Infectious Disease Consult

Hepatitis B infection in pregnancy: Essentials of antiviral therapy and immunoprophylaxis

OBG Manag. 2023 September;35(9):26-27, 34-36, 38 | doi: 10.12788/obgm.0306

References

Duff P. Maternal and fetal infections. In: Resnik R, Lockwood CJ, Moore TR, et al, eds. Creasy & Resnik’s Maternal-Fetal Medicine: Principles and Practice. 8th ed. Elsevier; 2019:862.
Bernstein HB, Lee MJ. Maternal and perinatal infection in pregnancy: viral. In: Landon MB, Galan HL, Jauniaux ERM, et al, eds. Gabbe’s Obstetrics. Normal and Problem Pregnancies. 8th ed. Elsevier; 2021;1092.
Dusheiko G, Agarwal K, Maini MK. New approaches to chronic hepatitis B. N Engl J Med. 2023;388:55-69.
Ma L, Alla NR, Li X, et al. Mother to child transmission of HBV: review of current clinical management and prevention strategies. Rev Med Virol. 2014; 24: 396-406.
Society for Maternal-Fetal Medicine; Dionne-Odom J, Tita ATN, Silverman NS. SMFM consult: preventing vertical transmission of hepatitis B. Contemporary OB/GYN. September 22, 2015. Accessed August 21, 2023. https://www .contemporaryobgyn.net/view/smfm-consult-preventing -vertical-transmission-hepatitis-b
Lok ASF. The maze of treatments for hepatitis B. N Engl J Med. 2005;352:2743-2746.
Shi Z, Yang Y, Wang H, et al. Breastfeeding of newborns by mothers carrying hepatitis B virus: a meta-analysis and systematic review. Arch Pediatr Adolesc Med. 2011;165:837-846.
Dusheiko G. A shift in thinking to reduce mother-to-infant transmission of hepatitis B. N Engl J Med. 2018;378:952-953.
Shi Z, Yang Y, Ma L, et al. Lamivudine in late pregnancy to interrupt in utero transmission of hepatitis B virus: a systematic review and meta-analysis. Obstet Gynecol. 2010;116:147-159.
Pan C, Duan Z, Dai E, et al; China Study Group for the Motherto-Child Transmission of Hepatitis B. Tenofovir to prevent hepatitis B transmission in mothers with high viral load. N Engl J Med. 2016;374:2324-2334.
Jourdain G, Ngo-Giang-Huong N, Harrison L, et al. Tenofovir versus placebo to prevent perinatal transmission of hepatitis B. N Engl J Med. 2018;378:911-923.
Wang M, Ran R, Zhu Y, et al. Comparison of tenofovir disoproxil fumarate and telbivudine in preventing hepatitis B transmission in mothers with high viral load. Int J Gynaecol Obstet. 2023:160:646-652.

Clinical presentation

Approximately 90% of adult patients who contract hepatitis B, either symptomatically or asymptomatically, will develop protective levels of antibody and clear the virus from their system. They will then have lifelong immunity to reinfection. Approximately 10% of patients will fail to develop protective levels of antibody and will become chronically infected, posing a risk to their household members, sexual contacts, and their fetus if they become pregnant. Persistence of the surface antigen in the patient’s serum for more than 6 months denotes chronic infection. A very small number of individuals—less than 1%—will develop acute liver failure and experience a fatal outcome.^1-3,5

In the United States, the prevalence of acute hepatitis B in pregnancy is 1 to 2 per 1,000. Clinical manifestations typically include anorexia, nausea, low-grade fever, right upper quadrant pain and tenderness, passage of clay-colored stools, and jaundice.

The prevalence of chronic infection in pregnancy is significantly higher, approximately 5 to 15 per 1,000. Over the long term, patients with chronic infection are at risk for progressive liver injury, including cirrhosis and even hepatocellular carcinoma. These serious sequelae are particularly likely to occur when the patient is co-infected with hepatitis C, D, or both. The overall risk of progression to chronic cirrhosis is approximately 15% to 30%. In patients who progress to cirrhosis, the annual incidence of hepatocellular carcinoma is 10%.^1-3

Diagnosis of hepatitis B infection

Patients with acute hepatitis B will test positive for HBsAg and immunoglobulin M (IgM) antibody to the core antigen. Some patients will also test positive for HBeAg. Assessment of the patient’s serum by polymerase chain reaction (PCR) allows quantitation of the viral load, which often is expressed as viral copies per milliliter. Alternatively, the quantitative hepatitis B DNA concentration may be expressed as international units per milliliter (IU/mL). The World Health Organization recommends this latter quantitative method. Multiplying the DNA in IU/mL by 5.6 provides the conversion to viral copies per milliliter.

Patients with chronic hepatitis B infection will test positive for the HBsAg and for immunoglobulin G (IgG) antibody to the core antigen. They may also have a positive test for the HBeAg, and PCR may be used to quantify the viral load.^1-3

Managing hepatitis B infection in pregnancy

General supportive measures. All pregnant patients should be tested for the HBsAg and HBsAb at the time of the first prenatal appointment. The tests should be repeated at the beginning of the third trimester in high-risk patients. Seropositive patients should have a hepatitis B genotype, a test for the e antigen, and tests for other sexually transmissible infections (gonorrhea, chlamydia, syphilis, HIV) and for hepatitis C and D. Liver function tests should be performed to assess for elevations in the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Patients with elevated transaminase enzymes should have a coagulation profile to be certain they are not at risk for a coagulopathy.

