The results of the study indicate that pregnancy and HBV infection is not an independent risk factor for PTB (< 37 weeks), but it significantly increases the risk of PTB before 34 weeks of gestation. For pregnant women with HBV infection with HBeAg negative and normal ALT, it may increase the risk of PTB before 34 weeks of gestation.
There is still some controversy about the relationship between HBV infection and PTB in China and worldwide[9–11]. Jue Liu et al. studied 489,965 pregnant women through a national cohort study and found that HBsAg positive patients increase the risk of premature delivery. The risk of premature delivery in HBeAg negative and HBeAg-positive pregnant women with HBV infection increased by 26% and 20%, respectively. In addition, the risk of PTB before 34 weeks increased by 18% and 34%[12]. This is partly contradictory to our findings that HBV infection is not an independent risk factor for PT[13]B before 37 weeks. Chen et al. reached similar conclusions to our findings; they investigated perinatal data and neonatal outcomes in 380 HBsAg positive and 428 HBsAg-negative women in Jiangsu province and found that the prevalence of PTB was relatively higher in HBsAg positive group (2.9% vs. 1.4%), but it failed to reach statistical significance (p = 0.140)[13]. Similarly, Jing Tan and colleagues conducted a retrospective cohort study of 21,947 singleton newborns and their mothers and found no statistically significant association between maternal HBsAg positivity and PTB (aOR 1.20, 95% CI 0.95–1.51)[14]. This may be related to the different characteristics of the study population. Jiangsu province and Fujian province are southeast coastal areas, where the prevalence of HBV infection is higher, while the PTB rate is lower than that in the southwest regions of China[5, 15], which may lead to insignificant results. In addition, the prospective study of Xu Zhuang et al. [16] suggested that AST, GGT, and elevated bilirubin are independent risk factors for PTB, rather than HBsAg positivity. In our study, after correcting ALT, AST, GGT and other indicators, we found that HBsAg positivity is an independent risk factor for PTB less than 34 weeks, suggesting that the correlation between HBV infection and PTB is not a single abnormal liver function (ALT, AST, GGT). This indicates that the mechanism by which HBV infection causes PTB may be much more complicated.
The related mechanism of HBV infection and PTB is not clear. Some studies believe that the occurrence of PTB is closely related to the maternal-fetal interface. The rich blood supply of the maternal-fetal interface and the immune tolerance microenvironment created by the interaction of immune cells are the key to embryo implantation. When delivery is approaching, the in situ or recruited immune cells form an inflammatory reaction environment locally at the maternal-fetal interface, prompting the fetus to be delivered by the mother. Therefore, the maternal-fetal interface immune microenvironment regulates all aspects of pregnancy and childbirth, and disorder or abnormality in its balance can lead to miscarriage or PTB[17]. The accumulation of HBV-DNA in the placenta and trophoblast cells may trigger the placental inflammatory response at the maternal-fetal interface, prompting the fetus to be discharged from the mother. Zhihua Wan et al. believe that HBV-DNA levels vary in different periods of pregnancy, and that placental inflammation may be caused by HBV-DNA in the second trimester, rather than HBV-DNA in the third trimester. In addition, HBV infects placental trophoblasts in the second trimester, leading to an increase in the level of interleukin-6 (IL-6) in the amniotic fluid secreted by placental trophoblasts[18]. This might be because HBV infection increases the risk of PTB before 34 weeks of gestation, but does not increase the risk of PTB before 37 weeks of gestation. In addition, CiIoannis S. Elefsiniotis et al. found that the presence of HBV-DNA in the cord blood was significantly related to spontaneous preterm delivery in pregnant women with chronic HBV infection [19], but the dose-response relationship needs to be further explored in future studies.
In addition, the relationship between HBV infection and other pregnancy complications and outcomes is controversial. In this study, by comparing the general baseline characteristics of the HBV infection group and the control group, we found that there was no significant difference in the incidence of GDM, PPROM, gestational hypertension, preeclampsia, HELLP, and between the two groups, which is similar to the findings of Bajema et al. [20] ,Reddick et al. [21]༌ Sirilert et al.[22], and Cui et al.[23]. At the same time, the difference in the incidence of miscarriage between the two groups was not statistically significant, which contradicts the previous belief that HBV infection is an independent risk factor for miscarriage by Ai-Ming Cui et al.. The reason for this difference may be attributed to the inclusion of pregnant women from 12–18 weeks and who underwent regular check-ups. Therefore, pregnant women who had miscarriages before 12 weeks were not included in the study. In addition, we also found that the two groups had statistically significant differences in intrahepatic cholestasis during pregnancy (P < 0.001). In the meta-analysis conducted by Jiang et al. [24], we found that HBV infection was a high-risk factor for intrahepatic cholestasis during pregnancy. Cai et al.[25] also reached a similar conclusion. As for neonatal outcomes, we found that the two groups had statistically significant differences in birth weight (weight of neonates, LBW, and SGA), which was different from the conclusions of Lao’s [26] and Connell’s [27] studies.
This study is a single-center retrospective cohort study. There are some limitations of retrospective studies such as selection shifts. However, as a tertiary hospital in Southeast China, the number of patients included in the study is representative, and the results have certain reference value. Nevertheless, further prospective cohort and multicenter research is warranted to expand the research results and promote the research conclusions.