Maternal Preconception Hepatitis B Virus Infection and Risk of Congenital Heart Diseases in Offspring Among Chinese Women Aged 20 to 49 Years

Hanbin Wu; Ying Yang; Jiajing Jia; Tonglei Guo; Jueming Lei; YuZhi Deng; Yuan He; Yuanyuan Wang; Zuoqi Peng; Ya Zhang; Hongguang Zhang; Qiaomei Wang; Haiping Shen; Yiping Zhang; Donghai Yan; Xu Ma

doi:10.1001/jamapediatrics.2023.0053

. 2023 Mar 13;177(5):498–505. doi: 10.1001/jamapediatrics.2023.0053

Maternal Preconception Hepatitis B Virus Infection and Risk of Congenital Heart Diseases in Offspring Among Chinese Women Aged 20 to 49 Years

Hanbin Wu ^1,², Ying Yang ^1,^2,^3,^✉, Jiajing Jia ^1,^2,^4,⁵, Tonglei Guo ^1,^2,^3,⁶, Jueming Lei ^1,², YuZhi Deng ^1,^2,³, Yuan He ^1,^2,³, Yuanyuan Wang ^1,^2,³, Zuoqi Peng ^1,², Ya Zhang ^1,², Hongguang Zhang ^1,², Qiaomei Wang ⁷, Haiping Shen ⁷, Yiping Zhang ⁷, Donghai Yan ⁷, Xu Ma ^1,^2,^3,^✉

¹National Research Institute for Family Planning, Beijing, China

²National Human Genetic Resource Center, National Human Reproduction and Health Resource Center, Beijing, China

³Graduate School of Peking Union Medical College, Beijing, China

⁴Department of Epidemiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

⁵Key Laboratory of Cardiovascular Epidemiology, Chinese Academy of Medical Sciences, Beijing, China

⁶NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

⁷Department of Maternal and Child Health, National Health and Family Planning Commission of the PRC, Beijing, China

Accepted for Publication: January 12, 2023.

Published Online: March 13, 2023. doi:10.1001/jamapediatrics.2023.0053

^✉

Corresponding Author: Ying Yang, PhD (angela-yy65@hotmail.com), and Xu Ma, MS (nfpcc_ma@163.com), National Research Institute for Family Planning, No. 12 Dahuisi Rd, Haidian District, Beijing 100081, China.

Author Contributions: Mr Wu and Dr Yang had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr Yang and Mr Ma contributed equally as corresponding authors.

Study concept and design: Wu, Yang, Ma.

Acquisition, analysis, or interpretation of data: Wu, Jia, Guo, Lei, Deng, He, Y. Wang, Peng, Ya Zhang, H. Zhang, Q. Wang, Shen, Yiping Zhang, Yan, Ma.

Drafting of the manuscript: Wu, Yang.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Wu, Yang, Ya Zhang, H. Zhang.

Obtained funding: Ma.

Administrative, technical, or material support: Wu, Yang, Jia, Lei, Deng, He, Y. Wang, Peng, Ya Zhang, H. Zhang, Q. Wang, Shen, Yiping Zhang, Yan, Ma.

Study supervision: Yang, Shen, Yiping Zhang, Yan, Ma.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by the National Key Research and Development Program of China (grants 2021YFC2700705 [Dr Yang] and 2016YFC100307 [Mr Ma]).

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2.

Additional Contributions: We thank all the health workers and countless participants throughout 31 provinces and cities for their considerable efforts and collaboration in the National Free Preconception Checkup Project.

^✉

Corresponding author.

PMCID: PMC10012042 PMID: 36912830

Key Points

Question

What is the association between maternal preconception hepatitis B virus (HBV) infection and congenital heart diseases (CHDs) in offspring?

Findings

In this matched cohort study including 3 690 427 participants, increased CHD risks in offspring were observed among women with preconception previous HBV infection.

Meaning

In this study, maternal preconception previous HBV infection, which might affect the formation of the ovum, was associated with risk of CHDs in offspring.

This cohort study explores the association of maternal preconception hepatitis B virus infection with congenital heart diseases in offspring.

Abstract

Importance

Maternal hepatitis B virus (HBV) infection during early pregnancy has been related to congenital heart diseases (CHDs) in offspring. However, no study to date has evaluated the association of maternal preconception HBV infection with CHDs in offspring.

Objective

To explore the association of maternal preconception HBV infection with CHDs in offspring.

Design, Setting, and Participants

This retrospective cohort study used nearest-neighbor (1:4) propensity score matching of 2013 to 2019 data from the National Free Preconception Checkup Project (NFPCP), a national free health service for childbearing-aged women who plan to conceive throughout mainland China. Women aged 20 to 49 years who got pregnant within 1 year after preconception examination were included, and those with multiple births were excluded. Data were analyzed from September to December 2022.

Exposures

Maternal preconception HBV infection statuses, including uninfected, previous, and new infection.

Main Outcomes and Measures

The main outcome was CHDs, which were prospectively collected from the birth defect registration card of the NFPCP. Logistic regression with robust error variances was used to estimate the association between maternal preconception HBV infection status and CHD risk in offspring, after adjusting for confounding variables.

Results

After matching with a 1:4 ratio, there were 3 690 427 participants included in the final analysis, where 738 945 women were infected with HBV, including 393 332 women with previous infection and 345 613 women with new infection. Approximately 0.03% (800 of 2 951 482) of women uninfected with HBV preconception and women newly infected with HBV carried an infant with CHDs, whereas 0.04% (141 of 393 332) of women with HBV infection prior to pregnancy carried an infant with CHDs. After multivariable adjustment, women with HBV infection prior to pregnancy had a higher risk of CHDs in offspring compared with women who were uninfected (adjusted relative risk ratio [aRR], 1.23; 95% CI, 1.02-1.49). Moreover, compared with couples who were uninfected with HBV prior to pregnancy (680 of 2 610 968 [0.026%]), previously infected women with uninfected men (93 of 252 919 [0.037%]) or previously infected men with uninfected women (43 of 95 735 [0.045%]) had a higher incidence of CHDs in offspring and were significantly associated with a higher risk of CHDs in offspring (previously infected women with uninfected men: aRR, 1.36; 95% CI, 1.09-1.69; previously infected men with uninfected women: aRR, 1.51; 95% CI, 1.09-2.09) with multivariable adjustment, while no significant association was observed between maternal new HBV infection and CHDs in offspring.