At the end of the second trimester, patients should have a PCR assessment to determine the viral load. This assessment will be important for deciding if specific antiviral therapy is indicated during the third trimester to enhance the effects of neonatal immunoprophylaxis (see below). Of note, patients who are positive for the e antigen may have a very high viral load and yet have normal or near-normal transaminase levels. This seemingly paradoxical finding reflects the non-cytopathic nature of hepatitis B.

The patient should optimize her nutrition and sleep. She should avoid, or at least minimize, medications such as acetaminophen that could cause further liver injury. Without question, she should refrain from consuming even small amounts of alcohol. She should be tested for immunity to hepatitis A; if found to be susceptible, she should be vaccinated with the hepatitis A vaccine. This agent is an inactivated vaccine and is safe for administration at any time in pregnancy.^1,2,5

Household contacts. In addition to the measures outlined above, the patient’s household contacts, particularly her sexual partner(s), should be tested for immunity to hepatitis B. If they do not have immunity by virtue of natural infection or previous vaccination, they should receive the hepatitis B vaccine series. It is also prudent to provide the sexual partner(s) with an initial dose of hepatitis B immune globulin (HBIG) to provide a temporary level of passive immunity.

Postdelivery care. After delivery, the patient should be referred to an infectious disease specialist or hepatologist for consideration of long-term treatment with antiviral agents, such as interferon alfa, pegylated interferon alfa, lamivudine, adefovir, entecavir, telbivudine, or tenofovir.⁶ The principal candidates for treatment are those who have cirrhosis and detectable levels of hepatitis B DNA. The ultimate goal of treatment is to reduce the serum hepatitis B DNA concentration to an undetectable level. Once the surface antigenemia is cleared, treatment can be stopped. A cure is defined when the absence of hepa-titis B DNA in the serum is sustained.

Key points: Hepatitis B infection in pregnancy

Hepatitis B is a DNA virus that is transmitted via sexual contact, exposure to infected blood, and from an infected mother to her fetus.
Most patients in our practice will most likely have chronic, asymptomatic infection, and the diagnosis will be established by detection of HBsAg in the patient’s serum.
All obstetric patients should be tested for both HBsAg and HBsAb.
Patients who are positive for the surface antigen should be tested for HIV infection and hepatitis C and D. They also should have a determination of the hepatitis B genotype and viral load and assessment of liver function (ALT, AST).
Patients who are chronically infected with hepatitis B should be vaccinated against hepatitis A to prevent further liver injury. They also should avoid medications that might cause hepatic injury.
Patients who have a viral DNA concentration greater than 200,000 IU/mL or a viral load greater than 1,120,000 million copies/mL should be treated with tenofovir, 300 mg daily, from week 28 until 4 to 8 weeks after delivery.
Infants delivered to infected mothers should receive HBIG within 12 hours of birth and then begin the 3-dose hepatitis B vaccine series. The first dose should be administered prior to hospital discharge.
Infants delivered to mothers who are negative for the surface antigen should begin the hepatitis B vaccine series prior to discharge from the hospital.
Mothers who test negative for HBsAb should be questioned about prior vaccination. If they have never been vaccinated, they should receive the 3-dose vaccine series. If they have been vaccinated, they should receive a single hepatitis B vaccine booster. The vaccine is safe for administration at any time during pregnancy.
Infected mothers may breastfeed as long as they do not have cracked or bleeding nipples or exudative skin lesions near the nipple(s).

Neonatal immunoprophylaxis

The Centers for Disease Control and Prevention recommends universal hepatitis B vaccination for all newborns. The first dose of the vaccine should be administered prior to hospital discharge. The second and third doses should be administered 1 and 6 months later.^1,2,5 There are few, if any, medical contraindications to neonatal vaccination. For the vast majority of infants, the immunity induced by vaccination is lifelong. For a small number, immunity may wane over time. Thus, reassessment of the HBsAb concentration is indicated in selected situations, for example, acute high-risk exposure to an infected person, development of an immunosuppressive disorder, or pregnancy.

Infants delivered to mothers who are infected with hepatitis B also should receive HBIG in addition to the vaccine. HBIG provides passive immunization to counteract the high viral inoculum encountered by the neonate during delivery. This preparation should be administered within 12 hours of birth.^1,2,5

In the absence of immunoprophylaxis, a neonate delivered to a mother who is seropositive for HBsAg has a 20% to 30% probability of becoming chronically infected. If the mother is positive for both the surface antigen and the e antigen, the risk of chronic infection increases to almost 90%. Approximately 90% of infants who are infected in the perinatal period subsequently develop chronic infection. However, with appropriate immunoprophylaxis in the neonatal period, the risk of perinatal transmission is reduced by 85% to 95%.^1,2,5

Cesarean delivery offers no additional protection beyond that provided by immunoprophylaxis. Moreover, because immunoprophylaxis is so effective, infected mothers may breastfeed without fear of transmitting infection to their infant. Shi and colleagues published a systematic review and meta-analysis of the risk associated with breastfeeding in hepatitis B–infected mothers.⁷ Infants who breastfed did not have a higher rate of mother-to-child transmission, regardless of whether they received combined immunoprophylaxis or only hepatitis B vaccine and regardless of whether the HBsAg was detected in the mother’s breast milk. The only precaution is the need to avoid breastfeeding if the nipples are cracked or bleeding or if exudative lesions are present on the skin near the nipple.

Continue to: Maternal antiviral therapy...