Of the estimated 350 million individuals chronically infected with HBV worldwide, it is generally accepted that at least 50% of cases acquired their infections during either the perinatal period or in early childhood, especially in areas of high endemicity. In China, where the prevalence of HBV is high, 85-90% of transmissions can be prevented successfully with proper immunoprophylaxis
]. However, approximately 10-15% of newborns from HBV carrier mothers suffer from HBV infection because of intrauterine transmission. MTCT, which includes intrauterine transmission, perinatal transmission and transmission during lactation, is an important reason for failure of immune prophylaxis
]. It has been demonstrated that active immunisation (HBVac) combined with passive immunisation (HBIG) can effectively prevent perinatal transmission and transmission during lactation
]. Nonetheless, the incidence of intrauterine HBV infection remains as high as 43% when maternal serum HBV DNA exceeds 108
], even with prompt administration of active and passive vaccination. del Canho et al.
also reported that intrauterine infection occurs only when maternal serum HBV DNA levels are high (> 150 pg/ml or 3.16
]. Intrauterine HBV transmission occurs primarily during the third trimester
] and is presumed to cause a minority of the infections not prevented by prompt immunisation. Probable reasons for transmission are thought to be the breach of the placental barrier caused by HBV
] and polymorphisms in some cytokine genes (such as those encoding for interferon-γ and tumour necrosis factor-α)
In general, it is not recommend to initiate antiviral therapy with nucleoside analogues in HBV-infected persons who are immune tolerant. However, they have the same risk of intrauterine infection as CHB patients for their high HBV DNA levels. Because the risk of HBV intrauterine infection is clearly related to the level of maternal viraemia, and most foetal organs have developed by the third trimester, a strategy to interrupt this process is maternal treatment with antiviral drug in late pregnancy. Interferon and peg-interferon are contraindicated during pregnancy largely because of their known anti-proliferative effects. Lamivudine, the first nucleoside analogue inhibitor to be approved for the treatment of CHB, has long been used for both HIV and HBV infection during pregnancy and has displayed reliable prevention effects
]. Even though lamivudine is classified as FDA pregnancy risk category C, the European Association for the study of the Liver also confirmed its safety during late pregnancy in 2009
]. However, it was also reported that reducing maternal HBV DNA levels even to undetectable status by lamivudine in late pregnancy could not guarantee prevention of intrauterine HBV infection in the newborns
]. Telbivudine was approved by the FDA in 2006 and the State Food and Drug Administration in 2007 for the treatment of patients with CHB, and has demonstrated faster and better efficacy than lamivudine in patients with HBeAg-positive and HBeAg-negative CHB disease.
A few studies have evaluated the efficacy of telbivudine application in preventing intrauterine HBV infection during late pregnancy. Therefore we conducted this meta-analysis to arrive at an evidence-based conclusion. In this meta-analysis, the treatment group consisted of 306 mothers who received 600 mg/d telbivudine from the second or third trimester of pregnancy until delivery or 1 month after delivery. The control group consisted of 270 mothers who did not receive any antiviral drug. All newborns received HBIG and HBVac after birth. The pooled results clearly showed that the seropositivity rate for HBsAg or HBV DNA was significantly lower in the telbivudine group, both at birth and at 6–12 months follow up. Meanwhile, maternal HBV DNA levels prior to delivery were significantly lower in the telbivudine group. We further conducted meta-analysis based on study type (RCT or NRCT) to minimise any potential heterogeneity and found that the type of study design did not affect the conclusion. However, we should pay more attention to the evidence grades of these included trials. Because published studies were limited, only six trials were included in the meta-analysis. Two trials contained randomised controls, but the details of the randomisation sequence were not provided. The other four trials included non-randomised controls. In the Han
] and Zhang, 2010
] studies, the mothers self-selected themselves into one arm or the other. When some demographic features were presented, more of the control group had abnormal ALT levels
]. In Yao’s study
], the mothers were divided into different groups according to baseline ALT levels. Thus, more high-quality, well-designed and randomised controlled multi-centre trails are necessary to verify the results in the future.
As an orally bioavailable L-nucleoside analogue with potent activity against HBV, telbivudine has shown no effects on human nucleotides and DNA synthesis
]. Toxicology research has also demonstrated that telbivudine has no significant organ toxicity, carcinogenicity, genotoxicity, mitochondrial toxicity in vitro
, teratogenicity, or embryo-foetal toxicity
]. In the phase III GLOBE trial, most adverse events reported were classified as mild or moderate in severity and were not attributed to telbivudine, and elevations in serum CK were more common in the telbivudine group. Based on its characteristics, telbivudine is listed by the FDA as a pregnancy category B drug. The treatment guidelines of the Asian Pacific Association for the Study of the Liver also designated telbivudine as a replacement antiviral therapy during pregnancy in 2008
]. In our meta-analysis we analysed elevations in serum CK, elevated ALT levels after drug withdrawal and other adverse events. Since the reported studies only evaluated the short-term effects of telbivudine and only a few studies reported adverse events, the long-term safety of telbivudine in infants still need to be assessed in the future. In addition, we found that the number of infected infants at age 6–12 months was less than the number of infected newborns. The probable reason for this decline is that maternal blood containing HBsAg and HBV DNA was introduced into the bodies of the newborns through the umbilical cord during delivery, which were later neutralised by anti-HBs of HBIG
To our knowledge, this is the first systematic meta-analysis of this topic. We are convinced that our search strategy was comprehensive and exhaustive. We comply with the standardized guidelines on the reporting of systematic reviews according to the PRISMA statement and the PRISMA checklist (see Additional file
). Two investigators (Min Deng and Xin Zhou) independently extracted data and entered them in a customised form. Disagreements were resolved by consensus when necessary. However, the following limitations of our meta-analysis should be considered. First, we searched for studies published only in English or Chinese. Second, due to limited published studies, we expanded the search to include NRCTs. Third, only a few studies were included and they had small sample sizes. For these reasons, we could not perform a deep analysis. Besides, all included studies were performed in mainland China. Therefore, more clinical studies performed in different populations and other regions are necessary to access the generalisability of the results.