Discussion

Risk of Perinatal HCV Transmission

Similar to other blood-borne pathogens, hepatitis C virus (HCV) can be transmitted from an infected mother to her child in the perinatal period (vertical transmission). When no preventive measures are taken to prevent transmission of HCV, human immunodeficiency virus (HIV), or hepatitis B virus (HBV), vertical transmission of HCV occurs relatively less frequently than with HIV or HBV. Reported estimates of perinatal HCV transmission range from 0 to 44%, with larger studies indicating a vertical transmission risk in the 4 to 10% range[1,2,3,4,5,6,7,8,9,10,11,12,13,14]. Studies examining HCV vertical transmission, however, vary widely in study design, sample size, population characteristics, diagnostic criteria, and duration of follow-up of potentially infected neonates. The largest studies (involving at least 50 maternal-infant pairs) report transmission rates ranging from 0-44% for mothers co-infected with HIV and 0 to 17% for mothers with HCV infection alone[1,2,3,4,5,6,7,8,9,10,11,12,13,14]. In a very large, prospective study involving HCV-infected mothers and their infants, the European Pediatric Hepatitis C Virus Network reported 91 (6.2%) of 1479 mothers transmitted HCV to their child[13]. In this study, however, the mother's HCV was poorly characterized, with only about one-third of the women undergoing HCV RNA testing during pregnancy.

Risk Factors for Perinatal HCV Transmission

The risk of HCV transmission to infants appears to increase with detectable hepatitis C viremia during pregnancy[2,5,6,8,9,10,11,12,14,15], maternal HIV co-infection[1,4,14], and female gender of the infant[13]. Studies examining the contribution of other factors, such as maternal HCV levels, stage of HIV disease, receipt of HIV antiretroviral therapy, injection drug use during pregnancy, acuity or genotype of HCV infection, blood loss or complications during delivery, mode of delivery (vaginal versus elective Cesarean section), prolonged rupture of membranes (PROM), or internal fetal monitoring, have generated conflicting results. In the large European Pediatric Hepatitis C Virus Network study, the rate of vertical transmission in HIV co-infected mothers was 8.3% compared with a rate of 5.5% in mothers not co-infected with HIV, but this difference did not reach statistical significance[13]. Interestingly, the adjusted multivariate analysis identified female gender of the infant as the only risk factor associated with higher vertical HCV transmission rates (Figure 1)[13]. Most studies agree that breastfeeding does not pose a significant risk for vertical HCV transmission, despite several studies that have identified HCV in colostrum and breast milk using highly sensitive HCV RNA assays[2,3,4,7,8,13,15].

Vertical Transmission of HCV in Mothers without Viremia

The vast majority of reported vertically transmitted HCV infections have occurred from anti-HCV positive mothers with detectable HCV RNA levels during the pregnancy, but reports as recent as 2005 describe HCV-infected children born to mothers who were anti-HCV positive but had no HCV RNA detected in their serum[13]. Indeed, in the European Pediatric Hepatitis C Virus Network study, vertical HCV transmission occurred in 5 (3.3%) of 153 women classified as not viremic during their pregnancy (based on a least one HCV RNA test)[13]. Potential explanations for this discrepancy include failure to detect intermittent viremia or use of a HCV RNA assay that did not have sufficient sensitivity to detect low levels of circulating HCV[5,10,13]. Unfortunately, because of these findings, non-viremic women cannot be assured they have no chance of infecting their neonates, although the risk appears to be very low[10,16]. A suspected HCV infection in a pregnant woman should be confirmed with a HCV RNA assay sufficiently sensitive to detect low levels of HCV RNA[17].

Screening for HCV Infection During Pregnancy

Routine screening for HCV infection is recommended for individuals who have risk factors known to be associated with acquisition of HCV, including injection drug use or receipt of a blood transfusion or organ transplanation prior to 1992[17,18]. In addition, diagnostic testing for HCV should be one component of the evaluation of any patient with acute or chronic liver disease of unknown etiology. Routine screening of pregnant women for HCV is not recommended in the United States because the overall seroprevalence of HCV is low, there are no current interventions known to prevent transmission, and at least one study has indicated that screening in asymptomatic pregnant women is not cost-effective[19]. The patient described in this case did not have an obvious risk factor that provided an indication for HCV screening, but the abnormal hepatic aminotransferase level appropriately prompted testing for HCV. Although most studies indicate that pregnancy does not exacerbate the course of chronic hepatitis C, the patient should be referred for further evaluation and follow-up as indicated by the presence of detectable serum HCV levels[7,17,20].

