REVIEws

Viral hepatitis and pregnancy

 ✉
Norah A. Terrault 1 , Miriam T. Levy 2, Ka Wang Cheung 3 and Gonzague Jourdain 4,5
Abstract | The management of viral hepatitis in the setting of pregnancy requires
special consideration. There are five liver-specific viruses (hepatitis A, B, C, D, E),
each with unique epidemiology, tendency to chronicity, risk of liver complications and
response to antiviral therapies. In the setting of pregnancy, the liver health of the
mother, the influence of pregnancy on the clinical course of the viral infection and the
effect of the virus or liver disease on the developing infant must be considered.
Although all hepatitis viruses can harm the mother and the child, the greatest risk to
maternal health and subsequently the fetus is seen with acute hepatitis A virus or
hepatitis E virus infection during pregnancy. By contrast, the primary risks for
hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus are related to the
severity of the underlying liver disease in the mother and the risk of mother-to-child
transmission (MTCT) for HBV and HCV. The prevention of MTCT is key to reducing
the global burden of chronic viral hepatitis, and prevention strategies must take into
consideration local health-care and socioeconomic challenges. This Review presents
the epidemiology of acute and chronic viral hepatitis infection in pregnancy, the effect
of pregnancy on the course of viral infection and, conversely, the influence of the viral
infection on maternal and infant outcomes, including MTCT.
viruses, but hepatitis E virus (HEV) implementation objectives can be
infection presents the greatest risk to achieved. This Review examines each
pregnant women with increased rates of hepatitis virus individually to address the
maternal mortality and subse quent fetal effect of pregnancy on the
deaths, with a distinct geographical distri natural history of infection and how the
bution associated with outbreaks related viral infections influence maternal and
to breaches in water safety. Hepatitis B infant outcomes. The unique
virus (HBV), hepatitis C virus (HCV) and opportunities and barriers to identifying
hepatitis D virus (HDV) are associated women with infections and providing the
with chronic infections and affect 325 appropriate interventions to protect
million people globally, accounting for infants and mothers from the
1
Keck School of Medicine, University of Southern 96% of the mortality from viral hepatitis1. complications of viral hepatitis are also
California, Los Angeles, USA. All five hepatitis viruses are associated highlighted.
2
Department of with specific fea tures and risks for
Gastroenterology and Liver, Liverpool Hospital, University pregnant women and their offspring. The Hepatitis A
of New South Wales, Sydney, New South Wales,
management of viral hepatitis in Hepatitis A is a vaccine-preventable
Australia.
3
pregnancy must take into consideration infection but an estimated 1.4 million
Department of Obstetrics and Gynaecology, Queen Mary
Hospital, University
the health of the mother and developing cases of hepatitis A occur glob ally every
of Hong Kong, Hong Kong, Hong Kong. infant as the immune suppressive state of year2. Hepatitis A virus (HAV) is a small,
4
French National Research Institute for Sustainable
pregnancy and hormonal changes during non-enveloped, single-stranded RNA
Development (IRD), pregnancy and the postpartum period virus of the Picornaviridae family with
Marseille, France. might alter the natural his tory of infection.seven known genotypes. HAV is found in
5
Chiang Mai University, Chiang Mai, Thailand. Although acute viral hepatitis occurs in blood or stool and is highly infec tious,
✉
e-mail: Terrault@usc.edu
pregnancy, the management of pregnant with spread occurring by close personal
https://doi.org/10.1038/
women with chronic viral hepatitis is a contact or through ingestion of
s41575-020-00361-w more common concern and the contaminated food or water. The
Worldwide, infections from one of the five prevention of mother-to-child prevalence of HAV infection varies by
hepatitis viruses (hepatitis A, B, C, D or transmission (MTCT) is paramount in geogra phy, reflecting socioeconomic
E virus) cause 1.34 million deaths per reducing the global burden of chronic conditions that prevent or facilitate
year, related to complications of liver cir viral hepatitis. Prevention strategies must faecal–oral transmission3. In regions with
rhosis and hepatocellular carcinoma1. take into consideration local health care high endemicity for HAV, infection
Acute hepatitis occurs with all five and socioeconomic challenges so that typically occurs in childhood, but it is
largely asymptomatic and results in susceptible as adults. Thus, in the women in their reproductive years vulner
protection through adulthood. However, in absence of HAV vaccination, as able to HAV increases, thereby increasing
regions with low or intermediate rates of socioeconomic conditions improve and the incidence of HAV infection during
HAV infection, fewer children are the likelihood of HAV exposure during pregnancy. For example,
exposed and, therefore, more are childhood declines, the pro portion of

