Hepatitis B in Pregnancy

Grant Whittaker, MD, Jorge L. Herrera, MD

South Med J. 2014;107(3):195-200.
Abstract
In the United States each year, 24,000 infants are born to women who are infected with the
hepatitis B virus (HBV) and an estimated 1000 newborns acquire the infection through
vertical transmission from their mother. The approach to a pregnant patient with HBV
infection includes assessing the need for therapy in the mother and evaluating possible
interventions that may reduce mother-to-child transmission of HBV infection. Rates of
mother-to-child transmission of HBV can be greatly reduced if the current guidelines for
screening and immunization are universally followed. The use of oral antiviral therapy in
highly viremic mothers to reduce mother-to-child transmission is controversial but should be
considered on a case-by-case basis, realizing that the available antiviral medications to treat
HBV are not approved by the Food and Drug Administration for use during pregnancy. We
review the literature and present our suggested management approach to the pregnant
patient with chronic HBV.

Introduction
An estimated 350 million people worldwide are infected with the hepatitis B virus (HBV). [1] In
the United States, 1.5 to 2 million people are infected, and approximately 24,000 infants are
born each year to HBV-infected mothers. Testing and reporting are incomplete; therefore, it
is estimated that the true number of perinatal HBV cases per year is 10 to 20 times the
amount reported.[24] The majority of nonimmunized infants exposed to HBV will develop
chronic hepatitis B and are at risk of developing complications later in life. Preventing vertical
transmission is key to avoiding these potentially fatal long-term sequelae. Recent clinical
studies suggest that the selective use of antiviral therapy during pregnancy further reduces
the risk of transmission.
Effects of Chronic HBV Infection on Pregnancy
Studies have found an increased risk of gestational diabetes, antepartum hemorrhage, and
threatened preterm labor in hepatitis B surface antigen (HBsAg)positive mothers, but no
association with preeclampsia or premature rupture of membranes.[1] A large study in China
found no deleterious effect of HBV infection on pregnancy outcome.[5] A small retrospective
study of 29 HBsAg-positive pregnant patients at a clinic in California[6] noted hepatic
decompensation in 4 patients, HBV reactivation in 1 case, gestational diabetes in 2 patients,
and no complications in 15 of the 29 patients; however, a larger study from
Florida[7] analyzed pregnancy outcomes from 1458 HBV-infected mothers and found no
increased risk of negative outcomes.
Chronic HBV does not appear to increase the risk of maternal or fetal mortality nor does it
increase the risk of congenital defects, but it may increase the rates of some pregnancy-
related complications. In general, women with chronic HBV infection who become pregnant
should expect stable disease activity but need careful monitoring by their obstetrician in
consultation with a gastroenterologist. Monitoring after delivery also is important because
reactivation of chronic HBV may occur.[8]
Assessing the Need for Therapy in the Mother
All pregnant women should be screened for HBsAg at the first prenatal visit, even if they
have been previously vaccinated or tested.[3] The initial assessment of a pregnant patient
with HBV should determine whether the mother has active liver disease in need of treatment.
Active disease is defined as an elevated viral load together with evidence of inflammation,
either biochemically (elevated transaminases) or histologic (inflammation and or
fibrosis).[9] An elevated viral load is defined as >20,000 IU/mL (105 copies per milliliter) in
hepatitis B e-antigen (HBeAg)positive patients, or >2000 IU/mL (104copies per milliliter) in
HBeAg-negative patients. Mothers who have low viral loads or high viral loads with no
evidence of inflammation do not require antiviral therapy but should be observed closely
during pregnancy to detect evidence of reactivation. Expectant mothers who meet treatment
criteria should be considered for antiviral treatment, because a healthy mother is an
important determinant for an uncomplicated pregnancy. Often, pregnant women diagnosed
as having chronic HBV are in the immune-tolerant phase of infection, characterized by
young age (younger than 35 years), normal aminotransferases, a positive HBeAg, and high
levels of viremia that often exceed 200,000 IU (108 copies per milliliter).[10]Current guidelines
recommend not treating immune-tolerant patients because there is little to no associated
liver inflammation. Mothers in the immune-tolerant phase of infection are at an increased risk
of transmitting the infection to their child because maternal viremia is the most critical factor
influencing the efficacy rates of neonatal immunoprophylaxis.[11]

