Chronic Hepatitis B in Pregnancy

Transcription

1 Chronic Hepatitis B in Pregnancy Tatyana Kushner M.D., M.S.C.E., * and Monika Sarkar M.D., M.A.S. More than 250 million individuals worldwide are infected with chronic hepatitis B virus (HBV), including approximately 65 million women of childbearing age. 1 Globally, perinatal transmission accounts for nearly half of the chronic disease burden. Although most adults exposed to HBV spontaneously clear the virus, 90% of infants with perinatal exposure in the absence of immunoprophylaxis become chronically infected. 1 The World Health Organization has therefore identified mother-tochild transmission (MTCT) as a key step in reduction of the global prevalence of HBV. 1 Within the United States there has also been an increase in incident acute hepatitis B among reproductive-aged adults that is related to injection drug use, adding to the potential public health implications of HBV exposure in pregnancy. 2 Hepatitis B surface antigen (HBsAg) testing is recommended for HBV screening in all pregnant women. Importantly, all at-risk women (>1 sexual partner within the past 6 months, history of injection drug use, or HBsAg-positive partner) who screen negative for HBV should undergo HBV vaccination during pregnancy. 3 Women with newly diagnosed HBV in pregnancy should be referred to a hepatitis B provider, with workup performed to determine whether the mother has indications for treatment. Establishing a relationship with an HBV provider during pregnancy can help to facilitate adherence to HBV care during pregnancy, as well as long-term management of chronic infection, including future need for HBV treatment and hepatocellular carcinoma screening, when appropriate. PREGNANCY EFFECTS ON THE NATURAL HISTORY OF HEPATITIS B Altered immune activity in pregnancy can affect the natural history of hepatitis B, including an increased risk for HBV flares. The prevalence of flares is reported in 6% to 14% of women during pregnancy, and between 10% and 50% of women during the postpartum period, depending on the population studied and the alanine Abbreviations: ALT, alanine aminotransferase; AVT, antiviral treatment; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; LAM, lamivudine; MTCT, mother-to-child transmission; TBV, telbivudine; TDF, tenofovir disoproxil fumarate; ULN, upper limit of normal. From the *Icahn School of Medicine at Mount Sinai, Department of Medicine, Division of Liver Diseases, New York, NY; and Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Francisco, San Francisco, CA. Potential conflict of interest: Nothing to report. Received 3 April 2018; accepted 5 May 2018 View this article online at wileyonlinelibrary.com 2018 by the American Association for the Study of Liver Diseases 24 Clinical CLINICAL Liver LIVER DISEASE, Disease, VOL 12, NO 1, JULY 2018 An Official Learning Resource of AASLD

