Study Design
This community-based, two-arm cluster-randomized controlled trial will evaluate the impact of an EmONC package introduced by EmONC cluster teams in intervention clusters compared to standard care in control clusters. The study includes 106 clusters (defined as distinct geographic areas with approximately 300-500 births per year) and encompasses all deliveries therein. All clusters have pre-existing independent maternal-newborn health registry systems, i.e. independent, prospective, population-based active surveillance mechanisms to assess rates of stillbirth, neonatal and maternal mortality, on which the outcome assessment will be based.
Study Outcomes
The primary outcome of the study is perinatal mortality, defined as the composite rate of stillbirth and 7-day neonatal mortality per 1000 births. We will collect outcome data on all births at 20 weeks gestation and greater, but the primary outcome will include events for those pregnancies that occur at ≥28 weeks or ≥1000 g. Secondary outcomes will include stillbirths, 7-day neonatal mortality, maternal death or severe morbidity (including obstetric fistula, eclampsia and obstetrical sepsis) and 28-day neonatal mortality. Other outcomes of interest include rates of transport to hospital of both mothers and newborns.
Enrollment - Trial sites
The study clusters are located at 7 sites in six countries. (Table ) All of these sites are research units of the Global Network (GN). From 2005 to 2007, five of the seven sites participated in a cluster-randomized trial of WHO Essential Newborn Care and Neonatal Resuscitation, the GN's FIRST BREATH trial [
57].
Interventions in intervention sites
The intervention is based on best practices from existing research and programmatic experience by the GN's EmONC Trial investigators, comprised of obstetricians, neonatologists and public health professionals well versed in and/or practicing MNH in low-resource settings. All activities detailed below are implemented throughout the intervention areas.
EmONC teams' goals
At each site, a Country Advisory Group and Cluster Teams in each intervention cluster seek to accomplish the following:
1. Work in partnership with the local health authorities.
2. Implement an organized process of community mobilization, and social and behavioral change based on a "Community Action Cycle" that strengthens communities' capacity to organize, explore MNH issues and set priorities, plan, implement, monitor, evaluate and share effective strategies and systems that increasingly improve EmONC care and MNH outcomes.
3. Analyze preventable causes of peripartum mortality and existing community resources for EmONC, including quality evaluation of the MNH care services.
4. Assist communities to identify and leverage available resources to address barriers to EmONC (e.g., communications and transport for EmONC).
5. Identify and assess capacity of available EmONC referral hospitals, work with hospital staff to accept transfers, perform appropriate cesarean sections/other procedures and review/maintain quality of care. Actively engage community members as advocates for improvement in quality of care.
6. Identify/train all community birth attendants/health workers, as appropriate, to (a) identify need for referral for severe maternal/newborn illnesses (b) facilitate transfer to an EmONC facility by identifying and arranging for locally available and sustainable methods of transportation (c) stabilize the woman/newborn prior to/during transport () communicate with hospital staff for timely and effective transport.
7. Establish a quality assurance review in each cluster to review each maternal, fetal or neonatal death to determine if it was preventable and how to prevent similar deaths in the future.
EmONC team tools
To accomplish the components of the intervention described above, master trainers will facilitate central and regional training of 1 to 2 Country trainers in each of the following areas: (1) community mobilization; (2) birth attendant training, and (3) EmONC referral facility improvement.
Community Mobilization Sustainable community mobilization must move beyond raising community awareness about an issue or persuade people to engage in predetermined activities. The Community Action Cycle (CAC), a comprehensive strategy, empowers communities to take charge of problems within their own context. The CAC has seven key phases: 1) Prepare to mobilize - the methodology to work with communities is designed, the study teams are established and trained, and they identify and train community facilitators; 2) Organize the community for action- the team enters the community, establishes credibility; raises community awareness about MNH; and works with communities to identify and invite those most likely to be affected by and interested in MNH issues to organize "core groups"; 3) Explore MNH issues and set priorities -core group members explore MNH problems and existing practices in their core groups and with the broader community and set priorities based on what they learn; 4) Plan together- core group members engage in a planning process with community leaders and resource people including health providers to develop a Community Action Plan and establish coordinating and monitoring mechanisms; 5) Act together - the community implements their plan and monitors progress, adjusting course as necessary; 6) Evaluate together- the community evaluates results, shares what it has learned, and prepares to begin the cycle again; 7) Prepare to scale-up - the community and/or the program team expands the approach to other communities.
Individuals from outside the community must establish relationships with communities built on mutual respect and allow the community to solve their problems in the most contextually appropriate way. The CAC works well with HBLSS as well as with efforts to strengthen of facility-based services.
