European Journal of Obstetrics & Gynecology and Reproductive Biology 234 (2019) 32–37

Contents lists available at ScienceDirect

European Journal of Obstetrics & Gynecology and

Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb

Review article

Antenatal corticosteroid therapy: Historical and scientific basis to

improve preterm birth management
Carlos Briceño-Péreza , Eduardo Reyna-Villasmilb , Paulino Vigil-De-Graciac,d,*
a
Department of Obstetrics and Gynecology, University of Zulia, Maracaibo, Venezuela
b
Hospital Central Dr. Urquinaona”, Maracaibo, Venezuela
c
Complejo Hospitalario de la Caja de Seguro Social, Panama
d
Investigador distinguido del Sistema Nacional de Investigación, SENACYT, Panama

A R T I C L E I N F O A B S T R A C T

Article history: Objective: The purpose of this review is to describe the historical and scientific basis of antenatal
Received 4 December 2018 corticosteroids (ACS) therapy, to improve the management of preterm birth and decreasing rates of
Received in revised form 18 December 2018 respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis and perinatal
Accepted 19 December 2018
mortality in premature infants.
Available online xxx
Study design: We searched MEDLINE/PubMed electronic database, the Cochrane Library, using medical
subheading search words such as “ACS”, “corticosteroids”, “betamethasone” or “dexamethasone”,
Keywords:
matching with “preterm birth”.
Antenatal corticosteroids
Therapy
Results: This practice was initiated by Liggins and Howie in 1972 and is supported by the initial
Betamethasone comprehensive meta-analysis of Crowley, Chambers and Keirse, in 1990, the NIH Consensus Development
Dexamethasone Conference in 1994, the second Consensus Conference to evaluate repeated courses of corticosteroids in
Fetal lung maturation 2000 and the practice recommendations of obstetric societies worldwide. ACS therapy before anticipated
preterm birth is one of the most important antenatal therapies and an important evidence-based practice for
reducing mortality, and decreasing rates of complications in premature infants.
Conclusions: Today, there is no controversy that women with preterm birth <34 weeks should be ACS
treated. Actually, rescue courses are recommended; while multiple, serial, repeated or weekly courses, are
not recommended. In any clinical conditions, as preterm premature rupture of membranes, multiple
pregnancies, severe preeclampsia/HELLP syndrome and fetal growth restriction; ACS is recommended.
© 2019 Elsevier B.V. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Antenatal corticosteroids therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
A single course of corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Multiple, repeated, serial or weekly courses of corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Rescue course of corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Partial course of corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
ACS in the term period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
ACS in the late preterm period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
ACS in the periviability period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
ACS in preterm premature rupture of membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
ACS in multiple pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
ACS in severe preeclampsia/HELLP syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
ACS in fetal growth restriction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Corticosteroids long-term risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

* Corresponding author at: Complejo Hospitalario de la Caja de Seguro Social, Panama.

E-mail address: pvigild@hotmail.com (P. Vigil-De-Gracia).

https://doi.org/10.1016/j.ejogrb.2018.12.025
0301-2115/© 2019 Elsevier B.V. All rights reserved.
 C. Briceño-Pérez et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 234 (2019) 32–37 33

Summary and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

Author contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Disclosure of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

