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Original Article

Factors associated with hepatitis B mother-to-child transmission in a national prevention program

Moran Ki1, Byung-Woo Kim1, Dahye Baik1, Jong-Hyun Kim2orcid
Clinical and Molecular Hepatology 2025;31(4):1298-1315.
Published online: June 24, 2025

1Department of Public Health & AI, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea

2Division of Pediatric Infectious Diseases, Department of Pediatrics, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

Corresponding author : Jong-Hyun Kim Division of Pediatric Infectious Diseases, Department of Pediatrics, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, 93 Jungbu-daero, Paldal-gu, Suwon 16247, Korea Tel: +82-31-249-7320, Fax: +82-31-257-9111, E-mail: jh00mn@catholic.ac.kr

Editor: Hyung Joon Yim, Korea University, Korea

• Received: February 24, 2025   • Revised: June 15, 2025   • Accepted: June 20, 2025

Copyright © 2025 by The Korean Association for the Study of the Liver

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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See letter "Redefining MTCT prevention strategies toward HBV elimination: Editorial on “Factors associated with hepatitis B mother-to-child transmission in a national prevention program”".
  • Background/Aims
    Hepatitis B virus (HBV) mother-to-child transmission (MTCT) remains a global health concern, with over 90% of perinatal infections leading to chronic HBV. To evaluate long-term trends in MTCT rates and associated factors within Korea’s national program.
  • Methods
    Population-based cohort study using linked data from the Perinatal Hepatitis B Prevention Program (PHBPP) and National Health Insurance Service in Korea. The study included HBsAg-positive mother-infant pairs with post-vaccination serologic results from 2002 to 2021.
  • Results
    Among the 154,478 mother-infant pairs, the overall MTCT rate after prophylaxis was 2.3%. Antiviral use lowered MTCT rates (0.9% vs. 2.4%) particularly in HBeAg-positivity (1.0% vs. 5.9%; adjusted odds ratio [aOR] 0.21; 95% confidence interval [CI] 0.14–0.32). Lower MTCT rates were observed for cesarean section vs. vaginal delivery (1.9% vs. 2.6%; aOR 0.78; 95% CI 0.73–0.84) and breastfeeding vs. formula feeding (1.8% vs. 2.8%; aOR 0.65; 95% CI 0.56–0.76). Annual MTCT rates decreased from 3.6% (2002–2005) to 1.3% (2018–2021). Antivirals reduced MTCT rates; initiation at 14–27 weeks (0.39%), or 28–32 weeks (0.44%) vs. ≥33 weeks (1.47%); postpartum continuation (0.55%) vs. antepartum discontinuation (1.44%); use ≥61 days (0.51%) vs. 1–60 days (1.67%). Lower MTCT risk was associated with maternal (old age, high income) and infant (female sex, preterm birth) factors.
  • Conclusions
    This comprehensive analysis of the PHBPP in Korea demonstrates that the use of antivirals, breastfeeding, and cesarean section, combined with conventional immunoprophylaxis, has significantly reduced MTCT rates. These results are crucial for global HBV elimination and can help to guide HBV MTCT prevention strategies.
  • Keywords: Breastfeeding; Cesarean section; Hepatitis B virus; Perinatal infection; Prevention and control
• This study provides comprehensive, population-level evidence that integrating antiviral administration, breastfeeding, and cesarean section delivery into conventional immunoprophylaxis significantly reduces HBV MTCT, offering critical insights into perinatal strategies to achieve WHO’s HBV elimination targets.
• The findings are pivotal for policymakers and clinicians in high-burden regions, as they demonstrate actionable, scalable interventions—such as prioritizing antiviral access for high-risk pregnancies and promoting breastfeeding—to refine national protocols and reduce disparities linked to maternal age, income, and healthcare access.
• The 20-year decline in MTCT rates (4.1% to 1.0%) underscores the program’s adaptability, urging tailored strategies in diverse settings.
Graphical Abstract
Hepatitis B virus (HBV) infection remains a significant global public health concern. Despite a slight decrease in new viral hepatitis infections, HBV caused 1.2 million new infections in 2022 with an increasing mortality rate [1,2]. Global initiatives aim to reduce new HBV infections among children by 95% [3] and decrease prevalence in 1-4-year-olds to 0.1% by 2030 [4]. Preventing mother-to-child transmission (MTCT) is critical, as over 90% of perinatal infections lead to chronic HBV [5-7].
In the Republic of Korea (hereafter referred to as Korea), HBV vaccination was introduced in 1982 and included in the national immunization program in 1995. The Perinatal Hepatitis B Prevention Program (PHBPP), launched in 2002, offers free immunoprophylaxis and post-vaccination serologic testing (PVST). From 2002 to 2013, the MTCT rate in Korea dropped from 4.2% to 1.5% [8]. Antiviral treatments against hepatitis B have been included in National Health Insurance Service (NHIS) coverage since 1999, with the recent inclusion of antiviral prophylaxis during pregnancy (antiviral prophylaxis) expected to further reduce MTCT rates.
However, maternal HBV DNA levels, HBeAg testing, and antiviral prophylaxis are not included in the PHBPP. There has also been no evaluation of the proportion of eligible mothers receiving antiviral prophylaxis or its association with MTCT rates. The WHO’s updated guidelines on HBV management in March 2024 highlighted several research gaps related to MTCT prevention and antiviral therapy timing [9].
This study aims to address these gaps by analyzing 20 years of linked national real-world data from Korea’s PHBPP. Specifically, we aim to 1) evaluate the long-term trends in MTCT rates and the impact of antiviral prophylaxis and 2) examine the relationships among several factors related to MTCT, including delivery types, feeding methods, and antivirals.
These findings will inform evidence-based strategies for MTCT prevention, refine guidelines, and support progress toward the WHO’s HBV elimination goals.
Data sources
This study utilized data from the PHBPP of the Korea Disease Control and Prevention Agency (KDCA) and the NHIS claims database. The KDCA dataset includes maternal HBV-related information, feeding method, infants’ gender, birth weight, gestational age, details on HBV vaccination, and administration of hepatitis B immunoglobulin (HBIG).
Maternal data from KDCA were linked to NHIS claims data using maternal identification numbers to obtain additional information on income level, delivery methods, multiple gestation and antiviral prescriptions.
Data cleaning and processing
The total maternal-infant registration data for the PHBPP by the KDCA from 2002 to 2021 comprised 233,455 pairs. After excluding 813 pairs due to missing maternal information and 36 pairs due to erroneous maternal age entries, 232,606 pairs remained. Of these, 228,381 pairs were successfully linked to the NHIS. Finally, 154,478 pairs with PVST results established by January 31st 2023 were analyzed for the MTCT rate (Fig. 1).
Measures
Information on maternal economic status, delivery methods, and multiple gestation was determined using NHIS data. Economic status was classified into upper (top 75%), middle (25–75%), and lower (bottom 25%, including medical aid) tiers based on household income at delivery. When current-year data were unavailable, previous-year data were used or classified as missing. Delivery methods were classified based on ICD-10 diagnostic codes as follows: vaginal delivery (O80.*, single spontaneous delivery; O81.*, single delivery by forceps and vacuum extractor; O83*, other assisted single delivery; O84.*, multiple delivery, all spontaneous; O84.1, multiple delivery, all by forceps and vacuum extractor), elective cesarean section (C-section) (O82.0), emergency C-section (O82.1), other C-section (O82, single delivery by C-section; O82.2, delivery by C-section hysterectomy; O82.8, other single delivery by C-section; O82.9, delivery by C-section, unspecified; O84.2, multiple delivery, all by C-section) and cases were classified as unknown when the diagnostic codes were unclear. Multiple gestation was identified by either the presence of specific ICD-10 codes (O30.*, multiple gestation; O31.*, complications specific to multiple gestation; O84.*, multiple delivery) or by identifying infants with similar dates of birth.
Antiviral prescription records were reviewed from six months pre-pregnancy to six months post-delivery. The initiation point was categorized as before-pregnancy, first trimester (weeks 1–13), second trimester (weeks 14–27), and third trimester (weeks 28–32 and beyond). The discontinuation point was classified as before-delivery and after-delivery. Prescription duration during pregnancy was categorized into 1–60 days or 61+ days. In this analysis, we assumed full compliance with prescribed medication.
The PHBPP includes HBIG and HBV birth dose administration within 12 hours, subsequent vaccination, and PVST between 9–15 months [8]. Four types of HBV vaccine were included: Euvax-B (recombinant vaccine, LG Chemical Co., Seoul, Korea; period of use 1992~), Hepavax-Gene TF (thimerosal-free recombinant vaccine, Berna Biotech Co., Incheon, Korea; 2004–2019), Hepavax-Gene (recombinant vaccine, GC Biopharma Co., Yongin, Korea; 1997–2005), and Hepaccine-B (plasma-derived vaccine, CJ CheilJedang Co., Seoul, Korea; 1986–2005). PVST was conducted up to three times if necessary (Supplementary Fig. 1). MTCT was defined as HBsAg positivity in infants, regardless of anti-HBs status.
Statistical analysis
Chi-square tests, standardized mean differences or Cramer’s V were used to compare characteristics between groups. Missing data patterns were evaluated for each variable and determined to be missing not at random; therefore, observations with missing values were analyzed as an “unknown” group without imputation, except for infant birth weight. For the 89 cases with unknown birth weight, values were imputed using the median birth weight of infants of the same sex and gestational age group.
Multivariable logistic regression analysis was used to calculate odds ratios (ORs) for MTCT rates, adjusted for maternal and infant characteristics. Using stepwise selection (entry P<0.05, removal P>0.05), all potential predictors were initially included, and non-significant variables were systematically removed to yield a final model. To examine potential interactions between HBeAg status and antiviral prescription, interaction terms were incorporated into the model, and their regression coefficients were assessed for statistical significance.
Subgroup analyses were performed based on antiviral prescription and maternal HBeAg status. For multiple comparisons under different antiviral treatment conditions, Fisher’s exact test with Bonferroni correction was applied to control type I error rate.
We constructed a directed acyclic graph (DAG) to visualize and analyze the causal relationships between maternal factors and MTCT. Variables were classified as exposure (maternal HBeAg status), outcome (MTCT), mediators (antiviral prescription, breastfeeding and C-section), confounder (maternal age), and interaction (HBeAg status × antiviral prescription). Relationships between variables were indicated by arrows, with positive (⊕) and negative (⊖) associations determined through our statistical analyses and supported by existing clinical evidence.
All data processing and statistical analyses were conducted using SAS Enterprise Guide 8.2 (SAS Institute Inc., Cary, NC, USA).
Ethical considerations
We were granted an exemption from the Institutional Review Board (IRB) at St. Vincent’s Hospital, The Catholic University of Korea (IRB Number. VC22ZADI0206). To ensure confidentiality, data linkage between KDCA and NHIS was conducted under the direct supervision of KDCA. Researchers accessed depersonalized data only, maintaining the anonymity of the subjects.
Characteristics of study population
Among 232,606 pairs of HBsAg-positive mothers and their infants registered in the KDCA’s PHBPP from July 2002 to December 2021, 154,478 (66.4%) had PVST results recorded.
In the PVST group, participant characteristics were examined, excluding missing data. Mothers’ mean (standard deviation [SD]) age was 31.3 (4.2) years, with 146,043 (94.5%) being Korean nationals and 32,994 (31.2%) HBeAg-positive. Preterm births (<37 weeks gestation) accounted for 9,167 (7.2%), while very low birth weight (<2,000 g) was 2,467 (1.6%). The C-section rate was 42.4% (n=63,745), and 18,196 (33.0%) of mothers exclusively breastfed for at least the first month after delivery. 102,789 (72.8%) of the infants received the same HBV vaccine type for all three doses of the primary series. The antiviral prescription rate was 4.0% (n=6,224).
Some differences were identified in the group without PVST: a slightly younger mean (SD) maternal age (30.9 [4.5] years), more non-Korean nationals, lower antiviral prescription rate, and higher rates of unknown status for several characteristics.
Chi-square tests revealed statistically significant differences between the groups for all characteristics (P<0.001). However, effect sizes indicated very weak associations for most characteristics (Cramer’s V<0.1), with exceptions in feeding method (Cramer’s V=0.396), consistent vaccine type for all three doses (Cramer’s V=0.366), and infant’s birth year group (Cramer’s V=0.242). Maternal age showed a small effect size (standardized mean difference=0.092) (Table 1).
Associated factors of HBV mother-to-child transmission
Among 154,478 infants enrolled in the PHBPP from 2002 to 2021, the final serological outcomes were as follows: 145,385 (94.1%) were HBsAg-negative and anti-HBs positive, indicating successful immunization outcome; 5,469 (3.5%) were HBsAg-negative and anti-HBs negative, suggesting vaccine non-response; 3,488 (2.3%) were HBsAg-positive and anti-HBs negative, indicating HBV infection; and 136 (0.1%) were HBsAg-positive and anti-HBs positive, potentially representing HBV surface gene mutant infection or false-positive test results (Supplementary Table 1).
The overall MTCT rate was 2.3% (n=3,624). This rate varied across several maternal factors: it declined as the mother grew older, from 5.1% in mothers under 25 to 1.3% in those aged 40 and older; it was higher in non-Korean mothers (3.4%) compared to Korean mothers (2.3%). Mothers with high economic status had an MTCT rate of 2.1%, which increased to 2.4% in those with middle status and 2.6% in those with low status. MTCT rate was higher in HBeAg-positive mothers (5.5%) compared to HBeAg-negative mothers (1.0%) and those with unknown HBeAg status (2.3%). Mothers who received antiviral prescriptions demonstrated a significantly lower MTCT rate of 0.9% compared to non-prescription mothers at 2.4%.
The interaction between maternal HBeAg status and antiviral prescription demonstrated statistical significance (P<0.001), necessitating the assessment of their joint effects. Compared to HBeAg-positive mothers without antiviral prescription (reference group), those who received antivirals showed a substantial risk reduction of approximately 80% (adjusted odds ratio [aOR] 0.21; 95% confidence interval [CI] 0.14–0.32). Among HBeAg-negative mothers, both the non-prescription and prescription groups also exhibited reduced risks (aOR 0.17; 95% CI 0.16–0.19; aOR 0.14; 95% CI 0.08–0.25, respectively); however, antiviral prescription provided only a marginal additional benefit of 3% in risk reduction (Fig. 2, Supplementary Table 2).
Based on infant factors, male infants had a slightly higher MTCT rate of 2.4% compared to females at 2.3%, with rates of 1.7%, 1.6%, 2.1%, and 3.1% for gestational ages of <32, 32–36, 37–40, and ≥41 weeks, respectively. Very low birth weight infants (<2,000 g) had a lower MTCT rate of 2.1% compared to 2.3% in infants weighing ≥2,000 g. In the comparison between singleton and multiple gestation, we observed that the MTCT rate was significantly lower in multiple gestation (1.7%) than in singleton gestation (2.4%) (OR 0.73; 95% CI 0.59–0.90). The detailed characteristics comparing singleton and multiple gestation are presented in Supplementary Table 3.
C-section resulted in a lower MTCT rate of 1.9% compared to vaginal delivery at 2.6% (aOR 0.78; 95% CI 0.73–0.84). Especially, MTCT rates were lowest with elective C-section (1.7%; OR 0.63; 95% CI 0.57–0.70), followed by emergency C-section (2.2%; OR 0.83; 95% CI 0.75–0.93), compared to vaginal delivery (2.6%; reference). Breastfeeding (1.8%), and mixed feeding (1.8%) showed lower aOR rates for MTCT than formula feeding (2.8%) (aOR 0.65; 95% CI 0.57–0.76; aOR 0.80; 95% CI 0.69–0.92, respectively) (Fig. 2). Analysis of characteristics between breastfeeding and formula feeding groups revealed most variables had effect sizes below 0.1, indicating clinically insignificant differences. Delivery type showed a small effect (effect size=0.102); interestingly, the breastfeeding group with lower MTCT rates had a higher proportion of vaginal deliveries, typically associated with higher MTCT risk, potentially diluting breastfeeding’s protective effect. Birth year demonstrated a moderate effect (effect size=0.158), with a trend toward increased formula feeding in recent years, though overall MTCT rates significantly declined over time due to improved prevention strategies (Supplementary Table 4).
