Impact of Postnatal Systemic Corticosteroids on Mortality and Cerebral Palsy in

Preterm Infants: Effect Modification by Risk for Chronic Lung Disease

Lex W. Doyle, Henry L. Halliday, Richard A. Ehrenkranz, Peter G. Davis and John C.
Sinclair
Pediatrics 2005;115;655-661
DOI: 10.1542/peds.2004-1238

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 Impact of Postnatal Systemic Corticosteroids on Mortality and
Cerebral Palsy in Preterm Infants: Effect Modification by
Risk for Chronic Lung Disease
Lex W. Doyle, MD*‡; Henry L. Halliday, MD§; Richard A. Ehrenkranz, MD㛳; Peter G. Davis, MD*‡; and
John C. Sinclair, MD#¶
ABSTRACT. Objective. In preterm infants, chronic
lung disease (CLD) is associated with an increased risk
for cerebral palsy (CP). However, systemic postnatal cor-
ticosteroid therapy to prevent or treat CLD, although
effective in improving lung function, may cause CP. The
objective of this study was to determine the effect of
systemic postnatal corticosteroid treatment on death and
CP and to assess any modification of effect arising from
risk for CLD.
Methods. Randomized, controlled trials of postnatal
corticosteroid therapy for prevention or treatment of
CLD in preterm infants that reported rates of both mor-
tality and CP were reviewed and their data were synthe-
sized. Twenty studies with data on 1721 randomized
infants met eligibility criteria. The relationship between
the corticosteroid effect on the combined outcome, death
or CP, and the risk for CLD in control groups was ana-
lyzed by weighted meta-regression.
Results. Among all infants who were randomized, a
significantly higher rate of CP after corticosteroid treat-
ment (typical risk difference [RD]: 0.05; 95% confidence
interval [CI]: 0.02, 0.08) was partly offset by a nonsignif-
icant reduction in mortality (typical RD: ⴚ0.02; 95% CI:
ⴚ0.06 to 0.02). Consequently, there was no significant
effect of corticosteroid treatment on the combined rate of
mortality or CP (typical RD: 0.03; 95% CI: ⴚ0.01 to 0.08).
However, on meta-regression, there was a significant
negative relationship between the treatment effect on
death or CP and the risk for CLD in control groups. With
risks for CLD below 35%, corticosteroid treatment signif-
icantly increased the chance of death or CP, whereas with
risks for CLD exceeding 65%, it reduced this chance.
Conclusions. The effect of postnatal corticosteroids
on the combined outcome of death or CP varies with the
level of risk for CLD. Pediatrics 2005;115:655–661; infant,
preterm, survival, cerebral palsy, corticosteroids.
From the *Division of Paediatrics, Royal Women’s Hospital, Melbourne,
Australia; ‡Departments of Obstetrics and Gynaecology and of Paediatrics,
University of Melbourne, Melbourne, Australia; §Department of Child
Health, Queen’s University, Belfast, Northern Ireland; 㛳Department of Pe-
diatrics, Yale University School of Medicine, New Haven, Connecticut;
¶Department of Pediatrics, McMaster University, Hamilton, Ontario, Can-
ada; and #Department of Pediatrics, Center for Clinical Research and Evi-
dence-Based Medicine, University of Texas Medical School, Houston, Texas.
Accepted for publication Aug 5, 2004.
doi:10.1542/peds.2004-1238
No conflict of interest declared.
Reprint requests to (L.W.D.) Department of Obstetrics and Gynaecology,
Royal Women’s Hospital, 132 Grattan St, Carlton 3053, Australia. E-mail:
lwd@unimelb.edu.au
PEDIATRICS (ISSN 0031 4005). Copyright © 2005 by the American Acad-
emy of Pediatrics.
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ABBREVIATIONS. CLD, chronic lung disease; CP, cerebral palsy;
RCT, randomized, controlled trial; RR, relative risk; RD, risk dif-
ference; CI, confidence interval; IQR, interquartile range.
