Vertical transmission of hepatitis C virus

INTRODUCTION — Worldwide, hepatitis B and C are the most common causes of chronic viral hepatitis in children and adults [1]. In industrialized nations, because of vaccination programs against hepatitis B, hepatitis C virus (HCV) has become the primary cause of chronic viral hepatitis in children [2], with vertical transmission becoming the leading source of infection [3-5]. Vertical transmission refers to viral transmission from the mother to the infant during pregnancy, at the time of delivery, or during the first 28 days after birth.

The issues surrounding vertical transmission of HCV are reviewed here. Discussion of the effects of pregnancy on HCV infection and HCV infection in children are discussed elsewhere. (See "Pregnancy in women with pre-existing chronic liver disease", section on 'Chronic hepatitis C virus' and "Hepatitis C virus infection in children".)

TIMING OF TRANSMISSION — The mechanisms underlying vertical transmission of HCV are poorly understood. Intrauterine transmission during pregnancy and infection at the time of delivery are both possible, although it appears that the majority of HCV-infected infants are infected perinatally (either late intrauterine or intrapartum).

The timing of transmission can be reflected by results of polymerase chain reaction (PCR) testing for HCV RNA, which may not be positive until several weeks following infection, when levels of viremia reach the detection threshold. In most infants, HCV RNA levels only become detectable several weeks after birth, suggesting perinatal infection [6-8]. However, detection of HCV RNA within a few days of delivery has also been described, suggesting that in utero infection earlier in pregnancy can also occur.

INCIDENCE — Vertical transmission of HCV has been documented in numerous studies, but estimates on the rate of transmission vary [9-23]. Some of the variability in estimates of may be the result of differences in study methodologies and maternal populations studied. Overall, it appears that the risk of vertical transmission is approximately five percent in viremic women, with higher rates in certain subgroups, namely women who are coinfected with HIV. (See 'HIV coinfection' below.).

One meta-analysis included 20 studies of pregnant women with chronic HCV infection (HCV antibody and RNA positive) that determined transmission by laboratory testing of the infant after at least 18 months of age [24]. The pooled transmission rate was 5.8 percent (95% CI 4.2-7.8) among women with HCV monoinfection and 10.8 percent (95% CI 7.6-15.2) among those with HCV/HIV coinfection. These results were generally consistent with a prior systematic review, in which the overall adjusted rate of vertical HCV transmission from anti-HCV antibody positive women was 1.7 percent, but 4.3 percent among HCV viremic women and up to 19.4 percent in HCV/HIV-coinfected women [25].

In the United States, given this risk of vertical transmission and the rising rates of HCV infection in women of childbearing age, the prevalence of HCV infection in children appears to be substantially underestimated. One study estimated that 29,000 women with HCV infection gave birth each year between 2011 and 2014 in the United States, which would translate to an estimated 1700 infants infected annually [26]. However, among children aged 2 to 13 years, only an average of 207 HCV infections were reported each year during that time period. Although advances in HCV treatment since the time of this study have the potential to reduce the burden of HCV infection among women of childbearing age, these data highlight the importance of identifying infected women and linking those with HCV infection to care. (See 'Screening and prevention' below and "Hepatitis C virus infection in children", section on 'Epidemiology'.)

ESTABLISHED RISK FACTORS FOR TRANSMISSION — Several risk factors have been associated with an increased risk of vertical transmission. The most consistent associations have been with maternal HCV viremia during pregnancy or at the time of delivery and with concomitant HIV infection [24,25]. However, other variables, such as maternal intravenous drug use and peripheral blood mononuclear cell infection, also appear to increase the risk of transmission.

HCV viremia — Vertical transmission is generally confined to women with detectable HCV RNA during pregnancy [10,18,19,22,27-34], though it has been reported in women without detectable HCV RNA [18,27,31]. This may have occurred because viremia can be intermittent, so a negative test earlier in pregnancy does not preclude viremia in the perinatal period. Mothers who have antibodies to HCV but are negative for HCV RNA virtually never transmit infection to their infants.