Infants who received three doses of the same type of hepatitis B vaccine had an MTCT rate of 2.3%, lower than the 2.7% rate in those who received different types. The annual MTCT rate dropped from 3.6% in 2002–2005 to 1.3% in 2018–2021, showing a significant decrease (aOR 0.62; 95% CI 0.47–0.82) (Fig. 2).
HBV mother-to-child transmission based on maternal HBeAg status
In the multivariable analysis stratified by maternal HBeAg status, the antiviral prescription was significantly associated with a reduction in MTCT rate except in the HBeAg-negative group (HBeAg-positive: aOR 0.18; 95% CI 0.12–0.27; HBeAg-unknown: aOR 0.59; 95% CI 0.37–0.94). MTCT rates significantly decreased as the mother grew older, regardless of HBeAg status. C-section, compared to vaginal delivery, was associated with significantly lower MTCT rates (HBeAg-positive: aOR 0.83; 95% CI 0.75–0.92; HBeAg-negative: aOR 0.76; 95% CI 0.64–0.89; HBeAg-unknown: aOR 0.73; 95% CI 0.64–0.84). Breastfeeding, compared to formula feeding, was associated with lower MTCT rates, statistically significant in the HBeAg-positive (aOR 0.75; 95% CI 0.61–0.91) and unknown (aOR 0.52; 95% CI 0.40–0.68) groups (Table 2).
HBV mother-to-child transmission and antiviral prescriptions
The prescription rate for antivirals for HBsAg-positive pregnant women has been increasing recently (Supplementary Table 5).
Subgroup analysis revealed similar directional trends for factors associated with MTCT in both antiviral prescription and non-prescription groups, but statistical significance was only observed in the antiviral non-prescription group. In this group, C-section was associated with lower MTCT rates compared to vaginal delivery (1.9% vs. 2.7%; aOR 0.78; 95% CI 0.73–0.84). Breastfeeding and mixed feeding showed lower MTCT rates compared to formula feeding (1.8%, 1.9%, and 3.0%, respectively; breastfeeding: aOR 0.65; 95% CI 0.57–0.76; mixed feeding: aOR 0.79; 95% CI 0.68–0.91) (Table 3).
Initiation of antivirals during the second trimester (14–27 weeks) or early third trimester (28–32 weeks) had lower MTCT rates (0.39% and 0.44%) compared to initiation at ≥33 weeks (1.47%). Pairwise comparisons using Fisher’s exact test with Bonferroni correction showed significant differences between ≥33 weeks vs. 14–27 weeks (P=0.0372), while no significant differences were found between ≥33 weeks vs. 28–32 weeks (P=0.1663), and between 14–27 weeks vs. 28–32 weeks (P=1.0). Discontinuation of antiviral after delivery showed a lower MTCT rate (0.55%) compared to early discontinuation before delivery (1.44%, P=0.0004). Among those who initiated antiviral treatment for chronic hepatitis B before pregnancy, discontinuing the prescription before delivery had higher MTCT rates (1.59%) than those after delivery (0.44%). Among those who had any prescription of antiviral during pregnancy, longer duration (≥61 days) of prescription showed lower MTCT rates (0.51%) than shorter duration (1–60 days) (1.67%, P<0.0001) (Supplementary Table 6).
Subgroup analysis based on maternal HBeAg status, HBeAg-positive, HBeAg-negative, and HBeAg-unknown, revealed MTCT rates with antivirals of 0.98%, 0.61%, and 0.99%, respectively. Initiating antivirals between 14 and 27 weeks showed lower MTCT rates in HBeAg-positive (0.20%), HBeAg-negative (0.26%), and HBeAg-unknown (0.74%). Maintaining the prescription of antivirals until after delivery and antiviral duration exceeding 61 days were associated with lower MTCT rates across all HBeAg status groups (Table 4).
Risk factors of HBV mother-to-child transmission by directed acyclic graph analysis
The DAG analysis, informed by our empirical findings and systematic literature review, elucidated the intricate relationships between maternal characteristics and MTCT. A strong direct causal link was identified between maternal HBeAg status and MTCT risk. The magnitude of antiviral therapy’s preventive effect was significantly modified by HBeAg status, indicating a substantial interaction effect. Maternal age emerged as a key confounder, showing positive associations with both antiviral treatment selection and C-section delivery, while demonstrating an inverse relationship with HBeAg positivity. A weak negative association was observed between HBeAg status and breastfeeding practices. Both cesarean delivery and breastfeeding were found to confer protective effects against MTCT (Fig. 3).
In this large population-based prospective cohort of HBsAg-positive mother-infant pairs in Korea, we established the MTCT rates and related factors, including antiviral prescriptions.
The overall MTCT rate was 2.3% (3,624/154,478). For babies of HBsAg-positive mothers receiving conventional immunoprophylaxis (3 doses of HBV vaccine with birth dose and HBIG) without maternal antivirals, the rate was 2.4% (3,570/148,254). For babies of HBeAg-positive and HBeAg-negative women with only conventional immunoprophylaxis, the MTCT rates were 5.9% and 1.0%, respectively, aligning closely with previous research showing rates of approximately 6% and 1%, respectively [10].
This analysis revealed higher MTCT risk in mothers who were HBeAg-positive, younger, and non-Korean. HBeAg positivity correlates with higher maternal HBV-DNA levels, and younger maternal age (10–30 years), particularly in Asians, has been linked to higher HBV-DNA levels [11]. In Korea, about 80% of non-Korean mothers are from neighboring Asian countries [12] and tend to be younger (mean age 27.6 years) than Korean mothers (31.4 years), potentially explaining their higher risk.
Infants with birth weighing <2,000 g showed a slightly lower risk of MTCT, which may be due to receiving 4 vaccinations compared to 3 vaccinations for those ≥2,000 g.
The proportion of multiple gestation demonstrated a substantial increase from 2.57% in 2002–2005 to 5.21% in 2018–2021, likely reflecting the increased use of in vitro fertilization procedures [13]. Compared to mothers with singleton gestation, those with multiple gestation exhibited distinct characteristics: advanced maternal age, higher proportion of high economic status, lower HBeAg positivity rate, and increased antiviral prescription rate. Variables demonstrating effect sizes exceeding 0.1 reflected characteristic features of multiple gestation, including reduced gestational age, lower birth weight, and elevated C-section rate. The observed lower MTCT rate in multiple gestation appear to be associated with the confluence of higher C-section rate, advanced maternal age, and increased antiviral prescription.
This research also indicated lower MTCT risk with C-section compared to vaginal delivery, especially in HBeAg-positive mothers. Previous meta-analyses showed mixed results: Chang et al. [14] and Yang et al. [15] observed significantly lower rates with C-section but noted limitations, such as variability in HBIG administration and early serologic testing (before 6 months). Chen et al. [16] found lower rates but no significant differences, while Pan et al. [17] and He et al. [18] reported significant MTCT reduction with C-section in tests conducted after 6 months. According to Pan et al. [19], elective C-section, performed before labor onset, can minimize newborn exposure to contaminated maternal body fluids including blood, thus reducing MTCT risk compared to emergency C-section. However, another study [20] found no significant difference between these two methods. In our study, emergency C-section showed higher MTCT rates compared to elective C-section. Unlike Pan et al.’s findings [19], our study demonstrated higher MTCT rates in vaginal delivery compared to all kinds of C-section. Although the American College of Obstetricians and Gynecologists (ACOG) does not recommend C-section solely for reducing HBV transmission [21], the 2023 European Association for the Study of the Liver (EASL) guidelines conditionally suggest C-section for Asian HBeAg-positive women with high HBV DNA who have not received antiviral prophylaxis [22].
This analysis found lower MTCT rates in breastfeeding, unknown feeding and mixed feeding compared to formula feeding, especially when maternal viral load was expected to be high. Previous studies have shown conflicting results; while some indicated no significant difference in MTCT rates with breastfeeding [16,23-25], a 2020 meta-analysis by Pan et al. [17] found lower MTCT risk in non-breastfeeding among HBeAg-positive mothers. This meta-analysis was based on 2,443 subjects (912 breast or mixed, 1,531 nonbreast). Also, previous studies related to feeding type and MTCT did not clearly describe the definition of breastfeeding [17,23-25], but we defined it as exclusively breastfed for at least the first month from birth.
We conducted extensive confounding variable analysis, particularly examining maternal HBeAg status. Our stratified and multivariate regression analyses consistently showed that HBeAg status had only a minimal confounding effect (6.6% change in OR) on the relationship between the feeding method and MTCT. This robust finding not only confirms the safety of breastfeeding in HBV-infected mothers but also demonstrates its protective effect in reducing MTCT rates compared to formula feeding.
Because of the many benefits of breastfeeding, the U.S. Centers for Disease Control and Prevention (CDC) recommend exclusive breastfeeding for at least 6 months [26]. MTCT prevention guidelines, including 2023 ACOG, do not oppose but rather encourage breastfeeding for HBV-infected mothers [21,27]. While historically there were concerns about potential MTCT risk through HBV-containing blood in breast milk, particularly for HBeAg-positive mothers (leading to recommendations for formula feeding) [28], our study, along with other researches [23-25], demonstrates that breastfeeding does not increase MTCT risk. Therefore, in alignment with current guidelines, breastfeeding should be actively encouraged.
The DAG analysis yielded several critical insights regarding HBV MTCT prevention. Maternal age was identified as a principal confounder, demonstrating bidirectional influences: an inverse association with HBeAg status and positive correlations with both antiviral prescription and C-section delivery, thereby exerting complex indirect effects on MTCT risk. The analysis substantiated the paramount importance of antiviral therapy, specifically in HBeAg-positive mothers, as evidenced by the significant effect modification of therapeutic efficacy by HBeAg status. While HBeAg positivity demonstrated a modest negative association with breastfeeding initiation, breastfeeding consistently exhibited protective effects against MTCT, independent of maternal HBeAg status.
Antiviral use during pregnancy significantly reduces MTCT risk, with reported ORs ranging from 0.10 to 0.17 [9]. This study, including multiple antivirals, found a similar result for HBeAg-positive mothers using antivirals, with an OR of 0.18 (95% CI 0.12–0.27).
Optimal timing for antiviral prophylaxis varies among guidelines, ranging from the second trimester [9,29], 24–28 weeks [19,30] to 28–32 weeks [18,31] of pregnancy. However, in this study, 57.3% of mothers taking antivirals started medication before pregnancy and about half of them discontinued before delivery, reflecting real-world practices where prescriptions serve both maternal health and MTCT prevention. Among those who discontinued their prescription before delivery, their MTCT rate was 1.59%, while the MTCT rate for mothers who maintained the prescription until or after delivery was lower at 0.44%. Considering the discontinuation time of prescription regardless of antiviral initiation time, our data showed the MTCT rate in those who continued prescription until or after delivery was lower (0.55%) than that in those who discontinued prescription before delivery (1.44%).
Previous studies suggested that the earlier initiation of antiviral prophylaxis may be more effective [9]. It is rather difficult to compare directly with this observational study, but we observed a similar trend in MTCT rates based on the timing of initiation, 14–27 weeks (0.39%), 28–32 weeks (0.44%), and over 33 weeks (1.47%), compared to previous reports.
The MTCT rate in this study had decreased from 3.6% (2002–2005) to 1.3% (2018–2021). This decreasing tendency appears to be associated with an increase in antiviral use during pregnancy from 0.3% to 12.1% which aligns with the recent widespread adoption of the antiviral prophylaxis recommendation and is also associated with a decline in HBeAg-positive rate of pregnant women from one-third to one-fourth. This decline may be related to an increase in their median age, which rose from 29 years in 2002 to 35 years in 2021. The increasing trend in antiviral use correlates with the evolution of the Korean Association for the Study of the Liver (KASL) guidelines, which progressed from very cautious use in 2011 (recommendation C1) [32] to careful consideration in 2015 (recommendation B1) [33], and finally to active recommendation of tenofovir disoproxil fumarate for HBV DNA ≥200,000 IU/mL in 2018 (recommendation A2), with suggested timing from 24–32 weeks of pregnancy until 2–12 weeks postpartum (recommendation B1) [34]. Additionally, since March 2021, national health insurance coverage for antiviral prophylaxis has been provided for cases with HBV DNA ≥200,000 IU/mL from pregnancy week 24 to 12 weeks postpartum, further facilitating medication access.
This study, while comprehensive, has certain limitations to consider. First, the analysis relied on nationality rather than race or ethnicity due to data constraints. Although 80% of non-Korean pregnant women were from neighboring Asian countries [12], their demographic characteristics differed from those of Koreans, necessitating cautious interpretation. Second, the program data were incomplete in some parameters, e.g., maternal HBeAg status, feeding type, and gestational age, which limited certain aspects of the analysis. Third, although we used HBeAg status as a surrogate marker, the absence of HBV DNA data in the PHBPP prevented us from analyzing MTCT risk according to maternal HBV DNA levels, which is the most important indicator. Fourth, the DAG framework may not encompass all unmeasured confounding variables, and the relative significance of individual pathways may vary across different healthcare contexts. Last, maternal antiviral use was based on prescription records, which may not accurately reflect actual compliance. Since many pregnant women included in this study had been prescribed treatment for chronic hepatitis B before pregnancy, it is important to consider that this represents a very different context from clinical trials focused on antiviral prophylaxis when interpreting the related antiviral results.
This study has several notable strengths. First, the data was collected through a country-led PHBPP, which demonstrated a high participation rate of approximately 94% among Korean HBsAg-positive pregnant women, ensuring a highly representative dataset. Second, the research analyzed large-scale, longitudinal data by linking program results for children born over 20 years (2002–2021) with NHIS data (2002–2023). Third, in Korea, antenatal maternal HBsAg screening rate was 99.7% in 2003 [35], a birth dose of the hepatitis B vaccine is routinely administered within 12 hours of birth even in general healthcare institutions, with a remarkably high 3-dose HBV vaccination coverage rate of 93.0% in 2000 [36] and 97.9% in 2018 for 1-year-olds [37]. This allows accurate evaluation of HBV infection rates after complete immunoprophylaxis. Fourth, the study employed a thorough serum testing protocol, with initial tests at 9–15 months after birth, additional vaccinations and tests if needed, and up to two follow-up tests to confirm MTCT. Last, by linking with NHIS data (with 99.4% enrollment), the study provided comprehensive real-world data analysis, including maternal antiviral prescription records from 6 months pre-pregnancy to 6 months post-delivery.
In conclusion, this nationwide study, analyzing 20 years of data from PHBPP in Korea, demonstrates associations between reduced MTCT and the use of antivirals, breastfeeding, and C-section. In particular, the increasing application of antiviral prophylaxis in conjunction with conventional immunoprophylaxis has led to an accelerated decline in MTCT rates. Our findings underscore the importance of implementing personalized intervention strategies based on maternal HBeAg status and individual characteristics. Moreover, the results provide compelling evidence supporting the safety of breastfeeding among HBV-infected mothers, irrespective of their HBeAg status. These findings have significant implications for global HBV elimination efforts. However, to achieve HBV elimination, more proactive national-level interventions are necessary. These should include quantitative HBV DNA testing for pregnant women and antiviral prophylaxis into PHBPP based on these results. These key representative steps are expected to contribute toward the ultimate goal of eliminating HBV transmission worldwide.