Nature Reviews | Gastroenterology & Hepatology

Reviews MtCt prevention

Key points
• Acute hepatitis A virus(HAV) infection during pregnancy
mightincrease the rates of adverse pregnancy outcomes;
casesleading to fetal liverinjury and mother-to-child transmission
(MTCT) ofHAV have been reported.
• Pregnant women with chronic hepatitis B virus(HBV) infection might
have an increased risk of preterm delivery and gestational diabetes.
• There isrisk of MTCT ofHBV, especially in mothers with high levels
ofHBVDNA, but thisrisk isreduced with the use of maternal
antiviraltherapy and prompt administration of
infantimmunoprophylaxis.
• Pregnant women with chronic hepatitisCvirus(HCV) infection have
increased rates of adverse pregnancy outcomes; MTCT occursin 5% although preclinical in vitro data suggest that sofosbuvir might
and islinked with invasive fetal monitoring and prolonged rupture of
membranes.
• Risksrelated to underlying cirrhosis can be more frequentin pregnant rarely . For women exposed to HAV during pregnancy,
women with hepatitisDvirus(HDV) infection; MTCT ofHDV israre and immune globulin prophylaxis after exposure is
managementisthe same asHBV monoinfection.
• Acute hepatitis E virus(HEV) infection in pregnancy is associated
with an increased risk of maternal death and infant mortality, including Disease Control and Prevention supports administration of
higherrates of preterm delivery and stillbirths; MTCT ofHEV can occur. hepatitis A vac
in South Korea, where the prevalence of HAV infection
among children and adolescents has decreased dramat
ically, incident HAV infections among women increased
from 151 cases in 2002 to 4,779 in 2009, with the largest
increase seen in women aged 20–39 years4. With a view
to preventing acute HAV infection in pregnancy, broader
use of vaccination in children, adolescents and women of
childbearing age could be considered, although data are
lacking on the most cost-efficient strategy in low-income
to middle-income regions.
With regard to the risks associated with HAV infec
tion during pregnancy (Box 1), acute HAV infection
might increase the rates of preterm labour, placental
abruption and premature rupture of membranes, but
data are sparse5,6. Acute liver failure due to HAV infec
tion is rarely reported in pregnancy7,8 but cases of acute
maternal HAV infection leading to fetal liver injury and
MTCT have been described9.
Treatment of acute HAV infection is supportive
(for example, hydration and antiemetics if needed) but
Box 1 | Hepatitis a virus and pregnancy
Maternal risks
• Acute infection associated with preterm labour, placental abruption
and premature rupture of membranes.
• Acute hepatitis; pregnancy does notseem to increase the risk of
acute liverfailure.
Fetal risks
• Rare case reports of fetal liverinjury.
MtCt risk and risk factors
• Very rare;too few casesto assessforrisk factors.
• No interventionsrequired.
Maternal follow-up
• If exposed during pregnancy, post-exposure prophylaxisif
non-immune.
Infant follow-up
• None needed.
MTCT, mother-to-child transmission
close follow-up of mothers is important in view of the risk of
preterm labour. No antiviral therapy is avail able for HAV,
have anti-HAV effects10. Liver transplantation for acute liver
failure in pregnancy due to HAV has been reported, albeit
7
recommended11. The HAV vaccine, which is produced from
inactivated HAV, seems safe in pregnancy: the Centers for
cine to pregnant women if medically indicated11; and no
significant increase in maternal or infant adverse events were
observed in a retrospective study of 1,140 pregnant women
given inactivated HAV vaccine compared with 652,684
pregnancies without receipt of HAV vaccine12,13.
Hepatitis B
In 2015, there were 257 million chronic HBV carriers
worldwide, including 65 million women of childbearing age,
and 887,000 people died because of HBV-related
complications mostly from cirrhosis and hepatocellu
lar carcinoma1. Effective antiviral treatment is available at an
affordable price but capacity to diagnose, assess liver disease
severity and treat remains limited in many regions1. HBV is an
enveloped, partially double-stranded DNA virus of the
Hepadnaviridae family, with ten geno
types (A–J)14. Acute and chronic infection are identified by the
presence of the HBV surface antigen (HBsAg) in blood, while
HBV e antigen (HBeAg) and HBV DNA reflect the level of viral
replication and guide the need for antiviral treatment. The
global prevalence of HBV infection is ~3.5% with Africa
(6.1%) and Western Pacific regions (6.2%) particularly
affected1. MTCT is a common route of HBV transmission in
high (HBsAg prevalence >8%) and intermediate (HBsAg
prevalence 2–8%) endemic areas, accounting for almost 90%
of the global prevalence15. Of those infected early in life,
in utero or during delivery or early infancy, 90% will develop
chronic infection16,17. Fortunately, with infant immunization
programmes, the estimated prevalence of HBV infection in
children less than 5 years old has decreased to ~1.3%,
compared with ~4.7% in the pre-vaccination era1.
An estimated 4.5 million women with chronic HBV infection
give birth annually, with the largest number living in Africa and
Western Pacific regions1. Reducing the prevalence of the
infection will result from regional immunization programmes • No role for caesarean delivery but avoid amniocentesis.
that reduce the number of women with chronic HBV infection • Postpartum maternal antiviral prophylaxis might be considered
and by effectively preventing MTCT in all women at risk of
transmission, including migrants from regions of high to
regions of low endemicity18–23. An estimated 16% reduction in
the global burden of chronic HBV would be achieved if a
vaccine birth dose was routinely given to prevent perinatal
trans mission of HBV24. Co-infections with human immuno
deficiency virus (HIV) and other hepatitis viruses can be
common in regions of high prevalence or in settings of shared
risk factors. For example, amongst pregnant women in
Cameroon, sub-Saharan Africa, the rates of HIV, HBV, HCV
and HDV co-infections were 8.5%, 6.4%, 0.8% and 4.0%,
respectively25. Self-awareness of
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in situations where infantHBIGnot available.
Maternal follow-up
• ALT flares after pregnancy are usually self-limiting; monitorfor 3–6
months. • Antiviraltreatment might be indicated for maternal liver
health.
Infant follow-up
• Check serology 3months after completing vaccination course,
usually at age 9months.
Implementation challenges to HBV management in pregnancy •
Screening,treatment and vaccination in remote sites mightrequire
optimization and nationalresourcing.
• Optimization mightinclude point of care testing, improved
orinnovation to birth dose vaccine implementation, and appropriate
infantfollow up.

MTCT, mother-to-child transmission

infection is poor: in 2015, only 9% of persons living with

Nature Reviews | Gastroenterology & Hepatology
HBV infection knew their status1.
Reviews
Hepatitis B infection and
pregnancy outcomes. Meta
analyses suggest that HBV infection in pregnancy
(Box 2) is associated with a 16% (21% if the woman is The effect of pregnancy on
seropositive for HBeAg) increased risk of preterm deliv chronic hepatitis B. Acute HBV infection
ery, although publication bias — that is, studies that did might differ in pregnant women com pared with non-pregnant
not find an increased risk were not published — and women. A study in 22 pregnant women with acute HBV
lack of well-controlled studies that adjusted for potential infection and 87 matched non pregnant women found fewer
confounders limit interpretation26,27. An increased risk of typical clinical symptoms and delayed HBsAg loss and
gestational diabetes mellitus (GDM) was identified in a seroconversion in the preg nant women than in the
Hong Kong case–control study of 253 HBsAg-positive non-pregnant women30. Acute liver failure due to HBV
women and 253 HBsAg-negative controls matched for infection during pregnancy has also been reported31.
age, parity and year of delivery28, and supported by a In women with chronic hepatitis B, serum HBV DNA levels
meta-analysis based on 23 cohort studies involving and viral antigens (HBsAg, HBeAg) are mostly stable during
3,529,223 participants29. The overall incidence of GDM pregnancy despite increased adre nal corticosteroid,
in HBsAg-positive women was 6.5% versus 3.4% in oestrogen and progesterone levels32,33. However, alanine
HBsAg-negative women, with an adjusted 35% higher aminotransferase (ALT) levels, which reflect the destruction of
odds of GDM in those positive for HBsAg, although infected hepatocytes by the immune system, are reduced,
significant heterogeneity across studies was present29. probably in relation to the relative immunosuppression during
pregnancy, although ALT flares have also been reported in
pregnant women with chronic hepatitis B32,34. Asymptomatic
Box 2 | HBV and pregnancy and mild increases in ALT are common during the postpar
tum period, presumably secondary to immunological
Maternal risks
35–37 2 cytokine pro
• Possible increased rates of preterm labour,though studies are mixed. restitution . T helper 1 (T H1) or TH files
• Increased risk of gestational diabetes mellitus but no major effect on suggest an enhanced, albeit inefficient, postpartum
other pregnancy outcomes. immunological response to HBV37. ALT flares, during
• Alanine aminotransferase (ALT) flares during pregnancy are usually pregnancy or the postpartum period, do not seem to lead to
self-limiting, and reflectimmunological and hormonal changes. HBeAg seroconversion38.
Fetal risks The frequency of ALT flares in women with HBV infection
during pregnancy and during the postpar tum period is
• Related to maternal preterm labour and gestational diabetes mellitus.
variable. In a cohort study in four US hospital-based clinics
MtCt from 2006 to 2015, 310 women with HBV infection,
• Extremely low risk when hepatitis B virus(HBV)DNA <200,000IU/ml predominantly of African or Asian descent but with incomplete
(5.3log10 IU/ml). • Substantialrisk whenHBVDNA is >7log10 IU/ml; data on HBeAg status, were followed during and after their
consider additionalstrategies and/or avoid invasive prenataltests. 388 pregnancies39. Antiviral prophylaxis was initiated in only
• There is a ‘grey zone’ between these cut-offs, and decisionsshould 21 women. ALT flares with levels ≥2 times the upper limit of
incorporate local data, including accessto timely hepatitis B immune normal were documented in 14% (42) of 311 pregnancies and
globulin (HBIG) and vaccination.
during the postpartum period in 16% (22) of 134 preg
MtCt prevention nancies. A positive HBeAg test and younger age, but not
• Timely neonatalHBIGand vaccine birth dose (assoon as possible antiviral therapy, were associated with the risk of ALT flare.
within 24hours of birth), followed by a standard course of vaccine. Among the 50 flares, jaundice developed in five women
• Maternal antiviral prophylaxis with tenofovir disoproxil fumarate before delivery and in one woman during the postpartum
starting at 28–30 weeks when risk issubstantial. period, and one woman with cirrhosis developed ascites and
jaundice during the postpartum period39. In controlled clinical
trials assessing antiviral agents for preventing MTCT of HBV,
ALT elevations of variable intensity, especially during the
postpartum period, have been reported in treated and
untreated groups, but no episodes of jaundice or liver
decompen sation were reported32,40–42. The American
Association for the Study of Liver Diseases (AASLD)
recommends postpartum ALT monitoring 43, although the
majority of ALT flares are self-limited. There is no evidence
that HBV antiviral therapy influences clinical or serological
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outcomes during pregnancy32,38,44,45.
MTCT of hepatitis B. Of infants infected
perinatally, 90% develop chronic HBV infection16,17. The risk of
MTCT varies by maternal HBeAg status (a marker of high
HBV DNA levels) 46 and the prevalence of HBeAg positivity
among pregnant women influences the rates of perinatal
infections globally1. Thus, infants born to mothers pos
itive for HBsAg are at 5–30% risk of perinatal infection

