The Ribavirin Pregnancy Registry: An Interim Analysis of Potential Teratogenicity at the Mid-Point of Enrollment

Susan M Sinclair, Judith K Jones, Richard K Miller, Michael F Greene, Paul Y Kwo, Willis C Maddrey, Susan M Sinclair, Judith K Jones, Richard K Miller, Michael F Greene, Paul Y Kwo, Willis C Maddrey

Abstract

Introduction: Significant teratogenic effects have been demonstrated in all animal species exposed to ribavirin. Ribavirin is prescribed for chronic hepatitis C and is contraindicated in women who are pregnant and in the male sexual partners of women who are pregnant. Both sexes are advised to avoid pregnancy for 6 months after exposure. The Ribavirin Pregnancy Registry was established in 2003 to monitor pregnancy exposures to ribavirin for signals of possible human teratogenicity.

Methods: This voluntary registry enrolls pregnant women with prenatal exposure to ribavirin. Exposure is classified as direct-women taking ribavirin during pregnancy or the 6 months prior to conception-or indirect-women exposed through sexual contact, 6 months prior to or during pregnancy, with a man who is taking or has taken ribavirin in the past 6 months. Women are followed until delivery and infants for 1 year. When enrollment is complete, birth defect rates will be compared with the Metropolitan Atlanta Congenital Defects Program's published rate of 2.67. Using data collected since inception in 2003 through February 2016, preliminary rates were calculated.

Results: The registry has enrolled 272 pregnant women, with 180 live births: there were seven birth defect cases among 85 directly exposed women [7/85 (8.2%) (95% confidence interval (CI) 3.4-16.2)] and four birth defect cases among 95 indirectly exposed women [4/95 (4.2%) (95% CI 1.2-10.4)]. Of the 11 infants, nine had structural defects and two had chromosomal anomalies. Patterns suggesting a common etiology or relationship with ribavirin exposure are not seen.

Conclusion: Based on the patterns of birth defects reported, preliminary findings do not suggest a clear signal of human teratogenicity for ribavirin. However, the current sample size is insufficient for definitive conclusions, and ribavirin exposure should be avoided during pregnancy and during the 6 months prior to pregnancy, in accordance with prescribing information.

Clinical trial registration: ClinicalTrials.gov identifier: NCT00114712.

Conflict of interest statement

Susan Sinclair serves as the principal investigator for the registry and is reimbursed for her time through INC Research. Judith K. Jones, Richard K. Miller, Paul Y. Kwo, and Willis C. Maddrey are members of the Scientific Advisory Board, reimbursed for their time by the sponsors, and have no conflicts of interest that are directly relevant to the content of this study. Michael F. Greene is an unpaid Scientific Advisory Board member and has no conflicts of interest that are directly relevant to the content of this study.

Figures

Fig. 1
Fig. 1
Overall registry enrollment from 23 December 2003 through 8 February 2016 (includes direct and indirect exposures)

