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Hepatitis B and Pregnancy An Underestimated Issue

Hepatitis B and Pregnancy An Underestimated Issue. Maureen M. Jonas, M.D. Hepatitis B in Pregnancy Important Issues. Effect of HBV on pregnancy and its outcome Effect of pregnancy on HBV Treatment of active HBV during pregnancy HCC during pregnancy

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Hepatitis B and Pregnancy An Underestimated Issue

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  1. Hepatitis B and PregnancyAn Underestimated Issue Maureen M. Jonas, M.D.

  2. Hepatitis B in PregnancyImportant Issues • Effect of HBV on pregnancy and its outcome • Effect of pregnancy on HBV • Treatment of active HBV during pregnancy • HCC during pregnancy • Decreasing the likelihood of vertical transmission • Are antivirals indicated? • Is amniocentesis contraindicated? • Is mode of delivery a factor? • What is the role of breast feeding in transmission?

  3. Effect of HBV on Pregnancy Acute HBV Infection • Usually has the same course as in the general population • Must be distinguished from • Intrahepatic cholestasis • AFLP • HELLP syndrome • No apparent increase in mortality

  4. Effect of HBV on Pregnancy Acute HBV Infection • Not teratogenic • Higher incidence of low birth weight and prematurity • 10% vertical transmission if first trimester, higher in later trimesters

  5. Effect of HBV on Pregnancy Chronic HBV Infection Conflicting data regarding outcomes: • No difference in prematurity, birth weight, perinatal mortality (Wong et al. Am J Perinatol 1999;16:485-8) • Association with gestational diabetes mellitus and antepartum hemorrhage (Tse et al. J Hepatol 2005;43:771-5)

  6. Effect of Pregnancy on HBV • Most women with chronic HBV do well during pregnancy • Corticosteroids increase HB viremia, estrogens decrease HB viremia, so hormonal milieu of pregnancy has a mixed effect • ALT levels tend to increase in late pregnancy and the post-partum period

  7. Effect of Pregnancy on HBV • Some women have post-partum hepatitis flares, with or without HBeAg seroconversion (12-17% rates reported) • Acute exacerbation, even FHF has been reported post-partum • This is not prevented by lamivudine during the third trimester • There is no association between PP HBeAg seroconversion and maternal age, parity or presence of pre-core or BCP mutations • Women should be monitored for several months after delivery

  8. Effect of Pregnancy on HBV • Retrospective analysis of HBV DNA levels during and after pregnancies in 55 women (9 HBeAg+): • HBV DNA increased by a mean of 0.4 log late in pregnancy or early post partum (in 4/16 eAg- women, by > 1 log) • Post partum ALT increased in both eAg+ and eAg- women • Vertical transmission only in eAg+ women with high levels of viremia Söderström A. Scand J Infect Dis 2003;35:814-9

  9. HBV/HIV Coinfection during Pregnancy • Sub-Saharan Africa: 13% of HIV infected pregnant women have HBV (no data on course, outcomes) • One American series*: 1.5% of 455 HIV infected pregnant women had HBV • Lower CD4 counts compared to HIV monoinfected or HIV/HCV coinfected women • No data regarding perinatal transmission risks *Santiago-Munoz et al. Am J Obstet Gynecol 2005;193:1270-3

  10. HCC and Pregnancy • Fetal outcome often satisfactory, occasional intrauterine death • High maternal mortality • 20/33 in a combined series died within a few days of initial presentation, most others within months • Hypothesis: Estrogen, “gestational immunosuppression” may accelerate the evolution of HCC Cobey et al. Am J Surg 2004;187:181-91. de la Rosa et al. J Obstet Gynaecol Res 2006;32:437-9

  11. Treatment of Active HBVduring Pregnancy 38 women receiving lam for chronic HBV and abnormal ALT became pregnant and elected to continue treatment: • HBV-DNA became negative in 35 patients (92.11%). • HBeAg became negative in 12 patients (31.58%). • The rate of eAg seroconversion was 26.32% (10/38). • ALT became normal in 73.68% (28/38). • The rate of lam resistance was 11.43% (4/35). Su GG, World J Gastroenterol, 2004;10:910-2

  12. Vertical Transmission of HBV • Perinatal • Majority of cases • Exposure to maternal blood and secretions at delivery • Preventable with immunoprophylaxis • Intrauterine • ± 5% of cases • In utero exposure to maternal blood • Preventable?

  13. HBsAg in the Placental Villi Vascular endothelial cells Trophoblasts HBV infection decreases gradually from the maternal to the fetal side of the placental cell layers. (XU et al. J Med Virol 2002;67:20-6)

  14. Susceptibility toIntrauterine HBV transmission • HBV DNA level • Placental barrier • Maternal immune status • HBV mutations? • Fetal factors? • 24 exposed infants with intrauterine HBV compared to 48 not infected: HLA-DRB1*07 was the only of 15 alleles in excess (OR 6.66) (Xu Y-Y. Int J Biol Sci 2008;4:111-5)

  15. HBV Perinatal TransmissionCurrent Strategy – U.S. • All pregnant women are tested for HBsAg • Infants of HBsAg women should receive HBIg within 12 hours and HBV vaccine prior to discharge • Vertical transmission occurs in approximately 5% of cases if appropriate newborn prophylaxis is provided (higher % with very high maternal viremia)

  16. Eurohep feasibility study - 2003

  17. HBV Vaccine • The major target for neutralizing antibody (anti-HBs) is the a determinant of the surface antigen protein. • Mutations in the S gene causing conformational changes in the a determinant have been found. • What is the risk of increased replication of these variants under immune pressure from vaccine? • Thus far, there is no evidence of immunization escape mutants in large-scale vaccine programs.