Introduction phosphate/acetate 24 mg and reducing the incidence of respiratory

distress syndrome and perinatal mortality was significant between
Preterm birth is the leading cause of neonatal mortality and the 2–7 days after starting treatment and before 32 pregnancy
most common reason for antenatal hospitalization. In the United weeks’ [10].
States of America (USA), approximately 12% of all live births occur In USA, in 1974, despite these results, there was no certainty of
before term, and preterm labor preceded approximately 50% of the effectiveness of ACS, therefore, the National Institutes of Health
these preterm births. Preterm birth account for approximately 70% (NIH) sponsored a workshop on "Possible mechanisms to facilitate
of neonatal deaths and 36% of infant deaths as well as 25–50% of lung maturity" and participants recommended perform a ran-
cases of long-term neurologic impairment in children [1–4]. domized controlled trial for these purposes. This research was
Antenatal corticosteroids (ACS) therapy before anticipated started in 1976 and published in 1981 [11]. This collaborative study
preterm birth is one of the most important antenatal therapies showed that maternal administration of dexamethasone before
available to improve newborn outcomes and an important the preterm birth (5 mg intramuscular every 12 h for four doses, a
evidence-based practice for reducing mortality, and decreasing total of 20 mg) decreased the incidence of respiratory distress
rates of respiratory distress syndrome, intraventricular hemor- syndrome in the newborn [11].
rhage, and necrotizing enterocolitis in premature infants [2,5–9]. Over the next 18 years (1972–1990), numerous other inves-
Other less well-described clinical benefits of corticosteroids may tigators would duplicate Liggins’ findings, confirming a decrease in
contribute to the survival of very preterm infants, as effects on respiratory distress syndrome and neonatal mortality, after
neonatal adaptation, increased blood pressure and cardiovascular corticosteroids administration. Eighteen years after Liggins’ initial
adaptation, better metabolic transition, improved kidney function work, clinicians were still divided on the appropriate course of
and skin cornification with less transdermal water loss.9 Cortico- action. No consensus had been reached among any of the
steroids have proved to be remarkably safe without short term governing bodies, such as the American College of Obstetricians
adverse effects being identified over many years of use [9]. Today, and Gynecologists (ACOG) and the NIH [12]. This began to change
there is no controversy that women with preterm birth <34 in 1990, with the publication of a meta-analysis by Crowley,
pregnancy weeks’ should be treated with ACS [1,2,6,7,9]. Chalmers and Keirse13 that analyzed the results of 12 randomized
Clinicians are not treating many patients who might benefit controlled trials incorporating over 3000 patient participants,
because of concerns about the efficacy of corticosteroids and the which clearly demonstrated benefit of corticosteroids in reducing
potential complications of treatment in certain conditions. Use of respiratory distress syndrome in all examined subgroups and this
this therapy is further impeded by lack of access to prenatal care decrease was associated with decreases intraventricular hemor-
and to appropriate delivery services [5]. rhage, necrotizing enterocolitis and neonatal death [12,13]. This led
The aim of this review is to describe the historical and scientific to in 1992, the Royal College of Obstetricians and Gynaecologists
basis of ACS, to improve the management of preterm birth and (RCOG) in the United Kingdom (UK), recommending its members,
decreasing rates of respiratory distress syndrome, intraventricular use ACS in all cases in which it had the possibility of respiratory
hemorrhage, necrotizing enterocolitis and perinatal mortality in distress syndrome may occur after delivery [14]. In USA, the
premature infants. routine use ACS for this purpose, remained low.
The use of corticosteroids began to increase in 1994 after an NIH
Materials and methods sponsored consensus conference [12]. In 1995, Dr. Patricia Crowley
published a great meta-analysis of 15 randomized controlled trials
We searched MEDLINE/PubMed electronic database, the on corticosteroids, carried out between 1972–1994, confined
Cochrane Library, using medical subheading search words such exclusively to randomized controlled trials [15]. In this trial,
as “ACS”, “corticosteroids”, “betamethasone” or “dexamethasone”, corticosteroids reduced by approximately 50%, the total risk of
matching with “preterm birth”; from june 2016 to december 2017. respiratory distress syndrome and showed a more marked benefit
Additional articles were obtained from the cross-references of the between 24 h and seven days. Unlike previous trials, the benefit
relevant publications for bibliographical purpose. Of all the found, was not confined only to 30–34 pregnancy weeks’ group, but <31
articles we chose meanly published in english language journals pregnancy weeks’ group also benefitted. Benefits over respiratory
and the english abstracts of original articles in other languages. morbidity had a domino effect on the reduction of cerebral
Eligibility and articles quality were assessed. We included studies intraventricular hemorrhage, necrotizing enterocolitis and possi-
that describe historical and relevant utility of the studied theme. In bly hyperbilirubinemia and not found effects on the ductus
the analysis, we selected 43 bibliographic references. arteriosus persistence. Neonatal mortality was substantially
reduced. Monitoring of physical growth in three trials (follow
Antenatal corticosteroids therapy up 3, 6 and up to 12 years old) showed no adverse long-term effects
and found no evidence of impaired lung growth. [15]. To meta-
A single course of corticosteroids analysis by Crowley et al. [13] in the UK with 12 randomized
controlled trials and by Crowley [15] in USA with 15 randomized
While researching the effects of dexamethasone on premature controlled trials, another meta-analysis added by Sinclair [16],
parturition in fetal sheep in 1969, Liggins found that there was with similar results. Therefore, in 1994, NIH sponsored a meeting
some inflation of the lungs of lambs born at gestations at which the entitled "Effects of corticosteroids for fetal maturation on perinatal
lungs would be expected to be airless. Liggins and Howie [10] outcomes" in 1994, in order to assess the available data on the
published the first randomized controlled trial in humans in 1972 prenatal treatment with ACS and develop a consensus, and
and many others followed [6]. They used betamethasone concluded that corticosteroids reduces respiratory distress
34 C. Briceño-Pérez et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 234 (2019) 32–37
