Hepatitis B in Pregnancy
In the US, the prevalence of chronic HBV infection in pregnancy is 0.2 to 6%, with rates varying by race and ethnicity. In a study of pregnant women from four urban US areas, Asian-American women had the highest prevalence of chronic HBV infection (6%), followed by blacks (1%), whites (0.6%) and Hispanics (0.14%). Newborn infants acquiring HBV infection by perinatal transmission have a greater than 95% chance of becoming chronic HBV carriers. Therefore, it is very important to institute maximally effective measures to prevent MTCT.
Diagnosis of Chronic Hepatitis B
Chronic HBV infection is diagnosed by the presence of hepatitis B surface antigen (HBsAg) in serum for longer than 6 months (Table 2 and Figure 1). Hepatitis B e antigen (HBeAg) is a marker of active viral replication and infectivity. Immune-tolerant chronic HBV patients have normal serum aspartate transaminase (AST) and alanine transaminase (ALT) levels, but have very high HBV DNA levels (>10 million IU ml; >6 × 7 log10 copies ml); they typically are children, teenagers or young adults. Inactive HBV carriers are HBsAg-positive, HBeAg-negative, hepatitis B e antibody positive, with undetectable or low (<1000 IU ml;<6 × 3 log10 copies ml) HBV DNA levels and normal liver function tests. Patients with chronic active HBV infection have increased AST and ALT levels, may be positive for HBeAg and have HBV DNA levels over 20 000 IU ml (>5 log10 copies ml).
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Figure 1.
Phases of chronic HBV infection. In the immune-tolerant phase of chronic HBV infection, ALT levels are normal whereas HBV DNA levels are markedly elevated. In the immune-reactive or chronic active phases, ALT and HBV DNA levels are elevated. In chonic inactive phases of HBV infection, ALT and HBV DNA levels are decreased; <1000 IU ml is equivalent to<6 × 3 log10 copies ml; >200 000 IU ml is>6 log10 copies ml.
Screening for Chronic HBV Infection
The Centers for Disease Control (CDC) recommends that all pregnant women should be screened for the presence of HBsAg at diagnosis of pregnancy (Figure 2). Repeat screening should be considered in HBsAg-negative women with risk factors for HBV infection (Asian, drug use, sexual exposure, incarceration, abnormal ALT) on admission for delivery.
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Figure 2.
HBsAg is checked in all pregnant women. HBsAg-positive patients should have HBV DNA level and HBeAg checked. We recommend checking HBsAb and immunizing HBsAb-negative patients.
HBsAg-positive patients should be checked for the presence of HBeAg, hepatitis B e antibody and for HBV DNA level. High HBV DNA levels and HBeAg-positivity are associated with increased risk for MTCT of HBV infection. Neonates of all HBsAg-positive mothers should receive immunoprophylaxis treatment with hepatitis B immune globulin (HBIG) and HBV vaccine at delivery to decrease MTCT of HBV infection.
Pregnancy is not a contraindication for vaccination to HBV. Therefore, pregnant women who are not immune to HBV should be vaccinated, because premature delivery may be increased if acute hepatitis B is acquired in the last trimester and because MTCT occurs in over 60% of pregnancies associated with acute HBV infection at or near term.
Impact of Pregnancy on Chronic HBV Infection
Pregnancy is well tolerated by women with chronic hepatitis B infection. HBV DNA levels may increase during pregnancy in association with a decrease in ALT levels, consistent with an HBV tolerance phase, followed by a post-partum decline in HBV DNA level that is associated with increased ALT levels and active hepatitis, consistent with a post-partum reconstitution of the immune system. This post-partum HBV reactivation may be associated with HBeAg seroconversion (i.e., clearance of HBeAg, development of hepatitis B e antibody positivity, decline in HBV DNA levels and normalization of ALT level) in 12.5 to 17% of patients.
