INTRODUCTION — Hepatitis B virus (HBV) infection during pregnancy presents with unique management issues for both the mother and the fetus. These include the effects of HBV on maternal and fetal health, the effects of pregnancy on the course of HBV infection, treatment of HBV during pregnancy, and prevention of mother-to-child transmission.
Prevention of mother-to-child transmission is an important component of global efforts to reduce the burden of chronic HBV since vertical transmission is responsible for approximately one-half of chronic infections worldwide. The risk of developing chronic HBV infection is inversely proportional to the age at time of exposure. The risk is as high as 90 percent in those exposed at birth without vaccination, while the risk is much lower (about 20 to 30 percent) in those exposed during childhood. Maternal screening programs and universal vaccination of infants have significantly reduced transmission rates.
This topic will review special considerations for the management of patients with acute and chronic HBV infection during pregnancy and the postpartum period, as well as prevention of mother-to-child transmission.
We recognize that not all pregnant, postpartum, and lactating individuals identify as women or mothers. Using gender-inclusive language, however, is not possible in all languages and all countries and for all our readers. The topics discussed here are based on risks driven by biological sex and not gender identify. Therefore, throughout this topic, we use the term "woman" to signify a person of the female sex (regardless of gender identity) and the term "mother" to signify the female biological parent of a child (regardless of gender identity).
Additional topic reviews that address prevention and management of HBV infection in children, and liver disease in pregnancy, are found elsewhere:
●(See "Acute fatty liver of pregnancy".)
ACUTE HEPATITIS B VIRUS INFECTION — Acute viral hepatitis is the most common cause of jaundice in pregnancy . Other causes include liver diseases associated with pregnancy, such as acute fatty liver of pregnancy, hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome, and intrahepatic cholestasis of pregnancy. (See "Approach to evaluating pregnant patients with elevated liver biochemical and function tests" and "Acute fatty liver of pregnancy" and "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)" and "Intrahepatic cholestasis of pregnancy".)
Acute hepatitis B virus (HBV) infection during pregnancy is usually mild and not associated with increased mortality or teratogenicity [1,2]. Thus, infection during gestation should not prompt consideration of termination of the pregnancy. However, there have been reports of an increased incidence of low birth weight and prematurity in infants born to mothers with acute HBV infection [2,3].
Acute HBV infection occurring early in the pregnancy has been associated with a 10 percent perinatal transmission rate . Transmission rates significantly increase if acute infection occurs at or near the time of delivery, with rates as high as 60 percent reported . Thus, serial monitoring should be performed throughout pregnancy, and if the mother remains hepatitis B surface antigen (HBsAg) positive or has detectable serum HBV DNA, the infant should receive hepatitis B immune globulin in addition to the first dose of the hepatitis B vaccine at birth. Antiviral therapy to reduce maternal viral load should also be considered if the mother has high serum HBV DNA levels near the time of delivery. (See 'Prevention of mother-to-child transmission' below.)
Treatment of acute infection is mainly supportive. Liver biochemical tests and prothrombin time should be monitored. Antiviral therapy is usually unnecessary, except in women who have acute liver failure or protracted severe hepatitis . (See "Hepatitis B virus: Overview of management", section on 'Acute infection'.)
For those with acute HBV infection who require antiviral therapy, the choice of which agent to use should be based upon the predicted duration of treatment and the accessibility and cost for the patient. Tenofovir disoproxil fumarate (TDF) (300 mg daily) or lamivudine (100 mg daily) are both suitable options in this setting because both have been safely used during pregnancy, and the risk of developing resistance is low since the duration of treatment is expected to be short . However, we prefer TDF as there is less risk of resistance. A more detailed discussion of the safety of antiviral agents for the treatment of HBV during pregnancy is found below. (See 'Safety of antiviral agents in pregnancy' below.)
CHRONIC HEPATITIS B VIRUS INFECTION
Impact of pregnancy on the natural history of chronic HBV — Pregnancy is generally well tolerated in women with chronic hepatitis B virus (HBV) infection who do not have advanced liver disease. However, pregnancy is considered to be an immune-tolerant state and is associated with high levels of adrenal corticosteroids that may modulate immune response. Thus, the following clinical manifestations may be seen in pregnant women with chronic HBV:
●Hepatic flares – The immunological changes during pregnancy and the postpartum period have been associated with hepatitis flares (including hepatic decompensation); however, flares with serious clinical sequelae appear to be uncommon [6,7]. A flare of HBV infection is typically defined as a greater than two- to threefold rise in the alanine aminotransferase (ALT) that is at least three to five times above the reference range. During the postpartum period, flares may be related to immune reconstitution, a situation immunologically analogous to flares that have been described following the withdrawal of immunosuppressive medications in nonpregnant patients with chronic HBV [8-10].
In a prospective study that followed 126 women during pregnancy and the postpartum period, two patients developed a flare during pregnancy whereas 27 (25 percent) developed a flare in the postpartum period . A subsequent retrospective study of 310 pregnant women in the United States with 388 pregnancies found the incidence of hepatitis flares to be low and similar during pregnancy and within six months postdelivery (14 and 16 percent, respectively), although this study was limited by a high percentage of women with missing hepatitis B e antigen (HBeAg) and HBV DNA during pregnancy and a high percentage with missing ALT postpartum .
Predictors of HBV flares during pregnancy have not been established. However, flares appear to be more common in women who are HBeAg positive [7,11]. In addition, flares have been associated with HBeAg seroconversion in approximately 12 to 17 percent of patients , a rate similar to what has been described in patients who are not pregnant. Limited evidence suggests that seroconversion is unrelated to maternal age, parity, or the presence of precore or basal core promotor mutations [8,12]. (See "Hepatitis B virus: Clinical manifestations and natural history", section on 'Immune-active, HBeAg-negative'.)
●Progression of liver disease – The immunologic, metabolic, and hemodynamic changes that occur during pregnancy have the potential to worsen or unmask underlying liver disease. Although progression to cirrhosis is not expected within such a short time for most patients, decompensation can occur in the setting of a severe flare.
