Although the number of FBS has greatly decreased because of the emergence of earlier, more accurate, and safer diagnostic modalities [12], in some centers with a high prevalence of certain genetic diseases, limited molecular diagnostic techniques, and the very delayed abnormal sonographic findings, FBS could not be completely replaced by chorionic villus sampling or amniocentesis [13, 14]. Most reported studies on FBS mainly focused on the procedure-related safety and efficacy [13,14,15,16]; however, the FBS-related risk of MTCT of blood-borne viruses, such as HBV, has not been assessed [7]. The present case series with one HBV-infected infant born to a HBeAg-positive and highly viraemic mother highlights the non-negligible concern on this issue.
HBV is the mostly transmitted from infected mothers to children during childbirth through contact with blood and other body fluids [1]. After implementation of universal HBIG plus HBV vaccine strategy, which is mainly targeted to the peripartum MTCT, intrauterine infection become an important cause of postnatal immunoprophylaxis failure. The possible mechanisms of the intrauterine infection include transplacental leakage, placental infection, peripheral blood leukocyte infection, and germline cell infection [17]. Invasive diagnostic procedures during pregnancy may imply the potential risk of transmission of HBV because of disruption of the maternal-fetal surface through needle passage and leading to placental leakage. The findings of two recent studies on the risk of MTCT after amniocentesis confirmed this hypothesis [10, 11]. FBS is a relatively invasive and time-consuming technique due to its penetration through one or more tissue layers into the umbilical cord than amniocentesis. Therefore, it theoretically has more potential for fetal exposure to maternal blood cells and higher risk of MTCT of HBV. In this case series, one in six infants born to an untreated HBsAg-positive mother who underwent transplacental FBS with post-procedure bleeding was finally considered as the MTCT case. This indicated that FBS might increase the risk of MTCT of HBV, and transplacental procedures should be avoided.
Similarly, the risk factors of MTCT after amniocentesis included maternal HBeAg-positive and HBV DNA > 7 log10 IU/mL [10, 11], which were also the most important features of this MTCT case after FBS. Serum HBV DNA level and HBeAg status are the two best indicators of viral replication; thus, high maternal viraemia and HBeAg positivity have always been the most prominent predictors for MTCT [2,3,4, 18, 19]. Antiviral agents, such as TDF, telbivudine, and lamivudine, can efficiently inhibit maternal HBV replication and significantly reduce MTCT rates [18, 20]. Moreover, no MTCT events occurred among women with HBeAg-negative or HBV DNA < 7 log10 IU/mL after invasive procedures in our previous study [11] and current case series. Presumably, short-term antiviral therapy to obtain the optimal threshold of HBV DNA levels before the procedure may be feasible to prevent MTCT. However, only one available study reported on this preventive strategy, without reaching statistical significance, a trend of decreasing MTCT rates was observed when amniocentesis was performed in highly viraemic mothers with antiviral therapy [11]. Meanwhile, in our case series, one HBeAg-positive mother with HBV DNA of 7.56 log10 IU/mL, after 6 weeks TDF treatment, achieved a relative low level of 4.52 log10 IU/mL before FBS, and her infant was persistent HBsAg-negative from birth to the age of 12 months. As for optimal maternal target viral load before invasive procedure, especially FBS, there is currently no recommendation and guideline due to paucity of data. In fact, it is controversial to use the recommended DNA level of 5.3 log10 IU/mL (200,000 IU/mL) before delivery [18] as an anticipated level before invasive procedures to prevent MTCT, because the amniocentesis and FBS are usually performed at 15–24 weeks and more than 20 weeks, respectively, which is well before the timing for postnatal immunoprophylaxis, even the risk of contact maternal blood is lower than in childbirth. Meanwhile, initiation of antiviral therapy in early pregnancy is another concern. To prevent MTCT among highly viraemic mothers, most international guidelines recommend the TDF treatment start at 24–28 weeks of gestation [18]. However, antiviral therapy before FBS may be initiated earlier than 24 gestational weeks. The safety issues associated with a relative longer fetal exposure to TDF including renal and bone toxicity should be cautious, even most studies on fetal TDF exposure found no significant risk of the adverse effects during childhood [21]. Therefore, the use of maternal antiviral treatment before FBS to prevent MTCT should be further studied in details.
On the other hand, it is worth noting that, with a higher HBsAg prevalence of 5–7.99%, both Thailand and China had been ranked as the high-intermediate endemic regions [22], where hundreds and thousands of FBS have been performed in many referral centers [12,13,14,15,16] although most data have not been published. MTCT risk assessment after FBS and feasible preventive strategies may be impossible if professionals are unaware of maternal HBV infection or MTCT risks. Therefore, maternal HBV serologic testing and awareness of the potential risk of MTCT before invasive procedures, including amniocentesis and FBS, should be the first step to consult patients and prevent transmission.
In summary, although no accurate rate of FBS-related MTCT of HBV can be drawn from these limited data, this case series highlights the concern of this issue and demonstrates that FBS may increase the risk of MTCT of HBV in women with HBeAg-positive and high viral loads. FBS, especially transplacental techniques, should be avoided in this high-risk population. Non-invasive cell-free DNA screening may be an alternative to these women but limitation of this screening should be fully informed and counselled. Meanwhile, antiviral therapy may be effective to decrease the risk of MTCT after FBS in highly viraemic women. Further studies that include more FBS cases with hepatitis B are needed to characterize the risk of MTCT after FBS.
