Abstract
Background
Vertical mother-to-child transmission (MTCT) of the hepatitis B virus (HBV) remains an important issue. Timely administration of hepatitis B immunoglobulin (HBIG) and of the HBV vaccine is effective in preventing MTCT in infants born to HBV-infected mothers. However, HBIG is often not easily available in low-income countries or regions.
Methods
We compared in a retrospective cohort study the HBV vaccine efficacy alone and in combination with HBIG in preventing vertical MTCT in infants born to HBeAg-negative carrier mothers in Jiangsu province, China. Based on the administration of the HBV vaccine and HBIG shortly after birth, children were divided into two groups: Group 1, administration of the HBV vaccine alone, and Group 2, concurrent use of HBIG and of the HBV vaccine.
Results
A total of 620 infants born to HBeAg-negative carrier mothers were enrolled into this study. Group 1 included 195 children who had received the HBV vaccine alone after birth, and Group 2, 425 children who had received both HBIG and the HBV vaccine. Children were followed up to the age of 68 and 42 months, respectively. MTCT of HBV occurred in 0% (0/195) in Group 1 (HBV vaccine alone) and 0% (0/425) in Group 2 (HBV vaccine and HBIG) (p = 1.00).
Conclusion
In this retrospective cohort study, we found that HBV vaccination alone shortly after birth was effective in preventing MTCT of HBV in infants born to HBeAg-negative carrier mothers.
Keywords: Hepatitis B virus, Mother-to-child transmission, Hepatitis B vaccine, Hepatitis B immunoglobulin, Hepatitis B e Antigen, Efficacy assessment
1. Introduction
Hepatitis B virus (HBV) infection is a global public health problem. It is estimated that around 250 million people are chronically infected with the virus.1 Vertical mother-to-child transmission (MTCT) is the major route of HBV transmission in many parts of the world. Before the availability of HBV immunoprophylaxis, 10–30% of infants born to hepatitis B surface antigen (HBsAg)-positive carrier mothers with negative hepatitis B e antigen (HBeAg) and 70–90% of those born to positive HBeAg carrier mothers were chronically infected with HBV, respectively.2, 3, 4
Immunoprophylaxis with the HBV vaccine is most effective in preventing infection and has been adopted in national immunization programs of 190 countries or regions.5 Because infants born to HBV-infected mothers are exposed to the virus at birth and during delivery, post-exposure immunoprophylaxis measures, or concurrent use of hepatitis B immunoglobulin (HBIG) and the HBV vaccine, are recommended by the World Health Organization (WHO) and many countries.6 After implementation of this strategy, MTCT of HBV was reduced to 0-<0.1% and 5–10% in infants born to HBeAg-negative and HBeAg-positive carrier mothers, respectively.7, 8, 9, 10, 11, 12
However, there are limitations to HBIG availability in many instances. Thus, its administration to infants born to HBV-infected mothers is not implemented in all countries or regions.6 Previous studies have shown that immunization with the HBV vaccine alone in infants born to HBV-infected HBeAg-negative carrier mothers had the same protective efficacy as combining vaccine and HBIG13,14 or that MTCT rates were not statistically different between children who had received the vaccine alone and those who had received both HBIG and the vaccine.15 The present retrospective cohort study reviews the use of the HBV vaccine alone and in combination with HBIG in the prevention of MTCT of HBV in infants born to HBV carrier HBeAg-negative mothers in Jiangsu province, China.
2. Methods
2.1. Study subjects
China has implemented a nationwide policy of universal HBV vaccination in all infants since 2002 with a free three dose HBV vaccine at 0, 1, and 6 months. In addition, HBIG has been recommended for newborns of HBsAg-positive mothers. However, the actual administration of HBIG had been suboptimal before the implementation of a nationwide program to administer free HBIG (100 IU) in all newborns of HBsAg-positive mothers which started from July 2011.16 Thus, a considerable proportion of infants of HBsAg-positive mothers born before July 2011 did not receive HBIG at birth.