However, it can be difficult to assess the progression of liver disease during pregnancy because of normal physiologic changes that can mimic clinical features of chronic liver disease. In particular, serum albumin and hematocrit often decrease, while alkaline phosphatase and alpha fetoprotein increase. Similarly, physical examination may reveal findings suggestive of stigmata of chronic liver disease such as palmar erythema, lower extremity edema, and spider angiomata.
●HBV DNA – The immunologic changes associated with pregnancy also have the potential to increase HBV viremia; however, most studies have found that HBV DNA levels remain stable during pregnancy [13,14].
Effect of chronic HBV on pregnancy outcomes — For mothers with chronic HBV, the impact of HBV infection on newborns is not well defined and data are conflicting [15-23]. As an example, one large study compared 824 hepatitis B surface antigen (HBsAg)-positive women with 6281 HBsAg-negative controls . No differences were seen in gestational age at delivery, birth weight, incidence of prematurity, neonatal jaundice, congenital anomalies, or perinatal mortality. However, other studies have found possible associations between chronic HBV and gestational diabetes mellitus [15,16,20], increased risk of prematurity , lower birth weight , and antepartum hemorrhage .
Women with cirrhosis are at significant risk for perinatal complications and poor maternal and fetal outcomes , including intrauterine growth restriction, intrauterine infection, premature delivery, and intrauterine fetal demise. The increased risk was demonstrated in a population-based study in Canada, which compared maternal and fetal outcomes in 399 patients with cirrhosis to a matched control group who delivered between 1993 and 2005 . Maternal complications including gestational hypertension, placental abruption, and peripartum hemorrhage were increased in the group with cirrhosis. In addition, 15 percent of mothers with cirrhosis developed hepatic decompensation. Overall mortality was significantly higher than controls (1.8 versus 0 percent). Infants born to mothers with cirrhosis also had higher rates of prematurity and growth restriction and significantly higher rates of fetal mortality (5.2 versus 2.1 percent). Other reports have described an increased risk of variceal bleeding, particularly during the third trimester and during labor because of increased intra-abdominal pressure and plasma volume expansion. (See "Pregnancy in women with pre-existing chronic liver disease", section on 'Cirrhosis and portal hypertension'.)
A discussion of mother-to-child transmission is found below. (See 'Mother-to-child transmission' below.)
Management considerations — Various factors need to be assessed when determining the management of pregnant women with chronic HBV during pregnancy, including the indications for treatment, the anticipated duration of therapy, the potential adverse effects to the fetus, the risk of developing drug resistance, and the accessibility and cost of the antiviral agents. The health of the mother and fetus must be considered independently when deciding on treatment. Pregnant women with chronic HBV should be managed in conjunction with a hepatologist.
Patients who are pregnant — Some patients with chronic HBV require antiviral therapy to prevent progression of liver disease (eg, those with immune-active hepatitis), while others can be observed.
●Patients who become pregnant while receiving antiviral therapy – Women should inform their clinician immediately if they become pregnant while receiving antiviral therapy, and the risks and benefits of continuing treatment should be discussed. Continuing treatment may pose a risk to the fetus while discontinuing treatment may pose a risk of hepatitis flare for the mother.
Discontinuing treatment can be considered in women without cirrhosis if the patient has achieved a therapeutic endpoint (see "Hepatitis B virus: Overview of management", section on 'Duration and treatment endpoints'). Otherwise, women receiving entecavir, adefovir, interferon, or tenofovir alafenamide (a formulation of tenofovir that was approved in 2016) can continue treatment by switching to an alternative agent, such as tenofovir disoproxil fumarate (TDF), which has more safety data available and appears to be safe for use in pregnancy. These women should be monitored closely during the transition period to ensure viral suppression. A more detailed discussion of the safety of antiviral agents during pregnancy is found below. (See 'Safety of antiviral agents in pregnancy' below.)
●Indications for antiviral therapy – The decision to initiate therapy while pregnant depends upon the presence or absence of cirrhosis, HBeAg, and hepatitis B e antibody (anti-HBe), as well as the HBV DNA and aminotransferase levels . (See "Hepatitis B virus: Overview of management", section on 'Indications for antiviral therapy' and "Hepatitis B virus: Overview of management".)
The indications for antiviral therapy in pregnant women are generally the same as those for patients who are not pregnant. Antiviral therapy is recommended for patients with a persistently elevated ALT >2 times the upper limit of normal and an elevated HBV DNA (HBV DNA >20,000 international units/mL in HBeAg-positive patients or HBV DNA ≥2000 international units/mL in HBeAg-negative patients) (table 1).
However, for those without cirrhosis, some scenarios may differ. As examples:
•During pregnancy, a person may choose to defer therapy until after delivery if there is only evidence of mild disease activity, such as aminotransferase levels just above the treatment threshold.
•By contrast, a person with a viral load >2 x 105 international units/mL during pregnancy should initiate therapy in the third trimester, even if the aminotransferase levels are normal. In this setting, the goal of therapy is to prevent transmission to the child. The use of antiviral therapy to prevent maternal fetal transmission is discussed below. (See 'Maternal antiviral therapy to prevent transmission' below.)
TDF is preferred if antiviral therapy is contemplated during pregnancy because of its potency; safety profile, including use during first trimester; and low risk of resistance. There is accumulating data that tenofovir alafenamide may also be safe in pregnancy [26-28]. (See 'Maternal antiviral therapy to prevent transmission' below and 'Safety of antiviral agents in pregnancy' below.)
●Monitoring those without indications for antiviral therapy – Women who are not on antiviral therapy during pregnancy should be monitored closely to evaluate for a flare (see 'Impact of pregnancy on the natural history of chronic HBV' above):
•We obtain liver biochemical tests every three months during pregnancy and for up to six months postpartum. Thereafter, monitoring will be the same as for other hepatitis B patients not requiring antiviral therapy, generally every six months for HBeAg-positive patients in the immune tolerant phase and every 6 to 12 months for those who are confirmed to be in the inactive carrier phase (table 2). (See "Hepatitis B virus: Overview of management".)
•HBV DNA should be tested concurrently or when there is ALT elevation. In addition, the HBV DNA should be measured at 26 to 28 weeks to determine if antiviral therapy should be offered to reduce the risk of mother-to-child transmission. (See 'Maternal antiviral therapy to prevent transmission' below.)
