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No. 342, April 2017

Hepatitis B and Pregnancy

This Clinical Practice Guideline has been prepared by the Gina Ogilvie, MD, Vancouver BC
Infectious Diseases committee, reviewed by the Family
Caroline Paquet, RM, Trois-Rivires QC
Physician Advisory, Clinical Practice e Obstetrics and
Guideline Management and Oversight Committees and Vanessa Poliquin, MD, Winnipeg MB
approved by the Board of the Society of Obstetricians and Julie van Schalkwyk, MD, Vancouver BC
Gynaecologists of Canada.
Mark H. Yudin (chair), MD, Toronto ON
Disclosure statements have been received from all members
Eliana Castillo, MD, Calgary AB of the committee(s).
Kellie Murphy, MD, Toronto ON Competing interests: None declared.
Julie van Schalkwyk, MD, Vancouver BC

Victoria Allen, MD, Halifax NS
Objective: To review the epidemiology, natural history, evaluation, and
Celine Bouchard, MD, Quebec QC treatment of hepatitis B virus (HBV) infection during pregnancy. This
Marc Boucher, MD, Montral QC will aid obstetric care providers in counseling their patients
regarding perinatal risks and management options available to
Isabelle Boucoiran, MD, Montral QC
pregnant women with hepatitis B.
Sheila Caddy, MD, Calgary AB
Outcomes: Outcomes evaluated include thresholds for HBV anti-viral
Eliana Castillo, MD, Calgary AB treatment for prevention of perinatal transmission and for invasive
Logan Kennedy, RN, Toronto ON procedures during pregnancy for women with hepatitis B infection.

Deborah Money, MD, Vancouver BC Evidence: Medline, EMBASE, and CINAHL were searched for articles in
English on subjects related to HBV infection, pregnancy, and perinatal
Kellie Murphy, MD, Toronto ON transmission from 1966 to March 2016. Results were restricted to
systematic reviews, randomized controlled trials/controlled clinical
trials, and observational studies. Other (unpublished) literature was
identied through searching the websites of health technology
assessment and health technology assessment-related agencies,
clinical practice guideline collections, clinical trial registries, and
Key Words: Hepatitis B, antiviral therapy, breast-feeding, chronic
national and international medical speciality societies.
hepatitis, immuno- prophylaxis, vertical transmission, viral load,
pregnancy Validation methods: The quality of the evidence is rated using the
criteria described in the Report of the Canadian Task Force on
Preventive Health Care (Table 1). Recommendations for practice
are ranked according to the method described in this Report.
Guideline update: The guideline will be reviewed 5 years after
J Obstet Gynaecol Can 2016;-(-):-e- publication to decide if an update is required. However, if important
Copyright 2016 Published by Elsevier Inc. on behalf of The Society of new evidence is published prior to the 5-year cycle, the review
Obstetricians and Gynaecologists of Canada/La Socit des process may be accelerated for a more rapid update of some
obsttriciens et gyncologues du Canada recommendations.

This document reects emerging clinical and scientic advances on the date issued, and is subject to change. The information should not be
construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions.
They should be well documented if modied at the local level. None of these contents may be reproduced in any form without prior written
permission of the publisher.
Women have the right and responsibility to make informed decisions about their care in partnership with their health care providers. In order to
facilitate informed choices, women should be provided with information and support that is evidence based, culturally appropriate, and tailored to
their needs. The values, beliefs, and individual needs of each woman and her family should be sought and the nal decision about the care and
treatment options chosen by the woman should be respected.

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Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on
Preventive Health Care
Quality of evidence assessmenta Classication of recommendationsb
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive
controlled trial action
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive
randomization action
II-2: Evidence from well-designed cohort (prospective or retrospective) C. The existing evidence is conicting and does not allow to make a
or case-control studies, preferably from more than one centre or recommendation for or against use of the clinical preventive action;
research group however, other factors may inuence decision-making
II-3: Evidence obtained from comparisons between times or places D. There is fair evidence to recommend against the clinical
with or without the intervention. Dramatic results in uncontrolled preventive action
experiments (such as the results of treatment with penicillin in the E. There is good evidence to recommend against the clinical
1940s) could also be included in the category preventive action
III: Opinions of respected authorities, based on clinical experience, L. There is insufcient evidence (in quantity or quality) to make a recom-
descriptive studies, or reports of expert committees mendation; however, other factors may inuence decision-making
The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive
Health Care.
Recommendations included in these guidelines have been adapted from the classication of recommendations criteria described in The Canadian Task Force on
Preventive Health Care.

