Abstract
Objective
Previous studies have indicated a potential association between maternal Hepatitis B virus (HBV) infection and impaired neurodevelopment in offspring. This study aimed to evaluate the relationship between maternal HBV infection and neurodevelopmental disorders (NDD) in children.
Methods
A retrospective cohort study was conducted utilizing data from the Korean National Health Insurance Service database, encompassing live births from 2005 to 2019. The cohort comprised children born to mothers who underwent Hepatitis B surface antigen testing. Subsequent diagnoses of NDD were monitored in these children. Propensity score matching, at a 1:3 ratio, was employed to compare children born to HBV-infected mothers with those born to uninfected mothers. This matching method adjusted for various maternal and pregnancy-related variables.
Results
The study encompassed 263,904 children born to HBV-infected mothers and 791,712 matched controls. Offspring of HBV-infected mothers exhibited a slightly elevated risk of NDD development (HR 1.03, 95 % CI: 1.01–1.04). Remarkably, children who were themselves infected with HBV demonstrated a further increased risk (HR 1.18, 95 % CI: 1.09–1.28).
Conclusions
Children born to HBV-infected mothers, particularly those directly infected, displayed a modestly heightened risk of NDD. These findings underscore the necessity for further investigation into the impact of maternal HBV infection on offspring neurodevelopment and the formulation of targeted interventions.
Keywords: Hepatitis B virus, Maternal viral infection, Neurodevelopmental disorders, Paediatric outcomes, Korean National Health Insurance Service
Highlights
-
•
Hepatitis B virus infection of mothers may affect the neurodevelopment of children.
-
•
Children with hepatitis B virus have a higher risk of neurodevelopmental disorders.
-
•
Children of hepatitis B virus-infected mothers need neurodevelopmental monitoring.
1. Introduction
Hepatitis B virus (HBV) infection presents a persistent global public health challenge, contributing substantially to morbidity and mortality worldwide (Korean Association for the Study of the Liver, 2022; European Association for the Study of the Liver, 2017). Chronic HBV infection afflicts millions, including women of reproductive age, posing risks not only to carriers but also to their progeny (Thio et al., 2015; World Health Organization, 2020). Vertical transmission of HBV from mother to child during birth represents a well-established route for perpetuating this infection, prompting endeavors to disrupt this cycle through antenatal screening and immunization interventions. Despite these efforts, the ramifications of maternal HBV infection transcend the immediate risk of transmission, potentially impacting the long-term health outcomes of offspring (Safir et al., 2010; Yoles et al., 2019; Huang et al., 2023), including their neurodevelopmental trajectory (Salemi et al., 2014; Yoles et al., 2022).
Neurodevelopmental disorders (NDDs), encompassing conditions such as autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), and intellectual disabilities, emerge early in life and exert profound effects on cognitive, social, and emotional functioning (Zablotsky et al., 2019). The prevalence of these disorders has surged, prompting investigations into their etiology, which implicates a multifactorial interplay of genetic, environmental, and prenatal influences (Chen et al., 2007). Among these, maternal infections during gestation have emerged as putative risk factors for NDDs in offspring (Brown et al., 2001; Meyer and Feldon, 2009; Brown et al., 2009; Driggers et al., 2016; Khandaker et al., 2013).
Despite mounting evidence of the nexus between infectious diseases and neurodevelopment, the precise link between maternal HBV infection and the risk of NDDs in offspring remains underexplored. Research on the association between maternal HBV infection and NDDs in offspring is sparse, with scant studies directly addressing this issue (Salemi et al., 2014; Yoles et al., 2022). Furthermore, existing research often lacks statistical power or specificity to yield definitive conclusions, particularly in populations with high HBV prevalence. This literature gap underscores the imperative for large-scale population-based studies to furnish more conclusive insights.
The Korean National Health Insurance database provides a distinctive avenue for examining this correlation within the Korean demographic, characterized by a notable prevalence of HBV and the availability of extensive health records. Utilizing this dataset, our research endeavors to scrutinize the occurrence of NDD among offspring born to mothers with HBV, juxtaposed with those born to uninfected counterparts. Additionally, our aim encompasses the assessment of whether children afflicted with HBV manifest a heightened susceptibility to NDD compared to uninfected cohorts.