Conclusions and Relevance

In this matched retrospective cohort study, maternal preconception previous HBV infection was significantly associated with CHDs in offspring. Moreover, among women with HBV-uninfected husbands, significantly increased risk of CHDs was also observed in previously infected women prior to pregnancy. Consequently, HBV screening and getting HBV vaccination-induced immunity for couples prior to pregnancy are indispensable, and those with previous HBV infection prior to pregnancy should also be taken seriously to decrease the CHDs risk in offspring.

Introduction

Congenital heart disease (CHD) is the most common congenital disease identified in newborns, accounting for roughly one-third of birth defects.^1,2,3 Because of significant advances in pediatric cardiac care and therapy, newborns with CHDs are able to live longer and maintain healthier lives.^4,5 However, CHDs still have a substantial impact on the health of children and adults; meanwhile, it also brings a heavy burden to society and families.^6,7

For years, many CHD-related risk factors have been identified; however, with the complex etiology, most CHDs still cannot be explained, which should be attributed to the interaction of genetic and environmental factors.^8,9,10 Since 1941, the first publication of the fatal effects of the rubella virus on the neonatal cardiovascular system, virus infection has been demonstrated to play an important role in CHD development in numerous studies during early pregnancy, including cytomegalovirus, coxsackievirus B3, and some others.^{11,12,13,14,15,16,17,18} Despite the bulk of these studies showing consistent associations, available information on the association between maternal hepatitis B virus (HBV) infection and CHDs in offspring is limited and contentious with the previous studies during early pregnancy.^14,16,17,18 As a significant global public health issue, HBV affects 3.1% to 10.0% of reproductive-aged women in China, a highly endemic area of HBV infection.^{19,20,21,22,23,24} Although the most recent study has reported that maternal HBV positivity is related to an increased risk of CHDs in offspring in early pregnancy,¹⁶ there is little evidence about the association of maternal preconception HBV infection with CHD risk. Given the possible mechanisms for HBV prenatal transmission, such as placental infection and transplacental transmission of HBV^25,26 or HBV-DNA existing in infected maternal oocytes or paternal sperms,^{27,28,29,30,31,32,33} there might be a potential correlation between maternal preconception HBV infection and CHDs in offspring.

In this study, a retrospective cohort study using propensity score matching was conducted to evaluate the association of maternal preconception HBV infection statuses with a wide spectrum of CHDs in offspring.

Methods

Data Source

This retrospective cohort was conducted by the National Free Preconception Checkups Project (NFPCP), a national free health service for childbearing-aged women who plan to conceive throughout mainland China, providing preconception examinations and professional counseling. Details about the project-related design, organization, and implementation can be found elsewhere.^34,35,36 This study was approved by the Institutional Review Board at the National Research Institute for Family Planning in Beijing, China, and conducted according to the guidelines laid down in the Declaration of Helsinki. Written informed consent was obtained from all participants at the beginning of the preconception examination stage. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Initially, 7 429 702 women aged 20 to 49 years, who participated from 2013 to 2019 and conceived within 1 year with a singleton before April 2020, were included with the completed pregnancy outcome information. After excluding women who had missing data regarding hepatitis B serological markers, a total of 7 398 885 women were recruited for propensity score matching, with 739 008 women infected with HBV and 6 659 877 women uninfected with HBV.

To minimize the potential bias of maternal preconception HBV infection status on comorbid conditions and confounding, propensity score matching was used, with covariates determined a priori (eTable 2 in Supplement 1). As included covariates with missing values of no more than 5% could be assumed to be missing at random, a new label, unknown, was generated for those variables with missing values. Finally, a 1:4 matched cohort of preconception HBV-infected women, including women with a previous and new infection, and uninfected women was generated with a nearest-neighbor matching algorithm with calipers of 0.02 without replacement; maternal age was matched exactly. Characteristics among the participants before and after matching were also compared (eTable 3 in Supplement 1). The flowchart of the study population selection is shown in the Figure.

Figure. — BMI indicates body mass index; HBcAb, hepatitis B core antibody; HBeAb, hepatitis B envelop antibody; HBeAg, hepatitis B envelop antigen; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; LMP, last menstrual period; NFPCP, National Free Preconception Checkup Project.

Study Exposure and Outcome

Both maternal and paternal blood samples, collected in the preconception examination, were separated and stored at −30 °C and examined using enzyme-linked immunosorbent assay kits for the presence of hepatitis B serological markers: hepatitis B surface antibody (HBsAb), hepatitis B surface antigen (HBsAg), hepatitis B core antibody, hepatitis B envelop antibody, and hepatitis B envelop antigen (HBeAg), which is consistent with the previous study.³⁷ The National Center of Clinical Laboratories for Quality Inspection and Detection was responsible for the external quality assessment and controlled biannually.

To evaluate the association of different maternal preconception HBV infection statuses with CHDs risk in offspring, women were split into 3 groups based on the clinical guideline³⁸ (eTable 1 in Supplement 1): uninfected (none of serum hepatitis B serological markers positive or only serum HBsAb positive), previous infection (both serum HBsAg and HBeAg negative), or new infection (serum HBsAg positive).

The outcome was any CHDs (including atrial septal defect, ventricular septal defect, atrioventricular septal defect, patent ductus arteriosus, Tetralogy of Fallot, pulmonary stenosis, and transposition of the great arteries), based on the birth defect registration card from the NFPCP, which is the same as the national health birth defect registration card.

Covariates

The propensity score matching and multivariable adjustment analyses included a set of covariates, some of which were previously identified as risk factors for CHDs. Demographic covariates include parental age, the time interval between examination and last menstrual period (LMP) (within 6 months or 6 months to 1 year), maternal nationality (Han or other), drinking (yes or no), smoking (yes or no), preconception harmful exposure (including exposure history of radial, high temperature, pesticide, new decoration, paint, other organic solvents, fever, common cold, or passive smoking; yes or no), history of adverse pregnancy outcomes (including spontaneous abortion, induced abortion, or preterm birth; yes or no), parental family history of CHDs (yes or no), parity (nulliparous or multiparous), maternal folic acid intake (yes or no), early pregnancy common cold (yes or no), passive smoking (yes or no), and medication (treatment use or no use).

Preconception clinical covariates included maternal body mass index (underweight [less than 18.5; calculated as weight in kilograms divided by height in meters squared], normal [18.5-23.9], overweight [24.0-27.9], or obese [28.0 or more]), diabetes (yes or no), hypertension (yes or no), other infection (including Neisseria gonorrhoeae, Chlamydia trachomatis, Toxoplasma gondii, cytomegalovirus, Treponema pallidum, or Rubella virus by detecting their specific-serum antibodies; yes or no), paternal serum HBsAg status (positive or negative), and HBV infection prior to pregnancy (yes or no); Men were also classified into 3 groups, which were similar to the classification of maternal preconception HBV infection status: uninfected, previous infection, and new infection). Details about the covariates’ definition are shown in eTable 2 in Supplement 1. All these tests were measured consists with National Guide to Clinical Laboratory Procedures.