syndrome, intraventricular hemorrhage and mortality in preterm
infants [5]. Although the beneficial effects are higher within 24 h of
starting treatment and seven days after use, outcomes improve
before 24 h too. Regarding the type of corticosteroids, preferred are
betamethasone and dexamethasone, because both have identical
biological activity, cross the placenta into its active form, are
devoid of mineralocorticoid activity, the immunosuppressive
effect is weak, has a duration of action greater than cortisol and
methylprednisolone and are the most searched. Treatment with a
single course (Table 1) uses betamethasone phosphate/acetate at
two intramuscular doses of 12 mg 24 h apart (total 24 mg); and
dexamethasone phosphate at four intramuscular doses of 6 mg
every 12 h (total 24 mg) [2,5,7,9,10]. These regimes were chosen to
be comparable to the physiological cortisol levels. Follow up
12 years old data, indicate that ACS therapy does not affect physical
growth or psychomotor development. This treatment is indicated
for women at risk of preterm birth, with very few exceptions, and
results in a substantial reduction in neonatal morbidity and
mortality; as well as substantial cost savings in health care [5].
ACS used for prevention of perinatal morbidity and mortality,
increased next years (1994–2000) after the NIH Consensus
Conference. In addition, there were some statements and some
health institutions established positions and endorsed the NIH
Consensus findings [2,7]. Today, there is no controversy that
women with preterm birth <32–34 pregnancy weeks’, should be
ACS treated [1,2,5,7,9,17]. Evidence supports the continued use of a
single course of antenatal corticosteroids to accelerate fetal lung
maturation in women at risk of preterm birth. A single course of
antenatal corticosteroids could be considered routine for preterm
delivery [6]. It is recommended for pregnant women between 24 0/
7 weeks and 33 6/7 weeks of gestation who are at risk of preterm
delivery within 7 days, including for those with ruptured
membranes and multiple gestations. It also may be considered
for pregnant women starting at 23 0/7 weeks of gestation who are
at risk of preterm delivery within 7 days, based on a family’s
decision regarding resuscitation, irrespective of membrane rup-
ture status and regardless of fetal number. Administration of
betamethasone may be considered in pregnant women between
34 0/7 weeks and 36 6/7 weeks of gestation who are at risk of
preterm birth within 7 days, and who have not received a previous
course of antenatal corticosteroids. A single repeat course of
antenatal corticosteroids should be considered in women who are
less than 34 0/7 weeks of gestation who are at risk of preterm
delivery within 7 days, and whose prior course of antenatal
corticosteroids was administered more than 14 days previously.
Rescue course corticosteroids could be provided as early as seven
days from the prior dose, if indicated by the clinical scenario [7].
Multiple, repeated, serial or weekly courses of corticosteroids
In August, 17th and 18th, 2000, NIH sponsored another
consensus meeting to discuss the usefulness of the corticosteroids
repeated courses [17]. In this meeting, the 1994 outcomes were
confirmed, in the type of used corticosteroids, reasons for use,
therapeutic regimens, clinical situations, gestational age and time
of administration. Moreover, the 1994 consensus panel had
Table 1
Scheme of a single course of antenatal corticosteroids.
Type of corticosteroid Salt Dose (mg)
Betamethasone Phosphate/acetate 12
Dexamethasone Phosphate 6 4
mg: milligrams h: hours.
reported that the benefits and risks of corticosteroids repeated
courses were unknown and urged to investigate this aspect. If
between 24–34 pregnancy weeks’ after giving the corticosteroids
initial single course before the imminent birth, weekly doses are
repeated, we are in the presence of multiple, repeated, serial or
weekly courses. The 2000 consensus panel issued the following
conclusions: [17] 1. The collective international data continue to
support unequivocally the use and efficacy of a single course of
corticosteroids, 2. The current benefit and risk data are insufficient
to support the routine use of repeat or rescue courses of
corticosteroids and, 3. Clinical trials are in progress to assess
potential benefits and risks of various regimens of repeat courses.
Repeat courses of corticosteroids, including rescue therapy, should
be reserved for patients enrolled in clinical trials.17
In the next years, the main scientific and health institutions
around the world have approved and supported the 2000 NIH
Consensus conclusions on corticosteroids repeated courses and the
1994 conclusions [2,7].
Rescue course of corticosteroids
Meanwhile, in the 2000s, there were doubts about the
persistence of the effect of corticosteroids after elapsed 1–2 weeks
of the starting simple course, so came the ability to manage a
rescue course (when after seven or more days of receiving a single
corticosteroids course, another course is received, the imminent
probability of preterm birth). In 2009, a randomized controlled
trial that used a rescue course in 437 patients who had received an
corticosteroids simple course before 30 pregnancy weeks’ and at
least 14 days before inclusion persistent preterm birth threat, and
found significant reduction of the respiratory distress syndrome,
need for surfactant and composed perinatal morbidity birth before
34 weeks. [18] In 2011, the ACOG recommended to administer a
rescue course if there is a history management a previous single
course, gestational age is <32.6 weeks and there is clinical
probability of preterm birth in the next 7 days [19]. In 2010 a
rescue curse of corticosteroids had been approved by the RCOG in
the UK [20].
Partial course of corticosteroids
Because corticosteroids for less than 24 h is still associated with
significant reduction in neonatal morbidity and mortality, a first
dose of corticosteroids should be administered even if the ability to
give the second dose is unlikely, based on the clinical scenario
[2,7,9,17].
ACS in the term period
Recently the administration of ACS beyond 34 pregnancy
weeks’ has been controversial. Regarding the term period ACS
administration, three randomized controlled trials have been
published [21–23]. These three trials demonstrated a low
incidence of respiratory related adverse outcomes such as
respiratory distress syndrome after cesarean delivery at term,
and the greatest effect of corticosteroids exposure in reduction of
Number of doses Dose interval Total dose (mg) Use
(h)
2 24 h apart 24 Intramuscularly
Every 24 Intramuscularly
6h
 C. Briceño-Pérez et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 234 (2019) 32–37
respiratory morbidity is related to transitory tachypnea of
newborn. However, a Cochrane review [24] concluded that
