The Antenatal Corticosteroids Trial (ACT): a secondary analysis to explore site differences in a multi-country trial
- Karen Klein1Email author,
- Elizabeth M. McClure2,
- Daniela Colaci1,
- Vanessa Thorsten2,
- Patricia L. Hibberd3,
- Fabian Esamai4,
- Ana Garces5,
- Archana Patel6,
- Sarah Saleem7,
- Omrana Pasha7,
- Elwyn Chomba8,
- Waldemar A. Carlo9,
- Nancy F. Krebs10,
- Shivaprasad Goudar11,
- Richard J. Derman12,
- Edward A Liechty13,
- Marion Koso-Thomas14,
- Pierre M. Buekens15,
- José M. Belizán1,
- Robert L. Goldenberg16 and
- Fernando Althabe1
© Klein et al. 2016
Received: 19 December 2015
Accepted: 5 May 2016
Published: 24 May 2016
The Antenatal Corticosteroid Trial (ACT) assessed the feasibility, effectiveness, and safety of a multifaceted intervention to increase the use of antenatal corticosteroids (ACS) in mothers at risk of preterm birth at all levels of care in low and middle-income countries. The intervention effectively increased the use of ACS but had no overall impact on neonatal mortality in the targeted <5th percentile birth weight infants. Being in the intervention clusters was also associated with an overall increase in neonatal deaths. We sought to explore plausible pathways through which this intervention increased neonatal mortality.
We conducted secondary analyses to assess site differences in outcome and potential explanations for the differences in outcomes if found. By site, and in the intervention and control clusters, we evaluated characteristics of the mothers and care systems, the proportion of the <5th percentile infants and the overall population that received ACS, the rates of possible severe bacterial infection (pSBI), determined from clinical signs, and neonatal mortality rates.
There were substantial differences between the sites in both participant and health system characteristics, with Guatemala and Argentina generally having the highest levels of care. In some sites there were substantial differences in the health system characteristics between the intervention and control clusters. The increase in ACS in the intervention clusters was similar among the sites. While overall, there was no difference in neonatal mortality among <5th percentile births between the intervention and control clusters, Guatemala and Pakistan both had significant reductions in neonatal mortality in the <5th percentile infants in the intervention clusters. The improvement in neonatal mortality in the Guatemalan site in the <5th percentile infants was associated with a higher level of care at the site and an improvement in care in the intervention clusters. There was a significant increase overall in neonatal mortality in the intervention clusters compared to the control. Across sites, this increase in neonatal mortality was statistically significant and most apparent in the African sites. This increase in neonatal mortality was accompanied by a significant increase in pSBI in the African sites.
The improvement in neonatal mortality in the Guatemalan site in the <5th percentile infants was associated with a higher level of care and an improvement in care in the intervention clusters. The increase in neonatal mortality in the intervention clusters across all sites was largely driven by the poorer outcomes in the African sites, which also had an increase in pSBI in the intervention clusters. We emphasize that these results come from secondary analyses. Additional prospective studies are needed to assess the effectiveness and safety of ACS on neonatal health in low resource settings.
Trial registration: clinicaltrials.gov (NCT01084096)
The use of antenatal corticosteroids (ACS) is believed to be among the most effective interventions to reduce neonatal mortality associated with preterm birth. However, the majority of research on its efficacy and safety has been conducted in high-resource settings [1–6]. Few studies on ACS were conducted in low-middle income countries (LMIC) where the overwhelming majority of deaths associated with preterm birth occur [7–9]. Of those studies which have been performed outside of developed countries, several have been in Latin America, with only a few in Asia or Africa and none in the regions of the highest burden of mortality [10–12].
The Global Network Antenatal Corticosteroid Trial (ACT), was a multi-country cluster randomized trial to assess the feasibility, effectiveness, and safety of a multifaceted intervention developed to increase the use of ACS at all levels of health care in LMICs [13, 14]. ACT, which was conducted in seven rural and semi-urban sites in sub-Saharan Africa, Asia and Latin America, showed that the intervention increased ACS use in the intervention clusters (46 % vs.10 % in women with <5th percentile birth weight live births), but it was not associated with a reduction in neonatal mortality in the targeted <5th percentile infants in the intervention clusters. An unexpected finding was that overall neonatal mortality was higher in intervention clusters, with the excess mortality occurring in infants born at >25th percentile site-specific birth weights.
