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World J Hepatol. Sep 27, 2026; 18(9): 122717
Published online Sep 27, 2026. doi: 10.4254/wjh.122717
Maternal hepatitis E virus infection: Immunopathogenesis, genotype-specific severity, and vertical transmission dynamics
Kashmi Sharma, Megha K Pandey, Department of Translational Medicine, All India Institute of Medical Sciences (AIIMS), Bhopal 462020, Madhya Pradesh, India
Ashutosh K Singh, School of Biosciences, Engineering and Technology, VIT Bhopal University, Bhopal 466114, Madhya Pradesh, India
Ashutosh K Singh, Bhavna Prajapati, Ram K Nema, Division of Environmental Biotechnology, Genetics and Molecular Biology, ICMR-National Institute for Research in Environmental Health, Bhopal 462030, Madhya Pradesh, India
Mudra Sikenis, Department of Life Science, Sharda School of Bio-science and Technology, Sharda University, Greater Noida, Noida 201310, Uttar Pradesh, India
Abhirami Jothish, Prudhvi L Bhukya, Rodent Experimentation Facility, ICMR-National Institute for Pre-Clinical Research, Genome Valley, Shamirpet, Hyderabad 500101, Telangana, India
Ashish K Vyas, Amrita Research Center Delhi NCR, Amrita Vishwa Vidyapeetham, Faridabad Campus, Faridabad 110070, Haryana, India
Bojana J Simovic Markovic, Irfan F Corovic, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34000, Serbia
Irfan F Corovic, Department of Internal Medicine, General Hospital Novi Pazar, Novi Pazar 36300, Serbia
ORCID number: Ashutosh K Singh (0009-0002-0593-9482); Ashish K Vyas (0000-0001-6333-0195); Bojana J Simovic Markovic (0000-0001-8408-4624); Irfan F Corovic (0009-0006-4675-4344); Ram K Nema (0009-0003-9151-4874).
Co-first authors: Kashmi Sharma and Megha K Pandey.
Co-corresponding authors: Irfan F Corovic and Ram K Nema.
Author contributions: Sharma K and Pandey MK contributed equally to this work by conceiving the study, performing the experiments, analyzing the data, and drafting the manuscript, as they are co-first authors; Singh AK contributed to study design, data interpretation, and manuscript preparation; Sikenis M, Prajapati B, Jothish A, Bhukya PL, and Vyas AK participated in data acquisition, experimental procedures, and manuscript revision; Simovic Markovic BJ contributed to the interpretation of immunological findings, scientific discussion, and critical revision of the manuscript; Corovic IF and Nema RK contributed equally as senior authors by supervising the study, providing critical intellectual input, interpreting the data, coordinating manuscript revision, and directing the overall scientific development of the study; all authors reviewed, approved, and agreed to be accountable for all aspects of the work and the final version of the manuscript.
AI contribution statement: Portions of this manuscript were edited using AI tools (ChatGPT, OpenAI, version 5.0) solely for language refinement. The authors carefully reviewed and verified all AI-assisted outputs and take full responsibility for the scientific content of the manuscript.
Conflict-of-interest statement: The authors declare no competing financial interests or personal relationships that could have influenced the work reported in this manuscript.
Corresponding author: Irfan F Corovic, MD, Research Fellow, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, Kragujevac 34000, Serbia. ira.corovic@gmail.com
Received: April 27, 2026
Revised: July 8, 2026
Accepted: July 29, 2026
Published online: September 27, 2026
Processing time: 144 Days and 18.1 Hours

Abstract

Hepatitis E virus (HEV) infection remains a major global health concern, particularly in regions with poor sanitation and limited access to safe water. Although usually self-limiting in immunocompetent individuals, HEV can cause severe maternal and fetal complications during pregnancy. This review summarizes current evidence on the clinical manifestations, immunopathogenesis, genotype-specific disease patterns, and transmission of HEV in pregnancy. Pregnancy-associated immune modulation, hormonal changes, and placental adaptations promote viral replication and impair antiviral responses, particularly in the later stages of gestation. Disease severity varies by genotype, with human-restricted genotypes 1 and 2 causing the most severe pregnancy outcomes, whereas zoonotic genotypes 3 and 4 generally result in milder disease. Despite advances in understanding HEV pathogenesis, important challenges remain in early diagnosis, risk stratification, and the development of safe preventive and therapeutic strategies for pregnant women.

