There are three possible stages of HBV infection by MTCT.
Prenatal transmission (in utero transmission)
HBV infection by MTCT may occur in utero (Fig. 2), which could explain immunoprophylaxis failure. HBV has been detected in the placenta, umbilical cord, and liver tissue of infants who died in utero, which implies that HBV infection occurred in utero.15–21 Strategies to prevent HBV infection by MTCT in the prenatal period include early detection by universal HBsAg screening during pregnancy followed by HBeAg screening. HBV DNA/viral load should be evaluated if HBsAg is positive. However, in areas with scant resources, the WHO recommends using HBeAg alone, instead of viral load, as an indicator for initiating antiviral therapy. A systematic review of 27 studies indicated that the sensitivity and specificity of HBeAg for the diagnosis of HBV viremia with a DNA threshold ≥5.3–6.2 log10 IU/mL were 88.2% [95% confidence interval (CI): 83.9–91.5] and 92.6% (95% CI: 90–94.5), respectively.1 To assess maternal health, women should be referred to specialists for disease evaluation and proper treatment following international guidelines.22,23
Invasive obstetric procedures during pregnancy increase the risk of HBV infection by MTCT (Fig. 2) and should be initially carefully considered in pregnant women who was positive in HBeAg screening.24 In a recent case–control study, the risk of MTCT of HBV was significantly higher in women with a high HBV DNA viral load (≥7 log10 copies/mL) who underwent amniocentesis than in those who did not (50% vs. 4.5%; odds ratio: 21.3; 95% CI: 2.96–153.77).25
Perinatal transmission
Most HBV infections by MTCT occur at birth, and studies have demonstrated the presence of viral pathogen in the placenta, umbilical cord, gastric content, amniotic fluid, and vaginal fluid, and very high viral loads in infant serum during the first 2–3 months of life.26 Complications of labor, including threatened preterm labor and threatened abortion, and history of MTCT in a previous pregnancy might increase the risk for MTCT.27 In cases of preterm labor, there is no evidence of a high rate of MTCT in preterm infants.15,28,29 Still, theoretically, these infants may be potentially exposed to infection by procedures that cause breaks in the skin or mucosal barrier (Fig. 2), such as fetal scalp blood sampling or vigorous suction after birth.27
There is a hypothesis that high maternal viral load associated with HBeAg positivity may result in a risk of infection in the perinatal stage. Lowering the viral burden during pregnancy could prevent HBV infection by MTCT at this stage. Most studies,30–32 including a systematic review,33 reported the effectiveness of antiviral therapy such as telbivudine, tenofovir, or lamivudine during the late stage of pregnancy compared with immunoprophylaxis alone in HBeAg-positive pregnant women with high viral loads without any severe side effects. Consequently, most national and international guidelines recommend antiviral therapy if the HBV DNA level is higher than the established threshold using telbivudine, tenofovir, or lamivudine during the third trimester. However, in 2018, Jourdain et al.34 conducted a randomized controlled trial study in Thailand to compare antiviral therapy (tenofovir) with immunoprophylaxis or immunoprophylaxis alone in HBeAg-positive mothers. They found no significant difference in the MTCT rates between the two groups. To our knowledge, that is the only RCT that questioned the efficacy of antiviral therapy to prevent MTCT. Another protective factor was the very early treatment with a birth dose at <3 h of life in the the study participants, which might be the reason for the high effectiveness of immunoprophylaxis.
Theoretically, passive immunity from HBIGs would prevent MTCT during labor. As HBV infection has a long incubation period, active immunity through HBV vaccination could prevent infection if given as soon as possible. As a result, immunoprophylaxis initiated in this stage has a high-cost effectiveness.35–37 At birth, the mainstay of prevention is active immunoprophylaxis with a series of at least three doses of HBV vaccine, as the timely birth dose within 12 to 24 h after birth.7,38,39 Passive immunoprophylaxis using HBIGs is recommended to increase the success rate of MTCT if given within 12 to 24 h.7,39 However, HBIG is not readily available in countries with scant resources given the requirement for the cold chain process, inadequate supplies, and high costs. Recent studies, including a systematic review, have demonstrated no significant difference in treatment with vaccine alone or in combination with HBIG to prevent HBV MTCT,40 especially in HBeAg-negative mothers.41 Poovorawan et al.39 found that in countries with limited HBIG resources, such as Thailand, a timely birth dose of HBV vaccine within 12 h of birth without HBIG or antiviral therapy during pregnancy could prevent MTCT, in which only 2 of 55 children were born HBV-positive, which implied an efficacy of up to 96%. Poovorawan et al.42 also compared infants who received an HBV vaccination series at birth, 1 month, and 6 months of life with HBIG and a HBV vaccine series alone. They reported a protective efficacy of 94.8% in infants receiving HBV vaccination series alone and 100% in infants receiving both HBV vaccination series and HBIG administration at birth. In Thailand, the protective efficacy of a birth dose of HBV vaccine, usually given at <3 h after birth, either alone or combined with HBIG, was very high. The very high protective efficacy of timely birth dose of HBV vaccination combined with HBIG might explain why antiviral therapy in HBeAg-positive mothers had no additional protective efficacy from HBV vaccination series combined with HBIG. A very prompt HBV vaccine birth dose within 12 h (usually <3 h) after birth might be an additional and simple strategy to increase the success rate of MTCT prevention. Further study investigating the efficacy of HBV vaccination alone within hours of birth is warranted, especially in undeveloped countries such as Sub-Saharan Africa where HBIG is less accessible.
