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 transmissionAll babies of HBsAg-positive mothers should:
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).
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).
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:
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:
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.
- Chu CM, Liaw YF. Natural history of chronic hepatitis B virus infection: an immunopathological study. Journal of Gastroenterology & Hepatology. 1997;12(9-10):S218–22.
- Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50(3):661–2.
- Wen W-H, Chang M-H, Zhao L-L, Ni Y-H, Hsu H-Y, Wu J-F, et al. Mother-to-infant transmission of hepatitis B virus infection: Significance of maternal viral load and strategies for intervention. Journal of Hepatology. 2013;59(1):24–30.
- Wiseman E, Fraser MA, Holden S, Glass A, Kidson BL, Heron LG, et al. Perinatal transmission of hepatitis B virus: an Australian experience. Medical Journal of Australia. 2009;190(9):489–92.
- Guo Z, Shi XH, Feng YL, Wang B, Feng LP, Wang SP, et al. Risk factors of HBV intrauterine transmission among HBsAg-positive pregnant women. Journal of Viral Hepatitis. 2013;20(5):317–21.
- Pan CQ, Zou HB, Chen Y, Zhang X, Zhang H, Li J, et al. Cesarean section reduces perinatal transmission of hepatitis B virus infection from hepatitis B surface antigen-positive women to their infants. Clinical Gastroenterology & Hepatology. 2013;11(10):1349–55.
- Yang J, Zeng X-m, Men Y-l, Zhao L-s. Elective caesarean section versus vaginal delivery for preventing mother to child transmission of hepatitis B virus – a systematic review. Virology Journal. 2008;5:100.
- Liaw YF, Omata M. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update. Hepatol Int. 2012;Hepatol Int(6):531–61.
- EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection. Journal of Hepatology. 2012;57(1):167–85.
- Levy M. Preventing Perinatal Transmission of HBV: An Australian Perspective. Current Hepatitis Reports. 2012;11(4):206–12.
- Giles M, Visvanathan K, Sasadeusz J. Antiviral therapy for hepatitis B infection during pregnancy and breastfeeding. Antiviral Therapy. 2011;16(5):621–8.
- van Zonneveld M, van Nunen AB, Niesters HGM, de Man RA, Schalm SW, Janssen HLA. Lamivudine treatment during pregnancy to prevent perinatal transmission of hepatitis B virus infection. Journal of Viral Hepatitis. 2003;10(4):294–7.
- Xu WM, Cui YT, Wang L, Yang H, Liang ZQ, Li XM, et al. Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B virus infection: a multicentre, randomized, double-blind, placebo-controlled study. Journal of Viral Hepatitis. 2009;16(2):94–103.
- Shi Z, Yang Y, Ma L, Li X, Schreiber A. Lamivudine in late pregnancy to interrupt in utero transmission of hepatitis B virus: a systematic review and meta-analysis. Obstetrics & Gynecology. 2010;116(1):147–59.
- Ayres A, Yuen L, Manoharan S, Glass A, Maley M, Levy M, et al. Ultradeep pyrosequencing identifies multidrug resistant HBV in pregnancy women undergoing lamivudine therapy. Hepatology. 2011;October 1074A.
- Galluzzo C, Liotta G, Andreotti M, Luhanga R, Jere H, Mancinelli S, et al. Emergence of lamivudine resistance hepatitis B virus mutations in pregnant women infected with HBV and HIV receiving antiretroviral prophylaxis for the prevention of mother-to-infant transmission in Malawi. Journal of Medical Virology. 2012;84(10):1553–7.
- Kitrinos KM, Corsa A, Liu Y, Flaherty J, Snow-Lampart A, Marcellin P, et al. No detectable resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with chronic hepatitis B. Hepatology. 2013.
- Greenup A-J, Tan PK, Nguyen V, Glass A, Davison S, Chatterjee U, et al. Efficacy and safety of tenofovir disoproxil fumarate in pregnancy to prevent perinatal transmission of Hepatitis B Virus. Heptology AASLD ABSTRACT. 2013.
