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,

MD, MSc

OBJECTIVE: To evaluate the effectiveness of antenatal

corticosteroids compared with placebo or no treatment
in neonates born before 24 weeks of gestation.

outcomes between neonates who received or did not

receive antenatal corticosteroids 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.

TABULATION, INTEGRATION, AND RESULTS: We performed 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, Development, and Evaluation (GRADE) system. There were 17
observational studies, and our primary outcome, mortality 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] 0.360.56; adjusted OR 0.48, 95%
CI 0.380.61; mortality to discharge 58.1% [intervention]
compared with 71.8% [control]) with a moderate quality of evidence based on the GRADE system. There were
no significant differences between the groups for severe
morbidity.

METHODS OF STUDY SELECTION: Studies considered

were published randomized or quasirandomized controlled 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. Cneyt
Tayman (Fatih Universitesi); Drs. David Bader and Brian Reichman (Israel Neonatal Network); Drs. Gustavo Rocha and Herclia Guimares (Hospital de Sao
Joao/Faculdade de Medicina, Universidade do Porto); Dr. Jos 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 OShea (Extremely Low
Gestational Age Newborn [ELGAN] study), Elizabeth Allred, and Alan Leviton
(ELGAN study & Developmental Epidemiology Network); Dr. Reese Clark (Pediatrix 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 Sekercioglu, 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.

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 considered for women at risk of imminent birth before
24 weeks of gestation who choose active postnatal
resuscitation.

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.

(Obstet Gynecol 2016;127:71525)

DOI: 10.1097/AOG.0000000000001355

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 (950229920). 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

reterm birth occurs in 518% of births worldwide

and remains the leading cause of neonatal mortality.1,2 Antenatal corticosteroid therapy is primarily
used to accelerate development of the lungs, enhancing 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

Copyright by The American College of Obstetricians

and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.

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
worldwide57 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 proportion 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 issues.1013 Therefore, the objective of this systematic
review was to estimate the association between neonatal 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 Handbook for Systematic Reviews of Interventions (Version 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 (Appendix 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 commencement of data extraction.
We searched four databases: MEDLINE, EMBASE,
Cumulative Index to Nursing and Allied Health Literature (CINAHL), and the Cochrane Central Register of
Controlled Trials. We developed separate search strategies 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 antenatal corticosteroid. We consulted experts in maternalfetal medicine and early preterm birth for
knowledge on studies published in this area. We
searched the references of included studies for additional articles of interest.
We imported all citations into bibliographic
software (Endnote X7),16 removed duplicates, and assigned each article an identification number.

716

Park et al

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 corticosteroids 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 mortality 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 hemorrhage (grades III and IV), necrotizing enterocolitis
(NEC), chronic lung disease at 36 weeks postmenstrual
age, retinopathy of prematurity, and neurologic impairment. These outcomes were selected for the quality of
evidence assessment using the Grading of Recommendations 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, conference proceedings, studies published only as abstracts), 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, 0.000.20, 0.210.40, 0.410.60, 0.610.80, and
0.811.00 as poor, slight, fair, moderate, substantial, and almost perfect agreement, respectively.20
We developed a data collection form and each
reviewer piloted the form before data abstraction of

Antenatal Corticosteroid Therapy Before 24 Weeks

OBSTETRICS & GYNECOLOGY

Copyright by The American College of Obstetricians

and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.

included studies. We extracted the following characteristics 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 overestimation 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 models, 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 generated summary effect estimates (relative risks or odds
ratios and standardized mean differences) with associated 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 Manager 5.3.21 We estimated statistical significance using
a two-sided P value of .05. As is typical in metaanalyses, we did not adjust the P value for multiple
secondary outcomes.
We assessed heterogeneity using I2 statistics. I2
values of 040%, 3060%, 5090%, and 75100%
were considered low, moderate, substantial, and considerable 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
Collaborations 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 funnel 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

VOL. 127, NO. 4, APRIL 2016

Park et al

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 consultation with a high-risk obstetrician (S.D.M.) and
neonatologist (T.I.). Outcomes were assessed separately 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 interventions true effect.14,25 We rated the quality of evidence for each outcome as high, moderate, low, or
very low.26 Randomized controlled trials initially
begin with a high quality of evidence and are downgraded if necessary, whereas observational studies
start with a low quality of evidence and could be upgraded 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; inconsistency 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 optimal 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 doseresponse and if all plausible confounding 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 Controlled 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

Copyright by The American College of Obstetricians

and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.

