Reproductive Sciences

https://doi.org/10.1007/s43032-020-00425-x

REVIEW

Corticosteroids in Pregnancy for Preventing RDS: Overview

of Systematic Reviews
Maria Laura Rodrigues Uggioni 1 & Tamy Colonetti
1
& Antonio José Grande
2
& Mateus Vinicius Barbosa Cruz
1
&
Maria Inês da Rosa 1

Received: 8 October 2020 / Accepted: 6 December 2020

# Society for Reproductive Investigation 2020

Abstract
The objective of this study was to analyze the available evidence of systematic reviews that evaluated the efficacy of antenatal
corticosteroids in order to contribute to a reduction in magnitude and transcendence of respiratory distress syndrome of the
newborn (RDS). Thus, an overview was conducted including all systematic reviews of randomized controlled trials (RCTs) that
evaluated women who received corticosteroid treatment during pregnancy to prevent RDS. Therefore, a search strategy was
developed using the terms “respiratory distress syndrome, newborn,” “corticosteroids,” “perinatal death,” “neonatal death,”
“neonate,” and “pregnancy.” The electronic databases searched were MEDLINE, EMBASE, Cochrane Library, LILACS, and
Google Scholar, for studies published until June 2020. We identified 354 references, 38 of which were relevant after the initial
screening. Ten systematic reviews met the inclusion criteria. For RDS, 1522 cases occurred in the control group composed of
8716 participants, while in the intervention group was 1088 in 8740 participants (RR = 0.67, 95% CI 0.60–0.75). For neonatal
death, 343 cases occurred in 5248 participants of the control group, while in the intervention group, there were 227 cases in 5246
participants (RR = 0.66, 95% CI 0.56–0.78). For perinatal death, there were 344 cases in 3345 participants in the control group,
while in the intervention group, the number of cases was 264 in 3384 participants (RR = 0.72, 95% CI 0.58–0.89). Thus, the use
of corticosteroids during pregnancy in women at risk of preterm birth is effective for the prevention of RDS in neonates and
reducing the number of neonatal and perinatal deaths in preterm. PROSPERO protocol no: CRD42017074604

Keywords Respiratory distress syndrome, newborn . Corticosteroids . Perinatal death . Neonatal death

Introduction

Preterm birth occurs before 37 weeks of pregnancy and is

one of the major causes of neonatal mortality and morbidity,
* Maria Laura Rodrigues Uggioni
lala.uggioni@unesc.net
being one of the main reasons for hospitalization during
prenatal care [1, 2]. More than 130 million births occur
Tamy Colonetti every year, with the overall incidence of preterm deliveries
tamycolonetti@hotmail.com at 12.5% per year [3, 4]. Premature birth can lead to respi-
Antonio José Grande
ratory distress syndrome of the newborn (RDS), which af-
grandeto@gmail.com fects about 60% of infants before 30 weeks of pregnancy,
leading to death in up to 40% of cases [5–7].
Mateus Vinicius Barbosa Cruz
mateus_cruz11@hotmail.com Corticosteroids simulate the action of glucocorticoids,
the hormones that influence and stimulate the synthesis of
Maria Inês da Rosa proteins and fetal peptides, responsible for differentiation
mir@unesc.net
and maturation of cells and not only the growth, especially
1
Translational Biomedicine Laboratory, University of the Extreme in the lungs. This type of drug has contributed to a 50%
South of Santa Catarina, Criciúma, SC, Brazil decrease in the frequency of RDS, as well as its severity
2
Evidence-Based Health Laboratory, State University of Mato Grosso [7, 8]. The most commonly used corticosteroids are
do Sul, Campo Grande, MS, Brazil betamethasone (BTM) and dexamethasone (DXM), which
 Reprod. Sci.

are able to cross the placental barrier and through the intra-
muscular (IM) route [9, 10].
This study aims to analyze the available evidence in sys-
tematic reviews that evaluated the efficacy of antenatal corti-
costeroids in order to contribute to a reduction in magnitude
and transcendence of this disease. Thus, an overview was
conducted including all systematic reviews of randomized
controlled trials (RCTs) that evaluated women who received
corticosteroid treatment during pregnancy to prevent RDS.
Methods
Protocol and Registration
First, the study protocol was registered at Prospective Register
of Ongoing Systematic Reviews (PROSPERO) with the pur-
pose of officializing the execution of this study worldwide.
The study was registered under the protocol
CRD42017074604.

Fig. 1 Flow chart for Overview

of Systematic Reviews. *Index
publication is the first occurence
of a primary publication in the
included reviews. ** Additional
eligible primary studies that had
not been initially indentified by
the search of the relevant reviews
by updating the search of the
included reviews
Table 1 Description of included studies

Authors, year Types Objectives Selection criteria Gestational Dose, drug, and regimens Participants Main Conclusions
Reprod. Sci.