The present study is a retrospective analysis of the outcome of HBV infection in 620 children born between August 2002 and June 2011 from a Jiangsu provincial population-based project on birth defects (205 children), Nanjing Drum Tower Hospital (252 children) in Nanjing city, and Zhenjiang Fourth People's Hospital (163 children) in Zhenjiang city, Jiangsu province (Fig. 1). Inclusion criteria for the mothers were: (1) HBsAg-positive and HBeAg-negative status during pregnancy; (2) an absence of anti-HBV agents use before pregnancy; (3) an absence of anti-HBV agents during pregnancy; and (4) an absence of co-infection with hepatitis A, C, D, and E, and the human immunodeficiency virus.
Fig. 1.
Flow of subject enrollment. Abbreviations: HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; anti-HBs, antibody against HBsAg; HBeAg, hepatitis B e antigen; HBIG, hepatitis B immunoglobulin.
HBV infection in the pregnant women taking part into the project on birth defects was defined in 2009 by retrospectively testing for HBV serological markers in 6398 archived serum samples collected at 15–20 week gestation between August 2002 and July 2004 (Fig. 1a).17 The use of HBIG and of the HBV vaccine in children of the mothers from the project on birth defects was checked using children's vaccination cards at follow-up visits conducted between October 2009 and March 2010, during which blood samples were collected after parents or guardians had given written signed consent.16 The mothers' HBV infection status from the Nanjing Drum Tower Hospital and Zhenjiang Fourth People's Hospital was checked using case records during their in-patient stay for delivery; the administration of HBIG and of the HBV vaccine in children born in these two hospitals was checked using case records and children's vaccination cards at follow-up visits, which were conducted from September 2011 to November 2012 (Fig. 1b). Blood sampling was performed after signed consent taken from their parents or guardians.
Based on the administration of the HBV vaccine and of HBIG shortly after birth, children were divided into two groups: Group 1, administration of the HBV vaccine alone, and Group 2, concurrent use of HBIG and of the HBV vaccine. Demographic and clinical characteristics, including age, maternal HBV DNA level, alanine amino transferase (ALT) level, and immunization records, were retrospectively collected from hospitalization charts or measured on archived serum samples.
This study was approved by the Institutional Review Board of the Ethics Committee of each hospital (Nanjing Drum Tower Hospital, XK200709E; Zhenjiang Fourth People's Hospital, 2011016). Written informed consent was obtained from the children's parents/guardians.
2.2. Laboratory tests
Serum samples collected from the study children were tested by commercial ELISA kits for HBsAg, antibody to HBsAg (anti-HBs), HBeAg, antibody to HBeAg (anti-HBe), and antibody to HBV core antigen (anti-HBc) at Nanjing Drum Tower Hospital. HBsAg was tested with an ELISA kit (Huakang Biotech, Shenzhen, China) or microparticle enzyme immunoassay (Architect HBsAg, Abbott, North Chicago, USA). Anti-HBs and HBeAg were quantified with a microparticle enzyme immunoassay (AxSYM AUSAB, Abbott).
HBV DNA levels were measured in mothers during pregnancy by fluorescent quantitative polymerase chain reaction (PCR) with a lower detection limit of 100 IU/ml (Shenyou Biotech, Shanghai, China).
2.3. Definitions and statistical analysis
Children were classified with perinatally-acquired HBV infection if they tested positive for HBsAg at the age of 7 months or older. If negative for HBsAg and with anti-HBs titers ≥10 mIU/mL, they were defined as responders to HBV immunization. Anti-HBs levels of 10–99.99 mIU/mL, 100–999.99 mIU/mL and ≥1000 mIU/mL were defined as low, medium, and high levels, respectively.
