Between 800,000-1.4 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 0.7-0.9% for chronic hepatitis B infection among pregnant women in the United States has been reported, with >25,000 infants at risk for chronic infection born annually to these women. Vertical transmission of HBV from infected mothers to their fetuses or newborns, either in utero or peripartum, remains a major source of perpetuating the reservoir of chronically infected individuals globally. Universal screening for hepatitis B infection during pregnancy has been recommended for many years. Identification of pregnant women with chronic HBV infection through universal screening has had a major impact in decreasing the risk of neonatal infection. The purpose of this document is to aid clinicians in counseling their patients regarding perinatal risks and management options available to pregnant women with hepatitis B infection in the absence of coinfection with HIV. We recommend the following: (1) perform routine screening during pregnancy for HBV infection with maternal HBsAg testing (grade 1A); (2) administer hepatitis B vaccine and HBV immunoglobulin within 12 hours of birth to all newborns of HBsAg-positive mothers or those with unknown or undocumented HBsAg status, regardless of whether maternal antiviral therapy has been given during the pregnancy (grade 1A); (3) In pregnant women with HBV infection, we suggest HBV viral load testing in the third trimester (grade 2B); (4) in pregnant women with HBV infection and viral load >6-8 log 10 copies/mL, HBV-targeted maternal antiviral therapy should be considered for the purpose of decreasing the risk of intrauterine fetal infection (grade 2B); (5) in pregnant women with HBV infection who are candidates for maternal antiviral therapy, we suggest tenofovir as a first-line agent (grade 2B); (6) we recommend that women with HBV infection be encouraged to breast-feed as long as the infant receives immunoprophylaxis at birth (HBV vaccination and hepatitis B immunoglobulin) (grade 1C); (7) for HBV infected women who have an indication for genetic testing, invasive testing (eg amniocentesis or chorionic villus sampling) may be offered–counseling should include the fact that the risk for maternal-fetal transmission may increase with HBV viral load >7 log 10 IU/mL (grade 2C); and (8) we suggest cesarean delivery not be performed for the sole indication for reduction of vertical HBV transmission (grade 2C).
All authors and Committee members have filed conflict of interest disclosure delineating personal, professional, and/or business interests that might be perceived as a real or potential conflict of interest in relation to this publication. Any conflicts have been resolved through a process approved by the Executive Board. The Society for Maternal-Fetal Medicine has neither solicited nor accepted any commercial involvement in the development of the content of this publication.
Introduction
Obstetric providers are challenged continuously with the evaluation of the potential benefits and harms of new diagnostic and therapeutic procedures or treatments for patients (mother and fetus), often in the setting of limited high-quality data (eg, from randomized clinical trials). The purpose of this document is to aid clinicians in counseling their patients regarding the risk and management options available after a positive hepatitis B surface antigen (HBsAg) test result.
What risks and potential impact does hepatitis B infection present during pregnancy?
Between 800,000-1.4 million people in the United States and >240 million people worldwide are infected with hepatitis B virus (HBV). From a global public health perspective, chronic HBV infection is the major source of hepatocellular carcinoma, leading to 50% of cases worldwide and 80% in high-endemic areas for HBV. Specific to pregnancy, an estimated prevalence of 0.7-0.9% for chronic hepatitis B infection among pregnant women in the United States has been reported, with >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 infection worldwide ( Table 1 ). Vertical transmission of HBV from infected mothers to their fetuses or newborns, either in utero or peripartum, remains a major source of perpetuating the reservoir of chronically infected individuals globally. It has been demonstrated that prenatal risk factor–based screening alone will miss many chronic HBV infections among pregnant women, thereby missing the opportunity to interrupt perinatal transmission via established neonatal protocols. For this reason, universal screening for hepatitis B infection during pregnancy at the first prenatal visit has been recommended for many years by both the American Congress of Obstetricians and Gynecologists and the US Preventative Services Task Force.
| Multiple sexual partners |
| Intravenous drug use |
| Household or sexual contacts of HBV carriers |
| Infants born to HBV-infected women |
| Patients and staff who work or live in an institutional setting |
| Hemodialysis patients |
| Health care workers with contact with patient blood |
| Persons born in countries with high HBV seroprevalence |
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. Chronic hepatitis B infection will develop in up to 90% of exposed neonates who do not receive appropriate immunoprophylaxis, in contrast to 10-25% of infected children and only 5-10% of exposed immunocompetent adults. Among all individuals with chronic HBV infection, regardless of the timing of infection, 20% will eventually die from complications of HBV infection including cirrhosis, end-stage liver disease, and liver cancer.
