11th Bengt Robertson Memorial Lecture
Neonatology 2019;115:384–391
DOI: 10.1159/000497422
Bronchopulmonary Dysplasia: 50 Years
after the Original Description
Eduardo Bancalari Deepak Jain
Division of Neonatology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, USA
Keywords
BPD · Premature · Prevention · Management
Abstract
Bronchopulmonary dysplasia (BPD) is one of the few diseas-
es in neonatal medicine that has continued to evolve since
its first description about 50 years ago. Over these years, ad-
vancements in neonatal medicine such as antenatal steroids
and exogenous surfactant therapy have significantly re-
duced neonatal mortality and lowered the limits of viability
for preterm infants. Although the incidence of BPD contin-
ues to be high, especially in extremely low birth weight in-
fants, the clinical picture has evolved into a milder disease
with low mortality or significant morbidities. This new BPD is
the result of complex interactions between altered alveolar
and vascular development, injury by ante- and postnatal
pathogenic factors, and reparative processes in the lung.
There has been significant progress in our understanding of
risk factors for BPD, but challenges persist in its definition,
and in finding effective preventive strategies. There are
promising developments with newer preventive interven-
tions such as mesenchymal stem cells, exosomes, immuno-
© 2019 S. Karger AG, Basel
E-Mail karger@karger.com
www.karger.com/neo
Published online: April 11, 2019
modulators, and growth factors, but they are still in preclini-
cal stage. The future challenges include finding ways to de-
fine BPD based on the severity of lung pathology, which can
better predict long-term outcomes, development of early
predictors of lung disease, and finding innovative and evi-
dence-based preventive and management strategies.
© 2019 S. Karger AG, Basel
Introduction
More than 50 years after its initial description by
Northway et al. [1], bronchopulmonary dysplasia (BPD)
continues to be one of the most significant chronic mor-
bidities affecting very preterm infants. Many advances in
the fields of obstetrics and neonatal medicine over these
years have resulted in better survival of very preterm in-
fants who are at higher risk of developing complications
associated with extreme prematurity. This has resulted in
significant change in the epidemiology, clinical course,
and pathologic picture of BPD posing new challenges for
clinicians and researchers vested in improving the out-
come of these preterm infants.
130.236.82.7 - 4/12/2019 11:22:16 AM
Eduardo Bancalari
Linköpings Universitetsbibliotek
Division of Neonatology, Department of Pediatrics
University of Miami Miller School of Medicine
1611 NW 12th Avenue, Miami, FL 33136 (USA)
Downloaded by:
E-Mail ebancalari @ med.miami.edu
 Progression from “Original” to “New BPD”
When first described in 1967, the term BPD was used
to define a group of relatively mature preterm infants
with severe respiratory failure who survived their initial
respiratory distress syndrome after receiving aggressive
respiratory support with high oxygen and positive pres-
sure ventilation. Their clinical course was characterized
by severe chronic respiratory failure with a radiographic
picture showing areas of hyperinflation alternating with
adjacent increased densities. Many of these infants died
later due to respiratory failure with postmortem lung ex-
amination showing widespread emphysema, interstitial
fibrosis, and airway epithelial changes.
During the ensuing decades, improvements in the
fields of obstetrics and neonatal medicine such as ante-
natal corticosteroids, surfactant therapy, and advance-
ments in neonatal care resulted in increased survival of
infants at lower gestational ages. This led to a decline in
BPD in the more mature infants and to changes in the
clinical presentation into a milder form of the respira-
tory disease in the extremely preterm infants, called
“New BPD” [2]. These infants are born at the late cana-
licular or early saccular stages of lung development, and
exposure to various antenatal and postnatal insults can
result in disruption of normal alveolar and vascular de-
velopment. As opposed to the original BPD, the patho-
logic picture in these infants is characterized by alveolar
simplification with fewer and dysmorphic capillaries, but
less evidence of emphysema, fibrosis, and airway chang-
es [3].
Clinical Presentation of BPD
The overall incidence of BPD in extremely preterm
infants has not changed significantly over the last decade
despite improvements in clinical care. This is likely due
to the increasing survival of sicker infants at lower gesta-
tional age [4]. Infants born at >28 weeks’ gestation, how-
ever, have lower incidence of BPD and when occurs, it is
usually milder. The incidence of BPD in extremely low
birth weight infants is about 40%, but this varies among
different centers likely due to variations in clinical prac-
tices, population characteristics, and definitions used [5].
