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Discordant outcome of perinatal transmission of hepatitis C in twin pregnancies
Journal of Clinical Virology 38 (2007) 91–95
Discordant outcome of perinatal transmission of hepatitis C in twin pregnancies Elizabeth Boxall a,b,∗ , Kristine Baumann a , Nicola Price b , Jaswant Sira a , Maxine Brown a , Deirdre Kelly a b
a Liver Unit, Birmingham Children’s Hospital NHS Trust, Birmingham B4 6NH, UK Health Protection Agency, Public Health Laboratory, Heart of England NHS Trust, Birmingham B9 5SS, UK
Received 12 November 2006; received in revised form 24 November 2006; accepted 27 November 2006
Abstract Background: Mother to infant transmission of hepatitis C virus (HCV) is dependent on significant HCV viraemia being present in the mother. As yet there are no appropriate interventions to prevent perinatal transmission. The investigation of twin pregnancies where only one twin is infected may reveal further information relating to transmission and specific risks. Evaluation of these risks could affect decisions about the management of the deliveries of these mothers while more appropriate interventions are evaluated. Study design: The laboratory database was searched for all twins referred for testing at the Children’s Hospital Liver Unit. The mothers and health care providers were contacted to gain more information about the pregnancies and deliveries of all of the twins. Results: Four sets of twins had been investigated for HCV. In all cases only one twin had been infected. In three out of four cases the second twin had become infected. All of the twins were girls and the larger twin in each pair became infected. Premature rupture of membranes was associated with transmission in the only case in which the first-born became infected. There was no invasive foetal monitoring or episiotomy in any of the deliveries Summary and conclusions: Transmission of HCV is more likely to affect the second twin, perhaps because placental separation during the delivery of the second twin exposes the infant to infection. Until effective interventions such as vaccination of newborns or antiviral treatment of mothers are evaluated, elective caesarean section could be recommended for HCV twin pregnancies in order to avoid premature membrane rupture and infection of the second twin. © 2006 Elsevier B.V. All rights reserved. Keywords: Hepatitis C; Mother to baby transmission; Discordant twins; Placental rupture
1. Introduction Vertical transmission of hepatitis C virus (HCV) from HCV-only infected mothers to their babies occurs in 4–10% of pregnancies and is associated with high maternal viraemia with levels >106 genome copies/ml more likely to transmit virus (Dal Molin et al., 2002; European Paediatric HCV Network, 2001; Giacchino et al., 1998; Gibb et al., 2000; ∗ Corresponding author at: Health Protection Agency, Public Health Laboratory, Heart of England NHS Trust, Birmingham B9 5SS, UK. Tel.: +44 121 424 2248; fax: +44 121 772 6229. E-mail addresses: [email protected], [email protected] (E. Boxall).
1386-6532/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jcv.2006.11.012
Granovsky et al., 1998; Lin et al., 1994; Matsubara et al., 1995; Resti et al., 1998; Steininger et al., 2003; Thomas et al., 1998; Tova et al., 1997; Zanetti et al., 1998). Coinfection with HIV is an additional risk (European Paediatric HCV Network, 2001; Gibb et al., 2000; Tova et al., 1997; Zanetti et al., 1998). Recent studies (European Paediatric HCV Network, 2005; Mast et al., 2005) have also observed that HCV infection rates are doubled in female to male infants and that virus transmission is increased with earlier membrane rupture. Breast-feeding does not correlate with transmission, but the effect of elective caesarean section is still unproven (European Paediatric HCV Network, 2001, 2005; Gibb et al., 2000; Mast et al., 2005; McIntyre et al., 2006). Intra-uterine and intrapartum hepatitis C infections
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E. Boxall et al. / Journal of Clinical Virology 38 (2007) 91–95
Diagnostic Systems, Branchburg, NJ). Four sets of twins were identified. Children’s and mothers’ notes were reviewed to establish as many risk parameters as possible.
occur whereas postpartum transmission is rare (Mok et al., 2005). Individual case reports exist showing different outcomes of vertical transmission of HCV in twin pregnancies (Barlow and Mok, 1993; Goncales et al., 2000; Inui et al., 2002). Multicentre studies into mother to baby transmission of HIV revealed a high risk of infection to first-born twins (Goedert et al., 1991). The risk was thought to occur to the first twin through direct contact with mucous membranes in the birth canal. These observations are the basis for the recommendation that all HIV infected women deliver by elective caesarean section before membrane rupture, unless the HIV viraemia is undetectable (The British HIV Assocition Guidelines, 2005). We describe the follow-up of four sets of twins born to HCV positive mothers. Factors influencing the risk of transmission were investigated, including birth order, delivery method, obstetric interventions, identical or non-identical twin pregnancies, sex, breast-feeding and maternal viraemia.
