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Received: 15 March 2022 | Revised: 18 August 2022 | Accepted: 19 August 2022

DOI: 10.1111/aogs.14448

S Y S T E M AT I C R E V I E W

Incidence of mother-­to-­child transmission of hepatitis B

in relation to maternal peripartum antiviral prophylaxis:
A systematic review and meta-­analysis

Naijuan Yao1 | Shan Fu1 | Yuchao Wu1 | Zhen Tian1 | Yali Feng1 | Juan Li1 |
Xufei Luo2 | Yuan Yang1 | Fanpu Ji3 | Yaolong Chen2 | Jinfeng Liu1 | Yingren Zhao1 |
Tianyan Chen1

1
Department of Infectious Diseases, The
First Affiliated Hospital of Xi'an Jiaotong Abstract
University, Xi'an, China
Introduction: Mother-­to-­child transmission (MTCT) of the hepatitis B virus (HBV) is
2
Evidence-­Based Medicine Center, School
of Basic Medical Sciences, Lanzhou
a serious public health challenge. Estimating HBV MTCT incidence by region under
University, Lanzhou, China different prophylaxis regimens is critical to understanding the regional disease bur-
3
Department of Infectious Diseases, den and prioritizing interventions. This study aimed to calculate HBV MTCT incidence
The Second Affiliated Hospital of Xi'an
Jiaotong University, Xi'an, China under different prophylaxis regimens globally and regionally and identify the HBV
DNA threshold for maternal peripartum antiviral prophylaxis.
Correspondence
Tianyan Chen, Department of Infectious Material and methods: This review was registered in advance in PROSPERO
Diseases, The First Affiliated Hospital of (CRD 42019120567). We searched PubMed, Embase, China National Knowledge
Xi'an Jiaotong University, Xi'an 710061,
China. Infrastructure, Clini​calTr​ials.gov, and Cochrane Library databases for studies on
Email: [email protected] MTCT in pregnant women with chronic HBV infection from their inception until June
Funding information 13, 2022. MTCT was defined as hepatitis B surface antigen (HBsAg) or HBV DNA
National Natural Science Foundation of seropositivity in infants aged 6–­12 months. We calculated the pooled HBV MTCT in-
China, Grant/Award Number: 81670537
and 81770594; Key Research and cidence using the DerSimonian-­L aird random-­effects model.
Development Project of Shaanxi, Grant/ Results: Among 300 studies, 3402 of 63 293 infants had HBV due to MTCT. Without
Award Number: 2018ZDXM-­SF-­037
prophylaxis regimens, the pooled HBV MTCT incidence was 31.3%, ranging from
0.0% (95% confidence interval [CI] 0.0%–­6.0%; European Region) to 46.1% (95% CI
29.7%–­63.0%; Western Pacific Region). Following the introduction of the hepatitis B
vaccine, the HBV MTCT incidence decreased from 82.9% to 15.9% in HBeAg-­positive
women and from 10.3% to 2.3% in HBeAg-­negative women. Maternal peripartum
antiviral treatment alongside infant immunoprophylaxis further decreased MTCT inci-
dence to 0.3% (95% CI 0.1%–­0.5%). Despite infant immunoprophylaxis, the incidences
of MTCT at maternal HBV DNA levels of <2.30, 2.00–­3.29, 3.00–­4.29, 4.00–­5.29,
5.00–­6.29, 6.00–­7.29 and ≥7.00 log10 IU/ml were 0.0% (95% CI 0.0%–­0.0%), 0.0%

Abbreviations: HBeAg, hepatitis B E antigen; HBIG, hepatitis B immunoglobulin; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; MTCT, mother-­to-­child transmission.

Naijuan Yao and Shan Fu contributed equally to this study.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in
any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2022 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of
Obstetrics and Gynecology (NFOG).

Acta Obstet Gynecol Scand. 2022;101:1197–1206.  wileyonlinelibrary.com/journal/aogs | 1197

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1198 YAO et al.

