Research

JAMA Pediatrics | Original Investigation

Revisiting the Definition of Bronchopulmonary Dysplasia

Effect of Changing Panoply of Respiratory Support
for Preterm Neonates
Tetsuya Isayama, MD; Shoo K. Lee, MBBS, PhD; Junmin Yang, MSc; David Lee, MD; Sibasis Daspal, MD;
Michael Dunn, MD; Prakesh S. Shah, MD, MSc; for the Canadian Neonatal Network and Canadian Neonatal
Follow-Up Network Investigators

Supplemental content
IMPORTANCE Several definitions of bronchopulmonary dysplasia are clinically used; however,
their validity remains uncertain considering ongoing changes in the panoply of respiratory
support treatment strategies used within neonatal units.

OBJECTIVE To identify the optimal definition of bronchopulmonary dysplasia that best

predicts respiratory and neurodevelopmental outcomes in preterm infants.

DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study at tertiary neonatal

intensive care units. Preterm infants born at less than 29 weeks’ gestation between 2010 and
2011 who were admitted to neonatal intensive care units participating in the Canadian
Neonatal Network and completed follow-up assessments in a Canadian Neonatal Follow-Up
Network clinic at 18 to 21 months.

EXPOSURES Various traditional bronchopulmonary dysplasia criteria based on respiratory

status at different postmenstrual ages.

MAIN OUTCOMES AND MEASURES Serious respiratory morbidity, neurosensory impairment at

18 to 21 months of age, and a composite outcome of respiratory or neurosensory morbidity or
death after discharge. Adjusted odds ratios (AORs) and 95% CIs were calculated.

RESULTS Of 1914 eligible survivors, 1503 were assessed (mean gestational age was 26.3
weeks; 68% were white, 9% were black, and 23% were other race/ethnicity), 88 had serious
respiratory morbidity, 257 infants had neurosensory impairment, and 12 infants died after
discharge. Definitions using oxygen requirement alone as the criterion at various
postmenstrual ages were less predictive compared with those using the criterion of
oxygen/respiratory support (RS) (receiving supplemental oxygen and/or positive-pressure
RS); among those, oxygen/RS at 36 weeks had the highest AOR and area under the curve
(AUC) for all outcomes. Further analyses of oxygen/RS at each week between 34 and 44
weeks’ postmenstrual age indicated that the predictive ability for serious respiratory
morbidity increased from 34 weeks (AOR, 1.8; 95% CI, 0.9-3.4, AUC, 0.721) to 40 weeks
(AOR, 6.1; 95% CI, 3.4-11.0; AUC, 0.799). For serious neurosensory impairment, the AOR and
AUC at 40 weeks’ PMA (AOR, 1.5, 95% CI, 1.0-2.1; AUC, 0.740) were only marginally below
their peak values at 37 weeks’ PMA (AOR, 1.8; 95% CI, 1.3-2.6; AUC, 0.743). Author Affiliations: Author
affiliations are listed at the end of this
article.
CONCLUSIONS AND RELEVANCE Defining bronchopulmonary dysplasia by the use of oxygen
Group Information: Investigators of
alone is inadequate because oxygen/RS is a better indicator of chronic respiratory the Canadian Neonatal Network and
insufficiency. In particular, oxygen/RS at 40 weeks’ PMA was identified as the best predictor Canadian Neonatal Follow-Up
for serious respiratory morbidity, while it also displayed a good ability to predict neurosensory Network are listed at the end of the
article.
morbidity at 18 to 21 months.
Corresponding Author: Prakesh S.
Shah, MD, MSc, Department of
Pediatrics, 19-231F, 600 University
Ave, Toronto, ON M5G 1X5, Canada,
JAMA Pediatr. doi:10.1001/jamapediatrics.2016.4141 (prakeshkumar.shah
Published online January 23, 2017. @sinaihealthsystem.ca).