Frequent MTCT • HBV — 10% Most common MTCT • HBV — Very rare MTCT • HBV — <1% •
• HCV — up to 25% (40% if ≥90% HCV — <1%
HIV–HCV coinfection) • HCV — ≥75%

Intrauterine Peripartum Postpartum

Potential mechanisms •
Maternal–fetal
transcytosis
• Trophoblastic cell infection
• Maternal placental dysfunction
• Intra-amniotic
bleeding related to chorionic
villus sampling,
amniocentesis
Potential mechanisms
• Infant exposure to infected blood vaccine
during delivery Risks if HCV+
• High maternal viral load
• Invasive infant monitoring
Potential
• Perineal or vaginal tear
mechanisms
• Prolonged rupture of membranes
• Forceps delivery • Infant blood
Risks if HBsAg+ transfusion or
• High maternal viral load other medical-care related
• HBeAg+ or HBsAg level >4 log10 IU/ml procedures after birth
• Failure to provide timely Not a risk
administration of HBIG and HBV • Breastfeeding

Fig. 1 | Mother-to-child transmission of virus in women with chronic viral hepatitis. Potential
opportunities for transmission of viral infection from mother to infant can occur in utero, or during the
peripartum and postpartum periods. Data on in-utero transmission of hepatitis viruses are limited and based
on detection of viraemia in newborns within days of birth. As prenatal invasive procedures can theoretically
lead to transfer of infectious blood or body secretions from the maternal to the fetal compartment, this risk
needs to be considered when contemplating their use. Mother-to-child transmission (MTCT) requires the
mother to be viraemic. Thus, the risk period in mothers experiencing acute hepatitis (from any of the
hepatitis viruses) will be shorter than in mothers with chronic hepatitis (hepatitis B virus (HBV), hepatitis C
virus (HCV) or hepatitis D virus infection). In women with chronic HBV or chronic HCV infection, the most
common period of transmission is during the peripartum period, and the risks associated with an increased
risk of transmission are primarily due to elevated maternal viral load. Mitigating these risks by optimal
management in pregnancy and at delivery are important. The postpartum risk of transmission is very low.
HBeAg, HBV e antigen; HBsAg, HBV surface antigen.
worldwide) starting with the birth dose, followed
in Asia but only 5% in Africa, reflecting a lower by three doses (as part of the pen tavalent
prev alence of HBeAg among women of vaccine schedule) at 2, 4 and 6 months of age is
reproductive age in Africa. Of new infections in the cornerstone of hepatitis B elimination
children, 68% are from the African and Western programmes53, universal HBsAg testing during
Pacific regions1. pregnancy enables iden tification of all infected
The primary risk period for HBV MTCT is the women at risk of transmission, providing an
per ipartum period. In-utero transmission could opportunity for additional preventative measures,
account for the 10% failure rate of neonatal such as antenatal maternal antiviral treatment or
vaccination47. Using seropositivity for HBV DNA administration of immune globulin to the
at birth, up to 40% of infants have evidence of newborn, beyond the universal vaccine birth
in-utero transmission, although HBV DNA is dose54. Using point of-care HBsAg testing might
detected in a substantial percentage of infants facilitate implementation in resource-limited
who do not become chronically infected48. Thus, settings55. HBsAg-positive women should
the exact proportion of in-utero transmission undergo virological (HBeAg and HBV DNA)
versus intrapartum transmission remains and biochemical evaluation (ALT level),
unknown49 (Fig. 1). Germline infection from preferably in the first or second trimester, to
infected sperm and ovum of HBV carriers is a identify maternal or fetal indications for antiviral
potential mechanism of in-utero infection50–52. therapy56 (Fig. 2). HBV DNA level most accurately
Although universal immunization (that is, predicts risk of MTCT but quantitative HBsAg
regardless of HBV maternal status and and HBeAg have been proposed as surrogates
 in resource-limited settings57–59. A meta
analysis in 2020 found HBeAg to have a pooled
sensi tivity of 88.2% and specificity of 92.6% in
identifying women with HBV DNA of ≥5.3log 10
IU/ml (ref.46).
MTCT is largely attributable to events during the
birth process, with the risk primarily influenced
by maternal viral load rather than obstetric
factors60. Prenatal inva sive tests can result in
in-utero transmission61,62. In a cohort study
examining the placenta of 158 women with
hepatitis B, HBsAg was detected within villous
troph oblast cells and vascular endothelial cells
by immuno histochemistry, and HBV DNA was
identified by in situ hybridization, with a gradient
of infected placental cells from the maternal to
fetal side, potentially explaining intrauterine HBV
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infection63. Amniocentesis, especially in highly
HBV viraemic women (that is, HBV DNA ≥7.0
log10 IU/ml), is associated with MTCT61,62. The
risks of chorionic villous sampling and
cordocentesis are not well described.
Counselling before any invasive procedure,
particularly in the setting of high HBV viral load,
and consideration of non-invasive prenatal test
ing alternatives, is recommended64. Antiviral
treatment to reduce maternal HBV DNA levels
before invasive testing requires evaluation.
There is no strong evidence that caesarean
section reduces MTCT in the setting of
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appropriate immunization65. Intrapartum internal fetal
monitoring should nevertheless be avoided if possible66.
The presence of high viral load or positive HBeAg
status is associated with failure of immunoprophylaxis
in 1–9% of infants born to HBsAg-positive mothers67–71.
Possible opportunities for MTCT of HBV are shown
in Fig. 1, with immunoprophylaxis reducing the risk of
peripartum and postpartum exposure. HIV co-infection
does not seem to increase the risk of HBV transmis
sion, perhaps because antiretroviral regimens for HIV
a globulin (HBIG)) compared with
Pregnant women
Universal HBsAg testing
Women positive for HBsAg
First or second trimester of pregnancy
• ALT levels and renal function test
• HBV DNA, HBeAg ± HBsAg level
Maternal indication to start antiviral treatment?
Yes
No
Start TDF for
maternal HBV disease
HBV DNA <5.3 log 10IU/ml (<200,000 IU/ml)
Immunoprophylaxis failure risk is low
Assess fetal indication to start antiviral
treatment: HBV DNA level
HBV DNA ≥5.3 log 10IU/ml
No prenatal antiviral prophylaxis TDF from early second trimester
activity, have not been
Start TDF from 28–30 weeks
extensively studied in preg
b
infection that include lamivudine or tenofovir also reduce HBV
DNA levels 72–74. Reports from the 1990s suggested that, in the
absence of immunization, infants born to mothers positive for
HBsAg and antibodies to HBeAg are at increased risk of acute
or fulminant hepatitis75–79. Similarly, a study from Taiwan of
fulmi
nant hepatitis in the vaccination era showed that among 43
infants <1 year of age with fulminant hepatitis, 84% of the
mothers were HBeAg negative, although this find ing is
potentially biased by different immunoprophylaxis protocols for
mothers positive for HBeAg (vaccine plus hepatitis B immune
mothers negative for HBeAg (vaccine alone)80. Geographical
variation in HBeAg positivity (which is partially related to
genotype) might contribute to the global variation in MTCT.
The rates of HBeAg positiv ity in pregnant women with chronic
HBV infection are 19% in Africa, whereas in China the
proportion is closer to 30%81,82. HBV DNA quantification more
accurately identifies women at risk of MTCT due to immuno
prophylaxis failure (Fig. 2), although testing for HBeAg will
remain an option until an affordable and rapid HBV DNA test
is available83. HBsAg quantification has been proposed as a
cheaper alternative57,84, with a HBsAg
best correlates with HBV DNA levels 86,87.
Immunoprophylaxis failure risk is high Importantly, testing for HBeAg and HBV
DNA is relevant only in settings where
Second trimester prenatal invasive test or high antiviral therapy can be considered in
risk of preterm delivery or HBV DNA ≥8 addition to immunoprophylaxis to further
log10IU/ml?
reduce MTCT.
No Yes New biomarkers, such as hepatitis B
cut-off of 4.0 log10 IU/ml recommended by core-related antigen (HBcrAg) and HBV
European Association for the Study of RNA, which reflects intra hepatic
the Liver (EASL) to identify mothers at covalently closed circular DNA
an increased risk of MTCT85. transcriptional
Confirmation of this threshold is needed,
with studies focused in HBeAg-positive
women, in whom HBsAg quantification
nancy88,89. In a non-pregnant had a sensitivity and a
cohort from Gambia, HBcrAg specificity of 91.4% and
 ≥200,000 IU/ml (ref.89), suggesting that antiviral prophylaxis are ongoing, including
HBcrAg might be an alternative to HBV during the postpartum period when HBIG is not
available
DNA quan tification in low-income and
middle-income regions. Further studies
Mother Neonatal HBV
to establish the clinical utility of these vaccination and HBIG.
Mode of delivery based on obstetric indication
Timely administration of HBIG and vaccine novel biomarkers in pregnancy are Infants are sus ceptible to HBV infection
needed. until they are immunized, especially
Afer delivery • Monitoring maternal ALT for possible flare afer
prophylaxis discontinuation • Antiviral treatment if those born to mothers positive for HBsAg
indicated for chronic hepatitis B due to a lack of maternally transferred
Newborn • HBV vaccine and HBIG to newborn within 24 anti-HBV for protection. Thus,
93.2%, respectively, in identifying hours of birth immunization of newborn infants
individuals with an HBV DNA level of - Studies assessing the efficacy of maternal
Fig. 2 | suggested management algorithm for women positive the importance of a timely birth dose through the com
for HBV. a | A multi faceted approach is needed to identify and munity or during antenatal visits and reimbursement
prevent mother-to-child transmission of hepatitis B virus (HBV). All from government after hospital delivery might improve
pregnant women need to be tested for HBV. For mothers positive the success of implemenation97. In the setting of home