I
mproved survival of preterm infants has been
accompanied by an increased rate of chronic lung
disease (CLD),1 most often defined as a depen-
dence on supplemental oxygen beyond 36 weeks’
postmenstrual age. From the mid-1980s, postnatal
corticosteroids were increasingly prescribed for pre-
vention or treatment of CLD, supported by evidence
of benefit on some short-term outcomes, including
earlier weaning from mechanical ventilation and a
reduction in CLD.2–4 In the era before postnatal cor-
ticosteroid treatment, the long-term neurodevelop-
mental outcome for survivors with CLD was worse
than that in similar infants without CLD.5,6 There-
fore, a reduction in CLD might be expected to reduce
the rate of adverse long-term sequelae. However,
corticosteroids can have direct toxic effects on the
developing brain, including neuronal necrosis, inter-
ference with healing, and inhibition of brain
growth.7,8 There is currently concern about possible
adverse long-term effects of postnatal corticoste-
roids, cerebral palsy (CP) having been reported to
occur more frequently in some randomized, con-
trolled trials (RCTs)9–11 and meta-analyses of
RCTs.2,12 Recently, the European Association of Peri-
natal Medicine issued a warning about postnatal
corticosteroids,13 and the American Academy of Pe-
diatrics and the Canadian Pediatric Society stated
that routine postnatal use of systemic dexametha-
sone (the most commonly prescribed corticosteroid)
for prevention or treatment of CLD is not recom-
mended.14
Clinicians currently have a dilemma when faced
with an infant who is increasingly ventilator depen-
dent: should they start corticosteroids in an attempt
to reduce ventilator and oxygen dependence and
possibly to improve long-term outcome, or should
they avoid corticosteroids because they may be in-
dependently harmful? Interpreting the RCTs of post-
natal corticosteroids is difficult as there are differ-
ences in the baseline risks for CLD, the timing and
the dose of corticosteroids according to the protocol,
and the rate of open-label corticosteroids given to
infants in the placebo group (the “contamination”
rate). The follow-up data also differ regarding the
age of children at follow-up, the follow-up rate, and
PEDIATRICS Vol. 115 No. 3 March 2005 655
the expertise of the personnel involved in the fol-
low-up assessments. Early death and CP among sur-
vivors are competing outcomes, and both must be
considered when evaluating the effect of corticoste-
roid treatment. The aims of this report were to syn-
thesize the data concerning mortality and CP from
all RCTs of postnatal systemic corticosteroids for
treatment or prevention of CLD in preterm infants
and to test the hypothesis that the effect of cortico-
steroids is modified by the level of risk for CLD.
METHODS
The literature was searched for all RCTs of postnatal cortico-
steroids, and additional unpublished data were sought from au-
thors of all known RCTs.2–4 The Medline search, updated through
May 2004, used the terms “adrenal cortex hormones” or “dexa-
methasone” or “betamethasone” or “hydrocortisone” or “ste-
roids” or “corticosteroids”; limits “randomized controlled trials,”
“human,” and “all infant: birth to 23 months.” Studies of only
inhaled steroids were excluded. All RCTs of postnatal corticoste-
roid treatment versus no treatment for prevention or treatment of
CLD in preterm infants that reported mortality and the long-term
outcome of CP were included. When there was ⬎1 report of
long-term outcomes from 1 RCT, we used data from the report
with outcomes described at the latest age of the study subjects. We
sought data on the rate of CLD in the control group (defined as
requiring oxygen therapy at 36 weeks’ postmenstrual age), the
contamination rate (percentage of control group ultimately given
corticosteroids), the dose of corticosteroids according to the pro-
tocol (in mg/kg dexamethasone equivalent), the age of the infants
when corticosteroids were started (first week ⫽ early; after first
week ⫽ later), the age of children at follow-up (in months),
whether they were assessed by experts who were blinded to
treatment group allocation, and the follow-up rate of survivors
(%). Descriptions in the RCTs of the types of participants, inter-
ventions, short-term outcome measures, study design, and valid-
ity assessment of the studies have already been reported.2–4
Data were analyzed in RevMan 4.2.2, with the endpoints being
mortality before follow-up; CP; and, to allow for the competing
risks of death and long-term morbidity, the combination of CP or
death. The measures of treatment effect for individual trials in-
cluded relative risk (RR); risk difference (RD); and, for the meta-
analyses the typical RR and typical RD, all with their 95% confi-
dence intervals (CIs). A fixed-effects model was assumed for
meta-analysis, with significant statistical heterogeneity defined as
P ⬍ .05. In addition to examining the effect of corticosteroids on
death and CP in all of the trials taken together, we conducted
subgroup analyses that were based on the postnatal age of starting
corticosteroids (early and later) and on the contamination rate (no
contamination, ⬎0% to ⬍35% contamination, and ⱖ35% contam-
ination).