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 Research Original Investigation
B
ronchopulmonary dysplasia (BPD) is an important
morbidity in preterm infants that has short- and
long-term serious adverse consequences for infants,
their families, and the health care system.1-3 Approximately
45% of preterm infants born at less than 29 weeks’ gestation
are diagnosed as having BPD.4 While accurate and timely
diagnosis of the condition is important to identify high-risk
infants in need of surveillance or special support, preva-
lence of BPD has also been proven to be a valuable short-
term indicator for benchmarking the quality of neonatal
care provided by institutions, networks, and countries.4
The term bronchopulmonary dysplasia was coined by
Northway et al5 in 1967 to describe a chronic pulmonary
condition observed in infants with respiratory distress syn-
drome and treated with high oxygen concentration and
mechanical ventilation, but it has since undergone numer-
ous revisions to accommodate different criteria.5 In 1978, a
clinical definition based on the dependency on oxygen at 30
days or 1 month of age with any radiographic abnormality
was proposed 6 and widely used. In 1988, Shennan et al 7
reported that oxygen use at 36 weeks’ postmenstrual age
(PMA) had a higher accuracy for predicting long-term respi-
ratory problems than that at 28 days of age or other PMAs,
which has become the most commonly used measure to
define BPD.8 In 2001, a workshop held by the National Insti-
tutes of Health proposed to define BPD as oxygen use for 28
days and categorized BPD into 3 severity levels (mild, mod-
erate, and severe) based on oxygen use and/or respiratory
support at 36 weeks’ PMA (or 56 days of age for infants at
≥32 weeks’ gestational age).9 An oxygen reduction test was
also recommended to confirm physiologic al oxygen
requirement.10,11
The validity of these BPD definitions based on respira-
tory status at 36 weeks’ PMA is uncertain because there
have been substantial changes in the perinatal and neonatal
management of preterm infants since the single-center
study by Shennan et al,7 particularly in respiratory support
modalities available for preterm neonates.12 This concern is
particularly relevant because many previous studies used
the Shennan et al definition8 and therefore did not capture
infants who might be on noninvasive respiratory support
but in room air, a situation that is not infrequent in modern-
day neonatal intensive care units (NICUs). Although the
National Institutes of Health definition 13 incorporated
respiratory support in room air to define severe BPD
while also requiring oxygen use for 28 days after birth
for BPD diagnosis, the validity of doing so has yet to be
determined.
Here, we compared various traditional BPD criteria used
in the literature to identify the best definition predictive of
serious long-term adverse respiratory or neurosensory out-
comes in preterm infants less than 29 weeks’ gestation in a
large, population-based cohort. Using this definition, we
conducted sensitivity analyses for the entire range of
infants between 34 and 44 weeks of PMA, with the aim to
identify the PMA associated with the best predictive charac-
teristics for serious adverse respiratory or neurosensory
outcomes.
E2 JAMA Pediatrics Published online January 23, 2017 (Reprinted)
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Bronchopulmonary Dysplasia Definitions and Outcomes
Key Points
Question What is the optimal definition of bronchopulmonary
dysplasia that best predicts respiratory and neurodevelopmental
outcomes in preterm infants and the postmentstrual age
associated with the best predictive characteristics for serious
adverse respiratory or neurosensory outcomes?
Findings In this cohort study, receipt of supplemental oxygen
and/or positive-pressure respiratory support at 40 weeks’
postmentstrual age was identified as the best predictor for serious
respiratory morbidity and displayed a good ability to predict
neurosensory morbidity at 18 to 21 months.
Meaning Defining BPD by the use of oxygen alone is inadequate
because oxygen and/or positive-pressure respiratory support is a
better indicator of chronic respiratory insufficiency.
Methods
Study Population and Data Collection
This retrospective cohort study included preterm infants born
at less than 29 weeks’ gestation from January 2010 to Septem-
ber 2011 who were admitted to tertiary NICUs participating in
the Canadian Neonatal Network. Those surviving until dis-
charge or transferred to step-down units and followed up in
affiliated clinics participating in the Canadian Neonatal Fol-
low-Up Network were included. We excluded infants who had
major congenital anomalies or were discharged or trans-
ferred to step-down units before 34 weeks’ PMA. Maternal and
infant data were collected by trained data abstractors based
on the Canadian Neonatal Network abstractor’s manual.14 All
26 Canadian Neonatal Follow-Up Network clinics provided fol-
low-up data for this study, making up approximately 80% of
neonates younger than 29 weeks’ gestation in 28 of 30 ter-
tiary NICUs in Canada. Experienced and trained health care
professionals obtained medical histories by interviews and con-
ducted physical and neurological examinations of children at
18 to 21 months of corrected age at Canadian Neonatal Fol-
low-Up Network clinics as previously described.15
This study was approved by the research ethics board of
Mount Sinai Hospital, Toronto. Neonatal data were collected
retrospectively after approval from ethics or quality improve-
ment committee at each unit without direct consent to en-
sure data collection of all neonates. For follow-up data, indi-
vidual written consent was obtained from parents when they
presented for assessment in clinics.
Definitions Compared
Respiratory support (RS) was defined as the use of any me-
chanical ventilation or noninvasive respiratory support that
provides positive end-expiratory pressure including continu-
ous positive airway pressure, biphasic continuous positive air-
way pressure, high flow of air or oxygen (>1.5 L/min), nonin-
vasive intermittent positive pressure ventilation, and
noninvasive high-frequency oscillation. Six different criteria
for classifying neonates with BPD were identified: (1) oxygen
at 28 days of age, (2) receiving supplemental oxygen and/or re-
spiratory positive-pressure support (oxygen/RS) at 28 days of
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 Bronchopulmonary Dysplasia Definitions and Outcomes
age, (3) oxygen at 36 weeks’ PMA, (4) oxygen/RS at 36 weeks’
PMA, (5) oxygen at 28 days and oxygen/RS at 36 weeks’
PMA, and (6) oxygen/RS at 28 days of age and at 36 weeks’
PMA. Once the best measure among these 6 definitions was
identified, sensitivity analyses were conducted to identify
the PMA at which the particular measure would perform
best for the prediction of serious adverse respiratory and
neurosensory outcomes.
Outcomes
Three long-term adverse outcomes were assessed including se-
rious respiratory morbidity, serious neurosensory impair-
ment, and a composite outcome of serious respiratory mor-
bidity and/or neurosensory impairment at 18 to 21 months
corrected age or death after NICU discharge and prior to 21
months corrected age. Serious respiratory morbidity was de-
fined as either (1) 3 or more rehospitalizations after NICU dis-
charge owing to respiratory problems (infectious or noninfec-
tious); (2) having a tracheostomy; (3) using respiratory
monitoring or support devices at home such as an apnea moni-
tor or pulse oximeter; and (4) being on home oxygen or con-
tinuous positive airway pressure at the time of assessment
between 18 and 21 months corrected age.16 At least 3 rehos-
pitalizations was chosen because the 95th percentile of the
number of readmissions owing to respiratory problems in
this cohort was 2 (which could be considered within normal
limits). Neurosensory impairment was defined as having
any of the following: (1) moderate to severe cerebral palsy
(Gross Motor Function Classification System ≥3)17; (2) severe
developmental delay (Bayley Scales of Infant and Toddler
Development Third Edition [Bayley III] composite score <70
in either cognitive, language, or motor domains)18; (3) hear-
ing aid or cochlear implant use; and (4) bilateral severe
visual impairment.16
Covariates
Covariates known to affect outcomes included maternal
age, hypertension, antenatal steroids, delivery mode, mul-
tiple births, sex, gestational age at birth, birth weight, small
for gestational age (birth weight <10th percentile), 5-minute
Apgar score less than 4, Score for Neonatal Acute Physiol-
ogy II score 19 greater than 20, severe cerebral injuries
defined as having severe intraventricular hemorrhage
(grade 3 or 4, based on the Papile et al grading),20 and/or
periventricular leukomalacia, necrotizing enterocolitis
(stage 2 or higher based on Bell criteria21), patent ductus
arteriosus requiring surgical or medical treatment, late-
onset sepsis (isolation of a pathogenic organism in blood or
cerebrospinal fluid in a symptomatic neonate after 2 days of
age), maternal race/ethnicity (white, black, and others), and
maternal education (completing college or higher).
Statistical Analyses
Covariates were compared between infants with and with-