Sponsors: This guideline was developed with resources funded by the 4. Hepatitis B surface antigen-positive pregnant women should
Society of Obstetricians and Gynaecologists of Canada receive counseling on prevention of hepatitis B virus transmission
to sexual partners and household contacts. (II-2A)
5. If hepatitis B surface antigen is negative but there is an ongoing
1. Pregnant women should be offered screening for hepatitis B virus
risk of infection (e.g., born in country where hepatitis B virus is
infection in early pregnancy by determination of their hepatitis B
endemic, illicit drug use, multiple sexual partners, multiple trans-
surface antigen. (I-A)
fusions, immunosuppression, hepatitis B positive partner, health
2. If status of hepatitis B surface antigen is unknown at time of care workers, incarceration, or abnormal alanine aminotrans-
maternal admission to hospital, this should be done immediately to ferase), screening should be repeated in late pregnancy.3 (II-3A)
inform infant management.1,2 (III-A)
6. Women at high risk for acquiring hepatitis B infection who are hep-
3. Hepatitis B surface antigen-positive pregnant women require atitis B surface antigen-negative and have not been vaccinated for
testing for hepatitis B envelope antigen, hepatitis B virus (HBV) hepatitis B must be counseled on risk factor modication and should
DNA level, alanine aminotransferase (I-A) and ultrasound of the be offered recombinant hepatitis B vaccine series: pregnancy is not a
liver (III-B) during pregnancy for the purposes of maternal health contraindication for immunization to hepatitis B virus. (II-2A)
and perinatal HBV transmission risk stratication. A specialist
7. Encourage non-invasive screening techniques for aneuploidy prior
referral is recommended. (III-L)
to invasive testing for women who are hepatitis B surface antigen-
positive and counsel women that risk of transmission in utero in-
creases if maternal hepatitis B virus DNA is > 200 000 IU/mL
(> 106 copies/mL) at the time of amniocentesis. (II-2B)
8. If possible, avoid intrapartum invasive procedures (e.g., fetal
ALT alanine aminotransferase electrocardiogram, scalp lactate) that may increase the infants risk
anti-HBe hepatitis B envelope antibody of percutaneous hepatitis B virus exposure. (III-L)
anti-HBs hepatitis B surface antibody 9. Cesarean section is not recommended for the sole purpose of
reducing the risk of perinatal transmission of hepatitis B virus. (II-2C)
CHB chronic hepatitis B
10. Vaccinate the neonate for hepatitis B and give hepatitis B immu-
CI condence interval noglobulin within the rst 12 hours of life to all neonates born to
DNA deoxyribonucleic acid women who are hepatitis B surface antigen-positive. (I-A)
FDA Food and Drug Administration 11. Breastfeeding does not pose an additional risk of hepatitis B virus
infection, even without neonatal vaccination, hence mothers with
GA gestational age
chronic hepatitis B infection who wish to breastfeed should be
HAV hepatitis A virus encouraged to do so. (II-2A)
HBeAg hepatitis B envelope antigen 12. Encourage families to complete the infant immunization series for
HBIG hepatitis B immunoglobulin hepatitis B virus according to local infant vaccination schedule and
obtain serological conrmation of protection after completion of hep-
HBsAg hepatitis B surface antigen atitis B vaccination series, no sooner than 9 to 12 months of age. (I-A)
HBV hepatitis B virus 13. In collaboration with an adult infectious diseases/gastroenterology or
HCC hepatocellular carcinoma hepatology specialist, consider antiviral treatment for viral suppres-
sion for prevention of perinatal transmission in women with hepatitis
HIV human immunodeciency virus
B DNA viral loads level > 200 000 IU/mL (> 106 copies/mL), starting
PEP post-exposure prophylaxis at 28 to 32 weeks GA and continuing until delivery. (II-B)

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Hepatitis B and Pregnancy

GENERAL CONSIDERATIONS Table 2. Interpretation of hepatitis B serologic test


H BV is an enveloped DNA virus. It has an outer

envelope component of HBsAg and an inner
nucleocapsid component of hepatitis B core antigen.
Susceptible to HBV
anti-HBcc Negative
HBeAg is typically measurable in serum when active viral anti-HBsd Negative
replication occurs. HBV DNA can be detected in serum HBsAg Negative Immune to HBV due to natural
and is used to monitor the degree of viral replication. Virus anti-HBc Positive infection
anti-HBs Positive
mutations that prevent HBeAg expression can develop,
HBsAg Negative Immune to HBV due to hepatitis
even when high viral loads exist, making HBeAg an un-
anti-HBc Negative B vaccination
predictable marker for HBV DNA level. Up to 30% of anti-HBs Positive
those with chronic infection may have such a mutation.4 HBsAg Positive Acute Infection
There are at least 10 different genotypes of HBV. anti-HBc Positive
Although some types are associated more often with dis- IgM anti-HBce Positive
anti-HBs Negative
ease progression, all types of HBV respond to antiviral
HBsAg Positive Chronic Infection
therapy, and HBV immunization is thought to be protec- anti-HBc Positive
tive against all genotypes. IgM anti-HBc Negative
anti-HBs Negative

EPIDEMIOLOGY HBsAg Negative Four possible interpretations:

anti-HBc Positive 1. Resolved infection (most common)
anti-HBs Negative 2. False-positive anti-HBc, thus
Prevalence rates of HBV infection vary widely based on the susceptible
global geographical region. Prevalence rates are greater than 3. Low level chronic infection
5% in sub-Saharan Africa, East Asia, the Pacic Islands, and 4. Resolving acute infection
the Amazon Basin of South America. Almost half of the Hepatitis B serologic testing involves measurement of several HBV-specic
antigens and antibodies. This is used to identify different phases of HBV
worlds population lives in areas of high endemicity.5 infection and to determine the existence of acute or chronic HBV infection,
immunity to HBV as a result of prior infection or vaccination, or susceptibility to
In Canada, the rate of CHB in the general population is infection.1
less than 1%. However, among certain Canadian pop- b
HBsAg: A protein on the surface of HBV; it can be detected in high levels in
serum during acute or chronic HBV infection. The presence of HBsAg indicates
ulations such as adults from Southeast Asia, prevalence that the person is infectious. The body normally produces antibodies to HBsAg
may approach 5% to 15%.6 HBsAg prevalence was re- as part of the normal immune response to infection. HBsAg is the antigen used
ported at 0.4% in the 1990s in one Canadian province7 and to make hepatitis B vaccine.
in almost one percent in a recent study from British Total hepatitis B core antibody (anti-HBc): Appears at the onset of symptoms
in acute hepatitis B and persists for life. The presence of anti-HBc indicates
Columbia.8 In this latter study, 18% of HBsAg-positive previous or ongoing infection with HBV in an undened time frame.
pregnant women were found to have active infection (i.e., d
Anti-HBs:The presence of anti-HBs is generally interpreted as indicating
were also HBeAg positive). Seven neonatal transmissions recovery and immunity from HBV infection. Anti-HBs also develops in a person
who has been successfully vaccinated against hepatitis B.
were documented within this cohort, six of whom were e
Immunoglobulin (IgM) antibody to anti-HBc:Positivity indicates recent infection
from mothers documented as HBeAg positive. All seven with HBV (< 6 mos).
infants received appropriate newborn HBV PEP.8 Even
though the majority (> 90%) of infants born to HBsAg-
positive women in Canada receives HBIG and more than which may result in death.9 CHB, which occurs in 5% to
80% receive three doses of HBV vaccine, perinatal trans- 90% of those acutely infected, is dened as being HBsAg
mission has been reported for about 1% to 2% of infants positive for more than six months. It is conrmed with
who receive appropriate newborn HBV PEP.7 persistence of HBsAg and the absence of anti-HBs, which
is a neutralizing antibody that can be detected after HBV
infection has been cleared or after successful HBV im-
munization. Anti-HBs and HBsAg, essentially, do not exist
Following transmission, HBV infects the liver and causes together. HBeAg is generally considered to be a marker of
inammation and hepatocellular necrosis. The mechanism by HBV replication and infectivity. It is usually associated with
which the virus infects hepatocytes is not well understood. high levels of HBV DNA in serum. Clearance of HBeAg
and seroconversion to anti-HBe occurs early in patients
Once infection occurs, the clinical course varies from with acute infection, well before clearance of HBsAg.
subclinical disease to acute hepatitis or fulminant infection, However, HBeAg seroconversion may be delayed for years