We examined the relationship between the corticosteroid effect
on the combined outcome, death or CP, and the risk for CLD
(indicated by the rate of CLD in the control group) by weighted
meta-regression analysis in Stata (version 7.0)15 to test the hypoth-
esis that the treatment effect on survival free of CP would be less
favorable in trials that were conducted in populations at low risk
for CLD and more favorable in trials that were conducted in
populations at high risk for CLD. Meta-regression fits models with
2 additive components of variance, one representing the variance
within studies, the other the variance between studies. Variance
within studies is related to sample size, and larger studies con-
tribute more to the overall results. We then adjusted for other
important study design variables, including timing (early versus
later) and total dose (ⱖ3.0 mg/kg, ⬍3.0 mg/kg) of corticosteroids,
the contamination rate (⬍35%, ⱖ35%), the follow-up rate (ⱖ90%,
⬍90%), assessment by blinded experts (yes, no), and age of fol-
low-up (ⱖ36 months, ⬍36 months). These cutpoints were chosen
either to be around the median (dose, contamination rate, and age
of follow-up) or because they represented desirable features of
follow-up studies (follow-up rate and outcome assessment). We
then repeated the meta-regression analyses to examine the rela-
tionship between the rate of CLD in the control group and the
corticosteroid effect on death and CP separately, without adjust-
656 POSTNATAL CORTICOSTEROIDS AND CEREBRAL PALSY
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ing for the other study variables. For all analyses, P ⬍ 0.05 was
considered statistically significant.
RESULTS
Description of Studies
Thirty-six RCTs of systemic postnatal corticoste-
roid therapy enrolling 4269 infants for whom mor-
tality data were reported were reviewed. Of these, 20
studies enrolling 2064 infants assessed effect on CP
either in which the data were published9–11,16–39 or
in which unpublished follow-up data were ob-
tained by personal communication with authors.40–45
Among 6 published follow-up studies, additional
details were clarified by the authors.10,11,18,20,24,28,36
In 3 multicenter studies, follow-up data were avail-
able for infants who were randomized from only 1 of
the study sites23,44,45; hence, there were potentially
1721 randomized infants with follow-up data. In
the 1721 infants randomized, there were 433 deaths
before follow-up, 1151 (89%) of 1288 of survivors
were examined, and there were 220 diagnoses of
CP. Of the 20 studies with follow-up data, in 14, data
on the rate of CLD in the control group were
obtained.11,18,24,25,28,30,32,34,37,38,42–45 In the 6 studies
without data on CLD,16,19,21,36,40,41 the corticosteroids
were started beyond the first week of life in all but 1
study.16
Clinical characteristics of the studies varied widely
(Table 1). In 9 studies, therapy started in the first
week of life, and in 11, therapy started after the first
week of life. The median cumulative dose of steroids
(in mg/kg dexamethasone equivalent) according to
the protocol was 3.0 (interquartile range [IQR]: 1.1–
5.0), the median contamination rate (available for 17
studies only) was 33% (IQR: 16%– 49%), and the me-
dian control group rate of CLD at 36 weeks’ post-
menstrual age in the 14 studies that reported this
outcome was 50% (IQR: 28%– 69%). Follow-up
method also varied widely (Table 1); the median age
at assessment was 36 months (IQR: 19 –58 months);
the follow-up rate was at least 90% in 70% (n ⫽ 14) of
studies; and in 70% (n ⫽ 14) of studies, children were
assessed by experts who were blinded to treatment
allocation.
