Clinical Management of Viral Hepatitis During Pregnancy ... · Clinical Management of Viral Hepatitis During Pregnancy and Breastfeeding Giuseppe Indolfi, Massimo Resti UO Pediatria

Clinical Management of Viral Clinical Management of Viral Hepatitis During Pregnancy and Hepatitis During Pregnancy and

BreastfeedingBreastfeeding

Giuseppe Indolfi, Massimo Resti

UO Pediatria Medica,Epatologia PediatricaAOU Meyer, Firenze

Roma, 23 Febbraio 2011

13th Pre- Meeting CourseDifficult Clinical Issue in Hepatology

Bortolotti et al. J Hepatol 2007;46:783-90

Epidemiological Profile of ItalianEpidemiological Profile of ItalianChildren with Hepatitis CChildren with Hepatitis C

transfusions

other parenteralexposure

infected mother

infected familycontact

unknown

before 1990 1990-94 1995-99 2000-04

200 (55%) 17 (10%) 0 0

40 (11%) 10 (5%) 3 (1.5%) 0

82 (22%) 123 (66%) 152 (84%) 52 (93%)

7 (2%) 3 (1%) 1 (0,5%) 0

26 (10%) 24 (18%) 20 (14%) 4 (7%)

Italian Observatory for Hepatitis C in Children

PRECONCEPTION PRECONCEPTION CARECARE

Resti et al. BMJ 1998;317:437-41

Mother to Child Transmission of Hepatitis C Virus Mother to Child Transmission of Hepatitis C Virus from HIV Seronegative Women from HIV Seronegative Women

Tuscany Study Group on Hepatitis C Virus Infection

HCV viraemic mothersHCV viraemic mothers: 275 (68%)275 (68%)

HCVHCV--infected mothersinfected mothers: 442 (1.7%)442 (1.7%)

mothermother--infant pairsinfant pairs: 25,65425,654

Yeung et al. Hepatology 2001;34:223-9

Epidemiology of Mother to Child TransmissionEpidemiology of Mother to Child Transmission

1.7% when the mother was anti-HCV positive irrespective of HCV RNA

4.3% when the mother was positive for HCV RNA

19.4% when the mother was coinfected with HCV and human immunodeficiency virus

Weighted Rate of Perinatal Transmission of HCV

Resti et al. BMJ 1998;317:437-41Tovo et al. J Infect Dis 2000;181:419–24Europ. Paediat Hepat. C Virus Network J Infect Dis 2005;192:1872–9

Maternal HCV ViraemiaMaternal HCV Viraemia

Tuscany Study Group on Hepatitis C Virus Infection

transmission from HVC-viraemic mothers: 5% (13/257)

transmission from HVC RNA negative mothers: 0

perinatal transmission is almost always confined to women with HCV viremia

Resti et al. BMJ 1998;317:437-41Conte et al. Hepatology 2000;31:751–5

Level of Maternal HCV ViraemiaLevel of Maternal HCV Viraemia

Conflicting Results

some studies reported that a high concentration of serum HCV RNA is associated with a higher risk of transmission

considerable overlapping in concentrations of HCV RNA between transmitting and non-transmitting mothers

Ceci et al. J Pediatr Gastroenterol Nutr 2001;33:570–75Okamoto et al. J Infect Dis 2000;182:1511–4

Gervais et al. J Hepatol 2000;32:293-9

HCV Infection in PregnancyHCV Infection in Pregnancy

Viraemia and Transaminases

Paternoster et al. Am J Gastroenterol 2001;96:2751-4


Viraemia

Serum HCV RNA (copies x 106/mL)

Paternoster et al. Am J Gastroenterol 2001;96:2751-4


Transaminases

AST and ALT (data are median values)

Viral FactorsViral Factors

HCV Genotype

no correlation between perinatal transmission of HCV and maternal HCV genotype has been demonstrated

Resti et al. BMJ 1998;317:437-41Zuccotti et al. J Pediatr 1995;127:278–80Zanetti et al. J Hepatol 1999;31:96–100Indolfi et al. J Med Virol 2006;78:911–4