With the exception of the major risk of perinatal transmission (see below), data are insufficient to suggest that acute or chronic HBV infection is associated with adverse pregnancy outcomes such as preterm birth, low birth weight, or gestational diabetes. However, cirrhosis due to chronic HBV may be associated with increased maternal and perinatal death, gestational hypertension, abruption, preterm birth, and fetal growth restriction.
What risks and potential impact does hepatitis B infection present during pregnancy?
Between 800,000-1.4 million people in the United States and >240 million people worldwide are infected with hepatitis B virus (HBV). From a global public health perspective, chronic HBV infection is the major source of hepatocellular carcinoma, leading to 50% of cases worldwide and 80% in high-endemic areas for HBV. Specific to pregnancy, an estimated prevalence of 0.7-0.9% for chronic hepatitis B infection among pregnant women in the United States has been reported, with >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 infection worldwide ( Table 1 ). Vertical transmission of HBV from infected mothers to their fetuses or newborns, either in utero or peripartum, remains a major source of perpetuating the reservoir of chronically infected individuals globally. It has been demonstrated that prenatal risk factor–based screening alone will miss many chronic HBV infections among pregnant women, thereby missing the opportunity to interrupt perinatal transmission via established neonatal protocols. For this reason, universal screening for hepatitis B infection during pregnancy at the first prenatal visit has been recommended for many years by both the American Congress of Obstetricians and Gynecologists and the US Preventative Services Task Force.
| Multiple sexual partners |
| Intravenous drug use |
| Household or sexual contacts of HBV carriers |
| Infants born to HBV-infected women |
| Patients and staff who work or live in an institutional setting |
| Hemodialysis patients |
| Health care workers with contact with patient blood |
| Persons born in countries with high HBV seroprevalence |
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. Chronic hepatitis B infection will develop in up to 90% of exposed neonates who do not receive appropriate immunoprophylaxis, in contrast to 10-25% of infected children and only 5-10% of exposed immunocompetent adults. Among all individuals with chronic HBV infection, regardless of the timing of infection, 20% will eventually die from complications of HBV infection including cirrhosis, end-stage liver disease, and liver cancer.
With the exception of the major risk of perinatal transmission (see below), data are insufficient to suggest that acute or chronic HBV infection is associated with adverse pregnancy outcomes such as preterm birth, low birth weight, or gestational diabetes. However, cirrhosis due to chronic HBV may be associated with increased maternal and perinatal death, gestational hypertension, abruption, preterm birth, and fetal growth restriction.
How are HBV-infected pregnant women identified and what have been traditional approaches to their pregnancies?
Identification of pregnant women with chronic HBV infection through universal screening has had a major impact in decreasing the risk of neonatal infection. Recent data demonstrate that 95% of pregnant women are currently screened prior to delivery for evidence of chronic HBV infection, with rates of perinatal transmission decreasing significantly over the past 2 decades.
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 with persistence of HBsAg and the absence of hepatitis B surface antibody (HBsAb), which is a neutralizing antibody that can be detected after HBV infection has been cleared. HBsAb and HBsAg essentially do not exist together. HBsAb is also detected after successful immunization with the HBV vaccine. Therefore, we suggest performing routine screening during pregnancy for HBV infection with maternal HBsAg testing (GRADE 1A). Hepatitis B core antibody, 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 ( Table 2 ). It is emphasized strongly that pregnancy is not a contraindication to hepatitis B vaccination. Pregnant women who are identified as being at risk for HBV infection during pregnancy (eg, having >1 sex partner during the previous 6 months, been evaluated or treated for a sexually transmitted disease, recent or current injection drug use, or having had an HBsAg-positive sex partner) should be vaccinated.
The most common risk for perinatal HBV infection occurs when the 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 since available data are conflicting and of poor quality. We suggest cesarean delivery not be performed for the sole indication for reduction of vertical HBV transmission (GRADE 2C). Similarly, in the setting of neonatal HBV immunoprophylaxis, breast-feeding is not contraindicated. Studies have documented no difference in rates of infection between breast-fed and formula-fed vaccinated infants born to HBV-infected women, with rates in both groups between 0-5%. We recommend that women with HBV infection be encouraged to breast-feed as long as the infant receives immunoprophylaxis at birth (HBV vaccination and hepatitis B immunoglobulin) (GRADE 1C).