Statistical Analysis

Categorical variables were demonstrated as counts and percentages, and continuous variables were expressed as means and SDs or medians and IQRs. The difference between each categorical and continuous variable was assessed by using the χ² test, Fisher exact test, or Kruskal-Wallis test.

In this matched cohort, the association between maternal preconception HBV infection status and CHDs in offspring was estimated using logistic regression with robust error variances. Separate models, fitted with or without adjustment for the listed covariates (eTable 2 in Supplement 1), were used to estimate the relative risk ratios (RRs) and 95% CIs of maternal preconception HBV infection with CHDs risk in offspring.

Considering the infectivity of HBV within couples and the potential impact of HBV infection on the formation of the gamete, paternal HBV infection might influence the association of maternal HBV infection prior to pregnancy with the risk of CHD in offspring. Therefore, participants were further divided into 9 different groups, and couples uninfected with HBV prior to pregnancy were defined as the reference group. All the covariates adjusted in the model are presented in eTable 2 in Supplement 1. All statistical analyses were performed using R software version 4.1.0 (R Foundation for Statistical Computing) with the packages tidyverse version 1.3.1, MatchIt version 4.3.2, lmtest version 0.9-40, and sandwich version 3.0-2.

Results

Initially, 7 398 885 participants were identified, including 1822 infants with CHDs in the cohort. Of 739 008 women infected with HBV prior to pregnancy, 604 408 (81.8%) got pregnant within 6 months, and more than half were nulliparous (437 463 of 739 008 [59.2%]), which was similar to the uninfected women before matching; however, 37 726 (5.1%) had preexisting diabetes, and 102 054 (13.8%) had harmful preconception exposure, which was higher than uninfected women. After propensity score matching (2 951 482 women uninfected with HBV and 738 945 women infected with HBV), characteristics were all well balanced between groups (eTable 3 in Supplement 1).

Among 2 951 482 women uninfected with HBV (80.0%), the median (IQR) length of time from baseline examination to LMP was 2.24 (0.79-4.89) months, with approximately 0.03% (800 of 2 951 482) carrying an infant with a CHD. In 393 332 women with prepregnant previous HBV infection (10.7%), the median (IQR) length of time from baseline examination to LMP was 2.38 (0.89-4.99) months, with approximately 0.04% (141 of 393 332) carrying an infant with a CHD. In 345 613 women with new HBV infection prior to pregnancy (9.3%), the median (IQR) length of time from baseline examination to LMP was 2.21 (0.83-4.79) months, with approximately 0.03% (90 of 345 613) carrying an infant with a CHD. Details of the baseline characteristics are shown in Table 1.

Table 1. Baseline Characteristics Among Different Hepatitis B Virus (HBV) Infection Status Groups.

Characteristic	No. (%)			P value^a
Characteristic	Uninfected women (n = 2 951 482)	Women with previous infection (n = 393 332)	Women with new infection (n = 345 613)	P value^a
Time interval between examination and LMP, median (IQR), mo	2.24 (0.79-4.89)	2.38 (0.89-4.99)	2.21 (0.83-4.79)	NA
Paternal age at LMP, y
Mean (SD)	28.60 (4.72)	29.20 (4.83)	28.90 (4.82)	<.001^b
Median (IQR)	28 (25-31)	28 (26-32)	28 (25-31)	<.001^b
Maternal nationality
Han	2 731 028 (92.5)	360 986 (91.8)	313 431 (90.7)	<.001
Other	134 008 (4.6)	24 690 (6.3)	24 499 (7.1)
Missing data	86 446 (2.9)	7656 (1.9)	7683 (2.2)
Maternal smoking
No	2 924 510 (99.1)	388 431 (98.8)	342 936 (99.2)	<.001
Yes	8538 (0.3)	1367 (0.3)	792 (0.2)
Missing data	18 434 (0.6)	3534 (0.9)	1885 (0.6)
Maternal early pregnancy common cold
No	2 937 873 (99.5)	391 225 (99.5)	344 197 (99.6)	<.001
Yes	13 609 (0.5)	2107 (0.5)	1416 (0.4)	<.001
Maternal early pregnancy medication
No	2 922 933 (99.0)	388 408 (98.8)	342 298 (99.0)	<.001
Yes	28 549 (1.0)	4924 (1.2)	3315 (1.0)	<.001
Paternal serum HBsAg status
Negative	2 745 540 (93.0)	334 768 (85.1)	295 572 (85.5)	<.001
Positive	155 620 (5.3)	48 420 (12.3)	42 654 (12.4)
Missing data	50 322 (1.7)	10 144 (2.6)	7387 (2.1)
Paternal HBV infection status
Uninfected	2 611 648 (88.5)	253 012 (64.3)	260 010 (75.2)	<.001
Previous infection	95 778 (3.3)	76 573 (19.5)	28 576 (8.3)
New infection	153 975 (5.2)	47 944 (12.2)	42 242 (12.2)
Missing data	90 081 (3.0)	15 803 (4.0)	14 785 (4.3)
Maternal family history of CHD
No	2 949 871 (99.9)	392 998 (99.9)	345 428 (99.9)	<.001
Yes	1611 (0.1)	334 (0.1)	185 (0.1)	<.001
Paternal family history of CHD
No	2 950 245 (99.9)	393 091 (99.9)	345 446 (99.9)	<.001
Yes	1237 (0.04)	241 (0.1)	167 (0.1)	<.001
Maternal early pregnancy folacin use
No	400 877 (13.6)	66 942 (17.0)	62 408 (18.1)	<.001
Yes	2 491 885 (84.4)	320 613 (81.5)	277 583 (80.3)
Missing data	58 720 (2.0)	5777 (1.5)	5622 (1.6)
Newborn with CHDs
No	2 950 682 (99.9)	393 191 (99.9)	345 523 (99.9)	.007
Yes	800 (0.03)	141 (0.04)	90 (0.03)	.007

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Abbreviations: CHDs, congenital heart diseases; HBsAg, hepatitis B surface antigen; LMP, last menstrual period; NA, not available.

^{^a}

The χ² test was used unless otherwise indicated.

^{^b}

The Kruskal-Wallis test was used.

Compared with uninfected women, women with HBV infection prior to pregnancy had a higher risk of carrying an infant with a CHD, with an adjusted RR (aRR) of 1.23 (95% CI, 1.02-1.49); however, no significant association was found between maternal preconception new HBV infection with CHDs in offspring (aRR, 0.99; 95% CI, 0.79-1.24) (Table 2).

