Inhaled Corticosteroids for

Bronchopulmonary Dysplasia:
A Meta-analysis
Eric S. Shinwell, MD,a Igor Portnov, MD,a Joerg J. Meerpohl, MD,b Tanja Karen, MD,c Dirk Bassler, MDc

CONTEXT: Bronchopulmonary dysplasia (BPD) in preterm infants remains a major health abstract
burden despite many therapeutic interventions. Inhaled corticosteroids (IC) may be a safe
and effective therapy.
OBJECTIVE: To assess the safety and efficacy of IC for prevention or treatment of BPD or death
in preterm infants.
DATA SOURCES: PubMed, the Cochrane Library, Embase, and CINAHL from their inception until
November 2015 together with other relevant sources.
STUDY SELECTION: Randomized controlled trials of ICs versus placebo for either prevention or
treatment of BPD.
DATA EXTRACTION: This meta-analysis used a random-effects model with assessment of quality of
evidence using the Grading of Recommendations Assessment, Development and Evaluation
(GRADE) system.
RESULTS: Thirty-eight trials were identified, and 16 met inclusion criteria. ICs were associated
with a significant reduction in death or BPD at 36 weeks postmenstrual age (risk ratio [RR]
= 0.86, 95% confidence interval [CI] 0.75 to 0.99, I2 = 0%, P = .03; 6 trials, n = 1285). BPD was
significantly reduced (RR = 0.77, 95% CI 0.65 to 0.91, I2 = 0%, 7 trials, n = 1168), although
there was no effect on death (RR = 0.97, 95% CI 0.42 to 2.2, I2 = 50%, 7 trials, n = 1270). No
difference was found for death or BPD at 28 days postnatal age. The use of systemic steroids
was significantly reduced in treated infants (13 trials, n = 1537, RR = 0.87, 95% CI 0.76
to 0.98 I2 = 3%,). No significant differences were found in neonatal morbidities and other
adverse events.
LIMITATIONS: Long-term follow-up data are awaited from a recent large randomized controlled
trial.
CONCLUSIONS: Very preterm infants appear to benefit from ICs with reduced risk for BPD and no
effect on death, other morbidities, or adverse events. Data on long-term respiratory, growth,
and developmental outcomes are eagerly awaited.

aDepartment of Neonatology, Ziv Medical Center, Faculty of Medicine in the Galil, Bar-Ilan University, Tsfat, Israel; bCentre de Recherche pidmiologie et Statistique Sorbonne Paris Cit
U1153, Inserm/Universit Paris Descartes, Cochrane France, Hpital Htel-Dieu, Paris, France; and cDepartment of Neonatology, University of Zurich and University Hospital Zurich, Zurich,
Switzerland

Dr Shinwell conceptualized and designed the study, drafted the initial manuscript, supervised the data collection, reviewed the analyses, and wrote all versions of
the manuscript including the nal manuscript as submitted; Dr Bassler jointly conceptualized and designed the study, reviewed the data, supervised the analyses

To cite: Shinwell ES, Portnov I, Meerpohl JJ, et al. Inhaled Corticosteroids for Bronchopulmonary Dysplasia: A Meta-analysis. Pediatrics. 2016;138(6):e20162511

