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 ABBREVIATIONS. CLD, chronic lung disease; CP, cerebral palsy;
lung disease (CLD) is associated with an increased risk RCT, randomized, controlled trial; RR, relative risk; RD, risk dif-
for cerebral palsy (CP). However, systemic postnatal cor- ference; CI, confidence interval; IQR, interquartile range.
ticosteroid therapy to prevent or treat CLD, although
effective in improving lung function, may cause CP. The

I
objective of this study was to determine the effect of mproved survival of preterm infants has been
systemic postnatal corticosteroid treatment on death and accompanied by an increased rate of chronic lung
CP and to assess any modification of effect arising from disease (CLD),1 most often defined as a depen-
risk for CLD. dence on supplemental oxygen beyond 36 weeks’
Methods. Randomized, controlled trials of postnatal postmenstrual age. From the mid-1980s, postnatal
corticosteroid therapy for prevention or treatment of corticosteroids were increasingly prescribed for pre-
CLD in preterm infants that reported rates of both mor- vention or treatment of CLD, supported by evidence
tality and CP were reviewed and their data were synthe- of benefit on some short-term outcomes, including
sized. Twenty studies with data on 1721 randomized earlier weaning from mechanical ventilation and a
infants met eligibility criteria. The relationship between reduction in CLD.2–4 In the era before postnatal cor-
the corticosteroid effect on the combined outcome, death ticosteroid treatment, the long-term neurodevelop-
or CP, and the risk for CLD in control groups was ana- mental outcome for survivors with CLD was worse
lyzed by weighted meta-regression.
than that in similar infants without CLD.5,6 There-
Results. Among all infants who were randomized, a
significantly higher rate of CP after corticosteroid treat-
fore, a reduction in CLD might be expected to reduce
ment (typical risk difference [RD]: 0.05; 95% confidence the rate of adverse long-term sequelae. However,
interval [CI]: 0.02, 0.08) was partly offset by a nonsignif- corticosteroids can have direct toxic effects on the
icant reduction in mortality (typical RD: ⴚ0.02; 95% CI: developing brain, including neuronal necrosis, inter-
ⴚ0.06 to 0.02). Consequently, there was no significant ference with healing, and inhibition of brain
effect of corticosteroid treatment on the combined rate of growth.7,8 There is currently concern about possible
mortality or CP (typical RD: 0.03; 95% CI: ⴚ0.01 to 0.08). adverse long-term effects of postnatal corticoste-
However, on meta-regression, there was a significant roids, cerebral palsy (CP) having been reported to
negative relationship between the treatment effect on occur more frequently in some randomized, con-
death or CP and the risk for CLD in control groups. With trolled trials (RCTs)9–11 and meta-analyses of
risks for CLD below 35%, corticosteroid treatment signif- RCTs.2,12 Recently, the European Association of Peri-
icantly increased the chance of death or CP, whereas with natal Medicine issued a warning about postnatal
risks for CLD exceeding 65%, it reduced this chance. corticosteroids,13 and the American Academy of Pe-
Conclusions. The effect of postnatal corticosteroids diatrics and the Canadian Pediatric Society stated
on the combined outcome of death or CP varies with the
that routine postnatal use of systemic dexametha-
level of risk for CLD. Pediatrics 2005;115:655–661; infant,
preterm, survival, cerebral palsy, corticosteroids.
sone (the most commonly prescribed corticosteroid)
for prevention or treatment of CLD is not recom-
mended.14
Clinicians currently have a dilemma when faced
From the *Division of Paediatrics, Royal Women’s Hospital, Melbourne, with an infant who is increasingly ventilator depen-
Australia; ‡Departments of Obstetrics and Gynaecology and of Paediatrics,
University of Melbourne, Melbourne, Australia; §Department of Child
dent: should they start corticosteroids in an attempt
Health, Queen’s University, Belfast, Northern Ireland; 㛳Department of Pe- to reduce ventilator and oxygen dependence and
diatrics, Yale University School of Medicine, New Haven, Connecticut; possibly to improve long-term outcome, or should
¶Department of Pediatrics, McMaster University, Hamilton, Ontario, Can- they avoid corticosteroids because they may be in-
ada; and #Department of Pediatrics, Center for Clinical Research and Evi-
dependently harmful? Interpreting the RCTs of post-
dence-Based Medicine, University of Texas Medical School, Houston, Texas.
