10/24/2012

Jeffrey C. Dunkelberg, MD, PhD University of Iowa Health Care

I have no financial relationship(s) to disclose within the past 12 months relevant to my presentation. AND My presentation does include discussion of off-label or investigational use.

Chronic Hepatitis B and C in Pregnancy

Jeffrey C. Dunkelberg, MD, PhD Clinical Professor of Medicine University of Iowa

Key Points

HBV, HCV and Pregnancy

Maternal HBV or HCV infection increases:

preterm birth low birth weight premature rupture of membranes gestational diabetes congenital abnormalities

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Key Points
HBV and Pregnancy MTCT of HBV - 5% with HBIG and HBV vaccine. - Up to 30% with high HBV DNA levels (>200,00 IU/mL). Anti-viral treatment for women with high HBV DNA levels decreases MTCT of HBV.

Key Points
HCV and Pregnancy MTCT of HCV occurs in 3-10% of pregnancies. Risks for MTCT of HCV: - high HCV RNA levels - HIV-HCV co-infection - PROM - fetal monitoring with scalp electrode No prophylactic measures prevent HCV MTCT.

Risks for Chronic Hepatitis B and C

Blood and blood product exposure
IVDU, inhaled drugs transfusion before 1992 tattoos

Sexual activity
HBV

Perinatal transmission

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U.S. Prevalence of Chronic HBV and HCV HBV: 0.4%

1 million Americans with chronic HBV

HCV: 1-2%
4 million Americans with chronic HCV

Chronic Viral Hepatitis in Pregnancy

Epidemiology
Prevalence of chronic HBV in pregnancy:
27-fold higher in Asians, 5-fold higher in African-Americans, 2-fold higher in Hispanics vs. whites.

HCV: more common in whites. Higher incidence of HIV with HBV or HCV Increased tobacco-, alcohol- and drug-abuse.
Connell, et al. 2011 Liver International Reddick, et al. 2011 Journal Viral Hepatitis

Pregnancy Outcomes with HBV and HCV

HBV and HCV
Preterm birth Low birth weight Premature rupture of membranes Gestational diabetes Congenital anomalies

HCV
Cholestasis of pregnancy NICU admission Neonatal abstinence syndrome
Connell, et al. 2011 Liver International Safir, et al. 2010 Liver International Berkley E, Leslie K, et al. 2008 Obstetrics and Gynecology

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HBV and HCV: Adverse Perinatal Outcomes

Maternal P value

Preterm Delivery (<37 w) PROM Abruption Labor induction Cesarean section

Neonatal

11.5 vs. 7.9% 8.9 vs. 6.9% 1.5 vs. 0.7% 33.9 vs. 28.1% 19.0 vs. 13.2% 2.3 vs. 1.3% 7.2 vs. 5.1% 10.4 vs. 7.8%

< 0.001 0.026 0.018 <0.001 <0.001 0.016 0.01 0.009

Perinatal mortality Congenital Anomalies LBW (<2500 g)

Safir, et al. 2010 Liver International

749 HBV or HCV/186,619 deliveries

Chronic Hepatitis B

Clinical Significance of Serological Markers for HBV Infection

HBV - Diagnosis

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Diagnosis of Chronic HBV

HBsAg-positive Immune-tolerant phase
Normal liver enzymes Very high HBV DNA level HBeAg +: marker of infectivity Children, teens, young adults

Inactive HBV carrier

Normal liver enzymes HBeAg -, HBeAb + Undetectable or low HBV DNA
(< 1000 IU/mL)

Chronic active HBV

Abnormal liver enzymes
(ALT > 1.5 x normal, ALT > 30)

HBeAg + HBV DNA > 20,000 IU/mL

Chronic Hepatitis B and Pregnancy

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Prevalence of HBV in Pregnancy

Varies by race and ethnicity:
Asian-Americans: 6% African-Americans: 1% Whites: 0.6% Hispanics: 0.14%
Euler, et al. 2003 Pediatrics

Impact of Pregnancy on HBV

Pregnancy is well-tolerated. HBV DNA levels do not change during pregnancy. Hepatitis flare during pregnancy is uncommon. HBV DNA levels decrease after delivery.

