Management Algorithm for Interrupting Mother-to-Child Transmission of Hepatitis B Virus

Open AccessPublished:October 09, 2018DOI:https://doi.org/10.1016/j.cgh.2018.10.007
      In areas where hepatitis B virus (HBV) is endemic, mother-to-child transmission (MTCT) is the major route of infection of children. Blocking MTCT of HBV therefore would reduce its prevalence. The China Foundation of Hepatitis Prevention and Control organized a team of specialists in infectious diseases, hepatology, immunology, obstetrics, and public health to develop an algorithm for interrupting MTCT of HBV, based on the most recent hepatitis B guidelines and latest evidence. This algorithm comprises 10 steps and has been adopted in clinical practice in China. Four aspects (screening, antiviral intervention during pregnancy, immunoprophylaxis, and postvaccination serologic testing) are the core components of preventing MTCT. Although the combination of passive and active immunization in newborns of hepatitis B surface antigen–positive mothers reduces MTCT of HBV, this immunoprophylaxis cannot completely eradicate MTCT. In the past decade, administration of antiviral agents to pregnant women has been shown to be safe and effective in reducing MTCT of HBV in combination with immunoprophylaxis. Aiming to achieve zero MTCT, this algorithm recommends the use of antivirals during pregnancy by women with high viral loads. Preventing MTCT is key to achieving the goal of eliminating HBV as a public health threat by 2030. Implementation and enhancement of the standardized algorithm for pregnant women with chronic HBV infection and their infants is urgently needed to prevent MTCT.

      Keywords

      Abbreviations used in this paper:

      ALT (alanine aminotransferase), anti-HBs (antibody to hepatitis B surface antigen), HBeAg (hepatitis B e antigen), HBIG (hepatitis B immune globulin), HBsAg (hepatitis B surface antigen), HBV (hepatitis B virus), LdT (telbivudine), MTCT (mother-to-child transmission), PVST (postvaccination serologic testing), TDF (tenofovir disoproxil fumarate), ULN (upper limit of normal), WHO (World Health Organization)
      The World Health Organization (WHO) has set the goal of eliminating hepatitis as a threat to public health by 2030, which includes reducing the prevalence of hepatitis B surface antigen (HBsAg) among children to 0.1%.
      World Health Organization
      Global health sector strategy on viral hepatitis 2016-2022.
      Mother-to-child transmission (MTCT) is the major route of hepatitis B virus (HBV) transmission, accounting for 40% to 50% of chronic infections worldwide.
      • Lamberth J.R.
      • Reddy S.C.
      • Pan J.J.
      • et al.
      Chronic hepatitis B infection in pregnancy.
      Therefore, blocking MTCT of HBV will be the key step in achieving this goal.
      The mainstay of preventing hepatitis B acquisition at birth comprises at least 3 doses of hepatitis B vaccine, including a birth dose administered in a timely manner (ie, within 24 hours of birth).
      World Health Organization
      Hepatitis B vaccines: WHO position paper.
      Active-passive immunoprophylaxis through use of hepatitis B immune globulin (HBIG) is recommended among infants born to women with chronic HBV infection.
      National Health Commission of the People’s Republic of China
      Immunization programs and instructions of national immunization program for Children. 2016.
      Although recent studies have suggested that vaccine alone may be as effective as the combination of vaccine and HBIG in preventing infection among neonates born to HBsAg-positive/hepatitis B e antigen (HBeAg)-negative women, the current standard recommendations include the use of HBIG for the prevention of MTCT.
      • Machaira M.
      • Papaevangelou V.
      • Vouloumanou E.K.
      • et al.
      Hepatitis B vaccine alone or with hepatitis B immunoglobulin in neonates of HBsAg+/HBeAg- mothers: a systematic review and meta-analysis.
      • Lu Y.
      • Liang X.F.
      • Wang F.Z.
      • et al.
      Hepatitis B vaccine alone may be enough for preventing hepatitis B virus transmission in neonates of HBsAg (+)/HBeAg (-) mothers.
      Known factors that increase the risk of MTCT include HBeAg positivity, high viral load among pregnant women, and instrumental deliveries at birth.
      • Wen W.H.
      • Chang M.H.
      • Zhao L.L.
      • et al.
      Mother-to-infant transmission of hepatitis B virus infection: significance of maternal viral load and strategies for intervention.
      • Zou H.
      • Chen Y.
      • Duan Z.
      • et al.
      Virologic factors associated with failure to passive-active immunoprophylaxis in infants born to HBsAg-positive mothers.
      • Yin Y.
      • Wu L.
      • Zhang J.
      • et al.
      Identification of risk factors associated with immunoprophylaxis failure to prevent the vertical transmission of hepatitis B virus.
      In the past 2 decades, multiple studies have documented the use of telbivudine (LdT) or tenofovir disoproxil fumarate (TDF) in reducing the risk of HBV MTCT. A systematic review suggested that antiviral therapy, compared with the administration of HBIG and vaccination, improved HBV suppression and reduced MTCT in women with a high viral load.
      • Brown Jr., R.S.
      • McMahon B.J.
      • Lok A.S.
      • et al.
      Antiviral therapy in chronic hepatitis B viral infection during pregnancy: a systematic review and meta-analysis.
      Other studies noted the proven effectiveness of antiviral therapy during the late stage of pregnancy in preventing MTCT among women with a high viral load.
      • Zhang H.
      • Pan C.
      • Pang Q.
      • et al.
      Telbivudine or lamivudine use in late pregnancy safely reduces perinatal transmission of hepatitis B virus in real-life practice.
      • Han G.R.
      • Cao M.K.
      • Zhao W.
      • et al.
      A prospective and open-label study for the efficacy and safety of telbivudine in pregnancy for the prevention of perinatal transmission of hepatitis B virus infection.
      • Pan C.Q.
      • Duan Z.
      • Dai E.
      • et al.
      China Study Group for the mother-to-child transmission of hepatitis B. Tenofovir to prevent hepatitis B transmission in mothers with high viral load.
      • Chen H.L.
      • Lee C.N.
      • Chang C.H.
      • et al.
      Efficacy of maternal tenofovir disoproxil fumarate in interrupting mother-to-infant transmission of hepatitis B virus.
      • Greenup A.J.
      • Tan P.K.
      • Nguyen V.
      • et al.
      Efficacy and safety of tenofovir disoproxil fumarate in pregnancy to prevent perinatal transmission of hepatitis B virus.
      However, there remains uncertainty regarding the effect of antiviral drug use because a recent multicenter, randomized, double-blinded clinical trial conducted in Thailand by Jourdain et al
      • Jourdain G.
      • Ngo-Giang-Huong N.
      • Harrison L.
      • et al.
      Tenofovir versus placebo to prevent perinatal transmission of hepatitis B.
      did not show a significant difference in MTCT rate between the intervention and control arms.
      Several sets of guidelines, including those of the American Association for the Study of Liver Diseases,
      • Terrault N.A.
      • Lok A.S.
      • Mcmahon B.J.
      • et al.
      Update on prevention, diagnosis, treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.
      the European Association for the Study of the Liver,
      European Association for the Study of the Liver
      EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection.
      the Asian Pacific Association for the Study of the Liver,
      • Sarin S.K.
      • Kumar M.
      • Lau G.K.
      • et al.
      Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update.
      and the National Institute for Health and Care Excellence,

