REVIEW ARTICLEPEDIATRICS Volume 138 , number 6 , December 2016 :e 20162511

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

abstractCONTEXT: Bronchopulmonary dysplasia (BPD) in preterm infants remains a major health

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 Épidémiologie et Statistique Sorbonne Paris Cité—

U1153, Inserm/Université Paris Descartes, Cochrane France, Hôpital Hôtel-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 fi 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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SHINWELL et al

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. 2 – 4 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

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-Analyses—Protocol

(PRISMA-P) guideline of 2015 and

reported according to PRISMA

guidelines (2009). 11 – 13 The objective

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

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PEDIATRICS Volume 138 , number 6 , December 2016 3

FIGURE 1Forest plots of effects of inhaled corticosteroids.

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SHINWELL et al

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,

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

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, 16 – 30

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

of the studies are to be found in

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

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PEDIATRICS Volume 138 , number 6 , December 2016

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

infant’s 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

5

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 2–4 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 3–14 d 4 wk 253 (123/130) <33 <1251 MV only

Merz 1999 Bud 3 d 10 d 23 (12/11) 25–32 750-1500 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 3 d 4 wk 60 (30/30) — <1250 MV only

Dugas 2005 Flut 28–60 d 4 wk 32 (16/16) <32 — MV, nasal, or O2

Bassler 2015 Bud <24 h To 32 wk 856 (437/419) 23–28 — MV or nasal

Total 1596 (804/792)

Beclo, beclomethasone; Bud, budesonide; BW, birth weight; Dex, dexamethasone; Flun, fl unisolide; Flut, fl uticasone; GA, gestational age; Med, medication; MV, mechanical ventilation; n/a,

not available; Rx/C, treatment/control.

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SHINWELL et al

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

with either cortisol levels or an

adrenocorticotropic hormone test in

4 studies with no adverse effect being

detected.

6

FIGURE 2Risk of bias of individual studies. +, low risk; −, high risk; ?, unclear risk of bias.

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PEDIATRICS Volume 138 , number 6 , December 2016

Long-term Outcome

Long-term health, growth, and

neurodevelopment were reported

in a single study at 3 years of age. 28

No significant difference was found

between the groups in incidence

of respiratory readmissions,

cerebral palsy, developmental delay,

blindness, or deafness.

Adverse Events

No significant effect was found on

the incidence of either any adverse

event reported (1 trial, n = 856,

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

specific adverse events, such as

hyperglycemia (5 trials, n = 1002,

RR = 0.96, 95% CI 0.74 to 1.24, I2 =

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

RR = 0.80, 95% CI 0.39 to 1.62, I2 =

0%) or gastrointestinal hemorrhage

or perforation (3 trials, n = 1139, RR

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

(see Supplemental Table 7).

DISCUSSION

This systematic review and meta-

analysis demonstrates a beneficial

effect of ICs on the incidence of BPD

at 36 weeks’ PMA with a number

needed to treat of 14. In addition,

the intervention was associated with

a reduction in the administration

of systemic steroids as a “rescue

therapy.” In contrast, there was no

evidence of an effect on the incidence

of death, neonatal morbidity, or other

adverse effects. Limited long-term

neurodevelopmental outcome data

are available but are expected to

be markedly expanded in the near

future with publication of data from

the Bassler et al study.

The absence of evidence for an effect

on mortality in the meta-analysis

is of particular importance in view

of the results of the Bassler et al

study that showed a significant

reduction in the incidence of BPD at

36 weeks. However, the composite

outcome of death or BPD was of

borderline significance as a result of

a nonsignificant trend to increased

7

TABL

E 2

Su

mm

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of F

ind

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Qu

alit

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sess

men

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o. o

f P

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ther

Con

sid

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s

ICs,

(%

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lace

bo,

(%)

Rel

ativ

e (9

5%

CI)

Abso

lute

(95

% C

I)

Dea

th o

r B

PD

at

28 d

PN

A (f

/u: 2

8 d

PN

A): 5

stu

die

s

RT

Not

ser

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ser

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Non

e10

4/21

2

(49.

1)

111/

217

(51.