Accepted for publication Aug 5, 2004. natal corticosteroids is difficult as there are differ-
doi:10.1542/peds.2004-1238 ences in the baseline risks for CLD, the timing and
No conflict of interest declared. the dose of corticosteroids according to the protocol,
Reprint requests to (L.W.D.) Department of Obstetrics and Gynaecology, and the rate of open-label corticosteroids given to
Royal Women’s Hospital, 132 Grattan St, Carlton 3053, Australia. E-mail:
lwd@unimelb.edu.au
infants in the placebo group (the “contamination”
PEDIATRICS (ISSN 0031 4005). Copyright © 2005 by the American Acad- rate). The follow-up data also differ regarding the
emy of Pediatrics. age of children at follow-up, the follow-up rate, and

PEDIATRICS Vol. 115 No. 3 March 2005 655

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the expertise of the personnel involved in the fol- ing for the other study variables. For all analyses, P ⬍ 0.05 was
low-up assessments. Early death and CP among sur- considered statistically significant.
vivors are competing outcomes, and both must be
RESULTS
considered when evaluating the effect of corticoste-
roid treatment. The aims of this report were to syn- Description of Studies
thesize the data concerning mortality and CP from Thirty-six RCTs of systemic postnatal corticoste-
all RCTs of postnatal systemic corticosteroids for roid therapy enrolling 4269 infants for whom mor-
treatment or prevention of CLD in preterm infants tality data were reported were reviewed. Of these, 20
and to test the hypothesis that the effect of cortico- studies enrolling 2064 infants assessed effect on CP
steroids is modified by the level of risk for CLD. 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
METHODS Among 6 published follow-up studies, additional
The literature was searched for all RCTs of postnatal cortico- details were clarified by the authors.10,11,18,20,24,28,36
steroids, and additional unpublished data were sought from au- In 3 multicenter studies, follow-up data were avail-
thors of all known RCTs.2–4 The Medline search, updated through
May 2004, used the terms “adrenal cortex hormones” or “dexa- able for infants who were randomized from only 1 of
methasone” or “betamethasone” or “hydrocortisone” or “ste- the study sites23,44,45; hence, there were potentially
roids” or “corticosteroids”; limits “randomized controlled trials,” 1721 randomized infants with follow-up data. In
“human,” and “all infant: birth to 23 months.” Studies of only the 1721 infants randomized, there were 433 deaths
inhaled steroids were excluded. All RCTs of postnatal corticoste-
roid treatment versus no treatment for prevention or treatment of
before follow-up, 1151 (89%) of 1288 of survivors
CLD in preterm infants that reported mortality and the long-term were examined, and there were 220 diagnoses of
outcome of CP were included. When there was ⬎1 report of CP. Of the 20 studies with follow-up data, in 14, data
long-term outcomes from 1 RCT, we used data from the report on the rate of CLD in the control group were
with outcomes described at the latest age of the study subjects. We obtained.11,18,24,25,28,30,32,34,37,38,42–45 In the 6 studies
sought data on the rate of CLD in the control group (defined as
requiring oxygen therapy at 36 weeks’ postmenstrual age), the without data on CLD,16,19,21,36,40,41 the corticosteroids
contamination rate (percentage of control group ultimately given were started beyond the first week of life in all but 1
corticosteroids), the dose of corticosteroids according to the pro- study.16
tocol (in mg/kg dexamethasone equivalent), the age of the infants Clinical characteristics of the studies varied widely
when corticosteroids were started (first week ⫽ early; after first (Table 1). In 9 studies, therapy started in the first
week ⫽ later), the age of children at follow-up (in months),
whether they were assessed by experts who were blinded to week of life, and in 11, therapy started after the first
treatment group allocation, and the follow-up rate of survivors week of life. The median cumulative dose of steroids
(%). Descriptions in the RCTs of the types of participants, inter- (in mg/kg dexamethasone equivalent) according to
ventions, short-term outcome measures, study design, and valid- the protocol was 3.0 (interquartile range [IQR]: 1.1–
ity assessment of the studies have already been reported.2–4
Data were analyzed in RevMan 4.2.2, with the endpoints being
5.0), the median contamination rate (available for 17
mortality before follow-up; CP; and, to allow for the competing studies only) was 33% (IQR: 16%– 49%), and the me-
risks of death and long-term morbidity, the combination of CP or dian control group rate of CLD at 36 weeks’ post-
death. The measures of treatment effect for individual trials in- menstrual age in the 14 studies that reported this
cluded relative risk (RR); risk difference (RD); and, for the meta- outcome was 50% (IQR: 28%– 69%). Follow-up
analyses the typical RR and typical RD, all with their 95% confi-
dence intervals (CIs). A fixed-effects model was assumed for method also varied widely (Table 1); the median age
meta-analysis, with significant statistical heterogeneity defined as at assessment was 36 months (IQR: 19 –58 months);
P ⬍ .05. In addition to examining the effect of corticosteroids on the follow-up rate was at least 90% in 70% (n ⫽ 14) of
death and CP in all of the trials taken together, we conducted studies; and in 70% (n ⫽ 14) of studies, children were
subgroup analyses that were based on the postnatal age of starting assessed by experts who were blinded to treatment
corticosteroids (early and later) and on the contamination rate (no
contamination, ⬎0% to ⬍35% contamination, and ⱖ35% contam- allocation.
