Abstract: BackgroundHepatitis B virus (HBV) is one of the most widespread viruses worldwide and a major cause of hepatitis, cirrhosis, and hepatocellular carcinoma. Previous studies have revealed the impacts of HBV infection on fertility. An increasing number of infertile couples with chronic hepatitis B (CHB) virus infection choose assisted reproductive technology (ART) to meet their fertility needs. Despite the high prevalence of HBV, the effects of HBV infection on assisted reproduction treatment remain limited and contradictory.
ObjectiveThe aim of this study was to provide a comprehensive overview of the effect of HBV infection on fertility and discuss its effects on pregnancy outcomes, vertical transmission, pregnancy complications, and viral activity during ART treatment.
MethodsWe conducted a literature search in PubMed for studies on HBV infection and ART published from 1996 to 2022.
ResultsHBV infection negatively affected fertility in both males and females. Existing research shows that HBV infection may increase the risk of pregnancy complications in couples undergoing assisted reproduction treatment. The impact of HBV infection on the pregnancy outcomes of ART is still controversial. Current evidence does not support that ART increases the risk of vertical transmission of HBV, while relevant studies are limited. With the development of ART, the risk of HBV reactivation (HBVr) is increasing, especially due to the wide application of immunosuppressive therapy.
ConclusionsRegular HBV infection screening and HBVr risk stratification and management are essential to prevent HBVr during ART. The determination of optimal strategy and timing of prophylactic anti-HBV therapy during ART still needs further investigation.

乙肝、不孕不育与辅助生殖

[1]AliBA, HuangTH, XieQD, 2005. Detection and expression of hepatitis B virus X gene in one and two-cell embryos from golden hamster oocytes in vitro fertilized with human spermatozoa carrying HBV DNA. Mol Reprod Dev, 70(1):30-36.

[2]AliBA, HuangTH, SalemHH, et al., 2006. Expression of hepatitis B virus genes in early embryonic cells originated from hamster ova and human spermatozoa transfected with the complete viral genome. Asian J Androl, 8(3):273-279.

[3]BeiHF, WeiRX, CaoXD, et al., 2017. Hepatitis B virus infection increases the incidence of immune infertility in males. Nat J Androl, 23(5):431-435 (in Chinese).

[4]BertolettiA, GehringAJ, 2006. The immune response during hepatitis B virus infection. J Gen Virol, 87(Pt 6):1439-1449.

[5]BourdonM, GarnierA, MaignienC, et al., 2021. Assisted reproductive technology outcomes in women with a chronic viral disease. AIDS, 35(7):1073-1081.

[6]BuZQ, KongHJ, LiJ, et al., 2014. Effect of male hepatitis B virus infection on outcomes of in vitro fertilization and embryo transfer treatment: insights from couples undergoing oocyte donation. Int J Clin Exp Med, 7(7):1860-1866.

[7]CaiQY, LiuHY, HanWH, et al., 2019. Maternal HBsAg carriers and adverse pregnancy outcomes: a hospital-based prospective cohort analysis. J Viral Hepat, 26(8):1011-1018.

[8]CantalloubeA, FerrarettoX, LepageJ, et al., 2021. Outcomes of cumulative transfers of fresh and frozen embryos in in vitro fertilization in women infected by hepatitis B virus. Gynecol Obstet Fertil Senol, 49(6):529-537.

[9]ChangY, JeongSW, JangJY, 2022. Hepatitis B virus reactivation associated with therapeutic interventions. Front Med (Lausanne), 8:770124.

[10]ChenH, GeHS, LvJQ, et al., 2014. Chronic hepatitis B virus infection in women is not associated with IVF/ICSI outcomes. Arch Gynecol Obstet, 289(1):213-217.

[11]ChengW, WuYN, WuHH, et al., 2022. Improved pregnancy outcomes of cyclosporine A on patients with unexplained repeated implantation failure in IVF/ICSI cycles: a retrospective cohort study. Am J Reprod Immunol, 87(4):e13525.

[12]CheungKW, WangWL, SoPL, et al., 2022. Relationship between viral load and pregnancy outcomes among hepatitis B carriers. Taiwan J Obstet Gynecol, 61(4):630-633.