Table 2. Association Between Maternal Preconception Hepatitis B Virus (HBV) Infection and Congenital Heart Diseases in Offspring.

Maternal preconception HBV infection status	Women, No. (%)	RR (95% CI)
Maternal preconception HBV infection status	Women, No. (%)	Model 1^a	Model 2^b	Model 3^c
Uninfected	800 (0.027)	1 [Reference]	1 [Reference]	1 [Reference]
Previous HBV infection	141 (0.036)	1.32 (1.11-1.58)	1.31 (1.09-1.57)	1.23 (1.02-1.49)
New HBV infection	90 (0.026)	0.96 (0.77-1.19)	0.99 (0.80-1.24)	0.99 (0.79-1.24)

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Abbreviation: RR, relative risk ratio.

^{^a}

Model 1 was a crude model.

^{^b}

Model 2 was adjusted for maternal family history of congenital heart diseases and paternal HBV infection status.

^{^c}

Model 3 was adjusted for maternal family history of congenital heart diseases, nationality, early pregnancy passive smoking, early pregnancy common cold, early pregnancy medication, early pregnancy folacin use, paternal HBV infection status, age, and family history of congenital heart diseases.

Considering the probable confounding effect of paternal HBV infection status prior to pregnancy on the association of maternal HBV infection with risk of CHDs in offspring, a further factorial design analysis was performed. As Table 3 demonstrates, compared with couples who were uninfected with HBV prior to pregnancy (680 of 2 610 968 [0.026%]), previously infected women with uninfected men (93 of 252 919 [0.037%]) or previously infected men with uninfected women (43 of 95 735 [0.045%]) had a higher incidence of CHDs in offspring and were significantly associated with a higher risk of CHDs in offspring (previously infected women with uninfected men: aRR, 1.36; 95% CI, 1.09-1.69; previously infected men with uninfected women: aRR, 1.51; 95% CI, 1.09-2.09) with multivariable adjustment. Although the aRRs of previously or newly infected couples, couples consisting of previously infected women and newly infected men, or couples consisting of newly infected women with previously infected men did not reach statistical significance, possibly due to the small sample size, relatively higher incidences of CHDs in offspring were still found compared with couples who were uninfected with HBV prior to pregnancy.

Table 3. Association Between the Combination of Parental Hepatitis B Virus (HBV) Infection Status on Congenital Heart Diseases in Offspring^a.

Measure	Men
Measure	Uninfected	Previous HBV infection	New HBV infection
Uninfected women
Participants, No.	2 610 968	95 735	153 938
CHD cases, No. (%)	680 (0.026)	43 (0.045)^b	37 (0.024)
aRR (95% CI)	1 [Reference]	1.51 (1.09-2.09)	0.93 (0.67-1.30)
Previous HBV infection
Participants, No.	252 919	76 548	47 930
CHDs cases, No. (%)	93 (0.037)^b	25 (0.033)	14 (0.029)
aRR (95% CI)	1.36 (1.09-1.69)	1.10 (0.72-1.66)	1.08 (0.64-1.84)
New HBV infection
Participants, No.	259 942	28 568	42 228
CHDs cases, No. (%)	68 (0.026)	8 (0.028)	14 (0.033)
aRR (95% CI)	1.00 (0.78-1.29)	1.04 (0.52-2.09)	1.28 (0.75-2.18)

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Abbreviations: aRR, adjusted relative risk ratio; CHDs, congenital heart diseases.

^{^a}

Model was adjusted for maternal family history of CHDs, nationality, early pregnancy passive smoking, early pregnancy common cold, early pregnancy medication, early pregnancy folacin use, paternal age, and family history of CHDs.

^{^b}

The χ² test was used for CHD incidence comparison.

Discussion

This matched retrospective cohort study, conducted in a population-based cohort with more than 7.3 million Chinese reproductive-aged women, demonstrates the association of maternal preconception HBV infection with risk of CHDs in offspring, allowing us to evaluate the associations of different infection statuses with risk of CHDs. In the current study, a potential link between maternal preconception previous HBV infection and a significantly increased risk of CHDs in offspring was observed. Although paternal HBV infection prior to pregnancy would also increase the risk of CHDs in offspring, an interaction effect between maternal and paternal HBV infection was not observed.

The main finding in this study is that increased risks of CHDs in offspring were observed among women with HBV infection, and women with the previous infection had a relatively higher risk. To date, only a few studies have reported an association between maternal HBV infection during early pregnancy and risk of CHDs in offspring, with inconsistent results (Liang et al¹⁴: n = 5381; odds ratio [OR], 1.38; 95% CI, 0.33-5.72; Wang et al¹⁶: n = 44 048; OR, 2.21; 95% CI, 1.66-2.95; Lai et al¹⁷: n = 1522; OR, 1.10; 95% CI, 0.46-26 088; and Guo et al¹⁸: n = 367; OR, 1448.83; 95% CI, 6.37-329 730.35), which might due to the different sample sizes and definitions of HBV infection. Detailed information on these studies is shown in eTable 4 in Supplement 1. Most noteworthy, to our knowledge, no study has been conducted to assess the association between maternal preconception HBV infection and risk of CHDs in offspring with a detailed definition of HBV infection status until now. This study focused on maternal preconception HBV infection and demonstrated that maternal preconception HBV infection could significantly increase the risk of CHDs in offspring, which is similar to findings from a 2022 Chinese cohort study¹⁶ conducted during early pregnancy including 44 048 pregnant women, which found that maternal HBV infection in early pregnancy was implicated in CHDs in offspring (RR , 2.21; 95% CI, 1.66-2.95). Moreover, our study indicated that women with a preconception previous infection had a relatively higher risk of CHDs in offspring than those with a new HBV infection, which might be because of increased attention and treatment in newly infected women. This study provided important evidence about the association between maternal preconception HBV infection and risk of CHDs in offspring, indicating that women who had a previous HBV infection prior to pregnancy should be paid more attention during the pregnancy period in case of the occurrence of CHDs in offspring.

Over the past decades, there have been advances in the understanding of CHD risk factors, but most investigations focused on maternal factors, while paternal factors were often neglected. To our knowledge, no previous studies have evaluated the interaction effect of both spouses’ HBV infection prior to pregnancy on risk of CHDs in offspring. HBV infection has been reported to affect not only oocytes but also sperm, and there may be an interaction effect of spouses’ preconception HBV infection statuses.^{27,28,29,30,31,32,33} In this study, increased CHD risks were observed only in women previously infected with HBV with uninfected men or previously infected men with uninfected women prior to pregnancy. Moreover, previously infected men with uninfected women had a higher prevalence of CHDs in offspring than previously infected women with uninfected men. Although other groups did not demonstrate significant results, which might be due to the small sample size or those with newly infected seeking treatment, different levels of increased CHD risk in offspring under various combinations of maternal and paternal preconception HBV infection were observed, which hinted that HBV infection might have a longer harmful effect on the formation of the gamete and the growth of the fertilized egg, which is worth further studies in the future. Therefore, paternal HBV infection status prior to pregnancy should not be overlooked, and couples should be encouraged to maintain an HBV-free status.

