10.0 Managing hepatitis B virus infection in pregnancy and children

  • All pregnant women should be tested for hepatitis B surface antigen (HBsAg). A woman identified as HBsAg positive should be tested for hepatitis B e antigen (HBeAg) and hepatitis B virus (HBV) DNA, to determine risk of transmission to the infant and the degree of infectivity.
  • If a pregnant woman has HBV, health professionals should take the opportunity to provide education about disease management, plan ongoing care, and test family and close contacts.
  • The risk of mother-to-child transmission of HBV can be significantly reduced. The baby should be given a combination of hepatitis B immunoglobulin (HBIG) and the first dose of hepatitis B vaccine within 12 hours of birth, followed by a full course of hepatitis B vaccine.
  • For HBsAg-positive women with high viral loads (>10 million IU/mL or 7 log IU), referral should be made to a specialist for consideration of antiviral therapy, to further reduce the risk of perinatal transmission.
  • There is no evidence of HBV transmission as a result of breastfeeding.
  • Children born to HBsAg-positive mothers should be followed up and tested for infection once vaccination has been completed.
  • Most children with chronic hepatitis B (CHB) are asymptomatic and have little liver damage, but have high viral loads.
  • Children with CHB should be monitored annually, with liver function tests and HBV serology/viral load.
  • Ensure adolescents are appropriately transferred from paediatric to adult care.

In some areas of the world, up to 20% of women of child-bearing age are infected with chronic hepatitis B (CHB). In Australia, individuals who have migrated from countries with high hepatitis B virus (HBV) prevalence are often unaware of their infection, because testing is not part of routine migration health assessment. Pregnancy is the only time universal testing for infection with HBV occurs; and as a result, this is often the first time women become aware of their HBV infection. HBV can have significant health implications for the mother and her baby, and the issues for each should be considered independently.

Assessment of the mother should include consideration of the likely duration of infection; any prior or current therapy; liver function tests; and pre-pregnancy liver ultrasound, liver biopsy or non-invasive assessment of liver fibrosis (e.g. FibroScan®). This consultation is an important educational opportunity. The mother should receive information about infection control, routes of transmission, vaccination, the phases of HBV infection and recommendations for follow up at each phase (see Appendix 2 for education resources). This is also an opportunity to offer testing to family members, and household and sexual contacts of the patient. Any treatment decisions (e.g. initiating or stopping therapy in the case of an unexpected pregnancy) should take into consideration the toxicity of therapies on the developing foetus, as discussed below.

HBV testing is universal in pregnancy, to allow for interventions to reduce transmission to the infant. This is important because more than 90% of infected infants will develop chronic infection, with the potential for significant adverse health outcomes. In contrast, 80% of older children and 95% of adults are able to clear HBV after infection. One hypothesis to explain the infant’s failure to resolve HBV infection is that maternal hepatitis B e antigen (HBeAg) crosses the placenta and has a negative effect on the developing foetal immune system (1).

Preventing perinatal transmission

All babies of HBsAg-positive mothers should:
  1. be given HBIG and the first dose of HBV vaccine within 12 hours of birth
  2. have three subsequent doses of HBV vaccine, at 2, 4 and 6 months of age
  3. be tested for HBsAg and anti-HBs after 9–12 months of age (at least 3 months after final dose of HBV vaccine).

During pregnancy, the mother’s viral load should be tested; if it is high (>7 log10 IU/mL or 10,000,000 IU/mL), third-trimester antiviral therapy should be considered.

 anti-HBs, antibodies to surface antigen; HBIG, hepatitis B immunoglobulin; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IU, international unit

The cornerstone of prevention of HBV perinatal transmission is the combination of hepatitis B immunoglobulin (HBIG) and the first dose of hepatitis B vaccine, which is delivered within 12 hours of birth, followed by a full course of hepatitis B vaccine. Babies should be checked after 9 –12 months of age for HBsAg to diagnose infection and antibodies to surface antigen (anti-HBs) to confirm vaccine response. Overall efficacy of this strategy is reported to be greater than 95% (2). There is no evidence that prematurity, premature rupture of membranes, low birth weight, meconium staining or breastfeeding lead to the failure of passive active immune prophylaxis (3). Such failure was thought to be largely the result of protocol error; however, it has become clear that failure of immune prophylaxis is related to HBeAg positivity and maternal HBV DNA level (3-5). In one Australian study, transmission despite appropriate prophylaxis was documented only in mothers with high viral load (>7 log10 IU/mL), at rates approaching 10% (4).

Based on available evidence, HBV transmission usually occurs during the birth process (as opposed to earlier in pregnancy). In support of this hypothesis, there has been some evidence that elective (but not urgent) caesarean section may be protective; however, the evidence for this is conflicting. The studies that support caesarean section are not high quality, and no international obstetric guidelines recommend this approach, and nor does the World Health Organization. Other strategies are more effective and are discussed below (5-7).

