The efficacy of antenatal corticosteroids to improve preterm newborn outcomes in low‐resource countries: Are we there yet?

Preterm birth is defined by the World Health Organization (WHO) as a birth before 37 completed weeks of gestation or fewer than 259 days since the first day of a woman's last menstrual period.1 Globally, preterm birth is estimated to affect 10.6% (95% CI 9.0–12.0) of all pregnant women, equating to approximately 14.84 million preterm neonates born each year. Over 80% of these preterm babies are born in sub-Saharan African and South Asian countries.2 Preterm birth complications are the leading cause of death in newborns and children under the age of 5 years, accounting for an estimated 1 million deaths each year.3 In comparison with term-born infants, preterm babies are at greater risk of multiple adverse short-term and long-term outcomes, particularly respiratory and other neonatal morbidities, neurodevelopmental disabilities, behavioural problems and learning difficulties.4-9 In addition, preterm birth and its sequelae can have substantial psychological impacts on parents and families, and impose a considerable financial burden.10, 11 The use of antenatal corticosteroids (ACS) is a critical intervention for improving the health outcomes of preterm babies.2 The treatment is administered via a course of intramuscular (IM) injections of dexamethasone phosphate, or betamethasone phosphate or acetate.12 When administered to pregnant women, ACS can cross the placenta, accelerating fetal lung maturation and increasing surfactant production.13 The first randomised trial of ACS in humans was conducted by Liggins and Howie in 1972, informed by the animal studies they conducted in the 1960s.14, 15 Since then, ACS therapy has become a mainstay of obstetric practice internationally. The last several years have been marked by significant developments in the evidence base on ACS efficacy, particularly regarding its use, benefits and possible harms in low-resource countries (Figure 1). In this article – more than 50 years after the publication of the landmark Liggins and Howie trial – we summarise these advances, emphasising the perspective of clinical practice in low- and middle-income countries (LMICs). We also explore WHO's latest recommendations, and the major knowledge gaps that remain to be addressed. The uptake of ACS for preterm birth increased sharply following the publication of the 1994 National Institutes of Health (NIH) Consensus Development Conference Statement,16 and the associated American College of Obstetricians and Gynaecologists committee opinion,17 recommending a single-course ACS administration to all pregnant women between 24 and 34 weeks of gestation at risk of delivery within 7 days. In 2015, serious concerns emerged regarding the benefits and harms of this intervention in low-resource countries, with the publication of the Antenatal Corticosteroids Trial (ACT).18 ACT was a community-based, cluster-randomised implementation trial conducted in Argentina, Guatemala, India, Kenya, Pakistan and Zambia to evaluate the feasibility, effectiveness and safety of a multifaceted intervention to improve ACS coverage. The intervention included training and tools for health providers to identify, treat and refer women at risk of preterm birth. Women eligible for ACS treatment were women presenting before 36 weeks of gestation with signs of labour or who were at high risk of preterm birth; 99 742 women were ultimately recruited across 101 clusters. Although the intervention conferred a more than fourfold increase in the coverage of ACS amongst babies born below the fifth percentile for birthweight (a proxy group for preterm babies), it did not reduce neonatal mortality amongst these babies (RR 0.96, 95% CI 0.87–1.06), and suspected maternal infection increased (OR 1.67, 95% CI 1.33–2.09). In the whole population (all mothers and babies of any birthweight), neonatal mortality (RR 1.12, 95% CI 1.02–1.22), stillbirth (RR 1.11, 95% CI 1.02–1.22) and suspected maternal infection (OR 1.45, 95% CI 1.33–1.58) were higher in the intervention group. These findings seemed to contradict the longstanding efficacy evidence that treatment with ACS was beneficial and did not cause any maternal or newborn harms.18 The findings of ACT informed the deliberations of the Guideline Development Group (GDG) that formulated the WHO's 2015 recommendations on ACS use.19, 20 The GDG identified that relatively few efficacy trials had been conducted in low-resource country settings.20 These recommendations were reasonably cautious, stipulating that ACS should only be used for women at 24–34 