(95% CI 0.0%–­0.0%), 0.0% (95% CI 0.0%–­0.5%), 0.6% (95% CI 0.0%–­2.6%), 1.0% (95%
CI 0.0%–­3.1%), 4.3% (95% CI 1.8%–­7.5%), and 9.6% (95% CI 7.0%–­12.5%), respectively.
Conclusions: HBV MTCT incidence varies across regions. The Western Pacific Region
bears the heaviest burden. Peripartum antiviral prophylaxis plus infant immuno-
prophylaxis is promising for interrupting HBV MTCT. Regarding the HBV DNA thresh-
old for peripartum antiviral prophylaxis, maternal HBV DNA of 4.00 log10 IU/ml or
greater seems justified.

KEYWORDS
hepatitis B virus, hepatitis B virus DNA threshold, incidence, infant immunoprophylaxis, meta-­
analysis, mother-­to-­child transmission, peripartum antiviral treatment, systematic review

1 | I NTRO D U C TI O N
Key message
Hepatitis B virus (HBV) infection remains a serious public health
The hepatitis B virus mother-­to-­child transmission inci-
issue, affecting an estimated 296 million persons worldwide in 2019
dence under different prophylaxis regimens differs by
and causing 820 000 deaths annually resulting from complications
region. Peripartum antiviral therapy plus infant immu-
of chronic HBV infection.1 With an assumed proportion of 25.3%,
noprophylaxis is a promising strategy to block mother-­
approximately 75 million women of reproductive age are chronically
to-­child transmission. Maternal hepatitis B virus DNA of
infected by HBV, 2 serving as a huge reservoir for mother-­to-­child
≥4.00 log10 IU/ml is a reasonable threshold for peripartum
transmission (MTCT) of HBV. HBV infections in infancy are chiefly
antiviral therapy.
attributed to MTCT, with a 95% risk of evolving into chronic HBV in-
fection later in life and a 40% life-­long risk of progressing to cirrhosis
and hepatocellular carcinoma.1,3 In the absence of interventions, the
high proportions of HBV MTCT and chronicity create a vicious circle
of HBV infections. incidence by hepatitis B E antigen (HBeAg) status is warranted, as
The regional estimation of HBV MTCT incidence is critical to HBeAg helps to identify high-­risk pregnant women in quantitative
understanding the regional disease burden and prioritizing in- HBV DNA-­limited settings.
terventions. Concerning HBV MTCT incidence in the absence of This systematic review and meta-­analysis set out to achieve the
prophylaxis, a systematic review (in 2016) in sub-­S aharan Africa following objectives: first, to assess the effectiveness of different
reported a lower HBV MTCT incidence than in individual Asian preventive measures by pooling the MTCT incidence of HBV; sec-
4
studies. However, whether this fits after systematic evaluation ond, to estimate the HBV MTCT risk under different prophylaxis
by region remains unclear. Regarding prophylaxis for HBV MTCT, regimens in HBeAg-­positive and HBeAg-­negative mothers; third,
the efficacy of at least three doses of the hepatitis B vaccine and to calculate MTCT incidence across regions and to assess the re-
birth doses of hepatitis B immunoglobulin (HBIG), targeted to en- sponse to different prophylaxis regimens by region; and fourth, to
5
hance infant resistance, has been proven. However, infant immu- identify the threshold viral load for antiviral prophylaxis initiation
noprophylaxis is insufficient for pregnant women with a high viral by grouping maternal HBV DNA levels in a narrow range. The goal
load.6 By reducing maternal HBV DNA to a safe level, peripartum of this systematic review is to help physicians to optimize prophy-
antiviral prophylaxis further reduces HBV MTCT risk with a good laxis regimens and determine the priority of MTCT prevention for
7–­9
safety profile. Previous systematic reviews have compared the policy-­makers.
benefits of prophylaxis regimens using odds ratios; however, the
extent of HBV MTCT risk reduction by each prophylaxis regimen
remains uncertain. 2 | M ATE R I A L A N D M E TH O DS
HBV DNA thresholds for peripartum antiviral therapy vary from
5.3 to 7.0 log10 IU/ml. However, current major guidelines have rec- This meta-­analysis was registered in advance in PROSPERO (CRD
ommended that pregnant women with high viral load receive antivi- 42019120567) and presented in accordance with Preferred
ral prophylaxis supplemented with infant immunoprophylaxis.10–­12 Reporting Items for Systematic Reviews and Meta-­analysis (PRISMA)
We identified a systematic review assessing the relation between guidelines. Two investigators independently performed the litera-
maternal viral load and MTCT risk.13 However, an important limita- ture search, study selection, information extraction, and quality as-
tion of this study was including original studies with inappropriate sessment. Discrepancies were resolved by consulting with the third
diagnostic criteria for MTCT. Moreover, the estimate of HBV MTCT investigator.
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YAO et al. 1199