●Patients with cirrhosis – The management of cirrhosis in a pregnant woman does not differ from that of nonpregnant patients. Variceal screening with endoscopy is still recommended and is safe during pregnancy. Active variceal bleeding should be managed the same way with banding. Indications for use of beta blockade for prophylactic or postvariceal bleeding management is the same as in nonpregnant individuals, but the use of beta blockers is associated with a small increase in risk of intrauterine growth restriction, fetal/neonatal bradycardia, neonatal hypoglycemia, and/or neonatal respiratory depression. Octreotide should not be given during management of acute variceal bleeding because of the risk of uterine ischemia. A more detailed discussion of the management of pregnant women with cirrhosis is found elsewhere. (See "Pregnancy in women with pre-existing chronic liver disease", section on 'Cirrhosis and portal hypertension'.)
Patients with childbearing potential — Indications for antiviral therapy are the same as those for patients who do not have childbearing potential. They are determined by the HBeAg status, the HBV DNA level, and the activity or stage of liver disease. (See "Hepatitis B virus: Overview of management".)
However, there are important considerations in women of child-bearing potential:
●Those with mild liver disease who are planning to conceive in the near future may choose to defer treatment and be observed until they have completed childbearing.
●Those who elect to undergo treatment before attempting pregnancy may opt for pegylated interferon because of its finite duration (48 weeks), provided they use contraception during treatment. However, if the patient chooses treatment with a nucleos(t)ide analogue, TDF is preferred because it has been shown to be safe in pregnancy, and the risk of drug resistance is low. (See 'Safety of antiviral agents in pregnancy' below.)
●Patients who become pregnant while on therapy should contact their provider immediately. The management of such patients is described above. (See 'Patients who are pregnant' above.)
Breastfeeding — Infants who received hepatitis B immune globulin (HBIG) and the first dose of hepatitis B vaccine at birth can be breastfed [23,29]. However, it is important that the infant complete the hepatitis B vaccine series. Mothers with chronic hepatitis B who are breastfeeding should also exercise care to prevent bleeding from cracked nipples. HBsAg-positive mothers should not participate in donating breast milk. Discussions of breastfeeding and HBV transmission and newborn immunization are found below. (See 'Breastfeeding and transmission' below and 'Newborn immunization' below.)
For women with chronic HBV who continue antiviral treatment after delivery, the safety data on the use of HBV antiviral therapy during breastfeeding is unclear. Thus, the benefits of breastfeeding, and the availability of alternatives to breastfeeding, should be discussed with women who require postpartum antiviral therapy. The decision to breastfeed should be based upon patient preference.
Drug labels have typically recommended that nucleos(t)ide analogues be avoided during breastfeeding because they are excreted into the breastmilk. However only low levels of tenofovir are detected among women receiving TDF [30-34], and these are unlikely to have any biologic effects on the nursing infant. As an example, one study found that the median breastmilk dose from mothers receiving TDF represented 0.03 percent of the proposed oral infant dose and simulated neonatal plasma concentrations were extremely low . Another study found that the ratio of tenofovir concentration in breast milk to that in maternal plasma was 0.07 and none of the infants had detectable tenofovir in their plasma . In addition, case reports of infants born to mothers with chronic HBV found no short-term adverse effects in infants who were breastfed while their mothers received TDF [36-39].
Data from HIV-infected women also support the safety of antiviral therapy during breastfeeding. As an example, a study evaluating tenofovir and emtricitabine in the breastmilk of five HIV-infected women in Africa found that the median amount of tenofovir and emtricitabine ingested via breastfeeding would be 0.03 and 2 percent, respectively, of the proposed oral infant doses . Additional discussions of breastfeeding in HIV-infected patients are found elsewhere. (See "Prevention of HIV transmission during breastfeeding in resource-limited settings" and "Antiretroviral selection and management in pregnant individuals with HIV in resource-rich settings".)
MOTHER-TO-CHILD TRANSMISSION — Mother-to-child transmission accounts for most of the burden of chronic HBV. The World Health Assembly adopted the Global Health Sector Strategy (GHSS) on viral hepatitis in 2016, calling for elimination of viral hepatitis B and C by 2030 . Administering the HBV birth dose vaccination (HepB-BD) and completing the three-dose vaccination series are the most important interventions in eliminating mother-to-child transmission. (See "Hepatitis B virus immunization in infants, children, and adolescents", section on 'Routine infant immunization'.)
Risk of transmission — The risk of mother-to-child transmission of hepatitis B virus (HBV) from hepatitis B surface antigen (HBsAg)-positive mothers to their infants has been reported to be as high as 90 percent without the use of active and passive immunization . Transmission can occur in utero, at birth, or after birth. (See 'Risk factors for transmission' below and 'Prevention of mother-to-child transmission' below.)
However, the risk of HBV transmission has been significantly reduced with the introduction of universal maternal HBV screening, hepatitis B vaccination of all newborns, and the use of prophylactic hepatitis B immune globulin (HBIG) for infants of HBsAg-positive mothers. As an example, perinatal HBV infection occurred in 1.1 percent of newborns in a cohort study that evaluated 9252 infants born to HBsAg-positive mothers in the United States . Approximately 95 percent of infants received hepatitis B vaccine and HBIG within 12 hours of birth and almost all completed ≥3 doses of the hepatitis B vaccine series. Transmission was significantly associated with having a mother who was hepatitis B e antigen (HBeAg) positive, had a HBV viral load >2000 international units/mL, or was <25 years old; transmission was also associated with receiving <3 doses of the hepatitis B vaccine series. In this study, the association between younger maternal age and HBV transmission may have been related to the mother's HBeAg status and viral load, since younger women in the cohort were more often HBeAg positive with higher HBV DNA levels, consistent with immune tolerant phase, compared with older women.
The high protective efficacy of neonatal vaccination suggests that most infections occur at birth when maternal secretions and blood in the birth canal come into contact with the infant's mucosal membranes. In support of this hypothesis, a study performed in China found that only 3.7 percent of babies who tested positive for HBsAg at birth were infected through intrauterine transmission .
Risk factors for transmission — The most important risk factors for mother-to-child transmission, despite proper administration of prophylaxis (HBIG and first dose of hepatitis B vaccine given within 12 hours of birth and completion of hepatitis B vaccine series), appear to be a positive HBeAg and/or a high HBV DNA level in the mother.