although the results of ASTECS study [21] are promising, more
studies are needed. Due to lack of evidence on the safety of steroid
use after 36 pregnancy weeks’, the RCOG in the UK, recommends
that rather than administer corticosteroids, C-sections should be
delayed until 39 weeks [20].
ACS in the late preterm period
Late preterm neonates (34.0 to 36.6 pregnancy weeks’) are at
risk for significant morbidities, including respiratory distress
syndrome because pulmonary maturation continues through the
late preterm period into early childhood [25]. ACS has not been
recommended for women during late preterm period birth
because of the lack of supportive data from randomized controlled
trials [25] and meta-analysis [6,13,15,16]. Recently, three studies
[26–28] have confirmed the previous 25 randomized controlled
trials findings that corticosteroids beyond 34 weeks does not
reduce the respiratory distress syndrome. On the other hand, four
recent data [29–32] suggest that betamethasone can be beneficial
in pregnant women at high risk of late preterm birth, between
34,0–36,6 weeks of gestation who have not received a prior course
of corticosteroids. In April 2016, was published the "Antenatal
betamethasone for women at risk for late preterm delivery" study
or ALPS study,[32] the largest (2.831 patients) and more
meticulous double blind randomized controlled trial, finding a
significant decrease in both the primary outcome consisting of
respiratory morbidity compound (respiratory distress syndrome,
transitory tachypnea of newborn and apnea, postnatal surfactant
use and postnatal need for immediate resuscitation) and mortality
in the first 72 h after birth as in other secondary parameters.32] So
strong results led to the Society for Maternal Fetal Medicine, [25] to
issue a statement which recommends administering a betame-
thasone single course to women with singleton pregnancies
between 34,0–36.6 weeks and risk of preterm birth in the next
seven days (but before 37 weeks). And recently, the ACOG
recommends to administer a single course of betamethasone for
pregnant women between 34.0–36.6 weeks of gestation at risk of
preterm birth within seven days, and who received a previous
course of corticosteroids [7]. There is no international consensus as
to the use of ACS > 34 weeks [9].
ACS in the periviability period
Periviable birth is delivery occurring from 20 0/7 weeks to 25 6/
7 weeks of gestation. [33] Data from large neonatal databases
document that infants born around the limits of viability have high
mortality and morbidity rates. Broad application of interventions
proven to be effective at more advanced gestational ages, such as
an corticosteroids single course. Two recent meta-analyses [6,34]
confirmed that published data do not demonstrate that ACS
improve outcomes at less than 26 weeks' gestation. However, the
small number of infants born at gestational ages around the
limits of viability and included in published trials limits these
results [6,34].
Data from an NICHD Neonatal Research Network observational
cohort [35] revealed a reduction in death and neurodevelopmental
impairment at 18–22 months for infants who had been exposed to
corticosteroids and born at 23 0/7 weeks through 23 6/7 weeks of
gestation, 24 0/7 weeks through 24 6/7 weeks of gestation and 25
0/7 weeks through 25 6/7 weeks of gestation [7,35]. At 22 0/7
weeks through 22 6/7 weeks of gestation, no significant difference
in these outcomes was noted [35]. In this study, corticosteroids
exposure also decreased incidence of death, intraventricular
hemorrhage, periventricular leukomalacia, and necrotizing
35
enterocolitis in infants born between 23 0/7 weeks and 25 6/7
weeks of gestation [35]. A single course of corticosteroids is
recommended for pregnant women between 24 0/7 weeks and 33
6/7 weeks of gestation, and may be considered for pregnant
women starting at 23 0/7 weeks of gestation who are at risk of
preterm delivery within seven days [2,7,36]. It is linked to a
family’s decision regarding resuscitation and should be considered
in that context [7,36].
ACS in preterm premature rupture of membranes
Current data suggest that ACS is not associated with increased
risks of maternal or neonatal infection regardless of gestational
age. [7] The overall evidence supports the administration of
corticosteroids in patients with preterm premature rupture of
membranes up to 32–34 weeks in the absence of chorioamnionitis.
However, delivery should not be delayed in the setting of clinical
chorioamnionitis to allow the administration of corticosteroids
[7,15,37].
A single course of corticosteroids is recommended for pregnant
women with ruptured membranes between 24 0/7 weeks and 33
6/7 weeks of gestation [5,7,17]. It also may be considered for
pregnant women starting at 23 0/7 of gestation who are at risk of
preterm delivery within seven days, irrespective of membrane
rupture status. Whether to administer a repeat or rescue course of
corticosteroids with preterm premature rupture of membranes is
controversial, and there is insufficient evidence to make a
recommendation for or against [7].
ACS in multiple pregnancy
While the number of studied twin gestations is relatively small,
there is evidence of a salutary effect of corticosteroids on neonatal
respiratory distress syndrome. It is also more important (than in
singletons) that treatment occurs within one to seven days before
delivery (rather than 10 or 14) to have the maximal effect on
respiratory distress syndrome [37].
Unless a contraindication exists, a single course of corticoste-
roids should be administered to all patients who are between 24 0/
7 weeks and 33 6/7 weeks of gestation and at risk of delivery
within seven days, regardless of fetal number [5,7,17]. In the
absence of data, it is reasonable to extend this so that ACS may be
administered for pregnant women starting at 23 0/7 weeks,
regardless of fetal number [7].
ACS in severe preeclampsia/HELLP syndrome
ACS is beneficial for preterm infants of women with HELLP
(hemolysis, elevated liver enzymes, low platelets) syndrome/
severe preeclampsia [37].
ACS in fetal growth restriction
The effect on corticosteroids administration on fetal growth
restriction is conflicting, with large cohort studies revealing
significantly lower rates of respiratory distress syndrome, intra-
ventricular hemorrhage and prenatal death. Accordingly, ACS for
these patients should be individualized. In the largest cohort study,
there were greater survival and less disability at two years of age
with steroid treatment. The benefit of maternal steroids in fetal
growth restriction outweighs the possible adverse effects [37].
Corticosteroids long-term risks
The concern that corticosteroids may have the potential to
adversely affect neurodevelopmental outcomes is largely based on
36 C. Briceño-Pérez et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 234 (2019) 32–37

