Maternal intramuscular dexamethasone versus betamethasone before preterm birth (ASTEROID): a multicentre, double-blind, randomised controlled trial

doi:10.1016/S2352-4642(19)30292-5

The Lancet Child & Adolescent Health

Volume 3, Issue 11, November 2019, Pages 769-780

https://doi.org/10.1016/S2352-4642(19)30292-5 Get rights and content

Summary

Background

Antenatal corticosteroids given to women before preterm birth improve infant survival and health. However, whether dexamethasone or betamethasone have better maternal, neonatal, and childhood health outcomes remains unclear. We therefore aimed to assess whether administration of antenatal dexamethasone to women at risk of preterm birth reduced the risk of death or neurosensory disability in their children at age 2 years compared with betamethasone. We also aimed to assess whether dexamethasone reduced neonatal morbidity, had benefits for the mother, or affected childhood body size, blood pressure, behaviour, or general health compared with betamethasone.

Methods

In this multicentre, double-blind, randomised controlled trial, we recruited pregnant women from 14 maternity hospitals in Australia and New Zealand that could provide care to preterm babies. Women were eligible for study inclusion if they were at risk of preterm birth before 34 weeks of gestation, had a singleton or twin pregnancy, and had no contraindications to antenatal corticosteroids. We randomly assigned women (1:1) to receive two intramuscular injections of either 12 mg dexamethasone (dexamethasone sodium phosphate) or 11·4 mg betamethasone (Celestone Chronodose), 24 h apart. The randomisation schedule used balanced, variable blocks that were stratified by hospital, gestational age, and number of fetuses (singleton or twins). We masked all participants, staff, and assessors to treatment groups. Analyses were by intention to treat. The primary outcome was death or neurosensory disability at age 2 years (corrected for prematurity). This study is registered with ANZCTR, ACTRN12608000631303.

Findings

Between Jan 28, 2009, and Feb 1, 2013, we randomly assigned 1346 (78%) women who were pregnant with 1509 fetuses to groups: 679 (50%) women were assigned to receive dexamethasone and 667 (50%) women were assigned to receive betamethasone. 27 (4%) fetuses, infants, or children in the dexamethasone group and 28 (4%) fetuses, infants, or children in the betamethasone group died before age 2 years. The primary outcome of death or neurosensory disability at age 2 years was determined for 603 (79%) of 763 fetuses whose mothers received dexamethasone and 591 (79%) of 746 fetuses whose mothers received betamethasone. We found a similar incidence of death or neurosensory disability in the dexamethasone (198 [33%] of 603 infants) and betamethasone groups (192 [32%] of 591 infants; adjusted relative risk [adjRR] 0·97, 95% CI 0·83 to 1·13; p=0·66). 18 (3%) of 679 women in the dexamethasone group and 28 of 667 (4%) women in the betamethasone group reported side-effects. Discomfort at the injection site, the most frequent side-effect, was less likely in the dexamethasone group than in the betamethasone group (six [1%] women vs 17 [3%] women; p=0·02).

Interpretation

The incidence of survival without neurosensory disability at age 2 years did not differ between dexamethasone and betamethasone treatment. Our findings indicate that either antenatal corticosteroid can be given to women before preterm birth to improve infant and child health.

Funding

National Health and Medical Research Council (Australia).

Introduction

Administration of the antenatal corticosteroids dexamethasone or betamethasone to women who are at risk of preterm birth increases the chance of their infant surviving, is associated with reduced neonatal morbidity,¹ and is recommended practice worldwide.2, 3, 4, 5 The choice between dexamethasone and betamethasone is affected by several factors, including opinion leaders, local availability, and cost.6, 7, 8 A full course of dexamethasone costs approximately US$1 versus $35 for betamethasone.⁷ There is a paucity of data about which corticosteroid results in better health outcomes for the mother and her infant. Retrospective studies provide conflicting results: some studies have found no differences in the risk of intraventricular haemorrhage,9, 10 periventricular leukomalacia,¹⁰ or mortality,9, 10 but other studies report that dexamethasone is associated with an increase in periventricular leukomalacia⁹ and neurosensory impairment.¹¹