[13]CitoG, CocciaME, FucciR, et al., 2019. Influence of male human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection on the reproductive outcomes in serodiscordant couples: a case-control study. Andrology, 7(6):852-858.

[14]CitoG, CocciaME, FucciR, et al., 2021. Hepatitis B surface antigen seropositive men in serodiscordant couples: effects on the assisted reproductive outcomes. World J Mens Health, 39(1):99-106.

[15]El JamalyH, EslickGD, WeltmanM, 2022. Meta-analysis: hepatitis B reactivation in patients receiving biological therapy. Aliment Pharmacol Ther, 56(7):1104-1118.

[16]ElefsiniotisIS, TsoumakasK, PapadakisM, et al., 2011a. Importance of maternal and cord blood viremia in pregnant women with chronic hepatitis B virus infection. Eur J Intern Med, 22(2):182-186.

[17]ElefsiniotisIS, PapadakisM, VlachosG, et al., 2011b. Presence of HBV-DNA in cord blood is associated with spontaneous preterm birth in pregnant women with HBeAg-negative chronic hepatitis B virus infection. Intervirology, 54(5):300-304.

[18]EtienneS, VosbeckJ, BernsmeierC, et al., 2022. Prevention of hepatitis B reactivation in patients receiving immunosuppressive therapy: a case series and appraisal of society guidelines. J Gen Intern Med, 38(2):490-501.

[19]European Association for the Study of the Liver, 2012. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol, 57(1):167-185.

[20]European Association for the Study of the Liver, 2017. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol, 67(2):370-398.

[21]FarsimadanM, RiahiSM, MuhammadHM, et al., 2021. The effects of hepatitis B virus infection on natural and IVF pregnancy: a meta-analysis study. J Viral Hepat, 28(9):1234-1245.

[22]FunkAL, LuY, YoshidaK, et al., 2021. Efficacy and safety of antiviral prophylaxis during pregnancy to prevent mother-to-child transmission of hepatitis B virus: a systematic review and meta-analysis. Lancet Infect Dis, 21(1):70-84.

[23]HanTT, HuangJH, GuJ, et al., 2021. Hepatitis B virus surface protein induces sperm dysfunction through the activation of a Bcl2/Bax signaling cascade triggering AIF/Endo G-mediated apoptosis. Andrology, 9(3):944-955.

[24]HeF, WangLS, ZhangCY, et al., 2018. Adverse effect of paternal hepatitis B virus infection on clinical pregnancy after frozen-thawed embryo transfer. Arch Gynecol Obstet, 298(4):827-832.

[25]HuXL, ZhouXP, QianYL, et al., 2011. The presence and expression of the hepatitis B virus in human oocytes and embryos. Hum Reprod, 26(7):1860-1867.

[26]HuangJM, HuangTH, QiuHY, et al., 2003. Effects of hepatitis B virus infection on human sperm chromosomes. World J Gastroenterol, 9(4):736-740.

[27]HuangQT, ChenJH, ZhongM, et al., 2014. The risk of placental abruption and placenta previa in pregnant women with chronic hepatitis B viral infection: a systematic review and meta-analysis. Placenta, 35(8):539-545.

[28]HuangQT, ChenJH, ZhongM, et al., 2016. Chronic hepatitis B infection is associated with decreased risk of preeclampsia: a meta-analysis of observational studies. Cell Physiol Biochem, 38(5):1860-1868.

[29]HuangTH, ZhangQJ, XieQD, et al., 2005. Presence and integration of HBV DNA in mouse oocytes. World J Gastroenterol, 11(19):2869-2873.

[30]HuangW, LuWY, LiQ, et al., 2020. Effects of cyclosporine A on proliferation, invasion and migration of HTR-8/SVneo human extravillous trophoblasts. Biochem Biophys Res Commun, 533(4):645-650.

[31]JiangRA, WangT, YaoYS, et al., 2020. Hepatitis B infection and intrahepatic cholestasis of pregnancy: a systematic review and meta-analysis. Medicine (Baltimore), 99(31):e21416.

