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This chapter should be cited as follows:
Kmush BL, Song KR, et al, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.419513

The Continuous Textbook of Women’s Medicine SeriesObstetrics Module

Volume 17

Maternal immunization

Volume Editors: Professor Asma Khalil, The Royal College of Obstetricians and Gynaecologists, London, UK; Fetal Medicine Unit, Department of Obstetrics and Gynaecology, St George’s University Hospitals NHS Foundation Trust, London, UK
Professor Flor M Munoz, Baylor College of Medicine, TX, USA
Professor Ajoke Sobanjo-ter Meulen, University of Washington, Seattle, WA, USA

Chapter

Preventing Hepatitis E Disease During Pregnancy

First published: May 2023

Study Assessment Option

By completing 4 multiple-choice questions (randomly selected) after studying this chapter readers can qualify for Continuing Professional Development awards from FIGO plus a Study Completion Certificate from GLOWM
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INTRODUCTION

Hepatitis E virus (HEV) is the leading cause of acute viral hepatitis in the world, with a disproportionately high burden of disease and death among pregnant women in developing regions. There are approximately 20 million infections, 70,000 deaths, and 3,000 stillbirths each year.1 However, the burden of disease is likely vastly underestimated due to limited public health resources in areas where HEV is most common. HEV is considered endemic in most of the world, however, most cases and outbreaks occur in South Asia and Africa. Populations most vulnerable to infection are those found in resource-limited regions with poor access to sanitation and clean water and in areas of conflict. A vaccine with high efficacy is registered in China and Pakistan but has yet to be pre-qualified by the World Health Organization, a designation which would facilitate use in countries where outbreaks occur.

HEPATITIS E VIRUS

Pathogen

HEV is a positive-sense single-stranded RNA virus, in the Hepeviridae family. Of the eight known HEV genotypes (gt), only four can infect humans (Figure 1). HEV gt 1 and 2 are endemic across South, Central, and Southeast Asia, Africa, and the Middle East. Gt 1 is responsible for large, recurrent outbreaks as well as substantial disease outside of outbreaks. Humans are the only known reservoir for these genotypes that are primarily transmitted fecal–orally through contaminated water. However, vertical transmission from a pregnant woman to the infant has also been documented. Gt 3 and gt 4 are zoonotic and have a wide host range, notably domestic and wild pigs.2 These genotypes are usually transmitted from eating undercooked, infected meat, although transmission via transfusion and solid organ transplantation can occur as well. HEV gt 3 is mostly found in North America and Europe. HEV gt 4 is more common in East Asia. Despite this heterogeneity in geographic distribution and mode of transmission, all four genotypes fall under one serotype.

1

Geographic distribution of HEV genotypes that infect humans.3 Figure available under Open Access.

Epidemiology

HEV gt 1 and 2 cause substantial disease throughout Asia and Africa. The earliest outbreak officially attributed to HEV occurred New Delhi, India from 1955–1956, with more than 29,000 suspected cases reported.4 Since then, recurrent outbreaks have been reported across South Asia, with cases often numbering in the thousands. These outbreaks are usually associated with contaminated water sources. Outside of outbreaks, approximately 50% of acute viral hepatitis cases are caused by HEV with gt 1 as the most commonly identified type.5 The earliest and largest outbreak in East Asia occurred in Xinjiang, China in 1986, with over 100,000 cases, attributed to gt 1. Since then, gt 4 has become the predominant type in China, and mostly sporadic cases are observed.6,7,8,9,10,11,12,13 Approximately 10% of acute hepatitis cases are attributed to HEV in East Asia.12,13

Multiple outbreaks of HEV have occurred in Africa, often associated with camps for displaced persons.14,15 These outbreaks are usually attributed to gt 1, although a few gt 2 outbreaks have occurred, and are often linked to contaminated water sources. While less well studied in Africa than in Asia, a large proportion of acute, viral hepatitis cases are caused by HEV, with up to 20% of jaundice cases attributed to HEV.16 These sporadic cases are attributed to both gt 1 and gt 2.