Risk of Mother-to-child Transmission

Prevention of vertical transmission is critical because the majority of exposed infants
become chronically infected.[1,12]Transmission mainly occurs at the time of delivery or after
birth, but rarely can occur in utero before. Several risk factors associated with infection in
utero have been identified. Acquiring acute HBV during the third trimester is associated with
a 60% to 90% vertical transmission rate.[13] Threatened premature labor also is associated
with an increased risk of infection, presumably from the mixing of maternal and fetal blood. [14]
Amniocentesis does not increase the risk of vertical transmission.[15,16] Mode of delivery is a
controversial risk factor. During delivery, the child is exposed to vaginal secretions and
possibly maternal blood, but there is no solid evidence that vaginal delivery increases the
risk of vertical transmission when compared with cesarean delivery.[15,17,18]Women with
children infected with HBV are at increased risk of transmitting the virus to all subsequent
children.[19]
The most important risk factor for vertical transmission from mother to child is the mother's
HBeAg status and HBV viral load. Without immunoprophylaxis, infants born to HBsAg-
positive/HBeAg-positive mothers have a 70% to 90% chance of developing chronic HBV, but
only a 10% to 20% chance if the mother is HBsAg positive/HBeAg negative.[20]
Several studies have demonstrated that a maternal HBV viral load >108 copies per milliliter
(20 million IU/mL) increases the risk of vertical transmission.[14,20] This outcome has led
many authors to conclude that it may be possible to reduce the risk of transmission of HBV
by reducing the maternal level of viremia before delivery.
Reducing the Risk of Vertical Transmission
The standard of care in the United States is passive and active immunization of all infants
born to HBsAg-positive mothers with hepatitis B immunoglobulin (HBIG) and HBV vaccine
within 12 hours of birth.[21] This protocol reduces the risk of transmission to <10% in infants
of HBsAg-positive/HBeAg-positive mothers and <1% in HBsAg-positive/HBeAg-negative
mothers.[1,21] The vaccination schedule of all infants should be completed with the second
dose at age 1 to 2 months and the third at 6 to 9 months old, according to current
guidelines.[21] Because the risk of vertical transmission is highest among HBeAg-positive
mothers with a high viral load at the time of delivery, the strategy of initiating antiviral therapy
during pregnancy to reduce vertical transmission has been studied and appears
promising.[22]
Treating HBV in Pregnancy
Antiviral therapy may be considered during pregnancy if the mother exhibits evidence of
active disease as indicated by an alanine aminotransferase level above the upper limit of
normal and a viral load >20,000 IU/mL. Alternatively, therapy may be considered if the fetus
is at increased risk of infection because the mother's viral load is >106 or >108 copies per
milliliter (>200,00020 million IU/mL). The treatment of HBV during pregnancy is
controversial because none of the drugs approved to treat HBV have been tested or
approved by the Food and Drug Administration for use in pregnant patients. The Food and
Drug Administration pregnancy classification for the drugs approved to treat HBV is shown
in Table 1. The data regarding safety in pregnancy are limited and large randomized
controlled trials do not exist.
Drugs for the treatment of HBV infection in pregnancy include tenofovir, telbivudine, and
lamivudine. Tenofovir and telbivudine are classified as pregnancy category B. Lamivudine is
classified as pregnancy category C (Table 1). Lamivudine and telbivudine have a low barrier
to resistance; however, if the duration of therapy is expected to be <6 months, development
of resistance is less likely. Tenofovir has the highest barrier to resistance and has potent
antiviral activity, making it an attractive option for therapy, particularly if long-term therapy is
anticipated.
The Antiretroviral Pregnancy Registry (APR; http://www.apregistry.com) is a voluntary
international registry used to report experience with the use of antivirals during pregnancy to
monitor for the increased risk of birth defects or adverse fetal outcomes. [23] Brown et al
analyzed the APR data and reported on the safety of lamivudine (10,094 cases) and
tenofovir (1731 cases) use during pregnancy. No increased risk of birth defects was reported
with lamivudine or tenofovir compared with population-based controls. No differences in the
rates of birth defects were noted if the exposure began in the first trimester versus the
second or third trimester. Limited data in the APR for entecavir, telbivudine, and adefovir
prevent conclusions concerning safety at this time.[23] Limitations of the data in the APR
include reliance on voluntary reporting and no evaluation of treatment efficacy or maternal
safety, which must be considered when making treatment decisions during pregnancy.
Telbivudine appears to be safe when used in late pregnancy, based primarily on animal
studies and small human pregnancy trials.[2426]
It is not completely understood why some infants acquire chronic HBV, despite proper