animal data and from studies of multiple corticosteroids courses
[7,38]. The Maternal Fetal Medicine Units study of repeat course
corticosteroids suggested that four or more courses may be
associated with the development of cerebral palsy [38]. However,
numerous studies have shown no evidence of long-term harm,
particularly as it relates to a single course of corticosteroids
administered at less than 34 0/7 weeks of gestation [6,7,39]. The
only data available about long-term neurocognitive outcomes after
late preterm administration of corticosteroids compared with
placebo come from the initial corticosteroids study [10]. The
31-year neurodevelopmental follow-up of this cohort [40] was
exposed to corticosteroids from 30.9 to 34.6 weeks of gestation and
delivered at a median of 35 weeks of gestation (range 33.4–38.0
weeks of gestation). Cognitive functioning, working memory and
attention and other neurocognitive assessments were not different
between exposure groups and concluded that prenatal exposure to
a single course of betamethasone does not alter cognitive
functioning, working memory and attention, psychiatric morbidi-
ty, handedness or health related quality of life in adulthood; and
that Obstetricians should continue to use a single course of
antenatal betamethasone for the prevention of neonatal respira-
tory distress syndrome [40].
The 30-year lung function follow-up of this cohort exposed to
corticosteroids was evaluated by Dalziel et al. [41] in 534 subjects
whose mothers had participated in the first randomized controlled
trial of antenatal betamethasone. There were no differences in lung
function between betamethasone and placebo exposed groups
forced vital capacity in the betamethasone and placebo groups,
forced expiratory volume in 1 s in the betamethasone and placebo
groups. They concluded that antenatal exposure to a single course
of betamethasone, does not alter lung function or the prevalence of
wheeze and asthma at age 30 [41].
The 30-year cardiovascular risk factors follow-up of this cohort
exposed to corticosteroids was published by Dalziel et al. [42] in
2005: they followed up at age 30 years 534 individuals whose
mothers participated in a double-blind, placebo-controlled,
randomized trial of antenatal betamethasone for the prevention
of neonatal respiratory distress syndrome. After a 75 g oral glucose
tolerance test, participants exposed to betamethasone had higher
plasma insulin concentrations at 300 and lower glucose concen-
trations at 1200 than did those exposed to placebo. They concluded
that antenatal exposure to betamethasone might result in insulin
resistance in adult offspring, but has no clinical effect on
cardiovascular risk factors at 30 years of age. Thus, obstetricians
should continue to use a single course of antenatal betamethasone
for the prevention of neonatal respiratory distress syndrome [42].
A final additional consideration regarding corticosteroids risks
is that in the context of maternal critical care, ACS is not
contraindicated, even in the setting of sepsis. [7,36,43]
Summary and conclusions
 ACS therapy before anticipated preterm birth is one of the most
important antenatal therapies and an important evidence-based
practice for reducing mortality, and decreasing rates of
respiratory distress syndrome, intraventricular hemorrhage,
and necrotizing enterocolitis in premature infants. The benefits
of treatment in the <34 week gestation time period clearly
outweigh the risks [2,6–8]. It is a rare example of a technology
that, in addition to improving health, produces substantial
savings in costs [5].
 Numerous studies have shown no evidence of long-term harm,
particularly as it relates to a single course of corticosteroids
administered at less than 34 0/7 weeks of gestation [6,7,15,39].
 This practice is supported by the initial comprehensive meta-
analysis of Crowley, Chambers and Keirse, in 1990, the NIH
Consensus Development Conference in 1994, the second
Consensus Conference to evaluate repeated courses of cortico-
steroids in 2000 and the practice recommendations of obstetric
societies worldwide [1,2,5,7,13,17].
 Today, there is no controversy that women with preterm
birth <34 pregnancy weeks’, should be ACS treated (Table 2)
[1,2,6,7,9].
 Rescue [19,20] and partial [2,7,17] courses actually are recom-
mended; while multiple, serial, repeated or weekly17] courses
are no recommended.
 In any clinical conditions, as preterm premature rupture of
membranes, multiple pregnancies, severe preeclampsia/HELLP
syndrome and fetal growth restriction; ACS is recommended too
[5,7,17,37].
 Continued surveillance of long-term outcomes after in utero
corticosteroids exposure, should be supported [7].