In Europe, gt 3 is predominant and no large outbreaks have been reported, although some small, foodborne outbreaks occur. There is increased recognition of autochthonous cases of HEV in Europe as testing has become more widespread. HEV in Europe is associated with eating raw or undercooked meat, particularly pork. Several occupations, mostly those who work with animals and wildlife, are also at increased risk for HEV infection.17

In general, hepatitis E is considered less prevalent in the Americas. Two outbreaks caused by gt 2 were reported from Mexico in the 1980s, but no other outbreaks have occurred since then. In recent years, the locally acquired clinical cases reported from the Americas are usually gt 3. Despite the paucity of clinical cases, seroprevalence estimates range from 1.4% in Cuba to 17% in the United States.18,19,20

Risk factors for hepatitis E include age, food and water sources, animal contact, and several pre-existing conditions including those with chronic liver conditions, transplant recipients, and other immunocompromised individuals including HIV/AIDS patients.21,22,23,24,25,26,27 In gt 1 and 2 endemic areas, most symptomatic cases occur in young adults, between 15 and 30 years of age. Men and women tend to be equally affected, although pregnant women are most likely to experience severe consequences. Interestingly, children in these areas are less likely to have clinical disease and less likely to have antibodies against HEV. However, there have been several outbreaks in Africa, where children are a major impacted group. It is surprising that children would have low antibodies to this fecal–oral pathogen despite, presumably ubiquitous exposure. In gt 3 and 4 endemic areas, older males are the most likely to present with clinical disease. Those with pre-existing liver disease and transplant recipients are also more likely to develop severe HEV infection. Antibody prevalence increases linearly with age in these areas, reflecting increasing cumulative risk during the lifespan.

Disease

The incubation period for HEV can range from 2–10 weeks, with an average of 5–6 weeks. Following HEV infection, an individual begins shedding the virus in stool from a few days prior to symptom onset to 3–4 weeks post onset. Hepatitis E disease symptoms are usually self-resolving within 2–6 weeks of symptom onset. However, in some cases HEV infection can develop into fulminant hepatitis leading to acute liver failure and death. Typical symptoms include fever, reduced appetite, nausea and vomiting, abdominal pain, itching (without skin lesions), rash, joint pain, jaundice, with dark urine and pale stools; and a slightly enlarged, tender liver. As the symptoms of hepatitis E are similar to other forms of viral hepatitis, a laboratory test is needed to confirm HEV as the causal pathogen using either polymerase chain reaction to detect HEV nucleic acid or antibody tests to detect anti-HEV IgM.

A key landmark feature of HEV is the high case fatality rate among infected pregnant women. While the case-fatality rate of hepatitis E in the general population ranges from 0.1–4%, 10–40% of infections during pregnancy are fatal.28,29,30,31 Symptomatic pregnant women may experience severe or fatal fulminant hepatitis, bleeding, eclampsia, and/or disseminated intravascular coagulation.32 Infection during pregnancy can also lead to poor outcomes for the fetus, including low birth weight, prematurity, and intrauterine fetal death or stillbirth.28,32,33 Immunocompromised patients such as those with solid organ transplants or untreated HIV infection may develop chronic HEV infection, with detectable virus for 6 months or more.32 Chronic HEV infection often leads to liver damage and cirrhosis. There is no specific treatment for hepatitis E, instead treatment involves supportive care focusing on relieving symptoms. In immune compromised patients with chronic HEV or in severe cases, ribavirin has been demonstrated to be effective to clear the virus and resolve symptoms.34 However, ribavirin is contraindicated during pregnancy due to its teratogenicity. Immediate delivery of the infant has been proposed as a treatment for hepatitis E during pregnancy, however, no improvement in outcomes has been observed, although this has only been tried in a limited number of women.28,35

Efforts to prevent and control HEV have primarily focused on improving access to clean drinking water and sanitation facilities, particularly in areas where gt 1 and 2 predominate. Proper food handling and cooking and screening of blood products have been demonstrated to prevent transmission of gt 3 and 4.

