Review
Antenatal Corticosteroid Therapy Before
24 Weeks of Gestation
A Systematic Review and Meta-analysis
Christina K. Park, MSc, Tetsuya Isayama, MD, and Sarah D. McDonald,
OBJECTIVE: To evaluate the effectiveness of antenatal
corticosteroids compared with placebo or no treatment
in neonates born before 24 weeks of gestation.
DATA SOURCES: We searched MEDLINE, EMBASE,
Cumulative Index to Nursing and Allied Health
Literature (CINAHL), and Cochrane Central Register of
Controlled Trials databases from 1990 to March 13, 2015,
and ClinicalTrials.gov.
METHODS OF STUDY SELECTION: Studies considered
were published randomized or quasirandomized con-
trolled trials and observational studies that compared
From the Departments of Clinical Epidemiology & Biostatistics, Obstetrics &
Gynecology, and Radiology, McMaster University, Hamilton, and the Neonatal
Intensive Care Unit, Sunnybrook Health Science Centre, Toronto, Ontario, Canada.
The authors thank the authors of the primary studies who provided additional data
for the meta-analyses: Drs. Abdel-Latif Mohamed and Kei Lui (New South Wales
[NSW] and the Australian Capital Territory [ACT] NICUs Group); Dr. Cüneyt
Tayman (Fatih Universitesi); Drs. David Bader and Brian Reichman (Israel Neo-
natal Network); Drs. Gustavo Rocha and Hercília Guimarães (Hospital de São
João/Faculdade de Medicina, Universidade do Porto); Dr. José Figueras-Aloy
(SEN1500 Spanish Neonatal Network); Dr. Karel Marsal (Extremely Preterm
Infants in Sweden Study [EXPRESS] group); Dr. Lilia Vakrilova (Maichin Dom
Neonatology Clinic), Drs. Matthew Laughon, Michael O’Shea (Extremely Low
Gestational Age Newborn [ELGAN] study), Elizabeth Allred, and Alan Leviton
(ELGAN study & Developmental Epidemiology Network); Dr. Reese Clark (Pe-
diatrix Medical Group); Dr. Rintaro Mori (Neonatal Research Network Japan);
and Dr. Soraya Abbasi and Mr. Emidio Sivieri (Pennsylvania Hospital, University
of Pennsylvania). The authors also thank the following individuals who have
assisted us with foreign language articles: Dr. Kari Tikkinen, Dr. Nigar Sekercio-
glu, Mr. Pavel Roshanov, Dr. Premsyl Bercik, and Ms. Sorina Stef. We value the
contribution of Ms. Neera Bhatnager, BSc, MLIS, Head of Systems, Coordinator of
Research and Graduate Education Support, Health Sciences Library, McMaster
University, for her assistance in developing the search strategies.
Corresponding author: Sarah D. McDonald, MD, MSc, Department of Obstetrics
and Gynecology, McMaster University, HSC 3N52B, 1280 Main Street, West,
Hamilton, Ontario, Canada L8S 4K1; e-mail: mcdonals@mcmaster.ca.
Financial Disclosure
Ms. Park is supported by a Canadian Institutes of Health Research (CIHR)
Training Program in Reproduction, Early Development and the Impact on
Health (TGF-96122). Dr. McDonald is supported by a CIHR Canada Research
Chair (950–229920). Dr. Isayama did not report any potential conflicts of
interest.
© 2016 by The American College of Obstetricians and Gynecologists. Published
by Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0029-7844/16
VOL. 127, NO. 4, APRIL 2016
Copyright ª by The American College of Obstetricians
and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
MD, MSc
outcomes between neonates who received or did not
receive antenatal corticosteroids born before 24 weeks
of gestation.
TABULATION, INTEGRATION, AND RESULTS: We per-
formed duplicate independent assessment of the title
and abstracts, full-text screening, inclusion of articles,
and data abstraction. We performed meta-analyses using
random-effects models and quality assessment with the
Grading of Recommendations Assessment, Develop-
ment, and Evaluation (GRADE) system. There were 17
observational studies, and our primary outcome, mor-
tality to discharge in neonates receiving active intensive
treatment, had a total of 3,626 neonates. The adjusted
odds of mortality to discharge were reduced by 52% in
the antenatal corticosteroid group compared with the
control group (crude adjusted odds ratio [OR] 0.45, 95%
confidence interval [CI] 0.36–0.56; adjusted OR 0.48, 95%
CI 0.38–0.61; mortality to discharge 58.1% [intervention]
compared with 71.8% [control]) with a “moderate” qual-
ity of evidence based on the GRADE system. There were
no significant differences between the groups for severe
morbidity.
CONCLUSION: The available data, all observational,
show reduced odds of mortality to discharge in
neonates born before 24 weeks of gestation who
received antenatal corticosteroids and active intensive