The numbers of infants who were randomized,
infants who died, survivors assessed, and survivors
with CP are shown in Table 2. Most studies had
small sample sizes (median: 43), and only 5 studies
with available long-term follow-up data randomized
⬎100 infants.
Effect on Death and CP: All Trials, Early Treatment
and Later Treatment Subgroups
There was no significant effect of corticosteroid
treatment on death before latest follow-up in any
individual study or in the meta-analyses, whether
those were based on all trials or on either the early
treatment or later treatment subgroups of trials (Ta-
ble 3). There was no evidence of benefit of cortico-
steroid treatment on the incidence of CP (Table 3).
Instead, a significantly higher rate of CP among chil-
dren who had been randomized to corticosteroid
treatment was found in 2 individual trials,10,11 in the
meta-analysis of all trials (in which the typical abso-
TABLE 1. Description of Studies That Assessed Effect of Postnatal Corticosteroids on CP
Study Postnatal Age Steroid Dose,* Contamination CLD (Control) Age at Follow-up Assessed
(First Author) at Start of mg/kg Rate,† % at 36 Weeks, % Follow-up, mo Rate, % by Blinded
Treatment, d Experts
Baden16,17 1 1.0 NS NS 12‡ 93 Yes
Ariagno40 21 4.0 17.6 NS 12–36‡ 96 NS
Cummings18 13–15 8.0 0 72.7 15 or 48‡ 100 Yes
Harkavy41 30 5.0 25.0 NS 5–24‡ 32 Yes
CDTG19,20 21 4.2 43.0 NS 36 94 No
Ohlsson21,22 21–35 5.6 46.2 NS 18 96 NS
Kari23,24 10 3.5 33.3 50.0 60 100 NS
Sanders42 ⬍1 1.0 14.3 23.8 Mean 62 100 Yes
Brozanski25,26 7 1.5 NS 59.0 12‡ 68 NS
Shinwell11,27 ⬍1 1.5 25.9 9.5 Mean 53 83 Yes
Subhedar28,29 4 4.5 41.7§ 61.9 30‡ 95 Yes
Yeh30,31 1 6.2 11.4 28.5 98 92 Yes
Vincer36 28 2.4 NS NS 24‡ 100 Yes
Kovacs43 7 1.5 60.0 46.7 Up to 90 70 NS
Romagnoli32,33 3 2.4 52.0 68.0 34–42‡ 100 Yes
Watterberg44 ⬍2 0.4 75.0§ 50.0¶ 11‡ 86# Yes
Romagnoli34,35 10 4.9 33.3 73.3 36–42‡ 100 Yes
Kothadia37,10 15–25 7.8 0 73.8 12 and 60‡ 98 Yes
Sinkin45 ⬍1 1.0 36.9 24.6¶ 12‡ 100# Yes
Stark38,39 1 0.9 51.4 45.0 18–22‡ 87 Yes
First reference reports original RCT; second reference reports follow-up (if different). CDTG indicates Collaborative Dexamethasone Trial
Group; NS, not specified.
* Cumulative dose in dexamethasone equivalent.
† Contamination rate refers to percentage of control group treated with open-label steroids.
‡ Age corrected for prematurity.
§ Not stated in original study in controls randomized, data from follow-up report.
¶ Rate of CLD in whole multicenter study: follow-up data from one center only.