HEPATITIS E VACCINE

The hepatitis E vaccine, Hecolin®, is a non-infectious recombinant protein vaccine developed by researchers at Xiamen University and commercialized by Xiamen Innovax Biotech Co., Ltd. (INNOVAX). The sequence is based on the capsid protein of an HEV gt 1 virus first isolated from a patient in the Xinjiang Uighur autonomous region in 1988 (DNA Data Bank of Japan [DDBJ] accession no. D11092).36 The vaccine protein contains the part of the capsid protein that is essential for viral–host interaction with known neutralizing epitopes. Antibodies developed against these specific neutralizing epitope structures prevented infection in experimental systems.37 The developers optimized the vaccine protein length so that the protein self-assembled into virus-like particles (VLP), which resemble an empty virus.38,39 The VLPs are then adsorbed to aluminum hydroxide (AlOH), an adjuvant common to many vaccines, to create the final vaccine product. Prior to trials in humans, the efficacy of the vaccine was evaluated in rhesus macaques and found to be protective against a direct viral challenge.40

The safety and efficacy of Hecolin® was evaluated in a randomized, double-blind, placebo-controlled, single-center phase III clinical trial conducted in a gt 4 endemic location, Dongtai, Jiangsu Province, China from August 2007 to May 2009.41 A total of 112,604 subjects 16–65 years of age were randomly assigned (1 : 1) to receive Hecolin® or a licensed hepatitis B control vaccine intramuscularly at 0, 1, and 6 months. Hepatitis E cases were identified by active surveillance performed at 205 sentinel sites. The trial’s primary objective was to evaluate prevention of hepatitis E during the first year of follow-up beginning 30 days after the last dose. Per-protocol vaccine efficacy was 100% (95% CI, 72.1–100) with no cases of hepatitis E among vaccine recipients and 15 cases among placebo recipients. In an intention-to-treat analysis considering all who received at least one dose, there was one case of hepatitis E among vaccine recipients (this participant had received only one dose). All remaining 22 cases were in the placebo group, resulting in a vaccine efficacy of 95.5% (95% CI, 66.3–99.4).41 Of note, the efficacy after administration of two doses measured during the 5-month interval between dose 2 and 3 was also 100% (95% CI, 9.1–100), which suggests that two doses administered 1 month apart in an emergency or outbreak setting might offer protection for at least 5 months.

In the extension of the phase III clinical trial, the blind was maintained, and all subjects were followed out for 4.5 years (55 months) using the same surveillance system. The efficacy of HEV 239 vaccine against clinically apparent hepatitis E disease according to the protocol case definition (ALT >2.5 times upper limit of normal) was 93.3% (95% CI, 78.6–97.9) in a per-protocol analysis and 85.1% (95% CI, 67.1–93.3) in an intention-to-treat analysis.42

As was expected in the geographic area of the clinical trial, 26 of 29 HEV isolates obtained from subjects were gt 4; the others were gt 1. The high efficacy afforded by the gt 1-derived vaccine against disease caused by gt 4 HEV supports the concept that Hecolin® could provide protection against all genotypes.41 Further supporting this concept are immunogenicity data generated with a monoclonal antibody competition assay using a broadly cross-neutralizing murine monoclonal antibody, which detected broadly cross-neutralizing antibody in serum specimens from Hecolin® recipients.43

Reactogenicity data in the phase III trial was collected from a subset of participants (∼2645) from one township; these subjects were followed for solicited and spontaneously reported adverse events. The proportion of all solicited local adverse events was higher in the vaccine group than the comparison group (hepatitis B vaccine) (13.5% vs. 7.1%).41 Most adverse events were mild.41 The frequency of solicited systemic adverse events were similar between the two groups (vaccine group, 20.3%, vs. comparison group, 19.8%).41 For all participants in the trial, the frequency of solicited local adverse events was higher in the Hecolin® group than the comparison group (2.8% vs. 1.9%), perhaps because of the 30 μg vs. 5 μg disparity in antigen content.41 The rates of serious adverse events (SAE) were similar between the vaccine and comparison arms in the first 19 months of the trial and over the extended 4.5-year follow-up period. None of the SAEs were attributed to the investigational vaccine.41,42

