The WHO ACTION-I (Antenatal CorticosTeroids for Improving Outcomes in preterm Newborns) Trial: A multi-country, multi-centre, two-arm, parallel, double-blind, placebo-controlled, randomized trial of antenatal corticosteroids for women at risk of imminent birth in the early preterm period in hospitals in low-resource countries to improve newborn outcomes

1.1.Background

The global burden of preterm birth

Every year, an estimated 15 million babies are born preterm, the majority of these births occur in the late preterm period (gestation 34 to <37 weeks)¹. Preterm birth complications are the leading cause of death among children under 5 years of age, responsible for approximately 1 million deaths in 2015 ². Approximately 80% of all preterm births occur in South Asia and Sub Saharan Africa. ¹Preterm neonates are at an increased risk of a range of short- and long-term respiratory, infectious and neurological morbidities. While these risks are substantially higher in infants born at earlier gestations, late preterm  infants, who account for approximately 85% of all preterm births¹, still experience a significantly higher rate of morbidity and mortality compared to term infants¹.

While neonatal mortality and morbidity rates are lower in late preterm infants compared to early preterm births, the prevalence of preterm births in the late preterm period is more than three times larger. Even if the benefits of antenatal corticosteroid (ACS) are modest (assuming no harms), overall impacts on preterm-associated morbidity, mortality and health care utilization will be significant at a population level, especially in low-resource settings, where the prevalence of preterm birth is higher, and their outcomes are generally poorer.

Efficacy of antenatal corticosteroids for preterm birth

Glucocorticoids play a very important role in normal foetal development³, especially on pulmonary maturation, brain development and foetal growth. ACS have long been regarded as a cornerstone intervention in preventing neonatal deaths and severe morbidities due to preterm birth⁴. The recently conducted ACTION I trial has laid to rest any controversy on the benefits (and harms) of ACS for births in the early preterm period (<34 weeks gestation).

However, the benefits of ACS in the late preterm period are less clear.

ACS in the late preterm period:

A recent Cochrane review by Roberts et al ⁴suggested that there was little need for further trials of a single course of ACS versus placebo in singleton pregnancies in high-income countries, data were sparse in lower-income settings. This review demonstrated a clear benefit of corticosteroids on RDS in six included studies that enrolled women from 34 weeks + 0 days gestation, (RR 0.71 [95% CI 0.56, 0.91]) but not with other primary outcomes. No differences on mortality outcomes including foetal, neonatal and perinatal deaths were seen, in the three studies that reported these. This could be attributed to the extremely low number of mortality events in these trials. It is important to note the ALPS trial ⁵, a large placebo controlled trial of antenatal betamethasone in the late preterm period done in the USA, comprised >75% of patients in this late preterm meta-analysis. The authors of the Cochrane review commended that the use of antenatal corticosteroids in women at risk of late preterm birth (34 to <36 weeks) needs to be considered in light of the balance of risks and benefits.

The ALPS trial (2016) – the largest trial of ACS in late preterm infants has shown benefits of ACS in reducing respiratory morbidity in newborns ⁵. The overall need for respiratory support, which was the primary outcome besides mortality, was lower in neonates of treated mothers [RR=0.80 (95%CI 0.66-0.97)]. here were no neonatal deaths or stillbirths in ACS or placebo groups that contributed to the primary outcome. This trial also showed that ACS increased the risk of hypoglycemia in newborns [RR=1.60 (95%CI 1.37-1.67)]. The ALPS trial was conducted in tertiary care facilities in the USA, where there is a high level of care available for preterm infants and their mothers. The findings of this trial are therefore not generalizable to lower-resource settings. Despite the positive results on the efficacy outcome in this trial, a benefit risk is still ambiguous.

