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Treatment of Key Populations and Unique Situations

Perinatal HCV Transmission

Lesson 8. Perinatal HCV Transmission

CME/CNE Earn CE credit for this module  PDF Share

Learning Objective Performance Indicators

  • Describe the current guidelines for HCV screening in pregnant women
  • Identify the risk of mother-to-child transmission of HCV and factors associated with increased risk of transmission
  • Summarize the impact of HCV on pregnancy outcomes
  • Describe interventions or prophylactic measures to reduce the risk of mother-to-child transmission of HCV
Last Updated: February 10th, 2021
Author:
Maria A. Corcorran, MD
Maria A. Corcorran, MD
Acting Instructor
Division of Infectious Diseases
University of Washington
Reviewer:
David H. Spach, MD
David H. Spach, MD
Professor of Medicine
Division of Infectious Diseases
University of Washington
Disclosures: None
Table of Contents

Background

The incidence of hepatitis C virus (HCV) is increasing in the United States, particularly among young men and women (Figure 1), including women of reproductive age (Figure 2).[1] In 2015, an estimated 0.38% of live births were delivered by mothers with HCV, with the highest HCV infection rate among mothers 20 through 29 years of age (Figure 3) and in American Indian and White women (Figure 4).[2] The five states with the highest HCV infection rates among pregnant women—West Virginia, Kentucky, Vermont, Montana, and Tennessee—include three states from the South (Figure 5).[2] In addition, more than 40% of the live births among women with HCV in the United States in 2015 occurred among women living in the South (Figure 6).[2] During the years 2011 through 2014, an estimated 29,000 women with HCV infection gave birth each year in the United States, with an estimated 6% of these births resulting in HCV transmission.[3] Thus, during these years approximately 1,700 new perinatal HCV infections occurred annually.[2,3] Despite the significant number of perinatal HCV transmissions that occur in the United States, screening for HCV during pregnancy has historically been inconsistent and use of HCV risk-based screening has been shown to underestimate the true prevalence of HCV among pregnant women.[4,5]

HCV Screening During Pregnancy

Recommendations for HCV Screening During Pregnancy

In the setting of increasing HCV prevalence among women of reproductive age and emerging data supporting the cost-effectiveness of universal screening for HCV during pregnancy, routine HCV screening is now recommended by multiple agencies for all pregnant women in the United States, as outlined below.[6,7]

  • Centers for Disease Control and Prevention (CDC): Routine HCV screening is recommended for all pregnant women during each pregnancy, except for in settings where the prevalence of HCV RNA positivity is less than 0.1% (a condition not currently met by any state in the United States).[6,8,9]
  • United States Preventive Services Task Force (USPSTF): The USPSTF recommends screening for HCV in adults aged 18 to 79 years, including pregnant persons.[10]
  • American Association for the Study of the Liver Diseases/Infectious Diseases Society of America (AASLD/IDSA): As part of prenatal care, all pregnant women should be tested for HCV infection with each pregnancy, ideally at the initial visit.[11]

Screening should be done through the serologic detection of antibodies to HCV (anti-HCV), followed by a nucleic acid amplification test (NAAT) for HCV RNA in patients with a positive anti-HCV screen.[6] Although an optimal time for HCV screening during pregnancy has not been identified, screening is often done at an early prenatal visit along with screening for other infectious diseases, such as HIV and hepatitis B virus (HBV). If a pregnant woman screens negative for HCV early on in pregnancy but has ongoing risk factors for HCV, a follow-up test can be considered later in pregnancy.[6]

Factors Associated with HCV Perinatal Transmission

Perinatal, or mother-to-child, transmission of HCV is confined to women who have an active HCV infection, defined by detectable HCV RNA, during pregnancy.[12,13,14,15,16] Among HCV viremic women, perinatal transmission occurs in approximately 5 to 6% of pregnancies.[17,18,19,20] The mechanism and timing of perinatal transmission is poorly understood, but most infections are thought to be acquired in-utero or at the time of birth.[21,22,23] In a study involving 54 children enrolled in the European Paediatric Hepatitis C Network, investigators found that 31% of children were HCV RNA positive within 3 days of birth, suggesting evidence of intrauterine transmission, while 50% of infants were HCV RNA negative at 3 days and subsequently positive at 3 months, suggesting late intrauterine or intrapartum transmission.[23] As outlined below, multiple factors have been examined that potentially correlate with increased risk for perinatal HCV transmission among mothers with HCV RNA-positive infection during pregnancy.