Birth Attendant Training Home Based Life Saving Skills (HBLSS), developed by the American College of Nurse Midwives, is a family/community-based program to reduce maternal/neonatal mortality with emphasis on basic life saving care at the community level; reduction in delays in reaching facilities and supporting birth preparedness involving key decision makers. HBLSS is a competency-based training intervention for community women and men, focusing on practices that are safe, feasible and acceptable to the community. HBLSS emphasizes community involvement during the administration of a 12-item curriculum of preventive/life saving skills. The pictorial HBLSS 'Take Action' cards are particularly useful in communities with low literacy levels. The core curriculum is complemented by activities to develop emergency transportation systems and involve community leaders, particularly men [
58]. We emphasize that the entire community, including traditional birth attendants, received HBLSS training.
Improvement in Quality of Care at Facilities The facility training utilized curriculum adapted from Jhpiego which includes a training curriculum and practice sessions in the following areas: emergency preparedness, essential newborn care, obstetrical care. The curriculum includes training on drills aimed at improving facility responses to emergency conditions such as hemorrhage and eclampsia, which are then to be conducted in-country, as are regularly occurring audits for all maternal, fetal and neonatal deaths. The site facility trainer is expected to visit each EMONC facility to conduct assessments of the facility each 6 months, and hold training sessions aimed at improving maternity and newborn care on a regular basis.
EmONC team intervention and implementation All the teams underwent a central, intensive two-week training of trainers (TOT) led by Master Trainers. Separate trainers were identified for each site to work in three major areas: EmONC Facility Improvement, HBLSS training and Community Mobilization. The TOT was followed by one week in-country training led by Country Trainers for key stakeholders and supported by Master Trainers at each site. Each team was provided all relevant materials for the CAC, HBLSS curriculum and the facility improvement methodology, as well as a common manual of operations for field implementation. Each team utilized the tools in the most contextually appropriate method for their site in order to achieve the study objectives.
Interventions in control clusters
The Maternal Newborn Health (MNH) registry detailed below is the only study-related activity in the control clusters.
Administrative Structures - The Global Network's Subcommittee for the EmONC Trial
The Global Network for Women's and Children's Health Research (Global Network) is a multi-site trial funded by the National Institute of Child Health and Human Development (NICHD). The trial is supervised by the Global Network's EmONC Trial Subcommittee which consists of all site investigators, and the principal investigator and a senior statistician from the Data Coordinating Center (DCC) and the NICHD Director of the Global Network (Figure ). The EmONC Trial Subcommittee convenes monthly by conference call and meets biannually to oversee study implementation, data analyses and publications.
Administrative Structures - The EmONC Trial Country Team
At each site, the senior in-country investigators work with key members of the team responsible for implementation of the intervention and for the process data collection, including:
• EmONC Country Coordinator: responsible for overseeing the conduct of the study
• Community Mobilization Trainer: responsible for the training of Community Mobilization facilitators
• Birth Attendant Trainer: responsible for birth attendant training
• EmONC Facility/Skilled Birth attendant Trainer: physician responsible for leading the quality improvement and training at the EmONC facilities and leading the training for the skilled birth attendants at the level one health clinics.
Administrative Structures - The EmONC Country Advisory Group
Each Country Team is supported by an EmONC Country Advisory Group consisting of the senior in-country investigator, EmONC Country Coordinator, a senior physician from a referral facility, three country trainers, a government health official, a community representative, a maternal representative and a birth attendant representative. The Advisory Groups facilitate buy-in for the intervention, assist in organizing trainings, death audits and community-based activities.
Administrative Structures - EmONC Cluster Teams
The Cluster Teams are led by Cluster Coordinators and are responsible to oversee and coordinate all community mobilization activities and HBLSS training in their respective clusters. The EmONC Cluster Teams at each site meet once a month with the Country Team to discuss progress and obstacles in the implementation of the trial.
Administrative Structures - Community (Village) Committees
These committees are formed through the CAC and are comprised of active community members who are responsible for coordinating implementation of the community's plan (e.g., improving transport, maintaining emergency funds, carrying out death audits, etc.) and monitoring results.
Administrative Structures - The Data Coordinating Center
RTI International is the DCC for this trial. They are responsible for maintaining the central study database. In addition, they also generate descriptive statistics to monitor enrollment and retention, as well as process indicators for implementation of the study intervention.
Informed Consent and Research Ethics
The study protocol and informed consent documents were reviewed and approved by the institutional review boards at all participating sites in as well as at the partner U.S. sites and DCC.
Informed consent was sought at two levels
• Community and Health Facility Consent: Agreement for study participation was sought from all participating communities and facilities in advance of randomization. Responsible community health authorities agreed to participate before beginning any activities. Communities were informed of their assignment to the control or intervention arm following randomization.
• Pregnant women and their offspring: Informed consent for data collection is sought from all pregnant women that are residents of or deliver within the study clusters.
Publications
The primary publication for the trial will follow CONSORT guidelines for randomized controlled trials. Criteria for authorship of all papers, presentations, and reports resulting from the study will conform to ICMJE standards.
