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Singapore Medical Journal logoLink to Singapore Medical Journal
. 2022 Oct 6;65(9):479–487. doi: 10.4103/SINGAPOREMEDJ.SMJ-2022-014

Antenatal corticosteroids in Singapore: a clinical and scientific assessment

Arundhati Gosavi 1, Zubair Amin 2, Sean William David Carter 3, Mahesh Arjandas Choolani 1, Erin Lesley Fee 3, Mark Amir Milad 4, Alan Hall Jobe 5, Matthew Warren Kemp 1,3,6,7,
PMCID: PMC11479002  PMID: 36254928

Abstract

Preterm birth (PTB; delivery prior to 37 weeks’ gestation) is the leading cause of early childhood death in Singapore today. Approximately 9% of Singaporean babies are born preterm; the PTB rate is likely to increase given the increased use of assisted reproduction technologies, changes in the incidence of gestational diabetes/high body mass index and the ageing maternal population. Antenatal administration of dexamethasone phosphate is a key component of the obstetric management of Singaporean women who are at risk of imminent preterm labour. Dexamethasone improves preterm outcomes by crossing the placenta to functionally mature the fetal lung. The dexamethasone regimen used in Singapore today affords a very high maternofetal drug exposure over a brief period of time. Drawing on clinical and experimental data, we reviewed the pharmacokinetic profile and pharmacodynamic effects of dexamethasone treatment regimen in Singapore, with a view to creating a development pipeline for optimising this critically important antenatal therapy.

Keywords: Antenatal corticosteroids, dexamethasone, pharmacodynamic, pharmacokinetic, preterm birth

INTRODUCTION

Preterm birth (PTB; delivery prior to 37 weeks’ gestation) remains the leading cause of early childhood mortality in Singapore and worldwide.[1,2] Lung immaturity is a key factor in most of the disease burden associated with prematurity. In Singapore, antenatal corticosteroids (ACS) are administered to most women judged at risk of imminent preterm delivery in order to hasten the maturation of the fetal lung.[3] Although efficacious when appropriately targeted, there is increasing awareness that ACS treatments are not risk-free, are largely unoptimised (i.e. choice of agent, dose administered, dosing regimen) and have variable benefit.[4,5,6,7] Research towards establishment of a ‘lowest possible efficacious dosing regimen’ for ACS therapy should now be a priority.

The ACS regimen used in Singapore[3] (i.e. two 12-mg maternal intramuscular injections of dexamethasone phosphate administered at 12–24 hours) is different from the regimens used in other parts of the world. The mother and the fetus are exposed to two high-amplitude plasma steroid concentrations over a comparatively brief period, relative to those receiving treatments in many other jurisdictions. This is concerning given the established dose response between adverse effects (i.e. immunosuppression, risk of fracture, sepsis, embolism)[8] and steroid exposures. High-amplitude steroid exposures are also of concern in gestational diabetes mellitus.[9] Despite the high peak exposures achieved, owing to the comparatively rapid clearance of dexamethasone and the short administration period, the duration of fetal steroid exposure from this regimen is predicted to be shorter than that achieved with several other regimens, potentially impacting treatment durability.

This review provides a detailed pharmacokinetic and pharmacodynamic assessment of the current ACS regimen used in Singapore and compares it with alternative ACS regimens. The data provides a timely review of the use of this important therapy in Singapore, and emphasises the existing opportunity to maximise the potential benefit of ACS therapy via an optimised dosing strategy.