2 TABLE 1. STUDIES EVALUATING PREGNANCY-ASSOCIATED HEPATITIS B FLARES Study Country Pregnancies (n) ALT Flare Definition 1 Prevalence of Flare Ter Borg et al. 21 (Journal of Viral Hepatitis, 2008) Netherlands 38 3 baseline 45% postpartum Nguyen et al. 17 (Alimentary Pharmacology & Australia Therapeutics, 2014) 101 pregnancies: 44 early AVT cessation 43 late AVT cessation 14 untreated women 5 ULN Postpartum flares: Early AVT cessation: 50% Late AVT cessation: 40% Untreated women: 29% Giles et al. 22 (Gut, 2015) Australia ULN 25% postpartum Chang et al. 23 (American Journal of Gastroenterology, 2016) United States ULN or 3 baseline 6% during pregnancy; 10% postpartum Kushner et al. 4 (Liver International, 2017) United States ULN 14% during pregnancy; 16% postpartum Liu et al. 24 (Clinical Gastroenterology & Hepatology, 2017) Abbreviation: AVT, antiviral therapy; ULN, upper limit of normal. 1 Normal ALT is defined by Liu et al. 24 as 20 U/L and in remainder of studies as 19 U/L. China ULN First trimester: 11.9% At delivery: 2.1% 1 month postpartum: 9.8% aminotransferase (ALT) threshold used to define a flare (Table 1). However, most flares appear to be mild and self-limited, and in the absence of advanced fibrosis or hepatitis delta co-infection, 4 few progress to hepatic decompensation or jaundice. Monitoring of ALT levels is reasonable to perform during the first 6 months after delivery or within the first 6 months after discontinuation of antivirals for mothers receiving third-trimester antiviral treatment (AVT). 5 Whether hepatitis B infection in turn affects pregnancy outcomes is less clear. An association of chronic HBV with gestational diabetes, antepartum hemorrhage, and threatened preterm labor has been reported, 6 although additional studies are needed to evaluate these findings. Similar to other causes of liver disease, women with HBV cirrhosis do have an increased risk for maternal and fetal mortality; 7 therefore women with advanced fibrosis should be comanaged by a high-risk obstetrician or maternal-fetal medicine specialist. HEPATITIS B TREATMENT DURING PREGNANCY Despite the receipt of passive and active vaccination, HBV transmission occurs in up to 25% of infants born to mothers with HBV DNA levels greater than 200,000 IU/ ml. 8,9 Therefore, most guidelines advise initiation of antivirals during the third trimester in these women, which appears to be safe and effective in decreasing MTCT. 5 The three antivirals that are considered safe in pregnancy are lamivudine (LAM), telbivudine (TBV), and tenofovir disoproxil fumarate (TDF). Lamivudine has a lower barrier of resistance and may be associated with slower decline in HBV DNA levels as compared with TDF. 10 Although TBV is effective at preventing MTCT, 11 it may be associated with increased creatinine kinase levels, and as noted later, it has limited safety data in breastfeeding mothers. 12 TDF is the preferred agent for treating HBV in pregnancy given its high barrier to resistance, favorable safety profile, and efficacy. 3,13 Neither LAM, TBV, nor TDF is associated with premature birth, lower Apgar scores, or congenital malformations. 14 Notably, a recent randomized controlled trial in Thailand did fail to detect a statistically significant difference in MTCT in highly viremic mothers receiving placebo versus TDF during the third trimester (2% versus 0%, respectively; P = 0.12), although administration of HBV vaccination in this trial was quite rapid, at a median of 1.2 hours after delivery. 15 The newly approved antiviral, tenofovir alafenamide, has not been studied in pregnancy; therefore, women who are taking tenofovir alafenamide who become pregnant should switch to TDF until additional safety data are available. 5 The exact timing of treatment initiation during the third trimester is not defined. We favor earlier initiation of treatment at week 28 to allow sufficient time for viral load decline to less than 200,000 IU/mL. For women who use antivirals for the sole indication of decreasing MTCT, treatment may be discontinued at delivery or within a month of delivery per provider preference. 5,16 Notably, delay in 25 Clinical Liver Disease, VOL 12, NO 1, JULY 2018 An Official Learning Resource of AASLD

3 FIG 1 Suggested algorithm for management of hepatitis B in pregnancy. Abbreviations: ULN, upper limit of normal' TDF, tenofovir disoproxil fumarate; LAM, lamivudine; TBV, telbivudine. stopping antiviral therapy until the first few months after delivery has not been shown to reduce risk for HBV flare. 17 The treatment course for women with immune-active hepatitis B, or with advanced fibrosis, should follow that of nonpregnant populations (Fig. 1). Whether obstetric factors are associated with MTCT is not clear. Risk for MTCT is largely due to infant exposure to vaginal blood and secretions at the time of delivery. Although cesarean section could theoretically reduce that risk, data on the benefit of cesarean section are conflicting. 18 Therefore, HBV infection status should not determine mode of delivery, which should instead be guided by obstetric indications. 3 Data on risk for HBV transmission with invasive procedures, such as chorionic villous sampling or amniocentesis, are limited, although one study identified a significantly higher transmission risk of 50% versus 4.5% (P = 0.006) among women who received amniocentesis compared with those who did not. However, increased transmission risk in this study was limited to women with HBV viral load 10 million copies/ml. 19 Even though invasive procedures should be performed when medically indicated, women with very high viral load should be informed of potential increased HBV transmission risk. 3 Breastfeeding has substantial benefits to mother and child, and does not appear to increase HBV transmission risk. 3 Moreover, there are increasing data on the safety of antivirals in breastfeeding infants, which providers can access using the LactMed database. LactMed is an online resource maintained by the National Institutes of Health, which includes updated registry and publication data, as well as clinical recommendations regarding 26 Clinical Liver Disease, VOL 12, NO 1, JULY 2018 An Official Learning Resource of AASLD

