Challenges in Implementation of the ANISA Protocol at the Odisha Site in India

Supplement

Radhanath Satpathy, MD,* Pritish Nanda, MPH,* Nimai C. Nanda, MD,† Himadri B. Bal, PhD,* Ranjita Mohanty, BDS,* Archana Mishra, MSc,* Tapoja Swain, MSc,* Keshab C. Pradhan, MBA,* Kalpana Panigrahi, PhD,‡ Ambarish Dutta, PhD,* Pravas R. Misra, MVSc,* Sailajanandan Parida, MD,§ and Pinaki Panigrahi, MD‡

antibiotic resistance and risk factors for neonatal infections. The Background: The Aetiology of Neonatal Infection in South Asia (ANISA) first phase of the study involves establishment of community- study is being carried out at 5 sites across Bangladesh, India and Pakistan, based pregnancy, birth and neonatal surveillance for identifying generating in-depth information on etiologic agents in the community setting. cases of possible serious bacterial infection (pSBI) in the 0–59 day Pregnancies are identified, births are registered and young infants are followed age group and collecting specimens for etiologic evaluation using up to 59 days old with regular assessments for possible serious bacterial infec- blood culture and state-of-the-art molecular techniques. Crucially, tion following a generic protocol. Specimens are collected from suspected controls are also enrolled to identify natural colonizers that do not cases. This article describes the challenges in implementing the generic ANISA produce disease.1,2 protocol and modifications made to accommodate the Odisha site, India. The Odisha state site research hubs are located in Rourkela Challenges: Primary challenges in implementing the protocol are the large and Bhubaneswar in eastern India, areas that continue to record geographic area, with a population of over 350,000, to be covered; assessing very high infant and neonatal mortality.3 The 2 sites were chosen to young infants at home and arranging timely transport of sick young infants participate in ANISA because of their diversity, including coastal, to study hospitals for physician confirmation of illness; and specimen col- rural, tribal, mining and periurban areas, as well as neonatal disease lection and treatment. A large workforce is deployed in a 3-tier system in the prevalence. The site investigators have previous experience con- field, while clinical, microbiology, laboratory and data management teams ducting large-scale community and hospital-based surveillance and collaborate dynamically. Mobile phones with text message capability, inte- intervention studies among neonates.4–8 Established rapport with gration with the Odisha State government’s health system, involvement of the state government health systems and availability of a trained local communities and strict monitoring at different levels have been critical workforce in the community, along with facilities for data manage- in addressing these challenges. ment, microbiological analyses and long-term storage of biological Conclusion: This article describes the challenges and modalities adopted specimens, were considered major strengths of the site. This article to collect complex and accurate data on etiology, timing of disease and outlines the diverse nature of the communities and the associated associated factors for community-acquired neonatal infections. Attention to operational, socio-cultural and scientific challenges faced while local culture and customs, training and employing community level workers implementing the ANISA protocol at Rourkela and Bhubaneswar and supervisors, involving existing government machinery, using technol- in Odisha. ogy (cell phones), and uninterrupted systematic monitoring are critical for implementing such complex protocols that aim to collect population-based data to drive policy. STUDY SITES AND POPULATION The state of Odisha, home to 3.4% of India’s population, Key Words: neonatal, surveillance, pSBI, etiology, ANISA, Odisha, Rour- records the second-highest infant mortality rate (62/1000 live births) kela, Bhubaneswar among the 29 states and 11 union territories in the country.3 Odisha (Pediatr Infect Dis J 2016;35:S74–S78) is divided into 30 districts and each district is divided into blocks, with a population of approximately 100,000 in each block. Odisha’s population density is 265/km2, and its birth rate is 20/1000 population.9 The 2 study hubs are located in the major cities of Rourkela, in he Aetiology of Neonatal Infection in South Asia (ANISA) Sundargarh District, and Bhubaneswar, in Khordha District, where Tstudy aims to identify the incidence, timing, etiologic agents, the neonatal mortality rates are 39 and 46/1000 live births, respectively (Fig. 1 and Table 1).9 These 2 areas are about 500 km apart, and their inhabitants are diverse in ethnic, socio-cultural, envi- Accepted for publication January 10, 2016. From the *Asian Institute of Public Health, Bhubaneswar, Odisha, India; †Ispat ronmental, occupational and economic characteristics. The study General Hospital, Rourkela, Odisha, India; ‡Center for Global Health and area in Rourkela covers about 480 km2 and in Bhubaneswar 161 Development, College of Public Health, University of Nebraska Medical km2. The 105 study units in the Rourkela site have a total popu- Center, Omaha, Nebraska; and §Sri Ramachandra Bhanj Medical College, lation of 204,000, and the 75 study units at the Bhubaneswar site Cuttack, Odisha, India. The ANISA study is funded by the Bill & Melinda Gates Foundation (Grant No. have a population of 156,000. These units comprise 3 to 7 villages OPPGH5307). The authors have no other funding or conflicts of interest to with populations of 600–1200 each. At the time of study initiation, disclose. there were 36,718 and 25,677 married women of reproductive age Address for correspondence: Pinaki Panigrahi, MD, PhD, Center for Global (13–49 years) in Rourkela and Bhubaneswar, respectively, for a total Health and Development, College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska 68198. E-mail: [email protected]. of 62,395 women eligible for enrollment in ANISA. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. This is an Villages around the Rourkela site are spread over hilly and open-access article distributed under the terms of the Creative Commons mining areas of Lathikata and Kuarmunda Blocks, with indige- Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permis- nous tribes predominating in the population. Many small villages sible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially. are dispersed in the study area, with the population living a tra- ISSN: 0891-3668/16/3505-0S74 ditional lifestyle with minimal outside interaction. The villagers DOI: 10.1097/INF.0000000000001112 earn their livelihood from forestry, rearing animals and raising