Key Words: Hepatitis E virus; Pregnancy; Immunopathogenesis; Vertical transmission; Genotype

Core Tip: Pregnancy increases the risk of severe hepatitis E virus infection through immune and hormonal adaptations. This review provides an updated overview of hepatitis E virus pathogenesis, genotype-specific disease, and key challenges in clinical management.



INTRODUCTION

Hepatitis E virus (HEV), a single-stranded RNA virus of the family hepeviridae, is a major cause of acute viral hepatitis worldwide, causing an estimated 20 million infections annually[1-3]. Transmission occurs predominantly via the fecal-oral route through contaminated water in endemic regions, whereas zoonotic transmission associated with genotypes 3 and 4 predominates in high-income countries[4]. In contrast, genotypes 1 and 2 are restricted to humans and are responsible for large waterborne outbreaks, often causing severe disease in vulnerable populations, particularly pregnant women[5]. Pregnancy markedly alters the clinical course of HEV infection. Women infected during the second and third trimesters are at increased risk of fulminant hepatic failure (FHF)[6,7]. HEV infection during pregnancy is also associated with miscarriage, stillbirth, fetal growth restriction, preterm delivery, and neonatal death. These adverse outcomes are thought to result from pregnancy-associated immunological and hormonal adaptations that impair antiviral responses, as well as from HEV’s ability to replicate within placental tissues and to undergo vertical transmission[8-12]. Despite increasing recognition of the substantial maternal and neonatal burden of HEV, the mechanisms underlying its pathogenicity, determinants of vertical transmission, and optimal therapeutic strategies during pregnancy remain poorly understood.

In this narrative review, we aim to provide a comprehensive synthesis of current knowledge on HEV infection during pregnancy, with a particular focus on immunopathogenesis, genotype-specific disease severity, and transmission dynamics. We further examine maternal and fetal outcomes, diagnostic and therapeutic challenges, and emerging insights into host-virus interactions. By integrating clinical, epidemiological, and molecular evidence, this review seeks to highlight key knowledge gaps and outline priorities for future research in this high-risk population.

TRANSMISSION DYNAMICS OF HEV

HEV transmission is influenced by viral genotype, environmental conditions, and host factors, resulting in distinct epidemiological patterns across geographic regions (Table 1)[13]. The virus is transmitted primarily through waterborne and zoonotic routes, whereas vertical transmission occurs less frequently but has important implications in maternal infection[14]. Understanding these transmission pathways is essential for the development of effective prevention and control strategies, particularly in endemic and high-risk settings. Waterborne transmission is the predominant route for HEV genotypes 1 and 2, which are restricted to humans and are responsible for large outbreaks in regions with inadequate sanitation infrastructure[15,16]. Contamination of drinking water with fecal matter remains the principal driver of infection, particularly in low- and middle-income countries where poor hygiene and limited access to safe water facilitate rapid viral spread[17]. Environmental factors, including seasonal flooding and monsoon-associated water contamination, further amplify transmission[18]. Consequently, HEV may spread rapidly in densely populated communities, causing substantial morbidity and mortality[19,20]. HEV genotype 1 is responsible for the majority of large waterborne outbreaks in Asia and remains the predominant genotype in highly endemic regions such as India, Pakistan, Bangladesh, and Nepal, where epidemics have affected tens of thousands of individuals and have been associated with high maternal mortality among pregnant women. In contrast, HEV genotype 2 has caused less frequent but epidemiologically similar waterborne outbreaks, although generally associated with lower maternal mortality than HEV-1, primarily occurring in Mexico and sub-Saharan Africa, including Namibia, Nigeria, Sudan, Chad, and the Central African Republic. Although HEV-2 is less extensively characterized, available evidence indicates that its transmission patterns and clinical manifestations closely resemble those of HEV-1, particularly in resource-limited settings with inadequate water sanitation[21,22]. Although these associations are well documented, most available evidence derives from outbreak-based studies in endemic regions, underscoring the need for standardized epidemiological data.