# Follow-up rate in 1 center of multicenter study.

TABLE 2. Frequency of Death, Follow-up Assessment, and CP in Individual Studies

Study Randomized, n Death Before Survivors CP, n
Follow-up, n Assessed, n
CS Controls CS Controls CS Controls CS Controls
Treatment started early
(first week of life)
Baden16,17 22 22 8 9 13 12 2 1
Sanders42 19 21 2 7 17 14 3 1
Shinwell27,11 132 116 31 27 79 80 38* 12*
Subhedar28,29 21 21 11 9 10 11 0 2
Yeh30,31 132 130 53 50 72 74 17 9
Romagnoli32,33 25 25 2 3 23 22 2 3
Watterberg44 13† (20) 13† (20) 3 2 10 8 1 2
Sinkin45 32† (189) 27† (195) 11 7 21 20 4 1
Stark38,39 111 109 26 30 76 67 11 12
Treatment started later
(after first week of life)
Ariagno40 17 17 5 5 11 12 1 3
Cummings18 25 11 7 6 18 5 5 2
Harkavy41 9 12 1 2 3 3 1 2
CDTG19,20 143 142 33 29 100 109 20 18
Kari23,24 11† (17) 12† (24) 1 2 10 10 3 2
Ohlsson21,22 12 13 1 0 11 13 1 3
Brozanski25,26 39 39 4 9 25 19 5 4
Vincer36 11 9 2 1 9 8 4 2
Kovacs43 30 30 8 5 15 18 1 1
Romagnoli34,35 15 15 0 0 15 15 2 3
Kothadia37,10 57 61 7 16 48 45 12* 4*
First reference reports original RCT; second reference reports follow-up (if different). CS indicates corticosteroids.
* Individual studies with statistically significant differences in rates between steroid and control groups in this variable (see text).
† Number randomized in the 1 center of multicenter study reporting follow-up data, with number in parentheses indicating total
randomized in complete study.

lute risk increase was 5% [95% CI: 2% to 8%]), and in
the early treatment subgroup of trials. For the com-
bined outcome, death before follow-up or CP, the
meta-analyses found no significant benefit of postna-
tal corticosteroid treatment. In 1 trial,11 there was a
significant increase in the combined outcome death
or CP in the corticosteroid group. In all studies com-
bined and in the early treatment subgroup, there was
a nonsignificant increase in the combined outcome
death or CP associated with corticosteroid treatment.

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TABLE 3. Effects on Death and CP: Results of Meta-analyses
No. of Steroids, % Controls, % RR* RD†
Studies (n/N) (n/N) (95% CI) (95% CI)
Death before follow-up among
all randomized in trials
assessing CP
All trials 20 24.7 (216/876) 25.9 (219/845) 0.94 (0.80–1.10) ⫺0.02 (⫺0.06 to 0.02)
Early treatment 9 29.0 (147/507) 29.8 (144/484) 0.98 (0.81–1.18) ⫺0.01 (⫺0.06 to 0.05)
Later treatment 11 18.7 (69/369) 20.8 (75/361) 0.87 (0.65–1.16) ⫺0.03 (⫺0.09 to 0.03)
CP among all randomized
All trials 20 15.2 (133/876) 10.3 (87/845) 1.45 (1.13–1.87) 0.05 (0.02 to 0.08)
Early treatment 9 15.4 (78/507) 8.9 (43/484) 1.70 (1.20–2.42) 0.06 (0.02 to 0.10)‡
Later treatment 11 14.9 (55/369) 12.2 (44/361) 1.20 (0.83–1.74) 0.02 (⫺0.02 to 0.07)
Death or CP among all
randomized
All trials 20 39.8 (349/876) 36.2 (306/845) 1.09 (0.96–1.22) 0.03 (⫺0.01 to 0.08)
Early treatment 9 44.4 (225/507) 38.6 (187/484) 1.15 (0.99–1.33) 0.06 (0.00 to 0.12)
Later treatment 11 33.6 (124/369) 33.0 (119/361) 0.99 (0.81–1.21) 0.00 (⫺0.07 to 0.06)
CP among survivors assessed
All trials 20 22.7 (133/586) 15.4 (87/565) 1.46 (1.14–1.86) 0.07 (0.03 to 0.12)§
Early treatment 9 24.3 (78/321) 14.0 (43/308) 1.75 (1.25–2.44) 0.11 (0.05 to 0.17)储
Later treatment 11 20.8 (55/265) 17.1 (44/257) 1.16 (0.81–1.66) 0.03 (⫺0.04 to 0.09)
* Typical RR: value ⬍1 favors steroid group; value ⬎1 favors controls.