2. Methods
2.1. Data source and study participants
We conducted a population-based retrospective cohort study utilizing data from the Korean National Health Insurance Service (K-NHIS) database, which encompasses the entire populace of South Korea. The database includes individual-level demographics and comprehensive records of diagnoses and healthcare utilization, such as drug prescriptions and medical procedures, obtained through inpatient, outpatient, and emergency department visits (Cheol Seong et al., 2017). Moreover, the K-NHIS claims database incorporates data from the National Health Screening Examination (NHSE), a standardized health-screening program administered to all insured individuals biennially (Cheol Seong et al., 2017).
Our cohort comprised all live births occurring from January 1, 2005, to December 31, 2019, with a washout period extending to 2004 and a follow-up period spanning 2020. We established links between the claims data of mothers and babies using personal identification numbers. To ensure the precision of our investigation into maternal HBV infection, we exclusively included children born to women who underwent at least one health screening, inclusive of Hepatitis B surface antigen (HBsAg) testing, during the study duration. Furthermore, we confined our study sample to children who were the firstborn offspring of women aged under 40 years, recognizing the substantial impact of maternal age on pregnancy outcomes (N = 2,804,434). Children born to women with hepatitis C virus (N = 36,654) or human immunodeficiency virus infection (N = 1951); severe liver diseases, including cirrhosis, ascites, encephalopathy, hepatic failure, spontaneous bacterial peritonitis, and varices (N = 46,334); and cancer (N = 54,696) were excluded. Consequently, the count of participants meeting one or more of the exclusion criteria and thus deemed eligible for inclusion in the registry was 2,673,059 (Fig. 1). Among the eligible participants, 263,904 were children born to mothers with HBV infection. Subsequently, we implemented a 1:3 matching scheme to pair controls with HBV-infected mothers based on propensity scores. The final analysis encompassed 263,904 children of HBV-infected mothers and 791,712 children of control (HBV-uninfected) mothers.
Fig. 1.
Flowchart of the study sample selection from the Korean National Health Insurance Service database for children born between 2005 and 2019. HCV, Hepatitis C virus; HIV, Human immunodeficiency virus; HBV, Hepatitis B virus.
The requirement for informed consent was waived because this study was conducted using anonymized claims data. Approval for the study protocol was obtained from the Institutional Review Board of Samsung Medical Center, South Korea (SMC 2021–08-107).
2.2. Measurement
K-NHIS claims for inpatient and outpatient visits, procedures, and prescriptions were coded using the 10th revision of the International Classification of Diseases (ICD-10) (Chun et al., 2009). Mothers with HBV infection were identified as those who tested positive for HBsAg, reported HBV infection in the NHSE, or had diagnostic records of HBV infection (ICD-10 codes B18.0, B18.1, and Z22.5) during the study period. Given that most HBV infections occur through vertical transmission in Korea and the HBV infection status rarely changes during a lifetime (Sarin et al., 2016), all examinations conducted during the study period were included. The last menstrual period was estimated using a previously validated algorithm to estimate gestational age in administrative healthcare databases (Margulis et al., 2013).
The study endpoint was the development of NDD in offspring, including autism spectrum disorder, ADHD, cerebral palsy, developmental delay, epileptic and febrile seizures, tics, and stereotypic behavior, identified using ICD-10 codes (Table S1, available online). These data are considered reliable and are used in numerous peer-reviewed publications, as K-NHIS routinely audits claims (Lee et al., 2017; Shin et al., 2016).
A broad range of covariates were considered as potential confounders and proxies of potential confounders. Age and income data at the time of the first screening were obtained from an insurance eligibility database. Income levels were categorized into quartiles: Q1 (lowest), Q2, Q3, and Q4 (highest). Residential areas at the time of the first screening examination were classified as metropolitan or rural. Maternal comorbidities, including hypertension, diabetes mellitus, hyperlipidemia, thyroid disorders, history of NDD, history of abortion, and stillbirth, were defined based on the ICD-10 codes (Table S1, available online). Patients with hypertension, gestational diabetes, or overt diabetes during pregnancy were included. Preterm birth was defined based on the presence of an ICD-10 code. Chromosomal abnormalities and metabolic disorders in the offspring, including congenital hypothyroidism, phenylketonuria, and diabetes, were obtained from the ICD-10 codes in the offspring from the K-NHIS database.