717

remained. There was full-text screening for 129 records,

and 17 studies were included18,3247 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 Whenever 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 unpublished data on the less than 24 weeks of gestation
population.3339,41,42,44,45,47 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 observational 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 typically two doses of betamethasone 24 hours apart or

Fig. 1. Flow diagram of study selection process. CENTRAL, Cochrane

Central Register of Controlled Trials;
CINAHL, Cumulative Index to Nursing and Allied Health Literature.
Park. Antenatal Corticosteroid Therapy
Before 24 Weeks. Obstet Gynecol 2016.

718

Park et al

Antenatal Corticosteroid Therapy Before 24 Weeks

OBSTETRICS & GYNECOLOGY

Copyright by The American College of Obstetricians

and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.

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.32,34,37,4244,47
The data for two outcomessevere 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 hemorrhage; and 2) the study provided the rate of both outcomes 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.

VOL. 127, NO. 4, APRIL 2016

Park et al

Antenatal Corticosteroid Therapy Before 24 Weeks

Copyright by The American College of Obstetricians

and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.

719

Fig. 4. Summary of adjusted pooled odds ratios (95% confidence interval [CI]) for the association between severe intraventricular 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. Neonates 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 NewcastleOttawa 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.

720

Park et al

Antenatal Corticosteroid Therapy Before 24 Weeks

OBSTETRICS & GYNECOLOGY

Copyright by The American College of Obstetricians

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

age, either through adjusted analysis or by stratifying
data to 2223 weeks of gestation (in publication or by

correspondence); but 2) only four studies controlled for

inborn and outborn status or mode of delivery.18,33,45,46
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)
Outcome
Mortality before
discharge
Respiratory distress
syndrome
Intraventricular
hemorrhage
Necrotizing enterocolitis
Chronic lung disease
ROP, stages greater than 2
Neurologic impairment,
1822 mo

No
Corticosteroids

Corticosteroids

Adjusted OR
(95% CI)

No. of Participants
(No. of Studies)

Quality of
Evidence

718/1,000

555/1,000 (505600)

0.48 (0.380.61)

3,646 (4)

Moderate

NA

NA

1.09 (0.691.73)

739 (2)

Very low

NA

NA

0.82 (0.551.21)

737 (2)

Very low

NA
785/1,000
NA
562/1,000

NA
756/1,000 (694809)
NA
587/1,000 (490680)

1.46
0.85
0.76
1.11

(0.862.48)
(0.621.16)
(0.115.43)
(0.751.66)

917
1,184
NA
601

(3)
(3)
(1)
(1)

Very low
Very lowk
Very low#
Very low#

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.

VOL. 127, NO. 4, APRIL 2016

Park et al

Antenatal Corticosteroid Therapy Before 24 Weeks

Copyright by The American College of Obstetricians

and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.

721

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 followup, 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 0.380.61]; Fig. 2). The
subgroup analysis stratified by gestational age (22
and 23 weeks of gestation) found no significant difference between the subgroups (P5.19; Fig. 2). Although
the result became nonsignificant in 22 weeks of gestation (adjusted OR 0.66, 95% CI 0.401.07), 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 0.360.46]) 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 primary 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 0.551.21]), NEC (adjusted OR
1.46 [95% CI 0.862.48]), chronic lung disease at 36
weeks postmenstrual age (adjusted OR 0.85 [95% CI
0.621.16]), severe retinopathy of prematurity
(adjusted OR 0.76 [95% CI 0.115.43]; for stages
greater than II only because data for all stages were
not available), and neurodevelopmental impairment
at 1822 months corrected age (adjusted OR 1.11
[95% CI 0.751.66]; Figs. 36). Data for pneumothorax or air leak syndrome were not available. Data for
all other secondary outcomes are in Appendices 641,
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