Antiviral therapy to prevent perinatal transmission of human immunodeficiency virus (HIV) infection is well established; antiviral therapy is also emerging as an effective strategy to reduce transmission in HBV infection. A number of reviews have been written on this topic, and guidelines suggest this approach; however, as yet, there are no standardised recommendations for the optimum choice or duration of agent, or even the HBV DNA threshold for initiating therapy (8-11).

Despite the paucity of randomised trials in this setting, the available data confirm the efficacy of antepartum lamivudine in reducing perinatal transmission, although the effect is modest and variable (12-14). Also, despite the short duration of antiviral exposure in this setting, lamivudine’s lack of antiviral potency and selection of HBV mutants resistant to antiviral therapy make this drug a suboptimal choice (15, 16).

Tenofovir has superior potency to lamivudine and telbivudine, and no emergence of resistance mutations has been described to date (17). There is limited evidence of the efficacy of tenofovir in pregnancy to reduce perinatal transmission, although no transmission was reported in two small series (18, 19).

Tenofovir is probably the optimal choice, and should be started at 32 weeks gestation in mothers with viral load above 7 log10 IU/mL. Optimal thresholds have not been clearly established (many studies report in copies/mL rather than IU, and therefore cannot be extrapolated). Therapy should continue for at least 2 weeks postpartum, and possibly up to 12 weeks (the latter may be preferable for reasons related to maternal health, as discussed below).

10.3.1 Antiviral safety

The Therapeutic Goods Administration (TGA) pregnancy categories for HBV therapies reflect the limited human safety data but absence of human toxicity; thus, all therapies are classified in category B. The differences lie in evidence of animal toxicity. Interferons (IFNs) are generally contraindicated in pregnancy and cessation should be recommended when a woman becomes pregnant. There is limited data on the safety of entecavir in pregnancy, and its use is therefore not recommended. Seeking specialist advice is recommended. Lamivudine and tenofovir are categorised by the TGA as B3 and telbivudine as B1, based on animal toxicity data. The lack of animal toxicity for telbivudine is of interest, although data on human pregnancy experience with this agent are lacking. The toxicity concern with tenofovir is based largely on animal models where, in the setting of high doses, effect on foetal growth and development was observed. Human data (albeit mainly in the setting of HIV) are available. Tenofovir has not been shown to be teratogenic; concerns about growth and bone density have not been completely resolved, but findings are reassuring overall (20).

Reassuring data regarding the safety of both tenofovir and lamivudine in human pregnancy are provided by a prospective registry, largely in the setting of HIV infection. The registry shows no increase in birth defects after exposure to either of these agents (21). However, the registry is limited by the voluntary reporting structure, review but not verification of submitted information, lack of long-term follow up or information on developmental delay, and low sensitivity (able to detect only a twofold increase in birth defect rates). Nevertheless, results of studies in the setting of HIV that more closely examine the effect of in utero exposure to tenofovir, with a follow up of up to 4 years, are reassuring, with only one report of isolated reduced growth parameters at age 1 year (but not 2) in one study (22).

Advice about breastfeeding
There is no evidence of HBV transmission as a result of breastfeeding. Tenofovir, and not the bioavailable pro-drug, tenofovir disoproxil fumarate, is present in the breast milk (11, 23). In addition, when used in children, tenofovir has been shown to be safe. Therefore, women should be provided the available information and not discouraged from breastfeeding. Although no definitive recommendation is possible, it is reasonable for a woman to consider breastfeeding after being given the available information (24).

A major consideration in care for a pregnant woman is for the optimal health of the developing foetus; however, the mother’s health is of prime importance. During the relatively immune-tolerant state of pregnancy, hepatitis B is commonly relatively silent, but a flare of hepatitis commonly occurs in the postpartum period (in 30–50% of HBeAg-positive mothers with high viral load), with onset at approximately 10 weeks postpartum (25). Postpartum flares have also been observed in HBeAg-negative mothers. Flares are usually asymptomatic and settle spontaneously (25). If a flare is noted, it can be observed for up to 6 months to assess whether it will resolve spontaneously, or require treatment. It does not appear that antiviral therapy in pregnancy will increase the rate or severity of postpartum flares (13, 26, 27), nor that extending antiviral therapy beyond birth prevents the postpartum flare, although data are limited (25). During the postpartum period, the mother’s liver function should be monitored every 1–2 months. All HBsAg-positive women should be enrolled in ongoing care, and have a plan formed for the management of their HBV. See Chapters 6 and 7 for more information on this topic.

In summary, although guidelines provide scant specific instruction, the goal is complete prevention of every case of perinatal HBV transmission. In Australia, the optimal regimen is tenofovir 300 mg daily, commencing at 32 weeks gestation, continuing for up to 12 weeks postpartum, with subsequent ongoing monitoring and care of the mother. Detailed discussion by experts with expectant parents is required to explain the risks and benefits of this strategy. Ongoing contribution to the international pregnancy registry of antiviral therapy or participation in observational research or data collection will help to improve the Safety Data Set.

