Pediatrics and Neonatology (2020) 61, 290e299

Available online at www.sciencedirect.com

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journal homepage: http://www.pediatr-neonatol.com

Original Article

Early prediction of moderate to severe

bronchopulmonary dysplasia in extremely
premature infants
Amit Sharma a,b,c, Yuemin Xin a, Xinguang Chen d,
Beena G. Sood a,b,c,*

a
Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Wayne State University, Detroit,
MI 48201, USA
b
Hutzel Women’s Hospital, Detroit, MI 48201, USA
c
Children’s Hospital of Michigan, Detroit, MI 48201, USA
d
University of Florida College of Medicine, College of Public Health, USA

Received May 3, 2019; received in revised form Nov 15, 2019; accepted Dec 16, 2019
Available online 23 December 2019

Key Words Background: Bronchopulmonary Dysplasia (BPD) is the commonest morbidity in extremely pre-
bronchopulmonary term infants (PTIs). Risk factors for BPD have been described in the era before the widespread
dysplasia; availability of non-invasive ventilation (NIV) in the delivery room (DR). The objective of this
extremely premature study is to identify risk factors for Moderate/Severe BPD in an era of widespread availability
infants; of NIV in the DR.
prediction Methods: Detailed antenatal and postnatal data were abstracted for PTIs, 230/7e276/7 weeks
GA. Multivariate logistic regression and classification and regression tree analyses (CART)
identified predictors for the primary outcome of Moderate/Severe BPD.
Results: Of 263 eligible infants, 59% had Moderate/Severe BPD. Moderate/Severe BPD was
significantly associated with birthweight, gender, DR intubation and surfactant compared to
No/Mild BPD. Of infants not intubated in the DR, 40% with No/Mild BPD and 80% with Moder-
ate/Severe BPD received intubation by 48 hours (p < 0.05). Infants with Moderate/Severe
BPD received longer duration of oxygen and mechanical (MV). On logistic regression, birth-
weight, gender, oxygen concentration, cumulative duration of oxygen and MV, surfactant,
and blood transfusions predicted Moderate/Severe BPD. Both CART analysis and logistic regres-
sion showed duration of oxygen and MV to be the most important predictors for Moderate/Se-
vere BPD.
Conclusions: In an era of increasing availability of NIV in the DR, lower birthweight, male
gender, surfactant treatment, blood transfusions and respiratory support in the first 2e3 weeks
after birth predict Moderate/Severe BPD with high sensitivity and specificity. The majority of

* Corresponding author. Department of Pediatrics, Wayne State University, Children’s Hospital of Michigan, 3901 Beaubien Blvd., Suite
3N027, Detroit, MI 48201, USA. Fax: þ1 313 745 5867.
E-mail address: bsood@med.wayne.edu (B.G. Sood).

https://doi.org/10.1016/j.pedneo.2019.12.001
1875-9572/Copyright ª 2020, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Early prediction of moderate to severe BPD 291

these infants received intubation within 48 hours of birth (97%). These data suggest that early
failures of NIV represent opportunities for improvement of NIV techniques and of non-invasive
surfactant to avoid intubation in the first 48 hours. Furthermore, these risk factors may allow
earlier identification of infants most likely to benefit from interventions to prevent or decrease
severity of BPD.
Copyright ª 2020, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).