  • Maternal HCV RNA Levels: In general, studies suggest that a higher maternal HCV viral load correlates with increased risk of perinatal transmission, but a precise viral threshold conferring increased risk of mother-to-child HCV transmission has not been identified.[14,24,25,26]
  • Coinfection with HIV: Several studies have shown that women with HCV viremia and coinfection with HIV have an increased risk of perinatal HCV transmission.[17,27,28,29] In a meta-analysis of 25 studies, the estimated rate of perinatal transmission was 5.8% among HCV viremic women without HIV coinfection and 10.8% among HCV viremic women with HIV coinfection.[17] The mechanism whereby HIV increases the risk of perinatal HCV transmission is not fully understood, but may relate to HIV-related increases in HCV RNA levels.[30]
  • Maternal Injection Drug Use: Several studies have shown that maternal injection drug use significantly increase the risk of perinatal HCV transmission.[16,31] The mechanism for this enhanced risk is not clearly known, but may result from the increased infection of peripheral blood mononuclear cells with HCV that occurs among persons who inject drugs, or superinfection with additional HCV variants during pregnancy.[31] 
  • Intrapartum Exchange of Fluids: Several factors have been identified that enhance the risk for perinatal HCV transmission at the time of delivery, including prolonged rupture of membranes (longer than 6 hours) and obstetric procedures (and intrapartum events) that result in infant exposure to maternal blood, such as internal fetal monitoring or vaginal/perineal lacerations.[25,32] In contrast, mother-to-child HCV transmission has not been associated with mode of delivery (e.g. vaginal vs. cesarean].[19,32] 
  • Breastfeeding: Although HCV RNA is detectable in colostrum, data from large cohorts of mothers with HCV infection and their exposed infants have demonstrated that breastfeeding does not increase the risk of HCV transmission from mothers to their babies, provided the mother’s nipples are not cracked or bleeding.[25,31,33] 

Impact of Chronic HCV Infection on Pregnancy

Impact of HCV on Pregnancy Outcomes

There are several studies linking maternal HCV infection with worse pregnancy outcomes, including higher rates of gestational diabetes, fetal death, preterm delivery, low birthweight, small for gestational age, antepartum and postpartum hemorrhage, and premature rupture of membranes.[26,34,35,36,37] Data clearly demonstrate that women with cirrhosis are at risk for worse maternal and neonatal outcomes.[38,39] In contrast, the association between HCV infection (without cirrhosis) and pregnancy outcomes is unclear due to common potential confounders, such as socioeconomic status and substance use.[38,39] Nonetheless, a meta-analysis of nine studies evaluating the association between maternal HCV and preterm birth found that preterm births were 62% more likely among mothers with HCV infection, an association that held true when stratified by maternal smoking, alcohol use, drug use, and coinfection with HBV and/or HIV.[35] Similarly, in a prospective observational study of 342 HCV antibody-positive pregnant women in Egypt, none of whom had a history of injection drug use, authors found that women with HCV had higher rates of antepartum hemorrhage, postpartum hemorrhage, anemia, gestational diabetes, premature rupture of membranes, and admission to an intensive care unit when compared to 170 control women.[37]

