Efficacy of antepartum administration of hepatitis B immunoglobulin in preventing mother‐to‐child transmission of hepatitis B virus

Abstract The aim of this study was to investigate the efficacy of antepartum administration of three doses of hepatitis B immunoglobulin (HBIG) in interrupting mother‐to‐child transmission (MTCT) of hepatitis B virus (HBV). In this trial, a total of 728 HBeAg‐positive pregnant women with chronic HBV infection who had an HBV DNA level higher than 6log10 copies/mL were enrolled. They were divided into three groups based on individual preference. Subjects in group A and group B received 200 IU (unit) HBIG and 400 IU (unit) HBIG intramuscularly once a month at the third, second and first month before delivery, respectively. Subjects in the control group (C) received no special treatment. All the infants received passive‐active immunoprophylaxis. The HBsAg‐positive rate of all infants at 7‐12 months of age was 5.1% (37/728). Specifically, the HBsAg‐positive rate of infants was comparable in all three groups (5.3% vs 5.1% vs 5%, P = 0.988). No significant difference was found in anti‐HBs levels between the infants aged 7‐12 months in the three groups (P = 0.469). HBV DNA levels of the umbilical cord blood in the HBV‐infected group were higher than those in the uninfected group (5.2 vs 3.4log10 copies/mL, P < 0.001), and these with family history of HBV infection were also higher (45.9% vs 28.5%, P = 0.034). To conclude, administration of passive‐active immunoprophylaxis to infants contributed to effective prevention of the MTCT of HBV; extra antepartum administration of HBIG during pregnancy could not decrease the rate of MTCT or increase the anti‐HBs levels of infants born to HBsAg‐positive mothers with HBV DNA higher than 6log10 copies/mL.

Specifically, the HBsAg-positive rate of infants was comparable in all three groups (5.3% vs 5.1% vs 5%, P = 0.988). No significant difference was found in anti-HBs levels between the infants aged 7-12 months in the three groups (P = 0.469). HBV DNA levels of the umbilical cord blood in the HBV-infected group were higher than those in the uninfected group (5.2 vs 3.4log 10 copies/mL, P < 0.001), and these with family history of HBV infection were also higher (45.9% vs 28.5%, P = 0.034). To conclude, administration of passive-active immunoprophylaxis to infants contributed to effective prevention of the MTCT of HBV; extra antepartum administration of HBIG during pregnancy could not decrease the rate of MTCT or increase the anti-HBs levels of infants born to HBsAg-positive mothers with HBV DNA higher than 6log 10 copies/ mL.

K E Y W O R D S
efficacy, hepatitis B immunoglobulin, hepatitis B virus, mother-to-child transmission, pregnancy

| INTRODUC TI ON
Hepatitis B virus (HBV) infection is still one of the most prominent public health problems in China. Mother-to-child transmission (MTCT) is considered as the main transmission route of chronic HBV infection. Fifty per cent of infants born to hepatitis B surface antigen (HBsAg)-positive mothers will become carriers without immunization. 1 Hence, the prevention of MTCT is essential in reducing the global burden of chronic HBV infection. [2][3][4][5] In the 1980s, studies showed that in newborns of HBsAg-positive mothers, the MTCT rate was reduced to 23% after vaccination without HBIG 6 and to 3%-7% after passive-active immunization. 7 In 2010, the chronic hepatitis B (CHB) guidelines of China suggested that infants born to HBsAg-positive mothers should be administrated passive-active immunization by injecting HBIG within 24 hours after birth (preferably within 12 hours) and 10 μg HB vaccine at a different anatomical site. 8 In addition, 10 μg of the HB vaccine was administered to infants at 1 and 6 months of age. But, 5%-10% of newborns born to HBsAg-positive mothers can still be chronically infected with HBV. 9 It has been recognized that pregnant women with high viral load are the reason for passive-active immunization failure. 10 Therefore, more and more scholars recommend application of antiviral drugs in the third trimester to block MTCT in pregnant women with high HBV DNA load. 11,12 However, it is still far from ideal in completely eradicating MTCT of HBV due to intrauterine infection and immunoprophylaxis failure in a small number of individuals. 13 HBIG is a purified solution of human immunoglobulin with high titres of antibody against hepatitis B surface antigen (anti-HBs). It is derived from plasma donated by individuals immune to HBV infection. 14 Early reports showed that the antepartum administration of HBIG during pregnancy decreased the HBV DNA levels of mothers and the MTCT rates. 15,16 However, recent reports suggested that antepartum administration of HBIG failed to improve the efficacy of preventing MTCT of HBV. Thus, the efficacy of antepartum administration of HBIG during pregnancy in preventing MTCT needs to be confirmed by further studies.

| Patients
In this trial, all of the 728 HBsAg-positive pregnant women were   All infants received passive-active immunoprophylaxis that received HBIG at birth and hepatitis B vaccine at birth and at 1 and 6 months.

| Laboratory methods
Maternal HBV DNA was tested before delivery; HBsAg, anti-HBs,

| Outcome assessment
HBsAg positivity of infants at the age of 7-12 months was considered to be immunoprophylaxis failure and HBV infection. Infants were defined as hepatitis B positive if HBsAg ≥ 0.05 IU/mL or HBV DNA ≥ 20 IU/mL. Immunity was defined as anti-HBs-positive ≥ 10 IU/ mL.