Transplacental transmission and transmission due to obstetrical procedures are infrequent causes, and breastfeeding does not appear to pose a substantial risk. In addition, the benefit of cesarean delivery in protecting against transmission has not been clearly established. Thus, the obstetrical approach should not be influenced by the HBV status of the mother.
HBV replicative status — The risk of transmission is increased in women who are HBeAg positive and/or have high levels of HBV DNA. In one series, transmission occurred in the absence of prophylaxis in 85 to 90 percent of infants born to HBeAg-positive mothers and 32 percent of infants born to HBeAg-negative mothers . Children born to HBeAg-positive mothers remain at risk for HBV infection, even if they receive hepatitis B vaccination and HBIG (approximately 9 percent in one large cohort study) . A description of the replicative phases of chronic HBV infection is found elsewhere. (See "Hepatitis B virus: Clinical manifestations and natural history", section on 'Phases of chronic HBV infection'.)
HBV DNA level — Maternal serum HBV DNA levels correlate with the risk of transmission. Vertical transmission of hepatitis B occurs in 9 to 39 percent of infants of highly viremic mothers despite postnatal vaccination [46-50]. The risk of HBV transmission is rare when maternal HBV DNA is <105 to 106 international units/mL. As examples:
●In a study of 773 HBsAg-positive mothers in Taiwan, the odds ratio for having an infected infant increased from 1 to 147 as the maternal serum HBV DNA levels increased from 5 pg/mL (approximately 150,000 international units/mL) to >1400 pg/mL (approximately 45,000,000 international units/mL) .
●In another study conducted in China involving 112 newborns of mothers with chronic HBV infection, the rate of infection increased from 0 percent in mothers with serum HBV DNA levels <20,000 international units/mL (<105 copies/mL) to 50 percent in those with HBV DNA levels approximately 109 international units/mL (between 9 and 10 log10 copies/mL) .
●A study conducted in Australia that included 138 babies born to HBV DNA-positive mothers showed a similar trend . HBV transmission was detected in four babies despite the use of HBIG and hepatitis B vaccination in three and the use of vaccine alone in one. All four babies were born to mothers with high HBV DNA levels (>108 copies/mL).
●A prospective observational study followed 303 mother-infant pairs in which the mother was HBsAg positive . Chronic HBV infection developed in 10 infants born to the 87 HBeAg-positive mothers whereas none of the infants born to the 216 HBeAg-negative mothers became infected. All of the infants born to HBeAg-positive mothers received a dose of hepatitis B vaccine within the first week and HBIG within 24 hours of birth. A multivariable logistic regression model predicted rates of maternally transmitted HBV infection at HBV DNA levels of 2 x 104, 2 x 105, 2 x 106, 2 x 107, and 2 x 108 international units/mL to be 0.9 percent (95% CI, 0.9–2.7 percent), 2.6 percent (95% CI, 1.1–6.2 percent), 6.6 percent (95% CI, 0.5–12.6 percent), 14.6 percent (95% CI, 5.6–23.6 percent), and 27.7 percent (95% CI, 13.1–42.4 percent) respectively.
●An observational study evaluated 4446 infants born to 3253 HBV-positive mothers between 1997 and 2010 . The majority of infants received HBIG and three doses of the hepatitis B vaccine. Mother-to-child transmission occurred in 3.4 percent of births to HBeAg-positive mothers and 0.04 percent of births to HBeAg-negative mothers. HBV DNA and HBeAg testing was available in 835 women. Among such women, three infants acquired HBV infection despite passive and active immunization. All three children were born to mothers who were HBeAg-positive and had an HBV DNA level >6 x 107 international units/mL. No HBV transmission occurred in mothers with viral loads less than 5 x 107 international units/mL, regardless of the mother's HBeAg status.
●A meta-analysis that included 13 studies found that among infants who received a timely birth dose (within 12 hours) of HBIG and HBV vaccine, none were infected when maternal HBV DNA was <200,000 international units/mL .
Transplacental transmission — Transplacental transmission appears to cause only a minority of infections. It can occur due to leakage, such as during a threatened abortion [57,58]. HBV has been found in the villous capillary endothelial cells and the trophoblasts of the placenta [43,59]. This supports the hypothesis that breach of the placental barrier is a possible mechanism for intra-uterine infection. As a result, when preterm labor or spontaneous abortion occurs, there may be mixing of maternal and fetal blood, which may result in HBV transmission . One study found that HBV is able to translocate through the placenta from the mother to the fetal trophoblast . The causes of transplacental infection are unclear. High maternal viral load and preterm labor have been described as risk factors, but the strength of these associations is uncertain [43,52,61].
Amniocentesis and other procedures — Diagnostic amniocentesis, if clinically indicated, should not be withheld. Transmission following amniocentesis has been described, but the risk appears to be low , particularly if the mother is HBeAg negative with a low HBV viral load, and the procedure is done using a 22-gauge needle under continuous guidance [63,64]. (See "Diagnostic amniocentesis".)
Most studies do not demonstrate an increased risk for in utero infection after amniocentesis in women with chronic HBV infection. In an illustrative study, women with HBV who underwent amniocentesis had a rate of vertical transmission that did not differ significantly from women with HBV who did not undergo amniocentesis (9 versus 11 percent) . However, one study found an increased risk when the maternal HBV DNA was >7 log international units/mL .
The Society for Maternal-Fetal Medicine recommends that for women with HBV who have an indication for genetic testing, invasive testing (eg, amniocentesis or chorionic villus sampling) may be offered; patients should be counseled that the risk for mother-to-child transmission of HBV may be increased with maternal HBV DNA >7 log international units/mL .
Preterm premature rupture of membranes — There are limited data that have examined preterm premature rupture of membranes as a risk factor for HBV transmission, and the available data are conflicting [67,68]. As a result, management of such patients should not differ from that of women with chronic HBV without preterm premature rupture of membranes.
Cesarean delivery — The benefit of cesarean delivery in protecting against HBV transmission has not been clearly established in well-conducted controlled trials, and available data are conflicting [69-73]. Thus, cesarean delivery is not routinely recommended for carrier mothers for the sole purpose of reducing HBV transmission [23,74].
Breastfeeding and transmission — Transmission of HBV through breastfeeding is unlikely, particularly in infants who received HBIG and hepatitis B vaccine at birth. Although HBV DNA has been detected in the colostrum of HBsAg-positive mothers, a study of 147 infants born to carrier mothers revealed no evidence of a relationship between breastfeeding and the subsequent development of chronic HBV infection in the babies . In another study involving 369 neonates born to mothers with chronic HBV infection, of whom all received and completed the HBV immunoprophylaxis program, none of the 101 breastfed infants and 9 formula-fed infants were positive for HBsAg . An additional discussion of breastfeeding is found above. (See 'Breastfeeding' above.)
Prevention of mother-to-child transmission — Preventing mother-to-child transmission involves screening pregnant women, providing antiviral therapy to women with high HBV DNA levels, and administering passive-active immunization to newborns of mothers who are HBsAg positive (algorithm 1).
Maternal screening — All pregnant persons should be screened for HBV, preferably at the first prenatal visit . Testing should be performed regardless of vaccination status and history of prior testing. Screening for hepatitis B will determine whether a person has current HBV infection and is at risk of transmitting HBV to the infant. This impacts the need for maternal antiviral therapy and post-exposure prophylaxis for the newborn. (See 'Maternal antiviral therapy to prevent transmission' below and 'Newborn immunization' below.)
The first time a pregnant person is screened they should be tested for HBsAg, anti-HBc, and anti-HBs. For subsequent pregnancies, HBsAg alone is sufficient.
●Pregnant persons who are HBsAg positive should have further testing to measure baseline HBeAg, hepatitis B e antibody (anti-HBe), HBV DNA, and aminotransferase levels. Those who have a high HBV DNA (ie, >2 x 105 international units/mL or >106 copies/mL), elevated aminotransferase levels, and/or a positive HBeAg should be referred to a hepatologist to see if early initiation of antiviral medications is needed (see 'Management considerations' above). In addition, the HBV status of any older children should be evaluated.
Those with low HBV DNA levels in the first trimester should have repeat HBV viral load testing around weeks 26 to 28. If the levels have increased, antiviral therapy should be considered. (See 'Maternal antiviral therapy to prevent transmission' below.)
●Patients without evidence of prior HBV infection or exposure (negative for anti-HBs and anti-HBc) should be vaccinated . In addition, those with risk factors for HBV (eg, injection drug use, having a sexual partner or household contact with chronic HBV, having had more than one sex partner in the previous six months, having been evaluated or treated for a STI) (table 3) should have HBsAg repeated late in pregnancy (approximately 28 weeks), if they are at risk of HBV infection.
●For those who have evidence of prior infection (HbsAg-negative, anti-HBc-positive, anti-HBs-positive) or immunity due to vaccination (HbsAg-negative, anti-HBc-negative, anti-HBs- positive), no further intervention is needed.
However, a booster dose of vaccine is reasonable for patients who have isolated anti-HBc positive to see if anti-HBs titers can increase to >10 milli-international units/mL, although the clinical importance of this is unclear. (See "Hepatitis B virus: Screening and diagnosis in adults", section on 'Approach to screening and testing'.)
Women who are not tested prenatally should be tested at the time of admission for delivery .
Maternal antiviral therapy to prevent transmission
●General approach – For HbsAg-positive pregnant women who do not have indications for HBV therapy based on HBV parameters (see 'Management considerations' above), we recheck an HBV DNA level at 26 to 28 weeks gestation and recommend antiviral therapy at 28 weeks in those with HBV DNA levels >2 x 105 international units/mL or >106 copies/mL.
Antiviral therapy should be given in addition to standard passive-active immunization of the infant to further reduce the risk of mother-to-child transmission (algorithm 1). The HBV DNA level threshold is based on the increased risk of transmission at these high viral loads despite postnatal vaccination. According to the World Health Organization (WHO), HbeAg may be used as an indicator for antiviral prophylaxis when testing for HBV DNA is not available . (See 'HBV replicative status' above and 'HBV DNA level' above.)
Although recommendations regarding when to start antiviral therapy have varied from week 24 to 32 [25,79,80], we start treatment around week 28 so there is sufficient time for the HBV viral load to decrease, even if the patient delivers early.
For women who start treatment before 32 weeks, we typically check an HBV DNA level approximately four weeks after starting therapy. In our experience, patients who are taking their medications almost always have a drop by at least 2 to 3 log in their HBV DNA level. If the viral load has not dropped, we assess for potential barriers to adherence.
The choice of agent and duration of therapy are discussed below.
Our approach to antiviral therapy is consistent with recommendations by the American Association for the Study of Liver Disease; National Academies of Sciences, Engineering, and Medicine; the Advisory Committee on Immunization Practices; and the WHO [25,56,78,81].
●Choice of agent – For those who require treatment, we prefer tenofovir disoproxil fumarate (TDF) rather than other antiviral agents since resistance to TDF is rare. This is important since many of these young mothers may require antiviral treatment for their liver disease in the future. In addition, this agent appears to be safe for use in pregnancy and has been evaluated in several prospective clinical trials [82-84].
A newer formulation of tenofovir, tenofovir alafenamide (TAF), is available. Although there is less bone and kidney toxicity with this agent compared with TDF, TAF has not been routinely recommended for treatment of HBV during pregnancy given the paucity of safety data.
However, there have been some observational studies evaluating the safety and efficacy of TAF for prevention of mother-to-child transmission. One prospective, observational study from China compared 116 mothers who received TAF to 116 mothers receiving TDF . Treatment was initiated from gestational weeks 24 to 35 to delivery in mothers who had HBV DNA levels greater than 200,000 IU/mL. Infants received immunoprophylaxis and were followed for up to six months postpartum. The safety profile between the TDF and TAF groups were comparable with no birth defects seen in either group. The HBsAg positivity rate was zero percent at seven months in all 233 infants.
A smaller prospective study, also from China, evaluated the safety and efficacy of TAF in both early (<14 weeks of gestation) and middle (14 to 28 weeks of gestation) stages of pregnancy . Infants were followed up to six months postpartum and all received immunoprophylaxis. Among the 98 mothers enrolled, TAF was initiated in 31 mothers in early pregnancy, while 57 mothers received TAF in middle pregnancy. At delivery, all mothers achieved complete HBV DNA suppression. Of the 98 infants born, none had congenital defects or malformations. There were no cases of mother-to-child transmission, and no severe adverse events were reported in either mothers or infants.