treatment. Antenatal corticosteroids should be con-
sidered for women at risk of imminent birth before
24 weeks of gestation who choose active postnatal
resuscitation.
(Obstet Gynecol 2016;127:715–25)
DOI: 10.1097/AOG.0000000000001355
P reterm birth occurs in 5–18% of births worldwide
and remains the leading cause of neonatal mortal-
ity.1,2 Antenatal corticosteroid therapy is primarily
used to accelerate development of the lungs, enhanc-
ing survival of preterm neonates at risk of respiratory
failure.3 The most recent Cochrane review from 2006,
which examined antenatal corticosteroids for women
OBSTETRICS & GYNECOLOGY 715
at risk of preterm birth, found an overall reduction in
neonatal death, but separate analyses for neonates
born before 24 weeks of gestation were not available.4
Given the current evidence, obstetric organizations
worldwide5–7 currently advocate for a single course of
corticosteroids for women between 24 and 34 weeks of
gestation at risk of preterm birth within 7 days. The
absence of guidance before 24 weeks of gestation is
contributing to regional and international variation in
practice,8,9 although there are growing proportions of
neonates receiving intensive care at 22 and 23 weeks of
gestation. Although these births occur in a small pro-
portion of neonates, they represent a critical group for
study as a result of its high mortality and morbidity,
increased health care costs, and difficult ethical is-
sues.10–13 Therefore, the objective of this systematic
review was to estimate the association between neona-
tal mortality and morbidity and receiving antenatal
corticosteroid therapy compared with not receiving
antenatal corticosteroid therapy in neonates born
before 24 weeks of gestation.
SOURCES
We followed the guidelines in the Cochrane Hand-
book for Systematic Reviews of Interventions (Ver-
sion 5.1.0)14 and the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses statement15
(Appendix 1, available online at http://links.lww.
com/AOG/A786). We drafted the protocol for this
systematic review before the literature search (Appen-
dix 2, available online at http://links.lww.com/AOG/
A786) with the exception of the decision to use the
Newcastle-Ottawa Scale for individual study risk of
bias assessment, which we made before commence-
ment of data extraction.
We searched four databases: MEDLINE, EMBASE,
Cumulative Index to Nursing and Allied Health Liter-
ature (CINAHL), and the Cochrane Central Register of
Controlled Trials. We developed separate search strate-
gies with the aid of an experienced research librarian for
each database, consisting of a combination of MeSH
headings and multipurpose terms (.mp) (Appendix 3,
available online at http://links.lww.com/AOG/A786).
We searched ClinicalTrials.gov to find completed
trials that were unpublished using the keywords “ante-
natal corticosteroid.” We consulted experts in mater-
nal–fetal medicine and early preterm birth for
knowledge on studies published in this area. We
searched the references of included studies for addi-
tional articles of interest.
We imported all citations into bibliographic
software (Endnote X7),16 removed duplicates, and as-
signed each article an identification number.
716 Park et al Antenatal Corticosteroid Therapy Before 24 Weeks
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STUDY SELECTION
We included all published observational studies, and
randomized controlled trials (RCTs) and quasi-RCTs,
with no language restrictions. We selected a starting
point of 1990, because there have been substantial
advances in neonatal resuscitation in recent years.17
The population included preterm neonates born
before 24 weeks of gestation. The intervention was
the receipt of a single course of antenatal corticoste-
roids in utero before 24 weeks of gestation for women
at risk of preterm birth within 7 days before birth. The
comparator group included those who received no
treatment or a placebo treatment.
Our primary outcome was neonatal mortality up
until discharge from the hospital, the period when the
vast majority of deaths occur and allows for robust
rates of follow-up.18 For the adjusted analysis for mor-
tality to discharge, we included only the studies with
neonates who were given active intensive postnatal
treatment (resuscitation) and not all liveborn neonates
because the inclusion of neonates who did not receive
treatment may bias the results to overestimate the
benefit of antenatal corticosteroid.19 If information
