Juniper Publishers: Hepatitis B in Pregnancy: Challenges and Solutions
Journal of Gynecology and Women’s Health-Juniper
Publishers
Authored by Dalia Rafat
Introduction
Hepatitis B is the most common serious liver
infection in the world, caused by the hepatitis B virus (HBV), which
attacks liver cells and can lead to liver failure, cirrhosis (scarring)
or cancer of the liver later in life. According to the World Health
Organization (WHO) estimates, two billion people have been infected
worldwide with the HBV, which accounts for one-third of the global
population, and more than 240 million are chronic carriers (4%-6% of the
world population). Approximately 600000 people die every year due to
the consequences of HBV infection [1].
Modes of transmission include both horizontal spread
via contact with infected blood or body fluids and vertically via mother
to child transmission (MTCT). A great majority of the transmission of
HBV in both high and low endemic areas occurs by vertical transmission
from an infected carrier mother to the neonate, during pregnancy or in
perinatal periods [2-4].
HBV infection during pregnancy is associated with a
high risk of maternal complications, has a high rate of vertical
transmission causing fetal and neonatal hepatitis and has been reported
as a leading cause of maternal mortality. Also, the risk of progression
to chronic HBV infection is inversely proportional to the age at which
the infection was acquired and vertical transmission of
HBV from infected mothers to their fetuses or newborns remains a major
source of perpetuating the reservoir of chronically infected
individuals. Therefore, proper management of infected mothers and
effective prevention of MTCT is a promising efficient approach to
interrupt chronic HBV infection [5].
Management of HBV infection in pregnancy is
challenging because of several peculiar and somewhat controversial
aspects associated with it, including the following:
- The effect of pregnancy on HBV infection and of HBV infection on pregnancy.
- The potential viral transmission from mother to newborn despite at-birth prophylaxis with immunoglobulin and vaccine
- Possible prevention of mother-to-child transmission through antiviral drugs
- The type of antiviral drug to use considering their efficacy and potential teratogenic effect, and the timing of their administration and discontinuation
- The use of elective caesarean section vs vaginal delivery in pregnant women with hepatitis B; and
- The possibility of breastfeeding.
This document will briefly discuss the solution to
these challenges which in turn will aid in better understanding of the
clinical, therapeutic, and prognostic aspects of HBV infection during
pregnancy.
Effect of HBV Infection on Pregnancy
Pregnant women with acute or chronic HBV infection
typically have a course not very different from that in the general
adult population and often no serious effects due to HBV infection are
found in pregnancy [6]. Slightly higher incidence of hyper emesis gravid
arum, low birth weight and prematurity has been reported in some
patients with acute and chronic HBV infection than in the general
population [4]. However, mothers with seriously abnormal liver function
are prone to postpartum hemorrhage, puerperal infection, fetal distress,
fetal death and neonatal asphyxia [7-10]. Patients with advanced
cirrhosis are at increased risk of maternal and fetal problems in about
50%
of cases [11].
Effect of Pregnancy on HBV Infection
Series of physiological changes in pregnancy, including
vigorous metabolism and increased nutrient consumption
occurs to promote the metabolic needs of the mother as well as
of the growing fetus. Aggravation of pre-existing liver diseases
and exacerbation of liver damage might occur owing to the need
of augmented metabolism and inactivation in the liver of the
increased sex hormone produced by the mother and dependence
of fetal metabolism and detoxification on the mother’s liver
[12,13]. During pregnancy there also occur several modifications
in the maternal immune system that contribute to a depressed
immune response against HBV resulting in an increase in HBV
DNA and a reduction in aminotransferase levels. After delivery,
with restoration of immune system opposite consequences
occurs; namely, a significant increase in alanine aminotransferase
(ALT) and a reduction of HBV DNA in this period [12]. These
modifications may result in viral exacerbations and higher
incidence of complications. Although HBV infection during
pregnancy can often be tolerated, severe hepatitis and hepatic
failure induced by perinatal hepatic flare reactions still occur,
and can have an unfavourable outcome [14]. Close monitoring
and timely interventions thus are recommended.
