Volume 94, Issue 1
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



Hepatitis E virus (HEV) infection is severe during pregnancy, with a pregnant case fatality rate around 30%. In Bangladesh, plasma samples from 1,100 women during the first trimester (TM) and third TM of pregnancy and 3 months postpartum (PP) were tested for anti-HEV IgG. During this time, 40 women developed antibody responses to HEV. These seroconverters are classified as the cases (incidence = 46 infections per 1,000 person-years). All except one seroconversion occurred between the third TM and 3 months PP. The cases and 40 matched non-seroconverters (controls) underwent analysis of a panel of 10 cytokines, 12 vitamins and minerals, and two markers of inflammation. Throughout pregnancy, seroconverting cases displayed higher concentrations of both pro- and anti-inflammatory cytokines compared with the non-seroconverting controls, even prior to infection. In the first TM, seroconverters had lower circulating zinc concentrations ( = 0.03), an increased prevalence of vitamin D deficiency (25-hydroxy vitamin D [25(OH)2D] < 50 nmol/L, = 0.08), and anemia (hemoglobin < 110 g/L, = 0.05) compared with controls. There were no differences in C-reactive protein or α-1-acid glycoprotein. Antecedent micronutrient deficiencies may lead to dysregulated cytokine expression and immunologic compromise, increasing the risk of HEV infection, especially during pregnancy. This exploratory analysis reveals potential novel associations that deserve further study.


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  1. Purcell RH, Emerson SU, , 2008. Hepatitis E: an emerging awareness of an old disease. J Hepatol 48: 494503.[Crossref] [Google Scholar]
  2. Khuroo MS, , 1991. Hepatitis E: the enterically transmitted non-A, non-B hepatitis. Indian J Gastroenterol 10: 96100. [Google Scholar]
  3. Zhuang H, Cao XY, Liu CB, Wang GM, , 1991. Epidemiology of hepatitis E in China. Gastroenterol Jpn 26 (Suppl 3) 135138. [Google Scholar]
  4. Dalton HR, Bendall RP, Rashid M, Ellis V, Ali R, Ramnarace R, Stableforth W, Headdon W, Abbott R, McLaughlin C, Froment E, Hall KJ, Michell NP, Thatcher P, Henley WE, , 2011. Host risk factors and autochthonous hepatitis E infection. Eur J Gastroenterol Hepatol 23: 12001205.[Crossref] [Google Scholar]
  5. Kuniholm MH, Purcell RH, McQuillan GM, Engle RE, Wasley A, Nelson KE, , 2009. Epidemiology of hepatitis E virus in the United States: results from the third National Health and Nutrition Examination Survey, 1988–1994. J Infect Dis 200: 4856.[Crossref] [Google Scholar]
  6. Labrique AB, Kuniholm MH, Nelson KE, Scheld WM, Grayson ML, Hughes JM, , 2010. The global impact of hepatitis E: new horizons for an emerging virus. , eds. Emerging Infections, 9th edition. Washington, DC: ASM Press, 5393. [Google Scholar]
  7. Navaneethan U, Mohajer MA, Shata MT, , 2008. Hepatitis E and pregnancy: understanding the pathogenesis. Liver Int 28: 11901199.[Crossref] [Google Scholar]
  8. Labrique AB, Sikder SS, Krain LJ, West KP, Jr Christian P, Rashid M, Nelson KE, , 2012. Hepatitis E, a vaccine-preventable cause of maternal deaths. Emerg Infect Dis 18: 14011404.[Crossref] [Google Scholar]
  9. Gurley ES, Halder AK, Streatfield PK, Sazzad HM, Huda TM, Hossain MJ, Luby SP, , 2012. Estimating the burden of maternal and neonatal deaths associated with jaundice in Bangladesh: possible role of hepatitis E infection. Am J Public Health 102: 22482254.[Crossref] [Google Scholar]
  10. Stoszek SK, Engle RE, Abdel-Hamid M, Mikhail N, Abdel-Aziz F, Medhat A, Fix AD, Emerson SU, Purcell RH, Strickland GT, , 2006. Hepatitis E antibody seroconversion without disease in highly endemic rural Egyptian communities. Trans R Soc Trop Med Hyg 100: 8994.[Crossref] [Google Scholar]