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PEDIATRICS Volume 138, number 6, December 2016:e20162511 REVIEW ARTICLE
Bronchopulmonary dysplasia
(BPD) remains a major cause of
mortality and early morbidity in
extremely low birth weight infants,
with a concomitant increase
in later neurodevelopmental
impairment.1 The pathogenesis
of BPD includes, but is not limited
to, inflammatory processes within
the immature lung.24 Because of
their antiinflammatory properties,
corticosteroids have been and
still are widely used for both the
prevention and treatment of BPD
in preterm infants. Early systemic
use of corticosteroids leads to a
significant reduction in BPD but is
unfortunately also associated with
significant adverse effects on growth
and neurodevelopmental outcome
with increased incidence of cerebral
palsy.5 Inhaled administration is an
attractive alternative that may offer
clinical efficacy without incurring
adverse effects. Over more than 2
decades, this intervention has been
studied in a number of randomized
controlled trials (RCTs).6,7 These
studies used a variety of drugs, at a
wide range of doses and that were
administered over assorted periods
of time, representing any 1 of early
prevention, later treatment, or
administration over a prolonged
period covering both options. In
addition, the combined samples have
been insufficient to establish either
safety or clear efficacy. A large recent
multicenter trial may significantly
alter the findings of the previous
published meta-analyses.8
Moreover, previous meta-analyses
have attempted to separate studies
of prevention and treatment,
despite significant overlap in ages
at administration of the inhaled
corticosteroid (IC). Shah et al
reported a meta-analysis of studies
of early postnatal ICs, defined as
administration that was started
before age 2 weeks. This analysis
included 7 trials with 492 infants,
although the primary and secondary
outcome variables were only
2 SHINWELL et al
reported in 5 of the 7 trials including
429 infants. The duration of the study
intervention varied from 10 days to 4
weeks. Onland et al reported a meta-
analysis of late studies defined as
treatment starting after age 7 days.
Because the entry criteria of these
2 analyses overlapped and both
included studies that started between
age 1 and 2 weeks, 1 study met
inclusion criteria for both analyses.
The late analysis included 8 studies
and 232 infants. However, most of
the main outcome variables were
reported in only a small number
of the studies with few infants
providing data.
In addition to these 2 meta-analyses,
there are 2 additional analyses
comparing inhaled and systemic
steroids for either prevention or
treatment of BPD.9,10 However, it is
not possible to include the inhaled
arm of these studies in a meta-
analysis of early or late inhaled
steroids as there is no appropriate
control group.
Accordingly, this up-to-date
systematic review and meta-
analysis offers useful information for
practitioners considering the role
of inhaled steroids for all preterm
infants at risk for BPD. In fact, this
systematic review adds a single, large
study that includes more infants than
all the previous studies together,
and by combining both approaches,
prevention and treatment, and
including preterm infants from birth
onward, the larger sample size helps
answer this important question.
METHODS
This systematic review and
meta-analysis was performed in
accordance with our published
protocol that was prepared according
to the 2015 Preferred Reporting
Items for Systematic Reviews
and Meta-AnalysesProtocol
(PRISMA-P) guideline of 2015 and
reported according to PRISMA
guidelines (2009).1113 The objective
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was to assess the efficacy and safety
of ICs administered to preterm
infants for either the prevention or
treatment of BPD while including all
relevant RCTs.
Criteria for inclusion of an RCT were
as follows: (1) preterm infants of
gestational age 22 0/7 to 36 6/7
weeks considered to be at risk for
BPD, including both ventilated
and nonventilated infants and (2)
an RCT comparing any IC versus
control (placebo or no treatment)
at any dose and any duration of
treatment and administered either
by a metered-dose inhaler or by
nebulization. Excluded were trials
either of systemic corticosteroids
or corticosteroids in liquid form
administered by direct tracheal
instillation.
The primary outcomes included the
composite outcome of mortality
or BPD defined as requirement for
supplemental oxygen at 28 days
PNA or 36 weeks postmenstrual age
(PMA), together with the individual
components of the composite
outcome. Secondary outcomes
included surrogate measures of
respiratory insufficiency, such as
duration of mechanical ventilation
or supplemental oxygen and rescue
administration of systemic steroids,
in addition to neonatal morbidities
and adverse events attributable to
the interventions (Fig 1).
The literature search (December
1, 2015) was conducted by using
PubMed.gov of the US National
Library of Medicine (Medline from
1966 onwards), the Cochrane
Library, Embase (from 1974),
and CINAHL (from 1982) (see
Supplemental Information). In
addition, we searched the trial
registers www.clinicaltrials.gov,
www.controlled-trials.com, and
www.who.int/trialsearch, as well
as lists of references from relevant
studies and abstracts from the
proceedings of relevant academic
meetings, including the Pediatric
Academic Societies and the European
FIGURE 1
Forest plots of effects of inhaled corticosteroids.