A systematic review by Saccone and Berghella⁶published in September 2016 summarized three studies which included 3200 women at 34⁰-36⁶ weeks’ gestation and having a high probability of premature delivery at the time of hospital admission. Infants of mothers who received ACS had a significantly lower incidence of transient tachypnea of the newborn (RR 0.72, 95% CI 0.56 to 0.92), severe RDS (0.60, 0.33 to 0.94), and use of surfactant (0.61, 0.38 to 0.99). The ALPS trial again contributed 88% of women randomized at 34⁰-36⁶ weeks’ gestation, who were included in the systematic review.  

Smaller subsequent studies (a trial and a prospective cohort) in LMIC settings (India and Lebanon respectively), investigating the effects of ACS in the late preterm period did not show a significant reduction in rates of RDS, transient tachypnoea of the newborn or neonatal intensive care unit admissions^7,8.

The Antenatal corticosteroid trial (ACT) was cluster-randomized trial in 6 low-resource countries. The trial compared a complex intervention to scale up ACS use, aimed at increasing ACS coverage. Women assessed to be at high risk of preterm birth (presenting before 36 weeks’ gestation with signs of labour, preterm premature rupture of membranes, pre-eclampsia or eclampsia, or obstetric hemorrhage) were eligible for ACS. In the intervention clusters, 13% of women were identified as being at risk of a preterm birth. Although 98% these women received ACS, only 16% actually experienced preterm birth. Among all preterm births (defined as a birth weight  <5^th centile) in the intervention arm, 45% of women received ACS compared to 10% in the control arm⁹.  Overall, neonatal mortality and still birth increased (i.e. in all babies), while mortality in infants born preterm did not differ between the intervention and the control clusters (RR 0.96, 95% CI 0.86–1.08). This harmful effect of excess mortality was concentrated among infants at and above the 25th percentile for birthweight- these infants could have been late preterm or term infants.  As the ACT trial was not an efficacy trial, ultrasound-based measurement of gestational age was not a mandatory requirement for ACS administration.  

Equipoise for the use of ACS in the late preterm period: Current evidence suggests there is equipoise on the question of the benefits and harms of use of ACS in late preterm birth, particularly in low resource settings. This position is supported by the 2017 Cochrane review on Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. The conclusions of this review, which included the ALPS trial, recommended that further studies on the role of ACS in late preterm were required.

Preterm birth rates are highest (80% of the global burden) in south Asia and sub-Saharan Africa. The majority of these preterm births (85%) occur in the late preterm period¹. The United Nations Inter-Agency Group for Child Mortality Estimation estimated that in 2019¹⁰, neonatal mortality rates in south Asia and sub Saharan Africa were 45 and 53 per 1000 live births, respectively, and that these two regions accounted for 70% of global newborn deaths. Preterm birth complications account for a third of all neonatal deaths. Given the high burden of preterm births in LMICS, particularly in the late preterm period, even a modest reduction in neonatal mortality and morbidity from preterm birth complications can translate in a large number of newborn lives saved. As shown above, there is lack of evidence on the effectiveness of ACS in the late preterm period from LMIC settings, a position supported by the authors of the 2017 Cochrane review on ACS for preterm birth ⁴. The ALPS trial which is the single largest trial on ACS in the late preterm period, was implemented exclusively in the US, and led to a recommendation by American College of Obstetrics and Gynaecologists¹¹to treat women at risk of imminent birth in the late preterm period with ACS. This recommendation has resulted in calls for caution from scientific community^12-14, given the limitations of the ALPS trial and the lack of an unambiguous benefit risk balance. In the UK, the Royal College of Obstetricians and Gynaecologists recommend the use of ACS up to 38⁺⁶ weeks, if an elective caesarean is planned.

The WHO guidelines on the use of ACS in preterm birth provides clear guidance on the use of ACS in early PTB. However, the guidelines currently do not provide a recommendation on the use of ACS in late preterm period because of a lack of conclusive evidence. The ACTION III trial will provide evidence to fill this gap and thereby, facilitate an update of the WHO guidelines on ACS use in the late preterm period.

