Hepatitis C Virus in Pregnancy: Are We Ready for Test and Treat?

One of the most significant consequences of the opioid epidemic is the increased prevalence of hepatitis C virus (HCV) among pregnant women, which carries the risk of perinatal transmission. This increased prevalence of HCV in pregnant women and children, along with the recent advent of direct-acting antivirals (DAAs), calls for the reevaluation of HCV management during pregnancy. In this article, we describe current HCV epidemiology, the most recent understanding of the interactions of HCV infection and pregnancy, and the current management of HCV in pregnant women and their children. We then share our perspective on the potential use of DAAs for pregnant women and children and on how HCV testing and treatment during pregnancy is critical to the mission of HCV eradication.

HCV IN WOMEN OF REPRODUCTIVE AGE AND CHILDREN IN THE UNITED STATES

The epidemiology of HCV has shifted over the last decade, driven by the well-publicized opioid epidemic in the United States. A new wave of HCV infections has occurred largely in young adults and teenagers, including women of childbearing age, and the prevalence now exceeds that among baby boomers. In 2017, authors from the Centers for Disease Control and Prevention (CDC) used data from a national referral laboratory to examine trends for HCV among women of childbearing age [1]. A significant increase in HCV detections from 2011 to 2014 was demonstrated.

Current estimates indicate that 29 000 HCV-infected women give birth to 1700 infected infants yearly, far exceeding prior projections. Overall, 1.34% of the women of childbearing age (aged 15–44 years) were HCV antibody positive, with marked geographic consistency (1.25% in the South, 1.36% in the Northeast, 1.37% in the West, and 1.63% in the Midwest), indicating that although there are areas of the country where the HCV prevalence is higher, the HCV epidemic is widespread nationally. The rate of HCV infection at the time of delivery has increased from 0.8 per 1000 live births in 2000 to 4.1 per 1000 live births in 2015 [2].

Vertical transmission is now the principal route of HCV acquisition among children, with a transmission rate of about 5% from mothers with HCV monoinfection. For this reason, all infants born to women with active HCV infection should be tested for HCV. For adults, HCV screening is conducted using HCV antibody testing. If an antibody test result is positive, then an HCV RNA test is performed, ideally reflexively from the same blood sample. The diagnosis of HCV in children is complicated by the passive placental transfer of maternal HCV immunoglobulin G antibodies to the infant. Owing to the presence of these antibodies, it is recommended that an HCV antibody test be performed at or after 18 months of age. However, the delay in testing for perinatal HCV transmission until age 18 months can result in missed opportunities.

Several studies in the United States have indicated that many HCV-exposed infants are not tested, and many cases of HCV infection in children are not detected [3–5]. Barriers to testing of infants who were perinatally exposed to HCV include lack of recognition of the risk because the exposure was not documented into the infant’s health record or the mother was not aware of her HCV status or suboptimal compliance with HCV testing because it requires venipuncture. Future efforts should focus on interventions to increase identification and testing of infants who have been exposed to HCV.

HCV INFECTION DURING PREGNANCY

The overall impact of HCV on pregnancy and the impact of pregnancy on the course of HCV are not completely clear owing to lack of data and well-controlled studies. Hepatocellular damage caused by chronic HCV infection is thought to be immune mediated, and pregnancy itself is associated with down-regulation of immune responses. In this state of relative immunosuppression, HCV replication increases and serum aminotransferase levels decrease [6], indicating an ameliorating effect of pregnancy on the course of HCV liver disease. In the postpartum period, however, as the immune system rebounds, there is a decrease in HCV viremia and an increase in serum aminotransferases. This immune rebound can cause a hepatitis flare, progression of liver fibrosis, or even spontaneous clearance of HCV. HCV can have untoward effects on pregnancy.

HCV has been associated with gestational diabetes in a handful of studies and intrahepatic cholestasis of pregnancy in many [7]. The mechanism for the association of HCV infection and intrahepatic cholestasis of pregnancy has not been elucidated; one hypothesis invokes down-regulation of the expression of multidrug resistance protein 2 or bile salt export pump transporter in the livers of infected women. Neonate complications include preterm delivery [8] intrauterine growth restriction [9], low birth weight, admission to the neonatal intensive care unit, and congenital anomalies. However, it is difficult to know with certainty whether the increased risk of such adverse fetal outcomes is due to the effect of HCV itself or to confounders such as alcohol, drug, or tobacco use in this population.

