Hepatitis B Infection Negatively Affects the Outcome of Fresh IVF/ICSI Cycles

Background: The study sought to determine whether hepatitis B infection in females and males plays a role in the outcome of the IVF/ICSI cycle. Methods: We performed a retrospective analysis of data collected from IVF/ICSI cycles carried out from January 2011 to December 2019 at the University Medical Centre Ljubljana. The data was analyzed using Pearson’s chi-square test, Fisher’s exact test, and Kruskal-Wallis test in order to determine the differences between the groups. Results: This study included 117 cycles with a past female hepatitis B infection (HF group), 91 cycles with couples with a past male hepatitis B infection (HM group), and 10,216 cycles with no past male or female hepatitis B infection (control group). There was no difference in sperm concentration, but total sperm motility was significantly higher in the HF and control groups compared to the HM group (p = 0.008 and p $<$ 0.001). Also, sperm morphology was significantly higher in the control group, compared to both, the HM group (p $<$ 0.001) and the HF group (p = 0.004). Furthermore, the rate of fertilized oocytes per number of retrieved oocytes was significantly higher in the HF (p $<$ 0.001) and control groups (p = 0.003) compared to the HM group, but on the contrary, the rate of immature oocytes was lower in the HM (p = 0.009) and control groups (p = 0.001) compared to the HF group. The number of obtained embryos, blastocyst, and embryo utilization rates were similar between the groups, although the rate of cryopreserved embryos was higher in the HF (p = 0.007) and the HM groups (p = 0.027) compared to the control group. No significant difference was observed in the pregnancy and live birth rate per embryo transfer, while a trend towards a lower birth rate per aspiration was observed in the HM and in HF groups, which can be explained with a significantly higher miscarriage rate observed in the HM (p $<$ 0.001) and HF groups (p = 0.042) compared to the control group. Gestational age was similar for all groups, although we observed a strong trend towards a higher birth weight of singletons in the HF group (p = 0.043) compared to the control group. Conclusions: The results indicate that hepatitis B infection could have a detrimental influence on sperm motility and morphology and cycle outcome, especially in terms of a higher miscarriage rate.

in vitro fertilization; hepatitis B; pregnancy; miscarriage

[1] Kurmanova AM, Kurmanova GM, Lokshin VN. Reproductive dysfunctions in viral hepatitis. Gynecological Endocrinology. 2016; 32: 37–40.

[2] Kong Y, Ye F, Jin Y, Shi J, Qiu H, Lin S. Hepatitis b virus expres-sion and replication in ovum and the influencing factors. Saudi Journal of Gastroenterology. 2016; 22: 215–219.

[3] Ye F, Yue Y, Li S, Chen T, Bai G, Liu M, et al. Presence of HBsAg, HBcAg, and HBVDNA in ovary and ovum of the pa-tients with chronic hepatitis B virus infection. American Journal of Obstetrics and Gynecology. 2006; 194: 387–392.

[4] Jin Y, Ye F, Shi J, Qiu H, Zhao Y, Lin S, et al. Hepatitis B virus infection and replication in primary cultured human granulosa cells. Archives of Virology. 2011; 156: 1–7.

[5] Liu W, Han R, Wu H, Han D. Viral threat to male fertility. An-drologia. 2018; 50: e13140.

[6] Vicari E, Arcoria D, Di Mauro C, Noto R, Noto Z, La Vignera S. Sperm output in patients with primary infertility and hepatitis B or C virus; negative influence of HBV infection during con-comitant varicocele. Minerva Medicolegale. 2006; 97: 65–77.

[7] Karamolahi S, Yazdi RS, Zangeneh M, Makiani MJ, Farhoodi B, Gilani MAS. Impact of hepatitis B virus and hepatitis C virus in-fection on sperm parameters of infertile men. International Jour-nal of Reproductive Biomedicine. 2019; 17: 551–556.

[8] Huang J, Huang T, Qiu H, Fang X, Zhuang T, Liu H, et al. Effects of hepatitis B virus infection on human sperm chromosomes. World Journal of Gastroenterology. 2003; 9: 736–740.

[9] Ali BA, Huang T, Salem H, Xie Q. Expression of hepatitis B virus genes in early embryonic cells originated from hamster ova and human spermatozoa transfected with the complete vi-ral genome. Asian Journal of Andrology. 2006; 8: 273–279.

[10] Qian L, Li Q, Li H. Effect of hepatitis B virus infection on sperm quality and oxidative stress state of the semen of infertile males. American Journal of Reproductive Immunology. 2016; 76: 183–185.

[11] Mocanu E, Drakeley A, Kupka MS, Lara-Molina EE, Le Clef N, Ombelet W, et al. ESHRE guideline: medically assisted repro-duction in patients with a viral infection/disease. Human Repro-duction Open. 2021; 2021: hoab037.

[12] Cito G, Coccia ME, Fucci R, Picone R, Cocci A, Sessa M, et al. Hepatitis B Surface Antigen Seropositive Men in Serodiscordant Couples: Effects on the Assisted Reproductive Outcomes. The World Journal of Men’s Health. 2021; 39: 99.