Dosing regimens of antenatal corticosteroids and foetal lung maturation

The concept of ACS to enhance foetal maturity began with observations by Liggins in the 1960s¹⁵.  Working with a sheep model to investigate mechanisms of parturition, he serendipitously observed that lambs born prematurely after dexamethasone infusion, had partial lung inflation. He proposed that corticosteroid exposure had accelerated foetal maturity, including lung development and surfactant production. This  observation led to a clinical trial of ACS in women in 1972, and the positive results reported have been confirmed in numerous subsequent trials⁴Liggins’ empiric selection of ACS at a dose of 12 mg (a combination of 6 mg betamethasone phosphate and 6 mg betamethasone acetate) given by maternal intramuscular injection, at recognition of a risk for preterm birth, and a second dose 24 h later, has become the most-used and tested antenatal corticosteroid regimen^4,16. For example, the ALPS trial in 2016 used the same regimen - 2 injections of 12 mg betamethasone (equal parts betamethasone sodium phosphate and betamethasone acetate), administered 24 hours apart.

Considering that ACS has been widely trialled and used in clinical settings for over 50 years, it is important to note that the dosing regimen commonly used today, was never optimised. Findings from animal studies suggest that the effect of ACS on foetal lung maturational response is similar even with much lower doses of steroids, which avoid unnecessary high peaks in steroid levels and yet maintain blood levels that are needed for a lung maturation effect ^17-19. Animal and more recently human pharmacokinetic studies have established that it is possible to obtain maternal blood levels necessary for a foetal lung maturity response with much lower doses ^20,21. Concurrent pharmacodynamic studies have shown that lower steroid doses have fewer unwanted side effects in non-pregnant women. High steroid peak levels are likely to mediate the unwanted side effects in newborns, while the lower more prolonged exposure is responsible for the efficacy and durability of the lung maturation response. These studies suggest that prolonged exposure of the foetus to 1-4ng/ml would be adequate to affect lung maturity.  Pharmacokinetic studies in non-pregnant women and subsequent modelling to determine an appropriate dose that would result in such a foetal exposure have been undertaken, on the basis of which a lower dose of ACS has been suggested. The possible side effects resulting from these high unnecessary peaks of steroid i.e. hypoglycaemia, sepsis in the newborn, are of particular relevance in LMIC settings, as they are a possible route for the increased mortality seen in babies above the 25^th centile by weight in the ACT trial. A post hoc analysis of the ACT suggests that neonatal deaths seen could have been mediated by infection (hypoglycaemia was not measured).

These studies have suggested that a dose of either 2mg dexamethasone phosphate IM q6h for 8 doses or 2mg betamethasone phosphate IM q12h for 4 doses, or until birth, which ever occurred earlier, would be appropriate to provide a foetal exposure of 1-4ng/ml. The pharmacodynamic effects of betamethasone phosphate and dexamethasone phosphate are very similar (both regimens are presently recommended by WHO for use in preterm birth to a total dose of 24mg for either). However, a key difference is the longer half-life of betamethasone phosphate, which allows a 12 hourly dosing schedule even at the lower dose. The quicker clearance and therefore shorter half-life of dexamethasone implies that at a lower dose, it would need to be administered more frequently i.e. 6hrly instead of 12hrly. This would mean a possible 8 injections per course for every woman. Because of this practical inconvenience with lower dose dexamethasone and given that the WHO recommends either betamethasone or dexamethasone, and the robust database of studies with lower dose betamethasone, the trial will use a lower dose of 2mg betamethasone phosphate IM q12h for a maximum of 4 doses.

Importantly, given the higher risk of adverse outcomes such as  hypoglycaemia in late preterm births, it is important to study the benefit risk balance of lower dose steroid in clinical trials in women at risk of late preterm.