References

    1. Rebetol® [US package insert]. Whitehouse Station: Merck & Co., Inc.; 2015.
    1. Copegus® [US package insert]. South San Francisco: Genentech USA, Inc.; 2016.
    1. INC Research. The Ribavirin Pregnancy Registry (RPR) [ identifier NCT00114712]. US National Institutes of Health, . . Accessed 1 July 2017.
    1. World Health Organization. Global hepatitis report 2017. Geneva: WHO; 2017. License: CC BY-NC-SA 3.0 IGO. . Accessed 15 May 2017.
    1. Edlin BR, Eckhardt BJ, Shu MA, Holmberg SD, Swan T. Toward a more accurate estimate of the prevalence of hepatitis C in the United States. Hepatology. 2015;62(5):1353–1363. doi: 10.1002/hep.27978.
    1. Committee on a National Strategy for the Elimination of Hepatitis B and C; Board on Population Health and Public Health Practice; Health and Medicine Division; National Academies of Sciences, Engineering, and Medicine; Buckley GJ, Strom BL, editors. Eliminating the public health problem of hepatitis B and C in the United States: phase one report. Washington (DC): National Academies Press (US); 2016. doi:10.17226/23407. . Accessed 15 May 2017.
    1. Institute of Medicine (US) Committee on the Prevention and Control of Viral Hepatitis InfectionColvin HM, Mitchell AE, editors. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Washington, DC: National Academies Press (US); 2010.
    1. Glue P. The clinical pharmacology of ribavirin. Semin Liver Dis. 1999;19(Suppl. 1):17–24.
    1. Wade J, Snoeck E, Duff F, Lamb M, Jorga K. Pharmacokinetics of ribavirin in patients with hepatitis C virus. Br J Clin Pharmacol. 2006;62(6):710–714. doi: 10.1111/j.1365-2125.2006.02704.x.
    1. Kilham L, Ferm V. Congenital anomalies induced in hamster embryos with ribavirin. Science. 1977;195(4276):413–414. doi: 10.1126/science.401547.
    1. Ferm V, Willhite C, Kilham L. Teratogenic effects of ribavirin on hamster and rat embryos. Teratology. 1978;17(1):93–101. doi: 10.1002/tera.1420170117.
    1. Kochhar D, Penner J, Knudsen T. Embryotoxic, teratogenic, and metabolic effects of ribavirin in mice. Toxicol Appl Pharmacol. 1980;52(1):99–112. doi: 10.1016/0041-008X(80)90252-5.
    1. Narayana K, D’Souza U, Rao K. Effect of ribavirin on epididymal sperm count in rat. Indian J Physiol Pharmacol. 2002;46(1):97–101.
    1. Narayana K, D’Souza U, Seetharama Rao K. Ribavirin-induced sperm shape abnormalities in Wistar rat. Mutat Res. 2002;513(1–2):193–196. doi: 10.1016/S1383-5718(01)00308-4.
    1. Rao KP, Narayana K. In vivo chromosome damaging effects of an inosine monophosphate dehydrogenase inhibitor: ribavirin in mice. Indian J Pharmacol. 2005;37:90–95. doi: 10.4103/0253-7613.15108.
    1. D’Souza U, Narayana K. Mechanism of cytotoxicity of ribavirin in the rat bone marrow and testis. Indian J Physiol Pharmacol. 2002;46(4):468–474.
    1. Vogel T, Speed R, Teague P, Cooke HJ. Mice with Y chromosome deletion and reduced Rbm genes on a heterozygous Dazl1 null background mimic a human azoospermic factor phenotype. Hum Reprod. 1999;14(12):3023–3029. doi: 10.1093/humrep/14.12.3023.
    1. Ellis M, Richardson A, Foster J, Smith FM, Widdowson PS, Farnworth MJ, et al. The reproductive toxicity of molinate and metabolites to the male rat: effects on testosterone and sperm morphology. Toxicol Appl Pharmacol. 1998;151(1):22–32. doi: 10.1006/taap.1998.8371.
    1. Lim C, Lewis S, Kennedy M, Donnelly E, Thompson W. Human sperm morphology and in vitro fertilization: sperm tail defects are prognostic for fertilization failure. Andrologia. 1998;30(1):43–47. doi: 10.1111/j.1439-0272.1998.tb01381.x.
    1. Mishkin D, Deschênes M. Conception soon after discontinuing interferon/ribavirin therapy: a successful outcome. Am J Gastroenterol. 2001;96(7):2285–2286. doi: 10.1111/j.1572-0241.2001.03996.x.
    1. Hegenbarth K, Maurer U, Kroisel PM, Fickert P, Trauner M, Stauber RE. No evidence for mutagenic effects of ribavirin: Report of two normal pregnancies. Am J Gastroenterol. 2001;96(7):2286–2287. doi: 10.1111/j.1572-0241.2001.03997.x.
    1. Maddrey W. Safety of combination interferon alfa-2b/ribavirin therapy in chronic hepatitis C-relapsed and treatment-naive patients. Semin Liver Dis. 1999;19(Suppl 1):67–75.