4 medication safety in nursing mothers. 12 LactMed does not advise against breastfeeding with either LAM or tenofovir, given minimal drug exposure in nursing infants. Although concern for bone toxicity has been raised with infants exposed to TDF, there appear to be no differences in bone growth at 2 years of infant follow-up. 20 Data on TBV safety in breastfeeding remain limited, further supporting use of alternate antivirals in pregnant and postpartum women meeting HBV treatment indications. SUMMARY Management of HBV in pregnancy provides a unique time for linkage of care, with implications for the mother's long-term health, as well as opportunities to discuss screening and vaccination of sexual partners and household contacts. A multidisciplinary approach including hepatologists and obstetricians can help to optimize maternal and fetal health. There remains a risk for MTCT, even with receipt of passive and active HBV vaccination; therefore, we advise third-trimester antiviral therapy for mothers with high viral load. Given the benefits of breastfeeding for the mother and baby, nursing should be encouraged in women with chronic HBV infection and is not contraindicated in those receiving antiviral therapy. CORRESPONDENCE Monika Sarkar, M.D., M.A.S., Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Francisco, 513 Parnassus Avenue, S-357, San Francisco, CA monika.sarkar@ucsf.edu REFERENCES 1) World Health Organization. WHO global health sector strategy on viral hepatitis, WHO Publication No. WHO/HIV/ Published June ) Harris AM, Iqbal K, Schillie S, et al. Increases in acute hepatitis B virus infections Kentucky, Tennessee, and West Virginia, MMWR Morb Mortal Wkly Rep 2016;65: ) Society for Maternal-Fet al Medicine (SMFM), Dionne-Odom J, Tita AT, Silverman AS. #38: hepatitis B in pregnancy screening, treatment, and prevention of vertical transmission. Am J Obstet Gynecol 2016;214: ) Kushner T, Shaw PA, Kalra A, Magaldi L, Monpara P, Bedi G, et al. Incidence, determinants and outcomes of pregnancy-associated hepatitis B flares: a regional hospital-based cohort study. Liver Int 2018;38: ) Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018;67: ) Tse KY, Ho LF, Lao T. The impact of maternal HBsAg carrier status on pregnancy outcomes: a case-control study. JHepatol 2005;43: ) Shaheen AA, Myers RP. The outcomes of pregnancy in patients with cirrhosis: a population-based study. Liver Int 2010;30: ) Liu Y, Wang M, Yao S, et al. Efficacy and safety of telbivudine in different trimesters of pregnancy with high viremia for interrupting perinatal transmission of hepatitis B virus. Hepatol Res 2016;46:E181-E188. 9) Zou H, Chen Y, Duan Z, et al. Virologic factors associated with failure to passive-active immunoprophylaxis in infants born to HBsAgpositive mothers. JViral Hepat 2012;19:e18-e25. 10) Xu WM, Cui YT, Wang L, et al. Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B virus infection: a multicentre, randomized, double-blind, placebo-controlled study. JViral Hepat 2009;16: ) Han GR, Cao MK, 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. JHepatol 2011;55: ) LactMed: A TOXNET Database. Bethesda, MD: National Institutes of Health. 13) Pan CQ, Mi LJ, Bunchorntavakul C, et al. Tenofovir disoproxil fumarate for prevention of vertical transmission of hepatitis B virus infection by highly viremic pregnant women: a case series. Dig Dis Sci 2012;57: ) Brown RS Jr, McMahon BJ, Lok AS, et al. Antiviral therapy in chronic hepatitis B viral infection during pregnancy: a systematic review and meta-analysis. Hepatology 2016;63: ) 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: ) Zeng QL, Xu GH, Wang B, Li ZQ, Yu ZJ. Prophylactic antiviral therapy for the prevention of mother-to-child transmission of hepatitis B virus can be stopped at delivery. J Viral Hepat 2018;25: ) Nguyen V, Tan PK, Greenup AJ, 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: ) Yang M, Qin Q, Fang Q, Jiang L, Nie S. Cesarean section to prevent mother-to-child transmission of hepatitis B virus in China: a meta-analysis. BMC Pregnancy Childbirth 2017;17: ) Yi W, Pan CQ, Hao J, et al. Risk of vertical transmission of hepatitis B after amniocentesis in HBs antigen-positive mothers. JHepatol 2014;60: Clinical Liver Disease, VOL 12, NO 1, JULY 2018 An Official Learning Resource of AASLD

5 20) Jacobson DL, Patel K, Williams PL, et al. Growth at 2 years of age in HIV-exposed uninfected children in the United States by trimester of maternal antiretroviral initiation. Pediatr Infect Dis J 2017;36: ) ter Borg MJ, Leemans WF, de Man RA, et al. Exacerbation of chronic hepatitis B infection after delivery. J Viral Hepat 2008;15: ) Giles M, Visvanathan K, Lewin S, et al. Clinical and virological predictors of hepatic flares in pregnant women with chronic hepatitis B. Gut 2015;64: ) Chang CY, Aziz N, Poongkunran M, et al. Serum Alanine Aminotransferase and Hepatitis B DNA flares in pregnant and postpartum women with chronic hepatitis B. Am J Gastroenterol 2016;111: ) Liu J, Wang J, Qi C, et al. Baseline hepatitis B virus titer predicts initial postpartum hepatic flare: a multicenter prospective study. J Clin Gastroenterol Clinical Liver Disease, VOL 12, NO 1, JULY 2018 An Official Learning Resource of AASLD