Cesarean section to prevent mother-to-child transmission of hepatitis B virus in China: A meta-analysis

Hepatitis B is a potentially life-threatening liver infection caused by hepatitis B virus (HBV). It is a major global health problem. It can cause chronic infection and puts people at high risk of death from cirrhosis and liver cancer. According to the World Health Organization, an estimated 240 million people have chronic hepatitis B infection [1]. More than 780,000 people die every year due to complications of hepatitis B infection, including cirrhosis and liver cancer [2]. Hepatitis B prevalence is highest in sub-Saharan Africa and East Asia, where 5–10% of the adult population is chronically infected. The infected population of China accounts for one-third of the infected population worldwide [3].

HBV is predominantly transmitted through mother-to-child transmission (MTCT). In China, 30–50% of HBV carriers are infected through vertical transmission [3, 4]. Since the introduction of universal screening of pregnant women, combined with passive and active immunoprophylaxis, the MTCT rate of HBV has declined significantly. Passive immunoprophylaxis consists of the administration of hepatitis B immune globulin (HBIG) at birth, and active immunoprophylaxis is performed by the administration of the hepatitis B vaccine according to the standard 3-dose schedule. Although HBIG and vaccines given at birth are able to reduce transmission in most cases, in 10% to 20% of cases of infected mothers, transmission still occurs, especially from mothers with high viral loads and who are positive for hepatitis B e antigen (HBeAg) [5, 6].

Previous studies demonstrated that cesarean section might reduce the risk of MTCT for some viruses, such as human immunodeficiency virus and herpes simplex virus [7‐9]. Numerous studies in China have sought to examine the relationship between delivery mode and rate of MTCT of HBV [10‐16]. However, the effect of different delivery modes on MTCT of HBV remains unclear. To elucidate the question of whether cesarean section, as compared to vaginal delivery, may reduce the risk of MTCT of HBV, we conducted this meta-analysis.

The flow diagram for literature research and study selection is shown in Fig. 1. After screening the title and/or abstract of 1489 potentially relevant articles, 166 articles were evaluated in detail. Of these, 3 articles [22‐24] were excluded for not having been conducted in China. Finally, 28 publications [10‐16, 25‐45] were eligible for inclusion in the meta-analysis.

Table 2 displays the main characteristics of the identified studies on the effect of delivery mode on MTCT of HBV. All included articles were published in the period between 2001 and 2015. Among the articles, 2 were case-control studies. All of the others were retrospective cohort studies. Seven were published in English, and the others were published in Chinese. Two articles reported the results grouped by maternal HBeAg status. Six studies were conducted exclusively in HBeAg + mothers, two were conducted solely in HBeAg-mothers, eight did not specify this information, and the remaining studies had mixed HBeAg + and HBeAg- populations (HBeAg + range from 3.83% to 67.19%). Two studies were conducted among pregnant women who all received HBIG administration, nine were conducted among those without HBIG administration, 15 did not specify, and four had mixed populations (HBIG range from 21.93 to 80%). One study was conducted with 7.81% of the mothers having received antiviral therapy, 14 were conducted among those who had not received antiviral therapy, and the remaining did not report whether antiviral therapy had been administered. Infants were tested for HBV within 24 h of birth before immunoprophylaxis in 6 studies. Among the studies with a follow-up period of more than 1 month, all infants received the hepatitis B vaccine in 24 studies. With regard to HBIG administration in infants in these 24 studies, 17 studies were conducted with 100% administration, 3 did not report this information, and 4 studies had a range from 53.3 to 84.34%.

In this meta-analysis, we found that cesarean section could significantly reduce the risk of MTCT of HBV in China. The significant effect was not affected by maternal HBeAg status and follow-up time, but was influenced by both maternal and infant HBIG administration. Our results are consistent with the findings of two previous meta-analyses [46, 47]; however, one only included 4 studies and another included 10 studies worldwide. In the meta-analysis reported by Chang et al. [46], most of the included studies were performed in China, but some Chinese articles were excluded owing to the lack of available translations. We were able to take full advantage of Chinese databases and include 28 studies performed in China in this meta-analysis, making it the largest and most robust meta-analysis to date.

The mechanism of MTCT of HBV remains unclear. Most MTCTs likely occur perinatally by microperfusion of maternal blood to the fetal circulation during the uterine contractions and tearing of the placenta at birth. Other possible modes of infection include swallowing amniotic fluid, vaginal secretions, or exposure to maternal blood during vaginal delivery [13]. Elective cesarean section results in the least amount of placental contraction and has been speculated to involve the least maternal-fetal transfusion [15]. It also limits direct contact of the fetus with infected secretions or blood in the maternal genital tract.

Several limitations of our meta-analysis should be acknowledged. Despite demonstrating the efficacy of cesarean section for preventing MTCT of HBV, the conclusion of this study must be considered with great caution. Firstly, the included studies were retrospective cohort and case-control studies, not randomized controlled trials. Some bias and confounding factors could not be well controlled in the retrospective studies. Secondly, the data on maternal HBV DNA level in the included studies were lacking, making it difficult to reach conclusions. The maternal HBV DNA level was considered as the most important independent risk factor for vertical transmission by many studies [5, 48, 49]. Thirdly, although we found the significant effect did not differ by maternal HBeAg status, in most of the studies we included, the authors did not report maternal HBeAg status, or the participants had mixed HBeAg statuses. HBeAg positivity had a close relationship with HBV DNA level. Finally, HBIG administration and antiviral therapy in pregnant women were not reported in most studies. The results may have been affected by the lack of these data. In addition, owing to missing clinical details on hepatitis B, varying study quality, and study heterogeneity, it would be difficult to justify a randomized trial of cesarean section, which is currently an unproven and invasive intervention. A detailed, well-designed observational study, where all infants receive HBIG and vaccination and all mothers experience perinatal hepatitis B care, might be a more appropriate next step.

Our meta-analysis found that cesarean section could reduce the risk of MTCT of HBV in comparison to vaginal delivery in China. Whether elective cesarean section can be recommended for clinical practice as a preventive measure against MTCT of HBV should be considered with caution. Future well-designed randomized control trials with adequate statistical power will be needed to confirm our findings.