for this population was not available in the primary
studies, we contacted the study authors.
The main secondary outcomes were respiratory
distress syndrome (RDS), severe intraventricular hem-
orrhage (grades III and IV), necrotizing enterocolitis
(NEC), chronic lung disease at 36 weeks postmenstrual
age, retinopathy of prematurity, and neurologic impair-
ment. These outcomes were selected for the quality of
evidence assessment using the Grading of Recommen-
dations Assessment, Development, and Evaluation
(GRADE) system. Other secondary outcomes focused
on common major morbidities and long-term outcomes.
We excluded other types of publications (eg,
reviews, editorials, commentaries, case studies, con-
ference proceedings, studies published only as ab-
stracts), studies without sufficient data, and duplicated
studies or data.
Two reviewers (C.K.P. and T.I.) independently
screened the titles and abstracts of all retrieved citations
with a low threshold for selecting studies for full-text
review. We independently screened the full texts to
determine inclusion and recorded reasons for exclusion.
We assessed interreviewer agreement study inclusion
using k statistics. We considered a k statistic of less than
0.00, 0.00–0.20, 0.21–0.40, 0.41–0.60, 0.61–0.80, and
0.81–1.00 as “poor,” “slight,” “fair,” “moderate,” “sub-
stantial,” and “almost perfect” agreement, respectively.20
We developed a data collection form and each
reviewer piloted the form before data abstraction of
OBSTETRICS & GYNECOLOGY
included studies. We extracted the following character-
istics from the included studies: first author and year of
publication, study design, country or region, years of
study, final sample size, inclusion and exclusion criteria,
description of intervention, and outcome measures. We
resolved discrepancies between reviewers through
discussion and consensus. A third reviewer (S.D.M.)
resolved any disagreements or uncertainties. For the
primary outcome, we included only neonates who
received active treatment to avoid a potential over-
estimation of the effect caused by including those who
did not receive active treatment. Authors of primary
studies were contacted and the study was excluded if it
was not possible to obtain these data.
We summarized the data quantitatively. Because
between-study heterogeneity was anticipated, we
performed meta-analyses using random-effects mod-
els, implementing an inverse variance method, which
adjusts study weights according to the magnitude of
variation among the intervention effects and could be
considered more conservative.14 We planned separate
analyses for RCTs and observational studies. We gen-
erated summary effect estimates (relative risks or odds
ratios and standardized mean differences) with associ-
ated 95% confidence intervals (CIs) for each outcome.
We pooled unadjusted (the raw number of events and
total) and adjusted analyses separately, if available.
The adjusted analyses were preferred because they
are an indication of the independent effect of antenatal
corticosteroids after accounting for confounders.
We performed all analyses using Review Man-
ager 5.3.21 We estimated statistical significance using
a two-sided P value of .05. As is typical in meta-
analyses, we did not adjust the P value for multiple
secondary outcomes.
We assessed heterogeneity using I2 statistics. I2
values of 0–40%, 30–60%, 50–90%, and 75–100%
were considered low, moderate, substantial, and con-
siderable heterogeneity, respectively.14 The a priori
hypotheses of sources of significant heterogeneity
were gestational age or multiple birth. Therefore,
where possible, we performed subgroup analyses for
gestational age and singleton or multiple pregnancies.
Two of the authors (C.K.P. and T.I.) independently
assessed risk of bias for each study using the Cochrane
Collaboration’s tool for assessing risk of bias for RCTs
and quasi-RCTs and a modified version of the
Newcastle-Ottawa Scale for observational studies.22,23
We quantitatively assessed publication bias with a fun-
nel plot for outcomes with 10 or more studies.24
The Newcastle-Ottawa Scale assesses selection,
comparability, and outcome. One of the items to
assess selection bias, demonstration that outcome of
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interest was not present at the start of the study, was
excluded, because neonatal outcomes would not have
been present at the time of administration of antenatal
corticosteroids. The most important confounder for
