Preventing Mother-to-Infant Transmission of HBV
Our study presents a large-scale data set of children born to HBsAg-carrier mothers after universal HBV immunization. Our study found that prenatal maternal HBeAg positivity accurately distinguished between the groups of their offspring with high and minimal breakthrough infection and HBsAg-carrier rates. There are several important implications from these data. First, the differences in the breakthrough infection rates between the maternal HBeAg-positive and HBeAg-negative groups are so large that applying different preventive strategies to the 2 groups within a population-based program can be justified. Second, we have identified breakthrough infection in a certain high-risk subpopulation under the current active/passive HBV immunization program; further reductions in the maternal-infant transmission rates should rely on novel preventive methods for this specific group, such as antiviral therapy in the third trimester of pregnancy to reduce the maternal viral load at the time of delivery. Third, with the major risk group for breakthrough infection in the immunized children identified, evidence-based, nationwide surveillance should be initiated for earlier detection, monitoring, and treatment of HBV carriers in the era of universal HBV immunization. Despite breakthrough infection still occurring, HBV-related complications (such as cirrhosis and HCC) in the next generation may be minimized as much as possible through a well-conducted surveillance and secondary preventive system and good antiviral therapies.
There have been scanty data on the infection rate among children born to HBeAg-negative mothers, particularly after the universal HBV immunization program. In the early vaccine trials and in the beginning years of universal immunization, the definition of "less infectious mothers" in previous reports largely was based on low HBsAg titers or HBeAg negativity using early HBeAg detection methods, rendering the early data not applicable to the current situation. In the current study, a strikingly low rate (<1%) of HBsAg positivity among children born to HBeAg-negative mothers was found. The data indicate that active immunization alone was effective in blocking most of the mother-to-infant transmission in infants of HBeAg-negative, HBsAg-carrier mothers (Table 1 and Table 3). Importantly, currently applied HBeAg laboratory tests are highly accurate in defining highly infectious and less-infectious groups. Because HBeAg-negative mothers comprise about 25%–75% of all HBsAg-carrier mothers in a population, the data on this group are very important for the development of a universal immunization program.
The benefit and necessity of HBIG for children born to HBeAg-negative, HBsAg-carrier mothers has been an issue of controversy for a long time. The limitation of this study was that in children born to HBeAg-negative mothers, the 2 groups with or without HBIG at birth were not randomized, but chosen by parental will. It is hard to conduct randomized trial because both strategies are formal government-supported programs (with no HBIG in Taiwan and with HBIG in the United States). Although we have found a seemingly 52% reduction in the HBsAg rates in those with HBIG compared with those without HBIG, the evidence to support the routine use of HBIG in infants born to HBeAg-negative, HBsAg-carrier mothers is inadequate because the anti-HBc rates and HBsAg-carrier rates in the vaccine-only group without HBIG were already very low: 1.88% and 0.29% (Table 1 and Table 2). An extremely large sample size would be needed to test the difference in the HBsAg(+) rates between the 2 groups, approximately 20,461 subjects would be required in each group (total, 40,922 subjects); and 3718 subjects would be required in each group (total, 7436 subjects) to detect the difference in the HBsAg(+) and anti-HBc(+) rates with an α value of .05 and statistical power = 0.9. Although it is still possible that there is a true difference in either the HBsAg(+) rates or the anti-HBc rates between the HBIG(−) and HBIG(+) children born to HBeAg(−) mothers, it does not seem feasible to detect.
An important concern associated with administering HBIG to children with HBeAg-negative mothers is preventing fatal fulminant hepatitis. Few studies have reported on fulminant hepatitis B in immunized infants. Aside from our previous nationwide survey of 25 cases, only 3 previous reports have described 4 cases of immunized infants developing fulminant hepatitis; 2 of them had received HBIG (Supplementary Table 2). We performed a brief cost-benefit analysis of preventing fulminant hepatitis by administering HBIG to the children of HBeAg-negative mothers, based on an estimate of 15,000 neonates born to HBeAg-negative mothers annually. Administering HBIG to these neonates would cost approximately $1,573,427. We assumed that fulminant hepatitis would develop in 1 of 1050 of these infants (0.00%–0.28%), and the cost associated with hospitalization, intensive care, transplantation, and potential mortality was estimated to be $2,132,867, yielding a cost-benefit ratio of 1.36 (0 –3.97 in the sensitivity analysis). The details are provided in Supplementary Table 3. The data support a policy of administering both HBIG and HBV vaccines to all the infants born to HBsAg-positive mothers in the United States, regardless of the maternal HBeAg status. The cost-benefit ratio of administering HBIG to the maternal HBeAg-negative group should be thoroughly considered in determining the strategy of universal immunization programs in each country.
