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An Unforeseen Threat: The Impact of Viral Hepatitis on Reproduction

Alexis P. Calloway, M.D.

Alexis P. Calloway, M.D.

By Alexis P. Calloway, M.D.

Much focus is given to the long- and short-term impact of commonly tested sexually transmitted infections such as HIV, chlamydia, gonorrhea and HPV on reproductive health. As the medical landscape of diagnosis and therapeutic options for infertility evolve, it is just as important to focus on viral hepatitis as well, with particular emphasis on Hepatitis B and C.

Viral Hepatitis in the United States
According to the Centers for Disease Control and Prevention (CDC), there were an estimated 33,900 new Hepatitis C virus ( HCV) infections in 2015, representing a 2.9-fold increase since 2010 with 75 percent to 85 percent of infections becoming chronic. The estimated number of new Hepatitis B virus (HBV) infections in 2015 was 21,900, however these rates are decreasing.

HCV is generally acquired through IV drug use and blood transfusions until changes in screening regulation for donations in the early 1990s. HCV can rarely also be acquired through sexual transmission. Alternatively, HBV is commonly acquired through sexual transmission, particularly in heterosexuals with multiple partners and unvaccinated men who have sex with men. Other common sources of transmission for HBV include mother-to- child transmission (MTCT), intravenous drug abuse and rarely through paternal transmission. (Iqbal et al., 2015) Chronic viral hepatitis, with HCV accounting for the majority of cases, is one of the most common causes of cirrhosis in the U.S. and carries a significant burden on the healthcare system. Given the multifaceted impact to the body, it is unknown what the specific burden to reproductive health may be.

Viral Hepatitis and Male Fertility
It is already known that many chronic viruses have the ability to infect sperm and adversely impact male fertility. Specifically in the last decade, it has been found that HCV causes a statistically significant decrease in semen volume, sperm count and progressive sperm motility and an increase in abnormal sperm morphology compared with healthy controls. Furthermore, the duration of HCV infection has been negatively correlated with semen volume and sperm motility where the HCV RNA viral load was negatively correlated with sperm count and sperm motility. (Hofny et al., 2011) In a study published in 2011, it was found that couples whose male partner was infected with HBV had a higher risk of low fertility rates after IVF, a risk which was independent from the initial sperm motility. (Oger et al., 2011)

As viral hepatitis may be asymptomatic until the onset of advanced disease, these barriers may not be identified as a potential etiology for infertility in younger populations. Targeted screening in this at-risk group may be of benefit in reproductive counseling, though no clear guidelines have been established. Some literature does attempt to address the issue of disparity of screening asymptomatic men in comparison to their heterosexual partners.

In a study of 1,243 male partners of 2,400 women who attended ultrasound examinations between 2010 and 2011, 430 accepted HIV and STI testing. It was ultimately found this is an acceptable time to feasibly engage the heterosexual male partner for screening. (Dhairyawan, Creighton, Sivyour, & Anderson, 2012) Other opportunities may arise to address screening and should be pursued on an individual basis by the patient’s healthcare provider.

Table 1. Pathology Structure of female reproductive system with HBV - and HCV- infection

Kurmanova, A.M., et al. (2016). “Reproductive dysfunctions in viral hepatitis.” Gynecol Endocrinol 32(sup2): 37-40.

Viral Hepatitis and Female Fertility
Menstrual disorders serve as the predominant cause of reproductive barriers in a patient affected with HBV and HCV due to intra- and extrahepatic pathology (as displayed in Table 1). (Kurmanova, Kurmanova, & Lokshin, 2016) Premenopausal women who are HCV positive or have chronic liver disease are at risk for premature ovarian failure impacting their lifelong fertility.

A study published in 2017 found that most new cases of HCV infection are among people who inject drugs, including reproductive-age females. Reproductive-age women who are HCV positive display markers of ovarian failure. This is associated with infertility and adverse pregnancy outcomes such as stillbirth, miscarriage, fewer live births and gestational diabetes. (Karampatou et al., 2017)

There is not much research surrounding the impact of HBV on reproduction in women specifically. One small study measuring pregnancy rates and implantation rates of HBV-sero- positive women and their partners found a higher rate of tubal blockage, often leading to signficantly higher rates of IVF and embryo transfer cycles if at least one partner was positive when compared to seronegative control couples. (Lam et al., 2010)

No matter the etiology, there are overarching impacts of cirrhosis on the reproductive health of women. Cirrhosis leading to generalized infertility and pregnancy is rare, but when it does occur specialized care is required.

Viral Hepatitis and the Pregnant Patient
Mother-to-child transmission is responsible for more than one third to one half of chronic HBV infections worldwide and can occur during pregnancy, delivery or after birth if not treated. Acute HBV infection during pregnancy is usually mild and not associated with increased mortality or teratogenicity. However, transmission rates significantly increase if acute infection occurs in the perinatal period, with rates as high as 60 percent reported. (Sookoian, 2006)

Chronic hepatitis B serves as a larger medical management consideration with emphasis on decision to treat during pregnancy with anti-retroviral therapy. This decision is generally influenced by ALT elevation greater than two times the upper limit of normal, HBV DNA levels, detection of Hepatitis B Surface Antigen (HBSAg) and anti-Hepatitis B e antibody (anti-HBe), and the presence or absence of cirrhosis.