Authors’ contribution

Concept and design: Moran Ki, Jong-Hyun Kim; Acquisition, analysis, or interpretation of data: Byung-Woo Kim, Moran Ki, Jong-Hyun Kim; Drafting of the manuscript: Moran Ki, Byung-Woo Kim, Dahye Baik; Critical review of the manuscript for important intellectual content: All authors; Statistical analysis: Byung-Woo Kim; Obtained funding: Jong-Hyun Kim; Administrative, technical, or material support: Byung-Woo Kim, Dahye Baik; Supervision: Moran Ki, Jong-Hyun Kim.

Acknowledgements

We thank the Division of Immunization Services of The KDCA for its role in the ongoing collection, maintenance, and support of the PHBPP. We also express our gratitude to the Department of Big Data Management of the National Health Insurance Service for providing the linked data and for granting access to the analysis facility. Additionally, we acknowledge the dedication and support of the staff at public health centers nationwide and PHBPP-participating health facilities whose contributions were essential to the successful conduct of this study. Our appreciation is extended to the PHBPP participants, including HBsAg-positive mothers and their infants, for their crucial role in this study. This work was mainly supported by the KDCA under grant No. 2022-10-013, and partially by the National Cancer Center, Korea under grant No. NCC-2310710 and SK bioscience under grant No. CMC 5-2023-D0731-00002.

Conflicts of Interest

Dr. Moran Ki reported receiving grants from the National Cancer Center of Korea during the conduct of the study. Dr. Jong-Hyun Kim reported receiving grants for vaccine development from SK bioscience Co., Ltd. (Seongnam, Korea) since 2023. No other disclosures were reported.