passive and active immunoprophylaxis at birth. Possible causes include high levels of
maternal viremia, intrauterine infection before delivery, or escape mutants that allow the
virus to bypass the protective benefits of passive and active immunization. Lowering the
maternal viral load during the third trimester of pregnancy to prevent transmission is an
attractive but controversial measure.
Van Zonneveld et al[27] treated eight pregnant women with high HBV DNA levels (>1.2
109 gEq/mL) with 150 mg lamivudine from week 34 of pregnancy until delivery and the
results compared with 24 historical controls. Only one of the eight children whose mothers
received lamivudine tested HBV DNA positive at 12 months of age; in contrast, 28% of
children in the historical control group were HBV DNA positive at 12 months of age. Xu et
al[28] randomized 114 pregnant mothers with high levels of viremia to 100 mg/day lamivudine
versus placebo, beginning at gestational week 32 and continuing until 4 weeks postpartum.
All of the infants received the standard HBIG and HBV vaccine at birth. At 1 year of age,
18% of the treated infants were HBsAg positive versus 39% in the control group (P = 0.014).
No significant differences in adverse events were reported. It should be noted that infants
lost to follow-up were considered treatment failures, and more infants were lost to follow-up
in the placebo group compared with the treatment group. When the data were reanalyzed
with only those infants who completed the study, there was no significant difference between
the lamivudine and placebo groups.
Su and colleagues[29] studied 38 Chinese patients with chronic HBV infection who became
pregnant while taking lamivudine and chose to continue therapy during pregnancy and
compared their outcome with a historical control group. At 6 months of age, all of the infants
born to mothers who continued lamivudine during pregnancy were negative for HBsAg and
HBV DNA. In contrast, 26% to 36% of the control group infants were infected with HBV.
Han et al[26] studied the efficacy of 600 mg/day telbivudine started before 32 weeks'
gestational age and continued 4 weeks postpartum versus an untreated control group in an
open-label trial of 229 HBeAg-positive mothers with HBV DNA >106 copies per milliliter. All
of the infants received passive and active immunoprophylaxis. At 28 weeks of age, 2.1% of
infants born to mothers treated with telbivudine were HBsAg positive compared with 13% of
infants born to mothers in the control group, with no increase in reported birth defects.
Pan et al[25] studied 88 HBeAg-positive pregnant women with a high viral load (>106 copies
per milliliter), 53 of whom chose to take telbivudine starting during the second or third
trimester of pregnancy. All of the infants received adequate immunoprophylaxis. Before
delivery, the cohort receiving telbivudine had a 4-log decrease in viral load, compared with
no change in those who did not take telbivudine. At 28 weeks of age, none of the infants
born to mothers who took telbivudine were HBsAg or HBV DNA positive, whereas 8.6% of
infants born to mothers who did not take telbivudine tested positive, and no complications
were reported.[25]
Tenofovir for the prevention of vertical transmission of HBV was studied in a small
retrospective review of 11 pregnant Asian women who were treated at a mean gestational
age of 29 weeks.[30] A significant reduction in viral load of 5.25 1.79 log10 was noted at the
time of delivery. All of the infants tested negative for HBsAg at 28 to 36 weeks of age and no
adverse events were noted. Salient points of the studies discussed are shown in Table 2.
Two meta-analyses have shown benefit in using lamivudine in late pregnancy to reduce risk
of transmission to the infant from highly viremic mothers.[31,32] An additional meta-analysis
and systematic review consisting of six trials with a total of 576 mothers, of whom 306
received telbivudine in late pregnancy, also showed efficacy in reducing transmission from
mother to child.[33]
These studies provide preliminary evidence that oral antiviral therapy may be beneficial in
selected HBeAg-positive mothers with high levels of viremia (>106108 copies per milliliter or
>200,00020 million IU/mL), but should be used only after discussing the potential risks and
benefits with the patient and all interested parties. A suggested approach to the pregnant
patient with chronic HBV infection is shown in the Figure.[34]
When to Stop Antiviral Therapy After Pregnancy
When to discontinue antiviral therapy after delivery is another area of controversy. If the
mother meets the criteria for treatment of chronic HBV during pregnancy (alanine
aminotransferase level above the upper limit of normal and HBV DNA level >20,000 IU/mL
or 105 copies per milliliter), then long-term antiviral therapy is recommended per
conventional end-of-treatment recommendations.[9] Mothers who were treated solely to
reduce the risk of transmission to the child may consider discontinuation of antiviral therapy
soon after delivery, usually within the first 4 weeks or at delivery if breast-feeding is being
considered. These mothers should be monitored carefully for an acute flare of HBV, which
may occur after withdrawal of therapy.