S74 | www.pidj.com The Pediatric Infectious Disease Journal • Volume 35, Number 5, Supplement 1, May 2016 The Pediatric Infectious Disease Journal • Volume 35, Number 5, Supplement 1, May 2016 Challenges in Odisha Site, India

FIGURE 1. Population-based study areas in the districts of Sundargarh and Khorda in Odisha state.

free. Capital Hospital, a large multispecialty government facil- TABLE 1. Neonatal Health Indicators in India and in ity in the city of Bhubaneswar, and Ispat General Hospital, an Odisha State Indian government undertaking with the steel industry in Rour- kela, serve as the research hubs for ANISA. Indicator India Odisha Neonatal mortality rate/1000 live births* 33 39 TRAINING AND RECRUITMENT OF PERSONNEL Infant mortality rate/1000 live births* 47 59 <5 mortality rate/1000 live births* 59 79 Anganwadi (meaning “courtyard shelter”) Centers have Crude birth rate/1000 population* 21.6 19.8 been functional for more than 4 decades in our study areas, pro- Current use of contraception (%)† 64.0 59.4 viding preschool mid-day meals, assessing nutritional status of Facility delivery rate (%)‡ 72.9 75.5 children, and acting as a common place for health education, *Census of India, 2013. immunization, minor health check-ups and referral services. †National Fertility Health Survey 3 (2005–2006). Female, high-school (or higher) educated Anganwadi workers are ‡Coverage Evaluation Survey 2009, UNICEF. from the same or nearby villages and have been critical partners in the implementation of ANISA in Odisha, particularly in building arid crops. Some of those who live close to townships work rapport with families and birth registration. A new cadre of vil- for daily wages, and others have salaried employment in local lage-level workers, Accredited Social Health Activists (ASHAs), coal and iron mines. In contrast, inhabitants of Balianata and has been introduced in the area and they are also part of the exist- Balipatana Blocks in Khordha District in the Bhubaneswar site ing community health structure. The ASHAs and the Anganwadi depend on irrigated agriculture and work in government offices workers were incorporated into the ANISA project design to help and small industries. They are relatively more affluent and live maintain regular surveillance and facilitate bringing pregnant in densely populated villages that are close to each other. Apart women to facilities for delivery. Both the Anganwadi workers and from primary and community health centers, each site has one ASHAs work in concert with our dedicated community health tertiary care municipal hospital that provides most health care for volunteers (CHVs).