A BRIEF INTRODUCTION TO ANTENATAL STEROIDS

Globally, some 15 million babies are born preterm each year, resulting in over one million deaths.[2] The first ACS randomised control trial data was published in 1972.[10] Following the 1994 National Institute of Health, USA Consensus Statement,[11] ACS have become one of the most important and widely used drugs in pregnancy and are the standard of care for women at risk of preterm delivery.[12,13,14]

There remains no clear consensus on dosing regimens and agents employed worldwide. The World Health Organization (WHO) endorses dexamethasone phosphate owing to its lower cost and wider availability, especially for low- and middle-income countries.[14] Combined use of betamethasone phosphate (a rapidly releasing agent) and betamethasone acetate (an extended-release slow-acting agent) is recommended in Australia and New Zealand.[15] Betamethasone phosphate alone is used in Japan and the United Kingdom (UK).[4] There are significant variations in the treatment efficacy and safety of ACS, and many regions (UK, USA, Canada) advocate the use of both dexamethasone and betamethasone.[16,17,18,19]

ACS reduce neonatal mortality, respiratory distress syndrome (RDS) and intraventricular haemorrhage, with the maximal effect observed in infants delivered from 24 hours to seven days after completion of ACS administration.[15,20] The 2020 Cochrane review of 27 studies investigating ACS in the setting of preterm birth further supports these findings; however, the review authors suggested that the treatment regimes, effectiveness and long-term outcomes of ACS should be further investigated.[21,22]

Current focus has shifted to the use of ACS treatment in the setting of late preterm deliveries and elective Caesarean section at term. The Antenatal Late Preterm Steroids study published in 2016 investigated the use of ACS in women at risk of late preterm delivery who were randomised between 34+0 and 36+5 weeks’ gestation. Although ACS use reduced the composite primary outcome of respiratory support (mainly with regard to the use of CPAP or nasal oxygen) without increased risk of maternal or neonatal infection, it increased the incidence of neonatal hypoglycaemia.[23,24] Further subgroup analysis based on gestational age revealed that ACS use after 36 weeks of gestation causes no significant difference in the primary outcome.[18] Recommendations regarding the use of ACS vary in clinical practice in different countries, with <34 weeks of gestation in the UK,[17] and <35 weeks in Australia, New Zealand and Canada,[15,18] compared to <37 weeks in USA.[19]

The Antenatal Steroids for Term Elective Cesarean Section (ASTEC) trial demonstrated that administration of ACS 48 hours prior to planned elective lower uterine segment Caesarean section (ELUSC) at 37–39 weeks’ gestation was associated with a significant reduction in respiratory distress by more than 50%, and reduced admissions to the neonatal intensive care unit (NICU).[25] There was no difference in Apgar scores, the number of babies requiring resuscitation or intubation, duration of oxygen support or duration of NICU stay between the groups.[25] Many countries now suggest consideration of ACS prior to ELUSC.[26] The 2018 Cochrane review of four trials investigating the use of ACS at elective term Caesarean section concluded that ACS appeared to reduce RDS, transient tachypnoea of the newborn and admission to NICU; however, this was low-quality evidence, and further investigation is required.[27]

ACS is commonly associated with maternal hyperglycaemia[9,28,29] and need for pharmacological intervention to control blood glucose levels for 2–4 days after treatment.[28,30,31] A recent trial assessed self-reported glucose readings in two groups of 30 women with controlled gestational diabetes mellitus randomised to either two 12-mg intramuscular injections of dexamethasone phosphate spaced by 12 hours or four 6-mg intramuscular injections of dexamethasone phosphate spaced by 12 hours. The authors noted an equivalent number of hyperglycaemic events over the three-day period, and a small but statistically significant increase in maternal hypoglycaemic events on Day 2 in those receiving the standard WHO-recommended four-dose 6-mg dexamethasone phosphate regimen. Although the authors noted that the 12-mg regimen may be preferable, some caution may be warranted given the data available (especially regarding control for circadian confounding and sleep disruption differences between the two regimens), the small study size, and the absence of fetal plasma glucose and cortisol data.[29]

Two points may be drawn from this study. Firstly, admissions for antenatal glycaemic control increase hospital bed occupancy, increase the risk of nosocomial infections, and place a significant burden on staff time and hospital resources. The potential number of additional or lengthened admissions are significant, as the prevalence of gestational diabetes mellitus in Singapore is 18.9%, significantly higher than the global prevalence of 13.8%[32]; therefore, the impact of hyperglycaemic events would be higher in Singapore than in the original study population. Secondly, given the three-day equivalence in hyperglycaemic events between the groups, it may be that the 6-mg dose of dexamethasone phosphate is already supra-pharmacological with regard to disruption of the maternal hypothalamic–pituitary–adrenal (HPA) axis.