Additionally, NHSE collects information on behaviors such as smoking, drinking, and physical activity through standard questionnaires, as well as anthropometric measurements, including body mass index, and laboratory tests, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyl transferase (Cheol Seong et al., 2017).
2.3. Statistical analysis
For 1:3 matching, a propensity score was generated utilizing birth date, income, residential area, maternal age at delivery, history of abortion, and history of stillbirth. Propensity score matching was executed to mitigate the potential influence of confounding variables on the exposure outcomes. Matching was conducted employing a greedy algorithm (caliper = 0.1), which sequentially pairs each subject with the best available match at the time, without reconsidering previous pairings.
The incidence of NDD was monitored from birth to the occurrence of NDD incidence, death, or the conclusion of follow-up (December 31, 2020), whichever transpired first. The annual incidence percentage per annum was computed as the number of events per 1000 person-years of follow-up. The cumulative incidence of NDDs was assessed utilizing Kaplan–Meier curves. Hazard ratios (HRs) and their corresponding 95 % confidence intervals (CIs) were derived using Cox proportional hazards models. All standardized mean differences (SMDs) after propensity score matching were below 0.1, indicating covariate balance; thus, no additional adjustments were made in the Cox models. The proportionality of the hazards was examined through visual inspection of log-minus log plots and Schoenfeld residuals.
Additionally, sensitivity analysis was conducted among those who received NHSE before delivery to eliminate the potential for HBV infection in the mother post-delivery and to manage behavioral factors, including pre-delivery drinking and smoking.
All analyses were two-sided, and P-values <0.05 were deemed statistically significant. Statistical analyses were carried out using SAS version 9.2 (SAS Institute Inc., Cary, NC, USA) and R software version 3.3.2 (Free Software Foundation Inc., Boston, MA, USA).
3. Results
Among the 2,673,059 first live births, 263,904 (9.9 %) mothers were infected with HBV. HBV-infected mothers were more likely to be older than the controls (Table S2, available online). Baseline characteristics after 1:3 propensity score matching are presented in Table 1.
Table 1.
Characteristics of neonates born in South Korea (2005–2019) and their mothers, by maternal hepatitis B virus infection.
| HBV-uninfected mothers (N = 791,712), n (%) |
HBV-infected mothers (N = 263,904), n (%) | SMD | |
|---|---|---|---|
| Maternal | |||
| Maternal age (years), mean (SD) | 32.2 (3.3) | 32.3 (3.4) | 0.04 |
| Income level | |||
| Q1 (Lowest) | 1664 (0.2) | 933 (0.4) | 0.03 |
| Q2 | 139,475 (17.6) | 50,723 (19.2) | 0.04 |
| Q3 | 432,849 (54.7) | 137,186 (52.0) | 0.05 |
| Q4 (Highest) | 202,248 (25.5) | 67,649 (25.6) | <0.01 |
| Unknown | 15,476 (2.0) | 7413 (2.8) | 0.06 |
| Rural areas | 229,931 (29.0) | 78,448 (29.7) | 0.02 |
| Comorbidities | |||
| Hypertension | 4593 (0.9) | 1782 (0.7) | 0.01 |
| Diabetes Mellitus | 7097 (0.9) | 3214 (1.2) | 0.03 |
| Hyperlipidemia | 20,021 (2.5) | 10,206 (3.9) | 0.08 |
| Thyroid disorders | 143,374 (18.1) | 55,316 (21.0) | 0.07 |
| History of NDD | 49,131 (6.2) | 17,641 (6.7) | 0.02 |
| History of abortion | 144,438 (18.2) | 54,418 (20.6) | 0.06 |
| History of stillbirth | 2630 (0.3) | 1430 (0.5) | 0.03 |
| Comorbidities during pregnancy | |||
| Hypertensive disorder | 182,251 (23.0) | 64,183 (24.3) | 0.03 |
| Diabetes | |||
| Overt diabetes | 164,602 (20.8) | 57,894 (21.9) | 0.03 |
| Gestational diabetes | 6794 (0.9) | 2540 (1.0) | 0.01 |
| Birth events | |||
| Cesarean delivery | 321,431 (40.6) | 108,190 (41.0) | 0.01 |
| Pre-term birth | 30,079 (3.8) | 10,944 (4.1) | 0.02 |
| Neonatal | |||
| Sex, male | 404,737 (51.1) | 135,545 (51.4) | 0.01 |
| Twin | 25,085 (3.2) | 9634 (3.7) | 0.02 |
| Chromosomal aneuploidies | 501 (0.1) | 165 (0.1) | <0.01 |
| Metabolic disorders | |||
| Congenital hypothyroidism | 3929 (0.5) | 1270 (0.5) | <0.01 |
| Phenylketonuria | 241 (0.0) | 88 (0.0) | <0.01 |
| Diabetes | 8184 (1.0) | 2936 (1.1) | 0.01 |
HBV, Hepatitis B virus; SMD, standardized mean difference; NDD, Neurodevelopmental disorder.