    1. De Santis M, Carducci B, Cavaliere AF, De Santis L, Lucchese A, Straface G, et al. Paternal exposure to ribavirin: pregnancy and neonatal outcome. Antivir Ther. 2003;8(1):73–75.
    1. Valentin M, Ducarme G, Yver C, Vuillard E, Belarbi N, Renier D, Luton D. Trigonocephaly and valproate: a case report and review of literature. Prenat Diagn. 2008;28(3):259–261. doi: 10.1002/pd.1948.
    1. Labarga P, Pinilla J, Cachorro I, Ruiz Y. Infant of 22 months of age with no anomalies born from a HCV- and HIV-infected mother under treatment with pegylated interferon, ribavirin and antiretroviral therapy during the first 16 weeks of pregnancy. Reprod Toxicol. 2007;24(3–4):414–416. doi: 10.1016/j.reprotox.2007.07.002.
    1. Rezvani M, Koren G. Pregnancy outcome after exposure to injectable ribavirin during embryogenesis. Reprod Toxicol. 2006;21(1):113–115. doi: 10.1016/j.reprotox.2005.06.005.
    1. Bianca S, Ettore G. Male periconceptional ribavir-interferon alpha-2b exposure with no adverse fetal effects. Birth Defects Res A Clin Mol Teratol. 2003;67(1):77–78. doi: 10.1002/bdra.10105.
    1. Hofer H, Donnerer J, Sator K, Staufer K, Scherzer TM, Dejaco C, et al. Seminal fluid ribavirin level and functional semen parameters in patients with chronic hepatitis C on antiviral combination therapy. J Hepatol. 2010;52(6):812–816. doi: 10.1016/j.jhep.2009.12.039.
    1. Pecou S, Moinard N, Walschaerts M, Pasquier C, Daudin M, Bujan L. Ribavirin and pegylated interferon treatment for hepatitis C was associated not only with semen alterations but also with sperm deoxyribonucleic acid fragmentation in humans. Fertil Steril. 2009;91(3):933.e917–922. doi: 10.1016/j.fertnstert.2008.07.1755.
    1. Roberts SS, Miller RK, Jones JK, Lindsay KL, Greene MF, Maddrey WC, et al. The Ribavirin Pregnancy Registry: findings after 5 years of enrollment, 2003–2009. Birth Defects Res A Clin Mol Teratol. 2010;88(7):551–559. doi: 10.1002/bdra.20682.
    1. Correa-Villaseñor A, Cragan J, Kucik J, O’Leary L, Siffel C, Williams L. The Metropolitan Atlanta Congenital Defects Program: 35 years of birth defects surveillance at the Centers for Disease Control and Prevention. Birth Defects Res A Clin Mol Teratol. 2003;67(9):617–624. doi: 10.1002/bdra.10111.
    1. Correa A, Cragan JD, Kucik JE, Alverson CJ, Gilboa SM, Balakrishnan R, et al. Reporting birth defects surveillance data 1968–2003 [errata appears in Birth Defects Res A Clin Mol Teratol 2008;82(1):41–62] Birth Defects Res A Clin Mol Teratol. 2007;79(2):65–186.
    1. Food and Drug Administration (FDA). Guidance for Industry: establishing pregnancy exposure registries. Rockville: FDA; 2002. . Accessed 15 May 2017.
    1. Ribavirin Pregnancy Registry. . Accessed 15 May 2017.
    1. Scheuerle A, Tilson H. Birth defect classification by organ system: a novel approach to heighten teratogenic signalling in a pregnancy registry. Pharmacoepidemiol Drug Saf. 2002;11(6):465–475. doi: 10.1002/pds.726.
    1. MACDP. Birth defects and genetic diseases branch 6-digit code for reportable congenital anomalies. 2007. . Accessed 15 May 2017.
    1. Polousky JD, Eilert RE. Orthopedics. In: Hay WW Jr, Levin MJ, Sondheimer JM, Deterding RR, editors. Current diagnosis and treatment: pediatrics. A LANGE Medical Book. 19. New York: The McGraw-Hill Companies, Inc.; 2009. p. 752.
    1. Lang K, Nuevo-Chiquero A. Trends in self-reported spontaneous abortions: 1970–2000. Demography. 2012;49(3):989–1009. doi: 10.1007/s13524-012-0113-0.
    1. Jatlaoui TC, Ewing A, Mandel MG, Simmons KB, Suchdev DB, Jamieson DJ, et al. Abortion surveillance—United States, 2013. MMWR Surveill Summ. 2016;65(12):1–44. doi: 10.15585/mmwr.ss6512a1.
    1. Tatar A, Ozkurt Z, Kiki I. Genotoxic effect of ribavirin in patients with Crimean-Congo hemorrhagic fever. Jpn J Infect Dis. 2005;58(5):313–315.
    1. 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.
    1. IRB Review of Research. Code of Federal Regulations Title 21, 931 Pt. 56.109c(1); 2009.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa