Hepatitis C, Infertility, and Biological Clocks
case report
I recently saw a 36-year-old woman who was found to be HCV infected in the course of a routine evaluation for infertility treatment. She was HIV negative. The patient was asymptomatic, had a single set of liver enzyme tests available (these were normal), and a plasma HCV RNA level of 100,000 copies/mL. Her virus was of genotype 5, a genotype rarely seen in the United States. She requested a liver biopsy; this revealed only minimal inflammation (1+) and no fibrosis. She asked the following questions:
• If she proceeded now and became pregnant, what was the risk of vertical transmission?
• Would delivery by cesarean section reduce the risk of vertical transmission?
• Are ova infected by HCV?
• If she were treated for HCV infection, could she become pregnant during treatment? If not, how long should she wait after treatment to become pregnant?
• Would treatment adversely affect her ova?
The risk of vertical transmission is often stated to be approximately 5% but, in fact, the reported incidence varies greatly from approximately 0% to 18% in mothers not coinfected with HIV. The reported risk depends upon, among other things, whether the maternal population evaluated is limited to those who are viremic since HCV transmission is limited, for all practical purposes, to infants born to viremic mothers.1,2 In addition, several studies (but not all) indicate that the risk of transmission appears to vary directly with the concentration of HCV RNA in maternal blood.3-5
In one Italian study, four of 45 (8.9%) children born to viremic mothers were infected.6 In another study in the same area of Italy, only two of 56 (3.6%) became infected.7
In a larger study, 13 children born to the 275 women with hepatitis C virus RNA acquired the infection (transmission rate 5%, 95% CI: 2-7%), whereas no child born to any of 128 HCV antibody positive but HCV RNA negative mothers was infected.8 In contrast to several other studies, the level of maternal viremia did not affect the risk of transmission. Furthermore, and with the caveat of small sample size, there was no significant difference in risk of transmission when infants born vaginally to those born by cesarean section (none electively) were compared. Consistent with other studies and with the finding of a number of investigators (but again not all) of an absence of HCV RNA in breast milk, breastfeeding did not constitute a risk of transmission.9 Of note is that six of the 13 infected children had detectable HCV RNA in blood immediately after birth, suggesting the presence of in utero transmission.8 Also important is that some infants with perinatal infection may spontaneously clear their viremia.4
The issue of the timing of vertical HCV transmission, however, remains moot. Not supporting the findings in the study above suggesting in utero transmission, a prospective study failed to find HCV RNA in the amniotic fluid of all but one of 16 viremic women during the fourth month of pregnancy.3 In the single case with a positive result, the concentration of virus in the amniotic fluid was only 230 copies/mL and the woman had an anterior placenta. Both of these factors suggest that this test may have been false-positive.
The risk of HCV vertical transmission is increased in the presence of HIV coinfection to a reported range of 6-36%.1 HIV and HCV coinfected parturient women appear to also have an increased risk of transmission of HIV relative to those not coinfected with HCV.10 For instance, in one study that found a 3.2% incidence of transmission from mothers infected with HCV alone, the comparable result for mothers coinfected with HIV was 22.5% (P < 0.0001).11
The preferred treatment for HCV infection involves the combination of interferon alpha and ribavirin. While interferon alpha is an FDA Pregnancy Category C drug ("studies have shown that the drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women"), the use of ribavirin is flatly contraindicated in pregnancy as well as in women who may become pregnant while receiving the drug (Category X).
Ribavirin is concentrated in erythrocytes where its half-life after a single dose is in excess of 24 hours.12 However, with repetitive dosing, drug accumulation increases over 2-4 weeks and the terminal plasma half-life after 16 weeks of dosing in HIV infected patients is 151 hours, although values as high as 298 hours have been reported.13,14 Thus, it would appear wise to wait several months to become pregnant after completing a course of therapy with ribavirin. Whether ribavirin affects subsequent fertility is, to my knowledge, not known. Pregnancy has been achieved after seven years of treatment with interferon alpha (with a boost from clomiphene).15
Thus, the best I could indicate to my non-HIV coinfected patient is that the average risk of vertical transmission in her case is approximately 5% and that, in contrast to data with HIV, there is no solid evidence that this risk of HCV transmission is diminished by delivery by cesarean section. In addition, I know of no data examining the infectability of human ova by HCV.
I pointed out that, given the mild nature of her liver disease, if the issue of vertical transmission were omitted from consideration for the moment, I would advise her against treatment at this time, despite the reasonable likelihood of achieving viral eradication. I indicated that if she chose to be treated, then she must delay pregnancy during the time of treatment. I suggested that it would then be wise to delay for at least another six months in order to determine if relapse occurs, as well as to allow drug "wash-out." (All this while she listens to her biological "clock tick.") Since I do not know the answer with regard to long-lasting effects on ova, she could also consider removing ova for future use prior to the insitution of therapy.
My patient is thinking these things over. What advice would you give her?
References
1. Hunt CM, et al. Hepatitis C in pregnancy. Obstet Gynecol 1997;89:883-890.
2. Thomas SL, et al. A review of hepatitis C virus (HCV) vertical transmission: Risks of transmission to infants born to mothers with and without HCV viraemia or human immunodeficiency virus infection. Int J Epidemiol 1998;27:108-117.
3. Delamare C, et al. Detection of hepatitis C virus RNA (HCV RNA) in amniotic fluid: A prospective study. J Hepatol 1999;31:416-420.
4. Spencer JD, 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;4:395-409.
5. Ohto H, et al. Transmission of hepatitis C from mothers to infants. The vertical transmission of hepatitis C virus collaborative study group. N Engl J Med 1994; 330:744-750.
6. Giacchino R, et al. Vertical transmission of hepatitis C virus infection: Usefulness of viremia detection in HIV-seronegative hepatitis C virus-seropositive mothers. J Pediatr 1998;132:167-169.
7. La Torre A, et al. Vertical transmission of HCV. Acta Obstet Gynecol Scand 1998;77:889-892.
8. Resti M, et al. Mother to child transmission of hepatitis C virus: Prospective study of risk factors and timing of infection in children born to women seronegative for HIV-1. BMJ 1998;317:437-441.
9. Polywka S, et al. Low risk of vertical transmission of hepatitis C virus by breast milk. Clin Infect Dis 1999; 29:1327-1329.
10. Hershow RC, et al. Increased vertical transmission of human immunodeficiency virus from hepatitis C virus-coinfected mothers. Women and infants transmission study. J Infect Dis 1997;176:414-420.
11. Zanetti AR, et al. A prospective study on mother-to-infant transmission of hepatitis C virus. Intervirology 1998;41:208-212.
12. Page T, Connor JD. The metabolism of ribavirin in erythrocytes and nucleated cells. Int J Biochem 1990; 22:379-383.
13. Lertora JJ, et al. Pharmacokinetics and long-term tolerance to ribavirin in asymptomatic patients infected with human immunodeficiency virus. Clin Pharmacol Ther 1991;50:442-449.
14. Glue P. The clinical pharmacology of ribavirin. Semin Liver Dis 1999;19(Suppl 1):17-24.
15. Lipton JH, et al. Alpha-interferon and pregnancy in a patient with CML. Hematol Oncol 1996;14:119-122.
Which of the following is correct?
a. Ribavirin is concentrated in erythrocytes.
b. The risk of vertical HCV transmission is lower in HIV coinfected women than in those infected with HCV alone.
c. The risk of vertical transmission of HCV is in excess of 70%.
d. HCV is routinely found in high concentration in the breast milk of infected mothers.
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