The early clinical course of BPD has evolved with a
majority of infants now presenting with mild or no initial
respiratory disease. These infants are usually managed
with noninvasive respiratory support, and if intubated,
require low ventilator pressures and oxygen. Over the
BPD: 50 Years after the Original
Description
subsequent days to weeks, many of these infants have
gradual worsening of their respiratory function necessi-
tating escalation in respiratory support [6]. Though the
exact cause of this deterioration is not always clear, often
it coincides with a hemodynamically significant patent
ductus arteriosus (PDA) or infection. Most of these in-
fants undergo a slow and steady improvement in their
respiratory status and are eventually weaned from respi-
ratory support prior to discharge. A minority of them
have a more severe respiratory course with progressive
worsening of respiratory failure commonly associated
with pulmonary hypertension and signs of right heart
failure. The radiographic picture of these infants some-
times resembles that of the “Original BPD.”
Evolution of BPD Definition
BPD is one of the few diseases in neonatology where
multiple definitions have been proposed, reflecting
changes in the at risk population, clinical presentation,
and the continued quest to better define the severity of
lung disease and predict long-term outcome. The early
definitions of BPD consisted of oxygen requirement at 28
days of age along with chest radiographic changes re-
flecting chronic lung pathology [7, 8]. Over the next de-
cade as more infants at lower gestational age survived
with less severe lung disease and inconsistent radio-
graphic picture, Shennan et al. [9] proposed a simpler
definition of oxygen need at 36 weeks’ post menstrual age
as a better predictor of later respiratory outcomes.
In 2001, a workshop sponsored by the National Heart,
Lung, and Blood Institute proposed a definition that for
the first time categorized BPD into mild, moderate, or
severe based on the oxygen or respiratory support re-
quirement at 36 weeks’ postmenstrual age. It also in-
cluded the need for supplemental oxygen for at least 28
days to reflect the chronicity of the lung derangement
[10]. This characterization of BPD into different severi-
ties improves prediction of respiratory and neurological
outcomes [11]. Since then, there have been some modi-
fications with attempts to standardize the need for oxy-
gen at 36 weeks by an oxygen reduction test as a more
physiological definition of BPD [12]. One of the criti-
cisms of the National Heart, Lung, and Blood Institute
definition of BPD has been the need for determining the
number of days on supplemental oxygen. This has re-
sulted in different variants of BPD definitions being
used for benchmarking as well as in clinical trials mak-
ing any comparison of outcomes very difficult [13–15].
130.236.82.7 - 4/12/2019 11:22:16 AM
Neonatology 2019;115:384–391 385
Linköpings Universitetsbibliotek
DOI: 10.1159/000497422
Downloaded by:
 Bronchopulmonary dysplasia pathogenesis
Antenatal factors
– IUGR, placental dysfunction
– Chorioamnionitis
– Bacterial colonization
– Maternal hypertension/
preeclampsia
– Maternal smoking/drugs
– Genetic predisposition
Fig. 1. Algorithm for pathogenesis of BPD. Modified from Abman et al. [55].
Some of the other shortcomings of current definitions
of BPD include potentially inaccurate classification of
infants requiring respiratory support for nonpulmonary
causes such as central apnea, or misclassification of in-
fants on newer modes of respiratory support such as
high flow nasal cannula. To overcome some of these
shortcomings, a recent Eunice Kennedy National Insti-
tute of Child health and Human Development work-
shop proposed some refinements to the 2001 definition
of BPD. This proposal attempts to categorize infants on
nasal cannula oxygen therapy, infants dying due to se-
vere lung disease prior to 36 weeks, as well as excluding
infants with transitory need for respiratory support at 36
weeks or nonpulmonary causes of respiratory failure
[16].
Changes in the Pathogenesis of BPD
With the changes in epidemiology, clinical picture and
antenatal and postnatal management of preterm neo-
nates over the last half century, the pathogenesis of BPD
has also evolved significantly. As opposed to the “original
BPD” resulting mainly from lung injury from high airway
pressures and oxygen toxicity, the “new BPD” seen today
is the result of complex interactions between altered al-
386 Neonatology 2019;115:384–391
DOI: 10.1159/000497422
Extreme prematurity
Postnatal factors
– Ventilator-induced lung injury
Lung injury/developmental arrest – Supplemental oxygen
Airway-vascular damage – Infection/Sepsis
Decreased alveoli and capillaries  – Patent ductus arteriosus
– Nutritional deficiencies 
Respiratory failure
Pulmonary hypertension
Early respiratory death
Repair/Regeneration
Disease resolution
Chronic respiratory disease: BPD
veolar and vascular development, injury by ante- and
postnatal pathogenic factors, and reparative processes in
the lung (Fig. 1).
Risk Factors
Immaturity is the most important risk factor for BPD
with its incidence being inversely related to gestational
age. The role of genetic predisposition for BPD has been
suggested by twin pair studies, but the search for specific
candidate genes has not been very successful so far [17].