3. Results The description of the four pregnancies is shown in Table 1. The characteristics of the children are shown in Table 2. In all cases only one twin in each family became infected. 3.1. Family A Mother A had a history of intravenous drug use (IVDU) and was found to be HCV positive antenatally. This was her fifth pregnancy. Her twins were born at 37 weeks by emergency section following premature rupture of membranes. TwinA2 was born 2 min after TwinA1. They were never breastfed. At 23 months TwinA1 was diagnosed with HCV genotype 1a, whereas her sister remained negative. TwinA1 remains under the care of the Liver Unit and will be considered for treatment.
2. Patients and methods The Liver Unit at Birmingham Children’s Hospital is a national referral centre for HCV infected children. Over 100 HCV infected children have been referred for specialist review in the last 10 years. Laboratory data files were searched to identify all children with the same surname and date of birth who were tested for anti-HCV by EIA (Ortho Clinical Diagnostics, Raritan, NJ), and HCVRNA (Roche
3.2. Family B Twins B were born to a mother known to be a hepatitis C carrier. They were born at 37 weeks by emergency section due to foetal distress. Postnatally both
Table 1 Obstetric information
Family A (twin 1) Family A (twin 2) Family B (twin 1) Family B (twin 2) Family C (twin 1) Family C (twin 2) Family D (twin 1) Family D (twin 2)
Birth order
Method of delivery
Gestational age (weeks)
Maternal age (years)
Birth weight (kg)
Breast fed
1 2 1 2 1 2 1 2
Caesarean Section Caesarean Section Caesarean Section Caesarean Section Normal delivery Breech extraction Normal delivery Normal delivery
37 37 37 37 37 37 37 37
34 34 36 36 30 30 27 27
2.17 1.66 2.14 2.25 2.1 2.4 2.58 2.78
No No No No 2–3 weeks 2–3 weeks No No
Table 2 Description of children Date of birth
Sex
Anti-HCV
HCVRNA
Genotype
Earliest age (years) HCVRNA positive
Age (years) last follow-up
Outcome
Family A (twin 1) Family A (twin 2)
20 July 2001 20 July 2001
F F
+ −
+ −
1a
1.9
3.7 2.7
Viraemic at 3.7 years Uninfected
Family B (twin 1) Family B (twin 2)
20 May 1998 20 May 1998
F F
− +
− +
1b
0.25
6.3 6.7
Uninfected Cleared vireamia after treatment
Family C (twin 1) Family C (twin 2)
15 September 1998 15 September 1998
F F
− +
− +
3a
1.2
2.0 6.3
Uninfected Response to treatment, but relapse on follow-up
Family D (twin 1) Family D (twin 2)
9 August 2001 9 August 2001
F F
− +
− +
3a
0.25
2.5 2.5
Uninfected Cleared vireamia at age of 2 years
E. Boxall et al. / Journal of Clinical Virology 38 (2007) 91–95
twins were found to be anti-HCV positive and PCR negative, however at 3 months TwinB2 was found to HCVRNA positive, genotype 1b. Her non-identical twin sister had cleared maternal antibodies at age of 2 years. At the age of 6 years TwinB2 cleared HCVRNA after 48 weeks of treatment with Peginterferon and Ribavirin. She remains HCVRNA negative 24 weeks after cessation of treatment.
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infected and in all cases the larger twin became infected. Infection was independent of the HCV genotype, the method of delivery and gestational age (Table 2). Two of the children are no longer infected, one resolved spontaneously and the other following treatment with Peginterferon and Ribavirin.