Supplementary material is available at Clinical and Molecular Hepatology website (http://www.e-cmh.org).
Supplementary Table 1.
Final outcomes* of perinatal hepatitis B prevention program by year, 2002–2021
cmh-2025-0214-Supplementary-Table-1.pdf
Supplementary Table 2.
Full multivariable logistic regression model for HBV mother-to-child-transmission risk analysis: interaction effects between maternal HBeAg status and antiviral prescription with adjusted covariates, 2002–2021
cmh-2025-0214-Supplementary-Table-2.pdf
Supplementary Table 3.
Comparison of characteristics between singleton and multiple gestation among infants born to HBsAg-positive mothers, 2002–2021
cmh-2025-0214-Supplementary-Table-3.pdf
Supplementary Table 4.
Comparison of characteristics between the breastfeeding and formula feeding groups among infants born to HBsAg-positive mothers, 2002–2021
cmh-2025-0214-Supplementary-Table-4.pdf
Supplementary Table 5.
Annual antiviral prescription* trends in HBsAg-positive pregnant women, 2002–2021
cmh-2025-0214-Supplementary-Table-5.pdf
Supplementary Table 6.
Hepatitis B mother-to-child transmission rates by antiviral prescription details, 2002–2021
cmh-2025-0214-Supplementary-Table-6.pdf
Supplementary Figure 1.
Strategies to prevent hepatitis B mother-to-child transmission in Korean national program. Birth dose was given within 12 hours, and the 1st serologic test was done at 9–15 months. Anti-HBs, antibody to hepatitis B surface antigen; HBIG, hepatitis B immunoglobulin; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HepB3-BD, hepatitis B 3rd dose vaccination with birth dose.
cmh-2025-0214-Supplementary-Fig-1.pdf
Figure 1.
Flow diagram of the study population, 2002–2021. 4,225 pairs were not linked among 232,606 mother-infant pairs. NHIS, National Health Insurance Service; MTCT, mother-to-child transmission. *Information about maternal economic status, delivery methods, multiple gestation and antivirals prescription status (2002–2023) was extracted from the linked NHIS database.
cmh-2025-0214f1.jpg
Figure 2.
Factors associated with hepatitis B mother-to-child transmission, 2002–2021. Antiviral in ‘Joint effect’, antiviral prescription; Csection, cesarean section; HBeAg, hepatitis B envelope antigen; HBsAg, hepatitis B surface antigen; N, no; NA, not applicable; OR, odds ratio; uk, unknown; Y, yes. *Adjusted odds ratios were estimated from multivariable logistic regression with stepwise selection, including interaction term between maternal HBeAg status and antiviral prescription (see Supplementary Table 2 for full model specifications and coefficients). †Classified based on total household income: upper (top 75%), middle (25–75%), and lower (bottom 25%, including medical aid recipients). ‡Based on ICD-10 codes: vaginal (ICD-10: O80.*, O81.*, O83.*, O84.0-1); elective C-section (O82.0); emergency C-section (O82.1); other C-section (O82, O82.2, O82.8-9, O84.2); unknown (unclear diagnostic codes). §Exclusively breastfed for at least the first one month from birth.
cmh-2025-0214f2.jpg
Figure 3.
Directed acyclic graph* of hepatitis B mother-to-child transmission pathways with effect modification.
Node colors: orange, exposure variable; blue, outcome variable; pink, mediator variables; green, confounder variable; yellow (dashed border), interaction term.
Node types: HBeAg status, primary exposure; MTCT, primary outcome; antiviral, breastfeeding and cesarean section, mediators; maternal age, confounder; HBeAg x Antiviral interaction, interaction between HBeAg status and antiviral prescription.
Arrow symbols: ⊕, positive association (increasing one variable increases the other); ⊖, negative association (increasing one variable decreases the other).
Relationships: maternal age positively affects (⊕) cesarean section and antiviral prescription; maternal age negatively affects (⊖) HBeAg status; HBeAg status negatively affects (⊖) breastfeeding; both breastfeeding and cesarean section negatively affect (⊖) MTCT; HBeAg status and antiviral prescription have an interaction effect on MTCT.
C-section, cesarean section; HBeAg, hepatitis B envelope antigen; MTCT, mother-to-child transmission. *Directed acyclic graph showing the causal relationships between maternal factors and mother-to-child transmission (MTCT) of hepatitis B virus.
cmh-2025-0214f3.jpg
cmh-2025-0214f4.jpg
Table 1.
Demographic characteristics of the study population
Table 1.
Variables With serologic results
 Without serologic results
 Effect size*
Number Percentage (%) % Except unknown Number Percentage (%)
Total 154,478 66.4 78,128 33.6
Maternal age (yr), mean (SD) 31.3 (±4.2) 30.9 (±4.5) 0.092
 <25 7,652 5.0 6,028 7.7 0.064
 25–29 43,273 28.0 23,401 30.0
 30–34 70,014 45.3 32,785 42.0
 35–39 29,194 18.9 13,621 17.4
 ≥40 4,345 2.8 2,293 2.9
Maternal nationality 0.043
 Korean 146,043 94.5 72,141 92.3
 Non-Korean 8,435 5.5 5,987 7.7
Maternal economic status† 0.034
 High 29,234 18.9 19.5 14,301 18.3
 Middle 93,921 60.8 62.7 46,126 59.0
 Low 26,563 17.2 17.7 14,418 18.5
 Unknown 4,760 3.1 - 3,283 4.2
Maternal HBeAg status 0.043
 Positive 32,994 21.4 31.2 17,387 22.3
 Negative 72,737 47.1 68.8 33,331 42.7
 Unknown 48,747 31.6 - 27,410 35.1
Maternal antiviral prescription 0.053
 No 148,254 96.0 76,569 98.0
 Yes 6,224 4.0 1,559 2.0
Sex of infants 0.007
 Female 75,292 48.7 37,479 48.0
 Male 79,186 51.3 40,649 52.0
Gestational age (wk) 0.084
 <32 984 0.6 0.8 715 0.9
 32–36 8,183 5.3 6.4 3,724 4.8
 37–40 112,263 72.7 87.9 51,585 66.0
 ≥41 6,250 4.0 4.9 3,200 4.1
 Unknown 26,798 17.3 - 18,904 24.2
Birth weight (g) 0.015
 ≥2,000 152,011 98.4 76,565 98.0
 <2,000 2,467 1.6 1,563 2.0
Delivery type‡ 0.033
 Vaginal 86,509 56.0 57.6 43,150 55.2
 Cesarean section 63,745 41.3 42.4 31,903 40.8
  Emergency 17,213 11.1 11.5 7,925 10.1
  Elective 28,980 18.8 19.3 16,030 20.5
  Other 17,552 11.4 11.7 7,948 10.2
 Unknown 4,224 2.7 - 3,075 3.9
Feeding method 0.396
 Formula 16,576 10.7 30.0 11 0.0
 Breast§ 18,196 11.8 33.0 14 0.0
 Mixed 20,441 13.2 37.0 14 0.0
 Unknown 99,265 64.3 - 78,089 99.95
All 3 same vaccine 0.366
 Yes 102,789 66.5 72.8 32,728 41.9
 No 38,435 24.9 27.2 15,213 19.5
 Unknown 13,254 8.6 - 30,187 38.6
Birth year of infants 0.242
 2002–2005 28,864 18.7 20,448 26.2
 2006–2009 35,515 23.0 25,841 33.1
 2010–2013 35,971 23.3 21,180 27.1
 2014–2017 37,438 24.2 4,773 6.1
 2018–2021 16,690 10.8 5,886 7.5

C-section, cesarean section; HBeAg, hepatitis B envelope antigen; SD, standard deviation.

*Effect sizes were presented as standardized mean difference (SMD) for continuous variables and as Cramer’s V for categorical variables.

†Classified based on total household income: upper (top 75%), middle (25–75%), and lower (bottom 25%, including medical aid recipients).

‡Based on ICD-10 codes: vaginal (ICD-10: O80.*, O81.*, O83.*, O84.0-1); elective C-section (O82.0); emergency C-section (O82.1); other C-section (O82, O82.2, O82.8-9, O84.2); unknown (unclear diagnostic codes).

§Exclusively breastfed for at least the first month from birth.

P-values obtained by χ² test were all <0.001.