There is increasing epidemiological and experimental ev-
idence that antenatal factors such as maternal smoking,
hypertension, white race, and male gender are important
contributors to not only the risk for BPD but also poor
childhood respiratory health [18]. Intrauterine growth
restriction has been shown to increase the risk for BPD.
The effect of chorioamnionitis on the risk for BPD is not
conclusive, suggesting that variability in definition of
chorioamnionitis, causative organism and inflammatory
response of the fetus may modulate this risk [19].
There is clear evidence from animal studies suggesting
mechanical trauma from high pressure or tidal volume
causes lung injury, but the clinical evidence is weak [20,
21]. The role of oxygen toxicity in the development of
BPD has been shown in both experimental models as well
as in clinical trials [22, 23].
130.236.82.7 - 4/12/2019 11:22:16 AM
Bancalari/Jain
Linköpings Universitetsbibliotek
Downloaded by:
Table 1. Strategies for prevention of BPD
Vitamin A [48] RR 0.88 (95% CI 0.77–0.99)**
Noninvasive respiratory support [38] OR 0.83 (95% CI 0.71–0.96)**, #
Lower oxygen target [23] RR 0.81 (95% CI 0.74–0.9)**, τ
High-frequency oscillatory ventilation [40] RR 0.86 (95% CI 0.78–0.96)**
Postnatal dexamethasone
Early [54] RR 0.79 (95% CI 0.71–0.88)**
Late [42] RR 0.76 (95% CI 0.66–0.88)**
Postnatal hydrocortisone [44] OR 1.48 (95% CI 1.02–2.16)*, ##
Postnatal surfactant + budesonide [45] RR 0.58 (95% CI 0.44–0.77)*, #
Strategies with inconclusive evidence
Antenatal steroids
Exogenous surfactant
Caffeine for apnea or extubation€
Volume-targeted ventilation€
Inhaled nitric oxide
Early PDA closure
Stem cell treatment

* Randomized controlled trial.

** Meta-analysis.
# BPD or death.
##
Survival without BPD.
τ BPD: oxygen at 36 weeks.
€ Lacking data from trials with BPD as primary outcome.

BPD, bronchopulmonary dysplasia.

While postnatal systemic or pulmonary infections in-
crease the risk for BPD, the role of antenatal colonization
with Ureaplasma urealyticum is still controversial. Data
from animal studies show that colonization of fetal lung
with Ureaplasma increases inflammation and alters al-
veolar development. Several epidemiological studies have
suggested an association between Ureaplasma coloniza-
tion of the respiratory tract and an increased risk for BPD
[24]. Despite this, the treatment of Ureaplasma coloniza-
tion with macrolides has not been consistently successful
in reducing BPD.
There is increasing interest in the possible role of lung
microbiome in the risk for BPD with several studies
showing that multiple antenatal and postnatal factors,
such as antibiotic use, nutrition, and sepsis can alter the
normal development of lung microbiome [25, 26]. The
potential role of lung dysbiosis in the development of
BPD needs to be further elucidated.
The role of the PDA in the pathogenesis of BPD has
been suggested for a long time and is still highly contro-
versial. Increased pulmonary blood flow due to left-to-
right ductal shunting can decrease lung compliance and
increase airway resistance, which in turn may prolong
need for mechanical ventilation and oxygen supplemen-
tation and increase the risk for lung injury. Several animal
and epidemiological studies have suggested the associa-
tion between a significant PDA and lung damage, but
prospective clinical trials evaluating different PDA clo-
sure strategies have failed to show a clear effect on inci-
dence of BPD [27–29].
Strategies for Prevention of BPD: “Hit – or – Miss”
The continual evolution of BPD as a disease process has
presented significant challenges to development of effec-
tive strategies for prevention with increasing realization
that absolute prevention of BPD may not be achievable
and effort may need to be focused on steps to minimize
lung injury and promote alveolar and vascular develop-
ment. Some of these strategies are presented in Table 1.
Since prematurity is a prerequisite for development of
BPD, any strategy that may decrease preterm birth is cru-
cial in reducing the incidence of BPD. Unfortunately,
this has not been very successful and in fact, the inci-
dence of preterm birth has been stable or increasing re-
cently in many countries [30]. Antenatal corticosteroids
have been used for accelerating lung maturity since the
1970s, and many randomized controlled trials have
shown reduction in mortality, and other neonatal mor-
130.236.82.7 - 4/12/2019 11:22:16 AM

BPD: 50 Years after the Original Neonatology 2019;115:384–391 387

Linköpings Universitetsbibliotek

Description DOI: 10.1159/000497422

Downloaded by:
bidities except BPD, which is not significantly affected
[31]. This may be explained by increased survival of ex-
tremely preterm infants born after antenatal steroids ex-
posure [32]. Though antenatal steroids are now standard
of care for preterm infants, several questions including
their effect on long-term outcomes in extremely preterm
infants, ideal formulation, and dosing schedule remain
to be answered.
