Sharda Patra, MS; Ashish Kumar, MD, DM; Shubha Sagar Trivedi, MS; Manju Puri, MS; Shiv Kumar Sarin, MD, DM
Note: This research was presented in the Plenary Award Session of the 14th Annual Conference of Asia-Pacific Association for the Study of Liver, Bali, Indonesia, 15–22 August 2005.
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Shiv Kumar Sarin, MD, DM, Department of Gastroenterology, G.B. Pant Hospital, Room 201, Academic Block, New Delhi 110 002, India; e-mail, email@example.com.
Current Author Addresses: Ms. Patra, Ms. Trivedi, and Ms. Puri: Lady Hardinge Medical College, New Delhi 110 001, India.
Dr. Kumar: Department of Gastroenterology, G.B. Pant Hospital, New Delhi 110 002, India.
Dr. Sarin: Department of Gastroenterology, G.B. Pant Hospital, Room 201, Academic Block, New Delhi 110 002, India.
Author Contributions: Conception and design: S. Patra, A. Kumar, S.S. Trivedi, M. Puri, S.K. Sarin.
Analysis and interpretation of the data: S. Patra, A. Kumar, M. Puri, S.K. Sarin.
Drafting of the article: S. Patra, A. Kumar, M. Puri, S.K. Sarin.
Critical revision of the article for important intellectual content: S. Patra, A. Kumar, S.S. Trivedi, S.K. Sarin.
Final approval of the article: S. Patra, A. Kumar, S.K. Sarin.
Provision of study materials or patients: S. Patra, A. Kumar, S.S. Trivedi, M. Puri, S.K. Sarin.
Administrative, technical or logistic support: A Kumar, S.S. Trivedi, M. Puri, S.K. Sarin.
Collection and assembly of data: S. Patra, A. Kumar, S.K. Sarin.
Patra S., Kumar A., Trivedi S., Puri M., Sarin S.; Maternal and Fetal Outcomes in Pregnant Women with Acute Hepatitis E Virus Infection. Ann Intern Med. 2007;147:28-33. doi: 10.7326/0003-4819-147-1-200707030-00005
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Published: Ann Intern Med. 2007;147(1):28-33.
Hepatitis E virus (HEV) is a single-stranded RNA virus that causes large-scale epidemics and sporadic cases of acute viral hepatitis in developing countries (1, 2). Infection with HEV also poses a significant risk for acute viral hepatitis to travelers in endemic areas (3). The main source of transmission of HEV is contaminated drinking water (4, 5). In men and nonpregnant women, the disease is usually self-limited and has a low case-fatality rate (<0.1%) (6). However in pregnant women, HEV infection is more severe, often leading to fulminant hepatic failure and death in up to 15% to 20% of cases. This high mortality rate was first reported in an epidemic setting in the early 1980s (7) and was reported again in a sporadic setting in 2003 (8).
Mohammad S Khuroo
Digestive Diseases Centre Dr. Khuroo's Medical Clinic Srinagar Kashmir India
July 8, 2007
Association of severity of HEV infection in the mother and vertically transmitted infection in fetus
To the editor: Patra et al have reconfirmed higher maternal mortality and worse obstetric and fetal outcomes of HEV-infected pregnant women (1). Recently we found strong association of severity of HEV infection in the mother and vertically-transmitted infection in the fetus/neonate (2, 3). Twenty-five (69.4%) infants borne to 36 HEV-infected mothers had vertically transmitted HEV infection and detected at birth. Neonatal infection occurred in 10 (50%) infants borne to 20 mothers with non- fulminant disease and 15 (93.8%) infants borne to 16 mothers with fulminant hepatic failure (FHF) (p=0.004). HEV-infection caused anicteric disease in 2 (8%), icteric disease in 9(36%) and fulminant disease in 14 (56%) neonates. FHF in neonates presented with unresponsiveness, hypoglycemia and hypothermia and died in the first week of life. Fulminant neonatal HEV infection occurred in 2 (10%) infants borne to 20 mothers with non-fulminant disease and in 12 (75%) infants borne to 16 mothers with fulminant disease (p=0.008). Ten of the 16 mothers with FHF died. Six mothers who survived FHF had shorter duration (2.3Â±1.0 days) between onset of encephalopathy to delivery than those who died (9.6Â±3.0 days; p=0.02). In fact 6 mothers with FHF delivered within 4 days of coma and had rapid clinical improvement soon after delivery. Of the 10 mothers with FHF who died, 7 presented with FHF and 3 developed FHF during hospital course while they were carrying undelivered babies with severe HEV infection. Nine of the 12 mothers with FHF who gave birth to babies with FHF had disseminated intravascular coagulopathy complicating the clinical course as against none of the 4 mothers who gave birth to healthy (n=1) or icteric nonfulminant HEV infected babies (n=3) (p=0.01). These data suggested that fetal disease influenced the course of maternal HEV infection. The possible mechanism of increased severity of liver disease in the mother was production of toxic metabolite in the fetus with FHF. Such toxins can cross over to maternal blood and overwhelm the mother's hepatic functions and lead to FHF and DIC and behave like mirror syndrome of pregnancy (4). Such a mechanism has been established in the pathogenesis of acute fatty liver of pregnancy. Fetuses are homozygous for long-chain-3-hydroxyacyl-coenzyme-A-dehydrogenase deficiency and produce large amounts of toxic omega-fatty-acids, which cross over to maternal blood. Such toxic fatty acids overwhelm the mother's fatty acid oxidation system and cause microvesicular steatosis, FHF and DIC. Termination of pregnancy leads to rapid improvement in maternal disease as seen in our patients with HEV-infected mothers with FHF (5). References:
1. Patra S, Kumar A, Trivedi SS, Puri M, Sarin SK. Maternal and fetal outcomes in pregnant women with acute hepatitis E infection. Ann Intern Med 2007; 147: 28-33.