We follow a 3-tier reporting and monitoring system that we The Odisha field sites started piloting in June 2012 and designed and have been using for the past 12 years. Considering the graduated to the main study activities in August 2013 based upon significant distance between the study units, an extra tier of block satisfactory fulfillment of performance indicators.10 Healthy con- coordinators is utilized in Rourkela. Otherwise, each study site has trol selection also began at that time. 1 CHV, a woman from the same village. About 10 CHVs are super- vised by 1 area coordinator, who reports either through block coordinators (in Rourkela only) or directly to program managers. A sen- ETHICAL CLEARANCE AND OTHER APPROVALS ior program officer is in charge of overall field operations (Fig. 2) The study protocol was approved by the Ethical Review After receiving centralized training at the Child Health Committee of the Asian Institute of Public Health which is respon- Research Foundation (CHRF) in Dhaka, senior clinicians, microbi- sible for the overall implementation of the study protocol at Odisha. ologists and senior program officers trained 185 CHVs, 25 area coor- Approval was also obtained from the Ispat General Hospital Ethical dinators, 6 block coordinators and 2 program managers on site. The Review Committee. Since government health systems were utilized, training lasted 6 or 7 days and included common protocols, use of we obtained additional approval from the Department of Health and the ANISA text messaging system, and a 1-day clinical observation Family Welfare of the Government of Odisha. The protocol was (newborn assessment, identification of pSBI cases admitted to hospi- then reviewed (including an external peer review) by the Foreign tal and other neonatal ailments). Three months after study initiation, Projects Department of the Indian Council of Medical Research. we conducted a retraining at the district-level ANISA field offices. Final clearance from the Health Ministry Screening Committee of Pre- and post-training tests were conducted using pretested questions, the Government of India was received along with approval from the and all personnel showed proficiency by the end of the pilot phase. Department of Home Affairs. During January and May, 2013, additional rooms were made available by study hospital authorities for clinical and data manage- CHALLENGES IN THE ADOPTION OF THE ANISA ment activities. The microbiology operations required many major PROTOCOL AND REMEDIAL ACTIONS changes, including controlled airflow in culture areas. Experts from CHRF and the US Centers for Disease Control and Prevention Field Activities (CDC), Atlanta, as well as University of Nebraska-based investiga- Reaching Newborns Within 24 Hours of Birth tors, provided hands-on training through troubleshooting and estab- Although 88%–94% of all births in the Odisha site now take lishing different steps of specimen collection, analyses, storage and place in hospitals, we faced the initial challenge of capturing these shipment. Information technology (IT) staff from CHRF helped the births early. A majority (55%–62%) of mothers live far from hospi- local IT manager in Bhubaneswar to install software remotely and tals, so it was difficult for CHVs and supervisors to reach the hospi- conducted a site visit to provide further training and troubleshoot- tals in time to collect initial information to enroll newborns within ing in various procedures for logging and tracking the text message 24 hours. During the first 3 months of the study, we captured only report generation and other ancillary IT-related activities. about half of all births within this time frame (Fig. 3). Although this rate improved to some extent after retraining, it was inconsistent and dropped during the cold season (December). We then employed nurses to cover both day and night shifts at the hospitals where most deliveries took place. January and February, 2014, showed an increase in reporting in the first 6 hours after birth. A second round of refresher training was conducted in April 2014, and helped to maintain this high level in the first 6 hours of life, with most other births recorded within the first 24 hours (Fig. 3). Ensuring Accurate Newborn Assessments and Referral of pSBI Cases to Study Hospitals from Villages Our second biggest challenge was identification of pSBI cases by CHVs at the community level and timely referral to study hospitals. Initially the identification rate was very low (2%–4%). A field office for each site was opened in the community for rigorous reinforcement of the protocol and training every fortnight. Utiliza- tion of our 3-tiered monitoring system using the mother-baby card (described below) along with routine use of mobile phones to call supervisory staff increased the rate to a steady 20% of all births

100 (% ) 80 ing

60 0-6 hrs 6-12 hrs 40 12-24 hrs 20

0 First postnatal visit tim

FIGURE 2. ANISA management structure at Odisha site, FIGURE 3. Time of first assessment of newborns at Odisha India. PI, principal investigator. site, July 2013–June 2014.