† Typical RD: negative value favors steroid group; positive value favors controls. Where 95% CI excludes 1 for RR or excludes 0 for RD,
P ⬍ .05.
Statistically significant heterogeneity of treatment effect with fixed effects model: ‡ P ⫽ .03; § P ⫽ .01; 储P ⫽ .001.

For CP among survivors examined, 1 trial11 found a
significant increase in CP in the corticosteroid group.
Corticosteroid treatment was associated with a sig-
nificant increase in CP among survivors examined in
the meta-analysis of all trials and in the early treat-
ment subgroup.
Subgroups by Contamination Rate
In 2 studies,10,18 which randomized 154 infants,
there was no contamination. Combining the results
from these 2 studies, there was a significant reduc-
tion in mortality (typical RD: ⫺0.17; 95% CI: ⫺0.30 to
⫺0.03; P ⫽ .02), a significant increase in CP among all
randomized (typical RD: 0.12; 95% CI: 0.01 to 0.23; P
⫽ .04), and no significant effect on the combined
outcome of death or CP (typical RD: ⫺0.05; 95% CI:
⫺0.20 to 0.10; P ⫽ .55).
In the subgroup analysis that was restricted to the
studies that had a contamination rate from ⬎0% to
⬍35% (7 studies, 658 infants), there was no signifi-
cant effect on mortality (typical RD: ⫺0.01; 95% CI:
⫺0.08 to 0.06; P ⫽ .75), a significant increase in CP
among all randomized (typical RD: 0.09; 95% CI: 0.04
to 0.14; P ⬍ .001), and a significant increase in the
combined outcome of death or CP (typical RD: 0.08;
95% CI: 0.01 to 0.16; P ⫽ .03). In the subgroup anal-
ysis that was restricted to studies that had a contam-
ination rate ⱖ35% (8 studies, 767 infants), there was
no significant effect on either mortality (typical RD:
0.02; 95% CI: ⫺0.04 to 0.08; P ⫽ .50) or CP among all
randomized (typical RD: ⫺0.01; 95% CI: ⫺0.05 to
0.04; P ⫽ .76) or the combined outcome of death or
CP (typical RD: 0.01; 95% CI: ⫺0.05 to 0.08; P ⫽ .69).
Meta-Regression Analysis: Relation of Treatment Effect
to Control Risk for CLD
Fourteen studies reported the rate of CLD at 36
weeks’ postmenstrual age in the control group; this
ranged from 9.5% to 73.8% (Table 1). Meta-analysis
of these 14 studies found no significant effect on the
combined rate of death or CP among children who
were randomized (typical RD: 0.04; 95% CI: ⫺0.02 to
0.09). However, there was a significant negative re-
lationship between the RD for death or CP and the
rate of CLD in the control group in these studies (Fig
1): for every 10% that the rate of CLD increased in the
control group, the RD for death or CP fell by 3.8%
(95% CI: 1.4% to 6.2%; P ⫽ .002). The regression line
crossed 0 (no effect on death or CP) at a rate of CLD
of ⬃50%. At control rates of CLD below ⬃35%, the
lower bound of the 95% CI for the regression line
was ⬎0, indicating a significantly increased rate of
death or CP with corticosteroid treatment. At control
rates of CLD above ⬃65%, the upper bound of the
95% CI for the regression line was ⬍0, indicating a
significant treatment benefit for this outcome.