HCV and Intrahepatic Cholestasis of Pregnancy

There is strong evidence linking chronic HCV to increased rates of intrahepatic cholestasis of pregnancy. In a retrospective review of 91 pregnant women with HCV, investigators from Marshall University found that 45% (41 of 91) of women were diagnosed with intrahepatic cholestasis of pregnancy.[40] In this study, women with HCV and intrahepatic cholestasis of pregnancy had significantly higher median HCV RNA levels when compared to those without intrahepatic cholestasis of pregnancy (495,000 copies/mL versus 8,000 copies/mL).[40] Similar findings were shown in a systematic review and meta-analysis that included three studies: women with chronic HCV had 20-fold higher odds of developing intrahepatic cholestasis of pregnancy than women without HCV.[41] Given the significantly increased risk of intrahepatic cholestasis of pregnancy among women with HCV, clinicians caring for pregnant women with HCV infection should be aware of this association, since early recognition and appropriate therapy can improve fetal outcomes.

Effect of Pregnancy on Chronic HCV

Although conflicting reports exist on the effect of pregnancy on liver disease in women with chronic HCV, it is generally believed that pregnancy has minimal impact on HCV-related progression of fibrosis.[42,43] Nevertheless, HCV has been associated with elevated alanine aminotransferase levels (ALT) levels in pregnancy, with one Italian cohort of 370 anti HCV-positive pregnant women reporting 56.4% of study participants experienced elevated ALT levels in the first month of pregnancy, 7.4% in the last trimester, and 54.5% in the postpartum period.[44] Other studies have suggested a decline in HCV RNA postpartum, with an estimated 10% of women experiencing spontaneous clearance of HCV after childbirth.[45,46,47] Because of these findings, pregnant HCV RNA-positive women should have HCV RNA testing performed 9 to 12 months after giving birth to assess for possible spontaneous HCV clearance.

Interventions to Prevent Mother-to-Child Transmission of HCV

There are no interventions or prophylactic measures that have been proven to prevent perinatal transmission of HCV. The following summarizes key recommendations to prevent HCV perinatal transmission.

  • Direct-Acting Antiviral (DAA) Therapy: The use of DAA therapy has been insufficiently studied during pregnancy, and there are no large-scale clinical trials on their safety and efficacy in pregnancy or in breastfeeding women.[48,49] In a phase 1 trial, 8 women with HCV received ledipasvir-sofosbuvir during pregnancy and the treatment was effective and safe.[50] Due to inadequate data, there are no recommendations to use DAAs during pregnancy. Instead, the AASLD-IDSA HCV Guidance recommends treating women of reproductive age before considering pregnancy, if practical and feasible, to reduce the risk of mother-to-child transmission of HCV.[48]
  • Invasive Monitoring During Gestation: If invasive monitoring is needed during pregnancy, the Society for Maternal-Fetal Medicine recommends amniocentesis, with avoidance of placental contact, over chorionic villus sampling, as amniocentesis has not been linked with increased rates of mother-to-child transmission of HCV.[26,48]
  • Intrapartum Procedures and Monitoring: Prolonged rupture of membranes (longer than 6 hours), obstetric procedures, and intrapartum events that lead to infant exposure to HCV-infected maternal blood, such as internal fetal monitoring or vaginal/perineal lacerations, should also be avoided to reduce the risk of perinatal transmission.[2,25,31,32]
  • Mode of Delivery: There are no data to suggest cesarean section reduces the risk of mother-to-child transmission of HCV compared with vaginal delivery, and as such, routine use of cesarean section to prevent perinatal HCV transmission is not recommended.[19,32]

Safety of HCV Treatment During Pregnancy and Breastfeeding

Direct-Acting Antiviral Agents

To date, there are limited data on the safety and efficacy for the use of DAAs during pregnancy and lactation. In animal studies, it appears that all commonly used DAA regimens cross the placenta and transfer into breast milk.[51] However, no adverse safety signals in animal studies have been identified, and available limited data of DAAs in humans during pregnancy suggest no increase in congenital abnormalities or complications.[26,50,51] In addition, a small phase 1 study evaluating ledipasvir-sofosbuvir in 8 pregnant women showed no safety concerns.[50] Despite these preliminary findings, further data on safety and efficacy of DAAs in pregnancy are needed.[48]

Ribavirin

Although infrequently used in the current DAA era, ribavirin is absolutely contraindicated during pregnancy due to known teratogenic effects. Women exposed to ribavirin and female partners of men taking ribavirin should delay pregnancy for at least 6 months following ribavirin exposure given the persistent risk of teratogenicity related to ribavirin.[48] Ribavirin has not been adequately studied in nursing mothers.