of age results
studies

Roberts et al., 2017 30 To assess the effects of Considered all randomized Between BTM IM: 7774 RDS: RR Evidence from this update
RC- administering a course of controlled comparisons of 35 wee- ● 12 mg for 1 dose, repeat women 0.66, supports the continued use
Ts corticosteroids to the mother antenatal corticosteroid ks + after 24 h if childbirth had and 95% of a single course of
prior to anticipated preterm administration with placebo, 0 days not occurred; 8158 CI 0.56 antenatal corticosteroids to
birth on fetal and neonatal or with no treatment, given and ● 12 mg for 2 doses, repeat infants to 0.77 accelerate fetal lung
morbidity and mortality, to women with a singleton 37 wee- after 12 h if childbirth had Neonatal maturation in women at risk
maternal mortality and or multiple pregnancies, ks + not occurred; death: of preterm birth. A single
morbidity, and on the child prior to anticipated preterm 0 days ● 12 mg every 24 h for 2 RR course of antenatal
in later life. delivery, regardless of other doses; 0.69, corticosteroids could be
co-morbidity, for inclusion ● 3 mg of acetate +3 mg of 95% considered routine for
in this review. Most women sodium phosphate every CI 0.59 preterm delivery.
in this review received a 12 h for 4 doses; to 0.81
single course of steroids; ● 24 mg every 24 h for 2 Perinatal
however, nine of the doses; death:
included trials allowed for ● 4 mg de phosphate every 8 h RR
women to have weekly for 6 doses; 0.72,
repeats. ● 6 mg de acetate +6 mg de 95%
phosphate every 24 h for 2 CI 0.58
doses, weekly repeated if to 0.89
childbirth had not occurred;
● 8 mg de phosphate +6 mg
de acetate, repeat after 24 h
if childbirth had not
occurred;
DXM IM:
● 6 mg every 12 h for 4 doses;
● 12 mg every 24 h for 2
doses;
● 6 mg de sodium phosphate
every 12 h for 4 doses;
● 5 mg every 12 h for 4 doses,
weekly repeated if childbirth
had not occurred;
● 4 mg of phosphate every 8 h
for 6 doses.
Mwansa-Kambafwile 18 Review the evidence for and Conducted systematic reviews Between > Single and repeated doses were 3956 RDS: RR Based on high-grade evidence,
et al., 2010 RC- estimate the effect on using standardized 31 wee- analyzed; infants 0.66, antenatal steroid therapy is
Ts cause-specific neonatal abstraction forms. Quality of ks and BTM IM: 95% very effective in preventing
mortality of administration evidence was assessed using after 12 mg every 12 h for 2 doses; CI 0.59 neonatal mortality and
of antenatal steroids to an adapted GRADE 36 wee- DXM IM: to 0.73 morbidity, yet remains at
women with anticipated approach. Existing ks 6 mg every 12 h for 4 doses; Neonatal low coverage in
preterm labor, with addi- meta-analyses were Administration was done death: low/middle-income coun-
tional analysis for the effect reviewed for relevance to within 24–48 h of RR tries. If fully scaled up, this
Table 1 (continued)

Authors, year Types Objectives Selection criteria Gestational Dose, drug, and regimens Participants Main Conclusions
of age results
studies