for the HBV surface antigen (HBsAg), a risk assessment for births, recruiting health volunteers to track pregnancies,
mother-to-child trans mission, maternal treatment if indicated and
notify health-care workers after delivery and organize
postnatal vaccination of all newborn infants are the elements that
outreach visits for the vaccine birth dose was successful
need to be implemented. An assessment of maternal HBV DNA
level in the first or second trimester and determination of the need
in enhancing a timely birth dose in rural Lao People’s
for antiviral prophyl axis is key. b | Caesarean section should be Democratic Republic98. HBV vaccine stored out of the
reserved for obstetric indications only. Timely administration of cold chain (that is, HBV vaccine that has been at ambi
neonatal hepatitis B immune globulin (HBIG) and vaccine is critical ent temperature for up to 4 weeks) has been shown to
and, in settings where HBIG is not available, extended duration of induce a similar level of protection and seroconver
maternal antiviral therapy to protect infants until they respond to sion as vaccine stored within the range of 2–8 °C99.
vaccination is a consideration. ALT, alanine aminotransferase; This finding has led to support by the WHO Strategic
HBeAg, HBVe antigen; TDF, tenofovir disoproxil fumarate. Advisory Group of Experts for countries to choose stor
age out of the cold chain for monovalent HBV vaccine
to help improve timely birth dose coverage99. Regional
Nature Reviews | Gastroenterology & Hepatology or national guidelines consistent with WHO recom
is the most critical and cost-effective strategy to pre vent mendations require sufficient funding and political
MTCT. Efficacy relies upon the timely provision of HBIG and commitment100.
vaccine birth doses90,91. In a systematic review of the risk of
MTCT, the mean estimated rates in the absence of Management of chronic HBV
vaccination, with vaccination alone and with vaccination plus infection during pregnancy
the HBIG birth dose were 75%, 21% and 6% in women and the postpartum period. A systematic
positive for HBeAg, respectively, and 10%, 3% and 1% in review has
women negative for HBeAg, respectively92. In women positive confirmed the safety of several approved HBV antiviral
for HBeAg, MTCT was notably low (only 2%) when the HBIG agents (lamivudine, telbivudine and tenofovir disoproxil
and vaccine birth doses were administered early (median 1.3 fumarate (TDF)) in pregnancy with no increase in con
and genital abnormalities, preterm delivery, postpartum
Reviews haemorrhage or elevated maternal creatine kinase46,47.
Lamivudine and TDF are not associated with terato
genicity even in the first trimester101. As lamivudine and
telbivudine select for antiviral agent-resistant mutants,
1.2 hours, respectively)42. Efficacy is reduced if the HBV even after short-term use102, TDF is the preferred
vaccine birth dose is missed or delayed beyond 24 hours treatment103. Tenofovir alafenamide (TAF), a formula
after birth90,91. Although HBIG can cross the placenta, tion with less renal and bone toxicity, is available in some
evidence supporting the effectiveness of antepartum regions but safety studies in pregnancy are limited101.
maternal HBIG in reducing MTCT is limited93. Maternal antiviral prophylaxis and timely neonatal
The World Health Organization (WHO) recom immunization can reduce immunoprophylaxis failure
mends that the HBV vaccine birth dose should be given in the infant40,42,46. The reported HBV DNA thresholds
within 24 hours; however, global coverage in 2015 associated with MTCT are influenced by differences in
remained low at 39%1. Studies in the Western Pacific, the HBV DNA quantification platforms and the timing
South East Asia and Africa found vaccination coverage of testing during pregnancy68–70. Earlier studies reported
rates of approximately 80%, 35% and 10%, respectively,
and rates of timely administration of the vaccine birth
dose (within 24 hours) were probably lower94–96. Barriers
to HBV vaccination at birth in some regions include the
availability of the pentavalent HBV vaccine only (that HBV DNA cut-offs in copies per millilitre, whereas more recent
is, with diphtheria, pertussis, tetanus and studies used standardized units of IU per millilitre. WHO
Haemophilus suggests a conversion factor of 5.3 (that is, 1IU/ml is
influenzae type b vaccines), which cannot be adminis equivalent to 5.3copies/ml) although in-house laboratory
tered within the first 6 weeks of life, lack of cold chain methodologies cannot be simply standardized by multiplication
vaccine storage (transporting and storing vaccines alone68,104,105. There is agreement that the risk of
within the safe temperature range of 2–8°C) and lack of immunoprophylaxis failure is extremely rare when HBV DNA is
appropriately skilled birth attendants94,95. Education on <5.3 log10 IU/ml (<200,000 IU/ml) and clinically significant
when HBV DNA is >7.0log 10 IU/ml (refs69,70). Controversy at increased risk born to women with a high viral load
remains when maternal HBV DNA levels are within the ‘grey (>5.3log10 IU/ml) or those infants who did not complete
zone’ (between 5.3 and 7.0log 10 IU/ml). The proportion of the recommended vaccinations. Infants infected via the
women falling into this grey zone varies widely from 6% to perinatal route are usually asymptomatic and have low
40%, reflecting assay variation and possibly cohort rates of cirrhosis and hepatocellular carcinoma in child
differences59,68. Societal guidelines suggest that antiviral hood, but require regular monitoring, with WHO sug
prophylaxis should be administered if the maternal HBV DNA gesting at least annual testing of HBeAg, ALT level and
is >200,000IU/ml, acknowledging that this cut-off is a HBV DNA level 115.
43,85
conservative choice to minimize any risk of MTCT .
Antiviral prophylaxis started at 28–32 weeks of ges tation Implementation barriers for HBV
enables adequate suppression of viral load and prevention of prevention and man
MTCT40,43,85. Suboptimal viral load reduc tion can occur in the agement. The ‘triple elimination’ strategy, promoted by
event of preterm delivery26, which justifies starting antiviral WHO to reduce MTCT of HIV, hepatitis B and syph
prophylaxis at 28 weeks rather than at 32 weeks. An ilis, might increase the success of goals for preventing
IU/ml) perinatal transmission of HBV116. Ideally, screening,
extremely high baseline viral load (defined as >8.0 log10
treatment and/or vaccination services for HBV should
might be a risk fac
tor for suboptimal HBV DNA suppression at be offered during antenatal, delivery and postnatal care,
delivery (that is, <200,000IU/ml) and warrants consideration of and well-child visits, as part of essential health service
initiation of antiviral prophylaxis earlier in the second packages, with access ensured and covered by public
trimester 40,106
. funding116. A major difficulty remains when pregnant
Antiviral agents can be discontinued at delivery to 3 months women do not present for antenatal care early enough
after delivery. Continuing antiviral ther apy beyond delivery for such interventions, and for those who deliver at
does not reduce the risk of ALT flares 43,85,107, and in women home. Service delivery then relies on outreach services
without clinical indications for ongoing HBV therapy and that are more complex and for which public health
whose infants received HBIG and vaccination, antivirals can systems have variable capacity. The triple elimination
be stopped at the time of delivery. In locations where infant certification requires service of remote areas. Gavi, the
vaccination alone is used as immunoprophylaxis, continuing Vaccine Alliance, supports immunization programmes
mater in the world’s poorest regions but does not support the
nal antiviral therapy during the postpartum period might provision of the HBV monovalent dose as it consid
protect the newborn from MTCT, although studies confirming ers that governments can purchase the vaccine (about
this benefit are currently lacking. US$0.20 per dose). However, Gavi might, in the near
108
Breastfeeding should not be restricted . Although HBV is future, provide logistic support for the implementation
present in breast milk, breastfed infants are at no higher risk ofof HBV vaccination at birth, which might be anticipated
HBV infection than formula-fed coun terparts, provided they to improve vaccination rates117.
receive vaccination at birth109. WHO recommends Beyond the objective of preventing MTCT in high
breastfeeding immunized infants without delay regardless of risk cases, scaling up HBV testing 118
of pregnant women
maternal HBV status . 110 (and their partners) is important and has been shown
Tenofovir has minimal transfer into breast milk and is secreted to be highly cost-effective in locations of intermediate
in a form that is poorly absorbed by infants111. Total infant endemicity such as China119. The elimination of viral
exposure is probably negligible, estimated by one study to be hepatitis as a major public health threat represents a chal
~0.03% of an oral dose112. A small concern with maternal TDF lenge for many regions, especially in Asia and Africa, but
use is the risk of phosphate wastage and secondary it is recognized that, even in the USA and Hong Kong,
osteopenia that might put the woman at additional risk of adequate care is not consistently available for pregnant
120,121
osteoporosis113. TAF, which has less renal and bone toxicity, is women with HBV infection . Thus, pregnancy
probably an advan tage for breastfeeding women but should be viewed as an opportunity to identify and
pharmacokinetic studies for TAF in breast milk are lacking. engage women positive for HBsAg for longitudinal care
of HBV infection.
Follow-up of infants born to
mothers positive for HBsAg. To enable Hepatitis C
identification of cases of MTCT or vaccination failure, HCV, an enveloped, single-stranded RNA virus of the
serological testing of infants for HBsAg and anti HBs is Flaviviridae family with seven known genotypes (1–7)
optimally performed at 9–12 months of age, at and 84 subtypes122, is spread by exposure to blood, often
as a result of unsafe injecting practices, although it
can be the result of transmission of unscreened blood
www.nature.com/nrgastro or blood products and infrequently, through sexual