Rationale

In summary, there is currently a lack of clarity on clinical benefits of ACS use in the late preterm period, and uncertainty about the potential for harm. While the ALPS trial suggests benefit for

late preterm newborns, the generalizability of these reported benefits to low-resource settings is unclear. The possibility of additional benefit for mortality and morbidity reduction in settings with high mortality amongst preterm newborns has also not been explored. However, the ACT Trial raised concerns that the use of ACS at lower level facilities in LMICs may not confer benefit or could cause maternal and newborn harm. The safety and efficacy of ACS in low-resource facilities in the late preterm period is thus in equipoise, and an efficacy trial is needed. This is particularly urgent, given the high burden of preterm births, particularly late preterm birth in these settings. Preterm births are the single largest contributor to the high neonatal mortality seen in many LMICs.  Also, recent studies indicate equipoise regarding the optimal regimen that could confer benefits while minimizing risks of harmful effects. WHO guidance on the use of ACS in preterm birth is currently restricted only to early preterm birth (< 34weeks of gestation). Further evidence on the efficacy and safety of ACS in late preterm birth is required before WHO recommendations on the use of ACS in late preterm period (>34 weeks to <37 weeks gestation) can be made.

1.2.Aims and Objectives

The aim of this trial is to assess the benefits and possible harms of two regimens of antenatal corticosteroids, dexamethasone phosphate 4x6mg IM q12h and betamethasone phosphate 4x2mg IM q12h, compared to placebo, when given to pregnant women in the late preterm period (gestation age of 34⁺⁰  to 36⁺⁵ weeks) when they are at risk of preterm birth. The trial will be conducted in hospitals in low-resource countries, where the WHO ACS treatment criteria can be met.

Primary Objectives:

1. To compare the effect of an ACS regimen of dexamethasone phosphate 6mg q12h for 4 doses or until birth, whichever is earlier (Dexa-4x6mg)  to placebo on a composite outcome of stillbirth, neonatal death or use of respiratory support within 72 hours of life, when given to pregnant women with a high probability birth in the late preterm period (34⁺⁰ to 36⁺⁵ weeks gestation) in hospitals in low resource settings.
2. To compare the effect of an ACS regimen of betamethasone phosphate 2mg q12h for 4 doses or until birth, whichever is earlier (Beta-4x2mg)  to placebo on a composite outcome of stillbirth, neonatal death or use of respiratory support  within 72 hours of life, when given to pregnant women with a high probability birth in the late preterm period (34⁺⁰ to 36⁺⁵ weeks gestation) in hospitals in low resource settings.

In the event of both ACS regimens being superior to placebo, and based on a benefit-risk assessment,  Beta-4x2mg regimen will be compared with Dexa-4x6mg regimen for non-inferiority of the composite outcome (DSMB will make this assessment at interim/final analysis and make recommendations on this objective to the TAG /TCU)

3. To compare the effect of an ACS regimen of dexamethasone phosphate 4x6mg q12h to a regimen of betamethasone phosphate 4x2mg IM q12h, on a composite outcome of stillbirth, neonatal death or use of respiratory support within 72 hours of life, when given to pregnant women with a high probability birth in the late preterm period (34⁺⁰ to 36⁺⁵ weeks gestation) in hospitals in low resource settings.

Secondary objectives:

1. To compare the effect of dexamethasone phosphate 4x6mg q12h regimen to placebo on (i) newborn safety and healthcare utilisation outcomes (ii) maternal safety and healthcare utilisation outcomes, when given to pregnant women (34⁺⁰ to 36⁺⁵ weeks gestation) with a high probability birth in the late preterm period in hospitals in low resource settings.
2. To compare the effect of betamethasone phosphate 4x2mg q12h regimen to placebo on (i) newborn safety and healthcare utilisation outcomes (ii) maternal safety and healthcare utilisation outcomes, when given to pregnant women (34⁺⁰ to 36⁺⁵ weeks gestation) with a high probability birth in the late preterm period in hospitals in low resource settings.