722

Park et al

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; Appendix 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. However, 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 development.51 The fetal lung at 2223 weeks of gestation is
at the end stage of the canalicular stage (1624 weeks
of gestation) of lung development followed by the
saccular stage (2440 weeks of gestation). Because
these critical lung developments start during the
end of the canalicular stage (2224 weeks of gestation),52 neonates at 2223 weeks of gestation are considered 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 explanation may be the misdiagnosis of RDS. It may be
difficult to ascertain RDS at 2223 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

Antenatal Corticosteroid Therapy Before 24 Weeks

OBSTETRICS & GYNECOLOGY

Copyright by The American College of Obstetricians

and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.

potentially easier. A third possibility is that corticosteroids are not effective at lowering morbidity in neonates 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 neonatal mortality in pooled analyses of two studies with
173 neonates at 2429 weeks of gestation (relative risk
0.86 [95% CI 0.481.53]). 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 management in both antenatal corticosteroid and control
groups minimizes selection bias favoring corticosteroids. 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 neuroprotection. 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 advances in care have opened the possibility of survival at
progressively early gestations. Increasingly, parents,

VOL. 127, NO. 4, APRIL 2016

Park et al

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 antenatal corticosteroids may be effective in reducing mortality in neonates born before 24 weeks of gestation.
REFERENCES
1. Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller AB,
Narwal R, et al. National, regional, and worldwide estimates of
preterm birth rates in the year 2010 with time trends since 1990
for selected countries: a systematic analysis and implications.
Lancet 2012;379:216272.
2. Kramer MS, Demissie K, Yang H, Platt RW, Sauv R, Liston R.
The contribution of mild and moderate preterm birth to infant
mortality. Fetal and Infant Health Study Group of the Canadian
Perinatal Surveillance System. JAMA 2000;284:8439.
3. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress
syndrome in premature infants. Pediatrics 1972;50:51525.
4. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating
fetal lung maturation for women at risk of preterm birth. The
Cochrane Database of Systematic Reviews 2006, Issue 3. Art.
No.: CD004454.
5. Periviable birth. Obstetric Care Consensus No. 3. American
College of Obstetricians and Gynecologists. Obstet Gynecol
2015;126:e8294.
6. Crane J, Armson A, Brunner M, De La Ronde S, Farine D,
Keenan-Lindsay L, et al. Antenatal corticosteroid therapy for
fetal maturation [in English, French]. J Obstet Gynaecol Can
2003;25:4552.
7. Antenatal corticosteroids to reduce neonatal morbidity and
mortality. Green-top Guideline No. 7. London (UK): Royal
College of Obstetricians and Gynaecologists; 2010.
8. Miracle X, Di Renzo GC, Stark A, Fanaroff A, CarbonellEstrany X, Saling E, et al. Guideline for the use of antenatal
corticosteroids for fetal maturation. J Perinat Med 2008;36:1916.
9. Leviton LC, Goldenberg RL, Baker CS, Schwartz RM,
Freda MC, Fish LJ, et al. Methods to encourage the use of
antenatal corticosteroid therapy for fetal maturation: a randomized controlled trial. JAMA 1999;281:4652.
10. Rysavy MA, Li L, Bell EF, Das A, Hintz SR, Stoll BJ, et al.
Between-hospital variation in treatment and outcomes in
extremely preterm infants. N Engl J Med 2015;372:180111.
11. Salihu HM, Salinas-Miranda AA, Hill L, Chandler K. Survival
of pre-viable preterm infants in the United States: a systematic
review and meta-analysis. Semin Perinatol 2013;37:389400.
12. Institute of Medicine (US) Committee on Understanding Premature Birth and Assuring Healthy Outcomes; Behrman RE,
Butler AS, editors. Preterm Birth: Causes, Consequences, and
Prevention. Washington (DC): National Academies Press (US);
2007.
13. Fanaroff JM, Hascoet JM, Hansen TW, Levene M, Norman M,
Papageorgiou A, et al. The ethics and practice of neonatal resuscitation at the limits of viability: an international perspective.
Acta Paediatr 2014;103:7018.
14. Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0. Available at: www.cochrane-handbook.org. 2011. Retrieved February 12, 2016.
15. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group.
Preferred reporting items for systematic reviews and

