Anales de Pediatría 96 (2022) 242---251

www.analesdepediatria.org

ORIGINAL ARTICLE

Epidemiology and risk factors for bronchopulmonary

dysplasia in preterm infants born at or less than 32
weeks of gestation夽
Andrea Sucasas Alonso a , Sonia Pértega Diaz b , Rebeca Sáez Soto c ,
Alejandro Avila-Alvarez a,c,∗

a
Unidad de Neonatología, Servicio de Pediatría, Complexo Hospitalario Universitario de A Coruña (CHUAC), SERGAS, A Coruña,
Spain
b
Unidad de Apoyo a la Investigación, Complexo Hospitalario Universitario A Coruña (CHUAC), SERGAS, Universidade da Coruña
(UDC), A Coruña, Spain
c
Instituto de Investigación Biomédica A Coruña (INIBIC), SERGAS, Spain

Received 7 January 2021; accepted 2 March 2021

Available online 4 March 2022

KEYWORDS Abstract
Bronchopulmonary Objectives: To describe risk factors of bronchopulmonary dysplasia in very preterm infants in
dysplasia; the first weeks of life.
Risk factors; Material and methods: Retrospective cohort study of preterm infants ≤ 32 weeks of gestational
Prematurity; age and birth weight ≤ 1500 g. A multivariate logistic regression analysis was performed to
Mechanical identify independent risk factors for bronchopulmonary dysplasia in the first weeks of life.
ventilation Results: A total of 202 newborns were included in the study (mean gestational age 29.5 ± 2.1
weeks), 61.4% never received invasive mechanical ventilation. The incidence of bronchopul-
monary dysplasia was 28.7%, and 10.4% of the patients were diagnosed with moderate-severe
bronchopulmonary dysplasia. Bronchopulmonary dysplasia was independently associated with
gestational age (P < 0.001; OR = 0.44 (95% CI = 0.30---0.65)), the need for mechanical ventila-
tion on the first day of life (P = 0.001; OR = 8.13 ((95% CI = 2.41---27.42)), nosocomial sepsis
(P < 0.001; OR = 9.51 ((95% CI = 2.99---30.28)) and FiO2 on day 14 (P < 0.001; OR = 1.39 ((95%
CI = 1.16---1.66)). Receiving mechanical ventilation at the first day of life (P = 0.008; OR = 5.39
((95% CI = 1.54---18.89)) and at the third day of life (P = 0.001; OR = 9.99 ((95% CI = 2.47---40.44))
and nosocomial sepsis (P = 0.001; OR = 9.87 ((95% CI = 2.58---37.80)) were independent risk
factors for moderate-severe bronchopulmonary dysplasia.

夽
Please cite this article as: Sucasas Alonso A, Pértega Díaz S, Sáez Soto R, Avila-Alvarez A. Epidemiología y factores de riesgo asociados
a displasia broncopulmonar en prematuros menores de 32 semanas de edad gestacional. An Pediatría. 2022;96:242---251.
∗ Corresponding author.

E-mail address: [email protected] (A. Avila-Alvarez).

2341-2879/© 2022 Asociación Española de Pediatrı́a. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 Anales de Pediatría 96 (2022) 242---251

Conclusions: Gestational age, mechanical ventilation in the first days of life and nosocomial
sepsis are early risk factors for bronchopulmonary dysplasia. The analysis of simple and objective
clinical data, allows us to select a group of patients at high risk of bronchopulmonary dysplasia
in whom it could be justified to act more aggressively, and shows areas for improvement to
prevent its development or reduce its severity.
© 2022 Asociación Española de Pediatrı́a. Published by Elsevier España, S.L.U. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/
4.0/).