in low- and middle-income

low-/middle-income treatment, with birth occur- 0.6, intervention could save up
countries. countries, and new ring within 7 days or more, 95% to 500,000 neonatal lives
meta-analysis was per- after treatment. CI 0.58 annually.
formed. to 0.81
McLaughlin et al., 7 Determine the risk of fetal, We included RCTs that Does not Single doses were analyzed in 862 RDS: RR Infants exposed to
2003 RC- neonatal and maternal compared women who specify pregnant women who women 0.72, corticosteroids more than
Ts mortality and morbidity for received a single course of weeks of received corticosteroids and and 862 95% 7 days before birth had no
women and their infants antenatal corticosteroids gestation did not deliver more than infants CI 0.49 reduction in risk of
who remained undelivered (BTM or DXM) with 7 days after treatment; The to 1.07 respiratory distress
more than 7 days following women who did not receive steroids were administered Neonatal syndrome but increased
a course of prenatal corticosteroids. Only trials BTM and DXM. death: perinatal mortality.
corticosteroids. reporting results for women Does not specify the dose or RR
who did not deliver for more how the application was 3.24,
than 7 days after treatment made. 95%
were included. CI 1.32
to 7.96
Perinatal
death:
RR
2.13,
95%
CI 1.27
to 3.57
Crowley, 1992 12 Determined the efficacy of Included RCTs that evaluated Between 30 DXM IM: 3000 RDS: The review states that
RC- DXM in women with women with RUPREME and 12 mg every 12 h for 2 doses women Odds corticosteroid therapy
Ts RUPREME at risk of who were at risk of preterm 34 wee- and Ratio should be initiated as soon
preterm delivery. delivery who were ks 3266 0.49, as possible in all cases of
randomly allocated for infants 95% RUPREME between 24 and
corticosteroid treatment or CI 0.41 36 weeks of gestation
placebo. to 0.60 unless immediate delivery is
indicated for antepartum
hemorrhage, cord prolapse,
or chorioamnionitis.
Harding et al., 2001 15 It has been found that antenatal We included RCTs that Between The study analyzed 1142 RDS: RR The available data indicate that
RC- corticosteroids help in the evaluated women at risk of 24 wee- applications of 6 mg of women 0.70, corticosteroid
Ts context of premature rupture preterm birth between 24 ks and short-acting BTM phos- and 95% administration is beneficial
of membranes. and 37 weeks gestation who 37 wee- phate +6 mg of long-acting 1218 CI 0.39 in the setting of rupture of
received a random injection ks BTM acetate; The adminis- infants to 1.28; membranes.
of a mixture of 6 mg of tration was performed intra- Neonatal
short-acting BTM, 6 mg of muscularly; there was repe- death:
long-acting BTM phosphate tition after 24 h. RR
and acetate, or an 0.69,
identical-looking placebo 95%
Reprod. Sci.
Table 1 (continued)
Authors, year Types Objectives Selection criteria Gestational Dose, drug, and regimens
of age
studies
injection of 6 mg of corti-
sone acetate. The diagnosis
of respiratory distress syn-
drome was performed by
blinded investigators for the
study of group allocation.
RUPREME evaluations
were also included in preg-
nant women.
Crowley et al., 1990 12 Evaluated the effects of The review used the Oxford
RC- corticosteroid Database of Perinatal
Ts administration before Trials criteria to determine
preterm delivery. the ECRs that would be
included.
Participants Main
Between Single and repeated doses were 3000
25 wee- analyzed;
ks and BTM IM:
37 wee- ● 12 mg every 24 h for 2
ks doses;
● 12 mg, every 12 h for 2
doses;
● 8 mg of phosphate +6 mg de
acetate, every 24 h for 2
doses;
● 5 mg for 4 doses;
● 12 mg every 24 h for 2
doses +125 mg of
methylprednisolone every
24 h for 2 doses +250 mg of
hydrocortisone every 24 h
for 2 doses;
● 12 mg every 24 h for 2
doses + treatment with
tocolytics (ethanol or
magnesium sulfate) for 48 h
to induce labor;
● 6 or 12 mg every 12 h for 2
doses + ritodrine or
terbutaline for 21 h to
induce labor;
● 4 mg every 8 h for 6 doses,
repeated after 48 h;
DXM IM:
● 4 mg every 8 h for 6 doses;
● 6 mg every 12 h for 4
doses.
Hydrocortisone IM:
Conclusions
Reprod. Sci.
results
CI 0.36
to 1.35
RDS: The review suggests that
women Odds corticosteroids reduce the
and Ratio occurrence of respiratory
3266 0.49, distress syndrome in general
infants 95% and in all subgroups of
CI 0.41 RCTs. This reduction in
to 0.60 respiratory morbidity was
Neonatal associated with reductions
death: in the risk of neonatal death.
Odds There is no strong evidence
Ratio suggesting adverse effects
0.59, of corticosteroids. The risks
95% of fetal and neonatal
CI 0.47 infection may be increased if
to 0.75. administered after
RUPREME, but this
possibility is not supported
by the results of the
available trials. Available
data on long-term follow-up
suggest that the short-term
beneficial effects of cortico-
steroids may be reflected in
the reduction of long-term
neurological morbidity.
Table 1 (continued)
Authors, year Types Objectives
of
studies
Peltoniemi et al., 2011 8 To systematically review the
RC- efficacy and safety of
Ts repeated antenatal
corticosteroid on neonatal
morbidity, growth, and later
development.
Roberge et al., 2011 8 To review the available
RC- evidence regarding the
Ts effect of fetal sex in the
prevention of RDS using