Propensity score matching was performed using maternal age, income level, residential area, and maternal history of abortion or stillbirth.
Throughout a median follow-up period of 7.7 years, 111,001 (14.57 per 1000 person-years) and 37,527 (15.08 per 1000 person-years) children born to control and HBV-infected mothers experienced NDD, respectively. The hazard ratio (HR) for any NDD among children born to HBV-infected mothers was 1.03 (95 % confidence interval [CI] = 1.01, 1.04; Table 2). Specifically, the HR for any NDD was elevated when comparing participants with HBV-infected children born to infected mothers to those born to uninfected mothers (HR = 1.18; 95 % CI = 1.09, 1.28; Table 2).
Table 2.
Risk of any neurodevelopmental disorder of children born in South Korea (2005–2019), by hepatitis B virus infection status of mothers and children.
| Neurodevelopmental disorder | Number of events (Incidence rate 1000 person-years) | Hazard ratio (95 % CI) |
|---|---|---|
| HBV infection status of mothers | ||
| Uninfected | 111,001 (14.6) | 1.00 |
| Infected | 37,527 (15.1) | 1.03 (1.01, 1.04) |
| HBV infection status of children | ||
| Uninfected | 36,900 (15.1) | 1.02 (1.01, 1.04) |
| Infected | 627 (16.5) | 1.18 (1.09, 1.28) |
HBV, Hepatitis B virus; CI, Confidence interval.
Propensity score matching was performed using maternal age, income level, residential area, and maternal history of abortion or stillbirth.
Upon analyzing the risk of each type of NDD, epileptic and febrile seizures were the most prevalent among this cohort, followed by developmental delays. The incidence of other NDDs was comparable between children born to HBV-infected mothers and those born to uninfected mothers. However, the risk of motor developmental delay (HR = 1.07; 95 % CI = 1.04, 1.10) and epileptic and febrile seizures (HR = 1.03; 95 % CI = 1.01, 1.05) was slightly higher in children born to HBV-infected mothers (Table 3). Notably, HBV-infected children born to infected mothers exhibited an increased risk of developmental cerebral palsy (HR = 1.97; 95 % CI = 1.35, 2.88), cognitive developmental delay (HR = 1.43; 95 % CI = 1.19, 1.73), and tics and stereotypic behavior (HR = 1.35; 95 % CI = 1.08, 1.68) compared to those born to uninfected mothers (Table 3).
Table 3.
Risk of each neurodevelopmental disorder of children born in South Korea (2005–2019) by hepatitis B virus infection status of mothers.