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PEDIATRICS Volume 138, number 6, December 2016 3
Society for Pediatric Research. Search
strategies are shown in Supplemental
Information.
References identified via the
literature search were screened
by 2 of the authors (I.P., T.K.), and
data were extracted independently
to standardized data extraction
forms, entered into Review Manager
(RevMan 5.3) by 1 of the reviewers,
and checked by a second reviewer.
Discrepancies were resolved
by group discussion. Extracted
data included the characteristics
of the study and its population,
description of the intervention and
comparisons, outcome measures
and measurements tools and results.
The risk of bias of included studies
was assessed using the Cochrane
risk of bias tool, including sequence
generation, allocation concealment,
blinding (of participants, personnel,
and outcome assessors), incomplete
outcome data, selective outcome
reporting, and other sources of bias
for the RCTs. Accordingly, these items
are described as having a low,
high, or unclear risk of bias.14
The quality of the evidence was
assessed according to the Grading
of Recommendations Assessment,
Development and Evaluation
(GRADE) approach for the suggested
5 criteria for downrating our
confidence in effects estimates (risk
of bias, inconsistency, imprecision,
indirectness, and publication bias)
and the 3 criteria for uprating our
confidence (large effect, dose-
response gradient, and opposing
confounding). On the basis of these
criteria, the quality of evidence
judgment can range from very low
(+) to high (++++).15
Measures of Treatment Effect
The meta-analysis used a random
effects model as primary analysis
to estimate treatment effects. The
treatment effects for dichotomous
outcomes are expressed as a risk
ratio (RR) with 95% confidence
intervals (CI). Continuous outcomes,
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4 SHINWELL et al
such as duration of oxygen therapy,
mechanical ventilation, and
hospitalization, were reported in
different formats across the studies,
and therefore meta-analysis is
restricted to a subset of studies,
and additional information is
provided regarding studies that
could not be included in the meta-
analysis. Supplemental information
was obtained from authors where
required. Certain authors (n = 2)
could not be contacted, despite
approaches via assorted media, and
in these cases, previously published
information from the Cochrane
analyses was used.6,7
The authors assessed the likelihood
of publication bias as low after an
extensive literature search process
that included clinical trials registries,
together with visual assessment that
did not reveal marked asymmetry of
funnel plots.
RESULTS
of the studies are to be found in
Literature Search
Thirty-eight trials were initially
identified with 16 trials meeting
inclusion criteria (see Table 1
and Supplemental Figure 3 and
Supplemental Table 3).8,1630
Thirteen studies were excluded
because they used a nonrandomized
design. Nine studies did not meet
inclusion criteria for the following
reasons: randomization after 36
weeks PMA in 2, comparison of
systemic versus inhaled steroid
treatment in 5, direct intratracheal
steroid instillation in 1, and
publication of substudy from an
included study in 1. Overall, the 16
studies included 1596 infants, 804
in the active intervention groups,
and 792 in the control groups. More
than half of the infants were studied
in 1 RCT,8 and together 4 of the 16
RCTs comprised 79% of the overall
sample.8,19,23,28
Description of Studies
All 16 studies were RCTs, 13 were
published as full reports, and 3 were
published only as abstracts.16,21,25
The ICs studied included
beclomethasone (6), budesonide
(4), fluticasone (3), flunisolide
(2), and dexamethasone (1) (see
Supplemental Information). The start
of the intervention varied from day
1 of life to age 60 days, although all
but 2 of the studies began therapy
within the first 2 weeks of life. In
addition, the duration of the study
interventions ranged from 1 week
to a potential maximum of 9 weeks
in 1 study that included infants
from 23 weeks gestational age and
continued therapy until 32 weeks or
weaning from oxygen and ventilation.
However, in practice, the mean
duration of the intervention in this
study was 33 days. Eleven of the
16 studies included only ventilated
infants, 4 added infants on nasal
ventilator support, and 1 study
also included infants receiving only
supplemental oxygen. Full details
the supplementary online material
(Supplemental Table 4).
The risk of bias was assessed as
low in 9 studies and as low/unclear
in 7, mostly because of limited
information regarding randomization
of study infants (see Fig 2; study data
available in Supplemental Table 4).
The Grading of Recommendations
Assessment, Development, and
Evaluation assessment of the quality
of evidence is shown in Table 2.
The data for the primary outcome
variable and the secondary variable,
BPD, were assessed as moderate
quality in view of a degree of
inconsistency in the results. The
quality was low for mortality data
because of both inconsistency and
imprecision.
Primary Outcome Variables
Death or BPD at 36 weeks PMA,
the primary outcome variable, was
significantly reduced in the treated
TABLE 1 Characteristics of Studies
Study Year Med Start Rx Duration n (Rx/C) GA (Weeks) BW (g) Resp. Support
Prokriefka 1993 Flun n/a 4 wk 14 (8/6) n/a n/a MV only
La Force 1993 Beclo 2 wk 4 wk 21 (10/11) <1500 MV only
Arnon 1996 Bud 2 wk 1 wk 20 (9/11) <33 <2000 MV only
Giep 1996 Beclo 14 wk 1 wk 19 (10/9) <1500 MV only
Denjean 1998 Beclo 10 d 4 wk 86 (43/43) <31 MV or nasal
Pappagallo 1998 Dex 1 wk 10 d 18 (9/9) <1500 MV only
Townsend 1998 Flun 24 d 10 d 32 (15/17) <28 <1100 MV only
Fok 1999 Flut <24 h 2 wk 53 (27/26) <32 <1500 MV only
Cole 1999 Beclo 314 d 4 wk 253 (123/130) <33 <1251 MV only
Merz 1999 Bud 3d 10 d 23 (12/11) 2532 750-1500 MV only
Yong 1999 Flut <18 h 2 wk 40 (20/20) <32 MV only
Jonsson 2000 Bud 1 wk 2 wk 30 (15/15) <1500 MV or nasal
Zimmerman 2000 Beclo <24 h 12 d 39 (20/19) <1300 MV or nasal
Jangaard 2002 Beclo 3d 4 wk 60 (30/30) <1250 MV only
Dugas 2005 Flut 2860 d 4 wk 32 (16/16) <32 MV, nasal, or O2
Bassler 2015 Bud <24 h To 32 wk 856 (437/419) 2328 MV or nasal
Total 1596 (804/792)
Beclo, beclomethasone; Bud, budesonide; BW, birth weight; Dex, dexamethasone; Flun, unisolide; Flut, uticasone; GA, gestational age; Med, medication; MV, mechanical ventilation; n/a,
not available; Rx/C, treatment/control.

