Received: 6 June 2023 | Revised: 27 June 2023 | Accepted: 30 June 2023
DOI: 10.1111/apa.16896
E S S AY
Antenatal corticosteroids revisited—­Novel approaches and
future perspectives
Ariadne Malamitsi-­Puchner | Despina D. Briana
Neonatal Intensive Care Unit, 3rd Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, Athens, Greece
Correspondence
Ariadne Malamitsi-­Puchner, Neonatal Intensive Care Unit, 3rd Department of Pediatrics, Medical School, National and Kapodistrian University of Athens,
Soultani 19, 10682 Athens, Greece.
Email: amalpu@med.uoa.gr
1 | A D M I N I S TE R I N G A NTE N ATA L
CO RTI COS TE RO I D S
Respiratory distress syndrome (RDS) is the most common complica-
tion of prematurity and is responsible for early neonatal mortality
and disability. The prevalence of RDS is inversely proportional to
gestational age. Data from 2018 showed that it affected 100% of
infants born below 28 weeks of gestation, 30% of infants between
28 and 34 weeks and 1%–­14% of infants after 34 weeks.1,2 RDS may
also affect infants born to diabetic mothers, even at an advanced
gestational age, and early term infants born by elective Caesarean
sections. 2
After Liggins and Howie published their paper in 1972, 3 antena-
tal corticosteroids gradually became the standard care for pregnant
women at risk of preterm delivery before 34 weeks of gestation.
Clinicians use antenatal corticosteroids to promote surfactant pro-
duction and lung fluid absorption and this is the most important
antenatal treatment for improving neonatal outcomes. Two options
are used when preterm birth is imminent within 7 days. The first
is two 12 mg doses of betamethasone over 24 h, with each dose
made up of 6 mg betamethasone phosphate and 6 mg betameth-
asone acetate. The second is four doses of 6 mg dexamethasone
over 12 h. The data do not support the use of one corticosteroid
over the other, as no differences in perinatal death have been ob-
4
served with either treatment. Both drugs have the same potency,
induce mild short-­term immunosuppression and present long-­term
respiratory and neurological benefits when administered to preg-
nancies between 24 and 34 weeks. Notably, betamethasone has a
longer half-­life, due to reduced clearance and a larger volume of
distribution. One additional dose is recommended when preterm
Abbreviation: RDS, respiratory distress syndrome.
© 2023 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd.
Acta Paediatrica. 2023;112:2465–2467. 
delivery is imminent within 72 h and a corticosteroid regimen has
been administered more than 1 week before that. 2
In 2016, the Antenatal Late Preterm Steroids trial reported that
antenatal corticosteroids also had a beneficial effect when it came
to reducing neonatal respiratory complications in late preterm de-
liveries from 34 + 0 to 36 + 6 weeks/days of gestation.5 As a conse-
quence, the American College of Obstetricians and Gynecologists
and the Society for Maternal-­Fetal Medicine also suggested the use
of antenatal corticosteroids at these gestations.6,7 This led to a con-
siderable increase in the administration of antenatal corticosteroids
in the United States for late preterm born infants.
This practice was extended to cases of elective Caesarean sec-
tions at 37 + 0 to 38 + 6 weeks, due to potential short-­term respira-
tory benefits.3 It is worth noting that approximately 50% of children,
who were antenatally exposed to antenatal corticosteroids, were
subsequently born at term.4,8
2 | I M PAC T O F A NTE N ATA L
CO RTI COS TE RO I DS O N TH E FE T U S
Foetal endogenous corticosteroids contribute to neurogenesis,
synaptogenesis and myelination and are crucial for foetal brain de-
velopment.9 Despite this, foetuses that are exposed to antenatal
corticosteroids incur a hypercortisolic milieu that is much higher
than needed. This may interfere with programming of the devel-
oping brain and the hypothalamic–­pituitary–­a drenal axis. 8 Under
normal conditions, the expression of 11b-­hydroxysteroid dehy-
drogenase type 2 acts as a protective mechanism against high con-
centrations of endogenous maternal cortisol. This is an enzyme
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2466
that converts endogenous corticosteroids to inactive metabolites
in the placenta and the foetal brain. However, this is not the case
with betamethasone and dexamethasone, which are potent exog-
enous antenatal corticosteroids. They are deficiently metabolised
by 11b-­hydroxysteroid dehydrogenase type 2, cross the placenta
and affect the foetal brain.9 The foetal brain is particularly sus-
ceptible at 34–­36 weeks of gestation, when myelin synthesising
oligodendrocytes grow at their fastest rate and large parts of the
cortex and cerebellum are incompletely shaped. Furthermore,
administration of antenatal corticosteroids at these gestational
weeks decreases the levels of neurotrophin-­3 , an important con-
tributor to foetal brain development. As a consequence, grey and/
or white matter may be harmed and neuronal death may occur.
In contrast, very preterm infants who receive antenatal corti-
costeroids experience increased neurotrophin levels, which have
beneficial neurodevelopmental effects and lower intraventricular
haemorrhage rates.9
Despite possible bias from various known or unknown con-
founders, several studies have referred to the important adverse
effects of antenatal corticosteroids, based on changes in how cor-
tisol is regulated. These include developmental, cognitive, neuro-
logical, behavioural and psychiatric problems, as well as increased
risks for metabolic, cardiac and autoimmune diseases later in life.