Statistical analysis was performed using the IBM SPSS Statistics version 26 (SPSS Inc., Chicago, USA). Students t-test was used to compare statistical significance of differences in maternal age, HBV DNA level, and children age at follow-up between the two groups. Chi-square test was used to compare maternal ALT levels, distribution of children gender and anti-HBs positive rate between the two groups. Anti-HBs levels were expressed as median and range and compared using Mann–Whitney U test. A p value < 0.05 was considered as statistically significant.
3. Results
3.1. Baseline characteristics of pregnant women and infants
Based on the administration of the HBV vaccine alone or in combination with HBIG shortly after birth, study children were divided into two groups: Group 1 with 195 children who had received the HBV vaccine alone, and Group 2 with 425 children who had received HBIG and the HBV vaccine. Demographic and clinical characteristics of these children and their mothers are shown in Fig. 2. Maternal age, ALT level and children's gender were comparable between the two groups with 95.3% in Group 1 and 99.1% in Group 2 having received the three-dose HBV vaccine (p = 0.683), respectively. The median age at follow-up in Group 1 (68 months) was higher than in Group 2 (42 months) (p < 0.001).
Fig. 2.
The primary demographic and clinical characteristics of enrolled mothers and their neonates.
Fig. 3 shows that maternal HBV DNA was detectable in 79.0% of the mothers in Group 1 and in 75.3% of Group 2 (P = 0.313) (Fig. 3A). Median maternal HBV DNA levels (2.78 log IU/mL) in Group 1 were relatively higher than (2.62 log IU/mL) in Group 2 (p = 0.025) (Fig. 3B).
Fig. 3.
(A) Detection rate and (B) distribution of HBV DNA levels among HBsAg-positive, HBeAg-negative pregnant women in the two groups.
3.2. HBV infection in children
The HBV infection rate was 0.0% (0/195) for infants immunized with the HBV vaccine alone and 0.0% (0/425) for those who had received both the HBV vaccine and HBIG. No significant difference was found between the two groups (p = 1.000).
3.3. Anti-HBs levels in infants
As shown in Fig. 4A, overall rates of positive anti-HBs results in Group 1 and Group 2 children were 57.9% (113/195) and 68.9% (292/424), respectively (p = 0.007). Among these children, 66 in Group 1 and 348 in Group 2 were assessed for anti-HBs levels. Proportions of anti-HBs levels ≥1000, 100–999.99, 10–99.99, and <9.99 mIU/ml in Group 1 and Group 2 children are presented in Fig. 4B, with 9.1% (6/66), 13.6% (9/66), 42.4% (28/66), and 34.8% (23/66), respectively, in children immunized with the HBV vaccine alone, and 7.8% (27/348), 26.7% (93/348), 37.9% (132/348), and 27.6% (96/348), respectively, in children immunized with both HBIG and the HBV vaccine. The anti-HBs response of infants born to HBeAg-negative mothers was comparable in the two groups (p = 0.186).
Fig. 4.
(A) Anti-HBs positive rate and (B) distribution of anti-HBs levels among the infants with different prophylactic strategies in two groups.
4. Discussion
In the present retrospective study from a Jiangsu provincial population-based project on birth defects, we have found that among 620 children born to HBsAg-positive/HBeAg-negative mothers, none of the 195 children who had received the HBV vaccine alone after birth had been infected with HBV and none of the 425 children who had received a combination of HBIG and of the HBV vaccine were infected either. These results indicate that while the concurrent use of HBIG and of the HBV vaccine can almost completely stop MTCT of HBV in infants born to HBeAg-negative HBV carrier mothers, HBV vaccination alone was not associated with a difference in transmission in our study.