ination). The numbers of infants who were randomized,
We examined the relationship between the corticosteroid effect infants who died, survivors assessed, and survivors
on the combined outcome, death or CP, and the risk for CLD with CP are shown in Table 2. Most studies had
(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-
small sample sizes (median: 43), and only 5 studies
esis that the treatment effect on survival free of CP would be less with available long-term follow-up data randomized
favorable in trials that were conducted in populations at low risk ⬎100 infants.
for CLD and more favorable in trials that were conducted in
populations at high risk for CLD. Meta-regression fits models with Effect on Death and CP: All Trials, Early Treatment
2 additive components of variance, one representing the variance and Later Treatment Subgroups
within studies, the other the variance between studies. Variance
within studies is related to sample size, and larger studies con- There was no significant effect of corticosteroid
tribute more to the overall results. We then adjusted for other treatment on death before latest follow-up in any
important study design variables, including timing (early versus individual study or in the meta-analyses, whether
later) and total dose (ⱖ3.0 mg/kg, ⬍3.0 mg/kg) of corticosteroids,
the contamination rate (⬍35%, ⱖ35%), the follow-up rate (ⱖ90%,
those were based on all trials or on either the early
⬍90%), assessment by blinded experts (yes, no), and age of fol- treatment or later treatment subgroups of trials (Ta-
low-up (ⱖ36 months, ⬍36 months). These cutpoints were chosen ble 3). There was no evidence of benefit of cortico-
either to be around the median (dose, contamination rate, and age steroid treatment on the incidence of CP (Table 3).
of follow-up) or because they represented desirable features of Instead, a significantly higher rate of CP among chil-
follow-up studies (follow-up rate and outcome assessment). We
then repeated the meta-regression analyses to examine the rela- dren who had been randomized to corticosteroid
tionship between the rate of CLD in the control group and the treatment was found in 2 individual trials,10,11 in the
corticosteroid effect on death and CP separately, without adjust- meta-analysis of all trials (in which the typical abso-

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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 significant increase in the combined outcome death
the early treatment subgroup of trials. For the com- or CP in the corticosteroid group. In all studies com-
bined outcome, death before follow-up or CP, the bined and in the early treatment subgroup, there was
meta-analyses found no significant benefit of postna- a nonsignificant increase in the combined outcome
tal corticosteroid treatment. In 1 trial,11 there was a death or CP associated with corticosteroid treatment.

ARTICLES 657
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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 of these 14 studies found no significant effect on the
significant increase in CP in the corticosteroid group. combined rate of death or CP among children who
Corticosteroid treatment was associated with a sig- were randomized (typical RD: 0.04; 95% CI: ⫺0.02 to
nificant increase in CP among survivors examined in 0.09). However, there was a significant negative re-
the meta-analysis of all trials and in the early treat- lationship between the RD for death or CP and the
ment subgroup. rate of CLD in the control group in these studies (Fig
1): for every 10% that the rate of CLD increased in the
Subgroups by Contamination Rate control group, the RD for death or CP fell by 3.8%
In 2 studies,10,18 which randomized 154 infants, (95% CI: 1.4% to 6.2%; P ⫽ .002). The regression line
there was no contamination. Combining the results crossed 0 (no effect on death or CP) at a rate of CLD
from these 2 studies, there was a significant reduc- of ⬃50%. At control rates of CLD below ⬃35%, the
tion in mortality (typical RD: ⫺0.17; 95% CI: ⫺0.30 to lower bound of the 95% CI for the regression line
⫺0.03; P ⫽ .02), a significant increase in CP among all was ⬎0, indicating a significantly increased rate of
randomized (typical RD: 0.12; 95% CI: 0.01 to 0.23; P death or CP with corticosteroid treatment. At control
⫽ .04), and no significant effect on the combined rates of CLD above ⬃65%, the upper bound of the
outcome of death or CP (typical RD: ⫺0.05; 95% CI: 95% CI for the regression line was ⬍0, indicating a
⫺0.20 to 0.10; P ⫽ .55). significant treatment benefit for this outcome.
