SMFM answers questions on preventing vertical transmission of hepatitis B during pregnancy.
Society for Maternal-Fetal Medicine (SMFM); Jodie Dionne-Odom, MD Alan TN Tita, MD, PhD; and Neil S Silverman, MD
This Maternal-Fetal Medicine (MFM) consult provides information regarding the risks, diagnosis, and management of hepatitis B in pregnancy and the prevention of vertical transmission. The purpose of this document is to aid clinicians in counseling their patients regarding the risk and management options available after a positive test for hepatitis B surface antigen (HBsAg).
Between 800,000 and 1.4 million people in the United States and more than 240 million people worldwide are infected with hepatitis B virus (HBV). Specific to pregnancy, an estimated prevalence of 0.7% to 0.9% for chronic hepatitis B infection among pregnant women in the United States has been reported, with more than 25,000 infants at risk for chronic infection born annually to these women.
While transmission through sexual intercourse and intravenous drug abuse are the major risk factors for acquisition of hepatitis B among adults in the United States, perinatal transmission is responsible for up to 50% of HBV infections worldwide (Table 1). Universal screening for hepatitis B infection during pregnancy is recommended by both the American College of Obstetricians and Gynecologists and the US Preventative Services Task Force at the first prenatal visit.
In contrast to HBV acquisition in adulthood, which more commonly leads to acute resolved infection and immunity, perinatal/neonatal HBV is more likely to lead to chronic infection and its long-term disease risks.
The presence of HBsAg in maternal blood more commonly represents chronic infection than acute infection. While some adults will be identified because of symptomatic illness, the vast majority of chronically infected adults are asymptomatic. The diagnosis of the chronic carrier state is confirmed by persistence of HBsAg and absence of hepatitis B surface antibody (HBsAb). HBsAb is also detected after successful immunization with the HBV vaccine. Hepatitis B core antibody (HBcAb), on the other hand, develops in the setting of natural infection, never from immunization, and persists regardless of whether the acute infection is cleared or becomes chronic.
The most common risk for perinatal HBV infection occurs when an infant comes into contact with infected vaginal blood and secretions at the time of delivery. Invasive procedures during labor and delivery (including internal monitors, episiotomy, and operative vaginal delivery) may theoretically increase the risk of transmission. However, the availability of neonatal HBV immunoprophylaxis is thought to ameliorate these risks, and current opinions do not support altering regular obstetric practices. Elective cesarean delivery has also been discussed as one way to reduce vertical transmission, but it is not recommended because available data are conflicting and of poor quality. Similarly, in the setting of neonatal HBV immunoprophylaxis, breastfeeding is not contraindicated.
Concerns have also been raised regarding invasive diagnostic procedures during pregnancy, such as amniocentesis, because they would occur well before the timing for immunoprophylaxis. However, the majority of reported earlier series did not demonstrate an increased risk of in utero infection after amniocentesis with chronic HBV infection. These series were conducted before routine use of HBV viral load testing as a disease marker; therefore, it may not apply to women with very high viral load, as defined below.
HBV viral load has been shown to be directly related to the risk of disease progression in infected adults. In interpreting studies reporting outcomes and indications for treatment in relation to viral load, the results are inconsistently reported in relation of HBV units. Some studies provide data in the form of copies/mL, while others report in IU/mL, despite the fact that the World Health Organization (WHO) has recommended that HBV DNA be expressed in terms of IU/mL. Conversion is straightforward: To convert from IU/mL to copies/mL, the IU/mL value should be multiplied by 5.6 (or the copies/mL value similarly divided).
In a large prospective cohort, an HBV-DNA level > 104 copies/mL was associated with significantly higher rates of cirrhosis, hepatocellular carcinoma, and death, independent of hepatitis B e-antigen (HBeAg) status as a surrogate marker of viremia. Randomized controlled trials were subsequently conducted evaluating the use of antivirals in HBV-infected adults. Some of the single-agent antivirals studied-specifically lamivudine and tenofovir-had been used to treat HIV infection. One of the earlier trials of lamivudine demonstrated significantly less progression of hepatic fibrosis and cirrhosis over 32 months compared to placebo, but a high proportion of patients also developed drug resistance. Subsequent trials of tenofovir and entecavir, another reverse transcriptase inhibitor, showed sustained viral suppression below detectable levels and reversal of hepatic histopathology without similar levels of resistance.
As a result, the American Association for the Study of Liver Diseases (AASLD) issued revised guidelines in 2009 for the treatment of chronic HBV infection, moving tenofovir and entecavir to first-line therapies, with lamivudine not a first-line agent due to resistance concerns.
While neonatal use of hepatitis B immune globulin (HBIG) and HBV vaccine has dramatically lowered rates of perinatal HBV transmission, concern persisted regarding the 5% to 15% of newborns who are infected despite receiving appropriate neonatal immunoprophylaxis. Maternal HBV-DNA level has been demonstrated to be the strongest predictor of neonatal immunoprophylaxis failure, with a lower prophylaxis effective rate directly related to a higher maternal viral load. Most recently, a maternal HBV-DNA level > 6 log10 ( > 1 million) copies/mL (5.2 log IU/mL) at delivery appears to be most important predictor of in utero mother-to-child transmission (MTCT) and prophylaxis failure.