Quality Assurance
Multiple mechanisms are in place to assure the fidelity of the intervention and the quality of data collection. Cluster Coordinators, selected by the EmONC Country Team based on their skills, received training and certification on data collection, with refresher training conducted as needed. Cluster Coordinators directly monitor all aspects of the study intervention. The Country Team members visit the participating communities routinely. The DCC performs inter and intra-form edits to assure data consistency and monitors double-data entry. In addition, the DCC statisticians perform data quality reviews on an ongoing basis.
Data Monitoring Committee, Interim Analyses and Stopping Rule
The NICHD-designated Data Monitoring Committee (DMC) reviews the data including enrollment, compliance, protocol violations, outcomes, and adverse events, at least every six months. Adverse events (including death, life-threatening events, and hospitalization) are monitored by onsite staff, submitted to the DCC and reported to the DMC.
Statistical Design and Sample Size
The cluster-randomized trial was designed to test the impact of the intervention on perinatal mortality with the cluster as the unit of randomization and analysis. We will test the primary hypothesis that the EmONC will reduce the risk of perinatal mortality (measured as the total number of stillbirths and 7-day neonatal deaths per 1000 deliveries) with a permutation test conducted at the cluster level. Secondary analyses of this same hypothesis controlling for individual-level covariates will be conducted using extensions of the generalized linear model that account for the correlation within cluster. An assessment of whether the 106 possible clusters available provided adequate power to test this hypothesis was conducted under the assumptions that on average the clusters will contribute 300 to 500 deliveries per year with a base mean rate of perinatal death of 40 to 50 per 1,000 deliveries and an intra-class correlation coefficient between 0.005 and 0.01 (based on preliminary data collected from these clusters). Using a two-sided hypothesis test at the 5% level of significance, these 106 clusters will provide a power of at least 80% across the full range of assumptions and greater than 90% across much of the range to detect a reduction of 30% in the perinatal mortality.
Enrollment - Inclusion Criteria
The clusters have at least 300 deliveries per year with a minimum of 50% occurring at home or first level facilities. This is an intent-to-treat design. Thus all pregnancy outcomes of women who deliver in the study clusters and provide consent are collected.
Enrollment - Exclusion Criteria
The intervention is intended to work by improving knowledge and affecting behavior change throughout pregnancy. Improved outcomes at delivery will depend on accrued benefits. Women who first move into the study area within 4 weeks of their actual delivery date are unlikely to derive adequate benefit from the intervention and will be excluded from the primary outcome.
Randomization procedures
Preliminary data collected by the GN from these 106 clusters formed the basis for randomization. The DCC stratified clusters based on a cross-classification of birth and perinatal mortality rates and randomized within one to three comparable strata to intervention or control cluster within each Global Network site.
Enrolment - Enlisting participants in the trial
The MNH Registry is an ongoing population-based pregnancy outcome data collection program in each of the clusters in the GN's 7 trial sites. The MNH Registry tracks all pregnancies, deliveries and delivery outcomes with its own staff which functions independently from the EMONC trial staff in order to reduce bias due to joint outcome data collection. The Registry in each cluster is managed by a Registry Administrator who, with assistants as needed, screens, enrolls, and tracks all pregnant women within the clusters. They obtain consent for data collection during pregnancy and collect delivery outcomes from all known pregnancies and all deaths of pregnant women up to and including 42 days post delivery/pregnancy termination, and 28-day neonatal outcomes. The Registry collects data during three visits to each mother including an enrollment visit as early as possible within pregnancy (targeted for 20 weeks gestation or greater), a second visit within 48 hours of delivery and a visit at day 42 after birth.
Data Collection and Management
Outcome and process data are collected separately for the trial. Outcome data are collected through the MNH Registry utilizing standardized instruments to measure maternal demographic data, health care utilization, MNH outcomes and serious adverse events. Data collected for the EmONC trial implementation are collected using standardized instruments in the intervention clusters; process data include cluster team activities, community mobilization activities and training logs. Facility and community-based death audit forms support the activities of the facility trainers and community mobilization teams that utilize them for teaching and discussion.
All data are collected prospectively in the local language using hard copy forms, with only the individual study identification number on each form in order to maintain confidentiality. The forms are keyed into computers at in each country using a common data management system. At intervals ranging from daily to once per week, data are transmitted to the DCC for inclusion in the central database. The hard copy forms are retained in-country in a secure location.
1 Robert L Goldenberg,2 Elizabeth M McClure,3 Sarah Saleem,1 Shivaprasad S Goudar,4 Fernando Althabe,5 Archana Patel,6 Fabian Esamai,7 Ana Garces,8 Elwyn Chomba,9 Manolo Mazariegos,10 Bhala Kodkany,4 Jose M Belizan,5 Richard J Derman,11 Patricia L Hibberd,12 Waldemar A Carlo,13 Edward A Liechty,14 K Michael Hambidge,15 Pierre Buekens,16 Dennis Wallace,3 Lisa Howard-Grabman,17 Suzanne Stalls,18 Marion Koso-Thomas,19 Alan H Jobe,20 and Linda L Wright19
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