Vertical Transmission of Hepatitis B Virus: Propositions and Future Directions

Vertical Transmission of Hepatitis B Virus: Propositions and Future Directions

Hepatitis B virus (HBV) infection remains a significant global health challenge, with vertical transmission—mother-to-child transmission during pregnancy, childbirth, or breastfeeding—being a major route for the persistence of chronic HBV infection, particularly in endemic regions such as China, Southeast Asia, and sub-Saharan Africa. Despite the widespread implementation of hepatitis B vaccination programs, which have reduced HBV prevalence by over 80%, vertical transmission continues to pose a critical barrier to the global elimination of HBV. This review explores the mechanisms, diagnostic criteria, and preventive strategies for vertical transmission, highlighting the gaps and future directions necessary to achieve the World Health Organization (WHO) goal of eliminating hepatitis B as a public health threat by 2030.

Routes of Vertical Transmission

Vertical transmission of HBV can occur at any stage of pregnancy, including intrauterine, peripartum, and postpartum periods. The success of postpartum immunoprophylaxis suggests that the majority of vertical transmissions occur during the peripartum period. However, intrauterine transmission is also a significant mechanism, supported by evidence of HBV markers and infected cells in placental tissues. Studies have shown a gradual reduction in HBV markers from the maternal to the fetal side of the placenta, indicating transplacental leakage or infection of placental cells. Additionally, HBV DNA levels in maternal blood are positively associated with the risk of intrauterine transmission.

Another proposed route of vertical transmission is through infected germ cells. HBV markers, including hepatitis B surface antigen (HBsAg), hepatitis B core antigen, and HBV DNA, have been detected in oocytes from female HBV carriers. However, the role of germ cells in vertical transmission remains controversial, as the integration of HBV DNA in embryonic cells has not been conclusively linked to transmission in offspring.

Breastfeeding, while a potential route of HBV transmission, has not been shown to increase the risk of infection in infants when appropriate immunoprophylaxis is administered at birth. HBV DNA and HBsAg can be detected in breast milk, but the benefits of breastfeeding outweigh the risks, especially when combined with vaccination and hepatitis B immune globulin (HBIG) administration.

Diagnostic Criteria for Vertical Transmission

The diagnosis of vertical transmission has historically been challenging due to the lack of universal diagnostic standards. The presence of HBsAg and/or HBV DNA in infants is considered indicative of infection, but the transplacental transfer of maternal antibodies can complicate diagnosis. Systematic reviews and meta-analyses have shown that the positive rates of HBV markers in infants are comparable at 6, 7, and 12 months of age, and significantly lower than at birth. Therefore, the detection of HBsAg and/or HBV DNA at 6 to 12 months of age is now considered the standard for diagnosing vertical transmission. In cases where testing is unavailable at this age, an assessment at 12 to 24 months is acceptable, provided that routine vaccination has been administered to exclude horizontal transmission.

Interventional Strategies for Vertical Transmission

Screening Strategy for HBV

Universal screening for HBsAg before or during pregnancy is a cornerstone of preventing vertical transmission. In endemic regions like China, universal screening has significantly reduced neonatal HBV infection by identifying infected mothers and enabling timely immunoprophylaxis. The combined administration of hepatitis B vaccine and HBIG immediately after birth is highly effective in preventing peripartum transmission. However, the necessity of universal screening is debated in regions where HBIG is unavailable, as screening alone does not provide additional management for infants of HBsAg-positive mothers.

The WHO has identified hepatitis B envelope antigen (HBeAg) as a sensitive predictor of immunoprophylaxis failure, making it a valuable marker for identifying high-risk pregnancies. Universal screening for HBsAg and HBeAg is recommended, with antiviral prophylaxis considered for infants of HBeAg-positive mothers. Additionally, testing for hepatitis B surface antibody (HBsAb) is advised in endemic regions to identify women who may require vaccination during pregnancy.

