Trial of the Use of Antenatal Corticosteroids in Developing Countries (ACT)

Multi-country two-arm, parallel cluster randomized controlled trial to reduce neonatal mortality through increasing the rate of antenatal corticosteroid administration to eligible women.

Study Overview

• Status: Completed
• Conditions: Preterm Birth
• Intervention / Treatment: Behavioral: Increasing use of Antenatal Corticosteroids (ACS)

Detailed Description

One of the United Nations Millennium Summit goals is to reduce the deaths of children <5 years by two-thirds for 2015 (UN, 2000). Given that 38% of all under-five deaths worldwide occur in the first four weeks of life, the goal seems unattainable unless a significant fraction of the neonatal deaths are prevented (Darmstadt et al., 2005). Thus, the provision of health care during the perinatal period in developing countries is a top priority. Preterm birth is a major cause of neonatal mortality, currently responsible for 28% of the deaths overall. As the contribution of preterm birth to neonatal deaths is well above 50% (MacDorman et al., 2005) in middle and high income countries, it is expected that as low income countries improve their development, the relative importance of this cause will increase. One of the most powerful perinatal interventions to reduce neonatal mortality is the administration of antenatal corticosteroids to pregnant women at high risk of preterm birth.

The primary objective will be to evaluate whether a cluster-level multifaceted intervention, including components to improve the identification of pregnancies at high risk of preterm birth and providing and facilitating the appropriate use of steroids, reduces neonatal mortality at 28 days of life in preterm newborns, compared with the standard delivery of care in selected populations of six African, Asian, and Latin American countries.

• Study Type: Interventional
• Enrollment (Actual): 103117
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Institute for Clinical Effectiveness and Health Policy (IECS)
• Guatemala
  • Guatemala City, Guatemala
    • Universidad Francisco Marroquin Facultad de Medicina
• India
  • Belgaum, India
    • JN Medical College
  • Nagpur, India
    • Lata Medical Research Foundation
• Kenya
  • Eldoret, Kenya
    • Moi University School of Medicine
• Pakistan
  • Karachi, Pakistan
    • Aga Khan University
• Zambia
  • Lusaka, Zambia
    • University of Zambia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

This is an intent-to-treat design and thus all pregnancy outcomes of women who deliver in the study clusters and provide consent will be collected. Cluster-level inclusion criteria include

• At least 250 deliveries per year.
• Birth attendants within the health cluster will be consented to participate

Participant-level inclusion criteria include all pregnant women living in and delivering in the study cluster who:

• Are between 24 and 36 weeks GA;
• Present with signs of preterm labor, amniotic fluid leakage, hemorrhage, or hypertension;
• Provide consent for injection or present to a facility where it is standard of care.

Exclusion Criteria:

