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


Hepatitis B virus has been considered as the tenth leading cause of death worldwide. It is estimated that 350 million individuals are chronic carriers of HBV.[16] HBV has also been considered as a significant cause of human reproductive failure in different studies; however, the true effects of HBV infection on the female reproductive system is not well-established. So, we conducted a meta-analysis to assess the effects of this virus in adverse pregnancy outcomes in both natural and IVF pregnancy. To the best of our knowledge, this is the first meta-analysis investigating the effect of HBV infection on pregnancy outcome and female fertility competence. Our results suggested that HBV infection had a positive correlation to GDM and preterm birth in natural pregnancy; however, it was not associated with higher rates of placenta previa, stillbirth, PROM, LBW and miscarriage. Furthermore, HBV infection was not significantly associated with pregnancy rates in undergoing IVF and was not related to decreased rates of fertilization among them.

Our findings regarding the effects of HBV infection on pregnancy are consistent with majority of previous clinical studies including the studies selected for this meta-analysis. Stokkeland et al. in an investigation on a group of 2990 pregnant females showed that the presence of HBV infection among women was significantly associated with different pregnancy complications including GDM, stillbirth and preterm birth.[17] However, this study suffers from lack of data regarding drug use, medication, diagnostic method and uncontrolled socio-economical factors that may influence the risk estimated. Moreover, they did not differ between acute or chronic viral infection in patients. Previous studies of mothers with liver diseases and other chronic inflammatory diseases have shown increased risk of preterm deliveries. Additionally, studies have revealed that alcohol consumption could influence the increased risk of preterm birth in women with viral hepatitis.[56,57]

The majority of studies included in this meta-analysis showed the strong correlation of HBV infection with GMD and preterm birth. Several studies did not find any statistically significant association between preterm birth and HBV infection.[25,32,41,44,47] The small sample size of these studies probably contributed to this nuance.[32,41] Furthermore, they did not perform a matching for age and parity that could impact the results. The findings of present study are consistent with the results of another meta-analysis by Ma et al. who investigated the effect of HBV infection on preterm birth in pregnant women and similar to our results reported that HBV infection could intensify the risk of preterm labour and birth in pregnant women.[58] Cui et al. in another meta-analysis study further confirmed these results and reported HBV infection a risk factor for preterm birth.[14]

Similarly, two different studies investigating the effect of HBV infection during pregnancy suggested that HBV infection represents a significant general risk for the development of GDM.[59] Contrasting results can be seen in another meta-analysis by Kong et al. who reported that HBV infection was not related to higher rates of GDM.[60] However, their meta-analysis included limited number of studies up until 2013 and was also limited to English articles.

According to our results, placental abruption and placenta previa did not show any significant correlation to HBV infection in pregnant women, the same as all the investigations included in our study. The same results were also observed in another meta-analysis study by Huang and coworkers. Their record indicated no evidence of significant associations between HBV infection and increased risk of placental abruption as well as placenta previa.[61]

Cui et al. and Karampatou et al. in two different studies investigating various pregnancy complications among HBV positive women showed that HBV-infected females had significantly higher rates of miscarriage compared to controls.[14,48] However, not considering some potential confounders which may influence pregnancy outcomes and fertility rates together with HBV infection is the major weakness in these studies. For example, sociodemographic factors like drug use, tobacco and alcohol consumption that might be risk factors for miscarriage which were not reported in these studies. Their results were further confirmed in different IVF studies.[11,49]

Several IVF studies investigated the impacts of HBV infection on female reproduction. So far IVF studies concerning the effect of HBV infection on PR has yielded conflicting results. While some studies showed the association of HBV infection with decreased pregnancy rates among women undergoing IVF treatment, other studies showed no significant effects of HBV infection on IVF or surprisingly indicated higher rates of pregnancy or livebirth.

Our meta-analysis revealed no significant difference between the number of good quality follicles, number of oocytes retrieved, number of fertilized oocytes and number of viable embryos in HBV+ patients compared with HBV− women; however, the number of viable embryos seemed to be higher among controls but it was not significant. The same results were shown in all the IVF investigations included in this meta-analysis study. Our results, similar to all the IVF studies included in this meta-analysis, confirmed that HBV infection did not significantly change the fertilization rates in HBV+ patients compared to HBV- women.

Surprisingly, among 190 women undergoing their first IVF and embryo transfer cycles, the ongoing PR and implantation rates as well as live birth rates in the HBV+ group were significantly higher compared to negative controls.[51] The authors of this study did not suggest any explanation for this unexpected improved treatment outcome. The level of HBV infection (acute hepatitis, chronic hepatitis, carriers) in women included in their study that could significantly affect their outcomes was not reported and is the major weakness of this study. In addition, the frequency of endometriosis was higher in the control group compared to HBV infected patients in this study which could significantly contribute to decreased rates of pregnancy among control group and should have been considered by the authors. Interestingly, HBV+ patients in another recent research showed higher PR, but the authors also reported higher miscarriage rates for HBV+ group.[11] Poor designing, lack of matched controls and also the limited number of HBV positive cases could justify the higher rates of PR in positive subjects compared with controls. The contrasting results observed in several studies. These studies showed significantly lower rates of pregnancy in HBV-infected patients compared with controls.[20,62] As opposed to these investigations, other studies showed that HBV infection did not impact the outcome of IVF pregnancy, nor considered to be a cause of infertility.[52–55] The results from this meta-analysis further supported these findings and showed no association between PR and HBV infection among patients.

There are a number of strengths and limitations that should be mentioned. Our meta-analysis included 42 studies of ⸛3 × 106 women which enabled a much greater possibility of drawing precise conclusions. Our inclusion of studies forms a large number of countries from different continents (twelve countries), which allowed us of reaching a more reliable conclusion. Furthermore, most of the included investigations in this study were cohort studies that could provide stronger evidence than other types of studies and enable us to reach a more confident conclusion. Finally, the results from the quality appraisal indicated that the methodological quality of the included studies was generally good.

Several limitations need to be considered in the interpretation of our results. First, there were differences across all trials in definition of outcomes and pregnancy characteristics which led to clinical heterogeneity. For example, the definition of preterm birth and live birth varies in different studies. Similarly, for livebirth rate, in several studies trial, livebirth was defined as delivery after 34 weeks, in one full-term delivery, and in others the definition was unclear. This diversity adds a challenge for meta-analyses in general, including the results from our analysis. Second, even though the age of patients is an important factor in assessing the risk but the information regarding the age of patients was not reported in all the studies included in this meta-analysis and we were unable to measure the impact of age in the incidence rates of the included complications.

In conclusion, this study revealed the association of GDM and preterm birth with HBV infection in pregnant women. The results from different IVF studies included in this research suggested that infected ovaries or oocytes may exhibit a different response to ovarian stimulation during IVF treatment and may have different rates of fertilization, embryogenesis and pregnancy. Our results demonstrated that HBV infection in patients undergoing IVF may not negatively influence the pregnancy outcome. In fact, IVF treatments could overcome some subfertility factors which may have inhibitory effects on the process of natural conceptions. Therefore, it may be rational to conclude that IVF treatment could be rather a safe and effective method for HBV+ females who desire to have children. Further investigations are needed to confirm these results. Future studies should be more focused on the effects of different viruses including HBV on female reproductive function in order to provide a better understanding of their epidemiology and pathogenesis, and to help developing targeted treatment.