 Antenatal Corticosteroids

Antenatal Corticosteroids
Introduction
The administration of corticosteroids during pregnancy (antenatal
corticosteroids) is a well-established practice for expected preterm deliveries before
the 34 weeks’ gestations. The benefits include the reduction of perinatal death risk,
decreased neonatal death, prevention of respiratory distress syndrome (RDS) and
intraventricular hemorrhage (IVH) (McGoldrick et al., 2020). In RDS, antenatal
corticosteroids (ACS) facilitate the production of surfactant. This in turn improves
the gas exchange and lung compliance. (Naumann et al., 2022; Morton and
Brodsky, 2016). Both of two mechanisms lead to reduction of the incidence of RDS
and/or transient tachypnea of newborn (TTN) in the late preterm and early term
neonates (Htun et al., 2021; Gyamfi-Bannerman, 2024).

Two types of antenatal corticosteroids are used: betamethasone and

dexamethasone. The cellular mechanisms to facilitate lung maturation include the
induction of pulmonary beta-adrenergic receptors, accelerating type 1 and 2
pneumocytes development, and upregulation of gene expression for the epithelial
Na+ channel. This leads to increased production and excretion of surfactant which
induced improvement in gas exchange and lung mechanics, in addition to increased
absorption of alveolar fluid before delivery (Williams et al., 2022).

The mechanism of action of glucocorticoids

The main circulating endogenous glucocorticoid (GC) in humans is cortisol.
Cortisol is produced and released from the adrenal cortex. This is regulated by the
hypothalamic- pituitary-adrenal axis (HPA-axis) (figure1) (Norberg, 2017).
Glucocorticoids play a very important role in the normal fetal development,
especially regarding pulmonary maturation, brain development and fetal growth.
Nevertheless, excessive transmission of glucocorticoids to the immature fetus could

3
 Antenatal Corticosteroids

have a negative impact on developmental programming, narrowing physiological

boundaries for health and increasing the risk of subsequent disease later in life
(Harris and Seckl, 2011)

Figure (1): The hypothalamic-pituitary-adrenal axis (HPA-axis)

During pregnancy, the fetus is protected from high levels of endogenous cortisol
from the mother via 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in the
placenta and fetal tissue. 11β- HSD2 converts active cortisol to inactive cortisone and
prevents the entry of maternal cortisol to the fetal compartment. In addition, the HPA-
axis in the immature fetus is inactivated which results in low fetal output of cortisol.
Hence, the fetal levels of cortisol are approximately 10% of those in maternal blood.
In contrast, the synthetic glucocorticoids betamethasone and dexamethasone used in
ACS treatment, are not inactivated by 11β-HSD2, which results in higher
concentrations of synthetic glucocorticoids in fetal blood (30% of those in maternal
blood) (Hallman, 2015).

Exposure to ACS leads to acceleration of fetal organ maturation at the expense

of growth. Variations in the expression of 11b-HSD2 may mediate these differences

4
 Antenatal Corticosteroids

and motivate prenatal glucocorticoid programming (Ling et al., 2024). A reduction

in fetal growth in utero may ‘programme’ the fetus to future cardiovascular disease,
insulin resistance and hypertension in adult life. ACS administration may also
programme the fetal hypothalamic–pituitary axis (HPA) leading to alterations in
neurological and endocrine function in later life (Chen and Wang, 2024;
Yaremenko et al., 2024; Sulyok et al., 2023).

Indications and Benefits of Antenatal Corticosteroids

The use of ACS in women at risk of preterm birth led to a reduction in RDS,
need for mechanical ventilation, neonatal death, NEC and intraventricular
hemorrhage (Roberts et al., 2017). The current guidelines recommend giving ACS
to women for whom preterm birth is imminent (within 7 days) between 24+0 and
33+6 weeks of gestation. This guidance encompasses women with preterm prelabour
rupture of membranes, spontaneous preterm labor and medically indicated/iatrogenic
preterm delivery. A complete course of ACS requires multiple doses of either
dexamethasone or betamethasone given intramuscularly. The two common regimes
for a course of ACS are two doses of intramuscular betamethasone 12 mg, given 24
hours apart, or four doses of intramuscular dexamethasone 6 mg, given 12 hours apart
(Williams et al., 2022).

I- Preterm delivery
Preterm birth, defined as delivery prior to 37 completed weeks, is a major
contributor of perinatal mortality and morbidity across all health care settings,
worldwide. It encompasses a broad spectrum of complications, ranging from
morbidities such as intraventricular hemorrhage, necrotizing enterocolitis,
bronchopulmonary dysplasia, retinopathy of prematurity and cerebral palsy to
perinatal death (Crump, 2020).

In Egypt, the incidence of preterm birth is reported to be around 11.9% of total

5
 Antenatal Corticosteroids

births, consistent with global trends but still a significant public health concern
(World Health Organization, 2021b). Antenatal steroids are recommended for
women judged at risk of imminent preterm delivery. The primary intent of Antenatal
steroids treatment is to rapidly mature the fetal lungs to reduce the risk of mortality
and lasting morbidity (Fee et al., 2023).