the comparability criteria was gestational age, and
secondary important confounders were inborn or
outborn status and mode of delivery (by adjustment,
matching, stratification or exclusion) chosen in con-
sultation with a high-risk obstetrician (S.D.M.) and
neonatologist (T.I.). Outcomes were assessed sepa-
rately for the outcome criteria. Overall, modified
awarded up to 8 points. We selected a score of greater
than 5 as the cutoff for low risk of bias, because there
are no validation studies that provide a cutoff score.
The GRADE system measures the quality of
a body of evidence, the confidence that an effect size
for a certain outcome is close to that of the inter-
vention’s true effect.14,25 We rated the quality of evi-
dence for each outcome as high, moderate, low, or
very low.26 Randomized controlled trials initially
begin with a high quality of evidence and are down-
graded if necessary, whereas observational studies
start with a low quality of evidence and could be up-
graded or downgraded.
The quality of evidence is downgraded in the
presence of risk of bias, inconsistency, indirectness,
imprecision, and publication bias. We assessed risk of
bias with the modified Newcastle-Ottawa Scale; incon-
sistency with high heterogeneity indicated by I2 values
unexplained by subgroup analyses27; indirectness with
differences in population, intervention, or outcome, or
indirect comparison28; imprecision with whether opti-
mal information sizes were met and whether the 95%
CIs overlapped no effect or failed to exclude appreciable
benefit or harm29; and publication bias with funnel plots
and industry sponsorships.30 The optimal information
size is the required sample size for a meta-analysis. We
calculated the optimal information sizes based on a 20%
relative risk reduction with a50.05 and b50.20.29 The
quality of evidence is upgraded in the presence of a large
effect size and a dose–response and if all plausible con-
founding would reduce a demonstrated effect or would
suggest a spurious effect when results show no effect.26
We summarized the results of the meta-analyses and
assessment of quality of evidence for each outcome
across included studies using GRADEpro GDT.31
RESULTS
The searches yielded 6,435 articles (MEDLINE51,929,
EMBASE53,887, Cochrane Central Register of Con-
trolled Trials5173, CINAHL5446; March 13, 2015;
Fig. 1) with 12 additional articles from ClinicalTrials.
gov. After removing duplicates, 4,479 records
Antenatal Corticosteroid Therapy Before 24 Weeks 717
remained. There was full-text screening for 129 records,
and 17 studies were included18,32–47 with “substantial”
agreement between reviewers (unweighted k50.62).
The most common reason for exclusion was because
data were unavailable for neonates born before 24
weeks of gestation. An RCT protocol was identified
in ClinicalTrials.gov, but the recruitment start date
was April 2015 and thus was not considered for this
review. This RCT has since been withdrawn.48 When-
ever applicable, authors of the original studies were
contacted by e-mail for data only on neonates born
before 24 weeks of gestation. Twelve research teams
clarified data and, where requested, contributed unpub-
lished data on the less than 24 weeks of gestation
population.33–39,41,42,44,45,47 For the primary outcome,
all of the data were contributed by the author of the
primary studies, except for one study, which already
included only neonates who received active intensive
resuscitation in both intervention and control groups.18
To ensure accuracy, we requested that the authors run
the same statistical analysis as the primary study with
the same data set used in the publication, but only with
neonates who received active intensive treatment. We
specifically requested authors to not include additional
data collected in subsequent years after the primary
study publication.
Years of study were from 1991 to 2010 and
published from 1999 to 2014 (Appendix 4, available
online at http://links.lww.com/AOG/A786). There
were three prospective and 14 retrospective observa-
tional studies. Six studies were from the United States,
two from Australia, and one each from the United
Kingdom, Portugal, Spain, Sweden, Bulgaria, Canada,
Japan, Israel, and Turkey. There were 3,626 neonates
for the primary outcome. Six studies had birth weight
as part of the inclusion criteria (eg, 1,500 g or
less).18,33,35,36,38,47 Studies that included dosage had typ-
ically two doses of betamethasone 24 hours apart or