AGC.
Selection criteria Gestational Dose, drug, and regimens
age
The review used the
MEDLINE and Cochrane
databases, selecting only a
bibliography of
English-language articles.
Blind controlled,
randomized,
placebo-controlled trials of
repeated antenatal cortico-
steroids in cases of threat-
ened preterm delivery were
evaluated. Primary out-
comes during the neonatal
period were RDS and post-
natal mortality.
Used only studies that showed Between 24 Single and repeated doses were 2062
data according to the fetal
sex. The selected trials were
categorized according to the
availability of data regarding
the sex of the neonate. Only
RCTs that investigated
women at risk of preterm
birth between 24 and
37 weeks’ gestation were
reviewed. Treatment with
corticosteroids, with or
without tocolytics, but
without other associated
treatment, was required to
be compared with a control
group allocated to no
Participants Main Conclusions
results
● 500 mg every 12 h for 4
doses.
Between 32 Repeated doses of BTM were 5460 RDS: RR Repeated corticosteroid
and analyzed; women 0.85, treatment decreased the risk
34 wee- BTM IM: and 95% of respiratory distress
ks ● 11,4 mg for 1 dose, weekly 5460 CI 0.77 syndrome among preterm
repeated if childbirth had infants to 0.93 infants.
not occurred or up to
34 weeks;
● 12 mg every 24 h for 2
doses;
● 12 mg every 24 h for 2
doses, weekly repeated if
childbirth had not occurred
or up to 34 weeks;
● 12 mg every 24 h for 2
doses, repeated for 14 days
before delivery or up to
33 weeks of gestation;
● 12 mg for 1 dose, weekly
repeated if childbirth had
not occurred;
● 12 mg every 24 h for 2
doses, weekly repeated if
childbirth had not occurred
or up to 33 weeks +6 days.
RDS: RR The effect of AGC for the
and analyzed; women 0.54, prevention of RDS is similar
37 wee- BTM IM: and 95% in females and males.
ks ● 12 mg for 2 doses, repeated 2077 CI 0.42 However, futures studies
after 24 h; infants to 0.69 should investigate the type
● 24 mg for 1 dose; of AGC according to
● 12 mg for 1 dose, repeated fetal/neonatal sex.
after 24 h or weekly
repeated if childbirth had
not occurred;
● 12 mg for 1 dose, repeated
after 24 h or weekly
repeated if childbirth had
not occurred or up to
34 weeks +6 days;
DXM IM:
Reprod. Sci.
Table 1 (continued)
Authors, year Types Objectives
of
studies
Saccone; Berghella, 6 To evaluate the effectiveness
2016
Sotiriadis et al., 2018 4 The objective of this review
Selection criteria
This review included all
RC- of antenatal corticosteroids
Ts given at ≥34 weeks’
gestation.
Randomized controlled trials At or after Administration of
RC- was to assess the effect of
T’s prophylactic corticosteroid
administration before
elective cesarean section at
term, as compared to usual
management without
corticosteroids, in reducing
neonatal respiratory
Gestational Dose, drug, and regimens
age
treatment or placebo. The
type of corticosteroids used
was BTM or DXM, and all
modes of administration and
doses were accepted as
treatment.
Between
randomized trials 34 wee-
comparing the use of ks and
antenatal corticosteroids 36 wee-
(intervention group) with ks
placebo or no treatment
(control group) in women
with a single gestation at 34
or more weeks of gestation.
We also included trials on
the use of prenatal steroids
in women who expected late
preterm delivery
(34–36 weeks) and women
with planned cesarean
delivery (≥3 7 weeks).
Trials on antenatal
prophylactic corticosteroids
administered in less than
34 weeks and those
including multiple
pregnancies and
near-randomized trials were
also excluded.
comparing prophylactic 37 wee-
antenatal corticosteroid ks of
administration gestation placebo or usual treatment
(betamethasone or
dexamethasone) with
placebo or with no
treatment, given before
Participants Main
● 20 mg every 12 h for 4
doses of 5 mg;
● 24 mg de every 12 h for 4
doses;
● 24 mg every 12 h for 4
doses, weekly repeated if
childbirth had not occurred;
● 10 mg or 20 mg,
administered at doses of
10 mg per day.
Single and repeated doses were 5698
analyzed; women
BTM IM: and
● 24 mg every 24 h for 2 5698
doses, repeated 48 h before infants
cesarean childbirth;
● 12 mg for 1 dose;
● 24 mg every 24 h for 2
doses at admission to
hospital.
DXM IM:
● 24 mg every 24 h for 2
doses, repeated 48 h before
cesarean childbirth;
● 32 mg every 8 h for 4 doses
of 8 mg, repeated 48 h
before cesarean childbirth.
3956
betamethasone or women
dexamethasone versus and
3893
without steroids in term neonates
elective cesarean section.
Women randomized to the
treatment group received
either two intramuscular
Conclusions
Reprod. Sci.
results
RDS: RR Prenatal steroids at ≥34 weeks
0.98, of gestation reduce neonatal
95% respiratory morbidity. A
CI 0.77 single course of
to 1.24. corticosteroids may be
Neonatal considered for women at
death: risk of imminent late
RR preterm delivery from 34 to
0.95, 36 weeks’ gestation, as well
95% as for women undergoing
CI 0.20 planned cesarean delivery at
to 4.58. ≥37 weeks of gestation.
RDS: RR Evidence suggests that there
0.48; might be a beneficial effect
95% of intramuscular
CI 0.27 corticosteroids in respiratory
to 0.87. outcomes of the neonate in
the immediate period after
birth. Given that only one
study has examined the
long-term effects, we cannot
 Reprod. Sci.