| Number of events (Incidence rate 1000 person-years) |
Hazard ratio (95 % CI) |
|||||
|---|---|---|---|---|---|---|
| HBV-uninfected mothers (N = 791,712) |
HBV-infected mothers |
HBV-uninfected mothers (N = 791,712) |
HBV-infected mothers |
|||
| HBV-uninfected children (N = 260,257) |
HBV-infected children (N = 3647) |
HBV-uninfected children (N = 260,257) |
HBV-infected children (N = 3647) |
|||
| Type of neurodevelopmental disorder | ||||||
| Autism | 5974 (0.7) | 1862 (0.7) | 35 (0.8) | 1.00 | 0.96 (0.91, 1.01) | 1.21 (0.87, 1.68) |
| ADHD | 23,031 (2.8) | 7529 (2.8) | 148 (3.5) | 1.00 | 1.02 (0.99, 1.04) | 1.26 (1.07, 1.48) |
| Cerebral palsy | 2925 (0.4) | 984 (0.4) | 27 (0.6) | 1.00 | 1.03 (0.96, 1.10) | 1.97 (1.35, 2.88) |
| Developmental delay | 31,145 (3.8) | 10,253 (3.9) | 192 (4.6) | 1.00 | 1.01 (0.99, 1.04) | 1.28 (1.11, 1.48) |
| Motor developmental delay | 15,698 (1.9) | 5452 (2.0) | 88 (2.1) | 1.00 | 1.07 (1.04 1.10) | 1.16 (0.94, 1.43) |
| Cognitive developmental delay | 16,352 (2.0) | 5103 (1.9) | 113 (2.7) | 1.00 | 0.96 (0.93, 0.99) | 1.43 (1.19, 1.73) |
| Epileptic and febrile seizures | 60,136 (7.6) | 20,219 (7.9) | 332 (8.3) | 1.00 | 1.03 (1.01, 1.05) | 1.17 (1.05, 1.31) |
| Tics and stereotypic behavior | 11,241 (1.3) | 3693 (1.4) | 77 (1.8) | 1.00 | 1.02 (0.98, 1.06) | 1.35 (1.08, 1.68) |
ADHD, Attention-deficit hyperactivity disorder; CI, Confidence interval.
Propensity score matching was performed using maternal age, income level, residential area, and maternal history of abortion or stillbirth.
In the sensitivity analysis involving 549,322 mothers who underwent NHSE screening before delivery, the characteristics were similar between the two groups, except for hyperlipidemia, AST, and ALT levels (Table S3, available online). The risk of any NDD was also higher in HBV-infected children born to HBV-infected mothers (adjusted HR = 1.21; 95 % CI = 1.08, 1.37; Table S4, available online).
4. Discussion
In our investigation, we examined the influence of chronic maternal HBV infection on neurodevelopmental outcomes and identified a statistically significant heightened risk of NDD in the progeny. Children born to mothers with HBV infections exhibited a slight elevation in risk (HR: 1.03; 95 % CI: 1.01–1.04), suggesting a potential contribution of maternal HBV status to offspring neurodevelopment. Additionally, this risk was higher among children who themselves were HBV-infected, with an HR of 1.18 (95 % CI: 1.09–1.28). These findings shed light on the varying risk profiles of NDDs among children, contingent upon their HBV infection status and maternal HBV infection, paving the way for further exploration of the underlying mechanisms and clinical implications of these relationships.
While there exists no definitive evidence indicating direct passage of HBV across the blood-brain barrier (BBB) (Pontisso et al., 1986), the impact of maternal HBV infection on offspring neurological development may involve indirect pathways. National studies and meta-analyses have demonstrated an association between HBV infection and an elevated risk of neuropsychiatric conditions like schizophrenia and severe mental illness (Bauer-Staeb et al., 2017; Hughes et al., 2016), which could indirectly affect neurodevelopmental outcomes. This influence might be mediated by HBV-infected mononuclear cells and lymphocytes capable of traversing the BBB, potentially impacting brain development without direct viral involvement (Yoffe et al., 1990). This mechanism suggests that maternal HBV status may influence the neurodevelopmental outcomes of children. Our study contributes to this understanding by highlighting that the milieu created by maternal HBV infection significantly influences offspring neurodevelopment, underscoring the necessity for further investigation in this domain. Nonetheless, a direct correlation between HBV infection in children and specific NDDs remains ambiguous, presenting a notable gap in our comprehension.
The observed elevation in the risk of NDDs among offspring born to HBV-infected mothers underscores the substantial impact of maternal immune activation (MIA) (Knuesel et al., 2014; Hall et al., 2023). MIA, resulting from environmental insults during gestation, is hypothesized to imprint the immune and developmental epigenetic signatures of the progeny, thereby modulating their predisposition to NDDs later in life (Han et al., 2021). This conceptual framework posits that exposure to a perturbed maternal immune milieu in utero perturbs fetal neurodevelopment, particularly during critical developmental windows characterize the d by rapid establishment of key cerebral processes and networks. Chronic HBV infection in the maternal host induces immunological alterations, encompassing heightened production of inflammatory cytokines, activation of type 1 interferon pathways, and mitochondrial perturbations (Cacoub, 2022). This intricate immunological rewiring suggests that HBV infection may potentially incite MIA responses, thereby influencing the vulnerability of offspring to NDDs. This conceptualization is consistent with observations from diverse viral infections, wherein maternal infection exerts indirect effects on fetal cerebral development (Brown et al., 2001; Meyer and Feldon, 2009; Brown et al., 2009; Driggers et al., 2016; Khandaker et al., 2013).