Table 1 Genotype-specific characteristics of hepatitis E virus infection in pregnancy.
Genotype
Host range
Transmission route
Geographic distribution
Maternal outcomes
Vertical transmission
Key features
HEV-1Human-restrictedFecal-oral (waterborne)Asia (India, Pakistan, Bangladesh, and Nepal)Fulminant hepatic failure, high mortality (15%-30%)High (pooled transmission rate is 36.9% with a range from 33%-100%)High placental tropism, strong cytokine response
HEV-2Human-restrictedFecal-oralAfrica, Central America Similar to HEV-1 (FHF, fetal loss)Moderate-high (limited evidence)Less studied, similar epidemiology to HEV-1
HEV-3ZoonoticFoodborne (pork, animals)Europe, North America, Asia
East Asia
Usually asymptomatic or mild hepatitisNot reportedCan cause chronic infection in immunocompromised; transfusion related
HEV-4ZoonoticFoodborneGenerally mild disease in pregnancyRareRare, adverse pregnancy outcome; transfusion related

Unlike HEV-1 and HEV-2, genotypes 3 and 4 are zoonotic and circulate in a broad range of animal reservoirs, including pigs, wild boars, deer, rabbits, and camels[23,24]. Human infection occurs predominantly through the consumption of undercooked meat or exposure to contaminated animal products. These genotypes are endemic in Europe, North America, and East Asia, where infections are typically sporadic, and foodborne transmission associated with pork products represents the principal source of autochthonous disease[24,25]. Moreover, in a study conducted in Taiwan, swine farmers had an approximately 3.5-fold increased risk for being seropositive for immunoglobulin G (IgG) anti-HEV as compared to the general population[26]. Consequently, prevention strategies differ according to transmission route. While improving water quality, sanitation, and hygiene remains the cornerstone of prevention in endemic regions, reducing zoonotic transmission additionally requires food safety measures and surveillance of animal reservoirs[27,28].

Beyond environmental and foodborne exposure, HEV may also be transmitted from mother to child. Vertical transmission is a clinically important route of infection, particularly in endemic regions, with a pooled transmission rate of 36.9% (95% confidence interval: 13.3%-64.2%), although reported rates range from 33% to 100% depending on maternal disease severity, viremia, and study population[12,29-31]. Marked genotype-specific differences have been observed. HEV-1 accounts for the vast majority of documented cases of vertical transmission[32], whereas evidence for HEV-2 remains limited despite a seemingly similar epidemiological profile[30]. In contrast, available clinical data suggest that HEV-3 rarely, if ever, undergoes mother-to-child transmission; notably, two autochthonous HEV-3 infections during pregnancy reported in France resulted in no neonatal infection[33]. Although less frequently reported than HEV-1, HEV-4 has been associated with vertical transmission and adverse pregnancy outcomes. Experimental infection of pregnant rhesus macaques demonstrated transplacental transmission with detection of HEV RNA and viral antigens in multiple fetal organs, accompanied by preterm delivery and fetal death, consistent with clinical observations from East Asia[34,35].

In addition to natural routes of transmission, HEV can also be transmitted through blood products. HEV RNA is detected in approximately 0.04%-0.12% of blood donations in Europe[36], and a landmark United Kingdom study demonstrated viremia in approximately one in 2850 donations, with transmission occurring in 42%-45% of exposed recipients[37]. In high-income countries, transfusion transmitted-HEV is almost exclusively caused by HEV-3 and HEV-4[38]. Immunocompromised recipients are particularly vulnerable to chronic HEV infection, prompting the European Association for the Study of the Liver to recommend universal nucleic acid testing of blood donations, although implementation remains heterogeneous and residual transfusion risk persists despite screening[39].