Women with high viral loads (HBV DNA) in the third trimester should be treated even in the setting of normal ALT to decrease the vertical transmission risk to the infant. Furthermore, neonates of HBSAg-positive mothers should receive monovalent hepatitis B vaccine and HBIG 0.5ml as soon after delivery as possible (preferably within 12-24 hours) regardless of birth weight. (Committee On Infectious, Committee On, & Newborn, 2017) As perinatal transmission of HCV is unlikely, decision to treat can be deferred until after delivery. Subspecialist assistance may serve valuable in determining patient candidacy and timing for treatment.

Though HCV can be detected in maternal colostrum, this is not considered a factor associated with vertical transmission. In a study of 76 samples of breast milk from 73 chronically HCV-infected mothers, none of the samples contained HCV RNA and only one of the breastfed infants had evidence of HCV one month after birth without clear correlation to breastfeeding itself. (Polywka, Schroter, Feucht, Zollner, & Laufs, 1999) It is accepted by multiple organizations that breastfeeding is considered generally safe in asymptomatic HCV-positive mothers.

Reproductive Planning
Though initially targeted for the baby boomer population, emerging and highly effective therapies for HCV may prove beneficial to improving infertility in reproductive-age individuals burdened with this disease as well. Rates of sustained virologic response (SVR) have been found to be in the high 90th percentile for patients with common genotypes of the virus undergoing eight or 12 weeks of treatment. (Terrault et al., 2016)

Additionally, treatment is beneficial as early menopause in patients with chronic HCV was associated with low likelihood of SVR likely due to inflammatory factors and physiologic variations in estrogen that change at menopause. (Villa et al., 2011) Vaccination should also be pursued in household and sexual contacts for those with HBV.

As providers, viral hepatitis should be a part of the reproductive health discussion, with appropriate screening and treatment as indicated in this special and occasionally missed population.


References
Committee On Infectious, D., Committee On, F., & Newborn. (2017). Elimination of Perinatal Hepatitis B: Providing the First Vaccine Dose Within 24 Hours of Birth. Pediatrics, 140(3). doi:10.1542/peds.2017-1870
Dhairyawan, R., Creighton, S., Sivyour, L., & Anderson, J. (2012). Testing the fathers: carrying out HIV and STI tests on partners of pregnant women. Sex Transm Infect, 88(3), 184-186. doi:10.1136/sextrans-2011-050232

Hofny, E. R., Ali, M. E., Taha, E. A., Nafeh, H. M., Sayed, D. S., Abdel-Azeem, H. G., . . . Mostafa, T. (2011). Semen and hormonal parameters in men with chronic hepatitis C infection. Fertil Steril, 95(8), 2557-2559. doi:10.1016/j.fertnstert.2011.05.014

Iqbal, K., Klevens, R. M., Kainer, M. A., Baumgartner, J., Gerard, K., Poissant, T., . . . Teshale, E. (2015). Epidemiology of Acute Hepatitis B in the United States From Population-Based Surveillance, 2006-2011. Clin Infect Dis, 61(4), 584-592. doi:10.1093/ cid/civ332

Karampatou, A., Han, X., Kondili, L. A., Taliani, G., Ciancio, A., Morisco, F., . . . Investigators, P. (2017). Premature ovarian senescence and a high miscarriage rate impair fertility in women with HCV. J Hepatol. doi:10.1016/j.jhep.2017.08.019

Kurmanova, A. M., Kurmanova, G. M., & Lokshin, V. N. (2016). Reproductive dysfunctions in viral hepatitis. Gynecol Endocrinol, 32(sup2), 37-40. doi:10.1080/0951 3590.2016.1232780

Lam, P. M., Suen, S. H., Lao, T. T., Cheung, L. P., Leung, T. Y., & Haines, C. (2010). Hepatitis B infection and outcomes of in vitro fertilization and embryo transfer treatment. Fertil Steril, 93(2), 480-485. doi:10.1016/j.fertnstert.2009.01.137

Oger, P., Yazbeck, C., Gervais, A., Dorphin, B., Gout, C., Jacquesson, L., . . . Rougier, N. (2011). Adverse effects of hepatitis B virus on sperm motility and fertilization ability during IVF. Reprod Biomed Online, 23(2), 207-212. doi:10.1016/j.rbmo.2011.04.008

Polywka, S., Schroter, M., Feucht, H. H., Zollner, B., & Laufs, R. (1999). Low risk of vertical transmission of hepatitis C virus by breast milk. Clin Infect Dis, 29(5), 1327-1329. doi:10.1086/313473

Sookoian, S. (2006). Liver disease during pregnancy: acute viral hepatitis. Ann Hepatol, 5(3), 231-236.

Terrault, N. A., Zeuzem, S., Di Bisceglie, A. M., Lim, J. K., Pockros, P. J., Frazier, L. M., . . . Group, H.-T. S. (2016). Effectiveness of Ledipasvir-Sofosbuvir Combination in Patients With Hepatitis C Virus Infection and Factors Associated With Sustained Virologic Response. Gastroenterology, 151(6), 1131-1140 e1135. doi:10.1053/j.gastro.2016.08.004

Villa, E., Karampatou, A., Camma, C., Di Leo, A., Luongo, M., Ferrari, A., . . . Francavilla, A. (2011). Early menopause is associated with lack of response to antiviral therapy in women with chronic hepatitis C. Gastroenterology, 140(3), 818-829. doi:10.1053/j.gastro.2010.12.027

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