Soderstrom, et al. 2003 Scandinavian J Inf Dis Rawal, et al. 1991 Am J Perinatology

HBV and Adverse Perinatal Outcome

Preterm Birth
Reddick, 814 HBV / 296,218 pts 21.9 vs. 12.1% P<0.001

LBW <2500 g
Not done

PROM
Not done

Gestational Diabetes

C-section
12.2 vs. 16.7% P=0.003

No diff

Connell, 1458 HBV/ 1,670,369 pts

10.8 vs. 8.8% P<0.001

8.6 vs. 6.4% P<0.0001

1.8 vs. 1.1% P=0.01

7.2 vs. 4.4% P<0.0001

No diff

Reddick, et al. 2011 Journal of Viral Hepatitis Connell, et al. 2011 Liver International

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Screening for HBV in Pregnancy

HBsAg +
HBeAg & HBeAb

HBsAb -

HBV DNA
Level predicts MTCT

HBV Vaccination

Mother-to-Child-Transmission of HBV
Pre - HBIG + HBV vaccine immunoprophylaxis era
10-40% rate of MTCT 90% MTCT with high HBV DNA and HBeAg-positive

With HBIG + HBV vaccine immunoprophylaxis

1-2% MTCT 5-10% MTCT if HBV DNA > 200,000 IU/mL
Alter, MJ. 2003 Journal of Hepatology Del Canho, et al. 1994 Journal of Hepatology Tovo, et al. 2005 Curr Opinion Inf Dis

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MTCT of HBV
Occurs in utero, intrapartum, or postpartum. Intrauterine: probably uncommon.
Threatened abortion Amniocentesis: low-risk for MTCT of HBV (9 vs. 11%)

Intrapartum
High efficacy of HBIG+vaccine MTCT occurs at or after birth. Forceps or vacuum, no increase in risk. No evidence that C-section prevents MTCT; not recommended.

Postpartum
Breastfeeding is not a risk.
Ohto, et al. 1987 Jour Med Virol Ko, et al. 1994 Arch Gynecol Obstet

Prevention of HBV Transmission by HBIG + HBV Vaccine

No HBIG or Vaccine
Infants without HBV

HBIG

HBIG + HBV Vaccine

5%

72%

95%

Ranger-Rogez 2004 Expert Rev Ant Infect Ther

Passive-Active Immunoprophylaxis

HBIG + HBV Vaccination

HBV Vaccine
MTCT of HBV

HBIG

HBIG + HBV Vaccine

26-36% 15-20%

5-10%

5-10% failure of HBIG + HBV vaccine?

Failure to complete immunization Failure to develop HBsAb (1-2%) Mothers with > 100 million IU/mL HBV DNA
Su, et al. 2004 World Journ Gastro MMWR. 2011 Pan, et al. 2012 Clinical Gastro Hepatol

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Mother-To-Child-Transmission

Failure of HBIG + HBV Vaccine

High HBV DNA levels and HBeAg-positivity!
8-32% rate of MTCT

Maternal HBV DNA level and MTCT of HBV

HBV DNA < 107 IU/mL HBV DNA > 107 IU/mL
(del Canho)

0% transmission 32% transmission

HBeAg and MTCT of HBV

HBeAg-negative 1.5% HBeAg-positive 18%
(Soleimani) Del Canho, et al. 1994 Journ Hepatol; Soleimani, et al. 2010 Journal of Clinical Virology

Antiviral Therapy for HBV in Pregnancy

Lamivudine
Cytosine analogue, inhibits HBV DNA reverse transcriptase. 97% reduction in HBV DNA levels in 2 weeks. Pregnancy Category C

Tenofovir (TDF)
Current 1st-line treatment for HBV. Pregnancy Category B Safely used in 1731 pregnant women with HIV. No increase in birth defects.

Breastfeeding not recommended by manufacturers.

Lai, et al. 1998 NEJM Pan, et al. 2012 Clinical Gastro and Hepatol Keeffe, et al. 2008 Clinical Gastro and Hepatol

Lamivudine for HBV in Pregnancy

15 RCTs and 2 meta-analyses.
Lamivudine reduces MTCT. Safe for mother and neonate.

2010 meta-analysis: 10 RCTs (Shi, et al.)