Since ACT was a multi-country intervention, we sought to explore whether regional differences were associated with the impact of the ACS intervention. ACT was pragmatic in design and there was limited data collection beyond the primary study outcomes. Thus, the ability to identify site specific associations is limited. Nonetheless, given that ACT is the largest trial of ACS use in low-income countries and the unanticipated results, in this paper, we further explore neonatal outcomes by site.
The objectives of this secondary analysis were: 1) to describe the effects of the ACT intervention on neonatal mortality, use of ACS, and possible severe neonatal bacterial infection (pSBI) by site; and 2) to assess whether the observed differences were correlated with either the use of ACS, differences in maternal characteristics or in aspects related to care.
Study design and participants
This is a secondary analysis of data collected during the ACT. The study intervention and methods are described in detail elsewhere . Briefly, the ACT was a two-arm, cluster-randomized trial conducted in seven sites of the Global Network for Women’s and Children’s Health Research (Argentina, Guatemala, Zambia, Kenya, Pakistan, Belgaum (India) and Nagpur (India)). Clusters were organized into strata based on the 28-day neonatal mortality rate by site, and then randomized by the data center (RTI International, Durham, NC, USA). Intervention clusters received a multifaceted intervention (health provider training, posters, pregnancy discs, uterine height tape, and antenatal corticosteroids kits). Providers in the intervention clusters were trained to administer one course of four doses of 6 mg of dexamethasone every 12 h to women identified at high-risk of preterm birth. Along with providers in the formal health systems, traditional birth attendants and community health workers were also trained to identify women at risk and initiate treatment. The intervention period was 18-months, with the start date between 2011 and 2012 varying by site based on the site approval date.
Outcome data were collected by trained registry administrators in a prospective, on-going, population-based maternal and newborn health (MNH) registry independent of the intervention team. The MNH registry was implemented in 2009 [15, 16] so all sites had at least 1 year of pretrial data was available. MNH data were collected during pregnancy, following delivery and at 6-weeks post-partum to determine basic information regarding use of antenatal and delivery care, stillbirth, neonatal mortality and morbidity. Data were collected on observable infant signs of illness which were used to determine possible severe bacterial infection (pSBI) based on the World Health Organization definition, as described in detail elsewhere [Hibberd PL, Hansen NI, Wang M, et al.: Trends in the Incidence of Possible Severe Bacterial Infection and Case Fatality Rates in Rural communities in Sub-Saharan Africa, South Asia and Latin America, 2010–2013: A multicenter prospective cohort study, forthcoming; 17, 18]. In addition, in the intervention clusters, we collected data on women, newborns and intervention process measures.
Generalized linear models were used to evaluate the relationship between covariates and the outcomes of interest (neonatal mortality and pSBI) and to develop point and interval estimates of relative risk (RR) associated with those risk factors. Generalized estimating equations accounted for the correlation of outcomes within cluster to develop appropriate confidence intervals. Analyses were adjusted for randomization strata. Models were log binomial when possible, otherwise Poisson models were utilized. Pre-trial data were analyzed to assess the status of various measures prior to trial implementation. All analyses were done by RTI International with SAS versions 9.3 and 9.4 (SAS Institute, Cary, NC, USA).
The trial was reviewed and approved by the ethics committees at each site. In addition, the World Health Organization and the Eunice Kennedy Shriver National Institute of Health and Human Development (NICHD) reviewed and approved the protocol. A Data Monitoring Committee reviewed the study enrollment and safety. All women provided informed consent prior to enrollment.