There is growing interest in optimizing respiratory
support strategies soon after birth with increasing avail-
ability of respiratory function and arterial oxygen satura-
tion monitoring. Currently, there is no clear evidence that
the use of respiratory function monitoring, or targeting
different tidal volumes or oxygen supplementation at
birth affects BPD [33]. Another strategy that showed
promise in reducing lung injury in animal models and
early clinical studies is sustained inflation at birth to im-
prove functional residual capacity. However, recent trials
have not shown beneficial effect on BPD and possibly
higher mortality with sustained inflation [34].
Exogenous surfactant is one of the landmark therapies
in the field of neonatology, which has been shown to de-
crease severity of RDS and mortality but without any re-
duction in the incidence of BPD in surviving infants [35].
As with antenatal steroids, this is most likely due to in-
creased survival of extremely preterm infants with the use
of surfactant [36]. Recently, there has been increasing in-
terest in novel ways of delivering surfactant avoiding the
need for endotracheal intubation and associated risks of
lung injury. These include less invasive, and nebulized
surfactant administration with some evidence of effec-
tiveness in decreasing the risk for BPD [37].
Respiratory support has evolved significantly since the
original description of BPD with an emphasis on provid-
ing the least amount of support required for adequate gas
exchange and oxygenation. One way for achieving this is
avoidance of invasive mechanical ventilation by using al-
ternatives such as nasal continuous positive airway pres-
sure with some evidence of a small reduction in BPD or
death [38]. Other noninvasive respiratory support strate-
gies such as nasal intermittent positive pressure ventila-
tion or high flow nasal cannula do not consistently reduce
the incidence of BPD. Use of invasive mechanical breaths
synchronized with spontaneous breaths and the accurate
monitoring and delivery of appropriate tidal volumes
have reduced the duration of exposure to mechanical
ventilation. There is some evidence that the use of high-
frequency oscillatory ventilation and volume-targeted
modes of ventilation may also lead to a small reduction in
BPD, but the evidence is not strong [39, 40].
388 Neonatology 2019;115:384–391
DOI: 10.1159/000497422
Since oxygen is both lifesaving and potentially injuri-
ous to the lung and other organs, its use needs to be ti-
trated very carefully. The ability to continuously and non-
invasively monitor arterial oxygen saturation (SpO2) has
been an important advancement in neonatal medicine.
The question of optimal oxygen saturation target range
for preterm infants has been partially answered recently
with 3 large randomized controlled trials comparing the
effect of 2 different targets, low (85–89%) and high (91–
95%), on neonatal mortality and morbidities. Meta-anal-
ysis of these trials showed a small decrease in the inci-
dence of BPD in low-target groups but higher risk of NEC
and mortality compared to the high-target range [41].
Postnatal steroid administration for prevention of
BPD has been extensively studied and facilitates weaning
from mechanical ventilation and reduces BPD but with
the potential risk of worse neurologic outcomes in infants
exposed to high-dose dexamethasone. There is increasing
evidence that short courses with lower doses of dexa-
methasone after the first postnatal week in infants at high
risk of BPD may be safe and improve outcomes [42, 43].
To avoid potential neurotoxic side effects of systemic
dexamethasone, other strategies that have been evaluated
include early systemic hydrocortisone and intra-tracheal
instillation of budesonide with surfactant [44, 45]. The
initial results of these interventions have been encourag-
ing, but further studies in different patient populations
and effect on long-term outcomes are needed.
Caffeine is a methylxanthine commonly used for ap-
nea of prematurity, and it decreases the incidence of BPD
compared to controls not exposed to the drug [46]. As a
result, there has been increasing use of caffeine outside
the established indication for apnea of prematurity or pri-
or to extubation. This is clearly an area that needs further
investigation [47]. Other therapies investigated for pre-
vention of BPD include vitamin A prophylaxis resulting
in a small but significant reduction in BPD compared to
controls [48] and prophylactic use of nitric oxide that has
not shown a consistent effect on BPD [49].
Some innovative strategies for prevention of BPD are
mesenchymal stem cells (MSCs) or their secretory prod-
ucts. Many studies have shown MSCs to be effective in
prevention and treatment of lung injury in animal models
of BPD [50]. Early clinical studies have shown promising
results, but extensive safety and efficacy studies need to
be performed prior to clinical use. There is increasing ev-
idence that the main effects of MSCs may be paracrine
with secretion of anti-inflammatory and trophic factors
that are contained in nano-sized vesicles like exosomes.