• There will not be any specific exclusion criteria for clusters or participants.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Intervention; Eligible women at high risk for preterm birth will be identified and four 6 mg doses of dexamethasone will be administered before delivery.	Behavioral: Increasing use of Antenatal Corticosteroids (ACS); Intervention clusters: Increasing administration of ACS to pregnant women at high risk of preterm birth (HRPB) by providing health providers with kits containing dexamethasone, syringes, and instructions. Eligible women receive four injections of 6 mg dexamethasone from the kit or regimen of choice at the site.; Improving identification of women at HRPB by diffusing recommendations for ACS use to health care providers, training health care providers to identify signs of preterm labor and eligibility criteria for ACS use, providing reminders to healthcare providers on the use of the kits, and using a color-coded tape to measure uterine height to estimate gestational age in women at HRPB with unknown gestational age. Control clusters: no specific intervention for comparison. Both intervention and control clusters: Birth attendants trained in essential newborn care of LBW infants and instructed to teach mothers how to provide care to premature infants.; Other Names: Four 6 mg doses of dexamethasone
No Intervention: Control; Control arm will not receive a specific intervention for comparison.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neonatal Mortality Rate at 28 Days in <5th Percentile Birth Weight Infants (as a Proxy Measure for Prematurity)	Neonatal deaths before 28 days per 1,000 live births among <5th %tile birth weight infants. The <5th %tile birth weight group was a proxy for preterm. Site-specific cutoffs from pretrial data were 2,450g-Argentina, 2,400g-Zambia, 2,267g-Guatemala, 2,000g-Belgaum, India, 2,150g-Pakistan, 2,000g-Nagpur, India, and 2,500g-Kenya. Infants were classified as <5th %tile on the basis of measured birth weights. Estimated weights by clinical assessment were used when measured weights were unavailable; those missing weights were classified as <5th %tile (since based on historical data, most of the missing data were for preterm infants). We used birth weight rather than gestational age (GA) for the primary analysis subgroup because many women in the registry had missing or uncertain GA, ultrasound was often unavailable, and the intervention was designed to improve estimation of GA, which could potentially bias GA-based analyses. All live births, including multiple births, are included.	Birth to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Use of Antenatal Corticosteroids in Women at Risk of Preterm Birth in All the Study Clusters	Antenatal corticosteroids provided antepartum assessed in women with a less-than-5th-percentile for birth weight infants. Site-specific cut offs were determined from pretrial data.	48 hours after identification of risk for preterm birth
Suspected Maternal Infection	Maternal safety was assessed through the frequency of suspected maternal infection, a composite of process outcomes including receipt of antibiotics plus hospital admission or referral, and receipt of intravenous fluids, surgery, or other treatment related to infection. The definition also included evidence of antepartum or post-partum infection for mothers with infants with a birthweight less than 2500 g. Additionally, use of antenatal corticosteroids, neonatal and perinatal mortality, and suspected maternal infection were measured for all births, irrespective of birthweight.	Pregnancy through 6 weeks postpartum
Maternal Mortality Rate	The denominator for maternal deaths through 42 days is pregnancy ending in live birth + all maternal deaths. Maternal mortality includes all maternal deaths through 42 days postpartum, irrespective of cause.	Pregnancy through 42 days postpartum
Neonatal Mortality Rate	Number of neonatal deaths before 28 days per 1,000 live births	Birth to 28 days
Stillbirth Mortality Rate	Number of stillbirths per 1,000 births	20 weeks' gestational age to birth

Collaborators and Investigators

• Sponsor: NICHD Global Network for Women's and Children's Health
• Collaborators: University of Colorado, Denver; Massachusetts General Hospital; University of Alabama at Birmingham; Columbia University; Christiana Care Health Services; Aga Khan University; Indiana University; Institute for Clinical Effectiveness and Health Policy; RTI International; University Teaching Hospital, Lusaka, Zambia; Lata Medical Research Foundation, Nagpur; Moi Univeristy; Jawaharlal Nehru Medical College; Universidad Francisco Marroquín; Tulane University School of Medicine
• Investigators: Principal Investigator: Fernando Althabe, M.D., Institute for Clinical Effectiveness and Health Policy (IECS), Buenos Aires, Argentina