1. Methods

ACTION III will be a parallel group, three-arm, individually randomized, double-blind, placebo-controlled randomised trial, of two ACS regimens (dexamethasone phosphate 6mg q12h and betamethasone phosphate 2mg IM q12h – each for 4 doses or until birth, whichever is earlier), given to women with a high probability of preterm birth in the late preterm period to improve neonatal outcomes. This multi-country and multi-centre trial will be done in  24 hospitals in Bangladesh, India, Kenya, Nigeria and Pakistan, where the WHO ACS treatment criteria can reasonably be met.  Trial activities will be facility-based, with community follow up of recruited women and newborns to 28 completed days of life.

Population:

The population of interest is women with a singleton or multiple pregnancy at 34⁺⁰ weeks to 36⁺⁵ weeks and a high probability of late preterm birth (up to 36⁺⁶ weeks).

High probability of late preterm birth (up to 36⁺⁶ weeks)  defined as birth expected between 12 hours and 7 days after randomization as a result of:

A. Membrane rupture without preterm labour (where preterm labour is defined as at least 6 regular contractions/hr and any one of the following: cervical dilatation of ≥3 cm or effacement ≥75%). OR

B. Preterm labor with intact membranes, defined as at least 6 regular contractions/hr and one of the following: (i) cervix ≥3cm dilated or (ii) 75% effaced; OR

C . Planned delivery by induction of labor or cesarean section between 24 hours and 7 days, as deemed necessary by the provider. An induction must be scheduled to start by 36⁺⁵ weeks at the latest, whereas a cesarean delivery must be scheduled by 36⁺⁶ weeks at the latest

Intervention:

The intervention regimens will be:

• Dexamethasone phosphate 4x6mg q12h (Dexa-4x6mg) regimen: A single course of 6mg IM dexamethasone sodium phosphate administered every 12 hours, to a total of four doses (starting immediately after randomisation at time points 0 hours, 12 hours, 24 hours and 36 hours) or until birth occurs, whichever comes first. If the full regimen is completed, the woman would have received a total of 24mg of dexamethasone in divided doses
• Betamethasone phosphate 4x2mg IM q12h (Beta-4x2mg) regimen:  A single course of 2mg IM betamethasone phosphate administered every 12 hours, to a total of four doses (starting immediately after randomisation at time points 0 hours, 12 hours, 24 hours and 36 hours) or until birth occurs, whichever comes first. If the full regimen is completed, the woman would have received a total of 8 mg betamethasone phosphate in divided doses

Comparison:

Identical placebo, given in exactly the same schedule as above,  i.e. administered every 12 hours, to a total of four doses (time points 0 hours, 12 hours, 24 hours and 36 hours) or until birth occurs, whichever comes first.

Packaging, appearance, labelling and volumes administered allow complete blinding of the three arms.

Primary outcome:

Stillbirth (post randomization) OR neonatal death within 72 hours of birth OR use of respiratory support within 72 hours of birth or until discharge from hospital, whichever is earlier.  Use of respiratory support consists of any one of the following: (i) mechanical ventilation (ii) continuous use of CPAP for 12 hours or more with an FiO₂ ≥0.4 at any time (iii) continuous use of supplementary oxygen for 24 hours or more with an FiO₂ ≥0.4 at any time

Secondary outcomes                                                                                                                                         

Newborn:

Efficacy outcomes:

1. Stillbirths
2. Neonatal death within 72 hours, 7 days, 28 days of birth
3. Resuscitation at birth i.e. use of positive pressure ventilation
4. Severe respiratory distress (SRD) within 72 hours after birth or until discharge from hospital, whichever is earlier. SRD is defined as any of the following clinical signs: respiratory rate ≥ 70/min, chest indrawing, grunting, or SpO2 < 90%, any of which are present at two or more consecutive 6 hourly assessments
5. Respiratory support: Use of respiratory support consists of any one of the following: (i) mechanical ventilation (ii) continuous use of CPAP for 12 hours or more with an FiO₂ ≥0.4 at any time (iii) continuous use of supplementary oxygen for 24 hours or more with an FiO₂ ≥0.4 at any time
6. Still birth OR neonatal death in 72h OR mechanical ventilation in 72h  OR need for very high CPAP settings (≥8 cm water pressure and ≥0.7 FiO₂) in 72h
7. Cause specific mortality