HEPATITIS E IN PREGNANCY

Morbidity and mortality

HEV causes substantial maternal morbidity and mortality in South Asia and Africa, largely attributed to gt 1, although a recent outbreak in Namibia with high case fatality rates during pregnancy may be due to gt 2.44,45 During the first recorded outbreak of HEV in Delhi, India from 1955–1956, nearly 40% of the deaths occurred in pregnant women.46 HEV is also responsible for between 20 and 80% of acute, sporadic viral hepatitis during pregnancy.47 The severity of HEV infection increases throughout the pregnancy, with pregnant women in the third trimester the most likely to experience adverse outcomes.28 HEV infection, increases the odds of maternal death, intrauterine fetal death, stillbirth, preterm delivery, small for gestational age, and low birth weight (Figure 2).48 This increase in morbidity and mortality in pregnant women has not been commonly observed with gt 3 and 4 infections. The case-fatality rates for gt 1 vary from 10 to 40% depending on the study site and design. A 2016 systematic review and meta-analysis found the average case-fatality rate from HEV for maternal mortality to be 20.8% (95% CI: 20.1–32%) and fetal mortality to be 34.2% (95% CI: 26.0–43.0%).49 These elevated case fatality rates during pregnancy are observed in both sporadic disease and outbreak settings.50 A prospective pregnancy cohort from Nepal found that the HEV caused maternal or fetal mortality rate was 2.9 per 1000.47 With over 35 million births each year in South Asia, HEV may contribute to as many as 60,000 preventable maternal or fetal deaths each year. Studies from Bangladesh have estimated that approximately 10% of all maternal mortality could be due to HEV, which would suggest over 10,000 deaths per year in South Asia.51,52 However, the lack of public health surveillance systems and diagnostic tests for HEV make it difficult to measure the burden during pregnancy in endemic areas.

2

Outcomes of HEV infection during pregnancy (data reproduced from Bigna et al. 202048).

Adverse outcomes to the fetus and neonate are also common, due both to direct infection of the fetus/neonate through vertical transmission and maternal complications of HEV infection.53 Hospital-based studies have found vertical transmission of HEV to the neonate in 40–80% of cases.54,55 Viral load, rather than severity of symptoms, has been associated with an increased risk of vertical transmission.55 HEV infection in neonates can cause severe hepatitis, including elevated liver enzymes and bilirubin, which can progress to fulminant hepatic failure.54 A 2019 meta-analysis found the median fetal case-fatality rate to be 33% (IQR: 17–41%) and neonatal case-fatality rate to be 8% (IQR: 3–20%).56 Low birth weight occurs in 57.4–86.7% of infants.56 In surviving infants, HEV infection is self-limiting, there have not been documented cases of chronic HEV resulting from vertical transmission.54

During pregnancy, a female’s immune system is altered to protect a fetus that is genetically different from the host. The suppressed T-cell activity increases the risk symptomatic viral and bacterial infections. However, it is unclear why HEV has such a severe pathogenesis during pregnancy, as these elevated rates of adverse outcomes are not seen with other hepatitis viruses. Increased levels of sex steroid hormones during the latter half of pregnancy along with diminished cellular immunity increase viral replication, including HEV replication.57 Recently, extra-hepatic replication of HEV in the placenta along with placental necrosis have been documented.58 New evidence suggests genotype-specific tropism to placental cells.59 In ex vivo studies, gt 1 has been demonstrated to replicate more efficiently in the placenta than gt 3, a pattern consistent with the severe disease seen in gt 1 but not gt 3.59 The increased viral replication together with the ability of HEV to replicate in the placenta could contribute to the severe outcomes during pregnancy.

