European Journal of Obstetrics & Gynecology and Reproductive Biology 169 (2013) 17–23

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European Journal of Obstetrics & Gynecology and

Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb

Review

Towards complete eradication of hepatitis B infection from perinatal

transmission: review of the mechanisms of in utero infection and the use of
antiviral treatment during pregnancy
K.W. Cheung *, M.T.Y. Seto, S.F. Wong
Department of Obstetrics and Gynaecology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China

A R T I C L E I N F O A B S T R A C T

Article history: Hepatitis B infection remains the most common form of chronic hepatitis. Mother to child transmission
Received 29 September 2012 occurs despite immunoprophylaxis with vaccination and immunoglobulin. In utero infection is
Received in revised form 27 December 2012 suggested to account for most of the cases with immunoprophylaxis failure. Infants who suffer from
Accepted 3 February 2013
hepatitis B infection at birth have a higher risk of becoming chronic carriers and may develop liver
cirrhosis or hepatocellular carcinoma in the future. Infected germ cells, transplacental infection, invasive
Keywords: prenatal diagnostic tests and various perinatal factors are possible factors leading to in utero infection
Hepatitis B virus
and subsequent immunoprophylaxis failure. Hepatitis B e antigen positive status and high viral load
Pregnancy
Infection transmission
increase the risk of immunoprophylaxis failure. Recent evidence shows promising results regarding the
Maternal–foetal use of antiviral treatment in late gestation to suppress viral load, so as to decrease the risk of vertical
Antiviral agent transmission. This review discusses the possible mechanisms of in utero infection and the use of antiviral
Immunization treatment during pregnancy.
ß 2013 Elsevier Ireland Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
2. Pathophysiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
3. Chronic hepatitis B infection and pregnancy . . . . . . . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
4. Vertical transmission: infection of the gametes and in utero infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
5. Importance of HBeAg status and maternal viraemia . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
6. Antiviral treatment during pregnancy . . . . . . . . . . . . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
6.1. Safety. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
6.2. Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
7. Follow up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
8. Future perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

1. Introduction

Abbreviations: CDC, Centers for Disease Control; HBV, hepatitis B virus; HBsAg,
hepatitis B surface antigen; HBeAg, hepatitis B e antigen; HBIG, hepatitis B
immunoglobulin; DNA, deoxyribonucleic acid; ALT, alanine amniotransferase;
HBcAg, hepatitis B core antigen; RNA, ribonucleic acid; HIV, human immunodefi-
ciency virus; FDA, Food and Drug Administration; APR, Antiretroviral Pregnancy
Registry; RCT, randomised controlled trial.
* Corresponding author at: 6/F, Professorial Block, Queen Mary Hospital, 102
Pokfulam Road, Hong Kong, China. Tel.: +852 92833029; fax: +852 28550947.
E-mail addresses: kelvincheung82@hotmail.com, kawangcheung@gmail.com
(K.W. Cheung).
Globally, hepatitis B virus (HBV) infection is the most common
form of chronic hepatitis. According to the World Health
Organization, more than 2 billion people have been infected with
HBV at some time, about 350 million people remain chronically
infected, 600,000 people die each year due to HBV and 25% of
chronic carriers since childhood later die from cirrhosis or liver
cancer [1]. In high endemic areas, like the central Asian republics,
Southeast Asia, Sub-Saharan Africa and the Amazon basin, the

0301-2115/$ – see front matter ß 2013 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ejogrb.2013.02.001
18 K.W. Cheung et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 169 (2013) 17–23
carrier rate is 8–20%. In low endemic areas, like North America,
Western and Northern Europe, Australia and parts of South
America, the carrier rate is less than 2%. The carrier rate is 2–8% in
the Middle East, some Eastern European countries and the
Mediterranean basin [2,3].
HBV infection can be acquired through vertical or horizontal
transmission. The chance of chronic infection depends on the age
of exposure, and the risk is highest during the perinatal period.
Ninety percent of newborns, 50% of 3-year-old children and 5%
of adults will become chronic carriers after HBV exposure [4].
Before the era of universal hepatitis B vaccination, the risk of a child
becoming a chronic carrier was about 10%–30% if born of a mother
who is hepatitis B surface antigen positive (HBsAg) (+) but hepatitis
B e antigen negative (HBeAg) ( ), and up to 90% if HBeAg (+) [5,6].