Further studies have linked fetal ACS exposure to potential long-term health outcomes. ACS-exposed babies have a reduced birthweight, head circumference and overall length.[33,34] Children exposed to exogenous steroids during the fetal period had lower academic ability, were more likely to have cognitive and behavioural challenges, and exhibited poor stress response.[35,36,37] In particular, the observed association between ACS treatment and increased risk of poor educational outcomes (8.5% vs. 17.7%, i.e., twice as many children in the lower quartile of academic achievement were from the ACS group at a median 12.2 years of age) in the ASTEC trial warrants further investigation.[35] A 30-year follow up of the inaugural Liggins cohort concluded that exposure to ACS was more likely to result in insulin resistance during adulthood.[38] However, other studies (including socioeconomic assessments) have also reported the benign impacts of ACS in adulthood.[38,39]

CLINICAL USE OF ANTENATAL STEROIDS IN SINGAPORE

In 2017, 9.5% of the 39,615 babies born in Singapore were preterm.[1,40,41] ACS are recommended for all cases with established and threatened preterm labour,[41] including cases complicated by chorioamnionitis.[39] Owing to high cost of the NICU and government subsidies being limited to eligible families, there is a low threshold to administer ACS. As a result, most patients with expected delivery from 24 to 35+6 weeks’ gestation with threatened or established preterm labour, a short cervical length, a positive fetal fibronectin test, antepartum haemorrhage, fetuses undergoing fetal therapy procedures and planned preterm deliveries receive ACS. More than 80% of Singaporean women at risk of preterm delivery are given ACS to accelerate fetal lung maturation.[3,41] Since 2019, at the National University Hospital (NUH), a repeat course of ACS is offered in situations where the risk of preterm delivery persists, four weeks have elapsed since the initial course of ACS was given prior to 28 weeks of gestation and the fetus is expected to be <34 weeks’ gestation at the commencement of the repeat course.

The regimen employed in Singapore today is not based on randomised control trial or pre-clinical data. To our knowledge, there is no record in the literature regarding scientific evaluation of the ACS regimen currently used in Singapore. Historical accounts gathered in the process of preparing this review conveyed that, in the late 1980s, a preparation similar to that of the MSD Celestone® Chronodose® injection (betamethasone sodium phosphate and betamethasone acetate) was used.[42] The course consists of two 11.4-mg doses of betamethasone phosphate and acetate administered by maternal intramuscular injection, 24 hours apart. A booster dose of 11.4 mg of betamethasone acetate and phosphate was also given weekly up to 34 weeks’ gestation.[43] The rationale for the change in agents and regimen at some point after 1989 is unclear, but could be related to unavailability and relative cost disadvantage of the preparation to ubiquitously available dexamethasone phosphate. Probably to ensure that mothers received both doses before delivering preterm, a shortened (12-hour) regimen of dexamethasone was subsequently adopted. This practice has prevailed at all government restructured units in Singapore since the early 1990s.

CLINICAL USE OF ACS IN OTHER SOUTHEAST ASIAN COUNTRIES

The practices and uptake of ACS vary widely between countries.[44,45] The SEA ORCHID study reported that dexamethasone phosphate was used as the ACS drug of choice in nine units across Indonesia, Malaysia, Thailand and the Philippines. Overall, 40% of women at risk of preterm birth from 24 to 34 weeks’ gestation received ACS, with coverage varying from 73% in Thailand and 55% in Malaysia but less than 10% in Indonesia and the Philippines. In Malaysia, the standard ACS regimen used in most units is two 12-mg doses of dexamethasone phosphate 12 hours apart,[46,47] which is similar to the regimen in Singapore. The Philippines, Indonesia, and Cambodia use 6 mg of dexamethasone phosphate every 12 hours for four doses from 24 and 36 completed weeks of gestation.[48,49] Data regarding repeat administration of courses of ACS is not readily available for other countries.

