Background
Intrahepatic cholestasis during pregnancy (ICP) is a common complication of pregnancy, characterized by elevated bile acid levels, skin pruritus, and elevated transaminase levels in the second half of pregnancy. ICP can lead to complications such as preterm delivery, fetal distress, MSAF, and perinatal morbidity and mortality [
1,
2].
Hepatitis B infection is caused by hepatitis B virus (HBV) and is a significant public health problem worldwide. There are nearly 87 million chronic HBV carriers in China, accounting for approximately one third of all chronic hepatitis B infection in the world [
3]. According to a nationally representative serological survey in China in 2014, the prevalence of hepatitis B surface antigen (HBsAg) positivity in women of childbearing age is approximately 4.4%-5.9% [
4].
The chronic HBV infection status has been traditionally characterized with four phases: immune-tolerant phase, HBeAg-positive immune-active phase, inactive CHB phase and HBeAg-negative immune reactivation phase. During pregnancy, immune imbalance, physiological and endocrine variation may lead to high replication of HBV, prompting hepatitis B activation or reactivation, resulting elevated ALT and high HBV DNA levels, and often accompanied with elevated total bile acid (TBA) and bile acids levels. However, it is unknown whether elevated bile acid levels differ between ICP and HBV infection and how they affect pregnancy outcomes.
Discussion
ICP and HBV infection affect each other, interact with each other, and are closely related. Hepatitis B during pregnancy may represent acute or chronic infection or the reactivation of a prior infection, causing abnormal ALT and increased serum bile acid and bilirubin levels and leading to adverse pregnancy outcomes, similar with 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. Our study is the first to report pregnant outcomes of ICP and ICP combined with HBV infection with different maternal liver function, and further explore the influence of ICP with HBeAg and HBV DNA status on adverse pregnancy outcomes.
Several studies have shown that HBV infection is linked to an increased risk of ICP [
9‐
11]. 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. 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). A large cross-sectional retrospective study in China found that women with HBsAg-positive status showed an increased risk of ICP, OR was 2.79 (95% CI 2.36–3.30) [
10]. However, these studies did not report pregnancy outcomes between ICP with or without HBV infection. Another study [
12] showed that ICP with HBV infection had more serious effects on newborns, aggravated ICP and virus infection symptoms in mothers. In this study, ICP with HBV infection patients had more adverse fetal outcomes including birth defects, fetal distress and neonatal asphyxia. We observed higher maternal ALT, AST, serum bile acid and bilirubin levels in HBV infected women with abnormal liver function, 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 the previous studies [
12,
13]. The advantage of our study is that we observed more comprehensive maternal and fetal outcomes and our sample size was larger. We also investigated the differences in pregnancy outcomes among liver dysfunction, biliary tract dysfunction, cholestasis and the difference between elevated TBA due to HBV activation and solitary TBA elevation. In addition, we found that there was no significant difference in pregnancy outcomes between HBV-infected pregnant women with ICP combined with normal liver function and solitary ICP (
p > 0.05), but adverse pregnancy outcomes such as liver injury, the rate of admitted to NICU and MSAF were more likely to occur in HBV-infected patients with ICP combined with abnormal liver function (
p < 0.05). Although the exact mechanism of the relationship between HBV infection and the progression of ICP is unclear, there are a few possible explanations. A possible explanation is that Hepatitis B virus infection causes an autoimmune reaction, ultimately leading to serious negative effects such as liver cell damage and placental dysfunction, increased cholestasis, significant hypoxia, fetal distress, premature birth or stillbirth. Several studies have shown that HBV infection is associated with oxidative stress, and oxidative stress plays an important role in the development of ICP. So ICP patients with HBV-infection and liver injury may have an increased oxidative stress resulted in significantly worse pregnancy outcomes [
14].
Our study also examined the effects of ICP with HBeAg and HBV DNA status on adverse pregnancy outcomes. Women of childbearing age who are infected with HBV are generally relatively young, and most of them are in the immune tolerance period. In this immune tolerance period, body of HBV patients were predominated of HBeAg-specific Th2 cells, inducing Th1/ Th2 imbalance. Many studies have reported a predominant Th2-type immunity and suppressed Th1-type immunity during pregnancy. This immunity status is more beneficial for fetus growth without rejection reaction. Compared with non-pregnant women, pregnant women have more Th2-type inflammatory factor [
15]. This imbalance status will induce HBV infection progression. Meanwhile, physiological variation, metabolic rate elevating and more liver burden lead to high replication of HBV, prompting hepatitis B activation or reactivation, resulting in liver function abnormalities.
A study in pregnant North American women with chronic hepatitis B infection found that among the 158 pregnant women with chronic HBV, serum ALT flares developed in 3.4% during pregnancy [
16]. Another study in Nanjing City of China found that there were 72 patients with HBeAg-positive immune active, accounting for about 20.2% (72/356) in the patients with HBeAg-positive, and 61 patients with HBeAg-negative immune active, accounting for about 9.9% (61/356) in the patients with HBeAg-negative [
17]. In our study, We found a much higher proportion(75.5%)of abnormal liver function among HBeAg-positive patients with ICP(77/102). This results might be related to the reason that our study population is HBV infection combined with ICP. Compared with pregnant women with solitary hepatitis B infection, the proportion of abnormal liver function is higher. We found that ICP patients with HBeAg positivity and high HBV-DNA viral load had a higher rate of adverse pregnancy outcomes, such as preterm birth, admitted to the NICU and MSAF as well as more severe liver injury, such as elavated ALT, TBA and TBIL. Cai et al. [
18] found that HBeAg positivity is associated with a higher risk of ICP, means that HBeAg positivity aggravates ICP and lead to higher levels of bile acids than in HBeAg-negative pregnant women. Ju et al. [
17] found that patients in the HBeAg positive or immune active phases had a higher incidence of ICP and the preterm birth rate. HBeAg may increase the risk of ICP by affecting bile acid metabolism [
19]. However, the research on HBeAg and ICP is limited, and more studies are needed.
Maternal HBeAg positive and a high HBV DNA viral load are considered markers of HBV replication and disease severity [
20], they also might aggravate the inflammatory response, which is a mediator of ICP [
21,
22] and increases the risk of pregnancy complications and adverse neonatal outcomes [
23,
24]. We mentioned above that oxidative stress is involved in the pathogenesis of ICP, HBV is a kind of hepatophilic virus that has been related to the development of oxidative stress. It is believed that HBV generates oxidative stress by altering mitochondrial function and modulating host gene expression. Another study further revealed that HBV virus altered the expression profile of bile acid metabolism genes by binding to cellular receptors [
25]. 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]. The higher preterm birth rate may account for the higher NICU admission rate and the lower birth weights and heights. That might be why the higher HBV DNA viral load with ICP have a significant negative impact on pregnancy outcomes. However, 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 [
26]. This results might due to that HBeAg was tested at recruitment time, but HBV DNA level was quantified at 28–30 weeks of gestation. Women with antiviral treatment during pregnancy for their high viral load or absence of HBV DNA result at 28–30 weeks for occurrence of premature delivery were excluded. This exclusion induced some different results with our study.
There are some limitations in this study. Firstly, in this single center retrospective study, we could not exclude selection and information bias. Secondly, we only analyzed maximum TBA levels and we did not determine the TBA levels after delivery. Thirdly, our study was limited in taking antiviral treatment into account since the data on antiviral treatments were not completely recorded. Further clinical trial should be conduct for more detail investigation in TBA levels and other complications.
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