For children who successfully were prevented from contracting HBV infection in infancy, we have shown that the humoral responses to the HBV vaccines were good. There have been concerns about the interference of the administration of HBIG on active immunization, which has not been found in our study. The anti-HBs rates in children born to HBeAg-negative mothers did not differ between those who did and those who did not receive HBIG at birth. Overall, neonatal immunization provided satisfactory protection against HBV infection for at least 10 years despite these children having close contact with their HBV-carrier mothers.
From the view of global HBV prevention, it is suggested that HBV vaccines be given universally to all newborns, irrespective of maternal HBsAg status, in both high- and low-endemic countries. It is noteworthy that the screening program of pregnant women has had great impact on the tightly linked, multistep strategies in maternal-child health in the control of HBV-related diseases. The choice of pregnant women HBsAg and/or HBeAg screening strategy not only lead to different children's immunization program, but also have impacts on maternal health related to HBV-associated disease/complications, and selects different target population for surveillance program of children with risk of breakthrough infection. The link between strategies of screening pregnant women, neonatal immunization, and surveillance of high-risk children is listed in Table 4. Compared with maternal viral load, HBeAg testing costs much less, is widely available, could be linked to screening pregnant women, and thus is a suitable screening marker with a high call rate (1 in 10 cases) to identify children with a risk of breakthrough HBV infection. Without screening pregnant women, the childhood postimmunization surveillance program could not possibly be established, and as a result the control of HBV in the second generation would be delayed. Furthermore, future strategies to lower the rate of breakthrough infection in children born to highly infectious mothers are being investigated actively. These strategies will be applied most readily in countries with adequate HBsAg and HBeAg screening of pregnant women.
In conclusion, the children born to HBeAg-positive mothers are a major risk group for breakthrough HBV infection in the era of universal immunization. A low (<1%) rate of HBsAg-positivity was observed in the children born to HBeAg-negative mothers with vaccinations only. HBIG administration in infants born to HBeAg-negative mothers has not been proven to reduce chronic HBV infection rates, but a benefit in preventing infantile fulminant hepatitis is still possible. Maternal HBsAg screening with HBeAg testing is suggested, not only as a useful maternal health marker, but also as being valuable for determining preventive strategies in their children, as well as for surveillance of children at risk for breakthrough infection. In the real world, the rates of HBV infection may be higher than the rates shown in this study, which reflect the results of optimal compliance with HBV vaccination on schedule and HBIG within 24 hours. The data from this study are important for further efforts to eliminate HBV infection using strategies to interrupt mother-to-infant transmission, for better care of HBV-infected women of childbearing age, and for treating children with chronic HBV infection and related liver diseases early in life.
Discussion
Our study presents a large-scale data set of children born to HBsAg-carrier mothers after universal HBV immunization. Our study found that prenatal maternal HBeAg positivity accurately distinguished between the groups of their offspring with high and minimal breakthrough infection and HBsAg-carrier rates. There are several important implications from these data. First, the differences in the breakthrough infection rates between the maternal HBeAg-positive and HBeAg-negative groups are so large that applying different preventive strategies to the 2 groups within a population-based program can be justified. Second, we have identified breakthrough infection in a certain high-risk subpopulation under the current active/passive HBV immunization program; further reductions in the maternal-infant transmission rates should rely on novel preventive methods for this specific group, such as antiviral therapy in the third trimester of pregnancy to reduce the maternal viral load at the time of delivery. Third, with the major risk group for breakthrough infection in the immunized children identified, evidence-based, nationwide surveillance should be initiated for earlier detection, monitoring, and treatment of HBV carriers in the era of universal HBV immunization. Despite breakthrough infection still occurring, HBV-related complications (such as cirrhosis and HCC) in the next generation may be minimized as much as possible through a well-conducted surveillance and secondary preventive system and good antiviral therapies.
There have been scanty data on the infection rate among children born to HBeAg-negative mothers, particularly after the universal HBV immunization program. In the early vaccine trials and in the beginning years of universal immunization, the definition of "less infectious mothers" in previous reports largely was based on low HBsAg titers or HBeAg negativity using early HBeAg detection methods, rendering the early data not applicable to the current situation. In the current study, a strikingly low rate (<1%) of HBsAg positivity among children born to HBeAg-negative mothers was found. The data indicate that active immunization alone was effective in blocking most of the mother-to-infant transmission in infants of HBeAg-negative, HBsAg-carrier mothers (Table 1 and Table 3). Importantly, currently applied HBeAg laboratory tests are highly accurate in defining highly infectious and less-infectious groups. Because HBeAg-negative mothers comprise about 25%–75% of all HBsAg-carrier mothers in a population, the data on this group are very important for the development of a universal immunization program.