Fig. 1. Flow diagram of study selec-

tion process. CENTRAL, Cochrane
Central Register of Controlled Trials;
CINAHL, Cumulative Index to Nurs-
ing and Allied Health Literature.
Park. Antenatal Corticosteroid Therapy
Before 24 Weeks. Obstet Gynecol 2016.

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Fig. 2. Summary of adjusted pooled odds ratios (95% confidence interval [CI]) for the association between mortality to
discharge and antenatal corticosteroid (ANCS) therapy compared with not receiving antenatal corticosteroid therapy. IV,
inverse variance; df, degrees of freedom.
Park. Antenatal Corticosteroid Therapy Before 24 Weeks. Obstet Gynecol 2016.

two to four doses of dexamethasone 12 hours apart,
totaling 24 mg.32,34,37,42–44,47
The data for two outcomes—severe intraventricular
hemorrhage or periventricular leukomalacia and NEC—
were not included from Carlo 2011,18 the largest
study, because 1) it provided a composite outcome of
both intraventricular hemorrhage or periventricular
leukomalacia instead of only intraventricular hemor-
rhage; and 2) the study provided the rate of both out-
comes among neonatal intensive care unit survivors

Fig. 3. Summary of adjusted pooled odds ratios (95% confidence interval [CI]) for the association between respiratory
distress syndrome and antenatal corticosteroid (ANCS) therapy compared with not receiving antenatal corticosteroid
therapy. IV, inverse variance; df, degrees of freedom.
Park. Antenatal Corticosteroid Therapy Before 24 Weeks. Obstet Gynecol 2016.

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Fig. 4. Summary of adjusted pooled odds ratios (95% confidence interval [CI]) for the association between severe intra-
ventricular hemorrhage (grades III and IV) and antenatal corticosteroid (ANCS) therapy compared with not receiving
antenatal corticosteroid therapy. IV, inverse variance; df, degrees of freedom.
Park. Antenatal Corticosteroid Therapy Before 24 Weeks. Obstet Gynecol 2016.

and not for all neonates including those who died. Neo-
nates with intraventricular hemorrhage, periventricular
leukomalacia, and NEC have a high risk of death after
developing these complications,49,50 and thus including
only neonates who survived could lead to bias.
The outcomes of all but four studies had a low
risk of bias according to the modified Newcastle-
Ottawa Scale (Appendix 5, available online at
http://links.lww.com/AOG/A786). In the “selection”
category: 1) most studies included an exposed cohort
that was truly or at least somewhat representative of
average pregnant women in a community, and in all
studies; 2) the nonexposed cohort was always drawn
from the same community; and 3) the ascertainment of
receiving the antenatal corticosteroid therapy during
pregnancy was assessed using secure records. For

Fig. 5. Summary of adjusted pooled odds ratios (95% confidence interval [CI]) for the association between necrotizing
enterocolitis and antenatal corticosteroid (ANCS) therapy compared with not receiving antenatal corticosteroid therapy. IV,
inverse variance; df, degrees of freedom.
Park. Antenatal Corticosteroid Therapy Before 24 Weeks. Obstet Gynecol 2016.

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and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
Fig. 6. Summary of adjusted pooled odds ratios (95% confidence interval [CI]) for the association between chronic lung
disease and antenatal corticosteroid (ANCS) therapy compared with not receiving antenatal corticosteroid therapy. IV,
inverse variance; df, degrees of freedom.
Park. Antenatal Corticosteroid Therapy Before 24 Weeks. Obstet Gynecol 2016.

“comparability”: 1) every study addressed gestational correspondence); but 2) only four studies controlled for
age, either through adjusted analysis or by stratifying inborn and outborn status or mode of delivery.18,33,45,46
data to 22–23 weeks of gestation (in publication or by Regarding “adequacy of follow-up”: Vakrilova et al36

Table 1. Summary of Adjusted Findings in a Systematic Review of Antenatal Corticosteroids in Neonates

Born Before 24 Weeks of Gestation (Grading of Recommendations Assessment, Development,
and Evaluation)

Anticipated Absolute Effects*

(95% CI)
No Adjusted OR No. of Participants Quality of
Outcome Corticosteroids Corticosteroids (95% CI) (No. of Studies) Evidence