13-24% decrease in MTCT of HBV with lamivudine

2011 meta-analysis: 15 RCTs, 1693 HBV-carrier mothers (Han)

60-70% decrease in MTCT of HBV with lamivudine

Chinese RCT of lamivudine (Xu, et al.)

100 mg/d beginning week 32. HBeAg-positive mothers with DNA > 200 million IU/mL Significant reduction in MTCT: 18% vs. 39%
Shi, et al. 2010 Obstet and Gynecol; Han, et al. 2011 World Journal Gastroent; Xu, et al. 2009 Journal of Viral Hepatitis

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Lamivudine in Pregnancy
Safety profile well-documented (Pan, 2012). Antiviral Pregnancy Registry (APR)
extensive experience shows safety www.apregistry.com

No evidence of teratogenicity or adverse effects on pregnancy. Consider for high HBV DNA level and HBeAg + mothers beginning at week 32.
Pan, et al. 2012 Clinical Gastro and Hepatol Keefe, et al. 2008 Clinical Gastro and Hepatol

Birth Defect Rates By Trimester of Earliest Exposure to Lamivudine, TDF Regimens and All ARV Regimens in APRa
Earliest Exposure to ARVs Number of Defects/ Live Births Prevalence (95% CI) Number of Defects/ Live Births Prevalence (95% CI) LAM Regimens 91/3089 2.9% (2.4-3.6%) 121/4631 2.6% (2.2-3.1%) TDF Regimens 14/606 2.3% (1.3-3.9%) 5/336 1.5 (0.5-3.4%) All ARV Regimens 126/4329 2.9% (2.4 - 3.5) 145/5618 2.6% (2.2 - 3.0)

1st Trimester

2nd/3rd Trimester

aData

collected January 1, 1989 July 31, 2008; APR interim report issued December 2008

CDC MACDP Birth Defect Rate = 2.72%

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APR Advisory Consensus Statementa

For the overall population exposed to antiretroviral drugs in this Registry, no increases in risk of overall birth defects or specific defects have been detected to date when compared with observed rates for early diagnoses in population-based birth defects surveillance systems or with rates among those with earliest exposure in the second or third trimester
aData

collected January 1, 1989 July 31, 2008; APR interim report issued December 2008

EASL Clinical Practice Guidelines.

Recommendations for Antiviral Therapy for HBV-Infected Women Who Desire Pregnancy
Mild liver disease, low viremia (chronic inactive HBV)
Pregnancy before treatment

Moderate liver disease, no cirrhosis (chronic active HBV)

Treatment before pregnancy; if responds, stop treatment before pregnancy Advanced liver disease (advanced fibrosis-cirrhosis) Treatment before, during and after pregnancy Mild liver disease, very high viremia (immunotolerant or CAH) Treatment in last trimester with a B category drug with postpartum discontinuation
EASL Clinical Practice Guidelines. 2012 Journal of Hepatology; 57;167-185.

Pan, et al. 2012 Clin Gastro Hepat.

Pregnant Mothers with Positive HBsAg

HBV DNA > 200,000 IU/mL or previous child failed HBIG + Vaccine HBV DNA < 200,000 IU/mL, previous child has successful prophylaxis

HBeAg (+) HBV DNA > 200,000 IU/mL

Threatened abortion

HBeAg (-) HBV DNA < 200,000 IU/mL

High Risk for MTCT

Lamivudine or Tenofovir at the 3rd trimester.
(Consider elective C-section if DNA > 20 million IU/mL at full term.)

Low Risk for MTCT

All infants receive HBIG + Vaccine within 12 hrs of birth and two vaccines later

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HBV and Pregnancy

Breastfeeding is Safe
Breast milk contains HBsAg. Breastfeeding does not increase rate of MTCT.
1975 study: 53% vs. 60% MTCT Normal liver enzymes HBeAg negative, HBeAb positive Undetectable or low HBV DNA (< 1000 IU/mL)

in breastfed vs. formula fed. American Academy of Pediatrics condones breastfeeding by HBV-positive mothers.