The benefit and necessity of HBIG for children born to HBeAg-negative, HBsAg-carrier mothers has been an issue of controversy for a long time. The limitation of this study was that in children born to HBeAg-negative mothers, the 2 groups with or without HBIG at birth were not randomized, but chosen by parental will. It is hard to conduct randomized trial because both strategies are formal government-supported programs (with no HBIG in Taiwan and with HBIG in the United States). Although we have found a seemingly 52% reduction in the HBsAg rates in those with HBIG compared with those without HBIG, the evidence to support the routine use of HBIG in infants born to HBeAg-negative, HBsAg-carrier mothers is inadequate because the anti-HBc rates and HBsAg-carrier rates in the vaccine-only group without HBIG were already very low: 1.88% and 0.29% (Table 1 and Table 2). An extremely large sample size would be needed to test the difference in the HBsAg(+) rates between the 2 groups, approximately 20,461 subjects would be required in each group (total, 40,922 subjects); and 3718 subjects would be required in each group (total, 7436 subjects) to detect the difference in the HBsAg(+) and anti-HBc(+) rates with an α value of .05 and statistical power = 0.9. Although it is still possible that there is a true difference in either the HBsAg(+) rates or the anti-HBc rates between the HBIG(−) and HBIG(+) children born to HBeAg(−) mothers, it does not seem feasible to detect.
An important concern associated with administering HBIG to children with HBeAg-negative mothers is preventing fatal fulminant hepatitis. Few studies have reported on fulminant hepatitis B in immunized infants. Aside from our previous nationwide survey of 25 cases, only 3 previous reports have described 4 cases of immunized infants developing fulminant hepatitis; 2 of them had received HBIG (Supplementary Table 2). We performed a brief cost-benefit analysis of preventing fulminant hepatitis by administering HBIG to the children of HBeAg-negative mothers, based on an estimate of 15,000 neonates born to HBeAg-negative mothers annually. Administering HBIG to these neonates would cost approximately $1,573,427. We assumed that fulminant hepatitis would develop in 1 of 1050 of these infants (0.00%–0.28%), and the cost associated with hospitalization, intensive care, transplantation, and potential mortality was estimated to be $2,132,867, yielding a cost-benefit ratio of 1.36 (0 –3.97 in the sensitivity analysis). The details are provided in Supplementary Table 3. The data support a policy of administering both HBIG and HBV vaccines to all the infants born to HBsAg-positive mothers in the United States, regardless of the maternal HBeAg status. The cost-benefit ratio of administering HBIG to the maternal HBeAg-negative group should be thoroughly considered in determining the strategy of universal immunization programs in each country.
For children who successfully were prevented from contracting HBV infection in infancy, we have shown that the humoral responses to the HBV vaccines were good. There have been concerns about the interference of the administration of HBIG on active immunization, which has not been found in our study. The anti-HBs rates in children born to HBeAg-negative mothers did not differ between those who did and those who did not receive HBIG at birth. Overall, neonatal immunization provided satisfactory protection against HBV infection for at least 10 years despite these children having close contact with their HBV-carrier mothers.
From the view of global HBV prevention, it is suggested that HBV vaccines be given universally to all newborns, irrespective of maternal HBsAg status, in both high- and low-endemic countries. It is noteworthy that the screening program of pregnant women has had great impact on the tightly linked, multistep strategies in maternal-child health in the control of HBV-related diseases. The choice of pregnant women HBsAg and/or HBeAg screening strategy not only lead to different children's immunization program, but also have impacts on maternal health related to HBV-associated disease/complications, and selects different target population for surveillance program of children with risk of breakthrough infection. The link between strategies of screening pregnant women, neonatal immunization, and surveillance of high-risk children is listed in Table 4. Compared with maternal viral load, HBeAg testing costs much less, is widely available, could be linked to screening pregnant women, and thus is a suitable screening marker with a high call rate (1 in 10 cases) to identify children with a risk of breakthrough HBV infection. Without screening pregnant women, the childhood postimmunization surveillance program could not possibly be established, and as a result the control of HBV in the second generation would be delayed. Furthermore, future strategies to lower the rate of breakthrough infection in children born to highly infectious mothers are being investigated actively. These strategies will be applied most readily in countries with adequate HBsAg and HBeAg screening of pregnant women.
In conclusion, the children born to HBeAg-positive mothers are a major risk group for breakthrough HBV infection in the era of universal immunization. A low (<1%) rate of HBsAg-positivity was observed in the children born to HBeAg-negative mothers with vaccinations only. HBIG administration in infants born to HBeAg-negative mothers has not been proven to reduce chronic HBV infection rates, but a benefit in preventing infantile fulminant hepatitis is still possible. Maternal HBsAg screening with HBeAg testing is suggested, not only as a useful maternal health marker, but also as being valuable for determining preventive strategies in their children, as well as for surveillance of children at risk for breakthrough infection. In the real world, the rates of HBV infection may be higher than the rates shown in this study, which reflect the results of optimal compliance with HBV vaccination on schedule and HBIG within 24 hours. The data from this study are important for further efforts to eliminate HBV infection using strategies to interrupt mother-to-infant transmission, for better care of HBV-infected women of childbearing age, and for treating children with chronic HBV infection and related liver diseases early in life.
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