[13] Bu Z, Kong H, Li J, Wang F, Guo Y, Su Y, et al. Effect of male hepatitis B virus infection on outcomes of in vitro fertilization and embryo transfer treatment: insights from couples undergo-ing oocyte donation. International Journal of Clinical and Exper-imental Medicine. 2014; 7: 1860–1866.

[14] Wang Z, Liu W, Zhang M, Wang M, Wu H, Lu M. Effect of Hepatitis B Virus Infection on Sperm Quality and Outcomes of Assisted Reproductive Techniques in Infertile Males. Frontiers in Medicine. 2021; 8:744350.

[15] Lubis HP, Halim B, Adenin I, Rusda M, Prasetiawan E. Hepatitis B virus infection on male partner has negative impact on in-vitro fertilization. IOP Conference Series: Earth and Environmental Science. 2018; 125: 012045.

[16] Lin S, Li R, Zheng X, Wang L, Ren X, Chen L, et al. Impact of hepatitis B virus carrier serostatus on neonatal outcomes af-ter IVF-ET. International Journal of Clinical and Experimental Medicine. 2015; 8: 6206–6211.

[17] Stimpfel M, Jancar N, Vrtacnik-Bokal E. Collecting semen sam-ples at home for IVF/ICSI does not negatively affect the outcome of the fresh cycle. Reproductive BioMedicine Online. 2021; 42: 391–399.

[18] Organization WH. WHO laboratory manual for the examination and processing of human semen. 6nd edn. World Health Orga-nization: Geneva. 2021.

[19] Han T, Huang J, Gu J, Xie Q, Zhong Y, Huang T. Hepatitis B virus surface protein induces sperm dysfunction through the ac-tivation of a Bcl2/Bax signaling cascade triggering AIF/Endo G–mediated apoptosis. Andrology. 2021; 9: 944–955.

[20] Kang X, Xie Q, Zhou X, Li F, Huang J, Liu D, et al. Effects of hepatitis B virus S protein exposure on sperm membrane in-tegrity and functions. PLoS ONE. 2012; 7: e33471.

[21] Shi L, Liu S, Zhao W, Zhou H, Ren W, Shi J. Hepatitis B virus infection reduces fertilization ability during in vitro fertilization and embryo transfer. Journal of Medical Virology. 2014; 86: 1099–1104.

[22] Zhou X, Hu X, Zhu Y, Qu F, Sun S, Qian Y. Comparison of semen quality and outcome of assisted reproductive techniques in Chinese men with and without hepatitis B. Asian Journal of Andrology. 2011; 13: 465–469.

[23] Oger P, Yazbeck C, Gervais A, Dorphin B, Gout C, Jacquesson L, et al. Adverse effects of hepatitis B virus on sperm motility and fertilization ability during IVF. Reproductive Biomedicine Online. 2011; 23: 207–212.

[24] Chen H, Ge H, Lv J, Wu X, Xi H, Huang J, et al. Chronic hepati-tis B virus infection in women is not associated with IVF/ICSI outcomes. Archives of Gynecology and Obstetrics. 2014; 289: 213–217.

[25] Lee VCY, Ng EHY, Yeung WSB, Ho PC. Impact of positive hepatitis B surface antigen on the outcome of IVF treatment. Re-productive Biomedicine Online. 2010; 21: 712–717.

[26] Mak JSM, Leung MBW, Chung CHS, Chung JPW, Cheung LP, Lao TT, et al. Presence of Hepatitis B virus DNA in follicular fluid in female Hepatitis B carriers and outcome of IVF/ICSI treatment: a prospective observational study. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2019; 239: 11–15.

[27] Wang L, Li L, Huang C, Diao L, Lian R, Li Y, et al. Mater-nal chronic hepatitis B virus infection does not affect pregnancy outcomes in infertile patients receiving first in vitro fertilization treatment. Fertility and Sterility. 2019; 112: 250–257. e1.

[28] Lam PM, Suen SH, Lao TT, Cheung LP, Leung TY, Haines C. Hepatitis B infection and outcomes of in vitro fertilization and embryo transfer treatment. Fertility and Sterility. 2010; 93: 480–485.

[29] Ye F, Jin Y, Kong Y, Shi JZ, Qiu HT, Zhang X, et al. The pres-ence of HBV mRNA in the fertilized in vitro embryo of HBV patients confirms vertical transmission of HBV via the ovum. Epidemiology and Infection. 2013; 141: 926–930.

[30] Nie R, Jin L, Zhang H, Xu B, Chen W, Zhu G. Presence of hep-atitis B virus in oocytes and embryos: a risk of hepatitis B virus transmission during in vitro fertilization. Fertility and Sterility. 2011; 95: 1667–1671.

[31] Hu XL, Zhou XP, Qian YL, Wu GY, Ye YH, Zhu YM. The pres-ence and expression of the hepatitis B virus in human oocytes and embryos. Human Reproduction. 2011; 26: 1860–1867.

[32] Mak JSM, Lao TT. Assisted reproduction in hepatitis carrier couples. Best Practice & Research Clinical Obstetrics & Gynae-cology. 2020; 68: 103–108.