In the subgroup analysis that was restricted to the None of the potential confounders (time of starting
studies that had a contamination rate from ⬎0% to treatment, dose, contamination, follow-up rate, age
⬍35% (7 studies, 658 infants), there was no signifi- at follow-up, and assessment by experts), either in-
cant effect on mortality (typical RD: ⫺0.01; 95% CI: dividually or in combination, significantly affected
⫺0.08 to 0.06; P ⫽ .75), a significant increase in CP the relationship between the corticosteroid effect on
among all randomized (typical RD: 0.09; 95% CI: 0.04 death or CP and the control risk for CLD. In an
to 0.14; P ⬍ .001), and a significant increase in the adjusted weighted meta-regression based on 13 stud-
combined outcome of death or CP (typical RD: 0.08; ies for which the required data were available, after
95% CI: 0.01 to 0.16; P ⫽ .03). In the subgroup anal- simultaneously adjusting for each of the candidate
ysis that was restricted to studies that had a contam- confounding variables, a statistically significant rela-
ination rate ⱖ35% (8 studies, 767 infants), there was tionship persisted between the corticosteroid treat-
no significant effect on either mortality (typical RD: ment effect on the combined rate of death or CP and
0.02; 95% CI: ⫺0.04 to 0.08; P ⫽ .50) or CP among all the control rate of CLD. Indeed, in the adjusted meta-
randomized (typical RD: ⫺0.01; 95% CI: ⫺0.05 to regression, the absolute size of the regression coeffi-
0.04; P ⫽ .76) or the combined outcome of death or cient was increased, although the CIs were wider: for
CP (typical RD: 0.01; 95% CI: ⫺0.05 to 0.08; P ⫽ .69). every 10% that the rate of CLD increased in the
control group, the RD for death or CP fell by 9.1%
Meta-Regression Analysis: Relation of Treatment Effect (95% CI: 1.0% to 17.2%; P ⫽ .028).
to Control Risk for CLD Meta-regression of RD for death alone against the
Fourteen studies reported the rate of CLD at 36 rate of CLD in the control group showed a nonsig-
weeks’ postmenstrual age in the control group; this nificant negative relationship (Y ⫽ 3.7 ⫺ 0.17X; P ⫽
ranged from 9.5% to 73.8% (Table 1). Meta-analysis .11). For every 10% increase in the rate of CLD in the

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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-
Fig 1. RD (%) for death or CP among all participants versus rate ship, overall, between postnatal corticosteroid treat-
of CLD (%) in the control group. Each study is shown by a circle ment and CP, in that this relationship was stronger in
whose area is proportional to that study’s weight. The control the trials with no or less contamination and weaker
rates for CLD in the individual studies are given in Table 1, or nonexistent in the trials with high rates of contam-
column 5. Regression line and its 95% CI are shown. Regression
equation: Y ⫽ 18.7 ⫺ 0.38X; P ⫽ .002. CS, corticosteroids. ination. In trials with low or no contamination, there
was a tendency for corticosteroid treatment to reduce
mortality. This pattern suggests that, overall, postna-
control group, the RD for death fell by 1.7% (95% CI: tal corticosteroid treatment, although maybe reduc-
⫺0.4% to 3.9%). Meta-regression of RD for CP alone ing mortality, causes CP in survivors.