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Figure 1. Natural history of HBV infection acquired Figure 2. Natural history of HBV infection acquired
during infancy during adulthood

to decades in patients with chronic HBV infection

(Table 2). an infected person, needle-sticks or sharp instrument ex-
posures, and sharing items such as razors or toothbrushes
It is estimated that up to two billion people have been with an infected person. HBV is not spread through food
infected with HBV, and there are currently 240 million or water, sharing eating utensils, breastfeeding, hugging,
individuals worldwide with CHB.5 Of those with CHB, kissing, hand holding, coughing, or sneezing.15
20% to 30% will develop complications including cirrhosis
or hepatocellular carcinoma. Each year, approximately 650 Perinatal transmission is the predominant mode of trans-
000 people die due to CHB. Ethnicity plays a role in dis- mission in high-prevalence areas. Horizontal transmission
ease progression; those of African descent have higher (i.e., child to child) in early childhood accounts for most
rates of developing HCC and do so at a younger age.10 cases of CHB in intermediate prevalence areas.16 Unpro-
tected sexual intercourse and intravenous drug use in
The degree of chronicity with HBV infection is inversely adults are the major routes of spread in low-prevalence
proportional to the age at which the virus was acquired. In areas like Canada.16
absence of PEP, if infected as a newborn, the likelihood of
chronic infection is 90% (Figure 1). Chronic infection oc-
curs in 20% to 60% of cases if infection occurs under the
age of ve and in < 5% if infected as adults11,12; most At the present time, there is no denitive cure for HBV
infections acquired during adulthood (w95%) do not infection. The goal of CHB treatment is to decrease he-
progress to chronic infection and resolve within a year patocyte histological damage by achieving sustained sup-
(Figure 2). pression of viral replication and, by doing so, to prevent
progression to cirrhosis, end-stage liver disease, HCC, and
MODE OF TRANSMISSION possibly death. Currently, the most effective strategy for
reducing HBV-related disease and death is through its
HBV is highly infectious, being 100 times more infectious prevention by immunization. Newborn and childhood
than HIV after a needle-stick exposure.13 The risk of immunization have signicantly reduced transmission;
acquiring HBV from a needle-stick injury ranges from 1% however, where available, immunization programs have
to 6% (source patient HBsAg-positive, HBeAg-negative) to been in existence for only a few decades. As such, the
22% to 40% (source patient HBsAg-positive, HBeAg- protective effect of immunization on the global burden of
positive).14 HBV is transmitted by percutaneous (i.e., HBV will be recognized only in time.
puncture through the skin) or mucous membrane exposure
to infected blood and, to a lesser degree, to other body CONSIDERATIONS IN PREGNANCY
uids15; HBV can also survive up to seven days on envi-
ronmental surfaces. Vertical transmission (mother to child) Overall, pregnancy is not known to alter the natural history
is the most common route of HBV transmission, but it can of HBV infection and HBV infection is not associated with
also be transmitted by having sex with an infected partner, increased risks of adverse pregnancy outcomes (except for
injection drug use, contact with blood or open sores of acute HBV infection in pregnancy e see below).

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Hepatitis B and Pregnancy

Figure 3. Risk of mother to child transmission according perinatal transmission have been 0% at maternal viral load
to maternal viral load < 106 copies/mL (200 000 IU/mL), 3.2% for 106-6.99
copies/mL (105-106 IU/mL), 6.6% for 107 copies/mL,
7.6% to 14.6% for 108 copies/mL (> 107 IU/mL) and
27.7% for 109 copies/mL, respectively (Figure 3).21,27

Antepartum transmission is rare but may occur with

antepartum haemorrhage, placental abruption, or threat-
ened preterm labour.28 Perinatal transmission has also
been associated with amniocentesis if maternal HBV DNA
is over 107 copies/mL.29 The mechanism for in-utero
HBV transmission is unknown, but HBV is found in the
villous capillary endothelial cells30 and the trophoblasts of
the placenta, supporting the hypothesis that breach of the
placental barrier is a mechanism for intra-uterine infection.