4. Discussion 3.3. Family C Mother C was a former IVD user known HCV positive who was on methadone during pregnancy. Labour was induced at 37 weeks. TwinC1 had a normal vaginal delivery. TwinC2 was born by breech extraction 3 min later. Cord blood was tested for both children, both were anti-HCV positive, but PCR negative. At the age of 14 months TwinC2 was found to be HCVRNA positive, genotype 3a. At 2 years of age TwinC1 had cleared maternal anti-HCV. At the age of 6 years TwinC2 was treated with a combination therapy of Peginterferon and Ribavirin for 24 weeks. She was HCVRNA negative after 24 weeks of treatment, but relapsed, becoming HCVRNA positive 24 weeks after completing treatment. 3.4. Family D Mother D had a history of IVDU and her twins were born at 37 weeks by normal vaginal delivery. TwinD2 was born 22 min after twinD1. At day 6 both twins were anti-HCV positive but HCVRNA negative by PCR. On follow-up TwinD2 was found to be HCVRNA positive, genotype 3a at 3 months, and went on to clear HCVRNA at the age of two without treatment. TwinD1 remained HCVRNA negative and cleared maternal antibodies at the age of 16 months. 3.5. Mothers The mean age of the mothers was 31.8 years (range 27–36 years); all were Caucasian, had a history of IVDU and delivered at 37 weeks gestation. Two deliveries were by caesarean section and two were vaginal deliveries, one of those involving a breech extraction of the second baby. Delivery trauma included: Mother A—premature rupture of membranes and Mother C, the breech extraction of the second baby. There was no invasive foetal monitoring or episiotomy in any of the deliveries (Table 1). 3.6. Children All children were female and were non-identical. Infection was not present immediately after birth in three cases with those children becoming HCVRNA positive on follow-up, suggesting perinatal rather than 1 ‘in utero’ infection. In the fourth family, the children were not tested until nearly 2 years old. In three out of four families the second born became
Transmission of HCV from infected mothers to their babies occurs in 4–10% of pregnancies and is associated with high maternal HCVRNA (>106 genome copies/ml) but is not related to the HCV genotype. No measurement of HCVRNA during pregnancy is available for our group of mothers, but it can be assumed that the level was significant as infection has been transmitted to an infant in each pregnancy. The twins under study were born between 1998 and 2001 and it is now part of the care of HCV infected pregnant women that HCVRNA would be measured in pregnancy as part of risk assessment and counselling. None of the mothers was co-infected with HIV. The infants were HCVRNA negative at delivery suggesting that in utero infection did not occur and that infection was acquired around the time of birth, which is the usual pattern for hepatitis C. Twin pregnancies discordant for transmission of hepatitis C have been described confirming that maternal viraemia and co-infection with HIV are not the only risk factors for infection as these would apply equally to both twins in a twin pregnancy. Those factors, which apply to only one infant in a dizygotic pregnancy, will be the individual infant’s genetic susceptibility and their own placental integrity. If there were placental leakage around the time of delivery this would affect only one of the infants. The longer the labour takes, the more opportunity for placental breakdown—a situation that would put the second baby at higher risk of infection. In family A, the exception, where the first baby was infected, there is evidence of ruptured membranes, which may have exposed the first infant. Although caesarean section did not reduce the risk of infection in our cases, it is possible that elective caesarean section could reduce the risk of placental leakage in single and twin pregnancies. Of the three discordant studies published, two were monozygotic twins and the other dizygotic. In one of the monozygotic cases (Inui et al., 2002) the second baby became infected and the authors suggest differing concentrations of maternal blood in the amnion of the second baby. In the other monozygotic pregnancy one twin showed HCV viraemia at birth and the other did not. On follow-up both twins showed HCV viraemia at 6 months which went on to clear spontaneously without treatment, suggesting Twin 1 was infected in utero and Twin 2 perinatally (Goncales et al., 2000). The most unusual case was in a dizygotic pregnancy, where the mother was infected with both HCV and HIV. Twin 1 became infected with HIV only and Twin 2 became infected with HCV only (Barlow and Mok, 1993). Such a pattern is very
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E. Boxall et al. / Journal of Clinical Virology 38 (2007) 91–95
difficult to explain as features, which would expose the infant to more maternal blood, would enhance the risk of infection to both viruses. The importance of the role of the placenta was emphasised as well as the genetic susceptibility of the infants. With twin pregnancies there is a risk of partial placental separation following the delivery of the first baby which breaches the placental integrity and therefore would expose the second child to maternal blood. The outcomes described in the three publications showed that the second twin was at a greater risk of perinatal infection as has been confirmed in three out four of our cases. A recent review which sought evidence for a policy of prelabour elective caesarean section in the reduction of risk for mother to baby transmission of hepatitis C failed to locate any randomised controlled trials (McIntyre et al., 2006). However, this review did not include studies on twin pregnancies. As yet there is no effective immune prophylaxsis for Hepatitis C which could be used postnatally as with hepatitis B (Lee et al., 2006) or any suitable antiviral treatment which could be used safely in pregnancy as with HIV (The British HIV Assocition Guidelines, 2005). In the meantime, treatment of HCV-infected adults and children with Peg-Interferon and Ribavirin can clear HCVRNA effectively (NICE Guidance, 2006) and such treatment of compliant women of childbearing age could reduce the risk of infection to their babies. However, appropriate follow-up of all children born to known HCV infected mothers by serology and PCR is necessary so that infected children can be referred for followup and treatment (Gonzalez-Peralta et al., 2005). Whether universal antenatal screening for HCV should be introduced will depend on a suitable intervention being evaluated. Although twin pregnancies are unusual they highlight the role of the placenta in transmission of HCV and the need to manage this during pregnancy.