Route and Timing of Perinatal HCV Transmission

The precise mechanism of vertical HCV transmission remains unclear, but infection appears to predominantly occur in utero or intrapartum, and not by breastfeeding. Long-term follow-up of HCV vertically infected infants and children has shown that a small proportion of neonates have hepatitis C viremia in the first month of life, whereas most do not become viremic until three or more months post-partum, thus suggesting intrapartum infection is more common than in utero infection[2,7,8,9,10,12,17,20]. Hepatitis C viral RNA has been detected in peripheral blood mononuclear cells, amniotic fluid, and vaginal secretions of chronically HCV-infected women and in cord blood of infected and noninfected neonates[12,21,22]. One study has suggested that HCV RNA detected in vaginal secretions represents the presence of non-viable viral particles, which may explain the relatively low rate of sexual and vertical transmission of HCV when compared with other blood borne pathogens[23]. As noted above, transmission of HCV through breast milk does not appear to be a significant source of infection, as demonstrated by the multiple transmission studies in which a proportion of HIV-uninfected women breastfed their neonates; in addition, several of these studies reported low rates of HCV RNA detection in breast milk[3,12].

Prevention in Utero and During Delivery

Currently there is no safe and effective intervention known to prevent perinatal transmission of HCV. An effective hepatitis C vaccine has not been developed and the drugs used most commonly to treat hepatitis C in both children and adults, interferon and ribavirin (Copegasys or Rebetol), are not recommended for use in pregnancy. Ribavirin has been shown to cause fetal malformations in controlled animal studies, is regarded as teratogenic, and is absolutely contraindicated at the time of conception for both men and women and in pregnancy (Food and Drug Administration [FDA] Category X)[24]. The Centers for Disease Control and Prevention (CDC) maintains a registry of individuals treated with ribavirin at the time of conception or during pregnancy. Inadvertent administration of ribavirin under these circumstances is rare and no consistent pattern of birth defects has been associated with fetal or embryonic exposure[25]. Interferon is classified as FDA Category C—it has been associated with teratogenicity in animals but controlled studies of its effects on pregnant animals or humans have not been performed. Concerns about the safety of interferon in pregnancy have limited studies of its use for treatment of pregnant women with acute or chronic hepatitis C and for the prevention of vertical HCV transmission[26]. No controlled trials have evaluated the impact of the mode of delivery on HCV transmission and prospective cohort studies comparing Cesarean section with vaginal delivery as a contributing factor have had contradictory results[27]. Elective Cesarean section is not recommended in the United States for prevention of vertical HCV transmission, but some perinatalogists recommend avoiding internal fetal monitoring and membrane rupture of 6 hours or longer, either of which may necessitate a Cesarean section[15,17,27]. Although the rate of vertical HCV transmission is low compared with other blood-borne viruses, effective prevention strategies are badly needed as the global burden of chronic hepatitis C increases.