out serious respiratory morbidity or neurosensory impair-
ment using the χ2 test or t test as appropriate. Initially, mul-
tiple logistic regression models were developed to assess
the association between the 6 traditional BPD definitions
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Original Investigation Research
with long-term outcomes adjusting for potential confound-
ers. The areas under the receiver operating characteristic
curves (AUCs) of the regression models were calculated for
each BPD definition.22 Area under the curve indicates the
predictive ability for discrimination, a quality that expresses
how well prediction models discriminate between patients
with and without the outcomes of interest. 22 The AUC
was used to select the best regression model to predict
outcomes.23 Furthermore, modified versions of the best tra-
ditional BPD definition (defined at different PMAs between
34-44 weeks) were evaluated by logistic regression analyses
to decide the best timing of the assessment of respiratory
status based on the associations with outcomes and the
AUC. Sensitivity, specificity, and positive or negative predic-
tive values of BPD definitions for predicting long-term out-
comes were also calculated.
Infants who were discharged or transferred to step-
down units without oxygen and without respiratory support
between 34 and 44 weeks’ PMA were assumed to not
require oxygen or respiratory support post-discharge or
post-transfer. Infants who were discharged home using
either oxygen or respiratory support were considered to use
oxygen/RS the week following discharge. If infants were
transferred to step-down units using either oxygen or respi-
ratory support, their oxygen use and RS were considered
unknown after the week of transfer. To assess the effect of
these inclusion/exclusion criteria of infants discharged or
transferred between 34 and 40 weeks’ PMA, 2 sensitivity
analyses were conducted assuming that (1) infants dis-
charged home on oxygen/RS were excluded from the analy-
ses after the week of discharge or (2) infants who trans-
ferred to step-down units on oxygen/RS were considered
using oxygen/RS after the week of transfer. We limited our
assessment up until 44 weeks’ PMA because neonates older
than 44 weeks are a very selective group of neonates with
additional complications necessitating their prolonged hos-
pital stay. All statistical analyses were conducted using SAS,
version 9.3 (SAS Institute Inc).
Results
Among 2760 infants at younger than 29 weeks’ gestational
age admitted to Canadian Neonatal Network NICUs during
the study period, 1914 infants were eligible for this study
(Figure 1). After excluding 411 infants (21%) without
follow-up data, 1503 infants were included. The proportion
of infants using oxygen/RS decreased from 63% to 9% from
34 to 44 weeks’ PMA (eFigure 1 in the Supplement). A total
of 321 infants (21%) had a composite outcome of respiratory
morbidity and/or neurosensory impairment or death after
discharge at 18 to 21 months’ corrected age, among which 12
infants (1%) died after initial discharge, 88 infants (6%) had
serious respiratory morbidity, and 257 infants (17%) had
serious neurosensory impairment (Table 1). Table 2 shows
maternal and infant characteristics of neonates with or
without serious respiratory morbidity or neurosensory
impairment. Infants of lower birth weight and gestational
(Reprinted) JAMA Pediatrics Published online January 23, 2017 E3
 Research Original Investigation
Figure 1. Study Population
2760 Neonates <29 wk admitted to
participating sites in the CNN
during study period
47 Moribund infants
119 Major congenital anomalies
409 Discharge/death
2185 Infants survived
271 Tranferred before 34 wk with
oxygen/RS
1914 Eligible infants
411 No follow-up data
1503 Follow-up data available from follow-up network sites
CNN indicates Canadian Neonatal Network and Oxygen/RS indicates receiving
supplemental oxygen and/or respiratory positive-pressure support.
age were more likely to display serious respiratory morbid-
ity (mean birth weight, 777 g vs 933 g; mean gestational age,
25.3 weeks vs 26.3 weeks; P < .001) and neurosensory
impairment (mean birth weight, 861 g vs 944 g; mean gesta-
tional age, 25.8 weeks vs 26.4 weeks; P < .001).
Infants with oxygen/RS at 28 days or 34 to 44 weeks’
PMA had a higher likelihood of all long-term adverse out-
comes (Figures 2 and 3). Four of 6 traditional BPD defini-
tions were significantly associated with all the 3 long-term
adverse outcomes after adjusting for potential confounders
(Figure 2). Among them, the definition of oxygen/RS at 36
weeks’ PMA displayed the highest predictive values for seri-
ous respiratory morbidity and neurosensory impairment,
suggesting oxygen requirement alone was not adequate cri-
teria. Based on this finding, subsequent analyses focused on
oxygen/RS at various PMAs between 34 and 44 weeks.
As the PMA for the assessment of oxygen/RS increased, the
specificity and positive predictive values increased while the
sensitivity decreased. Changes in negative predictive values
were minimal (eFigure 2 in the Supplement). In most cases,
oxygen/RS at 34 to 44 weeks’ PMA was significantly associ-
ated with adverse outcomes (Figure 3). For serious respira-
tory morbidity, the adjusted odds ratio (AOR) estimates in-
creased from 34 to 40 weeks’ PMA and decreased after 40
weeks’ PMA (Figure 3). The AUC also increased from 34 to 40
weeks’ PMA, from 0.721 to 0.799, and peaked at 40 weeks’ PMA
(Figure 3). For neurosensory impairment, the AORs and AUCs
between 34 and 44 weeks’ PMA were less different and those
at 40 weeks’ PMA (AOR, 1.5; 95% CI, 1.0-2.1; AUC, 0.740) were
only marginally below their peak values at 37 weeks’ PMA (AOR,
1.8; 95% CI, 1.3-2.6; AUC, 0.743). Marginal variations were also
observed for the composite outcome (AOR estimates, 1.6-2.3
and AUC, 0.724-0.746). Two sensitivity analyses uncovered
similar results: the AOR and AUC peaked at 40 weeks’ PMA for
serious respiratory morbidity and displayed minimal in-
creases for serious neurosensory impairment or the compos-
ite outcome between 34 and 44 weeks’ PMA (eTables 1 and 2
in the Supplement).
E4 JAMA Pediatrics Published online January 23, 2017 (Reprinted)
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Bronchopulmonary Dysplasia Definitions and Outcomes
Table 1. Adverse Long-Term Outcomes Among the Study Population at 18
to 21 Months of Corrected Age
Outcome No. (%)
Serious respiratory morbidity 88 (6)
≥3 Rehospitalizations owing to respiratory problems 58 (4)
Use of respiratory monitoring or support devices 44 (3)
Serious neurosensory impairment 257 (17)
Moderate to severe cerebral palsy, GMFCS ≥3 91 (6)
Bayley-III<70 in cognitive, language, or motor 208 (14)
Bayley-III composite score
<70 in cognitive 47 (3)
<70 in language 157 (11)
<70 in motor 87 (6)
Hearing aid or cochlear implant 35 (2)
Bilateral severe visual impairment 20 (1)
Death after initial discharge 12 (1)
Composite outcomea 321 (21)
Abbreviation: GMFCS, Gross Motor Function Classification System.
a
Composite outcome was defined as serious respiratory morbidity and/or
neurosensory impairment at 18 to 21 months corrected age, or death after
neonatal intensive care unit discharge before 21 months corrected age.
Discussion
In this large retrospective study with comprehensive evalua-
tion of respiratory and neurosensory impairment, we deter-
mined that oxygen/RS at 36 weeks’ PMA was the best among
all contemporary definitions of BPD to predict serious severe
respiratory morbidity at 18 to 21 months corrected age with the
highest AUC. Moreover, oxygen/RS at 40 weeks’ PMA was most
strongly associated with serious respiratory outcome among
those at each of 34 to 44 weeks’ PMA. For serious neurosen-
sory impairment and composite outcome, variations in pre-
diction ability and strength of association with oxygen/RS at
34 to 44 weeks’ PMA were marginal, with oxygen/RS at 37 to
40 weeks’ PMA resulting in similar estimates.
Several studies have evaluated accuracy or predictive abil-
ity of various diagnostic criteria of BPD for long-term adverse
respiratory outcomes. The original Shennan et al study7 evalu-
ated the diagnostic accuracy of oxygen use at 31 to 38 weeks’
PMA for predicting adverse respiratory outcomes in the first
2 years of life. Oxygen use at 36 weeks’ PMA had the highest
accuracy of 85%, with a sensitivity of 63% and specificity of
91%. The validity of this finding was limited by the fact that
(1) it was a single-center study that may not have been an ac-
curate representation of the general preterm infant popula-
tion, (2) the respiratory management strategies have been
changed since then, and (3) it only evaluated long-term ad-
verse respiratory outcomes and not neurodevelopmental im-
pairment. Davis et al24 reported that the diagnostic accuracy
of oxygen use at 36 weeks’ PMA for predicting poor respira-
tory outcome before 18 months of corrected age (63%) was simi-
lar to those at other PMAs between 32 and 40 weeks in a co-
hort from a multicenter trial. In contrast, our study revealed
that the AUC of oxygen/RS at 34 to 44 weeks’ PMA for predict-
ing long-term serious respiratory morbidity was highest at 40
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 Bronchopulmonary Dysplasia Definitions and Outcomes Original Investigation Research