Epidemiología y factores de riesgo asociados a displasia broncopulmonar en

PALABRAS CLAVE
prematuros menores de 32 semanas de edad gestacional
Displasia
broncopulmonar; Resumen
Factores de riesgo; Objetivos: Describir los factores de riesgo de displasia broncopulmonar en las primeras semanas
Prematuridad; de vida en recién nacidos muy prematuros.
Ventilación mecánica Material y métodos: Estudio observacional de cohortes retrospectivo en recién nacidos ≤32
semanas y ≤ 1500 gramos. Se realizó un análisis multivariante de regresión logística para
identificar factores de riesgo independientes en las primeras semanas de vida.
Resultados: Se incluyeron 202 recién nacidos con una edad gestacional media de 29,5 ± 2,1
semanas. El 61,4% de los pacientes no recibió ventilación mecánica invasiva. El 28,7% fue
diagnosticado de displasia broncopulmonar, y el 10,4% de displasia broncopulmonar moderada-
grave. La edad gestacional (p < 0,001; OR = 0,44 (95%IC = 0,30---0,65)), la ventilación mecánica
en el día 1 (p = 0,001; OR = 8,13 ((95%IC = 2,41---27,42)), la sepsis nosocomial (p < 0,001; OR = 9,51
((95%IC = 2,99---30,28)) y la FiO2 en el día 14 (p < 0,001; OR = 1,39 ((95%IC = 1,16---1,66)) fueron
los factores de riesgo independientes de displasia broncopulmonar. La ventilación mecánica
el día 1 (p = 0,008; OR = 5,39 ((95%IC = 1,54---18,89)) y 3 de vida (p = 0,001; OR = 9,99
((95%IC = 2,47---40,44)) y la sepsis nosocomial (p = 0,001; OR = 9,87 ((95%IC = 2,58---37,80))
se asociaron al desarrollo de displasia broncopulmonar moderada-grave.
Conclusiones: La edad gestacional, la ventilación mecánica en los primeros días de vida y la
sepsis nosocomial son factores de riesgo precoces de displasia broncopulmonar. El análisis de
datos clínicos sencillos y objetivos nos permite seleccionar a un grupo de pacientes con alto
riesgo de desarrollar displasia broncopulmonar en el que podría estar justificado actuar de
forma más agresiva, y nos muestra áreas de mejora para prevenir su desarrollo o disminuir su
gravedad.
© 2022 Asociación Española de Pediatrı́a. Publicado por Elsevier España, S.L.U. Este es un
artı́culo Open Access bajo la licencia CC BY-NC-ND (http://creativecommons.org/licenses/by-
nc-nd/4.0/).

Introduction diagnosis of BPD.10 Higgins et al.9 proposed that strategies

aimed at preventing BPD should be implemented prenatally
Bronchopulmonary dysplasia (BPD) is a chronic pulmonary or in the first days post birth, mainly around the first week
disease that affects approximately 50% of preterm neonates of life. Such interventions have been found to contribute to
delivered before 28 weeks of gestation and 30% of those reducing neonatal mortality and some complications associ-
delivered before 32 weeks.1,2 The mortality is higher in ated with prematurity.11,12 However, they have not resulted
infants that develop BPD,3 and those that survive are at in a significant reduction in the incidence of BPD. The
increased risk of pulmonary and cardiovascular disease and, increased survival of extremely preterm infants, in whom
above all, neurodevelopmental sequelae, all of which are BPD is more prevalent, could partly explain these results,
associated with a poorer quality of life and an increased use but they also reflect our inability to prevent the develop-
of health care resources.4---6 ment of BPD.13,14
The pathophysiology of BPD is multifactorial and has yet Thus, identifying neonates at higher risk of BPD is one of
to be fully elucidated.7 At its core is preterm birth,8 on the present challenges for neonatology and has been sub-
which various prenatal and postnatal factors act to mod- ject to multiple studies15 with 2 main aims. The first, at the
ulate the baseline probability of developing the disease.9 clinical level, is to enable the identification of patients in
Although multiple therapies have been investigated to pre- whom the benefits of currently available treatments out-
vent or treat BPD, a safe and effective treatment is not yet weigh their risks.16 The second, at the level of research,
available, and evidence is mounting that there is a window is to allow the adequate selection of candidates for new
of opportunity for treatment that far predates the clinical treatments in the context of clinical trials.

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 A. Sucasas Alonso, S. Pértega Diaz, R. Sáez Soto et al.

