ICP and HBV infection have a mutual influence on each other; hepatitis B during pregnancy may represent acute or chronic infection or the reactivation of a prior infection, causing abnormal AST and increased serum bile acid and bilirubin levels and leading to adverse pregnancy outcomes, sometimes similar to the biochemical characteristics of ICP. However, it is difficult to distinguish whether these clinical manifestations in pregnant women with HBV infection are caused by the reactivation of HBV or by the occurrence of ICP in middle and late pregnancy. The pathogenesis of ICP may be related to the interaction of genetic susceptibility[6], altered estrogen and progesterone levels during pregnancy[7,8], abnormalities in the body's immune system, and environmental factors, but the pathogenesis of HBV with ICP has not yet been reported and fully understood.
A recent meta-analysis from 2020[9] on the relationship between ICP and HBV infection found an increased risk of ICP among HBV-infected pregnant women and an increased risk of HBV infection among ICP patients. In that study, the odds ratio (OR) of ICP in HBV-infected pregnant women compared with non-HBV-infected pregnant women was 1.68 (95% CI 1.43–1.97), and the OR of HBV infection among ICP patients compared with non-ICP patients was 1.70 (95% CI 1.44–2.01); however, the study did not report pregnancy outcomes. Another study[10] found that ICP with HBV infection had more serious effects on newborns and aggravated ICP and virus infection symptoms in mothers. There is a certain correlation between HBV infection and ICP during pregnancy, and the incidence of ICP in pregnant women with HBV infection is higher than that in pregnant women without HBV infection[9,11]. In 2022, Zhang et al.[12] analyzed 106 HBV-infected ICP patients and 20 ICP patients from 2010 to 2017 and concluded that the HBV + ICP patients had more adverse pregnancy outcomes than the ICP patients. These studies only evaluated the effects of maternal HBsAg carrier status on pregnancy outcomes and did not analyze the association of maternal HBeAg and HBV DNA status, which indicates HBV replication, nor did they examine patients with active HBV infection. Our study is the first to report pregnancy outcomes of ICP patients with different maternal HBV infection statuses and to explore the influence of ICP with HBeAg and HBV DNA status on adverse pregnancy outcomes.
We observed higher maternal ALT, AST, serum bile acid and bilirubin levels in ICP + CHB patients, as well as adverse pregnancy outcomes such as MSAF, preterm delivery, low birth weight and admitted to the NICU (P < 0.05) (Table 1), which is consistent with a previous study[10,12]. However, we did not observe a significant difference in the occurrence of adverse pregnancy outcomes between ICP and ICP + HBV carrier patients (p > 0.05). Our study also found that HBsAg-infected ICP patients with HBeAg positivity and a high HBV DNA viral load had a higher risk of adverse maternal and fetal outcomes. One potential explanation is that HBeAg positive and a high HBV DNA viral load are considered markers of HBV replication and disease severity and used in the evaluation of antiviral therapy[13]. Maternal HBeAg positive and a high HBV DNA viral load might aggravate the inflammatory response, which is a mediator of ICP[14,15] and increases the risk of pregnancy complications and adverse neonatal outcomes[16,17].
We also found that women with HBeAg positivity and a high HBV-DNA viral load had similar adverse pregnancy outcomes, such as preterm birth, admitted to the NICU and MSAF, which confirms the results of previous studies[14]. For example, Wu et al. showed that the risks of ICP and neonatal asphyxia were higher in women with HBeAg positivity and a high HBV DNA viral load among HBsAg-positive pregnant women. Cai et al. found that HBeAg positivity is associated with a higher risk of ICP, meaning higher levels of bile acids[18]. The higher preterm birth rate may account for the higher NICU admission rate and the lower birth weights and heights. HBV infects the placenta, alters the intrauterine environment and changes the inflammatory response of the placenta, which causes respiratory, metabolic and nutritional insufficiency of the placenta and might contribute to preterm birth[19]. Cheung et al. reported that a seropositive HBeAg status or a higher HBV DNA viral load during pregnancy did not have a significant negative impact on pregnancy outcomes[20].
Adverse pregnancy outcomes associated with elevated bile acid and TBA levels are correlated between the mother and fetus, and elevated TBA levels are associated with adverse pregnancy outcomes[21]. Previous studies have shown that bile acid profiles differ significantly among liver disease patients with different etiologies of chronic liver disease[22]. Shao et al. showed that the serum bile acid profile of the ICP group was different from that of the healthy pregnant group, the cholelithiasis group and the HBV group[23]. Another study further revealed that HBV virus altered the expression profile of bile acid metabolism genes by binding to cellular receptors[24]. Therefore, we hypothesized that ICP with or without HBV infection may lead to different pregnancy outcomes related to the different components of TBA. According to serum TBA levels, we divided the patients into three groups: those with low levels (less than 40 µmol/L), medium levels (40–100 µmol/L), and high levels (greater than 100 µmol/L). We found that the CHB + ICP group continued to have the worst pregnancy outcomes and found no difference between the ICP and ICP + HBV carrier groups. Therefore, we believe that CHB + ICP patients had more adverse fetal outcomes than ICP + HBV carrier patients and ICP patients. Thus, it is necessary to emphasize the examination of HBV DNA viral load and that the liver function of HBsAg-positive women be monitored regularly. Active antiviral treatment might be considered for women with a high HBV DNA viral load when necessary to prevent the reactivation of a prior HBV infection and perinatal transmission[25].
There are some limitations to this study. First, in this retrospective study, we only analyzed the maximum TBA levels, and we did not determine the TBA levels after delivery. Second, we did not collect data on all adverse pregnancy outcomes, such as postpartum hemorrhage, and we did not classify preterm labor as medically or spontaneously induced. Third, our study was limited in taking antiviral treatment into account since the data on antiviral treatments were not completely recorded. Additionally, we did not investigate the physiological mechanisms of the association between HBsAg positivity and ICP.