Acknowledgements We gratefully acknowledge the help provided by the families and their health care workers in answering the questions we presented them with regarding the details of their pregnancies and deliveries. We also acknowledge the help of Miss E. Payne, Consultant Obstetrician at Heart of England NHS Trust who helped us to better understand the mechanisms and problems concerning twin deliveries.
References Barlow KM, Mok JY. Dizygotic twins discordant for HIV and hepatitis C virus. Arch Dis Child 1993;68:507. Dal Molin G, D’Agaro P, Ansalke F, Ciana G, Fertz C, Alberico S, et al. Mother-to-infant transmission of hepatitis C virus: rate of infection and assessment of viral load and IgM anti-HCV as risk factors. J Med Virol 2002;67:137–42.
European Paediatric Hepatitis C Virus Network. A significant sex-but not elective cesarean section-effect on mother-to-child transmission of hepatitis C virus infection. J Infect Dis 2005;192:1872– 9. Giacchino R, Rasso L, Timitili A, Castagnola E, Cristina E, Sinelli N, et al. Vertical transmission of hepatitis C virus infection; usefulness of viraemia detection in HIV-seronegative hepatitis C virus-positive mothers. J Paediatr 1998;132:167–9. Gibb DM, Goodall RL, Dunn DT, healy M, Neave P, Cafferkey M, et al. Mother-to-child transmission of hepatitis C virus: evidence for preventable peripartum transmission. Lancet 2000;356:904–7. Goedert JJ, Duliege AM, Amos CI, Felton S, Biggar RJ. High risk of HIV-1 infection for first-born twins. The International Registry of HIV-exposed Twins. Lancet 1991;338(8781):1471–5. Goncales FL, Stucchi RSB, Pavan MHP, et al. Hepatitis C virus in monozygotic twins. Rev Inst Med Trop S Paulo 2000;42:163–5. Gonzalez-Peralta RP, Kelly DA, Haber B, Molleston J, Murray KF, Jonas MM, et al., International Pediatric Hepatitis C Therapy Group. Interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis C in children: efficacy, safety, and pharmacokinetics. Hepatology 2005;42(5):1010–8. Granovsky MO, Minkoff HL, Tess BH, Waters D, Hatzakis A, Devoid DE, et al. Hepatitis C virus infection in the mothers and infants cohort study. Pediatrics 1998;102:355–9. Inui A, Fujisawa T, Sogo T, Komatsu H, Isozaki A, Sekine I. Different outcomes of vertical transmission of hepatitis C virus in a twin pregnancy. J Gastro Hepat 2002;17:n617–9. Lee C, Gong Y, Brok J, Boxall EH, Gluud C. Effect of hepatitis B immunisation in newborn infants of mothers positive for hepatitis B surface antigen: systematic review and meta-analysis. Br Med J 2006;332(7537):328–36 [Epub January 27, 2006]. Lin HH, Kao JH, Hsu HY, Ni YH, Hwang LH, Chang MH, et al. Possible role of high-titer maternal viraemia in perinatal transmission of hepatitis C virus. J Infect Dis 1994;169:638–41. Mast EE, Huang LY, Seto DSY, Nolte FS, Nainan OV, Wurtzal H, et al. Risk factors for perinatal transmission of hepatitis C virus (HCV) and the natural history of HCV infection acquired in infancy. J Infect Dis 2005;192:1880–9. Matsubara T, Sumazaki R, Takita H. Mother-to-infant transmission of hepatitis C virus: a prospective study. Eur J Pediatr 1995;154:973– 8. McIntyre PG, Tosh K, McGuire W. Caesarian section versus vaginal delivery for preventing mother to infant hepatitis C virus transmission. The Cochrane Library 2006(4) [Review] http://thecochranelibrary.com. Mok J, Pembrey L, Tovo PA, Newell ML, European Paediatric Hepatitis C Virus Network. When does mother to child transmission of hepatitis c virus occur? Arch Dis Child Fetal Neonatal Ed 2005;90:F156– 60. NICE Guidance. Hepatitis C-peginterferon alfa and ribavirin TA106. August 2006. Pembrey L, Tovo PA, Newell ML, European Paediatric HCV Network. Effects of mode of delivery and infant feeding on the risk of motherto-child transmission of hepatitis C virus. Br J Obstet Gynaecol 2001;108:371–7. Resti M, Azzari C, Manelli F, Moriondo M, Novembre E, de Martina M, et al. Mother to child transmission of hepatitis C virus; prospective study of risk factors and timing of infection in children born to women seronegative for HIV-1. Br Med J 1998;317:437–41. Steininger C, Kundi M, Jatzko G, Kiss H, Lischka A, Holzmann H. Increased risk of mother-to-child transmission of hepatitis C virus by intrapartum infantile exposure to maternal blood. J Infect Dis 2003;187:345– 51. The British HIV Association Guidelines for the Management of HIV infection in Pregnant Women and the Prevention of Mother-to-Child Transmission of HIV; March 31, 2005. www.bhiva.org/. Thomas SL, Newell ML, Peckham CS, Ades AE, Hall AJ. A Review of hepatitis C virus (HCV) vertical transmission: risks of transmis-