Beasley, et al. 1975 Lancet Gartner, et al. 2005 Pediatrics

Chronic Hepatitis C and Pregnancy

Background

HCV Infection and Pregnancy

The prevalence of HCV infection among women of childbearing age is about 1% (1), and Reaches 70-95% in pregnant women with IVDU (2). Vertical transmission of hepatitis C occurs in 3-10% of pregnancies complicated by maternal HCV infection (3) and is the leading cause of pediatric chronic HCV infection (4).
1. 2. 3. 4. Alter, MJ, et al. N Engl J Med, 1999; 341 (8): p. 556-62. Yeung LT, et al. Hepatology, 2001. 34(2): p. 223-9. Ohto H, et al. N Engl J Med, 1994. 330(11): p. 744-50. Bortolotti F, et al. J Pediatr, 1998. 133(3): p. 378-81.

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HCV and Pregnancy

Screening for HCV

Routine screening for HCV not recommended.
Interferon, ribavirin and HCV protease inhibitors cant be used in pregnancy. No prophylactic measures to prevent MTCT of HCV.

Screen for HCV in patients with risk factors or abnormal liver enzymes.
Screen infant for transmission of HCV infection. Young healthy women are ideal candidates for HCV treatment after breastfeeding completed.
Jonas, M. 1999 NEJM Zanetti, et al. 1999 Journal of Hepatology NIH Consensus 2002 Hepatology

Indications for HCV Screening in Pregnancy

Exposure to blood products before 1992 History of intravenous drug use Dialysis patients HIV or HBV infection Sexual partners of people with HIV, HBV, or HCV History of body piercing or tattoos Organ transplant before 1992 Unexplained elevation of AST or ALT Involved in in vitro fertilization from anonymous donors History of incarceration

HCV and Pregnancy

Diagnosis of HCV
HCV Ab-positive Check PCR for HCV RNA if HCV Ab-positive.
30-40% of young HCV Ab-positive women are HCV RNA-negative (cleared virus spontaneously). Only HCV RNA-positive women are at risk for MTCT.

Neonates of HCV RNA-positive women must be screened for HCV.

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HCV and Pregnancy

Effect of Pregnancy on HCV

Liver enzyme levels may improve.
Elevated ALT in 56% in 1st trimester, 7% in 3rd. (Conte)

HCV RNA levels increase in the 3rd trimester. Effect of pregnancy on immune response to HCV.

Conte, et al. 2000 Hepatology Gervais, et al. 2000 Journal of Hepatology Wegmann, et al. 1993 Immunology Today

HCV and Adverse Perinatal Outcome

Preterm Birth
Reddick, 555 HCV/ 296,218 pts No diff

LBW <2500 g
Not done

IUGR
No diff

Gestational Diabetes
4.7 vs. 2.5% P=0.45

Congenital Anomalies
Not done

Connell, 999 HCV/ 13.1 vs. 8.8% 10.7 vs. 6.4% 12.8 vs. 8.9% 1,670,369 pts P<0.0001 P<0.001 P<0.0001

6.0 vs. 4.4% P=0.02

4.6 vs. 3.8% P<0.0001

Reddick, et al. 2011 Journal of Viral Hepatitis Connell, et al. 2011 Liver International

Maternal Complications

Hepatitis C Ab + Hepatitis C Ab (n=159) (n=141)

p values

Cholestasis Preterm Delivery

Preeclampsia IUGR Oligohydramnios PPROM

10 (6.3%) 39 (24.5%)
5 (3.6) 4 (2.5) 9 (5.7) 12 (7.6)

0 21 (14.9%)
5 (3.1) 3 (2.1) 4 (2.8) 5 (3.6)

0.002 0.04
1.00 1.00 0.27 0.21

IUGR: Intrauterine Growth Restriction PPROM: Premature Preterm Rupture of Membranes

Berkley E, Leslie K, et al. 2008 Obstetrics and Gynecology

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Effect of HCV on Pregnancy

Cholestasis of Pregnancy
Increased incidence of cholestasis of pregnancy with HCV reported in 3 studies. New Mexico Study (Berkley, et al.)
6.3% incidence in HCV Ab-positive women 0% of HCV Ab-negative women All cholestasis occurred in Hispanics Cholestasis in 9.2% of Hispanic HCV Ab-pos women.
Berkley E, Leslie K, et al. 2008 Obstetrics and Gynecology Locatelli, et al. 1999 BJOG Paternoster, et al. 2002 Acta Obstet Gynecol Scandin