weeks of gestation in circumstances that could maximise the benefit and minimise the risks of possible harm. They recommended that ACS should only be used when: (i) accurate gestational age assessment is available; (ii) there is a high likelihood of the woman experiencing preterm birth within 7 days of starting ACS therapy; (iii) there is no clinical evidence of maternal infection; (iv) there is adequate childbirth care available for the woman; and (iv) there is adequate preterm newborn care available, including resuscitation, thermal care, feeding support, infection management and safe oxygen use.19 The recommendations acknowledged that these were consensus-based criteria that had not been specifically tested in a trial setting. The restriction to 34 weeks of gestation reflected the lack of compelling evidence of benefit from ACS when administered to women in the late preterm period (from 34 to <37 weeks of gestation). The GDG identified the need for efficacy trials of ACS in low-resource countries as a high priority for further research, noting that clinicians and stakeholders urgently needed to know whether and how to use ACS safely and effectively. To address this knowledge gap, the WHO ACTION-I (Antenatal Corticos Teroids for Improving Outcomes in preterm Newborns) trial was conducted.21, 22 ACTION-I was a multi-country, placebo-controlled, randomised trial to evaluate the efficacy and safety of antenatal dexamethasone for women at risk of preterm birth from 26 to <34 weeks of gestation. It was conducted in 29 secondary- and tertiary-level hospitals across Bangladesh, India, Kenya, Nigeria and Pakistan. All participating hospitals were selected through a standardised assessment to ensure that they could meet the maternal and newborn care requirements described in the WHO's 2015 ACS recommendations.19 The trial recruited 2852 women and their 3070 babies between December 2017 and November 2019, and reported that antenatal dexamethasone significantly reduced the risk of neonatal death (RR 0.84, 95% CI 0.72–0.97) and severe respiratory distress within 24 h of birth (RR 0.56, 95% CI 0.37–0.85), with no apparent harms to mothers and neonates.21 The Cochrane review on ACS for accelerating fetal lung maturation was subsequently updated in 2020.23 This review includes 27 trials (11 272 women and 11 925 neonates) from 20 countries, including 10 trials in LMICs. It shows that ACS administered to women at risk of imminent preterm birth significantly reduces the risk of perinatal mortality (RR 0.85, 95% CI 0.77–0.93), neonatal mortality (RR 0.78, 95% CI 0.70–0.87), respiratory distress syndrome (RR 0.71, 95% CI 0.65–0.78), intraventricular haemorrhage (RR 0.58, 95% CI 0.45–0.75) and childhood developmental delays (RR 0.51, 95% CI 0.27–0.97).23 The findings of this updated review are similar to previous iterations,24-26 although six trials were excluded from the 2020 update for methodological concerns. Overall, the review provides robust evidence on the efficacy of ACS in women at risk of imminent preterm birth prior to 34 weeks of gestation, including in low-resource countries. The evidence base on ACS in the late preterm period in low-resource countries is less clear. A 2016 trial in tertiary hospitals in the USA – the Antenatal Late Preterm Steroids (ALPS) trial – showed that a single course of antenatal betamethasone for women at risk of late preterm birth between 34 weeks 0 days and 36 weeks 5 days of gestation significantly reduced the primary outcome in newborns (a composite of respiratory complications, stillbirth and neonatal death in the first 72 h after birth).27 However, the risk of neonatal hypoglycaemia was increased with betamethasone (RR 1.60, 95% CI 1.37–1.87). Although this trial led to recommendations in some high-resource countries in favour of late preterm ACS use,28-30 an expert consultation convened by the WHO did not consider these findings sufficiently generalisable to low-resource countries, and stated that late preterm efficacy trials are needed.18 Therefore, alongside the ACTION-I trial, the WHO initiated a second trial – WHO ACTION-II – to assess the safety and efficacy of dexamethasone compared with placebo when given to women at risk of preterm birth between 34 weeks 0 days and 36 weeks 0 days of gestation.31 Although ACTION-II recruited 782 women and their 849 babies in four hospitals in India, it was stopped early because of slow recruitment and the prevalence of the primary outcome being lower than estimated. Although the trial demonstrated no differences between arms in terms of benefits or harms, the early termination of the trial meant that it was not