E. Boxall et al. / Journal of Clinical Virology 38 (2007) 91–95 sion to infants born to mothers with and without HCV viraemia or human immunodeficiency virus infection. Int J Epidemiol 1998;27:108– 17. Tova PA, Palomba E, Ferraris G, Principi N, Ruga E, Dallacasa P, et al. Increased risk of maternal-infant hepatitis C virus transmission for
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women co-infected with human immunodeficiency virus type 1. Clin Infect Dis 1997;25:1121–4. Zanetti AR, Tanzi E, Romano L, Zuin G, Minola E, Vacchi L, et al. A prospective study on mother-infant transmission of hepatitis C virus. Intervirology 1998;41:208–12.
Discordant outcome of perinatal transmission of hepatitis C in twin pregnancies Elizabeth Boxall a,b,∗ , Kristine Baumann a , Nicola Price b , Jaswant Sira a , Maxine Brown a , Deirdre Kelly a b
a Liver Unit, Birmingham Children’s Hospital NHS Trust, Birmingham B4 6NH, UK Health Protection Agency, Public Health Laboratory, Heart of England NHS Trust, Birmingham B9 5SS, UK
Received 12 November 2006; received in revised form 24 November 2006; accepted 27 November 2006
Abstract Background: Mother to infant transmission of hepatitis C virus (HCV) is dependent on significant HCV viraemia being present in the mother. As yet there are no appropriate interventions to prevent perinatal transmission. The investigation of twin pregnancies where only one twin is infected may reveal further information relating to transmission and specific risks. Evaluation of these risks could affect decisions about the management of the deliveries of these mothers while more appropriate interventions are evaluated. Study design: The laboratory database was searched for all twins referred for testing at the Children’s Hospital Liver Unit. The mothers and health care providers were contacted to gain more information about the pregnancies and deliveries of all of the twins. Results: Four sets of twins had been investigated for HCV. In all cases only one twin had been infected. In three out of four cases the second twin had become infected. All of the twins were girls and the larger twin in each pair became infected. Premature rupture of membranes was associated with transmission in the only case in which the first-born became infected. There was no invasive foetal monitoring or episiotomy in any of the deliveries Summary and conclusions: Transmission of HCV is more likely to affect the second twin, perhaps because placental separation during the delivery of the second twin exposes the infant to infection. Until effective interventions such as vaccination of newborns or antiviral treatment of mothers are evaluated, elective caesarean section could be recommended for HCV twin pregnancies in order to avoid premature membrane rupture and infection of the second twin. © 2006 Elsevier B.V. All rights reserved. Keywords: Hepatitis C; Mother to baby transmission; Discordant twins; Placental rupture
1. Introduction Vertical transmission of hepatitis C virus (HCV) from HCV-only infected mothers to their babies occurs in 4–10% of pregnancies and is associated with high maternal viraemia with levels >106 genome copies/ml more likely to transmit virus (Dal Molin et al., 2002; European Paediatric HCV Network, 2001; Giacchino et al., 1998; Gibb et al., 2000; ∗ Corresponding author at: Health Protection Agency, Public Health Laboratory, Heart of England NHS Trust, Birmingham B9 5SS, UK. Tel.: +44 121 424 2248; fax: +44 121 772 6229. E-mail addresses: [email protected], [email protected] (E. Boxall).