The aim of our study was to establish the incidence, Respiratory management protocol
clinical characteristics and risk factors of cases of BPD and
moderate-to-severe BPD in a contemporary sample of very There were no relevant changes in respiratory management
preterm infants, analysing prenatal variables and neonatal during the period under study. Resuscitation in the deliv-
outcomes in the first weeks post birth. ery room adhered to the recommendations of the working
group on resuscitation of the Sociedad Española de Neona-
tología (Spanish Society of Neonatology), with initiation of
respiratory support with non-invasive ventilation (NIV) with
Material and methods continuous positive airway pressure/non-invasive positive
pressure ventilation (CPAP/NIPPV) with a T-piece resusci-
Study design and sample tator and mask.23,24 In the NICU, NIPPV was used for early
rescue before contemplating orotracheal intubation (OTI)
We conducted a retrospective observational cohort study in in the case of unfavourable progression of hyaline mem-
the level IIIC neonatal intensive care unit (NICU) of a public brane disease. Surfactant was administered in the first
hospital in Spain. We included infants born preterm at or hours post birth if oxygen requirements in NIV exceeded
before 32 weeks of gestation with birthweights of 1500 g or 30% or the patient required OTI. The method of choice
less in this hospital and admitted to the NICU between Jan- for surfactant delivery in infants that were not intubated
uary 1, 2013 and August 30, 2020. We excluded infants with was the INtubation-SURfactant-Extubation (INSURE) proce-
major congenital malformations or deceased before 28 days dure, during which NIV was maintained, avoiding the use of
post birth. After applying the inclusion and exclusion crite- intermittent positive pressure breathing through the endo-
ria, we obtained a sample of 202 patients, which was large tracheal tube, and following premedication with caffeine,
enough to estimate the incidence of BPD with a confidence fentanyl and atropine. Caffeine was administered for pro-
of 95% and a precision of +/---6.5%, and to detect statisti- phylaxis to all neonates born before 28 weeks of gestation
cally significant relative risk (RR) values of 1.65 or greater and neonates delivered before 32 weeks if they developed
associated with a risk factor expected in 50% of the popula- apnoea of prematurity. Administration of a 22-day course of
tion with a confidence of 95% and a statistical power of 80%. hydrocortisone (total dose 72.5 mg/kg) was contemplated in
The protocol of the study was approved by the competent the case of intubated infants requiring a FiO2 greater than
research ethics committee before its initiation. 30% in week 3 post birth.25 Two patients received experi-
mental intravenous mesenchymal stem cell therapy in the
framework of a clinical trial.

Variables and definitions Statistical analysis

We collected data on demographic, prenatal and obstetric We performed a descriptive analysis, summarising quantita-
characteristics, resuscitation in the delivery room and res- tive variables as mean ± standard deviation and qualitative
piratory support in the first 2 weeks post birth (days 1, 3, 7 variables as absolute frequency and percentage distribu-
and 14), and the main outcomes associated with prematu- tions. We used the applicable tests in the univariate analysis:
rity. The primary outcomes were BPD and moderate-severe Student t or Mann---Whitney U test for quantitative data
BPD. We defined BPD as the need of supplemental oxygen and 2 or Fisher exact test for qualitative data. We con-
at 28 days post birth (based on the nationwide SEN1500 sidered p-values of less than 005 statistically significant. We
database in Spain) and classified its severity based on oxygen performed a multivariate analysis by means of logistic to
requirements and need of respiratory support at 36 weeks: identify risk factors for BPD. In this analysis, we included
mild if the infant no longer required oxygen, moderate if variables relating to the period before the diagnosis of BPD
the infant required a fraction of inspired oxygen (FiO2 ) of that were statistically significant in the univariate analysis
less than 30% and severe if the infant required a FiO2 of as well as variables that were not statistically significant
30% or greater or invasive mechanical ventilation (IMV).17 but that we considered clinically relevant. We excluded
We defined necrotising enterocolitis (NEC) as meeting the variables that were highly correlated to one another. We
criteria for Bell stage 2 or higher.18 Patent ductus arteriosus generated receiver operating characteristic (ROC) curves
(PDA) was diagnosed by means of echocardiography, ordered with calculation of the area under the curve (AUC) for the
based on the judgment of the clinician, and treated per final models and applied 2 predictive models for BPD previ-
the unit protocol. We defined intraventricular haemorrhage ously described in the literature to our study sample26,27 for
(IVH) based on the grading system proposed by Volpe.19 All comparison. All the statistical analyses were made with the
infants underwent screening for retinopathy or prematu- software SPSS version 24 (IBM Corp, Armonk, NY, USA).
rity (ROP), which was graded based on Spanish guidelines.20
We defined intrauterine growth restriction (IUGR) as a birth Results
weight z-score of less than ---1.5 based on the Fenton growth
charts.21 The diagnosis of nosocomial sepsis was based on In the period under study, a total of 241 neonates born
a positive result of blood culture. Metabolic bone disease preterm at or before 32 weeks of gestation with a birth-
of prematurity was diagnosed based on the serum levels weight of 1500 g or less. We excluded those with major
of inorganic phosphate and alkaline phosphatase on week congenital malformations (n = 16) and those deceased
3 post birth.22 before 28 days post birth, in who it was not possible

