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Hepatitis B and Pregnancy An Underestimated Issue Maureen M. Jonas, M.D.

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Presentation on theme: "Hepatitis B and Pregnancy An Underestimated Issue Maureen M. Jonas, M.D."— Presentation transcript:

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

2 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 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 HBV during 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 cellsTrophoblasts 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 to Intrauterine 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 Transmission Current 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)


17 Eurohep feasibility study - 2003

18 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.

19 HBV Vaccine is Safe and Effective in Pregnant Women 72 women 3 rd trimester: 84% sAb+, safe for mothers and neonates (Ayoola, Int J Gyn Obs1987) 10 women in 1 st 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)

20 Post-exposure Prophylaxis in 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

21 Is HBIg necessary for newborn prophylaxis?- a Meta-analysis 29 randomized clinical trials, 5 of “high quality” ComparisonRR neonatal HBV infection 95% CI Vaccine vs. placebo or nothing 0.280.20-0.40 HBIg vs. placebo or nothing 0.500.41-0.60 HBIg + vaccine vs placebo 0.080.03-0.17 Vaccine + HBIg vs vaccine alone 0.540.41-0.73 Lee et al, BMJ 2006;332:328-36

22 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

23 Lamivudine during Pregnancy Randomized, double-blind, placebo- controlled trial (Xu Hepatology 2004;40:272A) 114 Highly Viremic Pregnant Women Treatment (begin wk 32) Lamivudine N= 68 Placebo N=46 Virus < 1000 meq/ml 98%31% Infants HBsAg+ 18%39% Infants anti-HBs + 84%61%

24 No pregnancy complications with lamivudine treatment of Active HBV Abortion (%) Prematurity (%) Neonatal Asphyxia (%) Fetal Death (%) Congenital Anomaly (%) Lam0/38 Control16.7 (1/6) 43 (37/86) 15.6 (14/89) 4.5 (4/89) 10 (1/10) Su GG, World J Gastroenterol, 2004;10:910-2

25 HBIg during Pregnancy to decrease Vertical HBV Transmission StudyDesigneAg statusRegimen (begin 3 rd trimester) Outcome NB Outcome 6-12 mos Li, 200457 HBIG 55 control Mixed200 U IM monthly 10.5%vs 27.3% (variety) Xu, 200628 HBIG 24 control Positive200 U IV monthly CB HBV DNA 25% vs 83% Yuan, 2006 117 HBIG 133 control Positive400 U IM monthly sAg 22.9% vs 20% sAg 11% vs 12.8% Xiao, 2007 317 HBIG 152 control Mixed200 U IM monthly sAg 15.8% vs 38.7% sAg 7.4% vs 22.6%

26 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

27 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

28 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% Wang. Chin Med J 2002;115:1510-2 (No difference in rate of antiHBs)

29 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

30 HBV and Pregnancy Summary 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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