Mother-to-child-transmission of HBV Infection
It is estimated that 30 to 40% of chronic HBV infections in the US are a result of perinatal transmission or early childhood infection. The most important risk factor for MTCT of HBV infection is a maternal level of HBV DNA>200 000 IU ml (>6 log10 copies ml). Prior to neonatal prophylaxis with HBIG and HBV vaccination (see detailed description in the following section), the risk of perinatal transmission of HBV infection ranged from 10 to 40%, with 40 to 70% of those infants remaining chronically infected. The risk of MTCT was more than 90% when mothers had high HBV DNA levels and were HBeAg-positive (indicative of active viral replication and infectivity), and almost all of these infected infants became chronic HBsAg carriers. Young women in the immune-tolerant phase of chronic HBV infection are at high risk (up to 30%) for MTCT of HBV infection, regardless of neonatal immunoprophylaxis with HBIG and HBV vaccine. In contrast, chronic HBV infection occurred in fewer than 10% of infants of HBeAg-negative mothers. Other risk factors for MTCT of HBV include threatened preterm labor, prolonged labor and prior failure of immunoprophylaxis in siblings.
MTCT of HBV can occur at three stages of pregnancy: intrauterine, intra-partum or post-partum. MTCT of HBV infection is thought to occur predominantly at or after birth based on the high protective efficacy of immunoprophylaxis. Intrauterine MTCT of HBV is reported to occur in 10 to 16% of pregnancies and probably accounts for the small percentage of infants who do not respond to immunoprophylaxis treatment for HBV at birth. Intrauterine transplacental transmission due to leakage of maternal blood can occur during threatened abortion. The risk of transmission of HBV from amniocentesis is low; in one study, the rate of MTCT did not significantly differ between women with HBV who underwent amniocentesis from those who did not undergo amniocentesis (9 vs 11%). The effect of other invasive procedures during pregnancy (chorionic villus sampling, cordocentesis, fetal surgery) on the risk of HBV transmission is unknown. No association between forceps or vacuum extraction during delivery and risk of HBV transmission has been demonstrated.
Prevention of MTCT of HBV Infection
Successes and Failures of Immunoprophylaxis: HBIG and HBV Vaccination at Birth. Current standard of care for the prevention of MTCT of HBV infection is treatment of the newborn with HBIG and HBV vaccination (Table 3). At-risk neonates who received HBV vaccine alone at birth had a 26 to 36% chance of MTCT of HBV infection, whereas administration of HBIG alone at birth decreased the rate of perinatal HBV transmission to 15 to 20%. If HBIG and the HBV vaccine are administered to the neonate of an HBsAg-positive mother within 12 h of delivery, approximately 5% of infants become chronic HBV carriers, a reduction in MTCT of almost 90%. Overall, the use of HBIG and HBV vaccine has reduced MTCT to 5 to 10%.
The Centers for Disease Control and Prevention (CDC) and the Advisory Committee on Immunization Practices (ACIP) recommend administration of HBV vaccine and HBIG to at-risk infants within 12 h of delivery, followed by completion of the hepatitis B vaccine series within the first year of life. Newborns of mothers with unknown HBsAg status at the time of birth should receive the HBV vaccine within 12 h of birth; if the mother is found to be HBsAg-positive, the infant should receive HBIG as soon as possible (within 7 days of birth).
