The efficacy of two different doses of hepatitis B immunoglobulin in interrupting mother-to-child transmission of hepatitis B virus: a systematic review and meta-analysis

Background: There isn’t consensus about the optimal dose of hepatitis B immunoglobulin (HBIG) in combination with hepatitis B vaccine to preventing mother-to-child transmission (MTCT) of hepatitis B virus(HBV). Methods: We systematically searched MEDLINE, Embase, and Cochrane Library from database inception to Jan 16, 2019 for studies. The primary outcome was HBsAg and/or HBV DNA positive in infants at 6-12 months old. We performed a meta-analysis with a random-effects model to calculate a pooled estimate of MTCT. Results: We included 31 studies, comprising of 12151 infants. There wasn't significant differences in the pooled MTCT rates between 100 IU HBIG group and 200 IU HBIG group (5% vs 5%, P = 0.757). When further stratified according to HBeAg status, in HBeAg(+) mothers, 7% (95%CI 4%-11%) infants became chronic HBV infection in 100 IU HBIG group compared to 7% (95%CI 5%-9%in 200 IU group. The rates were 1% (95%CI 0%-2%) in 100IU group and 0% (95%CI 0%-1%) in 200IU group in infants born to HBeAg(-) mothers, respectively. When further comparing MTCT in infants from mothers with HBV DNA ≥ 1×10^6 IU/mL, the pooled MTCT rate was 12% (95%CI 7%-17%) in 100IU group and 8% (95%CI 5%-13%) in 200IU group, respectively. In addition, comparative analysis of four studies concerning two different dosages of HBIG further manifested the comparability. MTCT

The efficacy of two different doses of hepatitis B immunoglobulin in interrupting mother-tochild transmission of hepatitis B virus: a systematic review and meta-analysis The first affiliated hospital of Xi'an JiaoTong University MTCT in infants from mothers with HBV DNA≥1×10^6 IU/mL, the pooled MTCT rate was 12% (95%CI 7%-17%) in 100IU group and 8% (95%CI 5%-13%) in 200IU group, respectively. In addition, comparative analysis of four studies concerning two different dosages of HBIG further manifested the comparability.
Conclusion: 100 IU HBIG is sufficient in preventing MTCT for infants from chronic hepatitis B infected mothers, regardless of maternal HBeAg status or viral load.

Background
Hepatitis B virus (HBV) infection remains a major cause of chronic hepatitis and associated morbidity and mortality worldwide 1 . Interrupting mother-to-child transmission (MTCT) has become the main priority for elimination HBV infection, especially in epidemic regions. Universal implementation of hepatitis B vaccine is the key strategy to preventing vertical (mother-to-child transmission) and horizontal transmission, and has manifested prominent effectiveness in reducing MTCT 2,3 .
As a passive immune agent against HBV, the first reported use of hepatitis B immunoglobulin (HBIG) to prevent MTCT was in 1978 4 . A few studies has demonstrated that immediate administration of HBIG play an essential role in the prevention of perinatal HBV infection 5− 7 . Since then, active immunoprophylaxis with the hepatitis B vaccine in conjunction with HBIG were extensively administrated and the efficacy of has been fully confirmed 1 .
Nevertheless, there is no consensus on the recommended birth dosage of HBIG. At the very beginning, 0.5 ml HBIG per kg body-weight (1ml = 100 IU) displayed protection for MTCT 7 . A randomized blind controlled trial had further manifested the importance of HBIG (0.5 ml HBIG, 145 IU) in prevention of the perinatally transmission 8 . The recommended dosage of HBIG in different guidelines also varied among different countries. In the United States, the standard dose of HBIG was 0.5 mL for infants born to hepatitis B surface antigen positive (HBsAg(+)) women (HyperHEPATITIS B VACCINE S/D: 220 IU/mL, HepaGam: > 312 IU/mL, Nabi-HB: > 312 IU/mL) 9 . However, 100 IU HBIG was recommended to prevent MTCT in China 10 .
Various dosages have been conducted in clinical practice. 100 IU, 200 IU, or even two doses of 200 IU HBIG were given to infants 11− 13 . Whereas, considering efficacy and cost, the optimal dose of HBIG is still ambiguous. With the Decision Tree-Markov model and cost-benefit analysis, Yang and his colleagues suggested that the optimal strategies was 200 IU HBIG at birth together with 3 schedules of vaccination 14  Up to present, few studies has compared the efficacy of different dosages of HBIG combined with hepatitis B vaccine in preventing MTCT of hepatitis B virus, and systematic review is absent. Therefore, we performed a systematic review and meta-analysis to assess the effectiveness of 100 IU and 200 IU HBIG, which will provide evidence for developing strategies for MTCT prevention.