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 Anales de Pediatría 96 (2022) 242---251

the need of IMV in the first day post birth (OR, 8.13; 95%
CI = 2.41---27.42; P = 0.001), nosocomial sepsis (OR, 9.51;
95% CI = 2.99---30.28; P < 0.001) and the FiO2 on day 14 post
birth (OR, 1.39; 95% CI = 1.16---1.66; P < 0.001) (Fig. 3). The
AUC for the BPD model was 0.967 (95% CI, 0.944---0.990).
Table 3 summarises the results of the univariate analysis
for moderate-to-severe BPD. The most relevant independent
risk factors for moderate-severe BDP identified in the logis-
tic regression analysis were the need of IMV on days 1 (OR,
5.39; 95% CI = 1.54---18.89; P = 0.008) and 3 of life (OR, 9.99;
95% CI = 2.47---40.44; P = 0.001) and diagnosis of nosocomial
sepsis (OR, 9.87; 95% CI = 2.58---37.80; P = 0.001) (Fig. 3).
The AUC for the moderate-severe BPD model was 0.891 (95%
CI, 0.812---0.971).
The AUCs for the ROC curves of the previously published
models selected for comparison were smaller compared to
the AUCs obtained in our models. In the case of Gursoy
et al.,27 the model for prediction of BPD had an AUC of 0.869
(95% CI, 0.815−0.922) and the model for moderate-severe
BPD an AUC of 0.803 (95% CI, 0.711−0.895). In the case of
Hunt et al.,26 the model for prediction of BPD had an AUC of
0.600 (95% CI, 0.508−0.692) and the model for moderate-
severe BPD an AUC of 0.624 (95% CI, 0.480−0.767).

Discussion

A better understanding of the risk factors for BPD is a key

step toward the prevention and adequate management of
this disease. Our study, conducted in a consecutive sample
of infants delivered at or before 32 weeks of gestation with
birthweights of 1500 g or less, most of who were managed
with non-invasive support, and with an incidence of BPD sim-
ilar to the incidence described in the previous literature,
corroborated that lesser GA, the need of IMV in the first
days post birth and nosocomial infection are the main early
risk factors for BPD. The predictive ability of our models
Figure 1 Flowchart of the study sample. BPD, bronchopul- improved compared to past models.26,27
monary dysplasia; NICU, neonatal intensive care unit. In our patients, the incidence of moderate-severe BPD
was 10.4%, lower compared to the national mean (15.8%)
based on data from the SEN1500 study published by the iNeo
to diagnose BPD (n = 23, of who 8 died from respira- network,11 which reported a significantly higher global inci-
tory causes). The final sample included 202 very preterm dence for participating countries (25.5%). These improved
infants (106 female, 52.5%) (Fig. 1). The mean gesta- outcomes were also reflected in the survival free of
tional age was 29.5 ± 2.1 weeks and the mean birthweight moderate-severe BPD in infants delivered at or before 28
1142.1 ± 255.5 g. Table 1 presents the main perinatal char- weeks, which was of 79.2% in our sample, greater than the
acteristics of the sample and the most relevant neonatal national mean (61.4%), but similar to survival in hospitals
diagnosis and outcomes. in our region that have reported more favourable outcomes
A total of 58 patients (28.7%) received a diagnosis of (72.5%).28 A factor that may play a role in these results is
BPD, of who 21 (10.4% of the total) were classified as the lower frequency of extremely preterm infants in our case
cases of moderate-severe BPD; Fig. 2 presents the distri- series.
bution of cases by weeks of gestational age. Forty neonates It is widely accepted that gestational age is the best iso-
(19.8%) required intubation in the delivery room, and 101 lated predictor of BPD,7 although in most instances this is
(50%) required surfactant during the stay. Seventy-eight not a modifiable factor. At birth, the respiratory progno-
(38.6%) received IMV during the stay, and the rest of the sis is often influenced by the cause of preterm birth and
patients (n = 124) only required non-invasive respiratory by the resulting interruption of foetal lung maturation.7,9
support. None of the patients died after 28 days post Thus, gestational birth is a very important factor in the most
birth. premature infants, who are born at a very early stage of
Table 2 summarises the results of the univariate analysis lung maturation.7 It is highly probable that these infants
for BPD. The most relevant independent risk factors for BDP will develop BPD independently of how they are managed
identified in the logistic regression analysis were gestational after birth.9 Notwithstanding, there are multiple postna-
age (odds ratio [OR], 0.44; 95% CI = 0.30−0.65; P < 0.001), tal factors that can play a role in the severity of BPD and

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 A. Sucasas Alonso, S. Pértega Diaz, R. Sáez Soto et al.