Initial nonrandomized efforts to lower maternal HBV viremia in an effort to decrease MTCT rates used HBIG in variable dosing regimens during the third trimester.
A recent Cochrane analysis showed no benefit of HBIG when used in this manner, commenting on the poor methodologic quality of the studies in general, and raising concern for the development of immune complex disease in treated mothers who received repeated dosing of immunoglobulin.
As a result of the poor performance of HBIG as an intervention to lower the risk of in utero HBV infection, researchers turned to evaluating the use of HBV antivirals during pregnancy to potentially lower maternal viremia and reduce MTCT as a result. To date, small, mostly nonrandomized series have been published studying the use of lamivudine, telbivudine, entecavir, and tenofovir for this purpose. Lamivudine has been the agent used most frequently in recent trials, due to its better-established safety profile in pregnancy in the setting of maternal HIV infection, although tenofovir also has an enlarging body of registry-based data supporting its use in pregnancy. A recent meta-analysis of data on the use of lamivudine during pregnancy for this purpose included 10 trials, although only were placebo-controlled; compared to placebo, treatment with lamivudine starting at 24 to 32 weeks’ gestation through 4 weeks postpartum resulted in a (significant) 80% decrease in MTCT of HBV (OR 0.2 [0.10–0.39]; P < 0.001). Concerns still exist, however, about the use of lamivudine as a single agent for this purpose due its association with high rates of resistance, reported as up to 32% after 1 year, and its potential implications for treatment of the woman after delivery, should it become necessary. In addition, in one larger recent series, 62% of women treated during pregnancy with lamivudine experienced a significant postpartum flare in their liver function test (LFT) results when their medication was stopped.
Based on these studies and others, the use of lamivudine, tenofovir, or telbivudine after 28 to 32 weeks’ gestation for HBV-infected women with high viral loads (>106 108 copies/mL) has been suggested, in addition to administration of both HBV vaccine and HBIG within 12 to 24 hours of birth, to minimize in utero infection and to maximize neonatal HBV prevention.
Many pregnancy women with HBV/HIV coinfection are already being treated with dually active agents-tenofovir, emtricitabine, or lamivudine-and trials showing efficacy and safety in this population are ongoing. A recent analysis of antiretroviral registry data looking specifically at the fetal safety profiles of the subgroup of anti HIV agents also effective against HBV demonstrated no increase in exposure risk. Finally, regarding breastfeeding, the use of lamivudine and tenofovir in the postpartum period is not currently recommended solely for HBV prevention until additional data are available.
No guidelines currently exist in the United States regarding the use of antiviral therapy against HBV during pregnancy specifically for the goal of decreasing the risk of in utero infection and vertical transmission. Precedent for establishment of universal guidelines exists already in Europe, where both the European Association for the Study of the Liver (EASL) and the UK’s National Institute for Health and Care Excellence published such guidelines in 2012 and 2013, respectively. Both agencies currently advocate discussion of antiviral therapy with HBV-infected pregnant women with viral loads > 6–7 log 10 IU/mL (6.7–7.7 log 10 copies/mL), with treatment to be offered in the third trimester. HBV-targeted maternal antiviral therapy in the third trimester should be considered to reduce transmission in cases in which maternal viral load > 6–8 log 10 copies/mL.
Identification of a pregnant woman as chronically HBV-infected also presents an important opportunity to counsel her regarding risks to other family and household members. HBV is most easily transmitted via sexual exposure or blood exposure but can also be transmitted through casual shared use of household items such as eating utensils and toothbrushes, as well as through personal contact such as kissing or routine childcare. Therefore, family and household members should be evaluated for HBV status and referred for vaccination if found to be uninfected and non immune. The pregnant woman should also be assessed for immunity status for hepatitis A and offered vaccination if not immune, since coinfection with another viral hepatitis results in compounded morbidity. The woman should also be counseled regarding exposures to potentially hepatotoxic medications, even those available over the counter, such as acetaminophen, and avoidance of the use of alcohol even when not pregnant.
The majority of pregnant women diagnosed with chronic HBV infection will be asymptomatic and identified through routine screening with initial prenatal labs. To aid in counseling regarding risks and potential management options as outlined above, baseline liver function tests should also be drawn when a positive HBsAg test result is obtained, along with a baseline quantitative HBV-DNA level. Consideration should also be given to referral to a maternal-fetal medicine subspecialist or an infectious diseases specialist or hepatologist with experience managing hepatitis B to coordinate care and surveillance for the woman during and after pregnancy. If baseline HBV-DNA polymerase chain reaction testing is negative, it may be repeated in the third trimester, because that is usually the time when consideration is given to beginning antiviral treatment in women with high viral loads. Even if the maternal viral load is low and antiviral therapy during pregnancy is not recommended, the newborn should still receive standard prophylaxis with HBIG and HBV vaccine within 12 hours of birth, and ongoing surveillance of the woman’s hepatic function after pregnancy is indicated.