Received: 20 April 2019 | Accepted: 27 June 2019

DOI: 10.1002/ppul.24452

ORIGINAL ARTICLE: NEONATAL LUNG DISEASE

Long‐term effects of the intratracheal administration of

corticosteroids for the prevention of bronchopulmonary
dysplasia: A meta‐analysis

Yirong Zheng MD | Wenlong Xiu | Yunfeng Lin MD | Yanli Ren MD |

Baoquan Zhang MD | Changyi Yang MD

Department of Neonatology, Fujian Provincial

Maternity and Children’s Hospital, Affiliated
Hospital of Fujian Medical University, Fuzhou,
Fujian, China
Correspondence
Changyi Yang, Department of Neonatology,
Fujian Provincial Maternity and Children’s
Hospital, Affiliated Hospital of Fujian Medical
University, No. 18 Daoshan Rd, Gulou District,
Fuzhou, 350001 Fujian, China.
Email: cyyang996@qq.com
Abstract
Background: Bronchopulmonary dysplasia (BPD) is one of the most common
complications in premature infants. Since inflammation plays a crucial role in the
pathogenesis of BPD, anti‐inflammatory drugs, such as corticosteroids, have long
been the focus of prevention research. In this meta‐analysis, we aim to explore the
long‐term effects of the intratracheal administration of corticosteroids (IAC) in
preventing BPD.
Methods: EMBASE, MEDLINE, the Cochrane Library, Web of Science, CINAHL,
Clinicaltrials.gov, the ISRCTN registry, and gray literature were searched to identify
randomized controlled trials (RCTs) that evaluated the long‐term effects of IAC for
the prevention of BPD in premature infants.
Results: Five RCTs (n = 1515) were eligible for further analysis. The meta‐analysis
revealed that the incidence of neurodevelopmental impairment (NDI) did not
significantly differ between the IAC group and the control group (relative risk [RR]
0.9, 95% confidence interval [CI] 0.79 to 1.03, P = .14). There was no significant
reduction in long‐term mortality (RR, 1.13; 95% CI, 0.9 to 1.41; P = .3) or the incidence
of rehospitalization (RR, 0.99; 95% CI, 0.89 to 1.09, P = .82). No significant differences
were observed between the IAC group and the control group with regard to height,
weight and head circumference at the age of 18 to 36 months of postmenstrual age
(PMA) (mean difference [MD], 0.14; 95% CI, −0.26 to 0.54, P = .48).
Conclusions: Our study suggests that IAC in preterm infants does not have significant
long‐term benefits or adverse outcomes. However, before routine use, well‐designed
studies and studies involving large sample sizes are needed to confirm the
pharmacokinetics and long‐term effects of IAC.

KEYWORDS
bronchopulmonary dysplasia, corticosteroids, intratracheal, meta‐analysis, neurodevelopmental
outcomes, prematurity

Pediatric Pulmonology. 2019;1-13. wileyonlinelibrary.com/journal/ppul © 2019 Wiley Periodicals, Inc. | 1