2.1 | Data sources and search strategy evaluated, ie selection of study groups (0–­4 stars), comparability
(0–­2 stars), and outcome ascertainment (0–­3 stars). We categorized
We searched PubMed, Embase, China National Knowledge studies as follows: a score of less than or equal to 4 indicated a high
Infrastructure, Clini​calTr​ials.gov, and the Cochrane Library from incep- risk of bias, and moderate and low risks were indicated by scores of
tion until June 13, 2022. The search strategy included Medical Subject 5–­6 and more than or equal to 7, respectively. Then, we used the
Headings and free texts, using the following search terms and their var- Cochrane Risk of Bias Assessment tool for interventional studies.
iations: hepatitis B, mother, infant, and vertical transmission (Table S1). We made overall risk-­of-­bias judgments primarily based on two do-
In addition, we manually searched for additional relevant studies. mains: random sequence generation (selection bias) and incomplete
outcome data (attrition bias). Studies were at low risk of bias when
both domains were low risk, at high risk of bias when either domain
2.2 | Main outcomes measures was high risk, and at moderate risk of bias in the remaining cases.

This included HBV MTCT incidence.

2.6 | Data analysis

2.3 | Eligibility criteria We calculated MTCT incidences using the DerSimonian–­L aird
random-­effects model and adopted the score confidence interval.
We identified interventional, cohort, nested case–­control, and cross-­ To avoid deleting studies with zero events, we stabilized the avail-
sectional studies, or original data regarding the MTCT incidence of able data using the Freeman–­Tukey double arcsine transforma-
pregnant women with chronic HBV infection (hepatitis B surface anti- tion. We assessed the heterogeneity of included studies using the
gen [HBsAg] positive ≥6 months). MTCT was defined as the detection Cochran's Q statistic and the inconsistency (I2) statistic (p < 0.05 or
of HBsAg or HBV DNA in the infant at 6–­12 months of age. We chose I2 > 50%). In testing for publication bias, 0.5 was applied to zero cells,
the one with more subgroup data and/or the larger sample size if there and one was added to the study sample size. Regarding MTCT inci-
were duplicates. We excluded studies in which prophylaxis measures dence stratified by maternal HBV DNA levels, HBV DNA values in
against MTCT were unclear, outcomes were insufficient to extract, the copies per ml unit were converted to IU/ml by dividing them by 5.14
study sample size was less than 30, and patients were co-­infected with All analyses were performed using the “metaprop” command with
HIV and other viruses to enhance the homogeneity of this study. STATA version 13 (StataCorp).