[32]JinL, NieR, LiYF, et al., 2016. Hepatitis B surface antigen in oocytes and embryos may not result in vertical transmission to offspring of hepatitis B virus carriers. Fertil Steril, 105(4):1010-1013.

[33]JindalSK, RawlinsRG, MullerCH, et al., 2016. Guidelines for risk reduction when handling gametes from infectious patients seeking assisted reproductive technologies. Reprod BioMed Online, 33(2):121-130.

[34]KangXJ, XieQD, ZhouXL, et al., 2012. Effects of hepatitis B virus S protein exposure on sperm membrane integrity and functions. PLoS ONE, 7(3):e33471.

[35]KeaySD, BarlowR, EleyA, et al., 1998. The relation between immunoglobulin G antibodies to Chlamydia trachomatis and poor ovarian response to gonadotropin stimulation before in vitro fertilization. Fertil Steril, 70(2):214-218.

[36]KeckC, Gerber-SchäferC, CladA, et al., 1998. Seminal tract infections: impact on male fertility and treatment options. Hum Reprod Update, 4(6):891-903.

[37]KongY, YeF, JinY, et al., 2016. Hepatitis B virus expression and replication in ovum and the influencing factors. Saudi J Gastroenterol, 22(3):215-219.

[38]KongY, LiuY, LiuXJ, et al., 2017. Relationship between the mechanism of hepatitis B virus father-infant transmission and pregnancy outcome. Arch Gynecol Obstet, 295(1):253-257.

[39]LamPM, SuenSH, LaoTT, et al., 2010. Hepatitis B infection and outcomes of in vitro fertilization and embryo transfer treatment. Fertil Steril, 93(2):480-485.

[40]LaoTT, MakJSM, LiTC, 2017. Hepatitis B virus infection status and infertility causes in couples seeking fertility treatment-indicator of impaired immune response? Am J Reprod Immunol, 77(4):e12636.

[41]LeeVCY, NgEHY, YeungWSB, et al., 2010. Impact of positive hepatitis B surface antigen on the outcome of IVF treatment. Reprod BioMed Online, 21(5):712-717.

[42]LeeYS, BangSM, LeeYS, 2021. Benefits and risks of antiviral treatment during pregnancy in patients with chronic hepatitis B. J Clin Med, 10(11):2320.

[43]LiLF, WangLL, HuangCY, et al., 2019. Chronic hepatitis B infection alters peripheral immune response in women with reproductive failure. Am J Reprod Immunol, 81(3):e13083.

[44]LinSL, LiR, ZhengXY, et al., 2015. Impact of hepatitis B virus carrier serostatus on neonatal outcomes after IVF-ET. Int J Clin Exp Med, 8(4):6206-6211.

[45]LiuJ, ZhangSK, LiuM, et al., 2017. Maternal pre-pregnancy infection with hepatitis B virus and the risk of preterm birth: a population-based cohort study. Lancet Glob Health, 5(6):e624-e632.

[46]LiuJF, ChenTY, ZhaoYR, 2021. Vertical transmission of hepatitis B virus: propositions and future directions. Chin Med J (Engl), 134(23):2825-2831.

[47]LorussoF, PalmisanoM, ChironnaM, et al., 2010. Impact of chronic viral diseases on semen parameters. Andrologia, 42(2):121-126.

[48]LuciforaJ, ArzbergerS, DurantelD, et al., 2011. Hepatitis B virus X protein is essential to initiate and maintain virus replication after infection. J Hepatol, 55(5):996-1003.

[49]LutgensSPM, NelissenECM, van LooIHM, et al., 2009. To do or not to do: IVF and ICSI in chronic hepatitis B virus carriers. Hum Reprod, 24(11):2676-2678.

[50]MaXS, SunDH, LiCS, et al., 2018. Chronic hepatitis B virus infection and preterm labor(birth) in pregnant women—an updated systematic review and meta-analysis. J Med Virol, 90(1):93-100.

[51]MakJSM, LaoTT, 2020. Assisted reproduction in hepatitis carrier couples. Best Pract Res Clin Obstet Gynaecol, 68:103-108.