Our findings provide valuable insights into clinical and public health frameworks, emphasizing the importance of targeted screening and intervention strategies. These strategies could be tailored not only to prevent HBV transmission from mother to child but also to monitor and support the neurodevelopment of children born to HBV-infected mothers. Furthermore, understanding the indirect risk elevation in uninfected children highlights the importance of broader health and developmental surveillance in this study sample. While our study does not prescribe specific policy changes, it naturally suggests the potential benefits of integrating these insights into existing maternal and child health programs. Such integration could enhance the early identification and management of NDD risk, ultimately contributing to the well-being of children affected by maternal HBV status.
It is important to consider several limitations of this study when interpreting the results. The observational nature of the study means that, despite rigorous statistical adjustment, potential unaccounted-for confounders could have influenced the results. Additionally, the inherent constraints of observational research limit its ability to establish causality. Furthermore, 9.9 % of the mothers in the study were infected with HBV, which is higher than the HBsAg positivity rate reported in Korean nationwide surveys (Kim et al., 2013). This may reflect the inclusion of mothers born before universal HBV vaccination and the overrepresentation of HBV-infected patients in the K-NHIS database. However, the strengths of this study are notable and include the use of a large, nationally representative dataset from the K-NHIS, which enhances the generalizability of our findings. A unique aspect of our research was the ability to link maternal and child health records through identification codes, enabling a precise analysis of the impact of maternal HBV status on child health outcomes. This methodology not only strengthens the reliability of our results but also establishes a foundation for future research exploring the intergenerational effects of infectious diseases on neurodevelopment.
5. Conclusion
In our investigation, we observed a correlation between maternal HBV infection and an elevated susceptibility to NDD in offspring, particularly notable in children infected with HBV. These results enhance comprehension regarding the potential neurodevelopmental implications of HBV infection. However, interpretation of these findings should be approached with caution. This research underscores the imperative for additional studies to elucidate the mechanisms underlying the impact of HBV on neurodevelopment and to formulate precise interventions aimed at ameliorating these risks for both maternal and child population.
Clinical trial registration
Not applicable.
CRediT authorship contribution statement
Yewan Park: Writing – original draft, Conceptualization. Jihye Heo: Writing – original draft, Formal analysis, Conceptualization. Danbee Kang: Writing – review & editing, Supervision, Conceptualization. Geum-Youn Gwak: Writing – review & editing, Supervision, Conceptualization.
Patient consent statement
The requirement for informed consent was waived because this study was conducted using anonymized claims data.
Ethics approval statement
The study protocol was approved by the Institutional Review Board of the Samsung Medical Center, South Korea (SMC 2021-08-107).
Permission to reproduce material from other sources
Not applicable.
Funding sources
None to report.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Glossary
- ADHD: attention deficit hyperactivity disorder.
- ALT: alanine aminotransferase.
- AST: aspartate aminotransferase.
- BBB: blood-brain barrier.
- CIs: confidence intervals.
- HBV: hepatitis B virus.
- HBsAg: hepatitis B surface antigen.
- HRs: hazard ratios.
- ICD-10: International Classification of Diseases.
- K-NHIS: Korean National Health Insurance Service.
- MIA: maternal immune activation.
- NDDs: neurodevelopmental disorders.
- NHSE: National Health Screening Examination.
- SMDs: standardized mean differences.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.pmedr.2025.103116.
Contributor Information
Danbee Kang, Email: dbee.kang@skku.edu.
Geum-Youn Gwak, Email: gy.gwak@samsung.com.
Appendix A. Supplementary data
Supplementary material
Data availability
The data that has been used is confidential.