group (6 trials, n = 1285, RR = 0.86,
95% CI 0.75 to 0.99, I2 = 0%, P =
.03). Five smaller studies reported
the alternative composite variable
of death or BPD at age 28 days of life
and found no significant effect (5
trials, n = 429, RR = 0.98, 95% CI 0.88
to 1.11, I2 = 0%) (see Supplemental
Tables 5 and 6).
The incidence of BPD alone at 36
weeks PMA fell more markedly than
the composite variable (7 trials,
n = 1168, RR = 0.77, 95% CI 0.65 to
0.91, I2 = 0%, P = .003). However, the
incidence of BPD at 28 days PNA was
not found to be significantly altered
by the study intervention (7 trials, n =
528, RR = 0.92, 95% CI 0.76 to 1.11,
I2 = 46%). By comparison, the
incidence of death alone seems
unaffected by the study interventions
either at age 28 days or at 36 weeks
PMA (28 days: 6 trials, n = 480, RR =
0.69, 95% CI 0.30 to 1.56, I2 = 46%;
36 weeks: 7 trials, n = 1270, RR =
0.97, 95% CI 0.42 to 2.20, I2 = 50%).
Secondary Outcome Variables
A variety of measures were used
across the studies to attempt to
gauge the effect of inhaled steroids
on the severity or duration of BPD
to expand the assessment of the
overall treatment effect. Because
many of the studies initiated therapy
in ventilated infants, failure to
successfully extubate was considered
a measure of interest at various time
points that included 7, 14, and 21 to
28 days and at the latest reported
time point. Failure to extubate was
significantly reduced at day 14 (6
trials, n = 232, risk difference (RD)
0.21, 95% CI 0.41 to 0.00; P = .05,
I2 = 67%) and at the latest reported
time point (1 trial, n = 14, RD 0.46,
95% CI 0.91 to 0.01; P = .05). In
addition, there was a reduction of
borderline significance at day 7 (3
trials, n = 92, RD 0.19, 95% CI 0.48
to 0.10; P = .2, I2 = 73%) and at 21 to
28 days (3 trials, n = 294, RD 0.14,
95% CI 0.30 to 0.03, I2 = 58%, P =
.11). The Forest plots are available in
the online supplemental information
(Supplemental Figures 4A, 4B, 4C, 4D,
4E, 4F, 4G, and 4H).
Duration of mechanical ventilation
or oxygen supplementation was
reported as mean or median or total
days, and in the absence of raw data,
these data were not combined. In
studies reporting mean, no significant
effect was found on the duration
of mechanical ventilation (3 trials,
n = 113, mean difference [days]
3.91, 95% CI 15.42 to 7.61, I2 =
78%). Likewise, no significant effect
was found on duration of oxygen
supplementation (3 trials, n = 89,
mean difference [days] 2.15, 95%
CI 9.59 to 5.28, I2 = 0%). However,
these outcome measures were
available only in a small proportion
of the overall sample.
The use of systemic corticosteroids
as a rescue intervention, presumably
because of perceived failure of
other therapies to improve the
infants respiratory status, is another
commonly used intermediate
measure of the effect of the ICs. A
significant reduction was found in
administration at any time point (13
trials, n = 1537, RR = 0.87, 95% CI
0.76 to 0.98, I2 = 3%). No significant
effect was found in the subset of
studies reporting specifically at 36
weeks (3 trials, n = 352, RR = 0.87,
95% CI 0.47 to 1.61).
Neonatal Morbidity
ICs showed no significant effect on
the occurrence of major neonatal
morbidities. The incidence of sepsis
seems unaffected (12 trials, n =
1282, RR = 1.12, 95% CI 0.96 to
1.3, I2 = 0%). No significant effect
was found for the interventions on
central nervous system injury that
was reported in various forms. Any
grade of intraventricular hemorrhage
(IVH) was reported in 5 trials (n =
391, RR = 0.96, 95% CI 0.85 to 1.09,
I2 = 0%) while severe IVH (grades