Early studies using these MSCs derived exosomes in ani-
130.236.82.7 - 4/12/2019 11:22:16 AM
Bancalari/Jain
Linköpings Universitetsbibliotek
Downloaded by:
mal models of BPD have shown promising results in re-
ducing lung injury and preservation of lung structure and
function [51]. Other molecular therapies with promising
results in early clinical studies include Clara Cell protein
with anti-inflammatory and immunomodulatory prop-
erties, and insulin-like growth factor-1, a growth factor
involved in alveolar and vascular development [52].
Future Challenges and Opportunities in Prevention
and Management of BPD
One of the major challenges for clinicians and re-
searchers in the field of BPD is the need for a definition,
which can accurately reflect the degree of lung pathology
and differentiate a preterm infant with “normal” alveolar
and vascular development. A single, all-encompassing
definition of BPD is difficult to achieve, as the criteria for
ideal definition for different stakeholders may be contra-
dictory. While an epidemiologist may prefer to have a
simple definition that accurately reflects the disease pro-
cess, for researchers developing therapeutic strategies, the
effects on long-term outcomes may be paramount. Some
of the newer strategies including biomarkers for evalua-
tion of lung injury, innovative imaging studies, such as
functional magnetic resonance imaging and pulmonary
function studies, may provide tools to move toward a
pathophysiology-based definition of BPD.
Development of an effective preventive strategy for
BPD has been a major challenge so far. Multiple interven-
tions acting on different pathways leading to BPD, such
as blocking inflammatory response, preventing oxidative
injury, or providing growth factors, have been evaluated
in various animal models of BPD with great success. Most
of these interventions have either not transitioned to clin-
ical practice or had limited effect on the incidence of BPD
[53]. Whether it is due to oversimplification of BPD in
animal models or limitation of clinical definition of BPD
needs to be further evaluated. In addition, there is in-
creasing concern that prevention of BPD should be based
on longer-term outcomes rather than outcomes prior to
discharge from hospital.
Other challenges for optimal management of BPD in-
clude development of evidence-based treatment strate-
gies such as respiratory care for chronic respiratory fail-
ure, evaluation and management of associated pulmo-
nary hypertension, or postdischarge multidisciplinary
care of these infants.
Conclusion
Fifty years since its first description, the clinical pic-
ture, diagnosis, and pathogenesis of BPD have evolved
significantly making the current disease very different
from that described originally. Due to significant ad-
vancements in obstetrics and neonatal–perinatal medi-
cine, most infants with BPD today have a milder form of
respiratory failure with low mortality and less significant
morbidity. However, it is clear that there remain signifi-
cant gaps in our understanding of its pathogenesis, opti-
mal definition, effective preventive and management
strategies, which will require a concerted effort from re-
searchers and clinicians alike.
Disclosure Statement
The authors declare that no conflicts of interest related to this
paper exist.

References
  1 Northway WH Jr, Rosan RC, Porter DY. Pul-  
monary disease following respirator therapy
of hyaline-membrane disease. Bronchopul-
monary dysplasia. N Engl J Med. 1967 Feb;
276(7):357–68.
  2 Jobe AJ. The new BPD: an arrest of lung de-
velopment. Pediatr Res. 1999 Dec;46(6):641–
3.  
 3 Bancalari E, Jain D. Pathophysiology of
Bronchopulmonary Dysplasia. In: Polin RA,
Abman SH, Rowitch DH, Benitz WE, Fox
WW, editors. Fetal and Neonatal Physiolo-
gy. 5th ed. Vol 2. Elsevier; 2017. p. 1625–
1631.
4 Stoll BJ, Hansen NI, Bell EF, Walsh MC, Carlo  
WA, Shankaran S, et al.; Eunice Kennedy Shriv-
er National Institute of Child Health and Hu-
man Development Neonatal Research Net-
work. Trends in care practices, morbidity, and
mortality of extremely preterm neonates, 1993-
2012. JAMA. 2015 Sep;314(10):1039–51.  
5 Lapcharoensap W, Gage SC, Kan P, Profit J,
Shaw GM, Gould JB, et al. Hospital variation
and risk factors for bronchopulmonary dys-
plasia in a population-based cohort. JAMA  
Pediatr. 2015 Feb;169(2):e143676.
6 Laughon M, Allred EN, Bose C, O’Shea TM,
Van Marter LJ, Ehrenkranz RA, et al.; ELGAN
Study Investigators. Patterns of respiratory
disease during the first 2 postnatal weeks in
extremely premature infants. Pediatrics. 2009
Apr;123(4):1124–31.