IMMUNOPATHOGENESIS IN PREGNANCY

The mechanisms underlying HEV pathogenesis are complex and multifactorial, involving a dynamic interplay between immunological modulation, hormonal influences, and viral factors. A central feature of pregnancy is the physiological adaptation of the maternal immune system to tolerate the semi-allogeneic fetus. This is characterized by a shift from a T helper cell 1 (Th1)-dominant, cell-mediated immune response toward a Th2-biased, humoral profile, which suppresses cytotoxic T-cell activity essential for viral clearance[40]. This tolerogenic environment is further reinforced by increased production of interleukin (IL)-10 and transforming growth factor-β (TGF-β), key immunoregulatory cytokines that suppress Th1, cluster of differentiation 8+ T-cell, and natural killer cell responses while promoting regulatory T-cell expansion[41-43]. Although essential for maintaining maternal-fetal tolerance, these cytokines impair antiviral immunity, facilitating HEV replication and persistence[43,44]. Notably, TGF-β has emerged as a hallmark cytokine of severe HEV infection during pregnancy, with elevated circulating levels consistently associated with adverse maternal and fetal outcomes[45]. As a consequence, the host’s ability to control HEV infection is compromised, allowing enhanced viral replication and hepatocellular injury. In addition, dysregulated cytokine responses contribute to disease severity, with elevated levels of pro-inflammatory mediators, including tumor necrosis factor-α, IL-6, and interferon-γ, further amplifying hepatic inflammation and tissue damage[45,46]. Hormonal changes during pregnancy further modulate immune function and may exacerbate disease progression. Elevated levels of estrogen and progesterone influence cytokine signaling pathways and have been suggested to suppress interferon-mediated antiviral responses, thereby facilitating viral persistence[44]. However, the precise contribution of hormonal regulation to HEV pathogenesis remains incompletely defined and likely interacts with other host and viral determinants. The placenta has emerged as a critical site in the pathogenesis of HEV infection during pregnancy. Evidence demonstrates that HEV can replicate in placental trophoblasts, suggesting a direct role of placental infection in amplifying maternal disease severity and enabling vertical transmission[47]. Placental dysfunction, driven by viral replication and local inflammatory responses, may contribute to adverse outcomes such as preterm delivery, intrauterine fetal demise, and growth restriction. Genotype-specific differences further modulate disease severity. HEV-1 is consistently associated with more severe clinical outcomes in pregnancy, which may reflect enhanced viral replication capacity and distinct immune evasion mechanisms[48]. Its preferential replication within placental syncytiotrophoblasts, together with the genotype-specific open reading frame 4 (ORF4) protein that enhances viral replication, likely contributes to placental injury and facilitates transplacental transmission, although the role of ORF4 has not yet been fully validated in vivo or across all HEV-1 strains[47,49]. Nonetheless, the molecular basis of genotype-dependent pathogenicity remains incompletely understood. Overall, current evidence suggests that severe HEV infection in pregnancy results from a convergence of impaired antiviral immunity, exaggerated inflammatory responses, hormonal modulation, and placental involvement (Figure 1). Nevertheless, the relative contributions of these factors and their interactions remain an area of ongoing investigation.

Figure 1
Figure 1 Immunopathogenesis and clinical spectrum of hepatitis E virus infection in pregnancy. The figure summarizes how hepatitis E virus exposure and hepatic replication may progress to severe disease during pregnancy through pregnancy-associated immune modulation, hormonal effects, placental susceptibility, cytokine dysregulation, coagulation abnormalities, and high viral load. These mechanisms contribute to major maternal and fetal complications, including fulminant hepatic failure, disseminated intravascular coagulation, intrauterine growth restriction, preterm birth, stillbirth, and maternal or neonatal mortality. HEV: Hepatitis E virus; Th: T helper cell; P: Progesterone; ES: Estrogen; mPR: Mutated progesterone receptor; DIC: Disseminated intravascular coagulation; IUGR: Intrauterine growth restriction.
MATERNAL, FETAL, AND NEONATAL OUTCOMES OF HEV INFECTION IN PREGNANCY
Maternal outcomes