MOTHER-TO-CHILD TRANSMISSION

One of the most significant consequences of HCV infection in pregnancy is the risk of mother-to-child transmission (MTCT), which occurs in 5.8% (95% confidence interval, 4.2%–7.8%) of monoinfection cases and 10.8% (7.6%–15.2%) with maternal human immunodeficiency virus (HIV)–HCV coinfection [10]. There are limited data suggesting that the rate of perinatal transmission is increased with higher maternal HCV viral load, longer labor duration, use of amniocentesis or fetal scalp monitoring, and prolonged rupture of membranes [11]. It is thought that approximately two-thirds of MTCT cases occur during labor and delivery, and the other third antenatally [12]. Maternal factors associated with MTCT include HCV-HIV coinfection, history of intravenous drug use, and disease activity, as indicated by alanine aminotransferase values, in the year before pregnancy. Many of these risk factors could be related to HCV infection of the maternal peripheral blood mononuclear cells, but further study is warranted [13].

After vertical acquisition of HCV, the infection spontaneously clears in 25%–40% of infected children in the first 4 years of life [14], a rate slightly higher than that reported in adults. The spontaneous clearance rate of vertically acquired HCV infection may be affected by host factors, such as the IL28B gene and natural killer cell cytolytic function, as well as by viral characteristics, such as HCV genotype [15]. Chronic HCV infection is usually asymptomatic during childhood and tends to have a more indolent course than in adults. However, disease progression is well documented in children with longer follow-up and duration of infection, and progression is more likely 10 years after the onset of infection [16].

CURRENT MANAGEMENT OF HCV DURING PREGNANCY

The current antepartum management of pregnant women living with HCV does not differ substantially from that of pregnant women without HCV. It is recommended that women with HCV receive hepatitis A and B vaccination and abstain from alcohol and acetaminophen at doses of >2 g per day. Pregnant women with HCV are referred to hepatology or infectious diseases providers for postpartum treatment. Unfortunately, many women have difficulties being treated post partum. In a study of 369 pregnant women with HCV in Pittsburgh, Pennsylvania, 77% of the women were referred for treatment, but only 25% attended the visit and <2% were treated within 1 year post partum [17]. The postpartum period is a time of significant change and stress for new families and thus perhaps not the ideal time for HCV treatment.

Currently, there are no interventions available to reduce perinatal HCV transmission. A meta-analysis of 8 studies that included 641 mother-infant dyads to evaluate the impact of elective cesarean delivery failed to show an impact on transmissions rates [18]. Breastfeeding is not associated with increased rate of perinatal transmission; thus, women with HCV should breastfeed unless they have cracked or bleeding nipples [19]. Both the US Society for Maternal-Fetal Medicine and the American College of Obstetricians and Gynecologists recommend that obstetric care providers avoid internal fetal monitoring or prolonged rupture of membranes during labor or the use of operative delivery or episiotomy at delivery in women who are HCV positive to avoid contact between maternal HCV-infected blood and the neonate [20], even though there have been no studies to show efficacy of these practices. Furthermore, obstetric providers do not routinely use these interventions without clinical indication. Because most MTCT of HCV occurs either late in pregnancy or, most often, around the time of delivery, successful viral eradication during pregnancy would eliminate the majority of instances of perinatally acquired HCV.

POTENTIAL FOR TREATMENT IN PREGNANCY

DAAs for HCV are very safe and effective and have revolutionized the treatment of HCV, making the goal of eventual HCV eradication a reality. Pregnancy is a critical period of healthcare engagement, and HCV treatment would not only cure maternal HCV infection, but would also prevent most perinatal HCV transmission. The Department of Health and Human Services National Viral Action Plan 2017–2020 identified prevention of perinatal HCV transmission as a critical goal for the elimination of HCV. Women with HCV do not receive treatment during pregnancy owing to a lack of data regarding the safety and efficacy of highly effective DAAs in pregnancy. Thus, the fundamental first step toward the development of a clinical pathway for treating HCV during pregnancy is to establish safe and therapeutic drug exposures.