adequately powered to assess the primary outcome. In light of the evolving evidence base, the WHO updated its ACS recommendations for improving preterm birth outcomes in 2022.32, 33 These recommendations reiterated that ACS should be used up to 34 weeks of gestation (Box 1). In making its recommendations, the GDG drew on the 2020 Cochrane review,23 and also on evidence from a mixed-methods systematic review on factors affecting the implementation of ACS.34 The latter review highlighted that ensuring appropriate ACS use needs accurate gestational age assessment, consistent guidelines and training for providers, as well as sufficient supplies and trained, well-supported staff. Economic evidence shows that ACS is highly cost-effective, including in low-resource countries.35, 36 The GDG did not recommend in favour of late preterm ACS use, in light of the continuing uncertainties around the benefits and harms in this subgroup and the lack of substantive trial evidence from low-resource countries. The GDG was also aware that trials exploring late preterm ACS use are continuing, and elected to await these results before revisiting this recommendation. It is noteworthy that the ACS regimens that are widely used today are similar to those used by Liggins and Howie in 1972, which was two doses of 12 mg betamethasone (6 mg betamethasone phosphate and 6 mg betamethasone acetate), 24 h apart. Liggins himself acknowledged that it was unlikely that this dosing regimen was optimal.14 There is a growing concern that conventional ACS regimens – 24 mg of dexamethasone or betamethasone in divided doses – is higher than necessary, which might be causing avoidable harms. This concern stems from animal studies suggesting that the fetal lung maturational effect is related to the duration of ACS exposure, but not to peak steroid concentration, and that high ACS peaks are linked to harmful effects.37-40 Sheep studies suggest that reducing betamethasone dosing by up to 50% may be sufficient to induce the preterm lung maturational response.38, 41 Such an approach is consistent with the principle of primum non nocere. The question of whether the total dose of an ACS regimen could be reduced without compromising the efficacy is being explored in phase III trials. Recently, the BETADOSE trial conducted in France assessed whether a single dose was non-inferior to a full course (i.e. two-dose regimen) of antenatal betamethasone, in preventing the need for exogenous surfactant within 48 h after birth.42 The trial did not demonstrate the non-inferiority of the two-dose arm; however, the single-dose arm did not result in a higher incidence of adverse newborn outcomes, namely neonatal mortality, intraventricular haemorrhage, necrotising enterocolitis, severe retinopathy of prematurity and bronchopulmonary dysplasia. The uncertainties regarding the optimal ACS regimen and ACS efficacy in the late preterm period are not unrelated questions. As the ALPS trial has shown, late preterm ACS use may be associated with greater risks of adverse newborn outcomes, such as neonatal hypoglycaemia; hence, a reduced dosing regimen may be particularly advantageous in this population. The WHO has opted to address these two questions within a single trial – the WHO ACTION-III trial.43 ACTION-III is a parallel-group, three-arm, individually randomised, double-blind, placebo-controlled trial to assess the efficacy of two ACS regimens (6 mg dexamethasone phosphate injections at 12-hourly intervals for up to four doses, or 2 mg betamethasone phosphate injections at 12-hourly intervals for up to four doses), compared with an identical placebo regimen. Eligible women are those with a high probability of preterm birth from 34 weeks 0 days to 36 weeks 5 days of gestation. The trial is being conducted in 24 hospitals in Bangladesh, India, Kenya, Nigeria and Pakistan, and is expected to conclude in 2025.43 The coverage of ACS use in many LMICs is suboptimal, meaning many preterm newborn deaths could be avoided.44 Armed with the reassuring evidence base around its benefits prior to 34 weeks of gestation, national health programmes and policymakers are now faced with the challenge of how best to implement it at scale, while ensuring safety. Doing so will require evidence-based strategies that are tailored to limited-resource settings – although a 2020 Cochrane review of such strategies found insufficient evidence.45 These strategies will need to incorporate the WHO ACS treatment criteria around improving access to obstetric ultrasound for gestational age assessment, ensuring the right women are offered ACS at the right time, and that the requisite