Table 2
Antenatal corticosteroids therapy to pregnant women who are at risk of preterm birth within 7 days.

Condition Recommendation
23.0-23.6 WG A single course of corticosteroids is recommended, based on a family’s decision regarding resuscitation, irrespective of membrane
rupture status and regardless of fetal number.
24.0-33.6 WG A single course of corticosteroids is recommended, including for those with ruptured membranes and multiple gestations.
34.0-36.6 WG A single course of corticosteroids is recommended, in women who have not received a previous course of corticosteroids.
37.0-38.6 WG Due to lack of evidence on the safety of steroid use after 36 pregnancy weeks’, rather than administer corticosteroids, C-sections
should be delayed until 39 weeks
Single repeat course/Rescue A single repeat course of corticosteroids should be considered in women who are less than 34 0/7 weeks of gestation and whose
course. prior course of corticosteroids was administered more than 14 days previously. A rescue course corticosteroids could be provided as
early as 7 days from the prior dose, if indicated by the clinical scenario
Partial courses A first dose of corticosteroids should be administered even if the ability to give the second dose is unlikely, based on the clinical
scenario.
Multiple, serial, repeated or Actually are no recommended.
weekly courses.
PPROM A single course of corticosteroids is recommended between 24 0/7 weeks and 33 6/7 weeks of gestation. It also may be considered
starting at 23 0/7 of gestation, irrespective of membrane rupture status.
Multiple pregnancies Unless a contraindication exists, a single course of corticosteroids should be administered between 24.0-33.6 weeks of gestation
regardless of fetal number. In the absence of data, it is reasonable to extend this, so that corticosteroids may be administered for
pregnant women starting at 23 0/7 weeks, regardless of fetal number.
HELLP syndrome/severe A single course of corticosteroids is beneficial for preterm infants of women with HELLP syndrome/severe preeclampsia.
preeclampsia
FGR The effect is conflicting, with large cohort studies revealing significantly lower rates of respiratory distress syndrome,
intraventricular hemorrhage and prenatal death. Accordingly, antenatal corticosteroids therapy should be individualized. The
benefit of maternal corticosteroids outweighs the possible adverse effects.