Due to the high vulnerability and subsequent long term
complications from perinatal infection, strategies targeting the
elimination of vertical transmission are needed. HBV vaccination
and hepatitis B immunoglobulin (HBIG) have been introduced into
the national immunization programme in various countries and
have dramatically decreased the incidence of HBV infection (75–
90% drop in carrier rate), cirrhosis and hepatocellular carcinoma
[7–14]. This great success, however, does not result in complete
eradication of HBV disease because of in utero infection and
immunoprophylaxis failure.
The management of chronic HBV infection in pregnancy is
difficult and challenging. Recent evidence shows promising results
regarding the use of antiviral treatment in late gestation to
suppress viral load, so as to decrease the risk of vertical
transmission. The objectives of this review are to discuss the
possible mechanisms of in utero infection and the use of antiviral
treatment during pregnancy.
2. Pathophysiology
Hepatitis B disease is caused by an enveloped virus containing a
partially double-stranded, circular deoxyribonucleic acid (DNA)
genome and classified within the family hepadnavirus [1,2]. The
virus is spherical with a diameter of 42 nm. Intracellular HBV is not
cytopathic [15]. It replicates in hepatocytes and interferes with
hepatic functions. In order to eradicate the virus, the immune
system, particularly the cytotoxic T cell, is activated to fight against
the HBV protein-producing cells [2]. This results in inflammatory
reaction and cellular damage.
HBeAg is usually produced during replication and is
associated with high HBV DNA levels and varying degrees of
hepatic inflammation. Seroconversion from HBeAg (+) to ( ), or
even anti-HBe (+) can occur spontaneously, and is accompanied
by flare-up of hepatitis, elevation of alanine amniotransferase
(ALT) and presence of cellular necrosis. HBeAg (+) status
represents active viral replication which accounts for the
increased risk of transmission. HBV does not cross the placenta
while maternal HBeAg can pass through the placenta because of
its small size [16]. Maternal transfer of HBeAg through the
placenta induces T cell intolerance in utero. Due to the high
crossreactivity between HBeAg and hepatitis B core antigen
(HBcAg) in terms of T helper cell recognition, in utero exposure
to HBeAg may lead to foetal immunotolerance to HBeAg and
HBcAg [17,18]. This may lead to persistent HBV infection after
delivery.
3. Chronic hepatitis B infection and pregnancy
Women with chronic hepatitis B infection usually cope well
during pregnancy. In one study, there were no differences in the
gestational age at delivery, incidence of premature prelabour
rupture of membranes, small for gestational age, neonatal
jaundice, congenital anomalies and perinatal mortality [19].
Another study showed increased risks of gestational diabetes,
antepartum haemorrhage, threatened preterm labour and lower
Apgar scores [20].
During pregnancy, the immune system is modified to prevent
foetal rejection. There is a shift from helper T cell type 2
response with increased regulatory T cells [21]. Peripartum
reactivation of HBV leading to maternal death has been reported
[22]. Knowledge of HBV activity during pregnancy and
peripartum period would be crucial to facilitate the manage-
ment of these women. In one retrospective study, the HBV DNA
level and ALT were monitored serially in 33 HBsAg (+) mothers,
of whom 9 were HBeAg (+) [23]. HBV DNA level increased by a
mean of 0.4 log in late pregnancy or early postpartum, of which
four HBeAg ( ) mothers had >1 log change during pregnancy.
ALT level was significantly increased after delivery irrespective
of the HBeAg status. Similarly, flare-up of HBV within six
months of delivery was observed in another retrospective study
(defined by 3 increase in ALT) in 45% of women, and up to 62%
if lamvidine was started in the third trimester and stopped
immediately after delivery [24]. Unfortunately, no predictive
factor could be identified for postpartum HBV flare-up. The
median HBV DNA level increased during pregnancy and
decreased significantly after delivery [24]. One study showed
that postpartum HBV DNA level was static, increased or
decreased in one third of women respectively [25].
The immunosuppressive effect resulting from the increase in
adrenal corticosteroid in late gestation may account for the
postpartum exacerbation. The rapid withdrawal of cortisol after
delivery is similar to the effect of withdrawal of steroid treatment
in non-pregnant women, which results in reactivation of immune
response and elevation of ALT by the inflammatory process. This
could be accompanied by HBeAg seroconversion as shown by a
prospective study in which postpartum seroconversion was found
in 12.5% of 40 HBeAg (+) women [26].