Mortality before 718/1,000 555/1,000 (505–600) 0.48 (0.38–0.61)† 3,646 (4) Moderate
discharge
Respiratory distress NA NA 1.09 (0.69–1.73) 739 (2) Very low‡
syndrome
Intraventricular NA NA 0.82 (0.55–1.21) 737 (2) Very low§
hemorrhage
Necrotizing enterocolitis NA NA 1.46 (0.86–2.48) 917 (3) Very low¶
Chronic lung disease 785/1,000 756/1,000 (694–809) 0.85 (0.62–1.16) 1,184 (3) Very lowk
ROP, stages greater than 2 NA NA 0.76 (0.11–5.43) NA (1) Very low#
Neurologic impairment, 562/1,000 587/1,000 (490–680) 1.11 (0.75–1.66) 601 (1) Very low#
18–22 mo
CI, confidence interval; OR, odds ratio; NA, not available; ROP, retinopathy of prematurity.
* The risk in the intervention group is based on the assumed risk in the comparison group and the relative effect of the intervention.
†
Statistically significant.
‡
Optimal information sizes (OIS) was met, and CI overlapped no effect and failed to exclude appreciable benefit or harm.
§
OIS was not met, and CI overlapped no effect and failed to exclude appreciable benefit.
k
OIS was not met, and CI overlapped no effect and failed to exclude appreciable benefit or harm.
¶
OIS was met, but CI overlapped no effect and failed to exclude appreciable benefit.
#
Not enough information to calculate OIS, and CI overlapped no effect and failed to exclude appreciable benefit or harm.

