen at 56 days postnatal age or discharge, whichever comes first
Severe BPD Need* for ≥30% oxygen and/or positive pressure (PPV or nCPAP) at 36 weeks PMA or Need* for ≥30% oxygen and/or positive pressure (PPV or nCPAP) at 56 days postnatal age
discharge, whichever comes first or discharge, whichever comes first
BPD usually develops in neonates being treated with oxygen and PPV for respiratory failure, most commonly, respiratory distress syndrome. Persistence of clinical features of respiratory
disease (tachypnea, retractions, rales) are considered common to the broad description of BPD and have not been included in the diagnostic criteria describing the severity of BPD. Infants
treated with oxygen >21% and/or positive pressure for nonrespiratory disease (eg, central apnea or diaphragmatic paralysis) do not have BPD unless they also develop parenchymal lung
disease and exhibit clinical features of respiratory distress. A day of treatment with oxygen >21% means that the infant received oxygen >21% for more than 12 hours on that day. Treatment
with oxygen >21% and/or positive pressure at 36 weeks PMA, or at 56 days postnatal age or discharge, should not reflect an "acute" event but should rather reflect the infant's usual daily
therapy for several days preceding and following 36 weeks PMA, 56 days postnatal age, or discharge.
NICHD: National Institute of Child Health and Human Development; PMA: postmenstrual age; BPD: bronchopulmonary dysplasia; PPV: positive pressure ventilation; nCPAP: nasal continuous positive airway
pressure.
* A physiologic test confirming that the oxygen requirement at the assessment time point remains to be defined. This assessment may include a pulse oximetry saturation range.
Reproduced with permission from: Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001; 163:1723. Copyright © 2001 American Thoracic Society.

Definition of bronchopulmonary dysplasia
I. Oxygen supplementation alone

Oxygen supplementation either at 28 days postnatal age or 36 weeks PMA
II. Diagnostic criteria 2001 NICHD consensus workshop* [1]

Gestational age
<32 weeks ≥32 weeks
Time point of assessment 36 weeks PMA or discharge to home, whichever comes first >28 days but <56 days postnatal age or discharge to home, whichever comes first
Grade Treatment with oxygen >21% for at least 28 days plus Treatment with oxygen >21% for at least 28 days plus
Mild BPD Breathing room air at 36 weeks PMA or discharge, whichever Breathing room air by 56 days postnatal age or discharge, whichever comes first
comes first
Moderate BPD Need* for <30% oxygen at 36 weeks PMA or discharge, Need* for <30% oxygen at 56 days postnatal age or discharge, whichever comes first
whichever comes first
Severe BPD Need* for ≥30% oxygen and/or positive pressure (PPV or nCPAP) Need* for ≥30% oxygen and/or positive pressure (PPV or nCPAP) at 56 days postnatal age or
at 36 weeks PMA or discharge, whichever comes first discharge, whichever comes first
IIa. 2016 Revisions of NICHD criteria based on oxygen concentration (percentage) [2]¶
Grades Δ Invasive IPPV nCPAP, NIPPV, or nasal Nasal cannula flow of 1 to <3 Nasal cannula flow of <1 Hood O 2
cannula ≥3 L/min L/min L/min
I (mild) – 21 22 to 29 22 to 70 22 to 29
II (moderate) 21 22 to 29 ≥30 ≥70 ≥30
III (severe) >21 ≥30 – – –
III(A) ◊ – – – – –
III. 2019 Diagnosis based on prospective NICHD study [3]

Grades Δ Invasive PPV nCPAP or NIPPV Nasal cannula flow of >2 Nasal cannula flow of <2
L/min L/min
I (mild) – – – ≥21
II (moderate) – ≥21 ≥21 –
III (severe) ≥21 – – –
A preterm infant (<32 weeks gestational age) with BPD has persistent parenchymal lung disease confirmed by radiography, and at 36 weeks PMA requires 1 of the above interventions based on
FiO 2 ranges.
PMA: postmenstrual age; NICHD: National Institute of Child Health and Human Development; BPD: bronchopulmonary dysplasia; PPV: positive pressure ventilation; nCPAP: nasal continuous airway
pressure; IPPV: intubation and positive pressure ventilation; NIPPV: noninvasive intermittent positive pressure ventilation; O 2 : oxygen.
* Persistence of clinical features of respiratory disease (tachypnea, retractions, rales) are considered common to the broad description of BPD and have not been included in the diagnostic criteria