2 |
1 | INTRODUCTION
Due to advances in neonatal care, the population of premature
infants has increased globally. Nevertheless, the incidence of
bronchopulmonary dysplasia (BPD) has not decreased; BPD remains
one of the most frequent respiratory morbidities and the main cause
of mortality in premature infants.1,2 The incidence of BPD ranges
from 30% to 50% depending on the birth weight (BW) and
3,4
gestational age (GA). The commonly accepted definition of BPD
is based on oxygen dependence at 28 days of life and/or 36 weeks of
postmenstrual age (PMA).5 Multiple factors, such as immature lungs,
mechanical ventilation, oxidative stress, and inflammation, contribute
to the occurrence of BPD.6 Among these factors, inflammation is
considered to play a crucial role in the pathogenesis of BPD. Due to
their strong potential anti‐inflammatory effects, anti‐inflammatory
agents, such as corticosteroids, have always been the focus of
prevention research.7 Although the systemic application of corticos-
teroids may reduce BPD, this approach is associated with adverse
short‐ and long‐term effects, including increases in gastrointestinal
perforations, the neonatal mortality rate, rehospitalization, and
neurodevelopmental impairment (NDI).8-11 Therefore, the current
evidence indicates that the systemic administration of corticoster-
oids should not be recommended for routine use.12,13 As the
intratracheal administration (inhalation or instillation) of corticoster-
oids (IAC) has strong topical effects and a rapid action onset with low
doses and a lower risk of undesirable adverse effects than systemic
14,15
corticosteroids, IAC may be considered an alternative to
systemic corticosteroids for the prevention of BPD in preterm
infants.
Currently, IAC is widely used in neonatal centers. According to a
survey of 35 neonatal intensive care units (NICUs) in America, 25%
of preterm infants with a GA less than 29 weeks and BW less than
1500 g were given an application of inhaled corticosteroids.16
Another study conducted in Germany showed that up to 46% of
preterm infants received corticosteroids through inhalation.17 Pre-
vious studies have focused on the short‐term benefits and adverse
effects of IAC, such as decreases in the incidence of death or BPD at
36 weeks of PMA and the short‐term adverse outcomes of inhaled
corticosteroids.18,19 However, our understanding of the long‐term
effects of IAC against BPD, especially regarding the reduction in
long‐term mortality and the neurodevelopmental outcome of these
infants, is limited. This study aims to explore the long‐term effects of
IAC in the prevention and treatment of premature infants with BPD
through a meta‐analysis.
2 | METHODS
2.1 | Study selection
2.1.1 | Inclusion criteria
All published randomized controlled trials (RCTs) in which
corticosteroids were administered intratracheally to prevent
ZHENG ET AL.
BPD and long‐term (at least 18 months) follow‐up data were
reported were eligible for inclusion in this study. The long‐term
outcomes included the following: NDI, which was defined as any
of the following assessed at 18 to 36 months of PMA: cerebral
palsy (CP), a low psychomotor developmental index (PDI) score
and/or a low mental developmental index (MDI) score on the
Bayley Scales of Infant Development 2nd edition (BSID‐
II),20 blindness, or deafness. In addition, the rehospitalization
rate, mortality, and growth outcomes at 18 to 36 months of PMA
were included. The IAC group was compared with a group
receiving either a placebo or surfactant.
2.1.2 | Exclusion criteria
Studies were excluded if (a) the same data were presented in multiple
publications or (b) the article met any of the following criteria: non‐
IAC (such as intravenous administration); prenatal corticosteroid
therapy; no description of the long‐term outcomes on the nervous
system; non‐RCTs; and animal experiments.
2.2 | Search strategy
We searched EMBASE (1977 to August 2018), MEDLINE (PubMed;
1968 to August 2018), the Cochrane Library (1993 to June 2013),
Web of Science, and the Cumulative Index to Nursing and Allied
Health Literature (CINAHL; 1982 to April 2017). The reference lists
of the included studies were also searched to identify relevant
trials. To identify ongoing trials, we searched ClinicalTrials.gov and
the ISRCTN registry. In addition, we performed a search of gray
literature through the OpenGrey website. We applied the following
search terms: infant newborn, premature infant, preterm infant,
neonate, chronic lung disease, bronchopulmonary dysplasia, ster-
oids, glucocorticoids, corticosteroids, anti‐inflammatory agents,
budesonide, flunisolide, fluticasone propionate, beclomethasone
dipropionate, administration, inhalation, intratracheal, instillation,
long‐term, follow‐up, neurodevelopmental outcome, and rando-
mized controlled trial. No language restrictions were applied. The
protocol of this meta‐analysis was registered in PROSPERO
(CRD42019126389).
2.3 | Data extraction
The data extraction was carried out by two reviewers (Lin and Zhang)
using a predesigned form. We resolved any disagreements through
discussion or consensus with a third reviewer. We extracted the
following data: first author’s name, study design, publication year,
interventions, sample size, number of cases at the overall follow‐up,
follow‐up time, and outcome measures (CP, PDI and MDI scores,
blindness, deafness, rehospitalization, mortality, and growth out-
comes at 18 to 36 months of PMA).
ZHENG ET AL. | 3