2.4 | Data extraction 3 | R E S U LT S

We extracted the data using a standardized data extraction form. Our systematic search identified 11 722 records published between
Table S2 summarizes the detailed data extracted. Regarding prophy- 1983 and 2022. After excluding duplicates and screening based on
laxis regimens, we had the following four groups based on the particular title and abstract, 1930 records were retrieved for full-­text assess-
prophylaxis taken by the mother and infant: neither mother nor infant ment, and 300 of them were finally included (Figure 1), covering 22
received any preventive measures (no prophylaxis group); mother took countries/regions. The main characteristics of the included studies
no interventions, and the infant received hepatitis B vaccine (hepatitis are summarized in Tables S4 and S5. Subsequently, 258 studies were
B vaccine group) or co-­injected HBIG (combined immunoprophylaxis assessed for methodological quality (Table S6), of which 60/102 ob-
group); mother undertook peripartum antiviral therapy plus infant com- servational studies and 7/156 interventional studies had a low risk
bined immunoprophylaxis (antiviral therapy plus combined immuno- of bias; most were at moderate risk (37/102 for observation studies
prophylaxis group). Regarding HBV MTCT events, we adopted the first and 79/156 for interventional studies).
result with multiple outcomes between 6 and 12 months. Concerning
maternal information on HBV DNA levels, the data obtained during
pregnancy were applicable for mothers without antiviral prophylaxis; 3.1 | MTCT incidence of HBV under different
however, the one before delivery was employed among women with prophylaxis regimens
antiviral therapy during pregnancy. Moreover, we contacted the cor-
responding authors for additional information if necessary. The included 300 studies comprised 425 data sets, where 3402 of
63 293 infants were diagnosed with chronic HBV infection owing to
MTCT. The overall MTCT incidence of HBV was 31.3% (95% con-
2.5 | Study quality assessment fidence interval [CI] 15.8%–­49.3%) for the no prophylaxis group,
11.2% (95% CI 8.9%–­13.6%) for the hepatitis B vaccine group, 8.1%
We employed The Newcastle–­Ottawa Scale (Table S3) to assess (95% CI 7.2%–­9.0%) for the combined immunoprophylaxis group, and
the bias risk of observational studies, where three aspects were 0.3% (95% CI 0.1%–­0.5%) for the antiviral therapy plus combined
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1200 YAO et al.

F I G U R E 1 Flow diagram of study

selection. *Mother-­to-­child transmission
(MTCT) was assessed by finger/heel prick
blood or when the infant was <6 months
or >12 months of age

immunoprophylaxis group (Figure 2; Figure S1). Significant hetero- 3.3 | Regional MTCT incidence of HBV under
geneity existed in MTCT incidence analysis except for the antiviral different prophylaxis regimens
therapy plus combined immunoprophylaxis group. Funnel plots re-
vealed publication bias in the no prophylaxis group (Figure S2). Regional MTCT incidences of HBV were then summarized (Figure 3;
Table S7). Without prophylaxis regimens, the lowest MTCT inci-
dence occurred in the European Region (0.0%; 95% CI 0.0%–­6.0%),
3.2 | MTCT incidence of HBV under different with an increased MTCT incidence of HBV in South-­East Asia (15.3%;
prophylaxis regimens by maternal HBeAg status 95% CI 9.3%–­22.3%) and the African region (13.7%; 95% CI 6.8%–­
25.7%), respectively, and the highest one in the Western Pacific
Among 300 studies, 173 reported maternal HBeAg status. MTCT Region (46.1%; 95% CI 29.7%–­63.0%). When hepatitis B vaccine and
incidence decreased consistently over prophylaxis regimens regard- combined immunoprophylaxis were implemented independently,
less of HBeAg status (Figure 2; Figure S3). Upon comparing HBeAg-­ MTCT incidence decreased remarkably to 4.3% (95% CI 1.1%–­9.0%)
positive and HBeAg-­negative mothers, MTCT estimates were 82.9% and 1.0% (95% CI 0.1%–­2.6%), respectively, in the South-­East Asia
(95% CI 74.9%–­89.7%) vs. 10.3% (95% CI 0.5%–­28.2%) for the no Region, as well 12.7% (95% CI 10.3%–­15.2%) and 8.8% (95% CI
prophylaxis group, 15.9% (95% CI 12.1%–­20.0%) vs. 2.3% (95% CI 7.8%–­9.8%) in the Western Pacific Region. When antiviral prophy-
0.1%–­6.2%) for the hepatitis B vaccine group, and 9.6% (95% CI laxis was introduced to pregnant women, the pooled MTCT rate was
8.4%–­10.9%) vs. 0.5% (95% CI 0.1%–­1.0%) for the combined immu- close to 0% in most countries and regions, except for Turkey (1.7%;
noprophylaxis group (p < 0.001). When peripartum antiviral prophy- 95% CI 0.3%–­8.9%). However, the MTCT incidence in the European
laxis was introduced, the MTCT estimate did not significantly differ Region has remained consistently around zero. Notably, we identi-
between HBeAg-­positive and HBeAg-­negative mothers (0.3% vs. fied no studies available for analysis in the African Region on MTCT
0.0%, p = 0.938). incidence in the presence of prophylaxis.
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YAO et al. 1201