Although HEV infection is usually self-limiting in the general population, pregnant women, particularly during the second and third trimesters, are at markedly increased risk of severe disease and adverse maternal and fetal outcomes[50-52]. Disease severity is influenced by viral genotype, gestational age at infection, maternal immune status, and access to timely medical care[53]. Maternal mortality remains the most serious consequence, with case fatality rates of 15%-30% in endemic regions such as South Asia and sub-Saharan Africa, compared with less than 1% in non-pregnant individuals[54,55]. Increased susceptibility in late pregnancy is attributed to hormonal and immunological adaptations, greater hepatic metabolic demands, and limited access to supportive care in resource-limited settings[55,56]. FHF is the leading cause of maternal death and results from both direct viral injury and an exaggerated inflammatory response characterized by elevated pro-inflammatory cytokines[19,57]. Clinically, FHF presents with severe hepatic dysfunction, including marked aminotransferase elevation, coagulopathy, hyperbilirubinemia, and hepatic encephalopathy[58]. Pregnancy-associated impairment of liver regeneration may further aggravate disease. Disseminated intravascular coagulation, a frequent and life-threatening complication of FHF, develops due to profound disturbances in coagulation pathways caused by liver failure and systemic inflammation. Reduced synthesis of coagulation factors, together with the physiological hypercoagulable state of pregnancy, leads to consumptive coagulopathy and severe hemorrhagic complications[59,60]. The clinical spectrum of HEV infection during pregnancy is strongly genotype-dependent[61]. Among the eight recognized genotypes, HEV-1 to HEV-4 infect humans but differ substantially in clinical severity[62]. HEV-1 and HEV-2 are consistently associated with severe maternal and fetal outcomes, including FHF, coagulopathy, fetal demise, and maternal mortality, whereas HEV-3 and HEV-4 generally cause sporadic, asymptomatic, or mild infections[21,63-65]. The greater virulence of HEV-1 is attributed to enhanced replication, including in placental tissues, and stronger inflammatory responses. HEV-2 shares similar epidemiological and clinical characteristics, although its pathogenic mechanisms remain poorly understood. Both genotypes are associated with vertical transmission, with disease severity likely amplified by pregnancy-associated immune modulation and placental susceptibility[64,65]. In contrast, HEV-3 and HEV-4 have not been significantly associated with increased maternal mortality or severe obstetric complications[24,26,66]. However, these genotypes can establish chronic infection in immunocompromised individuals, including rare cases in pregnant women, raising concerns regarding prolonged viremia and fetal exposure[67,68]. Overall, viral genotype is a major determinant of clinical outcome in pregnancy, although the mechanisms underlying genotype-specific pathogenicity remain incompletely understood and warrant further investigation (see Tables 1 and 2).

Table 2 Maternal, fetal, and neonatal outcomes associated with hepatitis E virus infection during pregnancy.
Outcome category
Clinical outcome
Reported risk/findings
Key determinants
MaternalFulminant hepatic failureLeading cause of deathHEV-1 infection, 3rd trimester
Maternal mortality15%-30% (endemic regions)Viral load, delayed care
Disseminated intravascular coagulationCommon complication of FHFHepatic failure + bleeding + hypercoagulability
Liver dysfunctionALT > 1000 IU/L, coagulopathyCytokine storm, viral replication
FetalIntrauterine fetal demiseHigh frequencyMaternal instability, placental damage
StillbirthIncreased risk (OR approximately 2.6)Severe maternal disease
Preterm birthOR approximately 3.4Placental dysfunction
Low birth weightOR approximately 3.2Maternal illness, inflammation
IUGRIncreased riskPlacental insufficiency
NeonatalVertical transmission36.9% (range from 33%-100%)Maternal viral load
Neonatal mortalityApproximately 8% (median)Severe maternal disease
Acute hepatitisCommonViral replication
CoagulopathySevere casesLiver dysfunction
PrognosisSelf-limited if survivesViral clearance in weeks-months
Fetal and neonatal outcomes

Fetal outcomes are closely connected to how severe the mother’s disease is and when the infection occurs. Intrauterine fetal demise and stillbirth are among the most commonly reported complications, especially in infections during the third trimester[69]. These outcomes are likely influenced by a mix of the mother’s blood flow problems, issues with the placenta, and direct virus transmission[70]. Histopathological studies often show damage to the placenta, including inflammation, blood clots, and tissue death, which supports the idea that placental problems play a direct role in negative fetal outcomes[71]. Preterm delivery is another frequent result, happening either spontaneously due to placenta issues or as a medically necessary choice when the mother’s condition worsens. Neonates born preterm are often unstable, facing higher risks of low birth weight, metabolic issues, and death, especially in places without access to neonatal intensive care[72]. Intrauterine growth restriction (IUGR) is a subtle but important outcome, caused by placental insufficiency, ongoing maternal inflammation, and reduced nutrient delivery[73]. In resource-limited settings, IUGR is often underdiagnosed because of limited access to antenatal care, which leads to worse neonatal outcomes[74]. Clinical manifestations in neonates with vertically acquired infection are heterogeneous, ranging from asymptomatic or mild disease to severe hepatitis. In a prospective cohort study, 78.9% of neonates born to HEV-infected mothers demonstrated evidence of infection at birth, with clinical presentations including icteric hepatitis, anicteric hepatitis, and isolated hyperbilirubinemia. Notably, early neonatal mortality was high, with nearly half of infected neonates dying within the first week of life[75]. Adverse neonatal outcomes associated with maternal HEV infection are substantial. Systematic analyses have reported a median neonatal case-fatality rate of approximately 8% and fetal case-fatality rates approaching 33%[76]. The severity of neonatal outcomes is closely linked to maternal disease, with the highest mortality observed in cases complicated by FHF[76,77].