10.5.1 Natural history

Most children who have perinatally acquired HBeAg-positive HBV infection remain in the immune tolerance phase, with high viral loads and little liver damage. Cirrhosis is uncommon (although not unheard of) with 1.7–4.5% of children infected at birth having cirrhosis at liver biopsy; only 0.01–0.03% will develop hepatocellular carcinoma (HCC) during childhood (28). In specific populations a slow rate of seroconversion (from HBeAg to antibodies to e antigen [anti-HBe]) during childhood has been shown, with up to 25% in the first decade and up to 65% by the second decade becoming HBeAg-negative (29). After seroconversion, most patients will remain in the immune control phase, with normal liver function tests and low viral loads. In childhood, about 10% will develop HBeAg-negative chronic hepatitis with moderate or high viral loads and abnormal alanine aminotransferase (ALT), with a more severe disease progression and higher risk of HCC.

10.5.2 Clinical manifestations

Acute HBV infection in children is usually asymptomatic; however, when clinical manifestations do occur, they are generally similar to those in adults. Fulminant disease is uncommon, but in infants it appears to be associated with maternal HBeAg-negative CHB. Most CHB in children is asymptomatic, and is accompanied by normal physical examination and normal growth (30).

10.5.3 Management

Children diagnosed with HBV infection should be considered for referral to a paediatric hepatitis specialist. Management of children with CHB involves counselling the patient and family regarding the natural history of the disease, modes of transmission and treatment options. All susceptible household members should be tested for HBV infection, and vaccinated if not immune. The affected child should also be vaccinated against hepatitis A, if susceptible. Frequency of monitoring is based on low-quality evidence and (largely) on expert opinion. In general, children should be reviewed every 6 months from diagnosis – with clinical examination, liver function tests and hepatitis B eAg serology – and monitored every 6 –12 months for HCC if there is evidence of cirrhosis (30). Degree of fibrosis may be assessed using FibroScan® in children, and is available in specialist centres. In those with persistently abnormal liver function test whom are being considered for treatment, a liver biopsy may be required.

Monitoring of children with chronic hepatitis B
Children with chronic hepatitis B should have all of the following:
  • 6-monthly clinical review
  • liver function tests
  • hepatitis B virus serology (HBeAg and anti-HBe).

HBeAg, hepatitis B e antigen; anti-HBe, hepatitis B e antibody

Which children should be prioritised for referral?
Children should be prioritised for referral if they have:
  • abnormal liver function tests
  • signs of chronic liver disease (e.g. splenomegaly, spider naevi)
  • acquired hepatitis B virus overseas (such children should be assessed by a specialist soon after arrival, to determine the monitoring plan depending on viral genotype, degree of fibrosis, etc.).

10.5.4 Antiviral therapy

The selection of patients for antiviral therapy is based on an elevated ALT that is repeatedly more than 1.5 times the upper level of normal, DNA of over 2,000 IU/mL and moderate to severe inflammation or fibrosis on liver biopsy (31). The treatments studied in children to date are conventional interferon-alfa (IFN-alfa), lamivudine, a combination of IFN and lamivudine, and adefovir (6, 7). The advantages of IFN-alfa are the finite duration of therapy and lack of induction of antiviral resistance. IFN is tolerated better in children than in adults and may also be more effective – one study demonstrated an HBeAg seroconversion rate of 23%, with HBsAg loss in 10% of patients (32). The use of pegylated-IFN (PEG-IFN) to treat HBV in children is currently been investigated, with dosing based on trials in children with hepatitis C virus (HCV) infection. Entecavir has been used in children with abnormal liver functions tests in case reports and small case series, but is currently under study in a larger multicentre trial. Based on suggestive evidence from a small case series, clinical trials of combination therapy with PEG-IFN and lamivudine or entecavir for children in the immune tolerance phase of HBV are currently underway.

In general, treatment of HBV in children should only be undertaken after specialist review; currently available therapies generally reserved for children requiring treatment based on disease severity.

At the age of 18, or the end of secondary education, children should be transitioned to adult viral hepatitis care, either in primary care or an adult viral hepatitis clinic that is convenient to their place of study or work. Often the primary care practitioner is best placed to suggest a local specialist for ongoing care. If the patient has advanced disease, then the paediatric gastroenterologist may suggest an adult hepatologist service with expertise in management of HBV-related advanced liver disease.

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Miriam T Levy, Department of Medicine, The University of New South Wales and South Western Sydney Clinical School, Liverpool Hospital, Liverpool, NSW

Michelle Giles, Department of Infectious Diseases and Department of Obstetrics, Monash University, VIC

& Winita Hardikar, Department of Gastroenterology and Clinical Nutrition, Royal Children’s Hospital, Parkville, VIC