F I G U R E 2 Forest plot of mother-­to-­child transmission incidence of hepatitis B virus under different prophylaxis regimens

3.4 | MTCT incidence of HBV stratified by MTCT risk of HBV and the response to preventive measures varied
maternal viral load before delivery by region. Fourth, despite infant immunoprophylaxis, HBV MTCT ap-
peared at a maternal viral load of 4.00 log10 IU/ml, and the incidence
For this analysis, we only included studies presenting prenatal HBV markedly increased to a maternal viral load of 6.00 log10 IU/ml.
DNA within a narrow viral load increment (eg 2.00–­2.99, 3.00–­3.99, Vaccination caused the largest reduction in the MTCT incidence
or 4.00–­4.99 log10 IU/ml or log10 copies/ml, etc.). Finally, 22 studies of HBV. Cochrane review, by analyzing four trials, reported that the
(20 from China, one from Australia, and one from Israel; 268 infec- HBV vaccine significantly reduced HBV MTCT risk (relative risk 0.28;
tions from 6526 individuals) were available for stratified analysis, 95% CI 0.20–­0.40).5 In this meta-­analysis, we quantified the effect of
with HBV DNA units of IU/ml in 14 studies and copies/ml in eight the HBV vaccine by estimating HBV MTCT incidence. Regarding the
studies. All the infants received the hepatitis B vaccine (three or reduction of HBV MTCT incidence from 82.9% to 15.9% for HBeAg-­
more doses) with HBIG. After dividing copies/ml by 5 to unify as IU/ positive mothers and from 10.3% to 2.3% for HBeAg-­negative moth-
ml, we first combined all 22 studies. Aggregate analysis revealed that ers, we convincingly demonstrated that vaccination for infants is a
the pooled MTCT incidence strongly correlated with maternal HBV huge success. The prevalence of HBsAg infections for children under
DNA levels (Figure 4). Particularly, the estimated incidence was 0.0% 5 years of age (an indicator of new chronic HBV) has dropped from
when maternal viral load was less than 4.29 log10 IU/ml. They slightly 4.7% in the pre-­vaccine era to 1.3%. 2 However, given that the global
increased to 0.6% (95% CI 0.0%–­2.6%) and 1.0% (95% CI 0.0%–­3.1%) coverage of the hepatitis B birth dose vaccine was 42% in 2021,15
for infants where HBV DNA levels of their mothers were 4.00–­5.29 more effort is required to improve vaccine coverage.
and 5.00–­6.29 log10 IU/ml, respectively. Approximately four times The positive relation between maternal HBeAg status and MTCT
higher risk, 4.3% (95% CI 1.8%–­7.5%), occurred at a maternal HBV incidence has long been recognized; therefore, an HBeAg test is rec-
DNA of 6.00–­7.29 log10 IU/ml. In the worst case, the MTCT incidence ommended to identify high-­risk pregnant women when HBV DNA
increased to 9.6% (95% CI 7.0%–­12.5%) when the HBV DNA levels quantification is inaccessible.16 As expected, we observed a higher
were more than 7.00 log10 IU/ml for pregnant women. Subsequently, MTCT incidence in HBeAg-­positive mothers. A previous study re-
separated analysis according to original HBV DNA units (IU/ml or ported an almost zero risk of HBV MTCT in vaccinated infants from
copies/ml) displayed a similar tendency and threshold for immuno- HBeAg-­negative mothers.17 However, when the study included
prophylaxis failure (Figures S4 and S5). more extensive sample sizes and adopted more reliable diagnos-
tic criteria, HBV MTCT incidence in infants with vaccination from
HBeAg-­negative mothers was 2.3% (95% CI 0.1%–­6.2%), which was
4 | DISCUSSION small but not negligible.
Peripartum antiviral prophylaxis combined with infant immu-
This systematic review, including 300 studies with 63 293 individuals, noprophylaxis had the potential to block HBV MTCT completely,
provided four major findings relevant to clinical practice or policy deci- with a pooled HBV MTCT incidence of approximately zero. Several
sions. First, each prophylaxis regimen effectively reduced HBV MTCT reports have proved that maternal peripartum antiviral prophy-
incidence. Second, infants born to HBeAg-­negative mothers remained laxis effectively prevents HBV MTCT with a good safety profile.7–­9
at a small but not negligible risk of MTCT after vaccination. Third, the Compared with calculating odds ratios between the treated group
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1202 YAO et al.