50 25

20 40 rate (%) 15 30

10 20

5 Contamination 10

0 0 CHW referrals for PSBI (% of births)

FIGURE 4. Rate of CHV referral for pSBI compared with FIGURE 6. Rate of contamination at RKL-BBS site (July number of births, July 2013–May 2014. 2013–June 2014).

health monitoring in the most critical period of infancy. Since meta- (Fig. 4). During this transition and improvement, we worked hard bolic screens were still not part of routine care, we offered free thy- to prevent unnecessary referral. The regular presence of study phy- roid screening to rule out congenital hypothyroidism that can cause sicians in the field for confirmation or rejection of a diagnosis of serious morbidity. The offer of this screening, along with counseling pSBI made by the CHVs and comonitoring by area coordinators by field personnel and study physicians, allowed our site to recruit and program managers provided an additional level of confidence the required number of controls for this study. to the field workers to discern milder ailments while not missing any pSBI cases. We are now able to maintain specificity without Hospital and Laboratory Activities losing sensitivity; about half of the referred cases are admitted after QA/QC of Blood Culture evaluation by a study physician (Fig. 5). There were initial problems with contamination of blood cultures which needed to be addressed (Fig. 6). Allocation of a Large Study Area, Difficult Terrain, Delay in Case Identi- dedicated clean room for blood draws as well as training of nurses fication and Transport and completion of a physician-observed checklist helped maintain The distance to be covered by CHVs and area coordina- a contamination level below 5%. However, to achieve this level 2 tors in a 480 km area with forest and hills was a challenge in required constant vigilance. We found that even a small decrease Rourkela. The recruitment of 15 additional CHVs permitted in monitoring by laboratory staff resulted in increased contamina- strict home monitoring. While each CHV sometimes visited only tion at both locations. We continue to have problems of contamina- 3 or 4 homes (compared with more than 15 by others) because of tion in cases where the young infant requires immediate oxygen the terrain, the time involved was necessary and the only way to and other life support in the crowded pediatric ward and cannot be conduct true population-based surveillance in areas where many brought to the research sampling room. deaths occur due to lack of communication and timely transport of sick young infants to hospitals. Even in coastal areas, the time Uninterrupted Power Supply and Maintenance of Major taken for transportation of sick young infants and their parents Equipment was a challenge. Instead of utilizing one study vehicle in each We installed generators for freezers and automated blood area, we introduced a system where local owners of 3-wheeled culture machines, and uninterruptible power sources for all data auto-rickshaws provided transport upon receiving a phone call management equipment. Although there are maintenance con- and received immediate payment at the study hospital according tracts at each site, we have faced time lags for factory-approved to set rates. technicians to repair equipment. Our proactive measure was to provide a second −80°C freezer at each site which prevented thaw- Enrolling Healthy Controls ing of valuable specimens when one of the freezers was out of The enrollment of healthy controls was considered to be of order for nearly a week. paramount importance in the study to rule out normal colonizers that do not cause disease. The local institutional review board wanted International Shipment of Specimens study participants to perceive specific benefits apart from rigorous While there are multiple air couriers, it was difficult to find ones that allowed dry ice shipments and assured refilling during transit. In fact, our first shipment arrived at CDC when Atlanta was 75 experiencing an unusual ice storm, resulting in flight cancellations and road traffic problems. However, due to the availability of stor- 50 age facilities and the ability of the courier to refill the shipment

Referrals) with dry ice, all specimens were maintained at the required tem- 25 perature until delivery.

(% of CH V Unique Activities at the Odisha Site Physician-confirmed pSBI 0 Mother-baby Card and Manual of Newborn Care A mother-baby card written in the local language, Odia, is given to the mother in the last trimester of pregnancy for follow- FIGURE 5. Physician-confirmed pSBI rates among CHV- up. This card is kept with the mother throughout the study period. referred young infants, July 2013–June 2014. It bears a serial number (for internal tracking by field staff) and the

ANISA study identification number. There are spaces for record- Our thanks are also due to over 250 field staff, including the CHVs ing health status and the signatures of the CHV, area coordinator and supervisory staff, and all the Anganwadi workers and ASHAs and a third-level supervisor/study physician. These signatures, in the districts of Rourkela and Bhubaneswar for their sincere dis- with dates and times, in conjunction with scheduled and surprise charge of the duties assigned to them, as well as to the parents of visits by supervisors, provide a strict monitoring system for field the infants enrolled in this important study for their cooperation. workers. This card also serves as identification for the mother and We are grateful to Meghan Scott for her assistance in developing infant when they come to the study hospital for treatment. the manuscript.