None of the potential confounders (time of starting
treatment, dose, contamination, follow-up rate, age
at follow-up, and assessment by experts), either in-
dividually or in combination, significantly affected
the relationship between the corticosteroid effect on
death or CP and the control risk for CLD. In an
adjusted weighted meta-regression based on 13 stud-
ies for which the required data were available, after
simultaneously adjusting for each of the candidate
confounding variables, a statistically significant rela-
tionship persisted between the corticosteroid treat-
ment effect on the combined rate of death or CP and
the control rate of CLD. Indeed, in the adjusted meta-
regression, the absolute size of the regression coeffi-
cient was increased, although the CIs were wider: for
every 10% that the rate of CLD increased in the
control group, the RD for death or CP fell by 9.1%
(95% CI: 1.0% to 17.2%; P ⫽ .028).
Meta-regression of RD for death alone against the
rate of CLD in the control group showed a nonsig-
nificant negative relationship (Y ⫽ 3.7 ⫺ 0.17X; P ⫽
.11). For every 10% increase in the rate of CLD in the

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Fig 1. RD (%) for death or CP among all participants versus rate
of CLD (%) in the control group. Each study is shown by a circle
whose area is proportional to that study’s weight. The control
rates for CLD in the individual studies are given in Table 1,
column 5. Regression line and its 95% CI are shown. Regression
equation: Y ⫽ 18.7 ⫺ 0.38X; P ⫽ .002. CS, corticosteroids.
control group, the RD for death fell by 1.7% (95% CI:
⫺0.4% to 3.9%). Meta-regression of RD for CP alone
against the rate of CLD in the control group showed
a significant negative relationship (Y ⫽ 14.1 ⫺0.23X;
P ⫽ .023). For every 10% that the rate of CLD in-
creased in the control group, the RD for CP fell by
2.3% (95% CI: 0.3% to 4.3%)
DISCUSSION
Corticosteroid therapy was initially introduced in
chronically ventilator-dependent infants with the
hope of saving lives and possibly improving long-
term neurodevelopmental outcome if the severity
and duration of CLD could be reduced. As early
reports of short-term benefits appeared, there was an
increasing tendency to start corticosteroid treatment
on infants who were less critically ill and earlier in
their nursery stay. This tendency has been tempered
considerably with reports of an increase in CP
among survivors. However, it is possible that corti-
costeroids are now being withheld in some infants
who might benefit. There may be a point, defined by
the chance of developing CLD, below which the risks
of corticosteroid treatment on long-term outcome
outweigh the benefits and above which the benefits
outweigh the risks.
The 20 studies included in this review were all
randomized trials. Although all studies reported ef-
fects on some long-term outcomes, none was de-
signed primarily to assess long-term effects of treat-
ment. We attempted to obtain as complete a data set
as possible by contacting the investigators and re-
questing any unpublished data concerning long-
term outcomes. In the included studies, children
were assessed mostly early in childhood, before the
diagnosis of CP can be certain,46 not always by ex-
perts who were blinded to treatment group, not al-
ways using explicit and reproducible criteria for the
diagnosis of CP, and sometimes with potentially im-
portant (⬎10%) loss to follow-up.
Corticosteroids that are given after birth to pre-
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term infants with lung disease have proved short-
term benefits, including reductions in ventilator and
oxygen dependence and in incidence of CLD.2–4
These short-term benefits might be expected to lead
to a reduction in adverse neurodevelopmental out-
comes associated with CLD in preterm infants. How-
ever, among all trials, we found no evidence of ben-
efit of postnatal corticosteroid treatment on the rate
of CP, regardless of whether the competing risk for
death before follow-up was taken into account. In
fact, the direction of effects was generally that of
harm, reaching statistical significance for CP among
all randomized and among survivors examined.
The subgroup analyses that were based on con-
tamination rates of control groups in the various
trials support the interpretation of a causal relation-
ship, overall, between postnatal corticosteroid treat-
ment and CP, in that this relationship was stronger in
the trials with no or less contamination and weaker
or nonexistent in the trials with high rates of contam-
ination. In trials with low or no contamination, there
was a tendency for corticosteroid treatment to reduce
mortality. This pattern suggests that, overall, postna-
tal corticosteroid treatment, although maybe reduc-
ing mortality, causes CP in survivors.