Safety outcomes:

1. Clinically suspected neonatal sepsis (≤7d)
2. Neonatal hypoglycaemia (blood glucose < 45 mg% at 2, 6, 12, 24 or 36 h, or detected anytime < 36 h based on a test because of clinical suspicion)

Health service utilization outcomes:

1. Admission to neonatal care unit
2. Duration of hospitalization
3. Any parenteral antibiotic use

Maternal

Safety outcomes:

1. Possible maternal bacterial infection during hospital admission: Occurrence of maternal fever, or clinically suspected or confirmed infection, for which therapeutic antibiotics were used
2. Chorioamnionitis
3. Post-partum endometritis
4. Maternal death (from time of randomization to 28 completed days after birth)

Health service utilization outcomes:

1. Duration of hospital stay
2. Any therapeutic antibiotic use
3. Any antibiotic use

Main comparisons and sample size:

Main comparisons

1. Dexa-4x6mg regimen vs placebo (superiority)
2. Beta -2 regimen vs placebo (superiority)

In the event of both ACS regimens being superior to placebo, and based on a benefit-risk assessment,  Beta-4x2mg regimen will be compared with Dexa-4x6mg regimen for non inferiority of the composite outcome *(DSMB will make this assessment at interim/final analysis and make recommendations on this objective to the TAG /TCU)

3.  Beta-4x2mg vs Dexa-4x6mg regimens (non-inferiority)

Superiority comparisons: 4500 participants per arm

For the non-inferiority comparison: If the recommendation from the DSMB is to continue recruitment to assess non-inferiority, assuming a 9.6% outcome rate in each ACS arm, will mean a total of 7643 women recruited into each arm i.e. Dexa-4x6mg  and Beta-4x2mg arms. However, a final sample size can only be computed on the basis of the outcome rates in the three arms at the time of the DSMB recommendation.

Study sites: 24 hospitals in seven sites from five countries (Bangladesh, India-Belgaum, India-New Delhi, Kenya, Nigeria-Ibadan, Nigeria-Ile Ife, and Pakistan) will participate in the trial.

Fig A: Overall design of the trial

1.1.Outputs

Preterm birth is a global public health issue, however, a large proportion of global burden of preterm birth is shouldered by LMICs. This trial will provide urgently-needed evidence regarding the safety and efficacy of ACS in low-resource settings in the late preterm period. It will also provide information on whether a lower dose of ACS could be effective and safe. The findings will guide clinicians, programme managers and policymakers worldwide on efforts to scale up ACS in facility settings in low- and middle-income countries globally. 

There is equipoise with regard to the safety and efficacy of ACS in the late preterm period, when neonatal mortality and morbidity are considered, as the recent Cochrane review indicates. Smaller trials in low income settings are also equivocal.  Therefore, results from this trial while clearly having direct relevance to LMIC, will also be important to the global debate on ACS in the late preterm period. Further, given the safety risks of dexamethasone phosphate 4x6mg q12h in the late preterm period, and accumulating evidence on the pharmacokinetics of ACS, there is strong rationale to test a lower dose that can reduce harmful side effects in the newborn. The question of a lower dose of ACS is relevant globally, but very importantly in LMIC, where the adverse effects of the conventional regimen (dexamethasone phosphate 6mg q12h x 4 doses or the equivalent betamethasone 12mg q 24h x 2 doses) could contribute to the high burden of preterm related neonatal mortality and morbidity seen in these settings. 

The WHO guidelines on the use of ACS in preterm birth provides clear guidance on the use of ACS in early preterm birth. However, the guidelines currently do not provide a recommendation on the use of ACS in late preterm period because of a lack of conclusive evidence. The ACTION III trial will provide evidence to fill this gap and thereby, facilitate an update of the WHO guidelines on ACS use in the late preterm period.