2. Khuroo MS, Kamili S, Jameel S. Vertical transmission of hepatitis E virus. Lancet 1995; 345:1025-6.
3. Khuroo MS, Kamili S. Association of severity of hepatitis E virus infection in the mother and vertically transmitted infection in the fetus. JK-Practitioner 2006; 13(2):70-4.
4. Nakamura K, Itoh H, Sagawa N, Kakui K, Nakayama T, Yamada S, Fuji S. A case of peripartum cardiomyopathy with a transient increase of plasma interleukin-6 concentration occurred following mirror syndrome. J Perinatal Med 2002; 30:426-8.
5. Wilcken B, Leung K-C, Hammond J, Kamath R, Leonard JV. Pregnancy and fetal long-chain 3-hydroxacyl-coenzyme-A-dehydrogenase deficiency. Lancet 1993; 341: 40708.
Nely S Khatri
Patan Hospital, Lalitpur, Nepal.
July 30, 2007
The Hazard of Hepatitis E in pregnancy: Need for its Prevention
We read with interest the hepatitis E article (1) you recently published from New Delhi, India.
At Patan Hospital in Kathmandu, Nepal from April 2002 to April 2007, there were 108 patients with pregnancy and jaundice out of which 43 were diagnosed with Hepatitis E by ELISA testing for anti-HEV IgM antibody. The mean maternal age of patients with Hepatitis E was 24.6 years, and the mean gestational age was 26.5 weeks. 13 (30%) of these had fulminant hepatic failure and 7 (16.3%) mothers died. Deaths occurred exclusively in the third trimester or post-partum and all were women with fulminant hepatic failure. Interestingly, it was found that mothers deteriorated after delivery, especially when there was intrauterine foetal death. Of the 35 women who delivered at the hospital, 15 (42.9%) delivered pre-term. The perinatal mortality rate was 17.1%. 2 (4.7%) women showed Hepatitis E in the first trimester, 21 (48.8%) in the second trimester and 20 (46.5%) in the third trimester.
Clearly, this and other studies(2) show that this preventable disease continues to be a very important problem for pregnant women and their babies in South Asia. The provision of safe drinking water and sanitation lie at the cornerstone of all prevention measures of Hepatitis E. But that is unlikely to happen anytime soon in our part of the world. Until such a time, other strategies will have to be taken up. Recently, an effective vaccine against this illness was demonstrated (3). But no process has yet been undertaken to produce this vaccine commercially, one probable reason being the high cost of producing this vaccine compared to the low levels of projected profit when sold at a price affordable in the countries where the disease is most endemic (4). We would like to highlight the importance of commercial production of an affordable vaccine which on one hand would be invaluable in poor countries and on the other would also protect travelers from the more developed countries to places where the disease is endemic.
In addition, it is still unclear if the new vaccine would be safe if administered during pregnancy. It is important to carry out studies on the safety of this vaccine in pregnancy. As a result, the pregnant population could be specifically targeted for vaccination through national immunization campaigns in areas where the disease is endemic. Thus, the population most at risk of catastrophic consequences might be protected.
1. Patra S, Kumar A, Trivedi SS et al. Maternal and Fetal Outcomes in Pregnant Women with Acute Hepatitis E Virus Infection. Ann Intern Med 2007; 147:28 - 33.
2. Kumar A, Beniwal M, Kar P et al. Hepatitis E in pregnancy. Int J Gynaecol Obstet 2004; 85:240-4.
3. Shrestha MP, Scott RM, Joshi DM et al. Safety and efficacy of recombinant hepatitis E vaccine. N Engl J Med 2007;356:895-903.
4. Stevenson P. Nepal calls the shots in hepatitis E virus vaccine trial. Lancet 2000;355:1623-1623.
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