WG: weeks of gestation PPROM: preterm premature rupture of membranes HELLP: hemolysis, elevated liver enzymes, low platelets FGR: fetal growth restriction.
 C. Briceño-Pérez et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 234 (2019) 32–37
 Follow-up studies into childhood and adulthood, particularly in the
late preterm gestation and repeat courses groups, are needed [6].
 Quality improvement strategies to optimize appropriate and
timely ACS administration should be encouraged [7].
Author contributions
CB-P, ER-V and PV-D conceived the study. CB-P, ER-V and PV-D
contributed to its design. CB-P, ER-V and PV-D revised
the manuscript. All authors approved the final manuscript as
submitted.
Disclosure of interest
The authors report no conflict of interest.
References
[1] Wapner R, Jobe A. Controversy: antenatal steroids. Clin Perinatol
2011;38:529–45.
[2] American College of Obstetricians and Gynecologists. Management of preterm
labor. Practice bulletin No. 171. Obstet Gynecol 2016;128(4):e155–64.
[3] American College of Obstetricians and Gynecologists. Prediction and
prevention of preterm birth. Practice bulletin No. 130. Obstet Gynecol
2012;120:964–73.
[4] Briceño-Pérez C. Maduración pulmonar fetal. Prevención exitosa de compli-
caciones y muertes perinatales/Fetal lung maturation. Successful prevention
of perinatal complications and deaths. primera edición/first edition Caracas:
Amolca; 2008. www.amolca.com.
[5] National Institutes of Health Consensus Development Conference Statement.
Effect of corticosteroids for fetal maturation on perinatal outcomes. February
28-March 2, 1994. Am J Obstet Gynecol 1995;(173):246–52.
[6] Roberts D, Brown J, Medley N, Dalziel SR. Antenatal corticosteroids for
accelerating fetal lung maturation for women at risk of preterm birth.
Cochrane Database Syst Rev 2017(3), doi:http://dx.doi.org/10.1002/14651858.
CD004454.pub3 CD004454.
[7] American College of Obstetricians and Gynecologists Committee Opinion
Number 713. Antenatal corticosteroid therapy for fetal lung maturation.
August 2017. Obstet Gynecol 2017;130(2):493–4.
[8] Kamath-Rayne BD, Rozance PJ, Goldenberg RL, Jobe AH. Antenatal corticoste-
roids beyond 34 weeks gestation: What do we do now? Am J Obstet Gynecol
2016;215:423–30.
[9] Jobe A, Goldenberg R. Antenatal corticosteroids: an assessment of anticipated
benefits and potential risks. Am J Obstet Gynecol 2018;219:62–74.
[10] Liggins G, Howie R. A controlled trial of antepartum glucocorticoid treatment
for prevention of the respiratory distress syndrome in premature infants.
Pediatrics 1972;50:515–25.
[11] Collaborative group on antenatal steroid therapy. Effect of antenatal
dexamethasone administration on the prevention of respiratory distress
syndrome. Am J Obstet Gynecol 1981;141:276–87.
[12] Wapner R, Waters T. Introduction and historical perspective. Clin Obstet
Gyecol 2003;46(1):125–31.
[13] Crowley P, Chalmers I, Keirse M. The effects of corticosteroids administration
before preterm delivery: an overview of the evidence from controlled trials. Br
J Obstet Gynecol 1990;97:11–25.
[14] Scientific Advisory Committee. Royal College of Obstetricians and Gynecolo-
gist. Antenatal corticosteroid administration reduces the incidence of neonatal
respiratory distress syndrome. London: Royal College of Obstetricians and
Gynecologist; 1992.
[15] Crowley P. Antenatal corticosteroid therapy: a meta-analysis of the random-
ized trials, 1972 to 1994. Am J Obstet Gynecol 1995;173:322–35.
[16] Sinclair J. Meta-analysis of randomized controlled trials of antenatal
corticosteroid for the prevention of respiratory distress syndrome: discussion.
Am J Obstet Gynecol 1995;173:335–44.
[17] National Institutes of Health Consensus Development Conference Statement.
Antenatal corticosteroids revisited: repeat courses. August 17-18, 2000. Obstet
Gynecol. 2001;17(2):1–10.
[18] Garite TJ, Kurtzman J, Maurel K, Clark R. Impact of a ‘rescue course’ of antenatal
corticosteroids: a multicenter randomized placebo-controlled trial. Obstetrix
Collab Res Network Am J Obstet Gynecol 2009;200(248) e1-248.e9.
[19] American College of Obstetricians and Gynecologists. Antenatal corticosteroid
therapy for fetal lung maturation. Committee Opinion N 475. Obstet Gynecol
2011;117:422–4.
37
[20] Royal College of Obstetricians and Gynecologists. Antenatal corticosteroids to
prevent respiratory distress syndrome. Green top guideline number 7. London:
RCOG; 2010 October.
[21] Stuchfield P, Whitaker R, Russell I on behalf of the Antenatal Steroids for Term
Elective Caesarean Section (ASTECS) Research Team. Antenatal betamethasone
and incidence of neonatal respiratory distress after elective caesarean section:
pragmatic randomized trial. BMJ 2005;331:662–4.