Maternal HBV DNA level is the main determining factor for MTCT of HBV.18,19 Before the availability of HBIG and of the HBV vaccine, MTCT occurred in up to 70–90% of infants born to HBeAg-positive mothers, and in 5–30% of infants born to those who were HBeAg-negative.2, 3, 4 The relatively low rate of MTCT in infants born to HBeAg-negative carrier mothers is mainly attributed to a lower viral exposure20 with HBV DNA levels 10000–100000-fold lower than in HBeAg-positive mothers.8,21, 22, 23, 24 In the present study, none of the children born to HBeAg-negative carrier mothers were infected with HBV, irrespective of HBIG administration (Fig. 2), which indicates that HBV immunization alone in this population may have provided them with sufficient protection to prevent infection. An important parameter is the presence of low viral loads in the mothers with a median HBV DNA levels of 2.78 log IU/ml in Group 1 and of 2.62 log IU/ml in Group 2 (Fig. 3B).
Universal HBV immunization for infants had been introduced by the end of 2020 in the 190 Member States of the WHO, however, only 113 of them had introduced the HBV birth vaccine dose in neonates within 24 hours of birth, with a global overall coverage of 42%.5 This low coverage is probably responsible for the HBV transmission in infants born to HBV-infected mothers or those cared by HBV-infected parents or guardians. The WHO has reported that the HBV prevalence in children younger than 5 years old was reduced in 2015 to 0.9% in the Western Pacific Region, where the coverage of the birth dose reached 84%, but prevalence was higher at 3.0% in the African Region, where the coverage of birth dose was only 6%.1,6 In China, the coverage of a timely birth dose since 2012 has reached >95%, and the HBV prevalence in 2014 in children younger than 4 years old had declined to 0.3%, as compared to 10% before the availability of HBIG and HBV imminization.25,26
Several previous studies have demonstrated that the efficacy of HBV immunization on its own in infants of HBeAg-negative carrier mothers was almost equal to the concurrent use of HBIG and the HBV vaccine,13,14 with an absence of perinatal infection in infants who had received the HBV vaccine alone.27 Thus, some authors have considered that HBIG use in infants of HBeAg-negative carrier mothers had limited benefit in preventing MTCT.13,15,28 However, larger studies of children immunized with the HBV vaccine alone have shown that there was still some residual degree of MTCT of HBV which occurred in children of HBeAg-negative carrier mothers,15,29 whereas concurrent use of HBIG and the HBV vaccine almost completely prevented transmission.7, 8, 9, 10, 11, 12,30 As HBIG is safe and has no serious side-effects, the main concern remains its cost. However, because of the severe sequelae of chronic HBV acquired during infancy, it is cost-effective to use HBIG and the administration of the HBV vaccine alone is an option only when HBIG is not available. Therefore, every effort should be made to administer both HBIG and the HBV vaccine to infants of HBV-infected mothers, irrespective of maternal HBeAg status, to prevent MTCT of HBV.18,31,32
Ethics statement
This study was approved by the institutional review board of the ethics committee of each hospital (Nanjing Drum Tower Hospital, XK200709E; Zhenjiang Fourth People's Hospital, 2011016). Written informed consent was obtained from the parents/guardians, who signed the informed consent for children.
Author contributions
Wenjun Zhang, Chenyu Xu, Yanjing Rui, Yali Hu, Junhao Chen, and Yi-Hua Zhou designed the study. Chenyu Xu, Yanjing Rui, Jie Chen, Tingmei Chen, Yimin Dai, Yali Hu, and Yi-Hua Zhou followed up the participants. Wenjun Zhang, Chenyu Xu, Yanjing Rui, and Jie Chen performed laboratory testing. Biyun Xu performed the statistical analysis. Wenjun Zhang, Chenyu Xu, Yanjing Rui wrote the manuscript. Yali Hu, Junhao Chen, and Yi-Hua Zhou critically revised the manuscript. All authors interpreted the data, edited the manuscript, and approved the submitted version of manuscript.
Funding
This work was funded by the National Natural Science Foundation of China (81672002) and a grant from the Health Commission of Nanjing City (ZKX20021), China.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Contributor Information
Yali Hu, Email: dtylhu@126.com.
Junhao Chen, Email: nj_cjh@aliyun.com.
Yi-Hua Zhou, Email: zgr03summer@126.com.
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