Most evidence supports an increased risk of transmission with higher HCV viral loads [10,22,33-39]:

●In a meta-analysis of 10 observational studies that included over 1300 newborns of mothers with HCV infection, the pooled transmission rate among mothers with a viral level ≥1 x 10⁶ copies/mL was 9.6 percent, compared with 2.2 percent among mothers with a viral level <1 x 10⁶ copies/mL) [34].

However, not all have found an association between the maternal viral load and vertical transmission [19-21,40]. As an example, in a study of 403 infants born to women with HCV, 13 infants (3 percent) acquired HCV [19]. The HCV RNA levels did not differ significantly between the women who transmitted the infection and those who did not (4 x 10⁵ versus 2 x 10⁵ copies/mL).

HIV coinfection — Coinfection with HIV has been associated with a significantly increased risk of vertical transmission of HCV in numerous reports [6,11,18,21,24,37,41,42]. A systematic review that included 20 studies estimated that in women who had HIV coinfection, the risk of vertical transmission was increased approximately twofold compared with women who did not have HIV infection (10.8 versus 5.8 percent) [24].

The increased rate of vertical transmission in mothers with HIV coinfection may in part be explained by higher HCV RNA levels resulting from HIV-mediated immunosuppression [11,43]. For example, in one study, the average HCV RNA titers were approximately 10 times higher in women with HCV and HIV coinfection compared with women with HCV infection alone (7.8 x 10⁶ versus 9 x 10⁵ copies/mL) [11].

The importance of HIV-mediated immunosuppression was suggested in a series of 155 children born to HCV RNA-positive mothers who were followed for at least 12 months [40]. Although 15 mothers had HIV coinfection, none transmitted HCV to their offspring. All of women with HIV coinfection were taking antiretroviral therapy, and their mean HCV RNA titer was similar to mothers without HIV coinfection. Thus, whether HIV is an independent risk factor for vertical transmission of HCV or whether HIV confers increased risk of vertical transmission simply because mothers with HIV coinfection have higher HCV titers is uncertain. (See "Antiretroviral selection and management in pregnant individuals with HIV in resource-rich settings".)

Interestingly, infants of mothers with coinfection who acquire HIV infection have a greater risk of developing HCV infection compared with infants who do not acquire HIV infection (17 versus 5 percent in one series) [37]. Why this might occur is not clear.

Maternal intravenous drug use — Women with a history of intravenous drug use have higher transmission rates of HCV to their infants than women without such a history [15,16,18,44-47]. In a study of 1372 HCV-positive women, a history of intravenous drug use was a significant predictor of HCV transmission to the infant (adjusted odds ratio 1.5; 95% confidence interval 1.2-1.9) [47]. The higher transmission rate may be related to an increased frequency of peripheral blood mononuclear cell infection in women with a history of intravenous drug use [44,48]. (See 'Peripheral blood mononuclear cell infection' below.)

Peripheral blood mononuclear cell infection — Peripheral blood mononuclear cell (PBMC) infection is another factor associated with an increased risk of vertical transmission of HCV [44,49]. In a study of 48 mothers with HCV who transmitted the virus to their infants and 122 mothers with HCV who did not transmit the virus, PBMC infection was significantly more likely in mothers who transmitted the virus compared with mothers who did not (100 versus 54 percent). It has been hypothesized that PBMC infection may increase the risk of HCV transmission by serving as a vector for the HCV or because the viral variant of HCV that infects PBMCs is able to interact with and overcome the immune cells of the placenta [44].

POSSIBLE RISK FACTORS FOR TRANSMISSION — In addition to the established risk factors described above, other risk factors that are not as clearly established but that may increase the risk of vertical transmission of HCV included prolonged rupture of membranes and the performance of obstetric procedures.

Invasive prenatal testing — Invasive prenatal testing could theoretically increase the risk of transmission by increasing fetal exposure to maternal blood, although limited data have not suggested a clear risk with amniocentesis [50]. There are no data on the risk with chorionic villous sampling. In cases when invasive prenatal testing is indicated, amniocentesis is suggested over chorionic villus sampling [51]. (See "Diagnostic amniocentesis", section on 'Vertical transmission'.)