The 5% of children who develop chronic hepatitis B infection despite immunoprophylaxis either fail to receive the full regimen of HBV vaccination, fail to develop hepatitis B surface antibody (HBsAb) or are born to mothers with very high levels of HBV DNA (>200 000 IU ml or 6 log10 copies ml) or who are HBeAg-positive. Despite immunoprophylaxis, HBV is still transmitted from 8 to 30% of mothers with high levels of HBV DNA and HBeAg positivity. For example, a recent Chinese study demonstrated a dose-dependent correlation between maternal pre-delivery HBV DNA levels and rate of immunoprophylaxis failure. All infants who failed immunoprophylaxis were born to HBeAg-positive mothers with HBV DNA levels ≥6 log10 copies ml (≥200 000 IU ml). In a meta-analysis from the Netherlands, the only factor that significantly affected the efficacy of immunoprophylaxis was the maternal HBV DNA level. There was 100% efficacy with HBV DNA less than 150 pg ml (~10 IU ml; 6 × 7 log10 copies ml), but only 68% efficacy with HBV DNA levels greater than 150 pg ml which is consistent with another report that found a 25 to 50% rate of MTCT of HBV infection with maternal HBV DNA levels over 150 pg ml. Finally, in an Iranian study of infants who received HBIG and HBV vaccine at birth, the rate of HBV infection was 1.5% in infants born to women who were HBeAg-negative and 18% for infants born to women who were HBeAg-positive. HBV DNA levels were not analyzed.
Antiviral Therapy for HBV in Pregnancy. The significant rate of immunoprophylaxis failure in neonates of women with high HBV DNA levels led to the suggestion that antiviral therapy during the last trimester of pregnancy could decrease MTCT by reducing the level of HBV DNA at the time of delivery. To date, several antivirals have been examined, all of which are nucleos(t)ide analogues. In this section, we summarize those data.
Lamivudine, a cytosine analogue that acts as a nucleoside HBV reverse transcriptase inhibitor and thus is a potent replication inhibitor, produces a median 97% reduction in HBV DNA levels after 2 weeks. Multiple randomized controlled trials and two meta-analyses have demonstrated that lamivudine therapy significantly decreases the likelihood of MTCT of HBV infection and is safe for the mother and newborn. The most recent meta-analysis included 15 randomized controlled trials with 1693 HBV carrier mothers and demonstrated that lamivudine treatment beginning at week 28 of pregnancy significantly decreased MTCT of HBV infection (relative risk 0.33 to 0.43); efficacy was dependent on a decrease in maternal HBV DNA levels to less than 6 log10 copies ml (200 000 IU ml). A randomized controlled Chinese trial with lamivudine 100 mg per day in HBeAg-positive mothers with HBV DNA greater than 6 log10 copies ml in the third trimester of pregnancy demonstrated a significant reduction in immunoprophylaxis failure (18 vs 39%). Starting lamivudine therapy at week 32 of pregnancy has been suggested to achieve a sufficient reduction in HBV DNA level in case of an early delivery.
Although lamivudine is a pregnancy category C medication (based on studies in animals showing an adverse effect on the fetus), there are insufficient well-controlled studies in humans. However, potential benefits may warrant the use of the drug in pregnant women despite potential risks. In actuality, the safety profile of lamivudine during pregnancy in women has been reported. The Antiviral Pregnancy Registry documents an extensive experience with use of lamivudine during pregnancy, with no evidence for teratogenicity or adverse effects (www.apregistry.com). However, lamivudine is no longer a first-line option for long-term treatment of non-pregnant patients with chronic HBV because of the high rate of lamivudine-resistance (occurring in 15% of patients per year). Lamivudine has been replaced by tenofovir disoproxil fumarate (TDF) or entecavir for treatment of chronic active HBV infection in non-pregnant patients.
TDF may also be the preferred antiviral for HBV infection in pregnancy given its potency, safety profile and better resistance profile than lamivudine. TDF is a pregnancy category B medication; it has been found to be safe in animal models, but with limited data in humans. There are no prospective studies published for the use of TDF in pregnant women with HBV mono-infection; however, it has been safely used in 1731 pregnant women with HIV (some with HBV co-infection), and the rate of birth defects does not significantly differ from pregnancies not exposed to TDF. Given that TDF, 300 mg daily, is a first-line treatment for chronic active HBV infection, its use during the third trimester to prevent HBV transmission is an appropriate option for mothers who need long-term treatment after delivery, such as patients with chronic active HBV infection, AST or ALT levels greater than 1.5 to 2 times normal, and an HBV DNA level over 20 000 IU ml (5 log10 copies ml).