maternal and preterm newborn care measures are available. Implementation research methodologies can guide the development and testing of these strategies, as well as identifying the requisite health system components that are needed to optimise ACS scale-up. Multi-country, mixed-methods implementation research is currently underway in a number of low-resource countries, aiming to develop optimal implementation strategies in LMICs to achieve high coverage of safe ACS use and to evaluate its impact on neonatal mortality.46 Although ACS has been in widespread clinical use for decades, fundamental questions remain. Table 1 describes eight continuing or planned ACS trials that we identified through a search of the WHO International Clinical Trials Registry Platform (15 December 2022), which indexes 18 trial registries internationally. Three are efficacy trials of late preterm and early term ACS, two are efficacy trials in women with twin pregnancies, two are testing alternative ACS regimens and one relates to improving shared decision-making. RCT 24 hospitals in Bangladesh, India, Kenya, Nigeria and Pakistan RCT Hospitals in Australia and New Zealand RCT One hospital in Lebanon RCT 41 hospitals in Canada and Australia 5-year follow-up of the BETADOSE trial participants 37 hospitals in France Singleton child born from mother enrolled in the BETADOSE trial Gestational age at birth less than 32 weeks of gestation RCT 50 hospitals in the UK RCT 11 hospitals in Korea RCT 6 hospitals in Canada The 2022 WHO recommendations specified 11 high-priority research questions (Box 2). These priorities included 'implementation-side' questions, such as identifying barriers and enablers and developing effective strategies to scale-up safe ACS use, as well as strategies to empower women and families through shared decision-making. They also included outstanding effectiveness questions on optimal dosing and administration-to-birth intervals, as well as the effects of ACS in women with late preterm birth, multiple pregnancies or for women undergoing a prelabour or elective caesarean section. One of these priorities relates to the lack of knowledge around the long-term effects of ACS. There is currently insufficient evidence on the long-term effects of ACS on childhood growth and survival, as well as on neurodevelopmental and behavioural outcomes. The 2020 Cochrane review identified only five trials (600 children) that evaluated the long-term outcomes of ACS in childhood, none of which were from LMICs.23 It showed that ACS use is associated with a reduction in developmental delays in children aged between 2 and 12 years. However, there were little data for critical outcomes such as child mortality and measures of child growth. A recent systematic review of 30 cohort studies – most were conducted in high-income countries and none were conducted in LMICs – reported that a single course of ACS was associated with significantly lower neurodevelopmental impairment in children aged <2 years born prior to 34 weeks of gestation.47 However, the likelihood of developing a neurocognitive disorder after ACS exposure appeared to be higher in children born in the late preterm period and at term. Furthermore, a follow-up study of the ALPS trial demonstrated that late preterm ACS use did not affect neurodevelopmental outcomes in children aged ≥6 years.48 Preterm birth is the major driver of neonatal and child mortality globally. The evidence base for ACS is evolving rapidly, and there are important, practice-changing trials being conducted on this key intervention. Recent trials confirm that the use of ACS in the early preterm period in low-resource countries can prevent short-term adverse outcomes in preterm newborns, provided that the treatment is used under certain conditions, and that adequate maternal and preterm newborn care are available. Future research should prioritise the need for evidence-based implementation strategies to scale-up safe ACS use in low-resource countries, resolve the remaining uncertainties around optimising the efficacy and address the knowledge gaps around long-term effects on children. The first iteration of this article was drafted by SS, with revisions from JPV and OTO. This article represents the views of the named authors only, and not the views of their institutions. No funding was received for this article. JPV is supported by a National Health and Medical Research Council (NHMRC) Investigator Grant (GNT1194248) and SS is supported by Monash Graduate Scholarship and Monash International Tuition Scholarship. None declared. Not applicable.

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