Although other agents (eg, lamivudine, telbivudine) also reduce mother-to-child transmission and appear to be safe when administered during pregnancy [82,85-88], they are associated with high rates of antiviral resistance. Lamivudine may be a reasonable alternative if cost is a barrier to obtaining antiviral therapy and treatment is going to be administered for a short duration (ie, ≤3 months). However, it is important that patients have not received lamivudine in the past, since such patients are at risk of having lamivudine-resistant virus.
Additional information on the safety of antiviral agents in pregnancy is found below. (See 'Safety of antiviral agents in pregnancy' below.)
●Duration of antiviral therapy – Women who start antiviral therapy during pregnancy for the sole purpose of preventing mother-to-child transmission may stop antiviral therapy immediately after delivery, especially if they want to breastfeed. Some experts prefer to continue treatment for 4 to 12 weeks after delivery, in part to reduce the risk of a flare postpartum . However, in a prospective study where 91 women (101 pregnancies) received antiviral therapy to prevent transmission, extending antiviral therapy beyond delivery did not appear to reduce the frequency of HBV flares over a median of 48 weeks of follow-up .
Regardless of when antiviral therapy is discontinued, women should be monitored for a flare of their HBV disease by measuring the alanine aminotransferase (ALT) level every three months for six months after therapy has been stopped. For those that continue antiviral therapy after delivery (eg, for treatment of chronic HBV), the risks and benefits of breastfeeding must be discussed with the mother. (See 'Breastfeeding' above and 'Breastfeeding and transmission' above and "Hepatitis B virus: Overview of management", section on 'Indications for antiviral therapy' and "Hepatitis B virus: Overview of management", section on 'Overview of antiviral agents'.)
●Efficacy of antiviral therapy – Data from clinical trials and prospective studies support the use of maternal antiviral therapy to reduce HBV transmission. A systematic review and meta-analysis of 129 studies found a protective effect of antiviral therapy, regardless of the agent used, with the odds ratio of HBV infection being 0.16 (95% CI 0.10-0.26) for TDF, 0.17 (95% CI 0.13-0.22) for lamivudine, and 0.20 (95% CI 0.08-0.13) for telbivudine . In almost all the studies, infants received HBIG in addition to birth dose HBV vaccine. In an analysis of six studies that reported the risk of maternal HBV flare after discontinuation of TDF, the risk was similar between those who did and did not received TDF at a matched time-point (8 versus 6 percent, respectively).
In a meta-analysis of 26 studies, which included 3622 pregnant women, antiviral therapy (in addition to passive and active immunization of the newborn) significantly reduced neonatal HBV transmission as evidenced by a reduced risk of infant HbsAg seropositivity (risk ratio 0.3; 95% CI 0.2-0.4) and a reduced risk of HBV DNA seropositivity (risk ratio 0.3; 95% CI 0.2-0.5) . In addition, among mothers who received antiviral therapy and their newborns, there was no increased risk of adverse outcomes (eg, congenital malformations, prematurity, postpartum hemorrhage). However, there are concerns about the quality of the data in this analysis given the small numbers of events and the limited data on the safety of the antiviral agents in newborns.
One of the key trials evaluating antiviral therapy was a randomized trial of 200 pregnant women from China who were HbeAg positive and had HBV DNA >2 x 105 international units/mL (median 108 international units/mL) at baseline received either TDF (300 mg) or placebo, starting at 30 to 32 weeks gestation and continuing 4 weeks postpartum . All infants received standard immunoprophylaxis using HBIG and the hepatitis B vaccine. At postpartum week 28, the mother-to-child transmission rate was significantly lower for infants born to tenofovir-treated women compared with untreated women (5 versus 18 percent). Among the 92 mothers who received tenofovir and completed the trial, there was no transmission of HBV. In addition, no significant differences in the rate of birth defects between babies born to treated and untreated mothers (2.1 versus 1.1 percent) were noted. After treatment was discontinued, more of the mothers who received tenofovir had elevations in their alanine aminotransferase levels, but none of the mothers had severe flares or hepatic decompensation.
The efficacy of tenofovir in reducing mother-to-child transmission was also demonstrated in a prospective study of 118 pregnant women who had an HBV DNA ≥107.5 international units/mL and were positive for HbsAg and HbeAg . Women received tenofovir (300 mg daily), which was initiated at week 30 to 32 of gestation, or no antiviral therapy, and treatment was continued for one month postpartum. All infants received passive and active immunization. Newborns born to mothers who received tenofovir had significantly lower rates of HbsAg positivity at six months (1.5 versus 10.7 percent).
Conflicting results were found in a randomized trial in Thailand that evaluated the use of maternal TDF in 331 pregnant women with chronic HBV and a median HBV viral load of 108 international units/mL. In this trial, mothers initiated TDF or placebo at week 28 and continued therapy for two months postpartum . All newborns received HBIG plus hepatitis B vaccine at birth, and then four additional doses of hepatitis B vaccine at one, two, four, and six months. Among those women who completed the study (147 in each arm), there was no difference in rates of transmission (0 versus 2 percent, not significant). Approximately 10 percent of patients in each group were lost to follow-up; however, similar results were obtained if last available infection status was imputed or analysis was performed with missing data imputed as infected.
Although TDF did not demonstrate a clear benefit in this trial, these findings do not alter our approach to maternal antiviral therapy since the generalizability is limited. As an example, the adherence to the protocol for infant immunoprophylaxis in this trial may not be replicable in other settings. HBIG and birth-dose vaccine are not available in many countries despite recommendations from the WHO . Even in countries with birth-dose HBV vaccination programs, such as the United States, the recommended timing of HBV vaccine is within 12 hours of birth , and only 71.1 percent of infants receive birth-dose HBV vaccine by three days of life . In addition, infants in this study received four doses of HBV vaccine before assessment for HBV infection at six months, whereas most guidelines recommend only two to three doses before six months (table 4A). The results of this study do not refute the current recommendation to administer antiviral therapy to highly viremic mothers, but suggest that further investigation of postexposure immunization regimens may be warranted.
Newborn immunization — Newborns of mothers who test positive for HbsAg should receive passive-active immunization, with the first dose of the hepatitis B vaccine series and one dose of HBIG administered within 12 hours of delivery at different sites (table 4A-B). Infants should then complete the hepatitis B vaccine series. A more detailed discussion of HBV immunization in infants born to HbsAg-positive mothers is found elsewhere. (See "Hepatitis B virus immunization in infants, children, and adolescents", section on 'HBsAg-positive mother or mother with other evidence of HBV infection'.)
The importance of the timing of the birth-dose HBV vaccine was highlighted in a study in Cameroon of 1800 infants of HBsAg-positive mothers who received birth-dose vaccine and the three-dose pentavalent vaccine but no HBIG and none of the mothers received antiviral therapy . The prevalence of HBsAg among the children who received birth dose vaccine in less than 24 hours was 5.6 percent versus 16.7 percent in those who received the birth dose vaccine 48 to 96 hours after birth. One limitation of this study was the varying time when the children were tested for HBsAg; some children were tested after the age of three years, therefore, horizontal transmission could not be ruled out.
To eliminate viral hepatitis B by 2030, the World Health Assembly adopted the Global Health Sector Strategy (GHSS) on viral hepatitis in 2016 . Programmatic targets for vaccination are ≥90 percent coverage of timely hepatitis B birth dose and three doses of HBV vaccine (HepB3). By December 2020, 98 percent of WHO member states had introduced universal infant hepatitis B vaccination, and 57 percent of countries provided HepB-birth-dose vaccine to all newborns . However, only 54 percent had timely administration of the birth dose, and only 52 percent of countries had ≥90 percent HepB3 coverage. There was even a small decline in hepatitis B vaccine coverage in 2020, particularly HepB3, attributed to disruption in service caused by the COVID-19 pandemic.
There was a marked difference in hepatitis B vaccination coverage in different regions of the world, with the lowest in the African region and the highest in the Western Pacific region (16 percent versus 81 percent for HepB-BD, and 73 percent versus 94 percent for HepB3). These findings highlight the need to identify and overcome barriers to hepatitis B vaccination in the African region, where prevalence of hepatitis B remains high.
SAFETY OF ANTIVIRAL AGENTS IN PREGNANCY
Overview — Therapeutic options for the treatment of chronic hepatitis B virus (HBV) in nonpregnant women include oral nucleos(t)ide analogues and pegylated interferon. However, in pregnant women, interferon should be avoided because of concerns of pregnancy loss . (See "Hepatitis B virus: Overview of management", section on 'Antiviral therapy' and 'Other potential adverse events' below.)
Certain nucleos(t)ides appear safe (eg, tenofovir disoproxil fumarate [TDF]), although none of the HBV agents are approved by the US Food and Drug Administration (FDA) for use in pregnancy since there are no large studies that have addressed the safety of antiviral therapy in HBV-monoinfected women during pregnancy. Most safety data are from HIV-infected patients where combination antiviral regimens are used . (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Lamivudine' and "Safety and dosing of antiretroviral medications in pregnancy", section on 'Tenofovir'.)
Risk of teratogenicity — There are limited human data available on the risk of teratogenicity of antiviral agents used to treat HBV [82,83,85-88,97]. Available animal and human data have found no evidence of teratogenicity for TDF and telbivudine. Human studies also support the safety of lamivudine in pregnancy, although adverse events were observed in some animal studies. There are less safety data for tenofovir alafenamide, entecavir, or adefovir in pregnancy; thus, the risk of teratogenicity cannot be ruled out.
In 1989, The Antiretroviral Pregnancy Registry was established to evaluate the potential teratogenic effects of HIV agents. In 2003, the registry began collecting data on exposure to HBV agents as well. Information provided to the registry originates from clinical studies and retrospective reports of antiviral exposure. Data from the registry suggest the percentage of infants with birth defects who were born to HIV- and/or HBV-infected women exposed to antiviral agents was no greater than the 3 percent rate of birth defects found in the general population in the United States [98,99]. As examples:
●Lamivudine – 3.1 percent (170 of 5510) of infants born to mothers who took lamivudine during the first trimester developed birth defects, and 2.9 percent (218 of 7513) of infants born to mothers who took lamivudine during the second and third trimesters of pregnancy developed birth defects.
●Tenofovir disoproxil fumarate – 2.5 percent (115 of 4657) of infants born to mothers who took tenofovir disoproxil fumarate (TDF) during the first trimester developed birth defects, and 2.6 percent (51 of 1983) of infants born to mothers who took TDF during the second and third trimester of pregnancy developed birth defects.
●Tenofovir alafenamide – 3.5 percent (24 of 684) of infants born to mothers who took tenofovir alafenamide (TAF) during the first trimester developed birth defects, and 3.3 percent (5 of 152) of infants born to mothers who took TAF during the second/third trimester developed birth defects.
●Other agents – For entecavir, only 82 infants were reported to be exposed during the first trimester, only two during the second, and none during the third trimester, with only two birth defects reported in the first-trimester group. For adefovir, only 82 infants were reported to be exposed in the first trimester, four during the second/third trimester, with no reports of birth defects. There were a total of 253 exposures to telbivudine and three reports of birth defects in the first trimester; in addition, telbivudine had been studied and reported to be safe in several clinical trials [85,86].
The registry has also collected data on HBV-monoinfected patients. Through January 2022, the registry included data on 864 HBV-monoinfected pregnancies. Twelve birth defect cases were reported among 801 live births. There was no pattern among the types of birth defects reported .
There are important limitations to these observations. The registry depends upon voluntary reporting, and the information is not verified. Long-term follow-up is limited, and there are no efforts to confirm the diagnosis of birth defects. Furthermore, data are available for birth defects among live births, but there are no data on miscarriages or subsequent developmental delays. Much of the clinical data have been on lamivudine and TDF because these drugs are also used for treatment of HIV infection.
Other potential adverse events — A number of adverse events of nucleos(t)ide analogues have been described, including mitochondrial damage, lactic acidosis, acute fatty liver, and possibly bone abnormalities.