PRETERM OUTCOMES AND ANTENATAL STEROIDS IN SINGAPORE

Singapore’s infant (<1 year of age) mortality rate is 1.8 per 1,000 live births,[50] making it one of the lowest in the world. Perinatally originated conditions, which include preterm birth, and complications of labour and delivery, contribute to 41.5% of all causes of infant mortality in Singapore.[1]

The practice of active resuscitation at the borderline of viability, defined as gestational age <26 weeks at birth, varies somewhat between individual hospitals in Singapore. 24 weeks of gestation is generally taken as the cut-off age for resuscitation. At 23 weeks of gestation, parents are discouraged to choose active resuscitation unless there is a strong reason to pursue otherwise. At 25 weeks of gestation, active resuscitation is actively promoted. At 26 weeks and above, the default is active resuscitation. There is no prescribed minimum weight limit for resuscitation.

The rate of ACS administration varies among the three public hospitals; this could be attributed to different patient demographics among these hospitals and possibly exacerbated by a lack of national guidelines regarding the usage of ACS. For example, at KK Women’s and Children’s Hospital, approximately 65% mothers of very-low-birth-weight (VLBW) babies (babies weighing <1,500 g at birth) received at least one complete course of ACS.[51] At NUH, the corresponding figure is 81% (2016–20), whereas in Singapore General Hospital, 95% of mothers of VLBW babies had received at least one dose of ACS at the time of writing. There is no systematic data available on the use of repeated courses of antenatal steroids or on the outcomes of pregnancies that carried to term but were exposed to ACS for threatened preterm deliveries.

Consistent with the global trend in improving maternal and neonatal care, the outcomes of VLBW babies have been improving in Singapore. For example, Figure 1 shows the improvement in mortality among babies born at 24–26 weeks of gestation over the last 20 years at NUH. Figure 2 shows the medium-term (18–24 months) outcomes of a more recent cohort of babies born at <26 weeks of gestation (23–25 weeks) at NUH. Encouragingly, 70% of these babies born at <26 weeks of gestation had none or mild neurodevelopmental abnormalities.

Figure 1.

Figure 1

Chart shows increasing survival of premature babies born at 24, 25 and 26 weeks of gestation over the last two decades at National University Hospital, Singapore.

Figure 2.

Figure 2

Chart shows neurodevelopmental impairments at 18–24 months among survivors born at 23–25 weeks: (National University Hospital 2015–2020; n = 33/36). None/mild = no hearing or visual impairment, no cerebral palsy (CP), and Bayley Scale of Infant Development cognitive composite score >85; moderate = ≥1 mild/moderate CP, Gross Motor Function Classification System (GMFCS) score 2–3, cognitive composite score 70–85, unilateral hearing loss or bilateral loss not requiring aids, visual impairment requiring glasses at 2 years; severe = severe CP, GMFCS score 4–5, cognitive composite score <70, blindness or deafness.

Globally, as in Singapore, the incidence of bronchopulmonary dysplasia (BPD), the most frequent chronic complication of prematurity, has been increasing despite or perhaps because of advances in perinatal and neonatal care.[52] Many of these babies require postnatal steroids to prevent or treat BPD. The typical regimen used in BPD management is the DART Protocol,[53] which exposes the premature newborn to 0.89 mg/kg of cumulative doses of dexamethasone over 10–14 days. The postnatal steroid course is agnostic of fetal ACS exposure (i.e. the same dose of dexamethasone is administered regardless of whether the fetus was exposed to ACS or not).

Looking ahead, the debate in Singapore is expected to shift towards resuscitating babies at an earlier gestational age than the current age of 24 weeks and those who are born weighing below 400 g. Recent media publicity regarding the success of a baby born at 22 weeks of gestation[54] and babies born weighing <400 g[55] will encourage parents and healthcare professionals to push the boundary of neonatal resuscitation below 24 weeks of gestation, especially in pregnancies with favourable maternal, fetal and socioeconomic factors.