Table 1 Descriptive analysis of study sample.

Perinatal characteristics, mean ± SD Total sample n = 202 GA ≤ 28 wk, n = 77 GA 29−32 wk, n = 125
Gestational age (weeks) 29.50 ± 2.1 27.3 ± 1.2 30.8 ± 1.1
Birthweight (g) 1142.08 ± 255.5 956.52 ± 218.5 1250.84 ± 212.8
Weight z-score −0.46 ± 0.8 −0.01 ± 0.8 −0.74 ± 0.6
Maternal age (years) 34.19 ± 6.3 33.8 ± 6.6 34.4 ± 6.2
n (%)
Maternal HTN 46 (22.8%) 13 (16.9%) 33 (26.4%)
Chorioamnionitis 32 (15.8%) 21 (27.3%) 11 (8.8%)
Antenatal steroidsa 198 (98%) 77 (100%) 121 (96.8%)
Multiple birth 77 (38.1%) 22 (28.6%) 55 (44%)
Vaginal delivery 46 (22.8%) 20 (26%) 26 (20.8%)
IVF 51 (25.2%) 15 (19.5%) 36 (28.8%)
Sex (female) 106 (52.5%) 44 (57.1%) 62 (49.6%)
IUGR 18 (8.9%) 3 (3.9%) 15 (12%)
Neonatal outcomes
mean ± SD
Length of stay, NICU 26.39 ± 18.9 41.29 ± 19.1 17.2 ± 11.5
Length of stay, total 61.14 ± 55.6 85.8 ± 82.5 45.83 ± 14.2
n (%)
BPD 58 (28.7%) 50 (64.9%) 8 (6.4%)
moderate-severe BPD 21 (10.4%) 17 (22.1%) 4 (3.2%)
Oxygen at discharge 8 (4%) 6 (7.8%) 2 (1.6%)
PDA 41 (20.3%) 31 (40.3%) 10 (8%)
Pharmacological closure of PDA 29 (14.4%) 24 (31.2%) 5 (4%)
Surgical closure of PDA 12 (5.9%) 9 (11.7%) 3 (2.4%)
NEC 11 (5.4%) 7 (9.1%) 4 (3.2%)
ROP grade > II 22 (10.9%) 20 (26.3%) 14 (11.2%)
Nosocomial sepsis 73 (36.1%) 41 (53.2%) 32 (25.6%)
IVH grade > II 12 (5.9%) 11 (14.3%) 1 (0.8%)
PVL 13 (6.4%) 10 (13%) 3 (2.4%)
MBD 42 (20.8%) 21 (27.3%) 21 (16.8%)
AUC, area under the curve; BPD, bronchopulmonary dysplasia; GA, gestational age; HTN, hypertension; IQR, interquartile range; IUGR,
intrauterine growth restriction; IVF, in vitro fertilization; IVH, intraventricular haemorrhage; MBD, metabolic bone disease; NEC, necrotis-
ing enterocolitis; NICU, neonatal intensive care unit; PDA, patent ductus arteriosus; PVL, periventricular leukomalacia; ROP, retinopathy
of prematurity; SD, standard deviation; wk, week.
a Antenatal steroids: counts patients that received a full course for lung maturation.

therefore influence its outcomes, especially in less preterm ventilation.31 Today’s preterm infants do not have the same
infants. The activation of the inflammatory cascade and characteristics and are managed differently compared to
oxidative stress are 2 of the key pathophysiological path- the population in which BPD was first defined. Strate-
ways leading to the development of BPD. In association gies used to improve lung development outcomes (used
with this physiological basis, factors such as positive airway of synchronised ventilation modalities, standardization of
pressure, supplemental oxygen and postnatal sepsis have lung volumes, increased use of NIV, early administration
also been found to be related to BPD,7 as occurred in our of surfactant and antenatal steroids) have resulted in the
study. different population of patients we manage today.29 Every
Several studies have described patterns of disease that infant in our study was managed with these methods, as we
can usually be identified in the first weeks of life.29,30 First, obtained a consecutive sample of infants managed in the
there are infants with mild pulmonary disease at birth past decade. Thus, fewer than 4 in 10 patients received IMV
that recover gradually. Then, there are infants that expe- during the hospital stay, and fewer than 2 in 10 required
rience early persistent pulmonary deterioration and usually endotracheal intubation at birth. Notwithstanding, there is
require prolonged respiratory support starting from birth. still a group of patients in whom the need of intubation and
Lastly, there are infants who recover from initial lung dis- of IMV cannot be avoided.
ease but later experience respiratory decompensation.7 This When we analysed the relationship between IMV and BPD
goes beyond what Northway described in 1967 in patients in the sample, we found that the need of IMV in the first
with BPD, then defined as the pulmonary disease devel- days post birth was independently associated with the devel-
oped by preterm infants subjected to prolonged mechanical opment of BPD, as previously described.32,33 Sixty percent