Table 2. Maternal and Infant Characteristics

No. (%)
No Serious No Serious
Respiratory Serious Respiratory Neurosensory Serious Neurosensory
All Infants Morbidity Morbidity Impairment Impairment
Characteristics (n = 1503) (n = 1459) (n = 44) P Value (n = 1230) (n = 257) P Value
Maternal age, 30.7 (6) 30.7 (5.9) 30.8 (5.0) .88 30.8 (5.9) 30.2 (5.8) .12
mean (SD), y
Hypertensive disorders of 267 (18) 262 (18.2) 5 (11.4) .24 216 (17.8) 48 (19.0) .67
pregnancy
Antenatal steroids 1349 (92) 1310 (91.6) 39 (90.7) .83 1112 (92.2) 222 (88.5) .05
Rupture of membrane 325 (22) 314 (22.0) 11 (25.6) .58 173 (22.7) 50 (19.9) .34
>24 h
Chorioamnionitis 320 (27) 303 (26.2) 17 (48.6) <.001 261 (26.7) 55 (27.4) .84
Multiple birth 415 (28) 404 (27.7) 11 (25.0) .69 342 (27.8) 65 (25.3) .41
Cesarean section 876 (58) 850 (58.4) 26 (59.1) .93 721 (58.8) 145 (56.4) .48
Race/ethnicity
White 853 (68) 829 (67.9) 24 (60.0) 730 (69.7) 123 (57.8)
Black 112 (9) 108 (8.9) 4 (10.0) .56 83 (7.9) 29 (13.6) <.001
Other 296 (23) 284 (23.3) 12 (30.0) 235 (22.4) 61 (28.6)
Maternal education, 729 (53) 707 (53.2) 22 (55.0) .82 624 (54.6) 104 (46.0) .02
≥complete college
Male 775 (52) 750 (51.4) 25 (58.1) .39 606 (49.3) 162 (63.3) <.001
Gestational age, mean 26.3 (1) 26.3 (1.4) 25.3 (1.4) <.001 26.4 (1.4) 25.8 (1.5) <.001
(SD), wk
Birth weight, mean (SD), g 929 (226) 933 (225) 777 (169) <.001 944 (225) 861 (213) <.001
Small for gestational age 116 (8) 111 (7.6) 5 (11.6) .33 92 (7.5) 22 (8.6) .55
SNAP II score >20 410 (27) 387 (26.6) 23 (54.8) <.001 293 (23.9) 109 (42.9) <.001
Severe cerebral injuries 160 (11) 153 (10.6) 7 (16.7) .21 90 (7.4) 68 (26.7) <.001
Necrotizing enterocolitis 120 (8) 112 (7.7) 8 (19.1) .01 84 (6.8) 34 (13.3) <.001
Patent ductus arteriosus 903 (60) 868 (59.6) 35 (83.3) <.001 712 (58.0) 179 (69.9) <.001
Late onset sepsis 429 (29) 410 (28.1) 19 (43.2) .03 313 (25.5) 109 (42.4) <.001