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PEDIATRICS Volume 138, number 6, December 2016 5
3 and 4) was reported as a separate
variable in 3 trials (n = 362, RR =
1.43, 95% CI 0.76 to 2.69, I2 = 0%).
Periventricular leukomalacia was
reported in 3 trials (n = 362, RR =
1.17, 95% CI 0.55 to 2.48, I2 = 0%).
The study of Bassler et al found
no effect on a composite variable,
termed brain injury that included
IVH, periventricular leukomalacia,
and ventriculomegaly (n = 838, RR =
1.25, 95% CI 0.94 to 1.65). Similarly,
no effect was found on the incidence
of patent ductus arteriosus (PDA) as
reported in various forms (any PDA:
4 trials, n = 128, RR = 0.93, 95% CI
0.51 to 1.73, I2 = 57%; PDA requiring
drug treatment: 2 trials, n = 909, RR =
0.79, 95% CI 0.59 to 1.07, I2 = 50%;
PDA requiring surgery: 2 trials, n =
909, RR = 1.09, 95% CI 0.18 to 678,
I2 = 68%). The incidence of air leak
was unaffected by the interventions
(2 trials, n = 83, RR = 0.93, 95%
CI 0.14 to 6.04, I2 = 0%). No effect
was found for the intervention on
ophthalmic morbidities (retinopathy
of prematurity stage 2 or higher: 4
trials, n = 1086, RR = 1.12, 95% CI
0.93 to 1.35, I2 = 0%; retinopathy of
prematurity requiring treatment: 2
trials, n = 977, RR = 1.18, 95% CI 0.70
to 1.99; I2 = 36%); Cataract: 1 study,
n = 253, RR = 0.35, 95% CI 0.01 to
8.56). Necrotizing enterocolitis (NEC)
was similarly unaffected by the study
interventions (4 trials, n = 1192, RR =
0.76, 95% CI 0.54 to 1.06, I2 = 0%).

Growth in the neonatal period was

assessed by a variety of measures
in 6 studies. These included weight,
length, head circumference, and
rate of growth, and the measures
could not be combined for review.
However, no significant effects were
detected in the individual studies.
Assessment of a potential effect of ICs
on adrenal suppression was studied
FIGURE 2
with either cortisol levels or an Risk of bias of individual studies. +, low risk; , high risk; ?, unclear risk of bias.
adrenocorticotropic hormone test in
4 studies with no adverse effect being
detected.