Hecolin® use during pregnancy

There is strong evidence that Hecolin® is safe and efficacious in preventing hepatitis E associated disease in normal healthy adults. However, the specific outcome of vaccination preventing disease among pregnant women was not an outcome of the trial as pregnancy was an exclusion criterion. There is an ongoing study in Bangladesh (NCT02759991) to define the effectiveness of Hecolin® administered to women of childbearing age. This study targeted enrollment of 20,745 non-pregnant women aged 16–39 years. Participants were randomized to receive either three doses of Hecolin® or a hepatitis-B vaccine and surveillance for HEV occurred over several years following vaccination.60 The results from this important study should be available in 2023 and will provide some insight into whether the considerable protective effect of the vaccine extends into pregnancy.

In settings with either endemic or epidemic HEV, pregnant women are in peril and the risk versus benefit of vaccination should be considered. What evidence exists regarding the safety of the vaccine administered to women currently pregnant? Although pregnancy was an exclusion criterion for enrollment, there were 37 women in the vaccine group and 31 in the control group who were inadvertently vaccinated during pregnancy.61 Among the 37 women who had received Hecolin®, 22 received a single dose, 14 two doses, and 1 woman all three doses. The rates of adverse events were similar between the women in the Hecolin® group and the control vaccine recipients. Among the pregnant women who received Hecolin®, half (51%) underwent an elective abortion. Among the comparator group that received hepatitis B vaccine, 45% had an elective abortion. Thus, there were few evaluable infants for comparison. Nonetheless, the infants born in both groups were comparable regarding outcomes such as anthropometrics and gestational ages, and there were no congenital abnormalities identified.

The vaccine was licensed in China in 2011 for use in individuals 16 years of age or older at risk for HEV disease. The Global Advisory Committee on Vaccine Safety (GACVS) reviewed the safety of Hecolin® during a meeting in June 2014 and concluded that “The vaccine appeared to be well tolerated in pregnant women with rates of adverse events similar to those observed in matched non-pregnant women. However, the overall sample size was too small to allow a conclusive statement on the safety of Hecolin® in pregnant women and their babies”.62 A Developmental and Reproductive Toxicity (DART) study in animal models was commissioned by the product manufacturer with no concerning findings (report reviewed by author JAL). More recently, Hecolin® was used as a control/comparator vaccine in a phase 3 trial of a new HPV vaccine in China. The authors reported that 977 women from the investigational vaccine and 981 women from the control/Hecolin® group became pregnant at some time during or after the vaccine exposure. The outcome profiles for mothers and infants were similar with no occurrence of pregnancy complications or congenital anomalies in either group.63 With regard to administration to pregnant women, the Hecolin® package insert says “No relevant research data is available for these persons, and full consideration of the pros and cons should be taken to decide whether to use this product.”

Although the vaccine has not been submitted for pre-qualification review by the WHO, the Strategic Advisory Group of Experts (SAGE) on Immunization provided guidance, which resulted in the publication of a WHO Position Paper in 2015.64 They acknowledged the significant public health problem posed by hepatitis E, particularly among special populations such as pregnant women and individuals living in displaced persons' camps. Although Hecolin® was considered a promising vaccine, the WHO concluded that there were insufficient data to justify a recommendation for its routine use. It was acknowledged that national authorities may decide to use the vaccine based on their local epidemiology, and that certain high-risk situations, such as outbreaks, warranted consideration for vaccine use. The WHO suggested specific areas of additional study for Hecolin®, which included immunization of pregnant women.