[52]MakJSM, LeungMBW, ChungCHS, et al., 2019. Presence of hepatitis B virus DNA in follicular fluid in female hepatitis B carriers and outcome of IVF/ICSI treatment: a prospective observational study. Eur J Obstet Gynecol Reprod Biol, 239:11-15.

[53]MakJSM, LaoTT, LeungMBW, et al., 2020. Ovarian HBV replication following ovulation induction in female hepatitis B carriers undergoing IVF treatment: a prospective observational study. J Viral Hepat, 27(2):110-117.

[54]MorettiE, FedericoMG, GianneriniV, et al., 2008. Sperm ultrastructure and meiotic segregation in a group of patients with chronic hepatitis B and C. Andrologia, 40(5):286-291.

[55]NieR, WangMY, LiaoTT, et al., 2019. Assisted conception does not increase the risk for mother-to-child transmission of hepatitis B virus, compared with natural conception: a prospective cohort study. Fertil Steril, 111(2):348-356.

[56]OgerP, YazbeckC, GervaisA, et al., 2011. Adverse effects of hepatitis B virus on sperm motility and fertilization ability during IVF. Reprod BioMed Online, 23(2):207-212.

[57]OnoratoL, PisaturoM, CamaioniC, et al., 2021. Risk and prevention of hepatitis B virus reactivation during immunosuppression for non-oncological diseases. J Clin Med, 10(21):5201.

[58]PengSX, WanZH, LinXF, et al., 2019. Maternal hepatitis B surface antigen carrier status increased the incidence of gestational diabetes mellitus. BMC Infect Dis, 19:147.

[59]PerrilloRP, GishR, Falck-YtterYT, 2015. American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology, 148(1):221-244.e3.

[60]PirwanyIR, PhillipsS, KellyS, et al., 2004. Reproductive performance of couples discordant for hepatitis B and C following IVF treatment. J Assist Reprod Genet, 21(5):157-161.

[61]QianL, LiQ, LiHB, 2016. Effect of hepatitis B virus infection on sperm quality and oxidative stress state of the semen of infertile males. Am J Reprod Immunol, 76(3):183-185.

[62]ReddickKLB, JhaveriR, GandhiM, et al., 2011. Pregnancy outcomes associated with viral hepatitis. J Viral Hepat, 18(7):e394-e398.

[63]ReddyKR, BeaversKL, HammondSP, et al., 2015. American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology, 148(1):215-219.

[64]SafirA, LevyA, SikulerE, et al., 2010. Maternal hepatitis B virus or hepatitis C virus carrier status as an independent risk factor for adverse perinatal outcome. Liver Int, 30(5):765-770.

[65]SheikhansariG, PourmoghadamZ, DanaiiS, et al., 2020. Etiology and management of recurrent implantation failure: a focus on intra-uterine PBMC-therapy for RIF. J Reprod Immunol, 139:103121.

[66]ShiL, LiuS, ZhaoWQ, et al., 2014. Hepatitis B virus infection reduces fertilization ability during in vitro fertilization and embryo transfer. J Med Virol, 86(7):1099-1104.

[67]SirilertS, TongsongT, 2021. Hepatitis B virus infection in pregnancy: immunological response, natural course and pregnancy outcomes. J Clin Med, 10(13):2926.

[68]SirilertS, TraisrisilpK, SirivatanapaP, et al., 2014. Pregnancy outcomes among chronic carriers of hepatitis B virus. Int J Gynaecol Obstet, 126(2):106-110.

[69]StasiC, TiengoG, SadallaS, et al., 2021. Treatment or prophylaxis against hepatitis B virus infection in patients with rheumatic disease undergoing immunosuppressive therapy: an update. J Clin Med, 10(12):2564.

[70]SteyaertSR, Leroux-RoelsGG, DhontM, 2000. Infections in IVF: review and guidelines. Hum Reprod Update, 6(5):432-441.

[71]StokkelandK, LudvigssonJF, HultcrantzR, et al., 2017. Pregnancy outcome in more than 5000 births to women with viral hepatitis: a population-based cohort study in Sweden. Eur J Epidemiol, 32(7):617-625.