●Symptomatic lactic acidosis – Symptomatic lactic acidosis has been reported in infants born to HIV-infected mothers who were exposed to certain antiretroviral agents (which included nucleos(t)ide analogues) in utero, but it has not been observed in infants exposed to HBV antiviral agents in utero. Thus, monitoring for lactic acidosis in the infant is not necessary if the mother received HBV antiviral agents only. (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Mitochondrial toxicity'.)
●Bone abnormalities – TDF is associated with decreased bone mineral density, which usually stabilizes with continued use. There have been concerns about the effect of maternal TDF on fetal growth and development; however, studies evaluating infants born to women who received TDF during pregnancy are generally reassuring [100-103]. As an example, in the randomized trial described above , in which women with HBV monoinfection received TDF or placebo from 28 weeks gestational age to two months postpartum, there was no effect on maternal or infant bone density one year after delivery in the 140 mothers and 137 infants who were evaluated . Although another study found that infants born to HIV-infected mothers who were exposed to TDF had a 12 percent lower bone mineral content in the first month of life compared with those who had no tenofovir exposure , the clinical and long-term significance of these findings are uncertain.
A newer formulation of tenofovir, tenofovir alafenamide, may have less bone toxicity compared with TDF, but we do not use tenofovir alafenamide at this time during pregnancy given the lack of sufficient safety data. (See 'Maternal antiviral therapy to prevent transmission' above.)
●Effects on growth – Studies mainly in the HIV population have not revealed an effect of TDF on birth weight, although there are conflicting results regarding the effect on head circumference and growth (eg, length) [101,102,105,106]. However, in a study that evaluated 646 HIV-infected pregnant women receiving TDF, there was no association between duration of in utero tenofovir exposure and fetal long bone growth, which was assessed using ultrasound .
●Pregnancy loss – Interferon has been associated with abortifacient effects in rhesus monkeys . There are no such reports in humans ; however, since data are limited, all women receiving interferon therapy must use birth control, and interferon must be stopped if women become pregnant. (See 'Patients who are pregnant' above.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hepatitis B vaccination" and "Society guideline links: Management of hepatitis B".)
SUMMARY AND RECOMMENDATIONS
●Considerations for management of HBV in pregnancy – Hepatitis B virus (HBV) infection during pregnancy presents with unique management issues for both the mother and fetus. These include the effects of HBV on maternal and fetal health, the effects of pregnancy on the course of HBV infection, treatment of HBV during pregnancy, and prevention of mother-to-child transmission. (See 'Introduction' above.)
●Acute HBV in pregnancy – Acute HBV infection during pregnancy is usually not severe and is not associated with increased mortality or teratogenicity. Treatment is mainly supportive. However, acute HBV has been associated with mother-to-child transmission. If the mother remains hepatitis B surface antigen (HBsAg) positive or has a detectable HBV DNA, the infant should receive hepatitis B immune globulin (HBIG) in addition to routine hepatitis B vaccination. Antiviral therapy for the mother may also be indicated to reduce the risk of transmission (algorithm 1). (See 'Acute Hepatitis B virus infection' above and 'Prevention of mother-to-child transmission' above.)
●Chronic HBV in pregnancy – Pregnancy is generally well tolerated by women with chronic HBV who do not have advanced liver disease. However, HBsAg-positive mothers should be monitored closely during pregnancy and the postpartum period, since such women are at risk of developing a hepatitis flare. (See 'Impact of pregnancy on the natural history of chronic HBV' above.)
For mothers with chronic HBV, the impact of HBV infection on newborns is not well defined, and data are conflicting. However, women with cirrhosis are at significant risk for perinatal complications and poor maternal and fetal outcomes, including intrauterine growth restriction, intrauterine infection, premature delivery, and intrauterine fetal demise. (See 'Effect of chronic HBV on pregnancy outcomes' above.)
●Preventing mother to child transmission – The infection rate among infants born to HBsAg-positive mothers who do not receive any form of neonatal prophylaxis is as high as 90 percent. However, administering HBIG and hepatitis B vaccine to infants at delivery can reduce transmission by at least 95 percent. The most important risk factors for transmission, despite prophylaxis, appear to be a positive hepatitis B e antigen (HBeAg) in the mother and a high maternal HBV viral load (>200,000 international units/mL). (See 'Risk of transmission' above and 'Risk factors for transmission' above.)
•Maternal screening – For persons who are pregnant, we recommend screening for HBV (Grade 1B). The first time a person is screened they should be tested for HBsAg, anti-HBc, and anti-HBs. For subsequent pregnancies, HBsAg alone is sufficient. (See 'Maternal screening' above.)
Screening should ideally be performed at the first prenatal visit. HBsAg testing should be repeated late in pregnancy in those without evidence of infection or immunity if they are at high risk for HBV infection (table 3).
•Management of newborns – Newborns of HBsAg-positive mothers should receive passive-active immunization (HBIG and hepatitis B vaccine) within 12 hours of delivery and then complete the hepatitis B vaccine series (algorithm 1). (See 'Newborn immunization' above and "Hepatitis B virus immunization in infants, children, and adolescents", section on 'Routine infant immunization'.)
Infants who received HBIG and the first dose of hepatitis B vaccine at birth can be breastfed. It is important that such infants complete the course of vaccination. However, if maternal antiviral therapy is continued after delivery, low levels of tenofovir are detected in maternal breastmilk. Although this is unlikely to have any biological effects on the nursing infant, data are limited and the decision to breastfeed should be based upon patient preference. (See 'Breastfeeding and transmission' above and 'Breastfeeding' above.)
•Role of maternal antiviral therapy – In addition to passive-active immunization of newborns, antiviral therapy for the mother may reduce the risk of mother-to-child transmission. The importance of antiviral therapy increases with increasing viral load. For mothers not already on treatment, we test HBV DNA level at 26 to 28 weeks (algorithm 1).
For pregnant women with an HBV viral load >2 x 105 international units/mL (>106 copies/mL), we recommend antiviral therapy (Grade 1B). We initiate antiviral therapy at 28 weeks gestation. We prefer tenofovir disoproxil fumarate (TDF) since it appears safe in pregnancy, and the risk of drug resistance is low. Patients should be monitored for a flare if antiviral therapy is discontinued after delivery. (See 'Prevention of mother-to-child transmission' above and 'Safety of antiviral agents in pregnancy' above.)
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