Hepatitis B and PregnancyAn Underestimated Issue

Maureen M. Jonas, M.D.

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?

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

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

Effect of HBV on Pregnancy

Chronic HBV InfectionConflicting 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)

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

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

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

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

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

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

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?

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)

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)

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)

Eurohep feasibility study - 2003

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.

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)

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

Is HBIg necessary for newborn prophylaxis?- a Meta-analysis

29 randomized clinical trials, 5 of “high quality”

Comparison RR neonatal HBV infection

95% CI

Vaccine vs. placebo or nothing

0.28 0.20-0.40

HBIg vs. placebo or nothing

0.50 0.41-0.60

HBIg + vaccine vs placebo

0.08 0.03-0.17

Vaccine + HBIg vs vaccine alone

0.54 0.41-0.73

Lee et al, BMJ 2006;332:328-36

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

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

114 Highly ViremicPregnant Women

Treatment (begin wk 32)

LamivudineN= 68

PlaceboN=46

Virus < 1000 meq/ml

98% 31%

Infants HBsAg+

18% 39%

Infantsanti-HBs +

84% 61%

No pregnancy complications with lamivudine treatment of

Active HBV

Abortion (%)

Prematurity (%)

Neonatal Asphyxia

(%)

Fetal Death

(%)

Congenital Anomaly

(%)

Lam 0/38 0/38 0/38 0/38 0/38

Control

16.7(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

HBIg during Pregnancy to decrease Vertical HBV

TransmissionStudy Design eAg

statusRegime

n(begin

3rd trimeste

r)

Outcome NB

Outcome 6-12 mos

Li, 2004 57 HBIG55 control

Mixed 200 U IM monthly

10.5%vs 27.3%(variety)

Xu, 2006

28 HBIG24 control

Positive 200 U IVmonthly

CB HBV DNA25% vs 83%

Yuan, 2006

117 HBIG133 control

Positive 400 U IMmonthly

sAg 22.9% vs 20%

sAg 11% vs 12.8%

Xiao, 2007

317 HBIG152 control

Mixed 200 U IM monthly

sAg 15.8% vs 38.7%

sAg 7.4% vs 22.6%

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

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

Is Mode of Delivery a Factor in Vertical HBV Transmission?

301 infants

SpontaneousVaginal delivery

N=144

Forceps or Vacuum Extraction

N=40

Cesarean SectionN=117

HBIg at birthHBV 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)

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

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