7 Bancalari E, Abdenour GE, Feller R, Gannon
J. Bronchopulmonary dysplasia: clinical pre-
sentation. J Pediatr. 1979 Nov;95(5 Pt 2):819–
23.
8 Tooley WH. Epidemiology of bronchopul-
monary dysplasia. J Pediatr. 1979 Nov;95(5 Pt
2):851–8.
130.236.82.7 - 4/12/2019 11:22:16 AM

BPD: 50 Years after the Original Neonatology 2019;115:384–391 389

Linköpings Universitetsbibliotek

Description DOI: 10.1159/000497422

Downloaded by:
  9 Shennan AT, Dunn MS, Ohlsson A, Lennox
K, Hoskins EM. Abnormal pulmonary out-
comes in premature infants: prediction from
oxygen requirement in the neonatal period.
Pediatrics. 1988 Oct;82(4):527–32.
10 Jobe AH, Bancalari E. Bronchopulmonary
dysplasia. Am J Respir Crit Care Med. 2001
Jun;163(7):1723–9.
11 Ehrenkranz RA, Walsh MC, Vohr BR, Jobe
AH, Wright LL, Fanaroff AA, et al.; National
Institutes of Child Health and Human Devel-
opment Neonatal Research Network. Valida-
tion of the National Institutes of Health con-
sensus definition of bronchopulmonary dys-
plasia. Pediatrics. 2005 Dec;116(6):1353–60.
12 Walsh MC, Yao Q, Gettner P, Hale E, Collins
M, Hensman A, et al.; National Institute of
Child Health and Human Development Neo-
natal Research Network. Impact of a physio-
logic definition on bronchopulmonary dyspla-
sia rates. Pediatrics. 2004 Nov;114(5):1305–11.
13 Beam KS, Aliaga S, Ahlfeld SK, Cohen-
Wolkowiez M, Smith PB, Laughon MM. A
systematic review of randomized controlled
trials for the prevention of bronchopulmona-
ry dysplasia in infants. J Perinatol. 2014 Sep;
34(9):705–10.
14 Isayama T, Lee SK, Yang J, Lee D, Daspal S,
Dunn M, et al.; Canadian Neonatal Network
and Canadian Neonatal Follow-Up Network
Investigators. Revisiting the definition of
bronchopulmonary dysplasia: effect of chang-
ing panoply of respiratory support for pre-
term neonates. JAMA Pediatr. 2017 Mar;
171(3):271–9.
15 Bancalari E, Jain D. Bronchopulmonary dys-
plasia: can we agree on a definition? Am J Per-
inatol. 2018 May;35(6):537–40.
16 Higgins RD, Jobe AH, Koso-Thomas M, Ban-
calari E, Viscardi RM, Hartert TV, et al. Bron-
chopulmonary dysplasia: executive summary
of a workshop. J Pediatr. 2018 Jun;197:300–8.
17 Shaw GM, O’Brodovich HM. Progress in un-
derstanding the genetics of bronchopulmo-
nary dysplasia. Semin Perinatol. 2013 Apr;
37(2):85–93.
18 Manuck TA, Levy PT, Gyamfi-Bannerman C,
Jobe AH, Blaisdell CJ. Prenatal and perinatal
determinants of lung health and disease in
early life: A National Heart, Lung, and Blood
Institute Workshop Report. JAMA Pediatr.
2016 May;170(5):e154577.
19 Jobe AH. Effects of chorioamnionitis on the fe-
tal lung. Clin Perinatol. 2012 Sep;39(3):441–57.
20 Björklund LJ, Ingimarsson J, Curstedt T, John
J, Robertson B, Werner O, et al. Manual ven-
tilation with a few large breaths at birth com-
promises the therapeutic effect of subsequent
surfactant replacement in immature lambs.
Pediatr Res. 1997 Sep;42(3):348–55.
21 Mokres LM, Parai K, Hilgendorff A, Ertsey R,
Alvira CM, Rabinovitch M, et al. Prolonged
mechanical ventilation with air induces apop-
tosis and causes failure of alveolar septation
and angiogenesis in lungs of newborn mice.
Am J Physiol Lung Cell Mol Physiol. 2010 Jan;
298(1):L23–35.
390 Neonatology 2019;115:384–391
DOI: 10.1159/000497422
22 Buczynski BW, Maduekwe ET, O’Reilly MA.
The role of hyperoxia in the pathogenesis of
experimental BPD. Semin Perinatol. 2013
Apr;37(2):69–78.
23 Askie LM, Darlow BA, Finer N, Schmidt B,
Stenson B, Tarnow-Mordi W, et al.; Neonatal
Oxygenation Prospective Meta-analysis (NeO-
ProM) Collaboration. Neonatal Oxygenation
Prospective Meta-analysis (NeOProM) Collab-
oration: association between oxygen saturation
targeting and death or disability in extremely
preterm infants in the Neonatal Oxygenation
Prospective Meta-analysis Collaboration.