| Statistical analysis
The data were analysed using Statistical Package for Social Science (SPSS) for windows, version 23.0. Continuous variables conforming to the normal distribution were characterized by the mean and standard deviation (SD). The three groups were compared and analysed by one-way ANOVA. The comparison between the two groups was analysed by Student's t test. The characteristics of the continuous variables not consistent with the normal distribution were described using the median (25% to 75% IQR). The comparison between the three groups and the two groups were analysed by Kruskal-Wallis H and Mann-Whitney U test. Categorical variables were characterized by the proportion and analysed using the chi-squared (χ 2 ) test or Fisher's exact tests. Statistical significance was defined as P < 0.05. Baseline characteristics of mothers and infants stratified by different doses of HBIG injection were comparable (P > 0.05, Table 1).

| The outcomes of different doses of HBIG injection on mothers
Based on the comparison between the HBV DNA levels of mothers injected with different doses of HBIG before delivery, antepartum administration of HBIG was found incapable of decreasing the HBV DNA levels (7.1 vs 7.3 vs 7.4log 10 copies/mL, P = 0.555). AST, TBIL, GLU, HGB, PLT, CHE and CHOL of participants obtained in the three groups were comparable (P > 0.05, Table 2).
ALB between the control group, group A and group B exhibited statistically significant differences (P = 0.018). The control group had higher ALB than groups A and B (P = 0.011, P = 0.01). No significant difference in ALB was found between group A and group B (P > 0.05). Similarly, there were statistically significant differences in ALT levels between the three groups (P = 0.023), with ALT levels in group A lower than those in the control group and group B (P = 0.013, P = 0.027). No significant difference in ALT was found between the control group and group B (P > 0.05, Table 2). The levels of ALT and ALB in the three groups were within normal limits, so there was no clinical significance.

| The effects of infants born to mothers injected with different doses of HBIG
The HBsAg-positive rate of infants aged 7-12 months between the three groups were comparable (5.3% vs 5.1% vs 5%, P = 0.988).
No significant difference was found in the age of mothers whose infants had different anti-HBs levels (P = 0.633, Table 3). The anti-HBs-positive rate of infants at the age of 7-12 months who were born to mothers administrated 200 IU HBIG before delivery reached 100%. Although there were no significant differences in anti-HBs levels between infants aged 7-12 months in the three groups (P = 0.469, Figure 1), the proportion of infants

| Association of different clinical characteristics with HBV infection in infants
The maternal HBV DNA levels before delivery in the HBV-infected group and the uninfected group were comparable (7.5 vs 7.3log 10 Table 4).
Infants born to mothers with HBV family history were more likely to be infected by HBV (45.9% vs 28.5%, P = 0.034). HBV family history was defined as first-degree relatives of pregnant women who had chronic HBV infection. Infants in the uninfected group achieved higher birth weight than those in the HBV-infected group (P = 0.02). There was no significant difference in HBV infection status of infants born to mothers injected with different doses of HBIG (P = 0,988, Table 5).

| D ISCUSS I ON
Passive-active immunization is conducive to effective decrease in the rate of MTCT to 5%-10%. However, pregnant women with high viral load are associated with passive-active immunization failure. 10 Nucleoside/nucleotide analogs were useful and relatively safe in reducing the incidence of MTCT in pregnant women with high HBV DNA load. 11 However, the efficacy of preventing MTCT could not reach 100%.
Once the infection is already established, it is too late to stimulate the production of anti-HBs by the HB vaccine.
Some experts recommend that HBsAg-positive pregnant women receive small dosages of HBIG in their third trimester of pregnancy to interrupt HBV intrauterine infection. 16,19 In theory, The maternal HBV DNA was measured as log 10 copies/Ml.   In the present study, the maternal HBV DNA levels before delivery in the HBV-infected group and the uninfected group were comparable (7.5 vs 7.3log 10 copies/mL, P = 0.176); however, significant differences of HBV DNA levels were found in umbilical cord blood between the HBV-infected and the uninfected groups (5.2 vs 3.4log 10 copies/ mL, P < 0.001 Although there were statistically significant differences in ALT and ALB levels between the three groups, all the indicators were within the normal limits, so the clinical significance was considered to be small. In addition, HBV infection rates of infants born to mothers with family history were higher than those without family history (45.9% vs 28.5%, P = 0.034). We consider that blocking failure may be related to genetic sequences. Some studies have found that there is aggregation of nonresponders in nonresponse family members. The positive rate and average levels of anti-HBs of the first-degree relatives in nonresponders/low responders were significantly lower than those in high responders after three doses of the hepatitis B vaccine, indicating that the response ability to the hepatitis B vaccine of first-degree relatives in nonresponders/low responders was lower than that in strong responders, indicating that nonresponse/low response is related to the individual's genetic background. Studies have also shown that 'S' gene mutations cause immune escape, leading to vaccine immune failure. 33 McDermott et al 34 confirmed that DRBl*0701 and DQBl*02 were closely related to no response after vaccination. In addition, DRl4-DR52 was also associated with a low response to hepatitis B vaccine. 35 To conclude, administration of passive-active immunoprophylaxis to infants contributed to effective prevention of the MTCT of HBV; extra antepartum administration of HBIG during pregnancy could not decrease the rate of MTCT or increase the anti-HBs levels of infants born to HBsAg-positive mothers with HBV DNA higher than 6log 10 copies/mL.

CO N FLI C T O F I NTE R E S T
The authors do not have any conflict of interests to report.