Antenatal Corticosteroid Therapy Before 24 Weeks

Copyright by The American College of Obstetricians

and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.

723

meta-analyses: the PRISMA statement. J Clin Epidemiol 2009;

62:100612.

34. Rocha G, Guimares H. On the limit of viability extremely low

gestational age at birth. Acta Med Port 2011;24(suppl 2):1818.

16. EndNote X7. Available at: http://endnote.com/product-details/X7. Thomson Reuters; 2014. Retrieved February 12,
2016.

35. Tayman C, Tonbul A, Uras N, Kahveci H, Koseoglu B,

Mansur Tatli M. Evaluation of risk factors for necrotizing
enterocolitis in preterm infants [in Turkish]. Guncel Pediatri
2011;9:713.

17. Morley CJ, Davis PG. Advances in neonatal resuscitation: supporting transition. Arch Dis Child Fetal Neonatal Ed 2008;93:F3346.
18. Carlo WA, McDonald SA, Fanaroff AA, Vohr BR, Stoll BJ,
Ehrenkranz RA, et al. Association of antenatal corticosteroids
with mortality and neurodevelopmental outcomes among infants born at 22 to 25 weeks gestation. JAMA 2011;306:
234858.
19. Litmanovitz I, Reichman B, Arnon S, Boyko V, Lerner-Geva L,
Bauer-Rusak S, et al. Perinatal factors associated with active
intensive treatment at the border of viability: a populationbased study. J Perinatol 2015;35:70511.
20. Landis JR, Koch GG. The measurement of observer agreement
for categorical data. Biometrics 1977;33:15974.
21. Zhang J, Yu KF. Whats the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes. JAMA 1998;280:16901.
22. Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D,
Oxman AD, et al. The Cochrane Collaborations tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928.
23. Wells G, Shea B, OConnell D, Peterson J, Welch V, Losos M,
et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality
of nonrandomised studies in meta-analyses. Available at: http://
www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Ottawa
Hospital Research Institute; Retrieved February 12, 2016.
24. Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J,
et al. Recommendations for examining and interpreting funnel
plot asymmetry in meta-analyses of randomised controlled trials. BMJ 2011;343:d4002.
25. The GRADE working group. GRADE working group.
Available at: http://www.gradeworkinggroup.org/index.htm.
Retrieved February 12, 2016.
26. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al.
GRADE guidelines: 1. Introduction-GRADE evidence profiles
and summary of findings tables. J Clin Epidemiol 2011;64:38394.