F I G U R E 3 Mother-­to-­child transmission incidence of hepatitis B virus under different prophylaxis regimens by region. MTCT, mother-­
to-­child transmission. Filled and unfilled circle sizes are proportional to the number of assessed infants. Ten studies were analyzed by study
region, but the study population was not entirely derived from the study region
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1203

in the unit of copies per ml were converted to IU/ml by dividing by 5. All infants received at least three doses of hepatitis B vaccine and birth
F I G U R E 4 Mother-­to-­child transmission incidence of hepatitis B virus according to maternal viral load before delivery. HBV DNA values
|

doses of hepatitis B immunoglobulin

YAO et al.
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1204 YAO et al.

and the control groups in previous systematic reviews, our sys- The HBV DNA threshold for maternal peripartum antivi-
tematic review supported the high efficacy of antiviral prophy- ral prophylaxis is a major issue for HBV MTCT prevention. In this
laxis by a pooling HBV MTCT incidence of 0.3%. Notably, HBV study, HBV MTCT incidence was 1.0% at a maternal viral load of
MTCT occurred in 57 original studies despite employing maternal 5.00–­6.29 log10 IU/ml and increased sharply at a maternal viral
antiviral prophylaxis and neonatal combined immunoprophylaxis. load of 6.00 log10 IU/ml, similar to previous reviews that identified
Possible causes mentioned in the original studies were the irreg- 5.30 log10 IU/ml as a cut-­off HBV DNA level.13,16 However, differ-
ular administration of antivirals or amniocentesis. As an invasive ing from a zero risk,16 an MTCT incidence of 0.6% (95% CI 0.0%–­
procedure, amniocentesis may theoretically increase the risk of 2.6%) was observed at maternal viral loads of 4.00–­5.29 log10 IU/
MTCT by transmitting maternal blood. This hypothesis has been ml. This discrepancy could be attributed to excluding studies with
proven by published literature and is more pronounced in preg- peripartum antiviral prophylaxis in the previous review, result-
nant women with high viral load.18,19 Other obstetric factors with ing in a different MTCT incidence estimate in three studies. 23–­25
similar mechanisms, such as forceps delivery, did not affect HBV Nevertheless, using the same diagnostic criteria for MTCT, both re-
MTCT.19 Detailed reporting on HBV MTCT cases is encouraged, vealed a lower MTCT incidence than the 2.754% at a maternal viral
and further investigations of risk factors for antiviral prophylaxis load below 6.0 log10 copies/ml (5.3 log10 IU/ml) in another review,
failure are required to eliminate HBV MTCT. which included original studies with a wide definition for MTCT.13
We observed that HBV MTCT incidence varied considerably Our findings support the clinical practice guidelines' threshold HBV
across regions and countries. The European Region had virtually no DNA levels for peripartum antiviral treatment (6.0–­7.0 log10 IU/ml10
HBV MTCT risk, whereas the Western Pacific Region was the most or 5.3 log10 IU/ml11,12) and highlight the plausibility of antiviral treat-
2
affected, consistent with the HBV epidemic. However, the African ment in individuals with HBV DNA of 4.00 log10 IU/ml or greater. In
Region presented a lower HBV MTCT incidence than the Western addition, our earlier observations revealed that the threshold HBV
Pacific Region, despite a similarly high HBsAg prevalence in both DNA levels for MTCT incidence differed between HBeAg-­positive
20
regions. This finding was also reported in a systematic review on and HBeAg-­negative mothers. 26 Unfortunately, we could not assess
HBV MTCT risk in sub-­Saharan Africa, with a reported MTCT risk the MTCT incidence stratified by HBV DNA levels in combination
of 38.3% for HBeAg-­positive women and 4.8% for HBeAg-­negative with HBeAg status in this study because only a few data sets were
women in the absence of prophylaxis regimens.4 Horizontal trans- presented in the original studies, which is an important issue for fu-
mission during childhood rather than MTCT may dominate most ture studies.