Nature Reviews | Gastroenterology & Hepatology

least 2–3 months after completing the primary vaccine

course, to confirm vaccine response and to avoid detec
tion of passively acquired antibodies to HBsAg from
HBIG administered at birth or transient antigenaemia
from vaccine114. Non-infected vaccine non-responders
should be revaccinated because they are at risk of hori
zontal infection114. In resource-limited settings, sero
logical follow-up efforts should focus on those infants
Reviews
practices123. HCV causes acute and chronic infection, with the
rates of chronicity varying from 50% to 80% after exposure,
and leads to liver fibrosis and eventually cirrhosis and liver
cancer, typically after several decades of chronic infection123.
Safe and well-tolerated antiviral therapies are available that
can cure this chronic infec disease severity confound interpretation.
tion in more than 95% of those treated, with consequent HCV status might influence pregnancy outcomes
reductions in the risk of cirrhosis, liver cancer and liver (Box 3). Higher than average rates of intrauterine fetal
failure124. HCV remains a substantial public health challenge death (3.4%), preterm delivery (17.9%), small for
worldwide with an estimated global preva gestational age (11.3%), and low birthweight (12.5%)
lence of 2.5% (177.5 million) with women accounting for were reported in a Canadian prospective cohort of
approximately one third of cases125,126. Although prevalence 145 women with HCV infection142, but no association
varies between countries/regions, none is spared, and the between adverse outcomes and maternal HCV RNA sta
predominant mode of HCV trans tus was observed, and high rates of substance abuse and
mission differs depending on the region127. In western settings, low socioeconomic status were potential confounders.
the highest prevalence is amongst persons who inject drugs, In a meta-analysis of nine studies involving 5,218 women
whereas in developing parts of the world, a substantial with HCV infection, preterm births were ~60% more
proportion are due to non-sterile traditional practices or likely in this group compared with women without HCV
medical and dental procedures. Unlike the ‘baby boomer’ infection (OR 1.62, 95% CI 1.48–1.76). This association
cohort (born between 1946 and 1964) in whom HCV is more was independent of other factors usually associated with
common in men, the current HCV epidemic among younger preterm birth such as age, parity, and tobacco and alco
people (cohort aged 15–24 years) has been reported to occur hol use143. In this meta-analysis, there was no evidence of
in women and men equally128. US surveillance data suggest publication bias (that is, selective publication of studies
that 29,000 women with HCV infection give birth in the USA based on direction or strength of associations). Although
each year129, but global estimates of HCV infection among
pregnant women are lacking.
In the USA, routine HCV testing of pregnant women was
recommended in 2019 by the AASLD–Infectious Diseases
Society of America (IDSA) guidelines 130 and has been shown the effect of viraemia on the preterm birth rates could not be
to be cost-effective if the prevalence of HCV among pregnant ascertained, as HCV RNA data were not included to
women is 0.03% or above131. This finding is complementary to distinguish current from past infections, the authors postulated
the new univer that this effect might have been mediated by a chronic
sal screening recommendations of the US Preventive Servicesinflammatory state143. Finally, substantially worse maternal,
Task Force released in 2020 (ref.132). Multiple studies obstetric and fetal outcomes were also found in 342 pregnant
highlighting the limitations of risk-based and birth cohort women with HCV infection in Egypt compared with a control
screening are available. For example, in a prospective group of 170 uninfected pregnant women144. None of these
observational cohort of pregnant women attending an inner women had acquired HCV via drug use, thereby removing the
city obstetrics clinic, universal screening was more effective socioeconomic or addiction-related confounders. Increased
than risk-based select ive screening, identifying anti-HCV in rates of antepartum haemorrhage, postpartum haemorrhage,
3.18% (7 of 220) of tested women compared with 0.95% (4 of GDM, premature rupture of membranes, admission to
419) of those identified with risk-based screening133. It could intensive care units and maternal mortality were observed in
be that pregnant women seem unwilling to report their risks the HCV-infected group144. As the increased risk was
for fear of being stigmatized by health-care providers. In associated with prothrombin time prolongation, advanced liver
another study, risk factor questionnaires (including for prior disease rather than HCV itself might have been responsible
dental or surgical treatments) failed to identify 10% of HCV for these adverse outcomes.
cases found by universal testing among 1,250 pregnant Chronic hepatitis C has been linked with increased rates of
women in Egypt134. Moreover, risk fac tors for HCV infection intrahepatic cholestasis of pregnancy (ICP)145,146. A
such as female genital mutila meta-analysis (three European studies) found a 20-fold higher
tion, which still occurs in many African regions, might not be pooled odds ratio of ICP in women posi
captured by such surveys135. Universal screening of all tive for HCV compared with those negative for HCV146.
pregnant women overcomes these limitations. At the present Downregulation by HCV of multidrug resistance pro tein 2
time, obstetrical societies136 and the gen (MRP2), with consequent failure of toxic sub stance clearance
eral screening recommendations in most regions still rely on exacerbated by high oestrogen and progesterone levels in
the targeted risk or birth cohort-based screening strategies to pregnancy is a proposed mecha
identify pregnant women with HCV infec tion, but screening Box 3 | HCV and pregnancy
practices are likely to evolve as coun tries/regions tackle
Maternal risks
achieving HCV elimination goals137. For example, a consensus
• Increased rates of gestational diabetes mellitus, antepartum
statement for management of hepatitis C in Taiwan
138 haemorrhage, postpartum haemorrhage and premature rupture of
recommended testing all pregnant women .
membranes have been reported. • There is a 20-fold increased
Reviews likelihood of intrahepatic cholestasis of pregnancy.