Publications and helpful links

General Publications

• McGoldrick E, Stewart F, Parker R, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2020 Dec 25;12(12):CD004454. doi: 10.1002/14651858.CD004454.pub4.
• Rohwer AC, Oladapo OT, Hofmeyr GJ. Strategies for optimising antenatal corticosteroid administration for women with anticipated preterm birth. Cochrane Database Syst Rev. 2020 May 26;5(5):CD013633. doi: 10.1002/14651858.CD013633.
• Patel A, Prakash AA, Pusdekar YV, Kulkarni H, Hibberd P. Detection and risk stratification of women at high risk of preterm birth in rural communities near Nagpur, India. BMC Pregnancy Childbirth. 2017 Sep 19;17(1):311. doi: 10.1186/s12884-017-1504-4.
• Goldenberg RL, Thorsten VR, Althabe F, Saleem S, Garces A, Carlo WA, Pasha O, Chomba E, Goudar S, Esamai F, Krebs NF, Derman RJ, Liechty EA, Patel A, Hibberd PL, Buekens PM, Koso-Thomas M, Miodovnik M, Jobe AH, Wallace DD, Belizan JM, McClure EM. The global network antenatal corticosteroids trial: impact on stillbirth. Reprod Health. 2016 Jun 2;13(1):68. doi: 10.1186/s12978-016-0174-4.
• Berrueta M, Hemingway-Foday J, Thorsten VR, Goldenberg RL, Carlo WA, Garces A, Patel A, Saleem S, Pasha O, Chomba E, Hibberd PL, Krebs NF, Goudar S, Derman RJ, Esamai F, Liechty EA, Moore JL, McClure EM, Koso-Thomas M, Buekens PM, Belizan JM, Althabe F. Use of antenatal corticosteroids at health facilities and communities in low-and-middle income countries. Reprod Health. 2016 May 27;13(1):66. doi: 10.1186/s12978-016-0176-2.
• Klein K, McClure EM, Colaci D, Thorsten V, Hibberd PL, Esamai F, Garces A, Patel A, Saleem S, Pasha O, Chomba E, Carlo WA, Krebs NF, Goudar S, Derman RJ, Liechty EA, Koso-Thomas M, Buekens PM, Belizan JM, Goldenberg RL, Althabe F. The Antenatal Corticosteroids Trial (ACT): a secondary analysis to explore site differences in a multi-country trial. Reprod Health. 2016 May 24;13(1):64. doi: 10.1186/s12978-016-0179-z.
• Garces A, McClure EM, Figueroa L, Pineda S, Hambidge KM, Krebs NF, Thorsten VR, Wallace DD, Althabe F, Goldenberg RL. A multi-faceted intervention including antenatal corticosteroids to reduce neonatal mortality associated with preterm birth: a case study from the Guatemalan Western Highlands. Reprod Health. 2016 May 24;13(1):63. doi: 10.1186/s12978-016-0178-0.
• Althabe F, Belizan JM, McClure EM, Hemingway-Foday J, Berrueta M, Mazzoni A, Ciganda A, Goudar SS, Kodkany BS, Mahantshetti NS, Dhaded SM, Katageri GM, Metgud MC, Joshi AM, Bellad MB, Honnungar NV, Derman RJ, Saleem S, Pasha O, Ali S, Hasnain F, Goldenberg RL, Esamai F, Nyongesa P, Ayunga S, Liechty EA, Garces AL, Figueroa L, Hambidge KM, Krebs NF, Patel A, Bhandarkar A, Waikar M, Hibberd PL, Chomba E, Carlo WA, Mwiche A, Chiwila M, Manasyan A, Pineda S, Meleth S, Thorsten V, Stolka K, Wallace DD, Koso-Thomas M, Jobe AH, Buekens PM. 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 Feb 14;385(9968):629-639. doi: 10.1016/S0140-6736(14)61651-2. Epub 2014 Oct 15.
• Althabe F, Belizan JM, Mazzoni A, Berrueta M, Hemingway-Foday J, Koso-Thomas M, McClure E, Chomba E, Garces A, Goudar S, Kodkany B, Saleem S, Pasha O, Patel A, Esamai F, Carlo WA, Krebs NF, Derman RJ, Goldenberg RL, Hibberd P, Liechty EA, Wright LL, Bergel EF, Jobe AH, Buekens P. Antenatal corticosteroids trial in preterm births to increase neonatal survival in developing countries: study protocol. Reprod Health. 2012 Sep 19;9:22. doi: 10.1186/1742-4755-9-22.

Study record dates

Study Major Dates

• Study Start: October 1, 2011
• Primary Completion (Actual): March 1, 2014
• Study Completion (Actual): April 1, 2014

Study Registration Dates

• First Submitted: March 9, 2010
• First Submitted That Met QC Criteria: March 9, 2010
• First Posted (Estimated): March 10, 2010

Study Record Updates

• Last Update Posted (Actual): December 9, 2024
• Last Update Submitted That Met QC Criteria: October 23, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Antenatal Corticosteroids, Preterm Birth, Diffusion
• Additional Relevant MeSH Terms: Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Premature Birth; Antineoplastic Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone
• Other Study ID Numbers: GN ACT Study