against the rate of CLD in the control group showed Corticosteroid treatment was associated with a sig-
a significant negative relationship (Y ⫽ 14.1 ⫺0.23X; nificant increase in CP in the early treatment but not
P ⫽ .023). For every 10% that the rate of CLD in- the later treatment subgroup; however, even in the
creased in the control group, the RD for CP fell by later treatment subgroup, there was no trend toward
2.3% (95% CI: 0.3% to 4.3%) benefit. Given that preterm infants are more unstable
in the first days after birth, when events such as
DISCUSSION cerebrovascular hemorrhage are prone to occur, it is
Corticosteroid therapy was initially introduced in possible that any adverse effects of corticosteroids
chronically ventilator-dependent infants with the might be exacerbated at that time and that the
hope of saving lives and possibly improving long- marked adverse effects noted in the early treatment
term neurodevelopmental outcome if the severity subgroup could be attributed to postnatal age per se.
and duration of CLD could be reduced. As early However, the result of the meta-regression shown
reports of short-term benefits appeared, there was an in Fig 1 suggests an alternative explanation for the
increasing tendency to start corticosteroid treatment adverse effects observed in the early treatment trials.
on infants who were less critically ill and earlier in Postnatal corticosteroids in the doses used might not
their nursery stay. This tendency has been tempered only have had direct toxic effects on the developing
considerably with reports of an increase in CP brain7,8 but also an indirect benefit to the brain by
among survivors. However, it is possible that corti- improving lung function. The early treatment trials
costeroids are now being withheld in some infants enrolled infants who were generally at lower risk for
who might benefit. There may be a point, defined by CLD. Thus, infants who were treated early might
the chance of developing CLD, below which the risks have experienced net harm because they had less to
of corticosteroid treatment on long-term outcome gain in terms of the indirect benefit, but all were
outweigh the benefits and above which the benefits exposed to the direct harmful effects of corticosteroid
outweigh the risks. treatment. The significant negative association be-
The 20 studies included in this review were all tween treatment effect on death or CP and risk for
randomized trials. Although all studies reported ef- CLD supports this interpretation. None of the poten-
fects on some long-term outcomes, none was de- tial confounding variables was significantly related
signed primarily to assess long-term effects of treat- to the corticosteroid effect on the combined outcome
ment. We attempted to obtain as complete a data set of death or CP. Moreover, adjustment for these vari-
as possible by contacting the investigators and re- ables, including the time of starting treatment, did
questing any unpublished data concerning long- not eliminate the statistically significant negative re-
term outcomes. In the included studies, children lationship between the risk for CLD in controls and
were assessed mostly early in childhood, before the the effect on the rate of death or CP.
diagnosis of CP can be certain,46 not always by ex- We recognize that there are limitations of our
perts who were blinded to treatment group, not al- meta-regression analysis to explore effect modifica-
ways using explicit and reproducible criteria for the tion arising from risk for CLD. First, the analysis was
diagnosis of CP, and sometimes with potentially im- limited to a subset of studies (14 of 20) in which the
portant (⬎10%) loss to follow-up. control rate of CLD was reported. Second, in taking
Corticosteroids that are given after birth to pre- the control rate of CLD as a measure of control risk,

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lations. Third, we did not have access to individual 9. Yeh TF, Lin YJ, Huang CC, et al. Early dexamethasone therapy in
patient data, which would allow more sensitive anal- preterm infants: a follow up study. Pediatrics. 1998;101(5). Available at:
www.pediatrics.org/cgi/content/full/101/5/e7
ysis of the relations between risk factors known at
10. O’Shea TM, Kothadia JM, Klinepeter KL, et al. Randomized placebo-
baseline, subsequent development of CLD, and cor- controlled trial of a 42-day tapering course of dexamethasone to reduce the
ticosteroid effect on death or CP. Fourth, the list of duration of ventilator dependency in very low birth weight infants: out-
potential confounding variables that we examined come of study participants at 1-year adjusted age. Pediatrics. 1999;104:15–21
was limited by the data available and does not in- 11. Shinwell ES, Karplus M, Reich D, et al. Early postnatal dexamethasone