Prolonged rupture of membranes — Avoiding prolonged rupture of membranes in HCV-infected women is recommended [51]. Rupture of membranes for six or more hours prior to delivery has been identified as a risk factor for transmission in several studies [31,36,52,53], though not all studies confirm the association [54]. In a study of 244 infants born to HCV-positive women, prolonged rupture of membranes was significantly associated with an increased risk of HCV transmission (adjusted odds ratio 9.3; 95% confidence interval 1.5-180) [36].

Obstetric procedures — Invasive obstetric procedures, such as scalp electrode monitoring of the fetus during delivery, may increase the risk of HCV transmission by exposing the fetus to maternal blood. Obstetric management should minimize the duration of fetal exposure to maternal fluids and blood, and avoiding such invasive procedures is advised, although there are no data to demonstrate that doing so reduces transmission [51,55]. The possible risks of interventions during management of labor should be weighed against the obstetrical indications and benefits. (See "Intrapartum fetal heart rate monitoring: Overview".)

Data on the risk of such procedures are mixed. In a prospective study of 244 infants born to HCV-infected mothers, internal fetal monitoring was associated with an increased risk of transmission (odds ratio 6.7; 95% confidence interval 1.1-36) [36]. Fetal scalp monitoring was independently associated with HCV transmission in one [56] but not another retrospective study [42].

FACTORS NOT ASSOCIATED WITH TRANSMISSION

HCV genotype — HCV genotype does not appear to be associated with vertical transmission. One series included 63 pregnant women with detectable HCV RNA, 20 of whom (32 percent) were coinfected with HIV [16]. Genotype 1 was most common (59 percent), followed by genotypes 2 (20.5 percent), 3 (19 percent), and 4 (1.5 percent). There was no difference in transmission rates between the mother who transmitted the virus and those who did not with regard to HCV genotype. Similar results were seen in a second study with 113 women, in whom the HIV infection rate was lower (12 percent) [29]. Among the 69 women with detectable HCV RNA, HCV genotype was not associated with perinatal HCV transmission.

Mode of delivery — The mode of delivery does not appear to be associated with the risk of vertical transmission of HCV [53]. Theoretically, the mode of delivery may be important because exposure to HCV-infected blood as the infant passes through the birth canal could lead to HCV transmission. However, exposure to maternal blood can also occur with cesarean delivery. Currently, pregnant women infected with HCV are not advised to have cesarean delivery, unless indicated for other reasons [57]. (See "Cesarean birth: Preoperative planning and patient preparation", section on 'Indications'.)

Among women who are not infected with HIV, the mode of delivery does not appear to influence transmission rates. In a meta-analysis that included eight studies with 641 mother-infant pairs, there was no significant difference in HCV transmission among HIV-negative women who had a cesarean delivery and those who had a vaginal delivery [58].

However, among HIV-positive women, some older studies suggest cesarean delivery may decrease the risk of HCV transmission. In study of 1419 women with HCV, 503 (35 percent) were coinfected with HIV [42]. HCV infection was seen in 70 of the infants born to HIV-positive women (14 percent) and in 60 of the infants born to HIV-negative women (7 percent). Among the women with HIV for whom delivery information was available, 159 (33 percent) had a cesarean delivery and 329 (67 percent) had a vaginal delivery. On multivariable analysis, HCV transmission was significantly less likely to occur with cesarean delivery (odds ratio 0.4).

However, with widespread use of antiretroviral therapy for HIV, the benefit of cesarean delivery may no longer exist. In a subsequent study with 1479 mother-infant pairs, there was no benefit from cesarean delivery for women coinfected with HCV and HIV [31]. In that study, 83 percent of women who were coinfected with HIV received antiretroviral treatment for their HIV. Thus, recommendations regarding the mode of delivery in women who are coinfected with HIV depend upon the status of the patient's HIV infection at the time of delivery. (See "Prenatal evaluation of women with HIV in resource-rich settings", section on 'Viral load measurement'.)