[72]SuFH, ChangSN, SungFC, et al., 2014. Hepatitis B virus infection and the risk of male infertility: a population-based analysis. Fertil Steril, 102(6):1677-1684.

[73]SuJ, LimJK, 2019. Hepatitis B virus reactivation in the setting of immunosuppressive drug therapy. Gastroenterol Hepatol (N Y), 15(11):585-592.

[74]TajiriH, TanakaY, KagimotoS, et al., 2007. Molecular evidence of father-to-child transmission of hepatitis B virus. J Med Virol, 79(7):922-926.

[75]TanJ, MaoXY, ZhangGT, et al., 2018. Hepatitis B surface antigen positivity during pregnancy and risk of gestational diabetes mellitus: a systematic review and meta-analysis. J Viral Hepat, 25(11):1372-1383.

[76]TseKY, HoLF, LaoT, 2005. The impact of maternal HBsAg carrier status on pregnancy outcomes: a case-control study. J Hepatol, 43(5):771-775.

[77]VicariE, ArcoriaD, di MauroC, et al., 2006. Sperm output in patients with primary infertility and hepatitis B or C virus; negative influence of HBV infection during concomitant varicocele. Minerva Med, 97(1):65-77.

[78]WangLL, LiLF, HuangCY, et al., 2019. Maternal chronic hepatitis B virus infection does not affect pregnancy outcomes in infertile patients receiving first in vitro fertilization treatment. Fertil Steril, 112(2):250-257.e1.

[79]WangSS, PengGF, LiMM, et al., 2003. Identification of hepatitis B virus vertical transmission from father to fetus by direct sequencing. Southeast Asian J Trop Med Public Health, 34(1):106-113.

[80]WangSZ, LiuJ, WangQL, et al., 2018. The CDKN2A polymorphisms and the susceptibility of HBV-related gestational diabetes mellitus. J Clin Lab Anal, 32(6):e22423.

[81]WangZC, LiuWP, ZhangMM, et al., 2021. Effect of hepatitis B virus infection on sperm quality and outcomes of assisted reproductive techniques in infertile males. Front Med (Lausanne), 8:744350.

[82]WenWH, ChangMH, ZhaoLL, et al., 2013. Mother-to-infant transmission of hepatitis B virus infection: significance of maternal viral load and strategies for intervention. J Hepatol, 59(1):24-30.

[83]WuDY, 2019. Correlation of viral load of hepatitis B with the gestation period and the development of diabetes mellitus. Saudi J Biol Sci, 26(8):2022-2025.

[84]WuKQ, WangH, LiS, et al., 2020. Maternal hepatitis B infection status and adverse pregnancy outcomes: a retrospective cohort analysis. Arch Gynecol Obstet, 302(3):595-602.

[85]XiaWL, ShenY, ZhengSS, 2005. Inhibitory effect of cyclosporine a on hepatitis B virus replication in vitro and its possible mechanisms. Hepatobiliary Pancreat Dis Int, 4(1):18-22.

[86]XieHY, XiaWL, ZhangCC, et al., 2007. Evaluation of hepatitis B virus replication and proteomic analysis of HepG2.2.15 cell line after cyclosporine A treatment. Acta Pharmacol Sin, 28(7):975-984.

[87]XiongYQ, LiuCR, HuangSY, et al., 2021. Impact of maternal infection with hepatitis B virus on pregnancy complications and neonatal outcomes for women undergoing assisted reproductive technology treatment: a population-based study. J Viral Hepat, 28(4):613-620.

[88]XiongYQ, LiuCR, WeiW, et al., 2022. The impact of biparental hepatitis B virus infection on pregnancy outcomes in patients undergoing assisted reproductive technology treatment: a systematic review and meta-analysis. Arch Gynecol Obstet, 306(4):1253-1266.

[89]XuCL, BaoYR, ZuoJ, et al., 2021. Maternal chronic hepatitis B virus infection and the risk of preterm birth: a retrospective cohort analysis in Chinese women. J Viral Hepat, 28(10):1422-1430.