their magnitude. Larger ran-

long-term effects of this in-

Eligibility Criteria

conducted in order to con-

dergoing elective cesarean

there are risks and what is

population of women un-

be certain about whether

domized trials should be

tervention in the general

We included systematic reviews that used only RCTs. The

firm the short- and

population considered in the reviews included women at risk
of preterm birth who used antenatal corticosteroids for fetal
Conclusions

Legend: CI, confidence interval; RR, risk ratio; DXM, dexamethasone; BTM, betamethasone; IM, intramuscular; RCT, randomized controlled trial; RDS, respiratory distress syndrome
section.
maturation compared with women who received placebo or
received no intervention. Also, the neonates of the women
who received the intervention were compared with the neo-
nates whose mothers did not receive intervention.
results
Participants Main

Search Strategy

The searches for studies were carried out systematically in

MEDLINE, EMBASE, Cochrane Library, Scopus, Biomed
Central, Web of Science, IBECS, LILACS, Congress
group who received a saline
dexamethasone (two or four

37 weeks’ gestation or 48 h

Abstracts, and gray literature databases (Google Scholar and

the 48 h before delivery, or

doses) prior to delivery (at

doses of betamethasone in

before delivery), and were

British Library). The search was limited to studies in humans,

compared to the control

placebo or treatment as
Gestational Dose, drug, and regimens

there were no language restrictions, and revisions were pub-

lished until June 2020. The reference list of all selected pri-
intramuscular

mary studies was reviewed to identify other relevant citations.

The following keywords were used for the search: “respiratory
usual.

distress syndrome,” “newborn,” “corticosteroids,” “perinatal

death,” “neonatal death,” “neonate,” and “pregnancy.”