Corticosteroid treatment was associated with a sig-
nificant increase in CP in the early treatment but not
the later treatment subgroup; however, even in the
later treatment subgroup, there was no trend toward
benefit. Given that preterm infants are more unstable
in the first days after birth, when events such as
cerebrovascular hemorrhage are prone to occur, it is
possible that any adverse effects of corticosteroids
might be exacerbated at that time and that the
marked adverse effects noted in the early treatment
subgroup could be attributed to postnatal age per se.
However, the result of the meta-regression shown
in Fig 1 suggests an alternative explanation for the
adverse effects observed in the early treatment trials.
Postnatal corticosteroids in the doses used might not
only have had direct toxic effects on the developing
brain7,8 but also an indirect benefit to the brain by
improving lung function. The early treatment trials
enrolled infants who were generally at lower risk for
CLD. Thus, infants who were treated early might
have experienced net harm because they had less to
gain in terms of the indirect benefit, but all were
exposed to the direct harmful effects of corticosteroid
treatment. The significant negative association be-
tween treatment effect on death or CP and risk for
CLD supports this interpretation. None of the poten-
tial confounding variables was significantly related
to the corticosteroid effect on the combined outcome
of death or CP. Moreover, adjustment for these vari-
ables, including the time of starting treatment, did
not eliminate the statistically significant negative re-
lationship between the risk for CLD in controls and
the effect on the rate of death or CP.
We recognize that there are limitations of our
meta-regression analysis to explore effect modifica-
tion arising from risk for CLD. First, the analysis was
limited to a subset of studies (14 of 20) in which the
control rate of CLD was reported. Second, in taking
the control rate of CLD as a measure of control risk,
ARTICLES 659
we used data that were unavailable at trial entry.
Future application of these results in identifying suit-
able candidates for corticosteroid treatment would
require accurate prediction of CLD in at-risk popu-
lations. Third, we did not have access to individual
patient data, which would allow more sensitive anal-
ysis of the relations between risk factors known at
baseline, subsequent development of CLD, and cor-
ticosteroid effect on death or CP. Fourth, the list of
potential confounding variables that we examined
was limited by the data available and does not in-
clude other possible confounders, such as differences
between studies in mechanical ventilation strategies
used.
The main focus of our study was on CP because
this is the outcome that has been most controversial.
We have also taken into account the competing out-
come of death. Data on the effects of steroids on
other neurologic outcomes are also important but are
much more limited and are discussed in the existing
Cochrane reviews.2–4 There were too few studies that
reported both the effects of corticosteroids on neuro-
logic outcomes other than CP and the rate of CLD in
the control group to allow us to examine those asso-
ciations in meta-regression analyses.
Future research should be directed toward trying
to prevent CLD and hence the need for corticoste-
roids, to more accurate early prediction of CLD47 to
allow targeting of any postnatal corticosteroids to
those most likely to experience long-term benefit,
and to determination of the lowest dose of cortico-
steroid that is effective in reducing ventilator and
oxygen dependence and the incidence and severity
of CLD, without causing long-term harm. The anal-
yses reported here support future randomized trials
of postnatal corticosteroids specifically in preterm
infants who are accurately predicted to be at high
risk for CLD, with effects on neurodevelopment and
mortality as primary outcomes.
ACKNOWLEDGMENTS
This study was supported in part by Project Grant No. 108700
from the National Health and Medical Research Council
(NHMRC) of Australia and Contract N01-HD-6-3252 from the
National Institute of Child Health and Human Development. Pe-
ter Davis is supported in part by a Practitioner Fellowship from
the NHMRC.
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Impact of Postnatal Systemic Corticosteroids on Mortality and Cerebral Palsy in
Preterm Infants: Effect Modification by Risk for Chronic Lung Disease
Lex W. Doyle, Henry L. Halliday, Richard A. Ehrenkranz, Peter G. Davis and John C.
Sinclair
Pediatrics 2005;115;655-661
DOI: 10.1542/peds.2004-1238
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