2.4 | Assessment of the risk of bias evaluated 782 studies by reading titles and abstracts. In all, 753
were excluded as they did not meet the inclusion criteria. Full‐text
We used the Cochrane Risk of Bias Tool21 to assess the risk of bias of
were screened for 29 literatures, 20 of which were excluded for the
each study. The studies were determined to have a low risk of bias,
following reasons: non‐RCTs in 2, no report of the long‐term
unclear risk of bias, or high risk of bias based on the sequence
outcomes in 15, letters, or reviews in 3. Nine potentially relevant
generation, allocation concealment, the blinding of the participants
articles were identified. However, only five RCTs24-28 were included
and personnel, the blinding of the outcome assessment, reporting
in the meta‐analysis, and the remaining four were excluded due to a
bias, and other possible sources of bias.
lack of long‐term follow‐up data29-31 and comparing systemic
dexamethasone with inhaled budesonide.32 Figure 1 shows a flow
2.5 | Data analysis
diagram of the studies identified in this meta‐analysis.
We performed all statistical analyses using Review Manager 5.3.22 We
applied the relative risk (RR) to the analysis of the dichotomous outcomes
and weighted mean difference (WMD)/mean difference (MD) to the 3.2 | Characteristics of the included studies
analysis of the continuous outcomes with a 95% confidence interval (CI).
Five studies involving 1515 infants, including 765 infants in the
Heterogeneity was measured by using the P value and I2 statistic. If there
corticosteroids group and 750 infants in the control group, were
was no evidence of significant heterogeneity in the analysis (P > .10 or
included (Tables 1 and 2). The RCTs were published between
I2 < 50%), we adopted a fixed effects model; if significant heterogeneity
2002 and 2018 four studies25-28 were multicenter trials. The
was found (P < .10 or I2 ≥ 50%), we adopted a random effects model.
baseline characteristics were comparable between the IAC group
Subgroup analyses were performed based on the type of comparator
and the control group. The GA and BW of the enrolled preterm
(surfactant or placebo) to determine the different long‐term outcomes.
infants ranged from 26 to 34 weeks and 801 to 1591 g,
We applied sensitivity analysis to determine the influence of each
respectively. Type of drugs used for intervention included
individual study on the pooled effects. We reported the results according
budesonide, 25,27,28 budesonide‐surfactant combination, 25,27
to the Preferred Reporting Items for Systematic Reviews and Meta‐
fluticasone propionate,26 and beclomethasone dipropio-
analysis (PRISMA) statement.23 24
nate. Two studies 25,27 used surfactants as the control, and
three studies24,26,28 used placebo as the comparator. Among the
3 | RES U LTS
included studies, three 24,26,28 studies administered corticoster-
oids via inhalation, and two trials25,27 administered corticoster-
3.1 | Study selection
oids via instillation. What’s more, the duration of therapy,
In total, 960 citations were identified through the electronic search dosages, and administration schedules varied considerably
and other sources. After removing 178 duplicate studies, we between studies (Table 1). Infants were recruited between 4

F I G U R E 1 Flow diagram of study

selection process
4 | ZHENG ET AL.

and 96 hours after birth. Four studies25-28 administered corti-

Mode of delivery
costeroids to prevent BPD during the first 24 hours of life. Timing

Intratracheal

Intratracheal
instillation

instillation
of BPD assessment differed between studies. Three stu-
dies 25,27,28 reported BPD at 36 weeks of PMA, and two
MDI

MDI

MDI
studies24,26 reported this outcome at 28 days of life and/or 36

Abbreviations: BUD, budesonide; BDP, beclomethasone dipropionate; FPP, fluticasone propionate; MDI, metered‐dose inhaler; PMA, postmenstrual age; RCT, randomized controlled trial.
weeks of postmenstrual age (PMA). Regarding the long‐term
follow‐up data, five articles24-28 provided data regarding NDI,
400 μg Q12H for 14 d, 200 μg Q12H for 15 d, until extubation and no oxygen