Table 2.
Factors associated with hepatitis B mother-to-child transmission based on maternal HBeAg status, 2002–2021
Table 2.
Variable HBeAg (+) mothers (n=32,994)
 HBeAg (–) mothers (n=72,737)
 HBeAg (unknown) mothers (n=48,747)
HBsAg (+) infants
 HBsAg (+) infants
 HBsAg (+) infants
Number (%) OR (95% CI) aOR* (95% CI) Number (%) OR (95% CI) aOR* (95% CI) Number (%) OR (95% CI) aOR* (95% CI)
Total 1,822 (5.5) 699 (1.0) 1,103 (2.3)
Maternal age (yr), mean (SD) 29.8 (±4.4) 30.0 (±4.4) 30.0 (±4.4)
 <25 199 (8.4) 1 [reference] 1 [reference] 73 (2.6) 1 [reference] 1 [reference] 117 (4.8) 1 [reference] 1 [reference]
 25–29 645 (5.8) 0.68 (0.58–0.80) 0.75 (0.63–0.90) 267 (1.4) 0.54 (0.42–0.71) 0.58 (0.44–0.75) 375 (2.8) 0.57 (0.46–0.71) 0.64 (0.51–0.80)
 30–34 738 (5.2) 0.60 (0.51–0.70) 0.72 (0.60–0.87) 250 (0.7) 0.28 (0.22–0.36) 0.36 (0.28–0.48) 453 (2.1) 0.42 (0.34–0.52) 0.56 (0.45–0.70)
 35–39 210 (4.5) 0.52 (0.43–0.64) 0.70 (0.56–0.87) 99 (0.7) 0.25 (0.19–0.34) 0.37 (0.27–0.51) 140 (1.5) 0.30 (0.23–0.38) 0.46 (0.35–0.60)
 ≥40 30 (5.0) 0.58 (0.39–0.86) 0.83 (0.55–1.24) 10 (0.4) 0.17 (0.09–0.33) 0.26 (0.13–0.51) 18 (1.2) 0.24 (0.15–0.40) 0.40 (0.24–0.66)
Maternal nationality
 Korean 1,668 (5.4) 1 [reference] 1 [reference] 654 (0.9) 1 [reference] 1,014 (2.2) 1 [reference] 1 [reference]
 Non-Korean 154 (7.5) 1.43 (1.20–1.69) 1.30 (1.07–1.58) 45 (1.2) 1.27 (0.93–1.71) 89 (3.4) 1.56 (1.26–1.95) 1.45 (1.13–1.85)
Maternal economic status†
 High 315 (5.4) 1 [reference] 105 (0.8) 1 [reference] 186 (2.0) 1 [reference]
 Middle 1,102 (5.4) 1.01 (0.89–1.15) 437 (1.0) 1.32 (0.93–1.71) 670 (2.3) 1.15 (0.98–1.36)
 Low 347 (5.9) 1.11 (0.95–1.30) 138 (1.1) 1.47 (0.94–1.72) 203 (2.5) 1.26 (1.03–1.54)
 Unknown 58 (5.8) 1.08 (0.81–1.45) 19 (0.9) 1.17 (0.95–1.73) 44 (2.7) 1.40 (1.00–1.95)
Maternal antiviral prescription
 No 1,798 (5.9) 1 [reference] 1 [reference] 687 (1.0) 1 [reference] 1,085 (2.3) 1 [reference] 1 [reference]
 Yes 24 (1.0) 0.16 (0.11–0.24) 0.18 (0.12–0.27) 12 (0.6) 0.63 (0.35–1.11) 18 (1.0) 0.42 (0.26–0.67) 0.59 (0.37–0.94)
Sex of infants
 Female 857 (5.3) 1 [reference] 322 (0.9) 1 [reference] 524 (2.2) 1 [reference]
 Male 965 (5.7) 1.07 (0.98–1.18) 377 (1.0) 1.12 (0.96–1.30) 579 (2.3) 1.05 (0.93–1.18)
Gestational age (wk)
 <32 9 (5.0) 0.95 (0.49–1.87) 1.00 (0.51–1.96) 4 (1.1) 1.55 (0.57–4.16) 1.74 (0.65–4.70) 4 (0.9) 0.45 (0.17–1.21) 0.52 (0.19–1.40)
 32–36 63 (3.9) 0.73 (0.57–0.95) 0.79 (0.61–1.02) 22 (0.6) 0.88 (0.57–1.36) 0.98 (0.64–1.52) 50 (1.6) 0.81 (0.61–1.09) 0.90 (0.67–1.21)
 37–40 1,218 (5.2) 1 [reference] 1 [reference] 381 (0.7) 1 [reference] 1 [reference] 706 (2.0) 1 [reference] 1 [reference]
 ≥41 104 (7.6) 1.50 (1.22–1.85) 1.42 (1.15–1.75) 25 (0.8) 1.20 (0.80–1.80) 1.12 (0.75–1.68) 63 (3.3) 1.64 (1.26–2.13) 1.48 (1.14–1.92)
 Unknown 428 (6.6) 1.29 (1.15–1.45) 1.11 (0.78–1.59) 267 (2.2) 3.17 (2.71–3.71) 2.56 (2.15–3.04) 280 (3.4) 1.71 (1.48–1.97) 1.01 (0.67–1.52)
Birth weight (g)
 ≥2,000 1,794 (5.5) 1 [reference] 690 (1.0) 1 [reference] 1,088 (2.3) 1 [reference]
 <2,000 28 (6.0) 1.10 (0.75–1.61) 9 (0.9) 0.94 (0.49–1.83) 15 (1.5) 0.65 (0.39–1.08)
Delivery type‡
 Vaginal 1,131 (5.9) 1 [reference] 1 [reference] 427 (1.1) 1 [reference] 1 [reference] 711 (2.6) 1 [reference] 1 [reference]
 Cesarean section 606 (4.7) 0.79 (0.71–0.87) 0.83 (0.75–0.92) 222 (0.7) 0.68 (0.58–0.80) 0.76 (0.64–0.89) 356 (1.8) 0.67 (0.59–0.76) 0.73 (0.64–0.84)
  Emergency 194 (5.4) 0.90 (0.77–1.06) 65 (0.8) 0.78 (0.6–1.01) 119 (2.1) 0.79 (0.65–0.96)
  Elective 236 (4.3) 0.72 (0.62–0.83) 97 (0.7) 0.65 (0.52–0.81) 151 (1.6) 0.60 (0.50–0.72)
  Other 176 (4.7) 0.78 (0.66–0.91) 60 (0.7) 0.64 (0.49–0.84) 86 (1.7) 0.65 (0.52–0.81)
 Unknown 85 (8.0) 1.37 (1.09–1.73) 1.17 (0.91–1.50) 50 (2.6) 2.48 (1.84–3.34) 1.14 (0.83–1.56) 36 (2.9) 1.13 (0.80–1.58) 0.74 (0.52–1.05)
Feeding method
 Formula 275 (6.3) 1 [reference] 1 [reference] 59 (0.8) 1 [reference] 138 (2.7) 1 [reference] 1 [reference]
 Breast§ 171 (4.9) 0.78 (0.64–0.94) 0.75 (0.61–0.91) 53 (0.6) 0.75 (0.51–1.08) 96 (1.6) 0.57 (0.44–0.74) 0.52 (0.40–0.68)
 Mixed 196 (5.1) 0.81 (0.67–0.98) 0.86 (0.71–1.04) 75 (0.7) 0.87 (0.62–1.23) 99 (1.6) 0.57 (0.44–0.74) 0.66 (0.51–0.86)
 Unknown 1,180 (5.5) 0.88 (0.76–1.00) 0.79 (0.68–0.91) 512 (1.1) 1.33 (1.02–1.75) 770 (2.5) 0.90 (0.75–1.08) 0.78 (0.64–0.94)
All 3 same vaccine
 Yes 1,188 (5.5) 1 [reference] 441 (0.9) 1 [reference] 733 (2.2) 1 [reference]
 No 513 (5.7) 1.04 (0.94–1.16) 207 (1.2) 1.31 (1.11–1.54) 304 (2.5) 1.13 (0.99–1.30)
 Unknown 121 (4.9) 0.89 (0.74–1.08) 51 (0.7) 0.79 (0.59–1.06) 66 (1.8) 0.79 (0.61–1.02)
Birth year of infants
 2002–2005 460 (6.6) 1 [reference] 1 [reference] 277 (2.1) 1 [reference] 304 (3.4) 1 [reference] 1 [reference]
 2006–2009 551 (6.3) 0.95 (0.84–1.08) 1.02 (0.72–1.46) 114 (0.8) 0.37 (0.30–0.46) 338 (2.7) 0.79 (0.68–0.93) 0.80 (0.53–1.21)
 2010–2013 382 (4.8) 0.72 (0.63–0.83) 0.82 (0.57–1.18) 105 (0.7) 0.33 (0.26–0.41) 263 (2.0) 0.57 (0.48–0.68) 0.62 (0.41–0.94)
 2014–2017 321 (4.9) 0.72 (0.62–0.84) 0.91 (0.63–1.31) 160 (0.7) 0.33 (0.27–0.40) 127 (1.5) 0.43 (0.35–0.53) 0.50 (0.32–0.78)
 2018–2021 108 (4.0) 0.59 (0.48–0.73) 0.84 (0.56–1.25) 43 (0.5) 0.23 (0.17–0.32) 71 (1.3) 0.37 (0.29–0.48) 0.47 (0.29–0.75)

CI, confidence interval; C-section, cesarean section; HBeAg, hepatitis B envelope antigen; HBsAg, hepatitis B surface antigen; OR, odds ratio; aOR, adjusted odds ratio; SD, standard deviation.

*Multivariable logistic regression analysis with a stepwise variable selection was performed.

†Classified based on total household income: upper (top 75%), middle (25–75%), and lower (bottom 25%, including medical aid recipients).

‡Based on ICD-10 codes: vaginal (ICD-10: O80.*, O81.*, O83.*, O84.0-1); elective C-section (O82.0); emergency C-section (O82.1); other C-section (O82, O82.2, O82.8-9, O84.2); unknown (unclear diagnostic codes).

§Exclusively breastfed for at least the first one month from birth.

Table 3.
Factors associated with hepatitis B mother-to-child transmission and antiviral prescriptions, 2002–2021
Table 3.
Variables Antiviral non-prescription
 Antiviral prescription
Subject (n) HBsAg (+) infants
 Subject (n) HBsAg (+) infants
Number (%) OR (95% CI) aOR* (95% CI) Number (%) OR (95% CI) aOR* (95% CI)
Total 148,254 3,570 (2.4) 6,224 54 (0.9)
Maternal age (yr), mean (SD) 31.3 (±4.2) 29.9 (±4.4) 32.8 (±4.1) 31.5 (±4.7)
 <25 7,497 386 (5.1) 1 [reference] 1 [reference] 155 3 (1.9) 1 [reference]
 25–29 42,183 1,272 (3.0) 0.57 (0.51–0.64) 0.68 (0.60–0.77) 1,090 15 (1.4) 0.71 (0.20–2.47)
 30–34 67,135 1,422 (2.1) 0.40 (0.36–0.45) 0.59 (0.52–0.67) 2,879 19 (0.7) 0.34 (0.10–1.15)
 35–39 27,383 434 (1.6) 0.30 (0.26–0.34) 0.54 (0.46–0.62) 1,811 15 (0.8) 0.42 (0.12–1.48)
 ≥40 4,056 56 (1.4) 0.26 (0.19–0.34) 0.51 (0.38–0.68) 289 2 (0.7) 0.35 (0.06–2.14)
Maternal nationality
 Korean 140,121 3,288 (2.3) 1 [reference] 1 [reference] 5,922 48 (0.8) 1 [reference] 1 [reference]
 Non-Korean 8,133 282 (3.5) 1.50 (1.32–1.69) 1.32 (1.14–1.51) 302 6 (2.0) 2.48 (1.05–5.84) 2.48 (1.05–5.84)
Maternal economic status†
 High 27,834 597 (2.1) 1 [reference] 1,400 9 (0.6) 1 [reference]
 Middle 90,153 2,173 (2.4) 1.13 (1.03–1.24) 3,768 36 (1.0) 1.49 (0.72–3.10)
 Low 25,672 681 (2.7) 1.24 (1.11–1.39) 891 7 (0.8) 1.22 (0.45–3.30)
 Unknown 4,595 119 (2.6) 1.21 (0.99–1.48) 165 2 (1.2) 1.90 (0.41–8.85)
Maternal HBeAg status
 Positive 30,555 1,798 (5.9) 1 [reference] 1 [reference] 2,439 24 (1.0) 1 [reference]
 Negative 70,775 687 (1.0) 0.16 (0.14–0.17) 0.17 (0.16–0.19) 1,962 12 (0.6) 0.62 (0.31–1.24)
 Unknown 46,924 1,085 (2.3) 0.38 (0.35–0.41) 0.41 (0.38–0.44) 1,823 18 (1.0) 1.00 (0.54–1.85)
Sex of infants
 Female 72,191 1,678 (2.3) 1 [reference] 1 [reference] 3,101 25 (0.8) 1 [reference]
 Male 76,063 1,892 (2.5) 1.07 (1.00–1.15) 1.08 (1.01–1.16) 3,123 29 (0.9) 1.15 (0.67–1.97)
Gestational age (wk)
 <32 933 17 (1.8) 0.86 (0.53–1.39) 0.91 (0.56–1.48) 51 0 (0.0) NA
 32–36 7,694 129 (1.7) 0.79 (0.66–0.94) 0.84 (0.70–1.00) 489 6 (1.2) 1.48 (0.63–3.49)
 37–40 106,851 2,260 (2.1) 1 [reference] 1 [reference] 5,412 45 (0.8) 1 [reference]
 ≥41 6,067 192 (3.2) 1.51 (1.30–1.76) 1.41 (1.21–1.64) 183 0 (0.0) NA
 Unknown 26,709 972 (3.6) 1.75 (1.62–1.89) 1.21 (0.95–1.55) 89 3 (3.4) 4.16 (1.27–13.65)
Birth weight (g)
 ≥2,000 145,907 3,518 (2.4) 1 [reference] 6,099 54 (0.9) 1 [reference]
 <2,000 2,347 52 (2.2) 0.92 (0.70–1.21) 120 0 (0.0) NA
Delivery type‡
 Vaginal 83,284 2,239 (2.7) 1 [reference] 1 [reference] 3,225 30 (0.9) 1 [reference]
 Cesarean section 60,754 1,160 (1.9) 0.71 (0.66–0.76) 0.78 (0.73–0.84) 2,991 24 (0.8) 0.86 (0.50–1.48)
  Emergency 16,346 365 (2.2) 0.83 (0.74–0.93) 867 13 (1.5) 1.62 (0.84–3.12)
  Elective 27,798 480 (1.7) 0.64 (0.58–0.70) 1,182 4 (0.3) 0.36 (0.13–1.03)
  Other 16,610 315 (1.9) 0.70 (0.62–0.79) 942 7 (0.7) 0.80 (0.35–1.82)
 Unknown 4,216 171 (4.1) 1.53 (1.31–1.79) 1.03 (0.87–1.22) 8 0 (0.0) NA
Feeding method
 Formula 15,642 462 (3.0) 1 [reference] 1 [reference] 934 10 (1.1) 1 [reference]
 Breast§ 17,697 317 (1.8) 0.60 (0.52–0.69) 0.65 (0.57–0.76) 499 3 (0.6) 0.56 (0.15–2.04)
 Mixed 19,254 358 (1.9) 0.62 (0.54–0.72) 0.79 (0.68–0.91) 1,187 12 (1.0) 0.94 (0.41–2.19)
 Unknown 95,661 2,433 (2.5) 0.86 (0.78–0.95) 0.79 (0.71–0.88) 3,604 29 (0.8) 0.75 (0.36–1.54)
All 3 same vaccine
 Yes 98,675 2,326 (2.4) 1 [reference] 4,114 36 (0.9) 1 [reference]
 No 37,185 1,009 (2.7) 1.16 (1.07–1.25) 1,250 15 (1.2) 1.38 (0.75–2.52)
 Unknown 12,394 235 (1.9) 0.80 (0.70–0.92) 860 3 (0.3) 0.40 (0.12–1.29)
Birth year of infants
 2002–2005 28,763 1,038 (3.6) 1 [reference] 1 [reference] 101 3 (3.0) 1 [reference]
 2006–2009 35,133 999 (2.8) 0.78 (0.72–0.85) 0.90 (0.70–1.15) 382 4 (1.0) 0.35 (0.08–1.57)
 2010–2013 34,854 738 (2.1) 0.58 (0.53–0.64) 0.73 (0.57–0.94) 1,117 12 (1.1) 0.36 (0.10–1.28)
 2014–2017 34,837 583 (1.7) 0.46 (0.41–0.50) 0.72 (0.56–0.93) 2,601 25 (1.0) 0.32 (0.09–1.07)
 2018–2021 14,667 212 (1.4) 0.39 (0.34–0.46) 0.64 (0.48–0.85) 2,023 10 (0.5) 0.16 (0.04–0.60)