Ohto et al. N Engl J Med 1994;330:744–50Manzini et al. Hepatology 1995;21:328–32Paccagnini et al. Pediatr Infect Dis J 1995;14:195–9Zanetti et al. Lancet 1995;345:289–91Tovo et al. Clin Infect Dis 1997:25:1121–4Granovsky et al. Pediatrics 1998;102:355–9Thomas et al. J Infect Dis 1998;177:1480–8Gibb et al. Lancet 2000;356:904–7Europ. Paediat. Hepat. C Virus Network BJOG 2001;108:371–7

Mother to Child Transmission of HCVMother to Child Transmission of HCV

HIV Coinfection

maternal HCV-HIV coinfection is associated with an increased risk of perinatal transmission of HCV

MotherMother--toto--infant transmission of multiple bloodinfant transmission of multiple blood--borne borne viral infections from multiviral infections from multi--infected mothers.infected mothers.Indolfi et al. J Med Virol 2007;79:743Indolfi et al. J Med Virol 2007;79:743--77

Viral associations in the mothers

n (%) Viral associations in the infants (n)

HIV-1 HCV TTV HGV 4 (6.25) HGV (1)HIV-1 HCV TTV 12 (18.75) HIVHIV--1 1 –– TTV (1)TTV (1)

HIV-1 (2), HCV (1), TTV (2)HIV-1 HCV HGV 4 (6.25) HIV-1 (1), HGV (1)HIV-1 HCV 13 (20.31) HCV (1)HCV TTV 5 (7,81) HCV HCV –– TTV (2)TTV (2)

TTV (1), HCV (1)HCV HGV 3 (4,69) HCV HCV –– HGV (1)HGV (1)

HGV (1)

Resti et al. Acta Paediatr 1995;84:251–5Resti et al. J Infect Dis 2002;185:567–72Sabatino et al. Eur J Epidemiol 1996;12:443–7Granovsky et al. Pediatrics 1998;102:355–9Mazza et al. J Med Virol 1998;54:12–9Zanetti et al. Intervirology 1998;41:208–2Azzari et al. J Med Virol 1998;80:65–71Indolfi et al. J Med Virol 2008;80:1907-11


Maternal Intravenous Drug Use

Several but not all studies have shown that the maternal history of intravenous drug use involves a greater risk for perinatal transmission of HCV

Indolfi et al. J Med Virol 2006;78:911–4Hayashida et al. J Obstet Gynaecol Res 2007;33:417–22


Alanine Transaminase Concentration

abnormal alanine transaminase concentration during the last year before pregnancy and at delivery in mothers infected with HCV is associated significantly with perinatal transmission of HCV

Indolfi et al. J Med Virol 2008;80:1907–11


Infection of the Father/Sexual Partner

HCV infection of the fathers, who were also the sexual partners of the HCV-infected mothers, was predictive of HCV perinatal transmission

MOTHER TO CHILD TRANSMISSION OF HCVMOTHER TO CHILD TRANSMISSION OF HCV

VIRAEMIAVIRAEMIA

INTRAVENOUS INTRAVENOUS DRUG USEDRUG USE

HIVHIV--HCV HCV COINFECTIONCOINFECTION

INCREASED ALT INCREASED ALT BEFORE BEFORE

PREGNANCYPREGNANCY

HCV INFECTION HCV INFECTION OF THE FATHEROF THE FATHER


VIRAEMIAVIRAEMIA



PREGNANCYPREGNANCY



Azzari et al. Blood 2000;96:2045-8


PBMNC Infection

HCV RNA in maternal PBMNC is highly associated with transmission of HCV to the newborn

the presence of negative-strand HCV RNA (a marker of HCV replication in maternal PBMNC) is associated with mother to child transmission

Maternal drug use is a preeminent risk factor for motherMaternal drug use is a preeminent risk factor for mother--toto--child hepatitis C virus transmission: results from a child hepatitis C virus transmission: results from a multicenter study of 1372 mothermulticenter study of 1372 mother--infant pairs.infant pairs.Resti et al. J Infect Dis 2002;185:567Resti et al. J Infect Dis 2002;185:567--7272

intravenous drug useintravenous drug use

HIVHIV--1 coinfection1 coinfection

increase the risk of mother increase the risk of mother to child transmissionto child transmission

