Over 2 million adult cases of hepatitis E virus (HEV) are thought to occur annually in India alone, and HEV accounts for the majority of acute viral hepatitis hospitalizations worldwide, yet accurate population-based estimates of HEV burden remain scant. The hallmark and most concerning aspect of HEV is a high mortality in infected pregnant women. There have been few rigorous, population-based, prospective studies of HEV incidence, immunopathogenesis and natural history among pregnant women. Our current understanding of the risk factors and host characteristics that lead to severe consequences in pregnant women and neonates is largely based on hospital-based convenience samples. There is a need to carefully define the burden of HEV infection and disease in terms of maternal and neonatal consequences in a typical, endemic resource-poor population. To characterize the population- based epidemiology of HEV and describe maternal morbidity and mortality, pregnancy outcomes, and neonatal survival, we will 1) enroll and follow ~10,000 newly pregnant women through 3 months postpartum in a representative, rural Bangladesh population to identify the trimester-specific incidence of HEV infection, rates of illness, and risk factors for infection and hepatitis E disease and 2) recruit and follow pregnant women hospitalized with acute HEV infection and/or disease to characterize the immunologic, nutritional and other host factors associated with various treatment outcomes, including vertical transmission and neonatal survival. We will also isolate and sequence HEV from acutely ill women, for insight into the molecular epidemiology of HEV. We have over a decade of HEV research experience in this endemic population partnering with the ICDDR,B's Matlab Research Center, and we have estimated, in a smaller study, an incidence of HEV in pregnancy of ~40 per 1000 person-years. Diagnostic support will be provided by one of the most reputable HEV reference laboratories: Dr. Robert Purcell's Hepatitis Laboratory at the National Institutes of Health (Bethesda, Maryland). Co-investigators with expertise in immunology and access to the Johns Hopkins Becton Dickinson Immune Function Laboratory further strengthen this applications. The proposed project will be the first to quantify and characterize HEV infections in a large cohort of rigorously monitored pregnant women, and provide precise estimates of the burden and consequences of HEV in pregnancy and to the neonate. We will clarify the burden of this under recognized contributor to maternal mortality and morbidity in endemic areas, based on large population- based data, providing important information for future prevention and vaccine efforts.

Public Health Relevance

Hepatitis E Virus (HEV) is the main cause of acute viral hepatitis in the world, resulting in substantial maternal and newborn morbidity and mortality, primarily in South Asia. This prospective, population-based research will determine the disease burden and consequences of infection, and study the immunopathogenesis of HEV in 10,000 pregnant women and their newborn infants in South Asia. This will establish the foundation for population-level interventions (eg. vaccines) to improve maternal and infant survival in resource-poor settings.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
High Priority, Short Term Project Award (R56)
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Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
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Koshy, Rajen
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Johns Hopkins University
Public Health & Prev Medicine
Schools of Public Health
United States
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Kmush, Brittany L; Labrique, Alain; Li, Wei et al. (2016) The Association of Cytokines and Micronutrients with Hepatitis E Virus Infection During Pregnancy and the Postpartum Period in Rural Bangladesh. Am J Trop Med Hyg 94:203-11
Heaney, Christopher D; Kmush, Brittany; Navas-Acien, Ana et al. (2015) Arsenic exposure and hepatitis E virus infection during pregnancy. Environ Res 142:273-80