SMFM Consult Series #56: Hepatitis C in pregnancy: updated guidelines

Introduction

In the United States, the estimated prevalence of antenatal hepatitis C virus (HCV) infection is 1% to 4% in single-center studies.¹ A national multicenter prospective cohort study estimated an HCV antibody seroprevalence of 0.24% among an obstetric population screened between 2012 and 2015.²

The primary mode of HCV transmission is percutaneous exposure to blood from injection of illicit drugs. Other modes of transmission include sharing of contaminated devices for noninjection drug use, exposure to infected blood, and sexual intercourse.^3,4 Vertical transmission is the leading cause of HCV infection in children.⁵

HCV can cause both acute and chronic hepatitis. The first 6 months after exposure to HCV constitute the acute stage of infection 6.

For the 25% of cases that are symptopatic, symptoms include abdominal pain, nausea, anorexia, jaundice, and malaise.⁷ Those who do not clear the virus and do not receive treatment will develop chronic HCV infection.⁸

As with the acute stage of infection, chronic HCV infection is usually asymptomatic. Chronic infection accounts for most HCV-associated morbidity and mortality.

HCV infection is associated with higher rates of gestational diabetes, preterm birth, and low birth weight.^9-13 However, these associations are often complicated by confounding factors such as maternal age, race, substance use, and prenatal care usage.^14,15

Antenatal testing is not indicated in the setting of HCV diagnosis alone (grade 2C).

Intrahepatic cholestasis of pregnancy (ICP) is more prevalent in patients with chronic HCV infection than in uninfected patients.^16,17

We suggest screening for viral hepatitis in patients with a diagnosis of ICP at an early gestational age or with significant elevations of bile acids (grade 2C).

We empirically suggest that this screening be performed if the diagnosis of ICP is made at less than 24 weeks of gestation or if bile acids are greater than or equal to 100 µmol/L.

Screening

Screening recommendations are changing to be more inclusive because of an increase in the prevalence of HCV infection among women of reproductive age and emerging data suggesting that the majority of neonates are not identified with the current risk-based screening strategies.^18-20

A recent cost-analysis model demonstrated that universal prenatal HCV screening improved health outcomes of people with HCV infection and identification of neonates with infection and was cost-effective, even in areas with very low prevalence.²¹

The Centers for Disease Control and Prevention (CDC) now recommends universal screening for HCV during pregnancy.²² The United States Preventive Services Task Force (USPSTF) also recommends screening in all individuals ages 18 to 79 and specifically notes that pregnant women should be screened but does not recommend a frequency.²³

Early identification of HCV-positive patients during pregnancy can potentially facilitate more efficient linkage to care and treatment in the postpartum period because none of the antiviral therapies recommended for HCV infection are approved for use during pregnancy.

We recommend that obstetric providers screen all pregnant patients for HCV by testing for anti-HCV antibodies in every pregnancy (grade 1B).

Screening in the first trimester would theoretically identify the most patients at the earliest opportunity.

Diagnosis of HCV infection depends on the detection of anti-HCV antibodies and HCV RNA. Anti-HCV antibodies usually develop 2 to 6 months after exposure, during the acute phase of infection, and persist throughout life.²⁴

HCV viremia or the presence of HCV RNA indicates active infection and can be detected 1 to 3 weeks after exposure.^25,26

Treatment and outcomes

Considering common risk factors, we suggest that obstetric care providers screen HCV-positive pregnant patients for other sexually transmitted infections (if not done previously), including HIV, syphilis, gonorrhea, chlamydia, and hepatitis B virus (HBV) (grade 2C).

Pregnant patients with HCV should be screened for immunity to hepatitis A virus (HAV). We recommend vaccination against HAV and HBV (if not immune) for patients with HCV (grade 1B).

Among nonpregnant women, direct-acting antiviral (DAA) regimens are first-line treatments.³ Currently, none of the antiviral therapies recommended for HCV infection are approved for use during pregnancy.²⁷

Until more data exist, if a patient becomes pregnant while taking one of the DAA therapies, animal data do not suggest teratogenic risk but patients should be counseled that human data are lacking.^28,29In these scenarios, shared decision-making regarding risks and benefits of cessation versus continuation should occur.