PHARMACOKINETIC BASIS OF ACS THERAPY

Three primary agents are commonly used for ACS therapy: dexamethasone phosphate, betamethasone phosphate and betamethasone acetate (in combination with betamethasone phosphate).[4,5,7] Intramuscular injection is the standard route of administration, although there is evidence that betamethasone and dexamethasone phosphate have a similar bioavailability when administered orally.[56,57,58,59]

Recent work by Jobe et al.[59] provides an important summary of the maternal pharmacokinetics and pharmacodynamics of betamethasone and dexamethasone. In a crossover study performed in non-pregnant South Asian women, betamethasone phosphate was found to have a longer half-life (10.2 ± 2.5 hours vs. 5.2 ± 0.4 hours) and lower total apparent clearance (6,466 ± 805 mL/hr vs. 9,471 ± 1,139 mL/hr) than dexamethasone phosphate. Maximal concentration and time to reach maximal concentration were similar, with a 6-mg intramuscular dose giving a peak maternal plasma concentration of 67.6 ± 8.9 ng/mL of betamethasone or 65.0 ± 8.0 ng/mL of dexamethasone at three hours post injection.[59] Intramuscular administration of 6 mg of combined betamethasone acetate and phosphate preparation yielded a peak concentration lower than that of dexamethasone or betamethasone phosphate alone (35.4 ± 5.6 ng/mL) at three hours post administration.[59] The most striking difference was in the greatly extended half-life of betamethasone achieved with the inclusion of betamethasone acetate, which was increased to 59 ± 35 hours.[59] It is important to note that the dose of betamethasone acetate administered in this study was 3 mg, or 25% of that given in a standard clinical course of ACS therapy. Consistent with the extended exposure, this dose of betamethasone acetate also achieved the most sustained disruption of circulating glucose and cortisol levels.[59]

In humans, the ratio of maternal to cord plasma steroid concentrations at delivery is approximately 1:0.37.[60] In sheep, the ratio is approximately 1:0.1[57,61] and in non-human primates (Rhesus macaque), it is similar to that in humans at 1:0.4.[58] These interspecies differences in maternofetal steroid exposures are important for dose optimisation (i.e. for identifying the lowest possible dose and briefest exposure necessary to efficaciously mature the preterm fetal lung). Despite a far lower fetal exposure in sheep owing to the difference in maternofetal steroid gradient, identical treatments (i.e. two 11.4-mg doses of betamethasone acetate and phosphate spaced by 24 hours) elicit equivalent lung maturation across all three species.[10,58,61,62] Assuming broad equivalence in ACS responsiveness and downstream maturational pathways, this data suggests that the doses of ACS used in humans are likely significantly in excess of what is required.

Using the data generated by Jobe et al.[59] and considering the expected changes in clearance due to pregnancy,[63] we have established pharmacokinetic models for the following clinical ACS regimens: (1) two 12-mg maternal intramuscular injections of dexamethasone phosphate spaced by 12 hours (Singapore regimen); (2) four 6-mg maternal intramuscular injections of dexamethasone phosphate spaced by 12 hours (WHO regimen); and (3) two 12-mg maternal intramuscular injections of combined betamethasone phosphate and betamethasone acetate spaced by 24 hours (regimen proposed by Liggins and Howie and used in Australia and the USA). To assist with discussions regarding dose optimisation, we have also included a model of a putative low-dose dexamethasone regimen, consisting of four 1.5-mg maternal intramuscular injections of dexamethasone phosphate spaced by 12 hours.

The predicted pharmacokinetic summary data is shown in Table 1. Comparative maternal and fetal drug level projections for the three clinical and additional putative treatment are shown in Figure 3. We have previously suggested that in sheep, a fetal plasma betamethasone concentration range of 1–4 ng/mL likely represents the lower limit of efficacy. As such, we have arbitrarily set three low-range fetal plasma steroid concentration threshold values of 1.0 ng/mL (represented by the interrupted line on Figure 1), 0.5 ng/mL and 0.2 ng/mL to allow comparison of the low-amplitude exposures generated by each dosing regimen.

Table 1.