Acute hepatitis B infection during pregnancy usually results
Perinatal transmission remains the most common form of in a mild maternal illness and is not associated with
transmission of hepatitis B worldwide,17 and despite the
increased fetal mortality or teratogenicity. However,
availability of neonatal PEP, almost 70% of global births increased incidence of low birth weight and prematurity
remain at risk of hepatitis B infection.17
has been reported.31,32 Perinatal transmission rate in the
Perinatal transmission can occur in-utero or through the setting of acute HBV is 10% if maternal infection happens
process of labor and birth. Although the exact mechanism early in the pregnancy,32 but increases to 60% if maternal
of each of these modes of transmission is unknown, the infection occurs at or near the time of delivery.33
majority of perinatal transmission occurs predominantly at
or after birth based on the high protective efcacy of ASSESSMENT OF HBV INFECTION IN PREGNANCY
neonatal PEP (see below). In the absence of PEP, perinatal
transmission occurs in > 90% of deliveries where the The most common scenario that obstetric care providers
mother is HBeAg positive and in 15% of deliveries if the encounter is an asymptomatic pregnant woman found to
mother is HBeAg negative. be HBsAg positive on prenatal laboratory investigations. In
the absence of recent exposure or any symptoms of acute
The combination of HBIG and HBV immunization given hepatitis, most of these cases will represent a chronic rather
within 12 hours of birth has effectively reduced the rate of than acute HBV infection. Obstetric care providers should
perinatal transmission from > 90% to < 10%.11,18 arrange for HBeAg, anti-HBe, HBV DNA level, ALT, and
ultrasound of the liver for all HBsAg-positive pregnant
Despite appropriate neonatal PEP, perinatal transmission patients and arrange for specialist referral (see below) for
still occurs in approximately 2% of infants.19,20 Most of the purposes of maternal health and perinatal HBV
these cases occur in HBeAg-positive women with very high transmission risk stratication. In rural and remote areas in
viral loads, generally > 200 000 IU/mL (> 106 copies/ Canada where referral is not feasible or possible, expert
mL).21e23 advice should be obtained by phone or telehealth.
Several factors increase the risk of perinatal transmission, Referral to an adult hepatologist or infectious disease
such as maternal HBeAg, high HBV DNA viral loads, specialist is recommended for all newly diagnosed CHB
resistant virus, HBV genotype, and incomplete or off infections, including those diagnosed during pregnancy.
schedule PEP.24,25 HBV DNA level is the strongest single Only 20% of pregnant women with CHB receive appro-
risk factor driving perinatal transmission, even in the priate specialist care within a year after pregnancy.34
setting of appropriate neonatal PE.23,26 Even after
adjusting for several other factors, maternal viral load re- Newly diagnosed CHB infections require assessment for
mains the strongest predictor of perinatal transmission at other causes of liver disease, co-infections, and complica-
an adjusted odds ratio of 3.49 for each log10 copy/ml in- tions such as cirrhosis and HCC (see Table 3 for recom-
crease on maternal HBV viral load.27 Reported rates of mended investigations). CHB-related cirrhosis and portal

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Treatment for Maternal Health

Table 3. Recommended investigations for patients with a
new diagnosis of CHB including pregnant women Women known to have CHB prior to pregnancy should be
HBeAg and antibody status (anti-HBe, an indirect marker of lower evaluated and treated according to adult guidelines.36,37
levels of viraemia and infectivity) Similarly, pregnant women for whom treatment is indi-
HBV DNA level (quantitative direct measure of level of viraemia and cated for their own health should not have treatment
infectivity) withheld or interrupted during pregnancy.
IgM antibody to hepatitis B core antigen (evidence of recent infection
with HBV) If a pregnant woman remains untreated during pregnancy or
Hepatitis C virus antibody, hepatitis delta virus antibody, HIV discontinues HBV treatment during pregnancy or soon after
antibody, HAV antibody birth, close monitoring is necessary as there is a risk of
ALT, g-glutamyltransferase, serum albumin, total bilirubin, total hepatitis ares, especially in the postpartum period.38
globulins, full blood count, and prothrombin time
Postpartum HBV ares have been observed in up to 25%
Abdominal ultrasound for signs of cirrhosis, portal hypertension, and of women with CHB,39 and are thought to reect immune
reconstitution. HBV ares appear to be more common in
Surveillance for hepatocellular carcinoma with a-fetoprotein testing
after pregnancy women who are HBeAg positive,39 and among women
IgM, immunoglobulin.
undergoing HBeAg seroconversion. Flares can be asymp-
tomatic and only detected by liver enzyme elevation; up to
50% of women may have mild to severe fatigue, nausea, loss
hypertension are usually seen after the 4th or 5th decade, of appetite, jaundice, and right upper quadrant pain.
but they have been reporteddalbeit rarelydamong
women of reproductive age. Pregnancies complicated by Treatment for the Prevention of Perinatal
detection of cirrhosis and/or portal hypertension are Transmission
associated with severe maternal morbidity and mortality.35 Antiviral therapy with a nucleoside reverse transcriptase
Specialist referral needs to be expedited if there are any inhibitors, starting between 28 to 32 weeks GA, is rec-
signs of chronic liver disease on exam, abnormal ALT, ommended to reduce the risk of HBV perinatal trans-
detectable HBV DNA viral load and cirrhosis, or changes mission among HBsAg-positive pregnant women with an
suggestive of portal hypertension on ultrasound. Transient HBV DNA level > 200 000 IU/mL (> 106 copies/mL).36
elastography, a highly accurate, ultrasound-like, non-inva- Several studies done in settings where post exposure pro-
sive imaging technique that maps the elastic properties of phylaxis is routine showed no perinatal transmission where
soft tissue and is widely used for the detection cirrhosis, is mothers viral loads were < 106 copies/mL (< 200 000 IU/
currently not recommended for maternal assessment of mL).21,22,26 The same threshold was found in a meta-
CHB complications during pregnancy, as its safety and analysis of lamivudine for the prevention of perinatal
performance have not been established in pregnancy. transmission.26 Perinatal transmission has been documented
at higher HBV DNA viral load levels (see section above on
Obstetric care providers should be aware that women of perinatal transmission). A recent meta-analysis of 26 studies
African origin exhibit higher rates of HCC than other that incorporated data from 3622 women, demonstrated a
CHB-infected women and do so at a younger age.10 Adult 70% reduction in perinatal transmission (infant HBsAg at 6
guidelines recommend surveillance for HCC for African to 12 months, relative risk 0.3; 95% CI 0.2 to 0.4 or infant
patients starting at age 20 with periodic serum alpha- HBV DNA seropositivity at 6 to 12 months, relative risk
fetoprotein determinations and liver ultrasounds. Alpha- 0.3; 95% CI 0.2 to 0.5) with any antiretroviral use (lam-
fetoprotein is physiologically elevated during pregnancy, ivudine, tenofovir, and telbivudine) in the third trimester
consequently complete HCC surveillance needs to be de- among infants who received neonatal PEP.40
ferred to the postpartum period.
Choice of Antiviral Treatment
TREATMENT OF HBV INFECTION IN PREGNANCY At the present time, tenofovir represents the most
reasonable choice for treating pregnant women with HBV
Indications for antiviral treatment infection for either maternal or infant benet, as it is the
Antiviral treatment against HBV infection during pregnancy most potent nucleoside analogue with the lowest rate of
should be considered for two different reasons: a) for genotypic resistance,36,37 and available safety data for use
maternal health and b) for the prevention of perinatal during pregnancy.
transmission among those at the greatest risk of PEP failure
due to high HBV DNA viral loads. Treatment indications Tenofovir is a nucleoside reverse transcriptase inhibitor,
apply both to acute and chronic hepatitis B infections. FDA category B drug. The standard dosage of tenofovir is