Telbivudine is another category B anti-HBV agent. Recent prospective studies demonstrated the efficacy of telbivudine 600 mg per day in preventing MTCT when used during the second or third trimesters in HBeAg-positive mothers with HBV DNA>200 000 IU ml (>6 log10 copies ml). In the controlled trial by Han et al., the incidence of perinatal transmission of HBV infection was significantly lower in infants who completed follow-up born to the telbivudine-treated mothers than to controls (0 vs 8%). No differences in maternal adverse events or fetal congenital deformities were observed at 28 weeks after birth.
The safety of these antiviral agents is established by the Antiviral Pregnancy Registry, which has tracked spontaneously reported maternal and fetal outcomes in women receiving oral nucleoside drugs since 1989. As of 31 January 2008, 9889 pregnancies were reported during which the mother had received an oral nucleoside analogue. The overall prevalence of birth defects in infants exposed to any antiretroviral agent during the first trimester of 3.0 per 100 live births (117 of 3951), or in any trimester of 2.8 per 100 live births (261 of 9400), was not significantly different from that reported in the general US population of 2.72 per 100 live births. Only infants exposed to the anti-HIV medication didanosine had a significantly higher rate of birth defects than expected. The prevalence of birth defects with lamivudine exposure in the first trimester (3.1%, 85 of 2784) and with TDF (2.2%, 11 of 491) were similar to population controls. The safety data for telbivudine in the Antiviral Pregnancy Registry are limited.
Because of limited data on secretion of antiviral agents into human breast milk, breast feeding is not recommended by the makers of the nucleos(t)ide analogues if antiviral therapy is continued after delivery. There are scanty data on secretion of TDF or its metabolite, tenofovir, into animal or human breast milk. A single small human study found that small amounts of tenofovir, but not TDF, are present in breast milk of HIV-1-infected women taking TDF, representing 0.03% of the proposed oral HIV-prevention dose of tenofovir for infants. Infant exposure to tenofovir through breastfeeding may be negligible because pharmacologically, TDF is converted into its metabolite, tenofovir, prior to excretion of tenofovir into breast milk, and tenofovir is not absorbed by the adult gastrointestinal tract. Therefore, patients should be counseled regarding the scarcity of information on TDF and breastfeeding, as well as the known benefits of breastfeeding, to make an informed breastfeeding decision.
There are a few reports of lactic acidosis and hepatic steatosis in pregnant patients receiving nucleos(t)ide analogues, so monitoring of liver enzymes and electrolytes is recommended. Postpartum flares of hepatitis may occur after stopping lamivudine in patients who receive it during the last 4 weeks of pregnancy. For this reason, liver enzymes should be monitored after delivery.
Published Guidelines for use of Antiviral Therapy for HBV in Pregnancy. Recent clinical practice guidelines from the European Association for the Study of the Liver (EASL) address antiviral treatment in pregnancy for women with chronic HBV infection (Table 4). It is suggested that women with mild liver disease and low HBV DNA levels (chronic inactive HBV infection) complete pregnancy before antiviral treatment is considered; that women with moderate liver disease and no cirrhosis (chronic active HBV infection) undergo antiviral treatment and discontinue treatment before pregnancy if there is a viral response; that women with advanced liver disease (cirrhosis) receive antiviral treatment before, during and after pregnancy; and that women with mild liver disease and very high HBV DNA levels (immune-tolerant chronic HBV infection) receive a category B anti-viral agent (TDF or telbivudine) in the last trimester of pregnancy. The Asian Pacific Association for the Study of the Liver (APASL) also recommends prophylactic antiviral treatment in pregnant women with high levels of viremia.