4. Vertical transmission: infection of the gametes and in utero
infection
The possibility of vertical transmission via the germ line was
first proposed by Hadchouel et al. who detected HBV DNA in
seminal fluid and integrated HBV DNA in spermatozoa [27]. HBV
was shown to be able to enter male germ lines and integrate into
their genome, by visualizing the integration of HBV DNA
sequences into sperm chromosomes of HBV carriers using
fluorescent in situ hybridization [28]. Ali et al. detected HBV
genes in 1- and 2-cell embryos from zona-free hamster oocytes
fertilized in vitro with human sperms carrying HBV DNA
plasmid [29]. It suggested the possibility of human sperm
being a vector for HBV genes and accounted for the vertical
transmission. HBsAg, HBcAg and HBV DNA were found to be
expressed in different stages of ova and granular cells of ovaries,
using immunohistochemical staining and in situ hybridization
respectively, in surgically removed ovarian tissues from HBV
carriers [30]. The risk of oocyte or embryo infection was
correlated with maternal HBV DNA levels and HBeAg status
[31,32]. Nie et al. studied 72 couples for detection of HBV DNA
and RNA in oocytes and embryos. HBV DNA or RNA were
detected in the embryos of male HBsAg (+)/female HBsAg ( )
couples or male HBsAg ( )/female HBsAg (+) couples. They
found a 7.7% oocyte/embryo infection rate in maternal carriers,
and the risk increased to 50–100% if the mother was HBeAg (+)
or with detectable HBV DNA [31]. Hu et al. later also showed the
risk of oocyte or embryo infection correlated with maternal HBV
DNA levels using 6 log 10 copies/ml as cut-off [32]. These may
explain the increased vertical transmission and failure of
 K.W. Cheung et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 169 (2013) 17–23
immunoprophylaxis resulting from infected germ cells in
women who had high viral loads.
Transplacental transmission is possible during pregnancy [33–
36]. In a study of 402 HBsAg (+) mothers in China, Xu et al. found
that 3.7% of their newborn were HBsAg (+) within 24 h of birth. Of
the women who were HBeAg (+), the in utero infection rate was
9.8%. Analysis of 101 placental tissues from HBsAg (+) mothers for
HBsAg, HBcAg, and HBV DNA uncovered an overall placental
infection rate of 44.6% [33]. In other studies, the detection rate of
HBsAg, HBcAg, HBV DNA and the proportion of affected cells
gradually decreased from the maternal side to the foetal side, from
decidual cells, trophoblastic cells, villous mesenchymal cells to
villous capillary endothelial cells [34,35]. The risk of in utero HBV
infection was shown to be closely related to the proportion of
affected layers of placental cells, especially if the villous capillary
cells were infected. This suggested that ‘‘cellular transfer’’ of HBV
through the placenta may lead to in utero infection [34]. However,
6.8% of placentae were found to have reversed distribution which
may indicate that the foetus was infected first, followed by
different placental layers, suggesting routes of transmission other
than transplacental could be possible [35].
Theoretically, there should be an increased risk of vertical
transmission due to the possibility of foetal contamination by
maternal blood during prenatal invasive tests. Limited literature so
far did not confirm this assumption [37–41]. Lopez et al. reviewed
5 trials regarding the risk of vertical transmission after amniocen-
tesis. Only one study showed a non significant higher risk in HBeAg
(+) mothers [37] while others did not demonstrate transmission in
83 cases with amniocentesis done [41]. Amniocentesis was not
shown to increase the risk of in utero infection. It is therefore
generally considered to be acceptable after detailed counselling.
Further study would be needed to clarify the risk of transmission
during invasive procedures in HBeAg (+) or HBV DNA positive
mothers.