6 l - JOGC - 2016
Hepatitis B and Pregnancy

300 mg po once a day. It is started between 28 and 32 Perinatal Precautions and Mode of Delivery
weeks of pregnancy and continued until delivery. To Most cases of perinatal transmission occur when the infant
minimize the possibility of hepatitis ares post-partum,39 comes into contact with infected vaginal blood and se-
continuation of tenofovir until 4 to 12 weeks postpartum cretions at the time of delivery, so invasive procedures like
could be considered. internal fetal monitors, episiotomy, and/or operative
vaginal delivery can theoretically increase the risk of
Lamivudine has been studied most often for the pre- transmission. Premature rupture of membranes has been
vention of HBV perinatal transmission. It is recognized quoted as a risk factor for HBV transmission; however,
now that the use of this drug limits maternal future data have been inconsistent.20,49 Neonatal PEP should
treatment options as even short term use promotes ameliorate these risks, yet these factors should be consid-
lamivudine-resistant viral variants in at least 20% of ered during labour of women at the highest risk of peri-
users.41 Telbivudine is a synthetic thymidine nucleoside natal transmission (i.e., high HBV DNA viral loads).
analog and is a reverse transcriptase inhibitor, which also
acts to inhibit HBV DNA replication. Telbivudine has Cesarean delivery should not be performed for the sole
been reported to have better efcacy than lamivudine in indication of preventing perinatal transmission, as benet
clinical trials and is a FDA category B drug. There is no has not been found in well-conducted controlled trials.50,51
high-quality evidence comparing lamivudine, tenofovir,
and telbivudine. Breastfeeding
Breastfeeding does not pose an additional risk of HBV
Safety of Antiretrovirals During Pregnancy and infection, even without neonatal vaccination52,53; hence,
Lactation mothers with chronic hepatitis B infection who wish to
The safety prole of lamivudine, tenofovir, and telbivudine breastfeed should be encouraged to do so. Even though
has been reported by the Antiretroviral Pregnancy Regis- HBV DNA can be detected in breast milk, best available
try42 and by MotherRisk. The overall rate of congenital evidence has not documented an increased risk of vertical
anomalies with lamivudine and tenofovir is 2.8% (CI 2.5% HBV transmission among breastfed infants compared to
to 3.2%) which is similar and not signicantly different bottle-fed infants.52 Mothers with CHB who are breast-
from the baseline population risk.40 Despite the reassuring feeding should be advised to exercise care to prevent
safety proles, to date, no treatments have been approved bleeding from cracked nipples and to seek medical atten-
for the prevention of maternal to child transmission of tion if they do so.
hepatitis B by either Health Canada or the United States
Women who require continuation of HBV antiviral treat-
ment for their own health and wish to breastfeed should be
A recent study among infants born to HIV-infected supported based on available data and despite controversy
mothers reported that whole-body bone mineral content surrounding lactation while on tenofovir (see above).
among tenofovir-exposed infants was 12% lower Continuation of antiviral treatment should also be
compared to un-exposed infants.43 The long-term clinical considered for women likely to develop postpartum HBV
signicance of these changes is unknown, as no difference ares. Specialist (gastroenterology, infectious diseases, or
was seen in growth in prior studies,44 and differences were hepatology) input is needed to determine whether a
not apparent by two years of age.45 Most of these data are woman should continue therapy or not.
derived from studies of HIV-infected women on tenofovir,
and whether these results are applicable to HBV-infected OTHER ASPECTS OF MATERNAL CARE
women with third-trimester exposures is unknown.
Hepatitis B immunization is acceptable for use in pregnancy.
Lactation data for tenofovir are limited, but tenofovirs Pregnant women who are not immune to HBV maybe be
pharmacokinetic properties predict close to zero breast- vaccinated, and those who are at risk of HBV infection
milk levels. Tenofovir has been detected in breast milk, should be vaccinated during pregnancy (HBsAg-positive sex
but at negligible concentrations (0.03% of the recom- partner, evaluated or treated for a sexually transmitted dis-
mended pediatric dose).46,47 Furthermore, infants expo- ease, recent or current injection drug use, etc.).
sure to tenofovir from breastmilk is lower than exposure
in-utero.48 Pregnant women with CHB found to be susceptible to
hepatitis A should be offered HAV immunization, because
The safety of entecavir in pregnancy is not known, and HAV can follow a severe clinical course in pregnancy and
interferon therapy is contraindicated. another viral hepatitis results in compounded morbidity.