treatment and increased incidence of cerebral palsy. Arch Dis Child Fetal
clude other possible confounders, such as differences
Neonatal Ed. 2000;83:F177–F181
between studies in mechanical ventilation strategies 12. Barrington KJ. The adverse neuro-developmental effects of postnatal
used. steroids in the preterm infant: a systematic review of RCTs. BMC
The main focus of our study was on CP because Pediatr. 2001;1:1
this is the outcome that has been most controversial. 13. Halliday HL. Guidelines on neonatal steroids. Prenat Neonat Med. 2001;
6:371–373
We have also taken into account the competing out-
14. American Academy of Pediatrics, Committee on Fetus and Newborn,
come of death. Data on the effects of steroids on and Canadian Paediatric Society, Fetus and Newborn Committee. Post-
other neurologic outcomes are also important but are natal corticosteroids to treat or prevent chronic lung disease in preterm
much more limited and are discussed in the existing infants. Pediatrics. 2002;109:330 –338
Cochrane reviews.2–4 There were too few studies that 15. Intercooled Stata 7.0 for Windows. College Station, TX: Stata Corp; 2000
16. Baden M, Bauer CR, Colle E, Klein G, Taeusch HW Jr, Stern L. A
reported both the effects of corticosteroids on neuro- controlled trial of hydrocortisone therapy in infants with respiratory
logic outcomes other than CP and the rate of CLD in distress syndrome. Pediatrics. 1972;50:526 –534
the control group to allow us to examine those asso- 17. Fitzhardinge PM, Eisen A, Lejtenyi C, Metrakos K, Ramsay M. Sequelae
ciations in meta-regression analyses. of early steroid administration to the newborn infant. Pediatrics. 1974;
Future research should be directed toward trying 53:877– 883
18. Cummings JJ, D’Eugenio DB, Gross SJ. A controlled trial of dexameth-
to prevent CLD and hence the need for corticoste- asone in preterm infants at high risk for bronchopulmonary dysplasia.
roids, to more accurate early prediction of CLD47 to N Engl J Med. 1989;320:1505–1510
allow targeting of any postnatal corticosteroids to 19. Collaborative Dexamethasone Trial Group. Dexamethasone therapy in
those most likely to experience long-term benefit, neonatal chronic lung disease: an international placebo-controlled trial.
and to determination of the lowest dose of cortico- Pediatrics. 1991;88:421– 427
20. Jones R, Wincott E, Elbourne D, Grant A. Controlled trial of dexameth-
steroid that is effective in reducing ventilator and asone in neonatal chronic lung disease: a 3-year follow-up. Pediatrics.
oxygen dependence and the incidence and severity 1995;96:897–906
of CLD, without causing long-term harm. The anal- 21. Ohlsson A, Calvert SA, Hosking M, Shennan AT. Randomized con-
yses reported here support future randomized trials trolled trial of dexamethasone treatment in very-low-birth-weight in-
of postnatal corticosteroids specifically in preterm fants with ventilator-dependent chronic lung disease. Acta Paediatr.
1992;81:751–756
infants who are accurately predicted to be at high 22. Ohlsson A. Randomized Controlled Trial of Dexamethasone Treatment in
risk for CLD, with effects on neurodevelopment and Very-Low-Birth-Weight Infants With Ventilator-Dependent Chronic Lung
mortality as primary outcomes. Disease. Master’s thesis. Hamilton, Ontario, Canada: McMaster
University; 1990
ACKNOWLEDGMENTS 23. Kari MA, Heinonen K, Ikonen RS, Koivisto M, Raivio KO. Dexameth-
This study was supported in part by Project Grant No. 108700 asone treatment in preterm infants at risk for bronchopulmonary dys-
from the National Health and Medical Research Council plasia. Arch Dis Child. 1993;68:566 –569
(NHMRC) of Australia and Contract N01-HD-6-3252 from the 24. Mieskonen S, Eronen M, Malmberg LP, Turpeinen M, Kari MA, Hall-
National Institute of Child Health and Human Development. Pe- man M. Controlled trial of dexamethasone in neonatal chronic lung
ter Davis is supported in part by a Practitioner Fellowship from disease: an 8-year follow-up of cardiopulmonary function and growth.
the NHMRC. Acta Paediatr. 2003;92:896 –904
25. Brozanski BS, Jones JG, Gilmour CH, et al. Effect of pulse dexametha-
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MYOPIC GLOBALIZERS

”We may now all be benefiting from the communications revolution, and some
may see progress in the fact that the Egyptian Sphinx now stares directly at the
neon sign of a Kentucky Fried Chicken franchise . . . [but] too many globalizers and
policymakers have taken an Olympian view of the globalization process . . . they
do not have the ability to comprehend, however dimly, how other people live.“

DeSoto H. The Mystery of Capital. New York, NY: Basic Books; 2000

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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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