Breastfeeding — The available evidence suggests that breastfeeding by an HCV-infected mother does not appreciably increase the risk of transmitting HCV to her offspring. Multiple expert groups all support breastfeeding by HCV-infected mothers, although they suggest that women abstain from breastfeeding if their nipples are cracked or bleeding [51,55,59-61]. The situation is more complex in women who are coinfected with HIV and HCV, in whom the risk of HIV transmission also is an issue. (See "Prevention of HIV transmission during breastfeeding in resource-limited settings".)

HCV RNA is detectable in maternal colostrum [62]. However, acquisition of HCV via breastfeeding has not been documented. In one study, for example, none of the 76 samples of breast milk from 73 HCV antibody-positive (60 percent HCV RNA positive) mothers contained HCV RNA [63]. Only one of the 76 breast-fed infants had evidence of HCV infection by PCR; this infant's HCV infection was detected one month after birth, indicating that transmission via breast milk was unlikely. (See 'Timing of transmission' above.)

Other studies evaluating the effect of breastfeeding on HCV transmission concur with these findings [53]; either similar rates of infection are observed in breast-fed and bottle-fed groups, or no viral transmission was documented [19,64,65]. Breast milk itself may inhibit HCV infectivity. This was suggested by an in vitro study in which incubation in pre-frozen breast milk from uninfected donors, but not infant formula or milk from other species, reduced the infectivity of an experimental virus in a cell culture system, possibly through disruption of the viral envelope [66]. Other potential explanations as to why breast milk containing HCV RNA does not infect infants include inactivation of the virus by the acidity of the stomach and very low levels of HCV RNA in breast milk.

IL28B genotype — IL28B genotype is an important predictor of clearance versus persistence of HCV infection. However, it does not appear to be associated with the risk of vertical transmission [38]. (See "Clinical manifestations and natural history of chronic hepatitis C virus infection".)

SCREENING AND PREVENTION — The main strategy for reducing the risk of vertical HCV transmission is identifying and treating individuals with HCV infection prior to conception [55,67].

We agree with recommendations from the United States Centers for Disease Control and Prevention (CDC) to screening all pregnant women for HCV infection during each pregnancy [68].

Improved identification of HCV infection during pregnancy can improve risk stratification to inform intrapartum management; for example, it is prudent to avoid prolonged rupture of membranes and invasive obstetric procedures in the setting of HCV because of the possible risk of transmission (see 'Possible risk factors for transmission' above).

Additionally, identifying pregnant individuals with HCV infection can facilitate appropriate follow-up for at-risk infants. Issues related to HCV screening are discussed further separately. (See "Screening and diagnosis of chronic hepatitis C virus infection" and "Prenatal care: Initial assessment", section on 'Hepatitis C'.)

EVALUATION AND MANAGEMENT OF HCV IN PREGNANCY — Evaluation of pregnant individuals with HCV is generally similar to that for HCV in general, and includes assessment of the HCV RNA level and the stage of liver disease. Antiviral therapy during pregnancy is not an option since the safety and efficacy of direct-acting antiviral agents in pregnancy have not been evaluated (and they should thus not be used in pregnant patients). Further studies are needed to assess these issues and inform the potential role of these antiviral agents to treat maternal HCV infection and prevent transmission to the infant.

As discussed above, procedures that are potential transmission risks should be minimized, if possible. (See 'Possible risk factors for transmission' above.)

HCV monoinfection does not impact delivery route. Postpartum, women with HCV infection (without HIV infection) can breastfeed, but should abstain from breastfeeding when their nipples are cracked or bleeding. (See 'Factors not associated with transmission' above.)

The treatment of HCV in nonpregnant adults is discussed in detail elsewhere. Of note, females who were treated with a ribavirin-containing regimen should avoid pregnancy for at least nine months afterwards. (See "Screening and diagnosis of chronic hepatitis C virus infection" and "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults" and "Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults".)