As the use of vaccines and HBIG has prevented the majority of
perinatal transmission, it is likely that most of the transmission
occurs at the time of delivery. HBV is present in maternal vaginal
secretions and uterine contractions during labour are suggested to
increase the risk of transmission. HBV DNA was detected in vaginal
secretions in 52.5% in HBsAg (+) mothers [35]. A case control study
suggested that threatened preterm labour was associated with
transplacental HBV transmission [33]. Cord blood HBV DNA was
detected in 13 of 67 infants from HBsAg (+) mothers delivered
vaginally, but in none of 30 infants delivered by caesarean section
[42]. A later study, which included 184 vaginal deliveries and 117
Timing of infection Mechanism of infection
 Germ line infection
1. At conception  infected sperm [27-29]
 Infected ovum [30-32]
 Maternal blood contamination

CVS/ amniocentesis/
2. During pregnancy
Cordocentesis [37-41]
 Placental infection [33-36]
 Contact with maternal secretion
3. During labour  Vaginal delivery [42-44]
 Rupture of membrane [44-46]
Fig. 1. Possible mechanisms leading to immunoprophylaxis failure.
19
caesarean deliveries, showed the incidence of foetal HBsAg (+) at
one year was similar irrespective of the mode of delivery after
adequate immunoprophylaxis [43]. Song et al. found the mode of
delivery, premature rupture of membranes, preterm labour and
low birth weight were not associated with immunoprophylaxis
failure irrespective of HBeAg status or detectable HBV DNA level
[44]. Zou et al. studied 27 cases of immunoprophylaxis failure and
revealed similar findings, but they did not study the effects of
mode of delivery, maternal HBeAg status and HBV DNA level [45].
The risk of perinatal infection in premature rupture of membranes
in HBV carriers was suggested to be minimal and should not
influence obstetric management [44–46]. Although vaginal secre-
tion is infectious, evidence so far does not reveal any significant
harmful effect from premature rupture of membranes and vaginal
delivery, suggesting that immunoprophylaxis can protect for a
short period of HBV exposure. Therefore, caesarean delivery cannot
be recommended to prevent vertical transmission at this moment.
In summary, vertical transmission of HBV can occur in utero or
at the time of delivery. The majority of perinatal transmission is
prevented by the use of vaccines and HBIG while the issue of in
utero infection remains unsolved. In utero infection may lead to
immunoprophylaxis failure and the persistence of HBV nowadays.
The proposed mechanisms leading to immunoprophylaxis failure
are summarized in Fig. 1. Preliminary data showed that embryo
infection is possible by either infected sperms or ova. Gametes
infected with HBV may further proliferate and lead to in utero
infection. This is supported by cord blood HBV DNA (+) at birth
from paternal carriers with HBsAg ( ) mothers [47,48]. As high
HBV DNA levels and HBeAg (+) increase the risk of gametes/
embryo infection [31,32] and HBeAg (+) may be associated with
immunoprophylaxis failure from amniocentesis [37], HBV DNA
level and HBeAg status may be the determining factors in vertical
transmission.
5. Importance of HBeAg status and maternal viraemia
Maternal HBeAg (+) status [14,40,44,45,49] and high maternal
HBV DNA levels correlate with an increased risk of vertical
infection [14,34,36,40,44,45,49]. The risk of in utero infection
increases linearly with HBV DNA levels [34]. The HBV DNA levels
appear to be a more important factor than HBeAg status to evaluate
the chance of immunoprophylaxis failure. Song et al. showed a
higher incidence of immunoprophylaxis failure in infants whose
mothers had detectable HBV DNA level compared to those with
HBeAg (+) status (27% vs 21%) [44]. Zhu et al. found six infants
High HBV DNA [14, 34,36, 40, 44, HBV Vertical
45, 49]
transmission
HBeAg+ve [14, 40, 44, 45, 49]
20 K.W. Cheung et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 169 (2013) 17–23
suffered from immunoprophylaxis failure in 92 HBeAg (+)
mothers. In all six cases, the maternal HBV DNA level was
>8 log 10 copies/ml. The remaining 86 infants did not suffer from
HBsAg (+) at one year old [40]. Another study also showed similar
findings. All 27 infants who suffered from immunoprophylaxis
failure were born of mothers with HBeAg (+) and HBV DNA levels
>6 log 10 copies/ml. 5.6%, 6.1% and 7.6% infants born of HBeAg (+)
mothers, mothers with maternal HBV DNA level >6 log 10 copies/
ml and >8 log 10 copies/ml respectively [45]. Wiseman et al. found
that the rate of immunoprophylaxis failure was 7% in HBeAg (+)
mothers and 9% in mothers with viral loads >8 log 10 copies/ml
[49]. HBV DNA should be used in all HBsAg (+) mothers to assess
the risk of immunoprophylaxis failure, but the optimal cut off of
HBV DNA level is yet to be determined.