Maternal characteristics by site and by intervention (Int) and control (Ctr) clustersa
South Asia (n = 62,541)
Maternal age, %
20 - 35
No formal school %
Sub-Saharan Africa (n = 23,021)
Latin America (n = 14,180)
Maternal age, %
20 - 35
No formal school %
Process of care by site and by intervention (Int) and control (Ctr) clusters
Antenatal care (ANC) received, %
>3 ANC visits
ANC visit in 1st trimester
Delivery attendant, %
Traditional birth attendant
Delivery location, %
Antenatal care (ANC) received
> 3 ANC Visits
ANC in 1st trimester
Delivery attendant, %
Traditional birth attendant
Delivery location, %
Cesarean section, %
The metrics of care varied by intervention and control cluster status for both antenatal care and delivery care. In Belgaum, India, measures of ANC tended to be better in the control clusters, while these measures were better in the intervention clusters in Nagpur, India. Few substantial differences in ANC between the intervention and control clusters were observed for other sites. In the Argentinian and both Indian sites, rates of physician-delivery were higher in the control clusters compared to the intervention clusters, while Pakistan and Guatemala had higher physician-delivery rates in the intervention clusters. Both African sites had low rates (≤3 %) of physician delivery, which were similar across intervention groups. With the exception of the two African sites which had lower rates of hospital births among interventions clusters, the sites generally had higher rates of hospital deliveries in the intervention clusters compared to the control clusters (though differences in Argentina were negligible). In regard to the rates of hospital delivery, similar trends between the intervention and control clusters were observed in the sites during the pre-trial period (data now shown).
ACT intervention effect on antenatal corticosteroid use and 28-day neonatal mortality by site
ACS use among all women %
Neonatal mortality <28 daysa, N (Rate/1000)
Neonatal deaths <5th %tile
Neonatal deaths All births
ACT intervention effect on neonatal mortality < 28 daysa [RR (95 % CI)b] for intervention versus control
Neonatal deaths <5th %tile
0.96 (0.75, 1.22)
0.94 (0.72, 1.23)
0.89 (0.80, 0.99)
1.43 (0.90, 2.28)
1.30 (0.94, 1.81)
0.75 (0.69, 0.82)
1.60 (0.99, 2.58)
Neonatal deaths All births
1.13 (0.99, 1.27)
1.36 (1.09, 1.71)
0.93 (0.82, 1.07)
1.77 (1.42, 2.20)
1.47 (1.02, 2.12)
0.86 (0.72, 1.03)
1.06 (0.54, 2.09)
For infants of all birth weights, across all sites the intervention compared to the control clusters was associated with a significant increase in the risk of neonatal death (RR 1 · 12, 95 % CI 1.02–1.22, p = 0.0127). When we stratified by site, this relationship was evident in the African sites: Zambia (RR 1.77; 95 % CI 1.42–2.20) and Kenya (RR 1.47; 95 % CI 1.02–2.12), and to a lesser extent in Nagpur, India (RR 1.36; 95 % CI 1.09–1.71). A marginally significant increase was also seen in Belgaum, India (RR 1.13; 95 % CI 0.99–1.27) (Table 3; Fig. 2). A significant association was not seen in the other sites.
ACT is a large randomized trial to assess a program aimed at increasing ACS use among women at risk of preterm birth. The trial sites represented diverse LMIC settings across Latin America, Asia and sub-Saharan Africa. While there was no overall benefit to being in the intervention group across the entire study, sites in Guatemala and Pakistan had a significantly lower neonatal mortality in the intervention compared to the control clusters in the targeted (<5th percentile) infants, while there was no evidence of benefit or harm in < 5th percentile infants in the other sites.
Among all infants, the sites in Zambia, Kenya, and Belgaum and Nagpur (India) had a statistically or marginally significant increase in 28-day neonatal mortality in the intervention compared to the control clusters. The Zambian and Kenyan sites also had statistically significant increases in the risk of pSBI associated with the ACT intervention.
Considerable differences in ANC and obstetric care were found among the sites. Compared to the Asian and Latin American sites, the two sites in sub-Saharan Africa had substantially worse indicators of care. Few women delivered at a health facility, few deliveries were attended by a physician and the cesarean section rates were low.