It is noteworthy that such adverse effects prevail in late preterm,
and particularly early term children, who derive the least benefit
from antenatal corticosteroids. This is because they have consider-
ably fewer respiratory problems than preterm neonates born below
34 weeks of gestation.
Therefore, the administration of antenatal corticosteroids
should follow concise guidelines for threatened preterm birth. This
is defined as preterm labour with at least 3 cm of dilation or 75%
effacement, preterm premature rupture of membranes or expected
delivery for any other indication within 24 h to 7 days. Several ma-
ternal factors have been associated with increased risks for preterm
birth and these are a previous preterm delivery, multiple pregnancy,
diabetes mellitus or gestational diabetes, substance use, hyperten-
sion and infections. 2
The administration of antenatal corticosteroids is well es-
tablished for pregnancies below 34 weeks of gestation, but they
should only be administered in selected cases between 34 + 0 and
36 + 6 weeks/days. We know that antenatal corticosteroids lower
the prevalence of transient tachypnoea of the newborn, but not
RDS, while they increase neonatal hypoglycaemia. Antenatal cor-
ticosteroids are not indicated from 37 + 0 weeks/days of gestation,
even for planned Caesarean deliveries. 2,8
3 | C H A LLE N G E S A N D TA RG E T S
Two important challenges emerge when we consider the above is-
sues. First, we need to assess the risks of threatened preterm births
as accurately as possible. Second, we need to reconsider the use of
antenatal corticosteroids, the doses, the treatment intervals and
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MALAMITSI-­PUCHNER and BRIANA
what treatment intervals are most appropriate for specific drugs. It is
impressive that we are still using the two 12 mg doses of betametha-
sone 4 recommended by Liggins and Howie in 1972.3
We know that only 40% of cases who risk preterm delivery
benefit from the antenatal corticosteroids they receive. The re-
maining preterm cases miss the optimal administration window
of 24 h to less than 7 days before delivery and seem to be need-
lessly exposed to potential adverse effects. However, it should be
stressed that antenatal corticosteroids may reduce the mortality
of newborn infants, even if they are administered some hours be-
fore birth.10
Several tests have been developed to estimate the correct
gestational age of foetuses, together with any signs of imminent
delivery and organ problems, especially lung maturation. These
include common tests such as ultrasound imaging, transvaginal
sonographic cervical length and cervicovaginal foetal fibronectin.
There are also more novel tests, including non-­invasive measure-
ments of cell-­free RNA transcripts from foetal tissues in maternal
blood, which may predict gestational age more accurately. They
also include amniotic fluid transcriptome, which identifies expres-
sion patterns of selective cells and organs during the evolution of
pregnancy. This may help clinicians to estimate foetal organ matu-
rity, specifically of the lung. We also hope that a maternal blood
test will be developed that could point to foetal lung maturity and
that only cases at risk for preterm delivery and RDS will be treated
with antenatal corticosteroids.4
It is necessary to update several aspects of the administration
of antenatal corticosteroids.4,10 Animal and human studies, based
on estimated cord blood corticosteroid concentrations, have doc-
umented the minimum exposure to betamethasone or dexameth-
asone that is needed for foetal lung maturation. This has been
quantified as about 1 ng/mL for continuous exposure over 48 h,
which is considerably lower than the concentrations that are cur-
rently used. Liggins and Howie proposed combining equal doses
of betamethasone phosphate and betamethasone acetate and
this is still being applied. They recommended using betametha-
sone acetate as it is released slowly and prolongs foetal exposure,
but questions have been raised about whether this is appropriate.
Questions have also been raised about the efficacy and safety of
repeated treatment, as even low concentrations can harm foetal
lungs and brain within 5 h. This has been documented by tran-
scriptome changes.4,10 It has also been discussed whether a partial
course, with a single dose of betamethasone, would have the same
effect on foetal lung maturation as a complete course of two doses
administered 24 h apart.10
4 | CO N C LU S I O N
Antenatal corticosteroids should be administered at gestational
ages of 24 + 0 to 33 + 6 weeks/days if preterm birth is imminent
within the next 7 days. They should occasionally be considered
in the late preterm period, but should not be used for early term

MALAMITSI-­PUCHNER and BRIANA
deliveries. More precise determinations of threatened preterm
birth are needed and several issues related to antenatal corticoster-
oid doses and dosing intervals need to be updated. Future research
should focus on the synthesis of a drug that ideally targets just lung
maturity, without adversely affecting other foetal organs and tis-
sues, particularly the brain.
F U N D I N G I N FO R M AT I O N
No external funding.
C O N FL I C T O F I N T E R E S T S TAT E M E N T
The authors have no conflicts of interest to declare.
ORCID
Ariadne Malamitsi-­Puchner https://orcid.
org/0000-0001-9043-1573
Despina D. Briana https://orcid.org/0000-0002-0682-6036
10. Razaz N, Allen VM, Fahey J, Joseph KS. Antenatal corticosteroid
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How to cite this article: Malamitsi-­Puchner A, Briana DD.
Antenatal corticosteroids revisited—­Novel approaches and
future perspectives. Acta Paediatr. 2023;112:2465–2467.
https://doi.org/10.1111/apa.16896