JAMA. 2018 Jun;319(21):2190–201.
24 Viscardi RM, Kallapur SG. Role of ureaplas-
ma respiratory tract colonization in broncho-
pulmonary dysplasia pathogenesis: current
concepts and update. Clin Perinatol. 2015
Dec;42(4):719–38.
25 Lal CV, Travers C, Aghai ZH, Eipers P, Jilling
T, Halloran B, et al. The airway microbiome
at birth. Sci Rep. 2016 Aug;6(1):31023.
26 Pammi M, Lal CV, Wagner BD, Mourani PM,
Lohmann P, Luna RA, et al. Airway microbi-
ome and development of bronchopulmonary
dysplasia in preterm infants: a systematic re-
view. J Pediatr. 2019 Jan;204:126–133.e2.
27 McCurnin D, Seidner S, Chang LY, Waleh N,
Ikegami M, Petershack J, et al. Ibuprofen-in-
duced patent ductus arteriosus closure: phys-
iologic, histologic, and biochemical effects on
the premature lung. Pediatrics. 2008 May;
121(5):945–56.
28 Liebowitz M, Clyman RI. Prophylactic indo-
methacin compared with delayed conserva-
tive management of the patent ductus arterio-
sus in extremely preterm infants: effects on
neonatal outcomes. J Pediatr. 2017 Aug; 187:
119–126.e1.
29 Clyman RI, Liebowitz M, Kaempf J, Erdeve O,
Bulbul A, Hakansson S, et al.; PDA-TOLER-
ATE (PDA: To LEave it alone or Respond
And Treat Early) Trial Investigators: PDA-
TOLERATE Trial: An exploratory random-
ized controlled trial of treatment of mod-
erate-to-large patent ductus arteriosus at 1
week of age. J Pediatr. 2019 Feb;205:41–48.e6.
30 Blencowe H, Cousens S, Chou D, Oestergaard
M, Say L, Moller AB, et al.; Born Too Soon
Preterm Birth Action Group. Born too soon:
the global epidemiology of 15 million preterm
births. Reprod Health. 2013;10 Suppl 1:S2.
31 Roberts D, Brown J, Medley N, Dalziel SR.
Antenatal corticosteroids for accelerating fe-
tal lung maturation for women at risk of pre-
term birth. Cochrane Database Syst Rev. 2017
Mar;3:CD004454.
32 Chawla S, Natarajan G, Shankaran S, Pappas
A, Stoll BJ, Carlo WA, et al.; National Institute
of Child Health and Human Development
Neonatal Research Network. Association of
neurodevelopmental outcomes and neonatal
morbidities of extremely premature infants
with differential exposure to antenatal ste-
roids. JAMA Pediatr. 2016 Dec; 170(12):
1164–72.
33 Oei JL, Vento M, Rabi Y, Wright I, Finer N,
Rich W, et al. Higher or lower oxygen for de-
livery room resuscitation of preterm infants
below 28 completed weeks gestation: a meta-
analysis. Arch Dis Child Fetal Neonatal Ed.
2017 Jan;102(1):F24–30.
34 Fischer HS, Schmolzer GM, Cheung PY,
Buhrer C. Sustained inflations and avoiding
mechanical ventilation to prevent death or
bronchopulmonary dysplasia: a meta-analy-
sis. Eur Resp Rev. 2018;27(150).
35 Seger N, Soll R. Animal derived surfactant ex-
tract for treatment of respiratory distress syn-
drome. Cochrane Database Syst Rev. 2009
Apr;(2):CD007836.
36 Polin RA, Carlo WA; Committee on Fetus
and Newborn; American Academy of Pediat-
rics. Surfactant replacement therapy for pre-
term and term neonates with respiratory dis-
tress. Pediatrics. 2014 Jan;133(1):156–63.
37 Aldana-Aguirre JC, Pinto M, Featherstone
RM, Kumar M. Less invasive surfactant ad-
ministration versus intubation for surfactant
delivery in preterm infants with respiratory
distress syndrome: a systematic review and
meta-analysis. Arch Dis Child Fetal Neonatal
Ed. 2017 Jan;102(1):F17–23.
38 Fischer HS, Bührer C. Avoiding endotracheal
ventilation to prevent bronchopulmonary
dysplasia: a meta-analysis. Pediatrics. 2013
Nov;132(5):e1351–60.
39 Klingenberg C, Wheeler KI, McCallion N,
Morley CJ, Davis PG. Volume-targeted versus
pressure-limited ventilation in neonates. Co-
chrane Database Syst Rev. 2017 Oct;
10:CD003666.