C-section, cesarean section; HBeAg, hepatitis B envelope antigen; HBsAg, hepatitis B surface antigen; OR, odds ratio; aOR, adjusted odds ratio; SD, standard deviation.

*Multivariable logistic regression analysis with a stepwise variable selection was performed.

†Classified based on total household income: upper (top 75%), middle (25–75%), and lower (bottom 25%, including medical aid recipients).

‡Based on ICD-10 codes: vaginal (ICD-10: O80.*, O81.*, O83.*, O84.0-1); elective C-section (O82.0); emergency C-section (O82.1); other C-section (O82, O82.2, O82.8-9, O84.2); unknown (unclear diagnostic codes).

§Exclusively breastfed for at least the first one month from birth.

Table 4.
Hepatitis B mother-to-child transmission and antiviral prescription details by HBeAg status, 2002–2021
Table 4.
Variable Subject (n) HBsAg (+) infants, n (%) OR (95% CI) HBeAg (+) mothers
 HBeAg (–) mothers
 HBeAg (unknown) mothers
Number HBsAg (+) infants, n (%) Number HBsAg (+) infants, n (%) Number HBsAg (+) infants, n (%)
Antiviral prescription 6,224 54 (0.87) 2,439 24 (0.98) 1,962 12 (0.61) 1,823 18 (0.99)
Initiation time in GA* (wk)
 Before pregnancy 3,567 36 (1.01) 2.63 (1.03–6.71) 1,297 16 (1.23) 1,182 9 (0.76) 1,088 11 (1.01)
 14–27 1,294 5 (0.39) 1 [reference] 509 1 (0.20) 381 1 (0.26) 404 3 (0.74)
 28–32 684 3 (0.44) 1.14 (0.27–4.76) 309 0 (0.00) 196 1 (0.51) 179 2 (1.12)
 ≥33 679 10 (1.47) 3.85 (1.31–11.31) 324 7 (2.16) 203 1 (0.49) 152 2 (1.32)
Discontinuation time
 Before delivery 2,223 32 (1.44) 2.64 (1.53–4.56) 854 15 (1.76) 702 7 (1.00) 667 10 (1.50)
 After delivery 4,001 22 (0.55) 1 [reference] 1,585 9 (0.57) 1,260 5 (0.40) 1,156 8 (0.69)
Duration (d)
 1–60 1,914 32 (1.67) 3.31 (1.92–5.72) 832 17 (2.04) 595 7 (1.18) 487 8 (1.64)
 ≥61 4,310 22 (0.51) 1 [reference] 1,607 7 (0.44) 1,367 5 (0.37) 1,336 10 (0.75)

CI, confidence interval; GA, gestational age; HBeAg, hepatitis B envelope antigen; HBsAg, hepatitis B surface antigen; OR, odds ratio.

*No mothers started antiviral prescriptions in weeks 1–13 of pregnancy.

Anti-HBs

antibody to hepatitis B surface antigen

Antiviral prophylaxis

antiviral prophylaxis during pregnancy

C-section

Cesarean section

DAG

directed acyclic graph

HBeAg

hepatitis B envelope antigen

HBIG

hepatitis B immunoglobulin

HBsAg

hepatitis B surface antigen

HBV

hepatitis B virus

KDCA

Korea Disease Control and Prevention Agency

NHIS

National Health Insurance Service

NIP

national immunization program

MTCT

mother-to-child transmission

PHBPP

perinatal hepatitis B prevention program

PVST

post-vaccination serological testing

SD

standard deviation

TAF

tenofovir alafenamide

TDF

tenofovir disoproxil fumarate

WHO

World Health Organization
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Factors associated with hepatitis B mother-to-child transmission in a national prevention program
Clin Mol Hepatol. 2025;31(4):1298-1315.   Published online June 24, 2025
DOI: https://doi.org/10.3350/cmh.2025.0214
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Factors associated with hepatitis B mother-to-child transmission in a national prevention program
Clin Mol Hepatol. 2025;31(4):1298-1315.   Published online June 24, 2025
DOI: https://doi.org/10.3350/cmh.2025.0214
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Factors associated with hepatitis B mother-to-child transmission in a national prevention program
Image Image Image Image
Figure 1. Flow diagram of the study population, 2002–2021. 4,225 pairs were not linked among 232,606 mother-infant pairs. NHIS, National Health Insurance Service; MTCT, mother-to-child transmission. *Information about maternal economic status, delivery methods, multiple gestation and antivirals prescription status (2002–2023) was extracted from the linked NHIS database.
Figure 2. Factors associated with hepatitis B mother-to-child transmission, 2002–2021. Antiviral in ‘Joint effect’, antiviral prescription; Csection, cesarean section; HBeAg, hepatitis B envelope antigen; HBsAg, hepatitis B surface antigen; N, no; NA, not applicable; OR, odds ratio; uk, unknown; Y, yes. *Adjusted odds ratios were estimated from multivariable logistic regression with stepwise selection, including interaction term between maternal HBeAg status and antiviral prescription (see Supplementary Table 2 for full model specifications and coefficients). †Classified based on total household income: upper (top 75%), middle (25–75%), and lower (bottom 25%, including medical aid recipients). ‡Based on ICD-10 codes: vaginal (ICD-10: O80.*, O81.*, O83.*, O84.0-1); elective C-section (O82.0); emergency C-section (O82.1); other C-section (O82, O82.2, O82.8-9, O84.2); unknown (unclear diagnostic codes). §Exclusively breastfed for at least the first one month from birth.
Figure 3. Directed acyclic graph* of hepatitis B mother-to-child transmission pathways with effect modification. Node colors: orange, exposure variable; blue, outcome variable; pink, mediator variables; green, confounder variable; yellow (dashed border), interaction term. Node types: HBeAg status, primary exposure; MTCT, primary outcome; antiviral, breastfeeding and cesarean section, mediators; maternal age, confounder; HBeAg x Antiviral interaction, interaction between HBeAg status and antiviral prescription. Arrow symbols: ⊕, positive association (increasing one variable increases the other); ⊖, negative association (increasing one variable decreases the other). Relationships: maternal age positively affects (⊕) cesarean section and antiviral prescription; maternal age negatively affects (⊖) HBeAg status; HBeAg status negatively affects (⊖) breastfeeding; both breastfeeding and cesarean section negatively affect (⊖) MTCT; HBeAg status and antiviral prescription have an interaction effect on MTCT. C-section, cesarean section; HBeAg, hepatitis B envelope antigen; MTCT, mother-to-child transmission. *Directed acyclic graph showing the causal relationships between maternal factors and mother-to-child transmission (MTCT) of hepatitis B virus.
Graphical abstract

Figure 1.

Figure 2.

Figure 3.