Differences in care between the intervention and control clusters varied by site. While the clusters were stratified based on neonatal mortality rates prior to randomization, many of the differences in care observed between the intervention and control clusters appeared to precede the initiation of the ACT intervention. Overall, there were no clear patterns in the relationships between the outcomes and care when the intervention and control clusters were compared. For example, 28-day neonatal mortality was increased in the intervention clusters in Zambia despite increases in facility-based deliveries in those clusters. Similarly, the three sites with increased neonatal mortality had heterogeneous rates of skilled birth attendants at delivery. Kenya and Zambia had less care provided by traditional birth attendants or family birth attendants in the intervention compared to the control clusters, but an increase in overall neonatal mortality associated with the intervention. In the Pakistan site, where a slight benefit was associated with the intervention, no substantive differences in the processes of care were evident between the intervention and control clusters.
In contrast, in the Guatemala site, one of the two countries that showed positive effects associated with the intervention, care at delivery was better in the intervention compared to the control clusters including the use of ACS (which reached almost 50 % of the target group), delivery at a hospital or clinic, delivery by a physician and delivery by cesarean section. The findings in Guatemala are explored in detail elsewhere [Garces A, McClure EM, Figueroa L, et al.: A multi-faceted intervention including antenatal corticosteroids to reduce neonatal mortality associated with preterm birth: A case study from the Guatemalan Western Highlands, forthcoming].
The increased risk of pSBI in neonates associated with the intervention observed in the Kenyan and Zambian sites are consistent with the harmful effect on neonatal mortality also seen in the same countries. This finding is also in agreement with the overall increase in pSBI and death associated with the intervention reported in another paper of this series [Hibberd PL, Hansen NI, Wang M, et al.: Trends in the Incidence of Possible Severe Bacterial Infection and Case Fatality Rates in Rural communities in Sub-Saharan Africa, South Asia and Latin America, 2010–2013: A multicenter prospective cohort study, forthcoming]. Although these observations should be considered cautiously, they strengthen the plausibility that neonatal infection could have played a role in the observed harmful effect on neonatal mortality.
Across all the sites there was no reduction in neonatal mortality in the <5th percentile infants. However, Guatemala and to a lesser extent Pakistan had significant reductions in neonatal mortality in these infants. Guatemala, which had better indicators of care compared to some of the other sites and also in the intervention compared to the control clusters, showed benefit in the intervention compared to the control clusters in the targeted birth weight group. On the other hand, Kenya and Zambia showed a significant increase in neonatal mortality, as well as in suspected neonatal infection. Neonatal infection should be further investigated as a main outcome in future research studies.
These observations are intended as exploratory in nature and trends were not consistent across all sites. Because of the importance of identifying effective interventions to reduce neonatal mortality in the geographic areas with highest burden, further research is needed to define the impact of ACS across diverse settings in LMIC.
This study was funded by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant number U01 HD058322 U01 HD040477, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD058326, U01 HD040636). FA, JB and KK also received funding from the Bill & Melinda Gates Foundation. Study support was also provided by the World Health Organization. Supplies were donated by Becton Dickson.