6. Antiviral treatment during pregnancy
Antiviral treatment during pregnancy is usually not indicated
for maternal considerations in most HBsAg (+) women, unless the
woman is at risk of hepatic decompensation [50]. Some women
may have started treatment before pregnancy. The options are to
either continue or stop current treatment or to switch to another
treatment [50]. Liaison with a hepatologist is necessary and the
treatment plan should be based on the HBV DNA and ALT levels.
The principle of treatment in late pregnancy to prevent or
reduce perinatal transmission has been established in mothers
with human immunodeficiency virus (HIV) and genital herpes
[51,52]. In mothers with HIV infection, antiviral treatment is
recommended to decrease the risk of vertical transmission [51],
whereas in women with genital herpes, daily suppression therapy
can be used to decrease viral shedding of genital herpes during
labour [52]. The use of antiviral treatment in HBV carriers,
however, is controversial. Most of the mothers are asymptomatic
and do not require antiviral treatment [50]. Recently, it has been
advocated to use antiviral treatment during the third trimester in
highly viraemic mothers to suppress the viral load [50]. The risks of
viral resistance, possible teratogenicity, and adverse maternal and
foetal effects should be weighed against the potential benefit of
decreasing vertical transmission to the unborn child.
6.1. Safety
Safety is the most important issue. Telbivudine and tenofovir
are Food and Drug Administration (FDA) category B medications.
Lamivudine, entecavir and adefovir are FDA category C medica-
tions. Data concerning their safety profiles during pregnancy are
very limited. The ‘Antiretroviral Pregnancy Registry’ (APR) is an
international, prospective, voluntary registry to detect possible
teratogenicity in women exposed to antiviral drugs during
pregnancy. The collection of data on lamivudine and tenofovir
use during pregnancy started in 1989 and 2001 respectively. In one
recent study analysing the data from the APR, only lamivudine
(10,094 cases) and tenofovir (1731 cases) had sufficient cases from
which reasonable conclusions concerning the risk of birth defects
could be drawn. Birth defect was defined by APR as a foetus or
infant diagnosed with any major structural or chromosomal defect
by 6 years old or any cluster of two or more conditional
abnormalities [53]. The use of lamivudine and tenofovir was not
associated with a two fold increase in risk of birth defects. The risks
of birth defects in lamivudine were 3.1% (95% confidence interval
(CI) 2.5–3.7%) and 2.7% (95% CI 2.3–3.1%) if earliest exposure
occurred in the first and second/third trimester respectively; while
in tenofovir, the risks were 2.4% (95% CI 1.6–3.5%) and 2.0% (95% CI
1.1–3.5%) respectively. These risks were similar to the background
risk in the general population and in women exposed to other
antiviral medications. Furthermore, the use of antiviral treatment
in the first trimester did not result in a significantly higher risk of
birth defects when compared to later use. The above data should
provide a certain degree of reassurance to women and obste-
tricians concerning the use of lamivudine and tenofovir during
pregnancy. With acknowledgement of the limitation of self-
reporting system, possible underreporting and lack of long term
follow up data in APR, physicians are encouraged to report to this
registry regarding women on antiviral treatment (including
telbivudine, entecavir and adefovir) during pregnancy to increase
the volume of data available for future analysis.
The safety of lamivudine and tenofovir was further demon-
strated in HIV women on antiviral treatment. In a study looking
into the paediatric outcome following in utero exposure to
tenofovir, there was no significant difference in the number of
miscarriages, stillbirths and subsequent growth or major kidney
problem of the children in women with or without tenofovir use.
No bone fracture was noted in the studied children [54]. It was
noted that the damage to mitochondrial DNA associated with
lamivudine use would resolve once exposure ceased, and the risk
of antiviral therapy leading to mitochondrial disorders was very
small and the long term consequences maybe even smaller [55].
There are limited studies on the safety of telbivudine during
pregnancy. Telbivudine was shown to be well tolerated and not
associated with major birth defects in short-term follow-up by two
investigators involving 188 users [56,57]. No postpartum flare-up
was detected in patients who stopped telbivudine 4 weeks after
delivery [56]. There are insufficient data to comment on the effect
of entecavir and adefovir on pregnant women.
