Hepatitis%20B%20and%20Pregnancy%20An%20Underestimated%20Issue

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Hepatitis B and PregnancyAn Underestimated Issue

• Maureen M. Jonas, M.D.

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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?

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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

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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

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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
  199916485-8)
• Association with gestational diabetes mellitus
  and antepartum hemorrhage (Tse et al. J Hepatol
  200543771-5)

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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

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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

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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 gt 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 200335814-9
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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
20051931270-3
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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 2004187181-91. de la
Rosa et al. J Obstet Gynaecol Res 200632437-9
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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, 200410910-2
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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?

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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 20026720-6)
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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-DRB107 was the only of
  15 alleles in excess (OR 6.66) (Xu Y-Y. Int J
  Biol Sci 20084111-5)

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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)

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Eurohep feasibility study - 2003
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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.

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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)

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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 19935053-8
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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 2006332328-36
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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 200310294-7
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Lamivudine during PregnancyRandomized,
double-blind, placebo-controlled trial (Xu
Hepatology 200440272A)
114 Highly Viremic Pregnant Women 114 Highly Viremic Pregnant Women
Treatment (begin wk 32) Lamivudine N 68 Placebo N46
Virus lt 1000 meq/ml 98 31
Infants HBsAg 18 39
Infants anti-HBs 84 61
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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, 200410910-2
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HBIg during Pregnancy to decrease Vertical HBV
Transmission
Study Design eAg status Regimen (begin 3rd trimester) Outcome NB Outcome 6-12 mos
Li, 2004 57 HBIG 55 control Mixed 200 U IM monthly 10.5vs 27.3 (variety)
Xu, 2006 28 HBIG 24 control Positive 200 U IV monthly CB HBV DNA 25 vs 83
Yuan, 2006 117 HBIG 133 control Positive 400 U IM monthly sAg 22.9 vs 20 sAg 11 vs 12.8
Xiao, 2007 317 HBIG 152 control Mixed 200 U IM monthly sAg 15.8 vs 38.7 sAg 7.4 vs 22.6
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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 200391501-3
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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 20011841514-8
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Is Mode of Delivery a Factor in Vertical HBV
Transmission?
301 infants
Spontaneous Vaginal delivery N144
Forceps or Vacuum Extraction N40
Cesarean Section N117
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 20021151510-2
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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 2002991049-52
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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