Monitoring of Pregnant Women with HCV

Monitoring During Pregnancy

Since routine anti-HCV screening is recommended during each pregnancy, some women will have an initial diagnosis of HCV while pregnant. For those women who newly screen anti-HCV positive, it is important to obtain a quantitative HCV RNA level (if not already done) and routine liver function tests to assess the risk of mother-to-child transmission and severity of liver disease.[48] The initial evaluation of women with HCV infection diagnosed during pregnancy is generally similar to the initial evaluation of nonpregnant persons diagnosed with HCV (see Module 2 Initial Evaluation of Persons with Chronic Hepatitis C). In addition, a pregnant woman with HCV should have fibrosis staging if not previously done (see Module 2 Evaluation and Staging Monitoring of Liver Fibrosis). Given the elevated risk of intrahepatic cholestasis of pregnancy, women with HCV infection who develop pruritus or jaundice during pregnancy should undergo subsequent assessment of liver function testing to evaluate for this pathologic process.[48]

Monitoring in the Postpartum Period

Although HCV RNA levels tend to rise during pregnancy, they can drop quite substantially in the postpartum period.[48,49] This fluctuation in HCV RNA levels during pregnancy likely reflect the relatively immunosuppressed state of pregnancy, followed by immune reconstitution that occurs during the postpartum period.[26,49] The documented decline in HCV RNA levels in the postpartum period has also been associated with spontaneous clearance of HCV, and as such, HCV RNA-positive women should have repeat HCV RNA testing performed at 9 to 12 months postpartum to assess for the possibility of spontaneous clearance, which occurs in approximately 10% of postpartum women.[48]

Management of Neonates Born to Mothers with HCV Infection

All infants born to mothers with HCV should have follow-up HCV testing, but data from two large United States-based cohorts indicate that follow-up HCV testing for infants born to mothers with HCV often does not occur.[52,53] Early postnatal anti-HCV and HCV RNA testing are imperfect HCV diagnostic tests for infants born to mothers with HCV for several reasons: (1) passive transfer of anti-HCV to from mother to child can persist for up to 18 months (Figure 7), (2) transient infant viremia can occur in the first several months of life, and (3) children who perinatally acquire HCV can spontaneously clear the HCV infection.[54,55,56] As such, the AASLD-IDSA HCV Guidance and the CDC recommend antibody-based testing for HCV at 18 months of age for all children born to women with HCV.[6,57] Children who are anti-HCV positive at 18 months of age should undergo HCV RNA testing after age 3 to confirm chronic infection.[57] Although testing with HCV RNA can be considered during the first year of life (and as early as 2 months of age), there is considerable debate about the utility of HCV RNA testing early in life.[6,57] Although early HCV RNA testing can potentially identify infants with HCV earlier than antibody testing, the drawbacks are that HCV RNA testing is expensive, spontaneous clearance can occur, and there are no approved antiviral regimens to treat HCV in young children under the age of 3 years.[57]