158 mothers158 mothersHIVHIV--11--HCV coinfectedHCV coinfected

739 mothers739 motherswth HCV monoinfectionwth HCV monoinfection

multivariate analysisHIVHIV--1 coinfection1 coinfection

Maternal drug use is a preeminent risk factor for motherMaternal drug use is a preeminent risk factor for mother--toto--child hepatitis C virus transmission: results from a child hepatitis C virus transmission: results from a multicenter study of 1372 mothermulticenter study of 1372 mother--infant pairs.infant pairs.Resti et al. J Infect Dis 2002;185:567Resti et al. J Infect Dis 2002;185:567--7272

158 mothers158 mothersHIVHIV--11--HCV coinfectedHCV coinfected

739 mothers739 motherswth HCV monoinfectionwth HCV monoinfection


increases the risk of mother increases the risk of mother to child transmissionto child transmission

Injection drug use facilitates hepatitis C virus infection of Injection drug use facilitates hepatitis C virus infection of peripheral blood mononuclear cells.peripheral blood mononuclear cells.Resti et al. Clin Infect Dis 2002;35:236Resti et al. Clin Infect Dis 2002;35:236--99

51 HCV51 HCV--positive women with positive women with a previous history of a previous history of intravenous drug useintravenous drug use

57 HCV57 HCV--positive womenpositive women

previous history of previous history of intravenous drug use intravenous drug use

increases the risk of PBMNC increases the risk of PBMNC infection by HCVinfection by HCV

Higher risk of hepatitis C virus perinatal transmission Higher risk of hepatitis C virus perinatal transmission from drug user mothers is mediated by peripheral blood from drug user mothers is mediated by peripheral blood mononuclear cell infection.mononuclear cell infection.Azzari et al. J Med Virol 2008;80:65Azzari et al. J Med Virol 2008;80:65--7171

PBMNC infectionPBMNC infection

increases the risk of mother to increases the risk of mother to child transmissionchild transmission

48 HCV transmitting mothers48 HCV transmitting mothers 122 non122 non--transmitting motherstransmitting mothers


Higher risk of hepatitis C virus perinatal transmission Higher risk of hepatitis C virus perinatal transmission from drug user mothers is mediated by peripheral blood from drug user mothers is mediated by peripheral blood mononuclear cell infection.mononuclear cell infection.Azzari et al. J Med Virol 2008;80:65Azzari et al. J Med Virol 2008;80:65--7171

PBMNC infectionPBMNC infection



intravenous drug useintravenous drug use multivariate analisysmultivariate analisys

Intrafamilial transmission of hepatitis C virus.Intrafamilial transmission of hepatitis C virus.Indolfi et al. J Med Virol 2008;80:1907Indolfi et al. J Med Virol 2008;80:1907--1111




HCV infectionHCV infectionof the fatherof the father

Intrafamilial transmission of hepatitis C virus.Intrafamilial transmission of hepatitis C virus.Indolfi G, Resti M, et al. J Med Virol 2008;80:1907Indolfi G, Resti M, et al. J Med Virol 2008;80:1907--1111

casescases49 HCV transmitting mothers49 HCV transmitting mothers

controlscontrols557 non557 non--transmitting motherstransmitting mothers



HCV infection of the HCV infection of the fatherfather multivariate analisysmultivariate analisys


VIRAEMIAVIRAEMIA



PREGNANCYPREGNANCY

PBMC PBMC INFECTIONINFECTION




VIRAEMIAVIRAEMIA



PREGNANCYPREGNANCY

PBMC PBMC INFECTIONINFECTION



...