6.2. Efficacy
The use of lamivudine during the third trimester was suggested
to suppress the viral load at term, so as to decrease the risk of in
utero infection and immunoprophylaxis failure [58]. In the largest
randomized controlled trial (RCT), 150 mothers were randomized
to receiving either lamivudine 100 mg daily or placebo from 32
weeks gestation to 4 weeks after delivery [59]. Only 115 infants
were available for final analysis and they all received vaccines and
HBIG. Maternal HBV DNA level was reduced by 2 log 10 copies/ml
in the lamivudine group. There was a significant decrease in
infants’ HBsAg (+) at 52 weeks of age (18% vs 39%), HBV DNA (+) at
birth (13% and 41%) and at 52 weeks of age (20% and 46%) in the
lamivudine group, but the result was compromised by a high
default rate in the control group at one year (31%). Secondary
sensitivity analysis resulted only in a non-significantly lower rate
of HBsAg (+) in the treatment group. Subsequently, a meta-analysis
including 10 RCTs with 951 HBV mothers was reported [60]. In
most of these RCTs, lamivudine 100 mg daily was started from 28
weeks’ gestation to 4 weeks after delivery and all newborns
received vaccines and HBIG. They found a 13–23.7% lower
incidence of in utero infection in the lamivudine group, defined
by HBsAg (+) (p = 0.04) and HBV DNA (+) (p < 0.001) at birth. The
vertical transmission rate was 1.4–2% lower at 9–12 months,
defined by HBsAg (+) (p < 0.01) and HBV DNA (+) (p < 0.001). The
quality of the included trials was not high, however, due to the
study methodology. Another meta-analysis which included 1693
subjects showed a reduction in vertical transmission only if the
viral load was suppressed to <6 log 10 copies/ml by lamivudine
[61].
Telbivudine was evaluated in two studies to assess its efficacy
in prevention of vertical transmission. In one, 229 mothers with
HBeAg (+) and HBV DNA >7 log 10 copies/ml were randomized to
either receiving telbivudine 600 mg daily or placebo from 20 to 32
weeks gestation to 4 weeks after delivery [56]. All newborns
received vaccines and HBIG. In the treatment group, there was
higher viral load suppression, more mothers with undetectable
 K.W. Cheung et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 169 (2013) 17–23
HBV DNA levels at birth (33% vs 0%), and fewer infants with HBsAg
(+) and HBV DNA (+) at birth (0% vs 9.6%) and at 7 months (0% vs
7.9%). The other study also confirmed the use of telbivudine in
reducing the risk of immunoprophylaxis failure [57].
A retrospective study concerning the use of tenofovir was
recently published [62]. Eleven chronic hepatitis B mothers with
HBV DNA >6 log 10 copies/ml and history of tenofovir use during
pregnancy were included. They received tenofovir starting from
around 29 weeks of gestation. All infants received vaccines and
HBIG. Significant reduction in maternal viral loads was observed.
Viral study at birth was not available. None of the infants were
HBsAg (+) at 28–36 weeks of age. Despite the potent antiviral
property, only 55% (6/11) of the mothers had viral loads
<6 log 10 copies/ml at delivery.
To conclude, antiviral treatment can be considered in HBsAg (+)
women with high HBV DNA levels. Limited evidence so far suggests
that the use of lamivudine and telbivudine may be effective in
preventing vertical transmission and immunoprophylaxis failure
in chronic hepatitis B mothers with high viral loads. Although
lamivudine appears to be safe, concerns have been raised regarding
its use leading to development of resistant strains [63]. Data on
telbivudine in the APR are not sufficient to encourage its use at the
moment. Clinicians should also be aware that studies regarding the
long term safety of infants exposed to in utero antiviral treatment
are lacking. Tenofovir is recommended as the first-line treatment
for hepatitis B disease in view of its high barrier to resistance and
antiviral potency in non-pregnant subjects [64]. Its use appears to
be a reasonable option to be further explored in the future. Well-
designed trials concerning the use of antiviral treatment are
urgently needed.