1386-6532/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jcv.2006.11.012
Granovsky et al., 1998; Lin et al., 1994; Matsubara et al., 1995; Resti et al., 1998; Steininger et al., 2003; Thomas et al., 1998; Tova et al., 1997; Zanetti et al., 1998). Coinfection with HIV is an additional risk (European Paediatric HCV Network, 2001; Gibb et al., 2000; Tova et al., 1997; Zanetti et al., 1998). Recent studies (European Paediatric HCV Network, 2005; Mast et al., 2005) have also observed that HCV infection rates are doubled in female to male infants and that virus transmission is increased with earlier membrane rupture. Breast-feeding does not correlate with transmission, but the effect of elective caesarean section is still unproven (European Paediatric HCV Network, 2001, 2005; Gibb et al., 2000; Mast et al., 2005; McIntyre et al., 2006). Intra-uterine and intrapartum hepatitis C infections
92
E. Boxall et al. / Journal of Clinical Virology 38 (2007) 91–95
Diagnostic Systems, Branchburg, NJ). Four sets of twins were identified. Children’s and mothers’ notes were reviewed to establish as many risk parameters as possible.
occur whereas postpartum transmission is rare (Mok et al., 2005). Individual case reports exist showing different outcomes of vertical transmission of HCV in twin pregnancies (Barlow and Mok, 1993; Goncales et al., 2000; Inui et al., 2002). Multicentre studies into mother to baby transmission of HIV revealed a high risk of infection to first-born twins (Goedert et al., 1991). The risk was thought to occur to the first twin through direct contact with mucous membranes in the birth canal. These observations are the basis for the recommendation that all HIV infected women deliver by elective caesarean section before membrane rupture, unless the HIV viraemia is undetectable (The British HIV Assocition Guidelines, 2005). We describe the follow-up of four sets of twins born to HCV positive mothers. Factors influencing the risk of transmission were investigated, including birth order, delivery method, obstetric interventions, identical or non-identical twin pregnancies, sex, breast-feeding and maternal viraemia.
3. Results The description of the four pregnancies is shown in Table 1. The characteristics of the children are shown in Table 2. In all cases only one twin in each family became infected. 3.1. Family A Mother A had a history of intravenous drug use (IVDU) and was found to be HCV positive antenatally. This was her fifth pregnancy. Her twins were born at 37 weeks by emergency section following premature rupture of membranes. TwinA2 was born 2 min after TwinA1. They were never breastfed. At 23 months TwinA1 was diagnosed with HCV genotype 1a, whereas her sister remained negative. TwinA1 remains under the care of the Liver Unit and will be considered for treatment.