40 Cools F, Offringa M, Askie LM. Elective high
frequency oscillatory ventilation versus con-
ventional ventilation for acute pulmonary
dysfunction in preterm infants. Cochrane Da-
tabase Syst Rev. 2015 Mar;(3):CD000104.
41 Askie LM, Darlow BA, Davis PG, Finer N,
Stenson B, Vento M, et al. Effects of targeting
lower versus higher arterial oxygen satura-
tions on death or disability in preterm infants.
Cochrane Database Syst Rev. 2017 Apr;
4:CD011190.
42 Doyle LW, Ehrenkranz RA, Halliday HL. Late
(>7 days) postnatal corticosteroids for chron-
ic lung disease in preterm infants. Cochrane
Database Syst Rev. 2014 May;(5):CD001145.
43 Doyle LW, Halliday HL, Ehrenkranz RA, Da-
vis PG, Sinclair JC. Impact of postnatal sys-
temic corticosteroids on mortality and cere-
bral palsy in preterm infants: effect modifica-
tion by risk for chronic lung disease.
Pediatrics. 2005 Mar;115(3):655–61.
44 Baud O, Maury L, Lebail F, Ramful D, El
Moussawi F, Nicaise C, et al.; PREMILOC
trial study group. Effect of early low-dose
hydrocortisone on survival without bron-
chopulmonary dysplasia in extremely pre-
term infants (PREMILOC): a double-blind,
placebocontrolled, multicentre, rando­ mi­
sed trial. Lancet. 2016 Apr; 387(10030):
1827–36.
130.236.82.7 - 4/12/2019 11:22:16 AM
Bancalari/Jain
Linköpings Universitetsbibliotek
Downloaded by:
45 Yeh TF, Chen CM, Wu SY, Husan Z, Li TC,
Hsieh WS, et al. Intratracheal administration
of budesonide/surfactant to prevent broncho-
pulmonary dysplasia. Am J Respir Crit Care
Med. 2016 Jan;193(1):86–95.
46 Schmidt B, Roberts RS, Davis P, Doyle LW,
Barrington KJ, Ohlsson A, et al.; Caffeine for
Apnea of Prematurity Trial Group. Caffeine
therapy for apnea of prematurity. N Engl J
Med. 2006 May;354(20):2112–21.
47 Jobe AH. Caffeine: a lung drug for all very low
birth weight preterm infants? Am J Respir
Crit Care Med. 2017 Nov;196(10):1241–3.
48 Araki S, Kato S, Namba F, Ota E. Vitamin A
to prevent bronchopulmonary dysplasia in
extremely low birth weight infants: a system-
atic review and meta-analysis. PLoS One.
2018 Nov;13(11):e0207730.
BPD: 50 Years after the Original
Description
49 Donohue PK, Gilmore MM, Cristofalo E,
Wilson RF, Weiner JZ, Lau BD, et al. Inhaled
nitric oxide in preterm infants: a systematic
review. Pediatrics. 2011 Feb;127(2):e414–22.
50 Augustine S, Avey MT, Harrison B, Locke T,
Ghannad M, Moher D, et al. Mesenchymal
stromal cell therapy in bronchopulmonary
dysplasia: systematic review and meta-analy-
sis of preclinical studies. Stem Cells Transl
Med. 2017 Dec;6(12):2079–93.
51 Lesage F, Thébaud B. Nanotherapies for mi-
cropreemies: stem cells and the secretome in
bronchopulmonary dysplasia. Semin Perina-
tol. 2018 Nov;42(7):453–8.
Neonatology 2019;115:384–391
DOI: 10.1159/000497422
52 Ley D, Hallberg B, Hansen-Pupp I, Dani C,
Ramenghi LA, Marlow N, et al. rhIGF-1/
rhIGFBP-3 in preterm infants: a phase 2 ran-
domized controlled trial. J Pediatr. 2019 Mar;
206:56-65.e8.
53 Jobe AH. Animal models, learning lessons to
prevent and treat neonatal chronic lung dis-
ease. Front Med (Lausanne). 2015 Aug;2:49.
54 Doyle LW, Ehrenkranz RA, Halliday HL. Ear-
ly (<8 days) postnatal corticosteroids for pre-
venting chronic lung disease in preterm in-
fants. Cochrane Database Syst Rev. 2014
May;(5):CD001146.
55 Abman SH, Bancalari E, Jobe A. The Evolu-
tion of Bronchopulmonary Dysplasia after 50
Years. Am J Respir Crit Care Med. 2017 Feb;
195(4):421–4.
130.236.82.7 - 4/12/2019 11:22:16 AM
391
Linköpings Universitetsbibliotek
Downloaded by: