Data on etiologies and risk factors for community-acquired newborn infections are limited from developing countries where the burden of neonatal deaths is high and up to half of these deaths are attributable to infections.1–8 The Aetiology of Neonatal Infection in South Asia (ANISA) study, being conducted in Bangladesh, India and Pakistan, is designed to generate these critical data. The study objectives are to generate population-based data on bacterial and viral etiologies, risk factors and antibiotic resistance patterns of community-acquired infections in young infants less than 2 months old.
Bangladesh is one of the 10 countries of the world with the highest rates of neonatal mortality.9 The ANISA study is being conducted in Sylhet, Bangladesh, by the Project for Advancing Health of Newborns and Mothers (Projahnmo) study group, a research partnership of the Johns Hopkins University, Child Health Research Foundation, the International Centre for Diarrhoeal Disease Research and Shimantik (a Bangladeshi nongovernmental organization). Since 2001, Projahnmo has conducted 2 large cluster-randomized controlled trials10,11 and a dozen formative research and observational studies in the Sylhet site. Bimonthly community surveillance for identifying and recording pregnancies, births, neonatal morbidity and mortality is well established in the study areas. However, the site had not conducted an etiology study on this scale.
The ANISA study design and methodologies are described in separate articles in this supplement.12–14 Since the inception of ANISA in Sylhet, trained Community Health Workers (CHWs) follow all married women of reproductive age in a defined geographical area for identification of pregnancies and births. CHWs visit all newborns 10 times in the first 59 days of life (3 times in the first week and once a week for the subsequent 7 weeks). At every visit, CHWs assess newborns for signs of possible serious bacterial infection (pSBI) and refer ill-appearing newborns to a designated health care facility where they are evaluated by trained physicians and treated as per World Health Organization Integrated Management of Childhood Illness guidelines. Blood and nasopharyngeal-oropharyngeal (NP-OP) swabs are collected from physician-confirmed cases. Samples are also collected from randomly selected healthy young infants who are stratified by age and seasonality.15 These specimens are transported to the site laboratory in Sylhet and tested for viral and bacterial pathogens using conventional and molecular techniques. A text message-based system is used to record pregnancies, births, referral of sick young infants, enrollment of physician-confirmed pSBI cases and selection of healthy controls.15 In this article, we describe the contextual challenges encountered in implementing the ANISA study in the Sylhet site and the remedial measures the study team has undertaken to overcome these challenges.
STUDY SITE AND ITS DEMOGRAPHIC CHARACTERISTICS
The Sylhet site is located in the northeast of the country, 270 km from the capital city of Dhaka (Fig. 1). The ANISA study is conducted in 14 of the 18 unions (lowest administrative unit with average population of 25,000) of 2 subdistricts (Zakiganj and Kanaighat) with a total area of 670 km2, a population of ~400,000 and an estimated annual birth cohort of 9000. The remaining 4 unions were excluded because they were involved in an earlier randomized trial with interventions to reduce newborn infections. The study area represents a typical rural community in Bangladesh with the majority of the population employed in agriculture. The area was previously mapped and enumerated, and all households were surveyed for sociodemographic information. Geographic information system data were collected from the area, including coordinates of households, health workers’ residences and available health services in the vicinity.
Sylhet District has the poorest health indicators in Bangladesh.16 Selected health and family planning indicators of the study population are shown in Table 1.
The pilot phase was initiated in one third of the Sylhet site on June 20, 2011. The entire area was brought under full study coverage by the end of August 2011. The site’s performance was evaluated by the ANISA Technical Advisory Group against benchmark indicators (Table 2), and the site was incorporated into the main study in November 2011.
Project staffs are grouped into 4 teams: (1) field surveillance; (2) study hospital; (3) laboratory and 4) data management. Most of the field personnel were recruited from the pool of experienced staff working in previous studies. The field surveillance team is responsible for identification of pregnancies, births and cases of pSBI in the community. Female CHWs are the frontline staff for surveillance activities, each working in an area of ~3000 population. In most instances, a CHW has at least a 10th grade education and is a resident of her surveillance area. The hospital team consists of research assistants, phlebotomists, study physicians and porters. Research assistants help the team in overall study activities, while phlebotomists collect clinical specimens from young infants. Study physicians screen referred newborns for signs of pSBI, and the porters pick up and transport specimens to the site laboratory in Sylhet for processing, testing, storage and shipping to the reference laboratory in Dhaka. The data management team is responsible for data entry and cleaning, and regular upload of data to the central server located at the ANISA Data Coordination Center in Dhaka.
The ANISA Study Coordination team organized a 6-day master training in Dhaka for physicians and senior project staff from all sites. This training included field procedures, pSBI assessment of newborns and laboratory activities for site personnel. Standardized training materials include field manuals, laboratory operating procedures and data capture forms. The Sylhet team developed a site-specific training plan for staff in light of these materials. Study documents for field workers include the pregnant women register and CHW monthly planner. All tools have been translated into Bangla, the local language. pSBI assessment training for CHWs and field supervisors was organized in the pediatric and obstetric wards of Sylhet M.A.G. Osmani Medical College Hospital with sick and healthy newborns for training and standardizing the work of all field workers. Six-monthly refresher training is conducted for all field staff, and on-the-job training is imparted regularly to CHWs by supervisory staff.
The study protocol was reviewed and approved by the Ethical Review Committee of the International Centre for Diarrhoeal Disease Research and the Institutional Review Board of the Johns Hopkins Bloomberg School of Public Health.
CHALLENGES IN ADOPTION OF THE ANISA PROTOCOL AND REMEDIAL ACTIONS
Early First Postnatal Home Visit by CHW
Achieving 80% of first postnatal visits within 12 hours of birth, including 50% of visits within 6 hours, presents a great challenge to the team, even though 87% of first visits were conducted within 24 hours of birth in the Projahnmo study.17 The majority (80%) of births take place at home, and CHWs need to be notified as soon as possible after a birth has taken place so that they can plan and conduct a visit. Moreover, half the births take place at night, and it is difficult for the female CHWs in these rural communities to visit the newborns then due to limited availability of transport. We deployed a system to receive notifications as soon as possible via a mobile phone call to CHWs by family members (82% own a mobile phone) and trained birth attendants in that area. We also set up a 24-hour call center to facilitate real-time planning for early postnatal visits by CHWs based on birth notifications. We compensate CHWs for additional work hours and cover their transportation costs for working outside stipulated office hours to make an early postnatal visit (Table 3).
We conduct extensive community mobilization and family counseling activities highlighting the importance of the ANISA study, particularly for ensuring the security of CHWs while working during the early morning or late afternoon. These efforts have improved the proportion of birth notifications within 1 hour of delivery from less than 50% in the pilot phase to nearly 80% in the main study (study monitoring data). Almost 90% of neonates born in the surveillance area are successfully registered by CHWs within 7 days of birth. The proportion of newborns visited within 6, 12 and 24 hours after delivery has remained consistently high throughout the study period (Fig. 2). However, despite this high rate of early first postnatal visits, 43% (363/849) of neonatal deaths occur before the CHWs can reach newborns.
Referral Compliance of Sick Newborns to Designated Study Hospitals
Achieving high referral compliance for sick newborns to study hospitals is critical but has been a great challenge. Through dialogue with community leaders and stakeholders, we identified barriers to referral compliance, and designed and implemented various strategies to improve them.
Shortage of physicians and interrupted supply of drugs are 2 important shortcomings of the public sector health system in Bangladesh.18–20 Most of the families in the study area seek health care from private health care providers. To address this issue, we recruited full-time physicians at the government-run subdistrict hospitals and provide required medications at no cost to patients. Inability to pay transportation costs and unavailability of a family member to accompany the mother of a sick newborn to the hospital are 2 additional barriers to referral compliance. In response, we reimburse transportation costs to poor families from project funds. Upon a mother’s request, a CHW accompanies her and her sick newborn to a designated study hospital. Referral compliance has continued to improve with these efforts (Fig. 3).
Specimen Collection from Young Infants
Collection of blood and NP-OP specimens from young infants, particularly from healthy controls, has been a major challenge. Obtaining specimens for microbiologic diagnosis of pSBI is not a routine practice at subdistrict hospitals. We identify key community stakeholders, including local government representatives, schoolteachers and community leaders and hold regular meetings with them. Speaking in the local language and manner, we discuss the study’s purposes and its direct benefits to sick newborns as well as its long-term societal benefits. Our field monitoring data show rates of blood and NP-OP specimen collection from physician-confirmed pSBI cases to be 80% and 88%, respectively.
Transportation of Specimens from Study Hospitals
The average travel time between hospitals and the laboratory is 4 hours using public transport, making transportation of specimens to the site laboratory within 6 to 8 hours of collection (the time after which the probability of false negative results increases) challenging. We recruited additional porters and established hourly shipment from the hospitals so that specimens reach the laboratory within 6 hours of collection. Using this strategy, we can transport 85% of specimens within the required time. Specimens collected in late afternoon or at night are kept at the hospitals in incubators and are shipped the next morning. Blood culture bottles received at the site laboratory after 8 hours of inoculation are treated as delayed vial entry and are processed using improved laboratory techniques designed for this study.13
Contamination of Blood Culture
During the initial months of the study, we experienced a high contamination rate in blood cultures. Our team carried out several measures to contain the contamination rate at the acceptable level (<10%) set by the Technical Advisory Group. We deployed a team of 2 phlebotomists instead of one to assist each other in ensuring proper aseptic procedures. Supervision and monitoring of phlebotomists are enhanced by using a checklist and video recording of blood collection procedures. The study team holds weekly meetings to review findings of the checklists and videos. This strategy has been extremely helpful in identifying errors and undertaking subsequent remedial actions. Several measures have helped to bring down the contamination rate from 25% in the pilot phase to less than 10% and maintain it throughout the main study (Fig. 4): introduction of a separate specimen collection area with restricted entry; blood collection tables with easily cleanable surfaces; disposable sterile sheets for every young infant; regular cleaning of window screens and weekly fumigation of the rooms.
Data Management Activities
We faced several issues with data management at the beginning of the study. One major challenge was the training of CHWs on correctly sending text messages to the central server located in Dhaka, as the CHWs use mobile phones that differ in system configuration and network carrier. To overcome this issue, we provided one particular model of cell phone with a single carrier to all CHWs.
SUMMARY AND CONCLUSIONS
ANISA is a large etiology study that should generate invaluable data for future decision-making in improving young infant health in low-resource settings. The major objective of ANISA is to capture all episodes of infection in young infants (0–59 days) including early onset ones. This study should detect vertical transmission of infections, such as group B streptoccocus, in this population. We detect viral etiologies using sophisticated molecular techniques that will add useful data to the evidence base of neonatal infections. Blood and NP-OP specimens from healthy controls for molecular testing should help in interpreting the findings from pSBI cases.
Even in an established research site such as Sylhet, implementation of the ANISA protocol has not been easy. However, the Sylhet site team, with support from the ANISA Study Coordination Team, has successfully overcome most of the challenges in implementation. Lessons learned in this setting are expected to be of value to researchers in designing and implementing similar studies in resource-poor settings.
The authors thank the members of the Projahnmo study team and colleagues at the Bangladesh Ministry of Health and Family Welfare for their valuable help and advice. The authors also thank the individuals in Sylhet District who gave their time generously, including the community of the research site who are participating in this study.
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