We recommend that DAA regimens should be initiated only in the setting of a clinical trial during pregnancy and that individuals who become pregnant while taking a DAA should be counseled in a shared decision-making framework about the risks and benefits of continuation (grade 1C).

Referral to a hepatologist or infectious disease specialist during pregnancy for patients with HCV may be considered to expedite therapy following pregnancy.

Methods to reduce vertical transmission

Amniocentesis does not appear to increase the risk of vertical transmission, although this conclusion is based on small sample sizes and limited data that have not addressed the potential impact of viral load.³⁰

No studies have been published on the risk of vertical transmission of HCV with other prenatal testing modalities, including chorionic villus sampling.

We suggest that if prenatal diagnostic testing is requested, patients be counseled that data regarding the risk of vertical transmission are reassuring but limited (grade 2C).

When the need or desire for diagnostic testing arises in patients with HCV, shared decision-making regarding the limited data should occur.

Vaginal delivery has not been shown to be a risk factor for vertical transmission of HCV.^31,32 Because all published studies on the mode of delivery and the risk of vertical transmission of HCV are observational, and most did not assess viral load at the time of delivery, these results should be interpreted cautiously.³³

We recommend against cesarean delivery solely for the indication of HCV (grade 1B).

Several factors in labor management may be associated with an increased risk of vertical transmission of HCV, namely prolonged rupture of membranes, internal fetal monitoring, and episiotomy.^34-37

We suggest that obstetric care providers avoid internal fetal monitors and early artificial rupture of membranes when managing labor in patients with HCV, unless necessary in the course of management (ie, when unable to trace the fetal heart rate with external monitors and the alternative is proceeding with cesarean delivery) (grade 2B).

Expectant management of ruptured membranes should be avoided at term. Usual obstetric management for preterm premature rupture of the membranes should not be altered because of maternal HCV infection.

It is unclear whether a patient with a positive HCV antibody and a negative viral load should be managed in labor in the same fashion as one with a detectable viral load.

We suggest that if the confirmatory HCV antibody test result were negative that the result be considered a false-positive; thus, the additional precautions suggested above are likely unnecessary.

However, if the confirmatory test result is positive or if the test was not performed, then until further data are available, it may be safest in labor to follow the same suggestions as in a patient with a positive viral load because of the theoretical possibility of intermittent viral shedding.

Postnatal care related to HCV

Breastfeeding does not appear to affect the risk of vertical transmission of HCV.³¹ We recommend that HCV status not alter standard breastfeeding counseling and recommendations unless nipples are cracked or bleeding (grade 1A). In patients with cracked or bleeding nipples, breast milk should be expressed and discarded.

References

1. Prasad MR, Honegger JR. Hepatitis C virus in pregnancy. Am J Perinatol. 2013;30(2):149-159. doi:10.1055/s-0033-1334459

2. Prasad M, Saade GR, Sandoval G, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network. Hepatitis C virus antibody screening in a cohort of pregnant women: identifying seroprevalence and risk factors. Obstet Gynecol. 2020;135(4):778-788. doi:10.1097/AOG.0000000000003754

3. HCV guidance: recommendations for testing, managing, and treating hepatitis C. American Association for the Study of Liver Diseases; Infectious Diseases Society of America. Accessed January 10, 2021. https://www.hcvguidelines.org/

4. T ohme RA, Holmberg SD. Is sexual contact a major mode of hepatitis C virus transmission? Hepatology. 2010;52(4):1497-1505. doi:10.1002/hep.23808

5. Jhaveri R, Swamy GK. Hepatitis C virus in pregnancy and early childhood: current understanding and knowledge deficits. J Pediatric Infect Dis Soc. 2014;3 Suppl 1(Suppl 1):S13-S18. doi:10.1093/jpids/piu045