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 Anales de Pediatría 96 (2022) 242---251

Figure 2 Bar graph of the distribution of patients by weeks of gestational age at birth and number of patients with BPD and
moderate-severe BPD in each age group. BPD, bronchopulmonary dysplasia.

of the patients that required intubation during stabilization and of its own. Improving the rate of nosocomial infection
in the delivery room developed BPD, and the percentage through stricter protocols and limited use of invasive proce-
increased to 70% in those who required IMV in the first dures is another of the preventive strategies that should be
day of life. In contrast, only 14% of patients that were not prioritised.
intubated in the first day of life developed BPD. Similarly, There are limitations to our study, including its retro-
nearly 9 out of 10 patients that needed IMV on day 3 post spective design, performance in a single centre and small
birth developed BPD and more than 50% moderate-severe sample size, in addition to the inclusion of preterm infants
BPD. born between 28 and 32 weeks of gestation, in who the
Our findings evinced another opportunity for improve- baseline risk of BPD is low. The definition of BPD as oxygen
ment in the use of NIV for initial respiratory support. In dependence at 28 days post birth also carries intrinsic limita-
our sample of very and extremely preterm infants, 8 in tions, such as the discrepancy with the criterion established
10 received non-invasive respiratory support in the deliv- in the 2001 consensus (dependency for 28 days). This could
ery room. In the group of patients that developed BPD, 60% hinder comparisons with the results of other studies. The
had received CPAP/NIPPV at birth. However, this proportion values of the AUCs in the ROC curves of our models should be
decreased to 40% in the first 24 h post birth. Thus, there interpreted with caution, as we did not select variables for
was a sizeable group of patients in who NIV failed in the application at specific time points and we did not correct for
first hours post birth and who eventually developed BPD. the overestimation that may result from testing the model
This was consistent with the findings in other case series in the same patients from who it was derived. Our conclu-
in which CPAP failure was associated with an increase in sions should be analysed with prudence and are only directly
morbidity, including BPD.34 Thorough investigation of these applicable to the population under study. On the other hand,
cases to establish NIV protocols and improve the respiratory the study was conducted in a homogeneous consecutive sam-
management of these patients is an essential step that could ple spanning 7 years during which the same protocols were
help avoid IMV in a particularly important stage of disease applied and there were no significant changes in clinical
development.33,35,36 management, which was akin to clinical practice in other
Multiple previous studies have demonstrated the asso- facilities in our region.
ciation between postnatal sepsis and the development of In conclusion, the analysis of simple and objective data
pulmonary inflammation.37---39 Some have found evidence available in the first days post birth, such as GA at birth
suggestive of a causal relationship between postnatal infec- and the need of IMV in days 1 and 3 of life, can help iden-
tion, PDA and increased duration of IMV.37,39 All these factors tify a subset of patients at high risk of BPD in whom more
are probably interrelated. However, in our study nosoco- aggressive management may be warranted. Our findings
mial sepsis remained an independent risk factor in the final may provide the foundation to develop early-stage predic-
logistic regression model. In fact, its presence was associ- tive models or to compare the predictive power of new
ated with a more than 9-fold increase in the risk of BPD tools using clinical data that can be obtained at the bed-
as well as with the severity of BPD. Thus, in our popula- side.
tion, nosocomial sepsis should be considered a risk factor in

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 A. Sucasas Alonso, S. Pértega Diaz, R. Sáez Soto et al.

Table 2 Risk factors for bronchopulmonary dysplasia.