  11. Patra S, Kumar A, Trivedi SS, Puri M, Sarin SK, , 2007. Maternal and fetal outcomes in pregnant women with acute hepatitis E virus infection. Ann Intern Med 147: 2833.[Crossref] [Google Scholar]
  12. Rasheeda CA, Navaneethan U, Jayanthi V, , 2008. Liver disease in pregnancy and its influence on maternal and fetal mortality: a prospective study from Chennai, southern India. Eur J Gastroenterol Hepatol 20: 362364.[Crossref] [Google Scholar]
  13. Labrique AB, Kmush B, Engle R, Schulze K, West KPJ, Purcell R, Nelson K, , 2011. Seroincidence of Intrapartum Hepatitis E Virus Infections Declines in Pregnant Bangladeshi Women between 2001 and 2010. 3rd North American Congress of Epidemiology, Montreal, Quebec, Canada, June 22–24, 2011. [Google Scholar]
  14. Klein SL, Roberts CW, , eds., 2010. Sex Hormones and Immunity to Infection. New York, NY: Springer. [Google Scholar]
  15. Priddy KD, , 1997. Immunologic adaptations during pregnancy. J Obstet Gynecol Neonatal Nurs 26: 388394.[Crossref] [Google Scholar]
  16. Pal R, Aggarwal R, Naik SR, Das V, Das S, Naik S, , 2005. Immunological alterations in pregnant women with acute hepatitis E. J Gastroenterol Hepatol 20: 10941101.[Crossref] [Google Scholar]
  17. Luft BJ, Remington JS, , 1982. Effect of pregnancy on resistance to Listeria monocytogenes and Toxoplasma gondii infections in mice. Infect Immun 38: 11641171. [Google Scholar]
  18. Krishnan L, Guilbert LJ, Russell AS, Wegmann TG, Mosmann TR, Belosevic M, , 1996. Pregnancy impairs resistance of C57BL/6 mice to Leishmania major infection and causes decreased antigen-specific IFN-gamma response and increased production of T helper 2 cytokines. J Immunol 156: 644652. [Google Scholar]
  19. Menendez C, , 1995. Malaria during pregnancy: a priority area of malaria research and control. Parasitol Today 11: 178183.[Crossref] [Google Scholar]
  20. Raychaudhuri SP, Navare T, Gross J, Raychaudhuri SK, , 2003. Clinical course of psoriasis during pregnancy. Int J Dermatol 42: 518520.[Crossref] [Google Scholar]
  21. Ostensen M, Villiger PM, , 2002. Immunology of pregnancy—pregnancy as a remission inducing agent in rheumatoid arthritis. Transpl Immunol 9: 155160.[Crossref] [Google Scholar]
  22. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T, , 1998. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in multiple sclerosis group. N Engl J Med 339: 285291.[Crossref] [Google Scholar]
  23. Murphy KP, Travers P, Walport M, Janeway C, , 2008. Janeway's Immunobiology. New York, NY: Garland Science, 887. [Google Scholar]
  24. Piccinni MP, , 2005. T cells in pregnancy. Chem Immunol Allergy 89: 39.[Crossref] [Google Scholar]
  25. Wegmann TG, Lin H, Guilbert L, Mosmann TR, , 1993. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today 14: 353356.[Crossref] [Google Scholar]
  26. Wintergerst ES, Maggini S, Hornig DH, , 2007. Contribution of selected vitamins and trace elements to immune function. Ann Nutr Metab 51: 301323.[Crossref] [Google Scholar]
  27. Scrimshaw NS, Taylor CE, Gordon JE, , 1968. Interactions of nutrition and infection. Mongr Ser World Health Organ 57: 3329. [Google Scholar]
  28. Maggini S, Wintergerst ES, Beveridge S, Hornig DH, , 2007. Selected vitamins and trace elements support immune function by strengthening epithelial barriers and cellular and humoral immune responses. Br J Nutr 98 (Suppl 1): S29S35. [Google Scholar]
  29. Thurnham DI, Mburu AS, Mwaniki DL, De Wagt A, , 2005. Micronutrients in childhood and the influence of subclinical inflammation. Proc Nutr Soc 64: 502509.[Crossref] [Google Scholar]
  30. Shah D, Sachdev HP, , 2006. Zinc deficiency in pregnancy and fetal outcome. Nutr Rev 64: 1530.[Crossref] [Google Scholar]
