The Effects of Hepatitis B Virus Infection on Natural and IVF Pregnancy

A Meta-Analysis Study

Marziye Farsimadan; Seyed Mohammad Riahi; Huda Muhaddien Muhammad; Alireza Emamvirdizadeh; Mohsen Tabasi; Mohammad Motamedifar; Giandomenico Roviello


J Viral Hepat. 2021;28(9):1234-1245. 

In This Article

Abstract and Introduction


Background: Hepatitis B virus (HBV) has been considered a significant cause of human reproductive failure in different studies; however, there is a considerable disagreement on the true impacts of HBV on female reproduction. This study has evaluated the impact of HBV infection on pregnancy complications in natural pregnancy and also on pregnancy outcomes in women undergoing in vitro fertilization (IVF) treatment.

Method: We searched Embase, Web of Science, PubMed and Google Scholar databases to identify the potentially relevant studies. Summary odds ratio (OR) or standardized mean difference (SMD) with 95% confidence interval (CI) was applied to assess the relationship. Heterogeneity testing, sensitivity analysis and publication bias testing were also performed.

Results: A total of 42 studies concerning the effect of HBV infection on the natural and IVF pregnancy were included in this study. Our meta-analysis results revealed that HBV infection had a positive correlation to gestational diabetes mellitus (GDM) [OR = 1.32 (1.17–1.48) (p < 0.01)] and preterm birth [OR = 1.26 (1.14–1.40) (p < 0.01)] in natural pregnancy; however, HBV infection was not significantly associated with decreased fertility rates among the patients who underwent IVF.

Conclusion: This study revealed a strong association of GDM and preterm birth with higher rates of HBV infection in pregnant women. Also, our results suggested that HBV infection in patients undergoing IVF may not negatively influence the pregnancy outcome. It may be rational to conclude that IVF might be rather a safe and effective method for HBV+ females who desire to have children.


Infertility is a critical component of reproductive health and affects about 15% of couples throughout the world. There are two types of infertility: primary infertility and secondary infertility.[1] Primary infertility happens when couples have never been able to get pregnant after a year of trying without using any birth control, while in secondary infertility the couples have been able to get pregnant but now, they are not. Female infertility constitutes 37% of all infertility cases.[2]

Female infertility in different resources defines as a woman of reproductive age not being able to get pregnant after a year of trying or keeps having miscarriages.[3] Not being able to ovulate has been considered the major cause of infertility among women that can be a result of different factors including, social, genetic, endocrine, physiological and phycological factors as well as lifestyle habits (ie smoking and alcohol consumption).[4] However, approximately 15%–30% of cases of female infertility still remain unexplained.[5,6] Different studies have shown the significant role of microbiomes in human reproduction.[7,8] Data suggest that various viruses could negatively affect human reproductive functions, but it appears that women are heavily under the influence of viral infections and more than men suffer from their consequences. HBV is among the most commonly investigated viruses interfering with female reproductive ability.

Hepatitis B virus is an enveloped virus, belonging to the hepadnaviridae family, contains a circular, partially double-stranded DNA genome. HBV can be transmitted parenterally, sexually and perinatally. HBV is a major cause of acute and chronic hepatitis, cirrhosis and hepatocellular cancer. HBV can attack hepatocytes and replicate in these cells. The effects of HBV infection on human reproduction have been investigated frequently. Studies on the impacts of HBV on female reproduction have yielded conflicting results.[1] Some studies have shown that HBV infection could decrease pregnancy rates and lead to adverse pregnancy outcomes, while other studies have indicated no detrimental effects of HBV infection on female reproduction or have even shown the increased fertilization and pregnancy rates among HBV-infected women. Different investigations on the effect of HBV infection on the female reproduction have found a strong association between the presence of HBV and impairment of immune response and suggested HBV infection to be probably a surrogate for other infections and a leading cause of altered microbiome in the female genital tract that would contribute to infertility.[9] Previous studies have reported increased levels of proinflammatory cytokines such as IL-2, IL-6, IL-10, macrophage migration inhibitory factor and tumour necrosis factor-alpha in patients with chronic HBV infection.[10] These systemic inflammatory responses may account for the adverse pregnancy outcomes in HBV+ women. Lower rates of CD3+CD4+ helper T cells and peripheral NK function and toxicity have also been demonstrated to be significantly associated with higher rates of early miscarriage and adverse pregnancy outcome in HBV+ females.[11] In addition, tubal damages due to the increased risks of pelvic infection in HBV+ female partner significantly increased infertility among them.[12] Moreover, decreased fertility rates among female patients who had advanced chronic liver disease, regardless of the cause, was shown to be mainly due to the frequent occurrence of anovulatory cycles and amenorrhea among them.[13] Miscarriage rates,[14] preterm birth[15–17] and low birth weight[16] were significantly higher among HBV+ women; however, some investigations failed to show any relationship between the presence of HBV infection in women and higher rates of pregnancy complications or infertility among them. Thus, in this study, to further clarify the effect of this virus on female reproduction, we performed this meta-analysis to evaluate the effect of HBV infection on both natural and IVF pregnancy. To the best of our knowledge, this is the first meta-analysis study to investigate the effects of HBV infection on natural and IVF pregnancy.