Perinatal Transmission
Perinatal transmission is the most common mode of HBV
transmission worldwide, accounting for one third of HBV
infections. Because infection with HBV acquired prenatally often
leads to chronic disease, prevention of vertical transmission is a
worthy goal. Perinatal transmission of HBV is mediated via three
main modes:
- Intrauterine (transplacental transmission of HBV in utero);
- Intrapartum (transmission during delivery);
- Postnatal (transmission during care or through breast milk) [5,15-16].
Intrauterine transmission
Intrauterine transmission of HBV is proposed to be
the most important reason for the failure of passive-active
immunoprophylaxis in preventing MTCT [7,9]. Although
different diagnostic criteria [17-19] have been considered for the
diagnosis of HBV intrauterine infection, till now no consensus
have been formed on and the exact mechanism of intrauterine
transmission of HBV still remains to be illuminated. The most
frequently mentioned hypotheses involve: serum/body fluid
transmission, cellular transmission and genetic transmission
[20-22]. Known risk factors predisposing to intrauterine
infection include maternal HBeAg positivity, detectable HBV
DNA, specific allelic mutations in maternal HBV, a history of threatened preterm labour, and acute hepatitis B acquired in
pregnancy, particularly during the last trimester [23,24].
Intrapartum transimission
Transmission of HBV during delivery is the most common
method of vertical transmission. It is predominantly due to
contact of the newborn with the mother’s infected secretions or
blood at the time of delivery [25].
Postnatal transmission
Transmission of HBV postnatally may occur in as high as
34% of cases owing to close contact of the baby with the mother
[25,26]. However, breastfeeding is not considered as a risk factor
for HBV infection [25]. Without immune prophylaxis the risk
of mother-to-child transmission is very high. It varies with the
HBeAg status of mothers, being highest in HBsAg- and HBeAgpositive
mothers (transmission rate of 70%-90%) and low for
HBsAg-positive HBeAg-negative mothers (transmission rate of
10%-40%) [6,25]. A combination of active and passive immune
prophylaxis is the optimum strategy to prevent HBV infection in
babies of HBsAg positive mothers. Passive immunoprophylaxis
consists of the administration of hepatitis B immune
globulin (HBIG) whereas active immunoprophylaxis is the
administration of hepatitis B vaccine. Although passive-active
immunoprophylaxis in infants of HBV-infected mothers has
been demonstrably effective in reducing perinatal transmission,
a small percentage of infants still become HBV chronic carriers
and presumably this is because HBV exposure can occur in
utero prior to delivery. These facts adds to the concern that in
some cases, correct passive-active immunoprophylaxis given
at the time of birth may not prevent infection in those born
already infected and further supports the need to explore other
strategies like antiviral drugs or HBIG to the mother and mode
of delivery. Till now there is no consensus about the therapy choice for pregnant women who are HBsAg-positive and highly
viremic in the third trimester to prevent perinatal transmission.
Although in such cases, some studies have shown reduction in
the risk of vertical transmission by third trimester prophylaxis
with antiviral drugs like telbivudine or tenofovir but large,
appropriately designed trials to recognize the best drug for this
use are still pending [27].
Treatment of HBV During Pregnancy
Prior to considering treatment of HBV infection during
pregnancy, indication of treatment and the risks and benefits
must be weighed carefully. Firstly it is important to decide
whom to treat. HBV infection in pregnancy can either be acute
or chronic. Pregnant women acutely infected with HBV generally
don’t require antiviral unless there is evidence of acute liver
failure. These patients are managed conservatively but should
be monitored closely. Those infected chronically, indications for
treatment includes chronic chronic liver disease in mother and
prevention of vertical transmission in baby [28]. Next major issue
is the consequences of the treatment both for the mother and the fetus. Seven drugs have been approved by the United States Food
and Drug Administration (FDA) for the treatment of hepatitis
B: PEG-interferon alpha 2a, interferon alpha 2b, lamivudine,
adefovir, entecavir, telbivudine and tenofovir [29]. Interferon’s
are contraindicated in pregnancy. Among rest five antiviral
drugs all of them are category C except for last two namely
telbivudine and tenofovir, which are category B for pregnancy.