The first phase I clinical trial of HCV treatment during pregnancy with the DDA ledipasvir-sofosbuvir (LDV/SOF) has been conducted [21]., Nine women with HCV completed a 12-week course of LDV/SOF during pregnancy from 2017 to 2018, starting at 23–24 weeks of gestation. Because most organogenesis is complete by 16 weeks of gestation, this late second trimester start reduced the risk of teratogenicity. At 12 weeks after treatment, all of the participants were cured of HCV, and all infants are HCV negative to date. No significant pharmacokinetic changes were noted for LDV or SOF when they were administered during pregnancy. No maternal or neonatal safety concerns have been identified. Although these positive results suggest the need for a larger effectiveness trial of LDV/SOF during pregnancy, the combination is approved only for HCV genotypes 1, 4, 5, and 6, significantly limiting the ability of this regimen to provide treatment for all HCV-infected pregnant women. A similar and larger study of a pangenotypic regimen is needed.

TESTING ALL PREGNANT WOMEN FOR HCV—ARE WE THERE YET?

At present, there are conflicting recommendations regarding screening for HCV during pregnancy. The Society for Maternal Fetal Medicine [20] and American College of Obstetrics and Gynecology [22] recommend risk-based screening, whereas the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America recommend HCV screening of all pregnant women [23]. Recently, the CDC made a similar recommendation [24]. The American College of Obstetrics and Gynecology practice bulletin recommendation for risk-based screening [25] is based on the following reasoning: “Currently, no preventive measures are available to lower the risk of vertical HCV infection of neonates as there are for HBV (hepatitis B virus).” On the other hand, the rationale for universal screening has included the increased prevalence of HCV among pregnant women [26], the poor identification of risk factors in obstetrical practices to support risk-based screening, and the low compliance rate typically seen with this type of program [27]. If HCV-infected pregnant women are not identified, obstetrical practices recommended by Society for Maternal Fetal Medicine [20] cannot be instituted, women will not receive linkage to HCV treatment and care, and their infants will not be tested for perinatal transmission.

Universal HCV screening in pregnancy would be easy to implement because this practice is already in place for HIV and hepatitis B virus. Pregnancy is a time of increased healthcare engagement and an opportunity for HCV screening among women of reproductive age who might have difficulty accessing healthcare. Furthermore, several studies have shown that universal HCV screening is both efficient [27, 28] and cost-effective [29, 30]. The case for universal screening was summarized in a 2018 commentary [26] that also addressed reasonable concerns from the obstetrics community, such as the lack of clearly proven interventions, lack of approved treatment during pregnancy, and cost. Interventions such as avoidance of fetal scalp monitoring and amniocentesis can be used only when HCV infection is known to the obstetrician. Recently, the US Preventive Services Task Force has published a recommendation for universal HCV screening for all adults, including screening during prenatal care [31], and the CDC has made the same recommendation [24]. These recommendations indicate that universal HCV screening with HCV antibody and reflex HCV RNA testing could become standard practice in the United States shortly.

The increase in injection drug use due to the opioid epidemic has significantly changed the epidemiology of the HCV epidemic. The incidence of new HCV infections in young persons is increasing, and many infected individuals are women of childbearing potential. Although the effects of HCV on pregnancy outcomes and those of pregnancy on HCV infections are modest, recognition of the characteristics and management of this unique population is critical to linkage to care, the care cascade, and prevention of MTCT [32]. Many young persons with HCV live in rural areas and do not utilize routine medical care. Therefore, to engage this population, we must find windows of opportunity for HCV screening and treatment.

Pregnancy is one of those windows, where healthcare engagement as well as adherence is high and therefore is an ideal time to screen and treat for HCV. With the new guidance from the US Preventive Services Task Force and the CDC recommending universal HCV screening in pregnancy, it is anticipated that HCV testing during pregnancy will become routine within this year. HCV treatment during pregnancy is still a few years away, but it is coming, and with it the potential to eradicate most MTCT of HCV and thus most new childhood cases of HCV.

Text Box Summary

Hepatitis C virus (HCV) infection is increasing among young persons, including pregnant women. Pregnancy is a period of increased healthcare use and therefore an ideal time for HCV screening and treatment. All pregnant women should be screened for HCV, not only to facilitate treatment and improve maternal health, but also to identify infants who have been exposed to HCV during pregnancy and need to be screened for vertical HCV acquisition. DAAs have the potential for use during pregnancy for HCV treatment and prevention of perinatal transmission, but studies must be conducted to demonstrate that these medications are safe in pregnancy.

Note

Supplement sponsorship. This supplement is sponsored by educational grants from Gilead Sciences Inc. and Abbott Laboratories.

Potential conflicts of interest. Both authors: No reported. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.