2. Patients and methods The Liver Unit at Birmingham Children’s Hospital is a national referral centre for HCV infected children. Over 100 HCV infected children have been referred for specialist review in the last 10 years. Laboratory data files were searched to identify all children with the same surname and date of birth who were tested for anti-HCV by EIA (Ortho Clinical Diagnostics, Raritan, NJ), and HCVRNA (Roche
3.2. Family B Twins B were born to a mother known to be a hepatitis C carrier. They were born at 37 weeks by emergency section due to foetal distress. Postnatally both
Table 1 Obstetric information
Family A (twin 1) Family A (twin 2) Family B (twin 1) Family B (twin 2) Family C (twin 1) Family C (twin 2) Family D (twin 1) Family D (twin 2)
Birth order
Method of delivery
Gestational age (weeks)
Maternal age (years)
Birth weight (kg)
Breast fed
1 2 1 2 1 2 1 2
Caesarean Section Caesarean Section Caesarean Section Caesarean Section Normal delivery Breech extraction Normal delivery Normal delivery
37 37 37 37 37 37 37 37
34 34 36 36 30 30 27 27
2.17 1.66 2.14 2.25 2.1 2.4 2.58 2.78
No No No No 2–3 weeks 2–3 weeks No No
Table 2 Description of children Date of birth
Sex
Anti-HCV
HCVRNA
Genotype
Earliest age (years) HCVRNA positive
Age (years) last follow-up
Outcome
Family A (twin 1) Family A (twin 2)
20 July 2001 20 July 2001
F F
+ −
+ −
1a
1.9
3.7 2.7
Viraemic at 3.7 years Uninfected
Family B (twin 1) Family B (twin 2)
20 May 1998 20 May 1998
F F
− +
− +
1b
0.25
6.3 6.7
Uninfected Cleared vireamia after treatment
Family C (twin 1) Family C (twin 2)
15 September 1998 15 September 1998
F F
− +
− +
3a
1.2
2.0 6.3
Uninfected Response to treatment, but relapse on follow-up
Family D (twin 1) Family D (twin 2)
9 August 2001 9 August 2001
F F
− +
− +
3a
0.25
2.5 2.5
Uninfected Cleared vireamia at age of 2 years
E. Boxall et al. / Journal of Clinical Virology 38 (2007) 91–95
twins were found to be anti-HCV positive and PCR negative, however at 3 months TwinB2 was found to HCVRNA positive, genotype 1b. Her non-identical twin sister had cleared maternal antibodies at age of 2 years. At the age of 6 years TwinB2 cleared HCVRNA after 48 weeks of treatment with Peginterferon and Ribavirin. She remains HCVRNA negative 24 weeks after cessation of treatment.
93
infected and in all cases the larger twin became infected. Infection was independent of the HCV genotype, the method of delivery and gestational age (Table 2). Two of the children are no longer infected, one resolved spontaneously and the other following treatment with Peginterferon and Ribavirin.
4. Discussion 3.3. Family C Mother C was a former IVD user known HCV positive who was on methadone during pregnancy. Labour was induced at 37 weeks. TwinC1 had a normal vaginal delivery. TwinC2 was born by breech extraction 3 min later. Cord blood was tested for both children, both were anti-HCV positive, but PCR negative. At the age of 14 months TwinC2 was found to be HCVRNA positive, genotype 3a. At 2 years of age TwinC1 had cleared maternal anti-HCV. At the age of 6 years TwinC2 was treated with a combination therapy of Peginterferon and Ribavirin for 24 weeks. She was HCVRNA negative after 24 weeks of treatment, but relapsed, becoming HCVRNA positive 24 weeks after completing treatment. 3.4. Family D Mother D had a history of IVDU and her twins were born at 37 weeks by normal vaginal delivery. TwinD2 was born 22 min after twinD1. At day 6 both twins were anti-HCV positive but HCVRNA negative by PCR. On follow-up TwinD2 was found to be HCVRNA positive, genotype 3a at 3 months, and went on to clear HCVRNA at the age of two without treatment. TwinD1 remained HCVRNA negative and cleared maternal antibodies at the age of 16 months. 3.5. Mothers The mean age of the mothers was 31.8 years (range 27–36 years); all were Caucasian, had a history of IVDU and delivered at 37 weeks gestation. Two deliveries were by caesarean section and two were vaginal deliveries, one of those involving a breech extraction of the second baby. Delivery trauma included: Mother A—premature rupture of membranes and Mother C, the breech extraction of the second baby. There was no invasive foetal monitoring or episiotomy in any of the deliveries (Table 1). 3.6. Children All children were female and were non-identical. Infection was not present immediately after birth in three cases with those children becoming HCVRNA positive on follow-up, suggesting perinatal rather than 1 ‘in utero’ infection. In the fourth family, the children were not tested until nearly 2 years old. In three out of four families the second born became