      National Institute for Health and Care Excellence. Hepatitis B (chronic): diagnosis and management of chronic hepatitis B in children, young people and adults. London, 2013. Available from: http://www.nice.org.uk/guidance/CG165. Accessed: May 2013.

      recommend consideration of antiviral use among pregnant women with chronic HBV infection. The 2015 WHO guidelines for the treatment of hepatitis B do not formally recommend the use of antiviral agents for the prevention of MTCT because of the limited quantity and low quality of supporting evidence, comparison of antivirals, evaluation of potential harms, real-world studies, and programmatic implications based on the Grading of Recommendations Assessment Development and Evaluation review used by WHO.

      World Health Organization. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. Geneva, 2015. Available from: http://www.who.int/hiv/pub/hepatitis/hepatitis-b-guidelines/en. Accessed: March 2015.

      In China, various practices of antiviral drug use are implemented to prevent HBV MTCT. To harmonize and standardize clinical management to prevent MTCT of hepatitis B, several meetings were coordinated by the China Foundation for Hepatitis Prevention and Control, bringing together experts from across the country in infectious diseases, hepatology, immunology, obstetrics, and public health (referred to here as the Group) to design a consensus protocol for clinical practice based on reviewing major international and Chinese guidelines and current global evidence.
      The practice protocol for the care of HBsAg-positive pregnant women and their infants is as follows.

      Testing and Diagnosis

      Following the current national recommendations of the National Health Committee, all pregnant women should be screened for hepatitis B, syphilis, and human immunodeficiency virus at the first prenatal examination and/or as early as possible during antenatal care.

      National Health and Family Planning Commission of the People’s Republic of China. Action plan to prevent mother-to-child transmission of AIDS, syphilis, and hepatitis B 2015. Available from: http://www.nhfpc.gov.cn/ewebeditor/uploadfile/2015/06/20150615151817186.docx. Accessed: June 2015.

      The Group recommends that the HBV serologic marker HBsAg be tested as part of the screening. If the test result for HBsAg is negative, women should be counseled regarding their result and receive the usual standard of care for pregnant women. If the HBsAg test is positive, which indicates maternal HBV infection, the whole set of HBV serologic markers should be tested to assess the status of HBV infection. HBsAg-positive pregnant women should be managed jointly by an obstetrician for the well-being of the fetuses and women and by a hepatologist/gastroenterologist or infectious disease specialist for their hepatitis disease status during pregnancy, labor, delivery, and the postpartum period. Continued follow-up evaluation after delivery will be required.