In China, although HBV vaccination has been incorporated into the Chinese immunization program since the early 1990s, considering the serum HBsAb titers may decrease gradually with age, both women and men are recommended to regularly monitor their HBV infection status, and HBV-related health education should be strengthened, especially for couples who plan to conceive, to lower the risk of CHDs in offspring. In addition, for participants with a previous infection, even though they were not contagious, they should also be taken seriously to lower the risk of CHDs in offspring.

The etiology of CHDs is recognized to be complicated and multifactorial. Although the precise mechanism of CHDs cannot be well established, the association between maternal preconception HBV infection and CHDs in offspring might be explained by the following mechanisms. First, HBV could infect the ovum and replicate in it. HBV DNA sequences are also able to integrate into its’ chromosomes and be active during the embryo development,^{27,32,33,39,40} which might result in abnormal embryonic heart development consequently. Second, maternal preconception HBV infection may alter the epigenome profile in newborns,⁴¹ which could influence embryonic heart development.

Strengths and Limitations

To our knowledge, this matched retrospective cohort study was the first to evaluate the association between maternal preconception HBV infection and risk of CHDs in offspring. The association can be well evaluated with the propensity score matching and multivariate adjustment. Second, compared with previous studies during early pregnancy, our study provided more detailed classifications to better evaluate the association of the different maternal preconception HBV infection statuses with the risk of CHDs in offspring, providing important new evidence, especially for preconception care. Furthermore, our study demonstrated that paternal HBV infection status might also play an important role in increasing the CHDs risk, which needs to be better explored in the future.

However, our study has some limitations. First, missing diagnosis of CHDs within 28 days after delivery should be a concern. Second, with an unmeasured load of HBV DNA, the association of different HBV DNA loads with the risk of CHDs in offspring could not be assessed. Third, detailed CHD subtypes were not recorded, so we cannot evaluate the association of maternal preconception HBV infection with the risks of different CHD subtypes in offspring. Fourth, as with previous studies, not all potential confounders were adjusted, and the possibly unmeasured or unknown covariates could not be ruled out. Furthermore, because detailed maternal early pregnancy medication history was not well documented, the influence of antiviral medicines in infected women on the association between maternal preconception HBV infection and CHD cannot be assessed. In addition, no detailed records were available relating to complications in pregnancy, especially gestational diabetes, which might lead to a potentially biased estimation of the association of maternal preconception HBV infection with CHDs in offspring. Additionally, NFPCP, the basement cohort, provides preconception counseling, and women or men with a new HBV infection status were recommended to go to the hospital for further treatment; however, these medical records were not collected in this study, which may lead to an underestimation of the association of maternal preconception new HBV infection with the risk of CHDs in offspring.

Conclusions

In conclusion, our study provided new evidence of associations between maternal preconception HBV infection and risk of CHDs in offspring among Chinese childbearing-aged women, indicating the necessity of HBV screening in preparation for pregnancy, and the importance of staying free of HBV infection for women. For those women with previous HBV infection, even if they were not contagious, they should also be taken seriously to decrease the risk of CHDs in offspring.

Supplement 1.

eTable 1. Classification of Hepatitis B Virus Infection Status

eTable 2. Definition and Classification of Covariates

eTable 3. Baseline Characteristics of Female Participants in the Cohort Before and After Propensity Score Matching

eTable 4. Detailed Information on Previous Studies

Click here for additional data file.^{(373.8KB, pdf)}

Supplement 2.