BPD (n = 58) No BPD (n = 144) p AUC 95% CI
Perinatal characteristics
mean ± SD
Gestational agea 27.5 ± 1.7 30.3 ± 1.6 <0.001 0.888 0.77−1
Weight (g)b 938.7 ± 216.8 1224 ± 222.5 <0.001 0.790 0.62−0.96
Weight z-scoreb −0.2 ± 0.9 −0.6 ± 0.8 0.005 0.628 0.54−0.72
Maternal age (years) 34.2 ± 6.9 34.2 ± 6.1 0.980 0.500 0.41−0.59
n (%) RR 95% CI
Maternal hypertension 12 (20.7%) 34 (23.6%) 0.654 0.885 0.51−1.52
Chorioamnionitis 10 (17.2%) 22 (15.3%) 0.729 1107 0.63−1.95
Antenatal steroidsc 57 (98.3%) 141 (97.9%) 0.868 1515 0.21−6.37
Multiple birth 19 (32.8%) 58 (40.3%) 0.319 0.791 0.49−1.36
IVF 12 (20.7%) 39 (27.1%) 0.344 0.772 0.44−1.34
Vaginal delivery 17 (29.3%) 29 (20.1%) 0.160 1406 0.89−2.23
Female sex 27 (46.6%) 79 (54.8%) 0.285 0.789 0.51−1.22
IUGR 3 (5.2%) 15 (10.4%) 0.237 0.557 0.19−1.60
Resuscitation in delivery room
n (%) RR 95% CI
Oxygenb 55 (94.8%) 114 (79.2%) 0.006 3580 1.29−10.76
OTIb 24 (41.4%) 16 (11.1%) <0.001 2859 1.93−4.23
Cardiac massage 4 (6.9%) 6 (4.2%) 0.418 1422 0.64−3.14
Adrenaline 3 (5.2%) 4 (2.8%) 0.400 1519 0.63−3.68
Neonatal outcomes
mean ± SD AUC 95% CI
FiO2 day 1b 28.9 ± 13.1 23.9 ± 5.5 0.007 0.661 0.58−0.74
FiO2 day 3b 26 ± 7.5 22.3 ± 3.1 0.001 0.699 0.61−0.78
FiO2 day 7b 25.4 ± 6.2 21.7 ± 2.4 <0.001 0.709 0.62−0.80
FiO2 day 14a 27.8 ± 7.2 21.4 ± 1.9 <0.001 0.835 0.76−0.91
n (%) RR 95% CI
Surfactantb 50 (86.2%) 51 (35.4%) <0.001 6250 3.12−12.50
nCPAP 58 (100%) 137 (95.1%) 0.087 --- ---
NIPPVb 57 (98.3%) 53 (36.8%) <0.001 47,673 6.73−337.63
CMVb 50 (86.2%) 28 (19.4%) <0.001 9936 1.98−19.82
HFOVb 5 (8.6%) 3 (2.1%) 0.031 2288 1.28−4.10
IMV day 1 post birtha 36 (62.1%) 15 (10.4%) <0.001 4845 3.17−7.41
IMV day 3 post birthb 18 (31%) 3 (2.1%) <0.001 3878 2.80−5.36
IMV day 7 post birthb 12 (20.7%) 1 (0.7%) <0.001 3792 2.82−5.10
IMV day 14 post birthb 17 (29.3%) 1 (0.7%) <0.001 4238 3.16−5.68
PDAb 26 (44.8%) 15 (10.4%) <0.001 3190 2.16−4.70
Pharmacological closure of PDAb 20 (34.5%) 9 (6.3%) <0.001 3140 2.16−4.55
Surgical closure of PDAb 9 (15.5%) 3 (2.1%) <0.001 2908 1.94−4.36
Sepsis nosocomiala 41 (70.7%) 32 (22.2%) <0.001 4262 2.62−6.94
AUC, area under the curve; CI, confidence interval; CMV, conventional mechanical ventilation; HFOV, high-frequency oscillatory venti-
lation; HTN, hypertension; IMV, invasive mechanical ventilation; IUGR, intrauterine growth restriction; IVF, in vitro fertilization; nCPAP,
nasal continuous positive airway pressure; NIPPV, non-invasive positive pressure ventilation; OTI, orotracheal intubation; PDA, patent
ductus arteriosus; RR, relative risk; SD, standard deviation.
a Variables included as risk factors in the final logistic regression model of BPD.
b Statistically significant association with BPD.
c Antenatal steroids: counts patients that received a full course for lung maturation.

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Table 3 Risk factors for moderate-to-severe bronchopulmonary dysplasia.