Abbreviation: SNAP, Score for Neonatal Acute Physiology.

weeks. These differences may be owing to variations in cri-
teria for adverse respiratory outcomes, as well as differ-
ences in indices used (accuracy vs AUC). Unlike our study,
these previous studies included oxygen use at 40 weeks’
PMA or at discharge as a component of long-term adverse
respiratory outcomes that did not necessarily reflect func-
tionally important problems at follow-up. Furthermore,
they also included 1 or more, or more than 1, admissions as
long-term adverse respiratory outcomes, in contrast to our
study in which at least 3 admissions were required to be
classified as serious respiratory morbidity. A validation
study of the National Institutes of Health BPD definition
revealed a greater association between BPD and long-term
respiratory adverse outcomes as the severity of BPD
increased.13 The study also reported significant associations
between other various BPD definitions and long-term
adverse respiratory outcomes. However, unlike our study, it
did not assess the predictive ability of these BPD definitions
and did not evaluate the timing of the assessment of respi-
ratory status other than at 28 days of age and 36 weeks’
PMA.13
Our study confirmed the significant association between
BPD and neurosensory impairment that was previously
reported.1-3,25 Thus far, few groups have assessed the associa-
tion or predictive ability of oxygen use or RS at various PMAs
for neurosensory impairment. Davis et al24 reported that the
accuracy of oxygen use at 32 to 40 weeks’ PMA for predicting
neurosensory impairment at 18 months of corrected age in-
creased as the PMA for assessment increased (accuracy from
54% for the assessment at 32 weeks’ PMA to 68% for that at
40 weeks’ PMA). However, unlike our study, they did not ad-
just for important confounders.24 Given that other major mor-
bidities, such as severe cerebral injuries, necrotizing entero-
colitis, and sepsis, are associated with both BPD and
neurosensory impairment,13,25 adjustment for these poten-
tial confounders is critical for evaluating the independent as-
sociation and predictive ability of BPD for neurosensory im-
pairment.
This study is marked by several strengths. First, the study
cohort had a large sample size and contained a nearly popu-
lation-based sample from Canada. Second, this study as-
sessed not only the commonly used traditional BPD defini-
tions but also other promising alternatives including oxygen/RS
at each PMA between 34 and 44 weeks. Third, the adjust-
ment for potential confounders, including major neonatal mor-
bidities, enabled us to evaluate independent predictive abili-
ties of oxygen/RS at various PMAs using AUCs of logistic
regression models. Finally, the sensitivity analyses con-
firmed the robustness of the findings, especially for serious re-
spiratory morbidity.

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 Research Original Investigation Bronchopulmonary Dysplasia Definitions and Outcomes

Figure 2. Associations of 6 Traditional Bronchopulmonary Dysplasia (BPD) Definitions With Adverse Outcomes at 18 to 21 Months of Age

A Serious respiratory morbidity

Adverse Outcome Adverse Outcome
Traditional BPD Definitions in BPD (+) Infants in BPD (−) Infants AOR (95% CI)a
Oxygen, 28 d 71/893 (8.0) 17/513 (3.3) 1.3 (0.7-2.4) 0.72
Oxygen/RS, 28 d 81/1123 (7.2) 7/283 (2.5) 1.9 (0.7-5.0) 0.721
Oxygen, 28 d and Oxygen/RS 36 wk PMA 62/579 (10.7) 26/827 (3.1) 2.4 (1.4-4.2) 0.735
Oxygen/RS, 28 d and 36 wk PMA 66/620 (10.7) 22/786 (2.8) 2.9 (1.6-5.2) 0.743
Oxygen, 36 wk PMA 61/548 (11.1) 27/858 (3.2) 2.6 (1.5-4.4) 0.742
Oxygen/RS 36 wk PMA 69/652 (10.6) 19/754 (2.5) 3.4 (1.8-6.3) 0.75

0.5 1 2 5 10 0.71 0.73 0.75 0.77

AOR (95% CI) AUC

B Serious neurosensory impairment

Adverse Outcome Adverse Outcome
Traditional BPD Definitions in BPD (+) Infants in BPD (−) Infants AOR (95% CI)a
Oxygen, 28 d 192/892 (21.5) 55/511 (10.8) 1.3 (0.9-1.9) 0.729
Oxygen/RS, 28 d 217/1120 (19.4) 30/283 (10.6) 1.1 (0.7-1.8) 0.729
Oxygen, 28 d and Oxygen/RS 36 wk PMA 145/578 (25.1) 102/825 (12.4) 1.6 (1.1-2.2) 0.733
Oxygen/RS, 28 d and 36 wk PMA 153/619 (24.7) 94/784 (12.0) 1.7 (1.2-2.4) 0.737
Oxygen, 36 wk PMA 134/547 (24.5) 113/856 (13.2) 1.7 (1.2-2.3) 0.736
Oxygen/RS 36 wk PMA 158/651 (24.3) 89/752 (11.8) 1.7 (1.2-2.4) 0.738

0.5 1 2 5 10 0.71 0.73 0.75 0.77

AOR (95% CI) AUC

C Composite outcomeb
Adverse Outcome Adverse Outcome
Traditional BPD Definitions in BPD (+) Infants in BPD (−) Infants AOR (95% CI)a
Oxygen, 28 d 241/902 (26.7) 70/516 (13.6) 1.3 (0.9-1.8) 0.724
Oxygen/RS, 28 d 277/1134 (24.2) 34/284 (12.0) 1.4 (0.9-2.2) 0.725
Oxygen, 28 d and Oxygen/RS 36 wk PMA 185/586 (31.6) 126/832 (15.1) 1.7 (1.2-2.3) 0.731
Oxygen/RS, 28 d and 36 wk PMA 198/628 (31.5) 113/790 (14.3) 1.9 (1.4-2.7) 0.737
Oxygen, 36 wk PMA 174/556 (31.3) 137/862 (15.9) 1.8 (1.3-2.5) 0.733
Oxygen/RS 36 wk PMA 205/661 (31.0) 106/757 (14.0) 1.9 (1.4-2.7) 0.736