      Initial Assessment (Baseline) and Management Decisions

      The Group recommends staging of liver disease status for HBsAg-positive pregnant women to determine the degree of liver injury. Baseline tests include maternal HBV viral load (HBV DNA), HBV serologic markers, liver function tests, and upper abdominal ultrasound. Management decisions should consider the following.
      First, in HBeAg-positive pregnant women with HBV DNA levels greater than 20,000 IU/mL or HBeAg-negative pregnant women with HBV DNA levels greater than 2000 IU/mL and significant hepatic activity, alanine aminotransferase (ALT) level ≥5× the upper limit of normal (ULN) (excluding other potential etiologies), or cirrhosis, the consideration in starting antiviral therapy is the woman’s health. The drug of choice is TDF, which should be prescribed after clinical assessment, counseling, patient education, and receipt of informed consent by specialists in hepatology or infectious diseases. The decision to start antiviral treatment and the plan for patient management should be communicated to the obstetric team.
      Second, in pregnant women who are HBV DNA positive and who have ALT levels ≥2 but less than 5× ULN, antiviral therapy can be postponed. Close monitoring based on clinical symptoms and serology is required throughout pregnancy. The Group recommends, at a minimum, liver function monitoring every 4 weeks during pregnancy. If ALT level increases to ≥5× ULN, treatment decisions should follow first point; if the ALT level is reduced to <2× ULN, treatment management should follow third point; if the ALT level remains within the range of ≥2 to <5× ULN, clinicians should consider starting antiviral treatment at gestational week 24 using TDF after patient education and obtaining informed consent.
      Third, in pregnant women found to have viremia, an ALT level <2× ULN, and no cirrhosis, there is no indication to initiate antiviral therapy. Clinical and liver function monitoring is recommended. If there are signs of progression of liver disease (that is, ALT level ≥2× ULN) during the course of the pregnancy, treatment considerations should follow first or second point. accordingly. In addition, total bilirubin and prothrombin activity should be tested to evaluate the severity of liver disease.