KK, EMM, DC, VRT, PLH, RLG and FA developed the data analyses plan and participated in the initial writing of the manuscript. FE, AG, AP, SS, OP, EC, WAC, NFK, SG, RJD, EAL, MKT, PMB and JMB participated in the trial design and monitoring; VRT with KK and EMM performed data analyses. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2006;3:CD004454.PubMedGoogle Scholar
- McLaughlin KJ, Crowther CA, Walker N, Harding JE. Effects of a single course of corticosteroids given more than 7 days before birth: a systematic review. Aust N Z J Obstet Gynaecol. 2003;43(2):101–6.View ArticlePubMedGoogle Scholar
- Darmstadt G, Bhutta Z, Cousens S, Adam T, Walker N, de Bernis L. Evidence-based, cost-effective interventions: how many newborn babies can we save? Lancet. 2005;365:977–88.View ArticlePubMedGoogle Scholar
- Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics. 1972;50(4):515–25.PubMedGoogle Scholar
- Ballard PL, Gluckman PD, Liggins GC, Kaplan SL, Grumbach MM. Steroid and growth hormone levels in premature infants after prenatal betamethasone therapy to prevent respiratory distress syndrome. Pediatr Res. 1980;14(2):122–7.View ArticlePubMedGoogle Scholar
- Braun T, Sloboda DM, Tutschek B, Harder T, Challis JR, Dudenhausen JW, Plagemann A, Henrich W. Fetal and neonatal outcomes after term and preterm delivery following betamethasone administration. Int J Gynaecol Obstet. 2015;130(1):64–9.View ArticlePubMedGoogle Scholar
- Bhutta Z, Das J, Bahl R, The Lancet Newborn Interventions Review Group and The Lancet Every Newborn Study Group. Can available interventions end preventable deaths in mothers, newborn babies, and stillbirths, and at what cost? Lancet. 2014;384:347–70.View ArticlePubMedGoogle Scholar
- Lawn J, Blencowe H, Oza S, The Lancet Every Newborn Study Group. Every Newborn: progress, priorities, and potential beyond survival. Lancet. 2014;384:189–205.View ArticlePubMedGoogle Scholar
- Katz J, Lee A, Kozuki N, and the CHERG Small-for-Gestational-Age-Preterm Birth Working Group. Mortality risk in preterm and small-for-gestational-age infants in low-income and middle-income countries: a pooled country analysis. Lancet. 2013;382:417–25.View ArticlePubMedPubMed CentralGoogle Scholar
- Mwansa-Kambafwile J, Cousens S, Hansen T, Lawn J. Antenatal steroids in preterm labour for the prevention of neonatal deaths due to complications of preterm birth. Int J Epidemiol. 2010;39 suppl 1:122–33.View ArticleGoogle Scholar
- Vargas-Origel A, Leon Ramirez D, Zamora-Orozco J. Corticoesterides antenatales: empleo y actitud del personal medico ginecoobstetra. Ginecol Obstet Mex. 2000;68:291–95.PubMedGoogle Scholar
- Short J, McDonald S, Turner T, Martis R, SEA-ORCHID Study Group. Improving capacity for evidence-based practice in South East Asia: evaluating the role of research fellowships in the SEA-ORCHID Project. BMC Med Educ. 2010;10:37. doi:https://doi.org/10.1186/1472-6920-10-37.View ArticlePubMedPubMed CentralGoogle Scholar
- Althabe F, Belizán JM, Mazzoni A, et al. Antenatal corticosteroids trial in preterm births to increase neonatal survival in developing countries: study protocol. Reprod Health. 2012;9:22.View ArticlePubMedPubMed CentralGoogle Scholar
- Althabe F, Belizán JM, McClure EM, Hemingway-Foday J, Berrueta M, Mazzoni A, et al. 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. Lancet. 2015;385(9968):629–39.View ArticlePubMedGoogle Scholar
- Bose CL, Bauserman M, Goldenberg RL, Goudar SS, McClure EM, Pasha O, Carlo WA, Garces A, Moore JL, Miodovnik M, Koso-Thomas M. The Global Network Maternal Newborn Health Registry: a multi-national, community-based registry of pregnancy outcomes. Reprod Health. 2015;12 Suppl 2:S1.View ArticlePubMedPubMed CentralGoogle Scholar
- Goudar SS, Carlo WA, McClure EM, et al. The Maternal and Newborn Health Registry study of the Global Network for Women’s and Children’s Health Research. Int J Gynecol Obstet. 2012;118:190–93.View ArticleGoogle Scholar
- Young infants clinical signs study group. Clinical signs that predict severe illness in children under age 2 months: a multicentre study. Lancet. 2008;371(9607):135–42.Google Scholar
- Seale AC, Blencowe H, Manu AA, Nair H, Bahl R, Qazi SA, et al. Estimates of possible severe bacterial infection in neonates in sub-Saharan Africa, south Asia, and Latin America for 2012: a systematic review and metaanalysis. Lancet Infect Dis. 2014;14(8):731–41.Google Scholar