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Pregnancy also constitutes a window of opportunity for It is essential that we, as obstetric providers, encourage
prevention and education: women with CHB should be mothers with CHB to have their infants complete their
counseled against using hepatotoxic substances including HBV immunizations. In a recent cohort from British
prescription and over-the-counter medications, herbals, Columbia, only 79% received complete PEP, and 24% did
and alcohol even when not pregnant. They should be also not receive appropriate testing after PEP or were lost to
be counseled regarding risk of transmission to other family follow-up.8
and household members. Sexual partners and household
members should be evaluated for HBV status and referred PRIMARY PREVENTION IN CANADA
for immunization as appropriate.
In 1992, the World Health Organization recommended
that all countries include hepatitis B vaccine in their routine
immunization program. Canada has embraced this
recommendation: some provinces immunize during in-
As with the non-pregnant patient, susceptible patients fancy and others in pre-adolescence. However, current
exposed to HBV should receive HBIG and start the evidence suggests that directing hepatitis B immunization
hepatitis B vaccine series. Patients who become pregnant resources towards universal immunization of infants pro-
while receiving the vaccine series must be encouraged to vides the best protection at the most relevant age. Delaying
complete the series. Due to common mode of trans- HBV immunization until adolescence misses the critical
mission, HIV testing is recommended for all women with time period when risk of acquisition is the greatest (90%
documented hepatitis and all exposures to hepatitis B or C. vs. 5%), and the long-term risk of sequelae is higher.57 The
Canadian Paediatric Society has published a position
statement, calling for the harmonization of immunization
schedules in Canada and advocating for universal HBV
The most effective means to prevent perinatal transmission immunization during infancy.58 The Society of Obstetri-
is through neonatal PEP. PEP includes HBIG and re- cians and Gynaecologists of Canada agree with this posi-
combinant hepatitis B immunization series starting at birth. tion statement and echo the call for a harmonized
This regimen has been shown to be up to 95% effective in immunization schedule in Canada.
preventing perinatal transmission of hepatitis B.54
HBIG provides immediate protection through passive
immunity; the dose for newborns is 0.5 mL intramuscu- World Health Organization
larly. The rst immunization should be given within the
rst 12 hours of life; the dose is 0.5 mL intramuscularly Canadian Paediatric Society
and should be given at the same time as HBIG, but in Canadian Association for the Study of the Liver Consensus
different sites. Guidelines
In Canada, there are several authorized hepatitis B im-
munization schedules, so timing of second and third doses
can differ among provinces. In general, the second and
third vaccine should be given at approximately one month
1. Mast E, Margolis H, Fiore A, Brink E, Goldstein S, Wang S.
and six months of life (with at least four weeks between the A comprehensive immunization strategy to eliminate transmission of
rst and second vaccine, two months between the second hepatitis B virus infection in the United States: recommendations of the
and third vaccine, and four months between the rst and Advisory Committee on Immunization Practices (ACIP) part 1:
immunization of infants, children, and adolescents. MMWR Recomm Rep
third vaccine).55 Infants born to hepatitis B-positive 2005;54:1e31.
women and who are preterm or less than 2000 g require 2. USPSTF. Screening for hepatitis B virus infection in pregnancy: U.S.
four doses of vaccine.55 Preventive Services Task Force reafrmation recommendation statement.
Ann Intern Med 2009;150:869e73. W154.
HBsAg and anti-HBs need to be performed on the baby 1 3. Dionne-Odom J, Tita AT, Silverman NS. #38: Hepatitis B in pregnancy
to 4 months after completion of the hepatitis B vaccine screening, treatment, and prevention of vertical transmission. Am J
Obstet Gynecol. 2016 Jan;214(1):6e14. http://dx.doi.org/10.1016/j.ajog.
series and at age no younger than 9 to 12 months to 2015.09.100. Epub 2015 Oct 8.
determine if the child developed a protective immune
4. Chu CJ, Keeffe EB, Han SH, Perrillo RP, Min AD, Soldevila-Pico C, et al.
response to vaccination or if further management for Prevalence of HBV precore/core promoter variants in the United States.
hepatitis B infection is required.56 Hepatology 2003;38:619e28.