MDI, and mortality, three articles24,25,28 provided data regarding

0.25 mg/kg Q8H, until the infant required ≤ 0.4 of FIO2 or until extubation

0.25 mg/kg Q8H, until the infant required ≤ 0.4 of FIO2 or until extubation
CP, deafness, visual follow‐up, and rehospitalization, and two
articles25,27 provided PDI and growth data. The definition of NDI
varied between the studies. The follow‐up rate ranged from
57.8% to 88.6%, and the follow‐up duration ranged from 18 to 36
months. One article conducted by Nakamura et al 26 reported the
long‐term outcomes in two follow‐up periods (18 and 36 months).
Growth was measured by development in height, weight, and
head circumference at 18 to 36 months of PMA (Table 2). The
50 ug Q12H,until 6 wk of age or extubation

scale of the neurodevelopmental outcomes included the BSID‐II

and Kyoto Scale of Psychological Development (KSPD)33
(Table 3). We summarized the characteristics of the included
0.2 mg/kg/d, until 28 d of age

studies in Tables 1-3.

dependent or 32 wk PMA

3.3 | Sensitivity analysis and bias assessment

We conducted a sensitivity analysis by sequentially excluding each
Intervention

study to assess the stability of the results. The results of the

sensitivity analysis show that all studies had good homogeneity. The
risk of bias of the individual studies indicated that one trial was at a
low risk of bias, while the risk of bias in the other studies was unclear.
BUD + surfactant

BUD + surfactant

Figures 2 and 3 summarize the risks of bias of the studies. There was
no significant publication bias as assessed by the funnel plot
(Figure 4).
Drug
BUD

BDP
FPP

3.4 | Outcomes
Birth weight, g

3.4.1 | Long‐term neurodevelopmental outcomes

a

909 ± 268a

784 ± 131a
a

900 ± 192a
801 + 191

901 ± 190

Five included trials involving 1113 neonates (73.5%) reported the

long‐term neurodevelopmental outcomes (Table 2). There was no
significant heterogeneity among the included studies (Figure 5,
Gestational age, wk

P = .92; I2 = 0%). The results of the fixed effects model of the

meta‐analysis showed that the incidence of NDI did not
T A B L E 1 Characteristics of included studies

26 (25,27)b
a

26.7 + 2.2a

27.6 + 2.0a

significantly differ between the corticosteroid group and the

26.1 + 1.3

26.8 + 2.3

control group (5 studies, 24-28 RR, 0.9; 95% CI, 0.79 to 1.03;
P = .14) (Figure 5), and the incidence of NDS did not significantly
differ in the subgroup analysirs based on the type of comparators
Patients, n

Median (25th, 75th percentiles).

(placebo vs surfactant) applied in the control group (placebo,

three studies24,26,28 : RR, 0.93; 95% CI, 0.8 to 1.08; P = .35;
863

265

211
116

60

surfactant, two studies 25,27 : RR, 0.78; 95% CI, 0.55 to 1.11;
P = .16) (Figure 5). The groups did not significantly differ in the
Nakamura26 (JPN)

Jangaard24 (GER)

incidence of the components of NDI, including CP (three

(Taiwan)
Yeh27 (Taiwan)
Bassler (EUR)

studies24,26,28: RR, 1.1; 95% CI, 0.7 to 1.71; P = .69) (Figure 6), a
Means ± SD.
28

low MDI score (five studies 24-28: RR, 0.95; 95% CI, 0.81 to 1.10;
25
Study

P = .48) (Figure 7), a low PDI score (two studies 25,27 : RR, 0.85;
Kuo

95% CI, 0.58 to 1.24; P = .4) (Figure 8), blindness (three

b
a
 ZHENG
ET AL.

T A B L E 2 Long‐term outcomes of the intratracheal administration of corticosteroids in preterm infants