Postpartum Immunoprophylaxis

The hepatitis B vaccine, introduced in the early 1980s, remains the most cost-effective measure for preventing HBV infection. A timely birth dose of the vaccine, followed by two or more additional doses, has reduced the prevalence of chronic HBV by nearly 90% in infants of HBeAg-positive mothers and virtually eliminated transmission in infants of HBeAg-negative mothers. However, global coverage of the timely birth dose remains suboptimal, with only 46% of infants receiving the vaccine at birth and 87% completing the vaccination series. In highly endemic regions like Africa, coverage is even lower, highlighting the urgent need to scale up vaccination efforts.

HBIG, a purified product of human immunoglobulin containing high titers of HBsAb, provides additional protection when administered with the hepatitis B vaccine. The combination of HBIG and vaccine is particularly effective in preventing transmission in infants of HBeAg-positive mothers. However, the use of HBIG is limited by its cost, the need for cold chain storage, and the lack of evidence supporting its necessity in infants of HBeAg-negative mothers. Current guidelines recommend a dose of 100 IU of HBIG in China, while higher doses are used in the United States. Studies have shown that different doses of HBIG have similar efficacy, making the lower dose a cost-effective option.

Antiviral Prophylaxis During Pregnancy

Despite the success of immunoprophylaxis, approximately 10% of infants still acquire HBV infection, particularly those born to mothers with high viral loads. Antiviral therapy during pregnancy has emerged as a critical strategy for reducing vertical transmission in high-risk pregnancies. Tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are the preferred antiviral agents due to their high efficacy and safety profiles. TDF has been shown to be well-tolerated in pregnant women, with no significant increase in adverse events such as postpartum hemorrhage, cesarean section rates, or birth defects. Long-term follow-up studies have also demonstrated the safety of TDF exposure in infants, with no adverse effects on growth, renal function, or bone development.

The optimal viral load threshold for initiating antiviral prophylaxis remains debated. Recent studies suggest that a threshold of 2 × 10^5 IU/mL is appropriate, as the risk of vertical transmission increases continuously with higher viral loads. Antiviral prophylaxis is typically initiated before 28 weeks of gestation to achieve viral suppression before delivery. However, the long-term safety of antiviral agents, particularly TAF, requires further research.

Achievements in China

China, with its large population of HBsAg-positive individuals, has made significant strides in reducing HBV transmission through vertical transmission. Since 1992, hepatitis B vaccination has been integrated into the national immunization program, with a timely birth dose coverage exceeding 90%. The addition of HBIG for infants of HBsAg-positive mothers has further reduced transmission rates. Universal screening for HBV, syphilis, and HIV during pregnancy has also been implemented, leading to a significant decline in HBV prevalence among children. The use of TDF as an affordable and effective intervention has brought China closer to achieving zero vertical transmission.

Research Gaps

Despite the progress made, several gaps remain in our understanding of vertical transmission and its prevention. The necessity of universal screening and HBIG administration, particularly in infants of HBeAg-negative mothers, requires further investigation. The impact of co-infections with hepatitis C virus and HIV on vertical transmission is also poorly understood. Additionally, the influence of HBV genotypes on transmission and prevention strategies needs to be explored. In low-income countries, where vaccine coverage remains low, the use of antiviral prophylaxis during pregnancy may provide a cost-effective alternative. Long-term studies on the safety of TDF and TAF exposure in infants are also needed.

Conclusion

Preventing vertical transmission of HBV is essential for achieving the WHO goal of eliminating hepatitis B by 2030. Vaccination remains the cornerstone of prevention, with the timely birth dose being particularly critical. HBIG provides additional protection in high-risk pregnancies, but its use is limited by cost and availability. Antiviral prophylaxis during pregnancy has emerged as a powerful tool for reducing transmission in mothers with high viral loads. However, significant gaps remain in our understanding of the long-term safety of antiviral agents and the feasibility of implementing these strategies in low-income regions. Addressing these gaps will be crucial for achieving the global elimination of HBV.

doi.org/10.1097/CM9.0000000000001800

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