Figure.
Suggested approach to the
pregnant patient with
hepatitis B virus (HBV).
HBIG, hepatitis B
immunoglobulin; HBsAg,
hepatitis B surface antigen.
Adapted from Clinics in
Gastroenterology and
Hepatology, Vol 10, Pan
CQ, Duan ZP,
Bhamidimarri KR, et al, An
algorithm for risk
assessment and
intervention of motherto-
child transmission of
hepatitis B virus. Copyright
2012, with permission from
Elsevier.

Management of the Patient With HBV who Becomes Pregnant

For treatment-nave patients with normal transaminases and low levels of viremia, continued
monitoring without treatment until after delivery is the best option. Liver enzyme levels and
hepatitis B viremia should be measured every 2 to 3 months during pregnancy because
reactivation of viral hepatitis may occur. Should the viral load exceed 106 copies per milliliter
(>200,000 IU/mL) by the end of the second trimester, treatment may be considered to
decrease the risk of transmission to the child.
For patients already receiving antiviral therapy when they become pregnant, the decision to
continue or stop treatment during pregnancy should be individualized, taking into account
the severity of the mother's hepatitis and the relative lack of safety information regarding the
use of antiviral drugs during early pregnancy.
Postnatal Follow-up
Infants born to HBsAg-positive mothers should be tested for HBsAg and HBsAb 3 months
after the third vaccine dose, between the ages of 9 and 12 months. HBsAg-positive infants
should be referred to a specialist for evaluation. Testing for immunity before the infant is 9
months old can result in a false-positive result for HBsAb from the HBIG given at birth.
HBsAg-negative infants with HBsAb levels >10 mIU/mL are considered immune. Infants with
HBsAb <10 mIU/mL should be revaccinated with the three-dose series and subsequently
retested for immunity.[21] Detection of HBeAg before 1 year of age and HBcAb before 2 years
of age may represent transplacental maternal antibodies to HBV and should not be
interpreted as chronic HBV in the child.[24]
Breast-feeding is not contraindicated for infants born to HBsAg-positive mothers who are not
taking antiviral medications. The risk of transmission is low and is comparable between
infants who are breast-fed versus formula-fed infants.[35] Mothers receiving antiviral therapy
should not breast-feed because the antivirals are excreted in breast milk, the long-term
effects of which have not been studied.
Conclusions
Rates of mother-to-child transmission of HBV can be reduced greatly if the current
guidelines for screening and immunization are universally followed. All pregnant women
should be screened for chronic HBV in the first trimester, and all infants born in the United
States should be vaccinated with the HBV vaccine at ages 0, 1 to 2 months, and 6 months.
All infants born to HBsAg-positive mothers should be given HBIG within 12 hours of birth in
addition to vaccination. The use of lamivudine, telbivudine, or tenofovir should be considered
in HBsAg-positive/HBeAg-positive mothers with high levels of viremia (>106108 copies per
milliliter or >200,00020 million IU/mL) to decrease the risk of vertical transmission, with the
understanding that safety and efficacy data of this strategy are limited. Finally, there are no
contraindications to breast-feeding for mothers with chronic HBV who are not taking antiviral
medications.
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