      Management During Pregnancy

      In pregnant women with normal or slightly increased ALT levels, HBV DNA level should be quantified with the sensitive method of real-time polymerase chain reaction in the second trimester. For the prevention of HBV MTCT, antiviral treatment should be considered based on HBV DNA quantification.
      If HBV DNA level is greater than 2 × 106 IU/mL, antiviral treatment with either TDF or LdT (high quality, strong recommendation)
      • Zhang H.
      • Pan C.
      • Pang Q.
      • et al.
      Telbivudine or lamivudine use in late pregnancy safely reduces perinatal transmission of hepatitis B virus in real-life practice.
      • Han G.R.
      • Cao M.K.
      • Zhao W.
      • et al.
      A prospective and open-label study for the efficacy and safety of telbivudine in pregnancy for the prevention of perinatal transmission of hepatitis B virus infection.
      • Pan C.Q.
      • Duan Z.
      • Dai E.
      • et al.
      China Study Group for the mother-to-child transmission of hepatitis B. Tenofovir to prevent hepatitis B transmission in mothers with high viral load.
      • Chen H.L.
      • Lee C.N.
      • Chang C.H.
      • et al.
      Efficacy of maternal tenofovir disoproxil fumarate in interrupting mother-to-infant transmission of hepatitis B virus.
      • Greenup A.J.
      • Tan P.K.
      • Nguyen V.
      • et al.
      Efficacy and safety of tenofovir disoproxil fumarate in pregnancy to prevent perinatal transmission of hepatitis B virus.
      should be administered after patient education and informed consent at gestational weeks 24 to 28. The risks and benefits and the limited evidence for this approach should be discussed with the patient. The benefit of antiviral treatment is to protect the newborns from HBV infection and to control hepatitis activity in mothers with increased ALT levels. It has been reported that the rate of MTCT can be decreased further by antiviral treatment in HBsAg-positive mothers during late pregnancy.
      • Zhang H.
      • Pan C.
      • Pang Q.
      • et al.
      Telbivudine or lamivudine use in late pregnancy safely reduces perinatal transmission of hepatitis B virus in real-life practice.
      • Han G.R.
      • Cao M.K.
      • Zhao W.
      • et al.
      A prospective and open-label study for the efficacy and safety of telbivudine in pregnancy for the prevention of perinatal transmission of hepatitis B virus infection.
      • Pan C.Q.
      • Duan Z.
      • Dai E.
      • et al.
      China Study Group for the mother-to-child transmission of hepatitis B. Tenofovir to prevent hepatitis B transmission in mothers with high viral load.
      • Chen H.L.
      • Lee C.N.
      • Chang C.H.
      • et al.
      Efficacy of maternal tenofovir disoproxil fumarate in interrupting mother-to-infant transmission of hepatitis B virus.
      • Greenup A.J.
      • Tan P.K.
      • Nguyen V.
      • et al.
      Efficacy and safety of tenofovir disoproxil fumarate in pregnancy to prevent perinatal transmission of hepatitis B virus.
      At the same time, the patients should be informed about potential risks related to the administration of antivirals, such as side effects of drugs (renal injury, hypophosphatemia, myopathy), drug-resistant mutations, potential harm to the fetus, and postpartum hepatic flare. Generally, pregnancy category B drugs such as TDF and LdT are safe to use during pregnancy, and antiviral treatment with TDF or LdT has no influence on congenital abnormalities or neonatal growth percentiles. However, it should be noted that in a human immunodeficiency virus/acquired immune deficiency syndrome cohort study,
      • Van Dyke R.B.
      • Chadwick E.G.
      • Hazra R.
      • et al.
      The PHACS SMARTT study: assessment of the safety of in utero exposure to antiretroviral drugs.
      in utero exposure to TDF resulted in a 12% reduction in total mean whole-body bone mineral content (56.0 vs 63.8 g, respectively; P = .002). Moreover, the rate of postpartum hepatic flare was reported to be 40% to 50% in mothers who stopped antiviral treatment.
      • Nguyen V.
      • Tan P.K.
      • Greenup A.J.
      • et al.
      Anti-viral therapy for prevention of perinatal HBV transmission: extending therapy beyond birth does not protect against post-partum flare.
      Accumulating studies have shown that treatment using TDF or LdT during the third trimester is effective and safe for the prevention of MTCT in mothers with high viral loads,
      • Zhang H.
      • Pan C.
      • Pang Q.
      • et al.
      Telbivudine or lamivudine use in late pregnancy safely reduces perinatal transmission of hepatitis B virus in real-life practice.
      • Han G.R.
      • Cao M.K.
      • Zhao W.
      • et al.
      A prospective and open-label study for the efficacy and safety of telbivudine in pregnancy for the prevention of perinatal transmission of hepatitis B virus infection.
      • Pan C.Q.
      • Duan Z.
      • Dai E.
      • et al.
      China Study Group for the mother-to-child transmission of hepatitis B. Tenofovir to prevent hepatitis B transmission in mothers with high viral load.
      • Chen H.L.
      • Lee C.N.
      • Chang C.H.
      • et al.
      Efficacy of maternal tenofovir disoproxil fumarate in interrupting mother-to-infant transmission of hepatitis B virus.
      • Greenup A.J.
      • Tan P.K.
      • Nguyen V.
      • et al.
      Efficacy and safety of tenofovir disoproxil fumarate in pregnancy to prevent perinatal transmission of hepatitis B virus.
      and this approach has been recommended by major guidelines.
      • Terrault N.A.
      • Lok A.S.
      • Mcmahon B.J.
      • et al.
      Update on prevention, diagnosis, treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.
      European Association for the Study of the Liver
      EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection.
      • Sarin S.K.
      • Kumar M.
      • Lau G.K.
      • et al.
      Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update.

      National Institute for Health and Care Excellence. Hepatitis B (chronic): diagnosis and management of chronic hepatitis B in children, young people and adults. London, 2013. Available from: http://www.nice.org.uk/guidance/CG165. Accessed: May 2013.