Effect of chronic hepatitis C on
pregnancy. Chronic HCV
infection does not seem to directly affect fertility or
assisted-reproduction interventions139,140, although data
are limited. Some studies have shown reduced responses
to ovarian stimulation, and reduced rates of successful
implantation and pregnancy141. However, inconsistent
testing for HCV RNA and lack of adjustment for liver
Fetal risks
• Increased rates of intrauterine fetal death, preterm delivery,small for
gestational age and low birthweight have been reported.
MtCt
• ~5% transmission risk in women with viraemia and furtherincreased
to ~10% in women withHIV co-infection.
MtCt prevention
• Cure reproductive aged women priorto conception with direct acting
antiviral (DAA) therapy.
• DAA therapy during pregnancy to prevent mother-to-child tum period151 (Fig. 1). Limitations of the available data
transmission (MTCT) is probably effective butsafety studies are on the timing of transmission include small numbers of
lacking. mother–infant pairs and the mixing of results from HIV
• Caesarean delivery notrecommended but avoid intrapartum invasive co-infected and uninfected mothers.
monitoring. As part of national HCV elimination strategies, all
Maternal follow-up women of childbearing age should be identified and con
• Mothers with hepatitisCvirus(HCV) viraemia should be offered
sidered for HCV treatment. Case finding and treatment
antiviraltherapy after delivery and breastfeeding is complete. would eliminate MTCT by rendering women aviraemic
before future conception. Antiviral therapy is currently
Infant follow-up not recommended during pregnancy85,130. Understanding
• EarlyHCV RNA testing after 2 months hassome utility, butthere are the safety of HCV direct-acting antiviral (DAA) agents
false-positives due to transient viraemia. is nevertheless important, particularly for women who
• Delay anti-HCV testing until 12–18 monthsto avoid become pregnant during DAA therapy. In preclinical
false-positivesfrom passively transferred maternal antibody. studies, all of the currently approved drugs seem to
Implementation challenges to MtCt prevention cross the placenta and transfer into breast milk but no
• Universalscreening of pregnant women is betterthan risk safety signals from animal studies have been identified152.
153
factor-based screening if prevalence of anti-HCV in pregnant women is Human data, from small safety studies of ledipasvir–
0.03% or higher. sofosbuvir and from unplanned pregnancies whilst on
• Ensuring follow-up and testing of babies born to mothers withHCV DAA therapy (sofosbuvir plus daclatasvir) suggest no
viraemia to enable diagnosis and appropriate treatment(after age 3 increase in congenital or newborn complications154.
years based on available paediatric safety studies). Although not a practice endorsed by expert guide
nism for this association145. In view of the risk of adverse fetal lines, consideration and further study of HCV treatment
outcomes with ICP, recognition and appropriate therapy of this during pregnancy to reduce MTCT and cure women
condition is imperative147. who otherwise might lack access to HCV therapies are
warranted147. As HCV treatment is short (8–12 weeks)
Effect of pregnancy on the course and achievement of undetectable HCV RNA is rapid
of hepatitis C. The course of HCV infection might (typically within 4 weeks), antiviral therapy started in
be influenced by preg nancy (Box 3). In a large Italian cohort of the last trimester could achieve both desirable goals.
370 anti-HCV positive pregnant women (72% viraemic), If women have access to affordable HCV treatment after
elevated ALT levels were observed in 56.4% of the women in delivery and if antiviral therapies become more widely
the first month of pregnancy, decreasing to 7.4% in the last available for children as young as 3 years of age155,
trimester, and then increasing again after delivery (54.5%)148. then treatment in pregnancy might be unnecessary.
A subsequent prospective study of liver tests, viral load and Nevertheless, in the current climate where curative ther
cytokine levels during and after preg nancy, suggested two apies for young children are more limited156 and women
response patterns: elevated ALT levels, decreased HCV RNA of childbearing age cannot access affordable therapy157,
levels and an increase in TH1 cytokines during the postpartum further research on treatment of HCV in pregnancy
period were seen in two-thirds of viraemic mothers; and no is warranted. Importantly, 60% of 141 women in a US
change in ALT and no variations in either HCV RNA or T H1 survey reported a willingness to take antepartum DAA
cytokine levels were seen in the remainder. This find ing therapy if it lowered the risk of MTCT158.
suggests that hepatitis flare was related to immune
reconstitution during the postpartum period in some cases, but Management of women with HCV in
the clinical relevance seems limited. pregnancy and
postpartum. Prenatal invasive testing with
MTCT of hepatitis C. Only anti-HCV-positive amniocente
women with viraemia are at risk of MTCT of HCV148 and HIV sis has not been associated with increased rates of HCV
co-infection increases the risk further149. In a meta analysis of transmission but data are very limited159. If invasive
25 studies involving 2,017 pregnant women with HCV prenatal testing is necessary, experts recommend amni
viraemia without HIV co-infection and 495 women with HIV ocentesis (with avoidance of placental contact) over
co-infection, the estimated rate of MTCT of HCV was 5.8% chorionic villus sampling and fetal blood sampling136.
(95% CI 4.2–7.8%) and 10.8% (95% CI 7.6–15.2%), Mode of delivery has also not been associated with risk
respectively149. The level of HCV viraemia has been of HCV transmission and a caesarean section should
associated with the risk of MTCT, but a precise threshold has only be considered for obstetrical indications151,160.
not been identified. MTCT can occur intrapartum, peripartum Avoidance of invasive fetal monitoring, episiotomy and
or postpartum (Fig. 1). The exact route of transmission or the prolonged rupture of membranes is preferable, if pos
exact timing, sible without compromising a safe delivery. The risk of
MTCT increases with rupture of membranes beyond
6 hours (adjusted OR 9.3, 95% CI 1.5–180)161.
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Breastfeeding should not be restricted. HCV can be
detected in the breast milk of a minority of viraemic