36. Vakrilova L, Nikolov A, Yankova Y, Slancheva B,

Popivanova A, Frandeva B, et al. Short term outcome after
active obstetric management of very low birthweight infants
[in Bulgarian]. Akush Ginekol (Sofiia) 2011;50:1320.
37. Abbasi S, Oxford C, Gerdes J, Sehdev H, Ludmir J. Antenatal
corticosteroids prior to 24 weeks gestation and neonatal outcome of extremely low birth weight infants. Am J Perinatol
2010;27:616.
38. Bader D, Kugelman A, Boyko V, Levitzki O, Lerner-Geva L,
Riskin A, et al. Risk factors and estimation tool for death among
extremely premature infants: a national study. Pediatrics 2010;
125:696703.
39. Garg P, Abdel-Latif ME, Bolisetty S, Bajuk B, Vincent T, Lui K.
Perinatal characteristics and outcome of preterm singleton, twin
and triplet infants in NSW and the ACT, Australia (1994-2005).
Arch Dis Child Fetal Neonatal Ed 2010;95:F204.
40. Manktelow BN, Lal MK, Field DJ, Sinha SK. Antenatal corticosteroids and neonatal outcomes according to gestational age:
a cohort study. Arch Dis Child Fetal Neonatal Ed 2010;95:
F958.
41. EXPRESS Group, Fellman V, Hellstrm-Westas L, Norman M,
Westgren M, Klln K, et al. One-year survival of extremely
preterm infants after active perinatal care in Sweden. JAMA
2009;301:222533.
42. Laughon M, OShea MT, Allred EN, Bose C, Kuban K, Van
Marter LJ, et al. Chronic lung disease and developmental delay
at 2 years of age in children born before 28 weeks gestation.
Pediatrics 2009;124:63748.
43. Hayes EJ, Paul DA, Stahl GE, Seibel-Seamon J, Dysart K,
Leiby BE, et al. Effect of antenatal corticosteroids on survival
for neonates born at 23 weeks of gestation. Obstet Gynecol
2008;111:9216.

27. Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J,

Helfand M, et al. GRADE guidelines: 7. Rating the quality of
evidenceinconsistency. J Clin Epidemiol 2011;64:1294302.

44. Figueras-Aloy J, Serrano MM, Rodriguez JP, Prez CF,

Serradilla VR, Jimenez JQ, et al. Antenatal glucocorticoid treatment decreases mortality and chronic lung disease in survivors
among 23- to 28-week gestational age preterm infants. Am J
Perinatol 2005;22:4418.

28. Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J,

Helfand M, et al. GRADE guidelines: 8. Rating the quality of
evidenceindirectness. J Clin Epidemiol 2011;64:130310.

45. Guthrie SO, Gordon PV, Thomas V, Thorp JA, Peabody J,

Clark RH. Necrotizing enterocolitis among neonates in the
United States. J Perinatol 2003;23:27885.

29. Guyatt GH, Oxman AD, Kunz R, Brozek J, Alonso-Coello P,

Rind D, et al. GRADE guidelines 6. Rating the quality of evidenceimprecision. J Clin Epidemiol 2011;64:128393.

46. Chien LY, Ohlsson A, Seshia MM, Boulton J, Sankaran K,

Lee SK, et al. Variations in antenatal corticosteroid therapy:
a persistent problem despite 30 years of evidence. Obstet Gynecol 2002;99:4018.

30. Guyatt GH, Oxman AD, Montori V, Vist G, Kunz R, Brozek J,

et al. GRADE guidelines: 5. Rating the quality of evidence
publication bias. J Clin Epidemiol 2011;64:127782.
31. McMaster University and Evidence Prime Inc. GRADEpro
GDT. Available at: http://gradepro.org/. Retrieved February
12, 2016.
32. Wong D, Abdel-Latif M, Kent A; NICUS Network. Antenatal
steroid exposure and outcomes of very premature infants:
a regional cohort study. Arch Dis Child Fetal Neonatal Ed
2014;99:F1220.
33. Mori R, Kusuda S, Fujimura M; Neonatal Research Network
Japan. Antenatal corticosteroids promote survival of extremely
preterm infants born at 22 to 23 weeks of gestation. J Pediatr
2011;159:110114.e1.

724

Park et al

47. Leviton A, Dammann O, Allred EN, Kuban K, Pagano M,

Van ML, et al. Antenatal corticosteroids and cranial ultrasonographic abnormalities. Am J Obstet Gynecol 1999;181:100717.
48. Mednax Center for Research EaQ. Effectiveness of ACS in
extreme preemies. Available at: https://clinicaltrials.gov/ct2/
show/NCT02351310. Retrieved February 12, 2016.
49. Kono Y, Mishina J, Yonemoto N, Kusuda S, Fujimura M; NICU Network, Japan. Neonatal correlates of adverse outcomes
in very low-birthweight infants in the NICU Network. Pediatr
Int 2011;53:9305.
50. Fitzgibbons SC, Ching Y, Yu D, Carpenter J, Kenny M,
Weldon C, et al. Mortality of necrotizing enterocolitis expressed
by birth weight categories. J Pediatr Surg 2009;44:10725.