      • Hou J.
      • Wang G.
      • Wang F.
      • et al.
      Guideline of prevention and treatment for chronic hepatitis B (2015 update).
      Although the study by Jourdain et al
      • Jourdain G.
      • Ngo-Giang-Huong N.
      • Harrison L.
      • et al.
      Tenofovir versus placebo to prevent perinatal transmission of hepatitis B.
      in Thailand did not show a statistically significant benefit of TDF treatment over a placebo control, the findings might not be generalizable to other countries. Given the potentially insufficient sample size and relatively high rate of loss to follow-up evaluation in the study, the difference between the TDF (0%) and placebo (2%) arms could hardly be differentiated. In pregnant women with very high baseline viral loads (≥1 × 108 IU/mL), earlier initiation of antiviral therapy may be necessary to achieve viral suppression below the recommended threshold.
      • Pan C.Q.
      • Chang T.T.
      • Bae S.H.
      • et al.
      Viral kinetics in women of child bearing potential with chronic hepatitis B virus following treatment with tenofovir alafenamide or tenofovir disoproxil fumarate.
      Before delivery, HBV DNA quantification should be repeated to evaluate the efficacy of antiviral therapy and the risk of MTCT.
      If the HBV DNA level is ≤2 × 106 IU/mL, antiviral therapy is not recommended.
      • Hou J.
      • Wang G.
      • Wang F.
      • et al.
      Guideline of prevention and treatment for chronic hepatitis B (2015 update).
      Considering that the threshold of antiviral therapy to prevent MTCT is variable among current guidelines (Table 1) and MTCT still may occur in pregnant women with lower HBV DNA levels, options for antiviral therapy should be provided to those with HBV DNA levels ≤2 × 106 IU/mL and high-risk factors for MTCT, such as history of MTCT, threatened abortion, threatened premature labor, and indications of invasive procedures, after thorough evaluation and discussion.
      Table 1Recommendations for Antiviral Intervention to Prevent Mother-To-Child Transmission in Pregnant Women With Chronic HBV Infection
      SocietiesThreshold of HBV DNA levelInitiation timeCessation timeAntiviralsReference
      AASLD (2018)>2 × 105 IU/mL28–32 wkAt birth to 3 monthsTDF
      • Terrault N.A.
      • Lok A.S.
      • Mcmahon B.J.
      • et al.
      Update on prevention, diagnosis, treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.
      EASL (2017)>2 × 105 IU/mL24–28 wkUp to 12 weeks after deliveryTDF
      European Association for the Study of the Liver
      EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection.
      APASL (2015)>6–7 log10 IU/mL28–32 wkAt deliveryTDF LdT
      • Sarin S.K.
      • Kumar M.
      • Lau G.K.
      • et al.
      Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update.
      CMA (2015)>2 × 106 IU/mL24–28 wkAt deliveryTDF LdT LAM
      • Hou J.
      • Wang G.
      • Wang F.
      • et al.
      Guideline of prevention and treatment for chronic hepatitis B (2015 update).
      NICE (2013)>107 IU/mLThe third trimester4–12 weeks after birthTDF

      National Institute for Health and Care Excellence. Hepatitis B (chronic): diagnosis and management of chronic hepatitis B in children, young people and adults. London, 2013. Available from: http://www.nice.org.uk/guidance/CG165. Accessed: May 2013.

      AASLD, American Association for the Study of Liver Diseases; APASL, Asian Pacific Association for the Study of the Liver; CMA, Chinese Medical Association; EASL, European Association for the Study of the Liver; LAM, lamivudine; NICE, National Institute for Health and Care Excellence; TDF, tenofovir disoproxil fumarate.

      Delivery Management

       Mode of Delivery

      The mode of delivery should follow the usual obstetric indications. Routine cesarean section is not recommended for the prevention of HBV transmission. There is no clear and strong evidence to support cesarean section as the mode of choice for preventing MTCT of HBV. Among cases of HBV MTCT, a large proportion occur around labor and delivery, particularly with risk factors including high maternal viremia, transfusion of the mother’s blood to the fetus during labor contractions, infection after rupture of membranes, and direct contact of the fetus with infected secretions or blood from the maternal genital tract. At the time of delivery, clinical assessment of HBV-infected pregnant women should include liver function status. With consideration for the safety of the fetus, procedures that break the skin and mucosal barrier should be avoided as much as possible, including fetal scalp electrodes, fetal scalp blood sampling, and vigorous suctioning of the newborn’s airway at birth. Instrumental delivery, such as the use of vacuum extraction and forceps to expedite delivery during the second stage of labor, should follow obstetric indications. There is a small risk of traumatizing the fetal skin and risking transmission of HBV to the infant.

       Care of the Newborn

      Standard precautions should continue when handling the newborn. Visible blood, mucus, and amniotic fluid on the surface of the neonate and the cord should be gently wiped off. Standard procedures for cord cutting should be followed. Immunoprophylaxis to be delivered at birth, including the hepatitis B vaccine and HBIG, should be provided. The skin at the injection rite should be cleaned with an alcohol swab before the injection is administered.