PREGNANCY, PREGNANCY, DELIVERY and DELIVERY and

BREASTFEEDINGBREASTFEEDING

Minola et al. Hepatology 2001;33:1341–2

Obstetric Procedures and Intrapartum ExposureObstetric Procedures and Intrapartum Exposureto Maternal Blood Infected by HCVto Maternal Blood Infected by HCV

Amniocentesis

HCV was found in amniotic fluid in only 6.3% of HCV viremic mothers who underwent amniocentesis during the fourth month of pregnancy

one study demonstrated that amniocentesis is a potential risk for spreading HCV infection to the infant

Delamare et al. J Hepatol 1999;31:416–20

Exposing the Infant to Maternal Blood

invasive monitoring of the fetus in labor with a scalp, vaginal or perineal laceration during vaginal delivery increase the risk of perinatal transmission of HCV

Mast et al. J Infect Dis 2005;192:1880–9Steininger et al. J Infect Dis 2003;187:345–35

Obstetric Procedures and Intrapartum ExposureObstetric Procedures and Intrapartum Exposureto Maternal Blood Infected by HCVto Maternal Blood Infected by HCV

in twin pregnancies the transmission of HCV is more likely to affect the second twin

Boxall et al. Clin Virol 2007;38:91–5

Healey et al. Ir J Med Sci 2001;170:103–6

Prolonged Rupture of MembraneProlonged Rupture of Membraneand Delivery Complicationsand Delivery Complications

Conflicting Results

membrane rupture occurring more than 6 hr before delivery is associated with an increased risk of perinatal transmission of HCV

one study failed to demonstrate this association

Spencer et al. J Viral Hepat 1997;4:395–409European Paediatric Hepatitis C Virus Network J Infect Dis 2005;192:1872–9Mast et al. J Infect Dis 2005:192:1880–9

Factors Not Associated withFactors Not Associated withMother to Child Mother to Child TransmissionTransmission

Mode of Delivery

the mode of delivery (Caesarean section versus vaginal route) does not affect the risk of perinatal transmission of HCV

Tovo et al. Clin Infect Dis 1997;25:1121–1124Spencer et al. J Viral Hepat 1997;4:395–409Resti et al. BMJ 1998;317:437-41Conte et al. Hepatology 2000;31:751–5Ceci et al. J Pediatr Gastroenterol Nutr 2001;33:570–75Resti et al. J Infect Dis 2002;185:567–72Dal Molin et al. J Med Virol 2002;67:137–42Europ. Paed. Hepatitis C Virus Network J Infect Dis 2005;192:1872–9

Mode of DeliveryMode of Delivery

Elective Caesarian Section

delivery by elective Caesarean section before membrane rupture was associated with a lower risk of transmission than with delivery by vaginal route or by emergency Caesarean section

Gibb et al. Lancet 2000;356:904–7

currently, there is no evidence from randomised controlled trials upon which to base any practice recommendations regarding planned caesarean section versus vaginal delivery for preventing mother to infant hepatitis C virus transmission.

Cochrane Database Syst Rev 2006;4:CD005546

no good evidence to support using caesarean section for reducing mother to baby transmission of hepatitis C during labour and birth.

Subsequent Delivery of a Child InfectedSubsequent Delivery of a Child InfectedPerinatally with HCVPerinatally with HCV

Recurrence Risk

only one study evaluated the risk of recurrent perinatal transmission of HCV in offspring in subsequent pregnancies. The risk does not seem to increase in consecutive siblings of the same infected mother

Resti et al. J Pediatr Gastroenterol Nutr 2000;30:491-3

Factors Not Associated withFactors Not Associated withMother to Child TransmissionMother to Child Transmission

Mother–Child Human Leukocyte Antigen Concordance

mother–child HLA class-1 type discordance, previously shown to be protective for perinatal transmission of HIV and the HTLV-1, did not affect perinatal transmission of HCV

Azzari et al. Int J Immunopathol Pharmacol 2007;20:827–31

maternal HLA-DRB104 correlated with protection from vertical transmission

HLA-DRB110 in children was a risk factorHLA-DRB1 locus mismatch between mother and child was

a protective factor (p=0.017)

Bevilacqua et al. Virology 2009;390:64-70


HCV in human milk

HCV RNA has been detected in breast milk and colostrum

Lin et al. J Pediatr 1995;126:589–91Bernard. Acta Gastroenterol Belg 1998;61:192–4Ruiz-Extremera et al. Pediatr Infect Dis J 2000;19:511–6

isolated descriptions of perinatal infections attributed to breast-feeding are available

Kumar et al. J Hepatol 1998;29:191–7


data based on large cohorts of mothers infected by HCV and their exposed children demonstrated that breast-feeding in the absence of damaged, cracked, or bleeding nipples, does not increase the rate of perinatal transmission of HCV

Lin et al. J Pediatr 1995;126:589–91Spencer et al. J Viral Hepat 1997;4:395–409Ruiz-Extremera et al. Pediatr Infect Dis J 2000;19:511–6Conte et al. Hepatology 2000;31:751–5Gibb et al. Lancet 2000;356:904–7Resti et al. BMJ 1998;317:437-41Resti et al. J Infect Dis 2002;185:567–72European Paediatric Hepatitis C Virus Network. BJOG 2001;108:371–7Dal Molin et al. J Med Virol 2002;67:137–42

Timing of Mother to Child TransmissionTiming of Mother to Child Transmissionof Hepatitis C Virusof Hepatitis C Virus

PregnancyPregnancy9 months9 months First 18 months of lifeFirst 18 months of life

HCV AbHCV Ab

-- -- -- -- -- -- -- --HCV RNAHCV RNA

NOT INFECTEDNOT INFECTED

Timing of Mother to Child TransmissionTiming of Mother to Child Transmissionof Hepatitis C Virusof Hepatitis C Virus

PregnancyPregnancy9 months9 months First 18 months of lifeFirst 18 months of life

HCV AbHCV Ab

+ + + + + + ++ + + + + + +-- -- + + + + ++ + + + +

HCV RNAHCV RNA

INFECTEDINFECTED

-- -- -- -- -- -- --

Strategy for Prevention of HBV InfectionStrategy for Prevention of HBV Infection

universal immunisation of infants beginning at birth

prevention of perinatal HBV infection through:routine screening of all pregnant women

immunoprophylaxis of infants born toHBsAg-positive womenwomen with unknown HBsAg status

routine immunisation of children, adolescents and adults who previously have not been immunised

Red Book, Report of the Committee on Infectious DiseasesAmerican Academy of Pediatrics

Strategy for Prevention of HBV InfectionStrategy for Prevention of HBV Infection

maternal screening programs and universal active and passive immunoprophylaxis of newborn have reduced dramatically the HBV transmission rates by 95%


without immunoprophylaxis, up to 90% of infants born to HBeAg-positive mothers become infected.

Serologic Screening of Pregnant WomenSerologic Screening of Pregnant Women

all pregnant women should be tested for HBsAg during an early prenatal visit

testing should be repeated at the time of admission to the hospital for delivery for HBsAg negative women at high risk of HBV infection


Management of Infants Born to HBsAgManagement of Infants Born to HBsAg--Positive WomenPositive Women

infants born to HBsAg-positive mothers should receive the initial dose of hepatitis B vaccine within 12 hours of birth and HBIG (0.5 mL) should be given concurrently but at a different anatomic site

the interval of effectiveness of HBIG is unlikely to exceed 7 days


subsequent doses of vaccine should be given as recommended

Infants Born to Mothers Not Tested During PregnancyInfants Born to Mothers Not Tested During Pregnancy

test mother as soon as possible to determine HBsAg status

if the women is HBsAg positive, term infant should receive HBIG within 7 days of birth


subsequent doses of vaccine should be given as recommended

while awaiting results, the infants should receive the first HBV vaccine dose within 12 hours of birth

What About Immunisation Failure?What About Immunisation Failure?

infants born to mothers with very high levels of HBV DNA

incomplete administration of the regimen of vaccination

5% of the children born to HBsAg-positive mothers

should HBsAg-positive mothers with high levels of viremia be given antiviral therapy during the last trimester in order toreduce the level of virus at the time of delivery, the time at which actual transmission is thought to occur?