The use of antenatal corticosteroids to prevent morbidity and mortality prior to

34-35 weeks' gestation is now well established as an evidence-based
recommendation by guidelines around the world with subtle differences (National
Institute for Health and Care Excellence, 2015; Antenatal Corticosteroid
Clinical Practice Guidelines Panel, 2018; Skoll et al., 2018).

Figure (2): Preterm baby on mechanical ventilation

1 - Choice of corticosteroid
The choice of corticosteroid to use remains an area of uncertainty and
continuing research (Crowther et al., 2019). Betamethasone and dexamethasone are
fluorinated corticosteroids and are the most commonly prescribed corticosteroids for
the prevention of morbidity and mortality associated with preterm birth. International

6
 Antenatal Corticosteroids

guidelines recommend either the use of betamethasone or dexamethasone

intramuscularly as the antenatal corticosteroid of choice when preterm birth is
imminent (National Institute for Health and Care Excellence, 2015; Antenatal
Corticosteroid Clinical Practice Guidelines Panel, 2018; Skoll et al., 2018).

The ASTEROID trial, investigated whether antenatal betamethasone versus

dexamethasone given prior to 34 weeks of gestation reduced death or neurosensory
disability at 2 years of age. Incidence of the primary outcome was similar in both
groups, as was the number of infants with RDS, IVH and the severity of lung disease
in both groups (Crowther et al., 2019). These inconsistent and limited data are not
considered sufficient to recommend one corticosteroid regimen over the other
(American College of Obstetricians and Gynecologists, 2017)

The World Health Organization (WHO) includes dexamethasone phosphate

(Dex-PO4) on the list of essential medicines as it is inexpensive and readily available
and does not require refrigeration (unlike betamethasone), making it the preferred
option for low- income countries (World Health Organization, 2022)

2. Dose regimens
Typical treatment regimens (one course) are two doses of betamethasone
acetate/ phosphate 12 mg intramuscularly 24 h apart, or four doses of 6 mg
dexamethasone phosphate intramuscularly 6 h apart. However, other treatment
regimens have been used. It is vital to use an effective steroid formulation and the
correct dose regimen for the type of steroid used to ensure sustained fetal exposure
to the agent. Assuming this is achieved, there is no evidence that either is better for
reducing fetal or neonatal adverse outcomes (Norman et al., 2021). Optimal dosing
of antenatal corticosteroids should adhere to the principal of achieving the desired
effect at the lowest possible fetal exposure (Kemp et al., 2019).

7
 Antenatal Corticosteroids

3. Timing of administration
No large randomized trials compare different planned time intervals between
prenatal corticosteroid administration and preterm birth. (Norman et al., 2021)
Optimal timing of ACS is critical to ensuring efficacy and limiting potential
harm. Norman et al. (2017) demonstrated an overall reduction in infant mortality
when ACS were administered between 24 hours and 7 days prior to delivery in
women presenting between 24 and 31+6 weeks of gestation. Crucially, the greatest
benefit appears to be conferred when ACS are given between 18 and 36 hours prior
to delivery; here a 50% reduction in mortality was noted. A similar time-to-delivery
effect was reported by Norberg et al. (2017) in extremely premature infants born
between 22 and 26 weeks of gestation, where infant survival was greatest when ACS
were administered within 24–48 hours.

Reduction in severe brain injury was most significant where the birth occurred
48– 72 h after steroid administration. Almost all benefits of prenatal steroid
administration had disappeared if the birth occurred 1 week or later after steroid
administration (Norman et al., 2021).

4. Single or multiple courses of corticosteroids

Perhaps, the most contentious issue related to antenatal corticosteroids in the
preterm period is that of repeat doses when preterm delivery does not occur as
predicted after corticosteroid administration (Radford et al., 2018).

This has resulted in a tendency to administer antenatal corticosteroids when the

risk of preterm birth is thought to be high, even though retrospective studies have
shown that only about 33% of women who receive antenatal corticosteroids give birth
prior to 34+0 weeks' gestation (Sanya et al., 2014). Furthermore, even when preterm
birth was indicated, only 48% of women at a University Hospital in the United States
received antenatal corticosteroids within the optimal period of 7 days prior to birth
(Adams et al., 2015).
8
 Antenatal Corticosteroids

Undoubtedly, repeat courses of antenatal corticosteroids improve short-term

respiratory outcomes in neonates; however, no differences are seen in long-term
outcomes and potential harm has been observed in children who were exposed to
multiple courses of antenatal corticosteroids who are born after 34 weeks. For women
who remain at risk of preterm birth beyond the optimal treatment period after an
initial course of antenatal corticosteroids, international guidance varies, with most
guidelines only recommending one further single course of 24 mg betamethasone in
divided doses or up to a maximum of five further single injections of 12 mg
betamethasone for women who remain at risk of preterm birth prior to 32+6 weeks10
or 34+0 weeks. The limited data regarding long-term follow up of infants exposed to
repeat doses of antenatal corticosteroids support a conservative approach of adhering
to the principle of minimizing exposure (National Institute for Health and Care
Excellence, 2015; Antenatal Corticosteroid Clinical Practice Guidelines Panel,
2018; Skoll et al., 2018).