0.5 1 2 5 10 0.71 0.73 0.75 0.77

AOR (95% CI) AUC

The second and third columns show the number of infants with adverse
outcomes/the number of infants assessed at 18 to 21 months, with percentages
in brackets for infants with or without BPD defined in the first column. The
forest plots show the adjusted odds ratios (AORs; filled squares) and 95% CIs
(lines). AUC indicates area under the receiver operating characteristic curve;
Oxygen/RS, receiving supplemental oxygen and/or any respiratory
positive-pressure support; PMA, postmenstrual age.
a
Adjusted for gestational age, sex, small for gestational age, Score for Neonatal
Acute Physiology II score >20, maternal education, severe intraventricular
hemorrhage and/or periventricular leukomalacia, necrotizing enterocolitis,
and late-onset sepsis.
b
Composite outcome was defined as serious respiratory morbidity and/or
neurosensory impairment at 18 to 21 months’ corrected age or death after
neonatal intensive care unit discharge before 21 months’ corrected age.

Limitations
There were several limitations in our study. First, the poten-
tial for recall bias may exist in long-term adverse respiratory
morbidity findings because information was collected from
parents by interviewers in follow-up visits at 18 to 21 months
of age; however, recall items only included the number of hos-
pitalizations, which is very unlikely to be falsely reported. Sec-
ond, infants who were discharged home or were transferred
to step-down units before 44 weeks’ PMA using oxygen/RS did
not have data available on oxygen/RS after discharge/
transfer. The sensitivity analysis assessed the effect of this limi-
tation. Third, the oxygen challenge test was not mandatory to
assess oxygen requirement in this study and was unlikely to
have been conducted for the assessment at PMA other than 36
weeks. Although we may have overestimated oxygen use at
each PMA, its effect on the association or predictive abilities
was considered small. Fourth, 21% of infants did not have fol-
low-up outcomes; however, our previous comparisons have
revealed that those who were lost to follow-up were likely to
be less ill15 and thus, our estimates of association may be mod-
est. Finally, residual bias and confounding factors cannot be
ruled out based on the retrospective nature of our study.
Conclusions
From a predictive ability and strength of association perspec-
tive, oxygen/RS at 40 weeks’ PMA appears to be the optimal
criterion to define or diagnose BPD associated with serious re-
spiratory morbidity. This is particularly relevant for modern
neonatal care practice, whereby wide panoply of respiratory
support modalities are offered to preterm neonates. Given the

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 Bronchopulmonary Dysplasia Definitions and Outcomes Original Investigation Research

Figure 3. Association of Oxygen Use or Respiratory Support at 34 to 40 Weeks’ Postmenstrual Age With Adverse Outcomes at 18 to 21 Months of Age

A Serious respiratory morbidity

Traditional BPD Adverse Outcome Adverse Outcome

Definitions in BPD (+) Infants in BPD (−) Infants AOR (95% CI)a
34 wk PMA 72/939 (7.7) 16/552 (2.9) 1.8 (0.9-3.4) 0.721
35 wk PMA 70/780 (9.0) 18/673 (2.7) 2.6 (1.4-4.9) 0.732
36 wk PMA 69/652 (10.6) 19/754 (2.5) 3.4 (1.8-6.3) 0.75
37 wk PMA 67/555 (12.1) 19/821 (2.3) 4.2 (2.3-7.8) 0.766
38 wk PMA 65/467 (13.9) 20/879 (2.3) 5.2 (2.8-9.5) 0.785
39 wk PMA 60/392 (15.3) 22/928 (2.4) 5.6 (3.1-10.1) 0.792
40 wk PMA 59/362 (16.3) 23/942 (2.4) 6.1 (3.4-11.0) 0.799
41 wk PMA 45/315 (14.3) 30/966 (3.1) 4.0 (2.3-7.1) 0.778
42 wk PMA 43/294 (14.6) 32/974 (3.3) 3.9 (2.2-6.9) 0.779
43 wk PMA 40/272 (14.7) 29/981 (3.0) 4.6 (2.5-8.2) 0.782
44 wk PMA 41/269 (15.2) 28/980 (2.9) 5.1 (2.8-9.2) 0.789

0.5 1 2 5 10 20 0.7 0.75 0.8

AOR (95% CI) AUC

B Serious neurosensory impairment

Traditional BPD Adverse Outcome Adverse Outcome
Definitions in BPD (+) Infants in BPD (−) Infants AOR (95% CI)a
34 wk PMA 199/937 (21.2) 58/550 (10.6) 1.6 (1.1-2.3) 0.729
35 wk PMA 171/778 (27.0) 82/671 (12.2) 1.4 (1.0-2.1) 0.731
36 wk PMA 158/651 (24.3) 89/752 (11.8) 1.7 (1.2-2.4) 0.738
37 wk PMA 146/554 (26.4) 92/819 (11.2) 1.8 (1.3-2.6) 0.743
38 wk PMA 124/466 (26.6) 110/877 (12.5) 1.6 (1.2-2.3) 0.739
39 wk PMA 107/391 (27.4) 119/926 (12.9) 1.7 (1.2-2.4) 0.737
40 wk PMA 99/361 (27.4) 124/940 (13.2) 1.5 (1.0-2.1) 0.74
41 wk PMA 84/315 (26.7) 128/963 (13.3) 1.5 (1.0-2.1) 0.737
42 wk PMA 80/294 (27.2) 128/971 (13.2) 1.5 (1.0-2.2) 0.732
43 wk PMA 80/272 (29.4) 126/978 (12.9) 1.7 (1.1-2.5) 0.735
44 wk PMA 74/269 (27.5) 131/977 (13.4) 1.4 (0.9-2.1) 0.731