HCV IN INFANTS

Clinical manifestations — Newborn infants with HCV infection are usually asymptomatic, and a substantial proportion have normal or only mildly elevated serum alanine aminotransferase (ALT) concentrations [27,69,70]. In one study, for example, 104 infants with vertically acquired HCV infection were followed from birth for a mean of 49 months [27]. Although at least 90 percent of the infants had evidence of ongoing infection (based upon polymerase chain reaction [PCR] analysis for the detection of HCV RNA), clinical manifestations were rare. None of the infants had significant growth failure. Most had transient or persistent increases in serum ALT concentrations. The serum ALT usually was only mildly elevated or normal at birth, increasing at four to six months of age. Levels remained elevated for two years and declined substantially thereafter in most infants.

Twenty infants underwent liver biopsy. Although no single typical histologic feature was observed, all had histologic evidence of minimal to moderate chronic hepatitis, and three had some degree of fibrosis. Similar findings were reported in other studies [69-71]. Overall, the data suggest that vertically acquired HCV infection is usually asymptomatic during infancy but often is associated with elevation of ALT concentrations during the first 6 to 12 months of life.

Although progression to chronicity occurs in most infants with vertically acquired HCV, liver disease usually is mild throughout childhood. (See "Hepatitis C virus infection in children", section on 'Natural history'.)

One of the largest series with long-term follow-up of children with perinatally acquired HCV included 266 children who were followed for a median of 4.2 years [72]. Approximately 20 percent cleared the infection at a median age of 15 months, whereas 80 percent had chronic infection. Clearance was less likely in children who were persistently PCR positive during the first year of life and in those who remained PCR positive after the first year of life. Most children with chronic infection were asymptomatic.

Additional long-term follow-up studies are necessary to determine what proportion of infants with vertically acquired HCV will develop hepatic failure or hepatocellular carcinoma.

Diagnosis — Approach to diagnosis of HCV in infants is discussed in detail elsewhere. (See "Hepatitis C virus infection in children", section on 'How to test'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hepatitis C virus infection".)

SUMMARY AND RECOMMENDATIONS

●Incidence – Vertical transmission of hepatitis C virus (HCV) occurs exclusively among women with detectable HCV RNA in the blood. The transmission rate is approximately 5 percent among HCV-monoinfected women and approximately 10 percent among HCV/HIV-coinfected women. (See 'Incidence' above and 'HIV coinfection' above.)

●Risk factors – In addition to HIV coinfection, other risk factors for transmission include high HCV viral load, a history of intravenous drug use, and HCV infection of peripheral blood mononuclear cells. Prolonged rupture of membranes and the performance of obstetric procedures such as fetal scalp monitoring may also be associated with vertical transmission. When possible, obstetric procedures should be avoided in women with HCV. (See 'Established risk factors for transmission' above and 'Possible risk factors for transmission' above.)

●Factors not associated with vertical transmission – These include viral genotype, the mode of delivery (in women without HIV or in women with HIV who are taking antiretroviral therapy), and breastfeeding. Pregnant women with HCV are not advised to have cesarean delivery, unless indicated for other reasons. (See 'Factors not associated with transmission' above.)

●Screening and prevention – The main strategy for reducing the risk of vertical HCV transmission is identifying and treating HCV-infected women prior to conception. Screening is also suggested for all pregnant women during each pregnancy to help inform intrapartum care and identify infants who warrant follow-up. Issues related to HCV screening are discussed further separately. (See 'Screening and prevention' above and "Screening and diagnosis of chronic hepatitis C virus infection" and "Prenatal care: Initial assessment", section on 'Hepatitis C'.)

●No antiviral therapy during pregnancy – The safety and efficacy of direct-acting antiviral agents during pregnancy and in neonates have not yet been assessed, and these agents should not be used in such populations. The treatment of HCV in children is discussed in detail elsewhere. (See "Hepatitis C virus infection in children", section on 'Management of chronic hepatitis C virus'.)

●HCV in infants – Infants who acquire HCV perinatally are typically asymptomatic, although an elevated alanine aminotransferase level is common. Diagnosis of HCV in infants is discussed in detail elsewhere. (See 'Clinical manifestations' above and "Hepatitis C virus infection in children", section on 'How to test'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Sanjiv Chopra, MD, MACP, who contributed to an earlier version of this topic review.