and improved nutrition with variable results.10 A significant

Abbreviations
recent change is the increasing use of non-invasive venti-
ANCS antenatal corticosteroids lation (NIV) as a primary mode of respiratory support in the
BPD bronchopulmonary dysplasia delivery room (DR) as a lung-protective strategy.11,12 There
CART Classification and Regression Trees are limited data for prediction of Moderate/Severe BPD in
DR delivery room an era of widespread availability of NIV in the DR. Our
EPT extremely preterm infants center participated in the SUPPORT trial and, since publi-
FiO2 fractional inspired oxygen cation of the results of this trial, our unit adopted the
GA gestational age practice of early use of NIV including high flow nasal can-
HFNC high flow nasal cannula nula [HFNC], nasal continuous positive airway pressure
IVH intraventricular hemorrhage [NCPAP] and non-invasive positive pressure ventilation
MgSO4 magnesium sulfate [NIPPV] in the DR. The objective of this study was to
MV mechanical ventilation identify risk factors associated with Moderate/Severe BPD
NC nasal cannula in a comprehensive data set in extremely PTIs using logistic
NCPAP nasal continuous positive airway pressure regression and classification trees in the post-SUPPORT
NEC necrotizing enterocolitis period.
NICU neonatal intensive care unit
NIPPV non-invasive positive pressure ventilation 2. Methods
NIV non-invasive ventilation
PDA patent ductus arteriosus Preterm infants, 230/7e276/7 weeks gestational age (GA)
PMA post-menstrual age admitted to the Level III neonatal intensive care unit (NICU)
PTI preterm infant at Hutzel Women’s Hospital between January 2011 and
PVL periventricular leukomalacia February 2017 were eligible for this historical cohort study.
RBCT red blood cell transfusions Infants with major congenital anomalies were excluded.
RCT randomized controlled trial The study was approved by the IRB with waiver of parental
RDS respiratory distress syndrome consent.
ROP retinopathy of prematurity Trained research staff abstracted detailed maternal and
neonatal information from medical records. Information
regarding fractional inspired oxygen concentration (FiO2)
and respiratory support was collected both cross-
1. Introduction sectionally and cumulatively at pre-defined time points
(1, 3, 7, 14, 21, and 28 days of age and at 36 weeks PMA/
Bronchopulmonary Dysplasia (BPD), the commonest discharge). For cross sectional data, maximal FiO2 and
morbidity in extremely preterm infants (PTI), is defined by maximal mode of respiratory support were recorded at
the need for oxygen for 28 days and its severity catego- each time point. In addition, cumulative days of treatment
rized based on respiratory support at 36 weeks post- with oxygen and various modes of mechanical ventilation
menstrual age (PMA).1 The incidence of Moderate/Severe (MV) (conventional, high frequency and jet) and NIV (nasal
BPD, defined as receipt of oxygen and/or positive pressure cannula [NC], HFNC, NCPAP, NIPPV) up to the time point of
respiratory support at 36 weeks PMA/discharge, remains assessment were calculated from the sum of actual number
high at 42% (range 20e89%)2,3 and is reported to be of hours of exposure. Of note, the requirement for 28 days
increasing.2,4 Moderate/Severe BPD is associated with short of supplemental oxygen was computed from the sum of
and long-term adverse health, emotional, and financial hourly oxygen use over the entire hospital stay and not as
consequences.5,6 28 consecutive days of oxygen or need for oxygen at 28 days
Numerous publications on clinical prediction models for of age.13
BPD in PTIs emphasize the importance of respiratory sup- The primary outcome variable was Moderate/Severe
port in the first 28 days.7e9 Several lung protective strate- BPD, defined as receipt of oxygen for at least 28 days and
gies used to mitigate this risk include antenatal steroids, receipt of oxygen and/or positive pressure respiratory
surfactant, gentle ventilation, oxygen saturation targets, support at 36 weeks PMA/discharge as described in the
judicious use of postnatal steroids, caffeine and vitamin A, NICHD consensus statement; infants receiving low-flow or
292
high-flow nasal cannula were included in this group.1,14
Infants who received oxygen for <28 days (No BPD) or
those that received oxygen for at least 28 days but were
breathing room air at 36 weeks PMA (Mild BPD) were clas-
sified as No/Mild BPD. Infants discharged (n Z 6) or trans-
ferred (n Z 4) prior to 36 weeks PMA were classified based
on respiratory support at discharge/transfer. At our center
a physiologic test confirming oxygen requirement is per-
formed at 36 weeks PMA. Infants who died in the 1st 28 days
after birth were excluded from the statistical analyses for
the primary outcome as oxygen treatment for at least 28
days was used to define presence of BPD. The secondary
outcome for the study was the composite outcome of
Moderate/Severe BPD and/or Death prior to 36 weeks PMA;
all infants in the birth cohort were included in statistical