0.5 1 2 5 10 20 0.7 0.75 0.8

AOR (95% CI) AUC

C Composite outcomeb
Traditional BPD Adverse Outcome Adverse Outcome
Definitions in BPD (+) Infants in BPD (−) Infants AOR (95% CI)a
34 wk PMA 248/949 (26.1) 73/554 (13.2) 1.6 (1.1-2.2) 0.724
35 wk PMA 219/790 (27.7) 98/675 (14.5) 1.6 (1.1-2.2) 0.729
36 wk PMA 205/661 (31.0) 106/757 (14.0) 1.9 (1.4-2.7) 0.736
37 wk PMA 191/564 (33.9) 109/824 (13.2) 2.2 (1.6-3.1) 0.746
38 wk PMA 171/478 (35.8) 125/880 (14.2) 2.2 (1.6-3.0) 0.744
39 wk PMA 150/401 (37.4) 137/931 (14.7) 2.3 (1.6-3.2) 0.743
40 wk PMA 138/370 (37.3) 144/944 (15.3) 2.0 (1.4-2.8) 0.745
41 wk PMA 114/322 (35.4) 155/969 (16.0) 1.8 (1.3-2.6) 0.74
42 wk PMA 111/302 (36.8) 154/976 (15.8) 1.9 (1.4-2.8) 0.737
43 wk PMA 104/278 (37.4) 154/985 (15.6) 2.0 (1.4-2.8) 0.735
44 wk PMA 100/276 (36.2) 157/983 (16.0) 1.7 (1.2-2.5) 0.732

0.5 1 2 5 10 20 0.7 0.75 0.8

AOR (95% CI) AUC

The second and third columns show the number of infants with adverse
outcomes/the number of infants assessed at 18-21 months with percentages in
brackets for infants with or without bronchopulmonary dysplasia (BPD) defined in
the first column. The forest plots show the adjusted odds ratios (AORs; filled
squares) and 95% CIs (lines). AUC indicates area under the receiver operating
characteristic curve; Oxygen/RS, receiving supplemental oxygen and/or any
respiratory positive-pressure support; PMA, postmenstrual age.
a
Adjusted for gestational age, sex, small for gestational age, Score for Neonatal
Acute Physiology II score >20, maternal education, severe intraventricular
hemorrhage and/or periventricular leukomalacia, necrotizing enterocolitis,
and late-onset sepsis.
b
Composite outcome was defined as serious respiratory morbidity and/or
neurosensory impairment at 18 to 21 months’ corrected age, or death after
neonatal intensive care unit discharge before 21 months’ corrected age.

jamapediatrics.com (Reprinted) JAMA Pediatrics Published online January 23, 2017 E7