REFERENCES SUMMARY AND CONCLUSION 1. Islam MS, Baqui AH, Zaidi AK, et al. Infection surveillance protocol for a Implementing ANISA in a population of over 350,000 multicountry population-based study in South Asia to determine the inci- spread across a large area with diverse geographic, socio-cultural dence, etiology, and risk factors for infections among young infants 0 to 59 and economic backgrounds was a formidable task. Involvement days old. Pediatr Infect Dis J. 2016;35 (Suppl 1):S9–S15. and assistance from state health department personnel, hiring local 2. Islam MS, Rahman QS, Hossain T, et al. Using text messages for critical full-time study staff, enhancing individual family contacts, moti- real-time data capture in the ANISA study. Pediatr Infect Dis J. 2016;35 vating marginal and minority communities and providing direct (Suppl 1):S35–S38. support to needy cases at health service points played important 3. Directorate of Census Operations, Orissa. Provisional Population Totals – Orissa - Data Sheet: 2011. New Delhi, India: Office of the Registrar roles in attaining the necessary quality for our site to graduate from General and Census Commissioner; 2011. Available at: http://censusin- piloting to the main study phase in a relatively short time period. dia.gov.in/2011-prov-results/data_files/orissa/Data%20Sheet-%20Orissa- Implementation was a team effort with field staff, clinicians, micro- Provisional.pdf. Accessed September 19, 2014. biologists and data management staff working together on a regular 4. Panigrahi P. Effectiveness of a Lactobacillus plantarum synbiotic against basis. The ability of all our field staff to use mobile phones and late onset sepsis in neonates [Abstract 3618.2]. In: 24th Annual Meeting text messaging was invaluable. The assistance provided by skilled of Pediatric Academic Societies, Washington, DC; May 4–7,2013. The Woodlands, TX: Pediatric Academic Societies; 2013. domain experts at CHRF and CDC at every step was instrumental in addressing deficiencies in a timely fashion. Although the site is 5. Carlo M, Gouder S, Jehan I, et al. High mortality rates for very low birth weight infants in developing countries despite training. Pediatrics. halfway into the main study, reaching sick young infants and trans- 2010;126:e1072–1080. porting them to our study hospitals (and not to other private care 6. Carlo WA, Goudar SS, Jehan I, et al. Newborn-care training and perinatal providers or village doctors) will continue to be a challenge as we mortality in developing countries. N Engl J Med. 2010;362:614–623. attempt to track and collect biological specimens from every young 7. Panigrahi P, Parida S, Pradhan L, et al. Long-term colonization of a infant with pSBI for bacterial and viral analyses. Lactobacillus plantarum synbiotic preparation in the neonatal gut. J Pediatr Gastroenterol Nutr. 2008;47:45–53. 8. McClure EM, Wright LL, Goldenberg RL et al. The global network: a pro- ACKNOWLEDGMENTS spective study of stillbirths in developing countries. Am J Obstet Gynecol. The authors thank the officials at the Indian Council of 2007;197:247.e1–e5. Medical Research for reviewing this protocol. This study could not 9. Registrar General & Census Commissioner, India. Annual Health Survey have been implemented without the ownership and keen interest Bulletin 2011–12, Odisha. New Delhi, India: Office of the Registrar General of the Cabinet Minister and Principal Secretary, Department of and Census Commissioner; 2012. Available at: http://censusindia.gov.in/ vital_statistics/AHSBulletins/files2012/Odisha_Bulletin%202011–12.pdf. Health and Family Welfare, Government of Odisha. We are grate- Accessed September 19, 2014. ful to Mahendra Pradhan, Ranjan K. Raul, Basil Kullu, Karuna- 10. Connor NE, Islam MS, Arvay ML, et al. Methods employed in monitoring kar Panda, Sunita Patel, Sabita Behera, Janaki Shaw and Jyoti R. and evaluating field and laboratory systems in the ANISA study: ensuring Mohanty for their support in the data center, field and hospital. quality. Pediatr Infect Dis J. 2016;35 (Suppl 1):S39–S44.