8 l - JOGC - 2016
Hepatitis B and Pregnancy

5. Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of 25. Wu TW, Lin HH, Wang LY. Chronic hepatitis B infection in adolescents
hepatitis B virus infection: new estimates of age-specic HBsAg who received primary infantile vaccination. Hepatology 2013;57:37e45.
seroprevalence and endemicity. Vaccine 2012;30:2212e9.
26. Han L, Zhang HW, Xie JX, Zhang Q, Wang HY, Cao GW. A meta-analysis
6. Wong WW, Minuk GY. A cross-sectional seroepidemiologic survey of of lamivudine for interruption of mother-to-child transmission of hepatitis
chronic hepatitis B virus infections in Southeast Asian immigrants B virus. World J Gastroenterol 2011;17:4321e33.
residing in a Canadian urban centre. Clin Invest Med 1994;17:443e7.
27. Wen WH, Chang MH, Zhao LL, Ni YH, Hsu HY, Wu JF, et al. Mother-to-
7. Plitt SS, Somily AM, Singh AE. Outcomes from a Canadian public health infant transmission of hepatitis B virus infection: signicance of maternal
prenatal screening program for hepatitis B: 1997-2004. Can J Public viral load and strategies for intervention. J Hepatol 2013;59:24e30.
Health 2007;98:194e7. 28. Lin HH, Lee TY, Chen DS, Sung JL, Ohto H, Etoh T, et al. Transplacental
8. van Schalkwyk J, Nourmoussavi M, Massey A, Gustafson R, Brodkin E, leakage of HBeAg-positive maternal blood as the most likely route in
Petric M, et al. Missed opportunities for prevention of perinatal causing intrauterine infection with hepatitis B virus. J Pediatr
transmission of hepatitis B: a retrospective cohort study. Can J 1987;111:877e81.
Gastroenterol Hepatol 2014;28:525e8. 29. Yi W, Pan CQ, Hao J, Hu Y, Liu M, Li L, et al. Risk of vertical transmission
9. Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and of hepatitis B after amniocentesis in HBs antigen-positive mothers.
current and emerging prevention and control measures. J Viral Hepat J Hepatol 2014;60:523e9.
2004;11:97e107. 30. Xu DZ, Yan YP, Choi BC, Xu JQ, Men K, Zhang JX, et al. Risk factors and
10. Kew MC. Hepatocellular carcinoma in African Blacks: recent progress in mechanism of transplacental transmission of hepatitis B virus: a case-
etiology and pathogenesis. World J Hepatol 2010;2:65e73. control study. J Med Virol 2002;67:20e6.
31. Jonas MM. Hepatitis B and pregnancy: an underestimated issue. Liver Int
11. McMahon BJ. The natural history of chronic hepatitis B virus infection.
2009;29(Suppl 1):133e9.
Hepatology 2009;49:S45e55.
32. Hieber JP, Dalton D, Shorey J, Combes B. Hepatitis and pregnancy.
12. Hoofnagle JH, Doo E, Liang TJ, Fleischer R, Lok AS. Management of J Pediatr 1977;91:545e9.
hepatitis B: summary of a clinical research workshop. Hepatology
2007;45:1056e75. 33. Sookoian S. Liver disease during pregnancy: acute viral hepatitis. Ann
Hepatol 2006;5:231e6.
13. Gerberding JL. Incidence and prevalence of human immunodeciency
virus, hepatitis B virus, hepatitis C virus, and cytomegalovirus among 34. Chang MS, Tuomala R, Rutherford AE, Mutinga ML, Andersson KL,
health care personnel at risk for blood exposure: nal report from a Burman BE, et al. Postpartum care for mothers diagnosed with hepatitis
longitudinal study. J Infect Dis 1994;170:1410e7. B during pregnancy. Am J Obstet Gynecol 2015;212:365.e1e7.
14. Sepkowitz KA. Occupationally acquired infections in health care workers. 35. Shaheen AA, Myers RP. The outcomes of pregnancy in patients with
Part II. Ann Intern Med 1996;125:917e28. cirrhosis: a population-based study. Liver Int 2010;30:275e83.

15. CDC. Centers for Disease Control and Prevention. Hepatitis B: 36. Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH,
Information for Health Professionals 2015. Saunders; 28th August 2014. American Association for the Study of Liver Diseases. AASLD guidelines
p. 3904. Hardcover ISBN: 9781455748013, eBook ISBN: 9780323263733. for treatment of chronic hepatitis B. Hepatology 2016;63:261e83.