One of the most commonly cited American clinical guidelines for management of chronic hepatitis B, authored and updated by Keefe et al., states 'data from clinical studies indicate that women with chronic hepatitis B who have HBV DNA levels>10 copies ml and elevated ALT levels, or who have had an HBsAg-positive child, are candidates for antiviral therapy because of the increased risk for transmission to the newborn.'
A recent publication proposed 'an algorithm for risk assessment and patient management that is based on a review of the literature and the opinion of a panel of physicians with expertise in preventing MTCT'. The authors recommended that pregnant women with chronic HBV infection who are at high risk for MTCT (because of HBV DNA levels>200 000 IU ml or>6 log10 copies ml, a previous child failed HBIG and HBV vaccine, or who threaten abortion or premature delivery) receive antiviral treatment. The recommended antiviral treatment is lamivudine or telbivudine, or TDF for those with chronic active hepatitis B, beginning in the third trimester of pregnancy. (Figure 3)
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Figure 3.
Pregnant women with HBV DNA levels >200 000 IU ml (>6 log10 copies ml), or any HBsAg-positive woman with a threatened abortion, are at high risk for MTCT and should receive antiviral treatment in the third trimester.
Cesarean Section for Prevention of Intrapartum HBV Transmission. There has been little evidence that cesarean delivery prevents HBV transmission, and current guidelines do not recommend cesarean section to decrease the risk of MTCT in pregnant women with chronic HBV infection. Cesarean section would have to be performed before the onset of labor or before the rupture of membranes to be effective. A significant reduction in immunoprophylaxis failure with elective cesarean section for highly viremic mothers was supported by a systematic review and meta-analysis of four randomized trials involving 789 patients. However, it was stated that 'the conclusions of this review must be considered with great caution because of the high risk of bias in each included study (graded C).' Pan et al., analyzed data from 1409 infants born through vaginal delivery, elective cesarean section or urgent cesarean section to HBsAg-positive mothers who completed appropriate immunization against HBV. HBV infection was transmitted to a smaller percentage of infants born by elective cesarean section (1.4%) than by vaginal delivery (3.4%, P<0.032) or urgent cesarean section (4.2%, P<0.020). Urgent cesarean section had no effect on vertical transmission compared with vaginal delivery (P=0.593), whereas infants born by elective cesarean section had a significantly lower rate of vertical transmission than those born by non-elective cesarean section (1.4 vs 36%, P=0.17). Women with HBV DNA levels<6 log10 copies ml did not transmit the infection to their infants, regardless of the method of delivery, and there were no differences in maternal or infant morbidity and mortality among the groups. The authors conclude that elective cesarean sections for HBeAg-positive mothers with levels of HBV DNA ≥6 log10 copies ml could reduce vertical HBV transmission.
Prevention of MTCT of HBV in the Postpartum Period: Breastfeeding is Safe. Although breast milk contains HBsAg, breastfeeding does not increase the risk of MTCT of HBV. A 1975 study reported a 53% rate of HBV transmission in breastfed infants vs 60% in formula-fed infants. Multiple subsequent studies have shown breastfeeding to be safe for children with mothers with chronic HBV infection. Therefore, the American Academy of Pediatrics states that breastfeeding is not contraindicated. According to the prescribing information, use of lamivudine or TDF is not recommended during breastfeeding, though as discussed above, patients should be counseled regarding the scarcity of information on TDF and breastfeeding, as well as the known benefits of breastfeeding, to make an informed breastfeeding decision.
Postnatal Follow-up of Mother and Infant
HBV-infected mothers should be referred to a Hepatology Clinic for evaluation and follow-up. Therapy is considered for individuals infected with HBV who have elevated liver function tests and viral levels greater than 20 000 IU ml (5 log10 copies ml). Post-vaccination testing of the infant for HBsAg and HBsAb should be performed after completion of the vaccination series at 9 to 18 months. Testing performed before 9 months can detect HBsAb from HBIG administered during infancy and can miss late HBV infection.