Study Selection and Data Collection Process

age

Two reviewers independently selected the abstracts according

to the inclusion criteria of the study. The screening process
elective cesarean section at

was conducted at Covidence (www.covidence.org). Two

reviewers independently extracted the information using a
predefined Excel spreadsheet with information related to the
Selection criteria

articles included (intervention, comparison, outcome, study

characteristics). Any disagreement was resolved by
consensus or, where necessary, a third reviewer was
term.

consulted.
special care with respiratory
morbidity and admission to

Risk of Bias in Individual Studies and Quality of the

Evidence

Two different types of quality assessment were covered in this

complications.

overview. One was done through a measurement tool that

evaluated in a critical and practical way the rapid and repro-
Types Objectives

ducible analysis of the quality of the systematic reviews of

RCTs and their interventions, the AMSTAR (A MeaSure
Tool to Assess Systematic Reviews) [11]. All the included
studies

reviews were evaluated through a standard questionnaire,

of

composed of 16 questions, where the provision of an a priori

Table 1 (continued)

definition, the accomplishment of the selection of studies and

the extraction of data in duplicate form, the inclusion of un-
Authors, year

published studies (including and excluded), the evaluation and

documentation of the scientific quality of the included studies,
the use of the scientific quality of the studies included ade-
quately in the formulation of conclusions, and the use of
Reprod. Sci.

Table 2 AMSTAR assessment per reviews

First review author, Review title AMSTAR Criteria

year
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Roberts et al., 2017 Antenatal corticosteroids for accelerating fetal lung Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y

maturation for women at risk of preterm birth
Mwansa-Kambafwile Antenatal steroids in preterm labour for the prevention Y PY Y PY Y Y PY Y Y Y Y Y Y N Y Y
et al., 2010 of neonatal deaths due to complications of preterm
birth
McLaughlin et al., Effects of a single course of corticosteroids given more Y PY Y Y Y Y N Y Y Y Y Y Y Y N Y
2003 than 7 days before birth: a systematic review
Crowley, 1992 Corticosteroids after preterm premature rupture of Y N Y N N N N PY N Y Y N N N N Y
membranes
Harding et al., 2001 Do antenatal corticosteroids help in the setting of Y PY Y Y Y Y PY N N Y Y N N N N Y
preterm rupture of membranes?
Crowley et al., 1990 The effects of corticosteroid administration before Y PY Y N Y Y Y Y PY Y Y Y Y N N Y
preterm delivery: an overview of the evidence from
controlled trials
Peltoniemi; Kari; Repeated antenatal corticosteroid treatment: a Y PY Y PY Y Y N Y N Y Y N N Y N Y
Hallman, 2011 systematic review and meta-analysis
Roberge et al., 2011 Role of Fetal Sex in the Outcome of Antenatal Y PY Y Y Y Y Y Y PY Y Y Y Y Y N Y
Glucocorticoid Treatment to Prevent Respiratory
Distress Syndrome: Systematic Review and
meta-analysis
Saccone; Berghella, Antenatal corticosteroids for maturity of term or near Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
2016 term fetuses: systematic review and meta-analysis of
randomized controlled trials
Sotiriadis et al., 2018 Corticosteroids for preventing neonatal respiratory Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
morbidity after elective caesarean section at term

Legend: Y, yes; PY, partial yes; N, no

appropriate methods for combining study findings and the Results

presentation of conflicts of interest were verified, where they
were reported.
The other tool evaluated the quality of the evidence found
in the included reviews, using the evaluation, development,
and classification approach of recommendations through the
GRADEpro software [12, 13]. The GRADE approach con-
siders five domains: study design, risk of bias, inconsistency
and inaccuracy, publication bias, and plus size and trend in the
effect of each study. The application of these concepts, at each
systematic review, provides a useful approach to determine
the confidence of general prognostic estimates in broad pop-
ulations [14].
Study Selection
We found 354 studies of which 49 duplicate studies were
excluded. After the reading of titles and abstracts, 38 studies
were selected to read the full-texts. We excluded 28 studies for
different reasons: 17 studies were not classified as systematic
reviews, five studies were outdated versions of included re-
views, five had different outcomes than those analyzed by this
study, and, finally, one was misidentified. Subsequent to the
end, ten studies were then included in the overview [16–25]
(Fig. 1).

Data Synthesis and Statistical Analysis
The statistical analysis of the included studies in the systematic
reviews was performed in the RevMan 5.3 software (Review
Manager 5.3) (The Nordic Cochrane Center, The Cochrane
Collaboration). The heterogeneity of the study was determined
by the I2 statistic, in which numbers greater than 75% suggest
substantial heterogeneity. When substantial heterogeneity was
found, no combined estimate was provided [15].
Study Characteristics
The included systematic reviews were published between
1990 and 2018, bringing together RCTs that compare the
efficacy of corticosteroids use in pregnant women at risk of
preterm birth in order to prevent RDS, as well as neonatal and
perinatal death, compared to pregnant women who received
placebo or did not receive treatment. The impact of cortico-
steroid use on RDS was reported in all included reviews. Five
reviews [16, 18, 20, 23, 24] reported the impact on neonatal

Fig. 2 Forest-plot for RDS (a), neonatal death (b), and perinatal death (c)
death. While only two reviews [19, 24] reported the impact of
corticosteroid use on perinatal mortality. The systematic re-
views included in this overview are described in Table 1.
Risk of Bias
An overview of methodological quality using the AMSTAR
tool is shown in Table 2. Six revisions did not present a pro-
tocol developed and registered previously for conducting the
methodology and only one article did not clearly present its
methodology nor did it present the protocol. Two of the in-
cluded articles presented only superficially the methodology,
whereas the other two studies did not present the same clear
form, not even reporting keywords or bases researched. Two
Reprod. Sci.
articles presented the list of excluded articles, but did not
specify the reason for exclusion. Two other articles did not
present the articles excluded, nor did they justify the exclu-
sions made. Three articles did not satisfactorily demonstrate
how the rich biases were evaluated in the studies and did not
describe how they were treated when present. Two articles
only partially fulfilled this item, since they did not specify
the types of biases presented, only cited them as a criterion
of exclusion of studies. All studies provide the principles on
which the decision to perform the meta-analysis for the includ-
ed studies was based. In addition to addressing the extent to
which the studies were compatible, such as in patients, con-
trols, interventions, and using the single-effect value to com-
bine the results. Three articles did not mention whether the
Reprod. Sci.