  31. World Health Organization, 2009. Global Prevalence of Vitamin A Deficiency in Populations At Risk 1995–2005. Anonymous WHO Global Database on Vitamin A Deficiency. Geneva, Switzerland: World Health Organization. [Google Scholar]
  32. Lee AI, Okam MM, , 2011. Anemia in pregnancy. Hematol Oncol Clin North Am 25: 241259 vii.[Crossref] [Google Scholar]
  33. Dror DK, Allen LH, , 2010. Vitamin D inadequacy in pregnancy: biology, outcomes, and interventions. Nutr Rev 68: 465477.[Crossref] [Google Scholar]
  34. Khuroo MS, Teli MR, Skidmore S, Sofi MA, Khuroo MI, , 1981. Incidence and severity of viral hepatitis in pregnancy. Am J Med 70: 252255.[Crossref] [Google Scholar]
  35. Shrestha P, Bhandari D, Sharma D, Bhandari BP, , 2009. A study of viral hepatitis during pregnancy in Nepal Medical College Teaching Hospital. Nepal Med Coll J 11: 192194. [Google Scholar]
  36. West KP, Jr Shamim AA, Mehra S, Labrique AB, Ali H, Shaikh S, Klemm RD, Wu LS, Mitra M, Haque R, Hanif AA, Massie AB, Merrill RD, Schulze KJ, Christian P, , 2014. Effect of maternal multiple micronutrient vs iron-folic acid supplementation on infant mortality and adverse birth outcomes in rural Bangladesh: the JiVitA-3 randomized trial. JAMA 312: 26492658.[Crossref] [Google Scholar]
  37. Yu C, Engle RE, Bryan JP, Emerson SU, Purcell RH, , 2003. Detection of immunoglobulin M antibodies to hepatitis E virus by class capture enzyme immunoassay. Clin Diagn Lab Immunol 10: 579586. [Google Scholar]
  38. Engle RE, Yu C, Emerson SU, Meng XJ, Purcell RH, , 2002. Hepatitis E virus (HEV) capsid antigens derived from viruses of human and swine origin are equally efficient for detecting anti-HEV by enzyme immunoassay. J Clin Microbiol 40: 45764580.[Crossref] [Google Scholar]
  39. Yamini S, West KP, Jr Wu L, Dreyfuss ML, Yang DX, Khatry SK, , 2001. Circulating levels of retinol, tocopherol and carotenoid in Nepali pregnant and postpartum women following long-term beta-carotene and vitamin A supplementation. Eur J Clin Nutr 55: 252259.[Crossref] [Google Scholar]
  40. StataCorp, 2009. Stata Statistical Software. College Station, TX: StataCorp LP. [Google Scholar]
  41. Schulze KJ, Christian P, Wu LS, Arguello M, Cui H, Nanayakkara-Bind A, Stewart CP, Khatry SK, LeClerq S, West KP, Jr, 2014. Micronutrient deficiencies are common in 6- to 8-year-old children of rural Nepal, with prevalence estimates modestly affected by inflammation. J Nutr 144: 979987.[Crossref] [Google Scholar]
  42. Jiang T, Christian P, Khatry SK, Wu L, West KP, Jr, 2005. Micronutrient deficiencies in early pregnancy are common, concurrent, and vary by season among rural Nepali pregnant women. J Nutr 135: 11061112. [Google Scholar]
  43. James WP, Mascie-Taylor GC, Norgan NG, Bistrian BR, Shetty PS, Ferro-Luzzi A, , 1994. The value of arm circumference measurements in assessing chronic energy deficiency in Third World adults. Eur J Clin Nutr 48: 883894. [Google Scholar]
  44. Labrique AB, Kuniholm M, Engle RE, Rashid M, Ali H, Nelson KE, , 2009. Seroprevalence of Antibodies to Hepatitis E Virus (HEV) and HEV Incidence in Pregnant Women in Northwest Rural Bangladesh. 13th International Symposium on Viral Hepatitis and Liver Disease, Washington, DC, March 20–24, 2009. [Google Scholar]
  45. Cantorna MT, Zhu Y, Froicu M, Wittke A, , 2004. Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. Am J Clin Nutr 80: 1717S1720S. [Google Scholar]
  46. Fraker PJ, King LE, , 2004. Reprogramming of the immune system during zinc deficiency. Annu Rev Nutr 24: 277298.[Crossref] [Google Scholar]
  47. FAO/WHO/UNU Expert Consultation, 2001. Human Energy Requirements. Rome, Italy: FAO. [Google Scholar]

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  • Received : 26 Mar 2015
  • Accepted : 15 Oct 2015
  • Published online : 06 Jan 2016

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