Concerns have also been raised regarding invasive diagnostic procedures during pregnancy, such as amniocentesis, since these would occur well before the timing for immunoprophylaxis. However, the majority of reported earlier series did not demonstrate an increased risk for in utero infection after amniocentesis in women with chronic HBV infection. These series were conducted before the routine use of HBV viral load testing as a disease marker; therefore, it may not apply to women with very high viral load as will be defined in a later section. In fact, a recent series did demonstrate an increase in risk for in utero infection after amniocentesis in women with viral titers >7 log 10 copies/mL, compared to those women with titers below that cutoff (50% vs 4%; odds ratio, 21.3; P = .006). Such emerging data may have an impact on counseling surrounding invasive prenatal testing as data accumulate from more series using maternal HBV viral load titers. For HBV-infected women who have an indication for genetic testing, invasive testing (eg amniocentesis or chorionic villus sampling) may be offered. Counseling should include the fact that the risk for maternal-fetal transmission may increase with HBV viral load >7 log 10 copies/mL (GRADE 2C).
What has been the traditional approach to preventing neonatal HBV infection?
The mainstay of perinatal HBV infection prevention is a combination of active and passive immunization for exposed infants. Before the development of an HBV vaccine, HBV immunoglobulin (HBIG) alone, administered within 12 hours of delivery, was shown to be effective in providing transient passive immunity, but 25% of infants became infected through household contact by 1 year of age. When the vaccine became available in the 1980s, it was subsequently shown that a combination of HBV vaccine and HBIG given within the first 12 hours after birth gave the greatest degree of durable protection, conferring long-term immunity in 85-95% of cases. Immunoprophylaxis is also recommended for infants born to mothers with unknown or undocumented HBsAg status. Completion of the full 3-dose HBV vaccine series following the birth-dose vaccine is important for the newborn to gain maximal protection and is recommended for all infants irrespective of maternal HBV infection status. This approach has shown significant impact on longer-term disease outcome measures for newborns who received prophylaxis in areas that are endemic for HBV infection. In Taiwan, the institution of a universal screening and immunization program lowered the rate of chronic HBV infection among children from 10% to 1% during a 10-year period. Concurrently, the rate of childhood hepatocellular carcinoma was lowered by half in the same population, from 0.7 to 0.36 per 100,000. We recommend administering hepatitis B vaccine and HBIG within 12 hours of birth to all newborns of HBsAg-positive mothers or those with unknown or undocumented HBsAg status, regardless of whether maternal antiviral therapy has been given during the pregnancy (GRADE 1A).
How has the approach to treating HBV infection in general changed recently?
As was shown with the evolution of management of HIV-related illness, the use of HBV viral load as a predictor of disease progression and as a measure of treatment response has been a major factor regarding development of treatment models for HBV-related disease. This has resulted in development of treatment protocols for lowering and even eliminating viremia in HBV-infected adults, with evolving corollary implications for management during pregnancy.
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 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 from Taiwan, an HBV-DNA level >4 log 10 copies/mL was associated with significantly higher rates of cirrhosis, hepatocellular carcinoma, and death, independent of hepatitis B e-antigen status as a surrogate marker of viremia. Randomized controlled trials were subsequently conducted evaluating the use of antivirals in HBV-infected adults in an attempt to lower viremia and, in turn, lower long-term disease risks. Some of the single-agent antivirals studied had been used to treat HIV infection, specifically lamivudine and tenofovir. One of the earlier trials using lamivudine demonstrated significantly less progression of hepatic fibrosis and cirrhosis over 32 months compared to placebo, but also that drug resistance developed in a high proportion of patients. Subsequent trials using 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 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. More recent reports have demonstrated that in chronically infected adults, tenofovir monotherapy has maintained HBV-DNA suppression while used for up to 6 years of continuous treatment, with no evidence of tenofovir resistance, even in patients whose virus became resistant to lamivudine. Table 3 outlines the characteristics, results, and resistance risks of currently available and studied HBV antivirals.