Despite the low occurrence of HBsAg, a high frequency of transient occult HBV infection (OBI), defined by HBV DNA positivity but anti-HBcAg and HBsAg negativity at 1 year of age, was reported in 8.3–9.9% of immunized infants born to HBsAg-positive mothers.43 A recent study reported OBI in 6.8% of children (3/44) born to HBsAg-positive mothers. One in three children progressed to overt HBV infection or seropositivity for HBsAg and anti-HBcAg after 5–7 years of follow-up.44 However, the rapid administration of a timely HBV birth dose might be effective in preventing OBI. Lu et al.45 found that a birth dose administered within 6 h significantly reduced OBI occurrence at the 36-month follow-up. Therefore, a timely birth dose with a HBV vaccination series not only prevented overt infection but also reduced OBI occurrence. However, long-term follow-up and close monitoring of children with OBI is needed, as there might be an increased risk of overt HBV infection under these circumstances.46,47 Other OBI-associated factors and their clinical importance should be further investigated. Rarely, virological factors that could lead to immunoprophylaxis failure involve a viral escape mutant.48
A genetic analysis of a determinant in HBsAg might have a role. Interestingly, a recent systematic review study demonstrated the increased risk of MTCT from natural labor compared with cesarean section in HBeAg-positive mothers with high viral loads.4 The findings conflict with the recommendations of all the currently available guidelines1,3,49 that favor cesarean section or instrument assisted-delivery over obstetric indications such as labor dystocia, abnormal or indeterminate fetal heart rate tracing, previous cesarean section, breech presentation, HIV-positive pregnant woman with high viral loads, etc. However, there were the critical comments about the methodology of this meta-analysis study, especially the inclusion/exclusion of some studies,5,50 possible misrepresentation of a study, and merging data of urgent cesarean section into the vaginal delivery group, instead of merging data of urgent cesarean section into elective cesarean section before the analysis.5 Moreover, the cost–benefit and safety of elective cesarean section should be further evaluated before applying this strategy for MTCT prevention in all HBeAg-positive mothers with high viral load.
Postnatal transmission
Although HBV DNA can be detected in maternal breast milk and saliva, the viral load is very low compared with levels in the blood. Thus, most studies have found that breastfeeding and close contact did not appear to significantly increase the risk of MTCT.1,2,13,26,51 However, a systematic review and meta-analysis by Pan et al.4 showed that a non-breastfeeding modality had a significantly reduced risk of MTCT in HBeAg-positive mothers with high viral loads who did not receive antiviral therapy during pregnancy. From that study, the possibility of MTCT in breastfeeding might be attributed to the presence of cracked nipples or lesions of the infant skin that might have acted as the major route of HBV transmission via the bloodstream, not via breast milk. Unfortunately, no discussion exists about this crucial aspect on that meta-analysis study.4 Thus, we recommend continuing breastfeeding in mothers who received antiviral agents (tenofovir, lamivudine, or telbuvudine) in the third trimester of pregnancy. In mothers who do not receive an antiviral agent to lower the HBV viral load during pregnancy, breastfeeding should be postponed if they have cracked nipples, which would allow the virus to infect their infants via the bloodstream.
In addition, given its availability and cost effectiveness, active immunoprophylaxis is the mainstay of preventing MTCT. An HBV vaccination series is effective if administered at birth, 1 month, and 6 months of age.42 However, the schedule for the HBV vaccination series in Thailand differs from that in other countries, with 4–5 doses of HBV vaccine indicated by Thailand’s EPI. The policy is based on a study by Poovorawan et al.,52 which compared two regimens of HBV vaccination given at birth and at 2, 4, and 6 months versus HBV vaccine given at birth and at 1, 2, 4, and 6 months. They found a significantly improved effectiveness with five doses of HBV vaccine to prevent HBV infection in HBsAg-positive mothers. The study underlined the protective efficacy of a timely birth dose and multiple injections, especially if there were no delays in the second dose. As the rate of HBV vaccination failure in infants with HBsAg-positive mothers is very low even without antiviral therapy during pregnancy,34,42 we hypothesize that a robust active immunity resulted from the very prompt administration of a HBV vaccine birth dose (usually within 3 h of birth)34 and multiple HBV vaccination series in these high-risk infants might be another additional factor in reducing the risk of MTCT. In particular circumstances, such as preterm infants with body weights of <2,000 g, an additional dose should be administered, that is vaccinations at birth, body weight >2,000 gm, and 1, 2, 4, and 6 months of age.