Overall, the range of maternal, fetal, and neonatal outcomes in HEV infection reflects a complex interplay among viral virulence, host physiology, and access to healthcare (Figure 1 and Table 2). While severe complications are well documented, differences across studies indicate that other factors influencing disease severity remain poorly understood.

DIAGNOSTIC AND TREATMENT CHALLENGES
Diagnostic workup with differential diagnosis

HEV infection during pregnancy presents significant diagnostic and therapeutic challenges, particularly in low-resource settings where disease burden is highest. Limitations in both diagnostic accuracy and available treatment options contribute to delayed recognition and suboptimal clinical management. Diagnosis of HEV infection in pregnancy is complicated by the reduced sensitivity and variability of commonly used assays. Serological testing, particularly anti-HEV immunoglobulin M (IgM) detection, may yield false-negative results due to delayed or attenuated immune responses associated with pregnancy[78,79]. The physiological shift toward a Th2-dominant immune profile can delay seroconversion, thereby limiting the reliability of serology in early or active infection. In addition, considerable variability exists in the performance of commercially available enzyme-linked immunosorbent assay kits, further compromising diagnostic consistency[79]. Molecular detection of HEV RNA by polymerase chain reaction remains the most reliable method for confirming active infection and should be considered the diagnostic gold standard in pregnant patients. However, limited availability of molecular diagnostics in endemic regions restricts its widespread use. The differential diagnosis of HEV infection in pregnancy includes pregnancy-specific liver disorders, particularly intrahepatic cholestasis of pregnancy (ICP), acute fatty liver of pregnancy (AFLP), and hemolysis, elevated liver enzymes and low platelets count (HELLP) syndrome, all of which may present with jaundice, elevated aminotransferases, and right upper quadrant pain (Table 3)[80]. HEV is distinguished by a preceding viral prodrome (fever, malaise, anorexia), the absence of hypertension or proteinuria, and confirmation by HEV RNA or anti-HEV IgM testing. In contrast, HELLP syndrome is characterized by the triad of hemolysis, thrombocytopenia, and elevated liver enzymes, usually in the setting of hypertensive disease. AFLP is suggested by hypoglycemia, hyperammonemia, severe coagulopathy, renal dysfunction, and fulfillment of the Swansea criteria, whereas ICP typically presents with intense pruritus and elevated serum bile acids in the absence of significant coagulopathy or encephalopathy[81-84]. Importantly, because substantial clinical overlap exists, particularly between severe HEV infection, AFLP, and HELLP syndrome, molecular testing for HEV should be considered in all pregnant women presenting with acute liver dysfunction, especially in endemic regions.

Table 3 Simplified differential diagnosis of hepatitis E virus infection in pregnancy.
If the patient has etc.
Most likely diagnosis
Viral prodrome + positive HEV RNA/IgMHEV infection
Hypertension/proteinuria + thrombocytopenia + hemolysisHELLP syndrome
Hypoglycemia + hyperammonemia + severe coagulopathyAcute fatty liver of pregnancy
Severe pruritus + elevated bile acidsIntrahepatic cholestasis of pregnancy
Therapeutic approach

Therapeutic options for HEV infection during pregnancy remain extremely limited. No antiviral therapy is currently approved for pregnant patients, and management is primarily supportive, based on close clinical monitoring, correction of metabolic and coagulation abnormalities, avoidance of hepatotoxic drugs, and timely escalation to high-dependency or intensive care when liver failure develops. Symptomatic pregnant women should be hospitalized, particularly in endemic regions and in suspected HEV-1 or HEV-2 infection, because clinical deterioration may be rapid. In cases of acute liver failure, management requires a multidisciplinary approach involving hepatology, obstetrics, critical care, and neonatology, with prompt transfer to a liver transplant center if progressive encephalopathy, severe coagulopathy, renal failure, or multiorgan dysfunction occurs[85-88].