Follow‐up Outcomes, n
Hospital
Study Patients, n Case, n rate, % Age at follow‐up, mo NDI CP MDI PDI Blindness Deafness readmission Death Growth
28 c
Bassler (EUR) T 437 629 73.5 21.3 148 24 139 NA 3 1 NA 82 W: 30(9‐60)e, L: 29.5(8‐62)e, HC: 16(<3‐60)e
c
C 419 21.3 165 21 152 NA 6 4 NA 58 W: 26(5‐58)e, L: 24(5‐60)e, HC: 13(<3‐59.5)e
Yeh27 (Taiwan) T 131 172 66.9 30.1 + 3.9d 26 NA 18 24 NA NA NA 17 W: 11.7 + 1.8d, L: 86.7 + 5.2d, HC: 47.7 + 2.7d
d
C 134 31.8 + 3.6 34 NA 19 26 NA NA NA 22 W: 11.8 + 2.3d, L: 85.8 + 5.4d, HC: 46.9 + 2.8d
Nakamura26 T 107 187a 88.6a 18 18 NA 18 NA NA NA NA 12 NA
(JPN)
36 19 9 NA NA NA NA NA 12 NA
C 104 179b 84.8b 18 18 NA NA NA NA NA NA 8 NA
36 21 10 NA NA NA NA NA 8 NA
25 b
Kuo (Taiwan) T 60 67 57.8 31.8 + 3.6 11 NA 10 10 1 2 26 18 W: 11.6 + 2d, L: 85.4 + 5.9d, HC: 46.6 + 1.8d
b
C 56 31.8 + 3.6 13 NA 12 13 2 2 21 23 W: 11.9 + 3d, L: 86.7 + 5.1d, HC: 46.6 + 2.4d
Jangaard24(GER) T 30 58 96.7 36 10 4 5 NA 1 0 8 2 NA
C 30 36 10 3 4 NA 0 0 8 2 NA
Abbreviations: BUD, budesonide; BDP, beclomethasone dipropionate; BW, body weight; C, the number of cases initially recruited in placebo control group; CP, cerebral palsy; FPP, fluticasone propionate;
MDI, mental development index; NDI, neurodevelopmental impairment; PDI, psychomotor development index; L, length; T, the number of cases initially recruited in treatment group.
a
Follow up at 18 months.
b
Follow up at 36 months.
c
Median.
d
Means ± SD.
e
Median (denotes interquartile range).
|
5
6 | ZHENG ET AL.

T A B L E 3 Methods for evaluating neurodevelopmental outcomes and the definition of NDI

Study Scale Definition
28
Bassler (EUR) BSID II Neurodevelopmental disability: CP, cognitive delay, deafness, or blindness. CP: nonprogressive motor impairment
characterized by abnormal muscle tone and decreased range or control of movements. Cognitive delay: MDI < 85.
Deafness: presence of sensorineural hearing loss. Blindness: corrected visual acuity of less than 20/200.
Yeh27 (Taiwan) BSID II NDI: MDI < 70, PDI < 70, CP, bilateral blindness, or bilateral hearing impairment. CP: nonprogressive disorder
characterized by abnormal tone in at least one extremity and abnormal control of movement and posture. Vision
impairment: blindness in on or both eyes or need for corrective lenses. Hearing impairment: hearing aids in one or
both ears.
Nakamura26(JPN) KSPD NDI: CP, hearing impairment, visual impairment, and DQ < 70. CP: nonprogressive, nontransient central nervous
system disorder characterized by abnormal muscle tone in at least one extremity as well as abnormal movement
and postural control. Hearing impairment and visual impairment: not defined.
Kuo25 (Taiwan) BSID II NDI: MDI and/or PDI ≤ 69, and/or hearing deficit or bilateral blindness. Hearing deficit: requiring hearing aid.
Blindness: not defined.
Jangaard24 (GER) BSID II NDI: CP, MDI < 2 SD of mean, blindness or deafness Blindness or deafness: not defined.
Abbreviations: BSID, Bayley Scales of Infant Development; CP, cerebral palsy; KSPD, Kyoto Scale of Psychological Development; DQ, developmental
quotient; MDI, mental developmental index; NDI, neurodevelopmental impairment; PDI, psychomotor developmental index; SD, standard deviation.

studies24,25,28 : RR, 0.64; 95% CI, 0.22 to 1.86; P = .41) (Figure 9)
24,25,28
and deafness (three studies : RR, 0.48; 95% CI, 0.12 to
1.92; P = .3) (Figure 10). Because only one study reported the
neurodevelopmental outcome at 18 months of PMA, another
subgroup analysis was not performed. Due to the limited number
of studies investigating different corticosteroids, further sub-
group analysis was not possible.
3.4.2 | Mortality
All included studies reported the incidence of long‐term mortality
during follow‐up. The results of the meta‐analysis demonstrated no
evidence of a significant reduction in mortality (five studies24-28: RR,
1.13; 95% CI, 0.9 to 1.41; P = .3) (Figure 11).
3.4.3 | Rehospitalization
Three studies24,25,28 reported the rehospitalization rates after the
initial discharge. The meta‐analysis indicated no significant reduction
in the incidence of rehospitalization between the two groups (three
studies24,25: RR, 0.99; 95% CI, 0.89 to 1.09; P = .82) (Figure 12). We
carried out a subgroup analysis to compare admission due to
respiratory or other reasons (respiratory readmission, two stu-
dies24,25: RR, 1.1; 95% CI, 0.85 to 1.51; P = .57; various reasons, one
study28: RR, 0.97; 95% CI, 0.88 to 1.08; P = .63) (Figure 12).