Safety data in pregnancy are most robust with lamivudine and
tenofovir compared with other therapies [29,30]. Finally, if
the decision has been made to treat with antiviral, the next
worthy consideration is the goal of treatment and the timing of
administration of these medications. For pregnant women who
develop active liver disease the goal of treatment should be to
induce liver disease remission in the mother, in order to minimize
the risk of preterm delivery while for others the goal should be
to prevent transmission of HBV at birth by decreasing viral load
and/or decreasing activity of the virus [29-31]. Although still
controversial, but most studies have shown that if indicated
antivirals should be started in the third trimester of pregnancy
[31-33]. Careful discussion with the patient regarding the risks
and benefits of therapy is warranted.
Mode of Delivery
There is conflicting data in literature over the effect of mode
of delivery on perinatal HBV transmission [34,35]. Although the
mode of delivery to maximally reduce the incidence of vertical
transmission of HBV still remains controversial but measures
available to reduce the infection rate of HBV in labor should be
opted in all cases. Currently, there is no convincing evidence that
elective caesarean section reduces the rate of mother-to-child
transmission of HBV compared with vaginal delivery and so
most obstetric societies do not endorse routine use of caesarean
section to prevent perinatal transmission of HBV.
Breastfeeding by HBV-Infected Women
Transmission of HBV via breast milk is frequently an added
concern of HBV infected mothers. Currently, the presence of
HBsAg, HBeAg and HBV DNA in breast milk is confirmed but the
benefits of breastfeeding outweigh the potential risk of infection,
which is minimal. In addition, with universal immunoprophylaxis
at birth, any potential risk is further reduced. According to
current guidelines, all women with hepatitis B should be
encouraged to breastfeed their newborns [36]. For mothers on
antiviral therapy, breastfeeding is not recommended because
few data are available about the safety of antiviral exposure
during breastfeeding [37].
Conclusion
HBV infection in pregnancy is a challenging condition, but
providing solutions to these challenges is noteworthy and an
important opportunity to interrupt perinatal transmission
of HBV. Since maternal-fetal transmission is the major route
of acquisition of HBV worldwide and age of acquisition of
HBV infection is directly proportional to chronicity of disease, strategies to eradicate HBV or to decrease global burden of
disease must aim this critical step in HBV disease propagation.
Testing for HBsAg is recommended for every pregnant woman,
regardless of previous testing or vaccination. Standard passiveactive
immunoprophylaxis with HBIG plus HBV vaccine in
neonates within 12 h after delivery is proved to be successful in
preventing approximately 90% of vertical transmission of HBV.
However, in the cases of high maternal viremia, a small proportion
of newborns can acquire the infection (probably through in utero
transmission) despite the use of passive/active prophylaxis. In
such situations, antiviral treatment in the third trimester can be
considered. Administration of antiviral therapy is also needed in
those who have active liver disease during pregnancy.
The choice of antiviral should be restricted to those drugs
considered safe in this setting and the risks and benefits of
treatment must be weighed carefully. Chronic HBV infection does
not seem to increase risk of maternal fetal morbidity and mortality.
Additionally, standard vaginal delivery and breastfeeding do not
appear to increase the risk of HBV transmission.
There are still some controversial issues that require
further concerns, including HBIG injection during pregnancy,
breastfeeding of infants by mothers on antiviral therapy and the
potential long-term side effect of antiviral agents to both HBV
positive mothers and their infants. These challenges still need
solutions and calls for further research in this field.
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