Ribavirin, although effective in chronic HEV infection in immunocompromised individuals, is contraindicated during pregnancy because of well-established teratogenic and embryotoxic effects[89,90]. Similarly, interferon-alpha is avoided because of fetal safety concerns and its potential abortifacient effects[85]. Obstetric management should be individualized according to gestational age, fetal viability, and maternal severity. Early delivery may be considered in cases of progressive maternal deterioration, although current evidence does not support routine therapeutic termination solely for HEV-induced acute liver failure[85,87,91]. Overall, the absence of a safe and effective antiviral therapy represents a major unmet need, especially given the high mortality associated with HEV-1 infection in late pregnancy.

Management of neonatal HEV infection is centered on supportive care. This includes careful monitoring of liver function, bilirubin levels, and coagulation parameters, along with appropriate supportive measures in a neonatal intensive care unit for severe cases. Diagnosis is established through detection of anti-HEV IgM antibodies and/or HEV RNA in serum, with the recognition that maternal IgG antibodies may be passively transferred and should not be misinterpreted as evidence of active infection[75]. At present, antiviral therapy in neonates remains investigational. Although ribavirin has demonstrated efficacy in adult and immunocompromised populations, its safety and efficacy in neonates are not well established, and its use is not routinely recommended[92,93].

Prevention and breastfeeding

Preventive strategies are also limited. Although a recombinant HEV vaccine (Hecolin) has demonstrated high efficacy in the general population and is licensed in China, its safety profile in pregnant women has not been adequately established, and it is not widely available globally[94,95]. This represents a significant gap in prevention strategies, particularly in endemic regions where the burden of disease is greatest. HEV RNA and anti-HEV antibodies have been detected in breast milk, although no confirmed cases of breastfeeding-associated HEV transmission have been reported[96]. Available evidence, derived primarily from a single study in HEV-1/2 endemic regions, suggests that breastfeeding is generally safe in seropositive or recovered mothers, whereas caution and close neonatal monitoring may be warranted in mothers with active symptomatic infection and high viremia[96]. The presence of anti-HEV antibodies in breast milk may additionally provide passive neonatal immunity, although evidence remains limited, particularly for HEV-3 and HEV-4[96,97].

FUTURE PERSPECTIVES

Future therapeutic strategies should focus on pregnancy-safe antiviral and host-directed approaches. Sofosbuvir has emerged as a potential candidate because of experimental anti-HEV activity and a more favorable reproductive safety profile than ribavirin, but clinical data in pregnant women are lacking[98]. Increasing evidence also implicates NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation and pyroptosis in the pathogenesis of HEV-associated liver injury. Experimental studies have shown that pharmacological inhibition of the NLRP3 inflammasome attenuates IL-1β production and restores antiviral interferon responses, suggesting that host-directed modulation of inflammasome signaling may represent a promising adjunctive therapeutic strategy for severe HEV infection[99]. Other investigational approaches, including interferon-lambda, modulation of host autophagy pathways, zinc-mediated inhibition of viral polymerase activity, and microRNA-122 targeting, remain experimental and cannot currently be recommended in clinical practice[100-103]. Future research should prioritize prospective trials of pregnancy-safe antivirals, vaccine studies in women of reproductive age and pregnancy, and standardized management protocols for HEV-associated acute liver failure.

CONCLUSION

HEV infection during pregnancy remains a major global health challenge, particularly in endemic regions where HEV-1 and HEV-2 are associated with FHF, vertical transmission, and poor maternal and neonatal outcomes. Current evidence indicates that disease severity results from the interplay between pregnancy-associated immune and hormonal adaptations, placental susceptibility, and genotype-specific viral factors. Despite advances in understanding HEV immunopathogenesis and transmission dynamics, important gaps remain in early diagnosis, risk stratification, and the availability of safe antiviral therapies for pregnant women. Future efforts should focus on elucidating host-virus interactions, validating biomarkers of disease severity and vertical transmission, developing pregnancy-safe antiviral and host-directed therapies, expanding vaccine evaluation in women of reproductive age, and strengthening surveillance and public health measures. Addressing these priorities will be essential to reduce the global burden of HEV and improve maternal and neonatal outcomes.

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Footnotes

Peer review: Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Gastroenterology and hepatology

Country of origin: India

Peer-review report’s classification

Scientific quality: Grade B, Grade C

Novelty: Grade A, Grade C

Creativity or innovation: Grade B, Grade C

Scientific significance: Grade B, Grade C

P-Reviewer: Sudhamshu KC, PhD, Professor, Nepal; Yiğit H, Assistant Professor, PhD, Türkiye S-Editor: Fan M L-Editor: A P-Editor: Yang YQ

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