analyses for the secondary outcome.
2.1. Statistical analyses
Data were analyzed using SPSS 25.0. Statistical significance
was defined as a two-sided p-value <0.05. Categorical data
were analyzed using the c2- and Fisher’s exact test.
Continuous data were analyzed using independent t-test or
non-parametric tests as appropriate. Multivariate stepwise
logistic regression models were constructed to determine
predictors for the primary and secondary outcome after
controlling for maternal and neonatal characteristics that
were known or likely to be associated with BPD.
Classification and Regression Trees (CART) Analysis
(SPSS) was used to classify subjects into two BPD risk cat-
egories as defined in the primary outcome. CART uses
advanced recursive partitioning and machine learning
techniques to split the data into increasingly homogeneous
subgroups with an appropriate number of nodes.15,16 At
each node, the CART algorithm selects the explanatory
variable and splitting value to maximize sensitivity and
specificity of the classification to predict outcome. CART
models are designed to handle a large number of predictor
variables and are able to determine complex interactions
among variables in the final tree. The more closely associ-
ated a variable is in relation to the outcome, the higher it is
on the decision tree.7 Pruning is used to develop a tree with
the best size and lowest misclassification rate.
3. Results
Of 323 extremely PTIs, 317 met eligibility criteria after
exclusions (congenital anomalies Z 3, missing charts Z 3).
Seventy infants died; 54 infants died within 28 days after
birth. The median age at death was 5.6 days (interquartile
range 1.2e26.0 days). Seventy infants (26.6%) had no BPD;
Mild, Moderate and Severe BPD was diagnosed in 38 (14.4%),
78 (29.7%), and 77 (29.3%) of subjects respectively. Eligible
infants were classified into two groups: No/Mild BPD
(n Z 108, 41%) and Moderate/Severe BPD (n Z 155, 59%).
3.1. Bivariate analyses of maternal and neonatal
characteristics by BPD group
Maternal variables were similar in the two groups (Table 1).
Moderate/Severe BPD was significantly associated with
A. Sharma et al
lower birthweight and GA; intrauterine growth restriction,
lower 5-min Apgar score, DR intubation, intratracheal sur-
factant, and pulmonary hemorrhage compared to infants
with No/Mild BPD. These neonates were also more likely to
receive caffeine but at a later age, and more likely to
receive Vitamin A and furosemide. They were more likely to
receive red blood cell transfusions (RBCTs) and postnatal
steroids and have positive respiratory cultures in the first 14
days after birth compared to infants with No/Mild BPD.
Seventy-two percent of infants with No/Mild BPD
received intubation in the DR compared to 91% in the
Moderate/Severe BPD group (p < 0.001). Of 30 infants with
No/Mild BPD that were not intubated in the DR, 15 (50%)
were intubated subsequently at a median (IQR) age of 128
(7e319) hours. Of 14 infants with Moderate/Severe BPD
that were not intubated in the DR, 10 (71%) were intubated
subsequently at a median (IQR) age of 10 (0.5e41) hours.
Forty percent of infants with No/Mild BPD and 80% of in-
fants with Moderate/Severe BPD who were not intubated in
the DR received intubation by 48 hours of age (p < 0.05).
3.2. Bivariate analyses of respiratory support by
BPD group
3.2.1. Cross-sectional respiratory support (Supplemental
Fig. 1)
Maximal median daily FiO2 was higher in infants with Mod-
erate/Severe BPD compared to infants with No/Mild BPD
(p < 0.001) on postnatal days 1, 3, 7, 21, 28, and 36 weeks
PMA/discharge. Infants with Moderate/Severe BPD were
also more likely to receive invasive MV at all time points
(p < 0.001) compared to infants with No/Mild BPD.
3.2.2. Cumulative respiratory support (Supplemental
Fig. 2)
Infants with Moderate/Severe BPD received longer cumu-
lative duration of supplemental oxygen and invasive MV at
postnatal days 1, 3, 7, 21, 28, and 36 weeks PMA/discharge
(p < 0.001) compared to infants with No/Mild BPD.
Conversely, infants with No/Mild BPD received longer cu-
mulative duration of NIV at postnatal days 1, 3, 7, 21, and
28 (p < 0.001) compared to infants with Moderate/Severe
BPD; the difference was no longer significant at 36 weeks
PMA/discharge. Infants in the Moderate/Severe BPD group
were more likely to receive high frequency ventilation
during the hospital stay compared to infants with No/Mild
BPD (p < 0.001).
3.3. Bivariate analyses of neonatal outcomes by
BPD group
Compared to infants with No/Mild BPD, infants with Mod-
erate/Severe BPD were more likely to have a diagnosis of
PDA, pulmonary hypertension, grade IIIeIV IVH, and ROP
(Table 1). They were more likely to undergo PDA ligation
and at a later age, receive reservoir placement for post-
hemorrhagic ventriculomegaly, and laser photocoagulation
for ROP. Their z-scores for weight at 36 weeks PMA/
Discharge were significantly lower than those of infants
with No/Mild BPD.
Early prediction of moderate to severe BPD 293