Data Sharing Statement

Click here for additional data file.^{(15.6KB, pdf)}

References

1.van der Linde D, Konings EE, Slager MA, et al. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol. 2011;58(21):2241-2247. doi: 10.1016/j.jacc.2011.08.025 [DOI] [PubMed] [Google Scholar]
2.Bouma BJ, Mulder BJ. Changing landscape of congenital heart disease. Circ Res. 2017;120(6):908-922. doi: 10.1161/CIRCRESAHA.116.309302 [DOI] [PubMed] [Google Scholar]
3.Liu Y, Chen S, Zühlke L, et al. Global birth prevalence of congenital heart defects 1970-2017: updated systematic review and meta-analysis of 260 studies. Int J Epidemiol. 2019;48(2):455-463. doi: 10.1093/ije/dyz009 [DOI] [PMC free article] [PubMed] [Google Scholar]
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7.Wang T, Chen L, Yang T, et al. Congenital heart disease and risk of cardiovascular disease: a meta-analysis of cohort studies. J Am Heart Assoc. 2019;8(10):e012030. doi: 10.1161/JAHA.119.012030 [DOI] [PMC free article] [PubMed] [Google Scholar]
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16.Wang T, Li Q, Chen L, et al. Maternal viral infection in early pregnancy and risk of congenital heart disease in offspring: a prospective cohort study in Central China. Clin Epidemiol. 2022;14:71-82. doi: 10.2147/CLEP.S338870 [DOI] [PMC free article] [PubMed] [Google Scholar]
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19.Lao TT, Sahota DS, Law LW, Cheng YK, Leung TY. Age-specific prevalence of hepatitis B virus infection in young pregnant women, Hong Kong Special Administrative Region of China. Bull World Health Organ. 2014;92(11):782-789. doi: 10.2471/BLT.13.133413 [DOI] [PMC free article] [PubMed] [Google Scholar]
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23.Lao TT, Sahota DS, Cheng YK, Law LW, Leung TY. Maternal hepatitis B surface antigen status and incidence of pre-eclampsia. J Viral Hepat. 2013;20(5):343-349. doi: 10.1111/jvh.12037 [DOI] [PubMed] [Google Scholar]
24.Sheng QJ, Wang SJ, Wu YY, Dou XG, Ding Y. Hepatitis B virus serosurvey and awareness of mother-to-child transmission among pregnant women in Shenyang, China: an observational study. Medicine (Baltimore). 2018;97(22):e10931. doi: 10.1097/MD.0000000000010931 [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Bai H, Zhang L, Ma L, Dou XG, Feng GH, Zhao GZ. Relationship of hepatitis B virus infection of placental barrier and hepatitis B virus intra-uterine transmission mechanism. World J Gastroenterol. 2007;13(26):3625-3630. doi: 10.3748/wjg.v13.i26.3625 [DOI] [PMC free article] [PubMed] [Google Scholar]
26.Zhang SL, Yue YF, Bai GQ, Shi L, Jiang H. Mechanism of intrauterine infection of hepatitis B virus. World J Gastroenterol. 2004;10(3):437-438. doi: 10.3748/wjg.v10.i3.437 [DOI] [PMC free article] [PubMed] [Google Scholar]
27.Huang TH, Zhang QJ, Xie QD, Zeng LP, Zeng XF. Presence and integration of HBV DNA in mouse oocytes. World J Gastroenterol. 2005;11(19):2869-2873. doi: 10.3748/wjg.v11.i19.2869 [DOI] [PMC free article] [PubMed] [Google Scholar]
28.Wang Z, Liu W, Zhang M, Wang M, Wu H, Lu M. Effect of hepatitis B virus infection on sperm quality and outcomes of assisted reproductive techniques in infertile males. Front Med (Lausanne). 2021;8:744350. doi: 10.3389/fmed.2021.744350 [DOI] [PMC free article] [PubMed] [Google Scholar]
29.Han TT, Huang JH, Gu J, Xie QD, Zhong Y, Huang TH. Hepatitis B virus surface protein induces sperm dysfunction through the activation of a Bcl2/Bax signaling cascade triggering AIF/Endo G-mediated apoptosis. Andrology. 2021;9(3):944-955. doi: 10.1111/andr.12965 [DOI] [PMC free article] [PubMed] [Google Scholar]
30.Cheng L, Sun P, Xie X, et al. Hepatitis B virus surface protein induces oxidative stress by increasing peroxides and inhibiting antioxidant defences in human spermatozoa. Reprod Fertil Dev. 2020;32(14):1180-1189. doi: 10.1071/RD20130 [DOI] [PubMed] [Google Scholar]
31.Zhou XL, Sun PN, Huang TH, Xie QD, Kang XJ, Liu LM. Effects of hepatitis B virus S protein on human sperm function. Hum Reprod. 2009;24(7):1575-1583. doi: 10.1093/humrep/dep050 [DOI] [PubMed] [Google Scholar]
32.Hu XL, Zhou XP, Qian YL, Wu GY, Ye YH, Zhu YM. The presence and expression of the hepatitis B virus in human oocytes and embryos. Hum Reprod. 2011;26(7):1860-1867. doi: 10.1093/humrep/der103 [DOI] [PubMed] [Google Scholar]
33.Nie R, Jin L, Zhang H, Xu B, Chen W, Zhu G. Presence of hepatitis B virus in oocytes and embryos: a risk of hepatitis B virus transmission during in vitro fertilization. Fertil Steril. 2011;95(5):1667-1671. doi: 10.1016/j.fertnstert.2010.12.043 [DOI] [PubMed] [Google Scholar]
34.Zhang S, Wang Q, Shen H. Design of the national free proception health examination project in China. Zhonghua Yi Xue Za Zhi. 2015;95(3):162-165. [PubMed] [Google Scholar]
35.Wei Y, Xu Q, Yang H, et al. Preconception diabetes mellitus and adverse pregnancy outcomes in over 6.4 million women: a population-based cohort study in China. PLoS Med. 2019;16(10):e1002926. doi: 10.1371/journal.pmed.1002926 [DOI] [PMC free article] [PubMed] [Google Scholar]
36.Yang Y, Guo T, Fu J, et al. Preconception thyrotropin levels and risk of adverse pregnancy outcomes in Chinese women aged 20 to 49 years. JAMA Netw Open. 2021;4(4):e215723. doi: 10.1001/jamanetworkopen.2021.5723 [DOI] [PMC free article] [PubMed] [Google Scholar]
37.Liu J, Zhang S, Liu M, Wang Q, Shen H, Zhang Y. Maternal pre-pregnancy infection with hepatitis B virus and the risk of preterm birth: a population-based cohort study. Lancet Glob Health. 2017;5(6):e624-e632. doi: 10.1016/S2214-109X(17)30142-0 [DOI] [PubMed] [Google Scholar]
38.Obstetrics Subgroup CSoO, Gynecology CMA, Chinese Society of Perinatal Medicine CMA . 2020 Clinical guidelines on prevention of mother-to-child transmission of hepatitis B virus. J Clin Hepatol. 2020;36(7):1474-1481. doi: 10.3760/cma.j.cn112141-20200213-00101 [DOI] [PubMed] [Google Scholar]
39.Ye F, Yue Y, Li S, et al. Presence of HBsAg, HBcAg, and HBVDNA in ovary and ovum of the patients with chronic hepatitis B virus infection. Am J Obstet Gynecol. 2006;194(2):387-392. doi: 10.1016/j.ajog.2005.07.011 [DOI] [PubMed] [Google Scholar]
40.Heby O. DNA methylation and polyamines in embryonic development and cancer. Int J Dev Biol. 1995;39(5):737-757. [PubMed] [Google Scholar]
41.Cheng Q, Zhao B, Huang Z, et al. Epigenome-wide study for the offspring exposed to maternal HBV infection during pregnancy, a pilot study. Gene. 2018;658:76-85. doi: 10.1016/j.gene.2018.03.025 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eTable 1. Classification of Hepatitis B Virus Infection Status

eTable 2. Definition and Classification of Covariates

eTable 3. Baseline Characteristics of Female Participants in the Cohort Before and After Propensity Score Matching

eTable 4. Detailed Information on Previous Studies

Click here for additional data file.^{(373.8KB, pdf)}

Supplement 2.