6. 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(2):F156-F160. doi:10.1136/adc.2004.059436

7. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 86: Viral hepatitis in pregnancy. Obstet Gynecol. 2007;110(4):941-956. doi:10.1097/01.AOG.0000263930.28382.2a

8. Conte D, Fraquelli M, Prati D, Colucci A, Minola E. Prevalence and clinical course of chronic hepatitis C virus (HCV) infection and rate of HCV vertical transmission in a cohort of 15,250 pregnant women. Hepatology. 2000;31(3):751-755. doi:10.1002/hep.510310328

9. Gervais A, Bacq Y, Bernuau J, et al. Decrease in serum ALT and increase in serum HCV RNA during pregnancy in women with chronic hepatitis C. J Hepatol. 2000;32(2):293-299. doi:10.1016/s0168-8278(00)80075-6

10. Money D, Boucoiran I, Wagner E, et al. Obstetrical and neonatal outcomes among women infected with hepatitis C and their infants. J Obstet Gynaecol Can. 2014;36(9):785-794. doi:10.1016/S1701-2163(15)30480-1

11. Paternoster DM, Santarossa C, Grella P, et al. Viral load in HCV RNA-positive pregnant women. Am J Gastroenterol. 2001;96(9):2751-2754. doi:10.1111/j.1572-0241.2001.04135.x

12. Di Martino V, Lebray P, Myers RP, et al. Progression of liver fibrosis in women infected with hepatitis C: long-term benefit of estrogen exposure. Hepatology. 2004;40(6):1426-1433. doi:10.1002/hep.20463

13. Fontaine H, Nalpas B, Carnot F, Bréchot C, Pol S. Effect of pregnancy on chronic hepatitis C: a case-control study. Lancet. 2000;356(9238):1328-1329. doi:10.1016/S0140-6736(00)02823-3

14. Connell LE, Salihu HM, Salemi JL, August EM, Weldeselasse H, Mbah AK. Maternal hepatitis B and hepatitis C carrier status and perinatal outcomes. Liver Int. 2011;31(8):1163-1170. doi:10.1111/j.1478-3231.2011.02556.x

15. Pergam SA, Wang CC, Gardella CM, Sandison TG, Phipps WT, Hawes SE. Pregnancy complications associated with hepatitis C: data from a 2003-2005 Washington state birth cohort. Am J Obstet Gynecol. 2008;199(1):38.e1-38.e9. doi:10.1016/j.ajog.2008.03.052

16. Smith DD, Rood KM. Intrahepatic cholestasis of pregnancy. Clin Obstet Gynecol. 2020;63(1):134-151. doi:10.1097/GRF.0000000000000495

17. Williamson C, Geenes V. Intrahepatic cholestasis of pregnancy. Obstet Gynecol. 2014;124(1):120-133. doi:10.1097/AOG.0000000000000346

18. Delgado-Borrego A, Smith L, Jonas MM, et al. Expected and actual case ascertainment and treatment rates for children infected with hepatitis C in Florida and the United States: epidemiologic evidence from statewide and nationwide surveys. J Pediatr. 2012;161(5):915-921. doi:10.1016/j.jpeds.2012.05.002

19. Rossi RM, Wolfe C, Brokamp R, et al. Reported prevalence of maternal hepatitis C virus infection in the United States. Obstet Gynecol. 2020;135(2):387-395. doi:10.1097/AOG.0000000000003644

20. Sheffield JS, Argani CH. Hepatitis C virus infection in the pregnant woman: is it time for universal screening? Obstet Gynecol. 2020;135(4):770-772. doi:10.1097/AOG.0000000000003815

21. Tasillo A, Eftekhari Yazdi G, Nolen S, et al. Short-term effects and long-term cost-effectiveness of universal hepatitis C testing in prenatal care. Obstet Gynecol. 2019;133(2):289-300. doi:10.1097/AOG.0000000000003062