Graphical abstract

Factors associated with hepatitis B mother-to-child transmission in a national prevention program
Variables With serologic results
 Without serologic results
 Effect size*
Number Percentage (%) % Except unknown Number Percentage (%)
Total 154,478 66.4 78,128 33.6
Maternal age (yr), mean (SD) 31.3 (±4.2) 30.9 (±4.5) 0.092
 <25 7,652 5.0 6,028 7.7 0.064
 25–29 43,273 28.0 23,401 30.0
 30–34 70,014 45.3 32,785 42.0
 35–39 29,194 18.9 13,621 17.4
 ≥40 4,345 2.8 2,293 2.9
Maternal nationality 0.043
 Korean 146,043 94.5 72,141 92.3
 Non-Korean 8,435 5.5 5,987 7.7
Maternal economic status† 0.034
 High 29,234 18.9 19.5 14,301 18.3
 Middle 93,921 60.8 62.7 46,126 59.0
 Low 26,563 17.2 17.7 14,418 18.5
 Unknown 4,760 3.1 - 3,283 4.2
Maternal HBeAg status 0.043
 Positive 32,994 21.4 31.2 17,387 22.3
 Negative 72,737 47.1 68.8 33,331 42.7
 Unknown 48,747 31.6 - 27,410 35.1
Maternal antiviral prescription 0.053
 No 148,254 96.0 76,569 98.0
 Yes 6,224 4.0 1,559 2.0
Sex of infants 0.007
 Female 75,292 48.7 37,479 48.0
 Male 79,186 51.3 40,649 52.0
Gestational age (wk) 0.084
 <32 984 0.6 0.8 715 0.9
 32–36 8,183 5.3 6.4 3,724 4.8
 37–40 112,263 72.7 87.9 51,585 66.0
 ≥41 6,250 4.0 4.9 3,200 4.1
 Unknown 26,798 17.3 - 18,904 24.2
Birth weight (g) 0.015
 ≥2,000 152,011 98.4 76,565 98.0
 <2,000 2,467 1.6 1,563 2.0
Delivery type‡ 0.033
 Vaginal 86,509 56.0 57.6 43,150 55.2
 Cesarean section 63,745 41.3 42.4 31,903 40.8
  Emergency 17,213 11.1 11.5 7,925 10.1
  Elective 28,980 18.8 19.3 16,030 20.5
  Other 17,552 11.4 11.7 7,948 10.2
 Unknown 4,224 2.7 - 3,075 3.9
Feeding method 0.396
 Formula 16,576 10.7 30.0 11 0.0
 Breast§ 18,196 11.8 33.0 14 0.0
 Mixed 20,441 13.2 37.0 14 0.0
 Unknown 99,265 64.3 - 78,089 99.95
All 3 same vaccine 0.366
 Yes 102,789 66.5 72.8 32,728 41.9
 No 38,435 24.9 27.2 15,213 19.5
 Unknown 13,254 8.6 - 30,187 38.6
Birth year of infants 0.242
 2002–2005 28,864 18.7 20,448 26.2
 2006–2009 35,515 23.0 25,841 33.1
 2010–2013 35,971 23.3 21,180 27.1
 2014–2017 37,438 24.2 4,773 6.1
 2018–2021 16,690 10.8 5,886 7.5
Variable HBeAg (+) mothers (n=32,994)
 HBeAg (–) mothers (n=72,737)
 HBeAg (unknown) mothers (n=48,747)
HBsAg (+) infants
 HBsAg (+) infants
 HBsAg (+) infants
Number (%) OR (95% CI) aOR* (95% CI) Number (%) OR (95% CI) aOR* (95% CI) Number (%) OR (95% CI) aOR* (95% CI)
Total 1,822 (5.5) 699 (1.0) 1,103 (2.3)
Maternal age (yr), mean (SD) 29.8 (±4.4) 30.0 (±4.4) 30.0 (±4.4)
 <25 199 (8.4) 1 [reference] 1 [reference] 73 (2.6) 1 [reference] 1 [reference] 117 (4.8) 1 [reference] 1 [reference]
 25–29 645 (5.8) 0.68 (0.58–0.80) 0.75 (0.63–0.90) 267 (1.4) 0.54 (0.42–0.71) 0.58 (0.44–0.75) 375 (2.8) 0.57 (0.46–0.71) 0.64 (0.51–0.80)
 30–34 738 (5.2) 0.60 (0.51–0.70) 0.72 (0.60–0.87) 250 (0.7) 0.28 (0.22–0.36) 0.36 (0.28–0.48) 453 (2.1) 0.42 (0.34–0.52) 0.56 (0.45–0.70)
 35–39 210 (4.5) 0.52 (0.43–0.64) 0.70 (0.56–0.87) 99 (0.7) 0.25 (0.19–0.34) 0.37 (0.27–0.51) 140 (1.5) 0.30 (0.23–0.38) 0.46 (0.35–0.60)
 ≥40 30 (5.0) 0.58 (0.39–0.86) 0.83 (0.55–1.24) 10 (0.4) 0.17 (0.09–0.33) 0.26 (0.13–0.51) 18 (1.2) 0.24 (0.15–0.40) 0.40 (0.24–0.66)
Maternal nationality
 Korean 1,668 (5.4) 1 [reference] 1 [reference] 654 (0.9) 1 [reference] 1,014 (2.2) 1 [reference] 1 [reference]
 Non-Korean 154 (7.5) 1.43 (1.20–1.69) 1.30 (1.07–1.58) 45 (1.2) 1.27 (0.93–1.71) 89 (3.4) 1.56 (1.26–1.95) 1.45 (1.13–1.85)
Maternal economic status†
 High 315 (5.4) 1 [reference] 105 (0.8) 1 [reference] 186 (2.0) 1 [reference]
 Middle 1,102 (5.4) 1.01 (0.89–1.15) 437 (1.0) 1.32 (0.93–1.71) 670 (2.3) 1.15 (0.98–1.36)
 Low 347 (5.9) 1.11 (0.95–1.30) 138 (1.1) 1.47 (0.94–1.72) 203 (2.5) 1.26 (1.03–1.54)
 Unknown 58 (5.8) 1.08 (0.81–1.45) 19 (0.9) 1.17 (0.95–1.73) 44 (2.7) 1.40 (1.00–1.95)
Maternal antiviral prescription
 No 1,798 (5.9) 1 [reference] 1 [reference] 687 (1.0) 1 [reference] 1,085 (2.3) 1 [reference] 1 [reference]
 Yes 24 (1.0) 0.16 (0.11–0.24) 0.18 (0.12–0.27) 12 (0.6) 0.63 (0.35–1.11) 18 (1.0) 0.42 (0.26–0.67) 0.59 (0.37–0.94)
Sex of infants
 Female 857 (5.3) 1 [reference] 322 (0.9) 1 [reference] 524 (2.2) 1 [reference]
 Male 965 (5.7) 1.07 (0.98–1.18) 377 (1.0) 1.12 (0.96–1.30) 579 (2.3) 1.05 (0.93–1.18)
Gestational age (wk)
 <32 9 (5.0) 0.95 (0.49–1.87) 1.00 (0.51–1.96) 4 (1.1) 1.55 (0.57–4.16) 1.74 (0.65–4.70) 4 (0.9) 0.45 (0.17–1.21) 0.52 (0.19–1.40)
 32–36 63 (3.9) 0.73 (0.57–0.95) 0.79 (0.61–1.02) 22 (0.6) 0.88 (0.57–1.36) 0.98 (0.64–1.52) 50 (1.6) 0.81 (0.61–1.09) 0.90 (0.67–1.21)
 37–40 1,218 (5.2) 1 [reference] 1 [reference] 381 (0.7) 1 [reference] 1 [reference] 706 (2.0) 1 [reference] 1 [reference]
 ≥41 104 (7.6) 1.50 (1.22–1.85) 1.42 (1.15–1.75) 25 (0.8) 1.20 (0.80–1.80) 1.12 (0.75–1.68) 63 (3.3) 1.64 (1.26–2.13) 1.48 (1.14–1.92)
 Unknown 428 (6.6) 1.29 (1.15–1.45) 1.11 (0.78–1.59) 267 (2.2) 3.17 (2.71–3.71) 2.56 (2.15–3.04) 280 (3.4) 1.71 (1.48–1.97) 1.01 (0.67–1.52)
Birth weight (g)
 ≥2,000 1,794 (5.5) 1 [reference] 690 (1.0) 1 [reference] 1,088 (2.3) 1 [reference]
 <2,000 28 (6.0) 1.10 (0.75–1.61) 9 (0.9) 0.94 (0.49–1.83) 15 (1.5) 0.65 (0.39–1.08)
Delivery type‡
 Vaginal 1,131 (5.9) 1 [reference] 1 [reference] 427 (1.1) 1 [reference] 1 [reference] 711 (2.6) 1 [reference] 1 [reference]
 Cesarean section 606 (4.7) 0.79 (0.71–0.87) 0.83 (0.75–0.92) 222 (0.7) 0.68 (0.58–0.80) 0.76 (0.64–0.89) 356 (1.8) 0.67 (0.59–0.76) 0.73 (0.64–0.84)
  Emergency 194 (5.4) 0.90 (0.77–1.06) 65 (0.8) 0.78 (0.6–1.01) 119 (2.1) 0.79 (0.65–0.96)
  Elective 236 (4.3) 0.72 (0.62–0.83) 97 (0.7) 0.65 (0.52–0.81) 151 (1.6) 0.60 (0.50–0.72)
  Other 176 (4.7) 0.78 (0.66–0.91) 60 (0.7) 0.64 (0.49–0.84) 86 (1.7) 0.65 (0.52–0.81)
 Unknown 85 (8.0) 1.37 (1.09–1.73) 1.17 (0.91–1.50) 50 (2.6) 2.48 (1.84–3.34) 1.14 (0.83–1.56) 36 (2.9) 1.13 (0.80–1.58) 0.74 (0.52–1.05)
Feeding method
 Formula 275 (6.3) 1 [reference] 1 [reference] 59 (0.8) 1 [reference] 138 (2.7) 1 [reference] 1 [reference]
 Breast§ 171 (4.9) 0.78 (0.64–0.94) 0.75 (0.61–0.91) 53 (0.6) 0.75 (0.51–1.08) 96 (1.6) 0.57 (0.44–0.74) 0.52 (0.40–0.68)
 Mixed 196 (5.1) 0.81 (0.67–0.98) 0.86 (0.71–1.04) 75 (0.7) 0.87 (0.62–1.23) 99 (1.6) 0.57 (0.44–0.74) 0.66 (0.51–0.86)
 Unknown 1,180 (5.5) 0.88 (0.76–1.00) 0.79 (0.68–0.91) 512 (1.1) 1.33 (1.02–1.75) 770 (2.5) 0.90 (0.75–1.08) 0.78 (0.64–0.94)
All 3 same vaccine
 Yes 1,188 (5.5) 1 [reference] 441 (0.9) 1 [reference] 733 (2.2) 1 [reference]
 No 513 (5.7) 1.04 (0.94–1.16) 207 (1.2) 1.31 (1.11–1.54) 304 (2.5) 1.13 (0.99–1.30)
 Unknown 121 (4.9) 0.89 (0.74–1.08) 51 (0.7) 0.79 (0.59–1.06) 66 (1.8) 0.79 (0.61–1.02)
Birth year of infants
 2002–2005 460 (6.6) 1 [reference] 1 [reference] 277 (2.1) 1 [reference] 304 (3.4) 1 [reference] 1 [reference]
 2006–2009 551 (6.3) 0.95 (0.84–1.08) 1.02 (0.72–1.46) 114 (0.8) 0.37 (0.30–0.46) 338 (2.7) 0.79 (0.68–0.93) 0.80 (0.53–1.21)
 2010–2013 382 (4.8) 0.72 (0.63–0.83) 0.82 (0.57–1.18) 105 (0.7) 0.33 (0.26–0.41) 263 (2.0) 0.57 (0.48–0.68) 0.62 (0.41–0.94)
 2014–2017 321 (4.9) 0.72 (0.62–0.84) 0.91 (0.63–1.31) 160 (0.7) 0.33 (0.27–0.40) 127 (1.5) 0.43 (0.35–0.53) 0.50 (0.32–0.78)
 2018–2021 108 (4.0) 0.59 (0.48–0.73) 0.84 (0.56–1.25) 43 (0.5) 0.23 (0.17–0.32) 71 (1.3) 0.37 (0.29–0.48) 0.47 (0.29–0.75)
Variables Antiviral non-prescription
 Antiviral prescription
Subject (n) HBsAg (+) infants
 Subject (n) HBsAg (+) infants
Number (%) OR (95% CI) aOR* (95% CI) Number (%) OR (95% CI) aOR* (95% CI)
Total 148,254 3,570 (2.4) 6,224 54 (0.9)
Maternal age (yr), mean (SD) 31.3 (±4.2) 29.9 (±4.4) 32.8 (±4.1) 31.5 (±4.7)
 <25 7,497 386 (5.1) 1 [reference] 1 [reference] 155 3 (1.9) 1 [reference]
 25–29 42,183 1,272 (3.0) 0.57 (0.51–0.64) 0.68 (0.60–0.77) 1,090 15 (1.4) 0.71 (0.20–2.47)
 30–34 67,135 1,422 (2.1) 0.40 (0.36–0.45) 0.59 (0.52–0.67) 2,879 19 (0.7) 0.34 (0.10–1.15)
 35–39 27,383 434 (1.6) 0.30 (0.26–0.34) 0.54 (0.46–0.62) 1,811 15 (0.8) 0.42 (0.12–1.48)
 ≥40 4,056 56 (1.4) 0.26 (0.19–0.34) 0.51 (0.38–0.68) 289 2 (0.7) 0.35 (0.06–2.14)
Maternal nationality
 Korean 140,121 3,288 (2.3) 1 [reference] 1 [reference] 5,922 48 (0.8) 1 [reference] 1 [reference]
 Non-Korean 8,133 282 (3.5) 1.50 (1.32–1.69) 1.32 (1.14–1.51) 302 6 (2.0) 2.48 (1.05–5.84) 2.48 (1.05–5.84)
Maternal economic status†
 High 27,834 597 (2.1) 1 [reference] 1,400 9 (0.6) 1 [reference]
 Middle 90,153 2,173 (2.4) 1.13 (1.03–1.24) 3,768 36 (1.0) 1.49 (0.72–3.10)
 Low 25,672 681 (2.7) 1.24 (1.11–1.39) 891 7 (0.8) 1.22 (0.45–3.30)
 Unknown 4,595 119 (2.6) 1.21 (0.99–1.48) 165 2 (1.2) 1.90 (0.41–8.85)
Maternal HBeAg status
 Positive 30,555 1,798 (5.9) 1 [reference] 1 [reference] 2,439 24 (1.0) 1 [reference]
 Negative 70,775 687 (1.0) 0.16 (0.14–0.17) 0.17 (0.16–0.19) 1,962 12 (0.6) 0.62 (0.31–1.24)
 Unknown 46,924 1,085 (2.3) 0.38 (0.35–0.41) 0.41 (0.38–0.44) 1,823 18 (1.0) 1.00 (0.54–1.85)
Sex of infants
 Female 72,191 1,678 (2.3) 1 [reference] 1 [reference] 3,101 25 (0.8) 1 [reference]
 Male 76,063 1,892 (2.5) 1.07 (1.00–1.15) 1.08 (1.01–1.16) 3,123 29 (0.9) 1.15 (0.67–1.97)
Gestational age (wk)
 <32 933 17 (1.8) 0.86 (0.53–1.39) 0.91 (0.56–1.48) 51 0 (0.0) NA
 32–36 7,694 129 (1.7) 0.79 (0.66–0.94) 0.84 (0.70–1.00) 489 6 (1.2) 1.48 (0.63–3.49)
 37–40 106,851 2,260 (2.1) 1 [reference] 1 [reference] 5,412 45 (0.8) 1 [reference]
 ≥41 6,067 192 (3.2) 1.51 (1.30–1.76) 1.41 (1.21–1.64) 183 0 (0.0) NA
 Unknown 26,709 972 (3.6) 1.75 (1.62–1.89) 1.21 (0.95–1.55) 89 3 (3.4) 4.16 (1.27–13.65)
Birth weight (g)
 ≥2,000 145,907 3,518 (2.4) 1 [reference] 6,099 54 (0.9) 1 [reference]
 <2,000 2,347 52 (2.2) 0.92 (0.70–1.21) 120 0 (0.0) NA
Delivery type‡
 Vaginal 83,284 2,239 (2.7) 1 [reference] 1 [reference] 3,225 30 (0.9) 1 [reference]
 Cesarean section 60,754 1,160 (1.9) 0.71 (0.66–0.76) 0.78 (0.73–0.84) 2,991 24 (0.8) 0.86 (0.50–1.48)
  Emergency 16,346 365 (2.2) 0.83 (0.74–0.93) 867 13 (1.5) 1.62 (0.84–3.12)
  Elective 27,798 480 (1.7) 0.64 (0.58–0.70) 1,182 4 (0.3) 0.36 (0.13–1.03)
  Other 16,610 315 (1.9) 0.70 (0.62–0.79) 942 7 (0.7) 0.80 (0.35–1.82)
 Unknown 4,216 171 (4.1) 1.53 (1.31–1.79) 1.03 (0.87–1.22) 8 0 (0.0) NA
Feeding method
 Formula 15,642 462 (3.0) 1 [reference] 1 [reference] 934 10 (1.1) 1 [reference]
 Breast§ 17,697 317 (1.8) 0.60 (0.52–0.69) 0.65 (0.57–0.76) 499 3 (0.6) 0.56 (0.15–2.04)
 Mixed 19,254 358 (1.9) 0.62 (0.54–0.72) 0.79 (0.68–0.91) 1,187 12 (1.0) 0.94 (0.41–2.19)
 Unknown 95,661 2,433 (2.5) 0.86 (0.78–0.95) 0.79 (0.71–0.88) 3,604 29 (0.8) 0.75 (0.36–1.54)
All 3 same vaccine
 Yes 98,675 2,326 (2.4) 1 [reference] 4,114 36 (0.9) 1 [reference]
 No 37,185 1,009 (2.7) 1.16 (1.07–1.25) 1,250 15 (1.2) 1.38 (0.75–2.52)
 Unknown 12,394 235 (1.9) 0.80 (0.70–0.92) 860 3 (0.3) 0.40 (0.12–1.29)
Birth year of infants
 2002–2005 28,763 1,038 (3.6) 1 [reference] 1 [reference] 101 3 (3.0) 1 [reference]
 2006–2009 35,133 999 (2.8) 0.78 (0.72–0.85) 0.90 (0.70–1.15) 382 4 (1.0) 0.35 (0.08–1.57)
 2010–2013 34,854 738 (2.1) 0.58 (0.53–0.64) 0.73 (0.57–0.94) 1,117 12 (1.1) 0.36 (0.10–1.28)
 2014–2017 34,837 583 (1.7) 0.46 (0.41–0.50) 0.72 (0.56–0.93) 2,601 25 (1.0) 0.32 (0.09–1.07)
 2018–2021 14,667 212 (1.4) 0.39 (0.34–0.46) 0.64 (0.48–0.85) 2,023 10 (0.5) 0.16 (0.04–0.60)
Variable Subject (n) HBsAg (+) infants, n (%) OR (95% CI) HBeAg (+) mothers
 HBeAg (–) mothers
 HBeAg (unknown) mothers
Number HBsAg (+) infants, n (%) Number HBsAg (+) infants, n (%) Number HBsAg (+) infants, n (%)
Antiviral prescription 6,224 54 (0.87) 2,439 24 (0.98) 1,962 12 (0.61) 1,823 18 (0.99)
Initiation time in GA* (wk)
 Before pregnancy 3,567 36 (1.01) 2.63 (1.03–6.71) 1,297 16 (1.23) 1,182 9 (0.76) 1,088 11 (1.01)
 14–27 1,294 5 (0.39) 1 [reference] 509 1 (0.20) 381 1 (0.26) 404 3 (0.74)
 28–32 684 3 (0.44) 1.14 (0.27–4.76) 309 0 (0.00) 196 1 (0.51) 179 2 (1.12)
 ≥33 679 10 (1.47) 3.85 (1.31–11.31) 324 7 (2.16) 203 1 (0.49) 152 2 (1.32)
Discontinuation time
 Before delivery 2,223 32 (1.44) 2.64 (1.53–4.56) 854 15 (1.76) 702 7 (1.00) 667 10 (1.50)
 After delivery 4,001 22 (0.55) 1 [reference] 1,585 9 (0.57) 1,260 5 (0.40) 1,156 8 (0.69)
Duration (d)
 1–60 1,914 32 (1.67) 3.31 (1.92–5.72) 832 17 (2.04) 595 7 (1.18) 487 8 (1.64)
 ≥61 4,310 22 (0.51) 1 [reference] 1,607 7 (0.44) 1,367 5 (0.37) 1,336 10 (0.75)
Table 1. Demographic characteristics of the study population