Transmission of HCV from infected mothers to their babies occurs in 4–10% of pregnancies and is associated with high maternal HCVRNA (>106 genome copies/ml) but is not related to the HCV genotype. No measurement of HCVRNA during pregnancy is available for our group of mothers, but it can be assumed that the level was significant as infection has been transmitted to an infant in each pregnancy. The twins under study were born between 1998 and 2001 and it is now part of the care of HCV infected pregnant women that HCVRNA would be measured in pregnancy as part of risk assessment and counselling. None of the mothers was co-infected with HIV. The infants were HCVRNA negative at delivery suggesting that in utero infection did not occur and that infection was acquired around the time of birth, which is the usual pattern for hepatitis C. Twin pregnancies discordant for transmission of hepatitis C have been described confirming that maternal viraemia and co-infection with HIV are not the only risk factors for infection as these would apply equally to both twins in a twin pregnancy. Those factors, which apply to only one infant in a dizygotic pregnancy, will be the individual infant’s genetic susceptibility and their own placental integrity. If there were placental leakage around the time of delivery this would affect only one of the infants. The longer the labour takes, the more opportunity for placental breakdown—a situation that would put the second baby at higher risk of infection. In family A, the exception, where the first baby was infected, there is evidence of ruptured membranes, which may have exposed the first infant. Although caesarean section did not reduce the risk of infection in our cases, it is possible that elective caesarean section could reduce the risk of placental leakage in single and twin pregnancies. Of the three discordant studies published, two were monozygotic twins and the other dizygotic. In one of the monozygotic cases (Inui et al., 2002) the second baby became infected and the authors suggest differing concentrations of maternal blood in the amnion of the second baby. In the other monozygotic pregnancy one twin showed HCV viraemia at birth and the other did not. On follow-up both twins showed HCV viraemia at 6 months which went on to clear spontaneously without treatment, suggesting Twin 1 was infected in utero and Twin 2 perinatally (Goncales et al., 2000). The most unusual case was in a dizygotic pregnancy, where the mother was infected with both HCV and HIV. Twin 1 became infected with HIV only and Twin 2 became infected with HCV only (Barlow and Mok, 1993). Such a pattern is very
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difficult to explain as features, which would expose the infant to more maternal blood, would enhance the risk of infection to both viruses. The importance of the role of the placenta was emphasised as well as the genetic susceptibility of the infants. With twin pregnancies there is a risk of partial placental separation following the delivery of the first baby which breaches the placental integrity and therefore would expose the second child to maternal blood. The outcomes described in the three publications showed that the second twin was at a greater risk of perinatal infection as has been confirmed in three out four of our cases. A recent review which sought evidence for a policy of prelabour elective caesarean section in the reduction of risk for mother to baby transmission of hepatitis C failed to locate any randomised controlled trials (McIntyre et al., 2006). However, this review did not include studies on twin pregnancies. As yet there is no effective immune prophylaxsis for Hepatitis C which could be used postnatally as with hepatitis B (Lee et al., 2006) or any suitable antiviral treatment which could be used safely in pregnancy as with HIV (The British HIV Assocition Guidelines, 2005). In the meantime, treatment of HCV-infected adults and children with Peg-Interferon and Ribavirin can clear HCVRNA effectively (NICE Guidance, 2006) and such treatment of compliant women of childbearing age could reduce the risk of infection to their babies. However, appropriate follow-up of all children born to known HCV infected mothers by serology and PCR is necessary so that infected children can be referred for followup and treatment (Gonzalez-Peralta et al., 2005). Whether universal antenatal screening for HCV should be introduced will depend on a suitable intervention being evaluated. Although twin pregnancies are unusual they highlight the role of the placenta in transmission of HCV and the need to manage this during pregnancy.
Acknowledgements We gratefully acknowledge the help provided by the families and their health care workers in answering the questions we presented them with regarding the details of their pregnancies and deliveries. We also acknowledge the help of Miss E. Payne, Consultant Obstetrician at Heart of England NHS Trust who helped us to better understand the mechanisms and problems concerning twin deliveries.
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