chronic HBV infections in the African Region. 21 This study had several limitations. First, there was significant
Responses to HBV MTCT preventive measures differed by re- heterogeneity in the analysis of HBV MTCT incidence under dif-
gion, and vaccines were effective in all regions where data were ferent prophylaxis regimens because of differences in the study
available. Peripartum antiviral treatment further blocked HBV region, detection method for HBV markers, and the proportion of
MTCT in areas where MTCT was the predominant mode of HBV pregnant women at high risk for MTCT. Therefore, we advocate for
transmission. However, in HBV non-­endemic areas, the changes more detailed reporting of this information in the original studies
in HBV MTCT incidence were less prominent across prophylaxis in the future. Second, only the quality of four main types of studies
regimens because of the extremely low HBV MTCT risk in the was assessed, and no sensitivity analyses were conducted based on
absence of prophylaxis. Regional differences in HBV genotypes the risk of bias. Third, in the regional analysis, some studies included
may account for the differences in MTCT risk and responsiveness non-­native races. However, the conclusions would likely not change,
to prophylaxis regimens. 22 The above findings suggest that the given that HBV MTCT incidence remained low in regions including
focus of MTCT prophylaxis differs across regions. Regarding the races from endemic areas, such as the Americas. In addition, these
Western Pacific region and the African Region, accounting for 68% findings should be interpreted cautiously given the few countries in-
of the HBV infections, 2 peripartum antiviral therapy for high-­risk cluded in the regional analysis, ranging from one to six. Finally, in the
mothers and vaccines for infants are important for the Western analysis to identify the threshold for peripartum antiviral therapy,
Pacific Region. Furthermore, countries in the Western Pacific caution should be taken in generalizing the findings to all patients,
Region have devoted considerable efforts to expanding hepatitis as most of the studies included were from China. Nonetheless, this
B vaccine coverage. China achieved 99% coverage of the three-­ review provided an overview of HBV MTCT from the perspective of
dose hepatitis B vaccine in 2009.15 Identifying pregnant women MTCT incidence.
at high risk of MTCT and treating them will be the next critical
step. Unfortunately, we could not analyze MTCT incidence with
prophylaxis in the African Region. A possible explanation is that 5 | CO N C LU S I O N
we strictly excluded studies with small sample sizes and patients
with HIV co-­infection.4 However, we could speculate that expand- This study provide the following implications from the HBV MTCT
ing vaccine coverage is a priority for future efforts in the African incidence perspective: it reaffirms that the HBV vaccine is a funda-
Region as the three-­dose and birth dose of HBV vaccine coverage mental and critical step for preventing HBV MTCT; it calls attention
were as low as 71% and 17% in 2021, respectively.15 to HBeAg-­negative pregnant women; it suggests that peripartum
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risk and the priority of different prophylaxis regimens vary by region; 7. Brown RS Jr, McMahon BJ, Lok AS, et al. Antiviral therapy in
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and lastly, it highlights that although HBV DNA of 5.30 log10 IU/ml
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or more appears to be the optimal HBV DNA threshold for peri-
8. Hyun MH, Lee YS, Kim JH, et al. Systematic review with meta-­
partum antiviral prophylaxis, it is also reasonable to treat pregnant analysis: the efficacy and safety of tenofovir to prevent mother-­
women with HBV DNA of 4.00 log10 IU/ml or greater. Future ef- to-­child transmission of hepatitis B virus. Aliment Pharmacol Ther.
forts to develop individualized preventive strategies considering the 2017;45:1493-­1505.
9. Funk AL, Lu Y, Yoshida K, et al. Efficacy and safety of antiviral pro-
local socio-­economic situation, the prevalence of HBsAg, patient