Data Sharing Statement

Click here for additional data file.^{(15.6KB, pdf)}

[poi230002r1] 1.van der Linde D, Konings EE, Slager MA, et al. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol. 2011;58(21):2241-2247. doi: 10.1016/j.jacc.2011.08.025 [DOI] [PubMed] [Google Scholar]

[poi230002r2] 2.Bouma BJ, Mulder BJ. Changing landscape of congenital heart disease. Circ Res. 2017;120(6):908-922. doi: 10.1161/CIRCRESAHA.116.309302 [DOI] [PubMed] [Google Scholar]

[poi230002r3] 3.Liu Y, Chen S, Zühlke L, et al. Global birth prevalence of congenital heart defects 1970-2017: updated systematic review and meta-analysis of 260 studies. Int J Epidemiol. 2019;48(2):455-463. doi: 10.1093/ije/dyz009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi230002r4] 4.Tennant PWG, Pearce MS, Bythell M, Rankin J. 20-Year survival of children born with congenital anomalies: a population-based study. Lancet. 2010;375(9715):649-656. doi: 10.1016/S0140-6736(09)61922-X [DOI] [PubMed] [Google Scholar]

[poi230002r5] 5.Marelli AJ, Mackie AS, Ionescu-Ittu R, Rahme E, Pilote L. Congenital heart disease in the general population: changing prevalence and age distribution. Circulation. 2007;115(2):163-172. doi: 10.1161/CIRCULATIONAHA.106.627224 [DOI] [PubMed] [Google Scholar]

[poi230002r6] 6.Gurvitz MZ, Inkelas M, Lee M, Stout K, Escarce J, Chang R-K. Changes in hospitalization patterns among patients with congenital heart disease during the transition from adolescence to adulthood. J Am Coll Cardiol. 2007;49(8):875-882. doi: 10.1016/j.jacc.2006.09.051 [DOI] [PubMed] [Google Scholar]

[poi230002r7] 7.Wang T, Chen L, Yang T, et al. Congenital heart disease and risk of cardiovascular disease: a meta-analysis of cohort studies. J Am Heart Assoc. 2019;8(10):e012030. doi: 10.1161/JAHA.119.012030 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi230002r8] 8.Jenkins KJ, Correa A, Feinstein JA, et al. ; American Heart Association Council on Cardiovascular Disease in the Young . Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation. 2007;115(23):2995-3014. doi: 10.1161/CIRCULATIONAHA.106.183216 [DOI] [PubMed] [Google Scholar]

[poi230002r9] 9.Overall JC Jr. Intrauterine virus infections and congenital heart disease. Am Heart J. 1972;84(6):823-833. doi: 10.1016/0002-8703(72)90077-4 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi230002r10] 10.Pierpont ME, Brueckner M, Chung WK, et al. ; American Heart Association Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; and Council on Genomic and Precision Medicine . Genetic basis for congenital heart disease: revisited: a scientific statement from the American Heart Association. Circulation. 2018;138(21):e653-e711. doi: 10.1161/CIR.0000000000000606 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi230002r11] 11.Sharma V, Goessling LS, Brar AK, Joshi CS, Mysorekar IU, Eghtesady P. Coxsackievirus B3 infection early in pregnancy induces congenital heart defects through suppression of fetal cardiomyocyte proliferation. J Am Heart Assoc. 2021;10(2):e017995. doi: 10.1161/JAHA.120.017995 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi230002r12] 12.Ye Z, Wang L, Yang T, et al. Maternal viral infection and risk of fetal congenital heart diseases: a meta-analysis of observational studies. J Am Heart Assoc. 2019;8(9):e011264. doi: 10.1161/JAHA.118.011264 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi230002r13] 13.Xia YQ, Zhao KN, Zhao AD, et al. Associations of maternal upper respiratory tract infection/influenza during early pregnancy with congenital heart disease in offspring: evidence from a case-control study and meta-analysis. BMC Cardiovasc Disord. 2019;19(1):277. doi: 10.1186/s12872-019-1206-0 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi230002r14] 14.Liang Q, Gong W, Zheng D, Zhong R, Wen Y, Wang X. The influence of maternal exposure history to virus and medicine during pregnancy on congenital heart defects of fetus. Environ Sci Pollut Res Int. 2017;24(6):5628-5632. doi: 10.1007/s11356-016-8198-4 [DOI] [PubMed] [Google Scholar]

[poi230002r15] 15.Brown GC. Maternal virus infection and congenital anomalies. Arch Environ Health. 1970;21(3):362-365. doi: 10.1080/00039896.1970.10667251 [DOI] [PubMed] [Google Scholar]

[poi230002r16] 16.Wang T, Li Q, Chen L, et al. Maternal viral infection in early pregnancy and risk of congenital heart disease in offspring: a prospective cohort study in Central China. Clin Epidemiol. 2022;14:71-82. doi: 10.2147/CLEP.S338870 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi230002r17] 17.Lai J, Han L, Xu S. Discussion on risk factors of congenital heart disease in newborns. J Prevent Med Inf. 2001;17:370-371. doi: 10.3969/j.issn.1006-4028.2001.05.033 [DOI] [Google Scholar]

[poi230002r18] 18.Guo J, Hong X, Yao M. Analysis of risk factors for congenital heart disease in newborns. Chin J Neonatol. 2010;25:76-79. doi: 10.3969/j.issn.1673-6710.2010.02.006 [DOI] [Google Scholar]

[poi230002r19] 19.Lao TT, Sahota DS, Law LW, Cheng YK, Leung TY. Age-specific prevalence of hepatitis B virus infection in young pregnant women, Hong Kong Special Administrative Region of China. Bull World Health Organ. 2014;92(11):782-789. doi: 10.2471/BLT.13.133413 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi230002r20] 20.Zhang Y, Fang W, Fan L, et al. Hepatitis B surface antigen prevalence among 12,393 rural women of childbearing age in Hainan Province, China: a cross-sectional study. Virol J. 2013;10:25. doi: 10.1186/1743-422X-10-25 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi230002r21] 21.Zhang S, Li RT, Wang Y, Liu Q, Zhou YH, Hu Y. Seroprevalence of hepatitis B surface antigen among pregnant women in Jiangsu, China, 17 years after introduction of hepatitis B vaccine. Int J Gynaecol Obstet. 2010;109(3):194-197. doi: 10.1016/j.ijgo.2010.01.002 [DOI] [PubMed] [Google Scholar]

[poi230002r22] 22.Wang M, Li H, Ji Y, et al. Seroprevalence of hepatitis B surface antigen and hepatitis B e antigen among childbearing-age women in Mianyang, China. J Infect Dev Ctries. 2015;9(7):770-779. doi: 10.3855/jidc.6938 [DOI] [PubMed] [Google Scholar]

[poi230002r23] 23.Lao TT, Sahota DS, Cheng YK, Law LW, Leung TY. Maternal hepatitis B surface antigen status and incidence of pre-eclampsia. J Viral Hepat. 2013;20(5):343-349. doi: 10.1111/jvh.12037 [DOI] [PubMed] [Google Scholar]