22. Schillie S, Wester C, Osborne M, Wesolowski L, Ryerson AB. CDC recommendations for hepatitis C screening among adults - United States, 2020. MMWR Recomm Rep. 2020;69(2):1-17. doi:10.15585/mmwr.rr6902a1

23. Owens DK, Davidson KW, Krist AH, et al; US Preventive Services Task Force. Screening for hepatitis C virus infection in adolescents and adults: US Preventive Services Task Force recommendation statement. JAMA. 2020;323(10):970-975. doi:10.1001/jama.2020.1123

24. Maheshwari A, Thuluvath PJ. Management of acute hepatitis C. Clin Liver Dis. 2010;14(1):169-176; x. doi:10.1016/j.cld.2009.11.007

25. Workowski KA, Bolan GA; Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(RR-03):1-137.

26. Pessione F, Degos F, Marcellin P, et al. Effect of alcohol consumption on serum hepatitis C virus RNA and histological lesions in chronic hepatitis C. Hepatology. 1998;27(6):1717-1722. doi:10.1002/hep.510270635

27. Lewis JH, Stine JG. Review article: prescribing medications in patients with cirrhosis - a practical guide. Aliment Pharmacol Ther. 2013;37(12):1132-1156. doi:10.1111/apt.12324

28. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Centers for Disease Control and Prevention. MMWR Recomm Rep. 1998;47(RR-19):1-39.

29. Spera AM, Eldin TK, Tosone G, Orlando R. Antiviral therapy for hepatitis C: has anything changed for pregnant/lactating women? World J Hepatol. 2016;8(12):557-565. doi:10.4254/wjh.v8.i12.557

30. Gagnon A, Davies G, Wilson RD; Genetics Committee. Prenatal invasive procedures in women with hepatitis B, hepatitis C, and/or human immunodeficiency virus infections. J Obstet Gynaecol Can. 2014;36(7):648-653. doi:10.1016/S1701-2163(15)30546-6

31. Cottrell EB, Chou R, Wasson N, Rahman B, Guise JM. Reducing risk for mother-to-infant transmission of hepatitis C virus: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2013;158(2):109-113. doi:10.7326/0003-4819-158-2-201301150-0057532.

32. Ghamar Chehreh ME, Tabatabaei SV, Khazanehdari S, Alavian SM. Effect of cesarean section on the risk of perinatal transmission of hepatitis C virus from HCV-RNA+/HIV- mothers: a meta-analysis. Arch Gynecol Obstet. 2011;283(2):255-260. doi:10.1007/s00404-010-1588-9

33. McIntyre PG, Tosh K, McGuire W. Caesarean section versus vaginal delivery for preventing mother to infant hepatitis C virus transmission. Cochrane Database Syst Rev. 2006;(4):CD005546. doi:10.1002/14651858.CD005546.pub2

34. European Paediatric Hepatitis C Virus Network. Effects of mode of delivery and infant feeding on the risk of mother-to-child transmission of hepatitis C virus. European Paediatric Hepatitis C Virus Network. BJOG. 2001;108(4):371-377.

35. Garcia-Tejedor A, Maiques-Montesinos V, Diago-Almela VJ, et al. Risk factors for vertical transmission of hepatitis C virus: a single center experience with 710 HCV-infected mothers. Eur J Obstet Gynecol Reprod Biol. 2015;194:173-177. doi:10.1016/j.ejogrb.2015.09.009

36. Mast EE, Hwang LY, Seto DSY, 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(11):1880-1889. doi:10.1086/497701

37. Spencer JD, Latt N, Beeby PJ, et al. Transmission of hepatitis C virus to infants of human immunodeficiency virus–negative intravenous drug-using mothers: rate of infection and assessment of risk factors for transmission. J Viral Hepat. 1997;4(6):395-409. doi:10.1046/j.1365-2893.1997.00073.x

38. American Academy of Pediatrics. Hepatitis C. In: Kimberlin DW BM, Jackson MA, Long SS, eds. Red Book: 2018 Report of the Committee on Infectious Diseases. American Academy of Pediatrics; 2018:428-434.