      Discontinuation of Antivirals

      For pregnant women who have normal ALT levels and receive antiviral therapy to prevent MTCT during pregnancy, drugs can be discontinued immediately after delivery (moderate quality, weaker recommendation).
      • Nguyen V.
      • Tan P.K.
      • Greenup A.J.
      • et al.
      Anti-viral therapy for prevention of perinatal HBV transmission: extending therapy beyond birth does not protect against post-partum flare.
      • Hou J.
      • Wang G.
      • Wang F.
      • et al.
      Guideline of prevention and treatment for chronic hepatitis B (2015 update).
      Close monitoring of maternal ALT levels is warranted after withdrawal of antivirals because postpartum hepatitis may occur. The details of follow-up evaluation are described in section 10.2.
      The appropriate time to discontinue antivirals still is controversial among current guidelines because the evidence on this issue is not sufficient. In most studies on antiviral therapy during pregnancy to prevent MTCT, maternal antiviral therapy was discontinued at 1 to 3 months after delivery to avoid ALT flares. Based on these studies, the European Association for the Study of the Liver guidelines recommend that antiviral therapy be stopped up to 12 weeks after delivery for pregnant women who receive antivirals to prevent MTCT.
      European Association for the Study of the Liver
      EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection.
      However, extension of antiviral therapy for several weeks or months has not been shown to significantly prevent the occurrence of a postpartum hepatitis flare.
      • Nguyen V.
      • Tan P.K.
      • Greenup A.J.
      • et al.
      Anti-viral therapy for prevention of perinatal HBV transmission: extending therapy beyond birth does not protect against post-partum flare.
      Therefore, the Chinese Medical Association guidelines suggest that maternal antiviral therapy can be discontinued at delivery and that regular monitoring of ALT levels should be performed to detect postpartum hepatitis flares.
      • Hou J.
      • Wang G.
      • Wang F.
      • et al.
      Guideline of prevention and treatment for chronic hepatitis B (2015 update).
      It was reported that ALT flares occurred more frequently in mothers who previously had taken TDF than in those who had not received TDF (45% vs 30%).
      • Pan C.Q.
      • Duan Z.
      • Dai E.
      • et al.
      China Study Group for the mother-to-child transmission of hepatitis B. Tenofovir to prevent hepatitis B transmission in mothers with high viral load.
      Although postpartum hepatitis often is mild in severity and usually resolves spontaneously, severe ALT flares were observed in approximately 5% of mothers after discontinuation of antivirals.
      • Pan C.Q.
      • Duan Z.
      • Dai E.
      • et al.
      China Study Group for the mother-to-child transmission of hepatitis B. Tenofovir to prevent hepatitis B transmission in mothers with high viral load.
      Care should be taken to address the possibility of severe hepatitis, even fulminant hepatitis. Because the existing evidence is limited and insufficient, well-designed studies are needed to ascertain the appropriate time to stop antiviral therapy.
      For pregnant women who experience hepatitis flares and start antiviral therapy for their hepatitis, antiviral treatment should not be stopped after delivery. Such women should continue treatment for hepatitis under the direction of hepatologists/gastroenterologists or infectious disease specialists. The details of follow-up evaluation are described in section 10.1. Discontinuation of the antiviral therapy can be considered following the recommendations in the Chinese Guideline of Prevention and Treatment of Chronic Hepatitis B (2015 version).
      • Hou J.
      • Wang G.
      • Wang F.
      • et al.
      Guideline of prevention and treatment for chronic hepatitis B (2015 update).

      Neonatal Immunoprophylaxis

      Within 12 hours after delivery, preferably as soon as possible, 100 IU HBIG should be administered intramuscularly in the anterolateral thigh or deltoid muscle (A1).
      National Health Commission of the People’s Republic of China
      Immunization programs and instructions of national immunization program for Children. 2016.
      • Schille S.
      • Vellozzi C.
      • Reingold A.
      • et al.
      Prevention of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices.
      A prospective cohort study in China showed that 1 birth dose of 100 IU combined with the 3-dose hepatitis B vaccine series would be sufficient to prevent MTCT of HBV in infants born to HBeAg-positive mothers.
      • Wei K.P.
      • Zhu F.C.
      • Liu J.X.
      • et al.
      The efficacy of two different dosages of hepatitis B immunoglobulin combined with hepatitis B vaccine in preventing mother-to-child transmission of hepatitis B virus: a prospective cohort study.
      At the same time, the first dose of the recombinant yeast hepatitis B vaccine (10 μg/0.5 mL) should be administered in the anterolateral thigh or deltoid muscle on the opposite side of the body. The other 2 doses of 10 μg/0.5 mL hepatitis B vaccine are scheduled at 1 and 6 months of age following the national Chinese vaccination schedule (high quality, strong recommendation).
      Timely administration of HBIG and hepatitis B vaccine is critical for interrupting MTCT. The Centers for Disease Control and Prevention recommend that the birth dose of HBIG and hepatitis B vaccine be given within 12 hours after birth.
      • Schille S.
      • Vellozzi C.
      • Reingold A.
      • et al.
      Prevention of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices.
      Any delay beyond 48 hours in the administration of HBIG has a significant impact on the rate of MTCT. Timely administration of the first dose of hepatitis B vaccine can provide early postexposure protection and enhance compliance in completing the vaccination series.
      Center for Diseases Control and Prevention
      Assessing completeness of perinatal hepatitis B virus infection reporting through comparison of immunization program and surveillance data: United States.
      A delayed vaccination schedule also is possible. If the originally scheduled second dose of the hepatitis B vaccine is missed by up to 3 months, this dose should be injected as soon as possible, and the third dose of vaccine should be provided at 6 months. If, however, the second dose is delayed by more than 3 months from the planned visit, the dose should be given as soon as possible, and the third dose should be scheduled for 2 months later.
      For preterm and low-birth-weight infants (<2000 g), 100 IU HBIG plus hepatitis B vaccine (10 μg/0.5 mL) should be administered within 12 hours, with 3 subsequent doses of vaccine (10 μg/0.5 mL each) scheduled at 1, 2, and 7 months of age. Infants with unknown maternal HBsAg status should be treated as infants born to HBsAg-positive mothers. Those children’s mothers should be tested for HBsAg as soon as possible. If the mother is HBsAg negative, the 3 doses of vaccine can be started at 1 month of age or postponed until just before hospital discharge. The vaccination scheme still should be administered according to the 0-1-6 months schedule.