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6 SHINWELL et al
 TABLE 2 Summary of Findings
Quality Assessment No. of Patients Effect Quality Importance
No. of Studies Study Risk of Bias Inconsistency Indirectness Imprecision Other ICs, (%) Placebo, Relative (95% Absolute (95% CI)
Design Considerations (%) CI)
Death or BPD at 28 d RT Not serious Not serious Not serious Seriousa None 104/212 111/217 RR 0.98 (0.88 10 fewer per 1000 I
PNA (f/u: 28 d PNA): 5 (49.1) (51.2) to 1.11) (from 56 more Moderate
studies to 61 fewer)
Death or BPD at 36 wk RT Not serious Not serious Not serious Not serious None 227/649 256/636 RR 0.86 (0.75 56 fewer per 1000 C
PMA (f/u: 36 wk PMA): (35.0) (40.3) to 0.99) (from 4 fewer High
6 studies to 101 fewer)
Death at 28 d PNA (f/u: RT Not serious Not serious Not serious Seriousa None 19/237 31/243 RR 0.69 (0.30 40 fewer per 1000 I
28 d PNA): 6 studies (8.0) (12.8) to 1.56) (from 71 more Moderate
to 89 fewer)
Death at 36 wk PMA (f/u: RT Not serious Not serious Not serious Seriousb None 84/639 71/631 RR 0.97 (0.42 3 fewer per 1000 I

PEDIATRICS Volume 138, number 6, December 2016

36 wk PMA): 7 studies (13.1) (11.3) to 2.20) (from 65 fewer Moderate
to 135 more)
BPD at 28 d PNA (f/u: 28 RT Not serious Seriousc Not serious Seriousa None 127/261 141/267 RR 0.92 (0.76 42 fewer per 1000 I
d PNA): 7 studies (48.7) (52.8) to 1.11) (from 58 more Low
to 127 fewer)
BPD at 36 wk PMA (f/u: RT Not serious Not serious Not serious Not serious None 149/581 192/587 RR 0.77 (0.65 75 fewer per 1000 C
36 wk PMA): 7 studies (25.6) (32.7) to 0.91) (from 29 fewer High
to 114 fewer)
Use of systemic steroids: RT Not serious Not serious Not serious Not serious None 253/775 289/762 RR 0.87 (0.76 49 fewer per 1000 I
10 studies (32.6) (37.9) to 0.98) (from 8 fewer High
to 91 fewer)
The quality assessement is shown both graphically by the number of + signs and as low, moderate, or high quality. C, critical; f/u, follow-up; I, important; MD, mean difference; RT, randomized trials.
a The imprecision was considered serious because the total event number was smaller than optimal information size and 95%CI compatible with relevant harm as well as benet.
b The imprecision was considered serious because the 95% CIs of the relative as well as absolute risk estimates included an appreciable benet (CI = 0.42) and a harm effect (CI = 2.20), I2 = 50%.
c The inconsistency was considered serious for BPD at 28 d PNA because the point estimate of RR in the study by Yong 1999 was very different from the other studies. There were no overlaps of 95%CIs between the studies by Yong 1999 and

Zimmerman 2000 which is reected in I2 of 46%.

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DISCUSSION
Adverse Events
Long-term Outcome

the Bassler et al study.

blindness, or deafness.

(see Supplemental Table 7).

of respiratory readmissions,
Long-term health, growth, and

study that showed a significant

specific adverse events, such as
event reported (1 trial, n = 856,

outcome of death or BPD was of

of the results of the Bassler et al
of systemic steroids as a rescue
between the groups in incidence

are available but are expected to

at 36 weeks PMA with a number

on mortality in the meta-analysis

a reduction in the administration
needed to treat of 14. In addition,
hyperglycemia (5 trials, n = 1002,