[22] Ahmed MR, Sayed Ahmed WA, Mohammed TY. Antenatal steroids at 37 weeks,
does it reduce neonatal respiratory morbidity? A randomized trial. J Matern
Fetal Neonatal Med 2015;28(12):1486–90.
[23] Nada AM, Shafeek MM, El Maraghy MA, Nageeb AH, Salah El Din AS, et al.
Antenatal corticosteroid administration before elective caesarean section at
term to prevent neonatal respiratory morbidity: a randomized controlled trial.
Eur J Obstet Gynecol Reprod Biol 2016;199:88–91.
[24] Sotiriadis A, Makrydimas G, Papatheodorou S, Ioannidis JPA. Corticosteroids
for preventing neonatal respiratory morbidity after elective caesarean section
at term. Cochrane Database Syst Rev 2009(4), doi:http://dx.doi.org/10.1002/
14651858.CD006614.pub2 CD006614.
[25] Society for Maternal-Fetal Medicine (SMFM) Publications Committee.
Implementation of the use of antenatal corticosteroids in the late preterm
birth period in women at risk for preterm delivery. SMFM Statement. Am J
Obstet Gynecol 2016;215(2):B13–5.
[26] Feitosa-Porto AM, Coutinho IC, Barros-Correia J, et al. Effectiveness of
antenatal corticosteroids in reducing respiratory disorders in late preterm
infants: randomized clinical trial. BMJ 2011;342(8):d1696.
[27] Kamath-Rayne BD, De Franco EA, Marcotte MP. Antenatal steroids for
treatment of fetal lung immaturity after 34 weeks of gestation. An evaluation
of neonatal outcomes. Obstet Gynecol 2012;119:909–16.
[28] Ramadan MK, Hussein G, Saheb W, Rajab M, Mirza FG. Antenatal corticoste-
roids in the late preterm period: a prospective cohort study. J Neonatal
Perinatal Med 2016;9:15–22.
[29] Balci O, Ozdemir S, Mahmoud AS, Acar A, Colakoglu MC. The effect of antenatal
steroids on fetal lung maturation between the 34th and 36th week of
pregnancy. Gynecol Obstet Invest 2010;70:95–9.
[30] Yinon Y, Haas J, Mazaki-Tovi S, Lapidov N, Mazkereth R, Hourvitz A, et al.
Should patients with documented fetal lung immaturity after 34 weeks of
gestation be treated with steroids? Am J Obstet Gynecol 2012;207(222):e1–4.
[31] Kassab F. The effect of antenatal steroids on fetal outcome after the 34 weeks of
pregnancy in women at high risk of preterm labor. AAMJ 2013;10(4):262–72.
[32] Gyamfi-Bannerman C, Thom EA, Blackwell SC, Tita AT, Reddy UM, et al.
Antenatal betamethasone for women at risk for late preterm delivery. NICHD
Maternal-Fetal Medicine Units Network. N Engl J Med 2016;374:1311–20.
[33] Raju TN, Mercer BM, Burchfield DJ, Joseph Jr. 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. Obstet Gynecol 2014;123:1083–96.
[34] Onland W, de Laat MW, Mol BW, Offringa M. Effects of antenatal corticoste-
roids given prior to 26 weeks’ gestation: a systematic review of randomized
controlled trials. Am J Perinatol 2011;28(1):33–44.
[35] Carlo WA, McDonald SA, Fanaroff AA, Vohr BR, Stoll BJ, Ehrenkranz RA, et al.
Association of antenatal corticosteroids with mortality and neurodevelop-
mental outcomes among infants born at 22 to 25 weeks’ gestation. Eunice
kennedy Shriver National Institute of Child Health and Human Development
Neonatal Research Network. JAMA 2011;306:2348–58.
[36] American College of Obstetricians and Gynecologists. Periviable birth.
Obstetric care consensus No. 4. Obstet Gynecol 2016;127:e157–69.
[37] Magann EF, Haram K, Ounpraseuth S, Mortensen JH, Spencer HJ, Morrison JC.
Use of antenatal corticosteroids in special circumstances: a comprehensive
review. Acta Obstet Gynecol Scand 2017;96:395–409.
[38] Wapner RJ, Sorokin Y, Mele L, Johnson F, Dudley DJ, Spong CY, et al. Long-term
outcomes after repeat doses of antenatal corticosteroids. National Institute of
Child Health and Human Development Maternal-fetal Medicine Units
Network. N Engl J Med 2007;357:1190–8.
[39] Sotiriadis A, Tsiami A, Papatheodorou S, Baschat AA, Sarafidis K, Makrydimas
G. Neurodevelopmental outcome after a single course of antenatal steroids in
children born preterm: a systematic review and meta-analysis. Obstet Gynecol
2015;125:1385–96.
[40] Dalziel SR, Lim VK, Lambert A, McCarthy D, Parag V, Rodgers A, et al. Antenatal
exposure to betamethasone: psychological functioning and health related
quality of life 31 years after inclusion in randomised controlled trial. BMJ
2005;331:665.
[41] Dalziel SR, Rea HH, Walker NK, Parag V, Mantell C, Rodgers A, et al. Long term
effects of antenatal betamethasone on lung function: 30 year follow up of a
randomised controlled trial. Thorax 2006;61:678–83.
[42] Dalziel SR, Walker NK, Parag V, Mantell C, Rea HH, Rodgers A, et al.
Cardiovascular risk factors after antenatal exposure to betamethasone: 30-
year follow-up of a randomised controlled trial. Lancet 2005;365:1856–62.
[43] American College of Obstetricians and Gynecologists. Critical care in
pregnancy. Practice bulletin No. 170. Obstet Gynecol 2016;128:e147–54.