References
- Bauer-Staeb C., Jorgensen L., Lewis G., Dalman C., Osborn D.P.J., Hayes J.F. Prevalence and risk factors for HIV, hepatitis B, and hepatitis C in people with severe mental illness: a total population study of Sweden. Lancet Psychiatry. 2017;4(9):685–693. doi: 10.1016/S2215-0366(17)30253-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brown A.S., Cohen P., Harkavy-Friedman J., et al. A.E. Bennett Research Award. Prenatal rubella, premorbid abnormalities, and adult schizophrenia. Biol Psychiatry. 2001;49(6):473–486. doi: 10.1016/s0006-3223(01)01068-x. [DOI] [PubMed] [Google Scholar]
- Brown A.S., Vinogradov S., Kremen W.S., et al. Prenatal exposure to maternal infection and executive dysfunction in adult schizophrenia. Am. J. Psychiatry. 2009;166(6):683–690. doi: 10.1176/appi.ajp.2008.08010089. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cacoub P. Asselah T. Hepatitis B Virus Infection and Extra-Hepatic Manifestations: A Systemic Disease. Am J Gastroenterol. 2022;117(2):253–263. doi: 10.14309/ajg.0000000000001575. [DOI] [PubMed] [Google Scholar]
- Chen C.Y., Liu C.Y., Su W.C., Huang S.L., Lin K.M. Factors associated with the diagnosis of neurodevelopmental disorders: a population-based longitudinal study. Pediatrics. 2007;119(2):e435–e443. doi: 10.1542/peds.2006-1477. [DOI] [PubMed] [Google Scholar]
- Cheol Seong S., Kim Y.Y., Khang Y.H., et al. Data Resource Profile: The National Health Information Database of the National Health Insurance Service in South Korea. Int J Epidemiol. 2017;46(3):799–800. doi: 10.1093/ije/dyw253. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chun C.B., Kim S.Y., Lee J.Y., Lee S.Y. Republic of Korea. Health system review. Health systems in Transition. 2009;11(7):1–184. [Google Scholar]
- Driggers R.W., Ho C.Y., Korhonen E.M., et al. Zika Virus Infection with Prolonged Maternal Viremia and Fetal Brain Abnormalities. N Engl J Med. 2016;374(22):2142–2151. doi: 10.1056/NEJMoa1601824. [DOI] [PubMed] [Google Scholar]
- European Association for the Study of the Liver EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J. Hepatol. 2017;67(2):370–398. doi: 10.1016/j.jhep.2017.03.021. [DOI] [PubMed] [Google Scholar]
- Hall M.B., Willis D.E., Rodriguez E.L., Schwarz J.M. Maternal immune activation as an epidemiological risk factor for neurodevelopmental disorders: considerations of timing, severity, individual differences, and sex in human and rodent studies. Front. Neurosci. 2023;17:1135559. doi: 10.3389/fnins.2023.1135559. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Han V.X., Patel S., Jones H.F., Dale R.C. Maternal immune activation and neuroinflammation in human neurodevelopmental disorders. Nat. Rev. Neurol. 2021;17(9):564–579. doi: 10.1038/s41582-021-00530-8. [DOI] [PubMed] [Google Scholar]
- Huang S., Wang J., Xiong Y., et al. Impact of maternal hepatitis B carrier status on congenital abnormalities: a systematic review and meta-analysis. BMJ Open. 2023;13(3) doi: 10.1136/bmjopen-2022-066017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hughes E., Bassi S., Gilbody S., Bland M., Martin F. Prevalence of HIV, hepatitis B, and hepatitis C in people with severe mental illness: a systematic review and meta-analysis. Lancet Psychiatry. 2016;3(1):40–48. doi: 10.1016/S2215-0366(15)00357-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Khandaker G.M., Zimbron J., Lewis G., Jones P.B. Prenatal maternal infection, neurodevelopment and adult schizophrenia: a systematic review of population-based studies. Psychol. Med. 2013;43(2):239–257. doi: 10.1017/S0033291712000736. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kim H., Shin A.R., Chung H.H., et al. Recent trends in hepatitis B virus infection in the general Korean population. Korean J. Intern. Med. 2013;28(4):413–419. doi: 10.3904/kjim.2013.28.4.413. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Knuesel I., Chicha L., Britschgi M., et al. Maternal immune activation and abnormal brain development across CNS disorders. Nat. Rev. Neurol. 2014;10(11):643–660. doi: 10.1038/nrneurol.2014.187. [DOI] [PubMed] [Google Scholar]