[poi230002r24] 24.Sheng QJ, Wang SJ, Wu YY, Dou XG, Ding Y. Hepatitis B virus serosurvey and awareness of mother-to-child transmission among pregnant women in Shenyang, China: an observational study. Medicine (Baltimore). 2018;97(22):e10931. doi: 10.1097/MD.0000000000010931 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi230002r25] 25.Bai H, Zhang L, Ma L, Dou XG, Feng GH, Zhao GZ. Relationship of hepatitis B virus infection of placental barrier and hepatitis B virus intra-uterine transmission mechanism. World J Gastroenterol. 2007;13(26):3625-3630. doi: 10.3748/wjg.v13.i26.3625 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi230002r26] 26.Zhang SL, Yue YF, Bai GQ, Shi L, Jiang H. Mechanism of intrauterine infection of hepatitis B virus. World J Gastroenterol. 2004;10(3):437-438. doi: 10.3748/wjg.v10.i3.437 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi230002r27] 27.Huang TH, Zhang QJ, Xie QD, Zeng LP, Zeng XF. Presence and integration of HBV DNA in mouse oocytes. World J Gastroenterol. 2005;11(19):2869-2873. doi: 10.3748/wjg.v11.i19.2869 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi230002r28] 28.Wang Z, Liu W, Zhang M, Wang M, Wu H, Lu M. Effect of hepatitis B virus infection on sperm quality and outcomes of assisted reproductive techniques in infertile males. Front Med (Lausanne). 2021;8:744350. doi: 10.3389/fmed.2021.744350 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi230002r29] 29.Han TT, Huang JH, Gu J, Xie QD, Zhong Y, Huang TH. Hepatitis B virus surface protein induces sperm dysfunction through the activation of a Bcl2/Bax signaling cascade triggering AIF/Endo G-mediated apoptosis. Andrology. 2021;9(3):944-955. doi: 10.1111/andr.12965 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi230002r30] 30.Cheng L, Sun P, Xie X, et al. Hepatitis B virus surface protein induces oxidative stress by increasing peroxides and inhibiting antioxidant defences in human spermatozoa. Reprod Fertil Dev. 2020;32(14):1180-1189. doi: 10.1071/RD20130 [DOI] [PubMed] [Google Scholar]

[poi230002r31] 31.Zhou XL, Sun PN, Huang TH, Xie QD, Kang XJ, Liu LM. Effects of hepatitis B virus S protein on human sperm function. Hum Reprod. 2009;24(7):1575-1583. doi: 10.1093/humrep/dep050 [DOI] [PubMed] [Google Scholar]

[poi230002r32] 32.Hu XL, Zhou XP, Qian YL, Wu GY, Ye YH, Zhu YM. The presence and expression of the hepatitis B virus in human oocytes and embryos. Hum Reprod. 2011;26(7):1860-1867. doi: 10.1093/humrep/der103 [DOI] [PubMed] [Google Scholar]

[poi230002r33] 33.Nie R, Jin L, Zhang H, Xu B, Chen W, Zhu G. Presence of hepatitis B virus in oocytes and embryos: a risk of hepatitis B virus transmission during in vitro fertilization. Fertil Steril. 2011;95(5):1667-1671. doi: 10.1016/j.fertnstert.2010.12.043 [DOI] [PubMed] [Google Scholar]

[poi230002r34] 34.Zhang S, Wang Q, Shen H. Design of the national free proception health examination project in China. Zhonghua Yi Xue Za Zhi. 2015;95(3):162-165. [PubMed] [Google Scholar]

[poi230002r35] 35.Wei Y, Xu Q, Yang H, et al. Preconception diabetes mellitus and adverse pregnancy outcomes in over 6.4 million women: a population-based cohort study in China. PLoS Med. 2019;16(10):e1002926. doi: 10.1371/journal.pmed.1002926 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi230002r36] 36.Yang Y, Guo T, Fu J, et al. Preconception thyrotropin levels and risk of adverse pregnancy outcomes in Chinese women aged 20 to 49 years. JAMA Netw Open. 2021;4(4):e215723. doi: 10.1001/jamanetworkopen.2021.5723 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi230002r37] 37.Liu J, Zhang S, Liu M, Wang Q, Shen H, Zhang Y. Maternal pre-pregnancy infection with hepatitis B virus and the risk of preterm birth: a population-based cohort study. Lancet Glob Health. 2017;5(6):e624-e632. doi: 10.1016/S2214-109X(17)30142-0 [DOI] [PubMed] [Google Scholar]

[poi230002r38] 38.Obstetrics Subgroup CSoO, Gynecology CMA, Chinese Society of Perinatal Medicine CMA . 2020 Clinical guidelines on prevention of mother-to-child transmission of hepatitis B virus. J Clin Hepatol. 2020;36(7):1474-1481. doi: 10.3760/cma.j.cn112141-20200213-00101 [DOI] [PubMed] [Google Scholar]

[poi230002r39] 39.Ye F, Yue Y, Li S, et al. Presence of HBsAg, HBcAg, and HBVDNA in ovary and ovum of the patients with chronic hepatitis B virus infection. Am J Obstet Gynecol. 2006;194(2):387-392. doi: 10.1016/j.ajog.2005.07.011 [DOI] [PubMed] [Google Scholar]

[poi230002r40] 40.Heby O. DNA methylation and polyamines in embryonic development and cancer. Int J Dev Biol. 1995;39(5):737-757. [PubMed] [Google Scholar]

[poi230002r41] 41.Cheng Q, Zhao B, Huang Z, et al. Epigenome-wide study for the offspring exposed to maternal HBV infection during pregnancy, a pilot study. Gene. 2018;658:76-85. doi: 10.1016/j.gene.2018.03.025 [DOI] [PubMed] [Google Scholar]

PERMALINK

Maternal Preconception Hepatitis B Virus Infection and Risk of Congenital Heart Diseases in Offspring Among Chinese Women Aged 20 to 49 Years

Hanbin Wu, MS

Ying Yang, PhD

Jiajing Jia, PhD

Tonglei Guo, MS

Jueming Lei, MS

YuZhi Deng, BS

Yuan He, PhD

Yuanyuan Wang, PhD

Zuoqi Peng, MS

Ya Zhang, MS

Hongguang Zhang, BS

Qiaomei Wang, MS

Haiping Shen, MS

Yiping Zhang, MS

Donghai Yan, MD

Xu Ma, MS

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Exposures

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Data Source

Figure. Flowchart of the Study Population Selection.

Study Exposure and Outcome

Covariates

Statistical Analysis

Results

Table 1. Baseline Characteristics Among Different Hepatitis B Virus (HBV) Infection Status Groups.

Table 2. Association Between Maternal Preconception Hepatitis B Virus (HBV) Infection and Congenital Heart Diseases in Offspring.

Table 3. Association Between the Combination of Parental Hepatitis B Virus (HBV) Infection Status on Congenital Heart Diseases in Offspringa.

Discussion

Strengths and Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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Cited by other articles

Links to NCBI Databases

Table 3. Association Between the Combination of Parental Hepatitis B Virus (HBV) Infection Status on Congenital Heart Diseases in Offspring^a.