[90]YeF, YueYF, LiSH, et al., 2005. Expression of HBsAg and HBcAg in the ovaries and ova of patients with chronic hepatitis B. World J Gastroenterol, 11(36):5718-5720.

[91]YeF, YueYF, LiSH, et al., 2006. Presence of HBsAg, HBcAg, and HBVDNA in ovary and ovum of the patients with chronic hepatitis B virus infection. Am J Obstet Gynecol, 194(2):387-392.

[92]YeF, JinY, KongY, et al., 2013. The presence of HBV mRNA in the fertilized in vitro embryo of HBV patients confirms vertical transmission of HBV via the ovum. Epidemiol Infect, 141(5):926-930.

[93]YiW, LiMH, SunFF, et al., 2022. Impact of in vitro fertilization-embryo transfer on mother-to-infant transmission in women with chronic HBV infection. Liver Int, 42(10):2167-2174.

[94]YinWC, ChenBJ, YangYL, et al., 2021. Association between maternal hepatitis B virus carrier and gestational diabetes mellitus: a retrospective cohort analysis. Virol J, 18:226.

[95]YinWC, ChenBJ, LiuCN, et al., 2023. Reducing the risk of gestational diabetes mellitus in chronic hepatitis B virus carriers via more strict control of gestational weight gain. Int J Gynaecol Obstet, 161(3):903-910.

[96]YueDK, MolyneauxLM, RossGP, et al., 1996. Why does ethnicity affect prevalence of gestational diabetes? The underwater volcano theory. Diabet Med, 13(8):748-752.

[97]YuenMF, ChenDS, DusheikoGM, et al., 2018. Hepatitis B virus infection. Nat Rev Dis Primers, 4:18035.

[98]ZhangYL, ChenJC, LiaoTT, et al., 2020. Maternal HBsAg carriers and pregnancy outcomes: a retrospective cohort analysis of 85,190 pregnancies. BMC Pregnancy Childbirth, 20:724.

[99]ZhaoEY, ChenSL, SunL, et al., 2007. Influence of chronic HBV infection in the husband on the outcome of IVF-ET treatment. J South Med Univ, 27(12):1827-1829 (in Chinese).

[100]ZhaoM, YangSY, SuXJ, et al., 2022. Hepatitis B virus infection and increased risk of gestational diabetes regardless of liver function status: a Xiamen area population-based study. Front Physiol, 13:938149.

[101]ZhengSS, ZhangHL, ChenRX, et al., 2021. Pregnancy complicated with hepatitis B virus infection and preterm birth: a retrospective cohort study. BMC Pregnancy Childbirth, 21:513.

[102]ZhengZ, ZhaoXM, HongY, et al., 2016. The safety of intracytoplasmic sperm injection in men with hepatitis B. Arch Med Sci, 12(3):587-591.

[103]ZhongCY, LuH, HanTT, et al., 2017. CpG methylation participates in regulation of hepatitis B virus gene expression in host sperm and sperm-derived embryos. Epigenomics, 9(2):123-125.

[104]ZhongY, LiuDL, AhmedMMM, et al., 2017. Host genes regulate transcription of sperm-introduced hepatitis B virus genes in embryo. Reprod Toxicol, 73:158-166.

[105]ZhongZY, LiaoWT, DaiLY, et al., 2022. Average corticosteroid dose and risk for HBV reactivation and hepatitis flare in patients with resolved hepatitis B infection. Ann Rheum Dis, 81(4):584-591.

[106]ZhouGL, ChenC, HanGR, et al., 2022. Relationship between different hepatitis B virus infection status and gestational diabetes mellitus prevalence among pregnant women with chronic HBV infection: a retrospective study. J Viral Hepat, 29(8):596-603.

[107]ZhouXL, SunPN, HuangTH, et al., 2009. Effects of hepatitis B virus S protein on human sperm function. Hum Reprod, 24(7):1575-1583.

[108]ZhouXP, HuXL, ZhuYM, et al., 2011. Comparison of semen quality and outcome of assisted reproductive techniques in Chinese men with and without hepatitis B. Asian J Androl, 13(3):465-469.