Predicted values for: maximum (Cmax) and minimum (Cmin) fetal plasma concentrations; fetal drug exposure between time=0 and time=48 hours (Area Under the Curve; AUC0–48 hr) and across time (AUC0–inf); and total duration of fetal plasma steroid exposures above three hypothetical threshold minima (1.0, 0.5 and 0.2 ng drug per mL fetal plasma).

Parameter Dex IM 6 mg Q12H Dex IM 12 mg Q12H Dex IM 1.5 mg Q12H Celestone IM 12 mg Q24H
Cmax (ng/mL) 49.1 (27.8-89.5) 96.6 (51.2–178.4) 12.3 (6.9-22.4) 57.9 (29.5-89.5)

Cmin (ng/mL) 7 (2.2-16.3) 14 (4.4–32.6) 1.8 (0.6-4.1) 4.8 (2.9-12.5)

AUC 0-48 hr (ng.hr/mL) 1,281.4 (823.8-1,836.7) 1,314.2 (898.7-1,907.1) 320.4 (206-459.2) 1,078.1 (795.5-1,482.8)

AUC 0-inf (ng.hr/mL) 1,325 (921.5-1,916.1) 1325 (921.5-1916.1) 331.2 (230.4-479) 1,972.9 (1,492.3-2,706.5)

Fetal plasma time >1 ng/mL (hr) 52.6 31.6 46.8 >144

Fetal plasma time >0.5 ng/mL (hr) 55.8 34.9 49.7 >144

Fetal plasma time >0.2 ng/mL (hr) 60.5 40.4 53.5 >144

DEX IM 6mg Q12H received four doses, DEX IM 12mg Q12H received two doses, DEX IM 1.5mh Q12 received four doses and Celestone IM 12mg Q24H received two doses. Dex: dexamethasone, IM: intramuscular

Figure 3.

Figure 3

Chart shows comparative maternal and fetal drug level projections for the following antenatal steroid treatment regimens: (1) two 12-mg maternal intramuscular injections of dexamethasone phosphate spaced by 12 hours (Singapore regimen); (2) four 6-mg maternal intramuscular injections of dexamethasone phosphate spaced by 12 hours (WHO regimen used predominantly in low-resource jurisdictions; (3) two 12-mg maternal intramuscular injections of combined betamethasone phosphate and betamethasone acetate spaced by 24 hours (regimen proposed by Liggins and Howie and used in Australia and the USA); and (4) putative low-dose dexamethasone regimen, consisting of four 1.5-mg maternal intramuscular injections of dexamethasone phosphate spaced by 12 hours.

For the four modelled ACS regimens, peak maternal plasma steroid concentrations were predicted to be highest in the Singapore regimen (93.57 ng/mL) and lowest in the hypothetical 4× maternal intramuscular injections of 1.5 mg of dexamethasone phosphate spaced by 12 hours (11.76 ng/mL) regimen. Peak maternal concentrations in the WHO-recommended dexamethasone,[14] and combined betamethasone phosphate and acetate regimens[10] were 47.03 ng/mL and 52.54 ng/mL, respectively. Of note, peak fetal concentrations and the duration of elevated exposures mirrored those of the maternal compartment. However, in keeping with the accelerated clearance of dexamethasone from the maternal and fetal compartments, and the rapidity with which dexamethasone and betamethasone phosphate are converted into free drugs, the betamethasone regimen incorporating the use of slowly releasing betamethasone acetate had the longest duration of exposure above 1 ng/mL, at >144 hours. In contrast, the rapid, high-dose regimen employed in Singapore had the shortest duration of steroid exposure at all three theoretical threshold levels. From a pharmacodynamic perspective, the Singapore ACS regimen (high peak exposures, comparably short period of exposure) is the least compatible with the current thinking in relation to what constitutes an optimal dosing regimen, which is low peak concentrations (approximately 1-4 ng/mL of fetal plasma) with an extended duration of constant exposure.