phylaxis during pregnancy to prevent mother-­to-­child transmission
willingness, and the availability of prophylaxis regimens are highly of hepatitis B virus: a systematic review and meta-­analysis. Lancet
encouraged. Infect Dis. 2021;21:70-­8 4.
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guidelines on the management of hepatitis B: a 2015 update.
AU T H O R C O N T R I B U T I O N S
Hepatol Int. 2016;10:1-­98.
TYC is the guarantor of the article. NJY and SF contributed to study 11. Lampertico P, Agarwal K, Berg T, et al. EASL 2017 clinical prac-
design, study identification, data collection and extraction, quality tice guidelines on the management of hepatitis B virus infection. J
assessment, data analysis and interpretation, and manuscript draft- Hepatol. 2017;67:370-­398.
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ing and revision. YCW and ZT contributed to study design, study
diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepa-
identification, data analysis and interpretation, and critical revision titis B guidance. Hepatology. 2018;67:1560-­1599.
of the manuscript. YLF and JL contributed to data collection, qual- 13. Chen HL, Zha ML, Cai JY, Qin G. Maternal viral load and hepatitis
ity assessment, and manuscript revision. XFL and YY contributed to B virus mother-­to-­child transmission risk: a systematic review and
meta-­analysis. Hepatol Res. 2018;48:788-­8 01.
study design, search term design, and critical review of the manu-
14. WHO. Guidelines on Hepatitis B and C Testing. World Health
script. FPJ, YLC, and FJL contributed to study design, data analysis Organization; 2017.
and interpretation, and manuscript revision. YRZ and TYC contrib- 15. WHO. WHO-­UNICEF estimates of hepatitis B vaccination cover-
uted to study concept, study design, data analysis, interpretation of age. Accessed August 18, 2022. https://immun​izati​ondata.who.int/
pages/​cover​age/hepb.html
data, manuscript drafting and revision, quality control of algorithms,
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neonates: a systematic review and meta-­analysis. Lancet Infect Dis.
AC K N OW L E D G M E N T S 2021;21:85-­96.
We appreciate Vana Papaevangelou, Le Ye Lee, Qiuju Sheng, and 17. Machaira M, Maria V, Papaevangelou EK, Tansarli GS, Falagas ME.
Hepatitis B vaccine alone or with hepatitis B immunoglobulin in ne-
Xiaoguang Dou for supplying raw data for subgroup analysis.
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meta-­analysis. J Antimicrob Chemother. 2015;70:396-­4 04.
F U N D I N G I N FO R M AT I O N 18. Yi W, Pan CQ, Hao J, et al. Risk of vertical transmission of hepatitis
National Natural Science Foundation of China (Grant Nos. 81770594 B after amniocentesis in HBs antigen-­positive mothers. J Hepatol.
2014;60:523-­529.
and 81670537) & the Key Research and Development Project of
19. Han Z, Zhang Y, Bai X, Yin Y, Xu C, Hou H. Mother-­to-­child trans-
Shaanxi (2018ZDXM-­SF-­037). mission of hepatitis B virus after amniocentesis: a retrospective
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C O N FL I C T O F I N T E R E S T 20. Razavi-­Shearer D, Gamkrelidze I, Nguyen MH, et al. Global prev-
alence, treatment, and prevention of hepatitis B virus infec-
The authors declare that they have no competing interests.
tion in 2016: a modelling study. Lancet Gastroenterol Hepatol.
2018;3:383-­4 03.
ORCID 21. Edmunds WJ, Medley GF, Nokes DJ, O'Callaghan CJ, Whittle HC,
Tianyan Chen https://orcid.org/0000-0002-0721-5739 Hall AJ. Epidemiological patterns of hepatitis B virus (HBV) in highly
endemic areas. Epidemiol Infect. 1996;117:313-­325.
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1206 YAO et al.

epidemiological data from Shaanxi, China. Medicine (Baltimore).

2018;97:e11406. How to cite this article: Yao N, Fu S, Wu Y, et al. Incidence of
mother-to-child transmission of hepatitis B in relation to
maternal peripartum antiviral prophylaxis: A systematic
S U P P O R T I N G I N FO R M AT I O N
review and meta-analysis. Acta Obstet Gynecol Scand.
Additional supporting information can be found online in the
2022;101:1197-1206. doi: 10.1111/aogs.14448
Supporting Information section at the end of this article.