      Breastfeeding

      Mothers who were not treated with antivirals during pregnancy are encouraged to breastfeed if their newborns have received combined immunoprophylaxis composed of HBIG and hepatitis B vaccine (B1). If a postpartum hepatitis flare occurs during breastfeeding, mothers can be managed according to the Chinese Guideline of Prevention and Treatment of Chronic Hepatitis B (2015 version).
      • Hou J.
      • Wang G.
      • Wang F.
      • et al.
      Guideline of prevention and treatment for chronic hepatitis B (2015 update).
      For mothers on antiviral treatment for the prevention of MTCT, the antiviral treatment can be discontinued after delivery, and breastfeeding then can be allowed if the newborns have received combined immunoprophylaxis.
      If mothers receive antivirals to treat chronic hepatitis B and continue treatment after delivery, breastfeeding is not contraindicated (low quality, weaker recommendation). It has been reported that in the breast milk of TDF-treated mothers, the drug is present only at low concentrations, and its oral bioavailability is limited; thus, infants are exposed to only a minuscule amount of TDF.
      • Benaboud S.
      • Pruvost A.
      • Coffie P.A.
      • et al.
      Concentrations of tenofovir and emtricitabine in breast milk of HIV-1-infected women in Abidjan, Cote d'Ivoire, in the ANRS 12109 TEmAA Study, Step 2.

      Follow-Up Evaluation of Infants

      Infants born to HBsAg-positive mothers should be followed up for completion of hepatitis B vaccination and postvaccination serologic testing (PVST). PVST is important for evaluating the effect of hepatitis B immunization and identifying HBV infection in infants. WHO and the Centers for Disease Control and Prevention
      • Schille S.
      • Vellozzi C.
      • Reingold A.
      • et al.
      Prevention of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices.
      recommend PVST for infants born to HBV-infected women. PVST should be performed after completion of the hepatitis B vaccine series and at least 1 month after the last hepatitis B vaccine dose. Because of possible interference of the HBIG injection at birth and a decrease in antibody to hepatitis B surface antigen (anti-HBs), PVST should not be performed before completion of hepatitis B vaccination or after 12 months of age. It was reported that the highest anti-HBs level was observed in infants whose PVST was performed 1 to 2 months after the third dose of hepatitis B vaccine, and the anti-HBs level was substantially greater among infants tested at 7 to 12 months of age than among those tested at 13 to 24 months of age.
      • Wang F.
      • Zhang G.
      • Zheng H.
      • et al.
      Post-vaccination serologic testing of infants born to hepatitis B surface antigen positive mothers in 4 provinces of China.
      The assessment of PVST is described, along with corresponding measures, in the following section.

      Assessment of Postvaccination Serologic Testing for Hepatitis B Virus–Exposed Infants