Table 1 Maternal and neonatal characteristics by BPD group.

Variables No/Mild BPD (n Z 108) Moderate/Severe BPD (n Z 155)
Maternal characteristics:
Maternal age (years) e mean  SD 27.1  6.7 27.3  5.9
African American race e n (%) 91 (84) 129 (83)
Antenatal corticosteroids, any e n (%) 95 (88) 142 (92)
Delivery by C-section e n (%) 66 (61) 98 (63)
Maternal MgSO4 administration e (%) 94 (87) 132 (85)
Prolonged premature ROM e n (%) 28 (26) 33 (21)
Histological chorioamnionitis e n (%) 68 (68) 109 (80)
Delivery room course:
Birthweight (g) e mean  SD 918  174 727  169***
Gestational age (weeks) e mean  SD 26.0  1.1 24.7  1.3***
Small for gestational age e n (%) 3 (3) 21 (14)**
Male gender e n (%) 53 (49) 92 (59)
Apgar score at 5 min e median (IQR) 7 (6e8) 6 (4.5e7)***
DR intubation e n (%) 78 (72) 141 (91)***
NICU course and outcomes:
Surfactant e n (%) 77 (71) 147 (95)***
Surfactant > 2 doses e n (%) 7 (7) 62 (40)***
Pulmonary hemorrhage e n (%) 6 (6) 31 (20)**
Pneumothorax e n (%) 5 (5) 16 (10)
Caffeine treatment e n (%) 103 (95) 154 (99)*
Caffeine started < 3 days of age e n (%) 96 (89) 112 (72)**
Vitamin A e n (%) 16 (15) 43 (28)*
Treatment with Furosemide e n (%) 74 (69) 153 (99)***
Age at start of Furosemide (days) e mean  SD 20  18 12  10***
Culture proven sepsis e n (%) 34 (32) 59 (38)
Positive respiratory culture in first 14 days e n (%) 8 (7) 34 (22)**
Number of red blood cell transfusion e mean  SD 3.3  3.0 9.0  5.6***
Red blood cell transfusions > 2 e n (%) 53 (49) 146 (94)***
Postnatal steroids for CLD e n (%) 1 (0.9) 22 (14)***
PDA e treated e n (%) 29 (26.9) 90 (58.1)***
PDA e ligation e n (%) 8 (7.4) 60 (38.7)***
Age at PDA ligation (days) e median (IQR) 14 (12e20) 28 (17e35)**
NICU outcomes:
Pulmonary hypertension e n (%) 1 (0.9) 34 (21.9)***
Tracheostomy e n (%) 0 (0) 3 (1.1)
Duration of MV (d) e median (IQR) 3 (1e11) 36 (22e55)***
Duration of NIV (d) e median (IQR) 33 (23e47) 37 (21e49)
IVH grade 3 & 4 e n (%) 13 (12.0) 42 (27.1)**
IVH requiring reservoir e n (%) 5 (4.6) 24 (15.5)**
ROP requiring surgery e n (%) 3 (2.8) 24 (15.5)**
NEC (Stage 2e3) e n (%) 8 (7.4) 15 (9.7)
Surgical NEC e n (%) 6 (5.6) 15 (9.7)
Died e n (%) 5 (4.6) 11 (7.1)
Weight (z-score) at 36 weeks PMA/discharge e mean  SD 1.4  0.7 2.0  0.8***
Age at discharge (days) e median (IQR) 67 (57e79) 97 (81e117)***
Postmenstrual age at discharge (wks) e median (IQR) 37 (35e37) 39 (37e42)***
MgSO4 Z magnesium sulfate, ROM Z rupture of membranes, IQR Z interquartile range, DR Z delivery room, PDA Z patent ductus
arteriosus, IQR Z interquartile range, MV Z mechanical ventilation, NIV Z non-invasive ventilation, IVH Z intraventricular hemor-
rhage, ROP Z retinopathy of prematurity, NEC Z necrotizing enterocolitis, PMA Z postmenstrual age.
***p < 0.001, **p < 0.01, *p < 0.05.
294 A. Sharma et al

3.4. Multivariate logistic regression to predict the

19.496
13.069
Upper
0.997
0.744

2.580
6.232
5.680
primary outcome

Secondary outcome e Moderate/Severe BPD and/or death

95% C.I. for
Exp(B)
On logistic regression, higher birthweight and female
gender were protective whereas treatment with >2 doses

Lower
0.993
0.193
2.685
1.855
0.461
1.349
1.119
of surfactant, maximal FiO2 >40% on day 1, cumulative
oxygen for 5 days in first 14 days after birth, cumulative
MV for 7 days in first 21 days after birth and >2 blood
transfusions predicted Moderate/Severe BPD (Table 2).