OPTIMISATION OF ANTENATAL STEROID DOSING

Evidence highlighting the potential to improve ACS treatment safety and efficacy comes from animal trials. The most recent Cochrane Collaboration analysis assessed data from 27 trials.[21] Although five different agents (dexamethasone phosphate, betamethasone phosphate, betamethasone acetate, hydrocortisone and methylprednisolone) and a variety of different dosing regimens have been studied, most have used the same treatment regimen that was initially published by Liggins and Howie.[10] Some have used the WHO-recommended dexamethasone regimen. More recent studies have explored the utility of ACS in late gestation,[24] in low-and middle-income countries[64,65] and in association with elective Caesarean delivery. Therefore, much of the data describing outcomes from a single course of ACS in high-risk (i.e. <32 weeks’ gestation) infants is now historical.

Although dose, agent and dosing interval are considered superficially as variables, little attempt has been made to design trials based on how these interacting factors might combine to impact maternofetal steroid exposures. As such, little or no emphasis has been placed on how these differing exposures might, in turn, impact glucocorticoid receptor signalling and thus, treatment efficacy, safety and durability. Ballard et al.[60] have detailed a narrow dynamic range and rapid plateau-effect for steroid responsive elements (surfactant components surfactant protein A mRNA, dipalmitoyl phosphatidyl choline) in cell culture. Samtani et al.[66] demonstrated differential steroid concentration responses between surfactant proteins A and B. Surfactant protein B is essential for pulmonary function and causes rapid neonatal death in knockout models.[67,68] While not essential for lung function, surfactant protein A, but not surfactant protein B, is a strong predictor of glucocorticoid-induced lung maturation in sheep.[69] Whereas increasing the concentration and duration of steroid exposure had a stimulatory effect on the expression of surfactant protein B, a biphasic response for surfactant protein A has been reported, with higher concentration exposures reducing expression.[60] Similarly, in the sheep model, acute betamethasone exposures significantly higher than that achieved with current clinical treatments did not further increase glucocorticoid receptor pathway activation.[56] Additional studies in sheep and in the Rhesus macaque demonstrated that fetal steroid exposures significantly lower than those achieved with current clinical treatment are effective in inducing precocious maturation of the preterm lung.[58,61,62,70]

Recent sheep data published by Takahashi et al.[69] suggests that significantly elevated steroid exposures may, in fact, reduce the reliability of ACS treatments. Perhaps the best clinical evidence that higher fetal exposures do not confer additional benefit comes from the recent ASTEROID trial.[71] In this study, women were randomised to either two doses of 12 mg of dexamethasone phosphate or two doses of 11.4 mg of betamethasone phosphate and acetate, both spaced by 24 hours. In addition to having differing affinities for the glucocorticoid receptor,[60] a 12-mg injection of rapidly dephosphorylated dexamethasone is predicted to generate a peak maternal and fetal plasma concentration nearly twice that achieved with 11.4 mg of betamethasone phosphate and acetate. Despite this, the authors reported no short-term benefit in primary outcome (death or neurosensory disability at two years of age) associated with higher steroid exposures.[71]

Few studies have explored the impact of modifying dosing regimens on neonatal outcomes. Balci et al.[72] tested the efficacy of one 12-mg dose of betamethasone (presumably phosphate and acetate) against placebo in a group of 100 women at risk of preterm delivery between the 34th and 36th weeks of pregnancy. They reported a significant reduction in RDS, the need for resuscitation and improved Apgar scores in the steroid-treated group. More recently, Schmitz et al.[73] reported the initial findings of the BETADOSE trial, which assessed non-inferiority between a single 12-mg dose of betamethasone acetate and phosphate or two doses of the same spaced by 24 hours. In an assessment of 3,244 women with a singleton fetus at risk of delivery prior to 32 weeks’ gestation, the authors concluded that a half dose did not show non-inferiority to a full, two-dose treatment regimen.[74] Interestingly, the study was powered to detect a 4% non-inferiority difference, assuming that 20% of neonates receiving a full course of antenatal steroids would be expected to have RDS. This assumption was met for the single-dose group; however, the full-dose group reported a lower than expected respiratory distress rate of 17.5%.[73,74] An additional pilot study addressing this same question, the SNACS[75] trial, was also in development at the time of writing.