Research in context

Evidence before this study

Our previous Cochrane review, which assessed the effects of different corticosteroids for women at risk of preterm birth, included ten trials (comprising 1159 women and 1213 infants, and considered at moderate risk of bias) that compared dexamethasone and betamethasone use. We searched PubMed for studies published on or before March 31, 2019, with the search terms “dexamethasone OR betamethasone OR glucocorticoids” and “pregnancy OR premature birth”, with the randomised controlled trial filter applied and no language restrictions, and we found no additional trials. Although dexamethasone was associated with a lower risk of intraventricular haemorrhage than betamethasone in four trials (including 549 infants), we found no reported differences in perinatal mortality, risk of neonatal respiratory disease, or other neonatal morbidity, and long-term child outcome data were scarce. No data on maternal health outcomes were reported from any of the included trials. Indirect estimates on acceleration of fetal lung maturation from our Cochrane review suggested a higher risk of neonatal respiratory disease and maternal chorioamnionitis with dexamethasone than with betamethasone. Worldwide, substantial numbers of women at risk of preterm birth are eligible for antenatal corticosteroid treatment, so understanding the optimal drug to use is important. The summary of the evidence clearly highlighted a need for additional trials to compare dexamethasone and betamethasone use that included assessment of infant morbidity and mortality, long-term childhood health, and maternal outcomes.

Added value of this study

To our knowledge, this is the first large study to report on the comparative effects of dexamethasone and betamethasone on infant health outcomes beyond the neonatal period and into early childhood. We found no clear differences in effects of these two corticosteroids on the incidence of survival free of neurosensory disability in children at age 2 years after in-utero exposure. We have provided reliable, comparative data on the important maternal health outcomes of infectious morbidity and mode of birth that have not previously been reported. We also found that the risk of intraventricular haemorrhage with either corticosteroid is similar, which was an uncertain result in earlier, conflicting reports.

Implications of all the available evidence

There are known benefits of antenatal corticosteroid treatment being given to women at less than 35 weeks of gestation if they are at risk of preterm birth. Findings from our study provide reassurance that both dexamethasone and betamethasone have similar effects on neonatal health, including respiratory and neurological outcomes and neurodevelopmental outcomes in early childhood. We found that dexamethasone might have benefits for mothers, conferring a reduced need for caesarean birth, and for infants, conferring a lower risk of early childhood hypertension. Further research is needed to assess the effect of the different corticosteroids on mode of birth and to assess the effects of early childhood hypertension in later childhood. Our findings provide new information for pregnant women at risk of preterm birth, their families, and health practitioners to consider when making decisions as to which corticosteroid to use. Guideline developers, policy makers, and health-care funders can incorporate this new knowledge with information on availability and costs for local policy recommendations.

A systematic review¹² of ten randomised trials (which included 1159 women and 1213 infants) that compared the use of antenatal dexamethasone with betamethasone before preterm birth found no differences in the risk of neonatal mortality or respiratory distress syndrome, but a decreased risk of intraventricular haemorrhage with dexamethasone. None of the trials1, 13 reported on relevant maternal outcomes such as infectious morbidity or mode of birth (ie, vaginal or caesarean).

Although a reduction in intraventricular haemorrhage is an important outcome, it is arguably more important to attain improved long-term survival free from disability.¹⁴ Only one randomised trial¹⁵ has directly compared the long-term effects of dexamethasone with betamethasone: this trial followed up on children whose mothers were administered these corticosteroids, and this study reported on only 12 children up to age 18 months. Because of the inconsistent data on infant health and inadequate comparative information on child health outcomes following antenatal corticosteroid use, clinical practice guidelines have been unable to recommend one corticosteroid in preference to the other.2, 3, 4, 5 Investigators of cohort studies10, 11 and randomised controlled trials¹⁶ and the authors of the Cochrane review¹² have requested further randomised trials that include outcomes relating to survival and health of infants into childhood, and that assess all relevant maternal outcomes.

The ASTEROID trial aimed to assess whether administration of antenatal dexamethasone to women at risk of preterm birth before 34 weeks of gestation reduced the risk of death or neurosensory disability in their children at age 2 years (corrected for prematurity)—the primary outcome—and whether it reduced neonatal morbidity, had benefits for the mother, or affected childhood body size, blood pressure, behaviour, or general health, compared with betamethasone.