Nature Reviews | Gastroenterology & Hepatology

either intrauterine or peripartum is not well understood,
although available data suggest that in-utero transmis Reviews
sion might account for up to 40% of MTCT events,
based on detection of viraemia in infants within 3 days
of birth49,150. There is little to no risk during the postpar women but at low titres162,163 and there is no evidence of
associated MTCT. In the European Paediatric Hepatitis C infrastructure gaps. A national strategy supported by
Virus Network study, rates of hepatitis C in breast-fed versus adequate funding is required to achieve optimal testing,
bottle-fed infants was 8.3% versus 9.5% (OR 0.86, 95% CI tracking and treatment of HCV-infected children.
0.54–1.35)164. A systematic review of 14 cohort studies with
2,971 participants found no sta Hepatitis D
tistically significant association between breastfeeding and HDV is a single-stranded RNA virus of the genus
HCV transmission151. The antiviral activity of breast milk is Deltavirus, with eight known genotypes (1–8) and a
linked to endogenous lipase-dependent gener ation of free unique requirement for HBsAg for complete replication
fatty acids, which destroy the viral lipid envelope165. In the and the production of infectious virions174. Around 5%
event of cracked and bleeding nip ples, common sense of chronic carriers of HBV are co-infected with HDV,
suggests that breastfeeding should be temporarily leading to an estimated 12 million persons infected
discontinued. with HDV globally175. Large variations between coun
tries/regions have been reported with the highest prev
Follow-up of infants born to alence of 60% reported in Mongolia1,176. The exact HDV
mothers with HCV virae mia. Passive prevalence in pregnant women is unknown as most
transfer of anti-HCV from mother to child occurs and anti-HCV regions lack access to or do not conduct routine testing,
can persist until 18 months of age166. This situation is but HDV infection was identified in 14.7% of pregnant
exemplified in a study of 29 babies born to mothers with HCV women in Mauritania and 20.3% of pregnant women
viraemia who tested positive for anti-HCV after birth, although in Pakistan177,178. The establishment of a WHO standard
only 10% of these babies remained anti-HCV positive by has facilitated improvements in HDV diagnostics179 but
12–18 months of age, and only 5% were HCV RNA HDV RNA testing is limited in resource-constrained
positive beyond 12 months166. Unfortunately, early HCV RNA settings. For persons newly diagnosed with chronic
levels are imperfect as a measure of infection as transient hepatitis B, systematic evaluation for co-infections,
viraemia might be detected between 4 and 6 months of age167. including HCV, HDV and HIV, is endorsed by EASL and
The positive predictive value of HCV RNA increased from 33% Asian–Pacific clinical practice guidelines85,107.
at birth to 78% at 9 months of age, although the negative As HDV infection increases the risk of progressive
predictive value ranged from 96% to 99% at birth and at 9 liver disease and cirrhosis180, pregnant women with
months of age in a large European cohort study168. Delaying HDV infection might be more likely to have underlying
HCV RNA testing at least until 2 months of age is advanced fibrosis or cirrhosis than their counterparts
recommended130, and those positive on early testing should with HBV monoinfection. Assessing liver disease sever
have confirmatory test at or beyond 18 months90,130,169. ity is critical in pregnancy management as cirrhosis
increases the risk of caesarean delivery, low birthweight
Implementation barriers to and preterm delivery181. There is a paucity of longitu
preventing MTCT of HCV. The limitations of dinal studies of pregnant women with HDV infection,
a risk factor-based screening strategy in pregnancy are and thus our knowledge is limited on whether preg
recognized. To identify all pregnant women with HCV infection,nancy has any positive or negative consequences on
universal screening is required170. This approach would add a HDV-associated liver disease progression. Similarly,
small cost to the effective, evidenced and operational there are no published series on the fetal or infant out
universal screen comes of pregnancies in women with HDV infection,
ing policy for HBV171. Although barriers to treatment remain, but the risks are probably similar to those in women with
including access to subsidized medicines, and lack of HBV monoinfection (Box 2).
available pregnancy safety data for DAA agents, pregnancy MTCT of HDV is exceedingly rare. In a study of
provides an important opportunity to engage women in HCV 36 children born to 22 mothers with HDV infection, only
care. one was infected with HBV and none had evidence of
Appropriate follow-up of infants born to mothers with HCV HDV infection182. Breastfeeding is presumed to be safe.
infection is critical but poorly executed. In a US The only antiviral therapy for HDV infection is
population-based, retrospective cohort of 1,025 infants born to pegylated interferon, which is not recommended during
women with HCV infection between 2006 and 2014, only 96 pregnancy183. As HDV infection can only occur in the
(9%) were screened for HCV172. In another analysis of 537 presence of HBV infection, the principle of preventing
children born to 500 mothers positive for HCV identified within HDV MTCT is through prevention of HBV MTCT as
a Philadelphia, USA, hepatitis registry, only 16% had described above.
undergone testing173. Data on the completeness of infant
follow-up in other countries/regions are lacking. Given the Hepatitis E
availability of DAA agents for the treatment of children infected Hepatitis E is one of the most frequent causes of acute
with HCV, strategies to effectively identify infected mothers hepatitis worldwide and is endemic in many regions,
and ensure appropriate follow-up of their children requires including Asia, Africa, the Middle East and Central
urgent attention to prevent substantial health consequences. America184. HEV is a small, non-enveloped virus of
There are multiple possible explanations for the con siderable the Hepeviridae family with a single-stranded RNA
gap in the testing of children born to women genome with four known genotypes. Genotypes 1 and
Reviews