Moderate-severe No p AUC 95% CI
BPD (n = 21) moderate-severe
BPD (n = 181)
Perinatal characteristics
mean ± SD
Gestational ageb 27.78 ± 2 29.7 ± 2 <0.001 0.447 0.12−0.79
Weight (g)b 923.1 ± 268.3 1167.5 ± 242.2 <0.001 0.404 0.10−0.70
Weight z-score −0.5 ± 0.8 −0.4 ± 0.8 0.604 0.649 0.30−0.99
Maternal age (years) 33 ± 6.3 34.3 ± 6.3 0.365 0.429 0.30−0.56
n (%) RR 95% CI
Maternal HTN 6 (28.6%) 40 (22.1%) 0.503 1356 0.56−3.30
Chorioamnionitis 2 (9.5%) 30 (16.6%) 0.402 0.559 0.14−2.28
Antenatal steroidsa 20 (95.2%) 178 (98.3%) 0.334 0.404 0.07−2.32
Multiple birth 9 (42.9%) 68 (37.6%) 0.637 1217 0.54−2.75
IVF 4 (19%) 47 (26%) 0.490 0.696 0.25−1.97
Vaginal delivery 6 (28.6%) 40 (22.1%) 0.552 1356 0.56−3.30
Sex (female) 8 (38.1%) 98 (54.1%) 0.163 0.557 0.24−1.29
IUGR 1 (4.8%) 17 (9.4%) 0.481 0.511 0.07−3.60
Resuscitation in delivery room
n (%) RR 95% CI
Oxygenb 21 (100%) 148 (81.8%) 0.032 --- ---
OTIc 8 (38.1%) 32 (17.7%) 0.026 2492 1.11−5.60
Cardiac massage 1 (4.8%) 9 (5%) 0.966 0.960 0.14−6.45
Adrenaline 0 7 (3.9%) 0.359 --- ---
Neonatal outcomes
mean ± SD AUC 95% CI
FiO2 day 1b 32.9 ± 17.2 24.5 ± 6.6 0.007 0.733 0.61−0.85
FiO2 day 3b 27.7 ± 8.2 22.9 ± 4.3 0.037 0.716 0.59−0.85
FiO2 day 7b 26.6 ± 6.6 22.3 ± 3.7 0.015 0.709 0.57−0.84
FiO2 day 14b 29.7 ± 8.1 22.5 ± 4 0.009 0.826 0.72−0.93
n (%) RR 95% CI
Surfactantb 20 (95.2%) 81 (44.8%) <0.001 20,000 2.74−146.21
nCPAP 21 (100%) 174 (96.1%) 0.359 --- ---
NIPPVb 21 (100%) 89 (49.2%) 0.010 --- ---
CMVb 20 (95.2%) 58 (32%) <0.001 31,795 4.35−232.20
HFOVb 3 (14.3%) 5 (2.8%) 0.010 4042 1.49−10.95
IMV day 1 post birthc 16 (76.2%) 36 (19.9%) <0.001 9474 3.65−24.56
IMV day 3 post birthc 11 (52.4%) 10 (5.5%) <0.001 9481 4.58−19.62
IMV day 7 post birthb 6 (28.6%) 7 (3.9%) <0.001 5815 2.71−12.46
IMV day 14 post birthb 8 (38.1%) 10 (5.5%) <0.001 6290 3.01−13.13
PDAb 10 (47.6%) 31 (17.1%) 0.001 3570 1.63−7.82
Pharmacological closure of PDAb 7 (33.3%) 22 (12.2%) 0.009 2983 1.32−6.76
Surgical closure of PDAb 5 (23.8%) 7 (3.9%) <0.001 4948 2.18−11.20
Nosocomial sepsisc 17 (81%) 56 (30.9%) <0.001 7510 2.63−21.48
AUC, area under the curve; CI, confidence interval; CMV, conventional mechanical ventilation; HFOV, high-frequency oscillatory venti-
lation; HTN, hypertension; IMV, invasive mechanical ventilation; IUGR, intrauterine growth restriction; IVF, in vitro fertilization; nCPAP,
nasal continuous positive airway pressure; NIPPV, non-invasive positive pressure ventilation; OTI, orotracheal intubation; PDA, patent
ductus arteriosus; RR, relative risk; SD, standard deviation.
a Antenatal steroids: counts patients that received a full course for lung maturation.
b Statistically significant association with BPD.
c Variables included as risk factors in the final logistic regression model of BPD.

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