C-section, cesarean section; HBeAg, hepatitis B envelope antigen; SD, standard deviation.

Effect sizes were presented as standardized mean difference (SMD) for continuous variables and as Cramer’s V for categorical variables.

Classified based on total household income: upper (top 75%), middle (25–75%), and lower (bottom 25%, including medical aid recipients).

Based on ICD-10 codes: vaginal (ICD-10: O80.*, O81.*, O83.*, O84.0-1); elective C-section (O82.0); emergency C-section (O82.1); other C-section (O82, O82.2, O82.8-9, O84.2); unknown (unclear diagnostic codes).

Exclusively breastfed for at least the first month from birth.

P-values obtained by χ² test were all <0.001.

Table 2. Factors associated with hepatitis B mother-to-child transmission based on maternal HBeAg status, 2002–2021

CI, confidence interval; C-section, cesarean section; HBeAg, hepatitis B envelope antigen; HBsAg, hepatitis B surface antigen; OR, odds ratio; aOR, adjusted odds ratio; SD, standard deviation.

Multivariable logistic regression analysis with a stepwise variable selection was performed.

Classified based on total household income: upper (top 75%), middle (25–75%), and lower (bottom 25%, including medical aid recipients).

Based on ICD-10 codes: vaginal (ICD-10: O80.*, O81.*, O83.*, O84.0-1); elective C-section (O82.0); emergency C-section (O82.1); other C-section (O82, O82.2, O82.8-9, O84.2); unknown (unclear diagnostic codes).

Exclusively breastfed for at least the first one month from birth.

Table 3. Factors associated with hepatitis B mother-to-child transmission and antiviral prescriptions, 2002–2021

C-section, cesarean section; HBeAg, hepatitis B envelope antigen; HBsAg, hepatitis B surface antigen; OR, odds ratio; aOR, adjusted odds ratio; SD, standard deviation.

Multivariable logistic regression analysis with a stepwise variable selection was performed.

Classified based on total household income: upper (top 75%), middle (25–75%), and lower (bottom 25%, including medical aid recipients).

Based on ICD-10 codes: vaginal (ICD-10: O80.*, O81.*, O83.*, O84.0-1); elective C-section (O82.0); emergency C-section (O82.1); other C-section (O82, O82.2, O82.8-9, O84.2); unknown (unclear diagnostic codes).

Exclusively breastfed for at least the first one month from birth.

Table 4. Hepatitis B mother-to-child transmission and antiviral prescription details by HBeAg status, 2002–2021

CI, confidence interval; GA, gestational age; HBeAg, hepatitis B envelope antigen; HBsAg, hepatitis B surface antigen; OR, odds ratio.

No mothers started antiviral prescriptions in weeks 1–13 of pregnancy.

Table 1.

Table 2.

Table 3.

Table 4.

CMH : Clinical and Molecular Hepatology
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