Exp(B)

0.995
0.379
7.235
4.924
1.091
2.900
2.521
0.068
The probability of developing Moderate/Severe BPD can
be calculated using the equation specified by the regression
coefficients estimates in Table 27,1719

0.000
0.005
0.000
0.001
0.843
0.006
0.026
0.105
eaþb1 X 1 þb2 X 2 þb3 X 3 þb4 X 4 þb5 X 5 þb6 X 6 þb7 X 7

Sig.
pZ
1 þ eaþb1 X 1 þb2 X 2 þb3 X 3 þb4 X 4 þb5 X 5 þb6 X 6 þb7 X 7
where a represents the constant, b1e7 represents the

0.001
0.344
0.506
0.498
0.439
0.390
0.414
1.658
regression coefficients for the seven predictors and X1e7 rep-

S.E.
resents the corresponding values of the predictors in a given
subject. An interactive tool for the calculation of probability
for developing Moderate/Severe BPD in 230/7e276/7 weeks GA

0.005
0.970

2.687
1.979
1.594
0.087
1.065
0.925
PTIs based on this logistic regression can be accessed https://
waynestateprod-my.sharepoint.com/:x:/g/personal/af6410_

B
wayne_edu/EXgtHbRwyYdGnbRkc51KLaoBLwx4_
B3eJUOOy8vNAzjMmw?eZmLbso3. The final model had a

10.857
20.704
Upper
0.999
0.895
9.379

8.378
8.981
sensitivity of 89%, specificity of 76.6% and C-statistic (area

95% C.I. for

under the curve, AUC) of 0.90 (95% CI: 0.86, 0.94)20

ExpP(B)
(Supplemental Fig. 3).
Primary outcome e Moderate/Severe BPD
Multivariate logistic regression to estimate risk for primary and secondary outcomes.

Lower
0.994
0.200
1.307
1.264
1.637
1.643
1.177
3.5. Multivariate logistic regression to predict the
secondary outcome
Exp(B)

On multivariate logistic regression to predict the secondary

0.997
0.423
3.502
3.704
5.821
3.710
3.252
0.001
composite outcome of Moderate/Severe BPD and/or Death,
higher birthweight and female gender were protective
whereas treatment with >2 doses of surfactant, maximal

FiO2 Z fractional inspired oxygen, MV Z mechanical ventilation; O2 Z oxygen.

FiO2 >40% on day 1, cumulative MV for 7 days in first 21
0.007
0.024
0.013
0.017
0.007
0.002
0.023
0.003
Sig.

days after birth and >2 blood transfusions predicted

Moderate/Severe BPD and/or Death (Table 2). Cumulative
oxygen for 5 days in first 14 days after birth was not
0.001
0.382
0.503
0.549
0.647
0.416
0.518
predictive of the secondary outcome. 2.363
S.E.

3.6. CART analysis for the primary outcome

0.003
0.859

7.062
1.253
1.309
1.762
1.311
1.179

Predictor variables for the CART analysis included birth-

weight, gender, maximal FiO2 on day 1, treatment with >2
B

doses of surfactant, >2 RBCTs, treated PDA, surgical NEC

and cumulative receipt of oxygen and MV. Separate ana-
Cumulative MV in first 21 days  7 days
Cumulative O2 in first 14 days 5days

lyses were run to obtain predictive models at postnatal

days 14, 21, 28 and at 36 weeks PMA/discharge (Figs. 1 and
2). For all analyses the same set of predictor variables were
Red blood cell transfusion > 2

used; however, the cumulative duration of oxygen and MV

Day 1, maximal FiO2 40%

up to that time point was used in the individual analysis.

The maximum tree depth was 5, with a minimum number of
Surfactant > 2 doses

20 and 10 observations in each parent and child node

respectively.7 Sensitivity, specificity, positive and negative
Female gender

predictive value, and Area Under the Curve (AUC) for each
Birth weight

analysis were computed.