  18. HBV Vaccine is Safe andEffective in Pregnant Women • 72 women 3rd trimester: 84% sAb+, safe for mothers and neonates(Ayoola, Int J Gyn Obs1987) • 10 women in 1st trimester: safe for neonates(Levy, Am J Perinatol 1991) • 15 women received 3 doses: safe in mothers, high Ab titers (Reddy, Asia Ocean J Obst Gyn 1994) • 99 women, given either 2 or 3 doses during pregnancy: higher Ab levels at delivery, 2 and 4 months after 3 doses, no safety concerns (Gupta, J Obst Gyn Res 2003)

  19. Post-exposure Prophylaxisin Pregnant Women • 73 women after an outbreak of HBV due to in vitro fertilization treatment • HBIg (525 u) at months 0 and 1 • HBV vaccine at months 0, 1, 2 and 6 • 16 became pregnant (57 controls) • 1 had abortion 2 days after initial doses • No other side effects in women or newborns • No difference in seroconversion rate or GMT • Slower and lower immune response in pregnant women Grosheide PM et al. Eur J Obstet Gynecol Reprod Biol 1993;50:53-8

  20. Is HBIg necessary for newborn prophylaxis?- a Meta-analysis29 randomized clinical trials, 5 of “high quality” Lee et al, BMJ 2006;332:328-36

  21. Lamivudine during Pregnancy to Decrease Vertical HBV Transmission • Vertical transmission likelihood is associated with level of maternal viremia • 8 women with high levels of HBV DNA treated with 150 mg lam for last month of pregnancy; 24 infants as historical controls; all infants received passive/active immunization • Lam group: 1 (12.5%) HBsAg+ at 12 months Control group: 7 (28%) van Zonneveld M. J Viral Hepatitis 2003;10:294-7

  22. Lamivudine during PregnancyRandomized, double-blind, placebo-controlled trial (Xu Hepatology 2004;40:272A)

  23. No pregnancy complications with lamivudine treatment of Active HBV Su GG, World J Gastroenterol, 2004;10:910-2

  24. HBIg during Pregnancy to decrease Vertical HBV Transmission

  25. HBIg vs lamivudine during Pregnancy to decrease Vertical HBV Transmission • 56 women received HBIg every 4 weeks beginning at 28 weeks • 43 women received lam 100 mg daily beginning at 28 weeks • 52 women received no treatment • NB blood tested(before immunoprophylaxis) • HBV DNA in newborn: HBIg 16.1%, lam 16.3%, control 32.7% Li XM. World J Gastroenterol 2003;9:1501-3

  26. Is Amniocentesis Contraindicated in HBsAg + pregnant women? • Prospective longitudinal analysis of 47 HBsAg+ women who presented for amniocentesis • All samples analyzed for HBsAg and HBV DNA • Cord blood compared to samples from 72 infants from pregnancies w/o amniocentesis • AF: 32% HBsAg+, all HBV DNA- • CB: 27% HBsAg+, all HBV DNA- • CB (controls): 18% HBsAg+, 4% HBV DNA+ • Conclusion: risk of HBV transmission by amniocentesis is low Towers CV. Am J Obstet Gynecol 2001;184:1514-8

  27. Is Mode of Delivery a Factor in Vertical HBV Transmission? 301 infants Spontaneous Vaginal delivery N=144 Forceps or Vacuum Extraction N=40 Cesarean Section N=117 HBIg at birth HBV vaccine at 1, 2, 7 months Chronic Hepatitis B 7.3% 7.7% 6.8% (No difference in rate of antiHBs) Wang. Chin Med J 2002;115:1510-2

  28. Is Breast Feeding Contraindicated for HBsAg+ Women? • Prospective longitudinal study, infants followed up to 15 months • 369 infants received HBIg at birth and full HBV vaccine series • 101 breast fed (22% eAg+) vs 268 formula fed (26% eAg+) • Mean duration breast feeding 4.9 months (0.5-12) • None of the breast fed and 9 (3%) of the formula fed infants were HBsAg+ at f/u • Conclusion: No additional risk from breast feeding Hill, JB. Obstet Gynecol 2002;99:1049-52

  29. HBV and PregnancySummary Perinatal transmission accounts for the majority of chronic infections. Perinatal and obstetrical policies must be assessed with respect to • Detection of maternal infection and liver disease • Treatment during pregnancy • Safety for mother • Fetal affects • Prevention of perinatal transmission

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