Section snippets

Study design and participants

Results

Between Jan 28, 2009, and Feb 1, 2013, we screened 3549 women for study inclusion, of whom 1823 (51%) women were ineligible (figure). We invited 1726 (49%) eligible women to participate, of whom 380 (22%) did not provide consent to do so. We randomly assigned 1346 (78%) women pregnant with 1509 fetuses to groups: 679 (50%) women (who were pregnant with 763 fetuses) were assigned to receive dexamethasone and 667 (50%) women (who were pregnant with 746 fetuses) were assigned to receive

Discussion

In this multicentre, placebo-controlled randomised trial to compare dexamethasone with betamethasone given antenatally to women at risk of preterm birth, we found no significant difference in the primary outcome of death or neurosensory disability in their children at age 2 years (corrected for prematurity). Dexamethasone and betamethasone also had similar effects on infant health outcomes, including respiratory morbidity, intraventricular haemorrhage, and periventricular leukomalacia. Maternal

Data sharing statement

A de-identified dataset and a data dictionary used in the analyses can be requested 6 months after publication of this Article by contacting the Maternal and Perinatal Research Hub at the Liggins Institute, University of Auckland. Data will be shared with researchers who provide a methodologically sound proposal and have appropriate ethical approval, where necessary, to achieve the research aims in the approved proposal. Data requestors will be required to sign a Data Access Agreement before

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The preterm brain is susceptible to a broad spectrum of injury that ranges from diffuse nonnecrotic lesions to hemorrhage, to severe necrotic tissue destruction. This chapter addresses three common and frequently overlapping forms of preterm cerebral injury: intraventricular hemorrhage (IVH), white matter injury (WMI), and gray matter injury. The impact of preterm cerebral injury is considerable. Among children born very preterm, even with modern neonatal intensive care, 5% to 10% have major motor deficits, including cerebral palsy related to significant WMI, and more than half have significant cognitive, behavioral, or sensory deficits. Despite a gradual decline in the incidence of most grades of IVH, the increased survival of very low birth weight infants has resulted in an increase in the absolute number of infants with IVH. Cystic WMI is less common in current cohorts but when present is commonly associated with cerebral palsy, cortical visual impairment, and a spectrum of cognitive and learning disabilities. Preterm infants more commonly display diffuse WMI that results in myelination disturbances related to the death of oligodendrocyte progenitors. Diffuse WMI, often reflected in punctate WMI on diagnostic MRI, is linked to a broad spectrum of persistent neurobehavioral disabilities that include impairments in motor and cognitive skills. Chronic diffuse WMI is also accompanied by reduced cerebral gray matter growth that appears to be related to widespread disturbances in neuronal maturation. The spectrum of neurodevelopmental impairments that follow WMI in the preterm neonate are consistent with the dysmaturation in white matter and cerebral gray matter. These recently recognized forms of cerebral gray and white matter dysmaturation present new challenges for diagnosis and suggest new therapeutic strategies.
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ArticlesMaternal intramuscular dexamethasone versus betamethasone before preterm birth (ASTEROID): a multicentre, double-blind, randomised controlled trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Data sharing statement

Lancet

Lancet

Lancet

Am J Obstet Gynecol

J Pediatr

Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth

Cochrane Database Syst Rev

WHO recommendations on interventions to improve preterm birth outcomes

Committee opinion no. 713: antenatal corticosteroid therapy for fetal maturation

Obstet Gynecol

NICE guideline 25: preterm labour and birth

Antenatal corticosteroids given to women prior to birth to improve fetal, infant, child and adult health. Clinical practice guidelines

Use of antenatal corticosteroids prior to preterm birth in four South East Asian countries within the SEA-ORCHID project

BMC Pregnancy Childbirth

Dexamethasone versus betamethasone as an antenatal corticosteroid (ACS)

Antenatal glucocorticoid treatment and cystic periventricular leukomalacia in very premature infants

N Engl J Med

Betamethasone vs dexamethasone for the prevention of morbidity in very-low-birthweight neonates

Am J Obstet Gynecol

Neurodevelopmental outcomes of extremely low birth weight infants exposed prenatally to dexamethasone versus betamethasone

Pediatrics

Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth

Cochrane Database Syst Rev

Articles
Maternal intramuscular dexamethasone versus betamethasone before preterm birth (ASTEROID): a multicentre, double-blind, randomised controlled trial