Constant

In both the CART analysis and logistic regression, dura-

Table 2

tion of supplemental oxygen and MV were the most

important predictors for Moderate/Severe BPD. The sensi-
tivity and specificity of the CART models were comparable
Early prediction of moderate to severe BPD 295

Figure 1 CART analysis at postnatal days 14 and 21 to predict Moderate/Severe BPD. Pruned CART decision trees at postnatal
days 14 and 21. Predictive variables that are more strongly associated with the outcome are shown higher on the decision tree. For
each node in the tree, the numbers and percentages of No/Mild and Moderate/Severe BPD cases and the variable used to split the
parent node are displayed. The percentages under each terminal node represent the risk of Moderate/Severe BPD among those who
eventually reached this node.

to those of logistic regression (Supplemental Fig. 3), but
CART used fewer variables. The dichotomous cut points for
duration of supplemental oxygen and MV on CART analysis
increased with increasing age at CART analysis.
4. Discussion
This study of risk factors for Moderate/Severe BPD in
extremely PTIs since the widespread availability of NIV as the
primary mode of respiratory support showed that lower
birthweight, male gender, maximal FiO2 >40% on day 1,
cumulative oxygen for 5 days in first 14 days, cumulative
MV for 7 days in first 21 days and treatment with >2 doses
of surfactant or >2 RBCTs were associated with risk of
Moderate/Severe BPD. This information will facilitate early
prediction of BPD, allowing adoption of practices to mini-
mize risk factors identified as predictive for BPD, and inform
future clinical trials. Furthermore, 83% of extremely PTIs
received intubation in the DR; of infants not intubated in the
DR in our study, 40% with No/Mild BPD and 80% with Mod-
erate/Severe BPD received intubation by 48 hours. These
early failures represent opportunities for improvement of
NIV modes and of non-invasive surfactant delivery during NIV
to avert need for intubation in the first 48 hours.
To compare our data with other US centers in an era of
increasing use of non-invasive ventilation in the delivery
room, we used the prospective NICHD NRN Registry data for
2012 for 230/7 to 276/7 weeks GA infants surviving to 36
weeks PMA (Table 3).2 There was a higher rate of antenatal
antibiotic use and DR intubation, and lower use of drugs for
resuscitation in our cohort compared to the NRN data.
Postnatally, infants in our study were more likely to receive
MV and NIPPV as the highest level of support but less likely
to receive NCPAP as highest level of support. The incidence
of Grade 3e4 IVH was higher in our cohort; however, the
rate of Moderate/Severe BPD and other outcomes including
Stage 2e3 NEC were comparable in the two studies.
The high rates of intubation in the first 48 hours after
birth and BPD in extremely PTIs in our study and others,
despite efforts to avoid DR intubation and MV, suggest that
reducing BPD rates is more complicated than merely
reducing MV.2,21 Further improvements in NIV modes and
surfactant delivery during NIV are needed.22,23 In a recent
network meta-analysis, surfactant administration during
NIV was identified as the best strategy to decrease the
296 A. Sharma et al

Figure 2 CART analysis at 28 days of age and at 36 weeks PMA/Discharge to predict Moderate/Severe BPD. Pruned CART decision
trees at postnatal days 28 and at 36 weeks PMA/discharge. Predictive variables that are more strongly associated with the outcome
are shown higher on the decision tree. For each node in the tree, the numbers and percentages of No/Mild and Moderate/Severe
BPD cases and the variable used to split the parent node are displayed. The percentages under each terminal node represent the
risk of Moderate/Severe BPD among those who eventually reached this node.