2)

RR

0.9

8 (0

.88

to 1

.11)

10 f

ewer

per

100

0

(fro

m 5

6 m

ore

to 6

1 fe

wer

)

⨁⨁

⨁◯

Mod

erat

e

I

Dea

th o

r B

PD

at

36 w

k

PM

A (f

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6 w

k P

MA)

:

6 st

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RT

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ser

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ser

iou

sN

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Non

e22

7/64

9

(35.

0)

256/

636

(40.

3)

RR

0.8

6 (0

.75

to 0

.99)

56 f

ewer

per

100

0

(fro

m 4

few

er

to 1

01 f

ewer

)

⨁⨁

⨁⨁

Hig

h

C

Dea

th a

t 28

d P

NA

(f/u

:

28 d

PN

A): 6

stu

die

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ser

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us

Not

ser

iou

sS

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usa

Non

e19

/237

(8.0

)

31/2

43

(12.

8)

RR

0.6

9 (0

.30

to 1

.56)

40 f

ewer

per

100

0

(fro

m 7

1 m

ore

to 8

9 fe

wer

)

⨁⨁

⨁◯

Mod

erat

e

I

Dea

th a

t 36

wk

PM

A (f

/u:

36 w

k P

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: 7 s

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ser

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e84

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(13.

1)

71/6

31

(11.

3)

RR

0.9

7 (0

.42

to 2

.20)

3 fe

wer

per

100

0

(fro

m 6

5 fe

wer

to 1

35 m

ore)

⨁⨁

⨁◯

Mod

erat

e

I

BP

D a

t 28

d P

NA

(f/u

: 28

d P

NA)

: 7 s

tud

ies

RT

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ser

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usc

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ser

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e12

7/26

1

(48.

7)

141/

267

(52.

8)

RR

0.9

2 (0

.76

to 1

.11)

42 f

ewer

per

100

0

(fro

m 5

8 m

ore

to 1

27 f

ewer

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SHINWELL et al

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

statistically significant reduction

in the incidence of BPD using

budesonide administered from

birth until a maximum age of 32

weeks’ PMA. This is therefore

the most robust evidence for a

recommendation. To solidify this

recommendation, it will be necessary

to update this analysis when the

neurodevelopmental follow-up of

this study is published.

Prevention of BPD remains a major

challenge. Currently accepted

approaches include attempts at

minimizing injury associated with

mechanical ventilation and oxygen, and

these varied techniques have met with

some success. 31 – 33 Caffeine is effective

and widely used. 34 Likewise, systemic

steroids are known to be effective, and

thus, in the most challenging cases,

clinicians and families frequently

need to balance risks and benefits in

decision-making.5, 35 However, despite

all of this research activity, BPD

remains unacceptably frequent, and a

new potent therapeutic intervention

such as routine ICs for infants at risk

may significantly improve outcome for

these infants. 1

CONCLUSIONS

The implication of this analysis

is to establish the place of ICs,

possibly budesonide, in particular,

as a potentially efficacious and

safe therapy for the prevention or

treatment of BPD in preterm infants.

This analysis will require an update

with long-term follow-up data in the

future.

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8

ABBREVIATIONS

BPD:  bronchopulmonary

dysplasia

CI:  confidence interval

IC:  inhaled corticosteroids

IVH:  intraventricular

hemorrhage

PDA:  patent ductus arteriosus

PMA:  postmenstrual age

PNA:  postnatal age

PRISMA:  Preferred Reporting

Items for Systematic

Reviews and

Meta-analyses

RCT:  randomized controlled trial

RD:  risk difference

RR:  risk ratio

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 fi nal manuscript as submitted.

This trial has been registered with the International Prospective Register of Systematic Reviews (PROSPERO identifi er 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 fi 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 confl icts of interest to disclose.

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DOI: 10.1542/peds.2016-2511 originally published online November 23, 2016; 2016;138;Pediatrics 

Eric S. Shinwell, Igor Portnov, Joerg J. Meerpohl, Tanja Karen and Dirk BasslerInhaled Corticosteroids for Bronchopulmonary Dysplasia: A Meta-analysis

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