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 Research Original Investigation
persistent inconsistency of BPD definitions in the literature,
this unique information should be useful to develop a
future consensus on a BPD definition based on outcome
data. We strongly encourage incorporation of parental per-
spectives in defining what matters to them most as far as
ARTICLE INFORMATION
Accepted for Publication: October 23, 2016.
Published Online: January 23, 2017.
doi:10.1001/jamapediatrics.2016.4141
Author Affiliations: Department of Pediatrics,
University of Toronto, Toronto, Ontario, Canada
(Isayama, S. K. Lee, Dunn, Shah); Department of
Clinical Epidemiology and Biostatistics, McMaster
University, Hamilton, Ontario, Canada (Isayama);
Maternal-Infant Care Research Centre, Department
of Paediatrics, Mount Sinai Hospital, Toronto,
Ontario, Canada (S. K. Lee, Yang, Shah);
Department of Paediatrics, University of Western
Ontario, London, Ontario, Canada (D. Lee);
Department of Paediatrics, University of
Saskatchewan, Saskatoon, Canada (Daspal).
Author Contributions: Dr Shah had full access to all
the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data
analysis.
Concept and design: Isayama, S. K. Lee, D. Lee,
Daspal, Dunn, Shah.
Acquisition, analysis, or interpretation of data:
Isayama, S. K. Lee, Yang, Shah.
Drafting of the manuscript: Isayama, Daspal.
Critical revision of the manuscript for important
intellectual content: Isayama, S. K. Lee, Yang, D. Lee,
Dunn, Shah.
Statistical analysis: Isayama, Yang, Shah.
Obtained funding: S. K. Lee.
Administrative, technical, or material support: Lee,
Shah.
Supervision: S. K. Lee, D. Lee, Shah.
Group Information: Investigators of the Canadian
Neonatal Network and Canadian Neonatal Follow-
Up Network are listed here. Canadian Neonatal
Network investigators: Prakesh S Shah, MD, MSc
(Director, Canadian Neonatal Network and site
investigator), Mount Sinai Hospital, Toronto,
Ontario; Adele Harrison, MD, MBChB, Victoria
General Hospital, Victoria, British Columbia; Anne
Synnes, MDCM, MHSC, and Joseph Ting, MD,
British Columbia Women’s Hospital, Vancouver,
British Columbia; Zenon Cieslak, MD, Royal
Columbian Hospital, New Westminster, British
Columbia; Rebecca Sherlock, MD, Surrey Memorial
Hospital, Surrey, British Columbia; Wendy Yee, MD,
Foothills Medical Centre, Calgary, Alberta; Khalid
Aziz, MBBS, MA, MEd, and Jennifer Toye, MD, Royal
Alexandra Hospital, Edmonton, Alberta; Carlos
Fajardo, MD, Alberta Children’s Hospital, Calgary,
Alberta; Zarin Kalapesi, MD, Regina General
Hospital, Regina, Saskatchewan; Koravangattu
Sankaran, MD, MBBS, and Sibasis Daspal, MD, Royal
University Hospital, Saskatoon, Saskatchewan;
Mary Seshia, MBChB, Winnipeg Health Sciences
Centre, Winnipeg, Manitoba; Ruben Alvaro, MD, St.
Boniface General Hospital, Winnipeg, Manitoba;
Sandesh Shivananda, MBBS, MD, DM, Hamilton
Health Sciences Centre, Hamilton, Ontario; Orlando
Da Silva, MD, MSc, London Health Sciences Centre,
London, Ontario; Chuks Nwaesei, MD, Windsor
Regional Hospital, Windsor, Ontario; Kyong-Soon
Lee, MD, MSc, Hospital for Sick Children, Toronto,
E8 JAMA Pediatrics Published online January 23, 2017 (Reprinted)
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Bronchopulmonary Dysplasia Definitions and Outcomes
respiratory and neurodevelopmental outcomes are con-
cerned in future exercises. Future large prospective cohort
studies are also needed to confirm our study findings such
as the Prematurity and Respiratory Outcomes Program cur-
rently under way.26
Ontario; Michael Dunn, MD, Sunnybrook Health
Sciences Centre, Toronto, Ontario; Brigitte Lemyre,
MD, Children’s Hospital of Eastern Ontario and
Ottawa General Hospital, Ottawa, Ontario; Kimberly
Dow, MD, Kingston General Hospital, Kingston,
Ontario; Ermelinda Pelausa, MD, Jewish General
Hospital, Montréal, Québec; Keith Barrington,
MBChB, Hôpital Sainte-Justine, Montréal, Québec;
Christine Drolet, MD, and Bruno Piedboeuf, MD,
Centre Hospitalier Universitaire de Québec, Sainte
Foy Québec; Martine Claveau, and Daniel Faucher,
MD, McGill University Health Centre, Montréal,
Québec; Valerie Bertelle, MD, and Edith Masse, MD,
Centre Hospitalier Universitaire de Sherbrooke,
Sherbrooke, Québec; Roderick Canning, MD,
Moncton Hospital, Moncton, New Brunswick; Hala
Makary, MD, Dr Everett Chalmers Hospital,
Fredericton, New Brunswick; Cecil Ojah, MBBS, and
Luis Monterrosa, MD, Saint John Regional Hospital,
Saint John, New Brunswick; Akhil Deshpandey,
MBBS, MRCPI, Janeway Children’s Health and
Rehabilitation Centre, St. John’s, Newfoundland;
Jehier Afifi, MB BCh, MSc, IWK Health Centre,
Halifax, Nova Scotia; Andrzej Kajetanowicz, MD,
Cape Breton Regional Hospital, Sydney, Nova
Scotia; Shoo K Lee, MBBS, PhD (Chairman,
Canadian Neonatal Network), Mount Sinai Hospital,
Toronto, Ontario. Canadian Neonatal Follow-Up
Network investigators: Thevanisha Pillay, MD,
Victoria General Hospital, Victoria, British
Columbia; Anne Synnes, MDCM, MHSC (Director
CNFUN), British Columbia Women’s Hospital,
Vancouver, British Columbia; Reg Sauvé, MD, MPh,
Leonora Hendson MBBCH, MSc, Alberta’s Children’s
Hospital, Foothills Medical Centre, Calgary, Alberta;
Amber Reichert, MD, Glenrose Rehabilitation
Hospital, Edmonton, Alberta; Jaya Bodani, MD,
Regina General Hospital, Regina, Saskatchewan;
Koravangattu Sankaran, MD, Royal University
Hospital, Saskatoon, Saskatchewan; Diane
Moddemann, MD, Winnipeg Health Sciences
Centre, St. Boniface General Hospital, Winnipeg,
Manitoba; Chuks Nwaesei, MD, Windsor Regional
Hospital, Windsor, Ontario; Thierry Daboval, MD,
Children’s Hospital of Eastern Ontario, Ottawa,
Ontario; Kimberly Dow, Kingston General Hospital,
Kingston, Ontario; David Lee, MD, Children’s
Hospital London Health Sciences Centre, London,
Ontario; Linh Ly, MD, Hospital for Sick Children,
Toronto, Ontario; Edmond Kelly, MD, Mount Sinai
Hospital, Toronto, Ontario; Salhab el Helou, MD,
Hamilton Health Sciences Centre, Hamilton,
Ontario; Paige Church, MD, Sunnybrook Health
Sciences Centre, Toronto, Ontario; Ermelinda
Pelausa, MD, Jewish General Hospital, Montréal,
Québec; Patricia Riley, MD, Montréal Children’s
Hospital, Royal Victoria Hospital, Montréal, Québec;
Francine Levebrve, Centre Hospitalier Universitaire
Sainte-Justine, Montréal, Québec; Charlotte
Demers, Centre Hospitalier Universitaire de
Sherbrooke, Sherbrooke, Québec; Sylvie Bélanger,
MD, Centre Hospitalier Universitaire de Québec,
Québec City, Québec; Roderick Canning, MD,
Moncton Hospital, Moncton, New Brunswick; Luis
Monterrosa, MD, Saint John Regional Hospital,
Saint John, New Brunswick; Hala Makary, MD, Dr
Everett Chalmers Hospital, Fredericton, New
Brunswick; Michael Vincer, MD, IWK Health Centre,
Halifax, Nova Scotia; Phil Murphy, Charles Janeway
Children’s Health and Rehabilitation Centre, St.
John’s, Newfoundland.
Conflicts of Interest Disclosures: None reported.
Funding/Support: Organizational support was
provided by the Maternal-Infant Care Research
Centre at Mount Sinai Hospital in Toronto, Ontario,
Canada. Neonatal follow-up data were supported
by team grant FRN87518 from the Canadian
Institutes of Health Research awarded to Dr Lee,
and in-kind support from Mount Sinai Hospital. Dr
Isayama is supported by the Ontario Graduate
Scholarships program. Dr Shah holds an Applied
Research Chair in Reproductive and Child Health
Services and Policy Research awarded by the
Canadian Institutes of Health Research (APR-
126340).
Role of the Funder/Sponsor: The funders had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Additional Contributions: We gratefully
acknowledge all investigators and data abstractors
of the Canadian Neonatal and Follow-Up Networks.
We also thank Natasha Musrap, PhD, from the
Maternal-Infant Care Research Centre, for editorial
assistance in the preparation of the manuscript. She
received salaried compensation for her work from
funding support (grant FRN87518).
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