Two potential issues remain with this approach to ACS optimisation: firstly, they fail to address data that demonstrates that elevated steroid exposures achieved with a 12-mg dose of betamethasone acetate and phosphate or a 12-mg dose of dexamethasone phosphate are unnecessary for maturation of the fetal lung.[58,61,62,70] Secondly, additional data is emerging that the durability of ACS therapy is a function of the duration of low-concentration fetal exposure. The half-dose approach adopted in the BETADOSE and the planned SNACS trials may lead to reduced duration of effective fetal exposure (relative to two sequential treatments), potentially impacting treatment durability.

Few other studies have investigated modest modifications in the dosing of ACS regimens, yielding conflicting data. Two studies in the 1970s (Gamsu et al.,[76] six 4-mg doses of betamethasone phosphate spaced by eight hours; The Collaborative Group on Antenatal Steroid Therapy in the USA,[77] four 5-mg doses of dexamethasone phosphate spaced by 12 hours) one in the 1980s (Nelson et al.,[78] two 6-mg or 12-mg doses of betamethasone spaced by 12 hours) and one study in the 1990s (Silver et al.,[79] four 5-mg doses of dexamethasone phosphate spaced by 12 hours) have tested reduced doses, or the same dose administered over a longer interval. Given the positive benefit reported from larger, standard-dosing dexamethasone studies including those by Attawattanakul and Tansupswatdikul[80] (four 6-mg maternal intramuscular injections spaced by 12 hours administered to women at 34–36+6 weeks’ gestation; n = 96 in the intervention arm, n = 98 in the placebo arm), and more recently by the large WHO Action I trial[65] (four 6-mg maternal intramuscular injections spaced by 12 hours [n = 1,429] tested against a placebo [n = 1,423] but administered to women at 26+0–33+6 weeks’ gestation), the questionable efficacy in these modest dose modification studies appears to derive from the study design (i.e. small, unequal sample sizes) rather than the reductions in dose of agent tested.

Perhaps the most promising example of a clinical trial to address antenatal steroid dose optimisation is the impending Action III trial sponsored by the WHO in five low- and middle-income countries.[81] A multicentre, triple-arm, placebo-controlled study of 6,000 women at risk of late (34–36+6 weeks’ gestation) delivery, it will compare three regimens: placebo; the standard WHO ACS regimen (four 6-mg maternal intramuscular doses of dexamethasone phosphate spaced by 12 hours); and a low-dose regimen of four 2-mg maternal intramuscular doses of betamethasone phosphate spaced by 12 hours. The dosing regimen takes advantage of the extended half-life of betamethasone (relative to dexamethasone) and is designed to maintain fetal plasma betamethasone >1 ng/mL for at least 48 hours, and simultaneously eliminate the high maternofetal peak steroid concentrations achieved with 6-mg doses of dexamethasone.

CONCLUSION AND OPPORTUNITIES TO IMPROVE THERAPY

PTB remains a significant healthcare challenge. In the absence of highly predictive assessments for prematurity risk, effective interventions are key to reducing the burden of prematurity and maximising the potential quality of life for those born preterm. ACS therapy is one of the limited obstetric interventions conveying a demonstrable benefit to preterm outcomes.

Despite high levels of use across an expanding percentage of the at-risk pregnancy population, ACS dosing regimens have undergone limited optimisation. There is increasing interest in developing ACS regimens that minimise the magnitude of maternofetal steroid exposures and deliver an extended, low-amplitude treatment to the fetus. The ACS regimen used in Singapore generates high levels of plasma steroid concentrations in both mother and fetus, but with a limited duration of exposure. As several studies have shown that high-concentration exposures do not convey additional benefit and may increase the risk of harms, there is an opportunity for improved preterm outcomes in Singapore via the optimisation of ACS dosing regimen without causing harm to mothers and children.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Acknowledgement

The authors would like to thank Dr Dimple Rajgor, PhD, for expert assistance with the formatting and submission of this manuscript.

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