Fig. 2 continued.

studies that were included in the systematic review had only
low bias risk or, when studies with moderate or high risk of
bias were included, the impact of these biases on the results
was discussed. Six studies did not perform graphical or statis-
tical analysis for this type of bias, or discussed the likelihood
and magnitude of the impact of publication bias in the includ-
ed studies.
Synthesis of Results
RDS
For RDS, 44 RCTs were included. There were 1522 cases of
RDS in 8716 participants in the control group, while in the
intervention group the number of cases was 1088 in a group of
Table 3 GRADE evaluation

GRADEpro analysis for corticosteroids compared to placebo

Certainty assessment Summary of findings

No. of participants Risk of Inconsistency Indirectness Imprecision Publication Overall certainty of Study event rates (%) Relative effect Anticipated absolute effects
(studies) follow-up bias bias evidence (95% CI)
With With Risk with Risk difference with
placebo corticosteroids placebo corticosteroids

Corticosteroid for prevention of perinatal death

6729 (15 RCTs) Seriousa not serious not serious not serious none ⨁⨁⨁◯ 344/3345 264/3384 RR 0.72 (0.58 to 103 per 29 fewer per 1000 (34 fewer
MODERATE (10.3%) (7.8%) 0.89) 1.000 to 11 fewer)
Corticosteroid for prevention of neonatal death
10,494 (31 RCTs) Seriousa Not serious Not serious Not serious None ⨁⨁⨁◯ 343/5248 227/5246 RR 0.66 (0.56 to 65 per 22 fewer per 1000 (29 fewer
MODERATE (6.7%) (4.3%) 0.78) 1.000 to 15 fewer)
Corticosteroid for prevention of RDS
17,456 (44 RCTs) Seriousa Not serious Not serious Not serious None ⨁⨁⨁◯ 1522/8716 1088/8740 RR 0.67 (0.60 to 175 per 58 fewer per 1.000 (70 fewer
MODERATE (17.5%) (12.4%) 0.75) 1.000 to 44 fewer)

Legend: CI, confidence interval; RR, risk ratio

a
Lack of information in primary studies for risk of bias analysis—most of the judgments not clear
Reprod. Sci.
Reprod. Sci.
8740 participants. We found a relative risk found of 0.67 (95%
CI 0.60–0.75) (Fig. 2a).
Neonatal Death
For neonatal death, 31 RCTs were included in five systematic
reviews. There were 343 cases of neonatal death in 5248 par-
ticipants in the control group, while in the group receiving the
intervention, the number of cases was 227 cases in a group of
5246 participants. The relative risk found was 0.66 (95% CI
0.56–0.78) (Fig. 2b).
Perinatal Death
For perinatal death, 15 RCTs were included in two systematic
reviews. There were 344 cases of perinatal death in 3345
participants in the control group, while in the group receiving
the intervention, the number of cases was 264 cases in a group
of 3384 participants. The relative risk was found to be 0.72
(95% CI 0.58–0.89) (Fig. 2c).
Quality of Evidence
Regarding the evaluation by the GRADEpro software
(Table 3), for RDS, the placebo event rate was 17.5% and
corticosteroid use was 12.4%. For neonatal death, the placebo
event rate was 6.5%, and corticosteroid use was 4.3%. For
perinatal death, the placebo event rate was 10.3%, with corti-
costeroid use being 7.8%. The studies were classified as hav-
ing a serious risk of bias, as some primary studies did not
present enough information to analyze the risk of bias, making
most of the judgments not clear, as presented in the AMSTAR
evaluation. Thus, the general view of the degree of evidence
was classified as moderate for all three outcomes.
Discussion
The outcomes found in this overview also corroborate the
positive evidence that the use of corticosteroids in pregnant
women at risk of preterm birth is actually effective in reducing
the risk of RDS, neonatal death, and perinatal premature in-
fants. The meta-analyses found to reduce the risk of RDS,
neonatal death, and perinatal death were favorable for the
use of antenatal corticosteroids, supporting the use of the med-
ication in cases in which there is a risk of preterm delivery. In
eight of the nine systematic reviews included, the efficacy of
corticosteroids can be verified. The only review that showed
no effect for RDS and still reported increased neonatal death
and perinatal death was that of McLaughlin et al. [19].
However, these negative results presented by the authors did
not interfere with the positive result of the meta-analyses per-
formed in this overview.
In addition to the positive evaluations presented here in
systematic reviews with meta-analysis, positive results from
corticosteroid use are also expressed in cohort studies, such as
those of Drummond et al. [26], who monitored from 2006 to
2011, involving 220 patients. Of the 182 newborns exposed to
corticosteroid therapy, only 27 died, while 38 of the non-
exposed group died. Thus, the chance of mortality was three
times higher in the group that was not exposed to the inter-
vention. In a prospective study by Travers et al. [27], the
mortality rate due to RDS was lower in neonates exposed
(7.2%) to prenatal corticosteroids compared to that in unex-
posed neonates (13.2%). A retrospective study performed by
Meneguel et al. [28] demonstrated that RDS occurred in 52 of
205 patients exposed to corticosteroid therapy, while 101 of
205 unexposed patients suffered from morbidity. The results
showed that antenatal corticosteroids had a significant protec-
tive role, reducing the occurrence of RDS in the study popu-
lation by more than 50%.
In an overview of systematic reviews, performed by Lassi
et al. [29], which evaluated interventions capable of improv-
ing neonatal health and post-partum survival, it has been re-
ported that the administration of prenatal corticosteroids in
pregnant women at risk of preterm birth can prevent the deaths
of newborns with RDS. The overview suggests half of the risk
can reduce of death among those born prematurely, if effective
interventions, such as antenatal corticosteroids, are adopted
according to patient’s clinical indications, aiming for a neces-
sary improvement in neonatal and child outcomes across the
world, especially in low- and middle-income countries, where
health care resources are scarcer.
The evidence found in several published studies on the use of
the intervention in pregnant women at risk of preterm delivery
supported the increase of the use of the drug and with that, some
doubts arose, mainly regarding the effectiveness of the treatment
in different gestational periods in that the administration is per-
formed, in addition to the effectiveness of the use of single and
multiple applications. Therefore, new studies have emerged that
evaluate and address treatment for these outcomes. In the reviews
included in this overview, the best efficacy of the drugs occurs in
the earlier periods of pregnancy.
Another important factor to take into consideration is
whether the time that the delivery will take to occur after the
administration will be enough for the corticosteroid to take
effect. The study by Shahzad and Umar (2016) followed up
two groups receiving DXM, one received the drug during the
effective period, and delivery occurred after 48 h or before
7 days of administration, and the other group received after
delivery, and delivery occurred within 48 h or 7 days after
administration [30]. The group in which delivery occurred
after 24 h of the last dose of DXM and before 7 days had a
better efficacy compared to the other group.
As for the effect of multiple or single applications,
Walfisch et al. [31], who carried out a systematic review,