The other suggested prenatal treatment would be HBIG
injection. It has been shown that multiple intramuscular doses
of HBIG during pregnancy could reduce the chance of immuno-
prophylaxis failure in women with high HBV DNA levels. The
possible mechanism of this protective effect may be due to the
activation of the immunity system by binding of the HBIG to
HBsAg, leading to a reduction of the HBV DNA levels. Shi et al.
performed a meta-analysis which included 37 RCTs. 200 IU of
intramuscular HBIG was given to the mothers at around 28, 32 and
36 weeks in most of the RCTs [65]. The intervention group was
associated with a lower intrauterine infection rate (indicated by
HBsAg (+) at birth, OR 0.22, 95% CI [0.17, 0.29]) and vertical
transmission (indicated by HBsAg (+) at 9–12 months, OR 0.33, 95%
CI [0.21,0.51]). However, the issues of optimal dosage and timing of
HBIG, possibility of development of mutant HBV and blood–borne
infection remain unsolved. Maternal HBV DNA levels before and
during treatment would be valuable to assess the maternal
population suitable for prenatal HBIG. Again, further prospective
studies are required.
7. Follow up
After delivery, it is usually recommended to monitor the
maternal liver function for at least 6 months in view of possible
postpartum exacerbation [50]. For women who are started on
antiviral treatment in the third trimester to decrease the risk of
immunoprophylaxis failure, the optimal duration for postpartum
treatment is unclear. Antiviral treatment is usually continued for 4
weeks in view of possible exacerbation after treatment withdrawal
immediately postpartum [60].
Chronic HBV infection is defined by persistence of HBsAg in the
serum for six months. Current Centres for Disease Control (CDC)
guidelines recommend post-vaccination testing for anti-HBsAb
and for HBsAg at 9–18 months of age [66]. Neonatal HBsAg (+) at 9
to 12 months is usually used as a marker for chronic infection in
most studies evaluating immunoprophylaxis failure. Following up
21
on infants who are born of HBsAg (+) mothers is essential to ensure
immunity and to pick up chronic carriers.
8. Future perspective
There is still a long way before complete eradication of HBV is
possible and we need to know more about the exact mechanisms of
perinatal transmission and possible factors leading to immuno-
prophylaxis failure. Viral load is not the only factor leading to
immunoprophylaxis failure. It has been reported that immuno-
prophylaxis failure can occur despite adequate viral suppression
with lamivudine throughout pregnancy, suggesting that factors
other than viral load may influence the chance of perinatal
transmission [67]. Therefore, various maternal and obstetric
factors leading to immunoprophylaxis failure should be further
evaluated.
Paternal hepatitis B status and occult maternal hepatitis B
infection may play a role in HBV transmission. The cord blood was
positive for HBV DNA in 36 newborns from 161 HBsAg ( ) women
and HBsAg (+) men, and the risk of infection further increased if
paternal serum had HBV DNA levels 37 log 10 or HBeAg (+) [47].
This result was confirmed by a later study which excluded the
possibility of maternal occult hepatitis B carrier as a possible
factor leading to maternal vertical transmission [48]. Another
study showed high homology of HBV sequences between fathers
and aborted foetuses, suggesting transmission from fathers to
foetuses was possible [68]. Occult hepatitis B is a form of hepatitis
B which HBsAg is absent while HBV DNA is present in the serum
and usually at very low levels. Its contribution to vertical
transmission is not known because it will not be picked up by
antenatal screening of HBsAg alone. One study recruited 202
HBsAg ( ) pregnant women and screened them for occult
infection [69]. Six women were found positive for HBV DNA by
two different assays, of which only four cord blood samples were
available for analysis. HBsAg and HBV DNA were not detected in
any of the samples.
9. Conclusion
Perinatal transmission from the mother to the newborn is the
most important mode of transmission of hepatitis B infection.
Newborns are still infected with HBV in countries with universal
antenatal HBV screening and neonatal immunoprophylaxis.
Infected germ cells, transplacental infection, invasive prenatal
diagnostic tests and various perinatal factors are possible factors
leading to in utero infection and immunoprophylaxis failure.
Antiviral treatment can be effective in suppressing viral load, so as
to decrease the risk of vertical transmission, making it a reasonable
option in mothers with high viral load. Therefore, the HBV DNA
level should be tested at around 24–26 weeks to facilitate
discussion between women and obstetricians. If the woman
prefers to start antiviral treatment, it can be given from 28 weeks of
gestation till 4 weeks after delivery.
Conflict of interest
The authors have stated explicitly that there are no conflicts of
interest in connection with this article.
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