HCV and Pregnancy: Complications

Berkley E, Leslie K, et al. 2008 Obstetrics and Gynecology

Risk of Preterm Delivery

Multivariate Regression HCV Ab +
OR 9.27 CI 1-85.95, p=0.05

HCV Ab No risk

Methadone Use
No Methadone

No risk

No risk

Neonatal Outcomes and Complications

HCV Ab +
(n=159)

HCV Ab
(n=141)

p value 0.047
(Methadone)

Birthweight
(g, mean SD)

2803.6 623 54 (40.0%) 84 (52.8%) 33 ( 20.8%)

37.92 2.8

2942.9 581 26 (18.4%) 12 (8.5%) 17 (12.1%)

38.44 2.6

Birthweight <2500 g WithdrawalMethadone Wean NICU Admissions

Gestational Age at Delivery APGAR Score:
(1 min, mean SD) (5 min, mean SD)

0.003
(Methadone)

p<0.001
(Methadone)

0.045
(HCV Ab)

0.09
0.57 0.47

7.7 1.5 8.8 0.8

7.6 1.6 8.7 1.0

Berkley E, Leslie K, et al. 2008 Obstetrics and Gynecology

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Effect of HCV on Pregnancy

Neonatal Abstinence Syndrome

Occurred in 88% of neonates born to HCV Abpos mothers on methadone.
- vs 36% born to HCV Ab-neg women

Occurred in 75% of neonates born to HCV Ab-pos mothers on low-dose methadone.

- vs 0% born to HCV Ab-neg women on lowdose methadone
Berkley E, Leslie K, et al. 2008 Obstetrics and Gynecology

HCV and Pregnancy :

Maternal Complications Cholestasis of pregnancy

Should prompt evaluation for chronic HCV infection. Higher risk for intrauterine fetal demise and prematurity. Early delivery is recommended.
Berkley E, Leslie K, et al. 2008 Obstetrics and Gynecology

HCV and Pregnancy

Neonatal Complications Preterm delivery

Risk increased 9-fold in HCV Ab-positive mothers who used methadone.

NICU admission
Associated with HCV antibody positivity.

Neonatal abstinence syndrome

Significantly increased in HCV Ab-pos.

Lower birthweight
Associated with methadone use.
Berkley E, Leslie K, et al. 2008 Obstetrics and Gynecology

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Vertical Transmission of HCV

3-10% of pregnancies of HCV-infected mothers. Leading cause of pediatric chronic HCV. Risk factors Level of HCV viremia (> 600,000 IU/mL) HIV-HCV co-infection: increased 4-fold HAART decreases risk Prolonged rupture of membranes (> 6 hours) Invasive fetal monitoring, scalp electrodes C-section does not decrease risk of MTCT.
Yeung, et al. 2001 Hepatology Ohto, et al. 1994 NEJM Ferrero, et al. 2003 Acta Obstet Gynecol Scand Mast, et al. 2005 Journ Infect Dis Zanetti, et al. 1995 Lancet Ghamar Chehreh, et al. 2011 Arch Gyn Obst

Vertical Transmission of HCV

Breastfeeding is Safe
0/76 samples of breast milk contained HCV RNA. Multiple studies show no MTCT with breastfeed. American College of Obstetricians and American Academy of Pediatrics endorse breastfeeding by mothers with HCV.
Polywka, et al. 1999 Clinical Infect Dis Kumar, et al. 1998 Journ of Hepatology Resti, et al. 1998 BMJ Thomas, et al. 1998 Int Journ Epidem

Diagnosis of HCV in the Newborn

Early diagnosis requires PCR for HCV RNA.
May take 2-3 weeks for PCR to be positive.

Anti-HCV antibodies are passively transferred.

Maternal HCV-Ab can last to 12-15 months of life

Chronic HCV in the neonate

Detectable HCV-Ab at 18 months with a positive PCR for HCV RNA. Positive PCR for HCV RNA at 3-6 months

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Postnatal Follow-up of Mothers

Pegylated interferon + Ribavirin +/- HCV protease inhibitor combination therapy can lead to a sustained viral response, a cure of chronic hepatitis C, in 80% of patients. Refer for treatment.

Keefe, et al. 2008 Clinical Gastro and Hepatol

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