Summary Points

  • The prevalence of chronic HCV is increasing among women of reproductive age.
  • Routine HCV screening is recommended for all pregnant women and during each pregnancy, regardless of risk factors.
  • Among HCV viremic women, perinatal transmission occurs in approximately 5 to 6% of pregnancies.
  • Increased risk of perinatal HCV transmission has been associated with higher maternal HCV viral loads, maternal injection drug use, HIV coinfection, prolonged rupture of membranes; and obstetric procedures and intrapartum events that lead to infant exposure to maternal blood, such as internal fetal monitoring or vaginal/perineal lacerations.
  • Mother-to-child transmission of HCV has not been associated with mode of delivery (e.g. vaginal vs. cesarean), and there is no indication to pursue elective cesarean section based solely on a woman’s HCV status.
  • Breastfeeding is safe for mothers with HCV infection as long as they do not have damaged, cracked, or bleeding nipples.
  • Several studies have linked maternal HCV infection with worse pregnancy outcomes, including higher rates of fetal death, preterm delivery, low birthweight, small for gestational age, antepartum and postpartum hemorrhage, gestational diabetes and premature rupture of membranes.
  • Studies have shown a decline in HCV RNA postpartum, with an estimated 10% of women experiencing spontaneous clearance of HCV after childbirth. Women should have HCV RNA testing performed at 9 to 12 months postpartum to assess for the possibility of spontaneous HCV clearance.
  • Direct-acting antiviral (DAA) therapy has been insufficiently studied during pregnancy, and there are no large-scale clinical trials on their safety and efficacy in pregnancy or in breastfeeding women. As such, DAAs are not currently recommended in pregnant women. Ribavirin is strongly contraindicated during pregnancy due to known teratogenic effects.
  • The initial evaluation of women diagnosed with HCV during pregnancy is generally similar that of nonpregnant persons diagnosed with HCV and should include an HCV RNA level and fibrosis staging.
  • All children born to women with HCV infection should have HCV antibody-based testing at 18 months of age. Children who are anti-HCV positive at 18 months of age should undergo HCV RNA testing after age 3 to confirm chronic infection.
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Citations

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Additional References

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Figures

Figure 1. Reported Rate of Cases of Acute Hepatitis C, United States, by Sex, 2003-2018
Source: Centers for Disease Control and Prevention (CDC). Viral Hepatitis Statistics and Surveillance—United States, 2018. Published July 2020.
Figure 2. Reported Rate of Cases of Acute Hepatitis C, United States, by Age Group, 2003-2018
Source: Centers for Disease Control and Prevention (CDC). Viral Hepatitis Statistics and Surveillance—United States, 2018. Published July 2020.
These data for HCV positive rates are from the Centers for Disease Control and Prevention’s (CDC’s) National Center for Health Statistics (NCHS) Birth Certificate Data in the United States in 2015.
Figure 3. HCV Infection Among Women with Live Births, United States, by Age Group, 2015
These data for HCV positive rates are from the Centers for Disease Control and Prevention’s (CDC’s) National Center for Health Statistics (NCHS) Birth Certificate Data in the United States in 2015.
Source: Schillie SF, Canary L, Koneru A, et al. Hepatitis C Virus in Women of Childbearing Age, Pregnant Women, and Children. Am J Prev Med. 2018;55:633-41.
Figure 4. HCV Infection Among Women with Live Births, United States, by Race/Ethnicity, 2015
Source: Schillie SF, Canary L, Koneru A, et al. Hepatitis C Virus in Women of Childbearing Age, Pregnant Women, and Children. Am J Prev Med. 2018;55:633-41.
Figure 5. HCV Infection Among Women with Live Births, United States, 10 States with Highest Rates, 2015
Source: Schillie SF, Canary L, Koneru A, et al. Hepatitis C Virus in Women of Childbearing Age, Pregnant Women, and Children. Am J Prev Med. 2018;55:633-41.
Figure 6. HCV Infection Among Women with Live Births, United States, by Geographic Region, 2015
Source: Schillie SF, Canary L, Koneru A, et al. Hepatitis C Virus in Women of Childbearing Age, Pregnant Women, and Children. Am J Prev Med. 2018;55:633-41.
Figure 7. Anti-HCV among Infants Born to Mothers with HCV Infection: Clearance of Maternal Antibody in Children not Infected with HCV
Source: 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.
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