likelihood of death or BPD.24 The 2016 NICHD workshop on
BPD recommends several potential opportunities for DR and
early life interventions to prevent BPD.22
Although Northway first described BPD in ventilated PTI
with severe RDS who were treated for 24 h or more with an
FiO2 of 0.8e1.0, over the years the definitions of BPD have
evolved with the NICHD consensus statement defining BPD
as the need for oxygen for 28 days and its severity cate-
gorized based on respiratory support at 36 weeks post-
menstrual age (PMA).1,25 The physiologic definition of BPD
further refined this definition and recently several new
definitions are under discussion that still need to be vali-
dated.13,22,26,27 Jensen et al. have proposed 18 revised
pragmatic definitions of BPD using a data-driven approach
to better predict childhood morbidity. They identified an
optimal definition of BPD that demonstrated a c-statistic of
0.785 (sensitivity 36%, specificity 96%) and 0.747 (sensitivity
69%, specificity 68%) for predicting adverse respiratory
and neurodevelopmental outcomes, respectively.14 The
components of the composite poor respiratory outcomes
described in this study varied from need for tracheostomy
to supplemental oxygen use at follow-up and do not meet
the recommended criteria for composite outcomes in clin-
ical studies.28e30 Furthermore, in the study by Jensen
et al., the c-statistic for poor respiratory outcomes for the
optimal definition (0.785) did not differ much from that for
the 2001 NICHD definition of BPD (0.741); at best both
definitions provided only an acceptable ability to discrimi-
nate between poor respiratory outcomes.31
A problem with the current and proposed definitions is
that the diagnosis of BPD is made at a single point in time,
36 weeks of PMA, thus delaying the diagnosis of BPD and
precluding the diagnosis of BPD in infants with respiratory
failure that die before 36 weeks PMA.27 However, cases of
severe BPD need to be identified as early as possible in their
clinical course to design effective interventions to modify
disease risk.13,27 It is noteworthy that in our study of risk
factors for Moderate/Severe BPD in an era of increasing use
Early prediction of moderate to severe BPD 297