- Korean Association for the Study of the Liver KASL clinical practice guidelines for management of chronic hepatitis B. Clin. Mol. Hepatol. 2022;28(2):276–331. doi: 10.3350/cmh.2022.0084. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lee J., Lee J.S., Park S.H., Shin S.A., Kim K. Cohort Profile: The National Health Insurance Service-National Sample Cohort (NHIS-NSC), South Korea. Int J Epidemiol. 2017;46(2):e15. doi: 10.1093/ije/dyv319. [DOI] [PubMed] [Google Scholar]
- Margulis A.V., Setoguchi S., Mittleman M.A., Glynn R.J., Dormuth C.R., Hernandez-Diaz S. Algorithms to estimate the beginning of pregnancy in administrative databases. Pharmacoepidemiol. Drug Saf. 2013;22(1):16–24. doi: 10.1002/pds.3284. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Meyer U., Feldon J. Neural basis of psychosis-related behaviour in the infection model of schizophrenia. Behav. Brain Res. 2009;204(2):322–334. doi: 10.1016/j.bbr.2008.12.022. [DOI] [PubMed] [Google Scholar]
- Pontisso P., Schiavon E., Alberti A., Realdi G., Locasciulli A., Masera G. Does hepatitis B virus cross the blood-brain barrier? N. Engl. J. Med. 1986;314(8):518–519. doi: 10.1056/NEJM198602203140815. [DOI] [PubMed] [Google Scholar]
- Safir A., Levy A., Sikuler E., Sheiner E. Maternal hepatitis B virus or hepatitis C virus carrier status as an independent risk factor for adverse perinatal outcome. Liver Int. 2010;30(5):765–770. doi: 10.1111/j.1478-3231.2010.02218.x. [DOI] [PubMed] [Google Scholar]
- Salemi J.L., Whiteman V.E., August E.M., Chandler K., Mbah A.K., Salihu H.M. Maternal hepatitis B and hepatitis C infection and neonatal neurological outcomes. J. Viral Hepat. 2014;21(11):e144–e153. doi: 10.1111/jvh.12250. [DOI] [PubMed] [Google Scholar]
- Sarin S.K., Kumar M., Lau G.K., et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol. Int. 2016;10(1):1–98. doi: 10.1007/s12072-015-9675-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shin D.W., Cho B., Guallar E. Korean national health insurance database. JAMA Intern. Med. 2016;176(1):138. doi: 10.1001/jamainternmed.2015.7110. [DOI] [PubMed] [Google Scholar]
- Thio C.L., Guo N., Xie C., Nelson K.E., Ehrhardt S. Global elimination of mother-to-child transmission of hepatitis B: revisiting the current strategy. Lancet Infect. Dis. 2015;15(8):981–985. doi: 10.1016/S1473-3099(15)00158-9. [DOI] [PubMed] [Google Scholar]
- World Health Organization . 2020. Prevention of mother-to-child transmission of hepatitis B virus: Guidelines on antiviral prophylaxis in pregnancy. Available from: https://www.who.int/publications/i/item/978-92-4-000270-8 (Accessed January 2, 2024) [PubMed] [Google Scholar]
- Yoffe B., Burns D.K., Bhatt H.S., Combes B. Extrahepatic hepatitis B virus DNA sequences in patients with acute hepatitis B infection. Hepatology. 1990;12(2):187–192. doi: 10.1002/hep.1840120202. [DOI] [PubMed] [Google Scholar]
- Yoles I., Sheiner E., Abu-Freha N., Wainstock T. Maternal hepatitis B or C status and the long-term risk of gastrointestinal morbidity for offspring: a population-based cohort study. Liver Int. 2019;39(11):2046–2051. doi: 10.1111/liv.14193. [DOI] [PubMed] [Google Scholar]
- Yoles I., Sheiner E., Abu-Freha N., Wainstock T. Maternal hepatitis B or C carrier status and long-term risk for offspring neurological morbidity: a population-based cohort study. J. Dev. Orig. Health Dis. 2022;13(1):115–119. doi: 10.1017/S2040174420001397. [DOI] [PubMed] [Google Scholar]
- Zablotsky B., Black L.I., Maenner M.J., et al. Prevalence and trends of developmental disabilities among children in the United States: 2009-2017. Pediatrics. 2019;144(4) doi: 10.1542/peds.2019-0811. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary material
Data Availability Statement
The data that has been used is confidential.