Search strategy
This systematic review and meta-analysis was performed using a preplanned protocol (registered in PROSPERO: CRD42019130398). Systematic reviews about the efficacy of different dosages of HBIG in infants had not been found. Firstly, we searched the studies reporting on MTCT after passive-active immunoprophylaxis in HBV mothers, conforming to the Preferred Reporting Items for Systematic reviews and Meta Analysis (PRISMA) guidelines 16 .Two reviewers (SF and NJY) searched PubMed, Embase, and Cochrane Library, for studies published in English or Chinese from inception to Jan 16, 2019. Search strategy included terms related to HBV ( eg, "HBV" or "hepatitis B" or "hepatitis B virus"), infant ( eg, "neonate" or " newborn" or "infant") and Immunization ( eg, "Hepatitis B Vaccines" or "Vaccination" or "vaccin*" or "Hepatitis B immunoglobulin" or "Immunization" or "Immunoprophylaxis"). Additionally, we also manually screened the reference lists of primary studies and review articles for additional references.

Inclusion and exclusion criteria
Two independent reviewers (SF and NJY) screened the titles and abstracts for eligibility using pre-specified inclusion/exclusion criteria. No type of study restriction was imposed. Our rationale was that inclusion of publications reporting on children, from chronic hepatitis B infected (CHB) women without intervention during pregnancy, were administrated full-course implementation of hepatitis B vaccine and one birth dose of 100IU or 200IU HBIG. The studies were included if they presented the rate of immonoprophylaxis failure, which was defined as HBsAg and/or HBV DNA positive in infants at 6-12months old. We excluded studies in which pregnant women were co-infected with human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis D virus (HDV), syphilis, toxoplasmosis, herpes virus, rubella virus, or cytomegalovirus; infants were preterm, congenital abnormality or developmental disorders; sample size<10; or studies published as abstracts only. If there were more than one report from the same research center, we selected the most recent report or the report with the most complete data including subgroup data.

Data abstraction and quality assessment
Two reviewers independently extracted data according to inclusion/exclusion criteria. We developed a case report form (CRF) to extract the following information from each study: first authors' name, year of publication, study design, countries/regions, maternal hepatitis B e-antigen (HBeAg) status, maternal HBV DNA level before delivery, intervention for infants, dosage of HBIG, time of HBIG administered, time point of immunogenicity assessment, sample size, and relevant outcome data. Disagreements were resolved by consensus with the other authors.
We contacted authors to obtain clarification for studies with unclear methods or insufficient date. The quality of the randomized controlled trials (RCTs) was evaluated using the Cochrane Risk of Bias assessment tool, and studies were classified as low risk of bias, unclear/medium risk of bias or high risk of bias. With Newcastle-Ottawa scale (NOS), observational studies with a cumulative score ≥ 7, 4-6, and < 4 were considered as high, fair, and low quality, respectively.

Statistical analysis
We performed proportion meta-analyses to estimate the rate of immonoprophylaxis failure of two different doses of HBIG, and head-to-head meta-analyses to directly compare the efficacy of 100IU and 200IU HBIG. Statistical analysis was carried out according to the per-protocol analysis data, and relative risk (RR) and 95% confidence interval (95%CI) were estimated by the Mantel-Haenszel fixed-effects model, or the inverse variance random effects model. The heterogeneity test was assessed using the chi-squared test and I 2 statistics, with I 2 statistics 25%-50%, 50%-75%, and > 75% indicated a low, moderate, and high degree of heterogeneity, respectively. Subgroups analyses were performed for potential sources of heterogeneity. Stata (version 13.1; Stata, College Station, TX, USA) was used for proportion meta-analyses, and RevMan 5.3 (Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark) for head-to-head meta-analyses. P value < 0.05 was considered statistically significant.

Characteristics of the eligible studies
Of the 5789 citations and 6 additional manually searched articles evaluated, 359 studies were eligible for full-text review, thirty-one 11,12,15,17− 44 of which were included in our analysis. All studies except four 30,31,36,40 were published in English.
Included studies were conducted in five countries, China, Turkish, Greece, Australian, and Japan, from 1999 to 2018. Data on study characteristics were shown in Table 1. All enrolled infants were administered with HBIG within 24 h after birth.
The levels of HBsAg and/or HBV DNA were detected at 6-12 months old. The methodological quality of the included studies are reported in the appendix Table   S1 and Table S2.  (Fig. 2a). Of the four studies eligible for head-to-head meta-analyses, 894 infants received 100 IU and 1030 infants received 200 IU HBIG.

Subgroups analysis by maternal HBV DNA level
As we all known, HBV DNA load is closely correlated with MTCT, especially in CHB pregnant women with high viremia 45 . Efficacy of different doses HBIG based on HBV DNA level before delivery was carried out. 12 datasets including 1652 infants provided data of maternal HBV DNA ≥ 1 × 10^6 IU/mL before delivery. As showed in  Maternal high viremia is an independent risk factor for MTCT 50,51 . In this meta-

Availability of data and materials
All relevant data for this study have been added as additional files.

Ethics approval and consent to participate
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Figure 1
Flow chart of the study screening and selection for inclusion in the meta-analysis.

Figure 1
Flow chart of the study screening and selection for inclusion in the meta-analysis.  Pooled estimates of MTCT rates in infants born to HBsAg+/HBeAg-mothers Figure 4 Pooled estimates of MTCT rates in infants born to HBsAg+/HBeAg-mothers Pooled estimates of MTCT rates in infants born to high viremia mothers (HBV DNA ≥ 1×10^6 Figure 5 Pooled estimates of MTCT rates in infants born to high viremia mothers (HBV DNA ≥ 1×10^6