Barriers to use in pregnancy

Since the 2015 position paper, large outbreaks of HEV have occurred resulting in potentially preventable morbidity and mortality often disproportionately experienced by pregnant women.14,15,45,50,65,66 In a multi-year outbreak eventually reaching every district in Namibia from 2017 to 2020, 29% of all deaths occurred in pregnant or post-partum women. In a focal outbreak in rural Burkina Faso in 2020, 15 of the 16 deaths occurred in pregnant women. Although the WHO recommendations encourage considering vaccine use during an outbreak based on local risk–benefit judgement, the vaccine was used for the first time as a public health tool in one outbreak setting in South Sudan in March 2022.67,68

In order to better understand the continuing barriers to use, a group composed of HEV experts, representatives from global normative bodies and national vaccination implementation and regulatory agencies was convened for a series of discussions in August 2021.69 The case for use of vaccine in an outbreak setting may seem the clearest. However, without a WHO pre-qualification, public health and regulatory authorities in each country experiencing an outbreak must evaluate the vaccine through a national review process. Awareness regarding HEV and the vaccine has been low in communities particularly in Africa where many recent outbreaks have occurred. This broad lack of familiarity with HEV and Hecolin® increases the time required for risk versus benefit assessment. Additionally, the published information on clinical experience with Hecolin® in pregnant women is limited, and risk avoidance concerning interventions during pregnancy is high. Thus, decisions regarding implementation of vaccine, including among pregnant women in the outbreak population, are often delayed beyond the window in which they would have an impact.

In endemic settings, the current language in the WHO position paper does not support routine use largely because of uncertainty of the burden of disease and cost effectiveness. The limited availability of low-cost diagnostics severely hinders accurate estimates of disease burden and identification of settings where routine vaccination would be cost-effective. Recently, the WHO has initiated the process to add in vitro diagnostics for HEV in the Model Essential Diagnostics List, a step which could make these diagnostic tests more broadly available in high-risk settings and more clearly illuminate the particular burden among pregnant women.70

Getting beyond the barriers

Perceptions about using vaccines in pregnant women are changing with recommendations for routine use of several vaccines (e.g., tetanus, influenza), and new vaccines specifically targeting pregnancy (e.g., RSV, GBS) advancing in clinical trials. Other outbreak diseases of high consequence (e.g., Ebola, COVID-19) have challenged public health and regulatory authorities to make risk–benefit assessments of vaccine use in pregnant women with limited data with most countries recommending vaccine use for these high-profile diseases in pregnancy.71 As a non-replicating protein-based vaccine, Hecolin® has little theoretical risk to a mother–fetus pair, and the reproductive toxicology studies in animals revealed that the vaccine had no apparent toxicity to tested pregnant animals. Though there is no indication that Hecolin® would pose an increased risk to a pregnancy or would be less immunogenic in pregnant women, the risk–benefit decision-making regarding administration to pregnant women would be advanced by additional clinical experience and data. A randomized-controlled trial to evaluate the safety and immunogenicity of Hecolin® in pregnant women is currently in planning to inform future decision-making regarding use in pregnant individuals facing risk of HEV exposure, including outbreaks.

CONCLUSION

Pregnant women are at highest risk for morbidity and mortality with HEV infection. A safe and efficacious vaccine exists but there remain barriers to use of the vaccine in endemic or epidemic settings and particularly among pregnant women. Fortunately, concrete steps are being taken to fill in evidence gaps to more clearly define burden of disease and demonstrate the safety and effectiveness of the vaccine during pregnancy to inform individual and public health decision-making.

PRACTICE RECOMMENDATIONS

  • To prevent hepatitis E infection, clean drinking water and sanitation facilities are important in regions where HEV genotypes 1 and 2 are dominant; proper food handling and cooking is more important for regions where genotypes 3 and 4 circulate.
  • The diagnostic work-up for hepatitis during pregnancy should include testing for hepatitis E in settings where hepatitis E occurs, or if other causes have been excluded because pregnant women particularly in the third trimester are most likely to experience severe disease and death, fetal loss, or elevated neonatal mortality.
  • Treatment for hepatitis E infection is supportive care focusing on relieving symptoms.
  • Hecolin®, a vaccine to prevent hepatitis E registered in China but not yet prequalified by the WHO, should be considered for use in pregnant women based on a risk–benefit assessment.


CONFLICTS OF INTEREST

The author(s) of this chapter declare that they have no interests that conflict with the contents of the chapter.

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