with HCV infection: socioeconomic and health lit 2 exclusively infect humans, whereas genotypes 3 and 4 infect
eracy barriers in the mother; knowledge, motivation humans, pigs and several other mammalian spe cies. Similar
and capacity of health-care workers; and finally, health to HAV, the transmission of HEV is faecal– oral, usually
through contaminated drinking water184. Large outbreaks of
hepatitis E from water-born virus in Africa and Asia have infection during pregnancy include reduced background
predominantly been associated with genotypes 1 and 2, seroprevalence (where there might be reduced severity
whereas infections with genotypes 3 and 4 are zoonotic of disease in the setting of reinfection as opposed to first
infections from swine and swine products, that cause sporadic infection), the immunological changes of pregnancy,
hepatitis cases in indus trialized settings185,186. An estimated the effect of malnutrition and folate deficiency, and the
70,000 deaths are attributed to hepatitis E each year187. A HLA haplotype 200–202.
meta-analysis of HEV seroprevalence studies performed in
pregnant women in Africa found ~35% seropositivity, although Infant and neonatal outcomes and
rates seem to be declining188. The seroprevalence of HEV in MTCT. Hepatitis E
women of childbearing age in Lao People’s Democratic is reported to be responsible for ~3,000 stillbirths
Republic was 29%, and lower in women from urban areas annually worldwide203. The specific fetal effect is dif
than in women from rural areas (20% versus 38%), with ficult to interpret alongside severe maternal illness.
farming, slaughtering of pigs and lack of access to clean water A systematic review found median fetal and neonatal
identified as risk factors189. Although antibodies might case fatality rates attributed to HEV infection of 33%
disappear with time, and their absence is not proof of being at and 8%, respectively192. The clinical outcomes for sur
risk of infection, global estimates of HEV exposure indicate viving infants are extremely variable, ranging from mild
that the vast majority of women of childbearing age lack anicteric hepatitis to acute hepatic failure, as well as pre
protection against HEV190. Whilst hepatitis E has only one term birth with its associated complications196 (Box 4).
serotype, the operating char Thus, close neonatal monitoring is crucial in the setting
acteristics of different commercially available diagnostic of maternal HEV infection.
assays are imperfect and varied, which influences the MTCT of HEV can occur (in utero or in the peripar
interpretation of prevalence reports184. tum period) although the reported rates of transmission
In most people, HEV infection is a self-limiting dis ease with a vary, from 33% to 100%196,204. There are scant data avail
low case fatality rate191. By contrast, HEV infection carries a able on the timing and effect of this phenomenon. In a
substantially higher mortality risk in pregnant women than study from India of 144 pregnant women with HEV
non-pregnant women, and a much higher risk than acute infection and acute hepatitis or acute liver failure,
infection with other hepa titis viruses in pregnant women192,193. HEV RNA was detected in the cord blood in 46% of
This unfortu nate severe clinical picture of acute HEV infection infants (59 of 128) born to mothers positive for HEV
in pregnancy is exemplified by an outbreak in southeast ern IgM. Maternal viral load was found to be a statistically
Xinjiang China, an endemic area of HEV, which occurred from significant predictor of MTCT205.
1986 to 1988. There were 119,280 cases of HEV infection and
707 deaths, of which 404 occurred in pregnant women194.
Box 4 | HeV and pregnancy
Another retrospective study of 946 pregnant women in China
suggested that worse pregnancy outcomes occurred in those Maternal risks
with than in those without HEV infection, particularly in women • Increased risk of acquiring hepatitis E virus(HEV) compared with
with infection during the third trimester195. non-pregnant women. • Hepatitis varying from mild to acute hepatic
A meta-analysis of the clinical outcomes found in 23 studies failure.
predominantly from India, but also Pakistan and South Sudan, • Preterm and still birth rates elevated.
found that the maternal case fatality rate varied between 3.2%
(95% CI −0.4–6.9%) and 70% (95% CI 49.9–90.1%)192. ExceptFetal risks
for one study in this meta-analysis, the pregnant women were • Fetal and neonatal case fatality rates of 33% and 8%,respectively.
identified by presentation with symptomatic hepatitis E and • Hepatitis varying from mild anicteric to acute hepatic failure.
one required acute liver failure as an inclusion. This case • Preterm birth with its associated complications.
selection might have led to overestimation of the severity and
limited the generalizability of the data. MtCt
Adverse pregnancy outcomes (Box 4) have been reported in • Rates oftransmission vary,reported in the range 33–100%.
regions where epidemic outbreaks occur, such as the Indian • Increased maternal viral load seemsto increase the risk of
subcontinent, China, Southeast and central Asia, the Middle mother-to-child transmission (MTCT).
East and North and western Africa 184, and where HEV MtCt prevention
genotypes 1 and 2 typically pre • No prophylactic therapy available.
dominate196,197. Organ culture experiments of maternal decidua • Interferon and ribavirin are notsuitable for use in pregnancy.
and fetal placenta have revealed that, although all HEV
genotypes can infect the maternal–fetal inter face, HEV Maternal follow-up
genotype 1 replicates more efficiently, • Supportive care until liverrecovery.
Infant follow-up
www.nature.com/nrgastro • Intensive monitoring of infants born to women withHEV infection
isrequired to identify and manage consequence of MTCT if it occurs.

Nature Reviews | Gastroenterology & Hepatology

produces higher amounts of infectious progeny virions
and causes morphological alterations of greater severity
Reviews
with associated alterations in the cytokine, chemo
kine and growth factor networks than the other HEV
genotypes198,199. In addition to viral genotype, other Treatment and vaccination. The
putative factors related to worse outcomes with HEV broad-spectrum anti viral, ribavirin, is most frequently used
(sometimes with interferon-α) to treat HEV infection but is contrast, is associated with substantial maternal and fetal
unsuitable for use in pregnancy due to the risk of morbidity and mor tality, particularly if infection is acquired in
teratogenicity206. Treatment in pregnancy therefore is currently the second or third trimester. MTCT of HAV and HEV has
best sup portive care, which might include maternal monitoring been documented. Prevention through vaccination (HAV, and
for any signs of liver failure, preservation of nutrition and potentially in the future HEV) and improved sani
control of temperature where possible, as well as fetal tation are key to reducing maternal and fetal morbidity.
monitoring and early delivery in severe cases. Liver Treatment is supportive, with consideration of liver
transplantation might be considered in women with acute liver transplantation in appropriate cases.
failure207. Chronic viral infections — HBV, HCV and HDV — in pregnant
Active vaccination against HEV for women of child bearing age women are associated with pregnancy associated
requires further research. Prevention would make a major complications (GDM for HBV infection, ICP for HCV infection)
difference in endemic regions, particu larly directed to and the risk of MTCT of infection. Globally, chronic HBV
outbreaks, if not more broadly. Whilst not designed to study infection is of the greatest con cern, due to the number of
safety in pregnancy, in a phase III study in China in which women of childbearing age positive for HBsAg as well as the
31,391 women were vaccinated with HEV-239, 37 pregnant high risk of MTCT in the absence of prevention strategies.
women were inadvertently vaccinated and no adverse infant Screening to
or maternal outcomes were observed208. This vaccine has
been licensed in China since 2012 but not elsewhere209. A
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phase IV study of safety and efficacy of HEV-239 in women of
child bearing age is underway in Bangladesh210. The need to
protect women of childbearing age, either specifically or as identify infected mothers, provision of antiviral therapy
part of a universal strategy of vaccination, living in settings of in mothers with high viraemia and timely administra
endemic HEV or settings of high risk of out break is a critical tion of HBV vaccine and HBIG to infants are essential
public health imperative. Preliminary analysis suggests that components of the prevention strategy for HBV and
HEV vaccination of women of childbearing age would be a HDV infection. By contrast, for HCV infection, due to
cost-effective strategy211. the lack of an effective vaccine and lack of safety data
on the use of DAAs in pregnancy, the focus is on identi
Conclusions fying infected women, minimizing obstetrical contribu
The intersection of viral hepatitis and pregnancy has tions to risks of perinatal transmission and follow-up of
consequences for both mothers and infants. Each of the
hepatitis viruses presents unique challenges in pregnancy
management, but interventions are available to prevent or
reduce negative outcomes. Differences in national policies
and variable commitment of resources to test infants to identify those who acquired HCV via MTCT. Thus,
ing, treatment and prevention influence the success of these optimal management of pregnant women and their infants is
measures. vital to viral hepatitis elimination efforts. Region-specific
Acute infection due to hepatitis viruses A to E can occur in strategies are needed that reflect regional epidemiology and
pregnancy but maternal and fetal complications related to disease burden and supported by a national elimination plan
acute hepatitis are most frequent for HAV and HEV193. For and provision of sufficient resources for implementation.
pregnant women with symptomatic acute HAV, the primary
risks are to the fetus and are manifested by increased rates of Published online xx xx xxxx
preterm labour in later trimesters. Acute hepatitis E, by
reporting system after hepatitis a and hepatitis AB epidemiology and vaccination. Epidemiol. Rev. 28,
vaccines in pregnant women. Am. J. Obstet. Gynecol. 112–125 (2006).
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is an adviser or has received research grants from AbbVie,
Gilead Sciences, Merck/MSD and Bayer. G.J. owns equities
in Sanofi and has received grants from Gilead. K.W.C. has
no competing interests.
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Chen and the other, anonymous, reviewers for their
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Author contributions
All authors contributed equally to this article.

Competing interests
N.A.T. has received institutional grant support unrelated to
this work from Gilead Sciences and Roche/Genentech. M.T.L.