3.4.4 | Growth
Three studies25,27,28 reported growth outcomes at 18 to 36 months
of PMA. Two of these studies reported the data as the mean and
standard deviation, and the meta‐analysis showed that there were no
significant differences between the IAC and the control group with
regard to height, weight, and head circumference (two studies25,27:
MD, 0.14; 95% CI, −0.26 to 0.54; P = .48) (Figure 13). Another study28
reported the interquartile range; thus, this study was not included in
the pooled analysis.

4 | D I S C U SS I O N

4.1 | Main findings

Several systematic reviews and meta‐analyses of the intratracheal
F I G U R E 2 Risk of bias graph [Color figure can be viewed at inhalation or instillation of corticosteroids for the prevention or
wileyonlinelibrary.com] treatment of BPD have been performed.15,34,35 However, these
ZHENG ET AL. | 7

F I G U R E 3 Risk of bias summary for all

included records presented as percentages
[Color figure can be viewed at
wileyonlinelibrary.com]

F I G U R E 4 Funnel plot for publication

bias. IACs, intratracheal administration of
corticosteroids; RR, relative ratio [Color
figure can be viewed at
wileyonlinelibrary.com]

F I G U R E 5 Meta‐analysis: the long‐term effects of IACs on NDI in preterm infants. IACs, intratracheal administration of corticosteroids; NDI,
neurodevelopmental impairment [Color figure can be viewed at wileyonlinelibrary.com]
8 | ZHENG ET AL.

F I G U R E 6 Meta‐analysis: the long‐term effects of IACs on CP in preterm infants. IACs, intratracheal administration of corticosteroids; CP,
cerebral palsy [Color figure can be viewed at wileyonlinelibrary.com]

F I G U R E 7 Meta‐analysis: the long‐term effects of IACs on MDI in preterm infants. IACs, intratracheal administration of corticosteroids;
MDI, mental developmental index [Color figure can be viewed at wileyonlinelibrary.com]

F I G U R E 8 Meta‐analysis: the long‐term effects of IACs on PDI in preterm infants. IACs, intratracheal administration of corticosteroids; PDI,
psychomotor developmental index [Color figure can be viewed at wileyonlinelibrary.com]

F I G U R E 9 Meta‐analysis: the long‐term effects of IACs on blindness in preterm infants. IACs, intratracheal administration of corticosteroids
[Color figure can be viewed at wileyonlinelibrary.com]
ZHENG ET AL. | 9

F I G U R E 1 0 Meta‐analysis: the long‐term effects of IACs on deafness in preterm infants. IACs, intratracheal administration of
corticosteroids [Color figure can be viewed at wileyonlinelibrary.com]

F I G U R E 1 1 Meta‐analysis: the long‐term effects of IACs on mortality in preterm infants. IACs, intratracheal administration of
corticosteroids [Color figure can be viewed at wileyonlinelibrary.com]