II- The Late Preterm and Early Term Period

1. Late preterm administration
The majority of preterm births occur in the late preterm period between 34+0-
and 36+6-weeks' gestation, and whilst mortality rates in the late preterm period and
early term period are similar, morbidity and medical intervention rates are
significantly higher in the late preterm compared to the early term period (Baer et
al., 2016). As such, there is justifiable interest in improving outcomes for these
infants. Additionally, late preterm births make up a large percentage (>70%) of the
preterm population, posing significant social, financial, and economic costs (Office
for National Statistics 2020, Osterman et al., 2021). ACS has not been
recommended for women during late preterm period birth because of the lack of
supportive data from randomized controlled trials and meta-analysis (Roberts et al.,
2017).

9
 Antenatal Corticosteroids

On the other hand, other data suggested 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 (Gyamfi-
Bannerman et al., 2016). So, strong results led to the Society for Maternal Fetal
Medicine, to issue a statement which recommends administering a betamethasone
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) (Society for
Maternal-Fetal Medicine (SMFM) Publications Committee, 2016). After that, 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 (American College of
Obstetricians and Gynecologists Committee Opinion Number 713, 2017).

2. Antenatal Corticosteroids for elective caesarean section (CS) at term

Over the last 20 years, CS rates have increased substantially, and in 2020,
delivery by CS accounted for 21% of all births worldwide (Betran et al., 2021).
Babies delivered by CS are at a higher risk of neonatal morbidity, including
respiratory complications, than those born vaginally or with labor prior to CS delivery
(Sandall et al., 2018)

Due to the significantly increased risk of respiratory morbidity for fetuses born
via caesarean section prior to labor onset during the early term period, antenatal
corticosteroids have been proposed as a way of reducing adverse neonatal outcomes
(Saccone and Berghella, 2016). Two randomized trials from Egypt comparing
dexamethasone administration prior to caesarean section prior to labour onset
confirmed the significant reduction in neonatal nursery admission secondary to
respiratory morbidity, largely due to a reduction in transient tachypnea of the
newborn rather than respiratory distress syndrome (Ahmed et al., 2015; Nada et al.,
2016)

10
 Antenatal Corticosteroids

Figure (3): Antenatal steroids for elective caesarean section (CS) at term
(Stock et al., 2022)
However, it is relevant to note the unusually high rates of respiratory morbidity
in the placebo group in the trial reported by Ahmed et al. (2015), with approximately
23% having respiratory morbidity despite being born in the early term period. In
contrast, a non-blinded randomized trial comparing three doses of 8 mg of
intramuscular dexamethasone administered prior to elective caesarean section
beyond 38 weeks' gestation to standard care did not find any statistically significant
respiratory benefit in the treatment group (Nooh et al., 2018).
11
 Antenatal Corticosteroids

In Egypt, the use of ACS prior to elective cesarean deliveries has become
routine, with recommendations advocating for its administration primarily between
24 and 34 weeks of gestation. However, there is a delicate balance between
minimizing abnormal outcomes and recognizing potential side effects that can arise
when ACS is used too liberally in low-risk situations or before term deliveries
(Dawood and Salem, 2019)

III- ACS in special populations

1. Periviable gestation
Periviable birth is delivery occurring from 20 0/7 weeks to 25 6/ 7 weeks of
gestation. 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 (Raju et al., 2014).

Retrospective analysis of infants born between 22+0- and 23+0-weeks'

gestation revealed that antenatal corticosteroids were associated with a significant
reduction in death prior to hospital discharge of preterm infants born between 22+0-
and 23+0-weeks' gestation; however, no significant differences were seen in neonatal
morbidity between the corticosteroid exposed and unexposed infants during this
gestational period (Mori et al., 2011).

The lack of randomized controlled trial data has led to significant discordance
between the use of antenatal corticosteroids and resuscitation at these early
gestations, with a retrospective study demonstrating that 23.3% of live births at 23
weeks' gestation were resuscitated but not exposed to antenatal corticosteroids.
Improvements in neonatal care at periviable gestations will likely result in a
progressive reduction in the gestational age at which antenatal corticosteroids should
be offered (Rysavy et al., 2019).

12
 Antenatal Corticosteroids

Figure (4) :2-day-old premature baby born at 22 weeks and weighed just over 1
pound (McDaniel, 2022)
2. ACS in severe preeclampsia/HELLP syndrome
ACS is beneficial for preterm infants of women with HELLP (hemolysis,
elevated liver enzymes, and low platelets) syndrome/ severe preeclampsia (Magann
et al., 2017).

3. 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 (Magann et al., 2017).

13