describing the severity of BPD. Infants treated with oxygen >21% and/or positive pressure for nonrespiratory disease (eg, central apnea or diaphragmatic paralysis) do not have BPD unless they also develop
parenchymal lung disease and exhibit clinical features of respiratory distress. A day of treatment with oxygen >21% means that the infant received oxygen >21% for more than 12 hours on that day.
Treatment with oxygen >21% and/or positive pressure at 36 weeks PMA, or at 56 days postnatal age or discharge, should not reflect an "acute" event, but should rather reflect the infant's usual daily therapy
for several days preceding and following 36 weeks PMA, 56 days postnatal age, or discharge.
¶ A premature infant (<32 weeks gestational age) with BPD has persistent parenchymal lung disease, radiographic confirmation of parenchymal lung disease, and at 36 weeks PMA requires one of the
above interventions based on FiO 2 ranges.
Δ Grades have been renamed from the 2001 criteria.
◊ III(A) Early death (between 14 days of postnatal age and 36 weeks) owing to persistent parenchymal lung disease and respiratory failure that cannot be attributable to other neonatal morbidities (eg,
necrotizing enterocolitis, intraventricular hemorrhage, redirection of care, episodes of sepsis, etc).
References:
1. Reproduced with permission from: Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001; 163:1723. Copyright © 2001 American Thoracic Society.
2. Reproduced from: Higgins RD, Jobe AH, Koso-Thomas M, et al. Bronchopulmonary Dysplasia: Executive Summary of a Workshop. J Pediatr 2018; 197:300. Table used with the permission of Elsevier Inc. All rights
reserved.
3. Jensen EA, Dysart K, Gantz MG, et al. The Diagnosis of Bronchopulmonary Dysplasia in Very Preterm Infants: An Evidence-based Approach. Am J Respir Crit Care Med; 2019: 751.

Pathogenesis of bronchopulmonary dysplasia (BPD)
Exposure to antenatal pulmonary insults during the saccular state of lung development result in
developmental arrest or delay in pulmonary maturation ("new" bronchopulmonary dysplasia
[BPD]), whereas postnatal insults cause structural pulmonary injury ("old" BPD).
Adapted from: Baraldi E, Filippone M. Chronic lung disease after premature birth. N Engl J Med 2007; 357:1946.

Sequential chest radiographs of bronchopulmonary dysplasia (BPD) in a premature

infant


Image A is a chest radiograph taken after birth of a premature infant born at 25 weeks. The lungs are clear.
Image B is a chest radiograph taken two weeks later, which shows a coarsened interstitial pattern and diffuse
haziness. Image C is a radiograph that shows further coarsening of the lung markings five weeks after birth.
Image D shows pulmonary congestion after closure of a patent ductus arteriosus (arrow shows clip). Image E is
a magnification of image D and shows cystic changes in the lungs (arrows).

Contributor Disclosures
Eric C Eichenwald, MD Nothing to disclose Ann R Stark, MD Nothing to disclose Gregory Redding, MD Nothing to disclose Richard Martin,
MD Consultant/Advisory Boards: Windtree [Surfactant inhalation trial]; CareFusion in automated oxygenation control trial [STAMINA]. Melanie S Kim,
MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review
process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

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Bronchopulmonary dysplasia: Definition, pathogenesis, and clinical features

• Low birth weight (LBW) − BW less than 2500 g

• Very low birth weight (VLBW) − BW less than 1500 g

• Late preterm infants – GA between 34 weeks and <37 weeks

BPD definitions that have been used include:

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Suggested refinements to the 2001 NICHD definition include ( table 3):

● Adding radiographic evidence of pulmonary parenchymal disease to the definition.

● 22 weeks – 85 (0 to 100) percent

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● 24 weeks – 69 (31 to 100) percent

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PATHOGENESIS AND RISK FACTORS

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SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

● Basics topics (see "Patient education: Bronchopulmonary dysplasia (The Basics)")

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Classification of prematurity categorized by birth weight or gestational age

Low birth weight (LBW) <2500 g

Very low birth weight (VLBW) <1500 g

Extremely low birth weight (ELBW) <1000 g

Late preterm 34 weeks to <37 weeks

Moderate preterm 32 weeks to <34 weeks

Very preterm ≤32 weeks

Extremely preterm <28 weeks

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Definition of bronchopulmonary dysplasia: Diagnostic criteria 2001 NICHD consensus workshop

Treatment with oxygen >21% for at least 28 days plus

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Definition of bronchopulmonary dysplasia

I. Oxygen supplementation alone

II. Diagnostic criteria 2001 NICHD consensus workshop* [1]

<32 weeks ≥32 weeks

II (moderate) 21 22 to 29 ≥30 ≥70 ≥30

III (severe) >21 ≥30 – – –

III. 2019 Diagnosis based on prospective NICHD study [3]

II (moderate) – ≥21 ≥21 –

III (severe) ≥21 – – –

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Pathogenesis of bronchopulmonary dysplasia (BPD)