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received 5 points for mortality, because there was no
information on the adequacy of follow-up, and 4 points
for severe intraventricular hemorrhage, because there
was no information provided for both the length and
adequacy of follow-up. Abbasi et al37 received 4 points
for RDS and severe intraventricular hemorrhage, the
former as a result of poor assessment of outcome and
the latter as a result of inadequate follow-up of the
cohort. For mortality to discharge, all studies received
points for the assessment of outcome, length of follow-
up, and follow-up.
The odds of mortality to discharge were halved
(reduced by 52%) in the antenatal corticosteroid
group compared with the control group in the
adjusted analysis among neonates who received active
intensive treatment (58.1% compared with 71.8%,
adjusted OR 0.48 [95% CI 0.38–0.61]; Fig. 2). The
subgroup analysis stratified by gestational age (22
and 23 weeks of gestation) found no significant differ-
ence between the subgroups (P5.19; Fig. 2). Although
the result became nonsignificant in 22 weeks of gesta-
tion (adjusted OR 0.66, 95% CI 0.40–1.07), the 34%
reduction of the adjusted OR estimate indicated
a potential large effect of antenatal corticosteroids in
this group. In the unadjusted analyses, which included
more studies, a similar significant reduction in the
odds of mortality was observed before 24 weeks of
gestation (OR 0.45 [95% CI 0.36–0.46]) as well as
for each individual week of gestation (Appendix 6,
available online at http://links.lww.com/AOG/
A786). Subgroup analyses for singleton compared
with multiples were not conducted because the pri-
mary studies did not provide data, although some
controlled for this in the adjusted analyses.
There were no differences in secondary outcomes
including RDS (adjusted OR 1.09 [95% CI 0.69–
1.73]), severe intraventricular hemorrhage (adjusted
OR 0.82 [95% CI 0.55–1.21]), NEC (adjusted OR
1.46 [95% CI 0.86–2.48]), chronic lung disease at 36
weeks postmenstrual age (adjusted OR 0.85 [95% CI
0.62–1.16]), severe retinopathy of prematurity
(adjusted OR 0.76 [95% CI 0.11–5.43]; for stages
greater than II only because data for all stages were
not available), and neurodevelopmental impairment
at 18–22 months corrected age (adjusted OR 1.11
[95% CI 0.75–1.66]; Figs. 3–6). Data for pneumotho-
rax or air leak syndrome were not available. Data for
all other secondary outcomes are in Appendices 6–41,
available online at http://links.lww.com/AOG/A786.
The primary outcome of mortality to discharge
had a moderate quality of evidence because it was
upgraded from low to moderate as a result of the large
effect size. All secondary outcomes were considered
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to have very low quality of evidence because they
were downgraded from low to very low because of
serious or very serious imprecision (Table 1; Appen-
dix 7, http://links.lww.com/AOG/A786).
The risk of bias for all outcomes included for the
GRADE assessment was not serious. Inconsistency
was considered not serious for all outcomes because
they all had low values of heterogeneity. All outcomes
received a not serious allocation for indirectness. The
imprecision for the outcomes other than mortality to
discharge was considered serious or very serious
because their optimal information sizes were not
met or the 95% CI of the adjusted OR overlapped
no effect and failed to exclude appreciable benefit
(adjusted OR 0.75) or harm (adjusted OR 1.25).29 No
outcome was downgraded for publication bias
because there were too few studies for funnel plots.
There were no industry sponsorships.
DISCUSSION
In our analysis, which consisted exclusively of
observational data, we found a halving of the odds
of mortality to discharge in neonates before 24 weeks
of gestation who received antenatal corticosteroids
compared with those who did not. The subgroup
analysis at 22 compared with 23 weeks of gestation
found no difference in mortality to discharge. How-
ever, more data are needed, because the sample size
for 22 weeks of gestation was small and the CIs
around the adjusted, but not the unadjusted, odds
included the null value. At 22 weeks of gestation, the
fetus has limited but detectable alveolar develop-
ment.51 The fetal lung at 22–23 weeks of gestation is
at the end stage of the canalicular stage (16–24 weeks
of gestation) of lung development followed by the
saccular stage (24–40 weeks of gestation). Because
these critical lung developments start during the
end of the canalicular stage (22–24 weeks of gesta-
tion),52 neonates at 22–23 weeks of gestation are con-
sidered potentially viable.
No significant reduction in secondary outcomes
in the steroid group was contrary to a hypothesis that
the reduction of morbidities would lead to lower odds
of mortality. This may be because the optimal
information sizes were not met for these secondary
outcomes, unlike the primary outcome, indicating
insufficient sample sizes. Another possible explana-
tion may be the misdiagnosis of RDS. It may be
difficult to ascertain RDS at 22–23 weeks of gestation
if neonates immediately intubated and administered
surfactant as would occur in many institutions.
Slightly more mature neonates are often managed
without intubation, making the diagnosis of RDS
OBSTETRICS & GYNECOLOGY
potentially easier. A third possibility is that cortico-
steroids are not effective at lowering morbidity in neo-
nates delivered before 24 weeks of gestation.
Our results differed from two previous systematic
reviews examining outcomes of extremely preterm
birth, beginning at 24 weeks of gestation.4,53 The 2006
Cochrane review4 found that neonatal mortality was
significantly reduced with antenatal corticosteroids
before 32, 34, and 36 weeks of gestation, but not in
the two studies of 89 neonates at 24 to less than 28
weeks of gestation (relative risk 0.79 [95% CI 0.56–
1.12]). A more recent 2011 systematic review,53 also
of RCTs, did not find a significant reduction in neo-
natal mortality in pooled analyses of two studies with
173 neonates at 24–29 weeks of gestation (relative risk
0.86 [95% CI 0.48–1.53]). The point estimates of both
meta-analyses were similar, but the sample sizes were
modest. Further research is needed to investigate
short- and long-term morbidity.
A strength of this systematic review is the subgroup
analysis for 22 and 23 weeks of gestation, which is
clinically relevant. Studies were from diverse settings,
which increased generalizability. We performed the risk
of bias in individual studies and the quality of evidence
for outcomes. Our primary outcome was well powered,
exceeding the optimal information size. For the primary
outcome, we included only neonates who received
active treatment to avoid a potential overestimation of
the effect caused by including those who did not receive
active treatment. Including only neonates who received
active intensive treatment rather than expectant man-
agement in both antenatal corticosteroid and control
groups minimizes selection bias favoring corticoste-
roids. Adjusted data were pooled separately from
unadjusted data to estimate the independent effect of
antenatal corticosteroids to understand the absolute and
relative effects for survival. A limitation was that many
of the secondary outcomes lacked data with some
outcomes only containing one study, and all had “very
low” quality of evidence. The studies that contributed to
the adjusted analyses did not always control for the
same confounding variables. Some clinically relevant
aspects of care not reported included the time from
administration of steroids to birth, use of surfactant,
and use of magnesium sulfate for neonatal neuroprotec-
tion. Only observational studies have been published,
which are not as robust as RCTs.
Although variation exists in the literature on the
survival rates of neonates born before at 24 weeks of
gestation, it is agreed that family counseling and planning
of services are essential for these births,11,54 because ad-
vances in care have opened the possibility of survival at
progressively early gestations. Increasingly, parents,
VOL. 127, NO. 4, APRIL 2016 Park et al
Copyright ª by The American College of Obstetricians
and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
health care providers, the health care system, and society
are challenged by births occurring in the periviable
period in terms of both their health and other effects.10,11
The results of this systematic review indicate that ante-
natal corticosteroids may be effective in reducing mor-
tality in neonates born before 24 weeks of gestation.
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Copyright ª by The American College of Obstetricians

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Unauthorized reproduction of this article is prohibited.