cumulative treatment with oxygen for 5 days in the

Table 3 Comparison of study population with NICHD NRN
first 14 days was no longer a predictor on multivariate
reported data for infants 230/7e276/7 weeks GA in 2012.2
regression.
NICHD NRN Current study Risk factors for Moderate/Severe BPD identified in this
2012 2011e2017 study have been previously shown to be important by other
All infants N Z 1922 N Z 317 investigators during a period when NIV was not widely used
Antenatal corticosteroids 89.1 87.1 in the DR.32 Birthweight, gender and indices of respiratory
Antenatal antibiotics 73.8 58.0*** failure have been consistently reported to predict
Cesarean section 65.3 61.8 BPD.7e9,33e35 Laughon et al., reported respiratory support
Endotracheal intubation in the 73.5 84.9*** to be the most important predictor of Moderate/Severe BPD
DR from postnatal days 7e28 in a secondary analysis of the
Resuscitation drugs in the DR 5.0 0.6*** NICHD Neonatal Research Network Benchmarking Trial
Chest compressions in the DR 9.6 8.8 (2000e2004) and developed a Web-based “BPD estimator”
Surfactant 82.9 85.2 that has been used to identify infants at high-risk for BPD.9
Died 25.3 22.1 We have proposed a similar estimator based on a cohort in
Survived to discharge (d) 74.7 77.9 an era of widespread availability of NIV in the DR; however,
Infants surviving > 12 h N [ 1756 N [ 304 this needs to be validated in other settings in larger studies.
Postnatal corticosteroid 16.7 33.6 In our cohort, infants receiving >2 doses of surfactant
No HFV or CMV 9.7 5.9 and RBCTs had higher odds of Moderate/Severe BPD
Any HFV 42.2 44.4 compared to those who did not receive these therapies.
Any CMV 86.8 93.4** Although RBCTs have been recognized as a risk factor for
NIPPV as highest respiratory 2.6 4.9* BPD,36,37 association of higher doses of surfactant and BPD
support has not been reported. The association between higher
NCPAP as highest respiratory 10.8 0.3*** surfactant doses and RBCTs with BPD in our study may be an
support example of confounding by indication: sicker infants
Necrotizing enterocolitis (Stage 9.7 7.9 receiving respiratory support are more likely to develop
2e3) BPD and are also more likely to meet criteria for these
Early onset sepsis 2.1 2.6 therapies. However, even after controlling for respiratory
Infants surviving > 3 days N [ 1692 N [ 288 support, this relationship remained significant in our study,
Late onset sepsis 27.6 28.9 suggesting that other mechanisms may explain this
IVH grade 3e4 15.4 22.6** association.36,38
Periventricular leukomalacia 4.5 5.6 Similar to other studies, we did not find an association
Infants surviving to 36 weeks N [ 1540 N [ 252 between antenatal steroids and chorioamnionitis (clinical
PMA or histological) with BPD.8,9,39,40 Several variables that
Bronchopulmonary dysplasia 55.0 58.7 were significant on bivariate analyses but not on multivar-
iable regression, such as DR intubation, Apgar scores, small
***p < 0.001, **p < 0.01, *p < 0.05.
for gestational age, lower gestational age, diagnosis of PDA,
N Z sample size, numbers represent percentages.
CMV Z Conventional mechanical ventilation; DR Z Delivery PDA ligation, treatment with caffeine, respiratory in-
room; HFV Z High frequency ventilation; fections in the first 14 days, and postnatal growth failure,
IVH Z Intraventricular Hemorrhage; NCPAP Z Nasal continuous have been shown to be significantly associated with BPD by
positive airway pressure; NIPPV Z Non-invasive positive pres- other investigators.8,18,35,41e43
sure ventilation. The strengths of our study include a relatively large,
homogeneous sample of inborn extremely PTIs from a single
academic center; a rich dataset with details of hourly cu-
mulative and cross-sectional respiratory support, and pre-
of NIV in the DR, receipt of surfactant, blood transfusions, natal and postnatal medications; and performance of two
and cumulative treatment with 5 days of supplemental complementary approaches, logistic regression and CART
oxygen or 7 days of MV in the 1st 14 and 21 days of life analyses, to predict Moderate/Severe BPD. The AUC for the
predicted Moderate/Severe BPD with high sensitivity and CART and logistic regression models in this study exceed
specificity. This may facilitate early prediction of BPD prior 0.80 and for some models 0.9, which suggests excellent
to 36 weeks PMA/discharge and adoption of practices to ability to discriminate between No/Mild BPD and Moderate/
modify this risk, as well as design of future clinical trials. Severe BPD.31 Compared to logistic regression, CART anal-
Although cumulative treatment with oxygen for 5 days in ysis ranks the importance of the predictors and identifies
first 14 days was a predictor for the primary outcome of optimal cut points for these variables that may prove useful
Moderate/Severe BPD, it was not a predictor of the sec- for assessment of prognosis clinically and designing future
ondary composite outcome of Moderate/Severe BPD and/or studies.7 The graphical display of the results from a tree is
Death prior to 36 weeks PMA. This can be attributed to the easier to understand and apply in clinical settings as they
fact that infants who died before 28 days were excluded do not involve equations or calculations.16
from the analysis for the primary outcome but were Weaknesses of our study include its retrospective na-
included in the analysis for the secondary outcome. Since ture. Reliance on information in medical records, selection
the median age at death of infants included in the sec- bias, and unmeasured covariates are limitations of retro-
ondary analysis was 5.6 days, it is not surprising that spective studies; however, a cohort study design with clear
298
inclusion and exclusion criteria and detailed perinatal and
postnatal data minimized the potential for bias.23,44
Furthermore, while a relatively large, homogeneous sam-
ple of inborn extremely PTIs from a single academic center
ensured high internal validity, caution is needed when the
findings of this study are generalized to patients in other
clinical settings. External validity of the risk factors iden-
tified in this study needs to be established in other
settings.32
5. Conclusion
This study of risk factors for Moderate/Severe BPD in
extremely PTIs since the widespread availability of NIV as
the primary mode of respiratory support in the DR demon-
strates that lower birthweight, male gender, surfactant
treatment, blood transfusions and respiratory support in
the 1st 14e21 days after birth predict Moderate/Severe
BPD with high sensitivity and specificity. Furthermore, 83%
of extremely PTIs received intubation in the DR; of infants
not intubated in the DR in our study, 40% with No/Mild BPD
and 80% with Moderate/Severe BPD received intubation by
48 hours of age. These data suggest that the most impor-
tant modifiable factors to decrease the incidence of BPD
are avoidance of the need for intubation and MV. Im-
provements in NIV including non-invasive surfactant de-
livery may decrease the need for intubation within 48 hours
of birth. Logistic regression and CART analysis identified
optimal cut points of variables associated with Moderate/
Severe BPD that may facilitate early prediction of BPD prior
to 36 weeks PMA/discharge and adoption of practices to
modify this risk, as well as design of future clinical trials.23
A large multicenter study is needed to corroborate the re-
sults of our study.
Funding source
This study was supported by the Children’s Hospital of
Michigan Foundation grant (#25 SAY).
Declaration of Competing Interest
The authors have no conflicts of interest relevant to this
article to disclose.
Acknowledgments
We gratefully acknowledge the assistance of Jeffrey Irish,
Information Resources Technician, in providing assistance
with accessing medical literature.
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.pedneo.2019.12.001.