F I G U R E 1 2 Meta‐analysis: the long‐term effects of IACs on rehospitalization rate in preterm infants. IACs, intratracheal administration of
corticosteroids [Color figure can be viewed at wileyonlinelibrary.com]
10 | ZHENG
F I G U R E 1 3 Meta‐analysis: the long‐term effects of IACs on physical development in preterm infants. IACs, intratracheal administration of
corticosteroids [Color figure can be viewed at wileyonlinelibrary.com]
studies are mainly limited to the short‐term effects and do not
address the long‐term outcomes. This study represents the first
review to date to explore the long‐term outcome of using IAC to
prevent BPD in premature infants through a meta‐analysis. Our
meta‐analysis of five follow‐up studies demonstrated that IAC is not
associated with a significant difference in long‐term benefits and
adverse outcomes at 18 to 36 months of PMA.
Studies have shown that the postnatal application of systemic
corticosteroids for the prevention or treatment of BPD may facilitate
extubation and decrease the incidence of BPD.36,37 However,
systemic corticosteroids have been linked to NDI and CP, especially
in infants receiving dexamethasone during the first week after
birth.8,11 To minimize the adverse effects of systemic corticosteroid
administration, IAC has become a common strategy for the
prevention and treatment of BPD. Previous studies have shown that
IAC significantly reduces mucosal edema and mucus secretion,
improves the gas exchange and oxygenation index, and alleviates
respiratory hypersensitivity, airway resistance and the pulmonary
inflammatory response.38,39 A meta‐analysis carried out by Shinwell
40
et al concluded that inhaled corticosteroids could significantly
decrease the incidence of BPD at 36 weeks of PMA (RR, 0.77; 95%
CI, 0.65 to 0.91). Although the short‐term beneficial effects of IAC
for BPD have been confirmed, the neurodevelopmental outcome
remains unclear. All studies included in our research reported the
long‐term effects of IAC on the development of the nervous system
in preterm infants with a follow‐up duration of 18 to 36 months. The
results of this meta‐analysis showed no significant difference
between the two groups in the incidence of NDI and the components
of NDI, which may be because the inhalation or instillation of
corticosteroid therapy reduces the need for systemic corticosteroid
administration, subsequently alleviating the long‐term effects on the
ET AL.
nervous system. Similarly, a retrospective study conducted by Kelly
et al41 showed that inhaled corticosteroids were not associated with
an increased incidence of death and/or NDI. In contrast, systemic
corticosteroid administration before 4 weeks of age was linked to
adverse outcomes.
Although the pooled meta‐analysis indicated no significant
difference in mortality, one of the included studies conducted by
Bassler et al28 demonstrated an increase in long‐term mortality. This
large RCT investigating inhaled budesonide for BPD prevention from
the Neonatal European Study of Inhaled Steroids (NEUROSIS)
contributed to nearly half of the population in our meta‐analysis.
This trial was conducted at 40 centers across nine countries and
involved 863 premature infants. No difference was found in the
incidence of BPD and neurodevelopmental disability among the
survivors at 18 to 22 months of age between the intervention and
control groups. However, mortality was higher in the inhaled
budesonide group (19.9% vs 14.5%), and most infants died during
the first week of life. Therefore, we infer that perinatal illness might
lead to an increase in mortality or this finding may have been due to
chance. These findings suggest that more high‐quality multicenter
trials are needed to justify the prophylactic administration of
budesonide for BPD.
Infants with BPD are much more likely to be rehospitalized for
various reasons other than NDI problems. Smith et al42 conducted a
study involving 238 preterm infants and showed a high rate of
rehospitalization after discharge from the NICU (49% vs 23%). In our
study, the differences in hospital readmission between the two
groups were not statistically significant. Furthermore, no difference
was found in the long‐term effects of IAC on growth in the infants
with BPD. These findings may be related to the short duration and
relatively small dosage of corticosteroids, but further research is
ZHENG ET AL.
needed to support these findings. Because none of the included
studies reported pulmonary function in terms of long‐term outcomes,
there were insufficient data to perform a meta‐analysis on pulmonary
function.
It has been well established that preterm infants with BPD have a
low tidal volume and short respiratory cycles; thus, lung deposition
after the intratracheal administration of drugs is a challenge. In
recent years, the intratracheal instillation of corticosteroids com-
bined with surfactant to prevent and/or treat BPD has become a new
option. Studies have demonstrated that the intratracheal adminis-
tration of surfactant and corticosteroid mixtures might synergisti-
cally improve lung function, thereby reducing the incidence of
BPD38,43 because pulmonary surfactants can decrease surface