reported a favorable and well-established risk-benefit for sin-
gle antenatal corticosteroid applications in women at risk of
preterm birth. The multiple treatments with BTM, done with
weekly or biweekly repetitions, proved to be efficient for a
significant reduction in the incidence of RDS. However, that
drug repetition is detrimental to the intrauterine growth of the
fetus, leading to decreased head circumference, weight, and
length at birth, as observed in other studies.
Thus, studies demonstrate the use of the drug leads to pos-
itive responses regarding the reduction of the risk of RDS,
neonatal and perinatal death, when the application is per-
formed from the 24th week of gestation until the 34th week
of gestation, preferably in single doses, when delivery takes
place after 48 h or within 7 days of the application so that there
is sufficient time for the intervention have an effect. Similarly,
there was no meeting of major adverse effects in the neonate,
when followed these recommendations.
Conclusion
It has been found that the use of corticosteroids during preg-
nancy in pregnant women at risk of preterm birth is signifi-
cant, being effective for the prevention of RDS, in addition to
collaborating in reducing the number of neonatal deaths and
perinatal deaths.
Author Contributions MLR Uggioni: Protocol/project development, data
collection and management, data analysis, statistical analysis, and manu-
script writing/editing. T Colonetti: Data collection or management, data
analysis, and manuscript writing/editing. AJ Grande: Data collection or
management, data analysis, and manuscript writing/editing. MVB Cruz:
Manuscript writing/editing. MI Rosa: Protocol/project development, data
collection or management, data analysis, statistical analysis, and manu-
script writing/editing.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict of
interest.
References
1. Goldenberg R, Culhane JF, Iams J, Romero R. Epidemiology and
causes of preterm birth. Lancet. 2007;371:73–82.
2. Montenegro CAB, Rezende Filho J. (Org.). Rezende obstetrícia.
13. ed. Rio de Janeiro: Guanabara Koogan, 2017.
3. Iams JD, Berghella V. Care for women with prior preterm birth. Am
J Obstet Gynecol. 2010;203(2):89–100.
4. Hamilton BE, Martin JA, Ventura SJ. Births: preliminary data for
2007. Natl Vital Stat Rep. 2009;12:1–23.
5. Hodek JM, von der Schulenburg JM, Mittendorf T. Measuring
economic consequences of preterm birth-methodological recom-
mendations for the evaluation of personal burden on children and
their caregivers. Health economics reviews. 2011;1(1):6.
Reprod. Sci.
6. Nascimento Júnior FJM, da Silva JVF, Rodrigues APRA, Ferreira
ALC. A síndrome do desconforto respiratório do recém-nascido:
fisiopatologia e desafios assistenciais. Caderno de Graduação-
Ciências Biológicas e da Saúde-UNIT-ALAGOAS. 2014;2(2):
189–98.
7. Ramos JG, Urbanetz AA. Programa de Atualização em
Ginecologia e Obstetrícia (PROAGO). Artmed/Panamericana:
Porto Alegre; 2004.
8. Ballard PL, Ballard RA. Scientific basis and therapeutic regimens
for use of antenatal glucocorticoids. Am J Obstet Gynecol.
1995;173:254–62.
9. Bornia RG, Costa Júnior IB, Amim Junior J. Protocolos
assistenciais: Maternidade Escola da Universidade Federal do Rio
de Janeiro: coletânea de artigos: anestesiologia, neonatologia,
obstetrícia. Rio de Janeiro: Pod; 2013.
10. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal
lung maturation for women at risk of preterm birth. Cochrane
Database Syst Rev. 2006 Jul;19(3):CD004454. https://doi.org/10.
1002/14651858.CD004454.pub2.
11. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel
C, et al. Development of AMSTAR: a measurement tool to assess
the methodological quality of systematic reviews. BMC Med Res
Methodol. 2007;7(1):10.
12. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-
Coello P, et al. GRADE: an emerging consensus on rating quality of
evidence and strength of recommendations. BMJ. 2008;336(7650):
924–6.
13. Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S,
et al. Grading quality of evidence and strength of recommendations.
BMJ. 2004;328(7454):1490.
14. Iorio A, Spencer FA, Falavigna M, Alba C, Lang E, Burnand B,
et al. Use of GRADE for assessment of evidence about prognosis:
rating confidence in estimates of event rates in broad categories of
patients. BMJ. 2015;350:870.
15. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control
Clin Trials. 1986;7(3):177–88.
16. Crowley P, Chalmers I, Keirse MJ. The effects of corticosteroid
administration before preterm delivery: an overview of the evidence
from controlled trials. BJOG Int J Obstet Gynaecol. 1990;97(1):11–
25.
17. Crowley P. Corticosteroids after preterm premature rupture of
membranes. Obstet Gynecol Clin N Am. 1992;19(2):317–26.
18. Harding JE, Pang JM, Knight DB, Liggins GC. Do antenatal corti-
costeroids help in the setting of preterm rupture of membranes? Am
J Obstet Gynecol. 2001;184(2):131–9.
19. McLaughlin KJ, Crowther CA, Walker N, Harding JE. Effects of a
single course of corticosteroids given more than 7 days before birth:
a systematic review. Aust N Z J Obstet Gynaecol. 2003;43(2):101–
6.
20. Mwansa-Kambafwile J, Cousens S, Hansen T, Lawn JE. Antenatal
steroids in preterm labour for the prevention of neonatal deaths due
to complications of preterm birth. Int J Epidemiol. 2010;39(1):122–
33.
21. Roberge S, Lacasse Y, Tapp S, Tremblay Y, Kari A, Liu J, et al.
Role of fetal sex in the outcome of antenatal glucocorticoid treat-
ment to prevent respiratory distress syndrome: systematic review
and meta-analysis. J Obstet Gynaecol Can. 2011 Mar;33(3):216–
26.
22. Peltoniemi OM, Kari MA, Hallman M. Repeated antenatal cortico-
steroid treatment: a systematic review and meta-analysis. Acta
Obstet Gynecol Scand. 2011;90(7):719–2. https://doi.org/10.1111/
j.1600-0412.2011.01132.x.
23. Saccone G, Berghella V. Antenatal corticosteroids for maturity of
term or near term fetuses: systematic review and meta-analysis of
randomized controlled trials. BMJ. 2016;12:355–5044. https://doi.
org/10.1136/bmj.i5044.
Reprod. Sci.
24. Roberts D, Brown J, Medley N, Dalziel SR. Antenatal corticoste-
roids for accelerating fetal lung maturation for women at risk of
preterm birth. Cochrane Database Syst Rev. 2017;3:Cd004454.
25. Sotiriadis A, Makrydimas G, Papatheodorou S, Ioannidis JP,
McGoldrick E. Corticosteroids for preventing neonatal respiratory
morbidity after elective caesarean section at term. Cochrane
Database Syst Rev. 2018;8.
26. Drummond S, Souza TS, Lima FGD, Vieira AA. Correlação entre o
uso de corticoterapia antenatal, a reanimação e a mortalidade de
recém-nascidos prematuros de muito baixo peso. Rev Bras
Ginecol Obstet. 2014;36(5):211–5.
27. Travers CP, Carlo WA, McDonald SA, Das A, Bell EF,
Ambalavanan N, et al. Mortality and pulmonary outcomes of ex-
tremely preterm infants exposed to antenatal corticosteroids. Am J
Obstet Gynecol. 2018;218(1):130–e1.
28. Meneguel JF, Guinsburg R, Miyoshi MH, Peres CDA, Russo RH,
Kopelman BI, et al. Antenatal treatment with corticosteroids for
preterm neonates: impact on the incidence of respiratory distress
syndrome and intra-hospital mortality. Sao Paulo Med J.
2003;121(2):45–52.
29. Lassi ZS, Middleton PF, Crowther C, Bhutta ZA. Interventions to
improve neonatal health and later survival: an overview of system-
atic reviews. EBioMedicine. 2015;2(8):985–1000.
30. Shahzad F, Umar N. Impact of antenatal corticosteroids on frequen-
cy and mortality due to respiratory distress syndrome in preterm
neonates. Journal of Ayub Medical College Abbottabad.
2016;28(4):698–701.
31. Walfisch A, Hallak M, Mazor M. Multiple courses of antenatal
steroids: risks and benefits. Obstet Gynecol. 2001;98(3):491–7.
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