Evaluation of Neonates, Infants, and Children

Children suspected to have acquired HCV by vertical transmission should have follow-up for a minimum of 18 months to establish or rule out a diagnosis of HCV infection. The accuracy of diagnosing HCV infection in neonates and infants is confounded by several factors: the persistence of maternal antibody, late seroconversion, intermittently detectable viremia, and potential viral clearance in the first few years of life. Maternal anti-HCV freely crosses the placenta and thus is found in virtually all newborns of HCV-infected mothers[11]. During the 12 months after birth the proportion of newborns with positive anti-HCV gradually declines and only 15% of children who do not acquire HCV will retain serum maternal antibody until 12 months of age (Figure 2)[11]; among the approximately 15% who maintain maternal antibody at 12 months of age, nearly all have resolution of anti-HCV by 18 months of age[11]. Children who have vertically-acquired HCV infection will also lose maternal antibody during the first 18 months of life, but develop their own anti-HCV, either following resolution of the maternal anti-HCV, or overlapping with maternal anti-HCV[3,5,7,8,9,11,12]. Twenty percent or more of vertically infected children may spontaneously clear HCV RNA in the first three years of life[9,28]. The recommended methods for diagnosis of vertically-acquired HCV infection are the detection of serum anti-HCV in a child at least 18 months of age or detection of HCV RNA on two separate occasions[31,35]. In the United States, the 2009 guidelines from the American Association for the Study of Liver Diseases recommended delaying testing for HCV infection in children born to anti-HCV positive mothers until 18 months of age, when infection can be confirmed by the presence of serum anti-HCV antibody[17]. This recommendation is based on several factors, including the understanding that earlier diagnosis does not lead to intervention (therapy is not recommended by the AASLD for children younger than 2 years of age), a significant proportion of children spontaneously clear HCV during the first year of life, and early "false-positive" test results may generate significant unnecessary anxiety. These recommendations state that in the event an earlier diagnosis is desired, HCV RNA PCR testing may be performed at or after the infant's first well-child visit at 1 to 2 months[17]. Other experts have noted that detection of HCV RNA by nucleic acid amplification testing (NAAT) is more costly, less sensitive and less specific in the first 18 months of life compared with antibody testing at 18 or more months of age[17]. A more aggressive approach is proposed by European investigators: detection of HCV RNA by a NAAT at 2 to 3 months of age, followed by a second HCV RNA NAAT at 12 to 18 months and/or anti-HCV at 18 months[16,31,34].

Impact of Perinatal HCV Transmission

Approximately 75% of children vertically infected with HCV will develop chronic hepatitis C—80% with asymptomatic, inactive infection and 20% with active infection indicated by persistent viremia, elevated ALT and hepatomegaly[28]. Chronically infected children should be referred for further evaluation and follow-up, as management of their disease is similar to that of adults. Published clinical studies of vertically infected, untreated children followed to 16 years of age have found very little morbidity associated with chronic infection. Nevertheless, given the decades of infection required to produce substantial complications in HCV infected adults, further long-term outcome studies of vertical infection are indicated[28]. The 2009 AASLD Guidelines recommend considering treatment of hepatitis C in children 2 years of age and older, but identifying those children most likely to benefit from early therapy remains challenging[17]. In addition, the FDA has not approved these medications for the treatment of children less than 3 years of age. The newer medications that have recently been approved for hepatitis C treatment in adults (protease inhibitors) have not been sufficiently studied in children to recommend their use in this age group. Because of these multiple complicating issues, consultation with an expert is advised before consideration of treatment of hepatitis C in children.

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    Figure 1. Potential Maternal and Infant Characteristics Associated with Risk of HCV Transmission

    This figure represents an adjusted multivariate analysis of potential risk factors associated with vertical transmission of HCV. These data are from an analysis of 1220 children born to HCV-infected mothers (65 children perinatally infected with HCV and 1155 who were not infected). The odds ratios listed represent the relative risk of HCV vertical transmission based on the following comparisons: HIV-infected mothers compared with mothers who were HIV-uninfected (p=0.08), elective cesarean section (CS) compared with vaginal delivery or emergency CS (p=0.16), female baby compared with male baby (p=0.006), prematurity compared with birth at term (p=0.07), and breast fed compared with formula fed (p=0.68).

    Data from 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.

    Figure 1
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    Figure 2. Anti-HCV in 18 Months of Life in Infants Born to HCV-Infected Mothers: Clearance of Maternal Antibody in Children not Infected with HCV

    In this study, anti-HCV was measured at different time points during the first 18 months of life in 188 babies born to mothers who were anti-HCV positive. This graph shows data that includes babies born to HCV RNA-positive and HCV RNA-negative mothers. The bars in the figure represent the percentage of babies with positive anti-HCV. Note: These data may not be representative of general population of HCV-infected mothers since 21% of mothers in this study were co-infected with HIV and only 39% of the mothers were HCV RNA positive.

    Data from Ferrero S, Lungaro P, Bruzzone BM, Gotta C, Bentivoglio G, Ragni N. Prospective study of mother-to-infant transmission of hepatitis C virus: a 10-year survey (1990-2000). Acta Obstet Gynecol Scand. 2003;82:229-34.

    Figure 2