- Pan CQ, Mi LJ, Bunchorntavakul C, Karsdon J, Huang WM, Singhvi G, et al. Tenofovir disoproxil fumarate for prevention of vertical transmission of hepatitis B virus infection by highly viremic pregnant women: a case series. Digestive Diseases & Sciences. 2012;57(9):2423–9.
- Van Rompay KKA, Brignolo LL, Meyer DJ, Jerome C, Tarara R, Spinner A, et al. Biological effects of short-term or prolonged administration of 9-[2-(phosphonomethoxy)propyl]adenine (tenofovir) to newborn and infant rhesus macaques.[Erratum appears in Antimicrob Agents Chemother. 2994 Jan;48(6):2346]. Antimicrobial Agents & Chemotherapy. 2004;48(5):1469–87.
- Brown RS, Jr., Verna EC, Pereira MR, Tilson HH, Aguilar C, Leu C-S, et al. Hepatitis B virus and human immunodeficiency virus drugs in pregnancy: findings from the Antiretroviral Pregnancy Registry. Journal of Hepatology. 2012;57(5):953–9.
- Wang L, Kourtis AP, Ellington S, Legardy-Williams J, Bulterys M. Safety of Tenofovir During Pregnancy for the Mother and Fetus: A Systematic Review. Clinical Infectious Diseases. 2013.
- Van Rompay KKA, Hamilton M, Kearney B, Bischofberger N. Pharmacokinetics of tenofovir in breast milk of lactating rhesus macaques. Antimicrobial Agents & Chemotherapy. 2005;49(5):2093–4.
- Vigano A, Bedogni G, Manfredini V, Giacomet V, Cerini C, di Nello F, et al. Long-term renal safety of tenofovir disoproxil fumarate in vertically HIV-infected children, adolescents and young adults: a 60-month follow-up study. Clin Drug Investig. 2011;31(6):407–15.
- Nguyen V, Tan PK, Greenup AJ, Glass A, Davison S, Samarasinghe D, et al. Anti-viral therapy for prevention of perinatal HBV transmission: extending therapy beyond birth does not protect against post-partum flare. Aliment Pharmacol Ther. 2014;39(10):1225–34.
- ter Borg MJ, Leemans WF, de Man RA, Janssen HLA. Exacerbation of chronic hepatitis B infection after delivery. Journal of Viral Hepatitis. 2008;15(1):37–41.
- Pan C, guo-rong H, Jiang h-x, Zhao W, Cao M-k, Want C-m, et al. Telbivudine Prevents Vertical Transmission from HBeAg psotive women with Chroinic Hepatitis B. Clinical Gastroenterology & Hepatology. 2012;10:520–6.
- Bortolotti F, Guido M, Bartolacci S, Cadrobbi P, Crivellaro C, Noventa F, et al. Chronic hepatitis B in children after e antigen seroclearance: final report of a 29-year longitudinal study. Hepatology. 2006;43(3):556–62.
- Roushan MR, Bijani A, Ramzaninejad S, Roushan MH, Amiri MJ, Baiani M. HBeAg seroconversion in children infected during early childhood with hepatitis B virus. J Clin Virol. 2012;55(1):30–3.
- Sokal EM, Paganelli M, Wirth S, Socha P, Vajro P, Lacaille F, et al. Management of chronic hepatitis B in childhood: ESPGHAN clinical practice guidelines: consensus of an expert panel on behalf of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition. J Hepatol. 2013;59(4):814–29.
- Jonas MM, Block JM, Haber BA, Karpen SJ, London WT, Murray KF, et al. Treatment of children with chronic hepatitis B virus infection in the United States: patient selection and therapeutic options. Hepatology. 2010;52(6):2192–205.
- Sokal EM, Conjeevaram HS, Roberts EA, Alvarez F, Bern EM, Goyens P, et al. Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized controlled trial. Gastroenterology. 1998;114(5):988-95