Elsevier

The Lancet

Volume 385, Issue 9968, 14–20 February 2015, Pages 629-639
The Lancet

Articles
A population-based, multifaceted strategy to implement antenatal corticosteroid treatment versus standard care for the reduction of neonatal mortality due to preterm birth in low-income and middle-income countries: the ACT cluster-randomised trial

https://doi.org/10.1016/S0140-6736(14)61651-2Get rights and content

Summary

Background

Antenatal corticosteroids for pregnant women at risk of preterm birth are among the most effective hospital-based interventions to reduce neonatal mortality. We aimed to assess the feasibility, effectiveness, and safety of a multifaceted intervention designed to increase the use of antenatal corticosteroids at all levels of health care in low-income and middle-income countries.

Methods

In this 18-month, cluster-randomised trial, we randomly assigned (1:1) rural and semi-urban clusters within six countries (Argentina, Guatemala, India, Kenya, Pakistan, and Zambia) to standard care or a multifaceted intervention including components to improve identification of women at risk of preterm birth and to facilitate appropriate use of antenatal corticosteroids. The primary outcome was 28-day neonatal mortality among infants less than the 5th percentile for birthweight (a proxy for preterm birth) across the clusters. Use of antenatal corticosteroids and suspected maternal infection were additional main outcomes. This trial is registered with ClinicalTrials.gov, number NCT01084096.

Findings

The ACT trial took place between October, 2011, and March, 2014 (start dates varied by site). 51 intervention clusters with 47 394 livebirths (2520 [5%] less than 5th percentile for birthweight) and 50 control clusters with 50 743 livebirths (2258 [4%] less than 5th percentile) completed follow-up. 1052 (45%) of 2327 women in intervention clusters who delivered less-than-5th-percentile infants received antenatal corticosteroids, compared with 215 (10%) of 2062 in control clusters (p<0·0001). Among the less-than-5th-percentile infants, 28-day neonatal mortality was 225 per 1000 livebirths for the intervention group and 232 per 1000 livebirths for the control group (relative risk [RR] 0·96, 95% CI 0·87–1·06, p=0·65) and suspected maternal infection was reported in 236 (10%) of 2361 women in the intervention group and 133 (6%) of 2094 in the control group (odds ratio [OR] 1·67, 1·33–2·09, p<0·0001). Among the whole population, 28-day neonatal mortality was 27·4 per 1000 livebirths for the intervention group and 23·9 per 1000 livebirths for the control group (RR 1·12, 1·02–1·22, p=0·0127) and suspected maternal infection was reported in 1207 (3%) of 48 219 women in the intervention group and 867 (2%) of 51 523 in the control group (OR 1·45, 1·33–1·58, p<0·0001).

Interpretation

Despite increased use of antenatal corticosteroids in low-birthweight infants in the intervention groups, neonatal mortality did not decrease in this group, and increased in the population overall. For every 1000 women exposed to this strategy, an excess of 3·5 neonatal deaths occurred, and the risk of maternal infection seems to have been increased.

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Introduction

The use of antenatal corticosteroids for pregnant women at high risk of preterm delivery is among the most effective hospital-based interventions to reduce neonatal mortality associated with preterm birth, a leading cause of childhood mortality.1, 2, 3, 4, 5, 6 A systematic review3 of 21 randomised controlled trials of antenatal corticosteroids showed a 31% relative reduction in neonatal mortality (relative risk [RR] 0·69, 95% CI 0·58–0·81) and an even larger reduction in severe neonatal morbidity. However, a non-significant increased risk of puerperal sepsis (1·35, 0·93–1·95) was noted from eight studies.3 All of the trials were done in hospitals with neonatal intensive care and respiratory support. Similar reductions in neonatal mortality were seen in trials in both high-income countries and middle-income countries (Brazil, Jordan, South Africa, and Tunisia).3

On the basis of this strong evidence, the use of antenatal corticosteroids in hospitals for women at high risk of preterm birth is widely recommended by national and international health organisations.1, 6 Antenatal corticosteroids have been included in the UN list of life-saving commodities for women and children,7 and WHO has recommended dexamethasone for women at risk of preterm birth.7, 8

Whereas 80% of the women at high risk of preterm birth in high-income countries currently receive antenatal corticosteroids, less than 10% of women at risk in low-income countries receive the treatment, and proportions in middle-income countries range from 30% to 50%.6, 9, 10, 11, 12 An important determinant is that less than half of births in low-income countries occur in hospitals with antenatal corticosteroids available.13, 14 Although institutional delivery is increasing, access to tertiary care similar to that in hospitals in middle-income or high-income countries is poor for most women in low-income countries. Thus, to increase coverage of antenatal corticosteroids for women at risk in low-income countries, they would need to be made available in primary care facilities or through community strategies. So far, evidence for the reduction of neonatal mortality from antenatal corticosteroids comes solely from clinical trials done in hospitals with neonatal intensive care. Whether similar reductions would occur in settings, such as primary health-care clinics, in which intensive care for preterm infants might not be available and in which risk of preterm birth might be less accurately assessed, is unclear. Questions have also been raised about risks of infectious morbidity for women and their infants delivered in community settings related to the use of antenatal corticosteroids.15, 16

Many barriers limit effective coverage of antenatal corticosteroids in low-income countries. Estimation of gestational age can be suboptimum in these settings because of low availability of ultrasound, frequent uncertainty about the date of last menstrual period, and inadequate training in the assessment of gestational age.15, 16, 17, 18 Birth attendants in low-resource settings might not have the skills necessary to assess risk of preterm birth or to safely administer antenatal corticosteroids, even when authorised to do so by health authorities.18, 19 Additionally, birth attendants might be unaware of antenatal corticosteroids as a treatment and health-care facilities might have poor or sporadic access to the necessary supplies.19

We aimed to assess the feasibility, effectiveness, and safety of a multifaceted intervention designed to increase the use of antenatal corticosteroids at all levels of health care. The intervention included components to improve identification of women at risk of preterm birth and to facilitate appropriate use of antenatal corticosteroids.20

Section snippets

Trial design and participants

The Antenatal Corticosteroids Trial (ACT) was an 18-month, two-arm, parallel, cluster-randomised trial done in geographical clusters at seven sites of the Global Network for Women's and Children's Health Research.20, 21 Clusters were distinct geographical rural and semi-urban settings in Argentina, Zambia, Guatemala, Belgaum (India), Nagpur (India), Pakistan, and Kenya, described elsewhere.21, 22 Clusters that had established an effective birth registry with at least 300 births annually in the

Results

The ACT trial took place between October, 2011, and March, 2014, with start dates varying by site. 102 clusters were eligible for the study—six in Argentina, ten in Zambia, ten in Guatemala, 20 in Belgaum, India, 20 in Nagpur, India, 20 in Pakistan, and 16 in Kenya. We randomly assigned 51 clusters to the intervention group and 51 to control. One Guatemalan cluster assigned to the control group withdrew because of unrest and staff concerns about safety (unrelated to the trial). Therefore, 51

Discussion

In this study, we assessed the health effects of a population-based multifaceted strategy to identify women at high risk of preterm birth and administer antenatal corticosteroids in low-resource settings. The intervention effectively increased the use of antenatal corticosteroids to 45% of women delivering infants less than the 5th percentile for birthweight, compared with about 10% in control clusters. However, we also identified overtreatment with antenatal corticosteroids in the intervention

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