16. Thio C, Hawkins C. Hepatitis B virus and hepatitis Delta virus. In: J B, R D, 37. Cofn CS, Fung SK, Ma MM, Canadian Association for the Study of the
M B, editors. Mandell, Douglas, and Bennetts Principles and Practice of Liver. Management of chronic hepatitis B: Canadian Association for the
Infectious Diseases. Saunders; 2014. 1815e1830.e7. Study of the Liver consensus guidelines. Can J Gastroenterol
17. WHO. Guidelines for the prevention, care and treatment of persons with
chronic hepatitis B infection. In: WHO, editor. Global Hepatitis 38. ter Borg MJ, Leemans WF, de Man RA, Janssen HL. Exacerbation of
Programme - Department of HIV/AIDS. 2015. http://www.who.int/hiv/ chronic hepatitis B infection after delivery. J Viral Hepat 2008;15:37e41.
pub/hepatitis/hepatitis-b-guidelines/en/. 39. Giles M, Visvanathan K, Lewin S, Bowden S, Locarnini S, Spelman T, et al.
Clinical and virological predictors of hepatic ares in pregnant women with
18. Ceci O, Margiotta M, Marello F, Francavilla R, Loizzi P, Francavilla A, et al.
chronic hepatitis B. Gut 2015;64:1810e5.
Vertical transmission of hepatitis C virus in a cohort of 2,447 HIV-
seronegative pregnant women: a 24-month prospective study. J Pediatr 40. Brown Jr RS, McMahon BJ, Lok AS, Wong JB, Ahmed AT, Mouchli MA,
Gastroenterol Nutr 2001;33:570e5. et al. Antiviral therapy in chronic hepatitis B viral infection during
pregnancy: A systematic review and meta-analysis. Hepatology
19. del Canho R, Grosheide PM, Schalm SW, de Vries RR, Heijtink RA. Failure 2016;63:319e33.
of neonatal hepatitis B vaccination: the role of HBV-DNA levels in hepatitis
B carrier mothers and HLA antigens in neonates. J Hepatol 1994;20:483e6. 41. Ayres A, Yuen L, Jackson KM, Manoharan S, Glass A, Maley M, et al. Short
duration of lamivudine for the prevention of hepatitis B virus transmission
20. Song YM, Sung J, Yang S, Choe YH, Chang YS, Park WS. Factors in pregnancy: lack of potency and selection of resistance mutations. J Viral
associated with immunoprophylaxis failure against vertical transmission of Hepat 2014;21:809e17.
hepatitis B virus. Eur J Pediatr 2007;166:813e8.
42. Brown Jr RS, Verna EC, Pereira MR, Tilson HH, Aguilar C, Leu CS, et al.
21. Zou H, Chen Y, Duan Z, Zhang H, Pan C. Virologic factors associated with Hepatitis B virus and human immunodeciency virus drugs in pregnancy:
failure to passive-active immunoprophylaxis in infants born to HBsAg- ndings from the Antiretroviral Pregnancy Registry. J Hepatol
positive mothers. J Viral Hepat 2012;19:e18e25. 2012;57:953e9.
22. Wiseman E, Fraser MA, Holden S, Glass A, Kidson BL, Heron LG, et al. 43. Siberry GK, Jacobson DL, Kalkwarf HJ, Wu JW, DiMeglio LA, Yogev R,
Perinatal transmission of hepatitis B virus: an Australian experience. Med J et al. Lower Newborn Bone Mineral Content Associated With Maternal
Aust 2009;190:489e92. Use of Tenofovir Disoproxil Fumarate During Pregnancy. Clin Infect Dis
23. Kubo A, Shlager L, Marks AR, Lakritz D, Beaumont C, Gabellini K, et al.
Prevention of vertical transmission of hepatitis B: an observational study. 44. Siberry GK, Williams PL, Mendez H, Seage 3rd GR, Jacobson DL,
Ann Intern Med 2014;160:828e35. Hazra R, et al. Safety of tenofovir use during pregnancy: early growth
outcomes in HIV-exposed uninfected infants. AIDS (London, England)
24. Singh AE, Plitt SS, Osiowy C, Surynicz K, Kouadjo E, Preiksaitis J, et al. 2012;26:1151e9.
Factors associated with vaccine failure and vertical transmission of
hepatitis B among a cohort of Canadian mothers and infants. J Viral Hepat 45. Gibb DM, Kizito H, Russell EC, Chidziva E, Zalwango E, Nalumenya R,
2011;18:468e73. et al. Pregnancy and Infant Outcomes among HIV-Infected Women Taking

- JOGC - 2016 l 9

Long-Term ART with and without Tenofovir in the DART Trial. PLoS 52. Hill JB, Shefeld JS, Kim MJ, Alexander JM, Sercely B, Wendel GD. Risk of
Medicine 2012;9:e1001217. hepatitis B transmission in breast-fed infants of chronic hepatitis B carriers.
Obstet Gynecol 2002;99:1049e52.
46. Benaboud S, Pruvost A, Cofe PA, Ekouvi DK, Urien S, Arriv E, et al.
Concentrations of tenofovir and emtricitabine in breast milk of HIV-1- 53. Beasley R, Stevens C, Shiao I, Meng H. Evidence against breast-feeding as a
infected women in Abidjan, Cte dIvoire, in the ANRS 12109 TEmAA mechanism for vertical transmission of hepatitis B. Lancet 1975;2:740e1.
Study, Step 2. Antimicrobial Agents Chemother 2011;55:1315e7.
54. Lee C, Gong Y, Brok J, Boxall EH, Gluud C. Effect of hepatitis B
47. Corbett AH, Kayira D, White NR, Davis NL, Kourtis AP, Chasela C, et al. immunisation in newborn infants of mothers positive for hepatitis B
Antiretroviral pharmacokinetics in mothers and breastfeeding infants from surface antigen: systematic review and meta-analysis. BMJ
6 to 24 weeks post-partum: results of the BAN Study. Antivir Ther 2006;332:328e36.
55. PHAC. Canadian Immunization Guide. Part 4: Active Vaccines. Hepatitis B
48. Ehrhardt S, Xie C, Guo N, Nelson K, Thio CL. Breastfeeding while taking Vaccine. In: Canada PHAo, editor. Public Health Agency of Canada; 2015.
lamivudine or tenofovir disoproxil fumarate: a review of the evidence. Clin http://healthycanadians.gc.ca/publications/healthy-living-vie-saine/4-
Infect Dis 2015;60:275e8. canadian-immunization-guide-canadien-immunisation/index-eng.php?
49. Chen LZ, Zhou WQ, Zhao SS, Liu ZY, Wen SW. A nested case-control
study of maternal-neonatal transmission of hepatitis B virus in a Chinese 56. CDC. Update: Shortened interval for postvaccination serologic testing of
population. World J Gastroenterol 2011;17:3640e4. infants born to hepatitis B-infected mothers. MMWR Morb Mortal Wkly
Rep 2015;64:118e20.
50. Wang J, Zhu Q, Zhang X. Effect of delivery mode on maternal-infant
transmission of hepatitis B virus by immunoprophylaxis. Chin Med J 57. Mackie CO, Buxton JA, Tadwalkar S, Patrick DM. Hepatitis B
(Engl) 2002;115:1510e2. immunization strategies: timing is everything. CMAJ 2009;180:196e202.
51. Yang J, Zeng XM, Men YL, Zhao LS. Elective caesarean section versus 58. MacDonald NE, Bortolussi R. A harmonized immunization schedule for
vaginal delivery for preventing mother to child transmission of hepatitis Canada: A call to action. Paediatr Child Health 2011;16(1):29e31. https://
B virusea systematic review. Virology Journal 2008;5:100. www.ncbi.nlm.nih.gov/pmc/articles/PMC3043020/.

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