Antenatal Corticosteroid Therapy Before 24 Weeks

OBSTETRICS & GYNECOLOGY

Copyright by The American College of Obstetricians

and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.

51. Chetty A, Andersson S, Lassus P, Nielsen HC. Insulin-like

growth factor-1 (IGF-1) and IGF-1 receptor (IGF-1R) expression in human lung in RDS and BPD. Pediatr Pulmonol 2004;
37:12836.
52. Blackmon LR. Biologic limits of viability. NeoReviews 2003;4:
e1406.
53. Onland W, de Laat MW, Mol BW, Offringa M. Effects of
antenatal corticosteroids given prior to 26 weeks gestation:

a systematic review of randomized controlled trials. Am J Perinatol 2011;28:3344.

54. Raju TN, Mercer BM, Burchfield DJ, Joseph GF. Periviable
birth: executive summary of a Joint Workshop by the Eunice
Kennedy Shriver National Institute of Child Health and Human
Development, Society for Maternal-Fetal Medicine, American
Academy of Pediatrics, and American College of Obstetricians
and Gynecologists. J Perinatol 2014;34:33342.

ACOG Fellows and Journal Subscribers:

Get Obstetrics & Gynecology for Free on your iPad
The Green Journal app is available for the iPad from Apples App StoreSM. To view journal
content, ACOG Fellows and journal subscribers must rst register and activate an account
at www.greenjournal.org.
If You Have Not Registered at GreenJournal.org:
1. On www.greenjournal.org, click on the gear box at the top right corner of the screen
and select Register.
2. On the registration screen, choose a username and password and enter your e-mail
address. (Usernames must be at least 6 characters in length and contain no spaces or
symbols; passwords must be at least 8 characters in length and contain at least one
number and one letter.)
3. Click Continue to go to the next step of user registration.
4. On the next screen, enter your name and address and click Continue.
5. The next registration screen asks for additional information about you and your
practice to help us recommend articles and rich media that suit your area of specialty.
After entering this information, indicate your acceptance of the End User License
Agreement and click Complete Registration.
6. After you complete the registration, you will receive an e-mail from the site asking you
to conrm your registration. Click on the link in the e-mail within 48 hours.
7. The link in the e-mail leads to a web page where you will be asked if you want to
activate your online subscription. Click on Yes! I am a subscriber and want to activate
my online subscription.
8. Enter your ACOG Member ID or subscriber ID in the eld at the bottom of the next
screen. Be sure to enter all characters; note that the last digit for ACOG members is the
letter I, not the number 1. Then click on Activate Subscription.
If You Have Registered at GreenJournal.org But Not Activated Your Subscription:
1. On www.greenjournal.org, click on the gear box at the top right corner of the screen
and select Register.
2. Click on Activate Your Subscription at the top right of the page.
3. Enter your ACOG Member ID or subscriber ID in the eld at the bottom of the next
screen. Be sure to enter all characters; note that the last digit for ACOG members is the
letter I, not the number 1. Then click on Activate Subscription.
You are now registered for full-text access on both the app and the journal web site!
When you access the Green Journal app on your iPad, you will be asked to enter the
username and password that you created at www.greenjournal.org.
Need Help? Contact the Editorial Ofce at 202-314-2317 or obgyn@greenjournal.org.
Apple and iPad are trademarks of Apple Inc., registered in the U. S. and other countries. App Store is a service mark of Apple Inc.

VOL. 127, NO. 4, APRIL 2016

Park et al

rev 2/2015

Antenatal Corticosteroid Therapy Before 24 Weeks

Copyright by The American College of Obstetricians

and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.

725