      PVST examines 2 markers, namely, HBsAg and anti-HBs (antibody levels), which allow clinicians to determine whether an infant is immune and protected, infected, or uninfected and nonimmune. Quantification of anti-HBs antibody levels will help clinicians determine whether an infant is protected; the threshold of protection is defined as ≥10 mIU/mL.
      HBsAg-positive infants should be referred for appropriate clinical care and follow-up evaluation and their parents counseled.
      HBsAg-negative infants with anti-HBs levels ≥100 mIU/mL are protected against hepatitis B and do not require further medical management.
      HBsAg-negative infants with anti-HBs less than 10 mIU/mL should have their HBV DNA levels tested to rule out the possibility of occult HBV infection. If HBV DNA is undetectable, these infants should be revaccinated with a further 3 doses of hepatitis B vaccine (10 μg/0.5 mL) and undergo PVST 1 to 2 months after the final vaccine.
      An anti-HBs antibody level of ≥100 mIU/mL indicates a good immune response with protective immunity, while an antibody level of less than 10 mIU/mL indicates no significant response or immunity. An antibody level of ≥10 to <100 mIU/mL after vaccination indicates low response.
      Among infants born to HBsAg-positive mothers, the rate of nonresponse/low response to hepatitis B vaccine was reported to be 22.4% to 30.2%, compared with 5% to 10% in the general infant population.
      • Wang J.
      • Feng Y.L.
      • Liu M.H.
      • et al.
      Combined immunoprophylaxis induces changes in anti-hepatitis B surface protein titer in infants born to mothers with positivity for hepatitis B surface antigen.
      • Tang J.
      • Xu L.H.
      • Chen J.
      • et al.
      Effect of neonatal immunoprophylaxis in mother-to-fetus transmission of HBV and analysis on risk factor for transmission.
      • Bracciale L.
      • Fabbiani M.
      • Sansoni A.
      • et al.
      Impact of hepatitis B vaccination in children born to HBsAg positive mothers: a 20 years retrospective study.
      • Guo J.
      • Gao Y.
      • Wang S.P.
      • et al.
      The influence factors of non-responsiveness and low-responsiveness to hepatitis B vaccine of infants born to hepatitis B surface antigen positive mothers.
      The risk factors of nonresponse/low response to hepatitis B vaccine include high HBV DNA level, premature labor, low birth weight, type of hepatitis B vaccine, and so forth.
      • Wang B.
      • Xu X.X.
      • Wen H.X.
      • et al.
      Influencing factor for non/low response to hepatitis B vaccine in infants of HBsAg-positive mothers.
      • Li J.
      • Hu H.Y.
      • Pan Y.J.
      • et al.
      Study on non/low response and its determinants to recombinant yeast-derived hepatitis B vaccine among neonates after primary immunization in Shanghai.
      Several studies have shown that additional doses of hepatitis B vaccine could induce a robust anti-HBs response in most low-responding infants.
      • Belloni C.
      • Tinelli C.
      • Orsolini P.
      • et al.
      Revaccination against hepatitis B virus of non-responding and low-responding infants immunised at birth. A parallel evaluation of rubella and tetanus vaccine.
      • Pang L.
      • Wang C.Y.
      • He S.X.
      • et al.
      Risk factors and individual immunologic intervention of non- or low-response status of infants of HBsAg positive mothers after hepatitis B vaccination.
      An additional single dose of 10 μg hepatitis B vaccine should be administered to low-responding infants, given that the immune response of low-responding infants might be unstable and the potential risk of horizontal infection still exists under the circumstances of close contact between mother and infant. Further studies are needed to investigate the effectiveness of a booster dose for low-responding infants.

      Follow-Up Evaluation of Mothers After Delivery

      Mothers on antiviral treatment after delivery should be followed up according to the protocol for general chronic hepatitis B patients. Liver function and HBV DNA level should be checked every 3 months. HBV serology, α-fetoprotein tests, abdominal ultrasound, and transient elastography should be performed at 6-month intervals.
      Liver function and HBV DNA level should be checked at 6 to 8 weeks postpartum in mothers who discontinue antivirals after delivery. If liver function is normal, monitoring should be continued at intervals of 3 to 6 months. If liver function is abnormal at 6 to 8 weeks after delivery, patients should be managed following the recommendations in the Chinese Guideline of Prevention and Treatment of Chronic Hepatitis B (2015 updated version).
      • Hou J.
      • Wang G.
      • Wang F.
      • et al.
      Guideline of prevention and treatment for chronic hepatitis B (2015 update).
      Mothers not on antiviral treatment may experience ALT flares or exacerbation after delivery. Liver function should be monitored at postpartum weeks 3 to 4 and 9 to 12, especially in mothers with increased ALT and detectable HBV DNA levels at delivery.
      • Yi W.
      • Pan C.Q.
      • Li M.H.
      • et al.
      The characteristics and predictors of postpartum hepatitis flares in women with chronic hepatitis B.

      Practice Considerations

      Prevention of new infections of hepatitis B among infants is key to ensuring a generation free of hepatitis B. The current standards of care for HBV prevention (ie, 3 vaccines and HBIG), are highly effective, and additional interventions should be considered for HBV-infected women who are HBeAg positive and/or have high viral loads. In the implementation of these clinical practice protocols, physicians and the team caring for the well-being of the pregnant women and her fetus should establish good communication for multidisciplinary care. Local hospital protocols should be established to provide a reliable patient clinical pathway between hospital departments to ensure seamless care and good patient education (Figure 1; Supplementary Table 1).
      Figure thumbnail gr1
      Figure 1Management algorithm for interrupting mother-to-child transmission of hepatitis B virus.

      Acknowledgments

      The authors would like to thank Dr Po-Lin Chan and Dr Calvin Pan for their professional comments, and the authors are grateful to Dr Xueru Yin for her contribution in the proofreading and revision of the manuscript.

      Supplementary Material

      Supplementary Table 1Grading of Evidence and Recommendations
      NotesSymbol
      Grade of evidence
       High qualityMeta-analysis or randomized controlled trialsA
       Moderate qualityControlled trials without randomization

      Cohort or case-control analytical studies

      Multiple time series
      B
       Low qualityOpinions of experts; descriptive epidemiologyC
      Grade of recommendation
       StrongFactors influencing the strength of the recommendation include the quality of the evidence, presumed patient-important outcomes, and cost1
       WeakerWith more variability in preferences and values or greater uncertainty, a weak recommendation is more likely to be warranted

      Recommendations with higher costs or resource consumption are also made with less certainty
      2

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