This systematic review and meta-

No significant effect was found on

RR = 0.93, 95% CI 0.73 to 1.19) or

neurodevelopment were reported

be markedly expanded in the near

adverse effects. Limited long-term
analysis demonstrates a beneficial

therapy. In contrast, there was no

is of particular importance in view

36 weeks. However, the composite

RR = 0.80, 95% CI 0.39 to 1.62, I2 =
RR = 0.96, 95% CI 0.74 to 1.24, I2 =

a nonsignificant trend to increased

the incidence of either any adverse

neurodevelopmental outcome data

in a single study at 3 years of age.28
No significant difference was found

reduction in the incidence of BPD at

effect of ICs on the incidence of BPD

future with publication of data from

= 0.97, 95% CI 0.63 to 1.51, I2 = 0%)
0%) or gastrointestinal hemorrhage

borderline significance as a result of

or perforation (3 trials, n = 1139, RR
cerebral palsy, developmental delay,

The absence of evidence for an effect

the intervention was associated with

evidence of an effect on the incidence

0%), hypertension (5 trials, n = 1002,

of death, neonatal morbidity, or other

7
mortality in the treated group.
Although no other studies of ICs have
suggested an increase in mortality, it
is reassuring that the combination of
all 16 relevant trials showed no effect
on mortality.
The apparent discrepancy between
the effect of ICs on BPD at 36 weeks
and the lack of effect at 28 days may
relate to the markedly higher sample
size available at 36 weeks and also to
the relative insensitivity of BPD at 28
days as a predictor of BPD at
36 weeks.
After >2 decades of intermittent
investigation, our data suggest
that ICs may be considered for the
prevention or treatment of BPD
in preterm infants. However, the
marked heterogeneity of the studies
included in this analysis precludes
any unambiguous observations on
a number of important questions.
As described, clinical heterogeneity
was observed with regard to the
drug, dosage, timing, and duration.
Accordingly, no recommendations
may be offered on these issues.
However, it is worth noting that
more than half of the sample of
this analysis was derived from a
single study that demonstrated a CONCLUSIONS
statistically significant reduction The implication of this analysis
in the incidence of BPD using is to establish the place of ICs,
budesonide administered from possibly budesonide, in particular,
birth until a maximum age of 32 as a potentially efficacious and
weeks PMA. This is therefore safe therapy for the prevention or
the most robust evidence for a treatment of BPD in preterm infants.
recommendation. To solidify this This analysis will require an update
recommendation, it will be necessary with long-term follow-up data in the
to update this analysis when the future.
neurodevelopmental follow-up of
this study is published.
Prevention of BPD remains a major
challenge. Currently accepted ABBREVIATIONS
approaches include attempts at
BPD:bronchopulmonary
minimizing injury associated with
dysplasia
mechanical ventilation and oxygen, and
CI:confidence interval
these varied techniques have met with
IC:inhaled corticosteroids
some success.3133 Caffeine is effective
IVH:intraventricular
and widely used.34 Likewise, systemic
hemorrhage
steroids are known to be effective, and
PDA:patent ductus arteriosus
thus, in the most challenging cases,
PMA:postmenstrual age
clinicians and families frequently
PNA:postnatal age
need to balance risks and benefits in
PRISMA:Preferred Reporting
decision-making.5,35 However, despite
Items for Systematic
all of this research activity, BPD
Reviews and
remains unacceptably frequent, and a
Meta-analyses
new potent therapeutic intervention
RCT:randomized controlled trial
such as routine ICs for infants at risk
RD:risk difference
may significantly improve outcome for
RR:risk ratio
these infants.1

and all versions of the manuscript; Dr Meerpohl reviewed the data and conducted the analyses; Drs Portnov and Tanja carried out the data collection and
assisted with the analyses and reviewed and revised the manuscript; and all authors approved the nal manuscript as submitted.
This trial has been registered with the International Prospective Register of Systematic Reviews (PROSPERO identier CRD42015019628).
DOI: 10.1542/peds.2016-2511
Accepted for publication Sep 22, 2016
Address correspondence to Eric Shinwell, MD, Department of Neonatology, Ziv Medical Center, Rambam St, Tsfat 13100, Israel. E-mail: eric.s@ziv.health.gov.il
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright 2016 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no nancial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: Drs Shinwell and Bassler are authors of a study that is included in the systematic review. The other authors have indicated
they have no potential conicts of interest to disclose.

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SHINWELL et al
 Inhaled Corticosteroids for Bronchopulmonary Dysplasia: A Meta-analysis
Eric S. Shinwell, Igor Portnov, Joerg J. Meerpohl, Tanja Karen and Dirk Bassler
Pediatrics; originally published online November 23, 2016;
DOI: 10.1542/peds.2016-2511
Updated Information & including high resolution figures, can be found at:
Services /content/early/2016/11/21/peds.2016-2511.full.html
Supplementary Material Supplementary material can be found at:
/content/suppl/2016/11/21/peds.2016-2511.DCSupplemental.
html
References This article cites 32 articles, 6 of which can be accessed free
at:
/content/early/2016/11/21/peds.2016-2511.full.html#ref-list-1

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright 2016 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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Inhaled Corticosteroids for Bronchopulmonary Dysplasia: A Meta-analysis
Eric S. Shinwell, Igor Portnov, Joerg J. Meerpohl, Tanja Karen and Dirk Bassler
Pediatrics; originally published online November 23, 2016;
DOI: 10.1542/peds.2016-2511

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
/content/early/2016/11/21/peds.2016-2511.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2016 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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