Antiviral Treatment and PregnancyAntiviral Treatment and Pregnancy

interferon has antiproliferative actions and is considered contraindicated during pregnancy

tenofovir and telbivudine are considered “Category B”, indicating that they have been found to be safe in animal models and there is limited data in humans

Patients on Antiviral Therapy for Hepatitis BAre Asked to Practice Birth Control

lamivudine, adefovir and entecavir are considered “Category C”, indicating that their safety has not been shown adequately either in animal models or humans

Lamivudine and Perinatal Transmission of HBVLamivudine and Perinatal Transmission of HBV

8 women with high levels of HBV DNA (>109 genome equivalents/mL) were treated with lamivudine during the last 6 to 40 days of pregnancy

1/8 children born to treated mothers developed chronic hepatitis B, compared to 7/24 historical controls with similar levels of HBV DNA

Results

van Zonneveld et al. J Viral Hepat 2003;10:294-7


150 mothers with HBsAg and high levels of HBV DNA (>109 genome equivalents/mL)

randomized to receive lamivudine or placebo from week 32 of gestation to 4 weeks postpartum

Randomised Controlled Trial

Xu et al. J Viral Hepat 2009;16:94-103

evaluating children with complete data 3/49 (6%) infants of mothers given lamivudine compared to 5/41 (12%) given placebo had evidence of HBV transmission (p 0.368).


lamivudine from 24 to 32 weeks of gestation, until delivery to 1 month post-delivery

A Meta-Analysis

Sci et al. Obstet Gynecol 2010;116:147-159

newborns in the lamivudine treated group had:

13% to 24% lower incidence of intrauterine exposure1.4% to 2% lower perinatal infection rate at 9 to 12

months

Perinatal Transmission of HBV and Viral LoadPerinatal Transmission of HBV and Viral Load

although a high viral load is clearly important, it is not the only factor predisposing to failure of immunoprophylaxis. This is highlighted by a case in which a child developed chronic HBV infection, despite suppression of HBV DNA to undetectable levels in the mother with lamivudine therapy throughout gestation and appropriate immunoprophylaxis after birth

A Single Case

Kazim et al. Lancet 2002;359:1488–1489

HBIG in Pregnancy and Perinatal Transmission of HBVHBIG in Pregnancy and Perinatal Transmission of HBV

HBIG administered regularly during late pregnancy is potent to cut down HBV intrauterine infection

Li et al. World J Gastroenterol 2004;10:3215-7

the possibility of HBV intrauterine infection increases if maternal blood HBV DNA> or =108 copies/mL

Perinatal Transmission of HBV and Mode of DeliveryPerinatal Transmission of HBV and Mode of Delivery

elective caesarian section reduce the rate of mother to child transmission of HBV (ECS: 10.5%; vaginal delivery: 28.0%; RR 0.41, 95% CI 0.28 to 0.60, P < 0.000001)

Systematic Review

Yang et al. Virol J 2008;5:100

942 studies; 938 excluded, 4 studies (n 789), all performed in China, 1 published in English


de Martino et al. Arch Dis Child 1985;60:972-4

our experience

85 infants born to 84 mothers who were hepatitis B surface antigen positive (only 2 HBeAg-positive)

all infants received immunisation against hepatitis B virus


Petrova et al. World J Gastroenterol 2010;16:5042-6

Breastfeeding and TreatmentBreastfeeding and Treatment

little is known about the extent of exposure of antiviral agents during breastfeeding. Thus, little is known about the overall safety of breastfeeding in this setting.

for mothers on antiviral therapy, breastfeeding is not recommended

First Trimester HCV Ab

HCV RNA + HCV RNA -

Three monthsHCV RNA, LFTs

NEGATIVEPOSITIVE

CLOSE 3 months follow up 18 months HCV Ab

HCV Ab positiveTEST HCV RNA

Third trimester HBsAg

negative positive

Immunisation HBIG

Not determined

Immunisation

Check HBsAgIf +, HBIG

Complete immunisation

Documents

Clinical Management of Viral Hepatitis During Pregnancy ... · Clinical Management of Viral Hepatitis During Pregnancy and Breastfeeding Giuseppe Indolfi, Massimo Resti UO Pediatria