tension, and surface tension gradients facilitate corticosteroid
43
distribution to the periphery of the lungs. In addition, surfactants
may enhance the solubility of corticosteroids and increase corticos-
teroid absorption.44 However, corticosteroids may increase the
synthesis of surfactants and the gene transcription of the surfactant
45 35
proteins SP‐A and SP‐B. Venkataraman et al found that the
intratracheal administration of budesonide combined with surfac-
tants can decrease the incidence of BPD in very low BW infants. In a
study involving 265 very low BW infants with severe RDS, Yeh et al27
found that the incidence of BPD in the preterm infants who received
budesonide (0.25 mg/kg) in combination with surfactant (100 mg/kg)
was lower than that in the infants who received surfactant alone.
Moreover, this meta‐analysis demonstrates that the intratracheally
administered corticosteroid‐surfactant combination was not asso-
ciated with adverse long‐term outcomes in preterm infants. In the
future, the instillation of corticosteroids using surfactants as vehicles
may be a promising treatment for the prevention of BPD. However,
before this treatment is recommended as a routine therapeutic
regimen in NICUs, more powerful studies are warranted.
4.2 | Strengths and limitations
The main strength of our study is that we included a large number of
infants and provide detailed, long‐term follow‐up data. Except for the
study conducted by Kuo et al,25 the other studies were based on the
intention to treat principle, including data from all randomized
participants. Furthermore, our study incorporated searches using
multiple electronic databases and manual searches of gray literature
and the bibliographies of the included studies. Except for one
study,24 the remaining studies were multicenter RCTs with clear
allocation concealment and randomization protocols. The results of
the sensitivity analysis of these studies were consistent, and the
heterogeneity analysis indicated that the included studies had no
critical heterogeneity. Therefore, the overall quality and quality of
the evidence in the included studies were high. The findings of this
study could be used as a reference in weighing the benefits and risks
of IAC in the management of BPD.
The included follow‐up studies have some limitations. (a) The
number of included studies was limited, and the sample size in some
trials was small. Of the five studies included in the meta‐analysis,
| 11
one study24 was published 17 years ago, and the practices in NICUs
and incidence of BPD have changed since its publication. (b) There
was clinical heterogeneity among the studies. For instance, the GA
and BW in the included studies varied, and a subgroup analysis
could not be carried out due to the lack of information about
individual patients. The different definitions of NDI and follow‐up
durations might have resulted in a certain degree of clinical
heterogeneity. Additionally, the types of corticosteroids, dosages,
durations, and methods of administration varied among the studies,
which might have led to discrepancies in prognosis evaluation. (c)
BPD can affect the development of the nervous system in preterm
infants, resulting in CP, cognitive impairment, the failure to walk
and feed independently, or neurodevelopmental disabilities,46
which may have interfered with the results of the neurodevelop-
mental follow‐up. Moreover, the follow‐up rate was nearly 50% in
one study,25 which might have had an impact on the attrition bias.
Despite all these limitations, this study provides a detailed summary
of the field to date and may be an impetus for further research in
this field.
5 | CO NCL USION
In summary, our meta‐analysis shows that IAC in preterm children
does not exhibit significant long‐term benefits and adverse outcomes.
However, a large multicenter clinical trial, that is, the NEUROSIS
study,28 has raised concerns that inhaled corticosteroids may cause
higher mortality. In addition, the number of included studies was
limited, and the sample size in some included studies was small. Well‐
designed studies and studies carried out in multiple centers with
larger sample sizes are needed to confirm the choice of steroids,
dosing schedules, delivery techniques, efficacy, and potential risks of
IAC with particular attention to the long‐term effects of IAC,
especially regarding the respiratory and neurodevelopmental
outcomes.
AC KNO WL EDG M EN T
We are grateful to Xin He for his suggestions regarding the
manuscript.
CON F LI CT OF IN TE RES T S
The authors declare that there are no conflict of interests.
ORCI D
Yirong Zheng http://orcid.org/0000-0001-9468-3647
Wenlong Xiu http://orcid.org/0000-0003-3101-0466
Yunfeng Lin http://orcid.org/0000-0003-1753-2014
Yanli Ren http://orcid.org/0000-0003-1677-9728
Baoquan Zhang http://orcid.org/0000-0002-5879-5745
Changyi Yang http://orcid.org/0000-0003-3187-6841
12 | ZHENG
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How to cite this article: Zheng Y, Xiu W, Lin Y, Ren Y,
Zhang B, Yang C. Long‐term Effects of the Intratracheal
Administration of Corticosteroids for the Prevention of
Bronchopulmonary Dysplasia: A Meta‐analysis. Pediatric
Pulmonology. 2019;1‐13. https://doi.org/10.1002/ppul.24452